EA040208B1 - ANALOGUES OF ATAZANAVIR (ATV) FOR THE TREATMENT OF HIV INFECTIONS - Google Patents

Description

Cross-reference to related links

This patent application claims priority on U.S. Provisional Application No. 62/455,348, filed Feb. 6, 2017. The content of this application is incorporated into the present description by reference.

Technical field

The present invention relates to novel compounds for use in the treatment of infection caused by viruses of the Retroviridae family, including infection caused by the human immunodeficiency virus (HIV). The present invention also relates to intermediates for their preparation and to pharmaceutical compositions containing said compounds.

State of the art

Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) codes for three enzymes that are essential for virus replication: reverse transcriptase, protease, and integrase. Several protease inhibitors (PIs) are currently approved for use in AIDS or HIV. However, a disadvantage of many PI inhibitors is their rapid hepatic metabolism, which may require simultaneous administration of a booster or more frequent dosing. In addition, viral resistance is still a problem. Accordingly, there is a need for new agents that inhibit HIV replication.

Brief description of the invention

The present invention provides compounds for the treatment and methods of treating HIV infection. Accordingly, in one embodiment, the present invention provides a compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein

R ¹ is a 5-10-membered heterocycle containing from 1 to 5 heteroatoms selected from N, O and S, or a 5-10-membered heteroaryl containing from 1 to 5 heteroatoms selected from N, O and S, and said 5-10 membered heterocycle or said 5-10 membered heteroaryl is optionally substituted with 1-5 R ^a groups;

each R ² and R ³ is independently C1-4αalkyl, C3-6cycloalkyl, OR ^2A , C1-2alkyl-OR ^2A , N-(R ^3A )2 or C1-2alkyl-N-(R ^3A )2 where each R ^2A is independently C _1-4 alkyl, C _3-6 cycloalkyl or 4-10 membered heterocyclyl containing 1 to 5 heteroatoms selected from N, O and S, where each R ^3A is independently hydrogen, C _{1- 4} alkyl, C _3-6 cycloalkyl or COO(R ^e ), where each C _3-6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with 1-3 R ^f groups, where each R ^f is independently C _1-2 alkyl or halogen;

R ⁴ is C _1-4 alkyl or C _1-4 haloalkyl;

R ⁷ is C1-4 alkyl or C1-4 haloalkyl; each R ⁵ , R ⁶ , R ⁸ and R ⁹ is independently C 1-2 alkyl or C _1-2 haloalkyl;

and wherein two or more of R ⁴ , R ⁵ and R ⁶ or two or more of R ⁷ , R ⁸ and R ⁹ are optionally combined to form one or more C3-6 cycloalkyl groups which are optionally substituted with 1-4 groups selected from halogen, C _1-2 alkyl and C _1-2 haloalkyl;

each R ^10a and R ^10b is halogen;

each R ^a is independently halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4α alkoxy, C3-6 cycloalkyl, 4-10 membered heterocyclyl, or OR ^3B , wherein said C1-4 alkyl is optionally substituted with 1-2 groups selected from hydroxyl and C _1-4 alkoxy, said 4-10 membered heterocyclyl contains 1 to 5 heteroatoms selected from N, O and S, and said 4-10 membered heterocyclyl is optionally substituted with R ^a1 ;

- 1 040208 where R ^3B is C ₃ - ₆ cycloalkyl optionally substituted with R ^a1 , or 4-10 membered heterocyclyl containing 1 to 5 heteroatoms selected from N, O and S, optionally substituted with R ^a1 , where each R ^a1 is independently C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 haloalkyl or 4-8 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S;

X ¹ is a 6-10 membered aryl or a 5-10 membered heteroaryl containing from 1 to 3 heteroatoms selected from N, O and S, each 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted 1-4 groups R ^b ;

X ² is hydrogen or a 4-10 membered heterocyclyl containing from 1 to 5 heteroatoms selected from N, O and S, said 4-10 membered heterocyclyl is optionally substituted with one R ¹¹ group and optionally substituted with 1-5 R groups ^b ;

R ¹¹ is C=O(R ^c ), CH2(R ^d ), S(O) 1 . ₂ (C ₁ .4alkyl), S(O) ₁ . ₂ C ₃ . ₆ cycloalkyl, 4-10 membered heterocyclyl containing from 1 to 5 heteroatoms selected from N, O and S, or 5-9 membered heteroaryl containing from 1 to 5 heteroatoms selected from N, O and S, each 4-10 membered heterocyclyl or 5-9 membered heteroaryl is optionally substituted with 1-5 R ^b groups;

each R ^b is independently halogen, oxo, C1-4 alkyl, C1-4 haloalkyl, C1.4α alkoxu, or COO(R ^e ), wherein said C1_4 alkyl is optionally substituted with 1-2 groups selected from hydroxyl and C ₁ _4 alkoxy;

R ^c is C1_4 alkyl, C1-4 haloalkyl, C^alkoxy, N(R ^e )2, C _{3 -6} cycloalkyl or 4-6 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, said C3 -6-cycloalkyl and said 4-6 membered heterocyclyl are optionally substituted with 1-5 R ^b groups;

R ^d is COO(R ^e ), N(R ^e )2, C3-6 cycloalkyl or 4-6 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, said C3-6 cycloalkyl and said 4-6 membered heterocyclyl optionally substituted with 1-5 R ^b groups;

and each R ^e is independently hydrogen or C ₁ - ₄ alkyl.

Also provided is a pharmaceutical composition containing a therapeutically effective amount of a compound disclosed in the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, said pharmaceutical composition further comprises one, two, three, or four additional therapeutic agents.

Also provided is a method for treating or preventing an infection caused by the human immunodeficiency virus (HIV), comprising administering a therapeutically effective amount of a compound disclosed in the present invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

In some embodiments, the present description relates to a product containing a single dose of a compound disclosed in the present invention, or a pharmaceutically acceptable salt thereof.

Also provided is a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in therapy.

Also provided is a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in a method for treating or preventing a human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of said compound to a subject in need thereof.

Brief description of the drawings

In FIG. 1 shows the estimated hepatic clearance for some of the compounds and controls described in more detail in the biological examples in the present invention.

In FIG. 2 is a graph for intravenous (IV) pharmacokinetic studies in dogs for some compounds and control compounds, and a table that summarizes IV and oral pharmacokinetic (PK) data for these compounds, described in more detail in the examples in the present invention.

In FIG. 3 is a graph for IV pharmacokinetic studies in rats for some compounds and controls, and a table summarizing IV and oral pharmacokinetic (PK) data for these compounds, described in more detail in the examples in the present invention.

In FIG. 4 shows the fold change for some resistance mutations of the clinical isolate versus wild type for some of the compounds and controls described in more detail in the examples in the present invention.

In FIG. 5 shows the resistance breakthrough for some of the compounds and control compounds described in more detail in the examples in the present invention.

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Detailed description of the invention

The following is a list of abbreviations and abbreviations used in this specification:

Reduction Meaning °C Degree Celsius ATP Adenosine 5'-triphosphate ASON Acetic acid d doublet dd Doublet of doublets dhe 1,2-Dichloroethane DXM dichloromethane DIPEA Ν,Ν-diisopropylethylamine DME 1,2-Dimethoxyethane DMF Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-Bis(diphenylphosphino)ferrocene EGTA Ethylene glycoltetraacetic acid ETOAC ethyl acetate equiv./equiv. Equivalents IES Electrospray ionization ace Acetate

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Et Ethyl G grams go 2-(7-Aza-1 H-benzotriazol-1-yl)-1,1,3,3tetramethyluronium hexafluorophosphate hERG Gene specific potassium channels of the human heart (human Ether-a-go-go Related Gene) HPLC High Performance Liquid Chromatography h/h Watch HZ IC50 J Hertz Half-maximal inhibition concentration Interaction constant Kg Kilogram M Molar m multiplet m/z mass-to-charge ratio M+ Mass Rush M+N Mass peak plus hydrogen Me Methyl Meon Methyl alcohol/methanol mg Milligram MHz min/m Megahertz Minute ml Milliliter mm millimolar mmol Millimole MS Mass spectroscopy mw Microwave n. Normal mole mole NMP L/-methylpyrrolidinone NMR Nuclear magnetic resonance Ph Phenyl PPm parts per million prel RF Preparative Retention ratio RP reversed phase CT/c. T. Room temperature With Second S Singlet t Triplet TED Triethylamine TFU Trifluoroacetic acid TLC Thin layer chromatography TMS Trimethylsilyl dt δ wild type chemical shift mcg microgram µl microliter µM micromolar micron Micrometer µmol Micromol

Unless otherwise indicated, all technical and scientific terms in the context of this description have the same meanings that are usually understood by a person skilled in the art. It should be noted that in the context of the present specification and in the appended claims, singular forms include references to plural forms, unless the context clearly indicates otherwise. Thus, for example, a reference to a compound includes a plurality of such compounds, a reference to an assay includes a reference to one or more assays and their equivalents known to those skilled in the art, and so on.

A dash at the beginning or end of a chemical group is provided for convenience; chemical groups may be shown with or without one or more dashes without losing their normal meanings. A wavy line drawn across a line in a structure indicates where the group is attached, for example:

A dotted line indicates an optional relationship. When multiple substituent groups are indicated, the point of attachment is on the terminal substituent (for example, for alkylaminocarbonyl, the point of attachment is on the carbonyl substituent).

The prefix Cx-y indicates that the following group contains x (e.g. 1) to y (e.g. 6) carbon atoms, one or more of which in some groups (e.g., heteroalkyl, heteroaryl, heteroarylalkyl, etc.) ) may be replaced by one or more heteroatoms or heteroatomic groups. For example, C _1-6 αkil indicates that the alkyl group contains from 1 to 6 carbon atoms. Similarly, the term x-y-membered rings, where x and y are numerical ranges, such as 312-membered heterocyclyl, refers to a ring containing x-y atoms (e.g., 3-12), up to 80% of which may be heteroatoms. , such as N, O, S, P, and the remaining atoms are carbon atoms.

In addition, some commonly used alternative chemical names may or may not be applied. For example, a divalent group such as a divalent alkyl group, a divalent aryl group, etc. may also be referred to as an alkylene group, or an alkylenyl group, or an alkylyl group, an arylene group, or an arylenyl group, or an aryl group, respectively.

The compound described in the present invention or the compound according to the present description refers to compounds of formula (Ia), (Ic), (Id) and/or (Ie). Also included are specific compounds according to examples 1-245.

Alkyl refers to any group derived from a linear or branched saturated hydrocarbon. Alkyl groups include, but are not limited to, methyl, ethyl, propyl such as propan-1-yl, propan-2-yl (isopropyl), butyls such as butan-1-yl, butan-2-yl (sec- butyl), 2-methylpropan-1-yl (isobutyl), 2-methylpropan-2-yl (tert-butyl), pentyls, hexyls, octyls, decyls, and the like. Unless otherwise indicated, an alkyl group contains 1 to 10 carbon atoms, eg 1 to 6 carbon atoms, eg 1 to 4 carbon atoms.

Alkenyl refers to any group derived from a straight or branched hydrocarbon with 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 indicated, an alkenyl group contains 2 to 10 carbon atoms, eg 2 to 6 carbon atoms, eg 2 to 4 carbon atoms.

Alkynyl refers to any group derived from a straight or branched hydrocarbon with at least one carbon-carbon triple bond and includes groups containing one triple bond and one double bond. Examples of alkynyl groups include, but are not limited to, ethynyl (-C=C-), propargyl (-CH ₂ C=C-), (E)-pent-3-en-1-ynyl, and the like. Unless otherwise indicated, the alkynyl group contains 2 to 10 carbon atoms, eg 2 to 6 carbon atoms, eg 2 to 4 carbon atoms.

Amino refers to -NH2. Amino groups may also be substituted, as described herein, for example with alkyl, carbonyl, or other amino groups. The term alkylamino refers to an amino group substituted with one or two alkyl substituents (eg dimethylamino or propylamino).

The term aryl in the context of the present description refers to a single all-carbon aromatic ring or a system of several fused all-carbon rings, where at least one of these rings is aromatic. For example, in some embodiments, the aryl group contains 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple fused ring systems (e.g., ring systems containing 2, 3, or 4 rings) containing from about 9 to about 20 carbon atoms, in which at least one ring is aromatic and the other rings may be aromatic. or non-aromatic (that is, carbocyclic). Such multiple fused ring systems are optionally substituted with one or more

- 5 040208 (for example, 1, 2 or 3) oxo groups in any carbocyclic part of the system of several fused rings. Rings of a system of several fused rings can be connected to each other by condensation, with the help of spiro- and bridging bonds, if valency requirements allow. It should also be understood that when reference is made to an aryl with a range of number of atoms (eg, 6-10 membered aryl), said range of number of atoms refers to the total number of ring atoms of the specified 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 derived from acenaphthylene, anthracene, azulene, benzene, chrysene, 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.

Bridged refers to the condensation of rings where non-adjacent atoms in the ring are connected by a divalent substituent, such as an alkylenyl or heteroalkylenyl group, or a single heteroatom. Examples of bridged ring systems are quinuclidinyl and adamantanyl.

The term cycloalkyl refers to a single saturated or partially unsaturated all-carbon ring containing from 3 to 20 ring carbon atoms (i.e. C _{3 -20} cycloalkyl), for example from 3 to 12 ring atoms, for example from 3 to 10 ring atoms. The term cycloalkyl also includes systems of multiple fused saturated and partially unsaturated all carbon rings (eg ring systems containing 2, 3 or 4 carbocyclic rings). Accordingly, cycloalkyl includes multicyclic carbocycles such as bicyclic carbocycles (for example, bicyclic carbocycles containing from about 6 to 12 ring carbon atoms, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane) and polycyclic carbocycles (for example , tricyclic and tetracyclic carbocycles containing up to about 20 ring carbon atoms). Rings of a system of several fused rings can be connected to each other by condensation, with the help of spiro- and bridging bonds, if valency requirements allow. 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.

Halogen (halo) and halogen (halogen) refer to fluoro-, chlorine-, bromine- and iodine-.

Haloalkyl refers to alkyl in which each of one or more hydrogen atoms has been replaced by a halogen. Examples include, but are not limited to, -CH ₂ Cl, -CH2F, -CH ₂ Br, -CFClBr, CH ₂ CH ₂ Cl, -CH2CH2F, -CF ₃ , -CH2CF3, -CH ₂ CCl ₃ and the like, and also alkyl groups, such as perfluoroalkyl, in which all hydrogen atoms have been replaced by fluorine atoms.

Alkoxy or alkoxy refers to a moiety of the formula -O-alkyl, where the alkyl moiety is as defined above. For example, C ₁ .4αlkoxy refers to a moiety containing a 1-4 carbon alkyl group attached to an oxygen atom. Haloalkoxy or haloalkoxy refers to a moiety of the formula -O-haloalkyl, wherein the haloalkyl moiety is as defined above. For example, C ₁ .4 alkoxy refers to a moiety containing a 1-4 carbon haloalkyl group attached to an oxygen atom.

Heteroalkyl refers to alkyl in which each of one or more carbon atoms (and any associated hydrogen atoms) is independently replaced by the same or 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. The heteroalkyl group contains 1 to 10 carbon atoms and up to 3-4 heteroatoms, for example 1 to 6 carbon atoms and 1 to 2 heteroatoms.

Heteroaryl refers to a mono- or multicyclic aryl group in which one or more aromatic carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatoms or heteroatomic groups as defined above. Multicyclic ring systems are included in heteroaryl and may be ring-attached with a heteroatom or an aryl ring. Heteroaryl groups include, but are not limited to, groups derived from acridine, benzoimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, cinnoline, 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, pyrrolysine, quinoline, quinoline , quinolysine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene and the like. Heteroaryl groups may contain 5-12 elements, 5-10 elements or 5-6 elements.

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The term heterocyclyl or heterocycle in the context of the present description refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic system of several rings, which or which contains at least one heteroatom in the ring (i.e. at least one ring heteroatom selected from oxygen, nitrogen and sulfur). Unless otherwise indicated, a heterocyclyl group contains 5 to about 20 ring atoms, such as 3 to 12 ring atoms, such as 3 to 10 ring atoms, such as 5 to 10 ring atoms, or such as 5 to 6 ring atoms. Thus, the term includes individual saturated or partially unsaturated rings (for example, 3-, 4-, 5-, 6-, or 7-membered rings) containing 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. Rings of a system of several fused rings (eg, bicyclic heterocyclyl) can be connected to each other by condensation, using spiro- and bridging bonds, if valency requirements allow. 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-2H -thiopyran 1,1-dioxide, quinuclidine, N-bromopyrrolidine, N-chloropiperidine and the like. Heterocycles include spirocycles such as, for example, aza- or oxospiroheptanes. Heterocyclyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems with one aromatic ring and one non-aromatic ring, but not fully aromatic ring systems. Examples include dihydroquinolines, eg 3,4-dihydroquinoline, dihydroisoquinolines, eg 1,2dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc., indoline, isoindoline, isoindolones (eg, isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, spiro[ cyclopropan-1,1'isoindoline]-3'-one and the like. Additional examples of heterocycles include, for example, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-oxa7,9-diazabicyclo[3.3 .1 ]nonanyl and hexahydropyrazino[2,1-c][1,4]oxazinyl.

Hydroxyl and hydroxy are used interchangeably and refer to -OH.

1=0 or ko"

Oxo refers or * ⁱ

In the case where tautomeric forms of the compound exist, the hydroxyl group and the oxo group are interchangeable.

It is contemplated that combinations of chemical groups can be used and will be apparent to those skilled in the art. For example, a hydroxyalkyl group would refer to a hydroxyl group attached to an alkyl group. A significant number of such combinations can be easily imagined. Additional examples of combinations of substituents in the context of the present description include: C _1-6 alkylaminocarbonyl (for example, CH ₃ CH ₂ NHC(O-), C _1-6 alkoxycarbonyl (for example, CH ₃ O-C(O)-), 5-7- membered heterocyclyl-C _1-6 alkyl (e.g. piperazinyl-CH ₂ -), C _1-6 alkylsulfonyl 5-7 membered heterocyclyl (e.g. CH ₃ S(O) ₂ -morpholinyl-), 5-7 membered heterocyclyl C _1-6alkoxy 57-membered heterocyclyloxy, (4-7-membered heterocyclyl)-4-7-membered heterocyclyl (for example, oxetanylpyrrolidinyl-), C _3-6 cycloalkylaminocarbonyl (for example, cyclopropyl-NH-C(O)-), 5 -7-membered heterocyclyl-C _2-6 alkynyl (eg N-piperazinyl-CH ₂ C=CCH ₂ -) and C _6-10 arylaminocarbonyl (eg phenyl-NH-C(O)-).

Spiro refers to a ring substituent that is connected via two bonds on the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyldioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine, respectively, are spiro substituents. When combining substituents (R groups) (for example, when combining R ⁷ and R ⁸ ) they can be attached to the same place to form a spiro ring.

The phrase meta-position (3-position) relative to the site of attachment of the ring A refers to the position in the specified ring at which the substituent (for example, -CN) is attached, and the specified position is indicated by the arrow below, with z representing a carbon or nitrogen atom:

Similarly, substitution at the para position (4-position) refers to the addition of a substituent at the position indicated below, relative to the point of attachment (for example, ring B):

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Similarly, the ortho- or 2-position refers to the attachment of a substituent at the position indicated below, relative to the indicated point of attachment:

The compounds described herein include isomers, stereoisomers, and the like. In the context of the present description, the term isomers refers to various compounds that have the same molecular formula, but differ in the arrangement and configuration of atoms. Also in the context of the present description, the term stereoisomer refers to any of the various stereoisomeric configurations that may exist for a particular compound according to the present invention, and includes geometric isomers. It is contemplated that a substituent may be attached to a carbon atom representing a chiral center. Thus, the present invention includes the enantiomers, diastereomers or racemates of the compound.

The term fused refers to a ring that is bonded to an adjacent ring.

Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of enantiomer pairs is a racemic mixture.

Absolute stereochemistry is determined according to the Cahn-Ingold-Prelog R-S system. When a compound is the pure enantiomer, the stereochemistry at each chiral carbon atom can be defined as either R or S. Separated compounds whose absolute configuration is unknown may be denoted (+) or (-) depending on the direction (right- or left-handed), in which they rotate plane-polarized light at the wavelength of the sodium D-line. Some of the compounds described herein contain one or more asymmetric centers and thus can form enantiomers, diastereomers, and other stereoisomeric forms that can 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 obtained using chiral synthons or chiral reagents or separated using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in the cis or trans configuration. It is also intended that all tautomeric forms be included. Where compounds depicted in the present invention are presented as having specific stereochemistry, it will be appreciated by one skilled in the art that such compounds may contain some detectable or non-detectable amounts of compounds having the same structure but different stereochemistry.

IC ₉₅ or EC ₉₅ refers to the concentration of inhibition required to provide 95% of the maximum desired effect, which in the present invention in many cases is the inhibition of the HIV virus. The meanings of this term are derived using an in vitro assay evaluating concentration-dependent inhibition of wild-type HIV virus.

IC ₅ o or EC ₅ o refers to the concentration of inhibition required to provide 50% of the maximum desired effect, which in the present invention in many cases is the inhibition of the HIV virus. The meanings of this term are derived using an in vitro assay evaluating concentration-dependent inhibition of wild-type HIV virus.

IQ or coefficient of inhibition refers to the ratio between the minimum drug concentration (C _tau ) and the level of drug resistance of an HIV isolate, determined by IC ₉₅ (ie C _tau /IC ₉₅ ).

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

A pharmaceutically acceptable excipient includes, without limitation, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, coloring/coloring agent, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent , a solvent or emulsifier that has been approved by the US Food and Drug Administration as being acceptable for use in humans or pets.

A pharmaceutically acceptable salt refers to a salt of a compound that is pharmaceutically acceptable and that has (or can be converted to a form that has) the desired pharmacological activity of the parent compound. Such salts include acid addition salts prepared using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or derived from organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid , 2naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid and the like, and salts obtained when the acidic proton present in the parent compound is replaced by any a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, N-methylglucamine and the like. This definition also includes ammonium 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), 119 (1977) and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5, both of which are incorporated herein by reference.

The present invention also provides prodrugs of the compounds disclosed in the present invention. In the pharmaceutical field, a prodrug is defined as a biologically inactive derivative of a drug that, when administered to the human body, is converted to the biologically active parent drug by some chemical or enzymatic pathway.

Subject and subjects refer to humans, pets (e.g., dogs and cats), livestock (e.g., cattle, horses, sheep, goats, and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs , miniature pets (pocket pets), rabbits, dogs and monkeys) and the like.

In the context of the present description, the treatment or implementation of treatment is an approach to obtain positive or desired results. For the purposes of this disclosure, beneficial or desirable results include, but are not limited to, alleviation of a symptom, and/or reduction in the severity of a symptom, and/or prevention of worsening of a symptom associated with a disease or condition. In one embodiment, treating or administering treatment comprises one or more of the following: a) inhibiting a disease or condition (eg, ameliorating one or more symptoms resulting from said disease or condition and/or lessening the extent of the disease or condition); b) slowing or stopping the development of one or more symptoms associated with the disease or condition (eg, stabilizing the disease or condition, delaying the aggravation or progression of the disease or condition); and/or c) alleviating the disease or condition, eg, causing regression of clinical symptoms, improvement in disease state, delay in disease progression, improved quality of life, and/or prolongation of survival.

In the context of the present description, delaying the development of a disease or condition means delaying, hindering, slowing down, inhibiting, stabilizing and/or postponing the development of said disease or condition. This delay may be of varying duration depending on the medical history and/or the subject being treated. As will be appreciated by one of ordinary skill in the art, a sufficient or significant delay may actually cover prevention in the sense that the subject 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 developing a disease in a certain period of time and/or reduces the degree of the disease in a certain period of time compared to not using the method. Such comparisons may be based on clinical studies using a statistically significant number of subjects. For example, the development of AIDS can be detected using known methods such as confirming the subject's HIV positive (HIV ⁺ status) and assessing the subject's T cell count or other signs of AIDS development such as extreme fatigue, weight loss, persistent diarrhea. , high fever, swollen lymph nodes in the neck, armpits, or groin, or the presence of an opportunistic condition known to be associated with AIDS (eg, a condition that is not usually present in subjects with normally functioning immune systems but occurs in patients with AIDS). Development can also refer to the progression of a disease, which may initially be undetectable, and includes onset, relapse, and onset.

As used herein, prevention or implementation of prevention refers to a regimen that protects against the onset of a disease or disorder such that clinical symptoms of said disease do not develop. Thus, prevention refers to the administration of a therapy (e.g., administration of a therapeutic agent) to a subject before signs of a disease can be detected in said subject (e.g., administration of a therapeutic agent to a subject in the absence of a detectable infectious agent (e.g., a virus) in said subject). Said subject may be an individual at risk for developing a 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 prevention of HIV infection refers to administering to a subject who does not have detectable HIV infection an anti-HIV therapeutic agent. It is contemplated that the subject of HIV prevention therapy may be an individual at risk of contracting the HIV virus. Further, it is contemplated that prevention may not result in complete protection against the onset of a disease or disorder. In some cases, prevention includes reducing the risk of developing a disease or disorder. This risk reduction may not completely eliminate the risk of developing a disease or disorder.

In the context of the present description, an individual at risk is an individual who is at risk of developing a condition to be treated. An individual at risk may or may not have a detectable disease or condition and may or may not have developed a detectable disease prior to treatment with the methods described herein. At risk means 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 having one or more of the indicated risk factors is more likely to develop a disease or condition than an individual without the indicated risk factor(s). For example, individuals at risk for AIDS include individuals with HIV.

As used herein, the term therapeutically effective amount or effective amount refers to an amount that is effective to elicit a desired biological or medical response, including an amount of a compound that, when administered to a subject for the treatment of a disease, is sufficient to effect such treatment for said disease, or the amount which is effective in protecting against infection or the onset of a disease. The effective amount will vary depending on the compound, the disease and its severity, as well as the age, body weight, etc. of the subject being treated. An effective amount may include a range of amounts. As is clear from the prior art, the effective amount may be one or more doses, that is, 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 administering 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, the desired or beneficial result can be achieved or achieved. Suitable doses of any co-administered compounds may optionally be reduced due to the combined action (eg, additive or synergistic effects) of these compounds.

The compounds of the present invention include their solvates, hydrates, tautomers, stereoisomers and salt forms.

Compounds are also provided in which from 1 to n hydrogen atoms attached to a carbon atom can be replaced by deuterium or D atoms, with n being the number of hydrogen atoms in the molecule. As is known from the prior art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds may exhibit increased metabolic resistance and therefore may be suitable for use in extending the half-life of said compounds when administered to a mammal. See, for example, Foster, Deuterium Isotope Effects in Studies of Drug Metabolism, Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

Examples of isotopes that may be included in the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ^2H , ^3H , 11C, ^13C , ^14C , ^13N , ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I, respectively. Substitution with positron active isotopes such as 11C, ^18F , ^15O and ^13N may be suitable for use in positron emission tomography (PET) studies to study the degree of substrate receptor occupancy. Isotopically labeled compounds of formula (Ia) or (Ib) can generally be prepared using conventional techniques known to those skilled in the art, or by methods analogous to those described in the examples below, using the appropriate isotopically labeled reagent. instead of the unlabeled reagent used originally.

As stated in the present invention, darunavir is an HIV protease inhibitor having the structure:

- 10 040208 and having the IUPAC name [(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 marketed under the brand name PREZISTA®.

As stated in the present invention, 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-(methoxycarbonyl)-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®.

Connections

In some embodiments, a compound of Formula I is provided:

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is a 5-10-membered heterocycle containing from 1 to 5 heteroatoms selected from N, O and S, or a 5-10-membered heteroaryl containing from 1 to 5 heteroatoms selected from N, O and S, and said 5-10 membered heterocycle or said 5-10 membered heteroaryl is optionally substituted with 1-5 R ^a groups;

each R ² and R ³ is independently C _1-4 αkyl, C _3-6 cycloalkyl, O-R2A, C _1-2 alkyl-OR ^2A , N-(R ^3A )2 or C 1-2 alkyl-N-(R ^3A )2, where each R2A is independently C _1-4 alkyl, C _3-6 cycloalkyl or 4-10 membered heterocyclyl containing 1 to 5 heteroatoms selected from N, O and S, where each R ^3A is independently is hydrogen, C _1-4 αkyl, C _3-6 cycloalkyl, or COO(R ^e ), and where each C _3-6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with 1-3 R ^f groups, where each R ^f is independently is C _1-2 alkyl or halogen;

R ⁴ is C1-4αkyl or C1-4haloalkyl; R ⁷ is C 1-4 alkyl or C 1 _-4 haloalkyl;

each R ⁵ , R ⁶ , R ⁸ and R ⁹ is independently C _1-2 αkyl or C _1-2 haloalkyl;

and where two or more of R ⁴ , R ⁵ and R ⁶ or two or more of R ⁷ , R ⁸ and R ⁹ are optionally combined to form one or more C _3-6 cycloalkyl groups which are optionally substituted with 1- 4 groups selected from halogen, Cl _-2 alkyl and Cl _-2 haloalkyl; each R ^10a and R ^10b is halogen;

each R ^a is independently halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C3-6 cycloalkyl, 4-10 membered heterocyclyl, or OR ^3B , wherein said C1-4 alkyl is optionally substituted with 1-2 groups selected from hydroxyl and C _1-4 alkoxy, said 4-10 membered heterocyclyl contains 1 to 5 heteroatoms selected from N, O and S, and said 4-10 membered heterocyclyl is optionally substituted with R ^a1 ;

where R ^3B is C _3-6 cycloalkyl optionally substituted with R ^a1 , or 4-10 membered heterocyclyl containing 1 to 5 heteroatoms selected from N, O and S, optionally substituted with R ^a1 , where each R ^a1 is independently is C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 haloalkyl or 4-8 membered heterocyclyl containing from 1 to 3 heteroatoms selected from N, O and S; X ¹ is a 6-10 membered aryl or a 5-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, where each 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted 1-4 groups R ^b ;

X ² is hydrogen or a 4-10 membered heterocyclyl containing from 1 to 5 heteroatoms selected from N, O and S, said 4-10 membered heterocyclyl is optionally substituted with one R ¹¹ group and optionally substituted with 1-5 R groups ^b ;

R ¹¹ is C=O(R ^c ), CH2(R ^d ), S(O)1-2(C _1-4 alkyl), S(O) _1-2 C _3-6 cycloalkyl, 4-10- a membered heterocyclyl containing from 1 to 5 heteroatoms selected from N, O and S, or a 5-9 membered heteroaryl containing from 1 to 5 heteroatoms selected from N, O and S, where each 4-10-membered heterocyclyl or 5-9 membered heteroaryl is optionally substituted with 1-5 R ^b groups;

each R ^b is independently halo, oxo, C1-4alkylC1-4haloalkyl, C1-4alkoxy, or COO(R ^e ), wherein said C1-4alkyl is optionally substituted with 1-2 groups selected from hydroxyl and _C1-4alkoxy ;

R ^c is C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, N(R ^e )2, C _3-6 cycloalkyl or 4-6 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, wherein said C3-6 cycloalkyl and said 4-6 membered heterocyclyl are optionally substituted with 1-5 R ^b groups;

R ^d is COO(R ^e ), N(R ^e )2, C3-6 cycloalkyl or 4-6 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, said C3-6 cycloalkyl and said 4-6 membered heterocyclyl optionally substituted with 1-5 R ^b groups; and each R ^e is independently hydrogen or C _1-4 alkyl.

In some embodiments, a compound of formula (Ia) is a compound of formula (Ic):

where Z ¹ and Z ² are independently N or CH, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ R ^10a and R ^10b are as defined in the present invention.

In some embodiments, a compound of formula (Ia) is a compound of formula (Id):

- 12 040208

In some embodiments, a compound of formula (Ia) is a compound of formula (Ie):

where R ¹ , R ^a , R ¹¹ , X ¹ and X ² are as defined in the present invention.

In some embodiments of a compound of formula (Ia), (Ic), (Id), or (Ie), R ¹ is a 5-6 membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, or 5- 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, said 5-6 membered heterocycle or said 5-6 membered heteroaryl optionally substituted with 1-3 R ^a groups. In some embodiments of a compound of formula (Ia), (Ic), (Id), or (Ie), R ¹ is a 5-6 membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S, and is optionally substituted with 1- 3 groups R ^a . In some embodiments of a compound of formula (Ia), (Ic), (Id), or (Ie), R ¹ is:

- 13 040208

In some embodiments, R ¹ is

or

In some embodiments, R ¹ is

In some embodiments of a compound of formula (Ia), (Ic), (Id) or (Ie), R ^a is independently C _1-4 αkyl, C _1-4 alkyl substituted with 1-2 groups selected from hydroxyl and C _{1 -4} alkoxy, or C _1-4 haloalkyl.

In some embodiments of a compound of formula (Ia) or (Ie), X ¹ is a 6 membered aryl or 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, where each 6 membered aryl or 5-6 membered heteroaryl is optionally substituted with 1-4 R ^b groups. In some embodiments of a compound of formula (Ia) or (Ie), X ¹ is pyrimidine or pyridine optionally substituted with 1-4 R ^b groups. In some embodiments of the compounds of formula (Ia) or (Ie), X ¹ is pyrimidine or pyridine. In some embodiments of a compound of formula (Ia) or (Ie), X ¹ is:

In some embodiments of a compound of formula (Ia) or (Ie), X ¹ is

In some embodiments of a compound of formula (Ia) or (Ie), X ¹ is or

In some embodiments of a compound of formula (la), (Id), or (Ie), X ² is 4

A 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S and is optionally substituted with one R ¹¹ group and optionally substituted with 1-5 R ^b groups. In some embodiments, X ² may be substituted with R ¹¹ and R ^b groups. In some embodiments of a compound of formula (Ia), (Id), or (Ie), X ² is:

- 14 040208

In some embodiments of a compound of formula (Ia), (Id), or (Ie), X ² is

In some embodiments of a compound of formula (Ia), (Id), or (Ie), X ² is

In some embodiments of a compound of formula (Ia), (Id), or (Ie), X ² is

Where:

a) each R ^P1 , R ^P2 , R ^P3 and R ^P4 is hydrogen;

b) R ^P1 and R ^P3 are combined to form a -CH ₂ - or -CH ₂ CH ₂ - group, and each R ^P2 and R ^P4 is hydrogen;

- 15 040208

c) R ^P2 and R ^P4 are combined to form a -CH ₂ - or -CH ₂ CH ₂ - group, and each R ^P1 and R ^P3 is hydrogen.

d) R ^P1 and R ^P4 are combined to form a -CH ₂ - group, and each R ^P2 and R ^P3 is hydrogen; or

e) R ^P2 and R ^P3 are combined to form a —CH ₂ — group, and R ^P1 and R ^P4 are each hydrogen.

In some embodiments of a compound of formula (Ia), (Id), or (Ie), X ² is

Where:

R ^P1 and R ^P3 are combined to form a -CH ₂ - or -CH ₂ CH ₂ - group, and each R ^P2 and R ^P4 is hydrogen; or

R ^P2 and R ^P4 are combined to form a -CH ₂ - or -CH ₂ CH ₂ - group, and each R ^P1 and R ^P3 is hydrogen.

In some embodiments of a compound of formula (Ia), (Ic), (Id), or (Ie), X ² is optionally substituted with R ¹¹ . In some embodiments of a compound of formula (Ia), (Ic), (Id), or (Ie), R ¹¹ is a 4-10 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, implementation of the compounds of formula (Ia), (Ic), (Id) or (Ie) R ¹¹ is a 46-membered heterocycle containing one oxygen atom. In some embodiments of a compound of formula (Ia), (Ic), (Id), or (Ie), R ¹¹ is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. In some embodiments of a compound of formula (Ia), (Ic), (Id) or (Ie), R ¹¹ is oxetan-3-yl, tetrahydrofuran-3-yl, or tetrahydropyran-4-yl.

In some embodiments of the compounds of formula (Ia), (Ic) or (Id), R ² and R ³ may be the same or different. In some embodiments of a compound of formula (Ia), (Ic), or (Id), each R ² and R ³ is independently C1_4αkyl, C3-6 cycloalkyl, or OR ^2A , where R ^2A is _{C1_4} alkyl, C _3-6 cycloalkyl, or A 4-10 membered heterocyclyl containing 1 to 5 heteroatoms selected from N, O, and S. In some embodiments of a compound of formula (Ia), (Ic), or (Id), each R ² and R ³ is independently y° _x . uA; / ₀ ^ _or \-0

In some embodiments of a compound of formula (Ia), (Ic), or (Id), each R ² and R ³ is methoxy.

In some embodiments, each of X ¹ and X ² , whenever present, may be substituted with one or more R ^b groups. In some embodiments, each R ^b is independently halogen, oxo, C1_4 alkyl, C1_4 haloalkyl, C1_4 alkoxy, _or COO(R ^e ), wherein said _{C1_4} alkyl is optionally substituted with 1-2 groups selected from hydroxyl and _{C1_4} alkoxy. In some embodiments, each R ^b is independently oxo or halogen. In some embodiments of a compound of formula (Ib) or (Ic), one of Z ¹ and Z ² is N and the other is CH. In some embodiments of compounds of formula (Ib) or (Ic), both Z ¹ and Z ² are N.

As above, any of the values of the variables represented (for example, A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^10a , R ^10b , Z ¹ , Z ² , X ¹ and X ² ) can be combined and grouped with the values of other variables, whether they are specified together or not.

In some embodiments of a compound of formula (Ia), R ¹ is

PS XX, υΧ ^Ν - ^{κ ζ} , ⁷ or ';

R ^a is C ₁ _ ₄ haloalkyl;

X ¹ is pyrimidine or pyridine, each R ² and R ³ is methoxy, R ⁴ is CH3 or CF3, R ⁷ is CH3 or CF ₃ , each R ⁵ , R ⁶ , R ⁸ and R ⁹ is methyl , X ² represents

- 16 040208 R ^10a and R ^10b are each halogen; And

R ¹¹ is a 4-6 membered heterocycle containing one oxygen atom.

In some embodiments of a compound of formula (Ib), R ¹ is

R ^a is C _1-4 haloalkyl;

m is 0, Z ¹ and Z ² are independently N or CH, R ² and R ³ are each methoxy, R ⁴ is CH3 or CF3, R ⁷ is CH3 or CF ₃ , each R ⁵ , R ⁶ , R ⁸ and R ⁹ is methyl;

X ² represents

each R ^10a and R ^10b is halogen; And

R ¹¹ is a 4-6 membered heterocycle containing one oxygen atom.

In some embodiments of a compound of formula (Ic), R ¹ is

R ^a is C ₁ . ₄ haloalkyl;

Z ¹ and Z ² are independently N or CH, each R ² and R ³ is methoxy, R ⁴ is CH3 or CF3, R ⁷ is CH3 or CF ₃ , each R ⁵ , R ⁶ , R ⁸ and R ⁹ is methyl;

each R ^10a and R ^10b is halogen; And

R ¹¹ is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.

In some embodiments of a compound of formula (Id), R ¹ is

R ^a is -CHF2; X ¹ is pyrimidine or pyridine, each R ² and R ³ is methoxy, R ⁴ is CH3 or CF3, R ⁷ is CH3 or CF ₃ , each R ⁵ , R ⁶ , R ⁸ and R ⁹ is methyl , X ² represents

and each R ^10a and R ^10b is halogen, and R ¹¹ is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.

In some embodiments, said compound is:

- 17 040208

- 18 040208

or a pharmaceutically acceptable salt thereof.

In some embodiments, said compound is a compound according to any of Examples 1-245, or a pharmaceutically acceptable salt thereof.

In some embodiments, said compound is

- 19 040208

or a pharmaceutically acceptable salt thereof.

In some embodiments, said compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, said compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, said compound is

- 20 040208

F

or a pharmaceutically acceptable salt thereof.

In some embodiments, said compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, said compound is

F

or a pharmaceutically acceptable salt thereof.

In some embodiments, said compound is

- 21 040208

or a pharmaceutically acceptable salt thereof.

In some embodiments, said compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, said compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, said compound is

- 22 040208

F

or a pharmaceutically acceptable salt thereof.

In some embodiments, said compound is

or a pharmaceutically acceptable salt thereof.

Methods of treatment

Pharmaceutical compositions of compounds of formulas (Ia), (Ic), (Id) and (Ie) may be administered in single dose or multiple doses by any of the accepted routes of administration of agents having a similar use, for example, as described in those patents and patent applications, which are incorporated by reference, including rectal, buccal, intranasal and transdermal route, intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, inhalation, or by means of an impregnated or coated device such as, for example, a stent or a cylindrical polymer injected into an artery.

In one aspect, the compounds of the present invention may be administered orally. Oral administration may be by means of, for example, enteric-coated capsules or tablets. To create pharmaceutical compositions that contain at least one compound of formula (Ia) or a pharmaceutically acceptable salt, they are usually diluted with an excipient and/or enclosed within such a carrier, which may be in the form of a capsule, sachet, paper or other container. Where the excipient functions as a diluent, it may be in the form of a solid, paste or liquid (as described above) which 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, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a 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 prepackaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrups, and methylcellulose. The compositions may further contain: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

Compositions which contain at least one compound of formula (Ia) or pharmaceutical

- 23 040208 legally acceptable salt can be formulated to provide rapid, prolonged or delayed release of the active ingredient after administration to a subject using techniques known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer coated reservoirs or polymer matrix drug formulations. Examples of controlled release systems are given in US Pat. Such transdermal patches can be used to provide continuous or continuous infusion of the compounds of the present invention in controlled amounts. The manufacture and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, US Pat.

In some embodiments, the compositions may be formulated as unit dosage forms. The term unit dosage forms refers to physically discrete units suitable as unit doses for humans or other mammals; each unit contains a predetermined amount of the active substance, calculated to provide the desired therapeutic effect, in combination with a suitable pharmaceutical excipient (eg tablet, capsule, ampoule). The compounds are generally administered in pharmaceutically effective amounts. In some oral embodiments, each dosage unit contains about 10 mg to about 1000 mg of a compound of the present invention, e.g., about 50 mg to about 500 mg, e.g., 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 of the present invention. However, it should be understood that the amount of a compound actually administered will generally be determined by the clinician in light of relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered and its respective potency, the age, body weight and response to therapy of the individual subject, and the severity of symptoms in the individual. subject.

In some embodiments, dosage levels may 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. In some cases, such dosage levels may be suitable for use in the treatment of the above conditions. In other embodiments, dose 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 a carrier medium to form a single dosage form may vary depending on the patient and the particular route of administration. Unit dosage forms may contain from 1 mg to 1000 mg of the active ingredient.

The compounds disclosed in the present invention, or pharmaceutically acceptable salts thereof, may be administered to a subject in accordance with an effective dosage regimen for a predetermined period of time or duration, such as at least about one day, at least about one week, at least about one 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 embodiment, the compound is administered on a daily or divided schedule. In one embodiment, the compound is administered on a monthly schedule. In one embodiment, the compound is administered every two months. In one embodiment, the compound is administered every three months. In one embodiment, the compound is administered every four months. In one embodiment, the compound is administered every five months. In one embodiment, the compound is administered every 6 months.

The dose or frequency of administration of a compound disclosed in the present invention, or a pharmaceutically acceptable salt thereof, may be adjusted during treatment based on the decision of the physician responsible for administering the drug. The compound may be administered to the subject (eg, human) in an effective amount. In some embodiments, the compound is administered once a day.

For the preparation of compositions in solid dosage form such as tablets, the main active ingredient may be mixed with a pharmaceutical excipient to form a solid precomposition which contains a uniform mixture of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. By referring to said precompositions as homogeneous, the active ingredient can be distributed uniformly throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

Tablets or pills of the compounds described herein may be coated with both

- 24 040208 spoon or otherwise formed in order to obtain a dosage form that provides the advantage of prolonged action, or protection from the acidic environment of the stomach. For example, a tablet or pill may contain a dosage component inside or outside, the latter being in the form of a shell on top of the previous one. The two components may be separated by an enteric layer which serves to resist disintegration in the stomach and allows the internal component to pass unchanged into the duodenum or be delayed release. Various materials can be used as such an enteric layer or coating, such materials include numerous polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

In some embodiments, formulations suitable for parenteral administration (eg, intramuscular (IM) and subcutaneous (SC) administration) will contain one or more excipients. Excipients must be compatible with other ingredients of the composition and be physiologically safe for the subject receiving them. Examples of suitable excipients are well known to those skilled in the art of parenteral formulation and can be found, for example, in the Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009.

In some embodiments, the compounds of the present invention, or their pharmaceutically acceptable salts, may be administered by syringe. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is filled with a compound of the present invention or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be administered using an automatic medical injector containing a syringe. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is filled with a compound of the present invention or a pharmaceutically acceptable salt thereof.

In some embodiments, a method of treating or preventing a human immunodeficiency virus (HIV) infection is provided, which comprises administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, a method of treating a human immunodeficiency virus (HIV) infection is provided, which comprises administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the method includes administering a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents. In some embodiments, the subject is at risk of contracting HIV, in particular a subject that has one or more risk factors known to be associated with contracting HIV. In some embodiments, the subject may not have received antiviral therapy in the past (previously untreated). In some embodiments, the subject may have received (treated) antiviral therapy in the past. In some embodiments, the subject may have received antiviral therapy in the past and become resistant to previously received antiviral therapy.

In some embodiments, a method of treating or preventing a human immunodeficiency virus (HIV) infection is provided, comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, in combination with a therapeutically effective amount of one or more ( for example, 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 protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, inhibitors of HIV integrase, inhibitors of non-catalytic sites (or allosteric inhibitors) of HIV integrase, inhibitors of HIV entry, inhibitors of HIV maturation, latent-reversing agents, compounds that target the HIV capsid, immunostimulant inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and antibody-like therapeutic proteins, HIV p17 matrix protein inhibitors, interleukin-13 (IL-13) antagonists, peptidylprolyl cis/trans isomerase A modulators, protein disulfide isomerase inhibitors, antagonists of the C5a receptor of the complement system, DNA methyltransferase inhibitor, HIV vif gene modulators, viral infectivity factor (Vif) dimerization antagonists, HIV-1 virus infectivity factor inhibitors, transcription transactivator protein (TAT) inhibitors, negative regulatory factor modulators (Nef ) HIV-1, hematopoietic cellular kinase (Hck) tyrosine kinase modulators, mixed-line kinase 3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, virion protein expression regulator protein (Rev) inhibitors, antagonists

- 25 040208 integrins, nucleoprotein inhibitors, splicing factor modulators, COMMdomain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, cyclin-dependent kinase 9 (CDK-9) inhibitors, inhibitors of intercellular adhesion molecule trapping molecule 3 (ICAM-3) non-integrin 1 dendritic cells, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein converting PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, glucose- 6-phosphate dehydrogenase (G6PD) and NADH oxidase, pharmacokinetic enhancers, or any combination thereof. In some embodiments, 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 are selected from the group consisting of compounds that inhibit HIV protease, 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, glycoprotein 41 (gp41) inhibitors, CXC-chemokine 4 receptor (CXCR4) inhibitors, glycoprotein 120 (gp120) inhibitors ), CC chemokine receptor 5 (CCR5) inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for the treatment of HIV, or any combination thereof. In some embodiments, one or more additional therapeutic agents do not include a pharmacokinetic enhancer.

In some embodiments, a method for inhibiting HIV replication, treating AIDS, or delaying the onset of AIDS in a subject (eg, a human) is disclosed, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is disclosed for use in the medical treatment of an HIV infection (e.g., HIV-1, or replication of HIV (e.g., HIV-1) or AIDS, or delaying the onset of AIDS in a subject. (for example, in a person)).

In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is disclosed for use in the preparation of a medicament for the treatment of HIV infection, or HIV or AIDS replication, or delaying the onset of AIDS in a subject (e.g., a human). One embodiment provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of HIV infection or AIDS, or for use in the therapeutic treatment or delay of the onset of AIDS.

In some embodiments, the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for an HIV infection in a subject (eg, a human) is disclosed. In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is disclosed for use in the prophylactic or therapeutic treatment of an HIV infection.

In some embodiments, in methods of use, administration of a compound is to a subject (eg, human) in need of treatment. In some embodiments, in methods of use, administration of the compound is to a subject (eg, human) who is at risk of developing AIDS.

The compounds disclosed in the present invention or their pharmaceutically acceptable salts for use in therapy are provided. In one embodiment, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is for use in a method of treating HIV infection, or HIV replication, or AIDS, or delaying the onset of AIDS in a subject (e.g., a human).

Compounds disclosed in the present invention, or pharmaceutically acceptable salts thereof, are provided for use in a method for treating or preventing an HIV infection in a subject in need thereof. In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating an HIV infection in a subject in need thereof. In some embodiments, the subject in need of treatment is a human who is infected with HIV. In some embodiments, the subject in need of treatment is a human who is infected with HIV but has not developed AIDS. In some embodiments, the subject in need of treatment is a subject at risk for developing AIDS. In some embodiments, the subject in need of treatment is a human who is infected with HIV and has developed AIDS.

In one embodiment, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is provided 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 described herein, for use in a method of treating or preventing HIV infection in a subject in need thereof. In one of the options

said additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, inhibitors of HIV integrase, inhibitors of non-catalytic sites (or allosteric inhibitors) of HIV integrase, inhibitors HIV entry inhibitors, HIV maturation inhibitors, latent-reversing agents, compounds that target the HIV capsid, immunostimulants, phosphatidylinositol-3 kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and antibody-like therapeutic proteins, HIV p17 matrix protein inhibitors, IL-antagonists 13, peptidylprolylcis/trans-isomerase A modulators, protein disulfide isomerase inhibitors, complement C5 receptor antagonists, DNA methyltransferase inhibitors, modulators of the HIV vif gene, Vif dimerization antagonists, inhibitors of the infectivity factor vir HIV-1 strain inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed-line 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, ICAM-3 uptake non-integrin 1 dendritic cell inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, PC9 proprotein convertase stimulators, DDX3X ATP-dependent RNA helicase inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, or any combination thereof. In some embodiments, said additional therapeutic agents are selected from the group consisting of HIV protease inhibitor compounds, non-nucleoside HIV reverse transcriptase inhibitors, non-nucleotide HIV 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 the treatment of HIV, or any combination thereof.

In one embodiment, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is provided 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 said second additional therapeutic agent is emtricitabine, for use in a method of treating or preventing HIV infection in a subject in need thereof. In a particular embodiment, there is provided a compound of the present invention, 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 said the second additional therapeutic agent is emtricitabine, for use in a method of treating or preventing HIV infection in a subject in need thereof.

In a specific embodiment, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is provided for use in preventing contraction of an HIV infection when a subject is exposed to a virus and/or in order to prevent the virus from developing a permanent infection, and/or in order to prevent the onset of symptoms of a disease, and/or to prevent the virus from reaching detectable levels in the blood, such as in pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Accordingly, in some embodiments, methods for reducing the risk of acquiring HIV (eg, HIV-1 and/or HIV-2) are provided. For example, methods for reducing the risk of acquiring HIV (eg, HIV-1 and/or HIV-2) include administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, methods for reducing the risk of acquiring HIV (eg, HIV-1 and/or HIV-2) include administering a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents. In some embodiments, methods for reducing the risk of acquiring HIV (e.g., HIV-1 and/or HIV-2) include administering a pharmaceutical composition containing a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, methods for reducing the risk of acquiring HIV (eg, HIV-1 and/or HIV-2) include administering a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with safer sex. In some embodiments, methods for reducing the risk of acquiring HIV (eg, HIV-1 and/or HIV-2) include administering to a subject at risk of acquiring HIV. Examples of subjects at high risk of acquiring HIV include, but are not limited to, subjects who are at risk of sexual transmission of HIV.

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

In another embodiment, the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, is disclosed for the manufacture of a medicament for the treatment of an HIV infection in a human having or at risk of infection.

Also disclosed in the present invention is a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment or in delaying the onset of AIDS.

Also disclosed in the present invention is a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV infection.

In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, may be used as a research tool (eg, to study inhibition of HIV reverse transcriptase in a subject or in vitro).

Kits are provided which contain a compound of formula (Ia) or a pharmaceutically acceptable salt thereof in a suitable package. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit contains a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, and instructions for use of the compounds in the treatment of the disease or conditions described herein.

Articles are provided which contain a compound of formula (Ia) or a pharmaceutically acceptable salt thereof in a suitable container. Said container may be a vial, a jar, an ampoule, a pre-filled syringe, and an intravenous infusion bag.

Introduction of anti-HIV combination therapy

In some embodiments, a compound described herein is administered with one or more additional therapeutic agents. Co-administration of a compound of the present invention with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound of the present invention and one or more additional therapeutic agents such that therapeutically effective amounts of both, disclosed in the present invention, and one or more additional therapeutic agents. In the case of sequential administration, the combination may be administered over two or more administrations.

Co-administration includes the administration of single doses of the compounds disclosed in the present invention, before or after the administration of single doses of one or more additional therapeutic agents. For example, a compound of the present invention may be administered seconds, minutes, or hours after administration of one or more additional therapeutic agents. In some embodiments, a single dose of a compound of the present invention is first administered, followed by a single dose of one or more additional therapeutic agents over seconds or minutes. Alternatively, a single dose of one or more additional therapeutic agents is first administered, followed by a single dose of a compound disclosed in the present invention over seconds or minutes. In other embodiments, a single dose of a compound of the present invention is first administered, followed by a single dose of one or more additional therapeutic agents after a period of several hours (eg, 1-12 hours). In other embodiments, a single dose of one or more additional therapeutic agents is first administered, followed by a single dose of a compound of the present invention after a period of several hours (eg, 112 hours).

In some embodiments, a compound of the present invention is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, eg, as a solid dosage form for oral administration.

In some embodiments, the compound of formula (Ia) is formulated as a tablet, which may optionally contain one or more other compounds suitable for use in the treatment of HIV. In some embodiments, the tablet may contain another active ingredient for the treatment of HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, inhibitors of non-catalytic sites (or allosteric inhibitors) of HIV integrase , pharmacokinetic enhancers and combinations thereof.

In some embodiments, the compound of formula (Ia) is formulated as a tablet, which may optionally contain one or more other compounds suitable for use in the treatment of HIV. In some embodiments, the tablet may contain another active ingredient for the treatment of HIV, in particular compounds that target the HIV capsid, HIV protease inhibitors,

- 28 040208 non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, inhibitors of HIV integrase, inhibitors of non-catalytic sites (or allosteric inhibitors) of HIV integrase, pharmacokinetic enhancers and combinations thereof.

In some embodiments, the compounds that target the HIV capsid are selected from the group consisting of:

» And o or their pharmaceutically acceptable salt.

In some embodiments, such tablets are suitable for once daily administration. Combination therapy against HIV

In the above embodiments, the additional therapeutic agent may be an anti-HIV agent, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, inhibitors of non-catalytic sites (or allosteric inhibitors) of HIV integrase, HIV entry inhibitors, HIV maturation inhibitors, latent-reversing agents, compounds that target the HIV capsid, immunostimulants, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and antibody-like therapeutic proteins, HIV p17 matrix protein inhibitors, IL antagonists -13, peptidyl prolyl cis/trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, modulators of the HIV vif gene, Vif dimerization antagonists, virus infectivity factor inhibitors a HIV-1, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed-line 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 cell uptake ICAM-3 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, PC9 proprotein convertase stimulators, DDX3X ATP-dependent RNA helicase inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, and any combination thereof.

In some embodiments, the additional therapeutic agent is selected from immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifier, gene editors (such as CRISPR/Cas9, zinc finger protein domain nucleases, homing nucleases, artificial nucleases, transcription activator-like effector nucleases ( TALEN)), and cell therapies such as chimeric T cell antigen receptor, CAR-T (eg YESCARTA® (axicabtagen siloleucel)), and recombinant T cell receptors, TCR-T.

In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, inhibitors of non-catalytic sites (or allosteric inhibitors) of HIV integrase,

- 29 040208 HIV entry (fusion) inhibitors, HIV maturation inhibitors, latent reversing agents, capsid inhibitors, immunostimulants, PI3K inhibitors, HIV antibodies and bispecific antibodies and antibody-like therapeutic proteins, and combinations thereof.

HIV protease inhibitors

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 (PPL100), t-169, BL-008 and TMS-310911.

HIV reverse transcriptase inhibitors

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.

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.

Примеры нуклеозидных или нуклеотидных ингибиторов обратной транскриптазы ВИЧ включают адефовир, адефовира дипивоксил, азвудин, эмтрицитабин, тенофовир, тенофовира алафенамид, тенофовира алафенамида фумарат, тенофовира алафенамида гемифумарат, тенофовира дизопроксил, тенофовира дизопроксила фумарат, тенофовира дизопроксила гемифумарат, VIDEX® и VIDEX ЕС® (диданозин , ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fosivudine tidoxil, fazidinudine, lamivudine , zalcitabine, zidovudine, GS9131, GS-9148 and KP-1461.

HIV integrase inhibitors

Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, chicory acid, chicory acid derivatives, 3,5-dicapheoylquinic acid, 3,5-dicapheoylquinic acid derivatives, auryntricarboxylic acid, auryntricarboxylic acid derivatives, caffeic acid phenethyl ester, phenethyl ester derivatives. caffeic ester, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long acting injectable), diketoquinoline-4-1 derivatives, integrase inhibitor-LEDGF, LEDGINs, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC699174, stilbendisulfonic acid, t-169 and cabotegravir.

Examples of inhibitors of non-catalytic sites or allosteric inhibitors of HIV integrase (NCINI) include CX-05045, CX-05168 and CX-14442.

HIV entry inhibitors

Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO140, adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, C25P polypeptide, TD- 0680 and vMIP (Haimipu).

Examples of gp41 inhibitors include aluuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitors (P26-Bars), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

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

Examples of CXCR4 inhibitors include plerixaphor, ALT-1188, N15 peptide and vMIP (Haimipu).

HIV maturation inhibitors

Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

Latent reverse agents

Examples of latent reversing agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C activators (PKC), BET bromodomain 4 (BRD4) inhibitors, ionomycin, phorbol myristacetate (PMA), SAHA (suberoylanilide hydroxamic acid or suberoylanilide hydroxamic acid), IL -15, JQ1, disulfiram, amphotericin B and ubiquitin inhibitors, in particular largazol analogs and GSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat and panobinostat.

Examples of PCC activators include indolactam, prostratin, ingenol B, and DAG lactones.

Capsid inhibitors

Examples of capsid inhibitors include capsid polymerization inhibitors or capsid disrupting compounds, inhibitors of HIV p7 nucleocapsid assembly (NCp7) such as azodicarbonamide, HIV p24 capsid protein inhibitors, series AVI-621, AVI-101, AVI-201, AVI-301 and AVI-CAN1-15.

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In some embodiments, examples of capsid inhibitors include:

or their pharmaceutically acceptable salt.

In some embodiments, the capsid inhibitor is:

or their pharmaceutically acceptable salts.

In some embodiments, the capsid inhibitors are selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the capsid inhibitor is:

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or a pharmaceutically acceptable salt thereof.

Immunostimulants

Examples of immunostimulants include toll-like receptor modulators, in particular tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13; programmed cell death protein 1 (Pd-1) modulators; modulators of programmed cell death ligand 1 (Pd-L1); IL-15 agonists; DermaVir; interleukin-7; Plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferonalfa; interferon-alpha-2b; interferon-alpha-n3; pegylated interferon-alpha; interferongamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, a polymer of polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15/Fc fusion protein, normferon, peginterferon-alpha-2a, peginterferon-alpha-2b, recombinant interleukin-15, RPI-MN, GS-9620 and IR-103.

In some embodiments, examples of immunostimulants include toll-like receptor modulators, specifically tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed cell 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-p3; pegylated interferon-alpha; interferon-gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, a polymer of polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15/Fc fusion protein, normferon, peginterferon-alpha-2a, peginterferon-alpha-2b, recombinant interleukin-15, RPI-MN, GS-9620, STING modulators, RIG-I modulators, NOD2 modulators and IR-103.

Phosphatidylinositol 3-kinase (PI3K) inhibitors

Examples of PI3K inhibitors include idelicib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosin, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMH-319, AZD-8186, BAYD-8186 -1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB040093, LY-3023414, μλΝ-1117, PQR-309, RG -7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

Alpha-4/beta-7 antagonists

Examples of alpha-4/beta-7 integrin antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

HIV antibodies, bispecific antibodies and antibody-like therapeutic proteins

Examples of HIV antibodies, bispecific antibodies, and antibody-like therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bnABs (HIV-1 broad spectrum neutralizing antibody), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41, molecules involving antibodies targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120/CD4 bispecific antibodies, CCR5, single-domain anti-nef antibodies, anti-Rev antibody obtained from camelid anti-CD18 antibodies derived from camelid anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, HIV dr41 therapeutic antibodies, human recombinant mAbs (PGT-121), ibalizumab, Immuglo, MB-66.

Examples of antibodies targeting HIV in this way 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-WICHMAB080-00-AB, MGD-014 and VRC07.

In some embodiments, examples of antibodies that target HIV in this way 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-HIVMABO8O-OO-AB, VRC-HIVMAB060

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00-AB, MGD-014 and VRC07. An example of a bispecific HIV antibody includes MGD014.

Pharmacokinetic enhancers

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

Additional Therapeutic Agents

Examples of additional therapeutic agents include those disclosed 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 2014022136 (Gilead Sciences) ), US 20100143301 (Gilead Sciences) and WO 2013/091096 (Boehringer Ingelheim).

Combination therapy against HIV

In a particular embodiment, a compound of the present invention, 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 dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir 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 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine and zidovudine; abacavir; and abacavir sulfate.

Those skilled in the art will appreciate that the additional therapeutic agents listed above may fall into more than one of the classes listed above. The specific classes are not intended to limit the functionality of the compounds listed in the specified classes.

In a particular embodiment, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is combined with a nucleoside or nucleotide HIV reverse transcriptase inhibitor and a non-nucleoside HIV reverse transcriptase inhibitor. In another specific embodiment, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is combined with a nucleoside or nucleotide HIV reverse transcriptase inhibitor and an HIV protease inhibitory compound. In another embodiment, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is combined with at least one nucleoside HIV reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is combined with two nucleoside or nucleotide HIV reverse transcriptase inhibitors.

In a particular embodiment, a compound of the present invention, 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.

In a particular embodiment, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

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In a particular embodiment, a compound of the present invention, 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.

In a particular embodiment, a compound of the present invention, 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 tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein said second additional therapeutic agent is emtricitabine.

In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is combined with a capsid inhibitor(s) (eg, capsid polymerization inhibitors and/or capsid degrading compounds).

In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is combined with a capsid inhibitor (in an amount of about 10 to about 1000 mg) selected from:

or their pharmaceutically acceptable salt.

In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is combined with a capsid inhibitor selected from:

or their pharmaceutically acceptable salt.

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

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or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

The compound described in the present invention (for example, any compound of formula (Ia)), may be combined with one or more additional therapeutic agents in any dosage of the compound of formula (Ia) (for example, from 1 mg to 1000 mg of the compound).

In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg of tenofovir alafenamide in the form of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, or any salt of the solvate form of tenofovir alafenamide. In some embodiments, a compound of the present invention, 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 some 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 tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In some embodiments, a compound of the present invention, 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 some embodiments, a compound of the present invention, 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 according to the present disclosure (e.g., a compound of formula (Ia)) may be combined with the agents of the present invention at any dosage of the compound (e.g., 1 mg to 1000 mg of the compound), as if each combination dosages have been adjusted specifically and individually.

In some embodiments, a compound of the present invention, 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 some 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, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine. In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. A compound according to the present disclosure (e.g., a compound of formula (Ia)) may be combined with the agents of the present invention at any dosage of the compound (e.g., 1 mg to 1000 mg of the compound), the same as if each combination of dosages were given specifically and individually.

In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor and an integrase inhibitor. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with GS-9131 and bictegravir.

In one embodiment, kits are provided containing a compound of the present invention, 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.

Combination therapy with contraceptives (contraceptives)

Therapeutic agents used as contraceptives (contraceptives) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethinodiol, etonogestrel, levomefolate, levonorgestrel, linestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestromin acetate, norelgestromin acetate, norelgestromin acetate , norethisterone, noretinodrel, norgestimate, ormeloxifene, segesterson acetate, ulipristal acetate, and any combination thereof.

TCR-T cell therapy

TCR-T cells are engineered to target HIV-produced peptides present on the surface of virus-infected cells.

Some embodiments of the methods disclosed in the present invention exclude the introduction of a pharmacokinetic enhancer. For example, in some methods disclosed in the present invention, a pharmacokinetic enhancer, in particular cobicistat or ritonavir, is not administered to the subject during treatment with a compound disclosed in the present invention, or a pharmaceutically acceptable salt thereof. Thus, in some embodiments, a method of treating or preventing a human immunodeficiency virus (HIV) infection is provided, which comprises administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, said treatment not comprising administration of a pharmacokinetic enhancer. In some embodiments, a method for treating or preventing a human immunodeficiency virus (HIV) infection is provided, which comprises administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, once daily to a subject in need thereof, said treatment not involves the administration of a pharmacokinetic enhancer.

The present invention also provides all of the intermediates P, S, A and I described below in the examples section.

Examples

Methods for preparing the novel compounds described herein will be apparent to those skilled in the art in view of the appropriate techniques described, for example, in the reaction schemes and examples below.

Sections 1.1-1.8 provide exemplary synthetic schemes for assembling compounds of formula I. Sections 2.1-2.4 provide the preparation of Intermediate I, Intermediate P, Intermediate S and Intermediate A used in the present invention. Section 3 provides illustrative syntheses and compounds. Section 4 presents biological activity.

1. General schemes.

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Scheme 1.1

Scheme 1.1 shows the overall synthesis of a compound within formula I, starting with reductive amination of compound 1.1a with substituted benzaldehyde (intermediate P). Reductive amination can be carried out, for example, with a cyanoborohydride reagent such as sodium cyanoborohydride. Next, a metal-catalyzed coupling is carried out, such as a Sonogashira or Suzuki coupling. Sonogashira's coupling of compound 1.1b with the alkynyl intermediate S ^a provides a compound of formula I.

Compounds of Examples 1-130, 219 and 224-245 were prepared using the general strategy indicated (by reductive amination of the appropriate intermediate P with the appropriate organohalide peptide intermediate I followed by coupling Sonogashira with the appropriate intermediate S) . Example 1 provides illustrative reaction conditions and suitable reagents for the preparation of a compound of formula I according to Scheme 1.1.

Scheme 1.2

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Scheme 1.2 shows the general synthesis of a compound of formula I using reductive amination of compound 1.2a, which is a protected aminohydrazine ylophenylbutanol. Exemplary protecting groups (PG) for compound 1.2a include a tert-butylcarbonyl (BOC) protecting group and fluorenylmethyloxycarbonyl (FMOC). Reductive amination of compound 1.2a with intermediate P, which is a substituted benzaldehyde, allows compound 1.2b to be obtained after deprotection. Reductive amination can be carried out as a non-limiting example using sodium cyanoborohydride. HATU coupling of compound 1.2b with amino acid intermediate A ^m yields compound 1.2c. Sonogashira's coupling of compound 1.2c with the alkyne intermediate S ^a produces a compound of formula I.

Compounds of Examples 133-180 and 220 were prepared using the general strategy indicated (by reductive amination of the appropriate intermediate P with aminohydrazine ylophenylbutanol followed by HATU coupling with intermediate A ^m followed by coupling of Sonogashira with alkynyl intermediate S ^a ). Example 133 provides illustrative reaction conditions and suitable reagents for the preparation of a compound of formula I according to Scheme 1.2.

Scheme 1.3

1.3d

Scheme 1.3 shows the general synthesis of a compound of formula I, starting with reductive amination of the protected organohalide compound 1.3a with benzaldehyde intermediate P and removal of the Boc group to give compound 1.3b. Recovery aminiro

- 38 040208 can be carried out as a non-limiting example using sodium cyanoborohydride. Removal of the Boc group can be carried out as non-limiting examples with trifluoroacetic acid or hydrochloric acid. The HATU coupling of compound 1.3b with the amino acid Intermediate A ^m yields intermediate peptide 1.3c. Sonogashira's coupling of this peptide intermediate 1.3c and alkynyl intermediate S results in intermediate 1.3d. Subsequent reaction of compound 1.3d with acyl chloride affords a compound of formula I.

Compounds according to examples 183-186 were obtained using the indicated general strategy. Example 183 provides illustrative reaction conditions and suitable reagents for the preparation of a compound of the present invention according to Scheme 1.3.

Scheme 1.4

The X ¹ group can be inserted directly into the halophenyl as shown in Scheme 1.4. In this example, the organohalide intermediate S ^L (presented above, where L is iodine, bromine, or chlorine) is coupled to compound 1.4a via a borylation/Suzuki reaction. Compounds according to examples 188-201 were obtained using the methodology presented in scheme 1.4. Illustrative reaction conditions are contained in Example 188.

Scheme 1.5

Alternatively, the X ¹ group can be introduced by metal catalyzed coupling of boronic acid or boronic acid ester (intermediate S ^b ) with compound 1.5a. This reaction is carried out with XPhos Pd G2. Xphos is also known as XPhos and 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). Compounds according to examples 202-211 and 218 were obtained according to scheme 1.5. Example 202 provides illustrative reaction conditions for the indicated conversion.

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Scheme 1.6

The compound according to example 212 was obtained according to scheme 1.6. Example 212 provides illustrative reaction conditions for transformations according to Scheme 1.6.

Scheme 1.7

Scheme 1.7 shows an example of a Suzuki cross-coupling followed by Boc deprotection and amide bond formation. Illustrative reaction conditions can be found in Example 213. Examples 214-217 show the insertion of different R ² and R ³ groups using the same general strategy and the corresponding acid chloride.

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Scheme 1.8

Scheme 1.8 shows the overall synthesis of a compound within formula I, starting with reductive amination of compound 1.8a with substituted benzaldehyde (intermediate P). Reductive amination of compound 1.8a with intermediate P, which is a substituted benzaldehyde, affords compound 1.8b. Reductive amination can be carried out as a non-limiting example using sodium cyanoborohydride. Subsequent opening of the epoxy ring of tert-butyl-((S)-2-(4-iodophenyl)-1-((R)-oxiran-2yl)ethyl)carbamate affords compound 1.8c. Subsequent removal of the Boc group, followed by the formation of an amide bond, affords compound 1.8d. Removal of the Boc group can be carried out as non-limiting examples with trifluoroacetic acid or hydrochloric acid. The formation of an amide bond can be carried out as a non-limiting example using a carboxylic acid and a reagent such as HATU. Subsequent removal of the protecting group allows compound 1.8e to be obtained. Subsequent formation of an amide bond allows compound 1.8f to be obtained. The formation of an amide bond can be carried out as a non-limiting example using a carboxylic acid and a reagent such as HATU. Further, a metal catalyzed combination, such as a Sonogashira or Suzuki combination, can be performed. Sonogashira's coupling of compound 1.8d with the alkynyl intermediate S ^a provides a compound of formula I.

Compounds according to examples 221-223 were obtained using the indicated general strategy.

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2. Synthesis of intermediate compounds.

2.1 Synthesis of intermediates P.

4-(1-(Difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzaldehyde (P1).

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 hermetically sealed a 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 silica gel column chromatography (17-47% EtOAc/Hex) to give 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 orthophosphate (2 M, 3.3 ml) in dioxane (11 ml) and degassed with argon for 10 min, after which it was heated at 100° C during the night. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with EAAC and washed twice with brine, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (23-92% EtOAc/Hex) to give the desired P1 isomer. MS (ESI) m/z 259.2 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 10.32 (d, J = 1.1 Hz, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.63 (d, J = 1.3 Hz, 1H), 7.48-7.36 (m, 2H), 7.16 (t, J = 60.8 Hz, 1H).

4-(1-(Difluoromethyl)-1H-imidazol-4-yl)benzaldehyde (P2).

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

4-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)-2,6-difluorobenzaldehyde (P3).

To a heterogeneous solution of copper (II) bromide (3.8 g, 17 mmol) and tert-butyl nitrite (2.53 ml, 21.25 mmol) in MeCN (78 ml) in a three-necked flask equipped with a magnetic stir bar and side arm ( side arm inlet), 5-cyclopropyl-1,3,4-thiadiazol-2-amine (2 g, 14.16 mmol) was added slowly under argon due to the exothermicity of the reaction, and the resulting mixture was stirred at room temperature under argon overnight. The reaction mixture was quenched with 78 ml of a saturated solution of NH ₄ Cl (aq.) and subjected to extraction with diethyl ether, the organic layer was dried over MgSO ₄ , filtered and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (10-50% EtOAc/Hex). The resulting 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 orthophosphate (2 M, 1.34 ml) in dioxane (4.9 ml), and degassed with argon for 10 min, after which it was 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 twice with saline, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (21-100% EtOAc/Hex) to give the desired P3 isomer. MS (ESI) m/z 267.1 [M+H] ⁺ . 1H NMR (400 MHz, chloroform-d) δ 10.37 (s, 1H), 7.56 (d, J = 9.0 Hz, 2H), 5.30 (d, J = 0.7 Hz, 0H ), 2.47 (dt, J = 8.1, 3.7 Hz, 1H), 1.55 (s, 5H), 1.33 (dd, J = 8.3, 4.1 Hz, 2H) , 1.26 (d, J = 4.4 Hz, 5H), 0.92 - 0.79 (m, 2H).

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F

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

In a 150 ml pressure vessel, a suspension of 3-bromo-1Hpyrazole (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 Et ₂ O (30x150 ml). The filtrate was washed with brine, dried over sodium sulfate and carefully concentrated (bath temperature 20° C., vacuum 100 mbar) to give ~17 g of regioisomers and solvent still present in a ratio of 1.5:1. 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 resulting mixture was degassed with argon for 10 min, after which it was 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 twice with saline, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (5-15% EtOAc/Hex). The mixed fractions were recrystallized (5:1 Hex/EtOAc) to give the combined pure product P4. ¹ H NMR (400 MHz, chloroform-d) δ 10.35 (d, J = 1.0 Hz, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.46 (d, J = 9.6 Hz, 2H), 7.24 (t, J = 60.5 Hz, 1H), 6.80 (d, J = 2.8 Hz, 1H).

Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2-fluorobenzaldehyde (Р5).

The title compound P5 was prepared according to the procedure described for the synthesis of intermediate P4, but using (3-fluoro-4-formylphenyl)boronic acid. 1H NMR (400 MHz, chloroform-d) δ 10.41 (s, 1H), 7.97 (dd, J=8.0, 7.1 Hz, 1H), 7.71 (d, J= 1, 7 Hz, 1H), 7.50 - 7.34 (m, 2H), 6.55 (d, J= 1.7 Hz, 1H).

Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzaldehyde (Р6).

The title compound P6 was prepared according to the procedure described for the synthesis of intermediate P4, but using (4-formylphenyl)boronic acid. 1H NMR (400 MHz, chloroform-d) b 10.05 (s, 1H), 8.03 - 7.93 (m, 4H), 7.90 (d, J = 2.7 Hz, 1H), 6 .85 (d, J = 2.7 Hz, 1H).

Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzaldehyde (P7).

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 carbonate potassium (2.06 g, 14.93 mmol) in water (7 ml) and 1,4-dioxane (22 ml) in a test tube was degassed with argon for 10 min, after which the specified tube was sealed and heated at 100°C for night. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with EtOAc and washed twice with saline, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (10-25% EtOAc/Hex) to give compound P7. 1H NMR (400 MHz, chloroform-d) δ 10.32 (s,

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1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.23 (t, J = 60.4 Hz, 1H), 7.14 (d, J = 9.5 Hz, 2H).

Synthesis of 4-(1-(difluoromethyl)-1 H-pyrazol-4-yl)-2-fluorobenzaldehyde (Р8).

The title compound P8 was prepared according to the procedure described for the synthesis of intermediate P7, but using 4-bromo-2-fluorobenzaldehyde. ¹ H NMR (400 MHz, chloroform-d) dd 10.35 (d, J = 0.7 Hz, 1H), 8.15 (d, J = 0.7 Hz, 1H), 7.98 (q, J = 0.8 Hz, 1H), 7.91 (dd, J = 8.1, 7.3 Hz, 1H), 7.42 (yyy, J= 8.1, 1.7, 0.8 Hz , 1H), 7.31 (dd, J = 11.3, 1.6 Hz, 1H), 7.23 (s, 1H).

Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzaldehyde (P9). The title compound P9 was prepared according to the procedure described for the synthesis of intermediate P7 but using 4-bromobenzaldehyde. 1H NMR (400 MHz, chloroform-d) δ 10.02 (s, 1H), 8.16 (s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.96 -7 .90 (m, 2H), 7.71-7.66 (m, 2H), 7.24 (t, J = 0.14 Hz, 1H).

Synthesis of 3-bromo-1-(2,2-difluoroethyl)-1H-pyrazole (P10a).

A solution of 1,1- difluoro-2-iodoethane (24.68 g, 128.59 mmol) via addition funnel. The resulting reaction mixture 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (7-25% EtOAc/Hex) to give compound 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, 1H), 6.32 (d, J = 2.4 Hz, 1H), 6.06 (tt, J = 55.4, 4.3 Hz, 1H), 4.41 (td, J = 13.3, 4.3 Hz, 2H).

Synthesis of 4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzaldehyde (P10).

Compound P10a (4.31 g, 0.02 mol) was combined with 3,5-difluoro-4-formylphenylboronic acid (4.96 g, 24.49 mmol), PdCl ₂ (tBu ₂ PPh) ₂ (570 mg, 0 .92 mmol) and potassium orthophosphate monohydrate (1.0 M, 40.82 ml) in 2-methyltetrahydrofuran (20 ml) and water (20 ml), the resulting mixture was degassed with argon for 10 min, after which it was heated at 75°C during the night. The reaction mixture was cooled to room temperature, the organic layer was separated, the aqueous layer was subjected to extraction in EtOAc. The combined organic layers were washed with 1M HCl and then with brine, the filtrate was concentrated under reduced pressure, the residue was diluted with EtOAc and washed twice with brine, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure, recrystallized (using mixture 1 :3 EtOAc/hexanes). The separated solids contained a mixture of the desired isomer and unreacted boronic acid. This mixture was purified by silica gel column chromatography (70-100% DCM/Hex) to give compound 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, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.47 - 7.38 (m, 2H), 6.67 (d, J = 2.4 Hz, 1H), 6.15 (tt, J = 55.3, 4.3 Hz, 1H), 4.52 (td, J = 13.5, 4.3 Hz, 2H).

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

The title compound P11 was prepared according to the procedure described 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, 1H), 7.89 (dd, J = 8.1, 7.2 Hz, 1H), 7.70 -7.58 (m, 2H), 7.54 (d,

J = 2.4 Hz, 1H), 7.33 (dt, J = 8.0, 1.0 Hz, 0H), 7.26 (dd, J = 10.7, 1.5 Hz, 0H), 6.68 (d, J = 2.4 Hz, 1H), 6.42 (d, J = 1.9 Hz, 0H), 6.15 (tt, J = 55.4, 4.3 Hz, 1H ), 4.52 (td, J = 13.5, 4.3 Hz, 2H).

Synthesis of 4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)benzaldehyde (P12).

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

F

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

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 after which 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) were added in DCE (60 ml). The resulting reaction mixture was stirred at 65° C. for 48 hours. 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 NH ₄ Cl solution, the organic layer was washed with NH ₄ Cl, Na ₂ CO ₃ solution, brine, dried over Na ₂ SO ₄ and purified by silica gel column chromatography (10-35 % EtOAc/Hex) to give 3-bromo-1-cyclopropyl-1H-pyrazole.

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), PdCl ₂ (tBu ₂ PPh) ₂ (0.29 g, 0.41 mmol) and potassium orthophosphate monohydrate (4.71 g, 20.45 mmol) in 2-methyltetrahydrofuran (60 ml) and water (60 ml), the resulting mixture was degassed with argon in for 10 min, after which it was heated to reflux for 3 h. The reaction mixture was cooled to room temperature, the organic layer was separated, and the aqueous layer was subjected to extraction in EtOAc. The combined organic layers were washed with 1M HCl and then brine, filtered and concentrated under reduced pressure, the residue was diluted with EtOAc and washed twice with brine, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. This mixture was purified by silica gel column chromatography (50-100% DCM/Hex - 10% EtOAc/DCM) to give compound P13 (1.2 g, 49%). MS (ESI) m/z 249.2 [M+H] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 10.33 (s, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 10.1 Hz, 2H), 6.57 (d, J = 2.4 Hz, 1H), 3.66 (tt, J = 7.4, 3.9 Hz, 1H), 1.26 - 1.15 (m, 2H ), 1.09 (qd, J = 5.7, 2.4 Hz, 2H).

About F P14

Synthesis of 2,6-difluoro-4-(4-fluoropyridin-2-yl)benzaldehyde (P14).

Suspension of 2-bromo-5-fluoropyridine (0.95 g, 5.39 mmol), 3,5-difluoro-4-formylphenylboronic acid (0.8 g, 4.3 mmol), dichlorobis (triphenylphosphine) palladium (II) (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) were degassed with argon in for 10 min, after which it was heated at 85°C during the night. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with EtOAc and washed twice with brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (10-20% EtOAc/Hex) to give compound 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, 1H), 8.59 (d, J = 2.8

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Hz, 1H), 7.78 (yyy, J = 8.8, 4.2, 0.6 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.55 (yyy, J = 8.8, 7.8, 2.9 Hz, 1H).

F

Synthesis of 2,6-difluoro-4-(4-fluoropyridin-2-yl)benzaldehyde (P15).

The title compound P15 was prepared according to the procedure described for the synthesis of compound P14 but using 2-bromo-4-fluoropyridine. MS (ESI) m/z 238.2 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 10.39 (s, 1H), 8.70 (dd, J = 8.6, 5.5 Hz, 1H), 7.67 (d, J = 9, 9 Hz, 3H), 7.48 (dd, J = 9.8, 2.3 Hz, 1H), 7.11 (yyy, J = 7.9, 5.5, 2.3 Hz, 1H).

Synthesis of 2,6-difluoro-4-(pyrimidin-2-yl)benzaldehyde (P16). 2-Bromopyrimidine (1 g, 6.29 mmol) and tetrakis(triphenylphosphine)palladium (218.05 mg, 0.19 mmol) in 1,2-dimethoxyethane (30 mL) were degassed for 5 min after which water was added ( 15 ml) 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 resulting reaction mixture was heated at 85° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc and washed with saturated NaHCO ₃ solution and brine, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure.

The crude residue was purified by silica gel column chromatography (0-40% EtOAc/Hex) to give compound P16. 1H NMR (400 MHz, chloroform-d) δ 10.42 (d, J = 1.0 Hz, 1H), 8.87 (d, J = 4.9 Hz, 2H), 8.16-8.03 (m, 2H), 7.32 (t, J = 4.8 Hz, 1H).

F (S)-2,6-Difluoro-4-( 1 -(tetrahydrofuran-3-yl)-1 H-pyrazol-3-yl)benzaldehyde (Р17)/

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-ylmethanesulfonate (source: PCT International Application 2013068458) (998 mg, 6.01 mmol) in DMF (5 ml) was added and the resulting reaction mixture was heated to 100 °C during the night. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with brine. The organic layer was separated, dried over Na ₂ SO ₄ , concentrated in vacuo and the crude residue was purified by silica gel column chromatography (20-40% EtOAc/Hex) to give (S)-3-bromo-1-(tetrahydrofuran-3 -yl)-1H-pyrazole (0.17 g, 0.78 mmol). In a 20 ml microwave vial, the indicated substance was combined 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 resulting mixture was degassed with argon in within 5 min. The reaction mixture was treated with microwave radiation at 100°C for 1.5 h, then cooled to room temperature, concentrated under vacuum, then diluted with EtOAc and washed with water and brine. The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (20-40% EtOAc/hex) to give compound P17. MS (ESI) m/z 279.1 [M+H] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 10.32 (d, J = 1.0 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.48 - 7, 34 (m, 2H), 6.62 (d, J = 2.4 Hz, 1H), 5.03 (ddt, J = 8.2, 5.8, 3.4 Hz, 1H), 4.31 - 4.03 (m, 4H), 3.98 (td, J = 8.6, 5.5 Hz, 1H), 2.51 (dtd, J = 13.4, 8.3, 7.1 Hz , 1H), 2.43 -2.28 (m, 1H).

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

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

2,6-Difluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)benzaldehyde (P19)/

The title compound P19 was prepared according to the procedure described for the synthesis of compound P4, but using 1-chloro-2-methylpropan-2-ol. MS (ESI) m/z 281.0 [M+H] ⁺ . ¹ H NMR (400

MHz, chloroform-d) δ 10.33 (s, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.47-7.35 (m, 2H), 6.64 (d , J= 2.4 Hz, 1H), 4.13 (s, 2H), 1.22 (s, 7H).

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).

Suspension of compound 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) were degassed for 10 min. The reaction mixture was heated at 85°C for 3 hours. After cooling to room temperature, the mixture was diluted with EtOAc and washed with saturated NaHCO ₃ solution and brine, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0-40% EtOAc/Hex) to give compound P20 (99 mg, 62%). MS (ESI) m/z 387.2 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 10.33 (s, 1H), 8.55 (s, 1H), 7.11 (d, J = 9.8 Hz, 1H), 4.74 (t , J = 6.3 Hz, 1H), 4.61 (s, 1H), 4.40 (d, J = 12.8 Hz, 1H), 3.69 (s, 1H), 3.33-3 .02 (m, 3H), 1.86 (s, 1H), 1.65 (d, J = 8.1 Hz, 1H), 1.55 (s, 2H).

Synthesis of 4-(1-cyclopropyl-1H-pyrazol-3-yl)benzaldehyde (P21).

The title compound P21 was prepared according to the procedure described 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, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.92 - 7.86 (m, 2H), 7 .50 (d, J = 2.3 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H), 3.66 (tt, J = 7.4, 3.8 Hz, 1H) , 1.22-1.15 (m, 2H), 1.11-1.03 (m, 2H).

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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).

A suspension of compound 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 Cl ₂ Pd(tBu ₂ PPh) 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 hours. After cooling to room temperature, the mixture was diluted with EtOAc and washed with saturated NaHCO ₃ solution and brine, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (1-15% MeOH/(1% E3N in EtOAc)) to give compound P22 (470 mg, 85%). MS (ESI) m/z 372.2 [M+H] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 10.34 (s, 1H), 8.52 (d, J = 2.5 Hz, 1H), 7.76 (dd, J = 8.9, 2 .5 Hz, 1H), 7.16 (d, J = 10.4 Hz, 2H), 6.61 (d, J = 8.8 Hz, 1H), 4.71 (t, J = 6.2 Hz, 2H), 4.50 (s, 2H), 3.87 (t, J = 6.2 Hz, 3H), 3.57 (s, 4H), 2.78 (d, J = 7.3 Hz, 1H), 1.64 (d, J = 8.9 Hz, 1H).

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).

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

About CI 3. PCC

R24 R25

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

In a sealed tube, methyl 4-bromo-2,6-dichlorobenzoate (3.18 g, 11.2 mmol), 2(trimethylstannyl)pyridine (1.94 ml, 11.2 mmol) and tetrakis(triphenylphosphine)palladium ( 647.1 mg, 0.56 mmol) were suspended in DMF (25 ml). The resulting mixture was degassed with argon for 10 min, heated to 100°C for 18 h, and then reacted at room temperature. After 48 h the reaction mixture was diluted with EtOAc and washed with KF (3 g in 50 ml water) and brine (3 x) and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0-20% EtOAc/hexanes) to give methyl 2,6-dichloro-4-(pyridin-2-yl)benzoate (1.5 g, 47.5%). The indicated substance was dissolved in THF (25 ml), cooled to 0°C, after which lithium aluminum hydride (0.4 g, 10.63 mmol) was slowly added, and after completion of the addition, the resulting reaction mixture was slowly warmed to room temperature and stirred for 1 h, after which it was again cooled to 0°C, water (500 µl), then NaOH (2 M, 500 µl), then water (1500 µl) was added slowly (due to intense gas evolution). The resulting suspension was stirred at room temperature. After 1 h was added Na ₂ SO ₄ and then the resulting mixture was filtered through celite. The solid was rinsed with Et ₂ O (~200 ml) and the filtrate was concentrated under reduced pressure, the residue was diluted with EtOAc and washed with water, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue (1.5 g, 5.9 mmol) was combined with pyridinium chlorochromate (PCC) (1.91 g, 8.85 mmol) and celite (700 mg, 7 mmol), DCM (10 ml) was added, and the resulting the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered through a celite frit with a small layer of silica and rinsed several times with DCM/EtOAc, and then the filtrate was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to give compound P24 (392 mg, 26.3%); MS (ESI) m/z 252.0 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ

10.54 (s, 1H), 8.74 (yyy, J = 4.8, 1.8, 0.9 Hz, 1H), 8.06 (s, 2H), 7.83 (yyy, J = 8.0, 7.4, 1.8 Hz, 1H), 7.77 (dt, J =

8.0, 1.1 Hz, 1H), 7.36 (yyy, J = 7.4, 4.8, 1.2 Hz, 1H) and compound P25 (195 mg, 15.2%); MS (IER) m/z 218.1

[M+H]+; 1H NMR (400 MHz, chloroform-d) yyy 10.52 (d, J = 0.8 Hz, 1H), 8.74 (yyy, J = 4.8, 1.7, 1.0 Hz, 1H) ,

8.17 (dd, J = 1.6, 0.5 Hz, 1H), 8.07 - 7.95 (m, 2H), 7.91 - 7.75 (m, 2H), 7.39 - 7.29(m, 1H).

Synthesis of 4-bromo-2,6-difluorobenzaldehyde (P26a).

Diisobutylaluminum hydride (DIBAL, Dibal-H) (1 .0 M in toluene, 60 ml). After 4.5 h, the reaction mixture was quenched with MeOH (2.4 ml), then with NaOH (6.0 M, 2.4 ml), then with water (5 ml). The reaction mixture was stirred for 1 h, and then Na ₂ SO ₄ was added, filtered and concentrated under vacuum, the residue (4.96 g, 20.71 mmol) was dissolved in DCM (100 ml) and cooled to 5°C, after which pyridinium chlorochromate (6.27 g, 0.03 mol) was added and the resulting mixture was stirred overnight, allowing it to warm slowly to room temperature. Silica gel (10 g) was added and the resulting mixture was filtered through a 3.81 cm (1.5 in) pad of silica gel eluting with 5:1 DCM/EtOAc to give compound P26a (4.67 g, 92%). 1H NMR (400 MHz, chloroform-d) δ 10.38 (s, 1H), 7.54 - 7.41 (m, 1H), 7.31 (dd, J = 9.7, 1.8 Hz, 1H). ¹⁹ F NMR (377 MHz, chloroform-d) δ -113.31 (d, J = 9.7 Hz).

Synthesis of 2-chloro-6-fluoro-4-(pyridin-2-yl)benzaldehyde (P26).

₂ -pyridylzinc bromide ( _{0 .} 5 M in THF, 28.43 ml). The resulting reaction mixture was degassed with argon (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 NH ₄ Cl solution. The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (3-35% EtOAc in 1:1 DCM/hexane) to give compound 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, 1H), 8.74 (yyy, J = 4.8, 1.8, 1.0 Hz, 1H) , 7.96 (t, J = 1.4 Hz, 1H), 7.86 (d, J = 1.8 Hz, 0H), 7.85 - 7.80 (m, 1H), 7.78 ( q, J = 1.1 Hz, 1H), 7.77 - 7.74 (m, 1H), 7.36 (yyy, J = 7.4, 4.8, 1.2 Hz, 1H). ¹⁹ F NMR (377 MHz, chloroform-d) δ -114.35 (d, J = 11.6 Hz).

F

Synthesis of 4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-2,6-difluorobenzaldehyde (P27). 6,7Dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-amine (1 g, 0.01 mol) in CH3CN (5 ml) at 15°C was combined with copper (I) bromide (1.24 g, 0.01 mol) and copper (II) bromide (16.05 mg, 0.07 mmol), after which tert-butyl nitrite (1.11 ml, 0.01 mol) was added very slowly, the obtained the reaction mixture was stirred overnight. The mixture was quenched with aqueous NH4Cl, diluted with DCM, the layers were separated and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (7-40% EtOAc/hexanes), the resulting product (0.59 g, 2.91 mmol) was combined with 3,5-difluoro-4-formylphenylboronic acid (0.81 g, 4. 36 mmol), PdCl ₂ (tBu ₂ PPh) ₂ (0.08 g, 0.12 mmol) and potassium orthophosphate monohydrate (1.67 g, 7.27 mmol) in 2-methyltetrahydrofuran (25 ml) and water (60 ml), the resulting mixture was degassed with argon for 10 min, after which it was heated to 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was crystallized from EtOAc/ether to give compound P27 (486 mg, 63%) MS (ESI) m/z 265.1 [M+H] ⁺ .

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

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

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

The title compound P29 was prepared according to the procedure described 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]+.

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

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

BUT

1. YA1H ₄

2. PCC

Η

P31

Synthesis of bicyclo[2.2.1]heptane-1-carbaldehyde (Р31).

Bicyclo[2.2.1]heptane-1-carboxylic acid (1000 mg, 0.01 mol) was dissolved in methyltetrahydrofuran (3 ml), cooled to 0°C, after which lithium aluminum hydride (0.5 g, 14 mmol) was slowly added, and after completion of the addition, the resulting reaction mixture was slowly warmed to room temperature and stirred for 2 h, then the mixture was again cooled to 0°C, water (540 μl) was added slowly (due to intense gas evolution), then NaOH (2 M, 540 µl), then water (1500 µl). The resulting suspension was stirred at room temperature. After 1 h was added Na ₂ SO ₄ after which the resulting 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) to give the reaction mixture was allowed to slowly warm to room temperature and stirred for 48 hours. The reaction mixture was filtered through a celite frit with a small layer of silica and rinsed several times with DCM, and then the filtrate was concentrated under reduced pressure at 5°C to obtain the compound P31 ( 1.7 g, 95%). ¹ H NMR (400 MHz, chloroform-d) δ 9.85 (s, 1H), 2.41 (td, J = 4.2, 2.1 Hz, 1H), 2.04 - 1.27 (m , 10N).

Synthesis of 2,6-difluoro-4-(oxetan-3-yl)benzaldehyde (P32).

In a sealed tube were combined 3-iodoxetane (0.24 ml, 3 mmol), (3,5-difluoro-4formylphenyl)boronic acid (250 mg, 1.34 mmol), 4,4'-di-tert-butyl- 2,2'-dipyridyl (18.05 mg,

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0.07 mmol), Ni(NO3) ₂ -6H ₂ O (19.55 mg, 0.07 mmol) and potassium carbonate (557.51 mg, 4.03 mmol) in 1,4dioxane (5 ml). The resulting mixture was degassed with argon for 10 min, heated to 80°C for 12 hours, and then cooled to room temperature. After 48 h the reaction mixture was diluted with EtOAc and washed with brine (2x), then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (10-30% EtOAc/hexanes) to give compound P32 (49 mg, 18%). 1H NMR (400 MHz, chloroform-d) δ 10.26 (d, J = 1.2 Hz, 1H), 6.99 (d, J = 9.5 Hz, 2H), 5.04 (dd, J = 8.2, 6.3 Hz, 2H), 4.62 (t, J = 6.3 Hz, 2H), 4.14 (tt, J = 8.2, 6.2 Hz, 1H).

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

Combined 3,6-dihydro-2H-pyran-4-boronic acid pinacol 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 (2 M, 2.24 ml) in 1,4-dioxane (6 ml). The resulting mixture was degassed with argon for 10 min, heated to 80°C for 12 h, and then cooled to room temperature. The reaction mixture was diluted with EtOAc and washed with brine (2x), then dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20-50% EtOAc/hexanes), the resulting product (405 mg, 1.79 mmol) was dissolved in EtOAc (8 ml), palladium (10% on C, 38.1 mg) was added , 0.36 mmol) and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 18 hours. 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 resulting reaction mixture was stirred at room temperature for 48 hours. Then the reaction mixture filtered through celite and rinsed several times with DCM, the filtrate was concentrated under reduced pressure to give compound P33. 1H NMR (400 MHz, chloroform-d) δ 10.28 (d, J = 1.2 Hz, 1H), 6.85 (d, J = 10.0 Hz, 2H), 4.08 (dt, J = 11.5, 3.2 Hz, 2H), 3.60-3.33 (m, 2H), 2.90-2.71 (m, 1H), 1.83-1.70 (m, 4H ).

P34

Synthesis of 2,6-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzaldehyde (Р34).

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

O F P35

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

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

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

A mixture of 4-bromo-2,6-difluorobenzaldehyde (2 g, 9.05 mmol), bis(pinacolato)diboron (3.22 g, 12.67 mmol), dichloro-1,1'-bis(diphenylphosphino)ferrocenepalladium ( 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 to 90°C for 12 hours. After cooling 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 to room temperature. The resulting mixture was degassed by evacuation and refilling with argon (Ar) (3x), after which the reaction mixture was heated to 90°C for 12 h, cooled to room temperature, diluted with EtOAc and washed with brine. The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0-100% EtOAc/DCM) to give compound P36. MS (ESI) m/z 221.1 [M+H] ⁺ .

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

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

R38

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

A solution of reagent 2, which was 4-bromo-2,6-difluorobenzaldehyde (6 g, 27.15 mmol), CuI (517.06 mg, 2.71 mmol), PdCI ₂ (tBu ₂ PPh) ₂ (955.53 mg, 1.36 mmol), trimethylsilylacetylene (TMSA) (7.67 ml, 54.3 mmol) in 3:1 CH3CN (50 ml)/Et ₃ N (10 ml) was degassed with argon for 10 min. The reaction mixture was heated to 70° C. for 18 hours. After cooling to room temperature, the mixture was filtered through silica, the filtrate was concentrated and purified by silica gel column chromatography (1-15% EtOAc/Hex). The resulting product was dissolved in MeOH (5 ml) and potassium carbonate (1876.01 mg, 13.57 mmol) was added, the resulting mixture was stirred at room temperature. After 20 minutes, the reaction mixture was concentrated to dryness, then diluted with DCM and washed with brine. The organic extract was dried over Na ₂ SO ₄ to give compound p38 (2.99 g, 66%). ¹ H NMR (400 MHz, chloroform-d) δ 10.30 (d, J = 1.1 Hz, 1H), 7.04 (d, J = 9.1 Hz, 2H), 0.26 (s, 9H).

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

The title compound P39 was prepared according to the procedure described for the synthesis of compound P16, but using 2-bromo-5-methylpyridine.

Synthesis of 4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzaldehyde (P40). The title compound P40 was prepared according to the procedure described for the synthesis of compound P1, but using 2-bromo-5-cyclopropyl-1,3,4-oxadiazole. MS (ESI) m/z 251.1 [M+H] ⁺ .

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

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), carbonate sodium (8.72 g, 82.27 mmol) and tetrakis(triphenylphosphine)palladium (1.9 g, 1.64 mmol) in a mixture of 1,2-dimethoxyethane (84 ml) and water (36 ml) were degassed for 10 min. The reaction mixture was heated at 100° C. for 18 hours. After cooling to room temperature, the mixture was diluted, concentrated in vacuo, then diluted with EtOAc and washed with brine, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20-40% EtOAc/Hex) to give compound P41. MS (ESI) m/z 223.3 [M+H]+.

Synthesis of 2,6-difluoro-4-(1H-pyrazol-3-yl)benzaldehyde (P42). The title compound P42 was prepared according to the procedure described for the synthesis of compound P1, but using 3-bromo-1Hpyrazole. MS (ESI) m/z 209.1 [M+H] ⁺ .

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

Oxetan-3-ol (0.42 ml, 6.66 mmol) was added dropwise to a suspension of NaH (60%, 310.79 mg, 7.77 mmol) in THF (11 ml), the resulting mixture was stirred for 30 min. followed by the 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (30-60% EtOAc/Hex), the resulting 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)Cl ₂ (279.29 mg, 0.46 mmol) in DME (23 ml), and the resulting mixture was degassed by vacuum and refilled with argon (Ar) (5x) and heated to reflux for 3 hours. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water and brine, then dried over Na ₂ SO ₄ , filtered and concentrated at reduced pressure. The crude residue was purified by silica gel column chromatography (30-60% EtOAc/Hex) to give compound P43 (1.22 g, 80%). MS (ESI) m/z 292.1 [M+H] ⁺ .

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

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 azidomethyl pivalate (2.1 ml, 13.5 mmol) in

- 53 040208 for 5 min. By liquid chromatography/mass spectrometry (LC/MS) analysis, it was found that complete conversion occurred after 15 minutes. The reaction mixture was quenched with aqueous NaHCO3 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 a 1:1 MeOH:EtOH mixture and an aqueous solution of NaOH (2 M, 9.9 ml, 19.9 mmol) was added. After 30 minutes, aqueous NaHCO3 was added and the intermediate 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 the main one and was isolated in medium fractions. 1H NMR (400 MHz, chloroform-d) δ 10.36 (s, 1H), 8.31 (s, 1H), 7.62 (t, J = 58.8 Hz, 1H), 7.59 - 7 .51 (m, 2H). 19F NMR (377 MHz, chloroform-d) δ -95.78 (d, J = 58.9 Hz), -113.68 (d, J = 9.2 Hz).

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

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

Oh

J__.

^Br

T P46

H

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

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

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

The title compound P47 was prepared according to the procedure described 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, 1H), 8.86 (s, 2H), 7.30 - 7.14 (m, 3H), 2.82 (s , 3H).

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2.2 Synthesis of intermediates S.

oxetan-3-one, NaBH ₃ CN

1. Cui, PdCI ₂ (tBu ₂ PPh) ₂ , TMSA„

2. K ₂ CO ₃ , MeOH

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

Solution of tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (1 g, 4.38 mmol), 2-fluoro5-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 subjected to extraction in DCM. The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound S1a (1.57 g, 62.3%). MS (ESI) m/z 431.9 [M+H]+. ¹ H NMR (400 MHz, chloroformd) δ 8.30 (dd, J = 2.4, 0.7 Hz, 1H), 7.66 (dd, J = 9.0, 2.3 Hz, 1H), 6.44 (d, J = 9.0 Hz, 1H), 4.25 (d, J = 12.7 Hz, 1H), 4.21 - 4.00 (m, 3H), 3.97 - 3 .86 (m, 2H), 3.80 (t, J = 11.9 Hz, 2H), 3.26 (t, J = 15.1 Hz, 2H), 1.48 (s, 9H).

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

To a solution of compound 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 resulting reaction mixture was stirred at room temperature overnight. Next, the reaction mixture was concentrated to dryness. MS (ESI) m/z 332.0 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.26 (dd, J = 2.2, 0.7 Hz, 1H), 8.22 (yyy, J = 9.5, 2.2, 1, 0 Hz, 1H), 7.27 (d, J = 9.7 Hz, 1H), 4.60 (d, J = 14.4 Hz, 2H), 4.21 (dt, J = 13.5, 0.9 Hz, 2H), 4.08 (dt, J = 13.3, 2.4 Hz, 2H), 3.88 (d, J = 14.6 Hz, 2H), 3.81 (s, 2H).

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

To compound S1b (0.62 g, 8.62 mmol) suspended in NMP (6 ml) was added Et ₃ N (0.12 ml, 0.8 mmol), oxetan-3-one (0.51 ml, 8.5 mmol), and sodium cyanoborohydride (2.62 g, 41.72 mmol) was added and the resulting reaction mixture was stirred for 5 min, after which more Et ₃ N (0.18 ml, 0.1 mmol) was added , and the resulting mixture was stirred at room temperature for 4 h, after which it was heated to 30°C. After 2 hours the reaction mixture was cooled to room temperature, diluted with EtOAc and washed with brine. The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound S1c (0.84 g, 95%). MS (ESI) m/z 388.1 [M+H] ⁺ .

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

A solution of compound S1c (0.84 g, 0 mol), CuI (24.73 mg, 0.13 mmol), PdCl ₂ (tBu ₂ PPh) ₂ (45.7 mg, 0.06 mmol), trimethylsilylacetylene (0. 92 ml, 0.01 mol) in 3:1 CH3CN (9 ml)/Et ₃ N (3 ml) was degassed with argon for 10 min. The reaction mixture was heated to 40°C for 90 min. The reaction mixture was diluted with EtOAc and washed with NaHCO ₃ solution, then dried over Na ₂ SO ₄ , 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, the resulting mixture was stirred at room temperature. After 15 minutes, the reaction mixture was concentrated to dryness, then diluted with DCM and washed with brine. The organic extract was dried over Na ₂ SO ₄ to give compound 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, 1H), 7.40 (dd, J = 8.9, 2.3 Hz, 1H) , 6.35 (dd, J = 8.9, 0.8 Hz, 1H), 4.55 (t, J = 6.2 Hz, 2H), 4.42 (t, J = 5.9 Hz, 2H), 4.25 (p, J = 6.2 Hz, 1H), 3.84 (dt, J = 11.3, 2.2 Hz, 2H), 3.78 (d, J = 12.9 Hz, 2H), 3.71 (dt, J = 11.5, 0.9 Hz, 2H), 3.24 (yyy, J = 12.9, 4.9, 2.0 Hz, 2H), 2 .92 (s, 1H), 2.65-2.52 (m, 2H).

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

The title compound S2 was prepared according to the procedure described 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, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.52 (d, J = 8.9 Hz, 1H), 4.01 (d, J = 11.2 Hz,

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2H), 3.91 (d, J = 12.9 Hz, 2H), 3.85 (d, J = 11.2 Hz, 2H), 3.53 (yyy, J = 13.0, 4.8 , 2.0 Hz, 2H), 3.07 (s, 1H), 2.86

- 2.75 (m, 2H), 2.62 (s, 3H).

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

The title compound S3a was prepared according to the procedure described for the synthesis of compound S1f, but using tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) m/z 415.8 [M+H]+. ¹ H NMR (400 MHz, chloroform-d) δ 8.36 - 8.26 (m, 1H), 7.65 (dd, J = 9.0, 2.4 Hz, 1H), 6.40 (d , J = 9.0 Hz, 1H), 4.33 (s, 2H), 3.82 (d, J = 40.5 Hz, 2H), 3.05 (s, 2H), 1.94 (dd , J = 8.7, 4.6 Hz, 2H), 1.73 (d, J = 7.3 Hz, 2H), 1.47 (s, 9H).

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

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

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

The title compound S3c was prepared according to the method described for the synthesis of compound S1c, but using compound S3b. MS (ESI) m/z 372.1 [M+H] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 8.22 (d, J = 2.3 Hz, 1H), 7.57 (dd, J = 8.9, 2.4 Hz, 1H), 6, 30 (d, J = 9.0 Hz, 1H), 4.65 (t, J = 6.3 Hz, 2H), 4.52 (t, J = 5.8 Hz, 2H), 3.70 ( dd, J = 11.8, 2.4 Hz, 2H), 3.23 - 3.08 (m, 2H), 3.04 (dd, J = 11.7, 2.2 Hz, 2H), 1 .87-1.70 (m, 2H), 1.63 (d, J = 7.5 Hz, 2H).

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

The title compound S3 was prepared according to the procedure described for the synthesis of compound S1c, but using compound S3c. MS (ESI) m/z 244.0 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.16 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.66 (d, J = 8.9 Hz, 1H), 4.76 (t, J = 6.4 Hz, 3H), 4.57 (t, J = 5.8 Hz, 3H), 3.88 (dd , J = 12.2, 2.4 Hz, 3H), 3.78 (yyy, J = 11.9, 6.5, 5.4 Hz, 1H), 3.43 (s, 1H), 3, 29 (dd, J = 6.9, 1.7 Hz, 4H), 3.10 (dd, J = 11.9, 2.2 Hz, 3H), 1.93 (dd, J = 8.7, 4.4 Hz, 2H), 1.68 (t, J = 6.9 Hz, 2H).

'UCH 1 Cui, i Λ J IL Λ PdCI ₂ (tBu ₂ PPh) ₂ , Τ 1

NMU Γ''-' N N > TMSA N nJ

L In ----------” kl N _ \> ^Ν ·Βοο ² HCI S4a Ji ^{2 k} 2С°z. ^{Me0H S4} J?q

3. oxetan-3-one

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

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

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

The title compound S4 was prepared according to the method described for the synthesis of compound S1, but using compound S4a. MS (ESI) m/z 256.2 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.13 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 8.9, 2.3 Hz, 1H), 6, 55 (d, J = 8.9 Hz, 1H), 4.65 (t, J = 6.3 Hz, 2H), 4.36 (dd, J = 6.3, 4.7 Hz, 2H), 3.77 (dd, J = 19.2, 5.7 Hz, 3H), 3.44 (s, 4H), 3.37 (s, 1H), 2.61 (dt, J = 9.1, 6.2 Hz, 1H), 1.54 (d, J = 9.1 Hz, 1H).

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

Et ₃ N 9 (3.84 ml, 0.03 mol), the resulting mixture was stirred for 5 min (slight exothermic effect), after which it was heated to 30°C. The mixture was cooled to room temperature, diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO ₃ solution and brine, then dried over Na ₂ SO ₄ , 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, the resulting reaction mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature , diluted with isopropyl acetate, washed with water, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified using column chromatography (50-100% EtOAc/hexanes) to obtain compound 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, 2H), 7.54 - 7.45 (m, 2H), 7.40 (s, 1H), 4 .50 (s, 2H), 2.91 (s, 3H), 1.45 (d, J = 21.0 Hz, 9H).

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

Compound S5a solution (8 g, 0.02 mol), CuI (0.249 g, 1.0 mmol), PdCl ₂ (tBu ₂ PPh) ₂ (0.408 g, 0.655 mmol), trimethylsilylacetylene (12.44 ml, 0.09 mol) in a 3:1 mixture of CH ₃ CN/Et ₃ N (50 ml) was degassed with argon for 10 min. The reaction mixture was heated to 65° C. overnight. The reaction mixture was diluted with EtOAc and washed with NaHCO ₃ solution, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was used in the next step without purification (5.85 g, 70%). MS (ESI) m/z 384.3 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 7.66 (d, J=8.0 Hz, 2H), 7.45-7.31 (m, 3H), 4.84 (s, 2H), 2.91 (s, 4H), 1.46 (s, 9H), 0.23 (s, 9H).

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

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

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

The title compound S6a was prepared according to the procedure described 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]+. ¹ H NMR (400 MHz, chloroform-d) δ 8.25 (dd, J = 2.3, 0.8 Hz, 1H), 7.61 (yyy, J = 8.8, 2.3, 0, 6 Hz, 1H), 6.18 (dd, J = 8.8, 0.8 Hz, 1H), 4.71 - 4.58 (m, 3H), 4.52 (t, J = 6.1 Hz, 1H), 4.45 (t, J = 5.9 Hz, 1H), 4.05 - 3.85 (m, 1H), 3.55 (d, J = 2.4 Hz, 1H), 3.43 - 3.18 (m, 2H), 2.94 (dd, J = 9.5, 2.0 Hz, 1H), 2.83 (dd, J = 9.4, 1.4 Hz, 1H), 2.00 - 1.89 (m, 1H), 1.89 - 1.80 (m, 1H), 1.39 (t, J = 7.3 Hz, 1H).

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

The title compound S6 was prepared according to the procedure described for the synthesis of compound S1, but using compound 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, 1H), 7.37 (dd, J = 8.7, 2.3 Hz, 1H ), 6.23 - 5.98 (m, 1H), 4.54 (dt, J = 12.8, 6.5 Hz, 3H), 4.39 (t, J = 6.1 Hz, 1H) , 4.32 (t, J = 5.9 Hz, 1H), 3.90 - 3.75 (m, 1H), 3.31 - 3.10 (m, 2H), 2.93 (s, 1H ), 2.82 (dd, J = 9.5, 2.0 Hz, 1H), 2.73-2.60 (m, 1H), 1.82 (ddt, J = 9.7, 2.4 , 1.2 Hz, 1H), 1.73 (ddt, J = 9.8, 2.5, 1.2 Hz, 1H).

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

The title compound S7a was prepared according to the procedure described 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).

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

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

1H), 3.29-3.10 (m, 4H), 1.89-1.73 (m, 2H), 1.74-1.47 (m, 2H).

,χΝ F . 1 cui,

Ji J ηΧ PdCI ₂ (tBu ₂ PPh) ₂ ,

HN^ , ___.

LU 2 K ₂ CO ₃ , MeOH

S8a S8

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

The title compound S8a was prepared according to the procedure described 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]+.

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

The title compound S8 was prepared according to the method described for the synthesis of compound S1, but using compound 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, 1H), 7.54 (dd, J = 8.8, 2.3 Hz, 1H ), 6.56 (dd, J = 8.9, 0.8 Hz, 1H), 4.23 4.04 (m, 2H), 3.88 (dd, J = 11.4, 3.4 Hz , 1H), 3.81 (dd, J = 11.1, 3.1 Hz, 1H), 3.73 (t, J = 11.5 Hz, 1H), 3.32 (t, J = 10, 6 Hz, 1H), 3.13-3.01 (m, 2H), 2.86 (d, J = 11.4 Hz, 1H), 2.72 (d, J = 11.5 Hz, 1H) , 2.54 (t, J = 11.7 Hz, 1H), 2.49 - 2.25 (m, 2H).

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

The title compound S9a was prepared according to the procedure described 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] ⁺ .

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

The title compound S9 was prepared according to the method described for the synthesis of compound S1, but using compound 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, 1H), 7.54 (dd, J = 8.8, 2.3 Hz, 1H), 6.56 (dd, J = 8.9, 0.8 Hz, 1H), 4.23 4.04 (m, 2H), 3.88 (dd, J = 11.4, 3 .4 Hz, 1H), 3.81 (dd, J = 11.1, 3.1 Hz, 1H), 3.73 (t, J = 11.5 Hz, 1H), 3.32 (t, J = 10.6 Hz, 1H), 3.13-3.01 (m, 2H), 2.86 (d, J = 11.4 Hz, 1H), 2.72 (d, J = 11.5 Hz , 1H), 2.54 (t, J = 11.7 Hz, 1H),

2.49 - 2.25 (m, 2H).

Cui, PdCI ₂ (tBu ₂ PPh) ₂ TMSA

_K2CO3 , _MeOH

1-(5-Iodopyridin-2-yl)-4-(3-methyloxetan-3-yl)piperazine (S10a).

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 shaken in a hydrogenator overnight at 310 kPa (45 PSI). The reaction mixture was filtered through Celite, the filter cake was washed with 25% MeOH/DCM, and the filtrate was concentrated under reduced pressure. The residue was combined with 2-fluoro-5-iodopyridine to give the title compound S10a according to the method described for the synthesis of compound S1a. MS (ESI) m/z 360.0 [M+H]+. ¹ H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 6.48 (d, J = 9.0 Hz, 1H), 4.62 (d, J = 5.5 Hz, 2H), 4.26 (d, J = 5.5 Hz, 2H), 3.54 (s, 4H) , 2.44 (s, 5H), 1.37 (s, 3H).

-(5-Ethynylpyridin-2-yl)-4-(3-methyloxetan-3-yl)piperazine (S10).

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

cui,

PdCI ₂ (tBu ₂ PPh) ₂ , TMSA ^IN '|W ---------* Ύ J, ---------------* _Λ 2 K ₂ CO ₃ , MeOH Ί O

S3b HCl ^S11a Ly° ®

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

A solution of compound S3b (1.0 g, 3.173 mmol), (R)-tetrahydrofuran-3-ylmethanesulfonate (965 mg, 5.807 mmol) and potassium carbonate (1754 mg, 12.69 mmol) in CH3CN (15 ml) was heated at refluxing for 48 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with brine. The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0-5% MeOH/EtOAc) to give compound 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, 1H), 7.56 (dd, J = 8.9, 2.4 Hz, 1H) , 6.29 (dd, J = 9.0, 0.7 Hz, 1H), 3.96 - 3.84 (m, 2H), 3.76 (dt, J = 8.6, 7.6 Hz , 1H), 3.62 (yyy, J = 11.5, 8.9, 2.5 Hz, 2H), 3.55 (dd, J = 8.2, 6.9 Hz, 1H), 3, 33 (d, J = 4.7 Hz, 1H), 3.20 (d, J = 3.4 Hz, 1H), 3.11 2.97 (m, 3H), 2.02 (dtd, J = 12.1, 7.4, 4.7 Hz, 1H), 1.95 - 1.87 (m, 2H), 1.87 - 1.72 (m, 1H), 1.67 - 1.56 ( m,2H).

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

The title compound S11 was prepared according to the procedure described for the synthesis of compound S1, but using compound S11a. MS (ESI) m/z 284.1 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.22 - 8.10 (m, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.65 (dd, J = 9.1, 0.8 Hz, 1H), 3.97 (td, J = 8.1, 4.5 Hz, 2H), 3.89 - 3.74 (m, 3H), 3.63 (dd, J = 8.4, 6.6 Hz, 1H), 3.48 (d, J = 4.4 Hz, 1H), 3.42 (s, 1H), 3.35 (s, 1H) , 3.26 - 3.19 (m, 1H), 3.12 (dt, J = 12.2, 3.5 Hz, 2H), 2.15 (yyy, J = 11.8, 8.2, 4.5 Hz, 1H), 2.03 (dd, J = 14.4, 7.3 Hz, 2H), 1.85 (dq, J = 12.0, 7.8 Hz, 1H), 1, 69 (d, J = 9.1 Hz, 2H).

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

The title compound S12a was prepared according to the procedure described for the synthesis of compound S11a, but using (S)-tetrahydrofuran-3-ylmethanesulfonate. MS (ESI) m/z 386.1 [M+H] ⁺ . 1H NMR (400 MHz, chloroform-d) δ 8.28 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 9.0, 2.4 Hz, 1H), 6.36 (d, J = 9.0 Hz, 1H), 4.04 - 3.91 (m, 2H), 3.90 - 3.75 (m, 1H), 3.68 (yyy, J = 11.6 , 8.8, 2.5 Hz, 2H), 3.61 (dd, J = 8.2, 6.9 Hz, 1H), 3.39 (q, J = 2.7 Hz, 1H), 3 .26 (dt, J = 5.0, 2.1 Hz, 1H), 3.18 - 3.04 (m, 3H), 2.17 - 2.01 (m, 1H),

- 59 040208

1.97 (dd, J = 9.4, 5.6 Hz, 2H), 1.90-1.77 (m, 1H), 1.74-1.63 (m, 2H).

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

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

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

Suspension of compound 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 100 ml sealed tube was stirred at 70° C. for 48 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed twice with brine. The organic extract was dried over Na ₂ SO ₄ and filtered and the crude residue was purified by silica gel column chromatography (10-20% EtOAc/hexanes) to give 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, 1H), 7.61 (dd, J = 9.0, 2.4 Hz, 1H) , 6.51 - 6.27 (m, 1H), 4.37 - 4.07 (m, 4H), 3.84 (s, 2H), 3.79 - 3.72 (m, 2H), 3 .29 - 3.07 (m, 2H), 1.77 - 1.63 (m, 4H), 1.62 (s, 3H), 1.27 (t, J = 7.2 Hz, 6H).

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 resulting reaction mixture was gradually warmed to room temperature and stirred overnight. Dibal-H (1.0 M in DCM, 16 ml) was added, the resulting mixture was stirred for 1 h, and then cooled to 0°C and diluted with Et ₂ O. Water (4.4 ml), 15% was added slowly NaOH (4.4 ml) then water (10.9 ml), the resulting mixture was warmed to room temperature and stirred for 15 minutes. Na2SO4 was added, the resulting mixture was stirred for 15 min, after which the salts were filtered off to obtain 2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2 -methylpropane-1,3diol (2.059 g, 65%). MS (ESI) m/z 404.0 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.18 (dd, J = 2.4, 0.7 Hz, 1H), 7.69 (dd, J = 9.0, 2.4 Hz, 1H ), 6.54 (d, J = 9.1 Hz, 1H), 3.91 - 3.66 (m, 4H), 3.49 (s, 4H), 3.10 - 2.88 (m, 2H), 1.83 (d, J = 8.8 Hz, 2H), 1.72 (t, J = 6.6 Hz, 2H), 1.00 (s, 3H).

To a solution of 2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropan-1,3-diol (2.06 g, 5.106 mmol) and triethylamine (1.5 ml, 10.76 mmol) in THF (25 ml) methanesulfonyl chloride (0.40 ml, 5.169 mmol) was added at 0°C. The resulting reaction mixture 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 Na ₂ SO ₄ , filtered and the crude residue was purified by silica gel column chromatography (25-50% EtOAc/hexanes) to give 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, 1H), 7.62 (dd, J = 8.9, 2.4 Hz, 1H) , 6.35 (dd, J = 9.0, 0.7 Hz, 1H), 4.63 (s, 1H), 3.90 - 3.63 (m, 4H), 3.56 (d, J = 5.1 Hz, 1H), 3.35 (s, 1H), 3.06 (dt, J = 11.8, 3.0 Hz, 2H), 2.87 (t, J = 13.5 Hz , 1H), 2.66 (d, J = 14.0 Hz, 1H), 1.88 (dt, J = 9.9, 4.9 Hz, 2H), 1.76 - 1.63 (m, 2H), 1.57 (s, 3H).

To a solution of 3-chloro-2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropan-1ol (418.5 mg, 0.992 mmol) in THF (10 ml) at 0°C was added potassium tert-butoxide (1.0 M in THF, 3 ml). After 10 minutes 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 silica gel column chromatography (50-100% EtOAc/hexanes) to give compound 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, 1H), 7.61 (dd, J = 9.0, 2.4 Hz, 1H) , 6.35 (dd, J = 9.0, 0.7 Hz, 1H), 3.68 (yyy, J = 11.5, 4.4, 2.6 Hz, 2H), 3.49 - 3 .34 (m, 1H), 3.30 (q, J = 2.7 Hz, 1H), 3.07 (dd, J = 11.6, 2.5 Hz, 2H), 2.70 (dd, J = 5.0, 0.7 Hz, 1H), 2.64 - 2.53 (m, 2H), 2.39 (d, J = 13.2 Hz, 1H), 1.96 - 1.79 (m, 2H), 1.68 - 1.57 (m, 2H), 1.42 (d, J = 0.6 Hz, 3H).

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

The title compound S13 was prepared according to the method described for the synthesis of compound S1, but using compound 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, 1H), 7.53 (dd, J = 8.9, 2.3 Hz, 1H) , 6.64 (dd, J = 9.0, 0.8 Hz, 1H), 3.91 - 3.74 (m, 3H), 3.50 - 3.43 (m, 1H), 3.42 (s, 1H), 3.39 - 3.32 (m, 1H), 3.08 (dt, J = 11.7, 1.9 Hz, 3H), 2.72 (dd, J = 4.9 ,

- 60 040208

0.7 Hz, 2H), 2.66 (d, J = 13.3 Hz, 1H), 2.60 (d, J = 4.9 Hz, 1H), 2.43 (d, J = 13, 3 Hz, 1H), 1.94 (dd, J = 9.4, 5.5

Hz, 3H), 1.69 - 1.57 (m, 2H), 1.42 (d, J = 0.6 Hz, 4H).

1. Cui, PdCI ₂ (tBu ₂ PPh) ₂ TMSA

2. _{K2CO3 .} Meon

Synthesis of 1-(5-bromopyridin-2-yl)piperazine hydrochloride (S14a).

HCl (4.0 M in dioxanes, 18 ml, 72 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with 2N HCl. NaOH. The aqueous layer was extracted twice with DCM and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound S14a (3.2 g, 90.4%). MS (ESI) m/z 242.1 [M+H]+. ¹ H NMR (400 MHz, chloroform-d) δ 8.18 (dd, J = 2.6, 0.7 Hz, 1H), 7.52 (dd, J = 9.0, 2.6 Hz, 1H ), 6.53 (dd, J = 9.1, 0.7 Hz, 1H), 3.54-3.40 (m, 4H), 3.09-2.87 (m, 4H).

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

The title compound S14a was prepared according to the procedure described for the synthesis of compound S11a, but using compound S14a and (S)-tetrahydrofuran-3-ylmethanesulfonate. MS (ESI) m/z 312.1 [M+H] ⁺ . 1H NMR (400 MHz, chloroform-d) δ 8.19 (dd, J = 2.6, 0.7 Hz, 1H), 7.53 (dd, J = 9.0, 2.5 Hz, 1H) , 6.54 (dd, J = 9.0, 0.7 Hz, 1H), 3.96 (td, J = 8.6, 4.4 Hz, 1H), 3.91 (dd, J = 8 .7, 6.8 Hz, 1H), 3.80 (td, J = 8.4, 7.5 Hz, 1H), 3.69 (t, J = 7.7 Hz, 1H), 3.52 (t, J = 5.3 Hz, 4H), 3.01 (t, J = 7.3 Hz, 1H), 2.63 (d, J = 9.9 Hz, 2H), 2.57 - 2 .46 (m, 2H), 2.07 (yyy, J = 9.9, 7.1, 3.3 Hz, 1H), 1.90 (q,J = 11.1, 9.5 Hz, 1H ).

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

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

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

The title compound S15a was prepared according to the method described for the synthesis of compound S11a, but using compound 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, 1H), 7.52 (dd, J = 9.0, 2.6 Hz, 1H) , 6.53 (dd, J = 9.1, 0.7 Hz, 1H), 3.96 (td, J = 8.6, 4.4 Hz, 1H), 3.91 (dd, J = 8 .6, 6.8 Hz, 1H), 3.80 (td, J = 8.4, 7.5 Hz, 1H), 3.68 (dd, J = 8.7, 6.7 Hz, 1H) , 3.52 (dd, J = 5.9, 4.5 Hz, 4H), 3.00 (p, J = 7.1 Hz, 1H), 2.63 (dt, J = 10.7, 5 .2 Hz, 2H), 2.50 (dt, J = 10.8, 5.1 Hz, 2H), 2.17 - 1.99 (m, 1H), 1.99 - 1.79 (m, 1H).

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

The title compound S15 was prepared according to the method described for the synthesis of compound S1, but using compound 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, 1H), 7.47 (dd, J = 8.9, 2.3 Hz, 1H) , 6.66 (dd, J = 9.0, 0.8 Hz, 1H), 3.86 (dt, J = 8.6, 4.3 Hz, 1H), 3.80 (dd, J = 8 .9, 7.0 Hz, 2H), 3.67 (td, J = 8.4, 7.2 Hz, 1H), 3.59 (dd, J = 8.7, 6.6 Hz, 1H) , 3.49 (t, J = 5.2 Hz, 4H), 3.34 (s, 1H), 3.02 - 2.86 (m, 1H), 2.55 (dt, J = 10.7 , 5.2 Hz, 2H), 2.44 (dt, J = 11.1, 5.2 Hz, 2H), 2.10 - 1.94 (m, 2H), 1.86 - 1.71 ( m, 2H).

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

The title compound S16 was prepared according to the method described for the synthesis of compound S1, but using compound 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, 1H), 7.56 (dd, J = 8.9, 2.3 Hz, 1H) , 6.69 (dd, J = 8.9, 0.9 Hz, 1H), 4.45 - 4.30 (m, 2H), 4.04 - 3.95 (m, 2H), 3.43 (s, 1H), 3.02 (d, J = 12.2 Hz, 2H), 1.94 (dd, J = 8.7, 4.4 Hz, 2H), 1.75 (d, J = 7.3 Hz, 2H), 1.48 (s, 9H).

TMS

1. Cui,

PdCI ₂ (tBu ₂ PPh) ₂ , TMSA________ 2. CF ₃ CO ₂ H.

S17a ”boc S17b 'NH

1. oxetan-3-one

2. K2CO3, MeOH γγ

3. NaOH/water < D ______ ^N Ni

L-M

S17Lq

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

The title compound S17a was prepared according to the procedure described 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] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 8.28 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 6.14 (d, J = 8.7 Hz, 1H), 4.13 (s, 4H), 4.10 (s, 4H), 1.44 (s, 9H).

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

Compound S17a solution (1.048 mg, 2.612 mmol), CuI (0.111 g, 0.583 mmol), PdCI ₂ (tBu ₂ PPh)2 (0.163 g, 0.261 mmol), TMSA (2.1 ml, 14.75 mmol), Et ₃ N (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 NaHCO ₃ solution and dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified using column chromatography on silica gel (20-40% EtOAc/Hex) to give the desired product (760 mg, 78%). The indicated product (0.4 g, 1076.58 μmol) was dissolved in DCM (5 ml) and trifluoroacetic acid (1000 μl, 13.07 mmol) was added, the resulting 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 give compound S17b (0.54 g, 100.1%). MS (ESI) m/z 272.1 [M+H] ⁺ .

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

Oxetan-3-one ( 234 mg, 3.247 mmol) in 2-MeTHF (1 mL) followed by sodium cyanoborohydride (209 mg, 3.326 mmol). The resulting reaction mixture was stirred at room temperature. After 18 hours the reaction mixture was quenched with NaHCO3 solution and partitioned using EtOAc. The organic extract was dried over Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50-75% EtOAc/Hex). The resulting product was dissolved in MeOH (5 ml), potassium carbonate (0.28 g, 2.05 mmol) was added and the resulting mixture was stirred at room temperature. After 48 hours the reaction mixture was concentrated under reduced pressure, diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , 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, the resulting mixture was heated to 70°C for 18 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted through EtOAc, washed with saline, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain compound 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, 1H), 7.55 (dd, J = 8.7, 2.2 Hz, 1H) , 6.36 (dd, J = 8.7, 0.8 Hz, 1H), 4.72 (td, J = 6.7, 0.5

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Hz, 3H), 4.45 (yyy, J = 6.8, 4.9, 0.6 Hz, 3H), 4.13 (s, 5H), 3.76 (tt, J = 6.5, 4.9Hz, 1H), 3.50(s, 5H), 3.44(s,

1H).

Synthesis of tert-butyl-(3aR,6aS)-5-(5-iodopyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)carboxylate (S18a) The title compound S18a was prepared according to the method given 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]+. ¹ H NMR (400 MHz, chloroform-d) δ 8.28 (dd, J = 2.4, 0.8 Hz, 1H), 7.63 (dd, J = 8.9, 2.3 Hz, 1H ), 6.19 (d, J = 8.9 Hz, 1H), 3.66 (dd, J = 10.7, 7.0 Hz, 4H), 3.51 - 3.17 (m, 4H) , 2.99 (d, J = 5.9 Hz, 2H), 1.45 (s, 9H).

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

Compound S18a solution (0.986 g, 2.374 mmol), CuI (0.099 g, 0.522 mmol), PdCI ₂ (tBu ₂ PPh) ₂ (0.148 g, 0.237 mmol), TMSA (1.9 ml, 13.35 mmol), Et ₃ N (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 mixture was diluted with EtOAc and washed with NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (10-30% EtOAc/Hex), the resulting 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 resulting reaction mixture was stirred for 18 hours, diluted with DCM, washed with 2N HCl. NaOH solution. The aqueous layer was back-extracted with DCM and the combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 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, 1H), 7.73 (dd, J = 9.5, 2.1 Hz, 1H) , 6.88 (dd, J = 9.5, 0.9 Hz, 1H), 3.78-3.63 (m, 2H), 3.59-3.48 (m, 2H), 3.46 - 3.34 (m, 3H), 3.25 - 3.10 (m, 3H), -0.00 (s, 9H).

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

To a solution of compound S18b (0.25 g, 0.701 mmol) in DCE (6 ml) was added a solution of formaldehyde (0.30 ml, 8.143 mmol) and acetic acid (0.025 ml, 4.367 mmol). The resulting reaction mixture was heated at 60°C for 30 min. The mixture was cooled to room temperature and sodium cyanoborohydride (165.1 mg, 2.63 mmol) was added. The reaction mixture was heated at 60°C for 45 min, then cooled to room temperature, diluted with EtOAc, washed with brine, the aqueous layer was subjected to re-extraction with EtOAc, the extract was dried over Na2SO4, filtered and concentrated under reduced pressure, the residue was dissolved in MeOH (5 ml) and potassium carbonate (0.29 g, 2.1 mmol) was added, the resulting reaction mixture was stirred at room temperature. After 18 h the reaction mixture 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 give compound 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, 1H), 7.60 (dd, J = 8.8, 2.3 Hz, 1H) , 6.58 (dd, J = 8.9, 0.8 Hz, 1H), 3.70 - 3.59 (m, 1H), 3.54 - 3.45 (m, 3H), 3.10 (s, 3H), 2.97-2.84 (m, 2H), 2.54 (dd, J = 9.7, 4.0 Hz, 2H), 2.39 (s, 3H).

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

The title compound S19a was prepared according to the procedure described for the synthesis of compound S1c, but using compound S18a. MS (ESI) m/z 372.1 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.17 (dd, J = 2.3, 0.7 Hz, 1H), 7.71 (yyy, J = 8.9, 2.3, 0, 8 Hz, 1H), 6.43 (dd, J = 9.0, 0.7 Hz, 1H), 4.69 (t, J = 6.6 Hz, 2H), 4.64 - 4.55 ( m, 2H), 3.70 - 3.60 (m, 1H), 3.59 - 3.49 (m, 2H), 3.38 (dd, J = 10.8, 3.1 Hz, 2H) , 3.02 (td, J = 7.3, 3.7 Hz, 2H), 2.88 - 2.71 (m, 2H), 2.42 (dd, J = 9.4, 4.0 Hz , 2H).

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

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The title compound S19 was prepared according to the method described for the synthesis of compound S1, but using compound 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, 1H), 7.46 (dd, J = 8.8, 2.3 Hz, 1H) , 6.43 (dd, J = 8.9, 0.8 Hz, 1H), 4.68 - 4.58 (m, 2H), 4.59 - 4.44 (m, 2H), 3.64 - 3.45 (m, 2H), 3.40 -3.30 (m, 4H), 2.95 (dq, J = 7.5, 3.9 Hz, 2H), 2.70 (dd, J = 9.6, 7.1 Hz, 1H), 2.36 (dd, J = 9.5, 4.0 Hz, 2H).

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

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

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

To a solution of compound S20a (0.2 g, 0.7 mmol) in THF (6 ml) was added a solution of formaldehyde (0.13 ml, 3.5 mmol) and acetic acid (0.03 ml, 0.51 mmol). The resulting reaction mixture was stirred at room temperature overnight. Sodium cyanoborohydride (132.09 mg, 2.1 mmol) was added. After 5 hours, MeOH (2 ml) and NaOH (2N, 2 ml) were added and the resulting mixture was stirred for an additional 18 hours. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc, washed with brine, the aqueous layer was subjected to back extraction with EtOAc, extract dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, residue purified by silica gel column chromatography (100% EtOAc to 5-10% MeOH/EtOAc) to give compound S20 (62.6 mg, 39 .3%). MS (ESI) m/z 228.2 [M+H]+. ¹ H NMR (400 MHz, methanol d4) δ 8.16 (dd, J = 2.4, 0.8 Hz, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H) , 6.66 (dd, J = 8.9, 0.9 Hz, 1H), 3.86 (dd, J = 12.5, 2.4 Hz, 3H), 3.42 (s, 1H), 3.08 (dd, J = 12.3, 2.3 Hz, 3H), 2.36 (d, J = 2.4 Hz, 3H), 2.07 (dt, J = 7.1, 3, 2 Hz, 2H), 1.68 (t,J = 6.8 Hz, 2H).

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

To a solution of compound S20a (0.24 g, 0.83 mmol) in THF (5 ml) and MeOH (2 ml) were 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. The resulting mixture was stirred overnight, diluted with EtOAc, washed with brine, the aqueous layer was subjected to re-extraction with EtOAc, the extract was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (10-20 % MeOH/EtOAc) to give the product (0.12 g, 0.39 mmol) which was dissolved in MeOH (5 ml) and potassium carbonate (0.16 g, 1.17 mmol) was added, the resulting reaction mixture was stirred at room temperature. After 3 hours the reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 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, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H) , 6.65 (dd, J = 8.9, 0.9 Hz, 1H), 3.85 (dd, J = 12.5, 2.4 Hz, 2H), 3.44 (dd, J = 4 .6, 2.5 Hz, 2H), 3.41 (s, 1H), 3.09 (dd, J = 12.2, 2.2 Hz, 2H), 2.52 (q, J = 7, 2 Hz, 2H), 2.00 (dt, J = 7.0, 3.1 Hz, 2H), 1.67 (t, J = 6.8 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H).

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

To a solution of compound 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), the resulting mixture was stirred at 40°C. After 1 h, sodium cyanoborohydride (44.03 mg, 0.7 mmol) was added and the resulting reaction mixture was stirred at 40°C. After 12 hours, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with EtOAc, washed

- 64 040208 saturated NaHCO3 solution, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and purified by silica gel column chromatography (2% MeOH/EtOAc). The resulting 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 Na ₂ SO ₄ , filtered and concentrated with obtaining compound S22 (28 mg, 31.3%). MS (ESI) m/z 256.2 [M+H]+. ¹ H NMR (400 MHz, methanol^) δ 8.18 (d, J= 2.3 Hz, 1H), 7.57 (dd, J= 8.9, 2.4 Hz, 1H), 6.68 (d, J=8.9 Hz, 1H), 3.93-3.68 (m, 6H), 3.43 (s, 1H), 3.23-3.12 (m, 3H), 2, 86 (s, 2H), 2.07 - 1.92 (m, 3H), 1.75 (t, J= 6.6 Hz, 3H), 1.20 (d, J= 6.4 Hz, 8H ).

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

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

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

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

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

Dimethylcarbamoyl chloride (0.055 ml, 0.601 mmol) was added to a solution of compound S20a (200 mg, 0.558 mmol) and Et ₃ N (0.3 ml, 2.164 mmol) in DCM (5 ml) at 0°C. The resulting reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture 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 hours, the reaction mixture was concentrated, then diluted with EtOAc and washed with brine. The organic extracts were dried over Na ₂ SO ₄ to give compound 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, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H) , 6.69 (dd, J = 9.0, 0.8 Hz, 1H), 4.19 (dd, J = 4.5, 2.2 Hz, 3H), 3.98 (dd, J = 12 .4, 2.5 Hz, 3H), 3.42 (s, 1H), 3.11 (dd, J = 12.2, 2.1 Hz, 3H), 2.94 (s, 8H), 1 .88 (dd, J = 8.5, 4.4 Hz, 3H), 1.71 (q, J = 6.7 Hz, 2H).

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

To compound S20a suspended in CH ₂ Cl ₂ (10 ml) was added (S)-tetrahydrofuran-2-carboxylic acid (0.12 ml, 1 mmol), Et ₃ N (0.68 ml, 5 mmol), then HATU ( 0.48 g, 1 mmol). The resulting mixture was stirred for 1.5 hours. The mixture was diluted with DCM and washed with water. The organic layer was dried over Na ₂ SO ₄ 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 minutes, the reaction was quenched with water and brine, extracted into DCM, dried over Na2SO4, filtered, concentrated under reduced pressure, and the residue purified by silica gel column chromatography (60-100% EtOAc/hexanes to 5% MeOH/ EtOAc) to give compound 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, 1H), 7.54 (dt, J = 8.9, 2.4 Hz, 1H) , 6.48 (d, J = 8.8 Hz, 1H), 4.84 (t, J = 8.6 Hz, 1H), 4.66 (d, J = 6.8 Hz, 1H), 4 .56 (yyy, J = 14.9, 7.4, 5.7 Hz, 2H), 4.12 (yyy, J = 20.9, 12.7, 2.3 Hz, 1H), 3.99 - 3.73 (m, 4H), 3.21 (dd, J = 12.1, 2.3 Hz, 1H), 3.14 (dd, J = 12.0, 2.4 Hz, 1H), 3.07 (s, 1H), 3.06-3.02 (m, 0H), 2.41-2.21 (m, 1H), 2.15-1.70 (m, 5H).

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

The title compound S26a was prepared according to the procedure described 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, 1H), 7.70 (s, 1H), 6.46 (s, 1H), 4.45 (s , 2H), 3.78 (d, J = 52.7 Hz, 2H), 3.14 (dd, J = 50.9, 12.9 Hz, 2H), 2.06 - 1.77 (m, 4H), 1.45 (s, 12H).

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

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

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

The title compound S26 was prepared according to the method described for the synthesis of compound S18, but using oxetan-3-one. MS (ESI) m/z 270.2 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.18 (d, J = 2.3 Hz, 1H), 7.58 (dd, J = 8.8, 2.3 Hz, 1H), 6 .73 (d, J = 8.8 Hz, 1H), 4.61 (dt, J = 11.1, 5.5

Hz, 7H), 3.51 - 3.44 (m, 2H), 2.64 (dd, J = 10.9, 2.6 Hz, 3H), 2.23 (d, J = 10.7 Hz , 2H), 2.14 (t, J = 6.2 Hz, 2H),

1.99 (dd, J = 8.3, 4.2 Hz, 2H).

1. Cui,

PdCI ₂ (tBu ₂ PPh) ₂ ,

TMSA_______

2. K ₂ CO ₃ , MeOH

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

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

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

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

I..I.Cul, || 1 PdCI ₂ (tBu ₂ PPh) ₂ , III ^TMSA ------►

S1b ^ ^NH 2. K ₂ CO ₃ , MeOH _S2 g ^NH

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

The title compound S28 was prepared according to the method described for the synthesis of compound S1, but using compound S1b. MS (ESI) m/z 230.1 [M+H] ⁺ . 1H NMR (400 MHz, chloroform-d) δ 8.25 (s, 1H), 7.56 - 7.43 (m, 1H), 6.48 (d, J = 8.9 Hz, 1H), 4 .42 (d, J = 13.5 Hz, 2H), 4.12 (d, J = 12.1 Hz, 2H), 3.93 (d, J = 12.2 Hz, 2H), 3.59 (d, J = 13.6 Hz, 2H), 3.36 (s, 2H), 3.00 (d, J = 1.1 Hz, 1H).

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

The title compound S29a was prepared according to the procedure described for the synthesis of compound S7a, but using t-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, 2H), 4.79 (s, 1H), 4.69 (dt, J = 10.0, 6.5 Hz, 2H), 4 .55 (t, J = 6.1 Hz, 1H), 4.48 (t, J = 5.9 Hz, 1H), 3.98 (p, J = 6.3 Hz, 1H), 3.57 (s, 1H), 3.46 (dd, J = 11.0, 1.6 Hz, 1H), 3.36 (dd, J = 10.8, 2.0 Hz, 1H), 2.98 ( dd, J = 9.6, 2.0 Hz, 1H), 2.82 (d, J = 9.6 Hz, 1H), 1.97 (d, J = 9.9 Hz, 1H), 1, 86 (d, J = 9.8 Hz, 1H).

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

- 66 040208

The title compound S29 was prepared according to the method described for the synthesis of compound S1, but using compound S29a. MS (ESI) m/z 257.1 [M+H]+. ¹ H NMR (400 MHz, chloroform-d) δ 8.39 (s, 2H), 4.88 (s, 1H), 4.70 (dt, J = 9.5, 6.5 Hz, 2H), 4.52 (dt, J = 26.3, 6.0 Hz, 2H), 3.99 (p, J = 6.3 Hz, 1H), 3.58 (s, 1H), 3.52 (d , J = 10.9 Hz, 1H), 3.41 (dd, J = 11.0, 2.0 Hz, 1H), 3.18 (s, 1H), 2.99 (d, J = 9, 6 Hz, 1H), 2.83 (d, J = 9.6 Hz, 1H), 1.98 (d, J = 9.9 Hz, 1H), 1.87 (d, J = 9.8 Hz , 1H).

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

The title compound S30a was prepared according to the procedure described 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] ⁺ .

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

The title compound S30 was prepared according to the method described for the synthesis of compound S1, but using compound S30a. MS (ESI) m/z 256.2 [M+H] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 8.12 (dd, J = 2.3, 0.8 Hz, 1H), 7.36 (dd, J = 8.7, 2.3 Hz, 1H), 6.11 (d, J = 8.7 Hz, 1H), 4.59 (s, 1H), 4.53 (dt, J = 12.9, 6.5 Hz, 2H), 4, 36 (dt, J = 31.2, 5.3 Hz, 2H), 3.82 (p, J = 5.9 Hz, 1H), 3.44 (s, 1H), 3.17 (s, 1H ), 2.91 (s, 1H), 2.87 - 2.73 (m, 1H), 2.75 - 2.64 (m, 1H), 1.94 - 1.78 (m, 1H), 1.73 (d, J = 9.7 Hz, 1H).

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

The title compound S31a was prepared according to the procedure described for the synthesis of compound S1c, but using tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate followed by Boe deprotection in the same manner as in case of 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, 2H), 4.66 (dd, J = 7.2, 5.2 Hz, 2H), 4.10 (tt, J = 6.8, 5.2 Hz, 1H), 3.76 (dq, J = 5.0, 2.3 Hz, 2H), 3.51 (dd, J = 13.6, 2 .0 Hz, 2H), 3.41 - 3.33 (m, 2H), 2.31 - 2.21 (m, 2H), 2.11 - 1.95 (m, 2H).

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

The title compound S31b was prepared according to the procedure described for the synthesis of compound S1a, but using 2,6-dichloro-1,5-naphthyridine. MS (ESI) m/z 330.7 [M+H] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 7.95 (dd, J = 9.5, 0.8 Hz, 1H), 7.86 (dd, J = 8.8, 0.8 Hz, 1H ), 7.38 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 9.4 Hz, 1H), 4.71 (t, J = 6.2 Hz, 2H), 4.58 (t, J = 5.7 Hz, 2H), 4.05 (d, J = 11.3 Hz, 2H), 3.74-3.63 (m, 1H), 3.28 - 3 .20 (m, 5H), 1.86 (dd, J = 9.1, 4.4 Hz, 2H).

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

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

- 67 040208

Synthesis of 3,3'-(6-chloro-1,3,5-triazin-2,4-diyl)bis(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane) ( S32a).

The title compound S32a was prepared according to the procedure described for the synthesis of compound S1a, but using compound 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, 4H), 4.56 (s, 3H), 4.32 (d, J = 13.0 Hz, 2H ), 4.30 - 4.20 (m, 2H), 3.64 (h, J = 5.8 Hz, 2H), 3.21 - 3.04 (m, 8H), 1.89 - 1, 73 (m, 4H), 1.71-1.51 (m, 5H).

Synthesis of 3,3'-(6-ethynyl-1,3,5-triazin-2,4-diyl)bis(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane) ( S32).

The title compound S32 was prepared according to the method described for the synthesis of compound S1, but using compound S32a. MS (ESI) m/z 438.3 [M+H] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 4.55 (t, J = 6.2 Hz, 4H), 4.48 - 4.33 (m, 4H), 4.23 (d, J = 12 .5 Hz, 2H), 4.12 (t, J = 10.9 Hz, 2H), 3.49 (q, J = 5.7 Hz, 2H), 3.05 - 2.85 (m, 8H ), 2.78 (s, 1H), 1.71-1.57 (m, 4H), 1.52-1.34 (m, 4H).

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

The title compound S33a was prepared according to the procedure described 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, 1H), 7.74 (d, J = 1.5 Hz, 1H), 4.72 (t, J = 6.3 Hz, 2H), 4.58 (t, J = 5.8 Hz, 2H), 3.77 (dd, J = 11.6, 2.3 Hz, 2H), 3.69 (yyy , J = 11.9, 6.5, 5.5 Hz, 1H), 3.23 (dd, J = 4.8, 2.6 Hz, 2H), 3.18 (dd, J = 11.5 , 2.3 Hz, 2H), 1.92 - 1.83 (m, 2H), 1.73 - 1.65 (m, 2H).

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

The title compound S33 was prepared according to the method described for the synthesis of compound S1, but using compound S33a. MS (ESI) m/z 271.2 [M+H] ⁺ . 1H NMR (400 MHz, chloroform-d) δ 8.21 (d, J = 1.5 Hz, 1H), 7.98 (d, J = 1.5 Hz, 1H), 4.73 (dd, J = 6.3 Hz, 2H), 4.59 (t, J = 5.8 Hz, 2H), 3.90 (d, J = 10.5 Hz, 1H), 3.70 (p, J = 6 .0 Hz, 1H), 3.27-3.18 (m.4H), 3.17 (s, 1H), 1.94-1.83 (m.2H), 1.74-1.64 ( m, 2H), 1.57 (s, 1H).

. oxetan-3-one

_{K2CO3 .} MeOH

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

The title compound S34a was prepared according to the procedure described 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] ⁺ .

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

The title compound S34b was prepared according to the procedure described for the synthesis of compound S1c, but using compound S34a. MS (ESI) m/z 272.2 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.22 - 8.09 (m, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.93 (d, J = 1, 6 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 6.97

- 68 040208 (d, J = 9.2 Hz, 1H), 6.90 (d, J = 9.1 Hz, 1H), 5.87 (d, J = 2.8 Hz, 1H), 5, 47 (d, J = 2.7 Hz, 1H), 4.86 - 4.71 (m,

3H), 3.69 - 3.57 (m, 3H), 3.53 - 3.44 (m, 3H), 3.10 - 3.03 (m, 3H), 2.96 (d, J = 9.0 Hz, 2H), 2.02 - 1.95 (m, 1H),

0.00 (s, 9H).

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

The title compound S34 was prepared according to the method described for the synthesis of compound S1, but using compound S34b. MS (ESI) m/z 256.1 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 8.32 (d, J = 2.1 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 6.26 (d, J = 8.6 Hz, 1H), 4.56 (t, J = 6.8 Hz, 2H), 4.51 4.32 (m, 4H), 3.73 (s, 1H), 3.26 - 3.11 (m, 2H), 3.08 (s, 1H), 3.00 - 2.85 (m, 2H), 2.71 - 2.58 (m, 1H), 2.21 - 1 .98 (m, 1H).

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

The title compound S35aa was prepared according to the procedure described 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, 2H), 6.68-6.55 (m, 2H), 4.34 (s, 2H), 3.35 (dd, J = 11.2, 2.4 Hz, 2H), 2.97 (s, 2H), 2.00 - 1.80 (m, 4H), 1.46 (s, 9H).

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

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

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

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

1. Cui, PdCI ₂ (tBu ₂ PPh) ₂ , TMSA

2.HCl

3. K ₂ CO ₃ , MeOH

S36

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

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

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

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

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

The title compound S37a was prepared according to the procedure described 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] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 8.34 (s, 1H), 7.71 (s, 1H), 6.62 (s, 1H), 4.70 (s, 2H), 4, 37 (t, J = 6.5 Hz, 2H), 4.15 (t, J = 6.4 Hz, 3H), 3.29-3.05 (m, 3H), 3.02-2.80 (m, 1H), 2.17 (dd, J = 11.2, 2.3 Hz, 2H), 1.55 (s, 2H), 1.03 (s, 6H).

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

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

- 69 040208

11.3, 2.3 Hz, 2H), 1.55(s, 1H), 1.03(s, 6H).

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

To a solution of compound S20a (630 mg, 1.76 mmol) in DCM (10 ml) was added N,Ndiisopropylethylamine (1.22 ml, 0.01 mol), the resulting mixture was cooled to 5°C, and then methanesulfonyl chloride (0. 2 ml, 3.0 mmol). After 3 min, the reaction mixture was quenched with saturated NaHCO ₃ solution, the organic layer was separated, dried over Na ₂ SO ₄ , filtered, concentrated, the residue was dissolved in MeOH (15 ml), the resulting solution was cooled to 10°C, after which K ₂ CO ₃ was added (0.44 g, 0.01 mol). After 15 min the precipitate was filtered off, rinsed with 10% MeOH in water and dried under vacuum to give compound 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, 1H), 7.32 (dd, J = 8.8, 2.3 Hz, 1H) , 6.26 (d, J = 8.8 Hz, 1H), 4.12 (dd, J = 4.7, 2.4 Hz, 2H), 3.83 (dd, J = 12.3, 2 .5 Hz, 2H), 2.92 (dd, J = 12.1, 2.1 Hz, 2H),

2.84 (s, 1H), 2.75 (s, 3H), 1.89-1.76 (m, 2H), 1.65-1.56 (m, 2H).

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

The title compound S39a was prepared according to the procedure described 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] ⁺ .

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

The title compound S39b was prepared according to the procedure described for the synthesis of compound S1, but using compound S39a. MS (ESI) m/z 300.2 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 7.97 (d, J = 2.2 Hz, 1H), 7.74 (dd, J = 9.4, 2.2 Hz, 1H), 7 .10 (d, J = 9.3 Hz, 1H), 4.00 (d, J = 12.6 Hz, 2H), 3.30 (d, J = 13.0 Hz, 2H), 3.21 (t, J = 11.5 Hz, 2H), 3.12 (d, J = 13.0 Hz, 2H), 2.21 (s, 2H), 1.87 (d, J = 13.8 Hz , 1H), 1.78 (d, J = 13.7 Hz, 1H), 0.00 (s, 9H).

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

To a mixture of compound S39b (0.39 g, 1 mmol) and Et ₃ N (0.73 ml, 0.01 mol) in DCM (10 ml) was added acetic anhydride (0.14 ml, 1 mmol). After 5 min the reaction mixture was quenched with 1 M NaOH, the layers were separated and the organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and the residue was dissolved in MeOH (20 ml), after which was added K ₂ CO ₃ (0.44 g , 3 mmol). After 20 min, the reaction mixture was diluted with DCM, washed with water, the organic layer was dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (from 60-100% EtOAc/hexanes to 5% MeOH /EtOAc) to give compound 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, 1H), 7.48 (dd, J = 9.0, 2.4 Hz, 1H) , 6.69 (dd, J = 9.0, 0.8 Hz, 1H), 4.74-4.59 (m, 2H), 4.33-4.20 (m, 1H), 4.04 (d, J = 13.4 Hz, 1H), 3.42 (dt, J = 13.5, 2.7 Hz, 1H), 3.39 (s, 1H), 3.11 (dddd, J = 11.1, 8.0, 3.2, 2.2 Hz, 2H), 2.87 (dt, J = 13.5, 2.6 Hz, 1H), 2.06 (q, J = 3, 0 Hz, 2H), 2.01 - 1.94 (m, 2H), 1.84 (s, 3H).

- 70 040208

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

In a microwave tube, a mixture of compound 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 treated with microwave radiation at 130°C for 20 min, and then at 150°C for 20 min, after which the reaction mixture was diluted with DCM, washed with water, the organic layer was dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure , and the residue was purified by silica gel column chromatography to give compound 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, 1H), 7.93 (dd, J = 5.1, 2.0 Hz, 1H), 7.25 (dd, J = 9.0, 2.4 Hz, 1H), 7.25 - 7.16 (m, 1H), 6.39 (d, J = 8.7 Hz, 1H), 6.36 - 6.30 (m, 2H), 4.39 - 4.17 (m, 4H), 3.15 - 3.02 (m, 5H), 2.93 (s, 1H), 2.18 - 2.07 (m, 2H), 1.89 (d, J = 3.4 Hz, 2H).

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

The title compound S41 was prepared according to the procedure described for the synthesis of compound S1c, but using compound S39b. MS (ESI) m/z 284.3 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.17 - 7.96 (m, 1H), 7.46 (dd, J = 9.0, 2.4 Hz, 1H), 6.77 - 6 .49 (m, 1H), 4.41 (t, J = 6.4 Hz, 2H), 4.26 (t, J = 6.2 Hz, 2H), 4.19 (d, J = 12, 9 Hz, 2H), 3.31 (s, 1H), 3.23 - 3.12 (m, 3H), 2.80 - 2.65 (m, 2H), 2.13 - 1.91 (m , 4H), 1.91-1.76 (m, 1H), 1.73-1.61 (m, 1H).z

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

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

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

The title compound S43 was prepared according to the method described for the synthesis of compound S1, but using compound 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, 1H), 7.56 (dd, J = 8.9, 2.3 Hz, 1H) , 6.67 (dd, J = 8.9, 0.8 Hz, 1H), 4.46 (dq, J = 4.4, 2.3 Hz, 2H), 3.86 (dt, J = 12 .8, 1.1 Hz, 2H), 3.43 (s, 1H), 3.07 (d, J = 2.6 Hz, 1H), 3.03 (d, J = 2.6 Hz, 1H ), 2.02-1.74 (m, 4H).

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

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

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

The title compound S44 was prepared according to the methods described for the synthesis of compound S3, but using compound S44a. MS (ESI) m/z 284.2 [M+H] ⁺ . 1H NMR (400 MHz, chloroform-d) δ 8.24 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 2.3 Hz, 0H), 7.43 (dd, J = 2.1, 0.9 Hz, 1H), 7.30 (d, J = 1.9 Hz, 0H), 7.19 (d, J = 15.2 Hz, 0H), 5.80 ( d, J = 15.1 Hz, 0H), 5.30 (s, 0H), 4.70 (t, J = 6.2 Hz, 3H), 4.59 (s, 2H), 3.76 ( s, 1H), 3.35 - 3.26 (m, 2H), 3.18 (d, J = 30.6 Hz, 5H), 3.09 (s, 1H), 2.27 (s, 0H ), 2.24 (s, 3H), 1.96 - 1.79 (m, 5H), 0.24 (d, J = 7.3 Hz, 0H), 0.15 (d, J = 6, 0 Hz, 0H), 0.08 (s, 0H).

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

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

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

The title compound S45 was prepared according to the methods described for the synthesis of compound S3, but using compound S45a. MS (ESI) m/z 284.2 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 7.46 (d, J = 8.7 Hz, 1H), 6.28 (d, J = 8.7 Hz, 1H), 5.30 (s, 0H ), 4.72 (t, J = 6.3 Hz, 2H), 4.59 (t, J = 5.8 Hz, 2H), 4.07 (d, J = 12.6 Hz, 0H), 3.89 (d, J = 11.0 Hz, 2H), 3.71 (p, J = 6.0 Hz, 1H), 3.26 (d, J = 13.4 Hz, 1H), 3. 24 (s, 0H), 3.23 (s, 1H), 3.19 (s, 2H), 3.14-3.07 (m, 2H), 2.51 (s, 3H), 1.85 (dd, J = 11.5, 6.7 Hz, 2H), 1.70 (t, J = 6.7 Hz, 1H).

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

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

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

The title compound S46 was prepared according to the methods described for the synthesis of compound S3, but using compound S46a. MS (ESI) m/z 284.2 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 8.22 (s, 1H), 6.33 (s, 1H), 5.30 (s, 0H), 4.72 (t, J = 6.3 Hz , 2H), 4.59 (t, J = 5.8 Hz, 2H), 3.85 (dd, J = 11.8, 2.4 Hz, 2H), 3.70 (p, J = 6, 0 Hz, 1H), 3.24 (s, 0H), 3.23 (s, 1H), 3.22 - 3.09 (m, 4H), 2.34 (d, J = 0.7 Hz, 3H), 1.85 (dd, J = 8.9, 4.3 Hz, 2H), 1.72-1.66 (m, 2H).

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

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

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

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

5. K2CO3 S48

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

The title compound S48 was prepared according to the methods described 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, 1H), 7.56 (dd, J = 8.9, 2.3 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 4.70 (t, J = 6.6 Hz, 3H), 4.63 (t, J = 6.2 Hz, 3H), 3.68 - 3 .56 (m, 6H), 3.55 - 3.47 (m, 1H), 3.42 (s, 1H), 2.52 - 2.37 (m, 6H), 1.27 (d, J = 13.9 Hz, 0N).

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

The title compound S49 was prepared according to the methods described 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]+.

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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 described for the synthesis of compound S1, but using tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate and 4oxotetrahydropyran. MS (ESI) m/z 272.70 [M+H]+.

Synthesis of tert-butyl 3-((3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]ocgan-8-yl)methyl)azetidine1-carboxylate (S51).

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

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

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

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

The title compound S52 was prepared according to the method described for the synthesis of compound S1, but using compound S52a. MS (ESI) m/z 257.1 [M+H] ⁺ . 1H NMR (400 MHz, chloroform-d) δ 8.32 (s, 2H), 4.55 (t, J = 6.1 Hz, 2H), 4.32 (dd, J = 6.0, 4 .8 Hz, 2H), 3.72 (yyy, J = 11.1, 6.2, 4.9 Hz, 1H), 3.65 (d, J = 6.0 Hz, 2H), 3.50 (d, J = 13.3 Hz, 2H), 3.43 (d, J = 13.3 Hz, 2H), 3.06 (s, 1H), 2.58 (dt, J = 8.1,

6.1 Hz, 1H), 1.44 (d, J = 8.8 Hz, 1H).

he p

Bi Bis(pinacolato)diboron ]Q

Pd ₍ dppf) _CI2CH2CI2

N\>| _{CH3CO2K _}

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

A suspension of compound 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, after which it was heated at 90°C for 1 h. The mixture was cooled to room temperature, diluted with EtOAc and washed twice with 5% LiCl solution. The separated organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo, the residue was purified by HPLC and the resulting product was lyophilized to give compound S53. MS (ESI) m/z 276.2 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.35 (d, J = 1.7 Hz, 1H), 8.31 (dd, J =

9.0, 1.8 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 4.74 - 4.58 (m, 4H), 4.27 - 3.99 (m , 4H), 3.28 - 3.16 (m, 1H), 2.21 2.06 (m, 2H).

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

To a solution of compound S3 in acetone (1 ml) in a vial at 30°C was added methane (0.06 ml, 1.0 mmol), the resulting mixture was heated to 70°C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with ether, stirred for 5 min, the solids were filtered and dried in vacuo to give a 3:1 mixture of isomers (S54:S55) where the main product (S4) contains methyl in the syn position to bridge. MS (ESI) m/z 284.0 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.08 - 8.02 (m, 1H), 7.50 - 7.40 (m, 1H), 6.58 (d, J = 9.0 Hz , 0H), 6.54 (dd, J = 8.8, 0.9 Hz, 1H), 5.37 (t, J = 8.1 Hz, 1H), 4.86 -4.70 (m, 5H), 4.05 - 3.94 (m, 3H), 3.88 (d, J = 14.3 Hz, 3H), 3.54 (d, J = 14.7 Hz, 1H), 3, 45 (s, 1H), 3.37 (d,J = 2.1 Hz, 1H), 3.34 (s, 4H), 3.30 (s, 1H), 2.37 - 2.27 (m , 2H), 2.21-2.11 (m, 1H), 2.07-1.94 (m, 2H), 1.94 (s, 1H).

Υη 1. tmsa ^NN

S56

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

The title compound S56 was prepared according to the methods described 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] ⁺ .

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. ¹ H NMR and MS data are the same as for compound S14.

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

The title compound S58a was prepared according to the methods described 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).

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

To a solution of compound 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 minutes, methane (0.15 ml, 2.409 mmol) was added. The resulting reaction mixture was warmed to room temperature and stirred for 2 h, after which it was quenched with water and partitioned using EtOAc. The separated organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give compound S58 (124.9 mg, 100%). MS (ESI) m/z 217.1 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.45 (s, 2H), 4.37 (s, 2H), 4.18 - 4.03 (m, 2H), 3.65 (s, 1H) , 3.57 - 3.43 (m, 2H), 3.01 (s, 3H).

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TMSA

3. K ₂ CO ₃ , MeOH

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

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

HE

E Bis(pinacolato)dibor

L.I. Pd ₍ dppf) _CI2CH2CI2

N CH ₃ CO ₂ K ^N 7 A

--—----- _ccn S3c y _Q S60 Vo

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

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

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

A suspension of compound 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 during the night. 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 resulting mixture was stirred for 30 minutes. 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, 2H), 8.17 (dd, J = 2.4, 0.8 Hz, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.69 (dd, J = 9.0, 0.8 Hz, 1H), 6.64 (t, J = 4.8 Hz, 1H), 4.89 (dq, J = 4.6, 2.3 Hz, 3H), 4.02 (dd, J = 12.4, 2.3 Hz, 3H), 3.42 (s, 1H ), 3.13 (dd, J = 12.3, 2.3 Hz, 3H), 2.08 - 1.96 (m, 3H), 1.96 - 1.82 (m, 3H).

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

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

1. 2-Iodine-1,1

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

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Cesium carbonate of 99 purity 95% (0.21 g, 3.35 mmol). The resulting mixture was stirred at 60° C. overnight. The mixture was cooled to room temperature and 2,2 difluoroethyl trifluoromethanesulfonate (minimum 98% purity) (0.17 g, 0.78 mmol) was added. The resulting mixture was heated to 60° C. for 8 hours. The mixture was quenched with saline and subjected to extraction with EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified by silica gel column chromatography (10% EtOAc/Hex). The resulting 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 Na ₂ SO ₄ , filtered and concentrated with obtaining compound S63 (76 mg, 99.7%). MS (ESI) m/z 278.2 [M+H]+.

ABOUT

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

To compound S20a suspended in CH ₂ Cl ₂ (10 ml) was added 3-methyloxetane-3-carboxylic acid (0.12 g, 1 mmol), Et ₃ N (0.68 ml, 5 mmol), then HATU ( 0.48 g, 1 mmol). The resulting mixture was stirred for 1.5 hours. The mixture was diluted with DCM and washed with water. The organic layer was dried over Na ₂ SO ₄ 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 mixture was quenched with water and brine, subjected to extraction in DCM, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (from 60-100% EtOAc/hexanes to 5 % MeOH/EtOAc) to give compound S64. MS (ESI) m/z 312.22 [M+H].

2.3 Synthesis of intermediates A.

A1c Aid A1e

10% Pd/C

EUN

10% Pd/C

EtOH

A1 A2

Synthesis of ethyl 2-(1,1,1-trifluoropropan-2-ylidene)malonate (A1a) A mixture of dry THF (5000 ml) and dry CCl ₄ (600 ml) was cooled to 0°C and treated with TiCl ₄ (275 ml , 2.50 mol). received

- 76 040208 the yellow suspension was stirred at 0°C for 5 min, treated successively 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 subjected to extraction with EtOAc (1 L x3). The combined organic extracts were washed with brine and saturated NaHCO ₃ , dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:PE = 1:50) to give the title compound A1a (298 g, 94%). 1 H NMR (CDCl ₃ , 300 MHz): δ 4.32-4.23 (m, 4H), 2.20 (s, 3H), 1.33-1.24 (m, 6H).

Synthesis of diethyl 2-(1,1,1-trifluoro-2-methylpropan-2-yl)malonate (A1b).

A mixture of methylmagnesium iodide (3.0 mol/L in ether, 10 L, 30 mol) and copper (I) 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) for 30 min and stirred at room temperature for 30 min and then quenched by dropwise addition of ice water (1.5 L) followed by aqueous HCl (3 mol/L, 350 ml). The resulting mixture was then subjected to extraction with Et ₂ O (1 L x3). The combined organic extracts were washed with aqueous NaOH (1N), water and brine, dried (MgSO4), filtered and evaporated. The residue, which was crude compound A1b (90 g, 47%), was used directly in the next step without further purification. MS (ESI) m/z 271 [M+H]+. ¹ H NMR (CDCl ₃ , 300 MHz): δ 4.22-4.15 (m, 4H), 3.64 (s, 1H), 1.38 (s, 6H), 1.30-1.24 (m, 6H).

Synthesis of 2-(ethoxycarbonyl)-4,4,4-trifluoro-3,3-dimethylbutanoic acid (A1c).

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) in portions at 0°C and stirred at room temperature for 5 hours. The reaction mixture was evaporated to a syrup, dissolved in water (1 l) and subjected to extraction with Et ₂ O (2 l). The aqueous phase was acidified with 1 M HCl to pH 2.0 and subjected to extraction with EtOAc (1 L x3). The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and evaporated to give 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] ⁺ . 1 H NMR (CDCl ₃ , 300 MHz): δ 4.23 (q, J= 5.4 Hz, 2H), 3.69 (s, 1H), 1.40 (s, 6H), 1.27 (t , J= 5.1 Hz, 3H).

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

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 resulting reaction mixture was heated to reflux for 1 h, after which t-BuOH (46.7 g, 630 mmol) was added. The resulting mixture was heated to reflux overnight. The mixture was cooled to room temperature, the solvent was evaporated, and the residue was dissolved in EtOAc (1 l), washed with 5% NaHCO ₃ solution, dried (MgSO ₄ ), filtered and evaporated. The residue was purified by silica gel column chromatography (EtOAc:PE = 1:9) to give crude compound A1d (60 g, 46%), which was used directly in the next step without further purification. MS (ESI) m/z 313 [M+H] ⁺ . 1 H NMR (CDCl ₃ , 300 MHz): δ 5.20 (d, J= 5.7 Hz, 1H), 4.44 (d, J= 10.8 Hz, 1H), 4.25-4.16 (m, 2H), 1.44 (s, 9H), 1.39-1.26 (m, 6H), 1.19 (m, 3H).

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

LiOH.H2O (134 g, 3166 mmol) was added to a solution of compound A1d (380 g, 1214 mmol) in water (2000 ml) and ethanol (2000 ml). The resulting mixture was stirred overnight. The mixture was diluted with EtOAc, acidified to pH 2, subjected to extraction with EtOAc (2000 ml x3). The organic layer was washed with brine, dried over MgSO4 and concentrated to give compound Ale (300 g, 86%) as a white solid. 1 H NMR (CDCl ₃ , 300 MHz): δ 5.20 (d, J = 10.2 Hz, 1H), 4.48 (d, J = 10.2 Hz, 1H), 1.45 (s, 9H ), 1.30 (s, 3H), 1.25 (s, 3H). Synthesis of (S)-(S)-1phenylethyl-2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoate (A1g) Acid A1e (300 g, 1052 mmol) and N, N'-dicyclohexylcarbodiimide (DCC) (325 g, 1578 mmol) was combined in DCM (250 ml) and PhMe (4000 ml). The resulting solution was cooled to 0°C, and then 4(dimethylamino)pyridine (DMAP) (128 g, 1052 mmol) and (S)-(-)-1-phenylethanol (128 g, 1052 mmol) were added, and the resulting mixture was left warm to room temperature and stirred overnight. The mixture was concentrated and then the residue was taken up in a mixture of EtOAc/water and subjected to extraction with EtOAc (2000 ml x3). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated. The crude material was purified by silica gel column chromatography (0-8% EtOAc/PE) to give two compounds. The mixture of diastereomers was separated using a chiral column (IA; heptane; isopropyl alcohol (IPA) (70:30)). The fraction corresponding to the first peak was collected to give compound A1f (105 g, 25%), and the fraction corresponding to the second peak was collected to give compound A1e (80 g, 19%). 1H NMR compound A1f (CDCl ₃ ,

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300 MHz): δ 7.38-7.31 (m, 5H), 5.90 (q, J= 6.3 Hz, 1H), 5.18 (d, J= 9.6 Hz, 1H), 4.48 (d, J = 9.6 Hz, 1H), 1.56 (d,

J = 6.9 Hz, 3H), 1.44 (s, 9H), 1.31 (s, 3H), 1.21 (s, 3H). 1H NMR compound A1g (CDCl ₃ , 300 MHz): δ 7.347.30 (m, 5H), 5.92 (q, J = 6.3 Hz, 1H), 5.20 (d, J = 9.6 Hz , 1H), 4.44 (d, J= 9.6 Hz, 1H), 1.58 (d, J= 6.9 Hz, 3H),

1.45 (s, 9H), 1.21 (s, 3H), 1.11 (s, 3H).

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

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

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

Compound A1g (80 g, 205 mmol) was diluted with ethanol (800 ml). Pd/C (10%, wet,

d), and the air was replaced with hydrogen. After stirring for 5 hours, the mixture was filtered through celite while washing with EtOAc, and the filtrate was concentrated to give product A2 (45 g, 77%). MS (ESI) m/z 186 [M-Vos +1] ⁺ . 1H NMR (300 MHz, DMSO-d ₆ ): δ 7.18 (d, J=9.6 Hz, 1H), 4.25 (d,

J = 9.9 Hz, 1H), 1.36 (s, 9H), 1.14 (s, 6H).

1.HCI

2. CICO ₂ CH ₃

A1 A3

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

To a solution of compound A1 (10 g, 35.06 mmol) in DCM (160 ml) and MeOH (40 ml) was added HCl (4.0 M in dioxane, 40 ml). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture 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 hours, the reaction mixture was subjected to extraction with 2x100 ml DCM (removing organics) and the pH of the aqueous layer was adjusted to ~2 with 4 M HCl (~50 ml). This aqueous layer was extracted with 2x150 ml EtOAc, the combined layers of EtOAc were dried over sodium sulfate, filtered and concentrated to give compound 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, 1H), 3.66 (d, J = 2.1 Hz, 5H), 1.25 (d, J = 10, 0 Hz, 7H).

A1 A4

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

The title compound A4 was prepared according to the procedure described for the synthesis of compound A3, but using 4-nitrophenyloxetan-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, 1H), 5.37 (tt, J = 6.3, 5.1 Hz, 1H), 4.87 - 4.82 (m, 2H), 4.62 (tdd, J = 7.5, 5.1, 0.9 Hz, 2H), 4.49 - 4.41 (m, 1H), 1.28 ( s, 3H), 1.25 (s, 3H).

1. Ν,N'-Disuccinimidyl carbonate

2. L-mpem-leucine methyl ester. NS!

3.LiOH

A5

Synthesis of (S)-2-((cyclopropoxycarbonyl)amino)-3,3-dimethylbutanoic acid (A5).

To a solution of cyclopropanol (0.4 ml, 6.37 mmol) in CH ₃ CN (18 ml) at 0°C was added bis(2,5dioxopyrrolidin-1-yl)carbonate (DSC) (3.26 g, 12.74 mmol) followed by Et ₃ N (2.66 ml, 19.11 mmol). The resulting reaction mixture was heated to 40° C. and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue triturated with DCM, the solid was filtered, and the filtered material was purified by silica gel column chromatography (10-100% EtOAc/hexanes). The resulting product (663 mg, 3.33 mmol) was dissolved in THF (5 mL) and L-mpem-leucine methyl ester hydrochloride (0.91 g, 5 mmol) and Et3N (1.39 mL, 0.01 mol) were added. ), the resulting reaction mixture was heated to 40° C. for 18 h and then kept 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 methanol (4 ml)/water (2 ml), after which lithium hydroxide monohydrate (0 .56 g, 0.01 mol). After 16 h the mixture was concentrated, diluted with EtOAc, washed with brine, the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain compound A5. Ή NMR (400 MHz, chloroform-d) δ 4.19 (d, J = 9.6 Hz, 1H), 1.02 (s, 11H), 0.68 (d, J = 4.8 Hz, 5H ).

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

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

A7

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

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

to ³ G ³ _H2 X°n .JXoh

It

A8

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

The title compound A8 was prepared according to the procedure described 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, 1H), 3.65 (s, 3H), 1.97 (qd, J = 9.6, 1.7 Hz, 6H).

2.4 Synthesis of intermediates I.

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

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-ul) ethyl)carbamate (16.1 g, 41.4 mmol), the resulting mixture was dissolved dropwise in DCM (79 ml) for 1 h at 0°C. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The solvents were evaporated from the mixture, the mixture was diluted with water, filtered, washed with water and dried to give compound Pa (17.0 g, 97%). Ή NMR (300 MHz, CDCl ₃ ): δ 7.59 (d, J=7.8 Hz, 2H), 7.02-6.96 (m, 2H), 5.03 (d, J=9, 9 Hz, 1H), 3.78-3.66 (m, 2H), 2.85-2.67 (m, 4H), 2.04 (s, 3H), 1.38 (s, 9H).

Synthesis of methyl ester ((S)-1-{(1S,2S)-2-hydroxy-1-(4-iodobenzyl)-3-[N'-((S)-2-methoxycarbonylamino-3,3-dimethylbutyryl) hydrazino]propylcarbamoyl}-2,2-dimethylpropyl)carbamic acid (I1).

To a solution of compound Pa (34.0 g, 80.7 mmol) in CH ₂ Cl ₂ (990 ml) at room temperature to

- 79 040208 4 M hydrochloric acid (198 ml) was added. After stirring for 2 hours at 45° C., LC/MS indicated completion of the reaction and the mixture was concentrated in vacuo. To the obtained crude residue, suspended in CH ₂ Cl ₂ (700 ml) and cooled to -20°C, was added DIPEA (48.2 g, 373.9 mmol), Mos-tBu-Gly (25.53 g, 135, 1 mmol), then HATU (53.4 g, 140.5 mmol). The resulting mixture was slowly warmed to room temperature and stirred for 1 hour. The mixture was diluted with DCM (1 L) and washed successively with 1N HCl. aqueous HCI solution (400 ml), saturated aqueous NaHCO ₃ solution (400 ml), water (600 ml x2) and brine (600 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give a residue which was purified by silica gel column chromatography eluting with 2:1 EtOAc:petroleum ether to 100% EtOAc, then going to EtOAc:MeOH 50:1s obtaining product I1 (8.2 g, 19.4%). MS (ESI) m/z 664.0 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD): δ 7.53 (d, J= 8.1 Hz, 2H), 7.01 (d, J= 8.4 Hz, 2H), 4.10-4 .21 (m, 1H), 3.90 (s, 1H), 3.82 (s, 1H), 3.69-3.64 (m, 7H), 2.78-2.76 (m, 4H ), 0.95 (s, 9H), 0.91 (s, 9H).

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

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 to 80°C for 48 h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% EtOAc/DCM) to give compound 12a (4.86 g, 72.6%). MS (ESI) m/z 522.19 [M+H] ⁺ .

Synthesis of methyl-((5S,10S, 11S, 14S)-16,16,16-trifluoro-10-hydroxy-11-(4-iodobenzyl)-15,15-dimethyl3,6,13-trioxo-5-( 1 ,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate (I2).

Compound I2a (5.0 g, 10 mmol) was dissolved in DCM (15 ml) and HCl (4.0 M in dioxane, 36 ml). The resulting reaction mixture was stirred overnight, after which it was concentrated under reduced pressure. Compound A3 (4.96 g, 20 mmol) and HATU (8.02 g, 21 mmol) in DCM (100 ml) were added to the residue followed by N,N-diisopropylethylamine (16.7 ml, 96 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated NaHCO ₃ solution and brine, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (2-5% MeOH/DCM) to give compound 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, 2H), 6.99 (d, J = 8.2 Hz, 2H), 3.71 (q, J = 6.9 Hz, 7H), 3.65 (s, 3H), 1.37 (dd, J = 7.0, 1.7 Hz, 32H), 1.19-1.07 (m, 10H) .

Synthesis of tert-butyl-((2S,3S)-3-hydroxy-1-(4-iodophenyl)-4-(2-((S)-2-((methoxycarbonyl)amino)-3,3dimethylbutanoyl)hydrazinyl)butane -2-yl)carbamate (13a).

The title compound 13a was obtained according to the method described 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] ⁺ .

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

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

ABOUT

O O μ G\ H OH H Q H ngA^ HnN ^N Y°X>Q boc^y^n^A^n.^

XX

14a 14

Synthesis of (8)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3,3-dimethylbutanoic acid (I4a).

L-tert-leucine (2 g, 15.25 mmol) was dissolved in 10% Na ₂ CO ₃ solution (80 ml), the resulting solution was cooled to 0°C, after which 9-fluorenylmethyl chloroformate (Fmoc chloride) (4, 77 g, 18.44 mmol) in dioxane (31 ml). After 2 hours, the reaction mixture was diluted with water, washed with ether, and the pH of the aqueous layer was adjusted to ~2 with 6N HCl. HCl, and the specified aqueous layer was subjected to extraction with EtOAc.

The combined EtOAc layers were dried over Na ₂ SO ₄ , filtered and concentrated to give compound !4a. MS (ESI) m/z 353.8 [M+H]+.

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

To I4a (2.55 g, 7.22 mmol) was added Pa (3 g, 7.12 mmol), HATU (2.7 g, 7.1 mmol) and CH ₂ C1 ₂ /DMF (2: 1) (75 ml) followed by N,N-diisopropylethylamine (3 ml, 17.22 mmol). The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc and washed with saturated NH ₄ Cl solution and brine, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (2-5% MeOH/DCM) to give compound I4 (2.38 g, 44%). MS (ESI) m/z 757.1 [M+H] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 8.01 (s, 1H), 7.75 (t, J=7.5 Hz, 5H), 7.66-7.46 (m, 6H), 7.38 (q, J = 7.5 Hz, 4H), 7.34 - 7.27 (m, 1H), 6.95 (dd, J = 16.8, 8.0 Hz, 4H), 5 .52 (d, J = 47.2 Hz, 2H), 5.01 (dd, J = 19.2, 10.0 Hz, 1H), 4.48 (dd, J = 10.5, 6.5 Hz, 1H), 4.34 (dt, J = 28.9, 9.8 Hz, 2H), 4.19 (t, J = 6.8 Hz, 2H), 3.91 (dd, J = 45 .4, 14.8 Hz, 2H), 3.60 (d, J = 31.0 Hz, 2H), 1.39 (d, J = 16.0 Hz, 13H).

Synthesis of tert-butyl-((28.38)-4-(2-((8)-2-((cyclopropoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy-1-(4-iodophenyl )butan-2-yl)carbamate (I5).

The title compound I5 was prepared according to the procedure described for the synthesis of compound I2, but using compounds 14 and A5. MS (ESI) m/z 619.4 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 8.02 (s, 0H), 7.59 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 7.9 Hz, 2H ), 5.37 (s, 1H), 5.04 (s, 1H), 4.02 (s, 1H), 3.83 (s, 1H), 3.74 - 3.58 (m, 1H) , 2.95 (s, 1H), 2.88 (d, J = 0.7 Hz, 1H), 2.85 (d, J = 7.7 Hz, 1H), 2.80 (s, 6H) ,

1.38 (s, 8H), 1.01 (d, J = 10.5 Hz, 1H), 0.90 (s, 8H), 0.66 (d, J = 4.7 Hz, 4H).

1. HCI/dioxane

2. A3, HATU, DIPEA

11a I6a

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

The title compound I6a was prepared according to the method described for the synthesis of co

- 81 040208 unity I4, but using compound A7. MS (ESI) m/z 611.5 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 7.57 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H), 5.50 (s, 1H ), 4.97 (d, J = 9.8 Hz, 1H), 4.37 - 4.17 (m, 1H), 4.03 (td, J = 25.3, 23.8, 9.4 Hz, 2H), 3.68 (s, 4H), 3.50 (s, 0H), 3.17 (qd, J = 7.4, 4.4 Hz, 1H), 2.94 (s, 1H ), 2.82 (dt, J = 15.8, 5.5 Hz, 4H), 1.50 (t, J = 7.4 Hz, 1H), 1.46 (dd, J = 17.4, 6.7 Hz, 3H), 1.39 (s, 9H), 0.96 (s, 5H).

Synthesis of methyl-((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-tetraazahexadecan-14-yl)carbamate (I6).

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

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).

Methyl-(S)-(1-hydrazinyl-3,3-dimethyl-1-oxobutan-2-yl)carbamate (9.2 g, 45 mmol) and 4-bromo-2,6 difluorobenzaldehyde (10 g, 45 mmol) stirred in THF at room temperature for 60 min. 4-Methylbenzenesulfonic acid (TsOH) monohydrate (9.0 g, 48 mmol) was added and the resulting mixture was stirred for an additional 75 minutes. The mixture was cooled to 8°C followed by the addition of NaCNBH ₃ (3.8 g, 61 mmol). The reaction was found to be exothermic up to 30°C. The mixture was stirred for 4 hours at room temperature followed by dilution with DCM (200 ml) and quench with 1 M K ₃ PO ₄ to pH 12. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. 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 resulting mixture was stirred at reflux for 40 hours, after which it was cooled to room temperature and diluted with 15 ml of hexanes. The resulting product (I7a) was collected by filtration and the solids were rinsed with 20% IPA in hexanes. MS (ESI) m/z 797.8 [M+H] ⁺ . The title compound I7 was prepared according to the procedure described for the synthesis of compound I1, but using methyl-(S)-(1-(2-(4-bromo-2,6difluorobenzyl)hydrazinyl)-3,3-dimethyl-1- oxobutan-2-yl)carbamate (I7a). MS (ESI) m/z 869.72 [M+H]. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.53 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 6.9 Hz, 2H), 7.00 (d , J = 8.2 Hz, 2H), 4.16 - 4.03 (m, 2H), 3.95 - 3.83 (m, 2H), 3.76 - 3.57 (m, 11H), 2.90-2.72 (m, 6H), 0.86 (d, J=23.1 Hz, 18H).

- 82 040208

Synthesis of methyl-((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-3yl)pyridin-3-yl)ethynyl) benzyl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (I8).

Intermediates: I7 and S25. MS (ESI) m/z 1052.92 [M+H]. 1H NMR (400 MHz, methanold4) δ 8.19 (s, 1H), 7.79 (d, J= 8.8 Hz, 2H), 7.35 (d, J= 7.8 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 6.9 Hz, 2H), 6.98 (t, J = 10.5 Hz, 1H), 4, 69 (t, J = 6.8 Hz, 2H), 4.21 - 4.00 (m, 4H), 3.98 - 3.81 (m, 5H), 3.80 - 3.62 (m, 9H), 3.25-3.09 (m, 2H), 2.98-2.85 (m, 2H), 2.79 (d, J=6.6 Hz, 2H), 2.30-2 .08 (m, 1H), 2.02 - 1.72 (m, 6H), 0.87 (d, J = 21.7 Hz, 22H).

- 83 040208

Methyl-((S)-1-(2-((2S,3S)-3-((S)-2-amino-4,4,4-trifluoro-3,3-dimethylbutanamido)-2-hydroxy-4 -(4iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-III-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro3,3-dimethyl-1 -oxobutan-2-yl)carbamate (I9).

Methyl-(S)-(4,4,4-trifluoro-1-hydrazinyl-3,3-dimethyl-1oxobutan-2-yl)carbamate hydrochloride (HCl) salt solution (200 mg, 0.68 mmol) , and 4-(1-(difluoromethyl)-1H-pyrazol-3yl)-2,6-difluorobenzaldehyde (P4) (190 mg, 0.75 mmol) in ethanol (5 ml) and acetic acid (0.5 ml) stirred at 50°C for 1 h Then the reaction mixture was cooled to room temperature, diluted with EtOAc, rinsed with an aqueous solution of NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The crude mixture was redissolved in MeTHF (10 ml) and cooled to 5°C. Sodium cyanoborohydride (64 mg, 1.0 mmol) was added followed by 4-methylbenzenesulfonic acid monohydrate (155 mg, 0.82 mmol). After 1 h the reaction mixture was warmed to room temperature and additional sodium cyanoborohydride (64 mg, 1.0 mmol) and 4-methylbenzenesulfonic acid monohydrate (155 mg, 0.82 mmol) were added. After an additional 30 minutes, the reaction mixture was quenched with 2M NaOH until pH 14. The resulting mixture was then stirred at 40° C. for 30 minutes. The mixture was cooled to room temperature, diluted with EtOAc and the aqueous layer was removed. The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated in vacuo and purified by column chromatography (30%^70% EtOAc in hexanes) to give methyl-(S)-(1(2-(4-(1-( difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1oxobutan-2-yl)carbamate (I9a). 1H NMR (400 MHz, chloroform-d) δ 7.87 (d, J = 2.8 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.22 (t, J = 60.7 Hz, 1H), 6.72 (d, J = 2.8 Hz, 1H), 5.34 (d, J = 9.7 Hz, 1H), 4.30 (d, J = 9 .7 Hz, 1H), 4.17 (d, J = 12.9 Hz, 1H), 4.06 (d, J = 13.0 Hz, 1H), 3.67 (s, 3H), 1, 23 (s, 3H), 1.16 (s, 3H). MS (ESI) m/z 499.2 [M+H].

Methyl-(S)-(1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4trifluoro-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 resulting mixture was stirred at 90° C. in a sealed tube overnight. The crude mixture was cooled to room temperature, concentrated in vacuo, after which

- 84 040208 was 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 resulting mixture was stirred overnight, allowing it 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 salt HCl. MS (ESI) m/z 787.9 [M+H]. The indicated 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 mixture was quenched with an aqueous solution of NaOH, the organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The resulting mixture was redissolved in DCM, 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)-2amino-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 the HCl salt, which was used without further purification. MS (ESI) m/z 956.2 [M+H].

3. Illustrative compounds, their synthesis and characteristics.

Example 1

Synthesis of methyl-((5S,10S,11S, 14S)-8-(4-(1-(2,2-difluoroethyl)-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16, 16,16trifluoro-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-tetraazahexadecan-14-yl)carbamate (1a).

The combined compounds P10 (289.23 mg, 0.88 mmol) and I2 (486 mg, 0.63 mmol) were stirred in 3:1 THF/AcOH (7.0 mL) at 55°C for 1 h. cooled to room temperature and polymer-supported sodium cyanoborohydride (2.49 mmol/g, 780.02 mg, 1.94 mmol) was added and the resulting 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 using column chromatography (45-75% EtOAc/hexanes) to obtain compound 1a. MS (ESI) m/z 1028.3 [M+H] ⁺ .

Synthesis of methyl-((5S,10S,11S,14S)-8-(4-(1-(2,2-difluoroethyl)-1Н-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-3yl)ethynyl)benzyl)-3.6 ,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazahexadecan-14-yl)carbamate (1).

In a vial, a solution of compound 1a (28 mg, 0.027 mmol), compound 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 MeCN:Et ₃ N 3:1 (1 ml) was degassed and then heated to 25°C for 25 min. The mixture was concentrated under reduced pressure. The residue was purified by HPLC and lyophilized to give compound 1. MS (ESI) m/z 1131.2 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 8.10 (d, J = 9.3 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H ), 7.64 (d, J = 2.5 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.05 (d, J = 9.9 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 6.76 (d, J = 9.8 Hz, 1H), 6. 65 (d, J = 2.5 Hz, 1H), 6.32 - 5.96 (m, 1H), 4.96 (s, 1H), 4.61 (dd, J = 8.2, 4, 7 Hz, 1H), 4.58 - 4.49 (m, ZN), 4.45 (dd, J = 14.2,

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4.8 Hz, 1H), 4.37 (s, 1H), 4.21 (d, J = 9.9 Hz, 1H), 4.04 (d, J = 13.0 Hz, 2H), 3 .84 (d, J = 13.2 Hz, 1H), 3.74 (d, J = 11.9 Hz, 1H), 3.67 (d, J = 11.5 Hz, 2H), 3.54 (s, 4H), 3.47 (s, 3H), 2.92 - 2.73 (m, 4H), 2.73 - 2.62 (m, 1H),

2.24 (s, 2H), 1.05 (d, J = 4.5 Hz, 7H), 1.01 (s, 3H), 0.92 (s, 3H).

Example 2

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-9-hydroxy15,15-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-tetraazahexadecan14-yl)carbamate (2) Intermediates: I3, P1 and S7.

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

Example 3

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

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, 1H), 8.10 (d, J = 9.5 Hz, 1H), 7.69 (dd, J = 8.8, 2.3 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.36 (d , J = 8.0 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 9.7 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 10.0 Hz, 1H), 6.35 (d, J = 1 .9 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.81 - 4.76 (m, 2H), 4.47 (td, J = 13.6, 4, 3 Hz, 2H), 4.37 (dd, J = 19.3, 11.6 Hz, 2H), 4.25 (d, J = 9.7 Hz, 1H), 4.15 (s, 2H) , 3.99 (d, J = 9.2 Hz, 2H), 3.74 (s, 1H), 3.68 (s, 3H), 3.60 (s, 3H), 3.39 (s, 1H), 3.36 (s, 1H), 2.90 (d, J = 9.0 Hz, 2H), 2.86 - 2.72 (m, 1H), 2.22 (d, J = 8 .5 Hz, 2H), 2.07 (d, J = 8.6 Hz, 1H), 1.11 (s, 6H), 1.06 (s, 3H), 0.81 (s, 3H).

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Example 4

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

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

Example 5

Methyl-((5 S,8S,9S,14S)-11 -(4-(1-cyclopropyl-1 H-pyrazol-3 -yl)-2,6-difluorobenzyl)-9-hydroxy15,15-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-tetraazahexadecan-14yl)carbamate (5).

Intermediates: I3, P13 and S3. MS (ESI) m/z 1091.3 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.20 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.60 (dt, J = 5.5, 2.7 Hz, 2H), 7.24 (t, J = 7.8 Hz, 4H), 7.12 (d, J = 8.1 Hz, 2H), 6.77 ( d, J = 8.9 Hz, 1H), 6.71 (d, J = 9.9 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 4.95 4.85 (m, 2H), 4.71 (dd, J = 8.3, 5.0 Hz, 2H), 4.34 (d, J = 10.0 Hz, 1H), 4.26 (d, J = 14.3 Hz, 2H), 4.11 -3.94 (m, 4H), 3.87 (s, 1H), 3.84 (s, 0H), 3.67 (s, 1H), 3, 59 (s, 4H), 3.56 (s, 3H), 3.28 (d, J = 13.9 Hz, 2H), 2.80 (d, J = 9.1 Hz, 2H), 2, 69 (d, J = 8.9 Hz, 2H), 2.21 - 2.04 (m, 2H), 1.98 (d, J = 8.6 Hz, 2H), 1.04 (s, 4H ), 1.00 (s, 3H), 0.99 0.94 (m, 1H), 0.77 (s, 9H).

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Example 6

Methyl-((5 S,8S,9S,14S)-11-(4-(1 -(2,2-difluoroethyl)-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy15 ,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-tetraazahexadecan-14yl)carbamate (6) .

Intermediates: I3, P10 and S3. MS (ESI) m/z 1115.3 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.20 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 9.3 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 8.8, 2.3 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.23 ( d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 9.0 Hz, 1H), 6.72 (d, J = 9.9 Hz, 0H), 6.65 (d, J = 2.4 Hz, 1H), 6.12 (tt, J = 55.3, 4.0 Hz, 1H), 4.87 ( dd, J = 8.3, 7.0 Hz, 2H), 4.71 (dd, J = 8.3, 5.0 Hz, 2H), 4.54 - 4.42 (m, 2H), 4 .38 - 4.31 (m, 1H), 4.26 (d, J = 13.8 Hz, 2H), 4.13 - 3.97 (m, 4H), 3.85 (s, 0H), 3.67 (s, 1H), 3.59 (s, 2H), 3.55 (s, 3H), 3.30 (s, 1H), 3.26 (s, 1H), 2.81 (d , J = 9.3 Hz, 2H), 2.70 (d, J = 9.4 Hz, 2H), 2.17 - 2.06 (m, 2H), 1.98 (d, J = 8, 6 Hz, 2H), 1.05 (s, 3H), 1.01 (s, 3H), 0.77 (s, 9H).

Example 7

Methyl-((5 S,8S,9S,14S)-11-(4-(1 -(2,2-difluoroethyl)-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy15 ,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-tetraazahexadecan-14yl)carbamate (7) .

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

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Example 8

Methyl-((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy15.15 -dimethyl-8-(4-((6-(( 1 R,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-tetraazahexadecan14-yl )carbamate (8).

Intermediates: I3, P10 and S6. MS (ESI) m/z 1101.6 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.16 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 9.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 8.8, 2.2 Hz, 1H), 7.25 (dd, J = 21.0, 8.1 Hz, 3H), 7.12 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 10.3 Hz, 0H), 6.64 (d, J = 2.4 Hz, 1H), 6. 58 (d, J = 8.8 Hz, 1H), 6.12 (tt, J = 55.2, 3.9 Hz, 1H), 4.96 (s, 1H), 4.91 - 4.82 (m, 1H), 4.61 (dd, J = 8.4, 4.6 Hz, 1H), 4.57 - 4.42 (m, 3H), 4.41 (s, 1H), 4, 35 (d, J = 6.5 Hz, 1H), 4.02 (d, J = 13.2 Hz, 2H), 3.87 (d, J = 13.2 Hz, 1H), 3.72 - 3.61 (m, 3H), 3.59 (s, 3H), 3.55 (s, 2H), 2.80 (d, J = 8.7 Hz, 1H), 2.70 (d, J = 9.5 Hz, 2H), 2.24 (s, 2H), 1.05 (s, 3H), 1.01 (s, 3H), 0.77 (s, 8H).

Example 9

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)-16,16,16- trifluoro9-hydroxy-15,15-dimethyl-8-(4-((6-(( 1 R,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-tetraazahexadecan-14-yl)carbamate (9).

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, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 7.1 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8 .0 Hz, 2H), 6.76 (d, J = 10.1 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 4.96 (s, 1H), 4, 61 (s, 1H), 4.49 (t, J = 8.9 Hz, 1H), 4.41 (s, 1H), 4.35 (d, J = 9.7 Hz, 1H), 4, 18 (d, J = 9.9 Hz, 1H), 4.09 (d, J = 13.1 Hz, 1H), 3.87 (d, J = 13.1 Hz, 1H), 3.77 - 3.55 (m, 8H), 2.82 (d, J = 8.5 Hz, 3H), 2.71 (d, J = 10.1 Hz, 1H), 2.54 (s, 3H), 2.23 (s, 2H), 1.05 (d, J = 7.7 Hz, 9H), 0.92 (s, 3H).

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Example 10

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

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, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.65 (d, J = 2, 5 Hz, 1H), 7.61 (dd, J = 8.9, 2.3 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 8.9 Hz, 1H), 6.72 (d, J = 10, 0 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.30 - 5.97 (m, 1H), 4.51 (td, J = 14.2, 3.9 Hz, 3H), 4.35 (d, J = 9.7 Hz, 1H), 4.22 (d, J = 10.0 Hz, 1H), 4.04 (d, J = 12.4 Hz, 4H), 3.60 (s, 3H), 3.57 (s, 3H), 3.48 (d, J = 11.0 Hz, 1H), 2.89 - 2.61 (m, 5H), 1.08 (s, 4H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H).

Example 11.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)-16,16,16- trifluoro9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl) ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl )carbamate (11).

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, 1H), 8.08 (d, J = 9.4 Hz, 1H), 7.60 (dd, J = 8.9, 2.3 Hz, 1H), 7.48 (d, J = 7.1 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.13 (d , J = 8.1 Hz, 2H), 7.08 (d, J = 10.5 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 6.73 (d, J = 9.9 Hz, 1H), 4.93 - 4.82 (m, 2H), 4.74 - 4.63 (m, 2H), 4.34 (d, J = 9.9 Hz, 1H) , 4.26 (d, J = 13.5 Hz, 1H), 4.18 (d, J = 10.0 Hz, 1H), 4.09 (d, J = 17.9 Hz, 4H), 3 .88 (d, J = 13.1 Hz, 1H), 3.64 (s, 1H), 3.60 (d, J = 2.9 Hz, 6H), 3.28 (d, J = 13, 8 Hz, 2H), 2.82 (d, J = 8.6 Hz, 3H), 2.75 - 2.62 (m, 1H), 2.54 (s, 3H), 2.22 - 2, 06 (m, 2H), 1.98 (d, J = 8.6 Hz, 2H), 1.06 (s, 6H), 1.04 (s, 3H), 0.93 (s, 3H).

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Example 12.

Methyl-((5S,8S,9S,14S)-Π-(4-(1-(difluoromethyl)-III-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy15,15-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-tetraazahexadecan-14yl)carbamate (12).

Intermediates: I3, P4 and S4. MS (ESI) m/z 1087.8 [M+H]+. 1H NMR (400 MHz, methanold4) δ 8.33 (s, 1H), 8.15 (d, J = 9.4 Hz, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.52 (t, J = 59.9 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.33 (d , J = 7.8 Hz, 3H), 7.22 (d, J = 7.9 Hz, 3H), 6.93 (d, J = 2.7 Hz, 1H), 6.78 (d, J = 9.2 Hz, 2H), 4.70 - 4.57 (m, 2H), 4.44 (d, J = 9.7 Hz, 1H), 4.13 (d, J = 12.4 Hz , 3H), 3.97 (d, J = 13.0 Hz, 1H), 3.76 (s, 1H), 3.69 (s, 4H), 3.65 (s, 3H), 2.90 (d, J = 8.7 Hz, 2H), 2.80 (d, J = 11.1 Hz, 2H), 2.11 (d, J = 10.6 Hz, 1H), 1.39 - 1 .23 (m, 2H), 1.15 (s, 4H), 1.11 (s, 4H), 0.86 (s, 11H).

Example 13

Methyl-((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-15,15dimethyl-3,6, 13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14yl)carbamate (13).

Intermediates: I3, P4 and S8. MS (ESI) m/z 1073.9 [M+H]+. ¹ H NMR (400 MHz, methanold4) δ 8.30 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 9.3 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.75 - 7.59 (m, 2H), 7.56 (dd, J = 7.4, 3.4 Hz, 1H), 7.53 (t, J = 59 .8 Hz, 2H), 7.45 (d, J = 8.2 Hz, 3H), 7.32 (d, J = 7.9 Hz, 3H), 7.22 (d, J = 8.1 Hz, 3H), 7.03 - 6.88 (m, 3H), 6.82 (d, J = 10.0 Hz, 1H), 4.62 (dd, J = 22.7, 13.0 Hz , 2H), 4.44 (d, J = 9.7 Hz, 1H), 4.12 (d, J = 12.2 Hz, 6H), 3.97 (d, J = 13.1 Hz, 2H ), 3.85 (t, J = 12.6 Hz, 1H), 3.76 (s, 2H), 3.69 (s, 4H), 3.59 (d, J = 10.8 Hz, 2H ), 3.01-2.70 (m, 6H), 1.14 (s, 4H), 1.11 (s, 4H), 0.86 (s, 12H).

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Example 14

Methyl-((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-3yl )pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11, 12tetraazahexadecan- 14-yl)carbamate (14).

Intermediates: I2, P17 and S3. MS (ESI) m/z 1176.1 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.20 (d, J = 2.3 Hz, 1H), 8.11 (d, J = 9.3 Hz, 1H), 7.68 - 7, 58 (m, 2H), 7.25 (dd, J = 13.9, 8.3 Hz, 4H), 7.12 (d, J = 8.0 Hz, 2H), 6.75 (dd, J = 17.1, 9.4 Hz, 2H), 6.59 (d, J = 2.4 Hz, 1H), 4.97 (dq, J = 8.2, 3.8 Hz, 1H), 4 .87 (t, J = 7.6 Hz, 3H), 4.71 (dd, J = 8.3, 5.0 Hz, 3H), 4.52 - 4.32 (m, 1H), 4, 32 - 4.18 (m, 3H), 4.17 - 3.99 (m, 6H), 3.97 (d, J = 4.7 Hz, 2H), 3.84 (td, J = 8, 3, 5.4 Hz, 2H), 3.58 (d, J = 9.5 Hz, 8H), 3.27 (d, J = 13.9 Hz, 3H), 2.80 - 2.52 ( m, 4H), 2.45 - 2.33 (m, 1H), 2.33 - 2.23 (m, 1H), 2.13 (d, J = 10.7 Hz, 2H), 2.03 - 1.92 (m, 2H), 1.07 (s, 4H), 1.05 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H).

Example 15

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-((R)-tetrahydrofuran-3-yl)-1Н-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-3yl )pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11, 12tetraazahexadecan-14-yl)carbamate (15).

Intermediates: I2, P18 and S3. MS (ESI) m/z 1176.1 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 8.11 (d, J = 9.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H ), 7.60 (d, J = 8.8 Hz, 1H), 7.25 (dd, J = 14.4, 8.2 Hz, 4H), 7.12 (d, J = 8.0 Hz , 2H), 6.74 (t, J = 10.2 Hz, 2H), 6.59 (d, J = 2.4 Hz, 1H), 4.98 (dd, J = 8.3, 3, 9 Hz, 1H), 4.69 (t, J = 6.7 Hz, 2H), 4.35 (d, J = 9.9 Hz, 1H), 4.22 (d, J = 10.0 Hz , 1H), 4.03 (dd, J = 14.5, 7.1 Hz, 3H), 3.97 (d, J = 4.7 Hz, 2H), 3.90 - 3.79 (m, 2H), 3.63 (s, 1H), 3.58 (d, J = 9.2 Hz, 6H), 2.81 (d, J = 7.8 Hz, 2H), 2.68 (d, J = 10.0 Hz, 1H), 2.49 - 2.33 (m, 1H), 2.33 - 2.21 (m, 1H), 2.10 (s, 1H), 1.94 (s , 0H), 1.07 (s, 3H), 1.05 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H).

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Example 16

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-ul)benzyl)16.16 ,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1 ]octan-3yl)pyridine -3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecane- 14-yl)carbamate (16).

Intermediates: I2, P19 and S3. MS (ESI) m/z 1177.2 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.20 (s, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.61 (s, 1H), 7.59 (d , J = 2.3 Hz, 2H), 7.25 (dd, J = 12.2, 8.1 Hz, 4H), 7.12 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 9.0 Hz, 1H), 6.72 (d, J = 10.2 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 4.87 (t , J = 7.6 Hz, 3H), 4.71 (dd, J = 8.3, 5.0 Hz, 2H), 4.35 (d, J = 9.9 Hz, 1H), 4.30 - 4.13 (m, 2H), 4.03 (d, J = 12.6 Hz, 3H), 3.84 (d, J = 13.3 Hz, 1H), 3.58 (d, J = 8.2 Hz, 5H), 3.28 (d, J = 13.9 Hz, 2H), 2.81 (d, J = 7.8 Hz, 2H), 2.72 (d, J = 15, 2 Hz, 1H), 2.12 (s, 1H), 1.98 (d, J = 8.6 Hz, 2H), 1.10 (s, 6H), 1.07 (s, 3H), 1 .05 (s, 3H), 1.01 (s, 3H), 0.93 (s, 3H).

ABOUT

Example 17.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrαzol-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-trifluoro9-hydroxy-15,15-dimethyl-3 ,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (17).

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, 1H), 8.22 - 8.13 (m, 2H), 8.11 (s, 1H), 7 .86 (dd, J = 9.3, 2.2 Hz, 1H), 7.50 (s, 1H), 7.40 - 7.30 (m, 2H), 7.23 (dd, J = 8 .2, 5.7 Hz, 4H), 7.17 (d, J = 9.9 Hz, 1H), 7.10 (d, J = 9.3 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H), 4.50 - 4.37 (m, 1H), 4.35 - 4.23 (m, 3H), 4.12 (t, J = 11.1 Hz, 2H) , 4.00 - 3.87 (m, 3H), 3.66 (d, J = 10.3 Hz, 7H), 3.43 - 3.33 (m, 2H), 2.96 (s, 6H ), 2.94 - 2.69 (m, 2H), 1.96 (t, J = 5.3 Hz, 2H), 1.78 (t, J = 6.9 Hz, 2H), 1.26 -1.07 (m, 9H), 1.02 (s, 3H).

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ABOUT

Example 18.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-III-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8diazabicyclo[3.2.1]octane-3 -yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2oxa-4,7,11,12-tetraazahexadecan-14-yl) carbamate (18).

Intermediates: I2, P7 and S25. MS (ESI) m/z 1177.2 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.44 (s, 1H), 8.13 - 8.05 (m, 2H), 8.03 (s, 1H), 7.68 (t, J = 8.5 Hz, 1H), 7.41 (s, 1H), 7.31 - 7.22 (m, 2H), 7.20 - 7.05 (m, 5H), 6.96 - 6, 84 (m, 1H), 6.72 (d, J = 10.0 Hz, 1H), 4.75 - 4.65 (m, 5H), 4.60 (dd, J = 7.6, 6, 2 Hz, 2H), 4.40 - 4.26 (m, 1H), 4.25 - 4.12 (m, 1H), 4.10 - 3.87 (m, 4H), 3.87 - 3 .71 (m, 3H), 3.58 (d, J = 10.7 Hz, 6H), 3.17 - 2.96 (m, 2H), 2.89 - 2.59 (m, 4H), 2.19 - 1.93 (m, 2H), 1.93 - 1.67 (m, 4H), 1.15 - 0.96 (m, 9H), 0.94 (s, 3H).

Example 19.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-III-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate ( 19).

Intermediates: I2, P7 and S26. MS (ESI) m/z 1177.2 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.54 (d, J = 0.7 Hz, 1H), 8.26 - 8.22 (m, 1H), 8.17 (d, J = 9 .4 Hz, 1H), 8.12 (s, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.51 (s, 1H), 7.39 - 7.32 (m , 2H), 7.24 (t, J = 8.3 Hz, 4H), 7.17 (d, J = 9.8 Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H ), 6.81 (d, J = 9.9 Hz, 1H), 4.80 (ddtd, J = 4.5, 2.0, 1.0, 0.5 Hz, 1H), 4.76 - 4.69 (m, 4H), 4.50 - 4.37 (m, 1H), 4.36 4.25 (m, 1H), 4.13 (t, J = 10.7 Hz, 3H), 3.93 (d, J = 13.2 Hz, 1H), 3.68 (d, J = 10.5 Hz, 6H), 2.97 - 2.66 (m, 6H), 2.33 - 2 .10 (m, 3H), 1.26-1.08 (m, 9H), 1.03 (s, 3H).

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Example 20.

Methyl-((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-dimethyl3,6,13-trioxo -5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (20).

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

Example 21.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(2,2-difluoroethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro -9-hydroxy-15,15-dimethyl-8-(4-((6-(9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin3-yl)ethynyl )benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl) carbamate (21).

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, 1H), 8.06 (d, J = 9.3 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.58 (dd, J = 8.9, 2.3 Hz, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.23 (d , J = 8.0 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.02 (d, J = 9.7 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 6.71 - 6.61 (m, 2H), 6.12 (tt, J = 55.4, 4.0 Hz, 1H), 4.50 (td, J = 14.3, 3.9 Hz, 2H), 4.34 (d, J = 9.6 Hz, 1H), 4.29 - 4.18 (m, 1H), 4.04 (d, J = 13 .0 Hz, 6H), 3.84 (d, J = 13.2 Hz, 1H), 3.63 (s, 3H), 3.56 (s, 3H), 3.50 (s, 2H), 3.10 (s, 3H), 2.81 (d, J = 8.1 Hz, 2H), 2.69 (d, J = 9.4 Hz, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H).

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Example 22.

Methyl-((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-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-tetraazahexadecan-14-yl)carbamate (22).

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, 1H), 7.70 (dd, J = 8.8, 2.3 Hz, 1H), 7, 61 (d, J= 2.3 Hz, 1H), 7.33 (d, J= 7.7 Hz, 5H), 7.23 (d, J= 7.8 Hz, 2H), 6.86 ( d, J = 8.9 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.82 4.77 (m, 2H), 4.35 (d, J = 13.8 Hz, 2H), 4.13 (d, J = 13.4 Hz, 4H), 3.93 (s, 6H), 3.67 (d, J=6.4 Hz, 8H), 3.38 (d, J= 13.9 Hz, 2H), 3.00 - 2.77 (m, 5H), 2.31 - 2.20 ( m, 2H), 2.14 - 2.04 (m, 2H), 0.87 (d, J = 20.7 Hz, 21H).

Example 23.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-9-hydroxy15,15-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-tetraazahexadecan-14yl)carbamate (23).

Intermediates: I3, P4 and S7. MS (ESI) m/z 1102.5 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.53 (s, 2H), 8.20 (d, J = 9.4 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.53 (t, J = 59.9, 59.4 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H ), 7.23 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 2.8 Hz, 1H), 6.83 (d, J = 9.9 Hz, 1H), 5.03 - 4.92 (m, 2H), 4.83 - 4.76 (m, 2H), 4.44 (d, J = 10.0 Hz, 1H), 4.16 - 4.05 ( m, 2H), 3.97 (d, J = 13.2 Hz, 1H), 3.85 - 3.71 (m, 1H), 3.69 (s, 3H), 3.65 (s, 3H ), 3.54 - 3.39 (m, 2H), 2.96 - 2.72 (m, 3H), 2.27 - 2.13 (m, 2H), 2.04 - 1.91 (m , 2H), 1.14 (s, 3H), 1.11 (s, 3H), 0.86 (s, 9H).

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Example 24.

Methyl-((5 S,8S,9S,14S)-11 -(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15-dimethyl -8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5yl)ethynyl)benzyl )-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate ( 24).

Intermediates: I2, P16 and S29. MS (ESI) m/z 1104.3 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.87 (d, J = 4.9 Hz, 2H), 8.52 (s, 2H), 8.19 (d, J = 9.5 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.41 (t, J = 4.9 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H) , 7.24 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 10.1 Hz, 1H), 6.82 (d, J = 10.1 Hz, 1H), 5 .18 (s, 1H), 4.99 - 4.90 (m, 2H), 4.64 - 4.55 (m, 1H), 4.44 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.24 - 4.10 (m, 2H), 3.98 (d, J = 13.0 Hz, 1H), 3.90 (d , J = 12.5 Hz, 1H), 3.85 - 3.72 (m, 3H), 3.69 (s, 3H), 3.67 (s, 3H), 2.96 2.74 (m , 4H), 2.33 (s, 2H), 1.15 (s, 6H), 1.11 (s, 3H), 1.02 (s, 3H).

Example 25.

Methyl-((5S,8S,9S,14S)-11-(4-(1 -(2,2-difluoroethyl)-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16.16 ,16trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane -2yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa4,7,11, 12-tetraazahexadecan-14-yl)carbamate (25).

Intermediates: I2, P10 and S29. MS (ESI) m/z 1156.4 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.52 (s, 2H), 8.18 (d, J = 9.3 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.8 Hz, 1H) , 6.81 (d, J = 9.9 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.22 (tt, J = 55.5, 4.0 Hz, 1H), 5.18 (s, 1H), 5.01 - 4.90 (m, 2H), 4.72 (s, 1H), 4.60 (td, J = 14.1, 3.7 Hz , 4H), 4.52 (s, 0H), 4.44 (d, J = 9.9 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.20 - 4 .07 (m, 2H), 3.98 - 3.86 (m, 2H), 3.81 (d, J = 12.8 Hz, 1H), 3.76 - 3.71 (m, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 3.00-2.71 (m, 4H), 2.34 (s, 2H), 1.16 (s, 3H), 1 .14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

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Example 26.

Methyl-((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)-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy15,15-dimethyl-3 ,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (26).

Intermediates: 12, P4 and S28. MS (ESI) m/z 1115.4 [M+H] ⁺ . 1H NMR (400 MHz, ^methanol 4) 5 8.17 (d, J = 2.3 Hz, 1H), 8.07 (d, J = 9.4 Hz, 1H), 8.01 (d, J = 2.8 Hz, 1H), 7.56 (dd, J = 8.8, 2.4 Hz, 1H), 7.44 (t, J = 59.9 Hz, 1H), 7.36 (d , J = 8.3 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 2.7 Hz, 1H), 6.78 (d, J = 9.1 Hz, 1H), 6.69 (d, J = 10.0 Hz, 1H), 4.70 - 4.61 (m , 2H), 4.34 (d, J = 9.8 Hz, 1H), 4.21 (d, J = 10.0 Hz, 1H), 4.08 - 4.00 (m, 4H), 3 .94 (d, J = 13.0 Hz, 2H), 3.85 (d, J = 13.1 Hz, 1H), 3.64 (s, 1n), 3.60 (s, 3H), 3 .58 -3.54 (m, 4H), 3.42 (d, J = 14.4 Hz, 3H), 2.85 - 2.62 (m, 4H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H).

Example 27.

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

Intermediates: l2, P3 and S6. MS (ESI) m/z 1149.3 [M+H]+. ¹ H NMR (400 MHz, methanold4) δ 8.16 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 9.4 Hz, 1H), 7.60 (dd, J = 8.8, 2.3 Hz, 1H), 7.42 (d, J = 7.5 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 10.1 Hz, 1H), 6.71 (d, J = 10.0 Hz, 1H), 6.56 (d, J = 8.8 Hz, 1H), 4.96 (s, 1H), 4.92 - 4.78 (m, 2H), 4.61 (s, 1H), 4.55 - 4.44 (m, 1H ), 4.41 (s, 1H), 4.34 (d, J = 9.8 Hz, 1H), 4.19 (d, J = 10.0 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.87 (d, J = 13.1 Hz, 1H), 3.72 - 3.61 (m, 2H), 3.60 (s, 3H), 3.58 (s, 3H), 2.89 - 2.75 (m, 3H), 2.73 - 2.61 (m, 1H), 2.43 (δ, J = 13.1, 8.5, 4.9 Hz, 1H), 2.23 (s, 2H), 1.27-1.18 (m, 2H), 1.10-1.01 (m, 11H), 0.93 (s, 3H).

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Example 28.

Methyl-((5 S,8S,9S,14S)-11-(4-(1-cyclopropyl-1 H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15- dimethyl-8-(4-((6-(( 1 R,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-tetraazahexadecan-14yl) carbamate (28).

Intermediates: I2, P21 and S6. MS (ESI) m/z 1095.8 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.16 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 9.5 Hz, 1H), 7.62 - 7, 57 (m, 3H), 7.56 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.04 (s, 1H), 6.67 (d, J = 9.7 Hz, 1H), 6.56 ( d, J = 8.8 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 4.96 (s, 1H), 4.89 - 4.83 (m, 1H), 4.84 - 4.78 (m, 1H), 4.65 - 4.54 (m, 1H), 4.54 - 4.44 (m, 2H), 4.41 (s, 1H), 4, 30 (d, J = 9.9 Hz, 1H), 4.16 (d, J = 9.7 Hz, 1H), 4.12 - 4.00 (m, 1H), 3.88 (d, J = 13.2 Hz, 1H), 3.78 (d, J = 13.5 Hz, 1H), 3.73 - 3.60 (m, 2H), 3.60 - 3.53 (m, 4H) , 3.51 (s, 3H), 2.87 2.76 (m, 2H), 2.76 -2.59 (m, 2H), 2.23 (s, 2H), 1.07 - 0, 94 (m, 10H), 0.92 (s, 3H), 0.72 (s, 3H).

Example 29.

Methyl-((5 S,8S,9S,14S)-11-(4-(1 -(difluoromethyl)-1 H-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)pyridine- 3yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecane-14 -yl)carbamate (29).

Intermediates: I2, P6 and S6. MS (ESI) m/z 1105.9 [M+H] ⁺ . ¹ H NMR (400 MHz, methanold4) δ 8.25 (d, J = 2.2 Hz, 1H), 8.11 (d, J = 9.3 Hz, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.69 (dd, J = 8.8, 2.3 Hz, 1H), 7.49 (t, J = 59.7 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 9.4 Hz, 1H), 6.86 (d, J = 2.7 Hz, 1H), 6.77 (d, J = 9, 9 Hz, 1H), 6.66 (d, J = 8.7 Hz, 1H), 5.05 (s, 1H), 4.95 (dd, J = 8.4, 6.5 Hz, 1H) , 4.93 - 4.87 (m, 1H), 4.70 (dd, J = 8.5, 4.6 Hz, 1H), 4.66 - 4.53 (m, 2H), 4.50 (s, 1H), 4.40 (d, J = 9.9 Hz, 1H), 4.24 (d, J = 9.8 Hz, 1H), 4.21 - 4.12 (m, 1H) , 4.01 (d, J = 13.2 Hz, 1H), 3.88 (d, J = 13.2 Hz, 1H), 3.82 - 3.69 (m, 2H), 3.68 ( s, 3H), 3.59 (s, 3H), 2.96-2.66 (m, 4H), 2.33 (s, 2H), 1.12 (s, 3H), 1.10 (s , 3H), 1.02 (s, 3H), 0.83 (s, 3H).

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Example 30.

Methyl-((5S,8S,9S, 14S)-11-(4-(1-cyclopropyl-1 H-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)pyrimidin5-yl)ethynyl )benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl) carbamate (30).

Intermediates: I2, P21 and S29. MS (ESI) m/z 1096.7 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.51 (s, 2H), 8.10 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H ), 7.65 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 6.76 (d, J = 10.1 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 5. 18 (s, 1H), 4.93 (dt, J = 20.6, 7.3 Hz, 1H), 4.72 (s, 1H), 4.65-4.55 (m, 1H), 4 .51 (s, 0H), 4.40 (d, J = 7.8 Hz, 1H), 4.25 (d, J = 7.8 Hz, 1H), 4.15 (s, 1H), 4 .02 - 3.78 (m, 3H), 3.67 (s, 3H), 3.66 (d, J = 3.8 Hz, 1H), 3.59 (s, 3H), 2.94 - 2.67 (m, 4H), 2.41-2.30 (m, 2H), 2.05-1.99 (m, 1H), 1.93 (s, 1H), 1.15-1, 04 (m, 10H), 1.01 (s, 3H), 0.81 (s, 3H).

Example 31.

Methyl-((5S,8S,9S, 14S)-11-(4-(1-cyclopropyl-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy- 15,15-dimethyl-8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2yl)pyrimidin-5- yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa4,7,11,12-tetraazahexadecan-14-yl )carbamate (31).

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

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F

Example 32.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2yl)pyrimidin-5 -yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa4,7,11,12-tetraazahexadecane-14- yl) carbamate (32).

Intermediates: I2, P4 and S29. MS (ESI) m/z 1142.4 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.51 (s, 2H), 8.14 (d, J = 9.3 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H ), 7.52 (t, J = 59.9 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 9.6 Hz, 1H), 6.93 (d, J = 2.7 Hz, 1H), 6. 78 (d, J = 9.9 Hz, 1H), 5.18 (s, 1H), 4.93 (dt, J = 20.5, 7.3 Hz, 2H), 4.71 (s, 1H ), 4.60 (dq, J = 11.6, 6.2, 5.6 Hz, 2H), 4.51 (s, 1H), 4.44 (d, J = 9.8 Hz, 1H) , 4.30 (d, J = 9.9 Hz, 1H), 4.21 - 4.05 (m, 2H), 3.94 (d, J = 13.5 Hz, 1H), 3.90 ( d, J = 12.9 Hz, 1H), 3.80 (d, J = 12.6 Hz, 1H), 3.77 - 3.70 (m, 2H), 3.68 (s, 3H), 3.66 (s, 3H), 2.96-2.72 (m, 4H), 2.44-2.24 (m, 2H), 1.16 (s, 3H), 1.14 (s, 3H ), 1.11 (s, 3H), 1.02 (s, 3H).

Example 33.

Methyl-((5S,8S,9S, 14S)-11-(4-(1-cyclopropyl-1 H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9hydroxy-15,15-dimethyl -8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5yl)ethynyl)benzyl)-3.6, 13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (33).

Intermediates: I2, P21 and S7. MS (ESI) m/z 1142.4 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.52 (s, 2H), 8.10 (d, J = 9.5 Hz, 1H), 7.68 (d, J = 8.1 Hz, 2H ), 7.64 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 9.5 Hz, 1H), 6.75 (d, J = 9.7 Hz, 1H), 6. 56 (d, J = 2.4 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.82 - 4.71 (m, 3H), 4.39 (d, J = 9.9 Hz, 1H), 4.24 (d, J = 9.7 Hz, 1H), 4.20 - 4.06 (m, 2H), 3.97 (d, J = 13.2 Hz , 1H), 3.87 (d, J = 13.4 Hz, 1H), 3.77 - 3.71 (m, 1H), 3.67 (s, 4H), 3.59 (s, 3H) , 3.45 (d, J = 14.6 Hz, 2H), 2.93 - 2.86 (m, 2H), 2.85 - 2.67 (m, 1H), 2.31 - 2.15 (m, 2H), 2.06-1.93 (m, 2H), 1.15-1.03 (m, 10H), 1.01 (s, 3H), 0.82 (s, 3H).

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Example 34.

Methyl-((5S,8S,9S, 14S)-11-(4-(1-cyclopropyl-1 H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9hydroxy-15,15-dimethyl -8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)ethynyl)benzyl)-3.6, 13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (34).

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, 1H), 8.03 (d, J = 9.5 Hz, 1H), 7.66 - 7.58 (m, 3H), 7.56 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.9 Hz , 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 9.5 Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H ), 6.68 (d, J = 10.0 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 4.92 - 4.82 (m, 2H), 4.74 - 4.66 (m, 2H), 4.34 - 4.21 (m, 3H), 4.18 - 4.12 (m, 1H), 4.11 - 3.99 (m, 3H), 3 .88 (d, J = 13.1 Hz, 1H), 3.78 (d, J = 13.3 Hz, 1H), 3.65 (d, J = 9.0 Hz, 1H), 3.60 - 3.53 (m, 4H), 3.51 (s, 3H), 3.28 (d, J = 13.8 Hz, 2H), 2.86 - 2.76 (m, 2H), 2, 76 - 2.56 (m, 2H), 2.17 - 2.08 (m, 2H), 2.03 - 1.92 (m, 2H), 1.07 - 0.89 (m, 13H), 0.72 (s, 3H).

Example 35.

Methyl-((5S,8S,9S, 14S)-11-(4-(1-cyclopropyl-1 H-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-3yl)ethynyl)benzyl) -3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (35 ).

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, 1H), 8.16 (d, J = 9.4 Hz, 1H), 7.73 (dd, J = 9.0, 2.3 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.41 - 7.26 (m, 4H), 7.21 ( d, J = 8.2 Hz, 2H), 7.13 (d, J = 9.8 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 6.79 (d, J = 9.9 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 4.64 (d, J = 14.7 Hz, 2H), 4.53 - 4.41 ( m, 1H), 4.35 - 4.25 (m, 1H), 4.22 - 4.06 (m, 7H), 3.93 (d, J = 13.2 Hz, 1H), 3.78 (dt, J = 14.9, 3.0 Hz, 2H), 3.73 - 3.67 (m, 4H), 3.66 (s, 3H), 3.63 (s, 2H), 3, 19 (s, 3H), 2.94-2.72 (m, 4H), 1.21-0.99 (m, 16H).

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Example 36.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(2,2-difluoroethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro -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-4,7,11,12tetraazahexadecane-14- yl) carbamate (3 6).

Intermediates: I2, P10 and S7. MS (ESI) m/z 1170.9 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.53 (s, 2H), 8.19 (d, J = 9.3 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H ), 7.37 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 10.0 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6. 22 (tt, J = 55.3, 4.0 Hz, 1H), 5.02 - 4.93 (m, 2H), 4.83 - 4.78 (m, 2H), 4.77 (s, 1H), 4.60 (td, J = 14.3, 3.9 Hz, 2H), 4.44 (d, J = 10.0 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.22 - 4.03 (m, 4H), 3.93 (d, J = 13.2 Hz, 1H), 3.72 (s, 2H), 3.69 (s, 3H ), 3.66 (s, 3H), 3.51 - 3.40 (m, 2H), 2.96 - 2.81 (m, 3H), 2.81 - 2.72 (m, 1H), 2.27 - 2.12 (m, 2H), 2.04 - 1.94 (m, 2H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

Example 37.

Methyl-((5S,8S,9S, 14S)-11-(4-(1-cyclopropyl-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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-4,7,11,12tetraazahexadecan-14-yl)carbamate (3 7).

Intermediates: I2, P13 and S7. MS (ESI) m/z 1146.9 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.43 (s, 2H), 8.10 (d, J = 9.3 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H ), 7.25 (d, J = 8.0 Hz, 4H), 7.14 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 10.1 Hz, 1H), 6.72 (d, J = 10.0 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 4.93 - 4.82 (m, 2H), 4.75 - 4 .57 (m, 4H), 4.45-4.28 (m, 1H), 4.22 (d, J = 10.0 Hz, 1H), 4.14-3.97 (m, 4H), 3.83 (d, J = 13.2 Hz, 1H), 3.71 -3.61 (m, 1H), 3.59 (s, 3H), 3.57 (s, 3H), 3.42 - 3.32 (m, 2H), 2.86 - 2.63 (m, 4H), 2.17 - 2.05 (m, 2H), 1.94 - 1.82 (m, 2H), 1 .12 -1.06 (m, 3H), 1.06-0.95 (m, 10H), 0.93 (s, 3H).

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Example 38.

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

Intermediates: I2, P22 and S4. MS (ESI) m/z 1254.4 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.31 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.62 - 7.51 (m, 1H), 7.23 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 9.0 Hz, 1H), 6.60 (d, J = 8.9 Hz, 1H), 4.66 (t, J = 6.5 Hz, 4H), 4.40 - 4.31 (m, 6H), 4.04 (d, J = 12.6 Hz, 2H), 3, 89 - 3.80 (m, 3H), 3.77 (t, J = 6.3 Hz, 4H), 3.61 (d, J = 1.2 Hz, 3H), 3.57 (s, 3H ), 3.48 (d, J = 13.4 Hz, 8H), 2.89 - 2.55 (m, 6H), 1.57 (t, J = 8.8 Hz, 2H), 1.24 - 1.13 (m, 3H), 1.08 (s, 3H), 1.06 (s, 3H), 1.03 (s, 3H), 0.95 (s, 3H).

Example 39.

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

Intermediates: I2, P13 and S30. MS (ESI) m/z 1131.5 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.16 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 2.4 Hz, 2H), 7.59 (d, J = 2.2 Hz, 1H), 7.29 - 7.19 (m, 5H), 7.12 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 10.0 Hz, 1H), 6.63 - 6.52 (m, 2H), 4.95 (s, 1H), 4.89 4.83 ( m, 1H), 4.65 - 4.56 (m, 1H), 4.54 - 4.43 (m, 2H), 4.41 (s, 1H), 4.35 (d, J = 9, 9 Hz, 1H), 4.22 (d, J = 9.9 Hz, 1H), 4.12 - 3.97 (m, 2H), 3.83 (d, J = 13.2 Hz, 1H) , 3.70 (d, J = 11.8 Hz, 1H), 3.65 - 3.61 (m, 1H), 3.59 (s, 3H), 3.57 (s, 3H), 2, 86-2.60(m, 4H), 2.23(s, 2H), 1.10-0.95(m, 13H), 0.93(s, 3H).

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Example 40.

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

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, 1H), 8.09 (d, J = 9.5 Hz, 1H), 7.64 (dd, J = 8.8, 2.3 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.4, 3.3 Hz, 4H), 7 .12 (d, J = 8.1 Hz, 2H), 6.68 (d, J = 8.9 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 4.93 - 4.83 (m, 2H), 4.51 (dd, J = 8.2, 4.0 Hz, 2H), 4.34 (s, 1H), 4.27 - 4.18 (m, 1H ), 4.12 - 3.94 (m, 4H), 3.83 (d, J = 13.2 Hz, 1H), 3.65 - 3.60 (m, 1H), 3.59 (s, 3H), 3.56 (s, 3H), 2.85 - 2.62 (m, 4H), 2.01 (d, J = 11.0 Hz, 1H), 1.18 (d, J = 13 .9 Hz, 1H), 1.10-0.94 (m, 13H), 0.92 (s, 3H).

Example 41.

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

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, 1H), 8.10 (d, J = 9.3 Hz, 1H), 7.69 - 7.60 (m, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.1 Hz , 2H), 6.69 (d, J = 9.0 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.13 (tt, J = 55.3, 3, 9 Hz, 1H), 4.58 - 4.42 (m, 4H), 4.35 (s, 1H), 4.27 - 4.18 (m, 1H), 4.16 - 3.95 (m , 4H), 3.84 (d, J = 13.3 Hz, 1H), 3.63 (s, 2H), 3.60 (s, 3H), 3.57 (s, 3H), 2.86 - 2.72 (m, 3H), 2.72 - 2.58 (m, 1H), 2.02 (d, J = 11.0 Hz, 1H), 1.19 (d, J = 13.9 Hz, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H).

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Example 42.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((2-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3yl)pyrimidin-5-yl)ethynyl)benzyl )-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa4,7,11,12-tetraazahexadecan-14-yl)carbamate (42) .

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

Example 43.

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

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, 1H), 8.19 (d, J = 9.4 Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.69 (dd, J = 8.6, 2.3 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.32 (d , J = 7.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 9.9 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 6.39 - 6.05 (m, 1H), 5.06 - 5.02 (m, 1H) , 4.74 - 4.67 (m, 1H), 4.65 4.53 (m, 2H), 4.50 (s, 1H), 4.44 (d, J = 9.9 Hz, 1H) , 4.31 (d, J = 10.0 Hz, 1H), 4.13 (d, J = 13.4 Hz, 2H), 3.93 (d, J = 13.3 Hz, 1H), 3 .83 - 3.72 (m, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 2.94 - 2.72 (m, 2H), 2.33 (s, 2H ), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H).

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Example 44.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((6-(9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin3 -yl)ethynyl)benzyl)- 3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (44) .

Intermediates: I2, P4 and S2. MS (ESI) m/z 1130.0 [M+H]+. 1H NMR (400 MHz, methanold4) δ 8.18 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 9.3 Hz, 1H), 8.01 (d, J = 2 .7 Hz, 1H), 7.58 (dd, J = 9.2, 2.6 Hz, 1H), 7.44 (t, J = 59.7 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.09 - 7.00 (m , 1H), 6.85 (d, J = 2.8 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 6.72 (d, J = 10.0 Hz, 1H ), 4.35 (d, J = 9.9 Hz, 1H), 4.21 (d, J = 9.9 Hz, 1H), 4.13 - 3.94 (m, 5H), 3.85 (d, J = 13.2 Hz, 1H), 3.71 - 3.63 (m, 3H), 3.60 (s, 3H), 3.57 (s, 3H), 3.51 (s, 2H), 3.10 (s, 3H), 2.88-2.73 (m, 3H), 2.73-2.64 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 45.

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

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, 1H), 8.10 (d, J = 9.3 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.30 - 7.19 (m, 4H), 7.12 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 10.0 Hz, 1H) , 6.72 (d, J = 9.9 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 4 .96 (s, 1H), 4.86 (dd, J = 8.3, 6.4 Hz, 1H), 4.61 (dd, J = 8.5, 4.6 Hz, 1H), 4, 56 - 4.44 (m, 2H), 4.42 (s, 1H), 4.35 (d, J = 9.8 Hz, 1H), 4.22 (d, J = 10.0 Hz, 1H ), 4.08 - 3.98 (m, 2H), 3.83 (d, J = 13.2 Hz, 1H), 3.73 - 3.61 (m, 4H), 3.59 (s, 3H), 3.57 (s, 3H), 2.85-2.72 (m, 2H), 2.72-2.62 (m, 1H), 2.24 (s, 2H), 1.07 (s, 3H), 1.06-0.94 (m, 10H), 0.93 (s, 3H).

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Example 46.

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

Intermediates: I2, P10 and S3. MS (ESI) m/z 1169.4 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.30 (d, J = 2.3 Hz, 1H), 8.19 (d, J = 9.3 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 8.9, 2.3 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.33 ( d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.19 - 7.12 (m, 1H), 6.86 (d, J = 8 .9 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.22 (tt, J = 55.5 , 4.2 Hz, 1H), 4.97 (t, J = 7.6 Hz, 3H), 4.80 (dd, J = 8.2, 5.0 Hz, 2H), 4.60 (td , J = 14.2, 3.9 Hz, 2H), 4.44 (d, J = 9.9 Hz, 1H), 4.36 (d, J = 13.6 Hz, 2H), 4.31 (d, J = 10.0 Hz, 1H), 4.19 - 4.10 (m, 4H), 3.93 (d, J = 13.2 Hz, 1H), 3.77 - 3.71 ( m, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 3.37 (d, J = 13.8 Hz, 2H), 2.96 - 2.69 (m, 4H ), 2.29 -2.16 (m, 2H), 2.16 -2.03 (m, 2H), 1.17 (s, 3H), 1.14 (s, 3H), 1.11 ( s, 3H), 1.03 (s, 3H).

Example 47.

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

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, 1H), 8.16 - 8.10 (m, 2H), 8.09 (d, J = 8, 7 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.54 (t, J = 59.5 Hz, 1H), 7.52 (d, J = 9.6 Hz , 1H), 7.50 - 7.43 (m, 4H), 7.30 (d, J = 8.0 Hz, 2H), 7.22 - 7.13 (m, 1H), 6.95 ( d, J = 2.8 Hz, 1H), 6.85 (d, J = 10.0 Hz, 1H), 4.99 (t, J = 7.6 Hz, 2H), 4.84 (dd, J = 8.3, 5.0 Hz, 2H), 4.65 (d, J = 14.1 Hz, 2H), 4.45 (d, J = 9.9 Hz, 1H), 4.31 ( d, J = 9.9 Hz, 1H), 4.27 - 4.11 (m, 4H), 3.95 (d, J = 13.2 Hz, 1H), 3.84 - 3.74 (m , 1H), 3.71 (s, 3H), 3.67 (s, 3H), 2.99-2.83 (m, 3H), 2.83-2.74 (m, 1H), 2, 30-2.19 (m, 2H), 2.17 -2.06 (m, 2H), 1.17 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H) , 1.04 (s, 3H).

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Example 48.

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

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, 1H), 8.10 (d, J = 9.4 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.44 (t, J = 60.3 Hz, 1H), 7.36 (d, J = 8.2 Hz , 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 9.8 Hz, 1H ), 6.85 (d, J = 2.8 Hz, 1H), 6.73 (d, J = 10.6 Hz, 1H), 6.70 (d, J = 9.0 Hz, 1H), 5.55 - 5.45 (m, 1H), 5.00 - 4.83 (m, 4H), 4.35 (d, J = 9.9 Hz, 1H), 4.21 (d, J = 10.0 Hz, 1H), 4.14 (s, 2H), 4.12 - 3.94 (m, 4H), 3.85 (d, J = 13.2 Hz, 1H), 3.71 - 3.62 (m, 2H), 3.59 (d, J = 1.2 Hz, 3H), 3.57 (d, J = 1.5 Hz, 3H), 3.50 (d, J = 2 .0 Hz, 1H), 3.46 (s, 3H), 2.88 - 2.73 (m, 3H), 2.73 - 2.63 (m, 1H), 2.49 - 2.38 ( m, 1.5H), 2.28 (d, J = 11.3 Hz, 0.5H), 2.20 2.05 (m, 2H), 1.06 (s, 3H), 1.05 ( s, 3H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 49.

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

Intermediates: I2, P4 and S32. MS (ESI) m/z 1z2z.4 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.20 (d, J = 9.4 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.53 (t, J = 59.6 Hz, 1H), 7.50 - 7.40 (m, 4H), 7.20 7.11 (m, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.75 (d, J = 9.7 Hz, 1H), 5.00 - 4.91 (m, 4H), 4.83 - 4.68 (m, 4H), 4.54 4.39 (m , 3H), 4.33 - 4.27 (m, 1H), 4.21 - 4.04 (m, 6H), 3.94 (d, J = 13.1 Hz, 1H), 3.71 ( s, 3H), 3.66 (s, 3H), 3.51 - 3.39 (m, 5H), 3.00 - 2.72 (m, 4H), 2.37 - 2.11 (m, 4H), 2.03-1.84 (m, 4H), 1.16 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H), 1.03 (s, 3H ).

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F

Example 50.

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

Intermediates: I2, P4 and S33. MS (ESI) m/z 1156.5 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.34 (d, J = 1.3 Hz, 1H), 8.25 (s, 1H), 8.16 (d, J = 9.3 Hz, 1H ), 8.10 (d, J = 2.7 Hz, 1H), 7.53 (t, J = 59.4 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 2.8 Hz, 1H), 4, 97 (t, J = 7.6 Hz, 2H), 4.82 - 4.76 (m, 2H), 4.47 - 4.36 (m, 3H), 4.30 (d, J = 9, 9 Hz, 1H), 4.23 - 4.10 (m, 4H), 3.95 (d, J = 12.9 Hz, 1H), 3.78 - 3.72 (m, 1H), 3, 69 (s, 3H), 3.66 (s, 3H), 3.46 (d, J = 14.0 Hz, 3H), 2.96-2.71 (m, 4H), 2.27-2 .20 (m, 1H), 2.14 - 2.02 (m, 2H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1, 03 (s, 3H).

F

Example 51.

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

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, 1H), 8.08 (d, J = 9.4 Hz, 1H), 8.01 (d, J = 2, 7 Hz, 1H), 7.61 (dd, J = 8.8, 2.3 Hz, 1H), 7.44 (t, J = 59.7 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 6.89 - 6.79 (m, 2H), 4.60 - 4.44 (m, 1H), 4.34 (s, 1H), 4.25 - 4.18 (m, 1H), 4.11 - 3.98 (m, 4H) , 3.85 (d, J = 13.2 Hz, 1H), 3.76 (t, J = 12.6 Hz, 1H), 3.68 - 3.62 (m, 1H), 3.60 ( s, 3H), 3.57 (s, 3H), 3.54 - 3.35 (m, 2H), 2.85 - 2.74 (m, 4H), 2.73 - 2.64 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H).

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ABOUT

Example 52.

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

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

Example 53.

Methyl-((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-5( 1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (53).

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, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 9.3 Hz, 1H), 7.91 (s, 2H), 7.70 (dd, J = 8.7, 2.3 Hz, 1H), 7.60 (d, J = 8.5 Hz , 2H), 7.33 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.9 Hz, 1H ), 6.77 (d, J = 10.5 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.82 - 4.76 (m, 4H), 4.40 (dd, J = 33.8, 12.0 Hz, 3H), 4.16 (d, J = 12.1 Hz, 4H), 4.00 (d, J = 13.3 Hz, 1H), 3 .79 - 3.60 (m, 9H), 3.37 (d, J = 14.0 Hz, 3H), 2.95-2.77 (m, 4H), 2.22 (s, 2H), 2.08 (d, J = 8.7 Hz, 2H), 1.13 (d, J = 11.3 Hz, 6H), 0.86 (s, 10H).

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Example 54.

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

The title compound 54 was obtained according to the method described for the synthesis of compound 52, but using compound 112. MS (ESI) m/z 1145.9 [M+H]+. 1H NMR (400 MHz, methanold4) δ 8.31 (d, J = 2.2 Hz, 1H), 8.19 - 8.05 (m, 2H), 7.77 - 7.59 (m, 2H) , 7.59 - 7.51 (m, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.39 - 7.30 (m, 3H), 7.22 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 10.0 Hz, 1H), 7.01 - 6.88 (m, 2H), 6.77 (d, J = 9.9 Hz , 1H), 5.14 - 5.00 (m, 3H), 4.94 (dd, J = 8.1, 6.7 Hz, 2H), 4.47 (dd, J = 25.9, 10 .4 Hz, 3H), 4.37 - 4.24 (m, 1H), 4.14 (d, J = 13.0 Hz, 2H), 3.95 (d, J = 13.2 Hz, 1H ), 3.87 - 3.57 (m, 14H), 2.98 - 2.67 (m, 4H), 1.25 - 1.06 (m, 10H), 1.02 (s, 3H).

F

Example 55.

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

Intermediates: I2, P4 and S9. MS (ESI) m/z 1129.9 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.21 (dd, J = 2.2, 0.8 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.61 (dd , J = 8.9, 2.3 Hz, 1H), 7.44 (t, J = 59.6 Hz, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 6.90 - 6.83 (m, 2H), 4.60 - 4.44 ( m, 1H), 4.34 (s, 1H), 4.21 (s, 1H), 4.14 - 3.98 (m, 4H), 3.85 (d, J = 13.1 Hz, 1H ), 3.76 (t, J = 12.6 Hz, 1H), 3.67 - 3.62 (m, 1H), 3.60 (s, 3H), 3.57 (s, 3H), 3 .54 - 3.35 (m, 2H), 2.88 - 2.73 (m, 4H), 2.73 - 2.66 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H).

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Example 56.

Methyl-((5S,8S,9S,14S)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl) -3,8diazabicyclo[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-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (56).

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, 1H), 8.41 (t, J = 8.0 Hz, 1H), 8.36 - 8.25 (m, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 9.5 Hz, 1H), 7.88 (d, J = 8.0 Hz , 2H), 7.81 (t, J = 6.6 Hz, 1H), 7.74 - 7.63 (m, 3H), 7.33 (d, J = 7.9 Hz, 2H), 7 .23 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 9.9 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.81 (d, J = 9.8 Hz, 1H), 4.96 (dd, J = 8.1, 7.1 Hz, 2H), 4.81 (dd, J = 8.2, 5.0 Hz, 2H), 4.44 - 4.30 (m, 3H), 4.24 (d, J = 9.6 Hz, 1H), 4.16 (s, 2H), 4.08 (d, J = 13 .6 Hz, 1H), 3.99 (d, J = 13.4 Hz, 1H), 3.76 (s, 1H), 3.68 (s, 3H), 3.56 (s, 3H), 3.38 (d, J = 13.7 Hz, 2H), 2.98 - 2.72 (m, 3H), 2.27 - 2.16 (m, 2H), 2.12 - 2.03 ( m, 2H), 1.12 (s, 3H), 1.10 (s, 3H), 1.04 (s, 3H), 0.84 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.36, -77.68, -77.89.

Example 57.

Methyl-((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-3yl)pyridin-3 -yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4, 7,11,12tetraazahexadecan-14-yl)carbamate (57).

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, 1H), 8.18 (d, J = 9.3 Hz, 1H), 7.70 (dd, J = 8.9, 2.3 Hz, 1H), 7.42 - 7.31 (m, 4H), 7.22 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 9.9 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H), 6.48 (s, 1H), 4 .96 (t, J = 7.6 Hz, 2H), 4.85 (s, 2H), 4.81 (dd, J = 8.3, 5.0 Hz, 2H), 4.47 - 4, 39 (m, 1H), 4.35 (d, J = 14.5 Hz, 2H), 4.33 - 4.26 (m, 1H), 4.22 - 4.07 (m, 9H), 3 .93 (d, J = 13.3 Hz, 1H), 3.69 (s, 3H), 3.67 (s, 3H), 3.44 -3.35 (m, 2H), 2.96 - 2.71 (m, 4H), 2.27 - 2.17 (m, 2H), 2.08 (d, J = 8.6 Hz, 2H), 1.17 (s, 3H), 1.15 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.40, -77.74, -77.92, -115.37.

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F

Example 58.

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

Intermediates: I2, P4 and S3. MS (ESI) m/z 1155.6 [M+H]+. 1H NMR (400 MHz, methanold4) δ 8.29 (dd, J = 2.3, 0.7 Hz, 1H), 8.18 (d, J = 9.3 Hz, 1H), 8.11 (d , J = 2.7 Hz, 1H), 7.72 - 7.68 (m, 1H), 7.54 (d, J = 59.9 Hz, 1H), 7.45 (d, J = 8, 2 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 10.0 Hz , 1H), 6.94 (d, J = 2.7 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H ), 4.99 - 4.92 (m, 2H), 4.84 4.77 (m, 2H), 4.44 (d, J = 9.9 Hz, 1H), 4.40 - 4.26 (m, 3H), 4.22 - 4.09 (m, 4H), 3.94 (d, J = 13.2 Hz, 1H), 3.78 3.70 (m, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 3.38 (d, J = 13.9 Hz, 2H), 2.95 - 2.70 (m, 4H), 2.30 - 2, 15 (m, 2H), 2.15-2.03 (m, 2H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.40, 77.73, -77.90, -96.95 (dd, J=59.9, 19.6 Hz), -114.92.

F

Example 59.

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

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, 1H), 8.37 - 8.24 (m, 1H), 8.18 (d, J = 9, 3 Hz, 1H), 8.13 (s, 1H), 7.79 (dd, J = 8.6, 2.2 Hz, 1H), 7.51 (t, J = 59.7 Hz, 1H) , 7.34 (d, J = 8.2 Hz, 2H), 7.29 -7.20 (m, 4H), 7.18 (d, J = 9.8 Hz, 1H), 6.82 ( d, J = 9.8 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 4.77 (t, J = 7.6 Hz, 2H), 4.62 (d, J = 6.3 Hz, 2H), 4.53 (dd, J = 8.3, 5.1 Hz, 2H), 4.49 - 4.41 (m, 1H), 4.37 - 4.29 (m, 1H), 4.27 - 4.07 (m, 3H), 3.93 (d, J = 13.2 Hz, 1H), 3.69 (s, 3H), 3.68 - 3, 61 (m, 4H), 3.00 (dt, J = 10.2, 6.3 Hz, 1H), 2.94 - 2.72 (m, 4H), 2.09 - 1.98 (m, 1H), 1.17 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.39, -77.71, -77.96, -96.87 (d, J = 59.7 Hz), -115.01.

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Example 60.

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

Intermediates: I2, P7 and S4. MS (ESI) m/z 1141.3 [M+H]+. 1H NMR (400 MHz, methanold4) δ 8.54 (d, J = 0.7 Hz, 1H), 8.37 - 8.29 (m, 1H), 8.17 (d, J = 9.4 Hz , 1H), 8.13 (s, 1H), 7.74 (dd, J = 8.9, 2.3 Hz, 1H), 7.51 (t, J = 59.7 Hz, 1H), 7 .34 (d, J = 7.9 Hz, 2H), 7.24 (dd, J = 12.7, 8.2 Hz, 4H), 7.18 (d, J = 10.1 Hz, 1H) , 6.84 - 6.76 (m, 2H), 5.08 - 4.93 (m, 2H), 4.65 - 4.56 (m, 2H), 4.50 - 4.41 (m, 1H), 4.39 - 4.27 (m, 1H), 4.21 - 4.03 (m, 3H), 3.93 (d, J = 13.2 Hz, 1H), 3.78 - 3 .68 (m, 4H), 3.67 (s, 3H), 2.95 - 2.73 (m, 4H), 2.11 (d, J = 11.1 Hz, 1H), 1.17 ( s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.39, -77.72, -77.93, -96.87 (d, J = 59.7 Hz), -115.02.

Example 61.

Methyl-((5S,8S,9S, 14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyrimidin-5-yl)ethynyl)benzyl )-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa4,7,11,12-tetraazahexadecan-14-yl)carbamate (61) .

Intermediates: I2, P7 and S7. MS (ESI) m/z 1156.9 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.54 (d, J = 0.7 Hz, 1H), 8.53 (s, 2H), 8.18 (d, J = 9.2 Hz, 1H), 8.13 (s, 1H), 7.51 (t, J = 59.7 Hz, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.24 (t, J = 8 .1 Hz, 4H), 7.18 (d, J = 9.9 Hz, 1H), 6.82 (d, J = 9.9 Hz, 1H), 5.00 - 4.92 (m, 2H ), 4.84 - 4.77 (m, 2H), 4.44 (d, J = 9.9 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.21 - 4.07 (m, 3H), 3.79 - 3.70 (m, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.52 - 3.41 (m , 2H), 2.96 - 2.66 (m, 4H), 2.21 (d, J = 11.2 Hz, 2H), 1.99 (d, J = 9.1 Hz, 2H), 1 .17 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.39, 77.72, -77.86, -96.87 (d, J = 59.7 Hz), -115.03.

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Example 62.

Methyl-((58,88,98,148)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-((6-(1 ,5dimethyl-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)-2oxa-4,7,11,12-tetraazahexadecane -14-yl)carbamate (62).

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, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.17 (d, J = 9.3 Hz, 1H), 8.12 (s, 1H), 7.98 - 7.88 (m, 1H), 7.58 (t, J = 59.7 Hz, 1H), 7.38 - 7.33 (m, 2H), 7.25 (dd, J = 8.2, 5.8 Hz, 4H), 7.18 (d, J = 9.9 Hz, 1H), 6.80 ( d, J = 9.9 Hz, 1H), 4.83 - 4.75 (m, 1H), 4.65 (d, J = 13.5 Hz, 2H), 4.54 (t, J = 6 .8 Hz, 2H), 4.43 (d, J = 9.7 Hz, 1H), 4.35-4.16 (m, 3H), 4.13 (t, J = 11.3 Hz, 2H ), 4.02 (d, J = 12.4 Hz, 0H), 3.93 (d, J = 13.1 Hz, 1H), 3.72 (d, J = 10.4 Hz, 2H), 3.69 (d, J = 2.1 Hz, 3H), 3.66 (s, 3H), 3.53 - 3.44 (m, 1H), 2.99 - 2.71 (m, 4H) , 2.47 (d, J = 11.6 Hz, 2H), 1.17 (s, 4H), 1.14 (s, 3H), 1.11 (s, 4H), 1.07 (s, 5H), 1.03 (s, 3H). ¹⁹ F 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.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzyl)-16,16,16-trifluoro-9hydroxy-15,15- dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)ethynyl)benzyl)-3.6 ,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (63).

Intermediates: I2, P9 and S3. MS (ESI) m/z 1119.9 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.38 (s, 1H), 8.29 (d, J = 2.3 Hz, 1H), 8.09 (d, J = 9.7 Hz, 1H), 8.06 (s, 1H), 7.69 (dd, J = 8.9, 2.3 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.48 (t , J = 59.9 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 9.6 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.76 (d, J = 9 .8 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.81 (dd, J = 8.3, 5.1 Hz, 2H), 4.45 - 4.31 (m, 3H), 4.25 (d, J = 9.6 Hz, 1H), 4.15 (s, 3H), 3.98 (d, J = 13.2 Hz, 1H), 3.86 (d, J = 13.0 Hz, 1H), 3.74 (d, J = 8.3 Hz, 1H), 3.68 (s, 3H), 3.60 (s, 3H), 3.37 (d, J = 13.9 Hz, 2H), 2.95-2.67 (m, 4H), 2.30-2.19 (m, 2H), 2.07 (d, J = 8.6 Hz, 2H), 1.12 (s, 3H), 1.09 (s, 3H), 1.01 (s, 3H), 0.85 (s, 3H). ¹⁹ F NMR (376 MHz, methanol-d4) δ -77.41 , -77.66 , -77.73 , -96.57 (d, J = 59.9 Hz).

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Example 64.

Methyl-((5S,8S,9S,14S)-5-(tert-butyl)-11-(4-(5,6-difluoropyridin-3-yl)-2,6-difluorobenzyl)-9-hydroxy15.15 -dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan3-yl)pyridine -3-yl)ethynyl)benzyl)-2-oxa-4,7,P,12-tetraazahexadecan-14-yl)carbamate (64).

Intermediates: I8 and 3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. MS (ESI) m/z 1086.21 [M+H]+. ¹ H NMR (400 MHz, methanol^) δ 8.28 (t, J = 1.9 Hz, 1H), 8.24 - 8.06 (m, 2H), 7.79 (q, J = 8, 3 Hz, 2H), 7.42-7.14 (m, 7H), 6.99 (t, J= 10.5 Hz, 1H), 4.80-4.65 (m, 3H), 4, 25-3.84 (m, 10H), 3.77-3.58 (m, 9H), 3.19 (t, J= 12.3 Hz, 1H), 3.02 - 2.75 (m, 6H), 2.31 -1.76(m, 4H), 0.87 (d, J= 27.6 Hz, 20H).

Example 65.

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

Intermediates: I2, P7 and S41. MS (ESI) m/z 1169.8 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H), 8.38 (s, 1H), 8.14 (d, J = 9.5 Hz, 1H), 8.12 (s , 1H), 7.78 (d, J = 9.5 Hz, 1H), 7.58 (t, J = 59.7 Hz, 1H), 7.35 (d, J = 7.2 Hz, 2H ), 7.24 (t, J = 7.8 Hz, 4H), 7.14 (d, J = 9.8 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 10.0 Hz, 1H), 4.79 (t, J = 7.8 Hz, 2H), 4.50 - 4.24 (m, 5H), 4.19 - 4 .05 (m, 2H), 3.93 (d, J = 13.2 Hz,

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1H), 3.79 - 3.63 (m, 9H), 3.14 (d, J = 12.3 Hz, 2H), 3.00 - 2.72 (m, 4H), 2.46 (s , 2H), 2.13 - 1.92 (m, 2H), 1.17 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H). ¹⁹ F NMR (376 MHz, methanol-d4) δ -77.36, -77.70, -77.78, 96.88 (d, J = 59.8 Hz), -115.01.

Example 66.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9hydroxy -15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(7-(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3yl)pyridine -3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan14-yl)carbamate (66) .

Intermediates: I2, P7 and S40. MS (ESI) m/z 1190.7 [M+H]+. 1H NMR (400 MHz, methanol-c14) 5 8.52 (d, J = 0.7 Hz, 1H), 8.17 - 8.09 (m, 2H), 7.98 (d, J = 2, 2 Hz, 1H), 7.81 (δ, J = 9.1, 7.0, 1.8 Hz, 1H), 7.76 (δ, J = 6.4, 1.8, 0.7 Hz , 1H), 7.57 (dd, J = 9.2, 2.3 Hz, 1H), 7.50 (t, J = 59.7 Hz, 1H), 7.30 (d, J = 7, 9 Hz, 2H), 7.26 - 7.18 (m, 5H), 7.13 (d, J = 9.9 Hz, 1H), 6.93 (d, J = 9.3 Hz, 1H) , 6.79 (t, J = 6.7 Hz, 1H), 4.50 (d, J = 13.3 Hz, 2H), 4.46 - 4.38 (m, 1H), 4.24 ( d, J = 13.1 Hz, 2H), 4.20 - 4.05 (m, 2H), 3.93 (d, J = 13.1 Hz, 1H), 3.77 - 3.67 (m , 5H), 3.66 (s, 3H), 3.58 - 3.46 (m, 2H), 3.38 (d, J = 13.3 Hz, 2H), 2.96 - 2.71 ( m, 4H), 2.35 (s, 2H), 2.14 (t, J = 3.2 Hz, 2H), 1.17 (s, 3H), 1.15 (s, 3H), 1, 12 (s, 3H), 1.03 (s, 3H). ¹⁹ F NMR (376 MHz, methanold4) δ -77.34, -77.66, -77.97, -96.87 (d, J = 59.6 Hz), -115.00 (d, J = 8 .7 Hz).

Example 67.

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

Intermediates: I2, P7 and S39. MS (ESI) m/z 1155.9 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.44 (s, 1H), 8.07 (d, J = 9.5 Hz, 1H), 8.03 (s, 1H), 7.99 (d , J = 2.3 Hz, 1H), 7.75 (d, J = 9.4 Hz, 1H), 7.49 (t, J = 59.7 Hz, 1H), 7.26 (d, J = 7.9 Hz, 2H), 7.20 - 7.03 (m, 5H), 6.72 (d, J = 10.2 Hz, 1H), 4.61 (d, J =

- 118 040208

13.5 Hz, 1H), 4.38 - 4.29 (m, 3H), 4.24 - 4.17 (m, 1H), 4.04 (dt, J = 29.4, 13.9 Hz , 5H), 3.83 (d, J = 13.1 Hz,

1H), 3.66 - 3.61 (m, 1H), 3.59 (s, 3H), 3.57 (s, 3H), 3.44 - 3.26 (m, 4H), 2.87 - 2.62 (m, 6H), 2.11 (s, 3H), 1.95 (s, 3H), 1.80 (s, 3H), 1.08 (s, 3H), 1.05 ( s, 3H), 1.02 (s, 3H), 0.94 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ 77.38, -77.70, -77.88 (TFA peak), -96.88 (d, J = 59.8 Hz), -115.02.

F

Example 68.

Methyl-((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-dimethyl3,6,13 -trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (68).

Intermediates: 12, P7 and S43. MS (ESI) m/z 1100.8[M+H]+.1H NMR (400 MHz, methanol-d4) δ 8.44 (s, 1H), 8.11 - 8.04 (m, 2H), 8.03 (s, 1H), 7.73 (d, J = 9.4 Hz, 1H), 7.41 (t, J = 59.8 Hz, 1H), 7.26 (d, J = 7 .2 Hz, 3H), 7.15 (t, J = 7.6 Hz, 5H), 6.94 (d, J = 9.2 Hz, 1H), 4.47 - 4.38 (m, 2H ), 4.37 - 4.30 (m, 1H), 4.24 - 4.18 (m, 1H), 4.12 - 3.96 (m, 2H), 3.84 (d, J = 13 .1 Hz, 1H), 3.72 (d, J = 12.2 Hz, 2H), 3.66 - 3.61 (m, 1H), 3.59 (s, 3H), 3.57 (s , 3H), 3.18 - 3.12 (m, 2H), 2.86 - 2.63 (m, 5H), 1.97 - 1.85 (m, 2H), 1.81 - 1.73 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) 5 -77.38, -77.70, -77.94, 96.88 (d, J = 59.7 Hz), -115.02.

F

ABOUT

Example 69.

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

Intermediates: I2, P7 and S5. MS (ESI) m/z 1137.9 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.44 (s, 1H), 8.09 (d, J = 9.4 Hz, 1H), 8.03 (s, 1H), 7.73 (s, 1H ), 7.63 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 59.7 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.16 (dd, J = 8.3, 3.3 Hz, 4H), 7.09 (d, J = 9.9 Hz, 1H), 6 .71 (d, J = 10.0 Hz, 1H), 4.39 - 4.30 (m, 1H), 4.30 - 4.17 (m, 1H), 4.11 - 3.97 (m , 2H), 3.84 (d, J = 13.2 Hz, 1H), 3.68 - 3.62 (m, 1H), 3.61 (s, 3H), 3.57 (s, 3H) , 3.08 (s, 3H), 2.82 (d, J = 7.9 Hz, 2H), 2.78 - 2.61 (m, 2H), 1.08 (s, 3H), 1, 05 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.39, -77.70, -77.82, -119 040208

96.87 (d, J = 59.7 Hz), -115.00.

F

I

Example 70.

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

Intermediates: I2, P7 and S38. MS (ESI) m/z 1177.4 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.54 (s, 1H), 8.20 (d, J = 2.2 Hz, 1H), 8.12 (s, 1H), 7.73 (d , J = 9.4 Hz, 1H), 7.50 (d, J = 59.7 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 9.1 Hz, 1H), 4.43 (s, 1H), 4.39 (s, 2H), 4.30 (s, 1H), 4.18 - 4.01 (m, 4H), 3.93 (d, J = 13.1 Hz, 1H), 3.76 - 3.70 (m, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.21 (d, J = 11.9 Hz, 2H), 3.04 (s, 3H), 2.95 - 2.70 (m, 4H), 2.12 - 1.99 (m, 2H), 1.86 (t, J = 7.0 Hz, 2H), 1.17 (s , 4H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H). ¹⁹ F 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.

F

Example 71.

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

Intermediates: I2, P7 and S3. MS (ESI) m/z 1155.6 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.45 (s, 1H), 8.24 - 8.18 (m, 1H), 8.08 (d, J = 9.3 Hz, 1H), 8.03 (d, J = 0.7 Hz, 1H), 7.65 - 7.52 (m, 3H), 7.50 - 7.43 (m, 1H), 7.41 (d, J = 59.7 Hz, 1H), 7.23 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 8.9 Hz, 1H), 6.71 (d, J = 10.0 Hz, 1H), 4.87 (t, J = 7.6 Hz, 2H) , 4.71 (dd, J = 8.2, 5.0 Hz, 2H), 4.34 (d, J = 9.9 Hz, 1H), 4.26 (d, J = 13.8 Hz, 2H), 4.21 (d, J = 10.0 Hz, 1H), 4.11 - 3.97 (m, 5H), 3.83 (d, J = 13.2 Hz, 1H), 3, 66 - 3.61 (m, 1H), 3.59 (s, 3H), 3.57 (s, 3H), 3.28 (d, J = 13.9 Hz, 2H), 2.85 - 2 .63 (m, 4H), 2.19 - 2.09 (m, 2H), 2.02 - 1.95 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H ), 1.02 (s, 3H), 0.94 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.40, -77.72, -96.87 (d, J = 59.7 Hz), -115.02.

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Example 72.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-9-hydroxy15,15-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-tetraazahexadecan14-yl)carbamate (72).

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, 2H), 8.10 (d, J = 2.7 Hz, 1H), 7.80 (dd, J = 9, 2, 2.3 Hz, 1H), 7.53 (t, J = 59.9 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.28 - 7.18 (m, 2H), 7.01 (d, J = 9.2 Hz, 1H), 6.93 (d, J = 2.7 Hz, 1H), 6.80 (d, J = 9.9 Hz, 1H), 4.47 - 4.38 (m, 3H), 4.17 - 4.07 (m, 2H), 4.04 (dd , J = 12.3, 2.4 Hz, 2H), 3.96 (d, J = 13.1 Hz, 1H), 3.77 - 3.72 (m, 2H), 3.69 (s, 3H), 3.65 (s, 3H), 3.27 (dd, J = 12.1, 2.5 Hz, 2H), 3.04 (s, 3H), 2.97 - 2.71 (m , 4H), 2.13 - 2.04 (m, 2H), 1.90 - 1.81 (m, 2H), 1.14 (s, 3H), 1.11 (s, 3H), 0, 86(s, 9H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.32, -77.93, -96.91 (dd, J = 59.9, 15.2 Hz), -114.77.

Example 73.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-9-hydroxy15,15-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-tetraazahexadecan-14yl)carbamate (73).

Intermediates: I3, P4 and S3. MS (ESI) m/z 1102.2 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.29 (d, J = 2.2 Hz, 1H), 8.17 (d, J = 9.4 Hz, 1H), 8.10 (d, J = 2 .7 Hz, 1H), 7.71 (dd, J = 8.8, 2.3 Hz, 1H), 7.53 (d, J = 59.8 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 2 .8 Hz, 1H), 6.91 - 6.84 (m, 1H), 4.96 (dd, J = 8.2, 7.0 Hz, 2H), 4.83 (dd, J = 8, 2, 5.1 Hz, 2H), 4.61 - 4.49 (m, 1H), 4.43 (s, 1H), 4.40 - 4.29 (m, 2H), 4.19 - 4 .04 (m, 4H), 3.97 (d, J = 13.1 Hz, 1H), 3.81 - 3.72 (m, 2H), 3.69 (s, 3H), 3.65 ( s, 3H), 3.41 (dd, J = 14.2, 1.7 Hz, 2H), 2.99 - 2.70 (m, 4H), 2.32 - 2.18 (m, 2H) , 2.13 - 1.99 (m, 2H), 1.14 (s, 3H), 1.11 (s, 3H), 0.86 (s, 9H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.35, -78.05 (TFA peak), 96.93 (dd, J = 59.7, 14.5 Hz), -114.79.

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Example 74.

Methyl-((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15- 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-tetraazahexadecan-14yl)carbamate (74).

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, 1H), 8.35-8.27 (m, 1H), 8.19-8.11 (m, 2H), 8.03 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.70 (dd, J = 8.9, 2.3 Hz, 1H), 7, 69 - 7.64 (m, 1H), 7.63 - 7.57 (m, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 7, 9 Hz, 2H), 6.87 (dd, J = 9.0, 0.8 Hz, 1H), 4.96 (dd, J = 8.2, 7.1 Hz, 2H), 4.82 ( dd, J = 8.2, 5.1 Hz, 2H), 4.59 - 4.51 (m, 1H), 4.45 - 4.41 (m, 1H), 4.39 - 4.24 ( m, 5H), 4.20 - 4.11 (m, 4H), 4.05 (d, J = 12.7 Hz, 1H), 3.82 - 3.73 (m, 2H), 3.69 (s, 3H), 3.63 (s, 3H), 3.44 - 3.36 (m, 2H), 2.92 (t, J = 9.0 Hz, 3H), 2.81 (dd, J = 12.6, 9.5 Hz, 1H), 2.30 - 2.18 (m, 2H), 2.12 - 2.04 (m, 2H), 1.14 (s, 6H), 1 .12 (s, 3H), 1.00 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ 77.30, -77.68, -78.09 (TFA peak), -112.80.

Example 75.

Methyl-((58,88,98,148)-11-(4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridin-3-yl)ethynyl)benzyl )-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (75) .

Intermediates: I2, P3 and S3. MS (ESI) m/z 1163.9 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.32 - 8.26 (m, 1H), 8.12 (d, J = 9.4 Hz, 1H), 7.70 (dd, J = 8.8, 2.3 Hz, 1H), 7.51 (d, J = 7.5 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8, 0 Hz, 2H), 7.12 (d, J = 9.8 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.77 (d, J = 9.9 Hz , 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.79 (s, 1H), 4.43 (d, J = 9.8 Hz, 1H), 4.35 (d , J = 14.0 Hz, 2H), 4.28 (d, J = 10.0 Hz, 1H), 4.17 (s, 5H), 3.97 (d, J = 13.2 Hz, 1H ), 3.74 (d, J = 13.6 Hz, 1H), 3.69 (s, 3H), 3.67 (s, 3H), 3.38 (d, J = 13.9 Hz, 2H ), 3.02 - 2.84 (m, 3H), 2.82 - 2.74 (m, 1H), 2.53 (td, J = 8.6, 4.3 Hz, 1H), 2, 27 - 2.18 (m, 2H), 2.08 (d, J = 8.6 Hz, 2H), 1.35 - 1.30 (m, 2H), 1.27 (d, J = 16, 2 Hz, 0H), 1.20 - 1.13 (m, 9H), 1.12 (s, 3H), 1.03 (s, 3H). ¹⁹ F NMR (376 MHz, methanol-d4) δ -77.31, -77.67, -77.82, -113.25.

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Example 76.

Methyl-((58,88,98,148)-11-(4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-2,6-difluorobenzyl)-9-hydroxy15,15-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-tetraazahexadecan-14yl)carbamate (76).

Intermediates: I3, P3 and S3. MS (ESI) m/z 1110.1 [M+H]+. 1H NMR (400 MHz, methanold4) δ 8.32 - 8.27 (m, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.70 (dd, J = 8.7, 2.3 Hz, 1H), 7.51 (d, J = 7.5 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8, 0 Hz, 2H), 6.86 (d, J = 8.9 Hz, 1H), 6.78 (s, 0H), 4.96 (t, J = 7.6 Hz, 2H), 4.79 (s, 1H), 4.54 (s, 1H), 4.43 (d, J = 6.3 Hz, 1H), 4.35 (d, J = 13.9 Hz, 2H), 4.15 (s, 5H), 3.99 (d, J = 13.1 Hz, 1H), 3.74 (s, 1H), 3.69 (s, 4H), 3.65 (s, 3H), 3 .38 (d, J = 13.9 Hz, 2H), 3.34 (s, 1H), 3.00 - 2.75 (m, 2H), 2.51 (dq, J = 8.5, 4 .9, 4.3 Hz, 1H), 2.27 - 2.18 (m, 2H), 2.08 (d, J = 8.6 Hz, 2H), 1.36 - 1.30 (m, 2H), 1.19 - 1.13 (m, 6H), 1.12 (s, 3H), 0.85 (s, 10H). ¹⁹ F NMR (376 MHz, methanol-d4) δ -77.28, -77.92, -113.11.

Example 77.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-9-hydroxy15,15-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-tetraazahexadecan-14yl)carbamate (77).

Intermediates: I3, P1 and S3. MS (ESI) m/z 1102.0 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.30 (d, J = 2.1 Hz, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.74 - 7.66 (m, 1H), 7.57 (s, 1H), 7.42 (s, 0H), 7.39 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 7, 8 Hz, 2H), 7.21 (d, J = 8.0 Hz, 3H), 6.86 (d, J = 8.9 Hz, 1H), 4.97 (t, J = 7.6 Hz , 3H), 4.80 (d, J = 5.2 Hz, 1H), 4.43 (d, J = 9.8 Hz, 1H), 4.35 (d, J = 14.1 Hz, 2H ), 4.19 - 4.08 (m, 5H), 3.96 (d, J = 13.2 Hz, 1H), 3.76 (s, 1H), 3.69 (s, 4H), 3 .65 (s, 3H), 3.38 (d, J = 13.9 Hz, 3H), 2.90 (d, J = 8.1 Hz, 2H), 2.81 (s, 1H), 2 .22 (s, 2H), 2.08 (d, J = 8.7 Hz, 2H), 1.13 (d, J = 14.1 Hz, 8H), 0.86 (s, 12H). ¹⁹ F NMR (376 MHz, methanol-d4) δ -77.36, -77.93, -94.99 (d, J = 60.0 Hz), -115.00.

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Example 78.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15dimethyl- 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-tetraazahexadecan-14yl)carbamate (78).

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, 1H), 8.14 (d, J = 9.3 Hz, 1H), 7.98 - 7.85 (m, 2H), 7.61 (t, J = 8.1 Hz, 3H), 7.47 7.38 (m, 1H), 7.33 (d, J = 7.8 Hz, 3H), 7.22 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 9.9 Hz, 1H), 6.77 (d, J = 9.8 Hz, 1H), 6. 67 (d, J = 8.7 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.42 (dd, J = 25.4, 11.7 Hz, 2H), 4.33 - 4.27 (m, 1H), 4.22 - 4.10 (m, 4H), 3.98 (d, J = 13.0 Hz, 1H), 3.73 (s, 1H) , 3.68 (s, 4H), 3.63 (s, 3H), 3.35 (d, J = 14.0 Hz, 2H), 2.97 - 2.86 (m, 3H), 2, 84 - 2.75 (m, 1H), 2.56 (s, 4H), 2.25 - 2.16 (m, 2H), 2.13 - 2.01 (m, 2H), 1.28 ( d, J = 8.8 Hz, 0H), 1.16 (d, J = 2.7 Hz, 7H), 1.13 (s, 4H), 1.03 (s, 3H). ¹⁹ F NMR (376 MHz, methanol-d4) δ -77.35, -77.68, -114.72.

Example 79.

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

Intermediates: I2, P1 and S3. MS (ESI) m/z 1156.0 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.32 - 8.28 (m, 1H), 8.15 (d, J = 1.2 Hz, 1H), 8.13 (s, 0H), 8.00 (d, J = 1.3 Hz, 1H), 7.73 (s, 0H), 7.70 (dd, J = 8.8, 2.3 Hz, 1H), 7.58 (s, 1H) , 7.43 (s, 0H), 7.39 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 9.8 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.77 (d, J = 10, 0 Hz, 0H), 4.97 (t, J = 7.6 Hz, 2H), 4.82 - 4.78 (m, 2H), 4.53 (s, 1H), 4.44 (d, J = 6.5 Hz, 1H), 4.39 - 4.28 (m, 3H), 4.13 (d, J = 15.7 Hz, 4H), 3.94 (d, J = 13.3 Hz, 1H), 3.69 (s, 3H), 3.67 (s, 3H), 3.38 (d, J = 13.9 Hz, 2H), 2.97 - 2.72 (m, 6H ), 2.27 - 2.19 (m, 2H), 2.08 (d, J = 8.6 Hz, 2H), 1.21 (t, J = 7.3 Hz, 4H), 1.16 (d, J = 8.4 Hz, 6H), 1.11 (s, 3H), 1.03 (s, 3H). ¹⁹ F 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.

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EXAMPLE 80.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16-fluoro-9hydroxy-15.15 -dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)ethynyl)benzyl)-3, 6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (80).

Intermediates: I6, P7 and S3. MS (ESI) m/z 1119.5 [M+H]+. 1H NMR (400 MHz, methanold4) δ 8.54 (d, J = 0.7 Hz, 1H), 8.32 - 8.27 (m, 1H), 8.17 (d, J = 9.4 Hz , 1H), 8.12 (s, 1H), 7.88 - 7.73 (m, 0H), 7.70 (dd, J = 8.8, 2.3 Hz, 1H), 7.65 ( s, 0H), 7.51 (s, 1H), 7.38 - 7.30 (m, 2H), 7.24 (dd, J = 16.7, 8.2 Hz, 4H), 6.86 (d, J = 9.0 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H), 4.96 (dd, J = 8.1, 7.0 Hz, 2H), 4 .84 - 4.77 (m, 2H), 4.47 - 4.41 (m, 1H), 4.36 (d, J = 13.7 Hz, 2H), 4.22 (d, J = 9 .2 Hz, 1H), 4.18 - 4.03 (m, 5H), 4.00 (s, 1H), 3.98 - 3.91 (m, 2H), 3.71 (s, 0H) , 3.69 (s, 3H), 3.66 (s, 3H), 3.37 (d, J = 13.8 Hz, 2H), 3.04 (q, J = 7.4 Hz, 1H) , 2.99 (d, J = 0.5 Hz, 0H), 2.90 (d, J = 9.1 Hz, 2H), 2.86 (d, J = 0.7 Hz, 0H), 2 .79 (d, J = 9.6 Hz, 2H), 2.28 -2.19 (m, 2H), 2.11 2.02 (m, 2H), 1.29 (t, J = 7, 3 Hz, 1H), 1.13 (d, J = 10.8 Hz, 6H), 1.02 (t, J = 7.4 Hz, 0H), 0.93 - 0.84 (m, 6H) . ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.38, -77.88, -96.88 (d, J = 59.7 Hz), -114.92

Example 81.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14yl)carbamate (81).

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, 1H), 8.16 (d, J = 9.3 Hz, 1H), 8.10 (d, J = 2, 8 Hz, 1H), 7.77 (dd, J = 9.0, 2.3 Hz, 1H), 7.53 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H) , 7.34 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 9.9 Hz, 1H), 6 .98 - 6.91 (m, 2H), 6.80 (d, J = 9.9 Hz, 1H), 4.48 - 4.41 (m, 1H), 4.36 - 4.27 (m , 1H), 4.20 (s, 2H), 4.14 (d, J = 13.0 Hz, 2H), 3.96 (s, 1H), 3.95 - 3.87 (m, 3H) , 3.73 (s, 2H), 3.68 (d, J = 11.7 Hz, 6H), 3.60 - 3.51 (m, 2H), 3.04 (s, 3H), 2, 94 - 2.84 (m, 3H), 2.84 - 2.73 (m, 1H), 1.20 - 1.08 (m, 9H), 1.03 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.38, -77.71, -96.96 (dd, J = 59.8, 19.5 Hz), -114.92.

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Example 82.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)benzyl)-16,16,16-trifluoro-9hydroxy-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-tetraazahexadecan14-yl)carbamate (82).

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, 1H), 8.16 (d, J = 9.4 Hz, 1H), 7.70 (dd, J = 8.8, 2.3 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 6 .92 - 6.71 (m, 3H), 4.97 (dd, J = 8.1, 7.2 Hz, 2H), 4.83 - 4.74 (m, 2H), 4.58 4, 23 (m, 4H), 4.17 - 3.96 (m, 8H), 3.90 (d, J = 13.4 Hz, 1H), 3.74 - 3.58 (m, 8H), 3 .54 (td, J = 11.2, 3.9 Hz, 2H), 3.39 (d, J = 13.8 Hz, 2H), 3.03 - 2.60 (m, 5H), 2, 36 - 2.17 (m, 2H), 2.20 - 2.03 (m, 4H), 1.93 - 1.83 (m, 1H), 1.80 - 1.48 (m, 5H), 1.29 (d, J = 3.8 Hz, 1H), 1.20 - 1.05 (m, 11H), 0.95 (d, J = 41.7 Hz, 4H).

Example 83.

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

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, 1H), 8.15 (d, J = 9.4 Hz, 1H), 7.69 (dd, J = 8.8, 2.3 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6 .99 (d, J = 8.3 Hz, 2H), 6.92 - 6.70 (m, 2H), 5.05 (dd, J = 8.3, 6.1 Hz, 3H), 4, 95 (dd, J = 8.2, 7.0 Hz, 3H), 4.80 (dd, J = 8.0, 4.8 Hz, 3H), 4.67 (t, J = 6.3 Hz , 2H), 4.50 - 4.17 (m, 4H), 4.14 (d, J = 4.3 Hz, 3H), 3.68 (d, J = 1.5 Hz, 7H), 3 .38 (dd, J = 14.2, 1.7 Hz, 3H), 3.00 - 2.68 (m, 2H), 2.06 (d, J = 9.0 Hz, 1H), 1, 73 (d, J = 7.2 Hz, 0H), 1.64 - 1.49 (m, 1H), 1.42 - 1.25 (m, 25H), 1.17 - 1.05 (m, 11H), 1.01 (s, 3H), 0.96 (d, J = 6.6 Hz, 2H), 0.92 - 0.80 (m, 24H).

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Example 84.

Methyl-((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15dimethyl- 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-tetraazahexadecan-14-yl)carbamate (84).

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, 1H), 8.34 - 8.25 (m, 1H), 8.01 - 7.87 (m, 2H), 7.83 (d, J= 9.4 Hz, 1H), 7.70 (dd, J= 8.8, 2.3 Hz, 1H), 7.59 (d, J= 8.6 Hz, 2H), 7.44 (dd, J = 7.0, 5.0 Hz, 1H), 7.33 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 7 .9 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.84-4.79 (m, 1H ), 4.53 (s, 1H), 4.35 (d, J= 13.9 Hz, 2H), 4.15 (s, 6H), 4.00 (d, J= 13.1 Hz, 1H ), 3.90 (s, 1H), 3.80-3.58 (m, 9H), 3.40 (s, 1H), 3.03 - 2.80 (m, 5H), 2.34 - 2.20 (m, 3H), 2.07 (d, J = 8.6 Hz, 2H), 0.87 (d, J = 24.4 Hz, 19H).

Example 85.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzyl)-9-hydroxy-15,15-dimethyl8-(4-( (6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13trioxo-5 -( 1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (85).

Intermediates: I3, P6 and S3. MS (ESI) m/z 1066.1 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.25 (d, J= 2.3 Hz, 1H), 8.13-8.04 (m, 2H), 7.83-7.74 (m, 4H) , 7.47 (d, J = 8.2 Hz, 3H), 7.35 - 7.30 (m, 3H), 7.23 (d, J = 8.2 Hz, 3H), 6.99 ( d, J = 9.1 Hz, 2H), 6.86 (d, J = 2.7 Hz, 1H), 4.58 - 4.49 (m, 2H), 4.35 (t, J = 4 .9 Hz, 1H), 4.31 - 4.23 (m, 3H), 4.17 (d, J = 3.8 Hz, 3H), 4.03 - 3.89 (m, 2H), 3 .81 (s, 1H), 3.67 (s, 5H), 3.62 3.49 (m, 6H), 2.95 - 2.74 (m, 3H), 2.30 - 2.23 ( m, 2H), 2.07 (d, J= 8.8 Hz, 2H), 1.02 (d, J= 34.0 Hz, 6H), 0.74 (s, 10H). ¹⁹ F NMR (377 MHz, methanol^) δ -77.58, -96.21 (d, J = 59.7 Hz).

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Example 86.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-III-pyrazol-4-yl)-2,6-difluorobenzyl)-9-hydroxy15,15-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-tetraazahexadecan-14yl)carbamate (86).

Intermediates: I3, P7 and S3. MS (ESI) m/z 1066.1 [M+H]+. 1H NMR (400 MHz, methanold4) δ 8.53 (d, J= 0.7 Hz, 1H), 8.16 (d, J= 9.3 Hz, 1H), 8.11 (d, J= 0 .6 Hz, 1H), 7.72-7.69 (m, 1H), 7.37-7.30 (m, 3H), 7.27-7.19 (m, 5H), 6.87 ( dd, J= 9.1, 0.8 Hz, 1H), 6.80 (d, J=9.9 Hz, 1H), 4.98-4.94 (m, 2H), 4.84-4 .81 (m, 2H), 4.46-4.41 (m, 1H), 4.38-4.31 (m, 2H), 4.18-4.07 (m, 5H), 3.95 (d, J = 13.2 Hz, 1H), 3.76 (s, 1H), 3.67 (d, J = 15.6 Hz, 7H), 3.40 (dd, J = 14.2, 1.8 Hz, 2H), 2.93-2.87(m, 2H), 2.80(s, 2H), 2.26-2.20(m, 2H), 2.10-2.04 (m, 2H), 1.13 (d, J=11.9 Hz, 7H), 0.86 (s, 11H). ¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -78.10, -96.87 (d, J=59.7 Hz), 114.89.

Example 87.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan14-yl)carbamate (87).

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

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Example 88.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15-dimethyl- 8-(4-((2-(4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo5-(1,1,1 -trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (88).

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, 1H), 8.52 (s, 1H), 8.14 (d, J = 9.3 Hz, 0H ), 7.97 (d, J = 8.6 Hz, 1H), 7.40 (t, J = 4.9 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 10.0 Hz, 0H), 6.78 (d, J = 9.9 Hz, 0H), 4, 90 (t, J = 7.7 Hz, 1H), 4.51 - 4.26 (m, 2H), 4.25 - 4.09 (m, 2H), 3.98 (d, J = 13, 2 Hz, 1H), 3.67 (d, J = 8.1 Hz, 3H), 3.26 (s, 2H), 2.99 - 2.75 (m, 2H), 2.02 (s, 0H), 1.24 - 1.07 (m, 5H), 1.02 (s, 1H).

Example 89.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15-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-tetraazahexadecan14-yl)carbamate (89).

Intermediates: I2, P16 and S7. MS (ESI) m/z 1119.3 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.86 (d, J = 4.8 Hz, 1H), 8.52 (s, 1H), 8.15 (d, J = 9.4 Hz, 1H ), 7.97 (d, J = 8.6 Hz, 1H), 7.40 (t, J = 4.9 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 9.9 Hz, 0H), 6.78 (d, J = 9.9 Hz, 0H), 4, 96 (t, J = 7.6 Hz, 1H), 4.82 - 4.70 (m, 2H), 4.43 (d, J = 9.9 Hz, 0H), 4.30 (d, J = 10.0 Hz, 1H), 4.24 - 4.06 (m, 2H), 3.98 (d, J = 13.1 Hz, 1H), 3.68 (d, J = 8.7 Hz , 4H), 3.46 (d, J = 14.7 Hz, 1H), 2.99 - 2.70 (m, 2H), 2.27 - 2.10 (m, 1H), 1.99 ( d, J = 8.7 Hz, 1H), 1.19 - 1.05 (m, 5H), 1.02 (s, 2H).

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Example 90.

Methyl-((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy15,15-dimethyl-8-( 4-((6-((1R,4R)-5-(oxetan-3-ul)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3yl)ethynyl)benzyl)-3, 6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (90).

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, 1H), 8.15 (d, J = 9.4 Hz, 1H), 7.70 (dd, J = 11.1, 2.3 Hz, 2H), 7.43 - 7.27 (m, 4H), 7.21 (d, J = 7.9 Hz, 2H), 6.77 (d, J = 9.9 Hz, 0H), 6.73 - 6.58 (m, 2H), 5.05 (s, 1H), 5.00 - 4.88 (m, 2H), 4.71 (dd, J = 8.4, 4.6 Hz, 1H), 4.64 - 4.54 (m, 2H), 4.47 (d, J = 31.7 Hz, 2H), 4.10 (d, J = 13.2 Hz, 2H), 3.95 (d, J = 13.2 Hz, 1H), 3.82 - 3.56 (m, 13H), 3.33 (s, 1H), 2.89 ( d, J = 8.9 Hz, 2H), 2.33 (s, 2H), 1.21 - 0.99 (m, 11H), 0.86 (s, 10H).

Example 91.

Methyl-((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy15,15-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-tetraazahexadecan-14-yl)carbamate (91).

Intermediates: I3, P13 and S48. MS (ESI) m/z 1066.6 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.30 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 9.4 Hz, 1H), 7.79 - 7, 63 (m, 2H), 7.33 (dd, J = 8.2, 5.2 Hz, 4H), 7.21 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.9 Hz, 1H), 6.77 (d, J = 10.0 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 4.91 (t, J = 7 .7 Hz, 2H), 4.54 - 4.33 (m, 2H), 4.18 - 4.02 (m, 2H), 4.03 - 3.85 (m, 5H), 3.83 - 3.58 (m, 10H), 2.89 (d, J = 9.3 Hz, 2H), 1.27 (d, J = 13.9 Hz, 1H), 1.21 - 1.00 (m , 12H), 0.86 (s, 10H).

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Example 92.

Methyl-((5S,8S,9S, 14S)-11-(4-(1-cyclopropyl-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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-tetraazahexadecan-14yl)carbamate (92).

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, 1H), 8.14 (d, J = 9.4 Hz, 1H), 7.70 (dd, J = 9.2, 2.3 Hz, 2H), 7.64 - 7.51 (m, 0H), 7.33 (dd, J = 8.4, 4.0 Hz, 5H), 7.21 ( d, J = 8.0 Hz, 2H), 7.11 (d, J = 9.8 Hz, 1H), 6.94 (d, J = 8.9 Hz, 1H), 6.76 (d, J = 10.0 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 5.48 (s, 1H), 4.91 (dd, J = 8.3, 7.0 Hz, 3H), 4.51 - 4.38 (m, 2H), 4.31 (d, J = 9.9 Hz, 1H), 4.13 (dd, J = 15.3, 11.1 Hz , 3H), 3.93 (d, J = 13.0 Hz, 2H), 3.79 - 3.62 (m, 10H), 3.58 - 3.43 (m, 0H), 2.99 - 2.66 (m, 5H), 1.27 (d, J = 13.9 Hz, 1H), 1.21-0.97 (m, 19H).

Example 93.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15dimethyl- 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-tetraazahexadecan-14-yl)carbamate ( 93).

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, 1H), 8.28 - 8.20 (m, 0H), 8.14 (d, J = 9, 4 Hz, 0H), 7.96 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 8.8, 2.3 Hz, 1H), 7.40 (t, J = 4.9 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 6.74 - 6.65 (m, 1H), 5.05 (d, J = 2.0 Hz, 1H), 5.01 - 4.90 (m, 1H), 4.72 (dd, J = 8.4, 4.8 Hz, 1H ), 4.58 - 4.49 (m, 1H), 4.43 (t, J = 5.0 Hz, 0H), 4.40 - 4.26 (m, 1H), 4.18 (d, J = 12.8 Hz, 1H), 3.98 (d, J = 13.1 Hz, 1H), 3.87 - 3.63 (m, 5H), 3.34 (s, 0H), 3, 03 - 2.75 (m, 2H), 2.33 (s, 1H), 1.13 (d, J = 14.3 Hz, 5H), 1.02 (s, 2H).

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Example 94.

Methyl-((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-2methylpropan- 2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (94).

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, 1H), 8.29 (d, J = 2.2 Hz, 0H), 7.97 (d, J = 8.9 Hz, 1H), 7.70 (dd, J = 8.8, 2.3 Hz, 1H), 7.39 (t, J = 4.9 Hz, 1H), 7.32 (d , J = 7.8 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 6.95 (d, J = 8.9 Hz, 1H), 6.77 (d, J = 9.9 Hz, 0H), 4.84 (s, 15H), 4.57 -4.31 (m, 1H), 4.16 (d, J = 14.1 Hz, 1H), 3.98 (d, J = 35.4 Hz, 2H), 3.76 (s, 1H), 3.67 (d, J = 14.2 Hz, 4H), 3.04 - 2.69 (m, 2H) , 2.02 (s, 1H), 1.27 (d, J = 13.9 Hz, 1H), 1.12 (d, J = 14.5 Hz, 3H), 0.85 (s, 5H) .

Example 95.

Methyl-((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, 13trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (95).

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, 1H), 8.24 (d, J = 2.1 Hz, 0H), 8.15 (d, J = 9.3 Hz, 0H), 7.97 (d, J = 8.7 Hz, 1H), 7.70 (dd, J = 8.8, 2.2 Hz, 1H), 7.39 (t , J = 4.9 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 9.8 Hz, 0H), 6.67 (d, J = 8.8 Hz, 1H), 5.05 (s, 0H), 4.98 - 4.85 (m, 1H), 4.71 (dd, J = 8.4, 4.7 Hz, 1H), 4.66 4.55 (m, 1H), 4.53 - 4.41 (m, 1H), 4.16 (d, J = 13.7 Hz, 1H), 4.00 (d, J = 13.1 Hz, 1H), 3.87 - 3.61 (m, 6H), 3.30 (p, J = 1.6 Hz, 4H), 3.00 - 2.74 (m, 2H), 2.33 (s, 1H), 1.12 (d, J = 14.5 Hz, 3H), 0.85 (s, 5H).

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Example 96.

Methyl-((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-5( 1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (96).

Intermediates: I3, P16 and S3. MS (ESI) m/z 1063.5 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.86 (dd, J = 4.9, 0.8 Hz, 1H), 8.29 (d, J = 2.2 Hz, 0H), 8.15 (d, J = 9.4 Hz, 0H), 7.97 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.9, 2.3 Hz, 1H), 7 .40 (t, J = 4.9 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 6.77 (d, J = 10.0 Hz, 0H), 4.96 (t, J = 7.6 Hz, 1H), 4.83 (s , 20H), 4.39 (dd, J = 34.8, 11.8 Hz, 2H), 4.16 (d, J = 14.7 Hz, 2H), 4.01 (d, J = 13, 1 Hz, 1H), 3.84 - 3.60 (m, 4H), 3.37 (d, J = 13.9 Hz, 1H), 3.01 - 2.73 (m, 2H), 2, 33 - 2.17 (m, 1H), 2.07 (d, J = 8.6 Hz, 1H), 1.12 (d, J = 14.3 Hz, 3H), 0.85 (s, 5H ).

Example 97.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15- 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-tetraazahexadecan-14-yl)carbamate (97).

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, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 9.3 Hz, 1H), 7.95 (dd, J = 8.9, 4.2 Hz, 1H), 7.78 - 7.51 (m, 4H), 7.32 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 10.0 Hz, 1H), 6.94 (d, J = 8, 9 Hz, 1H), 6.77 (d, J = 9.9 Hz, 1H), 4.83 (s, 46H), 4.52 - 4.25 (m, 3H), 4.16 (d, J = 13.4 Hz, 2H), 3.96 (d, J = 13.1 Hz, 1H), 3.67 (d, J = 15.7 Hz, 7H), 3.26 (s, 5H) , 2.97-2.72(m, 4H), 2.02(s, 2H), 1.28-1.08(m, 10H), 1.02(s, 3H).

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F

Example 98.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15- 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-tetraazahexadecan-14-yl)carbamate (98).

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, 1H), 8.34 - 8.27 (m, 1H), 8.16 (d, J = 9.3 Hz, 1H), 7.86 (t, J = 8.4 Hz, 1H), 7.80 - 7.61 (m, 4H), 7.61 - 7.48 (m, 1H ), 7.33 (d, J = 7.9 Hz, 2H), 7.28 - 7.17 (m, 3H), 7.14 (d, J = 9.8 Hz, 1H), 6.99 - 6.92 (m, 1H), 6.79 (d, J = 10.0 Hz, 1H), 4.86 (s, 32H), 4.54 - 4.39 (m, 2H), 4, 35 - 4.26 (m, 1H), 4.17 (d, J = 13.1 Hz, 2H), 3.95 (t, J = 17.4 Hz, 4H), 3.67 (d, J = 16.6 Hz, 7H), 2.98 - 2.73 (m, 4H), 1.28 (d, J = 13.9 Hz, 5H), 1.20 - 1.08 (m, 10H) , 1.03 (s, 3H).

F

Example 99.

Methyl-((5S,8S,9S,14S)-11-(4-(5-(difluoromethyl)pyridin-2-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro9-hydroxy-15, 15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)ethynyl)benzyl)-3 ,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (99).

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, 1H), 8.10-8.00 (m, 3H), 7.72-7.60 (m, 4H), 7.33 (d, J= 7.9 Hz, 2H), 7.22 (d, J= 8.0 Hz, 2H), 7.11 (d, J= 18.4 Hz, 1H) , 6.88-6.75 (m, 3H), 4.96 (t, J = 7.6 Hz, 2H), 4.80 (d, J = 5.0 Hz, 1H), 4.54 ( s, 1H), 4.47 - 4.42 (m, 1H), 4.33 (dd, J = 16.8, 11.9 Hz, 4H), 4.20-4.12 (m, 4H) , 3.98 (d, J= 13.1 Hz, 1H), 3.67 (d, J= 17.6 Hz, 8H), 3.39 (d, J= 13.7 Hz, 2H), 2 .90 (dd, J= 10.5, 7.0 Hz, 3H), 2.84-2.77 (m, 1H), 2.27-2.19 (m, 2H), 2.11-2 .04 (m, 2H), 1.18-1.11 (m, 9H), 1.03 (s, 3H).

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Example 100.

Methyl-((5S,8S,9S,14S)-11 -(4-(6-(difluoromethyl)pyridin-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro9-hydroxy-15, 15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)ethynyl)benzyl)-3 ,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (100).

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, 1H), 8.31 - 8.22 (m, 2H), 7.79 (d, J = 8, 2 Hz, 1H), 7.73 - 7.61 (m, 2H), 7.34 (dd, J = 8.2, 3.3 Hz, 4H), 7.25 - 7.15 (m, 3H ), 6.93-6.84 (m, 2H), 6.77 (s, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.82-4.79 (m, 2H), 4.54 (s, 1H), 4.38 - 4.28 (m, 4H), 4.16 (s, 4H), 3.98 (d, J = 13.2 Hz, 1H), 3.67 (d, J = 21.9 Hz, 7H), 3.39 (d, J = 13.8 Hz, 2H), 2.96-2.76 (m, 5H), 2.28-2 .20 (m, 2H), 2.12-2.04 (m, 2H), 1.23-1.12 (m, 9H), 1.04 (s, 3H).

EXAMPLE 101.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15-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-tetraazahexadecan-14yl)carbamate (101).

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, 2H), 8.32-8.27 (m, 1H), 8.15 (d, J= 9.3 Hz, 1H), 7.97 (d, J= 8.5 Hz, 2H), 7.70 (dd, J= 8.8, 2.3 Hz, 1H), 7.44 - 7.29 (m, 4H), 7.24 (t, J = 9.4 Hz, 2H), 7.07 (t, J = 13.8 Hz, 1H), 6.81 (dd, J = 34 .9, 9.4 Hz, 2H), 4.96 (t, J = 7.6 Hz, 2H), 4.82 - 4.78 (m, 2H), 4.61 - 4.41 (m, 3H), 4.33 (dd, J= 18.6, 12.0 Hz, 4H), 4.16 (s, 4H), 3.99 (d, J= 13.1 Hz, 1H), 3, 68 (d, J= 8.8 Hz, 6H), 3.41 - 3.35 (m, 2H), 2.95 - 2.76 (m, 4H), 2.27 - 2.20 (m, 2H), 2.08 (d, J = 8.7 Hz, 2H), 1.15 (dd, J = 14.6, 11.3 Hz, 9H), 1.03 (s, 3H).

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Example 102.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15- 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-tetraazahexadecan-14-yl)carbamate (102).

Intermediates: I2, P14 and S3. MS (ESI) m/z 1135.4 [M+H]+. 1H NMR (400 MHz, methanol-d ₄ ) δ 8.54 (d, J = 2.9 Hz, 1H), 7.97-7.94 (m, 1H), 7.70-7.53 (m , 12H), 7.33 (d, J = 7.9 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 6.86 (d, J = 8.9 Hz, 1H ), 4.96 (t, J = 7.6 Hz, 2H), 4.84 - 4.81 (m, 1H), 4.54 (s, 1H), 4.44 (t, J = 5, 0 Hz, 1H), 4.38-4.29 (m, 3H), 4.15 (d, J=5.9 Hz, 4H), 3.98 (s, 1H), 3.67 (d, J = 15.3 Hz, 8H), 3.44 - 3.37 (m, 2H), 2.92 - 2.74 (m, 4H), 2.23 (dd, J = 9.6, 4, 5 Hz, 2H), 2.12-2.03 (m, 2H), 1.18-1.10 (m, 8H), 1.03 (s, 3H).

Example 103.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan14-yl)carbamate (103).

Intermediates: I2, P7 and S49. MS (ESI) m/z 1130.9 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.53 (d, J = 4.0 Hz, 3H), 8.19-8.11 (m, 3H), 7.38-7.32 (m, 3H) , 7.24 (t, J = 8.0 Hz, 5H), 7.16 (d, J = 9.9 Hz, 1H), 4.90 (t, J = 7.6 Hz, 3H), 4 .83-4.78 (m, 1H), 4.48-4.36 (m, 3H), 4.31 (d, J= 10.0 Hz, 1H), 4.17-4.08 (m , 4H), 3.93 (d, J = 13.3 Hz, 1H), 3.67 (d, J = 9.7 Hz, 9H), 2.93 - 2.72 (m, 6H), 1 .19-1.09 (m, 11H), 1.03 (s, 3H).

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Example 104.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (104).

Intermediates: I2, P4 and S50. MS (ESI) m/z 1158.2 [M+H]+. 1H NMR (400 MHz, methanol-d ₄ ) δ 8.31-8.29 (m, 1H), 8.16 (d, J=9.4 Hz, 1H), 8.10 (d, J=2 .7 Hz, 1H), 7.73-7.61 (m, 2H), 7.45 (d, J = 8.3 Hz, 3H), 7.33 (d, J = 7.8 Hz, 2H ), 7.22 (d, J = 8.0 Hz, 3H), 6.94 (dd, J = 5.7, 3.0 Hz, 2H), 4.30 (d, J=9.9 Hz , 1H), 4.19-4.06 (m, 5H), 3.95 (d, J = 13.2 Hz, 1H), 3.68 (d, J = 11.0 Hz, 10H), 3 .47 (yyy, J = 24.1, 12.1, 9.2 Hz, 5H), 2.93-2.74 (m, 5H), 2.11 (d, J = 10.4 Hz, 3H ), 1.77 (qd, J= 12.1, 4.6 Hz, 3H), 1.18-1.10 (m, 10H), 1.03 (s, 3H).

Example 105.

Methyl-((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-trioxo5- (1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (105).

Intermediates: I3, P14 and S3. MS (ESI) m/z 1081.1 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d ₄ ) δ 8.54 (d, J=2.9 Hz, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.15 (d, J=9.4Hz, 1H), 7.95(dd, J=8.9, 4.2Hz, 1H), 7.76-7.64(m, 2H), 7.60(d, J = 8.7 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.94 - 6.80 (m , 1H), 4.96 (t, J= 7.6 Hz, 2H), 4.85 (s, 14H), 4.54 (s, 1H), 4.43 (s, 1H), 4.39 -4.28 (m, 2H), 4.18-4.09 (m, 4H), 3.99 (d, J= 13.0 Hz, 1H), 3.82-3.58 (m, 8H ), 3.41-3.33(m, 2H), 3.00-2.71(m, 4H), 2.23 (dd, J= 9.8, 4.6 Hz, 2H), 2, 14 -2.01 (m, 2H), 1.13 (d, J = 12.5 Hz, 6H), 0.86 (s, 9H).

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Example 106.

Methyl-((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-trioxo5- (1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (106).

Intermediates: I3, P36 and S45. MS (ESI) m/z 1078.8 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.71 (s, 1H), 8.16 (d, J = 9.4 Hz, 1H), 7.72 (d, J = 8.3 Hz, 2H ), 7.62 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 7.8 Hz, 2H), 7.24 (s, 0H), 6.81 (d, J = 9.9 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.54 (s, 1H), 4.50-4.30 (m, 3H), 4.15 (t, J= 10.1 Hz, 4H), 4.01 (d, J= 13.1 Hz, 1H), 3.81 - 3 .55 (m, 7H), 3.37 (d, J = 13.8 Hz, 2H), 3.00 - 2.74 (m, 4H), 2.56 (s, 3H), 2.22 ( dd, J = 9.6, 4.4 Hz, 2H), 2.13-1.97 (m, 2H), 1.14 (d, J = 10.5 Hz, 6H), 0.85 (s , 9H).

Example 107.

Methyl-((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-5( 1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (107).

Intermediates: I3, P36 and S3. MS (IER) m/z 1064.3 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 9.15 (s, 1H), 8.59 (s, 1H), 8.32-8.26 (m, 1H), 7.76 -7.66 ( m, 3H), 7.33 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.89 - 6.84 (m, 1H), 6.79 (d, J = 9.8 Hz, 1H), 4.96 (t, J = 7.6 Hz, 3H), 4.84-4.79 (m, 3H), 4.54 (s , 1H), 4.44 (d, J = 6.5 Hz, 1H), 4.39 - 4.31 (m, 2H), 4.16 (d, J = 4.9 Hz, 4H), 4 .01 (d, J = 13.1 Hz, 1H), 3.78 -3.63 (m, 9H), 3.43-3.36 (m, 2H), 2.94-2.77 (m , 5H), 2.27-2.19 (m, 2H), 2.11-2.04 (m, 2H), 1.13 (d, J= 10.7 Hz, 6H), 0.86 ( s, 9H).

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Example 108.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((6-(8-((3-methyloxetan-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan3-yl)pyridin-3 - yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl )carbamate (108).

Intermediates: I2, P7 and S56. 1H NMR (400 MHz, methanol-d ₄ ) δ 8.52 (d, J = 0.7 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.75 - 7.61 (m, 2H), 7.57 - 7.46 (m, 1H), 7.39 - 7.30 (m, 2H), 7 .23 (dd, J= 10.8, 8.2 Hz, 4H), 7.12 (d, J= 9.9 Hz, 1H), 6.80 (dd, J= 31.1, 9.4 Hz, 2H), 4.61 (d, J=6.3 Hz, 2H), 4.50-4.36 (m, 3H), 4.30-4.23 (m, 3H), 4.12 (d, J= 12.2 Hz, 3H), 3.93 (d, J= 13.2 Hz, 1H), 3.81 (d, J=11.0 Hz, 0H), 3.68 (d , J= 10.0 Hz, 6H), 3.56 (s, 1H), 3.45 (d, J= 14.1 Hz, 1H), 2.98-2.64 (m, 4H), 2 .38 (d, J = 11.2 Hz, 2H), 2.19 - 2.05 (m, 2H), 1.62 (s, 2H), 1.22 - 1.08 (m, 9H), 1.00 (d, J = 26.6 Hz, 4H).

Example 109.

Methyl-((5S,8S,9S,14S)-8-(4-((6-(8-(azetidin-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridine3 -yl)ethynyl)benzyl)-11-(4-(1-(difluoromethyl)-1 H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9hydroxy-15,15 -dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (109).

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-d ₄ ) δ 8.51 (d, J= 0.7 Hz, 1H), 8.11 (s, 2H), 7.70 (dd, J= 8.9, 2 .3 Hz, 1H), 7.35 - 7.31 (m, 2H), 7.26 - 7.20 (m, 4H), 6.87 - 6.84 (m, 1H), 4.44 ( d, J = 6.5 Hz, 1H), 4.33 -4.22 (m, 6H), 4.19 - 4.04 (m, 7H), 3.93 (d, J = 13.2 Hz , 1H), 3.68 (d, J = 9.4 Hz, 9H), 3.54 (s, 3H), 3.43 (d, J = 13.7 Hz, 3H), 2.93 - 2 .73 (m, 5H), 2.28 (dd, J = 8.6, 3.7 Hz, 2H), 2.13-2.05 (m, 2H), 1.19-1.10 (m , 9H), 1.04 (s, 3H).

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Example 110.

Tert-butyl-3 -((3-(5-((4-((2S,3 S)-4-( 1-(4-(1 -(difluoromethyl)-1 H-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 (110).

Intermediates: I2, P7 and S51. MS (ESI) m/z 1268.3 [M+H]+. 1H NMR (400 MHz, methanol-d ₄ ) δ 8.51 (d, J= 0.7 Hz, 1H), 8.11 (s, 2H), 7.70 (dd, J= 8.9, 2 .3 Hz, 1H), 7.35-7.31 (m, 2H), 7.26-7.19 (m, 4H), 6.88-6.84 (m, 1H), 4.44 ( d, J=6.5 Hz, 1H), 4.33-4.22 (m, 6H), 4.19-4.05 (m, 7H), 3.93 (d, J= 13.2 Hz , 2H), 3.68 (d, J = 9.4 Hz, 16H), 3.54 (s, 3H), 3.43 (d, J = 13.7 Hz, 2H), 2.94 - 2 .74 (m, 6H), 2.28 (dd, J = 8.6, 3.7 Hz, 2H), 2.12-2.06 (m, 2H), 1.18-1.10 (m , 9H), 1.04 (s, 3H).

Example 111.

Methyl-((5S,8S,9S,14S)-16,16,16-trifluoro-11-(4-(5-fluoropyridin-2-yl)benzyl)-9-hydroxy-15,15dimethyl-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-tetraazahexadecan-14-yl)carbamate (111).

Intermediates: I2, P37 and S3. MS (ESI) m/z 1100.4 [M+H] ⁺ . 1 H NMR (400 MHz, methanol-d ₄ ) δ 8.50 (d, J=2.9 Hz, 1H), 7.88 (dd, J=8.7, 4.2 Hz, 3H), 7, 72 - 7.63 (m, 3H), 7.49 (d, J = 7.9 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.8 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.84 - 4.80 (m , 3H), 4.54 (s, 1H), 4.42-4.32 (m, 4H), 4.25 (d, J = 6.6 Hz, 1H), 4.15 (d, J= 4.7 Hz, 3H), 4.05 - 4.00 (m, 1H), 3.92 (d, J = 13.3 Hz, 1H), 3.75 (d, J = 8.3 Hz, 1H), 3.68 (s, 3H), 3.58 (s, 3H), 3.39 (d, J = 13.8 Hz, 3H), 2.93 2.71 (m, 5H), 2 .28 - 2.19 (m, 2H), 2.07 (d, J= 8.6 Hz, 2H), 1.11 (d, J= 8.0 Hz, 7H), 1.02 (s, 3H), 0.83 (s, 3H).

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Example 112.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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-tetraazahexadecan-14yl)carbamate (112).

Intermediates: I2, P4 and S48. MS (ESI) m/z 1129.9 [M+H]+. I NMR (400 MHz, methanol-d ₄ ) δ 8.33 - 8.29 (m, 1H), 8.14 (d, J=9.4 Hz, 1H), 8.10 (d, J=2 .7 Hz, 1H), 7.74-7.61 (m, 2H), 7.53 (s, 1H), 7.45 (t, J = 6.9 Hz, 2H), 7.39 - 7 .31 (m, 3H), 7.22 (d, J = 8.2 Hz, 3H), 7.09 (d, J = 9.9 Hz, 1H), 6.98 - 6.91 (m, 2H), 4.94 - 4.88 (m, 3H), 4.42 (td, J = 7.9, 7.2, 4.1 Hz, 2H), 4.35 - 4.27 (m, 2H), 4.20 - 4.11 (m, 3H), 3.95 (d, J = 13.2 Hz, 3H), 3.79 - 3.65 (m, 11H), 2.94 - 2 .84 (m, 3H), 2.83-2.74 (m, 1H), 1.21-1.10 (m, 9H), 1.04 (d, J=7.2 Hz, 3H).

Example 113.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzyl)-16,16,16-trifluoro-9hydroxy-15,15- dimethyl-8-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13trioxo-5 -(1,1 ,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (113).

Intermediates: I2, P9 and S48. MS (ESI) m/z 1093.9 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.38 (s, 1H), 8.31-8.28 (m, 1H), 8.06 (s, 1H), 7.70 (dd, J = 8.8, 2.3 Hz, 1H), 7.57-7.52 (m, 3H), 7.48 (s, 1H), 7.41 (d, J = 8.0 Hz, 2H ), 7.32 (d, J= 7.4 Hz, 2H), 7.21 (d, J= 8.1 Hz, 2H), 6.95 (d, J= 8.9 Hz, 1H), 4.944.89 (m, 3H), 4.85-4.80 (m, 2H), 4.45-4.37 (m, 3H), 4.25 (s, 1H), 4.15 (s, 1H), 4.01 -3.84 (m, 6H), 3.74 (d, J = 8.9 Hz, 1H), 3.68 (s, 3H), 3.60 (s, 3H), 2.89 (d, J= 8.9 Hz, 2H), 2.85-2.67 (m, 3H), 1.28 (d, J= 13.9 Hz, 5H), 1.11 (d , J= 12.5 Hz, 6H), 1.01 (s, 3H), 0.88-0.81 (m, 3H).

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Example 114.

Methyl-((5S,8S,9S, 14S)-11 -(4-( 1 -(difluoromethyl)-1 H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (114).

Intermediates: I2, P7 and S57. MS (ESI) m/z 1144.4 [M+H]+. ¹ H NMR (400 MHz, methanold4) δ 8.52 (s, 1H), 8.30 (d, J=2.2 Hz, 1H), 8.12 (s, 2H), 7.71 -7, 64 (m, 1H), 7.36-7.30 (m, 2H), 7.23 (dd, J= 11.8, 8.2 Hz, 4H), 7.13 (d, J= 9, 8 Hz, 1H), 6.93 (d, J= 8.9 Hz, 1H), 6.78 (d, J= 9.9 Hz, 1H), 4.46 - 4.41 (m, 1H) , 4.31 (d, J = 9.5 Hz, 1H), 4.21 - 4.00 (m, 7H), 3.97 - 3.85 (m, 3H), 3.78 - 3.65 (m, 9H), 3.42 (s, 5H), 2.94 - 2.74 (m, 5H), 2.43 (dtd, J = 12.8, 8.2, 4.3 Hz, 2H ), 2.24 (yyy, J= 13.7.9.2, 5.0 Hz, 1H), 1.20-1.10 (m, 9H), 1.03 (s, 3H).

Example 115.

Methyl-((5S,8S,9S,14S)-11 -(4-( 1 -(difluoromethyl)-1 H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9- hydroxy-15,15-dimethyl -3,6,13-trioxo-8-(4-((6-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1yl)pyridin-3-yl)ethynyl )benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (115).

Intermediates: I2, P7 and S50. MS (ESI) m/z 1158.0 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-dj δ 8.52 (d, J= 0.8 Hz, 1H), 8.30 (dd, J= 2.3, 0.8 Hz, 1H), 8.12 (d, J= 6.0 Hz, 2H), 7.70 (dd, J= 8.9, 2.3 Hz, 1H), 7.36 - 7.31 (m, 3H), 7.27 - 7.20 (m, 5H), 6.96 - 6.91 (m, 1H), 4.43 (d, J = 9.7 Hz, 2H), 4.31 (d, J = 9.9 Hz , 1H), 4.11 (dq, J= 11.3, 6.3, 4.7 Hz, 5H), 3.93 (d, J= 13.2 Hz, 2H), 3.68 (d, J = 10.2 Hz, 9H), 3.56 - 3.40 (m, 5H), 2.93 - 2.73 (m, 5H), 2.14 - 2.06 (m, 3H), 1 .77 (qd, J= 12.1, 4.7 Hz, 3H), 1.18-1.11 (m, 10H), 1.03 (s, 3H).

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Example 116.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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-tetraazahexadecan-14yl)carbamate (116).

Intermediates: 12, P7 and S48. MS (ESI) m/z 1130.4 [M+H]+. 1H NMR (400 MHz, methanol-d ₄ ) δ 8.53 (d, J=0.7 Hz, 1H), 8.31-8.28 (m, 1H), 8.13 (d, J=10 .9 Hz, 2H), 7.70 (dd, J = 8.9, 2.3 Hz, 1H), 7.36 - 7.30 (m, 3H), 7.23 (dd, J = 11, 5, 8.1 Hz, 5H), 7.13 (d, J= 10.0 Hz, 1H), 6.95 (d, J= 8.8 Hz, 1H), 4.90 (t, J= 7.7 Hz, 3H), 4.82 (s, 2H), 4.42 (δ, J= 9.9, 7.1, 3.6 Hz, 2H), 4.31 (d, J= 10 .0 Hz, 1H), 4.20 - 4.09 (m, 3H), 3.93 (d, J = 11.8 Hz, 5H), 3.68 (d, J = 10.1 Hz, 8H ), 2.95-2.73 (m, 5H), 1.21-1.10 (m, YuH), 1.03 (s, 4H).

Example 117.

Methyl-((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-4-yl)benzyl)-9-hydroxy-15,15-dimethyl8-(4-((6 -(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13trioxo-5 -(1, 1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (117).

Intermediates: I3, P46 and S3. MS (ESI) m/z 1056.2 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d ₄ ) δ 7.99 (s, 1H), 7.77 (s, 1H), 7.70 (dd, J = 8.9, 2.3 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.39 - 7.30 (m, 5H), 7.20 (d, J = 8.1 Hz, 2H), 6.86 (d , J = 8.9 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.82 (dd, J = 8.2, 5.1 Hz, 3H), 4.54 (s, 1H), 4.41-4.31 (m, 4H), 4.18-4.09 (m, 3H), 3.97-3.87 (m, 2H), 3.77 (d , J= 9.6 Hz, 1H), 3.73 - 3.60 (m, 9H), 3.44 - 3.36 (m, 2H), 2.96 - 2.75 (m, 4H), 2.26-2.19 (m, 2H), 2.10-2.04 (m, 2H), 1.15-0.97 (m, 11H), 0.77 (s, 9H).

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Example 118.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2-fluorobenzyl)-16,16,16-trifluoro9-hydroxy-15 ,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5yl)ethynyl)benzyl)- 3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (118) .

Intermediates: I2, P5 and S7. MS (ESI) m/z 1138.2 [M+H]+. 1H NMR (400 MHz, methanold4) δ 8.52 (d, J = 1.0 Hz, 2H), 8.10 (d, J = 9.4 Hz, 1H), 7.76 (d, J = 1 .7 Hz, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.45 (t, J = 58.0 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 7.26 - 7.18 (m, 4H), 7.16 (d, J = 9.8 Hz, 1H), 6.79 (d, J = 9.9 Hz, 1H), 6.56 (d, J = 1.7 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.76 (s, 1H), 4.48 - 4.36 (m , 1H), 4.28 - 4.18 (m, 2H), 4.14 (s, 3H), 4.08 (s, 1H), 3.98 (d, J = 13.7 Hz, 1H) , 3.75 (s, 1H), 3.58 (s, 3H), 3.47 (d, J = 14.5 Hz, 2H), 2.91 (d, J = 9.2 Hz, 2H) , 2.83 (d, J = 6.6 Hz, 2H), 2.27 - 2.15 (m, 2H), 1.99 (d, J = 8.8 Hz, 2H), 1.14 ( s, 3H), 1.13 (s, 3H), 1.09 (s, 3H), 0.95 (s, 3H).

Example 119.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(2-methylpyrimidin-5-yl)benzyl)-16,16,16-trifluoro-9hydroxy-15,15- dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5yl)ethynyl)benzyl)-3.6 ,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (119).

Intermediates: 12, P47 and S7. MS (ESI) m/z 1133.32 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.97 (s, 1H), 8.52 (s, 1H), 8.14 (d, J = 9.4 Hz, 1H), 7.34 (dd , J = 8.0, 5.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 10.0 Hz, 2H), 6.79 (d, J = 9.9 Hz, 2H), 4.96 (t, J = 7.6 Hz, 2H), 4.81 - 4.73 (m, 6H), 4.44 (d, J = 9.9 Hz, 2H), 4.29 (d, J = 10.0 Hz, 2H), 4.16 (d, J = 14.0 Hz, 2H), 3.96 (d, J = 13, 2 Hz, 1H), 3.67 (d, J = 15.8 Hz, 10H), 3.46 (d, J = 14.5 Hz, 1H), 3.20 - 3.12 (m, 2H) , 2.95 - 2.79 (m, 2H), 2.74 (s, 3H), 2.22 (dd, J = 14.5, 8.2 Hz, 1H), 1.99 (d, J = 8.8 Hz, 1H), 1.27 - 1.09 (m, 10H), 1.04 (s, 6H).

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Example 120.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane- 3yl)pyrimidin-5-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3 ,8diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2methylpropan-2-yl)- 2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (120).

Intermediates: I2, P20 and S7. MS (ESI) m/z 1284.4 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.73 (s, 2H), 8.53 (s, 2H), 8.19 (d, J = 9.4 Hz, 1H), 7.35 ( d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.5 Hz, 5H), 6.84 (d, J = 9.8 Hz, 1H), 5.04 - 4, 92 (m, 5H), 4.80 (d, J = 4.3 Hz, 2H), 4.44 (d, J = 9.9 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.15 (s, 6H), 3.95 (d, J = 13.2 Hz, 1H), 3.74 (s, 1H), 3.69 (s, 3H), 3, 66 (s, 3H), 3.47 (dd, J = 14.4, 9.6 Hz, 5H), 2.91 (d, J = 7.7 Hz, 2H), 2.79 (d, J = 9.6 Hz, 1H), 2.21 (s, 4H), 1.99 (t, J = 7.3 Hz, 5H), 1.17 (s, 3H), 1.14 (s, 3H ), 1.11 (s, 3H), 1.03 (s, 3H).

Example 121.

Methyl-((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-5yl)ethynyl) benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (121).

Intermediates: I1, P4 and S7. MS (IER) m/z 1048.4 [M+H] ⁺ . ¹ H NMR (400 MHz, methanold4) δ 8.44 (s, 2H), 8.01 (d, J = 2.7 Hz, 1H), 7.77 (d, J = 9.5 Hz, 1H) , 7.44 (t, J = 59.7 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7 .15 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 2.8 Hz, 1H), 4.87 (dd, J = 8.1, 7.0 Hz, 2H) , 4.71 (dd, J = 8.1, 5.1 Hz, 2H), 4.02 (d, J = 13.8 Hz, 4H), 3.87 (d, J = 13.4 Hz, 1H), 3.80 (s, 1H), 3.72-3.62 (m, 1H), 3.58 (s, 3H), 3.55 (s, 2H), 3.38 (d, J = 1.6 Hz, 1H), 3.34 (s, 1H), 2.83 (t, J = 7.0 Hz, 1H), 2.72 (s, 2H), 2.11 (s, 2H ), 1.89 (d, J = 9.1 Hz, 2H), 0.79 (s, 8H), 0.74 (s, 8H).

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Example 122.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9hydroxy-15,15- dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5yl)ethynyl)benzyl)-3.6 ,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (122).

Intermediates: I2, P6 and S7. MS (ESI) m/z 1121.0 [M+H]+. 1H NMR (400 MHz, methanold4) δ 8.52 (s, 2H), 8.09 (d, J = 9.4 Hz, 1H), 8.04 (d, J = 2.7 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.49 (t, J = 60.0 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7. 34 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 9.8 Hz, 1H), 6.86 ( d, J = 2.7 Hz, 1H), 6.76 (d, J = 9.9 Hz, 1H), 4.95 (t, J = 7.6 Hz, 2H), 4.82 - 4, 78 (m, 2H), 4.75 (s, 1H), 4.39 (d, J = 9.8 Hz, 1H), 4.24 (d, J = 9.8 Hz, 1H), 4. 18 (d, J = 8.3 Hz, 1H), 4.16 - 4.08 (m, 2H), 4.00 (d, J = 13.1 Hz, 1H), 3.88 (d, J = 13.4 Hz, 1H), 3.74 (s, 1H), 3.67 (s, 3H), 3.59 (s, 3H), 3.46 (d, J = 14.5 Hz, 2H ), 2.96 - 2.86 (m, 2H), 2.86 - 2.68 (m, 2H), 2.29 - 2.13 (m, 2H), 2.04 - 1.88 (m , 2H), 1.11 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H), 0.84 (s, 3H).

Example 123.

Methyl-((5S,8S,9S,14S)-Π-(4-(1-(difluoromethyl)-III-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-3,6,13-trioxo-8-(4-((2-(3-oxopiperazin-1-yl)pyrimidin-5yl)ethynyl)benzyl)-5-(1,1,1 -trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14yl)carbamate (123).

Intermediates: I2, P4 and S58a. MS (ESI) m/z 1088.2 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.49 (s, 2H), 7.53 (t, J = 59.7 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H ), 7.34 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 10.1 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.82 (d, J = 10.0 Hz, 1H), 4.50 - 4.39 (m, 1H), 4.38 (s , 2H), 4.34 - 4.26 (m, 1H), 4.14 (d, J = 12.5 Hz, 2H), 4.10 - 3.99 (m, 2H), 3.94 ( d, J = 13.1 Hz, 1H), 3.80 3.72 (m, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 3.45 - 3.38 ( m, 2H), 2.94 - 2.82 (m, 3H), 2.82 - 2.73 (m, 1H), 1.16 (s, 3H), 1.14 (s, 3H), 1 .11 (s, 3H), 1.06 - 0.99 (m, 3H).

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Example 124.

Methyl-((5S,8S,9S, 14S)-11 -(4-( 1 -(difluoromethyl)-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9- hydroxy-8-(4-((6-(8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)ethynyl)benzyl)-15,15-dimethyl -3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetr aazahexadecan-14-yl)carbamate (124 ).

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, 1H), 8.20 - 8.07 (m, 1H), 7.74 - 7.66 (m , 1H), 7.48 - 7.30 (m, 4H), 7.22 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 2.8 Hz, 1H), 6 .86 (d, J= 8.9 Hz, 1H), 4.44 (s, 1H), 4.31 (s, 1H), 4.28 (s, 3H), 4.14 (d, J= 12.1 Hz, 2H), 3.94 (d, J = 13.1 Hz, 1H), 3.83-3.77 (m, 2H), 3.68 (d, J = 12.0 Hz, 7H), 3.44 (s, 4H), 3.35 (s, 3H), 2.94 2.84 (m, 3H), 2.78 (dd, J = 12.6, 9.1 Hz, 1H), 2.32 - 2.24 (m, 2H), 2.06 (d, J = 8.6 Hz, 2H), 1.24 - 1.09 (m, 8H), 1.03 (s , 2H).

Example 125.

Methyl-((5S,8S,9S, 14S)-11 -(2,6-difluoro-4-(5-methylpyridin-2-yl)benzyl)-16,16,16-trifluoro-9hydroxy-15,15- dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)ethynyl)benzyl)-3.6 ,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (125).

Intermediates: I2, P39 and S3. MS (ESI) m/z 1128.8 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.56 (s, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 9.5 Hz, 1H), 8.01 - 7.88 (m, 2H), 7.70 (dd, J = 8.8, 2.3 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H ), 7.33 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.83 (dd, J = 28.9, 9.4 Hz , 2H), 4.96 (t, J = 7.6 Hz, 2H), 4.48 - 4.40 (m, 1H), 4.39 - 4.27 (m, 3H), 4.22 - 4.12 (m, 4H), 3.98 (d, J = 13.1 Hz, 1H), 3.75 (s, 1H), 3.70 (s, 3H), 3.64 (s, 3H ), 3.46 - 3.37 (m, 2H), 2.95 - 2.75 (m, 5H), 2.46 (s, 3H), 2.24 (dd, J = 9.9, 4 .5 Hz, 2H), 2.07 (d, J = 8.6 Hz, 2H), 1.34-1.21 (m, 1H), 1.19-1.06 (m, 9H), 1 .03 (s, 3H).

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Example 126.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15- 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-tetraazahexadecan-14yl)carbamate (126).

Intermediates: I2, P42 and S3. MS (ESI) m/z 1105.3 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.15 (d, J = 9.4 Hz, 1H), 7.70 (dd, J = 9.4, 2.8 Hz, 2H), 7, 35 (dd, J = 14.0, 8.3 Hz, 4H), 7.22 (d, J = 7.9 Hz, 2H), 6.86 (d, J = 8.9 Hz, 1H), 6.81 -6.72 (m, 2H), 4.97 (t, J = 7.6 Hz, 2H), 4.53 (s, 1H), 4.44 (d, J = 9.5 Hz , 1H), 4.34 (t, J= 12.5 Hz, 3H), 4.15 (s, 3H), 3.95 (d, J= 13.2 Hz, 1H), 3.68 (d , J \u003d 14.3 Hz, 10H), 3.39 (d, J \u003d 13.9 Hz, 2H), 2.94 - 2.76 (m, 4H), 2.27 - 2.19 (m, 2H), 2.08 (d, J = 8.5 Hz, 2H), 1.20 - 1.10 (m, 9H), 1.03 (s, 3H).

Example 127.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-(oxetan-3-yloxy)pyridin-2-yl)benzyl)-16,16,16trifluoro-9 -hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridin-3-yl) ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (127).

Intermediates: I2, P43 and S3. MS (ESI) m/z 1188.2 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.65 (d, J = 6.6 Hz, 1H), 8.32 - 8.26 (m, 1H), 7.70 (dd, J = 8 .8, 2.3 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.30 - 7.19 (m, 3H), 6.84 (dd, J = 21.8, 9.4 Hz, 1H), 5.76 - 5.64 (m, 1H), 5.11 (t, J = 6.9 Hz, 2H ), 4.95 (t, J= 7.6 Hz, 2H), 4.90-4.73 (m, 3H), 4.59-4.51 (m, 1H), 4.44 (t, J = 5.1 Hz, 1H), 4.32 (td, J = 14.6, 5.4 Hz, 3H), 4.25 - 4.12 (m, 4H), 4.05 - 3.95 (m, 1H), 3.68 (d, J = 17.7 Hz, 5H), 3.48 - 3.39 (m, 2H), 3.35 (s, 4H), 2.91 (d, J= 8.2 Hz, 2H), 2.83 (s, 1H), 2.24 (dd, J= 9.7, 4.5 Hz, 2H), 2.07 (d, J= 8.6 Hz, 2H), 1.15 (d, J=5.7 Hz, 8H), 1.04 (s, 2H).

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Example 128.

Methyl-((5S,8S,9S, 14S)-11 -(2,6-difluoro-4-(1-methyl-1 H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9hydroxy -15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)ethynyl)benzyl )-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate ( 128).

Intermediates: I2, P41 and S3. MS (ESI) m/z 1119.9 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.29 (d, J = 2.2 Hz, 1H), 7.77-7.67 (m, 1H), 7.61 (d, J = 2 .3 Hz, 1H), 7.33 (d, J= 8.2 Hz, 4H), 7.22 (d, J = 8.2 Hz, 2H), 6.88 (d, J= 8.9 Hz, 1H), 6.65 (d, J= 2.3 Hz, 1H), 4.95 (t, J= 7.6 Hz, 2H), 4.85 (dd, J= 8.2, 5 .1 Hz, 2H), 4.55 (p, J = 6.2 Hz, 1H), 4.45 (d, J = 8.5 Hz, 1H), 4.34 (dd, J = 14.5 , 2.5 Hz, 3H), 4.19-4.08 (m, 4H), 3.93 (s, 4H), 3.68 (d, J=9.4 Hz, 6H), 3.48 - 3.39 (m, 2H), 3.35 (s, 1H), 2.99 (s, 1H), 2.94-2.73 (m, 5H), 2.27-2.19 (m , 2H), 2.08 (t, J = 6.9 Hz, 2H), 1.35 - 1.26 (m, 1H), 1.24 - 1.09 (m, 9H), 1.03 ( s, 3H).

Example 129.

Methyl-((5S,8S,9S, 14S)-11 -(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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-4,7,11,12tetraazahexadecan-14-yl)carbamate (129).

Intermediates: I2, p4o and S3. MS (ESI) m/z 1147.4 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.33 - 8.26 (m, 1H), 8.16 (d, J = 9.4 Hz, 1H), 7.70 (dt, J = 9, 1, 2.4 Hz, 1H), 7.54 (d, J = 7.3 Hz, 2H), 7.37 - 7.32 (m, 2H), 7.23 (d, J = 8.2 Hz, 2H), 6.91 - 6.77 (m, 1H), 4.96 (t, J=7.6 Hz, 2H), 4.84 (dd, J=8.2, 5.1 Hz , 2H), 4.59-4.52 (m, 1H), 4.52-4.40 (m, 1H), 4.39-4.24 (m, 3H), 4.22-4.13 (m, 4H), 3.96 (d, J = 12.9 Hz, 1H), 3.75 (d, J = 9.0 Hz, 1H), 3.72 - 3.63 (m, 6H) , 3.46 - 3.38 (m, 2H), 2.91 (d, J = 8.7 Hz, 2H), 2.88 - 2.74 (m, 2H), 2.36 - 2.20 (m, 3H), 2.08 (d, J = 8.6 Hz, 2H), 1.32 - 1.16 (m, 6H), 1.15 (s, 4H), 1.13 (s, 3H), 1.03 (s, 2H), 0.89 (s, 1H).

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Example 130.

Methyl-((5 S,8S,9S,14S)-11 -(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15dimethyl -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-tetraazahexadecan-14-yl)carbamate (130).

Intermediates: I2, P28 and S3. MS (ESI) m/z 1116.6 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d ₄ ) δ 8.71 (s, 1H), 8.29 (d, J= 2.2 Hz, 1H), 8.17 (d, J= 8.5 Hz, 1H), 8.09 (t, J= 7.8 Hz, 1H), 8.01 (d, J= 7.9 Hz, 1H), 7.70 (dd, J= 8.8, 2.3 Hz, 1H), 7.64 - 7.52 (m, 3H), 7.34 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 9.5 Hz, 1H), 6.84 (dd, J = 25.9, 9.4 Hz, 2H), 4.96 (t, J = 7.6 Hz, 2H ), 4.83 (dd, J = 8.2, 5.1 Hz, 2H), 4.55 (d, J = 7.8 Hz, 1H), 4.48 - 4.41 (m, 1H) , 4.35 (dd, J = 14.5, 2.5 Hz, 3H), 4.19 - 4.13 (m, 4H), 3.99 (d, J = 7.6 Hz, 1H), 3.75 (s, 1H), 3.70 (s, 4H), 3.64 (s, 3H), 3.46-3.32 (m, 3H), 2.93 (s, 2H), 2 .24 (dd, J = 9.6, 4.6 Hz, 2H), 2.07 (d, J=8.6 Hz, 2H), 1.19-1.10 (m, 9H), 1, 03 (s, 3H).

Example 131.

S6. PdCI ₂ (PPh ₃ ) ₂ Pd(tBu ₂ PPh) ₂ CI ₂ KH ₂ PO ₄ ______

Methyl-((5S,10S,11S,14S)-8-(4-ethynyl-2,6-difluorobenzyl)-16,16,16-trifluoro-10-hydroxy-11 -(4iodobenzyl)-15.15 -dimethyl-3,6,13 -trioxo-5-(1,1,1 -trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12tetraazahexadecan-14-yl)carbamate (131a ).

The title compound 131a was prepared according to the procedure described for the synthesis of compound 1a, but using compound P38. MS (ESI) m/z 924.2 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 7.52 (d, J = 8.0 Hz, 2H), 7.00 (dd, J = 11.2, 7.8 Hz, 4H), 4.44 (s, 1H), 4.27 (s, 1H), 4.17-4.01 (m, 2H), 3.90 (d, J = 13.2 Hz, 1H), 3.71 (t, J = 5.9 Hz, 8H), 2.82 (d, J = 7.8 Hz, 2H), 2.77 - 2.67 (m, 1H), 1.17 (s, 3H), 1, 14 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H).

Methyl-((5S,8S,9S,14S)-11-(4-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)- 2,6difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1

- 150 040208 trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (131b).

To a solution of compound 131a (62 mg, 0.07 mmol) in THF (2 ml) was added copper (52 mg, 0.818 mmol), 10% CuSO ₄ (100 μl) and 1-azidobicyclo[1.1.1]pentane in CuSO ₄ (0.300 ml, 0.082 mmol). After 2 hours more 1-azidobicyclo[1.1.1]pentane in CuSO ₄ (0.300 mL, 0.082 mmol) was added. The resulting mixture was stirred for an additional 2 hours, more 1-azidobicyclo[1.1.1]pentane in CuSO ₄ (0.300 mL, 0.082 mmol) was added and then stirred for 48 hours. The reaction mixture was partitioned between EtOAc and brine. The organic extract was washed with NH4Cl solution and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (2575% EtOAc/hex) to give compound 131b. MS (ESI) m/z 1032.1 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 8.1 Hz, 2H), 4.44 (s, 1H), 4.30 (s, 1H), 4.17 - 4.03 (m, 3H), 3.93 (d, J = 13.2 Hz, 1H), 3.71 (s, 4H), 3.66 (s, 3H), 2.86 - 2.67 (m, 5H), 2.45 (s, 7H), 1.16 (s, 4H), 1.14 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H), 0.89 (d, J = 6.7 Hz, 1H).

Methyl-((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-3yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2- oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (131).

The title compound 131 was obtained according to the method described for the synthesis of compound 1, but using compounds 131b and S7. MS (ESI) m/z 1174.1 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.53 (s, 3H), 8.51 (s, 1H), 8.19 (d, J = 9.4 Hz, 1H), 7.43 (d , J = 8.1 Hz, 3H), 7.34 (d, J = 7.8 Hz, 3H), 7.23 (d, J = 7.8 Hz, 3H), 7.18 (d, J = 9.9 Hz, 1H), 6.83 (d, J = 10.1 Hz, 1H), 4.96 (t, J = 7.6 Hz, 3H), 4.80 (d, J = 7 .3 Hz, 6H), 4.44 (d, J = 9.6 Hz, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.15 (d, J = 6.5 Hz, 5H), 3.94 (d, J = 13.1 Hz, 1H), 3.72 (s, 2H), 3.68 (d, J = 9.6 Hz, 8H), 3.48 ( s, 2H), 3.44 (s, 1H), 2.96 -2.81 (m, 3H), 2.79 (d, J = 10.1 Hz, 1H), 2.74 (s, 1H ), 2.45 (s, 8H), 2.21 (d, J = 10.4 Hz, 3H), 1.99 (d, J = 9.2 Hz, 3H), 1.16 (s, 5H ), 1.14 (s, 8H), 1.11 (s, 4H), 1.02 (s, 4H).

Example 132.

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).

The title compound 132a was obtained according to the method described for the synthesis of compound 1a, but using compounds I2a and P7. MS (ESI) m/z 764.0 [M+H] ⁺ .

Synthesis of tert-butyl-2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-4-(4-((6-((2S,6R)-2,6-dimethylmorpholino)pyridine-3 -yl)ethynyl)phenyl)-2-hydroxybutyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6difluorobenzyl)hydrazine-1-carboxylate (132b).

The title compound 132b was prepared according to the method described for the synthesis of compound 1, but using compounds 132a and S23. MS (ESI) m/z 852.0 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H), 8.19 - 8.08 (m, 2H), 7.93 (d, J = 9.4 Hz, 1H), 7 .50 (t, J = 59.7 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.1 Hz, 5H), 4.07 (d, J = 12.9 Hz, 2H), 3.74 (yyy, J = 10.7, 6.3, 2.5 Hz, 1H), 3.62 (s, 1H), 2.87 - 2.69 (m, 3H), 1.37 (s, 7H), 1.31 (s, 5H), 1.27 (s, 3H), 1.25 (s, 3H).

Methyl-((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- 151 040208 dimethyl-3,6,13-trioxo -5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14yl)carbamate (132).

The title compound 132 was prepared according to the method described for the synthesis of intermediate I2, but using compound 132b. MS (ESI) m/z 1102.3 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.54 (d, J = 0.7 Hz, 1H), 8.25 - 8.10 (m, 3H), 7.83 (d, J = 9, 1 Hz, 1H), 7.51 (s, 1H), 7.35 (d, J = 7.3 Hz, 2H), 7.24 (t, J = 7.7 Hz, 4H), 7.15 (dd, J = 20.4, 9.7 Hz, 1H), 6.82 (d, J = 10.0 Hz, 1H), 4.44 (d, J = 9.8 Hz, 1H), 4 .31 (d, J = 9.9 Hz, 1H), 4.21 - 4.03 (m, 4H), 3.93 (d, J = 13.2 Hz, 1H), 3.81 - 3, 61 (m, 6H), 2.97-2.80 (m, 2H), 2.80-2.66 (m, 2H), 2.03 (s, 1H), 1.25 (d, J= 6.2 Hz, 6H), 1.17 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

Example 133.

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) A mixture of compounds I2a (0.28 g, 0.53 mmol) and P1 (172 mg, 0.67 mmol) was dissolved in mixtures of THF/AcOH (12 ml, 3:1)

After stirring at room temperature for 15 minutes, sodium cyanoborohydride (2.49 mmol/g on resin, 0.44 g, 1.09 mmol) was added. The resulting reaction mixture was stirred overnight, after which it was filtered, 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 give compound 133a (351.6 mg, 87.3%). MS (ESI) m/z 764.09 [M+H] ⁺ .

Synthesis of methyl-((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-2methylpropan-2-yl)-2-oxa-4,7 ,8,12-Tetraazahexadecan-14-yl)carbamate (133b).

Compound 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 resulting reaction mixture was stirred for 3 h, after which it was concentrated under reduced pressure, the resulting crude material was dissolved in DCM (10 ml) and HATU (0.24 g, 0.64 mmol), N,N-diisopropylethylamine (0.6 ml, 0 mol) followed by compound A3 (0.21 g, 0.86 mmol). The resulting reaction mixture 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 solution, saturated NaHCO ₃ solution and brine, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (30-70% EtOAc/Hex) to give compound 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, 1H), 8.01 (d, J = 1.3 Hz, 1H), 7.58 (t, J = 59.9 Hz, 1H), 7.52 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8 .2 Hz, 2H), 4.45 (s, 1H), 4.30 (s, 1H), 4.14 (s, 0H), 3.93 (d, J = 13.2 Hz, 1H), 3.71 (s, 3H), 3.66 (s, 3H), 2.92-2.67 (m, 4H), 1.16 (s, 3H), 1.14 (s, 3H), 1 .11 (s, 3H), 1.02 (s, 3H).

Methyl-((5S,10S,11S,14S)-8-(4-(1-(difluoromethyl)-1 H-imidazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-10- hydroxy- 15,15-dimethyl-11 - (4- ((2- (8- (oxetan-3 -yl) -3,8-diazabicyclo[3.2.1] octane-3 - 152 040208 yl) pyrimidin-5- yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa4,7,8,12-tetraazahexadecan-14-yl )carbamate (133).

In a vial, a solution of compound 133b (50 mg, 0.05 mmol), compound 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 MeCN:Et ₃ N 3:1 (1 ml) was degassed and then stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by HPLC and lyophilized to give compound 133. MS (ESI) m/z 1156.4 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.44 (s, 2H), 8.09 (d, J = 17.5 Hz, 2H), 7.93 (s, 1H), 7.49 (t , J = 60.0 Hz, 1H), 7.27 (dd, J = 18.4, 8.1 Hz, 3H), 7.14 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 9.9 Hz, 1H), 4.86 (d, J = 7.6 Hz, 2H), 4.72 (dd, J = 8.2, 5.0 Hz, 2H), 4 .35 (d, J = 8.7 Hz, 1H), 4.22 (d, J = 9.8 Hz, 1H), 4.03 (d, J = 12.8 Hz, 4H), 3.84 (d, J = 13.2 Hz, 1H), 3.58 (d, J = 8.6 Hz, 5H), 3.37 (d, J = 14.4 Hz, 2H), 2.90 - 2 .62 (m, 4H), 2.56 (s, 1H), 2.12 (d, J = 11.1 Hz, 2H), 1.90 (d, J = 9.0 Hz, 2H), 1 .07 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 0.93 (s, 3H).

Example 134.

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

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, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.75 - 7.50 (m, 6H), 7.46 (d, J = 16.5 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 9.5 Hz , 3H), 7.15 (d, J = 8.0 Hz, 3H), 6.85 (d, J = 2.7 Hz, 1H), 6.73 (d, J = 10.0 Hz, 1H ), 4.79 - 4.71 (m, 5H), 4.35 (d, J = 9.9 Hz, 1H), 4.22 (d, J = 10.0 Hz, 1H), 4.06 (d, J = 13.5 Hz, 3H), 3.85 (d, J = 13.0 Hz, 1H), 3.65 (s, 2H), 3.61 (s, 3H), 3.57 (s, 3H), 3.08 (s, 4H), 2.83 (d, J = 8.0 Hz, 2H), 2.73 - 2.62 (m, 1H), 1.07 (s, 4H), 1.05 (s, 3H), 1.02 (s, 4H), 0.94 (s, 3H).

Example 135.

Methyl-((5S,10S,11S,14S)-8-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-10hydroxy-15,15- dimethyl-11-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2yl)pyridin-3-yl)ethynyl) benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12- 153 040208 tetraazahexadecan-14-yl )carbamate(135).

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, 1H), 8.16 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.87 (dd, J = 8.8, 4.3 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.1 Hz, 3H), 6.74 (d, J = 10, 0 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 4.95 (s, 1H), 4.86 (dd, J = 8.4, 6.3 Hz, 1H) , 4.61 (s, 1H), 4.49 (dq, J = 11.2, 6.0, 5.5 Hz, 2H), 4.41 (s, 1H), 4.35 (d, J = 9.7 Hz, 1H), 4.21 (d, J = 10.0 Hz, 1H), 4.07 (d, J = 13.3 Hz, 2H), 3.87 (d, J = 13 .1 Hz, 1H), 3.74 - 3.62 (m, 2H), 3.60 (s, 3H), 3.55 (s, 3H), 2.87 - 2.73 (m, 3H) , 2.73 - 2.65 (m, 1H), 2.23 (s, 2H), 1.06 (d, J = 5.4 Hz, 6H), 1.02 (s, 3H), 0, 93 (s, 3H).

Example 136.

Methyl-((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-8-(4- ((6-((R)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9hydroxy-15,15-dimethyl- 3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (136).

Intermediates: P13, A3 and S8. MS (ESI) m/z 1118.6 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.22 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.61 (dt, J = 5.4, 2.6 Hz, 2H), 7.59 - 7.50 (m, 1H), 7.47 (dt, J = 7.7, 4.1 Hz, 1H), 7.30 - 7.19 (m, 4H), 7.13 (d, J = 8.1 Hz, 2H), 7.06 (s, 0H), 6.86 (d, J = 8.9 Hz, 1H) , 6.72 (d, J = 9.9 Hz, 1H), 6.55 (d, J = 2.5 Hz, 1H), 4.53 (dd, J = 22.7, 13.2 Hz, 2H), 4.42 - 4.30 (m, 1H), 4.26 4.18 (m, 1H), 4.03 (d, J = 13.2 Hz, 4H), 3.84 (d, J = 13.1 Hz, 1H), 3.76 (t, J = 12.7 Hz, 1H), 3.59 (d, J = 9.3 Hz, 6H), 3.49 (d, J = 11.0 Hz, 1H), 3.44 - 3.35 (m, 0H), 2.81 (d, J = 7.3 Hz, 3H), 2.72 - 2.63 (m, 1H), 1.08 (s, 3H), 1.05 (s, 4H), 1.04 (d, J = 2.8 Hz, 0H), 1.02 (s, 2H), 1.00 -0.95 (m, 1H), 0.94(s, 3H).

Example 137.

Methyl-((5 S,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(1 H)-yl)pyridin-3 -yl)ethynyl)benzyl)-9-hydroxy-15,15dimethyl- 3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14yl)carbamate (137).

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, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.11 (d, J = 9.3 Hz, 1H), 7.67 (dd, J = 10.3, 2.4 Hz, 1H), 7.61 (dd, J = 8.9, 2.2 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.16 - 7.08 (m, 3H), 6, 86 (d, J = 8.9 Hz, 1H), 6.74 (d, J = 10.0 Hz, 1H), 4.52 (dd, J = 23.4, 12.6 Hz, 2H), 4.35 (d, J = 10.0 Hz, 1H), 4.21 (d, J = 9.9 Hz, 1H), 4.07 (t, J = 10.4 Hz, 4H), 3, 87 (d, J = 13.2 Hz, 1H), 3.75 (t, J = 12.6 Hz, 1H), 3.64 (s,

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1H), 3.60 (s, 3H), 3.55 (s, 2H), 3.48 (d, J = 10.7 Hz, 1H), 3.39 (t, J = 10.4 Hz, 1H), 2.88 - 2.73 (m, 4H), 2.73 2.64 (m, 1H), 1.06 (d, J = 5.6 Hz, 6H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 138.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15- 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-tetraazahexadecan-14yl)carbamate (138).

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, 1H), 8.16 (s, 1H), 8.11 (d, J = 9, 5 Hz, 1H), 7.68 (d, J = 9.4 Hz, 1H), 7.58 (dd, J = 14.3, 8.7 Hz, 3H), 7.23 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.0 Hz, 4H), 6.74 (d, J = 10.2 Hz, 1H), 6.57 (d, J = 8, 8 Hz, 1H), 4.95 (s, 1H), 4.61 (s, 1H), 4.49 (dd, J = 11.6, 6.4 Hz, 1H), 4.41 (s, 1H), 4.35 (d, J = 10.0 Hz, 1H), 4.21 (d, J = 9.9 Hz, 1H), 4.08 (d, J = 12.8 Hz, 2H) , 3.87 (d, J = 13.0 Hz, 1H), 3.66 (d, J = 16.3 Hz, 2H), 3.60 (d, J = 1.1 Hz, 3H), 3 .55 (s, 3H), 2.81 (d, J = 7.8 Hz, 2H), 2.71 (d, J = 9.5 Hz, 1H), 2.23 (s, 2H), 1 .06 (d, J = 4.6 Hz, 6H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 139.

Methyl-((5S,10S,11S,14S)-8-(2,6-difluoro-4-(5-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-10hydroxy- 15,15- dimethyl-11 -(4-((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3yl)ethynyl)benzyl)-3.6 ,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12tetraazahexadecan-14-yl)carbamate (139).

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, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 9.3 Hz, 1H), 7.96 - 7.86 (m, 1H), 7.65 (dd, J = 8.8, 2.3 Hz, 1H), 7.59 (td, J = 8.5, 3.0 Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 9.9 Hz, 1H), 6.73 (d, J = 10.6 Hz, 1H), 6.69 (d, J = 8.9 Hz, 1H), 4.96 - 4.83 (m, 4H), 4.59 - 4.47 (m, 2H), 4.42 - 4.31 (m, 1H), 4.31 - 4.19 (m, 1H), 4.07 (d, J = 13.4 Hz, 4H), 3.87 (d, J = 13.2 Hz, 1H), 3.64 (s, 2H) , 3.60 (s, 3H), 3.56 (s, 3H), 2.82 (d, J = 8.4 Hz, 2H), 2.74 - 2.65 (m, 1H), 2, 02 (d, J = 11.0 Hz, 1H), 1.07 (s, 4H), 1.06 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H).

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Example 140.

Methyl-((5S,10S,11S,14S)-8-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-10hydroxy-15,15 - dimethyl-11-(4-((6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3yl)ethynyl)benzyl)-3.6 ,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12tetraazahexadecan-14-yl)carbamate (140).

Intermediates: P15, A3 and S4. MS (ESI) m/z 1120.2 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.66 (dd, J = 8.6, 5.6 Hz, 1H), 8.33 (s, 1H), 8.21 (d, J = 9 .3 Hz, 1H), 7.76 (t, J = 9.9 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 7.7 Hz, 3H), 6.84 (d, J = 10.1 Hz, OH), 6.78 (d, J = 8.9 Hz, 1H), 4.61 (dd, J = 8.2, 4.0 Hz, 2H), 4.45 (d, J = 10.0 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.18 (d, J = 12.4 Hz, 2H), 3.99 (s, 0H), 3.74 (s, 2H), 3.70 (s, 3H), 3, 65 (s, 2H), 2.91 (d, J = 8.1 Hz, 2H), 2.80 (d, J = 9.8 Hz, 1H), 2.11 (d, J = 10.9 Hz, 1H), 1.33 - 1.23 (m, 1H), 1.16 (s, 4H), 1.15 (s, 3H), 1.12 (s, 2H), 1.03 (s , 3H).

Example 141.

Methyl - ((5S, 8S, 9S, 14S) -11 - (4- ( 1 - (difluoromethyl) -1 H-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-3yl)ethynyl)benzyl)-3,6,13 -trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (141).

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, 1H), 8.08 (d, J = 9.4 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.62 - 7.42 (m, 3H), 7.36 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 7.9 Hz , 2H), 7.11 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 9.9 Hz, 1H), 6.85 (d, J = 2.8 Hz, 1H ), 6.72 (dd, J = 9.5, 5.4 Hz, 2H), 4.56 (d, J = 5.9 Hz, 2H), 4.34 (d, J = 9.9 Hz , 1H), 4.27 - 4.15 (m, 3H), 4.05 (d, J = 12.1 Hz, 2H), 3.85 (d, J = 13.1 Hz, 1H), 3 .64 (s, 2H), 3.60 (s, 3H), 3.56 (d, J = 8.7 Hz, 7H), 2.75 (dd, J = 44.1, 8.8 Hz, 4H), 2.46 (t, J = 5.0 Hz, 4H), 1.32 (s, 3H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 ( s, 3H), 0.94 (s, 3H).

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Example 142.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrαzol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1 ]octane -3-yl)pyridin-3 -yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa4,7,11,12-tetraazahexadecane-14- yl) carbamate (142).

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, 1H), 8.17 (d, J = 9.4 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.76 - 7.60 (m, 2H), 7.60 7.52 (m, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 9.8 Hz, 1H), 6, 94 (d, J = 2.7 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 10.0 Hz, 1H), 4.45 ( s, 0H), 4.42 - 4.27 (m, 2H), 4.23 (s, 1H), 4.20 - 4.05 (m, 2H), 4.05 - 3.89 (m, 3H), 3.88 - 3.56 (m, 8H), 3.06 - 2.85 (m, 3H), 2.85 - 2.69 (m, 1H), 2.50 (d, J = 12.5 Hz, 1H), 2.32 (s, 2H), 2.22 - 2.00 (m, 3H), 1.16 (s, 4H), 1.14 (s, 3H), 1, 11 (s, 3H), 1.03 (s, 3H).

Example 143.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrαzol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((R)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1 ]octane -3-yl)pyridin-3 -yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa4,7,11,12-tetraazahexadecane-14- yl) carbamate (143).

Intermediates: P4, A3 and S12. MS (ESI) m/z 1170.1 [M+H] ⁺ . Ή NMR (400 MHz, methanol-d4) δ 8.29 (d, J = 2.2 Hz, 1H), 8.17 (d, J = 9.3 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.74 - 7.60 (m, 2H), 7.59 7.50 (m, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 9.7 Hz, 1H), 6, 94 (d, J = 2.7 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 9.9 Hz, 1H), 4.44 ( d, J = 10.1 Hz, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.23 (s, 1H), 4.14 (d, J = 12.3 Hz, 2H), 3.97 (t, J = 14.4 Hz, 1H), 3.86 - 3.57 (m, 8H), 2.97 - 2.84 (m, 3H), 2.84 - 2 .68 (m, 1H), 2.49 (s, 1H), 2.32 (s, 2H), 2.22-2.04 (m, 3H), 1.16 (s, 4H), 1, 14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

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Example 144.

Methyl-((5 S,8S,9S,14S)-11-(4-(1 -(difluoromethyl)-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9 -hydroxy-15,15-dimethyl-8-(4-((6-(8-(3-methyloxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridin-3-yl )ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl) carbamate (144).

Intermediates: P4, A3 and S13. MS (ESI) m/z 1170.9 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.23 - 8.13 (m, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.57 (dd, J = 8 .9, 2.4 Hz, 1H), 7.53 (t, J = 59.8 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 2.7 Hz, 1H), 6.69 (d, J = 9 .0 Hz, 1H), 4.43 (s, 1H), 4.30 (s, 1H), 4.14 (d, J = 12.1 Hz, 2H), 3.95 (d, J = 13 .2 Hz, 1H), 3.84 (dt, J = 8.2, 4.5 Hz, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 3.49 (d , J = 7.1 Hz, 1H), 3.39 (s, 1H), 3.11 (dt, J = 11.9, 2.1 Hz, 2H), 2.90 (d, J = 8, 0 Hz, 2H), 2.83 - 2.76 (m, 1H), 2.73 (d, J = 5.0 Hz, 1H), 2.69 (s, 0H), 2.62 (d, J = 4.9 Hz, 1H), 2.46 (d, J = 13.4 Hz, 1H), 1.97 (s, 2H), 1.67 (d, J = 9.0 Hz, 2H) , 1.43 (s, 3H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

Example 145.

Methyl-((5 S,8S,9S,14S)-11-(4-(1 -(difluoromethyl)-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9 -hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(4-((S)-tetrahydrofuran-3-yl)piperazin-1yl)pyridin-3-yl) ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (145).

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, 1H), 8.19 (d, J = 9.2 Hz, 1H), 8.11 (d, J = 2, 7 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.67 - 7.61 (m, 0H) , 7.57 (dd, J = 7.3, 3.3 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.33 ( d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.15 (s, 1H), 6.99 - 6.86 (m, 2H), 6.81 (d, J = 10.1 Hz, 1H), 4.45 (s, 0H), 4.31 (d, J = 10.0 Hz, 1H), 4.26 - 4.02 (m , 5H), 4.00 - 3.82 (m, 3H), 3.75 (d, J = 8.4 Hz, 1H), 3.68 (d, J = 10.9 Hz, 6H), 2 .97 - 2.85 (m, 3H), 2.55 - 2.35 (m, 1H), 2.28 - 2.16 (m, 1H), 1.16 (s, 4H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H).

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Example 146.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1 H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9- hydroxy-15,15-dimethyl -3,6,13-trioxo-8-(4-((6-(4-((R)-tetrahydrofuran-3-yl)piperazin-1yl)pyridin-3-yl)ethynyl )benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (146).

Intermediates: P4, A3 and S14. MS (ESI) m/z 1143.5 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.30 (d, J = 2.3 Hz, 1H), 8.19 (d, J = 9.1 Hz, 1H), 8.11 (d, J = 2.8 Hz, 1H), 7.71 (d, J = 2.4 Hz, 0H), 7.69 (s, 1H), 7.68 - 7.61 (m, 1H), 7, 60 - 7.55 (m, 1H), 7.54 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H ), 7.23 (d, J = 8.1 Hz, 3H), 6.96 - 6.85 (m, 2H), 6.81 (d, J = 9.9 Hz, 1H), 4.44 (d, J = 9.8 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.23 - 4.07 (m, 4H), 3.95 (d, J = 13.3 Hz, 1H), 3.92 - 3.86 (m, 1H), 3.75 (d, J = 8.2 Hz, 2H), 3.69 (s, 4H), 3.66 ( s, 3H), 3.00 - 2.82 (m, 3H), 2.79 (d, J = 10.0 Hz, 1H), 2.42 (s, 0H), 2.21 (d, J = 8.5 Hz, 0H), 1.16 (s, 5H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H).

Example 147.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane- 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-methylpropane -2yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (147).

Intermediates: P22, A3 and S3. MS (ESI) m/z 1282.4 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.43 - 8.31 (m, 1H), 8.20 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 9 .0 Hz, 1H), 7.60 (dd, J = 8.8, 2.3 Hz, 1H), 7.24 (d, J = 7.9 Hz, 2H), 7.17 - 7.04 (m, 4H), 6.86 (d, J = 9.0 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 6.71 (d, J = 10.0 Hz , 1H), 4.87 (t, J = 7.7 Hz, 4H), 4.74 - 4.68 (m, 4H), 4.37 - 4.17 (m, 6H), 4.10 - 3.99 (m, 6H), 3.86 (d, J = 13.1 Hz, 1H), 3.67 - 3.62 (m, 1H), 3.60 (s, 3H), 3.56 (s, 3H), 3.34 - 3.25 (m, 5H), 2.81 (d, J = 7.7 Hz, 2H), 2.74 - 2.65 (m, 1H), 2, 19 - 2.10 (m, 4H), 2.03 - 1.93 (m, 4H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H) , 0.93 (s, 3H).

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Example 148.

Methyl-((5S,8S,9S,14S)-11-(2-chloro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15dimethyl-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-tetraazahexadecan-14-yl)carbamate (148).

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, 1H), 8.20 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 9.5 Hz, 1H), 7.94 - 7.85 (m, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.77 - 7.70 (m, 1H) , 7.65 (d, J = 8.1 Hz, 1H), 7.60 (dd, J = 8.8, 2.3 Hz, 1H), 7.42 - 7.32 (m, 1H), 7.24 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 8.8 Hz, 1H), 6. 71 (d, J = 10.3 Hz, 1H), 4.87 (t, J = 7.6 Hz, 2H), 4.73 - 4.66 (m, 2H), 4.31 (d, J = 10.0 Hz, 1H), 4.18 (d, J = 9.7 Hz, 1H), 4.14 - 4.03 (m, 3H), 3.99 (d, J = 14.2 Hz , 1H), 3.74 - 3.66 (m, 1H), 3.58 (s, 3H), 3.48 (s, 3H), 3.29 (s, 1H), 2.87 - 2, 68 (m, 2H), 2.21-2.07 (m, 1H), 2.03-1.93 (m, 2H), 1.05 (s, 3H), 1.02 (s, 3H) , 0.96 (s, 3H), 0.84 (s, 3H).

Example 149.

Methyl-((5S,8S,9S,14S)-11-(2,6-dichloro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15dimethyl- 8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6 ,13trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (149).

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, 1H), 8.20 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 9.4 Hz, 1H), 7.88 (s, 2H), 7.83 (d, J = 7.8 Hz, 2H), 7.64 - 7.54 (m, 1H), 7.33 (t, J = 5.7 Hz, 1H), 7.23 (d, J = 7.7 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.77 (d , J = 8.9 Hz, 1H), 6.71 (d, J = 10.1 Hz, 1H), 4.87 (t, J = 7.5 Hz, 2H), 4.71 (dd, J = 8.2, 4.9 Hz, 2H), 4.36 - 4.23 (m, 2H), 4.20 (d, J = 9.9 Hz, 1H), 4.12 - 3.98 ( m, 4H), 3.69 - 3.62 (m, 1H), 3.59 (s, 3H), 3.54 (s, 3H), 3.29 (s, 1H), 2.83 - 2 .75 (m, 2H), 2.72-2.62 (m, 1H), 2.17-2.08 (m, 1H), 2.03-1.93 (m, 2H), 1.05 (s, 6H), 0.99 (s, 3H), 0.89 (s, 3H).

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Example 150.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((5-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridin-3-yl )ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan- 14-yl) carbamate (150).

Intermediates: P4, A3 and S44. MS (ESI) m/z 1171.1 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.17 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 9.4 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.61 - 7.55 (m, 3H), 7.44 (s, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7, 30 - 7.22 (m, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 9.9 Hz, 1H), 6.84 (d, J = 2.8 Hz, 1H), 6.69 (d, J = 9.9 Hz, 1H), 4.88 - 4.80 (m, 2H), 4.73 - 4.68 (m, 2H) , 4.41 (s, 1H), 4.34 (d, J = 9.9 Hz, 1H), 4.21 (d, J = 10.0 Hz, 1H), 4.10 - 3.98 ( m, 4H), 3.85 (d, J = 13.2 Hz, 1H), 3.64 (s, 1H), 3.59 (s, 3H), 3.57 (s, 3H), 3, 48 (d, J = 13.5 Hz, 2H), 3.38 (d, J = 1.7 Hz, 1H), 3.35 (s, 1H), 3.25 (s, 1H), 2, 85-2.74 (m, 3H), 2.72-2.65 (m, 1H), 2.27 (s, 5H), 2.17-2.11 (m, 2H), 1.06 ( d, J = 6.7 Hz, 6H), 1.02 (s, 3H), 0.93 (s, 3H). ¹⁹ F 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.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((4-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridin-3-yl )ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl) carbamate (151).

Intermediates: P4, A3 and S46. MS (ESI) m/z 1171.3 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.20 (s, 1H), 8.17 (d, J = 9.3 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.68 (s, 0H), 7.53 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.38 (s, 0H), 7.34 ( d, J = 7.8 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 9.8 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.82 (s, 0H), 6.79 (s, 1H), 4.99 - 4.89 (m, 2H), 4.83 - 4.77 (m , 2H), 4.51 (s, 1H), 4.47-4.42 (m, 1H), 4.35 (s, 1H), 4.31 (s, 1H), 4.29 (s, 0H), 4.16 (s, 1H), 4.13 (s, 3H), 3.95 (d, J = 13.2 Hz, 1H), 3.74 (s, 1H), 3.68 ( s, 3H), 3.66 (s, 3H), 3.38 (s, 1H), 3.34 (s, 3H), 2.94-2.84 (m, 3H), 2.78 (dd , J = 12.5, 9.0 Hz, 1H), 2.44 (s, 3H), 2.25 - 2.18 (m, 2H), 2.10 - 2.04 (m, 2H), 1.16 (s, 4H), 1.13 (d, J = 12.7 Hz, 7H), 1.02 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ-77.38, -77.71, -77.82, -96.97 (dd, J=59.8, 18.6 Hz), -114.92 .

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Example 152.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((2-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridin-3-yl )ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan- 14-yl) carbamate (152).

Intermediates: P4, A3 and S45. MS (ESI) m/z 1170.6 [M+H]+. 'H NMR (400 MHz, methanol-d4) δ 8.17 (d, J = 9.3 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.68 (s, 0H), 7.62 (d, J = 8.7 Hz, 1H), 7.53 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.38 (s, 0H), 7.32 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 9.9 Hz, 1H) , 6.93 (d, J = 2.8 Hz, 1H), 6.80 (d, J = 9.8 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 4 .96 (dd, J = 8.2, 7.0 Hz, 2H), 4.81 (dd, J = 8.2, 5.1 Hz, 2H), 4.51 (s, 1H), 4, 47 - 4.43 (m, 1H), 4.38 (d, J = 13.8 Hz, 2H), 4.32 - 4.27 (m, 1H), 4.15 (d, J = 12, 2 Hz, 4H), 3.95 (d, J = 13.1 Hz, 1H), 3.73 (s, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3 .38 - 3.35 (m, 1H), 3.34 3.32 (m, 1H), 2.88 (dd, J = 18.8, 5.2 Hz, 3H), 2.78 (dd, J = 12.5, 9.0 Hz, 1H), 2.56 (s, 3H), 2.25 - 2.18 (m, 2H), 2.08 (t, J = 6.8 Hz, 2H ), 1.16 (s, 5H), 1.13 (d, J = 13.1 Hz, 7H), 1.02 (s, 3H). ¹⁹ F 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.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((5-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridin-3-yl )ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan- 14-yl) carbamate (153).

Intermediates: P7, A3 and S44. MS (ESI) m/z 1170.6 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H), 8.29 - 8.25 (m, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8 .12 (s, 1H), 7.70 - 7.60 (m, 2H), 7.55 (td, J = 7.4, 3.1 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.34 (s, 1H), 7.24 (dd, J = 8.2, 6.7 Hz, 4H), 7.16 (d , J = 10.0 Hz, 1H), 6.79 (d, J = 9.9 Hz, 1H), 4.94 (t, J = 7.6 Hz, 2H), 4.79 (dd, J = 8.2, 5.2 Hz, 3H), 4.49 (s, 1H), 4.47 4.41 (m, 1H), 4.34 - 4.27 (m, 1H), 4.15 (d, J = 8.8 Hz, 1H), 4.09 (d, J = 7.1 Hz, 3H), 3.93 (d, J = 13.2 Hz, 1H), 3.69 (s , 3H), 3.66 (s, 3H), 3.57 (d, J = 13.5 Hz, 2H), 3.51 (s, 0H), 3.47 (dt, J = 3.3, 1.7 Hz, 2H), 3.43 (s, 1H), 2.99 (s, OH), 2.91 (d, J = 7.8 Hz, 2H), 2.87 - 2.82 ( m, 1H), 2.81 - 2.73 (m, 1H), 2.36 (s, 4H), 2.34 (s, 0H), 2.24 (s, 2H), 2.04 - 1 .91 (m, 0H), 1.33 - 1.26 (m, 1H), 1.17 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1, 03 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.39, -77.51 , -77.71, -96.88 (d, J = 59.6 Hz), -115.03, -130, 01.

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Example 154.

Methyl-((5 S,8S,9S,14S)-11-(4-(1 -(difluoromethyl)-1 H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9 -hydroxy-15,15 -dimethyl-8-(4-((4-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridin-3 -yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecane-14- yl) carbamate (154).

Intermediates: P7, A3 and S46. MS (ESI) m/z 1169.5 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.52 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 8.11 (s, 1H), 7, 64 (s, 0H), 7.50 (s, 1H), 7.34 (d, J = 7.3 Hz, 2H), 7.24 (t, J = 7.8 Hz, 4H), 7. 11 (d, J = 9.9 Hz, 1H), 6.78 (s, 1H), 6.77 (s, 0H), 4.96 (t, J = 7.6 Hz, 2H), 4, 50 (s, 1H), 4.44 (d, J = 9.7 Hz, 1H), 4.36 -4.27 (m, 3H), 4.12 (d, J = 10.0 Hz, 4H ), 3.94 (d, J = 13.2 Hz, 1H), 3.70 (s, 2H), 3.68 (s, 3H), 3.66 (s, 3H), 3.38 (s , 1H), 3.34 (s, 3H), 2.94-2.73 (m, 4H), 2.44 (s, 3H), 2.27-2.17 (m, 2H), 2, 07 (d, J = 8.6 Hz, 2H), 1.29 (t, J = 7.4 Hz, 0H), 1.20 - 1.10 (m, 10H), 1.03 (s, 3H ). ¹⁹ F NMR (376 MHz, methanol-d4) δ -77.35, -77.62, -77.67, -96.90 (d, J = 59.9 Hz), -115.01.

Example 155.

Methyl-((5 S,8S,9S,14S)-11-(4-(1 -(difluoromethyl)-1 H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9 -hydroxy-15,15-dimethyl-8-(4-((2-methyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridin-3 -yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecane-14- yl) carbamate (155). Intermediates: P7, A3 and S45. MS (ESI) m/z 1169.7 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.52 (s, 1H), 8.12 (s, 2H), 7.64 (s, 0H), 7.53 (d, J = 8.6 Hz , 1H), 7.49 (s, 1H), 7.37 - 7.28 (m, 3H), 7.23 (dd, J = 15.6, 8.1 Hz, 5H), 4.44 ( s, 1H), 4.30 (s, 2H), 4.12 (d, J = 12.6 Hz, 3H), 3.94 (d, J = 13.1 Hz, 1H), 3.68 ( s, 4H), 3.66 (s, 4H), 2.90 (d, J = 8.2 Hz, 2H), 2.79 (d, J = 9.9 Hz, 1H), 2.53 ( s, 4H), 2.03 (s, 0H), 1.98 (s, 1H), 1.28 (d, J = 7.2 Hz, 3H), 1.17 (s, 5H), 1, 15 (s, 4H), 1.12 (s, 4H), 1.03 (s, 4H). ¹⁹ F NMR (376 MHz, methanol-d4) δ -77.36, -77.48, -77.68, -96.91 (d, J = 59.7 Hz).

- 163 040208

Example 156.

Cyclopropyl-((2S)-1-(2-((2S,3S)-3-((S)-2-((cyclopropoxycarbonyl)amino)-4,4,4-trifluoro-3,3dimethylbutanamido)-2- hydroxy-4-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin3-yl)ethynyl)phenyl)butyl)-2 -(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-4,4,4trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate (156).

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, 1H), 8.21 (d, J = 9.4 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.81 - 7.63 (m, 1H), 7.53 (s, 1H), 7.46 (d, J = 8.3 Hz, 2H) , 7.42 - 7.29 (m, 3H), 7.23 (d, J = 8.0 Hz, 3H), 6.94 (d, J = 2.8 Hz, 1H), 6.85 ( t, J = 8.7 Hz, 2H), 5.05 - 4.90 (m, 3H), 4.48 (d, J = 10.0 Hz, 1H), 4.34 (t, J = 12 .0 Hz, 3H), 4.24 - 3.84 (m, 7H), 3.75 (s, 1H), 3.01 - 2.66 (m, 5H), 2.22 (dd, J = 12.2, 6.4Hz, 2H), 2.03(s, 32H), 1.29(s, 1H), 1.19 - 1.07(m, 10H), 1.03(s, 3H ), 1.00 - 0.50 (m, 8H).

Example 157.

Methyl-((5 S, 8S, 9S, 14S) -11 - (4- ( 1 - (difluoromethyl) -1 H-pyrazol-4-yl) -2-fluorobenzyl) -16,16,16-trifluoro9-hydroxy -15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)ethynyl)benzyl )-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (157) .

Intermediates: P8, A3 and S3. MS (ESI) m/z 1138.1 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.43 (s, 1H), 8.28-8.25 (m, 1H), 8.07 (s, 1H), 7.68 (dd, J= 8.9, 2.3 Hz, 1H), 7.66 - 7.57 (m, 1H), 7.57 - 7.45 (m, 1H), 7.41 - 7.27 (m, 6H) , 7.20 (d, J = 8.2 Hz, 2H), 6.90 - 6.81 (m, 1H), 4.94 (dd, J = 8.1, 7.0 Hz, 3H), 4.81 (dd, J = 8.1, 4.9 Hz, 3H), 4.53 (d, J = 6.3 Hz, 1H), 4.45 - 4.21 (m, 5H), 4 .14 (dd, J = 4.7, 2.4 Hz, 4H), 4.08 3.83 (m, 3H), 3.70 (d, J = 24.6 Hz, 2H), 3.60 (s, 3H), 3.38 (dd, J = 14.1, 1.7 Hz, 3H), 3.29 (p, J = 1.6 Hz, 6H), 2.93 - 2.66 ( m, 5H), 2.28 - 2.02 (m, 3H), 1.11 (d, J = 14.3 Hz, 7H), 1.04 (s, 4H), 0.93 (s, 4H ).

- 164 040208

Example 158.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15- 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-tetraazahexadecan-14-yl)carbamate (158).

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, 1H), 8.16-7.99 (m, 2H), 7.84-7, 73 (m, 2H), 7.71-7.37 (m, 4H), 7.37-7.26 (m, 3H), 7.26-7.10 (m, 2H), 6.86 ( d, J = 2.7 Hz, 1H), 6.69 (dd, J = 9.0, 0.8 Hz, 1H), 4.76 (t, J = 6.4 Hz, 2H), 4, 58 (t, J = 5.8 Hz, 3H), 4.39 (s, 1H), 4.25 (s, 1H), 4.01 (d, J = 13.1 Hz, 1H), 3, 89 (dt, J = 13.1, 4.1 Hz, 4H), 3.85 - 3.74 (m, 1H), 3.60 (s, 3H), 3.12 (dd, J = 12, 0, 2.2 Hz, 3H), 2.98 - 2.60 (m, 4H), 1.96 - 1.86 (m, 3H), 1.69 (d, J = 7.8 Hz, 2H ), 1.11 (d, J = 9.3 Hz, 7H), 1.02 (s, 3H), 1.00-0.76 (m, 4H).

F

Example 159.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-5yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1 ,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (159).

Intermediates: P4, A3 and S58. MS (ESI) m/z 1102.2 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.50 (s, 2H), 8.20 (d, J = 9.5 Hz, 1H), 8.12 (s, 1H), 7.55 (t , J = 61.0 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 7.7 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 6.95 (s, 1H), 4.44 (s, 1H), 4.40 (s, 2H), 4.31 (s, 1H), 4.15 (d , J = 15.7 Hz, 4H), 3.95 (d, J = 12.9 Hz, 1H), 3.75 (s, 2H), 3.70 (s, 3H), 3.67 (s , 3H), 3.50 (s, 2H), 3.03 (d, J = 2.8 Hz, 3H), 2.90 (t, J = 12.3 Hz, 2H), 2.80 (d , J = 10.7 Hz, 1H), 1.17 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.04 (s, 3H).

- 165 040208

Example 160.

Methyl-((5 S,8S,9S,14S)-11-(4-(1 -(difluoromethyl)-1 H-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-trioxo5 ,14-bis(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2-oxa-4,7,11,12-tetraazatetradecan-14-yl)carbamate (160).

Intermediates: P4, A8 and S7. MS (ESI) m/z 1205.1 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.51 (s, 2H), 8.09 (d, J = 2.7 Hz, 1H), 7.52 (t, J = 60.0, 59, 5 Hz, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz , 2H), 6.91 (d, J = 2.7 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.81 (dd, J = 8.3, 5, 1 Hz, 2H), 4.76 (s, 1H), 4.33 - 4.23 (m, 1H), 4.18 - 4.12 (m, 3H), 4.08 (d, J = 18 .2 Hz, 2H), 4.03 (d, J = 13.5 Hz, 1H), 3.75 (d, J = 9.3 Hz, 1H), 3.66 (s, 3H), 3, 64 (s, 3H), 3.46 (d, J = 14.4 Hz, 2H), 3.04 - 2.85 (m, 3H), 2.79 (d, J = 12.7 Hz, 1H ), 2.20 (dd, J = 8.9, 3.9 Hz, 2H), 2.01 (dd, J = 12.2, 6.9 Hz, 2H), 1.86 -1.65 ( m, 12H).

Example 161.

tert-Butyl-3 -(5-((4-((2S,3S)-4-( 1 -(4-( 1 -(difluoromethyl)-1 H-pyrazol-3-yl)-2,6-difluorobenzyl )-2-((S)4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazinyl)-3-hydroxy-2-((S)-4,4,4trifluoro -2-((methoxycarbonyl)amino)-3,3-dimethylbutanamido)butyl)phenyl)ethynyl)pyridin-2-yl)-3,8diazabicyclo [3.2.1]octane-8-carboxylate (161a).

MS (ESI) m/z 1200.0 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.27 - 8.14 (m, 2H), 8.11 (d, J = 2.7 Hz, 1H), 7.84 (d, J = 9 .0 Hz, 1H), 7.53 (t, J = 59.7 Hz, 2H), 7.45 (d, J = 8.2 Hz, 3H), 7.35 (d, J = 7.9 Hz, 3H), 7.24 (d, J = 8.0 Hz, 3H), 7.15 (d, J = 9.5 Hz, 1H), 7.08 (d, J = 9.3 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.82 (d, J = 10.0 Hz, 1H), 4.44 (d, J = 11.9 Hz, 4H) , 4.30 (d, J = 10.0 Hz, 1H), 4.14 (d, J = 13.3 Hz, 3H), 4.02 - 3.87 (m, 4H), 3.67 ( d, J = 10.7 Hz, 10H), 3.28 - 3.18 (m, 3H), 3.03 - 2.85 (m, 4H), 2.82 - 2.69 (m, 1H) , 2.00 (dd, J = 9.0, 4.0 Hz, 3H), 1.81 (d, J = 7.7 Hz, 3H), 1.49 (s, 9H), 1.16 ( s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

Methyl-((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-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate 2,2,2-trifluoroacetate (161 ).

A solution of compound 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 hours, the reaction mixture was concentrated under reduced pressure and the residue was purified by HPLC, and the resulting product was lyophilized.

- 166 040208 was analyzed to give compound 161. MS (ESI) m/z 1200.0 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.32 - 8.26 (m, 1H), 8.18 (d, J = 9.4 Hz, 1H), 8.11 (d, J = 2 .7 Hz, 1H), 7.71 - 7.64 (m, 1H), 7.71 - 7.36 (m, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7 .32 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 10.0 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.82 (t, J = 9.9 Hz, 2H), 4.44 (d, J = 9.9 Hz, 1H), 4.36-4 .22 (m, 4H), 4.16 (d, J = 28.1 Hz, 4H), 3.94 (d, J = 13.2 Hz, 1H), 3.67 (d, J = 11, 1 Hz, 8H), 3.26 - 3.17 (m, 3H), 2.99 - 2.69 (m, 5H), 2.19 - 1.96 (m, 5H), 1.16 (s , 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H).

Example 162

_{CF3CO2H _}

Synthesis of tert-butyl-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]octane-8-carboxylate (162a).

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, 1H), 8.21 - 8.09 (m, 3H), 7.89 (dd, J = 9, 4, 2.2 Hz, 1H), 7.69 - 7.32 (m, 2H), 7.35 (s, 1H), 7.24 (dd, J = 8.4, 2.4 Hz, 4H ), 7.14 (d, J = 9.4 Hz, 2H), 4.43 (d, J = 4.2 Hz, 3H), 4.36 - 4.23 (m, 1H), 4.23 - 4.00 (m, 2H), 3.97 - 3.82 (m, 3H), 3.67 (d, J = 9.7 Hz, 5H), 3.28 (d, J = 9.6 Hz, 2H), 3.00 - 2.70 (m, 4H), 2.08 - 1.91 (m, 2H), 1.82 (t, J = 6.9 Hz, 2H), 1.49 (s, 9H), 1.23-1.08 (m, 9H), 1.03 (s, 3H).

Methyl-((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)-1 H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl3,6,13 - trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.

The title compound 162 was obtained according to the method described for the synthesis of compound 161, but using compound 162a. MS (ESI) m/z 1099.2 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.45 (s, 1H), 8.18 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 9.4 Hz, 1H ), 8.03 (s, 1H), 7.63 - 7.55 (m, 1H), 7.41 (s, 1H), 7.29 - 7.20 (m, 2H), 7.14 ( dd, J = 14.9, 8.2 Hz, 4H), 6.73 (t, J = 9.6 Hz, 2H), 4.34 (d, J = 9.7 Hz, 1H), 4, 28 - 4.13 (m, 4H), 4.13 - 3.91 (m, 4H), 3.83 (d, J = 13.1 Hz, 1H), 3.58 (d, J = 10, 5 Hz, 7H), 3.14 (d, J = 13.5 Hz, 2H), 2.75 (dd, J = 47.8, 9.1 Hz, 4H), 2.12 - 1.85 ( m, 3H), 1.16 - 0.97 (m, 9H), 0.94 (s, 3H).

Example 163.

Methyl-((5S,8S,9S,14S)-11 -(4-(1 -(difluoromethyl)-1 H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((6-(6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3yl)ethynyl)benzyl) -3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (163 ).

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, 2H), 8.01 (d, J = 2.7 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.44 (t, J = 59.8 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 9.8 Hz, 1H), 6.85 (d, J = 2, 8

Hz, 1H), 6.72 (d, J = 9.9 Hz, 1H), 6.50 (d, J = 8.9 Hz, 1H), 4.90 - 4.82 (m, 1H), 4.49 - 4.34 (m, 6H), 4.28 (s, 4H),

4.21 (d, J = 10.0 Hz, 1H), 4.05 (d, J = 13.0 Hz, 2H), 3.85 (d, J = 13.2 Hz, 1H), 3. 64 (s, 2H), 3.59 (s, 3H), 3.57 (s,

3H), 2.88 - 2.74 (m, 3H), 2.74 - 2.63 (m, 1H), 1.06 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H).

Example 164.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (164) .

Intermediates: P4, A3 and S18. MS (ESI) m/z 1114.3 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.19 - 8.05 (m, 2H), 8.01 (d, J = 2.7 Hz, 1H), 7.61 (dd, J = 8 .9, 2.2 Hz, 1H), 7.44 (t, J = 59.8 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 9.9 Hz, 1H), 6.85 (d, J = 2 .7 Hz, 1H), 6.72 (d, J = 10.0 Hz, 1H), 6.64 (d, J = 8.9 Hz, 1H), 4.35 (d, J = 9.8 Hz, 1H), 4.21 (d, J = 10.0 Hz, 1H), 4.05 (d, J = 12.6 Hz, 2H), 3.85 (d, J = 13.1 Hz, 2H), 3.65 (s, 1H), 3.58 (d, J = 10.7 Hz, 6H), 3.36 (d, J = 14.9 Hz, 2H), 2.84 (dd, J = 18.9, 9.2 Hz, 5H), 2.70 (d, J = 10.2 Hz, 1H), 1.06 (d, J = 6.3 Hz, 6H), 1.02 ( s, 3H), 0.93 (s, 3H).

Example 165.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((6-((3aR,6aS)-5-(oxetan-3-yl)hexahydropyrrolo[3,4-c]pyrrol2(1 H)-yl)pyridin- 3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa4,7,11,12-tetraazahexadecan-14 -yl)carbamate (165).

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, 2H), 8.01 (d, J = 2.7 Hz, 1H), 7.72 (dd, J = 8.9, 2.2 Hz, 1H), 7.44 (t, J = 59.8 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.25 (d , J = 7.9 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 9.9 Hz, 1H), 6.85 (d, J = 2.7 Hz, 1H), 6.81 - 6.67 (m, 2H), 4.63 (dd, J = 8.3, 5.1 Hz, 2H), 4.46 - 4.30 ( m, 2H), 4.21 (d, J = 10.0 Hz, 1H), 4.05 (d, J = 13.3 Hz, 2H), 3.85 (d, J = 13.2 Hz, 1H), 3.64 (d, J = 4.3 Hz, 6H), 3.59 (s, 3H), 3.57 (s, 3H), 3.32 (s, 3H), 2.87 - 2.62 (m, 4H), 1.06 (d, J = 6.2 Hz, 6H), 1.02 (s, 3H), 0.93 (s, 3H).

- 168 040208

Example 166.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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-4,7,11,12tetraazahexadecan-14-yl)carbamate (166).

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, 1H), 8.20 (s, 1H), 8.07 (d, J = 9.5 Hz, 1H ), 8.06 - 8.02 (m, 1H), 7.67 - 7.50 (m, 1H), 7.50 - 7.43 (m, 0H), 7.41 (s, 0H), 7.29 - 7.20 (m, 2H), 7.14 (dd, J = 13.7, 8.3 Hz, 3H), 6.73 (dd, J = 18.5, 9.6 Hz, 1H), 4.34 (t, J = 5.2 Hz, 3H), 4.30 - 4.15 (m, 3H), 4.13 - 3.94 (m, 3H), 3.84 (d , J = 13.2 Hz, 1H), 3.58 (d, J = 10.5 Hz, 6H), 3.17 (d, J = 2.4 Hz, 1H), 2.91 - 2.64 (m, 3H), 2.14 (d, J = 11.4 Hz, 2H), 1.95 (d, J = 8.6 Hz, 1H), 1.37 (d, J = 6.4 Hz , 6H), 1.12 - 0.97 (m, 9H), 0.94 (s, 3H).

Example 167.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-((6- (8ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15-dimethyl-3,6, 13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (167).

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, 1H), 8.19 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 21.7 Hz, 2H), 7.63 - 7.53 (m, 1H), 7.41 (s, 1H), 7.28 - 7.21 (m, 2H), 7.14 (dd, J = 13.9, 8.2 Hz, 4H), 6.73 (dd, J = 18.8, 9.5 Hz, 2H), 4.42 - 4.30 (m, 1H), 4.30 - 4.18 (m, 3H), 4.13 (d, J = 4.3 Hz, 2H), 4.02 (d, J = 12.6 Hz, 2H), 3.84 (d, J = 13.2 Hz, 1H), 3.58 (d, J = 10.5 Hz, 7H), 3.09 (q, J = 7.3 Hz, 2H), 2.92 - 2.72 (m, 3H), 2.72 - 2.61 (m, 1H), 2.24 - 2.13 (m, 2H), 1.96 (d, J = 8.7 Hz, 2H), 1.32 (t , J = 7.3 Hz, 3H), 1.11 - 0.98 (m, 9H), 0.94 (s, 3H).

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Example 168.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((6-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)ethynyl)benzyl)-3,6, 13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (168).

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, 1H), 8.24 - 8.16 (m, 1H), 8.08 (d, J = 9, 3 Hz, 1H), 8.03 (s, 1H), 7.63 - 7.54 (m, 1H), 7.41 (s, 1H), 7.28 - 7.21 (m, 2H), 7.14 (dd, J = 14.5, 8.2 Hz, 5H), 6.74 (dd, J = 15.5, 9.4 Hz, 2H), 4.34 (d, J = 9, 9 Hz, 1H), 4.24 (dd, J = 17.7, 11.9 Hz, 3H), 4.02 (d, J = 13.4 Hz, 4H), 3.83 (d, J = 13.2 Hz, 1H), 3.58 (d, J = 10.4 Hz, 7H), 3.16 (s, 1H), 3.06 - 2.96 (m, 0H), 2.85 - 2.58 (m, 6H), 2.31 - 2.13 (m, 2H), 2.05 - 1.89 (m, 2H), 1.13 - 0.96 (m, 9H), 0, 94 (s, 3H).

Example 169.

Oxetan-3-yl-((2S)-1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((2S,3S) -2hydroxy-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-3 ,3-dimethyl-1-oxobutan-2-yl)carbamate (169).

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, 1H), 8.09 (d, J = 9.4 Hz, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.52 (dd, J = 8.9, 2.4 Hz, 1H), 7.45 (t, J = 59.9 Hz, 1H), 7.37 (d , J = 8.2 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 6.85 (d, J = 2.8 Hz, 1H), 6.61 (d, J = 9.0 Hz, 1H), 5.29 (dp, J = 17.2, 5.7 Hz, 2H), 4.76 - 4 .73 (m, 4H), 4.67 (t, J = 6.4 Hz, 2H), 4.56 (yyy, J = 10.3, 7.3, 5.4 Hz, 2H), 4, 52 - 4.42 (m, 4H), 4.32 (s, 1H), 4.20 (s, 1H), 4.11 - 4.00 (m, 2H), 3.90 - 3.76 ( m, 3H), 3.77 - 3.60 (m, 2H), 3.08 - 2.97 (m, 2H), 2.89 - 2.75 (m, 3H), 2.73 - 2, 63 (m, 1H), 1.90-1.81 (m, 2H), 1.68-1.56 (m, 2H), 1.09 (s, 3H), 1.07 (s, 3H) , 1.03 (s, 3H), 0.95 (s, 3H).

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Example 170.

Methyl-((5S,8S,9S,14S)-11-(4-(1-cyclopropyl-1H-pyrazol-3-ul)-2,6-difluorobenzyl)-16,16,16-trifluoro9-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-tetraazahexadecan-14-yl)carbamate (170 ).

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, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.70 (td, J = 4.9, 4.4, 2.3 Hz, 2H), 7.39 - 7.27 (m, 4H), 7.22 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 9.9 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 9.9 Hz, 1H), 6. 64 (d, J = 2.4 Hz, 1H), 4.96 (dd, J = 8.2, 7.0 Hz, 2H), 4.81 (dd, J = 8.3, 5.1 Hz , 2H), 4.46 - 4.41 (m, 1H), 4.39 - 4.33 (m, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.19 - 4.07 (m, 4H), 3.93 (d, J = 13.2 Hz, 1H), 3.76 - 3.70 (m, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.40 - 3.34 (m, 2H), 2.95 - 2.70 (m, 4H), 2.30 - 2.18 (m, 2H), 2.12 - 2 .01 (m, 2H), 1.22 - 1.04 (m, 13H), 1.02 (s, 3H).

Example 171.

Methyl-((5S,8S,9S,14S)-11 -(4-(1-(difluoromethyl)-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyrimidin-5-yl)ethynyl) benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (171 ).

Intermediates: P4, A3 and S7. MS (ESI) m/z 1156.4 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.43 (s, 2H), 8.08 (d, J = 9.4 Hz, 1H), 8.01 (d, J = 2.8 Hz, 1H), 7.44 (d, J = 59.8 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H) , 7.14 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 9.9 Hz, 1H), 6.84 (d, J = 2.7 Hz, 1H), 6 .71 (d, J = 9.9 Hz, 1H), 4.87 (t, J = 7.6 Hz, 2H), 4.72 (dd, J = 8.2, 4.9 Hz, 2H) , 4.67 (s, 1H), 4.42-4.29 (m, 1H), 4.25-4.18 (m, 1H), 4.11-3.98 (m, 4H), 3 .85 (d, J = 13.1 Hz, 1H), 3.69 - 3.62 (m, 2H), 3.59 (s, 3H), 3.57 (s, 3H), 3.41 - 3.28 (m, 2H), 2.87 - 2.75 (m, 3H), 2.68 (dd, J = 12.6, 9.1 Hz, 1H), 2.18 - 2.06 ( m, 2H), 1.95 - 1.83 (m, 2H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.93 (s , 3H).

- 171 040208

Example 172.

Methyl-((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)-1 H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15dimethyl-3,6,13 -trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14yl)carbamate (172).

Intermediates: P4, A3 and S36. MS (ESI) m/z 1100.4 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.41 (s, 2H), 8.08 (d, J = 9.2 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.44 (d, J = 59.8 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H) , 7.14 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 2.8 Hz, 1H), 6 .70 (d, J = 10.2 Hz, 1H), 4.66 - 4.57 (m, 2H), 4.35 (d, J = 9.6 Hz, 1H), 4.26 - 4, 17 (m, 1H), 4.12 - 3.96 (m, 5H), 3.85 (d, J = 13.2 Hz, 1H), 3.69 - 3.62 (m, 2H), 3 .59 (s, 3H), 3.57 (s, 3H), 3.25 (s, 1H), 2.87 - 2.61 (m, 4H), 2.05 1.96 (m, 2H) , 1.90-1.82 (m, 2H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H).

Example 173.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1 H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9- hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2yl)pyridine- 3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecane- 14 -yl)carbamate (173).

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, 1H), 8.17 (d, J = 9.4 Hz, 1H), 8.10 (d, J = 2, 7 Hz, 1H), 7.69 (dd, J = 8.6, 2.1 Hz, 1H), 7.53 (t, J = 59.7 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 9, 8 Hz, 1H), 6.94 (d, J = 2.7 Hz, 1H), 6.80 (d, J = 10.2 Hz, 1H), 6.71 - 6.63 (m, 1H) , 5.07 - 5.01 (m, 1H), 4.72 4.68 (m, 1H), 4.64 - 4.54 (m, 2H), 4.52 - 4.49 (m, 1H ), 4.47 - 4.41 (m, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.20 - 4.08 (m, 2H), 3.94 (d, J = 13.1 Hz, 1H), 3.79 (d, J = 11.0 Hz, 1H), 3.72 (d, J = 11.7 Hz, 1H), 3.69 (s, 3H) , 3.66 (s, 3H), 2.93-2.82 (m, 3H), 2.81-2.73 (m, 1H), 2.33 (s, 2H), 1.16 (s , 3H), 1.15 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H).

- 172 040208

F

Example 174.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((6-((1S,4S)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2yl)pyridine-3 -yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecane-14- yl) carbamate (174).

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, 1H), 8.17 (d, J = 9.4 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.53 (t, J = 59.6 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 9, 9 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.80 (d, J = 9.9 Hz, 1H), 6.71 - 6.61 (m, 1H) , 5.05 (s, 1H), 4.99 - 4.93 (m, 1H), 4.70 (dd, J = 8.4, 4.5 Hz, 1H), 4.64 - 4.53 (m, 2H), 4.51 (s, 1H), 4.44 (d, J = 9.8 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.18 - 4.10 (m, 2H), 3.94 (d, J = 13.1 Hz, 1H), 3.79 (dd, J = 11.9, 2.2 Hz, 1H), 3.76 - 3.70 (m, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 2.94-2.73 (m, 4H), 2.33 (s, 2H), 1 .16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H).

Example 175.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15dimethyl- 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-tetraazahexadecan-14-yl)carbamate (175).

Intermediates: P28, A3 and S4. MS (ESI) m/z 1102.4 [M+H] ⁺ . 1H NMR (400 MHz, methanol-ph) δ 8.66 (d, J = 5.0 Hz, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 9.4 Hz, 1H), 8.03 - 7.88 (m, 2H), 7.74 (dd, J = 8.7, 2.3 Hz, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.46 (t, J = 6.1 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 7, 9 Hz, 2H), 7.11 (d, J = 9.4 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 4.97 (s, 3H), 4.62 (dd, J = 8.1, 4.1 Hz, 2H), 4.44 (d, J = 8.2 Hz, 1H), 4.34 - 4.26 (m, 1H), 4.26 - 4.07 (m, 4H), 3.98 (d, J = 13.1 Hz, 2H), 3.79 - 3.71 (m, 1H), 3.70 (s, 3H), 3.64 (s, 3H), 2.99 - 2.85 (m, 3H), 2.84 - 2.74 (m, 1H), 2.11 (d, J = 11.2 Hz, 1H), 1, 16 (s, 3H), 1.15 (s, 3H), 1.13 (s, 3H), 1.03 (s, 3H).

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Example 176.

Methyl-((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)pyridin3-yl)ethynyl )benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl) carbamate (176).

Intermediates: P4, A3 and S4. MS (ESI) m/z 1141.8 [M+H]+. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.33 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 9.3 Hz, 1H), 8.10 (d , J = 2.8 Hz, 1H), 7.74 (dd, J = 8.8, 2.2 Hz, 1H), 7.53 (t, J = 59.8 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.09 (d , J = 10.3 Hz, 1H), 6.93 (d, J = 2.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 5.07 - 4.91 (m, 3H), 4.61 (dd, J = 8.2, 4.1 Hz, 2H), 4.44 (d, J = 9.9 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.23 - 4.06 (m, 3H), 3.95 (d, J = 13.3 Hz, 1H), 3.70 (s, 3H), 3.66 ( s, 3H), 2.95 - 2.70 (m, 4H), 2.10 (d, J = 11.1 Hz, 1H), 1.16 (s, 3H), 1.15 (s, 3H ), 1.12 (s, 3H), 1.03 (s, 3H).

Example 177.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15dimethyl- 8-(4-((4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)ethynyl)benzyl)-3,6,13trioxo-5 -(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (177).

Intermediates: P28, A3 and S3. MS (ESI) m/z 1115.9 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.69 - 8.60 (m, 1H), 8.18 (d, J = 9.3 Hz, 1H), 7.94 (q, J = 7 .9 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.44 (t, J = 5.7 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 10.7 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 10.0 Hz, 1H), 5.01 - 4.92 (m, 3H), 4, 84 -4.76 (m, 2H), 4.44 (d, J = 9.9 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.23 - 4.10 (m, 4H), 3.97 (d, J = 13.1 Hz, 1H), 3.85 (d, J = 13.0 Hz, 2H), 3.79 - 3.72 (m, 1H) , 3.69 (s, 3H), 3.63 (s, 3H), 2.93-2.84 (m, 3H), 2.83-2.75 (m, 1H), 2.21 (q , J = 11.1, 10.5 Hz, 4H), 1.27 (d, J = 5.7 Hz, 1H), 1.16 (s, 3H), 1.14 (s, 3H), 1 .12 (s, 3H), 1.03 (s, 3H). ¹⁹ F NMR (377 MHz, methanold4) δ -77.39, -77.73, -77.85, -114.65.

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Example 178.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)phenyl)ethynyl)benzyl)-3, 6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (178).

Intermediates: P4, A3 and S3. MS (ESI) m/z 1154.4 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.07 (d, J = 9.4 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.44 (t, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 7. 11 (d, J = 8.1 Hz, 2H), 6.89 - 6.82 (m, 3H), 4.86 (t, J = 7.5 Hz, 2H), 4.72 - 4.64 (m, 2H), 4.35 (d, J = 6.4 Hz, 1H), 4.25 - 4.16 (m, 1H), 4.11 - 3.95 (m, 3H), 3, 85 (d, J = 12.5 Hz, 1H), 3.80 - 3.70 (m, 1H), 3.68 - 3.62 (m, 1H), 3.60 (s, 3H), 3 .57 (s, 3H), 2.85 - 2.63 (m, 4H), 2.18 - 1.99 (m, 4H), 1.22 - 1.18 (m, 2H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H). ¹⁹ F 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.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15dimethyl- 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-tetraazahexadecan-14yl)carbamate (179).

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, 1H), 8.21 - 8.10 (m, 2H), 8.02 - 7.82 (m, 3H), 7.60 (d, J = 8.6 Hz, 2H), 7.46 (t, J = 6.3 Hz, 1H), 7.36 (d, J = 7.9 Hz, 2H) , 7.25 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 9.4 Hz, 1H), 4.82 - 4.76 (m, 2H), 4.66 - 4.58 (m, 2H), 4.51-4.41 (m, 1H), 4.35-4.27 (m, 1H), 4.23-4.13 (m, 2H), 4. 13 - 3.89 (m, 7H), 3.78 - 3.72 (m, 2H), 3.69 (s, 3H), 3.68 - 3.65 (m, 3H), 3.63 ( s, 3H), 3.18-3.08 (m, 2H), 3.00-2.84 (m, 3H), 2.84-2.74 (m, 1H), 1.16 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.37, -77.71, -77.99, 114.58.

- 175 040208

F yN^ ^F yN

FyF

O YHO O' ^H [OH

H O h / x H / k o

N N

Lo

Example 180.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-((6-(9-(oxetan-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7yl)pyridin-3-yl )ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl) carbamate (180).

Intermediates: P4, A3 and S1. MS (ESI) m/z 1171.8 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.20 - 8.13 (m, 2H), 8.10 (d, J = 2.7 Hz, 1H), 7.87 (d, J = 8 .7 Hz, 1H), 7.60 (t, J = 59.8 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 9.5 Hz, 1H), 6.93 (d, J = 2.7 Hz, 1H), 4.80 - 4.75 (m, 1H), 4.74 - 4.67 (m, 1H), 4.62 (t, J = 5.7 Hz, 2H), 4.46 - 4 .40 (m, 1H), 4.32 - 4.25 (m, 1H), 4.21 - 4.00 (m, 6H), 3.99 - 3.89 (m, 3H), 3.78 - 3.71 (m, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.12 (d, J = 4.9 Hz, 2H), 2.98 - 2, 72 (m, 4H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H). ¹⁹ F 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.

Synthesis of tert-butyl-2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)-2(4-(1-(difluoromethyl)- 1 H-pyrazol-3 -yl)-2,6-difluorobenzyl)hydrazine-1-carboxylate (181a).

The title compound 181a was obtained according to the method described for the synthesis of compound 1a, but using compounds 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, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.53 (t, J = 59.8 Hz, 1H), 7.51 - 7.35 (m, 2H), 7.02 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 2.7 Hz , 1H), 4.03 (d, J = 26.8 Hz, 2H), 3.70 (d, J = 8.2 Hz, 1H), 3.57 (d, J = 9.0 Hz, 1H ), 2.79 (tdd, J = 20.0, 11.2, 6.9 Hz, 2H), 1.37 (s, 8H), 1.31 (s, 7H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -96.90 (d, J = 59.8 Hz), -115.32.

- 176 040208

Synthesis of tert-butyl-((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-2methylpropan-2-yl)-3 -oxa-5,8,9,13-tetraazaheptadecan-15-yl)carbamate (181b).

The title compound 181b was prepared according to the procedure described for the synthesis of intermediate I2, but using compounds 181a and A1. MS (ESI) m/z 1098.6 [M+H]+.

Synthesis of tert-butyl-((6S,11S,12S,15S)-9-(4-(1-(difluoromethyl)-1 H-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]octan3-yl) pyridin-3-yl)ethynyl)benzyl)-4,7,14-trioxo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-oxa-5,8,9,13tetraazaheptadecane -15-yl)carbamate (181c).

The title compound 181c was prepared according to the method described for the synthesis of compound 133, but using compounds 181b and S3. MS (ESI) m/z 1239.9 [M+H]+.

(2S)-N-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((S) -4,4,4-trifluoro3,3-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).

To a solution of compound 181c (355 mg, 0.29 mmol) in DCM (10 ml) was added trifluoroacetic acid (2 ml), the resulting mixture was stirred, and after 18 h the reaction mixture was concentrated under reduced pressure, and the resulting crude substance 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 resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by HPLC to give compound 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, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.74 - 7.37 (m, 4H), 7.37 - 7.23 (m, 2H), 7.23 - 7.12 (m, 2H), 6.95 (d, J = 2.8 Hz, 1H ), 6.70 (dd, J = 9.1, 0.8 Hz, 1H), 4.83 - 4.71 (m, 3H), 4.66 (s, 1H), 4.59 (dd, J = 6.3, 5.4 Hz, 3H), 4.23 - 4.13 (m, 2H), 4.00 - 3.84 (m, 4H), 3.84 - 3.70 (m, 1H), 3.13 (dd, J = 12.0, 2.2 Hz, 3H), 2.95 - 2.71 (m, 4H), 2.21 (ttd, J = 7.5, 5, 0, 2.3 Hz, 4H), 1.97 - 1.90 (m, 2H), 1.70 (d, J = 7.8 Hz, 2H), 1.18 (d, J = 9.3 Hz, 7H), 1.16 -1.00 (m, 13H).

Example 182.

(2S)-2-acetamido-N-((2S,3S)-4-(2-((S)-2-acetamido-4,4,4-trifluoro-3,3-dimethylbutanoyl)-1-(4 -(1(difluoromethyl)-1 H-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).

The title compound 182 was obtained according to the method described 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, 1H), 8.09 (d, J = 2.7 Hz, 1H), 7.72 - 7.35 (m, 4H), 7.35 - 7.24 (m, 2H), 7.20 - 7.11 (m, 2H), 6.94 (d, J = 2.8 Hz, 1H ), 6.69 (dd, J = 9.0, 0.8 Hz, 1H), 4.76 (dd, J = 12.8, 6.4 Hz, 3H), 4.63 (d, J = 1.4 Hz, 1H), 4.57 (dd, J = 6.3, 5.4 Hz, 3H), 4.15 (d, J = 13.4 Hz, 2H), 3.98 - 3, 65 (m, 5H), 3.11 (dd, J = 12.0, 2.2 Hz, 3H), 2.98 - 2.67 (m, 4H), 2.13 (d, J = 10, 3 Hz, 0H), 1.98 1.83 (m, 9H), 1.68 (d, J = 7.8 Hz, 2H), 1.17 (d, J = 6.2 Hz, 6H), 1.12 (s, 3H), 1.04 (s, 3H), 0.88 (d, J = 6.7 Hz, 0H).

- 177 040208

Example 183.

Synthesis of (9H-fluoren-9-yl)methyl-((S)-1-(2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4(4-iodophenyl) butyl)-2-(4-(1-(difluoromethyl)-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-3,3dimethyl-1-oxobutan-2-yl)carbamate (183a) .

The title compound 183a was obtained according to the method described for the synthesis of compound 133a, but using compounds I4 and P4. MS (ESI) m/z 999.3 [M+H]+.

Synthesis of (9H-fluoren-9-yl)methyl-((5S,8S,9S, 14S)-11 -(4-(1-(difluoromethyl)-1H-pyrazol-3 -yl)-2,6difluorobenzyl)- 9-hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan2-yl)-2-oxa-4, 7,11,12-tetraazahexadecan-14-yl)carbamate (183b).

The title compound 183b was prepared according to the method described for the synthesis of compound 133b, but using compounds 4a and A3. MS (ESI) m/z 1124.6 [M+H] ⁺ .

Synthesis of methyl-((2S)-1-(((2S,3S)-4-(2-((S)-2-amino-3,3-dimethylbutanoyl)-1-(4-(1-(difluoromethyl) -1Hpyrazol-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 (183с ).

The title compound 183c was prepared according to the method described for the synthesis of compound 133, but using compounds 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, 1H), 8.14 - 8.07 (m, 2H), 7.75 - 7, 65 (m, 1H), 7.53 (d, J = 59.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.25 - 7.18 (m, 2H), 6.94 (d, J = 2.8 Hz, 1H), 6.86 (dd, J = 9.0, 0.9 Hz , 1H), 6.78 (d, J = 9.9 Hz, 1H), 4.99 - 4.93 (m, 3H), 4.84 (d, J = 5.2 Hz, 1H), 4 .82 (d, J = 5.0 Hz, 1H), 4.54 (s, 1H), 4.42 - 4.30 (m, 3H), 4.26 - 4.06 (m, 5H), 3.81 (t, J = 6.6 Hz, 1H), 3.65 (s, 1H), 3.45-3.36 (m, 3H), 2.97-2.76 (m, 4H) , 2.28 - 2.19 (m, 2H), 2.11 - 2.03 (m, 2H), 1.09 (s, 3H), 1.06 (s, 3H), 0.97 (s , 9H).

Synthesis of methyl-((2S)-1-(((2S,3S)-4-(2-((S)-2-(cyclopropanecarboxamido)-3,3-dimethylbutanoyl)-1-(4(1 -(difluoromethyl )-1 H-pyrazol-3 -yl)-2,6-difluorobenzyl)hydrazinyl)-3-hydroxy-1-(4-((6-(8-(oxetan-3yl)-3,8-diazabicyclo[3.2 .1]octan-3-yl)pyridin-3-yl)ethynyl)phenyl)butan-2-yl)amino)-4,4,4-trifluoro- 178 040208

3,3-dimethyl-1-oxobutan-2-yl)carbamate (183).

To a solution of compound 183c (45 mg, 0.33 mmol) in DCM (1 ml) was added Et ₃ N (0.03 ml, 0.23 mmol) at 5°C, after which cyclopropanecarbonyl chloride (3.54 μl, 0 .39 mmol) and the resulting mixture was stirred for 10 min, after which it was diluted with MeOH, concentrated under reduced pressure, and the residue was purified by HPLC to give compound 183. MS (ESI) m/z 1111.5 [M+H ]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.35 - 8.26 (m, 1H), 8.18 (d, J = 9.4 Hz, 1H), 8.11 (d, J = 2 .7 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.71 (dd, J = 8.8, 2.3 Hz, 1H), 7.53 (t, J = 59.7 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8 .1 Hz, 2H), 6.94 (d, J = 2.8 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 9.9 Hz, 1H), 5.03 - 4.94 (m, 2H), 4.84 - 4.77 (m, 3H), 4.44 (d, J = 9.9 Hz, 1H), 4.41 - 4.31 (m, 1H), 4.21 4.06 (m, 5H), 3.96 (d, J = 13.1 Hz, 1H), 3.81 - 3.72 (m, 1H) , 3.70 (s, 3H), 3.39 (s, 1H), 2.91 (d, J = 7.7 Hz, 2H), 2.88 - 2.73 (m, 2H), 2, 29 - 2.19 (m, 2H), 2.15 - 2.04 (m, 2H), 1.74 - 1.67 (m, 1H), 1.31 (t, J = 7.5 Hz, 1H), 1.14 (s, 3H), 1.10 (s, 3H), 0.89 (s, 9H), 0.75 (dd, J = 8.2, 3.6 Hz, 2H).

F

Example 184.

Methyl-((2S)-1-(((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2- ((S)-3,3dimethyl-2-(((oxetan-3-yloxy)carbonyl)amino)butanoyl)hydrazinyl)-3-hydroxy-1-(4-((6-(8-(oxetan-3yl) -3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)phenyl)butan-2-yl)amino)-4,4,4-trifluoro3,3-dimethyl-1- oxobutan-2-yl)carbamate.

Intermediates: P4, A3, S3 and 4-nitrophenyloxetan-3-yl carbonate. MS (ESI) m/z 1143.6 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.25 -8.19 (m, 1H), 8.09 (d, J = 9.3 Hz, 1H), 8.01 (d, J = 2, 7 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.44 (t, J = 59.7 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H) , 7.23 (d, J = 7.9 Hz, 3H), 7.13 (d, J = 8.0 Hz, 3H), 6.85 (d, J = 2.7 Hz, 1H), 6 .77 (d, J = 8.9 Hz, 1H), 6.71 (d, J = 9.6 Hz, 1H), 4.87 (t, J = 7.6 Hz, 3H), 4.76 - 4.68 (m, 2H), 4.51 (dt, J = 23.0, 6.4 Hz, 2H), 4.31 - 4.22 (m, 2H), 4.12 - 3.99 (m, 5H), 3.87 (d, J = 13.1 Hz, 1H), 3.70 - 3.62 (m, 2H), 3.59 (s, 3H), 3.30 (s, 1H), 2.89 - 2.60 (m, 5H), 2.18 - 2.10 (m, 2H), 2.03 - 1.95 (m, 2H), 1.24 - 1.17 ( m, 2H), 1.05 (s, 3H), 1.01 (s, 3H), 0.78 (s, 9H).

F

Example 185.

Methyl-((2S)-1-(((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-2 -((S)-3,3dimethyl-2-propionamidobutanoyl)hydrazinyl)-3-hydroxy-1-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyc- 179 040208 lo [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.

Intermediates: P4, A3, S3 and propionyl chloride MS (ESI) m/z 1099.6 M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.22 - 8.18 (m, 1H), 8.08 (d, J = 9.2 Hz, 1H), 8.01 (d, J = 2 .7 Hz, 1H), 7.61 (dd, J = 8.9, 2.3 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 59.9 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8 .1 Hz, 2H), 6.84 (d, J = 2.8 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 6.69 (d, J = 9.9 Hz, 1H), 4.87 (dd, J = 8.1, 6.9 Hz, 2H), 4.73 - 4.69 (m, 2H), 4.36 - 4.31 (m, 1H) , 4.30 - 4.19 (m, 3H), 4.09 - 4.02 (m, 4H), 4.01 3.96 (m, 1H), 3.86 (d, J = 13.2 Hz, 1H), 3.68 - 3.62 (m, 1H), 3.59 (s, 3H), 3.31 - 3.24 (m, 2H), 2.84 - 2.64 (m, 3H), 2.18 - 2.07 (m, 2H), 2.03 - 1.94 (m, 2H), 1.04 (s, 3H), 1.03 - 0.97 (m, 6H) , 0.77 (s, 9H).

Example 186.

Methyl-((2S)-1-(((2S,3S)-4-(2-((S)-2-(cyclopropanecarboxamido)-4,4,4-trifluoro-3,3-dimethylbutanoyl)-1( 4-( 1 - (difluoromethyl) -1 H-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-3,3dimethyl-1- oxobutan-2-yl)carbamate (186).

Intermediates: P4, A3, S7 and cyclopropanecarboxylic acid. MS (ESI) m/z 1167.0 M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.52 (s, 2H), 8.22 (d, J = 9.6 Hz, 1H), 8.14 (d, J = 9.4 Hz, 1H), 8.09 (d, J = 2.7 Hz, 1H), 7.52 (t, J = 59.9 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H) , 7.34 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 2.8 Hz, 1H), 6 .75 (d, J = 9.9 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.82 - 4.77 (m, 2H), 4.75 (s, 1H), 4.65 (d, J = 9.7 Hz, 1H), 4.43 (d, J = 9.9 Hz, 1H), 4.23 - 4.07 (m, 4H), 3, 92 (d, J = 13.0 Hz, 1H), 3.74 (d, J = 8.6 Hz, 1H), 3.69 (s, 3H), 3.45 (d, J = 14.5 Hz, 2H), 2.97-2.82 (m, 3H), 2.81-2.69(m, 1H), 2.27-2.10 (m, 2H), 2.03-1, 89 (m, 2H), 1.74-1.63 (m, 1H), 1.19 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 0.97-0.88 (m, 1H), 0.87-0.70 (m, 3H).

Example 187.

Synthesis of cyclopropyl-((S)-1-(2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl- 180 040208 nyl)butyl)-2 -(4-(1-(difluoromethyl)-III-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazinyl)-3,3-dimethyl-1oxobutan-2-yl)carbamate (187a).

The title compound 187a was prepared according to the procedure described for the synthesis of compound 133a, but using compounds 15 and P4. MS (ESI) m/z 861.1 [M+H]+.

Synthesis of cyclopropyl-((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-oxa4,7,11,12-tetraazahexadecane-14 -yl)carbamate (187b).

The title compound 187b was prepared according to the method described for the synthesis of compound 133b, but using compound 5a. MS (ESI) m/z 986.5 [M+H] ⁺ .

Synthesis of cyclopropyl-((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-3yl)ethynyl)benzyl)-3.6, 13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (187).

The title compound 187 was prepared according to the method described for the synthesis of compound 133, but using compounds 187b and S3. MS (ESI) m/z 1127.4 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.33 - 8.25 (m, 1H), 8.18 (d, J = 9.3 Hz, 1H), 8.10 (d, J = 2 .7 Hz, 1H), 7.74 - 7.66 (m, 1H), 7.53 (d, J = 59.7 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H ), 7.32 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 2.7 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 9.9 Hz, 1H), 4.96 (t, J = 7.5 Hz, 2H), 4. 81 (dd, J = 8.2, 5.2 Hz, 2H), 4.44 (d, J = 10.0 Hz, 1H), 4.35 (d, J = 13.6 Hz, 2H), 4.23 - 4.06 (m, 4H), 4.03 - 3.92 (m, 2H), 3.82 - 3.74 (m, 1H), 3.69 (s, 3H), 3, 40 - 3.33 (m, 2H), 2.97 - 2.73 (m, 3H), 2.31 - 2.18 (m, 2H), 2.11 - 2.04 (m, 2H), 1.16-1.12 (m, 3H), 1.10 (s, 3H), 0.85 (s, 9H), 0.68-0.58 (m, 4H).

Example 188.

Synthesis of methyl-((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrαzol-3-ul)-2,6-difluorobenzyl)-16.16, 16trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2yl )pyridin-3-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecane- 14-yl)carbamate (188).

Suspension of compound 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(PPh ₃ ) ₂ Cl ₂ (2.8 mg, 0.004 mmol) in 2-MeTHF (1 ml) was degassed with argon for 15 min, after which it was heated at 90° C. overnight. The mixture was cooled to room temperature, after which 1 M potassium phosphate in H ₂ O (0.39 ml) was added, the resulting mixture was degassed for 5 minutes. Pd(tBu ₂ PPh) ₂ Cl ₂ (4.5 mg, 0.007 mmol) and compound 1a (100 mg, 0.1 mmol) in 2-MeTHF (1 mL) were added and the resulting mixture was degassed for another 5 min. The mixture was heated at 65°C. The reaction mixture was cooled to room temperature. The mixture was diluted with EtOAc and washed with brine. The separated organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo, the residue was purified by HPLC and the resulting product was lyophilized to give compound 188. MS (ESI) m/z 1131.2 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 8.10 (d, J = 9.3 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H) , 7.05 (d, J = 9.9 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 6.76 (d, J = 9.8 Hz, 1H), 6 .65 (d, J = 2.5 Hz, 1H), 6.32 - 5.96 (m, 1H), 4.96 (s, 1H), 4.61 (dd, J = 8.2, 4 .7 Hz, 1H), 4.58 - 4.49 (m, 3H), 4.45 (dd, J = 14.2, 4.8 Hz, 1H), 4.37 (s, 1H), 4 .21 (d, J = 9.9 Hz, 1H), 4.04 (d, J = 13.0 Hz, 2H), 3.84 (d, J = 13.2 Hz, 1H), 3.74 (d, J = 11.9 Hz, 1H), 3.67 (d, J = 11.5 Hz, 2H), 3.54 (s, 4H), 3.47 (s, 3H), 2.92 - 2.73 (m, 4H), 2.73 - 2.62 (m, 1H), 2.24 (s, 2H), 1.05 (d, J = 4.5 Hz, 7H), 1, 01 (s, 3H), 0.92 (s, 3H).

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Example 189.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-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-tetraazahexadecan-14-yl)carbamate (189 ).

Intermediates: I2, P1 and S7a. MS (ESI) m/z 1132.9 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.65 (s, 2H), 8.19 (d, J = 7.9 Hz, 2H), 8.02 (s, 1H), 7.59 (t , J = 60.2 Hz, 1H), 7.32 (d, J = 7.8 Hz, 2H), 7.17 (d, J = 10.0 Hz, 1H), 6.88 (d, J = 9.9 Hz, OH), 4.96 (t, J = 7.6 Hz, 2H), 4.83 (dd, J = 8.3, 5.3 Hz, 2H), 4.47 (d , J = 7.2 Hz, 2H), 4.39 - 4.23 (m, 1H), 4.13 (d, J = 13.3 Hz, 5H), 3.93 (d, J = 13, 3 Hz, 1H), 3.75 (s, 1H), 3.65 (s, 3H), 3.56 (s, 3H), 3.47 (d, J = 14.5 Hz, 2H), 3 .03 - 2.73 (m, 4H), 2.29 - 2.11 (m, 2H), 2.01 (d, J = 9.1 Hz, 2H), 1.14 (d, J = 5 .2 Hz, 6H), 1.10 (s, 3H), 1.02 (s, 3H).

F

Example 190.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-9-hydroxy15,15-dimethyl-8 -(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13trioxo-5 -(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (190).

Intermediates: I3, P1 and S7a. MS (ESI) m/z 1079.3 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.56 (s, 2H), 8.20 - 8.03 (m, 2H), 7.92 (d, J = 1.3 Hz, 1H), 7 .49 (t, J = 59.9 Hz, 1H), 7.31 (dd, J = 9.9, 8.2 Hz, 4H), 7.22 (d, J = 7.8 Hz, 2H) , 6.79 (d, J = 10.0 Hz, 0H), 4.87 (t, J = 7.6 Hz, 2H), 4.75-4.63 (m, 2H), 4.54- 4.34 (m, 1H), 4.11 - 3.95 (m, 3H), 3.86 (d, J = 13.2 Hz, 1H), 3.66 (s, 1H), 3.54 (s, 3H), 3.47 (s, 2H), 3.37 (d, J = 14.4 Hz, 2H), 2.83 (t, J = 8.0 Hz, 2H), 2.71 (d, J = 8.8 Hz, 2H), 2.20 - 2.07 (m, 2H), 1.92 (d, J = 8.9 Hz, 2H), 1.04 (s, 3H) , 1.00 (s, 3H), 0.75 (s, 8H).

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Example 191.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(2,2-difluoroethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro -9-hydroxy-15,15-dimethyl-8-(4-(2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2yl) pyrimidin-5-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecane-14 -yl)carbamate. (191).

Intermediates: I2, P10 and S6a. MS (ESI) m/z 1132.8 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.64 (s, 2H), 8.14 (d, J = 9.4 Hz, 1H), 7.87 (d, J = 8.6 Hz, 0H ), 7.73 (d, J = 2.4 Hz, 1H), 7.55 (dt, J = 15.4, 7.4 Hz, 1H), 7.50 - 7.21 (m, 6H) , 7.09 (d, J = 9.9 Hz, 1H), 6.83 (d, J = 9.8 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6 .21 (tt, J = 55.3, 3.9 Hz, 1H), 5.18 (s, 1H), 5.02 - 4.89 (m, 2H), 4.73 (d, J = 5 .1 Hz, 1H), 4.59 (td, J = 14.1, 13.7, 6.4 Hz, 3H), 4.52 (s, 1H), 4.46 (d, J = 9, 7 Hz, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.13 (d, J = 13.1 Hz, 2H), 3.99 - 3.87 (m, 2H) , 3.87 - 3.69 (m, 3H), 3.64 (s, 3H), 3.57 (s, 2H), 2.97 - 2.84 (m, 3H), 2.84 - 2 .73 (m, 1H), 2.34 (s, 2H), 1.44 (d, J = 16.1 Hz, 1H), 1.29 (s, 2H), 1.26 (s, 2H) , 1.14 (d, J = 4.9 Hz, 6H), 1.10 (s, 3H), 1.02 (s, 3H).

Example 192.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15dimethyl-8 -(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6,13-trioxo5 -(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (192).

Intermediates: I3, P4 and S7a. MS (ESI) m/z 1078.1 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.65 (s, 3H), 8.14 (d, J = 9.1 Hz, 1H), 8.09 (d, J = 2.8 Hz, 2H ), 7.52 (t, J = 59.8 Hz, 2H), 7.43 (dd, J = 12.4, 8.0 Hz, 6H), 7.31 (d, J = 7.8 Hz , 3H), 6.92 (d, J = 2.8 Hz, 2H), 6.83 (d, J = 9.8 Hz, 1H), 4.96 (t, J = 7.6 Hz, 3H ), 4.46 (d, J = 9.6 Hz, 2H), 4.13 (d, J = 13.6 Hz, 7H), 3.97 (d, J = 13.1 Hz, 2H), 3.75 (s, 2H), 3.62 (s, 5H), 3.56 (s, 4H), 3.46 (d, J = 14.3 Hz, 4H), 2.92 (t, J = 8.5 Hz, 2H), 2.81 (d, J = 10.7 Hz, 3H), 2.21 (d, J = 11.4 Hz, 3H), 2.01 (d, J = 9 .0 Hz, 3H), 1.27 (d, J = 13.9 Hz, 1H), 1.13 (s, 6H), 1.10 (s, 5H), 0.84 (s, 14H).

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Example 193.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15 ,15dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzyl)-3,6 ,13-trioxo5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (193).

Intermediates: I3, P10 and S7a. MS (ESI) m/z 1092.3 [M+H]+. 1H NMR (400 MHz, methanol D4) δ 8.65 (s, 2H), 8.14 (d, J = 9.2 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.39 (dd, J = 17.0, 8.2 Hz, 4H), 7.31 (d, J = 7.8 Hz, 2H), 6.83 (d, J = 9.8 Hz, 1H ), 6.73 (d, J = 2.4 Hz, 1H), 6.21 (tt, J = 55.4, 3.9 Hz, 1H), 4.96 (t, J = 7.6 Hz , 2H), 4.76 (s, 1H), 4.59 (td, J = 14.3, 4.0 Hz, 2H), 4.49 - 4.41 (m, 1H), 4.12 ( d, J = 20.4 Hz, 4H), 3.96 (d, J = 13.1 Hz, 1H), 3.76 (s, 2H), 3.62 (s, 3H), 3.56 ( s, 3H), 3.47 (d, J = 14.5 Hz, 2H), 2.92 (t, J = 8.4 Hz, 2H), 2.80 (d, J = 9.5 Hz, 2H), 2.26 - 2.10 (m, 2H), 2.01 (d, J = 9.2 Hz, 2H), 1.13 (s, 3H), 1.09 (s, 3H), 0.85 (s, 9H).

Example 194.

Methyl-((5S,8S,9S, 14S)-11-(4-(1-cyclopropyl-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy- 15,15-dimethyl-8-(4-(6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2yl)pyridin-3-yl )benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate ( 194).

Intermediates: I2, P13 and S6a. MS (ESI) m/z 1092.3 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) 5 8.20 (s, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H ), 7.60 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 7.9 Hz, 2H), 7.23 (dd, J = 14.4, 8.2 Hz , 4H), 6.76 (d, J = 9.4 Hz, 2H), 6.54 (d, J = 2.4 Hz, 1H), 4.93 (s, 1H), 4.61 - 4 .53 (m, 1H), 4.52 - 4.46 (m, 1H), 4.45 - 4.27 (m, 2H), 4.21 (d, J = 9.9 Hz, 1H), 4.03 (d, J = 13.0 Hz, 2H), 3.83 (d, J = 13.0 Hz, 1H), 3.72 (d, J = 9.6 Hz, 1H), 3. 66 - 3.56 (m, 1H), 3.55 (s, 3H), 3.46 (s, 3H), 2.82 (d, J = 7.2 Hz, 0H), 2.70 (d , J = 9.8 Hz, 1H), 2.22 (s, 2H), 1.05 (d, J = 5.1 Hz, 8H), 0.98 (d, J = 16.3 Hz, 3H ), 0.92 (s, 2H).

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Example 195.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(2,2-difluoroethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro -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-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl )carbamate (195).

Intermediates: I2, P10 and S3c. MS (ESI) m/z 1146.1 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.29 (s, 1H), 8.07 (d, J = 9.3 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H ), 7.64 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 9.8 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H), 6. 74 (d, J = 9.8 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 6.12 (tt, J = 55.3, 3.9 Hz, 1H), 4.86 (t, J = 7.6 Hz, 2H), 4.74 4.66 (m, 2H), 4.51 (td, J = 14.3, 3.9 Hz, 2H), 4, 45 - 4.33 (m, 2H), 4.26 - 4.09 (m, 3H), 4.03 (d, J = 8.7 Hz, 4H), 3.84 (d, J = 13, 2 Hz, 1H), 3.67 (s, 1H), 3.54 (s, 3H), 3.46 (s, 2H), 3.32 (s, 1H), 3.29 (d, J = 1.7 Hz, 1H), 2.91 2.73 (m, 2H), 2.70 (d, J = 9.4 Hz, 1H), 2.14 (t, J = 6.4 Hz, 2H ), 2.01 (d, J = 8.5 Hz, 2H), 1.05 (d, J = 3.7 Hz, 6H), 1.01 (s, 3H), 0.92 (s, 2H ).

F

Example 196.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-(6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2yl)pyridin-3 - yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (196).

Intermediates: I2, P4 and S6a. MS (ESI) m/z 1117.2 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.20 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H ), 7.88 (d, J = 8.9 Hz, 1H), 7.44 (t, J = 59.8 Hz, 1H), 7.34 (dd, J = 11.9, 8.1 Hz , 3H), 7.21 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 10.0 Hz, 1H), 6.84 (d, J = 2.7 Hz, 1H ), 6.75 (t, J = 10.2 Hz, 1H), 5.01 - 4.89 (m, 1H), 4.59 (dd, J = 8.3, 4.8 Hz, 1H) , 4.51 (dd, J = 8.0, 5.0 Hz, 1H), 4.37 (dd, J = 19.9, 10.1 Hz, 3H), 4.20 (d, J = 10 .0 Hz, 1H), 4.06 (d, J = 13.2 Hz, 2H), 3.85 (d, J = 13.2 Hz, 1H), 3.81 - 3.61 (m, 2H ), 3.56 (d, J = 4.6 Hz, 3H), 3.53 - 3.43 (m, 2H), 2.82 (d, J = 9.0 Hz, 2H), 2.75 - 2.61 (m, 1H), 2.22 (s, 2H), 1.05 (s, 6H), 1.01 (s, 3H), 0.92 (s, 3H).

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Example 197.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(2,2-difluoroethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro -9-hydroxy-15,15-dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyrimidin-5-yl) benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (197 ).

Intermediates: I2, P10 and S7a. MS (ESI) m/z 1146.4 [M+H] ¹ H NMR (400 MHz, methanol-d4) δ 8.65 (s, 2H), 8.15 (d, J = 9.4 Hz, 1H ), 7.73 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.10 (d, J = 9.9 Hz, 1H), 6.84 (d, J = 9.7 Hz, 1H), 6. 73 (d, J = 2.4 Hz, 1H), 6.21 (tt, J = 55.3, 4.0 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.84 - 4.73 (m, 4H), 4.60 (td, J = 14.3, 3.9 Hz, 2H), 4.49 4.42 (m, 1H), 4.33 - 4 .26 (m, 1H), 4.21 - 4.08 (m, 4H), 3.94 (d, J = 13.2 Hz, 1H), 3.81 - 3.71 (m, 1H), 3.63 (s, 3H), 3.56 (s, 3H), 3.47 (d, J = 14.4 Hz, 2H), 2.99 - 2.74 (m, 4H), 2.28 - 2.12 (m, 2H), 2.05 - 1.91 (m, 2H), 1.15 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H). ¹⁹ F 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.

Methyl-((5S,8S,9S, 14S)-11-(4-(1-cyclopropyl-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy- 15,15-dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyrimidin-5-yl)benzyl)-3, 6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecano-14-yl)carbamate (198).

Intermediates: I2, P13 and S7a. MS (ESI) m/z 1122.5 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.56 (s, 2H), 8.07 (d, J = 9.3 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 7.9 Hz, 2H), 7.28 - 7.16 (m, 4H), 7.03 (d, J = 10.0 Hz, 1H), 6, 75 (d, J = 9.8 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 4.87 (t, J = 7.6 Hz, 2H), 4.76 4 .70 (m, 2H), 4.67 (s, 1H), 4.37 (d, J = 9.9 Hz, 1H), 4.21 (d, J = 10.0 Hz, 1H), 4 .12 - 3.99 (m, 4H), 3.84 (d, J = 13.2 Hz, 1H), 3.66 (s, 1H), 3.60 (tt, J = 7.3, 3 .9 Hz, 1H), 3.55 (s, 3H), 3.47 (s, 3H), 3.38 (d, J = 14.3 Hz, 2H), 2.89 - 2.62 (m , 4H), 2.18-2.06 (m, 2H), 1.96-1.85 (m, 2H), 1.12-0.93 (m, 13H), 0.93 (s, 3H ).

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F

Example 199.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyrimidin-5-yl)benzyl)-3 ,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (199).

Intermediates: I2, P4 and S7a. MS (ESI) m/z 1132.9 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.56 (s, 2H), 8.08 (d, J = 9.4 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H ), 7.44 (t, J = 59.9, 59.5 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.1 Hz , 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 9.9 Hz, 1H), 6.84 (d, J = 2.7 Hz, 1H ), 6.77 (d, J = 9.9 Hz, 1H), 4.87 (t, J = 7.6 Hz, 2H), 4.72 (dd, J = 8.3, 5.0 Hz , 2H), 4.69 (s, 2H), 4.37 (d, J = 9.8 Hz, 1H), 4.20 (d, J = 10.0 Hz, 1H), 4.12 -3 .96 (m, 4H), 3.85 (d, J = 13.1 Hz, 1H), 3.67 (s, 1H), 3.55 (s, 3H), 3.47 (s, 3H) , 3.37 (d, J = 14.3 Hz, 2H), 2.87 -2.75 (m, 3H), 2.75 - 2.66 (m, 1H), 1.92 (d, J = 9.2 Hz, 2H), 1.05 (s, 6H), 1.01 (s, 3H), 0.93 (s, 3H).

F

Example 200.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1,5naphthyridin-2-yl )benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate ( 200).

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, 3H), 8.01 (d, J = 2.7 Hz, 2H), 7.85 (d, J = 7, 9 Hz, 2H), 7.44 (t, J = 59.7 Hz, 1H), 7.41 (d, J = 9.5 Hz, 1H), 7.36 (d, J = 8.2 Hz , 2H), 7.30 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 2.8 Hz, 1H), 4.89 (t, J = 7.6 Hz, 2H ), 4.74 (dd, J = 8.2, 5.1 Hz, 2H), 4.53 (d, J = 14.1 Hz, 2H), 4.37 (s, 1H), 4.21 (s, 1H), 4.16 - 4.01 (m, 4H), 3.86 (d, J = 13.1 Hz, 1H), 3.71 (s, 1H), 3.54 (s, 3H), 3.44 (d, J = 13.8 Hz, 2H), 3.41 - 3.33 (m, 3H), 2.95 - 2.63 (m, 5H), 2.22 - 2 .10 (m, 2H), 2.11 - 1.96 (m, 2H), 1.25 - 1.16 (m, 1H), 1.05 (s, 6H), 1.02 (s, 3H ), 0.93 (s, 3H).

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Example 201.

Methyl-((5 S,8S,9S,14S)-11 -(2,6-difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy15,15-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-tetraazahexadecan-14yl)carbamate (201).

Intermediates: I2, P16 and S7a. MS (ESI) m/z 1094.8 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.86 (d, J = 4.9 Hz, 1H), 8.65 (s, 1H), 8.14 (d, J = 9.4 Hz, 0H), 7.96 (d, J = 8.6 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.32 (d, J = 7.9 Hz, 1H), 7, 08 (d, J = 10.0 Hz, 0H), 6.83 (d, J = 9.9 Hz, 0H), 4.96 (t, J = 7.6 Hz, 1H), 4.83 ( s, 8H), 4.53 - 4.41 (m, 0H), 4.37 - 4.25 (m, 1H), 4.23 - 4.07 (m, 2H), 3.98 (d, J = 13.1 Hz, 1H), 3.78 (s, 0H), 3.65 (s, 2H), 3.56 (s, 1H), 3.52 - 3.39 (m, 1H), 3.00 - 2.75 (m, 2H), 2.26-2.14 (m, 1H), 2.02 (t, J = 7.0 Hz, 1H), 1.12 (d, J = 13.2 Hz, 5H), 1.02 (s, 1H).

Example 202.

F

Methyl-((5 S,8S,9S,14S)-11-(4-(1 -(difluoromethyl)-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9 -hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2yl)-2-oxa-4,7 ,11,12-Tetraazahexadecan-14-yl)carbamate (202a).

The title compound 202a was prepared according to the procedure described for the synthesis of compound 1a, but using compound P4. MS (ESI) m/z 1014.4 [M+H] ⁺ .

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-(6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin3-yl)benzyl)-3 ,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14yl)carbamate (202).

In a 20 ml vial, a solution of compound 202a (50 mg, 0.05 mmol), compound 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 orthophosphate (106 mg, 0.5 mmol) in dioxane (3 ml) and water (1 ml) were degassed with argon in within 10 min. The mixture was heated to 100° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with MeOH, filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by HPLC, the resulting product was lyophilized to obtain compound 202. MS (ESI) m/z 1117.5 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.31 (s, 1H), 8.11 (d, J = 9.3 Hz, 1H), 8.02 (d, J = 2.7 Hz, 1H ), 7.90 (d, J = 8.8 Hz, 1H), 7.44 (t, J = 59.8 Hz, 1H), 7.35 (dd, J = 8.1, 3.9 Hz , 4H), 7.22 (d, J = 7.9 Hz, 2H), 7.05 (d, J = 10.0 Hz, 1H), 6.90 6.80 (m, 2H), 6, 78 (d, J = 9.8 Hz, 0H), 4.88 (t, J = 7.3 Hz, 2H), 4.52 (dd, J = 8.1, 4.3 Hz, 4H), 4.38 (d, J = 9.5 Hz,

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1H), 4.21 (d, J = 9.9 Hz, 1H), 4.06 (d, J = 12.5 Hz, 4H), 3.87 (t, J = 14.4 Hz, 3H) , 3.68 (s, 1H), 3.55 (s, 3H), 3.46 (s, 2H), 2.94-2.76 (m, 3H), 2.76-2.64 (m , 1H), 2.03 (d, J = 11.1 Hz, 1H), 1.05 (s, 6H), 1.01 (s, 3H), 0.91 (s,

3H).

Example 203.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane- 3yl)pyridin-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl))-3, 8diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2yl)-2-oxa -4,7,11,12-tetraazahexadecan-14-yl)carbamate (203).

Intermediates: I2, P22 and S60. MS (ESI) m/z 1259.4 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.47 (s, 1H), 8.37 (s, 1H), 8.18 (s, 1H), 7.94 (s, 2H), 7.42 (d, J = 7.9 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 6.99 (dd , J = 19.7, 9.0 Hz, 2H), 4.95 (dd, J = 7.5, 2.8 Hz, 4H), 4.85 - 4.72 (m, 5H), 4, 61 - 4.24 (m, 7H), 4.16 (s, 6H), 3.73 - 3.44 (m, 6H), 3.44 - 3.34 (m, 3H), 2.99 - 2.73 (m, 2H), 2.35-2.21 (m, 3H), 1.29 (s, 18H), 1.19-0.96 (m, 10H).

Example 204.

Methyl-((5S,8S,9S, 14S)-11-(4-(1-cyclopropyl-1 H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy- 15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridin-3-yl)benzyl)-3, 6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (204).

Intermediates: I2, P13 and S60. MS (ESI) m/z 1121.2 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.37 (s, 1H), 8.19 (s, 0H), 7.69 (d, J = 2.5 Hz, 1H), 7.53 - 7 .22 (m, 7H), 6.98 (d, J = 8.8 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 4.54 (d, J = 59, 0 Hz, 0H), 4.38 - 4.24 (m, 4H), 4.24 - 3.93 (m, 6H), 3.64 (d, J = 6.0 Hz, 5H), 3, 56 - 3.39 (m, 6H), 2.09 (d, J = 8.5 Hz, 2H), 1.42 - 0.62 (m, 16H).

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Example 205.

Methyl-((58,88,98,148)-11-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridin-3-yl)benzyl)-3 ,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (205).

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, 1H), 8.10 (dd, J = 19.9, 9.2 Hz, 2H), 7.53 (d, J = 7.3 Hz, 3H), 7.45 (d, J = 7.9 Hz, 3H), 7.32 (d, J=7.9 Hz, 3H), 7.13 (dd, J= 21.7, 9.5 Hz, 2H), 4.99 - 4.83 (m, 4H), 4.61 - 4.50 (m, 2H), 4.50 - 4.43 (m, 1H) , 4.35 - 4.24 (m, 5H), 4.18 (d, J = 11.8 Hz, 5H), 3.78 (s, 1H), 3.67 (s, 4H), 3, 59 (d, J = 13.0 Hz, 7H), 3.01 2.76 (m, 5H), 2.35 - 2.23 (m, 4H), 2.14 (t, J = 6.9 Hz, 3H), 1.32-1.10 (m, 19H), 1.10-0.95 (m, 5H).

Example 206.

Methyl-((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9hydroxy- 15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)benzyl)-3, 6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (206).

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, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.36 -7.28 (m, 4H), 7.07 (d, J= 9.0 Hz, 1H), 6.64 (d, J= 2.3 Hz , 1H), 4.95 (t, J= 7.5 Hz, 2H), 4.83 (dd, J= 8.0, 5.1 Hz, 2H), 4.53 (dq, J= 12, 1, 6.2, 5.7 Hz, 1H), 4.28 (dd, J= 14.1, 2.4 Hz, 2H), 4.19-4.06 (m, 4H), 4.00 -3.89 (m, 5H), 3.75 (s, 2H), 3.60 (d, J= 16.6 Hz, 6H), 3.49 (d, J= 13.6 Hz, 2H) , 2.95 (td, J= 12.3, 11.7, 7.2 Hz, 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).

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Example 207.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9hydroxy- 15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)benzyl)-3, 6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14yl)carbamate (207).

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, 1H), 8.15 (d, J = 9.3 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.33 (dd, J = 8.2, 5.3 Hz, 4H), 7.12 ( dd, J = 19.4, 9.5 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 4.95 (t, J = 7.5 Hz, 2H), 4, 85 (dd, J= 8.1, 5.1 Hz, 2H), 4.58-4.44 (m, 2H), 4.35-4.23 (m, 3H), 4.22-4, 09 (m, 4H), 3.93 (s, 4H), 3.65 (s, 3H), 3.60 - 3.52 (m, 4H), 3.01 - 2.89 (m, 2H) , 2.88-2.74 (m, 2H), 2.30-2.23 (m, 2H), 2.14 (t, J=6.9 Hz, 2H), 1.181.08 (m, 8H ), 1.02 (s, 3H).

Example 208.

Methyl-((5S,8S,9S, 14S)-11-(4-(1 -(difluoromethyl)-1H-pyrazol-3 -yl)-2,6-difluorobenzyl)-16,16,16trifluoro-9-hydroxy -15,15-dimethyl-8-(4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridin-3-yl)benzyl)-3 ,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecan-14-yl)carbamate (208).

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, 1H), 8.16-8.02 (m, 2H), 7.44 (h, J=4, 1, 3.5 Hz, 3H), 7.40 - 7.29 (m, 2H), 7.14 (d, J = 9.1 Hz, 1H), 6.93 (d, J = 2.7 Hz, 1H), 4.95 (t, J = 7.5 Hz, 2H), 4.58 - 4.43 (m, 2H), 4.34-4.23 (m, 3H), 4.21 4.11(m, 3H), 4.00-3.91(m, 1H), 3.77(s, 1H), 3.67-3.52(m, 6H), 3.01-2, 86(m, 3H), 2.80(dd, J=12.6, 9.1Hz, 1H), 2.31-2.23(m, 2H), 2.22-2.08(m, 2H), 1.13 (d, J=14.1 Hz, 7H), 1.03 (s, 2H).

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Example 209.

Methyl-((58,88,98,148)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-8-(4-(1(difluoromethyl)- 1 H-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-4,7,11,12-tetraazahexadecan-14-yl)carbamate (209).

Intermediates: I2, P4 and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-pyrazole. MS (ESI) m/z 1004.5 [M+H]+. ¹ H NMR (400 MHz, methanol-p) δ 8.32 (s, 2H), 8.09 (d, J = 2.7 Hz, 2H), 8.02 (s, 2H), 7.66 ( d, J = 19.3 Hz, 1H), 7.56-7.31 (m, 13H), 7.24 (d, J= 8.0 Hz, 5H), 6.91 (d, J= 2 .7 Hz, 2H), 4.46 (s, 2H), 4.31 (s, 2H), 4.20-4.07 (m, 5H), 3.93 (d, J = 13.1 Hz , 2H), 3.76 (s, 2H), 3.64 (s, 6H), 3.56 (s, 6H), 3.35 (s, 1H), 2.95-2.84 (m, 7H), 2.79 (dd, J = 12.6, 9.2 Hz, 3H), 1.24-1.09(m, 28H), 1.02 (s, 6H).

Example 210.

Cyclopropyl-((S)-1-(2-((2S,3S)-3-((S)-2-((cyclopropoxycarbonyl)amino)-4,4,4-trifluoro-3,3dimethylbutanamido)-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-oxobutan2-yl)carbamate (210).

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^) δ 8.53 (d, J = 0.8 Hz, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.52 - 7.45 (m, 4H), 7.25 (d, J = 8.2 Hz, 4H), 4.47 (s, 1H), 4.32 (s, 1H), 4.14 (s, 1H), 4.01 (td, J= 5.6, 3.0 Hz, 1H), 3.93 (d, J= 12.1 Hz, 2H), 3.76 (d , J= 8.5 Hz, 1H), 2.94-2.73 (m, 5H), 2.01 (s, 2H), 1.23 (t, J= 7.1 Hz, 2H), 1 .17-1.09 (m, 10H), 1.02 (s, 3H), 0.69-0.51 (m, 8H).

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Example 211.

Methyl-((5 S,8S,9S, 14S)-11 -(4-(1-(difluoromethyl)-1 H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-(1 (difluoromethyl)-1 H-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-4,7,11,12-tetraazahexadecan-14-yl)carbamate (211).

Intermediates: I2, P7 and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-pyrazole. MS (ESI) m/z 1004.2 [M+H]+. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.44 (d, J=0.7 Hz, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.41 (s, 1H), 7.39-7.35 (m, 3H), 7.25 (d, J = 10.6 Hz, 1H), 7.15 (d, J=8.1 Hz, 4H), 4.35(s, 1H), 4.20(s, 1H), 4.05-3.98(m, 3H), 3.85(s, 1H), 3.54 (s, 4H), 3.46 (s, 3H), 2.82-2.65 (m, 4H), 1.91 (s, 1H), 1.08-0.99 (m, 9H), 0.92 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ-76.33-79.41 (m), -96.67 (dd, J=145.1, 59.7 Hz).

Example 212.

Synthesis of methyl-((5S,10S,11S,14S)-11-(4-(1 -(2,2-difluoroethyl)-1 H-pyrazol-3-yl)benzyl)-16,16,16trifluoro-10- hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa4,7,8,12-tetraazahexadecane-14- yl) carbamate (212a).

The title compound 212a was prepared according to the procedure described for the synthesis of compound 188, but using compounds I2 and P10a. MS (ESI) m/z 776.3 [M+H] ⁺ .

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane- 3yl)pyrimidin-5-yl)benzyl)-8-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9- 193 040208 hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12tetraazahexadecane-14- yl) carbamate (212).

The title compound 212 was prepared according to the procedure described for the synthesis of compound 1a, but using compounds 212a and P20. MS (ESI) m/z 1146.3 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.71 (s, 2H), 8.11 (d, J = 9.7 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H ), 7.64 (d, J = 7.9 Hz, 2H), 7.25 (s, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 10.1 Hz, 1H), 6.78 (d, J = 10.1 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 6.19 (tt, J = 55 .6, 3.9 Hz, 1H), 4.96 (t, J = 7.5 Hz, 2H), 4.56 (td, J = 14.3, 3.9 Hz, 2H), 4.43 (d, J = 9.7 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 4.23 - 4.08 (m, 4H), 3.95 (d, J = 13.5 Hz, 1H), 3.73 (s, 1H), 3.63 (s, 3H), 3.55 (s, 3H), 3.52 3.43 (m, 2H), 2.93 - 2.73 (m, 3H), 2.25 - 2.17 (m, 2H), 2.06 - 1.94 (m, 2H), 1.15 - 1.12 (m, 6H), 1 .11 (s, 3H), 1.01 (s, 3H).

Example 213.

Synthesis of tert-butyl-((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-2methylpropan-2-yl)-3 -oxa-5,8,12,13-tetraazaheptadecan-15-yl)carbamate (213a).

The title compound 213a was obtained according to the method described for the synthesis of compound 188, but using compounds I2a, A1 and P4.

Synthesis of tert-butyl-((6S,9S,10S,15S)-12-(4-(1 -(difluoromethyl)-1 H-pyrazol-3 -yl)-2,6-difluorobenzyl)-9-(4 (1-(difluoromethyl)-1 H-pyrazol-4-yl)benzyl)-17,17,17-trifluoro-10-hydroxy-2,2,16,16-tetramethyl-4,7,14trioxo-6-( 1,1,1-trifluoro-2-methylpropan-2-yl)-3-oxa-5,8,12,13-tetraazaheptadecan-15-yl)carbamate (213b).

The title compound 213b was prepared according to the procedure described for the synthesis of compound 218, but using compound 213a and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl) -1H-pyrazole. MS (ESI) m/z 1088.5 [M+H] ⁺ .

Synthesis of N-((S)-1-(2-((2S,3S)-3-((S)-2-(cyclopropanecarboxamido)-4,4,4-trifluoro-3,3-dimethylbutanamido)-4- (4-( 1 - (difluoromethyl) -1 H-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).

To a solution of compound 213a (255 mg, 0.23 mmol) in CH ₂ Cl ₂ (5 ml) at room temperature was added 4 M hydrochloric acid (0.8 ml). After stirring for 18 hours, the reaction mixture was concentrated in vacuo. To the obtained crude residue, dissolved in DMF (3 ml), were 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 resulting mixture was stirred for 48 h before being purified by HPLC and lyophilized to give compound 212. MS (ESI) m/z 1146.3 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.34 (d, J = 0.7 Hz, 1H), 8.25 (d, J = 9.8 Hz, 1H), 8.20 - 8.06 (m, 2H), 8.06 7.95 (m, 2H), 7.56-7.45 (m, 4H), 7.48-7.31 (m, 2H), 7.24 (d, J = 8.1 Hz, 1H), 6.93 (dd, J = 5.4, 2.7 Hz, 1H),

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4.73 - 4.61 (m, 1H), 4.16 (d, J = 13.2 Hz, 2H), 3.93 (d, J = 13.2 Hz, 1H), 3.77 (s , 1H), 2.93 - 2.74 (m, 4H), 1.69 (dd, J = 8.5, 4.1 Hz, 1H), 1.58 (tt, J = 8.2, 4 .6 Hz, 1H), 1.36 - 1.20 (m, 1H), 1.17 (d, J = 13.5 Hz, 9H), 1.07 (s,

3H), 0.91 (q, J = 10.2, 9.5 Hz, 1H), 0.89-0.66 (m, 1H), 0.65-0.54 (m, 1H).

Example 214.

N-((S)-1-(2-((2S,3S)-3-((S)-2-(cyclopropanecarboxamido)-4,4,4-trifluoro-3,3-dimethylbutanamido)-4-( 4(1 -(difluoromethyl)-1 H-pyrazol-4-yl)phenyl)-2-hydroxybutyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6difluorobenzyl )hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)cyclopropanecarboxamide (214).

The title compound 214 was prepared according to the method described for the synthesis of compound 213, but using compound P7. MS (ESI) m/z 1024.5 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H), 8.33 (d, J= 0.7 Hz, 1H), 8.27 (d, J= 9.8 Hz, 1H ), 8.13-8.09 (m, 2H), 8.03-7.96 (m, 2H), 7.64 (d, J = 10.5 Hz, 1H), 7.52-7, 45 (m, 3H), 7.34 (d, J = 10.7 Hz, 1H), 7.24 (t, J=8.5 Hz, 4H), 4.81 - 4.78 (m, 1H ), 4.69-4.64 (m, 1H), 4.12 (d, J= 12.4 Hz, 2H), 3.91 (d, J= 13.2 Hz, 1H), 3.74 (d, J= 8.9 Hz, 1H), 2.88 (d, J= 7.6 Hz, 3H), 2.77 (dd, J= 12.5, 9.3 Hz, 1H), 1 .69 (dt, J = 8.0, 3.7 Hz, 1H), 1.57 (tt, J = 8.3, 4.6 Hz, 1H), 1.29 (d, J = 0.6 Hz, 1H), 1.24 (d, J= 7.7 Hz, 1H), 1.21 - 1.12 (m, 9H), 1.06 (s, 2H), 0.94 - 0.68 (m, 7H), 0.59 (d, J = 8.0 Hz, 1H).

Example 215.

(S)-N-((2S,3S)-4-(1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-2-((S) -4,4,4-trifluoro3,3-dimethyl-2-propionamidobutanoyl)hydrazinyl)-1-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-3hydroxybutan-2-yl)- 4,4,4-trifluoro-3,3-dimethyl-2-propionamidobutanamide (215).

The title compound 215 was prepared according to the method described for the synthesis of compound 213, but using compound P7 and propionic acid. MS (ESI) m/z 1000.5 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol A) δ 8.54 (d, J= 0.7 Hz, 1H), 8.35 (d, J= 0.7 Hz, 1H), 8.14-8.00 ( m, 5H), 7.71 (d, J = 9.8 Hz, 1H), 7.64 (d, J = 10.9 Hz, 1H), 7.52 - 7.44 (m, 4H), 7.25 (t, J = 8.6 Hz, 5H), 4.78 - 4.74 (m, 1H), 4.67 4.63 (m, 1H), 4.14 (d, J = 13 .2 Hz, 2H), 3.92 (d, J = 13.2 Hz, 1H), 3.73 (d, J = 8.7 Hz, 1H), 2.88 (d, J = 8.7 Hz, 4H), 2.76 (dd, J = 12.7, 9.3 Hz, 1H), 2.25 - 1.99 (m, 6H), 1.25 - 0.95 (m, 24H) .

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Example 216.

N-((S)-1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-2-((2S,3 S)-4- (4-(1-(difluoromethyl)1H-pyrazol-4-yl)phenyl)-2-hydroxy-3-((S)-4,4,4-trifluoro-3,3-dimethyl-2-(1- methylcyclopropan-1-carboxamido)butanamido)butyl)hydrazinyl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)-1-methylcyclopropan-1carboxamide (216).

The title compound 216 was prepared according to the method described for the synthesis of compound 213, but using compound P7 and 1-methylcyclopropanecarboxylic acid. MS (ESI) m/z 1052.7 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.17 (s, 1H), 7.97 (s, 1H), 7.87 (d, J = 9.5 Hz, 1H), 7.75 (s, 1H), 7.65 (s, 1H), 7.15-7.07 (m, 4H), 6.87 (t, J = 8.2 Hz, 4H), 6.42 (d, J = 9.6 Hz, 1H), 6.17 (d, J = 9.6 Hz, 1H), 4.38 (d, J = 9.5 Hz, 1H), 4.27 (d, J = 9.5 Hz, 1H), 3.89 - 3.73 (m, 2H), 3.58 - 3.48 (m, 1H), 3.39 (s, 1H), 2.50 (t, J = 7.6 Hz, 3H), 2.41 (dd, J = 12.6, 9.0 Hz, 1H), 0.95 - 0.54 (m, 25H), 0.22 (d, J = 3.8 Hz, 2H), 0.13 (yyy, J = 9.8, 6.4, 3.6 Hz, 1H).

Example 217.

(S)-2-acetamido-N-((2S,3S)-4-(2-((S)-2-acetamido-4,4,4-trifluoro-3,3-dimethylbutanoyl)-1-(4 -(1(difluoromethyl)-1 H-pyrazol-4-yl)-2,6-difluorobenzyl)hydrazinyl)-1-(4-(1 -(difluoromethyl)-1H-pyrazol-4yl)phenyl)-3- hydroxybutan-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide (217).

The title compound 217 was prepared according to the procedure described for the synthesis of compound 213, but using compound P7 and acetic anhydride. MS (ESI) m/z 972.5 [M+H]+. 1H NMR (400 MHz, methanol^) δ 8.55 (s, 1H), 8.36 (s, 1H), 8.16 (d, J = 21.4 Hz, 2H), 8.07 (d, J = 20.2 Hz, 2H), 7.52 - 7.46 (m, 3H), 7.25 (t, J = 8.3 Hz, 4H), 5.48 (d, J=0.6 Hz, 2H), 4.78-4.73 (m, 1H), 4.66-4.61 (m, 1H), 4.16 (s, 1H), 3.95-3.88 (m, 1H), 3.74 (d, J=8.5 Hz, 1H), 2.91-2.84 (m, 3H), 2.77 (dd, J= 12.7, 9.2 Hz, 1H ), 2.15 (s, 1H), 2.03 (d, J=0.5 Hz, 15H), 1.93 (s, 2H), 1.81 (s, 2H). ¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -76.14--79.22 (m), 96.72 (dd, J= 133.4, 59.8 Hz).

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Example 218.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-8-(4-(1(difluoromethyl )-1 H-pyrazol-4-yl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2methylpropan-2-yl)- 2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (218).

To a solution of methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9hydroxy-8-(4- iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa4,7,11,12-tetraazahexadecan-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 orthophosphate (0.01 ml) as a solution in water (0.01 ml). Argon was bubbled through the resulting slurry for 5 minutes, and then said slurry was placed in a 100° C. aluminum heating block and allowed to stir while heating overnight under argon. Upon completion, the residue was purified by reverse phase high performance liquid chromatography (20-83% acetonitrile in water, buffer containing 0.1% TFA). The collected product fractions were quenched with sodium bicarbonate (saturated aqueous solution), subjected to extraction with ethyl acetate and further purified by normal phase silica gel chromatography (0-8% methanol in dichloromethane) to give methyl ((5S,8S,9S,14S)-11 -(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-8-(4-(1-(difluoromethyl)-1Hpyrazol-4-yl)benzyl)-9- hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2oxa-4,7,11,12-tetraazahexadecane-14- yl) carbamate. ER/MS m/z 950.542 [M+H]+.

Example 219.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-1,2,3-triazol-4-yl)-2,6-difluorobenzyl)-16.16 ,16trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidine -5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12- tetraazahexadecan-14-yl)carbamate (219).

Intermediates: P44, A3 and S7. MS (ESI) m/z 1157.9 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.97 (s, 1H), 8.53 (s, 2H), 8.17 (d, J = 9.8 Hz, 1H), 8.00 ( t, J = 58.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 9.9 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H), 4.96 (dd, J = 8.2, 7.1 Hz, 2H), 4.83 - 4.78 (m, 3H), 4.50 - 4.41 (m, 1H), 4.30 (d, J = 10.0 Hz , 1H), 4.21 - 4.08 (m, 4H), 3.96 (d, J = 13.2 Hz, 1H), 3.74 (d, J = 8.8 Hz, 1H), 3 .69 (s, 3H), 3.67 (s, 3H), 3.47 (d, J = 14.5 Hz, 2H), 2.98 - 2.84 (m, 3H), 2.82 - 2.74 (m, 1H), 2.29 - 2.17 (m, 2H), 2.02 - 1.94 (m, 2H), 1.16 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.37, -77.70, -77.82, -98.78 (d, J = 58.6 Hz), -114.26.

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Example 220.

Oxetan-3-yl-((2S)-1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-2-((2S,3S) -2hydroxy-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-3 ,3-dimethyl-1-oxobutan-2-yl)carbamate (220).

Intermediates: P4, A4 and S7. MS (ESI) m/z 1240.3 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.45 (s, 2H), 8.12 (d, J = 9.3 Hz, 1H), 8.02 (d, J = 2.7 Hz, 1H ), 7.45 (t, J = 59.8 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 3H), 7.07 (d, J = 10.0 Hz, 1H), 6.85 (d, J = 2.8 Hz, 1H), 5. 37 - 5.21 (m, 2H), 4.92 - 4.83 (m, 2H), 4.73 - 4.69 (m, 2H), 4.56 (yyy, J = 12.4, 7 .3, 5.2 Hz, 2H), 4.50 - 4.44 (m, 2H), 4.33 (d, J = 10.0 Hz, 1H), 4.20 (d, J = 9, 9 Hz, 1H), 4.13 - 3.98 (m, 4H), 3.85 (d, J = 13.1 Hz, 1H), 3.67 (s, 1H), 3.39 -3, 32 (m, 3H), 2.86 - 2.78 (m, 3H), 2.68 (dd, J = 12.6, 8.9 Hz, 1H), 2.14 - 2.08 (m, 2H), 1.92 - 1.83 (m, 2H), 1.09 (s, 3H), 1.07 (s, 3H), 1.05 - 0.99 (m, 3H), 0.99 - 0.93 (m, 3H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.46, -77.56, -77.78, -96.92 (d, J = 59.7 Hz), -114.94.

F yN fXf ^f 'C=4

XL ^H / f

O H O I O H ^V H O H o =

N A N N

Vo

Example 221.

Methyl-((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)-4,4,4-trifluoro-3,3dimethyl-1-oxobutan-2-yl)carbamate (221).

Intermediate 19 was acylated with cyclopropylcarbonyl chloride in the presence of 2 M aqueous NaOH solution followed by coupling with compound S7 in a similar manner to Example 1. MS (ESI) m/z 1166.9 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.42 (s, 2H), 8.07 (d, J = 9.4 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.89 (d, J = 9.7 Hz, 1H), 7.44 (t, J = 59.7 Hz, 1H), 7.36 (d, J = 8.3 Hz, 2H) , 7.26 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 9.7 Hz, 1H), 6 .85 (d, J = 2.7 Hz, 1H), 4.90 4.83 (m, 2H), 4.74 - 4.68 (m, 3H), 4.21 (d, J = 10, 0 Hz, 1H), 4.11 - 3.98 (m, 4H), 3.85 (d, J = 13.0 Hz, 1H), 3.57 (s, 3H), 3.41 - 3, 31 (m, 2H), 2.86 - 2.75 (m, 3H), 2.73 - 2.61 (m, 1H), 2.19 - 2.01 (m, 2H), 1.93 - 1.82 (m, 2H), 1.64 - 1.51 (m, 1H), 1.10 (s, 3H), 1.07 (s, 3H), 1.07 (s, 3H), 0 .94 (s, 3H), 0.90 - 0.83 (m, 1H), 0.79 - 0.62 (m,

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2H). ¹⁹ F 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.

Methyl-((5S,8S,11S,12S,17S)-8-(tert-butyl)-14-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2, 6difluorobenzyl)-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-tetraoxo-2-oxa-4,7,10,14,15pentaazanonedecan-17-yl)carbamate (222).

MS (ESI) m/z 1147.4 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.50 (s, 2H), 7.87 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H ), 7.50 (d, J = 9.4 Hz, 1H), 7.35 - 7.24 (m, 4H), 7.16 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 2.5 Hz, 1H), 6.13 (tt, J = 55.3, 3.9 Hz, 1H), 4.58 - 4.44 (m, 4H), 4.39 ( s, 0H), 4.16 (d, J = 9.2 Hz, 1H), 4.07 - 3.92 (m, 2H), 3.90 - 3.77 (m, 2H), 3.67 (s, 1H), 3.59 (s, 1H), 3.55 (s, 3H), 3.55 (s, 3H), 2.90 -2.66 (m, 3H), 2.06 - 1.86 (m, 2H), 0.85 (s, 9H), 0.79 (d, J = 6.8 Hz, 3H), 0.76 (s, 9H), 0.72 (d, J = 6.8 Hz, 3h). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.64, -115.17, -125.29 (dt, J = 55.2, 14.2 Hz).

Example 223.

Methyl-((5S,8S,11S,12S,17S)-5,8-di-tert-butyl-14-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)- 2,6difluorobenzyl)-12-hydroxy-18,18-dimethyl-11-(4-((2-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3yl)pyrimidine -5-yl)ethynyl)benzyl)-3,6,9,16-tetraoxo-2-oxa-4,7,10,14,15-pentaazanonedecane-17yl)carbamate (223).

MS (ESI) m/z 1174.4 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.21 (d, J = 2.3 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 8.8, 2.3 Hz, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.28 (d , J = 8.4 Hz, 2H), 7.24 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 8.9 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 6.13 (tt, J = 55.3, 3.9 Hz, 1H), 4.92 - 4 .83 (m, 2H), 4.74 - 4.68 (m, 2H), 4.51 (td, J = 14.3, 3.9 Hz, 2H), 4.26 (d, J = 13 .7 Hz, 2H), 4.16 (d, J = 9.3 Hz, 1H), 4.09 - 3.94 (m, 3H), 3.91 (s, 1H), 3.85 (d , J = 13.1 Hz, 1H), 3.70 - 3.64 (m, 1H), 3.63 - 3.57 (m, 2H), 3.55 (s, 3H), 3.54 ( s, 3H), 3.28 (d, J = 13.9 Hz, 2H), 2.89 - 2.66 (m, 4H), 2.17 - 2.08 (m, 2H), 2.02 -1.95 (m, 2H), 0.85 (s, 9H), 0.80 (s, 9H), 0.75 (s, 9H). ¹⁹ F NMR (377 MHz, methanol-d4) δ-77.71, 115.18, -125.29 (dt, J=55.3, 14.2 Hz).

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Example 224.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13trioxo- 8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)ethynyl)benzyl)-5 -(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14yl)carbamate (224).

Intermediates: P28, I3 and S25. MS (ESI) m/z 1104.4 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.58 (d, J = 5.0 Hz, 1H), 8.14-8.01 (m, 2H), 7.93 (t, J = 7 .7 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 8.7 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.43 - 7.35 (m, 1H), 7.25 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 9.8 Hz, 1H), 4.63 - 4.54 (m, 1H), 4.39 - 4.29 (m, 1H), 4.11 - 3.73 ( m, 8H), 3.66 (s, 1H), 3.59 (s, 3H), 3.53 (s, 3H), 3.13 (d, J = 12.1 Hz, 1H), 2, 90 - 2.64 (m, 4H), 2.20 - 1.67 (m, 10H), 1.05 (s, 4H), 1.02 (s, 3H), 0.76 (s, 9H) . ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.33, -78.06, -114.28.

Example 225.

Methyl-((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15dimethyl- 3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridine-3- yl)ethynyl)benzyl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (225).

Intermediates: P28, I1 and S25. MS (ESI) m/z 1050.4 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.67 (dt, J = 4.9, 1.4 Hz, 1H), 8.19 (d, J = 2.8 Hz, 1H), 8.00 (t, J = 7.7 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.89 - 7.74 (m, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.48 (t, J = 6.2 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 7, 8 Hz, 2H), 7.08 - 6.89 (m, 1H), 4.73 - 4.64 (m, 1H), 4.23 - 3.81 (m, 8H), 3.75 (s , 1H), 3.73 - 3.69 (m, 1H), 3.68 (s, 3H), 3.63 (s, 3H), 3.24 - 3.14 (m, 1H), 2, 99 - 2.79 (m, 4H), 2.32 - 1.75 (m, 9H), 0.90 (s, 9H), 0.84 (s, 9H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -78.01, -114.33.

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Example 226.

Methyl-((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-III-pyrazol-3-yl)benzyl)-9hydroxy- 15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-(pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3yl)pyridin- 3-yl)ethynyl)benzyl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (226).

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, 2H), 8.07 (d, J = 2.1 Hz, 1H), 7.76 (d, J = 9.3 Hz, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.29 - 7.19 (m , 4H), 7.14 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 9.3 Hz, 1H), 6.61 (t, J = 4.9 Hz, 1H ), 6.56 (d, J = 2.4 Hz, 1H), 4.92 - 4.84 (m, 2H), 4.08 - 3.97 (m, 2H), 3.89 (d, J = 13.0 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 1H), 3.66 (s, 1H), 3.64 - 3.59 (m, 1H), 3.58 (s, 3H), 3.56 (s, 3H), 2.87-2.62 (m, 3H), 2.06-1.95 (m, 2H), 1.84 (q, J = 7.2, 6.6 Hz, 2H), 0.79 (s, 9H), 0.74 (s, 9H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.75, -115.32.

Example 227.

Methyl-((5S,8S,9S,14S)-5-(tert-butyl)-11-(2,6-difluoro-4-(1-methyl-III-pyrazol-3-yl)benzyl)-9hydroxy- 15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]octane- 3-yl)pyridin-3-yl)ethynyl)benzyl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate (227).

Intermediates: I1, P41 and S25. MS (ESI) m/z 1053.3 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.10 (s, 1H), 7.79 - 7.64 (m, 2H), 7.52 (d, J = 2.3 Hz, 1H), 7 .28 - 7.19 (m, 4H), 7.14 (d, J = 8.0 Hz, 2H), 6.89 (t, J = 10.6 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 4.63 - 4.55 (m, 1H), 4.09 - 3.89 (m, 3H), 3.84 (s, 3H), 3.81 - 3 .73 (m, 2H), 3.66 (s, 1H), 3.64-3.60 (m, 1H), 3.58 (s, 3H), 3.56 (s, 3H), 3, 10 (d, J = 12.2 Hz, 1H), 2.90 2.61 (m, 4H), 2.18 - 1.67 (m, 7H), 0.80 (s, 9H), 0, 75(s, 9H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.94, 115.33.

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Example 228.

Methyl-((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-2oxa-4,7,11 ,12-Tetraazahexadecan-14-yl)carbamate (228).

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, 1H), 7.73 (d, J = 9.4 Hz, 1H), 7.65 (dd, J = 9.0, 2.3 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.32 - 7.18 (m, 4H), 7.14 ( d, J = 8.1 Hz, 2H), 6.88 (d, J = 9.2 Hz, 1H), 4.10 - 3.97 (m, 2H), 3.90 - 3.76 (m , 5H), 3.70 - 3.50 (m, 15H), 2.90 - 2.78 (m, 2H), 2.72 (d, J = 7.9 Hz, 2H), 2.06 ( s, 3H), 0.80 (s, 9H), 0.75 (s, 9H). ¹⁹ F NMR (377 MHz, methanol-d4) δ -77.88, -115.32.

Example 229.

Methyl-((5S,8S,9S, 14S)-11 -(2,6-difluoro-4-(5-methylpyridin-2-yl)benzyl)-16,16,16-trifluoro-9hydroxy-15,15- dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)ethynyl)benzyl)-3.6 ,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate ($$$).

Intermediates: I2, P39, S3. MS (ESI) m/z 1030.2 [M+H] ⁺ . 1H NMR (400 MHz, methanold4) δ 8.55 (s, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.13 (d, J = 9.4 Hz, 1H), 8.01 - 7.87 (m, 2H), 7.69 (dd, J = 8.8, 2.3 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7 .33 (d, J= 7.9 Hz, 2H), 7.22 (d, J= 8.0 Hz, 2H), 7.12 (d, J= 9.9 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 9.9 Hz, 1H), 4.95 (t, J = 7.6 Hz, 2H), 4.85 - 4 .78 (m, 2H), 4.58 - 4.49 (m, 1H), 4.48 - 4.40 (m, 1H), 4.40 - 4.26 (m, 3H), 4.23 - 4.09 (m, 4H), 3.98 (d, J= 13.1 Hz, 1H), 3.79-3.71 (m, 1H), 3.69 (s, 3H), 3, 64 (s, 3H), 3.46-3.35 (m, 2H), 2.94-2.87 (m, 3H), 2.80 (t, J = 10.9 Hz, 1H), 2 .45 (s, 3H), 2.30-2.19 (m, 2H), 2.12-2.00 (m, 2H), 1.16 (s, 3H), 1.15 (s, 3H ), 1.12 (s, 3H), 1.03 (s, 3H).

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Example 230.

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

Intermediates: I3, P8 and S3. MS (ESI) m/z 1083.8 [M+H]+. 1H NMR (400 MHz, methanold4) δ 8.11 (d, J = 21.6 Hz, 4H), 7.72 - 7.55 (m, 3H), 7.42 - 7.29 (m, 5H) , 7.22 (d, J = 8.1 Hz, 2H), 6.88 - 6.77 (m, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.81 ( dd, J = 8.2, 5.0 Hz, 2H), 4.54 (s, 1H), 4.42 - 4.32 (m, 3H), 4.16 (s, 3H), 4.08 3.91 (m, 2H), 3.81-3.60 (m, 9H), 3.42-3.34 (m, 2H), 2.98-2.70 (m, 4H), 2, 27 -2.20 (m, 2H), 2.11 -2.03 (m, 2H), 1.08 (d, J = 22.3 Hz, 6H), 0.80 (s, 10H).

Example 231.

Methyl-((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorobenzyl)-16-fluoro-5-(1-fluoro2- methylpropan-2-yl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan3-yl )pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.

Intermediates: Na, A7, P8 and S3. MS (ESI) m/z 1083.8 [M+H] ⁺ . 1H NMR (400 MHz, methanol-d4) δ 8.48 - 8.06 (m, 3H), 7.70 (dd, J = 8.9, 2.3 Hz, 2H), 7.66 - 7, 55 (m, 1H), 7.43 - 7.30 (m, 5H), 7.24 (d, J = 8.1 Hz, 3H), 4.96 (t, J = 7.6 Hz, 2H ), 4.82 (dd, J = 8.3, 5.1 Hz, 3H), 4.54 (s, 1H), 4.35 (d, J = 13.4 Hz, 2H), 4.24 -3.89 (m, 12H), 3.83 - 3.59 (m, 8H), 3.39 (d, J = 13.8 Hz, 2H), 3.00 - 2.72 (m, 4H ), 2.28 - 2.19 (m, 2H), 2.12 - 2.00 (m, 2H), 0.92 - 0.75 (m, 13H).

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F

Example 232.

Methyl-((5S,8S,9S,14S)-5-(tert-butyl)-11-(4-(1-(difluoromethyl)-III-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-3yl)ethynyl) benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.

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, 1H), 8.09 (d, J = 2.7 Hz, 1H), 7.80 (d, J = 9 .4 Hz, 1H), 7.68 (dd, J = 9.0, 2.5 Hz, 2H), 7.48 - 7.31 (m, 5H), 7.23 (d, J = 8, 0 Hz, 2H), 6.93 (d, J = 2.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.94 (t, J = 7.5 Hz , 2H), 4.46 (s, 1H), 4.30 (d, J = 13.8 Hz, 2H), 4.18 - 4.02 (m, 5H), 4.02 - 3.88 ( m, 3H), 3.79 - 3.63 (m, 9H), 3.35 (d, J = 13.7 Hz, 2H), 2.98 - 2.77 (m, 5H), 2.24 - 2.16 (m, 2H), 2.04 (d, J = 8.4 Hz, 2H), 0.87 (d, J = 21.8 Hz, 19H).

Example 233.

Methyl-((5 S,8S,9S,14S)-11 -(4-( 1 -(difluoromethyl)-1 H-pyrazol-4-yl)-2,6-difluorobenzyl)-16-fluoro-5-( 1-fluoro2-methylpropan-2-yl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1 ]octan-3yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.

Intermediates: Pa, A7, P7 and S3. MS (ESI) m/z 1084.0 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d4) δ 8.31-8.28 (m, 1H), 8.12 (s, 1H), 7.88 (d, J = 9.4 Hz, 1H), 7.70 (dd, J = 8.8, 2.3 Hz, 1H), 7.37 - 7.21 (m, 7H), 6.86 (d, J = 8.9 Hz, 1H), 4 .96 (t, J = 7.6 Hz, 2H), 4.81 (dd, J = 8.0, 5.2 Hz, 3H), 4.52 (s, 1H), 4.35 (d, J = 14.0 Hz, 2H), 4.25 - 3.89 (m, 13H), 3.67 (d, J = 8.3 Hz, 8H), 3.37 (d, J = 13.8 Hz, 2H), 2.95 -2.78 (m, 4H), 2.26 2.19 (m, 2H), 2.07 (d, J = 8.6 Hz, 2H), 0.95 - 0.83 (m, 13H).

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Example 234.

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

Intermediates: Pa, 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, 1H), 8.31 - 8.28 (m, 1H), 7.91 (q, J = 13, 2, 11.5 Hz, 4H), 7.73 - 7.65 (m, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 4.96 (t, J = 7.6 Hz, 2H), 4.81 (dd, J = 8.3, 5.0 Hz, 3H), 4.52 (s, 1H), 4.35 (d, J = 14.1 Hz, 2H), 4.30 -3.96 (m, 12H), 3.73 (s, 1H), 3.66 (d, J = 16.2 Hz , 6H), 3.38 (d, J = 13.8 Hz, 2H), 2.99 -2.78 (m, 5H), 2.23 (d, J = 10.7 Hz, 2H), 2 .07 (d, J = 8.7 Hz, 2H), 0.93 - 0.81 (m, 13H).

Example 235.

Methyl-((5S,8S,9S,14S)-16,16,16-trifluoro-11-(2-fluoro-4-(5-fluoropyridin-2-yl)benzyl)-9-hydroxy15,15-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-tetraazahexadecan-14-yl)carbamate.

Intermediates: I2, P14 and S3. MS (ESI) m/z 1116.4 [M+H] ⁺ .

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Example 236.

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

Intermediates: P4, A3 and S63. MS (ESI) m/z 1078.4 [M+H]+. Ή NMR (400 MHz, methanol-d4) δ 8.29 - 8.24 (m, 1H), 8.18 - 8.08 (m, 2H), 7.74 - 7.61 (m, 3H), 7.59 - 7.51 (m, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.39 - 7.31 (m, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 2.7 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 4.33 - 4.28 (m, 1H), 4.27 - 4.10 (m, 7H), 3.95 (d, J = 13.2 Hz, 1H), 3.68 (d, J = 10.7 Hz, 10H), 3, 42 (d, J = 13.5 Hz, 2H), 2.95 -2.73 (m, 4H), 2.29 (d, J = 10.5 Hz, 2H), 2.08 (d, J = 8.6 Hz, 2H), 1.20 - 1.08 (m, 10H), 1.03 (s, 3H).

Example 237.

Methyl-((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-ul)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)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.

Intermediates: I3, P26 and S3. MS (ESI) m/z 1060.3 [M+H] ⁺ . Ή NMR (400 MHz, methanol-d4) δ 8.65 (d, J = 4.8 Hz, 1H), 8.12 (d, J = 9.4 Hz, 1H), 7.92 (dd, J = 18.0, 8.2 Hz, 3H), 7.73 - 7.65 (m, 2H), 7.42 (t, J = 5.5 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.9 Hz, 1H), 4.96 (t, J = 7, 6 Hz, 2H), 4.81 - 4.76 (m, 3H), 4.46 - 4.23 (m, 5H), 4.18 - 4.03 (m, 5H), 3.68 (s , 5H), 3.62 (s, 3H), 3.37 (d, J = 14.0 Hz, 3H), 2.96 - 2.75 (m, 4H), 2.23 (d, J = 10.2 Hz, 2H), 2.08 (d, J = 8.7 Hz, 2H), 1.12 (d, J = 16.0 Hz, 7H), 0.84 (s, 10H).

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F

Example 238.

Methyl-((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-yl)benzyl)-8-(4-((6-(8-(2 ,2-difluoroethyl)-3,8diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-16-fluoro-5-(1-fluoro-2-methylpropan-2-yl) -9hydroxy-15,15-dimethyl-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.

Intermediates: Na, A7, P26 and S63. MS (ESI) m/z 1068.6 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.65 (d, J=4.9 Hz, 1H), 8.28-8.24 (m, 1H), 8.00-7.82 (m , 4H), 7.75 - 7.65 (m, 2H), 7.47 - 7.41 (m, 1H), 7.34 (d, J = 7.9 Hz, 2H), 7.24 ( d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.9 Hz, 1H), 4.31 - 3.95 (m, 15H), 3.66 (d, J = 15 .6 Hz, 10H), 3.43 (d, J = 13.4 Hz, 2H), 2.99 - 2.79 (m, 4H), 2.34 - 2.24 (m, 2H), 2 .08 (t, J = 7.0 Hz, 2H), 0.96-0.80 (m, 14H).

Example 239.

Methyl-((5S,8S,9S,14S)-11-(2,6-difluoro-4-(4-fluoropyridin-2-yl)benzyl)-16,16,16-trifluoro-9hydroxy-15,15- dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3yl)ethynyl)benzyl)-3.6 ,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.

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, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.12 (d, J = 9.5 Hz, 1H), 7.78 - 7.61 (m, 5H), 7.33 (d, J = 7.8 Hz, 2H), 7.25 - 7.18 ( m, 3H), 6.85 (d, J = 8.9 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.53 (s, 1H), 4.44 ( d, J = 9.7 Hz, 1H), 4.33 (dd, J = 19.5, 12.0 Hz, 4H), 4.17 (d, J = 14.3 Hz, 5H), 3, 98 (d, J = 13.1 Hz, 1H), 3.67 (d, J = 16.2 Hz, 8H), 3.38 (d, J = 13.8 Hz, 2H), 2.96 - 2.75 (m, 5H), 2.23 (d, J = 11.2 Hz, 2H), 2.08 (d, J = 8.6 Hz, 2H), 1.18-1.10 (m , 10H), 1.03 (s, 3H).

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Example 240.

Methyl-((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 -3,6,13trioxo-5 - (1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.

Intermediates: I2, P28 and S22. MS (ESI) m/z 1102.1 [M+H]+.

Example 241.

Methyl-((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-3,6,13trioxo-5 -(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.

Intermediates: I2, P28 and S21. MS (ESI) m/z 1088.1 [M+H] ⁺ .

Example 242.

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

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Intermediates: I2, P28 and S20. MS (ESI) m/z 1074.4 [M+H]+. ¹ H NMR (400 MHz, methanol-d4) δ 8.65 (d, J = 5.1 Hz, 1H), 8.29 (s, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 9.0 Hz, 1H), 7.60 (d, J =

8.6 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8, 9 Hz, 1H), 4.44 (d, J = 9.7 Hz, 1H),

4.33 (dd, J = 19.0, 11.6 Hz, 3H), 4.20-4.06 (m, 5H), 3.98 (d, J = 13.0 Hz, 1H), 3 .66 (d, J = 21.3 Hz, 8H), 3.26 (s,

1H), 2.91 (d, J = 7.9 Hz, 7H), 2.31 (s, 2H), 2.07 (d, J = 8.8 Hz, 2H), 1.19 - 1, 10 (m, 11H), 1.03 (s, 3H).

Example 243.

Methyl-((5 S,8S,9S,14S)-11-(4-(1 -(difluoromethyl)-1 H-pyrazol-4-yl)benzyl)-9-hydroxy-15,15-dimethyl8-(4 -((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13trioxo-5 -(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.

Intermediates: I3, P9 and S3. MS (ESI) m/z 1065.6 [M+H] ⁺ . ¹ H NMR (400 MHz, methanold4) δ 8.39 - 8.28 (m, 2H), 8.08 (d, J = 26.3 Hz, 2H), 7.70 (dd, J = 8.8 , 2.3 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.48 (s, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.88 - 6.73 (m, 2H), 4.96 (t , J = 7.6 Hz, 2H), 4.81 (dd, J = 8.2, 5.0 Hz, 2H), 4.52 (s, 1H), 4.37 (t, J = 13, 2 Hz, 3H), 4.15 (s, 3H), 3.95 (t, J = 10.7 Hz, 2H), 3.78 (d, J = 9.5 Hz, 1H), 3.69 (d, J = 10.5 Hz, 5H), 3.62 (s, 3H), 3.38 (d, J = 13.9 Hz, 2H), 2.90 (t, J = 7.0 Hz , 2H), 2.79 (t, J = 11.1 Hz, 2H), 2.23 (d, J = 11.0 Hz, 2H), 2.07 (d, J = 8.6 Hz, 2H ), 1.09 (s, 3H), 1.01 (s, 3H), 0.76 (s, 10H).

Example 244.

Methyl-((5S,8S,9S,14S)-11-(2-chloro-6-fluoro-4-(pyridin-2-yl)benzyl)-16-fluoro-5-(1-fluoro-2-methylpropane2 -yl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[ 3.2.1]octan3-yl)pyridin-3-yl)ethynyl)benzyl)-2-oxa-4,7,11,12-tetraazahexadecan-14-yl)carbamate.

Intermediates: Pa, 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, 1H), 7.99-7.80 (m, 5H), 7.71-7.61 (m, 2H) , 7.59 - 7.51 (m, 1H), 7.44 (dd, J = 7.1, 5.1 Hz, 1H), 7.36 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 4.30-3.96 (m, 10H), 3.90 (d, J = 9.1 Hz, 1H), 3.84 (d , J = 11.5 Hz, 2H), 3.77-3.46 (m, 10H), 3.23-3.11 (m, 3H), 2.99-2.80 (m, 5H), 2.08-1.98 (m, 3H), 1.78 (t, J = 7.1 Hz, 2H), 0.95-0.80 (m, 12H).

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Example 245.

Methyl-((5S,8S,9S,14S)-16,16,16-trifluoro-11-(2-fluoro-4-(pyridin-2-yl)benzyl)-9-hydroxy-15,15dimethyl-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-tetraazahexadecan-14-yl)carbamate (ABC).

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, 1H), 8.29 (d, J = 2.3 Hz, 1H), 8.11 (d, J = 9, 1 Hz, 1H), 7.92 (dd, J = 18.5, 7.8 Hz, 2H), 7.75 - 7.62 (m, 4H), 7.33 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 9.9 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 4.96 (t, J = 7.6 Hz, 3H), 4.82 - 4.76 (m, 2H), 4.53 - 4.12 (m, 10H), 3.99 (d , J = 13.7 Hz, 3H), 3.76 (s, 1H), 3.68 (s, 3H), 3.58 (s, 3H), 3.37 (d, J = 14.0 Hz , 2H), 2.86 (dd, J = 31.3, 7.8 Hz, 4H), 2.22 (d, J = 10.8 Hz, 2H), 2.07 (d, J = 8, 8 Hz, 2H), 1.18-1.05 (m, 9H), 0.94 (s, 3H).

4. Biological methods of analysis.

HIV analysis in MT-4

Compounds were tested in a 384-well high speed 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 further diluted 200-fold in complete RPMI medium (10% FBS, 1% P/S) using Biotek Micro Flow and an acoustic dispenser. Agilent ECHO. Each plate contained up to 8 test compounds, a negative control (no drug) and 5 μM AZT as a positive control. MT-4 cells were pre-infected with either 10 μl RPMI (sham-infected) or freshly prepared 1:250 dilution of HIV-1 stock (NIB) (concentrated virus stock). Infected and uninfected MT-4 cells were further diluted with RPMI Complete Culture Medium and seeded into each plate using a Micro Flow Dispenser. After 5 days of incubation in a temperature-controlled humid chamber (37° C.), Cell Titer Glo (Promega) was added to assay plates to quantify luciferase. The EC ₅₀ and CC ₅₀ values were defined as the compound concentration causing a 50% reduction in the luminescence signal and were calculated using a sigmoidal dose-dependent curve-fitting model. Data on specific compounds are presented below in table. 1.

Analysis of antiviral activity to HIV high resolution on MT-4 (MT-4 HIV high resolution antiviral assay)

The analysis protocol is identical to that described for the analysis of antiviral activity on MT-4 with the following changes: each drug substance was analyzed in 2 series in four replications at different starting concentrations for each series, and 19 dilutions of 1.5 times were performed on the plate. Based on this, an inhibition curve was constructed with 40 points for each compound. The data were analyzed and the Hill coefficient was determined in Graph Pad Prism (San Diego, CA). EC ₉₅ was calculated using the formula EC ₉₅ = (19) ^1/factor . ^Hippa x EC ₅₀ . For specific compounds, HD values were determined, which are presented in Table 1 below. 5 as shown in the illustrative example.

Protocol for determination of stability in liver microsomes

Test compounds and one control compound (verapamil) were analyzed in duplicate on three different species.

General terms and Conditions.

Test compound concentration: 1 µM.

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 min.

The composition of the reaction mixture (in each incubation well) includes:

- 210 040208 µl compound (50 µM stock solution, 50:50 ACN:H2O) µl NRS solution

6.25 µl 20 mg/ml liver microsomes

213.75 µl 100 mM KPO4, pH 7.4

250 µl total volume

The reaction was initiated at an incubation temperature of 37°C by adding the NADPH regeneration system, at each time point 25 µl of the reaction mixture was removed and added to a plate with 225 µl of a quench solution (50% MeOH, 25% ACN, 25% H ₂ O and 200 nM labetalol as internal standard). After the tablets were subjected to mixing in a vortex method, centrifuged for 30 min to remove proteins. Approximately 100 μl of the 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 observe the effect of the compounds. The measured in vitro t1/2 value was used to calculate the CLint values. The data are given below in table. 1 and in FIG. 1.

Table 1

Compound EU ₅₀ (nM) Assumption clearance in rat (l/h/kg) Assumption dog clearance (l/h/kg) Assumption clearance in humans (l/h/kg) 1 - - - 2 2.64 3 6.95 4 2.82 5 4.37 6 3.56 0.22 <0.11 7 3.61 0.21 <0.11 8 2.46 9 10.13 10 3.46 eleven 3.72 0.18 0.18 12 3.11

- 211 040208

- 212 040208

36 3.68 0.27 <0.11 37 6.75 0.32 <0.11 38 6.13 39 2.57 0.54 0.15 40 3.89 0.5 0.13 41 3.58 42 3.18 43 2.87 1.01 1.66 0.16 44 3.97 2.54 0.13 45 2.56 0.92 <0.11 46 4.34 0.19 1.64 <0.11 47 7.18 48 114.29 0.18 <0.11 49 37.3 50 4.31 <0.18 <0.11 51 2.8 <0.11 52 8.15 <0.18 0.14 53 2.98 0.2 0.51 54 8.47 55 4.44 56 3.59 0.19 1.47 0.17 57 2.91 <0.18 <0.11 58 4.79 0.24 <0.11

- 213 040208

59 3.38 0.83 0.6 60 3.42 0.65 0.12 61 4.11 <0.18 <0.11 62 8.83 63 4.25 0.2 0.86 <0.11 64 5.4 65 77 66 14.52 67 6.25 1.43 0.41 68 7.25 0.61 <0.11 69 3.24 <0.18 <0.11 70 4.79 <0.18 <0.11 71 3.37 <0.18 0.47 <0.11 72 5.19 <0.18 0.14 73 4.72 <0.18 0.13 74 6.79 0.2 1.53 0.17 75 3.41 0.21 <0.11 76 3.53 77 2.49 0.25 <0.11 78 6.27 <0.18 <0.11 79 3.53 <0.18 <0.11 80 3.13 81 4.39 0.39 <0.11

- 214 040208

82 4.4 0.44 0.82 83 17.25 84 3.23 85 3.78 0.19 0.13 86 2.61 <0.18 <0.11 87 4.26 0.23 0.13 88 4.57 <0.18 1.63 <0.11 89 3.32 <0.18 1.67 <0.11 90 3.45 0.67 0.14 91 3.69 92 3.72 93 2.49 1.13 0.19 94 2.57 95 2.44 1.39 0.38 96 2.33 97 4.54 0.31 0.46 98 4.97 0.65 0.26 99 7.96 0.26 <0.11 100 7.96 101 4.22 <0.18 <0.11 102 5.68 <0.18 0.18 103 4.84 0.32 0.16 104 4.97

- 215 040208

- 216 040208

- 217 040208

- 218 040208

- 219 040208

197 2.61 0.32 <0.11 198 2.19 0.33 <0.11 199 2.72 0.48 0.91 <0.11 200 4.36 0.19 <0.11 201 2.67 0.49 0.27 202 9.67 203 5.02 1.09 0.32 204 3.18 0.48 0.19 205 5.25 206 3.7 1.03 0.41 207 2.46 0.92 0.25 208 2.51 0.74 0.16 209 3.19 1.21 1.12 210 14.98 <0.18 0.18 211 5.75 212 4.97 0.33 0.33 213 4.86 214 12.33 <0.18 <0.11 215 18.21 216 114.29 217 113.31 218 2.99 0.45 0.92 219 4.1 0.24 0.19 <0.11

- 220 040208

220 7.66 0.34 0.46 <0.11 221 4.49 0.28 0.14 <0.11 222 12.93 223 12.88 224 4.12 225 4.26 226 14.93 227 2.9 228 1.66 229 7.86 0.26 <0.11 230 3.97 231 2.77 232 2.47 233 2.71 <0.18 <0.11 234 2.54 235 16.74 236 37.03 237 4.89 238 12.3 239 4.45 <0.18 <0.11 240 5.62 241 6.57 242 3.45 243 5.32 244 19.53 245 3.59 Darunavir (DRV) 2.8 1.2 1.2 Atazanavir (ATV) 3.7 1.4 1.07

- 221 040208

Determination of estimated clearance in humans using tritium (3H)

For some compounds, tritium-labeled analogs were prepared for subsequent higher resolution determination of their estimated human clearance. These studies were performed as described above using tritiated analogues. Data on these compounds are given below in table. 2 and also shown in Fig. 1 (note: ATV and DRV were not labeled with tritium).

table 2

Compound 23 36 46 51 58 88 73 75 89 101 112 153 170 171 173 176 199 208 239

Estimated clearance in humans using ST 0.07 0.1 0.04 0.11 0.05 0.08 0.09 0.11 0.08 0.08 0.11 0.43 0.05 0.02 0.14 0.09 0.15 0.11 0.13

Determination of the PK profile in the dog

For intravenous infusion, the test compound was prepared in 5% EtOH, 55% PEG 300 and 40% water (pH 2, HCl), and also for oral administration was prepared in 5% ethanol, 55% PEG 300, 1% Tween 80 and 39% water (pH 2). Each compound treatment group consisted of three previously exposed male beagles. At the time of administration, the body weight of the animals ranged from 9 to 12 kg. Animals were not fed during the night before dosing and up to 4 hours after dosing. The test sample was administered by intravenous infusion over 30 minutes. The infusion rate was adjusted according to the body weight of each individual to deliver a dose of 0.5 or 1.0 mg/kg. In the oral group, the test sample was administered orally via a gastric tube at a volume dose of 2 ml/kg.

Serial venous blood samples (approximately 1.0 ml each) were taken from each animal in the i.v. administration group before dosing and after 0.25; 0.48; 0.58; 0.75; 1.0; 1.5; 2; 4; 8; 12 and 24 hours after dosing; in the oral group, blood samples were taken before the dose and after 0.25; 0.50; 1; 24; 6; 8; 12 and 24 hours after dosing. Blood samples were taken into Vacutainer™ tubes containing EDTA-K2 as an anticoagulant and immediately placed on liquid ice prior to centrifugation to obtain plasma. Plasma concentration of test compound was measured using the LC/MS/MS method. For plasma concentration-time data, a non-compartmental pharmacokinetic analysis was performed. Compound-specific data are presented in FIG. 2 and in table. 3. Vss = apparent volume of distribution, t1/2 = elimination half-life, F = oral bioavailability.

Table 3

Compound CL (l/h/kg) i.v. dog Vss (l/kg) i.v. in a dog Ϊ1/2 (h) with i.v. in a dog F (%) with p / o in a dog DOSE (mg/kg) for p/o in a dog 58 0.47 6.34 13.8 18 2 63 0.28 2.4 8.16 170 1.39 4.35 7.62 2.45 2 171 0.26 3.12 13.4 23 2 DRV 2.7 0.87 0.37 38 2 ATV 1.0 0.90 1.3 48 10

FC in the rat

For intravenous infusion, the test compound was prepared in 5% ethanol, 55% PEG 300 and 40% water (pH 2), for oral administration it was prepared in 5% ethanol, 55% PEG 300, 1% Tween 80 and 39% water ( pH 2). Each compound treatment group consisted of three previously naive male SD rats. At the time of administration, the body weight of the animals ranged from 0.27 to 0.32 kg. Animals were not fed during the night prior to dosing. The test sample was administered by intravenous infusion over 30 minutes. The infusion rate was adjusted according to the body weight of each individual to deliver a dose of 0.5 or 1.0 mg/kg. In the oral group, the test sample was administered orally via a gastric tube. In the animals in the IV administration group, serial venous blood samples (approximately 0.3 ml each) were taken before the dose and after 0.25; 0.48; 0.58; 0.75; 1.0; 1.5, 3, 6, 8, 12 and 24 hours after dosing. In animals in the oral group, blood samples were taken before dosing and after 0.25; 0.50, 1, 2, 4, 6, 8, 12 and 24 hours post-dose. Blood samples were taken into Vacutainer™ tubes containing EDTA-K2 as an anticoagulant and immediately placed on liquid ice prior to centrifugation to obtain plasma. Plasma concentration of test compound was measured using the LC/MS/MS method. For plasma concentration-time data, a non-compartmental pharmacokinetic analysis was performed.

Data on specific compounds are presented, respectively, in table. 4 in FIG. 3.

- 223 040208

Table 4

Compound CL (l/h/kg) i.v. in rat Vss (l/kg) i.v. in rat Т1/2 (h) with i / v in a rat F (%) with p / o in rats DOSE (mg/kg) po in rat 36 0.32 5.99 15.7 16.4 2.5 46 0.45 4.22 9.22 13 2.5 56 0.85 7.44 8.77 34.1 2.5 57 0.36 2.45 6.28 23.2 2.5 58 0.48 6.68 12.8 37.2 2.5 61 0.43 6.5 12.9 18.5 2.5 63 0.42 5.46 11.9 19 2.5 71 0.9 7.26 9.27 24.6 2.5 73 0.32 3.34 9.43 35 2.5 74 0.39 5.07 11.6 35.8 2.5 79 0.77 4.07 5.13 13.1 2.5 89 0.3 3.53 10.2 44.2 2.5 101 0.48 6.07 10 38.4 2.5 130 0.39 5.27 11.5 55.7 2.5 170 0.35 3.32 9.38 36.6 2.5 171 0.32 8.11 22.5 39 2.5 180 0.39 0.52 2.81 4.29 2.5 199 0.46 1.07 2.09 14.7 2.5 221 0.32 4.41 11.5 19.9 2.5 239 0.4 5.49 12.9 26.3 2.5 DRV 2.2 0.73 0.32 24 2.0 ATV 2.7 0.87 0.37 38 5.0

Screening for resistance to protease inhibitors

EC50 values for some compounds against IP-resistant mutant viruses were determined in a 5-day multicycle cell viability assay with cytopathic protective effect (CPE). Briefly, MT-2 cells at a density of 2x106 cells/ml were infected in bulk (bulk infected) with WT or mutant viruses at a MOI of 0.01 with slow culture shaking for 3 h at 37°C and then added in triplicate to 96-well plates (Corning Life Sciences, Tewksbury, MA, USA). Cells were incubated in RPMI complete nutrient medium containing drug at 10 points with a three-fold serial dilution (DMSO with a final concentration of 0.5%) for five days at 37°C in 5% CO 2 . After this time, 100 μl of CellTiter-Glo reagent (Promega, Madison, Wl, USA) was added to each well and the number of luminescence signals was counted on an EnVision plate analyzer (Perkin-Elmer, Inc., Waltham, MA, USA). EC ₅₀ values, defined as the drug concentration inducing 50% protection against HIV-induced cell killing, were calculated from at least three independent quadruple experiments using XLFit™ software (IDBS, Ltd., Guildford, Surrey, UK ) and non-linear regression analysis. As an illustrative example, below in FIG. 4 shows data for Example 58 (GSPI1) compared to other HIV protease inhibitors (atazanavir and darunavir).

- 224 040208

Virological breakthrough analysis in MT-2 cells

MT-2 cells were infected with HIV-1 _111B (Advanced Biotechnologies, Eldersburg, MD, USA) at a relatively high multiplicity of infection (MOI=0.05) for 3 hours and plated in 24-well plates at 2x105 cells per well. Drugs were added to the wells 16 hours later in at least four replications with a fixed series (fixed mutiples) of their EC ₅₀ values.

Every 3-4 days, cells were diluted (1:5) in freshly prepared cell culture medium containing drug concentrations in the same series (multiple of) EC ₅₀ values and observed for virus-induced cytopathic effects (CPE) for 32 days . Cell-free viral supernatants showing CPP >80% were collected from the wells and stored frozen at -80° C. until further analysis. As an illustrative example, below in FIG. 5 shows data relating to Example 58 (GSPI1) compared to other HIV protease inhibitors (atazanavir, darunavir) and efavirenz.

Genotypic Analysis of Breakthrough Viruses

Total RNA was purified from cell-free supernatants obtained from each well positive for CPE and p24 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 were subjected to DNA sequencing. Sequence changes were identified by alignment with the introduced virus sequences using a Sequencher (Gene Codes Corp., Ann Arbor, Jr., USA) and amino acid substitutions determined.

Equilibrium dialysis method

Pooled plasma (from at least 3 males and 3 females) was obtained from Bioreclamation IVT. EDTA sodium salt was used as an anticoagulant. 10% plasma was diluted in 0.133 M phosphate buffer containing 1.5% (w/v) EDTA sodium salt. RPMI cell culture medium containing 10% PBS was provided by the Biology Department of Gilead Sciences, Inc.

Plasma protein binding assay

The studies were carried out in two or three repetitions using a Dianorm Equilibrium dialyzer (Harvard Apparatus, Holliston MA), each cell in which consisted of a semi-permeable membrane (working diameter - 2.4 cm) 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 testing, the dialysis membrane was soaked for about 1 hour in 0.133 M phosphate buffer, pH 7.4. 10% plasma and cell culture medium supplemented with 1 μM compound (1 ml) were placed on opposite sides of the assembled dialysis cell, and then the dialysis cells were slowly rotated in a water bath at 37°C. After equilibrium was established, the samples containing the matrix on both sides were cast into pre-weighed polypropylene tubes. 10% plasma samples after dialysis were transferred into centrifuge tubes containing 1 ml of pure medium for growing cell cultures. Samples of the medium for growing cell cultures after dialysis were transferred into centrifuge tubes containing 1 ml of pure 10% plasma. The mass of all samples was measured and recorded to calculate the change in volume (volume shift) and the degree of extraction (recovery).

Samples were separated from proteins by treating four volumes of a mixture of acetonitrile 90% (v/v) and methanol 10% (v/v) containing an internal LC-MS standard. Samples were centrifuged at 15,000 rpm at 4°C for 15 min and 200 µl aliquots of the supernatant were removed and mixed with an equal volume of water. Samples were vortexed for 2 minutes, then aliquots (10 μl) were subjected to LC/MS/MS analysis.

Data analysis

The extent of analyte binding in plasma compared to cell culture medium was calculated using the following equation:

Degree of Binding = C10% Plasma/CfCR where C ₁₀ % _Plasma is the post-dialysis concentration in 10% plasma (determined by PAR), and C _CR is the post-dialysis concentration in cell culture medium (determined by PAR), respectively. Each concentration was adjusted gravimetrically for changes in fluid volume in the dialysis cells during dialysis.

Protease Ki analysis

Inhibitor activity was measured using a fluorogenic readout enzyme assay. 2.5 nM recombinant HIV protease and the test compound at one of the various concentrations. After a 20-minute pre-incubation, the enzymatic reaction was started by adding the fluorogenic substrate (2aminobenzoyl)Thr-Ile-Nle-(p-nitro)Phe-Gln-Arg (Bachem) to a final concentration of 40 μM. The total volume of the analyzed solution was 100 µl. The reaction was evaluated for 20 min on a Tecan Infinite M1000 plate analyzer at an excitation wavelength of 320 nm and a detection wavelength of 420 nm. The slopes of the process curves were a measure of the rate of reactions. Reaction rates have been delayed

- 225 040208 as a function of inhibitor concentration, and the data obtained were suitable for calculating Ki values using the strong binding equation described by Morrison (Biochim. Biophys. Acta

1969, 185, 269-286).

Table 5 Activity of Compound 58, DRV and ATV

Compound 58 Darunavir Atazanavir Ki (nM) 0.060 <0.030 0.035 ECso (nM) 6.8 7.2 9.7 Coefficient Hilla 5.8 2.9 3.1 EC95 (nM) 11.4 19.9 25 EC95 (nM) corrected for proteins 353 42 75

CLAIM

Claims (16)

1. Compound of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: R ¹ is a 5-10-membered heterocycle containing from 1 to 5 heteroatoms selected from N, O and S, or a 5-10-membered heteroaryl containing from 1 to 5 heteroatoms selected from N, O and S, and said 5-10 membered heterocycle or said 5-10 membered heteroaryl is optionally substituted with 1-5 R ^a groups; each R ² and R ³ is independently C1-4alkyl, C3-6cycloalkyl, OR ^2A , C1-2alkyl-OR ^2A , N-(R ^3A )2 or C1-2alkyl-N-(R ^3A )2, where each R ^2A is independently C _1-4 alkyl, C _3-6 cycloalkyl or 4-10 membered heterocyclyl containing 1 to 5 heteroatoms selected from N, O and S, where each R ^3A is independently hydrogen, C _{1- 4} alkyl, C _3-6 cycloalkyl, or COO(R ^e ), and wherein each C _3-6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with 1-3 R ^f groups, where each R ^f is independently C _1-2 alkyl or halogen; R ⁴ is C _1-4 alkyl or C _1-4 haloalkyl; R ⁷ is C _1-4 alkyl or C _1-4 haloalkyl; each R ⁵ , R ⁶ , R ⁸ and R ⁹ is independently C _1-2 alkyl or C _1-2 haloalkyl; and where two or more of R ⁴ , R ⁵ and R ⁶ or two or more of R ⁷ , R ⁸ and R ⁹ are optionally combined to form one or more C _3-6 cycloalkyl groups which are optionally substituted with 1-4 groups selected from from halogen, C _1-2 alkyl and C _1-2 haloalkyl; each R ^10a and R ^10b is halogen; each R ^a is independently halogen, C1-4 dlkyl, C1-4 haloalkyl, C1-4 dlkoxy, C3-6 cycloalkyl, 4-10 membered heterocyclyl, or OR ^3B , wherein said C1-4 alkyl is optionally substituted with 1-2 groups selected from hydroxyl and C _1-4 alkoxy, said 4-10 membered heterocyclyl contains 1 to 5 heteroatoms selected from N, O and S, and said 4-10 membered heterocyclyl is optionally substituted with R ^a1 ; where R ^3B is C _3-6 cycloalkyl optionally substituted with R ^a1 , or 4-10 membered heterocyclyl containing 1 to 5 heteroatoms selected from N, O and S, optionally substituted with R ^a1 , where each R ^a1 is independently is C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 haloalkyl or 4-8-226 040208 membered heterocyclyl containing from 1 to 3 heteroatoms selected from N, O and S; X ¹ is a 6-10 membered aryl or a 5-10 membered heteroaryl containing from 1 to 3 heteroatoms selected from N, O and S, where each 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted 1-4 groups R ^b ; X ² is hydrogen or a 4-10 membered heterocyclyl containing 1 to 5 heteroatoms selected from N, O and S, said 4-10 membered heterocyclyl optionally substituted with one R ¹¹ and optionally substituted with 1-5 R ^b groups ; R ¹¹ is C=O(R ^c ), CH2(R ^d ), S(O)1-2(C _1-4 αkyl), S(O) _1-2 C _3-6 cycloalkyl, 4-10- a membered heterocyclyl containing from 1 to 5 heteroatoms selected from N, O and S, or a 5-9 membered heteroaryl containing from 1 to 5 heteroatoms selected from N, O and S, where each 4-10-membered heterocyclyl or 5-9 membered heteroaryl is optionally substituted with 1-5 R ^b groups; each R ^b is independently halogen, oxo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or COO(R ^e ), wherein said C1-4 alkyl is optionally substituted with 1-2 groups selected from hydroxyl and C _1-4 αlkoxy; R ^c is C1-4αkyl, C1-4halogenαalkyl, C1-4alkoxy, N(R ^e )2, _C3-6 cycloalkyl or 4-6 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, wherein said C _3-6 cycloalkyl and said 4-6 membered heterocyclyl are optionally substituted with 1-5 R ^b groups; R ^d is COO(R ^e ), N(R ^e ) ₂ , C _3-6 cycloalkyl or 4-6 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, said C _{3- 6} cycloalkyl and said 4-6 membered heterocyclyl are optionally substituted with 1-5 R ^b groups; and each R ^e is independently hydrogen or C _1-4 alkyl. 2. The compound of claim 1 wherein each R ² and R ³ is independently C 1-4 alkyl, C 3-6 cycloalkyl, or OR ^2A , where R ^2A is C 1-4 alkyl, C _3-6 cycloalkyl, or 4-10 membered a heterocyclyl containing from 1 to 5 heteroatoms selected from N, O and S. 3. A compound according to claim 1 or 2, wherein R ⁵ and R ⁶ are C _1-2 alkyl. 4 ATV, 2 mg/kg iv/10 mg/kg po o- ¹⁰⁰⁰ 4 FC in a dog GS-PI1 DRV ATV « 1 V s CL, l/h/kg* 0.47 2.7 1.0 s ti/2-13.8 4 —————————— s Vss, l/kg 6.3 0.87 0.90 _to 100 ί ' %F 18 38 48 O. '4,, tl/2, h 13.8 0.37 1.3 t u \ £ 1 4. A compound according to any one of claims 1 to 3, wherein R ⁸ and R ⁹ are C1. ₂ alkyl. 5. The compound according to any one of claims 1-4, in which R ¹ is a 5-6 membered heterocycle containing from 1 to 3 heteroatoms selected from N, O and S, or a 5-6 membered heteroaryl containing from 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heterocycle or said 5-6 membered heteroaryl is optionally substituted with 1-3 R ^a groups. 6/2=0.37, 1.3 h; 0.1 .................................................. .1 I------------------------------'---------------- --------------1----------------- ¹ ----- ¹ --------1 0 4 8 12 16 20 24 Time, h Fig. 2 - 295 040208 Pharmacokinetics of GS-RI, DRV and ATV when administered intravenously Plasma concentration, nM 10000 ,-j GS-PI1.0.5 mg/kg IV/2.5 mg/kg orally DRV, 0.5 mg/kg iv/2 mg/kg po FA in rat GS-PI1 DRV ATV ^{: :} 'ATV, 1 mg/kg iv/5 mg/kg po ιυυϋ/h CL, l/h/kg 0.48 2.2 2.7 J Vss, l/kg 6.7 0.73 0.87 Al 100 4 l b / 2 \u003d 12.8 h : 1 · %F 29 24 38 tl/2, h 12.8 032 0.37 -- : ''A:·.:. i GS-PI1.0.5 mg/kg iv, 2.5 mg/kg po; darunavir, 0.5 mg/kg IV, θ \ 2 mg/kg orally; atazanavir 1 mg/kg IV, 5 mg/kg PO 4/2=0.32, 0.37 h 1 i 1 0.1 --.-----------------,-------------------, 0 4 8 12 16 20 24 Time, h Fig. 3 fold change from wild type for clinically significant resistance-associated mutations Mutant virus Fig. 4 - 296 040208 Breakthrough analysis driven by resistance 100 1 80 60 40 20 -i—·--·--r®--·---·“ 6. A compound according to any one of claims 1 to 5, wherein R ¹ is independently: 7. A compound according to any one of claims 1-6, wherein R ^a is independently C _1-4 alkyl, C _1-4 alkyl substituted with 1-2 groups selected from hydroxyl and C _1-4 alkoxy, or C _{1 -4} haloalkyl. 8. The compound according to any one of claims 1-7, in which X ¹ is a 6-membered aryl or a 5-6 membered heteroaryl containing from 1 to 3 heteroatoms selected from N, O and S, where each 6-membered aryl or 5-6 membered heteroaryl is optionally substituted with 1-4 R ^b groups. 9. A compound according to any one of claims 1-8, wherein X ² is a 4-10 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S and is optionally substituted with one R ¹¹ and is optionally substituted with 1 -5 groups R ^b . 10. A compound according to any one of claims 1-9, wherein R ¹¹ is a 4-10 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S. 11. A compound according to any one of claims 1 to 10, wherein said compound of formula (Ia) is - 227 040208 compound (i) of formula (Ic): or a pharmaceutically acceptable salt thereof, where: Z ¹ and Z ² are independently N or CH; or (ii) formulas (Id): or a pharmaceutically acceptable salt thereof; or (iii) formulas (Ie): or a pharmaceutically acceptable salt thereof. 12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from: - 228 040208 example 1 example 2 example 4 - 229 040208 example 5 example 6 example 7 - 230 040208 example 8 example 9 example 10 - 231 040208 example 11 example 12 example 13 - 232 040208 example 14 example 15 example 16 - 233 040208 example 17 example 18 example 19 - 234 040208 example 20 example 21 example 22 - 235 040208 example 23 example 24 example 25 - 236 040208 example 26 example 27 example 31 - 237 040208 example 32 example 35 example 36 - 238 040208 example 37 example 38 example 39 - 239 040208 example 40 example 41 example 42 - 240 040208 example 43 example 44 example 45 - 241 040208 example 46 example 47 F example 48 - 242 040208 example 50 example 51 example 52 - 243 040208 example 53 example 54 example 55 - 244 040208 example 57 example 58 example 59 - 245 040208 example 60 example 61 example 62 - 246 040208 example 64 example 65 F example 66 - 247 040208 example 67 F example 68 example 69 F - 248 040208 example 70 fXf o 'ο ^Λ ν\ Η ο φ 0 γ 'Ό^Λ Η 0 φ 0 γ Η 0 F nn ^X f н σ ^Η | he NyM _N AXO ₄ Η A o ΤΙ ^{Ν Ν} ^ο *<Ν. _έ 4Ο 1 example 71 F ν- _ν Τ FU Η / F Η O 1 he ν^Α^ ^ν νΑ^ν _τ ο^ γ/γ n Λ o tP Ν Ν'Λϊ Vo example 72 F Z' ⁿ ^ ^f yN р -CH H / F H 0 1 OH ΛΥ A ° ^N1N VP ^ ^H 8 \u003d O 1 - 249 040208 example 73 F example 74 example 75 - 250 040208 example 76 example 77 example 78 - 251 040208 example 79 example 80 example 81 - 252 040208 example 82 example 84 example 86 - 253 040208 example 87 example 88 example 89 - 254 040208 example 90 example 91 example 92 - 255 040208 example 93 example 94 example 95 - 256 040208 example 96 example 97 example 98 - 257 040208 example 99 example 100 example 101 - 258 040208 example 102 example 103 example 104 - 259 040208 example 105 example 106 example 107 - 260 040208 example 108 example 109 example 110 - 261 040208 example 112 example 114 example 115 - 262 040208 example 116 example 119 example 120 - 263 040208 example 121 example 123 example 124 - 264 040208 example 125 example 126 example 127 - 265 040208 example 128 example 129 example 130 - 266 040208 example 131 example 132 F example 133 - 267 040208 example 134 example 135 example 136 - 268 040208 example 137 example 138 example 139 - 269 040208 example 140 example 141 example 142 - 270 040208 example 143 example 144 example 145 - 271 040208 example 146 example 147 example 149 - 272 040208 example 150 example 151 example 152 - 273 040208 example 153 example 154 example 155 - 274 040208 example 156 example 159 example 160 - 275 040208 example 161 example 162 example 163 - 276 040208 example 164 example 165 example 166 - 277 040208 example 167 example 168 example 169 - 278 040208 example 170 example 171 example 172 - 279 040208 example 173 FyF o ν' Η 0 FyF ο γ' O ^A mu Η 0 FyF ο γ Ό-Ά Η 0 F /-n'^f yN X 1 F Η Ο' ^Η ι OH Ν^^ΝΝ^ΝγΟ^ Η 1 0 χΎ Ν Vo example 174 F Jn^f yN FO 1 F H 0'^ | OH NyM-X^ s^, Η λ o ZhTu Vo example 175 _/ ^{N F-} C=/ η σ ^Η | o ^F h •ΝγΑΝ-^ΝγΟ^ ιΓ1 Ν VEn^^ Vo - 280 040208 example 176 example 177 example 178 - 281 040208 example 179 example 180 example 181 - 282 040208 example 182 example 183 example 184 - 283 040208 example 185 example 186 example 187 - 284 040208 example 219 example 220 example 221 - 285 040208 example 224 example 225 - 286 040208 example 226 example 227 - 287 040208 example 228 example 229 example 232 - 288 040208 example 233 example 234 example 236 - 289 040208 example 237 example 23 8 example 239 - 290 040208 example 240 example 241 example 242 - 291 040208 example 244 13. The compound according to claim 1, which is F or a pharmaceutically acceptable salt thereof. 14. The compound according to claim 1, which is F or a pharmaceutically acceptable salt thereof. 15. A compound, or a pharmaceutically acceptable salt thereof, which is: - 292 040208 example 49 example 83 example 222 - 293 040208 example 223 16. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 17. The pharmaceutical composition of claim 16 further comprising one, two, three or four additional therapeutic agents, wherein said additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide reverse transcriptase inhibitors. HIV transcriptase, HIV integrase inhibitors, inhibitors of non-catalytic sites (or allosteric inhibitors) of HIV integrase, HIV entry inhibitors, HIV maturation inhibitors, latent-reversing agents, compounds that target the HIV capsid, immunostimulants, phosphatidylinositol 3-kinase (PI3K) inhibitors , antibodies to HIV, bispecific antibodies and antibody-like therapeutic proteins, HIV p17 matrix protein inhibitors, interleukin-13 (IL-13) antagonists, peptidylprolyl-cis/trans-isomerase A modulators, protein disulfide isomerase inhibitors, antagonists of the C5a receptor component of the complement system NTA, DNA methyltransferase inhibitor, HIV vif gene modulators, Viral infectivity factor (Vif) dimerization antagonists, HIV-1 infectivity factor inhibitors, transcription transactivator protein (TAT) inhibitors, HIV-1 negative regulatory factor (Nef) modulators, tyrosine kinase modulators, which is a hematopoietic cellular kinase (Hck), mixed-line kinase 3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, virion protein expression regulator (Rev) inhibitors, integrin antagonists, nucleoprotein inhibitors, modulators of splicing factors, modulators of COMM- domain-containing protein 1, HIV ribonuclease H inhibitors, retrocyclin modulators, cyclin-dependent kinase 9 (CDK-9) inhibitors, non-integrin 1 dendritic cell-capturing intercellular adhesion molecule 3 (ICAM-3) inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kin inhibitors zy, inhibitors of cyclin-dependent kinase, stimulators of PC9 proprotein convertase, inhibitors of ATP-dependent RNA helicase DDX3X, inhibitors of the reverse transcriptase priming complex, inhibitors of glucose-6-phosphate dehydrogenase (G6PD) and NADH oxidase, pharmacokinetic enhancers, or any combination thereof. 18. A method of treating or preventing human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of a compound of any one of claims 115, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 19. The method of claim 18, wherein said method comprises administering said compound, or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents, wherein said additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, inhibitors of non-catalytic sites (or allosteric inhibitors) of HIV integrase, inhibitors of HIV entry, inhibitors of HIV maturation, latent-reversing agents, compounds that target the HIV capsid , immunostimulants, phosphatidylinositol-3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and antibody-like therapeutic proteins, HIV p17 matrix protein inhibitors, interleukin-13 (IL-13) antagonists, peptidylprolyl cis/trans isomerase A modulators, inhibitors protein disulfide isomerase, antagonists of the C5a receptor component of the complement system, DNA methyltransferase inhibitor, modulators - 294 040208 HIV vif gene, virus infectivity factor (Vif) dimerization antagonists, HIV-1 virus infectivity factor inhibitors, transcription transactivator protein (TAT) inhibitors, HIV-1 negative regulatory factor (Nef) modulators, modulators of tyrosine kinase, which is a hematopoietic cellular kinase (Hck), mixed-line kinase 3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, virion protein expression regulator (Rev) inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, modulators of COMM domain-containing protein 1 , HIV ribonuclease H inhibitors, retrocyclin modulators, cyclin-dependent kinase 9 (CDK-9) inhibitors, non-integrin 1 dendritic cell intercellular adhesion molecule 3 (ICAM3) capture inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors , deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors , stimulators of PC9 proprotein convertase, inhibitors of the ATP-dependent RNA helicase DDX3X, inhibitors of the reverse transcriptase priming complex, inhibitors of glucose-6-phosphate dehydrogenase (G6PD) and NADH oxidase, pharmacokinetic enhancers, or any combination thereof. Estimated clearance (microsomes with cofactors) Estimated clearance, l / h / kg View GS-R1 DRV ATV Rat 0.10 2.8 3.7 Dog 0.45 1.2 1.4 Man | 0.05 1.20 1.07 Hepatic extraction in humans (microsomes with cofactors) GS-FH DRV ATV Fig. 1 Pharmacokinetics of GS-PI1, DRV and ATV when administered intravenously GS-PI1 0.5 mg/kg IV/2 mg/kg PO 10,000 DRV mg/kg IV/2 mg/kg po 16 24 32 -•-GS-PI1 (IQ=1) -•-GS-PI1 (IQ=2) -•-GS-PI1 (IQ=4) -•-GS-PI1 (IQ=8) -•-GS-PI1 (IQ=12) Day Day GS-PI1 did not break through at IQ 1; EFV and RPV showed a breakthrough at their clinical IQs; in case of ATV - no