BR102018002152B1 - COMPOUNDS, PHARMACEUTICAL COMPOSITIONS AND THEIR USES AS HIV INHIBITORS - Google Patents

Abstract

The invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of Formula I, processes for preparing the compounds of Formula I, therapeutic methods for treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS symptoms in a mammal using the compounds of Formula I.

Description

CROSS-REFERENCE TO RELATED ORDERS

[001] This patent application claims the benefit of priority from U.S. Provisional Patent Application Serial No. 62/455,348, filed on February 6, 2017. The contents of that application are incorporated herein by reference.

FIELD

[002] The present description relates to novel compounds for use in the treatment of a viral infection by Retroviridae including an infection caused by the HIV virus. The present description also relates to intermediates for their preparation and to pharmaceutical compositions containing these compounds.

BACKGROUND

[003] Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes that are required for viral replication: reverse transcriptase, protease, and integrase. Several protease inhibitors (PIs) are currently approved for use in AIDS or HIV. However, many PIs suffer from high rates of hepatic metabolism, which may require coadministration of a booster or more frequent dosing. In addition, viral resistance continues to be a problem. Consequently, there is a need for new agents that inhibit HIV replication.

SUMMARY

[004] The present disclosure provides compounds and methods for treating an HIV infection. Accordingly, in one embodiment, the invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 5- to 10-membered heterocycle having 1 to 5 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 5- to 10-membered heterocycle or 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 Ra groups; R 2 and R 3 are each independently C 1-4 alkyl, C 3- 6 cycloalkyl, O-R 2A, C 1-2 alkyl-O-R 2A, N-(R 3A) 2 , or C 1-2 alkyl-N-(R 3A) 2 , wherein each R 2A is independently C 1-4 alkyl, C 3- 6 cycloalkyl, or a 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein each R3A is independently hydrogen, C1-4alkyl, C3-6cycloalkyl, or COO(Re), and wherein each C3-6cycloalkyl or 4- to 10-membered heterocyclyl is optionally substituted with 1 to 3 Rf groups, wherein each Rf is independently C1-2alkyl or halogen; R4 is hydrogen, halo, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C1-4alkoxy, or C1-4haloalkoxy; R7 is hydrogen, halo, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C1-4alkoxy, or C1-4haloalkoxy; R5, R6, R8, and R9 are each independently hydrogen, halo, C1-2alkyl, C1-2 haloalkyl, or C3-6cycloalkyl; and wherein two or more of R4, R5, and R6 or two or more of R7, R8, and R9 optionally join together to form one or more C3-6cycloalkyl groups which are optionally substituted with 1 to 4 groups selected from halogen, C1-2alkyl, and C1-2 haloalkyl; each R10 is independently halogen, cyano, C1-4alkoxy, C1-6alkyl, or C3-6cycloalkyl; n is 0 to 4; each Ra is independently halogen, C1-4alkyl, C1-4alkyl with 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, C1-4 haloalkyl, C1-4alkoxy, C3-6 cycloalkyl, 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S that are optionally substituted with Ra1, or O-R3B, wherein R3B is C3-6cycloalkyl optionally substituted with Ra1 or a 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S optionally substituted with Ra1, wherein each Ra1 is independently C1-4alkyl, C3-6cycloalkyl, C1-4haloalkyl, or 4- to 8-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S; A is ethynyl or a bond; X1 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein each 6- to 10-membered or 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 Rb groups; X2 is hydrogen or a 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is optionally substituted with one R11 and optionally substituted with 1 to 5 Rb groups; R11 is C=O(Rc), CH2(Rd), S(O)1-2(C1-4alkyl), S(O)1-2C3-6cycloalkyl, a 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, or a 5- to 9-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein each 4- to 10-membered heterocyclyl or 5- to 9-membered heteroaryl is optionally substituted with 1 to 5 Rb groups; each Rb is independently halogen, oxo, C1-4alkyl, C1-4alkyl with 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, C1-4 haloalkyl, C1-4 alkoxy, or COO(Re); Rc is C1-4alkyl, C1-4 haloalkyl, C1-4alkoxy, N(Re)2, C3-6cycloalkyl, or a 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C3-6 cycloalkyl, and the 4- to 6-membered heterocyclyl are optionally substituted by 1 to 5 Rb groups; Rd is COO(Re), N(Re)2, C3-6 cycloalkyl, or a 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C3-6 cycloalkyl, and the 4- to 6-membered heterocyclyl are optionally substituted by 1 to 5 Rb groups; each R12 is C1-2alkyl, halo, -OC1-2alkyl, or cyano; each p is 0 to 4; and each Re is independently hydrogen or C1-4alkyl.

[005] Likewise, provided is a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition also comprises one, two, three, or four additional therapeutic agents.

[006] Likewise, provided is a method of treating or preventing a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[007] In certain embodiments, the current disclosure relates to an article of manufacture comprising a unit dosage of a compound described herein, or a pharmaceutically acceptable salt thereof.

[008] Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in therapy.

[009] A compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of said compound to a subject in need thereof, is also provided.

DESCRIPTION OF DRAWINGS

[0010] Figure 1 depicts the predicted hepatic clearance for certain compounds and reference compounds as more fully described in the biological examples herein.

[0011] Figure 2 depicts a graph of IV dog pharmacokinetic studies for certain compounds and reference compounds and a table summarizing the oral and IV PK data for these compounds as more fully described in the examples herein.

[0012] Figure 3 depicts a graph of IV rat pharmacokinetic studies for certain compounds and reference compounds and a table summarizing the oral and IV PK data for these compounds as more fully described in the examples herein.

[0013] Figure 4 depicts a duplication vs. wild-type shift for certain clinical isolate resistance mutations to certain compounds and reference compounds as more fully described in the examples herein.

[0014] Figure 5 depicts the advancement of resistance for certain compounds and reference compounds as more fully described in the examples herein.

DETAILED DESCRIPTION

[0015] The following is a list of abbreviations and acronyms used throughout the application:Abbreviation °C Meaning Degrees Celsius ATP Adenosine-5'-triphosphate AcOH Acetic acid d Doublet dd Doublet of doublets DCE 1,2-dichloroethane DCM Dichloromethane DIPEA N,N-diisopropylethylamine DME 1,2-dimethoxyethane DMF Dimethylformamide DMSO Dimethyl sulfoxide dppf EGTA 1,1'-Bis(diphenylphosphino)ferrocene Ethylene glycol tetraacetic acid ETOAC Ethyl acetate eq ESI Equivalents Electrospray ionization Ac Acetate Et Ethyl eq HATU Grams 2-(7-Aza-1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate hERG Gene Related to Human ether-à-go-go HPLC High-performance liquid chromatographyh/hr HoursHz HertzIC50 Near-maximal inhibitory concentrationJ Coupling constantKgM KilogramMolarm Multipleton/z Mass-to-charge ratioM+ Mass peakM+H Mass peak plus hydrogenMe MethylMeOH Methyl alcohol/methanolmgMHz MilligramMegahertzmin/m Minuteml/mL MillilitromM Millimolarmmol MillimolarMS Mass spectroscopymw MicrowaveN Normalmol MolNMP N-methylpyrrolidinoneNMR Nuclear magnetic resonancePh Phenylappm Parts per millionprepRf PreparativeRetention factorRP Reversed phase RT/rt Room temperature Seconds Singlett TripletTEA TriethylamineTFA Trifluoroacetic acidTLC Thin-layer chromatographyTMS trimethylsilylWT Wild typeδ Chemical shiftμgμL/ μl μM MicrogramMicroliterMicromolarμm μmol MicrometerMicromol

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It should be noted that, as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those of ordinary skill in the art, and so forth.

[0017] A dash at the front or end of a chemical group is a matter of convenience; chemical groups can be represented with or without one or more dashes without losing their common meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group, for example:

[0018] A dashed line indicates an optional bond. Where multiple substituent groups are identified, the point of attachment is at the terminal substituent (e.g., for "alkylaminocarbonyl" the point of attachment is at the carbonyl substituent).

[0019] The prefix "Cx-y" indicates that the following group has x (e.g., 1) to y (e.g., 6) carbon atoms, one or more of which, in certain groups (e.g., heteroalkyl, heteroaryl, heteroarylalkyl, etc.), may be replaced with one or more heteroatom(s) or heteroatomic group(s). For example, "C1-6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms. Likewise, the term "x-y membered rings", where x and y are numerical ranges, such as "3- to 12-membered heterocyclyl", refers to a ring containing x-y atoms (e.g., 3-12), of which up to 80% may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.

[0020] Likewise, certain commonly used alternative chemical names may or may not be used. For example, a divalent group, such as a divalent "alkyl" group, a divalent "aryl" group, etc., may similarly be referred to as an "alkylene" group or an "alkylenyl" group, or alkylyl group, an "arylene" group or an "arylenyl" group, or arylyl group, respectively.

[0021] "A compound described herein" or "a compound of the present description" refers to compounds of Formula (I), (Ia), (Ib), (Ic), (Id), and/or (Ie). Also included are the specific compounds of Examples 1-245.

[0022] "Alkyl" refers to any group derived from a straight or branched saturated hydrocarbon. Alkyl groups include, but are not limited to, methyl, ethyl, propyl, such as propan-1-yl, propan-2-yl (iso-propyl), butyls, such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (iso-butyl), 2-methyl-propan-2-yl (t-butyl), pentyls, hexyls, octyls, dectyls, and the like. Unless otherwise specified, an alkyl group has from 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms.

[0023] "Alkenyl" refers to any group derived from a straight or branched hydrocarbon having at least one carbon-carbon double bond. Alkenyl groups include, but are not limited to, ethenyl (vinyl), propenyl (allyl), 1-butenyl, 1,3-butadienyl, and the like. Unless otherwise specified, an alkenyl group has from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms.

[0024] "Alkynyl" refers to any group derived from a straight or branched hydrocarbon having at least one carbon-carbon triple bond and includes those groups having one triple bond and one double bond. Examples of alkynyl groups include, but are not limited to, ethynyl (-C=C-), propargyl (-CH2C=C-), (E)-pent-3-en-1-ynyl, and the like. Unless otherwise specified, an alkynyl group has from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms.

[0025] "Amino" refers to -NH2. Amino groups may likewise be substituted as described herein, such as with alkyl, carbonyl, or other amino groups. The term "alkylamino" refers to an amino group substituted with one or two alkyl substituents (e.g., dimethylamino or propylamino).

[0026] The term "aryl" when used herein refers to a single full carbon aromatic ring or a multiple condensed full carbon ring system in which at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical. Aryl likewise includes multiple condensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings) having about 9 to 20 carbon atoms, in which at least one ring is aromatic and in which the other rings may be aromatic or non-aromatic (i.e., carbocycle). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocycle portion of the multiple condensed ring system. The rings of the multiple condensed ring system may be connected to each other by means of fused, spiro and bridging bonds when permitted by valency requirements. It should likewise be understood that when reference is made to a certain aryl atom range (e.g., 6-10 membered aryl), the atom range is for the total ring atoms of the aryl. For example, a 6-membered aryl would include phenyl, and a 10-membered aryl would include naphthyl and 1,2,3,4-tetrahydronaphthyl. Aryl groups include, but are not limited to, those groups derived from acenaphthylene, anthracene, azulene, benzene, chrysene, a cyclopentadienyl anion, naphthalene, fluoranthene, fluorene, indane, perylene, phenalene, phenanthrene, pyrene, and the like. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.

[0027] "Bridged" refers to a ring fusion in which nonadjacent atoms in a ring are joined by a substituent, such as an alkylenyl or heteroalkylenyl group or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems.

[0028] The term "cycloalkyl" refers to a single saturated or partially unsaturated full carbon ring having 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), for example from 3 to 12 ring atoms, for example from 3 to 10 ring atoms. The term "cycloalkyl" likewise includes multiple condensed saturated and partially unsaturated full carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Suitably, cycloalkyl includes multicyclic carbocycles such as bicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12 ring carbon atoms, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane) and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles having up to about 20 ring carbon atoms). The rings of a multiple condensed ring system may be mutually connected via fused, spiro, and bridging bonds when permitted by valence requirements. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, spiro[3.3]heptane, and 1-cyclohex-3-enyl.

[0029] "Halo" and "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0030] "Haloalkyl" refers to an alkyl in which one or more hydrogen atoms are each replaced by a halogen. Examples include, but are not limited to, -CH2Cl, -CH2F, -CH2Br, -CFClBr, -CH2CH2Cl, -CH2CH2F, -CF3, -CH2CF3, -CH2CCl3, and the like, as well as alkyl groups, such as perfluoroalkyl, in which all of the hydrogen atoms are replaced by fluorine atoms.

[0031] "Alkoxy" or "alkoxyl" refers to a moiety of the formula -O-alkyl, wherein the alkyl moiety is as defined above. For example, C1-4 alkoxy refers to a moiety having a 1-4 carbon alkyl group attached to an oxygen. "Haloalkoxy" or "haloalkoxyl" refers to a moiety of the formula -O-haloalkyl, wherein the haloalkyl moiety is as defined above. For example, C1-4 alkoxy refers to a moiety having a 1-4 carbon haloalkyl group attached to an oxygen.

[0032] "Heteroalkyl" refers to an alkyl in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or a different heteroatom or heteroatomic group. Heteroatoms include, but are not limited to, N, P, O, S, etc. Heteroatomic groups include, but are not limited to, -NR-, -O, -S-, -PH-, -P(O)2-, -S(O)-, -S(O)2-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or cycloheteroalkyl. Heteroalkyl groups include, but are not limited to, -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, -CH2NRCH3, -CH2OH, and the like, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. A heteroalkyl group comprises from 1 to 10 carbons and up to four "four three" heteroatoms, for example, from 1 to 6 carbons and from 1 to 2 heteroatoms.

[0033] "Heteroaryl" refers to a mono- or multicyclic aryl group in which one or more of the aromatic carbon atoms (and any associated hydrogen atoms) are independently substituted with the same or a different heteroatom or heteroatomic group, as defined above. Multicyclic ring systems are included in heteroaryl and may be linked in the ring with the heteroatom or in the aryl ring. Heteroaryl groups include, but are not limited to, groups derived from acridine, benzoimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, cinoline, furan, imidazole, imidazopyridine, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyridone, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. Heteroaryl groups may be 5-12 membered, 5-10 membered, or 5-6 membered.

[0034] The term "heterocyclyl" or "heterocycle" when used herein refers to a single saturated or partially unsaturated non-aromatic ring system or a non-aromatic multiple ring system having at least one ring heteroatom (i.e., at least one ring heteroatom selected from oxygen, nitrogen and sulfur). Unless otherwise specified, a heterocyclyl group has from 5 to about 20 ring atoms, e.g., from 3 to 12 ring atoms, e.g., from 3 to 10 ring atoms, e.g., from 5 to 10 ring atoms or e.g., from 5 to 6 ring atoms. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having from about 1 to 6 ring carbon atoms and from about 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The rings of the multiple condensed ring system (e.g., bicyclic heterocyclyl) may be mutually connected by fused, spiro, and bridging bonds when permitted by valence requirements. Heterocycles include, but are not limited to, groups derived from azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, tetrahydro-1,1-dioxide-2H-thiopyran, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, and the like. Heterocycles include spirocycles, such as, for example, aza- or oxo-spiroheptanes. Heterocyclyl groups also include partially unsaturated ring systems containing one or more double bond(s), including fused ring systems with one aromatic ring and one nonaromatic ring, but not fully aromatic ring systems. Examples include dihydroquinolines, e.g., 3,4-dihydroquinoline, dihydroisoquinolines, e.g., 1,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc., indoline, isoindoline, isoindolones (e.g., isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, spiro[cyclopropane-1,1'-isoindolin]-3'-one, and the like. Additional examples of heterocycles include 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, and hexahydropyrazino[2,1-c][1,4]oxazinyl, for example.

[0035] "Hydroxyl" and "hydroxy" are used interchangeably and refer to -OH. "Oxo" refers to . Where the stautomeric forms of the compound exist, hydroxyl and oxo groups are interchangeable.

[0036] It is understood that combinations of chemical groups may be used and will be recognized by those of ordinary skill in the art. For example, the group "hydroxyalkyl" would refer to a hydroxyl group attached to an alkyl group. A large number of such combinations can be readily anticipated. Additional examples of substituent combinations used herein include: C1-6 alkylaminocarbonyl (e.g., CH3CH2NHC(O)-), C1-6 alkoxycarbonyl (e.g., CH3O-C(O)-), 5-7 membered heterocyclyl-C1-6 alkyl (e.g., piperazinyl-CH2-), 5-7 membered C1-6 alkylsulfonyl heterocyclyl (e.g., CH3S(O)2-morpholinyl-), 5-7 membered heterocyclyloxy-C1-6 alkoxy-5-7 membered heterocyclyl, (4-7 membered heterocyclyl)-4-7 membered heterocyclyl (e.g., oxetanyl-pyrrolidinyl-), C3-6 cycloalkylaminocarbonyl (e.g., cyclopropyl-NH-C(O)-), 5-7 membered heterocyclyl-C2-6 alkynyl (e.g. example, N-piperazinyl-CH2CHCCH2-) and C6_warylaminocarbonyl (for example, phenyl-NH-C(O)-).

[0037] "Spiro" refers to a ring substituent that is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyldioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine, respectively, are the spiro substituents. When the substituents (R groups) join together (e.g., when R7 and R8 join together), they can be employed from the same point of attachment to form a spiro ring.

[0038] The phrase "meta position (3) with respect to the point of attachment of ring A" refers to the position on the ring where the substituent (e.g., -CN) is added and is shown with an arrow, where z represents a carbon or nitrogen atom:

[0039] Similarly, positional substitution for (4) refers to the attachment of a substituent at the position indicated below, with respect to the point of attachment (e.g., of ring B):

[0040] Similarly, ortho or 2-position refers to the attachment of a substituent at the position indicated below, with respect to the point of attachment:

[0041] The compounds described herein include isomers, stereoisomers, and the like. When used herein, the term "isomers" refers to different compounds that have the same molecular formula but differ in the arrangement and configuration of the atoms. Likewise when used herein, the term "a stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached to a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound.

[0042] The term "fused" refers to a ring that is bonded to an adjacent ring.

[0043] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture.

[0044] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by R or S. Resolved compounds whose absolute configuration is unknown may be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate the plane of polarized light at the sodium D-line wavelength. Certain compounds described herein contain one or more asymmetric center(s) and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R) and (S) isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be of the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are likewise intended to be included. To the extent that compounds depicted herein are depicted as having a particular stereochemistry, it is understood by one of skill in the art that such compounds may contain some detectable or undetectable levels of compounds sharing the same structure but having different stereochemistry.

[0045] "IC95" or "EC95" refers to the inhibitory concentration required to achieve 95% of the maximum desired effect, which in many cases herein is inhibition of the HIV virus. This term is obtained using an in vitro assay assessing concentration-dependent inhibition of wild-type HIV virus.

[0046] "IC50" or "EC50" refers to the inhibitory concentration required to achieve 50% of the maximum desired effect, which in many cases is inhibition of the HIV virus. This term is obtained using an in vitro assay evaluating concentration-dependent inhibition of wild-type HIV virus.

[0047] "IQ" or "inhibitory quotient" refers to the relationship between the minimum drug concentration (Ctau) and the level of drug resistance of the HIV isolate as determined by IC95 (i.e., Ctau/IC95).

[0048] "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that are useful in the preparation of a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0049] "Pharmaceutically acceptable excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0050] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glycoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinated with an organic base such as diethanolamine, triethanolamine, N-methylglyamine, and the like. Also included in this definition are ammonia and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977) and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilquins, Philadelphia, PA, (2005), at p. 732, Table 38-5, both of which are hereby incorporated by reference herein.

[0051] The present description likewise provides prodrugs of the compounds described herein. A "prodrug" is defined in the pharmaceutical field as a biologically inactive derivative of a drug that after administration to the human body is converted to the biologically active parent drug according to some chemical or enzymatic pathway.

[0052] "Individual" and "individuals" refers to humans, domestic animals (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats, and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, pets, rabbits, dogs, and monkeys), and the like.

[0053] As used herein, "treatment" or "treating" is a method of achieving beneficial or desired results. For purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviating a symptom and/or decreasing the extent of a symptom and/or preventing the worsening of a symptom associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or decreasing the extent of the disease or condition); b) reducing or stopping the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, slowing the worsening or progression of the disease or condition); and/or c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, improving the status of the disease, slowing the progression of the disease, increasing the quality of life, and/or prolonging survival.

[0054] As used herein, "delaying" the development of a disease or condition means to postpone, hinder, reduce, delay, stabilize, and/or postpone the development of the disease or condition. Such delay may be for varying lengths of time, depending on the history of the disease and/or individual being treated. As is apparent to one of skill in the art, a sufficient or significant delay may in fact encompass prevention, in that the individual does not develop the disease or condition. For example, a method that "delays" the development of AIDS is a method that reduces the likelihood of the disease developing over a given period of time, when compared to not using the method. Such comparisons may be based on clinical studies using a statistically significant number of individuals. For example, the development of AIDS may be detected using known methods, such as confirmation of the individual's HIV+ status and assessment of the individual's T-cell count or other indication of the development of AIDS, such as extreme fatigue, weight loss, persistent diarrhea, high fever, enlarged lymph nodes in the neck, armpits, or groin, or the presence of an opportunistic condition known to be associated with AIDS (e.g., a condition that is not usually present in individuals with a functioning immune system but occurs in patients with AIDS). Development may also refer to the progression of the disease that may initially be undetectable and includes occurrence, recurrence, and onset.

[0055] As used herein, "prevention" or "preventing" refers to a regimen that protects against the onset of the disease or disorder, so that clinical symptoms of the disease do not develop. Thus, "prevention" refers to the administration of a therapy (e.g., the administration of a therapeutic substance) to an individual before signs of the disease are detectable in the individual (e.g., the administration of a therapeutic substance to an individual in the absence of a detectable infectious agent (e.g., virus) in the individual). The individual may be an individual at risk of developing the disease or disorder, such as an individual who has one or more risk factors known to be associated with the development or onset of the disease or disorder. Thus, the term "preventing HIV infection" refers to administering to an individual who does not have a detectable HIV infection an anti-HIV therapeutic substance. It is understood that the individual for preventive anti-HIV therapy may be an individual at risk of acquiring the HIV virus. Furthermore, it is understood that prevention may not result in complete protection against the onset of the disease or disorder. In some cases, prevention includes reducing the risk of developing the disease or disorder. Risk reduction may not result in completely eliminating the risk of developing the disease or disorder.

[0056] As used herein, an "at-risk" individual is an individual who is at risk of developing a condition to be treated. An "at-risk" individual may or may not have a detectable disease or condition, and may or may not have exhibited a detectable disease prior to treatment with the methods described herein. "At-risk" denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition and are known in the art. An individual with one or more of these risk factors is more likely to develop the disease or condition than an individual without such risk factor(s). For example, individuals at risk for AIDS are those who have HIV.

[0057] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect such treatment for the disease or an amount that is effective to protect against the contraction or onset of a disease. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated. The effective amount may include a range of amounts. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired result of treatment. An effective amount may be considered in the context of the administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Appropriate doses of any co-administered compounds may optionally be reduced due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0058] The compounds of the invention include solvates, hydrates, tautomers, stereoisomers and salt forms thereof.

[0059] Also provided are compounds in which from 1 to n hydrogen atoms bonded to a carbon atom may be replaced by a deuterium or D atom, where n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such displayed compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, e.g., to employ starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0060] Examples of isotopes that may be incorporated into the compounds described in the same manner include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. Substitution of positron emitting isotopes, such as 11C, 18F, 15O, and 13N, may be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of Formula (Ia) or (Ib) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as mentioned below using an appropriate isotopically labeled reagent in place of the previously employed unlabeled reagent.

[0061] As referred to herein, darunavir is an HIVprotease inhibitor having the structure: and having the name IUPAC[(3aS,4R,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate. Darunavir (DRV) is sold under the brand name PREZISTA®.

[0062] As referred to herein, atazanavir is an HIV protease inhibitor having the structure: and having the IUPAC name methyl N-[(2S)-1-[2-[(2S,3S)-2-hydroxy-3-[[(2S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoyl]amino]-4-phenylbutyl]-2-[(4- pyridin-2-ylphenyl)methyl]hydrazinyl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate. Atazanavir (ATV) is sold under the brand name REYATAZ®.Compounds

[0063] In certain embodiments, a compound of Formula I is provided: or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 5- to 10-membered heterocycle having 1 to 5 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 5- to 10-membered heterocycle or 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 Ra groups; R 2 and R 3 are each independently C 1-4 alkyl, C 3- 6 cycloalkyl, O-R 2A, C 1-2 alkyl-O-R 2A, N-(R 3A) 2 , or C 1-2 alkyl-N-(R 3A) 2 , wherein each R 2A is independently C 1-4 alkyl, C 3- 6 cycloalkyl, or a 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein each R3A is independently hydrogen, C1-4alkyl, C3-6cycloalkyl, or COO(Re), and wherein each C3-6cycloalkyl or 4- to 10-membered heterocyclyl is optionally substituted with 1 to 3 Rf groups, wherein each Rf is independently C1-2alkyl or halogen; R4 is hydrogen, halo, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C1-4alkoxy, or C1-4haloalkoxy; R7 is hydrogen, halo, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C1-4alkoxy, or C1-4haloalkoxy; R5, R6, R8, and R9 are each independently hydrogen, halo, C1-2alkyl, C1-2 haloalkyl, or C3-6cycloalkyl; and wherein two or more of R4, R5, and R6 or two or more of R7, R8, and R9 optionally join together to form one or more C3-6cycloalkyl groups that are optionally substituted with 1 to 4 groups selected from halogen, C1-2alkyl, and C1-2 haloalkyl; each R10 is independently halogen, cyano, C1-4alkoxy, C1-6alkyl, or C3-6cycloalkyl; n is 0 to 4; each Ra is independently halogen, C1-4alkyl, C1-4alkyl with 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, C1-4 haloalkyl, C1-4alkoxy, C3-6 cycloalkyl, 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S that are optionally substituted with Ra1, or O-R3B, in wherein R3B is C3-6 cycloalkyl optionally substituted with Ra1 or a 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S optionally substituted with Ra1, wherein each Ra1 is independently C1-4 alkyl, C3-6 cycloalkyl, C1-4haloalkyl, or 4- to 8-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S; A is ethynyl or a bond; X1 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein each 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 Rb groups; X2 is hydrogen or a 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is optionally substituted with one R11 and optionally substituted with 1 to 5 Rb groups; R11 is C=O(Rc), CH2(Rd), S(O)1-2(C1-4alkyl), S(O)1-2C3-6cycloalkyl, a 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, or a 5- to 9-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein each 4- to 10-membered heterocyclyl or 5- to 9-membered heteroaryl is optionally substituted with 1 to 5 Rb groups; each Rb is independently halogen, oxo, C1-4alkyl, C1-4alkyl with 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, C1-4 haloalkyl, C1-4 alkoxy, or COO(Re); Rc is C1-4alkyl, C1-4 haloalkyl, C^ alkoxy, N(Re)2, C3-6cycloalkyl, or a 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C3-6 cycloalkyl and the 4- to 6-membered heterocyclyl are optionally substituted by 1 to 5 Rb groups; Rd is COO(Re), N(Re)2, C3-6 cycloalkyl, or a 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C3-6 cycloalkyl and the 4- to 6-membered heterocyclyl are optionally substituted by 1 to 5 Rb groups; each R12 is C1-2alkyl, halo, -OC1-2alkyl, or cyano; each p is 0 to 4; and each Re is independently hydrogen or C1-4alkyl.

[0064] In certain embodiments, the compound of Formula I is a compound of Formula (Ia): wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X1, and X2 are as defined herein and R10a and R10b are independently halogen, cyano, C1-4alkoxy, C1-6alkyl, or C3-6cycloalkyl.

[0065] In certain embodiments, the compound of Formula I or Formula (Ia) is a compound of Formula (Ib) wherein: Z1 and Z2 are independently N or CH; m is 0 to 2, R10a and R10b are independently halogen, cyano, C1-4alkoxy, C1-6alkyl, or C3-6cycloalkyl, and R1, R2, R3, R4, R5, R6, R7, R8, R9, and X2 are as defined herein.

[0066] In certain embodiments, the compound of Formula I, (Ia), or (Ib), is a compound of Formula (Ic): wherein Z1 and Z2 are independently N or CH, R10a and R10b are independently halogen, cyano, C1-4alkoxy, C1-6alkyl, or C3-6cycloalkyl, and R1, R2, R3, R4, R5, R6, R7, R8, and R9, are as defined herein.

[0067] In certain embodiments, the compound of Formula I or (Ia) is a compound of Formula (Id): wherein R10a and R10b are independently halogen, cyano, C1-4alkoxy, C1-6alkyl, or C3-6cycloalkyl, and R1, R2, R3, R4, R5, R6, R7, R8, R9, X1, and X2 are as defined herein.

[0068] In certain embodiments, the compound of Formula I or (Ia) is a compound of Formula (Ie): where R1, Ra, R11, X1 and X2 are as defined here.

[0069] In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R4 and R7 can be the same or different. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R4 is hydrogen, C1-4alkyl, or C1-4haloalkyl. In certain embodiments, R4 is C1-4haloalkyl. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R4 is CF3. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R7 is hydrogen, C1-4alkyl, or C1-4haloalkyl. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R7 is C1-4haloalkyl. In certain embodiments, R7 is CF3. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R4 and R7 are CF3 or methyl. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R5, R6, R8, and R9 can be the same or different. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R5, R6, R8, and R9 are each independently hydrogen, halo, C1-2alkyl, C1-2 haloalkyl, or C3-6cycloalkyl. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R5, R6, R8, and R9 are hydrogen, methyl, or fluorine. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R5 and R6 are C1-alkyl. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R5 and R6 are methyl. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R8 and R9 are C1-alkyl. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R8 and R9 are methyl. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), two or more of R4, R5, and R6 or R7, R8, and R9 can join together to form one or more C3-6cycloalkyl groups which are optionally substituted with halogen.

[0070] In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R1 is a 5- to 6-membered heterocycle having 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 5- to 6-membered heterocycle or 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 Ra groups. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R1 is a 5- to 6-membered heterocycle having 1 to 3 heteroatoms selected from N, O, and S and is optionally substituted with 1 to 3 Ra groups. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R1 is: In certain embodiments, R1 is . In certain embodiments, R1 is:

[0071] In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), Ra is independently C1-4alkyl, C1-4alkyl having 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, C1-4 haloalkyl, or a 4 to 8 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with Ra1. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), Ra is independently C1-4alkyl, C1-4alkyl having 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, C1-4 haloalkyl, furanyl, oxetanyl, or 3,8-diazabicyclo[3.2.1]octanyl optionally substituted with Ra1. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), Ra is independently C1-4alkyl, C1-4alkyl having 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, or C1-4 haloalkyl. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), Ra is:

[0072] In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), Ra is C1-4 haloalkyl. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), Ra is: .

[0073] In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), Ra can be replaced with Ra1. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), Ra is replaced with a Ra1 group. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), Ra1 is C1-4alkyl, C3-6cycloalkyl, C1-4haloalkyl, or 4- to 8-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), the 4- to 8-membered heterocyclyl contains 1 to 2 nitrogen heteroatoms or 1 to 2 oxygen atoms.

[0074] In certain embodiments of a compound of Formula (I), (Ia), or (Ie), X1 is a 6-membered aryl or a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein each 6-membered aryl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 Rb groups. In certain embodiments of a compound of Formula (I), (Ia), or (Ie), X1 is pyrimidine or pyridine optionally substituted with 1 to 4 Rb groups. In certain embodiments of a compound of Formula (I), (Ia), or (Ie), X1 is pyrimidine or pyridine. In certain embodiments of a compound of Formula (I), (Ia), or (Ie), X1 is: In certain embodiments of a compound of Formula (I), (Ia), or (Ie), X1 is . In certain embodiments of a compound of Formula (I), (Ia), or (Ie), X1 is

[0075] In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Id) or (Ie), X2 is a 4- to 10-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S and is optionally substituted with one R11 and optionally substituted with 1 to 5 Rb groups. In certain embodiments, X2 can be substituted with R11 and Rb. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Id) or (Ie) X2 is:

[0076] In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Id) or (Ie), X2 and: . In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Id) or (Ie), X2 is:

[0077] In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Id) or (Ie) X2 is where:a) RP1, RP2, RP3, and RP4 are each hydrogen; b) RP1 and RP3 are used together to form a -CH2- or -CH2CH2- group and RP2 and RP4 are each hydrogen;c) RP2 and RP4 are used together to form a -CH2- or -CH2CH2- group and RP1 and RP3 are each hydrogen.d) RP1 and RP4 are used together to form a -CH2- group and RP2 and RP3 are each hydrogen; ore) RP2 and RP3 are used together to form a -CH2- group and RP1 and RP4 are each hydrogen.

[0078] In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Id) or (Ie) X2 is , where:RP1 and RP3 are used together to form a -CH2- or -CH2CH2- group and RP2 and RP4 are each hydrogen; orRP2 and RP4 are used together to form a -CH2- or -CH2CH2- group and RP1 and RP3 are each hydrogen.

[0079] In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), X2 is optionally substituted with R11. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), R11 is a 4- to 10-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), R11 is a 4- to 6-membered heterocycle having one oxygen. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), R11 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R11 is oxetan-3-yl, tetrahydrofuran-3-yl, or tetrahydropyran-4-yl.

[0080] In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R2 and R3 can be the same or different. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R2 and R3 are each independently C1-4alkyl, C3-6cycloalkyl, or O-R2A, wherein R2A is C1-4alkyl, C3-6cycloalkyl, or a 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R2 and R3 are each independently In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), R2 and R3 are each methoxy.

[0081] In certain embodiments of a compound of Formula (I), each R10 can be the same or different when n is greater than one. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), n=0, 1, or 2. In certain embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), each R10 is halogen. In certain embodiments, each R10 is chlorine or fluorine.

[0082] In certain embodiments of a compound of Formula (Ia), (Ib), (Ic), or (Id), R10a and R10b can be the same or different. In certain embodiments of a compound of Formula (Ia), (Ib), (Ic), or (Id), R10a and R10b are each halogen. In certain embodiments of a compound of Formula (Ia), (Ib), (Ic), or (Id), R10a and R10b are each chlorine or fluorine.

[0083] In certain embodiments of the compound of Formula I, A is ethynyl. In certain embodiments of a compound of Formula I, A is a bond.

[0084] In certain embodiments, whenever present, each of X1 and X2 can be substituted with one or more Rb groups. In certain embodiments, each Rb is independently halogen, oxo, C1-4alkyl, C1-4alkyl with 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, C1-4 haloalkyl, C1-4 alkoxy, or COO(Re). In certain embodiments, each Rb is independently oxo or halo.

[0085] In certain embodiments of a compound of Formula I, each R12 is C1-2alkyl, halo, -OC1-2alkyl, or cyano. In certain embodiments of a compound of Formula I, R12 is fluorine, chlorine, or methyl.

[0086] In certain embodiments of a compound of Formula (Ib) or (Ic), one of Z1 and Z2 is N, and the other is CH. In certain embodiments of a compound of Formula (Ib) or (Ic), both of Z1 and Z2 are N.

[0087] As described above, any of the definitions for the variables provided (e.g., A, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R10a, R10b, Z1, Z2, X1, and X2) may be combined and grouped with other variables, whether or not specifically related together.

[0088] In certain embodiments of a compound of Formula (Ia), R1 is Ra is C1-4 haloalkyl; X1 is pyrimidine or pyridine, R2 and R3 are each methoxy, R4 is CH3 or CF3, R7 is CH3 or CF3, R5, R6, R8, and R9 are each methyl, X2 is: ;R10a and R10b are each halogen; and R11 is a 4- to 6-membered heterocycle having one oxygen.

[0089] In certain embodiments of a compound of Formula (Ib), L N-RaR1 is Ra is C1-4 haloalkyl; m is 0, Z1 and Z2 are independently N or CH, R2 and R3 are each methoxy, R4 is CH3 or CF3, R7 is CH3 or CF3, R5, R6, R8, and R9 are each methyl; X2 is: ' R10a and R10b are each halogens; and R11 is a 4- to 6-membered heterocycle having one oxygen.

[0090] In certain embodiments of a compound of Formula (Ic), Ra is C1-4 haloalkyl; Z1 and Z2 are independently N or CH, R2 and R3 are each methoxy, R4 is CH3 or CF3, R7 is CH3 or CF3, R5, R6, R8, and R9 are each methyl; R10a and R10b are each halogen; and R11 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0091] In certain embodiments of a compound of Formula (Id), Ra is -CHF2; X1 is pyrimidine or pyridine, R2 and R3 are each methoxy, R4 is CH3 or CF3, R7 is CH3 or CF3, R5, R6, R8, and R9 are each methyl, X2 is and R10a and R10b are each halogen, and R11 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0092] In certain embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[0093] In certain embodiments, any of Examples 1-245, or a pharmaceutically acceptable salt thereof.

[0094] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[0095] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[0096] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[0097] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[0098] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[0099] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[00100] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[00101] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[00102] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[00103] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[00104] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof.

TREATMENT METHODS

[00105] Pharmaceutical compositions of the compounds of Formula (I) (including compounds of Formulae (Ia)-(Ie)) may be administered in single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example, as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal, and transdermal routines, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhaler, or by means of an impregnated or coated device, such as a stent, for example, or a cylindrical polymer inserted into the artery.

[00106] In one aspect, the compounds described herein can be administered orally. Oral administration can be by way of, for example, enteric coated capsules or tablets. In preparing pharmaceutical compositions that include at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, it is typically diluted by an excipient and/or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid or liquid material (as above) that acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, seals, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[00107] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations may additionally include: lubricating agents, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents, such as methyl and propyl hydroxy benzoates; sweetening agents; and flavoring agents.

[00108] Compositions including at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the subject using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be constructed for continuous, pulsatile, or demand delivery of pharmaceutical agents.

[00109] The compositions may, in some embodiments, be formulated in a unitary dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for humans and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. In some embodiments, for oral administration, each dosage unit contains from about 10 mg to about 1000 mg of a compound described herein, for example from about 50 mg to about 500 mg, for example from about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In other embodiments, for parenteral administration, each dosage unit contains from 0.1 to 700 mg of a compound described herein. It will be understood, therefore, that the amount of the compound actually administered will generally be determined by a physician in the light of the relevant circumstances, including the condition being treated, the administration routine chosen, the actual compound administered and its relative activity, the age, weight and response of the particular individual, and the severity of the individual's symptoms.

[00110] In certain embodiments, dosage levels can be from 0.1 mg to 100 mg per kilogram of body weight per day, for example from about 1 mg to about 50 mg per kilogram, for example from about 5 mg to about 30 mg per kilogram. Such dosage levels may, in certain instances, be useful in treating the conditions listed above. In other embodiments, dosage levels can be from about 10 mg to about 2000 mg per subject per day. The amount of active ingredient that can be combined with the carrier to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Dosage unit forms can contain from 1 mg to 1000 mg of an active ingredient.

[00111] The compounds described herein, or a pharmaceutically acceptable salt thereof, can be administered to a subject according to an effective dosage regimen over a desired period of time or duration, such as at least about a day, at least about a week, at least about a month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compound is administered on a daily or intermittent schedule. In one variation, the compound is administered on a monthly schedule. In one variation, the compound is administered every other month. In one variation, the compound is administered every three months. In one variation, the compound is administered every four months. In one variation, the compound is administered every five months. In one variation, the compound is administered every 6 months.

[00112] The dosage frequency or dosage of a compound described herein, or a pharmaceutically acceptable salt thereof, may be adjusted throughout treatment, based on the diagnosis of the administering physician. The compound may be administered to an individual (e.g., a human) in an effective amount. In certain embodiments, the compound is administered once daily.

[00113] To prepare solid compositions, such as tablets, the main active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be uniformly dispersed throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[00114] Tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and to permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, such materials including various polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[00115] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) will include one or more excipients. The excipients should be compatible with the other ingredients of the formulation and physiologically innocuous to the recipient. Examples of suitable excipients are well known to one of skill in the art of parenteral formulation and can be found, for example, in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009.

[00116] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt thereof, can be administered with a syringe. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-loaded with a compound described herein, or a pharmaceutically acceptable salt thereof.

[00117] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt thereof, can be administered with an autoinjector comprising a syringe. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with a compound described herein, or a pharmaceutically acceptable salt thereof.

[00118] In certain embodiments, a method of treating or preventing a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof is provided. In certain embodiments, a method of treating a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof is provided. In certain embodiments, the method comprises administering a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents. In certain embodiments, a subject is at risk of contracting the HIV virus, such as a subject who has one or more risk factors known to be associated with contracting the HIV virus. In certain embodiments, the subject may not have previously received antiviral treatment ("treatment naïve"). In certain embodiments, the individual may have previously received antiviral treatment (experienced treatment). In certain embodiments, the individual may have previously received antiviral treatment and developed resistance to the previously received antiviral treatment.

[00119] In certain embodiments, a method of treating or preventing a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents selected from the group consisting of HIV combination drugs, other drugs to treat HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds that target an HIV capsid, therapies immune-based, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-transisomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV Vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV inhibitors ribonuclease H, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 collector non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combinations thereof, is provided. In certain embodiments, the one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agent(s) is/are selected from the group consisting of HIV protease inhibiting compositions, HIV non-nucleoside reverse transcriptase inhibitors, HIV non-nucleotide reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or any combinations thereof. In certain embodiments, the one or more additional therapeutic agent(s) does not include a pharmacokinetic enhancer.

[00120] In certain embodiments, a method of inhibiting the replication of the HIV virus, treating AIDS, or delaying the onset of AIDS in a subject (e.g., a human), comprising administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject is described.

[00121] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof for use in the medical therapy of an HIV infection (e.g., HIV-1 or the replication of the HIV virus (e.g., HIV-1) or AIDS or delaying the onset of AIDS in an individual (e.g., a human)) is described.

[00122] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating an HIV infection or the replication of the HIV virus or AIDS or delaying the onset of AIDS in a subject (e.g., a human) is described. One embodiment relates to a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV infection or AIDS or for use in the therapeutic treatment or delaying the onset of AIDS.

[00123] In certain embodiments, the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for an HIV infection in a subject (e.g., a human) is described. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV infection is described.

[00124] In certain embodiments, in the methods of use, the administration is to an individual (e.g., a human) in need of the treatment. In certain embodiments, in the methods of use, the administration is to an individual (e.g., a human) who is at risk of developing AIDS.

[00125] The compounds described herein, or a pharmaceutically acceptable salt thereof, for use in therapy are provided. In one embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is for use in a method of treating an HIV infection or HIV virus replication or AIDS or delaying the onset of AIDS in an individual (e.g., a human).

[00126] The compounds described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing HIV infection in a subject in need thereof is provided. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a subject in need thereof is provided. In certain embodiments, the subject in need thereof is a human who has been infected with HIV. In certain embodiments, the subject in need thereof is a human who has been infected with HIV but has not developed AIDS. In certain embodiments, the subject in need thereof is an individual at risk of developing AIDS. In certain embodiments, the subject in need thereof is a human who has been infected with HIV and who has developed AIDS.

[00127] In one embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents as described herein for use in a method of treating or preventing HIV infection in a subject in need thereof is provided. In one embodiment, said additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs to treat HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds that target an HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, receptor antagonists complement C5a, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 sink non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, kinase inhibitors cyclin-dependent inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combinations thereof. In certain embodiments, said additional therapeutic agents are selected from the group consisting of HIV protease inhibiting compositions, HIV non-nucleoside reverse transcriptase inhibitors, HIV non-nucleotide reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or any combinations thereof.

[00128] In one embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with a first additional therapeutic agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine, is provided for use in a method of treating or preventing HIV infection in a subject in need thereof. In a particular embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with a first additional therapeutic agent selected from the group consisting of tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine, is provided for use in a method of treating or preventing HIV infection in a subject in need thereof.

[00129] In a particular embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is provided for use to prevent HIV infection from taking hold if the individual is exposed to the virus, and/or to prevent the virus from establishing a permanent infection, and/or to prevent the onset of symptoms of the disease, and/or to prevent the virus from reaching detectable levels in the blood, e.g., for pre-exposure prophylaxis (PREP) or post-exposure prophylaxis (PEP). Accordingly, in certain embodiments, methods for reducing the risk of acquiring HIV (e.g., HIV-1 and/or HIV-2) are provided. For example, methods for reducing the risk of acquiring HIV (e.g., HIV-1 and/or HIV-2) comprise administering a compound described herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, methods for reducing the risk of acquiring HIV (e.g., HIV-1 and/or HIV-2) comprise administering a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agent(s). In certain embodiments, methods for reducing the risk of acquiring HIV (e.g., HIV-1 and/or HIV-2) comprise administering a pharmaceutical composition comprising a therapeutically effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[00130] In certain embodiments, methods for reducing the risk of acquiring HIV (e.g., HIV-1 and/or HIV-2) comprise administering a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with safer sex practices. In certain embodiments, methods for reducing the risk of acquiring HIV (e.g., HIV-1 and/or HIV-2) comprise administering to an individual at risk of acquiring HIV. Examples of individuals at high risk of acquiring HIV include, without limitation, an individual who is at risk of sexual transmission of HIV.

[00131] In certain embodiments, the reduction in the risk of acquiring HIV is at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In certain embodiments, the reduction in the risk of acquiring HIV is at least about 75%. In certain embodiments, the reduction in the risk of acquiring HIV is about 80%, 85%, or 90%.

[00132] In another embodiment, the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an HIV infection in a human being having, having, or at risk of having the infection is described.

[00133] Also described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment or delay of the onset of AIDS.

[00134] Also described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV infection.

[00135] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, can be used as a research tool (e.g., to study HIV reverse transcriptase inhibition in a subject or in vitro).

[00136] Kits that include a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and suitable packaging are provided. In one embodiment, a kit also includes instructions for use. In one aspect, a kit includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and instructions for use of the compounds in treating the diseases or conditions described herein.

[00137] Articles of manufacture comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a suitable container are provided. The container may be a vial, jar, ampoule, pre-filled syringe, and intravenous bag.Administration of HIV Combination Therapy

[00138] In certain embodiments, a compound described herein is administered with one or more additional therapeutic agent(s). Co-administration of a compound described herein with one or more additional therapeutic agent(s) generally refers to the simultaneous or sequential administration of a compound described herein and one or more additional therapeutic agent(s), such that therapeutically effective amounts of the compound described herein and the one or more additional therapeutic agent(s) are both present in the patient's body. When administered sequentially, the combination can be administered in two or more administrations.

[00139] Co-administration includes administration of unit dosages of the compounds described herein before or after administration of unit dosages of one or more additional therapeutic agent(s). For example, the compound described herein can be administered within seconds, minutes, or hours of administration of the one or more additional therapeutic agent(s). In some embodiments, a unit dose of a compound described herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agent(s). Alternatively, a unit dose of one or more additional therapeutic agent(s) is administered first, followed by administration of a unit dose of a compound described herein within seconds or minutes. In other embodiments, a unit dose of a compound described herein is administered first, followed after a period of hours (e.g., 1-12 hours) by administration of a unit dose of one or more additional therapeutic agent(s). In still other embodiments, a unit dose of one or more additional therapeutic agent(s) is administered first, followed after a period of hours (e.g., 1-12 hours) by administration of a unit dose of a compound described herein.

[00140] In certain embodiments, a compound described herein is combined with one or more additional therapeutic agent(s) in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.

[00141] In certain embodiments, a compound of Formula (I) is formulated as a tablet, which may optionally contain one or more other compound(s) useful for treating HIV. In certain embodiments, a tablet may contain another active ingredient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[00142] In some embodiments, a compound of Formula (I) is formulated as a tablet, which may optionally contain one or more other compound(s) useful for treating HIV. In certain embodiments, the tablet may contain another active ingredient for treating HIV, such as compounds that target an HIV capsid, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[00143] In some embodiments, compounds that target an HIV capsid are selected from the group consisting of: and or a pharmaceutically acceptable salt thereof.

[00144] In certain embodiments, such tablets are suitable for once-daily dosing.HIV Combination Therapy

[00145] In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds that target an HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 sink non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[00146] In some embodiments, the additional therapeutic agent is selected from immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zinc-linker nucleases, homing nucleases, synthetic nucleases, TALENs), and cellular therapies, such as chimeric antigen receptor T cell, CAR-T (e.g., YESCARTA® (axicabtagene ciloleucel)) and engineered T cell receptors, TCR-T.

[00147] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination drugs, other drugs to treat HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof. HIV Combination Drugs

[00148] Examples of combination drugs include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat ; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate ; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine , and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, and lamivudine; Vacc-4x and rometopsin; and APH-0812.Other HIV Drugs

[00149] Examples of other drugs to treat HIV include acemannan, alisporivir, BanLec, deferiprone, Gamimun, met-enkephalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110,TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.HIV Inhibitors protease

[00150] Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17 , TMB-657 (PPL-100), T-169, BL-008, and TMC-310911. HIV reverse transcriptase inhibitors

[00151] Examples of non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, AIC-292, KM-023, and VM-1500.

[00152] In some embodiments, examples of non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, AIC-292, KM-023, PC-1005, and VM-1500.

[00153] Examples of HIV nucleoside or nucleotide reverse transcriptase inhibitors include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine, tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, and KP-1461.HIV Integrase Inhibitors

[00154] Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long-acting injection), diketo quinolin-4-1 derivatives, LEDGF-integrase inhibitor, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T-169, and cabotegravir.

[00155] Examples of HIV non-catalytic, or allosteric integrase inhibitors (NCINI) include CX-05045, CX-05168, and CX-14442.HIV Entry Inhibitors

[00156] Examples of HIV entry (fusion) include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 ligation inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

[00157] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, C25P polypeptide, TD-0680, and vMIP (Haimipu).

[00158] Samples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[00159] Examples of CD4 binding inhibitors include ibalizumab and CADA analogues.

[00160] Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[00161] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).HIV Maturation Inhibitors

[00162] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.Latent Reversal Agents

[00163] Examples of latency reversal agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberanylhydroxamic acids, suberoyl, anilide and hydroxamic acid), IL-15, JQ1, disulfram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, and GSK-343.

[00164] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[00165] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactones. Capsid Inhibitors

[00166] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid disruption compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301 and AVI-CAN1-15 series;

[00167] In some embodiments, examples of capsid inhibitors include: and , or a pharmaceutically acceptable salt thereof.

[00168] In some embodiments, the capsid inhibitor is selected from: and , or a pharmaceutically acceptable salt thereof

[00169] In some embodiments, the capsid inhibitor is: or a pharmaceutically acceptable salt thereof

[00170] In some embodiments, the capsid inhibitor is: or a pharmaceutically acceptable salt thereof.Immune-Based Therapies

[00171] Examples of immune-based therapies include modulators of bell-like receptors such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (Pd-L1) modulators; IL-15 agonists; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its mycophenolate mofetil ester derivative (MMF); ribavirin; rintatolimod, polyethyleneimine (PEI) polymer; gepon; Rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15/Fc fusion protein, normferon, peginterferon alfa-2a, peginterferon alfa-2b, recombinant interleukin-15, RPI-MN, GS-9620, and IR-103.

[00172] In some embodiments, immune-based therapies include modulators of bell-knell-like receptors such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (Pd-L1) modulators; IL-15 agonists; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its mycophenolate mofetil ester (MMF) derivative; ribavirin; Rintatolimod, polyethyleneimine (PEI) polymer; gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15/Fc fusion protein, normferon, peginterferon alfa-2a, peginterferon alfa-2b, recombinant interleukin-15, RPI-MN, GS-9620, STING modulators, RIG-I modulators, NOD2 modulators, and IR-103. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[00173] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG- 319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY- 3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR- 245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474. Antagonists of alpha-4/beta-7

[00174] Examples of alpha-4/beta-7 integrin antagonists include antibodies PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab. HIV Antibodies, Bispecific Antibodies, and "Antibody-Like" Therapeutic Proteins

[00175] Examples of HIV antibodies, bispecific antibodies, and antibody-like therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bnABs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360 and those targeting HIV gp120 or gp41, Antibody Recruitment Molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecific antibodies, anti-nef single domain antibodies, anti-Rev antibody, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, antibodies targeting gp140, therapeutic antibodies gp41-based HIV, human recombinant mAbs (PGT-121), ibalizumab, Imuglo, MB-66.

[00176] Examples of those that target HIV in such a manner include bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145, PGT121, MDX010(ipilimumab), VRC01, A32, 7B2, 10E8, VRC-07-523, VRC-HIVMAB080-00-AB, MGD-014, and VRC07.

[00177] In some embodiments, examples of those that target HIV in such a manner include, bavituximab, UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC60, 10-1074, PGT145, PGT121, PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, VRC01 PGDM1400, A32, 7B2, 10E8,10E8v4, CAP256-VRC26.25, DRVIA7, VRC-07-523, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, MGD-014 and VRC07. Example of HIV bispecific antibodies include MGD014.Pharmacokinetic Enhancers

[00178] Examples of pharmacokinetic enhancers include cobicistat and ritonavir.Additional Therapeutic Agents

[00179] Examples of additional therapeutic agents include the compounds described in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380 (Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013/091096 (Boehringer Ingelheim).HIV vaccines

[00180] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, liver vector vaccines, DNA vaccines, CD4-derived peptide vaccines, combination vaccines, rgp120 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), MonTeric Gp120 HIV-1 subtype C monomeric vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, recombinant adenovirus-5 (rAd5) multiclade DNA, Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvant vaccines, TatImmune, GTU-multiHIV (FIT-06), gp140 [delta] V2.TV1 + MF-59, rVSVIN HIV-1 anti-gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV -PT4, DNA- HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C + Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401,ETV-01, CDX-1401, rcAD26. MOS1.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and virus-like particle vaccines such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B/C fusion vaccine, GTU-based DNA vaccine, gag/pol/nef/env HIV DNA vaccine, anti-TAT HIV vaccine, polypeptide conjugate vaccine, dendritic cell vaccines, gag-based DNA vaccine, GI-2010, HIV-1 gp41 vaccine, HIV vaccine (PIKA adjuvant), I-key epitope/MHC class hybrid peptide vaccines II, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, HCMV pp71-deficient virus HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, variant gp120 polypeptide vaccine, rAd5 gag-pol env A/B/C vaccine.

[00181] In some embodiments, examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, combination vaccines, rgp120 (AIDSVAX), ALVAC HIV (VCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, recombinant adenovirus multiclade DNA-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly- ICLC adjuvant vaccines, TatImmune, GTU-multiHIV (FIT-06), gp140 [delta] V2.TV1 + MF- 59, rVSVIN HIV-1 gag vaccine, SeV-Ga g vaccine, AT-20, DNK- 4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX -B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C + Ad4-mGag), EN41- UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, vaccinercAD26.MOS1.HIV-Env, Ad26.Mod.HIV, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and virus-like particle vaccines such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B/C fusion vaccine, GTU-based DNA vaccine, gag/pol/nef/env HIV vaccine, anti-TAT HIV vaccine, conjugated polypeptides, dendritic cell vaccines, gag-based DNA vaccine, GI-2010, HIV-1 gp41 vaccine, HIV vaccine (PIKA adjuvant), I-key epitope/MHC class II hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, HIV gag vaccine with pp71-deficient HCMV virus, recombinant peptide vaccine (HIV infection), NCI HIV vaccine, rgp160, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, gp120 variable polypeptide vaccine, rAd5 gag-pol env A/B/C vaccine, DNA.HTI and MVA.HTI.HIV Combination Therapy

[00182] In a particular embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®, rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine, TDF + FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); adefovir; adefovir dipivoxyl; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenifovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir and lamivudine); dolutegravir, abacavir sulfate and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®, lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®, abacavir sulfate and lamivudine, ABC + 3TC); TRIZIVIR® (abacavir sulfate, zidovudine and lamivudine, ABC + AZT + 3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptor); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine and zidovudine; abacavir; and abacavir sulfate.

[00183] It will be recognized by one of skill in the art that the additional therapeutic agents listed above may be included in more than one of the classes listed above. The particular classes are not intended to limit the functionality of the compounds listed in those classes.

[00184] In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV protease inhibitor compound. In a further embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with two nucleotide or HIV nucleotide reverse transcriptase inhibitors.

[00185] In a particular embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[00186] In a particular embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[00187] In a particular embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[00188] In a particular embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenifovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[00189] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a capsid inhibitor(s) (e.g., capsid polymerization inhibitors and/or capsid disruption compounds).

[00190] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with (about 10 to about 1000 mg) of a capsid inhibitor selected from: and or a pharmaceutically acceptable salt thereof

[00191] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a capid inhibitor selected from: , or a pharmaceutically acceptable salt thereof.

[00192] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with: or a pharmaceutically acceptable salt thereof.

[00193] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with: or a pharmaceutically acceptable salt thereof

[00194] A compound as described herein (e.g., any compound of Formula (I)) may be combined with one or more additional therapeutic agent(s) at any dosage strength of the compound of Formula (I) (e.g., from 1 mg to 1000 mg of the compound).

[00195] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 530 mg of tenofovir alafenamide, in the form of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, or any salt of solvate form of tenofovir alafenamide. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. A compound as described herein (e.g., a compound of formula (I)) can be combined with the agents provided herein at any dosage count of the compound (e.g., from 1 mg to 1000 mg of the compound), the same as if each combination dosage were specifically and individually listed.

[00196] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300400, or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. A compound as described herein (e.g., a compound of formula (I)) can be combined with the agents provided herein at any dosage count of the compound (e.g., from 1 mg to 1000 mg of the compound), the same as if each dosage combination were specifically and individually listed.

[00197] In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor and an integrase inhibitor. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with GS-9131 and bictegravir.

[00198] In one embodiment, kits comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided. Combination Birth Control (Contraceptive) Therapy

[00199] Therapeutic agents used for birth control (contraception) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norelgestromin, norethindrone, noretynodrel, norgestimate, ormeloxifene, segesterone acetate, ulipristal acetate, and any combinations thereof. Gene Therapy and Cell Therapy

[00200] Gene Therapy and Cell Therapy including genetic modification to silence a gene; genetic methods to directly kill infected cells; the infusion of engineered immune cells to replace most of the patient's own immune system to enhance the immune response to infected cells, or activate the patient's own immune system to kill infected cells, or find and kill infected cells; genetic methods to modify cellular activity to further alter the endogenous immune response against infection.

[00201] Examples of dendritic cell therapy include AGS-004. Gene Editors

[00202] The genome editing system is selected from the group consisting of: a CRISPR/Cas9 system, a zinc-linker nuclease system, a TALEN system, a homing endonuclease system, and a meganuclease system.

[00203] Examples of HIV-targeting CRISPR/Cas9 systems include EBT101.CAR-T cell therapy

[00204] A population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen-binding domain. The HIV antigen includes an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, the CD4-induced binding site on gp120, N glycan on gp120, the V2 of gp120, the membrane proximal region on gp41. The immune effector cell is a T cell or an NK cell. In some embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or a combination thereof.

[00205] Examples of HIV CAR-T include VC-CAR-T.TCR-T Cell Therapy

[00206] TCR-T cells are engineered to target HIV-derived peptides present on the surface of virally infected cells.

[00207] Certain embodiments of the methods described herein exclude the administration of a pharmacokinetic enhancer. For example, in certain methods described herein, the subject is not administered a pharmacokinetic enhancer, such as cobicistat or ritonavir, during treatment with a compound described herein, or a pharmaceutically acceptable salt thereof. Thus, in certain embodiments, a method of treating or preventing a human immunodeficiency virus (HIV) infection is provided, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the treatment does not comprise the administration of a pharmacokinetic enhancer. In certain embodiments, a method of treating or preventing a human immunodeficiency virus (HIV) infection is provided, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, once daily to a subject in need thereof, wherein the treatment does not comprise administering a pharmacokinetic enhancer.

[00208] The present description likewise provides all of the P, S, A, and I intermediates described in the Examples section below.

EXAMPLES

[00209] Methods for preparing the compounds described herein will be apparent to those skilled in the art with suitable procedures being described, for example, in the reaction schemes and examples below.

[00210] Sections 1.1 - 1.8 provide exemplary synthetic schemes for assembly of compounds of Formula I. Sections 2.1 - 2.4 show the preparation of Intermediate I, Intermediate P, Intermediate S, and Intermediate A, when used herein. Section 3 provides the syntheses of exemplary compounds. Section 4 shows the biological activity.1. GENERAL SCHEMESSCHEME 1.1

[00211] Scheme 1.1 shows a general synthesis of a compound within the scope of Formula I starting with reductive amination of compound 1.1a with a substituted benzaldehyde (Intermediate P). The reductive amination can be carried out, for example, with a cyanoborohydride reagent such as sodium cyanoborohydride. Subsequent metal catalyzed coupling such as Sonogashira or Suzuki couplings. Sonogashira coupling of compound 1.1b with an alkynyl intermediate Sa yields a compound of Formula I.

[00212] Examples 1-130, 219, and 224-245 were prepared by this general strategy (by reductive amination of the appropriate Intermediate P with the corresponding organohalide peptide Intermediate I, followed by Sonogashira coupling with the appropriate Intermediate S). Example 1 provides exemplary reaction conditions and appropriate reagents for preparing a compound of Formula I according to Scheme 1.1. SCHEME 1.2

[00213] Scheme 1.2 shows a general synthesis of a compound within the scope of Formula I with reductive amination of a protected amino hydrazinyl iodophenyl butanol, compound 1.2a. Exemplary protecting groups (PG) for compound 1.2a include t-butylcarbonyl (BOC) and fluorenylmethyloxycarbonyl (FMOC) protecting groups. Reductive amination of compound 1.2a with a substituted benzaldehyde Intermediate P affords compound 1.2b after removal of the protecting groups. Reductive amination can be accomplished, by way of non-limiting example, with sodium cyanoborohydride. HATU coupling of compound 1.2b with an amino acid Intermediate Am affords compound 1.2c. Sonogashira coupling of compound 1.2c with an alkyne Intermediate Sa affords a compound of Formula I.

[00214] Examples 133-180 and 220 were prepared by this general strategy (reductive amination of P with an appropriate amino hydrazinyl iodophenyl butanol, followed by AmHATU coupling, which is then followed by Sonogashira coupling with an alkynyl Sa intermediate). Example 133 provides exemplary reaction conditions and appropriate reagents for preparing a compound of Formula I according to Scheme 1.2. SCHEME 1.3

[00215] Scheme 1.3 shows a general synthesis of a compound within the scope of Formula I starting with reductive amination of a protected organohalide compound 1.3a with a benzaldehyde intermediate P and removal of Boc to yield compound 1.3b. Reductive amination can be accomplished, by way of non-limiting example, with sodium cyanoborohydride. Removal of Boc can be accomplished, by way of non-limiting example, with trifluoroacetic acid or hydrochloric acid. HATU coupling of compound 1.3b with an amino acid intermediate Am yields peptide intermediate 1.3c. Sonogashira coupling of peptide intermediate 1.3c and an alkynyl intermediate S yields intermediate 1.3d. Subsequent reaction of compound 1.3d with an acyl chloride yields a compound of Formula I.

[00216] Examples 183-186 were prepared by this general strategy. Example 183 provides exemplary reaction conditions and suitable reagents for preparing a compound of the invention according to Scheme 1.3. SCHEME 1.4

[00217] X1 can be installed directly on the halophenyl as exemplified in Scheme 1.4. In this example, an organohalide intermediate SL (shown above where L is iodine, bromine, or chlorine) is coupled with compound 1.4a by a borylation-Suzuki reaction. Examples 188-201 were prepared using the methodology shown in Scheme 1.4. Exemplary reaction conditions are found in Example 188. SCHEME 1.5

[00218] Alternatively, X1 can be installed by metal-catalyzed coupling of a boronic acid or boronic ester (Intermediate Sb) with compound 1.5a. The reaction is conducted with XPhos Pd G2. XPhos is also known as XPhos is 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. Pd G2 is chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II). Examples 202-211 and 218 were prepared according to Scheme 1.5. Example 202 provides exemplary reaction conditions for this transformation. SCHEME 1.6

[00219] Example 212 was carried out in accordance with Scheme 1.6. Example 212 provides exemplary reaction conditions for transformations according to Scheme 1.6.SCHEME 1.7

[00220] Scheme 1.7 shows an example of a Suzuki cross-coupling, followed by Boc deprotection and amide bond formation. Exemplary reaction conditions can be found in Example 213. Examples 214-217 show installation of different R2 and R3 groups using the same general strategy, and the appropriate acid chloride. SCHEME 1.8

[00221] Scheme 1.8 shows a general synthesis of a compound within the scope of Formula I starting with reductive amination of compound 1.8a with a substituted benzaldehyde (Intermediate P). Reductive amination of compound 1.8a with a substituted benzaldehyde Intermediate P yields compound 1.8b. Reductive amination can be accomplished, by way of non-limiting example, with sodium cyanoborohydride. Subsequent epoxide opening of tert-butyl ((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate yields compound 1.8c. Subsequent Boc removal, followed by subsequent amide bond formation yields compound 1.8d. Boc removal can be accomplished, by way of non-limiting example, with trifluoroacetic acid or hydrochloric acid. Amide bond formation can be accomplished, by way of non-limiting example, with a carboxylic acid and a reagent such as HATU. Subsequent removal of the protecting group yields compound 1.8e. Subsequent amide bond formation yields compound 1.8f. Amide bond formation can be accomplished, by way of non-limiting example, with a carboxylic acid and a reagent such as HATU. Subsequent metal catalyzed coupling such as Sonogashira or Suzuki couplings can be accomplished. Sonogashira coupling of compound 1.8d with an alkynyl intermediate Sa yields a compound of Formula I.

[00222] Examples 221-223 were prepared by this general strategy.2. Synthesis of Intermediates2.1 Synthesis of Intermediates P

[00223] 4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzaldehyde (P1).

[00224] A suspension of 4-bromo-1H-imidazole (1 g, 6.8 mmol), cesium carbonate (44430 mg, 136.36 mmol), and difluoroiodomethane (10 wt % in THF, 20 mL, 10.62 mmol) in a sealed 75 mL vessel was heated at 50 °C overnight. The reaction mixture was cooled to room temperature and then filtered through Celite. The filter cake was washed with EtOAc. The filtrate was washed with brine, dried over sodium sulfate, and carefully concentrated. The residue was purified by column chromatography on silica (17% to 47% EtOAc/Hex) to yield 1.3 g of a mixture of regioisomers. This mixture was combined with 3,5-Difluoro-4-formylphenylboronic acid (1.6 g, 8.58 mmol), XPhos Pd G2 (0.4 g, 0.26 mmol), 2-(Dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (0.12 g, 0.26 mmol), Potassium phosphate tribasic (2 M, 3.3 mL) in dioxane (11 mL) and degassed for 10 min with argon then heated at 100 °C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with EtOAc and washed with brine 2x then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (23% to 92% EtOAc/Hex) to afford the desired isomer P1. MS (ESI) m/z 259.2 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 10.32 (d, J = 1.1 Hz, 1 H), 7.91 (d, J = 1.3 Hz, 1 H), 7.63 (d, J = 1.3 Hz, 1 H), 7.48−7.36 (m, 2 H), 7.16 (t, J = 60.8 Hz, 1 H).

[00225] 4-(1-(difluoromethyl)-1H-imidazol-4-yl)benzaldehyde (P2).

[00226] The title compound P2 was prepared according to the method presented for the synthesis of intermediate P1, but using (4-formylphenyl)boronic acid. MS (ESI) m/z 223.2 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 10.02 (s, 1 H), 8.01 - 7.89 (m, 5 H), 7.62 (d, J = 1.3 Hz, 1 H), 7.15 (t, J = 60.9 Hz, 1 H).

[00227] 4-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)-2,6-difluorobenzaldehyde (P3). To a heterogeneous solution of Cupric bromide (3.8 g, 17 mmol) and tert-butyl nitrite (2.53 mL, 21.25 mmol) in MeCN (78 mL) in a 3-neck flask loaded with a stir bar, side arm inlet, under argon, was added 5-cyclopropyl-1,3,4-thiadiazol-2-amine (2 g, 14.16 mmol) slowly due to exothermic reaction, and stirred at room temperature under argon overnight. The reaction mixture was quenched with 78 mL of saturated NH4Cl (aq) and extracted with diethyl ether, and the organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography on silica (10% to 50% EtOAc/Hex). The product (0.28 g, 1.34 mmol) was combined with 3,5-difluoro-4-formylphenylboronic acid (0.5 g, 2.69 mmol), XPhos Pd G2 (0.15 g, 0.09 mmol), 2-(Dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (45.06 mg, 0.09 mmol), potassium phosphate tribasic (2 M, 1.34 mL) in dioxane (4.9 mL) and degassed for 10 min with argon then heated at 100 °C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with EtOAc and washed with brine 2x then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (21% to 100% EtOAc/Hex) to yield the desired isomer P3. MS (ESI) m/z 267.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 10.37 (s, 1 H), 7.56 (d, J = 9.0 Hz, 2 H), 5.30 (d, J =0.7 Hz, 0 H), 2.47 (dt, J = 8.1, 3.7 Hz, 1 H), 1.55 (s, 5 H), 1.33 (dd, J =8.3, 4.1 Hz, 2 H), 1.26 (d, J = 4.4 Hz, 5 H), 0.92 - 0.79 (m, 2 H).

[00228] Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2, 6-difluorobenzaldehyde (P4).

[00229] In a 150 mL pressure vessel, a suspension of 3-bromo-1H-pyrazole (8 g, 54.43 mmol), cesium carbonate (53.2 g, 163.29 mmol), and difluoroiodomethane (10 wt % in THF, 200 mL, 106.23 mmol) was heated at 45 °C overnight. The reaction mixture was cooled to room temperature and then filtered through Celite. The filter cake was washed with Et2O (3 × 150 mL). The filtrate was washed with brine, dried over sodium sulfate, and carefully concentrated (20 °C bath, 100 mb vacuum) to yield ~17 g of a 1.5:1 ratio of regioisomers and solvent still present. This crude material was combined with 3,5-difluoro-4-formylphenylboronic acid (12.65 g, 68.03 mmol), palladium acetate (0.31 g, 1.381 mmol), butyldi-1-adamantylphosphine (1.171 g, 3.265 mmol), and potassium carbonate (22.80 g, 164.96 mmol) in dioxane (150 mL) and water (50 mL), the mixture was degassed for 10 min with argon then heated at 100 °C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with EtOAc and washed with brine 2x, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (5% to 15% EtOAc/Hex). The mixed fractions were recrystallized (5:1 Hex/EtOAc) and the combined pure product afforded P4. 1H NMR (400 MHz, Chloroform-d) δ 10.35 (d, J = 1.0 Hz, 1 H), 7.92 (d, J = 2.8 Hz, 1 H), 7.46 (d, J = 9.6 Hz, 2 H), 7.24 (t, J = 60.5 Hz, 1 H), 6.80 (d, J = 2.8 Hz, 1 H).

[00230] Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2-fluorobenzaldehyde (P5). The title compound P5 was prepared according to the method presented for the synthesis of intermediate P4 but using (3-fluoro-4-formylphenyl)boronic acid. 1H NMR (400 MHz, Chloroform-d) δ 10.41 (s, 1 H), 7.97 (dd, J = 8.0, 7.1 Hz, 1 H), 7.71 (d, J = 1.7 Hz, 1 H), 7.50 - 7.34 (m, 2 H), 6.55 (d, J = 1.7 Hz, 1 H).

[00231] Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzaldehyde (P6). The title compound P6 was prepared according to the method presented for the synthesis of intermediate P4 but using (4-formylphenyl)boronic acid. 1H NMR (400 MHz, Chloroform-d) δ 10.05 (s, 1 H), 8.03 - 7.93 (m, 4 H), 7.90 (d, J = 2.7 Hz, 1 H), 6.85 (d, J = 2.7 Hz, 1 H).

[00232] Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzaldehyde (P7). A suspension of 1-Difluoromethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.47 g, 6.03 mmol), 4 -bromo-2,6-difluorobenzaldehyde (1.1 g, 4.98 mmol), palladium acetate (0.03 g, 0.12 mmol), butyldi-1-adamantylphosphine (0.11 g, 0.3 mmol ) and potassium carbonate (2.06 g, 14.93 mmol) in water (7 ml) and 1,4-dioxane (22 ml) in a tube was degassed for 10 min with argon, then the tube was sealed and heated to 100 °C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with EtOAc and washed with brine 2x, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography silica (10% to 25% EtOAc/Hex) to afford P7. 1H NMR (400 MHz, Chloroform-d) δ 10.32 (s, 1 H), 8.16 (s, 1 H), 7.96 (s, 1 H), 7.23 (t, J = 60.4 Hz, 1 H), 7.14 (d, J = 9.5 Hz, 2 H).

[00233] Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorobenzaldehyde (P8). The title compound P8 was prepared according to the method presented for the synthesis of intermediate P7, but using 4-bromo-2-fluorobenzaldehyde. 1H NMR (400 MHz, Chloroform-d) δ 10.35 (d, J = 0.7 Hz, 1 H), 8.15 (d, J = 0.7 Hz, 1 H), 7.98 (q, J = 0.8 Hz, 1 H), 7.91 (dd, J = 8.1, 7.3 Hz, 1 H), 7.42 (ddd, J = 8.1, 1.7, 0.8 Hz, 1 H), 7.31 (dd, J = 11.3, 1.6 Hz, 1 H), 7.23 (s, 1 H).

[00234] Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzaldehyde (P9). The title compound P9 was prepared according to the method presented for the synthesis of intermediate P7 but using 4-bromobenzaldehyde. 1H NMR (400 MHz, Chloroform-d) δ 10.02 (s, 1 H), 8.16 (s, 1 H), 8.01 (d, J = 0.8 Hz, 1 H), 7.96 - 7.90 (m, 2 H), 7.71 - 7.66 (m, 2 H), 7.24 (t, J = 0.14 Hz, 1 H). Synthesis of 3-bromo-1-(2,2-difluoroethyl)-1H-pyrazole (P10a). To a solution of 3-bromo-1H-pyrazole (6 g, 42.86 mmol) and potassium carbonate (20.73 g, 150.03 mmol) in DMF (20 mL) at 35 °C was added a solution of 1,1-difluoro-2-iodoethane (24.68 g, 128.59 mmol) dropwise via an addition funnel. The reaction was stirred overnight, then cooled to room temperature, diluted with ether/hexanes, and washed with brine and NH4Cl solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (7% to 25% EtOAc/Hex) to afford P10a (5.4 g 63.6%). MS (ESI) m/z 211.0 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 7.36 (d, J = 2.4 Hz, 1 H), 6.32 (d, J = 2.4 Hz, 1 H), 6.06 (tt, J = 55.4, 4.3 Hz, 1 H), 4.41 (td, J = 13.3, 4.3 Hz, 2 H).

[00235] Synthesis of 4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzaldehyde (P10). P10a (4.31 g, 0.02 mol) was combined with 3,5-Difluoro-4-formylphenylboronic acid (4.96 g, 24.49 mmol), PdCl2(tBu2PPh)2 (570 mg, 0.92 mmol), and potassium phosphate tribasic monohydrate (1.0 M, 40.82 ml) in 2-methyltetrahydrofuran (20 ml) and water (20 ml), the mixture was degassed for 10 min with argon then heated at 75 °C overnight. The reaction was cooled to room temperature, the organic layer was separated, and the aqueous layer was extracted into EtOAc. The combined organic layers were washed with 1 M HCl then brine, the filtrate was concentrated under reduced pressure, the residue was diluted with EtOAc and washed with brine 2x, then dried over Na2SO4, filtered and concentrated under reduced pressure and recrystallized (1:3 EtOAc/hexanes). The separated solids contained a mixture of the desired isomer and unreacted boronic acid. This mixture was purified by column chromatography on silica (70% to 100% DCM/Hex) to afford P10 (2.3 g, 41%) MS (ESI) m/z 273.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 10.34 (d, J = 1.0 Hz, 1 H),7.55 (d, J = 2.4 Hz, 1 H), 7.47 - 7.38 (m, 2 H), 6.67 (d, J = 2.4 Hz, 1 H), 6.15 (tt, J = 55.3, 4.3 Hz, 1 H), 4.52 (td, J = 13.5, 4.3 Hz, 2 H).

[00236] Synthesis of 4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2-fluorobenzaldehyde (P11).

[00237] The title compound P11 was prepared according to the method presented for the synthesis of intermediate P10, but using (3-fluoro-4-formylphenyl)boronic acid. 1H NMR (400 MHz, Chloroform-d) δ 10.34 (d, J = 0.8 Hz, 1 H), 7.89 (dd, J = 8.1, 7.2 Hz, 1 H), 7.70 - 7.58 (m, 2 H), 7.54 (d, J = 2.4 Hz, 1 H), 7.33 (dt, J = 8.0, 1.0 Hz, 0 H), 7.26 (dd, J = 10.7, 1.5 Hz, 0 H), 6.68 (d, J = 2.4 Hz, 1 H), 6.42 (d, J = 1.9 Hz, 0 H), 6.15 (tt, J = 55.4, 4.3 Hz, 1 H), 4.52 (td, J = 13.5, 4.3 Hz, 2 H).

[00238] Synthesis of 4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)benzaldehyde (P12). The title compound P12 was prepared according to the method presented for the synthesis of compound P10, but using (4-formylphenyl)boronic acid. MS (ESI) m/z 273.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 10.34 (d, J = 1.0 Hz, 1 H), 7.55 (d, J = 2.4 Hz, 1 H), 7.47 - 7.38 (m, 2 H), 6.67 (d, J = 2.4 Hz, 1 H), 6.15 (tt, J = 55.3, 4.3 Hz, 1 H), 4.52 (td, J = 13.5, 4.3 Hz, 2 H).

[00239] Synthesis of 4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzaldehyde (P13).

[00240] A suspension of anhydrous copper(II) acetate (3.7 g, 20.41 mmol) and 2,2'-bipyridyl (3.2 g, 20.41 mmol) in DCE (40 mL) was degassed, heated to 50 °C, and stirred for 10 min before addition to 3-bromo-1H-pyrazole (3 g, 20.41 mmol), cyclopropylboronic acid (5.3 g, 20.41), and sodium carbonate (4.8 g, 44.91 mmol) in DCE (60 mL). The reaction was stirred at 65 °C for 48 h. The reaction mixture was cooled to room temperature, filtered through a Celite frit, and rinsed with EtOAc. The filtrate was concentrated under reduced pressure, the residue was partitioned between EtOAc and NH4Cl solution, the organic layer was washed with NH4Cl, Na2CO3 solution and brine, dried over Na2SO4 and purified by column chromatography on silica (10% to 35% EtOAc/Hex) to afford 3-bromo-1-cyclopropyl-1H-pyrazole.

[00241] 3-Bromo-1-cyclopropyl-1H-pyrazole (1.5 g, 8.18 mmol) was combined with 3,5-difluoro-4-formylphenylboronic acid (1.8 g, 9.8 mmol), PdCl2(tBu2PPh)2 (0.29 g, 0.41 mmol), and potassium phosphate tribasic monohydrate (4.71 g, 20.45 mmol) in 2-methyltetrahydrofuran (60 mL), and water (60 mL) was degassed for 10 min with argon then heated at reflux for 3 h. The reaction mixture was cooled to room temperature, the organic layer was separated, and the aqueous layer was extracted into EtOAc. The combined organic layers were washed with 1M HCl, then brine, filtered, and concentrated under reduced pressure, the residue was diluted with EtOAc and washed with brine 2x, then dried over Na2SO4, filtered, and concentrated under reduced pressure. This mixture was purified by column chromatography on silica (50% to 100% DCM/Hex-10% EtOAc/DCM) to afford P13 (1.2 g, 49%) MS (ESI) m/z 249.2 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 10.33 (s, 1 H), 7.52 (d, J = 2.4 Hz, 1 H), 7.42 (d, J = 10.1 Hz, 2 H), 6.57 (d, J = 2.4 Hz, 1 H), 3.66 (tt, J = 7.4, 3.9 Hz, 1 H), 1.26 - 1.15 (m, 2 H), 1.09 (qd, J = 5.7, 2.4 Hz, 2 H).

[00242] Synthesis of 2,6-difluoro-4-(4-fluoropyridin-2-yl)benzaldehyde (P14). A suspension of 2-bromo-5-fluoropyridine (0.95 g, 5.39 mmol), 3,5-difluoro-4-formylphenylboronic acid (0.8 g, 4.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (302 mg, 0.43 mmol), and potassium carbonate (1.49 g, 10.76 mmol) in a mixture of DME (10 mL) and water (5 mL) was degassed for 10 min with argon, then heated at 85 °C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, the residue was diluted with EtOAc and washed with brine 2x, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (10% to 20% EtOAc/Hex) to afford P14 (122 mg, 12%). MS (ESI) m/z 238.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 10.38 (d, J = 1.2 Hz, 1 H), 8.59 (d, J = 2.8 Hz, 1 H), 7.78 (ddd, J = 8.8, 4.2, 0.6 Hz, 1 H), 7.68 - 7.60 (m, 2 H), 7.55 (ddd, J = 8.8, 7.8, 2.9 Hz, 1 H).

[00243] Synthesis of 2,6-difluoro-4-(4-fluoropyridin-2-yl)benzaldehyde (P15). The title compound P15 was prepared according to the method presented for the synthesis of compound P14, but using 2-bromo-4-fluoropyridine. MS (ESI) m/z 238.2 [M+H]+. 1HRMN (400 MHz, Chloroform-d) δ 10.39 (s, 1 H), 8.70 (dd, J = 8.6, 5.5 Hz, 1 H), 7.67 (d, J = 9.9 Hz, 3 H), 7.48 (dd, J = 9.8, 2.3 Hz, 1 H), 7.11 (ddd, J = 7.9, 5.5, 2.3 Hz, 1 H).

[00244] Synthesis of 2,6-difluoro-4-(pyrimidin-2-yl)benzaldehyde (P16). 2-Bromopyrimidine (1 g, 6.29 mmol) and tetracycline(triphenylphosphine)palladium (218.05 mg, 0.19 mmol) in 1,2-dimethoxyethane (30 mL) were degassed for 5 min, then water (15 mL) was added, followed by 3,5-difluoro-4-formylphenylboronic acid (1.4 g, 7.55 mmol) and sodium bicarbonate (1.0 M in THF, 1.59 g, 18.87 mmol). The reaction mixture was heated at 85 °C overnight. After cooling to room temperature, the mixture was diluted with EtOAc and washed with saturated NaHCO3 solution and brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (0% to 40% EtOAc/Hex to afford P16. 1H NMR (400 MHz, Chloroform-d) δ 10.42 (d, J = 1.0 Hz, 1 H), 8.87 (d, J = 4.9 Hz, 2 H), 8.16−8.03 (m, 2 H), 7.32 (t, J = 4.8 Hz, 1 H).

[00245] (S)-2,6-difluoro-4-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)benzaldehyde (P17).

[00246] To a solution of 3-bromo-1H-pyrazole (583 mg, 3.97 mmol) in DMF (15 mL) cooled in an ice bath was added sodium hydride (60% dispersion in oil, 241 mg, 6.03 mmol). After stirring for 1.5 h, a solution of (R)-tetrahydrofuran-3-yl methanesulfonate (Ref.: PCT Int. Ped. 2013068458) (998 mg, 6.01 mmol) in DMF (5 mL) was added, and the reaction mixture was heated at 100 °C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and the crude residue was purified by column chromatography on silica (20% to 40% EtOAc/Hex to afford (S)-3-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazole (0.17 g, 0.78 mmol). This material was combined in a 20 mL microwave vial with 3,5-Difluoro-4-formylphenylboronic acid (0.19 g, 1 mmol), palladium acetate (6.5 mg, 0.03 mmol), butyldi-1-adamantylphosphine (21.4 mg, 0.06 mmol), and potassium carbonate (0.33 g, 2.4 mmol) in a mixture of water (2 mL) and 1,4-dioxane (6 mL). The mixture was degassed with argon for 5 min. min. The reaction was microwaved at 100 °C for 1.5 h, then cooled to room temperature, concentrated in vacuo , then diluted with EtOAc and washed with water and brine. The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure. This mixture was purified by column chromatography on silica (20% to 40% EtOAc/hex) to afford P17. MS (ESI) m/z 279.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 10.32 (d, J = 1.0 Hz, 1 H), 7.55 (d, J = 2.4 Hz, 1 H), 7.48 - 7.34 (m, 2 H), 6.62 (d, J = 2.4 Hz, 1 H), 5.03 (ddt, J = 8.2, 5.8, 3.4 Hz, 1 H), 4.31 - 4.03 (m, 4 H), 3.98 (td, J = 8.6, 5.5 Hz, 1 H), 2.51 (dtd, J = 13.4, 8.3, 7.1 Hz, 1 H), 2.43 - 2.28 (m, 1 H).

[00247] (R)-2,6-difluoro-4-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)benzaldehyde (P18).

[00248] The title compound P18 was prepared according to the method presented for the synthesis of compound P17, but using (S)-tetrahydrofuran-3-yl methanesulfonate (Reference: PCT Int. Ped. 2013068458). MS (ESI) m/z 279.1 [M+H] +. 1H NMR (400MHz, Chloroform-d) δ 10.34 (d, J = 1.1 Hz, 1 H), 7.56 (d, J = 2.4 Hz, 1 H), 7.50 - 7.33 (m, 2 H), 6.63 (d, J = 2.4 Hz, 1 H), 5.04 (ddt, J = 9.0, 6.6, 3.5 Hz, 1 H), 4.27 - 4.04 (m, 4 H), 3.99 (td, J = 8.6, 5.5 Hz, 1 H), 2.52 (dtd, J = 13.3, 8.2, 7.1 Hz, 1 H), 2.38 (dddd, J = 13.3, 8.0, 5.5, 3.4 Hz, 1 H).

[00249] 2,6-difluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)benzaldehyde (P19).

[00250] The title compound P19 was prepared according to the method presented for the synthesis of compound P4 but using 1-chloro-2-methylpropan-2-ol. MS (ESI) m/z 281.0 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 10.33 (s, 1 H), 7.52 (d, J = 2.3 Hz, 1 H), 7.47 - 7.35 (m, 2 H), 6.64 (d, J = 2.4 Hz, 1 H), 4.13 (s, 2 H), 1.22 (s, 7 H).

[00251] Synthesis of 2,6-difluoro-4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzaldehyde (P20). A suspension of S7a (0.14 g, 3.7 mol), (3,5-difluoro-4-formylphenyl)boronic acid (110.29 mg, 5.9 mol), potassium carbonate (0.15 g, 1 mmol), and tetrakis(triphenylphosphine)palladium (20 mg, 0.19 mmol) in a mixture of dioxane (15 ml) and water (15 ml) was degassed for 10 min. The reaction mixture was heated at 85 °C for 3 h. After cooling to room temperature, the mixture was diluted with EtOAc and washed with sat. NaHCO3 solution and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (0% to 40% EtOAc/Hex to afford P20 (99 mg, 62%). MS (ESI) m/z 387.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 10.33 (s, 1 H), 8.55 (s, 1 H), 7.11 (d, J = 9.8 Hz, 1 H), 4.74 (t, J = 6.3 Hz, 1 H), 4.61 (s, 1 H), 4.40 (d, J = 12.8 Hz, 1 H), 3.69 (s, 1 H), 3.33 - 3.02 (m, 3 H), 1.86 (s, 1 H), 1.65 (d, J = 8.1 Hz, 1 H), 1.55 (s, 2 H).

[00252] Synthesis of 4-(1-cyclopropyl-1H-pyrazol-3-yl)benzaldehyde (P21). The title compound P21 was prepared according to the method presented for the synthesis of compound P13, but using (4-formylphenyl)boronic acid. MS (ESI) m/z 213.2 [M+H] +. 1H NMR(400 MHz, Chloroform-d) δ 10.01 (s, 1 H), 7.97 (d, J = 8.3 Hz, 2 H),7.92 - 7.86 (m, 2 H), 7.50 (d, J = 2.3 Hz, 1 H), 6.61 (d, J = 2.3 Hz, 1 H),3.66 (tt, J = 7.4, 3.8 Hz, 1 H), 1.22 - 1.15 (m, 2 H), 1.11 - 1.03 (m, 2 H).

[00253] Synthesis of 2,6-difluoro-4-(6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)benzaldehyde (P22)

[00254] A suspension of S4a (0.53 g, 1 mmol), (3,5-difluoro-4-formylphenyl)boronic acid (413.8 mg, 2.0 mmol), potassium carbonate (0.16 g, 4 mmol), and Cl2Pd(tBu2PPh)2 (0.02 g, 0.37 mmol) in a mixture of dioxane (15 mL) and water (15 mL) was degassed for 10 min. The reaction mixture was heated at 60 °C for 3 h. After cooling to room temperature, the mixture was diluted with EtOAc and washed with sat. NaHCO3 solution and brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (1% to 15% (MeOH/ (1% E3N in EtOAc)) to afford P22 (470 mg, 85%). MS (ESI) m/z 372.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 10.34 (s, 1 H), 8.52 (d, J = 2.5 Hz, 1 H), 7.76 (dd, J = 8.9, 2.5 Hz, 1 H), 7.16 (d, J = 10.4 Hz, 2 H), 6.61 (d, J = 8.8 Hz, 1 H), 4.71 (t, J = 6.2 Hz, 2 H), 4.50 (s, 2 H), 3.87 (t, J = 6.2 Hz, 3 H), 3.57 (s, 4 H), 2.78 (d, J = 7.3 Hz, 1 H), 1.64 (d, J = 8.9 Hz, 1 H).

[00255] Synthesis of 2,6-difluoro-4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzaldehyde (P23).

[00256] The title compound P23 was prepared according to the method presented for the synthesis of compound P20, but using S3c. MS (ESI) m/z 386.1 [M+H] +.

[00257] Synthesis of 2,6-dichloro-4-(pyridin-2-yl)benzaldehyde (P24) and 2-chloro-4-(pyridin-2-yl)benzaldehyde (P25).

[00258] In a sealed tube, methyl 4-bromo-2,6-dichlorobenzoate (3.18 g, 11.2 mmol) and 2-(trimethylstannyl)pyridine (1.94 mL, 11.2 mmol) and tetrakis(triphenylphosphine)palladium (647.1 mg, 0.56 mmol) are suspended in DMF (25 mL). The mixture was degassed with argon for 10 min, heated at 100 °C for 18 h, and then at room temperature. After 48 h, the reaction was diluted with EtOAc and washed with KF (3 g in 50 mL water) and brine (3x), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (0% to 20% EtOAc/hexanes) to afford methyl 2,6-dichloro-4-(pyridin-2-yl)benzoate (1.5 g, 47.5%). This material was dissolved in THF (25 mL), cooled to 0 °C, then lithium aluminum hydride (0.4 g, 10.63 mmol) was added slowly, after the addition was complete, the reaction mixture was warmed slowly to room temperature and stirred for 1 h, then cooled again to 0 °C, water (500 uL) was added slowly (vigorous gas evolution), followed by NaOH (2 M, 500 uL), then water (1500 uL). The suspension was stirred at room temperature. After 1 h, Na 2 SO 4 was added, and then the mixture was filtered through Celite. The solid was rinsed with Et2O (~200 mL), and the filtrate was concentrated under reduced pressure, the residue was diluted with EtOAc and washed with water, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue (1.5 g, 5.9 mmol) was combined with pyridinium chlorochromate (1.91 g, 8.85 mmol) and Celite (700 mg, 7 mmol), DCM (10 mL) was added, and the reaction mixture was stirred at room temperature for 48 h. The reaction was filtered through a Celite frit with a small silica plug, and rinsed several times with DCM/EtOAc, and then the filtrate was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica to afford P24 (392 mg, 26.3%). MS (ESI) m/z 252.0 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 10.54 (s, 1 H), 8.74 (ddd, J = 4.8, 1.8, 0.9 Hz, 1 H), 8.06 (s, 2 H), 7.83 (ddd, J = 8.0, 7.4, 1.8 Hz, 1 H), 7.77 (dt, J = 8.0, 1.1 Hz, 1H), 7.36 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H) and P25 (195 mg, 15.2%). MS (ESI) m/z 218.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 10.52 (d, J = 0.8 Hz, 1 H), 8.74 (ddd, J = 4.8, 1.7, 1.0 Hz, 1 H), 8.17 (dd, J = 1.6, 0.5 Hz, 1 H), 8.07 - 7.95 (m, 2 H), 7.91 - 7.75 (m, 2 H), 7.39 - 7.29 (m, 1 H).

[00259] Synthesis 4-bromo-2,6-difluorobenzaldehyde (P26a)

[00260] To a solution of methyl 4-bromo-2-chloro-6-fluorobenzoate (5.6 g, 20.94 mmol) in DCM (100 mL) at -78 °C was added dropwise diisobutylaluminum hydride (1.0 M in toluene, 60 mL). After 4.5 h, the reaction mixture was quenched with MeOH (2.4 mL) then NaOH (6.0 M, 2.4 mL), followed by water (5 mL). The reaction was stirred for 1 h, and then Na2SO4 was added, filtered, and concentrated in vacuo, the residue (4.96 g, 20.71 mmol) was dissolved in DCM (100 mL) and cooled to 5 °C, then pyridinium chlorochromate (6.27 g, 0.03 mol) was added, and the mixture was stirred overnight, allowing to slowly warm to room temperature. Silica gel (10 g) was added, the mixture was filtered through a 3.81 cm (1.5 in) silica gel pad eluting with 5:1 DCM/EtOAc to yield P26a (4.67 g, 92%). 1HRMN (400 MHz, Chloroform-d) δ 10.38 (s, 1 H), 7.54 - 7.41 (m, 1 H), 7.31 (dd, J = 9.7, 1.8 Hz, 1 H). 19F NMR (377 MHz, Chloroform-d) δ - 113.31 (d, J = 9.7 Hz).

[00261] Synthesis of 2-chloro-6-fluoro-4-(pyridin-2-yl)benzaldehyde(P26)

[00262] To a solution of P26a (2.5 g, 10.53 mmol) and Pd(tBu2PPh)2Cl2 (213 mg, 0.34 mmol) in methyl tetrahydrofuran (7 mL) at room temperature was added 2-pyridylzinc bromide (0.5 M in THF, 28.43 mL). The reaction was degassed with Ar for 10 min, and then heated to 60 °C. After 3 h, the mixture was cooled to room temperature, diluted with EtOAc, and washed with saturated NH4Cl solution. The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (3% - 35% EtOAc in 1:1 DCM/hexane) to afford P26 (1.09 g, 41%) MS (ESI) m/z 236.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 10.49 (d, J = 1.1 Hz, 1 H), 8.74 (ddd, J = 4.8, 1.8, 1.0 Hz, 1 H), 7.96 (t, J = 1.4 Hz, 1 H), 7.86 (d, J = 1.8 Hz, 0 H), 7.85 - 7.80 (m, 1 H), 7.78 (q, J = 1.1 Hz, 1 H), 7.77 - 7.74 (m, 1 H), 7.36 (ddd, J = 7.4, 4.8, 1.2 Hz, 1 H). 19F NMR (377 MHz, Chloroform-d) δ -114.35 (d, J = 11.6 Hz).

[00263] Synthesis of 4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-2,6-difluorobenzaldehyde (P27).

[00264] 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine (1 g, 0.01 mol) in CH3CN (5 mL) at 15°C was combined with cuprous bromide (1.24 g, 0.01 mol) and cupric bromide (16.05 mg, 0.07 mmol), then tert-butyl nitrite (1.11 mL, 0.01 mol) was added very slowly, and the reaction was stirred overnight. The mixture was quenched with aqueous NH4Cl, diluted with DCM, the layers were divided, and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (7%-40% EtOAc/hexanes), and the product (0.59 g, 2.91 mmol) was combined with 3,5-difluoro-4-formylphenylboronic acid (0.81 g, 4.36 mmol), PdCl2(tBu2PPh)2 (0.08 g, 0.12 mmol), and potassium phosphate tribasic monohydrate (1.67 g, 7.27 mmol) in 2-methyltetrahydrofuran (25 mL) and water (60 mL). Degassed with argon for 10 min, the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water, 5% citric acid solution, and brine. The separated organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was crystallized from EtOAc/ether to afford P27 (486 mg, 63 %) MS (ESI) m/z 265.1 [M+H] +.

[00265] Synthesis of 2,6-difluoro-4-(pyridin-2-yl)benzaldehyde (P28).

[00266] The title compound P28 was prepared according to the method presented for the synthesis of compound P20, but using 2-bromopyridine. MS (ESI) m/z 202.2 [M+H] +.

[00267] Synthesis of 2,6-difluoro-4-(pyridin-2-yl)benzaldehyde (P29).

[00268] The title compound P29 was prepared according to the method presented for the synthesis of compound P20, but using 2-bromopyridine and (3-fluoro-4-formylphenyl)boronic acid. MS (ESI) m/z 220.2 [M+H] +.

[00269] Synthesis of 4-(pyridin-2-yl)benzaldehyde (P30).

[00270] The title compound P30 was prepared according to the method presented for the synthesis of compound P20, but using 2-bromopyridine and (4-formylphenyl)boronic acid. MS (ESI) m/z 184.1 [M+H] +.

[00271] Synthesis of bicyclo[2.2.1]heptane-1-carbaldehyde (P31)

[00272] Bicyclo[2.2.1]heptane-1-carboxylic acid (1000 mg, 0.01 mol) was dissolved in methyl tetrahydrofuran (3 mL), cooled to 0 °C, then lithium aluminum hydride (0.5 g, 14 mmol) was added slowly, after the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 2 h, the mixture was cooled again to 0 °C, and water (540 uL) was added slowly (vigorous gas evolution), followed by NaOH (2 M, 540 uL), then water (1500 uL). The suspension was stirred at room temperature. After 1 h, Na2SO4 was added, then the mixture was filtered through Celite. The solid was rinsed with DCM (~200 mL), and the filtrate was concentrated under reduced pressure. The crude residue (900 mg, 7.13 mmol) was dissolved in DCM (10 mL), cooled in an ice bath, and combined with pyridinium chlorochromate (2.61 g, 12.12 mmol) and Celite (700 mg, 7 mmol), the reaction was allowed to warm to room temperature slowly, and stirred for 48 h. The reaction was filtered through a Celite frit with a small silica plug, and rinsed several times with DCM, and then the filtrate was concentrated under reduced pressure at 5 °C to afford P31 (1.7 g, 95%). 1H NMR (400 MHz, Chloroform-d) δ 9.85 (s, 1 H), 2.41 (td, J = 4.2, 2.1 Hz, 1 H), 2.04 – 1.27 (m, 10 H).

[00273] Synthesis of 2,6-difluoro-4-(oxetan-3-yl)benzaldehyde (P32)

[00274] In a sealed tube, 3-Iodooxetane (0.24 mL, 3 mmol), (3,5-difluoro-4-formylphenyl)boronic acid (250 mg, 1.34 mmol), 4,4'-Di- tert -butyl-2,2'-dipyridyl (18.05 mg, 0.07 mmol), Ni(NO3)2 - 6H20 (19.55 mg, 0.07 mmol), and Potassium carbonate (557.51 mg, 4.03 mmol) in 1,4-Dioxane (5 mL) were combined. The mixture was degassed with argon for 10 min, heated at 80 °C for 12 h, and then cooled to room temperature. After 48 h, the reaction was diluted with EtOAc and washed with brine (2x) and dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (10% to 30% EtOAc/hexanes) to afford P32 (49 mg, 18%). 1H NMR (400 MHz, Chloroform-d) δ 10.26 (d, J = 1.2 Hz, 1 H), 6.99 (d, J = 9.5 Hz, 2 H), 5.04 (dd, J = 8.2, 6.3 Hz, 2 H), 4.62 (t, J = 6.3 Hz, 2 H), 4.14 (tt, J = 8.2, 6.2 Hz, 1 H).

[00275] Synthesis of 2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)benzaldehyde (P33)

[00276] Pinacol 3,6-Dihydro-2H-pyran-4-boronic acid ester (414.48 mg, 1.97 mmol), 4-bromo-2,6-difluorobenzyl alcohol (0.4 g, 2 mmol), tetrakis(triphenylphosphine)palladium (103.63 mg, 0.09 mmol), and sodium carbonate (2M, 2.24 mL) in 1,4-dioxane (6 mL) were combined. The mixture was degassed with argon for 10 min, heated at 80 °C for 12 h, and then cooled to room temperature. The reaction was diluted with EtOAc and washed with brine (2x) and dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (20% to 50% EtOAc/hexanes), the product (405 mg, 1.79 mmol) was dissolved in EtOAc (8 mL), palladium (10% on C, 38.1 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature under hydrogen for 18 h. The mixture was filtered through Celite and rinsed several times with EtOAc, the filtrate was concentrated under reduced pressure. The crude residue (450 mg, 1.97 mmol) was dissolved in DCM (10 mL) and combined with pyridinium chlorochromate (637.49 mg, 2.96 mmol), the reaction was stirred at room temperature for 48 h. The reaction was then filtered through Celite and rinsed several times with DCM, the filtrate was concentrated under reduced pressure to afford P33. 1H NMR (400 MHz, Chloroform-d) δ 10.28 (d, J = 1.2 Hz, 1 H), 6.85 (d, J = 10.0 Hz, 2 H), 4.08 (dt, J = 11.5, 3.2 Hz, 2 H), 3.60 - 3.33 (m, 2 H), 2.90 - 2.71 (m, 1 H), 1.83 - 1.70 (m, 4 H).

[00277] Synthesis of 2,6-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzaldehyde (P34).

[00278] The title compound P34 was prepared according to the method presented for the synthesis of compound P1, but using 2-bromo-5-methyl-1,3,4-oxadiazole. MS (ESI) m/z 225.1 [M+H] +

[00279] Synthesis of 4-(5-(difluoromethyl)pyridin-2-yl)-2,6-difluorobenzaldehyde (P35).

[00280] The title compound P35 was prepared according to the method presented for the synthesis of compound P1, but using 2-bromo-5-(difluoromethyl)pyridine. MS (ESI) m/z 270.1 [M+H] +

[00281] Synthesis of 2,6-difluoro-4-(pyrazin-2-yl)benzaldehyde (P36).

[00282] A mixture of 4-bromo-2,6-difluorobenzaldehyde (2 g, 9.05 mmol), bis(pinacolato)diboron (3.22 g, 12.67 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane (739.04 mg, 0.9 mmol), and potassium acetate (1776.34 mg, 18.1 mmol) in 1,4-dioxane (18 mL) was heated at 90 °C for 12 h. After cooling to room temperature, 2-bromopyrazine (1.64 mL, 18.1 mmol), tetrakis(triphenylphosphine)palladium (1.05 g, 0.9 mmol), and potassium carbonate (2 M, 11.31 mL) were added. The mixture was degassed by pulling vacuum and recharging with Ar (3x), then the reaction was heated at 90 °C for 12 h, cooled to room temperature, diluted with EtOAc, and washed with saturated brine. The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (0% - 100% EtOAc /DCM/) to afford P36 MS (ESI) m/z 221.1 [M+H]+.

[00283] Synthesis of 4-(5-fluoropyridin-2-yl)benzaldehyde (P37).

[00284] The title compound P37 was prepared according to the method presented for the synthesis of compound P14, but using (4-formylphenyl)boronic acid. MS (ESI) m/z 202.14 [M+H] +.

[00285] Synthesis of 4-ethynyl-2,6-difluorobenzaldehyde (P38).

[00286] A solution of Reagent 2 4-bromo-2,6-difluorobenzaldehyde (6 g, 27.15 mmol), CuI (517.06 mg, 2.71 mmol), PdCl2(tBu2PPh)2 (955.53 mg, 1.36 mmol), trimethylsilylacetylene (7.67 mL, 54.3 mmol) in a 3:1 mixture of CH3CN (50 mL)/Et3N (10 mL) was degassed with Argon for 10 min. The reaction mixture was heated at 70 °C for 18 h. After cooling to room temperature, the mixture was filtered through silica, the filtrate was concentrated, and purified by column chromatography on silica (1% - 15% EtOAc/Hex). The product was dissolved in MeOH (5 mL) and potassium carbonate (1876.01 mg, 13.57 mmol) was added, and the mixture was stirred at room temperature. After 20 min, the reaction was concentrated to dryness, then diluted with DCM and washed with brine. The organic extract was dried over Na2SO4 to yield p38 (2.99 g, 66 %). 1H NMR (400 MHz, Chloroform-d) δ 10.30 (d, J = 1.1 Hz, 1 H), 7.04 (d, J = 9.1 Hz, 2 H), 0.26 (s, 9 H).

[00287] Synthesis of 2,6-difluoro-4-(5-methylpyridin-2-yl)benzaldehyde (P39).

[00288] The title compound P39 was prepared according to the method presented for the synthesis of compound P16, but using 2-bromo-5-methylpyridine.

[00289] Synthesis of 4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzaldehyde (P40).

[00290] The title compound P40 was prepared according to the method presented for the synthesis of compound P1, but using 2-bromo-5-cyclopropyl-1,3,4-oxadiazole. MS (ESI) m/z 251.1 [M+H] +.

[00291] Synthesis of 2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzaldehyde (P41)

[00292] A solution of 3-bromo-1-methyl-1H-pyrazole (0.14 g, 3.7 mol), (3,5-difluoro-4-formylphenyl)boronic acid (9.19 g, 49.43 mmol), sodium carbonate (8.72 g, 82.27 mmol) and tetracycline(triphenylphosphine)palladium (1.9 g, 1.64 mmol) in a mixture of 1,2-dimethoxyethane (84 mL) and water (36 mL) was degassed for 10 min. The reaction mixture was heated at 100 °C for 18 h. After cooling to room temperature, the mixture was concentrated in vacuo, then diluted with EtOAc and washed with brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (20% to 40% EtOAc/Hex to afford P41. MS (ESI) m/z 223.3 [M+H] +.

[00293] Synthesis of 2,6-difluoro-4-(1H-pyrazol-3-yl)benzaldehyde(P42).

[00294] The title compound P42 was prepared according to the method presented for the synthesis of compound P1, but using 3-bromo-1H-pyrazole. MS (ESI) m/z 209.1 [M+H] +.

[00295] Synthesis of 2,6-difluoro-4-(4-(oxetan-3-yloxy)pyridin-2-yl)benzaldehyde (P43).

[00296] To a suspension of NaH (60%, 310.79 mg, 7.77 mmol) in THF (11 mL) was added oxetan-3-ol (0.42 mL, 6.66 mmol) dropwise, the mixture was stirred for 30 min, followed by addition of 2-chloro-4-fluoropyridine (0.5 mL, 5.55 mmol). The reaction mixture was stirred overnight, diluted with EtOAc and washed with water and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (30% to 60% EtOAc/Hex), the product (849 mg, 4.57 mmol) was combined with (3,5-difluoro-4-formylphenyl)boronic acid (1020.52 mg, 5.49 mmol), potassium carbonate (2 M, 5.49 mL), and Pd(dppf)Cl2 (279.29 mg, 0.46 mmol) in DME (23 mL), the mixture was degassed by pulling vacuum and recharging with Ar (5x) and heated at reflux for 3 h. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water and brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (30% to 60% EtOAc/Hex) to afford P43 (1.22 g, 80%). MS (ESI) m/z 292.1 [M+H] +.

[00297] Synthesis of 4-(1-(difluoromethyl)-1H-1,2,3-triazol-4-yl)-2,6-difluorobenzaldehyde (P44).

[00298] 4-Ethynyl-2,6-difluorobenzaldehyde (1.5 g, 9.0 mmol) was dissolved in THF (10 mL). Copper(I) thiophene-2-carboxylate (115.71 mg, 0.9 mmol) was added, followed by azidomethylpivalate (2.1 mL, 13.5 mmol) over 5 min. After 15 min, complete conversion was observed by LCMS analysis. The reaction was quenched with aqueous NaHCO 3 , and the intermediate was extracted into ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo . The crude mixture was suspended in 40 mL of 1:1 MeOH:EtOH, and aqueous NaOH solution was added (2M, 9.9 mL, 19.9 mmol). After 30 min, aqueous NaHCO3 was added, and the intermediate product was extracted into ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was transferred using THF (20 mL) to a 500 mL pressure vessel containing potassium carbonate (4.4 g, 32 mmol) and a magnetic stir bar. A solution of difluoroiodomethane (10% in THF, 68 mL, 36 mmol) was added, and the vessel was sealed. The mixture was stirred overnight at 50 °C. The crude mixture was filtered, concentrated in vacuo , and purified by flash column chromatography (0^25% EtOAc in 1:1 hexanes:DCM). The desired regioisomer was major and was isolated in the middle fractions. 1H NMR (400 MHz, Chloroform-d) δ 10.36 (s, 1 H), 8.31 (s, 1 H), 7.62 (t, J = 58.8 Hz, 1 H), 7.59 - 7.51 (m, 2 H). 19F NMR (377 MHz, Chloroform-d) δ -95.78 (d, J = 58.9 Hz), -113.68 (d, J = 9.2 Hz).

[00299] Synthesis of 4-(6-(difluoromethyl)pyridin-3-yl)-2,6-difluorobenzaldehyde (P45).

[00300] The title compound P45 was prepared according to the method presented for the synthesis of compound P16 but using 5-bromo-2-(difluoromethyl)pyridine. 1H NMR (400 MHz, Chloroform-d) δ 10.40 (s, 1 H), 8.94 - 8.79 (m, 1 H), 8.04 (dd, J = 8.2, 2.3 Hz, 1 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.25 (d, J = 9.3 Hz, 2 H), 6.70 (t, J = 55.2 Hz, 1 H). 19F NMR (377 MHz, Chloroform-d) δ -113.37 (d, J = 9.3 Hz), -116.56 (d, J = 55.5 Hz).

[00301] Synthesis of 4-(1-cyclopropyl-1H-pyrazol-4-yl)benzaldehyde(P46).

[00302] The title compound P46 was prepared according to the method presented for the synthesis of compound P7, but using (4-formylphenyl)boronic acid and 4-bromo-1-cyclopropyl-1H-pyrazole. MS (ESI) m/z 213.2 [M+H] +.

[00303] Synthesis of 2,6-difluoro-4-(2-methylpyrimidin-5-yl)benzaldehyde (P47).

[00304] The title compound P47 was prepared according to the method presented for the synthesis of compound P16, but using 5-bromo-2-methylpyrimidine. MS (ESI) m/z 235.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 10.38 (t, J = 1.0 Hz, 1 H), 8.86 (s, 2 H), 7.30 - 7.14 (m, 3 H), 2.82 (s, 3 H).2.2 SYNTHESIS OF INTERMEDIATE S

[00305] Synthesis of tert-butyl 7-(5-iodopyridin-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (S1a).

[00306] A solution of tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (1 g, 4.38 mmol), 2-fluoro-5-iodopyridine (1.12 g, 5.04 mmol), and sodium carbonate (0.84 g, 7.88 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was heated at 85 °C overnight. The mixture was cooled to room temperature, diluted with water, and extracted into DCM. The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica to afford S1a (1.57 g, 62.3 %). MS (ESI) m/z 431.9 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.30 (dd, J = 2.4, 0.7 Hz, 1 H), 7.66 (dd, J = 9.0, 2.3 Hz, 1 H), 6.44 (d, J = 9.0 Hz, 1 H), 4.25 (d, J = 12.7 Hz, 1 H), 4.21 - 4.00 (m, 3 H), 3.97 - 3.86 (m, 2 H), 3.80 (t, J = 11.9 Hz, 2 H), 3.26 (t, J = 15.1 Hz, 2 H), 1.48 (s, 9 H).

[00307] Synthesis of 7-(5-iodopyridin-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane (S1b).

[00308] To a solution of S1a (1.57 g, 0.004 mol) in DCM (15 mL) in a water bath at room temperature was added HCl (4.0 M in dioxane, 4.6 mL). The reaction was stirred at room temperature overnight. The reaction was concentrated to dryness. MS (ESI) m/z 332.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.26 (dd, J = 2.2, 0.7 Hz, 1 H), 8.22 (ddd, J = 9.5, 2.2, 1.0 Hz, 1 H), 7.27 (d, J = 9.7 Hz, 1 H), 4.60 (d, J = 14.4 Hz, 2 H), 4.21 (dt, J = 13.5, 0.9 Hz, 2 H), 4.08 (dt, J = 13.3, 2.4 Hz, 2 H), 3.88 (d, J = 14.6 Hz, 2 H), 3.81 (s, 2 H).

[00309] Synthesis of 7-(5-iodopyridin-2-yl)-9-(oxetan-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane (S1c).

[00310] To S1b (0.62 g, 8.62 mmol) suspended in NMP (6 mL), Et3N (0.12 mL, 0.8 mmol), oxetan-3-one (0.51 mL, 8.5 mmol), and sodium cyanoborohydride (2.62 g, 41.72 mmol) were added, and the reaction mixture was stirred for 5 min, then additional Et3N (0.18 mL, 0.1 mmol), stirred at room temperature for 4 h, then heated to 30 °C. After 2 h, the reaction was cooled to room temperature, diluted with EtOAc, and washed with brine. The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford S1c (0.84 g, 95 %). MS (ESI) m/z 388.1 [M+H] +.

[00311] Synthesis of 7-(5-ethynylpyridin-2-yl)-9-(oxetan-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane (S1)

[00312] A solution of S1c (0.84 g, 0 mol), CuI (24.73 mg, 0.13 mmol), PdCl2(tBu2PPh)2 (45.7 mg, 0.06 mmol), trimethylsilylacetylene (0.92 mL, 0.01 mol), in a 3:1 mixture of CH3CN (9 mL)/Et3N (3 mL) was degassed with argon for 10 min. The reaction mixture was heated at 40 °C for 90 min. The reaction was diluted with EtOAc and washed with NaHCO3 solution and dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was dissolved in MeOH (5 mL) and potassium carbonate (0.45 g, 3.0 mmol) was added, and the mixture was stirred at room temperature. After 15 min, the reaction was concentrated to dryness, then diluted with DCM and washed with brine. The organic extract was dried over Na2SO4 to yield S1 (300 mg 48 %). MS (ESI) m/z 286.2 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 8.17 (dd, J = 2.3, 0.8 Hz, 1 H), 7.40 (dd, J = 8.9, 2.3 Hz, 1 H), 6.35 (dd, J = 8.9, 0.8 Hz, 1 H), 4.55 (t, J = 6.2 Hz, 2 H), 4.42 (t, J = 5.9 Hz, 2 H), 4.25 (p, J = 6.2 Hz, 1 H), 3.84 (dt, J = 11.3, 2.2 Hz, 2 H), 3.78 (d, J = 12.9 Hz, 2 H), 3.71 (dt, J = 11.5, 0.9Hz, 2H), 3.24 (ddd, J = 12.9, 4.9, 2.0 Hz, 2 H), 2.92 (s, 1 H), 2.65 - 2.52 (m, 2 H).

[00313] Synthesis of 7-(5-ethynylpyridin-2-yl)-9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane.

[00314] The title compound S2 was prepared according to the method presented for the synthesis of compound S1, but using formaldehyde. MS (ESI) m/z 244.2 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.33 (d, J = 2.3 Hz, 1 H), 7.55 (dd, J = 8.9, 2.3 Hz, 1 H), 6.52 (d, J = 8.9 Hz, 1 H), 4.01 (d, J = 11.2 Hz, 2 H), 3.91 (d, J = 12.9 Hz, 2 H), 3.85 (d, J = 11.2 Hz, 2 H), 3.53 (ddd, J = 13.0, 4.8, 2.0 Hz, 2 H), 3.07 (s, 1 H), 2.86 - 2.75 (m, 2 H), 2.62 (s, 3 H).

[00315] Synthesis of tert-butyl 3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (S3a)

[00316] The title compound S3a was prepared according to the method presented for the synthesis of compound S1a, but using tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) m/z 415.8 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.36 - 8.26 (m, 1 H), 7.65 (dd, J = 9.0, 2.4 Hz, 1 H), 6.40 (d, J = 9.0 Hz, 1 H), 4.33 (s, 2 H), 3.82 (d, J = 40.5 Hz, 2 H), 3.05 (s, 2 H), 1.94 (dd, J = 8.7, 4.6 Hz, 2 H), 1.73 (d, J = 7.3 Hz, 2 H), 1.47 (s, 9 H).

[00317] Synthesis of 3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (S3b)

[00318] The title compound S3b was prepared according to the method presented for the synthesis of compound S1b, but using S3a. MS (ESI) m/z 316.1 [M+H] +.

[00319] Synthesis of 3-(5-iodopyridin-2-yl)-8-(oxetan-3-yl)-3,8 diazabicyclo[3.2.1]octane (S3c)

[00320] The title compound S3c was prepared according to the method presented for the synthesis of compound S1c, but using S3b. MS (ESI) m/z 372.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.22 (d, J = 2.3 Hz, 1 H), 7.57 (dd, J = 8.9, 2.4 Hz, 1 H), 6.30 (d, J = 9.0 Hz, 1 H), 4.65 (t, J = 6.3 Hz, 2 H), 4.52 (t, J = 5.8 Hz, 2 H), 3.70 (dd, J = 11.8, 2.4 Hz, 2 H), 3.23 - 3.08 (m, 2 H), 3.04 (dd, J = 11.7, 2.2 Hz, 2 H), 1.87 - 1.70 (m, 2 H), 1.63 (d, J = 7.5Hz, 2H).

[00321] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S3)

[00322] The title compound S3 was prepared according to the method presented for the synthesis of compound S1c, but using S3c. MS (ESI) m/z 244.0 [M+H] +. 1H NMR (400 MHz,Methanol-d4) δ 8.16 (d, J = 2.3 Hz, 1 H), 7.55 (dd, J = 8.9, 2.3 Hz, 1 H), 6.66 (d, J = 8.9 Hz, 1 H), 4.76 (t, J = 6.4 Hz, 3 H), 4.57 (t, J = 5.8 Hz, 3H), 3.88 (dd, J = 12.2, 2.4 Hz, 3 H), 3.78 (ddd, J = 11.9, 6.5, 5.4 Hz, 1H), 3.43 (s, 1 H), 3.29 (dd, J = 6.9, 1.7 Hz, 4 H), 3.10 (dd, J = 11.9, 2.2Hz, 3H), 1.93 (dd, J = 8.7, 4.4Hz, 2H), 1.68 (t, J = 6.9Hz, 2H).

[00323] Synthesis of 3-(5-iodopyridin-2-yl)-6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane (S4a)

[00324] The title compound S4a was prepared according to the method presented for the synthesis of compound S1c, but using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate. MS (ESI) m/z 358.0 [M+H] +.

[00325] Synthesis of 3-(5-ethynylpyridin-2-yl)-6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane (S4).

[00326] The title compound S4 was prepared according to the method presented for the synthesis of compound S1, but using S4a. MS (ESI) m/z 256.2 [M+H] +. 1H NMR (400 MHz,Methanol-d4) δ 8.13 (d, J = 2.3 Hz, 1 H), 7.53 (dd, J = 8.9, 2.3 Hz, 1 H), 6.55 (d, J = 8.9 Hz, 1 H), 4.65 (t, J = 6.3 Hz, 2 H), 4.36 (dd, J = 6.3, 4.7 Hz, 2 H), 3.77 (dd, J = 19.2, 5.7 Hz, 3 H), 3.44 (s, 4 H), 3.37 (s, 1 H), 2.61 (dt, J = 9.1, 6.2 Hz, 1 H), 1.54 (d, J = 9.1 Hz, 1 H).

[00327] Synthesis of tert-butyl ((4-(4-bromophenyl)-1H-imidazol-2-yl)methyl)(methyl)carbamate (S5a)

[00328] To a solution of N-(tert-butoxycarbonyl)-N-methylglycine (4.81 g, 25.41 mmol) and 2,4'-dibromoacetophenone (6.42 g, 23.1 mmol) in MeCN (50 mL) was added Et3N9 (3.84 mL, 0.03 mol), the mixture was stirred for 5 min (slight exotherm) then heated to 30 °C. The mixture was cooled to room temperature, diluted with EtOAc and washed with saturated NH4Cl, saturated NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was suspended in a mixture of isopropanol (10 mL) and toluene (100 mL), and ammonium acetate (37 g, 0.48 mol) was added, and the reaction was refluxed for 4 h. Cooled to room temperature, diluted with isopropyl acetate, washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography (50% to 100% EtOAc/Hexanes) to afford S5a (8.0 g, 90%) MS (ESI) m/z 368 [M+H] + . 1H NMR (400 MHz, Methanol-d4) δ 7.61 (d, J = 8.1 Hz, 2 H), 7.54 - 7.45 (m, 2 H), 7.40 (s, 1 H), 4.50 (s, 2 H), 2.91 (s, 3 H), 1.45 (d, J = 21.0 Hz, 9 H).

[00329] Synthesis of tert-butyl methyl((4-(4-((trimethylsilyl)ethynyl)phenyl)-1H-imidazol-2-yl)methyl)carbamate (S5b)

[00330] A solution of S5a (8 g, 0.02 mol), CuI (0.249 g, 1.0 mmol), PdCl2(tBu2PPh)2 (0.408 g, 0.655 mmol), and trimethylsilylacetylene (12.44 mL, 0.09 mol) in a 3:1 CH3CN/Et3N mixture (50 mL) was degassed with argon for 10 min. The reaction mixture was heated at 65 °C overnight. The reaction was diluted with EtOAc and washed with NaHCO3 solution and dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was used for the next step without purification (5.85 g, 70 %). MS (ESI) m/z 384.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 7.66 (d, J = 8.0 Hz, 2 H), 7.45 - 7.31 (m, 3 H), 4.84 (s, 2 H), 2.91 (s, 4 H), 1.46 (s, 9 H), 0.23 (s, 9 H).

[00331] Synthesis of 2-(4-ethynylphenyl)-7-methyl-7,8-dihydroimidazo[1,2-a]pyrazin-6(5H)-one (S5)

[00332] To an ice-cooled solution of S5b (1450 mg, 0 mol) in 2-methyl tetrahydrofuran (3 ml) was added sodium hydride (60%, 0.21 g, 0.01 mol). After 10 min, methyl bromoacetate (0.72 ml, 0.01 mol) was added; the mixture was stirred for 5 min, then warmed to room temperature. After 30 min, the reaction was diluted with EtOAc, rinsed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography (20% to 55% EtOAc/Hexanes). The product was dissolved in DCE (10 mL) and HCl (4.0 M in dioxane, 11.69 mL) and heated to 25 °C. After 2 h, the reaction was concentrated in vacuo. The residue was dissolved in DMF (10 mL), cesium carbonate (3.05 g, 0.01 mol) was added, heated at 65 °C for 45 min, cooled to room temperature, MeOH (10 mL) was added, and stirred for 25 min. Slowly diluted with ~40 mL of water and stirred for 20 min. The precipitated solids were filtered, rinsing with 30% MeOH in water. Concentrated under reduced pressure, and the crude material was carried on without further purification (0.479 g, 62%) MS (ESI) m/z 252.1 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 8.0 Hz, 2 H), 7.59 (s, 1 H), 7.40 (d, J = 8.0 Hz, 2 H), 4.65 (s, 2 H), 4.56 (s, 2 H), 4.11 (s, 1 H), 2.95 (s, 3 H).

[00333] Synthesis of (1R,4R)-2-(5-iodopyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane (S6a)

[00334] The title compound S6a was prepared according to the method presented for the synthesis of compound S1c, but using tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. MS (ESI) m/z 358.0 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.25 (dd, J = 2.3, 0.8 Hz, 1 H), 7.61 (ddd, J = 8.8, 2.3, 0.6 Hz, 1 H), 6.18 (dd, J = 8.8, 0.8 Hz, 1 H), 4.71 4.58 (m, 3 H), 4.52 (t, J = 6.1 Hz, 1 H), 4.45 (t, J = 5.9 Hz, 1 H), 4.05 - 3.85 (m, 1 H), 3.55 (d, J = 2.4 Hz, 1 H), 3.43 - 3.18 (m, 2 H), 2.94 (dd, J = 9.5, 2.0 Hz, 1 H), 2.83 (dd, J = 9.4, 1.4 Hz, 1 H), 2.00 - 1.89 (m, 1 H), 1.89 - 1.80 (m, 1 H), 1.39 (t, J = 7.3 Hz, 1 H).

[00335] Synthesis of (1R,4R)-2-(5-ethynylpyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane (S6)

[00336] The title compound S6 was prepared according to the method presented for the synthesis of compound S1, but using S6a. MS (ESI) m/z 256.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.13 (dd, J = 2.2, 0.9 Hz, 1 H), 7.37 (dd, J = 8.7, 2.3 Hz, 1 H), 6.23 - 5.98 (m, 1 H), 4.54 (dt, J = 12.8, 6.5 Hz, 3 H), 4.39 (t, J = 6.1 Hz, 1 H), 4.32 (t, J = 5.9 Hz, 1 H), 3.90 - 3.75 (m, 1 H), 3.31 - 3.10 (m, 2 H), 2.93 (s, 1 H), 2.82 (dd, J = 9.5, 2.0 Hz, 1 H), 2.73 - 2.60 (m, 1 H), 1.82 (ddt, J = 9.7, 2.4, 1.2 Hz, 1 H), 1.73 (ddt, J = 9.8, 2.5, 1.2 Hz, 1 H).

[00337] Synthesis of 3-(5-iodopyrimidin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S7a)

[00338] The title compound S7a was prepared according to the method presented for the synthesis of compound S1c but using 2-chloro-5-iodopyrimidine. MS (ESI) m/z 373.0 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.37 (s, 2H), 4.71 (t, J = 6.3 Hz, 2H), 4.59 (s, 2H), 4.21 (d, J = 12.4 Hz, 2H), 3.68 (s, 1H), 3.15 (s, 4H), 1.83 (s, 2H), 1.62 (s, 2H).

[00339] Synthesis of 3-(5-ethynylpyrimidin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S7)

[00340] The title compound S7 was prepared according to the method presented for the synthesis of compound S1 but using S7a. MS (ESI) m/z 271.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.38 (s, 1 H), 4.71 (t, J = 6.2 Hz, 2 H), 4.67 - 4.46 (m, 2 H), 4.40 - 4.24 (m, 2 H), 3.69 (p, J = 6.1 Hz, 1 H), 3.29 - 3.10 (m, 4 H), 1.89 - 1.73 (m, 2 H), 1.74 - 1.47 (m, 2 H).

[00341] Synthesis of (R)-8-(5-iodopyridin-2-yl)octahydropyrazino[2,1-c][1,4]oxazine (S8a).

[00342] The title compound S8a was prepared according to the method presented for the synthesis of compound S1a, but using (R)-octahydropyrazino[2,1-c][1.4]oxazine dihydrochloride. MS (ESI) m/z 346.1 [M+H] +.

[00343] Synthesis of (R)-8-(5-ethynylpyridin-2-yl) octahydropyrazino[2,1-c][1,4]oxazine (S8).

[00344] The title compound S8 was prepared according to the method presented for the synthesis of compound S1, but using S8a. MS (ESI) m/z 244.2 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.30 (dd, J = 2.3, 0.8 Hz, 1 H), 7.54 (dd, J = 8.8, 2.3 Hz, 1 H), 6.56 (dd, J = 8.9, 0.8 Hz, 1 H), 4.23 - 4.04 (m, 2 H), 3.88 (dd, J = 11.4, 3.4 Hz, 1 H), 3.81 (dd, J = 11.1, 3.1 Hz, 1 H), 3.73 (t, J = 11.5 Hz, 1 H), 3.32 (t, J = 10.6 Hz, 1 H), 3.13 - 3.01 (m, 2 H), 2.86 (d, J = 11.4 Hz, 1 H), 2.72 (d, J = 11.5 Hz, 1 H), 2.54 (t, J = 11.7 Hz, 1 H), 2.49 - 2.25 (m, 2 H).

[00345] Synthesis of (S)-8-(5-iodopyridin-2-yl)octahydropyrazino[2,1-c][1,4]oxazine (S9a).

[00346] The title compound S9a was prepared according to the method presented for the synthesis of compound S1a, but using (R)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride. MS (ESI) m/z 346.1 [M+H] +.

[00347] Synthesis of (S)-8-(5-ethynylpyridin-2-yl) octahydropyrazino[2,1-c][1,4]oxazine (S9).

[00348] The title compound S9 was prepared according to the method presented for the synthesis of compound S1, but using S9a. MS (ESI) m/z 244.2 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.30 (dd, J = 2.3, 0.8 Hz, 1 H), 7.54 (dd, J = 8.8, 2.3 Hz, 1 H), 6.56 (dd, J = 8.9, 0.8 Hz, 1 H), 4.23 - 4.04 (m, 2 H), 3.88 (dd, J = 11.4, 3.4 Hz, 1 H), 3.81 (dd, J = 11.1, 3.1 Hz, 1 H), 3.73 (t, J = 11.5 Hz, 1 H), 3.32 (t, J = 10.6 Hz, 1 H), 3.13 - 3.01 (m, 2 H), 2.86 (d, J = 11.4 Hz, 1 H), 2.72 (d, J = 11.5 Hz, 1 H), 2.54 (t, J = 11.7 Hz, 1 H), 2.49 - 2.25 (m, 2 H).

[00349] 1-(5-iodopyridin-2-yl)-4-(3-methyloxetan-3-yl)piperazine(S10a).

[00350] 1-Benzyl-4-(3-methyloxetan-3-yl)piperazine (6.75 g, 27.4 mmol) and palladium (10% on carbon, 1.46 g, 1.37 mmol) in EtOH (55 mL) were combined in a PARR flask and stirred on the hydrogenator overnight at 3.16 kg/cm2 (45 PSI). The reaction was filtered through Celite, the filter cake was washed with 25% MeOH/DCM, and the filtrate was concentrated under reduced pressure. The residue was taken up in 2-fluoro-5-iodopyridine to prepare the title compound S10a according to the method shown for the synthesis of compound S1a. MS (ESI) m/z 360.0 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J = 2.3 Hz, 1 H), 7.66 (d, J = 9.0 Hz, 1 H), 6.48 (d, J = 9.0 Hz, 1 H), 4.62 (d, J = 5.5 Hz, 2 H), 4.26 (d, J = 5.5 Hz, 2 H), 3.54 (s, 4 H), 2.44 (s, 5 H), 1.37 (s, 3 H).

[00351] 1-(5-ethynylpyridin-2-yl)-4-(3-methyloxetan-3-yl)piperazine (S10).

[00352] The title compound S10 was prepared according to the method presented for the synthesis of compound S1, but using S10a. MS (ESI) m/z 258.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.18 (dd, J = 2.3, 0.8 Hz, 1 H), 7.56 (dd, J = 8.9, 2.3 Hz, 1 H), 6.76 (dd, J = 9.0, 0.8 Hz, 1 H), 4.78 - 4.52 (m, 2 H), 4.28 (d, J = 5.9 Hz, 2 H), 3.65 - 3.48 (m, 4 H), 3.43 (s, 1 H), 2.59 - 2.39 (m, 4 H), 1.38 (d, J = 0.7 Hz, 3 H).

[00353] Synthesis of 3-(5-iodopyridin-2-yl)-8-((S)-tetrahydrofuran-3-yl)-3,8-diazabicyclo [3.2.1]octane (S11a).

[00354] A solution of S3b (1.0 g, 3.173 mmol), (R)-tetrahydrofuran-3-yl methanesulfonate (965 mg, 5.807 mmol), and potassium carbonate (1754 mg, 12.69 mmol) in CH3CN (15 mL) was heated at reflux for 48 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0% to 5% MeOH/EtOAc) to afford S11a (355.2 mg, 29 %) MS (ESI) m/z 386.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.22 (dd, J = 2.3, 0.7 Hz, 1 H), 7.56 (dd, J = 8.9, 2.4 Hz, 1 H), 6.29 (dd, J = 9.0, 0.7 Hz, 1 H), 3.96 - 3.84 (m, 2 H), 3.76 (dt, J = 8.6, 7.6 Hz, 1 H), 3.62 (ddd, J = 11.5, 8.9, 2.5 Hz, 2 H), 3.55 (dd, J = 8.2, 6.9 Hz, 1 H), 3.33 (d, J = 4.7 Hz, 1 H), 3.20 (d, J = 3.4 Hz, 1 H), 3.11 - 2.97 (m, 3 H), 2.02 (dtd, J = 12.1, 7.4, 4.7 Hz, 1 H), 1.95 - 1.87 (m, 2 H), 1.87 - 1.72 (m, 1 H), 1.67 - 1.56 (m, 2 H).

[00355] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-((S)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1]octane (S11).

[00356] The title compound S11 was prepared according to the method presented for the synthesis of compound S1, but using S11a. MS (ESI) m/z 284.1 [M+H] +. 1H NMR (400 MHz,Methanol-d4) δ 8.22 - 8.10 (m, 1 H), 7.55 (dd, J = 8.9, 2.3 Hz, 1 H), 6.65 (dd, J = 9.1, 0.8 Hz, 1 H), 3.97 (td, J = 8.1, 4.5 Hz, 2 H), 3.89 - 3.74 (m, 3 H), 3.63 (dd, J = 8.4, 6.6 Hz, 1 H), 3.48 (d, J = 4.4 Hz, 1 H), 3.42 (s, 1 H), 3.35 (s, 1 H), 3.26 - 3.19 (m, 1 H), 3.12 (dt, J = 12.2, 3.5 Hz, 2 H), 2.15 (ddd, J = 11.8, 8.2, 4.5 Hz, 1 H), 2.03 (dd, J = 14.4, 7.3 Hz, 2 H), 1.85 (dq, J = 12.0, 7.8 Hz, 1 H), 1.69 (d, J = 9.1Hz, 2H).

[00357] Synthesis of 3-(5-iodopyridin-2-yl)-8-((R)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1] octane (S12a).

[00358] The title compound S12a was prepared according to the method presented for the synthesis of compound S11a, but using (S)-tetrahydrofuran-3-yl methanesulfonate. MS (ESI) m/z 386.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J = 2.3 Hz, 1 H), 7.62 (dd, J = 9.0, 2.4 Hz, 1 H), 6.36 (d, J = 9.0 Hz, 1 H), 4.04 - 3.91 (m, 2 H), 3.90 - 3.75 (m, 1 H), 3.68 (ddd, J = 11.6, 8.8, 2.5 Hz, 2 H), 3.61 (dd, J = 8.2, 6.9 Hz, 1 H), 3.39 (q, J = 2.7 Hz, 1 H), 3.26 (dt, J = 5.0, 2.1 Hz, 1 H), 3.18 - 3.04 (m, 3 H), 2.17 - 2.01 (m, 1 H), 1.97 (dd, J = 9.4, 5.6 Hz, 2 H), 1.90 - 1.77 (m, 1 H), 1.74 - 1.63 (m, 2 H).

[00359] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-((R)-tetrahydrofuran-3-yl)-3,8diazabicyclo[3.2.1] octane (S12).

[00360] The title compound S12 was prepared according to the method presented for the synthesis of compound S1, but using S12a. MS (ESI) m/z 284.1 [M+H] +. 1H NMR (400 MHz,Methanol-d4) δ 8.22 - 8.07 (m, 1 H), 7.55 (dd, J = 8.9, 2.3 Hz, 1 H), 6.65 (dd, J = 8.8, 0.9 Hz, 1 H), 3.96 (td, J = 8.1, 4.5 Hz, 2 H), 3.88 - 3.74 (m, 3 H), 3.63 (dd, J = 8.4, 6.6 Hz, 1 H), 3.48 (s, 1 H), 3.42 (s, 1 H), 3.35 (s, 1 H), 3.24 (t, J = 7.0 Hz, 1 H), 3.12 (dt, J = 12.1, 3.4 Hz, 2 H), 2.26 - 2.09 (m, 1 H), 2.03 (dd, J = 14.1, 7.5 Hz, 2 H), 1.85 (dq, J = 12.0, 8.0 Hz, 1 H), 1.69 (d, J = 9.1 Hz, 2 H).

[00361] Synthesis of 3-(5-iodopyridin-2-yl)-8-(3-methyloxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S13a)

[00362] A suspension of S3b (3 g, 9.519 mmol), diethyl 2-bromo-2-methylmalonate (2.25 mL, 11.78 mmol), and sodium carbonate (1.19 g, 19.19 mmol) in NMP (30 mL) in a sealed 100 mL tube was stirred at 70 °C for 48 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with brine 2x. The organic extract was dried over Na2SO4, filtered, and the crude residue was purified by column chromatography on silica (10%-20% EtOAc/hexanes) to afford diethyl 2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylmalonate (2.32 g, 50%). MS (ESI) m/z 488.0 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.27 (dd, J = 2.4, 0.7 Hz, 1 H), 7.61 (dd, J = 9.0, 2.4 Hz, 1 H), 6.51 - 6.27 (m, 1 H), 4.37 - 4.07 (m, 4 H), 3.84 (s, 2 H), 3.79 - 3.72 (m, 2 H), 3.29 - 3.07 (m, 2 H), 1.77 - 1.63 (m, 4 H), 1.62 (s, 3 H), 1.27 (t, J = 7.2 Hz, 6 H).

[00363] To a solution of diethyl 2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylmalonate (907.9 mg, 1.863 mmol) in DCM (40 mL) at -78 °C was added Dibal-H (1.0 M in toluene, 93 mL). The reaction was gradually warmed to room temperature and stirred overnight. Dibal-H (1.0 M in DCM, 16 mL) was added, stirred for 1 h, then cooled to 0 °C and diluted with Et2O. Water (4.4 mL) and 15% NaOH (4.4 mL) were slowly added, followed by water (10.9 mL), warmed to room temperature and stirred for 15 min. Na2SO4 was added, stirred for 15 min, then the salts were filtered to yield 2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropane-1,3-diol (2.059 g, 65%). MS (ESI) m/z 404.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.18 (dd, J = 2.4, 0.7 Hz, 1 H), 7.69 (dd, J = 9.0, 2.4 Hz, 1 H), 6.54 (d, J = 9.1 Hz, 1 H), 3.91 - 3.66 (m, 4 H), 3.49 (s, 4 H), 3.10 - 2.88 (m, 2 H), 1.83 (d, J = 8.8 Hz, 2 H), 1.72 (t, J = 6.6 Hz, 2 H), 1.00 (s, 3 H).

[00364] To a solution of 2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropane-1,3-diol (2.06 g, 5.106 mmol) and triethylamine (1.5 mL, 10.76 mmol) in THF (25 mL) at 0 °C was added methanesulfonyl chloride (0.40 mL, 5.169 mmol). The reaction was gradually warmed to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic extract was dried over Na2SO4, filtered, and the crude residue was purified by column chromatography on silica (25%-50% EtOAc/hexanes) to afford 3-chloro-2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropan-1-ol (441.6 mg, 20.5%). MS (ESI) m/z 422.2 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.27 (dd, J = 2.4, 0.7 Hz, 1 H), 7.62 (dd, J = 8.9, 2.4 Hz, 1 H), 6.35 (dd, J = 9.0, 0.7 Hz, 1 H), 4.63 (s, 1 H), 3.90 - 3.63 (m, 4 H), 3.56 (d, J = 5.1 Hz, 1 H), 3.35 (s, 1 H), 3.06 (dt, J = 11.8, 3.0 Hz, 2 H), 2.87 (t, J = 13.5 Hz, 1 H), 2.66 (d, J = 14.0 Hz, 1H), 1.88 (dt, J = 9.9, 4.9 Hz, 2 H), 1.76 - 1.63 (m, 2 H), 1.57 (s, 3 H).

[00365] To a solution of 3-chloro-2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropan-1-ol (418.5 mg, 0.992 mmol) in THF (10 mL) at 0 °C was added potassium tert-butoxide (1.0 M THF, 3 mL). After 10 min, the reaction mixture was quenched with water, diluted with EtOAc, and washed with brine. The organic extract was dried over Na 2 SO 4 , filtered, and the crude residue was purified by column chromatography on silica (50%-100% EtOAc/hexanes) to afford S13a (222.8 mg, 58% yield). MS (ESI) m/z 386.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.27 (dd, J = 2.4, 0.7 Hz, 1 H), 7.61 (dd, J = 9.0, 2.4 Hz, 1 H), 6.35 (dd, J = 9.0, 0.7 Hz, 1 H), 3.68 (ddd, J = 11.5, 4.4, 2.6 Hz, 2 H), 3.49 - 3.34 (m, 1 H), 3.30 (q, J = 2.7 Hz, 1 H), 3.07 (dd, J = 11.6, 2.5 Hz, 2 H), 2.70 (dd, J = 5.0, 0.7 Hz, 1 H), 2.64 - 2.53 (m, 2 H), 2.39 (d, J = 13.2 Hz, 1 H), 1.96 - 1.79 (m, 2 H), 1.68 - 1.57 (m, 2 H), 1.42 (d, J = 0.6 Hz, 3 H).

[00366] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-(3-methyloxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S13).

[00367] The title compound S13 was prepared according to the method presented for the synthesis of compound S1, but using S13a. MS (ESI) m/z 284.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.15 (dd, J = 2.3, 0.8 Hz, 1 H), 7.53 (dd, J = 8.9, 2.3 Hz, 1 H), 6.64 (dd, J = 9.0, 0.8 Hz, 1 H), 3.91 - 3.74 (m, 3 H), 3.50 - 3.43 (m, 1 H), 3.42 (s, 1 H), 3.39 - 3.32 (m, 1 H), 3.08 (dt, J = 11.7, 1.9 Hz, 3 H), 2.72 (dd, J = 4.9, 0.7 Hz, 2 H), 2.66 (d, J = 13.3 Hz, 1H), 2.60 (d, J = 4.9 Hz, 1 H), 2.43 (d, J = 13.3 Hz, 1 H), 1.94 (dd, J = 9.4, 5.5 Hz, 3 H), 1.69 - 1.57 (m, 2 H), 1.42 (d, J = 0.6 Hz, 4 H).

[00368] Synthesis of 1-(5-bromopyridin-2-yl)piperazine hydrochloride (S14a)

[00369] To a solution of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (5 g, 14.61 mmol) in DCM (60 mL) and MeOH (18 mL) was added HCl (4.0 M in dioxanes, 18 mL, 72 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with DCM and washed with 2N NaOH. The aqueous layer was extracted with DCM 2x, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford S14a (3.2 g, 90.4 %). MS (ESI) m/z 242.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.18 (dd, J = 2.6, 0.7 Hz, 1 H), 7.52 (dd, J = 9.0, 2.6 Hz, 1 H), 6.53 (dd, J = 9.1, 0.7 Hz, 1 H), 3.54 - 3.40 (m, 4 H), 3.09 - 2.87 (m, 4 H).

[00370] Synthesis of (R)-1-(5-bromopyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S14b).

[00371] The title compound S14a was prepared according to the method presented for the synthesis of compound S11a, but using S14a and (S)-tetrahydrofuran-3-yl methanesulfonate. MS (ESI) m/z 312.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.19 (dd, J = 2.6, 0.7 Hz, 1 H), 7.53 (dd, J = 9.0, 2.5 Hz, 1 H), 6.54 (dd, J = 9.0, 0.7 Hz, 1 H), 3.96 (td, J = 8.6, 4.4 Hz, 1 H), 3.91 (dd, J = 8.7, 6.8 Hz, 1 H), 3.80 (td, J = 8.4, 7.5 Hz, 1 H), 3.69 (t, J = 7.7 Hz, 1 H), 3.52 (t, J = 5.3 Hz, 4 H), 3.01 (t, J = 7.3Hz, 1 H), 2.63 (d, J = 9.9 Hz, 2 H), 2.57 - 2.46 (m, 2 H), 2.07 (ddd, J = 9.9, 7.1, 3.3 Hz, 1 H), 1.90 (q, J = 11.1, 9.5 Hz, 1 H).

[00372] Synthesis of (R)-1-(5-ethynylpyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S14).

[00373] The title compound S14 was prepared according to the method presented for the synthesis of compound S1, but using S14b. MS (ESI) m/z 258.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.18 (d, J = 2.3 Hz, 1 H), 7.56 (dd, J = 8.8, 2.3 Hz, 1 H), 6.76 (d, J = 8.8 Hz, 1 H), 3.95 (dt, J = 8.5, 4.3 Hz, 1 H), 3.90 (dd, J = 8.8, 7.0 Hz, 2 H), 3.76 (q, J = 8.2 Hz, 1 H), 3.68 (dd, J = 8.8, 6.6 Hz, 1 H), 3.58 (t, J = 5.2 Hz, 4 H), 3.43 (s, 1 H), 3.09 - 2.97 (m, 1 H), 2.65 (dt, J = 10.6, 5.2 Hz, 2 H), 2.54 (dt, J = 11.2, 5.2 Hz, 2 H), 2.20 - 2.06 (m, 1 H), 1.96 - 1.83 (m, 1 H).

[00374] Synthesis of (S)-1-(5-bromopyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S15a).

[00375] The title compound S15a was prepared according to the method presented for the synthesis of compound S11a, but using S14a. MS (ESI) m/z 312.2 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.18 (dd, J = 2.6, 0.7 Hz, 1 H), 7.52 (dd, J = 9.0, 2.6 Hz, 1 H), 6.53 (dd, J = 9.1, 0.7 Hz, 1 H), 3.96 (td, J = 8.6, 4.4 Hz, 1 H), 3.91 (dd, J = 8.6, 6.8 Hz, 1 H), 3.80 (td, J = 8.4, 7.5 Hz, 1 H), 3.68 (dd, J = 8.7, 6.7 Hz, 1 H), 3.52 (dd, J = 5.9, 4.5 Hz, 4 H), 3.00 (p, J = 7.1 Hz, 1 H), 2.63 (dt, J = 10.7, 5.2 Hz, 2 H), 2.50 (dt, J = 10.8, 5.1 Hz, 2 H), 2.17 - 1.99 (m, 1 H), 1.99 - 1.79 (m, 1 H).

[00376] Synthesis of (S)-1-(5-ethynylpyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S15).

[00377] The title compound S15 was prepared according to the method presented for the synthesis of compound S1, but using S15a. MS (ESI) m/z 258.1 [M+H] +. 1H NMR (400 MHz,Methanol-d4) δ 8.09 (dd, J = 2.4, 0.8 Hz, 1 H), 7.47 (dd, J = 8.9, 2.3 Hz, 1 H), 6.66 (dd, J = 9.0, 0.8 Hz, 1 H), 3.86 (dt, J = 8.6, 4.3 Hz, 1 H), 3.80 (dd, J = 8.9, 7.0 Hz, 2 H), 3.67 (td, J = 8.4, 7.2 Hz, 1 H), 3.59 (dd, J = 8.7, 6.6 Hz, 1 H), 3.49 (t, J = 5.2 Hz, 4 H), 3.34 (s, 1 H), 3.02 - 2.86 (m, 1 H), 2.55 (dt, J = 10.7, 5.2 Hz, 2 H), 2.44 (dt, J = 11.1, 5.2 Hz, 2 H), 2.10 - 1.94 (m, 2 H), 1.86 - 1.71 (m, 2 H).

[00378] Synthesis of tert-butyl 3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (S16).

[00379] The title compound S16 was prepared according to the method presented for the synthesis of compound S1, but using S3a. MS (ESI) m/z 313.9 [M+H] +. 1H NMR (400 MHz,Methanol-d4) δ 8.18 (dd, J = 2.3, 0.8 Hz, 1 H), 7.56 (dd, J = 8.9, 2.3 Hz, 1 H), 6.69 (dd, J = 8.9, 0.9 Hz, 1 H), 4.45 - 4.30 (m, 2 H), 4.04 - 3.95 (m, 2 H), 3.43 (s, 1 H), 3.02 (d, J = 12.2 Hz, 2 H), 1.94 (dd, J = 8.7, 4.4 Hz, 2 H), 1.75 (d, J = 7.3 Hz, 2 H), 1.48 (s, 9 H).

[00380] Synthesis of tert-butyl 6-(5-iodopyridin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate (S17a).

[00381] The title compound S17a was prepared according to the method presented for the synthesis of compound S1a but using tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate. MS (ESI) m/z 401.9 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J = 2.2 Hz, 1 H), 7.67 (d, J = 8.7 Hz, 1 H), 6.14 (d, J = 8.7 Hz, 1 H), 4.13 (s, 4 H), 4.10 (s, 4 H), 1.44 (s, 9 H).

[00382] Synthesis of 6-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-2-azaspiro[3.3]heptane (S17b).

[00383] A solution of S17a (1.048 mg, 2.612 mmol), CuI (0.111 g, 0.583 mmol), PdCl2(tBu2PPh)2 (0.163 g, 0.261 mmol), TMSA (2.1 mL, 14.75 mmol), Et3N (2.7 mL, 19.48 mmol) in CH3CN (20 mL) at 0°C was degassed with Argon for 10 min. The reaction mixture was stirred at reflux overnight, then cooled to room temperature, diluted with EtOAc, washed with NaHCO3 solution, dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography on silica (20% to 40% EtOAc/Hex) to afford (760 mg, 78%) of desired product. This product (0.4 g, 1076.58 μmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (1000 μL, 13.07 mmol) was added, and the mixture was stirred at 0 °C. After 4 h, the reaction mixture was concentrated under reduced pressure, diluted with toluene (5 mL), and concentrated to afford S17b (0.54 g, 100.1%). MS (ESI) m/z 272.1 [M+H] +.

[00384] Synthesis of 6-(5-ethynylpyridin-2-yl)-2-(oxetan-3-yl)-2-azaspiro[3.3]heptane (S17)

[00385] A suspension of S17b (538 mg, 1.08 mmol) with triethylamine (0.3 mL, 2.154 mmol) in 2-MeTHF (4 mL) and AcOH (0.2 mL), was added oxetan-3-one (234 mg, 3.247 mmol) in 2-Me-THF (1 mL), followed by sodium cyanoborohydride (209 mg, 3.326 mmol). The reaction was stirred at room temperature. After 18 h, the reaction mixture was quenched with NaHCO3 solution and partitioned with EtOAc. The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography on silica (50% to 75% EtOAc/Hex). The product was dissolved in MeOH (5 mL), potassium carbonate (0.28 g, 2.05 mmol) was added, and the mixture was stirred at room temperature. After 48 h, the reaction mixture was concentrated under reduced pressure, diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in methanol (2.0 mL), and sodium hydroxide solution (2 M, 2 mL) was added and heated at 70 °C for 18 h. The reaction was cooled to room temperature and concentrated under reduced pressure; the residue was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford S17 MS (ESI) m/z 256.1 [M+H] +. 1H NMR (400 MHz,Methanol-d4) δ 8.09 (dd, J = 2.2, 0.8 Hz, 1 H), 7.55 (dd, J = 8.7, 2.2 Hz, 1 H), 6.36 (dd, J = 8.7, 0.8 Hz, 1 H), 4.72 (td, J = 6.7, 0.5 Hz, 3 H), 4.45 (ddd, J = 6.8, 4.9, 0.6 Hz, 3 H), 4.13 (s, 5 H), 3.76 (tt, J = 6.5, 4.9 Hz, 1 H), 3.50 (s, 5 H), 3.44 (s, 1 H).

[00386] Synthesis of (3aR,6aS)-5-(5-iodopyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-tert-butyl carboxylate (S18a)

[00387] The title compound S18a was prepared according to the method presented for the synthesis of compound S1a, but using tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. MS (ESI) m/z 415.8 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.28 (dd, J = 2.4, 0.8 Hz, 1 H), 7.63 (dd, J = 8.9, 2.3 Hz, 1 H), 6.19 (d, J = 8.9 Hz, 1 H), 3.66 (dd, J = 10.7, 7.0 Hz, 4 H), 3.51 - 3.17 (m, 4 H), 2.99 (d, J = 5.9 Hz, 2 H), 1.45 (s, 9 H).

[00388] Synthesis of (3aR,6aS)-2-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole (S18b).

[00389] A solution of S18a (0.986 g, 2.374 mmol), CuI (0.099 g, 0.522 mmol), PdCl2(tBu2PPh)2 (0.148 g, 0.237 mmol), TMSA (1.9 mL, 13.35 mmol), and Et3N (2.5 mL, 18.04 mmol) in CH3CN (8 mL) was degassed with argon for 10 min. The reaction mixture was heated to 60 °C and stirred overnight. The reaction was diluted with EtOAc and washed with NaHCO3 solution, dried over Na2SO4, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography on silica (10% to 30% EtOAc/Hex), The product (0.68 g, 1.75 mmol) was dissolved in a mixture of DCM (8 mL) and MeOH (2 mL), and HCl (4.0 M in dioxanes, 2 mL) was added. The reaction was stirred for 18 h, diluted with DCM, and washed with 2N NaOH solution. The aqueous layer was re-extracted with DCM, and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford S18b (0.56 g, 112.7 %). MS (ESI) m/z 286.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 7.82 (dd, J = 2.1, 0.7 Hz, 1 H), 7.73 (dd, J = 9.5, 2.1 Hz, 1 H), 6.88 (dd, J = 9.5, 0.9 Hz, 1 H), 3.78 - 3.63 (m, 2 H), 3.59 - 3.48 (m, 2 H), 3.46 - 3.34 (m, 3 H), 3.25 - 3.10 (m, 3 H), -0.00 (s, 9 H).

[00390] Synthesis of (3aR,6aS)-2-(5-ethynylpyridin-2-yl)-5-methylocta-hydropyrrolo[3,4-c]pyrrole (S18).

[00391] To a solution of S18b (0.25 g, 0.701 mmol) in DCE (6 mL) was added formaldehyde solution (0.30 mL, 8.143 mmol) and acetic acid (0.025 mL, 4.367 mmol). The reaction mixture was heated at 60 °C for 30 min, cooled to room temperature, and sodium cyanoborohydride (165.1 mg, 2.63 mmol) was added. The reaction was heated at 60 °C for 45 min, then cooled to room temperature, diluted with EtOAc, washed with brine, the aqueous layer was re-extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure, and the residue was dissolved in MeOH (5 mL) and Potassium carbonate (0.29 g, 2.1 mmol) was added, and the reaction mixture was stirred at room temperature. After 18 h, the reaction was concentrated under reduced pressure, and the residue was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford S18 (0.15 g, 87%). MS (ESI) m/z 228.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.19 (dd, J = 2.3, 0.8 Hz, 1 H), 7.60 (dd, J = 8.8, 2.3 Hz, 1 H), 6.58 (dd, J = 8.9, 0.8 Hz, 1 H), 3.70 - 3.59 (m, 1 H), 3.54 - 3.45 (m, 3 H), 3.10 (s, 3 H), 2.97 - 2.84 (m, 2 H), 2.54 (dd, J = 9.7, 4.0 Hz, 2 H), 2.39 (s, 3 H).

[00392] Synthesis of (3aR,6aS)-2-(5-iodopyridin-2-yl)-5-(oxetan-3-yl)octahydropyrrolo[3,4-c]pyrrole (S19a)

[00393] The title compound S19a was prepared according to the method presented for the synthesis of compound S1c, but using S18a. MS (ESI) m/z 372.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.17 (dd, J = 2.3, 0.7 Hz, 1 H), 7.71 (ddd, J = 8.9, 2.3, 0.8 Hz, 1 H), 6.43 (dd, J = 9.0, 0.7 Hz, 1 H), 4.69 (t, J = 6.6 Hz, 2 H), 4.64 - 4.55 (m, 2 H),3.70 - 3.60 (m, 1 H), 3.59 - 3.49 (m, 2 H), 3.38 (dd, J = 10.8, 3.1 Hz, 2 H),3.02 (td, J = 7.3, 3.7 Hz, 2 H), 2.88 - 2.71 (m, 2H), 2.42 (dd, J = 9.4, 4.0Hz, 2H).

[00394] Synthesis of (3aR,6aS)-2-(5-ethynylpyridin-2-yl)-5-(oxetan-3-yl)octahydropyrrolo[3,4-c]pyrrole (S19).

[00395] The title compound S19 was prepared according to the method presented for the synthesis of compound S1, but using S19a. MS (ESI) m/z 270.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.05 (dd, J = 2.2, 0.8 Hz, 1 H), 7.46 (dd, J = 8.8, 2.3 Hz, 1 H), 6.43 (dd, J = 8.9, 0.8 Hz, 1 H), 4.68 - 4.58 (m, 2 H), 4.59 - 4.44 (m, 2 H), 3.64 - 3.45 (m, 2 H), 3.40 - 3.30 (m, 4 H), 2.95 (dq, J = 7.5, 3.9 Hz, 2 H), 2.70 (dd, J = 9.6, 7.1 Hz, 1 H), 2.36 (dd, J = 9.5, 4.0 Hz, 2 H).

[00396] Synthesis of 3-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (S20a)

[00397] The title compound S20a was prepared according to the method presented for the synthesis of compound S19a, but using S3a. MS (ESI) m/z 286.1 [M+H] +.

[00398] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-methyl-3,8-diazabicyclo[3.2.1]octane (S20)

[00399] To a solution of S20a (0.2 g, 0.7 mmol) in THF (6 mL) was added formaldehyde solution (0.13 mL, 3.5 mmol) and acetic acid (0.03 mL, 0.51 mmol). The reaction mixture was stirred at room temperature overnight. Sodium cyanoborohydride (132.09 mg, 2.1 mmol) was added. After 5 h, MeOH (2 mL) and NaOH (2 N, 2 mL) were added, and the mixture was stirred for another 18 h. The reaction was concentrated under reduced pressure, diluted with EtOAc, washed with brine, the aqueous layer was re-extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography on silica (100% EtOAc to 5% - 10% MeOH/EtOAc) to afford S20 (62.6 mg, 39.3%). MS (ESI) m/z 228.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.16 (dd, J = 2.4, 0.8 Hz, 1 H), 7.55 (dd, J = 8.9, 2.3 Hz, 1 H), 6.66 (dd, J = 8.9, 0.9 Hz, 1 H), 3.86 (dd, J = 12.5, 2.4 Hz, 3 H), 3.42 (s, 1 H), 3.08 (dd, J = 12.3, 2.3 Hz, 3 H), 2.36 (d, J = 2.4 Hz, 3 H), 2.07 (dt, J = 7.1, 3.2 Hz, 2 H), 1.68 (t, J = 6.8 Hz, 2 H).

[00400] Synthesis of 8-ethyl-3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S21)

[00401] To a solution of S20a (0.24 g, 0.83 mmol) in THF (5 mL) and MeOH (2 mL) was added acetaldehyde (0.5 mL, 8.90 mmol) and acetic acid (0.04 mL, 0.7 mmol). After 18 h, sodium cyanoborohydride (314 mg, 5.0 mmol) was added. Stirred overnight, diluted with EtOAc, washed with brine, and the aqueous layer was re-extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography on silica (10%–20% MeOH/EtOAc) to afford (0.12 g, 0.39 mmol) of product, which was dissolved in MeOH (5 mL), and potassium carbonate (0.16 g, 1.17 mmol) was added, and the reaction mixture was stirred at room temperature. After 3 h, the reaction was concentrated under reduced pressure, and the residue was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford S21 (0.09 g, 44%). MS (ESI) m/z 242.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.16 (dd, J = 2.3, 0.8 Hz, 1 H), 7.55 (dd, J = 8.9, 2.3 Hz, 1 H), 6.65 (dd, J = 8.9, 0.9 Hz, 1 H), 3.85 (dd, J = 12.5, 2.4 Hz, 2 H), 3.44 (dd, J = 4.6, 2.5 Hz, 2 H), 3.41 (s, 1 H), 3.09 (dd, J = 12.2, 2.2 Hz, 2 H), 2.52 (q, J = 7.2 Hz, 2 H), 2.00 (dt, J = 7.0, 3.1 Hz, 2H), 1.67 (t, J = 6.8 Hz, 2 H), 1.15 (t, J = 7.2 Hz, 3 H).

[00402] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-isopropyl-3,8-diazabicyclo[3.2.1]octane (S22)

[00403] To a solution of S20a (0.1 g, 0.35 mmol) in methanol (1.2 mL) was added sodium acetate (28.74 mg, 0.35 mmol), acetic acid (21.04 mg, 0.35 mmol), and acetone (20.35 mg, 0.35 mmol), and the mixture was stirred at 40 °C. After 1 h, sodium cyanoborohydride (44.03 mg, 0.7 mmol) was added, and the reaction was stirred at 40 °C. After 12 h, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with EtOAc, washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography on silica (2% MeOH/EtOAc). The product was dissolved in methanol (1 mL), potassium carbonate (0.05 g, 0.35 mmol) was added and after 1 h, the mixture was concentrated, diluted with EtOAc, washed with water, dried over Na2SO4, filtered and concentrated to afford S22 (28 mg, 31.3%). MS (ESI) m/z 256.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.18 (d, J = 2.3 Hz, 1 H), 7.57 (dd, J = 8.9, 2.4 Hz, 1 H), 6.68 (d, J = 8.9 Hz, 1 H), 3.93 - 3.68 (m, 6 H), 3.43 (s, 1 H), 3.23 - 3.12 (m, 3 H), 2.86 (s, 2 H), 2.07 - 1.92 (m, 3 H), 1.75 (t, J = 6.6 Hz, 3 H), 1.20 (d, J = 6.4 Hz, 8 H).

[00404] Synthesis of (2S,6R)-4-(5-iodopyridin-2-yl)-2,6- (2S,6R)-4-(5-iodopyridin-2-yl)-2,6-dimethylmorpholine (S23a)

[00405] The title compound S23a was prepared according to the method presented for the synthesis of compound S1a, but using (2S,6R)-2,6-dimethylmorpholine. MS (ESI) m/z 319.0 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 2.3 Hz, 1 H), 7.69 (d, J = 8.9 Hz, 1 H), 6.49 (d, J = 9.0 Hz, 1 H), 4.00 (d, J = 12.6 Hz, 2 H), 3.70 (ddd, J = 10.6, 6.3, 2.6 Hz, 2 H), 2.53 (t, J = 11.6 Hz, 2 H), 1.26 (d, J = 6.2 Hz, 6 H).

[00406] Synthesis of (2S,6R)-4-(5-ethynylpyridin-2-yl)-2,6-dimethylmorpholine (S23)

[00407] The title compound S23 was prepared according to the method presented for the synthesis of compound S1, but using S23a. MS (ESI) m/z 217.1 [M+H] +.

[00408] Synthesis of 3-(5-ethynylpyridin-2-yl)-N,N-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxamide (S24)

[00409] To a solution of S20a (200 mg, 0.558 mmol) and Et3N (0.3 mL, 2.164 mmol) in DCM (5 mL) at 0 °C, dimethylcarbamoyl chloride (0.055 mL, 0.601 mmol) was added. The reaction was gradually warmed to room temperature and stirred overnight. The reaction was concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and K2CO3 (313 mg, 2.236 mmol) was added. After stirring at room temperature for 48 h, the reaction was concentrated, then diluted with EtOAc and washed with brine. The organic extracts were dried over Na2SO4 to afford S24 (123.9 mg, 78 %). MS (ESI) m/z 276.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.17 (dd, J = 2.3, 0.8 Hz, 1 H), 7.55 (dd, J = 8.9, 2.3 Hz, 1 H), 6.69 (dd, J = 9.0, 0.8 Hz, 1 H), 4.19 (dd, J = 4.5, 2.2 Hz, 3 H), 3.98 (dd, J = 12.4, 2.5 Hz, 3 H), 3.42 (s, 1 H), 3.11 (dd, J = 12.2, 2.1 Hz, 3 H), 2.94 (s, 8 H), 1.88 (dd, J = 8.5, 4.4 Hz, 3 H), 1.71 (q, J = 6.7 Hz, 2 H).

[00410] Synthesis of (3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((S)-tetrahydrofuran-2-yl)methanone (S25 )

[00411] To S20a suspended in CH2Cl2 (10 mL) was added (S)-tetrahydrofuran-2-carboxylic acid (0.12 mL, 1 mmol), Et3N (0.68 mL, 5 mmol), followed by HATU (0.48 g, 1 mmol). The mixture was stirred for 1.5 h. The mixture was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in MeOH (20 mL) and cooled to 5 °C, and potassium carbonate (0.4 g, 3 mmol) was added. After 30 min, the reaction was quenched with water and brine, extracted into DCM, dried over Na2SO4, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography on silica (60%-100% EtOAc/hexanes to 5% MeOH/EtOAc) to afford S25 (0.23 g, 74.3%). MS (ESI) m/z 312.2 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 8.29 (dd, J = 2.3, 0.8 Hz, 1 H), 7.54 (dt, J = 8.9, 2.4 Hz, 1 H), 6.48 (d, J = 8.8 Hz, 1 H), 4.84 (t, J = 8.6 Hz, 1 H), 4.66 (d, J = 6.8 Hz, 1 H), 4.56 (ddd, J = 14.9, 7.4, 5.7 Hz, 2 H), 4.12 (ddd, J = 20.9, 12.7, 2.3 Hz, 1 H), 3.99 - 3.73 (m, 4 H), 3.21 (dd, J = 12.1, 2.3 Hz, 1 H), 3.14 (dd, J = 12.0, 2.4 Hz, 1 H), 3.07 (s, 1 H), 3.06 - 3.02 (m, 0 H), 2.41 - 2.21 (m, 1 H), 2.15 - 1.70 (m, 5 H).

[00412] Synthesis of tert-butyl 8-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (S26a)

[00413] The title compound S26a was prepared according to the method presented for the synthesis of compound S1a, but using tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate. MS (ESI) m/z 415.8 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J = 2.2 Hz, 1 H), 7.70 (s, 1 H), 6.46 (s, 1 H), 4.45 (s, 2 H), 3.78 (d, J = 52.7 Hz, 2 H), 3.14 (dd, J = 50.9, 12.9 Hz, 2 H), 2.06 - 1.77 (m, 4 H), 1.45 (s, 12 H).

[00414] Synthesis of 8-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S26b).

[00415] The title compound S26b was prepared according to the method presented for the synthesis of compound S17b, but using S26a. MS (ESI) m/z 286.2 [M+H] +.

[00416] Synthesis of 8-(5-ethynylpyridin-2-yl)-3-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S26).

[00417] The title compound S26 was prepared according to the method presented for the synthesis of compound S18, but using oxetan-3-one. MS (ESI) m/z 270.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.18 (d, J = 2.3 Hz, 1 H), 7.58 (dd, J = 8.8, 2.3 Hz, 1 H), 6.73 (d, J = 8.8 Hz, 1 H), 4.61 (dt, J = 11.1, 5.5 Hz, 7 H), 3.51 - 3.44 (m, 2 H), 2.64 (dd, J = 10.9, 2.6 Hz, 3 H), 2.23 (d, J = 10.7 Hz, 2 H), 2.14 (t, J = 6.2 Hz, 2 H), 1.99 (dd, J = 8.3, 4.2 Hz, 2 H).

[00418] Synthesis of 5-iodo-2-(2-oxaspiro[3.3]heptan-6-yl)pyridine (S27a).

[00419] The title compound S27a was prepared according to the method presented for the synthesis of compound S1a but using 2-oxa-6-azaspiro[3.3]heptane. 1H NMR (400 MHz, Chloroform-d) δ 8.16 (dd, J = 2.4, 0.7 Hz, 1 H), 7.52 (dd, J = 8.8, 2.4 Hz, 1 H), 6.20 (d, J = 8.8 Hz, 1 H), 4.84 (s, 4 H), 4.17 (s, 5 H).

[00420] Synthesis of 5-ethynyl-2-(2-oxaspiro[3.3]heptan-6-yl)pyridine (S27).

[00421] The title compound S27 was prepared according to the method presented for the synthesis of compound S1, but using S27a. MS (ESI) m/z 201.1 [M+H] +.

[00422] Synthesis of 7-(5-ethynylpyridin-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane (S28).

[00423] The title compound S28 was prepared according to the method presented for the synthesis of compound S1, but using S1b. MS (ESI) m/z 230.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.25 (s, 1 H), 7.56 - 7.43 (m, 1 H), 6.48 (d, J = 8.9 Hz, 1 H), 4.42 (d, J = 13.5 Hz, 2 H), 4.12 (d, J = 12.1 Hz, 2 H), 3.93 (d, J = 12.2 Hz, 2 H), 3.59 (d, J = 13.6 Hz, 2 H), 3.36 (s, 2 H), 3.00 (d, J = 1.1 Hz, 1 H).

[00424] Synthesis of (1R,4R)-2-(5-iodopyrimidin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1] heptane (S29a)

[00425] The title compound S29a was prepared according to the method presented for the synthesis of compound S7a, but using tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. MS (ESI) m/z 359.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.37 (s, 2 H), 4.79 (s, 1 H), 4.69 (dt, J = 10.0, 6.5 Hz, 2 H), 4.55 (t, J = 6.1 Hz, 1 H), 4.48 (t, J = 5.9 Hz, 1 H), 3.98 (p, J = 6.3 Hz, 1 H), 3.57 (s, 1 H), 3.46 (dd, J = 11.0, 1.6 Hz, 1 H), 3.36 (dd, J = 10.8, 2.0 Hz, 1H), 2.98 (dd, J = 9.6, 2.0 Hz, 1 H), 2.82 (d, J = 9.6 Hz, 1 H), 1.97 (d, J = 9.9 Hz, 1 H), 1.86 (d, J = 9.8 Hz, 1 H).

[00426] Synthesis of (1R,4R)-2-(5-ethynylpyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane (S29)

[00427] The title compound S29 was prepared according to the method presented for the synthesis of compound S1, but using S29a. MS (ESI) m/z 257.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.39 (s, 2 H), 4.88 (s, 1 H), 4.70 (dt, J = 9.5, 6.5 Hz, 2 H), 4.52 (dt, J = 26.3, 6.0 Hz, 2 H), 3.99 (p, J = 6.3 Hz, 1 H), 3.58 (s, 1 H), 3.52 (d, J = 10.9 Hz, 1 H), 3.41 (dd, J = 11.0, 2.0 Hz, 1 H), 3.18 (s, 1 H), 2.99 (d, J = 9.6 Hz, 1 H), 2.83 (d, J = 9.6 Hz, 1 H), 1.98 (d, J = 9.9 Hz, 1 H), 1.87 (d, J = 9.8 Hz, 1 H).

[00428] Synthesis of (1S,4S)-2-(5-iodopyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane (S30a)

[00429] The title compound S30a was prepared according to the method presented for the synthesis of compound S1c, but using tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. MS (ESI) m/z 358.0 [M+H] +.

[00430] Synthesis of (1S,4S)-2-(5-ethynylpyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1] heptane (S30)

[00431] The title compound S30 was prepared according to the method presented for the synthesis of compound S1, but using S30a. MS (ESI) m/z 256.2 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.12 (dd, J = 2.3, 0.8 Hz, 1 H), 7.36 (dd, J = 8.7, 2.3 Hz, 1 H), 6.11 (d, J = 8.7 Hz, 1 H), 4.59 (s, 1 H), 4.53 (dt, J = 12.9, 6.5 Hz, 2 H), 4.36 (dt, J = 31.2, 5.3 Hz, 2 H), 3.82 (p, J = 5.9 Hz, 1 H), 3.44 (s, 1 H), 3.17 (s, 1 H), 2.91 (s, 1 H), 2.87 - 2.73 (m, 1 H), 2.75 - 2.64 (m, 1 H), 1.94 - 1.78 (m, 1 H), 1.73 (d, J = 9.7 Hz, 1 H).

[00432] Synthesis of 8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane 2,2,2-trifluoroacetate S31a).

[00433] The title compound S31a was prepared according to the method presented for the synthesis of compound S1c, but using tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, followed by Boc deprotection in the same manner as the synthesis of compound S17b. MS (ESI) m/z 169.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 4.79 (t, J = 6.9 Hz, 2 H), 4.66 (dd, J = 7.2, 5.2 Hz, 2 H), 4.10 (tt, J = 6.8, 5.2 Hz, 1 H), 3.76 (dq, J = 5.0, 2.3 Hz, 2 H), 3.51 (dd, J = 13.6, 2.0 Hz, 2 H), 3.41 - 3.33 (m, 2 H), 2.31 - 2.21 (m, 2 H), 2.11 - 1.95 (m, 2 H).

[00434] Synthesis of 2-chloro-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1,5-naphthyridine (S31b).

[00435] The title compound S31b was prepared according to the method presented for the synthesis of compound S1a, but using 2,6-dichloro-1,5-naphthyridine. MS (ESI) m/z 330.7 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 7.95 (dd, J = 9.5, 0.8 Hz, 1 H), 7.86 (dd, J = 8.8, 0.8 Hz, 1 H), 7.38 (d, J = 8.7 Hz, 1 H), 7.07 (d, J = 9.4 Hz, 1 H), 4.71 (t, J = 6.2 Hz, 2 H), 4.58 (t, J = 5.7 Hz, 2 H), 4.05 (d, J = 11.3 Hz, 2 H), 3.74 - 3.63 (m, 1 H), 3.28 - 3.20 (m, 5 H), 1.86 (dd, J = 9.1, 4.4Hz, 2H).

[00436] Synthesis of 2-ethynyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1,5-naphthyridine (S31).

[00437] The title compound S31 was prepared according to the method presented for the synthesis of compound S1, but using S31b. MS (ESI) m/z 321.2 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 7.93 (d, J = 9.5 Hz, 1 H), 7.77 (d, J = 8.6 Hz, 1 H), 7.47 (d, J = 8.6 Hz, 1 H), 7.00 (d, J = 9.5 Hz, 1 H), 4.63 (t, J = 6.2 Hz, 2 H), 4.50 (t, J = 5.8 Hz, 2 H), 4.01 (d, J = 11.8 Hz, 2 H), 3.61 (p, J = 6.0 Hz, 1 H), 3.27 - 3.07 (m, 4 H), 3.06 (s, 1 H), 1.77 (dd, J = 8.9, 4.3 Hz, 2H), 1.66 - 1.52 (m, 2H).

[00438] Synthesis of 3,3'-(6-chloro-1,3,5-triazine-2,4-di-yl)bis(8-(oxetan-3-yl)-3,8-diazabicyclo [3.2 .1]octane) (S32a)

[00439] The title compound S32a was prepared according to the method presented for the synthesis of compound S1a, but using S31a and 2,4,6-trichloro-1,3,5-triazine. MS (ESI) m/z 448.3 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 4.70 (t, J = 6.2 Hz, 4 H), 4.56 (s, 3 H), 4.32 (d, J = 13.0 Hz, 2 H), 4.30 - 4.20 (m, 2 H), 3.64 (h, J = 5.8 Hz, 2 H), 3.21 - 3.04 (m, 8 H), 1.89 - 1.73 (m, 4 H), 1.71 - 1.51 (m, 5 H).

[00440] Synthesis of 3,3'-(6-ethynyl-1,3,5-triazine-2,4-di-yl)bis(8-(oxetan-3-yl)-3,8-diazabicyclo [3.2 .1]octane) (S32).

[00441] The title compound S32 was prepared according to the method presented for the synthesis of compound S1, but using S32a. MS (ESI) m/z 438.3 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 4.55 (t, J = 6.2 Hz, 4 H), 4.48 - 4.33 (m, 4 H), 4.23 (d, J = 12.5 Hz, 2 H), 4.12 (t, J = 10.9 Hz, 2 H), 3.49 (q, J = 5.7 Hz, 2 H), 3.05 - 2.85 (m, 8 H), 2.78 (s, 1 H), 1.71 - 1.57 (m, 4 H), 1.52 - 1.34 (m, 4 H).

[00442] Synthesis of 3-(5-chloropyrazin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S33a)

[00443] The title compound S33a was prepared according to the method presented for the synthesis of compound S1c, but using 2,5-dichloropyrazine MS (ESI) m/z 281.3 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 1.4 Hz, 1 H), 7.74 (d, J = 1.5 Hz, 1 H), 4.72 (t, J = 6.3 Hz, 2 H), 4.58 (t, J = 5.8 Hz, 2 H), 3.77 (dd, J = 11.6, 2.3 Hz, 2 H), 3.69 (ddd, J = 11.9, 6.5, 5.5 Hz, 1 H), 3.23 (dd, J = 4.8, 2.6 Hz, 2 H), 3.18 (dd, J = 11.5, 2.3 Hz, 2 H), 1.92 - 1.83 (m, 2 H), 1.73 - 1.65 (m, 2 H).

[00444] Synthesis of 3-(5-ethynylpyrazin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S33)

[00445] The title compound S33 was prepared according to the method presented for the synthesis of compound S1, but using S33a. MS (ESI) m/z 271.2 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.21 (d, J = 1.5 Hz, 1 H), 7.98 (d, J = 1.5 Hz, 1 H), 4.73 (dd, J = 6.3 Hz, 2 H), 4.59 (t, J = 5.8 Hz, 2 H), 3.90 (d, J = 10.5 Hz, 1 H), 3.70 (p, J = 6.0 Hz, 1 H), 3.27 - 3.18 (m, 4 H), 3.17 (s, 1 H), 1.94 - 1.83 (m, 2 H), 1.74 - 1.64 (m, 2 H), 1.57 (s, 1 H).

[00446] Synthesis of tert-butyl 6-(5-iodopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (S34a)

[00447] The title compound S34a was prepared according to the method presented for the synthesis of compound S1a, but using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate. MS (ESI) m/z 401.8 [M+H] +.

[00448] Synthesis of 6-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (S34b).

[00449] The title compound S34b was prepared according to the method presented for the synthesis of compound S1c, but using S34a. MS (ESI) m/z 272.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.22 - 8.09 (m, 1 H), 8.01 (d, J = 1.9 Hz, 1 H), 7.93 (d, J = 1.6 Hz, 1 H), 7.78 (d, J = 8.7 Hz, 1 H), 6.97 (d, J = 9.2 Hz, 1 H), 6.90 (d, J = 9.1 Hz, 1 H), 5.87 (d, J = 2.8 Hz, 1 H), 5.47 (d, J = 2.7 Hz, 1 H), 4.86 - 4.71 (m, 3 H), 3.69 - 3.57 (m, 3 H), 3.53 - 3.44 (m, 3H), 3.10 - 3.03 (m, 3 H), 2.96 (d, J = 9.0 Hz, 2 H), 2.02 - 1.95 (m, 1 H), 0.00 (s, 9 H).

[00450] Synthesis of 6-(5-ethynylpyridin-2-yl)-3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane (S34).

[00451] The title compound S34 was prepared according to the method presented for the synthesis of compound S1, but using S34b. MS (ESI) m/z 256.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 2.1 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 6.26 (d, J = 8.6 Hz, 1 H), 4.56 (t, J = 6.8 Hz, 2 H), 4.51 - 4.32 (m, 4 H),3.73 (s, 1 H), 3.26 - 3.11 (m, 2 H), 3.08 (s, 1 H), 3.00 - 2.85 (m, 2 H),2.71 - 2.58 (m, 1 H), 2.21 - 1.98 (m, 1 H).

[00452] Synthesis of tert-butyl 3-(4-iodophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (S35a).

[00453] The title compound S35aa was prepared according to the method presented for the synthesis of compound S1c but using 1,4-diiodobenzene. MS (ESI) m/z 414.9 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 7.56 - 7.43 (m, 2 H), 6.68 - 6.55 (m, 2 H), 4.34 (s, 2 H), 3.35 (dd, J = 11.2, 2.4 Hz, 2 H), 2.97 (s, 2 H), 2.00 - 1.80 (m, 4 H), 1.46 (s, 9 H).

[00454] Synthesis of 3-(4-iodophenyl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S35b).

[00455] The title compound S35b was prepared according to the method presented for the synthesis of compound S1c, but using S35a. MS (ESI) m/z 371.2 [M+H] +.

[00456] Synthesis of 3-(4-ethynylphenyl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S35).

[00457] The title compound S35 was prepared according to the method presented for the synthesis of compound S1, but using S35b. MS (ESI) m/z 269.2 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 7.19 - 7.08 (m, 2 H), 6.53 - 6.40 (m, 2 H), 4.49 (t, J =6.3 Hz, 2 H), 4.36 (s, 2 H), 3.50 (s, 1 H), 3.18 (dd, J = 11.0, 2.5 Hz, 2 H), 3.00 (s, 2 H), 2.84 (d, J = 10.7 Hz, 2 H), 2.75 (s, 1 H), 1.72 - 1.47 (m, 4 H).

[00458] Synthesis of tert-butyl 3-(5-iodopyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (S36a).

[00459] The title compound S36a was prepared according to the method presented for the synthesis of compound S1a, but using 2-chloro-5-iodopyrimidine. MS (ESI) m/z 416.8 [M+H]+.

[00460] Synthesis of 3-(5-ethynylpyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S36).

[00461] The title compound S36 was prepared according to the method presented for the synthesis of compound S1, but using S36a. MS (ESI) m/z 215.2 [M+H]+.

[00462] Synthesis of 3-(5-iodopyridin-2-yl)-1,5-dimethyl-7-(oxetan-3-yl)-3,7-diazabicyclo[3.3.1] nonan-9-one (S37a ).

[00463] The title compound S37a was prepared according to the method presented for the synthesis of compound S1c, but using 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one. MS (ESI) m/z 428.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.34 (s, 1 H), 7.71 (s, 1 H), 6.62 (s, 1 H), 4.70 (s, 2 H), 4.37 (t, J = 6.5 Hz, 2 H), 4.15 (t, J = 6.4 Hz, 3 H), 3.29 - 3.05 (m, 3 H), 3.02 - 2.80 (m, 1 H), 2.17 (dd, J = 11.2, 2.3 Hz, 2 H), 1.55 (s, 2 H), 1.03 (s, 6 H).

[00464] Synthesis of 3-(5-ethynylpyridin-2-yl)-1,5-dimethyl-7-(oxetan-3-yl)-3,7-diazabicyclo[3.3.1] nonan-9-one (S37 )

[00465] The title compound S37 was prepared according to the method presented for the synthesis of compound S1, but using S37a. MS (ESI) m/z 326.3 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.34 (d, J = 2.2 Hz, 1 H), 7.59 (d, J = 8.8 Hz, 1 H), 6.69 (d, J = 8.9 Hz, 1 H), 4.80 (d, J = 13.4 Hz, 2 H), 4.34 (t, J = 6.4 Hz, 2 H), 4.12 (t, J = 6.2 Hz, 2 H), 3.24 - 2.99 (m, 3 H), 2.91 (d, J = 10.9 Hz, 2 H), 2.17 (dd, J = 11.3, 2.3 Hz, 2 H), 1.55 (s, 1 H), 1.03 (s, 6 H).

[00466] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octane (S38).

[00467] To a solution of S20a (630 mg, 1.76 mmol) in DCM (10 mL) was added N,N-diisopropylethylamine (1.22 mL, 0.01 mol), the mixture was cooled to 5 °C, and then methanesulfonyl chloride (0.2 mL, 3.0 mmol) was added. After 3 min, the reaction was quenched with saturated NaHCO3 solution, the organic layer was separated, dried over Na2SO4, filtered, and concentrated, and the residue was dissolved in MeOH (15 mL), the solution was cooled to 10 °C, and then K2CO3 (0.44 g, 0.01 mol) was added. After 15 min, the precipitate was filtered, rinsed with 10% MeOH in water, and dried under vacuum to yield S38 (477 mg, 93.1 %) MS (ESI) m/z 292.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.07 (dd, J = 2.3, 0.8 Hz, 1 H), 7.32 (dd, J = 8.8, 2.3 Hz, 1 H), 6.26 (d, J = 8.8 Hz, 1 H), 4.12 (dd, J = 4.7, 2.4 Hz, 2 H), 3.83 (dd, J = 12.3, 2.5 Hz, 2 H), 2.92 (dd, J = 12.1, 2.1 Hz, 2 H), 2.84 (s, 1 H), 2.75 (s, 3 H), 1.89 - 1.76 (m, 2 H), 1.65 - 1.56 (m, 2H).

[00468] Synthesis of tert-butyl 7-(5-iodopyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (S39a).

[00469] The title compound S39a was prepared according to the method presented for the synthesis of compound S1a, but using tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate. MS (ESI) m/z 430.2 [M+H] +.

[00470] Synthesis of 3-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (S39b).

[00471] The title compound S39b was prepared according to the method presented for the synthesis of compound S1, but using S39a. MS (ESI) m/z 300.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 7.97 (d, J = 2.2 Hz, 1 H), 7.74 (dd, J = 9.4, 2.2 Hz, 1 H), 7.10 (d, J = 9.3 Hz, 1 H), 4.00 (d, J = 12.6 Hz, 2 H), 3.30 (d, J = 13.0 Hz, 2 H), 3.21 (t, J = 11.5 Hz, 2 H), 3.12 (d, J = 13.0 Hz, 2 H), 2.21 (s, 2 H), 1.87 (d, J = 13.8 Hz, 1 H), 1.78 (d, J = 13.7 Hz, 1 H), 0.00 (s, 9 H).

[00472] Synthesis of 1-(7-(5-ethynylpyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl)ethan-1-one (S39).

[00473] To a mixture of S39b (0.39 g, 1 mmol) and Et3N (0.73 ml, 0.01 mol) in DCM (10 mL), acetic anhydride (0.14 ml, 1 mmol) was added. After 5 min, the reaction was quenched with 1 M NaOH, the layers were separated, and the organic layer was dried over Na2SO4, filtered, and concentrated, and the residue was dissolved in MeOH (20 mL), then K2CO3 (0.44 g, 3 mmol) was added. After 20 min, the reaction was diluted with DCM, washed with water, the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography on silica (60%–100% EtOAc/hexanes to 5% MeOH/EtOAc) to yield S39 (111 mg, 39%) MS (ESI) m/z 270.2 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.12 (dd, J = 2.3, 0.8 Hz, 1 H), 7.48 (dd, J = 9.0, 2.4 Hz, 1 H), 6.69 (dd, J = 9.0, 0.8 Hz, 1 H), 4.74 - 4.59 (m, 2 H), 4.33 - 4.20 (m, 1 H), 4.04 (d, J = 13.4 Hz, 1 H), 3.42 (dt, J = 13.5, 2.7 Hz, 1 H), 3.39 (s, 1 H), 3.11 (dddd, J = 11.1, 8.0, 3.2, 2.2 Hz, 2 H), 2.87 (dt, J = 13.5, 2.6 Hz, 1 H), 2.06 (q, J = 3.0 Hz, 2 H), 2.01 - 1.94 (m, 2 H), 1.84 (s, 3 H).

[00474] Synthesis of 3-(5-ethynylpyridin-2-yl)-7-(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane (S40).

[00475] In a microwave tube, a mixture of S39b (0.21 g, 0.6 mmol), 2-Fluoropyridine (0.1 mL, 1 mmol), sodium bicarbonate (0.24 g, 3 mol) in NMP (1 mL) was microwaved at 130 °C for 20 min, then at 150 °C for 20 min, the reaction was diluted with DCM, washed with water, the organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure, and the residue was purified by column chromatography on silica to afford S40 (9 mg, 5%) MS (ESI) m / z 305.2 [M+H] + . 1H NMR (400 MHz, Chloroform- d) δ 8.06 (d, J = 2.3 Hz, 1 H), 7.93 (dd, J = 5.1, 2.0 Hz, 1 H), 7.25 (dd, J = 9.0, 2.4 Hz, 1 H), 7.25 - 7.16 (m, 1 H), 6.39 (d, J = 8.7 Hz, 1 H), 6.36 - 6.30 (m, 2 H), 4.39 - 4.17 (m, 4 H), 3.15 - 3.02 (m, 5 H), 2.93 (s, 1 H), 2.18 - 2.07 (m, 2 H), 1.89 (d, J = 3.4Hz, 2H).

[00476] Synthesis of 3-(5-ethynylpyridin-2-yl)-7-(oxetan-3-yl)-3,7-diazabicyclo[3.3.1]nonane (S41).

[00477] The title compound S41 was prepared according to the method presented for the synthesis of compound S1c, but using S39b. MS (ESI) m/z 284.3 [M+H] +. 1H NMR (400 MHz,Methanol-d4) δ 8.17 - 7.96 (m, 1 H), 7.46 (dd, J = 9.0, 2.4 Hz, 1 H), 6.77 - 6.49 (m, 1 H), 4.41 (t, J = 6.4 Hz, 2 H), 4.26 (t, J = 6.2 Hz, 2 H), 4.19(d, J = 12.9 Hz, 2 H), 3.31 (s, 1 H), 3.23 - 3.12 (m, 3 H), 2.80 - 2.65 (m, 2 H), 2.13 - 1.91 (m, 4 H), 1.91 - 1.76 (m, 1 H), 1.73 - 1.61 (m, 1H).z

[00478] Synthesis of3-(5-iodopyridin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (S43a).

[00479] The title compound S43a was prepared according to the method presented for the synthesis of compound S1a, but using 8-oxa-3-azabicyclo[3.2.1]octane. MS (ESI) m/z 317.1 [M+H] +.

[00480] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (S43b).

[00481] The title compound S43 was prepared according to the method presented for the synthesis of compound S1, but using S43a. MS (ESI) m/z 215.2 [M+H] +. 1H NMR (400 MHz,Methanol-d4) δ 8.17 (dd, J = 2.3, 0.8 Hz, 1 H), 7.56 (dd, J = 8.9, 2.3 Hz, 1 H), 6.67 (dd, J = 8.9, 0.8 Hz, 1 H), 4.46 (dq, J = 4.4, 2.3 Hz, 2 H), 3.86 (dt, J = 12.8, 1.1 Hz, 2 H), 3.43 (s, 1 H), 3.07 (d, J = 2.6 Hz, 1 H), 3.03 (d, J = 2.6 Hz, 1 H), 2.02 - 1.74 (m, 4 H).

[00482] Synthesis of 3-(3-methyl-5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1] octane (S44a)

[00483] The title compound S44a was prepared according to the methods presented for the synthesis of compound S3, but using 2-fluoro-5-iodo-3-methylpyridine. MS (ESI) m/z 300.3 [M+H] +.

[00484] Synthesis of 3-(5-ethynyl-3-methylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1] octane (S44).

[00485] The title compound S44 was prepared according to the methods presented for the synthesis of compound S3, but using S44a. MS (ESI) m/z 284.2 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J = 2.2 Hz, 1 H), 8.05 (d, J = 2.3 Hz, 0 H), 7.43 (dd, J = 2.1, 0.9 Hz, 1 H), 7.30 (d, J = 1.9 Hz, 0 H), 7.19 (d, J =15.2 Hz, 0 H), 5.80 (d, J = 15.1 Hz, 0 H), 5.30 (s, 0 H), 4.70 (t, J = 6.2Hz, 3 H), 4.59 (s, 2 H), 3.76 (s, 1 H), 3.35 - 3.26 (m, 2 H), 3.18 (d, J =30.6 Hz, 5 H), 3.09 (s, 1 H), 2.27 (s, 0 H), 2.24 (s, 3 H), 1.96 - 1.79 (m, 5 H), 0.24 (d, J = 7.3 Hz, 0 H), 0.15 (d, J = 6.0 Hz, 0 H), 0.08 (s, 0 H).

[00486] Synthesis of 3-(6-methyl-5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1] octane (S45a)

[00487] The title compound S45a was prepared according to the methods presented for the synthesis of compound S3, but using 6-fluoro-3-iodo-2-methylpyridine. MS (ESI) m/z 300.3 [M+H] +.

[00488] Synthesis of 3-(5-ethynyl-6-methylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S45).

[00489] The title compound S45 was prepared according to the methods presented for the synthesis of compound S3, but using S45a. MS (ESI) m/z 284.2 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 7.46 (d, J = 8.7 Hz, 1 H), 6.28 (d, J = 8.7 Hz, 1 H), 5.30 (s, 0 H), 4.72 (t, J = 6.3 Hz, 2 H), 4.59 (t, J = 5.8 Hz, 2 H), 4.07 (d, J = 12.6 Hz, 0 H), 3.89 (d, J = 11.0 Hz, 2 H), 3.71 (p, J = 6.0 Hz, 1 H), 3.26 (d, J = 13.4 Hz, 1 H), 3.24 (s, 0 H), 3.23 (s, 1 H), 3.19 (s, 2H), 3.14 - 3.07 (m, 2 H), 2.51 (s, 3 H), 1.85 (dd, J = 11.5, 6.7 Hz, 2 H), 1.70 (t, J = 6.7 Hz, 1 H).

[00490] Synthesis of 3-(4-methyl-5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1] octane (S46a)

[00491] The title compound S46a was prepared according to the methods presented for the synthesis of compound S3, but using 2-fluoro-5-iodo-4-methylpyridine. MS (ESI) m/z 300.4 [M+H] +.

[00492] Synthesis of 3-(5-ethynyl-4-methylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1] octane (S46).

[00493] The title compound S46 was prepared according to the methods presented for the synthesis of compound S3, but using S46a. MS (ESI) m/z 284.2 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.22 (s, 1 H), 6.33 (s, 1 H), 5.30 (s, 0 H), 4.72 (t, J = 6.3 Hz, 2 H), 4.59 (t, J = 5.8 Hz, 2 H), 3.85 (dd, J = 11.8, 2.4 Hz, 2 H), 3.70 (p, J = 6.0 Hz, 1 H), 3.24 (s, 0 H), 3.23 (s, 1 H), 3.22 - 3.09 (m, 4 H), 2.34 (d, J = 0.7 Hz, 3 H), 1.85 (dd, J = 8.9, 4.3 Hz, 2H), 1.72 - 1.66 (m, 2 H).

[00494] Synthesis of 4-(5-iodopyridin-2-yl)-1-methylpiperazin-2-one(S47a).

[00495] The title compound S47a was prepared according to the methods presented for the synthesis of compound S1a, but using 1-methylpiperazin-2-one hydrochloride. MS (ESI) m/z 318.0 [M+H] +.

[00496] Synthesis of 3-(5-ethynyl-4-methylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1] octane 4-(5-ethynylpyridin-2 -yl)-1-methylpiperazin-2-one (S47).

[00497] The title compound S47 was prepared according to the methods presented for the synthesis of compound S3, but using S47a. MS (ESI) m/z 216.1 [M+H] +.

[00498] Synthesis of 1-(5-ethynylpyridin-2-yl)-4-(oxetan-3-yl)piperazine (S48).

[00499] The title compound S48 was prepared according to the methods presented for the synthesis of compound S1, but using 1-(oxetan-3-yl)piperazine. MS (ESI) m/z 244.16 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.18 (d, J = 2.2 Hz, 1 H), 7.56 (dd, J = 8.9, 2.3 Hz, 1 H), 6.75 (d, J = 8.9 Hz, 1 H), 4.70 (t, J = 6.6 Hz, 3 H), 4.63 (t, J = 6.2 Hz, 3 H), 3.68 - 3.56 (m, 6 H), 3.55 - 3.47 (m, 1 H), 3.42 (s, 1 H), 2.52 - 2.37 (m, 6 H), 1.27 (d, J = 13.9 Hz, 0 H).

[00500] Synthesis of 5-ethynyl-2-(4-(oxetan-3-yl)piperazin-1-yl)pyrimidine (S49).

[00501] The title compound S49 was prepared according to the methods presented for the synthesis of compound S1, but using tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate. MS (ESI) m/z 245.2 [M+H] +.

[00502] Synthesis of 5-ethynyl-2-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyrimidine (S50). The title compound S50 was prepared according to the methods presented for the synthesis of compound S1, but using tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate and 4-Oxotetrahydropyran. MS (ESI) m/z 272.70 [M+H] +.

[00503] Synthesis of tert-butyl 3-((3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)azetidine-1-carboxylate (S51) .

[00504] The title compound S51 was prepared according to the methods presented for the synthesis of compound S1, but using S3b and tert-butyl 3-formylazetidine-1-carboxylate. MS (ESI) m/z 383.05 [M+H] +.

[00505] Synthesis of 3-(5-iodopyrimidin-2-yl)-6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane (S52a)

[00506] The title compound S52a was prepared according to the method presented for the synthesis of compound S1c, but using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate and 2-chloro-5-iodopyrimidine. MS (ESI) m/z 359.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.47 (s, 2 H), 4.70 (t, J = 6.2 Hz, 2 H), 4.48 (t, J = 5.5 Hz, 2 H), 3.87 (p, J = 5.5 Hz, 1 H), 3.81 (d, J = 6.1 Hz, 2 H), 3.56 (q, J = 13.2 Hz, 4 H), 2.74 (q, J = 7.8 Hz, 1 H), 1.58 (d, J = 8.9 Hz, 1 H).

[00507] Synthesis of 3-(5-ethynylpyrimidin-2-yl)-6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane (S52)

[00508] The title compound S52 was prepared according to the method presented for the synthesis of compound S1, but using S52a. MS (ESI) m/z 257.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.32 (s, 2 H), 4.55 (t, J = 6.1 Hz, 2 H), 4.32 (dd, J = 6.0, 4.8 Hz, 2 H), 3.72 (ddd, J = 11.1, 6.2, 4.9 Hz, 1 H), 3.65 (d, J = 6.0 Hz, 2 H), 3.50 (d, J = 13.3 Hz, 2 H), 3.43 (d, J = 13.3 Hz, 2 H), 3.06 (s, 1 H), 2.58 (dt, J = 8.1, 6.1 Hz, 1 H), 1.44 (d, J = 8.8 Hz, 1H).

[00509] Synthesis of (6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)boronic acid (S53)

[00510] A suspension of S4a (0.17 g, 0.47 mmol) Bis(Pinacolato)Diboron (0.18 g, 0.72 mmol), potassium acetate (0.17 g, 1.68 mmol), and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.04 g, 0.05 mmol) in DMF (4.5 mL) was degassed with argon for 5 min, then heated at 90 °C for 1 h, cooled to room temperature, diluted with EtOAc, and washed with 5% LiCl solution 2x. The separated organic layer was dried over Na2SO4 and concentrated in vacuo, the residue was purified by HPLC, and the product was lyophilized to afford S53. MS (ESI) m/z 276.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.35 (d, J = 1.7 Hz, 1 H), 8.31 (dd, J = 9.0, 1.8 Hz, 1 H), 7.18 (d, J = 9.0 Hz, 1 H), 4.74 - 4.58 (m, 4 H), 4.27 - 3.99 (m, 4 H), 3.28 - 3.16 (m, 1 H), 2.21 - 2.06 (m, 2 H).

[00511] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-methyl-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-io iodide (S54 and S55).

[00512] To a solution of S3 in acetone (1 mL) in a vial at 30 °C was added iodomethane (0.06 mL, 1.0 mmol), warmed to 70 °C, and the mixture stirred overnight. After cooling to room temperature, the reaction was diluted with ether and stirred for 5 min, the solids were filtered and dried in vacuo to afford a 3:1 mixture of isomers (S54 : S55) in which the major product (S4) has the methyl syn for the bridge. MS (ESI) m/z 284.0 [M+H] +. 1H NMR (400 MHz, Methanol-d) Hz, 1 H), 4.86 - 4.70 (m, 5 H), 4.05 - 3.94 (m, 3 H), 3.88 (d, J = 14.3 Hz, 3 H), 3.54 (d, J = 14.7 Hz, 1 H), 3.45 (s, 1 H), 3.37 (d, J = 2.1 Hz, 1 H), 3.34 (s, 4 H), 3.30 (s, 1 H), 2.37 - 2.27 (m, 2 H),2.21 - 2.11 (m, 1 H), 2.07 - 1.94 (m, 2 H), 1.94 (s, 1 H).

[00513] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-((3-methyloxetan-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane (S56).

[00514] The title compound S56 was prepared according to the methods presented for the synthesis of compound S1, but using 3-(5-iodopyridin-2-yl)-8-((3-methyloxetan-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane. MS (ESI) m/z 298.19 [M+H] +.

[00515] Synthesis of 1-(5-ethynylpyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S57). The title compound S57 was prepared according to the methods described for the synthesis of compound S50, but using dihydrofuran-3(2H)-one. 1H-NMR and MS data identical to S14.

[00516] Synthesis of 4-(5-ethynylpyrimidin-2-yl)piperazin-2-one (S58a).

[00517] The title compound S58a was prepared according to the methods set forth for the synthesis of compound S47 but using piperazin-2-one and 2-chloro-5-iodopyrimidine MS (ESI) m/z 303.0 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 2H), 6.11 (s, 1H), 4.46 (s, 2H), 4.16 - 3.91 (m, 2H), 3.47 (td, J = 5.4, 2.7 Hz, 2H), 3.19 (s, 1H).

[00518] Synthesis of 4-(5-ethynylpyrimidin-2-yl)-1-methylpiperazin-2-one (S58).

[00519] To a solution of S58a (115 mg, 0.57 mmol) in THF (5 mL) and DMF (1 mL) at 0 °C was added sodium hydride, (60% dispersion in oil, 59 mg, 1.475 mmol). After 15 min, iodomethane (0.15 mL, 2.409 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2 h, then quenched with water and partitioned with EtOAc. The separated organic layer was dried over Na2SO4 and concentrated in vacuo to afford S58 (124.9 mg, 100%). MS (ESI) m/z 217.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 2 H), 4.37 (s, 2 H), 4.18 - 4.03 (m, 2 H), 3.65 (s, 1 H), 3.57 - 3.43 (m, 2 H), 3.01 (s, 3 H).

[00520] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane (S59).

[00521] The title compound S59 was prepared according to the methods presented for the synthesis of compound S3, but using 2-methoxyacetaldehyde. MS (ESI) m/z 303.02 [M+H] +.

[00522] Synthesis of (6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)boronic acid (S60).

[00523] The title compound S60 was prepared according to the methods presented for the synthesis of compound S53, but using S3c. MS (ESI) m/z 290.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.33 (s, 1 H), 8.08 (d, J = 9.2 Hz, 1 H), 7.04 (d, J = 8.9 Hz, 1 H), 4.91 (t, J = 7.3 Hz, 3 H), 4.76 (dd, J = 7.7, 5.2 Hz, 2 H), 4.36 (s, 1 H), 4.17 (d, J = 13.4 Hz, 3 H), 4.00 (s, 2 H), 3.46 (d, J = 13.2 Hz, 2 H), 2.28 - 2.10 (m, 2 H), 2.01 (d, J = 8.4 Hz, 2 H).

[00524] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-(pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S61).

[00525] A suspension of S20a (0.15 g, 0.42 mmol), sodium bicarbonate (250 mg, 2.9 mmol), and 2-chloropyrimidine (0.17 g, 1.5 mmol) in isopropanol (1.5 mL) was stirred at 65 °C overnight. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and filtered through celite. The crude mixture was concentrated in vacuo and redissolved in methanol (5 mL). Potassium carbonate (0.29 g, 2.1 mmol) was added, and the mixture was stirred for 30 min. The reaction was quenched with water, and the crude product was extracted into DCM, dried over sodium sulfate, filtered, concentrated in vacuo , and purified by column chromatography (30%^70% EtOAc^hexanes). MS(ESI) m/z 292.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.35 (d, J = 4.8 Hz, 2 H), 8.17 (dd, J = 2.4, 0.8 Hz, 1 H), 7.55 (dd, J = 8.9, 2.3 Hz, 1 H), 6.64 (t, J = 4.8 Hz, 1 H), 4.89 (dq, J =4.6, 2.3 Hz, 3 H), 4.02 (dd, J = 12.4, 2.3 Hz, 3 H), 3.42 (s, 1 H), 3.13 (dd, J = 12.3, 2.3 Hz, 3 H), 2.08 - 1.96 (m, 3 H), 1.96 - 1.82 (m, 3 H).

[00526] 3-(5-ethynylpyridin-2-yl)-8-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octane (S62).

[00527] The title compound S62 was prepared according to the methods presented for the synthesis of compound S63, but using 2,2,2-trifluoroethyl trifluoromethanesulfonate. MS (ESI) m/z 296.20 [M+H] +.

[00528] Synthesis of 8-(2,2-difluoroethyl)-3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S63).

[00529] To a suspension of Reagent 1 (0.2 g, 0.56 mmol) and 2-Iodo-1,1-difluoroethane (0.15 g, 0.78 mmol) in 1,4-Dioxane (3 mL) was added 99.95% Cesium carbonate (0.21 g, 3.35 mmol). The mixture was stirred at 60 °C overnight, cooled to room temperature, and 2,2-difluoroethyl trifluoromethanesulfonate (98% min) (0.17 g, 0.78 mmol) was added. The mixture was heated at 60 °C for 8 h, quenched with brine, and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by column chromatography on silica (10% EtOAc/Hex). The product was dissolved in methanol (3 mL), potassium carbonate (0.11 g, 0.82 mmol) was added, and after 1 h, the mixture was concentrated, diluted with EtOAc, washed with water, dried over Na2SO4, filtered, and concentrated to yield S63 (76 mg, 99.7%). MS (ESI) m/z 278.2 [M+H] +

[00530] Synthesis (3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(3-methyloxetan-3-yl)methanone (S64)

[00531] To S20a suspended in CH2Cl2 (10 mL) was added 3-methyloxetane-3-carboxylic acid (0.12 g, 1 mmol) and Et3N (0.68 mL, 5 mmol), followed by HATU (0.48 g, 1 mmol). The mixture was stirred for 1.5 h. The mixture was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in MeOH (20 mL), cooled to 5 °C, and potassium carbonate (0.4 g, 3 mmol) was added. After 30 min, the reaction was quenched with water and brine, extracted into DCM, dried over Na2SO4, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography on silica (60%–100% EtOAc/hexanes to 5% MeOH/EtOAc) to yield S64.

[00532] MS (ESI) m/z 312.22 [M+H].2.3 SYNTHESIS OF INTERMEDIATE A

[00533] Synthesis of ethyl 2-(1,1,1-trifluoropropan-2-ylidene)malonate (A1a)

[00534] A mixture of dry THF (5000 mL) and dry CCl4 (600 mL) was cooled to 0 °C and treated with TiCl4 (275 mL, 2.50 mol). The resulting yellow suspension was stirred at 0 °C for 5 min, treated sequentially with 1,1,1-trifluoropropan-2-one (140 g, 1.25 mol) and freshly distilled diethyl malonate (200 g, 1.25 mol), and then stirred at 0 °C for 0.5 h. The reaction mixture was then treated with a solution of dry pyridine (400 mL) in dry THF (500 mL) and stirred at 0 °C for 1 h and then at room temperature overnight. The reaction mixture was quenched with water and extracted with EtOAc (1 L x 3). The combined organic extracts were washed with brine and saturated NaHCO3, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc:PE = 1:50) to afford the title compound A1a (298 g, 94%).

[00535] 1H NMR (CDCl3, 300 MHz): δ 4.32-4.23 (m, 4 H), 2.20 (s, 3H), 1.33-1.24 (m, 6 H).

[00536] Synthesis of diethyl 2-(1,1,1-trifluoro-2-methylpropan-2-yl)malonate (A1b)

[00537] A mixture of methylmagnesium iodide (3.0 mol/L in ether, 10 L, 30 mol) and cuprous chloride (3.5 g, 35 mmol) was stirred at 0 °C, treated with a solution of compound A1a (178 g, 700 mmol) in dry Et2O (1000 mL) over 30 min and stirred at rt for 30 min and then quenched with the dropwise addition of ice-cold water (1.5 L) followed by aq HCl (3 mol/L, 350 mL). The mixture was then extracted with Et2O (1 L x 3). The combined organic extracts were washed with aq NaOH (1 N), water and brine, dried (MgSO4), filtered and evaporated. The residual crude compound A1b (90 g, 47 %) was used directly in the next step without further purification. MS (ESI) m/z 271 [M+H] + 1H NMR (CDCl3, 300 MHz): δ 4.22–4.15 (m, 4 H), 3.64 (s, 1 H), 1.38 (s, 6 H), 1.30–1.24 (m, 6 H).

[00538] Synthesis of 2-(ethoxycarbonyl)-4,4,4-trifluoro-3,3-dimethylbutanoic acid (A1c)

[00539] A solution of compound A1b (144 g, 0.53 mol) in a mixture of EtOH (500 mL) and water (500 mL) was treated with NaOH (19 g, 0.48 mmol) portionwise at 0 °C and stirred at room temperature for 5 h. The reaction mixture was evaporated to a syrup, dissolved in water (1 L), and extracted with Et2O (2 L). The aqueous phase was acidified with 1 M HCl to pH = 2.0 and extracted with EtOAc (1 L x 3). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and evaporated to afford the title compound A1c (107 g, 84 %), which was used directly in the next step without further purification. MS (ESI) m/z 241 [M+H] +. 1H NMR (CDCl3, 300 MHz): δ 4.23 (q, J = 5.4 Hz, 2 H), 3.69 (s, 1 H), 1.40 (s, 6 H), 1.27 (t, J = 5.1 Hz, 3 H).

[00540] Synthesis of ethyl 2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoate (A1d)

[00541] A solution of compound A1c (110 g, 454 mmol) in dry toluene (600 mL) was treated with triethylamine (45.4 g, 454 mmol) and diphenylphosphoryl azide (125 g, 454 mmol), the reaction mixture was refluxed for 1 h, then t-BuOH (46.7 g, 630 mmol) was added. The mixture was refluxed overnight, cooled to rt, the solvent was evaporated, and the residue was dissolved in EtOAc (1 L), washed with 5% NaHCO3 solution, dried (MgSO4), filtered, and evaporated. The remainder was purified by column chromatography on silica gel (EtOAc:PE = 1:9) to afford crude compound A1d (60 g, 46%), which was used directly in the next step without further purification. MS (ESI) m/z 313 [M+H] +. 1H NMR (CDCl3, 300 MHz): δ 5.20 (d, J = 5.7 Hz, 1 H), 4.44 (d, J = 10.8 Hz, 1 H), 4.25-4.16 (m, 2 H), 1.44 (s, 9 H), 1.39-1.26 (m, 6 H), 1.19 (m, 3H).

[00542] Synthesis of 2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoic acid (A1e)

[00543] To a solution of compound A1d (380 g, 1214 mmol) in water (2000 mL) and ethanol (2000 mL) was added LiOH.H2O (134 g, 3166 mmol). The mixture was stirred overnight, diluted with EtOAc, acidified to pH = 2, and extracted with EtOAc (2000 mL x 3). The organic layer was washed with brine, dried over MgSO4, and concentrated to afford compound A1e (300 g, 86%) as a white solid. 1H NMR (CDCl3, 300 MHz): δ 5.20 (d, J = 10.2 Hz, 1 H), 4.48 (d, J = 10.2 Hz, 1 H), 1.45 (s, 9 H), 1.30 (s, 3 H), 1.25 (s, 3 H).

[00544] Synthesis of (S)-(S)-1-phenylethyl 2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoate (A1g)

[00545] Acid Al (300 g, 1052 mmol) and (N,N'-Dicyclohexylcarbodiimide) (325 g, 1578 mmol) were combined in DCM (250 mL) and PhMe (4000 mL). The solution was cooled to 0 °C, and then 4-(Dimethylamino)pyridine (128 g, 1052 mmol) and (S)-(-)-1-Phenylethanol (128 g, 1052 mmol) were added, and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated, and then the residue was taken up in EtOAc/water, and extracted with EtOAc (2000 mL × 3). The combined organic layers were washed with brine, dried over MgSO 4 , and concentrated. The crude was purified by column chromatography on silica gel (0-8% EtOAc/PE) to afford two compounds. The mixture of diastereomers was separated by chiral column (IA; Heptane; IPA (70:30)). The first peak was collected to afford compound A1f (105 g, 25 %), and the second peak was collected to afford compound A1g (80 g, 19 %). 1H NMR of compound A1f (CDCl3, 300 MHz): δ 7.38-7.31 (m, 5 H), 5.90 (q, J = 6.3 Hz, 1 H), 5.18 (d, J = 9.6 Hz, 1 H), 4.48 (d, J = 9.6 Hz, 1 H), 1.56 (d, J = 6.9 Hz, 3 H), 1.44 (s, 9 H), 1.31 (s, 3 H), 1.21 (s, 3 H). 1H NMR of compound A1g (CDCl3, 300 MHz): δ 7.34-7.30 (m, 5 H), 5.92 (q, J = 6.3 Hz, 1 H), 5.20 (d, J = 9.6 Hz, 1 H), 4.44 (d, J = 9.6 Hz, 1 H), 1.58 (d, J = 6.9 Hz, 3 H), 1.45 (s, 9 H), 1.21 (s, 3 H), 1.11 (s, 3 H).

[00546] Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoic acid (A1)

[00547] Compound A1f (83 g, 214 mmol) was diluted with ethanol (1000 mL). Pd/C (10%, moisture, 17 g) was added, and the atmosphere was replaced with hydrogen. After stirring for 5 h, the mixture was filtered through celite, washing with EtOAc, and the filtrate was concentrated to afford product A1 (50 g, 82%). MS (ESI) m/z 186 [M-Boc +1] +. 1H NMR (300 MHz, DMSO-d6): δ 12.98 (br s, 1 H), 7.18 (d, J = 9.6 Hz, 1 H), 4.27 (d, J = 9.9 Hz, 1 H), 1.36 (s, 9 H), 1.14 (s, 6 H).

[00548] Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoic acid (A2)

[00549] Compound A1g (80 g, 205 mmol) was diluted with ethanol (800 mL). Pd/C (10%, moisture, 15 g) was added, and the atmosphere was replaced with hydrogen. After stirring for 5 h, the mixture was filtered through celite, washing with EtOAc, and the filtrate was concentrated to afford product A2 (45 g, 77%). MS (ESI) m/z 186 [M-Boc +1]+. 1H NMR (300 MHz, DMSO-d6): δ7.18 (d, J = 9.6 Hz, 1 H), 4.25 (d, J = 9.9 Hz, 1 H), 1.36 (s, 9 H), 1.14 (s, 6 H).

[00550] Synthesis of (S)-4, 4, 4-trifluoro-2-((methoxycarbonyl) amino)-3, 3-dimethylbutanoic acid (A3)

[00551] To a solution of A1 (10 g, 35.06 mmol) in DCM (160 mL) and MeOH (40 mL), HCl (4.0 M in dioxane, 40 mL) was added. The reaction was stirred at room temperature overnight. The reaction was concentrated to dryness (foamy). The residue was dissolved in a mixture of dioxane and 2 M NaOH (90 mL), stirred for 5 min, and then methyl chloroformate (5.7 mL, 73.33 mmol) was added. After 4 h, the reaction was extracted with 2 × 100 mL DCM (discard organics), and the aqueous layer was adjusted to pH ~2 with 4 M HCl (~50 mL). The aqueous layer was extracted with 2 x 150 mL EtOAc, the combined EtOAc layers were dried over sodium sulfate, filtered, and concentrated to yield A3 (8.54 g, 100%). MS (ESI) m/z 244.0 [M+H] + . 1H NMR (400 MHz, Methanol-d4) δ 4.57 - 4.41 (m, 1 H), 3.66 (d, J = 2.1 Hz, 5 H), 1.25 (d, J = 10.0 Hz, 7 H).

[00552] Synthesis of (S)-4,4,4-trifluoro-3,3-dimethyl-2- (((oxetan-3-yloxy)carbonyl)amino)butanoic acid (A4).

[00553] The title compound A4 was prepared according to the method presented for the synthesis of compound A3 but using 4-nitrophenyl oxetan-3-yl carbonate. MS (ESI) m/z 285.5 [M+H] + . 1H NMR (400 MHz, Methanol-d4) δ 7.66 (d, J = 9.9 Hz, 1 H), 5.37 (tt, J = 6.3, 5.1 Hz, 1 H), 4.87 - 4.82 (m, 2 H), 4.62 (tdd, J = 7.5, 5.1, 0.9 Hz, 2 H), 4.49 - 4.41 (m, 1 H), 1.28 (s, 3 H), 1.25 (s, 3 H).

[00554] Synthesis of (S)-2-((cyclopropoxycarbonyl)amino)-3, 3-dimethylbutanoic acid (A5)

[00555] To a solution of cyclopropanol (0.4 mL, 6.37 mmol) in CH3CN (18 mL) at 0 °C was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (DSC) (3.26 g, 12.74 mmol), followed by Et3N (2.66 mL, 19.11 mmol). The reaction mixture was heated to 40 °C and stirred overnight. After cooling to room temperature, the reaction was concentrated under reduced pressure, and the residue triturated with DCM, the solid filtered, and the filtrate was purified by column chromatography on silica (10%-100% EtOAc/hexanes). The product (663 mg, 3.33 mmol) was dissolved in THF (5 mL), and L- tert -leucine methyl ester hydrochloride (0.91 g, 5 mmol) and Et 3 N (1.39 mL, 0.01 mol) were added, the reaction was heated at 40 °C for 18 h, then at room temperature for 48 h, diluted with EtOAc, and washed with water. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure, and the residue (760 mg, 3.31 mmol) was dissolved in a methanol (4 mL)/water (2 mL) mixture, and lithium hydroxide monohydrate (0.56 g, 0.01 mol) was added. After 16 h, the mixture was concentrated, diluted with EtOAc and washed with brine, the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford A5 1H NMR (400 MHz, Chloroform-d) δ 4.19 (d, J = 9.6 Hz, 1 H), 1.02 (s, 11 H), 0.68 (d, J = 4.8 Hz, 5 H).

[00556] Synthesis of (S)-2-((cyclopropoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoic acid (A6)

[00557] The title compound A6 was prepared according to the method shown for the synthesis of compound A3 but using (2,5-dioxopyrrolidin-1-yl)cyclopropyl carbonate. 1H NMR (400 MHz, Chloroform-d) δ 5.33 (d, J = 9.8 Hz, 1 H), 4.53 (d, J = 9.9 Hz, 1 H), 4.08 - 4.01 (m, 1 H), 1.35 (s, 3 H), 1.26 (s, 3 H), 0.81 - 0.52 (m, 4 H).

[00558] Synthesis of (S)-4-fluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoic acid (A7)

[00559] The title compound A7 was prepared according to the method presented for the synthesis of compound A3, but using (S)-2-((tert-butoxycarbonyl)amino)-4-fluoro-3,3-dimethylbutanoic acid (US 2013/0183629 A1 (pp. 178-179))

[00560] Synthesis of (S)-2-((methoxycarbonyl)amino)-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetic acid (A8).

[00561] The title compound A8 was prepared according to the method presented for the synthesis of compound A3 but using (S)-2-amino-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetic acid. MS (ESI) m/z 267.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 4.35 - 4.26 (m, 1 H), 3.65 (s, 3 H), 1.97 (qd, J = 9.6, 1.7 Hz, 6 H).2.4 SYNTHESIS OF INTERMEDIATE I

[00562] Synthesis of ((2S,3S)-4-hydrazinyl-3-hydroxy-1-(4-iodophenyl)butan-2-yl) tert-butyl carbamate (I1a).

[00563] To a solution of NH2NH2 (48.3 g, 0.82 mol) in iPrOH (157 mL) was added tert-butyl ((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate (16.1 g, 41.4 mmol) dissolved in DCM (79 mL) dropwise over 1 h at 0 °C. The ice bath was removed, and the reaction mixture was stirred at rt for 16 h. The mixture was evaporated, and the solvents diluted with water, filtered, washed with water, and dried to afford compound I1a (17.0 g, 97%). 1H NMR (300 MHz, CDCl3): δ 7.59 (d, J = 7.8 Hz, 2 H), 7.02-6.96 (m, 2 H), 5.03 (d, J = 9.9 Hz, 1 H), 3.78-3.66 (m, 2 H), 2.85-2.67 (m, 4 H), 2.04 (s, 3 H), 1.38 (s, 9 H).

[00564] Synthesis of acid methyl ester ((S)-1-{(1S,2S)-2-hydroxy- 1-(4-iodo-benzyl)-3-[N'-((S)-2- methoxycarbonylamino-3,3-dimethyl-butyryl)-hydrazino]-propylcarbamoyl}-2,2-dimethyl-propyl)-carbamic (I1).

[00565] To a solution of I1a (34.0 g, 80.7 mmol) in CH2Cl2 (990 mL) at room temperature was added 4 M hydrochloric acid (198 mL). After stirring for 2 h at 45 °C, LC/MS indicated completion of the reaction, and the mixture was concentrated in vacuo. To this crude residue suspended in CH2Cl2 (700 mL) and cooled to -20 °C was added DIPEA (48.2 g, 373.9 mmol), Moc-tBu-Gly (25.53 g, 135.1 mmol), followed by HATU (53.4 g, 140.5 mmol). The mixture was warmed to room temperature slowly and stirred for 1 h. The mixture was diluted with DCM (1 L) and washed with 1N aqueous HCl solution (400 mL), saturated aqueous NaHCO3 solution (400 mL), water (600 mL × 2), and brine (600 mL) in sequence. The organic layer was dried over Na2SO4, and concentrated in vacuo to afford the residue, which was purified by column chromatography on silica gel and eluted with EtOAc:petroleum ether = 2:1 to 100% EtOAc to EtOAc:MeOH = 50:1 to afford product I1 (8.2 g, 19.4%). MS (ESI) m/z 664.0 [M+H] +. 1H NMR (300 MHz, CD3OD): δ 7.53 (d, J = 8.1 Hz, 2 H), 7.01 (d, J = 8.4 Hz, 2 H), 4.10-4.21 (m, 1 H), 3.90 (s, 1 H), 3.82 (s, 1 H), 3.69-3.64 (m, 7 H), 2.78-2.76 (m, 4H), 0.95 (s, 9H), 0.91 (s, 9H);

[00566] Synthesis of 2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl) tert-butyl hydrazine-1-carboxylate (I2a)

[00567] A mixture of tert-butyl ((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate (5 g, 12.85 mmol) and tert-butylhydrazinecarboxylate (3.4 g, 25.69 mmol) in isopropanol (60 mL) was heated at 80 °C for 48 h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 40% EtOAc/DCM) to afford 12a (4.86 g, 72.6 %) MS (ESI) m/z 522.19 [M+H] +

[00568] Synthesis of ((5S,10S,11S,14S)-16,16,16-trifluoro-10-hydroxy-11-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo- 5-(1,1,1- methyl trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetra-azahexadecan-14-yl)carbamate (I2).

[00569] I2a (5.0 g, 10 mmol) was dissolved in DCM (15 mL) and HCl (4.0 M in dioxane, 36 mL). The reaction was stirred overnight, and then concentrated under reduced pressure. To the residue was added A3 (4.96 g, 20 mmol) and HATU (8.02 g, 21 mmol) in DCM (100 mL), followed by N,N-diisopropylethylamine (16.7 mL, 96 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 and brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (2% to 5% MeOH/DCM) to afford I2 (7.39 g, 60%) MS (ESI) m/z 773.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 7.52 (d, J = 8.1 Hz, 2 H), 6.99 (d, J = 8.2 Hz, 2 H), 3.71 (q, J = 6.9 Hz, 7 H), 3.65 (s, 3 H), 1.37 (dd, J = 7.0, 1.7 Hz, 32 H), 1.19 - 1.07 (m, 10 H).

[00570] Synthesis of ((2S,3S)-3-hydroxy-1-(4-iodophenyl)-4-(2-((S)-2- ((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl tert-butyl)butan-2-yl)carbamate (I3a).

[00571] The title compound I3a was prepared according to the method presented for the synthesis of compound I1, but using methyl (S)-(1-hydrazinyl-3,3-dimethyl-1-oxobutan-2-yl)carbamate. MS (ESI) m/z 593.1 [M+H] +.

[00572] Synthesis of methyl ((5S,10S,11S,14S)-5-(tert-butyl)-16,16,16-trifluoro-10-hydroxy-11-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate.

[00573] The title compound I3 was prepared according to the method presented for the synthesis of compound I2, but using I3a and A3. MS (ESI) m/z 718.7 [M+H] +.

[00574] Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3,3-dimethylbutanoic acid (I4a).

[00575] L-tert-Leucine (2 g, 15.25 mmol) was dissolved in 10% Na2CO3 solution (80 mL), the solution was cooled to 0 °C, then 9-Fluorenylmethyl chloroformate (4.77 g, 18.44 mmol) in dioxane (31 mL) was added. After 2 h, the reaction mixture was diluted with water, washed with ether, and the aqueous layer was adjusted to pH ~2 with 6N HCl and extracted with EtOAc. The combined EtOAc layers were dried over Na2SO4, filtered, and concentrated to yield I4a. MS (ESI) m/z 353.8 [M+H] +.

[00576] Synthesis of (((S)-1-(2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)hydrazinyl)- 9H-fluoren-9-yl)methyl 3,3-dimethyl-1-oxobutan-2-yl)carbamate (I4).

[00577] To I4a (2.55 g, 7.22 mmol) was added I1a (3 g, 7.12 mmol), HATU (2.7 g, 7.1 mmol), and a mixture of CH2Cl2/DMF (2:1) (75 mL), followed by N,N-diisopropylethylamine (3 mL, 17.22 mmol). The reaction was stirred at room temperature for 4 h. The reaction mixture was diluted with EtOAc and washed with saturated NH4Cl and brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (2% to 5% MeOH/DCM) to afford I4 (2.38 g, 44%) MS (ESI) m/z 757.1 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.01 (s, 1 H), 7.75 (t, J = 7.5 Hz, 5 H), 7.66 - 7.46 (m, 6 H), 7.38 (q, J = 7.5 Hz, 4 H), 7.34 - 7.27 (m, 1 H), 6.95 (dd, J = 16.8, 8.0 Hz, 4 H), 5.52 (d, J = 47.2 Hz, 2 H), 5.01 (dd, J = 19.2, 10.0 Hz, 1 H), 4.48 (dd, J = 10.5, 6.5 Hz, 1 H), 4.34 (dt, J = 28.9, 9.8Hz, 2 H), 4.19 (t, J = 6.8 Hz, 2 H), 3.91 (dd, J = 45.4, 14.8 Hz, 2 H), 3.60 (d, J = 31.0 Hz, 2 H), 1.39 (d, J = 16.0 Hz, 13 H).

[00578] Synthesis of ((2S,3S)-4-(2-((S)-2-((cyclopropoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy-1-(4-iodophenyl tert-butyl)butan-2-yl)carbamate (I5).

[00579] The title compound I5 was prepared according to the method presented for the synthesis of compound I2, but using I4 and A5. MS (ESI) m/z 619.4 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 8.02 (s, 0 H), 7.59 (d, J = 8.0 Hz, 2 H), 7.00 (d, J = 7.9 Hz, 2 H), 5.37 (s, 1 H), 5.04 (s, 1 H), 4.02 (s, 1 H), 3.83 (s, 1 H), 3.74 - 3.58 (m, 1 H),2.95 (s, 1 H), 2.88 (d, J = 0.7 Hz, 1 H), 2.85 (d, J = 7.7 Hz, 1 H), 2.80(s, 6 H), 1.38 (s, 8 H), 1.01 (d, J = 10.5Hz, 1H), 0.90 (s, 8 H), 0.66 (d,J = 4.7 Hz, 4 H).

[00580] Synthesis of ((2S,3S)-4-(2-((S)-4-fluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy-1- tert-butyl (4-iodophenyl)butan-2-yl)carbamate (I6a).

[00581] The title compound I6a was prepared according to the method presented for the synthesis of compound I4, but using A7. MS (ESI) m/z 611.5 [M+H] +. 1H NMR (400 MHz, Chloroform-d) δ 7.57 (d, J = 8.0 Hz, 2 H), 6.98 (d, J = 8.1 Hz, 2 H), 5.50 (s, 1 H), 4.97 (d, J = 9.8 Hz, 1 H), 4.37 - 4.17 (m, 1 H), 4.03 (td, J = 25.3, 23.8, 9.4 Hz, 2 H), 3.68 (s, 4 H), 3.50 (s, 0 H), 3.17 (qd, J = 7.4, 4.4 Hz, 1 H), 2.94 (s, 1 H), 2.82 (dt, J = 15.8, 5.5 Hz, 4H), 1.50 (t, J = 7.4 Hz, 1 H), 1.46 (dd, J = 17.4, 6.7 Hz, 3 H), 1.39 (s, 9 H), 0.96 (s, 5 H).

[00582] Synthesis of ((5S,8S,9S,14S)-16-fluoro-9-hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1 ,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (I6).

[00583] The title compound I6 was prepared according to the method presented for the synthesis of compound I2, but using I6a.MS (ESI) m/z 736.1 [M+H] +.

[00584] Synthesis of methyl ((5S,8S,9S,14S)-11-(4-bromo-2,6-difluorobenzyl)-5-(tert-butyl)-9-hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (I7).

[00585] (S)-(1-hydrazinyl-3,3-dimethyl-1-oxobutan-2-yl)methylcarbamate (9.2 g, 45 mmol) and 4-bromo-2,6-difluorobenzaldehyde (10 g, 45 mmol) were stirred in THF at room temperature for 60 min. 4-Methylbenzenesulfonic acid monohydrate (9.0 g, 48 mmol) was added, and the mixture was stirred for a 75 min addition. The mixture was cooled to 8 °C, followed by addition of NaCNBH3 (3.8 g, 61 mmol). The reaction was observed until exotherm at 30 °C. The mixture was stirred for 4 h at room temperature, followed by dilution with DCM (200 mL) and quenching with 1 M K3PO4 to pH 12. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was combined with tert-butyl ((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate (8.5 g, 22 mmol) in isopropanol (30 mL) and heptanes (40 mL). The mixture was stirred at reflux for 40 h, after which it was cooled to room temperature and diluted with 15 mL of hexanes. The product (I7a) was collected by filtration, and the solids rinsed with 20% IPA in hexanes. MS (ESI) m/z 797.8 [M+H] +.

[00586] The title compound I7 was prepared according to the method presented for the synthesis of compound I1 but using methyl (S)-(1-(2-(4-bromo-2,6-difluorobenzyl)hydrazinyl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (I7a) MS (ESI) m/z 869.72 [M+H]. 1H NMR (400 MHz, Methanol-d4) δ 7.53 (d, J = 7.9 Hz, 2 H), 7.16 (d, J = 6.9 Hz, 2 H), 7.00 (d, J = 8.2 Hz, 2 H), 4.16 - 4.03 (m, 2 H), 3.95 - 3.83 (m, 2 H), 3.76 - 3.57 (m, 11 H), 2.90 - 2.72 (m, 6 H), 0.86 (d, J = 23.1 Hz, 18 H).

[00587] Synthesis of ((5S,8S,9S,14S)-11-(4-bromo-2,6-difluorobenzyl)-5-(tert-butyl)-9-hydroxy-15,15-dimethyl-3, 6,13-trioxo-8- (4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl) -2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)methyl carbamate (I8).

[00588] Intermediates: I7 and S25. MS (ESI) m/z 1052.92 [M+H]. 1H NMR (400 MHz, Methanol-d4) δ 8.19 (s, 1 H), 7.79 (d, J = 8.8 Hz, 2 H),7.35 (d, J = 7.8 Hz, 2 H), 7.23 (d, J = 8.1 Hz, 2 H), 7.17 (d, J = 6.9 Hz, 2 H), 6.98 (t, J = 10.5 Hz, 1 H), 4.69 (t, J = 6.8 Hz, 2 H), 4.21 - 4.00 (m, 4 H), 3.98 - 3.81 (m, 5 H), 3.80 - 3.62 (m, 9 H), 3.25 - 3.09 (m, 2 H), 2.98 - 2.85 (m, 2 H), 2.79 (d, J = 6.6 Hz, 2 H), 2.30 - 2.08 (m, 1 H), 2.02- 1.72 (m, 6 H), 0.87 (d, J = 21.7 Hz, 22 H).

[00589] ((S)-1-(2-((2S,3S)-3-((S)-2-amino-4,4,4-trifluoro-3,3-dimethylbutanamido)-2-hydroxy-4-( 4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4- methyl trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate (I9).

[00590] A solution of methyl (S)-(4,4,4-trifluoro-1-hydrazinyl-3,3-dimethyl-1-oxobutan-2-yl)carbamate (200 mg, 0.68 mmol) and 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzaldehyde (P4) (190 mg, 0.75 mmol) in ethanol (5 mL) and acetic acid (0.5 mL) was stirred at 50 °C for 1 h. The reaction was then cooled to room temperature, diluted with EtOAc, rinsed with aq. NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was redissolved in MeTHF (10 mL) and cooled to 5 °C. SODIUM CYANOBORON HYDRIDE (64 mg, 1.0 mmol) was added, followed by 4-methylbenzenesulfonic acid monohydrate (155 mg, 0.82 mmol). After 1 h, the reaction was warmed to room temperature and additional SODIUM CYANOBORON HYDRIDE (64 mg, 1.0 mmol) and 4-methylbenzenesulfonic acid monohydrate (155 mg, 0.82 mmol) were added. After an additional 30 min, the reaction was quenched with 2 M NaOH to pH 14. The mixture was then stirred at 40 °C for 30 min. The mixture was cooled to room temperature, diluted with EtOAc, and the aqueous layer was removed. The organic layer was dried over Na2SO4, filtered, concentrated in vacuo , and purified by column chromatography (30%^70% EtOAc in hexanes) to afford methyl (S)-(1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate (I9a). 1H NMR (400 MHz, Chloroform-d) δ 7.87 (d, J = 2.8 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 2 H), 7.22 (t, J = 60.7 Hz, 1 H), 6.72 (d, J = 2.8 Hz, 1 H), 5.34 (d, J = 9.7 Hz, 1 H), 4.30 (d, J = 9.7 Hz, 1 H), 4.17 (d, J = 12.9 Hz, 1 H), 4.06 (d, J = 13.0 Hz, 1 H), 3.67 (s, 3 H), 1.23 (s, 3 H), 1.16 (s, 3 H). MS (ESI) m/z 499.2 [M+H].

[00591] Methyl (S)-(1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate (I9a). (0.25 g, 0.50 mmol) was combined with tert-butyl ((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate (0.21 g, 0.55 mmol) in heptanes (4 mL) and IPA (2 mL). The mixture was stirred at 90 °C in a sealed tube overnight. The crude mixture was cooled to room temperature, concentrated in vacuo , and redissolved in DCM (10 mL) and cooled to 5 °C. 4 M hydrochloric acid (4.0 M in dioxane, 0.89 mL) was added, and the mixture was stirred overnight, allowing to slowly warm to room temperature. Concentration in vacuo gave methyl ((S)-1-(2-((2S,3S)-3-amino-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate (I9b) as an HCl salt. MS (ESI) m/z 787.9 [M+H]. This crude salt (I9b) was combined in DCM (5 mL) with (S)-2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoic acid (A1) (0.11 g, 0.38 mmol) and DIPEA (0.27 mL, 2 mmol). HATU (0.14 g, 0.36 mmol) was added. After 20 min, the reaction was quenched with aq. NaOH, the organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting mixture was redissolved in DCM and 4 M HCl in dioxane (0.76 mL) was added. After 3.5 h, the mixture was concentrated in vacuo to give methyl ((S)-1-(2-((2S,3S)-3-((S)-2-amino-4,4,4-trifluoro-3,3-dimethylbutanamido)-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate as an HCl salt which was used without further purification. MS (ESI) m/z 956.2 [M+H].3. Example Compounds, Synthesis and Characterization EXAMPLE 1

[00592] Synthesis of ((5S,10S,11S,14S)-8-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16, 16,16-trifluoro-10-hydroxy-11- (4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8, Methyl 12-tetra-aza-hexadecan-14-yl)carbamate (1a).

[00593] Combined P10 (289.23 mg, 0.88 mmol) and I2 (486 mg, 0.63 mmol) were stirred in a 3:1 mixture of THF/AcOH (7.0 mL) at 55 °C for 1 h. The mixture was cooled to room temperature and polymer-supported sodium cyanoborohydride (2.49 mmol/g, 780.02 mg, 1.94 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h, and then at 28 °C overnight and 35 °C for 3 h. The mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (45% to 75% EtOAc/Hexanes) to afford 1a MS (ESI) m/z 1028.3 [M+H] + .

[00594] Synthesis of ((5S,10S,11S,14S)-8-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16, 16,16-trifluoro-10-hydroxy- 15,15-dimethyl-11-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,8,12-tetra-aza-hexadecan-14-yl)carbamate (1).

[00595] In a vial, a solution of 1a (28 mg, 0.027 mmol), S6 (10.4 mg, 0.041 mmol), copper(I) iodide (0.52 mg, 0.002 mmol), trans-Dichlorobis(triphenylphosphine)palladium(II) (99%, 0.87 mg, 0.004 mmol) in a mixture of MeCN:Et3N 3:1 (1 mL) was degassed and then heated at 25 °C for 25 min and concentrated under reduced pressure. The residue was purified by HPLC and lyophilized to afford 1. MS (ESI) m/z 1131.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.19 (s, 1 H), 8.10 (d, J = 9.3 Hz, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.64 (d, J = 2.5 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 7.9 Hz, 2 H), 7.05 (d, J = 9.9 Hz, 1 H), 6.82 (d, J = 9.0 Hz, 1 H), 6.76 (d, J = 9.8 Hz, 1 H), 6.65 (d, J = 2.5 Hz, 1 H), 6.32 - 5.96 (m, 1 H), 4.96 (s, 1 H), 4.61 (dd, J = 8.2, 4.7 Hz, 1 H), 4.58 - 4.49 (m, 3 H), 4.45 (dd, J = 14.2, 4.8 Hz, 1 H), 4.37 (s, 1 H), 4.21 (d, J = 9.9 Hz, 1 H), 4.04 (d, J = 13.0 Hz, 2 H), 3.84 (d, J = 13.2 Hz, 1 H), 3.74 (d, J = 11.9 Hz, 1 H), 3.67 (d, J = 11.5 Hz, 2 H), 3.54 (s, 4 H), 3.47 (s, 3 H), 2.92 - 2.73 (m, 4 H), 2.73 - 2.62 (m, 1 H), 2.24 (s, 2 H), 1.05 (d, J = 4.5 Hz, 7 H), 1.01 (s, 3 H), 0.92 (s, 3 H). EXAMPLE 2

[00596] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15- dimethyl-8-(4-((2-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (2).

[00597] Intermediates: I3, P1, and S7. MS (ESI) m/z 1102.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J = 0.8 Hz, 2 H), 8.21 (d, J = 9.3 Hz, 1 H), 8.17 (d, J = 1.2 Hz, 1 H), 8.02 (d, J = 1.3 Hz, 1 H), 7.59 (t, J = 59.9 Hz, 1 H), 7.37 (dd, J = 19.9, 8.1 Hz, 5 H), 7.23 (d, J = 7.9 Hz, 3 H), 6.83 (d, J = 9.9 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 3 H), 4.81 (dd, J = 8.2, 5.0Hz, 3 H), 4.44 (d, J = 9.9 Hz, 1 H), 4.12 (d, J = 19.4 Hz, 6 H), 3.95 (d, J = 13.2 Hz, 1 H), 3.75 (d, J = 10.1 Hz, 3 H), 3.69 (d, J = 0.8 Hz, 4 H), 3.65 (s, 4 H), 3.46 (d, J = 14.4 Hz, 3 H), 2.90 (d, J = 8.9 Hz, 2H), 2.79 (d, J = 8.9 Hz, 2 H), 2.25 - 2.12 (m, 3 H), 1.99 (d, J = 8.8 Hz, 2 H), 1.14 (s, 4 H), 1.10 (s, 4 H), 0.86 (s, 12 H). EXAMPLE 3

[00598] ((5S,10S,11S,14S)-8-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-10 -hydroxy-15,15-dimethyl-11-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetra-aza-hexadecan-14-yl)carbamate methyl (3).

[00599] Intermediates: I2, P12, and S3. MS (ESI) m/z 1133.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 2.2 Hz, 1 H), 8.10 (d, J = 9.5 Hz, 1 H), 7.69 (dd, J = 8.8, 2.3 Hz, 1 H), 7.60 (d, J = 1.9 Hz, 1 H), 7.53 (d, J = 7.9 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.15 (d, J = 9.7 Hz, 1 H), 6.85 (d, J = 8.8 Hz, 1 H), 6.78 (d, J = 10.0 Hz, 1 H), 6.35 (d, J = 1.9 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.81 - 4.76 (m, 2 H), 4.47 (td, J = 13.6, 4.3 Hz, 2 H), 4.37 (dd, J = 19.3, 11.6 Hz, 2 H), 4.25 (d, J = 9.7 Hz, 1 H), 4.15 (s, 2 H), 3.99 (d, J = 9.2 Hz, 2 H), 3.74 (s, 1 H), 3.68 (s, 3 H), 3.60 (s, 3 H), 3.39 (s, 1 H), 3.36 (s, 1 H), 2.90 (d, J = 9.0 Hz, 2 H), 2.86 - 2.72 (m, 1 H), 2.22 (d, J = 8.5 Hz, 2 H), 2.07 (d, J = 8.6 Hz, 1 H), 1.11 (s, 6 H), 1.06 (s, 3 H), 0.81 (s, 3 H). EXAMPLE 4

[00600] ((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9-hydroxy- 15 ,15-dimethyl-8-(4-((6-(8-(3-methyloxethane-3-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3- methyl yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (4).

[00601] Intermediates: 11, P41, and S64. MS (ESI) m/z 1053.33 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.21 (dd, J = 2.2, 0.7 Hz, 1 H), 7.90 - 7.69 (m, 2 H), 7.61 (d, J = 2.3 Hz, 1 H), 7.33 (t, J = 8.4 Hz, 5 H), 7.24 (d, J = 8.0 Hz, 2 H), 6.98 (d, J = 9.2 Hz, 1 H), 6.65 (d, J = 2.3 Hz, 1 H), 5.06 (s, 1 H), 4.93 (s, 1 H), 4.41 (d, J = 6.0 Hz, 2 H), 4.22 - 4.02 (m, 4 H), 3.91 (d, J = 13.2 Hz, 6 H), 3.79 - 3.54 (m, 9 H), 3.20 (d, J = 12.0 Hz, 2 H), 2.92 (h, J = 5.7, 4.9 Hz, 2 H), 2.81 (d, J = 7.9 Hz, 2 H), 2.08 - 1.80 (m, 6 H), 1.69 (s, 3 H), 0.87 (d, J = 20.1 Hz, 21 H). EXAMPLE 5

[00602] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl- 8-(4-((6-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (5).

[00603] Intermediates: I3, P13, and S3. MS (ESI) m/z 1091.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (d, J = 2.3 Hz, 1 H), 8.10 (d, J = 9.4 Hz, 1 H), 7.60 (dt, J = 5.5, 2.7 Hz, 2 H), 7.24 (t, J = 7.8 Hz, 4 H), 7.12 (d, J = 8.1 Hz, 2 H), 6.77 (d, J = 8.9 Hz, 1 H), 6.71 (d, J = 9.9 Hz, 1 H), 6.54 (d, J = 2.4 Hz, 1 H), 4.95 - 4.85 (m, 2 H), 4.71 (dd, J = 8.3, 5.0 Hz, 2H), 4.34 (d, J = 10.0 Hz, 1 H), 4.26 (d, J = 14.3 Hz, 2 H), 4.11 - 3.94 (m, 4 H), 3.87 (s, 1 H), 3.84 (s, 0 H), 3.67 (s, 1 H), 3.59 (s, 4 H), 3.56 (s, 3 H), 3.28 (d, J = 13.9 Hz, 2 H), 2.80 (d, J = 9.1 Hz, 2 H), 2.69 (d, J = 8.9 Hz, 2 H), 2.21 - 2.04 (m, 2 H), 1.98 (d, J = 8.6 Hz, 2 H), 1.04 (s, 4 H), 1.00 (s, 3 H), 0.99 - 0.94 (m, 1 H), 0.77 (s, 9 H). EXAMPLE 6

[00604] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy- 15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (6).

[00605] Intermediates: I3, P10, and S3. MS (ESI) m/z 1115.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (d, J = 2.2 Hz, 1 H), 8.10 (d, J = 9.3 Hz, 1 H), 7.64 (d, J = 2.4 Hz, 1 H), 7.61 (dd, J = 8.8, 2.3 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.12 (d, J = 8.1 Hz, 2 H), 6.77 (d, J = 9.0 Hz, 1 H), 6.72 (d, J = 9.9 Hz, 0 H), 6.65 (d, J = 2.4 Hz, 1H), 6.12 (tt, J = 55.3, 4.0 Hz, 1 H), 4.87 (dd, J = 8.3, 7.0 Hz, 2 H), 4.71 (dd, J = 8.3, 5.0 Hz, 2 H), 4.54 - 4.42 (m, 2 H), 4.38 - 4.31 (m, 1 H), 4.26 (d, J = 13.8 Hz, 2 H), 4.13 - 3.97 (m, 4 H), 3.85 (s, 0 H), 3.67(s, 1 H), 3.59 (s, 2 H), 3.55 (s, 3 H), 3.30 (s, 1 H), 3.26 (s, 1 H), 2.81 (d, J = 9.3Hz, 2H), 2.70 (d, J = 9.4 Hz, 2 H), 2.17 - 2.06 (m, 2 H), 1.98 (d,J = 8.6 Hz, 2 H), 1.05 (s, 3 H), 1.01 (s, 3 H), 0.77 (s, 9 H). EXAMPLE 7

[00606] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy- 15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (7).

[00607] Intermediates: I3, P10, and S7. MS (ESI) m/z 1117.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 2 H), 8.11 (d, J = 9.4 Hz, 1 H), 7.64 (d, J = 2.4 Hz, 1 H), 7.26 (dd, J = 14.0, 8.2 Hz, 4 H), 7.14 (d, J = 8.1 Hz, 2 H), 6.73 (d, J = 10.0 Hz, 1 H), 6.65 (d, J = 2.5 Hz, 1 H), 6.12 (tt, J = 55.3, 4.0 Hz, 1 H), 4.95 - 4.82 (m, 2 H), 4.74 - 4.62 (m, 3 H), 4.51 (td, J = 14.3, 4.0 Hz, 2 H), 4.35 (d, J = 9.9 Hz, 1 H), 4.02 (d, J = 19.0 Hz, 4 H), 3.86 (d, J = 13.2 Hz, 1 H), 3.67 (s, 1 H), 3.59 (s, 3 H), 3.55 (s, 3 H), 3.37 (d, J = 14.5 Hz, 2 H), 2.81 (d, J = 8.9 Hz, 2 H), 2.70 (d, J = 9.3 Hz, 2 H), 2.23 - 2.02 (m, 2 H), 1.98 - 1.83 (m, 2 H), 1.04 (s, 3 H), 1.01 (s, 3H), 0.77 (s, 9 H). EXAMPLE 8

[00608] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy- 15,15-dimethyl-8-(4-((6-((1R,4R)-5- (oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate of methyl (8).

[00609] Intermediates: I3, P10, and S6. MS (ESI) m/z 1101.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.16 (d, J = 2.2 Hz, 1 H), 8.08 (d, J = 9.4 Hz, 1 H), 7.64 (d , J = 2.4 Hz, 1 H), 7.61 (dd, J = 8.8, 2.2 Hz, 1 H), 7.25 (dd, J = 21.0, 8.1 Hz, 3 H), 7.12 (d, J = 8.0 Hz, 2 H), 6.70 (d, J = 10.3 Hz, 0 H ), 6.64 (d, J = 2.4 Hz, 1 H), 6.58 (d, J = 8.8 Hz, 1 H), 6.12 (tt, J = 55.2, 3.9 Hz, 1 H), 4.96 (s, 1 H), 4.91 - 4.82 (m, 1 H), 4.61 (dd, J = 8.4, 4.6 Hz, 1 H), 4.57 - 4.42 (m, 3 H), 4.41 (s, 1 H), 4.35 (d, J = 6.5 Hz, 1 H), 4.02 (d, J = 13.2 Hz, 2 H), 3.87 (d, J = 13.2 Hz, 1 H), 3.72 - 3.61 (m, 3 H) , 3.59 (s, 3 H), 3.55 (s, 2 H), 2.80 (d, J = 8.7 Hz, 1 H), 2.70 (d, J = 9.5Hz, 2H), 2.24 (s, 2 H), 1.05 (s, 3 H), 1.01 (s, 3 H), 0.77 (s, 8 H). EXAMPLE 9

[00610] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)-16,16,16 -trifluoro-9-hydroxy-15,15-dimethyl-8-(4- ((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3, 6,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (9).

[00611] Intermediates: I2, P34, and S6. MS (ESI) m/z 1101.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.16 (d, J = 2.1 Hz, 1 H), 8.10 (d, J = 9.4 Hz, 1 H), 7.60 (d, J = 8.3 Hz, 1 H), 7.48 (d, J = 7.1 Hz, 2 H), 7.23 (d, J = 7.9 Hz, 2 H), 7.13 (d, J = 8.0 Hz, 2 H), 6.76 (d, J = 10.1 Hz, 1 H), 6.57 (d, J = 8.8 Hz, 1 H), 4.96 (s, 1 H), 4.61 (s, 1 H), 4.49 (t, J = 8.9 Hz, 1 H), 4.41 (s, 1 H), 4.35 (d, J = 9.7 Hz, 1 H), 4.18 (d, J = 9.9 Hz, 1 H), 4.09 (d, J = 13.1 Hz, 1 H), 3.87 (d, J = 13.1 Hz, 1 H), 3.77 - 3.55(m, 8 H), 2.82 (d, J = 8.5 Hz, 3 H), 2.71 (d, J = 10.1 Hz, 1 H), 2.54 (s, 3H), 2.23 (s, 2 H), 1.05 (d, J = 7.7 Hz, 9 H), 0.92 (s, 3 H). EXAMPLE 10

[00612] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifl uoro-8-(4-((6-((R)-hexahydropyrazino[2,1-c][1.4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9 - hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- 2-yl)-2-oxa-4,7,11,12-tetra- methyl aza-hexadecan-14-yl)carbamate (10).

[00613] Intermediates: I2, P10, and S8. MS (ESI) m/z 1143.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.26 - 8.19 (m, 1 H), 8.10 (d, J = 9.4 Hz, 1 H), 7.65 (d, J = 2.5 Hz, 1 H), 7.61 (dd, J = 8.9, 2.3 Hz, 1 H), 7.29 (d, J = 8.5 Hz, 2 H), 7.24 (d, J = 7.9 Hz, 2 H), 7.13 (d, J = 8.1 Hz, 2 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.72 (d, J = 10.0 Hz, 1 H), 6.66 (d, J = 2.4 Hz, 1 H), 6.30 - 5.97 (m, 1 H), 4.51 (td, J = 14.2, 3.9 Hz, 3 H), 4.35 (d, J = 9.7 Hz, 1 H), 4.22 (d, J = 10.0 Hz, 1 H), 4.04 (d, J = 12.4 Hz, 4 H), 3.60 (s, 3 H), 3.57 (s, 3 H), 3.48 (d, J = 11.0 Hz, 1 H), 2.89 - 2.61 (m, 5 H), 1.08 (s, 4 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.94 (s, 3 H). EXAMPLE 11

[00614] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)-16,16,16 -trifluoro-9-hydroxy-15,15-dimethyl-8-(4- ((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (11).

[00615] Intermediates: I2, P34, and S3. MS (ESI) m/z 1121.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (d, J = 2.3 Hz, 1 H), 8.08 (d, J = 9.4 Hz, 1 H), 7.60 (dd, J = 8.9, 2.3 Hz, 1 H), 7.48 (d, J = 7.1 Hz, 2 H), 7.24 (d, J = 7.9 Hz, 2 H), 7.13 (d, J = 8.1 Hz, 2 H), 7.08 (d, J = 10.5 Hz, 1 H), 6.77 (d, J = 9.0 Hz, 1 H), 6.73 (d, J = 9.9 Hz, 1 H), 4.93 - 4.82 (m, 2 H), 4.74 - 4.63 (m, 2 H), 4.34 (d, J = 9.9 Hz, 1 H), 4.26 (d, J = 13.5 Hz, 1 H), 4.18 (d, J = 10.0 Hz, 1 H), 4.09 (d, J = 17.9 Hz, 4 H), 3.88 (d, J = 13.1 Hz, 1 H), 3.64 (s, 1 H), 3.60 (d, J = 2.9 Hz, 6 H), 3.28 (d, J = 13.8 Hz, 2 H), 2.82 (d, J = 8.6 Hz, 3 H), 2.75 - 2.62 (m, 1 H), 2.54 (s, 3 H), 2.22 - 2.06 (m, 2 H), 1.98 (d, J = 8.6 Hz, 2 H), 1.06 (s, 6 H), 1.04 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 12

[00616] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15- dimethyl-8-(4-((6-(6-(oxetan-3-yl)- 3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (12).

[00617] Intermediates: I3, P4, and S4. MS (ESI) m/z 1087.8 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.33 (s, 1 H), 8.15 (d, J = 9.4 Hz, 1 H), 8.10 (d, J = 2.8 Hz, 1 H), 7.78 - 7.71 (m, 1 H), 7.52 (t, J = 59.9 Hz, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 7.8 Hz, 3 H), 7.22 (d, J = 7.9 Hz, 3 H), 6.93 (d, J = 2.7 Hz, 1 H), 6.78 (d, J = 9.2 Hz, 2 H), 4.70 - 4.57(m, 2H), 4.44 (d, J = 9.7 Hz, 1 H), 4.13 (d, J = 12.4 Hz, 3 H), 3.97 (d, J= 13.0 Hz, 1 H), 3.76 (s, 1 H), 3.69 (s, 4 H), 3.65 (s, 3 H), 2.90 (d, J =8.7 Hz, 2 H), 2.80 (d, J = 11.1 Hz, 2 H), 2.11 (d, J = 10.6 Hz, 1 H), 1.39- 1.23 (m, 2 H), 1.15 (s, 4 H), 1.11 (s, 4 H), 0.86 (s, 11 H). EXAMPLE 13

[00618] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-8-(4-((6-(( R) -hexahydropyrazino[2,1-c][1.4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9-hydroxy-15,15- dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14- il)methyl carbamate (13).

[00619] Intermediates: I3, P4, and S8. MS (ESI) m/z 1073.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.30 (d, J = 2.2 Hz, 1 H), 8.19 (d, J = 9.3 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.75 - 7.59 (m, 2 H), 7.56 (dd, J = 7.4, 3.4 Hz, 1 H), 7.53 (t, J = 59.8 Hz, 2 H), 7.45 (d, J = 8.2 Hz, 3 H), 7.32 (d, J = 7.9 Hz, 3 H), 7.22 (d, J = 8.1 Hz, 3 H), 7.03 - 6.88 (m, 3 H), 6.82 (d, J = 10.0 Hz, 1 H), 4.62 (dd, J = 22.7, 13.0 Hz, 2 H), 4.44 (d, J = 9.7 Hz, 1 H), 4.12 (d, J = 12.2 Hz, 6 H), 3.97 (d, J = 13.1 Hz, 2 H), 3.85 (t, J = 12.6 Hz, 1 H), 3.76 (s, 2 H), 3.69 (s, 4 H), 3.59 (d, J = 10.8 Hz, 2 H), 3.01 - 2.70 (m, 6 H), 1.14 (s, 4 H), 1.11 (s, 4 H), 0.86 (s, 12 H). EXAMPLE 14

[00620] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl) benzyl)-16,16,16-trifluoro-9-hydroxy- 15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl) benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (14).

[00621] Intermediates: I2, P17, and S3. MS (ESI) m/z 1176.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (d, J = 2.3 Hz, 1 H), 8.11 (d, J = 9.3 Hz, 1 H), 7.68 - 7.58 (m, 2 H), 7.25 (dd, J = 13.9, 8.3 Hz, 4 H), 7.12 (d, J = 8.0 Hz, 2 H), 6.75 (dd, J = 17.1, 9.4 Hz, 2 H), 6.59 (d, J = 2.4 Hz, 1 H), 4.97 (dq, J = 8.2, 3.8 Hz, 1 H), 4.87 (t, J = 7.6 Hz, 3 H), 4.71 (dd, J = 8.3, 5.0 Hz, 3 H), 4.52 - 4.32 (m, 1 H), 4.32 - 4.18 (m, 3 H), 4.17 - 3.99 (m, 6 H), 3.97 (d, J = 4.7 Hz, 2 H), 3.84 (td, J = 8.3, 5.4 Hz, 2 H), 3.58 (d, J = 9.5 Hz, 8 H), 3.27 (d, J = 13.9 Hz, 3 H), 2.80 - 2.52 (m, 4 H), 2.45 - 2.33 (m, 1 H), 2.33 - 2.23 (m, 1 H), 2.13 (d, J = 10.7 Hz, 2 H), 2.03 - 1.92 (m, 2 H), 1.07 (s, 4 H), 1.05 (s, 3 H), 1.00 (s, 3 H), 0.94 (s, 3 H). EXAMPLE 15

[00622] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl) benzyl)-16,16,16-trifluoro-9-hydroxy- 15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl) benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (15).

[00623] Intermediates: I2, P18, and S3. MS (ESI) m/z 1176.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.19 (s, 1 H), 8.11 (d, J = 9.4 Hz, 1 H), 7.63 (d, J = 2.4 Hz, 1 H), 7.60 (d, J = 8.8 Hz, 1 H), 7.25 (dd, J = 14.4, 8.2 Hz, 4 H), 7.12 (d, J = 8.0 Hz, 2 H), 6.74 (t, J = 10.2 Hz, 2 H), 6.59 (d, J = 2.4 Hz, 1 H), 4.98 (dd, J = 8.3, 3.9 Hz, 1 H), 4.69 (t, J = 6.7 Hz, 2 H), 4.35 (d, J = 9.9 Hz, 1 H), 4.22 (d, J = 10.0 Hz, 1 H), 4.03 (dd, J = 14.5, 7.1 Hz, 3 H), 3.97 (d, J = 4.7 Hz, 2 H), 3.90 - 3.79 (m, 2 H), 3.63 (s, 1 H), 3.58 (d, J = 9.2 Hz, 6 H), 2.81 (d, J = 7.8 Hz, 2 H), 2.68 (d, J = 10.0 Hz, 1 H), 2.49 - 2.33 (m, 1 H), 2.33 - 2.21 (m, 1 H), 2.10 (s, 1 H), 1.94 (s, 0 H), 1.07 (s, 3 H), 1.05 (s, 3 H), 1.00 (s, 3 H), 0.94 (s, 3 H). EXAMPLE 16

[00624] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)benzyl)-16 ,16,16-trifluoro-9-hydroxy- 15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl) benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (16).

[00625] Intermediates: I2, P19, and S3. MS (ESI) m/z 1177.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1 H), 8.10 (d, J = 9.2 Hz, 1 H), 7.61 (s, 1 H), 7.59 (d, J = 2.3 Hz, 2 H), 7.25 (dd, J = 12.2, 8.1 Hz, 4 H), 7.12 (d, J = 8.0 Hz, 2 H), 6.77 (d, J = 9.0 Hz, 1 H), 6.72 (d, J = 10.2 Hz, 1 H), 6.60 (d, J = 2.4 Hz, 1 H), 4.87 (t, J = 7.6 Hz, 3 H), 4.71 (dd, J = 8.3, 5.0 Hz, 2 H), 4.35 (d, J = 9.9 Hz, 1 H), 4.30 - 4.13 (m, 2 H), 4.03 (d, J = 12.6 Hz, 3 H), 3.84 (d, J = 13.3 Hz, 1 H), 3.58 (d, J = 8.2 Hz, 5 H), 3.28 (d, J = 13.9 Hz, 2 H), 2.81 (d, J = 7.8 Hz, 2 H), 2.72 (d, J = 15.2 Hz, 1 H), 2.12 (s, 1 H), 1.98 (d, J = 8.6 Hz, 2 H), 1.10 (s, 6 H), 1.07 (s, 3 H), 1.05 (s, 3H), 1.01 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 17

[00626] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-((6-(8 - (dimethylcarbamoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-16,16,16- trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11, Methyl 12-tetra-aza-hexadecan-14-yl)carbamate (17).

[00627] Intermediates: I2, P7, and S24. MS (ESI) m/z 1177.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J = 0.7 Hz, 1 H), 8.22 - 8.13 (m, 2 H), 8.11 (s, 1 H), 7.86 (dd, J = 9.3, 2.2 Hz, 1 H), 7.50 (s, 1 H), 7.40 - 7.30 (m, 2 H), 7.23 (dd, J = 8.2, 5.7 Hz, 4 H), 7.17 (d, J = 9.9 Hz, 1 H), 7.10 (d, J = 9.3 Hz, 1 H), 6.81 (d, J = 9.9 Hz, 1 H), 4.50 - 4.37 (m, 1 H), 4.35 - 4.23 (m, 3 H), 4.12 (t, J = 11.1 Hz, 2 H), 4.00 - 3.87 (m, 3 H), 3.66 (d, J = 10.3 Hz, 7 H), 3.43 - 3.33 (m, 2 H), 2.96 (s, 6 H), 2.94 - 2.69 (m, 2 H), 1.96 (t, J = 5.3 Hz, 2 H), 1.78 (t, J = 6.9 Hz, 2 H), 1.26 - 1.07 (m, 9 H), 1.02 (s, 3 H). EXAMPLE 18

[00628] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-3,6,13- trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl) ethynyl)benzyl)-5-(1,1,1- methyl trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (18).

[00629] Intermediates: I2, P7, and S25. MS (ESI) m/z 1177.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1 H), 8.13 - 8.05 (m, 2 H), 8.03 (s, 1 H), 7.68 (t, J = 8.5 Hz, 1 H), 7.41 (s, 1 H), 7.31 - 7.22 (m, 2 H), 7.20 - 7.05 (m, 5 H), 6.96 - 6.84 (m, 1 H), 6.72 (d, J = 10.0 Hz, 1 H), 4.75 - 4.65 (m, 5 H), 4.60 (dd, J = 7.6, 6.2 Hz, 2 H), 4.40 - 4.26 (m, 1 H), 4.25 - 4.12 (m, 1 H), 4.10 - 3.87 (m, 4 H), 3.87 - 3.71 (m, 3 H), 3.58 (d, J = 10.7 Hz, 6 H), 3.17 - 2.96 (m, 2 H), 2.89 - 2.59 (m, 4 H), 2.19 - 1.93 (m, 2 H), 1.93 - 1.67 (m, 4 H), 1.15 - 0.96 (m, 9 H), 0.94 (s, 3 H). EXAMPLE 19

[00630] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(3-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (19).

[00631] Intermediates: I2, P7, and S26. MS (ESI) m/z 1177.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (d, J = 0.7 Hz, 1 H), 8.26 - 8.22 (m, 1 H), 8.17 (d, J = 9.4 Hz, 1 H), 8.12 (s, 1 H), 7.78 (d, J = 8.9 Hz, 1 H), 7.51 (s, 1 H), 7.39 - 7.32 (m, 2 H), 7.24 (t, J = 8.3 Hz, 4 H), 7.17 (d, J = 9.8 Hz, 1 H), 7.01 (d, J = 9.0 Hz, 1 H), 6.81 (d, J = 9.9 Hz, 1 H), 4.80 (ddtd, J = 4.5, 2.0, 1.0, 0.5 Hz, 1 H), 4.76 - 4.69 (m, 4 H), 4.50 - 4.37 (m, 1 H), 4.36 - 4.25 (m, 1 H), 4.13 (t, J = 10.7 Hz, 3 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.68 (d, J = 10.5 Hz, 6 H), 2.97 - 2.66 (m, 6 H), 2.33 - 2.10 (m, 3 H), 1.26 - 1.08 (m, 9 H), 1.03 (s, 3 H). EXAMPLE 20

[00632] ((5S,8S,9S,14S)-8-(4-((6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl)ethynyl)benzyl) -11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)- 2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13- trioxo-5-(1,1,1-trifluoro-2-methylpropan-2- yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (20).

[00633] Intermediates: I2, P7, and S27. MS (ESI) m/z 1086.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (s, 1 H), 8.17 (d, J = 9.2 Hz, 1H), 8.12 (s, 1 H), 8.08 (d, J = 1.9 Hz, 1 H), 7.93 (dd, J = 9.4, 2.0 Hz, 1H), 7.69 - 7.60 (m, 1 H), 7.56 (dd, J = 7.2, 3.3 Hz, 0 H), 7.51 (s, 0 H),7.40 - 7.33 (m, 2 H), 7.25 (d, J = 8.0 Hz, 4 H), 7.17 (d, J = 9.9 Hz, 1 H), 6.83 (d, J = 9.3 Hz, 1 H), 4.86 (s, 4 H), 4.49 (s, 4 H), 4.43 (d, J = 3.7 Hz, 1 H), 4.36 - 4.25 (m, 1 H), 4.24 - 4.05 (m, 2 H), 3.92 (d, J = 13.1 Hz, 1 H), 3.67 (d, J = 7.6 Hz, 7 H), 2.99 - 2.70 (m, 4 H), 1.23 - 1.06 (m, 9 H), 1.03 (s, 3 H). EXAMPLE 21

[00634] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16, 16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4- ((6-(9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5- (1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (21).

[00635] Intermediates: I2, P10, and S2. MS (ESI) m/z 1143.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.18 (d, J = 2.3 Hz, 1 H), 8.06 (d, J = 9.3 Hz, 1 H), 7.64 (d, J = 2.5 Hz, 1 H), 7.58 (dd, J = 8.9, 2.3 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.12 (d, J = 8.1 Hz, 2 H), 7.02 (d, J = 9.7 Hz, 1 H), 6.77 (d, J = 9.0 Hz, 1 H), 6.71 - 6.61 (m, 2 H), 6.12 (tt, J = 55.4, 4.0 Hz, 1 H), 4.50 (td, J = 14.3, 3.9 Hz, 2 H), 4.34 (d, J = 9.6 Hz, 1 H), 4.29 - 4.18 (m, 1 H), 4.04 (d, J = 13.0 Hz, 6 H), 3.84 (d, J = 13.2 Hz, 1 H), 3.63 (s, 3 H), 3.56 (s, 3 H), 3.50 (s, 2 H), 3.10 (s, 3 H), 2.81 (d, J = 8.1 Hz, 2 H), 2.69 (d, J = 9.4 Hz, 1 H), 1.07 (s, 3 H), 1.05 (s, 3H), 1.02 (s, 3 H), 0.94 (s, 3 H). EXAMPLE 22

[00636] ((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9 -hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3- il)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13- trioxo-2-oxa-4,7,11,12- demethyl tetra-azahexadecan-14-yl)carbamate (22).

[00637] Intermediates 11, P41, and S3. MS (ESI) m/z 1011.29 [M+H] +. 1H NMR (400 MHz, Methanol-d4)) δ 8.30 (d, J = 2.2 Hz, 1 H), 7.70 (dd, J = 8.8, 2.3 Hz, 1 H), 7.61 (d, J = 2.3 Hz, 1 H), 7.33 (d, J = 7.7 Hz, 5 H),7.23 (d, J = 7.8 Hz, 2 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.65 (d, J = 2.3 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.82 - 4.77 (m, 2 H), 4.35 (d, J = 13.8 Hz, 2 H), 4.13 (d, J = 13.4 Hz, 4 H), 3.93 (s, 6 H), 3.67 (d, J = 6.4 Hz, 8H), 3.38 (d, J = 13.9 Hz, 2 H), 3.00 - 2.77 (m, 5 H), 2.31 - 2.20 (m, 2 H), 2.14 - 2.04 (m, 2 H), 0.87 (d, J = 20.7 Hz, 21 H). EXAMPLE 23

[00638] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15- dimethyl-8-(4-((2-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (23).

[00639] Intermediates: I3, P4 and S7. MS (ESI) m/z 1102.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 2 H), 8.20 (d, J = 9.4 Hz, 1 H), 8.11 (d, J = 2.7 Hz, 1 H), 7.53 (t, J = 59.9, 59.4 Hz, 1 H), 7.45 (d, J = 8.2 - 4.76 (m, 2 H), 4.44 (d, J = 10.0 Hz, 1 H), 4.16 - 4.05 (m, 2 H), 3.97 (d, J = 13.2 Hz, 1 H), 3.85 - 3.71 (m, 1 H), 3.69 (s, 3 H), 3.65 (s, 3 H), 3.54 - 3.39 (m, 2 H), 2.96 - 2.72 (m, 3 H), 2.27 - 2.13 (m, 2 H), 2.04 - 1.91 (m, 2 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 0.86 (s, 9 H). EXAMPLE 24

[00640] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((2-((1R,4R)-5- (oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate of methyl (24).

[00641] Intermediates: I2, P16, and S29. MS (ESI) m/z 1104.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.87 (d, J = 4.9 Hz, 2 H), 8.52 (s, 2 H), 8.19 (d, J = 9.5 Hz, 1 H), 7.98 (d, J = 8.5 Hz, 2 H), 7.41 (t, J = 4.9 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.24 (d, J = 8.1 Hz, 2 H), 7.12 (d, J = 10.1 Hz, 1 H), 6.82 (d, J = 10.1 Hz, 1 H), 5.18 (s, 1 H), 4.99 - 4.90 (m, 2 H), 4.64 - 4.55 (m, 1 H), 4.44 (d, J = 10.0 Hz, 1 H), 4.30 (d, J = 10.0 Hz, 1 H), 4.24 - 4.10 (m, 2 H), 3.98 (d, J = 13.0 Hz, 1 H), 3.90 (d, J = 12.5 Hz, 1 H), 3.85 - 3.72 (m, 3 H), 3.69 (s, 3 H), 3.67 (s, 3 H), 2.96 - 2.74 (m, 4 H), 2.33 (s, 2 H), 1.15 (s, 6 H), 1.11 (s, 3 H), 1.02 (s, 3 H). EXAMPLE 25

[00642] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16, 16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4- ((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3, 6,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (25).

[00643] Intermediates: I2, P10, and S29. MS (ESI) m/z 1156.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 2 H), 8.18 (d, J = 9.3 Hz, 1 H), 7.37 (d, J = 8.5 Hz, 2 H), 7.34 (d, J = 8.1 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.14 (d, J = 8.8 Hz, 1 H), 6.81 (d, J = 9.9 Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1 H), 6.22 (tt, J = 55.5, 4.0 Hz, 1 H), 5.18 (s, 1 H), 5.01 - 4.90 (m, 2H), 4.72 (s, 1 H), 4.60 (td, J = 14.1, 3.7 Hz, 4 H), 4.52 (s, 0 H), 4.44 (d, J = 9.9 Hz, 1 H), 4.31 (d, J = 10.0 Hz, 1 H), 4.20 - 4.07 (m, 2 H), 3.98 - 3.86 (m, 2 H), 3.81 (d, J = 12.8 Hz, 1 H), 3.76 - 3.71 (m, 2 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.00 - 2.71 (m, 4 H), 2.34 (s, 2 H), 1.16 (s, 3 H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H). EXAMPLE 26

[00644] ((5S,8S,9S,14S)-8-(4-((6-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl) ethynyl)benzyl)-11-(4-(1- (difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1 ,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14- il)methyl carbamate (26).

[00645] Intermediates: I2, P4, and S28. MS (ESI) m/z 1115.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.17 (d, J = 2.3 Hz, 1 H), 8.07 (d, J = 9.4 Hz, 1 H), 8.01 (d, J = 2.8 Hz, 1 H), 7.56 (dd, J = 8.8, 2.4 Hz, 1 H), 7.44 (t, J = 59.9 Hz, 1 H), 7.36 (d, J = 8.3 Hz, 2 H), 7.23 (d, J = 7.9 Hz, 2 H), 7.12 (d, J = 8.1 Hz, 2 H), 6.84 (d, J = 2.7 Hz, 1 H), 6.78 (d, J = 9.1 Hz, 1 H), 6.69 (d, J = 10.0 Hz, 1 H), 4.70 - 4.61 (m, 2 H), 4.34 (d, J = 9.8 Hz, 1 H), 4.21 (d, J = 10.0 Hz, 1 H), 4.08 - 4.00 (m, 4 H), 3.94 (d, J = 13.0 Hz, 2 H), 3.85 (d, J = 13.1 Hz, 1 H), 3.64 (s, 1 H), 3.60 (s, 3 H),3.58 - 3.54 (m, 4 H), 3.42 (d, J = 14.4 Hz, 3 H), 2.85 - 2.62 (m, 4 H), 1.07 (s, 3 H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H). EXAMPLE 27

[00646] ((5S,8S,9S,14S)-11-(4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-2,6-difluorobenzyl)-16,16,16- trifluoro-9-hydroxy-15,15-dimethyl-8-(4- ((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3, 6,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (27).

[00647] Intermediates: I2, P3, and S6. MS (ESI) m/z 1149.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.16 (d, J = 2.2 Hz, 1 H), 8.06 (d, J = 9.4 Hz, 1 H), 7.60 (dd, J = 8.8, 2.3 Hz, 1 H), 7.42 (d, J = 7.5 Hz, 2 H), 7.23 (d, J = 7.9 Hz, 2 H), 7.13 (d, J = 8.1 Hz, 2 H), 7.06 (d, J = 10.1 Hz, 1 H), 6.71 (d, J = 10.0 Hz, 1 H), 6.56 (d, J = 8.8 Hz, 1 H), 4.96 (s, 1 H), 4.92 - 4.78 (m, 2 H), 4.61 (s, 1 H), 4.55 - 4.44 (m, 1 H), 4.41 (s, 1 H), 4.34 (d, J = 9.8 Hz, 1 H), 4.19 (d, J = 10.0 Hz, 1 H), 4.12 - 4.01 (m, 2 H), 3.87 (d, J = 13.1 Hz, 1 H), 3.72 - 3.61 (m, 2 H), 3.60 (s, 3 H), 3.58 (s, 3 H), 2.89 - 2.75 (m, 3 H), 2.73 - 2.61 (m, 1 H), 2.43 (ddd, J = 13.1, 8.5, 4.9Hz, 1H), 2.23 (s, 2 H), 1.27 - 1.18 (m, 2 H), 1.10 - 1.01 (m, 11 H), 0.93 (s, 3 H). EXAMPLE 28

[00648] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((6-((1R,4R)- 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1, 1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (28).

[00649] Intermediates: I2, P21, and S6. MS (ESI) m/z 1095.8 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.16 (d, J = 2.2 Hz, 1 H), 8.02 (d, J =9.5 Hz, 1 H), 7.62 - 7.57 (m, 3 H), 7.56 (d, J = 2.4 Hz, 1 H), 7.31 (d, J =8.0 Hz, 2 H), 7.23 (d, J = 7.9 Hz, 2 H), 7.12 (d, J = 8.1 Hz, 2 H), 7.04 (s, 1 H), 6.67 (d, J = 9.7 Hz, 1 H), 6.56 (d, J = 8.8 Hz, 1 H), 6.47 (d, J = 2.4 Hz, 1 H), 4.96 (s, 1 H), 4.89 - 4.83 (m, 1 H), 4.84 - 4.78 (m, 1 H),4.65 - 4.54 (m, 1 H), 4.54 - 4.44 (m, 2 H), 4.41 (s, 1 H), 4.30 (d, J = 9.9 Hz, 1 H), 4.16 (d, J = 9.7 Hz, 1 H), 4.12 - 4.00 (m, 1 H), 3.88 (d, J = 13.2 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 3.73 - 3.60 (m, 2 H), 3.60 - 3.53 (m, 4 H), 3.51 (s, 3 H), 2.87 - 2.76 (m, 2 H), 2.76 - 2.59 (m, 2 H), 2.23 (s, 2 H), 1.07 - 0.94 (m, 10 H), 0.92 (s, 3 H), 0.72 (s, 3 H). EXAMPLE 29

[00650] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((6-((1R,4R)- 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1, 1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (29).

[00651] Intermediates: I2, P6, and S6. MS (ESI) m/z 1105.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.25 (d, J = 2.2 Hz, 1 H), 8.11 (d, J = 9.3 Hz, 1 H), 8.05 (d, J = 2.7 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 2 H), 7.69 (dd, J = 8.8, 2.3 Hz, 1 H), 7.49 (t, J = 59.7 Hz, 1 H), 7.45 (d, J = 8.1 Hz, 2 H), 7.32 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.1 Hz, 2 H), 7.12 (d, J = 9.4 Hz, 1 H), 6.86 (d, J = 2.7 Hz, 1 H), 6.77 (d, J = 9.9 Hz, 1 H), 6.66 (d, J= 8.7 Hz, 1 H), 5.05 (s, 1 H), 4.95 (dd, J = 8.4, 6.5 Hz, 1 H), 4.93 - 4.87(m, 1 H), 4.70 (dd, J = 8.5, 4.6 Hz, 1 H), 4.66 - 4.53 (m, 2 H), 4.50 (s, 1H), 4.40 (d, J = 9.9 Hz, 1 H), 4.24 (d, J = 9.8 Hz, 1 H), 4.21 - 4.12 (m, 1 H), 4.01 (d, J = 13.2 Hz, 1 H), 3.88 (d, J = 13.2 Hz, 1 H), 3.82 - 3.69 (m, 2 H), 3.68 (s, 3 H), 3.59 (s, 3 H), 2.96 - 2.66 (m, 4 H), 2.33 (s, 2 H), 1.12 (s, 3 H), 1.10 (s, 3 H), 1.02 (s, 3 H), 0.83 (s, 3 H). EXAMPLE 30

[00652] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((2-((1R,4R)- 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1, 1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (30).

[00653] Intermediates: I2, P21, and S29. MS (ESI) m/z 1096.7 [M+H] +. 1H NMR (400MHz, Methanol-d4) δ 8.51 (s, 2H), 8.10 (d, J = 9.0Hz, 1H), 7.68 (d, J = 8.0Hz, 2H), 7.65 (d, J = 2.4Hz, 1H), 7.40 (d, J = 7.9Hz, 2H), 7.34 (d, J = 7.8 Hz, 2 H), 7.22 (d, J = 7.9 Hz, 2 H), 6.76 (d, J= 10.1 Hz, 1 H), 6.56 (d, J = 2.4 Hz, 1 H), 5.18 (s, 1 H), 4.93 (dt, J = 20.6, 7.3 Hz, 1H), 4.72 (s, 1 H), 4.65 - 4.55 (m, 1 H), 4.51 (s, 0 H),4.40 (d, J = 7.8 Hz, 1 H), 4.25 (d, J = 7.8 Hz, 1 H), 4.15 (s, 1 H), 4.02 -3.78 (m, 3 H), 3.67 (s, 3 H), 3.66 (d, J = 3.8 Hz, 1 H), 3.59 (s, 3 H), 2.94 - 2.67 (m, 4 H), 2.41 - 2.30 (m, 2 H), 2.05 - 1.99 (m, 1 H), 1.93 (s, 1 H), 1.15 - 1.04 (m, 10H), 1.01 (s, 3 H), 0.81 (s, 3 H). EXAMPLE 31

[00654] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((2- ((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13- trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)- methyl 2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate(31).

[00655] Intermediates: I2, P13, and S29. MS (ESI) m/z 1132.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 2 H), 8.15 (d, J = 9.4 Hz, 1 H), 7.69 (d, J = 2.4 Hz, 1 H), 7.38 - 7.27 (m, 4 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.10 (d, J = 10.0 Hz, 1 H), 6.77 (d, J = 9.8 Hz, 1 H), 6.63 (d, J = 2.4 Hz, 1 H), 5.18 (s, 1 H), 4.93 (dt, J = 20.5, 7.3 Hz, 2 H), 4.72 (s, 1 H), 4.60 (td, J = 12.1, 11.2, 5.5 Hz, 1 H), 4.51 (s, 1 H), 4.46 - 4.39 (m, 1 H), 4.36 - 4.24 (m, 1 H), 4.18 - 4.07 (m, 2 H), 3.93 (d, J = 11.4 Hz, 1 H), 3.89 (s, 1 H), 3.80 (d, J = 12.7 Hz, 1 H), 3.76 - 3.67 (m, 5 H), 3.66 (s, 2 H), 2.96 - 2.70 (m, 4 H), 2.33 (s, 2 H), 1.22 - 1.04 (m, 12 H), 1.02 (s, 3 H). EXAMPLE 32

[00656] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3, 6,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (32).

[00657] Intermediates: I2, P4, and S29. MS (ESI) m/z 1142.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 2 H), 8.14 (d, J = 9.3 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.52 (t, J = 59.9 Hz, 1 H), 7.44 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 9.6 Hz, 1 H), 6.93 (d, J = 2.7 Hz, 1 H), 6.78 (d, J = 9.9 Hz, 1 H), 5.18 (s, 1 H), 4.93 (dt, J = 20.5, 7.3 Hz, 2 H), 4.71 (s, 1 H), 4.60 (dq, J = 11.6, 6.2, 5.6 Hz, 2 H), 4.51 (s, 1 H), 4.44 (d, J = 9.8 Hz, 1 H), 4.30 (d, J = 9.9 Hz, 1 H), 4.21 - 4.05 (m, 2 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.90 (d, J = 12.9 Hz, 1 H), 3.80 (d, J = 12.6 Hz, 1 H), 3.77 - 3.70 (m, 2 H), 3.68 (s, 3 H), 3.66 (s, 3 H), 2.96 - 2.72 (m, 4 H), 2.44 - 2.24 (m, 2 H), 1.16 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.02 (s, 3 H). EXAMPLE 33

[00658] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((2-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (33).

[00659] Intermediates: I2, P21, and S7. MS (ESI) m/z 1142.4 [M+H] +. 1H NMR (400MHz, Methanol-d4) δ 8.52 (s, 2H), 8.10 (d, J = 9.5Hz, 1H), 7.68 (d, J = 8.1Hz, 2H), 7.64 (d, J = 2.3Hz, 1H), 7.40 (d, J = 8.0Hz, 2H), 7.34 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.11 (d, J = 9.5 Hz, 1 H), 6.75 (d, J = 9.7 Hz, 1 H), 6.56 (d, J = 2.4 Hz, 1 H), 4.96(t, J = 7.6Hz, 2 H), 4.82 - 4.71 (m, 3 H), 4.39 (d, J = 9.9 Hz, 1 H), 4.24(d, J = 9.7 Hz, 1 H), 4.20 - 4.06 (m, 2 H), 3.97 (d, J = 13.2 Hz, 1 H), 3.87 (d, J = 13.4 Hz, 1 H), 3.77 - 3.71 (m, 1 H), 3.67 (s, 4 H), 3.59 (s, 3 H), 3.45 (d, J = 14.6 Hz, 2 H), 2.93 - 2.86 (m, 2 H), 2.85 - 2.67 (m, 1 H), 2.31 - 2.15 (m, 2H), 2.06 - 1.93 (m, 2 H), 1.15 - 1.03 (m, 10 H), 1.01 (s, 3 H), 0.82 (s, 3 H). EXAMPLE 34

[00660] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (34).

[00661] Intermediates: I2, P21, and S3. MS (ESI) m/z 1109.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (d, J = 2.3 Hz, 1 H), 8.03 (d, J = 9.5 Hz, 1 H), 7.66 - 7.58 (m, 3 H), 7.56 (d, J = 2.4 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 7.9 Hz, 2 H), 7.12 (d, J = 8.1 Hz, 2 H), 7.07 (d, J = 9.5 Hz, 1 H), 6.76 (d, J = 8.9 Hz, 1 H), 6.68 (d, J = 10.0 Hz, 1 H), 6.47 (d, J = 2.4 Hz, 1 H), 4.92 - 4.82 (m, 2 H), 4.74 - 4.66 (m, 2 H), 4.34 - 4.21 (m, 3 H), 4.18 - 4.12 (m, 1 H), 4.11 - 3.99 (m, 3 H), 3.88 (d, J = 13.1 Hz, 1 H), 3.78 (d, J = 13.3 Hz, 1 H), 3.65 (d, J = 9.0 Hz, 1 H), 3.60 - 3.53 (m, 4 H), 3.51 (s, 3 H), 3.28 (d, J = 13.8 Hz, 2 H), 2.86 - 2.76 (m, 2 H), 2.76 - 2.56 (m, 2 H), 2.17 - 2.08 (m, 2 H), 2.03 - 1.92 (m, 2 H), 1.07 - 0.89 (m, 13 H), 0.72 (s, 3 H). EXAMPLE 35

[00662] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((6-(9- methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1- methyl trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (35).

[00663] Intermediates: I2, P13, and S2. MS (ESI) m/z 1119.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.27 (dd, J = 2.3, 0.7 Hz, 1 H), 8.16 (d, J = 9.4 Hz, 1 H), 7.73 (dd, J = 9.0, 2.3 Hz, 1 H), 7.69 (d, J = 2.4 Hz, 1 H), 7.41 - 7.26 (m, 4 H), 7.21 (d, J = 8.2 Hz, 2 H), 7.13 (d, J = 9.8 Hz, 1 H), 6.96 (d, J = 9.0 Hz, 1 H), 6.79 (d, J = 9.9 Hz, 1 H), 6.63 (d, J = 2.4 Hz, 1H), 4.64 (d, J = 14.7 Hz, 2 H), 4.53 - 4.41 (m, 1 H), 4.35 - 4.25 (m, 1 H), 4.22 - 4.06 (m, 7 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.78 (dt, J = 14.9, 3.0 Hz, 2 H), 3.73 - 3.67 (m, 4 H), 3.66 (s, 3 H), 3.63 (s, 2 H), 3.19 (s, 3 H), 2.94 - 2.72 (m, 4 H), 1.21 - 0.99 (m, 16 H). EXAMPLE 36

[00664] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16, 16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4- ((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (36).

[00665] Intermediates: I2, P10, and S7. MS (ESI) m/z 1170.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 2 H), 8.19 (d, J = 9.3 Hz, 1 H), 7.74 (d, J = 2.4 Hz, 1 H), 7.37 (d, J = 8.5 Hz, 2 H), 7.34 (d, J = 8.1 Hz, 2 H), 7.23 (d, J = 8.1 Hz, 2 H), 7.15 (d, J = 10.0 Hz, 1 H), 6.81 (d, J = 9.9 Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1 H), 6.22 (tt, J = 55.3, 4.0 Hz, 1 H), 5.02 - 4.93 (m, 2 H), 4.83 - 4.78 (m, 2 H), 4.77 (s, 1 H), 4.60 (td, J = 14.3, 3.9 Hz, 2 H), 4.44 (d, J = 10.0 Hz, 1 H), 4.31 (d, J = 10.0 Hz, 1 H), 4.22 - 4.03 (m, 4 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.72 (s, 2 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.51 - 3.40 (m, 2 H), 2.96 - 2.81 (m, 3 H), 2.81 - 2.72 (m, 1 H), 2.27 - 2.12 (m, 2 H), 2.04 - 1.94 (m, 2 H), 1.16 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H). EXAMPLE 37

[00666] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((2-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (37).

[00667] Intermediates: I2, P13, and S7. MS (ESI) m/z 1146.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 2 H), 8.10 (d, J = 9.3 Hz, 1 H), 7.60 (d, J = 2.4 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 4 H), 7.14 (d, J = 8.1 Hz, 2 H), 7.07 (d, J = 10.1 Hz, 1 H), 6.72 (d, J = 10.0 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 4.93 - 4.82 (m, 2 H), 4.75 - 4.57 (m, 4 H), 4.45 - 4.28 (m, 1 H), 4.22 (d, J = 10.0 Hz, 1 H), 4.14 - 3.97 (m, 4 H), 3.83 (d, J = 13.2 Hz, 1 H), 3.71 - 3.61 (m, 1 H), 3.59 (s, 3 H), 3.57 (s, 3 H), 3.42 - 3.32 (m, 2 H), 2.86 - 2.63 (m, 4 H), 2.17 - 2.05 (m, 2 H), 1.94 - 1.82 (m, 2 H), 1.12 - 1.06 (m, 3 H), 1.06 - 0.95 (m, 10 H), 0.93 (s, 3 H). EXAMPLE 38

[00668] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan -3-yl)pyridin-3-yl)benzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4-((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3- yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza- hexadecan-14-yl)methyl carbamate (38).

[00669] Intermediates: I2, P22, and S4. MS (ESI) m/z 1254.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.31 (d, J = 2.4 Hz, 1 H), 8.15 (d, J = 2.1 Hz, 1 H), 7.80 (d, J = 9.0 Hz, 1 H), 7.62 - 7.51 (m, 1 H), 7.23 (d, J = 7.8 - 4.31 (m, 6 H), 4.04 (d, J = 12.6 Hz, 2 H), 3.89 - 3.80 (m, 3 H), 3.77 (t, J = 6.3 Hz, 4 H), 3.61 (d, J = 1.2 Hz, 3 H), 3.57 (s, 3 H), 3.48 (d, J = 13.4 Hz, 8 H), 2.89 - 2.55 (m, 6 H), 1.57 (t, J = 8.8 Hz, 2 H), 1.24 - 1.13 (m, 3 H), 1.08 (s, 3 H), 1.06 (s, 3 H), 1.03 (s, 3 H), 0.95 (s, 3 H). EXAMPLE 39

[00670] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((6- ((1S,4S)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13- trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (39).

[00671] Intermediates: I2, P13, and S30. MS (ESI) m/z 1131.5 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.16 (d, J = 2.2 Hz, 1 H), 8.10 (d, J = 9.2 Hz, 1 H), 7.61 (d, J = 2.4 Hz, 2 H), 7.59 (d, J = 2.2 Hz, 1 H), 7.29 - 7.19 (m, 5 H), 7.12 (d, J = 8.0 Hz, 2 H), 6.73 (d, J = 10.0 Hz, 1H), 6.63 - 6.52 (m, 2 H), 4.95 (s, 1 H), 4.89 - 4.83 (m, 1 H), 4.65 - 4.56 (m, 1 H), 4.54 - 4.43 (m, 2 H), 4.41 (s, 1 H), 4.35 (d, J = 9.9 Hz, 1 H),4.22 (d, J = 9.9 Hz, 1 H), 4.12 - 3.97 (m, 2 H), 3.83 (d, J = 13.2 Hz, 1H), 3.70 (d, J = 11.8 Hz, 1 H), 3.65 - 3.61 (m, 1 H), 3.59 (s, 3 H), 3.57 (s, 3 H), 2.86 - 2.60 (m, 4 H), 2.23 (s, 2 H), 1.10 - 0.95 (m, 13 H), 0.93 (s, 3 H). EXAMPLE 40

[00672] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((6-(6- (oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate of methyl (40).

[00673] Intermediates: I2, P13, and S4. MS (ESI) m/z 1131.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.23 (d, J = 2.3 Hz, 1 H), 8.09 (d, J = 9.5 Hz, 1 H), 7.64 (dd, J = 8.8, 2.3 Hz, 1 H), 7.60 (d, J = 2.4 Hz, 1 H), 7.23 (dd, J = 8.4, 3.3 Hz, 4 H), 7.12 (d, J = 8.1 Hz, 2 H), 6.68 (d, J = 8.9 Hz, 1 H), 6.54 (d, J = 2.4 Hz, 1 H), 4.93 - 4.83 (m, 2 H), 4.51 (dd, J = 8.2, 4.0 Hz, 2H), 4.34 (s, 1 H), 4.27 - 4.18 (m, 1 H), 4.12 - 3.94 (m, 4 H), 3.83 (d, J = 13.2 Hz, 1 H), 3.65 - 3.60 (m, 1 H), 3.59 (s, 3 H), 3.56(s, 3 H), 2.85 - 2.62 (m, 4 H), 2.01 (d, J = 11.0 Hz, 1 H), 1.18 (d, J =13.9 Hz, 1 H), 1.10 - 0.94 (m, 13 H), 0.92 (s, 3 H). EXAMPLE 41

[00674] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16, 16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4- ((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (41).

[00675] Intermediates: I2, P10, and S4. MS (ESI) m/z 1155.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.24 (d, J = 2.2 Hz, 1 H), 8.10 (d, J =9.3 Hz, 1 H), 7.69 - 7.60 (m, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.24 (d, J =7.9 Hz, 2 H), 7.13 (d, J = 8.1 Hz, 2 H), 6.69 (d, J = 9.0 Hz, 1 H), 6.65 (d, J = 2.5 Hz, 1 H), 6.13 (tt, J = 55.3, 3.9 Hz, 1 H), 4.58 - 4.42 (m, 4H), 4.35 (s, 1 H), 4.27 - 4.18 (m, 1 H), 4.16 - 3.95 (m, 4 H), 3.84 (d, J =13.3 Hz, 1 H), 3.63 (s, 2 H), 3.60 (s, 3 H), 3.57 (s, 3 H), 2.86 - 2.72 (m, 3 H), 2.72 - 2.58 (m, 1 H), 2.02 (d, J = 11.0 Hz, 1 H), 1.19 (d, J = 13.9 Hz, 1 H), 1.07 (s, 3 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 42

[00676] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((2-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (42).

[00677] Intermediates: I2, P4, and S52. MS (ESI) m/z 1143.8 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 2 H), 8.19 (d, J = 9.4 Hz, 0 H), 8.11 (d, J = 2.8 Hz, 1 H), 7.70 - 7.51 (m, 4 H), 7.44 (d, J = 8.2 Hz, 2 H), 7.36 (d, J = 7.9 Hz, 2 H), 7.28 - 7.20 (m, 2 H), 6.93 (d, J = 2.8 Hz, 1 H), 4.65 (d, J = 7.4 Hz, 2 H), 4.49 - 4.41 (m, 2 H), 4.37 - 4.28 (m, 2 H), 4.27 - 4.11 (m, 4 H), 3.91 (dd, J = 25.4, 13.9 Hz, 2 H), 3.73 (s, 2 H), 3.70 (s, 3 H), 3.67 (s, 3 H), 2.94 - 2.83 (m, 3 H), 2.83 - 2.70 (m, 1 H), 2.09 (t, J = 11.9 Hz, 1 H), 1.18 - 1.13 (m, 6 H), 1.12 (s, 3 H), 1.02 (s, 3 H). EXAMPLE 43

[00678] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16, 16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4- ((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3, 6,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (43).

[00679] Intermediates: I2, P10, and S6. MS (ESI) m/z 1155.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.25 (d, J = 1.9 Hz, 1 H), 8.19 (d, J = 9.4 Hz, 1 H), 7.74 (d, J = 2.5 Hz, 1 H), 7.69 (dd, J = 8.6, 2.3 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 7.8 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 6.82 (d, J = 9.9 Hz, 1 H), 6.75 (d, J = 2.4 Hz, 1 H), 6.66 (d, J = 8.8 Hz, 1 H), 6.39 - 6.05 (m, 1 H), 5.06 - 5.02 (m, 1 H), 4.74 - 4.67 (m, 1 H), 4.65 - 4.53 (m, 2 H), 4.50 (s, 1 H), 4.44 (d, J = 9.9 Hz, 1 H), 4.31 (d, J = 10.0 Hz, 1 H), 4.13 (d, J = 13.4 Hz, 2 H), 3.93 (d, J = 13.3 Hz, 1 H), 3.83 - 3.72 (m, 2 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 2.94 - 2.72 (m, 2 H), 2.33 (s, 2 H), 1.16 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.02 (s, 3 H). EXAMPLE 44

[00680] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5- (1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (44).

[00681] Intermediates: I2, P4, and S2. MS (ESI) m/z 1130.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.18 (d, J = 2.3 Hz, 1 H), 8.10 (d, J = 9.3 Hz, 1 H), 8.01 (d , J = 2.7 Hz, 1 H), 7.58 (dd, J = 9.2, 2.6 Hz, 1 H), 7.44 (t, J = 59.7 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.23 (d, J = 7.8 Hz, 2 H), 7.12 (d , J = 8.0 Hz, 2 H), 7.09 - 7.00 (m, 1 H), 6.85 (d, J = 2.8 Hz, 1 H), 6.78 (d, J = 8.9 Hz, 1 H), 6.72 (d, J = 10.0 Hz, 1 H), 4.35 (d, J =9.9 Hz, 1 H), 4.21 (d, J = 9.9 Hz, 1 H), 4.13 - 3.94 (m, 5 H), 3.85 (d, J = 13.2 Hz, 1 H), 3.71 - 3.63 (m, 3 H), 3.60 (s, 3 H), 3.57 (s, 3 H), 3.51 (s, 2 H), 3.10 (s, 3 H), 2.88 - 2.73 (m, 3 H), 2.73 - 2.64 (m, 1 H), 1.07 (s, 3 H), 1.05 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H). EXAMPLE 45

[00682] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((6- ((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13- trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (45).

[00683] Intermediates: I2, P13, and S6. MS (ESI) m/z 1130.0 [M+H] +.1H NMR (400 MHz, Methanol-d4) δ 8.16 (d, J = 2.2 Hz, 1 H), 8.10 (d, J =9.3 Hz, 1 H), 7.65 - 7.55 (m, 2 H), 7.30 - 7.19 (m, 4 H), 7.12 (d, J = 8.0Hz, 2H), 7.08 (d, J = 10.0Hz, 1H), 6.72 (d, J = 9.9Hz, 1H), 6.58 (d, J = 8.8Hz, 1H), 6.55 (d, J = 2.4Hz, 1H), 4.96 (s, 1 H), 4.86 (dd, J = 8.3,6.4 Hz, 1 H), 4.61 (dd, J = 8.5, 4.6 Hz, 1 H), 4.56 - 4.44 (m, 2 H), 4.42(s, 1 H), 4.35 (d, J = 9.8 Hz, 1 H), 4.22 (d, J = 10.0 Hz, 1 H), 4.08 - 3.98 (m, 2 H), 3.83 (d, J = 13.2 Hz, 1 H), 3.73 - 3.61 (m, 4 H), 3.59 (s, 3 H), 3.57 (s, 3 H), 2.85 - 2.72 (m, 2 H), 2.72 - 2.62 (m, 1 H), 2.24 (s, 2 H), 1.07 (s, 3 H), 1.06 - 0.94 (m, 10 H), 0.93 (s, 3 H). EXAMPLE 46

[00684] ((5S,10S,11S,14S)-8-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16, 16-trifluoro-10-hydroxy-15,15-dimethyl-11- (4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13 -trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,8,12-tetra-aza-hexadecan-14-yl)carbamate (46).

[00685] Intermediates: I2, P10, and S3. MS (ESI) m/z 1169.4 [M+H] +. 1H NMR (400 MHz, Methanol-d) J = 8.4 Hz, 2 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.19 - 7.12 (m, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.81 (d, J = 9.9 Hz, 1 H), 6.74 (d, J = 2.5 Hz, 1 H), 6.22 (tt, J = 55.5, 4.2 Hz, 1 H), 4.97 (t, J= 7.6 Hz, 3 H), 4.80 (dd, J = 8.2, 5.0 Hz, 2 H), 4.60 (td, J = 14.2, 3.9Hz, 2 H), 4.44 (d, J = 9.9 Hz, 1 H), 4.36 (d, J = 13.6 Hz, 2 H), 4.31 (d, J = 10.0 Hz, 1 H), 4.19 - 4.10 (m, 4 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.77 - 3.71 (m, 2 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.37 (d, J = 13.8 Hz, 2 H), 2.96 - 2.69 (m, 4 H), 2.29 - 2.16 (m, 2 H), 2.16 - 2.03 (m, 2 H), 1.17 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H). EXAMPLE 47

[00686] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1,5-naphthyridin-2-yl)ethynyl)benzyl)-3,6 ,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (47).

[00687] Intermediates: I2, P4, and S31. MS (ESI) m/z 1206.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.23 (d, J = 9.4 Hz, 1 H), 8.16 - 8.10 (m, 2 H), 8.09 (d, J = 8.7 Hz, 1 H), 7.77 (d, J = 8.7 Hz, 1 H), 7.54 (t, J = 59.5 Hz, 1 H), 7.52 (d, J = 9.6 Hz, 1 H), 7.50 - 7.43 (m, 4 H), 7.30 (d, J= 8.0 Hz, 2 H), 7.22 - 7.13 (m, 1 H), 6.95 (d, J = 2.8 Hz, 1 H), 6.85 (d, J= 10.0Hz, 1 H), 4.99 (t, J = 7.6 Hz, 2 H), 4.84 (dd, J = 8.3, 5.0 Hz, 2H), 4.65 (d, J = 14.1 Hz, 2 H), 4.45 (d, J = 9.9 Hz, 1 H), 4.31 (d, J = 9.9 Hz, 1 H), 4.27 - 4.11 (m, 4 H), 3.95 (d, J = 13.2 Hz, 1 H), 3.84 - 3.74(m, 1 H), 3.71 (s, 3 H), 3.67 (s, 3 H), 2.99 - 2.83 (m, 3 H), 2.83 - 2.74(m, 1 H), 2.30 - 2.19 (m, 2 H), 2.17 - 2.06 (m, 2 H), 1.17 (s, 3 H), 1.15(s, 3 H), 1.12 (s, 3 H), 1.04 (s, 3 H). EXAMPLE 48

[00688] 3-(5-((4-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)- 2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy- 2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanamido)butyl)phenyl)ethynyl)pyridin-2-yl)-8-methyl-8-( oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-ium (48).

[00689] Intermediates: I2, P4, and S54 and S55. MS (ESI) m/z 1169.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.21 (d, J = 2.5 Hz, 1 H), 8.10 (d, J = 9.4 Hz, 1 H), 8.01 (d , J = 2.7 Hz, 1 H), 7.64 - 7.57 (m, 1H), 7.44 (t, J = 60.3 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.23 (d, J = 7.9 Hz, 2 H), 7.13 (d, J = 8, 0 Hz, 2 H), 7.07 (d, J = 9.8 Hz, 1 H), 6.85 (d, J = 2.8 Hz, 1 H), 6.73 (d, J = 10.6 Hz, 1 H), 6.70 (d, J = 9.0 Hz, 1 H),5.55 - 5.45 (m, 1 H), 5.00 - 4.83 (m, 4 H), 4.35 (d, J = 9.9 Hz, 1 H), 4.21 (d, J = 10.0 Hz, 1 H), 4.14 (s, 2 H), 4.12 - 3.94 (m, 4 H), 3.85 (d, J = 13.2 Hz, 1 H), 3.71 - 3.62 (m, 2 H ), 3.59 (d, J = 1.2 Hz, 3 H), 3.57 (d, J = 1.5 Hz, 3 H), 3.50 (d, J = 2.0Hz, 1H), 3.46 (s, 3 H), 2.88 - 2.73 (m, 3 H), 2.73 - 2.63 (m, 1 H), 2.49 - 2.38 (m, 1, 5 H), 2.28 (d, J = 11.3 Hz, 0.5 H), 2.20 - 2.05 (m, 2 H), 1.06 (s, 3 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 49

[00690] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((4-((1R,5S)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-(oxetan-3-yl) -3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2- yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (49).

[00691] Intermediates: I2, P4, and S32. MS (ESI) m/z 1323.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (d, J = 9.4 Hz, 1 H), 8.11 (d, J = 2.7 Hz, 1 H), 7.53 (t, J = 59.6 Hz, 1 H), 7.50 - 7.40 (m, 4 H), 7.20 - 7.11 (m, 1 H), 6.94 (d, J = 2.8 Hz, 1 H), 6.75 (d, J = 9.7 Hz, 1 H), 5.00 - 4.91 (m, 4 H), 4.83 - 4.68 (m, 4 H), 4.54 - 4.39 (m, 3 H), 4.33 - 4.27 (m, 1 H), 4.21 - 4.04 (m, 6 H), 3.94 (d, J = 13.1 Hz, 1 H), 3.71 (s, 3 H), 3.66 (s, 3 H), 3.51 - 3.39 (m, 5 H), 3.00 - 2.72 (m, 4 H), 2.37 - 2.11 (m, 4 H), 2.03 - 1.84 (m, 4 H), 1.16 (s, 3 H), 1.13 (s, 3 H), 1.10 (s, 3 H), 1.03 (s, 3 H). EXAMPLE 50

[00692] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((5-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrazin-2-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (50).

[00693] Intermediates: I2, P4, and S33. MS (ESI) m/z 1156.5 [M+H] +. 1H NMR (400 MHz, Methanol-d) 7.45 (d, J = 8.3 Hz, 2 H), 7.40 (d, J = 8.0 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 6.93 (d, J = 2.8 Hz, 1 H), 4.97 (t, J = 7.6 Hz, 2 H), 4.82 -4.76 (m, 2 H), 4.47 - 4.36 (m, 3 H), 4.30 (d, J = 9.9 Hz, 1 H), 4.23 - 4.10 (m, 4 H), 3.95 (d, J = 12.9 Hz, 1 H), 3.78 - 3.72 (m, 1 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.46 (d, J = 14.0 Hz, 3 H), 2.96 - 2.71 (m, 4 H), 2.27 - 2.20 (m, 1 H), 2.14 - 2.02 (m, 2 H), 1.16 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H). EXAMPLE 51

[00694] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-triflu oro-8-(4-((6-((R)-hexahydropyrazino[2,1-c][1.4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9 - hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra- methyl aza-hexadecan-14-yl)carbamate (51).

[00695] Intermediates: I2, P4, and S8. MS (ESI) m/z 1129.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.24 - 8.15 (m, 1 H), 8.08 (d, J = 9.4 Hz, 1 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.61 (dd, J = 8.8, 2.3 Hz, 1 H), 7.44 (t, J = 59.7 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 7.13 (d, J = 8.1 Hz, 2 H), 6.89 - 6.79 (m, 2 H), 4.60 - 4.44 (m, 1 H), 4.34 (s, 1 H), 4.25 - 4.18 (m, 1 H), 4.11 - 3.98 (m, 4 H), 3.85 (d, J = 13.2 Hz, 1 H), 3.76 (t, J = 12.6 Hz, 1 H), 3.68 - 3.62 (m, 1 H), 3.60 (s, 3 H), 3.57 (s, 3 H), 3.54 - 3.35 (m, 2 H), 2.85 - 2.74 (m, 4 H), 2.73 - 2.64 (m, 1 H), 1.07 (s, 3 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 52

[00696] (9aR)-8-(5-((4-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl) 5-oxide -2,6-difluorobenzyl)-2-((S)-4,4,4- trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)- 3-hydroxy-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3, 3-dimethylbutanamido)butyl)phenyl) ethynyl)pyridin-2-yl)octahydro-5H-pyrazino[2,1-c][1.4]oxazine (52).

[00697] To a solution of 51 (17 mg, 0.02 mmol) in CH3CN (1 mL) was added 3-chloroperoxybenzoic acid (77%, 3.9 mg, 0.02 mmol), the mixture was stirred for 5 min, then purified by HPLC to afford 52. MS (ESI) m/z 1146.1 [M+H] +. 1H NMR (400MHz, Methanol-d4) δ 8.38 - 8.23 (m, 1 H), 8.17 - 8.06 (m, 2 H), 7.99 - 7.88 (m, 0 H), 7.73 - 7.65 (m, 1 H), 7.59 - 7.40 (m, 3 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.10 (d, J = 10.2 Hz, 1 H), 6.98 - 6.91 (m, 2 H), 6.77 (d, J = 10.1 Hz, 1 H), 4.59 (d, J = 14.5 Hz, 1H),4.41 (dd, J = 21.3, 12.0 Hz, 2 H), 4.28 (dd, J = 17.0, 11.1 Hz, 2 H), 4.14(d, J = 12.9 Hz, 2 H), 4.10 - 3.87 (m, 6 H), 3.67 (d, J = 10.5 Hz, 8 H),3.26 - 3.12 (m, 1 H), 3.00 - 2.73 (m, 4 H), 2.02 (s, 2 H), 1.24 - 1.10 (m,10 H), 1.02 (s, 3 H). EXAMPLE 53

[00698] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6 -( 8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- Methyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (53).

[00699] Intermediates: I3, P28, and S3. MS (ESI) m/z 1062.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.64 (d, J = 4.9 Hz, 1 H), 8.30 (d, J = 2.2 Hz, 1 H), 8.15 (d, J = 9.3 Hz, 1 H), 7.91 (s, 2 H), 7.70 (dd, J = 8.7, 2.3 Hz, 1 H), 7.60 (d, J = 8.5 Hz, 2 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.77 (d, J = 10.5 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.82 - 4.76 (m, 4 H), 4.40 (dd, J = 33.8, 12.0 Hz, 3 H), 4.16 (d, J = 12.1 Hz, 4 H), 4.00 (d, J = 13.3 Hz, 1 H), 3.79 - 3.60 (m, 9 H), 3.37 (d, J = 14.0 Hz, 3 H), 2.95 - 2.77 (m, 4 H), 2.22 (s, 2 H), 2.08 (d, J = 8.7 Hz, 2 H), 1.13 (d, J = 11.3 Hz, 6 H), 0.86 (s, 10 H). EXAMPLE 54

[00700] 4-(5-((4-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-) pyrazol-3-yl)-2,6-difluorobenzyl)-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy -2- ((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanamido)butyl)phenyl) ethynyl)pyridin-2-yl)-1-(oxetan-3-yl)piperazine (54).

[00701] The title compound 54 was prepared according to the method presented for the synthesis of compound 52, but instead using 112. MS (ESI) m/z 1145.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.31 (d, J = 2.2 Hz, 1 H), 8.19 - 8.05 (m, 2 H), 7.77 - 7.59 (m, 2 H), 7.59 - 7.51 (m, 1 H), 7.44 (d, J = 8.2 Hz, 2 H), 7.39 - 7.30 (m, 3 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 10.0 Hz, 1 H), 7.01 - 6.88 (m, 2 H), 6.77 (d, J = 9.9 Hz, 1 H), 5.14 - 5.00 (m, 3 H), 4.94 (dd, J = 8.1, 6.7 Hz, 2 H), 4.47 (dd, J = 25.9, 10.4 Hz, 3 H), 4.37 - 4.24 (m, 1 H), 4.14 (d, J = 13.0 Hz, 2 H), 3.95 (d, J = 13.2 Hz, 1 H), 3.87 - 3.57 (m, 14 H), 2.98 - 2.67 (m, 4 H), 1.25 - 1.06 (m, 10 H), 1.02 (s, 3 H). EXAMPLE 55

[00702] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-triflu oro-8-(4-((6-((S)-hexahydropyrazino[2,1-c][1.4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9 - hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- 2-yl)-2-oxa-4,7,11,12-tetra- methyl aza-hexadecan-14-yl)carbamate (55).

[00703] Intermediates: I2, P4, and S9. MS (ESI) m/z 1129.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.21 (dd, J = 2.2, 0.8 Hz, 1 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.61 (dd, J = 8.9, 2.3 Hz, 1 H), 7.44 (t, J = 59.6 Hz, 1 H), 7.36 (d, J = 8.3 Hz, 2 H), 7.24 (d, J = 7.9 Hz, 2 H), 7.13 (d, J = 8.1 Hz, 2 H), 6.90 - 6.83 (m, 2 H), 4.60 - 4.44 (m, 1 H), 4.34 (s, 1 H), 4.21 (s, 1 H), 4.14 - 3.98 (m, 4 H), 3.85 (d, J = 13.1 Hz, 1 H), 3.76 (t, J = 12.6 Hz, 1 H), 3.67 - 3.62 (m, 1 H), 3.60 (s, 3 H), 3.57 (s, 3 H), 3.54 - 3.35 (m, 2 H), 2.88 - 2.73 (m, 4 H), 2.73 - 2.66 (m, 1 H), 1.07 (s, 3 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 56

[00704] ((5S,8S,9S,14S)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl )-3,8-diazabicyclo[3.2.1]octan-3- yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-11-(4-(pyridin-2-yl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan Methyl -2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (56).

[00705] Intermediates: I2, P30, and S3. MS (ESI) m/z 1081.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 5.6 Hz, 1 H), 8.41 (t, J = 8.0 Hz, 1 H), 8.36 - 8.25 (m, 1 H), 8.20 (d, J = 8.2 Hz, 1 H), 8.09 (d, J = 9.5 Hz, 1 H), 7.88 (d, J = 8.0 Hz, 2 H), 7.81 (t, J = 6.6 Hz, 1 H), 7.74 - 7.63 (m, 3 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.18(d, J = 9.9 Hz, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.81 (d, J = 9.8 Hz, 1 H),4.96 (dd, J = 8.1, 7.1 Hz, 2 H), 4.81 (dd, J = 8.2, 5.0 Hz, 2 H), 4.44 -4.30 (m, 3 H), 4.24 (d, J = 9.6 Hz, 1 H), 4.16 (s, 2 H), 4.08 (d, J = 13.6 Hz, 1 H), 3.99 (d, J = 13.4 Hz, 1 H), 3.76 (s, 1 H), 3.68 (s, 3 H), 3.56 (s, 3 H), 3.38 (d, J = 13.7 Hz, 2 H), 2.98 - 2.72 (m, 3 H), 2.27 - 2.16 (m, 2 H), 2.12 - 2.03 (m, 2 H), 1.12 (s, 3 H), 1.10 (s, 3 H), 1.04 (s, 3 H), 0.84 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.36, -77.68, -77.89. EXAMPLE 57

[00706] ((5S,8S,9S,14S)-11-(4-(6,7-dihydro-4H-pyrazolo[5,1-c][1.4]oxazin-2-yl)-2, 6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy- 15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl) benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (57).

[00707] Intermediates: I2, P27, and S3. MS (ESI) m/z 1161.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 2.3 Hz, 1 H), 8.18 (d, J = 9.3 Hz, 1 H), 7.70 (dd, J = 8.9, 2.3 Hz, 1 H), 7.42 - 7.31 (m, 4 H), 7.22 (d, J = 8.1 Hz, 2 H), 7.17 (d, J = 9.9 Hz, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.81 (d, J = 9.9 Hz, 1 H), 6.48 (s, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.85 (s, 2 H), 4.81 (dd, J = 8.3, 5.0 Hz, 2 H), 4.47 - 4.39 (m, 1 H), 4.35 (d, J = 14.5 Hz, 2 H), 4.33 - 4.26 (m, 1 H), 4.22 - 4.07 (m, 9 H), 3.93 (d, J = 13.3 Hz, 1 H), 3.69 (s, 3 H), 3.67 (s, 3 H), 3.44 - 3.35 (m, 2 H), 2.96 - 2.71 (m, 4 H), 2.27 - 2.17 (m, 2 H), 2.08 (d, J = 8.6 Hz, 2 H), 1.17 (s, 3 H), 1.15 (s, 3H), 1.11 (s, 3 H), 1.02 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.40, -77.74, -77.92, -115.37. EXAMPLE 58

[00708] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (58) (GS-PI1).

[00709] Intermediates: I2, P4, and S3. MS (ESI) m/z 1155.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.29 (dd, J = 2.3, 0.7 Hz, 1 H), 8.18 (d, J = 9.3 Hz, 1 H), 8.11 (d, J = 2.7 Hz, 1 H), 7.72 - 7.68 (m, 1 H), 7.54 (d, J = 59.9 Hz, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.2 Hz, 2 H), 7.15 (d, J = 10.0 Hz, 1 H), 6.94 (d, J = 2.7 Hz, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.81 (d, J = 9.9 Hz, 1 H), 4.99 - 4.92 (m, 2 H), 4.84 - 4.77 (m, 2 H), 4.44 (d, J = 9.9 Hz, 1 H), 4.40 - 4.26 (m, 3 H), 4.22 - 4.09 (m, 4 H), 3.94 (d, J = 13.2 Hz, 1 H), 3.78 - 3.70 (m, 2 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.38 (d, J = 13.9 Hz, 2 H), 2.95 - 2.70 (m, 4 H), 2.30 - 2.15 (m, 2 H), 2.15 - 2.03 (m, 2 H), 1.16 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.40, -77.73, -77.90, -96.95 (dd, J = 59.9, 19.6 Hz), -114.92. EXAMPLE 59

[00710] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (59).

[00711] Intermediates: I2, P7, and S34. MS (ESI) m/z 1141.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (d, J = 0.8 Hz, 1 H), 8.37 - 8.24 (m, 1 H), 8.18 (d, J = 9.3 Hz, 1 H), 8.13 (s, 1 H), 7.79 (dd, J = 8.6, 2.2Hz, 1 H), 7.51 (t, J = 59.7 Hz, 1 H), 7.34 (d, J = 8.2 Hz, 2 H), 7.29 -7.20 (m, 4 H), 7.18 (d, J = 9.8 Hz, 1 H), 6.82 (d, J = 9.8 Hz, 1 H), 6.73 (d, J = 8.7 Hz, 1H), 4.77 (t, J = 7.6 Hz, 2 H), 4.62 (d, J = 6.3 Hz, 2 H), 4.53 (dd, J = 8.3, 5.1 Hz, 2 H), 4.49 - 4.41 (m, 1 H), 4.37 - 4.29 (m, 1H), 4.27 - 4.07 (m, 3 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.69 (s, 3 H), 3.68 - 3.61 (m, 4 H), 3.00 (dt, J = 10.2, 6.3 Hz, 1 H), 2.94 - 2.72 (m, 4 H), 2.09 - 1.98 (m, 1 H), 1.17 (s, 3 H), 1.15 (s, 3 H), 1.12 (s, 3 H), 1.03 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.39, -77.71, -77.96, -96.87 (d, J = 59.7 Hz), -115.01. EXAMPLE 60

[00712] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (60).

[00713] Intermediates: I2, P7, and S4. MS (ESI) m/z 1141.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (d, J = 0.7 Hz, 1 H), 8.37 - 8.29 (m, 1 H), 8.17 (d, J = 9.4 Hz, 1 H), 8.13 (s, 1 H), 7.74 (dd, J = 8.9, 2.3 Hz, 1 H), 7.51 (t, J = 59.7 Hz, 1 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.24 (dd, J = 12.7, 8.2 Hz, 4 H), 7.18 (d, J = 10.1 Hz, 1 H), 6.84 - 6.76 (m, 2 H), 5.08 - 4.93 (m, 2 H), 4.65 - 4.56 (m, 2 H), 4.50 - 4.41 (m, 1 H), 4.39 -4.27 (m, 1 H), 4.21 - 4.03 (m, 3 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.78 -3.68 (m, 4 H), 3.67 (s, 3 H), 2.95 - 2.73 (m, 4 H), 2.11 (d, J = 11.1 Hz, 1H), 1.17 (s, 3 H), 1.15 (s, 3 H), 1.12 (s, 3 H), 1.03 (s, 3 H). 19F NMR(377 MHz, Methanol-d4) δ -77.39, -77.72, -77.93, -96.87 (d, J = 59.7 Hz), -115.02 EXAMPLE 61

[00714] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (61).

[00715] Intermediates: I2, P7, and S7. MS (ESI) m/z 1156.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (d, J = 0.7 Hz, 1 H), 8.53 (s, 2 H), 8.18 (d, J = 9.2 Hz, 1 H), 8.13 (s, 1 H), 7.51 (t, J = 59.7 Hz, 1 H), 7.34 (d, J = 8.2 Hz, 2 H), 7.24 (t, J = 8.1 Hz, 4 H), 7.18 (d, J = 9.9 Hz, 1 H), 6.82 (d, J = 9.9 Hz, 1 H), 5.00 - 4.92 (m, 2 H), 4.84 - 4.77 (m, 2 H), 4.44 (d, J = 9.9 Hz, 1 H), 4.31 (d, J = 10.0 Hz, 1 H), 4.21 - 4.07 (m, 3 H), 3.79 - 3.70 (m, 1 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.52 - 3.41 (m, 2 H), 2.96 - 2.66 (m, 4 H), 2.21 (d, J = 11.2 Hz, 2 H), 1.99 (d, J = 9.1 Hz, 2 H), 1.17 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.39, -77.72, -77.86, -96.87 (d, J = 59.7 Hz), -115.03. EXAMPLE 62

[00716] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-((6 -(1,5-dimethyl-7-(oxetan-3-yl)-9-oxo-3,7- diazabicyclo[3.3.1]nonan-3-yl)pyridin-3-yl)ethynyl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5 -(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (62)

[00717] Intermediates: I2, P7, and S37. MS (ESI) m/z 1229.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (d, J = 0.8 Hz, 1 H), 8.27 (d, J = 2.2 Hz, 1 H), 8.17 (d, J = 9.3 Hz, 1 H), 8.12 (s, 1 H), 7.98 - 7.88 (m, 1 H), 7.58 (t, J = 59.7 Hz, 1 H), 7.38 - 7.33 (m, 2 H), 7.25 (dd, J = 8.2, 5.8 Hz, 4 H), 7.18 (d, J = 9.9 Hz, 1 H), 6.80 (d, J = 9.9 Hz, 1 H), 4.83 - 4.75(m, 1 H), 4.65 (d, J = 13.5 Hz, 2 H), 4.54 (t, J = 6.8 Hz, 2 H), 4.43 (d, J = 9.7 Hz, 1 H), 4.35 - 4.16 (m, 3 H), 4.13 (t, J = 11.3 Hz, 2 H), 4.02 (d, J = 12.4 Hz, 0 H), 3.93 (d, J = 13.1 Hz, 1 H), 3.72 (d, J = 10.4 Hz, 2 H), 3.69 (d, J = 2.1 Hz, 3 H), 3.66 (s, 3 H), 3.53 - 3.44 (m, 1 H), 2.99 - 2.71(m, 4H), 2.47 (d, J = 11.6 Hz, 2 H), 1.17 (s, 4 H), 1.14 (s, 3 H), 1.11 (s, 4 H), 1.07 (s, 5 H), 1.03 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ - 77.38, -77.71 (d, J = 5.6 Hz), -77.97, -96.87 (d, J = 59.7 Hz), -115.02. EXAMPLE 63

[00718] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (63).

[00719] Intermediates: I2, P9, and S3. MS (ESI) m/z 1119.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.38 (s, 1 H), 8.29 (d, J = 2.3 Hz, 1 H), 8.09 (d, J = 9.7 Hz, 1 H), 8.06 (s, 1 H), 7.69 (dd, J = 8.9, 2.3 Hz, 1 H), 7.54 (d, J = 8.1 Hz, 2 H), 7.48 (t, J = 59.9 Hz, 1 H), 7.41 (d, J = 8.1 Hz, 2 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.14 (d, J = 9.6Hz, 1H), 6.86 (d, J = 8.9 Hz, 1 H), 6.76 (d, J = 9.8 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.81 (dd, J = 8.3, 5.1 Hz, 2 H), 4.45 - 4.31 (m, 3 H), 4.25 (d, J = 9.6 Hz, 1 H), 4.15 (s, 3 H), 3.98 (d, J = 13.2 Hz, 1 H), 3.86(d, J = 13.0 Hz, 1 H), 3.74 (d, J = 8.3 Hz, 1 H), 3.68 (s, 3 H), 3.60 (s, 3H), 3.37 (d, J = 13.9 Hz, 2 H), 2.95 - 2.67 (m, 4 H), 2.30 - 2.19 (m, 2 H),2.07 (d, J = 8.6 Hz, 2 H), 1.12 (s, 3 H), 1.09 (s, 3 H), 1.01 (s, 3 H), 0.85(s, 3 H). 19F NMR (376 MHz, Methanol-d4) δ -77.41, -77.66, -77.73, - 96.57 (d, J = 59.9 Hz). EXAMPLE 64

[00720] ((5S,8S,9S,14S)-5-(tert-butyl)-11-(4-(5,6-difluoropyridin-3-yl)-2,6-difluorobenzyl)-9-hydroxy- 15,15-dimethyl-3,6,13-trioxo-8-(4-((6- (8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-2-oxa-4, Methyl 7,11,12-tetra-aza-hexadecan-14-yl)carbamate (64).

[00721] Intermediates: I8, and 3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

[00722] MS (ESI) m/z 1086.21 [M+H] +. 1H NMR (400 MHz,Methanol-d4) δ 8.28 (t, J = 1.9 Hz, 1 H), 8.24 - 8.06 (m, 2 H), 7.79 (q, J= 8.3 Hz, 2 H), 7.42 - 7.14 (m, 7 H), 6.99 (t, J = 10.5 Hz, 1 H), 4.80 - 4.65 (m, 3 H), 4.25 - 3.84 (m, 10 H), 3.77 - 3.58 (m, 9 H), 3, 19 (t, J =12.3 Hz, 1 H), 3.02 - 2.75 (m, 6 H), 2.31 - 1.76 (m, 4 H), 0.87 (d, J = 27.6 Hz, 20 H). EXAMPLE 65

[00723] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(7-(oxetan-3-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate(65).

[00724] Intermediates: I2, P7 and S41. MS (ESI) m/z 1169.8 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1 H), 8.38 (s, 1 H), 8.14 (d, J = 9.5 Hz, 1 H), 8.12 (s, 1 H), 7.78 (d, J = 9.5 Hz, 1 H), 7.58 (t, J = 59.7 Hz, 1 H), 7.35 (d, J = 7.2 Hz, 2 H), 7.24 (t, J = 7.8 Hz, 4 H), 7.14 (d, J = 9.8 Hz, 1 H), 7.01 (d, J = 8.9 Hz, 1 H), 6.79 (d, J = 10.0 Hz, 1 H), 4.79 (t, J = 7.8 Hz, 2 H), 4.50 - 4.24 (m, 5 H), 4.19 - 4.05 (m, 2 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.79 - 3.63 (m, 9 H), 3.14 (d, J = 12.3 Hz, 2 H), 3.00 - 2.72 (m, 4 H), 2.46 (s, 2 H), 2.13 - 1.92 (m, 2 H), 1.17 (s, 3 H), 1.15 (s, 3 H), 1.12 (s, 3 H), 1.03 (s, 3 H). 19F NMR (376 MHz, Methanol-d4) δ - 77.36, -77.70, -77.78, -96.88 (d, J = 59.8 Hz), -115.01. EXAMPLE 66

[00725] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-3,6,13- trioxo-8-(4-((6-(7-(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl)pyridin-3-yl)ethynyl)benzyl)-5 -(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (66).

[00726] Intermediates: I2, P7, and S40. MS (ESI) m/z 1190.7 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.52 (d, J = 0.7 Hz, 1 H), 8.17 - 8.09 (m, 2 H), 7.98 (d, J = 2.2 Hz, 1 H), 7.81 (ddd, J = 9.1, 7.0, 1.8 Hz, 1 H), 7.76 (ddd, J = 6.4, 1.8, 0.7 Hz, 1 H), 7.57 (dd, J = 9.2, 2.3 Hz, 1 H), 7.50 (t, J = 59.7 Hz, 1 H), 7.30 (d, J = 7.9 Hz, 2 H), 7.26 - 7.18 (m, 5 H), 7.13 (d, J = 9.9 Hz, 1 H), 6.93 (d, J = 9.3 Hz, 1 H), 6.79 (t, J = 6.7 Hz, 1 H), 4.50 (d, J = 13.3 Hz, 2 H), 4.46 - 4.38 (m, 1 H), 4.24 (d, J = 13.1 Hz, 2 H), 4.20 - 4.05 (m, 2 H), 3.93 (d, J = 13.1 Hz, 1 H), 3.77 - 3.67 (m, 5 H), 3.66 (s, 3 H), 3.58 - 3.46 (m, 2 H), 3.38 (d, J = 13.3 Hz, 2 H), 2.96 - 2.71 (m, 4 H), 2.35 (s, 2 H), 2.14 (t, J = 3.2 Hz, 2 H), 1.17 (s, 3 H), 1.15 (s, 3 H), 1.12 (s, 3 H), 1.03 (s, 3 H). 19F NMR (376 MHz, Methanol-d4) δ -77.34, -77.66, -77.97, -96.87 (d, J = 59.6 Hz), -115.00 (d, J = 8.7 Hz). EXAMPLE 67

[00727] ((5S,8S,9S,14S)-8-(4-((6-(7-acetyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)pyridin-3-yl) ethynyl)benzyl)-11-(4-(1- (difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1 ,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14- il)methyl carbamate (67).

[00728] Intermediates: I2, P7, and S39. MS (ESI) m/z 1155.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1 H), 8.07 (d, J = 9.5 Hz, 1 H), 8.03 (s, 1 H), 7.99 (d, J = 2.3 Hz, 1 H), 7.75 (d, J = 9.4 Hz, 1 H), 7.49 (t, J = 59.7 Hz, 1 H), 7.26 (d, J = 7.9 Hz, 2 H), 7.20 - 7.03 (m, 5 H), 6.72 (d, J = 10.2 Hz, 1 H), 4.61 (d, J = 13.5 Hz, 1 H), 4.38 - 4.29 (m, 3 H), 4.24 - 4.17 (m, 1 H), 4.04 (dt, J = 29.4, 13.9 Hz, 5 H), 3.83 (d, J = 13.1 Hz, 1 H), 3.66 - 3.61 (m, 1 H), 3.59 (s, 3 H), 3.57 (s, 3 H), 3.44 - 3.26 (m, 4 H), 2.87 - 2.62 (m, 6 H), 2.11 (s, 3 H), 1.95 (s, 3 H), 1.80 (s, 3 H), 1.08 (s, 3 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.94 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.38, -77.70, -77.88 (TFA peak), -96.88 (d, J = 59.8 Hz), -115.02. EXAMPLE 68

[00729] ((5S,8S,9S,14S)-8-(4-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl) benzyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)- 2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13- trioxo-5-(1,1,1-trifluoro-2-methylpropan-2- yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (68).

[00730] Intermediates: I2, P7, and S43. MS (ESI) m/z 1100.8 [M+H]+.1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1 H), 8.11 - 8.04 (m, 2 H), 8.03 (s, 1 H), 7.73 (d, J = 9.4 Hz, 1 H), 7.41 (t, J = 59.8 Hz, 1 H), 7.26 (d, J = 7.2 Hz, 3 H), 7.15 (t, J = 7.6 Hz, 5 H), 6.94 (d, J = 9.2 Hz, 1 H), 4.47 - 4.38 (m, 2 H), 4.37 - 4.30 (m, 1 H), 4.24 - 4.18 (m, 1 H), 4.12 -3.96 (m, 2 H), 3.84 (d, J = 13.1 Hz, 1 H), 3.72 (d, J = 12.2 Hz, 2 H),3.66 - 3.61 (m, 1 H), 3.59 (s, 3 H), 3.57 (s, 3 H), 3.18 - 3.12 (m, 2 H), 2.86 - 2.63 (m, 5 H), 1.97 - 1.85 (m, 2 H), 1.81 - 1.73 (m, 2 H), 1.08 (s, 3 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.94 (s, 3 H). 19F NMR (377 MHz,Methanol-d4) δ -77.38, -77.70, -77.94, -96.88 (d, J = 59.7 Hz), -115.02. EXAMPLE 69

[00731] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((4-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)phenyl)ethynyl)benzyl)-3,6,13- trioxo-5-(1,1,1-trifluoro-2-methylpropan-2- yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)methyl carbamate (69).

[00732] Intermediates: I2, P7, and S5. MS (ESI) m/z 1137.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1 H), 8.09 (d, J = 9.4 Hz, 1 H), 8.03 (s, 1 H), 7.73 (s, 1 H), 7.63 (d, J = 8.3 Hz, 2 H), 7.51 (d, J = 8.3 Hz, 2 H), 7.41 (d, J = 59.7 Hz, 1 H), 7.32 - 7.25 (m, 2 H), 7.16 (dd, J = 8.3, 3.3 Hz, 4 H), 7.09 (d, J = 9.9 Hz, 1 H), 6.71 (d, J = 10.0 Hz, 1 H), 4.39 - 4.30 (m, 1 H), 4.30 - 4.17 (m, 1 H), 4.11 - 3.97 (m, 2 H), 3.84 (d, J = 13.2 Hz, 1 H), 3.68 - 3.62 (m, 1 H), 3.61 (s, 3 H), 3.57 (s, 3 H), 3.08 (s, 3 H), 2.82 (d, J = 7.9 Hz, 2 H), 2.78 - 2.61 (m, 2 H), 1.08 (s, 3 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.94 (s, 3 H). 19F NMR (377 MHz, Methanol- d4) δ -77.39, -77.70, -77.82, -96.87 (d, J = 59.7 Hz), -115.00. EXAMPLE 70

[00733] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1 ,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (70).

[00734] Intermediates: I2, P7, and S38. MS (ESI) m/z 1177.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (s, 1 H), 8.20 (d, J = 2.2 Hz, 1 H), 8.12 (s, 1 H), 7.73 (d, J = 9.4 Hz, 1 H), 7.50 (d, J = 59.7 Hz, 1 H), 7.33 (d, - 4.01 (m, 4 H), 3.93 (d, J = 13.1 Hz, 1 H), 3.76 - 3.70 (m, 1 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.21 (d, J = 11.9 Hz, 2 H), 3.04 (s, 3 H), 2.95 - 2.70 (m, 4 H), 2.12 - 1.99 (m, 2 H), 1.86 (t, J = 7.0 Hz, 2 H), 1.17 (s, 4 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.40 (d, J = 5.6 Hz), -77.71, -77.90, -96.88 (d, J = 59.7 Hz), -115.01. EXAMPLE 71

[00735] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (71).

[00736] Intermediates: I2, P7, and S3. MS (ESI) m/z 1155.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1 H), 8.24 - 8.18 (m, 1 H), 8.08 (d, J = 9.3 Hz, 1 H), 8.03 (d, J = 0.7 Hz, 1 H), 7.65 - 7.52 (m, 3 H), 7.50 - 7.43 (m, 1 H), 7.41 (d, J = 59.7 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 2 H), 7.16 (d, J = 8.4 Hz, 2 H), 7.13 (d, J = 8.1 Hz, 2 H), 6.77 (d, J = 8.9 Hz, 1 H), 6.71 (d, J = 10.0 Hz, 1 H), 4.87 (t, J = 7.6 Hz, 2 H), 4.71 (dd,J = 8.2, 5.0 Hz, 2 H), 4.34 (d, J = 9.9 Hz, 1 H), 4.26 (d, J = 13.8 Hz, 2H), 4.21 (d, J = 10.0 Hz, 1 H), 4.11 - 3.97 (m, 5 H), 3.83 (d, J = 13.2 Hz, 1 H), 3.66 - 3.61 (m, 1 H), 3.59 (s, 3 H), 3.57 (s, 3 H), 3.28 (d, J = 13.9 Hz, 2 H), 2.85 - 2.63 (m, 4 H), 2.19 - 2.09 (m, 2 H), 2.02 - 1.95 (m, 2 H), 1.08 (s, 3 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.94 (s, 3 H). 19F NMR(377 MHz, Methanol-d4) δ -77.40, -77.72, -96.87 (d, J = 59.7 Hz), - 115.02. EXAMPLE 72

[00737] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8 -(4-((6-(8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3- yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza -hexadecan-14-yl)methyl carbamate (72).

[00738] Intermediates: I3, P4, and S38. MS (ESI) m/z 1123.8 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.24 - 8.14 (m, 2 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.80 (dd, J = 9.2, 2.3 Hz, 1 H), 7.53 (t, J = 59.9 Hz, 1 H), 7.44 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.28 - 7.18 (m, 2 H), 7.01 (d, J = 9.2 Hz, 1 H), 6.93 (d, J = 2.7 Hz, 1 H), 6.80 (d, J = 9.9 Hz, 1 H), 4.47 - 4.38 (m, 3 H), 4.17 - 4.07 (m, 2 H), 4.04 (dd, J = 12.3, 2.4 Hz, 2 H), 3.96 (d, J = 13.1 Hz, 1 H), 3.77 - 3.72 (m, 2 H), 3.69 (s, 3 H), 3.65 (s, 3 H), 3.27 (dd, J = 12.1, 2.5 Hz, 2 H), 3.04 (s, 3 H), 2.97 - 2.71 (m, 4 H), 2.13 - 2.04 (m, 2 H), 1.90 - 1.81 (m, 2 H), 1.14 (s, 3 H), 1.11 (s, 3H), 0.86 (s, 9 H). 19F NMR (377 MHz, Methanol-d4) δ -77.32, -77.93, - 96.91 (dd, J = 59.9, 15.2 Hz), -114.77. EXAMPLE 73

[00739] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15- dimethyl-8-(4-((6-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (73).

[00740] Intermediates: I3, P4, and S3. MS (ESI) m/z 1102.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 2.2 Hz, 1 H), 8.17 (d, J = 9.4 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.71 (dd, J = 8.8, 2.3 Hz, 1 H), 7.53 (d, J = 59.8 Hz, 1 H), 7.44 (d, J = 8.3 Hz, 2 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 6.93 (d, J = 2.8 Hz, 1 H), 6.91 - 6.84 (m, 1 H), 4.96 (dd, J = 8.2, 7.0 Hz, 2 H), 4.83 (dd, J = 8.2, 5.1 Hz, 2 H),4.61 - 4.49 (m, 1 H), 4.43 (s, 1 H), 4.40 - 4.29 (m, 2 H), 4.19 - 4.04 (m, 4 H), 3.97 (d, J = 13.1 Hz, 1 H), 3.81 - 3.72 (m, 2 H), 3.69 (s, 3 H), 3.65(s, 3 H), 3.41 (dd, J = 14.2, 1.7 Hz, 2 H), 2.99 - 2.70 (m, 4 H), 2.32 - 2.18 (m, 2 H), 2.13 - 1.99 (m, 2 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 0.86 (s, 9 H). 19F NMR (377 MHz, Methanol-d4) δ -77.35, -78.05 (TFA peak), -96.93 (dd, J = 59.7, 14.5 Hz), -114.79. EXAMPLE 74

[00741] ((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (74).

[00742] Intermediates: I2, P26, and S3. MS (ESI) m/z 1133.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.71 (d, J = 5.2 Hz, 1 H), 8.35 - 8.27 (m, 1 H), 8.19 - 8.11 (m, 2 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.88 (s, 1 H), 7.70 (dd, J = 8.9, 2.3 Hz, 1 H), 7.69 - 7.64 (m, 1 H), 7.63 - 7.57 (m, 1H), 7.33 (d, J = 7.9 Hz, 2 H), 7.23 (d, J = 7.9 Hz, 2 H), 6.87 (dd, J = 9.0,0.8 Hz, 1H), 4.96 (dd, J = 8.2, 7.1 Hz, 2 H), 4.82 (dd, J = 8.2, 5.1 Hz, 2H), 4.59 - 4.51 (m, 1 H), 4.45 - 4.41 (m, 1 H), 4.39 - 4.24 (m, 5 H), 4.20 - 4.11 (m, 4 H), 4.05 (d, J = 12.7 Hz, 1 H), 3.82 - 3.73 (m, 2 H), 3.69 (s, 3 H), 3.63 (s, 3 H), 3.44 - 3.36 (m, 2 H), 2.92 (t, J = 9.0 Hz, 3 H), 2.81 (dd, J = 12.6, 9.5 Hz, 1 H), 2.30 - 2.18 (m, 2 H), 2.12 - 2.04 (m, 2 H), 1.14 (s, 6 H), 1.12 (s, 3 H), 1.00 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.30, -77.68, -78.09 (TFA peak), -112.80. EXAMPLE 75

[00743] ((5S,8S,9S,14S)-11-(4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-2,6-difluorobenzyl)-16,16,16- trifluoro-9-hydroxy-15,15-dimethyl-8-(4- ((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (75).

[00744] Intermediates: I2, P3, and S3. MS (ESI) m/z 1163.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.32 - 8.26 (m, 1 H), 8.12 (d, J = 9.4 Hz, 1 H), 7.70 (dd, J = 8.8, 2.3 Hz, 1 H), 7.51 (d, J = 7.5 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.12 (d, J = 9.8 Hz, 1 H),6.86 (d, J = 8.9 Hz, 1 H), 6.77 (d, J = 9.9 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2H), 4.79 (s, 1 H), 4.43 (d, J = 9.8 Hz, 1 H), 4.35 (d, J = 14.0 Hz, 2 H), 4.28 (d, J = 10.0 Hz, 1 H), 4.17 (s, 5 H), 3.97 (d, J = 13.2 Hz, 1 H), 3.74 (d, J = 13.6 Hz, 1 H), 3.69 (s, 3 H), 3.67 (s, 3 H), 3.38 (d, J = 13.9 Hz, 2 H), 3.02 - 2.84 (m, 3 H), 2.82 - 2.74 (m, 1 H), 2.53 (td, J = 8.6, 4.3 Hz, 1H), 2.27 - 2.18 (m, 2 H), 2.08 (d, J = 8.6 Hz, 2 H), 1.35 - 1.30 (m, 2 H), 1.27 (d, J = 16.2 Hz, 0 H), 1.20 - 1.13 (m, 9 H), 1.12 (s, 3 H), 1.03 (s, 3 H). 19F NMR (376 MHz, Methanol-d4) δ -77.31, -77.67, -77.82, -113.25. EXAMPLE 76

[00745] ((5S,8S,9S,14S)-11-(4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-2,6-difluorobenzyl)-9-hydroxy-15, 15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (76).

[00746] Intermediates: I3, P3, and S3. MS (ESI) m/z 1110.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.32 - 8.27 (m, 1 H), 8.13 (d, J = 9.2 Hz, 1 H), 7.70 (dd, J = 8.7, 2.3 Hz, 1 H), 7.51 (d, J = 7.5 Hz, 2 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.78 (s, 0 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.79 (s, 1 H), 4.54 (s, 1 H), 4.43 (d, J = 6.3 Hz, 1 H), 4.35 (d, J = 13.9 Hz, 2 H), 4.15 (s, 5 H), 3.99 (d, J = 13.1 Hz, 1 H), 3.74 (s, 1 H), 3.69 (s, 4 H), 3.65 (s, 3 H), 3.38 (d, J = 13.9 Hz, 2 H), 3.34 (s, 1 H), 3.00 - 2.75 (m, 2 H), 2.51 (dq, J = 8.5, 4.9, 4.3 Hz, 1 H), 2.27 - 2.18 (m, 2 H), 2.08 (d, J = 8.6 Hz, 2 H), 1.36 - 1.30 (m, 2 H), 1.19 - 1.13 (m, 6 H), 1.12 (s, 3 H), 0.85 (s, 10 H). 19F NMR (376 MHz, Methanol-d4) δ -77.28, -77.92, -113.11. EXAMPLE 77

[00747] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15- dimethyl-8-(4-((6-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (77).

[00748] Intermediates: I3, P1, and S3. MS (ESI) m/z 1102.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.30 (d, J = 2.1 Hz, 1 H), 8.15 (s, 1 H), 8.00 (s, 1 H), 7.74 - 7.66 (m, 1 H), 7.57 (s, 1 H), 7.42 (s, 0 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 7.8 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 3 H), 6.86 (d, J = 8.9 Hz, 1 H), 4.97 (t, J = 7.6 Hz, 3 H), 4.80 (d, J = 5.2 Hz, 1 H), 4.43 (d, J = 9.8 Hz, 1 H), 4.35 (d, J = 14.1 Hz, 2 H), 4.19 - 4.08 (m, 5 H), 3.96 (d, J = 13.2 Hz, 1 H), 3.76 (s, 1 H), 3.69 (s, 4 H), 3.65 (s, 3 H), 3.38 (d, J = 13.9 Hz, 3 H), 2.90 (d, J = 8.1 Hz, 2 H), 2.81 (s, 1 H), 2.22 (s, 2 H), 2.08 (d, J = 8.7 Hz, 2 H), 1.13 (d, J = 14.1 Hz, 8 H), 0.86 (s, 12H). 19F NMR (376 MHz, Methanol-d4) δ -77.36, -77.93, -94.99 (d, J = 60.0 Hz), -115.00 EXAMPLE 78

[00749] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((2-methyl-6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (78).

[00750] Intermediates: I2, P28, and S45. MS (ESI) m/z 1131.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (d, J = 5.0 Hz, 1 H), 8.14 (d, J = 9.3 Hz, 1 H), 7.98 - 7.85 (m, 2 H), 7.61 (t, J = 8.1 Hz, 3 H), 7.47 - 7.38 (m, 1 H), 7.33 (d, J = 7.8 Hz, 3 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 9.9 Hz, 1 H), 6.77 (d, J = 9.8 Hz, 1 H), 6.67 (d, J = 8.7 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.42 (dd, J = 25.4, 11.7 Hz, 2 H), 4.33 -4.27 (m, 1 H), 4.22 - 4.10 (m, 4 H), 3.98 (d, J = 13.0 Hz, 1 H), 3.73 (s, 1 H), 3.68 (s, 4 H), 3.63 (s, 3 H), 3.35 (d, J = 14.0 Hz, 2 H), 2.97 -2.86 (m, 3 H), 2.84 - 2.75 (m, 1 H), 2.56 (s, 4 H), 2.25 - 2.16 (m, 2 H),2.13 - 2.01 (m, 2 H), 1.28 (d, J = 8.8 Hz, 0 H), 1.16 (d, J = 2.7 Hz, 7 H), 1.13 (s, 4 H), 1.03 (s, 3 H). 19F NMR (376 MHz, Methanol-d4) δ - 77.35, -77.68, -114.72. EXAMPLE 79

[00751] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (79).

[00752] Intermediates: I2, P1, and S3. MS (ESI) m/z 1156.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.32 - 8.28 (m, 1 H), 8.15 (d, J = 1.2 Hz, 1 H), 8.13 (s, 0 H), 8.00 (d, J = 1.3 Hz, 1 H), 7.73 (s, 0 H), 7.70 (dd, J = 8.8, 2.3 Hz, 1 H), 7.58 (s, 1 H), 7.43 (s, 0 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.12 (d, J = 9.8 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1 H), 6.77 (d, J = 10.0 Hz, 0 H), 4.97 (t, J = 7.6 Hz, 2 H), 4.82 - 4.78 (m, 2 H), 4.53 (s, 1 H), 4.44 (d, J = 6.5 Hz, 1 H), 4.39 - 4.28 (m, 3 H), 4.13 (d, J = 15.7 Hz, 4 H), 3.94 (d, J = 13.3 Hz, 1 H), 3.69 (s, 3 H), 3.67 (s, 3 H), 3.38 (d, J = 13.9 Hz, 2 H), 2.97 - 2.72 (m, 6 H), 2.27 - 2.19 (m, 2 H), 2.08 (d, J = 8.6 Hz, 2 H), 1.21 (t, J = 7.3 Hz, 4 H), 1.16 (d, J = 8.4 Hz, 6 H), 1.11 (s, 3 H), 1.03 (s, 3 H). 19F NMR (376 MHz, Methanol-d4) δ -74.51, -76.39, -77.39, -77.71, -77.89, - 94.98 (d, J = 60.0 Hz), -97.37 (d, J = 59.1 Hz), -115.13 EXAMPLE 80

[00753] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16-fluoro-9-hydroxy- 15,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (80).

[00754] Intermediates: I6, P7, and S3. MS (ESI) m/z 1119.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (d, J = 0.7 Hz, 1 H), 8.32 - 8.27 (m, 1 H), 8.17 (d, J = 9.4 Hz, 1 H), 8.12 (s, 1 H), 7.88 - 7.73 (m, 0 H), 7.70 (dd, J = 8.8, 2.3 Hz, 1 H), 7.65 (s, 0 H), 7.51 (s, 1 H), 7.38 - 7.30 (m, 2 H), 7.24 (dd, J = 16.7, 8.2 Hz, 4 H), 6.86 (d, J = 9.0 Hz, 1 H), 6.81 (d, J = 9.9 Hz, 1 H), 4.96 (dd, J = 8.1, 7.0 Hz, 2 H), 4.84 - 4.77 (m, 2 H), 4.47 - 4.41 (m, 1 H), 4.36 (d, J = 13.7 Hz, 2 H), 4.22 (d, J = 9.2 Hz, 1 H), 4.18 - 4.03 (m, 5 H), 4.00 (s, 1 H), 3.98 - 3.91 (m, 2 H), 3.71 (s, 0 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.37 (d, J = 13.8 Hz, 2 H), 3.04 (q, J = 7.4 Hz, 1 H), 2.99 (d, J = 0.5 Hz, 0 H), 2.90 (d, J = 9.1 Hz, 2 H), 2.86 (d, J = 0.7 Hz, 0 H), 2.79 (d, J = 9.6 Hz, 2 H), 2.28 - 2.19 (m, 2 H), 2.11 - 2.02 (m, 2 H), 1.29 (t, J = 7.3 Hz, 1 H), 1.13 (d, J = 10.8 Hz, 6 H), 1.02 (t, J = 7.4 Hz, 0 H), 0.93 - 0.84 (m, 6 H). 19F NMR (377 MHz, Methanol-d4) δ -77.38, -77.88, -96.88 (d, J = 59.7 Hz), -114.92 EXAMPLE 81

[00755] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan Methyl -2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (81).

[00756] Intermediates: I2, P4, and S47. MS (ESI) m/z 1102.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.25 - 8.21 (m, 1 H), 8.16 (d, J = 9.3 Hz, 1 H), 8.10 (d, J = 2.8 Hz, 1 H), 7.77 (dd, J = 9.0, 2.3 Hz, 1 H), 7.53 (s, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.13 (d, J = 9.9 Hz, 1 H), 6.98 - 6.91 (m, 2 H), 6.80 (d, J = 9.9 Hz, 1 H), 4.48 - 4.41 (m, 1 H), 4.36 - 4.27 (m, 1 H), 4.20 (s, 2 H), 4.14 (d, J = 13.0 Hz, 2 H), 3.96 (s, 1 H), 3.95 - 3.87 (m, 3 H), 3.73 (s, 2 H), 3.68 (d, J = 11.7 Hz, 6 H), 3.60 - 3.51 (m, 2 H), 3.04 (s, 3 H), 2.94 - 2.84 (m, 3 H), 2.84 - 2.73 (m, 1 H), 1.20 - 1.08 (m, 9 H), 1.03 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.38, -77.71, -96.96 (dd, J = 59.8, 19.5 Hz), -114.92. EXAMPLE 82

[00757] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)benzyl)-16,16,16-trifluoro-9 -hydroxy-15,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (82).

[00758] Intermediates: I2, P33, and S3. MS (ESI) m/z 1123.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.30 (dd, J = 2.4, 0.7 Hz, 1 H), 8.16 (d, J = 9.4 Hz, 1 H), 7.70 (dd, J = 8.8, 2.3 Hz, 1 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.21 (d, J = 8.3 Hz, 2 H), 6.92 - 6.71 (m, 3 H), 4.97 (dd, J = 8.1, 7.2 Hz, 2 H), 4.83 - 4.74 (m, 2 H), 4.58 - 4.23 (m, 4 H), 4.17 - 3.96 (m, 8 H), 3.90 (d, J = 13.4 Hz, 1 H), 3.74 - 3.58 (m, 8 H), 3.54 (td, J = 11.2, 3.9 Hz, 2 H), 3.39 (d, J = 13.8 Hz, 2 H), 3.03 - 2.60 (m, 5 H), 2.36 - 2.17 (m, 2 H), 2.20 - 2.03 (m, 4 H), 1.93 - 1.83 (m, 1 H), 1.80 - 1.48 (m, 5 H), 1.29 (d, J = 3.8 Hz, 1 H), 1.20 - 1.05 (m, 11 H), 0.95 (d, J = 41.7 Hz, 4 H EXAMPLE 83

[00759] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(oxetan-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((6-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (83).

[00760] Intermediates: I2, P32, and S3. MS (ESI) m/z 1095.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.28 (dd, J = 2.3, 0.7 Hz, 1 H), 8.15 (d, J = 9.4 Hz, 1 H), 7.69 (dd, J = 8.8, 2.3 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.20 (d, J = 8.1 Hz, 2 H), 6.99 (d, J = 8.3 Hz, 2 H), 6.92 - 6.70 (m, 2 H), 5.05 (dd, J = 8.3, 6.1 Hz, 3 H), 4.95 (dd, J = 8.2, 7.0 Hz, 3 H), 4.80 (dd, J = 8.0, 4.8 Hz, 3 H), 4.67 (t, J = 6.3 Hz, 2 H), 4.50- 4.17 (m, 4 H), 4.14 (d, J = 4.3 Hz, 3 H), 3.68 (d, J = 1.5 Hz, 7 H), 3.38 (dd, J = 14.2, 1.7 Hz, 3 H), 3.00 - 2.68 (m, 2 H), 2.06 (d, J = 9.0Hz, 1 H), 1.73 (d, J = 7.2 Hz, 0 H), 1.64 - 1.49 (m, 1 H), 1.42 - 1.25 (m, 25 H), 1.17 - 1.05 (m, 11 H), 1.01 (s, 3H), 0.96 (d, J = 6.6 Hz, 2 H), 0.92 - 0.80 (m, 24 H). EXAMPLE 84

[00761] ((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15 -dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetra-aza-hexadecan-14 -yl)methyl carbamate(84).

[00762] Intermediates: 11, P28, and S3. MS (ESI) m/z 1009.35 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (d, J = 4.9 Hz, 1 H), 8.34 - 8.25 (m, 1 H), 8.01 - 7.87 (m, 2 H), 7.83 (d, J = 9.4 Hz, 1 H), 7.70 (dd, J = 8.8, 2.3 Hz, 1 H), 7.59 (d, J = 8.6 Hz, 2 H), 7.44 (dd, J = 7.0, 5.0 Hz, 1 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.24 (d, J = 7.9 Hz, 2 H), 6.86 (d, J = 8.7 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2 H), 4.84 - 4.79 (m, 1 H), 4.53 (s, 1 H), 4.35 (d, J = 13.9 Hz, 2 H), 4.15 (s, 6 H), 4.00 (d, J = 13.1 Hz, 1 H), 3.90 (s, 1 H), 3.80 - 3.58 (m, 9 H), 3.40 (s, 1 H), 3.03 - 2.80 (m, 5 H), 2.34 - 2.20 (m, 3 H), 2.07 (d, J = 8.6 Hz, 2 H), 0.87 (d, J = 24.4 Hz, 19 H). EXAMPLE 85

[00763] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-( 4-((6-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (85).

[00764] Intermediates: I3, P6, and S3. MS (ESI) m/z 1066.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.25 (d, J = 2.3 Hz, 1 H), 8.13 - 8.04(m, 2 H), 7.83 - 7.74 (m, 4 H), 7.47 (d, J = 8.2 Hz, 3 H), 7.35 - 7.30 (m, 3 H), 7.23 (d, J = 8.2 Hz, 3 H), 6.99 (d, J = 9.1 Hz, 2 H), 6.86 (d, J = 2.7 Hz, 1 H), 4.58 - 4.49 (m, 2 H), 4.35 (t, J = 4.9 Hz, 1 H), 4.31 - 4.23 (m, 3 H), 4.17 (d, J = 3.8 Hz, 3 H), 4.03 - 3.89 (m, 2 H), 3.81 (s, 1 H), 3.67 (s, 5 H), 3.62 - 3.49 (m, 6 H), 2.95 - 2.74 (m, 3 H), 2.30 - 2.23 (m, 2 H), 2.07 (d, J = 8.8 Hz, 2 H), 1.02 (d, J = 34.0 Hz, 6 H), 0.74 (s, 10 H). 19F NMR (377 MHz, Methanol-d4) δ -77.58, -96.21 (d, J = 59.7 Hz). EXAMPLE 86

[00765] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15- dimethyl-8-(4-((6-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (86)

[00766] Intermediates: I3, P7, and S3. MS (ESI) m/z 1066.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J = 0.7 Hz, 1 H), 8.16 (d, J = 9.3 Hz, 1 H), 8.11 (d, J = 0.6 Hz, 1 H), 7.72 - 7.69 (m, 1 H), 7.37 - 7.30(m, 3 H), 7.27 - 7.19 (m, 5 H), 6.87 (dd, J = 9.1, 0.8 Hz, 1 H), 6.80 (d, J= 9.9 Hz, 1 H), 4.98 - 4.94 (m, 2 H), 4.84 - 4.81 (m, 2 H), 4.46 - 4.41(m, 1 H), 4.38 - 4.31 (m, 2 H), 4.18 - 4.07 (m, 5 H), 3.95 (d, J = 13.2Hz, 1 H), 3.76 (s, 1 H), 3.67 (d, J = 15.6 Hz, 7 H), 3.40 (dd, J = 14.2, 1.8 Hz, 2 H), 2.93 - 2.87 (m, 2 H), 2.80 (s, 2 H), 2.26 - 2.20 (m, 2 H), 2.10 - 2.04 (m, 2 H), 1.13 (d, J = 11.9 Hz, 7 H), 0.86 (s, 11 H). 19F NMR (377 MHz, Methanol-d4) δ -78.10, -96.87 (d, J = 59.7 Hz), -114.89. EXAMPLE 87

[00767] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((2-(4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13- trioxo-5-(1,1,1-trifluoro- Methyl 2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (87).

[00768] Intermediates: I2, P4, and S49. MS (ESI) m/z 1130.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1 H), 8.20 - 8.01 (m, 1 H), 7.67 (s, 0 H), 7.52 (s, 0 H), 7.44 (d, J = 8.2 Hz, 1 H), 7.40 - 7.29(m, 1 H), 7.23 (d, J = 8.2 Hz, 1 H), 7.09 (d, J = 9.9 Hz, 0 H), 6.93 (d, J= 2.8 Hz, 1 H), 6.77 (d, J = 9.9 Hz, 0 H), 4.90 (t, J = 7.7 Hz, 1 H), 4.52 - 4.27 (m, 2H), 4.14 (d, J = 13.5 Hz, 2 H), 3.94 (d, J = 13.1 Hz, 1 H),3.67 (d, J = 10.3 Hz, 4 H), 2.98 - 2.72 (m, 2 H), 1.28 - 1.06 (m, 5 H), 1.02 (s, 1 H). EXAMPLE 88

[00769] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((2-(4-(oxetan-3- il)piperazin-1-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa Methyl -4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (88).

[00770] Intermediates: I2, P16, and S49. MS (ESI) m/z 1092.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.86 (d, J = 4.8 Hz, 1 H), 8.52 (s, 1 H), 8.14 (d, J = 9.3 Hz, 0 H), 7.97 (d, J = 8.6 Hz, 1 H), 7.40 (t, J = 4.9 Hz, 1 H), 7.34 (d, J = 7.9 Hz, 1 H), 7.23 (d, J = 8.2 Hz, 1 H), 7.08 (d, J = 10.0 Hz, 0 H), 6.78 (d, J = 9.9 Hz, 0 H), 4.90 (t, J = 7.7 Hz, 1 H), 4.51 - 4.26 (m, 2H), 4.25 - 4.09 (m, 2 H), 3.98 (d, J = 13.2 Hz, 1 H), 3.67 (d, J = 8.1 Hz, 3 H), 3.26 (s, 2 H), 2.99 - 2.75 (m, 2 H), 2.02 (s, 0 H), 1.24 - 1.07 (m, 5H), 1.02 (s, 1H). EXAMPLE 89

[00771] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((2-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (89).

[00772] Intermediates: I2, P16, and S7. MS (ESI) m/z 1119.3 [M+H] +. 1H NMR (400 MHz, Methanol-d) 7.34 (d, J = 7.9 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.09 (d, J= 9.9 Hz, 0 H), 6.78 (d, J = 9.9 Hz, 0 H), 4.96 (t, J = 7.6 Hz, 1 H), 4.82 -4.70 (m, 2 H), 4.43 (d, J = 9.9 Hz, 0 H), 4.30 (d, J = 10.0 Hz, 1 H), 4.24 - 4.06 (m, 2 H), 3.98 (d, J = 13.1 Hz, 1 H), 3.68 (d, J = 8.7 Hz, 4 H), 3.46 (d, J = 14.7 Hz, 1 H), 2.99 - 2.70 (m, 2 H), 2.27 - 2.10 (m, 1 H), 1.99 (d, J = 8.7 Hz, 1 H), 1.19 - 1.05 (m, 5 H), 1.02 (s, 2 H). EXAMPLE 90

[00773] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl- 8-(4-((6-((1R,4R)-5-(oxetan- 3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)- 3,6,13-trioxo-5-(1,1,1-trifluoro -2-methylpropan-2-yl)-2-oxa-4,7,11,12- tetra-azahexadecan-14-yl)methyl carbamate (90).

[00774] Intermediates: I3, P13, and S6. MS (ESI) m/z 1078.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.25 (d, J = 2.2 Hz, 1 H), 8.15 (d, J = 9.4 Hz, 1 H), 7.70 (dd , J = 11.1, 2.3 Hz, 2 H), 7.43 - 7.27 (m, 4 H), 7.21 (d, J = 7.9 Hz, 2 H), 6.77 (d, J = 9.9 Hz, 0 H), 6.73 - 6.58 (m, 2 H), 5.05 (s, 1 H) , 5.00 - 4.88 (m, 2 H), 4.71 (dd, J = 8.4, 4.6 Hz, 1 H), 4.64 - 4.54 (m, 2 H), 4.47 (d, J = 31.7 Hz, 2 H), 4.10 (d, J = 13.2 Hz, 2 H), 3.95 (d, J = 13.2 Hz, 1 H), 3.82 - 3.56 (m, 13 H), 3.33 (s, 1 H), 2.89 (d, J = 8.9 Hz, 2 H), 2.33 (s, 2 H), 1.21 - 0.99 (m, 11 H), 0.86 (s, 10 H). EXAMPLE 91

[00775] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl- 8-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl) benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14 -yl)methyl carbamate (91). Intermediates: I3, P13, and S48.

[00776] MS (ESI) m/z 1066.6 [M+H] +. 1H NMR (400 MHz, Methanol- d4) δ 8.30 (d, J = 2.2 Hz, 1 H), 8.15 (d, J = 9.4 Hz, 1 H), 7.79 - 7 .63 (m, 2 H), 7.33 (dd, J = 8.2, 5.2 Hz, 4 H), 7.21 (d, J = 8.0 Hz, 2 H), 6.95 (d, J = 8.9 Hz, 1 H), 6.77 (d, J = 10.0 Hz, 1 H), 6.63 (d, J = 2.4 Hz, 1 H), 4.91 (t, J = 7.7 Hz, 2 H), 4.54 - 4.33 (m, 2 H), 4.18 - 4.02 (m, 2 H), 4.03 - 3.85 (m, 5 H), 3.83 - 3.58 (m, 10 H), 2.89 (d, J = 9.3 Hz , 2 H), 1.27 (d, J = 13.9 Hz, 1 H), 1.21 - 1.00 (m, 12 H), 0.86 (s, 10 H). EXAMPLE 92

[00777] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((6-(4- (oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl )-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (92).

[00778] Intermediates: I2, P13, and S48. MS (ESI) m/z 1119.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 2.2 Hz, 1 H), 8.14 (d, J = 9.4 Hz, 1 H), 7.70 (dd, J = 9.2, 2.3 Hz, 2 H), 7.64 - 7.51 (m, 0 H), 7.33 (dd, J = 8.4, 4.0 Hz, 5 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.11 (d, J = 9.8 Hz, 1 H), 6.94 (d, J = 8.9 Hz, 1 H), 6.76 (d, J = 10.0 Hz, 1 H), 6.63 (d, J = 2.4 Hz, 1 H), 5.48 (s, 1 H), 4.91 (dd, J = 8.3, 7.0 Hz, 3 H), 4.51 - 4.38 (m, 2 H), 4.31 (d, J = 9.9 Hz, 1 H), 4.13 (dd, J = 15.3, 11.1 Hz, 3 H), 3.93 (d, J = 13.0 Hz, 2 H), 3.79 - 3.62 (m, 10 H), 3.58 - 3.43 (m, 0 H), 2.99 - 2.66 (m, 5 H), 1.27 (d, J = 13.9 Hz, 1 H), 1.21 - 0.97 (m, 19 H). EXAMPLE 93

[00779] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((6-((1R,4R)-5- (oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (93).

[00780] Intermediates: I2, P16, and S6. MS (ESI) m/z 1103.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.86 (d, J = 4.8 Hz, 1 H), 8.28 - 8.20 (m, 0 H), 8.14 (d, J = 9.4 Hz, 0 H), 7.96 (d, J = 8.5 Hz, 1 H), 7.71 (dd, J = 8.8, 2.3 Hz, 1 H), 7.40 (t, J = 4.9 Hz, 1 H), 7.32 (d, J = 7.9 Hz, 1 H), 7.22 (d, J = 8.1 Hz, 1 H), 6.74 - 6.65 (m, 1 H), 5.05 (d, J = 2.0 Hz, 1 H), 5.01 - 4.90 (m, 1 H), 4.72 (dd, J = 8.4, 4.8 Hz, 1 H), 4.58 - 4.49 (m, 1 H), 4.43 (t, J = 5.0 Hz, 0 H), 4.40 - 4.26 (m, 1 H), 4.18 (d, J = 12.8 Hz, 1 H), 3.98 (d, J = 13.1 Hz, 1 H), 3.87 - 3.63 (m, 5 H), 3.34 (s, 0 H), 3.03 - 2.75 (m, 2 H ), 2.33 (s, 1 H), 1.13 (d, J = 14.3 Hz, 5 H), 1.02 (s, 2 H). EXAMPLE 94

[00781] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4- ((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin- 3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)- 2-oxa-4,7,11,12-tetra -aza-hexadecan-14-yl)methyl carbamate(94).

[00782] Intermediates: I3, P16, and S48. MS (ESI) m/z 1037.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.86 (d, J = 4.8 Hz, 1 H), 8.29 (d, J = 2.2 Hz, 0 H), 7.97 (d, J = 8.9 Hz, 1 H), 7.70 (dd, J = 8.8, 2.3 Hz, 1 H), 7.39 (t, J = 4.9 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.21 (d, J = 7.9 Hz, 1 H), 6.95 (d, J = 8.9 Hz, 1 H), 6.77 (d, J = 9.9 Hz, 0 H), 4.84 (s, 15 H), 4.57 - 4.31 (m, 1 H), 4.16 (d, J = 14.1 Hz, 1 H), 3.98 (d, J = 35.4 Hz, 2 H), 3.76 (s, 1 H), 3.67 (d, J = 14.2 Hz, 4 H), 3.04 - 2.69 (m, 2 H), 2.02 (s, 1 H), 1.27 (d, J = 13.9 Hz, 1 H), 1.12 (d, J = 14.5 Hz, 3 H), 0.85 (s, 5 H). EXAMPLE 95

[00783] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6 -((1R, 4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- Methyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (95).

[00784] Intermediates: I3, P16, and S6. MS (ESI) m/z 1050.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.86 (d, J = 4.9 Hz, 1 H), 8.24 (d, J = 2.1 Hz, 0 H), 8.15 (d , J = 9.3 Hz, 0 H), 7.97 (d, J = 8.7 Hz, 1 H), 7.70 (dd, J = 8.8, 2.2 Hz, 1 H), 7.39 (t, J = 4.9 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.21 (d, J = 7.9 Hz, 1 H), 6.78 (d, J = 9.8 Hz, 0 H), 6.67 (d, J = 8.8 Hz, 1 H), 5.05 (s, 0 H), 4.98 - 4.85 (m, 1 H), 4.71 (dd, J = 8.4, 4.7 Hz, 1 H), 4.66 - 4.55 ( m, 1 H), 4.53 - 4.41 (m, 1 H), 4.16 (d, J = 13.7 Hz, 1 H), 4.00 (d, J = 13.1 Hz, 1 H), 3.87 - 3.61 (m, 6 H), 3.30 (p, J = 1.6 Hz, 4 H), 3.00 - 2.74 ( m, 2 H), 2.33 (s, 1 H), 1.12 (d, J = 14.5 Hz, 3 H), 0.85 (s, 5 H). EXAMPLE 96

[00785] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6 - (8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- Methyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (96).

[00786] Intermediates: I3, P16, and S3. MS (ESI) m/z 1063.5 [M+H] +. 1H NMR (400MHz, Methanol-d4) δ 8.86 (dd, J = 4.9, 0.8Hz, 1H), 8.29 (d, J = 2.2Hz, 0H), 8.15 (d, J = 9.4Hz, 0H), 7.97 (d, J = 8.6Hz, 1H),7.69 (dd, J = 8.9, 2.3 Hz, 1 H), 7.40 (t, J = 4.9 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 6.85 (d, J = 8.9 Hz, 1 H), 6.77 (d, J = 10.0 Hz, 0H), 4.96 (t, J = 7.6 Hz, 1 H), 4.83 (s, 20 H), 4.39 (dd, J =34.8, 11.8 Hz, 2 H), 4.16 (d, J = 14.7 Hz, 2 H), 4.01 (d, J = 13.1 Hz, 1H), 3.84 - 3.60 (m, 4 H), 3.37 (d, J = 13.9 Hz, 1 H), 3.01 - 2.73 (m, 2 H), 2.33 - 2.17 (m, 1 H), 2.07 (d, J = 8.6 Hz, 1 H), 1.12 (d, J = 14.3 Hz, 3 H), 0.85 (s, 5 H). EXAMPLE 97

[00787] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((6-(4- (oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl )-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (97).

[00788] Intermediates: I2, P14, and S48. MS (ESI) m/z 1108.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (d, J = 2.9 Hz, 1 H), 8.29 (d, J = 2.2 Hz, 1 H), 8.14 (d, J = 9.3 Hz, 1 H), 7.95 (dd, J = 8.9, 4.2 Hz, 1 H), 7.78 - 7.51 (m, 4H), 7.32 (d, J = 7.8Hz, 2H), 7.22 (d, J = 8.0Hz, 2H), 7.11 (d, J = 10.0Hz, 1H), 6.94 (d, J = 8.9Hz, 1H), 6.77 (d, J = 9.9Hz, 1H), 4.83 (s, 46 H), 4.52 - 4.25 (m, 3 H), 4.16 (d, J = 13.4 Hz, 2 H),3.96 (d, J = 13.1 Hz, 1 H), 3.67 (d, J = 15.7 Hz, 7 H), 3.26 (s, 5 H), 2.97 - 2.72 (m, 4 H), 2.02 (s, 2 H), 1.28 - 1.08 (m, 10 H), 1.02 (s, 3 H). EXAMPLE 98

[00789] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((6-(4- (oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl )-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (98).

[00790] Intermediates: I2, P15, and S48. MS (ESI) m/z 1109.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.66 (dd, J = 8.6, 5.6 Hz, 1 H), 8.34 - 8.27 (m, 1 H), 8.16 (d, J = 9.3 Hz, 1 H), 7.86 (t, J = 8.4 Hz, 1 H), 7.80 - 7.61 (m, 4 H), 7.61 - 7.48 (m, 1 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.28 - 7.17 (m, 3 H), 7.14 (d, J = 9.8 Hz, 1 H), 6.99 - 6.92 (m, 1 H), 6.79 (d, J = 10.0Hz, 1 H), 4.86 (s, 32 H), 4.54 - 4.39 (m, 2 H), 4.35 - 4.26 (m, 1 H), 4.17 (d, J = 13.1 Hz, 2 H), 3.95 (t, J = 17.4 Hz, 4 H), 3.67 (d, J = 16.6 Hz, 7 H), 2.98 - 2.73 (m, 4 H), 1.28 (d, J = 13.9 Hz, 5 H), 1.20 - 1.08 (m, 10 H), 1.03 (s, 3 H). EXAMPLE 99

[00791] ((5S,8S,9S,14S)-11-(4-(5-(difluoromethyl)pyridin-2-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (99).

[00792] Intermediates: I2, P35, and S3. MS (ESI) m/z 1167.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.15 (d, J = 9.4 Hz, 1 H), 8.10 - 8.00 (m, 3 H), 7.72 - 7.60 (m, 4 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.11 (d, J = 18.4 Hz, 1 H), 6.88 - 6.75 (m, 3 H), 4.96 (t, J =7.6 Hz, 2 H), 4.80 (d, J = 5.0 Hz, 1 H), 4.54 (s, 1 H), 4.47 - 4.42 (m, 1H), 4.33 (dd, J = 16.8, 11.9 Hz, 4 H), 4.20 - 4.12 (m, 4 H), 3.98 (d, J =13.1 Hz, 1 H), 3.67 (d, J = 17.6 Hz, 8 H), 3.39 (d, J = 13.7 Hz, 2 H), 2.90 (dd, J = 10.5, 7.0 Hz, 3 H), 2.84 - 2.77 (m, 1 H), 2.27 - 2.19 (m, 2 H), 2.11 - 2.04 (m, 2 H), 1.18 - 1.11 (m, 9 H), 1.03 (s, 3 H). EXAMPLE 100

[00793] ((5S,8S,9S,14S)-11-(4-(6-(difluoromethyl)pyridin-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (100).

[00794] Intermediates: I2, P45, and S3. MS (ESI) m/z 1165.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.91 (d, J = 1.8 Hz, 1 H), 8.31 - 8.22 (m, 2 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.73 - 7.61 (m, 2 H), 7.34 (dd, J = 8.2, 3.3 Hz, 4 H), 7.25 - 7.15 (m, 3 H), 6.93 - 6.84 (m, 2 H), 6.77 (s, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.82 - 4.79 (m, 2 H), 4.54 (s, 1 H), 4.38 - 4.28 (m, 4 H), 4.16 (s, 4 H), 3.98 (d, J = 13.2Hz, 1H), 3.67 (d, J = 21.9Hz, 7H), 3.39 (d, J = 13.8Hz, 2H), 2.96 - 2.76 (m, 5H), 2.28 - 2.20 (m, 2H), 2.12 - 2.04 (m, 2 H), 1.23 - 1.12 (m, 9 H), 1.04 (s, 3 H). EXAMPLE 101

[00795] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((6-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (101).

[00796] Intermediates: I2, P16, and S3. MS (ESI) m/z 1116.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.87 (dd, J = 4.9, 4.1 Hz, 2 H), 8.32 - 8.27 (m, 1 H), 8.15 (d, J = 9.3 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 2 H), 7.70 (dd, J = 8.8, 2.3 Hz, 1 H), 7.44 - 7.29 (m, 4 H), 7.24 (t, J = 9.4 Hz, 2 H), 7.07 (t, J = 13.8 Hz, 1 H), 6.81 (dd, J = 34.9, 9.4 Hz, 2 H), 4.96 (t, J =7.6 Hz, 2H), 4.82 - 4.78 (m, 2 H), 4.61 - 4.41 (m, 3 H), 4.33 (dd, J =18.6, 12.0 Hz, 4 H), 4.16 (s, 4 H), 3.99 (d, J = 13.1 Hz, 1 H), 3.68 (d, J = 8.8 Hz, 6 H), 3.41 - 3.35 (m, 2 H), 2.95 - 2.76 (m, 4 H), 2.27 - 2.20(m, 2 H), 2.08 (d, J = 8.7 Hz, 2 H), 1.15 (dd, J = 14.6, 11.3 Hz, 9 H), 1.03 (s, 3 H). EXAMPLE 102

[00797] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (102).

[00798] Intermediates: I2, P14, and S3. MS (ESI) m/z 1135.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (d, J = 2.9 Hz, 1 H), 7.97 - 7.94 (m, 1 H), 7.70 - 7.53 (m, 12 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 6.86 (d, J = 8.9 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.84 - 4.81 (m, 1 H), 4.54 (s, 1 H), 4.44 (t, J = 5.0 Hz, 1 H), 4.38 - 4.29 (m, 3 H), 4.15 (d, J = 5.9 Hz, 4 H), 3.98 (s, 1 H), 3.67 (d, J = 15.3 Hz, 8 H), 3.44 - 3.37 (m, 2 H), 2.92 - 2.74 (m, 4 H), 2.23 (dd, J = 9.6, 4.5 Hz, 2 H), 2.12 - 2.03 (m, 2 H), 1.18 - 1.10 (m, 8 H), 1.03 (s, 3 H). EXAMPLE 103

[00799] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((2-(4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13- trioxo-5-(1,1,1-trifluoro- Methyl 2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (103).

[00800] Intermediates: I2, P7, and S49. MS (ESI) m/z 1130.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J = 4.0 Hz, 3 H), 8.19 - 8.11 (m, 3 H), 7.38 - 7.32 (m, 3 H), 7.24 (t, J = 8.0 Hz, 5 H), 7.16 (d, J = 9.9Hz, 1 H), 4.90 (t, J = 7.6 Hz, 3 H), 4.83 - 4.78 (m, 1 H), 4.48 - 4.36 (m, 3 H), 4.31 (d, J = 10.0 Hz, 1 H), 4.17 - 4.08 (m, 4 H), 3.93 (d, J = 13.3 Hz, 1 H), 3.67 (d, J = 9.7 Hz, 9 H), 2.93 - 2.72 (m, 6 H), 1.19 - 1.09 (m, 11 H), 1.03 (s, 3 H). EXAMPLE 104

[00801] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-3,6,13- trioxo-8-(4-((6-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1 methyl,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (104).

[00802] Intermediates: I2, P4, and S50. MS (ESI) m/z 1158.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.31 - 8.29 (m, 1 H), 8.16 (d, J = 9.4 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.73 - 7.61 (m, 2 H), 7.45 (d, J = 8.3 Hz, 3 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 3 H), 6.94 (dd, J = 5.7, 3.0 Hz, 2 H), 4.30 (d, J = 9.9 Hz, 1 H), 4.19 - 4.06 (m, 5 H), 3.95 (d, J = 13.2 Hz, 1 H), 3.68 (d, J = 11.0 Hz, 10 H), 3.47 (ddd, J = 24.1, 12.1, 9.2 Hz, 5 H), 2.93 - 2.74 (m, 5 H), 2.11 (d, J = 10.4 Hz, 3 H), 1.77 (qd, J = 12.1, 4.6 Hz, 3 H), 1.18 - 1.10 (m, 10 H), 1.03 (s, 3 H). EXAMPLE 105

[00803] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-( 4-((6-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (105).

[00804] Intermediates: I3, P14, and S3. MS (ESI) m/z 1081.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (d, J = 2.9 Hz, 1 H), 8.29 (d, J = 2.2 Hz, 1 H), 8.15 (d, J = 9.4 Hz, 1 H), 7.95 (dd, J = 8.9, 4.2 Hz, 1 H), 7.76 - 7.64 (m, 2 H), 7.60 (d, J = 8.7 Hz, 2 H), 7.32 (d, J = 7.9 Hz, 2 H),7.21 (d, J = 8.0 Hz, 2 H), 6.94 - 6.80 (m, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.85 (s, 14H), 4.54 (s, 1 H), 4.43 (s, 1 H), 4.39 - 4.28 (m, 2 H), 4.18 -4.09 (m, 4 H), 3.99 (d, J = 13.0 Hz, 1 H), 3.82 - 3.58 (m, 8 H), 3.41 -3.33 (m, 2 H), 3.00 - 2.71 (m, 4 H), 2.23 (dd, J = 9.8, 4.6 Hz, 2 H), 2.14 - 2.01 (m, 2 H), 1.13 (d, J = 12.5 Hz, 6 H), 0.86 (s, 9 H). EXAMPLE 106

[00805] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-( 4-((6-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (106).

[00806] Intermediates: I3, P36, and S45. MS (ESI) m/z 1078.8 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.71 (s, 1 H), 8.16 (d, J = 9.4 Hz, 1 H), 7.72 (d, J = 8.3 Hz, 2 H), 7.62 (d, J = 8.7 Hz, 1 H), 7.32 (d, J = 7.8Hz, 2 H), 7.24 (s, 0 H), 6.81 (d, J = 9.9 Hz, 1 H), 6.67 (d, J = 8.7 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2 H), 4.54 (s, 1 H), 4.50 - 4.30 (m, 3 H), 4.15 (t, J = 10.1Hz, 4 H), 4.01 (d, J = 13.1 Hz, 1 H), 3.81 - 3.55 (m, 7 H), 3.37(d, J = 13.8 Hz, 2 H), 3.00 - 2.74 (m, 4 H), 2.56 (s, 3 H), 2.22 (dd, J =9.6, 4.4 Hz, 2 H), 2.13 - 1.97 (m, 2 H), 1.14 (d, J = 10.5 Hz, 6 H), 0.85 (s, 9 H). EXAMPLE 107

[00807] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrazin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6 -( 8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- Methyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (107).

[00808] Intermediates: I3, P36, and S3. MS (ESI) m/z 1064.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 9.15 (s, 1 H), 8.59 (s, 1 H), 8.32 - 8.26 (m, 1 H), 7.76 - 7.66 (m, 3 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 6.89 - 6.84 (m, 1 H), 6.79 (d, J = 9.8 Hz, 1 H), 4.96 (t, J= 7.6 Hz, 3 H), 4.84 - 4.79 (m, 3 H), 4.54 (s, 1 H), 4.44 (d, J = 6.5 Hz, 1H), 4.39 - 4.31 (m, 2 H), 4.16 (d, J = 4.9 Hz, 4 H), 4.01 (d, J = 13.1 Hz, 1 H), 3.78 - 3.63 (m, 9 H), 3.43 - 3.36 (m, 2 H), 2.94 - 2.77 (m, 5 H),2.27 - 2.19 (m, 2 H), 2.11 - 2.04 (m, 2 H), 1.13 (d, J = 10.7 Hz, 6 H),0.86 (s, 9 H). EXAMPLE 108

[00809] ((5s,8s,9s,14s)-11-(4-(1-(difluoromethyl)-1h-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(8-((3-methyloxetan-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6 ,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (108).

[00810] Intermediates: I2, P7, and S56. 1H NMR (400 mhz, Methanol- d4) δ 8.52 (d, j = 0.7 Hz, 1 H), 8.28 (d, j = 2.4 Hz, 1 H), 8.13 (d, j = 8.4 Hz, 2 H), 7.75 - 7.61 (m, 2 H), 7.57 - 7.46 (m, 1 H), 7.39 - 7.30 (m, 2 H), 7.23 (dd, j = 10.8, 8.2 Hz, 4 H), 7.12 (d, j = 9.9 Hz, 1 H), 6.80 (dd, j = 31.1, 9.4 Hz, 2 H), 4.61 (d, j = 6.3 Hz, 2 H), 4.50 - 4.36 (m, 3 H),4.30 - 4.23 (m, 3 H), 4.12 (d, j = 12.2 Hz, 3 H), 3.93 (d, j = 13.2 Hz, 1H), 3.81 (d, j = 11.0 Hz, 0 H), 3.68 (d, j = 10.0 Hz, 6 H), 3.56 (s, 1 h),3.45 (d, j = 14.1 Hz, 1 H), 2.98 - 2.64 (m, 4 H), 2.38 (d, j = 11.2 Hz, 2H), 2.19 - 2.05 (m, 2 H), 1.62 (s, 2 H), 1.22 - 1.08 (m, 9 H), 1.00 (d, j = 26.6 Hz, 4 h). EXAMPLE 109

[00811] ((5S,8S,9S,14S)-8-(4-((6-(8-(azetidin-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl) pyridin-3-yl)ethynyl)benzyl)-11-(4-(1- (difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1 ,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14- il)methyl carbamate (109).

[00812] Intermediates: I2, P7, and S51, followed by treatment with trifluoroacetic acid to remove the Boc group. MS (ESI) m/z 1169.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.51 (d, J = 0.7 Hz, 1 H), 8.11 (s, 2 H), 7.70 (dd, J = 8.9, 2.3 Hz, 1 H), 7.35 - 7.31 (m, 2 H), 7.26 - 7.20 (m, 4 H), 6.87 - 6.84 (m, 1 H), 4.44 (d, J = 6.5 Hz, 1 H), 4.33 - 4.22 (m, 6 H), 4.19 - 4.04 (m, 7 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.68 (d, J = 9.4 Hz, 9 H), 3.54 (s, 3 H), 3.43 (d, J = 13.7 Hz, 3 H), 2.93 - 2.73 (m, 5 H), 2.28 (dd, J = 8.6, 3.7 Hz, 2 H), 2.13 - 2.05 (m, 2 H), 1.19 - 1.10 (m, 9 H), 1.04 (s, 3H). EXAMPLE 110

[00813] 3-((3-(5-((4-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6 -difluorobenzyl)-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy- 2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanamido)butyl)phenyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2 .1]octan-8-yl)methyl)azetidine-1-carboxylate detert-butyl (110).

[00814] Intermediates: I2, P7, and S51. MS (ESI) m/z 1268.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.51 (d, J = 0.7 Hz, 1 H), 8.11 (s, 2 H), 7.70 (dd, J = 8.9, 2.3 Hz, 1 H), 7.35 - 7.31 (m, 2 H), 7.26 - 7.19 (m, 4 H), 6.88 - 6.84 (m, 1 H), 4.44 (d, J = 6.5 Hz, 1 H), 4.33 - 4.22 (m, 6 H), 4.19 - 4.05 (m, 7 H), 3.93 (d, J = 13.2 Hz, 2 H), 3.68 (d, J = 9.4 Hz, 16 H), 3.54 (s, 3 H), 3.43 (d, J = 13.7 Hz, 2 H), 2.94 - 2.74 (m, 6 H), 2.28 (dd, J = 8.6, 3.7 Hz, 2 H), 2.12 - 2.06 (m, 2 H), 1.18 - 1.10 (m, 9 H), 1.04 (s, 3H). EXAMPLE 111

[00815] ((5S,8S,9S,14S)-16,16,16-trifluoro-11-(4-(5-fluoropyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8 -(4-((6-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (111).

[00816] Intermediates: I2, P37, and S3. MS (ESI) m/z 1100.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.50 (d, J = 2.9 Hz, 1 H), 7.88 (dd, J = 8.7, 4.2 Hz, 3 H), 7.72 - 7.63 (m, 3 H), 7.49 (d, J = 7.9 Hz, 2 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 6.86 (d, J = 8.8 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.84 - 4.80 (m, 3 H), 4.54 (s, 1 H), 4.42 - 4.32 (m, 4 H), 4.25 (d, J = 6.6 Hz, 1 H), 4.15 (d, J = 4.7 Hz, 3 H), 4.05 - 4.00 (m, 1 H), 3.92 (d, J = 13.3 Hz, 1 H), 3.75 (d, J = 8.3 Hz, 1 H), 3.68 (s, 3 H), 3.58 (s, 3 H), 3.39 (d, J = 13.8 Hz, 3 H), 2.93 - 2.71 (m, 5 H), 2.28 - 2.19 (m, 2 H), 2.07 (d, J = 8.6 Hz, 2 H), 1.11 (d, J = 8.0 Hz, 7 H), 1.02 (s, 3H), 0.83 (s, 3 H). EXAMPLE 112

[00817] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13- trioxo-5-(1,1,1-trifluoro- Methyl 2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (112).

[00818] Intermediates: I2, P4, and S48. MS (ESI) m/z 1129.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.33 - 8.29 (m, 1 H), 8.14 (d, J = 9.4 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.74 - 7.61 (m, 2 H), 7.53 (s, 1 H), 7.45 (t, J = 6.9 Hz, 2 H), 7.39 - 7.31 (m, 3 H), 7.22 (d, J = 8.2 Hz, 3 H), 7.09 (d, J = 9.9 Hz, 1 H), 6.98 - 6.91 (m, 2 H), 4.94 - 4.88 (m, 3 H), 4.42 (td, J = 7.9, 7.2, 4.1 Hz, 2 H), 4.35 - 4.27 (m, 2 H), 4.20 - 4.11 (m, 3 H), 3.95 (d, J = 13.2 Hz, 3 H), 3.79 - 3.65 (m, 11 H), 2.94 - 2.84 (m, 3 H), 2.83 - 2.74 (m, 1 H), 1.21 - 1.10 (m, 9 H), 1.04 (d, J = 7.2 Hz, 3 H). EXAMPLE 113

[00819] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((6-(4- (oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl )-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (113).

[00820] Intermediates: I2, P9, and S48. MS (ESI) m/z 1093.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.38 (s, 1 H), 8.31 - 8.28 (m, 1 H), 8.06 (s, 1 H), 7.70 (dd, J = 8.8, 2.3 Hz, 1 H), 7.57 - 7.52 (m, 3 H), 7.48 (s, 1 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 7.4 Hz, 2 H), 7.21 (d, J = 8.1 Hz, 2 H), 6.95 (d, J = 8.9 Hz, 1 H), 4.94 - 4.89 (m, 3 H), 4.85 - 4.80(m, 2H), 4.45 - 4.37 (m, 3 H), 4.25 (s, 1 H), 4.15 (s, 1 H), 4.01 - 3.84(m, 6 H), 3.74 (d, J = 8.9 Hz, 1 H), 3.68 (s, 3 H), 3.60 (s, 3 H), 2.89 (d, J = 8.9 Hz, 2 H), 2.85 - 2.67 (m, 3 H), 1.28 (d, J = 13.9 Hz, 5 H), 1.11 (d, J = 12.5 Hz, 6 H), 1.01 (s, 3 H), 0.88 - 0.81 (m, 3 H) EXAMPLE 114

[00821] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-3,6,13- trioxo-8-(4-((6-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro Methyl -2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (114).

[00822] Intermediates: I2, P7, and S57. MS (ESI) m/z 1144.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1 H), 8.30 (d, J = 2.2 Hz, 1 H), 8.12 (s, 2 H), 7.71 - 7.64 (m, 1 H), 7.36 - 7.30 (m, 2 H), 7.23 (dd, J = 11.8, 8.2 Hz, 4 H), 7.13 (d, J = 9.8 Hz, 1 H), 6.93 (d, J = 8.9 Hz, 1 H), 6.78 (d, J = 9.9 Hz, 1 H), 4.46 - 4.41 (m, 1 H), 4.31 (d, J = 9.5 Hz, 1 H), 4.21 - 4.00 (m, 7 H), 3.97 - 3.85 (m, 3 H), 3.78 - 3.65 (m, 9 H), 3.42 (s, 5 H), 2.94 - 2.74 (m, 5 H), 2.43 (dtd, J = 12.8, 8.2, 4.3 Hz, 2 H), 2.24 (ddd, J = 13.7, 9.2, 5.0 Hz, 1 H), 1.20 - 1.10 (m, 9 H), 1.03 (s, 3 H). EXAMPLE 115

[00823] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-3,6,13- trioxo-8-(4-((6-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1 methyl,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (115).

[00824] Intermediates: I2, P7, and S50. MS (ESI) m/z 1158.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.52 (d, J = 0.8 Hz, 1 H), 8.30 (dd, J = 2.3, 0.8 Hz, 1 H), 8.12 (d, J = 6.0 Hz, 2 H), 7.70 (dd, J = 8.9, 2.3 Hz, 1 H), 7.36 - 7.31 (m, 3 H), 7.27 - 7.20 (m, 5 H), 6.96 - 6.91 (m, 1 H), 4.43 (d, J = 9.7 Hz, 2 H), 4.31 (d, J = 9.9 Hz, 1 H), 4.11 (dq, J = 11.3, 6.3, 4.7Hz, 5 H), 3.93 (d, J = 13.2 Hz, 2 H), 3.68 (d, J = 10.2 Hz, 9 H), 3.56 - 3.40 (m, 5 H), 2.93 - 2.73 (m, 5 H), 2.14 - 2.06 (m, 3 H), 1.77 (qd, J = 12.1, 4.7 Hz, 3 H), 1.18 - 1.11 (m, 10 H), 1.03 (s, 3 H). EXAMPLE 116

[00825] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13- trioxo-5-(1,1,1-trifluoro- Methyl 2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (116).

[00826] Intermediates: I2, P7, and S48. MS (ESI) m/z 1130.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J = 0.7 Hz, 1 H), 8.31 - 8.28 (m, 1 H), 8.13 (d, J = 10.9 Hz, 2 H), 7.70 (dd, J = 8.9, 2.3 Hz, 1 H), 7.36 - 7.30 (m, 3 H), 7.23 (dd, J = 11.5, 8.1 Hz, 5 H), 7.13 (d, J = 10.0 Hz, 1 H), 6.95 (d, J = 8.8 Hz, 1 H), 4.90 (t, J = 7.7 Hz, 3 H), 4.82 (s, 2 H), 4.42 (ddd, J = 9.9, 7.1, 3.6 Hz, 2 H), 4.31 (d, J = 10.0 Hz, 1 H), 4.20 - 4.09 (m, 3 H), 3.93 (d, J = 11.8 Hz, 5 H), 3.68 (d, J = 10.1 Hz, 8 H), 2.95 - 2.73 (m, 5 H), 1.21 - 1.10 (m, 10 H), 1.03 (s, 4 H). EXAMPLE 117

[00827] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-4-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4- ((6-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (117).

[00828] Intermediates: I3, P46, and S3. MS (ESI) m/z 1056.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 7.99 (s, 1 H), 7.77 (s, 1 H), 7.70 (dd,J = 8.9, 2.3 Hz, 1 H ), 7.45 (d, J = 8.1 Hz, 2 H), 7.39 - 7.30 (m, 5 H),7.20 (d, J = 8.1 Hz, 2 H), 6.86 (d, J = 8.9 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2H), 4.82 (dd, J = 8.2, 5.1 Hz, 3 H), 4.54 (s, 1 H), 4.41 - 4.31 (m, 4 H),4.18 - 4.09 (m, 3 H), 3.97 - 3.87 (m, 2 H), 3.77 (d, J = 9.6 Hz, 1 H), 3.73 - 3.60 (m, 9 H), 3 .44 - 3.36 (m, 2 H), 2.96 - 2.75 (m, 4 H), 2.26 - 2.19 (m, 2 H), 2.10 - 2.04 (m, 2 H), 1.15 - 0.97 (m, 11 H), 0.77 (s, 9 H). EXAMPLE 118

[00829] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2-fluorobenzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((2-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (118).

[00830] Intermediates: I2, P5, and S7. MS (ESI) m/z 1138.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.52 (d, J = 1.0 Hz, 2 H), 8.10 (d, J = 9.4 Hz, 1 H), 7.76 (d, J = 1.7 Hz, 1 H), 7.67 (t, J = 7.7 Hz, 1 H), 7.45 (t, J = 58.0 Hz, 1 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.26 - 7.18 (m, 4 H), 7.16 (d, J = 9.8 Hz, 1 H), 6.79 (d, J = 9.9 Hz, 1 H), 6.56 (d, J = 1.7 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.76 (s, 1 H), 4.48 - 4.36 (m, 1 H), 4.28 - 4.18 (m, 2 H), 4.14 (s, 3 H), 4.08 (s, 1 H), 3.98 (d, J = 13.7 Hz, 1 H), 3.75 (s, 1 H), 3.58 (s, 3 H), 3.47 (d, J = 14.5 Hz, 2 H), 2.91 (d, J = 9.2 Hz, 2 H), 2.83 (d, J = 6.6 Hz, 2 H), 2.27 - 2.15 (m, 2 H), 1.99 (d, J = 8.8 Hz, 2 H), 1.14 (s, 3 H), 1.13 (s, 3 H), 1.09 (s, 3 H), 0.95 (s, 3 H). EXAMPLE 119

[00831] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(2-methylpyrimidin-5-yl)benzyl)-16,16,16-trifluoro-9-hyd roxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5- yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza -hexadecan-14-yl)methyl carbamate (119).

[00832] Intermediates: 12, P47, and S7. MS (ESI) m/z 1133.32 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.97 (s, 1 H), 8.52 (s, 1 H), 8.14 (d, J = 9.4 Hz, 1 H), 7.34 (dd, J = 8.0, 5.0 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 10.0 Hz, 2 H), 6.79 (d, J = 9.9 Hz, 2 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.81 - 4.73 (m, 6 H), 4.44 (d, J = 9.9 Hz, 2 H), 4.29 (d, J = 10.0 Hz, 2H), 4.16 (d, J = 14.0 Hz, 2 H), 3.96 (d, J = 13.2 Hz, 1 H), 3.67 (d, J = 15.8 Hz, 10 H), 3.46 (d, J = 14.5 Hz, 1 H), 3.20 - 3.12 (m, 2H), 2.95 - 2.79 (m, 2 H), 2.74 (s, 3 H), 2.22 (dd, J = 14.5, 8.2 Hz, 1 H),1.99 (d, J = 8.8 Hz, 1 H), 1.27 - 1.09 (m, 10 H), 1.04 (s, 6 H). EXAMPLE 120

[00833] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan -3-yl)pyrimidin-5-yl)benzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5- yl)ethynyl)benzyl)-3,6,13- methyl trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (120).

[00834] Intermediates: I2, P20, and S7. MS (ESI) m/z 1284.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.73 (s, 2 H), 8.53 (s, 2 H), 8.19 (d, J= 9.4 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 2 H), 7.23 (d, J = 8.5 Hz, 5 H), 6.84(d, J = 9.8 Hz, 1 H), 5.04 - 4.92 (m, 5 H), 4.80 (d, J = 4.3 Hz, 2 H), 4.44(d, J = 9.9 Hz, 1 H), 4.31 (d, J = 10.0 Hz, 1 H), 4.15 (s, 6 H), 3.95 (d, J = 13.2Hz, 1 H), 3.74 (s, 1 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.47 (dd, J = 14.4, 9.6 Hz, 5 H), 2.91 (d, J = 7.7 Hz, 2 H), 2.79 (d, J = 9.6 Hz, 1 H), 2.21 (s, 4 H), 1.99 (t, J = 7.3 Hz, 5 H), 1.17 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H). EXAMPLE 121

[00835] ((5S,8S,9S,14S)-5-(tert-butyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)- 9-hydroxy-15,15-dimethyl-8-(4-((2-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7 methyl,11,12-tetra-aza-hexadecan-14-yl)carbamate (121).

[00836] Intermediates: I1, P4, and S7. MS (ESI) m/z 1048.4 [M+H] +. 1H NMR (400MHz, Methanol-d4) δ 8.44 (s, 2H), 8.01 (d, J = 2.7Hz, 1H), 7.77 (d, J = 9.5Hz, 1H), 7.44 (t, J = 59.7Hz, 1H), 7.35 (d, J = 8.2Hz, 2H), 7.26 (d, J = 8.0 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 6.84 (d, J= 2.8 Hz, 1 H), 4.87 (dd, J = 8.1, 7.0 Hz, 2 H), 4.71 (dd, J = 8.1, 5.1 Hz, 2 H), 4.02 (d, J = 13.8 Hz, 4 H), 3.87 (d, J = 13.4 Hz, 1 H), 3.80 (s, 1H), 3.72 - 3.62 (m, 1 H), 3.58 (s, 3 H), 3.55 (s, 2 H), 3.38 (d, J = 1.6 Hz, 1 H), 3.34 (s, 1 H), 2.83 (t, J = 7.0 Hz, 1 H), 2.72 (s, 2 H), 2.11 (s, 2 H), 1.89 (d, J = 9.1 Hz, 2 H), 0.79 (s, 8 H), 0.74 (s, 8 H). EXAMPLE 122

[00837] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((2-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (122).

[00838] Intermediates: I2, P6, and S7. MS (ESI) m/z 1121.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 2 H), 8.09 (d, J = 9.4 Hz, 1 H), 8.04 (d, J = 2.7 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 2 H), 7.49 (t, J = 60.0 Hz, 1 H), 7.44 (d, J = 8.1 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 9.8 Hz, 1 H), 6.86 (d, J = 2.7 Hz, 1 H), 6.76 (d, J = 9.9Hz, 1 H), 4.95 (t, J = 7.6 Hz, 2 H), 4.82 - 4.78 (m, 2 H), 4.75 (s, 1 H), 4.39 (d, J = 9.8 Hz, 1 H), 4.24 (d, J = 9.8 Hz, 1 H), 4.18 (d, J = 8.3 Hz, 1 H), 4.16 - 4.08 (m, 2 H), 4.00 (d, J = 13.1 Hz, 1 H), 3.88 (d, J = 13.4 Hz, 1 H), 3.74 (s, 1 H), 3.67 (s, 3 H), 3.59 (s, 3 H), 3.46 (d, J = 14.5 Hz, 2 H), 2.96 - 2.86 (m, 2 H), 2.86 - 2.68 (m, 2 H), 2.29 - 2.13 (m, 2 H), 2.04 - 1.88 (m, 2 H), 1.11 (s, 3 H), 1.09 (s, 3 H), 1.02 (s, 3 H), 0.84 (s, 3 H). EXAMPLE 123

[00839] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-3,6,13- trioxo-8-(4-((2-(3-oxopiperazin-1-yl)pyrimidin-5-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (123).

[00840] Intermediates: I2, P4, and S58a. MS (ESI) m/z 1088.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 2 H), 7.53 (t, J = 59.7 Hz, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 7.8 Hz, 2 H), 7.23 (d, J = 8.1 Hz, 2 H), 7.14 (d, J = 10.1 Hz, 1 H), 6.94 (d, J = 2.8 Hz, 1 H), 6.82 (d, J = 10.0 Hz, 1 H), 4.50 - 4.39 (m, 1 H), 4.38 (s, 2 H), 4.34 - 4.26 (m, 1 H), 4.14 (d, J = 12.5 Hz, 2 H), 4.10 - 3.99 (m, 2 H), 3.94 (d, J = 13.1 Hz, 1 H), 3.80 - 3.72 (m, 2 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.45 - 3.38 (m, 2 H), 2.94 - 2.82 (m, 3 H), 2.82 - 2.73 (m, 1 H), 1.16 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.06 - 0.99 (m, 3 H). EXAMPLE 124

[00841] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-8-(4-((6-(8-(2- methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1 ,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14- il)methyl carbamate (124).

[00842] Intermediates: I2, P4, and S59. MS (ESI) m/z 1157.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.28 (d, J = 2.2 Hz, 1 H), 8.20 - 8.07 (m, 1 H), 7.74 - 7.66 (m, 1 H), 7.48 - 7.30 (m, 4 H), 7.22 (d, J = 8.0 Hz, 2 H), 6.93 (d, J = 2.8 Hz, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 4.44 (s, 1 H), 4.31 (s, 1 H), 4.28 (s, 3 H), 4.14 (d, J = 12.1 Hz, 2 H), 3.94 (d, J = 13.1 Hz, 1 H), 3.83 - 3.77 (m, 2 H), 3.68 (d, J = 12.0 Hz, 7 H), 3.44 (s, 4 H), 3.35 (s, 3 H), 2.94 - 2.84 (m, 3 H), 2.78 (dd, J = 12.6, 9.1 Hz, 1 H), 2.32 - 2.24 (m, 2 H), 2.06 (d, J = 8.6 Hz, 2 H), 1.24 - 1.09 (m, 8 H), 1.03 (s, 2 H). EXAMPLE 125

[00843] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-methylpyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (125).

[00844] Intermediates: I2, P39, and S3. MS (ESI) m/z 1128.8 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1 H), 8.29 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 9.5 Hz, 1 H), 8.01 - 7.88 (m, 2 H), 7.70 (dd, J = 8.8, 2.3Hz, 1 H), 7.56 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.23 (d, J= 8.0 Hz, 2 H), 6.83 (dd, J = 28.9, 9.4 Hz, 2 H), 4.96 (t, J = 7.6 Hz, 2H), 4.48 - 4.40 (m, 1 H), 4.39 - 4.27 (m, 3 H), 4.22 - 4.12 (m, 4 H), 3.98 (d, J = 13.1 Hz, 1 H), 3.75 (s, 1 H), 3.70 (s, 3 H), 3.64 (s, 3 H), 3.46 - 3.37 (m, 2 H), 2.95 - 2.75 (m, 5 H), 2.46 (s, 3 H), 2.24 (dd, J = 9.9, 4.5 Hz, 2 H), 2.07 (d, J = 8.6 Hz, 2 H), 1.34 - 1.21 (m, 1 H), 1.19 - 1.06 (m, 9 H), 1.03 (s, 3H). EXAMPLE 126

[00845] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (126).

[00846] Intermediates: I2, P42, and S3. MS (ESI) m/z 1105.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.15 (d, J = 9.4 Hz, 1 H), 7.70 (dd, J = 9.4, 2.8 Hz, 2 H), 7.35 (dd, J = 14.0, 8.3 Hz, 4 H), 7.22 (d, J = 7.9 Hz, 2 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.81 - 6.72 (m, 2 H), 4.97 (t, J = 7.6 Hz, 2 H), 4.53 (s, 1 H), 4.44 (d, J = 9.5 Hz, 1 H), 4.34 (t, J = 12.5 Hz, 3 H), 4.15 (s, 3H), 3.95 (d, J = 13.2 Hz, 1 H), 3.68 (d, J = 14.3 Hz, 10 H), 3.39 (d, J = 13.9 Hz, 2 H), 2.94 - 2.76 (m, 4 H), 2.27 - 2.19 (m, 2 H), 2.08 (d, J = 8.5 Hz, 2 H), 1.20 - 1.10 (m, 9 H), 1.03 (s, 3 H). EXAMPLE 127

[00847] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-(oxetan-3-yloxy)pyridin-2-yl)benzyl)-16,16,16- trifluoro-9-hydroxy-15,15-dimethyl-8- (4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13 -trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (127).

[00848] Intermediates: I2, P43, and S3. MS (ESI) m/z 1188.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (d, J = 6.6 Hz, 1 H), 8.32 - 8.26 (m, 1 H), 7.70 (dd, J = 8.8, 2.3 Hz, 1 H), 7.62 - 7.52 (m, 2 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.30 - 7.19 (m, 3 H), 6.84 (dd, J = 21.8, 9.4 Hz, 1 H), 5.76 - 5.64 (m, 1 H), 5.11 (t, J = 6.9 Hz, 2 H), 4.95 (t, J = 7.6 Hz, 2 H), 4.90 - 4.73 (m, 3 H), 4.59 - 4.51 (m, 1 H), 4.44 (t, J = 5.1 Hz, 1 H), 4.32 (td, J = 14.6, 5.4 Hz, 3 H), 4.25 - 4.12 (m, 4 H), 4.05 - 3.95 (m, 1 H), 3.68 (d, J = 17.7 Hz, 5 H), 3.48 - 3.39 (m, 2 H), 3.35 (s, 4 H), 2.91 (d, J = 8.2 Hz, 2 H), 2.83 (s, 1 H), 2.24 (dd, J = 9.7, 4.5 Hz, 2 H), 2.07 (d, J = 8.6Hz, 2H), 1.15 (d, J = 5.7 Hz, 8 H), 1.04 (s, 2 H). EXAMPLE 128

[00849] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy- 15,15-dimethyl-8-(4-((6-(8-(oxe tan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1 -trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (128).

[00850] Intermediates: I2, P41, and S3. MS (ESI) m/z 1119.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 2.2 Hz, 1 H), 7.77 - 7.67(m, 1 H), 7.61 (d, J = 2.3 Hz, 1 H), 7.33 (d, J = 8.2 Hz, 4 H), 7.22 (d, J =8.2 Hz, 2H), 6.88 (d, J = 8.9Hz, 1H), 6.65 (d, J = 2.3Hz, 1H), 4.95 (t,J = 7.6Hz, 2H), 4.85 (dd, J = 8.2, 5.1Hz, 2H), 4.55 (p, J = 6.2Hz, 1H), 4.45 (d, J = 8.5 Hz, 1 H), 4.34 (dd, J = 14.5, 2.5 Hz, 3 H), 4.19 -4.08 (m, 4 H), 3.93 (s, 4 H), 3.68 (d, J = 9.4 Hz, 6 H), 3.48 - 3.39 (m, 2H), 3.35 (s, 1 H), 2.99 (s, 1 H), 2.94 - 2.73 (m, 5 H), 2.27 - 2.19 (m, 2H), 2.08 (t, J = 6.9 Hz, 2 H), 1.35 - 1.26 (m, 1 H), 1.24 - 1.09 (m, 9 H), 1.03 (s, 3 H). EXAMPLE 129

[00851] ((5S,8S,9S,14S)-11-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-16,16,16- trifluoro-9-hydroxy-15,15-dimethyl-8-(4- ((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (129).

[00852] Intermediates: I2, P40, and S3. MS (ESI) m/z 1147.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.33 - 8.26 (m, 1 H), 8.16 (d, J = 9.4 Hz, 1 H), 7.70 (dt, J = 9.1, 2.4 Hz, 1 H), 7.54 (d, J = 7.3 Hz, 2 H), 7.37 - 7.32 (m, 2 H), 7.23 (d, J = 8.2 Hz, 2 H), 6.91 - 6.77 (m, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.84 (dd, J = 8.2, 5.1 Hz, 2 H), 4.59 - 4.52 (m, 1 H), 4.52 - 4.40 (m, 1 H), 4.39 - 4.24 (m, 3 H), 4.22 - 4.13 (m, 4 H), 3.96 (d, J = 12.9 Hz, 1 H), 3.75 (d, J = 9.0 Hz, 1 H), 3.72 - 3.63 (m, 6 H), 3.46 - 3.38 (m, 2 H), 2.91 (d, J = 8.7 Hz, 2 H), 2.88 - 2.74 (m, 2 H), 2.36 - 2.20 (m, 3 H), 2.08 (d, J = 8.6 Hz, 2 H), 1.32 - 1.16 (m, 6 H), 1.15 (s, 4 H), 1.13 (s, 3 H), 1.03 (s, 2 H), 0.89 (s, 1 H). EXAMPLE 130

[00853] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((6-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (130).

[00854] Intermediates: I2, P28, and S3. MS (ESI) m/z 1116.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.71 (s, 1 H), 8.29 (d, J = 2.2 Hz, 1 H), 8.17 (d, J = 8.5 Hz, 1 H), 8.09 (t, J = 7.8 Hz, 1 H), 8.01 (d, J = 7.9 Hz, 1 H), 7.70 (dd, J = 8.8, 2.3 Hz, 1 H), 7.64 - 7.52 (m, 3 H), 7.34 (d, J = 7.8 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.14 (d, J = 9.5 Hz, 1 H), 6.84(dd, J = 25.9, 9.4 Hz, 2 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.83 (dd, J = 8.2, 5.1 Hz, 2 H), 4.55 (d, J = 7.8 Hz, 1 H), 4.48 - 4.41 (m, 1 H), 4.35 (dd, J = 14.5, 2.5 Hz, 3 H), 4.19 - 4.13 (m, 4 H), 3.99 (d, J = 7.6 Hz, 1 H), 3.75 (s, 1 H), 3.70 (s, 4 H), 3.64 (s, 3 H), 3.46 - 3.32 (m, 3 H), 2.93 (s, 2H), 2.24 (dd, J = 9.6, 4.6 Hz, 2 H), 2.07 (d, J = 8.6 Hz, 2 H), 1.19 - 1.10 (m, 9 H), 1.03 (s, 3 H). EXAMPLE 131

[00855] ((5S,10S,11S,14S)-8-(4-ethynyl-2,6-difluorobenzyl)-16,16,16-trifluoro-10-hydroxy-11-(4-iodobenzyl)-15, 15-dimethyl-3,6,13-trioxo-5- Methyl (1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetra-azahexadecan-14-yl)carbamate (131a).

[00856] The title compound 131a was prepared according to the method presented for the synthesis of compound 1a, but using P38. MS (ESI) m/z 924.2 [M+H] +. 1H NMR (400 MHz,Methanol-d4) δ 7.52 (d, J = 8.0 Hz, 2 H), 7.00 (dd, J = 11.2, 7.8 Hz, 4 H), 4.44 (s, 1 H), 4.27 (s, 1 H), 4.17 - 4.01 (m, 2 H), 3.90 (d, J = 13.2 Hz, 1 H), 3.71 (t, J = 5.9 Hz, 8 H), 2.82 (d, J = 7.8 Hz, 2 H), 2.77 - 2.67 (m, 1 H), 1.17 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.02 (s, 3 H).

[00857] ((5S,8S,9S,14S)-11-(4-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl) -2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-8- (4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11, Methyl 12-tetra-aza-hexadecan-14-yl)carbamate (131b).

[00858] To a solution of 131a (62 mg, 0.07 mmol) in THF (2 mL) was added copper (52 mg, 0.818 mmol), 10% CuSO4 (100 uL), and 1-azidobicyclo[1.1.1]pentane in CuSO4 (0.300 mL, 0.082 mmol). After 2 h, more 1-azidobicyclo[1.1.1]pentane in CuSO4 (0.300 mL, 0.082 mmol) was added. Stirred for another 2 h, more 1-azidobicyclo[1.1.1]pentane in CuSO4 (0.300 mL, 0.082 mmol) was added, then stirred for 48 h. The reaction was partitioned with EtOAc and brine. The organic extract was washed with NH4Cl solution and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (25% - 75% EtOAc/hex) to yield 131b. MS (ESI) m/z 1032.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1 H), 7.52 (d, J = 8.0 Hz, 2 H), 7.43 (d, J = 8.1 Hz, 2 H), 6.99 (d, J = 8.1 Hz, 2 H), 4.44 (s, 1 H), 4.30 (s, 1H), 4.17 - 4.03 (m, 3 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.71 (s, 4 H), 3.66(s, 3 H), 2.86 - 2.67 (m, 5 H), 2.45 (s, 7 H), 1.16 (s, 4 H), 1.14 (s, 3 H),1.11 (s, 3 H), 1.02 (s, 3 H), 0.89 (d, J = 6.7 Hz, 1 H).

[00859] ((5S,8S,9S,14S)-11-(4-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl) -2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15- dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3 ,6,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (131).

[00860] The title compound 131 was prepared according to the method presented for the synthesis of compound 1, but using 131b and S7. MS (ESI) m/z 1174.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 3 H), 8.51 (s, 1 H), 8.19 (d, J = 9.4 Hz, 1 H), 7.43 (d, J = 8.1 Hz, 3 H),7.34 (d, J = 7.8 Hz, 3 H), 7.23 (d, J = 7.8 Hz, 3 H), 7.18 (d, J = 9.9 Hz, 1H), 6.83 (d, J = 10.1 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 3 H), 4.80 (d, J = 7.3 Hz, 6 H), 4.44 (d, J = 9.6 Hz, 1 H), 4.30 (d, J = 9.9 Hz, 1 H), 4.15 (d, J = 6.5 Hz, 5 H), 3.94 (d, J = 13.1 Hz, 1 H), 3.72 (s, 2 H), 3.68 (d, J = 9.6 Hz, 8 H), 3.48 (s, 2 H), 3.44 (s, 1 H), 2.96 - 2.81 (m, 3 H), 2.79 (d, J = 10.1 Hz, 1 H), 2.74 (s, 1 H), 2.45 (s, 8 H), 2.21 (d, J = 10.4 Hz, 3 H), 1.99 (d, J = 9.2 Hz, 3 H), 1.16 (s, 5 H), 1.14 (s, 8 H), 1.11 (s, 4 H), 1.02 (s, 4 H).EXAMPLE 132

[00861] Synthesis of tert-butyl 2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)hydrazine-1-carboxylate (132a).

[00862] The title compound 132a was prepared according to the method presented for the synthesis of compound 1a, but using I2a and P7. MS (ESI) m/z 764.0 [M+H]+.

[00863] Synthesis of 2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-4- (4-((6-((2S,6R)-2,6-dimethyl morpholino)pyridin-3-yl)ethynyl)phenyl)-2-hydroxybutyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)hydrazine-1-carboxylate tert-butyl (132b).

[00864] The title compound 132b was prepared according to the method presented for the synthesis of compound 1, but using 132a and S23. MS (ESI) m/z 852.0 [M+H] +. 1H NMR (400 MHz, Methanol- d4) δ 8.53 (s, 1 H), 8.19 - 8.08 (m, 2 H), 7.93 (d, J = 9.4 Hz, 1 H), 7.50 (t, J = 59.7 Hz, 1 H), 7.40 (d, J = 8.2 Hz, 2 H), 7.28 (d, J = 8.1 Hz, 5 H), 4.07 (d, J = 12.9 Hz, 2 H), 3.74 (ddd, J = 10.7, 6.3, 2.5 Hz, 1 H), 3.62 (s, 1 H), 2.87 - 2.69 (m, 3 H), 1.37 (s, 7 H), 1.31 (s, 5 H), 1.27 (s, 3 H), 1.25 (s, 3 H).

[00865] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-((6 -((2S,6R)-2,6-dimethylmorpholino)pyridin-3- yl)ethynyl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13- trioxo-5-(1,1,1-trifluoro-2-methylpropan-2- yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (132).

[00866] The title compound 132 was prepared according to the method presented for the synthesis of intermediate I2, but using 132b. MS (ESI) m/z 1102.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (d, J = 0.7 Hz, 1 H), 8.25 - 8.10 (m, 3 H), 7.83 (d, J = 9.1 Hz, 1 H), 7.51 (s, 1 H), 7.35 (d, J = 7.3 Hz, 2 H), 7.24 (t, J = 7.7 Hz, 4 H), 7.15 (dd, J = 20.4, 9.7 Hz, 1 H), 6.82 (d, J = 10.0 Hz, 1 H), 4.44 (d, J = 9.8 Hz, 1 H), 4.31 (d, J = 9.9 Hz, 1 H), 4.21 - 4.03 (m, 4 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.81 - 3.61 (m, 6 H), 2.97 - 2.80 (m, 2 H), 2.80 - 2.66 (m, 2 H), 2.03 (s, 1 H), 1.25 (d, J = 6.2 Hz, 6 H), 1.17 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H).EXAMPLE 133

[00867] Synthesis of tert-butyl 2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)hydrazine-1-carboxylate (133a).

[00868] A mixture of I2a (0.28 g, 0.53 mmol) and P1 (172 mg, 0.67 mmol) was dissolved in a mixture of THF/AcOH (12 mL, 3:1). After stirring at room temperature for 15 min, sodium cyanoborohydride (2.49 mmol/gr on resin, 0.44 g, 1.09 mmol) was added. The reaction mixture was stirred overnight, then filtered, and the filtered resin was rinsed several times with EtOAc. The combined filtrate was concentrated under reduced pressure; the residue was recrystallized/precipitated from EtOAc/hexanes to afford 133a (351.6 mg, 87.3%). MS (ESI) m/z 764.09 [M+H] +

[00869] Synthesis of ((5S,10S,11S,14S)-8-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-16,16,16- trifluoro-10-hydroxy-11-(4- iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetra -aza-hexadecan-14- yl)methyl carbamate (133b).

[00870] 133a (75%, 0.3 g, 0.29 mmol) was dissolved in DCM (10 mL) and HCl (4.0 M in dioxane, 2.6 mL). The reaction was stirred for 3 h, then concentrated under reduced pressure, and the crude material was dissolved in DCM (10 mL) and HATU (0.24 g, 0.64 mmol), and N,N-diisopropylethylamine (0.6 mL, 0 mol) was added, followed by A3 (0.21 g, 0.86 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with 5 mL of MeOH and concentrated. The crude residue was diluted with EtOAc and washed with 5% LiCl, saturated NaHCO3, and brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica (30% to 70% EtOAc/Hex) to afford 133b (296 mg, 67%). MS (ESI) m/z 1014.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.15 (d, J = 1.2 Hz, 1 H), 8.01 (d, J = 1.3 Hz, 1 H), 7.58 (t, J = 59.9 Hz, 1 H), 7.52 (d, J = 7.9 Hz, 2 H), 7.38 (d, J = 8.4 Hz, 2 H), 6.99 (d, J = 8.2 Hz, 2 H), 4.45 (s, 1 H), 4.30 (s, 1 H), 4.14 (s, 0 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.71 (s, 3 H), 3.66 (s, 3 H), 2.92 - 2.67 (m, 4 H), 1.16 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.02 (s, 3 H).

[00871] ((5S,10S,11S,14S)-8-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 10-hydroxy-15,15-dimethyl-11- (4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13 -trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,8,12-tetra-aza-hexadecan-14-yl)carbamate (133).

[00872] In a vial, a solution of 133b (50 mg, 0.05 mmol), S7 (17 mg, 0.06 mmol), copper(I) iodide (4.0 mg, 0.02 mmol), trans- Dichlorobis(triphenylphosphine)palladium(II) (99%, 11.1 mg, 0.02 mmol) in a mixture of and MeCN : Et 3 N 3:1 (1 mL) was degassed and then stirred at room temperature overnight. Concentrated under reduced pressure. Purified by HPLC and lyophilized to yield 133. MS (ESI) m/z 1156.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 2 H), 8.09 (d, J = 17.5 Hz, 2 H), 7.93 (s, 1 H), 7.49 (t, J = 60.0 Hz, 1 H), 7.27 (dd, J = 18.4, 8.1 Hz, 3 H), 7.14 (d, J = 8.0 Hz, 2 H), 6.73 (d, J = 9.9 Hz, 1 H), 4.86 (d, J = 7.6 Hz, 2 H), 4.72 (dd, J = 8.2, 5.0 Hz, 2 H), 4.35 (d, J = 8.7 Hz, 1 H), 4.22 (d, J = 9.8 Hz, 1 H), 4.03 (d, J = 12.8 Hz, 4 H), 3.84 (d, J = 13.2 Hz, 1 H), 3.58 (d, J = 8.6 Hz, 5 H), 3.37 (d, J = 14.4 Hz, 2 H), 2.90 - 2.62 (m, 4 H), 2.56 (s, 1 H), 2.12 (d, J = 11.1 Hz, 2 H), 1.90 (d, J = 9.0 Hz, 2 H), 1.07 (s, 3 H), 1.05 (s, 3 H), 1.01 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 134

[00873] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((4-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)phenyl)ethynyl)benzyl)-3,6,13- trioxo-5-(1,1,1-trifluoro-2-methylpropan-2- il)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)methyl carbamate

[00874] Intermediates: P4, A3, and S5. MS (ESI) m/z 1137.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.11 (d, J = 9.4 Hz, 1 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.75 - 7.50 (m, 6 H), 7.46 (d, J = 16.5 Hz, 2 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.28 (d, J = 9.5 Hz, 3 H), 7.15 (d, J = 8.0 Hz, 3 H), 6.85 (d, J = 2.7 Hz, 1 H), 6.73 (d, J = 10.0 Hz, 1 H), 4.79 - 4.71 (m, 5 H), 4.35 (d, J = 9.9 Hz, 1 H), 4.22 (d, J = 10.0 Hz, 1 H), 4.06 (d, J = 13.5 Hz, 3 H), 3.85 (d, J = 13.0 Hz, 1 H), 3.65 (s, 2 H), 3.61 (s, 3 H), 3.57 (s, 3 H), 3.08 (s, 4 H), 2.83 (d, J = 8.0 Hz, 2 H), 2.73 - 2.62 (m, 1 H), 1.07 (s, 4 H), 1.05 (s, 3 H), 1.02 (s, 4 H), 0.94 (s, 3 H). EXAMPLE 135

[00875] ((5S,10S,11S,14S)-8-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-10-hydroxy-15 ,15-dimethyl-11-(4-((6- ((1R,4R)-5-(oxetan-3-yl)-2,5 diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) -2- methyl oxa-4,7,8,12-tetra-aza-hexadecan-14-yl)carbamate (135).

[00876] Intermediates: P14, A3, and S6. MS (ESI) m/z 1120.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.46 (d, J = 2.9 Hz, 1 H), 8.16 (d, J = 2.1 Hz, 1 H), 8.11 (d , J = 9.2 Hz, 1 H), 7.87 (dd, J = 8.8, 4.3 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.51 (d, J = 8.7Hz, 2H), 7.23 (d, J = 7.9Hz, 2H), 7.13 (d, J = 8.1 Hz, 3 H), 6.74 (d, J = 10.0 Hz, 1 H), 6.57 (d, J = 8.8 Hz, 1 H), 4.95 (s, 1 H), 4.86 (dd, J = 8.4, 6.3 Hz, 1 H), 4.61 (s, 1 H),4.49 (dq, J = 11.2, 6.0, 5.5 Hz, 2 H), 4.41 (s, 1 H), 4.35 (d, J = 9.7 Hz, 1H), 4.21 (d, J = 10.0 Hz, 1 H), 4.07 (d, J = 13.3 Hz, 2 H), 3.87 (d, J = 13.1 Hz, 1 H), 3, 74 - 3.62 (m, 2 H), 3.60 (s, 3 H), 3.55 (s, 3 H), 2.87 - 2.73 (m, 3 H), 2.73 - 2.65 (m, 1 H), 2.23 (s, 2 H), 1.06 (d, J = 5.4 Hz, 6 H), 1.02 (s, 3 H), 0.93 (s, 3H). EXAMPLE 136

[00877] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro o-8-(4-((6-((R)-hexahydropyrazino[2,1-c][1.4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9 - hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- 2-yl)-2-oxa-4,7,11,12-tetra- methyl aza-hexadecan-14-yl)carbamate (136).

[00878] Intermediates: P13, A3, and S8. MS (ESI) m/z 1118.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.22 (d, J = 2.3 Hz, 1 H), 8.10 (d, J = 9.4 Hz, 1 H), 7.61 (dt, J = 5.4, 2.6 Hz, 2 H), 7.59 - 7.50 (m, 1 H), 7.47 (dt, J = 7.7, 4.1 Hz, 1 H), 7.30 - 7.19 (m, 4 H), 7.13 (d, J = 8.1 Hz, 2 H), 7.06 (s, 0 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.72 (d, J = 9.9 Hz, 1 H), 6.55 (d, J = 2.5 Hz, 1 H), 4.53 (dd, J = 22.7, 13.2 Hz, 2 H), 4.42 - 4.30 (m, 1 H), 4.26 - 4.18 (m, 1 H), 4.03 (d, J = 13.2 Hz, 4 H), 3.84 (d, J = 13.1 Hz, 1 H), 3.76 (t, J = 12.7 Hz, 1 H), 3.59 (d, J = 9.3 Hz, 6 H), 3.49 (d, J = 11.0 Hz, 1 H), 3.44 - 3.35 (m, 0 H), 2.81 (d, J = 7.3 Hz, 3 H), 2.72 - 2.63 (m, 1 H), 1.08 (s, 3 H), 1.05 (s, 4 H), 1.04 (d, J = 2.8 Hz, 0 H), 1.02 (s, 2 H), 1.00 - 0.95 (m, 1 H), 0.94 (s, 3 H). EXAMPLE 137

[00879] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-8-(4- ((6-((R)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1, 1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (137).

[00880] Intermediates: P15, A3, and S8. MS (ESI) m/z 1118.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.56 (dd, J = 8.6, 5.6 Hz, 1 H), 8.21 (d, J = 2.2 Hz, 1 H), 8.11 (d, J = 9.3 Hz, 1 H), 7.67 (dd, J = 10.3, 2.4 Hz, 1 H), 7.61 (dd, J = 8.9, 2.2 Hz, 1 H), 7.56 (d, J = 8.5 Hz, 2 H),7.24 (d, J = 7.9 Hz, 2 H), 7.16 - 7.08 (m, 3 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.74 (d, J = 10.0Hz, 1H), 4.52 (dd, J = 23.4, 12.6 Hz, 2 H), 4.35 (d, J = 10.0 Hz, 1 H), 4.21 (d, J = 9.9 Hz, 1 H), 4.07 (t, J = 10.4 Hz, 4 H), 3.87 (d, J = 13.2 Hz, 1 H), 3.75 (t, J = 12.6 Hz, 1 H), 3.64 (s, 1 H), 3.60 (s, 3 H), 3.55 (s, 2 H), 3.48 (d, J = 10.7 Hz, 1 H), 3.39 (t, J = 10.4 Hz, 1 H), 2.88 - 2.73 (m, 4 H), 2.73 - 2.64 (m, 1 H), 1.06 (d, J = 5.6 Hz, 6 H), 1.02 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 138

[00881] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((6-((1R,4R)- 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1, 1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (138).

[00882] Intermediates: P15, A3, and S6. MS (ESI) m/z 1120.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.56 (dd, J = 8.6, 5.6 Hz, 1 H), 8.16 (s, 1 H), 8.11 (d, J = 9.5 Hz, 1 H), 7.68 (d, J = 9.4 Hz, 1 H), 7.58 (dd, J = 14.3, 8.7 Hz, 3 H), 7.23 (d, J = 7.9 Hz, 2 H), 7.13 (d, J = 8.0 Hz, 4 H), 6.74 (d, J = 10.2 Hz, 1 H), 6.57 (d, J = 8.8 Hz, 1 H), 4.95 (s, 1 H), 4.61 (s, 1 H), 4.49 (dd, J = 11.6, 6.4 Hz, 1 H), 4.41 (s, 1 H), 4.35 (d, J = 10.0 Hz, 1 H), 4, 21 (d, J = 9.9 Hz, 1 H), 4.08 (d, J = 12.8 Hz, 2 H), 3.87 (d, J = 13.0 Hz, 1 H), 3.66 (d, J = 16.3 Hz, 2 H), 3.60 (d, J = 1.1 Hz, 3 H), 3.55 (s, 3 H), 2.81 (d, J = 7.8 Hz, 2 H), 2.71 (d, J = 9.5 Hz, 1 H), 2.23 (s, 2 H), 1.06 (d, J = 4.6 Hz, 6 H), 1.02 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 139

[00883] ((5S,10S,11S,14S)-8-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-10-hydroxy-15 ,15-dimethyl-11-(4-((6-(6- (oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetra-aza-hexadecan-14-yl)carbamate methyl (139).

[00884] Intermediates: P14, A3, and S4. MS (ESI) m/z 1120.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.46 (d, J = 2.9 Hz, 1 H), 8.24 (d, J = 2.3 Hz, 1 H), 8.10 (d , J = 9.3 Hz, 1 H), 7.96 - 7.86 (m, 1 H), 7.65 (dd, J = 8.8, 2.3 Hz, 1 H), 7.59 (td, J = 8.5, 3.0 Hz, 1 H), 7.51 (d, J = 8.6 Hz, 2 H), 7.24 (d, J = 7.9 Hz, 2 H), 7.13 (d, J = 8.0 Hz, 2 H), 7.08 (d, J = 9.9 Hz, 1 H), 6.73 (d, J = 10.6 Hz, 1 H), 6.69 (d, J = 8.9 Hz, 1 H), 4.96 - 4.83 (m, 4 H), 4, 59 - 4.47 (m, 2 H), 4.42 - 4.31 (m, 1 H), 4.31 - 4.19 (m, 1 H), 4.07 (d, J = 13.4 Hz, 4 H), 3.87 (d, J = 13.2 Hz, 1 H), 3.64 (s, 2 H), 3.60 (s, 3 H), 3.56 (s, 3 H), 2.82 (d, J = 8.4 Hz, 2 H), 2.74 - 2.65 (m, 1 H), 2.02 (d, J = 11.0 Hz, 1 H), 1.07 (s, 4 H), 1.06 (s, 3 H), 1.02 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 140

[00885] ((5S,10S,11S,14S)-8-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-10-hydroxy-15 ,15-dimethyl-11-(4-((6-(6- (oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetra-aza-hexadecan-14-yl)carbamate methyl (140).

[00886] Intermediates: P15, A3, and S4. MS (ESI) m/z 1120.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.66 (dd, J = 8.6, 5.6 Hz, 1 H), 8.33 (s, 1 H), 8.21 (d, J = 9.3 Hz, 1 H), 7.76 (t, J = 9.9 Hz, 2 H), 7.66 (d,J = 8.5 Hz, 2 H), 7.34 (d, J = 7.8 Hz, 2 H), 7.23 (d, J = 7.7 Hz, 3 H),6.84 (d, J = 10.1 Hz, 0 H), 6.78 (d, J = 8.9 Hz, 1 H), 4.61 (dd, J = 8.2, 4.0 Hz, 2 H), 4.45 (d, J = 10.0 Hz, 1 H), 4.31 (d, J = 10.0 Hz, 1 H), 4.18 (d, J = 12.4 Hz, 2 H), 3.99 (s, 0 H), 3.74 (s, 2 H), 3.70 (s, 3 H), 3.65 (s, 2 H), 2.91 (d, J = 8.1 Hz, 2 H), 2.80 (d, J = 9.8 Hz, 1 H), 2.11 (d, J = 10.9 Hz, 1 H), 1.33 - 1.23 (m, 1 H), 1.16 (s, 4 H), 1.15 (s, 3 H), 1.12 (s, 2 H), 1.03 (s, 3 H). EXAMPLE 141

[00887] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)- 3,6,13-trioxo-5-(1,1,1- methyl trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)methyl carbamate (141).

[00888] Intermediates: P4, A3, and S10. MS (ESI) m/z 1143 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.12 (d, J = 2.3 Hz, 1 H), 8.08 (d, J = 9.4 Hz, 1 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.62 - 7.42 (m, 3 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.22 (d, J = 7.9 Hz, 2 H), 7.11 (d, J = 8.1 Hz, 2 H), 7.06 (d, J = 9.9 Hz, 1 H), 6.85 (d, J = 2.8 Hz, 1 H), 6.72 (dd, J = 9.5, 5.4 Hz, 2 H), 4.56 (d, J = 5.9 Hz, 2 H), 4.34 (d, J = 9.9 Hz, 1 H), 4.27 - 4.15 (m, 3 H), 4.05 (d, J = 12.1 Hz, 2 H), 3.85 (d, J = 13.1 Hz, 1 H), 3.64 (s, 2 H), 3.60 (s, 3 H), 3.56 (d, J = 8.7 Hz, 7 H), 2.75 (dd, J = 44.1, 8.8 Hz, 4 H), 2.46 (t, J = 5.0 Hz, 4 H), 1.32 (s, 3 H), 1.07 (s, 3 H), 1.05 (s, 3 H), 1.02 (s, 3H), 0.94 (s, 3 H). EXAMPLE 142

[00889] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-3,6,13- trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl) ethynyl)benzyl)-5-(1,1,1- methyl trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (142).

[00890] Intermediates: P4, A3, and S11. MS (ESI) m/z 1170.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 2.3 Hz, 1 H), 8.17 (d, J = 9.4 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.76 - 7.60 (m, 2 H), 7.60 - 7.52 (m, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.13 (d, J = 9.8 Hz, 1 H), 6.94 (d, J = 2.7 Hz, 1 H), 6.84 (d, J = 8.9 Hz, 1 H), 6.79 (d, J = 10.0 Hz, 1 H), 4.45 (s, 0 H), 4.42 - 4.27 (m, 2 H), 4.23 (s, 1 H), 4.20 - 4.05 (m, 2 H), 4.05 - 3.89 (m, 3 H), 3.88 - 3.56 (m, 8 H), 3.06 - 2.85 (m, 3 H), 2.85 - 2.69 (m, 1 H), 2.50 (d, J = 12.5 Hz, 1 H), 2.32 (s, 2 H), 2.22 - 2.00 (m, 3 H), 1.16 (s, 4 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H). EXAMPLE 143

[00891] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-3,6,13- trioxo-8-(4-((6-(8-((R)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl) ethynyl)benzyl)-5-(1,1,1- methyl trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (143).

[00892] Intermediates: P4, A3, and S12. MS (ESI) m/z 1170.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 2.2 Hz, 1 H), 8.17 (d, J = 9.3 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.74 - 7.60 (m, 2 H), 7.59 - 7.50 (m, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.13 (d, J = 9.7 Hz, 1 H), 6.94 (d, J = 2.7 Hz, 1 H), 6.84 (d, J = 8.9 Hz, 1 H), 6.79 (d, J = 9.9 Hz, 1 H), 4.44 (d, J = 10.1 Hz, 1 H), 4.30 (d, J = 9.9 Hz, 1 H), 4.23 (s, 1 H), 4.14 (d, J = 12.3 Hz, 2 H), 3.97 (t, J = 14.4 Hz, 1 H), 3.86 - 3.57 (m, 8 H), 2.97 - 2.84 (m, 3 H),2.84 - 2.68 (m, 1 H), 2.49 (s, 1 H), 2.32 (s, 2 H), 2.22 - 2.04 (m, 3 H), 1.16 (s, 4 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H). EXAMPLE 144

[00893] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(8-(3-methyloxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13- trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (144).

[00894] Intermediates: P4, A3, and S13. MS (ESI) m/z 1170.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.23 - 8.13 (m, 1 H), 8.10 (d, J = 2.8 Hz, 1 H), 7.57 (dd, J = 8.9, 2.4 Hz, 1 H), 7.53 (t, J = 59.8 Hz, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.31 (d, J = 7.9 Hz, 2 H), 7.20 (d, J = 8.1 Hz, 2 H), 6.94 (d, J = 2.7 Hz, 1 H), 6.69 (d, J = 9.0 Hz, 1 H), 4.43 (s, 1 H), 4.30 (s, 1 H), 4.14 (d, J = 12.1 Hz, 2 H), 3.95 (d, J = 13.2 Hz, 1 H), 3.84(dt, J = 8.2, 4.5 Hz, 2 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.49 (d, J = 7.1 Hz, 1 H), 3.39 (s, 1 H), 3.11 (dt, J = 11.9, 2.1 Hz, 2 H), 2.90 (d, J = 8.0 Hz, 2 H), 2.83 - 2.76 (m, 1 H), 2.73 (d, J = 5.0 Hz, 1 H), 2.69 (s, 0 H), 2.62 (d, J = 4.9Hz, 1H), 2.46 (d, J = 13.4 Hz, 1 H), 1.97 (s, 2 H), 1.67 (d, J = 9.0 Hz, 2 H), 1.43 (s, 3 H), 1.16 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H). EXAMPLE 145

[00895] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-3,6,13- trioxo-8-(4-((6-(4-((S)-tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1 methyl,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (145).

[00896] Intermediates: P4, A3, and S15. MS (ESI) m/z 1143.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.36 - 8.26 (m, 1 H), 8.19 (d, J = 9.2 Hz, 1 H), 8.11 (d, J = 2.7 Hz, 1 H), 7.71 (d, J = 2.3 Hz, 1 H), 7.69 (d, J = 2.1 Hz, 1 H), 7.67 - 7.61 (m, 0 H), 7.57 (dd, J = 7.3, 3.3 Hz, 1 H), 7.54 (s, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.0Hz, 2 H), 7.15 (s, 1 H), 6.99 - 6.86 (m, 2 H), 6.81 (d, J = 10.1 Hz, 1 H), 4.45 (s, 0 H), 4.31 (d, J = 10.0 Hz, 1 H), 4.26 - 4.02 (m, 5 H), 4.00 - 3.82 (m, 3 H), 3.75 (d, J = 8.4 Hz, 1 H), 3.68 (d, J = 10.9 Hz, 6 H), 2.97 - 2.85 (m, 3 H), 2.55 - 2.35 (m, 1 H), 2.28 - 2.16 (m, 1 H), 1.16 (s, 4 H), 1.15 (s, 3 H), 1.12 (s, 3 H), 1.03 (s, 3 H). EXAMPLE 146

[00897] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-3,6,13- trioxo-8-(4-((6-(4-((R)-tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1 methyl,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (146).

[00898] Intermediates: P4, A3, and S14. MS (ESI) m/z 1143.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.30 (d, J = 2.3 Hz, 1 H), 8.19 (d, J = 9.1 Hz, 1 H), 8.11 (d, J = 2.8 Hz, 1 H), 7.71 (d, J = 2.4 Hz, 0 H), 7.69 (s, 1 H), 7.68 - 7.61 (m, 1 H), 7.60 - 7.55 (m, 1 H), 7.54 (s, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.23 (d, J = 8.1 Hz, 3 H), 6.96 - 6.85 (m, - 3.86 (m, 1 H), 3.75 (d, J = 8.2 Hz, 2 H), 3.69 (s, 4 H), 3.66 (s, 3 H), 3.00 - 2.82 (m, 3 H), 2.79 (d, J = 10.0 Hz, 1 H), 2.42 (s, 0H), 2.21 (d, J = 8.5 Hz, 0 H), 1.16 (s, 5 H), 1.15 (s, 3 H), 1.12 (s, 3 H),1.03 (s, 3 H). Example 147

[00899] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan -3-yl)pyridin-3-yl)benzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl) ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate methyl (147).

[00900] Intermediates: P22, A3, and S3. MS (ESI) m/z 1282.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.43 - 8.31 (m, 1 H), 8.20 (d, J = 2.3 Hz, 1 H), 7.84 (d, J = 9.0 Hz, 1 H), 7.60 (dd, J = 8.8, 2.3 Hz, 1 H), 7.24 (d, J = - 4.68 (m, 4 H), 4.37 - 4.17 (m, 6 H), 4.10 - 3.99 (m, 6 H), 3.86 (d, J = 13.1 Hz, 1 H), 3.67 - 3.62 (m, 1 H), 3.60 (s, 3 H), 3.56 (s, 3H), 3.34 - 3.25 (m, 5 H), 2.81 (d, J = 7.7 Hz, 2 H), 2.74 - 2.65 (m, 1 H), 2.19 - 2.10 (m, 4 H), 2.03 - 1.93 (m, 4 H), 1.07 (s, 3 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 148

[00901] ((5S,8S,9S,14S)-11-(2-chloro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl -8-(4-((6-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (148).

[00902] Intermediates: P25, A3, and S3. MS (ESI) m/z 1114.7 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.55 (d, J = 5.0 Hz, 1 H), 8.20 (d, J = 2.1 Hz, 1 H), 8.04 (d, J = 9.5 Hz, 1 H), 7.94 - 7.85 (m, 1 H), 7.82 (d, J = 8.1 Hz, 1 H), 7.77 - 7.70 (m, 1 H), 7.65 (d, J = 8.1 Hz, 1 H), 7.60 (dd, J = 8.8, 2.3 Hz, 1 H), 7.42 - 7.32 (m, 1 H), 7.24 (d, J = 7.9 Hz, 2 H), 7.13 (d, J = 8.0 Hz, 2 H), 6.77 (d, J = 8.8 Hz, 1 H), 6.71 (d, J = 10.3 Hz, 1 H), 4.87 (t, J = 7.6 Hz, 2 H), 4.73 - 4.66 (m, 2 H), 4.31 (d, J = 10.0 Hz, 1 H), 4.18 (d, J = 9.7 Hz, 1 H), 4.14 - 4.03 (m, 3 H), 3.99 (d, J = 14.2 Hz, 1 H), 3.74 - 3.66 (m, 1 H), 3.58 (s, 3 H), 3.48 (s, 3 H), 3.29 (s, 1 H), 2.87 - 2.68 (m, 2 H), 2.21 - 2.07 (m, 1 H), 2.03 - 1.93 (m, 2 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.96 (s, 3 H), 0.84 (s, 3 H). EXAMPLE 149

[00903] ((5S,8S,9S,14S)-11-(2,6-dichloro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((6-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (149).

[00904] Intermediates: P24, A3, and S3. MS (ESI) m/z 1148.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.56 (d, J = 5.0 Hz, 1 H), 8.20 (d, J = 2.2 Hz, 1 H), 8.04 (d, J = 9.4 Hz, 1 H), 7.88 (s, 2 H), 7.83 (d, J = 7.8 Hz, 2 H), 7.64 - 7.54 (m, 1 H), 7.33 (t, J = 5.7 Hz, 1 H), 7.23 (d, J = 7.7 Hz, 2 H), 7.12 (d, J = 8.0 Hz, 2 H), 6.77 (d, J = 8.9 Hz, 1 H), 6.71 (d, J = 10.1 Hz, 1H), 4.87 (t, J = 7.5 Hz, 2 H), 4.71 (dd, J = 8.2, 4.9 Hz, 2 H), 4.36 - 4.23 (m, 2 H), 4.20 (d, J = 9.9 Hz, 1 H), 4.12 - 3.98 (m, 4 H), 3.69 - 3.62 (m, 1 H), 3.59 (s, 3 H), 3.54 (s, 3 H), 3.29 (s, 1 H), 2.83 - 2.75 (m, 2 H), 2.72 - 2.62 (m, 1 H), 2.17 - 2.08 (m, 1 H), 2.03 - 1.93 (m, 2 H), 1.05 (s, 6H), 0.99 (s, 3H), 0.89 (s, 3H). EXAMPLE 150

[00905] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((5-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6, 13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)- Methyl 2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (150).

[00906] Intermediates: P4, A3, and S44. MS (ESI) m/z 1171.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.17 (d, J = 2.2 Hz, 1 H), 8.07 (d, J = 9.4 Hz, 1 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.61 - 7.55 (m, 3 H), 7.44 (s, 1 H), 7.35 (d, J = 8.3 Hz, 2 H), 7.30 - 7.22 (m, 2 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.02 (d, J = 9.9 Hz, 1 H), 6.84 (d, J = 2.8 Hz, 1 H), 6.69 (d, J = 9.9 Hz, 1H), 4.88 - 4.80 (m, 2 H), 4.73 - 4.68 (m, 2 H), 4.41 (s, 1 H), 4.34 (d, J = 9.9 Hz, 1 H), 4.21 (d, J = 10.0 Hz, 1 H), 4.10 - 3.98 (m, 4 H), 3.85 (d, J = 13.2 Hz, 1 H), 3.64 (s, 1 H), 3.59 (s, 3 H), 3.57 (s, 3 H), 3.48 (d, J = 13.5 Hz, 2 H), 3.38 (d, J = 1.7 Hz, 1 H), 3.35 (s, 1 H), 3.25 (s, 1 H), 2.85 - 2.74 (m, 3 H), 2.72 - 2.65 (m, 1 H), 2.27 (s, 5 H), 2.17 - 2.11 (m, 2 H), 1.06 (d, J = 6.7 Hz, 6 H), 1.02 (s, 3 H), 0.93 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.38, -77.71, -77.88, -96.97 (dd, J = 59.8, 18.8 Hz), -114.92. EXAMPLE 151

[00907] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((4-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6, 13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)- Methyl 2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (151) .

[00908] Intermediates: P4, A3, and S46. MS (ESI) m/z 1171.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1 H), 8.17 (d, J = 9.3 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.68 (s, 0 H), 7.53 (s, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.38 (s, 0 H), 7.34 (d, J = 7.8 Hz, 2 H), 7.23 (d, J = 8.1 Hz, 2 H), 7.11 (d, J = 9.8 Hz, 1 H), 6.94 (d, J = 2.8 Hz, 1 H), 6.82 (s, 0H), 6.79 (s, 1 H), 4.99 - 4.89 (m, 2 H), 4.83 - 4.77 (m, 2 H), 4.51 (s, 1 H), 4.47 - 4.42 (m, 1 H), 4.35 (s, 1 H), 4.31 (s, 1 H), 4.29 (s, 0 H), 4.16(s, 1 H), 4.13 (s, 3 H), 3.95 (d, J = 13.2 Hz, 1 H), 3.74 (s, 1 H), 3.68 (s, 3 H), 3.66 (s, 3 H), 3.38 (s, 1 H), 3.34 (s, 3 H), 2.94 - 2.84 (m, 3 H), 2.78 (dd, J = 12.5, 9.0 Hz, 1 H), 2.44 (s, 3 H), 2.25 - 2.18 (m, 2 H), 2.10 - 2.04 (m, 2 H), 1.16 (s, 4 H), 1.13 (d, J = 12.7 Hz, 7 H), 1.02 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.38, -77.71, -77.82, -96.97 (dd, J = 59.8, 18.6 Hz), -114.92. EXAMPLE 152

[00909] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((2-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6, 13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)- Methyl 2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (152) .

[00910] Intermediates: P4, A3, and S45. MS (ESI) m/z 1170.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.17 (d, J = 9.3 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.68 (s, 0 H), 7.62 (d, J = 8.7 Hz, 1 H), 7.53 (s, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.38 (s, 0 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.1 Hz, 2 H), 7.11 (d, J = 9.9 Hz, 1 H), 6.93 (d, J = 2.8 Hz, 1 H), 6.80 (d, J = 9.8 Hz, 1 H), 6.67 (d, J = 8.8 Hz, 1 H), 4.96 (dd, J = 8.2, 7.0 Hz, 2 H), 4.81 (dd, J = 8.2, 5.1 Hz, 2 H), 4.51 (s, 1 H), 4.47 - 4.43 (m, 1 H), 4.38 (d, J = 13.8 Hz, 2 H), 4.32 - 4.27 (m, 1 H), 4.15 (d, J = 12.2 Hz, 4 H), 3.95 (d, J = 13.1 Hz, 1 H), 3.73 (s, 1 H), 3.68 (s, 3 H), 3.66 (s, 3 H), 3.38 - 3.35 (m, 1 H), 3.34 - 3.32 (m, 1 H), 2.88 (dd, J = 18.8, 5.2 Hz, 3 H), 2.78 (dd, J = 12.5, 9.0 Hz, 1 H), 2.56 (s, 3 H), 2.25 - 2.18 (m, 2 H), 2.08 (t, J = 6.8 Hz, 2 H), 1.16 (s, 5 H), 1.13 (d, J = 13.1 Hz, 7 H), 1.02 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.39, -77.71, -77.86, -96.97 (dd, J = 59.9, 18.5 Hz), -114.92. EXAMPLE 153

[00911] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((5-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6, 13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)- Methyl 2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (153) .

[00912] Intermediates: P7, A3, and S44. MS (ESI) m/z 1170.6 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1 H), 8.29 - 8.25 (m, 1 H), 8.16 (d, J = 9.2 Hz, 1 H), 8.12 (s, 1 H), 7.70 - 7.60 (m, 2 H), 7.55 (td, J= 7.4, 3.1 Hz, 1 H), 7.50 (s, 1 H), 7.36 (d, J = 2.1 Hz, 1 H), 7.34 (s, 1H), 7.24 (dd, J = 8.2, 6.7 Hz, 4 H), 7.16 (d, J = 10.0 Hz, 1 H), 6.79 (d, J = 9.9Hz, 1 H), 4.94 (t, J = 7.6 Hz, 2 H), 4.79 (dd, J = 8.2, 5.2 Hz, 3 H),4.49 (s, 1 H), 4.47 - 4.41 (m, 1 H), 4.34 - 4.27 (m, 1 H), 4.15 (d, J = 8.8Hz, 1 H), 4.09 (d, J = 7.1 Hz, 3 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.57 (d, J = 13.5 Hz, 2 H), 3.51 (s, 0 H), 3.47 (dt, J = 3.3, 1.7Hz, 2H), 3.43 (s, 1 H), 2.99 (s, 0 H), 2.91 (d, J = 7.8 Hz, 2 H), 2.87 - 2.82 (m, 1 H), 2.81 - 2.73 (m, 1 H), 2.36 (s, 4 H), 2.34 (s, 0 H), 2.24 (s, 2 H), 2.04 - 1.91 (m, 0 H), 1.33 - 1.26 (m, 1 H), 1.17 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H). 19F NMR (377 MHz, Methanol- d4) δ -77.39, -77.51, -77.71, -96.88 (d, J = 59.6 Hz), -115.03, -130.01. EXAMPLE 154

[00913] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((4-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6, 13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)- Methyl 2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (154) .

[00914] Intermediates: P7, A3 and S46. MS (ESI) m/z 1169.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1 H), 8.20 (s, 1 H), 8.14 (s, 1 H), 8.11 (s, 1 H), 7.64 (s, 0 H), 7.50 (s, 1 H), 7.34 (d, J = 7.3 Hz, 2 H), 7.24 (t, J = 7.8 Hz, 4 H), 7.11 (d, J = 9.9 Hz, 1 H), 6.78 (s, 1 H), 6.77 (s, 0 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.50 (s, 1 H), 4.44 (d, J = 9.7 Hz, 1 H), 4.36 - 4.27 (m, 3 H), 4.12 (d, J = 10.0 Hz, 4 H), 3.94 (d, J = 13.2 Hz, 1 H), 3.70 (s, 2 H), 3.68 (s, 3 H), 3.66 (s, 3 H), 3.38 (s, 1 H), 3.34 (s, 3 H), 2.94 - 2.73 (m, 4 H), 2.44 (s, 3 H), 2.27 - 2.17 (m, 2 H), 2.07 (d, J = 8.6 Hz, 2 H), 1.29 (t, J = 7.4 Hz, 0 H), 1.20 - 1.10 (m, 10 H), 1.03 (s, 3H). 19F NMR (376 MHz, Methanol-d4) δ -77.35, -77.62, -77.67, -96.90 (d, J = 59.9 Hz), -115.01. EXAMPLE 155

[00915] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((2-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6, 13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)- Methyl 2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (155) .

[00916] Intermediates: P7, A3, and S45. MS (ESI) m/z 1169.7 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1 H), 8.12 (s, 2 H), 7.64 (s, 0 H), 7.53 (d, J = 8.6 Hz, 1 H), 7.49 (s, 1 H), 7.37 - 7.28 (m, 3 H), 7.23 (dd, J = 15.6, 8.1 Hz, 5 H), 4.44 (s, 1 H), 4.30 (s, 2 H), 4.12 (d, J = 12.6 Hz, 3 H), 3.94 (d, J = 13.1 Hz, 1 H), 3.68 (s, 4 H), 3.66 (s, 4 H), 2.90 (d, J = 8.2 Hz, 2 H), 2.79 (d, J = 9.9 Hz, 1 H), 2.53 (s, 4 H), 2.03 (s, 0 H), 1.98 (s, 1 H), 1.28 (d, J = 7.2 Hz, 3 H), 1.17 (s, 5 H), 1.15 (s, 4 H), 1.12 (s, 4 H), 1.03 (s, 4 H). 19F NMR (376 MHz, Methanol-d4) δ - 77.36, -77.48, -77.68, -96.91 (d, J = 59.7 Hz). EXAMPLE 156

[00917] ((2S)-1-(2-((2S,3S)-3-((S)-2-((cyclopropoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanamido) -2-hydroxy-4-(4-((6-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)phenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6- cyclopropyl difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate (156).

[00918] Intermediates: P4, A6 and S3. MS (ESI) m/z 1208.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.30 (dd, J = 2.3, 0.7 Hz, 1 H), 8.21 (d, J = 9.4 Hz, 1 H), 8.11 (d, J = 2.7 Hz, 1 H), 7.81 - 7.63 (m, 1 H), 7.53 (s, 1 H), 7.46 (d, J = 8.3 Hz, 2 H), 7.42 - 7.29 (m, 3 H), 7.23 (d, J = 8.0 Hz, 3 H), 6.94 (d, J = 2.8 Hz, 1 H), 6.85 (t, J = 8.7 Hz, 2 H), 5.05 - 4.90 (m, 3 H), 4.48 (d, J = 10.0 Hz, 1 H), 4.34 (t, J = 12.0 Hz, 3 H), 4.24 - 3.84 (m, 7 H), 3.75 (s, 1 H), 3.01 - 2.66 (m, 5 H), 2.22 (dd, J = 12.2, 6.4 Hz, 2 H), 2.03 (s, 32 H), 1.29 (s, 1 H), 1.19 - 1.07 (m, 10 H), 1.03 (s, 3 H), 1.00 - 0.50 (m, 8 H). EXAMPLE 157

[00919] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorobenzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (157).

[00920] Intermediates: P8, A3, and S3. MS (ESI) m/z 1138.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1 H), 8.28 - 8.25 (m, 1 H), 8.07 (s, 1 H), 7.68 (dd, J = 8.9, 2.3 Hz, 1 H), 7.66 - 7.57 (m, 1 H), 7.57 - 7.45 (m, 1 H), 7.41 - 7.27 (m, 6 H), 7.20 (d, J = 8.2 Hz, 2 H), 6.90 - 6.81 (m, 1 H), 4.94 (dd, J = 8.1, 7.0 Hz, 3 H), 4.81 (dd, J = 8.1, 4.9 Hz, 3 H), 4.53 (d, J = 6.3 Hz, 1 H), 4.45 - 4.21 (m, 5 H), 4.14 (dd, J = 4.7, 2.4 Hz, 4 H), 4.08 - 3.83 (m, 3 H), 3.70 (d, J = 24.6 Hz, 2 H), 3.60 (s, 3 H), 3.38 (dd, J = 14.1, 1.7 Hz, 3 H), 3.29 (p, J = 1.6 Hz, 6 H), 2.93 - 2.66 (m, 5 H), 2.28 - 2.02 (m, 3 H), 1.11 (d, J = 14.3 Hz, 7 H), 1.04 (s, 4 H), 0.93 (s, 4 H). EXAMPLE 158

[00921] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (158).

[00922] Intermediates: P6, A3, and S3. MS (ESI) m/z 1120.2 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (dd, J = 2.3, 0.7 Hz, 1 H), 8.16 - 7.99 (m, 2 H), 7.84 - 7.73 (m, 2 H), 7.71 - 7.37 (m, 4 H), 7.37 - 7.26 (m, 3 H), 7.26 - 7.10 (m, 2 H), 6.86 (d, J = 2.7 Hz, 1 H), 6.69 (dd, J = 9.0, 0.8 Hz, 1 H), 4.76 (t, J = 6.4 Hz, 2 H), 4.58 (t, J = 5.8 Hz, 3 H), 4.39 (s, 1 H), 4.25 (s, 1 H), 4.01 (d, J = 13.1 Hz, 1 H), 3.89 (dt, J = 13.1, 4.1 Hz, 4 H), 3.85 - 3.74 (m, 1 H), 3.60 (s, 3 H), 3.12 (dd, J = 12.0, 2.2 Hz, 3 H), 2.98 - 2.60 (m, 4 H), 1.96 - 1.86 (m, 3 H), 1.69 (d, J = 7.8 Hz, 2 H), 1.11 (d, J = 9.3 Hz, 7 H), 1.02 (s, 3 H), 1.00 - 0.76 (m, 4 H). EXAMPLE 159

[00923] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan Methyl -2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (159).

[00924] Intermediates: P4, A3, and S58. MS (ESI) m/z 1102.2 [M+H] +. 1H NMR (400MHz, Methanol-d4) δ 8.50 (s, 2H), 8.20 (d, J = 9.5Hz, 1H), 8.12 (s, 1H), 7.55 (t, J = 61.0Hz, 1H), 7.46 (d, J = 8.6Hz, 2H), 7.35 (d, J = 7.7 Hz, 2 H), 7.24 (d, J = 8.3 Hz, 2 H), 6.95 (s, 1 H), 4.44 (s, 1 H), 4.40 (s, 2 H), 4.31 (s, 1 H), 4.15 (d, J = 15.7 Hz, 4 H), 3.95 (d, J = 12.9Hz, 1 H), 3.75 (s, 2 H), 3.70 (s, 3 H), 3.67 (s, 3 H), 3.50 (s, 2 H), 3.03 (d, J = 2.8 Hz, 3 H), 2.90 (t, J = 12.3 Hz, 2 H), 2.80 (d, J = 10.7 Hz, 1 H), 1.17 (s, 3 H), 1.15 (s, 3 H), 1.12 (s, 3 H), 1.04 (s, 3 H). EXAMPLE 160

[00925] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-8-(4 -((2-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13- trioxo-5,14-bis(3-(trifluoromethyl)bicyclo[1.1.1]pentan- methyl 1-yl)-2-oxa-4,7,11,12-tetra-azatetradecan-14-yl)carbamate (160).

[00926] Intermediates: P4, A8, and S7. MS (ESI) m/z 1205.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 2 H), 8.09 (d, J = 2.7 Hz, 1 H), 7.52 (t, J = 60.0, 59.5 Hz, 1 H), 7.48 (d, J = 8.3 Hz, 2 H), 7.39 (d, J = - 4.23 (m, 1 H), 4.18 - 4.12 (m, 3 H), 4.08 (d, J = 18.2 Hz, 2 H), 4.03 (d, J = 13.5 Hz, 1 H), 3.75 (d, J = 9.3 Hz, 1 H), 3.66 (s, 3 H), 3.64 (s, 3 H), 3.46 (d, J =14.4 Hz, 2 H), 3.04 - 2.85 (m, 3 H), 2.79 (d, J = 12.7 Hz, 1 H), 2.20 (dd, J = 8.9, 3.9 Hz, 2 H), 2.01 (dd, J = 12.2, 6.9 Hz, 2 H), 1.86 - 1.65 (m, 12H). EXAMPLE 161

[00927] 3-(5-((4-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)- 2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)- 3,3-dimethylbutanoyl) hydrazinyl)-3-hydroxy-2-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanamido)butyl)phenyl)ethynyl)pyridin-2-yl)- tert-butyl 3,8-diazabicyclo[3.2.1] octane-8-carboxylate (161a).

[00928] MS (ESI) m/z 1200.0 [M+H] +. 1H NMR (400 MHz, Methanol- d4) δ 8.27 - 8.14 (m, 2 H), 8.11 (d, J = 2.7 Hz, 1 H), 7.84 (d, J = 9.0 Hz, 1 H), 7.53 (t, J = 59.7 Hz, 2 H), 7.45 (d, J = 8.2 Hz, 3 H), 7.35 (d, J = 7.9 Hz, 3 H), 7.24 (d, J = 8.0 Hz, 3 H), 7.15 (d, J = 9, 5 Hz, 1 H), 7.08 (d, J = 9.3 Hz, 1 H), 6.94 (d, J = 2.8 Hz, 1 H), 6.82 (d, J = 10.0 Hz, 1H), 4.44 (d, J = 11.9 Hz, 4 H), 4.30 (d, J = 10.0 Hz, 1 H), 4.14 (d, J = 13.3 Hz, 3 H), 4.02 - 3.87 (m, 4 H), 3.67 (d, J = 10.7 Hz, 10 H), 3.28 -3.18 (m, 3 H), 3.03 - 2.85 (m, 4 H), 2.82 - 2.69 (m, 1 H), 2.00 (dd , J =9.0, 4.0 Hz, 3 H), 1.81 (d, J = 7.7 Hz, 3 H), 1.49 (s, 9 H), 1.16 (s, 3H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H).

[00929] ((5S,8S,9S,14S)-8-(4-((6-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl) -11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)- 2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13- trioxo-5-(1,1,1-trifluoro-2-methylpropan-2- il)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate 2,2,2-trifluoroacetate methyl (161).

[00930] A solution of 161a (57.8 mg, 0.040 mmol) and trifluoroacetic acid (0.150 mL, 1.96 mmol) in DCM (2 mL) was stirred at room temperature. After 3 h, the reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC, and the product lyophilized to afford 161. MS (ESI) m/z 1200.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.32 - 8.26 (m, 1 H), 8.18 (d, J = 9.4 Hz, 1 H), 8.11 (d, J = 2.7 Hz, 1 H), 7.71 - 7.64 (m, 1 H), 7.71 - 7.36 (m, 1 H), 7.45 (d, J = 8.1 Hz, 2 H), 7.32 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2 H), 7.15 (d, J = 10.0 Hz, 1 H), 6.94 (d, J = 2.8 Hz, 1 H), 6.82 (t, J = 9.9Hz, 2 H), 4.44 (d, J = 9.9 Hz, 1 H), 4.36 - 4.22(m, 4 H), 4.16 (d, J = 28.1 Hz, 4 H), 3.94 (d, J = 13.2 Hz, 1 H), 3.67 (d,J = 11.1 Hz, 8 H), 3.26 - 3.17 (m, 3 H), 2.99 - 2.69 (m, 5 H), 2.19 - 1.96 (m, 5 H), 1.16 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.02 (s, 3 H).EXAMPLE 162

[00931] Synthesis 3-(5-((4-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-2-( (S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy-2- ((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanamido)butyl)phenyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1 tert-butyl octane-8-carboxylate (162a).

[00932] Intermediates: P7, A3, and S16. MS (ESI) m/z 1199.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J = 0.7 Hz, 1 H), 8.21 - 8.09 (m, 3 H), 7.89 (dd, J = 9.4, 2.2 Hz, 1 H), 7.69 - 7.32 (m, 2 H), 7.35(s, 1 H), 7.24 (dd, J = 8.4, 2.4 Hz, 4 H), 7.14 (d, J = 9.4 Hz, 2 H), 4.43(d, J = 4.2 Hz, 3 H), 4.36 - 4.23 (m, 1 H), 4.23 - 4.00 (m, 2 H), 3.97 - 3.82 (m, 3 H), 3.67 (d, J = 9.7 Hz, 5 H), 3.28 (d, J = 9.6 Hz, 2 H), 3.00 -2.70 (m, 4 H), 2.08 - 1.91 (m, 2 H), 1.82 (t, J = 6.9 Hz, 2 H), 1.49 (s, 9H), 1.23 - 1.08 (m, 9 H), 1.03 (s, 3 H).

[00933] ((5S,8S,9S,14S)-8-(4-((6-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl) -11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)- 2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13- trioxo-5-(1,1,1-trifluoro-2-methylpropan-2- yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate.

[00934] The title compound 162 was prepared according to the method presented for the synthesis of compound 161 , but using 162a. MS (ESI) m/z 1099.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1 H), 8.18 (d, J = 2.3 Hz, 1 H), 8.08 (d, J = 9.4 Hz, 1 H), 8.03 (s, 1 H), 7.63 - 7.55 (m, 1 H), 7.41 (s, 1 H), 7.29 - 7.20 (m, 2 H), 7.14 (dd, J = 14.9, 8.2 Hz, 4 H), 6.73 (t, J = 9.6 Hz, 2 H), 4.34 (d, J = 9.7 Hz, 1 H), 4.28 - 4.13 (m, 4 H), 4.13 - 3.91 (m, 4H), 3.83 (d, J = 13.1 Hz, 1 H), 3.58 (d, J = 10.5 Hz, 7 H), 3.14 (d, J = 13.5 Hz, 2 H), 2.75 (dd, J = 47.8, 9.1 Hz, 4 H), 2.12 - 1.85 (m, 3 H), 1.16 - 0.97 (m, 9 H), 0.94 (s, 3 H). EXAMPLE 163

[00935] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5- (1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (163).

[00936] Intermediates: P4, A3, and S17. MS (ESI) m/z 1141.7 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.17 - 8.03 (m, 2 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.66 (d, J = 8.9 Hz, 1 H), 7.44 (t, J = 59.8 Hz, 1 H), 7.36 (d, J = 8.2 6.50 (d, J = 8.9 Hz, 1 H), 4.90 - 4.82 (m, 1 H), 4.49 - 4.34 (m, 6H), 4.28 (s, 4 H), 4.21 (d, J = 10.0 Hz, 1 H), 4.05 (d, J = 13.0 Hz, 2 H), 3.85 (d, J = 13.2 Hz, 1 H), 3.64 (s, 2 H), 3.59 (s, 3 H), 3.57 (s, 3 H),2.88 - 2.74 (m, 3 H), 2.74 - 2.63 (m, 1 H), 1.06 (s, 3 H), 1.05 (s, 3 H),1.02 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 164

[00937] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13 -trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)- Methyl 2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate(164).

[00938] Intermediates: P4, A3, and S18. MS (ESI) m/z 1114.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.19 - 8.05 (m, 2 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.61 (dd, J = 8.9, 2.2 Hz, 1 H), 7.44 (t, J = 59.8 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.24 (d, J = 7.9 Hz, 2 H), 7.13 (d, J = 8.0 Hz, 2 H), 7.05 (d, J = 9.9 Hz, 1 H), 6.85 (d, J = 2.7 Hz, 1 H), 6.72 (d, J = 10.0 Hz, 1 H), 6.64 (d, J = 8.9 Hz, 1 H), 4.35 (d, J = 9.8 Hz, 1 H), 4.21(d, J = 10.0 Hz, 1 H), 4.05 (d, J = 12.6 Hz, 2 H), 3.85 (d, J = 13.1 Hz, 2 H), 3.65 (s, 1 H), 3.58 (d, J = 10.7 Hz, 6 H), 3.36 (d, J = 14.9 Hz, 2 H), 2.84 (dd, J = 18.9, 9.2 Hz, 5 H), 2.70 (d, J = 10.2 Hz, 1 H), 1.06 (d, J =6.3 Hz, 6 H), 1.02 (s, 3H), 0.93 (s, 3 H). EXAMPLE 165

[00939] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-((3aR,6aS)-5-(oxetan-3-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)ethynyl)benzyl)- 3,6,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (165).

[00940] Intermediates: P4, A3, and S19. MS (ESI) m/z 1156.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.09 (d, J = 2.3 Hz, 2 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.72 (dd, J = 8.9, 2.2 Hz, 1 H), 7.44 (t, J = 59.8 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.25 (d, J = 7.9 Hz, 2 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.05 (d, J = 9.9 Hz, 1 H), 6.85 (d, J = 2.7 Hz, 1 H), 6.81 - 6.67 (m, 2 H), 4.63 (dd, J = 8.3, 5.1 Hz, 2 H), 4.46 - 4.30 (m, 2 H), 4.21 (d, J = 10.0 Hz, 1 H), 4.05 (d, J = 13.3 Hz, 2 H), 3.85 (d, J = 13.2 Hz, 1 H), 3.64 (d, J = 4.3 Hz, 6 H), 3.59 (s, 3 H), 3.57 (s, 3 H), 3.32 (s, 3 H), 2.87 - 2.62 (m, 4 H), 1.06 (d, J = 6.2 Hz, 6 H), 1.02 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 166

[00941] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-8-(4-((6-(8-isopropyl- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1- trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (166).

[00942] Intermediates: P7, A3, and S22. MS (ESI) m/z 1142.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.44 (d, J = 0.7 Hz, 1 H), 8.20 (s, 1 H), 8.07 (d, J = 9.5 Hz, 1 H), 8.06 - 8.02 (m, 1 H), 7.67 - 7.50 (m, 1 H), 7.50 - 7.43 (m, 0 H), 7.41 (s, 0 H), 7.29 - 7.20 (m, 2 H), 7.14 (dd, J = 13.7, 8.3 Hz, 3 H), 6.73 (dd, J = 18.5, 9.6 Hz, 1 H), 4.34 (t, J = 5.2 Hz, 3 H), 4.30 - 4.15 (m, 3 H), 4.13 - 3.94 (m, 3 H), 3.84 (d, J = 13.2 Hz, 1 H), 3.58 (d, J = 10.5 Hz, 6 H), 3.17 (d, J = 2.4 Hz, 1 H), 2.91 - 2.64 (m, 3 H), 2.14 (d, J = 11.4 Hz, 2 H), 1.95 (d, J = 8.6 Hz, 1 H), 1.37 (d, J = 6.4 Hz, 6 H), 1.12 - 0.97 (m, 9 H), 0.94 (s, 3 H). EXAMPLE 167

[00943] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-((6 -(8-ethyl-3,8-diazabicyclo[3.2.1]octan-3- yl)pyridin-3-yl)ethynyl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl- 3,6,13-trioxo-5-(1,1,1-trifluoro- methyl 2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (167).

[00944] Intermediates: P7, A3, and S21. MS (ESI) m/z 1128.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.44 (d, J = 0.7 Hz, 1 H), 8.19 (d, J = 2.2 Hz, 1 H), 8.06 (d, J = 21.7 Hz, 2 H), 7.63 - 7.53 (m, 1 H), 7.41 (s, 1 H), 7.28 - 7.21 (m, 2 H), 7.14 (dd, J = 13.9, 8.2 Hz, 4 H), 6.73 (dd, J = 18.8, 9.5 Hz, 2 H), 4.42 - 4.30 (m, 1 H), 4.30 - 4.18 (m, 3 H), 4.13 (d, J = 4.3Hz, - 2.61 (m, 1 H), 2.24 - 2.13 (m, 2 H), 1.96 (d, J = 8.7 Hz, 2 H), 1.32 (t, J = 7.3 Hz, 3 H), 1.11 - 0.98 (m, 9 H), 0.94 (s, 3 H). EXAMPLE 168

[00945] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1 methyl,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (168).

[00946] Intermediates: P7, A3 and S20. MS (ESI) m/z 1113.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.45 (d, J = 0.7 Hz, 1 H), 8.24 - 8.16 (m, 1 H), 8.08 (d, J = 9.3 Hz, 1 H), 8.03 (s, 1 H), 7.63 - 7.54 (m, 1 H), 7.41 (s, 1 H), 7.28 - 7.21 (m, 2 H), 7.14 (dd, J = 14.5, 8.2 Hz, 5 H), 6.74 (dd, J = 15.5, 9.4 Hz, 2 H), 4.34 (d, J = 9.9 Hz, 1 H), 4.24 (dd, J = 17.7, 11.9Hz, 3 H), 4.02 (d, J = 13.4 Hz, 4 H), 3.83 (d, J = 13.2 Hz, 1 H), 3.58 (d, J = 10.4 Hz, 7 H), 3.16 (s, 1 H), 3.06 - 2.96 (m, 0 H), 2.85 - 2.58 (m, 6 H), 2.31 - 2.13 (m, 2 H), 2.05 - 1.89 (m, 2 H), 1.13 - 0.96 (m, 9 H), 0.94 (s, 3 H). EXAMPLE 169

[00947] ((2S)-1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((2S,3S)-2- hydroxy-4-(4-((6-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)phenyl)-3-((S)-4,4,4-trifluoro-3,3-dimethyl-2-(((oxetan -3-yloxy)carbonyl)amino)butanamido)butyl)hydrazinyl)-4,4,4-trifluoro- Oxetan-3-yl 3,3-dimethyl-1-oxobutan-2-yl)carbamate (169).

[00948] Intermediates: P4, A4, and S3. MS (ESI) m/z 1239.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.13 (d, J = 2.3 Hz, 1 H), 8.09 (d, J = 9.4 Hz, 1 H), 8.02 (d, J = 2.8 Hz, 1 H), 7.52 (dd, J = 8.9, 2.4 Hz, 1 H), 7.45 (t, J = 59.9 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 2 H), 7.21 (d, J = 7.9 Hz, 2 H), 7.12 (d, J = 7.9 Hz, 2 H), 6.85 (d, J = 2.8 Hz, 1 H), 6.61 (d, J = 9.0 Hz, 1 H), 5.29 (dp, J = 17.2, 5.7 Hz, 2 H), 4.76 - 4.73 (m, 4 H), 4.67 (t, J = 6.4 Hz, 2 H), 4.56 (ddd, J = 10.3, 7.3, 5.4 Hz, 2 H), 4.52 - 4.42 (m, 4 H), 4.32 (s, 1 H), 4.20 (s, 1 H), 4.11 - 4.00 (m, 2 H), 3.90 - 3.76 (m, 3 H), 3.77 - 3.60 (m, 2 H), 3.08 - 2.97 (m, 2 H), 2.89 - 2.75 (m, 3 H), 2.73 - 2.63 (m, 1 H), 1.90 - 1.81 (m, 2 H), 1.68 - 1.56 (m, 2 H), 1.09 (s, 3 H), 1.07 (s, 3 H), 1.03 (s, 3 H), 0.95 (s, 3 H). EXAMPLE 170

[00949] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (170).

[00950] Intermediates: P13, A3, and S3. MS (ESI) m/z 1146.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.29 (dd, J = 2.3, 0.8 Hz, 1 H), 8.18 (d, J = 9.2 Hz, 1 H), 7.70 (td, J = 4.9, 4.4, 2.3 Hz, 2 H), 7.39 - 7.27 (m, 4 H), 7.22 (d, J = 8.1 Hz, 2 H), 7.16 (d, J = 9.9 Hz, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.80 (d, J = 9.9 Hz, 1 H), 6.64 (d, J = 2.4 Hz, 1 H), 4.96 (dd, J = 8.2, 7.0 Hz, 2 H), 4.81 (dd, J = 8.3, 5.1 Hz, 2 H), 4.46 - 4.41(m, 1 H), 4.39 - 4.33 (m, 1 H), 4.31 (d, J = 10.0 Hz, 1 H), 4.19 - 4.07(m, 4 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.76 - 3.70 (m, 1 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.40 - 3.34 (m, 2 H), 2.95 - 2.70 (m, 4 H), 2.30 - 2.18 (m, 2 H), 2.12 - 2.01 (m, 2 H), 1.22 - 1.04 (m, 13 H), 1.02 (s, 3 H). EXAMPLE 171

[00951] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (171).

[00952] Intermediates: P4, A3, and S7. MS (ESI) m/z 1156.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 2 H), 8.08 (d, J = 9.4 Hz, 1 H), 8.01 (d, J = 2.8 Hz, 1 H), 7.44 (d, J = 59.8 Hz, 1 H), 7.35 (d, J = 8.2 Hz, 2 H), 7.25 (d, J = 7.9 Hz, 2 H), 7.14 (d, J = 8.1 Hz, 2 H), 7.03 (d, J = 9.9 Hz, 1 H), 6.84 (d, J = 2.7 Hz, 1 H), 6.71 (d, J = 9.9 Hz, 1 H), 4.87 (t, J = 7.6Hz, 2 H), 4.72 (dd, J = 8.2, 4.9 Hz, 2 H), 4.67 (s, 1 H), 4.42 - 4.29 (m, 1 H), 4.25 - 4.18 (m, 1 H), 4.11 - 3.98 (m, 4 H), 3.85 (d, J = 13.1 Hz, 1 H), 3.69 - 3.62 (m, 2 H), 3.59 (s, 3 H), 3.57 (s, 3 H), 3.41 - 3.28 (m, 2 H), 2.87 - 2.75 (m, 3 H), 2.68 (dd, J = 12.6, 9.1 Hz, 1 H), 2.18 - 2.06 (m, 2H), 1.95 - 1.83 (m, 2 H), 1.07 (s, 3 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 172

[00953] ((5S,8S,9S,14S)-8-(4-((2-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl) -11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)- 2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13- trioxo-5-(1,1,1-trifluoro-2-methylpropan-2- yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (172).

[00954] Intermediates: P4, A3, and S36. MS (ESI) m/z 1100.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.41 (s, 2 H), 8.08 (d, J = 9.2 Hz, 1 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.44 (d, J = 59.8 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 2 - 4.57 (m, 2 H), 4.35 (d, J = 9.6 Hz, 1 H), 4.26 - 4.17 (m, 1 H), 4.12 - 3.96 (m, 5 H), 3.85 (d, J = 13.2 Hz, 1 H), 3.69 - 3.62 (m, 2 H), 3.59 (s, 3 H), 3.57 (s, 3 H), 3.25 (s, 1 H), 2.87 - 2.61 (m, 4 H), 2.05 - 1.96 (m, 2 H), 1.90 - 1.82 (m, 2 H), 1.07 (s, 3 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.94 (s, 3H). EXAMPLE 173

[00955] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3, 6,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (173).

[00956] Intermediates: P4, A3, and S6. MS (ESI) m/z 1141.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.29 - 8.23 (m, 1 H), 8.17 (d, J = 9.4 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.69 (dd, J = 8.6, 2.1 Hz, 1 H), 7.53 (t, J = 59.7 Hz, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.1 Hz, 2 H), 7.13 (d, J = 9.8 Hz, 1 H), 6.94 (d, J = 2.7 Hz, 1 H), 6.80 (d, J = 10.2 Hz, 1 H), 6.71 - 6.63 (m, 1 H), 5.07 - 5.01 (m, 1 H), 4.72 - 4.68 ( m, 1 H), 4.64 - 4.54 (m, 2 H), 4.52 - 4.49 (m, 1 H), 4.47 - 4.41 (m, 1 H), 4.30 (d, J = 10.0 Hz, 1 H), 4.20 - 4.08 (m, 2 H), 3.94 (d, J = 13 .1 Hz, 1 H), 3.79 (d, J = 11.0 Hz, 1 H), 3.72 (d, J = 11.7 Hz, 1 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 2.93 - 2.82 (m, 3 H), 2.81 - 2.73 (m, 1 H), 2.33 (s, 2 H), 1, 16 (s, 3 H), 1.15 (s, 3 H), 1.11 (s, 3 H), 1.02 (s, 3 H). EXAMPLE 174

[00957] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-((1S,4S)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)ethynyl)benzyl)-3, 6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)- Methyl 2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate(174).

[00958] Intermediates: P4, A3, and S30. MS (ESI) m/z 1141.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.25 (dd, J = 2.2, 0.8 Hz, 1 H), 8.17 (d, J = 9.4 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.74 - 7.68 (m, 1 H), 7.53 (t, J = 59.6 Hz, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.1 Hz, 2 H), 7.13 (d, J = 9.9 Hz, 1 H), 6.94 (d, J = 2.8 Hz, 1 H), 6.80 (d, J = 9.9 Hz, 1 H), 6.71 - 6.61 (m, 1 H), 5.05 (s, 1 H), 4.99 - 4.93 (m, 1 H), 4.70 (dd, J = 8.4, 4.5 Hz, 1 H), 4.64 - 4.53 (m, 2 H), 4.51 (s, 1 H), 4.44 (d, J = 9.8 Hz, 1 H), 4.30 (d, J = 10.0 Hz, 1 H), 4.18 - 4.10 (m, 2 H), 3.94 (d, J = 13.1 Hz, 1 H), 3.79 (dd, J = 11.9, 2.2 Hz, 1 H), 3.76 - 3.70 (m, 1 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 2.94 - 2.73 (m, 4 H), 2.33 (s, 2 H), 1.16 (s, 3 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.02 (s, 3 H). EXAMPLE 175

[00959] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((6-(6-(oxetan-3-yl)- 3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- methyl 2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (175).

[00960] Intermediates: P28, A3, and S4. MS (ESI) m/z 1102.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.66 (d, J = 5.0 Hz, 1 H), 8.33 (d, J = 2.2 Hz, 1 H), 8.14 (d, J = 9.4 Hz, 1 H), 8.03 - 7.88 (m, 2 H), 7.74 (dd, J = 8.7, 2.3 Hz, 1 H), 7.60 (d, J = 8.5 Hz, 2 H), 7.46 (t, J = 6.1 Hz, 1 H), 7.34 (d, J = 7.8 Hz, 2 H), 7.23 (d, J = 7.9 Hz, 2 H), 7.11 (d, J = 9.4 Hz, 1 H), 6.78 (d, J = 8.8 Hz, 2 H), 4.97 (s, 3 H), 4.62 (dd, J = 8.1, 4.1 Hz, 2 H), 4.44 (d, J = 8.2 Hz, 1 H), 4.34 - 4.26 (m, 1 H), 4.26 - 4.07 (m, 4 H), 3.98 (d, J = 13.1 Hz, 2 H), 3.79 - 3.71 (m, 1 H), 3.70 (s, 3 H), 3.64 (s, 3 H), 2.99 - 2.85 (m, 3 H), 2.84 - 2.74 (m, 1 H), 2.11 (d, J = 11.2 Hz, 1 H), 1.16 (s, 3H), 1.15 (s, 3 H), 1.13 (s, 3 H), 1.03 (s, 3 H). EXAMPLE 176

[00961] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (176).

[00962] Intermediates: P4, A3, and S4. MS (ESI) m/z 1141.8 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.33 (d, J = 2.1 Hz, 1 H), 8.14 (d, J = 9.3 Hz, 1 H), 8.10 (d, J = 2.8 Hz, 1 H), 7.74 (dd, J = 8.8, 2.2 Hz, 1 H), 7.53 (t, J = 59.8 Hz, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 10.3 Hz, 1 H), 6.93 (d, J = 2.8 Hz, 1H), 6.78 (d, J = 8.8Hz, 2H), 5.07 - 4.91 (m, 3H), 4.61 (dd, J = 8.2, 4.1Hz, 2H), 4.44 (d, J = 9.9Hz, 1H), 4.31 (d, J = 10.0Hz, 1H), 4.23 - 4.06 (m, 3 H), 3.95 (d, J = 13.3 Hz, 1 H), 3.70 (s, 3 H), 3.66 (s, 3 H), 2.95 - 2.70 (m, 4 H), 2.10 (d, J = 11.1 Hz, 1 H), 1.16 (s, 3 H), 1.15 (s, 3 H), 1.12 (s, 3 H), 1.03 (s, 3 H). EXAMPLE 177

[00963] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((4-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (177).

[00964] Intermediates: P28, A3, and S3. MS (ESI) m/z 1115.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.69 - 8.60 (m, 1 H), 8.18 (d, J = 9.3 Hz, 1 H), 7.94 (q, J = 7.9 Hz, 2 H), 7.60 (d, J = 8.6 Hz, 2 H), 7.44 (t, J = 5.7 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 2 H), 7.31 (d, J = 7.9 Hz, 2 H), 7.21 (d, J = 8.1 Hz, 2 H), 7.17 (d, J = 10.7 Hz, 1 H), 6.96 (d, J = 8.8 Hz, 2 H), 6.79 (d, J = 10.0 Hz, 1 H), 5.01 - 4.92 (m, 3 H), 4.84 - 4.76 (m, 2 H), 4.44 (d, J = 9.9 Hz, 1 H), 4.31 (d, J = 10.0 Hz, 1 H), 4.23 - 4.10 (m, 4 H), 3.97 (d, J = 13.1 Hz, 1 H), 3.85 (d, J = 13.0 Hz, 2 H), 3.79 - 3.72 (m, 1 H), 3.69 (s, 3 H), 3.63 (s, 3 H), 2.93 - 2.84 (m, 3 H), 2.83 - 2.75 (m, 1 H), 2.21 (q, J = 11.1, 10.5 Hz, 4 H), 1.27 (d, J = 5.7 Hz, 1 H), 1.16 (s, 3 H), 1.14 (s, 3 H), 1.12 (s, 3 H), 1.03 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.39, -77.73, -77.85, - 114.65 . EXAMPLE 178

[00965] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)ethynyl)benzyl)-3,6,13-trioxo-5-(1 ,1,1-trifluoro-2-methylpropan-2- yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)methyl carbamate (178).

[00966] Intermediates: P4, A3, and S3. MS (ESI) m/z 1154.4 [M+H] +. 1H NMR (400MHz, Methanol-d4) δ 8.07 (d, J = 9.4Hz, 1H), 8.01 (d, J = 2.7Hz, 1H), 7.44 (t, 1H), 7.36 (d, J = 8.2Hz, 2H), 7.30 (d, J = 8.5Hz, 2H), 7.21 (d, J = 7.9 Hz, 2 H), 7.11 (d, J = 8.1 Hz, 2 H), 6.89 - 6.82 (m, 3 H), 4.86 (t, J = 7.5 Hz, 2 H), 4.72 - 4.64 (m, 2 H), 4.35 (d, J = 6.4 Hz, 1 H), 4.25 - 4.16 (m, 1 H), 4.11 - 3.95 (m, 3 H), 3.85 (d, J = 12.5 Hz, 1 H), 3.80 - 3.70 (m, 1 H), 3.68 - 3.62 (m, 1 H), 3.60 (s, 3 H), 3.57 (s, 3 H), 2.85 - 2.63 (m, 4 H), 2.18 - 1.99 (m, 4 H),1.22 - 1.18 (m, 2 H), 1.07 (s, 3 H), 1.05 (s, 3 H), 1.02 (s, 3 H), 0.93 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.40, -77.49, -77.73, -96.96 (dd, J = 60.0, 18.7 Hz), -114.92. EXAMPLE 179

[00967] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((6-(9-(oxetan-3-yl)-3- oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2- methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (179).

[00968] Intermediates: P28, A3, and S1. MS (ESI) m/z 1133.1[M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.66 (d, J = 4.8 Hz, 1 H), 8.21 - 8.10 (m, 2 H), 8.02 - 7.82 (m, 3 H), 7.60 (d, J = 8.6 Hz, 2 H), 7.46 (t, J = 6.3 Hz, 1 H), 7.36 (d, J = 7.9 Hz, 2 H), 7.25 (d, J = 8.1 Hz, 2 H), 7.19 (d, J = 9.4 Hz, 1 H), 4.82 - 4.76 (m, 2 H), 4.66 - 4.58 (m, 2 H), 4.51 - 4.41 (m, 1 H), 4.35 - 4.27 (m, 1 H), 4.23 - 4.13 (m, 2 H), 4.13 - 3.89 (m, 7 H), 3.78 - 3.72 (m, 2 H), 3.69 (s, 3 H), 3.68 - 3.65 (m, 3 H), 3.63 (s, 3 H), 3.18 - 3.08 (m, 2 H), 3.00 - 2.84 (m, 3 H), 2.84 - 2.74 (m, 1 H), 1.16 (s, 3 H), 1.15 (s, 3 H), 1.12 (s, 3 H), 1.03 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.37, -77.71, - 77.99, -114.58 . EXAMPLE 180

[00969] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4- ((6-(9-(oxetan-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl)ethynyl)benzyl)-3,6, 13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- methyl oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (180).

[00970] Intermediates: P4, A3, and S1. MS (ESI) m/z 1171.8 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.20 - 8.13 (m, 2 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.87 (d, J = 8.7 Hz, 1 H), 7.60 (t, J = 59.8 Hz, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 2 H), 7.24 (d, J = 8.1 Hz, 2 H), 7.15 (d, J = 9.5 Hz, 1 H), 6.93 (d, J = 2.7 Hz, 1 H), 4.80 -4.75 (m, 1 H), 4.74 - 4.67 (m, 1 H), 4.62 (t, J = 5.7 Hz, 2 H), 4.46 -4.40 (m, 1 H), 4.32 - 4.25 (m, 1 H), 4.21 - 4.00 (m, 6 H), 3.99 - 3.89 (m, 3 H), 3.78 - 3.71 (m, 1 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.12 (d, J= 4.9 Hz, 2 H), 2.98 - 2.72 (m, 4 H), 1.16 (s, 3 H), 1.14 (s, 3 H), 1.11(s, 3 H), 1.03 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.38, -77.71, -77.85, -96.97 (dd, J = 59.7, 19.1 Hz), -114.93. EXAMPLE 181

[00971] Synthesis of tert-butyl 2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazine-1-carboxylate (181a).

[00972] The title compound 181a was prepared according to the method presented for the synthesis of compound 1a, but using I2a and P4. MS (ESI) m/z 764.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.09 (d, J = 2.7 Hz, 1 H), 7.56 (d, J = 8.1 Hz, 2 H), 7.53 (t, J = 59.8 Hz, 1 H), 7.51 - 7.35 (m, 2 H), 7.02 (d, J = 8.0 Hz, 2 H), 6.93 (d, J = 2.7 Hz, 1 H), 4.03 (d, J = 26.8 Hz, 2 H), 3.70 (d, J = 8.2 Hz, 1 H), 3.57 (d, J = 9.0 Hz, 1 H), 2.79 (tdd, J = 20.0, 11.2, 6.9Hz, 2 H), 1.37 (s, 8 H), 1.31 (s, 7 H). 19F NMR (377 MHz, Methanol- d4) δ -96.90 (d, J = 59.8 Hz), -115.32

[00973] Synthesis of ((6S,11S,12S,15S)-9-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-17,17,17- trifluoro-11-hydroxy-12-(4- iodobenzyl)-2,2,16,16-tetramethyl-4,7,14-trioxo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-oxa-5,8,9 tert-butyl ,13-tetra-azaheptadecan-15-yl)carbamate (181b).

[00974] The title compound 181b was prepared according to the method presented for the synthesis of intermediate I2, but using 181a and A1. MS (ESI) m/z 1098.6 [M+H] +.

[00975] Synthesis of ((6S,11S,12S,15S)-9-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-17,17,17- trifluoro-11-hydroxy- 2,2,16,16-tetramethyl-12-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3- yl)ethynyl)benzyl)-4,7,14-trioxo- tert-Butyl 6-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-oxa-5,8,9,13-tetra-azheptadecan-15-yl)carbamate (181c)

[00976] The title compound 181c was prepared according to the method presented for the synthesis of compound 133 , but using 181b and S3. MS (ESI) m/z 1239.9 [M+H] +.

[00977] (2S)-N-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((S) -4,4,4- trifluoro-3,3-dimethyl-2-propionamidobutanoyl)hydrazinyl)-3-hydroxy-1-(4-((2-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)phenyl)butan-2-yl)-4,4,4-trifluoro-3,3-dimethyl-2-propionamidobutanamide (181).

[00978] To a solution of 181c (355 mg, 0.29 mmol) in DCM (10 mL) was added trifluoroacetic acid (2 mL), the mixture was stirred, and after 18 h, the reaction mixture was concentrated under reduced pressure, and the crude material was dissolved in DMF (3 mL) and HATU (35.28 mg, 0.16 mmol), N,N-diisopropylethylamine (0.13 mL, 0.74 mmol) was added, followed by propionic acid (0.01 mL, 0.16 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was purified by HPLC to afford 181. MS (ESI) m/z 1152.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (dd, J = 2.3, 0.7 Hz, 1 H), 8.11 (d, J = 2.7 Hz, 1 H), 7.74 - 7.37 (m, 4 H), 7.37 - 7.23 (m, 2 H), 7.23 - 7.12 (m, 2 H), 6.95 (d, J = 2.8 Hz, 1 H), 6.70 (dd, J = 9.1, 0.8 Hz, 1 H), 4.83 - 4.71 (m, 3 H), 4.66 (s, 1 H), 4.59 (dd, J = 6.3, 5.4 Hz, 3 H), 4.23 - 4.13 (m, 2 H), 4.00 - 3.84 (m, 4 H), 3.84 - 3.70 (m, 1 H), 3.13 (dd, J = 12.0, 2.2 Hz, 3 H), 2.95 - 2.71 (m, 4 H), 2.21 (ttd, J = 7.5, 5.0, 2.3 Hz, 4 H), 1.97 - 1.90 (m, 2 H), 1.70 (d, J = 7.8 Hz, 2 H), 1.18 (d, J = 9.3 Hz, 7 H), 1.16 - 1.00 (m, 13 H). EXAMPLE 182

[00979] (2S)-2-acetamido-N-((2S,3S)-4-(2-((S)-2-acetamido-4,4,4-trifluoro-3,3-dimethylbutanoyl)-1 -(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)- 2,6-difluorobenzyl)hydrazinyl)-3-hydroxy-1-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin -3-yl)ethynyl)phenyl)butan-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide (182).

[00980] The title compound 182 was prepared according to the method presented for the synthesis of compound 181 , but using Intermediates: P4, A1, S3 and acetic acid. MS (ESI) m/z 1123.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.18 (dd, J = 2.3, 0.7 Hz, 1 H), 8.09 (d, J = 2.7 Hz, 1 H), 7.72 - 7.35 (m, 4 H), 7.35 - 7.24 (m, 2 H), 7.20 - 7.11 (m, 2 H), 6.94 (d, J = 2.8 Hz, 1 H), 6.69 (dd, J = 9.0, 0.8 Hz, 1 H), 4.76 (dd, J = 12.8, 6.4 Hz, 3 H), 4.63 (d, J = 1.4 Hz, 1 H), 4.57 (dd, J = 6.3, 5.4Hz, 3 H), 4.15 (d, J = 13.4 Hz, 2 H), 3.98 - 3.65 (m, 5 H), 3.11 (dd, J = 12.0, 2.2 Hz, 3 H), 2.98 - 2.67 (m, 4 H), 2.13 (d, J = 10.3 Hz, 0 H), 1.98 - 1.83 (m, 9 H), 1.68 (d, J = 7.8 Hz, 2 H), 1.17 (d, J = 6.2 Hz, 6 H), 1.12 (s, 3 H), 1.04 (s, 3 H), 0.88 (d, J = 6.7 Hz, 0 H). EXAMPLE 183

[00981] Synthesis of ((S)-1-(2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)-2-( 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-3,3- (9H-fluoren-9-yl)methyl dimethyl-1-oxobutan-2-yl)carbamate (183a).

[00982] The title compound 183a was prepared according to the method presented for the synthesis of compound 133a , but using I4 and P4. MS (ESI) m/z 999.3 [M+H] +.

[00983] Synthesis of ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-8- (4-iodobenzyl)-15,15- dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14- (9H-fluoren-9-yl)methyl yl)carbamate (183b).

[00984] The title compound 183b was prepared according to the method presented for the synthesis of compound 133b , but using 4a and A3. MS (ESI) m/z 1124.6 [M+H] +.

[00985] Synthesis of ((2S)-1-(((2S,3S)-4-(2-((S)-2-amino-3,3-dimethylbutanoyl)-1-(4-(1-( difluoromethyl)-1H-pyrazol-3-yl)-2,6- difluorobenzyl)hydrazinyl)-3-hydroxy-1-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl )ethynyl)phenyl)butan-2-yl)amino)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate demethyl (183c).

[00986] The title compound 183c was prepared according to the method presented for the synthesis of compound 133 , but using 183b and S3. MS (ESI) m/z 1043.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.29 (dd, J = 2.3, 0.7 Hz, 1 H), 8.14 - 8.07 (m, 2 H), 7.75 - 7.65 (m, 1 H), 7.53 (d, J = 59.8 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.25 - 7.18 (m, 2 H), 6.94 (d, J = 2.8 Hz, 1 H), 6.86 (dd, J = 9.0, 0.9 Hz, 1 H), 6.78 (d, J = 9.9 Hz, 1 H), 4.99 - 4.93 (m, 3 H), 4.84 (d, J = 5.2 Hz, 1 H), 4.82 (d, J = 5.0 Hz, 1 H), 4.54 (s, 1 H), 4.42 - 4.30 (m, 3 H), 4.26 - 4.06 (m, 5 H), 3.81 (t, J = 6.6 Hz, 1 H), 3.65 (s, 1 H), 3.45 - 3.36 (m, 3 H), 2.97 - 2.76 (m, 4 H), 2.28 - 2.19 (m, 2 H), 2.11 - 2.03 (m, 2 H), 1.09 (s, 3 H), 1.06 (s, 3 H), 0.97 (s, 9 H).

[00987] Synthesis of ((2S)-1-(((2S,3S)-4-(2-((S)-2-(cyclopropanecarboxamido)-3,3-dimethylbutanoyl)-1-(4-(1 -(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-3- hydroxy-1-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)phenyl)butan- Methyl 2-yl)amino)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate (183).

[00988] To a solution of 183c (45 mg, 0.33 mmol) in DCM (1 mL) was added Et3N (0.03 mL, 0.23 mmol) at 5 °C, cyclopropanecarbonyl chloride (3.54 μL, 0.39 mmol) was added, and the mixture was stirred for 10 min, then diluted with MeOH, concentrated under reduced pressure, and the residue was purified by HPLC to afford 183. MS (ESI) m/z 1111.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.35 - 8.26 (m, 1 H), 8.18 (d, J = 9.4 Hz, 1 H), 8.11 (d, J = 2.7 Hz, 1 H), 7.91 (d, J = 8.9 Hz, 1 H), 7.71 (dd, J = 8.8, 2.3 Hz, 1 H), 7.53 (t, J = 59.7 Hz, 1 H), 7.46 (d, J = 8.3 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.1 Hz, 2 H), 6.94 (d, J = 2.8 Hz, 1 H), 6.87 (d, J = 8.9 Hz, 1 H), 6.78 (d, J = 9.9 Hz, 1 H), 5.03 - 4.94 (m, 2 H), 4.84 - 4.77 (m, 3 H), 4.44 (d, J = 9.9 Hz, 1 H), 4.41 - 4.31 (m, 1 H), 4.21 - 4.06 (m, 5 H), 3.96 (d, J = 13.1 Hz, 1 H), 3.81 - 3.72 (m, 1 H), 3.70 (s, 3 H), 3.39 (s, 1 H), 2.91 (d, J = 7.7 Hz, 2 H), 2.88 - 2.73 (m, 2 H), 2.29 - 2.19 (m, 2 H), 2.15 - 2.04 (m, 2 H), 1.74 - 1.67 (m, 1 H), 1.31 (t, J = 7.5 Hz, 1 H), 1.14 (s, 3 H), 1.10 (s, 3 H), 0.89 (s, 9 H), 0.75 (dd, J = 8.2, 3.6Hz, 2H). EXAMPLE 184

[00989] ((2S)-1-(((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-(( S)-3,3-dimethyl-2-(((oxetan-3-yloxy)carbonyl)amino)butanoyl)hydrazinyl)-3-hydroxy-1-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)phenyl)butan-2-yl)amino)-4,4,4-trifluoro Methyl -3,3-dimethyl-1-oxobutan-2-yl)carbamate.

[00990] Intermediates: P4, A3, S3 and 4-nitrophenyl oxetan-3-yl carbonate. MS (ESI) m/z 1143.6 [M+H] +. 1H NMR (400 MHz, Methanol- d4) δ 8.25 - 8.19 (m, 1 H), 8.09 (d, J = 9.3 Hz, 1 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.65 - 7.59 (m, 1 H), 7.44 (t, J = 59.7 Hz, 1 H), 7.36 (d, J = 8.1 Hz, 2 H), 7.23 (d, J = 7.9 Hz, 3 H), 7.13 (d, J = 8.0 Hz , 3 H), 6.85 (d, J = 2.7 Hz, 1 H), 6.77 (d, J = 8.9 Hz, 1 H), 6.71 (d, J = 9.6 Hz, 1 H), 4.87 (t, J = 7.6 Hz, 3 H), 4.76 - 4.68 (m, 2 H), 4.51 (dt, J = 23.0, 6 .4 Hz, 2 H), 4.31 - 4.22 (m, 2 H), 4.12 - 3.99 (m, 5 H), 3.87 (d, J = 13.1 Hz, 1 H), 3.70 - 3.62 (m, 2 H), 3.59 (s, 3 H), 3.30 (s, 1 H), 2, 89 - 2.60 (m, 5 H), 2.18 - 2.10 (m, 2 H), 2.03 - 1.95 (m, 2 H), 1.24 - 1.17 (m, 2 H), 1.05 (s, 3 H), 1.01 (s, 3 H), 0.78 (s, 9 H). EXAMPLE 185

[00991] ((2S)-1-(((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-(( S)-3,3-dimethyl-2-propionamidobutanoyl)hydrazinyl)-3-hydroxy-1-(4-((6-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)phenyl)butan-2-yl)amino)-4,4,4-trifluoro-3,3-dimethyl-1 -oxobutan-2-yl)demethyl carbamate.

[00992] Intermediates: P4, A3, S3 and propionyl chloride MS (ESI) m/z 1099.6 M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.22 - 8.18 (m, 1 H), 8.08 (d, J = 9.2 Hz, 1 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.61 (dd, J = 8.9, 2.3 Hz, 1 H), 7.56 (d, J = 9.2 Hz, 1 H), 7.43 (d, J = 59.9 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.12 (d, J = 8.1 Hz, 2 H), 6.84 (d, J = 2.8 Hz, 1 H), 6.77 (d, J = 8.9 Hz, 1 H), 6.69 (d, J = 9.9 Hz, 1 H), 4.87 (dd, J = 8.1, 6.9 Hz, 2 H), 4.73 - 4.69 (m, 2 H), 4.36 - 4.31 (m, 1 H), 4.30 - 4.19 (m, 3 H), 4.09 - 4.02 (m, 4 H), 4.01 - 3.96 (m, 1 H), 3.86 (d, J = 13.2 Hz, 1 H), 3.68 - 3.62 (m, 1 H), 3.59 (s, 3 H), 3.31 - 3.24 (m, 2 H), 2.84 - 2.64 (m, 3H), 2.18 - 2.07 (m, 2 H), 2.03 - 1.94 (m, 2 H), 1.04 (s, 3 H), 1.03 - 0.97 (m, 6 H), 0.77 (s, 9 H). EXAMPLE 186

[00993] ((2S)-1-(((2S,3S)-4-(2-((S)-2-(cyclopropanecarboxamido)-4,4,4-trifluoro-3,3-dimethylbutanoyl)-1 -(4-(1-(difluoromethyl)-1H- pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-3-hydroxy-1-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1] octan-3-yl)pyrimidin-5-yl)ethynyl)phenyl)butan-2-yl)amino)-4,4,4-trifluoro-3,3-dimethyl-1- methyl oxobutan-2-yl)carbamate (186).

[00994] Intermediates: P4, A3, S7 and cyclopropanecarboxylic acid. MS (ESI) m/z 1167.0 M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 2 H), 8.22 (d, J = 9.6 Hz, 1 H), 8.14 (d, J = 9.4 Hz, 1 H), 8.09 (d, J = 2.7 Hz, 1 H), 7.52 (t, J = 59.9 Hz, 1 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 6.92 (d, J = 2.8 Hz, 1 H), 6.75 (d, J = 9.9 Hz, 1 H), 4.96 (t, J = 7.6Hz, 2 H), 4.82 - 4.77 (m, 2 H), 4.75 (s, 1 H), 4.65 (d, J = 9.7 Hz, 1 H), 4.43 (d, J = 9.9 Hz, 1 H), 4.23 - 4.07 (m, 4 H), 3.92 (d, J = 13.0 Hz, 1 H), 3.74 (d, J = 8.6 Hz, 1 H), 3.69 (s, 3 H), 3.45 (d, J = 14.5 Hz, 2 H), 2.97 - 2.82 (m, 3 H), 2.81 - 2.69 (m, 1 H), 2.27 - 2.10 (m, 2 H), 2.03 - 1.89 (m, 2H), 1.74 - 1.63 (m, 1 H), 1.19 (s, 3 H), 1.13 (s, 3 H), 1.10 (s, 3 H), 1.06 (s, 3 H), 0.97 - 0.88 (m, 1 H), 0.87 - 0.70 (m, 3 H).EXAMPLE 187

[00995] Synthesis of ((S)-1-(2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)-2-( 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-3,3- cyclopropyl dimethyl-1-oxobutan-2-yl)carbamate (187a).

[00996] The title compound 187a was prepared according to the method presented for the synthesis of compound 133a , but using I5 and P4. MS (ESI) m/z 861.1 [M+H] +.

[00997] Synthesis of ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-8- (4-iodobenzyl)-15,15- dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14- il)cyclopropyl carbamate(187b).

[00998] The title compound 187b was prepared according to the method presented for the synthesis of compound 133b , but using 5a. MS (ESI) m/z 986.5 [M+H] +.

[00999] Synthesis of ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15, 15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate cyclopropyl (187).

[001000] The title compound 187 was prepared according to the method presented for the synthesis of compound 133 , but using 187b and S3. MS (ESI) m/z 1127.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.33 - 8.25 (m, 1 H), 8.18 (d, J = 9.3 Hz, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 7.74 - 7.66 (m, 1 H), 7.53 (d, J = 59.7 Hz, 1 H), 7.46 (d, J = 8.3 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.1 Hz, 2 H), 6.93 (d, J = 2.7 Hz, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.80 (d, J = 9.9 Hz, 1 H), 4.96 (t, J = 7.5 Hz, 2 H), 4.81 (dd, J = 8.2, 5.2 Hz, 2 H), 4.44 (d, J = 10.0 Hz, 1 H), 4.35 (d, J = 13.6 Hz, 2 H), 4.23 - 4.06 (m, 4 H), 4.03 - 3.92 (m, 2 H), 3.82 - 3.74 (m, 1 H), 3.69 (s, 3 H), 3.40 - 3.33 (m, 2 H), 2.97 - 2.73 (m, 3 H), 2.31 - 2.18 (m, 2 H), 2.11 - 2.04 (m, 2 H), 1.16 - 1.12 (m, 3 H), 1.10 (s, 3 H), 0.85 (s, 9 H), 0.68 - 0.58 (m, 4 H).EXAMPLE 188

[001001] Synthesis of ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16, 16,16-trifluoro-9-hydroxy-15,15- dimethyl-8-(4-(6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)benzyl )-3,6,13-trioxo-5- Methyl (1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (188).

[001002] A suspension of S6a (59.8 mg, 0.167 mmol), bis(neopentylglycolate)diboron (38 mg, 0.168 mmol), potassium propionate (44.5 mg, 0.397 mmol), and Pd(PPh3)2Cl2 (2.8 mg, 0.004 mmol) in 2-MeTHF (1 mL) was degassed with argon for 15 min, then heated at 90 °C overnight. Cooled to room temperature, then 1 M potassium phosphate in H2O (0.39 mL) was added and degassed for 5 min. Added Pd(tBu2PPh)2Cl2 (4.5 mg, 0.007 mmol) and 1a (100 mg, 0.1 mmol) in 2-MeTHF (1 mL) and degassed for an additional 5 min. Heated to 65 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with brine. The separated organic layer was dried over Na2SO4 and concentrated in vacuo, the residue was purified by HPLC and the product was lyophilized to afford 188. MS (ESI) m/z 1131.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.19 (s, 1 H), 8.10 (d, J = 9.3 Hz, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.64 (d, J = 2.5 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 7.9 Hz, 2 H), 7.05 (d, J = 9.9 Hz, 1 H), 6.82 (d, J = 9.0 Hz, 1 H), 6.76 (d, J = 9.8 Hz, 1 H), 6.65 (d, J = 2.5 Hz, 1 H), 6.32 - 5.96 (m, 1 H), 4.96 (s, 1 H), 4.61 (dd, J = 8.2, 4.7 Hz, 1 H), 4.58 - 4.49 (m, 3 H), 4.45 (dd, J = 14.2, 4.8 Hz, 1 H), 4.37 (s, 1 H), 4.21 (d, J = 9.9 Hz, 1 H), 4.04 (d, J = 13.0 Hz, 2 H), 3.84 (d, J = 13.2 Hz, 1 H), 3.74 (d, J = 11.9 Hz, 1 H), 3.67 (d, J = 11.5 Hz, 2 H), 3.54 (s, 4 H), 3.47 (s, 3 H), 2.92 - 2.73 (m, 4 H), 2.73 - 2.62 (m, 1 H), 2.24 (s, 2 H), 1.05 (d, J = 4.5 Hz, 7 H), 1.01 (s, 3 H), 0.92 (s, 3 H). EXAMPLE 189

[001003] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4-(2- (8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1 ,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (189).

[001004] Intermediates: I2, P1 and S7a. MS (ESI) m/z 1132.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (s, 2 H), 8.19 (d, J = 7.9 Hz, 2 H), 8.02 (s, 1 H), 7.59 (t, J = 60.2 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 2 H), 7.17 (d, J = 10.0 Hz, 1 H), 6.88 (d, J = 9.9 Hz, 0 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.83 (dd, J = 8.3, 5.3 Hz, 2 H), 4.47 (d, J = 7.2 Hz, 2 H), 4.39 - 4.23 (m, 1 H), 4.13 (d, J = 13.3 Hz, 5 H), 3.93 (d, J = 13.3 Hz, 1 H),3.75 (s, 1 H), 3.65 (s, 3 H), 3.56 (s, 3 H), 3.47 (d, J = 14.5 Hz, 2 H),3.03 - 2.73 (m, 4 H), 2.29 - 2.11 (m, 2 H), 2.01 (d, J = 9.1 Hz, 2 H), 1.14 (d, J = 5.2 Hz, 6 H), 1.10 (s, 3 H), 1.02 (s, 3 H). EXAMPLE 190

[001005] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15- dimethyl-8-(4-(2-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2- yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (190).

[001006] Intermediates: I3, P1 and S7a. MS (ESI) m/z 1079.3 [M+H] +.1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 2 H), 8.20 - 8.03 (m, 2 H),7.92 (d, J = 1.3 Hz, 1 H), 7.49 (t, J = 59.9 Hz, 1 H), 7.31 (dd, J = 9.9,8.2 Hz, 4 H), 7.22 (d, J = 7.8 Hz, 2 H), 6.79 (d, J = 10.0 Hz, 0 H), 4.87(t, J = 7.6 Hz, 2 H), 4.75 - 4.63 (m, 2 H), 4.54 - 4.34 (m, 1 H), 4.11 -3.95 (m, 3 H), 3.86 (d, J = 13.2 Hz, 1 H), 3.66 (s, 1 H), 3.54 (s, 3 H),3.47 (s, 2 H), 3.37 (d, J = 14.4 Hz, 2 H), 2.83 (t, J = 8.0 Hz, 2 H), 2.71(d, J = 8.8 Hz, 2 H), 2.20 - 2.07 (m, 2 H), 1.92 (d, J = 8.9 Hz, 2 H), 1.04(s, 3 H), 1.00 (s, 3 H), 0.75 (s, 8 H). EXAMPLE 191

[001007] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16, 16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(2- ((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa- 4,7,11,12-tetra-aza-hexadecan-14-yl)methyl carbamate. (191)

[001008] Intermediates: I2, P10 and S6a. MS (ESI) m/z 1132.8 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.64 (s, 2 H), 8.14 (d, J = 9.4 Hz, 1 H), 7.87 (d, J = 8.6 Hz, 0 H), 7.73 (d, J = 2.4 Hz, 1 H), 7.55 (dt, J = 15.4, 7.4 Hz, 1 H), 7.50 - 7.21 (m, 6 H), 7.09 (d, J = 9.9 Hz, 1 H), 6.83 (d, J = 9.8 Hz, 1 H), 6.73 (d, J = 2.4 Hz, 1 H), 6.21 (tt, J = 55.3, 3.9 Hz, 1 H), 5.18 (s, 1 H), 5.02 - 4.89 (m, 2 H), 4.73 (d, J = 5.1 Hz, 1 H), 4.59 (td, J = 14.1, 13.7, 6.4 Hz, 3 H), 4.52 (s, 1 H), 4.46 (d, J = 9.7 Hz, 1 H), 4.30 (d, J = 9.9 Hz, 1 H), 4.13 (d, J = 13.1 Hz, 2 H), 3.99 - 3.87 (m, 2 H), 3.87 - 3.69 (m, 3 H), 3.64 (s, 3 H), 3.57 (s, 2 H), 2.97 - 2.84 (m, 3 H), 2.84 - 2.73 (m, 1 H), 2.34 (s, 2 H), 1.44 (d, J = 16.1 Hz, 1 H), 1.29 (s, 2 H), 1.26 (s, 2 H), 1.14 (d, J = 4.9 Hz, 6 H), 1.10 (s, 3 H), 1.02 (s, 3 H). EXAMPLE 192

[001009] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15- dimethyl-8-(4-(2-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2- yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (192).

[001010] Intermediates: I3, P4 and S7a. MS (ESI) m/z 1078.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (s, 3 H), 8.14 (d, J = 9.1 Hz, 1 H), 8.09 (d, J = 2.8 Hz, 2 H), 7.52 (t, J = 59.8 Hz, 2 H), 7.43 (dd, J = 12.4, 8.0 Hz, 6 H), 7.31 (d, J = 7.8 Hz, 3 H), 6.92 (d, J = 2.8 Hz, 2 H), 6.83 (d, J = 9.8 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 3 H), 4.46 (d, J = 9.6 Hz, 2H), 4.13 (d, J = 2.81 (d, J = 10.7 Hz, 3 H), 2.21 (d, J = 11.4 Hz, 3 H), 2.01 (d, J = 9.0 Hz, 3 H), 1.27 (d, J = 13.9 Hz, 1 H), 1.13 (s, 6 H), 1.10 (s, 5 H), 0.84 (s, 14 H). EXAMPLE 193

[001011] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy- 15,15-dimethyl-8-(4-(2-(8-(oxetan-3-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2- yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (193).

[001012] Intermediates: I3, P10 and S7a. MS (ESI) m/z 1092.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (s, 2 H), 8.14 (d, J = 9.2 Hz, 1 H), 7.72 (d, J = 2.4 Hz, 1 H), 7.39 (dd, J = 17.0, 8.2 Hz, 4 H), 7.31 (d, J = 7.8 Hz, 2 H), 6.83 (d, J = 9.8 Hz, 1 H), 6.73 (d, J = 2.4 Hz, 1 H), 6.21 (tt, J = 55.4, 3.9 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.76 (s, 1 H), 4.59 (td, J = 14.3, 4.0 Hz, 2 H), 4.49 - 4.41 (m, 1 H), 4.12 (d, J = 20.4 Hz, 4 H), 3.96 (d, J = 13.1 Hz, 1 H), 3.76 (s, 2 H), 3.62 (s, 3 H), 3.56 (s, 3 H), 3.47 (d, J = 14.5 Hz, 2 H), 2.92 (t, J = 8.4 Hz, 2 H), 2.80 (d, J = 9.5 Hz, 2 H), 2.26 - 2.10 (m, 2 H), 2.01 (d, J = 9.2 Hz, 2 H), 1.13 (s, 3 H), 1.09 (s, 3 H), 0.85 (s, 9 H). EXAMPLE 194

[001013] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-(6- ((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa- Methyl 4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (194).

[001014] Intermediates: I2, P13 and S6a. MS (ESI) m/z 1092.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1 H), 8.10 (d, J = 9.2 Hz, 1 H), 7.87 (d, J = 9.0 Hz, 1 H), 7.60 (d, J = 2.4 Hz, 1 H), 7.32 (d, J = 7.9 Hz, 2 H), 7.23 (dd, J = 14.4, 8.2 Hz, 4 H), 6.76 (d, J = 9.4 Hz, 2 H), 6.54 (d, J = 2.4 Hz, 1 H), 4.93 (s, 1 H), 4.61 - 4.53 (m, 1 H), 4.52 - 4.46 (m, 1 H), 4.45 - 4.27 (m, 2 H), 4.21 (d, J = 9.9 Hz, 1 H), 4.03 (d, J = 13.0 Hz, 2 H), 3.83 (d, J = 13.0 Hz, 1 H), 3.72 (d, J = 9.6 Hz, 1 H), 3.66 - 3.56 (m, 1 H), 3.55 (s, 3 H), 3.46 (s, 3 H), 2.82 (d, J = 7.2 Hz, 0 H), 2.70 (d, J = 9.8 Hz, 1 H), 2.22 (s, 2 H), 1.05 (d, J = 5.1 Hz, 8 H), 0.98 (d, J = 16.3 Hz, 3H), 0.92 (s, 2 H). EXAMPLE 195

[001015] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16, 16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6- (8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)- 3,6,13-trioxo-5-(1,1 methyl,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (195).

[001016] Intermediates: I2, P10 and S3c. MS (ESI) m/z 1146.1 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.29 (s, 1 H), 8.07 (d, J = 9.3 Hz, 1 H), 7.83 (d, J = 9.0 Hz, 1 H), 7.64 (d, J = 2.4 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 2 H), 7.28 (d, J = 8.4 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 2 H), 7.02 (d, J = 9.8 Hz, 1 H), 6.89 (d, J = 8.9 Hz, 1 H), 6.74 (d, J = 9.8 Hz, 1 H), 6.64 (d, J = 2.5Hz, 1 H) 4.26 - 4.09 (m, 3 H), 4.03 (d, J = 8.7 Hz, 4 H), 3.84 (d, J = 13.2 Hz, 1 H), 3.67 (s, 1 H), 3.54 (s, 3 H), 3.46 (s, 2 H), 3.32 (s, 1 H), 3.29 (d, J = 1.7 Hz, 1 H), 2.91 - 2.73 (m, 2 H), 2.70 (d, J = 9.4 Hz, 1 H), 2.14 (t, J = 6.4 Hz, 2 H), 2.01 (d, J = 8.5 Hz, 2 H), 1.05 (d, J = 3.7 Hz, 6 H), 1.01 (s, 3 H), 0.92 (s, 2 H). EXAMPLE 196

[001017] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4-(6- ((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo- 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa- Methyl 4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate (196).

[001018] Intermediates: I2, P4 and S6a. MS (ESI) m/z 1117.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1 H), 8.07 (d, J = 9.2 Hz, 1 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.88 (d, J = 8.9 Hz, 1 H), 7.44 (t, J = 59.8 Hz, 1 H), 7.34 (dd, J = 11.9, 8.1 Hz, 3 H), 7.21 (d, J = 7.9 Hz, 2 H), 7.02 (d, J = 10.0 Hz, 1 H), 6.84 (d, J = 2.7 Hz, 1 H), 6.75 (t, J = 10.2 Hz, 1 H), 5.01 - 4.89 (m, 1 H), 4.59 (dd, J = 8.3, 4.8 Hz, 1 H), 4.51 (dd,J = 8.0, 5.0 Hz, 1 H), 4.37 (dd, J = 19.9, 10.1 Hz, 3 H), 4.20 (d, J = 10.0Hz, 1 H), 4.06 (d, J = 13.2 Hz, 2 H), 3.85 (d, J = 13.2 Hz, 1 H), 3.81 - 3.61 (m, 2 H), 3.56 (d, J = 4.6 Hz, 3 H), 3.53 - 3.43 (m, 2 H), 2.82 (d, J = 9.0 Hz, 2H), 2.75 - 2.61 (m, 1 H), 2.22 (s, 2 H), 1.05 (s, 6 H), 1.01 (s,3 H), 0.92 (s,3 H). EXAMPLE 197

[001019] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16, 16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(2- (8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1 ,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (197).

[001020] Intermediates: I2, P10 and S7a. MS (ESI) m/z 1146.4 [M+H] 1H NMR (400 MHz, Methanol-d4) δ 8.65 (s, 2 H), 8.15 (d, J = 9.4 Hz, 1 H), 7.73 (d, J = 2.4 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 7.9 Hz, 2 H), 7.10 (d, J = 9.9 Hz, 1 H), 6.84 (d, J = 9.7 Hz, 1 H), 6.73 (d, J = 2.4 Hz, 1 H), 6.21 (tt, J = 55.3, 4.0 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.84 - 4.73 (m, 4 H), 4.60 (td, J = 14.3, 3.9 Hz, 2 H), 4.49 - 4.42 (m, 1 H), 4.33 - 4.26 (m, 1 H), 4.21 - 4.08 (m, 4 H), 3.94 (d, J = 13.2 Hz, 1 H), 3.81 - 3.71 (m, 1 H), 3.63 (s, 3 H), 3.56 (s, 3 H), 3.47 (d, J = 14.4 Hz, 2 H), 2.99 - 2.74 (m, 4 H), 2.28 - 2.12 (m, 2 H), 2.05 - 1.91 (m, 2 H), 1.15 (s, 3 H), 1.14 (s, 3 H), 1.10 (s, 3 H), 1.02 (s, 3 H). 19F NMR (376 MHz, Methanol-d4) δ -77.37, -77.69, -77.80, -115.42, -125.27 (dt, J = 55.2, 14.3 Hz). EXAMPLE 198

[001021] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-(2-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)- 3,6,13-trioxo-5-(1,1,1- methyl trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)methyl carbamate (198).

[001022] Intermediates: I2, P13 and S7a. MS (ESI) m/z 1122.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 2 H), 8.07 (d, J = 9.3 Hz, 1 H), 7.60 (d, J = 2.4 Hz, 1 H), 7.32 (d, J = 7.9 Hz, 2 H), 7.28 - 7.16 (m, 4H), 7.03 (d, J = 10.0 Hz, 1 H), 6.75 (d, J = 9.8 Hz, 1 H), 6.54 (d, J = 2.4Hz, 1 H), 4.87 (t, J = 7.6 Hz, 2 H), 4.76 - 4.70 (m, 2 H), 4.67 (s, 1 H), 4.37 (d, J = 9.9 Hz, 1 H), 4.21 (d, J = 10.0 Hz, 1 H), 4.12 - 3.99 (m, 4H), 3.84 (d, J = 13.2 Hz, 1 H), 3.66 (s, 1 H), 3.60 (tt, J = 7.3, 3.9 Hz, 1H), 3.55 (s, 3 H), 3.47 (s, 3 H), 3.38 (d, J = 14.3 Hz, 2 H), 2.89 - 2.62 (m, 4 H), 2.18 - 2.06 (m, 2 H), 1.96 - 1.85 (m, 2 H), 1.12 - 0.93 (m, 13 H), 0.93 (s, 3H). EXAMPLE 199

[001023] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4-(2- (8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1 ,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (199).

[001024] Intermediates: I2, P4 and S7a. MS (ESI) m/z 1132.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 2 H), 8.08 (d, J = 9.4 Hz, 1 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.44 (t, J = 59.9, 59.5 Hz, 1 H), 7.35 (d, J = 8.4 4.87 (t, J = 7.6 Hz, 2 H), 4.72 (dd, J = 8.3, 5.0 Hz, 2 H), 4.69 (s, 2 H), 4.37 (d, J = 9.8 Hz, 1 H), 4.20 (d, J = 10.0 Hz, 1 H), 4.12 - 3.96 (m, 4 H), 3.85 (d, J = 13.1 Hz, 1 H), 3.67 (s, 1 H), 3.55 (s, 3 H), 3.47 (s, 3 H), 3.37 (d, J = 14.3 Hz, 2 H), 2.87 - 2.75 (m, 3 H), 2.75 - 2.66 (m, 1 H), 1.92 (d, J = 9.2Hz, 2H), 1.05 (s, 6 H), 1.01 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 200

[001025] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4-(6- (8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1,5-naphthyridin-2-yl)benzyl)-3,6,13-trioxo-5 -(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa- 4,7,11,12-tetra-aza-hexadecan-14-yl)methyl carbamate (200).

[001026] Intermediates: I2, P4 and S31b. MS (ESI) m/z 1182.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.22 - 8.04 (m, 3 H), 8.01 (d, J = 2.7 Hz, 2 H), 7.85 (d, J = 7.9 Hz, 2 H), 7.44 (t, J = 59.7 Hz, 1 H), 7.41 (d, J = 9.5 Hz, 1H), 7.36 (d, J = 8.2Hz, 2H), 7.30 (d, J = 8.5Hz, 2H),6.84 (d, J = 2.8Hz, 1H), 4.89 (t, J = 7.6Hz, 2H), 4.74 (dd, J = 8.2, 5.1Hz, 2H), 4.53 (d, J = 14.1 Hz, 2 H), 4.37 (s, 1 H), 4.21 (s, 1 H), 4.16 - 4.01 (m, 4 H), 3.86 (d, J = 13.1 Hz, 1 H), 3.71 (s, 1 H), 3.54 (s, 3 H), 3.44 (d, J = 13.8 Hz, 2 H), 3.41 - 3.33 (m, 3 H), 2.95 - 2.63 (m, 5 H), 2.22 - 2.10 (m, 2 H), 2.11 - 1.96 (m, 2 H), 1.25 - 1.16 (m, 1 H), 1.05 (s, 6 H), 1.02 (s, 3 H), 0.93 (s, 3 H). EXAMPLE 201

[001027] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2 -oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (201).

[001028] Intermediates: I2, P16 and S7a. MS (ESI) m/z 1094.8 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.86 (d, J = 4.9 Hz, 1 H), 8.65 (s, 1 H), 8.14 (d, J = 9.4 Hz, 0 H), 7.96 (d, J = 8.6 Hz, 1 H), 7.48 - 7.37 (m, 2H), 7.32 (d, J = 7.9 Hz, 1 H), 7.08 (d, J = 10.0 Hz, 0 H), 6.83 (d, J = 9.9 Hz, 0 H), 4.96 (t, J = 7.6 Hz, 1 H), 4.83 (s, 8 H), 4.53 - 4.41 (m, 0 H), 4.37 - 4.25 (m, 1 H), 4.23 - 4.07 (m, 2 H), 3.98 (d, J = 13.1 Hz, 1 H), 3.78 (s, 0 H), 3.65 (s, 2 H), 3.56 (s, 1 H), 3.52 - 3.39 (m, 1 H), 3.00 -2.75 (m, 2 H), 2.26 - 2.14 (m, 1 H), 2.02 (t, J = 7.0 Hz, 1 H), 1.12 (d, J =13.2 Hz, 5 H), 1.02 (s, 1 H).EXAMPLE 202

[001029] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-8-(4-iodobenzyl)- 15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza- methyl hexadecan-14-yl)carbamate(202a).

[001030] The title compound 202a was prepared according to the method presented for the synthesis of compound 1a, but using P4. MS (ESI) m/z 1014.4 [M+H] +.

[001031] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4-(6- (6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)benzyl)- 3,6,13-trioxo-5-(1,1 ,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate methyl (202).

[001032] In a 20 mL vial, a solution of 202a (50 mg, 0.05 mmol), S53 (38.1 mg, 0.08 mmol), XPhos Pd G2 (16.4 mg, 0.01 mmol), 2-(Dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (5.6 mg, 0.01 mmol), and Potassium phosphate tribasic (106 mg, 0.5 mmol) in dioxane (3 mL) and water (1 mL) was degassed for 10 min with argon. The mixture was heated at 100 °C for 1 h. The reaction was cooled to room temperature, diluted with MeOH, filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by HPLC, and the product was lyophilized to afford 202 MS (ESI) m/z1117.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.31 (s, 1 H), 8.11(d, J = 9.3 Hz, 1 H), 8.02 (d, J = 2.7 Hz, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.44 (t, J = 59.8 Hz, 1 H), 7.35 (dd, J = 8.1, 3.9 Hz, 4 H), 7.22 (d, J =7.9 Hz, 2 H), 7.05 (d, J = 10.0 Hz, 1 H), 6.90 - 6.80 (m, 2 H), 6.78 (d, J = 9.8 Hz, 0 H), 4.88 (t, J = 7.3Hz, 2 H), 4.52 (dd, J = 8.1, 4.3 Hz, 4 H),4.38 (d, J = 9.5 Hz, 1 H), 4.21 (d, J = 9.9 Hz, 1 H), 4.06 (d, J = 12.5 Hz, 4 H), 3.87 (t, J = 14.4 Hz, 3 H), 3.68 (s, 1 H), 3.55 (s, 3 H), 3.46 (s, 2 H), 2.94 - 2.76 (m, 3 H), 2.76 - 2.64 (m, 1 H), 2.03 (d, J = 11.1 Hz, 1 H), 1.05 (s, 6 H), 1.01 (s, 3 H), 0.91 (s, 3H). EXAMPLE 203

[001033] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan -3-yl)pyridin-3-yl)benzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl )-3,6,13-trioxo-5- Methyl (1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (203).

[001034] Intermediates: I2, P22 and S60. MS (ESI) m/z 1259.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1 H), 8.37 (s, 1 H), 8.18 (s, 1 H), 7.94 (s, 2 H), 7.42 (d, J = 7.9 Hz, 2 H), 7.30 (d, J = 7.9 Hz, 2 H), 7.19 (d, J = 8.4 Hz, 2 H), 6.99 (dd, J = 19.7, 9.0 Hz, 2 H), 4.95 (dd, J = 7.5, 2.8 Hz, 4 H), 4.85 - 4.72 (m, 5 H), 4.61 - 4.24 (m, 7 H), 4.16 (s, 6 H), 3.73 - 3.44 (m, 6 H), 3.44 - 3.34 (m, 3 H), 2.99 - 2.73 (m, 2 H), 2.35 - 2.21 (m, 3 H), 1.29 (s, 18 H), 1.19 - 0.96 (m, 10 H). EXAMPLE 204

[001035] ((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9- hydroxy-15,15-dimethyl-8-(4-(6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)- 3,6,13-trioxo-5-(1,1,1- methyl trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)methyl carbamate (204).

[001036] Intermediates: I2, P13 and S60. MS (ESI) m/z 1121.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1 H), 8.19 (s, 0 H), 7.69 (d, J = 2.5 Hz, 1 H), 7.53 - 7.22 (m, 7 H), 6.98 (d, J = 8.8 Hz, 1 H), 6.63 (d, J = 2.5 Hz, 1 H), 4.54 (d, J = 59.0 Hz, 0 H), 4.38 - 4.24 (m, 4 H), 4.24 - 3.93 (m, 6 H), 3.64 (d, J = 6.0 Hz, 5 H), 3.56 - 3.39 (m, 6 H), 2.09 (d, J = 8.5Hz, 2 H), 1.42 - 0.62 (m, 16 H). EXAMPLE 205

[001037] ((5S,8S,9S,14S)-11-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-16,16,16- trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6- (8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)- 3,6,13-trioxo-5-(1,1 methyl,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (205).

[001038] Intermediates: i3, p40 and s60. MS (ESI) m/z 1123.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.39 - 8.33 (m, 1 H), 8.10 (dd, J = 19.9, 9.2 Hz, 2 H), 7.53 ( d, J = 7.3 Hz, 3 H), 7.45 (d, J = 7.9 Hz, 3 H), 7.32 (d, J = 7.9 Hz, 3 H), 7.13 (dd, J = 21.7, 9.5 Hz, 2 H), 4.99 - 4.83 (m, 4 H), 4.61 - 4 .50 (m, 2 H), 4.50 - 4.43 (m, 1 H), 4.35 - 4.24 (m, 5 H), 4.18 (d, J = 11.8 Hz, 5 H), 3.78 (s, 1 H), 3.67 (s, 4 H), 3.59 (d, J = 13.0 Hz, 7 H), 3.01 - 2.76 (m, 5 H), 2.35 - 2.23 (m, 4 H), 2.14 (t, J = 6.9 Hz, 3 H), 1.32 - 1.10 (m, 19 H), 1.10 - 0.95 (m, 5 H). EXAMPLE 206

[001039] ((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9 -hydroxy-15,15-dimethyl-8-(4-(6-(8-(oxetan-3- il)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo- 2-oxa-4,7,11,12-tetra- aza-hexadecan-14-yl)methyl carbamate(206).

[001040] Intermediates: I1, P41 and S60. MS (ESI) m/z 987.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.36 (d, J = 2.4 Hz, 1 H), 7.61 (d, J = 2.3 Hz, 1 h), 7.44 (d, J = 7.9 Hz, 2 H), 7.36 - 7.28 (m, 4 H), 7.07 (d, J = 9.0 Hz, 1 H), 6.64 (d, J = 2.3 Hz, 1 H), 4.95 (t, J = 7.5 Hz, 2 H), 4.83(dd, J = 8.0, 5.1 Hz, 2 H), 4.53 (dq, J = 12.1, 6.2, 5.7 Hz, 1 H), 4.28(dd, J = 14.1, 2.4 Hz, 2 H), 4.19 - 4.06 (m, 4 H), 4.00 - 3.89 (m, 5 H), 3.75 (s, 2 H), 3.60 (d, J = 16.6 Hz, 6 H), 3.49 (d, j = 13.6 Hz, 2 H), 2.95 (td, J = 12.3, 11.7, 7.2Hz, 2H), 2.87 - 2.79 (m, 2H), 2.29 - 2.21 (m, 2H), 2.20 - 2.08 (m, 2H), 0.88 (s, 9H), 0.82 (s, 9H). EXAMPLE 207

[001041] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9 -hydroxy-15,15-dimethyl-8-(4-(6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)- 3,6,13-trioxo-5-(1,1,1- methyl trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)methyl carbamate (207).

[001042] Intermediates: I2, P41 and S60. MS (ESI) m/z 1095.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.36 (d, J = 2.3 Hz, 1 H), 8.15 (d, J = 9.3 Hz, 1 H), 7.62 (d, J = 2.3 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 2 H), 7.33 (dd, J = 8.2, 5.3Hz, 4H), 7.12 (dd, J = 19.4, 9.5Hz, 1H), 6.65 (d, J = 2.3Hz, 1H), 4.95 (t, J = 7.5Hz, 2H), 4.85 (dd, J = 8.1, 5.1Hz, 2H), 4.58 - 4.44 (m, 2 H), 4.35 - 4.23 (m, 3 H), 4.22 - 4.09 (m, 4 H), 3.93 (s, 4 H), 3.65 (s, 3 H), 3.60 - 3.52 (m, 4 H), 3.01 - 2.89 (m, 2 H), 2.88 - 2.74 (m, 2 H), 2.30 - 2.23 (m, 2 H), 2.14 (t, J = 6.9 Hz, 2 H), 1.18 - 1.08 (m, 8 H), 1.02 (s, 3 H). EXAMPLE 208

[001043] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro- 9-hydroxy-15,15-dimethyl-8-(4-(6- (8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)- 3,6,13-trioxo-5-(1,1 methyl,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (208).

[001044] Intermediates: I2, P4 AND S60. MS (ESI) m/z 1131.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.36 (d, J = 2.3 Hz, 1 H), 8.16 - 8.02 (m, 2 H), 7.44 (h, J = 4.1, 3.5 Hz, 3 H), 7.40 - 7.29 (m, 2 H), 7.14 (d, J =9.1 Hz, 1 H), 6.93 (d, J = 2.7 Hz, 1 H), 4.95 (t, J = 7.5 Hz, 2 H), 4.58 -4.43 (m, 2 H), 4.34 - 4.23 (m, 3 H), 4.21 - 4.11 (m, 3 H), 4.00 - 3.91 (m,1 H), 3.77 (s, 1 H), 3.67 - 3.52 (m, 6 H), 3.01 - 2.86 (m, 3 H), 2.80 (dd,J = 12.6, 9.1 Hz, 1 H), 2.31 - 2.23 (m, 2 H), 2.22 - 2.08 (m, 2 H), 1.13 (d, J = 14.1 Hz, 7 H), 1.03 (s, 2 H). EXAMPLE 209

[001045] ((5s,8s,9s,14s)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-8-(4-(1- (difluoromethyl)-1H-pyrazol-4-yl)benzyl)- 16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa- methyl 4,7,11,12-tetra-azahexadecan-14-yl)carbamate (209).

[001046] Intermediates: I2, P4 and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI) m/z 1004.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.32 (s, 2 H), 8.09 (d, J = 2.7 Hz, 2 H), 8.02 (s, 2 H), 7, 66 (d, J = 19.3 Hz, 1 H), 7.56 - 7.31 (m, 13 H), 7.24 (d, J = 8.0 Hz, 5 H), 6.91 (d, J = 2.7 Hz, 2 H), 4.46 (s, 2 H), 4.31 (s, 2 H), 4.20 - 4.07 (m, 5 H), 3.93 (d, J = 13.1 Hz, 2 H), 3.76 (s, 2 H), 3.64 (s, 6 H), 3.56 (s, 6 H), 3.35 (s, 1 H), 2.95 - 2.84 (m, 7 H), 2.79 (dd, J = 12.6, 9.2 Hz , 3 H), 1.24 - 1.09 (m, 28 H), 1.02 (s, 6 H). EXAMPLE 210

[001047] ((S)-1-(2-((2S,3S)-3-((S)-2-((cyclopropoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanamido) -4-(4-(1-(difluoromethyl)-1H- pyrazol-4-yl)phenyl)-2-hydroxybutyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4- cyclopropyl trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate (210).

[001048] Intermediates: I2a, A4, P7 and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole MS (ESI) m/z 1056.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J = 0.8 Hz, 1 H), 8.33 (s, 1 H), 8.12 (s, 1 H), 8, 03 (s, 1 H), 7.52 - 7.45 (m, 4 H), 7.25 (d, J = 8.2 Hz, 4 H), 4.47 (s, 1 H), 4.32 (s, 1 H), 4.14 (s, 1 H), 4.01 (td, J = 5.6, 3.0 Hz, 1 H) , 3.93 (d, J = 12.1 Hz, 2 H), 3.76 (d, J = 8.5 Hz, 1 H), 2.94 - 2.73 (m, 5H), 2.01 (s, 2 H), 1.23 (t, J = 7.1 Hz, 2 H), 1.17 - 1.09 (m, 10 H), 1.02 (s, 3 H) , 0.69 - 0.51 (m, 8 H). EXAMPLE 211

[001049] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-(1- (difluoromethyl)-1H-pyrazol-4- yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (211).

[001050] Intermediates: I2, P7 and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole MS (ESI) m/ z 1004.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.44 (d, J = 0.7 Hz, 1 H), 8.24 (s, 1 H), 8.03 (s, 1 H), 7, 93 (s, 1 H), 7.41 (s, 1 H), 7.39 - 7.35 (m, 3 H), 7.25 (d, J = 10.6 Hz, 1 H), 7.15 (d, J = 8.1 Hz, 4 H), 4.35 (s, 1 H), 4.20 (s, 1 H), 4.05 - 3.98 (m, 3 H), 3.85 (s, 1 H), 3.54 (s, 4 H), 3.46 (s, 3 H), 2.82 - 2.65 (m, 4 H), 1.91 (s, 1 H), 1.08 - 0.99 (m, 9 H), 0.92 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -76.33 - -79.41 (m), -96.67 (dd, J = 145.1, 59.7 Hz). EXAMPLE 212

[001051] Synthesis of ((5S,10S,11S,14S)-11-(4-(1-(2,2-difluoroethyl)- 1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro -10-hydroxy-15,15-dimethyl- 3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetra-azahexadecan-14-yl) methyl carbamate (212a).

[001052] The title compound 212a was prepared according to the method presented for the synthesis of compound 188 , but using I2 and P10a. MS (ESI) m/z 776.3 [M+H]+.

[001053] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan -3-yl)pyrimidin-5-yl)benzyl)-8-(4-(1-(2,2- difluoroethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro Methyl -2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (212).

[001054] The title compound 212 was prepared according to the method presented for the synthesis of compound 1a, but using 212a and P20. MS (ESI) m/z 1146.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.71 (s, 2 H), 8.11 (d, J = 9.7 Hz, 1 H), 7.68 (d, J = 2.4 Hz, 1 H), 7.64 (d, J = 7.9 Hz, 2 H), 7.25 (s, 1 H), 7.21 (d, J = 8.3 Hz, 1 H), 7.13 (d, J = 10.1 Hz, 1 H), 6.78 (d, J = 10.1 Hz, 1 H), 6.63 (d, J = 2.4 Hz, 1 H), 6.19 (tt, J = 55.6, 3.9 Hz, 1 H), 4.96 (t, J = 7.5Hz, 2 H), 4.56 (td, J = 14.3, 3.9 Hz, 2 H), 4.43 (d, J = 9.7 Hz, 1 H), 4.29 (d, J = 10.0 Hz, 1 H), 4.23 - 4.08 (m, 4 H), 3.95 (d, J = 13.5 Hz, 1 H), 3.73 (s, 1 H), 3.63 (s, 3 H), 3.55 (s, 3 H), 3.52 - 3.43 (m, 2 H), 2.93 - 2.73 (m, 3 H), 2.25 - 2.17 (m, 2 H), 2.06 - 1.94 (m, 2 H), 1.15 - 1.12 (m, 6 H), 1.11 (s, 3 H), 1.01 (s, 3 H).EXAMPLE 213

[001055] Synthesis of ((6S,9S,10S,15S)-12-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-17,17,17- trifluoro-10-hydroxy-9-(4- iodobenzyl)-2,2,16,16-tetramethyl-4,7,14-trioxo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-oxa-5,8,12 tert-butyl ,13-tetra-azaheptadecan-15-yl)carbamate (213a).

[001056] The title compound 213a was prepared according to the method presented for the synthesis of compound 188, but using I2a, A1, and P4.

[001057] Synthesis of ((6S,9S,10S,15S)-12-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-(4-( 1-(difluoromethyl)-1H-pyrazol-4- yl)benzyl)-17,17,17-trifluoro-10-hydroxy-2,2,16,16-tetramethyl-4,7,14-trioxo-6-(1,1,1-trifluoro-2-methylpropan- tert-butyl 2-yl)-3-oxa-5,8,12,13-tetra-azaheptadecan-15-yl)carbamate (213b).

[001058] The title compound 213b was prepared according to the method presented for the synthesis of compound 218 , but using 213a and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI) m/z 1088.5 [M+H] +.

[001059] Synthesis of N-((S)-1-(2-((2S,3S)-3-((S)-2-(cyclopropanecarboxamido)-4,4,4-trifluoro-3,3-dimethylbutanamido )- 4-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-2-hydroxybutyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2 ,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)cyclopropanecarboxamide (213).

[001060] To a solution of 213a (255 mg, 0.23 mmol) in CH2Cl2 (5 mL) at room temperature was added 4 M hydrochloric acid (0.8 mL). After stirring the reaction for 18 h, the mixture was concentrated in vacuo. To this crude residue dissolved in DMF (3 mL) was added cyclopropanecarboxylic acid (29.97 μL, 0.4 mmol), HATU (93.32 mg, 0.4 mmol), and DIPEA (0.34 mL, 1.96 mmol). The mixture was stirred for 48 h, then purified by HPLC and lyophilized to yield 212. MS (ESI) m/z 1146.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.34 (d, J = 0.7 Hz, 1 H), 8.25 (d, J = 9.8 Hz, 1 H), 8.20 - 8.06 (m, 2 H), 8.06 - 7.95 (m, 2 H), 7.56 - 7.45 (m, 4 H), 7.48 - 7.31 (m, 2 H), 7.24 (d, J = 8.1 Hz, 1 H), 6.93 (dd, J = 5.4, 2.7 Hz, 1 H), 4.73 - 4.61 (m, 1 H), 4.16 (d, J = 13.2 Hz, 2 H), 3.93 (d, J = 13.2Hz, 1 H), 3.77 (s, 1 H), 2.93 - 2.74 (m, 4 H), 1.69 (dd, J = 8.5, 4.1 Hz, 1 H), 1.58 (tt, J = 8.2, 4.6 Hz, 1 H), 1.36 - 1.20 (m, 1 H), 1.17 (d, J = 13.5 Hz, 9 H), 1.07 (s, 3 H), 0.91 (q, J = 10.2, 9.5 Hz, 1 H), 0.89 - 0.66 (m, 1 H), 0.65 - 0.54 (m, 1 H). EXAMPLE 214

[001061] N-((S)-1-(2-((2S,3S)-3-((S)-2-(cyclopropanecarboxamido)- 4,4,4-trifluoro-3,3-dimethylbutanamido)- 4-(4-(1-(difluoromethyl)-1H- pyrazol-4-yl)phenyl)-2-hydroxybutyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4- trifluoro-3,3-dimethyl-1-oxobutan-2-yl)cyclopropanecarboxamide (214).

[001062] The title compound 214 was prepared according to the method presented for the synthesis of compound 213 but using P7. MS (ESI) m/z 1024.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1 H), 8.33 (d, J = 0.7 Hz, 1 H), 8.27 (d, J = 9.8 Hz, 1 H), 8.13 - 8.09 (m, 2 H), 8.03 - 7.96 (m, 2 H), 7.64 (d, J = 10.5 Hz, 1 H), 7.52 - 7.45 (m, 3 H), 7.34 (d, J = 10.7 Hz, 1 H), 7.24 (t, J = 8.5 Hz, 4 H), 4.81 - 4.78 (m, 1 H), 4.69 - 4.64 (m, 1 H), 4.12 (d, J = 12.4 Hz, 2 H), 3.91 (d, J = 13.2 Hz, 1 H), 3.74 (d, J = 8.9 Hz, 1 H), 2.88 (d, J = 7.6 Hz, 3 H), 2.77 (dd, J = 12.5, 9.3 Hz, 1 H), 1.69 (dt, J = 8.0, 3.7 Hz, 1 H), 1.57 (tt, J = 8.3, 4.6 Hz, 1 H), 1.29 (d, J = 0.6 Hz, 1 H), 1.24 (d, J = 7.7 Hz, 1 H), 1.21 - 1.12 (m, 9 H), 1.06 (s, 2 H), 0.94 - 0.68 (m, 7 H), 0.59 (d, J = 8.0 Hz, 1 H). EXAMPLE 215

[001063] (S)-N-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-2-((S) -4,4,4-trifluoro-3,3-dimethyl-2-propionamidobutanoyl)hydrazinyl)-1-(4-(1-(difluoromethyl)-1H-pyrazol- 4-yl)phenyl)-3-hydroxybutan-2-yl)-4,4,4-trifluoro-3,3-dimethyl-2-propionamidobutanamide (215).

[001064] The title compound 215 was prepared according to the method presented for the synthesis of compound 213 but using P7 and propionic acid. MS (ESI) m/z 1000.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (d, J = 0.7 Hz, 1 H), 8.35 (d, J = 0.7 Hz, 1 H), 8.14 - 8.00 (m, 5 H), 7.71 (d, J = 9.8 Hz, 1 H), 7.64 (d, J = 10.9 Hz, 1 H), 7.52 - 7.44 (m, 4 H), 7.25 (t, J = 8.6 Hz, 5 H), 4.78 - 4.74 (m, 1 H), 4.67 - 4.63 (m, 1 H), 4.14 (d, J = 13.2 Hz, 2 H), 3.92 (d, J = 13.2Hz, 1 H), 3.73 (d, J = 8.7 Hz, 1 H), 2.88 (d, J = 8.7 Hz, 4 H), 2.76 (dd, J = 12.7, 9.3 Hz, 1 H), 2.25 - 1.99 (m, 6 H), 1.25 - 0.95 (m, 24 H). EXAMPLE 216

[001065] N-((S)-1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6- difluorobenzyl)-2-((2S,3S)-4-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-2-hydroxy-3-((S)-4,4, 4-trifluoro-3,3-dimethyl-2-(1-methylcyclopropane-1-carboxamido)butanamido)butyl)hydrazinyl)- 4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)-1-methylcyclopropane-1-carboxamide (216).

[001066] The title compound 216 was prepared according to the method presented for the synthesis of compound 213 , but using P7 and 1-Methylcyclopropanecarboxylic acid. MS (ESI) m/z 1052.7 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.17 (s, 1 H), 7.97 (s, 1 H), 7.87 (d, J = 9.5 Hz, 1 H), 7.75 (s, 1 H), 7.65 (s, 1 H), 7.15 - 7.07 (m, 4 H), 6.87 (t, J = 8.2 Hz, 4 H), 6.42 (d, J = 9.6 Hz, 1 H), 6.17 (d, J = 9.6 Hz, 1 H), 4.38 (d, J = 9.5 Hz, 1 H), 4.27 (d, J = 9.5 Hz, 1 H), 3.89 - 3.73 (m, 2 H), 3.58 - 3.48 (m, 1 H), 3.39 (s, 1 H), 2.50 (t, J = 7.6 Hz, 3 H), 2.41 (dd, J = 12.6, 9.0 Hz, 1 H), 0.95 - 0.54 (m, 25 H), 0.22 (d, J = 3.8 Hz, 2 H), 0.13 (ddd, J = 9.8, 6.4, 3.6 Hz, 1 H). EXAMPLE 217

[001067] (S)-2-acetamido-N-((2S,3S)-4-(2-((S)-2-acetamido-4,4,4-trifluoro-3,3-dimethylbutanoyl)-1 -(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)- 2,6-difluorobenzyl)hydrazinyl)-1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-3-hydroxybutan-2-yl)-4,4,4-trifluoro-3 ,3-dimethylbutanamide (217).

[001068] The title compound 217 was prepared according to the method presented for the synthesis of compound 213 , but using P7 and acetic anhydride. MS (ESI) m/z 972.5 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.55 (s, 1 H), 8.36 (s, 1 H), 8.16 (d, J = 21.4 Hz, 2 H), 8.07 (d, J = 20.2 Hz, 2 H), 7.52 - 7.46 (m, 3 H), 7.25 (t, J = 8.3 Hz, 4 H), 5.48 (d, J = 0.6 Hz, 2 H), 4.78 - 4.73 (m, 1 H), 4.66 - 4.61 (m, 1 H), 4.16 (s, 1 H), 3.95 - 3.88 (m, 1 H), 3.74 (d, J = 8.5 Hz, 1 H), 2.91 - 2.84 (m, 3 H), 2.77 (dd, J = 12.7, 9.2 Hz, 1 H), 2.15 (s, 1 H), 2.03 (d, J = 0.5 Hz, 15 H), 1.93 (s, 2 H), 1.81 (s, 2 H). 19F NMR (377 MHz, Methanol-d4) δ -76.14 - -79.22 (m), -96.72 (dd, J = 133.4, 59.8 Hz). EXAMPLE 218

[001069] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-8-(4-(1- (difluoromethyl)-1H-pyrazol-4-yl)benzyl)-9- hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan- 2-yl)-2-oxa-4,7,11,12-tetra- methyl aza-hexadecan-14-yl)carbamate (218).

[001070] To a solution of methyl ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy -8-(4- iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra -aza-hexadecan-14-yl)carbamate (0.02 g, 0.02 mmol) in 1,4-dioxane (0.3 mL) was added 1-(Difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.01 g, 0.04 mmol), XPhos Pd G2 (0.005 g, 0.003 mmol), XPhos (0.001 g, 0.003 mmol) and Potassium phosphate tribasic (0.01 ml) as an aqueous solution in water (0 ,01mL). The resulting suspension was sparged with argon for 5 minutes and subsequently placed on an aluminum heating block at 100°C and allowed to stir, heating overnight under an argon atmosphere. Upon completion, the residue was purified by reversed-phase high-pressure liquid chromatography (20-83% acetonitrile in water, 0.1% TFA buffer). The collected product fractions were quenched with sodium bicarbonate (aqueous, saturated), extracted with ethyl acetate and further purified by normal phase silica gel chromatography (0-8% methanol in dichloromethane) to yield methyl ((5S, 8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-8-(4-(1-(difluoromethyl)-1H-pyrazole -4-yl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-ox- 4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate. ES/MS m/z 950.542[M+H] +. EXAMPLE 219

[001071] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-1,2,3-triazol-4-yl)-2,6-difluorobenzyl)-16,16,16 -triflu oro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin- 5- yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza -hexadecan-14-yl)methyl carbamate (219).

[001072] Intermediates: P44, A3, and S7. MS (ESI) m/z 1157.9 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.97 (s, 1 H), 8.53 (s, 2 H), 8.17 (d, J = 9.8 Hz, 1 H), 8.00 (t, J = 58.6 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 7.9 Hz, 2 H), 7.24 (d, J = 8.1 Hz, 2 H), 7.14 (d, J = 9.9 Hz, 1 H), 6.81 (d, J = 9.9 Hz, 1 H), 4.96 (dd, J = 8.2, 7.1 Hz, 2 H), 4.83 - 4.78 (m, 3 H), 4.50 - 4.41 (m, 1 H), 4.30 (d, J = 10.0 Hz, 1 H), 4.21 - 4.08 (m, 4 H), 3.96 (d, J = 13.2 Hz, 1 H), 3.74 (d, J = 8.8 Hz, 1 H), 3.69 (s, 3 H), 3.67 (s, 3 H), 3.47 (d, J = 14.5 Hz, 2 H), 2.98 - 2.84 (m, 3 H), 2.82 - 2.74 (m, 1 H), 2.29 - 2.17 (m, 2 H), 2.02 - 1.94 (m, 2 H), 1.16 (s, 3 H), 1.15 (s, 3 H), 1.12 (s, 3 H), 1.03 (s, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.37, -77.70, -77.82, -98.78 (d, J = 58.6 Hz), -114.26. EXAMPLE 220

[001073] ((2S)-1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((2S,3S)-2- hydroxy-4-(4-((2-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)phenyl)-3-((S)-4,4,4-trifluoro-3,3-dimethyl-2-(((oxetan -3-yloxy)carbonyl)amino)butanamido)butyl)hydrazinyl)-4,4,4-trifluoro- oxetan-3-yl 3,3-dimethyl-1-oxobutan-2-yl)carbamate (220).

[001074] Intermediates: P4, A4, and S7. MS (ESI) m/z 1240.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 2 H), 8.12 (d, J = 9.3 Hz, 1 H), 8.02 (d, J = 2.7 Hz, 1 H), 7.45 (t, J = 59.8 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 2 H), 7.25 (d, J = 8.0 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 3 H), 7.07 (d, J = 10.0 Hz, 1 H), 6.85 (d, J = 2.8 Hz, 1 H), 5.37 - 5.21 (m, 2 H), 4.92 - 4.83 (m, 2H), 4.73 - 4.69 (m, 2 H), 4.56 (ddd, J = 12.4, 7.3, 5.2 Hz, 2 H), 4.50 - 4.44 (m, 2 H), 4.33 (d, J = 10.0 Hz, 1 H), 4.20 (d, J = 9.9 Hz, 1 H), 4.13 - 3.98 (m, 4 H), 3.85 (d, J = 13.1 Hz, 1 H), 3.67 (s, 1 H), 3.39 - 3.32 (m, 3 H), 2.86 - 2.78 (m, 3 H), 2.68 (dd, J = 12.6, 8.9 Hz, 1 H), 2.14 - 2.08 (m, 2 H), 1.92 - 1.83 (m, 2 H), 1.09 (s, 3 H), 1.07 (s, 3 H), 1.05 - 0.99 (m, 3 H), 0.99 - 0.93 (m, 3 H). 19F NMR (377 MHz, Methanol-d4) δ -77.46, -77.56, -77.78, -96.92 (d, J = 59.7 Hz), -114.94. EXAMPLE 221

[001075] ((2S)-1-(2-((2S,3S)-3-((S)-2-(cyclopropanecarboxamido)-4,4,4-trifluoro-3,3-dimethylbutanamido)-2- hydroxy-4-(4-((2-(8-(oxetan- 3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)phenyl)butyl)- 2-(4-(1-(difluoromethyl)-1H-pyrazol- 3-yl)-2,6-difluorobenzyl)hydrazinyl)- Methyl 4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate(221).

[001076] Intermediate I9 was acylated with cyclopropyl carbonyl chloride in the presence of 2M aqueous NaOH, followed by coupling with S7 analogously to the procedure given for Example 1. MS (ESI) m/z 1166.9 [M+H] +. 1H NMR (400 MHz,Methanol-d4) δ 8.42 (s, 2 H), 8.07 (d, J = 9.4 Hz, 1 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.89 (d, J = 9.7 Hz, 1 H), 7.44 (t, J = 59.7 Hz, 1 H), 7.36 (d, J = 8.3 Hz, 2 H), 7.26 (d, J = 8.1 Hz, 2 H), 7.12 (d, J = 8.1 Hz, 2 H), 7.06(d, J = 9.7 Hz, 1 H), 6.85 (d, J = 2.7 Hz, 1 H), 4.90 - 4.83 (m, 2H), 4.74 - 4.68 (m, 3 H), 4.21 (d, J = 10.0 Hz, 1 H), 4.11 - 3.98 (m, 4 H), 3.85 (d, J = 13.0 Hz, 1 H), 3.57 (s, 3 H), 3.41 - 3.31 (m, 2 H), 2.86 - 2.75 (m, 3 H), 2.73 - 2.61 (m, 1 H), 2.19 - 2.01 (m, 2 H), 1.93 - 1.82 (m, 2 H), 1.64 - 1.51 (m, 1 H), 1.10 (s, 3 H), 1.07 (s, 3 H), 1.07 (s, 3 H), 0.94 (s, 3 H),0.90 - 0.83 (m, 1 H), 0.79 - 0.62 (m, 2 H). 19F NMR (377 MHz,Methanol-d4) δ -77.41, -77.71, -77.73, -96.95 (dd, J = 59.9, 20.5 Hz), - 114.88 . EXAMPLE 222

[001077] ((5S,8S,11S,12S,17S)-8-(tert-butyl)-14-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2 ,6-difluorobenzyl)-12-hydroxy-5- isopropyl-18,18-dimethyl-11-(4-((2-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-5-yl) ethynyl)benzyl)-3,6,9,16- methyl tetraoxo-2-oxa-4,7,10,14,15-pentaazanonadecan-17-yl)carbamate (222).

[001078] MS (ESI) m/z 1147.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 2 H), 7.87 (d, J = 9.2 Hz, 1 H), 7.64 (d, J = 2.4 Hz , 1 H),7.50 (d, J = 9.4 Hz, 1 H), 7.35 - 7.24 (m, 4 H), 7.16 (d, J = 8.0 Hz, 2 H),6.65 (d, J = 2.5 Hz, 1 H), 6.13 (tt, J = 55.3, 3.9 Hz , 1 H), 4.58 - 4.44 (m, 4 H), 4.39 (s, 0 H), 4.16 (d, J = 9.2 Hz, 1 H), 4.07 - 3.92 (m, 2 H), 3.90 - 3.77 (m, 2 H), 3.67 (s, 1 H), 3.59 (s, 1 H), 3.55 (s, 3 H), 3.55 (s, 3 H), 2.90 - 2.66 (m, 3 H), 2.06 - 1.86 (m, 2 H), 0.85 (s, 9 H), 0.79 (d, J = 6.8 Hz, 3 H), 0.76 (s, 9 H), 0.72 (d, J = 6.8 Hz, 3H). 19F NMR (377 MHz,Methanol-d4) δ -77.64, -115.17, -125.29 (dt, J = 55.2, 14.2 Hz). EXAMPLE 223

[001079] ((5S,8S,11S,12S,17S)-5,8-di-tert-butyl-14-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl) -2,6-difluorobenzyl)-12-hydroxy-18,18- dimethyl-11-(4-((2-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3 ,6,9,16-tetraoxo-2-oxa-4,7,10,14,15-pentaazanonedecan-17-yl)methyl carbamate (223).

[001080] MS (ESI) m/z 1174.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.21 (d, J = 2.3 Hz, 1 H), 7.87 (d, J = 9.0 Hz, 1 H), 7.64 (d , J =2.4 Hz, 1 H), 7.61 (dd, J = 8.8, 2.3 Hz, 1 H), 7.53 (d, J = 9.2 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.24 (d, J = 8.1 Hz, 1 H), 7.15 (d , J = 8.1 Hz, 2 H), 6.77 (d, J = 8.9 Hz, 1 H), 6.65 (d, J = 2.4 Hz, 1 H), 6.13 (tt, J =55.3, 3.9 Hz, 1 H), 4.92 - 4.83 (m, 2 H), 4.74 - 4.68 (m, 2 H), 4.51 ( td, J= 14.3, 3.9 Hz, 2 H), 4.26 (d, J = 13.7 Hz, 2 H), 4.16 (d, J = 9.3 Hz, 1 H), 4.09 - 3.94 (m, 3 H), 3.91 (s, 1 H), 3.85 (d, J = 13.1 Hz, 1 H) , 3.70 - 3.64 (m, 1 H), 3.63 - 3.57 (m, 2 H), 3.55 (s, 3 H), 3.54 (s, 3H), 3.28 (d, J = 13.9 Hz, 2 H), 2.89 - 2.66 (m, 4 H), 2.17 - 2.08 (m, 2 H), 2.02 - 1.95 ( m, 2 H), 0.85 (s, 9 H), 0.80 (s, 9 H), 0.75 (s, 9 H). 19F NMR (377 MHz, Methanol-d4) δ -77.71, -115.18, -125.29 (dt, J = 55.3, 14.2 Hz). EXAMPLE 224

[001081] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13 -trioxo-8-(4-((6-(8-((S)-tetrahydrofuran- 2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl )-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)methyl carbamate (224).

[001082] Intermediates: P28, I3, and S25. MS (ESI) m/z 1104.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.58 (d, J = 5.0 Hz, 1 H), 8.14 - 8.01 (m, 2 H), 7.93 (t, J = 7.7 Hz, 1 H), 7.86 (d, J = 7.9 Hz, 1 H), 7.72 (t, J = 8.7 Hz, 1 H), 7.50 (d, J = 8.5 Hz, 2 H), 7.43 - 7.35 (m, 1 H), 7.25 (d, J = 7.8 Hz, 2 H), 7.14 (d, J = 8.0 Hz, 2 H), 6.72 (d, J = 9.8 Hz, 1 H), 4.63 - 4.54 (m, 1 H), 4.39 - 4.29 (m, 1 H), 4.11 - 3.73 (m, 8 H), 3.66 (s, 1 H), 3.59 (s, 3 H), 3.53 (s, 3 H), 3.13 (d, J = 12.1 Hz, 1 H), 2.90 - 2.64 (m, 4 H), 2.20 - 1.67 (m, 10 H), 1.05 (s, 4 H), 1.02 (s, 3 H), 0.76 (s, 9 H). 19F NMR (377 MHz, Methanol-d4) δ -77.33, -78.06, -114.28. EXAMPLE 225

[001083] ((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15 -dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)- tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-2-oxa-4,7,11,12-tetra- methyl aza-hexadecan-14-yl)carbamate (225).

[001084] Intermediates: P28, I1 and S25. MS (ESI) m/z 1050.4 [M+H] +. - 7.74 (m, 2H), 7.59 (d, J = 8.5Hz, 2H), 7.48 (t, J = 6.2Hz, 1H), 7.35 (d, J = 7.9Hz, 2H), 7.25 (d, J = 7.8Hz, 2H), 7.08 - 6.89 (m, 1H), 4.73 - 4.64 (m, 1 H), 4.23 - 3.81 (m, 8 H), 3.75 (s, 1 H), 3.73 - 3.69 (m, 1 H), 3.68 (s, 3 H), 3.63 (s, 3 H), 3.24 - 3.14 (m, 1 H), 2.99 - 2.79 (m, 4 H), 2.32 - 1.75 (m, 9 H), 0.90 (s, 9 H), 0.84 (s, 9 H). 19F NMR (377 MHz, Methanol-d4) δ -78.01, -114.33. EXAMPLE 226

[001085] ((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9 -hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6- (8-(pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-2-oxa-4,7,11,12- methyl tetra-aza-hexadecan-14-yl)carbamate (226).

[001086] Intermediates: I1, P41 and S61. MS (ESI) m/z 1033.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.31 (d, J = 4.9 Hz, 2 H), 8.07 (d, J = 2.1 Hz, 1 H), 7.76 (d, J = 9.3 Hz, 1 H), 7.68 (d, J = 9.1 Hz, 1 H), 7.52 (d, J = 2.3 Hz, 1 H), 7.29 - 7.19 (m, 4 H), 7.14 (d, J = 8.1 Hz, 2 H), 6.90 (d, J = 9.3 Hz, 1 H), 6.61 (t, J = 4.9 Hz, 1 H), 6.56 (d, J = 2.4 Hz, 1 H), 4.92 - 4.84 (m, 2 H), 4.08 - 3.97 (m, 2 H), 3.89 (d, J = 13.0 Hz, 2 H), 3.84 (s, 3 H), 3.80 (s, 1 H), 3.66 (s, 1 H), 3.64 - 3.59 (m, 1 H), 3.58 (s, 3 H), 3.56 (s, 3 H), 2.87 - 2.62 (m, 3 H), 2.06 - 1.95 (m, 2 H), 1.84 (q, J = 7.2, 6.6 Hz, 2 H), 0.79 (s, 9 H), 0.74 (s, 9 H). 19F NMR (377 MHz, Methanol-d4) δ -77.75, -115.32. EXAMPLE 227

[001087] ((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9 -hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6- (8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-2-oxa-4, 7,11,12-tetra-aza-hexadecan-14-yl)methyl carbamate (227).

[001088] Intermediates: I1, P41 and S25. MS (ESI) m/z 1053.3 [M+H] +. 1H NMR (400MHz, Methanol-d4) δ 8.10 (s, 1H), 7.79 - 7.64 (m, 2H), 7.52 (d, J = 2.3Hz, 1H), 7.28 - 7.19 (m, 4H), 7.14 (d, J = 8.0Hz, 2H),6.89 (t, J = 10.6 Hz, 1 H), 6.56 (d, J = 2.4 Hz, 1 H), 4.63 - 4.55 (m, 1H), 4.09 - 3.89 (m, 3 H), 3.84 (s, 3 H), 3.81 - 3.73 (m, 2 H), 3.66 (s, 1H), 3.64 - 3.60 (m, 1 H), 3.58 (s, 3 H), 3.56 (s, 3 H), 3.10 (d, J = 12.2 Hz, 1 H), 2.90 - 2.61 (m, 4 H), 2.18 - 1.67 (m, 7 H), 0.80 (s, 9 H), 0.75 (s, 9 H). 19F NMR (377 MHz, Methanol-d4) δ -77.94, -115.33. EXAMPLE 228

[001089] ((5S,8S,9S,14S)-8-(4-((6-(4-acetylpiperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-5-(tert-butyl) -11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3- yl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)methyl carbamate (228 ).

[001090] Intermediates: I1, and P41. MS (ESI) m/z 971.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.12 (dd, J = 2.2, 0.7 Hz, 1 H), 7.73 (d, J = 9.4 Hz, 1 H), 7.65 (dd, J = 9.0, 2.3 Hz, 1 H), 7.52 (d, J = 2.3 Hz, 1 H), 7.32 - 7.18 (m, 4 H), 7.14 (d, J = 8.1 Hz, 2 H), 6.88 (d, J = 9.2 Hz, 1 H), 4.10 - 3.97 (m, 2 H), 3.90 - 3.76 (m, 5 H), 3.70 - 3.50 (m, 15 H), 2.90 - 2.78 (m, 2 H), 2.72 (d, J = 7.9 Hz, 2 H), 2.06 (s, 3 H), 0.80 (s, 9 H), 0.75 (s, 9 H). 19F NMR (377 MHz, Methanol-d4) δ -77.88, -115.32. EXAMPLE 229

[001091] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-methylpyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl (229).

[001092] Intermediates: I2, P39 S3. MS (ESI) m/z 1030.2 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.55 (s, 1 H), 8.29 (d, J = 2.2 Hz, 1 H), 8.13 (d, J = 9.4 Hz, 1 H), 8.01 - 7.87 (m, 2 H), 7.69 (dd, J = 8.8, 2.3 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.12 (d, J = 9.9 Hz, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.79 (d, J = 9.9Hz, 1 H), 4.95 (t, J = 7.6 Hz, 2 H), 4.85 - 4.78 (m, 2 H), 4.58 - 4.49 (m, 1 H), 4.48 - 4.40 (m, 1 H), 4.40 - 4.26 (m, 3 H), 4.23 - 4.09 (m, 4 H), 3.98 (d, J = 13.1 Hz, 1 H), 3.79 - 3.71 (m, 1 H), 3.69 (s, 3 H), 3.64 (s, 3 H), 3.46 - 3.35 (m, 2 H), 2.94 - 2.87 (m, 3 H), 2.80 (t, J = 10.9 Hz, 1 H), 2.45 (s, 3 H), 2.30 - 2.19 (m, 2 H), 2.12 - 2.00 (m, 2 H), 1.16 (s, 3 H), 1.15 (s, 3 H), 1.12 (s, 3 H), 1.03 (s, 3 H). EXAMPLE 230

[001093] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)- 2-fluorobenzyl)-9-hydroxy-15,15-dimethyl- 8-(4-((6-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate.

[001094] Intermediates: I3, P8, and S3. MS (ESI) m/z 1083.8 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.11 (d, J = 21.6 Hz, 4 H), 7.72 -7.55 (m, 3 H), 7.42 - 7.29 (m, 5 H), 7.22 (d, J = 8.1 Hz, 2 H), 6.88 - 6.77(m, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.81 (dd, J = 8.2, 5.0 Hz, 2 H), 4.54 (s, 1 H), 4.42 - 4.32 (m, 3 H), 4.16 (s, 3 H), 4.08 - 3.91 (m, 2 H), 3.81 -3.60 (m, 9H), 3.42 - 3.34 (m, 2 H), 2.98 - 2.70 (m, 4 H), 2.27 - 2.20 (m, 2 H), 2.11 - 2.03 (m, 2 H), 1.08 (d, J = 22.3 Hz, 6 H), 0.80 (s, 10 H). EXAMPLE 231

[001095] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorobenzyl)-16-fluoro-5-(1-fluoro -2-methylpropan-2-yl)-9-hydroxy- 15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl) benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate methyl.

[001096] Intermediates: I1a, A7, P8, and S3. MS (ESI) m/z 1083.8 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.48 - 8.06 (m, 3 H), 7.70 (dd, J = 8.9, 2.3 Hz, 2 H), 7.66 - 7.55 (m, 1 H), 7.43 - 7.30 (m, 5 H), 7.24 (d, J = 8.1 Hz, 3 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.82 (dd, J = 8.3, 5.1Hz, 3 H), 4.54 (s, 1 H), 4.35 (d, J = 13.4 Hz, 2 H), 4.24 - 3.89 (m, 12 H), 3.83 - 3.59 (m, 8 H), 3.39 (d, J = 13.8 Hz, 2 H), 3.00 - 2.72 (m, 4 H),2.28 - 2.19 (m, 2 H), 2.12 - 2.00 (m, 2 H), 0.92 - 0.75 (m, 13 H). EXAMPLE 232

[001097] ((5S,8S,9S,14S)-5-(tert-butyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)- 9-hydroxy-15,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7 methyl,11,12-tetra-aza-hexadecan-14-yl)carbamate.

[001098] Intermediates: I1, P4, and S3. MS (ESI) m/z 1047.5 [M+H] +. 1H 1H NMR (400 MHz, Methanol-d4) δ 8.30 - 8.26 (m, 1 H), 8.09 (d, J = 2.7 Hz, 1 H), 7.80 (d, J = 9.4 Hz, 1 H), 7.68 (dd, J = 9.0, 2.5 Hz, 2 H), 7.48 - 7.31 (m, 5 H), 7.23 (d, J = 8.0 Hz, 2 H), 6.93 (d, J = 2.8 Hz, 1 H), 6.84 (d, J = 8.8 Hz, 1 H), 4.94 (t, J = 7.5 Hz, 2 H), 4.46 (s, 1 H), 4.30 (d, J = 13.8 Hz, 2 H), 4.18 - 4.02 (m, 5 H), 4.02 - 3.88 (m, 3 H), 3.79 - 3.63 (m, 9 H), 3.35 (d, J = 13.7 Hz, 2 H), 2.98 - 2.77 (m, 5 H), 2.24 - 2.16 (m, 2 H), 2.04 (d, J = 8.4 Hz, 2 H), 0.87 (d, J = 21.8 Hz, 19 H). EXAMPLE 233

[001099] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16-fluoro-5-(1 -fluoro-2-methylpropan-2-yl)-9- hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl) ethynyl)benzyl)-3,6,13-trioxo- Methyl 2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate.

[001100] Intermediates: I1a, A7, P7, and S3. MS (ESI) m/z 1084.0 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.31 - 8.28 (m, 1 H), 8.12 (s, 1 H), 7.88 (d, J = 9.4 Hz, 1 H), 7.70 (dd, J = 8.8, 2.3 Hz, 1 H), 7.37 - 7.21 (m, 7 H), 6.86 (d, J = 8.9 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.81 (dd, J = 8.0, 5.2 Hz, 3 H), 4.52 (s, 1 H), 4.35 (d, J = 14.0 Hz, 2 H), 4.25 - 3.89 (m, 13 H), 3.67 (d, J = 8.3 Hz, 8 H), 3.37 (d, J = 13.8 Hz, 2 H), 2.95 - 2.78 (m, 4 H), 2.26 - 2.19 (m, 2 H), 2.07 (d, J = 8.6 Hz, 2 H), 0.95 - 0.83 (m, 13 H). EXAMPLE 234

[001101] ((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-yl)benzyl)-16-fluoro-5-(1-fluoro-2- methylpropan-2-yl)-9-hydroxy-15,15- dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3 methyl,6,13-trioxo-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate.

[001102] Intermediates: I1a, A7, P26, and S3. MS (ESI) m/z 1060.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (d, J = 4.8 Hz, 1 H), 8.31 - 8.28 (m, 1 H), 7.91 (q, J = 13.2, 11.5 Hz, 4 H), 7.73 - 7.65 (m, 2 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.81 (dd, J = 8.3, 5.0 Hz, 3 H), 4.52 (s, 1 H), 4.35 (d, J = 14.1 Hz, 2 H), 4.30 - 3.96 (m, 12 H), 3.73 (s, 1 H), 3.66 (d, J = 16.2 Hz, 6 H), 3.38 (d, J = 13.8 Hz, 2 H), 2.99 - 2.78 (m, 5 H), 2.23 (d, J = 10.7 Hz, 2 H), 2.07 (d, J = 8.7 Hz, 2 H), 0.93 - 0.81 (m, 13 H). EXAMPLE 235

[001103] ((5S,8S,9S,14S)-16,16,16-trifluoro-11-(2-fluoro-4-(5-fluoropyridin-2-yl)benzyl)-9-hydroxy-15,15 -dimethyl-8-(4-((6-(8-(oxetan- 3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro Methyl -2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate.

[001104] Intermediates: I2, P14, and S3. MS (ESI) m/z 1116.4 [M+H] +. EXAMPLE 236

[001105] ((5S,8S,9S,14S)-8-(4-((6-(8-(2,2-difluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl) pyridin-3-yl)ethynyl)benzyl)-11-(4-(1- (difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1 ,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14- il)methyl carbamate.

[001106] Intermediates: P4, A3, and S63. MS (ESI) m/z 1078.4 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.29 - 8.24 (m, 1 H), 8.18 - 8.08 (m, 2 H), 7.74 - 7.61 (m, 3 H), 7.59 - 7.51 (m, 2 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.39 - 7.31 (m, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 6.93 (d, J = 2.7 Hz, 1 H), 6.88 (d, J = 8.9 Hz, 1 H), 4.33 - 4.28 (m, 1 H), 4.27 - 4.10 (m, 7 H), 3.95 (d, J = 13.2 Hz, 1 H), 3.68 (d, J = 10.7 Hz, 10 H), 3.42 (d, J = 13.5 Hz, 2 H), 2.95 - 2.73 (m, 4 H), 2.29 (d, J = 10.5 Hz, 2 H), 2.08 (d, J = 8.6 Hz, 2 H), 1.20 - 1.08 (m, 10 H), 1.03 (s, 3 H). EXAMPLE 237

[001107] ((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-( 4-((6-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate.

[001108] Intermediates: I3, P26, and S3. MS (ESI) m/z 1060.3 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (d, J = 4.8 Hz, 1 H), 8.12 (d, J = 9.4 Hz, 1 H), 7.92 (dd, J = 18.0, 8.2 Hz, 3 H), 7.73 - 7.65 (m, 2 H), 7.42 (t, J = 5.5 Hz, 1 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H),6.86 (d, J = 8.9 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.81 - 4.76 (m, 3 H),4.46 - 4.23 (m, 5 H), 4.18 - 4.03 (m, 5 H), 3.68 (s, 5 H), 3.62 (s, 3 H),3.37 (d, J = 14.0 Hz, 3 H), 2.96 - 2.75 (m, 4 H), 2.23 (d, J = 10.2 Hz, 2H), 2.08 (d, J = 8.7 Hz, 2 H), 1.12 (d, J = 16.0 Hz, 7 H), 0.84 (s, 10 H). EXAMPLE 238

[001109] ((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-yl)benzyl)-8-(4-((6-(8-( 2,2-difluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl)pyridin-3-yl)ethynyl)benzyl)-16-fluoro-5-(1-fluoro-2-methylpropan-2-yl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo Methyl -2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate.

[001110] Intermediates: I1a, A7, P26 and S63. MS (ESI) m/z 1068.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (d, J = 4.9 Hz, 1 H), 8.28 - 8.24 (m, 1 H), 8.00 - 7.82 (m, 4 H), 7.75 - 7.65 (m, 2 H), 7.47 - 7.41 (m, 1 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 6.88 (d, J = 8.9 Hz, 1 H), 4.31 - 3.95 (m, 15 H), 3.66 (d, J = 15.6 Hz, 10 H), 3.43 (d, J = 13.4Hz, 2H), 2.99 - 2.79 (m, 4 H), 2.34 - 2.24 (m, 2 H), 2.08 (t, J = 7.0 Hz, 2 H), 0.96 - 0.80 (m, 14 H). EXAMPLE 239

[001111] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15 ,15-dimethyl-8-(4-((6-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1, 1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate methyl.

[001112] Intermediates: I2, P15, and S3. MS (ESI) m/z 1134.4 [M+H] +.1H NMR (400 MHz, Methanol-d4) δ 8.65 (dd, J = 8.6, 5.6 Hz, 1 H), 8.29(d, J = 2.2 Hz, 1 H), 8.12 (d, J = 9.5 Hz, 1 H), 7.78 - 7.61 (m, 5 H), 7.33(d, J = 7.8 Hz, 2 H), 7.25 - 7.18 (m, 3 H), 6.85 (d, J = 8.9 Hz, 1 H), 4.96(t, J = 7.6 Hz, 2 H), 4.53 (s, 1 H), 4.44 (d, J = 9.7Hz, 1 H), 4.33 (dd, J = 19.5, 12.0 Hz, 4 H), 4.17 (d, J = 14.3 Hz, 5 H), 3.98 (d, J = 13.1 Hz, 1 H), 3.67 (d, J = 16.2 Hz, 8 H), 3.38 (d, J = 13.8 Hz, 2 H), 2.96 - 2.75 (m, 5 H), 2.23 (d, J = 11.2 Hz, 2 H), 2.08 (d, J = 8.6 Hz, 2 H), 1.18 - 1.10 (m, 10 H), 1.03 (s, 3 H). EXAMPLE 240

[001113] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-8-(4-( (6-(8-isopropyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-15,15-dimethyl- 3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl) methyl carbamate.

[001114] Intermediates: I2, P28, and S22. MS (ESI) m/z 1102.1 [M+H]+. EXAMPLE 241

[001115] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-8-(4-((6-(8-ethyl-3,8- diazabicyclo[3. 2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13- methyl trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate.

[001116] Intermediates: I2, P28, and S21. MS (ESI) m/z 1088.1 [M+H]+. EXAMPLE 242

[001117] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15 -dimethyl-8-(4-((6-(8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate.

[001118] Intermediates: I2, P28, and S20. MS (ESI) m/z 1074.4[M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (d, J = 5.1 Hz, 1 H), 8.29 (s, 1 H), 7.92 (d, J = 8.1 Hz, 2 H), 7.68 (d, J = 9.0 Hz, 1 H), 7.60 (d, J = 8.6 Hz, 2 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.9 Hz, 1 H), 4.44 (d, J = 9.7 Hz, 1 H), 4.33 (dd, J = 19.0, 11.6 Hz, 3 H), 4.20 - 4.06 (m, 5 H), 3.98 (d, J = 13.0 Hz, 1 H), 3.66 (d, J = 21.3 Hz, 8 H), 3.26 (s, 1 H), 2.91 (d, J = 7.9 Hz, 7 H),2.31 (s, 2 H), 2.07 (d, J = 8.8 Hz, 2 H), 1.19 - 1.10 (m, 11 H), 1.03 (s, EXAMPLE 243

[001119] ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-( 4-((6-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-aza-hexadecan-14-yl)carbamate.

[001120] Intermediates: I3, P9, and S3. MS (ESI) m/z 1065.6 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.39 - 8.28 (m, 2 H), 8.08 (d, J = 26.3 Hz, 2 H), 7.70 (dd, J = 8.8, 2.3 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 2 H), 7.48 (s, 1 H), 7.43 (d, J = 8.1 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 6.88 - 6.73 (m, 2 H), 4.96 (t, J = 7.6 Hz, 2 H), 4.81 (dd, J = 8.2, 5.0 Hz, 2 H), 4.52 (s, 1 H), 4.37 (t, J = 13.2 Hz, 3 H), 4.15 (s, 3 H), 3.95 (t, J = 10.7 Hz, 2 H), 3.78 (d, J = 9.5 Hz, 1 H), 3.69 (d, J = 10.5 Hz, 5 H), 3.62 (s, 3 H), 3.38 (d, J = 13.9 Hz, 2 H), 2.90 (t, J = 7.0 Hz, 2 H), 2.79 (t, J = 11.1 Hz, 2 H), 2.23 (d, J = 11.0 Hz, 2 H), 2.07 (d, J = 8.6 Hz, 2 H), 1.09 (s, 3H), 1.01 (s, 3H), 0.76 (s, 10H). EXAMPLE 244

[001121] ((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-yl)benzyl)-16-fluoro-5-(1-fluoro-2- methylpropan-2-yl)-9-hydroxy-15,15- dimethyl-3,6,13-trioxo-8-(4-((6-(8-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin- Methyl 3-yl)ethynyl)benzyl)-2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate.

[001122] Intermediates: I1a, A7, P26, and S62. MS (ESI) m/z 1086.4 [M+H] +. 1H 1H NMR (400 MHz, Methanol-d4) δ 8.67 - 8.62 (m, 1 H), 7.99 - 7.80 (m, 5 H), 7.71 - 7.61 (m, 2 H), 7.59 - 7.51 (m, 1 H), 7.44 (dd, J = 7.1, 5.1 - 3.46 (m, 10 H), 3.23 - 3.11 (m, 3 H), 2.99 - 2.80 (m, 5 H), 2.08 - 1.98 (m, 3 H), 1.78 (t, J = 7.1 Hz, 2 H), 0.95 - 0.80 (m, 12 H). EXAMPLE 245

[001123] ((5S,8S,9S,14S)-16,16,16-trifluoro-11-(2-fluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl -8-(4-((6-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl) Methyl -2-oxa-4,7,11,12-tetra-azahexadecan-14-yl)carbamate (ABC).

[001124] Intermediates: I2, P29 and S3. MS (ESI) m/z 1098.7 [M+H] +. 1H NMR (400 MHz, Methanol-d4) δ 8.65 - 8.61 (m, 1 H), 8.29 (d, J = 2.3 Hz, 1 H), 8.11 (d, J = 9.1 Hz, 1 H), 7.92 (dd, J = 18.5, 7.8 Hz, 2 H), 7.75 - 7.62 (m, 4 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.15 (d, J = 9.9 Hz, 1 H), 6.85 (d, J = 8.9 Hz, 1 H), 4.96 (t, J = 7.6 Hz, 3 H), 4.82 - 4.76 (m, 2 H), 4.53 - 4.12 (m, 10 H), 3.99 (d, J = 13.7 Hz, 3 H), 3.76 (s, 1 H), 3.68 (s, 3 H), 3.58 (s, 3 H), 3.37 (d, J = 14.0 Hz, 2 H), 2.86 (dd, J = 31.3, 7.8 Hz, 4 H), 2.22 (d, J = 10.8 Hz, 2 H), 2.07 (d, J = 8.8 Hz, 2 H), 1.18 - 1.05 (m, 9 H), 0.94 (s, 3 H).4. Biological AssaysHIV assay in MT-4.

[001125] Compounds were tested in a 384-well high-throughput assay format for their ability to inhibit HIV-1(IIIB) replication in MT-4 cells. Compounds were serially diluted (1:3) in DMSO in 384-well polypropylene plates and diluted 200-fold in complete RPMI media (10% FBS, 1% P/S) using the Biotek Micro Flow acoustic dispenser and Agilent ECHO. Each plate contained up to 8 test compounds, with negative controls (No Drug Control) and 5 uM AZT positive control. MT-4 cells were pre-infected with 10 uL RPMI (mock infected) or a fresh 1:250 dilution of a concentrated HIV-1(IIIB) virus stock. Infected and uninfected MT-4 cells were further diluted in complete RPMI medium and added to each plate using a Micro Flow dispenser. After 5 days of incubation in a humidified, temperature-controlled incubator (37 °C), Cell Titer Glo (Promega) was added to the assay plates to quantify the amount of luciferase. EC50 and CC50 values were defined as the concentration of compound that causes a 50% decrease in luminescence signal and were calculated using a sigmoidal dose-response model to generate curve fits. Data for selected compounds are reported in Table 1 below. MT-4 High-Resolution HIV Antiviral Assay

[001126] The assay protocol is identical to that described for the MT-4 antiviral assay with the following modifications: each drug is run in 2 quadruplicate series with different starting concentrations for each series and 19 1.5-fold dilutions performed on the plate. This results in an inhibition curve with 40 data points for each compound. Data are analyzed and Hill coefficients determined on Graph Pad Prism (San Diego, CA). EC95s were determined by the formula EC95 = (19)1/Hill coefficient x EC50. HD values were determined for certain compounds and reported in Table 5 below as an illustrative example. Liver Microsomal Stability Protocol

[001127] The test compounds and a control compound (verapamil) were tested in 3 different species in duplicate sets.General Conditions:

[001128] Test compound concentration: 1 uM; Protein concentration: 0.5 mg/mL (for dog, rat, and human liver microsomes); Cofactor: NADPH regeneration system (NRS) solution; Time points: 2, 12, 25, 45, and 65 minutes.

[001129] The reaction composition (in each incubation well) contains:

[001130] At an incubation temperature of 37°C, the reaction was initiated by the addition of NADPH Regeneration System, at each time point, 25 μL of the reaction mixture was removed and added to a plate with 225 μL of quench solution (50% MeOH, 25% ACN, 25% H2O and 200 nM labetalol as internal standard). After the plates were vortexed, they were centrifuged for 30 minutes to remove proteins. Approximately 100 μL of supernatant was removed to a new plate and diluted with 150 μL of water. Approximately 20 μL of the mixture was injected into the LC/MS/MS system to monitor the compound response. In vitro measured T1/2 was used to calculate Clint values. The data are presented in Table 1 below and in Figure 1. TABLE 1 3H Human Predictable Clearance Assay:

[001131] For certain compounds, tritiated analogs (H3) were prepared to also determine their predicted human clearance with increased resolution. These studies were performed as described above using the tritiated analogs. Data for these compounds are found in Table 2 below and reported in Figure 1 (note: ATV and DRV were not tritiated).TABLE 2 Pharmacokinetic ProfilesPK of Dog

[001132] The test compound was formulated in 5% EtOH, 55% PEG 300, and 40% water (pH 2, HCl) for intravenous infusion administration and was formulated in 5% ethanol, 55% PEG 300, 1% Tween 80, and 39% water (pH 2) for oral administration. Each dosing group consisted of three non-naive male beagle dogs. At dosing, animals weighed between 9 and 12 kg. Animals were fasted overnight prior to dosing and for up to four hours following dosing. The test article was administered by intravenous infusion over 30 minutes. The infusion rate was adjusted according to each animal's body weight to deliver a dose of 0.5 or 1.0 mg/kg. For the oral dosing group, the test article was administered by oral gavage at a dose volume of 2 mL/kg.

[001133] Serial venous blood samples (approximately 1.0 mL each) were collected at pre-dose and 0.25, 0.48, 0.58, 0.75, 1.0, 1.5, 2, 4, 8, 12, and 24 hours post-dose from each animal for the IV dosing group; blood samples were collected at pre-dose, 0.25, 0.50, 1.2 4, 6, 8,12, and 24 hours post-dose for the oral dosing group. Blood samples were collected in VacutainerTM tubes containing EDTA-K2 as an anticoagulant and were immediately placed on wet ice pending centrifugation for plasma. An LC/MS/MS method was used to measure the concentration of the test compound in plasma. Non-compartmental pharmacokinetic analysis was performed on the plasma concentration-time data. Data for selected compounds are reported in Figure 2 and Table 3 below. VSS = apparent volume of distribution, t1/2 = half-life, F = oral bioavailability.TABLE 3 Rat PK:

[001134] The test article was formulated in 5% ethanol, 55% PEG 300, and 40% water (pH 2) for IV infusion administration and was formulated in 5% ethanol, 55% PEG 300, 1% Tween 80, and 39% water (pH 2) for oral administration. Each dosing group consisted of 3 naïve SD rats. At dosing, animals weighed between 0.27 and 0.32 kg. Animals were fasted overnight prior to dosing. The test article was administered by intravenous infusion over 30 min. The infusion rate was adjusted according to each animal's body weight to deliver a dose of 0.5 or 1.0 mg/kg. For the oral dosing group, the test article was administered to animals by oral gavage administration. Serial venous blood samples (approximately 0.30 mL each) were collected at pre-dose and 0.25, 0.48, 0.58, 0.75, 1.5, 3, 6, 8, 12, and 24 hours post-dose for animals in the IV dosing group. Blood samples were collected at post-dose, 0.25, 0.50, 1, 2, 4, 6, 8, 12, and 24 hours post-dose for animals in the oral group. Blood samples were collected in VacutainerTM tubes containing EDTA-K2 as an anticoagulant and were immediately placed on wet ice pending centrifugation for plasma. An LC/MS/MS method was used to measure the concentration of the test compound in plasma. Non-compartmental pharmacokinetic analysis was performed on the plasma concentration-time data.

[001135] Data for certain compounds are reported in Table 4 and Figure 3 accordingly.TABLE 4 Protease Resistance Screening.

[001136] Drug EC50 values versus PI-resistant mutant viruses for selected compounds were determined in a 5-day multiple cycle cell viability assay with cytopathic effect (CPE) measurement protection. Briefly, MT-2 cells were mass infected at a density of 2 x106 cells/mL with WT or mutant viruses at a multiplicity of infection (MOI) of 0.01, gently rocking the culture for 3 hours at 37°C, and then added in triplicate to 96-well plates (Corning Life Sciences, Tewksbury, MA, USA). Cells were incubated in complete RPMI medium containing a 10-point 3-fold serial drug dilution (0.5% DMSO final concentration) for five days at 37°C in 5% CO2. After this time, 100 μL of CellTiter-Glo reagent (Promega, Madison, WI, USA) was added to each well, and the luminescence signals quantified in an EnVision plate reader (Perkin-Elmer, Inc., Waltham, MA, USA). EC50 values, defined as the drug concentration that induces 50% protection from HIV-induced cell death, were calculated from a minimum of three independent experiments performed in quadruplicate using XLFit™ software (IDBS, Ltd., Guildford, Surrey, UK) and nonlinear regression analysis. As an illustrative example, the data associated with the compound of Example 58 (GSPI1) are presented in Figure 4 below in comparison with other HIV protease inhibitors (atazanavir and darunavir).MT-2 cell viral penetration assay.

[001137] MT-2 cells were infected with HIV-1IIIB (Advanced Biotechnologies, Eldersburg, MD, USA) at a relatively high multiplicity of infection (MOI = 0.05) for 3 hours and seeded in 24-well plates at 2 x 105 cells per well. Drugs were added 16 hours later to a minimum of quadruplicate wells at fixed multiples of their EC50 values. Every 3-4 days, cells were diluted (1:5) into freshly prepared cell culture media containing drug concentrations at the same multiple of EC50 values and monitored for virus-induced cytopathic effects (CPE) over a 32-day period. Cell-free virus supernatants were harvested from wells with >80% CPE and kept frozen at -80°C until further analysis. As an illustrative example, data associated with the compound of Example 58 (GSPI1) are presented in Figure 5 below in comparison with other HIV protease inhibitors (atazanavir, darunavir) and efavirenz.Genotypic analysis of penetration viruses.

[001138] Total RNA was purified from cell-free supernatants obtained from each CPE-positive and p24-positive well using the Qiagen Viral RNA Isolation kit (Qiagen, Valencia, CA, USA). The coding regions targeted by each drug were amplified by One-Step RT-PCR (Qiagen) and the products subjected to DNA sequencing. Sequence changes were identified by alignment with input virus sequences using Sequencher (Gene Codes Corp., Ann Arbor, MI, USA) and amino acid substitutions were determined. Equilibrium dialysis assay

[001139] Pooled plasma (from at least 3 males and 3 females) was from Bioreclamation IVT. Sodium EDTA was used as anticoagulant. 10% plasma was diluted in 0.133M phosphate buffer consisting of 1.5% (w/v) sodium EDTA.

[001140] RPMI cell culture medium consisting of 10% FBS was provided by the Biology Department, Gilead Sciences, Inc.

[001141] Plasma Protein Binding Assay: Studies were performed in duplicate or triplicate using a Dianorm Equilibrium Dialyser (Harvard Apparatus, Holliston MA) with each cell consisting of a semipermeable membrane (2.4 cm working diameter) separating two 1 mL PTFE half-cells (Weder HG, Schildknecht J, Kesselring P. A new equilibrium dialyzing system. American Laboratory. 1971; 10: 15-21). Prior to the study, the dialysis membrane was soaked for approximately one hour in 0.133 M phosphate buffer, pH 7.4. 10% plasma and cell culture media supplemented with 1 μM compound (1 mL) were placed on opposite sides of the pooled dialysis cells, and the dialysis cells were then slowly rotated in a 37°C water bath. After the equilibration period, matrix-containing samples from both sides were drained into pre-weighed polypropylene tubes. The 10% post-dialysis plasma samples were transferred to centrifuge tubes containing 1 mL of blank cell culture media. The post-dialysis cell culture media samples were transferred to centrifuge tubes containing 1 mL of blank 10% plasma. All sample weights were measured and recorded for volume change and recovery calculations.

[001142] Samples were deproteinated by treatment with four volumes of 90% (v/v) acetonitrile, 10% (v/v) methanol containing the LC-MS internal standard. Samples were centrifuged at 15,000 rpm at 4°C for 15 min and 200 μL aliquots of the supernatants were added and mixed with an equal volume of water. Samples were vortexed for 2 min and then aliquots (10 μL) were subjected to LC-MS/MS analysis. Data analysis

[001143] The agglutination ratio for an analyte in plasma versus cell culture media was calculated using the following equations:Ratio = C10% plasma/CCCMwhere C10% plasma is the post-dialysis 10% plasma concentration (determined by PAR) and CCCM is the post-dialysis cell culture media concentration (determined by PAR) respectively. Each concentration was gravimetrically corrected for changes in fluid volume in the dialysis cells that occurred during dialysis. Protease Ki Assay

[001144] Inhibitor potency was measured using an enzymatic assay with a fluorogenic readout. To a reaction buffer containing 100 mM ammonium acetate at pH 5.3, 100 mM NaCl, 1 mM EDTA, 1 mM DTT, 0.25 mg/mL BSA, and 1% DMSO were added 2.5 nM recombinant HIV protease and test compound at one of several concentrations. After a 20-minute preincubation, the enzymatic reaction was initiated by the addition of the fluorogenic substrate (2-aminobenzoyl)Thr-Ile-Nle-(p-nitro)Phe-Gln-Arg (Bachem) to a final concentration of 40 μM. The total volume of the assay solution was 100 μL. The reaction was measured over 20 minutes on a Tecan Infinite M1000 plate reader using an excitation wavelength of 320 nm and a detection wavelength of 420 nm. The slopes of the progress curves were a measure of the reaction rates. The reaction rates were plotted as a function of inhibitor concentration and the data were fitted using the tight binding equation described by Morrison (Biochim. Biophys. Acta 1969, 185, 269-286) to produce Ki values. Table 5: Potency of Compound 58, DRV and ATV

Claims (14)

1. Compound, characterized by the fact that it presents the Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 5- to 10-membered heterocycle having 1 to 5 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 5- to 10-membered heterocycle or 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 Ra groups; R 2 and R 3 are each independently C 1-4 alkyl, C 3- 6 cycloalkyl, O-R 2A, C 1-2 alkyl-O-R 2A, N-(R 3A) 2, or C 1-2 alkyl-N-(R 3A) 2, wherein each R 2A is independently C 1-4 alkyl, C 3- 6 cycloalkyl, or a 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein each R3A is independently hydrogen, C1-4alkyl, C3-6cycloalkyl, or COO(Re), and wherein each C3-6cycloalkyl or 4- to 10-membered heterocyclyl is optionally substituted with 1 to 3 Rf groups, wherein each Rf is independently C1-2alkyl or halogen; R4 is hydrogen, halo, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C1-4alkoxy, or C1-4haloalkoxy; R7 is hydrogen, halo, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C1-4alkoxy, or C1-4haloalkoxy; R5, R6, R8, and R9 are each independently hydrogen, halo, C1-2alkyl, C1-2 haloalkyl, or C3-6cycloalkyl; and wherein two or more of R4, R5, and R6 or two or more of R7, R8, and R9 optionally join together to form one or more C3-6cycloalkyl groups which are optionally substituted by 1 to 4 groups selected from halogen, C1-2alkyl, and C1-2 haloalkyl; each R10 is independently halogen, cyano, C1-4alkoxy, C1-6alkyl, or C3-6cycloalkyl; n is 0 to 4; each Ra is independently halogen, C1-4alkyl, C1-4alkyl having 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, C1-4 haloalkyl, C1-4alkoxy, C3-6 cycloalkyl, 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S that are optionally substituted by Ra1, or O-R3B, wherein R3B is C3-6cycloalkyl optionally substituted by Ra1 or a 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S optionally substituted by Ra1, wherein each Ra1 is independently C1-4alkyl, C3-6 cycloalkyl, C1-4haloalkyl, or 4- to 8-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S; A is ethynyl; X1 is a 6- to 10-membered or a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein each 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 Rb groups; X2 is hydrogen or a 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is optionally substituted by one R11 and optionally substituted by 1 to 5 Rb groups; R11 is C=O(Rc), CH2(Rd), S(O)1-2(C1-4alkyl), S(O)1-2C3-6cycloalkyl, a 4- to 10-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, or a 5- to 9-membered heterocyclyl having 1 to 5 heteroatoms selected from N, O, and S, wherein each 4- to 10-membered heterocyclyl or 5- to 9-membered heteroaryl is optionally substituted by 1 to 5 Rb groups; each Rb is independently halogen, oxo, C1-4alkyl, C1-4alkyl with 1 to 2 groups selected from hydroxyl and C1-4 alkoxy, C1-4 haloalkyl, C1-4 alkoxy, or COO(Re); Rc is C1-4alkyl, C1-4 haloalkyl, C1-4alkoxy, N(Re)2, C3-6cycloalkyl, or a 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C3-6cycloalkyl and the 4- to 6-membered heterocyclyl are optionally substituted by 1 to 5 groups Rb;Rd is COO(Re), N(Re)2, C3-6 cycloalkyl, or a 4- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the C3-6 cycloalkyl and the 4- to 6-membered heterocyclyl are optionally substituted with 1 to 5 Rb groups;each R12 is C1-2alkyl, halo, -OC1-2alkyl, or cyano;each p is 0 to 4;and each Re is independently hydrogen or C1-4alkyl. 2. Compound according to claim 1, characterized in that the compound of Formula (I) is a compound of:(i) Formula (Ia): wherein R10a and R10b are independently halogen, C1-6alkyl, or C3-6cycloalkyl, or a pharmaceutically acceptable salt thereof; or(ii) Formula (Ib): or a pharmaceutically acceptable salt thereof, wherein:Z1 and Z2 are independently N or CH; and m is 0 to 2; or(iii) Formula (Ic): or a pharmaceutically acceptable salt thereof, wherein:or a pharmaceutically acceptable salt thereof, whereinZ1 and Z2 are independently N or CH; or(iv) Formula (Id): or a pharmaceutically acceptable salt thereof; or (v) Formula (Ie): or a pharmaceutically acceptable salt thereof. 3. Compound, characterized by selected from or a pharmaceutically acceptable salt thereof. 4. Compound according to any one of claims 1 to 3, characterized in that it is or a pharmaceutically acceptable salt thereof. 5. Compound according to any one of claims 1 to 3, characterized in that it is or a pharmaceutically acceptable salt thereof. 6. Pharmaceutical composition, characterized by the fact that it comprises a therapeutically effective amount of a compound as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 7. Pharmaceutical composition according to claim 6, characterized in that it also comprises one, two, three, or four additional therapeutic agents. 8. The pharmaceutical composition of claim 7, wherein the additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds that target an HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, non-integrin 1 dendritic ICAM-3 sink inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combinations thereof. 9. Pharmaceutical composition according to claim 7 or 8, characterized in that the additional therapeutic agents are selected from the group consisting of: i) abacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate; or ii) tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate; oriii) abacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, emtricitabine, lamivudine, GS-9131, dolutegravir, and cabotegravir; oriv) bictegravir, emtricitabine, and GS-9131; orv) a compound selected from: and or a pharmaceutically acceptable salt thereof. 10. Use of a compound as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition as defined in any one of claims 7 to 9, characterized in that it is for the manufacture of a composition or medicament for treating or preventing an infection by the human immunodeficiency virus (HIV). 11. Use according to claim 10, characterized in that said use comprises administering one, two, three or four additional therapeutic agents. 12. Use according to claim 11, characterized in that the additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs to treat HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds that target an HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, non-integrin 1 dendritic ICAM-3 grabbing inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combinations thereof. 13. Use according to claim 11, characterized in that said compound is combined with: i) abacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate; or ii) tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate; oriii) abacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, emtricitabine, lamivudine, GS-9131, dolutegravir, and cabotegravir; oriv) bictegravir, emtricitabine, and GS-9131; orv) a compound selected from: and or a pharmaceutically acceptable salt thereof. 14. Use according to claim 11, characterized in that said compound is combined with: i) a first additional therapeutic agent selected from the group consisting of abacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine; or ii) a first additional therapeutic agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine; oriii) a first additional therapeutic agent selected from the group consisting of tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.