Therapeutic compounds

Abstract

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

Description

THERAPEUTIC COMPOUNDS INTRODUCTION

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

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

[0003] The α4β7 integrin receptor, which is highly expressed on lymphocytes, including B and T lymphocytes, directs the homing of lymphocytes to the intestine via binding to its primary ligand, MAdCAM-1, which is expressed predominantly on intestinal endothelial cells (DOI: 10.1046 / j.1365-2567.1996.d01-706.x; DOI: 10.4049 / jimmunol.0902407; DOI: 10.1111 / j.1365- 2567.2005.02225.x PMCID: PMC1857942). Therefore, inhibiting α4β7 from binding toMAdCAM-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 α4β1 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] In this specification the term “alkyl” includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only. For example, “(1-6C)alkyl” includes (1- 4C)alkyl, (1-3C)alkyl, propyl, isopropyl and t-butyl. A similar convention applies to other radicals, for example “phenyl(1-6C)alkyl” includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

[0022] In this specification the term “alkylene” includes both straight and branched chain divalent alkyl groups. For example, “C1-4alkylene” includes methylene (-CH2-), ethylene (- CH2CH2-), propylene and butylene.

[0023] In this specification the term “alkoxy” includes both straight and branched chain alkyl groups singularly bonded to oxygen. For example, “C1-4alkoxy” includes methoxy, ethoxy, isopropoxy and t-butoxy.

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

[0025] The term “halo” refers to fluoro, chloro, bromo and iodo.

[0026] The term “haloalkyl” is used herein to refer to an alkyl group respectively in which one or more hydrogen atoms have been replaced by halogen (e.g. fluorine) atoms. Examples of haloalkyl groups include fluoroalkyl groups such as –CHF2, –CH2CF3, or perfluoroalkyl / alkoxy groups such as –CF3, or –CF2CF3.

[0027] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ringsystem(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Conveniently, the heterocyclic group is a 4- to 10-membered heterocyclyl. Suitable 4- to 10-membered heterocyclyl groups comprise monocyclic and bicyclic heterocycles. Conveniently, the monocyclic heterocycles contain 4 to 6 ring atoms with 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Conveniently, the bicyclic heterocycles contain 8 to 10 ring atoms with 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Suitable bicyclic heterocyclyl groups comprise 8- to 10-membered spiro bicyclic heterocyclic ring systems (such as 2-azaspiro[4.5]decanyl, 2-azaspiro[4.4]nonanyl, 2,8- diazaspiro[4.5]decanyl, 8-oxa-2-azaspiro[4.5]decanyl, or 1,3-diazaspiro[4.5]decanyl). Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, 1,2-diazacyclohexanyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, dihydroisoxazolyl (such as 4,5-dihydroisoxazolyl), dihydropyridinyl (such as 1,2-dihydropyridinyl or 1,6-dihydropyridinyl), tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydro-dioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=O) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2- oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5- dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. Suitably, the term “heterocyclyl”, “heterocyclic” or “heterocycle” will refer to 4, 5, 6 or 7 membered monocyclic rings as defined above, unless specified otherwise.

[0028] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted.

[0029] Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

[0030] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically. Compounds of the Invention

[0031] In a first aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:wherein: L1 is a 7-carbon straight chain or branched chain alkylene linker; R1is selected from fluoro, methyl, and cyclopropyl; R2is selected from fluoro, chloro, methyl, ethyl, isopropyl, and trifluoromethyl; R3is L2-NR5R6, or a 4-, 5-, or 6-membered heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from fluoro, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, and C1-2alkylene-O-C1-2alkyl; R4is selected from hydrogen, methyl, ethyl, propyl, C1-3haloalkyl, C1-2alkoxy, C1-2haloalkoxy, and hydroxy; L2is a 2- or 3-carbon alkylene linker optionally substituted with one or two methyl groups; R5and R6are independently selected from methyl and ethyl; or R5and R6, taken together with the nitrogen to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring wherein the heterocyclyl ring is:i) optionally spiro-attached to a cyclopropyl or cyclobutyl ring; and ii) optionally substituted with one or more substituents independently selected from fluoro, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, and C1-2alkylene-O- C1-2alkyl.

[0032] Particular compounds of the invention include, for example, compounds of the formula I, or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of L1, R1, R2, R3, R4, R5, R6, and L2has any of the meanings defined hereinbefore or in any of paragraphs (1) to (57) hereinafter. For the avoidance of doubt, the scope of the present invention encompasses compounds of formula I, or pharmaceutically acceptable salts thereof, wherein any of the substituent definitions defined herein may be combined with any of the other substituent definitions also defined herein: (1) L1 is a 7-carbon straight chain alkylene linker; (2) L1 is a 7-carbon branched chain alkylene linker; (3) L1 is selected from:, wherein b is the point of attachment to the phenyl ring; (4) L1is:, wherein b is the point of attachment to the phenyl ring; (5) R1is selected from fluoro and cyclopropyl; (6) R1is selected from fluoro and methyl; (7) R1is cyclopropyl; (8) R1is methyl; (9) R1is fluoro; (10) R2is selected from fluoro, methyl, ethyl, isopropyl, and trifluoromethyl; (11) R2is selected from fluoro, methyl, ethyl, and trifluoromethyl; (12) R2is selected from fluoro, methyl, and trifluoromethyl; (13) R2is selected from methyl, isopropyl, and trifluoromethyl; such as from methyl and trifluoromethyl; (14) R2is methyl;(15) R2is trifluoromethyl; (16) R3is L2-NR5R6, or a 4-, 5-, or 6-membered heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from fluoro, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, and C1-3haloalkoxy; (17) R3is L2-NR5R6, or a 4-, 5-, or 6-membered heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, and C1-3haloalkoxy; (18) R3is L2-NR5R6, or a 4-, 5-, or 6-membered heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from C1- 3alkyl, and C1-3haloalkyl; (19) R3is L2-NR5R6, or a 4-, 5-, or 6-membered heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with one or more independently selected C1-3alkyl substituents; (20) R3is L2-NR5R6, or a 4-, 5-, or 6-membered heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with a C1-3alkyl substituent; (21) R3is L2-NR5R6, or a 4-, 5-, or 6-membered heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with a methyl substituent; (22) R3is L2-NR5R6, or a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from fluoro, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, and C1-2alkylene-O-C1-2alkyl; (23) R3is L2-NR5R6, or a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from fluoro, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, and C1- 3haloalkoxy; (24) R3is L2-NR5R6, or a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, and C1-3haloalkoxy; (25) R3is L2-NR5R6, or a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from C1-3alkyl, and C1-3haloalkyl; (26) R3is L2-NR5R6, or a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with one or more independently selected C1-3alkyl substituents;(27) R3is L2-NR5R6, or a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with a C1-3alkyl substituent; (28) R3is L2-NR5R6, or a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with a methyl substituent; (29) R3is L2-NR5R6, or a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl ring wherein the heterocyclyl ring is optionally substituted on a nitrogen atom with a C1-3alkyl substituent; (30) R3is L2-NR5R6, or a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl ring wherein the heterocyclyl ring is optionally substituted on a nitrogen atom with a methyl substituent; (31) R3is L2-NR5R6; (32) R3is a 4-, 5-, or 6-membered heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from fluoro, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, and C1-2alkylene-O-C1-2alkyl; (33) R4is selected from hydrogen, methyl, ethyl, propyl, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, methoxy, trifluoromethoxy, and hydroxy; (34) R4is selected from hydrogen, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, and hydroxy; (35) R4is selected from hydrogen, methyl, ethyl, difluoromethyl, methoxy, and hydroxy; (36) R4is selected from hydrogen, methyl, ethyl, difluoromethyl, and hydroxy; (37) R4is selected from methyl, ethyl, and difluoromethyl; (38) R4is methyl; (39) R4is ethyl; (40) R4is difluoromethyl; (41) L2 is a 2- or 3-carbon alkylene linker optionally substituted with a methyl group; (42) L2 is a 2- or 3-carbon alkylene linker; (43) L2 is a 2-carbon alkylene linker; (44) L2is a 3-carbon alkylene linker; (45) One of R5and R6is methyl, and the other is ethyl; (46) R5and R6are both ethyl;(47) R5and R6are both methyl; (48) R5and R6, taken together with the nitrogen to which they are attached, form a 4-, or 5- membered heterocyclyl ring wherein the heterocyclyl ring is: i) optionally spiro-attached to a cyclopropyl or cyclobutyl ring; and ii) optionally substituted with one or more substituents independently selected from fluoro, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, and C1-2alkylene-O-C1-2alkyl; (49) R5and R6, taken together with the nitrogen to which they are attached, form a 4-, or 5- membered heterocyclyl ring wherein the heterocyclyl ring is: i) optionally spiro-attached to a cyclopropyl or cyclobutyl ring; and ii) optionally substituted with one or more substituents independently selected from fluoro, methyl, ethyl, C1-3haloalkyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, and CH2-OMe; (50) R5and R6, taken together with the nitrogen to which they are attached, form a 4-, or 5- membered heterocyclyl ring wherein the heterocyclyl ring is: i) optionally spiro-attached to a cyclopropyl or cyclobutyl ring; and ii) optionally substituted with one or two substituents independently selected from fluoro, methyl, ethyl, C1-3haloalkyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, and CH2-OMe; (51) R5and R6, taken together with the nitrogen to which they are attached, form a 4-, or 5- membered heterocyclyl ring optionally substituted with one or two substituents independently selected from fluoro, methyl, ethyl, C1-3haloalkyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, and CH2-OMe; (52) R5and R6, taken together with the nitrogen to which they are attached, form a 4-, or 5- membered heterocyclyl ring optionally substituted with one or two substituents independently selected from fluoro, methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy; (53) R5and R6, taken together with the nitrogen to which they are attached, form a 4-, or 5- membered heterocyclyl ring optionally substituted with one or two substituents independently selected from fluoro, methyl, and methoxy; (54) R5and R6, taken together with the nitrogen to which they are attached, form an azetidine ring optionally substituted with one or two substituents independently selected from fluoro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, and CH2-OMe;(55) R5and R6, taken together with the nitrogen to which they are attached, form an azetidine ring optionally substituted with one or two substituents independently selected from fluoro, methyl, ethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy; (56) R5and R6, taken together with the nitrogen to which they are attached, form an azetidine ring optionally substituted with one or two substituents independently selected from fluoro, methyl, and methoxy; (57) R5and R6, taken together with the nitrogen to which they are attached, form a 4-, or 5- membered heterocyclyl ring wherein the heterocyclyl ring is optionally spiro-attached to a cyclopropyl or cyclobutyl ring.

[0033] In an embodiment there is provided a compound of formula IA, IB, IC, ID, or IE, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, and L2 are as defined herein:.

[0034] In an embodiment there is provided a compound of formula IA, IB, IC, ID, or IE, or a pharmaceutically acceptable salt thereof, wherein R1is as defined in any one of paragraphs (5) to (9) above; R2is as defined in any one of paragraphs (10) to (15) above; R3is as defined in any one of paragraphs (16) to (32) above; R4is as defined in any one of paragraphs (33) to(40) above; R5and R6are as defined in any one of paragraphs (45) to (57) above; and L2is as defined in any one of paragraphs (41) to (44) above.

[0035] In an embodiment there is provided a compound of formula IA, IB, IC, ID, or IE, or a pharmaceutically acceptable salt thereof, wherein R1is as defined in any one of paragraphs (5) to (9) above; R2is as defined in paragraph (13) above; R3is as defined in any one of paragraphs (16) to (32) above; R4is as defined in any one of paragraphs (36) to (40) above; R5and R6are as defined in paragraph (47) or paragraph (56) above; and L2is as defined in any one of paragraphs (43) to (44) above.

[0036] In an embodiment, the compound according to formula I is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)-14,24-difluoro- 16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-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-oxopyrimidin-1(2H)-yl)-14,24-difluoro- 16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyrimidin-1(2H)-yl)-14,24-difluoro-16-methyl-5- oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Diethylamino)ethyl)-4-methyl-2-oxopyrimidin-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-methyl-6-(4-methyl-2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)pyrimidin- 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-(Ethyl(methyl)amino)ethyl)-4-methyl-2-oxopyrimidin-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-methoxyazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- 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-6-(4-methyl-2-oxo-5-(3-(pyrrolidin-1-yl)propyl)pyrimidin- 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)-4-ethyl-2-oxopyrimidin-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-hydroxy-2-oxopyrimidin-1(2H)-yl)-14,24-difluoro- 16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Azetidin-1-yl)propyl)-4-methyl-2-oxopyrimidin-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-methoxyazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- 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-methoxyazetidin-1-yl)ethyl)-2-oxopyrimidin-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)-4-methyl-2-oxopyrimidin-1(2H)-yl)-24-fluoro-14,16- dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-14-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)- 24-fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-fluoro-3-methylazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxopyrimidin-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)-4-methyl-2-oxopyrimidin-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-(Azetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-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-fluoro-3-methylazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-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-(3,3-Difluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-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-(3-Ethoxyazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-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-methyl-6-(4-methyl-2-oxo-5-(2-(3-(trifluoromethoxy)azetidin-1- yl)ethyl)pyrimidin-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-isopropoxyazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- 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-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-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-(3-(3-methoxyazetidin-1-yl)propyl)-4-methyl-2-oxopyrimidin- 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)-24-Fluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-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-(3,3-Dimethylazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-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-(3-(Difluoromethoxy)azetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-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-(5-Azaspiro[2.3]hexan-5-yl)ethyl)-4-methyl-2-oxopyrimidin-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-methoxy-3-methylazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-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-Cyclopropyl-24-fluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid;2-((3S,6S)-6-(4-(Difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyrimidin-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-methoxy-3-methylazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-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)-4-methoxy-2-oxopyrimidin-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-oxopyrimidin-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-methyl-6-(4-methyl-2-oxo-5-(2-(3-(2,2,2-trifluoroethyl)azetidin-1- yl)ethyl)pyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-propylpyrimidin-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-methyl-6-(4-methyl-5-(1-methylpiperidin-4-yl)-2-oxopyrimidin- 1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(4-Ethyl-5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyrimidin-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-(4-Ethyl-5-(3-(3-methoxyazetidin-1-yl)propyl)-2-oxopyrimidin-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-methyl-6-(4-methyl-5-(1-methylazetidin-3-yl)-2-oxopyrimidin- 1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(4-Ethyl-5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyrimidin-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; and2-((3S,6S)-14,24-Difluoro-25-isopropyl-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.

[0037] The various functional groups and substituents making up the compounds of the present invention are typically chosen such that the molecular weight of the compound does not exceed 1000. More usually, the molecular weight of the compound will be less than 800, for example less than 750, or less than 700.

[0038] Suitable or preferred features of any compounds of the present invention may also be suitable features of any other aspect.

[0039] 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.

[0040] 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”.

[0041] 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 particularcompound in the specification and claims is intended to include both individual enantiomers, diastereoisomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess α4β7 inhibition activity.

[0042] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D) and3H (T); C may be in any isotopic form including12C,13C, and14C; and O may be in any isotopic form, including16O and18O; and the like. In an embodiment, present invention also encompasses deuterated analogues of the compounds of the invention defined by formula I.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] Compounds of the invention containing an amine function may also form N-oxides. A reference herein to a compound of the formula I that contains an amine function alsoincludes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N- Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

[0047] The compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro- drug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the invention and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the invention.

[0048] Accordingly, the present invention includes those compounds of the formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the formula I may be a synthetically-produced compound or a metabolically-produced compound.

[0049] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0050] 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.

[0051] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C1-6alkyl esters such as methyl, ethyl and tert-butyl, C1-6alkoxymethyl esters such as methoxymethyl esters, C1-6alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C3- 8cycloalkylcarbonyloxy- C1-6alkyl esters such as cyclopentylcarbonyloxymethyl and 1- cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2- oxo-1,3-dioxolen-4-ylmethyl esters and C1-6alkoxycarbonyloxy-C1-6alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.

[0052] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the formula I containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-10alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-10alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-6)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups 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.

[0053] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-4alkyl)2amine 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.

[0054] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-10alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-4alkyl)piperazin-1- ylmethyl.

[0055] The in vivo effects of a compound of the formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the formula I. As stated hereinbefore, the in vivo effects of a compound of the formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).

[0056] It shall also be appreciated that compounds of the formula I may also be covalently linked (at any suitable position) to other groups such as, for example, solubilising moieties (for example, PEG polymers), moieties that enable them to be bound to a solid support (such as, for example, biotin-containing moieties), and targeting ligands (such as antibodies or antibody fragments). Synthesis

[0057] The compounds of the disclosure may be prepared using methods disclosed herein and routine modifications thereof which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds of Formula (I), e.g., compounds having structures described by Formula (I), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analogue thereof, may be accomplished as described in the following examples.

[0058] 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, reactiontemperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0059] 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.

[0060] Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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, orby 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.

[0065] The person skilled in the art will recognise that the compounds of the invention may be prepared, in known manner, in a variety of ways. Compounds of formula I can be prepared by the methods given below, by the methods given in the experimental or by analogous methods. The routes described are merely illustrative of some of the methods that can be employed for the synthesis of compounds of formula I and the person skilled in the art will appreciate that the order of the reaction steps is not limited to those described. It will also be appreciated that the assignment of nucleophile and electrophile is not limited to that described herein and in some cases it may be appropriate for the assignment to be reversed. Different approaches to synthetic chemistry strategy are described in “Organic Synthesis: The Disconnection Approach”, 2ndedition, S. Warren and P. Wyatt (2008). General Methods

[0066] Compounds of Formula (I) may be prepared by a process involving first deprotection, i.e. cleavage of an ester group, followed optionally by conversion to a salt, of a compound of formula (A1) where E is defined as C1-6alkyl, for example tert-butyl or methyl, and all other variables are defined according to the scope of the present invention.

[0067] The deprotection of compounds of formula (A1), where E is tert-butyl, may be accomplished by acid hydrolysis using for example hydrochloric, sulfuric or trifluoroacetic acid, in a suitable solvent, such as dichloromethane, tetrahydrofuran or 1,4-dioxane. Where E is methyl, deprotection may be accomplished by base hydrolysis using for example lithium or sodium hydroxide in the presence of water and a suitable solvent such as methanol, ethanol, tetrahydrofuran or 1,4-dioxane.

[0068] After the cleavage of the ester group, the resulting product may be converted to the required salt by methods well known to those skilled in the art.

[0069] Compounds of formula (A1) may be prepared, for example, from intermediates of formula (A3), via an olefin metathesis reaction in the presence of a suitable metal catalyst such as the ruthenium based catalysts reported by Robert H. Grubbs and Amir H. Hoveyda (DOI: 10.1021 / ja952676d. DOI: 10.1021 / ja983222u, DOI: 10.1021 / ol990909q and DOI: 10.1021 / ja001179g). The metathesis reaction may be conducted in a suitable solvent, such as tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane or toluene, at an elevated temperature under nitrogen atmosphere. As a skilled person in the art of synthetic chemistry will understand, different olefin-terminal alkyl chains, other than the 6C and 3C chains exemplified in intermediates of formula (A3), may be used provided the total number of carbons on the two olefin-terminal alkyl chains is 9, so that after the metathesis reaction the cyclised product comprises a 7C linker L1.

[0070] Compounds of formula (A1) may be prepared from compounds of formula (A2) by reduction of the double bond. The reduction may be accomplished by catalytic hydrogenation with hydrogen in the presence of a noble metal catalyst such as Pt, Pd, Rh, Ru or Raney nickel. The hydrogenation reaction is conducted in a solvent such as methanol, ethanol, tetrahydrofuran or mixtures thereof. Depending on the reaction conditions the pyrimidinone ring might be reduced to the corresponding dihydropyrimidinone ring. If this happens the desired compounds of formula (A1) can be readily generated by oxidisation using a suitable oxidant such as manganese dioxide or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

[0071] Intermediates of formula (A3) may be prepared from intermediates of formula (A7), where LG1 represents a suitable leaving group, for example mesylate, triflate, tosylate, bromide, chloride and the like. The reaction between intermediates of formula (A7) and the pyrimidinone group may be conducted in the presence of a base, for example sodium hydride, sodium methoxide, potassium tert-butoxide or potassium carbonate, and an inert solvent like dimethylacetamide, dimethylformamide, acetonitrile and the like.

[0072] Intermediates of formula (A7) can be obtained from intermediates of formula (A6) using methods well known to those of skill in the art. For example, mesylate, triflate, tosylate, bromine and chlorine leaving groups can be introduced by reacting the alcohol functionality in (A6) with, respectively, mesyl chloride, trifluoromesyl chloride, tosyl chloride, phosphorus tribromide and thionyl chloride in a solvent, such as diethyl ether, tetrahydrofuran, toluene or cyclohexane or mixtures thereof, in the presence of a base such as triethylamine, diisopropylethylamine or pyridine.

[0073] Intermediates of formula (A6) can be prepared by forming an amide bond between intermediates of formula (A4) and (A5) using the standard amide bond formation chemistry. In particular, the reaction may be carried out using a coupling agent, for example N,N′- carbonyldiimidazole (CDI), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide (EDCI) or benzotriazol-1-yl-oxy-tris-pyrrolidino- phosphonium hexafluorophosphate (commercially available as PyBOP), in a solvent such as tetrahydrofuran, dichloromethane, chloroform or 1,2-dichloroethane. The reaction is preferably conducted in the presence of a base such as triethylamine, diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Intermediates of formula (A5) are commercially available or can be prepared according to methodologies known to the skilled in the art.

[0074] Intermediates of formula (A4) may be prepared from intermediates of formula (A8) and (A9), followed by deprotection of the amine protecting group (PG2) in intermediates of formula (A10).

[0075] In the procedure of the above scheme, the coupling of intermediates of formula (A8) and (A9) to give intermediates of formula (A10) can be achieved via a transition metal catalysed cross-coupling reaction, in which X1and X2represent a pair of reactive moieties capable of undergoing a transition metal catalysed cross-coupling reaction. Exemplary reactive moieties include, but are not limited to, halide, triflate and boron-containing functional groups. When one of X1or X2is halide or triflate, the other X1or X2is a boron-containing functional group of the formula -B(OR)2, where each R can independently be hydrogen or alkyl. When R is alkyl, it is preferred that the two R substituents and boron atom form a ring (e.g., a pinacol boronic ester). The cross-coupling reaction can be conducted in the presence of a suitable catalyst, such as Pd(PPh3)4, Pd2(dba)3 or Pd(dppf)Cl2 and a mild base, such as K2CO3 and Na2CO3, in a suitable solvent, such as 1,4-dioxane, toluene, ethanol, water and mixtures thereof, at an elevated temperature. The selection of catalyst, base, solvent and reaction conditions (i.e., time, temperature, pressure, choice of atmosphere, etc.) are known to those skilled in the art.

[0076] Removal of the amine protecting group (PG2) in intermediates of formula (A10) to give intermediates of formula (A4) can be accomplished following procedures known in the art. For example, when a Boc protecting group is used, the deprotection methods of choice are trifluoroacetic acid in dichloromethane, or hydrochloric acid in 1,4-dioxane.

[0077] Intermediates of formula (A8), where X2represents a reactive moiety capable of undergoing a transition metal catalysed cross-coupling reaction (e.g., halide, triflate, boronic acid and boronic ester) are commercially available, or can be prepared according to methodologies known to those skilled in the art.

[0078] Intermediates of formula (A9) where X1represents a pinacol boronic ester, which are intermediates of formula (A14), can be prepared from intermediates of formula (A11) by a process involving first protection of the acid functionality with a suitable protecting group (E) to give intermediates of formula (A12), followed by protection of the amine functionality in (A12) with a suitable protecting group (PG2) to give intermediates of formula (A13) and then by a cross-coupling reaction with bis(pinacolato)diboron to give intermediates of formula (A14).

[0079] In the procedure of the above scheme, protection of the acid functionality in intermediates of formula (A11) with a suitable protecting group (E) to give intermediates of formula (A12) can be accomplished by reacting together intermediates of formula (A11) and a C1-6alkyl alcohol (e.g., methanol or ethanol) with removal of water either physically, e.g. by azeotropical water removal or chemically by using a dehydrating agent. The aminefunctionality in intermediates of formula (A12) is protected with a suitable amine protecting group (as defined above) PG1to give intermediates of formula (A13). Conversion of the bromine functionality in intermediates of formula (A13) to the pinacol boronic ester functionality in (A14) can be accomplished using the conditions described above for the cross-coupling of intermediates of formula (A8) and (A9) to give intermediates of formula (A10).

[0080] The synthesis of intermediate β-amino acids of formula (A11), can be accomplished using well known procedures described in the literature, such as Enantioselective Synthesis of β-Amino Acids, (John Wiley & Sons, 2005); Ellman et.al., Acc. Chem. Res.2002, 35, 984- 995, Franklin A. Davis and Bang-Chi, Chen Chem. Soc. Rev., 1998, 27, 13-18; Mikkel F. Jacobsen and Troels Skrydstrup, J. Org. Chem.2003, 68, 7122; Tony P. Tang and Jonathan A. Ellman, J. Org. Chem.2002, 67, 7819; and Tony P. Tang and Jonathan A. Ellman, J. Org. Chem.1999, 64, 12.

[0081] Alternatively, intermediates of formula (A4) may be prepared from intermediates of formula (A22) – as shown below – by deprotection of the analogous tert-butylsulfinyl amine, for example by treatment of intermediates of formula (A22) with HCl in a suitable solvent such as dioxane. Intermediates of formula (A22) may be prepared by reacting intermediates of formula (A20) with an intermediate of formula (A21) which has been converted to the equivalent organozinc compound, for example by reaction of an intermediate of formula (A21) with zinc and a halotrialkylsilane (such as chlorotrimethylsilane). Intermediates of formula (A20) may be prepared by reacting intermediates of formula (A19) with (R)-2-methylpropane- 2-sulfinimide, for example in the presence of titanium ethoxide. Intermediates of formula (A19) may be prepared from intermediates of formula (A18) and a suitable terminal-olefin alkylboronate, in this case 5-hexenylboronic acid, under standard transition metal catalysed cross-coupling conditions such as a Pd-catalysed cross-coupling. Triflate intermediates of formula (A18) may be prepared from the equivalent alcohol intermediates of formula (A17), for example by using a triflating reagent, such as triflic anhydride or phenyl triflimide, in the presence of a suitable base, such as caesium carbonate. Intermediates of formula (A17) may be prepared via a transition metal catalysed cross-coupling reaction of intermediates of formula (A15) and intermediates of formula (A16), in which X1and X2represent a pair of reactive moieties capable of undergoing a transition metal catalysed cross-coupling reaction. The transition metal catalysed cross-coupling reaction may be carried out using the conditions described above for the cross-coupling of intermediates of formula (A8) and (A9) to give intermediates of formula (A10).

[0082] Pyrimidinone intermediates of formula (A23) may be prepared from methoxypyrimidine intermediates of formula (A24), as shown below, by demethylation of the intermediates of formula (A24) under suitable conditions, such as HBr in acetic acid.

[0083] Intermediates of formula (A24), wherein R3is C2-alkylene-NR5R6, referred to below as intermediates of formula (A25), may be prepared by hydrolysis of enol ether intermediates of formula (A26) to the corresponding aldehyde (e.g. using TFA), followed by reaction with amine intermediates of formula (A27) under reducing conditions (e.g. addition of sodium triacteoxyborohydride).

[0084] Intermediates of formula (A24), wherein R3is C3-alkylene-NR5R6, referred to below as intermediates of formula (A28), may be prepared by conversion of alcohol intermediates of formula (A32) to the corresponding alkyl halides under Appel reaction conditions (e.g. using CBr4 and triphenylphosphine), followed by reaction with amine intermediates of formula (A27). Intermediates of formula (A32) may be prepared by deprotection of the PG3 protecting group in intermediates of formula (A31). The PG3 protecting group is a suitable alcohol protecting group, such as a silyl protecting group (e.g. TBMDS) which may be deprotected using a suitable reagent such as TBAF. Intermediates of formula (A31) may be prepared by reductionof intermediates of formula (A30) under suitable conditions, such as hydrogen over a suitable metal (e.g. Pd on C) catalyst. Intermediates of formula (A30) may be prepared by reacting intermediates of formula (A29) with a suitably protected (PG3) propynyl alcohol in the presence of a suitable metal catalyst (e.g. CuI).

[0085] Intermediates of formula (A26) and (A29) are commercially available, or readily available through synthesis procedures known in the art. Pharmaceutical Compositions

[0086] The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Therefore, according to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of Formula I as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0087] The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.

[0088] 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).

[0089] 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. methylparabens 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.

[0090] 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.

[0091] Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.

[0092] 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.

[0093] 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 theinvention. 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).

[0094] 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).

[0095] 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.

[0096] The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0097] 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

[0098] 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).

[0099] 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.

[0100] 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

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] Examples of inflammatory diseases that the compounds of Formula I and their pharmaceutically acceptable salts may be used to treat are inflammatory bowel diseases such as ulcerative colitis or Crohn’s disease, eosinophilic gastrointestinal diseases, and pouchitis.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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

[0113] 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.

[0114] It is commonplace to use combination therapies to treat certain medical conditions.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents in association with a pharmaceutically acceptable diluent or carrier.

[0120] 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.

[0121] 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

[0122] 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.

[0123] 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.

[0124] 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

[0126] 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.

[0127] A person skilled in the art will appreciate that reaction temperatures, reaction times and reagent quantities may be varied from those stated herein.

[0128] Flash chromatography carried out using Combiflash® Nextgen 300+ and automated reverse-phase chromatography carried out on Interchim Puriflash® 4100.

[0129] Photochemical reactions were carried out using an Evoluchem Photobox Reactor by Hepatochem.

[0130] Where compounds described in the invention are characterized by 1H NMR spectroscopy, Bruker 500 MHz spectrometer instrument or Bruker Ultrashield 400 MHzspectrometer. 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.

[0131] Where compounds described in the invention are characterized by LCMS data, retention time and molecular weight are determined using the conditions listed below. 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 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 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 NH4HCO3in water [eluent A], MeCN [eluent B]. Gradient: 0 - 95% B over 2 min, hold at 95% B for 2 min. Method 37: Waters Acquity I-Class Plus (Waters Acquity PDA 210 – 400 nm and Waters Acquity SQ detector). Column: Acquity UPLC BEH C181.7 µm 2.1 x 50 mm (Flow 0.5 mL / min)at 40 °C. Conditions: 0.1% TFA in water [eluent A], MeCN [eluent B]. Gradient: 3 - 95% B over 7 min, hold at 95% B for 2 min.

[0132] Preparative HPLC was performed using Waters 2545 Binary Gradient Module with 2998 PDA and 2767 Sample Manager, Waters SFO module.

[0133] Preparative SFC was performed using Waters SFC-150-I; Waters SFC-150-II; Waters SFC-200; Buchi Sepiatec-200. Abbreviations AcOH Acetic acid BF3.OEt2 Boron trifluoride diethyl etherate Boc tert-Butyloxycarbonyl Co(acac)2 Cobalt (II) acetylacetonate Cs2CO3 Cesium carbonate DAST (Diethylamino)sulfur trifluoride DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE 1,2-Dichloroethane DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide EDCI N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride EtOAc Ethyl acetate 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 HATU 3-oxid hexafluorophosphate HBr Hydrogen bromide HCl Hydrogen chloride HOBt Hydroxybenzotriazole HPLC High Performance Liquid Chromatography IPA Isopropyl alcohol [4,4’-Bis(1,1-dimethylethyl)-2,2’-bipyridine-N1,N1’]bis[3,5-difluoro-2- (Ir[dF(CF3)ppy]2(dtbpy))PF6 [5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate K2CO3 Potassium carbonate K3PO4Potassium phosphateLCMS Liquid Chromatography Mass Spectrometry MeCN Acetonitrile MeOH Methanol MgSO4 Magnesium sulfate min Minute(s) NH4HCO3Sodium bicarbonateNa2CO3 Sodium carbonate Na2SO4 Sodium sulfate NMR Nuclear Magnetic Resonance Pd(dppf)Cl2 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride Pd(dppf)Cl2.DCM dichloromethane complex 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′- RuPhosPdG3 amino-1,1-biphenyl)]palladium(II) methanesulfonate SFC Super critical fluid chromatography STAB Sodium triacetoxyborohydride 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- XPhosPdG2 (2′-amino-1,1′-biphenyl)]palladium(II) Synthesis of Intermediates Intermediate 19: Ethyl (S)-3-amino-3-(5-bromo-2-fluoro-3-(trifluoromethyl)- phenyl)propanoate

[0134] 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 NaHCO3and 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

[0135] 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 33: 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- (trifluoromethyl)benzaldehyde

[0136] A solution of 5-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (0.50 g, 1.85 mmol, CAS 1291487-26-7) and bis(pinacolato)diboron (0.56 g, 2.21 mmol) in 1,4-dioxane (20 mL) was degassed with nitrogen. To the solution was then added potassium acetate (0.36 g, 3.69 mmol) and Pd(dppf)Cl2(75 mg, 0.05 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, eluting 50% EtOAc in petroleumether) to provide the title compound (7.0 g).1H NMR (400 MHz; CDCl3) δ: 10.28 (s, 1H), 8.39 (dd, 1H), 8.16 (dd, 1H), 1.27 (s, 12H). Intermediate 34: 4,4'-Difluoro-2'-hydroxy-6'-methyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3- carbaldehyde

[0137] A mixture of Intermediate 33 (1.20 g, 3.77 mmol), 2-bromo-5-fluoro-3-methylphenol (0.70 g, 3.42 mmol, CAS 1807192-21-7) and K3PO4(1.45 g, 6.85 mmol) in toluene (9 mL) and water (4.6 mL) was degassed with nitrogen. To this was added palladium acetate (77 mg, 0.34 mmol) and tricyclohexyl phosphine (96 mg, 0.34 mmol) and the mixture stirred at 85 °C for 18 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, eluting 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)- biphenyl]-2-yltrifluoromethanesulfonate

[0138] To a solution of Intermediate 34 (2.11 g, 6.67 mmol) in DCM (40 mL) was added phenyl triflimide (2.38 g, 6.67 mmol, CAS 37595-74-7) and Cs2CO3 (2.61 g, 8.01 mmol) then the mixture was stirred at RT for 2 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 (25 g silica gel, eluting 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)- biphenyl]-3-carbaldehyde

[0139] Prepared in an analogous manner to Intermediate 34 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, eluting 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

[0140] To a solution of Intermediate 36 (1.37 g, 3.59 mmol) in THF (24 mL) was added (R)- 2-methylpropane-2-sulfinimide (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

[0141] 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, eluting 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

[0142] 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, eluting 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)- biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate

[0143] To a solution of Intermediate 39 (0.83 g, 1.76 mmol) and (2R)-2-hydroxypent-4-enoic acid (0.31 g, 2.64 mmol, CAS 413622-10-3) in MeCN (24 mL) was added DIPEA (0.92 mL, 5.28 mmol), HOBt (0.26 g, 1.94 mmol) and EDCI (0.41 g, 2.64 mmol) and the mixture was stirred at RT for 18 h. The mixture was diluted with water and extracted into EtOAc. Theorganic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel, eluting 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)- biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0144] To a solution of Intermediate 40 (0.41 g, 0.72 mmol) and triethylamine (0.20 mL, 1.44 mmol) in DCM (8 mL) was added methanesulfonyl chloride (83 µL, 1.08 mmol) and the mixture stirred at 0 °C 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 (0.51 g). LCMS (Method 15): 2.73 min, 646.1 [M+H]+. Intermediate 61: 5-Fluoro-2-iodo-3-methylphenol

[0145] 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, eluting 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- biphenyl]-3-carbaldehyde

[0146] Prepared in an analogous manner to Intermediate 34 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, eluting 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- biphenyl]-2-yltrifluoromethanesulfonate

[0147] Prepared in an analogous manner to Intermediate 35 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,eluting 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

[0148] Prepared in an analogous manner to Intermediate 34 using 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, eluting 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: -N-((4,4'-Difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)methylene)-2- 2-sulfinamide

[0149] Prepared in an analogous manner to Intermediate 37 using Intermediate 64 (1.72 g, 5.24 mmol), (R)-2-methylpropane-2-sulfinimide (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

[0150] 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, 13.1 mmol) 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, eluting 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-biphenyl]-3-yl)propanoate

[0151] 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 NaHCO3and 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- biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate

[0152] Prepared in an analogous manner to Intermediate 40 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, eluting 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

[0153] Prepared in an analogous manner to Intermediate 41 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 70: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-4-en-1-yl)-5,6'-dimethyl- biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl) enamido)propanoate

[0154] To a solution of Intermediate 98 (0.56 g, 0.92 mmol) and 5-[2-(dimethylamino)ethyl]- 4-methyl-1H-pyrimidin-2-one (0.18 g, 1.02 mmol, CAS 2955527-96-3) in MeCN (11 mL) was added K2CO3 (0.38 g, 2.77 mmol) and the mixture stirred at reflux 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 (40 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.24 g). LCMS (Method 15): 2.74 min, 691.3 [M+H]+. Intermediate 71: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)-14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphan- 9-en-3-yl)acetate

[0155] To a solution of Intermediate 70 (0.24 g, 0.35 mmol) in DCE (0.17 L) with bubbling nitrogen through, was added Grubbs II (30 mg, 35 µmol) and the mixture was stirred at 50 °C for 1 h. The mixture was cooled and concentrated under reduced pressure. The crude product was purified by flash chromatography (25 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.15 g). LCMS (Method 15): 2.55 min, 649.3 [M+H]+.Intermediate 72: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)-14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0156] To a solution of Intermediate 71 (0.15 g, 0.20 mmol) in EtOAc (16 mL) was added 10% palladium on carbon (21 mg) and the mixture was stirred under a hydrogen atmosphere at RT for 20 h. The mixture was filtered through Celite®, washing with EtOAc, and concentrated under reduced pressure. The crude product was purified by flash chromatography (4 g silica gel, eluting 0-5% MeOH in DCM) to provide the title compound (0.11 g). LCMS (Method 15): 2.53 min, 651.3 [M+H]+. Intermediate 73: Methyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-1(2H)- 4-enamido)propanoate

[0157] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.48 g, 0.67 mmol), 5-[2-(dimethylamino)ethyl]-4-methyl-1H-pyrimidin-2-one (0.13 g, 0.74 mmol, CAS 2955527-96-3) and K2CO3 (0.28 g, 2.01 mmol) in MeCN (8 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.17 g). LCMS (Method 15): 2.61 min, 717.3 [M+H]+. Intermediate 74: Methyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin- 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

[0158] Prepared in an analogous manner to Intermediate 71 using Intermediate 73 (0.17 g, 0.23 mmol) and Grubbs II (20 mg, 23 µmol) in DCE (0.12 L) at 50 °C for 5 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.11 g). LCMS (Method 15): 2.49 min, 689.3 [M+H]+. Intermediate 75: Methyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0159] Prepared in an analogous manner to Intermediate 72 using Intermediate 74 (0.11 g, 0.12 mmol) and 10% palladium on carbon (13 mg) in EtOAc (16 mL) under a hydrogen atmosphere at RT for 30 h. Purified by flash chromatography (4 g silica gel, eluting 0-5% MeOH in DCM) to provide the title compound (65 mg). LCMS (Method 15): 2.52 min, 691.3 [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

[0160] To a stirred suspension of Intermediate 67 (6.39 g, 7.69 mmol) and Boc anhydride (2.01 g, 9.22 mmol) in DCM (77 mL) was added DIPEA (2.0 mL, 11.5 mmol) and the mixture stirred at RT for 18 h. The mixture was diluted with DCM and washed with 1 M aqueous HCl, water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (80 g silica gel, eluting 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

[0161] 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), Hantzch 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, eluting 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-biphenyl]-3-yl)propanoate hydrochloride

[0162] 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- biphenyl]-3-yl)-3-((R)-2-hydroxyhex-5-enamido)propanoate

[0163] Prepared in an analogous manner to Intermediate 40 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, eluting 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- biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)hex-5-enamido)propanoate

[0164] Prepared in an analogous manner to Intermediate 41 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 104: -N-(3-bromo-5-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide

[0165] 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- sulfinimide (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

[0166] 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, eluting 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

[0167] 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, eluting 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

[0168] To a stirred suspension of Intermediate 106 (2.49 g, 7.66 mmol) and Boc anhydride (2.01 g, 9.20 mmol) in DCM (20 mL) was added DIPEA (2.00 mL, 11.5 mmol) and the mixture stirred for 5 h at RT. The mixture was washed with 1 M aqueous HCl, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel, eluting 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-2-fluoro-3-(prop-1- en-2-yl)phenyl)propanoate

[0169] Prepared in an analogous manner to Intermediate 295 using Intermediate 107 (20.0 g, 42.4 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (17.8 g, 0.11 mol, CAS 126726-62-3), Pd(dppf)Cl2.DCM (1.73 g, 2.12 mmol) and K2CO3(11.7 g, 84.8 mmol) in 1,4-dioxane (0.2 L) and water (20 mL) at 90 °C for 12 h. Purified by flash chromatography (200 g silica gel, eluting 0-10% EtOAc in hexane) to provide the title compound (16.0 g). LCMS (Method 34): 1.72 min, 286.2 [M-Boc+H]+. Intermediate 109: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2'-hydroxy-6'- methyl-5-(prop-1-en-2-yl)-[1,1'-biphenyl]-3-yl)propanoate

[0170] Prepared in an analogous manner to Intermediate 34 using Intermediate 108 (25.0 g, 62.8 mmol), Intermediate 191 (21.7 g, 81.7 mmol), Cs2CO3 (61.4 g, 0.19 mol), XPhosPdG2 (5.31 g, 6.28 mmol) in 1,4-dioxane (0.25 L) and water (25 mL) at 90 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-20% EtOAc in petroleum ether) to provide the title compound (18.5 g). LCMS (Method 34): 1.62 min, 476.5 [M+H]+. Intermediate 110: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2'-hydroxy-5- isopropyl-6'-methyl-[1,1'-biphenyl]-3-yl)propanoate

[0171] Prepared in an analogous manner to Intermediate 72 using Intermediate 109 (18.5 g, 32.7 mmol) and 10% palladium on carbon (18.5 g) in ethanol (0.25 L) under a hydrogen atmosphere at RT for 1.5 h to provide the title compound (17.4 g). LCMS (Method 34): 1.63 min, 378.4 [M-Boc+H]+. Intermediate 111: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-5-isopropyl-2'- methyl-6'-(((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-yl)propanoate

[0172] Prepared in an analogous manner to Intermediate 35 using Intermediate 110 (17.4 g, 31.3 mmol), phenyl triflimide (12.3 g, 34.5 mmol, CAS 37595-74-7) and Cs2CO3 (12.3 g, 37.6 mmol) in DCM (0.25 L) at RT for 2 h. Purified by flash chromatography (12 g silica gel, eluting 0–20% EtOAc in petroleum ether) to provide the title compound (21.0 g). LCMS (Method 35): 1.28 min, 608.3 [M-H]-. Intermediate 112: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4,4'-difluoro-2'-(hex-5-en-1- yl)-5-isopropyl-6'-methyl- biphenyl]-3-yl)propanoate

[0173] Prepared in an analogous manner to Intermediate 34 using Intermediate 111 (21.0 g, 26.2 mmol), 5-hexenylboronic acid (5.03 g, 39.3 mmol, CAS 1072952-16-9), K2CO3(10.9 g, 78.5 mmol), palladium acetate (0.59 g, 2.62 mmol) and RuPhos (1.83 g, 3.93 mmol) in toluene (0.30 L) and water (30 mL) at 90 °C for 2 h. Purified by flash chromatography (silica gel, eluting 0-20% EtOAc in petroleum ether) to provide the title compound (12.5 g). LCMS (Method 32): 10.98 min, 544.6 [M+H]+.Intermediate 113: Ethyl (S)-3-amino-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5-isopropyl-6'-methyl- [1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0174] A suspension of Intermediate 112 (2.60 g, 4.54 mmol) in 4 M HCl in 1,4-dioxane (26 mL) and DCM (13 mL) was stirred at RT for 3 h. The mixture was concentrated under reduced pressure to provide the title compound (2.10 g). LCMS (Method 35): 0.96 min, 444.5 [M+H]+. Intermediate 114: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5-isopropyl-6'-methyl-[1,1'- biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate

[0175] Prepared in an analogous manner to Intermediate 40 using Intermediate 113 (2.10 g, 4.20 mmol), (2R)-2-hydroxypent-4-enoic acid (0.49 g, 4.20 mmol, CAS 413622-10-3), DIPEA (3.66 mL, 21.0 mmol), and HATU (2.40 g, 6.30 mmol) in DMF (21 mL) at RT for 16 h. Purified by flash chromatography (silica gel, 0-40% EtOAc in petroleum ether) to provide the title compound (1.60 g). LCMS (Method 34): 1.86 min, 542.7 [M+H]+. Intermediate 115: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5-isopropyl-6'-methyl-[1,1'- biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0176] Prepared in an analogous manner to Intermediate 41 using Intermediate 114 (0.60 g, 0.72 mmol), triethylamine (0.30 mL, 2.16 mmol) and methanesulfonyl chloride (84 µL, 1.08 mmol) in DCM (12 mL) at RT for 3 h. Purified by flash chromatography (silica gel, 0-30% EtOAc in hexane) to provide the title compound (0.54 g). LCMS (Method 34): 1.89 min, 620.7 [M+H]+. Intermediate 116: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5-isopropyl-6'-methyl-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2- - yl)pent-4-enamido)propanoate

[0177] Prepared in an analogous manner to Intermediate 70 using Intermediate 115 (0.25 g, 0.33 mmol), Intermediate 278 (0.11 g, 0.49 mmol) and K2CO3 (0.14 g, 0.98 mmol) in MeCN (10 mL) at reflux for 18 h. Purified by flash chromatography (silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (80 mg). LCMS (Method 36): 3.79 min, 745.5 [M+H]+. Intermediate 117: Ethyl 2-((3S,6S)-14,24-difluoro-25-isopropyl-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-yl)acetate

[0178] Prepared in an analogous manner to Intermediate 71 using Intermediate 116 (80 mg, 88 µmol) and Grubbs II (13 mg, 15 µmol) in DCE (80 mL) at 45 °C for 16 h, to provide the title compound (80 mg). LCMS (Method 35): 0.93 min, 719.8 [M+H]+.Intermediate 118: Ethyl 2-((3S,6S)-14,24-difluoro-25-isopropyl-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

[0179] Prepared in an analogous manner to Intermediate 262 using Intermediate 117 (80 mg, 97 µmol) and 10% palladium on carbon (80 mg) in ethanol (10 mL) under a hydrogen atmosphere at RT for 2 h. Followed by manganese dioxide (0.17 g, 1.94 mmol) in DCM (10 mL) at RT for 16 h to provide the title compound (70 mg). LCMS (Method 34): 1.48 min, 721.8 [M+H]+. Intermediate 126: -N-(5-Bromo-2-fluoro-3-methylbenzylidene)-2-methylpropane-2-sulfinamide

[0180] 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- sulfinimide (0.92 g, 7.60 mmol, CAS 196929-78-9) and titanium ethoxide (2.36 g, 10.4 mmol) in THF (25 mL) at 40 °C for 2.5 h to provide the title compound (90 mg). LCMS (Method 7): 2.29 min, 322.0 [M+H]+. Intermediate 127: Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate

[0181] 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, eluting 1-10% MeOH in DCM) to provide the title compound (1.55 g). LCMS (Method 8): 2.07 min, 410.3 [M+H]+. Intermediate 128: Ethyl (S)-3-amino-3-(5-bromo-3-methyl-2-fluorophenyl)propanoate hydrochloride

[0182] 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

[0183] To a stirred suspension of Intermediate 128 (3.22 g, 9.45 mmol) and Boc anhydride (2.48 g, 11.3 mmol) in DCM (100 mL) was added DIPEA (2.5 mL, 14.2 mmol) and the mixture stirred for 2 h at RT. The mixture was diluted with DCM and washed with 1 M aqueous HCl, water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography (12 g silica gel, eluting 0-30% EtOAc in petroleum ether) to provide the title compound (3.11 g). LCMS (Method 4): 1.78 min, 305.8 [M-Boc+H]+. Intermediate 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

[0184] 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, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (2.98 g).1H NMR (400 MHz; CDCl3) δ: 7.59 – 7.52 (m, 2H), 5.47 – 5.43 (m, 1H), 5.34 – 5.28 (m, 1H), 4.10 – 3.99 (m, 2H), 2.90 – 2.66 (m, 2H), 2.25 (s, 3H), 1.42 (s, 9H), 1.32 (s, 12H), 1.18 (t, 3H). Intermediate 172: 3-(2-Methoxy-4-methylpyrimidin-5-yl)-N,N-dimethylprop-2-yn-1-amine

[0185] A mixture of 5-bromo-2-methoxy-4-methylpyrimidine (0.46 g, 2.28 mmol, CAS 38696- 23-0), Pd(PPh3)2Cl2 (0.12 g, 0.16 mmol) and copper(I) iodide (30 mg, 0.16 mmol) in MeCN (15 mL) was degassed with nitrogen. Triethylamine (2.23 mL, 16.0 mmol) and N,N- dimethylpropargylamine (1.72 mL, 16.0 mmol) were added and the mixture stirred at 80 °C for 40 h. The mixture was filtered and concentrated under reduced pressure. The crude was purified by flash chromatography (40 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.35 g). LCMS (Method 15): 1.39 min, 206.1 [M+H]+. Intermediate 173: 3-(2-Methoxy-4-methylpyrimidin-5-yl)-N,N-dimethylpropan-1-amine

[0186] Prepared in an analogous manner to Intermediate 72 using Intermediate 172 (0.75 g, 3.66 mmol) and 10% palladium on carbon (0.20 g) in EtOAc (44 mL) under a hydrogen atmosphere at RT for 1.5 h to provide the title compound (0.65 g). LCMS (Method 15): 1.32 min, 210.1 [M+H]+. Intermediate 174: 5-(3-(Dimethylamino)propyl)-4-methylpyrimidin-2(1H)-one

[0187] A solution of Intermediate 173 (0.65 g, 3.10 mmol) in 33% HBr in AcOH (10.7 mL, 62.0 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 (10 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.52 g). LCMS (Method 15): 0.87 min, 196.1 [M+H]+. Intermediate 175: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(5-(3-(dimethylamino)propyl)-4-methyl-2-oxopyrimidin-1(2H)- 4-enamido)propanoate

[0188] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.33 g, 0.51 mmol), Intermediate 174 (0.11 g, 0.56 mmol) and K2CO3(0.21 g, 1.53 mmol) in MeCN (7 mL) at reflux for 16 h. Purified by flash chromatography (25 g silica gel, 0-20% MeOH in DCM) to provide the title compound (0.23 g). LCMS (Method 15): 2.72 min, 745.4 [M+H]+. Intermediate 176: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-4-methyl-2-oxopyrimidin- 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

[0189] Prepared in an analogous manner to Intermediate 71 using Intermediate 175 (0.23 g, 0.26 mmol) and Grubbs II (22 mg, 26 µmol) in DCE (0.26 L) at 50 °C for 1 h. Purified by flash chromatography (25 g silica gel, eluting 0-20% MeOH in DCM) to provide the title compound (0.17 g). LCMS (Method 15): 2.61 min, 717.3 [M+H]+. Intermediate 177: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)propyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0190] Prepared in an analogous manner to Intermediate 72 using Intermediate 176 (0.16 g, 0.20 mmol) and 10% palladium on carbon (21 mg) in EtOAc (15 mL) under a hydrogen atmosphere at RT for 23 h to provide the title compound (0.11 g). LCMS (Method 21): 5.44 min, 719.3 [M+H]+. Intermediate 189: 5-Fluoro-2-iodo-1-(methoxymethoxy)-3-methylbenzene

[0191] 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

[0192] 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, eluting 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

[0193] 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 205: (S)-2-Hydroxy-4-methylpent-4-enoic acid

[0194] 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, and the reulting mixture was stirred at 0 °C for 1.5 h. The mixture was treated with methylamine (2 M in THF, 9.65 mL) at 0 °C for 30 min, then 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, 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 258: 2-(2-Methoxypyrimidin-5-yl)-N,N-dimethylethan-1-amine

[0195] A solution of (E)-5-(2-ethoxyvinyl)-2-methoxypyrimidine (0.50 g, 2.78 mmol, CAS 2955528-07-9) in DCM (5 mL) and TFA (6.4 mL) was stirred at RT for 11 h. The mixture was concentrated under reduced pressure then dissolved in DCM (14 mL). Dimethylamine (2 M in THF, 2.8 mL, 5.55 mmol), triethylamine (0.77 mL, 5.55 mmol) and 4 Å molecular sieves were added and stirred at RT for 10 min. STAB (1.18 g, 5.55 mmol) was added and stirred at RT for 16 h. The mixture was filtered concentrated under reduced pressure. The crude product was purified by flash chromatography (25 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.40 g). LCMS (Method 15): 1.13 min, 182.1 [M+H]+. Intermediate 259: 5-(2-(Dimethylamino)ethyl)pyrimidin-2(1H)-one

[0196] A solution of Intermediate 258 (0.37 g, 2.04 mmol) in 33% HBr in AcOH (7.0 mL, 40.8 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 (10 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.28 g). LCMS (Method 15): 0.34 min, 168.1 [M+H]+. Intermediate 260: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxopyrimidin-1(2H)-yl)pent-4- propanoate

[0197] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.34 g, 0.53 mmol), Intermediate 259 (0.11 g, 0.63 mmol) and K2CO3(0.22 g, 1.59 mmol) in MeCN(8 mL) at reflux for 16 h. Purified by flash chromatography (25 g silica gel, 0-20% MeOH in DCM) to provide the title compound (0.12 g). LCMS (Method 15): 2.65 min, 717.3 [M+H]+. Intermediate 261: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyrimidin-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

[0198] Prepared in an analogous manner to Intermediate 71 using Intermediate 260 (0.12 g, 0.14 mmol) and Grubbs II (14 mg, 17 µmol) in DCE (46 mL) at 50 °C for 2 h. Purified by flash chromatography (40 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (69 mg). LCMS (Method 21): 5.19 min, 689.2 [M+H]+. Intermediate 262: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyrimidin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0199] Prepared in an analogous manner to Intermediate 72 using Intermediate 261 (69 mg, 85 µmol) and 10% palladium on carbon (9.1 mg) in ethanol (5 mL) under a hydrogen atmosphere at RT for 3 h. The crude product was dissolved in DCM (4 mL) then manganese dioxide (0.10 g, 1.17 mmol) was added and stirred at RT for 18 h. The mixture was filtered through Celite®, washing with DCM and the filtrate concentrated under reduced pressure to provide the title compound (50 mg). LCMS (Method 27): 1.71 min, 691.3 [M+H]+. Intermediate 263: N,N-Diethyl-2-(2-methoxy-4-methylpyrimidin-5-yl)ethan-1-amine

[0200] Prepared in an analogous manner to Intermediate 258 using (E)-5-(2-ethoxyvinyl)- 2-methoxy-4-methylpyrimidine (0.96 g, 4.95 mmol, CAS 2955527-94-1) in DCM (6.8 mL) and TFA (11.5 mL) at RT for 4.5 h. Then diethylamine (1.28 mL, 12.4 mmol), triethylamine (0.83 mL, 5.94 mmol) in DCM (27 mL) with 4 Å molecular sieves at RT for 10 min, followed by STAB (2.62 g, 12.4 mmol) at RT for 72 h. Purified by flash chromatography (25 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.55 g). LCMS (Method 15): 1.53 min, 224.1 [M+H]+. Intermediate 264: 5-(2-(Diethylamino)ethyl)-4-methylpyrimidin-2(1H)-one

[0201] A solution of Intermediate 263 (0.55 g, 2.45 mmol) in 33% HBr in AcOH (8.5 mL, 49.0 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 (10 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.53 g). LCMS (Method 15): 0.94 min, 210.1 [M+H]+.Intermediate 265: Ethyl (S)-3-((S)-2-(5-(2-(diethylamino)ethyl)-4-methyl-2-oxopyrimidin- 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

[0202] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.46 g, 0.71 mmol), Intermediate 264 (0.15 g, 0.71 mmol) and K2CO3 (0.29 g, 2.11 mmol) in DMF (8 mL) at 85 °C for 3 h. Purified by flash chromatography (25 g silica gel, eluting 2-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.17 g). LCMS (Method 15): 2.61 min, 759.3 [M+H]+. Intermediate 266: Ethyl 2-((3S,6S)-6-(5-(2-(diethylamino)ethyl)-4-methyl-2-oxopyrimidin- 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

[0203] Prepared in an analogous manner to Intermediate 71 using Intermediate 265 (0.17 g, 0.21 mmol) and Grubbs II (18 mg, 21 µmol) in DCE (0.11 L) at 45 °C for 1.5 h. Purified by flash chromatography (40 g silica gel, eluting 2-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.15 g). LCMS (Method 15): 2.69 min, 731.3 [M+H]+. Intermediate 267: Ethyl 2-((3S,6S)-6-(5-(2-(diethylamino)ethyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0204] Prepared in an analogous manner to Intermediate 262 using Intermediate 266 (0.15 g, 0.21 mmol) and 10% palladium on carbon (22 mg) in ethanol (18 mL) under a hydrogen atmosphere at RT for 2 h. Followed by manganese dioxide (0.10 g, 1.17 mmol) in DCM (7.4 mL) at RT for 4 h to provide the title compound (58 mg). LCMS (Method 15): 2.74 min, 733.3 [M+H]+. Intermediate 268: 2-Methoxy-4-methyl-5-(2-(pyrrolidin-1-yl)ethyl)pyrimidine

[0205] Prepared in an analogous manner to Intermediate 258 using (E)-5-(2-ethoxyvinyl)- 2-methoxy-4-methylpyrimidine (1.0 g, 5.15 mmol, CAS 2955527-94-1) in DCM (7.1 mL) and TFA (11.9 mL) at RT for 6 h. Then pyrrolidine (1.30 mL, 12.9 mmol), triethylamine (0.86 mL, 6.18 mmol) in DCM (28 mL) with 4 Å molecular sieves at RT for 10 min, followed by STAB (2.73 g, 12.9 mmol) at RT for 20 h. Purified by flash chromatography (25 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.71 g). LCMS (Method 15): 1.42 min, 222.1 [M+H]+. Intermediate 269: 4-Methyl-5-(2-(pyrrolidin-1-yl)ethyl)pyrimidin-2(1H)-one

[0206] A solution of Intermediate 268 (0.71 g, 3.14 mmol) in 33% HBr in AcOH (10.8 mL, 62.7 mmol) was stirred at 65 °C for 1 h. The mixture was cooled and concentrated underreduced pressure. The crude product was purified by catch and release chromatography (10 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.62 g). LCMS (Method 15): 0.87 min, 208.1 [M+H]+. Intermediate 270: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(4-methyl-2-oxo-5-(2-(pyrrolidin-1-yl)ethyl)pyrimidin-1(2H)- 4-enamido)propanoate

[0207] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.53 g, 0.82 mmol), Intermediate 269 (0.17 g, 0.82 mmol) and K2CO3 (0.34 g, 2.45 mmol) in MeCN (8 mL) at reflux for 2 h. Purified by flash chromatography (25 g silica gel, eluting 2-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.28 g). LCMS (Method 15): 2.77 min, 757.4 [M+H]+. Intermediate 271: Ethyl 2-((3S,6S)-14,24-difluoro-16-methyl-6-(4-methyl-2-oxo-5-(2- (pyrrolidin-1-yl)ethyl)pyrimidin-1(2H)-yl)-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 71 using Intermediate 270 (0.32 g, 0.40 mmol) and Grubbs II (34 mg, 40 µmol) in DCE (0.20 L) at 50 °C for 5 h. Purified by flash chromatography (25 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.21 g). LCMS (Method 15): 2.63 min, 729.3 [M+H]+. Intermediate 272: Ethyl 2-((3S,6S)-14,24-difluoro-16-methyl-6-(4-methyl-2-oxo-5-(2- (pyrrolidin-1-yl)ethyl)pyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0209] Prepared in an analogous manner to Intermediate 262 using Intermediate 271 (0.21 g, 0.27 mmol) and 10% palladium on carbon (29 mg) in ethanol (14 mL) under a hydrogen atmosphere at RT for 7 h. Followed by manganese dioxide (0.51 g, 6.00 mmol) in DCM (14 mL) at RT for 6 h to provide the title compound (0.15 g). LCMS (Method 15): 2.69 min, 731.3 [M+H]+. Intermediate 273: N-Ethyl-2-(2-methoxy-4-methylpyrimidin-5-yl)-N-methylethan-1-amine

[0210] Prepared in an analogous manner to Intermediate 258 using (E)-5-(2-ethoxyvinyl)- 2-methoxy-4-methylpyrimidine (1.0 g, 5.15 mmol, CAS 2955527-94-1) in DCM (7.1 mL) and TFA (11.9 mL) at RT for 4 h. Then N-ethyl-N-methylamine (1.08 mL, 12.9 mmol), triethylamine (0.86 mL, 6.18 mmol) in DCM (28 mL) with 4 Å molecular sieves at RT for 10 min, followed by STAB (2.73 g, 12.9 mmol) at RT for 20 h. Purified by flash chromatography (25 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.70 g). LCMS (Method 15): 1.34 min, 209.9 [M+H]+.Intermediate 274: 5-(2-(Ethyl(methyl)amino)ethyl)-4-methylpyrimidin-2(1H)-one

[0211] A solution of Intermediate 273 (0.70 g, 3.17 mmol) 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. The crude product was purified by catch and release chromatography (20 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.62 g). LCMS (Method 27): 0.22 min, 196.1 [M+H]+. Intermediate 275: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(5-(2-(ethyl(methyl)amino)ethyl)-4-methyl-2-oxopyrimidin-1(2H)- 4-enamido)propanoate

[0212] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.46 g, 0.71 mmol), Intermediate 274 (0.17 g, 0.85 mmol) and K2CO3 (0.29 g, 2.11 mmol) in MeCN (7.4 mL) at reflux for 16 h. Purified by flash chromatography (25 g silica gel, eluting 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.24 g). LCMS (Method 15): 2.73 min, 745.3 [M+H]+. Intermediate 276: Ethyl 2-((3S,6S)-6-(5-(2-(ethyl(methyl)amino)ethyl)-4-methyl-2- oxopyrimidin-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

[0213] Prepared in an analogous manner to Intermediate 71 using Intermediate 275 (0.24 g, 0.33 mmol) and Grubbs II (28 mg, 32 µmol) in DCE (0.11 L) at 40 °C for 1.5 h. Purified by flash chromatography (25 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.19 g). LCMS (Method 15): 2.62 min, 717.3 [M+H]+. Intermediate 277: Ethyl 2-((3S,6S)-6-(5-(2-(ethyl(methyl)amino)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0214] Prepared in an analogous manner to Intermediate 262 using Intermediate 276 (0.19 g, 0.27 mmol) and 10% palladium on carbon (28 mg) in ethanol (4 mL) under a hydrogen atmosphere at RT for 2.5 h. Followed by manganese dioxide (0.23 g, 2.65 mmol) in DCM (4 mL) at RT for 18 h to provide the title compound (0.16 g). LCMS (Method 15): 2.62 min, 719.3 [M+H]+. Intermediate 278: 5-(2-(3-Methoxyazetidin-1-yl)ethyl)-4-methylpyrimidin-2(1H)-one

[0215] 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, eluting 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 279: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- -yl)pent-4-enamido)propanoate

[0216] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.15 g, 0.23 mmol), Intermediate 278 (57 mg, 0.26 mmol) and K2CO3 (96 mg, 0.70 mmol) in MeCN (2.9 mL) at reflux for 5 h. Purified by flash chromatography (25 g silica gel, eluting 0-20% MeOH in DCM) to provide the title compound (53 mg). LCMS (Method 15): 2.60 min, 773.4 [M+H]+. Intermediate 280: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4- methyl-2-oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0217] Prepared in an analogous manner to Intermediate 71 using Intermediate 279 (0.20 g, 0.26 mmol) and Grubbs II (22 mg, 26 µmol) in DCE (0.16 L) at 50 °C for 4.5 h. Purified by flash chromatography (25 g silica gel, eluting 0-20% MeOH in DCM) to provide the title compound (0.14 g). LCMS (Method 15): 2.47 min, 745.3 [M+H]+. Intermediate 281: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4- methyl-2-oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0218] Prepared in an analogous manner to Intermediate 262 using Intermediate 280 (0.14 g, 0.16 mmol) and 10% palladium on carbon (17 mg) in ethanol (16 mL) under a hydrogen atmosphere at RT for 8 h. Followed by manganese dioxide (0.14 g, 1.64 mmol) in DCM (5 mL) at RT for 18 h to provide the title compound (92 mg). LCMS (Method 15): 2.51 min, 747.3 [M+H]+. Intermediate 282: 5-(3-((tert-Butyldimethylsilyl)oxy)prop-1-yn-1-yl)-2-methoxy-4- methylpyrimidine

[0219] Prepared in an analogous manner to Intermediate 172 using 5-bromo-2-methoxy-4- methylpyrimidine (0.50 g, 2.07 mmol, CAS 38696-23-0), Pd(PPh3)2Cl2(75 mg, 0.11 mmol),copper(I) iodide (80 mg, 0.42 mmol), triethylamine (1.5 mL, 10.7 mmol) and tert- butyldimethyl(2-propynyloxy)silane (2.1 mL, 10.4 mmol) in DMF (10 mL) at 110 °C for 3 h. Purified by flash chromatography (40 g silica gel, eluting 0-20% EtOAc in petroleum ether) to provide the title compound (0.13 g). LCMS (Method 15): 2.52 min, 293.1 [M+H]+. Intermediate 283: 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-2-methoxy-4-methylpyrimidine

[0220] Prepared in an analogous manner to Intermediate 72 using Intermediate 282 (64 mg, 0.22 mmol) and 10% palladium on carbon (11.7 mg) in ethanol (2.6 mL) under a hydrogen atmosphere at RT for 1 h to provide the title compound (61 mg). LCMS (Method 15): 2.50 min,297.1 [M+H]+. Intermediate 284: 3-(2-Methoxy-4-methylpyrimidin-5-yl)propan-1-ol

[0221] To a solution of Intermediate 283 (61 mg, 0.19 mmol) in THF (1.7 mL) was added TBAF (1 M in THF, 0.57 mL, 0.57 mmol) at 0 °C then stirred at RT for 18 h. The mixture was diluted with water and extracted with EtOAc. The organics were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure, then purified by flash chromatography (12 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (20 mg). LCMS (Method 15): 1.02 min, 183.1 [M+H]+. Intermediate 285: 2-Methoxy-4-methyl-5-(3-(pyrrolidin-1-yl)propyl)pyrimidine

[0222] To a solution of Intermediate 284 (0.40 g, 2.15 mmol) in DCM (8 mL) was added carbon tetrabromide (1.07 g, 3.23 mmol) and triphenylphosphine (1.13 g, 4.30 mmol) then stirred at RT for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in MeCN (8 mL) then pyrrolidine (1.26 mL, 15.1 mmol) and K2CO3 (0.59 g, 4.23 mmol) were added and stirred at RT for 2 h. The mixture was concentrated under reduced pressure, then purified by flash chromatography (24 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.34 g). LCMS (Method 15): 1.52 min, 236.1 [M+H]+. Intermediate 286: 4-Methyl-5-(3-(pyrrolidin-1-yl)propyl)pyrimidin-2(1H)-one

[0223] A solution of Intermediate 285 (0.34 g, 1.45 mmol) in 33% HBr in AcOH (5.0 mL, 28.9 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 (20 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.26 g). LCMS (Method 15): 0.95 min, 222.1 [M+H]+. Intermediate 287: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(4-methyl-2-oxo-5-(3-(pyrrolidin-1-yl)propyl)pyrimidin-1(2H)- 4-enamido)propanoate

[0224] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.47 g, 0.68 mmol), Intermediate 286 (0.17 g, 0.75 mmol) and K2CO3(0.28 g, 2.05 mmol) in MeCN (8 mL) at reflux for 2 h. Purified by flash chromatography (12 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.27 g). LCMS (Method 15): 2.87 min, 771.5 [M+H]+. Intermediate 288: Ethyl 2-((3S,6S)-14,24-difluoro-16-methyl-6-(4-methyl-2-oxo-5-(3- (pyrrolidin-1-yl)propyl)pyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0225] Prepared in an analogous manner to Intermediate 71 using Intermediate 287 (0.27 g, 0.34 mmol) and Grubbs II (29 mg, 34 µmol) in DCE (0.19 L) at 50 °C for 3 h. Purified by flash chromatography (12 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.22 g). LCMS (Method 15): 2.90 min, 743.4 [M+H]+. Intermediate 289: Ethyl 2-((3S,6S)-14,24-difluoro-16-methyl-6-(4-methyl-2-oxo-5-(3- (pyrrolidin-1-yl)propyl)pyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0226] Prepared in an analogous manner to Intermediate 262 using Intermediate 288 (0.20 g, 0.27 mmol) and 10% palladium on carbon (28 mg) in ethanol (16 mL) under a hydrogen atmosphere at RT for 4 h. Followed by manganese dioxide (0.23 g, 2.67 mmol) in DCM (8 mL) at RT for 18 h to provide the title compound (0.17 g). LCMS (Method 15): 2.79 min, 745.4 [M+H]+. Intermediate 290: 2-(4-Ethyl-2-methoxypyrimidin-5-yl)-N,N-dimethylethan-1-amine

[0227] Prepared in an analogous manner to Intermediate 258 using (E)-5-(2-ethoxyvinyl)- 2-methoxy-4-ethylpyrimidine (1.28 g, 6.13 mmol, CAS 2955528-55-7) in DCM (9 mL) and TFA (14.1 mL) at RT for 2 h. Then dimethylamine (2 M in THF, 6.13 mL, 12.3 mmol), triethylamine (1.03 mL, 7.35 mmol) in DCM (36 mL) with 4 Å molecular sieves at RT for 10 min, followed by STAB (3.25 g, 15.3 mmol) at RT for 16 h. Purified by flash chromatography (25 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (1.08 g). LCMS (Method 15): 1.39 min, 210.1 [M+H]+. Intermediate 291: 5-(2-(Dimethylamino)ethyl)-4-ethylpyrimidin-2(1H)-one

[0228] A solution of Intermediate 290 (1.08 g, 4.95 mmol) in 33% HBr in AcOH (17.9 mL, 99.1 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 (20 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.93 g). LCMS (Method 15): 0.76 min, 196.1 [M+H]+.Intermediate 292: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-ethyl-2-oxopyrimidin-1(2H)- 4-enamido)propanoate

[0229] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.46 g, 0.71 mmol), Intermediate 291 (0.16 g, 0.75 mmol) and K2CO3 (0.29 g, 2.12 mmol) in MeCN (7 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, eluting 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.26 g). LCMS (Method 15): 2.72 min, 745.4 [M+H]+. Intermediate 293: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-ethyl-2-oxopyrimidin- 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

[0230] Prepared in an analogous manner to Intermediate 71 using Intermediate 292 (0.28 g, 0.37 mmol) and Grubbs II (32 mg, 37 µmol) in DCE (0.19 L) at 50 °C for 2 h. Purified by flash chromatography (25 g silica gel, eluting 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.24 g). LCMS (Method 27): 1.57 min, 717.4 [M+H]+. Intermediate 294: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-ethyl-2-oxopyrimidin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0231] Prepared in an analogous manner to Intermediate 262 using Intermediate 293 (0.24 g, 0.31 mmol) and 10% palladium on carbon (33 mg) in ethanol (18 mL) under a hydrogen atmosphere at RT for 6 h. Followed by manganese dioxide (0.39 g, 4.51 mmol) in DCM (15 mL) at RT for 18 h to provide the title compound (0.23 g). LCMS (Method 15): 2.64 min, 719.4 [M+H]+. Intermediate 295: (E)-5-(2-Ethoxyvinyl)-2,4-dimethoxypyrimidine

[0232] A mixture of 5-bromo-2,4-dimethoxypyrimidine (2.5 g, 11.4 mmol, CAS 56686-16-9), trans-2-ethoxyvinylboronic acid pinacol ester (2.49 g, 12.6 mmol, CAS 1201905-61-4), and Na2CO3 (2.42 g, 22.8 mmol) in 1,4-dioxane (44 mL) and water (6 mL) was degassed with nitrogen. To this was added Pd(dppf)Cl2(0.42 g, 0.57 mmol) and the mixture was stirred at 105 °C for 18 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 (40 g silica gel, eluting 0-20% EtOAc in petroleum ether) to provide the title compound (1.64 g). LCMS (Method 15): 1.73 min, 211.1 [M+H]+. Intermediate 296: 2-(2,4-Dimethoxypyrimidin-5-yl)-N,N-dimethylethan-1-amine

[0233] Prepared in an analogous manner to Intermediate 258 using Intermediate 295 (1.63 g, 7.74 mmol) in DCM (16 mL) and TFA (17.9 mL) at RT for 4 h. Then dimethylamine (2 M in THF, 7.74 mL, 15.5 mmol), triethylamine (2.16 mL, 15.5 mmol) in DCM (46 mL) with 4 Å molecular sieves at RT for 10 min, followed by STAB (3.28 g, 15.5 mmol) at RT for 16 h. Purified by flash chromatography (40 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.82 g). LCMS (Method 15): 1.41 min, 212.1 [M+H]+. Intermediate 297: 5-(2-(Dimethylamino)ethyl)-4-hydroxypyrimidin-2(1H)-one

[0234] A solution of Intermediate 296 (0.81 g, 3.83 mmol) in 33% HBr in AcOH (13.2 mL, 76.7 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 (20 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.59 g). LCMS (Method 15): 0.37 min, 184.0 [M+H]+. Intermediate 298: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl- biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-hydroxy-2-oxopyrimidin-1(2H)-yl) enamido)propanoate

[0235] Prepared in an analogous manner to Intermediate 70 using Intermediate 69 (0.40 g, 0.68 mmol), Intermediate 297 (0.15 g, 0.74 mmol) and K2CO3 (0.28 g, 2.03 mmol) in MeCN (8 mL) at reflux for 4 h. Purified by flash chromatography (25 g silica gel, 0-30% EtOAc in petroleum ether) to provide the title compound (0.20 g). LCMS (Method 15): 2.60 min, 679.4 [M+H]+. Intermediate 299: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-hydroxy-2-oxopyrimidin- 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

[0236] Prepared in an analogous manner to Intermediate 71 using Intermediate 298 (0.20 g, 0.28 mmol) and Grubbs II (24 mg, 28 µmol) in DCE (0.14 L) at 50 °C for 1 h. Purified by flash chromatography (12 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.14 g). LCMS (Method 15): 2.46 min, 651.4 [M+H]+. Intermediate 300: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-hydroxy-2-oxopyrimidin- 1(2H)-yl)-14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0237] Prepared in an analogous manner to Intermediate 72 using Intermediate 299 (0.14 g, 0.13 mmol) and 10% palladium on carbon (14 mg) in ethanol (10 mL) under a hydrogen atmosphere at RT for 1 h to provide the title compound (0.12 g). LCMS (Method 15): 2.50 min, 653.4 [M+H]+.Intermediate 301: 5-(3-(Azetidin-1-yl)propyl)-2-methoxy-4-methylpyrimidine

[0238] Prepared in an analogous manner to Intermediate 285 using Intermediate 284 (0.30 g, 1.61 mmol), carbon tetrabromide (0.80 g, 2.42 mmol) and triphenylphosphine (1.85 g, 3.23 mmol) in DCM (6 mL) at RT for 1 h, then azetidine (0.76 mL, 11.3 mmol) and K2CO3(0.44 g, 3.18 mmol) in MeCN (6 mL) at RT for 2 h. Purified by flash chromatography (24 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.21 g). LCMS (Method 15): 1.39 min, 222.1 [M+H]+. Intermediate 302: 5-(3-(Azetidin-1-yl)propyl)-4-methylpyrimidin-2(1H)-one

[0239] A solution of Intermediate 301 (0.21 g, 0.94 mmol) in 33% HBr in AcOH (3.25 mL, 18.8 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, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.17 g). LCMS (Method 15): 0.83 min, 208.1 [M+H]+. Intermediate 303: Methyl (S)-3-((S)-2-(5-(3-(azetidin-1-yl)propyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)pent-4-enamido)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)-biphenyl]-3-yl)propanoate

[0240] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.50 g, 0.70 mmol), Intermediate 302 (0.16 g, 0.77 mmol) and K2CO3 (0.29 g, 2.09 mmol) in MeCN (9 mL) at reflux for 4 h. Purified by flash chromatography (25 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.18 g). LCMS (Method 15): 2.75 min, 743.4 [M+H]+. Intermediate 304: Methyl 2-((3S,6S)-6-(5-(3-(azetidin-1-yl)propyl)-4-methyl-2-oxopyrimidin- 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

[0241] Prepared in an analogous manner to Intermediate 71 using Intermediate 303 (0.18 g, 0.25 mmol) and Grubbs II (21 mg, 25 µmol) in DCE (0.13 L) at 50 °C for 2 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.15 g). LCMS (Method 15): 2.59 min, 715.3 [M+H]+. Intermediate 305: Methyl 2-((3S,6S)-6-(5-(3-(azetidin-1-yl)propyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0242] Prepared in an analogous manner to Intermediate 262 using Intermediate 304 (0.13 g, 0.18 mmol) and 10% palladium on carbon (19 mg) in ethanol (10 mL) under a hydrogen atmosphere at RT for 10 h. Purified by catch and release chromatography (5 g SCX, elutingMeOH followed by 1 M ammonia in MeOH). Followed by manganese dioxide (0.15 g, 1.78 mmol) in DCM (5 mL) at RT for 18 h to provide the title compound (0.11 g). LCMS (Method 15): 2.65 min, 717.3 [M+H]+. Intermediate 306: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)pent-4- enamido)propanoate

[0243] Prepared in an analogous manner to Intermediate 70 using Intermediate 69 (0.59 g, 0.99 mmol), Intermediate 278 (0.27 g, 1.09 mmol) and K2CO3 (0.41 g, 2.97 mmol) in MeCN (10 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, eluting 0-20% MeOH in DCM) to provide the title compound (0.23 g). LCMS (Method 15): 2.55 min, 719.4 [M+H]+. Intermediate 307: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4- methyl-2-oxopyrimidin-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 71 using Intermediate 306 (0.23 g, 0.31 mmol) and Grubbs II (26 mg, 31 µmol) in DCE (0.19 L) at 50 °C for 3.5 h. Purified by flash chromatography (25 g silica gel, eluting 0-20% MeOH in DCM) to provide the title compound (0.18 g). LCMS (Method 21): 2.43 min, 691.5 [M+H]+. Intermediate 308: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4- methyl-2-oxopyrimidin-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 262 using Intermediate 307 (0.18 g, 0.18 mmol) and 10% palladium on carbon (19 mg) in ethanol (15 mL) under a hydrogen atmosphere at RT for 11 h. Followed by manganese dioxide (0.15 g, 1.77 mmol) in DCM (6 mL) at RT for 16 h to provide the title compound (0.17 g). LCMS (Method 15): 2.46 min, 693.4 [M+H]+. Intermediate 314: 1-(Benzyloxy)-2-bromo-3,5-dimethylbenzene

[0246] Prepared in an analogous manner to Intermediate 70 using 2-bromo-3,5- dimethylphenol (9.63 g, 47.9 mmol), benzyl bromide (9.01 g, 52.7 mmol) and K2CO3(8.61 g, 62.3 mmol) in MeCN (0.20 L) at 65 °C for 16 h to provide the title compound (14.3 g).1H NMR (400 MHz; CDCl3) δ: 7.50 (d, 2H), 7.40 (t, 2H), 7.30 (t, 1H), 6.71 (s, 1H), 6.62 (s, 1H), 5.13 (s, 2H), 2.39 (s, 3H), 2.27 (s, 3H). Intermediate 315: (2-(Benzyloxy)-4,6-dimethylphenyl)boronic acid

[0247] A mixture of magnesium (0.13 g, 5.15 mmol), iodomethane (8 µL, 0.12 mmol) and Intermediate 314 (1.0 g, 3.43 mmol) in THF (6.9 mL) were heated at 60 °C under nitrogen for 20 min. Trimethyl borate (0.77 mL, 6.87 mmol) in THF (6.9 mL) was added dropwise at -5 to 0 °C over 2 h. Run in two batches then combined crude was acidified to pH 4 using 2 M aqueous HCl. The mixture was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated in n-pentane to provide the title compound (1.49 g).1H NMR (400 MHz; CDCl3) δ: 7.42 – 7.36 (m, 5H), 6.72 (s, 1H), 6.67 (s, 1H), 5.78 (br s, 2H), 5.10 (s, 2H), 2.53 (s, 3H), 2.23 (s, 3H). Intermediate 316: Ethyl (S)-3-(2'-(benzyloxy)-4-fluoro-4',6'-dimethyl-5-(trifluoromethyl)-biphenyl]-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate

[0248] Prepared in an analogous manner to Intermediate 34 using Intermediate 315 (0.41 g, 1.08 mmol), Intermediate 20 (0.42 g, 1.62 mmol), K3PO4 (0.69 g, 3.24 mmol) and XPhosPdG2 (85 mg, 0.11 mmol) in 1,4-dioxane (37 mL) and water (6 mL) at 110 °C for 1.5 h. Purified by flash chromatography (25 g silica gel, eluting 10-100% EtOAc in petroleum ether) to provide the title compound (1.39 g).1H NMR (400 MHz; CDCl3) δ: 7.49 (s, 2H), 7.32 – 7.20 (m, 3H), 7.20 – 7.14 (m, 2H), 6.75 (d, 2H), 5.86 (d, 1H), 5.46 (s, 1H), 4.98 (s, 2H), 4.07 – 3.87 (m, 2H), 2.96 – 2.71 (m, 2H), 2.36 (s, 3H), 2.08 (s, 3H), 1.30 (s, 9H), 1.12 (t, 3H). Intermediate 317: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2'-hydroxy-4',6'- dimethyl-5-(trifluoromethyl)- biphenyl]-3-yl)propanoate

[0249] Prepared in an analogous manner to Intermediate 72 using Intermediate 316 (1.02 g, 1.73 mmol), ammonium formate (2.18 g, 34.6 mmol), 10% palladium on carbon (0.18 g, 0.17 mmol) in ethanol (17 mL) at 80 °C for 24 h. Additional ammonium formate (2.18 g, 34.6 mmol) and 10% palladium on carbon (0.18 g, 0.17 mmol) were added and heating continued for 5 h to provide the title compound (0.85 g). LCMS (Method 7): 2.20 min, 400.9 [M-Boc+H]+. Intermediate 318: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2',4'-dimethyl-5- (trifluoromethyl)-6'-(((trifluoromethyl)sulfonyl)oxy)- biphenyl]-3-yl)propanoate

[0250] Prepared in an analogous manner to Intermediate 35 using Intermediate 317 (0.36 g, 0.72 mmol) phenyl triflimide (0.26 g, 0.72 mmol, CAS 37595-74-7) and Cs2CO3(0.28 g, 0.86 mmol) in DCM (4 mL) at RT for 2 h. Purified by flash chromatography (40 g silica gel, eluting 0–50% EtOAc in petroleum ether) to provide the title compound (0.54 g). LCMS (Method 22): 2.03 min, 630.2 [M-H]-. Intermediate 319: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2'-(hex-5-en-1-yl)- 4',6'-dimethyl-5-(trifluoromethyl)- biphenyl]-3-yl)propanoate

[0251] Prepared in an analogous manner to Intermediate 34 using Intermediate 318 (1.37 g, 1.95 mmol), 5-hexenylboronic acid (0.37 g, 2.92 mmol, CAS 1072952-16-9), K2CO3(0.81 g, 5.84 mmol), palladium acetate (44 mg, 0.20 mmol) and RuPhos (0.15 g, 0.29 mmol) in toluene (44 mL) and water (9 mL) at reflux for 3.5 h. Purified by flash chromatography (40 g silica gel, eluting 0-100% EtOAc in petroleum ether) to provide the title compound (1.04 g). LCMS (Method 15): 2.95 min, 466.2 [M-Boc+H]+. Intermediate 320: Ethyl (S)-3-amino-3-(4-fluoro-2'-(hex-5-en-1-yl)-4',6'-dimethyl-5- (trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0252] A suspension of Intermediate 319 (2.16 g, 3.62 mmol) in 4 M HCl in 1,4-dioxane (9 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (1.80 g). LCMS (Method 22): 2.18 min, 466.1 [M+H]+. Intermediate 321: Ethyl (S)-3-(4-fluoro-2'-(hex-5-en-1-yl)-4',6'-dimethyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate

[0253] Prepared in an analogous manner to Intermediate 40 using Intermediate 320 (1.80 g, 3.59 mmol), (2R)-2-hydroxypent-4-enoic acid (0.62 g, 5.38 mmol, CAS 413622-10-3), DIPEA (1.87 mL, 10.8 mmol), HOBt (0.48 g, 3.59 mmol) and EDCI (0.82 g, 4.30 mmol) in MeCN (25 mL) at RT for 16 h. Purified by flash chromatography (40 g silica gel, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (1.59 g). LCMS (Method 15): 2.76 min, 564.2 [M+H]+. Intermediate 322: Ethyl (S)-3-(4-fluoro-2'-(hex-5-en-1-yl)-4',6'-dimethyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0254] Prepared in an analogous manner to Intermediate 41 using Intermediate 321 (0.75 g, 1.22 mmol), triethylamine (0.34 mL, 2.45 mmol) and methanesulfonyl chloride (0.14 mL, 1.84 mmol) in DCM (9 mL) at 0 °C for 10 min, then RT for 1.5 h to provide the title compound (0.84 g). LCMS (Method 15): 2.81 min, 640.2 [M-H]-. Intermediate 323: 2-Methoxy-5-(2-(3-methoxyazetidin-1-yl)ethyl)pyrimidine

[0255] Prepared in an analogous manner to Intermediate 258 using 5-[(E)-2-ethoxyvinyl]- 2-methoxypyrimidine (0.75 g, 4.16 mmol, CAS 2955528-07-9) in DCM (30 mL) and TFA (32 mL) at RT for 4 h. Then 3-methoxyazetidine hydrochloride (1.05 g, 8.50 mmol), triethylamine (3.0 mL, 5.17 mmol) in DCM (30 mL) with 4 Å molecular sieves at RT for 10 min, followed by STAB (1.80 g, 8.49 mmol) at RT for 17 h. Purified by catch and release chromatography (20 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.53 g). LCMS (Method 11): 1.11 min, 224.1 [M+H]+. Intermediate 324: 5-(2-(3-Methoxyazetidin-1-yl)ethyl)pyrimidin-2(1H)-one

[0256] A solution of Intermediate 323 (0.53 g, 2.24 mmol) in DCM (10 mL) and chloroform (10 mL) was treated with iodotrimethylsilane (1.6 mL, 11.2 mmol) and the mixture was stirred at RT for 7 days. The mixture was concentrated under reduced pressure. The crude product was purified by catch and release chromatography (20 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.49 g). LCMS (Method 22): 0.23 min, 210.1 [M+H]+. Intermediate 325: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyrimidin-1(2H)- 4-enamido)propanoate

[0257] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.46 g, 0.71 mmol), Intermediate 324 (0.31 g, 1.16 mmol) and K2CO3 (0.30 g, 2.17 mmol) in MeCN (10 mL) at reflux for 20 h. Purified by flash chromatography (40 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.35 g). LCMS (Method 27): 1.92 min, 759.4 [M+H]+. Intermediate 326: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2- oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0258] Prepared in an analogous manner to Intermediate 71 using Intermediate 325 (0.35 g, 0.46 mmol) and Grubbs II (39 mg, 46 µmol) in DCE (0.15 L) at 40 °C for 3 h. Purified by flash chromatography (25 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.14 g). LCMS (Method 27): 2.48 min, 731.4 [M+H]+. Intermediate 327: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2- oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0259] Prepared in an analogous manner to Intermediate 262 using Intermediate 326 (0.14 g, 0.19 mmol) and 10% palladium on carbon (20 mg) in ethanol (4 mL) under a hydrogen atmosphere at RT for 4 h. Followed by manganese dioxide (0.16 g, 1.86 mmol) in DCM (9 mL) at RT for 16 h to provide the title compound (0.14 g). LCMS (Method 15): 2.51 min, 731.3 [M+H]+. Intermediate 328: Ethyl (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)pent-4-enamido)-3-(4-fluoro-2'-(hex-5-en-1-yl)-4',6'-dimethyl-5-(trifluoromethyl)-biphenyl]-3-yl)propanoate

[0260] Prepared in an analogous manner to Intermediate 70 using Intermediate 322 (0.47 g, 0.71 mmol), 5-[2-(dimethylamino)ethyl]-4-methyl-1H-pyrimidin-2-one (0.13 g, 0.71 mmol,CAS 2955527-96-3) and K2CO3(0.29 g, 2.11 mmol) in MeCN (10 mL) and DMF (1 mL) at 85 °C for 18 h. Purified by flash chromatography (40 g silica gel, 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.15 g). LCMS (Method 27): 2.31 min, 727.4 [M+H]+. Intermediate 329: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)-24-fluoro-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0261] Prepared in an analogous manner to Intermediate 71 using Intermediate 328 (0.15 g, 0.21 mmol) and Grubbs II (18 mg, 21 µmol) in DCE (0.11 L) at 50 °C for 2 h. Purified by flash chromatography (12 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.12 g). LCMS (Method 27): 2.15 min, 699.6 [M+H]+. Intermediate 330: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)-24-fluoro-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0262] Prepared in an analogous manner to Intermediate 262 using Intermediate 329 (0.12 g, 0.17 mmol) and 10% palladium on carbon (18 mg) in ethanol (10 mL) under a hydrogen atmosphere at RT for 17 h. Followed by manganese dioxide (0.15 g, 1.71 mmol) in DCM (5 mL) at RT for 3 h to provide the title compound (59 mg). LCMS (Method 27): 2.00 min, 701.3 [M+H]+. Intermediate 331: 5-Bromo-2-iodo-3-methylphenol

[0263] To a solution of 2-amino-5-bromo-3-methylphenol (3.06 g, 12.4 mmol, CAS 1194760- 84-3) in THF (80 mL) and MeCN (80 mL) at -40 °C was added BF3.OEt2 (4.44 mL, 37.3 mmol) and stirred at -40 °C for 10 min. To this was added t-butyl nitrite (2.46 mL, 18.6 mmol) and the mixture was stirred at -40 °C for 1 h. Petroleum ether was added to form a precipitate, then the supernatant was decanted off and the residue taken up in MeCN (80 mL). To this solution was added potassium iodide (3.05 g, 0.12 mol) and iodine (11.7 g, 46.0 mmol) and was stirred at 55 °C for 18 h. The reaction was quenched with saturated aqueous sodium thiosulfate and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, 0–25% EtOAc in petroleum ether) to provide the title compound (3.30 g).1H NMR (400 MHz; CDCl3) δ: 7.00 – 6.98 (m, 2H), 5.48 (s, 1H), 2.42 (s, 3H). Intermediate 332: Ethyl (S)-3-(4'-bromo-4-fluoro-2'-hydroxy-5,6'-dimethyl- biphenyl]-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate

[0264] Prepared in an analogous manner to Intermediate 34 using Intermediate 130 (1.50 g, 3.23 mmol), Intermediate 331 (1.14 g, 3.66 mmol), Na2CO3(1.06 g, 9.97 mmol) and Pd(dppf)Cl2(0.27 g, 0.33 mmol) in 1,4-dioxane (30 mL) and water (3 mL) at 85 °C for 18 h. Purified by flash chromatography (40 g silica gel, eluting 0-20% EtOAc in petroleum ether) to provide the title compound (0.76 g). LCMS (Method 11): 2.29 min, 510.5 [M-H]-. Intermediate 333: Ethyl (S)-3-((tert-Butoxycarbonyl)amino)-3-(4'-cyclopropyl-4-fluoro-2'- hydroxy-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0265] Prepared in an analogous manner to Intermediate 34 using Intermediate 332 (1.06 g, 1.96 mmol), cyclopropaneboronic acid (0.67 g, 7.84 mmol), K3PO4 (1.25 g, 5.88 mmol), palladium acetate (44 mg, 0.20 mmol) and tricyclohexyl phosphine (55 mg, 0.20 mmol) in toluene (20 mL) and water (4 mL) at 120 °C for 18 h. Additional cyclopropaneboronic acid (0.34 g, 3.92 mmol), palladium acetate (22 mg, 0.10 mmol) and tricyclohexyl phosphine (27 mg, 0.10 mmol) were added and stirred at 120 °C for 18 h. Purified by flash chromatography (40 g silica gel, eluting 0-25% EtOAc in petroleum ether) to provide the title compound (0.79 g). LCMS (Method 15): 2.31 min, 494.1 [M+Na]+. Intermediate 334: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-cyclopropyl-4-fluoro-2',5- dimethyl-6'-(((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-yl)propanoate

[0266] Prepared in an analogous manner to Intermediate 35 using Intermediate 333 (1.30 g, 2.76 mmol), phenyl triflimide (0.99 g, 3.31 mmol, CAS 37595-74-7) and Cs2CO3 (1.08 g, 3.31 mmol) in DCM (21 mL) at RT for 16 h. Purified by flash chromatography (12 g silica gel, eluting 0–20% EtOAc in petroleum ether) to provide the title compound (1.47 g). LCMS (Method 15): 2.77 min, 504.2 [M-Boc+H]+. Intermediate 335: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-cyclopropyl-4-fluoro-2'-(hex- 5-en-1-yl)-5,6'-dimethyl- biphenyl]-3-yl)propanoate

[0267] Prepared in an analogous manner to Intermediate 34 using Intermediate 334 (1.47 g, 2.43 mmol), 5-hexenylboronic acid (0.47 g, 3.64 mmol, CAS 1072952-16-9), K2CO3 (1.01 g, 7.29 mmol), palladium acetate (54 mg, 0.24 mmol) and RuPhos (0.17 g, 0.36 mmol) in toluene (47 mL) and water (10 mL) at 100 °C for 18 h. Purified by flash chromatography (40 g silica gel, eluting 0-40% EtOAc in petroleum ether) to provide the title compound (1.0 g). LCMS (Method 22): 2.30 min, 438.1 [M-Boc+H]+. Intermediate 336: Ethyl (S)-3-amino-3-(4'-cyclopropyl-4-fluoro-2'-(hex-5-en-1-yl)-5,6'- dimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0268] A suspension of Intermediate 335 (1.03 g, 1.82 mmol) in 4 M HCl in 1,4-dioxane (9.1 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to provide the title compound (1.02 g). LCMS (Method 15): 2.82 min, 438.2 [M+H]+. Intermediate 337: Ethyl (S)-3-(4'-cyclopropyl-4-fluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'- biphenyl]-3-yl)-3-((R)-2-hydroxypent-4-enamido)propanoate

[0269] Prepared in an analogous manner to Intermediate 40 using Intermediate 336 (1.02 g, 1.67 mmol), (2R)-2-hydroxypent-4-enoic acid (0.29 g, 2.51 mmol, CAS 413622-10-3), DIPEA (1.17 mL, 6.69 mmol), HOBt (0.25 g, 1.84 mmol) and EDCI (0.48 g, 2.51 mmol) in MeCN (22 mL) at RT for 18 h. Purified by flash chromatography (40 g silica gel, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (0.73 g). LCMS (Method 22): 2.16 min, 536.2 [M+H]+. Intermediate 338: Ethyl (S)-3-(4'-cyclopropyl-4-fluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-biphenyl]-3-yl)-3-((R)-2-((methylsulfonyl)oxy)pent-4-enamido)propanoate

[0270] Prepared in an analogous manner to Intermediate 41 using Intermediate 337 (0.73 g, 1.36 mmol), triethylamine (0.38 mL, 2.71 mmol) and methanesulfonyl chloride (63 µL, 0.81 mmol) in DCM (26 mL) at 0 °C for 10 min, then RT for 2 h to provide the title compound (0.80 g). LCMS (Method 22): 2.17 min, 614.3 [M+H]+. Intermediate 339: Ethyl (S)-3-(4'-cyclopropyl-4-fluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl) enamido)propanoate

[0271] Prepared in an analogous manner to Intermediate 70 using Intermediate 338 (0.50 g, 0.69 mmol), 5-[2-(dimethylamino)ethyl]-4-methyl-1H-pyrimidin-2-one (0.14 g, 0.76 mmol, CAS 2955527-96-3) and K2CO3 (0.28 g, 2.06 mmol) in MeCN (8 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 0-10% MeOH in DCM) to provide the title compound (97 mg). LCMS (Method 27): 2.21 min, 699.4 [M+H]+. Intermediate 340: Ethyl 2-((3S,6S)-14-cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-24-fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0272] Prepared in an analogous manner to Intermediate 71 using Intermediate 339 (97 mg, 0.14 mmol) and Grubbs II (12 mg, 14 µmol) in DCE (70 mL) at 50 °C for 1 h. Purified by flash chromatography (4 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (97 mg). LCMS (Method 11): 2.62 min, 669.7 [M-H]-.Intermediate 341: Ethyl 2-((3S,6S)-14-cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-24-fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0273] Prepared in an analogous manner to Intermediate 262 using Intermediate 340 (97 mg, 0.13 mmol) and 10% palladium on carbon (14 mg) in ethanol (9 mL) under a hydrogen atmosphere at RT for 8 h. Followed by manganese dioxide (0.11 g, 1.29 mmol) in DCM (9 mL) at RT for 6 h to provide the title compound (78 mg). LCMS (Method 11): 2.61 min, 673.5 [M+H]+. Intermediate 342: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl- biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoro-3-methylazetidin-1-yl)ethyl)-4-methyl-2- (2H)- yl)pent-4-enamido)propanoate

[0274] Prepared in an analogous manner to Intermediate 70 using Intermediate 69 (0.47 g, 0.73 mmol), 5-(2-(3-fluoro-3-methylazetidin-1-yl)ethyl)-4-methylpyrimidin-2(1H)-one (0.21 g, 0.88 mmol, CAS 2955528-21-7) and K2CO3 (0.31 g, 2.21 mmol) in MeCN (20 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.35 g). LCMS (Method 15): 2.66 min, 721.5 [M+H]+. Intermediate 343: Ethyl 2-( -14,24-difluoro-6-(5-(2-(3-fluoro-3-methylazetidin-1-yl)ethyl)-4-methyl-2- -yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0275] Prepared in an analogous manner to Intermediate 71 using Intermediate 342 (0.35 g, 0.48 mmol) and Grubbs II (41 mg, 48 µmol) in DCE (0.30 L) at 50 °C for 1 h. Purified by flash chromatography (25 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.25 g). LCMS (Method 11): 2.55 min, 693.4 [M+H]+. Intermediate 344: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-fluoro-3-methylazetidin-1- yl)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)-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 262 using Intermediate 343 (0.25 g, 0.36 mmol) and 10% palladium on carbon (38 mg) in ethanol (25 mL) under a hydrogen atmosphere at RT for 6 h. Followed by manganese dioxide (0.31 g, 3.61 mmol) in DCM (25 mL) at RT for 24 h to provide the title compound (0.23 g). LCMS (Method 27): 1.75 min, 695.4 [M+H]+. Intermediate 345: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxopyrimidin-1(2H)-yl)pent-4-enamido)propanoate

[0277] Prepared in an analogous manner to Intermediate 70 using Intermediate 69 (0.55 g, 0.83 mmol), Intermediate 259 (0.28 g, 1.25 mmol) and K2CO3(0.35 g, 2.50 mmol) in MeCN (10 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.25 g). LCMS (Method 27): 1.91 min, 663.4 [M+H]+. Intermediate 346: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyrimidin-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

[0278] Prepared in an analogous manner to Intermediate 71 using Intermediate 345 (0.25 g, 0.30 mmol) and Grubbs II (26 mg, 31 µmol) in DCE (0.15 L) at 50 °C for 1.5 h. Purified by flash chromatography (25 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.15 g). LCMS (Method 27): 1.51 min, 635.4 [M+H]+. Intermediate 347: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyrimidin-1(2H)-yl)- 14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetate

[0279] Prepared in an analogous manner to Intermediate 262 using Intermediate 346 (0.15 g, 0.18 mmol) and 10% palladium on carbon (20 mg) in ethanol (10 mL) under a hydrogen atmosphere at RT for 5 h. Followed by manganese dioxide (0.16 g, 1.84 mmol) in DCM (10 mL) at RT for 18 h to provide the title compound (92 mg). LCMS (Method 15): 2.53 min, 637.4 [M+H]+. Intermediate 348: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- -yl)pent-4-enamido)propanoate

[0280] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.25 g, 0.38 mmol), 5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methylpyrimidin-2(1H)-one (80 mg, 0.38 mmol, CAS 2955529-21-0) and K2CO3 (0.16 g, 1.14 mmol) in MeCN (5 mL) at reflux for 4 h. Purified by flash chromatography (40 g silica gel, 2-12% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.15 g). LCMS (Method 15): 2.63 min, 761.4 [M+H]+. Intermediate 349: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4- methyl-2-oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0281] Prepared in an analogous manner to Intermediate 71 using Intermediate 348 (0.17 g, 0.22 mmol) and Grubbs II (19 mg, 22 µmol) in DCE (0.10 L) at 45 °C for 1.5 h. Purified by flash chromatography (25 g silica gel, eluting 0-10% (0.1% ammonia MeOH) in DCM) to provide the title compound (0.14 g). LCMS (Method 11): 2.36 min, 733.5 [M+H]+.Intermediate 350: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4- methyl-2-oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0282] Prepared in an analogous manner to Intermediate 262 using Intermediate 349 (0.14 g, 0.19 mmol) and 10% palladium on carbon (21 mg) in ethanol (17 mL) under a hydrogen atmosphere at RT for 2 h. Followed by manganese dioxide (0.15 g, 1.71 mmol) in DCM (11 mL) at RT for 16 h to provide the title compound (0.10 g). LCMS (Method 15): 2.53 min, 735.4 [M+H]+. Intermediate 351: 5-(2-Ethoxyethyl)-2-methoxy-4-methylpyrimidine

[0283] Prepared in an analogous manner to Intermediate 72 using (E)-5-(2-ethoxyvinyl)-2- methoxy-4-methylpyrimidine (0.26 g, 1.35 mmol, CAS 2955527-94-1) and 10% palladium on carbon (22 mg) in EtOAc (10 mL) under a hydrogen atmosphere at RT for 3 h, to provide the title compound (0.26 g). LCMS (Method 15): 1.38 min, 197.1 [M+H]+. Intermediate 352: 5-(2-Bromoethyl)-4-methylpyrimidin-2(1H)-one

[0284] A solution of Intermediate 351 (0.26 g, 1.32 mmol) in 33% HBr in AcOH (13.7 mL, 79.2 mmol) was stirred at 85 °C for 30 h. The mixture was cooled and concentrated under reduced pressure. The crude product was purified by catch and release chromatography (5 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.26 g). LCMS (Method 30): 1.62 min, 216.9 [M+H]+. Intermediate 353: 2-(4-Methyl-2-oxo-1,2-dihydropyrimidin-5-yl)ethyl acetate

[0285] To a solution of Intermediate 352 (0.56 g, 0.92 mmol) in AcOH (22 mL) was added sodium acetate (0.39 g, 4.77 mmol) and the mixture stirred at 125 °C for 48 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel, 5-10% MeOH in DCM) to provide the title compound (0.19 g). LCMS (Method 30): 0.22 min, 197.1 [M+H]+. Intermediate 354: Ethyl (S)-3-((S)-2-(5-(2-acetoxyethyl)-4-methyl-2-oxopyrimidin-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

[0286] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.46 g, 0.71 mmol), Intermediate 353 (0.14 g, 0.71 mmol) and K2CO3(0.29 g, 2.11 mmol) in MeCN (9 mL) at reflux for 16 h. Purified by flash chromatography (24 g silica gel, 50-100% EtOAc in petroleum ether) to provide the title compound (0.21 g). LCMS (Method 15): 2.65 min, 746.3 [M+H]+.Intermediate 355: Ethyl 2-((3S,6S)-6-(5-(2-acetoxyethyl)-4-methyl-2-oxopyrimidin-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

[0287] Prepared in an analogous manner to Intermediate 71 using Intermediate 354 (0.21 g, 0.28 mmol) and Grubbs II (24 mg, 28 µmol) in DCE (0.14 L) at 45 °C for 1.5 h. Purified by flash chromatography (25 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (0.17 g). LCMS (Method 15): 2.54 min, 718.3 [M+H]+. Intermediate 356: Ethyl 2-((3S,6S)-6-(5-(2-acetoxyethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)- 14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0288] Prepared in an analogous manner to Intermediate 262 using Intermediate 355 (0.17 g, 0.24 mmol) and 10% palladium on carbon (26 mg) in ethanol (21 mL) under a hydrogen atmosphere at RT for 2 h. Followed by manganese dioxide (0.21 g, 2.40 mmol) in DCM (15 mL) at RT for 16 h. Purified by flash chromatography (12 g silica gel, 50-100% EtOAc in petroleum ether) to provide the title compound (0.13 g). LCMS (Method 15): 2.57 min, 720.4 [M+H]+. Intermediate 357: 2-((3S,6S)-14,24-Difluoro-6-(5-(2-hydroxyethyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0289] Intermediate 356 (35 mg, 49 µmol) was dissolved in THF (0.7 mL), MeOH (0.4 mL) and water (0.4 mL) then lithium hydroxide (3.5 mg, 0.15 mmol) was added and stirred at RT for 1 h. The mixture was adjusted to pH 4 with 2 M aqueous HCl and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound (29 mg). LCMS (Method 15): 1.54 min, 650.3 [M+H]+. Intermediate 358: Methyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-hydroxyethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0290] Intermediate 357 (35 mg, 49 µmol) was dissolved in MeOH (2.2 mL) and 4 M aqueous HCl (45 µL) and stirred at RT for 16 h. The mixture was concentrated under reduced pressure. The residue was taken up in DCM and saturated aqueous NaHCO3and the organic layer separated and concentrated under reduced pressure to provide the title compound (34 mg). LCMS (Method 15): 2.33 min, 664.3 [M+H]+.Intermediate 359: Methyl 2-((3S,6S)-6-(5-(2-(azetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0291] Prepared in an analogous manner to Intermediate 285 using Intermediate 358 (29 mg, 51 µmol), carbon tetrabromide (34 mg, 0.10 mmol) and triphenylphosphine (29 mg, 0.10 mmol) in DCM (1.2 mL) at RT for 1.5 h, then azetidine (35 µL, 0.51 mmol) and K2CO3(14 mg, 0.10 mmol) in MeCN (1.2 mL) at RT for 2 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (19 mg). LCMS (Method 15): 2.51 min, 703.4 [M+H]+. Intermediate 360: 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-fluoro-3-methylazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)pent-4-enamido)propanoate

[0292] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.51 g, 0.70 mmol), 5-(2-(3-fluoro-3-methylazetidin-1-yl)ethyl)-4-methylpyrimidin-2(1H)-one (0.19 g, 0.85 mmol, CAS 2955528-21-7) and K2CO3 (0.29 g, 2.13 mmol) in MeCN (22 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, 0-6% MeOH in DCM) to provide the title compound (0.31 g). LCMS (Method 11): 2.54 min, 776.5 [M+H]+. Intermediate 361: Ethyl 2-( -14,24-difluoro-6-(5-(2-(3-fluoro-3-methylazetidin-1-yl)ethyl)-4-methyl-2- -yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0293] Prepared in an analogous manner to Intermediate 71 using Intermediate 360 (0.31 g, 0.40 mmol) and Grubbs II (34 mg, 40 µmol) in DCE (0.27 L) at 50 °C for 1 h. Purified by flash chromatography (25 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.28 g). LCMS (Method 15): 2.57 min, 748.4 [M+H]+. Intermediate 362: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-fluoro-3-methylazetidin-1- yl)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0294] Prepared in an analogous manner to Intermediate 262 using Intermediate 361 (0.28 g, 0.37 mmol) and 10% palladium on carbon (39 mg) in ethanol (28 mL) under a hydrogen atmosphere at RT for 6 h. Followed by manganese dioxide (0.32 g, 3.68 mmol) in DCM (28 mL) at RT for 24 h to provide the title compound (0.24 g). LCMS (Method 11): 2.49 min, 750.5 [M+H]+. Intermediate 363: 5-(2-(3,3-Difluoroazetidin-1-yl)ethyl)-2-methoxy-4-methylpyrimidine

[0295] Prepared in an analogous manner to Intermediate 258 using (E)-5-(2-ethoxyvinyl)- 2-methoxy-4-methylpyrimidine (1.4 g, 5.15 mmol, CAS 2955527-94-1) in DCM (8.5 mL) and TFA (17 mL) at RT for 4.5 h. Then 3,3-difluoroazetidine hydrochloride (1.4 g, 10.8 mmol, CAS 288315-03-7), triethylamine (2.21 mL, 15.9 mmol) in DCM (34 mL) with 4 Å molecular sieves at RT for 10 min, followed by STAB (3.82 g, 18.0 mmol) at RT for 16 h. Purified by catch and release chromatography (20 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.76 g). LCMS (Method 15): 1.35 min, 244.1 [M+H]+. Intermediate 364: 5-(2-(3,3-Difluoroazetidin-1-yl)ethyl)-4-methylpyrimidin-2(1H)-one

[0296] A solution of Intermediate 363 (0.76 g, 3.10 mmol) in 33% HBr in AcOH (11.2 mL, 62.1 mmol) was stirred at 65 °C for 1.5 h. The mixture was cooled and concentrated under reduced pressure. The crude product was purified by catch and release chromatography (10 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) and then by reverse phase chromatography (55 g C18, 0-5% MeCN in 0.1% aqueous ammonia) to provide the title compound (0.24 g). LCMS (Method 30): 0.57 min, 230.1 [M+H]+. Intermediate 365: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- -yl)pent-4-enamido)propanoate

[0297] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.49 g, 0.75 mmol), Intermediate 364 (0.17 g, 0.75 mmol) and K2CO3 (0.31 g, 2.26 mmol) in MeCN (7.5 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 0-100% EtOAc in petroleum ether then 0-5% MeOH in DCM) to provide the title compound (0.29 g). LCMS (Method 15): 2.69 min, 779.4 [M+H]+. Intermediate 366: Ethyl 2-((3S,6S)-6-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-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

[0298] Prepared in an analogous manner to Intermediate 71 using Intermediate 365 (0.28 g, 0.36 mmol) and Grubbs II (31 mg, 36 µmol) in DCE (0.19 L) at 50 °C for 1 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.29 g). LCMS (Method 27): 1.79 min, 751.3 [M+H]+. Intermediate 367: Ethyl 2-((3S,6S)-6-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0299] Prepared in an analogous manner to Intermediate 262 using Intermediate 366 (0.29 g, 0.38 mmol) and 10% palladium on carbon (41 mg) in ethanol (23 mL) under a hydrogenatmosphere at RT for 9 h. Followed by manganese dioxide (0.39 g, 4.45 mmol) in DCM (15 mL) at RT for 18 h to provide the title compound (0.27 g). LCMS (Method 31): 2.08 min, 753.5 [M+H]+. Intermediate 368: Methyl 2-((3S,6S)-6-(5-(2-(3-ethoxyazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0300] Prepared in an analogous manner to Intermediate 285 using Intermediate 358 (46 mg, 69 µmol), carbon tetrabromide (46 mg, 0.14 mmol) and triphenylphosphine (36 mg, 0.14 mmol) in DCM (1.7 mL) at RT for 1.5 h, then 3-ethoxyazetidine hydrochloride (35 mg, 0.25 mmol, CAS 535924-73-3) and DIPEA (92 µL, 0.22 mmol) in MeCN (1.7 mL) at RT for 2 h. Purified by catch and release chromatography (1 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (32 mg). LCMS (Method 15): 2.52 min, 747.3 [M+H]+. Intermediate 369: Methyl 2-((3S,6S)-14,24-difluoro-16-methyl-6-(4-methyl-2-oxo-5-(2-(3- (trifluoromethoxy)azetidin-1-yl)ethyl)pyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0301] Prepared in an analogous manner to Intermediate 285 using Intermediate 358 (38 mg, 57 µmol), carbon tetrabromide (38 mg, 0.12 mmol) and triphenylphosphine (30 mg, 0.12 mmol) in DCM (1.4 mL) at RT for 2 h, then 3-(trifluoromethoxy)azetidine hydrochloride (41 mg, 0.23 mmol, CAS 1803590-72-8) and DIPEA (50 µL, 0.29 mmol) in MeCN (1.5 mL) at RT for 16 h. Purified by catch and release chromatography (1 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (31 mg). LCMS (Method 15): 2.64 min, 787.3 [M+H]+. Intermediate 370: Methyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-isopropoxyazetidin-1-yl)ethyl)- 4-methyl-2-oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0302] Prepared in an analogous manner to Intermediate 285 using Intermediate 358 (42 mg, 63 µmol), carbon tetrabromide (42 mg, 0.13 mmol) and triphenylphosphine (33 mg, 0.13 mmol) in DCM (1.6 mL) at RT for 1.5 h, then 3-isopropoxyazetidine hydrochloride (55 mg, 0.36 mmol, CAS 871657-49-7) and DIPEA (0.11 mL, 0.42 mmol) in MeCN (1.6 mL) at RT for 4 h. Purified by catch and release chromatography (1 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (22 mg). LCMS (Method 15): 2.58 min, 761.4 [M+H]+.Intermediate 371: Methyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4- methyl-2-oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0303] Prepared in an analogous manner to Intermediate 285 using Intermediate 395 (19 mg, 31 µmol), carbon tetrabromide (21 mg, 62 µmol) and triphenylphosphine (16 mg, 62 µmol) in DCM (0.7 mL) at RT for 1.5 h, then 3-fluoroazetidine hydrochloride (10 mg, 93 µmol, CAS 617718-46-4) and DIPEA (21 µL, 0.12 mmol) in MeCN (0.7 mL) at RT for 48 h. Purified by catch and release chromatography (1 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (10 mg). LCMS (Method 15): 2.43 min, 667.3 [M+H]+. Intermediate 372: 2-Methoxy-5-(3-(3-methoxyazetidin-1-yl)propyl)-4-methylpyrimidine

[0304] Prepared in an analogous manner to Intermediate 285 using Intermediate 284 (0.46 g, 2.48 mmol), carbon tetrabromide (1.23 g, 3.72 mmol) and triphenylphosphine (1.30 g, 4.96 mmol) in DCM (9 mL) at RT for 1 h, then 3-methoxyazetidine hydrochloride (0.92 g, 7.44 mmol, CAS 148644-09-1) and K2CO3 (2.06 g, 14.9 mmol) in MeCN (9 mL) at RT for 24 h. Purified by flash chromatography (24 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.21 g). LCMS (Method 11): 1.28 min, 252.2 [M+H]+. Intermediate 373: 5-(3-(3-Methoxyazetidin-1-yl)propyl)-4-methylpyrimidin-2(1H)-one

[0305] A solution of Intermediate 372 (0.23 g, 0.81 mmol) in 33% HBr in AcOH (2.8 mL, 16.2 mmol) was sonicated at RT for 10 s. The mixture was concentrated under reduced pressure. The crude product was purified by catch and release chromatography (5 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.20 g). LCMS (Method 15): 0.85 min, 238.0 [M+H]+. Intermediate 374: 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)-4-methyl-2-oxopyrimidin- 1(2H)-yl)pent-4-enamido)propanoate

[0306] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.46 g, 0.71 mmol), Intermediate 373 (0.23 g, 0.86 mmol) and K2CO3 (0.30 g, 2.14 mmol) in MeCN (8.8 mL) at reflux for 3 h. Purified by flash chromatography (40 g silica gel, 0-20% (0,5% ammonia MeOH) in DCM) to provide the title compound (0.28 g). LCMS (Method 15): 2.64 min, 787.4 [M+H]+. Intermediate 375: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(3-(3-methoxyazetidin-1-yl)propyl)-4- methyl-2-oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0307] Prepared in an analogous manner to Intermediate 71 using Intermediate 374 (0.27 g, 0.34 mmol) and Grubbs II (29 mg, 34 µmol) in DCE (0.20 L) at 50 °C for 2 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.22 g). LCMS (Method 15): 2.51 min, 759.4 [M+H]+. Intermediate 376: Ethyl 2-((3S,6S)-14,24-difluoro-6-(5-(3-(3-methoxyazetidin-1-yl)propyl)-4- methyl-2-oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0308] Prepared in an analogous manner to Intermediate 262 using Intermediate 375 (0.22 g, 0.29 mmol) and 10% palladium on carbon (31 mg) in ethanol (16 mL) under a hydrogen atmosphere at RT for 5 h. Followed by manganese dioxide (0.25 g, 2.88 mmol) in DCM (8 mL) at RT for 20 h to provide the title compound (0.20 g). LCMS (Method 27): 1.71 min, 761.4 [M+H]+. Intermediate 377: Ethyl (S)-3-(4-fluoro-2'-(hex-5-en-1-yl)-4',6'-dimethyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- -yl)pent-4-enamido)propanoate

[0309] Prepared in an analogous manner to Intermediate 70 using Intermediate 322 (0.47 g, 0.74 mmol), Intermediate 278 (0.20 g, 0.89 mmol) and K2CO3 (0.31 g, 2.22 mmol) in MeCN (25 mL) at reflux for 16 h. Purified by flash chromatography (24 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.15 g). LCMS (Method 15): 2.70 min, 769.5 [M+H]+. Intermediate 378: Ethyl 2-((3S,6S)-24-fluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4- methyl-2-oxopyrimidin-1(2H)-yl)-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0310] Prepared in an analogous manner to Intermediate 71 using Intermediate 377 (0.15 g, 0.19 mmol) and Grubbs II (16 mg, 19 µmol) in DCE (63 mL) at 40 °C for 3 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.10 g). LCMS (Method 15): 2.57 min, 741.4 [M+H]+. Intermediate 379: Ethyl 2-((3S,6S)-24-fluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4- methyl-2-oxopyrimidin-1(2H)-yl)-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0311] Prepared in an analogous manner to Intermediate 262 using Intermediate 378 (0.10 g, 0.14 mmol) and 10% palladium on carbon (15 mg) in ethanol (8 mL) under a hydrogen atmosphere at RT for 12 h. Followed by manganese dioxide (0.15 g, 1.71 mmol) in DCM (6mL) at RT for 18 h to provide the title compound (98 mg). LCMS (Method 15): 2.61 min, 743.5 [M+H]+. Intermediate 380: 5-(2-(3,3-Dimethylazetidin-1-yl)ethyl)-2-methoxy-4-methylpyrimidine

[0312] Prepared in an analogous manner to Intermediate 258 using (E)-5-(2-ethoxyvinyl)- 2-methoxy-4-methylpyrimidine (0.5 g, 2.44 mmol, CAS 2955527-94-1) in DCM (3.3 mL) and TFA (5.5 mL) at RT for 5 h. Then 3,3-dimethylazetidine hydrochloride (0.31 g, 2.53 mmol, CAS 89381-03-3), triethylamine (1.35 mL, 9.66 mmol) in DCM (21 mL) with 4 Å molecular sieves at RT for 30 min, followed by STAB (1.28 g, 6.03 mmol) at RT for 17 h. Purified by catch and release chromatography (20 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.38 g). LCMS (Method 15): 1.58 min, 236.1 [M+H]+. Intermediate 381: 5-(2-(3,3-Dimethylazetidin-1-yl)ethyl)-4-methylpyrimidin-2(1H)-one

[0313] A solution of Intermediate 380 (0.38 g, 1.47 mmol) in 33% HBr in AcOH (2.53 mL, 14.7 mmol) was stirred at RT for 5 min. The mixture was concentrated under reduced pressure. The crude product was purified by catch and release chromatography (5 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.28 g). LCMS (Method 11): 1.02 min, 222.2 [M+H]+. Intermediate 382: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(5-(2-(3,3-dimethylazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- -yl)pent-4-enamido)propanoate

[0314] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.18 g, 0.25 mmol), Intermediate 381 (60 mg, 0.27 mmol) and K2CO3 (0.10 g, 0.74 mmol) in MeCN (10 mL) at reflux for 16 h. Purified by flash chromatography (25 g silica gel, 0-10% MeOH in DCM) to provide the title compound (83 mg). LCMS (Method 15): 2.81 min, 771.4 [M+H]+. Intermediate 383: Ethyl 2-((3S,6S)-6-(5-(2-(3,3-dimethylazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-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

[0315] Prepared in an analogous manner to Intermediate 71 using Intermediate 382 (0.14 g, 0.17 mmol) and Grubbs II (21 mg, 26 µmol) in DCE (85 mL) at 50 °C for 1.5 h. Purified by catch and release chromatography (1 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.13 g). LCMS (Method 15): 2.71 min, 743.4 [M+H]+. Intermediate 384: Ethyl 2-((3S,6S)-6-(5-(2-(3,3-dimethylazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-14,24-difluoro-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 262 using Intermediate 383 (0.13 g, 0.14 mmol) and 10% palladium on carbon (14 mg) in ethanol (18 mL) under a hydrogen atmosphere at RT for 5 h. Followed by manganese dioxide (0.12 g, 1.36 mmol) in DCM (5.6 mL) at RT for 18 h to provide the title compound (74 mg). LCMS (Method 15): 2.75 min, 745.4 [M+H]+. Intermediate 385: Methyl 2-((3S,6S)-6-(5-(2-(3-(difluoromethoxy)azetidin-1-yl)ethyl)-4- methyl-2-oxopyrimidin-1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0317] Prepared in an analogous manner to Intermediate 285 using Intermediate 358 (65 mg, 98 µmol), carbon tetrabromide (65 mg, 0.20 mmol) and triphenylphosphine (51 mg, 0.20 mmol) in DCM (2.4 mL) at RT for 2 h, then 3-(difluoromethoxy)azetidine hydrochloride (63 mg, 0.39 mmol, CAS 1619991-11-5) and DIPEA (80 µL, 0.46 mmol) in MeCN (2.4 mL) at RT for 2 h. Purified by catch and release chromatography (1 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (27 mg). LCMS (Method 15): 2.52 min, 769.4 [M+H]+. Intermediate 386: 5-(2-(2-Methoxy-4-methylpyrimidin-5-yl)ethyl)-5-azaspiro[2.3]hexane

[0318] Prepared in an analogous manner to Intermediate 258 using (E)-5-(2-ethoxyvinyl)- 2-methoxy-4-methylpyrimidine (0.5 g, 2.44 mmol, CAS 2955527-94-1) in DCM (3.3 mL) and TFA (5.5 mL) at RT for 5 h. Then 5-azaspiro[2.3]hexane hydrochloride (0.30 g, 2.53 mmol, CAS 1536169-63-7), triethylamine (1.35 mL, 9.66 mmol) in DCM (21 mL) with 4 Å molecular sieves at RT for 30 min, followed by STAB (1.28 g, 6.03 mmol) at RT for 17 h. Purified by catch and release chromatography (20 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.45 g). LCMS (Method 15): 1.48 min, 234.1 [M+H]+. Intermediate 387: 5-(2-(5-Azaspiro[2.3]hexan-5-yl)ethyl)-4-methylpyrimidin-2(1H)-one

[0319] A solution of Intermediate 386 (0.23 g, 0.93 mmol) in 33% HBr in AcOH (1.60 mL, 9.26 mmol) was stirred at RT for 30 min. The mixture was concentrated under reduced pressure. The crude product was purified by catch and release chromatography (5 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.18 g). LCMS (Method 15): 0.91 min, 220.0 [M+H]+. Intermediate 388: Ethyl (S)-3-((S)-2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-4-methyl-2- oxopyrimidin-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

[0320] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.45 g, 0.37 mmol), Intermediate 387 (0.14 g, 0.59 mmol) and K2CO3(0.18 g, 1.32 mmol) in MeCN(14 mL) at reflux for 4.5 h. Purified by flash chromatography (25 g silica gel, 0-10% MeOH in DCM) to provide the title compound (0.10 g). LCMS (Method 15): 2.69 min, 769.5 [M+H]+. Intermediate 389: Ethyl 2-( -6-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)- 16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphanen-3-yl)acetate

[0321] Prepared in an analogous manner to Intermediate 71 using Intermediate 388 (0.13 g, 0.16 mmol) and Grubbs II (40 mg, 47 µmol) in DCE (78 mL) at 50 °C for 2.5 h. Purified by catch and release chromatography (5 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.10 g). LCMS (Method 15): 2.62 min, 741.4 [M+H]+. Intermediate 390: Ethyl 2-((3S,6S)-6-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0322] Prepared in an analogous manner to Intermediate 262 using Intermediate 389 (0.10 g, 0.11 mmol) and 10% palladium on carbon (12 mg) in ethanol (14 mL) under a hydrogen atmosphere at RT for 28 h. Followed by manganese dioxide (94 mg, 1.08 mmol) in DCM (6 mL) at RT for 22 h to provide the title compound (72 mg). LCMS (Method 27): 2.66 min, 743.4 [M+H]+. Intermediate 391: Ethyl (S)-3-((S)-2-(5-(2-acetoxyethyl)-4-methyl-2-oxopyrimidin-1(2H)- yl)pent-4-enamido)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl- biphenyl]-3-yl)propanoate

[0323] Prepared in an analogous manner to Intermediate 70 using Intermediate 69 (0.31 g, 0.52 mmol), Intermediate 353 (0.10 g, 0.52 mmol) and K2CO3 (0.22 g, 1.56 mmol) in MeCN (6 mL) at reflux for 16 h. Purified by flash chromatography (24 g silica gel, 50-100% EtOAc in petroleum ether) to provide the title compound (0.14 g). LCMS (Method 15): 2.61 min, 692.3 [M+H]+. Intermediate 392: Ethyl 2-((3S,6S)-6-(5-(2-acetoxyethyl)-4-methyl-2-oxopyrimidin-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

[0324] Prepared in an analogous manner to Intermediate 71 using Intermediate 391 (0.14 g, 0.20 mmol) and Grubbs II (17 mg, 20 µmol) in DCE (89 mL) at 45 °C for 1.5 h. Purified by flash chromatography (12 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (0.11 g). LCMS (Method 15): 2.49 min, 664.3 [M+H]+.Intermediate 393: Ethyl 2-((3S,6S)-6-(5-(2-acetoxyethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)- 14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetate

[0325] Prepared in an analogous manner to Intermediate 262 using Intermediate 392 (0.11 g, 0.16 mmol) and 10% palladium on carbon (18 mg) in ethanol (13 mL) under a hydrogen atmosphere at RT for 2 h. Followed by manganese dioxide (0.14 g, 1.63 mmol) in DCM (9 mL) at RT for 4 h. Purified by flash chromatography (12 g silica gel, eluting 50-100% EtOAc in petroleum ether) to provide the title compound (75 mg). LCMS (Method 15): 2.52 min, 666.4 [M+H]+. Intermediate 394: 2-((3S,6S)-14,24-difluoro-6-(5-(2-hydroxyethyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid

[0326] Prepared in an analogous manner to Intermediate 357 using Intermediate 393 (35 mg, 49 µmol) and lithium hydroxide (8.1 mg, 0.34 mmol) in THF (1.5 mL), MeOH (3.0 mL) and water (1.5 mL) at RT for 1 h, to provide the title compound (67 mg). LCMS (Method 15): 1.46 min, 596.4 [M+H]+. Intermediate 395: Methyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-hydroxyethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0327] Prepared in an analogous manner to Intermediate 358 using Intermediate 394 (67 mg, 0.11 mmol) and 4 M aqueous HCl (0.11 mL) in MeOH (4.9 mL) at RT for 16 h to provide the title compound (65 mg). LCMS (Method 15): 2.27 min, 610.4 [M+H]+. Intermediate 396: Methyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-methoxy-3-methylazetidin-1- yl)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0328] Prepared in an analogous manner to Intermediate 285 using Intermediate 395 (44 mg, 0.32 mmol), carbon tetrabromide (71 mg, 0.21 mmol) and triphenylphosphine (56 mg, 0.21 mmol) in DCM (2.3 mL) at RT for 2 h, then 3-methoxy-3-methylazetidine hydrochloride (44 mg, 0.32 mmol, CAS 905843-93-8) and DIPEA (75 µL, 0.43 mmol) in MeCN (2.3 mL) at RT for 3 h. Purified by catch and release chromatography (1 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (58 mg). LCMS (Method 15): 2.46 min, 693.4 [M+H]+.Intermediate 397: Ethyl (S)-3-(4'-cyclopropyl-4-fluoro-2'-(hex-5-en-1-yl)-5,6'-dimethyl-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-1 - yl)pent-4-enamido)propanoate

[0329] Prepared in an analogous manner to Intermediate 70 using Intermediate 338 (0.44 g, 0.64 mmol), Intermediate 278 (0.21 g, 0.96 mmol) and K2CO3 (0.26 g, 1.91 mmol) in MeCN (10 mL) at reflux for 17 h. Purified by flash chromatography (40 g silica gel, 0-5% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.12 g). LCMS (Method 15): 2.70 min, 741.5 [M+H]+. Intermediate 398: Ethyl 2-((3S,6S)-14-cyclopropyl-24-fluoro-6-(5-(2-(3-methoxyazetidin-1- yl)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0330] Prepared in an analogous manner to Intermediate 71 using Intermediate 397 (0.12 g, 0.15 mmol) and Grubbs II (12 mg, 15 µmol) in DCE (76 mL) at 50 °C for 2 h. Purified by flash chromatography (12 g silica gel, eluting 0-7% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.10 g). LCMS (Method 15): 2.57 min, 713.4 [M+H]+. Intermediate 399: Ethyl 2-((3S,6S)-14-cyclopropyl-24-fluoro-6-(5-(2-(3-methoxyazetidin-1- yl)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0331] Prepared in an analogous manner to Intermediate 262 using Intermediate 398 (0.10 g, 0.11 mmol) and 10% palladium on carbon (12 mg) in ethanol (14 mL) under a hydrogen atmosphere at RT for 11 h. Followed by manganese dioxide (97 mg, 1.11 mmol) in DCM (4.4 mL) at RT for 48 h to provide the title compound (66 mg). LCMS (Method 15): 2.62 min, 715.5 [M+H]+. Intermediate 400: 5-Bromo-2-methoxypyrimidine-4-carbaldehyde

[0332] To a solution of 5-bromo-2-methoxy-4-methylpyrimidine (2.55 g, 12.6 mmol) in 1,4- dioxane (75 mL) was added selenium dioxide (1.67 g, 15.1 mmol) and the mixture was stirred at 85 °C for 16 h. Additional selenium dioxide (1.67 g, 15.1 mmol) was added and the mixture was stirred at 85 °C for 16 h. The mixture was filtered through Celite® and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel, eluting 0-40% EtOAc in petroleum ether) to provide the title compound (2.02 g). LCMS (Method 15): 0.87 min, 218.9 [M+H]+. Intermediate 401: 5-Bromo-4-(difluoromethyl)-2-methoxypyrimidine

[0333] To a solution of Intermediate 400 (1.0 g, 4.61 mmol) in DCM (46 mL) at 0 °C was added DAST (0.73 mL, 5.53 mmol) and the mixture was stirred at RT for 20 h. The mixturewas washed with saturated aqueous NaHCO3, the organic layer dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel, eluting 0-50% EtOAc in petroleum ether) to provide the title compound (0.67 g). LCMS (Method 15): 1.55 min, 240.9 [M+H]+. Intermediate 402: (E)-4-(Difluoromethyl)-5-(2-ethoxyvinyl)-2-methoxypyrimidine

[0334] Prepared in an analogous manner to Intermediate 295 using Intermediate 401 (0.75 g, 3.16 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (1.04 g, 5.36 mmol, CAS 1201905-61-4), Pd(dppf)Cl2 (0.18 g, 0.24 mmol) and Na2CO3 (0.67 g, 6.31 mmol) in 1,4- dioxane (11 mL) and water (1.6 mL) at 100 °C for 4 days. Purified by flash chromatography (40 g silica gel, eluting 0-30% EtOAc in petroleum ether) to provide the title compound (0.51 g). LCMS (Method 15): 1.76 min, 231.0 [M+H]+. Intermediate 403: 2-(4-(Difluoromethyl)-2-methoxypyrimidin-5-yl)-N,N-dimethylethan-1- amine

[0335] Prepared in an analogous manner to Intermediate 258 using Intermediate 402 (0.51 g, 2.22 mmol) in DCM (3.2 mL) and TFA (5.1 mL) at RT for 3 h. Then dimethylamine (2 M in THF, 2.22 mL, 4.44 mmol), triethylamine (0.37 mL, 2.66 mmol) in DCM (13 mL) with 4 Å molecular sieves at RT for 10 min, followed by STAB (1.18 g, 5.55 mmol) at RT for 16 h. Purified by catch and release chromatography (10 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.29 g). LCMS (Method 15): 1.42 min, 232.1 [M+H]+. Intermediate 404: 4-(Difluoromethyl)-5-(2-(dimethylamino)ethyl)pyrimidin-2(1H)-one

[0336] A solution of Intermediate 403 (0.29 g, 1.26 mmol) in 33% HBr in AcOH (4.56 mL, 25.2 mmol) was stirred at 65 °C for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by catch and release chromatography (5 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.28 g). LCMS (Method 15): 0.56 min, 218.1 [M+H]+. Intermediate 405: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyrimidin- -yl)pent-4-enamido)propanoate

[0337] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.45 g, 0.70 mmol), Intermediate 404 (0.15 g, 0.70 mmol) and K2CO3(0.29 g, 2.10 mmol) in MeCN (7 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.42 g). LCMS (Method 27): 2.31 min, 767.4 [M+H]+.Intermediate 406: Ethyl 2-((3S,6S)-6-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2- oxopyrimidin-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

[0338] Prepared in an analogous manner to Intermediate 71 using Intermediate 405 (0.42 g, 0.50 mmol) and Grubbs II (53 mg, 62 µmol) in DCE (0.20 L) at 50 °C for 3.5 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% MeOH in DCM) to provide the title compound (0.13 g). LCMS (Method 27): 1.95 min, 739.3 [M+H]+. Intermediate 407: Ethyl 2-((3S,6S)-6-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2- oxopyrimidin-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 262 using Intermediate 406 (0.13 g, 0.17 mmol) and 10% palladium on carbon (18 mg) in ethanol (10 mL) under a hydrogen atmosphere at RT for 7 h. Followed by manganese dioxide (0.21 g, 2.42 mmol) in DCM (8 mL) at RT for 72 h. Then manganese dioxide (0.21 g, 2.42 mmol) in DCE (4 mL) at 50 °C for 24 h, to provide the title compound (71 mg). LCMS (Method 27): 2.01 min, 741.4 [M+H]+. Intermediate 408: Methyl 2-((3S,6S)-14,24-difluoro-6-(5-(2-(3-methoxy-3-methylazetidin-1- yl)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0340] Prepared in an analogous manner to Intermediate 285 using Intermediate 358 (55 mg, 83 µmol), carbon tetrabromide (55 mg, 0.17 mmol) and triphenylphosphine (43 mg, 0.17 mmol) in DCM (2 mL) at RT for 4 h, then 3-methoxy-3-methylazetidine hydrochloride (23 mg, 0.17 mmol, CAS 905843-93-8) and K2CO3 (69 mg, 0.50 mmol) in MeCN (2 mL) at RT for 24 h. Purified by catch and release chromatography (1 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (43 mg). LCMS (Method 15): 2.50 min, 745.4 [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

[0341] Prepared in an analogous manner to Intermediate 34 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)- biphenyl]-3-yl)propanoate

[0342] Prepared in an analogous manner to Intermediate 35 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

[0343] Prepared in an analogous manner to Intermediate 34 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

[0344] 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)- biphenyl]-3-yl)-3-((R)-2-hydroxy-4-methylpent-4-enamido)propanoate

[0345] Prepared in an analogous manner to Intermediate 40 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 2-((3S,6R)-14,24-difluoro-6-hydroxy-16,8-dimethyl-5-oxo-25- (trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphan-8-en-3-yl)acetate

[0346] Prepared in an analogous manner to Intermediate 71 using Intermediate 454 (0.40 g, 0.71 mmol) and Grubbs II (60 mg, 70 µmol) in toluene (0.28 L) at 50 °C for 2 h. Purified by flash chromatography (40 g silica gel, eluting 0-30% EtOAc in petroleum ether) to provide the title compound (0.17 g). LCMS (Method 15): 2.48 min, 540.2 [M+H]+. Intermediate 456: Ethyl 2-((3S,6R)-14,24-difluoro-6-hydroxy-16,8-dimethyl-5-oxo-25- (trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3-yl)acetate

[0347] Prepared in an analogous manner to Intermediate 72 using Intermediate 455 (0.17 g, 0.27 mmol) and 10% palladium on carbon (28 mg) in ethanol (30 mL) under a hydrogen atmosphere at RT for 6 h to provide the title compound (0.13 g). LCMS (Method 15): 2.54 min, 542.2 [M+H]+. Intermediate 457: Ethyl 2-((3S,6R)-14,24-difluoro-16,8-dimethyl-6-((methylsulfonyl)oxy)-5- oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclododecaphane-3-yl)acetate

[0348] Prepared in an analogous manner to Intermediate 41 using Intermediate 456 (42 mg, 78 µmol), triethylamine (22 µL, 0.16 mmol) and methanesulfonyl chloride (9 µL, 0.12 mmol) in DCM (1 mL) at RT for 1 h to provide the title compound (62 mg). LCMS (Method 15): 2.61 min, 620.2 [M+H]+. Intermediate 458: Ethyl 2-((3S,6S)-6-(4-ethyl-5-(2-(3-methoxyazetidin-1-yl)ethyl)-2- oxopyrimidin-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

[0349] Prepared in an analogous manner to Intermediate 70 using Intermediate 457 (45 mg, 61 µmol), Intermediate 528 (16 mg, 67 µmol) and DBU (27 µL, 0.18 mmol) in MeCN (2 mL) at reflux for 3 h. Purified by flash chromatography (4 g silica gel, 0-10% MeOH in DCM) to provide the title compound (16 mg). LCMS (Method 15): 2.57 min, 761.4 [M+H]+. Intermediate 500: 5-Bromo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-2(1H)- one

[0350] To a solution of 5-bromo-2,4-dimethoxypyrimidine (5.0 g, 22.8 mmol, CAS 56686-16- 9) in MeCN (57 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (6.06 g, 34.2 mmol) and Na2CO3 (7.26 g, 68.5 mmol) and the mixture was stirred at 85 °C for 24 h. The mixture was filtered through Celite® and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel, 0-60% EtOAc in petroleum ether) to provide the title compound (3.30 g). LCMS (Method 11): 1.96 min, 337.1 [M+H]+. Intermediate 501: (E)-5-(2-ethoxyvinyl)-4-methoxy-1-((2- (trimethylsilyl)ethoxy)methyl)pyrimidin-2(1H)-one

[0351] Prepared in an analogous manner to Intermediate 295 using Intermediate 500 (3.02 g, 9.01 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (1.96 g, 9.91 mmol, CAS 1201905-61-4), Pd(dppf)Cl2(0.33 g, 0.45 mmol) and Na2CO3(1.91 g, 18.0 mmol) in 1,4- dioxane (40 mL) and water (5 mL) at 100 °C for 4 h. Purified by flash chromatography (40 g silica gel, eluting 0-30% EtOAc in petroleum ether) to provide the title compound (0.56 g). LCMS (Method 15): 2.11 min, 327.2 [M+H]+. Intermediate 502: 5-(2-(Dimethylamino)ethyl)-4-methoxypyrimidin-2(1H)-one

[0352] Prepared in an analogous manner to Intermediate 258 using Intermediate 501 (0.56 g, 1.72 mmol) in DCM (5.6 mL) and TFA (4.0 mL) at RT for 4 h. Then dimethylamine (2 M in THF, 1.72 mL, 3.44 mmol), triethylamine (0.45 mL, 3.43 mmol) in DCM (16 mL) with 4 Å molecular sieves at RT for 10 min, followed by STAB (0.73 g, 3.43 mmol) at RT for 2 h. Purified by catch and release chromatography (20 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.16 g). LCMS (Method 15): 0.98 min, 198.0 [M+H]+. Intermediate 503: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methoxy-2-oxopyrimidin-1(2H)- 4-enamido)propanoate

[0353] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.44 g, 0.67 mmol), Intermediate 502 (0.15 g, 0.74 mmol) and K2CO3 (0.28 g, 2.02 mmol) in DMF (9 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 (0.16 g). LCMS (Method 15): 2.63 min, 733.3 [M-Me+H]+. Intermediate 504: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-methoxy-2-oxopyrimidin- 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 71 using Intermediate 503 (0.19 g, 0.12 mmol) and Grubbs II (9.9 mg, 12 µmol) in DCE (0.13 L) at 50 °C for 1 h. Purified by flash chromatography (12 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.10 g). LCMS (Method 15): 2.61 min, 719.3 [M+H]+. Intermediate 505: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-4-methoxy-2-oxopyrimidin- 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 72 using Intermediate 504 (80 mg, 80 µmol) and 10% palladium on carbon (8.5 mg) in ethanol (11 mL) under a hydrogen atmosphere at RT for 6 h to provide the title compound (45 mg). LCMS (Method 15): 2.66 min, 721.4 [M+H]+. Intermediate 506: 3-(2-Methoxy-4-methylpyrimidin-5-yl)-2-methylpropanal

[0356] A mixture of 5-bromo-2-methoxy-4-methylpyrimidine (1.50 g, 7.09 mmol, CAS 38696- 23-0), 2-methylprop-2-en-1-ol (1.02 g, 14.2 mmol, CAS 513-42-8), N,N- dicyclohexylmethylamine (1.67 mL, 7.80 mmol) in 1,4-dioxane (9 mL) was degassed with nitrogen. To this was added Pd2(dba)3(32 mg, 35 µmol) and tri-tert-butyl phosphine (14 mg, 71 µmol) and the mixture stirred at 80 °C for 16 h. The mixture was diluted with water andextracted 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, eluting 0-100% EtOAc in petroleum ether) to provide the title compound (0.83 g). LCMS (Method 15): 1.26 min, 195.1 [M+H]+. Intermediate 507: 3-(2-Methoxy-4-methylpyrimidin-5-yl)-N,N,2-trimethylpropan-1-amine

[0357] To a solution of Intermediate 506 (0.50 g, 2.78 mmol) and triethylamine (1.80 mL, 12.9 mmol) in DCM (11 mL) was added dimethylamine (2 M in THF, 2.6 mL, 5.20 mmol) and MgSO4 and the mixture was stirred at RT for 2 h. STAB (1.82 g, 8.59 mmol) was added and stirred at RT for 20 h. The mixture was diluted with saturated aqueous NaHCO3 then extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by catch and release chromatography (10 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.79 g). LCMS (Method 15): 1.51 min, 224.2 [M+H]+. Intermediate 508: 5-(3-(Dimethylamino)-2-methylpropyl)-4-methylpyrimidin-2(1H)-one

[0358] A solution of Intermediate 507 (0.79 g, 3.55 mmol) in 33% HBr in AcOH (6.43 mL, 35.5 mmol) was stirred at 20 °C for 10 min. The mixture was concentrated under reduced pressure. The crude product was purified by catch and release chromatography (10 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.83 g). LCMS (Method 11): 0.99 min, 210.3 [M+H]+. Intermediate 509: Ethyl (3S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((2S)-2-(5-(3-(dimethylamino)-2-methylpropyl)-4-methyl-2- 1(2H)-yl)pent-4-enamido)propanoate

[0359] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.51 g, 0.75 mmol), Intermediate 508 (0.18 g, 0.75 mmol) and K2CO3 (0.31 g, 2.26 mmol) in MeCN (12 mL) at reflux for 16 h. Purified by flash chromatography (4 g silica gel, 0-8% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.24 g). LCMS (Method 27): 2.42 min, 759.4 [M+H]+. Intermediate 510: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)-2-methylpropyl)-4-methyl-2- oxopyrimidin-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

[0360] Prepared in an analogous manner to Intermediate 71 using Intermediate 509 (0.26 g, 0.33 mmol) and Grubbs II (28 mg, 33 µmol) in DCE (0.16 L) at 50 °C for 2 h. Purified by flash chromatography (25 g silica gel, eluting 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.20 g). LCMS (Method 27): 2.07 min, 731.3 [M+H]+.Intermediate 511: Ethyl 2-((3S,6S)-6-(5-(3-(dimethylamino)-2-methylpropyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0361] Prepared in an analogous manner to Intermediate 262 using Intermediate 510 (0.20 g, 0.28 mmol) and 10% palladium on carbon (29 mg) in ethanol (17 mL) under a hydrogen atmosphere at RT for 10 h. Followed by manganese dioxide (0.24 g, 2.76 mmol) in DCM (8 mL) at RT for 22 h, to provide the title compound (0.10 g). LCMS (Method 31): 2.45 min, 733.6 [M+H]+. Intermediate 512: Methyl 2-((3S,6S)-14,24-difluoro-16-methyl-6-(4-methyl-2-oxo-5-(2-(3- (2,2,2-trifluoroethyl)azetidin-1-yl)ethyl)pyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetate

[0362] Prepared in an analogous manner to Intermediate 285 using Intermediate 358 (81 mg, 0.12 mmol), carbon tetrabromide (81 mg, 0.24 mmol) and triphenylphosphine (64 mg, 0.24 mmol) in DCM (3 mL) at RT for 2 h, then 3-(2,2,2-trifluoroethyl)azetidine hydrochloride (86 mg, 0.49 mmol, CAS 1394041-81-6) and DIPEA (99 µL, 0.57 mmol) in MeCN (3 mL) at RT for 4 h. Purified by catch and release chromatography (1 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (31 mg). LCMS (Method 15): 2.61 min, 785.4 [M+H]+. Intermediate 513: 5-Bromo-2-methoxy-4-propylpyrimidine

[0363] To a vial containing 5-bromo-2-methoxypyrimidine (0.60 g, 3.17 mmol, CAS 14001- 66-2), iron(II) sulfate heptahydrate (44 mg, 0.16 mmol), pyridine-2-carboxylic acid (39 mg, 0.32 mmol) and sodium bromate (0.96 g, 6.35 mmol) was added a degassed mixture of 1:1 DMSO / water (14 mL) followed by butyric acid (2.8 g, 31.8 mmol). The stirred mixture was irradiated at 450 nm / 30 W under nitrogen for 18 h. Note – the above was run in 4 vials (4 x 0.60 g of CAS 14001-66-2) concurrently and combined for work up. The mixture was diluted with DCM and saturated aqueous NaHCO3. 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, eluting 0-5% EtOAc in petroleum ether) to provide the title compound (1.09 g). LCMS (Method 15): 1.97 min, 230.9 [M+H]+. Intermediate 514: (E)-5-(2-Ethoxyvinyl)-2-methoxy-4-propylpyrimidine

[0364] Prepared in an analogous manner to Intermediate 295 using Intermediate 513 (1.23 g, 5.33 mmol), trans-2-ethoxyvinylboronic acid pinacol ester (1.69 g, 8.53 mmol, CAS 1201905-61-4), Pd(dppf)Cl2(0.32 g, 0.43 mmol) and Na2CO3(1.13 g, 10.7 mmol) in 1,4- dioxane (23 mL) and water (3 mL) at 100 °C for 40 h. Purified by flash chromatography (40 gsilica gel, eluting 0-20% EtOAc in petroleum ether) to provide the title compound (0.86 g). LCMS (Method 15): 1.96 min, 223.1 [M+H]+. Intermediate 515: 2-(2-Methoxy-4-propylpyrimidin-5-yl)-N,N-dimethylethan-1-amine

[0365] Prepared in an analogous manner to Intermediate 258 using Intermediate 514 (0.86 g, 3.86 mmol) in DCM (5.2 mL) and TFA (8.9 mL) at RT for 4.5 h. Then dimethylamine (2 M in THF, 2.89 mL, 5.79 mmol), triethylamine (1.18 mL, 8.49 mmol) in DCM (21 mL) with 4 Å molecular sieves at RT for 10 min, followed by STAB (2.05 g, 9.65 mmol) at RT for 16 h. Purified by catch and release chromatography (10 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.50 g). LCMS (Method 15): 1.57 min, 224.1 [M+H]+. Intermediate 516: 5-(2-(Dimethylamino)ethyl)-4-propylpyrimidin-2(1H)-one

[0366] A solution of Intermediate 515 (0.50 g, 2.23 mmol) in 33% HBr in AcOH (7.69 mL, 44.5 mmol) was stirred at 65 °C for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by catch and release chromatography (5 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.46 g). LCMS (Method 15): 0.80 min, 210.1 [M+H]+. Intermediate 517: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-propylpyrimidin-1(2H)- 4-enamido)propanoate

[0367] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.38 g, 0.58 mmol), Intermediate 516 (0.13 g, 0.64 mmol) and K2CO3 (0.24 g, 1.74 mmol) in MeCN (5.8 mL) at reflux for 18 h. Purified by flash chromatography (24 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.18 g). LCMS (Method 15): 2.76 min, 759.5 [M+H]+. Intermediate 518: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-propylpyrimidin- 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

[0368] Prepared in an analogous manner to Intermediate 71 using Intermediate 517 (0.24 g, 0.31 mmol) and Grubbs II (27 mg, 31 µmol) in DCE (0.14 L) at 45 °C for 1.5 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.22 g). LCMS (Method 15): 2.64 min, 731.4 [M+H]+. Intermediate 519: Ethyl 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxo-4-propylpyrimidin- 1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0369] Prepared in an analogous manner to Intermediate 262 using Intermediate 518 (0.22 g, 0.30 mmol) and 10% palladium on carbon (32 mg) in ethanol (16 mL) under a hydrogen atmosphere at RT for 5 h. Followed by manganese dioxide (69 mg, 0.79 mmol) in DCM (10 mL) at RT for 64 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.14 g). LCMS (Method 15): 2.68 min, 733.4 [M+H]+. Intermediate 520: tert-Butyl 4-(2-methoxy-4-methylpyrimidin-5-yl)piperidine-1-carboxylate

[0370] A vial containing nickel(II) chloride ethylene glycol dimethyl ether complex (15 mg, 69 µmol) and 4,4'-di-tertbutyl-2,2'-bipyridine (37 mg, 0.14 mmol) in degassed diethylene glycol diethyl ether (10 mL) was sonicated at RT for 15 min. This mixture was added to a vial containing 5-bromo-2-methoxy-4-methylpyrimidine (0.70 g, 3.45 mmol, CAS 38696-23-0), tert- butyl 4-bromopiperidine-1-carboxylate (2.28 g, 8.62 mmol, CAS 180695-79-8), Na2CO3 (0.73 g, 6.90 mmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (19.5 mg, 17 µmol) and tris(trimethylsilyl)silane (1.07 mL, 3.45 mmol) and the stirred mixture was irradiated at 405 nm / 18 W under nitrogen for 5 h. Note – the above was run in 2 batches (2 x 0.70 g of CAS 38696-23-0) concurrently and combined for work up. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (80 g silica gel, eluting 0-60% EtOAc in petroleum ether) to provide the title compound (1.66 g). LCMS (Method 22): 1.54 min, 308.1 [M+H]+. Intermediate 521: 2-Methoxy-4-methyl-5-(piperidin-4-yl)pyrimidine

[0371] A suspension of Intermediate 520 (1.10 g, 3.40 mmol) in 4 M HCl in 1,4-dioxane (3.4 mL) was stirred at RT for 72 h. The mixture was concentrated under reduced pressure and purified by catch and release chromatography (20 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.65 g). LCMS (Method 15): 1.11 min, 208.1 [M+H]+. Intermediate 522: 2-Methoxy-4-methyl-5-(1-methylpiperidin-4-yl)pyrimidine

[0372] Prepared in an analogous manner to Intermediate 507 using Intermediate 521 (0.56 g, 2.72 mmol) and formaldehyde (0.61 mL, 8.15 mmol) in THF (11 mL) at RT for 18 h, followed by STAB (1.15 g, 5.43 mmol) and AcOH (0.62 mL, 10.9 mmol) at RT for 20 h. Purified by catch and release chromatography (20 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.60 g). LCMS (Method 15): 1.35 min, 222.1 [M+H]+. Intermediate 523: 4-Methyl-5-(1-methylpiperidin-4-yl)pyrimidin-2(1H)-one

[0373] A solution of Intermediate 522 (0.50 g, 2.08 mmol) in 33% HBr in AcOH (3.60 mL, 20.8 mmol) was stirred at RT for 10 min. The mixture was concentrated under reduced pressure. The crude product was purified by catch and release chromatography (5 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.44 g). LCMS (Method 21): 1.64 min, 208.1 [M+H]+. Intermediate 524: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(4-methyl-5-(1-methylpiperidin-4-yl)-2-oxopyrimidin-1(2H)- 4-enamido)propanoate

[0374] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.49 g, 0.75 mmol), Intermediate 523 (0.26 g, 1.13 mmol) and K2CO3 (0.31 g, 2.26 mmol) in MeCN (12 mL) at reflux for 18 h. Purified by flash chromatography (24 g silica gel, 0-5% (0.5% ammonia MeOH) in DCM) to provide the title compound (98 mg). LCMS (Method 15): 2.66 min, 757.4 [M+H]+. Intermediate 525: Ethyl 2-((3S,6S)-14,24-difluoro-16-methyl-6-(4-methyl-5-(1- methylpiperidin-4-yl)-2-oxopyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0375] Prepared in an analogous manner to Intermediate 71 using Intermediate 524 (0.11 g, 0.14 mmol) and Grubbs II (12 mg, 14 µmol) in DCE (62 mL) at 50 °C for 2 h. Purified by flash chromatography (12 g silica gel, eluting 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.11 g). LCMS (Method 15): 2.50 min, 729.4 [M+H]+. Intermediate 526: Ethyl 2-((3S,6S)-14,24-difluoro-16-methyl-6-(4-methyl-5-(1- methylpiperidin-4-yl)-2-oxopyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0376] Prepared in an analogous manner to Intermediate 262 using Intermediate 525 (0.11 g, 0.13 mmol) and 10% palladium on carbon (13 mg) in ethanol (13 mL) under a hydrogen atmosphere at RT for 10 h. Followed by manganese dioxide (0.11 g, 1.26 mmol) in DCM (4 mL) at RT for 48 h, to provide the title compound (86 mg). LCMS (Method 27): 1.63 min, 731.4 [M+H]+. Intermediate 527: 4-Ethyl-2-methoxy-5-(2-(3-methoxyazetidin-1-yl)ethyl)pyrimidine

[0377] Prepared in an analogous manner to Intermediate 258 using (E)-5-(2-ethoxyvinyl)- 2-methoxy-4-ethylpyrimidine (1.02 g, 4.90 mmol, CAS 2955528-55-7) in DCM (7.2 mL) and TFA (11.3 mL) at RT for 4 h. Then 3-methoxyazetidine hydrochloride (1.21 mg, 9.80 mmol), triethylamine (0.82 mL, 5.88 mmol) in DCM (29 mL) with 4 Å molecular sieves at RT for 10 min, followed by STAB (2.60 g, 12.2 mmol) at RT for 16 h. Purified by flash chromatography(25 g silica gel, eluting 0-20% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.53 g). LCMS (Method 15): 1.42 min, 252.1 [M+H]+. Intermediate 528: 4-Ethyl-5-(2-(3-methoxyazetidin-1-yl)ethyl)pyrimidin-2(1H)-one

[0378] A suspension of sodium iodide (0.75 g, 4.97 mmol) and chlorotrimethylsilane (0.63 mL, 4.97 mmol) in MeCN (45 mL) was stirred at RT for 10 min then a solution of Intermediate 527 (0.25 g, 1.00 mmol) in MeCN (4.5 mL) was added and stirred at RT for 16 h. The mixture was directly purified by catch and release chromatography (20 g SCX, eluting MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.23 g). LCMS (Method 15): 0.86 min, 238.1 [M+H]+. Intermediate 529: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(4-ethyl-5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyrimidin- -yl)pent-4-enamido)propanoate

[0379] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.27 g, 0.42 mmol), Intermediate 528 (0.12 g, 0.46 mmol) and K2CO3 (0.17 g, 1.25 mmol) in MeCN (13 mL) at reflux for 18 h. Purified by flash chromatography (40 g silica gel, 0-6% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.14 g). LCMS (Method 15): 2.66 min, 787.4 [M+H]+. Intermediate 530: Ethyl 2-((3S,6S)-6-(4-ethyl-5-(2-(3-methoxyazetidin-1-yl)ethyl)-2- oxopyrimidin-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 71 using Intermediate 529 (0.18 g, 0.22 mmol) and Grubbs II (28 mg, 33 µmol) in DCE (0.11 L) at 50 °C for 4.5 h. Purified by catch and release chromatography (20 g SCX, eluting MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.18 g). LCMS (Method 15): 2.53 min, 759.4 [M+H]+. Intermediate 531: Ethyl 2-((3S,6S)-6-(4-ethyl-5-(2-(3-methoxyazetidin-1-yl)ethyl)-2- oxopyrimidin-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 262 using Intermediate 530 (0.18 g, 0.20 mmol) and 10% palladium on carbon (21 mg) in ethanol (25 mL) under a hydrogen atmosphere at RT for 17 h. Followed by manganese dioxide (0.17 g, 1.96 mmol) in DCM (25 mL) at RT for 48 h, to provide the title compound (0.12 g). LCMS (Method 15): 2.57 min, 761.4 [M+H]+. Intermediate 532: 5-Bromo-4-ethyl-2-methoxypyrimidine

[0382] Prepared in an analogous manner to Intermediate 513 using 5-bromo-2- methoxypyrimidine (1.20 g, 6.35 mmol, CAS 14001-66-2), iron(II) sulfate heptahydrate (88 mg, 0.32 mmol), pyridine-2-carboxylic acid (78 mg, 0.64 mmol), sodium bromate (1.92 g, 12.7 mmol) and propionic acid (4.7 g, 63.5 mmol) in 1:1 DMSO / water (14 mL) irradiated at 450 nm / 30 W under nitrogen for 18 h. Note – the above was run in 2 vials (2 x 0.60 g of CAS 14001-66-2) concurrently and combined for work up. Purified by flash chromatography (80 g silica gel, eluting 0-5% EtOAc in petroleum ether) to provide the title compound (0.66 g). LCMS (Method 15): 1.77 min, 216.9 [M+H]+. Intermediate 533: 3-(4-Ethyl-2-methoxypyrimidin-5-yl)propanal

[0383] Prepared in an analogous manner to Intermediate 506 using Intermediate 532 (0.77 g, 3.37 mmol), allyl alcohol (0.59 g, 10.1 mmol, CAS 107-18-6), N,N-dicyclohexylmethylamine (0.87 mL, 4.04 mmol), Pd2(dba)3 (0.15 g, 0.17 mmol) and tri-tert-butyl phosphine (98 mg, 0.34 mmol) in 1,4-dioxane (26 mL) at 70 °C for 2 h. Purified by flash chromatography (40 g silica gel, eluting 0-100% EtOAc in petroleum ether) to provide the title compound (0.47 g). LCMS (Method 15): 1.22 min, 195.1 [M+H]+. Intermediate 534: 4-Ethyl-2-methoxy-5-(3-(3-methoxyazetidin-1-yl)propyl)pyrimidine

[0384] Prepared in an analogous manner to Intermediate 507 using Intermediate 533 (0.58 g, 2.66 mmol) and 3-methoxyazetidine hydrochloride (0.66 g, 5.33 mmol) in DCM (25 mL) at RT for 18 h, followed by STAB (1.41 g, 6.66 mmol) at RT for 20 h. Purified by catch and release chromatography (20 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.37 g). LCMS (Method 15): 1.45 min, 266.1 [M+H]+. Intermediate 535: 4-Ethyl-5-(3-(3-methoxyazetidin-1-yl)propyl)pyrimidin-2(1H)-one

[0385] Prepared in an analogous manner to Intermediate 528 using sodium iodide (1.47 g, 9.86 mmol) chlorotrimethylsilane (1.25 mL, 9.86 mmol) in MeCN (20 mL) and Intermediate 534 (0.25 g, 1.00 mmol) in MeCN (5 mL) at RT for 21 h. Purified by catch and release chromatography (20 g SCX, eluting MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.26 g). LCMS (Method 15): 0.97 min, 252.1 [M+H]+. Intermediate 536: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(4-ethyl-5-(3-(3-methoxyazetidin-1-yl)propyl)-2-oxopyrimidin- -yl)pent-4-enamido)propanoate

[0386] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.22 g, 0.34 mmol), Intermediate 535 (97 mg, 0.37 mmol) and K2CO3(0.14 g, 1.00 mmol) in MeCN (21 mL) at reflux for 6 h. Purified by flash chromatography (25 g silica gel, 0-10% (0.5%ammonia MeOH) in DCM) to provide the title compound (74 mg). LCMS (Method 15): 2.71 min, 801.5 [M+H]+. Intermediate 537: Ethyl 2-((3S,6S)-6-(4-ethyl-5-(3-(3-methoxyazetidin-1-yl)propyl)-2- oxopyrimidin-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

[0387] Prepared in an analogous manner to Intermediate 71 using Intermediate 536 (0.10 g, 0.12 mmol) and Grubbs II (10 mg, 12 µmol) in DCE (62 mL) at 50 °C for 1.5 h. Purified by flash chromatography (12 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (91 mg). LCMS (Method 15): 2.58 min, 773.5 [M+H]+. Intermediate 538: Ethyl 2-((3S,6S)-6-(4-ethyl-5-(3-(3-methoxyazetidin-1-yl)propyl)-2- oxopyrimidin-1(2H)-yl)-14,24-difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0388] Prepared in an analogous manner to Intermediate 262 using Intermediate 537 (91 mg, 0.10 mmol) and 10% palladium on carbon (31 mg) in ethanol (10 mL) under a hydrogen atmosphere at RT for 10 h. Followed by manganese dioxide (0.30 g, 3.40 mmol) in DCM (25 mL) at RT for 26 h, to provide the title compound (91 mg). LCMS (Method 27): 1.92 min, 775.4 [M+H]+. Intermediate 539: tert-Butyl 3-(2-methoxy-4-methylpyrimidin-5-yl)azetidine-1-carboxylate

[0389] Prepared in an analogous manner to Intermediate 520 using nickel(II) chloride ethylene glycol dimethyl ether complex (6.5 mg, 30 µmol) and 4,4'-di-tertbutyl-2,2'-bipyridine (16 mg, 59 µmol) in degassed diethylene glycol diethyl ether (15 mL) sonicated at RT for 15 min, then 5-bromo-2-methoxy-4-methylpyrimidine (0.60 g, 2.96 mmol, CAS 38696-23-0), tert- butyl 3-bromoazetidine-1-carboxylate (1.74 g, 7.39 mmol, CAS 1064194-10-0), Na2CO3 (0.63 g, 5.91 mmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (33 mg, 30 µmol) and tris(trimethylsilyl)silane (0.91 mL, 2.96 mmol) irradiated at 405 nm / 18 W under nitrogen for 18 h (run in 2 batches (2 x 0.30 g of CAS 38696-23-0) concurrently and combined for work up. Purified by flash chromatography (40 g silica gel, eluting 0-60% EtOAc in petroleum ether) to provide the title compound (0.85 g). LCMS (Method 15): 1.68 min, 280.1 [M+H]+. Intermediate 540: 5-(Azetidin-3-yl)-2-methoxy-4-methylpyrimidine TFA salt

[0390] A solution of Intermediate 539 (0.65 g, 2.20 mmol) in TFA (8.3 mL) and DCM (13 mL) was stirred at RT for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (0.39 g). LCMS (Method 15): 0.99 min, 180.1 [M+H]+. Intermediate 541: 2-Methoxy-4-methyl-5-(1-methylazetidin-3-yl)pyrimidine

[0391] Prepared in an analogous manner to Intermediate 507 using Intermediate 540 (0.39 g, 2.20 mmol) and formaldehyde (0.49 mL, 6.60 mmol) in THF (25 mL) at RT for 18 h, followed by STAB (0.93 g, 4.40 mmol) at RT for 18 h. Purified by catch and release chromatography (10 g SCX, eluting MeOH followed by 1 M ammonia in MeOH) to provide the title compound (0.27 g). LCMS (Method 15): 1.14 min, 194.1 [M+H]+. Intermediate 542: 4-Methyl-5-(1-methylazetidin-3-yl)pyrimidin-2(1H)-one

[0392] Prepared in an analogous manner to Intermediate 528 using sodium iodide (0.83 g, 5.51 mmol) chlorotrimethylsilane (1.40 mL, 11.0 mmol) in MeCN (12 mL) and Intermediate 541 (0.22 g, 1.10 mmol) in MeCN (1.2 mL) at RT for 20 h. Purified by catch and release chromatography (5 g SCX, eluting MeOH followed by 3.5 M ammonia in MeOH) to provide the title compound (0.17 g). LCMS (Method 30): 0.22 min, 180.1 [M+H]+. Intermediate 543: Ethyl (S)-3-(4,4'-difluoro-2'-(hex-5-en-1-yl)-6'-methyl-5-(trifluoromethyl)- biphenyl]-3-yl)-3-((S)-2-(4-methyl-5-(1-methylazetidin-3-yl)-2-oxopyrimidin-1(2H)- 4-enamido)propanoate

[0393] Prepared in an analogous manner to Intermediate 70 using Intermediate 41 (0.52 g, 0.34 mmol), Intermediate 542 (0.19 g, 1.04 mmol) and K2CO3 (0.33 g, 2.42 mmol) in MeCN (32 mL) at reflux for 16 h. Purified by flash chromatography (40 g silica gel, 0-3% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.28 mg). LCMS (Method 15): 2.60 min, 729.4 [M+H]+. Intermediate 544: Ethyl 2-((3S,6S)-14,24-difluoro-16-methyl-6-(4-methyl-5-(1-methylazetidin- 3-yl)-2-oxopyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphan-8-en-3-yl)acetate

[0394] Prepared in an analogous manner to Intermediate 71 using Intermediate 543 (0.28 g, 0.39 mmol) and Grubbs II (33 mg, 39 µmol) in DCE (0.25 L) at 50 °C for 1.5 h. Purified by flash chromatography (12 g silica gel, 0-10% (0.5% ammonia MeOH) in DCM) to provide the title compound (0.21 g). LCMS (Method 15): 2.47 min, 701.4 [M+H]+. Intermediate 545: Ethyl 2-((3S,6S)-14,24-difluoro-16-methyl-6-(4-methyl-5-(1-methylazetidin- 3-yl)-2-oxopyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetate

[0395] Prepared in an analogous manner to Intermediate 262 using Intermediate 544 (0.21 g, 0.29 mmol) and 10% palladium on carbon (31 mg) in ethanol (21 mL) under a hydrogen atmosphere at RT for 12 h. Followed by manganese dioxide (0.25 g, 2.93 mmol) in DCM (21 mL) at RT for 48 h, to provide the title compound (0.19 g). LCMS (Method 30): 1.61 min, 703.3 [M+H]+.Synthesis of Examples Example 1: 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)- 14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid

[0396] Intermediate 72 (0.11 g, 0.17 mmol) was dissolved in THF (4.5 mL), MeOH (2 mL) and water (0.9 mL) then lithium hydroxide (12 mg, 0.51 mmol) was added and stirred at RT for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (29 mg).1H NMR (400 MHz, CD3OD) δ: 8.04 (s, 1H), 7.09 (dd, 1H), 6.91 – 6.79 (m, 3H), 5.91 (dd, 1H), 5.29 (dd, 1H), 3.14 – 2.72 (m, 4H), 2.70 – 2.57 (m, 7H), 2.54 – 2.41 (m, 4H), 2.40 – 2.30 (m, 5H), 2.24 – 2.12 (m, 1H), 1.99 (s, 3H), 1.73 – 0.99 (m, 11H). LCMS (Method 11): 1.51 min, 623.5 [M+H]+. Example 2: 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-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

[0397] Prepared in an analogous manner to Example 1 using Intermediate 75 (0.11 g, 0.17 mmol) and lithium hydroxide (12 mg, 0.51 mmol) in THF (4.5 mL), MeOH (2 mL) and water (0.9 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 30-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (29 mg).1H NMR (400 MHz, CD3OD) δ: 8.02 (s, 1H), 7.58 (dd, 1H), 7.34 (dd, 1H), 6.97 – 6.85 (m,2H), 5.95 (dd, 1H), 5.30 (dd, 1H), 3.19 – 2.75 (m, 4H), 2.75 – 2.58 (m, 7H), 2.58 – 2.37 (m, 5H), 2.31 – 2.14 (m, 2H), 2.00 (s, 3H), 1.70 – 1.45 (m, 2H), 1.44 – 0.91 (m, 9H). LCMS (Method 15): 1.69 min, 677.3 [M+H]+. Example 3: 2-((3S,6S)-6-(5-(3-(Dimethylamino)propyl)-4-methyl-2-oxopyrimidin-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

[0398] Prepared in an analogous manner to Example 1 using Intermediate 177 (0.11 g, 0.14 mmol) and lithium hydroxide (16 mg, 0.67 mmol) in THF (3 mL), MeOH (1.5 mL) and water (1.5 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (31 mg).1H NMR (400 MHz, CD3OD) δ: 8.00 (s, 1H), 7.59 (dd, 1H), 7.33 (dd, 1H), 6.98 – 6.85 (m, 2H), 5.98 (dd, 1H), 5.27 (dd, 1H), 2.94 – 2.73 (m, 2H), 2.71 – 2.36 (m, 13H), 2.36 – 2.25 (m, 1H), 2.23 – 2.10 (m, 1H), 2.00 (s, 3H), 1.99 – 1.83 (m, 2H), 1.71 – 1.57 (m, 1H), 1.55 – 0.86 (m, 11H). LCMS (Method 15): 1.68 min, 691.3 [M+H]+. Example 4: 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyrimidin-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

[0399] Prepared in an analogous manner to Example 1 using Intermediate 262 (50 mg, 72 µmol) and lithium hydroxide (6.9 mg, 0.29 mmol) in THF (1 mL), MeOH (1 mL) and water (1mL) at RT for 1.5 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (11 mg).1H NMR (400 MHz, CD3OD) δ: 8.56 (d, 1H), 8.20 (d, 1H), 7.62 (dd, 1H), 7.32 (dd, 1H), 6.97 – 6.84 (m, 2H), 5.90 (dd, 1H), 5.34 (dd, 1H), 3.03 – 2.70 (m, 4H), 2.69 (dd, 1H), 2.57 (dd, 1H), 2.48 (s, 6H), 2.48 – 2.37 (m, 1H), 2.37 – 2.26 (m, 1H), 2.25 – 2.12 (m, 1H), 2.01 (s, 3H), 1.74 – 1.59 (m, 1H), 1.57 – 0.83 (m, 10H). LCMS (Method 15): 1.58 min, 663.3 [M+H]+. Example 5: 2-((3S,6S)-6-(5-(2-(Diethylamino)ethyl)-4-methyl-2-oxopyrimidin-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

[0400] Prepared in an analogous manner to Example 1 using Intermediate 267 (58 mg, 79 µmol) and lithium hydroxide (5.7 mg, 0.24 mmol) in THF (1 mL), MeOH (0.5 mL) and water (0.5 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (44 mg).1H NMR (400 MHz, CD3OD) δ: 8.01 (s, 1H), 7.56 (dd, 1H), 7.34 (dd, 1H), 6.97 – 6.83 (m, 2H), 5.96 (dd, 1H), 5.28 (dd, 1H), 3.37 – 3.05 (m, 6H), 2.98 – 2.77 (m, 2H), 2.63 (dd, 1H), 2.55 – 2.35 (m, 5H), 2.30 – 2.12 (m, 2H), 1.99 (s, 3H), 1.73 – 1.58 (m, 1H), 1.57 – 0.86 (m, 16H). LCMS (Method 15): 1.66 min, 705.3 [M+H]+. Example 6: 2-((3S,6S)-14,24-difluoro-16-methyl-6-(4-methyl-2-oxo-5-(2-(pyrrolidin-1- yl)ethyl)pyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0401] Prepared in an analogous manner to Example 1 using Intermediate 272 (0.15 g, 0.21 mmol) and lithium hydroxide (20 mg, 0.82 mmol) in THF (2 mL), MeOH (1 mL) and water (1 mL) at RT for 4 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (44 mg).1H NMR (400 MHz, CD3OD) δ: 8.02 (s, 1H), 7.55 (dd, 1H), 7.33 (dd, 1H), 6.97 – 6.84 (m, 2H), 5.92 (dd, 1H), 5.32 (dd, 1H), 3.37 – 3.05 (m, 6H), 3.03 – 2.73 (m, 2H), 2.60 (dd, 1H), 2.53 – 2.33 (m, 5H), 2.31 – 2.12 (m, 2H), 2.12 – 2.00 (m, 4H), 1.98 (s, 3H), 1.69 – 1.45 (m, 2H), 1.43 – 0.96 (m, 9H). LCMS (Method 15): 1.79 min, 703.3 [M+H]+. Example 7: 2-((3S,6S)-6-(5-(2-(Ethyl(methyl)amino)ethyl)-4-methyl-2-oxopyrimidin-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

[0402] Prepared in an analogous manner to Example 1 using Intermediate 277 (0.16 g, 0.22 mmol) and lithium hydroxide (21 mg, 0.89 mmol) in THF (2 mL), MeOH (1 mL) and water (1 mL) at RT for 4 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (44 mg).1H NMR (400 MHz, CD3OD) δ: 8.01 (s, 1H), 7.57 (dd, 1H), 7.32 (dd, 1H), 6.99 – 6.79 (m, 2H), 5.93 (dd, 1H), 5.28 (dd, 1H), 3.17 – 2.72 (m, 6H), 2.71 – 2.55 (m, 4H), 2.55 – 2.35 (m, 5H), 2.32 – 2.11 (m, 2H), 1.99 (s, 3H), 1.73 – 1.56 (m, 1H), 1.56 – 0.87 (m, 13H). LCMS (Method 15): 1.68 min, 691.3 [M+H]+.Example 8: 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0403] Prepared in an analogous manner to Example 1 using Intermediate 281 (92 mg, 0.11 mmol) and lithium hydroxide (13 mg, 0.55 mmol) in THF (2.5 mL), MeOH (1.2 mL) and water (1.2 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 30-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (41 mg).1H NMR (400 MHz, CD3OD) δ: 7.95 (s, 1H), 7.59 (dd, 1H), 7.34 (dd, 1H), 6.99 – 6.84 (m, 2H), 5.97 (dd, 1H), 5.33 (dd, 1H), 4.33 – 4.05 (m, 3H), 3.86 – 3.53 (m, 2H), 3.36 (s, 3H), 3.35 – 3.07 (m, 2H), 3.02 – 2.77 (m, 1H), 2.72 – 2.57 (m, 2H), 2.55 – 2.36 (m, 5H), 2.30 – 2.12 (m, 2H), 2.00 (s, 3H), 1.72 – 0.83 (m, 11H). LCMS (Method 15): 1.66 min, 719.3 [M+H]+. Example 9: 2-((3S,6S)-14,24-Difluoro-16-methyl-6-(4-methyl-2-oxo-5-(3-(pyrrolidin-1- yl)propyl)pyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0404] Prepared in an analogous manner to Example 1 using Intermediate 289 (0.17 g, 0.23 mmol) and lithium hydroxide (17 mg, 0.69 mmol) in THF (6.4 mL), MeOH (2.9 mL) and water (1.2 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 40-50% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound(56 mg).1H NMR (400 MHz, CD3OD) δ: 8.00 (s, 1H), 7.58 (dd, 1H), 7.34 (dd, 1H), 6.98 – 6.84 (m, 2H), 6.00 (dd, 1H), 5.27 (dd, 1H), 3.38 – 2.74 (m, 6H), 2.68 – 2.36 (m, 7H), 2.36 – 2.23 (m, 1H), 2.22 – 2.11 (m, 1H), 2.11 – 1.84 (m, 8H), 1.73 – 1.56 (m, 1H), 1.55 – 0.66 (m, 12H). LCMS (Method 15): 1.93 min, 717.3 [M+H]+. Example 10: 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-4-ethyl-2-oxopyrimidin-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

[0405] Prepared in an analogous manner to Example 1 using Intermediate 294 (0.23 g, 0.33 mmol) and lithium hydroxide (23 mg, 0.98 mmol) in THF (9 mL), MeOH (4 mL) and water (1.7 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (56 mg).1H NMR (400 MHz, CD3OD) δ: 8.05 (s, 1H), 7.63 (dd, 1H), 7.34 (dd, 1H), 6.97 – 6.84 (m, 2H), 5.97 (dd, 1H), 5.32 (dd, 1H), 3.20 – 2.97 (m, 2H), 2.97 – 2.50 (m, 12H), 2.50 – 2.37 (m, 1H), 2.33 – 2.13 (m, 2H), 2.00 (s, 3H), 1.78 – 0.82 (m, 14H). LCMS (Method 15): 1.72 min, 691.3 [M+H]+. Example 11: 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-4-hydroxy-2-oxopyrimidin-1(2H)-yl)- 14,24-difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid

[0406] Prepared in an analogous manner to Example 1 using Intermediate 300 (58 mg, 22 µmol) and lithium hydroxide (1.6 mg, 67 µmol) in THF (3 mL), MeOH (0.5 mL) and water (1 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 37- 42% MeCN in water with 0.1% ammonia over 18 min) to provide the title compound (3.3 mg).1H NMR (400 MHz, CD3OD) δ: 7.56 (s, 1H), 7.18 – 6.98 (m, 1H), 6.97 – 6.72 (m, 3H), 5.90 (dd, 1H), 5.10 (dd, 1H), 3.50 – 3.18 (m, 2H), 3.06 – 2.51 (m, 8H), 2.49 (dd, 1H), 2.44 – 2.11 (m, 6H), 1.97 (s, 3H), 1.62 – 0.77 (m, 12H). LCMS (Method 15): 1.72 min, 625.4 [M+H]+. Example 12: 2-((3S,6S)-6-(5-(3-(Azetidin-1-yl)propyl)-4-methyl-2-oxopyrimidin-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

[0407] Prepared in an analogous manner to Example 1 using Intermediate 305 (0.11 g, 0.15 mmol) and lithium hydroxide (11 mg, 0.46 mmol) in THF (4.3 mL), MeOH (1.9 mL) and water (0.8 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 30-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (30 mg).1H NMR (400 MHz, CD3OD) δ: 7.99 (s, 1H), 7.59 (dd, 1H), 7.33 (dd, 1H), 6.97 – 6.84 (m, 2H), 5.99 (dd, 1H), 5.27 (dd, 1H), 4.05 – 3.52 (m, 4H), 3.08 – 2.70 (m, 2H), 2.65 (dd, 1H), 2.60 – 2.50 (m, 3H), 2.49 – 2.22 (m, 6H), 2.21 – 2.08 (m, 1H), 2.00 (s, 3H), 1.90 – 1.56 (m, 3H), 1.55 – 0.84 (m, 11H). LCMS (Method 15): 1.72 min, 703.3 [M+H]+. Example 13: 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0408] Prepared in an analogous manner to Example 1 using Intermediate 308 (0.17 g, 0.15 mmol) and lithium hydroxide (18 mg, 0.75 mmol) in THF (3.4 mL), MeOH (1.7 mL) and water (1.7 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 30-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (44 mg).1H NMR (400 MHz, CD3OD) δ: 7.99 (s, 1H), 7.10 (dd, 1H), 6.98 – 6.77 (m, 3H), 5.91 (dd, 1H), 5.31 (dd, 1H), 4.26 – 3.85 (m, 3H), 3.70 – 3.42 (m, 2H), 3.35 (s, 3H), 3.29 – 3.00 (m, 2H), 2.98 – 2.72 (m, 1H), 2.69 – 2.56 (m, 2H), 2.47 (dd, 1H), 2.42 (s, 3H), 2.41 – 2.27 (m, 5H), 2.26 – 2.12 (m, 1H), 1.99 (s, 3H), 1.70 – 1.47 (m, 2H), 1.47 – 0.82 (m, 9H). LCMS (Method 15): 1.50 min, 665.4 [M+H]+. Example 14: 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyrimidin- 1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0409] Prepared in an analogous manner to Example 1 using Intermediate 327 (0.14 g, 95 µmol) and lithium hydroxide (5 mg, 0.21 mmol) in THF (2 mL), MeOH (2 mL) and water (1 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 30-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (28 mg).1H NMR (400 MHz, CD3OD) δ: 8.55 (d, 1H), 8.13 (d, 1H), 7.60 (d, 1H), 7.34 (dd, 1H), 6.99 – 6.81 (m, 2H), 5.93 (dd, 1H), 5.29 (dd, 1H), 4.38 – 3.81 (m, 3H), 3.70 – 3.36 (m, 2H), 3.32 (s, 3H), 3.24 – 2.98 (m, 2H), 2.86 – 2.50 (m, 4H), 2.50 – 2.37 (m, 1H), 2.33 – 2.13 (m, 2H), 1.99 (s, 3H), 1.78 – 1.58 (m, 1H), 1.58 – 0.82 (m, 10H). LCMS (Method 15): 1.59 min, 705.3 [M+H]+.Example 15: 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)-24- fluoro-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0410] Prepared in an analogous manner to Example 1 using Intermediate 330 (59 mg, 85 µmol) and lithium hydroxide (6.1 mg, 0.25 mmol) in THF (2.4 mL), MeOH (1.1 mL) and water (0.5 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (17 mg).1H NMR (400 MHz, CD3OD) δ: 8.01 (s, 1H), 7.56 (dd, 1H), 7.29 (dd, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 5.95 (dd, 1H), 5.29 (dd, 1H), 3.25 – 2.95 (m, 2H), 2.95 – 2.75 (m, 2H), 2.69 (s, 6H), 2.64 (dd, 1H), 2.47 (dd, 1H), 2.44 (s, 3H), 2.44 – 2.34 (m, 1H), 2.33 (s, 3H), 2.27 – 2.11 (m, 2H), 1.94 (s, 3H), 1.72 – 0.77 (m, 11H). LCMS (Method 15): 1.72 min, 673.3 [M+H]+. Example 16: 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-fluoro-3-methylazetidin-1-yl)ethyl)-4-methyl- 2-oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0411] Prepared in an analogous manner to Example 1 using Intermediate 344 (0.24 g, 0.34 mmol) and lithium hydroxide (24 mg, 1.02 mmol) in THF (9.6 mL), MeOH (4.3 mL) and water (1.8 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 30-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (40 mg).1H NMR (400 MHz, CD3OD) δ: 8.02 (s, 1H), 7.10 (dd, 1H), 6.96 – 6.75 (m, 3H), 5.88 (dd, 1H), 5.30 (dd, 1H), 3.91 – 3.44 (m, 4H), 3.14 – 2.82 (m, 2H), 2.80 – 2.46 (m, 4H), 2.41 (s,3H), 2.40 – 2.28 (m, 5H), 2.24 – 2.09 (m, 1H), 1.99 (s, 3H), 1.63 (d, 3H), 1.63 – 0.85 (m, 11H). LCMS (Method 15): 1.63 min, 667.3 [M+H]+. Example 17: 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxopyrimidin-1(2H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid

[0412] Prepared in an analogous manner to Example 1 using Intermediate 347 (67 mg, 42 µmol) and lithium hydroxide (10 mg, 0.42 mmol) in THF (1 mL), MeOH (1 mL) and water (1 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 30- 35% MeCN in water with 0.1% ammonia over 22 min) to provide the title compound (10 mg).1H NMR (400 MHz, CD3OD) δ: 8.59 (d, 1H), 8.16 (d, 1H), 7.07 (dd, 1H), 6.99 – 6.73 (m, 3H), 5.89 (dd, 1H), 5.30 (dd, 1H), 3.40 – 3.05 (m, 2H), 2.96 – 2.50 (m, 9H), 2.50 – 2.13 (m, 7H), 1.97 (s, 3H), 1.74 – 0.80 (m, 11H). LCMS (Method 15): 1.68 min, 609.3 [M+H]+. Example 18: 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0413] Prepared in an analogous manner to Example 1 using Intermediate 350 (0.10 g, 0.14 mmol) and lithium hydroxide (10 mg, 0.43 mmol) in THF (2 mL), MeOH (1 mL) and water (1 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (51mg).1H NMR (400 MHz, CD3OD) δ: 7.95 (s, 1H), 7.57 (dd, 1H), 7.34 (dd, 1H), 6.97 – 6.84 (m, 2H), 5.96 (dd, 1H), 5.43 – 5.10 (m, 2H), 4.39 – 4.13 (m, 2H), 4.09 – 3.75 (m, 2H), 3.38 – 3.13 (m, 2H), 2.85 (dt, 1H), 2.74 – 2.57 (m, 2H), 2.50 (dd, 1H), 2.47 – 2.37 (m, 4H), 2.29 – 2.11 (m, 2H), 1.99 (s, 3H), 1.71 – 0.84 (m, 11H). LCMS (Method 21): 1.77 min, 707.3 [M+H]+. Example 19: 2-((3S,6S)-6-(5-(2-(Azetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-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

[0414] Prepared in an analogous manner to Example 1 using Intermediate 359 (35 mg, 50 µmol) and lithium hydroxide (3.6 mg, 0.15 mmol) in THF (1 mL), MeOH (0.5 mL) and water (0.5 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (17 mg).1H NMR (400 MHz, CD3OD) δ: 7.94 (s, 1H), 7.58 (dd, 1H), 7.33 (dd, 1H), 7.00 – 6.82 (m, 2H), 5.97 (dd, 1H), 5.32 (dd, 1H), 4.35 – 3.61 (m, 4H), 3.47 – 3.05 (m, 2H), 2.93 – 2.74 (m, 1H), 2.73 – 2.56 (m, 2H), 2.56 – 2.30 (m, 7H), 2.29 – 2.12 (m, 2H), 1.99 (s, 3H), 1.74 – 0.80 (m, 11H). LCMS (Method 21): 1.94 min, 689.3 [M+H]+. Example 20: 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-fluoro-3-methylazetidin-1-yl)ethyl)-4-methyl- 2-oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0415] Prepared in an analogous manner to Example 1 using Intermediate 362 (0.24 g, 0.26 mmol) and lithium hydroxide (19 mg, 0.77 mmol) in THF (4 mL), MeOH (2 mL) and water (1 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 30-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (68 mg).1H NMR (400 MHz, CD3OD) δ: 7.99 (s, 1H), 7.59 (dd, 1H), 7.32 (dd, 1H), 6.98 – 6.84 (m, 2H), 5.92 (dd, 1H), 5.31 (dd, 1H), 4.04 – 3.54 (m, 4H), 3.31 – 3.00 (m, 2H), 2.98 – 2.35 (m, 8H), 2.32 – 2.12 (m, 2H), 1.99 (s, 3H), 1.64 (d, 3H), 1.62 – 0.90 (m, 11H). LCMS (Method 11): 1.63 min, 721.4 [M+H]+. Example 21: 2-((3S,6S)-14-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-24-fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0416] Prepared in an analogous manner to Example 1 using Intermediate 341 (78 mg, 0.12 mmol) and lithium hydroxide (8.3 mg, 0.35 mmol) in THF (3.3 mL), MeOH (1.3 mL) and water (0.7 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (16 mg).1H NMR (400 MHz, CD3OD) δ: 8.05 (s, 1H), 7.09 (dd, 1H), 6.94 – 6.67 (m, 3H), 5.88 (dd, 1H), 5.28 (dd, 1H), 3.00 – 2.65 (m, 4H), 2.62 (dd, 1H), 2.52 (s, 6H), 2.52 – 2.43 (m, 1H), 2.42 (s, 3H), 2.42 – 2.23 (m, 5H), 2.21 – 2.06 (m, 1H), 1.94 (s, 3H), 1.92 – 1.81 (m, 1H), 1.72 – 0.99 (m, 11H), 0.98 – 0.85 (m, 2H), 0.76 – 0.60 (m, 2H). LCMS (Method 11): 1.59 min, 645.5 [M+H]+. Example 22: 2-((3S,6S)-6-(5-(2-(3,3-Difluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- 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

[0417] Prepared in an analogous manner to Example 1 using Intermediate 367 (0.27 g, 0.36 mmol) and lithium hydroxide (26 mg, 1.09 mmol) in THF (10 mL), MeOH (4.5 mL) and water (2 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (54 mg).1H NMR (400 MHz, CD3OD) δ: 8.05 (s, 1H), 7.62 (dd, 1H), 7.32 (dd, 1H), 6.98 – 6.80 (m, 2H), 5.88 (t, 1H), 5.29 (dd, 1H), 3.95 – 3.53 (m, 4H), 3.05 – 2.77 (m, 2H), 2.73 (dd, 1H), 2.66 (dd, 1H), 2.59 (t, 2H), 2.51 – 2.27 (m, 5H), 2.21 – 2.08 (m, 1H), 2.00 (s, 3H), 1.73 – 1.55 (m, 1H), 1.54 – 0.82 (m, 10H). LCMS (Method 11): 1.56 min, 725.4 [M+H]+. Example 23: 2-((3S,6S)-6-(5-(2-(3-Ethoxyazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-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

[0418] Prepared in an analogous manner to Example 1 using Intermediate 368 (32 mg, 43 µmol) and lithium hydroxide (3.1 mg, 0.13 mmol) in THF (1 mL), MeOH (0.5 mL) and water (0.5 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (7 mg).1H NMR (400 MHz, CD3OD) δ: 7.98 (s, 1H), 7.60 (dd, 1H), 7.33 (dd, 1H), 7.05 – 6.80 (m, 2H), 5.94 (dd, 1H), 5.32 (dd, 1H), 4.36 – 4.21 (m, 1H), 4.20 – 3.89 (m, 2H), 3.52 (q, 2H), 3.52 – 3.23 (m, 2H), 3.21 – 2.97 (m, 2H), 2.88 – 2.43 (m, 5H), 2.42 (s, 3H), 2.33 – 2.14 (m, 2H), 2.01 (s, 3H), 1.75 – 0.82 (m, 14H). LCMS (Method 15): 1.65 min, 733.3 [M+H]+.Example 24: 2-((3S,6S)-14,24-Difluoro-16-methyl-6-(4-methyl-2-oxo-5-(2-(3- (trifluoromethoxy)azetidin-1-yl)ethyl)pyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid

[0419] Prepared in an analogous manner to Example 1 using Intermediate 369 (31 mg, 39 µmol) and lithium hydroxide (2.8 mg, 0.12 mmol) in THF (1 mL), MeOH (0.5 mL) and water (0.5 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (9 mg).1H NMR (400 MHz, CD3OD) δ: 8.03 (s, 1H), 7.61 (dd, 1H), 7.32 (dd, 1H), 6.98 – 6.80 (m, 2H), 5.89 (dd, 1H), 5.29 (dd, 1H), 5.04 – 4.89 (m, 1H), 4.06 – 3.75 (m, 2H), 3.64 – 3.32 (m, 2H), 3.02 – 2.77 (m, 2H), 2.75 – 2.51 (m, 4H), 2.50 – 2.25 (m, 5H), 2.22 – 2.10 (m, 1H), 2.00 (s, 3H), 1.71 – 0.84 (m, 11H). LCMS (Method 15): 1.75 min, 773.3 [M+H]+. Example 25: 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-isopropoxyazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0420] Prepared in an analogous manner to Example 1 using Intermediate 370 (22 mg, 29 µmol) and lithium hydroxide (2.1 mg, 87 µmol) in THF (1 mL), MeOH (0.5 mL) and water (0.5 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35- 45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (5 mg).1H NMR (400 MHz, CD3OD) δ: 7.98 (s, 1H), 7.59 (dd, 1H), 7.32 (dd, 1H), 6.99 – 6.80 (m, 2H),5.92 (dd, 1H), 5.31 (dd, 1H), 4.46 – 4.24 (m, 1H), 4.21 – 3.84 (m, 2H), 3.77 – 3.62 (m, 1H), 3.55 – 2.92 (m, 4H), 2.83 – 2.42 (m, 5H), 2.42 (s, 3H), 2.35 – 2.11 (m, 2H), 2.00 (s, 3H), 1.73 – 0.82 (m, 17H). LCMS (Method 15): 1.70 min, 747.3 [M+H]+. Example 26: 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0421] Prepared in an analogous manner to Example 1 using Intermediate 371 (10 mg, 15 µmol) and lithium hydroxide (1.1 mg, 45 µmol) in THF (1 mL), MeOH (0.5 mL) and water (0.5 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35- 45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (2.1 mg).1H NMR (400 MHz, CD3OD) δ: 8.03 (s, 1H), 7.11 (dd, 1H), 6.96 – 6.73 (m, 3H), 5.87 (dd, 1H), 5.29 (dd, 1H), 5.29 – 4.90 (m, 1H), 4.03 – 3.77 (m, 2H), 3.62 – 3.37 (m, 2H), 3.03 – 2.76 (m, 2H), 2.72 – 2.48 (m, 4H), 2.41 (s, 3H), 2.41 – 2.33 (m, 1H), 2.33 (s, 3H), 2.21 – 2.08 (m, 1H), 1.99 (s, 3H), 1.75 – 0.78 (m, 12H). LCMS (Method 15): 1.54 min, 653.3 [M+H]+. Example 27: 2-((3S,6S)-14,24-Difluoro-6-(5-(3-(3-methoxyazetidin-1-yl)propyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0422] Prepared in an analogous manner to Example 1 using Intermediate 376 (0.21 g, 0.28 mmol) and lithium hydroxide (26 mg, 1.10 mmol) in THF (1.5 mL), MeOH (1.5 mL) and water (1 mL) at RT for 2 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 30-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (82 mg).1H NMR (400 MHz, CD3OD) δ: 7.96 (s, 1H), 7.56 (dd, 1H), 7.34 (dd, 1H), 6.98 – 6.82 (m, 2H), 6.04 (dd, 1H), 5.23 (dd, 1H), 4.35 – 4.07 (m, 3H), 3.94 – 3.62 (m, 2H), 3.33 (s, 3H), 3.15 – 2.88 (m, 2H), 2.68 – 2.34 (m, 8H), 2.33 – 2.09 (m, 2H), 1.99 (s, 3H), 1.99 – 1.85 (m, 1H), 1.84 – 1.68 (m, 1H), 1.67 – 1.55 (m, 1H), 1.54 – 0.82 (m, 10H). LCMS (Method 15): 1.66 min, 733.3 [M+H]+. Example 28: 2-((3S,6S)-24-Fluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0423] Prepared in an analogous manner to Example 1 using Intermediate 379 (98 mg, 0.12 mmol) and lithium hydroxide (4 mg, 0.17 mmol) in THF (1 mL), MeOH (1 mL) and water (0.5 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (34 mg).1H NMR (400 MHz, CD3OD) δ: 7.95 (s, 1H), 7.57 (dd, 1H), 7.29 (dd, 1H), 7.02 – 6.91 (m, 2H), 5.96 (dd, 1H), 5.31 (dd, 1H), 4.36 – 3.96 (m, 3H), 3.85 – 3.54 (m, 2H), 3.35 (s, 3H), 3.31 – 2.97 (m, 2H), 2.95 – 2.77 (m, 1H), 2.74 – 2.56 (m, 2H), 2.49 (dd, 1H), 2.42 (s, 3H), 2.42 – 2.33 (m, 1H), 2.33 (s, 3H), 2.29 – 2.07 (m, 2H), 1.94 (s, 3H), 1.70 – 0.86 (m, 11H). LCMS (Method 15): 1.68 min, 715.4 [M+H]+. Example 29: 2-((3S,6S)-6-(5-(2-(3,3-Dimethylazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- 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

[0424] Prepared in an analogous manner to Example 1 using Intermediate 384 (74 mg, 64 µmol) and lithium hydroxide (7.6 mg, 0.32 mmol) in THF (1.4 mL), MeOH (0.7 mL) and water (0.7 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 40-50% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (18 mg).1H NMR (400 MHz, CD3OD) δ: 7.98 (s, 1H), 7.60 (dd, 1H), 7.31 (dd, 1H), 6.96 – 6.82 (m, 2H), 5.91 (dd, 1H), 5.31 (dd, 1H), 3.55 – 2.83 (m, 6H), 2.80 – 2.36 (m, 8H), 2.34 – 2.11 (m, 2H), 2.00 (s, 3H), 1.70 – 0.81 (m, 17H). LCMS (Method 15): 1.89 min, 717.3 [M+H]+. Example 30: 2-((3S,6S)-6-(5-(2-(3-(Difluoromethoxy)azetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-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

[0425] Prepared in an analogous manner to Example 1 using Intermediate 385 (27 mg, 35 µmol) and lithium hydroxide (2.5 mg, 0.11 mmol) in THF (1 mL), MeOH (0.5 mL) and water (0.5 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 40-50% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (14 mg).1H NMR (400 MHz, CD3OD) δ: 8.00 (s, 1H), 7.60 (dd, 1H), 7.32 (dd, 1H), 6.97 – 6.82 (m, 2H), 6.46 (t, 1H), 5.92 (dd, 1H), 5.30 (dd, 1H), 4.12 – 3.80 (m, 2H), 3.69 – 3.15 (m, 3H), 3.09 – 2.80 (m, 2H), 2.77 – 2.51 (m, 4H), 2.49 – 2.41 (m, 1H), 2.41 (s, 3H), 2.36 – 2.24 (m, 1H), 2.23 – 2.10 (m, 1H), 2.00 (s, 3H), 1.72 – 0.78 (m, 11H). LCMS (Method 15): 1.87 min, 755.3 [M+H]+.Example 31: 2-((3S,6S)-6-(5-(2-(5-Azaspiro[2.3]hexan-5-yl)ethyl)-4-methyl-2-oxopyrimidin- 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

[0426] Prepared in an analogous manner to Example 1 using Intermediate 390 (72 mg, 78 µmol) and lithium hydroxide (9.3 mg, 0.39 mmol) in THF (1.8 mL), MeOH (0.9 mL) and water (0.9 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (19 mg).1H NMR (400 MHz, CD3OD) δ: 8.01 (s, 1H), 7.61 (dd, 1H), 7.31 (dd, 1H), 6.98 – 6.79 (m, 2H), 5.90 (dd, 1H), 5.31 (dd, 1H), 3.97 – 3.40 (m, 4H), 3.16 – 2.80 (m, 2H), 2.78 – 2.51 (m, 4H), 2.50 – 2.11 (m, 6H), 2.00 (s, 3H), 1.73 – 0.83 (m, 11H), 0.67 (s, 4H). LCMS (Method 15): 1.89 min, 715.4 [M+H]+. Example 32: 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-methoxy-3-methylazetidin-1-yl)ethyl)-4- methyl-2-oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0427] Prepared in an analogous manner to Example 1 using Intermediate 396 (58 mg, 84 µmol) and lithium hydroxide (6 mg, 0.25 mmol) in THF (1 mL), MeOH (0.5 mL) and water (0.5 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35- 45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (6 mg).1H NMR (400 MHz, CD3OD) δ: 8.00 (s, 1H), 7.10 (dd, 1H), 6.96 – 6.73 (m, 3H), 5.88 (dd, 1H), 5.30 (dd, 1H), 3.97 – 3.39 (m, 4H), 3.27 (s, 3H), 3.18 – 2.87 (m, 2H), 2.83 – 2.68 (m, 1H), 2.67– 2.55 (m, 2H), 2.48 (dd, 1H), 2.42 (s, 3H), 2.39 – 2.33 (m, 1H), 2.33 (s, 3H), 2.26 – 2.11 (m, 1H), 1.98 (s, 3H), 1.74 – 0.77 (m, 15H). LCMS (Method 15): 1.67 min, 679.4 [M+H]+. Example 33: 2-((3S,6S)-14-Cyclopropyl-24-fluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4- methyl-2-oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0428] Prepared in an analogous manner to Example 1 using Intermediate 399 (66 mg, 92 µmol) and lithium hydroxide (6.6 mg, 0.28 mmol) in THF (3.4 mL), MeOH (0.6 mL) and water (1.1 mL) at RT for 30 min. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 18 min) to provide the title compound (19 mg).1H NMR (400 MHz, CD3OD) δ: 8.02 (s, 1H), 7.10 (dd, 1H), 6.95 – 6.69 (m, 3H), 5.87 (dd, 1H), 5.28 (dd, 1H), 4.21 – 4.04 (m, 1H), 4.01 – 3.65 (m, 2H), 3.31 (s, 3H), 3.31 – 3.16 (m, 2H), 3.03 – 2.74 (m, 2H), 2.72 – 2.45 (m, 4H), 2.44 – 2.22 (m, 8H), 2.21 – 2.07 (m, 1H), 1.94 (s, 3H), 1.92 – 1.82 (m, 1H), 1.71 – 0.83 (m, 13H), 0.76 – 0.60 (m, 2H). LCMS (Method 11): 1.72 min, 687.4 [M+H]+. Example 34: 2-((3S,6S)-6-(4-(Difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyrimidin- 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

[0429] Prepared in an analogous manner to Example 1 using Intermediate 407 (71 mg, 96 µmol) and lithium hydroxide (6.9 mg, 0.29 mmol) in THF (5 mL), MeOH (2.5 mL) and water (1mL) at RT for 1.5 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (25 mg).1H NMR (400 MHz, d6-DMSO) δ: 10.21 – 9.53 (br m, 1H), 8.32 (s, 1H), 7.70 (dd, 1H), 7.36 (dd, 1H), 7.10 – 6.96 (m, 2H), 6.80 (t, 1H), 5.60 (q, 1H), 5.17 (dd, 1H), 2.76 – 2.61 (m, 2H), 2.58 – 2.28 (m, 5H), 2.27 – 2.12 (m, 7H), 2.10 – 1.96 (m, 1H), 1.91 (s, 3H), 1.59 – 0.77 (m, 11H). LCMS (Method 15): 1.77 min, 713.3 [M+H]+. Example 35: 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-methoxy-3-methylazetidin-1-yl)ethyl)-4- methyl-2-oxopyrimidin-1(2H)-yl)-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0430] Prepared in an analogous manner to Example 1 using Intermediate 408 (43 mg, 58 µmol) and lithium hydroxide (4.1 mg, 0.17 mmol) in THF (1.6 mL), MeOH (0.7 mL) and water (0.3 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (6.5 mg).1H NMR (400 MHz, CD3OD) δ: 8.06 (s, 1H), 7.63 (dd, 1H), 7.30 (dd, 1H), 6.96 – 6.82 (m, 2H), 5.86 (t, 1H), 5.30 (dd, 1H), 3.41 – 3.10 (m, 9H), 2.90 – 2.51 (m, 5H), 2.49 – 2.28 (m, 4H), 2.21 – 2.06 (m, 1H), 2.00 (s, 3H), 1.73 – 0.83 (m, 14H). LCMS (Method 11): 1.54 min, 733.4 [M+H]+. Example 36: 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-4-methoxy-2-oxopyrimidin-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

[0431] Prepared in an analogous manner to Example 1 using Intermediate 505 (46 mg, 50 µmol) and lithium hydroxide (3.6 mg, 0.15 mmol) in THF (2.4 mL), MeOH (0.4 mL) and water (0.8 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (10 mg).1H NMR (400 MHz, CD3OD) δ: 7.91 (s, 1H), 7.61 (dd, 1H), 7.30 (dd, 1H), 6.97 – 6.81 (m, 2H), 5.88 (dd, 1H), 5.27 (dd, 1H), 3.99 (s, 3H), 3.00 – 2.23 (m, 14H), 2.21 – 2.07 (m, 1H), 2.00 (s, 3H), 1.69 – 0.79 (m, 11H). LCMS (Method 15): 1.77 min, 693.4 [M+H]+. Example 37: 2-((3S,6S)-6-(5-(3-(Dimethylamino)-2-methylpropyl)-4-methyl-2-oxopyrimidin- 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

[0432] Example 37 was prepared in an analogous manner to Example 1 using Intermediate 511 (0.10 g, 0.14 mmol) and lithium hydroxide (10 mg, 0.43 mmol) in THF (4.1 mL), MeOH (1.6 mL) and water (0.9 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (42 mg). LCMS (Method 15): 1.86 min, 705.3 [M+H]+.

[0433] Example 37 was then further purified by preparative SFC (Chiralpak®IE, 30 x 250 mm x 5 µm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 50% CO2 with 50% (0.1% ammonia in 1:1 MeCN / MeOH) modifier) to provide Example 37A (9.2 mg, Peak 1 – Diastereomer 1) and Example 37B (6.2 mg, Peak 2 - Diastereomer 2).

[0434] Example 37A:1H NMR (400 MHz, DMSO-d6) δ: 9.55 – 9.23 (br m, 1H), 7.86 (s, 1H), 7.77 (dd, 1H), 7.41 (dd, 1H), 7.09 – 6.95 (m, 2H), 5.71 (q, 1H), 5.19 (dd, 1H), 2.75 – 2.35 (m, 4H), 2.32 – 1.88 (m, 16H), 1.85 – 1.72 (m, 1H), 1.53 – 0.90 (m, 12H), 0.85 (d, 3H) – OH not observed; LCMS (Method 37): 4.56 min, 705.5 [M+H]+; Example 37B: DMSO-d6) δ: 9.48 – 9.23 (br m, 1H), 7.85 (s, 1H), 7.77 (dd, 1H), 7.42 (dd, 1H), 7.08 – 6.96 (m, 2H), 5.72 (q, 1H), 5.30 (dd, 1H), 2.79 – 2.37 (m, 4H), 2.32 – 1.88 (m, 16H), 1.86 – 1.72 (m, 1H), 1.55 – 0.89 (m, 12H), 0.80 (d, 3H) – OH not observed; LCMS (Method 37): 4.62 min, 705.5 [M+H]+.Example 38: 2-((3S,6S)-14,24-Difluoro-16-methyl-6-(4-methyl-2-oxo-5-(2-(3-(2,2,2- trifluoroethyl)azetidin-1-yl)ethyl)pyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid

[0435] Prepared in an analogous manner to Example 1 using Intermediate 512 (28 mg, 36 µmol) and lithium hydroxide (2.6 mg, 0.11 mmol) in THF (1.0 mL), MeOH (0.5 mL) and water (0.5 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 40-50% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (16 mg).1H NMR (400 MHz, CD3OD) δ: 7.95 (s, 1H), 7.58 (dd, 1H), 7.33 (dd, 1H), 6.97 – 6.84 (m, 2H), 5.96 (dd, 1H), 5.32 (dd, 1H), 4.20 – 3.89 (m, 2H), 3.88 – 3.52 (m, 2H), 3.32 – 2.91 (m, 3H), 2.87 – 2.73 (m, 1H), 2.72 – 2.42 (m, 6H), 2.42 (s, 3H), 2.30 – 2.13 (m, 2H), 1.99 (s, 3H), 1.73 – 0.82 (m, 11H). LCMS (Method 15): 1.89 min, 771.3 [M+H]+. Example 39: 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-propylpyrimidin-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

[0436] Prepared in an analogous manner to Example 1 using Intermediate 519 (0.14 g, 0.19 mmol) and lithium hydroxide (14 mg, 0.57 mmol) in THF (1.0 mL), MeOH (0.5 mL) and water (0.5 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (58 mg).1H NMR (400 MHz, CD3OD) δ: 7.99 (s, 1H), 7.56 (dd, 1H), 7.33 (dd, 1H), 6.97 – 6.84 (m, 2H), 5.97 (dd, 1H), 5.29 (dd, 1H), 3.30 – 3.07 (m, 2H), 3.05 – 2.90 (m, 1H), 2.90 – 2.56(m, 10H), 2.52 – 2.37 (m, 2H), 2.28 – 2.12 (m, 2H), 1.98 (s, 3H), 1.85 – 1.70 (m, 2H), 1.69 – 1.05 (m, 11H), 1.05 (t, 3H). LCMS (Method 15): 1.69 min, 705.4 [M+H]+. Example 40: 2-((3S,6S)-14,24-Difluoro-16-methyl-6-(4-methyl-5-(1-methylpiperidin-4-yl)-2- oxopyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0437] Prepared in an analogous manner to Example 1 using Intermediate 526 (86 mg, 0.12 mmol) and lithium hydroxide (8.5 mg, 0.35 mmol) in THF (4.4 mL), MeOH (0.7 mL) and water (1.5 mL) at RT for 30 min. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-45% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (20 mg).1H NMR (400 MHz, CD3OD) δ: 7.96 (s, 1H), 7.59 (dd, 1H), 7.31 (dd, 1H), 6.99 – 6.82 (m, 2H), 5.96 (dd, 1H), 5.25 (dd, 1H), 3.40 – 3.17 (m, 2H), 2.97 – 2.38 (m, 11H), 2.38 – 2.26 (m, 1H), 2.20 – 2.06 (m, 1H), 2.00 (s, 3H), 2.00 – 1.90 (m, 2H), 1.90 – 1.73 (m, 2H), 1.70 – 1.57 (m, 1H), 1.55 – 0.80 (m, 11H). LCMS (Method 15): 1.63 min, 703.4 [M+H]+. Example 41: 2-((3S,6S)-6-(4-Ethyl-5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyrimidin-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

[0438] Prepared in an analogous manner to Example 1 using Intermediate 531 (0.12 g, 0.13 mmol) and lithium hydroxide (9 mg, 0.38 mmol) in THF (5 mL), MeOH (2 mL) and water (1 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 30-41% MeCN in water with 0.1% ammonia over 18 min) to provide the title compound (44mg).1H NMR (400 MHz, CD3OD) δ: 7.92 (s, 1H), 7.58 (dd, 1H), 7.34 (dd, 1H), 6.97 – 6.84 (m, 2H), 5.98 (dd, 1H), 5.33 (dd, 1H), 4.48 – 4.15 (m, 3H), 4.15 – 3.62 (m, 2H), 3.36 (s, 3H), 3.32 – 3.20 (m, 2H), 2.95 – 2.83 (m, 1H), 2.82 – 2.57 (m, 4H), 2.55 – 2.37 (m, 2H), 2.35 – 2.10 (m, 2H), 1.99 (s, 3H), 1.70 – 0.82 (m, 14H). LCMS (Method 15): 1.67 min, 733.4 [M+H]+. Example 42: 2-((3S,6S)-6-(4-Ethyl-5-(3-(3-methoxyazetidin-1-yl)propyl)-2-oxopyrimidin- 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

[0439] Prepared in an analogous manner to Example 1 using Intermediate 538 (91 mg, 53 µmol) and lithium hydroxide (3.8 mg, 0.16 mmol) in THF (5 mL), MeOH (2 mL) and water (1 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35- 45% MeCN in water with 0.1% ammonia over 18 min) to provide the title compound (7.5 mg).1H NMR (400 MHz, CD3OD) δ: 7.98 (s, 1H), 7.59 (dd, 1H), 7.32 (dd, 1H), 6.98 – 6.82 (m, 2H), 5.98 (dd, 1H), 5.26 (dd, 1H), 4.25 – 3.80 (m, 3H), 3.69 – 3.41 (m, 2H), 3.31 (s, 3H), 3.03 – 2.78 (m, 2H), 2.77 – 2.04 (m, 8H), 1.99 (s, 3H), 1.93 – 0.79 (m, 17H). LCMS (Method 15): 1.71 min, 747.4 [M+H]+. Example 43: 2-((3S,6S)-14,24-Difluoro-16-methyl-6-(4-methyl-5-(1-methylazetidin-3-yl)-2- oxopyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid

[0440] Prepared in an analogous manner to Example 1 using Intermediate 545 (0.18 g, 0.17 mmol) and lithium hydroxide (12 mg, 0.50 mmol) in THF (3 mL), MeOH (1.5 mL) and water (0.8 mL) at RT for 1 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 35-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (41 mg).1H NMR (400 MHz, CD3OD) δ: 8.00 (s, 1H), 7.56 (dd, 1H), 7.33 (dd, 1H), 6.98 – 6.83 (m, 2H), 6.14 – 5.92 (m, 1H), 5.27 (dd, 1H), 4.41 – 3.45 (m, 4H), 3.03 – 2.37 (m, 7H), 2.28 (s, 3H), 2.26 – 2.11 (m, 1H), 1.99 (s, 3H), 1.76 – 1.58 (m, 1H), 1.57 – 0.81 (m, 11H). LCMS (Method 15): 1.86 min, 675.2 [M+H]+. Example 44: 2-((3S,6S)-6-(4-Ethyl-5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyrimidin-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

[0441] Prepared in an analogous manner to Example 1 using Intermediate 458 (15 mg, 20 µmol) and lithium hydroxide (1.4 mg, 59 µmol) in THF (1.5 mL), MeOH (0.7 mL) and water (0.5 mL) at RT for 0.5 h. Purified by preparative HPLC (XBridge C18, 30 x 250 mm 5 µm, eluting 30-40% MeCN in water with 0.1% ammonia over 15 min) to provide the title compound (2 mg).1H NMR (400 MHz, CD3OD) δ: 8.17 (s, 1H), 7.67 (dd, 1H), 7.35 (dd, 1H), 6.98 – 6.78 (m, 2H), 5.35 (dd, 1H), 4.97 (dd, 1H), 4.21 – 4.01 (m, 1H), 3.96 – 3.59 (m, 2H), 3.30 (s, 3H), 3.28 – 3.08 (m, 2H), 3.01 – 2.54 (m, 8H), 2.53 – 2.33 (m, 2H), 2.26 – 2.08 (m, 1H), 2.02 (s, 3H), 1.52 – 1.02 (m, 11H), 0.93 (d, 3H). LCMS (Method 15): 1.59 min, 733.3 [M+H]+. Example 45: 2-((3S,6S)-14,24-Difluoro-25-isopropyl-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

[0442] Prepared in an analogous manner to Example 1 using Intermediate 118 (70 mg, 57 µmol) and lithium hydroxide (7.2 mg, 0.17 mmol) in THF (1 mL), MeOH (0.5 mL) and water (0.5 mL) at RT for 2 h. Purified by preparative HPLC (XBridge C8, 19 x 250 mm 5 µm, eluting 20-65% MeCN in 10 mM aqueous NH4HCO3 over 15 min) to provide the title compound (8.2 mg).1H NMR (400 MHz, DMSO-d6) δ: 9.48 – 9.00 (br m, 1H), 7.83 (s, 1H), 7.20 (dd, 1H), 7.05 – 6.93 (m, 2H), 6.91 (dd, 1H), 5.74 (q, 1H), 5.14 (dd, 1H), 4.08 – 3.92 (m, 1H), 3.78 – 3.52 (m, 2H), 3.35 – 3.20 (m, 1H), 3.18 (s, 3H), 3.12 – 2.94 (m, 2H), 2.82 – 2.63 (m, 2H), 2.62 – 2.18 (m, 8H), 2.09 – 1.95 (m, 1H), 1.92 (s, 3H), 1.56 – 0.88 (m, 18H) – OH not observed. LCMS (Method 32): 7.14 min, 693.6 [M+H]+. Biological Testing Cell Adhesion Assays

[0443] Cell adhesion assays were used to measure the ability of the compounds described herein to inhibit the interaction of α4β7 receptors and MAdCAM ligand, or α4β1 receptors and VCAM ligand. RPMI8866 cells express high levels of α4β7 and low levels of α4β1 receptors, and Jurkat cells express high levels of α4β1 and low levels of α4β7 (DOI: 10.1124 / jpet.102.047704). The assays described are as follows: Assay 1 - adhesion of RPMI8866 cells to immobilized MAdCAM in the presence of high protein levels, using a luminescence endpoint

[0444] To coat the assay plates with ligand, 20 μL recombinant human MAdCAM-1 Fc chimera protein (Biotechne) at 3 μg / ml in PBS was added to wells of 384-well white cell culture assay plates (Corning 3570), which were sealed and incubated overnight at 22°C. The following day, solution was removed from the wells by flicking the plates, and the wells were then blocked by incubation with 30 μL PUCKS buffer (5.37 mM KCl, 137 mM NaCl, 4 mM NaHCO3, 5.5 mM D-glucose, 25 mM HEPES (pH7.0)) containing 1% (w / v) BSA for 1 hour at room temperature. Meanwhile, ECHO acoustic dispensing was used to prepare compound plates containing dose-response curves of doubling dilutions of compounds at twice thedesired final assay concentration in PUCKS buffer containing 4% (w / v) HSA and 0.6% (v / v) DMSO. After removal of blocking solution from the assay plates, 10 μL was transferred from the compound plates to the assay plates using a BIOMEK liquid handler. RPMI8866 cells were harvested by centrifugation and resuspended at 4 x 106 cells / mL in PBS + 2 mM MnCl2.10 μL cell suspension was then added per well to the assay plates and incubated for 1 hour at 22°C. Final conditions in the adhesion step were 40000 cells / well, 2% (w / v) HSA, 0.3% (v / v) DMSO and 1 mM MnCl2. After removal of the solutions and washing of the wells thrice with 20 μL PUCKS + 1% (w / v) BSA, 20 μL CellTiter-Glo reagent (Promega) was added to the wells and plates were incubated for 1 hour in the dark at room temperature. Luminescence was read on a CLARIOstar (BMG Labtech) and % inhibition was calculated for each well, using 30 µM of the commercially available α4β1 / α4β7 antagonist firategrast for 100% inhibition controls, and no compound for 0% inhibition controls. IC50 values were calculated using Dotmatics studies using 4-parameter non-linear regression curve fit. Assay 2 - adhesion of Jurkat cells to immobilized VCAM in the presence of high protein levels, using a luminescence endpoint

[0445] This was performed as Assay 1 with the following modifications - assay plates were coated with 20 μL recombinant human VCAM-1 protein (Biotechne) at 1.5 μg / ml in PBS; and Jurkat cells were used.

[0446] The assay results are provided in Table 1 as mean IC50 values (n ≥ 2). Table 1 α4β7 IC50α4β1 IC50α4β7 IC50α4β1 IC50Example (nM) (nM) Example (nM) (nM) (Assay 1) (Assay 2) (Assay 1) (Assay 2) 1 0.4 1116 25 5.9 14910 2 1.2 1966 26 16 7244 3 0.8 3715 27 4.2 7025 4 2.5 14130 28 16 28350 5 1.5 720 29 3.5 4750 6 1.1 1276 30 9.4 7244 7 1.2 656 31 5.5 5843 8 1.6 1748 32 4.5 1698 9 1.6 3020 33 35 24550 10 2.0 2661 34 7.4 22730 11 1.5 2723 35 3.0 5559 12 1.3 2692 36 16.7 >29510 13 2.2 1535 37 0.5 753 14 6.1 24740 37A 1.3 7542 15 2.4 18340 37B 0.5 631 16 32 17510 38 8.3 21630 17 2.7 10880 39 3.2 1876018 5.7 5580 40 1.0 1306 19 0.9 4501 41 5.1 17920 20 9.6 9441 42 7.6 13490 21 6.3 10470 43 1.9 14680 22 8.5 4898 44 84 >29510 23 4.5 9404 45 8.2 22560 24 22 23040

[0447] As can be seen from the data in Table 1, the compounds of the present invention are potent α4β7 integrin inhibitors, and additionally show selectivity for α4β7 over α4β1. Whole Blood Assays

[0448] Compounds were assessed for their ability to inhibit the interaction of MAdCAM or LDV with α4β7 or α4β1 respectively, on CD4+ cells using a human whole blood assay. Assay 3 - Human whole blood MadCAM assay

[0449] Three-fold dose response curves of compounds were prepared in DMSO and diluted in PBS, so the compounds were at 10-fold the final assay concentration in PBS with 5% DMSO.2.5 µl of these compound dilutions were mixed with 2.5 µl of human MAdCAM labelled with Alexa Fluor 647, diluted to 10x final assay concentration in PBS, in 96-well V bottom assay plates. Meanwhile, mouse anti-CD4 antibody labelled with Alexa Fluor 488 was added to fresh heparinised human blood along with Manganese (II) chloride solution. Then 20 µl of this whole blood mixture was added to the 5 µl compound / hMAdCAM mixture. The final assay concentrations were 4 mM Manganese and 1 µg / ml hMAdCAM. Following 1 hour of incubation, at room temperature in the dark, cells were pelleted by centrifugation. The cells were then resuspended in 200 µl of 1x lyse / fix solution, and incubated for 10 min at 37 °C, to lyse the red blood cells and fix the leukocytes. Following further centrifugation, the cell pellets were resuspended in 200 µl 0.5% formaldehyde in PBS, stored in the dark until analysis using a BD Accuri C6 flow cytometer. % inhibition was calculated for each well, using 10 μM of a potent α4β7 inhibitor for 100% inhibition controls, and no compound for 0% inhibition controls. IC50 values were calculated using 4-parameter non-linear regression curve fit. Assay 4 - Human whole blood LDV assay

[0450] Three-fold dose response curves of compounds were prepared in DMSO and diluted in PBS, so the compounds were at 10-fold the final assay concentration in PBS with 5% DMSO.5 µl of these compound dilutions were mixed with 5 µl of LDV-FITC diluted to 10x final assay concentration in PBS, in 96-well deep (0.5ml) V bottom plates. Meanwhile, mouse anti- CD4 antibody labelled with PE-Cy7 was added to fresh heparinised human blood along with Manganese (II) chloride solution. Then 40 µl of this whole blood mixture was added to the 10µl compound / LDV mixture. The final assay concentrations were 4 mM Manganese and 1 µM LDV-FITC. Following 1 hour of incubation, at room temperature in the dark, cells were pelleted by centrifugation. The cells were then resuspended in 500 µl of 1x lyse / fix solution and incubated for 10 mins at 37 °C, to lyse the red blood cells and fix the leukocytes. Following further centrifugation, the cell pellets were washed twice with 250 µl of stain buffer. Finally, the cells were suspended in 200 µl 0.5% formaldehyde in PBS, stored in the dark until analysis using a BD Accuri C6 flow cytometer. % inhibition was calculated for each well, using 50 μM of BIO5192 for 100% inhibition controls, and no compound for 0% inhibition controls. IC50 values were calculated using 4-parameter non-linear regression curve fit.

[0451] The whole blood assay results are provided in Table 2 as mean IC50 values (n ≥ 2). Table 2 α4β7 IC (nM) α4β1 IC (nM) Example 50 50 (Assay 3) (Assay 4) 2 37 >50000 3 20 -- In Vivo PD Model

[0452] Compounds were assessed for their ability to inhibit the migration of T-cells into gastrointestinal tissue. Mouse Gut Homing T-cell model

[0453] α4β7HIcells were labelled with CellTrace™ Far Red. Cells were re-suspended in the stain diluted 1:1000 with PBS. Cells were incubated for 20 minutes at 37 °C and then washed with complete media. Then 50 million cells were injected into B6.SJL recipient mice, 15 minutes after PO dosing of compound or vehicle. In addition, DATK32, a mouse anti-α4β7 antibody was tested as a positive control in this model, along with an isotype control. With DATK32 and in its isotype control, mice were dosed one hour prior to the cell transfer. Two hours after cell transfer animals were euthanised and blood, spleen, mesenteric lymph and nodes were collected. Cells were stained with an antibody to detect α4β7HIcells, then samples analysed by flow cytometry for α4β7HIcells and CTRF dye. The percentage of total live cells that were α4β7HIcells was calculated.

Claims

Claims 1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:wherein: L1 is a 7-carbon straight chain or branched chain alkylene linker; R1is selected from fluoro, methyl, and cyclopropyl; R2is selected from fluoro, chloro, methyl, ethyl, isopropyl, and trifluoromethyl; R3is L2-NR5R6, or a 4-, 5-, or 6-membered heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from fluoro, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, and C1-2alkylene-O-C1-2alkyl; R4is selected from hydrogen, methyl, ethyl, propyl, C1-3haloalkyl, C1-2alkoxy, C1- 2haloalkoxy, and hydroxy; L2 is a 2- or 3-carbon alkylene linker optionally substituted with one or two methyl groups; R5and R6are independently selected from methyl and ethyl; or R5and R6, taken together with the nitrogen to which they are attached, form a 4-, 5-, or 6-membered heterocyclyl ring wherein the heterocyclyl ring is: i) optionally spiro-attached to a cyclopropyl or cyclobutyl ring; and ii) optionally substituted with one or more substituents independently selected from fluoro, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, and C1-2alkylene-O-C1-2alkyl.

2. The compound according to claim 1 L1is selected from:, wherein b is the point of attachment to the phenyl ring.

3. The compound according to claim 1 or claim 2, wherein R1is methyl or fluoro.

4. The compound according to any one of claims 1 to 3, wherein R2is selected from fluoro, methyl, ethyl, isopropyl, and trifluoromethyl.

5. The compound according to claim 4, wherein R2is selected from methyl, isopropyl and trifluoromethyl; such as methyl and trifluoromethyl.

6. The compound according to any one of claims 1 to 5, wherein R3is L2-NR5R6, or a 4-, 5-, or 6-membered heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from C1-3alkyl, C1- 3haloalkyl, C1-3alkoxy, and C1-3haloalkoxy.

7. The compound according to claim 6, wherein R3is L2-NR5R6, or a 4-, 5-, or 6-membered heterocyclyl ring wherein the heterocyclyl ring is optionally substituted with a C1-3alkyl substituent.

8. The compound according to claim 6, wherein R3is L2-NR5R6.

9. The compound according to any one of claims 1 to 8, wherein L2 is a 2- or 3-carbon alkylene linker.

10. The compound according to any one of claims 1 to 9, wherein R5and R6are both methyl.

11. The compound according to any one of claims 1 to 9, wherein R5and R6, taken together with the nitrogen to which they are attached, form a 4-, or 5-membered heterocyclyl ring wherein the heterocyclyl ring is: i) optionally spiro-attached to a cyclopropyl or cyclobutyl ring; and ii) optionally substituted with one or more substituents independently selected from fluoro, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, and C1-2alkylene-O-C1-2alkyl.

12. The compound according to claim 11, wherein R5and R6, taken together with the nitrogen to which they are attached, form a 4-, or 5-membered heterocyclyl ring optionally substituted with one or two substituents independently selected from fluoro, methyl, ethyl, C1-3haloalkyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, and CH2-OMe.

13. The compound according to claim 11, wherein R5and R6, taken together with the nitrogen to which they are attached, form an azetidine ring optionally substituted withone or two substituents independently selected from fluoro, methyl, ethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

14. The compound according to any one of claims 1 to 13, wherein R4is selected from hydrogen, methyl, ethyl, propyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, trifluoromethoxy, and hydroxy.

15. The compound according to claim 14, wherein R4is selected from hydrogen, methyl, ethyl, difluoromethyl, and hydroxy.

16. The compound according to claim 14, wherein R4is selected from methyl, ethyl and difluoromethyl.

17. The compound according to claim 1, wherein the compound is a compound of formula IA, IB, IC, ID, or IE, or a pharmaceutically acceptable salt thereof:.

18. The compound according to claim 17, wherein R1is selected from methyl and fluoro.

19. The compound according to claim 17 or claim 18, wherein R2is selected from methyl, isopropyl, and trifluoromethyl; such as methyl and trifluoromethyl.

20. The compound according to any one of claims 17 to 19, wherein R4is selected from hydrogen, methyl, ethyl, difluoromethyl, and hydroxy.

21. The compound according to any one of claims 17 to 20, wherein L2is a 2- or 3-carbon alkylene linker.

22. The compound according to any one of claims 17 to 21, wherein R5and R6are both methyl.

23. The compound according to any one of claims 17 to 21, wherein R5and R6, taken together with the nitrogen to which they are attached, form an azetidine ring optionally substituted with one or two substituents independently selected from fluoro, methyl, and methoxy.

24. A compound selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-1(2H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-4-methyl-2-oxopyrimidin-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-oxopyrimidin-1(2H)-yl)-14,24- difluoro-16-methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(dimethylamino)ethyl)-2-oxopyrimidin-1(2H)-yl)-14,24-difluoro-16- methyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Diethylamino)ethyl)-4-methyl-2-oxopyrimidin-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-methyl-6-(4-methyl-2-oxo-5-(2-(pyrrolidin-1- yl)ethyl)pyrimidin-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-(Ethyl(methyl)amino)ethyl)-4-methyl-2-oxopyrimidin-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-methoxyazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-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-6-(4-methyl-2-oxo-5-(3-(pyrrolidin-1- yl)propyl)pyrimidin-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)-4-ethyl-2-oxopyrimidin-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-hydroxy-2-oxopyrimidin-1(2H)-yl)-14,24- difluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)-dibenzenacyclotridecaphane-3- yl)acetic acid; 2-((3S,6S)-6-(5-(3-(Azetidin-1-yl)propyl)-4-methyl-2-oxopyrimidin-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-methoxyazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-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-methoxyazetidin-1-yl)ethyl)-2-oxopyrimidin-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)-4-methyl-2-oxopyrimidin-1(2H)-yl)-24-fluoro- 14,16-dimethyl-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14-Cyclopropyl-6-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyrimidin- 1(2H)-yl)-24-fluoro-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-14,24-Difluoro-6-(5-(2-(3-fluoro-3-methylazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxopyrimidin-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)-4-methyl-2-oxopyrimidin- 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-(Azetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-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-fluoro-3-methylazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-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-(3,3-Difluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-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-(3-Ethoxyazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-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-methyl-6-(4-methyl-2-oxo-5-(2-(3- (trifluoromethoxy)azetidin-1-yl)ethyl)pyrimidin-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-isopropoxyazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-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-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- 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-(3-(3-methoxyazetidin-1-yl)propyl)-4-methyl-2- oxopyrimidin-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)-24-Fluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- 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-(3,3-Dimethylazetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin-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-(3-(Difluoromethoxy)azetidin-1-yl)ethyl)-4-methyl-2-oxopyrimidin- 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-(5-Azaspiro[2.3]hexan-5-yl)ethyl)-4-methyl-2-oxopyrimidin-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-methoxy-3-methylazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-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-Cyclopropyl-24-fluoro-6-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-1(2H)-yl)-16,25-dimethyl-5-oxo-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(4-(Difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyrimidin-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-methoxy-3-methylazetidin-1-yl)ethyl)-4-methyl-2- oxopyrimidin-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)-4-methoxy-2-oxopyrimidin-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-oxopyrimidin-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-methyl-6-(4-methyl-2-oxo-5-(2-(3-(2,2,2- trifluoroethyl)azetidin-1-yl)ethyl)pyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza- 1(1,2),2(1,3)-dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-propylpyrimidin-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-methyl-6-(4-methyl-5-(1-methylpiperidin-4-yl)-2- oxopyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(4-Ethyl-5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyrimidin-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-(4-Ethyl-5-(3-(3-methoxyazetidin-1-yl)propyl)-2-oxopyrimidin-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-methyl-6-(4-methyl-5-(1-methylazetidin-3-yl)-2- oxopyrimidin-1(2H)-yl)-5-oxo-25-(trifluoromethyl)-4-aza-1(1,2),2(1,3)- dibenzenacyclotridecaphane-3-yl)acetic acid; 2-((3S,6S)-6-(4-Ethyl-5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxopyrimidin-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; and 2-((3S,6S)-14,24-Difluoro-25-isopropyl-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.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

26. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25, for use in therapy.

27. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25, for use in the treatment of diseases or disorders mediated by α4β7.

28. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25, for use in the treatment of an inflammatory bowel disease.

29. The compound or the pharmaceutical composition for the use according to claim 28, wherein the inflammatory bowel disease is selected from ulcerative colitis and Crohn’s disease.

30. The compound or the pharmaceutical composition for the use according to claim 28 or claim 29, in combination with one or more additional therapeutic agents.

31. 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 any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25.

32. A method of treating an inflammatory bowel disease comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25.

33. The method according to claim 32, wherein the inflammatory bowel disease is ulcerative colitis or Crohn’s disease.

34. The method according to claim 32 or claim 33, 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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