Compositions and methods for targeted inhibition and degradation of proteins in an insect cell

Abstract

Provided herein are compositions, compounds, and methods for modulating the levels of target proteins in insects and insect cells. The compounds may contain one or more protein targeting moieties that each independently bind a protein that is expressed by an insect cell; one or more ligase targeting moieties that each independently bind a ubiquitin ligase that is functional in the insect cell; and a linker covalently bonded to the one or more protein targeting moieties and the one or more ligase targeting moieties; or a salt or a solvate thereof.

Description

COMPOSITIONS AND METHODS FOR TARGETED INHIBITION ANDDEGRADATION OF PROTEINS IN AN INSECT CELLCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] The present application claims priority to International Patent Application Serial Number PCT / US2023 / 031716, filed August 31, 2023, the full disclosure of which is incorporated by reference in its entirety for all purposes.FIELD

[0002] This disclosure describes compositions, compounds, and methods for modulating the levels of target proteins in the cells of arthropods, in particular in insect cells, and cells of representatives of the order Acarina. In particular, this disclosure describes compositions comprising one or more protein targeting moi eties, one or more ligase targeting moi eties, and a linker covalently bonded to the one or more protein targeting moieties and the one or more ligase targeting moieties, as well as methods for the use of such compositions.BACKGROUND

[0003] Arthropod pests, including insects and members of the order Acarina, continue to be a major cause of crop losses. In the US alone, billions of dollars are lost every year due to infestation by various genera of insects. In addition to losses in field crops, insect pests also cause burdens to vegetable and fruit growers and producers of ornamental flowers, making insects a general nuisance to gardeners and homeowners. Numerous commercially valuable plants, including common agricultural crops, are susceptible to attack by plant pests including insect and nematode pests, causing significant reductions in crop yield and quality.

[0004] Compositions for controlling insect infestations in plants have typically been in the form of chemical insecticides. However, there are several disadvantages to using chemical insecticides. For example, chemical insecticides are generally not selective. Additionally, applications of chemical insecticides intended to control insect pests in crop plants can exert their effects on non-target insects (including pollinators) and other invertebrates. Chemical insecticides often persist in the environment and may be slow to degrade, thus potentially accumulating in the food chain. Furthermore, the use of persistent chemical insecticides can result in the development of resistance in the target insect species.

[0005] Biological pest control agents, such as Bacillus thuringiensis strains expressing pesticidal polypeptides, have been applied to crop plants with satisfactory results, thus offering an alternative or complement to chemical pesticides. The expression of Cry proteins in transgenic plants has provided efficient protection against certain insect pests, and transgenic plants expressing such proteins have been commercialized, allowing farmers to reduce or eliminate applications of chemical insect control agents.

[0006] Although the usage of transgenic plants expressing Cry proteins has been shown to be extremely effective, insect pests have developed resistance against the Cry proteins expressed in certain transgenic plants. Therefore, there remains a need to identify new and effective pest control agents. Particularly, control agents that are targeted to a wider spectrum of economically important insect pests and that have a high specific activity against insect pests that are or could become resistant to existing insect control agents are needed. Thus, there has been a long-felt need for more environmentally friendly methods for controlling or eradicating insect infestation on or in plants, e. g., methods which are environmentally inert, non-persistent, biodegradable, and that fit well into pest resistance management schemes.

[0007] The Von Hippel -Lindau (VHL) protein is a key component of a type of E3 ubiquitin ligase complex known as the Cullin-RING ligase (CRL) complex, specifically the CRL2 complex. This complex plays a critical role in targeting proteins for ubiquitination and subsequent degradation by the proteasome. The CRL complex is composed of several core components, including a cullin protein that serves as a scaffold, a RING-box protein (RBX1 or RBX2) that recruits an E2 ubiquitin-conjugating enzyme, and the substrate recognition subunit (SRS) that determines the specificity of the complex for its substrates. In the case of the CRL2VHLcomplex, VHL acts as the SRS.

[0008] The primary function of the CRL2VHLcomplex is to regulate the abundance of certain proteins within the cell, including the degradation of HIF-la under normoxic conditions. This regulation is crucial for cellular responses to oxygen levels and has implications in various physiological and pathological processes, including tumorigenesis. The oxygen sensing HIF / Prolyl Hydroxylase Domain (PHD) / VHL pathway appears to be conserved across invertebrates including fruit flies, nematodes, and placozoans.

[0009] Cereblon is a protein that, in arthropods (e.g., insects), is encoded by the CRBN gene. CRBN orthologs are highly conserved from plants to humans, which underscores its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex is capable of ubiquitinating a number of other proteins. Through a mechanism which has not been completely elucidated, cereblon ubiquiti nation of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates a number of developmental processes, such as limb and auditory vesicle formation. In the absence of cereblon, DDB1 forms a complex with DDB2 that functions as a DNA damage-binding protein.

[0010] An example of a protein of interest (POI) for controlling arthropod populations is the Bromodomain-containing protein 3 (BRD3), also known as RING3-like protein (RINGa3L). BRD3 is a member of the Bromodomain and Extra-Terminal motif (BET) protein family and regulates a wide range of biological processes including protein scaffolding, mitosis, cell cycle progression, and transcriptional regulation. There are four isoforms in Spodoptera frugiperda, with the longest sequence hit (XP_035429406.2) annotated as bromodomain-containing protein- 3 (sfBRD3). It is noted that residues 369-474 of sfBRD3 are the second of the two bromodomains, which has the highest homology with hsBRD4, both globally (72% identical) and within the binding site, to the second bromodomain of human BRD4 (residues 349-455). This domain (bromodomain 2, BD2) can be referenced as sfBRD3(BD2).BRIEF SUMMARY

[0011] The terms “invention,” “the invention,” “this invention,” and “the present invention,” as used in this document, are intended to refer broadly to all of the subject matter of this patent application and the claims below. Statements containing these terms should be understood not to limit the subject matter described herein or to limit the meaning or scope of the patent claims below. Covered embodiments of the invention are defined by the claims, not this summary. This summary is a high-level overview of various aspects of the invention and introduces some of the concepts that are described and illustrated in the present document and the accompanying figures. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used in isolation to determine the scope of the claimed subjectmatter. The subject matter should be understood by reference to appropriate portions of the entire specification, any or all figures, and each claim. Some of the exemplary embodiments of the present invention are discussed below.

[0012] Provided herein are compounds, compositions, and methods for the targeted inhibition and degradation of proteins in arthropods, and in particular in insects and representatives of the order Acarina. Compounds include bifunctional compounds that target an insect protein of interest to a cellular pathway. In some instances, the pathway leads to degradation or inhibition of the insect protein. The bifunctional compounds can be selected from proteolysis targeting chimeras (PROTACs), molecular glues, phosphatase recruiting chimeras (PhoRCs), deubiquitinase-targeting chimeras (DUBTAC), ribonuclease targeting chimeras (RIBOTACs), autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), lysosome-targeting chimeras (LYTACs), and Chaperone-mediated Protein Degradation / Degrader (CHAMP) molecules.

[0013] In some embodiments, the methods utilize PROTACs to direct degradation or inhibition of a protein of interest in an insect. PROTACs are a class of bifunctional molecules that utilize the endogenous protein homeostasis machinery to degrade a protein of interest (POI). PROTACs of the invention induce proximity between an insect ligase and a POI by forming a ternary complex that results in the ubiquitination and subsequent degradation of the POI by the proteasome. Accordingly, the PROTAC bifunctional compounds comprise a binding ligand for a ubiquitin ligase and a second binding ligand for a POI, the target protein, to mediate ubiquitin transfer to, and degradation of, the protein of interest through the proteasome. The first binding ligand is also referred to as a ligase targeting moiety (LTM), while the second binding ligand is referred to as a protein targeting moiety (PTM). It is recognized that when using the term moiety, the moiety itself, a derivative of the moiety, or an analog of the moiety are intended and can be used in the practice of the disclosed methods. Furthermore, the compounds disclosed herein include enantiomers, diastereomers, stereoisomers or agriculturally acceptable salts thereof.

[0014] The provided compounds, compositions, and methods are advantageous as smaller amounts of the PROTAC compositions are needed for administration to control insects. In some embodiments, the bifunctional compounds provided herein can include more than one ligase binding moiety, more than one insect protein targeting moiety, and / or more than one linker.

[0015] Compounds according to the disclosure may possess any number of benefits including, inter alia, advantageous levels of biological activity for protecting plants against insects. The provided compounds, compositions, and methods are advantageous as smaller amounts of the bifunctional compound may be needed for administration to control insects. The compounds disclosed herein may provide additional improved properties for use as agrochemical active ingredients (for example, greater biological activity, an advantageous spectrum of activity, an increased safety profile, improved physico-chemical properties, or increased biodegradability or environmental profile). In particular, the disclosed compounds may show an advantageous safety profile with respect to non-target arthropods, in particular pollinators such as honeybees (most particularly, Apis mellifera), solitary bees, and bumble bees.

[0016] In another aspect the present disclosure provides a composition comprising an insecticidally or acaricidally effective amount of a compound of Formula (I), or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, and, optionally, an auxiliary or diluent.

[0017] In a further aspect the present disclosure provides a method of combating and controlling arthropods, including insects and members of the order Acarina. The method comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest an insecticidally or acaricidally effective amount of a compound of Formula (I), or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide thereof, or a composition as defined above.

[0018] The bifunctional compounds of the invention can be provided in compositions comprising suitable agricultural carriers for delivery directly to the insect pests, and to the locus of the insect pests, including plants, surfaces, and areas where they are ready for contact by insects. Compositions may further include insects, insect cells, plants, plant cells, plant parts and treated surfaces comprising the bifunctional compounds provided herein.

[0019] In one aspect, the disclosure is to a compound or a salt or a solvate thereof. The compound includes one or more protein targeting moieties that each independently bind a protein that is expressed by an insect cell. The compound further includes one or more ligase targeting moieties that each independently bind a ubiquitin ligase that is functional in the insect cell. Thecompound further includes a linker covalently bonded to the one or more protein targeting moieties and the one or more ligase targeting moieties.

[0020] In another aspect, the disclosure provides an agricultural composition comprising at least one bifunctional compound, as disclosed herein, or a salt or solvate thereof, and at least one agriculturally acceptable carrier. More than one bifunctional compound may be used in agricultural compositions. Additionally, bifunctional compounds may be used in combination with other active compounds, including other degradation-inducing compounds.

[0021] In another aspect, the disclosure provides insects, insect cells, plants, plant cells, plant parts, and treated surfaces comprising at least one bifunctional compound as provided herein.

[0022] In another aspect, the disclosure provides methods of controlling the amount or activity of a target protein in an insect or insect cell. The methods include contacting the insect, the insect cell, a plant, a plant cell, plant parts, or surfaces that the insect may contact, with an effective amount of a compound as described herein or a composition containing the compound. In another aspect, controlling the amount of the target protein includes modulating ubiquitination and degradation of the target protein. In another aspect, controlling the activity of the target protein includes inhibiting the target protein.

[0023] In another aspect, the disclosure provides a method for the protection of a plant from attack by arthropods, including insects and members of the order Acarina. The method comprises treating the plant or the site where the plant is planted with an effective amount of a compound as described herein or a composition containing the compound.DETAILED DESCRIPTION

[0024] Compounds, compositions, and methods for inhibiting and modulating protein levels in an insect are provided. In some embodiments, the bifunctional compounds are PROTACs, and methods comprise their use in targeting and modulating the levels of proteins of interest (POI) in an insect cell. The PROTAC compositions function to recruit endogenous proteins to an insect ubiquitin ligase enzyme for ubiquitination and subsequent degradation or inhibition. The compounds may be designed to target any protein of interest present in an insect cell. The compounds may be provided in agricultural compositions.

[0025] Other classes of heterobifunctional molecules provided herein depend on non- ubiquitin-proteasome system pathways to degrade a POI. These classes include autophagytargeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), lysosometargeting chimeras (LYTACs), molecular glues, and antibody-based PROTACs (AbTACs). Collectively, AUTACs and ATTECs are also macroautophagy degradation-targeting chimeras (MADTACs). Like PROTACs, AUTECs and ATTECs focus on intracellular triggering of targeted protein degradation, while LYTACs and AbTACs trigger intercellular degradation via an extracellular process. AUTACs link a warhead for the POI to a guanine derivative that tags the protein for degradation by the autophagy machinery. ATTECs link a POI warhead to a ligand that binds to the autophagy protein LC3 (microtubule-associated protein 1 light chain 3a) glue, thereby bypassing the ubiquitin pathways by directly tethering the POI to the autophagosome. LYTACs bind a membrane-bound POI and the extracellular domains of a lysosome-shuttling receptor, which then drags the POI into the lysosome for degradation. AbTACs are bispecific antibodies that recruit membrane bound E3 ligases to a membrane POI for degradation by the lysosome degradation pathway. Molecular glues are small molecules that act as adhesives by making two proteins bind each other. Molecular glues engage the E3 ligase, allowing that complex to recruit its target. CHAMPs are bifunctional molecules similar to PROTACs. CHAMPs recruit the POI via a chaperone protein complex, leading to the ubiquitination of the POI and then the degradation of the POI via the proteasome system. Chaperones can interact with a diverse collection of E3 ligases. Importantly, the key chaperone HSP90 (enabling the use of CHAMPs for human therapeutics) is highly conserved in insects: e.g., 81% (bitscore of 1,131) between humans and fall armyworm (Spodoptera frugiperdd) with 14 out of 15 key amino acid residues perfectly identical in the binding site being used to bind to HSP90.

[0026] Presently described are compositions and methods that relate to the surprising and unexpected discovery that levels of target proteins expressed in an insect cell may be controlled with compounds comprising one or more protein targeting moieties (PTM) that each independently bind a target protein, one or more ligase targeting moieties (LTM) that each independently bind a ubiquitin ligase that is functional in an insect cell and a linker covalently bonded to the one or more protein targeting moieties and the one or more ligase targeting moieties. An E3 ubiquitin ligase protein (e.g., Von Hippel-Lindau E3 ubiquitin ligase (VHL) or Cereblon (CRBN)) ubiquitinates a target protein once it and the target protein are placed inproximity by a bifunctional or chimeric construct that binds the E3 ubiquitin ligase protein and the target protein. Accordingly, the present disclosure provides such compounds and compositions comprising an E3 ubiquitin ligase binding moiety coupled to a protein target binding moiety, which result in the ubiquitination of a chosen target protein and leads to degradation of the target protein by the proteasome.

[0027] In certain aspects, the present disclosure provides compounds that comprise a ligand, e.g., a small molecule ligand (i.e., having a molecular weight of below 2,000 Daltons, 1,000 Daltons, 500 Daltons, or 200 Daltons) that is capable of binding to a ubiquitin ligase, such as VEIL or CRBN. The compounds also comprise a moiety that is capable of binding to target protein in such a way that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and / or inhibition) of that protein.A. DEFINITIONS

[0028] The abbreviations used herein have their conventional meaning within the chemical and biological arts. Description of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and / or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, or physiological conditions. Where substituent groups are specified by their conventional chemical formula, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0029] As used herein, the singular forms “a,” “an,” and “the” include plural referents, unless the content clearly dictates otherwise. Thus, for example, reference to “a polymer” optionally includes a combination of two or more polymers, and the like.

[0030] As used herein, the term “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or ”)•

[0031] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field, for example ± 20%, ± 10%, or ± 5%, are within the intended meaning of the recited value.

[0032] As used herein, the terms “including,” “comprising,” “having,” “containing,” and variations thereof, are inclusive and open-ended and do not exclude additional, unrecited elements or method steps beyond those explicitly recited. As used herein, the phrase “consisting of’ is closed and excludes any element, step, or ingredient not explicitly specified. As used herein, the phrase “consisting essentially of’ limits the scope of the described feature to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the disclosed feature.

[0033] As used herein, the term “arthropod” refers to any plant pest in the phylum Arthropoda including the subphylum Hexapoda, which includes class Insecta (e.g., insects), and the subphylum Chelicerata, which includes class Arachnida (e.g., spiders, mites). As used herein, the terms “insect,” “insecticidal,” “insecticidally,” and variations thereof, unless expressly referring to a specific insect pest, instead refer to any arthropod plant pests, including those in the phylum Arthropoda and the class Arachnida, controlled by the compounds and compositions of the present disclosure.

[0034] In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. For example, where hydrogen is designated in a compound, the hydrogen may be protium (’H), deuterium (2H or D), and tritium (3H).

[0035] As used herein, the term “alkyl,” by itself or as part of another substituent, refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. A branched alkyl may include one or branches having a geminal, vicinal, and / or isolated pattern. For example, an alkyl may include gem-methyl groups. Alkyl may include any number of carbons, such as C1-2, C1-3, C1-4, C1-5, C1-6, C1-7, Ci-s, C1-9, C1-10, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6, and C5-6. For example, C1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl may also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groups may be substituted or unsubstituted. Unless otherwise specified,“substituted alkyl” groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0036] As used herein, the terms “hydroxyalkyl” or “alkylhydroxy” refer to an alkyl group, as defined above, where at least one of the hydrogen atoms is replaced with a hydroxy group. As for the alkyl group, alkylhydroxy groups can have any suitable number of carbon atoms, such as C1-6. Exemplary alkylhydroxy groups include, but are not limited to, hydroxy-methyl, hydroxy ethyl (where the hydroxy is in the 1- or 2-position), hydroxypropyl (where the hydroxy is in the 1-, 2-, or 3-position), hydroxybutyl (where the hydroxy is in the 1-, 2-, 3-, or 4-position), hydroxypentyl (where the hydroxy is in the 1-, 2-, 3-, 4-, or 5-position), hydroxyhexyl (where the hydroxy is in the 1-, 2-, 3-, 4-, 5-, or 6-position), 1,2-dihydroxy ethyl, and the like.

[0037] As used herein, the term “heteroalkyl,” by itself or as part of another substituent, refers to an alkyl group of any suitable length and having from 1 to 3 heteroatoms such as N, O and S. Additional heteroatoms may also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. For example, heteroalkyl may include ethers, thioethers and alkyl-amines. The heteroatom portion of the heteroalkyl may replace a hydrogen of the alkyl group to form a hydroxy, thio, or amino group. Alternatively, the heteroatom portion may be the connecting atom, or be inserted between two carbon atoms. Heteroalkyl groups may be substituted or unsubstituted.

[0038] As used herein, the term “alkylene” or “alkylenyl” by itself or as part of another substituent, refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moi eties linked to the alkylene may be linked to the same atom or different atoms of the alkylene group. For instance, a straight chain alkylene may be the bivalent radical of -(CH2)n- where n is 1, 2, 3, 4, 5, or 6. A branched alkylene may include one or branches having a geminal, vicinal, and / or isolated pattern. For example, an alkylene may include gem- methyl groups. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene. Alkylene groups may be substituted or unsubstituted.

[0039] As used herein, the term “alkoxy” refers to a substituted alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. As for the unsubstitutedportion of the alkyl group, alkoxy groups may have any suitable number of carbon atoms, such as C1-6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2butoxy, isobutoxy, secbutoxy, tertbutoxy, pentoxy, hexoxy, etc.

[0040] As used herein, the term “halogen” refers to fluorine, chlorine, bromine and iodine.

[0041] As used herein, the term “haloalkyl” refers to a substituted alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms. As for the unsubstituted portion of the alkyl group, haloalkyl groups may have any suitable number of carbon atoms, such as C1-6. For example, haloalkyl includes trifluoromethyl, fluoromethyl, etc. In some instances, the term “perfluoro” may be used to define a compound or radical where all the hydrogens are replaced with fluorine. For example, perfluoromethane includes 1,1,1- tri fluoromethyl.

[0042] As used herein, the term “haloalkoxy” refers to an alkoxy group where some or all of the hydrogen atoms are substituted with halogen atoms. As for the unsubstituted portion of the alkyl group, haloalkoxy groups may have any suitable number of carbon atoms, such as C1-6. The alkoxy groups may be substituted with 1, 2, 3, or more halogens. When all the hydrogens are replaced with a halogen, for example by fluorine, the compounds are persubstituted, for example, perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2- trifluoroethoxy, perfluoroethoxy, etc.

[0043] As used herein, the term “amino” refers to a moiety -NR2, wherein each R group is H or alkyl. An amino moiety may be ionized to form the corresponding ammonium cation.

[0044] As used herein, the terms “alkyl amine” or “alkylamino” refer to a substituted alkyl group as defined above, having one or more amino groups. The amino groups may be primary, secondary or tertiary. The alkyl amine may be further substituted with a hydroxy group to form an amino-hydroxy group. Alkyl amines useful in the present disclosure include, but are not limited to, ethyl amine, propyl amine, isopropyl amine, ethylene diamine and ethanolamine. The amino group may link the alkyl amine to the point of attachment with the rest of the compound, be at the omega position of the alkyl group, or link together at least two carbon atoms of the alkyl group. One of skill in the art will appreciate that other alkyl amines are useful in the present disclosure.

[0045] As used herein, the term “amido” refers to a moiety -NRC(O)R or -C(O)NR2, wherein each R group is H or alkyl.

[0046] As used herein, the term “acyl” refers to an RC(O) group, where the R group is alkyl.

[0047] As used herein, the term “cycloalkyl,” by itself or as part of another substituent, refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl may include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, Ce-8, C3-9, C3-10, C3-11, and C3-12. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, bicyclo[l. l.l]pentane, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups may also be partially unsaturated, having one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. When cycloalkyl is a saturated monocyclic C3-8 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When cycloalkyl is a saturated monocyclic C3-6 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups may be substituted or unsubstituted. Unless otherwise specified, “substituted cycloalkyl” groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy. The term “lower cycloalkyl” refers to a cycloalkyl radical having from three to seven carbons including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0048] As used herein, the term “aryl,” by itself or as part of another substituent, refers to an aromatic ring system having any suitable number of carbon ring atoms and any suitable number of rings. Aryl groups may include any suitable number of carbon ring atoms, such as C&, C7, Cs, C9, C10, C11, C12, C13, C14, C15, or Ci6, as well as Ce-io, C6-12, or Ce-14. Aryl groups may be monocyclic, fused to form bicyclic (e g., benzocyclohexyl) or tricyclic groups, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl.Other aryl groups include benzyl, having a methylene linking group. Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. Aryl groups may be substituted or unsubstituted. Unless otherwise specified, “substituted aryl” groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0049] As used herein, the term “aralkyl” refers to a substituted alkyl, as defined above, where some or all of the hydrogen atoms are replaced with an aryl group as defined above. As for the unsubstituted portion of the alkyl group, aralkyl groups may have any suitable number of carbon atoms, such as C1-6.

[0050] As used herein, the term “heteroaryl,” by itself or as part of another substituent, refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms may also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms may be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O)2-. Heteroaryl groups may include any number of ring atoms, such as C5-6, C3-8, C4-8, C5-8, Ce-8, C3-9, C3-10, C3-11, or C3-12, wherein at least one of the carbon atoms is replaced by a heteroatom. Any suitable number of heteroatoms may be included in the heteroaryl groups, such as 1, 2, 3, 4; or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. For example, heteroaryl groups may be C5-8 heteroaryl, wherein 1 to 4 carbon ring atoms are replaced with heteroatoms; or C5-8 heteroaryl, wherein 1 to 3 carbon ring atoms are replaced with heteroatoms; or C5-6 heteroaryl, wherein 1 to 4 carbon ring atoms are replaced with heteroatoms; or C5-6 heteroaryl, wherein 1 to 3 carbon ring atoms are replaced with heteroatoms. The heteroaryl group may include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups may also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups includeheteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups may be substituted or unsubstituted. Unless otherwise specified, “substituted heteroaryl” groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0051] The heteroaryl groups may be linked via any position on the ring. For example, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3- and 4-pyridine, imidazole includes 1-, 2-, 4-, and 5-imidazole, pyrazole includes 1-, 3-, 4-, and 5-pyrazole, triazole includes 1-, 4-, and 5- triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5-, and 6- pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-, 5-, and 6-triazine, 1,3, 5-triazine includes 2-triazine, thiophene includes 2- and 3- thiophene, furan includes 2- and 3-furan, thiazole includes 2-, 4-, and 5-thiazole, isothiazole includes 3-, 4-, and 5 -isothiazole, oxazole includes 2-, 4-, and 5-oxazole, isoxazole includes 3-, 4-, and 5-isoxazole, indole includes 1-, 2-, and 3-indole, isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3-, and 4-quinoline, isoquinoline includes 1-, 3-, and 4-isoquinoline, quinazoline includes 2- and 4-quinazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene includes 2- and 3 -benzothiophene, and benzofuran includes 2- and 3 -benzofuran.

[0052] Some heteroaryl groups include those having from 5 to 10 ring members and from 1 to 3 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those having from 5 to 8 ring members and from 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those having from 9 to 12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran and bipyridine. Still other heteroaryl groups include those having from 5 to 6 ring members and from 1 to 2 ring heteroatoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0053] As used herein the term “heterocyclyl,” by itself or as part of another substituent, refers to a saturated heterocyclyl ring system having from 3 to 15 ring members, a partially unsaturated non-aromatic ring, or a partially unsaturated, non-aromatic multiple-ring system in which one or more of the carbon atoms are each independently replaced with the same or different heteroatom such as N, O and S. Additional heteroatoms may also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms may be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O)2-. Heterocyclyl groups may include any number of ring atoms, such as, C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, Ce-8, C3-9, C3-10, C3-11, C3-12, or C3-15, wherein at least one of the carbon atoms is replaced by a heteroatom. Any suitable number of carbon ring atoms may be replaced with heteroatoms in the heterocyclyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocyclyl group may include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. One or more heterocyloalkyl rings of heterocyclyl groups may also be fused to aromatic or non-aromatic rings to form members including, but not limited to, indoline. Heterocyclyl groups thus 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, e.g., 3,4-dihydroquinoline, dihydroisoquinolines, e.g., 1,2-dihydroisoquinoline, tetrahydroquinolines, e.g., 1,2,3,4-tetrahydroquinoline, tetrahydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc., isoindoline, isoindolones (e.g., isoindolin-l-one), isatin, dihydrophthalazine, quinolinone, spiro[cyclopropane-l,T-isoindolin]-3'-one, and the like. Heterocyclyl groups may have 3-15 members, or 3-12 members, or 3-10 members, or 3-7 members, or 5-6 members. Heterocyclyl groups may be unsubstituted or substituted. Unless otherwise specified, “substituted heterocyclyl” groups may be substituted with one or more groups selected from halo, hydroxy, amino, oxo (=0), alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0054] The heterocyclyl groups may be linked via any position on the ring. For example, aziridine may be 1- or 2-aziridine, azetidine may be 1- or 2- azetidine, pyrrolidine may be 1-, 2-, or 3 -pyrrolidine, piperidine may be 1-, 2-, 3-, or 4-piperidine, pyrazolidine may be 1-, 2-, 3-, or4-pyrazolidine, imidazolidine may be 1-, 2-, 3-, or 4-imidazolidine, piperazine may be 1-, 2-, 3-, or 4-piperazine, tetrahydrofuran may be 1- or 2-tetrahydrofuran, oxazolidine may be 2-, 3-, 4-, or5-oxazolidine, isoxazolidine may be 2-, 3-, 4-, or 5-isoxazolidine, thiazolidine may be 2-, 3-, 4-, or 5-thiazolidine, isothiazolidine may be 2-, 3-, 4-, or 5- isothiazolidine, and morpholine may be 2-, 3-, or 4-morpholine.

[0055] As used herein, the term “nitro” refers to the moiety -NCh.

[0056] As used herein, the term “cyano” refers to a carbon atom triple-bonded to a nitrogen atom (i.e., the moiety -ON).

[0057] As used herein, the term “sulfonyl” refers to a moiety -SO2R, wherein the R group is alkyl, haloalkyl, aryl, or halogen. “Alkylsulfonyl” refers to a sulfonyl moiety wherein the R group is alkyl. “Sulfonyl halide” refers to a sulfonyl moiety wherein the R group is halogen.

[0058] As used herein, the term “salt” refers to acid or base salts of the compounds of the present disclosure. An “agriculturally acceptable salt” is one that is compatible with other ingredients of a formulation composition containing the compound, and that is not deleterious to a recipient thereof. It is thus understood that the agriculturally acceptable salts are non-toxic. Illustrative examples of salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. Salts of the acidic compounds of the present disclosure are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts. Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0059] As used herein, the term “solvate” refers to a compound that is complexed to at least one solvent molecule. The compounds of the present disclosure may be complexed with from 1 to 10 solvent molecules. In some embodiments, the solvent is water and the solvate is a hydrate.

[0060] As used herein, the term “agriculturally acceptable carrier” refers to a substance that aids the administration of an active agent to and absorption by an agricultural crop and may be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the agricultural crop. An agriculturally acceptable carriers is thus compatible with the other ingredients of the formulation and not deleterious to the environment or organism (e.g., plant) to which it is applied. Non-limiting examples of agriculturally acceptable carriers include water, NaCl, normal saline solutions, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, and the like. One of skill in the art will recognize that other agriculturally acceptable carriers are useful in the present disclosure.

[0061] As used herein, the term “effective amount” refers to an administered amount of a compound, composition, or component, when used within the context of its intended use, effects an intended result. The term effective subsumes all other effective amount or effective concentration terms, which are otherwise described or used in the present application.

[0062] As used herein, the term “agriculturally effective amount” where used herein means the quantity of such a compound or combination of compounds that is capable of producing a desired agricultural effect. For example, when the composition is an insecticidal composition, i.e., a composition including an insecticide compound such as any bifunctional compound disclosed herein, the desired agricultural effect may include the controlling of the growth or development of insects, such controlling including, but not limited to, reducing the emergence and / or growth of the insects or killing undesired insects. The exact amount can vary depending on conditions (e.g., soil, humidity, pH, temperature, growing season, amount of daily light, etc.), the concentration and type of components as described herein, as well as the type of insect to which each composition is applied and will be ascertainable by one skilled in the art using known techniques.

[0063] As used herein, the term “degradation efficiency” refers to a measure of an ability of a molecule (e.g., a targeted protein degrader) to induce degradation of a particular substance (e.g., a targeted protein). The degradation efficiency of a molecule can be measured in terms of, forexample, a half-maximal degradation concentration (DC50) or a maximal degradation (Dmax). The half-maximal degradation concentration (DCso) of a molecule is the concentration of the molecule at which degradation of 50% of the targeted substance has been induced. The maximal degradation (Dmax) of a molecule is the maximal observed percent of the targeted substance that the molecule induces the degradation of.B. COMPOUNDS

[0064] In one aspect, the disclosure provides a compound that is a proteolysis targeting chimera (PROTAC). A PROTAC according to the present invention is a bifunctional compound having the following general structure of formula (I):PTM-L-LTM (I) wherein, PTM represents a protein targeting moiety, LTM represents an E3 ubiquitin ligase targeting moiety including but not limited to VHL and / or cereblon, and L represents a linker, e.g., a bond or a chemical linker moiety. The bound protein is then targeted for degradation through the ubiquitin-proteasome system. PROTACs may be used to inhibit or degrade essentially any protein of interest in an insect (e.g., proteins required for the insect and / or arachnid to maintain its normal physiological and biochemical functions, proteins that limit the insect's and / or arachnid’s ability to feed, grow, or survive, or proteins involved in processes such as development, metabolism, or neurotransmission). The provided PROTACs may be designed by considering multiple factors, including the type of ligase being targeted, the selected configuration of the PROTAC linker, the choice of the POI ligand and its binding site, the choice of the ligase ligand and its binding site, and the nature of the protein-protein interaction interface between the ligase and the POI. All these factors may affect the structure and stability of ternary complexes formed by the PROTAC, the POI, and the ligase, e.g., an E3 ligase such as cereblon E3 ubiquitin ligase (CRBN) or the von Hippel-Lindau E3 ubiquitin ligase (VHL).

[0065] The dissociation constant (KD) may be used to describe the affinity between a ligand and a protein, i.e., how tightly a ligand binds to a particular protein. The KD corresponds to the ligand concentration at which half of the proteins are occupied at equilibrium. The smaller the KD, the more tightly bound the ligand is, or the higher the affinity between ligand and protein. The KD values may be determined according to any method known in the art such as, forexample, ligand displacement, surface plasmon resonance (SPR), enzyme linked immunosorbent assay (ELISA) or ALPHALISA® assays.

[0066] In some embodiments described herein, the LEM exhibits a binding affinity to the E3 ubiquitin ligase (e.g., CRBN or VHL) with a KD of less than about 1 mM. For example, in some embodiments described herein, the LTMs described herein demonstrate an activity with a KD of less than about 500 pM, less than about 200 pM, less than about 100 pM, less than about 50 pM, less than about 10 pM, less than about 5 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 500 pM, less than about 100 pM, less than about 50 pM, less than about 10 pM, less than about 1 pM, less than about 0.5 pM, less than about 0.1 pM, less than about 0.05 pM, less than about 0.01 pM, less than about 0.005 pM, or less than about 0.001 pM.

[0067] In some embodiments described herein, the PTM exhibits a binding affinity to the protein of interest (e.g., BRD3) with a KD of less than about 1 mM. For example, in some embodiments described herein, the LTMs described herein demonstrate an activity with a KD of less than about 500 pM, less than 200 pM, less than about 100 pM, less than about 50 pM, less than about 10 pM, less than about 5 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 500 pM, less than about 100 pM, less than about 50 pM, less than about 10 pM, less than about 1 pM, less than about 0.5 pM, less than about 0.1 pM, less than about 0.05 pM, less than about 0.01 pM, less than about 0.005 pM, or less than about 0.001 pM.

[0068] In some embodiments described herein, the bifunctional compounds described herein exhibit a dissociation constant (Knapp) for a ternary complex consisting of the E3 ubiquitin ligase (e.g., CRBN or VHL), the target protein (i.e., BRD3), and the bifunctional compound of less than about 200 pM, less than about 100 pM, less than about 50 pM, less than about 10 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 500 pM, less than about 100 pM, less than about 50 pM, less than about 10 pM, less than about 1 pM, less than about 0.5 pM, less than about 0.1 pM, less than about 0.05 pM, less than about 0.01 pM, less than about 0.005 pM, or less than about 0.001 pM.

[0069] The half-maximal inhibitory concentration (IC50) values of the LTMs and the bifunctional compounds, described herein, are measures of the binding affinity exhibited by the LTMs and bifunctional compounds, respectively. The IC50 values may be determined according to any method known in the art such as, for example, a fluorescent polarization assay.

[0070] In some embodiments described herein, the LTM exhibits a binding affinity to the E3 ubiquitin ligase (e.g., VHL or CRBN) with an IC50 of less than about 1 mM. For example, in some embodiments described herein, the LTMs described herein demonstrate an activity with an IC50 of less than about 500 pM, less than 200 pM, less than about 100 pM, less than about 50 pM, less than about 10 pM, less than about 5 pM, or less than about 1 pM.

[0071] In some embodiments described herein, the bifunctional compounds described herein exhibit a binding affinity to the E3 ubiquitin ligase (e.g., VHL or CRBN) and / or the target protein (i.e., BRD3) with an IC50 of less than about 500 pM, less than 200 pM, less than about 100 pM, less than about 50 pM, less than about 10 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 500 pM, less than about 100 pM, less than about 50 pM, less than about 10 pM, less than about 1 pM, less than about 0.5 pM, less than about 0.1 pM, less than about 0.05 pM, less than about 0.01 pM, less than about 0.005 pM, or less than about 0.001 pM.

[0072] In some embodiments described herein, the PTM exhibits a binding affinity to the protein of interest (i.e., BRD3) with an IC50 of less than about 1 mM. For example, in some embodiments described herein, the LTMs described herein demonstrate an activity with an IC50 of less than about 500 pM, less than about 200 pM, less than about 100 pM, less than about 50 pM, less than about 10 pM, less than about 5 pM, or less than about 1 pM.

[0073] In some embodiments described herein, the maximal degradation (DMax) of the bifunctional compounds described herein may be determined according to any method known in the art such as, for example, a western blot analysis. In some embodiments described herein, the bifunctional compounds have a DMax greater than or equal to 80%. In some embodiments described herein, the bifunctional compounds have a DMax greater than 30%>, greater than 50%, greater than 75%, or greater than or equal to 80%. In some embodiments described herein, the bifunctional compounds have a DMax greater than 50%. In some embodiments described herein, the bifunctional compounds have a DMax greater than 75%.

[0074] In some embodiments described herein, the half-maximal degradation constant (DCso) value of the bifunctional compounds described herein may be determined according to any method known in the art such as, for example, a western blot analysis. In some embodiments described herein, the DCso value of the bifunctional compounds is less than about 10 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 50 nM, less than about 100 nM, less than about 50 nM, less than about 10 nM, or less than about 2.5 nM. In some embodiments described herein, the DCso value of the bifunctional compounds is less than 10 nM. In some embodiments described herein, the DCso value of the bifunctional compounds is less than 2.5 nM.

[0075] In some embodiments described herein, the bifunctional compounds have a DMax greater than 30%, greater than 50%, greater than 75%, or greater than or equal to 80%, and the DCso value of the bifunctional compounds is less than about 10 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 50 nM, less than about 100 nM, less than about 50 nM, less than about 10 nM, or less than 2.5 nM.

[0076] In some embodiments described herein, the bifunctional compound includes compounds having a DCso of < about 2.5 nM, wherein the DCso is optionally determined as described herein. In some embodiments described herein, the bifunctional compound includes compounds having a DCso that is > about 2.5 nM and < about 10 nM, wherein the DCso is optionally determined as described herein. In some embodiments described herein, the bifunctional compound includes compounds having a DCso of > about 2.5 nM and < about 30 nM, wherein the DCso is optionally determined as described herein. In some embodiments described herein, the bifunctional compound includes compounds having a DCso of > about 30 nM, wherein the DCso is optionally determined as described herein. In some embodiments described herein, a compound or compounds having a DCso of > about 30 nM is or are excluded. In some embodiments described herein the DCso value of the bifunctional compounds described herein can be determined according to any method known in the art, such as, for example, a western blot analysis.

[0077] In some embodiments described herein, the bifunctional compound includes compounds having a DMax of > about 75% degraded, wherein the DMax is optionally determined as described herein. In some embodiments described herein, the bifunctional compound includescompounds having a Dxiax that is > about 50% degraded and < about 75% degraded, wherein the Dkiax is optionally determined as described herein. In some embodiments described herein, the bifunctional compound includes compounds having a DMax of < about 30% degraded, wherein the DMax is optionally determined as described herein. In some embodiments described herein a compound or compounds having a DMax of < about 30 % degraded is or are excluded, wherein the DMax may be determined as described herein. In some embodiments described herein a compound or compounds having a DMax of < about 50 % degraded is or are excluded, wherein the DMax may be determined as described herein. In some embodiments described herein the DMax value of the bifunctional compounds described herein can be determined according to any method known in the art, such as, for example, a western blot analysis or as described herein.1. Insect ubiquitin ligases and ligase targeting moieties (LTMs)

[0078] In some embodiments, cheminformatics and computational chemistry approaches (e.g., ligand conformational sampling, PROTAC conformational sampling, 3D docking, proteinprotein docking, molecular dynamics, machine learning) are used to design ligands for insect ligases. Such structures may then be optimized through rational medicinal chemistry optimization. See, for example, Ishida, T. and Ciulli, A. (2021) SLAS Discovery 26(4) 484-502.

[0079] In some embodiments, one or more known ubiquitin ligase binders are used in the compounds and methods provided herein. Such binders are disclosed in U.S. Patent Nos: 9,694,084; 9,938,264; 10,071,164; 10,239,888; 10,336,744; 10,450,310; 10,464,925; 10,584,101; 10,723,717; 10,730,862; 10,730,870; 10,772962; 11,242,344; U.S. Patent Application Publication Nos: 2015 / 0291562; 2015 / 0119435; 2016 / 0058872; 2017 / 0008904; 2018 / 0147202; 2019 / 0127359; and PCT Publication Nos: WO 2000 / 047220; WO 2018 / 144649; WO 2021 / 127278. All of these are herein incorporated by reference in their entirety. Other E3 ligase ligands include those described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed.2016, 55, 1966; T. Uehara et al. Nature Chemical Biology 2017, 13, 675; WO 2017 / 176708; US 2017 / 0281784; WO 2017 / 161119; WO 2017 / 176957; WO 2017 / 176958; WO 2015 / 160845; US 2015 / 0291562; WO 2016 / 197032; WO 2016 / 105518; US 2018 / 0009779; WO 2017 / 007612; WO 2018 / 0134684; WO 2013 / 106643; US 2014 / 0356322; WO 2002 / 020740; US 2002 / 0068063;WO 2012 / 078559; US 2014 / 0302523; WO 2012 / 003281; US 2013 / 0190340; US 2016 / 0022642; WO 2014 / 063061; US 2015 / 0274738; WO 2016 / 118666; US 2016 / 0214972; WO 2016 / 149668;US 2016 / 0272639; WO 2016 / 169989; US 2018 / 0118733; WO 2016 / 197114; US 2018 / 0147202; WO 2017 / 011371; US 2017 / 0008904; WO 2017 / 011590; US 2017 / 0037004; WO 2017 / 079267; US 2017 / 0121321; WO 2017 / 117473; WO 2017 / 117474; WO 2013 / 106646; WO 2014 / 108452; WO 2017 / 197036; US 2019 / 0076540; WO 2017 / 197046; US 2019 / 0076542; WO 2017 / 197051; US 2019 / 0076539; WO 2017 / 197055; US 2019 / 0076541; and WO 2017 / 197056, the entirety of each of which is herein incorporated by reference.

[0080] In some embodiments, the ubiquitin ligase is cereblon (CRBN). Cereblon is a protein that in arthropods (e g., insects) is encoded by the CRBN gene. CRBN orthologs are highly conserved from plants to humans, which underscores its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins. Through a mechanism, which has not been completely elucidated, cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates a number of developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb outgrowth in embryos. In the absence of cereblon, DDB1 forms a complex with DDB2 that functions as a DNA damage-binding protein.

[0081] In some embodiments, one or more known ligase targeting moieties for a cereblon E3 ligase may be used in the compounds and methods provided herein. Such cereblon binders include any of the target binders disclosed in International Patent Application Publication Nos. WO 2019 / 060693 and WO 2024 / 020221; and US Patent Application No. 2015 / 0291562, the entirety of each of which is herein incorporated by reference.

[0082] In some embodiments, the cereblon targeting moiety selected from moieties having the structure of formula (C-a) through formula (C-k):wherein:W of formulas (C-a) through (C-i) is independently selected from the group CH2, O, CHR, C=O, SO2, NH, N, optionally substituted cyclopropyl group, optionally substituted cyclobutyl group, and N-alkyl;W3of formula (C-i) is selected from C or N;X of formulas (C-a) through (C-i) is independently selected from the group absent, O, S and CH2;XIof formulas (C-j) and (C-k) is a bivalent moiety independently selected from a covalent bond,Y of formulas (C-a) through (C-i) is independently selected from the group CH2, -C=CR’, NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;Z of formulas (C-a) through (C-i) is independently selected from the group absent, O, and S or CH2 except that both X and Z cannot be CH2 or absent;G and G’ of formulas (C-a) through (C-i) are independently selected from the group hydrogen, optionally substituted linear or branched alkyl, OH, R’OCOOR, R’OCONRR”, CH2- heterocyclyl optionally substituted with R’, and benzyl optionally substituted with R’;Q1- Q4of formulas (C-a) through (C-i) represent a carbon C or N substituted with a group independently selected from H, R, N or N-oxide;Ring B of formula (C-j) is a bi- or tricyclic ring selected fromwherein Ring C of formula (C-j) is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7-membered partially saturated carbocyclyl, 5 to 7- membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring D of formula (C-k) is a mono- or bicyclic ring selected fromRing E of formula (C-k) is a bi- or tricyclic ring selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;A of formulas (C-a) through (C-k) is independently selected from the group hydrogen, halogen, - CN, -OR2, -SR2, -S(O)R2, -S(O)2R2, -N(R2)2, an optionally substituted linear or branched alkyl, or an optionally substituted cycloalkyl, or when W3of Formula (C-i) is N, A is absent;R of formulas (C-a) through (C-i) represents H, -C(=O)R’, -CONR’R”, -OR’, -NR’R”, -SR’, - SO2R’, -SO2NR’R”, -CR’R”-, -CR’NR’R”-, (-CR’O)nR”, optionally substituted heterocyclyl, optionally substituted aryl, (e.g., an optionally substituted aryl), optionally substituted alkyl-aryl (e.g., an alkyl-aryl comprising at least one of an optionally substituted C1-C6alkyl, an optionally substituted C5-C7 aryl, or combinations thereof), optionally substituted heteroaryl, optionally substituted alkyl (e.g., a C1-C6linear or branched alkyl optionally substituted with one or morehalogen, cycloalkyl (e g., a Cj-Ce cycloalkyl), or aryl (e g., C5-C7 aryl)), optionally substituted alkoxyl group (e g., a methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; wherein the alkoxyl may be substituted with one or more halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), optionally substituted cycloalkyl, optionally substituted heterocyclyl, - P(O)(OR’)R”, -P(O)R’R”, -OP(O)(OR’)R”, -OP(O)R’R”, - Cl, -F, -Br, -I, -CF3, -CN, - NR’SC NR’R”, -NR’CONR’R”, -CONR’COR”, - NR’C(=N-CN)NR’R”, -C(=N-CN)NR’R”, - NR’C(=N-CN)R”, -NR’C(=C-NO2)NR’R”, -SChNR’COR”, -NO2, -CO2R’, -C(C=N-OR’)R”, - CR’=CR’R”, -CCR’, -S(C=O)(C=N-R’)R”, -SFs and -OCF3; or wherein both of two adjacent Q'-Q4groups are R, the attached atoms may form an optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted alkyl-aryl, optionally substituted heteroaryl, or optionally substituted cycloalkyl;R’ and R” of formulas (C-a) through (C-f) are independently selected from hydrogen, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, -C(=O)R, optionally substituted heterocyclyl;R1of formulas (C-j) and (C-k) are independently selected from hydrogen, R6, halogen, -CN, - NO2, -OR2, -SR2, -N(R2)2, -S(O)2N(R2)2, -S(O)R2, -C(O)R2, -C(O)N(R2)2, -C(O)N(R2)OR2, - OC(O)R2, -OC(O)N(R2)2, -N(R2)C(O)OR2, -N(R2)C(O)R2, -N(R2)C(O)N(R2)2, or - N(R2)S(O)2R2; each R2of formulas (C-j) and (C-k) are independently selected from hydrogen, or an optionally substituted group select from C1-C6alkyl, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R2groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;R3of formula (C-j) is selected from hydrogen, halogen, -OR2, -N(R2)2, or -SR2;each R4of formulas (C-j) and (C-k) is independently hydrogen, -R6, halogen, -CN, -NCh, -OR2, - SR2, -N(R2)2, -S(O)2R2, -S(O)2NR2, -S(O)R2, -C(O)R2, -C(O)OR2, -C(O)N(R2)2, - C(O)N(R2)OR2, -OC(O)R2, -OC(O)N(R2)2, -N(R2)C(O)OR2, -N(R2)C(O)R2, -N(R2)C(O)N(R2)2, or -N(R2)S(O)2R2;R5is hydrogen, C1-C4 alkyl, or -CN;R6of formulas (C-j) and (C-k) are independently selected from C1-C6alkyl, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;M of formula (C-k) is 0, 1, or 2; n of formulas (C-a) through (C-j) represents an integer from 0 to 10 (e.g., 0-5, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); p of formula (C-k) is 0 or 1, wherein when p is 0, the bond connecting Ring D and Ring E terminates in a hydrogen; each of x, y, and z are independently 0, 1, 2, 3, 4, 5, or 6; represents a single bond or a double bond; and r" of formulas (Ila) through (Hi) represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific;of formulas (C-j) and (C-k) represents the point of attachment to the compounds of formulas (C-j) and (C-k); and wherein at least one W, X, Y, Z, G, G’, R, R’, R”, R1, R2, R3, R4, R\ R6, QLQ4, or A is modified to be covalently joined to a chemical linking group (L), an LTM, or combination thereof.

[0083] In some embodiments, the ubiquitin ligase is VHL. The von Hippel-Lindau tumor suppressor (VHL) is an E3 ubiquitin ligase. VHL comprises the substrate recognition subunit / E3 ubiquitin ligase complex VCB, which includes elongins B and C, and a complex includingCullin-2 and Rbxl . The primary substrate of VHL is Hypoxia Inducible Factor 1 a (HIF-1 a), a transcription factor. In this instance, targeting moieties may be selected from those disclosed in US Patent Nos. 10,730,870; 10,071,164; 10,730,862; 10,772,962; and 11,242,344; all of which are herein incorporated by reference.

[0084] In some embodiments, the VHL targeting moiety has a structure according to the formula (V-I):wherein R5aand R5bmay each independently be hydrogen, hydroxy, amine, haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxyl alkyl, optionally substituted alkylamine, optionally substituted amide, optionally substituted alkyl-amide, optionally substituted alkyl-cyano, optionally substituted alkyl-phosphate, optionally substituted aryl, optionally substituted alkyl-aryl, optionally substituted heteroalkyl, optionally substituted alkyl-heterocyclyl, optionally substituted alkoxy-heterocyclyl, COR14, alkyl-COR14, CONR15aR15b, NHCOR14, NHCH3COR14, or -X-L1. Alternatively, R5aand R5bare combined with the carbon atom to which they are attached to form an optionally substituted 3- to 5-membered cycloalkyl, heterocyclyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not epoxide or aziridine. Each R6may independently be C1-6 alkyl, halogen, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C6-12 aryl, C5-12 heteroaryl, C3-15 heterocyclyl, cyano, nitro, NR15aR15b, OR14, CONR15aR15b, NR15aCOR15b, SO2NR15aR15b, NR15aSO2R15b, or -X-L1, wherein the alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with 1 to 4 R6agroups. R8may be an optionally substituted aryl, optionally substituted heteroaryl, or. R9and R10may independently be hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substitutedhydroxyalkyl, optionally substituted heteroaryl, haloalkyl, or. Alternatively, R9and R10may be combined with the carbon atom to which they are attached to form an optionally substituted cycloalkyl. R2and R3of formula V-I may each independently be hydrogen, C1-6 alkyl, or C1-6 hydroxyalkyl. Alternatively, R2and R3of formula V-I may be combined with the carbon to which they are attached to form a C3-8 cycloalkyl, C6-12 aryl, or C5-12 heteroaryl, wherein the cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 4 R2agroups. R4may be hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, or -X-L. R11may be an optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,R1of formula V-I may be hydrogen, optionally substituted alkyl, optionally substituted alkyl carbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted(heterocyclyl)carbonyl, optionally substituted aralkyl, -C(O)Rla, or -C(O)-X-L1. Rlamay be C1-6alkyl, C3-8 cycloalkyl, C6-12 aryl, or C5-12 heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted with 1 to 4 Rlbgroups. Each Rlb, R2a, and R6amay independently be C1-6 alkyl, cyano, halogen, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, or -X-L1. R12may be hydrogen or optionally substituted alkyl. Each R13may independently be hydrogen, halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or -X-L1. Each R14may independently be hydrogen, OH, O-C1-6 alkyl, optionally substituted alkyl, or NR15aR15b. R15aand R15bmay each independently be hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl, or are combined with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl. R16is hydroxy, a group that can be metabolized to hydroxy, or sulfonyl halide. “A” may be optionally substituted phenyl, optionally substituted napthyl, or an optionally substituted 5- to 10- membered heteroaryl. X may be a bond, CH2, NH, NMe, O, or S. L1is a site of attachment to the linker (L). The subscripts n and p may each independently be an integer from 0 to 4. At least one -X-L1is present in the compoundof formula (V-I) when the compound is a bifunctional compound, e g., PROTAC, having the general structure LTM-L-PTM.

[0085] In some embodiments, the VHL targeting moiety has a structure according to the formulawherein features of formula (V-Ia) are as described above for formula (V-I).R12■> ifl ,

[0086] In some embodiments, R11is . In some embodiments, R1is -C(O)Rlaor -C(O)- X-L1. In some embodiments, R1is -C(O)Rla. In some embodiments, Rlais C1-6 alkyl or C3-8 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 to 4 Rlbgroups. In some embodiments, Rlais C1-6 alkyl or cyclopropyl, wherein the cyclopropyl is optionally substituted with 1 to 4 Rlbgroups. In some embodiments, Rlais cyclopyropyl optionally substituted with 1 to 4 Rlbgroups. In some embodiments, Rlais fluorocyclopropyl. In some embodiments, Rlais C1-6 alkyl. In some embodiments, Rlais methyl. In some embodiments, R1is - C^-X-L1.

[0087] In some embodiments, R2and R3are each independently C1-6 alkyl. In some embodiments, R2and R3are each methyl.

[0088] In some embodiments, R4is C1-6 alkyl or -X-L1. In some embodiments, R4is C1-6 alkyl. In some embodiments, R4is methyl. In some embodiments, R4is -X-L1. In some embodiments, R4is -SL1.

[0089] In some embodiments, Rais hydrogen, C1-6alkyl, hydroxy, C1-6alkoxy or -X-L1. In some embodiments, R5ais hydrogen, methyl or -X-L1.

[0090] In some embodiments, each R6is independently C1-6alkyl, hydroxy, C1-6alkoxy, C6-12 aryl, C5-12 heteroaryl, or -X-L1, wherein the aryl and heteroaryl are optionally substituted with 1to 4 R6agroups. In some embodiments, each R6is independently C5-12 heteroaryl and -X-L1, wherein the heteroaryl is optionally substituted with 1 to 4 R6agroups. In some embodiments, each R6is independently thiazole or -X-L1, wherein the thiazole is optionally substituted with 1 to 4 R6agroups. In some embodiments, one R6is thiazole optionally substituted with 1 to 4 R6agroups. In some embodiments, one R6is thiazole optionally substituted with 1 to 4 C1-6 alkyl groups. In some embodiments, one R6is methylthiazole. In some embodiments, one R6is -X-L1. In some embodiments, one R6is -O-L1. In some embodiments, one R6is methoxy. In some embodiments, n is 2 and one R6is methylthiazole and one R6is methoxy. In some embodiments, n is 2 and one R6is methylthiazole and one R6is -X-L1.

[0091] In some embodiments, R16is hydroxy. In some embodiments, R16is sulfonyl halide. In some embodiments, R16is sulfonyl fluoride.

[0092] In some embodiments, subscript n is 1 or 2. In some embodiments, subscript n is 1. In some embodiments, subscript n is 2.

[0093] In some embodiments, the VHL targeting moiety has a structure according to the formula(V-Ib) wherein R2, R3, R4, R5a, R6, R11, and R16are as defined above.

[0094] In some embodiments, the VHL targeting moiety has a structure that iswherein Rlb, R2, R3, R4, R5a, R6, R13, X, L1, and p are as defined above.2. Linkers

[0095] A linker (L) is generally used to connect the PTM to the LTM. In some embodiments, is a bond (i.e., absent). In some embodiments, L is a chemical linker. In some embodiments, the linker is a connector with a linear non-hydrogen atom number in the range of 1 to 30, e.g., in the range of 1 to 12, in the range of 3 to 14, in the range of 5 to 16, in the range of 7 to 18, or in the range of 9 to 20. The connector may contain functional groups including, but not limited to, ethers, amides, alkanes and alkyl groups, alkenes and alkenyl groups, alkynes and alkynylgroups, ketones, hydroxyls, carboxylic acids, thioethers, sulfoxides, and sulfones. The linker may contain aryl groups, heteroaryl groups, cyclic groups (including heterocyclic and carbocyclic monocycles, bicycles, tricycles). Substitution including, but not limited to, one or more of halo, such as Cl, F, Br, I, hydroxy, alkyl, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy may be included in the linker. Examples of suitable linker moieties include, but are not limited to, those disclosed in International Patent Application Publication Nos. WO 2013 / 106643, WO 2015 / 160845, WO 2016 / 149668, WO 2016 / 197032, WO 2017 / 011371, WO 2017 / 011590, WO 2018 / 144649, and WO 2019 / 148055, which are incorporated herein by reference in their entirety.

[0096] Judicious linker design facilitates binding to the target protein and the ubiquitin ligase, influencing degradation efficiency as well as having a significant influence on the overall molecular properties of the PROTAC. The linker structure contributes to achieving appropriate biological function by providing a beneficial combination of cellular uptake, ternary complex geometry, stability, and aqueous solubility. The choice of linker may be informed by, for example, the E3 ligase ligand, the target-binding ligand, and both the identity and attachment positions of the linker. Linkers as disclosed herein may be tested with ligase targeting moieties and protein targeting moieties in various combinations.

[0097] In certain embodiments, the linker group, L, is a group comprising one or more covalently connected structural units (e.g., -ALi ..(AL)q- or -(AL)q-), wherein one of ALi or ALqgroup coupled to a PTM, and one of ALi or ALqis a group coupled to an LTM.

[0098] In some embodiments, the linker (L) to LTM (e.g., CLM or VLM,) connection or coupling is a stable L-LTM connection. For example, in any aspect or embodiment described herein, when a linker (L) and a LTM is connected via a heteroatom, any subsequent heteroatom, if present, is separated by at least one single carbon atom (e.g., -CH2-), such as with an acetal or aminal group.

[0099] In some embodiments, the linker group L is a bond or a chemical linker group represented by the formula -(AL)q-, wherein A is a chemical moiety and q is an integer from 1- 100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, or 80), and wherein L is covalently bound to both the PTM and the LTM, and provides for binding of the PTM to the protein target and the LTM to an E3 ubiquitin ligase to effectuate target protein ubiquitination.

[0100] In some embodiments, the linker group L is a bond or a chemical linker group represented by the formula -(AL)q-, wherein A is a chemical moiety and q is an integer from 1- 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25), and wherein L is covalently bound to both the PTM and the LTM, and provides for binding of the PTM to the protein target and the LTM to an E3 ubiquitin ligase in sufficient proximity to result in target protein ubiquitination.

[0101] In some embodiments, the linker group L is -(AL)q-, wherein: (AL)qis a group that is connected to at least one of a LTM moiety, a PTM moiety, or a combination thereof; q of the linker is an integer greater than or equal to 1; each ALis independently selected from the group consisting of, a bond, CRL1RL2, O, S, SO, SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SO2NRL4, CO, CRL1=CRL2, C=C, SiRL1RL2, P(O)RL1, P(O)ORL1, NRL3C(=NCN)NRL4, NRL3C(=NCN), NRL3C(=CNO2)NRL4, (C3-Cn)cycloalkyl optionally substituted with 0-6 RL1and / or RL2groups, (C5-Ci3)spirocycloalkyl optionally substituted with 0-9 RL1and / or RL2groups, (C3-C11)heterocyclyl optionally substituted with 0-6 RL1and / or RL2groups, (C5-Ci3)spiroheterocyclyl optionally substituted with 0-8 RL1and / or RL2groups, aryl optionally substituted with 0-6 RL1and / or RL2groups, and heteroaryl optionally substituted with 0-6 RL1and / or RL2groups, where RL1or RL2each independently are optionally linked to other groups to form a cycloalkyl and / or heterocyclyl moiety, optionally substituted with 0-4 RL5groups; and each RL1RL2, RL3, RL4and RL5is independently hydrogen, halogen, (Ci-Cs)alkyl, O(Ci-Cs)alkyl, S(C1-C8)alkyl, NH(C1-C8)alkyl, N((C1-C8)alkyl)2, (C3-C11)cycloalkyl, aryl, heteroaryl, (C3-C11)heterocyclyl, O(C3-C8)cycloalkyl, S(C3-C8)cycloalkyl, NH(C3-C8)cycloalkyl, N((C3-C8)cycloalkyl)2, N(C3-C8)cycloalkyl)((C1-C8)alkyl), OH, NH2, SH, SO2(C1-C8)alkyl, P(O)(O(C1-C8)alkyl)(C1-C8)alkyl), P(O)(O(Ci-8)alkyl)2, CC-(C1-C8)alkyl, CCH, CH=CH((Ci- C8)alkyl), C((C1-C8)alkyl)=CH((C1-C8)alkyl), C((C1-C8)alkyl)=C((C1-C8)alkyl)2, Si(OH)3, Si((C1-C8)alkyl)3, Si(OH)((C1-C8)alkyl)2, CO(C1-C8)alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH(Ci-Cs)alkyl, SO2N((C1-C8)alkyl)2, SONH(C1-C8)alkyl, SON((C1-C8)alkyl)2, CONH(C1-C8)alkyl, CON((C1-C8)alkyl)2, N((C1-C8)alkyl)CONH((C1-C8)alkyl), N((Ci-C8)alkyl)CON((C1-C8)alkyl)2, NHCONH((C1-C8)alkyl), NHCON((C1-C8)alkyl)2, NHCONH2, N((C1-C8)alkyl)SO2NH((C1-C8) alkyl), N((C1-C8)alkyl) SO2N((C1-C8)alkyl)2, NH SO2NH((CI- C8)alkyl), NH SO2N((C1-C8)alkyl)2, or NH SO2NH2.

[0102] In some embodiments, each ALis independently selected from the group consisting of CRL1RL2, O, NRL3, CONRL3, CO, CRL1=CRL2, C=C, (C3-C11)cycloalkyl optionally substituted with 1-6 RL1and / or RL2groups, (C3-C11)heterocyclyl optionally substituted with 1-6 RL1and / or RL2groups, aryl optionally substituted with 1-6 RL1and / or RL2groups, and heteroaryl optionally substituted with 1-6 RL1and / or RL2groups, where RL1or RL2, each independently are optionally linked to other groups to form cycloalkyl and / or heterocyclyl moiety, optionally substituted with 1-4 RL5groups, and RL1, RL2, RL3, and RL5are, each independently, halogen, (C1-C8)alkyl, O(Ci- C8)alkyl, NH(C1-C8)alkyl, N((C1-C8)alkyl)2, (C3-C11)cycloalkyl, aryl, heteroaryl, (C3- C11)heterocyclyl, O(C3-C8)cycloalkyl, NH(C3-C8)cycloalkyl, N((C3-C8)cycloalkyl)((Ci- Cs)alkyl), OH, NH2, CCH, CO(C1-C8)alkyl, CO2H, CN, CF3, CHF2, CH2F, or NO2.

[0103] In some embodiments, q of the linker is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1.

[0104] In some embodiments, e.g., where q of the linker is 2, ALqis a group that is connected to ALi and to a LTM or PTM.

[0105] In some embodiments, e.g., where q of the linker is 1, the structure of the linker group L is -ALi~, and ALi is a group that is connected to a LTM moiety and a PTM moiety.

[0106] In some embodiments, the unit ALof linker L comprises a group represented by a general structure selected from the group consisting of: -NR(CH2)n-((C1-C8)alkyl)-, -NR(CH2)n- ((C1-C8)alkoxyl)-, -NR(CH2)n-((C1-C8)alkoxyl)-OCH2-, -NR(CH2)n-((C1-C8)alkoxyl)-( (Ci- C8)alkyl)-OCH2-, -NR(CH2)n-(cycloalkyl)-( (C1-C8)alkyl)-OCH2-, -NR(CH2)n- (heterocycloalkyl)-, -NR(CH2CH2O)n-((C1-C8)alkyl)-O-CH2-, -NR(CH2CH2O)n- (heterocycloalkyl)-O-CH2-, -NR(CH2CH2O)n-Aryl-O-CH2-, -NR(CH2CH2O)n-(heteroaryl)-O- CH2-, -NR(CH2CH2O)n-(cycloalkyl)-O-(heteroaryl)-O-CH2-, -NR(CH2CH2O)n-(cycloalkyl)-O- Aryl-O-CH2-, -NR(CH2CH2O)n-((C1-C8)alkyl)-NH-Aryl-O-CH2-, -NR(CH2CH2O)n-((Ci- C8)alkyl)-O-Aryl-CH2, -NR(CH2CH2O)n-cycloalkyl-O-Aryl-, -NR(CH2CH2O)n-cycloalkyl-O- (heteroaryl)-, -NR(CH2CH2)n-(cycloalkyl)-O-(heterocyclyl)-CH2. -NR(CH2CH2)n-(heterocyclyl)-(heterocyclyl)-CH2, and -N(RiR2)-(heterocyclyl)-CH2; where n of the linker can be 0 to 10; R of the linker L can be H or lower alkyl; and Ri and R2 of the linker L can form a ring with the connecting N.

[0107] In some embodiments, the L comprises at least one moiety selected from:wherein: each of m, n, o, p, q, and t of L is independently selected from the integers 0, 1, 2, 3 and 4 (preferably 0, 1, or 2); and u, w, and v of L are each independently selected from integers 0 and 1; XL of L is -C(CH2)-, -C(CH3)H, -CH2-, -O-, C=O, or -NH-CH2-; RL of L is H, OH, F, Cl, or methyl; WL2of L is selected from an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene (e.g. a 6- to 12-membered or 8- to 12-membered spirocycloalkylene or spiroheterocyclylene substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, (C1-C3)alkoxy, (C1-C3)alkyl, (C1-C3)haloalkyl, or amino), , WL3 of L is selected from an optionallysubstituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene (e.g. a 6- to 12- membered or 8- to 12-membered spirocycloalkylene or spiroheterocyclylene substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, (C1-C3)alkoxy, (C1-C3)alkyl, (Ci-C3)haloalkyl, or amino), andwL5of L is selected from an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene (e.g. a 6- to 12- membered or 8- to 12-membered spirocycloalkylene or spiroheterocyclylene substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, (C1-C3)alkoxy, (C1-C3)alkyl, (C1-C3”C3)haloalkyl, or amino), , and WL6 of L is selected from anoptionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene (e g. a 6- to 12-membered or 8- to 12-membered spirocycloalkylene or spiroheterocyclylene substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, (C1-C3)alkoxy, (C1-C3)alkyl, (Ci-C3)haloalkyl, or amino),WL7 of L is selected from anoptionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene (e.g. a 6- to 12-membered or 8- to 12-membered spirocycloalkylene or spiroheterocyclylene substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, (C1-C3)alkoxy, (C1-C3)alkyl, (Ci-C3)haloalkyl, or amino),, an ; and WLS of L is selected from an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene (e.g. a 6- to 12-membered or 8- to 12-membered spirocycloalkylene or spiroheterocyclylene substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, (C1-C3)alkoxy, (C1-C3)alkyl, (Ci-C3)haloalkyl, or amino),

[0108] In some embodiments, WL2 is selected from,

[0110] In some embodiments, Wi,5 is selected from

[0111] In some embodiments, WL6 is selected from

[0112] In some embodiments, WL? is selected from

[0113] In some embodiments, WLS is selected from

[0114] In some embodiments, WL7 is selected from, and / orWLS is selected from

[0115] In some embodiments, each m, n, o, p, q, and t of the chemical linking moiety (L) is independently selected from the integers 0, 1, or 2.

[0116] In some embodiments, the L comprises at least one moiety selected from:

[0117] In some embodiments, the linker (L) comprises at least one moiety selected from, but not limited to the structures shown below, where a dashed line indicates the attachment point to the PTM or LTM moieties:wherein: WL1and WL2of L are each independently absent or a 4- to 8-membered ring with 0-4 heteroatoms, optionally substituted with RQ, each RQis independently H, halogen, OH, CN, CF3, optionally substituted linear or branched C1-C6alkyl, or optionally substituted linear or branched C1-C6alkoxy, or two RQgroups taken together with the atom to which they are attached to form a 4- to 8-membered ring system containing 0-4 heteroatoms; each YL1of L is independently a bond, C1-C6 alkyl (linear, branched, optionally substituted) in which optionally one or more Catoms are replaced with O; or C1-6 alkoxy (linear, branched, optionally substituted); n is an integer from 0 to 10; andindicates the attachment point to the PTM or the LTM.

[0118] In some embodiments, the linker (L) comprises a structure selected from, but not limited to the structures shown below, where a dashed line indicates the attachment point to the PTM or LTM moi eties:wherein: WL1and WL2of L are each independently absent, aryl, heteroaryl, cyclic, heterocyclyl, (Ci-Cs)alkyl where optionally one or more C atoms are replaced with O or N, (C2-C6) alkenyl where optionally one or more C atoms are replaced with O, (C3-C6)alkynyl where optionally one or more C atoms are replaced with O, bicyclic, biaryl, biheteroaryl, or biheterocyclyl, each optionally substituted with RQ, each RQof WL1or is independently H, halo, OH, CN, CF3, hydroxyl, nitro, C= CH, (C2-Ce)alkenyl, (C3-Ce)alkynyl, optionally substituted linear or branched (C1-C6)alkyl, optionally substituted linear or branched (C1-C6)alkoxy, optionally substituted O(C1-C3)alkyl (e.g., optionally substituted by 1 or more -F), OH, NH2, NRY1RY2, or CN, or two RQgroups together with the atom to which they are attached form a 4- to 8-membered ring system containing 0-4 heteroatoms; each YL1of L is independently a bond, NRYL1, O, S, NRYL2, CRYL1RYL2, C=O, C=S, SO, SO2, C1-C6alkyl (linear, branched, optionally substituted) where optionally one or more C atoms are replaced with O; or (C1-C6)alkoxy (linear, branched, optionally substituted); QLof L is a 3- to 6-membered alicyclic or aromatic ring with 0-4heteroatoms, where the ring is optionally bridged and optionally substituted with 0-6 RQ, each RQof QLis independently H, linear or branched C1-6alkyl optionally substituted by 1 or more halo or C1-6alkoxyl, or 2 RQgroups taken together with the atom to which they are attached form a 3- to 8-membered ring system containing 0-2 heteroatoms; RL1, RYL2of L are each independently H, OH, (C1-C6)alkyl (linear, branched, optionally substituted by 1 or more halo, (Ci-C6)alkoxyl), or two RQtogether with the atom to which they are attached form a 3- to 8- membered ring system containing 0-2 heteroatoms); n is an integer from 0 to 10; andindicates the attachment point to the PTM or the LTM or to another element of the linker.

[0119] In some embodiments, the linker group compriseswherein each m is independently 1 or 2.

[0120] In some embodiments, the linker group is optionally substituted (poly)ethyleneglycol having between 1 and about 100 ethylene glycol units, between about 1 and about 50 ethylene glycol units, between 1 and about 25 ethylene glycol units, between about 1 and 10 ethylene glycol units, between 1 and about 8 ethylene glycol units and 1 and 6 ethylene glycol units, between 2 and 4 ethylene glycol units, or optionally substituted alkyl groups interdispersed with optionally substituted, O, N, S, P or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclyl group. In certain embodiments, the linker may be asymmetric or symmetrical.

[0121] In some embodiments, the linker group may be any suitable moiety as described herein. In some embodiments, the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units.

[0122] In some embodiments, the bifunctional compounds comprises a PTM group, which binds to a target protein or polypeptide (e g., BRD3), which is ubiquitinated by a ubiquitin ligase and is chemically linked directly to the LTM group or through a linker moiety L; and L is a linker moiety as described above which may be present or absent and which chemically(covalently) links LTM to PTM, or an agriculturally acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.

[0123] In some embodiments, the linker group L is a group comprising one or more covalently connected structural units independently selected from:wherein the X of L is selected from the group consisting of O, N, S, S(O) and SO2; n is integerfrom 1 to 5; R1is hydrogen or alkyl, is a mono- or bicyclic aryl or heteroaryl optionally substituted with 1-3 substituents selected from alkyl, halogen, haloalkyl, hydroxy,alkoxy or cyano; is a mono- or bicyclic cycloalkyl or a heterocyclyl optionally substituted with 1-3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy or cyano; and the phenyl ring fragment can be optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano. In some embodiments, the linker group L comprises up to 10 covalently connected structural units, as described above.3. Insect proteins of interest and protein targeting moieties (PTMs)

[0124] Generally, any protein in an insect may be targeted by the compounds, compositions, and methods provided herein. Where the goal is to control insect pests, the target protein is a protein that is essential to the growth, development, reproduction, and / or survival of the target insect pest. Target proteins include proteins required for the insect and / or arachnid to maintain its normal physiological and biochemical functions. Inhibition or degradation of the target protein limits the insect's and / or arachnid’s ability to feed, grow, or survive. Examples of insect and / or arachnid proteins that may targeted by the provided compounds, compositions, and methodsinclude essential proteins, proteins involved in processes such as development, metabolism, or neurotransmission, and proteins that are targets of existing insecticides and / or arachnids. In a preferred embodiment, the target protein functions in pathways required for one or more cellular functions such as transcription, translation, formation of the cytoskeleton, cell-cycle, metabolism (anabolism or catabolism), endocytosis, intracellular and intercellular transport, calcium binding, nucleus import and export, nucleic acid binding, signal peptidase-protein binding, the proteasome, vesicle transport, neuro-transmission, water-balance, ion-balance, splicing, mitosis, meiosis, chromosome organization, stability or integrity, micro RNAs, siRNAs, posttranslational protein modifications, electron transport, apoptosis, membrane integrity, and cell adhesion. Examples of insect and / or arachnid proteins that may be targeted by the provided compounds, compositions, and methods include essential proteins, proteins involved in processes such as development, metabolism, or neurotransmission, and proteins that are targets of existing insecticides.

[0125] In particular, the PTM is a molecule that binds to a BRD3 -containing protein.

[0126] It will be understood that the general structures are exemplary, and the respective moieties can be arranged spatially in any desired order, number, or configuration.

[0127] In further embodiments, the description provides a bifunctional compound having a structure selected from the group consisting of Examples C-l to C-58, a salt, a polymorph, and a prodrug thereof.

[0128] In another aspect, the description provides compositions comprising compounds as described herein, and an agriculturally acceptable carrier. In certain embodiments, the compositions are agricultural compositions comprising an effective amount of a compound as described herein and an agriculturally acceptable carrier. In certain embodiments, the agricultural compositions comprise an additional biologically active agent, e.g., an agent effective for the control of insects.

[0129] In certain embodiments of the compounds as described herein, the BRD3 ligand suitable as the PTM in the present disclosure, can be known BRD3 inhibitors reported in the literature. These ligands are referred to as protein targeting moiety (PTM); and in this case, the targeted protein or proteins are BRD3. The following are some of the representative examples ofPTM. The actual PTM as BRD3 ligands are not limited to these PTM examples. The dotted line in the structure indicates the linker attachment point.

[0130] In certain embodiments, the PTM comprises a tricyclic diazepine or tricyclic azepine BRD3 ligand with the general structure PTM-a, where the dashed lines indicate the linker connection trajectory and three sites are defined to attach linkers.wherein:A and B are independently an aromatic ring, a heteroaromatic ring, a 5-membered carbocyclic, a 6-membered carbocyclic, a 5-membered heterocyclic, a 6-membered heterocyclic, a thiophene, a pyrrole, a pyrazole, a pyridine, a pyrimidine, a pyrazine, optionally substituted by alkyl, alkoxy, halogen, nitrile or another aromatic or heteroaromatic ring, where A is fused to the central azepine (Yi=C) or diazepine (Yi=N) moiety;Yi, Y2, and Y3, of PTM-a, are each independently selected from carbon, nitrogen or oxygen for to form a fused 5-membered aromatic ring as triazole or isoxazole; andZi is methyl, or C1-C6alkyl group.

[0131] The fragment of PTM-a as BRD3 ligand is described in the literature (e.g., in International Patent Application Publication Nos. WO 2016 / 069578; WO 2014 / 001356; WO 2016 / 050821; WO 2015 / 195863; WO 2014 / 128111).

[0132] In some embodiments comprising the structure UTM-L-PTM-a, PTM-a can be represented by the following general structures PTM-aa through PTM-ai, where a dashed line indicates a linker connection point. In structures PTM-aa through PTM-ai, the substitution pattern of X and Y can be mono- or bis-substitution.

[0133] In some embodiments, the PTM is PTM-aa.

[0134] In some embodiments, the structures PTM-al through PTM-a36 are representatives of PTM-a as the BRD3 ligand. The dashed line indicates the connection point between the BRD3 ligand and the linkers. These are examples only and do not limit the ligand that can be used in the bifunctional degraders useful to degrade BRD3.

[0135] In some embodiments, the PTM is PTM-al .

[0136] In some embodiments, the PTM comprises a carbazole derived BRD3 ligand with the general structure described as PTM-b. The fragment of PTM-b as BRD3 ligand is described in the literature (US 2016 / 0176864).PTM-b wherein:R’ is a H, halogen, CN, C1-C6alkyl, fluorine substituted C1-C6alkyl, carboxylic acid, carboxamide, reverse amide, sulfonamide, hydroxyl alkyl, substituted hydroxyl alkyl, OH, alkoxy, or fluorine substituted alkoxy;R” is H, halogen, CN, C1-C6alkyl, fluorine substituted C1-C6alkyl, carboxylic acid, carboxamide, reverse amide, sulfonamide, hydroxyl alkyl, substituted hydroxyl alkyl, OH, alkoxy, or fluorine substituted alkoxy;R”’ is H, CN, halogen, C1-C6alkyl, or fluorine substituted C1-C6alkyl;Y4 and Ys are independently selected from H, C1-C6alkyl, C1-C6alkyl substituted with cycloalkyl, C1-C6alkyl substituted with aryl, C1-C6alkyl substituted with heterocycle, C1-C6alkyl substituted with heteroaryl, aryl, and heteroaryl;Ye is selected from H, alkoxy, C1-C6alkyl, substituted C1-C6alkyl, heterocyclic alkyl, cyclic alkyl, carboxamide, sulfonamide, and carbamate.

[0137] In some embodiments, the PTM comprises a BRD3 ligand with the general structure of PTM-b.wherein:M of PTM-b is an optionally substituted heterocyclyl or heteroaryl, wherein the substituents are one or more R; wherein,R of PTM-b is independently one or more hydrogen, CD3, halogen, haloalkyl, hydroxyalkyl, CN, CF3, CH2F, CHF2, optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, optionally substituted (C3-C6)cycloalkyl, optionally substituted heterocyclo, -OR4, -CONR3R4, - NR3R4, NR3R4(C1-C6)alkyl-, -NR6OCOR3, -NR6COR3, NR6COR3(C1-C6)alkyl-, -NR6CO2R3,NR6CO2R3(C1-C6)alkyl-,-NR6CONR3R4, -SO2NR3R4, SO2(C1-C6)alkyl-, -NR6SO2NR3R4, - NR6SO2R4, or NR6SO2R4(C1-C6)alkyl-;Y4and Y?of PTM-b are independently selected from hydrogen, optionally substituted (Ci- Ce)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;Y6of PTM-b is hydrogen, halogen, -OH, alkyl, substituted alkyl, cyclic alkyl, heterocyclic alkyl, (C1-C6) alkyl, (C1-C6) alkoxy, -NR3R4, -CONR3R4, -OCONR3R4, -NR6OCOR3, -NR6CONR3R4, -NR6SO2NR3R4, or -NR6SO2R4;R’ of PTM-b is, independently at each occurrence, one or more hydrogen, halogen, -CN, -OR4, - NR3R4, -CONR3R4, -COOH, -OCONR3R4, -NR6OCOR3, -NR6CONR3R4, -NR6SO2NR3R4, - NR6SO2R4, optionally substituted (C1-C6)alkyl, optionally substituted, (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C1-C6)alkoxy, optionally substituted (C3- Cs)cycloalkyl, optionally substituted (C3-C8)cycloalkyl (Ci-C6)alkyl, optionally substituted (C3- Cs)cycloalkyl-CO-, optionally substituted (C3-C8)cycloalkyl-SO2-, optionally substituted aryl (C1-C6)alkoxy, optionally substituted (C3-C8)cycloalkyl (Ci-C6)alkoxy, optionally substituted heterocyclyl-CO-, optionally substituted heterocyclyl, optionally substituted (Ci-C6)alkyl-SO2-, -NR6SO2-, optionally substituted (C1-C6)alkyl, - NR6SO2-optionally substituted heterocyclo, optionally substituted (C1-C6)alkyl-NR6SO2-, or optionally substituted heterocyclo-NR6SO2-;R” of PTM-b is hydrogen, halogen, -CN, OH, -CONR3R4, -NR6COOR4, -NR6CONR3R4, NR6COR4, -NR6SO2R3, -SO2NR3R4, -NR6SO2NR3R4, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted aryl, optionally substituted (C1-C6)alkyl-SO2-, optionally substituted aryl-SO2, optionally substituted heteroaryl, or optionally substituted heterocyclyl;R3of PTM-b is hydrogen, optionally substituted (C1-C6)alkyl, optionally substituted (C3- C8)cycloalkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, cyano(C1-C6)alkyl, hydroxy(C1-C6)alkyl, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, optionally substituted aryloxy(C1-C6)alkyl, optionally substituted (C1-C6)alkyl- SO2-, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C1-C6)alkyl, optionally substituted heteroaryl, or optionally substituted heteroaryl(Ci-C6)alkyl,R4of PTM-b is hydrogen, optionally substituted (Ci-C6)alkyl, or optionally substituted (C3- Cs)cycloalkyl; or R3and R4of PTM-b may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C4-Cs) heteroaryl, or (C4-Cs) heterocyclic ring;R5of PTM-b is hydrogen, optionally substituted (C1-C6)alkyl, optionally substituted (C3- Cs)cycloalkyl, optionally substituted (C2-Ce)alkenyl, optionally substituted (C2-Ce)alkynyl, cyano(C1-C6)alkyl, hydroxy(C1-C6)alkyl, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, optionally substituted aryloxy(C1-C6)alkyl, optionally substituted (C1-C6)alkyl- SO2-, optionally substituted heterocyclyl, optionally substituted heterocyclyl(Ci-C6)alkyl, optionally substituted heteroaryl, or optionally substituted heteroaryl(C1-C6)alkyl;R6of PTM-b is hydrogen or optionally substituted (C1-C6)alkyl;R’” of PTM-b is hydrogen, optionally substituted (C1-C6)alkyl, -OR4, CN or halogen; and / or an agriculturally acceptable salt, tautomer, or stereoisomer thereof.

[0138] In some embodiments, the PTM comprises a BRD3 ligand with the general structure of PTM-ba, PTM-bb, PTM-bc, PTM-bd, PTM-be, or PTM-bf. The dashed line indicates the site of linker attachment. These are examples only and do not limit the ligand that can be used to degrade BRD3.wherein:Y7is CH3 or CD3;Ys is selected from hydrogen, CH3, CD3, CF3;R is independently selected from H, halogen, or C1-C6 alkyl groups, wherein R can be mono-, bis- or tri-substituted; andY9is selected from H, C1-C6alkyl, cycloalkyl, or heterocycle.

[0139] In some embodiments, Y9 is tetrahydropyran, cyclobutane, methyl, alkoxy, tetrahydrofuran, or oxetane.

[0140] In some embodiments, the PTM comprises a carbazole derived BRD3 ligand with the general structure PTM-c. The fragment of PTM-c as BRD3 ligand is described in the literature (US 2014 / 0256700).PTM-c wherein:M of PTM-c is a heterocyclic aromatic group, preferably a 5-membered heteroaromatic, more preferably isoxazole or triazole, optionally substituted with halogen, C1-C6alkyl, fluorinated Ci- Ce alkyl, or CN;R’ and R” of PTM-c are independently hydrogen, halogen, CN, C1-C6alkyl, fluorine substituted C1-C6 alkyl, carboxylic acid, carboxamide, reverse amide, sulfonamide, hydroxyl alkyl, substituted hydroxyl alkyl, OH, alkoxy, or fluorine substituted alkoxy;Y4 and Y5 of PTM-c are independently selected from H, C1-C6alkyl, C1-C6alkyl substituted with cycloalkyl, C1-C6alkyl substituted with aryl, C1-C6alkyl substituted with heterocycle, C1-C6 alkyl substituted with heteroaryl, aryl, heteroaryl; andYg of PTM-C is selected from H, alkyl, substituted alkyl, cyclic alkyl, heterocyclic alkyl, alkoxy, C1-C6alkyl, carboxamide, sulfonamide, carbamate.

[0141] In some embodiments the PTM comprises a BRD3 ligand with the general structure PTM-ca, PTM-cb, or PTM-cd. The dashed line indicates the site of linker attachment. These are examples only and do not limit the ligand that can be used to degrade BRD3.whereinY7is CH3or CD3;Ys is selected from H, CH3, CD3, and CF3R is independently selected from H, halogen, and C1-C6alkyl groups, wherein R can be mono-, bis- or tri-substituted;Y9 is selected from H, C1-C6alkyl, cycloalkyl and heterocycle.

[0142] In some embodiments, Y9 is tetrahydropyran, cyclobutane, methyl, alkoxy, tetrahydrofuran, or oxetane.

[0143] In some embodiments, the PTM comprises pyrrol opyri done chemotype BRD3 ligand with the general structure of PTM-da, PTM-db, or PTM-dc. The dashed line indicates the site of linker attachment. These are examples only and do not limit the ligand that can be used to degrade BRD3. The fragments of these ligands are described in the literature (US 2015 / 0148342).wherein:Ra, Rb and Rc of PTM-da, PTM-db, and PTM-dc are each independently selected from H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, ORa3, C(O)Rb3, C(O)NRc3Rd3,wherein said C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO2, ORa3, SR33C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Ra3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3) NRc3Rd3, NRe3Rd3, NRc3C(O)Rb3, NRc3C(O)ORe3, NRC3C (O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3, and wherein said phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each independently substituted by 1, 2, or 3 substituents independently selected from halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, CN, NO2, ORa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3,Ra3, Rb3, Rc3, Rd3and Re3of PTM-da, PTM-db, and PTM-dc are independently selected from H, C1-C6alkyl, C1-C4 haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-C10aryl-C1-C6alkyl, C3-C10cycloalky-C1-C6alkyl, (5-10 membered heteroaryl)-Ci-C6 alkyl, and (4-10 membered heterocycloalkyl)-Ci-C6 alkyl, wherein said C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C6-C10aryl, C3-C10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C6alkyl, C3-C10cycloalky-C1-C6alkyl, (5-10 membered heteroaryl)-C1-C6alkyl, and (4- 10 membered heterocycloalkyl)-Ci-C6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, halo, CN, OR's, SR's,Rb5, Rc5, and Rd5of PTM-da, PTM-db, and PTM-dc are independently selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, and C2-C4 alkynyl, optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylamino, di(Ci-C4 alkyl) amino, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0144] In some embodiments, the PTM comprises tetrahydroquinoline chemotype BRD3 ligand with the general structure of PTM-e. The fragments of these ligands are described in the literature (WO 2015 / 074064).wherein:R of PTM-e is hydrogen or C1-C6alkyl; (CH2)Ra, (CH2)ORa, C(O)Ra, C(O)ORa, C(O)NRaRb, S(O)2Ra, S(O)2N RaRb, C1-C6haloalkyl, C1-C6haloalkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo; andRaand Rbof PTM-e have the meaning as defined above with respect to PTM-da, PTM-db, and PTM-dc.

[0145] In some embodiments, the PTM comprises a triazol opyrazine chemotype BRD3 ligand with the general structure of PTM-fa or PTM-fb. The fragments of these ligands are described in the literature (WO / 2015 / 067770).wherein:R of PTM-fa and PTM-fb is selected from halogen, CN, NH2, -O-C1-C3 alkyl, N(CI-C3 alkyl)?, C(0)N(CI-C3 alkyl)2, a C1-C5 alkyl wherein, C1-C5 alkyl is optionally substituted with one or more groups selected from halogen or CN, a 4-7 membered heterocycloalkyl, wherein the heterocycloalkyl group can be optionally substituted with one or more C1-C3 alkyl, and a C3-C6 cycloalkyl wherein the cycloalkyl group can be optionally substituted with one or more groups independently selected from C1-C3 alkyl, C1-C3 haloalkyl and halogen.

[0146] In some embodiments, the PTM comprises a pyridone type of chemotype BRD3 ligand with the general structure of PTM-g. The fragments of these ligands are described in the literature (WO 2015 / 022332).wherein:R of PTM-g is selected from H, halogen, NH2, C1-C3 alkyl, C3-C6 cycloalkyl, SO2N(CI-C3 alky 1)2 and 5-6 membered heterocycloalkyl, where heterocycloalkyl can be optionally substituted with one or more groups independently selected from =0, C1-C3 alkyl, and C1-C5haloalkyl; and the cycloalkyl group can be optionally and independently substituted with one or more groups independently selected from C1-C3 alkyl, C1-C3 haloalkyl, and halogen.

[0147] In some embodiments, the PTM comprises a quinazolinone chemotype BRD3 ligand with the general structure of PTM-h. The fragments of these ligands are described in the literature (WO 2015 / 015318).PTM-h wherein:R of PTM-h is selected from amino, 5- and 6-membered carbocycles and heterocycles.

[0148] In certain embodiments, the PTM comprises a dihydropyridopyrazinone chemotype BRD3 ligand with the general structure of PTM-i. The fragments of these ligands are described in the literature (WO 2015 / 011084).PTM-i

[0149] In some embodiments, the PTM comprises tetracyclic BRD3 ligand with the general structure of PTM-h. The fragment of PTM-j as BRD3 ligand is described in the literature (WO 2014 / 139324).wherein:Y1is N or CH;R1is CD3, C1-C3 alkyl, or C1-C3 haloalkyl;R2is H or C1-C3 alkyl;Y3is N or CR3;R3is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6haloalkyl, -CN, -C(O)R3a, - C(O)OR34, -C(O)NR3bR3c, -S(O)R3d, -S(O)2R3a, -S(O)2NR3bR3c, or G1; wherein the C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G1, -CN, -C(O)R3a, -C(O)OR3a, - C(O)NR3bR3c, -C(O)N(R3b)NR3bR3c, -S(O)R3d, -S(O)2R34, -S(O)2NR3bR3c:, -OR3a, -0C(0)R3d, - NR3bR3c, N(R3b)C(O)R3d, N(R3b)SO2R3d, N(R3b)C(O)OR3d, N(R3b)C(O)NR3bR3c, N(R3b)SO2NR3bR3c, and N(R3b)C(NR3bR3c)=NR3bR3c;Y2is C(O), S(O)2, or CR4R3;R4is H, C1-C6alkyl, halogen, or C1-C6haloalkyl;R5is H, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6haloalkyl, -C(O)R5a, - C(O)OR5a, -C(O)NR5bR5c, -S(O)R5d, -S(O)2R5a, -S(O)2NR5bR5c, or G1; wherein the C1-C6alkyl, C1-C6 alkenyl, and C2-C6alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G1, -CN, -C(O)R5a, -C(O)OR5a- O(O)NR5bR5c, C(O)N(R5b)NR5bR5c, -S(O)R5d, -S(O)2R5a, -S(O)2NR5bR5c, -OR5a-OC(O)R5d, -R3a, R3b, R3C, R5aand R5b, at each occurence, are each independently H, C1-C6alkyl, C2-C6 alkenyl, C2-C6alkynyl, C1-C6haloalkyl, G1, or -(C1-C6alkylenyl -G1;R5C, at each occurrence, is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, G1, -(C1-C6alkylenyl -G1, -(C1-C6alkylenyI)-CN, -(C1-C6alkylenyl)-ORa, or -(C1-C6alkylenyl)-C(O)ORa;R3d, at each occurrence, is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl,1lR5d, at each occurrence, is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, G1, -(C1-C6alkylenyl -G1, -(C1-C6alkylenyl)-NRcRd, or -(C1-C6alkylenyl)- N(Ra)C(O)O(Rb);G1, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G1is optionally substituted with 1, 2, 3, 4, or 5 Rlegroups;R6is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6haloalkyl, -C(O)R6a, - C(O)OR6a, -C(O)NR6bR6c, -S(O)2R6a, -S(O)2NR6bR6c, or G2; wherein the C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of G2, -CN, -C(O)R6a, -C(0)0R6a,R6a, R6b, and R6c, at each occurrence, are each independently H, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl haloalkyl, G2, -(C1-C6alkylenyl)-G2, -(C1-C6alkylenyl)-ORa, -(C1-C6alkylenyl)- S(O)2Rb, -(C1-C6alkylenyl)-S(O)2NRcRd, -(C1-C6alkylenyl)-C(O)Ra, -(C1-C6alkylenyl)- C(O)ORa-(C1-C6alkylenyl)-C(O)NRcRd, -(C1-C6alkylenyl)-NRcRd, -(C1-C6alkylenyl)- N(Ra)C(O)Rb, -(C1-C6alkylenyl)-NCRc)S(O)2Rb, -(C1-C6alkylenyl)-N(Rc)C(O)O(Rb), -(C1-C6alkylenyl)-N(Rc)C(O)NRcRd, -(C1-C6alkylenyl)-N(Rc)S(O)2NRcRd, or the point of linker attachment;R6d, at each occurrence, is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloalkyl. G2, -(C1-C6alkylenyO-G1, -(C1-C6alkylenyl)-ORa, -(C1-C6alkylenyl)-S(O)2Ra, -(C1-C6alkylenyl)-S(O)2NRcRd, -(C1-C6alkylenyl)-C(O)Ra, -(C1-C6alkylenyl)-C(O)ORa, -(C1-C6alkylenyl)-C(O)NRcRd, -(C1-C6alkylenyl)-NRcRd, -(C1-C6alkylenyl)-N(Rc)C(O)Rb, -(C1-C6alkylenyl)-N(Rc)S(O)2Rb, -(C1-C6alkylenyl)-N(Rc)C(O)O(Rb), -(C1-C6alkylenyl)- N(Rc)C(O)NRcRd, or -(C1-C6alkylenyl)-N(Rc)S(O)2NRcRd;G2, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G is optionally substituted with 1, 2, 3, 4, or 5 R2ggroups; A1is C(R7) or N; A2is C(R8) or N; A3is C(R9) or N; and A4is C(R10) or N; or wherein zero, one, or two of A1, A2, A3, and A4are N;R7, R8, and R9, are each independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6 haloalkyl, -CN, NO2, -ORrl, -OC(O)Rr2, -OC(O)NRr3Rr4, -SRrl, -S(O)2Rrl, -S(O)2NR13Rr4, -C(O)Rrl, -C(O)ORrl, -C(O)NRr3R14, -NRr3Rr4, -N(Rr3)C(O)Rr4, -N(Rr3)S(O)2Rr2, - N(Rr3)C(O)O(Rr2), -N(Rr3)C(O)NRr3Rr4, -N(Rr3)S(O)2NRr3Rr4, G3, -(C1-C6alkylenyl)-CN, -(Ci- Ce alkylenyl)-ORrl, -(C1-C6alkylenyl)-OC(O)Rr2, -(C1-C6alkylenyl)-OC(O)NRr3Rr4, -(C1-C6alkylenyl)-S(O)2Rrl, -(C1-C6alkylenyl)-S(O)2NRr3Rr4, -(C1-C6alkylenyl)-C(O)Rrl, -(C1-C6alkylenyl)-C(O)ORri, -(C1-C6alkylenyl)-C(O)NRr3Rr4, -(C1-C6alkylenyl)-NRr3Rr4, -(C1-C6alkylenyl)-N(Rr3)C(O)Rr2, -(C1-C6alkylenyl)-N(Rr3)S(O)2Rr2, -(C1-C6alkylenyl)- N(Rr3)C(O)O(Rr2), -(C1-C6 alkylenyl)-N(Rr3)C(O)NRr3Rr4, -(C1-C6alkylenyl)- N(Rr3)S(O)2NRr3Rr4, -(C1-C6 alkylenyl)-CN, or -(C1-C6alkylenyl)-G3;Rrl, R13, and Rr4, at each occurrence, are each independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, G3, -(C1-C6alkylenyl)-G3, -(C1-C6alkylenyl)-ORa-(C1-C6alkylenyl)- S(O)2Ra, -(C1-C6 alkylenyl)-S(O)2NRcRd, -(C1-C6alkylenyl)-C(O)Ra, -(C1-C6alkylenyl)- C(O)ORa, -(C1-C6alkylenyl)-C(O)NRcRd, -(C1-C6alkylenyl)-NRcRd, -(C1-C6alkylenyl)- N(Rc)C(O)Rb, -(C1-C6 alkylenyl)-N(Rc)S(O)2Rb, -(C1-C6alkylenyl)-N(Rc)C(O)O(Rb), -(C1-C6alkylenyl)-N(Rc)C(O)NRcRd, or -(C1-C6alkyl enyl)-N(Rc)S(O)2NRcRd;Rr2, at each occurrence, is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl C1-C6haloalkyl, G3, -(C1-C6alkylenyl)-G3, -(C1-C6alkylenyl)-ORa, -(C1-C6alkylenyl)- S(O)2Ra, -(Cl- C6 alkylenyl)-S(O)2NRcRd, -(C1-C6alkylenyl)-C(O)Ra, -(C1-C6alkyl enyl)-C(O)ORa-(C1-C6alkylenyl)-C(O)NRcRd, -(C1-C6alkylenyl)-NRcRd, -(C1-C6alkylenyl)-N(Rc)C(O)Rb, -(C1-C6alkylenyl)-N(Rc)S(O)2Rb, -(C1-C6alkylenyl)-N(Rc)C(O)O(Rb), -(C1-C6alkylenyl)- N(Rc)C(O)NRcRd, or -(C1-C6alkylenyl)-N(Rc)S(O)2NRcRd;G3, at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; and each G3 group is optionally substituted with 1, 2, 3, 4, or 5 R4agroups;R10is H, C1-C3 alkyl, halogen, C1-C3 haloalkyl, or -CN;Rlg, R2g, and R4g, at each occurrence, is independently selected from the group consisting of oxo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6haloalkyl, -CN, NO2, G2a-ORa, - OC(O)Rb, -OC(O)NRcRd, -SRa, -S(O)2Ra, -S(O)2NReRd, -C(O)Ra, -C(O)ORa, -C(O)NRcRd- NRcRd, -N(Rc)C(O)Rb, -N(Rc)S(O)2Rb, -N(Rc)C(O)O(Rb), -N(Rc)C(O)NRcRd, - N(Rc)S(O)2NRcRd, -(C1-C6 alkylenyl)-CN, -(C1-C6alkylenyl)-G2a, -(C1-C6alkylenyl)-ORa, -(Ci- Ce alkylenyl)-OC(O)Rb, -(C1-C6alkylenyl)-OC(O)NRcRd, -(C1-C6alkylenyl)-S(O)2Ra, -(C1-C6alkylenyl)-S(O)2NRcRd, -(C1-C6alkylenyl)-C(O)Ra, -(C1-C6alkylenyl)-C(O)ORa-(C1-C6alkylenyl)-C(O)NRcRd, -(C1-C6alkylenyl)-NRcRd, -(C1-C6alkylenyl)-N(Rc)C(O)Rb, -(C1-C6alkylenyl)-N(Rc)S(O)2Rb, -(C1-C6 alkylenyl)-N(Rc)C(O)O(Rb), -(C1-C6alkylenyl)- N(Rc)C(O)NRcRd, -(C1-C6alkylenyl)-N(Rc)S(O)2NRcRd, or -(C1-C6alkylenyl)-CN;Ra, Re, Rd, and Re, at each occurrence, are each independently H, C1-C6 alkyl, C2-C6 alkenyl C2- C6 alkynyl, C1-C6haloalkyl G2a, -(C1-C6alkylenyl)-ORrl, -(C1-C6alkylenyl)-NRr3Rr4, -(C1-C6alkylenyl)-C(O)NRr3Rr4, or -(C1-C6alkyl enyl)-G2a;Rb, at each occurrence, is independently C1-C6 alkyl, C2-C6alkenyl. C2-C6alkynyl, C1-C6haloalkyl, G2a, or -(C1-C6alkylenyl)-G2a;G2aat each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each G2agroup is optionally substituted with 1, 2, 3, 4, or 5 R3ggroups;R3g, at each occurrence, is independently oxo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6haloalkyl, -CN, NO2, -ORS1, -OC(O)Rs2, -OC(O)NRs3Rs4, -SRS1, -S(O)2RS1, - S(O)2NRS3RS4, -C(O)RS2, -C(O)ORS2, -C(O)NRS3RS4, -NRS3RS4, -N(RS3)C(O)RS2, - N(RS3)S(O)2RS2,-N(RS3)C(O)O(RS1), -N(RS3)C(O)NRS3RS4, -N(RS3)S(O)2NRS3RS4, -(C1-C6 alkylenyl)-ORsl, -(C1-C6alkylenyl)-OC(O)Rs2, -(C1-C6alkylenyl)-OC(O)NRs3Rs4,-(C1-C3alkylenyl)-S(O)2Rsl, -(C1-C6alkylenyl)-S(O)2NRs3Rs4, -(C1-C6alkylenyl)-C(O)Rsl, -(C1-C6alkylenyl)-C(O)ORsl, -(C1-C6alkylenyl)-C(O)NRs3Rs4, -(C1-C6) alkylenyl)-NRs3Rs4, -(C1-C6alkylenyl)-N(Rs3)C(O)Rs2, -(C1-C6) alkylenyl)-N(Rs3)S(O)2Rs2, -(C1-C6alkylenyl)-N(RS3)C(O)O(RS2), -(CI-C6alkylenyl)-N(Rs3)C(O)NRs3Rs4, -(C1-C6alkylenyl)- N(RS3)S(O)2NRS3RS4, or -(C1-C6alkylenyl)-CN;Rsl, Rs3, and Rs4, at each occurrence, are each independently H, C1-C6alkyl, C2-C6alkenyl, C2- Ce alkynyl, or C1-C6haloalkyl; andRs2, at each occurrence, is independently C1-C6alkyl, C1-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl.

[0150] In some embodiments, the PTM is PTM-j having the formula PTM-ja:

[0151] In some embodiments, the PTM comprises tetrahydroquinoline chemotype BRD3 ligand with the general structure of PTM-k. The fragments of these ligands are described in the literature (WO 2011 / 054848).wherein:A represents a bond or C1-C4alkyl;X represents: i) a 6 to 10 membered aromatic group, or ii) a 5 to 10 membered heteroaromatic comprising 1, 2, or 3 heteroatoms selected from O, N and S;R1represents: i) phenyl optionally substituted by 1 or 2 substituents independently selected from halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, SO2C1-C6alkyl, and -COR7, ii) a 5 to 10 membered heteroaromatic comprising 1, 2, or 3 heteroatoms selected from the group consisting of O, N and S optionally substituted by 1 or 2 substituents independently selected from halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and -COR7, or iii) cyclohexyl;R2represents C1-C6alkyl;R3represents C1-C6alkyl;R4represents: i) H, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6hydroxyalkyl, SO2C1-C6alkyl, -C(O)NR8R9, C(O)R10, - C0-C6alkyl -NR1 XR12, or ii) -Om C0-C6alkyl substituted by a 5 or 6 membered heterocyclyl or heteroaromatic each comprising 1, 2, 3, or 4 heteroatoms independently selected from N, O and S and wherein said heterocyclyl or heteroaromatic is optionally substituted by 1, 2, or 3 groups independently selected from halogen, cyano, C1-C6alkyl, C1-C6haloalkyl and C1-C6alkoxy, wherein when the heterocyclyl or heteroatomic is linked through a heteroatom and m is 1, then the heteroatom and O are not directly linked if the resultant arrangement would be unstable;R4arepresents H, halogen C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6hydroxyalkyl;R5represents H, halogen, - C1-C6alkyl, or - C1-C6alkoxy;R6represents H, - C1-C6alkyl, - Co-Ce alkylcyano, - Co-Ce alkyl C1-C6alkoxy, or C0-C2 alkylCOR7;R7represents hydroxyl, C1-C6alkoxy, -NH2, -NH C1-C6alkyl, or N(C1-C6alkyl)2;R8and R9independently represent: i) H, C1-C6alkyl, - Co-Ce alkylphenyl, - Co-Ce alkylheteroaromatic, C3-C6 cycloalkyl, or ii) R8and R9together with the N to which they are attached form a 5 or 6 membered heterocyclyl or heteroaromatic wherein said heterocyclyl or heteroaromatic may comprise 1, 2, or 3 further heteroatoms independently selected from O, N and S;R10represents hydroxyl, C1-C6alkoxy or a 5 or 6 membered heterocyclyl or heteroaromatic comprising 1, 2, 3, or 4 heteroatoms selected from O, N and S;R11and R12independently represent: i) H, C1-C6alkyl; or ii) R11and R12together with the N to which they are attached form a 5 or 6 membered heterocyclyl or heteroaromatic wherein said heterocyclyl or heteroaromatic may comprise 1, 2, or 3 further heteroatoms independently selected from O, N and S; and m represents 0 or 1.

[0152] In some embodiments, the PTM is PTM-k having the formula PTM-ka:

[0153] Suitable BRD3 PTMs include those known in the art and described in, for example, Doroshow et al, Annals of Oncology, 2017, 28, 1776-1787; Perez-Salviaa and Esteller Epigenetics, 2017, 12, 323-339; Klein, RMD Open, 2018, 4:e000744; Ocana et al, Oncotarget, 2017, 8, 71285-71291; Hogg et al, Blood, 2017, 130, 2537; International Patent Application Publications WO 2009 / 084693, WO 2011 / 054843, WO 2014 / 193951 (counterpart to U.S. Patent Application No. 2016 / 0095867), WO 2015 / 022332, WO 2015 / 058160, WO 2016 / 146755 (counterpart to U.S. Patent Application No. 2018 / 0117165), WO 2016 / 197032, WO 2017 / 030814, WO 2017 / 180417, and WO 2018 / 081475; US Patent Application Publication Nos. 2016 / 0095867 and 2018 / 0117165; and Japanese Patent Application Publication No. JP2008- 156311.

[0154] In some embodiments, the BRD3 binders, i.e., PTMs, include those selected from, but not limited to, olinone (CAS No. 1770789-37-1), JQ1 (CAS No. 1268524-70-4), Apabetalone / RVX-208 / RVX000222 (CAS No. 1044870-39-4), PF-1 (1403764-72-6), Mivebresib / ABBV-075 (CAS No. 1445993-26-9), BAY1238097 (CAS No. 1564268-08-1), BI 894999 (CAS No. 1660117-38-3), BMS-986158 (CAS No. 1800340-40-2), CPI-0610 (CAS No. 1380087-89-7), FT-1101 (CAS No. 1776060-36-6), Al obresib / GS-5829 (CAS No. 1637771-14- 2), I-BET151 (CAS No. 1300031-49-5), INCB054329 (CAS No. 1628607-64-6), Birabresib / OTX015 / MK-8628 (CAS No. 202590-98-5), PLX51107 (CAS No. 1627929-55-8), RG6870810 / TEN-010 / RG6146 / JQ-35 (CAS No. 1349719-98-7), ZEN-3694 (CAS No. 1643947- 30-1), CPI203 (CAS No. 1446144-04-2), ReMS436 (Cas No. 1395084-25-9), RVX2135 (CAS No. 1253733-17-3), BAY-299 (CAS No. 2080306-23-4), GSK 1324726 A / I-BET726 (CAS No. 1300031-52-0), Molibresib / I-BET762 / GSK525762 (CAS No. 1260907-17-2), RVX297 (CAS No. 1044871-04-6), SF1126 (CAS No. 936487-67-1), INCB054329 (CAS No. 1628607-64-6), INCB057643 (CAS No. 1820889-23-3), LY294002 (CAS No. 154447-36-6), AZD5153 (CAS No. 1869912-40-2), MT-1 (CAS No. 2060573-82-0), and MS645 (CAS No. 2250091-96-2) and analogues and derivatives thereof. Such compounds, or their agriculturally acceptable salts, may be useful in the present invention.C. SYNTHETIC METHODS

[0155] Compounds of the present disclosure may be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readilyprepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations may be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5.sup.th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts. P.G.M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to an agriculturally acceptable salt, ester, or prodrug thereof. Suitable synthetic routes are depicted in the schemes herein.

[0156] Those skilled in the art will recognize if a stereocenter exists in the compounds disclosed herein. Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley- Interscience, 1994).

[0157] The compounds of the present disclosure may be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present disclosure may be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those methods described herein.

[0158] Non-limiting examples of protecting groups (e.g., TV-terminal protecting groups) that may be employed for synthesis of the compounds provided herein include Fmoc, Boc, allyloxycarbonyl (Alloc), benzyloxycarbonyl (Z), and photolabile protecting groups. Sidechain protecting groups include, but are not limited to, Fmoc; Boc; cyclohexyloxycarbonyl (Hoc); allyloxycarbonyl (Alloc); mesityl-2-sulfonyl (Mts); 4-(N-methylamino)butanoyl (Nmbu); 2,4- dimethylpent-3-yl oxy carbonyl (Doc); l-(4,4-dimethyl-2,6-dioxocyclohex-l-ylidene)-3-ethyl (Dde); l-(4,4-dimethyl-2,6-dioxocyclohex-l-ylidene)-3 -methylbutyl (ivDde); 4-methyltrityl (Mtt). Additional protecting groups and methods for their addition and removal from peptides are described, for example, by Isidro-Llobet et al. Chem. Rev. 2009, 19: 2455-2504.

[0159] A base may be used to activate or complete the activation of amino acids prior to exposing the amino acids to reaction partners. Any suitable base may be used. In certain embodiments, the base is a Lewis base. In some embodiments, the base is a non-nucleophilic base, such as triisopropylethylamine, N,N-diisopropylethylamine, certain tertiary amines, or collidine, that are non-reactive to or react slowly with protected peptides to remove protecting groups. In general, the base has a sufficient pKa to allow for deprotonation of the amino acid carboxylic acid.

[0160] A coupling agent may be used to form a bond with the carboxylate moiety of an amino acid to facilitate the coupling reaction and the formation of an amide bond. The coupling agent may be used to form activated amino acids before combination with a coupling partner (e g., an amine) to produce the peptide product. Any suitable coupling agent may be used. In some embodiments, the coupling agent is a carbodiimide, a guanidinium salt, a phosphonium salt, or a uronium salt. Examples of carbodiimides include, but are not limited to, N,N'- dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and the like. Examples of phosphonium salts include, but are not limited to, (benzotriazol-1- yloxy)tripyrrolidino-phosphonium hexafluorophosphate (PyBOP); bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP); and the like. Examples of guanidinium / uronium salts include, but are not limited to, O-(benzotriazol-l-yl)- N,N,N',N'- tetramethyluronium hexafluorophosphate (HBTU); 2-(7-aza-lH-benzotriazole-l- yl)-l, 1,3,3 - tetramethyluronium hexafluorophosphate (HATU); l-[(l-(cyano-2-ethoxy-2- oxoethylideneaminooxy) dimethylaminomorpholino)] uronium hexafluorophosphate (COMU);and the like. Other coupling agents such as propan ephosphonic acid anhydride (T3P) may also be used.

[0161] While peptide bond formation may be conducted with a carboxylic acid (e.g., RC(O)OH), a base, and a coupling agent as described above, activated acid derivatives (e g., RC(O)X, wherein X is a leaving group) may also be employed. Activated acid derivatives include, but are not limited to, anhydrides (including symmetric, mixed, or cyclic anhydrides), activated esters (e.g., p-nitrophenyl esters, pentafluorophenyl esters, N-succinimidyl esters, and the like), acylazoles (e.g., acylimidazoles, prepared using carbonyl diimidazole, and the like), acyl azides, and acid halides (e.g., acid chlorides).

[0162] In some instances, it may be advantageous to prepare particular products, or peptidic portions of such products, via solid-phase peptide synthesis. Non-limiting examples of support materials for solid-phase peptide synthesis include polystyrene (e.g., microporous polystyrene resin, mesoporous polystyrene resin, macroporous polystyrene resin; including commercially available Wang resins, Rink amide resins, and trityl resins), glass, polysaccharides (e.g., cellulose, agarose), polyacrylamide resins, polyethylene glycol, or copolymer resins (e.g., comprising polyethylene glycol, polystyrene, etc.). The solid support may have any suitable form factor. For example, the solid support may be in the form of beads, particles, fibers, or in any other suitable form factor.D. APPLICATIONS IN INSECTS AND INSECT CELLS

[0163] In another aspect, the disclosure provides methods for controlling a level of a target protein that is expressed in an insect cell. The target protein, according to the present disclosure, is a BRD3 protein present in an insect or insect cell. The methods generally include contacting the insect cell with an effective amount of any of the bifunctional compounds, e.g., PROTAC compound, described herein. For example, the bifunctional compound can have one or more protein targeting moieties covalently bonded via a linker to one or more ligase targeting moieties, where the ligase targeting moieties can have the chemical structure of any of the formulas provided herein. In some embodiments, the ligase targeting moiety has a structure according to any one of the formulas described in Section B.l, the linker is any of those described in Section B.2, and / or the protein targeting moiety is any of those described in SectionB.3. Tn some embodiments, the compound contacted with the insect cell includes one or more compounds having any of the structures set forth in Tables 1-2 of the Examples.

[0164] The effective amount of the compound contacted with the insect cell in the provided methods for controlling a target protein level can be a pesticidally effective amount, referred to herein as an effective amount. An “effective amount” is an amount of a compound that causes the death of at least one pest (i.e., insect) or that noticeably reduces pest growth, feeding, or normal physiological development. This amount will vary depending on such factors as, for example, the specific target pests to be controlled, the specific environment, location, plant, crop, or agricultural site to be treated, the environmental conditions, and the method, rate, concentration, stability, and quantity of application of the compound. Decreases in pest numbers, pest growth, pest feeding or pest normal development resulting from contact with an effective amount of a provided compound can include any statistically significant decrease. For example, an effective amount of a provided compound can cause an insect growth, feeding, and / or development decrease of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 85%, 90%, 95% or greater.

[0165] In general, contacting an insect cell with an effective amount of a provided compound controls a level of a target protein by inducing degradation of the target protein within the insect cell. For example, the amount of the compound contacted with the insect cell may induce degradation of the target protein, where the degradation has an effective degradation efficiency. An effective degradation efficiency may be one having a DC so and / or Dmax satisfying a particular cutoff. Exemplary values of DCso and Dmax indicating effective degradation efficiency can be any of those described in Section B of this disclosure.

[0166] The bifunctional compounds disclosed herein display activity against a variety of insect pests, which may include economically important agronomic, forest, greenhouse, nursery, ornamentals, food and fiber, public and animal health, domestic and commercial structure, household, and stored product pests. Insect pests include insects selected from the orders Coleoptera, Diptera, Hymenoptera, Lepidoptera, Mallophaga, Homoptera, Hemiptera, Orthoptera, Thysanoptera, Dermaptera, Isoptera, Anoplura, Siphonaptera, Trichoptera, etc., particularly Lepidoptera.

[0167] Insects of the order Coleoptera affected by the provided compounds include weevils from the families Anthribidae Bruchidae and Curculionidae (including, but not limited to: Anthonomus grandis (boll weevil); Lissorhoptrus oryzophilus (rice water weevil); Sitophilus granarius (granary weevil); S. oryzae (rice weevil); Hypera punctata (clover leaf weevil); Cylindrocopturus adspersus (sunflower stem weevil); Smicronyx fulvus (red sunflower seed weevil); S. sordidus (gray sunflower seed weevil); Sphenophorus maidis (maize billbug)); flea beetles, cucumber beetles, rootworms, leaf beetles, potato beetles, and leafminers in the family Chrysomelidae (including, but not limited to: Leptinotarsa decemlineata (Colorado potato beetle); Diabrotica virgifera virgifera (western corn rootworm); D. barberi (northern com rootworm); D. undecimpunctata howardi (southern corn rootworm); Chaetocnema pulicaria (corn flea beetle); Phyllotreta cruciferae (corn flea beetle); Colaspis brunnea (grape colaspis); Oulema melanopus (cereal leaf beetle); Zygogramma exclamationis (sunflower beetle)); beetles from the family Coccinellidae (including, but not limited to: Epilachna varivestis (Mexican bean beetle)); chafers and other beetles from the family Scarabaeidae (including, but not limited to: Popillia japonica (Japanese beetle); Cyclocephala borealis (northern masked chafer, white grub); C. immaculata (southern masked chafer, white grub); Rhizotrogus majalis (European chafer); Phyllophaga crinita (white grub); Ligyrus gibbosus (carrot beetle)); carpet beetles from the family Dermestidae, wireworms from the family Elateridae, Eleodes spp., Melanotus spp.; Conoderus spp.; Limonius spp.; Agriotes spp.; Ctenicera spp.; Aeolus spp.; bark beetles from the family Scolytidae,' and beetles from the family Tenebrionidae .

[0168] Insects of the order Lepidoptera affected by the provided compounds include, but are not limited to, armyworms, cutworms, loopers, and heliothines in the family Noctuidae Spodoptera frugiperda (fall armyworm); . exigua (beet armyworm); S. litura (tobacco cutworm, cluster caterpillar); Mamestra configurata (bertha armyworm); M. brassicae (cabbage moth); Agrotis ipsilon (black cutworm); A. orthogonia (western cutworm); A. subterranea (granulate cutworm); Alabama argillacea (cotton leaf worm); Trichoplusia ni (cabbage looper); Pseudoplusia includens (soybean looper); Anticarsia gemmatalis (velvetbean caterpillar); Hypena scabra (green cloverworm); Heliothis virescens (tobacco budworm); Pseudaletia unipuncta (armyworm); Athetis mindara (rough skinned cutworm); Euxoa messoria (darksided cutworm); Earias insulana (spiny bollworm); E. viltella (spotted bollworm); Helicoverpa armigera (American bollworm); H. zea (corn earworm or cotton bollworm); Melanchra picta(zebra caterpillar); Egira (Xylomyges) curialis (citrus cutworm); borers, casebearers, webworms, coneworms, and skeletonizers from the family Pyralidae Ostrinia nubilalis (European corn borer); Amyelois transitella (naval orangeworm); Anagasta kuehniella (Mediterranean flour moth); Cadra cautella (almond moth); Chilo suppressalis (rice stem borer); C. partellus, (sorghum borer); Corcyra cephalonica (rice moth); Crambus caliginosellus (corn root webworm); C. teterrellus (bluegrass webworm); Cnaphalocrocis medinalis (rice leaf roller);Desmia funeralis (grape leaffolder); Diaphania hyalinata (melon worm); D. nitidalis (pickleworm); Diatraea grandiosella (southwestern corn borer), D. saccharalis (surgarcane borer); Eoreuma loftini (Mexican rice borer); Ephestia elutella (tobacco (cacao) moth); Galleria mellonella (greater wax moth); Herpetogramma licarsisalis (sod webworm); Homoeosoma electellum (sunflower moth); Elasmopalpus lignosellus (lesser cornstalk borer); Achroia grisella (lesser wax moth); Loxostege sticticalis (beet webworm); Orthaga thyrisalis (tea tree web moth); Maruca testulalis (bean pod borer); Plodia interpunctella (Indian meal moth); Scirpophaga incertulas (yellow stem borer); Udea rubigalis (celery leaftier); and leafrollers, budworms, seed worms, and fruit worms in the family Tortricidae Acleris gloverana (Western blackheaded budworm); A. variana (Eastern blackheaded budworm); Archips argyrospila (fruit tree leaf roller); A. rosana (European leaf roller); and other Archips species, Adoxophyes orana (summer fruit tortrix moth); Cochylis hospes (banded sunflower moth); Cydia latiferreana (filbertworm);C. pomonella (coding moth); Platynota flavedaiia (variegated leafroller); P. stultana (omnivorous leafroller); Lobesia botrana (European grape vine moth); Spilonota ocellana (eyespotted bud moth); Endopiza viteana (grape berry moth); upoecilia ambiguella (vine moth); Bonagota salubricola (Brazilian apple leafroller); Grapholita molesta (oriental fruit moth); Suleima helianthana (sunflower bud moth); Argyrotaenia spp.; and Choristoneura spp.

[0169] Insects in the order Lepidoptera affected by the provided compounds further include, but are not limited to, Alsophila pometaria (fall cankerworm); Anarsia lineatella (peach twig borer); Anisota senatoria (orange striped oakworm); Antheraea pernyi (Chinese Oak Silkmoth); Bombyx mori (Silkworm); Bucculatrix thurberiella (cotton leaf perforator); Colias eurytheme (alfalfa caterpillar); Datana integerrima (walnut caterpillar); Dendrolimus sibiricus (Siberian silk moth), Ennomos subsignaria (elm spanworm); Erannis tiliaria (linden looper); Huproctis chrysorrhoea (browntail moth); Harrisina americana (grapeleaf skeletonizer); Hemileuca oliviae (range caterpillar); Hyphantria cunea (fall webworm); Keiferia ly coper sicella (tomato pinworm);Lambdina fiscellaria fiscellaria (Eastern hemlock looper); L. fiscellaria lugubrosa (Western hemlock looper); Leucoma salicis (satin moth); Lymantria dispar (gypsy moth); Manduca quinquemaculata (five spotted hawk moth, tomato hornworm); M. sexta (tomato homworm, tobacco homworm); Operophtera brumata (winter moth); Paleacrita vernata (spring cankerworm); Papilio cresphontes (giant swallowtail, orange dog); Phryganidia californica (California oakworm); Phyllocnistis citrella (citrus leafminer); Phyllonorycter blancardella (spotted tentiform leafminer); Pieris brassicae (large white butterfly); P. rapae (small white butterfly); P. napi (green veined white butterfly); Platyptilia carduidactyla (artichoke plume moth); Plutella xylostella (diamondback moth); Pectinophora gossypiella (pink bollworm); Pontia protodice (Southern cabbageworm); Sabulodes aegrotata (omnivorous looper); Schizura concinna (red humped caterpillar); Sitotroga cerealella (Angoumois grain moth); Thaumetopoea pityocampa (pine processionary caterpillar); Tineola bisselliella (webbing clothesmoth); Tula absoluta (tomato leafminer); Yponomeuta padella (ermine moth); Heliothis subflexa Malacosoma spp. and Orgyia spp.

[0170] Immature insects of the order Diptera affected by the provided compounds include leafminers such as Agromyza parvicornis (corn blotch leafminer); midges (including, but not limited to, Contarinia sorghicola (sorghum midge); Mayetiola destructor (Hessian fly);Sitodiplosis mosellana (wheat midge); Neolasiopteranrurtfeldtiana, (sunflower seed midge)); fruit flies ( Tephritidaey Oscinella frit (frit flies); maggots (including, but not limited to: Delia platura (seedcorn maggot); D. coarctata (wheat bulb fly); and other Delia spp., Meromyza americana (wheat stem maggot); Musca domestica (house flies); Fannia canicularis F. femoralis (lesser house flies); Stomoxys calcitrans (stable flies)); face flies, horn flies, blow flies, Chrysomya spp.; Phormia spp.; and other muscoid fly pests, horse flies Tabanus spp.; bot flies Gastrophilus spp.; Oestrus spp.; cattle grubs Hypoderma spp.; deer flies Chrysops spp.;Melophagus ovinus (keds); and other Hrachycera. mosquitoes Aedes spp. (including, but not limited to, A. aegypti and A. albopictusf Anopheles spp. (including, but not limited to, An. gambiae An. quadrimaculatus and An. stephensiy, Culex spp.; black flies Prosimulium spp.; Simulium spp.; biting midges, sand flies, sciarids, and other Nematocera.

[0171] Insects of the orders Hemiptera and Homoptera affected by the provided compounds include insects such as, but not limited to, adelgids from the family Adelgidae, plant bugs fromthe family Miridae, cicadas from the family Cicadidae, leafhoppers, Empoasca spp.; from the family Cicadellidae , planthoppers from the families Cixiidae, Flatidae, Fulgoroidea, Issidae and Delphacidae, treehoppers from the family Membracidae, psyllids from the family Psyllidae, whiteflies from the family Aleyrodidae, aphids from the family Aphididae, phylloxera from the family Phylloxeridae , mealybugs from the family Pseudococcidae, scales from the families Aster ole canidae, Coccidae, Daclylopiidae, Diaspididae, Eriococcidae, Ortheziidae, Phoenicococcidae and Margarodidae , lace bugs from the family Tingidae, stink bugs from the family Pentatomidae, cinch bugs, Blissus spp.; and other seed bugs from the family Lygaeidae, spittlebugs from the family Cercopidae squash bugs from the family Coreidae, and red bugs and cotton stainers from the family Pyrrhocoridae .

[0172] Agronomically important members from the order Homoptera affected by the provided compounds further include, but are not limited to: Acyrthisiphon pisum (pea aphid); Aphis craccivora (cowpea aphid); A. fabae (black bean aphid); A. gossypii (cotton aphid, melon aphid); A. maidiradicis (com root aphid); A. pomi (apple aphid); A. spiraecola (spirea aphid);Aulacorthum solani (foxglove aphid); Chaetosiphon fragaefolii (strawberry aphid); Diuraphis noxia (Russian wheat aphid); Dysaphis plantaginea (rosy apple aphid); Eriosoma lanigerum (woolly apple aphid); Brevicoryne brassicae (cabbage aphid); Hyalopterus pruni (mealy plum aphid); Lipaphis erysimi (turnip aphid); Metopolophium dirrhodum (cereal aphid); Macrosiphum euphorbiae (potato aphid); Myzus persicae (peach-potato aphid, green peach aphid); Nasonovia ribisnigri (lettuce aphid); Pemphigus spp. (root aphids and gall aphids); RJiopalosiphum maidis (corn leaf aphid); R. padi (bird cherry-oat aphid); Schizaphis graminum (greenbug); Sipha flava (yellow sugarcane aphid); Sitobion avenae (English grain aphid); Therioaphis maculata (spotted alfalfa aphid); Toxoptera aurantii (black citrus aphid); and T. citricida (brown citrus aphid); Adelges spp. (adelgids); Phylloxera devastatrix (pecan phylloxera); Bemisia tabaci (tobacco whitefly, sweetpotato whitefly); B. argentifolii (silverleaf whitefly); Dialeurodes citri (citrus whitefly); Trialeurodes abutiloneus (bandedwinged whitefly) and T. vaporariorum (greenhouse whitefly); Empoasca fabae (potato leafhopper); Laodelphax striatellus (smaller brown planthopper); Macrolestes quadri lineatus (aster leafhopper); Nephotettix cinticeps (green leafhopper); N. nigropictus (rice leafhopper); Nilaparvata lugens (brown planthopper);Peregrinus maidis (com planthopper); Sogatella furcifera (white-backed planthopper); Sogatodes orizicola (rice delphacid); Typhlocyba pomaria (white apple leafhopper);Erythroneoura spp. (grape leafhoppers); Magicicada septendecim (periodical cicada); Icerya purchasi (cottony cushion scale); Quadraspidiotus perniciosus (San Jose scale); Pianococcus citri (citrus mealybug); Pseudococcus spp. (other mealybug complex); Cacopsylla pyricola (pear psylla); and Trioza diospyri (persimmon psylla).

[0173] Agronomically important species from the order Hemiptera affected by the provided compounds include, but are not limited to: Acrosternum hilare (green stink bug); Anasa tristis (squash bug); Blissus leucopterus leucopterus (chinch bug); Corythuca gossypii (cotton lace bug); Cyrtopeltis modesta (tomato bug); Dysdercus suturellus (cotton stainer); Euschistus servus (brown stink bug); E. variolarius (one-spotted stink bug); Graptostethus spp. (complex of seed bugs); Leptoglossus corculus (leaf-footed pine seed bug); Lygus lineolaris (tarnished plant bug); L. Hesperus (Western tarnished plant bug); L. pratensis (common meadow bug); L. rugulipennis (European tarnished plant bug); Lygocoris pabulinus (common green capsid); Nezara viridula (southern green stink bug); Oebalus pugnax (rice stink bug); Oncopeltus fasciatus (large milkweed bug); Pseudatomoscelis seriatus (cotton fleahopper). Insects included in the order Hemiptera include: Calocoris norvegicus (strawberry bug); Orthops campestris\ Plesiocoris rugicollis (apple capsid); Cyrtopeltis modestus (tomato bug); Cyrtopeltis notatus (suckfly); Spanagonicus albofasciatus (whitemarked fleahopper); Diaphnocoris chlorionis (honeylocust plant bug); Labopidicola allii (onion plant bug); Pseudatomoscelis seriatus (cotton flea hopper); Adelphocoris rapidus (rapid plant bug); Poecilocapsus lineatus (four-lined plant bug); Nysius ericae (false chinch bug); Nysius raphanus (false chinch bug); Nezara viridula (Southern green stink bug); Eurygaster spp.; Coreidae spp.; Pyrrhocoridae spp.; Timidae spp.; Blostomatidae spp.; Reduviidae spp.; and Cimicidae spp.

[0174] Insects of the order Acari (mites) affected by the provided compounds include Aceria tosichella (wheat curl mite); Petrobia latens (brown wheat mite); spider mites and red mites in the family Tetranychidae. Panonychus ulmi (European red mite); Tetranychus urticae (two spotted spider mite); (7. mcdanieli (McDaniel mite); T. cinnabarinus (carmine spider mite); T. turkestani (strawberry spider mite); flat mites in the family Tenuipalpidae , Brevipalpus lewisi (citrus flat mite); rust and bud mites in the family Eriophyidae and other foliar feeding mites and mites important in human and animal health, i.e., dust mites in the family Epidermoptidae, follicle mites in the family Demodicidae, grain mites in the family Glycyphagidae , ticks in theorder Ixodidae. Jxodes scapularis (deer tick); I. holocyclus (Australian paralysis tick);Dermacentor variabilis (American dog tick); Amblyomma americanum (lone star tick); and scab and itch mites in the families Psoroptidae, Pyemotidcte. and Sarcoptidae .

[0175] Insect pests of the order Thysanura affected by the provided compounds include Lepisma saccharina (silverfish); Thermobia domestics (firebrat). Additional arthropod pests include: spiders in the order Araneae such as Loxosceles reclusa (brown recluse spider); and the Latrodectus mactans (black widow spider); and centipedes in the order Scutigeromorphci such as Scutigera coleoptrata (house centipede).

[0176] The pesticidal activity of the compositions disclosed herein may be tested in insect pests in their early developmental stages, e.g., as larvae or other immature forms. A wide variety of bioassay techniques are known to one skilled in the art. General procedures include addition of the experimental compound or organism to the diet source in an enclosed container. Bioassays may be performed as described in Czapla and Lang (1990) J. Econ. Entomol. 83 (6): 2480-2485, Andrews etal., (1988) Biochem. J. 252: 199-206; Marrone et al., (1985) J. of Economic Entomology 78:290-293 and U.S. Pat. No. 5,743,477, all of which are herein incorporated by reference in their entirety. Generally, the protein is mixed and used in feeding assays. See, for example Marrone et al., (1985) J. of Economic Entomology 78:290-293. Methods of rearing insect larvae and performing bioassays are well known to one of ordinary skill in the art.Measurable indicia of pesticidal activity include, but are not limited to, changes in mortality, weight loss, attraction, repellency, and other behavioral and physical changes after feeding and exposure for an appropriate length of time. See, for example US Patent No. 7,619,064.E. COMPOSITIONS

[0177] The bifunctional compounds disclosed herein may be formulated into compositions for use. Such compositions comprise one or more provided bifunctional compounds, and one or more agriculturally acceptable carriers, surfactants or application-promoting adjuvants customarily employed in the art of formulation. As used herein, the term "agriculturally- acceptable carrier" covers all adjuvants, inert components, dispersants, surfactants, tackifiers, binders, etc. that are ordinarily used in pesticide formulation technology; these are well known to those skilled in pesticide formulation. Suitable carriers and adjuvants may be solid or liquid and correspond to the substances ordinarily employed in formulation technology, e.g., natural orregenerated mineral substances, solvents, dispersants, wetting agents, tackifiers, binders or the like. The compositions may comprise more than one type of bifunctional compound, as well as additional agents, such as insecticides, fertilizers, herbicides, and plant supplements. Likewise, the formulations may be prepared into edible "baits" or fashioned into pest "traps" to permit feeding or ingestion by a target pest of the pesticidal formulation.

[0178] In some embodiments, the bifunctional compounds of the present disclosure are used in combination with additional insecticides, either simultaneously or sequentially. Suitable insecticides that can be used with the bifunctional compounds and the compositions comprising at least one bifunctional compound of the present disclsoure include:(1) Acetylcholinesterase (AChE) inhibitors, preferably carbamates selected from alanycarb, aldicarb, bendiocarb, benfuracarb, butocarboxim, butoxycarboxim, carbaryl, carbofuran, carbosulfan, ethiofencarb, fenobucarb, formetanate, furathiocarb, isoprocarb, methiocarb, methomyl, metolcarb, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, triazamate, trimethacarb, XMC and xylylcarb; or organophosphates selected from acephate, azamethiphos, azinphos-ethyl, azinphos-methyl, cadusafos, chlorethoxyfos, chlorfenvinphos, chlormephos, chlorpyrifos, chlorpyrifos-methyl, coumaphos, cyanophos, demeton-S-methyl, diazinon, dichlorvos / DDVP, dicrotophos, dimethoate, dimethylvinphos, disulfoton, EPN, ethion, ethoprophos, famphur, fenamiphos, fenitrothion, fenthion, fosthiazate, heptenophos, imicyafos, isofenphos, isopropyl O-(methoxyaminothiophosphoryl) salicylate, isoxathion, malathion, mecarbam, methamidophos, methidathion, mevinphos, monocrotophos, naled, omethoate, oxydemeton-methyl, parathion, parathion-methyl, phenthoate, phorate, phosalone, phosmet, phosphamidon, phoxim, pirimiphos-methyl, profenofos, propetamphos, prothiofos, pyraclofos, pyridaphenthion, quinalphos, sulfotep, tebupirimfos, temephos, terbufos, tetrachlorvinphos, thiometon, triazophos, triclorfon, and vamidothion;(2) GABA-gated chloride channel blockers, preferably cyclodiene-organochlorines selected from chlordane and endosulfan; or phenylpyrazoles (fiproles) selected from ethiprole and fipronil;(3) Sodium channel modulators, preferably pyrethroids selected from acrinathrin, allethrin, d-cis- trans allethrin, d-trans allethrin, bifenthrin, kappa-bifenthrin, bioallethrin, bioallethrin S- cyclopentenyl isomer, bioresmethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, gamma-cyhalothrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin,theta-cypermethrin, zeta-cypermethrin, cyphenothrin [(IR)-trans-isomer], deltamethrin, empenthrin [(EZ)-(lR)-isomer], esfenvalerate, etofenprox, fenpropathrin, fenvalerate, flucythrinate, flumethrin, tau-fluvalinate, halfenprox, imiprothrin, kadethrin, epsilon- metofluthrin, momfluorothrin, permethrin, phenothrin [(IR)-trans-isomer], prallethrin, pyrethrins (pyrethrum), resmethrin, silafluofen, tefluthrin, kappa-tefluthrin, tetramethrin, tetramethrin [(1R)- isomer)], tralomethrin, and transfluthrin; or DDT or methoxychlor;(4) Nicotinic acetylcholine receptor (nAChR) competitive modulators, preferably neonicotinoids selected from acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid and thiamethoxam; or nicotine, or sulfoximines selected from sulfoxaflor; or butenolids selected from flupyradifurone; or mesoionics selected from dicloromezotiaz, fenmezoditiaz, and triflumezopyrim; or pyridylidenes selected from flupyrimin;(5) Nicotinic acetylcholine receptor (nAChR) allosteric modulators (Site 1), preferably spinosyns selected from spinetoram and spinosad;(6) Glutamate-gated chloride channel (GluCl) allosteric modulators, preferably avermectins / milbemycins selected from abamectin, emamectin benzoate, lepimectin and milbemectin;(7) Juvenile hormone receptor modulators, preferably juvenile hormone analogues selected from hydroprene, kinoprene, and methoprene; or fenoxycarb; or pyriproxyfen;(8) Miscellaneous non-specific (multi-site) inhibitors, preferably alkyl halides selected from 1,3- dichloropropene, methyl bromide and other alkyl halides; or chloropicrin; or fluorides selected from cryolite (sodium aluminum fluoride), and sulfuryl fluoride; or borates selected from borax, boric acid, disodium octoborate, sodium borate, and sodium metaborate; or tartar emetic; or methyl isocyanate generators selected from dazomet, metam, and methyl isothiocyanate;(9) Chordotonal organ TRPV channel modulators, preferably pyridine azomethine derivatives selected from pymetrozine, and pyrifluquinazone; or pyropenes selected from afidopyropen;(10) Mite growth inhibitors, preferably selected from clofentezine, diflovidazin, hexythiazox, and etoxazole;(11) Microbial disruptors of insect gut membranes, preferably Bacillus thuringiensis and the insecticidal proteins they produce selected from Bacillus thuringiensis subspecies israelensis,Bacillus thuringiensis subspecies aizawai, Bacillus thuringiensis subspecies kurstaki, Bacillus thuringiensis subspecies tenebrionis, and pesticidally active proteins, e.g., originating from Bacillus thuringiensis selected from CrylAb, CrylAc, CrylFa, Cry 1A.105, Cry2Ab, Vip3A, mCry3A, Cry3Ab, Cry3Bb, and Cry 34 Ab 1 / Cry 35 Ab 1; or Bacillus sphaericus,'(12) Inhibitors of mitochondrial ATP synthase that are ATP disruptors, preferably diafenthiuron; or organotin miticides selected from azocyclotin, cyhexatin, and fenbutatin oxide; or propargite; or tetradifon;(13) Uncouplers of oxidative phosphorylation via disruption of the proton gradient, selected from chlorfenapyr, DNOC, and sulfluramid;(14) Nicotinic acetylcholine receptor channel blockers, preferably nereistoxin analogues selected from bensultap, cartap hydrochloride, thiocylam, and thiosultap-sodium;(15) Inhibitors of chitin biosynthesis affecting CHS1, preferably benzoylureas selected from bistrifluron, chlorfluazuron, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, teflubenzuron, and triflumuron;(16) Inhibitors of chitin biosynthesis, type 1 selected from buprofezin;(17) Moulting disrupter (in particular for Diptera, i.e., Dipterans) selected from cyromazine;(18) Ecdysone receptor agonists, preferably diacylhydrazines selected from chromafenozide, halofenozide, methoxyfenozide, and tebufenozide;(19) Octopamine receptor agonists, selected from amitraz;(20) Mitochondrial complex III electron transport inhibitors - Qo site, selected from hydramethylnone, acequinocyl, fluacrypyrim, and bifenazate;(21) Mitochondrial complex I electron transport inhibitors, preferably METI acaricides selected from fenazaquin, fenpyroximate, pyridaben, pyrimidifen, tebufenpyrad and tolfenpyrad; or rotenone (Derris);(22) Voltage-dependent sodium channel blockers selected from indoxacarb and metaflumizone;(23) Inhibitors of acetyl CoA carboxylase, preferably tetronic and tetramic acid derivatives selected from spidoxamat, spirobudifen, spirodi cl ofen, spiromesifen, spiropidion, and spirotetramat;(24) Mitochondrial complex IV electron transport inhibitors, preferably phosphides selected from aluminium phosphide, calcium phosphide, phosphine, and zinc phosphide; or cyanides selected from calcium cyanide, potassium cyanide, and sodium cyanide;(25) Mitochondrial complex II electron transport inhibitors, preferably beta-ketonitrile derivatives selected from cyenopyrafen, and cyflumetofen; or carboxanilides selected from pyflubumide;(28) Ryanodine receptor modulators, preferably diamides selected from chlorantraniliprole, cyantraniliprole, cyclaniliprole, flubendiamide, and tetraniliprole;(29) Chordotonal organ nicotinamidase inhibitors selected from flonicamid;(30) GABA-gated chloride channel allosteric modulators, preferably meta-diamides or isoxazolines selected from broflanilide, fluxametamide, and isocycloseram;(31) Baculoviruses, preferably Granuloviruses (GVs) selected from Cydia pomonella GV, and Thaumatotibia leucotreta GV; or Nucleopolyhedroviruses (NPVs) selected from Anticarsia gemmatalis MNPV, and Helicoverpa armigerci NPV;(32) Nicotinic Acetylcholine Receptor (nAChR) Allosteric Modulators - Site II selected from GS-omega / kappa HXTX-Hv la peptide;(33) Calcium-activated potassium channel (KCa2) modulators selected from acynonapyr;(34) Mitochondrial complex III electron transport inhibitors - Qi site selected from flometoquin;(35) RNA Interference mediated target suppressors selected from ledprona;(36) Chorotonal organ modulators - undefined target site selected from dimpropyridaz; and / or(UN) Further insecti ci dally and / or acaricidally active compounds of unknown, uncertain, or yet to be classified modes of action selected from afoxolaner, azadirachtin, benzoximate, benzpyrimoxan, bromopropylate, chinomethionat, chloroprallethrin, cyclobutrifluram, cycloxaprid, cyetpyrafen, cyhalodiamide, cyproflanilide (CAS 23751 10-88-4), dicofol, fluazaindolizine, flucypyriprole (CAS 1771741-86-6), fluensulfone, flufenerim, flufenoxystrobin, flufiprole, fluhexafon, fluopyram, flupentiofenox, flupyroxystrobin, fluralaner, fufenozide, guadipyr, heptafluthrin, imidaclothiz, indazapyroxamet, iodomethane, iprodione, lotilaner, meperfluthrin, mivorilaner, modoflaner, ni cofluprole (CAS 1771741-86-6),oxazosulfyl, paichongding, pyridalyl, pyrifluquinazon, pyriminostrobin, sarolaner, spirobudiclofen, sulfiflumin, sulfur, tetramethylfluthrin, tetrachlorantraniliprole, tigolaner, tioxazafen, thiofluoximate, trifluenfuronate, tyclopyrazoflor, umifoxolaner, l-{2-fluoro-4- methyl-5-[(2,2,2-trifluoroethyl)sulphinyl]phenyl}-3-(trifluoromethyl)-lH-l,2,4-triazole-5-amine (known from W02006 / 043635) (CAS 885026-50-6), 2-chloro-N-[2-{l-[(2E)-3-(4- chlorophenyl)prop-2-en-l-yl]piperidin-4-yl}-4-(trifluoromethyl)phenyl]isonicotinamide (known from W02006 / 003494) (CAS 872999-66-1), 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8- methoxy-l,8-diazaspiro[4.5]dec-3-en-2-one (known from WO 2010 / 052161) (CAS 1225292-17- 0), 3-(4-chloro-2,6-dimethylphenyl)-8-methoxy-2-oxo-l,8- diazaspiro[4.5]dec-3-en-4-yl ethyl carbonate (known from EP2647626) (CAS 1440516-42-6), PF1364 (known from JP2010 / 018586) (CAS 1204776-60-2), (3E)-3-[l-[(6-chloro-3-pyridyl)methyl]-2-pyridylidene]- l,l,l-trifluoro-propan-2-one (known from WO 2013 / 144213) (CAS 1461743-15-6), N-[3- (benzylcarbamoyl)-4-chlorophenyl]-l-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-lH- pyrazole-5- carboxamide (known from WO 2010 / 051926) (CAS 1226889-14-0), 5-bromo-4- chloro-N-[4-chloro-2-methyl-6-(methylcarbamoyl)phenyl]-2-(3-chloro-2-pyridyl)pyrazole-3- carboxamide (known from CN103232431) (CAS 1449220-44-3), 4-[5-(3,5-dichlorophenyl)-4,5- dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(cis-l-oxido-3-thietanyl)-benzamide, 4- [5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N -(trans- 1- oxido-3-thietanyl)-benzamide and 4-[(5S)-5-(3,5-dichlorophenyl)-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-2-methyl-N -(cis-l-oxido-3-thietanyl) benzamide (known from WO 2013 / 050317) (CAS 1332628-83-7), N-[3-chloro-l-(3-pyridinyl)-lH-pyrazol-4-yl]-N-ethyl- 3-[(3,3,3-trifluoropropyl)sulfmyl]-propanamide, (+)-N-[3-chloro-l-(3-pyridinyl)-lH-pyrazol-4- yl]-Nethyl-3-[(3,3,3-trifluoropropyl)sulfinyl]-propanamide and (-)-N-[3-chloro-l-(3-pyridinyl)- lH-pyrazol-4-yl]-N-ethyl-3-[(3,3,3-trifluoropropyl)sulfinyl]-propanamide (known from WO 2013 / 162715, WO 2013 / 162716, US 2014 / 0213448 (CAS 1477923-37-7), 5-[[(2E)-3-chloro-2- propen-l-yl]amino]-l-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-lH- pyrazole-3 -carbonitrile (known from CN 101337937) (CAS 1105672-77-2), 3-bromo-N-[4- chloro-2-methyl-6-[(methylamino)thioxomethyl]phenyl]-l-(3-chloro-2-pyridinyl)-lH-pyrazole-5- carboxamide, (Liudaibenjiaxuanan, known from CN 103109816A) (CAS 1232543-85-9); N-[4- chloro-2-[[(l,l-dimethylethyl)amino]carbonyl]-6-methylphenyl]-l-(3-chloro-2-pyridinyl)-3- (fluoromethoxy)-lH-pyrazole-5-carboxamide (known from WO 2012 / 034403) (CAS 1268277-22-0), N-[2-(5-amino-l,3,4-thiadiazol-2-yl)-4-chloro-6-methylphenyl]-3-bromo-l-(3-chloro-2- pyridinyl)-lH-pyrazole-5-carboxamide (known from WO 2011 / 085575) (CAS 1233882-22-8), 4- [3-[2,6-dichloro-4-[(3,3-dichloro-2-propen-l-yl)oxy]phenoxy]propoxy]-2-methoxy-6- (trifluoromethyl)-pyrimidine (known from CN 101337940A) (CAS 1108184-52-6); 2E)- and 2(Z)-2-[2-(4-cyanophenyl)-l-[3-(trifluoromethyl) phenyl] ethylidene]-N-[4- (difluoromethoxy)phenyl]-hydrazinecarboxamide (known from CN 101715774A) (CAS 1232543-85-9); 3-(2,2-dichloroethenyl)-2,2-dimethyl-4-(lH-benzimidazol-2-yl)phenyl- cyclopropanecarboxylic acid ester (known from CN 103524422A) (CAS 1542271-46-4); (4aS)- 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-[(trifluoromethyl)thio]phenyl]amino]carbonyl]- indeno[l,2-e][l,3,4]oxadiazine-4a(3H)-carboxylic acid methyl ester (known from CN 102391261A) (CAS 1370358-69-2); 6-deoxy-3-O-ethyl-2,4-di-O-methyl-l-[N-[4-[l-[4- (1,1,2,2,2-pentafluoroethoxy) phenyl]- 1H-1, 2, 4-triazol -3-yl]phenyl]carbamate]-a-L- mannopyranose (known from US 2014 / 0275503) (CAS 1181213-14-8); 8-(2- cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-pyridazin-3-yl)-3-aza- bicyclo[3.2.1]octane (CAS 1253850-56-4), (8-«w / z)-8-(2-cyclopropylmethoxy-4-trifluoromethyl- phenoxy)-3-(6-trifluoromethyl-pyridazin-3-yl)-3-aza- bicyclo[3.2.1 ]octane (CAS 933798-27-7), (8-s n)-8-(2-cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-pyridazin-3- yl)-3-aza-bicyclo[3.2.1]octane (known from WO 2007040280, WO 2007040282) (CAS 934001- 66-8), N-[4-(aminothioxomethyl)-2-methyl-6- [(methylamino)carbonyl]phenyl]-3-bromo-l-(3- chloro-2-pyridinyl)-lH-pyrazole-5-carboxamide (known from CN 103265527A) (CAS 1452877- 50-7), 3-(4-chl oro-2, 6-dimethylphenyl)-8-methoxy-l-methyl-l,8-diazaspiro[4.5]decane-2, 4-dione (known from WO 2014 / 187846) (CAS 1638765-58-8), 3-(4-chloro-2,6-dimethylphenyl)-8- methoxy-l-methyl-2-oxo-l,8-diazaspiro[4.5]dec-3-en-4-yl-carbonic acid ethyl ester (known from WO 2010 / 066780, WO 2011 / 151146) (CAS 1229023-00-0), N-[l-(2,6-difluorophenyl)-lH- pyrazol-3-yl]-2-(trifluoromethyl)benzamide (known from WO 2014 / 053450) (CAS 1594624-87- 9), N-[2-(2,6-difluorophenyl)-2H-l,2,3-triazol-4-yl]-2-(trifluoromethyl)benzamide (known from WO 2014 / 053450) (CAS 1594637-65-6), N-[l-(3,5-difluoro-2-pyridinyl)-lH-pyrazol-3-yl]-2- (trifhjoromethyl)benzamide (known from WO 2014 / 053450) (CAS 1594626-19-3), (3R)-3-(2- chloro-5-thiazolyl)-2,3-dihydro-8-methyl-5,7-dioxo-6-phenyl-5H-thiazolo[3,2-a]pyrimidinium inner salt (known from WO 2018 / 177970) (CAS 2246757-58-2); 3-(2-chloro-5-thiazolyl)-2,3- dihydro-8-methyl-5,7-dioxo-6-phenyl-5H-thiazolo[3,2-a]pyrimidinium inner salt (known fromWO 2018 / 177970) (CAS 2246757-56-0); N-[3-chloro-l-(3-pyridinyl)-lH-pyrazol-4-yl]-2-(m ethyl sulfonyl)- propanamide (known from WO 2019 / 236274) (CAS 2396747-83-2), N-[2- bromo-4-[l,2,2,2- tetrafluoro- 1 -(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]-2-fluoro-3-[(4- fluorobenzoyl)amino]-benzamide (known from WO 2019059412) (CAS 1207977-87-4), and 3- bromo-l-(3-chloro-2-pyridinyl)-N-[4,6-dichloro-3-fluoro-2-[(methylamino)carbonyl]phenyl]-lH- Pyrazole-5-carboxamide (fluchlorodiamide; known from CN110835330A, CN106977494A) (CAS 2129147-03-9).

[0179] The compositions may be applied to the environment of an insect pest by, for example, spraying, atomizing, dusting, scattering, coating or pouring, introducing into or on the soil, introducing into irrigation water, by seed treatment or general application or dusting at the time when the pest has begun to appear or before the appearance of pests as a protective measure. For example, the provided compositions may be mixed with grain to protect the grain during storage. It is generally important to obtain good control of pests in the early stages of plant growth, as this is the time when the plant may be most severely damaged. Provided embodiments include granular forms of the composition comprising an agrochemical such as, for example, an herbicide, an insecticide, a fertilizer, an inert carrier, and the like.

[0180] Also provided are methods of applying an active ingredient or a composition where the active ingredient or composition contains at least one of the bifunctional compounds disclosed herein. In some embodiments, the methods include application to the insect pests, application to the plant or plant locus, e.g., leaf application, seed coating and soil application, or application to other surfaces in the environment in which the insect is present. The number of applications and the rate of application depend on the intensity of infestation by the corresponding pest.

[0181] In some embodiments, the composition is formulated as a powder, dust, pellet, granule, spray, emulsion, colloid, solution or the like. In some embodiments, the composition is prepared by desiccation, lyophilization, homogenization, extraction, filtration, centrifugation, sedimentation, or concentration. In some embodiments, the bifunctional compounds is present in a concentration of from about 1% to about 99% by weight, e.g., from about 1 wt% to about 60 wt%, from about 10 wt% to about 70 wt%, from about 20 wt% to about 80 wt%, from about 30 wt% to about 90 wt%, or from about 40 wt% to about 100 wt%.

[0182] In some embodiments, the composition is applied to any plant species for control of a pest. Plants of interest include grain plants that provide seeds of interest, oil-seed plants, leguminous plants, vegetables, ornamentals, trees, turfgrass, and the like. Seeds of interest include grain seeds, such as corn, wheat, barley, rice, sorghum, rye, millet, etc. Oil-seed plants include cotton, soybean, safflower, sunflower, Brassica, maize, alfalfa, palm, coconut, flax, castor, olive, etc. Leguminous plants include beans and peas. Beans include guar, locust bean, fenugreek, soybean, garden beans, cowpea, mungbean, lima bean, fava bean, lentils, chickpea, etc. It is recognized that the provided compositions and compounds may be applied to the surface of the plant. Some of the bifunctional compounds may be taken up by the plant. In any event, the compounds are accessible to insect pest by feeding on the plants.

[0183] Examples of plants of interest include, but are not limited to, corn (Zea mays), Brassica sp. (e.g., B. napus, B. rapa, B. juncea), particularly those Brassica species useful as sources of seed oil, alfalfa (Medicago sativa), rice (Oryza sativa), rye (Secale cereale), sorghum (Sorghum bicolor, Sorghum vulgare), millet (e.g., pearl millet (Pennisetum glaucum), proso millet (Panicum miliaceum), foxtail millet (Setaria italica), finger millet (Eleusine coracana)), sunflower (Helianthus annuus), safflower (Carthamus tinctorius), wheat (Triticum aestivum), soybean (Glycine max), tobacco (Nicotiana tabacum), potato (Solanum tuberosum), peanuts (Arachis hypogaea), cotton (Gossypium barbadense, Gossypium hirsutum), sweet potato (Ipomoea batatus), cassaya (Manihot esculenta), coffee (Coffea spp ), coconut (Cocos nucifera), pineapple (Ananas comosus), citrus trees (Citrus spp.), cocoa (Theobroma cacao), tea (Camellia sinensis), banana (Musa spp.), avocado (Persea americana), fig (Ficus casica), guava (Psidium guajava), mango (Mangifera indica), olive (Olea europaea), papaya (Carica papaya), cashew (Anacardium occidentale), macadamia (Macadamia integrifolia), almond (Prunus amygdalus), sugar beets (Beta vulgaris), sugarcane (Saccharum spp.), oats, barley, vegetables, ornamentals, and conifers.F. EXEMPLARY EMBODIMENTS

[0184] The following embodiments are contemplated. All combinations of features and embodiments are contemplated.

[0185] Embodiment 1 . A method of controlling a level of a target protein that is expressed in an insect cell, the method comprising contacting the insect cell with an effective amount of a compound of formula (I)PTM-L-LTM (I) the compound comprising: one or more BRD3 protein targeting moieties (PTM) that each independently bind the target BRD3 protein; one or more ligase targeting moieties (LTM) that each independently bind a ubiquitin ligase that is functional in the insect cell; and a linker (L) covalently bonded to the one or more protein targeting moieties and the one or more ligase targeting moieties.

[0186] Embodiment 2. The method of Embodiment 1, wherein the ubiquitin ligases that the one or more ligase targeting moieties bind to comprise the von Hippel-Lindau tumor suppressor (VHL) or cereblon.

[0187] Embodiment 3. The method of Embodiment 2, wherein at least one of the one or more ligase targeting moieties is a VHL targeting moiety and has a structure according to the formula (V-I):whereinR5aand R5bare each independently hydrogen, hydroxyl, amine, haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxyl alkyl, optionally substituted alkylamine, optionally substituted amide, optionally substituted alkyl-amide, optionally substituted alkyl-cyano, optionally substituted alkyl-phosphate, optionally substituted aryl, optionally substituted alkyl-aryl, optionally substituted heteroalkyl, optionally substituted alkyl- heterocyclyl, optionally substituted alkoxy-heterocyclyl, COR14, alkyl-COR14, CONR15aR15b,NHCOR14, NHCH3COR14or -X-L1, or are combined with the carbon atom to which they are attached to form an optionally substituted 3- to 5-membered cycloalkyl, heterocyclyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not epoxide or aziridine; each R6is independently C1-6 alkyl, halogen, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C6-12 aryl, C5-12 heteroaryl, C3-15 heterocyclyl, cyano, nitro, NR15aR15b, OR14, CONR15aR15b, NR15aCOR15b, SO2NR15aR15b, NR15aSO2R15b, or -X-L1, wherein the alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with 1 to 4 R6agroups;R8is an optionally substituted aryl, optionally substituted heteroaryl, orR9and R10are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, haloalkyl, or, or are combined with the carbon atom to which they are attached to form an optionally substituted cycloalkyl;R2and R3are each independently hydrogen, C1-6 alkyl, or C1-6 hydroxyalkyl, or are combined with the carbon to which they are attached to form a C3-8 cycloalkyl, C6-12 aryl, or C5-12 heteroaryl, wherein the cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 4 R2agroups;R4is hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, or -X-L1;R11 is an optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,R1is hydrogen, optionally substituted alkyl, optionally substituted alkyl carbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, optionally substituted aralkyl, -Rlais C1-6alkyl, C3-8 cycloalkyl, C6-12 aryl, or C5-12 heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted with 1 to 4 Rlbgroups; each Rlb, R2a, and R6ais independently C1-6 alkyl, cyano, halogen, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, or -X-L1;R12is hydrogen or optionally substituted alkyl;each R13is independently hydrogen, halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or -X- L1; each R14is independently hydrogen, OH, O-C1-6 alkyl, optionally substituted alkyl, or NR15aR13b;R1?aand R1?bare each independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl, or are combined with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl;R16is hydroxy, a group that can be metabolized to hydroxy, or sulfonyl halide;A is optionally substituted phenyl, optionally substituted napthyl, or an optionally substituted 5- to 10- membered heteroaryl;X is a bond, CH2, NH, NMe, O, or S;L1is a site of attachment to the linker (L); and the subscripts n and p are each independently an integer from 0 to 4.

[0188] Embodiment 4. The method of Embodiment 3, wherein at least one of the one or more ligase targeting moieties has a structure according to the formula:wherein R1is hydrogen, C1-6 alkyl, -C(O)Rla, or -C(O)-X-L1; R4is hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, or -X-L1; R5ais hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkyl-amide, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy or -X-L1; and each R6is independently C1-6 alkyl, halogen, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C6-12 aryl, C5-12 heteroaryl, OR14, or -X-L1, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted with 1 to 4 R6agroups.

[0189] Embodiment 5. The method of Embodiment 3, wherein R1is -C(O)Rlaor -C(O)-X- L1; and Rlais C1-6alkyl or C3-8 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 to 4 Rlbgroups.

[0190] Embodiment 6. The method of Embodiment 3 wherein R2and R3are each independently C1-6 alkyl.

[0191] Embodiment 7. The method of Embodiment 3, wherein R4is C1-6 alkyl or -X-L1.

[0192] Embodiment 8. The method of Embodiment 3, wherein R5ais hydroxy or methyl.

[0193] Embodiment 9. The method of Embodiment 3, wherein at least one of the one or more ligase targeting moi eties has a structure according to the formula:(V-Ib).

[0194] Embodiment 10. The method of Embodiment 9, wherein at least one of the one or more ligase targeting moieties has the structure:

[0195] Embodiment 11. The method of Embodiment 2, wherein at least one of the one or more ligase targeting moieties is a cereblon targeting moiety of one or more of formulas (C-a) to (C-k) as described herein.

[0196] Embodiment 12. The method of any one of Embodiments 1-11, wherein the one or more BRD3 protein targeting moieties is selected from one or more of formulas PTM-a, PTM-b,PTM-c, PTM-da, PTM-db, PTM-dc, PTM-e, PTM-fa, PTM-fb, PTM-g, PTM-h, PTM-i, PTM-j, or PTM-k as described herein.

[0197] Embodiment 13. The method of Embodiment 12, wherein the one or more BRD3 protein targeting moieties is selected from one or more of formulas PTM-aa through PTM-ai, PTM-ba through PTM-bf, PTM-ca through PTM-cc, PTM-ja, or PTM-ka as described herein.

[0198] Embodiment 14. The method of Embodiment 13, wherein the one or more BRD3 protein targeting moieties is selected from one or more of formulas PTM-al through PTM-a36 as described herein.

[0199] Embodiment 15. The method of any one of Embodiments 1-14, wherein the linker (L) is a chemical linking moiety connecting the LTM and the PTM, and having a structure according to the formula -(AL)q-, wherein: (AL)qis a group that is connected to at least one of LTM, PTM, or both; q is an integer greater than or equal to 1; each ALis CRL1RL2, O, SO2, NRL3, CONRL3, CO, CRL1=CRL2, C=C, (C3-C11) cycloalkyl optionally substituted with 1-6 RL1and / or R12groups, (C3-C11) heterocyclyl optionally substituted with 1-6 R1 1and / or R1 2groups, aryl optionally substituted with 1-6 RL1and / or RL2groups, or heteroaryl optionally substituted with 1-6 RL1and / or RL2groups, where RL1or RL2, each independently are optionally linked to other groups to form a cycloalkyl and / or heterocyclyl moiety, optionally substituted with 1-4 RL5groups; and each RL1, RL2, RL3, RL4and RL5is independently hydrogen, halogen, (Ci-Cs)alkyl, O(C1-C8)alkyl, NH(Ci-Cs)alkyl, N((Ci-Cs)alkyl)2, (C3-C11)cycloalkyl, aryl, heteroaryl, (C3- Cn)heterocyclyl, O(C3-C8)cycloalkyl, NH(C3-C8)cycloalkyl, N((C3-C8)cycloalkyl)((Ci- C8)alkyl), OH, NH2, CC-(C1-C8)alkyl, CCH, CH=CH(C1-C8)alkyl, C((C1-C8)alkyl)=CH(Ci- C8)alkyl), C((C1-C8)alkyl)=C((C1-C8)alkyl)2, CO(C1-C8)alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2CONH(C1-C8)alkyl, or CON((C1-C8)alkyl)2.

[0200] Embodiment 16. The method of Embodiment 15, wherein the linker has a linear non-hydrogen atom number from 1 to 30.

[0201] Embodiment 17. The method of Embodiment 15, wherein the linker (L) comprises at least one moiety selected from:wherein: m, n, o, p, q, and t are each independently 0, 1, 2, 3 or 4; and u, w, and v are each independently selected from integers 0 and 1; XL is -C(CH2)-, -C(CH3)H-, -CH2-, -O-, C=O, or - NH-CH2-; and RL is H, OH, F, Cl, or methyl; and WL2, WL3, WL4, WLS, WL6, WL7, and WLS are each independently 6- to 12-membered spirocycloalkylene or spiroheterocyclylene, eachoptionally substituted with 0, 1 , or 2 substituents selected from hydroxy, halogen, (C1-C3)alkoxy, (C1-C3)alkyl, (C1-C3)haloalkyl, or amino.

[0202] Embodiment 18. The method of Embodiment 15, wherein the linker (L) comprises, wherein each m is independently 1 or 2.

[0203] Embodiment 19. The method of any one of Embodiments 1-18, wherein the insect cell is a cell of an insect, and wherein the contacting of the insect cell with an effective amount of the compound or composition comprises applying the compound or composition to an environment in which the insect is present.

[0204] Embodiment 20. The method of any one of Embodiments 1-19, wherein the compound or composition is applied to an insect pest, a plant, a seed, the soil, or other surface in the environment in which the insect is present.

[0205] Embodiment 21. The method of any one of Embodiments 1-20, wherein the insect cell is a cell of an insect that is a member of the order Lepidoptera, Coleoptera, Diptera, Hymenoptera, Mallophaga, Homoptera, Hemiptera, Orthoptera, Thysanoptera, Dermaptera, Isoptera, Anoplura, Siphonaptera, or Trichoptera.

[0206] Embodiment 22. The method of Embodiment 21, wherein the insect is a member of the order Lepidoptera.

[0207] Embodiment 23. A composition comprising the compound of any one of Embodiments 1-22 or a salt or solvate thereof, and an agriculturally acceptable carrier.

[0208] Embodiment 24. A method of controlling a level of a BRD3 protein in an insect cell, the method comprising contacting the insect cell with an effective amount of the compound of any one of Embodiments 1-22, or with an effective amount of the composition of Embodiment 23.

[0209] Embodiment 25. The method of Embodiment 24, wherein the controlling of the level of the BRD3 protein comprises degrading the target protein.

[0210] Embodiment 26. A compound of formula C-l through C-27, C-56, or C-57 according to Table 1, or a salt or solvate thereof.

[0211] Embodiment 27. A composition comprising the compound of Embodiment 26 or a salt or solvate thereof, and an agriculturally acceptable carrier.

[0212] Embodiment 28. A method of controlling a level of a BRD3 protein in an insect cell, the method comprising contacting the insect cell with an effective amount of the compound of Embodiment 26, or with an effective amount of the composition of Embodiment 27.

[0213] Embodiment 29. The method of Embodiment 28, wherein the controlling of the level of the BRD3 protein comprises degrading the target protein.

[0214] Embodiment 30. The method of Embodiment 28 or 29, wherein the insect cell is a cell of an insect, and wherein the contacting of the insect cell with an effective amount of the compound or composition comprises applying the compound or composition to an environment in which the insect is present.

[0215] Embodiment 31. The method of any one of Embodiments 28-30, wherein the compound or composition is applied to an insect pest, a plant, a seed, the soil, or other surface in the environment in which the insect is present.EXAMPLES

[0216] The present disclosure will be better understood in view of the following non-limiting examples. The following examples are intended for illustrative purposes only and do not limit in any way the scope of the embodiments.

[0217] Table 1 comprises bifunctional compounds having VHL ligase targeting moieties and BRD3 protein targeting moieties. The compounds set forth in Table 1 were synthesized as described in detail below in Examples C-l to C-57.Table 1ʼnll

[0218] Table 2 comprises a bifunctional compound having cereblon ligase targeting moieties and BRD3 protein targeting moieties. The compounds set forth in Table 2 were commercially available as described in detail below.EXAMPLE C-L SYNTHESIS OF 4-[(5-CYCLOPROPYL-2-ETHYL-PYRAZOL-3-YL)AMINO]-7-(3,5-DIMETHYLISOXAZOL-4-YL)-N-[8-[[(lS)-l-[(2S,4R)-4-HYDROXY-2-[[4-(4-METHYLTHIAZOL-5-YL)PHENYL]METHYLCARBAMOYL]PYRROLIDINE- l-CARBONYL]-2,2-DIMETHYL-PROPYL]AMINO]-8-OXO-OCTYL]-6-METHOXY-9H-PYRIMIDO [4,5-B] INDOLE-2-CARBOXAMIDEA. Step 1100 °C, 16 h

[0219] A mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (20.34 g, 91.19 mmol), l-bromo-4-fluoro-2-methoxy-5-nitro-benzene (19.0 g, 75.99 mmol), K2CO3 (31.51 g, 227.98 mmol) and Pd(dppf)C12 (5.56 g, 7.60 mmol) in dioxane (140 mL) and H2O (60 mL) was heated to 100 °C and stirred for 16 hours under N2. The reaction mixture was diluted with water (150 mL). The mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (200 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 1 / 1) to afford the desired product 4-(4-fluoro-2-methoxy-5- nitro-phenyl)-3,5-dimethyl-isoxazole (13.0 g, crude) as a yellow solid. LCMS: m / z 267.0 [M+H]B. Step 2

[0220] To a solution of methyl 2-cyanoacetate (5.81 g, 58.60 mmol, 5.17 mL) in THF (150 mL) was added NaH (3.91 g, 97.66 mmol, 60% purity in oil) at 0 °C under N2. The mixture was stirred at 25 °C for 0.5 hour. To the mixture was added 4-(4-fluoro-2-methoxy-5 -nitro-phenyl )- 3,5-dimethyl-isoxazole (13 g, 48.83 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 16 hours under N2. The reaction mixture was quenched with saturated aqueous NH4CIsolution (200 mL) and extracted with ethyl acetate (200 mh x 3). The combined organic phase was washed with brine (200 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 1 / 1) to afford the desired product methyl 2-cyano-2-[4-(3,5-dimethylisoxazol-4-yl)-5- methoxy -2 -nitro-phenyl] acetate (13.0 g, 36.89 mmol, 75.56% yield, 98% purity) as a yellow oil.’H NMR: DMSO-d / e, 400 MHz. 3 8.23 (s, 1H), 7.51 (s, 1H), 6.24 (s, 1H), 3.97 (s, 3H), 3.78 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H). LCMS: RT = 0.400 min, m.z 346.0 [M+H]+.C. Step 3

[0221] To a solution of methyl 2-cyano-2-[4-(3,5-dimethylisoxazol-4-yl)-5-methoxy-2-nitro- phenyl] acetate (13 g, 37.65 mmol) in AcOH (100 mL) was added Zn (9.85 g, 150.59 mmol) at 25 °C under N2. The mixture was heated to 85 °C and stirred for 3 hours. The reaction mixture was cooled, filtered, and washed with AcOH. The reaction mixture was diluted with water (50 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 2 / 1) to afford the desired product methyl 2-amino-6-(3,5-dimethylisoxazol-4-yl)-5- methoxy-lH-indole-3-carboxylate (5.3 g, 15.97 mmol, 42.41% yield, 95% purity) as a red solid. ’HNMR: DMSO4, 400 MHz. 3 10.48 (s, 1H), 7.25 (s, 1H), 6.89 (s, 1H), 6.70 (brs, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 2.24 (s, 3H), 2.05 (s, 3H). LCMS: RT = 0.409 min, m / z 316.0 [M+H]+.D. Step 4

[0222] A mixture of methyl 2-amino-6-(3,5-dimethylisoxazol-4-yl)-5-methoxy-l / / -indole-3- carboxylate (500 mg, 1.59 mmol) and ethyl cyanoformate (1.57 g, 15.86 mmol, 1.55 mL) in HCl / dioxane (2 M in dioxane, 6.0 mmol, 3.0 mL) was heated to 80 °C and stirred for 3 hours under N2. The reaction mixture was concentrated in vacuo. The mixture was triturated with Petroleum ether (100 mL). The resultant precipitate solid was collected by fdtration and dried in vacuo to afford the desired product ethyl 7-(3,5-dimethylisoxazol-4-yl)-4-hydroxy-6-methoxy- 9 / / -pyrimido[4,5-b]indole-2-carboxylate (5 g, crude, nine batch) as a yellow solid. 'H NMR: DMSO-t / 6, 400 MHz. d 12.56 (brs, 1H), 12.47 (s, 1H), 7.64 (s, 1H), 7.34 (s, 1H), 4.39 (q, J= 7.2 Hz, 2H), 3.85 (s, 3H), 2.29 (s, 3H), 2.09 (s, 3H), 1.37 (t, J= 12 Hz, 3H). LCMS: RT = 0.376 min, m / z 383.1 [M+H]+.E. Step 5

[0223] A mixture of ethyl 7-(3,5-dimethylisoxazol-4-yl)-4-hydroxy-6-methoxy-9 / 7- pyrimido[4,5-b]indole-2-carboxylate (3 g, 7.85 mmol) in POCLs (16.45 g, 107.28 mmol, 10 mL) and CHCh (20 mL) was heated to 90 °C and stirred for 5 hours under N2. The reaction mixture was concentrated in vacuo. The mixture was poured into water (80 mL) slowly. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 2 / 1) to afford the desired product ethyl 4-chloro-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-9J / -pyrimido[4,5- b]indole-2-carboxylate (3 g, crude) as a yellow solid. 'H NMR: DMSO-d6, 400 MHz. 6 13.05 (brs, 1H), 7.90 (s, 1H), 7.54 (s, 1H), 4.42 (q, J= 7.2 Hz, 2H), 3.93 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H), 1.38 (t, J = 12 Hz, 3H).F. Step 6

[0224] A mixture of ethyl 4-chloro-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-97T- pyrimido[4,5-b]indole-2-carboxylate (500 mg, 1.25 mmol), 5-cyclopropyl-2-ethyl-pyrazol-3- amine (282.94 mg, 1.87 mmol), BrettPhos-Pd-Gs (226.16 mg, 249.49 prnol) and CS2CO3 (812.89 mg, 2.49 mmol) in dioxane (5 mL) was heated to 100 °C and stirred for 16 hours under N2. The reaction mixture was diluted with water (10 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was triturated in Petroleum ether / Ethyl acetate (1 / 1, 10 mL). The resultant precipitate solid was collected by fdtration and dried in vacuo to afford the desired product ethyl 4-[(5-cyclopropyl-2-ethyl-pyrazol-3-yl)amino]-7-(3,5- dimethylisoxazol-4-yl)-6-methoxy-97 / -pyrimido[4,5-b]indole-2-carboxylate (880 mg, crude) as a yellow solid. LCMS: RT = 0.462 min, m / z 516.2 [M+H]+.G. Step 7

[0225] To a solution of ethyl 4-[(5-cyclopropyl-2-ethyl-pyrazol-3-yl)amino]-7-(3,5- dimethylisoxazol-4-yl)-6-methoxy-9H-pyrimido[4,5-b]indole-2-carboxylate (880 mg, 1.71 mmol) in THF (5 mL) and H2O (2 mL) was added LiOHH2O (214.88 mg, 5.12 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 16 hours under N2. The reaction mixture was diluted with water (5 mL). The pH of the mixture was adjusted to 5 by addition of 1 M aqueous HC1 solution. The mixture was extracted with dichloromethane / methanol (10 / 1, 10 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, fdteredand concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA) - ACN]; gradient: 23%-53% B over 10 min) to afford the desired product 4-[(5-cyclopropyl-2-ethyl-pyrazol-3-yl)amino]-7-(3,5- dimethylisoxazol-4-yl)-6-methoxy-9H-pyrimido[4,5-b]indole-2-carboxylic acid (25 mg, 51.28 pmol) as a yellow solid. 'H NMR: DMSO-d6, 400 MHz. 3 13.05 (brs, 1H), 12.25 (s, 1H), 9.28 (s, 1H), 7.50 (s, 1H), 7.34 (s, 1H), 5.89 (s, 1H), 3.95 - 3.91 (m, 2H), 3.82 (s, 3H), 2.33 - 2.31 (m, 1H), 2.30 (s, 3H), 2.09 (s, 3H), 1.33 (t, J= 7.2 Hz, 3H), 0.87 - 0.83 (m, 2H), 0.63 - 0.60 (m, 2H). LCMS: RT = 0.407 min, m / z 488.1 [M+H]+.H. Step 8

[0226] To a solution of (2S,4R)-l-[(2,S’)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (200 mg, 428.24 pmol, HC1 salt), 8-( tert-butoxycarbonylamino)octarioic acid (126.68 mg, 428.24 pmol) and DIPEA (332.09 mg, 2.57 mmol, 447.55 pL) in DMF (2 mL) were added TPTU (190.82 mg, 642.37 μmol) and HOBt (86.80 mg, 642.37 pmol) at 0 °C. The mixture was stirred at 25 °C for 16 hours under N2. The reaction mixture was diluted with water (2 mL). The mixture was extracted with dichloromethane / methanol (10 / 1, 5 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC on silica gel (Diehl oromethane / Methanol = 10 / 1) to afford the desired product tert-butyl / V-[8-[[(lS)-l-[(25,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5- yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]amino]-8-oxo- octyl]carbamate (220 mg, 314.34 pmol, 73.40% yield, 96% purity) as a yellow oil. 'H NMR: DMSO-tA, 400 MHz. 3 8.98 (s, 1H), 8.59 - 8.51 (m, 1H), 7.86 - 7.80 (m, 1H), 7.43 - 7.37 (m, 4H), 6.74 (brs, 1H), 5.13 - 5.10 (m, 1H), 4.56 - 4.52 (m, 1H), 4.47 - 4.39 (m, 2H), 4.37 - 4.33 (m,1H), 4.25 - 4.18 (m, 1H), 3.69 - 3.59 (m, 3H), 3.19 - 3.12 (m, 1H), 2.44 (s, 3H), 1.36 (s, 9H), 1.26 - 1.21 (m, 14H), 0.93 (s, 9H). LCMS: RT = 0.457 min, m'z 694.3 [M+Na]+.I. Step 9

[0227] To a solution of ze / 7-butyl Ar-[8-[[(15’)-l-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5- yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]amino]-8-oxo- octyl] carbamate (220 mg, 327.44 pmol) in CH2CI2 (3 mL) was added HCI / dioxane (4 M in dioxnae, 12.0 mmol, 3.0 mL) at 25 °C under N2. The reaction mixture was stirred at 25 °C for 1 hour under N2. The reaction mixture was concentrated tn vacuo to afford the desired product (2S,4R)-l-[(2S)-2-(8-aminooctanoylamino)-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (185 mg, 298.08 pmol, 91.03% yield, 98% purity, HC1 salt) as a yellow solid. LCMS: RT = 0.328 min, m z 572.4 [M+H]+.J. Step 10

[0228] To a solution of (25,4R)-l-[(2S)-2-(8-aminooctanoylamino)-3,3-dimethyl-butanoyl]-4- hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (24.95 mg, 41.02 μmol, HC1 salt), 4-[(5-cyclopropyl-2-ethyl-pyrazol-3-yl)amino]-7-(3,5-dimethylisoxazol- 4-yl)-6-methoxy-9 / 7-pyrimido[4,5-b]indole-2-carboxylic acid (20 mg, 41.02 pmol) and DIPEA (31.81 mg, 246.15 pmol, 42.87 pL) in DMF (0.5 mL) were added EDCI (11.80 mg, 61.54 pmol)and HOBt (8.32 mg, 61 .54 pmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour under N2. The reaction mixture was diluted with water (2 mL). The mixture was extracted with dichloromethane / methanol (10 / 1, 5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna Cl 8 150*25mm*10um; mobile phase: [water (FA) - ACN]; gradient: 36% - 66% B over 10 min) to afford the desired product 4-[(5- cyclopropyl-2-ethyl-pyrazol-3-yl)amino]-7-(3,5-dimethylisoxazol-4-yl)- / V-[8-[[(lS)-l-[(2S,4R)- 4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2- dimethyl-propyl]amino]-8-oxo-octyl]-6-methoxy-9 / / -pyrimido[4,5-b]indole-2-carboxamide (5.42 mg, 5.19 pmol, 12.65% yield, 99.669% purity) as an off-white solid. 'H NMR DMSO-tL, 400 MHz. 3 12.21 (brs, 1H), 9.28 (brs, 1H), 8.97 (s, 1H), 8.57 - 8.53 (m, 1H), 8.18 - 8.13 (m, 1H), 7.86 - 7.82 (m, 1H), 7.60 - 7.52 (m, 1H), 7.41 - 7.37 (m, 4H), 7.34 (s, 1H), 5.94 (s, 1H), 5.12 - 5.11 (m, 1H), 4.55 - 4.53 (m, 1H), 4.45 - 4.40 (m, 2H), 4.36 - 4.32 (m, 1H), 4.24 - 4.18 (m, 1H), 3.97 - 3.93 (m, 2H), 3.82 (s, 3H), 3.67 - 3.63 (m, 2H), 3.25 - 3.23 (m, 2H), 2.43 (s, 3H), 2.29 (s, 3H), 2.27 - 2.23 (m, 1H), 2.15 - 2.12 (m, 1H), 2.09 (s, 3H), 2.06 - 1.98 (m, 2H), 1.93 - 1.85 (m, 3H), 1.51 - 1.45 (m, 4H), 1.32 - 1.27 (m, 11H), 0.92 (s, 9H). LCMS: m / z 1041.7 [M+H]+.EXAMPLE C-2. SYNTHESIS OF (2S,4R)-l-[(2S)-2-[ll-[[4-[(2S,4R)-l-ACETYL-4-(4- CHLOROANILINO)-2-METHYL-3,4-DIHYDRO-2H-QUINOLIN-6- YL]BENZOYL]AMINO]UNDECANOYLAMINO]-3,3 DIMETHYL-BUTANOYL]-4- HYDROXY-N-[[4-(4-METHYLTHIAZOL-5-YL)PHENYL]METHYL]PYRROLIDINE-2- CARBOXAMIDEA. Step 1

[0229] To a solution of (2lS’,4 / ?)-l-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (190 mg, 406.83 pmol, HC1 salt) and 1 1 -( tert-butoxycarbonylamino)undecanoic acid (122.63 mg, 406.83 pmol) in DMF (2 mL) were added DIEA (315.48 mg, 2.44 mmol, 425.18 pL), TPTU (181.28 mg, 610.25 pmol) and HOBt (82.46 mg, 610.25 pmol) at 0 °C under N2. The mixture was stirred at 25 °C for 2 hours under N2. The reaction mixture was diluted with water (5 mL) and extracted with Dichloromethane / Methanol (10 / 1, 5 mL x 3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na2SCU, filtered and concentrated in vacuo. The residue was purified by preparative TLC on silica gel (Dichloromethane / Methanol = 10 / 1) to afford the desired product tert-butyl A-[l l-[[(lS)-l-[(25',4R)-4-hydroxy-2-[[4-(4-methylthiazol-5- yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]amino]-l 1-oxo- undecyl]carbamate (210 mg, 294.13 pmol, 72.30% yield) as a yellow oil. ’H NMR: CDCh, 400 MHz. 3 8.21 (s, 1H), 8.03 (brs, 1H), 7.43 - 7.28 (m, 6H), 6.04 (brs, 1H), 4.79 - 4.72 (m, 1H), 4.64 - 4.62 (m, 1H), 4.55 - 4.49 (m, 2H), 4.40 - 4.31 (m, 1H), 4.20 - 4.11 (m, 1H), 3.75 - 3.55 (m, 2H), 3.12 -3.09 (m, 1H), 2.65 - 2.58 (m, 1H), 2.55 (s, 3H), 2.23 - 2.13 (m, 3H), 1.48 - 1.42 (m, 13H), 1.30 - 1.24 (m, 12H), 0.94 (s, 9H). LCMS: m / z 714.4 [M+H]+.B. Step 2

[0230] To a solution of tert-butyl A-[l l-[[(15)-l-[(2S,4R)-44iydroxy-2-[[4-(4-methylthiazol-5- yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]amino]-l 1-oxo- undecyl]carbamate (210 mg, 294 13 pmol) in CH2CI2 (2 mL) was added HCI / dioxane (4 M in dioxane, 8.0 mmol, 2.0 mL) under N2. The mixture was stirred at 25 °C for 0.5 hour under N2. The mixture was concentrated in vacuo to afford the desired product (2S,4R)-l-[(25)-2-(l l- aminoundecanoylamino)-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (190 mg, 292.17 pmol, 99.33% yield, HO salt) as a yellow solid. LCMS: m z 614.3 [M+H]+.C. Step 3

[0231] To a solution of (2S,4R)-l-[(25)-2-(l l-aminoundecanoylamino)-3,3-dimethyl- butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (125.60 mg, 193.14 pmol, HC1 salt) and 4-[(2S,4R)-l-acetyl-4-(4-chloroanilino)-2-methyl-3,4- dihydro-2H-quinolin-6-yl]benzoic acid (70 mg, 160.95 pmol) in DMF (1.5 mL) were added TPTU (71.72 mg, 241.43 pmol), HOBt (32.62 mg, 241.43 pmol) and DIEA (124.81 mg, 965.71 pmol, 168.21 μL) at 0 °C under N2. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (5 mL) and extracted with Dichloromethane / Methanol (10 / 1, 5 mL x 3). The combined organic phase was dried with anhydrous Na2SCU, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Daisogel SP ODS RPS 150*25mm*5um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 50% - 80% B over 10 min) to afford the desired product (2S,4R)-l-[(25)-2-[l l-[[4-[(25,4R)-l-acetyl-4-(4- chloroanilino)-2-methyl-3,4-dihydro-2H-quinolin-6-yl]benzoyl]amino]undecanoylamino]-3,3- dimethyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2- carboxamide (62.22 mg, 60.36 pmol, 37.50% yield) as a white solid. ’H NMR: DMSO-d6, 400 MHz. 3 8.98 (s, 1H), 8.55 (t, J= 6.0 Hz, 1H), 8.42 (t, J= 5.2 Hz, 1H), 7.90 - 7.80 (m, 3H), 7.63 -7.57 (m, 3H), 7.46 - 7.36 (m, 6H), 7.12 (d, J= 8.8 Hz, 2H), 6.74 (d, J= 8.8 Hz, 2H), 6.29 (d, J = 8.4 Hz, 1H), 5.11 (d, .7= 3.6 Hz, 1H), 4.76 - 4.66 (m, 1H), 4.54 (d, J = 9.2 Hz, 1H), 4.47 - 4.39 (m, 2H), 4.37 - 4.27 (m, 2H), 4.23 - 4.21 (m, 1H), 3.70 - 3.60 (m, 2H), 3.25 - 3.22 (m, 2H), 2.65 -2.58 (m, 1H), 2.44 (s, 3H), 2.30 - 2.22 (m, 1H), 2.14 (s, 3H), 2.11 - 1.98 (m, 2H), 1.94 - 1.84 (m, 1H), 1.55 - 1.43 (m, 4H), 1.29 - 1.21 (m, 12H), 1.09 (d, J = 6.4 Hz, 3H), 0.93 (s, 9H). LCMS: m z 1030.8 [M+H]+.EXAMPLE C-3. SYNTHESIS OF (2S,4R)-l-[(2R)-2-[3-[8-[[4-[(2S,4R)-l-ACETYL-4-(4- CHLOROANILINO)-2-METHYL-3,4-DIHYDRO-2H-QUINOLIN-6- YL]BENZOYL]AMINO]OCTOXY]ISOXAZOL-5-YL]-3-METHYL-BUTANOYL]-4- HYDROXY-N- [ [4-(4-METHYLTHIAZOL-5- YL)PHENYL| METHYL] PYRROLIDINE-2-CARBOXAMIDEA. Step 1

[0232] To a mixture of 5-methylisoxazol-3-ol (25 g, 252.30 mmol) and PPTS (3.17 g, 12.62 mmol) in CH2CI2 (500 mL) was added DHP (25.47 g, 302.76 mmol, 27.68 mL) at 0 °C under N2. The mixture was warmed to 25 °C and stirred for 15 hours under N2. The reaction mixture was diluted with water (1000 mL). The pH of the mixture was adjusted to 7 - 8 by addition of aqueous Nal ICO3 solution. The mixture and extracted with dichloromethane (2500 mL). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to afford the desired product 5-methyl-3-tetrahydropyran-2- yloxy-isoxazole (90 g, 488.31 mmol, 96.77% yield, 99.4% purity) as a light yellow solid. 'H NMR: DMSO4, 400 MHz. 3 5.47 (s, 1H), 5.34 - 5.30 (m, 1H), 4.07 - 4.01 (m, 1H), 3.70 - 3.57 (m, 1H), 2.25 (s, 3H), 2.15 - 1.96 (m, 2H), 1.88 - 1.79 (m, 1H), 1.71 - 1.50 (m, 3H). LCMS: m / z 183.9 [M+H]+.B. Step 2

[0233] To a mixture of 5-methyl-3-tetrahydropyran-2-yloxy-isoxazole (22.5 g, 122.81 mmol) in THF (400 mL) was added dropwise KHMDS (1 M in THF, 147.38 mmol, 147.38 mL) under N2 at -78 °C. The mixture was stirred at -78 °C for 1 hour under N2. Then the mixture was bubbled with CO2 at -78 °C for 1 hour. The mixture was stirred at 25 °C for 14 hours under CO2 (15 Psi). The reaction mixture was diluted with aqueous NH4CI solution (2500 mL). The mixture was extracted with ethyl acetate (1000 mL x 2). The pH of the mixture was adjusted to 2 ~ 3 by addition of 1 M aqueous HC1 solution. Then the mixture was extracted with ethyl acetate (1000 x6). The combined organic phase was dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to afford the desired product 2-(3-tetrahydropyran-2-yloxyisoxazol-5-yl)acetic acid (70 g, 308.08 mmol, 62.71% yield, four batch) as a white solid. 'H NMR: DMSO-d6, 400 MHz. d 12.97 (brs, 1H), 5.78 (s, 1H), 5.24 - 5.20 (m, 1H), 3.90 - 3.86 (m, 1H), 3.74 (s, 2H), 3.59 - 3.48 (m, 1H), 1.98 - 1.84 (m, 2H), 1.81 - 1.72 (m, 1H), 1.69 - 1.57 (m, 1H), 1.51 - 1.38 (m, 2H). LCMS: RT = 0.170 min, m / z 250.0 [M+Na]+.C. Step 3

[0234] To a mixture of 2-(3-tetrahydropyran-2-yloxyisoxazol-5-yl)acetic acid (23 g, 101.23 mmol) in MeOH (500 mL) were added DCC (25.06 g, 121.47 mmol, 24.57 mL) and DMAP (12.37 g, 101.23 mmol) at 0 °C under N2. The mixture was warmed to 25 °C and stirred for 15 hours under N2. The mixture was concentrated in vacuo. The pH of the mixture was adjusted to 6 - 7 by addition of 2 M aqueous HC1 solution. The mixture was extracted with ethyl acetate (1000 mL x 3). The combined organic phase was washed with brine (500 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to afford the desired product methyl 2-(3- tetrahydropyran-2-yloxyisoxazol-5-yl) acetate (40 g, 165.81 mmol, 54.60% yield, three batch) as a yellow oil. ^ NMR: DMSO-d6, 400MHz.<5 5.93 (s, 1H), 5.25 - 5.21 (m, 1H), 3.90 - 3.86 (m, 3H), 3.67 (s, 3H), 3.57 - 3.48 (m, 1H), 1.95 - 1.86 (m, 2H), 1.79 - 1.75 (m, 1H), 1.66 - 1.62 (m, 1H), 1.49 - 1.41 (m, 2H). LCMS: m / z 264.0 [M+Na]+.D. Step 4

[0235] To a mixture of methyl 2-(3-tetrahydropyran-2-yloxyisoxazol-5-yl) acetate (38 g, 157.52 mmol) in DMF (300 mL) was added Z-BuOK (1 M in THF, 173.27 mmol, 173.27 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 hour under N2. Then to the mixture was added 2-iodopropane (29.45 g, 173.27 mmol, 17.30 mL) at 0 °C and stirred for 0.5 hour underN2. The mixture was warmed to 25 °C and stirred for 1 hour under N2. The reaction mixture was diluted with water (500 mL). The mixture was extracted with ethyl acetate (1000 mL x 2). The combined organic phase was washed with brine (500 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to afford the desired product methyl 3-methyl-2-(3- tetrahydropyran-2-yloxyisoxazol-5-yl) butanoate (32 g, 112.95 mmol, 71.70% yield) as a yellow oil. ^NMR: DMSO-t / / ,, 400MHz. 3 5.87 - 5.83 (m, 1H), 5.25 - 5.21 (m, 1H), 3.92 - 3.83 (m, 1H), 3.69 (s, 3H), 3.63 - 3.59 (m, 1H), 3.56 - 3.49 (m, 1H), 2.34 - 2.25 (m, 1H), 1.92 - 1.86 (m, 2H), 1.79 - 1.74 (m, 1H), 1.66 - 1.58 (m, 1H), 1.47 - 1.41 (m, 2H), 0.94 (d, J= 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H).E. Step 5

[0236] To a mixture of methyl 3-methyl-2-(3-tetrahydropyran-2-yloxyisoxazol-5-yl)butanoate (30 g, 105.89 mmol) in MeOH (300 mL) was added HCI / MeOH (4 M in the MeOH, 217.07 mmol, 54.27 mL) at 25 °C under N2. The mixture was stirred at 25 °C for 2 hours under N2. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 2 / 1) to afford the desired product methyl 2-(3- hydroxyisoxazol-5-yl)-3-methyl-butanoate (18 g, 90.36 mmol, 85.34% yield) as a yellow oil.'HNMR: 400MHz. d 11.22 (s, 1H), 5.94 (s, 1H), 3.65 (s, 3H), 3.62 - 3.60 (m, 1H), 2.32 - 2.22 (m, 1H), 0.92 (d, J= 6.8 Hz, 3H), 0.84 (d, J= 6.8 Hz, 3H). LCMS: m / z 199.9 [M+H]+.F. Step 6

[0237] To a mixture of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoate (3 g, 15.06 mmol), Z / 7-butyl / V-(8-hydroxyoctyl)carbamate (4.80 g, 19.58 mmol) in THF (40 mL) wereadded tributylphosphane (9.14 g, 45.18 mmol, 11.15 mL) and TMAD (6.48 g, 37.65 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 15 hours under N2. The reaction mixture was diluted with water (200 mL). The mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to afford the desired product methyl 2-[3-[8-( tert- butoxycarbonylamino)octoxy]isoxazol-5-yl]-3-methyl-butanoate (5.4 g, crude) as a yellow oil. 'HNMR: DMSO-d6, 400MHz. d 6.78 - 6.72 (m 1H), 6.18 (s, 1H), 4.13 (t, J= 6.4 Hz, 2H), 3.66 - 3.64 (m, 4H), 2.89 - 2.86 (m, 2H), 2.32 - 2.23 (m, 1H), 1.73 - 1.65 (m, 2H), 1.37 - 1.35 (m, 15H), 1.24 - 1.20 (m, 4H), 0.92 (d, J= 6.8 Hz, 3H), 0.84 (d, J= 6.8 Hz, 3H). LCMS: / ?Lz 449.2 [M+Na]+.G. Step 7

[0238] To a mixture of methyl 2-[3-[8-(terAbutoxycarbonylamino)octoxy]isoxazol-5-yl]-3- methyl-butanoate (2 g, 4.69 mmol) in THF (10 mL), MeOH (10 mL) and H2O (2 mL) was added LiOH H2O (590.28 mg, 14.07 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 16 hours under N2. The residue was purified by preparative HPLC (column: Daisogel C18 250*70mm*10um; Smobile phase: [water (NH4HCO3)-ACN]; gradient: 10%-40% B over 25 min) to afford the desired product 2-[3-[8-(to7-butoxycarbonylamino)octoxy]isoxazol-5-yl]-3- methyl-butanoic acid (1.5 g, 3.64 mmol, 77.55% yield, 100% purity) as a white solid. 'HNMR: DMSO-t / 6, 400MHz.d 6.74 (brs, 1H), 5.98 (s, 1H), 4.11 (t, J= 6.4 Hz, 2H), 3.27 (d, J= 9.2 Hz, 2H), 2.90 - 2.88 (m, 3H), 2.26 - 2.15 (m, 1H), 1.76 - 1.63 (m, 2H), 1.39 - 1.32 (m, 15H), 1.25 - 1.21 (m, 4H), 0.93 (d, J= 6.8 Hz, 3H), 0.79 (d, J= 6.8 Hz, 3H). LCMS: m,z 435.3 [M+Na]+.H. Step 8

[0239] To a mixture of 2-[3-[8-( / ert-butoxycarbonylamino)octoxy]isoxazol-5-yl]-3-methyl- butanoic acid (1.22 g, 2.97 mmol), (25,4R)-4-hydroxy-A-[[4-(4-methylthiazol-5- yl)phenyl]methyl]pyrrolidine-2-carboxamide (700 mg, 1.98 mmol, HC1 salt) in DMF (1 mL) were added DIEA (1.53 g, 11.87 mmol, 2.07 mL), HOBt (534.58 mg, 3.96 mmol) and TPTU (1.18 g, 3.96 mmol) at 0 °C under N2. The mixture was warmed to 25 °C and stirred for 4 hours under N2. The reaction mixture was diluted with water (20 mL). The mixture was extracted with dichloromethane / methanol (10 / 1, 50 mL x 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna Cl 8 (250*70mm*15um); mobile phase: [water (NH4HCO3)-ACN]; gradient: 40%-70% B over 22 min) to afford the mixture product (LCMS-mix, SFC-mix). The mixture product was separated by chiral SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm*10um); mobile phase: [CO2-MeOH (0.1% NH3 H2O)]; B%: 25%, isocratic elution mode) to afford the desired product tert-butyl A-[8-[5- [(lA)-l-[(2S,4A)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l- carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxyoctyl]carbamate (620 mg, 870.90 pmol, 44.03% yield, 100% purity) as a yellow oil and the desired product tert-butyl A-[8-[5-[(lS)-l-[(2S,4R)-4- hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2- methyl-propyl]isoxazol-3-yl]oxyoctyl]carbamate (600 mg, 842.80 pmol, 42.61% yield, 100% purity). 'H NMR: DMSO4, 400MHz. d 8.98 (s, 1H), 8.45 (t, J= 5.6 Hz, 1H), 7.48 - 7.38 (m, 3H), 7.33 - 7.30 (m, 1H), 6.75 - 6.70 (m, 1H), 6.04 (s, 1H), 5.12 (d, J= 3.2 Hz, 1H), 4.48 - 4.22 (m, 6H), 3.77 - 3.74 (m, 1H), 3.57 - 3.55 (m, 1H), 3.46 - 3.39 (m, 1H), 2.90 - 2.85 (m, 2H), 2.45 (s, 3H), 2.27 - 2.20 (m, 1H), 2.09 - 2.00 (m, 1H), 1.94 - 1.86 (m, 1H), 1.68 - 1.58 (m, 2H), 1.37 - 1.34 (m, 13H), 1.27 - 1.21 (m, 6H), 0.96 (d, J= 6.8 Hz, 3H), 0.83 (d, J= 6.8 Hz, 3H). LCMS: RT = 0.500 min, m / z 712.4 [M+H]+. 'H NMR: DMSO-d6, 400MHz. d 8.98 (s, 1H), 8.51 (t, J =6.0 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.40 - 7.35 (m, 2H), 6.75 - 6.72 (m, 1H), 6.07 (s, 1H), 5.10 (d, J= 3.6 Hz, 1H), 4.38 - 4.30 (m, 4H), 4.13 - 4.10 (m, 1H), 3.77 - 3.75 (m, 1H), 3.67 - 3.64 (m, 1H), 3.47 - 3.40 (m, 2H), 2.93 - 2.86 (m, 2H), 2.45 (s, 3H), 2.30 - 2.21 (m, 1H), 2.10 - 1.99 (m, 1H), 1.95 - 1.87 (m, 1H), 1.72 - 1.63 (m, 2H), 1.37 - 1.34 (m, 13H), 1.29 - 1.21 (m, 6H), 0.94 (d, J= 6.8 Hz, 3H), 0.80 (d, J= 6.8 Hz, 3H). LCMS: RT = 0.499 min, m / z 712.4 [M+H]+.I. Step 9

[0240] To a mixture of tert-butyl / V-[8-[5-[(I A>)- l -[(2\4 / ?)-4-hydroxy-2-[[4-(4-methylthiazol- 5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2-methyl-propyl]isoxazol-3- yl]oxyoctyl]carbamate (600 mg, 842.80 gmol) in CH2CI2 (4 mL) was added TFA (2 mL) at 0 °C under N2. The mixture was warmed to 25 °C and stirred for 2 hours under N2. The reaction mixture was concentrated in vacuo to afford the desired product (2S,4R)-l-[(2R)-2-[3-(8- aminooctoxy)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5- yl)phenyl]methyl]pyrrolidine-2-carboxamide (550 mg, 757.77 pmol, 89.91% yield, TFA salt) as a yellow oil. LCMS: RT = 0.588 min, m / z 612.6 [M+H]+.J. Step 10

[0241] To a mixture of (2S,4R)-l-[(2A)-2-[3-(8-aminooctoxy)isoxazol-5-yl]-3-methyl- butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(200 mg, 275.55 pmol, TFA salt), 4-[(25’,4R)-l-acetyl-4-(4-chloroanilino)-2-methyl-3,4-dihydro- 2H-quinolin-6-yl]benzoic acid (119.84 mg, 275.55 pmol) in DMF (1 mL) were added DIEA (213.68 mg, 1.65 mmol, 287.98 μL) and HATU (209.55 mg, 551.10 pmol) at 0 °C under N2. The mixture was warmed to 25 °C and stirred for 2 hours under N2. The reaction mixture was diluted with water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 250*50mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 47%-77% B over 10 min) to afford the desired product (25,4R )-l-[(2R)-2-[3-[8-[[4-[(21S’,4R)-l-acetyl-4-(4- chloroanilino)-2-methyl-3,4-dihydro-2 / / -quinolin-6-yl]benzoyl]amino]octoxy]isoxazol-5-yl]-3- methyl-butanoyl]-4-hydroxy-7V-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2- carboxamide (71.78 mg, 68.17 pmol, 24.74% yield, 97.7% purity) as a white solid. 'H NMR: DMSO-d6, 400 MHz. 3 8.98 (s, 1H), 8.52 (t, J= 6.0 Hz, 1H), 8.43 (t, J = 5.6 Hz, 1H), 7.90 - 7.88 (m, 2H), 7.61 - 7.57 (m, 3H), 7.45 - 7.40 (m, 4H), 7.39 - 7.35 (m, 2H), 7.12 (d, J= 8.8 Hz, 2H), 6.74 (d, J= 8.8 Hz, 2H), 6.29 (d, J= 8.0 Hz, 1H), 6.07 (s, 1H), 5.11 (d, J= 3.6 Hz, 1H), 4.74 - 4.67 (m, 1H), 4.38 - 4.27 (m, 5H), 4.12 (t, J= 6.4 Hz, 2H), 3.80 - 3.73 (m, 1H), 3.67 - 3.64 (m, 1H), 3.46 - 3.42 (m, 1H), 3.27 - 3.21 (m, 2H), 2.65 - 2.60 (m, 1H), 2.45 (s, 3H), 2.29 - 2.20 (m, 1H), 2.14 (s, 3H), 2.08 - 2.00 (m, 1H), 1.96 - 1.85 (m, 1H), 1.73 - 1.63 (m, 2H), 1.54 - 1.48 (m, 2H), 1.37 - 1.24 (m, 9H), 1.09 (d, J= 6.0 Hz, 3H), 0.94 (d, J= 6.4 Hz, 3H), 0.81 - 0.76 (m, 3H). LCMS: RT = 2.766 min, m / z 1028.7 [M+H]+.EXAMPLE C-4. SYNTHESIS OF (2S,4R)-l-[(2S)-2-[3-[8-[[4-[(2S,4R)-l-ACETYL-4-(4- CHLOROANILINO)-2-METHYL-3,4-DIHYDRO-2H-QUINOLIN-6- YL]BENZOYL]AMINO]OCTOXY]ISOXAZOL-5-YL]-3-METHYL-BUTANOYL]-4- HYDROXY-N- [ [4-(4-METHYLTHIAZOL-5- YL)PHENYL] METHYL] PYRROLIDINE-2- CARBOXAMIDEA. Step 1

[0242] To a mixture of tert-butyl A-[8-[5-[(15)-l -[(2.S',4R)-4-hydroxy-2-[[4-(4-methylthiazol- 5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2-methyl-propyl]isoxazol-3- yl]oxyoctyl]carbamate (600 mg, 842.80 pmol) in CH2CI2 (4 mL) was added TFA (2 mL) at 0 °C under N2. The mixture was warmed to 25 °C and stirred for 2 hours under N2. The reaction mixture was concentrated in vacuo to afford the desired product (2S,4R)-l-[(25)-2-[3-(8- aminooctoxy)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5- yl)phenyl]methyl]pyrrolidine-2-carboxamide (520 mg, 716.43 pmol, 85.01% yield, TFA salt) as a yellow oil. LCMS: m / z 612.3 [M+H]+.B. Step 2

[0243] To a mixture of (2S,4R)-l-[(25)-2-[3-(8-arninooctoxy)isoxazol-5-yl]-3-methyl- butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (200 mg, 275.55 pmol, TFA salt), 4-[(2S,4R)-l-acetyl-4-(4-chloroanilino)-2-methyl-3,4-dihydro- 2 / / -quinolin-6-yl]benzoic acid (119.84 mg, 275.55 pmol) in DMF (1 mL) were added DIEA (213.67 mg, 1.65 mmol, 287.97 pL) and HATU (209.55 mg, 551.10 pmol) at 0 °C under N2. The mixture was warmed to 25 °C and stirred for 2 hours under N2. The reaction mixture was diluted with water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC ((column: Waters Xbridge BEH C18 250*50mm*10um;mobile phase: [water (NH4HCO3) - ACN]; gradient: 47% - 77% B over 10 min) to afford the desired product (2S,4R)-l-[(25T)-2-[3-[8-[[4-[(25,4R)-l-acetyl-4-(4- chloroanilino)-2-methyl-3,4-dihydro-2 / / -quinolin-6-yl]benzoyl]amino]octoxy]isoxazol-5-yl]-3- methyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2- carboxamide (71.78 mg, 68.17 pmol, 24.74% yield, 97.7% purity) as a white solid. 'H NMR: DMSO-fifc, 400MHz. 6 8.98 (s, 1H), 8.52 (t, J= 6.0 Hz, 1H), 8.43 (t, J= 5.6 Hz, 1H), 7.89 - 7.87(m, 2H), 7.61 - 7.57 (m, 3H), 7.47 - 7.40 (m, 4H), 7.39 - 7.35 (m, 2H), 7.12 (d, J = 8.8 Hz, 2H), 6.74 (d, .7= 8.8 Hz, 2H), 6.29 (d, J= 8.0 Hz, 1H), 6.07 (s, 1H), 5.11 (d, J= 3.6 Hz, 1H), 4.77 - 4.66 (m, 1H), 4.40 - 4.23 (m, 5H), 4.12 (t, J= 6.4 Hz, 2H), 3.80 - 3.73 (m, 1H), 3.67 - 3.65 (m, 1H), 3.45 - 3.43 (m, 1H), 3.27 - 3.21 (m, 2H), 2.65 - 2.57 (m, 1H), 2.45 (s, 3H), 2.28 - 2.20 (m, 1H), 2.14 (s, 3H), 2.07 - 1.99 (m, 1H), 1.95 - 1.85 (m, 1H), 1.74 - 1.63 (m, 2H), 1.54 - 1.48 (m, 2H), 1.36 - 1.21 (m, 9H), 1.09 (d, J= 6.4 Hz, 3H), 0.94 (d, J= 6.4 Hz, 3H), 0.84 - 0.76 (m, 3H). LCMS: m / z 1028.6 [M+H]+.EXAMPLE C-5. SYNTHESIS OF (2S,4R)-l-[(2S)-2-[[2-[9-[2-[[4-[(2S,4R)-l-ACETYL-4-(4- CHLOROANILINO)-2-METHYL-3,4-DIHYDRO-2H-QUINOLIN-6- YL]BENZOYL]AMINO]ETHYL]-3,9-DIAZASPIRO[5.5]UNDECAN-3- YL]ACETYL]AMINO]-3,3-DIMETHYL-BUTANOYL]-4-HYDROXY-N-[[4-(4- METHYLTHIAZOL-5-YL)PHENYL]METHYL]PYRROLIDINE-2-CARBOXAMIDEA. Step 1

[0244] To a mixture of Ze / 7-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2 g, 7.86 mmol), methyl 2-bromoacetate (1.80 g, 11.79 mmol, 1.12 mL), K2CO3 (3.26 g, 23.59 mmol) and KI (1.31 g, 7.86 mmol) in MeCN (20 mL) was stirred at 60 °C under N2 for 15 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SO4, fdtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 20 / 1) to afford the desired product ze / 7-butyl 9-(2-methoxy-2-oxo- ethyl)-3, 9-diazaspiro [5.5] undecane-3 -carboxylate (650 mg, 1.99 mmol, 25.33% yield) as a yellow oil. *HNMR: CDCh, 400MHz. d 3.73 (s, 3H), 3.39 - 3.35 (m, 4H), 3.26 (s, 2H), 2.56 (s, 4H), 1.61 - 1.57 (m, 4H), 1.47 - 1.44 (m, 13H).B. Step 2

[0245] To a solution of / <77-butyl 9-(2-methoxy-2-oxo-ethyl)-3, 9-diazaspiro [5.5] undecane-3- carboxylate (650 mg, 1.99 mmol) in CH2CI2 (6 mL) was added HCl / dioxane (4 M in dioxane, 24.0 mmol, 6 mL). The mixture was stirred at 25 °C under N2 for 1 hour. The reaction mixture was concentrated in vacuo to afford the desired product methyl 2-(3,9-diazaspiro[5.5]undecan-3- yl)acetate (590 mg, 1.95 mmol, 98.03% yield, 99% purity, 2HC1 salt) as a white solid.LCMS: m / z 226.9 [M+H]+.C. Step 3

[0246] A mixture of methyl 2-(3, 9-diazaspiro [5.5] undecan-3-yl) acetate (540 mg, 1.80 mmol, 2HC1 salt), 2-(tert-butoxy carbonylamino) ethyl 4-methylbenzenesulfonate (853.71 mg, 2.71 mmol), K2CO3 (748.24 mg, 5.41 mmol) and KI (299.56 mg, 1.80 mmol) in MeCN (10 mL) was heated to 60 °C and stirred for 15 hours under N2. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 1% - 25% B over 8 min) to afford the desired product methyl 2-[9-[2-(tert-butoxy carbonylamino) ethyl]-3, 9-diazaspiro [5.5] undecan-3-yl] acetate (700 mg, crude) as a yellow oil. LCMS: m / z 370.0 [M+H]+.D. Step 4

[0247] To a mixture of methyl 2-[9-[2-(tert-butoxy carbonylamino) ethyl]-3, 9-diazaspiro [5.5] undecan-3-yl] acetate (650 mg, 1.76 mmol) in THF (5 mL) and H2O (1 mL) was addedLiOH H2O (221.46 mg, 5.28 mmol). The mixture was stirred at 25 °C under N2 for 2 hours. The reaction mixture was concentrated in vacuo. Then the residue was adjusted to pH 7 by additionof 1 N aqueous HC1 solution. The residue was purified by preparative HPLC (column: Daisogel SP ODS RPS 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 5%-35% B over 10 min) to afford the desired product 2-[9-[2-(tert-butoxycarbonylamino)ethyl]-3,9- diazaspiro[5.5]undecan-3-yl]acetic acid (180 mg, 503.84 pmol, 28.64% yield, 99.5% purity) as a white solid. LCMS: m / z 356.0 [M+H]+.E. Step 5

[0248] To a mixture of 2-[9-[2-(tert-butoxycarbonylamino)ethyl]-3,9- diazaspiro[5.5]140ndecane-3-yl]acetic acid (180 mg, 506.37 pmol), (25,4R)-l-[(2 )-2-amino- 3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2- carboxamide (236.49 mg, 506.37 pmol, HC1 salt) and DIEA (261.78 mg, 2.03 mmol, 352.80 Ml) in DMF (2 mL) were added TPTU (300.84 mg, 1.01 mmol) and HOBt (136.84 mg, 1.01 mmol) at 0 °C. The mixture was stirred at 25 °C under N2 for 2 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was washed with brine (2 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC on silica gel (Dichloromethane / M ethanol = 5 / 1). to afford the desired product tert-butyl iV-[2-[3-[2-[[(15)-l-[(2S,4R)-4-hydroxy-2-[[4-(4- methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl- propyl]amino]-2-oxo-ethyl]-3,9-diazaspiro[5.5]140ndecane-9-yl]ethyl]carbamate (380 mg, 494.78 pmol, 97.71% yield) as a yellow oil. LCMS: m,z 768.5 [M+H]+.F. Step 6

[0249] To a solution of tert-butyl 7V-[2-[3-[2-[[(l1S)-l-[(2£,4R)-4-hydroxy-2-[[4-(4- methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl- propyl]amino]-2-oxo-ethyl]-3,9-diazaspiro[5.5]undecan-9-yl]ethyl]carbamate (380 mg, 494.78 pmol) in CH2CI2 (4 mL) was added HCl / dioxane (4 M in dioxane, 16.00 mmol, 4 mL). The mixture was stirred at 25 °C under N2 for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Ultimate C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 5%-35% B over 2 min) to afford the desired product (2S,4A)-l-[(2S)-2-[[2-[9-(2-aminoethyl)-3,9-diazaspiro[5.5]undecan-3- yl]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5- yl)phenyl]methyl]pyrrolidine-2-carboxamide (30 mg, 42.34 pmol, 8.56% yield, 99.4% purity, HC1 salt) as a colorless oil. LCMS: m / z 668.5 [M+H]1.G. Step 7

[0250] To a solution of mixture of (2S,4R)-l-[(2S)-2-[[2-[9-(2-aminoethyl)-3,9- diazaspiro[5.5]undecan-3-yl]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (25 mg, 35.49 pmol, HC1 salt) and4-[(2S,4R)-l -acetyl -4-(4-chloroanilino)-2-methyl-3,4-dihydro-2H-quinolin-6-yl]benzoic acid (15.44 mg, 35.49 pmol) in DMF (1 mL) were added DIEA (18.35 mg, 141.97 pmol, 24.73 gL) and TBTU (22.79 mg, 70.99 gmol) at 0 °C. The mixture was stirred at 25 °C under N2 for 0.5 hour. The reaction mixture was diluted with water (1 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with brine (1 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 17% - 47% B over 10 min) to afford the desired product (2S,4R)-l-[(25)-2-[[2-[9-[2-[[4-[(2S,4R)-l- acetyl-4-(4-chloroanilino)-2-methyl-3,4-dihydro-2H-quinolin-6-yl]benzoyl]amino]ethyl]-3,9- diazaspiro[5.5]undecan-3-yl]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (11.02 mg, 10.16 gmol, 28.62% yield) as a white solid. 'H NMR: DMSO-tfc, 400MHz. d 8.99 (s, 1H), 8.60 (t, J= 5.6 Hz, 1H), 8.39 (t, J= 5.2 Hz, 1H), 8.20 (s, 1H), 7.90 -7.87 (m, 2H), 7.80 (d, J= 10.0 Hz, 1H), 7.63 - 7.60 (m, 3H), 7.47 - 7.37 (m, 6H), 7.14 - 7.12 (m, 2H), 6.74 (d, J= 8.8 Hz, 2H), 6.29 (d, J= 8.0 Hz, 1H), 5.20 - 5.08 (m, 1H), 4.78 - 4.67 (m, 1H), 4.51 - 4.22 (m, 7H), 3.65 - 3.59 (m, 2H), 2.99 - 2.89 (m, 2H), 2.64 - 2.59 (m, 1H), 2.47 - 2.37 (m, 13H), 2.14 (s, 3H), 2.08 - 1.89 (m, 2H), 1.48 - 1.37 (m, 8H), 1.26 - 1.22 (m, 1H), 1.09 (d, J = 6.4 Hz, 3H), 0.93 (s, 9H). LCMS: m / z 1084.7 [M+H]+.EXAMPLE C-6. SYNTHESIS OF (2S,4R)-l-[(2S)-2-[[2-[4-[4-[[[4-[(2S,4R)-l-ACETYL-4- (4-CHLOROANILINO)-2-METHYL-3,4-DIHYDRO-2H-QUINOLIN-6- YL]BENZOYL]AMINO]METHYL]PHENYL]PHENYL]ACETYL]AMINO]-3,3- DIMETHYL-BUTANOYL]-4-HYDROXY-N-[[4-(4-METHYLTHIAZOL-5- YL)PHENYL] METHYL] PYRROLIDINE-2-C ARBOXAMIDEA. Step 1

[0251] To a mixture of tert-butyl A-[(4-bromophenyl)methyl]carbamate (1.8 g, 6.29 mmol), methyl 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]acetate (1.74 g, 6.29 mmol) and K2CO3 (1.74 g, 12.58 mmol) in dioxane (15 mL) and H2O (1.5 mL) was added Pd(dppf)C12(920.50 mg, 1 .26 mmol) at 25 °C. The mixture was heated to 90 °C and stirred for 16 hours under N2. The reaction mixture was filtered and diluted with water (15 mL), extracted with dichloromethane (15 mL x 3). The combined organic layer was washed with brine (30 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 1 / 3). to afford the desired product methyl 2-[4-[4-[( / e / 7-butoxycarbonylamino) methyl] phenyl] phenyl] acetate (2.05 g, 5.50 mmol, 87.39% yield, 95.3% purity) as a yellow oil^H NMR: CDCI3, 400MHz. 3 7.58 - 7.51 (m, 4H), 7.39 - 7.33 (m, 4H), 4.88 (brs, 1H), 4.37 (d, J= 5.2 Hz, 2H), 3.73 (s, 3H), 3.68 (s, 2H), 1.48 (s, 9H). LCMS: m / z 378.2 [M+Na]+.B. Step 2

[0252] To a solution of methyl 2-[4-[4-[(tert- butoxycarbonylamino)methyl]phenyl]phenyl]acetate (2 g, 5.63 mmol) in THF (6 mL), H2O (6 mL) and MeOH (6 mL) was added LiOH FLO (708.39 mg, 16.88 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 hours. The pH of the reaction mixture was adjusted to 7 by addition of 1 M aqueous HC1 solution. The reaction mixture was diluted with water (10 mL) and extracted with Dichloromethane / Methanol (10 / 1, 15 mL x 3). The combined organic layer was washed with brine (30 mL x 3), dried over anhydrous NasSCL, fdtered and concentrated in vacuo to afford the desired product 2-[4-[4-[( / c / 7-butoxycarbonylamino)methyl]phenyl]phenyl]acetic acid (1.6 g, 4.49 mmol, 79.78% yield, 95.79% purity) as pale yellow solid. 'HNMR: CDCI3, 400MHz. 3 12.35 (brs, 1H), 7.64 - 7.54 (m, 4H), 7.42 - 7.40 (m, 1H), 7.36 - 7.28 (m, 4H), 4.16 (d, J= 6.0 Hz, 2H), 3.33 (s, 2H), 1.40 (s, 9H). LCMS: m / z 364.2 [M+Na]+.C. Step 3

[0253] To a mixture of (2S,4R)-l-[(25)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (500 mg, 1.07 mmol), DIEA (553.48 mg, 4.28 mmol, 745.92 pL) and 2-[4-[4-[(tert- butoxycarbonylamino)methyl]phenyl]phenyl]acetic acid (438.61 mg, 1.28 mmol) in DMF (8 mL) was added TPTU (636.07 mg, 2.14 mmol) and HOBt (289.33 mg, 2.14 mmol) at 0 °C. The mixture was warmed to 25 °C and stirred for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC on silica gel (Dichloromethane / Methanol = 10 / 1) to afford the desired product tert-butyl A-[[4-[4-[2-[[(lS)-l-[(2S,4R)-4-hydroxy-2-[[4-(4- methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl- propyl]amino]-2-oxo-ethyl]phenyl]phenyl]methyl]carbamate (550 mg, 701.77 pmol, 65.55% yield, 96.2% purity) as a brown oil. LCMS: m / z 754.4 [M+H] ,I). Step 4

[0254] To a mixture of tert-butyl A-[[4-[4-[2-[[(15)-l-[(2S,4R)-4-hydroxy-2-[[4-(4- methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]phenyl]phenyl]methyl]carbamate (200 mg, 265.27 pmol) in CH2CI2 (2 mL) was added HCl / dioxane (4 M in dioxane, 6.4 mmol, 1.60 mL) at 0 °C. The mixture was warmed to 25 °C and stirred for 1 hour. The reaction mixture was concentrated in vacuo to afford the desired product (21S',4J?)-l-[(2S)-2-[[2-[4-[4-(aminomethyl)phenyl]phenyl]acetyl]amino]-3,3- dimethyl-butanoyl]-4-hydroxy-Ar-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2- carboxamide (180 mg, crude, HC1 salt) as a yellow solid. LCMS: m z 654.4 [M+H]+.E. Step 5

[0255] To a mixture of 4-[(2S,4R)-l-acetyl-4-(4-chloroanilino)-2-methyl-3,4-dihydro-2H- quinolin-6-yl]benzoic acid (80 mg, 183.94 pmol), DIEA (95.09 mg, 735.78 pmol, 128.16 pL) and (25',4R)-l-[(25’)-2-[[2-[4-[4-(aminomethyl)phenyl]phenyl]acetyl]amino]-3,3-dimethyl- butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (126.98 mg, 183.94 pmol, HC1 salt) in DMF (2 mL)was added TBTU (118.12 mg, 367.89 pmol) at 0 °C. The mixture was warmed to 25 °C and stirred for 1 hour. The reaction mixture was diluted with water (5 mL) and extracted with Dichloromethane / Methanol (10 / 1, 5 mL x 3). The combined organic layer were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient:50% - 80% B over 10 min) to afford the desired product (2S,4R)-l-[(25)-2-[[2-[4-[4-[[[4-[(2<S',4R)-l- acetyl-4-(4-chloroanilino)-2-methyl-3,4-dihydro-2H-quinolin-6- yl]benzoyl]amino]methyl]phenyl]phenyl]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-A- [[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (81.27 mg, 75.10 pmol, 40.83% yield, 98.95% purity) as a white solid. ’H NMR: DMSO-rL, 400MHz.J 9.08 (t, J= 5.6 Hz, 1H), 8.98 (s, 1H), 8.61 - 8.53 (m, 1H), 8.15 (d, J= 9.2 Hz, 1H), 7.99 - 7.92 (m, 2H), 7.65 - 7.54 (m, 7H), 7.46 - 7.32 (m, 10H), 7.15 - 7.09 (m, 2H), 6.77 - 6.70 (m, 2H), 6.29 (d, J= 8.0 Hz,1H), 5.12 (d, J= 3.6 Hz, 1H), 4.75 - 4.66 (m, 1H), 4.54 - 4.50 (m, 2H), 4.47 - 4.39 (m, 2H), 4.35- 4.26 (m, 2H), 4.24 - 4.18 (m, 1H), 3.71 - 3.61 (m, 3H), 3.50 - 3.47 (m, 1H), 2.65 - 2.56 (m, 2H), 2.44 (s, 3H), 2.14 (s, 3H), 2.06 - 1.97 (m, 1H), 1.93 - 1.85 (m, 1H), 1.27 - 1.20 (m, 1H), 1.09 (d, J= 6.4 Hz, 3H), 0.92 (s, 9H). LCMS: m z 1070.7 [M+H]+.EXAMPLE C-7. SYNTHESIS OF (2S,4R)-l-[(2S)-2-[[2-[4-[5-[[4-[(2S,4R)-l-ACETYL-4-(4- CHLOROANILINO)-2-METHYL-3,4-DIHYDRO-2H-QUINOLIN-6-YL]BENZOYL]AMINO]PENTYL]PIPERAZIN-l-YL]ACETYL]AMINO]-3,3- DIMETHYL-BUTANOYL]-4-HYDROXY-N-[[4-(4-METHYLTHIAZOL-5- YL)PHENYL] METHYL] PYRROLIDINE-2-CARBOXAMIDEA. Step 1

[0256] To a solution of ter / -butyl piperazine-1 -carboxylate (3 g, 16.1 1 mmol), methyl 2- bromoacetate (3.20 g, 20.94 mmol, 1.98 mL) in MeCN (80 mL) was added KI (2.67 g, 16.11 mmol) and CS2CO3 (10.50 g, 32.21 mmol) at 25 °C. The mixture was heated to 60 °C and stirred for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with Ethyl acetate (40 mL x 3). The combined phase was washed with brine (40 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 2 / 1) to afford the desired producttert-butyl 4-(2-methoxy-2-oxo-ethyl)piperazine-l -carboxylate (2.68 g, 10.38 mmol, 64.41% yield) as a yellow oil. 'HNMR: CDCI3, 400 MHz. 53.74 (s, 3H), 3.53 - 3.47 (m, 4H), 3.26 (s, 2H), 2.56 - 2.53 (m, 4H), 1.47 (s, 9H).B. Step 2

[0257] To a solution of tert-butyl 4-(2-methoxy-2-oxo-ethyl)piperazine-l -carboxylate (2.68 g, 10.38 mmol) in CH2CI2 (10 mL) was added HCI / dioxane (4 M in dioxane, 40.0 mmol, 10 mL).The mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated in vacuo toafford the desired product methyl 2-piperazin-l-ylacetate (2 g, 10.27 mmol, 99.03% yield, HC1 salt) as a yellow solid. 'H NMR: DMSO-d / 6, 400 MHz. <39.65 (s, 2H), 4.06 (s, 2H), 3.71 (s, 3H), 3.36 - 3.33 (m, 8H).C. Step 3

[0258] To a solution of methyl 2-piperazin-l-ylacetate (2 g, 10.27 mmol, HC1 salt) and tertbutyl ,¥-(5-bromopentyl)carbamate (3.56 g, 13.36 mmol) in MeCN (50 mL) was added CS2CO3 (6.70 g, 20.55 mmol), KI (1.71 g, 10.27 mmol) at 25 °C. The mixture was heated to 60 °C and stirred for 12 hours under N2. The reaction mixture was diluted with water (3 mL) and extracted with Ethyl acetate (5 mL x 3). The combined phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 10 / 1) to afford the desired product methyl 2-[4-[5-(tertbutoxycarbonylamino)pentyl]piperazin-l-yl]acetate (3.2 g, 9.32 mmol, 90.68% yield) as a light yellow oil. 'H NMR: CDCI3, 400 MHz. <34.54 (brs, 1H), 3.73 (s, 3H), 3.23 (s, 2H), 3.14 - 3.07 (m, 2H), 2.68 - 2.57 (m, 6H), 2.44 - 2.36 (m, 2H), 1.59 - 1.47 (m, 6H), 1.45 (s, 9H), 1.37 - 1.30 (m, 2H). LCMS: m / z 344.3 [M+H]+.D. Step 4

[0259] To a solution of methyl 2-[4-[5-(tert-butoxycarbonylamino)pentyl]piperazin- l - yl]acetate (3.2 g, 9.32 mmol) in THF (10 mL), H2O (10 mL) and MeOH (10 mL) was added LiOH tbO (1.56 g, 37.27 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture concentrated in vacuo. The pH of the mixture was adjusted to 6 by 2M aqueous HC1 solution. The residue was purified by preparative HPLC (column: YMC Triart Cl 8 70*250mm*7um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 5%-35% B over 20 min) to afford the desired product 2-[4-[5-(ter / -butoxycarbonylamino)pentyl]piperazin-l-yl]acetic acid(2.5 g, 7.59 mmol, 81.45% yield) as a yellow oil. ‘HNMR: DMSO-cL, 400 MHz. <76.75 (t, J = 10.8 Hz, 1H), 3.12 (s, 2H), 2.30 - 2.87 (m, 2H), 2.67 - 2.64 (m, 4H), 2.41 - 2.38 (m, 4H), 2.24 - 2.21 (m, 2H), 1.42 - 1.37 (m, 4H), 1.36 (s, 9H), 1.25 - 1.16 (m, 2H). LCMS: m z 330.2 [M+H]+.E. Step 5

[0260] To a solution of (25,4R)-l-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (350 mg, 749.43 pmol, HC1 salt) and 2-[4-[5-( tert-butoxycarbonylamino)pentyl]piperazin- l -yl]acetic acid (350.00 mg, 1.06 mmol) in DMF (3 mL) were added DIEA (387.43 mg, 3.00 mmol, 522.15 pL), TPTU (445.25 mg, 1.50 mmol) and HOBt (202.53 mg, 1.50 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (3 mL) and extracted with Dichloromethane / Methanol (10 / 1, 5 mL x 3). The combined phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Daisogel SP ODS RPS 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACNj; gradient: 35%-65% B over 10 min) to afford the desired product tertbutyl N- [5 - [4- [2-[ [( 1 S)- 1 - [(25,4R)-4-hy droxy-2-[ [4-(4-methylthiazol-5 - yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo- ethyl]piperazin-l-yl]pentyl]carbamate (240 mg, 323.46 pmol, 43.16% yield) as a light yellow solid. LCMS: m,z 742.4[M+H]+.F. Step 6

[0261] To a solution of ze / 7-butyl A-[5-[4-[2-[[(15)-l-[(25,4R)-4-hydroxy-2-[[4-(4- methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl- propyl]amino]-2-oxo-ethyl]piperazin-l-yl]pentyl]carbamate (240 mg, 323.46 pmol) in CH2CI2 (4 mL) was added HCl / dioxane (4 M in dioxane, 16.0 mmol, 4.0 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuo to afford the desired product (2S, 4R)- 1 - [(25)-2- [ [2-[4-(5 -aminopentyl)piperazin- 1 -yl] acetyl] amino] -3 , 3 -dimethyl -butanoyl] -4- hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (242 mg, 322.13 pmol, 99.59% yield, 3HC1 salt) as a light yellow solid. LCMS: m / z 642.3 [M+H]+.G. Step 7

[0262] To a solution of (2S,4R)-l-[(25)-2-[[2-[4-(5-aminopentyl)piperazin-l-yl]acetyl]amino]- 3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2- carboxamide (122 mg, 162.40 pmol, 3HC1 salt), DIEA (83.21 mg, 643.81 pmol, 112.14 pL) and 4-[(2S,4R)-l-acetyl-4-(4-chloroanilino)-2-methyl-3,4-dihydro-2 / f-quinolin-6-yl]benzoic acid (70 mg, 160.95 pmol) in DMF (1 mL) was added TBTU (103.36 mg, 321.90 pmol) at 0°C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (3 mL) and extracted with Dichloromethane / Methanol (10 / 1, 5 mL x 3). The combined phase was washedwith brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Ultimate C18 150*25mm*5um; mobile phase: [water (FA)-ACN]; gradient: 20%-50% B over 10 min) to afford the desired product (25,4R)-l-[(21S)-2-[[2-[4-[5-[[4-[(2S,4R)-l-acetyl-4-(4-chloroanilino)-2-methyl-3,4- dihydro-277-quinolin-6-yl]benzoyl]amino]pentyl]piperazin-l-yl]acetyl]amino]-3,3-dimethyl- butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (56.29 mg, 51.80 pmol, 32.18% yield, 97.42% purity) as a white solid. H NMR: DMSO-d6, 400 MHz. d 8.98 (s, 1H), 8.61 - 8.59 (m, 1H), 8.51 - 8.35 (m, 1H), 7.88 (d, J= 8.0 Hz, 2H), 7.81 - 7.69 (m, 1H), 7.65 - 7.55 (m, 3H), 7.48 - 7.34 (m, 6H), 7.12 (d, J = 8.4 Hz, 2H), 6.74 (d, J= 8.8 Hz, 2H), 6.30 (d, J= 8.0 Hz, 1H), 5.21 - 5.04 (m, 1H), 4.80 - 4.60 (m, 1H), 4.50 - 4.23 (m, 6H), 3.66 - 3.58 (m, 2H), 3.26 - 3.22 (m, 4H), 3.01 - 2.90 (m, 2H), 2.67 - 2.57 (m, 2H), 2.44 (s, 3H), 2.40 - 2.31 (m, 3H), 2.26 - 2.20 (m, 2H), 2.14 (s, 3H), 2.08 - 2.00 (m, 1H), 1.94 - 1.83 (m, 1H), 1.53 - 1.36 (m, 4H), 1.35 - 1.16 (m, 4H), 1.09 (d, J= 6.0 Hz, 3H), 0.93 (s, 9H). LCMS: m / z 1058.7 [M+H] .EXAMPLE C-8. SYNTHESIS OF 8-(3,5-DIFLUORO-2-PYRIDYL)-N-[8-[5-[(lR)-l- [(2S,4R)-4-HYDROXY-2-[[4-(4-METHYLTHIAZOL-5- YL)PHENYL]METHYLCARBAMOYL]PYRROLIDINE-l-CARBONYL]-2-METHYL- PROPYL] ISOXAZOL-3-YL] OXYOCTYL] - 15-METHYL-4- (METHYLSULFONYLMETHYL)- 14-OXO-8, 12,15- TRIAZATETRACYCLO[8.6.1.02,7.013,17]HEPTADECA-1(16),2(7),3,5,10,13(17)- HEXAENE-5-CARBOXAMIDEA. Step 1

[0263] To a solution of methyl 2-methyl-5-nitro-benzoate (45 g, 230.57 mmol) in DCE (1000 mL) was added NBS (45.14 g, 253.62 mmol) and BPO (5.59 g, 23.06 mmol). The mixture was stirred at 83 °C for 2.5 hours. The mixture was concentrated in vacuo. The mixture was triturated with Petroleum ether / Ethyl acetate (20 / 1, 200 mL). The resultant precipitate solid was collected by fdtration, washed with methanol (40 mL*3) and dried in vacuo to afford the desired product methyl 2-(bromomethyl)-5-nitro-benzoate (32 g, 116.76 mmol, 50.64% yield) as a white solid.'H NMR: CDCI3, 400 MHz. 6 8.81 (s, 1H), 8.33 (d, J= 8.4 Hz, 1H), 7.69 (d, J= 8.4 Hz, 1H), 5.00 (s, 2H), 4.01 (s, 3H).B. Step 2

[0264] A mixture of methyl 2-(bromomethyl)-5-nitro-benzoate (32 g, 116.76 mmol) and sodium;methanesulfinate (23.84 g, 233.52 mmol) in DMF (500 mL) was heated to 60 °C and stirred for 12 hours. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 1 / 1) to afford the desired product methyl 2-(methylsulfonylmethyl)-5-nitro-benzoate (25 g, 91.49 mmol, 78.36% yield) as a yellow solid. 'H NMR: CDCI3, 400 MHz.J 8.80 (s, 1H), 8.35 - 8.31 (m, 1H), 7.73 (d, J= 8.4 Hz, 1H), 4.99 (s, 2H), 3.94 (s, 3H), 2.85 (s, 3H).C. Step 3

[0265] To a solution of methyl 2-(methylsulfonylmethyl)-5-nitro-benzoate (25 g, 91.49 mmol) in H2O (225 ml) and EtOH (900 ml) was added Fe (25.55 g, 457.44 mmol) and NH4C1 (24.47 g, 457.44 mmol) at 25 °C. The mixture was heated to 60 °C and stirred for 12 hours. The mixture was fdtered and the filtrate was concentrated in vacuo. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (200 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the desired product methyl 5-amino-2-(methylsulfonylmethyl)benzoate (22 g, 90.43mmol, 98.85% yield) as a yellow solid. *H NMR: CDCh, 400 MHz / )’ 7.36 - 7.28 (m, 2H), 6.86 - 6.83 (m, 1H), 4.75 (s, 2H), 3.90 (s, 3H), 2.76 (s, 3H).D. Step 4

[0266] To a solution of methyl 5-amino-2-(methylsulfonylmethyl)benzoate (5 g, 20.55 mmol) in DMF (100 mL) was added NIS (5.09 g, 22.61 mmol) at 20 °C. The mixture was stirred for 12 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 2 / 1). The mixture was triturated in MeOH (50 mL). The resultant precipitate solid was collected by filtration and dried in vacuo to afford the desired product methyl 5-amino-4-iodo-2-(methylsulfonylmethyl)benzoate (13.1 g, 35.48 mmol, 43.16% yield) as a yellow solid. 'H NMR: DMSO-d6, 400 MHz. d 7.72 (s, 1H), 7.25 (s, 1H), 5.68 (s, 2H), 4.70 (s, 2H), 3.78 (s, 3H), 2.81 (s, 3H).E. Step 5

[0267] A mixture of methyl 5-amino-4-iodo-2-(methylsulfonylmethyl)benzoate (2.6 g, 7.04 mmol), 6-methyl-l-(ptolylsulfonyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3- c]pyridin-7-one (3.02 g, 7.04 mmol), Na2CO3(1.49 g, 14.09 mmol) and Pd(dppf)C12 (515.32 mg,704.27 nmol) in dioxane (25 mL) and H2O (5 mL) was heated to 90 °C and stirred for 12 hours under N2. The reaction mixture was diluted with water (20 mL). The resultant precipitate solid was collected by filtration and dried in vacuo to afford the desired product methyl 5-amino-4-[6- methyl-7-oxo-l-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-4-yl]-2-(methylsulfonylmethyl)benzoate (1.6 g, 2.94 mmol, 41.79% yield) as an orange solid. 'H NMR: DMSO-de, 400 MHz. 3 8.05 - 7.91 (m, 3H), 7.52 - 7.39 (m, 3H), 7.31 (s, 1H), 7.15 (s, 1H), 6.36 (s, 1H), 5.43 (s, 2H), 4.74 (s, 2H), 3.81 (s, 3H), 3.44 (s, 3H), 2.82 (s, 3H), 2.39 (s, 3H). LCMS: m / z 544.0 [M+H]+.F. Step 6

[0268] A mixture of methyl 5-amino-4-[6-methyl-7-oxo-l-(p-tolylsulfonyl)pyrrolo[2,3- c]pyridin-4-yl]-2-(methylsulfonylmethyl)benzoate (1.6 g, 2.94 mmol), 2-bromo-3,5-difluoro- pyridine (1.71 g, 8.83 mmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy- palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (533.62 mg, 588.66 pmol) and CS2CO3 (1.92 g, 5.89 mmol) in dioxane (20 mL) was heated to 90 °C and stirred for 12 hours under N2. The reaction mixture was diluted with water (20 mL). The resultant precipitate solid was collected by filtration and dried in vacuo to afford the desired product methyl 5 -[(3 , 5 -difluoro-2-py ri dy l)amino]-4- [6-methyl-7-oxo- 1 -(p- tolylsulfonyl)pyrrolo[2,3-c]pyridin-4-yl]-2-(methylsulfonylmethyl)benzoate (1.8 g, 2.74 mmol, 93.13% yield) as a gray solid. ’H NMR: DMSO-de, 400 MHz. 3 8.27 (s, 1H), 8.15 (s, 1H), 7.92 - 7.87 (m, 3H), 7.85 (d, J = 2.4 Hz, 1H), 7.73 - 7.66 (m, 1H), 7.48 (d, J = 6.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.30 (d, J= 3.6 Hz, 1H), 4.93 (s, 2H), 3.84 (s, 3H), 3.40 (s, 3H), 2.93 (s, 3H), 2.39 (s, 3H). LCMS: m / z 657.2 [M+H]+.G. Step 7

[0269] A mixture of methyl 5-[(3,5-difhioro-2-pyridyl)amino]-4-[6-methyl-7-oxo-l-(p- tolylsulfonyl)pyrrolo[2,3-c]pyridin-4-yl]-2-(methylsulfonylmethyl)benzoate (1.8 g, 2.74 mmol) and NaOH (274.09 mg, 6.85 mmol) in MeOH (5 mL), H2O (5 mL) and THF (5 mL) was heated to 60°C and stirred for 3 hours under N2. The mixture was concentrated in vacuo. The mixture was diluted with water (20 mL). The pH of the aqueous phase was adjusted to 5 by addition of 2 N aqueous HC1 solution. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the desired product 5-[(3,5-difluoro-2- pyridyl)amino]-4-(6-methyl-7-oxo-l / / -pyrrolo[2,3-c]pyridin-4-yl)-2- (methylsulfonylmethyl)benzoic acid (1.20 g, 2.45 mmol, 89.48% yield) as a yellow solid. 'H NMR: DMSO-d6, 400 MHz. 6 13.09 (brs, 1H), 12.09 (s, 1H), 8.45 (s, 1H), 7.98 - 7.95 (m, 1H), 7.89 (s, 1H), 7.78 - 7.69 (m, 1H), 7.53 (s, 1H), 7.33 (s, 1H), 7.26 (t, J= 2.8 Hz, 1H), 6.09 - 6.05 (m, 1H), 5.01 (s, 2H), 3.53 (s, 3H), 2.92 (s, 3H). LCMS: mz 489.0 [M+H]1.H. Step 8

[0270] The mixture of 5-[(3,5-difluoro-2-pyridyl)amino]-4-(6-methyl-7-oxo-l / / -pyrrolo[2,3- c]pyridin-4-yl)-2-(methylsulfonylmethyl)benzoic acid (1.2 g, 2.46 mmol), (HCHO)n (600 mg) in AcOH (10 mL) was stirred at 90 °C for 0.5 hour under N2. The mixture was concentrated in vacuo. The mixture was diluted with water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous Na SO4, filtered and concentrated in vacuo to afford the desired product 8-(3,5- difluoro-2-pyridyl)-l 5-methyl-4-(methylsulfonylmethyl)- 14-oxo-8, 12, 15- triazatetracyclo[8.6.1.02,7.013,17]heptadeca-l(16),2(7),3,5,10,13(17)-hexaene-5-carboxylic acid (1.05 g, 2.10 mmol, 85.40% yield) as a yellow solid. ^NMR: DMSO-d6, 400 MHz. 6 12.88 (brs, 1H), 11.94 (s, 1H), 8.09 (d, J= 2.4 Hz, 1H), 8.00 - 7.95 (m, 1H), 7.83 - 7.78 (m, 1H), 7.69 - 7.60 (m, 1H), 7.60 - 7.56 (m, 1H), 7.28 (d, J= 2.4 Hz, 1H), 6.08 - 5.71 (m, 1H), 5.34 - 4.77 (m, 2H), 4.47 - 4.09 (m, 1H), 3.63 (s, 3H), 2.93 (s, 3H). LCMS: RT = 0.350 min, m / z 501.0 [M+H]+.

[0271] To a solution of (2S,4R)-l-[(2A)-2-[3-(8-aminooctoxy)isoxazol-5-yl]-3-methyl- butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (145.03 mg, 199.81 pmol, TFA salt) and 8-(3,5-difluoro-2-pyridyl)-15-methyl-4- (methylsulfonylmethyl)-14-oxo-8,12,15-triazatetracyclo[8.6.1.02,7.013,17]heptadeca- l(16),2(7),3,5,10,13(17)-hexaene-5-carboxylic acid (100 mg, 199.81 pmol) in DMF (2 mL) were added DIEA (103.30 mg, 799.24 pmol, 139.21 pL), HOBt (54.00 mg, 399.62 pmol) and EDCI (76.61 mg, 399.62 pmol) at 0 °C. The mixture was warmed to 25 °C and stirred for 12 hours. The mixture was diluted with water (5 mL) and extracted with dichloromethane / methanol (10 / 1,5 mL x 3). The combined organic phase was washed with brine (5mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Daisogel SP ODS RPS 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 36%-66% B over 10 min) to afford the desired product 8-(3,5-difluoro-2-pyridyl)-A / -[8- [5-[(1R)-l-[(25,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5- yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxy octyl]- 15-methyl-4-(m ethylsulfonylmethyl)- 14-oxo-8, 12,15- triazatetracyclo[8.6.1.02,7.013,17]heptadeca-l(16),2(7),3,5,10,13(17)-hexaene-5-carboxamide (30.23 mg, 26.39 pmol, 13.21% yield, 95.5% purity) as a white solid. 'H NMR: DMSO-ds, 400 MHz. <5 11.92 (s, 1H), 8.98 - 8.93 (m, 1H), 8.45 (t, J= 6.0 Hz, 1H), 8.39 (t, J= 5.6 Hz, 1H), 8.07 - 8.03 (m, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.64 - 7.57 (m, 1H), 7.42 - 7.37 (m, 2H), 7.33 - 7.28 (m, 2H), 7.28 - 7.25 (m, 2H), 6.05 - 6.02 (m, 1H), 5.12 (d, J= 3.6 Hz, 1H), 4.45 - 4.40 (m, 1H), 4.37 - 4.19 (m, 4H), 4.13 - 4.02 (m, 2H), 3.76 - 3.74 (m, 1H), 3.62 (s, 3H), 3.58 - 3.53 (m, 1H), 3.42 (m, 4H), 3.16 - 3.11 (m, 2H), 2.90 (s, 3H), 2.44 - 2.42 (m, 3H), 2.24 (m, 1H), 2.09 - 2.01 (m, 1H), 1.94 - 1.85 (m, 1H), 1.66 - 1.57 (m, 2H), 1.47 - 1.40 (m, 2H), 1.28 - 1.19 (m, 8H), 1.03 - 0.74 (m, 6H). LCMS: m / z 1094.7 [M+H]+.EXAMPLE C-9. SYNTHESIS OF 8-(3,5-DIFLUORO-2-PYRIDYL)-N-[8-[5-[(lS)-l- [(2S,4R)-4-HYDROXY-2-[[4-(4-METHYLTHIAZOL-5-YL)PHENYL]METHYLCARBAMOYL]PYRROLIDINE-l-CARBONYL]-2-METHYL-PROPYL] ISOXAZOL-3- YL] OXYOCTYL] - 15-METHYL-4- (METHYLSULFONYLMETHYL)- 14-OXO-8, 12,15- TRIAZATETRACYCLO[8.6.1.02,7.013,17]HEPTADECA-1(16),2(7),3,5,10,13(17)-HEXAENE-5-CARBOXAMIDE

[0272] To a solution of (25,4R)-l-[(2S)-2-[3-(8-aminooctoxy)isoxazol-5-yl]-3-methyl- butanoyl]-4-hydroxy-jV-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(145.03 mg, 199.81 pmol, TFA salt) and 8-(3,5-difluoro-2-pyridyl)-15-methyl-4- (methylsulfonylmethyl)-14-oxo-8,12,15-triazatetracyclo[8.6.1.02,7.013,17]heptadeca- l(16),2(7),3,5,10,13(17)-hexaene-5-carboxylic acid (100 mg, 199.81 pmol) in DMF (2 mL) were added DIEA (103.30 mg, 799.24 pmol, 139.21 pL), HOBt (54.00 mg, 399.62 pmol) and EDCI (76.61 mg, 399.62 pmol) at 0 °C. The mixture was warmed to 25 °C and stirred for 12 hours. The mixture was diluted with water (5 mL) and extracted with dichloromethane / methanol (10 / 1, 5 mL x 3). The combined organic phase was washed with brine (5mL x 3), dried over anhydrous Na2SC>4, fdtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA) - ACN]; gradient: 35% - 65% B over 10 min) to afford the desired product 8-(3,5-difluoro-2-pyridyl)-A-[8-[5- [(lS)-l-[(25,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l- carbonyl]-2-methyl-propyl]isoxazol-3-yl]oxyoctyl]-15-methyl-4-(methylsulfonylmethyl)-14- oxo-8,12,15-triazatetracyclo[8.6.1.02,7.013,17]heptadeca-l(16),2(7),3,5,10,13(17)-hexaene-5- carboxamide (30.23 mg, 26.39 pmol, 13.21% yield, 95.5% purity) as a white solid. 'H NMR: DMSO-de, 400 MHz. 3 11.93 (s, 1H), 8.99 (s, 1H), 8.58 - 8.37 (m, 2H), 8.12 - 8.06 (m, 1H), 7.92 (s, 1H), 7.76 (s, 1H), 7.66 - 7.59 (m, 1H), 7.45 - 7.39 (m, 3H), 7.37 (s, 1H), 7.29 - 7.25 (m, 2H), 6.08 (s, 1H), 5.20 - 5.09 (m, 1H), 4.41 - 4.31 (m, 4H), 4.14 - 4.12 (m, 2H), 3.79 - 3.74 (m, 1H), 3.68 - 3.61 (m, 5H), 3.47 - 3.43 (m, 2H), 3.16 (m, 4H), 2.91 (s, 3H), 2.46 (s, 3H), 2.28 - 2.24 (m, 1H), 2.06 - 2.01 (m, 1H), 1.93 - 1.89 (m, 1H), 1.72 - 1.66 (m, 2H), 1.49 - 1.43 (m, 2H), 1.34 - 1.24 (m, 8H), 0.95 (d, ,7 = 6.8 Hz, 3H), 0.80 (d, .7= 6.8 Hz, 3H). LCMS: m / z 1094.7 [M+H]+.EXAMPLE C-10. SYNTHESIS OF 8-(3,5-DIFLUORO-2-PYRIDYL)-N-[[4-[4-[2-[[(lS)-l- [(2S,4R)-4-HYDROXY-2-[[4-(4-METHYLTHIAZOL-5-YL)PHENYL]METHYLCARBAMOYL]PYRROLIDINE-l-CARBONYL]-2,2-DIMETHYL-PROPYL]AMINO]-2-OXO-ETHYL]PHENYL]PHENYL]METHYL]-15-METHYL-4-(METHYLSULFONYLMETHYL)-14-OXO-8,12,15-TR1AZATETRACYCLO [8.6.1.02, 7.013, 17JHEPTADECA-1(16), 2(7), 3,5, 10, 13(17)-HEXAENE-5-CARBOXAMIDE

[0273] To a mixture of (2S,4R)-l-[(2S)-2-[[2-[4-[4- (aminomethyl)phenyl]phenyl]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (200 mg, 289.73 pmol, HC1 salt), DIPEA (224.68 mg, 1.74 mmol, 302.80 pL) and 8-(3,5-difluoro-2-pyridyl)-15-methyl-4- (methylsulfonylmethyl)-14-oxo-8,12,15-triazatetracyclo[8.6.1.02,7.013,17]heptadeca- l(16),2(7),3,5,10,13(17)-hexaene-5-carboxylic acid (140.00 mg, 279.73 pmol) in DMF (2 mL) was added HATU (220.33 mg, 579.46 pmol) at 0 °C. The mixture was warmed to 25 °C and stirred for 1 hour under N2. The reaction mixture was diluted with water (5 mL) and extracted with Dichloromethane / Methanol (10 / 1, 5 mL x 3). The combined organic layer were washed with brine (10 mL x 3), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 37%-57% B over 10 min ) to afford the desired product 8-(3,5-difluoro-2-pyridyl)-A-[[4-[4-[2-[[(lS)-l-[(2S,4R)-4-hydroxy-2-[[4-(4- methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl- propyl]amino]-2-oxo-ethyl]phenyl]phenyl]methyl]-15-methyl-4-(methylsulfonylmethyl)- 14-oxo- 8, 12, 15-triazatetracyclo[8.6.1 .02,7.013, 17]heptadeca-l (16), 2(7), 3, 5, 10, 13(17)-hexaene-5- carboxamide (49.84 mg, 43.12 pmol, 14.88% yield, 98.3% purity) as a white solid. 'HNMR: DMSO-tL, 400MHz. <5 11.93 (s, 1H), 9.02 - 8.97 (m, 2H), 8.58 (t, J= 6.0 Hz, 1H), 8.17 (d, J =9.6 Hz, 1H), 8.09 - 8.06 (m, 1H), 7.94 (s, 1H), 7.77 (s, 1H), 7.68 - 7.61 (m, 1H), 7.58 - 7.55 (m, 4H), 7.44 - 7.40 (m, 4H), 7.38 - 7.33 (m, 5H), 7.29 - 7.27 (m, 1H), 6.14 - 4.77 (m, 2H), 4.56 - 4.54 (m, 1H), 4.47 - 4.40 (m, 4H), 4.36 - 4.33 (m, 1H), 4.25 - 4.19 (m, 1H), 3.75 - 3.58 (m, 7H), 3.52 - 3.45 (m, 1H), 2.89 (s, 3H), 2.45 - 2.42 (m, 5H), 2.07 - 2.00 (m, 1H), 1.93 - 1.87 (m, 1H), 0.93 (s, 9H).LCMS: m 'z 1136.6 [M+H]+.EXAMPLE C-1L SYNTHESIS OF 8-(3,5-DIFLUORO-2-PYRIDYL)-N-[2-[3-[2-[[(lS)-l- [(2S,4R)-4-HYDROXY-2-[[4-(4-METHYLTHIAZOL-5- YL)PHENYL]METHYLCARBAMOYL]PYRROLIDINE-l-CARBONYL]-2,2-DIMETHYL-PROPYL]AMINO]-2-OXO-ETHYL]-3,9-DIAZASPIRO[5.5]UNDECAN-9- YL] ETHYL] - 15-METHYL-4-(METHYLSULFONYLMETHYL)-l 4-0X0-8,12, 15- TRIAZATETRACYCLO[8.6.1.02,7.013,17]HEPTADECA-1(16),2(7),3,5,10,13(17)- HEXAENE-5-CARBOXAMIDE

[0274] To a mixture of (2S,4R)-l-[(2S)-2-[[2-[9-(2-aminoethyl)-3,9-diazaspiro[5.5]undecan-3- yl]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5- yl)phenyl]methyl]pyrrolidine-2-carboxamide (170.84 mg, 219.79 pmol, 3HC1 salt) and 8-(3,5- difluoro-2-pyridyl)-15-methyl-4-(methylsulfonylmethyl)- 14-oxo-8, 12, 15- triazatetracyclo[8.6.1.02,7.013,17]heptadeca-l(16),2(7),3,5,10,13(17)-hexaene-5-carboxylic acid (100 mg, 199.81 pmol) in DMF (1 mL) were added EDCI (76.61 mg, 399.62 pmol), HOBt (54.00 mg, 399.62 pmol) and DIEA (103.29 mg, 799.24 pmol, 139.21 pL) at 0 °C. The mixture was stirred at 25 °C under N2 for 2 hours. The reaction mixture was diluted with water (1 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with brine (1 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC(column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 7% - 37% B over 10 min) to afford the desired product 8-(3,5-difluoro-2-pyridyl)-A-[2-[3-[2-[[(lS)-l-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5- yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethyl]- 3, 9-diazaspiro[5.5]undecan-9-yl]ethyl]-15-methyl-4-(methylsulfonylmethyl)- 14-oxo-8, 12, 15- triazatetracyclo[8.6.1.02,7.013,17]heptadeca-l(16),2(7),3,5,10,13(17)-hexaene-5-carboxamide (34.17 mg, 29.20 pmol, 14.61% yield, 98.3% purity) as a yellow solid. 'HNMR: DMSO-d6., 400 MHz. 3 11.93 (s, 1H), 8.97 (s, 1H), 8.60 (t, J = 6.0 Hz, 1H), 8.34 (t, J= 5.6 Hz, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.83 - 7.77 (m, 1H), 7.75 (s, 1H), 7.63 - 7.61 (m, 1H), 7.44 - 7.40 (m, 4H), 7.29 - 7.22 (m, 2H), 6.12 - 4.92 (m, 2H), 4.51 - 4.34 (m, 4H), 4.31 - 4.19 (m, 2H), 3.69 - 3.56 (m, 7H), 2.91 (s, 3H), 2.44 - 2.30 (m, 16H), 2.14 - 1.81 (m, 4H), 1.43 - 1.34 (m, 6H), 0.94 (s, 9H). LCMS: RT = 2.058 min, m'z 1150.8 [M+H]+.EXAMPLE C-12. SYNTHESIS OF 8-(3,5-DIFLUORO-2-PYRIDYL)-N-[[l-[6-[[(lS)-l- [(2S,4R)-4-HYDROXY-2-[[4-(4-METHYLTHIAZOL-5- YL)PHENYL]METHYLCARBAMOYL]PYRROLIDINE-l-CARBONYL]-2,2- DIMETHYL-PROPYL] AMINO] -6-OXO-HEXYL] -4-PIPERIDYL] METHYL] - 15- METHYL-4-(METHYLSULFONYLMETHYL)-14-OXO-8,12,15- TRIAZATETRACYCLO[8.6.1.02,7.013,17]HEPTADECA-1(16),2(7),3,5,10,13(17)- HEXAENE-5-CARBOXAMIDEA. Step 1

[0275] A mixture of tert-butyl 7V-(4-piperidylmethyl)carbamate (1 g, 4.67 mmol), methyl 6- bromohexanoate (1.46 g, 7.00 mmol), K2CO3 (1.93 g, 14.00 mmol) and KI (774.61 mg, 4.67 mmol) in ACN (10 mL) was heated to 60 °C and stirred for 16 hours under N2. The mixture was diluted with water (10 mL) and extracted with dichloromethane / methanol (10 / 1, 20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 20 / 1) to afford the desired product methyl 6-[4-[(tert- butoxycarbonylamino)methyl]-l-piperidyl]hexanoate (900 mg, 2.63 mmol, 56.32% yield) as a yellow solid. 'H NMR: DMSO-d6, 400 MHz. 3 7.04 - 6.86 (m, 1H), 3.59 (s, 3H), 3.53 - 3.39 (m, 2H), 3.27 - 3.11 (m, 1H), 3.05 - 2.94 (m, 2H), 2.92 - 2.71 (m, 4H), 2.33 (t, J = 7.4 Hz, 2H), 1.84 - 1.71 (m, 2H), 1.63 - 1.54 (m, 4H), 1.37 (s, 9H), 1.32 - 1.19 (m, 4H).B. Step 2

[0276] To a solution of methyl 6-[4-[(tert-butoxycarbonylamino)methyl]-l- piperidyl]hexanoate (900 mg, 2.63 mmol) in THF (10 mL) and H2O (2 mL) was addedLiOH H2O (330.83 mg, 7.88 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: YMC Triart C18 70*250mm*7um; mobile phase: [water (NH4HCO3) - ACN]; gradient: 5% - 35% B over 20 min) to afford the desired product 6-[4-[(tert-butoxycarbonylamino)methyl]-l- piperidyl]hexanoic acid (560 mg, 1.71 mmol, 64.88% yield) as a yellow oil. 'H NMR: DMSO- d6, 400 MHz. 6 6.95 - 6.67 (m, 1H), 2.84 - 2.73 (m, 4H), 2.24 - 2.12 (m, 4H), 1.83 - 1.73 (m, 2H), 1.59 - 1.45 (m, 4H), 1.43 - 1.34 (m, 11H), 1.32 - 1.20 (m, 3H), 1.11 - 0.99 (m, 2H). LCMS: m z 329.0 [M+H]+.C. Step 3

[0277] To a solution of 6-[4-[(tert-butoxycarbonylamino)methyl]-l -piperidyl]hexanoic acid (150 mg, 456.70 pmol), (25,4 / ?)-l-[(25T)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (213.29 mg, 456.70 pmol, HC1 salt) and DIEA (354.15 mg, 2.74 mmol, 477.29 pL) in DMF (2 mL) were added HOBt (92.57 mg, 685.04 μmol) and TPTU (203.50 mg, 685.04 pmol) at 0 °C under N2. The mixture was warmed to 25 °C and stirred for 1 hour under N2. The mixture was diluted with water (5 mL) andextracted with dichloromethane / methanol (10 / 1 , 10 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (HC1) - ACN]; gradient: 12% - 42% B over 8 min) to afford the desired product tert-butyl A-[[l-[6-[[(15)-l-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5- yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]amino]-6-oxo-hexyl]- 4-piperidyl]methyl]carbamate (125 mg, crude) as a white solid. ’H NMR: DMSO4>, 400 MHz. d 8.61 - 8.50 (m, 1H), 7.90 - 7.77 (m, 2H), 7.56 - 7.49 (m, 1H), 7.45 - 7.33 (m, 4H), 7.31 - 7.22 (m, 2H), 6.91 - 6.82 (m, 1H), 4.58 - 4.34 (m, 4H), 3.71 - 3.59 (m, 3H), 3.09 - 3.03 (m, 2H), 2.84 - 2.77 (m, 2H), 2.44 (s, 3H), 2.28 - 1.88 (m, 7H), 1.68 - 1.59 (m, 2H), 1.53 - 1.43 (m, 4H), 1.37 (s, 9H), 1.26 - 1.15 (m, 6H), 0.93 (s, 9H).D. Step 4

[0278] To a solution of tert-butyl / V-[[l-[6-[[(15)-l-[(25',4J?)-4-hydroxy-2-[[4-(4- methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl- propyl]amino]-6-oxo-hexyl]-4-piperidyl]methyl]carbamate (125 mg, 168.69 pmol, crude) in CH2CI2 (2 mL) was added HCl / dioxane (4 M in dioxane, 8.0 mmol, 2 mL) at 25 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated in vacuo to afford (2S,4R)-1-[(2ST)- 2-[6-[4-(aminomethyl)-l-piperidyl]hexanoylamino]-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (120 mg, 163.07 pmol, 96.67% yield, 97% purity, 2HC1 salt) as a white solid. LCMS: m / z 641.4 [M+H],E. Step 5

[0279] To a solution of (25,4R)-l-[(2S)-2-[6-[4-(aminomethyl)-l-piperidyl]hexanoylamino]- 3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2- carboxamide (95 mg, 133.09 pmol, 2HC1 salt), 8-(3,5-difluoro-2-pyridyl)-15-methyl-4- (methylsulfonylmethyl)-14-oxo-8,12,15-triazatetracyclo[8.6.1.02,7.013,17]heptadeca- l(16),2(7),3,5,10,13(17)-hexaene-5-carboxylic acid (66.61 mg, 133.09 pm ol) and DIEA (103.21 mg, 798.54 pmol, 139.09 pL) in DMF (1 mL) was added HATU (50.61 mg, 133.09 pmol) at 0 °C under N2. The mixture was warmed to 25 °C and stirred for 1 hour under N2. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna Cl 8 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 11% - 41% B over 10 min) to afford 8-(3,5-difluoro-2-pyridyl)-A-[[l-[6-[[(lS)-l-[(25,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5- yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]amino]-6-oxo-hexyl]- 4-piperidyl]methyl]-15-methyl-4-(methylsulfonylmethyl)-14-oxo-8,12,15- triazatetracyclo[8.6.1.02,7.013,17]heptadeca-l(16),2(7),3,5,10,13(17)-hexaene-5-carboxamide (46.18 mg, 40.29 pmol, 30.27% yield, 98% purity) as a white solid. 'H NMR: DMSO-d6, 400 MHz. d 11.92 (s, 1H), 8.98 (s, 1H), 8.60 - 8.52 (m, 1H), 8.49 - 8.40 (m, 1H), 8.22 - 8.17 (m, 1H), 8.11 - 8.03 (m, 1H), 7.95 - 7.88 (m, 1H), 7.86 - 7.81 (m, 1H), 7.78 - 7.72 (m, 1H), 7.65 - 7.57 (m, 1H), 7.43 - 7.36 (m, 4H), 7.30 - 7.25 (m, 2H), 6.07 - 5.73 (m, 1H), 5.27 - 5.06 (m, 1H), 4.56 - 4.52 (m, 1H), 4.46 - 4.39 (m, 2H), 4.37 - 4.33 (m, 1H), 4.24 - 4.18 (m, 1H), 3.71 - 3.64 (m, 4H),3.62 (s, 3H), 3.07 - 3.02 (m, 2H), 2.93 - 2.88 (m, 5H), 2.44 (s, 3H), 2.37 - 2.31 (m, 2H), 2.28 -2.21 (m, 1H), 2.15 - 1.88 (m, 6H), 1.68 - 1.60 (m, 2H), 1.52 - 1.42 (m, 4H), 1.25 - 1.11 (m, 4H), 0.93 (s, 9H). LCMS: m / z 1123.7 [M+H]+.EXAMPLE C-13. SYNTHESIS OF 8-(3,5-DIFLUORO-2-PYRIDYL)-N-[5-[4-[2-[[(lS)-l- [(2S,4R)-4-HYDROXY-2-[[4-(4-METHYLTHIAZOL-5- YL)PHENYL]METHYLCARBAMOYL]PYRROLIDINE-l-CARBONYL]-2,2-DIMETHYL-PROPYL] AMINO] -2-OXO-ETHYL]PIPERAZIN- 1-YL] PENTYL] - 15- METHYL-4-(METHYLSULFONYLMETHYL)- 14-0X0-8,12, 15-TRIAZATETRACYCLO[8.6.1.02,7.013,17]HEPTADECA-1(16),2(7),3,5,10,13(17)- HEXAENE-5-CARBOXAMIDE

[0280] To a solution of (2S,4R)-l-[(25)-2-[[2-[4-(5-aminopentyl)piperazin-l-yl]acetyl]amino]- 3,3-dimethyl-butanoyl]-4-hydroxy- / V-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2- carboxamide (120.09 mg, 159.85 pmol, 3HC1 salt) and 8-(3,5-difluoro-2-pyridyl)-15-methyl-4- (methylsulfonylmethyl)-14-oxo-8,12,15-triazatetracyclo[8.6.1.02,7.013,17]heptadeca- l(16),2(7),3,5,10,13(17)-hexaene-5-carboxylic acid (80 mg, 159.85 pmol) in DMF (1 mL) were added DIEA (123.95 mg, 959.09 pmol, 167.05 pL) and HATU (60.78 mg, 159.85 pmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was diluted with water (2 mL) and extracted with Dichloromethane / Methanol (10 / 1, 5 mL x 3). The combined phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna Cl 8 150*25mm*10um; mobile phase: [water (FA) - ACN]; gradient:16% - 36% B over 10 min) to afford the desired product 8-(3,5-difluoro-2-pyridyl)-A-[5-[4-[2-[[(15)-l-[(2S,4R)-4-hydroxy-2- [[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl- propyl]amino]-2-oxo-ethyl]piperazin-l -yl]pentyl]-15-methyl-4-(methylsulfonylmethyl)- 14-oxo-8, 12, 15-triazatetracyclo[8.6.1 .02,7.013, 17]heptadeca-l (16), 2(7), 3, 5, 10, 13(17)-hexaene-5- carboxamide (42.08 mg, 37.02 pmol, 23.16% yield, 98.9% purity) as a white solid. ’HNMR: DMSO-tfc, 400 MHz. d 11.93 (s, 1H), 8.96 (s, 1H), 8.60 - 8.58 (m, 1H), 8.42 - 8.40 (m, 1H), 8.14 (s, 1H), 8.09 - 8.04 (m, 1H), 7.91 (s, 1H), 7.82 - 7.74 (m, 2H), 7.64 - 7.57 (m, 1H), 7.41 - 7.38 (m, 3H), 7.29 - 7.26 (m, 2H), 6.12 - 5.78 (m, 1H), 5.16 - 5.13 (m, 2H), 4.55 - 4.19 (m, 8H), 3.68 - 3.48 (m, 8H), 3.19 - 2.97 (m, 6H), 2.91 (s, 3H), 2.43 (s, 3H), 2.38 - 2.29 (m, 2H), 2.09 - 2.00 (m, 1H), 1.95 - 1.83 (m, 1H), 1.51 - 1.38 (m, 5H), 1.32 - 1.18 (m, 3H), 0.94 (s, 9H). LCMS: m / z 1124.5 [M+H]~.EXAMPLE C-14. SYNTHESIS OF (2S,4R)-l-[(2R)-2-ACETAMIDO-3-[2-[4-[2-[[2-[(9S)-7-(4-CHLOROPHENYL)-4,5, 13-TRIMETHYL-3-THIA- 1,8,11,12-TETRAZATRICYCLO[8.3.0.02,6]TRIDECA-2(6),4,7,10,12-PENTAEN-9-YL] ACETYL] AMINO] ETHYL] PIPERAZIN- 1-YL] ETHYLSULFANYL] -3-METHYL-BUTANOYL]-4-HYDROXY-N-[[4-(4-METHYLTHIAZOL-5-YL)PHENYL] METHYL] PYRROLIDINE-2-C ARBOXAMIDE

[0281] To a mixture of (2R)-2-(tert-butoxycarbonylamino)-3-methyl-3-tritylsulfanyl-butanoic acid (3.06 g, 6.22 mmol), (2N,4R)-4-hydroxy-7V-[[4-(4-methylthiazol-5- yl)phenyl]methyl]pyrrolidine-2-carboxamide (2 g, 5.65 mmol, HC1 salt) and DIPEA (2.92 g, 22.61 mmol, 3.94 ml) in DMF (20 mL) was added TBTU (2.72 g, 8.48 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hours under N2. The reaction mixture was diluted with water (20 mL). The mixture was extracted with Dichloromethane / Methanol (10 / 1, 25 mL x 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate= 0 / 1) to afford the desired product tert-butyl JV-[( 1R)- 1- [(25,4R)- 4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2-methyl-2-tritylsulfanylpropyl]carbamate (3.2 g, 4.05 mmol, 71.58% yield). 'H NMR: DMSO-de, 400 MHz. d 8.99 (s, 1H), 8.49 - 8.39 (m, 1H), 7.51 - 7.47 (m, 6H), 7.33 - 7.25 (m, 10H), 7.21 - 7.16 (m, 3H), 6.84 - 6.76 (m, 1H), 4.36 - 4.18 (m, 4H), 3.52 - 3.36 (m, 4H), 2.41 (s, 3H), 2.02 - 1.95 (m, 2H), 1.88 - 1.80 (m, 1H), 1.41 (s, 9H), 1.03 (s, 3H), 0.86 (s, 3H).B. Step 2

[0282] To a solution of tert-butyl TV-[(1R)-1-[(25, 4R)-4-hydroxy-2-[[4-(4-methylthiazol-5- yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2-methyl-2-tritylsulfanyl-propyl]carbamate (3.2 g, 4.05 mmol) in CH2CI2 (30 mL) was added HCI / dioxane (2 M in dioxane, 30 mmol, 15.0 mL) at 25 °C. The mixture was stirred at 25 °C for 2 hours under N2. The reaction mixture was concentrated in vacuo to afford the desired product (25, 45)-l-[(25)-2-amino-3-methyl-3- sulfanyl-butanoyl]-4-hydroxy-7V-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2- carboxamide (1.9 g, 3.92 mmol, 96.83% yield, HC1 salt) as a white solid. 'H NMR: DMSO-d / e, 400 MHz. d 9.03 (s, 1H), 8.86 - 8.73 (m, 1H), 8.42 - 8.33 (m, 2H), 7.41 - 7.33 (m, 4H), 4.58 - 4.52 (m, 1H), 4.47 - 4.39 (m, 4H), 4.27 - 4.22 (m, 2H), 3.84 - 3.67 (m, 2H), 2.45 (s, 3H), 2.17 - 1.86 (m, 2H), 1.51 (s, 3H), 1.37 (s, 3H).

[0283] To a mixture of (25, 4R )-l -[(2R )-2-amino-3-methyl-3-sulfanyl-butanoyl]-4-hydroxy- / V- [[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (1.9 g, 3.92 mmol, HC1 salt)and EtsN (792.73 mg, 7.83 mmol, 1 .09 mL) in CH2CI2 (20 mL) was added AC2O (399.89 mg, 3.92 mmol, 367.88 uL, ) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. The reaction mixture was diluted with water (20 mL). The mixture was extracted with Dichloromethane (25 mL x 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 20 / 1) to afford the desired product (2S,4R)-l-[(2A)-2- acetamido-3-methyl-3-sulfanyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5- yl)phenyl]methyl]pyrrolidine-2-carboxamide (1.55 g, 3.16 mmol, 80.65% yield). ’HNMR: DMSO-t / 6, 400 MHz. d 8.98 (s, 1H), 8.61 (t, J= 6.0 Hz, 1H), 8.13 (d, J= 9.6 Hz, 1H), 7.44 -7.37 (m, 4H), 5.28 - 5.08 (m, 1H), 4.84 (d, J= 9.6 Hz, 1H), 4.48 - 4.33 (m, 3H), 4.29 - 4.24 (m, 1H), 3.91 - 3.83 (m, 1H), 3.67 - 3.61 (m, 1H), 2.44 (s, 3H), 2.14 - 1.93 (m, 2H), 1.91 (s, 3H),1.38 (s, 3H), 1.28 (s, 3H).D. Step 4

[0284] To a mixture of (2S,4R)-l-[(2R)-2-acetamido-3-methyl-3-sulfanyl-butanoyl]-4- hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (400 mg, 815.27 pmol), tert-butyl 4-(2-chloroethyl)piperazine-l -carboxylate (243.36 mg, 978.32 pmol) and TBAB (1.05 g, 3.26 mmol) in EtOAc (5 mL)was added saturated aqueous NaHCCh solution(2.16 g, 25.70 mmol, 1.00 mL) at 0 °C. The mixture was heated to 60 °C and stirred for 16 hours. The reaction mixture was diluted with water (5 mL). The mixture was extracted with Dichloromethane / Methanol (10 / 1, 8 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 20 / 1) to afford the desired product / c / 7-butyl 4-[2-[(2A)-2-acetamido-3-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-l-yl]- 1,1 -dimethyl -3-oxo- propyl]sulfanylethyl]piperazine-l-carboxylate (550 mg, 782.44 pmol, 95.97% yield) as a white solid. 'HNMR: DMSO-t / 6, 400 MHz. <5 8.98 (s, 1H), 8.51 - 8.44 (m, 1H), 8.18 - 8.10 (m, 1H), 7.42 - 7.38 (m, 4H), 5.18 - 5.13 (m, 1H), 4.87 - 4.80 (m, 1H), 4.51 - 4.36 (m, 3H), 4.27 - 4.19 (m, 1H), 3.77 - 3.64 (m, 2H), 3.26 - 3.21 (m, 4H), 3.19 - 3.13 (m, 1H), 2.67 - 2.58 (m, 2H), 2.44 (s, 3H), 2.41 - 2.35 (m, 2H), 2.29 - 2.26 (m, 2H), 2.08 - 1.92 (m, 2H), 1.89 (s, 3H), 1.39 - 1.37 (m, 12H), 1.28 (s, 3H).E. Step 5

[0285] To a solution of tert-butyl 4-[2-[(2R)-2-acetamido-3-[(25,4R)-4-hydroxy-2-[[4-(4- methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin- 1 -y 1 ] - 1 , 1 -dimethyl-3 -oxo- propyl]sulfanylethyl]piperazine-l-carboxylate (550 mg, 782.44 pmol) in CH2CI2 (6 mL) was added TFA (89.22 mg, 782.44 pmol, 58.12 uL) at 25 °C and stirred for 1 hour under N2. The reaction mixture was concentrated in vacuo to afford the desired product (25,4R)- 1-[(2R)-2- acetamido-3 -methyl -3-(2 -piperazin- 1-yl ethylsulfanyl)butanoyl]-4-hydroxy-N-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (620 mg, 746.22 pmol, 95.37% yield, 2TFA salt) as a yellow oil. 'H NMR: DMSO-t / 6, 400 MHz. 3 9.17 (brs, 1H), 9.00 (s, 1H), 8.67 - 8.59 (m, 1H), 8.33 - 8.26 (m, 1H), 7.43 - 7.39 (m, 4H), 4.89 - 4.80 (m, 1H), 4.47 - 4.21 (m, 5H), 3.78 - 3.63 (m, 2H), 3.34 - 3.08 (m, 6H), 2.89 - 2.81 (m, 2H), 2.45 (s, 3H), 2.30 - 1.99 (m, 2H), 1.92 (s, 3H), 1.90 - 1.86 (m, 1H), 1.60 - 1.53(m, 1H), 1.47 - 1.41 (m, 3H), 1.33 (s, 3H), 1.31 - 1.20 (m, 2H).F. Step 6

[0286] A mixture of (2S,4R)-l-[(2R)-2-acetamido-3-methyl-3-(2-piperazin-l- ylethylsulfanyl)butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2- carboxamide (620 mg, 746.22 pmol, 2TFA salt), 2-(tertbutoxycarbonylamino)ethyl 4- methylbenzenesulfonate (282.41 mg, 895.46 pmol), K2CO3 (309.40 mg, 2.24 mmol) and KI (123.87 mg, 746.22 pmol) in DMF (6 mL) was heated to 60 °C and stirred for 16 hours under N2. The reaction mixture was diluted with water (5 mL). The mixture was extracted with Dichloromethane / Methanol (10 / 1, 6 mL x 3). The combined organic phase was washed with brine (8 mL), dried with anhydrous Na2SO4, fdtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 10 / 1) to afford the desired product tert-butyl A-[2-[4-[2-[(2A)-2-acetamido-3-[(2S,4R)-4-hydroxy-2-[[4-(4- methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin- 1 -y 1 ] - 1 , 1 -dimethyl-3 - oxopropyl]sulfanylethyl]piperazin-l-yl]ethyl]carbamate (300 mg, crude) as a colorless oil. LCMS: m / z 746.3 [M+H]+.G. Step 7

[0287] To a solution of Zc / 7-butyl A-[2-[4-[2-[(2R)-2-acetamido-3-[(25',4R)-4-hydroxy-2-[[4- (4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-l-yl]-l,l-dimethyl-3-oxo- propyl]sulfanylethyl]piperazin-l-yl]ethyl]carbamate (300 mg, 402.15 pmol) in CH2CI2 (3 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL) at 25 °C. The mixture was stirred at 25 °C for 1 hour under N2. The reaction mixture was concentrated in vacuo to afford the desired product (2S,4A)-l-[(2A)-2-acetamido-3-[2-[4-(2-aminoethyl)piperazin-l-yl]ethylsulfanyl]-3-methyl- butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (390 mg, crude, 3 TFA salt) as a yellow oil. LCMS: m / z 646.3 [M+H]+.H. Step 8

[0288] To a mixture of (2S,4A)-l-[(2A)-2-acetamido-3-[2-[4-(2-aminoethyl)piperazin-l- yl]ethylsulfanyl]-3-methylbutanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5- yl)phenyl]methyl]pyrrolidine-2-carboxamide (15 mg, 19.86 pmol, 3HC1 salt), 2-[(95)-7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]acetic acid (7.96 mg, 19.86 pmol) and DIPEA (10.27 mg, 79.44 pmol, 13.84 uL) in DMF (0.5 mL) was added TBTU (9.57 mg, 29.79 pmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour under N2. The reaction mixture was diluted with water (1 mL) and extracted with Dichloromethane / Methanol (10 / 1, 2 mL x 3). The combined organic phase was washed with brine (3 mL), dried with anhydrous Na2SCU, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*25mm*10um; mobile phase: [water (FA) - ACN]; gradient: 20% - 50% B over 8 min) to afford the desired product (2S,4R)-1- [(2A)-2-acetamido-3-[2-[4-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-l, 8,11,12- tetrazatri cyclo[8.3.0.02, 6]trideca-2(6), 4, 7, 10,12-pentaen-9-yl]acetyl]amino]ethyl]piperazin-l-yl]ethylsulfanyl]-3-methyl-butanoyl]-4-hydroxy-7V-[[4-(4-methylthiazol-5- yl)phenyl]methyl]pyrrolidine-2-carboxamide (3.79 mg, 3.60 pmol, 18.15% yield, 97.847% purity) as a white solid. 'H NMR: DMSO-t / 6, 400 MHz. d 8.99 (s, 1H), 8.53 - 8.37 (m, 1H), 8.16- 8.09 (m, 2H), 7.50 - 7.46 (m, 2H), 7.44 - 7.38 (m, 6H), 5.24 - 5.05 (m, 1H), 4.90 - 4.76 (m, 1H), 4.52 - 4.33 (m, 4H), 4.29 - 4.20 (m, 1H), 3.78 - 3.63 (m, 2H), 3.26 - 3.14 (m, 6H), 2.59 (s, 3H), 2.46 - 2.43 (m, 4H), 2.41 (s, 3H), 2.37 - 2.32 (m, 8H), 2.06 - 1.94 (m, 2H), 1.89 (s, 3H), 1.62 (s, 3H), 1.37 (s, 3H), 1.32 - 1.20 (m, 6H). LCMS: m / z 1028.6 [M+H]+.EXAMPLE C-15. SYNTHESIS OF (2S,4R)-l-[(2R)-2-ACETAMIDO-3-[2-[4-[2-[[2-[(9S)-7- (4-CHLOROPHENYL)-4,5, 13-TRIMETHYL-3-THIA- 1 ,8, 11 , 12- TETRAZATRICYCLO[8.3.0.02,6]TRIDECA-2(6),4,7,10,12-PENTAEN-9- YL]ACETYL]AMINO]ETHYL]PHENYL]ETHYLSULFANYL]-3-METHYL-BUTANOYL]-4-HYDROXY-N-[[4-(4-METHYLTHIAZOL-5-YL)PHENYL] METHYL] PYRROLIDINE-2-CARBOXAMIDEA. Step 1

[0289] To a solution of 2-[4-(2-hydroxyethyl)phenyl]ethanol (2.8 g, 16.85 mmol) and CBr4 (16.76 g, 50.54 mmol) in CH2CI2 (30 mL) was added PPM (13.25 g, 50.54 mmol) at 0 °C under N2. Then the mixture was stirred at 25 °C for 15 hours. The reaction mixture was diluted with water (50 mL) and extracted with Dichloromethane (50 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 15 / 1) to afford the desired product l,4-bis(2-bromoethyl)benzene (4.6 g, 15.75 mmol, 93.51% yield) as a white solid. 'H NMR: CDCl3, 400 MHz. 6 7.20 - 7.16 (m, 4H), 3.57 (t, J= 7.2 Hz, 4H), 3.16 (t, J= 8.0 Hz, 4H).B. Step 2

[0290] To a solution of l,4-bis(2-bromoethyl)benzene (4.60 g, 15.74 mmol) and tert-butyl N- tertebutoxy carbonylcarbamate (2.28 g, 10.49 mmol) in ACN (50 mL) were added CS2CO3 (6.84 g, 20.99 mmol) and KI (174.21 mg, 1.05 mmol) under N2. The mixture was heated to 60 °C and stirred for 15 hours. The reaction mixture was diluted with water (50 mL) and extracted with Ethyl acetate (50 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 15 / 1) to afford the desired product tert-butyl A-[2-[4-(2- bromoethyl)phenyl]ethyl]- / V- / ert-butoxycarbonyl-carbamate (1.66 g, 3.86 mmol, 36.82% yield) as a yellow oil. 'H NMR: CDCh, 400 MHz. 3 7.18 - 7.14 (m, 4H), 3.80 - 3.77 (m, 2H), 3.55 (t, J = 7.6 Hz, 2H), 3.17 - 3.11 (m, 2H), 2.88 - 2.84 (m, 2H), 1.50 (s, 18H).C. Step 3

[0291] To a mixture of (2S,4R)-l-[(2A)-2-acetamido-3-methyl-3-sulfanyl-butanoyl]-4- hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (50 mg, 101.91 pmol), tert-butyl A-[2-[4-(2-bromoethyl)phenyl]ethyl]-A-tert-butoxycarbonyl-carbamate (52.38 mg, 122.29 pmol) and TBAB (131.41 mg, 407.63 pmol) in EtOAc (1 mL) was added saturated NaHCOs solution (302.00 mg, 3.59 mmol, 0.2 mL) at 0 °C. The mixture was stirred at 60 °C for 15 hours. The reaction mixture was diluted with water (5 mL) and extracted with Ethyl acetate (5 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC on silica gel (Dichloromethane / Methanol = 20 / 1) to afford the desired product tert-butyl A-[2-[4-[2-[(2R)-2- acetamido-3-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5- yl)phenyl]methylcarbamoyl]pyrrolidin-l-yl]-l,l-dimethyl-3-oxo-propyl]sulfanylethyl]phenyl]ethyl]-Ntertbutoxycarbonyl-carbamate (40 mg, 47.73 μmol,46.83% yield) as a yellow oil. LCMS: m / z 838.3 [M+H]+.D. Step 4

[0292] To a solution of tert-butyl A-[2-[4-[2-[(2R)-2-acetamido-3-[(25',4R)-4-hydroxy-2-[[4- (4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-l-yl]-l,l-dimethyl-3-oxo- propyl]sulfanylethyl]phenyl]ethyl]-A-tertbutoxycarbonyl-carbamate (40 mg, 47.73 pmol) in CH2CI2(0.5 mL) was added TFA (153.50 mg, 1.35 mmol, 0.1 mL) under N2. Then the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated in vacuo to afford the desired product (25,4R)-l-[(2R)-2-acetamido-3-[2-[4-(2-aminoethyl)phenyl]ethylsulfanyl]-3-methyl- butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (40 mg, 53.20 pmol, 98.15% yield, TFA salt) as a yellow oil. LCMS: m / z 638.3 [M+H]+.E. Step 5

[0293] To a solution of (2S,4R)-l-[(2R)-2-acetamido-3-[2-[4-(2- aminoethyl)phenyl]ethylsulfanyl]-3-methyl-butanoyl]-4-hydroxy-Af-[[4-(4-methylthiazol-5- yl)phenyl]methyl]pyrrolidine-2-carboxamide (40 mg, 53.20 pmol, TFA salt) and 2-[(95)-7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]acetic acid (21.33 mg, 53.20 pmol) in DMF (1 mL) were added DIEA (34.38 mg, 266.00 pmol, 46.33 μL) and TBTU (34.16 mg, 106.40 pmol) at 0 °C under N2. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (5 mL) and extracted with Ethyl acetate (5 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 35%-65% B over 8 min) to afford the desired product (2S,4R)-l-[(2R)-2-acetamido-3-[2-[4-[2-[[2-[(9S)-7- (4-chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethyl]phenyl]ethylsulfanyl]-3-methyl-butanoyl]-4- hydroxy -,V-[[4-(4-methylthiazol-5-yl )phenyl]methyl]pyrrolidine-2-carboxamide (23.43 mg, 22.01 pmol, 41.38% yield, 95.9% purity) as a white solid. ^ NMR: DMSO-d6, 400 MHz. 6 8.97 (s, 1H), 8.42 (t, J= 5.6 Hz, 1H), 8.29 (t, J = 5.2 Hz, 1H), 8.16 - 8.13 (m), 7.49 - 7.46 (m, 2H), 7.42 - 7.38 (m, 6H), 7.12 (s, 4H), 5.14 (d, J = 3.6 Hz, 1H), 4.86 (d, J = 9.6 Hz, 1H), 4.51 (t, J = 6.8 Hz, 1H), 4.43 - 4.33 (m, 3H), 4.27 - 4.20 (m, 1H), 3.73 - 3.64 (m, 2H), 3.24 - 3.21 (m, 2H), 2.83 - 2.61 (m, 8H), 2.59 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H), 2.09 - 1.92 (m, 2H), 1.89 (s, 3H), 1.62 (s, 3H), 1.38 (s, 3H), 1.28 (s, 3H). LCMS: m^z 1020.6 [M+H]+.EXAMPLE C-16. SYNTHESIS OF 8-(3,5-DIFLUORO-2-PYRIDYL)-N-[2-[3-[3-[2-[[(lS)- l-[(2S,4R)-4-HYDROXY-2-[[4-(4-METHYLTHIAZOL-5- YL)PHENYL]METHYLCARBAMOYL]PYRROLIDINE-l-CARBONYL]-2,2- DIMETHYL-PROPYL] AMINO] -2-OXO-ETHOXY] PROPOXY] PROPOXY]ETHYL]-15- METHYL-4-(METHYLSULFONYLMETHYL)-14-OXO-8,12,15- TRIAZATETRACYCLO[8.6.1.02,7.013,17]HEPTADECA-1(16),2(7),3,5,10,13(17)- HEXAENE-5-CARBOXAMIDEA. Step 1

[0294] To a solution of 2-bromoethoxymethylbenzene (10 g, 46.49 mmol, 7.35 mL) and 3-(3- hydroxypropoxy)propan-l-ol (12.48 g, 92.99 mmol) in dioxane (100 mL) were added KOH (13.04 g, 232.46 mmol) and TBAB (7.49 g, 23.25 mmol) at 25 °C. The mixture was heated to 80 °C and stirred for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (150 mL), dried over anhydrous Na SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 5 / 1) to afford 3-[3-(2- benzyloxyethoxy)propoxy]propan-l-ol (7 g, 26.09 mmol, 56.11% yield) as a yellow oil. 'H NMR: CDCh, 400MHz. 3 7.40 - 7.29 (m, 5H), 4.60 (s, 2H), 3.72 - 3.64 (m, 4H), 3.54 - 3.49 (m, 4H), 3.37 - 3.30 (m, 3H), 1.17 - 1.09 (m, 6H). LCMS: m / z 269.2 [M+H]+.B. Step 2

[0295] To a solution of 3-[3-(2-benzyloxyethoxy)propoxy]propan-l-ol (6.9 g, 25.71 mmol) in THF (50 mL) was added / -BuOK (1 M in THF, 51.43 mmol, 51.43 mL) at 0 °C under N2. The mixture was stirred at 40 °C for 0.5 hour. To the mixture was added methyl 2-bromoacetate (11.80 g, 77.14 mmol, 7.30 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 12 hours under N2. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250*70mm*10um); mobile phase: [water (FA) - ACN]; gradient: 30% - 70% B over 10 min) to afford methyl 2-[3-[3-(2-benzyloxy ethoxy )propoxy]propoxy]acetate (1.6 g, 4.70 mmol, 18.28% yield) as a brown oil. 'H NMR: CDCh, 400MHz. 3 7.38 - 7.29 (m, 5H), 4.58 (s, 2H), 4.30 - 4.19 (m, 2H), 3.75 - 3.39 (m, 13H), 1.23 - 1.12 (m, 6H). LCMS: m / z 363.2 [M+Na]+.C. Step 3

[0296] To a solution of methyl 2-[3-[3-(2-benzyloxyethoxy)propoxy]propoxy] (1.6 g, 4.70 mmol) in THF (10 mL) was added Pd / C (800 mg, 751.74 pmol, 10% purity) under N2. The mixture was degassed and recharged with H2 for 3 times. The mixture was stirred at 25 °C for 12 hours under H2 (45 Psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford methyl 2-[3-[3-(2-hydroxyethoxy)propoxy]propoxy]acetate (1.16 g, 4.63 mmol, 98.61% yield) as a light brown oil. 'H NMR: CDCh, 400MHz. d 4.32 - 4.19 (m, 2H), 3.78 - 3.44 (m, 14H), 1.23 - 1.12 (m, 6H).D. Step 4

[0297] To a solution of methyl 2-[3-[3-(2-hydroxyethoxy)propoxy]propoxy]acetate (2.15 g, 8.59 mmol), EtsN (4.35 g, 42.95 mmol, 5.98 mL) and DMAP (524.71 mg, 4.30 mmol) in CH2CI2 (15 mL) was added TosCI (4.91 g, 25.77 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (15 mL) and extracted with di chloromethane (15 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 3 / 1) to afford methyl 2-[3-[3-[2-(p- tolylsulfonyloxy)ethoxy]propoxy]propoxy]acetate (2.06 g, 5.09 mmol, 59.29% yield) as a brown oil. 'H NMR: CDCh, 400MHz. b 7.81 (d, J= 8.4 Hz, 2H), 7.35 (d, J= 8.0 Hz, 2H), 4.26 - 4.11 (m, 4H), 3.76 - 3.68 (m, 5H), 3.60 - 3.34 (m, 6H), 2.46 (s, 3H), 1.21 - 1.15 (m, 3H), 1.11 - 1.06 (m, 3H). LCMS: m / z 427.1 [M+Na]+.E. Step 5

[0298] To a solution of methyl 2-[3-[3-[2-(p- tolylsulfonyloxy)ethoxy]propoxy]propoxy]acetate (2.01 g, 4.97 mmol) and -butyl A-tert- tert butoxycarbonylcarbamate (2.16 g, 9.94 mmol) in MeCN (15 mL) were added CS2CO3 (3.24 g,9.94 mmol) and KI (412.47 mg, 2.48 mmol) at 25 °C. The mixture was heated to 60 °C and stirred for 12 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na?SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 9 / 1) to afford methyl 2-[3-[3-[2- [bis( / c77-butoxycarbonyl)amino]ethoxy]propoxy]propoxy]acetate (1.71 g, 3.80 mmol, 76.55% yield) as a brown oil. ‘HNMR: CDCI3, 400MHz. 34.30 - 4.17 (m, 2H), 3.80 - 3.71 (m, 5H), 3.65 - 3.3O (m, 8H), 1.51 (s, 18H), 1.23 - 1.10 (m, 6H). LCMS: m 'z 472.2 [M+Na]+.F. Step 6

[0299] To a solution of methyl 2-[3-[3-[2-[bis(tert butoxycarbonyl)amino]ethoxy]propoxy]propoxy]acetate (1.71 g, 3.80 mmol) in THF (12 mL) and H2O (6 mL) was added LiOH H2O (798.13 mg, 19.02 mmol). The mixture was stirred at 25 °C for 12 hours. The pH of the reaction mixture was adjusted to 7 by addition of 12 M aqueous HC1 solution. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Daisogel C18 250*70mm*10um; mobile phase: [water (NH4HCO3) - ACN]; gradient: 10% - 40% B over 22 min) to afford 2-[3-[3-[2-[bis(tert- butoxycarbonyl)amino]ethoxy]propoxy]propoxy]acetic acid (960 mg, 2.20 mmol, 57.95% yield) as a white oil. 'H NMR: CDCI3, 400MHz. δ 4.35 - 4.20 (m, 2H), 4.07 - 3.93 (m, 2H), 3.81 - 3.75 (m, 2H), 3.68 - 3.58 (m, 4H), 3.51 - 3.46 (m, 2H), 1.51 (s, 18H), 1.22 - 1.11 (m, 6H). LCMS: m / z 458.1 [M+Na]1.G. Step 7

[0300] To a solution of 2-[3-[3-[2-[bis(tert- butoxycarbonyl)amino]ethoxy]propoxy]propoxy]acetic acid (242.45 mg, 556.72 pmol), (25,4R)- l-[(25)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-JV-[[4-(4-methylthiazol-5- yl)phenyl]methyl]pyrrolidine-2-carboxamide (200 mg, 428.24 pmol, HC1 salt) and DIEA (276.74 mg, 2.14 mmol, 372.96 pL) in DMF (1 mL) were added TPTU (254.43 mg, 856.49 pmol) and HOBt (115.73 mg, 856.49 pmol, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, fdtered and concentrated in vacuo. The residue was purified by preparative TLC on silica gel (Dichloromethane / Methanol = 10 / 1) to afford tert-butyl / V-tert-butoxycarbonyl-A-[2-[3-[3-[2- [[(1R)-l-[(2R,45)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine- l-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]propoxy]propoxy]ethyl]carbamate (195 mg, 229.94 pmol, 53.69% yield) as a yellow oil. LCMS: m z 870.4 [M+Na]+.H. Step 8

[0301] To a solution of Zc / 7-butyl -tert-butoxycarbonyl-A-[2-[3-[3-[2-[[(1R)-l-[(2R,45’)-4- hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2- dimethyl-propyl]amino]-2-oxo-ethoxy]propoxy]propoxy]ethyl]carbamate (195 mg, 229.94 pmol) in CH2CI2 (2 mL) was added HCl / dioxane (2 M in dioxane, 8.0 mmol, 4.0 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuo to afford (2R,4A)-l-[(2A)-2-[[2-[3-[3-(2-aminoethoxy)propoxy]propoxy]acetyl]amino]-3,3-dimethyl- butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (160 mg, crude, HC1 salt) as a yellow oil. LCMS: m / z 648.3 [M+H]+.I. Step 9

[0302] To a solution of (2R,4S)-l-[(2A)-2-[[2-[3-[3-(2- aminoethoxy)propoxy]propoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (145 mg, 211.90 pmol, HC1 salt), 8-(3,5-difluoro-2-pyridyl)-15-methyl-4-(methylsulfonylmethyl)- 14-oxo-8, 12, 15- triazatetracyclo[8.6.1.02,7.013,17]heptadeca-l(16),2(7),3,5,10,13(17)-hexaene-5-carboxylic acid (100 mg, 199.81 pmol) and DIEA (154.94 mg, 1.20 mmol, 208.82 pL) in DMF (2 mL) were added HOBt (54.00 mg, 399.62pmol) and TPTU (118.71 mg, 399.62 pmol) at 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (5 mL) and extracted with Dichloromethane / Methanol (10 / 1, 3 mL x 3). The organic phase was washed with brine (5 mL), dried over anhydrous Na2SCU, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 25%-55% B over 10 min) to afford 8-(3,5-difluoro-2-pyridyl)-A-[2- [3-[3-[2-[[(15)-l-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5- yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo- ethoxy]propoxy]propoxy]ethyl]-15-methyl-4-(methylsulfonylmethyl)-14-oxo-8,12,15- triazatetracyclo[8.6.1.02,7.013,17]heptadeca-l(16),2(7),3,5,10,13(17)-hexaene-5-carboxamide (22.27 mg, 18.23 pmol, 9.12% yield, 92.5% purity) as a yellow solid. 'H NMR: DMSO-d6, 400MHz. 3 11.91 (s, 1H), 8.96 (s, 1H), 8.70 - 8.32 (m, 2H), 8.06 - 7.91 (m, 2H), 7.74 (s, 1H), 7.59 - 7.57 (m, 1H), 7.47 - 7.23 (m, 8H), 5.14 (d, J= 3.2 Hz, 1H), 4.65 - 4.20 (m, 6H), 4.05 - 3.87 (m, 2H), 3.71 - 3.32 (m, 15H), 2.89 (s, 3H), 2.45 - 2.41 (m, 4H), 2.21 - 1.87 (m, 3H), 1.10 - 0.91 (m, 15H). LCMS: RT = 2.233 min, m'z 1130.7 [M+H]+.EXAMPLE C-17. SYNTHESIS OF 8-(3,5-DIFLUORO-2-PYRIDYL)-N-[2-[3-[2-[[(lS)-l- [(2S,4R)-4-HYDROXY-2-[[4-(4-METHYLTHIAZOL-5- YL)PHENYL]METHYLCARBAMOYL]PYRROLIDINE-l-CARBONYL]-2,2- DIMETHYL-PROPYL] AMINO] -2-OXO-E THOXY] PROPOXY] ETHYL] - 15-METHYL- 4-(METHYLSULFONYLMETHYL)-14-OXO-8,12,15- TRIAZATETRACYCLO[8.6.1.02,7.013,17]HEPTADECA-1(16),2(7),3,5,10,13(17)- HEXAENE-5-CARBOXAMIDEA. Step 1

[0303] To a solution of 2-bromoethoxymethylbenzene (10 g, 46.49 mmol, 7.35 mL) and propane-1, 3-diol (7.08 g, 92.99 mmol, 6.72 mL) in toluene (30 mL) were added TBAB (7.49 g, 23.25 mmol), KI (3.86 g, 23.25 mmol) and KOH (13.04 g, 232.46 mmol) at 25 °C. The mixture was heated to 60 °C and stirred for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with Ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 2 / 1) to afford the desired product 3-(2-benzyloxyethoxy)propan-l-ol (5.6 g, 26.63 mmol, 57.28% yield) as a yellow oil. 'H NMR: CDCl3, 400 MHz. 3 7.38 - 7.28 (m, 5H), 4.57 (s, 2H), 3.82 - 3.77 (m, 2H), 3.71 - 3.67 (m, 2H), 3.66 - 3.61 (m, 4H), 1.90 - 1.80 (m, 2H). LCMS: RT = 0.348 min, m / z 233.0 [M+Na]+.B. Step 2

[0304] To a solution of 3 -(2 -benzyloxy ethoxy )propan-l-ol (5.54 g, 26.35 mmol) in THF (50 mL) was added Z-BuOK (1 M in THF, 52.69 mmol, 52.69 mL) at 0 °C. The mixture was stirred at 40 °C for 0.5 hour. To the mixture was added methyl 2-bromoacetate (12.09 g, 79.04 mmol, 7.48 mL) at 0 °C. The mixture was stirred at 25 °C for 11.5 hours. The reaction mixture was diluted with water (30 mL) and extracted with Ethyl acetate (40 mL x 3). The combined organic phase was washed with brine (50 mL x 3), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 1 / 1) to afford the desired product methyl 2-[3-(2- benzyloxyethoxy)propoxy]acetate (2.34 g, 8.29 mmol, 31.46% yield) as a yellow oil. 'H NMR: CDCh, 400 MHz. d 7.40 - 7.28 (m, 5H), 4.60 - 4.56 (m, 2H), 4.10 - 4.01 (m, 2H), 3.80 - 3.74 (m, 2H), 3.64 - 3.61 (m, 5H), 3.60 - 3.53 (m, 2H), 3.45 (s, 2H), 2.0 - 1.87 (m, 2H). LCMS: RT = 0.449 min, m z 305 [M+Na]+.C. Step 3

[0305] To a solution of methyl 2-[3-(2-benzyloxyethoxy)propoxy]acetate (2.34 g, 8.29 mmol) in THF (40 mL) was added Pd / C (1 g, 939.67 pmol, 10% purity) under N2. The mixture was stirred at 25 °C for 12 hours under H2 (45 Psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the desired product methyl 2- [3 -(2- hydroxyethoxy)propoxy]acetate (1.35 g, crude) as a yellow oil. ’HNMR: CDCh, 400 MHz. <5 4.12 - 4.00 (m, 2H), 3.78 - 3.72 (m, 3H), 3.71 - 3.52 (m, 6H), 3.50 - 3.40 (m, 2H), 1.99 - 1.87 (m, 2H).D. Step 4

[0306] To a solution of methyl 2-[3-(2-hydroxyethoxy)propoxy]acetate (1.3 g, 6.76 mmol) in CH2CI2 (10 mL) was added EtsN (2.74 g, 27.05 mmol, 3.77 mL) and TosCI (3.87 g, 20.29 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with H2O (8 mL) and extracted with Dichloromethane (15 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 1 / 1) to afford the desired product methyl 2-[3-[2-(p- tolylsulfonyloxy)ethoxy]propoxy]acetate (1.9 g, 5.49 mmol, 81.10% yield) as a yellow oil. ’H NMR: CDCh, 400 MHz. 3 7.84 - 7.78 (m, 2H), 7.37 - 7.34 (m, 2H), 4.22 - 4.14 (m, 3H), 4.08 - 4.02 (m, 2H), 3.76 (s, 2H), 3.64 - 3.61 (m, 2H), 3.58 - 3.50 (m, 2H), 3.49 - 3.45 (m, 2H), 2.46 (s, 3H), 1.92 - 1.79 (m, 2H). LCMS: RT = 0.450 min, m / z 369.0 [M+Na]+.E. Step 5

[0307] To a solution of methyl 2-[3-[2-(p-tolylsulfonyloxy)ethoxy]propoxy]acetate (1.75 g, 5.05 mmol) and tert-butyl / ' / - / crt-butoxycarbonyl carbarn ate (1.65 g, 7.58 mmol) in MeCN (30 mL) was added KI (838.65 mg, 5.05 mmol) and CS2CO3 (4.94 g, 15.16 mmol) at 25 °C. The mixture was heated to 60 °C and stirred for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with Ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether / Ethyl acetate = 3 / 1) to afford the desired product methyl 2-[3-[2-[bis(tert- butoxycarbonyl)amino]ethoxy]propoxy]acetate (470 mg, 1.20 mmol, 23.77% yield) as a yellow oil. 'H NMR: CDCh, 400 MHz. 4' 4.08 (s, 2H), 3.81 - 3.78 (m, 2H), 3.76 (s, 3H), 3.63 - 3.59 (m,2H), 3.56 (s, 2H), 3.55 - 3.53 (m, 2H), 1.89 - 1.85 (m, 2H), 1.51 (s, 18H). LCMS: RT = 0.523 min, m / z 414.0 [M+Na] ,F. Step 6

[0308] To a solution of methyl 2-[3-[2-[bis( / er / - butoxycarbonyl)amino]ethoxy]propoxy]acetate (470 mg, 1.20 mmol) in THF (2 mL), MeOH (2 mL) and H2O (2 mL) was added LiOH H2O (151.14 mg, 3.60 mmol). The mixture was stirred at 25 °C for 2 hours. The pH of the reaction mixture was adjusted to 6 by addition of 2 N aqueous HC1 solution. The mixture was diluted with water (3 mL) and extracted with Ethyl acetate (5 mL x 3). The combined phase was washed with brine (6 mL x 3), dried over anhydrous Na2SO4, filtered and filtrate concentrated in vacuo to afford the desired product 2-[3-[2-(tert- butoxycarbonylamino)ethoxy]propoxy]acetic acid (290 mg, 1.05 mmol, 87.10% yield) as a yellow oil. ‘HNMR: CDCh, 400 MHz. d 4.74 - 4.63 (m, 1H), 4.04 - 3.91 (m, 2H), 3.70 - 3.56 (m, 6H), 3.36 - 3.25 (m, 2H), 1.94 - 1.89 (m, 2H), 1.45 (s, 9H). LCMS: RT = 0.274 min, m / z 299.8 [M+Na]+.G. Step 7

[0309] To a solution of 2-[3-[2-(tert-butoxycarbonylamino)ethoxy]propoxy]acetic acid (106.88 mg, 385.42 pmol) and (2S,4R)-l-[(25)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-A- [[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (150 mg, 321.18 pmol, HC1 salt) in DMF (2 mL) were added DIEA (166.04 mg, 1.28 mmol, 223.77 μL), TPTU (190.82 mg, 642.37 pmol) and HOBt (86.80 mg, 642.37 pmol) at 0 °C. The mixture was stirred at 25 °C for 2hours. The reaction mixture was diluted with water (2 mL) and extracted with Dichloromethane / Methanol (10 / 1, 4 mL x 3). The combined phase was washed with brine (6 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC on silica gel (Dichloromethane / Methanol = 10 / 1) to afford the desired producttert-butyl 7V-[2-[3-[2-[[(15)-l-[(25,4J?)-4-hydroxy-2-[[4-(4-methylthiazol-5- yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo- ethoxy]propoxy]ethyl]carbamate (170 mg, 246.43 pmol, 76.72% yield) as a yellow oil. LCMS: RT = 0.449 min, m / z 690.3 [M+H]+.H. Step 8

[0310] To a solution of tert-butyl 7V-[2-[3-[2-[[(15)-l-[(25,4R)-4-hydroxy-2-[[4-(4- methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl- propyl]amino]-2-oxo-ethoxy]propoxy]ethyl]carbamate (170 mg, 246.43 pmol) in CH2CI2 (6 mL) was added HCl / dioxane (2 M in dioxane, 4.0 mmol, 2.0 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuo to afford the desired product (25,4 / ?)- l-[(25)-2-[[2-[3-(2-aminoethoxy)propoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-7V- [[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (150 mg, 239.54 pmol, 97.20% yield, HC1 salt) as a yellow oil. 'HNMR: DMSO-d / g, 400 MHz. 3 9.02 (s, 1H), 8.67 - 8.60 (m, 1H), 7.90 (brs, 3H), 7.44 - 7.38 (m, 4H), 4.61 - 4.52 (m, 1H), 4.47 - 4.22 (m, 6H), 3.94 - 3.88(m, 4H), 3.55 - 3.47 (m, 6H), 3.17 - 3.08 (m, 2H), 2.98 - 2.91 (m, 2H), 2.45 (s, 3H), 1.85 - 1.77 (m, 2H), 0.94 (s, 9H). LCMS: RT = 0.324 min, m / z = 590.2 [M+H]+.I. Step 9

[0311] To a solution of 8-(3,5-difhioro-2-pyridyl)-15-methyl-4-(methylsulfonylmethyl)-14- oxo-8,12,15-triazatetracyclo[8.6.1.02,7.013,17]heptadeca-l(16),2(7),3,5,10,13(17)-hexaene-5- carboxylic acid (100 mg, 199.81 μmol) and (25',4J?)-l-[(25)-2-[[2-[3-(2- aminoethoxy)propoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-A-[[4-(4-methylthiazol- 5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (137.63 mg, 219.79 pmol, HC1 salt) in DMF (2 mL) were added DIEA (154.94 mg, 1.20 mmol, 208.82 pL) and EDCI (114.91 mg, 599.43 pmol) and HOBt (81.00 mg, 599.43 pmol) at 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (2 mL) and extracted with Dichloromethane / Methanol (10 / 1, 4 mL x 3). The combined phase was washed with brine (10 mL x 3), dried over anhydrous Na?SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 22%-52% B over 10 min) to afford the desired product 8-(3,5-difluoro-2-pyridyl)-A-[2-[3-[2- [[(15)-l-[(25’,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-l- carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]propoxy]ethyl]-15-methyl-4- (methylsulfonylmethyl)- 14-oxo-8, 12, 15-triazatetracyclo[8.6.1.02, 7.013, 17]heptadeca- l(16),2(7),3,5,10,13(17)-hexaene-5-carboxamide (34.56 mg, 31.80 pmol, 15.91% yield, 98.6% purity) as a yellow solid. ’H NMR: DMSO-d6, 400 MHz. 3 11.90 (s, 1H), 8.96 (s, 1H), 8.57 (s, 1H), 8.48 - 8.40 (m, 1H), 8.06 (d, J= 2.8 Hz, 1H), 7.92 (s, 1H), 7.75 (s, 1H), 7.64 - 7.56 (m, 1H), 7.45 - 7.38 (m, 5H), 7.29 - 7.25 (m, 2H), 6.14 - 4.94 (m, 2H), 4.60 - 4.20 (m, 7H), 3.90 (s, 2H), 3.70 - 3.56 (m, 6H), 3.53 - 3.41 (m, 8H), 2.89 (s, 3H), 2.43 (s, 3H), 2.08 - 2.03 (m, 1H), 1.92 - 1.89 (m, 1H), 1.75 - 7.72 (m, 2H), 0.94 (s, 9H). LCMS: RT = 1.992 min, m / z 1072.6 [M+H]+.EXAMPLE C-18. SYNTHESIS OF 8-(3,5-DIFLUORO-2-PYRIDYL)-N-[2-[2-[2-[2-[[(lS)- l-[(2S,4R)-4-HYDROXY-2-[[(lS)-l-[4-(4-METHYLTHIAZOL-5-YL)PHENYL] ETHYL] CARBAMOYL] PYRROLIDINE- 1-CARBONYL] -2,2-DIMETHYL-PROPYL] AMINO] -2-OXO-ETHOXY] ETHOXY] ETHOXY] ETHYL] - 15-METHYL-4-(METHYLSULFONYLMETHYL)-14-OXO-8,12,15-TRIAZATETRACYCLO[8.6.L02,7.013,17]HEPTADECA-1(16),2(7),3,5,10,13(17)- HEXAENE-5-CARBOXAMIDEA. Step 1

[0312] To a mixture of 2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]acetic acid (250 mg, 813.43 pmol), (2S,4R)-l-[(25)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-A- [(lS)-l-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (469.56 mg, 976.12 pmol, HC1 salt), HOBt (164.87 mg, 1.22 mmol) and DIPEA (630.78 mg, 4.88 mmol, 850.11 pL) in DMF (3 mL) was added TPTU (362.46 mg, 1.22 mmol) at 0 °C. Then the mixture was warmed to 25 °C and stirred for 1 hour. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC on silica gel (Dichloromethane / Methanol = 5 / 1) to afford the desired producttert-butyl A-[2-[2-[2-[2-[[(lS)-l-[(2S,4R)-4-hydroxy-2-[[(15)-l-[4-(4- methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl- propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethyl]carbamate (420 mg, 568.27 pmol, 69.86% yield, 99.3% purity) as a yellow oil. 'H NMR: CDCE, 400 MHz. d 8.68 (s, 1H), 7.50 - 7.30 (m, 6H), 5.12 - 5.07 (m, 1H), 4.76 (t, J= 8.0 Hz, 1H), 4.63 - 4.48 (m, 2H), 4.14 - 4.03 (m, 2H), 3.75 - 3.69 (m, 4H), 3.68 - 3.60 (m, 5H), 3.55 (t, J= 5.2 Hz, 2H), 3.50 (s, 2H), 3.38 - 3.24 (m, 2H), 2.56 - 2.50 (m, 4H), 2.18 - 2.00 (m, 1H), 1.49 (d, .7= 7.2 Hz, 3H), 1.44 (s, 9H), 1.08 (s, 9H). LCMS: RT = 0.450 min, m,z 734.2 [M+H]+.B. Step 2

[0313] To a solution of tert-butyl N-[2-[2-[2-[2-[[(lS)-l-[(25,4R)-4-hydroxy-2-[[(16’)-l-[4-(4- methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl- propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethyl]carbamate (420 mg, 568.27 pmol) in CH2CI2 (5 mL) was added HCl / dioxane (4 M in dioxane, 20.00 mmol, 5 mL) at 25 °C. Then the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated in vacuo to afford the desired product (25,4R)-l-[(25)-2-[[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl- butanoyl]-4-hydroxy-N-[(16’)-l-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide (380 mg, 566.38 pmol, 99.67% yield, 99.9% purity, HC1 salt) as a yellow solid. LCMS: RT = 0.317 min, m / z 634.2 [M+H]+.C. Step 3

[0314] To a mixture of 8-(3,5-difluoro-2-pyridyl)-15-methyl-4-(methylsulfonylmethyl)-14- oxo-8,12,15-triazatetracyclo[8.6.1.02,7.013,17]heptadeca-l(16),2(7),3,5,10,13(17)-hexaene-5- carboxylic acid (49.78 mg, 99.46 pmol), (2S,4R)-l-[(25)-2-[[2-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-A-[(lS)-l-[4-(4- methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (80 mg, 119.36 pmol, HC1 salt) and DIPEA (77.13 mg, 596.78 pmol, 103.95 pL) in DMF (1 mL) were added HOBt (20.16 mg, 149.20 pmol) and EDCI (28.60 mg, 149.20 pmol) at 0 °C. Then the mixture was warmed to 25 °C and stirred for 3 hours. The mixture was filtered and the filtrate was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA) - ACN]; gradient: 27% - 57% B over 10 min) to afford the desired product 8-(3,5-difluoro-2-pyridyl)-7V- [2-[2-[2-[2-[[(15)-l-[(2S,4R)-4-hydroxy-2-[[(15)-l-[4-(4-methylthiazol-5- yl)phenyl]ethyl]carbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo- ethoxy]ethoxy]ethoxy]ethyl]-l 5-methyl-4-(methylsulfonylmethyl)- 14-oxo-8, 12, 15- triazatetracyclo[8.6.1.02,7.013,17]heptadeca-l(16),2(7),3,5,10, 13(17)-hexaene-5-carboxamide (66.22 mg, 58.61 pmol, 58.93% yield, 98.8% purity) as a white solid. 'H NMR: DMSO-<A, 400 MHz. 3 11.92 (s, 1H), 9.07 - 8.91 (m, 1H), 8.52 - 8.40 (m, 2H), 8.11 - 8.03 (m, 1H), 7.96 - 7.89 (m, 1H), 7.75 (s, 1H), 7.66 - 7.56 (m, 1H), 7.45 - 7.33 (m, 6H), 7.29 (s, 1H), 6.07 - 5.80 (m, 1H), 5.15 - 5.10 (m, 1H), 4.95 - 4.85 (m, 1H), 4.61 - 4.19 (m, 5H), 3.95 (s, 2H), 3.64 - 3.47 (m, 18H), 2.90 (s, 3H), 2.45 (s, 3H), 2.09 - 2.00 (m, 1H), 1.81 - 1.71 (m, 1H), 1.35 (d, J= 7.2 Hz, 3H), 0.93 (s, 9H). LCMS: RT = 2.196 min, m / z 1116.6 [M+H]+.EXAMPLE C-19. SYNTHESIS OF 8-(3,5-DIFLUORO-2-PYRIDYL)-N-[2-[4-[[4-[2-[[(lS)- l-[(2S,4R)-4-HYDROXY-2-[[4-(4-METHYLTHIAZOL-5-YL)PHENYL]METHYLCARBAMOYL]PYRROLIDINE-l-CARBONYL]-2,2- DIMETHYL-PROPYL]AMINO]-2-OXO-ETHYL]PIPERAZIN-l-YL]METHYL]-l- PIPERIDYL]ETHYL]-15-METHYL-4-(METHYLSULFONYLMETHYL)-14-OXO- 8,12,15-TRIAZATETRACYCLO[8.6.1.02,7.013,17]HEPTADECA-1(16),2(7),3,5,10,13(17)- HEXAENE-5-CARBOXAMIDEA. Step 1

[0315] A mixture of benzyl 4-(piperazin-l-ylmethyl)piperidine-l -carboxylate (2 g, 5.12 mmol, 2HC1 salt), methyl 2-bromoacetate (1.02 g, 6.66 mmol, 630.52 pL), CS2CO3 (3.34 g, 10.25 mmol) and KI (850.53 mg, 5.12 mmol) in MeCN (20 mL) was heated to 60 °C and stirred for 2 hours under N2. The reaction mixture was diluted with water (20 mL) and extracted with Dichloromethane / Methanol (10 / 1, 20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 10 / 1) to afford the desired product benzyl 4-[[4-(2-methoxy-2-oxo-ethyl)piperazin-l- yl]methyl]piperidine-l -carboxylate (1.4 g, 3.59 mmol, 70.15% yield) as a yellow oil. ’HNMR: DMSO-de, 400 MHz. 3 7.43 - 7.26 (m, 5H), 5.05 (s, 2H), 3.99 - 3.96 (m, 2H), 3.60 (s, 3H), 3.19 (s, 2H), 2.86 - 2.70 (m, 2H), 2.49 - 2.44 (m, 4H), 2.35 - 2.30 (m, 4H), 2.10 - 2.08 (m, 2H), 1.68 - 1.65 (m, 3H), 1.00 - 0.90 (m, 2H). LCMS: RT = 0.288 min, m z 390.2 [M+H]+.B. Step 2

[0316] To a solution of benzyl 4-[[4-(2-methoxy-2-oxo-ethyl)piperazin-l- yl]methyl]piperidine-l -carboxylate (1.4 g, 3.59 mmol) in MeOH (15 mL) was added Pd / C (500 mg, 469.84 pmol, 10% purity) at 25 °C under N2. The mixture was stirred at 25 °C for 16 hours under H2 (45 psi). The mixture was filtered and the filtrate was concentrated in vacuo to afford the desired product methyl 2-[4-(4-piperidylmethyl)piperazin-l-yl]acetate (750 mg, 2.94 mmol, 81.71% yield) as a white solid. ‘HNMR: DMSO-fifc, 400 MHz. 3 3.60 (s, 3H), 3.18 (s, 2H), 2.89 - 2.86 (m, 2H), 2.48 - 2.38 (m, 6H), 2.34 - 2.28 (m, 4H), 2.07 - 2.05 (m, 2H), 1.60 - 1.49 (m, 3H), 0.96 - 0.87 (m, 2H). LCMS: RT = 0.131 min, m / z 256.2 [M+H]+.C. Step 3

[0317] A mixture of methyl 2-[4-(4-piperidylmethyl)piperazin-l-yl]acetate (745 mg, 2.92 mmol), 2-(tert-butoxycarbonylamino)ethyl 4-methylbenzenesulfonate (1.20 g, 3.79 mmol), CS2CO3 (1.90 g, 5.84 mmol) and KI (484.31 mg, 2.92 mmol) in MeCN (10 mL) was heated to 60 °C and stirred for 2 hours under N2. The reaction mixture was diluted with water (10 mL) and extracted with Dichloromethane / Methanol (10 / 1, 10 mL x 3). The combined organic phase was washed with brine (lOmL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Dichloromethane / Methanol = 10 / 1) to afford the desired product methyl 2-[4-[[l-[2-(tert-butoxycarbonylamino)ethyl]-4- piperidyl]methyl]piperazin-l-yl]acetate (690 mg, 1.73 mmol, 59.34% yield) as a light yellow oil. 'HNMR: DMSO4, 400 MHz. 3 6.61 (brs, 1H), 3.60 (s, 3H), 3.19 (s, 2H), 3.02 - 3.01 (m, 2H), 2.84 - 2.80 (m, 2H), 2.49 - 2.44 (m, 4H), 2.31 - 2.29 (m, 6H), 2.09 - 2.07 (m, 2H), 1.91 - 1.90 (m, 2H), 1.64 - 1.61 (m, 2H), 1.47 - 1.41 (m, 1H), 1.37 (s, 9H), 1.11 - 1.01 (m, 2H). LCMS: RT = 0.164 min, w / z 399.3 [M+H]+. / ). Step 4

[0318] To a solution of methyl 2-[4-[[l-[2-(tert-butoxycarbonylamino)ethyl]-4- piperidyl]methyl]pip...

Claims

WHAT IS CLAIMED IS:

1. A method of controlling a level of a target protein that is expressed in an insect cell, the method comprising contacting the insect cell with an effective amount of a compound of formula (I)PTM-L-LTM (I) the compound comprising: one or more BRD3 protein targeting moieties (PTM) that each independently bind a target BRD3 protein; one or more ligase targeting moieties (LTM) that each independently bind a ubiquitin ligase that is functional in an insect cell; and a linker (L) covalently bonded to the one or more protein targeting moieties and the one or more ligase targeting moieties.

2. The method of claim 1, wherein the ubiquitin ligases that the one or more ligase targeting moieties bind to comprise the von Hippel-Lindau tumor suppressor (VHL) or cereblon.

3. The method of claim 2, wherein at least one of the one or more ligase targeting moieties is a VHL targeting moiety and has a structure according to the formula (V-I):whereinR5aand R5bare each independently hydrogen, hydroxyl, amine, haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxyl alkyl, optionally substituted alkylamine, optionally substituted amide, optionally substituted alkyl-amide, optionally substituted alkyl-cyano, optionally substitutedalkyl -phosphate, optionally substituted aryl, optionally substituted alkyl-aryl, optionally substituted heteroalkyl, optionally substituted alkyl-heterocyclyl, optionally substituted alkoxy-heterocyclyl, COR14, alkyl-COR14, CONR15aR15b, NHCOR14, NHCH3COR14, or -X-L1, or are combined with the carbon atom to which they are attached to form an optionally substituted 3- to 5-membered cycloalkyl, heterocyclyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not epoxide or aziridine; each R6is independently C1-6 alkyl, halogen, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C6-12 aryl, C5-12 heteroaryl, C3-15 heterocyclyl, cyano, nitro, NR15aR15b, OR14, CONR15aR15b, NR15aCOR15b, SO2NR15aR15b, NR15aSO2R13b, or -X-L1, wherein the alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with 1 to 4 R6agroups;R8is an optionally substituted aryl, optionally substituted heteroaryl, or;R9and R10are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, haloalkyl, or, or are combined with the carbon atom to which they are attached to form an optionally substituted cycloalkyl;R2and R3are each independently hydrogen, C1-6 alkyl, or C1-6 hydroxyalkyl, or are combined with the carbon to which they are attached to form a C3-8 cycloalkyl, C6-12 aryl, or C5-12 heteroaryl, wherein the cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 4 R2agroups;R4is hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, or -X-L1;Rn is an optionally substituted heterocyclyl, optionally substituted alkoxy, optionallyR1is hydrogen, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkyl carbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, optionally substituted aralkyl, -C(O)Rla, or -C(O)-X-L1;Rlais C1-6alkyl, C3-8 cycloalkyl, C6-12 aryl, or C5-12 heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted with 1 to 4 Rlbgroups; each Rlb, R2a, and R6ais independently C1-6 alkyl, cyano, halogen, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, or -X-L1;R12is hydrogen or optionally substituted alkyl; each R13is independently hydrogen, halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or -X-L1; each R14is independently hydrogen, OH, O-C1-6 alkyl, optionally substituted alkyl, or NR15aR15b;R15aand R15bare each independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl, or are combined with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl;R16is hydroxy, a group that can be metabolized to hydroxy, or sulfonyl halide;A is optionally substituted phenyl, optionally substituted napthyl, or an optionally substituted 5- to 10- membered heteroaryl;X is a bond, CH2, NH, NMe, O, or S;L1is a site of attachment to the linker (L); and the subscripts n and p are each independently an integer from 0 to 4.

4. The method of claim 3, wherein at least one of the one or more ligase targeting moieties has a structure according to the formula:wherein when R11is , R1is hydrogen, C1-6alkyl, -C(O)Rla, or -QC^-X-L1;R4is hydrogen, C1-6alkyl, C1-6hydroxyalkyl, or -X-L1;R5ais hydrogen, C1-6alkyl, halogen, C1-6haloalkyl, C1-6alkyl-amide, hydroxy, C1-6alkoxy, C1-6haloalkoxy or -X-L1; and each R6is independently C1-6alkyl, halogen, C1-6haloalkyl, hydroxy, C1-6alkoxy, C1-6haloalkoxy, C3-8cycloalkyl, C6-12aryl, C5-12heteroaryl, OR14, or -X-L1, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted with 1 to 4 R6agroups.

5. The method of claim 3, wherein at least one of the one or more ligase targeting moieties has a structure according to the formula:

6. The method of claim 5, wherein at least one of the one or more ligase targeting moieties has the structure:

7. The method of claim 2, wherein at least one of the one or more ligase targeting moieties is a cereblon targeting moiety of one or more of formulas (C-a) to (C-k) as described herein.

8. The method of claim 1, wherein the one or more BRD3 protein targeting moieties is selected from one or more of formulas PTM-a, PTM-b, PTM-c, PTM-da, PTM-db, PTM-dc, PTM-e, PTM-fa, PTM-fb, PTM-g, PTM-h, PTM-i, PTM-j, or PTM-k as described herein.

9. The method of claim 8, wherein the one or more BRD3 protein targeting moieties is selected from one or more of formulas PTM-aa through PTM-ai, PTM-ba through PTM-bf, PTM-ca through PTM-cc, PTM-ja, or PTM-ka as described herein.

10. The method of claim 9, wherein the one or more BRD3 protein targeting moieties is selected from one or more of formulas PTM-al through PTM-a36 as described herein.

11. The method of claim 1, wherein the linker (L) is a chemical linking moiety connecting the LTM and the PTM, and having a structure according to the formula -(AL)q-, wherein:(AL)qis a group that is connected to at least one of LTM, PTM, or both; q is an integer greater than or equal to 1; eachcycloalkyl optionally substituted with 1-6 RL1and / or RL2groups, (C3-C11) heterocyclyl optionally substituted with 1-6 RL1and / or RL2groups, aryl optionally substituted with 1-6 RL1and / or RL2groups, or heteroaryl optionally substituted with 1-6 RL1and / or RL2groups, where RL1or RL2, each independently are optionally linked to other groups to form a cycloalkyl and / or heterocyclyl moiety, optionally substituted with 1-4 RL5groups; and each RL1, RL2, RL3, RL4and R'° is independently hydrogen, halogen, (C1-C8)alkyl, O(Ci- C8)alkyl, NH(Ci-Cs)alkyl, N((Ci-Cs)alkyl)2, (C3-C11)cycloalkyl, aryl, heteroaryl, (C3-C11)heterocyclyl, O(C3-C8)cycloalkyl, NH(C3-C8)cycloalkyl, N((C3- C8)cycloalkyl)((Ci-Cs)alkyl), OH, NH2, CC-(C1-C8)alkyl, CCH, CH=CH(Ci- C8)alkyl, C((C1-C8)alkyl)=CH(C1-C8)alkyl), C((C1-C8)alkyl)=C((C1-C8)alkyl)2, CO(C1-C8)alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2CONH(C1-C8)alkyl, or CON((C1-C8)alkyl)2.

12. The method of claim 11, wherein the linker (L) has a linear non-hydrogen atom number from 1 to 30.

13. The method of claim 11, wherein the linker (L) comprises at least one moiety selected from:m, n, o, p, q, and t are each independently 0, 1, 2, 3 or 4; and u, w, and v are each independently selected from integers 0 and 1;XL is -C(CH2)-, -C(CH3)H-, -CH2-, -O-, C=O, or -NH-CH2-; andRL is H, OH, F, Cl, or methyl; andWL2, WL3, WL4, WLS, WL6, WL7, and WLS are each independently 6- to 12- membered spirocycloalkylene or spiroheterocyclylene, each optionally substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, (C1-C3)alkoxy, (C1-C3)alkyl, (C1-C3)haloalkyl, or amino.

14. The method of claim 13, wherein the linker (L) compriseswherein each m is independently 1 or 2.

15. The method of claim 1, wherein the insect cell is a cell of an insect that is a member of the order Lepidopt era, Coleoptera, Diptera, Hymenoptera, Mallophaga, Homoptera, Hemiptera, Orthoptera, Thysanoptera, Dermaptera, Isoptera, Anoplura, Siphonaptera, or Trichoptera.

16. The method of claim 15, wherein the insect is a member of the order Lepidoptera.

17. A compound of formula C-l through C-27, C-56, or C-57 according to Table 1, or a salt or solvate thereof.

18. A composition comprising the compound of claim 17 or the salt or solvate thereof, and an agriculturally acceptable carrier.

19. A method of controlling a level of a BRD3 protein in an insect cell, the method comprising contacting the insect cell with an effective amount of the compound of claim 17, or with an effective amount of the composition of claim 18.

20. The method of claim 19, wherein the controlling of the level of the BRD3 protein comprises degrading the target protein.

21. The method of claim 19, wherein the insect cell is a cell of an insect, and wherein the contacting of the insect cell with an effective amount of the compound or composition comprises applying the compound or composition to an environment in which the insect is present.

22. The method of claim 19, wherein the compound or composition is applied to an insect pest, a plant, a seed, the soil, or other surface in the environment in which the insect is present.

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