Sortilin binders and bifunctional compounds thereof

Abstract

The present disclosure provides compounds able to bind sortilin, compositions comprising said compounds and uses thereof. Disclosed herein are also bifunctional compounds having a moiety which binds to sortilin linked to a moiety that binds to a target protein of interest, compositions comprising said bifunctional compounds and uses thereof. The bifunctional compounds herein described may be used to treat diseases or conditions by removing the target protein of interest from the plasma or extracellular space in a patient in need thereof.

Description

[0001] Sortil in binders and bifunctional compounds thereof

[0002] Technical field

[0003] The present disclosure relates to a compounds able to bind sortilin, compositions comprising said compounds and uses thereof. Disclosed herein are also bifunctional compounds having a moiety which binds to sortilin linked to a moiety that binds to a target protein of interest, compositions comprising said bifunctional compounds and uses thereof. The bifunctional compounds herein described may be used to treat diseases or conditions by removing the target protein of interest from the plasma or extracellular space in a patient in need thereof.

[0004] Background

[0005] Protein degradation is an important part of turn-over and renewal of biomolecules and is a natural occurring process in all cells. Cytoplasmic proteins are commonly degraded in proteasomes following ubiquitination while extracellular biomolecules are degraded in lysosomal compartments. Specific ubiquitination of cytoplasmic disease associated proteins (DAP) is facilitated by bi-functional molecules termed PROteolysis TArgeting Chimeras (PROTACs) (Sun et al.). PROTACs are bifunctional molecules composed in one end of a DAP binding warhead, which is linked to E3 ubiquitin ligase binding small molecule at the other end. PROTACs thereby link the E3 ligase to DAPs, resulting in ubiquitination and subsequent degradation in the proteasome, effectively functioning as chemical DAP knockdown. However, as PROTACs rely on the proteasome for function it is only applicable for intracellular proteins. Data have shown that non-cytosolic proteins can be directed for degradation in lysosomal compartments by engaging the protein sorting mannose-6 phosphate receptor (M6P-R) using bi-functional molecules (Banik et al.). Banik et al. showed that antibodies tagged with a M6P-R binding sugar moiety facilitated lysosomal degradation of extracellular and membrane bound targets, and these types of molecules were termed LYsosomal TArgeting Chimeras (LYTACs), this provided first preclinical proof-of-concept (PoC) that enhancing lysosomal delivery and degradation of DAP’s has therapeutic potential. The M6P-R binding motif is a phosphorylated sugar polymer, and substantial effort would therefore be required to develop an orally available modality. Both PROTACs and LYTACs are designed to hitchhike on natural cellular mechanisms, and as such the warheads are not required to provide functionality on their own. This is particular advantageous relative to traditional drug development, as warhead development simply requires optimisation of binding affinity and linker conjugation strategy. Additionally, the lack of these requirements further enables engagement against targets which are considered un-druggable due to current restraints.

[0006] The functionality of LYTACs rely on successful recruitment of a lysosomal transport receptor, exemplified by the M6P-R (Banik et al.). Another lysosomal receptor protein is sortilin. Sortilin possess a number of common features with the M6P-R including rapid internalisation from the cell surface and trafficking of cargo to lysosomes (Braulke et al.). Sortilin is expressed in most tissues and facilitates lysosomal degradation of several known ligands (Lefrancois et al. , Ni et al. , Hu et al.). The internalisation capacity of sortilin is illustrated by plasma accumulation of the natural ligand and frontotemporal lobar dementia (FTD) associated protein Progranulin, which is 3.5 fold increased in plasma of mice (Hu et al., Lee et al.) lacking sortilin. Increasing extracellular Progranulin levels by inhibition of sortilin mediated degradation of Progranulin is considered a therapeutic approach for treatment / prevention of FTD and several independent efforts have been explored to inhibit this interaction. The result is numerous small molecule high-affinity sortilin binders with different pharmacological profiles (Schroder et al., Andersen et al., Stachel et al.), including oral bioavailable compounds and compounds with CNS exposure (Schroder et al.).

[0007] The interleukin (IL)-17 is a family of cytokines including IL-17A through IL-17F which play a significant role in regulating inflammation and immune responses. These cytokines act through the binding of the IL-17 receptor (IL-17R) family, which includes several members. Functional IL-17R is a transmembrane receptor complex usually consisting of one IL-17RA subunit and a second other subunit, thus forming heteromeric receptors binding different ligands. IL-17A binds to heteromeric IL-17RA / RC receptor complex (Toy et al.).

[0008] IL17-A recruits and activates immune cells, promotes the production of other cytokines and chemokines, and facilitates the recruitment of neutrophils to sites of infection or inflammation. While IL-17A is crucial for immune defense, dysregulation of its production or activity can contribute to the development of various autoimmune and inflammatory diseases, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, spondyloarthritis, and multiple sclerosis. Therefore, IL-17A has been a target for therapeutic interventions of autoimmune and inflammatory diseases, and drugs that block IL-17A or its receptor have been developed and approved for clinical use. Strategies targeting IL-17A have focused on inhibition of protein-protein interactions that mediate signalling of IL-17A. For example, binding IL-17A to block downstream effects, targeting IL-17RA or indirect targeting via the IL-17 pathway (Beringer et al.). These strategies are predominantly exemplified by anti-IL-17A antibodies, such as Secukinumab, which is approved for treatment of psoriasis and psoriatic arthritis.

[0009] Antibody mediated therapies suffer from lack of oral availability and incur the risk of inducing immune responses to the therapy in some cases. So far, small-molecule inhibitors to IL-17A have been unsuccessful in treating IL-17A mediated conditions. At present, no alternative strategies to address IL-17A mediated conditions have been proposed.

[0010] It remains a challenge to develop compounds that can reliably induce targeted protein degradation of diverse target molecules mediated by lysosomal pathways. For example, there is a strong unmet need in the art to provide for alternative therapeutic strategies for the management of IL-17A mediated conditions that can overcome these deficiencies and expand the therapeutic scope of targeting IL-17A.

[0011] Summary

[0012] The present invention provides a solution to the above-mentioned problems by providing compounds able to bind sortilin and able to induce degradation of extracellular target proteins. Thus, the invention serves as an alternative therapeutic strategy that goes beyond inhibition of protein-protein interactions. The inventors have produced small molecule bifunctional compounds that are able to induce sortilin-mediated protein degradation of target proteins. In one main aspect, the present disclosure relates to a bifunctional compound of Formula (I): wherein

[0013] SL is a moiety that binds to Sortilin according to formula A-l wherein RLdenotes the attachment with U;

[0014] Li is a linker or a bond; and

[0015] TL is a moiety that binds an extracellular target molecule, or a pharmaceutically acceptable salt thereof.

[0016] Sortilin is a lysosomal receptor protein that induces rapid internalisation from the cell surface and trafficking of cargo to lysosomes (Barulke et al.). Sortilin is expressed in most tissues and facilitates lysosomal degradation of several known ligands (Lefrancois et al., Ni X. et al, Hu F. et al.). Human sortilin is encoded by the SORT 1 gene.

[0017] The inventors have shown that bifunctional compounds according to formula (I) are able to bind extracellular target moieties and induce sortilin-mediated internalization via lysosomal pathways in sortilin-expressing cells. This has the advantage of addressing conditions mediated by target proteins with a new mechanism focused on protein degradation rather than inhibition of the target protein directly. The bifunctional compounds of the present disclosure are able to bind both the target molecule and sortilin to form ternary complexes, thereby mediating internalization and degradation of the target molecule in the intracellular compartments. Sortilin is a high affinity receptor for low abundance ligands, which offers an advantage compared to other receptors for lysosomal targeted degradation which are low affinity lysosome sorting receptors for highly abundant ligands e.g. the low-density lipoprotein receptor (LDLR), the receptor LRP2 / megalin and the mannose 6-phosphate receptor (M6PR).

[0018] The inventors have found that bifunctional compounds derived from sortilin binders of formula A-l provide for high affinity of binding to sortilin and mediate targeted protein degradation, while providing improved drug-like properties, such as reduced lipophilicity and reduced liver microsome clearance compared to analogs of formula A-l where the tert-butyl ether is replaced by a neopentyl group (replacement of (CHsh-C-O- to (CHsh- C-CH2-). These properties indicate an unexpected reduction of first pass metabolism, which is beneficial for oral dosing.

[0019] In another aspect, the present disclosure provides for a pharmaceutical composition comprising a bifunctional compound as described herein.

[0020] In another aspect, the present disclosure provides for a bifunctional compound as described herein for use as a medicament.

[0021] In another aspect, the present disclosure provides for a compound according to formula (A-l I): or pharmaceutically acceptable salt thereof, or an entatiomer thereof, or a mixture thereof; wherein

[0022] R1is H, halogen, alkoxy, -CF3, or an optionally substituted C1-5 hydrocarbon chain, wherein one or more carbon groups of the C1-C5 hydrocarbon chain are optionally individually replaced by one or more of the groups consisting of -O-, -NH-, -C(O)-, ester, amide, carbamate, thiourea, sulphonamide, urea, , , an optionally substituted carbocycle; an optionally substituted heterocycle, or ; wherein X is NH or O.

[0023] The compounds of formula (A-ll) binds sortilin with high affinity while having advantageous biophysical properties, and thus have potential in therapy of sortilin mediated conditions. The examples show that compounds of formula (A-ll) bind sortilin with higher affinity compared to analogs of formula A-ll where the tert-butyl ether is replaced by a neopentyl group (replacement of (CHsh-C-O- to (CHsh-C-CFk-).

[0024] In one aspect, the present disclosure provides for the compound of formula (A-ll) for use as a medicament.

[0025] The inventors have discovered small molecule bifunctional compounds that are able to induce sortilin-mediated protein degradation of IL-17A. Thus, viewed from another aspect the present disclosure relates to a bifunctional compound according to formula (X):

[0026] TA-L - LI - SA-L (X) wherein

[0027] SA-L is a moiety that binds to Sortilin;

[0028] Li is a linker or a bond; and

[0029] TA-L is a moiety that binds interleukin 17-A (IL-17A), or a pharmaceutically acceptable salt thereof.

[0030] The inventors have surprisingly shown that compounds according to formula (X) are able to produce degradation of IL-17A by simultaneously binding both IL-17A and the receptor sortilin forming a ternary complex, which induces internalization of IL-17 A into the lysosomal space and its degradation.

[0031] The examples herein demonstrate that bifunctional compounds according to the present disclosure bind both IL-17A and sortilin and form ternary complexes with IL-17A and sortilin. Furthermore, the examples show that bifunctional compounds of formula (X) described herein induce uptake of IL-17A from the extracellular space into cells expressing sortilin receptor and confirm that internalised IL-17A is degraded in the lysosomes. Therefore, the present invention discloses a unique way of addressing relevantprotein-mediated conditions, such as IL-17A-mediated conditions, with a newmechanism focused on protein degradation rather than inhibition of the protein mediator directly or indirectly. The advantages of the present invention include one or more of the following: ●Ability to induce targeted degradation of the protein mediator, such as IL-17A;● Addressing protein mediators of disease (e.g. IL-17A) with a different strategythan direct inhibition; ●Ability to target protein mediators of disease (e.g. IL-17A) in a wide range of bodycompartments where there is expression of sortilin: bloodstream, CNS, PNS,CSF, cells of the immune system and tumor subtypes; ●The compounds of the disclosure are small molecules, hence providing a newclass of compounds different than therapeutics based on antibodies, or fragments thereof, to address protein-mediated conditions, for example antiIL-17- A antibodies, or fragments thereof; ●Enhanced therapeutic outcomes in treatment of conditions mediated byextracellular target molecules that bind TL or TA-L; ●Improved biophysical properties and improved administration, distribution,metabolism and excretion (ADME) properties; ●Improved pharmacokinetics, reduced toxicity or side effects compared to otherknown therapies for conditions involving selected extracellular target molecules. In one aspect, the present disclosure provides for a composition comprising the compound of formula (VI) as described herein. Description of Drawings Figure 1: Ternary complex formation between bifunctional compounds, sortilin and IL-17A as measured by HTRF FRET. Figure 2: Cellular uptake curve of IL-17A into sortilin expressing cells mediated by bifunctional compounds studied over a concentration of 2 nM to 2 µM. Figure 3: Cell lysate luminescent signal in sortilin expressing cells after 24 h incubation with nanoluc-IL-17A and 100 nM of bifunctional compound X-065, in the presence of 3 monofunctional IL-17A binders acting as competitive inhibitors.

[0032] Figure 4: Removal of IL-17A from extracellular media in sortilin expressing cells following 48h incubation with a dilution series of bifunctional compound X-017 and different concentrations of IL-17A.

[0033] Figure 5: Luminescent signal in cell lysate of sortilin expressing cells after 24 h incubation with nanoluc-IL-17A and bifunctional compound X-062 in the presence of lysosomal protease inhibitor leupeptin and control of without leupeptin.

[0034] Definitions

[0035] The term “alkyl” as used herein refers to a linear or branched hydrocarbon moiety.

[0036] The term "alkoxy" as used herein refers to a group of formula -O- alkyl, wherein alkyl is defined as above. In particular, C1-C3 -alkoxy is intended to indicate such hydrocarbon having 1 , 2 or 3 carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, n- propoxy, and isopropoxy.

[0037] The term “haloalkyl” as used herein refers to an alkyl group wherein one or more hydrogen atoms have been replaced by a halogen atom, for example one or more hydrogen atoms replace by any of F, Cl, Br or I.

[0038] As used herein the term “cycloalkyl” or “carbocycle” refers to a monocylcic or polycyclic system. The term “cycloalkyl” also used herein can optionally contain one or more unsaturations or substituents

[0039] The term "heterocyclic" or “heterocycle” as used herein, alone or in combination, refers to saturated or unsaturated aromatic or nonaromatic rings containing from 3 to 7 ring atoms where at least one the ring atoms are heteroatom(s). The term "heteroaromatic" or “heteroaryl” as used herein, alone or in combination, refers to an aromatic ring containing from 5 to 6 ring atoms where at least one of the ring atoms are heteroatom(s). By "heteroatom" is intended to mean sulfur, oxygen or nitrogen.

[0040] The term "aromatic" or “aryl” refers to a cyclic or polycyclic moiety having a conjugated unsaturated (4r|+2)TT electron system (where n is a positive integer), sometimes referred to as a delocalized TT electron system. The term "alkenyl" embraces radicals having at least one carbon-carbon double bond. The terms "substituents" or "substituted" as used herein, alone or in combination, refer to groups which may be used to replace hydrogen. The substituted molecule may itself be further substituted in some embodiments of the invention. As referred here a “substituent derived from” refer to a group of atoms derived from a specific molecule or formula at any position of said molecule or formula. In some embodiments, a substituent derived from a molecule is the corresponding molecule wherein a hydrogen atom has been removed. For example, –CH3is an example of a substituent derived from CH4. The dissociation constant (KD) or binding affinity is a measure of the extent of a reversible association between two molecular species. The smaller the dissociation constant, the stronger the affinity of binding. As described herein, a ternary complex is a complex containing three different molecules that are bound together. As described herein, the bifunctional compounds are able to form ternary complexes between sortilin and the target molecules. This means, a three member complex where sortilin is bound to the bifunctional compound at the same time as the target protein.As used herein, TNF-alpha may be referred to as TNFa, TNF-a, TNF-^^ TNF^^^orTNFalpha.

[0041] Detailed description Bifunctional compound In one main aspect, the present disclosure relates to a bifunctional compound of to Formula (I): TL – LI – SL (I)wherein SLis a moiety that binds to Sortilin according to formula A-I wherein RLdenotes the attachment with LI; LIis a linker or a bond; and TLis a moiety that binds an extracellular target molecule, or a pharmaceutically acceptable salt thereof. In one embodiment, SL is according to formula (A-Ia): wherein RLdenotes the attachment with LI. In one embodiment, SL is according to formula (A-Ib): formula (A-Ib), wherein RLdenotes the attachment with LI. Linker The linker joins the sortilin binder moiety and the targeting moiety. In one embodiment, the linker is according to formula (II): Formula (II) wherein * denotes the attachment to either TLor SL; L1 and L2 are each independently selected from the group consisting of a bond, -C(H2)-, -O- , -N(H)-, a functional group selected from carbonyl, ester, amide, carbamate,thiourea, urea, sulphonamide and triazole; and a C1-C3 hydrocarbon chain wherein one or more methylene groups are individually and optionally replaced with a carbonyl, ester, amide, carbamate, thiourea, urea, sulphonamide and triazole; Z is selected from the group consisting of: a bivalent, saturated or unsaturated, straight or branched, C1-C30 hydrocarbon chain wherein one or more methylene groups are individually and optionally replaced by one or more of the groups selected from: -O-, – N(H)-, -N(RL1)-, -OC(=O)-, -C(=O)O-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)- , -C(=O)N(H)-, -NHC(O)NH-, -NHC(O)O- -C(=O)N(RL1)-, -S-, -S(=O)-, -S(=O)2-, - N(RL1)S(=O)2-, -S(=O)2N(RL1)-; an optionally substituted aromatic group; an optionally substituted carbocycle; an optionally substituted heterocycle; an optionally substitutedaromatic heterocycle; ; , , ,, -C(RL2)H- and -N(RL2)-;RL1is selected from the group consisting of C1-5alkyl; RL2is –(CH2)L-RX; Rxis -OH, or -C(=O)NH2; L is an Integer from 0 to 3; n and w each individually integers from 1 to 9. In one embodiment, the C1-C30 hydrocarbon chain is C5-C30 hydrocarbon chain, such as a C8-C30 hydrocarbon chain, such as a C10-C30 hydrocarbon chain, such as a C12-C30 hydrocarbon chain. In one embodiment, the C1-C30 hydrocarbon chain is a C10-C25 hydrocarbon chain, such as a C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24 or C25 hydrocarbon chain. In one embodiment, the C1-C30 hydrocarbon chain is a C14-C20 hydrocarbon chain. In one embodiment, the C1-C30 hydrocarbon chain is a C7-C13 hydrocarbon chain. In one embodiment, one or more methylene group of Z, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 methylene groups of the hydrocarbon chain in Z are individually and optionally replaced by one or more of the groups selected from-O-, –N(H)-, -N(RL1)-, -OC(=O)- , -C(=O)O-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -C(=O)N(H)-, -C(=O)N(RL1)-, -S- , -S(=O)-, -S(=O)2-, -N(RL1)S(=O)2-, -S(=O)2N(RL1)-, -CH2-CH2-O-, an optionally substituted carbocycle; an optionally substituted heterocycle and a triazole; wherein RL1is C1-5 alkyl.In one embodiment, Z comprises one or more groups –NH-SO2- groups. In oneembodiment, Z comprises one or more triazole groups. In one embodiment, Z comprises one or more groups selected from: an optionally substituted carbocycle group(s) and an optionally substituted heterocycle group(s).In one embodiment, Z comprises two groups each individually selected from: a triazole,an optionally substituted carbocycle group(s) and an optionally substituted heterocyclegroup(s). In one embodiment, Z comprises three groups each individually selected from:a triazole, an optionally substituted carbocycle group(s) and an optionally substituted heterocycle group(s). wherein n is aninteger selected from 0, 1, 2 or 3. In one embodiment, Z comprises one or more heterocycle groups. In one embodiment, the heterocycle group may be an optionally substituted 3 to 6 membered ring wherein one or two carbon atoms of the ring have been replaced by N. In one embodiment, the heterocycle group is according to , wherein n is an integer selected from 0, 1, 2 or 3. In one embodiment, Z comprises three groups each individually selected from the groups shown Table Z: Table Z In one embodiment, Z comprises 1, 2 or 3 groups selected from any one of the groups in Table Z. In one embodiment, Z comprises 1 groups selected from any one of the groups in Table Z. In one embodiment, Z comprises 2 groups selected from any one of the groups in Table Z. In one embodiment, Z comprises 3 groups selected from any one of the groups in Table Z. In one embodiment, Z comprises one or more groups selected from the groups shown in Table Z-I: Table Z-I wherein n and / or n’ are each individually integers from 1 to 10 and t, t’ and / or w are each individually integers from 1 to 20. In one embodiment, Z comprises 1 group selected from any one of the groups in Table Z-I. In one embodiment, Z comprises or , wherein n is an integer from 1 to 10. an integer from 1 to 10 and t or w is an integer from 1 to 20.In one embodiment, Z comprises , wherein n is an integerfrom 1 to 10 and each of t and t’ is individually an integer from 1 to 20. In one embodiment, Z comprises , wherein eachof n and n’ is individually an integer from 1 to 10 and t is an integer from 1 to 20. In one embodiment, Z comprises one or more, such as one, two or three branches bearing polar groups, said branch(es) being each independently -C(RL2)H-, or -N(RL2)-, wherein RL2 is –(CH2)L-RX; Rx is -OH, or -C(=O)NH2; and L is an integer from 0 to 3. Inone embodiment, Z comprises one branch bearing polar groups, said branch being - C(RL2)H-, or -N(RL2)-; wherein RL2 is –(CH2)L-RX; Rx is -OH, or -C(=O)NH2; and L is aninteger from 0 to 3. The inventors have shown that when Z comprises branches bearingpolar groups, un-specific protein binding in the plasma is reduced. In one embodiment, Z comprises -C(RL2)H-, wherein RL2 is –(CH2)L-RX; Rxis -OH, -C(=O)NH2; and L is an integer from 0 to 3. In one embodiment, Zcomprises -N(RL2)-, wherein RL2 is –(CH2)L-RX; Rx is -OH, or -C(=O)NH2; and L is aninteger from 0 to 3. In one embodiment, L is 0, 1, 2 or 3. In one embodiment L is 0, 1 or 2. In one embodiment, L is 0 or 1. In one embodiment L is 0. In one embodiment L is 1. In one embodiment L is 2. In one embodiment Rxis -OH. In one embodiment, Rxis –C(=O)NH2. In one embodiment, Z comprises one or more moieties selected from the group consisting of:

[0042] ,, In one embodiment, Z comprises one and only one of the group selected from: , ,

[0043] In one embodiment, wherein Z comprises . In one embodiment, L1or L2are a triazole group. In one embodiment, L1and L2are a triazole group. In one embodiment, L1or L2are –O-. In one embodiment, L1and L2are –O-. In one embodiment, L1or L2are –NH-. In one embodiment, L1and L2are –NH-. In one embodiment, L1or L2are –S(=O)2-. In one embodiment, L1and L2are –S(=O)2-. In one embodiment, L1or L2are . In one embodiment, L1and L2are . 12 In one embodiment, L or L are . 1 In one embodiment, L and L2are . . In one embodiment, L1and / or L2are . 12 In one embodiment, L and / or L are , wherein X is an atom selected from N or O. In one embodiment, L1and / or L2are , wherein X is an atom selected from N or O. In one embodiment, L1and L2are different groups. In one embodiment, L1and L2are identical.In one embodiment, the linker (LI) is according to any one of the structures II-1 to II-98as shown in table Z-II:Table Z-II:

[0044] wherein * denotes the attachment with TLor SL. As shown herein, when any of the structures in Table Z-II contain a stereocenter, that center may have any configuration R or S according to Cahn-Ingold-Prelog rules. For example, in one embodiment the stereocenter has R configuration. In one embodiment, the stereocenter has S configuration.In one embodiment, the linker LI is according to any one of formulas II-1 to II-98 in TableZ-II. The linker as shown in table Z-II, such as formulas II-1 to II-98, may be connectedto SL and TL at any attachment marked with *, respectively. For example, in oneembodiment, the linkers shown in table Z-II are connected to TLthrough attachment marked with * that appears in the left of the formula shown in Table Z-II, and connectedto SL through the attachment marked with * that appears in the right of the formula shownin Table Z-II. In one embodiment, the bifunctional compound according to the present disclosure is able to bind sortilin with a dissociation constant (KD) of less than 50 ^M, such as less than 40 ^M, such as less than 30 ^M, such as less than 20 ^M, such as less than 10 ^M, such as less than 5 ^M, such as less than 4 ^M, such as less than 3 ^M, such as less than 2 ^M, such as less than 1 ^M, such as less than 0.8 ^M, such as less than 0.6 ^M, such as less than 0.5 ^M, such as less than 0.4 ^M, such as less than 0.3 ^M, such as less than 0.2 ^M, such as less than 0.1 ^M, such as less than 0.05 ^M, such as less than 0.04 ^M, such as less than 0.03 ^M, such as less than 0.02 ^M such as less than 0.01 ^M. In one embodiment, the bifunctional compound according to the present disclosure is able to bind sortilin with a dissociation constant (KD) between 50 ^M and 0.001 ^M, such as between 50 ^M and 40 ^M, such as between 40 ^M and 30 ^M, such as between 30 ^M and 20 ^M, such as between 20 ^M and 10 ^M, such as between 10 ^M and 5 ^M, such as between 5 ^M and 4 ^M, such as between 4 ^M and 3 ^M, such as between 3 ^M and 2 ^M, such as between 2 ^M and 1 ^M, such as between 1 ^M and 0.9 ^M, such as between 0.9 ^M and 0.8 ^M, such as between 0.8 ^M and 0.7 ^M, such as between 0.7 ^M and 0.6 ^M, such as between 0.5 ^M and 0.4 ^M, such as between 0.4 ^M and 0.3 ^M, such as between 0.3 ^M and 0.2 ^M, such as between 0.2 ^M and 0.1 ^M, such as between 0.1 ^M and 0.05 ^M, such as between 0.05 ^M and 0.01 ^M, such as between 0.01 ^M and 0.001 ^M. The binding with the target protein or sortilin may be measured through different methods as it is known to someone of skill in the art. For example, microscale thermophoresis (MST). Targeting moiety and target extracellular molecule The bifunctional compounds according to the present disclosure comprise a moiety able of binding an extracellular target molecule or protein, such as a growth factor, a cytokine, a hormone, a lipoprotein, a neurotransmitter, a capsid, an extracellular secreted protein, an antibody. In one embodiment, the extracellular target molecule is a protein. An extracellular protein, as described herein refers to proteins that are not fully enclosed inside a cell. This means for example, a protein that is completely outside of a cell, but also membrane-bound or membrane associated proteins with an extracellular domain.In an embodiment, TL is a substituent of a small organic molecule (i.e., a non-biologic)that adequately binds to the target molecule, or a substituent derived from a pharmaceutically active compound that binds to the target extracellular protein, or a peptide, protein or biologic or a binding fragment thereof that adequately binds to the extracellular target molecule. The TL moiety may be for example, but not limited to, a substituent derived from of an approved or clinical stage drug, or a substituent derived from of a compound that would be reviewed as a drug by a regulatory organization such as the FDA or EMA. The extracellular target protein can be any amino acid sequence to which the bifunctional compound comprising a TL can be bound which through degradation thereof, results in a beneficial therapeutic effect. In one embodiment, the target protein is a non-endogenous peptide such as that from a pathogen or toxin. In another embodiment, the Target Protein can be an endogenous protein that mediates a disorder. The endogenous protein can be either the normal form of the protein or an aberrant form. For example, the Target Protein can be an extracellular mutant protein, or a protein, forexample, where a partial, or full, gain-of-function or loss-of- function is encoded bynucleotide polymorphisms. In some embodiments, the bifunctional compound targets the aberrant form of the protein and not the normal form of the protein. The Targeting Ligand (TL) moiety of the bifunctional compound according to this disclosure is a ligand which covalently or non-covalently binds to a Target Protein which has been selected for lysosomal degradation. A number of exemplary extracellular proteins targeted for medical therapy described below have characterizing structural information in the well-known Protein Data Bank (“PDB”), which is a database for the three-dimensional structural information for large biological molecules such as proteins and nucleic acids. PDB includes x-ray crystallography and other information submitted by scientists around the world and isfreely accessible. See for example www.rcsb.org: wwwrwwpdb.org and www.uniprot.orgin connection with the codes provided below. For example, the skilled artisan can use available visualization tools, including those available on the PDB website, to determine where TL docks into to the Extracellular Protein. The skilled artisan can also import the crystal structure and the selected TL of interest into modeling software (including for example PyMOL, Glide, Maestro, RasMol, Visual Molecular Dynamics, Jrnol, and AutoDock) to determine what portion of the Extracellular Protein Targeting Ligand is bound to the Extracellular Protein. The bifunctional compound TL is then bound to the linker (LI) or sortilin binding group (SL) at a point that does not unduly adversely affect binding to the extracellular protein. Non-limiting examples of extracellular proteins: In one embodiment the extracellular target protein is one selected from the group consisting of: PCSK9, TNF-^, ANGPTL-3, an antibody light chain, IgG, IgE, IgA IL-1, IL- 2 , IL-6, IFN-γ, VEGF, TFG-^1, IL-21, IL-22, IL-5, IL-10, IL-8, cholinestearase,human CCL2, carboxypeptidase B-2, neutrophil elastase, Factor Xa, Factor XI, Factor XIa, Factor XII, Factor XIII, prothrombin, coagulation factor VII, coagulation factor IX, fibroblast growth factor 1, FGF-2, fibronectin 1, kallikrein-1, lipoprotein lipase, human matrix metallopeptidase 1, macrophage migration inhibitory factor, transformin growth factor-p (TGF-p), thrombospondin-1 (TSP-T), CD40 ligand, urokinase-type plasminogen activator, plasminogen activator tissue type (TPA), Plasminogen (PLG), Plasminogen Activator Inhibitor-1, Placenta Growth Factor, Phospholipase A2 Group IB, Phospholipase A2 Group IIA, Complement factor B, Complement factor D, complement factor H, Complement Component 5 and complement C1s. Immunoglobulin G (IgG) In some embodiments, the Target Protein is a human immunoglobulin G (IgG). IgG represents approximately 75% of serum antibodies in humans. IgG is the most common type of antibody found in blood circulation. IgG antibodies are large globular proteins with a molecular weight of about 150 kDa made of four peptide chains. It contains two identical g (gamma) heavy chains of about 50 kDa and two identical light chains of about 25 kDa, thus a tetrameric quaternary structure. The two heavy chains are linked to each other and to a light chain each by disulfide bonds. The resulting tetramer has two identical halves, which together form the Y-like shape. Each end of the fork contains an identical antigen binding site. The various regions and domains of a typical IgG are depicted in the figure to the left. The Fc regions of IgGs bear a highly conserved N-glycosylation site at asparagine 297 in the constant region of the heavy chain. The N-glycans attached to this site are predominantly core-fucosy fated biantennary structures of the complex type. In addition, small amounts of these N-glycans also bear bisecting G!cNAc and a-2,6- iinked sialic acid residues. The N-glycan composition in IgG has been linked to severalautoimmune, infectious, and metabolic diseases. In addition, overexpression of IgG4 hasbeen associated with IG4- related diseases, which generally include multiple organs, anddisorders include type 1 autoimmune pancreatitis, interstitial nephritis, Riedel's thyroiditis, Mikulicz's disease, Kuttner's tumor, inflammatory' pseudotumors (in various sites of the body), mediastinal fibrosis and some cases of retroperitoneal fibrosis, aortitis, retroperitoneal fibrosis, proximal biliary strictures, tubulointerstitial nephritis, pachymeningitis, pancreatic enlargement and pericarditis. The Protein Data Bank website provides the crystal structure of IgG searchable by 1H3X (Krapp, S., et a!., J. Mol. Biol., 2003, 325: 979); and 5V43 (Lee, C.H., et al., Nat. Immunol., 2017, 18: 889-898); as well as the crystal structure of IgG bound to various compounds searchable by 5YC5 (Kiyoshi M., et ah, Sei. Rep., 2018, 8: 3955-3955); 5XJE (Sakae Y., et al., Sci. Rep., 2017, 7: 13780-13780); 5GSQ (Chen, C. L., et al., ACS Chem Biol, 2017, 12: 1335-1345); and 1HZH (Saphire E. ()., et. al, Science, 2001, 293: 1155-1159). Additionally, Kiyoshi, M., et al, provides insight into the structural basis for binding of human IgGl to its high-affinity human receptor FcyRI. (Kiyosi M., et al, Nat Commun., 2015, 6, 6866). The bifunctional compounds according to the present invention are able to bind sortilin through the sortilin binding moiety (SL) and a target protein throught the protein targeting moiety (TL). Thus in one embodiment, the bifunctional compounds of the present invention are able to bind to sortilin and to the target protein at the same time. This means, that the bifunctional compounds according to the present disclosure form a ternary complexes with sortilin and the target protein. In a ternary complex, sortilin and the target protein are bound simultaneously to the bifunctional compound. The formation of ternary complexes can be measured in different ways as known in the art. For example, ternary complex formation can be measure through Förster’s resonance energy transfer (FRET) assays or through timer-resolved Förster’s resonance energy transfer (TR-FRET) assays. As measured by these assays an increase in the homogeneous time-resolved fluorescence (HTRF) ratio indicates formation of ternary complexes. As demonstrated in the examples, bifunctional compounds according to the present disclosure are able to bind both sortilin and target proteins, and form ternary complexes. In one embodiment, the bifunctional compound according to the present disclosure is able to bind to sortilin at the cell surface. In another embodiment, the bifunctional compound is able to form a ternary complex with sortilin and the target molecule at the cell surface. In one embodiment, upon binding of SL to sortilin located on the cell surface and binding of TL to the target protein, the target protein is internalized into said cell. In one embodiment, the target protein is degraded after internalization into said cell. In one embodiment, the degradation of the target protein happens in the lysosomal compartments. In one embodiment, the bifunctional compound according to the present disclosure has a dissociation constant of binding to sortilin of of less than 50 ^M, such as less than 40 ^M, such as less than 30 ^M, such as less than 20 ^M, such as less than 10 ^M, such as less than 5 ^M, such as less than 4 ^M, such as less than 3 ^M, such as less than 2 ^M, such as less than 1 ^M, such as less than 0.8 ^M, such as less than 0.6 ^M, such as less than 0.5 ^M, such as less than 0.4 ^M, such as less than 0.3 ^M, such as less than 0.2 ^M, such as less than 0.1 ^M, such as less than 0.05 ^M, such as less than 0.01 ^M and a dissociation constant of binding to the target protein of less than 50 ^M, such as less than 40 ^M, such as less than 30 ^M, such as less than 20 ^M, such as less than 10 ^M, such as less than 5 ^M, such as less than 4 ^M, such as less than 3 ^M, such as less than 2 ^M, such as less than 1 ^M, such as less than 0.8 ^M, such as less than 0.6 ^M, such as less than 0.5 ^M, such as less than 0.4 ^M, such as less than 0.3 ^M, such as less than 0.2 ^M, such as less than 0.1 ^M. TNF-alphaIn some embodiments, the Target Protein is human TNF-^ (UniProtKB - PC) 1375(TNFA_HUMAN)). TNF-^is a pro-inflammatory cytokine active in the bodily immuneresponse and serious inflammatory diseases. TNF-^ has been implicated in several ofdisorders, including but not limited to rheumatoid arthritis, inflammatory bowel disease, graft-vs-host disease, ankylosing spondylitis, psoriasis, hidradenilis suppurativa, refractory asthma, systemic lupis erthyematosus, diabetes, and the induction ofcachexia. As used herein, TNF-alpha may be referred to as TNFa, TNF-a, TNF-^ orTNF^^or TNFalpha.The Protein Data Bank website provides the crystal structure of TNF-^ searchable by6RMJ (Va!entinis, B., et al, Int. J. Mol. Sci., 2019, 20), 5UUI (Carrington et al., Biophys J., 2017, 113371-380); 600Y, 600Z and 60PO (O’Connell, J., et al., Nat. Commun.,2019, 105795- 5795), and 5TSVV (Cha, S. S., J Biol Che ., 1998, 2732153-2160); aswell as the crystal structure of TNF-^ bound to various compounds searchable by 5YOY(Ono et al., Protein Sci., 2018, 271038-1046 ); 2AZ5 (He., M. VI. et af, Science, 2005, 310: 1022-1025); 5WUX (Lee, J. U., Int J Mol Sci., 2017, 18); 5MU8 (Blevitt et al., J Med Chem., 2017, 603511-3517); 4Y60 (Feldman J. I,., et al., Biochemistry, 2015, 543037-3050); 3WD5 (Hu, S., et al., J Biol Chem, 2013, 28827059- 27067); and 4G3Y (Liang, S.Y., J Biol Chem., 2013, 28813799-13807).Proprotein Convertase Suhtilisin / Kexm Type 9 (PCSK-9)In some embodiments, the Target Protein is human proprotein convertasesubtilisin / kexin type 9 (PCSK-9) (UniProtKB - Q8NBP7 (PCSK9_HUMAN)). PCSK-9 is acrucial player in the regulation of plasma cholesterol homeostasis. PCSK-9 binds to low- density lipid receptor family members: low density lipoprotein receptor (LDLR), very low- density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1 / APOER) and apolipoprotein receptor 2 (LRP8 / APOER2), and promotes their degradation in intracellular acidic compartments. It acts via a non-proteoiytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAPl / ARH-mediated pathway, and may prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. PCSK-9 has been implicated in high blood cholesterol and the development of cardiovascular disease. The Protein Data Bank website provides the crystal structure of PCSK-9 searchable by 2P4E (Cunningham, D., et al., Nat Struct Mol Biol., 2007, 14413-419); as well as the crystal structure of PCSK-9 bound to various compounds searchable by 3BPS (Kwon, H. J , et al, Proc Natl Acad Sei U S A, 2008, 1051820-1825); 6U26, 6U2N, 6U2P, 6U36, 6U38, and 6U3X (Petrilli, W. L., et al., Ceil Chem Biol., 2019, 2732-40. e3); 50CA (Gustafsen, C., et al., Nat Commun., 2017, 8503-503); 4NE9 (Schroeder, C. L, et a!., Chem Biol., 2014, 21284-294); 40V6 (Mitchell, T., et. al., J Pharmacol Exp Ther., 2014, 350412-424); and 4NMX (Zhang, Y., et. al., J Biol Chem., 2014, 289942-955). Additionally, Piper et al., provides insight into the crystal structure of PCSK9 (Piper, D. E., et ah, Structure, 2007, 15(5), 545-52). In one embodiment, TL is according to any one of formulas B-I or B-II: wherein RLdenotes the attachment with LI . TNFalpha In one embodiment, the target protein is TNFa. Thus, in one embodiment, the bifunctional compound according to the present disclosure is able to form a ternary complex between sortilin and TNFa. In one embodiment, the bifunctional compound is able to bind to sortilin and TNFa at the same time. In one embodiment, the bifunctional compound according to the present disclosure has a dissociation constant of the binding of SLto sortilin is of less than 50 µM, such as less than 2 µM, such as less than 0.5 µM, preferably less than 0.1 µM and the dissociation constant of the binding of TLto TNFa is of less than 100 µM, such as less than 0.5 µM, such as less than 0.1 µM. In one embodiment, the bifunctional compound according to the present disclosure has a dissociation constant of the binding to sortilin is of less than 50 µM, such as less than 2 µM, such as less than 0.5 µM, preferably less than 0.1 µM and the dissociation constant of to TNFa is of less than 100 µM, such as less than 0.5 µM, such as less than 0.1 µM. In one embodiment, the bifunctional compound provides that upon binding of SLto sortilinlocated on the cell surface and binding of TL TNFa, TNFa is internalized into said cell. Toassess that the target proteins are internalized, methods like detection of the target protein in the supernatant of cell cultures may be used. Any suitable methods such as ELISA, detection of fluorescence of conjugates, HPLC, gel electrophoresis combined with staining, like SDS-PAGE or western blotting, or other well known techinques in the art may be used. The presence of the target protein or its fragments inside cells may also be assessed with similar methods, after lysis of the cells. The example demonstrate that bifunctional compounds according to the present disclosure are able to promote internalization of target proteins into cells through sortilin mediated binding. The examples also demonstrate that the internalization leads to degradation of the target proteins. In one embodiment, TNFa is degraded after internalization into the cell. The bifunctional compound according to any one of the preceding claims, wherein TL is according to any one of formulas (B-III-1) to (B-III-8):

[0045] wherein RLdenotes attachment with LI.In one embodiment, TLis according to formula (B-III-1). In one embodiment, TLis according to formula (B-III-2). In one embodiment, TLis according to formula (B-III-3). In one embodiment, TL is according to formula (B-III-4). In one embodiment, TL is according to formula (B-III-5). In one embodiment, TL is according to formula (B-III-6). In one embodiment, TL is according to formula (B-III-7). In one embodiment, TL is according to formula (B-III-8). In one embodiment, the bifunctional the compound is according to any one of formulas IV-B1 to IV-B8 :

[0046] In one embodiment, the bifunctional compound is according to formula IV-B1. In oneembodiment, the bifunctional compound is according to formula IV-B2. In one embodiment, the bifunctional compound is according to formula IV-B3. In one embodiment, the bifunctional compound is according to formula IV-B4. In one embodiment, the bifunctional compound is according to formula IV-B5. In one embodiment, the bifunctional compound is according to formula IV-B6. In one embodiment, the bifunctional compound is according to formula IV-B7. In oneembodiment, the bifunctional compound is according to formula IV-B8. In oneembodiment, the present disclosure provides a bifunctional compound according to anyone of formulas IV-B1, IV-B2, IV-B3, IV-B4, IV-B5, IV-B6, IV-B7, and IV-B8, wherein thelinker (LI) is selected form any one of the formulas II-1 to II-98 as shown in Table Z-II.

[0047] In one embodiment, the bifunctional compound is according to formula V-B1. In oneembodiment, the bifunctional compound is according to formula V-B2. In one embodiment, the bifunctional compound is according to formula V-B3. In one embodiment, the bifunctional compound is according to formula V-B4. In one embodiment, the bifunctional compound is according to formula V-B5. In one embodiment, the bifunctional compound is according to formula V-B6. In one embodiment, the bifunctional compound is according to formula V-B7. In one embodiment, the bifunctional compound is according to formula V-B8. In one embodiment, the present disclosure relates to a bifunctional compound according to anyone of formulas V-B1, V-B2, V-B3, V-B4, V-B5, V-B6, V-B7, and V-B8, wherein the linker(LI) is selected form any one of the formulas II-1 to II-98 as shown in Table Z-II.In one embodiment, the bifunctional compound is according to formula IV-B7. In one embodiment, the bifunctional compound is according to formula V-B7.In one embodiment, the compound is able to bind to sortilin and TNFα at the sametime. The bifunctional compound according to any one of the preceding claims, whereinupon binding of SL to sortilin located on the cell surface and binding of TL TNFα, TNFαis internalized into said cell. The bifunctional compound according to any one of the preceding claims, wherein TNFα is degraded after internalization into the cell. In one embodiment, the bifunctional compound is according to any one of thecompounds A-001 to A-003 depicted in Table A in the “Detailed description”, or apharmaceutically acceptable salt thereof. Table A In one embodiment, the bifunctional compound is A-003, or a pharmaceutically acceptable salt thereof. IL-17A In one embodiment, the target protein is interleukin 17-A (IL-17A). In one embodiment, TLis moiety that binds IL-17A. The inventors have produced small molecule bifunctional compounds that are able to induce sortilin-mediated protein degradation of IL-17A. Thus, viewed from another aspect the present disclosure relates to a bifunctional compound according to formula (X): TA-L– LI – SA-L (X)wherein SA-L is a moiety that binds to Sortilin; LI is a linker or a bond; and TA-L is a moiety that binds interleukin 17-A (IL-17A), or a pharmaceutically acceptable salt thereof.In one embodiment, the bifunctional compound of formula X as described herein hasSA-L according to formula X-I, or X-II:

[0048] wherein RLdenotes the attachment with LI. In one embodiment, the bifunctional compound of formula X as described herein has SA-L according to formula X-I: formula (X-I) wherein RLdenotes the attachment with LI. In one embodiment, the bifunctional compound of formula X as described herein has SA-L according to formula X-II: formula (X-II), wherein RLdenotes the attachment with LI.

[0049] In one embodiment, the bifunctional compound as described herein has TA-L is asubstituent derived from any one of the following:

[0050] In one embodiment, TA-L has a structure according to formula X-B-I. In one embodiment,TA-L has a structure according to formula X-B-II. In one embodiment, TA-L has a structure according to formula X-B-III. In one embodiment, TA-L has a structure according to formula X-C-I. In one embodiment, TA-L has a structure according to formula X-D-I. In one embodiment, TA-L has a structure according to formula X-D-II. In one embodiment,TA-L has a structure according to formula X-D-III. In one embodiment, TA-L has a structureaccording to formula X-D-IV. In one embodiment, LI of formula X is according to any of the embodiments of the linker as defined in the section the “Linker”. For example, LI of formula X is in some embodiments according to formula (II), wherein L1, L2and Z are each as defined hereinin any one of the embodiments in the section “Linker”. In one embodiment, the LI offormula X is according to any one of the structures II-1 to II-98 as shown in table Z-II inthe section “Linker”. The linker as shown in table Z-II, such as formulas II-1 to II-98, may be connected to SA-L and TA-L at any attachment marked with *, respectively. For example, in one embodiment, the linkers shown in table Z-II are connected to TA-L through attachment marked with * that appears in the left of the formula shown in Table Z-II, and connected to SA-Lthrough the attachment marked with * that appears in the right of the formula shown in Table Z-II. In one embodiment, the bifunctional compound is according to any one of formula formula X-III, or a pharmaceutically acceptable salt thereof; wherein LIis a linker or a bond; and TA-Lis a moiety that binds interleukin 17-A (IL-17A). In one embodiment, the bifunctional compound is according to any one of formulasX-III-B1 to X-III-D4 as shown below:

[0051] In one embodiment, the bifunctional compound is according to formula X-III-B1. In oneembodiment, the bifunctional compound is according to formula X-III-B2. In one embodiment, the bifunctional compound is according to formula X-III-B3. In one embodiment, the bifunctional compound is according to formula X-III-C1. In one embodiment, the bifunctional compound is according to formula X-III-D1. In one embodiment, the bifunctional compound is according to formula X-III-D2. In one embodiment, the bifunctional compound is according to formula X-III-D3. In one embodiment, the bifunctional compound is according to formula X-III-D4.In one embodiment, the present disclosure provides a bifunctional compound accordingto any one of formulas X-III-B1, X-III-B2, X-III-B3, X-III-C1, X-III-D1, X-III-D2, X-III-D3and X-III-D4, wherein the linker (LI) is selected form any one of the formulas II-1 to II-98as shown in Table Z-II. In one embodiment, the bifunctional compound is according to any one of formula X- or a pharmaceutically acceptable salt thereof; wherein LIis a linker or a bond; and TA-Lis a moiety that binds interleukin 17-A (IL-17A). In one embodiment, the bifunctional compound is according to any one of formulas X-IV-B1 to X-IV-D4 as shown below:

[0052] In one embodiment, the bifunctional compound is according to formula X-IV-B1. In oneembodiment, the bifunctional compound is according to formula X-IV-B2. In one embodiment, the bifunctional compound is according to formula X-IV-B3. In one embodiment, the bifunctional compound is according to formula X-IV-C1. In one embodiment, the bifunctional compound is according to formula X-IV-D1. In one embodiment, the bifunctional compound is according to formula X-IV-D2. In one embodiment, the bifunctional compound is according to formula X-IV-D3. In one embodiment, the bifunctional compound is according to formula X-IV-D4.In one embodiment, the present disclosure provides a bifunctional compound accordingto any one of formulas X-IV-B1, X-IV-B2, X-IV-B3, X-IV-C1, X-IV-D1, X-IV-D2, X-IV-D3and X-IV-D4, wherein the linker (LI) is selected form any one of the formulas II-1 to II-98as shown in Table Z-II. In one embodiment, the bifunctional compound is according to any one of formula X-V: formula (X-V), or a pharmaceutically acceptable salt thereof; wherein LIis a linker or a bond; and TA-Lis a moiety that binds interleukin 17-A (IL-17A). In one embodiment, the bifunctional compound is according to any one of formulas X-V-B1 to X-V-D4 as shown below:

[0053] In one embodiment, the bifunctional compound is according to formula X-V-B1. In oneembodiment, the bifunctional compound is according to formula X-V-B2. In one embodiment, the bifunctional compound is according to formula X-V-B3. In one embodiment, the bifunctional compound is according to formula X-V-C1. In one embodiment, the bifunctional compound is according to formula X-V-D1. In one embodiment, the bifunctional compound is according to formula X-V-D2. In one embodiment, the bifunctional compound is according to formula X-V-D3. In one embodiment, the bifunctional compound is according to formula X-V-D4.In one embodiment, the present disclosure provides a bifunctional compound accordingto any one of formulas X-V-B1, X-V-B2, X-V-B3, X-V-C1, X-V-D1, X-V-D2, X-V-D3 andX-V-D4, wherein the linker (LI) is selected form any one of the formulas II-1 to II-98 asshown in Table Z-II. In one embodiment, the bifunctional compound is according to any one of thecompounds X-001 to X-098 depicted in Table X, or a pharmaceutically acceptable saltthereof. Table X

[0054]

[0055] N »-N \ H N«, / KKNY

[0056] C Av V 1 _Ho^zXJ zs

[0057] 009d8£SZd

[0058] As shown herein, when any of the structures in Table X contain a stereocenter wherethe stereochemistry of that center is not specified, that center may have any configuration R or S according to Cahn-Ingold-Prelog rules. For example, in one embodiment the stereocenter has R configuration. In one embodiment, the stereocenter has S configuration. In one embodiment, the bifunctional compound is able to form a ternary complex with sortilin and IL-17A. The formation of ternary complexes can be measured in different ways as known in the art. For example, ternary complex formation can be measure through Förster’s resonance energy transfer (FRET) assays or through timer-resolved Förster’s resonance energy transfer (TR-FRET) assays. As measured by these assays an increase in the homogeneous time-resolved fluorescence (HTRF) ratio indicatesformation of ternary complexes. In one embodiment, the bifunctional compound is able to bind to bind to sortilin and IL17-A at the same time. In one embodiment, the bifunctional compound is able to bind to sortilin at the cell surface. In one embodiment, the bifunctional compound is able to induce internalization of IL-17A into cells expressing sortilin. In one embodiment, upon binding of SA-Lto sortilin located on the cell surface and binding of TA-Lto the IL-17A, the target protein is internalized into said cell. Cellular uptake may be determined using cellular uptake assays where IL-17A can be detected using tags, for example fluorescent tags or a tag able to produce or react to produce luminescence. Then the tagged IL-17A can be detected using methods known to someone of skill in the art, such as measurements in cell lysates, flow cytometry, imaging techniques among others. The removal of IL-17A from the extracellular media can also be used as an assay of cellular uptake. In one embodiment, IL17-A is degraded after internalization into the cell. In one embodiment, IL-17A is degraded in the lysosomes. The examples demonstrate that the bifunctional compounds induce degradation of IL-17A in the lysosomes by using experiments with a control that inhibits lysosomal proteases. The binding with the target protein or sortilin may be measured through different methods as it is known to someone of skill in the art. For example, microscale thermophoresis (MST). In one embodiment, the dissociation constant (KD) of the binding of SA-L to sortilin is of less than 50 µM, such as less than 2 µM, such as less than 0.5 µM, preferably less than 0.1 µM and the dissociation constant of the binding of TA-L to its target is of less than 100 µM, such as less than 0.5 µM, such as less than 0.1 µM.In one embodiment, the dissociation constant (KD) of the binding of TA-L to IL 17-A islower than 500 nM, such as lower than 250 nM, such as lower than 100 nM, such as lower than 50 nM. The present invention demonstrates several bifunctional compounds able to bind IL-17A. As shown in the examples, these compounds have affinity for IL17-A. As it will be understood to someone of skill in the art, fragments of the bifunctional compoundsencompassing TA-L, and a part or all of LI , will also perform as IL-17A binders. Thus, inone embodiment, the present disclosure provides an IL-17A binder as described by anycombination of TA-L-LI,or a fragment thereof, as described herein above.In one embodiment, the present disclosure provides compound selected from any oneof the compounds shown in Table B, or a pharmaceutically acceptable salt thereof: Table B Medical use The present invention focuses on the degradation of circulating extracellular proteins that mediate diseases, for example, involving immunity, inflammation, hematopoiesis / blood disorders (including those caused or exacerbated by blood vessel formation) and abnormal cellular proliferation such as tumors and cancer. The bifunctional compounds of the present invention can he administered in any manner that allows the bifunctional compound to bind to the Extracellular Protein, typically in the blood stream, and carry it to the sortilin bearing cells for endocytosis and degradation. As such, examples of methods to deliver the degraders of the present invention include, but are not limited to, oral, intravenous, buccal, sublingual, subcutaneous and transnasal. In one aspect, the invention provides bifunctional compounds for the use in the targeted sortilin-mediated lysosomal degradation of extracellular target molecules. In one embodiment, the target molecule is a disease or disorder associated protein.In another aspect, the present disclosure provide the use of bifunctional compounds asdescribed herein for use as a medicament. The present disclosure is directed to pharmaceutical compositions comprising a bifunctional compound as described herein. In yet another aspect, the present disclosure relates to a method of targeted lysosomal degradation of an extracellular target protein, comprising administering a bifunctional compound as described herein to a subject in need thereof. In another aspect, the present disclosure relates to a method to reduce the plasma levels of a target molecule, comprising administering a bifunctional compound as described herein to a subject in need thereof. In one aspect, the present disclosure provides bifunctional compounds as described herein for use in the treatment of a disorder or condition mediated by an extracellular protein in a subject in need thereof. In one aspect, the present disclosure relates bifunctional compounds as described herein for use in the removal of an extracellular target molecule from the plasma of a subject. In one embodiment, the disorder or disease is linked to abnormal levels of the extracellular protein. In one embodiment, the disorder or disease is linked to abnormally high levels of the extracellular target protein. In one embodiment, the disorder or disease is linked to a mutated or misfolded extracellular protein. In one embodiment, the extracellular target protein is selected from the group consisting of: TNF-^^^PCSK9, ^^ANGPTL-3, an antibody light chain, IgG, IgE, IgA IL-1, IL-2 , IL-6, IFN-^, VEGF, TFG-^1, IL-21, IL-22, IL-5, IL-10, IL-8, cholinestearase,human CCL2, carboxypeptidase B-2, neutrophil elastase, Factor Xa, Factor XI, Factor XIa, Factor XII, Factor XIII, prothrombin, coagulation factor VII, coagulation factor IX, fibroblast growth factor 1, FGF-2, fibronectin 1, kallikrein-1, lipoprotein lipase, human matrix metallopeptidase 1, macrophage migration inhibitory factor, transformin growth factor-p (TGF-p), thrombospondin-1 (TSP-T), CD40 ligand, urokinase-type plasminogen activator, plasminogen activator tissue type (TPA), Plasminogen (PLG), Plasminogen Activator Inhibitor-1, Placenta Growth Factor, Phospholipase A2 Group IB, Phospholipase A2 Group IIA, Complement factor B, Complement factor D, complement factor H, Complement Component 5 and complement C1s. In one embodiment, the extracellular protein is TNF-^. In a further embodiment, theextracellular target protein is TNF-^ and the disorder or condition is selected from thegroup consisting of rheumatoid arthritis, inflammatory bowel disease, graft-vs-host disease, ankylosing spondylitis, psoriasis, hidradenitis suppurativa, refractory asthma, systemic lupis erthyematosus, diabetes, and the induction of cachexia. In a furtherembodiment, the disorder is linked to abnormal TNF-^ levels. In one embodiment, thedisorder or condition is an inflammatory disease. In one embodiment, the disorder or condition is an autoimmune disease. In one embodiment, the disorder or condition is a cancer. Thus, in one aspect the present disclosure provides for a method of targeted lysosomal degradation of TNFa, comprising administering an effective amount of the bifunctional compound as described herein. In another aspect, the present disclosure provides for a method of removal of TNFa from the plasma of a patient or subject in need thereof, comprising administering a bifunctional compound as described herein. In another aspect, the present disclosure provides for the use of a bifunctional compound according as described herein for the manufacture of a medicament for the treatment of a disease or condition. In another aspect, the present disclosure provides for the use of a bifunctional compound according as described herein for the manufacture of a medicament for the treatment of a disorder or condition mediated by TNFa. In one aspect, the present disclosure provides for a method of treatment of a disease or condition comprising administering a bifunctional compound as described herein to a subject in need thereof. In one aspect, the present disclosure provides for a method of treatment of a disorder or condition mediated by TNFa, comprising administering a bifunctional compoundaccording to to the present disclosure to a subject in need thereof.The examples show that the bifunctional compounds described herein wherein TA-LbindsIL17-A are able to form ternary complexes with IL17-A and sortilin, induce cellular-uptakeof IL-17A and degradation in the lysosomes.Thus, in one aspect, the present disclosure provides a bifunctional of formula (X) asdescribed herein, for use in a method of removing IL-17A from the blood plasma of a subject in need thereof, the method comprising administering to the subject an effective amount of the bifunctional compound. In one embodiment, the method of removing IL-17A comprises forming a ternary complex with the bifunctional compound, sortilin and IL-17A. In one embodiment, the method of removing IL-17A comprises binding of sortilin and IL-17A to the bifunctional compound at the same time. In one embodiment, the method of removing IL-17A comprises binding of the bifunctional compound to sortilin at the cell surface of a sortilin-expressing cell. In one embodiment, upon binding of SA-L to sortilin located on the cell surface and binding of TA-L to the IL-17A, the target protein is internalized into said cell. In one embodiment, IL17-A is degraded after internalization into the cell. In one embodiment, IL-17A is degraded in the lysosomes. High levels of IL-17A are known to be associated with several chronic inflammatory diseases inflammatory conditions.Thus, in one aspect, the present disclosure provides a bifunctional compound of formula(X) as described herein, or a pharmaceutically acceptable salt thereof, for use intreatment or prevention of inflammation or an inflammatory condition.In one aspect, the present disclosure provides a bifunctional compound of formula (X)as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treatment or prevention of inflammation or an inflammatory condition, the method comprising administering to the subject an effective amount of the bifunctional compound. The present disclosure relates to a method of treatment or prevention of inflammation or an inflammatory condition, the method comprising administering to the subject aneffective amount of the bifunctional compound of formula (X), or a pharmaceuticallyacceptable salt thereof. In one aspect, the present invention to use of a bifunctional compound as described herein, in the manufacture of a medicament for treatment or prevention of inflammation or an inflammatory condition, the method comprising administering to the subject aneffective amount of the bifunctional compound of formula (X), or a pharmaceuticallyacceptable salt thereof. In one embodiment, the inflammation or inflammatory condition is characterized by high levels of IL-17A.Thus, in one aspect, the present disclosure provides a bifunctional compound of formula(X) as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treatment or prevention of a condition characterized by overexpression of IL- 17A, the method comprising administering to the subject an effective amount of the bifunctional compound.Thus, in one aspect, the present disclosure provides a bifunctional compound of formula(X) as described herein, or a pharmaceutically acceptable salt thereof, for use in treatment or prevention of one selected from the group consisting of: psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitisIn one aspect, the present disclosure provides a bifunctional compound of formula (X)as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treatment or prevention of psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis; the method comprising administering to the subject an effective amount of the bifunctional compound. A method of treatment or prevention of psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis; the method comprising administering to the subject an effective amountof a bifunctional compound of formula (X) as described herein.Use of a bifunctional compound of formula (X) as described herein, in the manufactureof a medicament for the treatment or prevention of psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, anky1osing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis. In one embodiment, the subject is a mammal. In one embodiment, the mammal is a human. Preparation of bifunctional compoundsIn general, the compounds according to Formula (I) or Formula (X) and related formulaeof this invention may be prepared from readily available starting materials. If such starting materials are not commercially available, they may be prepared by standard synthetictechniques. In general, the synthesis pathways for any individual compound of Formula(I) and related formulae will depend on the specific substituents of each molecule, such factors being appreciated by those having ordinary skill in the art. The following general methods and procedures described hereinafter in the examples may be employed to prepare compounds of Formula (I) and related formulae. Reaction conditions depicted in the following schemes, such as temperatures, solvents, or co-reagents, are given as examples only and are not restrictive. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art, using routine optimisation procedures. For all the protection and deprotection methods, see Philip J. Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in Organic Synthesis”, Wiley Interscience, 3rdEdition 1999. Depending on the nature of TL(or TA-L), LIand SL(or SA-L), different synthetic strategies may be selected for the synthesis of compounds of Formula (I). In the process illustrated in the following schemes, TL, LIand SLare as above-defined in the description unless otherwise mentioned. Compounds of formula (I), wherein TL, LIand SLare defined as above, can be preparedfrom the reaction of compound composed with TL – LI moieties with SL or from thereaction of compound composed with LI – SL moieties with TL using methods andreactions known by a person skilled in the art. Such reactions can be but are not limited to amide bond formation, ether bond formation, aromatic substitution, alkylation, metal catalysed cross-coupling reaction, and click chemistry using conditions known by a person skilled in the art and as described below in the examples (Scheme 1). Scheme 1 TL – LI + SL → TL – LI – SLTL + LI – SL → TL – LI – SLAs it will be appreciated for someone of skill in the art, a precursor of TL (pTL) or a precursor of SL (pSL) may be first coupled to LI, or a precursor of LI (pLI). Subsequently, different reaction steps can be employed to complete the TL, SL or LI moieties. Such reactions can be but are not limited to amide bond formation, ether bond formation, aromatic substitution, alkylation, metal catalysed cross-coupling reaction, and click chemistry using conditions known by a person skilled in the art and as described below in the examples (Scheme 1). Suitable protecting groups may be employed in 86ther to avoid incompatibility of functional groups. For example, preferred protecting groups are: Carbobenzyloxy (Cbz), p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert- Butyloxycarbonyl (BOC) group, 9-Fluorenylmethyloxycarbonyl (FMOC) group, Alkanoyl group, such as the Acetyl (Ac) group, Benzoyl (Bz) group, Benzyl (Bn) group, Carbamate group, p-Methoxybenzyl (PMB), 4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) group, Arylsulfonyl group such as the Tosyl (Ts) or benzolsulfonyl group. For example, schematic ways to prepare bifunctional compounds include the following: Scheme 2 (1) pTL + pLI → pTL – pLI , (2) pTL – pLI →…→…→ TL – LI(1) TL + pLI → TL – pLI , (2) TL – pLI →…→…→ TL – LI(1) pTL + LI → pTL – LI, (2) pTL – LI →…→…→ TL – LI(1) pSL + pLI → pSL – pLI , (2) pSL – pLI →…→…→ SL – LI(1) SL + pLI → SL – pLI , (2) SL – pLI →…→…→ SL – LI(1) pSL + LI → pSL – LI, (2) pSL – LI →…→…→ SL – LIScheme 3 (1) pSL + pLI → pSL – pLI , (2) pSL – pLI →…→…→ pSL –LI,(3) pSL –LI →…→…→ SL –LI, (4) SL –LI + pTL → SL – LI – pTL,(5) SL – LI – pTL →…→…→ SL – LI –TL(1) pTL + pLI → pTL – pLI , (2) pTL – pLI →…→…→ pTL –LI,(3) pTL –LI →…→…→ TL –LI, (4) TL –LI + pSL → pSL – LI –TL,(5) pSL – LI –TL →…→…→ SL – LI –TLAs used in schemes 2 and 3, indicates successive synthetic steps of transformation of a precursor with any suitable chemical reactions or a combination of reactions. For example, with any number of the abovementioned reactions or combinations thereof. In schemes 2 and 3, pTL, pSL and pLI refer to a precursor of TL, SL or LI respectively. A precursor of TL, SL or LI is a moiety that can be converted to TL, SL or LI respectively, using common reactions as described herein. Compounds of formula (X) may be prepared in analogous manner as described above and illustrated in Schemes 1, 2 and 3, using appropriate TA-L and SA-L (or pTA-L and pSA-L)groups instead of TL and SL (or pTL and pSL ) groups respectively.For example, whenTA-L is according to formula C-I, the person of skill in the art will find guidance of suitable synthesis of intermediates and precursors of TA-L as well as suitable reaction conditionsin WO 2020 / 146194. Modifications with common reagents and reactions as mentionedabove to join with LI, pLI, SL-LI, pSL-pLI, pSL-LI, or SL-pLIwill be known to someone of skill in the art.When, TA-L is according to formulas B-I, B-II, B-III, D-I, D-II, D-III or D-IV the person ofskill in the art will find guidance of suitable synthesis of intermediates and precursors ofTL in WO 2020 / 127685 and WO 2021 / 250194. Modifications with common reagents andreactions as mentioned above to join with LI, pLI, SL-LI, pSL-pLI, pSL-LI, or SL-pLIwill be known to someone of skill in the art. A compound In another aspect, the present disclosure provides for a compound of formula (A-II): formula (A-II), or pharmaceutically acceptable salt thereof, or an entatiomer thereof, or a mixture thereof; whereinR1 is H, halogen, alkoxy, -CF3, or an optionally substituted C1-5 hydrocarbon chain,wherein one or more carbon groups of the C1-C5 hydrocarbon chain are optionallyindividually replaced by one or more of the groups consisting of –O-, -NH-, -C(O)-, ester, amide, carbamate, thiourea, sulphonamide, urea, , , , an optionally substituted carbocycle; an optionallysubstituted heterocycle, or ; wherein X is NH or O. In one embodiment, the compound is according to formula (A-IIa), pharmaceutically acceptable salt thereof. In one embodiment, the compound is according to formula (A-IIb), pharmaceutically acceptable salt thereof. In one embodiment, the compound is according to formula (A-II-1): pharmaceutically acceptable salt thereof.In one embodiment, R1 is H. In one embodiment, R1 is selected from halogen or –CF3.In one embodiment, R1is an optionally substituted C1-C5 alkyl, wherein one or more methylene group(s) of the C1-5 alkyl are optionally individually replaced by one or more of the groups consisting of –O-, -NH-, -C(O)-, ester, amide, carbamate, thiourea and . In one embodiment the compound is any one of the compounds in Table C, or a pharmaceutically acceptable salt thereof. Table C In one embodiment, the compound is O-(tert-butyl)-N-(6-phenoxynicotinoyl)serine (B-001). An alternative name of said compound is O-(tert-butyl)-N-(6-phenoxynicotinoyl)-L- serine. In one embodiment, the compound is (2S)-3-tert-butoxy-2-[[6-[3-(2-methoxyethoxy)phenoxy]pyridine-3-carbonyl]amino]propanoic acid (B-002). Analternative name of said compound is O-(tert-butyl)-N-(6-(3-(2- methoxyethoxy)phenoxy)nicotinoyl)-L-serine. The compound of formula (A-II) or (VI-a) as described herein may be prepared from commercially available starting materials by reactions according to the below scheme (illustrated for compound C-001): First in step 1 an alkyl ester of 2-amino-3-tert-butoxy-propanoic acid (e.g compound 2, methyl O-(tert-butyl)serinate) is reacted with 6-(3-tert-butoxycarbonylphenoxy)pyridine-3-carboxylic acid (compound 1) to form an amide (compound 3). Then in step 2, ester isdeprotected to obtain the sortilin binder compound 4. As it will be known by someone of skill in the art, different reaction conditions will be available to form the amide in compound 3. For example, conditions commonly used in the formation of peptide bonds using coupling agents like N,N′-Dicyclohexylcarbodiimide(DCC), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or HexafluorophosphateAzabenzotriazole Tetramethyl Uronium (HATU) in the presence of tertiary amines liketriethylamine, N,N-diisopropylethylamine (DIPEA, or DIEA) in an organic solvent – i.eDMF, DMSO. In step 1, other suitable esters of 2-amino-3-tert-butoxy-propanoic acid may be used, such as any C1-C10alkyl ester of 2-amino-3-tert-butoxy-propanoic acid. In step 2, the deprotection of the compound may be performed by hydrolysis of the ester under acidic or basic conditions. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art, using routine optimisation procedures. For all the protection anddeprotection methods, see Philip J. Kocienski, in “Protecting Groups”, Georg ThiemeVerlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in“Protective Groups in Organic Synthesis”, Wiley Interscience, 3rd Edition 1999. In oneembodiment, deprotection is performed using an alkali metal hydroxide, such as LiOH, under aqueous conditions or a mixture of an organic solvent and an aqueous medium. Compound 4 contains a stereocenter. By using optically pure or optically enriched starting materials, such as an enantiopure alkyl ester of 2-amino-3-tert-butoxy-propanoic acid, it is possible to produce compound 4 with high enantiomeric excess of its enantiomers. For example, in one embodiment the compound is O-(tert-butyl)-N-(6- phenoxynicotinoyl)-L-serine and the starting material used is O-(tert-butyl)-L-serine. In one aspect, the present disclosure provides for the compound of formula (A-II), or a pharmaceutically acceptable salt thereof, or an enantiomer thereof or a mixture thereof use as a medicament. The compound of formula (A-II) binds sortilin with high affinity, and thus has potential intherapy of sortilin mediated conditions. In addition, it is shown that formula (A-II) hasimproved durg-like properties, such as reduced lipophilicity and liver microsomeclearance. These properties indicate an unexpected reduction of first pass metabolism,which is beneficial for oral dosing. In one aspect, the present disclosure provides for a composition comprising the compound of formula (A-II) or a pharmaceutically acceptable salt thereof, or anenantiomer thereof or a mixture thereof as described herein.The present invention demonstrates several bifunctional compounds able to bind sortilin. As shown in the examples, these compounds have affinity for sortilin. As it will be understood to someone of skill in the art, fragments of the bifunctional compoundsencompassing SL, and a part or all of LI, will also perform as sortilin binders. Thus, inone embodiment, the present disclosure provides for a sortilin binder as described by any combination of SL-LI,or a fragment thereof, as described herein. In addition, the present disclosure provides for a compound able to bind sortilin, wherein said compound is an intermediate in the preparation of a bifunctional compound as described herein in the section “Synthetic protocols”. ExamplesExample 1: Binding of small molecule compound to sortilinAim In this example the equilibrium dissociation constant (KD) describing the binary binding between small molecule compounds and the soluble ectodomain of sortilin-6his is measured by microscale thermophoresis (MST). Materials and Methods A 12-point titration series of compound solutions was prepared in TTP LVDS 384-well plates (SPT Labtech) in a 1.2 µL total volume using an LV Mosquito pipetting robot (SPT Labtech) in a buffer composed of 16.7 % DMSO (v / v) and 0.05 % Tween20 (v / v). The plate was spun down before addition of 8.8 µL 114 nM sortilin-6his and 28.4 nM RED-tris-NTA (Nanotemper) in 57 mM Bis-Tris Propane pH 9, 57 mM NaCl, 0.05 % Tween20 (v / v) to each well. The plate was sealed with adhesive strip and placed on an Eppendorf thermomixer at 600 rpm for 3 min before spinning on a Fisherbrand plate- spinner for 15 seconds and further incubation 1 hrs at RT. MST was measured on a Monolith NT. Automated (Nanotemper) in standard-treated capillaries at 5 % LED- power and high MST-power. Dose-response was extracted at 20 sec hot-time. All experiments were performed in duplicates. Results The results are shown in Table 1.Table 1: Kd values for compound binding to sortilin (nM). Table 1a: Kd values for compound binding to sortilin. KD<0.2 nM: **, KD>0.2 nM: * Sordini binder C-002 was studied and compared to analog C-002carb, which differs only in a single atom as shown below: Table 1b: The KD of sortilin binding of comound C-002 and analog with 1 atomreplacement. Conclusion Compounds of the invention bind sortilin. Example 2: Bifunctional compounds mediate internalization of extracellular target proteins in cells Aim Addressed in this example is the ability of sortilin to facilitate internalization of an extracellular target by a bifunctional compound where SLis derived from a small molecule. Materials and MethodsCellular uptake of Neutravidin-650 (NA650) was investigated in HEK293 cells expressingfull length sortilin receptor (Petersen et. al.). Cells were seeded in poly-L-lysine coated96-well plates (Perkin Elmer) (40K / well) in 50 μL culture medium (DMEM (Lonza) + 10 % FBS (SigmaAldrich) + 1 % penicillin-streptomycin (SigmaAldrich) + 1 % GlutaMAX (Gibco) + 100 μg / mL Zeocin (Invitrogen)) and incubated overnight in cell incubator (37 °C, humidified, 5% CO2). Culture medium was replaced with assay medium (DMEM (Lonza) + 10 % fetal bovine serum (SigmaAldrich) + 1 % penicillin-streptomycin (SigmaAldrich) + 1% GlutaMAX (Gibco)) containing NA650 (Invitrogen) (100 nM) (Thermo Fischer) and bifunctionalcompounds of the invention (9.8 nM to 10 μM). Cells were incubated for 3h in cellincubator before they were washed in dPBS (Bionordika). The DyLight650 signal in the cell layer was detected using a fluorescence plate reader (BMG Labtech Clariostar). A similar protocol was used to evaluate internalization of a fluorescently-labelled anti- AlexaFluor488-anti-DNP antibody (Thermo Fisher). For assessment of cellular uptake of TNF-alpha a similar methodology was applied in HEK293 cells, detection of mouse anti-TNFalpha (Invitrogen, MA5-23720) was done by Western blot. Control cells were incubated without addition of compounds and TNFalpha or with TNFalpha alone. The efficacy of bifunctional compound internalization was assessed as the area under the curve of signal response. Results The results are shown in Table 2.Table 2: AUC of target protein internalization. Scoring AUC of target internalization:Neutravidine (AUC scores - AUC<100: +; AUC>100 ++). Anti-DNP (AUC scores -AUC<10000: +; AUC>10000 ++). TNFa ( AUC>25000: ++++; AUC 10000-25000:+++; AUC1000-10000:++; AUC<1000: +) Conclusion The bifunctional compounds of the invention mediate cellular uptake of target proteins. Example 3: Binding of small molecule compounds to IL-17A. Aim In this example the equilibrium dissociation constant (KD) describing binary binding between small molecule compounds and IL-17A is measured by microscale thermophoresis (MST). Materials and Methods A 12-point titration series of compound solutions was prepared in TTP LVDS 384-well plates (SPT Labtech) in a 5 µL total volume using a 16-channel multipipette in a buffer composed of 20 mM Bis-Tris Propane pH 9.5, 300 mM NaCl, 0.1% Tween20 (v / v), 0.1 % Protease free BSA (w / v). The plate was spun down before addition of 5 µL 40 nM IL17A-NHS in 20 mM Bis-Tris Propane pH 9.5, 300 mM NaCl, 0.1% T20, 0.1 % Protease free BSA. The plate was sealed with an adhesive strip and placed on an Eppendorf Thermomixer at 600 rpm for 3 min before spinning on a Fisherbrand plate-spinner for 15 seconds and further incubation 1 hrs at RT. MST was measured on a Monolith NT. Automated (Nanotemper) in standard-treated capillaries at 20% LED power and medium MST power. Dose-response was extracted at 20 sec on-time. All experiments were performed in duplicates. Table 3: KD values of compound binding to IL-17A. KD<50 nM: ***, KD 50-250 nM: **, KD>250 nM: *

[0059] Conclusion Compounds of the invention bind IL-17A. Example 4: Formation of ternary complex facilitated by bifunctional compounds wherein SL is derived from a small molecule Aim To demonstrate the ability of bifunctional compounds to form ternary complexes with sortilin and IL-17A. Materials and Methods In these experiments, bifunctional compounds were titrated in 5 µL total volume over 12- point in a 384-well TTP LVDS plate (SPT Labtech) to a final buffer composition of 50 mM HEPES pH 7.5, 1 mM EDTA, 300 mM NaCl, 0.1 % Protease free BSA (w / v) and 10%DMSO using a 16-channel multipipette.To a black 384-well plate (Corning) the following were added: 4 µL 10 nM mAb Anti-6HIS Tb (Cisbio) in 50 mM HEPES pH 7.5, 1 mM EDTA, 300 mM NaCl, 0.1 % Protease free BSA (w / v), 4 µL 250 µL Streptavidin-d2 (Cisbio) in 50 mM HEPES pH 7.5, 1 mM EDTA, 300 mM NaCl, 0.1 % Protease free BSA (w / v), 4 µL 750 nM IL17A-biotin in 50 mM HEPES pH 7.5, 1 mM EDTA, 300 mM NaCl, 0.1 % Protease free BSA (w / v), 4 µL 250 nM Sortilin-6his in 50 mM HEPES pH 7.5, 1 mM EDTA, 300 mM NaCl, 0.1 % Protease free BSA (w / v), and 4 µL bifunctional compound in 50 mM HEPES pH 7.5, 1 mM EDTA, 300 mM NaCl, 0.1 % Protease free BSA (w / v) and 10% DMSO. After a 16-hour incubation at room temperature the HTRF signal ratio 665 / 620 nm was determined on a ClarioStar plate reader (BMG Labtech). All reactions were run in duplicates.Fig 1 shows the resulting HTRF (665 / 620 nm) signal (Gaussian fit curve) baselinecorrected to the lowest local signal plotted against compound concentration (40 µM-9.5 pM). Ternary complex formation between bifunctional compound, sortilin and IL-17A was observed as a bell shaped response curve as demonstrated by X-017 (Fig 1A) and X-018 (Fig 1B). Table 4: Ternary complex formation calculated as AUC of HTRF Conclusion Bifunctional compounds of the invention mediate ternary complex formation between sortilin and IL-17A. Example 5: Bifunctional compounds mediate internalization of extracellular IL-17A in cells Aim Addressed in this example is the ability of sortilin to facilitate internalization of extracellular IL-17A by a bifunctional compound. Materials and Methods Cellular uptake of IL-17A was investigated in HEK293 cells expressing sortilin receptor (Petersen et al.). Cells were seeded in poly-L-lysin coated 96-well plates (Perkin Elmer)(40K / well) in 50 μL culture medium (DMEM (Lonza) + 10 % FBS (SigmaAldrich) + 1 %penicillin-streptomycin (SigmaAldrich) + 1 % GlutaMAX (Gibco) + 100 μg / mL Zeocin (Invitrogen)) and incubated overnight in cell incubator (37 °C, humidified, 5% CO2). Culture medium was replaced with assay medium (DMEM (Lonza) + 10 % fetal bovine serum (SigmaAldrich) + 1 % penicillin-streptomycin (SigmaAldrich) + 1% GlutaMAX (Gibco)) containing bifunctional compounds (2 nM to 2 μM), and leupeptin (80 µM) (Sigma) and conditioned media from cells transiently expressing IL-17A (Q16552.1) N- terminally tagged with nanoluc (nanoluc-IL-17A) produced using the ExpiCHOTMexpression system (ThermoFisher). Cells were incubated 24 h in cell incubator before they were washed with dPBS (Bionordika) and lysed in lysis buffer (Passive Lysis Buffer (Promega)). Cell lysates were added nanoluc substrate in substrate buffer (Nano-Glo Luciferase Assay System (Promega)) and luminescent signal was evaluated (BMG Labtech Clariostar).Fig 2 shows cell lysate luminescent signal in %RLU with gaussian fit curve following 24h incubation of HEK293 / sortilin with a concentration series (2nM to 2 µM) of compounds X-062, X-064, and X-065 together with nanoluc-IL-17A.Table 5: Target internalization calculated as peak-2-peak (P2P) AUC of % RLU.AUC>500: ***, AUC 100-500: **, AUC<100: *

[0060] Conclusion Compounds of the invention mediate cellular internalisation of IL-17A. Example 6: Cellular uptake of extracellular target is inhibited by competitive binding. In a different experiment, cells were incubated for 24h with nanoluc-IL-17A, and bifunctional compound (100 nM) (as described in example 4) together with dilution series(2 nM- 2 µM) of a monofunctional IL-17A binder as competitor of IL-17A binding.Fig 3 shows cell lysate luminescent signal following 24 h incubation of HEK293 / sortilin with nanoluc-IL-17A, 100 nM X-065 and a concentration series (2nM to 2 µM) ofmonofunctional IL-17A binders M005, M008, and M009.Conclusion Cellular internalisation of IL-17A mediated by bifunctional compounds of the invention is inhibited by addition of monofunctional target binders. Example 7: Bifunctional compounds mediate depletion of target from extracellular cell culture medium Aim Addressed in this example is the ability of bifunctional compounds to deplete IL-17A from the extracellular space. This is investigated by evaluation of IL-17A in cell culture supernatant after incubation of cells with bifunctional molecules and IL-17A. Materials and Methods HEK293 / sortilin cells were seeded (40k cells / 96-well) in culture media and incubate for 24h (as described in example 4). Culture media were replaced with assay medium (as described in example 4) with addition of purified recombinant IL-17A and dilution seriesof bifunctional compound (0.3 nM - 2 µM). Following 48h incubation, remaining IL-17Ain cell culture supernatant was assessed using hIL-17A ELISA (BioLegend) according to manufacturer’s protocol.Fig 4 shows Gaussian fit curve of IL-17A clearance (%) from HEK293 / sortilin cell culturesupernatant following 48h incubation with IL-17A (0.1, 1.0, 10, or 100 nM) and dilution series of X-017. Conclusion This example provides data demonstrating that bifunctional compounds can mediate depletion of target from cell culture supernatant. Example 8: Internalised IL-17A is degraded in lysosomes Aim This example investigates the ability of bifunctional molecules to induce degradation IL-17A in lysosomes following internalisation, as studied by assessing IL-17A in cell lysates following inhibition of lysosomal function in cells. Materials and Methods Intracellular IL-17A levels following inhibition of lysosomal function, was investigated in HEK293 / sortilin cells.40K cells were seeded in 96-well plates and incubated overnight as described in Example 4, before replacement of culture medium with assay medium with nanoluc-IL-17A (as described in Example 5), dilution series of bifunctional compounds (1.5 nM-10 µM) with leupeptin (80 μM) (Sigma Aldrich). Control cells were incubated without leupeptin for 24h before evaluation on intracellular IL-17A as described in Example 5.Fig 5 shows Gaussian fit curve of luminescent signal in lysate of HEK293 / sortilinharvested after 24 h incubation with nanoluc-IL-17A and X-062 with and without addition of leupeptin. Cells incubated with leupeptin show markedly elevated luminescent signal compared to control cells. Conclusion This example provides data demonstrating intracellular accumulation of IL-17A in cells incubated with lysosomal cysteine protease inhibitor leupeptin compared to control cells. This shows that internalization mediated by bifunctional compounds results in lysosomal degradation of IL-17A. Example 9: Protein binding Aim Study the protein binding of different bifunctional compounds. Materials and MethodsThe test compound or the positive control, warfarin, is spiked into 10% plasma* fromCD-1 mouse. The test compound is tested at the concentration of 2 µM, warfarin is testedat 2 µM. Spiked plasma samples are pre-incubated at 37°C and then centrifuged to pellet the plasma protein, enabling separation from the free compound in the supernatant. Concentrations of the test compound, warfarin in the spiked plasma and the supernatant samples are determined using liquid chromatography-tandem mass spectrometry (LC- MS / MS). *10% plasma: On the day of experiment, the plasma was thawed under running cold tap water and centrifuged at 3220 ×g for 5 min to remove any clots. The pH value was checked and recorded. The pH of the resulting plasma is measured and adjusted to 7.4 ± 0.1 using 1% phosphoric acid or 1 M sodium hydroxide, as required. Plasma (1 mL) was then added into 9 mL PBS as the test matrix. Results The results are shown in Table 6. Table 6. Protein bound fraction for different bifunctional binders. Conclusion Addition of branches with polar groups in the linker reduces protein binding.Example 10: Lipophilicity and liver clearance studiesAim To study the effect of different sortilin binders in bifunctional compounds of the invention. Materials and MethodsMicrosome clearance. Test compounds were incubated at 37°C with liver microsomes(pooled from multiple donors) at 1.0 µM in the presence of a NADPH regeneratingsystem (~1.0 mM) at 0.5 mg / mL microsomal protein. Reference controls includedTestosterone (3A4 substrate), Propafenone (2D6) and Diclofenac (2C9). They wereincubated with microsomes in the presence of a NADPH regenerating system.Time samples (0, 5, 15, 30, 45 and 60 minutes) were removed, immediately mixedwith cold acetonitrile containing internal standard (IS). Test compound incubated withmicrosomes without NADPH regenerating system for 60min were also included.Single point was done for each test condition (n=1). Samples were analyzed by LC-MS / MS; disappearance of test compound was assessed base on peak area ratios of analyte / IS. The following equations was used to calculate the microsome clearance: To calculate the liver clearance CLint(mic) was used in the following equation: mg microsomal protein / g liver weight were 45 mg / gLiver wt / body weight: 20 g / kg and 88 g / kg for human and mouse, respectively.logD. The Log D assay was a miniaturized 1-octanol / buffer shake flask method followedby LC / MS / MS analysis. Since logD is pH dependent, the pH of the aqueous phase isspecified and is commonly measured at pH 7.4, the physiological pH of body fluids.Appropriate test compounds were dissolved in 100% DMSO to 10 mM solutions andtransferred (10 mM in DMSO; 2 µL / well) and control samples (10 mM in DMSO; 2µL / well) from storage tubes to the 96-well polypropylene cluster tubes. Then were added buffer-saturated 1-octanol (149 µL / well) and 1-octanol saturated buffer(149 µL / well) to the well and each of the tubes were Vigorously mixed on their sides for3 minutes and then shaken at a speed of 880 rpm at room temperature for 1 hour. Thenthe tubes were centrifuged the tubes at 4000 rpm for 5 minutes.The samples of buffer layer were diluted by a factor of 20 fold and the sample of1-octanol layer by a factor of 200 fold with internal standard (IS) solution.Samples were analyzed using a triple quadrupole mass spectrometer, with correction ofthe peak areas by dilution factors and embedded internal standard, and the ratio of thecorrected peak areas was used to calculate the results (Log D value).The control samples are used to monitor the process Log D determination. . These compounds differ only on a single atom in the sortilin binder (O vs. C). Results Table 7 shows the results of logD, human and mouse liver clearance. It can be seen thatX-098 had reduced lipophilicity by more than one logarithmic unit and displayed a lowerclearance in liver microsomes. These properties indicate an unexpected reduction of firstpass metabolism, which is beneficial for oral dosing.Table 7. Comparison of lipophilicity and liver clearance studies. Conclusions The modification of a single atom in the sortilin binder significantly improved drug-like properties of the bifunctional compounds. Example S1: Synthetic protocols.As used herein the term “rac” in a chemical name next to the label of a stereocenterindicates that the sterecenter may have any configuration (R or S) according to the Cahn- Ingold-Prelog rules. For example “rac-(2S)-2-amino-3-tert-butoxy-propanoate” indicates the reagent used had both (2S)-2-amino-3-tert-butoxy-propanoate and (2R)-2-amino-3- tert-butoxy-propanoate. A-001: (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a- hexahydrothieno[3,4-d]imidazol-4- yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarb amoyl]phenoxy]pyridine-3-carbonyl]amino]-3-tert-butoxy-propanoic acid1. General procedure for preparation of tert-butyl 3-[[5-[[rac-(1S)-1-(tert-butoxymethyl)-2-methoxy-2-oxo-ethyl]carbamoyl]-2-pyridyl]oxy]benzoate： To a solution of 6-(3-tert-butoxycarbonylphenoxy)pyridine-3-carboxylic acid (1 g, 3.17 mmol, 1 eq) and methyl rac-(2S)-2-amino-3-tert-butoxy-propanoate (555.70 mg, 3.17 mmol, 1 eq) in DMF (15 mL) was added HATU (2.41 g, 6.34 mmol, 2 eq) and DIEA (1.23 g, 9.51 mmol, 1.66 mL, 3 eq) at 0°C. The mixture was stirred at 15°C for 2 hr. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (column: C1820- 40 um 100 A 330 g; mobile phase: [water-ACN]; B%: 0%-82% @ 100 mL / min) to give tert-butyl 3-[[5-[[rac-(1S)-1-(tert-butoxymethyl)-2-methoxy-2-oxo-ethyl]carbamoyl]-2- pyridyl]oxy] benzoate (700 mg, 1.48 mmol, 46.71% yield) as a yellow oil. Data: LCMS (ESI+): m / z 473.1 (M+H)+2. General procedure for preparation of 3-[[5-[[rac-(1S)-1-(tert-butoxymethyl)-2-methoxy-2-oxo-ethyl]carbamoyl]-2-pyridyl]oxy]benzoic acid： To a solution of tert-butyl 3-[[5-[[rac-(1S)-1-(tert-butoxymethyl)-2-methoxy-2-oxo- ethyl]carbamoyl]-2-pyridyl]oxy]benzoate (700 mg, 1.48 mmol, 1 eq) in DCM (8 mL) was added TFA (3.07 g, 26.92 mmol, 2 mL, 18.18 eq). The mixture was stirred at 0 °C for 6 hr. The reaction mixture was concentrated under reduced pressure to remove solvent and purified by prep-HPLC(column: C1820-40 um 100 A 120 g; mobile phase: [water- ACN]; B%: 0%-45% @ 80mL / min) to give 3-[[5-[[rac-(1S)-1-(tert-butoxymethyl)-2- methoxy-2-oxo-ethyl]carbamoyl]-2-pyridyl]oxy]benzoic acid (197 mg, 473.08 μmol, 31.93% yield) as a white solid. Data: LCMS (ESI+): m / z 417.3 (M+H)+3. General procedure for preparation of methyl rac-(2S)-3-tert-butoxy-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[rac-(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a- hexahydrothieno[3,4-d]imidazol-4- yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethylcarbamoyl]phenoxy]pyridine-3- carbonyl]amino]propanoate： To a solution of 3-[[5-[[rac-(1S)-1-(tert-butoxymethyl)-2-methoxy-2-oxo- ethyl]carbamoyl]-2-pyridyl]oxy]benzoic acid (80 mg, 192.11 μmol, 1 eq) and N-[2-[2-[2- [2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]- 5-[rac-(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4- yl]pentanamide (144.63 mg, 192.11 μmol, 1 eq, TFA) in DMF (5 mL) was added DIEA (74.49 mg, 576.34 μmol, 100.39 μL, 3 eq) and HATU (146.09 mg, 384.22 μmol, 2 eq) at 0°C. The mixture was stirred at 15°C for 1 hr. The reaction mixture was filtered and the filtrate was purified by prep-HPLC(column: C1820-40 um 100 A 80g; mobile phase: [water-ACN]; B%: 0%-48% @ 50 mL / min) to give methyl rac-(2S)-3-tert-butoxy-2-[[6-[3- [2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[rac-(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4- d]imidazol-4- yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenoxy]pyridine-3-carbonyl]amino]propanoate (139 mg, 134.01 μmol, 69.76%yield) as a yellow oil.. Data: LCMS (ESI+): m / z 1037.7 (M+H)+4. General procedure for preparation of rac-(2S)-3-tert-butoxy-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[rac-(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4- d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethylcarbamoyl]phenoxy]pyridine-3-carbonyl]amino]propanoic acid： To a solution of methyl rac-(2S)-3-tert-butoxy-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[rac- (3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4- yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarb amoyl]phenoxy]pyridine-3-carbonyl]amino]propanoate (139 mg, 134.01 μmol, 1 eq) in THF (1 mL) and H2O (1 mL) was added LiOH.H2O (11.25 mg, 268.02 μmol, 2 eq). The mixture was stirred at 0 °C for 0.5 hr. The THF was removed under reduced pressure and the residue was acidified with FA to pH=2. The mixture was purified by prep-HPLC (column: C1820-40 um 100 A 40 g; mobile phase: [water-ACN]; B%: 0%-34% @ 80 mL / min) to give rac-(2S)-3-tert-butoxy-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[rac- (3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4- yl]pentanoylamino]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenoxy]pyridine-3- carbonyl]amino]propanoic acid (61.1 mg, 58.48 μmol, 43.64% yield, 97.940% purity) as a yellow solid.Subsequent purification using supercritical fluid chromatography (SFC) in conditionsallowing separation of chiral compounds resulted in the final pure product A-001.Data: LCMS (ESI+): m / z 1023.5 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.63 (d, J = 2.4 Hz, 1H), 8.54 (br t, J = 5.1 Hz,1H), 8.28 (dd, J = 2.5, 8.6 Hz, 1H), 8.02 - 7.96 (m, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.66 (t,J = 1.9 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.39 - 7.31 (m, 1H), 7.10 (d, J = 8.6 Hz, 1H),4.76 (t, J = 4.4 Hz, 1H), 4.48 (dd, J = 4.8, 7.8 Hz, 1H), 4.30 (dd, J = 4.5, 7.9 Hz, 1H),3.90 (dd, J = 5.1, 9.4 Hz, 1H), 3.79 (dd, J = 3.8, 9.4 Hz, 1H), 3.69 - 3.56 (m, 32H), 3.55- 3.51 (m, 2H), 3.38 - 3.33 (m, 2H), 3.24 - 3.15 (m, 1H), 2.92 (dd, J = 4.9, 12.7 Hz, 1H),2.70 (d, J = 12.6 Hz, 1H), 2.21 (t, J = 7.4 Hz, 2H), 1.79 - 1.53 (m, 4H), 1.44 (q, J = 7.4Hz, 2H), 1.20 (s, 9H) A-002: (2S)-3-tert-butoxy-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[2-(2,4- dinitroanilino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]pheno xy]pyridine-3-carbonyl]amino]propanoic acid1. General procedure for preparation of 6-[3-[2-[2-[2-[2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]et hylcarbamoyl]phenoxy]pyridine-3-carboxylate

[0061] To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (500 mg, 1.07 mmol, 1 eq) in DCM (10 mL) was added 3-[(5-methoxycarbonyl-2- pyridyl)oxy]benzoic acid (320.72 mg, 1.17 mmol, 1.1 eq), HATU (608.59 mg, 1.60 mmol, 1.5 eq) and DIEA (206.86 mg, 1.60 mmol, 278.79 μL, 1.5 eq). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was quenched by saturated H2O (15 mL) and extracted with ethyl acetate (50 mL * 3). The combined organic phase was washed with brine (50 mL * 1), dried over anhydrous Na2SO4, filtered and concentrated give methyl 6-[3-[2-[2-[2-[2-[2-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamo yl]phenoxy]pyridine-3-carboxylate (600 mg, crude) as a yellow oil, which was used in next step directly. Data: LCMS (ESI+): m / z 724.4 (M+H)2. General procedure for preparation of methyl 6-[3-[2-[2-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]ph enoxy]pyridine-3-carboxylate: To a solution of methyl 6-[3-[2-[2-[2-[2-[2-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamo yl]phenoxy]pyridine-3-carboxylate (600 mg, 828.95 μmol, 1 eq) in DCM (10 mL) was added TFA (5 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was adjusted to pH= 8~9 by NaHCO3（5 ml）. The aqueous phase was extracted with ethyl acetate (30 mL * 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated give methyl 6-[3-[2-[2-[2-[2-[2-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenoxy]pyrid ine-3-carboxylate (680 mg, crude) was obtained as a yellow oil, which was used in next step directly. Data: LCMS (ESI+): m / z 624.4 (M+H)3. General procedure for preparation of methyl 6-[3-[2-[2-[2-[2-[2-[2-[2-[2-(2,4-dinitroanilino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarba moyl]phenoxy]pyridine-3-carboxylate： To a solution of methyl 6-[3-[2-[2-[2-[2-[2-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenoxy]pyrid ine-3-carboxylate (400 mg, 641.34 μmol, 1 eq) in DMF (5 mL) was added K2CO3 (177.27 mg, 1.28 mmol, 2 eq) and 1-fluoro-2,4-dinitro-benzene (119.35 mg, 641.34 μmol, 80.53 μL, 1 eq) at 0 °C under N2. The mixture was stirred at 20 °C for 12 hr under N2 atmosphere. The reaction mixture was added to H2O (50 mL) and extracted with EA (30 mL * 3). The combined organic layers were washed with brine (30 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give methyl 6- [3-[2-[2-[2-[2-[2-[2-[2-[2-(2,4- dinitroanilino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]pheno xy]pyridine-3-carboxylate (290 mg, 367.19 μmol, 57.25% yield) as yellow oil.Data: LCMS (ESI+): m / z 790.5 (M+H)+4. General procedure for preparation of 6-[3-[2-[2-[2-[2-[2-[2-[2-[2-(2,4-dinitroanilino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarba moyl]phenoxy]pyridine-3-carboxylic acid: To a solution of methyl 6-[3-[2-[2-[2-[2-[2-[2-[2-[2-(2,4- dinitroanilino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]pheno xy]pyridine-3-carboxylate (260 mg, 329.21 μmol, 1 eq) in THF (3 mL) and H2O (0.5 mL) was added LiOH·H2O (69.07 mg, 1.65 mmol, 5 eq). The mixture was stirred at 25°C for 4 hr. The reaction mixture was adjusted to pH=5~6 by 1 M HCl（5 ml. The aqueous phase was extracted with ethyl acetate (15 mL * 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated give a residue. The residue was purified by prep-HPLC (FA condition) to give 6-[3-[2-[2-[2-[2-[2-[2-[2-[2-(2,4- dinitroanilino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]pheno xy]pyridine-3-carboxylic acid (180 mg, 232.03 μmol, 70.48% yield) as a yellow oil. Data: LCMS (ESI+): m / z 776.4 (M+H)5. General procedure for preparation of rac-(2S)-3-tert-butoxy-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[2-(2,4- dinitroanilino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarba moyl]phenoxy]pyridine-3-carbonyl]amino]propanoic acid： To a solution of 6-[3-[2-[2-[2-[2-[2-[2-[2-[2-(2,4- dinitroanilino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]pheno xy]pyridine-3-carboxylic acid (90 mg, 116.02 μmol, 1 eq) in DMF (3 mL) was added HATU (66.17 mg, 174.02 μmol, 1.5 eq), DIEA (22.49 mg, 174.02 μmol, 30.31 μL, 1.5 eq). The mixture was stirred for 30 mins and to the mixture was added rac-(2S)-2- amino-3-tert-butoxy-propanoic acid (28.05 mg, 174.02 μmol, 1.5 eq). The mixture was stirred at 25 °C for 18 hr. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-HPLC (FA condition) to give rac-(2S)-3-tert-butoxy-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[2-(2,4- dinitroanilino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]pheno xy]pyridine-3-carbonyl]amino]propanoic acid (13.9 mg, 15.08 μmol, 13.00% yield, 99.7% purity) as a yellow oil. Subsequent purification using supercritical fluid chromatography (SFC) in conditions allowing separation of chiral compounds resulted in the final pure product A-002. Data: LCMS (ESI+): m / z 919.4 (M+H)1H NMR (400 MHz, METHANOL-d4) δ ppm 9.01 (d, J=2.75 Hz, 1 H) 8.61 (d, J=2.50Hz, 1 H) 8.29 - 8.24 (m, 2 H) 7.76 - 7.70 (m, 1 H) 7.65 - 7.62 (m, 1 H) 7.53 (t, J=7.94Hz, 1 H) 7.36 - 7.30 (m, 1 H) 7.20 (d, J=9.51 Hz, 1 H) 7.10 - 7.07 (m, 1 H) 4.75 (t,J=4.32 Hz, 1 H) 3.92 - 3.87 (m, 1 H) 3.82 - 3.76 (m, 3 H) 3.68 - 3.55 (m, 30 H) 1.20 (s,9 H) A-003: (2S)-3-tert-butoxy-2-[[6-[3-[[1-[2-[2-[2-[[1-[2-[(2R)-4-[5-[7-chloro-8-[[(1R)-1-(5-cyano-2- fluoro-phenyl)ethyl]amino]-3-fluoro-6-methyl-1,5-naphthyridin-2-yl]pyrimidin-2-yl]-2- methyl-piperazin-1-yl]-2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy]ethoxy]acetyl]-4- piperidyl]oxy]phenoxy]pyridine-3-carbonyl]amino]propanoic acid1. General procedure for preparation of methyl 6-[3-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]phenoxy]pyridine-3-carboxylate： To a solution of methyl 6-(3-hydroxyphenoxy)pyridine-3-carboxylate (1 g, 4.08 mmol, 1 eq) and tert-butyl 4-(ptolylsulfonyloxy)piperidine-1-carboxylate (1.45 g, 4.08 mmol, 1 eq) in DMF (25 mL) was added Cs2CO3(2.66 g, 8.16 mmol, 2 eq). The mixture was stirred at 80 °C for 13 hr. The mixture was quenched with H2O (20 mL) and extracted with EA (90 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleumether / Ethyl acetate=10 / 1 to 1 / 1) to give methyl 6-[3-[(1-tert-butoxycarbonyl-4- piperidyl)oxy]phenoxy]pyridine-3-carboxylate (1.1 g, 2.57 mmol, 62.96% yield) as a colourless oil. Data: LCMS (ESI+): m / z 429.2 (M+H)+2. General procedure for preparation of methyl 6-[3-(4-piperidyloxy)phenoxy]pyridine-3-carboxylate： To a solution of methyl 6-[3-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]phenoxy]pyridine-3- carboxylate (500 mg, 1.17 mmol, 1 eq) in DCM (5 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 11.54 eq). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated to give methyl 6-[3-(4-piperidyloxy)phenoxy]pyridine-3- carboxylate (500 mg, crude, TFA) as a brown oil. Data: LCMS (ESI+): m / z 329.1 (M+H)+3. General procedure for preparation of methyl 6-[3-[[1-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]acetyl]-4-piperidyl]oxy]phenoxy]pyridine-3-carboxylate ： To a solution of methyl 6-[3-(4-piperidyloxy)phenoxy]pyridine-3-carboxylate (500 mg, 1.13 mmol, 1 eq, TFA) and 2-[2-(2-prop-2-ynoxyethoxy)ethoxy]acetic acid (228.54 mg, 1.13 mmol, 1 eq) in DMF (8 mL) was added HATU (859.50 mg, 2.26 mmol, 2 eq) and DIEA (584.29 mg, 4.52 mmol, 787.45 μL, 4 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered and the filtrate was purified by reversed- phase HPLC (column: C1820-35um 100A 40g; mobile phase: [water-ACN]; B%: 0%- 75% @ 60mL / min) to give methyl 6-[3-[[1-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]acetyl]-4- piperidyl]oxy]phenoxy]pyridine-3-carboxylate (263.8 mg, 514.68 μmol, 45.54% yield) as a brown oil. Data: LCMS (ESI+): m / z 513.4 (M+H)+4. General procedure for preparation of methyl 6-[3-[[1-[2-[2-[2-[[1-[2-oxo-2-[rac-(2R)-4-[5-[7-chloro-3-fluoro-6-methyl-8-[[rac-(1R)-1-(5-cyano-2-fluoro-phenyl) ethyl]amino]-1,5-naphthyridin-2-yl]pyrimidin-2-yl]-2-methyl-piperazin-1- yl]ethyl] triazol-4-yl]methoxy]ethoxy]ethoxy]acetyl]-4-piperidyl]oxy]phenoxy]pyridine- 3-carboxylate： To a solution of methyl 6-[3-[[1-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]acetyl]-4- piperidyl]oxy]phenoxy]pyridine-3-carboxylate (140 mg, 273.14 μmol, 1 eq) and 4-fluoro- 3-[rac-(1R)-1-[[3-chloro-7-fluoro-2-methyl-6-[2-[rac-(3R)-4-(2-azidoacetyl)-3-methyl- piperazin-1-yl]pyrimidin-5-yl]-1,5-naphthyridin-4-yl]amino]ethyl]benzonitrile (168.81 mg, 273.14 μmol, 1 eq) in t-BuOH (1.5 mL) and H2O (1.5 mL) was added CuSO4.5H2O (68.20 mg, 273.14 μmol, 1eq) and sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy- 5-oxo-2H-furan-3-olate (54.11 mg, 273.14 μmol, 1.00 eq). The mixture was stirred at 50 °C for 1 hr. The reaction mixture was filtered and the filtrate was purified by reversed-phase HPLC (column: C1820-35um 100A 40g; mobile phase: [water-ACN]; B%: 0%-75% @ 60mL / min) to give methyl 6-[3-[[1-[2-[2-[2-[[1-[2-oxo-2-[rac-(2R)-4-[5- [7-chloro-3-fluoro-6-methyl-8-[[rac-(1R)-1-(5-cyano-2-fluoro-phenyl)ethyl]amino]-1,5- naphthyridin-2-yl]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]ethyl]triazol-4- yl]methoxy]ethoxy]ethoxy]acetyl]-4-piperidyl]oxy]phenoxy]pyridine-3-carboxylate (103.2 mg, 91.28 μmol, 33.42% yield) as a yellow solid. Data: LCMS (ESI+): m / z 1130.4 (M+H)+5. General procedure for preparation of 6-[3-[[1-[2-[2-[2-[[1-[2-oxo-2-[rac-(2R)-4-[5-[7-chloro-3-fluoro-6-methyl-8-[[rac-(1R)-1-(5-cyano-2-fluoro- phenyl)ethyl]amino]-1,5-naphthyridin-2-yl]pyrimidin-2-yl]-2-methyl-piperazin- 1-yl]ethyl]triazol-4- yl]methoxy]ethoxy]ethoxy]acetyl]-4-piperidyl]oxy]phenoxy]pyridine-3- carboxylic acid： To a solution of methyl 6-[3-[[1-[2-[2-[2-[[1-[2-oxo-2-[rac-(2R)-4-[5-[7-chloro-3-fluoro-6- methyl-8-[[rac-(1R)-1-(5-cyano-2-fluoro-phenyl)ethyl]amino]-1,5-naphthyridin-2-yl] pyrimidin-2-yl]-2-methyl-piperazin-1-yl]ethyl]triazol-4-yl]methoxy]ethoxy]ethoxy]acetyl]- 4-piperidyl]oxy]phenoxy]pyridine-3-carboxylate (93.2 mg, 82.43 μmol, 1 eq) in THF (1 mL) and H2O (1 mL) was added LiOH.H2O (13.84 mg, 329.74 μmol, 4 eq). The mixture was stirred at 0 °C for 1hr. The reaction mixture was filtered and the filtrate was purified by reversed-phase HPLC (column: C1820-35um 100A 40g; mobile phase: [water-ACN]; B%: 0%-75% @ 60mL / min) to give 6-[3-[[1-[2-[2-[2-[[1-[2-oxo-2-[rac-(2R)- 4-[5-[7-chloro-3-fluoro-6-methyl-8-[[rac-(1R)-1-(5-cyano-2-fluoro-phenyl)ethyl]amino]- 1,5-naphthyridin-2-yl]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]ethyl]triazol-4- yl]methoxy]ethoxy]ethoxy] acetyl]-4-piperidyl]oxy]phenoxy]pyridine-3-carboxylic acid (55 mg, 49.26 μmol, 59.75%yield) as a green solid. Data: LCMS (ESI+): m / z 1118.3 (M+H)+6. General procedure for preparation of (2,5-dioxopyrrolidin-1-yl) 6-[3-[[1-[2-[2-[2-[[1-[2-oxo-2-[rac-(2R)-4-[5-[7-chloro-3-fluoro-6-methyl-8-[[rac-(1R)-1-(5-cyano- 2-fluorophenyl)ethyl]amino]-1,5-naphthyridin-2-yl]pyrimidin-2-yl]-2-methyl- piperazin-1-yl]ethyl]triazol-4-yl]methoxy]ethoxy]ethoxy]acetyl]-4- piperidyl]oxy] phenoxy]pyridine-3-carboxylate： To a solution of 6-[3-[[1-[2-[2-[2-[[1-[2-oxo-2-[rac-(2R)-4-[5-[7-chloro-3-fluoro-6-methyl- 8-[[rac-(1R)-1-(5-cyano-2-fluoro-phenyl)ethyl]amino]-1,5-naphthyridin-2-yl]pyrimidin-2- yl]-2-methyl-piperazin-1-yl]ethyl]triazol-4-yl]methoxy]ethoxy]ethoxy]acetyl]-4-piperidyl] oxy]phenoxy]pyridine-3-carboxylicacid (45 mg, 40.30 μmol, 1 eq) and HOSu (4.64 mg, 40.30 μmol, 1 eq) in DMF (1 mL) was added EDCI (15.45 mg, 80.60 μmol, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. Compound (2,5-dioxopyrrolidin-1-yl) 6-[3- [[1-[2-[2-[2-[[1-[2-oxo-2-[rac-(2R)-4-[5-[7-chloro-3-fluoro-6-methyl-8-[[rac-(1R)-1-(5- cyano-2-fluorophenyl)ethyl]amino]-1,5-naphthyridin-2-yl]pyrimidin-2-yl]-2-methyl- piperazin-1-yl]ethyl]triazol-4-yl]methoxy]ethoxy]ethoxy]acetyl]-4- piperidyl]oxy]phenoxy]pyridine-3-carboxylate (50 mg, crude) in DMF (1 mL) was obtained as brown liquid.7. General procedure for preparation of rac-(2S)-3-tert-butoxy-2-[[6-[3-[[1-[2-[2-[2-[[1-[2-oxo-2-[rac-(2R)-4-[5-[7-chloro-3-fluoro-6-methyl-8-[[rac-(1R)-1-(5-cyano- 2-fluoro-phenyl)ethyl]amino]-1,5-naphthyridin-2-yl]pyrimidin-2-yl]-2-methyl- piperazin-1-yl]ethyl]triazol-4-yl]methoxy]ethoxy]ethoxy]acetyl]-4-piperidyl] oxy]phenoxy]pyridine-3-carbonyl]amino]propanoic acid： To a solution of (2,5-dioxopyrrolidin-1-yl) 6-[3-[[1-[2-[2-[2-[[1-[2-oxo-2-[rac-(2R)-4-[5-[7- chloro-3-fluoro-6-methyl-8-[[rac-(1R)-1-(5-cyano-2-fluoro-phenyl)ethyl]amino]-1,5- naphthyridin-2-yl]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]ethyl]triazol-4-yl]methoxy] ethoxy]ethoxy]acetyl]-4-piperidyl]oxy]phenoxy]pyridine-3-carboxylate (50 mg, 41.20 μmol, 1 eq) and rac-(2S)-2-amino-3-tert-butoxy-propanoic acid (6.64 mg, 41.20 μmol, 1 eq) in DMF (1 mL) was added DIEA (10.65 mg, 82.40 μmol, 14.35 μL, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:35%-65% B over 8.0 min) to give rac-(2S)-3-tert-butoxy-2-[[6-[3-[[1-[2-[2-[2-[[1-[2-oxo-2-[rac-(2R)-4- [5-[7-chloro-3-fluoro-6-methyl-8-[[rac-(1R)-1-(5-cyano-2-fluoro-phenyl)ethyl]amino]-1,5- naphthyridin-2-yl]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]ethyl]triazol-4- yl]methoxy]ethoxy]ethoxy]acetyl]-4-piperidyl]oxy]phenoxy]pyridine-3- carbonyl]amino]propanoic acid (16 mg, 11.76 μmol, 29.63% yield, 92.595% purity) as a light yellow solid. Subsequent purification using supercritical fluid chromatography (SFC) in conditions allowing separation of chiral compounds resulted in the final pure product A-003. Data: LCMS (ESI+): m / z 1259.5 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.85 (d, J = 1.1 Hz, 2H), 8.61 (d, J = 2.4 Hz,1H), 8.22 (dd, J = 2.4, 8.6 Hz, 1H), 8.03 - 7.94 (m, 1H), 7.84 - 7.80 (m, 1H), 7.79 (d, J =2.0 Hz, 1H), 7.62 (m, J = 2.1, 4.7, 8.4 Hz, 1H), 7.32 (t, J = 8.2 Hz, 1H), 7.20 (dd, J = 8.7, 10.1 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.87 (dd, J = 2.1, 8.3 Hz, 1H), 6.80 (d, J =2.0 Hz, 1H), 6.72 (dd, J = 1.6, 8.0 Hz, 1H), 6.42 (q, J = 6.7 Hz, 1H), 5.71 - 5.52 (m, 1H),5.49 - 5.37 (m, 1H), 4.85 - 4.67 (m, 4H), 4.66 (s, 2H), 4.61 (m, J = 3.8, 7.0 Hz, 1H),4.38 (d, J = 8.2 Hz, 1H), 4.26 (d, J = 2.0 Hz, 2H), 3.91 - 3.63 (m, 14H), 3.54 - 3.46 (m,1H), 3.45 - 3.37 (m, 2H), 3.23 - 3.03 (m, 1H), 2.67 (s, 3H), 2.03 - 1.91 (m, 2H), 1.72 (d,J = 6.8 Hz, 5H), 1.40 - 1.27 (m, 2H), 1.21 (s, 1H), 1.18 (s, 9H)X-001: (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[4-[[4-[4-[[(2S)-3,3-dicyclopropyl-2-[(2- methylpyrazole-3-carbonyl)amino]propanoyl]amino] phenyl]-5-methyl-1H-pyrazol-3-yl]methoxy]butyl]triazol-4-yl]methoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoic acid：5. General procedure for preparation of methyl (2S)-5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-[2-[2-[2-[2-(2-prop-2- ynoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]ethoxy]phenoxy]pyridi ne-3-carbonyl]amino]hexanoate： To a solution of 2-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl-pentyl]carbamoyl]-2- pyridyl]oxy]phenoxy]acetic acid (200 mg, 358.10 μmol, 1 eq, TFA) , 2-[2-[2-[2-[2-(2-prop- 2-ynoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethanamine (125.81 mg, 393.91 μmol, 1.1 eq) in DMF (2 mL) was added HATU (272.32 mg, 716.20 μmol, 2 eq) at 0 °C, then DIEA (138.85 mg, 1.07 mmol, 187.12 μL, 3 eq) was added into the reaction mixture at 0 °C. The mixture was stirred at 15 °C for 1 hr. The reaction mixture was quenched by addition H2O 2 mL, and extracted with EtOAc 9 mL (3 mL * 3). The combined organic layers were washed with brine 20 mL (10 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Ethyl acetate : Methanol = 10 : 1) to give compound methyl (2S)-5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-[2-[2-[2-[2-(2- prop-2-ynoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]ethoxy]phenoxy]pyridine- 3-carbonyl]amino]hexanoate (250 mg, 335.19 μmol, 93.60% yield) as a yellow oil. Data: LCMS (ESI+): m / z 746.2 (M+H)+6. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[4-[[4-[4-[[(2S)-3,3-dicyclopropyl-2-[(2-methylpyrazole-3- carbonyl)amino]propanoyl]amino]phenyl]-5-methyl-1-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]methoxy]butyl]triazol-4- yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of N-[(1S)-1-[[4-[3-(4-azidobutoxymethyl)-5-methyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]carbamoyl]-2,2-dicyclopropyl-ethyl]-2- methyl-pyrazole-3-carboxamide (83.25 mg, 120.67 μmol, 0.9 eq) and methyl (2S)-5,5- dimethyl-2-[[6-[3-[2-oxo-2-[2-[2-[2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethoxy] ethoxy]ethylamino]ethoxy]phenoxy]pyridine-3-carbonyl]amino]hexanoate (100 mg, 134.07 μmol, 1 eq) in t-BuOH (1 mL) and H2O (1 mL) was added copper;sulfate (10.70 mg, 67.04 μmol, 10.29 μL, 0.5 eq) and sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4- hydroxy-5-oxo-2H-furan-3-olate (26.56 mg, 134.07 μmol, 1 eq). The mixture was stirred at 50 °C for 0.5 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: C18 20-35μm 100A 40g; mobile phase: [water-ACN]; B%: 0%-77% @ 80 mL / min) to give compound methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[4-[[4-[4-[[(2S)-3,3- dicyclopropyl-2-[(2-methylpyrazole-3-carbonyl)amino]propanoyl]amino]phenyl]-5- methyl-1-(2-trimethylsilylethoxymethyl) pyrazol-3-yl]methoxy]butyl]triazol-4-yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (96 mg, 66.86 μmol, 49.87% yield) as a light yellow oil. Data: LCMS (ESI+): m / z 1435.4 (M+H)+7. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[4-[[4-[4-[[(2S)-3,3-dicyclopropyl-2-[(2-methylpyrazole-3-carbonyl)amino] propanoyl]amino]phenyl]-5-methyl-1H-pyrazol-3-yl]methoxy]butyl]triazol- 4-yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： A mixture of methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[4-[[4-[4-[[(2S)-3,3-dicyclopropyl- 2-[(2-methylpyrazole-3-carbonyl)amino]propanoyl]amino]phenyl]-5-methyl-1-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]methoxy]butyl]triazol-4-yl]methoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl] amino]-5,5-dimethyl-hexanoate (96 mg, 66.86 μmol, 1 eq) in DCM (2 mL) and TFA (1 mL) was stirred at 15 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give compound methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[4-[[4-[4-[[(2S)- 3,3-dicyclopropyl-2-[(2-methylpyrazole-3-carbonyl)amino]propanoyl]amino]phenyl]-5- methyl-1H-pyrazol-3-yl]methoxy]butyl]triazol-4-yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl- hexanoate (100 mg, crude, TFA) as a yellow oil. Data: LCMS (ESI+): m / z 1305.2 (M+H)+8. General procedure for preparation of (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[4-[[4-[4-[[(2S)-3,3-dicyclopropyl-2-[(2-methylpyrazole-3- carbonyl)amino]propanoyl]amino]phenyl]-5-methyl-1H-pyrazol-3- yl]methoxy]butyl]triazol-4- yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[4-[[4-[4-[[(2S)-3,3- dicyclopropyl-2-[(2-methylpyrazole-3-carbonyl)amino]propanoyl]amino]phenyl]-5- methyl-1H-pyrazol-3-yl]methoxy]butyl]triazol-4-yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl- hexanoate (100 mg, 70.45 μmol, 1 eq, TFA) in THF (1 mL) and H2O (1 mL) was added LiOH.H2O (5.91 mg, 140.89 μmol, 2 eq). The mixture was stirred at 15 °C for 0.5 hr. THF was removed. The aqueous layer was adjusted pH to 5 with FA. The residue was purified by prep-HPLC (neutral condition; column: Waters Xbridge Prep OBD C18 150*40mm*10μm;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:25%-65% B over 8.0 min) to give compound X-001 (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[4-[[4-[4-[[(2S)- 3,3-dicyclopropyl-2-[(2-methylpyrazole-3-carbonyl)amino]propanoyl]amino]phenyl]-5- methyl-1H-pyrazol-3-yl]methoxy]butyl]triazol-4-yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl- hexanoic acid (46.6 mg, 36.08 μmol, 51.22% yield, 100% purity) as a white solid. Data: LCMS (ESI+): m / z 1291.4 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.62 (d, J = 2.0 Hz, 1H), 8.23 (dd, J = 2.5, 8.6Hz, 1H), 7.88 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 2.1 Hz, 1H), 7.40 - 7.30 (m,3H), 6.98 (d, J = 8.8 Hz, 1H), 6.91 - 6.86 (m, 2H), 6.82 (t, J = 2.1 Hz, 1H), 6.78 (br d, J =8.1 Hz, 1H), 4.91 (d, J = 7.3 Hz, 1H), 4.59 (s, 2H), 4.53 (s, 2H), 4.52 - 4.48 (m, 1H), 4.42(s, 2H), 4.33 (t, J = 7.0 Hz, 2H), 4.10 (s, 3H), 3.63 - 3.53 (m, 22H), 3.49 - 3.42 (m, 4H),2.30 (s, 3H), 2.03 - 1.73 (m, 4H), 1.51 (quin, J = 6.9 Hz, 2H), 1.39 - 1.29 (m, 2H), 0.91(s, 9H), 0.89 - 0.74 (m, 3H), 0.58 - 0.51 (m, 1H), 0.51 - 0.33 (m, 4H), 0.32 - 0.21 (m, 3H).X-017: (2S)-2-[[6-[3-[2-[2-[[1-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4- yl]methoxy]acetyl]-4-piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoic acid：1. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[[1-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl) pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4- yl]methoxy]acetyl]-4-piperidyl]oxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-[[1-(2-prop-2-ynoxyacetyl)- 4-piperidyl]oxy]ethylamino]ethoxy]phenoxy]pyridine-3-carbonyl]amino]hexanoate (50 mg, 74.99 μmol, 1 eq) and 2-(6-azidohexyl)-N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5- dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole-3- carboxamide (51.59 mg, 74.99 μmol, 1 eq) in t-BuOH (1 mL) and H2O (1 mL) was added CuSO4.5H2O (9.36 mg, 37.49 μmol, 0.5 eq) and sodium;(2R)-2-[(1S)-1,2- dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (14.86 mg, 74.99 μmol, 1 eq) at 20 °C. The mixture was stirred at 50 °C for 1 h. The residue was purified by reversed-phase HPLC flash C18 gel chromatography (ISCO; 40g SepaFlash C18 Flash Column, eluent of 0-100% MeCN / H2O 60 mL / min) to give compound methyl (2S)-2-[[6-[3-[2-[2-[[1-[2-[[1- [6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]hexyl]triazol-4-yl]methoxy]acetyl]-4-piperidyl]oxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (50 mg, 36.91 μmol, 49.22% yield) as a white solid. Data: LCMS (ESI+): m / z 1354.4 (M+H)+2. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[[1-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2- oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]acetyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]- 5,5-dimethyl-hexanoate： A mixture of methyl (2S)-2-[[6-[3-[2-[2-[[1-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4- [3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]acetyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoate (50 mg, 36.91 μmol, 1 eq) in DCM (1.5 mL) and TFA (0.7 mL) was stirred at 20 °C for 3.5 hr. The reaction mixture was concentrated under reduced pressure to give compound methyl (2S)-2-[[6-[3-[2-[2-[[1-[2-[[1-[6-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]acetyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoate (49 mg, crude, TFA) as a yellow oil. Data: LCMS (ESI+): m / z 1224.3 (M+H)+3. General procedure for preparation of (2S)-2-[[6-[3-[2-[2-[[1-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]acetyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]- 5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[2-[2-[[1-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)- 2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]hexyl]triazol-4-yl]methoxy]acetyl]-4-piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy] pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (49 mg, 36.61 μmol, 1 eq, TFA) in THF (1.2 mL) and H2O (0.6 mL) was added LiOH.H2O (38.41 mg, 915.22 μmol, 25 eq) at 0 °C until the pH~8. The mixture was stirred at 20 °C for 0.5 h. The residue was concentrated under the reduced pressure to remove THF, the residue was adjusted pH~4 by using formic acid to give a solution. The residue was purified by reversed- phase HPLC flash C18 gel chromatography (ISCO; 40g SepaFlash C18 Flash Column, eluent of 0-100% MeCN / H2O 60 mL / min) to give compound X-017 (2S)-2-[[6-[3-[2-[2-[[1- [2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2- oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]acetyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoic acid (34.7 mg, 27.48 μmol, 75.08% yield, 95.872% purity) as a white solid. Data: LCMS (ESI+): m / z 1210.5 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.61 (d, J = 2.2 Hz, 1H), 8.25 - 8.21 (m, 1H),7.93 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 2.1 Hz, 1H), 7.33 (t, J = 8.2 Hz, 1H),7.23 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 1H), 6.89 - 6.85 (m, 2H), 6.81 - 6.75 (m,2H), 4.63 - 4.41 (m, 8H), 4.29 (t, J = 7.0 Hz, 2H), 4.21 (s, 2H), 3.74 - 3.66 (m, 1H), 3.55- 3.49 (m, 4H), 3.45 (br s, 2H), 3.23 - 3.15 (m, 1H), 2.22 (s, 6H), 2.01 - 1.91 (m, 1H), 1.88- 1.69 (m, 8H), 1.52 - 1.43 (m, 2H), 1.35 (dt, J = 4.9, 11.9 Hz, 2H), 1.29 - 1.22 (m, 4H),0.91 (s, 9H), 0.88 - 0.75 (m, 3H), 0.58 - 0.52 (m, 1H), 0.50 - 0.43 (m, 2H), 0.42 - 0.35 (m,2H), 0.32 - 0.23 (m, 3H).X-024: (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5- dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4- yl]methoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoic acid1. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4- yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-[2-[2-[2-[2-(2-prop-2- ynoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]ethoxy]phenoxy]pyridine-3- carbonyl]amino]hexanoate (70 mg, 93.85 μmol, 1 eq) and 2-(6-azidohexyl)-N-[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]pyrazole-3-carboxamide (51.65 mg, 75.08 μmol, 0.8 eq) in t-BuOH (0.5 mL) and H2O (0.5 mL) was added copper;sulfate (7.49 mg, 46.93 μmol, 7.20 μL, 0.5 eq) and sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (18.59 mg, 93.85 μmol, 1 eq). The mixture was stirred at 50 °C for 0.5 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: C1820-35μm 100A 40g; mobile phase: [water-ACN]; B%: 0%-80% @ 80 mL / min) to give compound methyl (2S)- 2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1- (2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]hexyl]triazol-4-yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (80 mg, 55.80 μmol, 59.45% yield) as a colorless oil. Data: LCMS (ESI+): m / z 1433.4 (M+H)+2. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]- 2-oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate： A mixture of methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxoethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (160 mg, 111.59 μmol, 1 eq) in DCM (2 mL) and TFA (1 mL) was stirred at 15 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give compound methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6- [5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl- hexanoate (290 mg, crude, TFA) as a colorless oil. Data: LCMS (ESI+): m / z 1303.3 (M+H)+3. General procedure for preparation of (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2- oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4- yl]methoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl] pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino] -2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (290 mg, 204.58 μmol, 1 eq, TFA) in THF (2 mL) and H2O (1 mL) was added LiOH.H2O (17.17 mg, 409.15 μmol, 2 eq). The mixture was stirred at 15 °C for 1 hr. THF was removed. The aqueous layer was adjusted pH to 5 with FA. The residue was purified by prep- HPLC (neutral condition; column: Waters Xbridge Prep OBD C18150*40mm*10μm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:40%-70% B over 8.0 min) to give compound X-024 (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4- yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo-ethoxy]phenoxy] pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid (61.6 mg, 47.77 μmol, 23.35% yield, 100% purity) as a white solid. Data: LCMS (ESI+): m / z 1289.4 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.63 (d, J = 2.2 Hz, 1H), 8.24 (dd, J = 2.4, 8.7 Hz, 1H), 7.89 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 2.1 Hz, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.7 Hz, 1H), 6.89 (dd, J = 2.1, 8.3 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.83 (t, J = 2.2 Hz, 1H), 6.78 (dd, J = 1.7, 8.1 Hz, 1H), 4.89 (d,J = 7.5 Hz, 1H), 4.58 (s, 2H), 4.56 - 4.42 (m, 5H), 4.29 (t, J = 7.0 Hz, 2H), 3.61 (s, 4H),3.59 - 3.53 (m, 18H), 3.49 - 3.41 (m, 2H), 2.22 (s, 6H), 2.06 - 1.91 (m, 1H), 1.88 - 1.73(m, 5H), 1.35 (ddd, J = 5.1, 8.8, 11.8 Hz, 2H), 1.30 - 1.24 (m, 4H), 0.91 (s, 9H), 0.89 -0.74 (m, 3H), 0.59 - 0.51 (m, 1H), 0.51 - 0.43 (m, 2H), 0.43 - 0.34 (m, 2H), 0.33 - 0.21(m, 3H). X-008: 2S) -2-[[6-[3-[2-[2-[[1-[2-[[1-[4-[[4-[4-[[ (2S) -3,3-dicyclopropyl-2-[ (2-methylpyrazole-3- carbonyl) amino]propanoyl]amino]phenyl]-3-methyl-1H-pyrazol-5- yl]methoxy]butyl]triazol-4-yl]methoxy]acetyl]-4-piperidyl]oxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of 4-azidobutan-1-olTo a solution of 4-bromobutan-1-ol (10 g, 65.35 mmol, 1 eq) in DMF (150 mL) was added NaN3(4.44 g, 68.29 mmol, 1.05 eq) at 20°C slowly, then the reaction was stirred for 12 hr at 20 °C. The reaction mixture was diluted with H2O 100 mL and extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were washed with brine 400 mL (200 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4- azidobutan-1-ol (9 g, crude) as a yellow oil, which was used to next step without purification. Data:1H NMR (400 MHz, CHLOROFORM-d) δ = 3.68 (t, J = 6.1 Hz, 1H), 3.33 (t, J = 6.5 Hz,2H), 1.76 - 1.60 (m, 4H)2. General procedure for preparation of 4-azidobutyl 4-methylbenzenesulfonateTo a solution of 4-azidobutan-1-ol (4 g, 34.74 mmol, 1 eq) in DCM (100 mL) was added TEA (7.03 g, 69.48 mmol, 9.67 mL, 2 eq) and TosCl (9.94 g, 52.11 mmol, 1.5 eq) at 0 °C, then the reaction was stirred for 2 hr at 15 °C. The reaction mixture was diluted with H2O 30 mL and extracted with EA 90 mL (30 mL * 3). The combined organic layers were washed with brine (80 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 10 / 1) to give 4-azidobutyl 4-methylbenzenesulfonate (2.5 g, 9.28 mmol, 26.72% yield) as a yellow oil. Data:1H NMR (400 MHz, CHLOROFORM-d) δ = 7.80 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz,2H), 4.07 (t, J = 6.1 Hz, 2H), 3.27 (t, J = 6.6 Hz, 2H), 2.46 (s, 3H), 1.81 - 1.71 (m, 2H),1.70 - 1.59 (m, 2H).3. General procedure for preparation of 2-[[3-(4-azidobutoxymethyl)-5-methyl-4-(4-nitrophenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane To a solution of [5-methyl-4-(4-nitrophenyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-3- yl]methanol (4 g, 11.00 mmol, 1 eq) in DMF (70 mL) was added NaH (660.22 mg, 16.51 mmol, 60% purity, 1.5 eq) at 0°C, the reaction was stirred for 0.5 hr at 0°C, 4-azidobutyl 4-methylbenzenesulfonate (2.96 g, 11.00 mmol, 1 eq) in DMF (5 mL) was added, then the reaction was stirred at 15°C for 3 h. The reaction was added slowly into saturated NH4Cl solution 100 mL at 0°C, then extracted with EtOAc 3 * 100 mL. The organic layer was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 10 / 1) to give 2-[[3-(4-azidobutoxymethyl)-5-methyl-4-(4-nitrophenyl)pyrazol-1- yl]methoxy]ethyl-trimethyl-silane (2 g, 4.34 mmol, 39.46% yield) as a yellow oil. Data: LCMS (ESI+): m / z 461.3 (M+H)+1H NMR (400 MHz, CHLOROFORM-d) δ = 8.36 - 8.22 (m, 2H), 7.66 - 7.52 (m, 2H), 5.47(s, 2H), 4.44 (s, 2H), 3.68 - 3.61 (m, 2H), 3.52 (br t, J = 5.8 Hz, 2H), 3.26 (t, J = 6.4 Hz,2H), 2.42 (s, 3H), 1.70 - 1.62 (m, 4H), 0.97 - 0.90 (m, 2H), 0.04 - 0.02 (m, 9H)4. General procedure for preparation of 4-[3-(4-azidobutoxymethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]aniline To a solution of 2-[[3-(4-azidobutoxymethyl)-5-methyl-4-(4-nitrophenyl)pyrazol-1- yl]methoxy]ethyl-trimethyl-silane (1.9 g, 4.13 mmol, 1 eq) in EtOH (20 mL) and H2O (2 mL) was added Fe (1.15 g, 20.63 mmol, 5 eq) and NH4Cl (1.10 g, 20.63 mmol, 5 eq), the reaction was stirred at 50 °C for 72 hr. The mixture was filtered and the filtrate was extracted with EA 100 mL (50 mL * 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 3 / 1) to give 4-[3-(4-azidobutoxymethyl)-5-methyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]aniline (1.5 g, 3.48 mmol, 84.44% yield) as a yellow oil. Data:1H NMR (400 MHz, CHLOROFORM-d) δ = 7.17 (d, J = 8.3 Hz, 2H), 6.76 (d, J = 8.3 Hz,2H), 5.43 (s, 2H), 4.41 (s, 2H), 3.66 - 3.58 (m, 2H), 3.49 (br t, J = 5.3 Hz, 2H), 3.28 - 3.19(m, 2H), 2.34 (s, 3H), 1.69 - 1.60 (m, 4H), 0.96 - 0.86 (m, 2H), 0.02 - 0.03 (m, 9H).5. General procedure for preparation of tert-butyl N-[(1S)-1-[[4-[3-(4-azidobutoxymethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]phenyl]carbamoyl]-2,2-dicyclopropyl-ethyl]carbamate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid (965.40 mg, 3.58 mmol, 1.05 eq) and 4-[3-(4-azidobutoxymethyl)-5-methyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]aniline (1.47 g, 3.41 mmol, 1 eq) in DMF (30 mL) was added DIEA (1.32 g, 10.24 mmol, 1.78 mL, 3 eq) and HATU (1.95 g, 5.12 mmol, 1.5 eq), then the reaction was stirred for 12 hr at 15°C. The reaction mixture was diluted with H2O 30 mL and extracted with EA 90 mL (30 mL * 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 3 / 1) to give tert-butyl N-[(1S)-1-[[4-[3-(4- azidobutoxymethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]phenyl]carbamoyl]-2,2-dicyclopropyl-ethyl]carbamate (1.75 g, 2.57 mmol, 75.17%yield) as a yellow oil.Data:1H NMR (400 MHz, CHLOROFORM-d) δ = 7.58 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz,2H), 5.44 (s, 3H), 4.45 - 4.35 (m, 3H), 3.66 - 3.59 (m, 2H), 3.53 - 3.46 (m, 2H), 3.24 (brt, J = 6.4 Hz, 2H), 2.36 (s, 3H), 1.67 - 1.60 (m, 4H), 1.49 (s, 9H), 1.00 - 0.86 (m, 4H),0.83 - 0.73 (m, 2H), 0.60 - 0.43 (m, 4H), 0.38 - 0.24 (m, 4H), -0.01 (s, 9H).6. General procedure for preparation of (2S)-2-amino-N-[4-[3-(4-azidobutoxymethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]phenyl]-3,3-dicyclopropyl-propanamide A mixture of tert-butyl N-[(1S)-1-[[4-[3-(4-azidobutoxymethyl)-5-methyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]carbamoyl]-2,2-dicyclopropyl- ethyl]carbamate (1.75 g, 2.57 mmol, 1 eq) in 4M HCl / MeOH (20 mL) was stirred for 1 hr at 15 °C. The reaction was concentrated to give (2S)-2-amino-N-[4-[3-(4- azidobutoxymethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]-3,3- dicyclopropyl-propanamide (1.59 g, crude, HCl) as a yellow solid, which was used to next step without purification. Data: LCMS (ESI+): m / z 582.4 (M+H)+7. General procedure for preparation of N-[(1S)-1-[[4-[3-(4-azidobutoxymethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]carbamoyl]-2,2- dicyclopropyl-ethyl]-2-methyl-pyrazole-3-carboxamide To a solution of (2S)-2-amino-N-[4-[3-(4-azidobutoxymethyl)-5-methyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]-3,3-dicyclopropyl-propanamide (1.49 g, 2.41 mmol, 1 eq, HCl) and 2-methylpyrazole-3-carboxylic acid (364.70 mg, 2.89 mmol, 1.2 eq) in DMF (20 mL) was added DIEA (934.37 mg, 7.23 mmol, 1.26 mL, 3 eq) and HATU (1.37 g, 3.61 mmol, 1.5 eq), then the reaction was stirred for 0.5 hr at 15°C. The reaction mixture was diluted with H2O 30 mL and extracted with EA 90 mL (30 mL * 3). The combined organic layers was washed with brine (100 mL * 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 1 / 1) to give N-[(1S)-1-[[4-[3-(4-azidobutoxymethyl)-5-methyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]carbamoyl]-2,2-dicyclopropyl-ethyl]-2- methyl-pyrazole-3-carboxamide (1.6 g, 2.32 mmol, 96.23% yield) as a yellow solid. Data: LCMS (ESI+): m / z 690.4 (M+H)+1H NMR (400 MHz, CHLOROFORM-d) δ = 7.94 (s, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.11 (br d, J = 8.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 5.45 (s, 2H), 4.83 (dd, J = 4.8, 8.0 Hz, 1H), 4.42 (s, 2H), 4.19 (s, 3H), 3.66 - 3.59 (m, 2H), 3.49 (br t, J = 5.5 Hz, 2H), 3.23 (br t, J = 6.3 Hz, 2H), 2.36 (s, 3H), 1.66 -1.58 (m, 4H), 0.96 - 0.85 (m, 5H), 0.71 - 0.63 (m, 1H), 0.62 - 0.53 (m, 3H), 0.47 - 0.35(m, 2H), 0.27 (q, J = 4.8 Hz, 2H), -0.01 (s, 9H).8. General procedure for preparation of benzyl 4-[2-(tert-butoxycarbonylamino)ethoxy]piperidine-1-carboxylate To a solution of benzyl 4-hydroxypiperidine-1-carboxylate (5 g, 21.25 mmol, 1 eq) in DMF (100 mL) was added NaH (1.02 g, 25.50 mmol, 60% purity, 1.2 eq) at 0°C, then the reaction was stirred for 1 hr at 0 °C. Tert-butyl 2,2-dioxooxathiazolidine-3-carboxylate (5.69 g, 25.50 mmol, 1.2 eq) was added to above mixture and the reaction was stirred at 25°C for 11 h. The reaction mixture was quenched with Sat.NH4Cl 100 mL and extracted with Ethyl acetate 500 mL (100 mL *5). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 0 / 1 to 8 / 1) to give benzyl 4-[2-(tert-butoxycarbonylamino)ethoxy]piperidine-1- carboxylate (8.22 g, 21.72 mmol, 82.20% yield) as a colorless oil. Data: LCMS (ESI+): m / z 279.2 (M-100+H)+9. General procedure for preparation of tert-butyl N-[2-[[1-(2-prop-2-ynoxyacetyl)-4-piperidyl]oxy]ethyl]carbamate: To a solution of benzyl 4-[2-(tert-butoxycarbonylamino)ethoxy]piperidine-1-carboxylate (8 g, 21.14 mmol, 1 eq) in THF (100 mL) was added Pd / C (4.5 g, 10% purity) under N2. The reaction was degassed and purged with H2 for 3 times, and then stirred at 15°C for 1 hr under H2 atmosphere (15 psi). The catalyst was removed by filtration through celite, which was then washed with MeOH (300 ml). The filtrate was concentrated to give compound tert-butyl N-[2-(4-piperidyloxy)ethyl]carbamate (4.5 g, crude) as a colorless oil.10. General procedure for preparation of tert-butyl N-[2-[[1-(2-prop-2-ynoxyacetyl)-4-piperidyl]oxy]ethyl]carbamate: To a solution of tert-butyl N-[2-(4-piperidyloxy)ethyl]carbamate (2 g, 8.19 mmol, 1 eq), 2- prop-2-ynoxyacetic acid (933.98 mg, 8.19 mmol, 1 eq) in DMF (35 mL) was added DIEA (3.17 g, 24.56 mmol, 4.28 mL, 3 eq) and HATU (4.67 g, 12.28 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 15 °C for 2 hr. The mixture was diluted with water 100 mL, and then extracted with EtOAc 600 mL (200 mL * 3). The combined organic layer was washed with sat. NaCl 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 120 g SepaFlash Silica Flash Column, Eluent of 0~93% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give compound tert-butyl N-[2-[[1- (2-prop-2-ynoxyacetyl)-4-piperidyl]oxy]ethyl]carbamate (1.8 g, 5.29 mmol, 90.00% yield) as a brown oil. Data:1H NMR (400 MHz, CHLOROFORM-d) δ = 4.89 - 4.79 (m, 1H), 4.29 (d, J = 2.4 Hz, 2H),4.26 (s, 2H), 3.93 - 3.81 (m, 1H), 3.73 - 3.61 (m, 1H), 3.59 - 3.46 (m, 3H), 3.43 - 3.21 (m,4H), 2.52 - 2.44 (m, 1H), 1.91 - 1.79 (m, 2H), 1.65 - 1.52 (m, 2H), 1.45 (s, 9H)11. General procedure for preparation of 1-[4-(2-aminoethoxy)-1-piperidyl]-2-prop-2-ynoxy-ethanone: A solution of tert-butyl N-[2-[[1-(2-prop-2-ynoxyacetyl)-4-piperidyl]oxy]ethyl]carbamate (1.7 g, 4.99 mmol, 1 eq) in DCM (10 mL) and TFA (5 mL) was stirred at 15 °C for 3 hr. The DCM and TFA was removed under reduced pressure to give compound 1-[4-(2- aminoethoxy)-1-piperidyl]-2-prop-2-ynoxy-ethanone (1.2 g, crude, TFA) as a colorless oil.12. General procedure for preparation of methyl (2S)-5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-[[1-(2-prop-2-ynoxyacetyl)-4- piperidyl]oxy]ethylamino]ethoxy]phenoxy]pyridine-3- carbonyl]amino]hexanoate: To a solution of 1-[4-(2-aminoethoxy)-1-piperidyl]-2-prop-2-ynoxy-ethanone (258.15 mg, 728.59 μmol, 8.14e-1 eq, TFA), 2-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl- pentyl]carbamoyl]-2-pyridyl]oxy]phenoxy]acetic acid (500 mg, 895.26 μmol, 1 eq, TFA)in DMF (20 mL) was added HATU (510.60 mg, 1.34 mmol, 1.5 eq) and DIEA (347.12mg, 2.69 mmol, 467.81 μL, 3 eq) at 0 °C. The mixture was stirred at 15°C for 1.5 hr. The mixture was diluted with water 10 mL, and then extracted with EtOAc 60 mL (20 mL * 3). The combined organic layer was washed with sat.NaCl 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (column: C18 20-35μm 100A 80g; mobile phase: [water-ACN]; B%: 0%-54% @ 65 mL / min) to give compound methyl (2S)-5,5-dimethyl- 2-[[6-[3-[2-oxo-2-[2-[[1-(2-prop-2-ynoxyacetyl)-4- piperidyl]oxy]ethylamino]ethoxy]phenoxy]pyridine-3-carbonyl]amino]hexanoate (143 mg, 214.47 μmol, 23.96% yield) as a colorless oil. Data: LCMS (ESI+): m / z 667.5 (M+H)+13. General procedure for preparation of methyl (2S) -2-[[6-[3-[2-[2-[[1-[2-[[1-[4-[[4-[4-[[ (2S) -3,3-dicyclopropyl-2-[ (2-methylpyrazole-3-carbonyl) amino]propanoyl]amino]phenyl]-5-methyl-1- (2-trimethylsilylethoxymethyl)pyrazol-3-yl]methoxy]butyl]triazol-4-yl]methoxy]acetyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]- 5,5-dimethyl-hexanoate：To a solution of methyl (2S) -5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-[[1- (2-prop-2-ynoxyacetyl)-4-piperidyl]oxy]ethylamino]ethoxy]phenoxy]pyridine-3-carbonyl]amino]hexanoate (65mg, 97.49 μmol, 1 eq) and N-[ (1S) -1-[[4-[3- (4-azidobutoxymethyl) -5-methyl-1- (2-trimethylsilylethoxymethyl) pyrazol-4-yl]phenyl]carbamoyl]-2,2-dicyclopropyl-ethyl]-2- methyl-pyrazole-3-carboxamide (67.26 mg, 97.49 μmol, 1 eq) in t-BuOH (1 mL) and H2O (1 mL) was added sodium; (2R) -2-[ (1S) -1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan- 3-olate (19.31 mg, 97.49 μmol, 1 eq) and copper;sulfate;pentahydrate (12.17 mg, 48.74 μmol, 11.70 μL, 0.5 eq), then the reaction was stirred for 1 hr at 50 °C. The reaction mixture was filtered and the filter was purified by reversed-phase HPLC (column: C18 20-35μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-75% @ 50 mL / min) to give methyl (2S) -2-[[6-[3-[2-[2-[[1-[2-[[1-[4-[[4-[4-[[ (2S) -3,3-dicyclopropyl-2-[ (2-methylpyrazole-3-carbonyl) amino]propanoyl]amino]phenyl]-5-methyl-1- (2-trimethylsilylethoxymethyl) pyrazol-3-yl]methoxy]butyl]triazol-4-yl]methoxy]acetyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoate (100 mg, 73.71 μmol, 75.61% yield) as a white solid. Data: LCMS (ESI+): m / z 1356.8 (M+H)+14. General procedure for preparation of methyl (2S) -2-[[6-[3-[2-[2-[[1-[2-[[1-[4-[[4-[4-[[ (2S) -3,3-dicyclopropyl-2-[ (2-methylpyrazole-3-carbonyl) amino]propanoyl]amino]phenyl]-5-methyl-1H-pyrazol-3- yl]methoxy]butyl]triazol-4-yl]methoxy]acetyl]-4-piperidyl]oxy]ethylamino]-2- oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： A solution of methyl (2S)-2-[[6-[3-[2-[2-[[1-[2-[[1-[4-[[4-[4-[[(2S) -3,3-dicyclopropyl-2-[(2- methylpyrazole-3-carbonyl)amino]propanoyl]amino]phenyl]-5-methyl-1-(2- trimethylsilylethoxymethyl) pyrazol-3-yl]methoxy]butyl]triazol-4-yl]methoxy]acetyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoate (100 mg, 73.71 μmol, 1 eq) in DCM (0.9 mL) and TFA (460.50 mg, 4.04 mmol, 0.3 mL, 54.79 eq) was stirred for 3 hr at 15 °C. The reaction was concentrated by N2to give methyl (2S) -2-[[6-[3-[2-[2-[[1-[2-[[1-[4-[[4-[4-[[ (2S) -3,3- dicyclopropyl-2-[ (2-methylpyrazole-3-carbonyl) amino]propanoyl]amino]phenyl]-5- methyl-1H-pyrazol-3-yl]methoxy]butyl]triazol-4-yl]methoxy]acetyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoate (90 mg, crude) as a yellow oil, which was used to next step without purification. Data: LCMS (ESI+): m / z 1226.7 (M+H)+15. General procedure for preparation of (2S) -2-[[6-[3-[2-[2-[[1-[2-[[1-[4-[[4-[4-[[(2S) -3,3-dicyclopropyl-2-[ (2-methylpyrazole-3-carbonyl) amino]propanoyl]amino]phenyl]-3-methyl-1H-pyrazol-5- yl]methoxy]butyl]triazol-4-yl]methoxy]acetyl]-4-piperidyl]oxy]ethylamino]-2- oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid: A solution of methyl (2S)-2-[[6-[3-[2-[2-[[1-[2-[[1-[4-[[4-[4-[[ (2S) -3,3-dicyclopropyl-2-[ (2- methylpyrazole-3-carbonyl) amino]propanoyl]amino]phenyl]-3-methyl-1H-pyrazol-5- yl]methoxy]butyl]triazol-4-yl]methoxy]acetyl]-4-piperidyl]oxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (90 mg, 73.38 μmol, 1 eq) and LiOH.H2O (6.16 mg, 146.77 μmol, 2 eq) in THF (0.5 mL) and H2O (0.5 mL) was stirred for 0.5 hr at 0°C. 1M HCl was added to the reaction until pH~6, the mixture was filtered and the filtrate was purified by prep-HPLC (neutral condition; column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [H2O (10mM NH4HCO3) -ACN]; gradient: 25%-55% B over 8.0 min) to give the compound X-008 (2S) -2-[[6-[3-[2-[2-[[1-[2-[[1-[4-[[4-[4-[[ (2S) -3,3-dicyclopropyl-2-[ (2-methylpyrazole-3- carbonyl) amino]propanoyl]amino]phenyl]-3-methyl-1H-pyrazol-5- yl]methoxy]butyl]triazol-4-yl]methoxy]acetyl]-4-piperidyl]oxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid (41.4 mg, 34.10 μmol, 46.46% yield, 99.85% purity) as a white solid. Data: LCMS (ESI+): m / z 1212.4 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.61 (d, J = 2.2 Hz, 1H), 8.23 (dd, J = 2.5, 8.6Hz, 1H), 8.13 - 8.07 (m, 0.5H), 7.89 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 2.1 Hz,1H), 7.38 - 7.30 (m, 3H), 6.98 (d, J = 8.7 Hz, 1H), 6.91 - 6.84 (m, 2H), 6.83 - 6.75 (m,2H), 4.91 (d, J = 7.2 Hz, 1H), 4.63 (s, 2H), 4.54 (s, 2H), 4.51 (dd, J = 5.1, 8.5 Hz, 1H),4.43 (s, 2H), 4.32 (t, J = 7.1 Hz, 2H), 4.22 (s, 2H), 4.09 (s, 3H), 3.75 - 3.67 (m, 1H), 3.56- 3.40 (m, 9H), 3.24 - 3.15 (m, 1H), 2.29 (s, 3H), 2.02 - 1.91 (m, 1H), 1.90 - 1.80 (m, 3H),1.79 - 1.71 (m, 2H), 1.55 - 1.44 (m, 4H), 1.39 - 1.29 (m, 2H), 0.91 (s, 9H), 0.88 - 0.74 (m,3H), 0.57 - 0.51 (m, 1H), 0.51 - 0.42 (m, 2H), 0.41 - 0.32 (m, 2H), 0.32 - 0.19 (m, 3H).X-023: (2S)-2-[[6-[3-[2-[2-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4- yl]methoxy]ethoxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoic acid1. General procedure for preparation of methyl (2S)-5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-(2-prop-2-ynoxyethoxy)ethylamino]ethoxy]phenoxy]pyridine-3- carbonyl]amino]hexanoate： To a solution of 2-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl-pentyl]carbamoyl]-2- pyridyl]oxy]phenoxy]aceticacid (600 mg, 1.07 mmol, 1 eq, TFA) and 2-(2-prop-2- ynoxyethoxy) ethanamine (123.06 mg, 859.45 μmol, 0.8 eq) in DMF (6 mL) was added HATU (816.97 mg, 2.15 mmol, 2 eq) and DIEA (694.23 mg, 5.37 mmol, 935.62 μL, 5 eq) at 0°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture was quenched by addition H2O 5 mL, and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~87% Ethyl acetate / Petroleum ethergradient @ 100 mL / min) to give methyl (2S)-5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-(2- prop-2-ynoxyethoxy)ethylamino]ethoxy]phenoxy]pyridine-3-carbonyl]amino]hexanoate (529 mg, 928.65 μmol, 86.44%yield) as a light brown oil. Data: LCMS (ESI+): m / z 570.3 (M+H)2. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]ethoxy]ethylamino]-2- oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-5, 5-dimethyl-2-[[6-[3-[2-oxo-2-[2-(2-prop-2- ynoxyethoxy)ethylamino]ethoxy]phenoxy]pyridine-3-carbonyl]amino]hexanoate (99.36 mg, 174.43 μmol, 1.2 eq), 2-(6-azidohexyl)-N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3, 5- dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole-3- carboxamide (100 mg, 145.36 μmol, 1 eq) in t-BuOH (1 mL) and H2O (1 mL) was added sodium; (2R)-2-[(1S)-1, 2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (28.80 mg, 145.36 μmol, 1eq) and copper; sulfate (11.60 mg, 72.68 μmol, 11.15 μL, 0.5 eq), then the reaction was stirred for 3 hr at 50°C. The product was purified by reversed-phase HPLC (column: C1820-35um 100A 80g; mobile phase: [water-ACN]; B%: 0%-89% @ 80mL / min) to give methyl (2S)-2-[[6-[3-[2-[2-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2- [4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]ethoxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (150mg, 119.28 μmol, 82.06% yield) as a yellow oil. Data: LCMS (ESI+): m / z 688.5 (M+H)3. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2- oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4- yl]methoxy]ethoxy]ethylamino]-2-oxoethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate： A solution of methyl (2S)-2-[[6-[3-[2-[2-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4- [3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]ethoxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5, 5-dimethyl-hexanoate (150 mg, 119.28 μmol, 1 eq) in DCM (1 mL) and TFA (0.5 mL) was stirred for 1 hr at 25°C. The mixture was concentrated and was adjusted with NH3.H2O to pH=7. The mixture was diluted with water 10 mL, and then extracted with methylene dichlorid (5 mL * 3). The combined organic layers were washed with sat. NaCl 10mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl (2S)-2-[[6-[3-[2-[2-[2-[[1-[6-[5- [[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]ethoxy]ethylamino]-2- oxoethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (134 mg, 118.86 μmol, 99.66% yield) as a yellow solid. Data: LCMS (ESI+): m / z 1128.5 (M+H)4. General procedure for preparation of (2S)-2-[[6-[3-[2-[2-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]ethoxy]ethylamino]-2- oxoethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[2-[2-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4- (3,5-dimethyl-1Hpyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4- yl]methoxy]ethoxy]ethylamino]-2-oxoethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoate (134 mg, 118.86 μmol, 1 eq) in H2O (1 mL)and THF (1 mL) was added LiOH.H2O (9.98 mg, 237.73 μmol, 2 eq), then the reaction was stirred for 1 hr at 25°C. The residue was adjusted with FA to pH=5. The mixture was filtered and the filtrate was purified by prep-HPLC (neutral condition; column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 30%- 60%B over 8.0 min) to give (2S)-2-[[6-[3-[2-[2-[2-[[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)- 2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]hexyl]triazol-4-yl]methoxy]ethoxy]ethylamino]-2-oxoethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid (X-023) (30.7 mg, 27.58 μmol, 23.20% yield,100%purity) as a white solid. Data: LCMS (ESI+): m / z 1113.4 (M+H)1H NMR (400 MHz, DMSO-d6) δ = 10.43 - 10.24 (s, 1H), 8.66 - 8.58 (m, 2H), 8.52 (brd, J = 6.1 Hz, 1H), 8.27 (dd, J = 2.4, 8.6 Hz, 1H), 8.11 (br t, J = 5.6 Hz, 1H), 8.01 (s, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 2.0 Hz, 1H), 7.33(t, J = 8.1 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 1.8,8.1Hz, 1H), 6.79 - 6.74 (m, 2H), 4.87 - 4.77 (m, 1H), 4.54 - 4.38 (m, 6H), 4.29 - 4.19(m, 3H), 3.50 (br d, J = 3.5 Hz,4H), 3.43 - 3.41 (m, 2H), 3.27 (br d, J = 5.7 Hz, 2H),2.17 (s, 6H), 1.79 (br dd, J = 5.9, 11.7 Hz, 1H), 1.75 - 1.62 (m,5H), 1.31 - 1.15 (m, 6H),0.85 (s, 9H), 0.80 (br d, J = 5.7 Hz, 3H), 0.51 - 0.41 (m, 1H), 0.40 - 0.32 (m, 2H), 0.30 -0.10 (m, 5H) X-038: (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo- ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxoethyl]triazol-4- yl]methoxy]ethoxy]propylcarbamoyl] azetidin-3-yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate ： A mixture of methyl (2S)-5,5-dimethyl-2-[[6-[3-[1-[3-(2-prop-2- ynoxyethoxy)propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3-carbonyl]amino] hexanoate (65 mg, 104.05 μmol, 1 eq), 2-[3-[(2-azidoacetyl)amino]propyl]-N-[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]pyrazole-3-carboxamide (73.14 mg, 104.05 μmol, 1 eq), copper;sulfate (8.30 mg, 52.02 μmol, 7.98 μL, 0.5 eq), sodium;(2R)-2-[(1S)-1,2- dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (20.61 mg, 104.05 μmol, 1 eq) in t- BuOH (2 mL) and H2O (0.5 mL) was degassed and purged with N23 times, and then the mixture was stirred at 50°C for 0.5 h under N2atmosphere. Several new peaks were shown on LC-MS and 61% of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: C1820-35um 100A 40g; mobile phase: [water-ACN]; B%: 0%-60% @ 60mL / min) to give methyl (2S)-2-[[6-[3-[1-[3-[2-[[1- [2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]propylamino]-2-oxoethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (80 mg, 60.26 μmol, 57.91% yield) as a white solid. Data: LCMS (ESI+): m / z 1328.7 (M+H)2. General procedure for preparation of methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2- oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2- [4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxoethyl]triazol-4-yl]methoxy]ethoxy] propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl- hexanoate (80 mg, 60.26 μmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 223.41 eq). The mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3- [5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (140 mg, crude) as yellow oil.Data: LCMS (ESI+): m / z 1197.7 (M+H)3. General procedure for preparation of (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2- [4-(3,5-dimethyl-1Hpyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]propylamino]-2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (130 mg, 108.57 μmol, 1 eq) in THF (1 mL) and H2O (1 mL) was added LiOH.H2O (9.11 mg, 217.14 μmol, 2 eq) at 0°C. The mixture was stirred at 20°C for 1.5 h. The THF was removed under reduced pressure and the residue acidize with FA to pH=2. The mixture was filtered andthe filtrate was purified by prep-HPLC (FA condition:HPLC: column: 3_PhenomenexLuna C1875*30mm*3um;mobile phase: [H2O(0.2% FA)-ACN];gradient:35%-65% B over 8.0 min) to give (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5- dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2- oxo-ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid (20.5 mg, 16.91 μmol, 15.57% yield, 97.604% purity) as a white solid. Data: LCMS (ESI+): m / z 1184.6 (M+H)1H NMR (400 MHz, METHANOL-d4) δ ppm 8.61 (d, J=2.32 Hz, 1 H) 8.20 - 8.28 (m, 2 H)7.97 (s, 1 H) 7.66 (d, J=8.68 Hz, 2 H) 7.53 (d, J=2.08 Hz, 1 H) 7.33 (t, J=8.25 Hz, 1 H) 7.25 (d, J=8.56 Hz, 2 H) 6.97 (d, J=8.68 Hz, 1 H) 6.88 (d, J=2.08 Hz, 1 H) 6.73 (ddd,J=15.04, 8.31, 1.71 Hz, 2 H) 6.65 (t, J=2.26 Hz, 1 H) 5.09 (s, 2 H) 4.94 - 5.01 (m, 1 H)4.89 (br s, 1 H) 4.56 - 4.64 (m, 3 H) 4.47 - 4.56 (m, 2 H) 4.24 - 4.32 (m, 2 H) 3.88 (dd,J=9.23, 3.85 Hz, 2 H) 3.61 - 3.66 (m, 2 H) 3.54 - 3.59 (m, 2 H) 3.44 - 3.53 (m, 2 H) 3.11- 3.23 (m, 4 H) 2.27 (s, 6 H) 1.99 - 2.08 (m, 2 H) 1.91 - 1.99 (m, 1 H) 1.76 - 1.88 (m, 1 H)1.71 (quin, J=6.39 Hz, 2 H) 1.27 - 1.43 (m, 2 H) 0.91 (s, 9 H) 0.75 - 0.90 (m, 3 H) 0.56(dt, J=8.16, 4.29 Hz, 1 H) 0.43 - 0.52 (m, 2 H) 0.34 - 0.43 (m, 2 H) 0.28 (ddt, J=13.89,9.46, 4.95, 4.95 Hz, 3 H) X-043: (2S)-2-[[6-[3-[2-[2-[[1-[3-[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4- yl]propylsulfonyl]-4-piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of methyl (2S)-5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-[(1-pent-4-ynylsulfonyl-4- piperidyl)oxy]ethylamino]ethoxy]phenoxy]pyridine-3- carbonyl]amino]hexanoate： To a solution of 2-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl-pentyl]carbamoyl]-2- pyridyl]oxy]phenoxy]acetic acid (718.97 mg, 1.29 mmol, 1 eq, TFA), 2-[(1-pent-4- ynylsulfonyl-4-piperidyl)oxy]ethanamine (0.5 g, 1.29 mmol, 1 eq, TFA) in DMF (5 mL) was added DIEA (499.13 mg, 3.86 mmol, 672.69 μL, 3 eq) and HATU (1.47 g, 3.86 mmol, 3 eq) at 0°C. The mixture was stirred at 25°C for 0.5 hr. The mixture was filtered and the filtrate was purified by reversed-phase HPLC (column: C1820-35μm 100A 120 g; mobile phase: [water-ACN]; B%:0%-70% @100 mL / min) to give methyl (2S)-5,5- dimethyl-2-[[6-[3-[2-oxo-2-[2-[(1-pent-4-ynylsulfonyl-4- piperidyl)oxy]ethylamino]ethoxy]phenoxy]pyridine-3-carbonyl]amino]hexanoate (370 mg, 527.94 μmol, 41.01% yield) as a colorless oil.2. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[[1-[3-[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl) pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4- yl]propylsulfonyl]-4-piperidyl]oxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-[(1-pent-4-ynylsulfonyl-4- piperidyl)oxy]ethylamino]ethoxy]phenoxy]pyridine-3-carbonyl]amino]hexanoate (0.32 g, 456.59 μmol, 1 eq), 2-(6-azidohexyl)-N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl- 1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole-3- carboxamide (314.11 mg, 456.59 μmol, 1 eq) in t-BuOH (1 mL) and H2O (1 mL) was added copper;sulfate (36.44 mg, 228.30 μmol, 35.04 μL, 0.5 eq) and sodium;(2R)-2- [(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (90.45 mg, 456.59 μmol, 1 eq). The mixture was stirred at 50 °C for 1 hr. The mixture was filtered and the filtrate was purified by reversed-phase HPLC (column: C18 20-35 μm 100A 120 g; mobile phase: [water-ACN]; B%:0%-70% @100 mL / min) to give methyl (2S)-2-[[6-[3-[2-[2-[[1- [3-[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]hexyl]triazol-4-yl]propylsulfonyl]-4-piperidyl]oxy] ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (0.5 g, 360.03 μmol, 78.85% yield) as a white solid. Data: LCMS (ESI+): m / z 1389.9 (M+H)+3. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[[1-[3-[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2- oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]propylsulfonyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]- 5,5-dimethyl-hexanoate： To a solution of methyl (2S)-2-[[6-[3-[2-[2-[[1-[3-[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2- [4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]propylsulfonyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoate (0.49 g, 352.83 μmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 38.16 eq). The mixture was stirred at 25 °C for 12 hr. The DCM and TFA was removed under reduced pressure to give methyl (2S)-2-[[6-[3-[2-[2-[[1-[3-[1-[6- [5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]propylsulfonyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoate (1 g, crude, TFA) as a colorless oil.4. General procedure for preparation of (2S)-2-[[6-[3-[2-[2-[[1-[3-[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]propylsulfonyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]- 5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[2-[2-[[1-[3-[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2- [4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]hexyl]triazol-4-yl]propylsulfonyl]-4-piperidyl]oxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (0.9 g, 655.71 μmol, 1 eq, TFA) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (82.55 mg, 1.97 mmol, 3 eq). The mixture was stirred at 0 °C for 1 hr. The water layer was acidified by FA (1 M) till pH=4. The mixture was filtered and the filtrate was purified by prep-HPLC (neutral condition: column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:25%-55% B over 8.0 min) to give (2S)-2- [[6-[3-[2-[2-[[1-[3-[1-[6-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol- 4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]propylsulfonyl]-4- piperidyl]oxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoic acid (193.4 mg, 155.40 μmol, 23.70% yield, 100% purity) as a white solid. Date: LCMS (ESI+): m / z 1244.6 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.62 (d, J = 2.4 Hz, 1H), 8.23 (dd, J = 2.5, 8.6Hz, 1H), 8.15 - 8.10 (m, 1H), 7.70 (s, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 2.1 Hz,1H), 7.34 (t, J = 8.2 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 1H), 6.89 -6.85 (m, 2H), 6.82 - 6.74 (m, 2H), 4.89 (br s, 1H), 4.59 - 4.42 (m, 5H), 4.26 (t, J = 7.0 Hz,2H), 3.57 - 3.50 (m, 2H), 3.46 - 3.40 (m, 3H), 3.39 - 3.32 (m, 2H), 3.06 (ddd, J = 3.6, 7.8,11.9 Hz, 2H), 3.00 - 2.95 (m, 2H), 2.78 (t, J = 7.4 Hz, 2H), 2.22 (s, 6H), 2.07 (quin, J =7.5 Hz, 2H), 2.01 - 1.91 (m, 1H), 1.88 - 1.73 (m, 7H), 1.63 - 1.52 (m, 2H), 1.42 - 1.21 (m,6H), 0.90 (s, 9H), 0.86 (br d, J = 5.4 Hz, 3H), 0.59 - 0.51 (m, 1H), 0.50 - 0.44 (m, 2H),0.43 - 0.35 (m, 2H), 0.32 - 0.22 (m, 3H)X-049: (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl] azetidin-3-yl]oxyethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoic acid1. General procedure for preparation of methyl 2-[3-(tert-butoxycarbonylamino)propyl]pyrazole-3-carboxylate： A mixture of tert-butyl N-(3-hydroxypropyl)carbamate (10 g, 57.07 mmol, 9.76 mL, 1 eq), methyl 1H-pyrazole-5-carboxylate (7.20 g, 57.07 mmol, 1 eq) and PPh3(19.46 g, 74.19 mmol, 1.3 eq) in THF (300 mL) was degassed and purged with N2for 3 times, then DEAD (12.92 g, 74.19 mmol, 13.49 mL, 1.3 eq) was added at 0°C dropwise, and then the mixture was stirred at 20°C for 12 hr under N2atmosphere. The reaction mixture was quenched by addition H2O 200 mL and extracted with EA 600mL (200mL * 3). The combined organic layers were washed with brine 300 mL (100 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash® Silica Flash Column, Eluent of 0~31% Ethyl acetate / Petroleum ether gradient @ 100mL / min) to give methyl 2-[3-(tert-butoxycarbonylamino)propyl] pyrazole-3-carboxylate (15.2 g, 53.65 mmol, 94.01% yield) as a colorless oil. Data: LCMS (ESI+): m / z 284.1 (M+H)+1HNMR: 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.50 (d, J = 2.0 Hz, 1H), 6.88 - 6.80(m, 1H), 4.98 (br s, 1H), 4.64 (t, J = 6.6 Hz, 2H), 3.89 (s, 3H), 3.07 (q, J = 6.1 Hz, 2H), 2.03 (quin, J = 6.5 Hz, 2H), 1.45 (s, 9H)2. General procedure for preparation of methyl 2-(3-aminopropyl)pyrazole-3-carboxylate： To a solution of methyl 2-[3-(tert-butoxycarbonylamino)propyl]pyrazole-3-carboxylate (15 g, 52.94 mmol, 1 eq) in DCM (150 mL) was added TFA (50 mL). The mixture was stirred at 20 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give compound methyl 2-(3-aminopropyl)pyrazole-3-carboxylate (15 g, crude, TFA) as a yellow oil. Data: LCMS (ESI+): m / z 184.1 (M+H)+3. General procedure for preparation of methyl 2-[3-[(2-azidoacetyl)amino]propyl]pyrazole-3-carboxylate： To a solution of methyl 2-(3-aminopropyl)pyrazole-3-carboxylate (2 g, 6.73 mmol, 1 eq, TFA) and 2-azidoacetic acid (680.04 mg, 6.73 mmol, 1 eq) in DMF (40 mL) was added HATU (5.12 g, 13.46 mmol, 2 eq) and DIEA (1.74 g, 13.46 mmol, 2.34 mL, 2 eq) at 0°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture was quenched by addition H2O 50mL and extracted with EA 150 mL (50 mL * 3). The combined organic layers were washed with brine 150 mL (50 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~69% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give compound methyl 2-[3-[(2- azidoacetyl)amino]propyl]pyrazole-3-carboxylate (2 g, crude) as a yellow oil. Data: LCMS (ESI+): m / z 267.1 (M+H)+1HNMR: 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.52 (d, J = 1.9 Hz, 1H), 6.85 (d, J= 1.9 Hz, 1H), 4.65 (t, J = 6.4 Hz, 2H), 3.96 (s, 2H), 3.89 (s, 3H), 3.25 (q, J = 6.2 Hz, 2H),2.13 - 2.04 (m, 2H)4. General procedure for preparation of 2-[3-[(2-azidoacetyl)amino]propyl]pyrazole-3-carboxylic acid： To a solution of methyl 2-[3-[(2-azidoacetyl)amino]propyl]pyrazole-3-carboxylate (1.5 g, 5.63 mmol, 1 eq) in THF (10 mL) and H2O (10 mL) was added LiOH.H2O (472.82 mg, 11.27 mmol, 2 eq). The mixture was stirred at 15 °C for 1 hr. The THF was removed under reduced pressure and the residue was acidified by 2M HCl until pH=4. The mixture was purified by prep-HPLC (column: C1820-40 um 100 A 330 g; mobile phase: [water- ACN]; B%: 0%-5% @ 100 mL / min) to give Compound 2-[3-[(2- azidoacetyl)amino]propyl]pyrazole-3-carboxylic acid (570 mg, 2.26 mmol, 40.11% yield) as a colorless oil. Data: LCMS (ESI+): m / z 253.1 (M+H)+5. General procedure for preparation of 3,5-dimethyl-4-(4-nitrophenyl)-1H-pyrazole： A mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.43 g, 33.47mmol, 1 eq), 1-iodo-4-nitro-benzene (10 g, 40.16 mmol, 1.2 eq), cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron (2.73 g, 3.35 mmol, 0.1 eq) and K2CO3(11.56 g, 83.67 mmol, 2.5 eq) in dioxane (200 mL) and H2O (20 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 36 hr under N2atmosphere. The reaction mixture was cooled to 20°C and diluted with water 70 mL, and then extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were washed with sat.NaCl (2*100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 2 / 1) to give compound 3,5-dimethyl-4-(4-nitrophenyl)-1H-pyrazole (5 g, 23.02 mmol, 68.78% yield) as a light yellow solid. Data:1H NMR (400 MHz, DMSO-d6) δ = 12.54 (br s, 1H), 8.41 - 8.10 (m, 2H), 7.64 - 7.47 (m,2H), 2.26 (br s, 6H)6. General procedure for preparation of 2-[[3,5-dimethyl-4-(4-nitrophenyl)pyrazol-1-yl]methoxy]ethyltrimethyl-silane To a stirred solution of 3,5-dimethyl-4-(4-nitrophenyl)-1H-pyrazole (5 g, 23.02mmol, 1 eq) in DMF (60 mL) was added NaH (1.84 g, 46.04 mmol, 60% purity, 2 eq) at 0 °C, then the reaction was stirred for 0.5 hr at 0°C, SEMCl (5.76 g, 34.53 mmol, 6.11 mL, 1.5 eq) was added at 0°C, then the reaction was stirred for 1 hr at 20°C. The mixture was quenched with saturated NH4Cl solution(100 mL) at 0°C and extracted with EtOAc 450 mL (150 mL *3) . The combined organic layers were washed with sat.NaCl (100 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.The residue was purified by column chromatography (SiO2, Petroleum ether / Ethylacetate=10 / 1 to 7 / 1) to give compound 2-[[3,5-dimethyl-4-(4-nitrophenyl)pyrazol-1- yl]methoxy]ethyltrimethyl-silane (7.5 g, 21.58 mmol, 93.77% yield) as a light yellow oil. Data:1H NMR (400 MHz, DMSO-d6) δ = 8.27 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 5.39(s, 2H), 3.57 (t, J = 7.9Hz, 2H), 2.33 (s, 3H), 2.21 (s, 3H), 0.88 - 0.83 (m, 2H), -0.04 (s,9H)7. General procedure for preparation of 4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]aniline To a solution of 2-[[3,5-dimethyl-4-(4-nitrophenyl)pyrazol-1-yl]methoxy]ethyl-trimethyl- silane (7.5 g, 21.58 mmol, 1 eq) in EtOH (80 mL) and H2O (16 mL) was added Fe(6.03 g, 107.92 mmol, 5 eq) and NH4Cl (5.77 g, 107.92 mmol, 5 eq). The mixture was stirred at 50°C for 2 hr. The reaction mixture was cooled to 20 °C, filtered and the filtrate was concentrated under reduced pressure, the mixture was diluted with water 70 mL, and then extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were washed with sat.NaCl (2*100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 2 / 1) to give compound 4-[3,5-dimethyl-1- (2-trimethylsilylethoxymethyl)pyrazol-4-yl]aniline (5.5 g, 17.32 mmol, 80.26% yield) as a yellow solid. Data:1H NMR (400 MHz, DMSO-d6) δ = 6.90 (d, J = 8.3 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 5.30 (s, 2H), 5.05 (s, 2H), 3.54(t, J = 7.9 Hz, 2H), 2.20 (s, 3H), 2.09 (s, 3H), 0.83 (t, J = 7.9 Hz, 2H), -0.04 (s, 9H)8. General procedure for preparation of tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamate： To a solution of 4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]aniline (1.89 g, 5.94 mmol, 1 eq), (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid (1.6 g, 5.94 mmol, 1 eq) in DMF (40 mL) was added HATU (4.52 g, 11.88 mmol, 2 eq) and DIEA (1.54 g, 11.88 mmol, 2.07 mL, 2 eq) at 0°C. The mixture was stirred at 15°C for 1hr. The mixture was quenched with saturated H2O solution (50 mL) and extracted with EA 150mL (50 mL *3), washed with brine 150 mL (50mL *3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give compound tert-butyl N-[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]carbamate (2.8 g, 4.92 mmol, 82.86% yield) as a colorless oil. Data:1H NMR (400 MHz, DMSO-d6) δ = 9.93 (s, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.82 (br d, J = 9.1 Hz, 1H), 5.34 (s, 2H), 4.30 (br s, 1H), 3.55 (t, J = 7.9 Hz, 2H),2.25 (s, 3H), 2.13 (s, 3H), 1.37 (br s, 9H), 0.88 - 0.81 (m, 3H), 0.79 - 0.72 (m, 1H), 0.56(br d, J = 7.0 Hz, 1H), 0.48 - 0.42 (m, 1H), 0.37 - 0.23 (m, 3H), 0.18 (td, J = 4.7, 8.9 Hz,4H), -0.02 - -0.06 (m, 9H)9. General procedure for preparation of (2S)-2-amino-3,3-dicyclopropyl-N-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]propanamide： A solution of tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamate (2.7 g, 4.75 mmol, 1 eq) in 4M HCl / MeOH (30 mL) was stirred at 15°C for 2 hr. The solution was concentrated under reduced pressure to give compound (2S)-2-amino-3,3-dicyclopropyl- N-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]propanamide (2.1 g, crude, HCl) as a light yellow solid. Data: LCMS (ESI+): m / z 469.5 (M+H)+10. General procedure for preparation of 2-[3-[(2-azidoacetyl)amino]propyl]-N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole-3- carboxamide To a solution of 2-[3-[(2-azidoacetyl)amino]propyl]pyrazole-3-carboxylic acid (434.39 mg, 1.72 mmol, 1 eq) and (2S)-2-amino-3,3-dicyclopropyl-N-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]propanamide (870 mg, 1.72 mmol, 1 eq, HCl) in DMF (15 mL) was added HATU (1.31 g, 3.44 mmol, 2 eq) and DIEA (667.75 mg, 5.17 mmol, 899.93 μL, 3 eq) at 0°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture was quenched by addition H2O 20 mL and extracted with EA 45 mL (15 mL *3). The combined organic layers were washed with brine 45 mL (15mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give compound 2-[3-[(2-azidoacetyl)amino]propyl]-N-[(1S)-1-(dicyclopropylmethyl)-2- [4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]pyrazole-3-carboxamide (930 mg, 1.32 mmol, 76.82% yield) as a white solid. Data: LCMS (ESI+): m / z 703.5 (M+H)+1H NMR (400 MHz, CHLOROFORM-d) δ = 8.07 (s, 1H), 7.60 (d, J = 8.6 Hz, 2H), 7.56(d, J = 2.0 Hz, 1H), 7.40 - 7.32 (m, 1H), 7.24 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.2 Hz, 1H),6.62 (d, J = 2.0 Hz, 1H), 5.40 (s, 2H), 4.85 (dd, J = 5.0, 8.2 Hz, 1H), 4.75 - 4.66 (m, 1H),4.61 - 4.50 (m, 1H), 3.91 (s, 2H), 3.67 - 3.59 (m, 2H), 3.23 (br d, J = 6.1 Hz, 2H), 2.31 (s,3H), 2.26 - 2.21 (m, 3H), 2.16 - 2.08 (m, 2H), 1.02 - 0.90 (m, 3H), 0.89 - 0.78 (m, 2H),0.67 (dt, J = 4.0, 8.4 Hz, 1H), 0.62 - 0.52 (m, 3H), 0.46 - 0.34 (m, 2H), 0.28 (br d, J = 3.7Hz, 2H), -0.01 (s, 9H)11. General procedure for preparation of (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-[1-(2-prop-2- ynoxyacetyl)azetidin-3-yl]oxyethylamino]ethoxy]phenoxy]pyridine-3- carbonyl]amino]hexanoate (90 mg, 140.91 μmol) and 2-[3-[(2-azidoacetyl)amino]propyl]- N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl) pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole-3-carboxamide (79.24 mg, 112.73 μmol) in DMSO (1 mL) was added cuprous;acetonitrile;hexafluorophosphate (194.32 mg, 521.37 μmol). The mixture was stirred at 20°C for 1 hr. The mixture was filtered and the filtrate was purified by reversed-phase-HPLC(column: C1820-35um 100A 330g; mobile phase: [water-ACN]; B%: 0%-65% @ 100mL / min) to give the compound methyl (2S)-2-[[6-[3-[2- [2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]propylamino]-2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2- oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (22 mg, 16.40 μmol, 11.64% yield) as a white solid. Data: LCMS (ESI+): m / z 1341.6 (M+H)+12. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2- oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (22 mg, 16.40 μmol) in DCM (0.1 mL) was added TFA (30.70 mg, 269.24 μmol, 0.02 mL). The mixture was stirred at 0 °C for 0.5 hr. The mixture concentrated under reduced pressure to give the compound methyl (2S)- 2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (20 mg, 15.09 μmol, 92.02% yield, TFA) as a yellow oil. Data: LCMS (ESI+): m / z 606.6 (M / 2+H)+13. General procedure for preparation of (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4-yl]methoxy]acetyl] azetidin-3-yl]oxyethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoate (35 mg, 26.41 μmol, TFA) in THF (0.1 mL) and H2O (0.1 mL) was added LiOH.H2O (2.22 mg, 52.81 μmol). The mixture was stirred at 0 °C for 0.5 hr. The mixture was filtered and the filtrate was purified by prep-HPLC(column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:19%- 49% B over 8.0 min) to give the compound X-049 (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5- [[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4-yl]methoxy]acetyl] azetidin-3-yl]oxyethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoic acid (5.1 mg, 4.19 μmol, 15.87% yield, 98.38% purity) as a white solid. Data: LCMS (ESI+): m / z 1197.5 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.61 (d, J = 2.4 Hz, 1H), 8.23 (dd, J = 2.5, 8.7Hz, 1H), 8.03 (s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.37 - 7.30 (m,1H), 7.22 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.7 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.81 (t, J =2.1 Hz, 1H), 6.79 - 6.74 (m, 1H), 5.11 (s, 2H), 4.87 (br d, J = 7.4 Hz, 1H), 4.64 - 4.57 (m,3H), 4.56 - 4.48 (m, 4H), 4.37 - 4.31 (m, 1H), 4.29 - 4.23 (m, 1H), 4.13 (br d, J = 10.0 Hz,1H), 4.05 - 3.98 (m, 3H), 3.79 - 3.72 (m, 1H), 3.49 - 3.43 (m, 4H), 3.23 - 3.11 (m, 2H),2.22 (s, 6H), 2.08 - 1.92 (m, 3H), 1.87 - 1.75 (m, 1H), 1.41 - 1.28 (m, 2H), 0.90 (s, 9H),0.90 - 0.71 (m, 3H), 0.60 - 0.53 (m, 1H), 0.52 (br s, 2H), 0.43 - 0.35 (m, 2H), 0.33 - 0.22(m, 3H). X-059: (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5-[[(S)-(4,4-difluorocyclohexyl)-[7-[(1S)-2- methoxy-1-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]ethyl]imidazo[1,2-b]pyridazin- 2-yl]methyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of methyl 2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexylidene)acetate： The reaction was set up in 5 parallel batches. To a solution of methyl 2-(benzyloxycarbonylamino)-2-dimethoxyphosphoryl-acetate (8 g, 24.15 mmol, 1 eq) in NMP (200 mL) was added DBU (3.68 g, 24.15 mmol, 3.64 mL, 1 eq) at 0 °C, then the reaction was stirred for 0.5 hr, and then 4,4-difluorocyclohexanone (4.05 g, 30.19 mmol, 1.25 eq) in NMP (50 mL) was added in the mixture. The mixture was stirred at 15 °C for 3 hr. The mixture was quenched with saturated H2O solution (300 mL) at 0 °C and extracted with EtOAc 900 mL (300 mL *3), washed by brine 900 mL (300 mL *3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to give compound methyl 2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexylidene)acetate (40 g, 117.88 mmol, 97.62% yield) as a white solid. Data:1H NMR (400 MHz, DMSO-d6) δ = 7.42 - 7.29 (m, 5H), 5.11 - 5.03 (m, 2H), 3.63 (s, 3H),2.61 (br t, J = 6.3 Hz, 2H), 2.37 (br t, J = 6.3 Hz, 2H), 2.00 - 1.93 (m, 4H)2. General procedure for preparation of methyl 2-amino-2-(4,4-difluorocyclohexyl)acetate： The reaction was set up in 2 parallel batches. To a solution of methyl 2-(benzyloxycarbonylamino)-2-(4,4- difluorocyclohexylidene)acetate (8 g, 23.58 mmol, 1 eq) in EtOAc (50 mL) was added Pd / C (3.76 g, 3.54 mmol, 10% purity, 0.15 eq) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 20 °C for 6 hr. The combined reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound methyl 2-amino-2-(4,4- difluorocyclohexyl)acetate (12 g, crude) as a colorless oil.3. General procedure for preparation of methyl 2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetate： The reaction was set up in 2 parallel batches. To a solution of methyl 2-amino-2-(4,4-difluorocyclohexyl)acetate (6 g, 28.96 mmol, 1 eq) in DCM (90 mL) was added TEA (5.86 g, 57.91 mmol, 8.06 mL, 2 eq) and CbzCl (7.41 g, 43.43 mmol, 6.20 mL, 1.5 eq) at 0 ℃. The mixture was stirred at 20 °C for 4 hr. The mixture was acidified with HCl (2 M) until pH = 5~6 at 0 ℃. Then the mixture was extracted with DCM 450 mL (150 mL * 3). The combined organic layers were washed with sat. NaCl 300 mL (150 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 4 / 1, TLC, PE / EA = 3 : 1 showed the spot with Rf = 0.5 was the desired product) to give compound methyl 2- (benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetate (10 g, crude) as a colorless oil. The crude product was purified by reversed-phase HPLC (column: C1820-40 um 100 A 330 g; mobile phase: [water-ACN]; B%: 0%-85% @ 100 mL / min) to give compound methyl 2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetate (5.5 g, 16.11 mmol, 55.00% yield) as a colorless oil. Data:1H NMR (400 MHz, DMSO-d6) δ = 7.82 (br d, J = 8.2 Hz, 1H), 7.40 - 7.30 (m, 5H), 5.04(s, 2H), 4.09 - 4.05 (m, 1H), 3.64 (s, 3H), 2.04 - 2.00 (m, 1H), 1.93 - 1.82 (m, 2H), 1.81 -1.69 (m, 2H), 1.66 (br d, J = 8.9 Hz, 2H), 1.45 - 1.33 (m, 1H), 1.32 - 1.23 (m, 1H)4. General procedure for preparation of 2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid： To a solution of methyl 2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetate (5.5 g, 16.11 mmol, 1 eq) in THF (55 mL) and H2O (55 mL) was added LiOH.H2O (1.35 g, 32.23 mmol, 2 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hr. The mixture was acidified with HCl (1 M) until Ph = 5~6. Then the mixture was extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were washed with sat. NaCl 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 2 / 1, TLC, PE / EA = 3:1 showed the spot with Rf = 0.2 was the desired product) to give compound 2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid (3.3 g, 10.08 mmol, 62.57% yield) as a white solid.5. General procedure for preparation of tert-butyl 4-(benzyloxycarbonylamino)-4-(4,4-difluorocyclohexyl)-3-oxo-butanoate： To a solution of 2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid (2.8 g, 8.55 mmol, 1 eq) in THF (45 mL) was added CDI (1.53 g, 9.41 mmol, 1.1 eq) at 20 °C, the mixture was stirred at 20 °C for 1.5 h (solution A) . To a solution of tert-butyl acetate (3.18 g, 27.37 mmol, 3.67 mL, 3.2 eq) in THF (45 mL) was added LiHMDS (1 M, 27.37 mL, 3.2 eq) at -70 °C under N2 atmosphere, it was stirred at -70 °C for 1 h, then solution A was added into the above mixture at -70 °C under N2 atmosphere. The resulting mixture was stirred at -70 °C for 1 h. The reaction mixture was added into ice sat. NH4Cl solution 200 mL and then extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 100 mL / min, Petroleum ether : Ethyl acetate = 3 : 1) to give compound tert-butyl 4-(benzyloxycarbonylamino)-4-(4,4-difluorocyclohexyl)-3- oxo-butanoate (2.75 g, crude) as a yellow oil. Data: LCMS (ESI-): m / z 424.2 (M-H)-1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H) 1.52 (br d, J=15.65 Hz, 1 H) 1.62 -1.87 (m, 4 H) 1.99 (s, 4 H) 3.46 - 3.59 (m, 2 H) 4.16 (dd, J=8.62, 6.17 Hz, 1 H) 5.03 -5.06 (m, 2 H) 7.31 - 7.39 (m, 5 H) 7.81 (d, J=8.68 Hz, 1 H)6. General procedure for preparation of tert-butyl 4-(benzyloxycarbonylamino)-2-bromo-4-(4,4-difluorocyclohexyl)-3-oxo-butanoate： To a solution of tert-butyl 4-(benzyloxycarbonylamino)-4-(4,4-difluorocyclohexyl)-3-oxo- butanoate (2.75 g, 6.46 mmol, 1 eq) in MeOH (65 mL) was added 2,6-dimethylpyridine (55.41 mg, 517.08 μmol, 60.22 μL, 0.08 eq) and NBS (1.06 g, 5.95 mmol, 0.92 eq) at 20 °C. The mixture was stirred at 20 °C for 2 hr. The reaction mixture was added into ice water 200 mL and then extracted with EtOAc 400 mL (200 mL * 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 100 mL / min, Petroleum ether : Ethyl acetate = 3 : 1) to give compound tert-butyl 4-(benzyloxycarbonylamino)-2-bromo-4-(4,4- difluorocyclohexyl)-3-oxo-butanoate (2.55 g, crude) as a light yellow oil. Data: LCMS (ESI-): m / z 502.2 (M-H)-1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (d, J=3.42 Hz, 9 H) 1.41 - 1.91 (m, 5 H) 1.95- 2.17 (m, 4 H) 4.44 - 4.54 (m, 1 H) 5.00 - 5.12 (m, 2 H) 5.59 - 5.73 (m, 1 H) 7.30 - 7.40(m, 5 H) 7.92 (dd, J=9.41, 3.30 Hz, 1 H)7. General procedure for preparation of benzyl N-[3-bromo-1-(4,4-difluorocyclohexyl)-2-oxo-propyl]carbamate： To a solution of tert-butyl 4-(benzyloxycarbonylamino)-2-bromo-4-(4,4- difluorocyclohexyl)-3-oxo-butanoate (2.55 g, 5.06 mmol, 1 eq) in Tol. (30 mL) was added TFA (3.25 mL) at 20 °C. The mixture was stirred at 80 °C for 2 h. The reaction mixture was added into water 50 mL and then extracted with EtOAc 80 mL (40 mL * 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 100 mL / min, Petroleum ether : Ethyl acetate = 3 : 1) to give compound benzyl N-[3-bromo-1-(4,4-difluorocyclohexyl)-2-oxo- propyl]carbamate (1.6 g, 3.96 mmol, 78.28% yield) as a white solid.8. General procedure for preparation of benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxo-propyl]carbamate： The residue was separated by SFC (column: ChiralPak IH, 250*30mm, 10μm; mobile phase: [CO2-IPA];B%:12%, isocratic elution mode) to give compound benzyl N-[(1S)-3- bromo-1-(4,4-difluorocyclohexyl)-2-oxo-propyl]carbamate (820 mg, crude) as a white solid Data:1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (q, J=12.51 Hz, 2 H) 1.48 - 1.65 (m, 2 H) 1.67- 1.88 (m, 2 H) 2.00 (br s, 3 H) 4.34 (dd, J=8.31, 6.36 Hz, 1 H) 4.41 - 4.54 (m, 2 H) 5.05(s, 2 H) 7.28 - 7.41 (m, 5 H) 7.86 (d, J=8.56 Hz, 1 H)9. General procedure for preparation of N-(6-chloro-5-methyl-pyridazin-3-yl)-2,2-dimethyl-propanamide： The reaction was set up in 3 parallel batches. To a solution of 6-chloro-5-methyl-pyridazin-3-amine (25 g, 174.13 mmol, 1 eq) in NMP (100 mL) was added Py (27.41 g, 346.51 mmol, 27.97 mL, 1.99 eq) and 2,2- dimethylpropanoyl chloride (27.50 g, 228.11 mmol, 28.07 mL, 1.31 eq) at 15 °C under N2 atmosphere. The mixture was stirred at 15 °C for 1 hr under N2 atmosphere. Then the mixture was warmed to 35 °C and stirred for another 0.5 hr until the reaction become clear. The three reactions were cooled to 15 °C and combined for work up. The combined reaction mixture was added H2O 405 (mL), then the mixture was stirred at 5 °C for 1 hr. Then the resulting thick slurry is filtered to collect the solids, which was washed with cold water (315 mL) to give compound N-(6-chloro-5-methyl-pyridazin-3- yl)-2,2-dimethyl-propanamide (121 g, crude) as a white solid Data: LCMS (ESI+): m / z 228.2 (M+H)+1H NMR (400 MHz, CHLOROFORM-d) δ = 8.73 (br s, 1H), 8.42 (s, 1H), 2.39 (s, 3H), 1.32 (s, 9H)10. General procedure for preparation of N-[6-chloro-5-[(E)-2-(dimethylamino)vinyl]pyridazin-3-yl]-2,2-dimethyl-propanamide： The reaction was set up in 3 parallel batches. A mixture of N-(6-chloro-5-methyl-pyridazin-3-yl)-2,2-dimethyl-propanamide (40 g, 175.68 mmol, 1 eq) and 1,1-diethoxy-N,N-dimethyl-methanamine (103.45 g, 702.71 mmol, 120.43 mL, 4 eq) in DMF (16 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 120 °C for 12 hr under N2atmosphere. The three reactions were cooled to 20 °C and combined for workup. The combined reaction mixture was stand at 20 °C for 2 hr, during this time, large yellow crystals are deposited on the bottom of the flask. The resulting solids are filtered, rinsed with TBME (500 mL) to give compound N-[6-chloro-5-[(E)-2-(dimethylamino)vinyl]pyridazin-3-yl]-2,2- dimethyl-propanamide (35 g, crude) as a yellow solid. Data: LCMS (ESI+): m / z 283.3 (M+H)+H NMR (400 MHz, CHLOROFORM-d) δ = 8.31 - 8.24 (m, 2H), 7.24 (d, J = 3.5 Hz, 1H),5.13 (d, J = 13.2 Hz, 1H), 2.97 (s, 6H), 1.31 (s, 9H)11. General procedure for preparation of N-(6-chloro-5-formyl-pyridazin-3-yl)-2,2-dimethyl-propanamide： To a solution of N-[6-chloro-5-[(E)-2-(dimethylamino)vinyl]pyridazin-3-yl]-2,2-dimethyl- propanamide (17.5 g, 61.89 mmol, 1 eq) in THF (110 mL) and H2O (110 mL) was added NaIO4(46.33 g, 216.61 mmol, 12.00 mL, 3.5 eq). The mixture was stirred at 15 °C for 45 min. The reaction was filtered and rinsed with EtOAc (300 ml). The resulting filtrate was extracted with EtOAc 400 mL (200 mL *2). The combined organic layers were washed with brine 800 mL( 400 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethylacetate / Petroleum ether gradient @ 100 mL / min, Petroleum ether : Ethyl acetate = 1 : 1) to give compound N-(6-chloro-5-formyl-pyridazin-3-yl)-2,2-dimethyl-propanamide (14.5 g, crude) as a yellow solid. The crude product was triturated with PE : EA = 10 : 1 (150 mL) at 20 °C for 1 h to give compound N-(6-chloro-5-formyl-pyridazin-3-yl)-2,2- dimethyl-propanamide (25.5 g, crude) as a yellow solid. Data:1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 9 H) 8.71 (br s, 1 H) 8.88 (s, 1 H) 10.39 (s, 1 H)12. General procedure for preparation of N-[6-chloro-5-(oxiran-2-yl)pyridazin-3-yl]-2,2-dimethyl-propanamide： The reaction was set up in 2 parallel batches. To a solution of trimethylsulfonium;iodide (11.58 g, 56.75 mmol, 2.16 eq) in THF (70 mL) and DMSO (70 mL) was added NaH (1.89 g, 47.30 mmol, 788.25 μL, 60% purity, 1.8 eq) at 0 °C. After addition, the mixture was stirred at 0 °C for 0.5 hr, and then N-(6-chloro- 5-formyl-pyridazin-3-yl)-2,2-dimethyl-propanamide (6.35 g, 26.28 mmol, 1 eq) wasadded at 0 °C. The resulting mixture was stirred at 20 °C for 1.5 hr. The reaction mixturewas quenched by addition NH4Cl 150 mL at 0 °C, and then diluted with H2O 50 mL and extracted with EtOAc 600 mL (200 mL * 3). The combined organic layers were washed with brine 600 mL (200 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~25%Ethylacetate / Petroleum ether gradient @ 120 mL / min, PE : EA = 2 : 1) to give compound N-[6-chloro-5-(oxiran-2-yl)pyridazin-3-yl]-2,2-dimethyl-propanamide (6.5 g, 25.42 mmol, 48.37% yield) as a yellow oil. Data: LCMS (ESI+): m / z 256.2 (M+H)+1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 9 H) 2.75 (dd, J=5.75, 2.38 Hz, 1 H) 3.29 (dd, J=5.63, 4.25 Hz, 1 H) 4.10 (br d, J=2.25 Hz, 1 H) 8.40 (s, 1 H) 8.50 (br s, 1 H)13. General procedure for preparation of N-[6-chloro-5-(1-hydroxy-2-methoxy-ethyl)pyridazin-3-yl]-2,2-dimethyl-propanamide： The reaction was set up in 2 parallel batches. To a solution of N-[6-chloro-5-(oxiran-2-yl)pyridazin-3-yl]-2,2-dimethyl-propanamide (6.75 g, 26.40 mmol, 1 eq) in DMA (60 mL) was added NaOMe (9.51 g, 52.80 mmol, 2 eq) at 20 °C. The mixture was stirred at 50 °C for 2 hr. The reaction mixture was quenched by addition H2O 100 mL, and extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were washed with brine 600 mL (300 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~36% Ethyl acetate / Petroleum ether gradient @ 120 mL / min, PE : EA = 1 : 1) to give compound N-[6-chloro-5-(1-hydroxy-2-methoxy- ethyl)pyridazin-3-yl]-2,2-dimethyl-propanamide (5.01 g, 17.41 mmol, 33.40% yield) as a white solid. Data: LCMS (ESI+): m / z 288.3 (M+H)+1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 - 1.36 (m, 9 H) 3.39 - 3.48 (m, 4 H)3.76 (dd, J=9.83, 3.04 Hz, 1 H) 5.13 (dd, J=7.09, 3.04 Hz, 1 H) 8.58 (br d, J=9.42 Hz, 1 H) 8.77 (s, 1 H)14. General procedure for preparation of N-[6-chloro-5-(2-methoxyacetyl)pyridazin-3-yl]-2,2-dimethyl-propanamide： To a solution of N-[6-chloro-5-(1-hydroxy-2-methoxy-ethyl)pyridazin-3-yl]-2,2-dimethyl- propanamide (4.9 g, 17.03 mmol, 1 eq) in DCM (150 mL) was added DMP (9.39 g, 22.14 mmol, 6.86 mL, 1.3 eq) at 20 °C. The mixture was stirred at 20 °C for 2 hr. The reaction mixture was added into water 150 mL and extracted with DCM 400 mL (200 mL * 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~35% Ethyl acetate / Petroleum ether gradient @ 100 mL / min, Petroleum ether : Ethyl acetate = 2 : 1) to give compound N-[6-chloro-5-(2-methoxyacetyl)pyridazin-3-yl]-2,2- dimethyl-propanamide (3.5 g, crude) as a yellow solid. Data: LCMS (ESI+): m / z 286.2 (M+H)+1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 9 H) 3.47 (s, 3 H) 4.49 (s, 2 H) 8.62 (s, 1 H) 8.68 (br s, 1 H)15. General procedure for preparation of N-[5-[1-[[(2S)-2-amino-3,3,3-trifluoro-propyl]amino]-2-methoxy-ethyl]-6-chloro-pyridazin-3-yl]-2,2-dimethyl- propanamide： The reaction was set up in 10 parallel batches. To a solution of (2S)-3,3,3-trifluoropropane-1,2-diamine (77.39 mg, 384.98 μmol, 1.1 eq, 2HCl) in MeOH (3.5 mL) was added Ambersep 900 (OH), ion exchange until the pH~8, then the mixture was stirred at 20 °C for 0.5 h, then it was filtered to give the filtrate which was added N-[6-chloro-5-(2-methoxyacetyl)pyridazin-3-yl]-2,2-dimethyl-propanamide (100 mg, 349.99 μmol, 1 eq) and 4A MS (300 mg, 349.99 μmol) and it was stirred at 20 °C for 3 min, and then AcOH (31.53 mg, 524.98 μmol, 30.05 μL, 1.5 eq) was added until the pH~5, then the reaction was stirred at 65 °C for 5 h. Then the reaction was added NaBH3CN (109.97 mg, 1.75 mmol, 5 eq) at 20 °C and it was stirred at 65 °C for 12 h. The combined reaction mixture was filtered with celatom, the filtrate was concentrated under reduced pressure to give a residue. The residue was added sat.NaHCO3solution 50 mL and then extracted with DCM 150 mL (50 mL * 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 0 / 1, Petroleum ether : Ethyl acetate = 0 : 1) to give compound N-[5-[1-[[(2S)-2-amino-3,3,3-trifluoro-propyl]amino]-2-methoxy-ethyl]-6- chloro-pyridazin-3-yl]-2,2-dimethyl-propanamide (680 mg, crude) as a brown oil. Data: LCMS (ESI+): m / z 398.3 (M+H)+16. General procedure for preparation of N-[6-chloro-5-[(1S)-2-methoxy-1-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]ethyl]pyridazin-3-yl]-2,2-dimethyl- propanamide： The reaction was set up in 9 parallel batches. A mixture of N-[5-[1-[[(2S)-2-amino-3,3,3-trifluoro-propyl]amino]-2-methoxy-ethyl]-6- chloro-pyridazin-3-yl]-2,2-dimethyl-propanamide (0.1 g, 251.37 μmol, 1 eq), CDI (81.52 mg, 502.74 μmol, 2 eq) in THF (2.5 mL) was stirred at 60 °C for 12 h. The combined reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18 100*40mm*3 μm; mobile phase: [H2O(0.2% FA)-ACN];gradient:20%-50% B over 8.0 min) to give compound N-[6-chloro-5-[(1S)-2-methoxy-1-[(4S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl]ethyl]pyridazin-3-yl]-2,2-dimethyl-propanamide (235 mg, crude) as a pale yellow solid and to give compound N-[6-chloro-5-[(1R)-2-methoxy- 1-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]ethyl]pyridazin-3-yl]-2,2-dimethyl- propanamide (220 mg, crude) as a pale yellow solid. Data: LCMS (ESI+): m / z 424.1 (M+H)+17. General procedure for preparation of (4S)-1-[(1S)-1-(6-amino-3-chloro-pyridazin-4-yl)-2-methoxy-ethyl]-4-(trifluoromethyl)imidazolidin-2-one： To a solution of N-[6-chloro-5-[(1S)-2-methoxy-1-[(4S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl]ethyl]pyridazin-3-yl]-2,2-dimethyl-propanamide (200 mg, 471.90 μmol, 1 eq) in MeOH (0.84 mL) was added HCl (3 mL) (5M). The mixturewas stirred at 110 °C for 0.5 h. The reaction mixture was added 15% NaOH solutionuntil pH~9 at 0 °C, then extracted with EtOAc 20 mL (10 mL * 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give compound (4S)-1-[(1S)-1-(6-amino-3-chloro-pyridazin-4-yl)-2-methoxy-ethyl]-4- (trifluoromethyl)imidazolidin-2-one (180 mg, crude) as a yellow solid. Data: LCMS (ESI+): m / z 340.2 (M+H)+18. General procedure for preparation of benzyl N-[(S)-[6-chloro-7-[(1S)-2-methoxy-1-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]ethyl]imidazo[1,2- b]pyridazin-2-yl]-(4,4-difluorocyclohexyl)methyl]carbamate： To a solution of (4S)-1-[(1S)-1-(6-amino-3-chloro-pyridazin-4-yl)-2-methoxy-ethyl]-4- (trifluoromethyl)imidazolidin-2-one (180 mg, 529.88 μmol, 1 eq) and benzyl N-[(1S)-3- bromo-1-(4,4-difluorocyclohexyl)-2-oxo-propyl]carbamate (214.20 mg, 529.88 μmol, 1 eq) in THF (5 mL) was added NaHCO3 (111.28 mg, 1.32 mmol, 51.54 μL, 2.5 eq). The mixture was stirred at 70 °C for 12 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Ethyl acetate : Methanol = 10 : 1) to give compound benzyl N-[(S)-[6- chloro-7-[(1S)-2-methoxy-1-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl]ethyl]imidazo[1,2-b]pyridazin-2-yl]-(4,4-difluorocyclohexyl)methyl]carbamate (245 mg, crude) as a yellow solid. Data: LCMS (ESI+): m / z 645.3 (M+H)+19. General procedure for preparation of (4S)-1-[(1S)-1-[2-[(S)-amino-(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]pyridazin-7-yl]-2-methoxy-ethyl]-4- (trifluoromethyl)imidazolidin-2-one： To a solution of benzyl N-[(S)-[6-chloro-7-[(1S)-2-methoxy-1-[(4S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl]ethyl]imidazo[1,2-b]pyridazin-2-yl]-(4,4- difluorocyclohexyl)methyl]carbamate (245 mg, 379.83 μmol, 1 eq) in MeOH (13 mL) was added Pd / C (50 mg, 10% purity) at 20 °C. Then the reaction was degassed and purged with H2 for 3 times, the mixture was stirred at 20 °C for 12 h under H2 atmosphere (15 PSI). The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give compound (4S)-1-[(1S)-1-[2-[(S)-amino-(4,4- difluorocyclohexyl)methyl]imidazo[1,2-b]pyridazin-7-yl]-2-methoxy-ethyl]-4-(trifluoromethyl)imidazolidin-2-one (195 mg, crude, HCl) as a yellow solid.Data: LCMS (ESI+): m / z 477.3 (M+H)+20. General procedure for preparation of 2-(6-azidohexyl)-N-[(S)-(4,4-difluorocyclohexyl)-[7-[(1S)-2-methoxy-1-[(4S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl]ethyl]imidazo[1,2-b]pyridazin-2- yl]methyl]pyrazole-3-carboxamide： To a solution of (4S)-1-[(1S)-1-[2-[(S)-amino-(4,4-difluorocyclohexyl)methyl]imidazo[1,2- b]pyridazin-7-yl]-2-methoxy-ethyl]-4-(trifluoromethyl)imidazolidin-2-one (50 mg, 97.48 μmol, 1 eq, HCl) and 2-(6-azidohexyl)pyrazole-3-carboxylic acid (27.75 mg, 116.98 μmol, 1.2 eq) in DMF (2 mL) was added HATU (55.60 mg, 146.23 μmol, 1.5 eq) and DIEA (37.80 mg, 292.45 μmol, 50.94 μL, 3 eq) at 20 °C. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was filtered to give the filtrate. The filtrate was purified by reversed-phase HPLC (column: C1820-35μm 100A 40g; mobile phase: [water-ACN]; B%: 0%-60% @ 60 mL / min) to give compound 2-(6-azidohexyl)-N-[(S)-(4,4- difluorocyclohexyl)-[7-[(1S)-2-methoxy-1-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl]ethyl]imidazo[1,2-b]pyridazin-2-yl]methyl]pyrazole-3-carboxamide (56 mg, 80.50 μmol, 82.57% yield) as a white solid. Data: LCMS (ESI+): m / z 696.5 (M+H)+21. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5-[[(S)-(4,4-difluorocyclohexyl)-[7-[(1S)-2-methoxy-1-[(4S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl]ethyl]imidazo[1,2-b]pyridazin-2- yl]methyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4- yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-[2-[2-[2-[2-(2-prop-2- ynoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]ethoxy]phenoxy]pyridine-3- carbonyl]amino]hexanoate (53 mg, 71.06 μmol, 1 eq) and 2-(6-azidohexyl)-N-[(S)-(4,4- difluorocyclohexyl)-[7-[(1S)-2-methoxy-1-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl]ethyl]imidazo[1,2-b]pyridazin-2-yl]methyl]pyrazole-3-carboxamide (49.44 mg, 71.06 μmol, 1 eq) in t-BuOH (1 mL) and H2O (1 mL) was added CuSO4.5H2O (8.87 mg, 35.53 μmol, 0.5 eq) and sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3- olate (14.08 mg, 71.06 μmol, 1 eq) at 20 °C. The mixture was stirred at 50 °C for 1 hr. The reaction mixture was filtered to give the filtrate. The filtrate was purified by reversed- phase HPLC (column: C1820-35μm 100A 40g; mobile phase: [water-ACN]; B%: 0%- 60% @ 55 mL / min) to give compound methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5- [[(S)-(4,4-difluorocyclohexyl)-[7-[(1S)-2-methoxy-1-[(4S)-2-oxo-4-(trifluoromethyl) imidazolidin-1-yl]ethyl]imidazo[1,2-b]pyridazin-2-yl]methyl]carbamoyl]pyrazol-1- yl]hexyl]triazol-4-yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (96 mg, crude) as a pale yellow solid. Data: LCMS (ESI+): m / z 1441.9 (M+H)+22. General procedure for preparation of (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5-[[(S)-(4,4-difluorocyclohexyl)-[7-[(1S)-2-methoxy-1-[(4S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl]ethyl]imidazo[1,2-b]pyridazin-2- yl]methyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5-[[(S)-(4,4- difluorocyclohexyl)-[7-[(1S)-2-methoxy-1-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl]ethyl]imidazo[1,2-b]pyridazin-2-yl]methyl]carbamoyl]pyrazol-1-yl]hexyl]triazol-4- yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (96 mg, 66.60 μmol, 1 eq) in THF (1 mL) and H2O (0.5 mL) was added LiOH.H2O (5.59 mg, 133.19 μmol, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The residue was concentrated under the reduced pressure to remove THF, the residue was adjusted pH~5 by using formic acid to give a solution. The residue was purified by prep-HPLC (neutral condition; column: Waters Xbridge BEH C18100*30mm*10μm; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:40%-70% B over 8.0 min) to give compound X- 059 (2S)-2-[[6-[3-[2-[2-[2-[2-[2-[2-[2-[[1-[6-[5-[[(S)-(4,4-difluorocyclohexyl)-[7-[(1S)-2- methoxy-1-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]ethyl]imidazo[1,2-b]pyridazin- 2-yl]methyl]carbamoyl] pyrazol-1-yl]hexyl]triazol-4-yl]methoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino] -2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid (45.5 mg, 31.87 μmol, 47.86% yield, 100.000% purity) as a white solid. Data: LCMS (ESI+): m / z 1427.7 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.63 (d, J = 2.1 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.25 (dd, J = 2.4, 8.7 Hz, 1H), 8.11 (s, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.89 (dd, J = 2.1, 8.1 Hz,1H), 6.85 - 6.81 (m, 2H), 6.78 (dd, J = 1.5, 8.1 Hz, 1H), 5.24 - 5.17 (m, 2H), 4.61 (s, 2H),4.54 (s, 2H), 4.52 - 4.44 (m, 3H), 4.41 - 4.33 (m, 1H), 4.30 (t, J = 7.1 Hz, 2H), 4.02 - 3.90(m, 3H), 3.65 - 3.60 (m, 4H), 3.60 - 3.50 (m, 19H), 3.48 - 3.42 (m, 5H), 2.26 - 2.15 (m,1H), 2.12 - 1.91 (m, 4H), 1.87 - 1.68 (m, 7H), 1.68 - 1.59 (m, 1H), 1.53 - 1.30 (m, 4H),1.28 - 1.17 (m, 4H), 0.90 (s, 9H)X-082: (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethyl-(2-hydroxyethyl)amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of 1-[3-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]ethoxy]azetidin-1-yl]-2-prop-2-ynoxy- ethanone： To a solution of 1-[3-(2-aminoethoxy)azetidin-1-yl]-2-prop-2-ynoxy-ethanone (200 mg, 612.99 μmol, TFA) and 2-bromoethoxy-tert-butyl-dimethyl-silane (146.64 mg, 612.99 μmol) in DMF (2 mL) was added DIEA (237.67 mg, 1.84 mmol, 320.32 μL). The mixture was stirred at 50°C for 12 hr. The mixture was used to next step without purification togive 1-[3-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]ethoxy]azetidin-1-yl]-2-prop-2-ynoxy-ethanone (200 mg, crude) in DMF (2 mL) as a brown liquid.Date: LCMS (ESI+): m / z 371.3 (M+H)+2. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-[2-[1-(2-prop-2-ynoxyacetyl)azetidin-3- yl]oxyethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoate： To a solution of 1-[3-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]ethoxy]azetidin-1-yl]-2- prop-2-ynoxy-ethanone (200 mg, 539.73 μmol) and 2-[3-[[5-[[(1S)-1-methoxycarbonyl- 4,4-dimethyl-pentyl]carbamoyl]-2-pyridyl]oxy]phenoxy]acetic acid (301.44 mg, 539.73 μmol, TFA) in DMF (2 mL) was added DIEA (209.27 mg, 1.62 mmol, 282.03 μL) and HATU (307.83 mg, 809.59 μmol) at 0°C. The mixture was stirred at 20°C for 1 hr. The mixture was filtered and the filtrate was purified by reversed-phase-HPLC (column: C18 20-35 μm 100A 80 g; mobile phase: [water-ACN]; B%: 0%-80% @ 80 mL / min) to give methyl (2S)-2-[[6-[3-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-[2-[1-(2-prop-2- ynoxyacetyl)azetidin-3-yl]oxyethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (75 mg, 94.10 μmol, 17.43% yield) as a white solid. Date: LCMS (ESI+): m / z 797.6 (M+H)+3. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate: To a solution of methyl (2S)-2-[[6-[3-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-[2-[1-(2-prop- 2-ynoxyacetyl)azetidin-3-yl]oxyethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (70 mg, 87.83 μmol) and 2-[3-[(2- azidoacetyl)amino]propyl]-N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole-3-carboxamide (92.60 mg, 131.74 μmol) in t-BuOH (0.2 mL) and H2O (0.2 mL) was added copper;sulfate;pentahydrate (10.96 mg, 43.91 μmol) and sodium;(2R)-2-[(1S)-1,2- dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (17.40 mg, 87.83 μmol). The mixture was stirred at 50°C for 1 hr. The mixture was filtered and the filtrate was purified by reversed-phase-HPLC (column: C1820-35 μm 100A 80 g; mobile phase: [water-ACN]; B%: 0%-85% @ 80 mL / min) to give methyl (2S)-2-[[6-[3-[2-[2-[tert- butyl(dimethyl)silyl]oxyethyl-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5- dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (30 mg, 20.00 μmol, 22.77% yield) as a white solid. Date: LCMS (ESI+): m / z 1499.9 (M+H)+4. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2- oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethyl-(2-hydroxyethyl)amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate: To a solution of methyl (2S)-2-[[6-[3-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-[2-[1-[2-[[1- [2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]propylamino]-2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethyl]amino]-2- oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (27 mg, 18.00 μmol) in DCM (0.5 mL) was added TFA (153.50 mg, 1.35 mmol, 0.1 mL). The mixture was stirred at 20°C for 3 hr. The DCM and TFA was removed under reduced pressure to give methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4- (3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]- 2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethyl-(2-hydroxyethyl)amino]-2- oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (24 mg, crude, TFA) as a yellow oil. Date: LCMS (ESI+): m / z 1255.8 (M+H)+5. General procedure for preparation of (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethyl-(2-hydroxyethyl)amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid: To a solution of methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethyl-(2-hydroxyethyl)amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (24 mg, 17.53 μmol, TFA) in THF (0.2 mL) and H2O (0.2 mL) was added LiOH.H2O (1.47 mg, 35.05 μmol) at 0°C. The mixture was stirred at 20°C for 1 hr. The THF was removed under reduced pressure and the residue acidized with FA to pH = 2. The mixture was filteredand the filtrate was purified by reversed-phase HPLC (column: C1820-35 μm 100A 40g; mobile phase: [water-ACN]; B%: 0%-54% @ 65 mL / min) to give (2S)-2-[[6-[3-[2-[2-[1- [2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]- 2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethyl-(2-hydroxyethyl)amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid (11.7 mg, 9.34 μmol, 53.30% yield, 99.116% purity) as a pale yellow solid. Date: LCMS (ESI+): m / z 1241.6 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.62 (d, J = 2.1 Hz, 1H), 8.21 (td, J = 3.1, 8.6Hz, 1H), 8.00 (d, J = 14.1 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.53 (d, J = 1.9 Hz, 1H), 7.36 -7.26 (m, 1H), 7.22 (dd, J = 2.2, 8.6 Hz, 2H), 6.94 (dd, J = 2.7, 8.7 Hz, 1H), 6.89 - 6.81(m, 2H), 6.80 - 6.75 (m, 1H), 6.72 (dd, J = 2.6, 7.9 Hz, 1H), 5.10 (d, J = 4.8 Hz, 2H), 4.96(d, J = 3.3 Hz, 2H), 4.65 - 4.56 (m, 3H), 4.56 - 4.46 (m, 2H), 4.40 - 4.21 (m, 2H), 4.18 -4.09 (m, 1H), 4.08 - 3.97 (m, 3H), 3.84 - 3.47 (m, 10H), 3.25 - 3.09 (m, 2H), 2.22 (s, 6H),2.04 (quin, J = 6.5 Hz, 2H), 2.00 - 1.90 (m, 1H), 1.88 - 1.74 (m, 1H), 1.40 - 1.28 (m, 2H),0.91 (s, 9H), 0.90 - 0.76 (m, 3H), 0.61 - 0.52 (m, 1H), 0.47 (ddd, J = 4.8, 8.6, 13.3 Hz,2H), 0.43 - 0.34 (m, 2H), 0.33 - 0.20 (m, 3H)X-083: (2S)-2-[[6-[3-[2-[(2-amino-2-oxo-ethyl)-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of 2-[2-[1-(2-prop-2-ynoxyacetyl)azetidin-3-yl]oxyethylamino]acetamide： To a solution of 1-[3-(2-aminoethoxy)azetidin-1-yl]-2-prop-2-ynoxy-ethanone (200 mg, 612.99 μmol, TFA) and 2-bromoacetamide (126.86 mg, 919.49 μmol) in EtOH (3 mL) was added DIEA (222.60 mg, 1.72 mmol, 0.3 mL). The mixture was stirred at 20°C for 12 hr. The EtOH was removed under reduced pressure to give 2-[2-[1-(2-prop-2- ynoxyacetyl)azetidin-3-yl]oxyethylamino]acetamide (140 mg, 519.87 μmol, 84.81% yield) as a yellow oil. Date: LCMS (ESI+): m / z 270.3 (M+H)+2. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[(2-amino-2-oxo-ethyl)-[2-[1-(2-prop-2-ynoxyacetyl)azetidin-3-yl]oxyethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of 2-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl-pentyl]carbamoyl]-2- pyridyl]oxy]phenoxy]acetic acid (200 mg, 358.10 μmol, TFA) and 2-[2-[1-(2-prop-2- ynoxyacetyl)azetidin-3-yl]oxyethylamino]acetamide (96.44 mg, 358.10 μmol) in DMF (3 mL) was added DIEA (92.56 mg, 716.20 μmol, 124.75 μL) and HATU (204.24 mg, 537.15 μmol) at 0°C. The mixture was stirred at 20°C for 1 hr. The mixture was filtered and the filtrate was purified by reversed-phase-HPLC (column: C18 20-35 μm 100A 120 g; mobile phase: [water-ACN]; B%: 0%-68% @ 80 mL / min) to give methyl (2S)-2-[[6-[3-[2- [(2-amino-2-oxo-ethyl)-[2-[1-(2-prop-2-ynoxyacetyl)azetidin-3-yl]oxyethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (60 mg, 86.24μmol, 24.08% yield) as a white solid. Date: LCMS (ESI+): m / z 696.5 (M+H)+3. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[(2-amino-2-oxo-ethyl)-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1- (2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate: To a solution of methyl (2S)-2-[[6-[3-[2-[(2-amino-2-oxo-ethyl)-[2-[1-(2-prop-2- ynoxyacetyl)azetidin-3-yl]oxyethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (55 mg, 79.05 μmol) and 2-[3-[(2- azidoacetyl)amino]propyl]-N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole-3-carboxamide (55.57 mg, 79.05 μmol) in H2O (0.5 mL) and t-BuOH (0.5 mL) was added CuSO4.5H2O (9.87 mg, 39.53 μmol) and sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo- 2H-furan-3-olate (15.66 mg, 79.05 μmol). The mixture was stirred at 50°C for 1 hr. The mixture was filtered and the filtrate was purified by reversed-phase-HPLC (column: C18 20-35 μm 100A 80 g; mobile phase: [water-ACN]; B%: 0%75% @ 80 mL / min) to give methyl (2S)-2-[[6-[3-[2-[(2-amino-2-oxo-ethyl)-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (80 mg, 57.20 μmol, 72.35% yield) as a white solid. Date: LCMS (ESI+): m / z 1398.9 (M+H)+4. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[(2-amino-2-oxo-ethyl)-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate: To a solution of methyl (2S)-2-[[6-[3-[2-[(2-amino-2-oxo-ethyl)-[2-[1-[2-[[1-[2-[3-[5-[[(1S)- 1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (80 mg, 57.20 μmol) in DCM (1 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL). The mixture was stirred at 20°C for 3 hr. The DCM and TFA was removed under reduced pressure to give methyl (2S)-2-[[6-[3-[2-[(2- amino-2-oxo-ethyl)-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5- dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2- oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (78 mg, crude, TFA) as a yellow oil. Date: LCMS (ESI+): m / z 1268.8 (M+H)+5. General procedure for preparation of (2S)-2-[[6-[3-[2-[(2-amino-2-oxo-ethyl)-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol- 4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid: To a solution of methyl (2S)-2-[[6-[3-[2-[(2-amino-2-oxo-ethyl)-[2-[1-[2-[[1-[2-[3-[5-[[(1S)- 1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (75 mg, 54.25 μmol, TFA) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (4.55 mg, 108.50 μmol). The mixture was stirred at 0°C for 1 hr. The mixture was filtered and the filtrate was purified by prep-HPLC. Themixture was purified by prep-HPLC (FA condition column: Phenomenex luna C18100*40mm*3 μm; mobile phase: [H2O(0.2% FA)-ACN];gradient:30%-60% B over 8.0 min to give (2S)-2-[[6-[3-[2-[(2-amino-2-oxo-ethyl)-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoic acid (5.4 mg, 4.23 μmol, 7.79% yield, 98.188% purity) as a white solid. Date: LCMS (ESI+): m / z 1276.5 (M+Na)+1H NMR (400 MHz, METHANOL-d4) δ = 8.61 (d, J = 1.6 Hz, 1H), 8.25 - 8.17 (m,1H), 8.02 (d, J = 15.4 Hz, 1H), 7.69 - 7.58 (m, 2H), 7.53 (d, J = 2.1 Hz, 1H),7.30 (q, J = 8.1 Hz, 1H), 7.22 (dd, J = 1.9, 8.6 Hz, 2H), 6.94 (d, J = 8.7 Hz, 1H),6.89 (d, J = 2.2 Hz, 1H), 6.87 - 6.81 (m, 1H), 6.77 (s, 1H), 6.75 - 6.69 (m, 1H),5.10 (d, J = 5.5 Hz, 2H), 5.00 (s, 2H), 4.69 - 4.47 (m, 6H), 4.43 - 4.24 (m, 2H),4.23 - 3.98 (m, 6H), 3.87 - 3.75 (m, 1H), 3.70 - 3.42 (m, 4H), 3.25 - 3.06 (m,2H), 2.22 (s, 6H), 2.10 - 1.99 (m, 2H), 1.99 - 1.90 (m, 1H), 1.88 - 1.74 (m, 1H),1.43 - 1.28 (m, 2H), 0.93 - 0.90 (m, 9H), 0.89 - 0.74 (m, 3H), 0.61 - 0.53 (m,1H), 0.48 (dt, J = 4.2, 8.7 Hz, 2H), 0.44 - 0.35 (m, 2H), 0.28 (tdd, J = 4.7, 9.0,13.1 Hz, 3H) X-084: (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl-(2-hydroxyethyl)amino]- 2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of methyl 2-[3-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]propyl]pyrazole-3-carboxylate： TEA (102.13 mg, 1.01 mmol, 140.48 μL, 1 eq) was added to a solution of methyl 2-(3- aminopropyl)pyrazole-3-carboxylate (300 mg, 1.01 mmol, 1 eq, TFA) in MeOH (3 mL) until pH = 8~9, then the reaction was stirred for 5 min at 20°C, then 2-[tert- butyl(dimethyl)silyl]oxyacetaldehyde (123.16 mg, 706.52 μmol, 134.60 μL, 0.7 eq) was added, AcOH (60.61 mg, 1.01 mmol, 57.78 μL, 1 eq) was added to adjust pH<5 , then the reaction was stirred for 5 min at 20°C, then NaBH3CN (126.86 mg, 2.02 mmol, 2 eq) were added to the reaction, then the reaction was stirred for 20 min at 20°C. The residue was purified by reversed-phase HPLC (column: C1820-35 μm 100A 40 g; mobile phase:[water-ACN]; B%: 0%-42% @ 80 mL / min) to give methyl 2-[3-[2-[tert-butyl (dimethyl)silyl] oxyethylamino] propyl] pyrazole-3-carboxylate (0.2 g, 585.62 μmol, 58.02% yield) as a yellow oil. Data: LCMS (ESI+): m / z 342.3 (M+H)+2. General procedure for preparation of methyl 2-[3-[(2-azidoacetyl)-[2-[tert-butyl(dimethyl)silyl]oxyethyl]amino]propyl]pyrazole-3-carboxylate： To a solution ofmethyl 2-[3-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]propyl]pyrazole-3- carboxylate (0.19 g, 556.34 μmol, 1 eq), 2-azidoacetic acid (112.45 mg, 1.11 mmol, 2 eq) in DMF (2 mL) was added HATU (317.30 mg, 834.50 μmol, 1.5 eq) and DIEA (215.71 mg, 1.67 mmol, 290.71 μL, 3 eq) at 0°C, then the reaction was stirred for 0.5 hr at 20°C. The residue was purified by reversed-phase HPLC (column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-60% @ 80 mL / min) to give methyl 2-[3-[(2- azidoacetyl)-[2-[tert-butyl(dimethyl)silyl]oxyethyl]amino]propyl]pyrazole-3-carboxylate (130 mg, 306.19 μmol, 55.04% yield) as a yellow oil. Data: LCMS (ESI+): m / z 425.3 (M+H)+3. General procedure for preparation of 2-[3-[(2-azidoacetyl)-[2-[tert-butyl(dimethyl)silyl]oxyethyl]amino]propyl]pyrazole-3-carboxylic acid： To a solution of methyl 2-[3-[(2-azidoacetyl)-[2-[tert-butyl (dimethyl) silyl] oxyethyl] amino] propyl] pyrazole-3-carboxylate (0.13 g, 306.19 μmol, 1 eq) in H2O (0.5 mL) and THF (0.5 mL) was added LiOH.H2O (19.27 mg, 459.29 μmol, 1.5 eq). The mixture wasstirred at 0°C for 0.5 hr. The water layer was acidified by HCl (1 M) till pH = 3. Theresidue was purified by reversed-phase HPLC (column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-60% @ 80 mL / min) to give 2-[3-[(2-azidoacetyl)-[2-[tert- butyl (dimethyl) silyl] oxyethyl] amino] propyl] pyrazole-3-carboxylic acid (0.15 g, crude) as a yellow oil. Data: LCMS (ESI+): m / z 411.4 (M+H)+4. General procedure for preparation of 2-[3-[(2-azidoacetyl)-(2-hydroxyethyl)amino]propyl]-N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5- dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]pyrazole-3-carboxamide： To a solution of 2-[3-[(2-azidoacetyl)-[2-[tert- butyl(dimethyl)silyl]oxyethyl]amino]propyl]pyrazole-3-carboxylic acid (0.12 g, 292.30 μmol, 1 eq), (2S)-2-amino-3,3-dicyclopropyl-N-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]propanamide (118.13 mg, 233.84 μmol, 0.8 eq, HCl) in DMF (2 mL) was added HATU (166.71 mg, 438.44 μmol, 1.5 eq) and DIEA (113.33 mg, 876.89 μmol, 152.74 μL, 3 eq) at 0°C, then the reaction was stirred for 1.5 hr at 20°C. The residue was purified by reversed-phase HPLC (column: C1820- 35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-62% @ 80 mL / min) to give 2-[3- [(2-azidoacetyl)-[2-[tert-butyl(dimethyl)silyl]oxyethyl]amino]propyl]-N-[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]pyrazole-3-carboxamide (40 mg, 46.45 μmol, 15.89% yield) as a yellow oil and to give 2-[3-[(2-azidoacetyl)-(2-hydroxyethyl)amino]propyl]-N-[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]pyrazole-3-carboxamide (28 mg, 37.48 μmol, 12.82% yield) as a yellow oil.. Data: LCMS (ESI+): m / z 747.6 (M+H)+5. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propyl-(2-hydroxyethyl)amino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of the 2-[3-[(2-azidoacetyl)-(2-hydroxyethyl)amino]propyl]-N-[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]pyrazole-3-carboxamide (28 mg, 37.48 μmol, 1 eq) and methyl (2S)-5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-[1-(2-prop-2-ynoxyacetyl)azetidin-3- yl]oxyethylamino]ethoxy]phenoxy]pyridine-3-carbonyl]amino]hexanoate (23.94 mg, 37.48 μmol, 1 eq) in t-BuOH (0.5 mL) and H2O (0.5 mL)was added copper; sulfate (5.98 mg, 37.48 μmol, 5.75 μL, 1 eq) sodium; (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5- oxo-2H-furan-3-olate (7.43 mg, 37.48 μmol, 1 eq), the reaction was stirred for 0.5 hr at 50°C. The residue was purified by reversed-phase HPLC (column: C1820-35 μm 100A40 g; mobile phase: [water-ACN]; B%: 0%-60% @ 80 mL / min) to give methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]propyl-(2-hydroxyethyl)amino]-2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3- yl]oxyethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl- hexanoate (30 mg, 21.65 μmol, 57.76% yield) as a yellow oil. Data: LCMS (ESI+): m / z 1385.9 (M+H)+6. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2- oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl-(2-hydroxyethyl)amino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl-(2-hydroxyethyl)amino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (30 mg, 21.65 μmol, 1 eq) in DCM (0.8 mL) was added TFA (0.2 mL). The mixture was stirred at 25°C for 0.5 hr. The mixture was concentrated under reduced pressure to give methyl (2S)- 2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl-(2-hydroxyethyl)amino]- 2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (30 mg, crude, TFA) as a yellow oil. Data: LCMS (ESI+): m / z 1255.6 (M+H)+7. General procedure for preparation of (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propyl-(2-hydroxyethyl)amino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propyl-(2-hydroxyethyl)amino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (25 mg, 18.26 μmol, 1 eq, TFA) in H2O (0.5 mL) and THF (0.5 mL) was added LiOH.H2O (1.15 mg, 27.38 μmol, 1.5 eq). The mixture was stirred at 0°C for 0.5 hr. The water layer was acidified by HCl (1 M) till pH = 3. The residue was purified by prep-HPLC (neutral condition: column: Phenomenex luna C18 100*40mm*3 μm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 30%-60% B over 8.0min) to give (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl-(2- hydroxyethyl)amino]-2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3- yl]oxyethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl- hexanoic acid (4.6 mg, 3.67 μmol, 20.08% yield, 98.930% purity) as a yellow gum. Data: LCMS (ESI+): m / z 1241.6 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.63 - 8.58 (m, 1H), 8.22 (dd, J = 2.5, 8.6 Hz,1H), 7.95 - 7.89 (m, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.58 - 7.49 (m, 1H), 7.34 (t, J = 8.2Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.7 Hz, 1H), 6.92 - 6.84 (m, 2H), 6.84 -6.74 (m, 2H), 5.52 - 5.35 (m, 2H), 4.75 - 4.41 (m, 8H), 4.39 - 4.23 (m, 2H), 4.18 - 4.09(m, 1H), 4.07 - 3.97 (m, 3H), 3.82 - 3.73 (m, 1H), 3.71 - 3.59 (m, 2H), 3.56 - 3.38 (m,8H), 2.23 (s, 7H), 2.14 - 2.04 (m, 1H), 2.02 - 1.90 (m, 1H), 1.89 - 1.74 (m, 1H), 1.41 -1.27 (m, 2H), 0.91 (s, 10H), 0.86 - 0.75 (m, 2H), 0.60 - 0.44 (m, 3H), 0.39 (dt, J = 5.0,8.6 Hz, 2H), 0.34 - 0.22 (m, 3H)X-085: (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl-(2-hydroxyethyl)amino]- 2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[2-[tert- butyl(dimethyl)silyl]oxyethyl-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5- dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo-ethyl]triazol-4- yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution ofmethyl (2S)-5,5-dimethyl-2-[[6-[3-[1-[3-(2-prop-2- ynoxyethoxy)propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]hexanoate (30 mg, 48.02 μmol, 1.03 eq) and 2-[3-[(2-azidoacetyl)-[2- [tert-butyl(dimethyl)silyl]oxyethyl]amino]propyl]-N-[(1S)-1-(dicyclopropylmethyl)-2-[4- [3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole- 3-carboxamide (40 mg, 46.45 μmol, 1 eq) in t-BuOH (0.5 mL) and H2O (0.5 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (9.20 mg, 46.45 μmol, 1 eq) and copper;sulfate;pentahydrate (5.80 mg, 23.22 μmol, 0.5 eq). The mixture was stirred at 50°C for 0.5 hr. The mixture was filtered and the filtrate was purified by reversed-phase HPLC (column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-78% @ 100 mL / min) to give methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[2- [tert-butyl(dimethyl)silyl]oxyethyl-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl- 1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]propyl]amino]-2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (40 mg, 26.92 μmol, 57.96% yield) as a colorless oil. Data: LCMS (ESI+): m / z 1486.0 (M+H)+2. General procedure for preparation of methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2- oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl-(2-hydroxyethyl)amino]-2-oxo- ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： A solution of methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-[3-[5- [[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]propyl]amino]-2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (35 mg, 23.55 μmol, 1 eq) in DCM (0.5 mL) and TFA (0.1 mL) was stirred at 25°C for 0.5 hr. The DCM and TFA was removed under reduced pressure to give methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3- [5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propyl-(2-hydroxyethyl)amino]-2-oxo-ethyl]triazol-4- yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (30 mg, crude, TFA) as a yellow oil. Data: LCMS (ESI+): m / z 1241.4 (M+H)+3. General procedure for preparation of (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propyl-(2-hydroxyethyl)amino]-2-oxo- ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2- [4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl-(2- hydroxyethyl)amino]-2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl] azetidin-3-yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (30 mg, 22.13 μmol, 1 eq, TFA) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (1.86 mg, 44.27 μmol, 2 eq). The mixture was stirred at 25°C for 20 min. The THF was removed under reduced pressure and the residue was acidized with FA to pH = 2. The mixture was filtered and the filtrate was purified by reversed-phase HPLC (column: C18 20-35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-53% @ 80 mL / min) to give (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl-(2-hydroxyethyl)amino]- 2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid (8.7 mg, 6.75 μmol, 30.48% yield, 95.185% purity) as a yellow oil. Data: LCMS (ESI+): m / z 1227.8 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.64 - 8.58 (m, 1H), 8.22 (dd, J = 2.4, 8.7 Hz,1H), 7.91 - 7.86 (m, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.57 - 7.49 (m, 1H), 7.33 (t, J = 8.2 Hz,1H), 7.27 - 7.19 (m, 2H), 6.96 (d, J = 8.7 Hz, 1H), 6.92 - 6.83 (m, 1H), 6.79 - 6.69 (m,2H), 6.67 - 6.61 (m, 1H), 5.49 - 5.37 (m, 2H), 5.01 - 4.93 (m, 1H), 4.66 - 4.41 (m, 6H),4.28 (td, J = 6.6, 9.1 Hz, 2H), 3.92 - 3.83 (m, 2H), 3.69 - 3.54 (m, 6H), 3.53 - 3.45 (m,4H), 3.45 - 3.34 (m, 2H), 3.24 - 3.16 (m, 2H), 2.23 (s, 6H), 2.14 - 2.05 (m, 1H), 2.02 -1.90 (m, 1H), 1.88 - 1.76 (m, 1H), 1.76 - 1.67 (m, 2H), 1.44 - 1.24 (m, 3H), 0.91 (s, 9H),0.90 - 0.75 (m, 3H), 0.60 - 0.45 (m, 3H), 0.44 - 0.35 (m, 2H), 0.34 - 0.21 (m, 3H)X-086: (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of methyl 2-[3-[(2-amino-2-oxo-ethyl)amino]propyl]pyrazole-3-carboxylate： To a solution of methyl 2-(3-aminopropyl) pyrazole-3-carboxylate (0.5 g, 1.68 mmol, 1 eq, TFA), 2-bromoacetamide (46.42 mg, 336.44 μmol, 0.2 eq) in EtOH (5 mL) was added DIEA (652.24 mg, 5.05 mmol, 879.02 μL, 3 eq). The mixture was stirred at 25 °C for 12 hr. The residue was purified by reversed-phase HPLC (column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-0% @ 80 mL / min) to give methyl 2-[3-[(2-amino- 2-oxo-ethyl) amino] propyl] pyrazole-3-carboxylate (1 g, crude) as a yellow oil. Data: LCMS (ESI+): m / z 241.1 (M+H)+2. General procedure for preparation of methyl 2-[3-[(2-amino-2-oxo-ethyl)-(2-azidoacetyl)amino]propyl]pyrazole-3-carboxylate： To a solution of methyl 2-[3-[(2-amino-2-oxo-ethyl)amino]propyl]pyrazole-3-carboxylate (0.9 g, 3.75 mmol, 1 eq), 2-azidoacetic acid (757.16 mg, 7.49 mmol, 2 eq) in DMF (10 mL) was added HATU (2.14 g, 5.62 mmol, 1.5 eq) and DIEA (1.45 g, 11.24 mmol, 1.96 mL, 3 eq) at 0°C, then the reaction was stirred for 0.5 hr at 20 °C. The residue was purified by prep-HPLC (neutral condition; column: Waters Xbridge Prep OBD C18 150*40mm*10 μm; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 10%-45% Bover 8.0 min) to give methyl 2-[3-[(2-amino-2-oxo-ethyl)-(2-azidoacetyl) amino] propyl]pyrazole-3-carboxylate (70 mg, 216.51 μmol, 5.78% yield) as a yellow oil. Data: LCMS (ESI+): m / z 324.1 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 7.53 (dd, J = 2.0, 11.7 Hz, 1H), 6.89 (dd, J =2.0, 10.7 Hz, 1H), 4.59 (q, J = 7.1 Hz, 2H), 4.09 - 4.00 (m, 4H), 3.89 (d, J = 1.5 Hz, 3H),3.44 - 3.32 (m, 2H), 2.19 - 2.05 (m, 2H)3. General procedure for preparation of 2-[3-[(2-amino-2-oxo-ethyl)-(2-azidoacetyl)amino]propyl]pyrazole-3-carboxylic acid： To a solution of methyl 2-[3-[(2-amino-2-oxo-ethyl)-(2-azidoacetyl) amino] propyl] pyrazole-3-carboxylate (50 mg, 154.65 μmol, 1 eq) in H2O (0.5 mL) and THF (0.5 mL) was added LiOH.H2O (9.73 mg, 231.98 μmol, 1.5 eq). The mixture was stirred at 0 °Cfor 0.5 hr. The water layer was acidified by HCl (1 M) till pH=3. The residue was purifiedby reversed-phase HPLC (column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-0% @ 60 mL / min) to give 2-[3-[(2-amino-2-oxo-ethyl)-(2-azidoacetyl)amino]propyl]pyrazole-3-carboxylic acid (45 mg, 145.50 μmol, 94.08% yield) as a yellow oil. Data: LCMS (ESI+): m / z 310.2 (M+H)+4. General procedure for preparation of 2-[3-[(2-amino-2-oxo-ethyl)-(2-azidoacetyl)amino]propyl]-N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl- 1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole-3- carboxamide： To a solution of 2-[3-[(2-amino-2-oxo-ethyl)-(2-azidoacetyl)amino]propyl]pyrazole-3- carboxylic acid (35 mg, 113.17 μmol, 1 eq), (2S)-2-amino-3,3-dicyclopropyl-N-[4-[3,5- dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]propanamide (57.17 mg, 113.17 μmol, 1 eq, HCl) in DMF (2 mL)was added HATU (64.54 mg, 169.75 μmol, 1.5 eq) and DIEA (43.88 mg, 339.50 μmol, 59.13 μL, 3 eq) at 0°C, then the reaction was stirred for 0.5 hr at 20°C. The residue was purified by reversed-phase HPLC (column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-60% @ 70 mL / min) to give 2-[3-[(2-amino-2-oxo-ethyl)-(2-azidoacetyl)amino]propyl]-N-[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]pyrazole-3-carboxamide (80 mg, 105.27 μmol, 93.02% yield) as a yellow oil. Data: LCMS (ESI+): m / z 760.4 (M+H)+5. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of the methyl (2S)-5,5-dimethyl-2-[[6-[3-[2-oxo-2-[2-[1-(2-prop-2- ynoxyacetyl)azetidin-3-yl]oxyethylamino]ethoxy]phenoxy]pyridine-3- carbonyl]amino]hexanoate (25.21 mg, 39.48 μmol, 1 eq) and 2-[3-[(2-amino-2-oxo- ethyl)-(2-azidoacetyl)amino]propyl]-N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl- 1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole-3- carboxamide (30 mg, 39.48 μmol, 1 eq) in t-BuOH (0.5 mL) and H2O (0.5 mL)was added copper; sulfate (6.30 mg, 39.48 μmol, 6.06 μL, 1 eq), sodium; (2R)-2-[(1S)-1,2- dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (7.82 mg, 39.48 μmol, 1 eq). The reaction was stirred for 0.5 hr at 50°C. The mixture was purified by reversed-phase HPLC (column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-68% @ 80 mL / min) to give methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5- [[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]propyl]amino]-2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2- oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (30 mg, 21.45 μmol, 54.33% yield) as a yellow oil. Data: LCMS (ESI+): m / z 1398.5 (M+H)+6. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)- 1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl) pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (25 mg, 17.87 μmol, 1 eq) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °Cfor 2hr. The mixture was concentrated under reduced pressure to give methyl (2S)-2- [[6-[3-[2-[2-[1-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4- (3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]- 2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (25 mg, crude, TFA) as a yellow oil. Data: LCMS (ESI+): m / z 1268.7 (M+H)+7. General procedure for preparation of (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4- yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)- 1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (20 mg, 14.47 μmol, 1 eq, TFA) in H2O (0.5 mL) and THF (0.5 mL) was added LiOH.H2O (910.64 μg, 21.70 μmol, 1.5 eq). The mixture was stirred at 0 °C for 0.5 hr. The water layer was acidified by FA (1 M) till pH=3. The residue was purified by reversed-phase HPLC (column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%:0%-68% @ 70 mL / min) to give (2S)-2-[[6-[3-[2-[2-[1-[2-[[1-[2- [(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxyethylamino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid (6.9 mg, 5.47 μmol, 37.82% yield, 99.477% purity) as a yellow gum. Data: LCMS (ESI+): m / z 1254.5 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.61 (t, J = 2.7 Hz, 1H), 8.22 (dd, J = 2.5, 8.6Hz, 1H), 7.95 (d, J = 4.3 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.54 (dd, J = 2.0, 15.9 Hz, 1H),7.34 (t, J = 8.2 Hz, 1H), 7.22 (dd, J = 2.0, 8.6 Hz, 2H), 6.97 (d, J = 8.7 Hz, 1H), 6.92 -6.85 (m, 2H), 6.83 - 6.79 (m, 1H), 6.77 (dd, J = 1.8, 8.0 Hz, 1H), 5.54 - 5.21 (m, 2H), 4.70- 4.42 (m, 8H), 4.38 - 4.23 (m, 2H), 4.19 - 4.07 (m, 2H), 4.06 - 3.97 (m, 4H), 3.82 - 3.73(m, 1H), 3.55 - 3.34 (m, 6H), 2.23 (s, 7H), 2.14 - 2.04 (m, 1H), 2.01 - 1.91 (m, 1H), 1.88- 1.77 (m, 1H), 1.40 - 1.28 (m, 2H), 0.91 (s, 10H), 0.87 - 0.74 (m, 2H), 0.61 - 0.43 (m,3H), 0.43 - 0.34 (m, 2H), 0.33 - 0.21 (m, 3H)X-087: (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2- [4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]propyl]amino]-2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo-ethyl]triazol-4- yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution ofmethyl (2S)-5,5-dimethyl-2-[[6-[3-[1-[3-(2-prop-2- ynoxyethoxy)propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]hexanoate (24.66 mg, 39.48 μmol, 1 eq) and 2-[3-[(2-amino-2-oxo- ethyl)-(2-azidoacetyl)amino]propyl]-N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl- 1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole-3- carboxamide (30 mg, 39.48 μmol, 1 eq) in t-BuOH (0.5 mL) and H2O (0.5 mL) was added sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (7.82 mg, 39.48 μmol, 1 eq) and copper;sulfate;pentahydrate (4.93 mg, 19.74 μmol, 0.5 eq). The mixture was stirred at 50°C for 0.5 hr. The mixture was filtered and the filtrate was purified by reversed-phase HPLC (column: C1820-35μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-70% @ 70 mL / min) to give methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[(2- amino-2-oxo-ethyl)-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]propyl]amino]-2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (24 mg, 17.33 μmol, 43.91% yield) as a yellow oil. Data: LCMS (ESI+): m / z 1384.8 (M+H)+2. General procedure for preparation of methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo- ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： A solution of methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo-ethyl]triazol-4- yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (24 mg, 17.33 μmol, 1 eq) in DCM (1 mL) and TFA (0.5 mL) was stirred at 25°C for 2 hr. The DCM and TFA was removed under reduced pressure to give methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5- [[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo-ethyl]triazol-4- yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (24 mg, crude, TFA) as a yellow oil. Data: LCMS (ESI+): m / z 628.2 (M / 2+H)+3. General procedure for preparation of (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4- yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo- ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propyl]amino]-2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy] propylcarbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl- hexanoate (24 mg, 17.54 μmol, 1 eq, TFA) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (1.47 mg, 35.08 μmol, 2 eq). The mixture was stirred at 0°C for 20 min. The mixture was filtered and the filtrate was purified by reversed-phase HPLC (column: C18 20-35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-45% @ 70 mL / min) to give (2S)-2-[[6-[3-[1-[3-[2-[[1-[2-[(2-amino-2-oxo-ethyl)-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2- [4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]propyl]amino]-2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy]propylcarbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid (4.2 mg, 3.39 μmol, 19.31% yield, 100% purity) as a pale yellow solid. Data: LCMS (ESI+): m / z 1240.6 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.61 (t, J = 2.8 Hz, 1H), 8.21 (dd, J = 2.3, 8.7 Hz, 1H), 7.91 (d, J = 5.6 Hz, 1H), 7.61 (dd, J = 1.7, 8.5 Hz, 2H), 7.53 (dd, J = 2.0, 16.0 Hz, 1H), 7.33 (t, J = 8.2 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.7 Hz, 1H), 6.88(dd, J = 2.1, 15.5 Hz, 1H), 6.73 (ddd, J = 2.0, 8.2, 12.9 Hz, 2H), 6.67 - 6.60 (m, 1H), 5.50- 5.24 (m, 2H), 4.96 (br d, J = 4.0 Hz, 1H), 4.69 - 4.40 (m, 6H), 4.33 - 4.24 (m, 2H), 4.14(d, J = 3.5 Hz, 1H), 4.01 (s, 1H), 3.87 (br d, J = 8.7 Hz, 2H), 3.66 - 3.54 (m, 4H), 3.54 -3.41 (m, 4H), 3.20 (t, J = 6.6 Hz, 2H), 2.23 (s, 7H), 2.13 - 2.04 (m, 1H), 2.02 - 1.91 (m,1H), 1.88 - 1.76 (m, 1H), 1.72 (quin, J = 6.2 Hz, 2H), 1.42 - 1.27 (m, 2H), 0.91 (s, 9H),0.88 - 0.74 (m, 3H), 0.54 (br dd, J = 4.5, 7.5 Hz, 1H), 0.52 - 0.43 (m, 2H), 0.38 (br dd, J= 4.3, 9.0 Hz, 2H), 0.33 - 0.20 (m, 3H)

[0062] X-089: (2S)-2-[[6-[3-[2-[[2-amino-1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5- dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2- oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-oxo-ethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of benzyl 3-[2-(tert-butoxycarbonylamino)-3-methoxy-3-oxo-propoxy]azetidine-1-carboxylate： To a solution of benzyl 3-hydroxyazetidine-1-carboxylate (10.30 g, 49.70 mmol, 2 eq), O1-tert-butyl O2-methyl aziridine-1,2-dicarboxylate (5 g, 24.85 mmol, 1 eq) in CHCl3(50 mL) was added BF3.Et2O (705.34 mg, 4.97 mmol, 611.21 μL, 0.2 eq). The mixture was stirred at 25 °C for 20 hr. The mixture was filtered and the filtrate was purified by prep- HPLC. The residue was purified by prep-HPLC (neutral condition, column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:45%-75% B over 8.0 min) to give benzyl 3-[2-(tert-butoxycarbonylamino)- 3-methoxy-3-oxo-propoxy]azetidine-1-carboxylate (630 mg, 1.54 mmol, 6.21% yield) as a colorless oil. Data:1H NMR (400 MHz, CHLOROFORM-d) δ = 7.39 - 7.31 (m, 5H), 5.39 - 5.32 (m, 1H), 5.10(s, 2H), 4.46 (s, 1H), 4.26 - 4.22 (m, 1H), 4.13 - 4.09 (m, 1H), 3.92 - 3.81 (m, 2H), 3.79 -3.74 (m, 3H), 3.61 (dd, J = 3.2, 9.4 Hz, 1H), 1.46 (s, 9H)2. General procedure for preparation of benzyl 3-[3-amino-2-(tert-butoxycarbonylamino)-3-oxo-propoxy]azetidine-1-carboxylate： A solution of benzyl 3-[2-(tert-butoxycarbonylamino)-3-methoxy-3-oxo- propoxy]azetidine-1-carboxylate (0.5 g, 1.22 mmol, 1 eq) in NH3 / MeOH (3 mL) was stirred at 25 °C for 12 hr. The mixture was filtered and the filtrate was purified by prep- HPLC. The crude product was purified by reversed-phase HPLC (column: C1820-35 μm 100A 120 g; mobile phase: [water-ACN]; B%:0%-40% @ 100 mL / min) to give benzyl 3-[3-amino-2-(tert-butoxycarbonylamino)-3-oxo-propoxy]azetidine-1-carboxylate (330 mg, 838.77 μmol, 68.52% yield) as a white solid.3. General procedure for preparation of benzyl 3-(2,3-diamino-3-oxo-propoxy)azetidine-1-carboxylate： To a solution of benzyl 3-[3-amino-2-(tert-butoxycarbonylamino)-3-oxo- propoxy]azetidine-1-carboxylate (0.3 g, 762.52 μmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 17.66 eq). The mixture was stirred at 25 °C for 3 hr. The DCM and TFA was removed under reduced pressure to give benzyl 3-(2,3-diamino- 3-oxo-propoxy)azetidine-1-carboxylate (300 mg, crude, TFA) as a colorless oil.4. General procedure for preparation of benzyl 3-[3-amino-2-[[2-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl-pentyl]carbamoyl]-2- pyridyl]oxy]phenoxy]acetyl]amino]-3-oxo-propoxy]azetidine-1-carboxylate： To a solution of benzyl 3-(2,3-diamino-3-oxo-propoxy)azetidine-1-carboxylate (0.29 g, 711.93 μmol, 1 eq, TFA), 2-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl- pentyl]carbamoyl]-2-pyridyl]oxy]phenoxy]acetic acid (397.62 mg, 711.93 μmol, 1 eq, TFA) in DMF (1 mL) was added HATU (541.40 mg, 1.42 mmol, 2 eq) and DIEA (276.04 mg, 2.14 mmol, 372.02 μL, 3 eq) at 0°C. The mixture was stirred at 25°C for 0.5 hr. The mixture was filtered and the filtrate was purified by reversed-phase HPLC. The crude product was purified by reversed-phase HPLC (column: C1820-35 μm 100A 80 g; mobile phase: [water-ACN]; B%:0%-60% @ 100 mL / min) to give benzyl 3-[3-amino-2-[[2-[3-[[5- [[(1S)-1-methoxycarbonyl-4,4-dimethyl-pentyl]carbamoyl]-2- pyridyl]oxy]phenoxy]acetyl]amino]-3-oxo-propoxy]azetidine-1-carboxylate (0.26 g, 361.22 μmol, 50.74% yield) as a white solid. Data: LCMS (ESI+): m / z 720.4 (M+H)+5. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[[2-amino-1-(azetidin-3-yloxymethyl)-2-oxo-ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine- 3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of benzyl 3-[3-amino-2-[[2-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl- pentyl]carbamoyl]-2-pyridyl]oxy]phenoxy]acetyl]amino]-3-oxo-propoxy]azetidine-1- carboxylate (100 mg, 138.93 μmol, 1 eq) in DCM (2 mL) was added PdCl2 (49.27 mg, 277.86 μmol, 2 eq) and TEA (72.70 mg, 718.46 μmol, 0.1 mL, 5.17 eq)，then triethylsilane (48.46 mg, 416.79 μmol, 66.57 μL, 3 eq) was added into the reaction. And TFA (47.52 mg, 416.79 μmol, 30.96 μL, 3 eq) was added into the reaction after 0.5 hr and the mixture was stirred at 25 °C for 0.5 hr. The mixture was filtered and the filtrate was purified by reversed-phase HPLC (column: C1820-35 μm 100A 80 g; mobile phase: [water-ACN]; B%:0%-60% @ 100 mL / min) to give methyl (2S)-2-[[6-[3-[2-[[2-amino-1- (azetidin-3-yloxymethyl)-2-oxo-ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (45 mg, 76.84 μmol, 55.31% yield) as a white solid.6. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[[2-amino-2-oxo-1-[[1-(2-prop-2-ynoxyacetyl)azetidin-3-yl]oxymethyl]ethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-2-[[6-[3-[2-[[2-amino-1-(azetidin-3-yloxymethyl)-2-oxo- ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (40 mg, 68.30 μmol, 1 eq) and 2-prop-2-ynoxyacetic acid (7.79 mg, 68.30 μmol, 1 eq) inDMF (2 mL) was added HATU (51.94 mg, 136.60 μmol, 2 eq) and DIEA (17.65 mg,136.60 μmol, 23.79 μL, 2 eq) at 0°C. The mixture was stirred at 25°C for 0.5 hr. The mixture was filtered and the filtrate was purified by reversed-phase HPLC. The crude product was purified by reversed-phase HPLC (column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%:0%-60% @ 100 mL / min) to give methyl (2S)-2-[[6-[3-[2-[[2- amino-2-oxo-1-[[1-(2-prop-2-ynoxyacetyl)azetidin-3-yl]oxymethyl]ethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (30 mg, 44.01 μmol, 64.43% yield) as a colorless oil. Data:1H NMR (400 MHz, CHLOROFORM-d) δ = 8.66 - 8.60 (m, 1H), 8.19 (br d, J = 8.3 Hz,1H), 7.42 - 7.34 (m, 2H), 7.05 - 6.75 (m, 5H), 6.25 (br d, J = 1.1 Hz, 1H), 5.60 - 5.47 (m,1H), 4.78 (q, J = 6.6 Hz, 1H), 4.68 - 4.63 (m, 1H), 4.58 (s, 2H), 4.48 - 4.28 (m, 2H), 4.26- 4.19 (m, 3H), 4.17 - 4.12 (m, 2H), 3.94 - 3.84 (m, 2H), 3.79 (s, 3H), 3.60 - 3.48 (m, 1H),2.49 (br d, J = 2.0 Hz, 1H), 2.51 - 2.44 (m, 1H), 1.99 - 1.87 (m, 1H), 1.82 - 1.70 (m, 1H),1.32 (br d, J = 5.1 Hz, 1H), 1.18 (br s, 1H), 1.25 - 1.17 (m, 1H), 0.88 (s, 9H)7. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[[2-amino-1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-oxo-ethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-2-[[6-[3-[2-[[2-amino-2-oxo-1-[[1-(2-prop-2- ynoxyacetyl)azetidin-3-yl]oxymethyl]ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (25 mg, 36.67 μmol, 1 eq) and 2-[3-[(2- azidoacetyl)amino]propyl]-N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole-3-carboxamide (27.38 mg, 36.67 μmol, 1 eq) in t-BuOH (1 mL) and H2O (1 mL) was added sodium;(2R)- 2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (7.26 mg, 36.67 μmol, 1 eq) and copper;sulfate;pentahydrate (4.58 mg, 18.34 μmol, 0.5 eq). The mixture was stirred at 50°C for 0.5 hr. The mixture was filtered and the filtrate was purified by reversed-phase HPLC(column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%:0%-70% @ 100 mL / min) to give methyl (2S)-2-[[6-[3-[2-[[2-amino-1-[[1-[2-[[1-[2-[3- [5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]propylamino]-2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-oxo- ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (30 mg, 21.67 μmol, 59.08% yield) as a colorless oil.8. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[[2-amino-1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4- yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-oxo-ethyl]amino]- 2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-2-[[6-[3-[2-[[2-amino-1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-oxo-ethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (30 mg, 21.67 μmol, 1 eq) in DCM (1.5 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 310.67 eq). The mixture was stirred at 25 °C for 2 hr. The DCM and TFA was removed under reduced pressure to give methyl (2S)-2-[[6-[3-[2-[[2-amino-1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl] pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3- yl]oxymethyl]-2-oxo-ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoate (30 mg, crude, TFA) as a colorless oil.9. General procedure for preparation of (2S)-2-[[6-[3-[2-[[2-amino-1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]- 2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-oxo-ethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[2-[[2-amino-1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl] pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3- yl]oxymethyl]-2-oxo-ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoate (25 mg, 18.27 μmol, 1 eq, TFA) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (1.53 mg, 36.54 μmol, 2 eq). The mixture was stirred at 0 °C for 20 min. The mixture was filtered and the filtrate was purified by reversed-phase HPLC(column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%:0%-50% @ 60 mL / min) to give (2S)-2-[[6-[3-[2-[[2-amino-1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-oxo-ethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid (3.4 mg, 2.57 μmol, 14.05% yield, 93.672% purity) as a pale yellow solid. Date: LCMS (ESI+): m / z 1240.6 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.61 (s, 1H), 8.24 - 8.19 (m, 1H), 8.01 (d, J =4.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.34 (t, J = 8.2 Hz, 1H),7.22 (d, J = 7.7 Hz, 2H), 6.97 (dd, J = 2.1, 8.7 Hz, 1H), 6.91 - 6.86 (m, 2H), 6.83 - 6.80(m, 1H), 6.77 (br d, J = 8.2 Hz, 1H), 5.11 (d, J = 2.1 Hz, 2H), 4.66 (br s, 3H), 4.60 - 4.57(m, 3H), 4.55 (br s, 3H), 4.36 - 4.24 (m, 2H), 4.15 - 4.07 (m, 1H), 4.04 - 3.97 (m, 3H),3.80 - 3.70 (m, 2H), 3.68 - 3.61 (m, 1H), 3.23 - 3.11 (m, 2H), 2.22 (s, 6H), 2.03 (br t, J =6.7 Hz, 2H), 1.98 - 1.90 (m, 1H), 1.86 - 1.76 (m, 1H), 1.40 - 1.27 (m, 2H), 0.91 (s, 9H),0.89 - 0.77 (m, 3H), 0.59 - 0.52 (m, 1H), 0.47 (ddd, J = 4.8, 8.4, 13.1 Hz, 2H), 0.43 - 0.35(m, 2H), 0.33 - 0.21 (m, 3H)X-090: (2S)-2-[[6-[3-[1-[[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo- ethyl]triazol-4-yl]methoxy]ethoxy]-2-hydroxy-propyl]carbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of 3-(2-prop-2-ynoxyethoxy)prop-1-ene： To a solution of 2-prop-2-ynoxyethanol (2 g, 19.98 mmol, 1 eq) in DMF (30 mL)was added NaH (1.20 g, 29.97 mmol, 60% purity, 1.5 eq) at 0°C, the reaction was stirred at 0°C for 0.5 h. Then 3-bromoprop-1-ene (2.42 g, 19.98 mmol, 1 eq) was added to the mixture. The mixture was stirred at 25°C for 0.5 h. The reaction mixture was added to sat.NH4Cl (30 mL), extracted with ethyl acetate (30 mL * 3), washed with brine (50 mL). The organic layer was dried over Na2SO4, concentrated to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1) to give 3-(2-prop-2-ynoxyethoxy)prop-1-ene (1.62 g, 11.56 mmol, 57.85% yield) as a colourless oil. Data:1H NMR (400 MHz, CHLOROFORM-d) δ = 5.92 (tdd, J = 5.6, 11.0, 16.9 Hz, 1H), 5.37 -5.12 (m, 2H), 4.22 (d, J = 2.1 Hz, 2H), 4.03 (d, J = 5.5 Hz, 2H), 3.76 - 3.68 (m, 2H), 3.66- 3.58 (m, 2H), 2.43 (t, J = 2.1 Hz, 1H)2. General procedure for preparation of 2-(2-prop-2-ynoxyethoxymethyl)oxirane： To a solution of 3-(2-prop-2-ynoxyethoxy)prop-1-ene (1.52 g, 10.84 mmol, 1 eq) in DCM (20 mL) was added m-CPBA (3.30 g, 16.26 mmol, 85% purity, 1.5 eq). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was quenched by sat.Na2SO3(20 mL), extracted with EtOAc (30 mL * 3). The organic layer was dried over Na2SO4, concentrated to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1) to give 2-(2-prop-2- ynoxyethoxymethyl)oxirane (1.7 g, crude) as a colourless oil. Data:1H NMR (400 MHz, CHLOROFORM-d) δ = 4.15 (d, J = 2.3 Hz, 2H), 3.74 (dd, J = 3.1,11.6 Hz, 1H), 3.70 - 3.57 (m, 4H), 3.37 (dd, J = 5.9, 11.7 Hz, 1H), 3.11 (tdd, J = 2.9, 4.1,5.8 Hz, 1H), 2.74 (t, J = 4.6 Hz, 1H), 2.55 (dd, J = 2.8, 5.0 Hz, 1H), 2.37 (t, J = 2.3 Hz, 1H)3. General procedure for preparation of 1-amino-3-(2-prop-2-ynoxyethoxy)propan-2-ol: A mixture of 2-(2-prop-2-ynoxyethoxymethyl)oxirane (400 mg, 2.56 mmol, 1 eq) in NH3 / MeOH (4 mL) (7 M) was stirred at 50 °C for 5 hr. The reaction mixture was concentrated to give 1-amino-3-(2-prop-2-ynoxyethoxy)propan-2-ol (440 mg, crude) as a colourless oil.4. General procedure for preparation of tert-butyl N-[2-hydroxy-3-(2-prop-2-ynoxyethoxy)propyl]carbamate: To a solution of 1-amino-3-(2-prop-2-ynoxyethoxy)propan-2-ol (440 mg, 2.54 mmol, 1 eq) in DCM (10 mL) was added TEA (514.10 mg, 5.08 mmol, 707.15 μL, 2 eq) and Boc2O (831.61 mg, 3.81 mmol, 875.38 μL, 1.5 eq). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was added into water (2 mL) and extracted with DCM (3 mL *3). The combined organic layers were washed with brine (8 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 1 : 1) to give tert-butyl N-[2-hydroxy- 3-(2-prop-2-ynoxyethoxy)propyl]carbamate (312 mg, 1.14 mmol, 44.94% yield) as a colourless oil. Data:1H NMR (400 MHz, CHLOROFORM-d) δ = 5.12 - 5.01 (m, 1H), 4.22 (d, J = 2.3 Hz, 2H),3.94 - 3.85 (m, 1H), 3.77 - 3.65 (m, 4H), 3.60 - 3.53 (m, 1H), 3.51 - 3.43 (m, 1H), 3.37(br d, J = 13.6 Hz, 1H), 3.20 - 3.11 (m, 1H), 2.47 (t, J = 2.3 Hz, 1H), 1.46 (s, 9H)5. General procedure for preparation of 1-amino-3-(2-prop-2-ynoxyethoxy)propan-2-ol: To a solution of tert-butyl N-[2-hydroxy-3-(2-prop-2-ynoxyethoxy)propyl]carbamate (150 mg, 548.80 μmol, 1 eq) in DCM (1 mL) was added TFA (0.3 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to give 1-amino-3-(2-prop-2- ynoxyethoxy)propan-2-ol (150 mg, crude, TFA) as a colourless oil.6. General procedure for preparation of methyl (2S)-2-[[6-[3-(azetidin-3-yloxy)phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate: To a solution of tert-butyl 3-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl- pentyl]carbamoyl]-2-pyridyl]oxy]phenoxy]azetidine-1-carboxylate (200 mg, 369.25 μmol, 1 eq) in DCM (1 mL) was added TFA (0.2 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to give methyl (2S)-2-[[6-[3-(azetidin-3- yloxy)phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (400 mg, crude, TFA) as a brown oil. Data:LCMS (ESI+): m / z 442.1 (M+H)+7. General procedure for preparation of (4-nitrophenyl) 3-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl-pentyl]carbamoyl]-2- pyridyl]oxy]phenoxy]azetidine-1-carboxylate: To a solution of methyl (2S)-2-[[6-[3-(azetidin-3-yloxy)phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (350 mg, 630.02 μmol, 2 eq, TFA) in DMF (4 mL)was added DIEA (122.14 mg, 945.02 μmol, 164.61 μL, 3 eq) and bis(4-nitrophenyl)carbonate (95.83 mg, 315.01 μmol, 1 eq). The mixture was stirred at 25 °C for 1 hr. Thereaction mixture was filtered and the filtrate was purified by reversed-phase HPLC(column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-75% @ 80 mL / min) to give (4-nitrophenyl) 3-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl- pentyl]carbamoyl]-2-pyridyl]oxy]phenoxy]azetidine-1-carboxylate (105 mg, 173.09 μmol, 54.95% yield) as a white solid. Data:LCMS (ESI+): m / z 607.2 (M+H)+8. General procedure for preparation of methyl (2S)-2-[[6-[3-[1-[[2-hydroxy-3-(2-prop-2-ynoxyethoxy)propyl]carbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate: To a solution of 1-amino-3-(2-prop-2-ynoxyethoxy)propan-2-ol (40.25 mg, 140.12 μmol, 1 eq, TFA) and (4-nitrophenyl) 3-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl- pentyl]carbamoyl]-2-pyridyl]oxy]phenoxy]azetidine-1-carboxylate (85 mg, 140.12 μmol,1.00 eq) in DMF (1 mL) was added DIEA (54.33 mg, 420.36 μmol, 73.22 μL, 3 eq) andHOBt (28.40 mg, 210.18 μmol, 1.5 eq). The mixture was stirred at 50 °C for 4 hr. Then the mixture was stirred at 50 °C for 12 hr. The reaction mixture was filtered and the filtrate was purified by reversed-phase HPLC(column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-75% @ 60 mL / min) to give methyl (2S)-2-[[6-[3-[1-[[2-hydroxy-3- (2-prop-2-ynoxyethoxy)propyl]carbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (40 mg, 62.43 μmol, 44.55% yield) as a white solid. Data:LCMS (ESI+): m / z 641.2 (M+H)+9. General procedure for preparation of methyl (2S)-2-[[6-[3-[1-[[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxyme- thyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2- oxo-ethyl]triazol-4-yl]methoxy]ethoxy]-2-hydroxy-propyl]carbamoyl]azetidin- 3-yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate: To a solution of methyl (2S)-2-[[6-[3-[1-[[2-hydroxy-3-(2-prop-2- ynoxyethoxy)propyl]carbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3-carbonyl]amino]- 5,5-dimethyl-hexanoate (40.00 mg, 62.43 μmol, 1 eq) and 2-[3-[(2- azidoacetyl)amino]propyl]-N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole-3-carboxamide (43.88 mg, 62.43 μmol, 1 eq) in t-BuOH (0.5 mL) and H2O (0.5 mL) was added CuSO4.5H2O (15.59 mg, 62.43 μmol, 1 eq) and sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]- 4-hydroxy-5-oxo-2H-furan-3-olate (12.37 mg, 62.43 μmol, 1 eq). The mixture was stirred at 50 °C for 1 hr. The reaction mixture was filtered and the filtrate was purified by reversed-phase HPLC(column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-75% @ 60 mL / min) to give methyl (2S)-2-[[6-[3-[1-[[3-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]ethoxy]-2-hydroxy-propyl]carbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (56 mg, 41.68 μmol, 66.76% yield) as a yellow solid. Data: LCMS (ESI+): m / z 1343.5 (M+H)+10. General procedure for preparation of methyl (2S)-2-[[6-[3-[1-[[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyraz-ol-4-yl)anilino]-2- oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4-yl]meth- oxy]ethoxy]-2-hydroxy-propyl]carbamoyl]azetidin-3-yl]oxyphenoxy]pyridine- 3-carbonyl]amino]-5,5-dimethyl-hexanoate: To a solution of methyl (2S)-2-[[6-[3-[1-[[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)- 2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy]-2- hydroxy-propyl]carbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoate (30 mg, 22.33 μmol, 1 eq) in DCM (0.6 mL) was added TFA (307.00 mg, 2.69 mmol, 0.2 mL, 120.59 eq). The mixture was stirred at 0°C for 1 hr. The mixture was stirred at 25°C for 11 hr. The reaction mixture was concentrated to give methyl (2S)- 2-[[6-[3-[1-[[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H- pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo- ethyl]triazol-4-yl]methoxy]ethoxy]-2-hydroxy-propyl]carbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (30 mg, crude, TFA) as a colourless oil. Data: LCMS (ESI+): m / z 1213.5 (M+H)+11. General procedure for preparation of (2S)-2-[[6-[3-[1-[[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyraz-ol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4-yl]meth- oxy]ethoxy]-2-hydroxy-propyl]carbamoyl]azetidin-3-yl]oxyphenoxy]pyridine- 3-carbonyl]amino]-5,5-dimethyl-hexanoic acid: To a solution of methyl (2S)-2-[[6-[3-[1-[[3-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)- 2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1- yl]propylamino]-2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy]-2-hydroxy- propyl]carbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl- hexanoate (30 mg, 24.72 μmol, 1 eq) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (4.15 mg, 98.90 μmol, 4 eq). The mixture was stirred at 0 °C for 1 hr. The reaction mixture was filtered and the filtrate was purified by prep-HPLC(FA condition; column: Phenomenex luna C18100*40mm*3 μm; mobile phase: [H2O(0.2% FA)-ACN]; gradient:35%-65% B over 8.0 min) to give (2S)-2-[[6-[3-[1-[[3-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4-yl]methoxy]ethoxy]-2- hydroxy-propyl]carbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5- dimethyl-hexanoic acid (10 mg, 8.10 μmol, 32.78% yield, 97.202% purity) as a white solid. Data: LCMS (ESI+): m / z 1221.5 (M+Na)+1H NMR (400 MHz, METHANOL-d4) δ = 8.62 (d, J = 2.2 Hz, 1H), 8.29 - 8.18 (m, 1H),7.99 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 1.7 Hz, 1H), 7.33 (t, J = 8.3 Hz, 1H),7.22 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 1.7 Hz, 1H), 6.80 - 6.67(m, 2H), 6.64 (s, 1H), 5.10 (s, 2H), 4.98 (br d, J = 3.4 Hz, 1H), 4.66 - 4.45 (m, 5H), 4.31(br t, J = 7.6 Hz, 2H), 3.91 (br d, J = 8.8 Hz, 2H), 3.76 (quin, J = 5.4 Hz, 1H), 3.63 (br dd,J = 5.2, 14.2 Hz, 4H), 3.49 - 3.39 (m, 2H), 3.29 - 3.09 (m, 4H), 2.22 (s, 6H), 2.09 - 2.00(m, 2H), 1.99 - 1.90 (m, 1H), 1.87 - 1.73 (m, 1H), 1.40 - 1.27 (m, 2H), 0.90 (s, 9H), 0.89- 0.73 (m, 3H), 0.62 - 0.52 (m, 1H), 0.48 (ddd, J = 4.6, 8.5, 13.1 Hz, 2H), 0.43 - 0.34 (m,2H), 0.33 - 0.20 (m, 3H)X-092: (2S)-2-[[6-[3-[2-[[1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl- 1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-hydroxy-ethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of 3-[tert-butyl(dimethyl)silyl]oxy-2-(dibenzylamino)propan-1-ol： To a solution of 2-(dibenzylamino)propane-1,3-diol (2 g, 7.37 mmol, 1 eq) in DMF (35 mL) was added imidazole (551.94 mg, 8.11 mmol, 1.1 eq) and TBSCl (999.80 mg, 6.63 mmol, 816.16 μL, 0.9 eq) at 25 °C. The mixture was stirred at 25 °C for 48 hr. The reaction mixture was added into ice water (100 mL) and then extracted with EtOAc (40 mL * 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 100 mL / min, Petroleum ether : Ethyl acetate = 5:1) to give 3-[tert-butyl(dimethyl)silyl]oxy-2-(dibenzylamino)propan-1-ol (1.28 g, crude) as a colorless oil. Data: LCMS (ESI+): m / z 386.4 (M+H)+2. General procedure for preparation of N,N-dibenzyl-1-[tert-butyl(dimethyl)silyl]oxy-3-iodo-propan-2-amine： To a solution of 3-[tert-butyl(dimethyl)silyl]oxy-2-(dibenzylamino)propan-1-ol (1 g, 2.59 mmol, 1 eq) in DCM (35 mL) was added imidazole (264.81 mg, 3.89 mmol, 1.5 eq) and PPh3(816.21 mg, 3.11 mmol, 1.2 eq) and I2(756.92 mg, 2.98 mmol, 600.73 μL, 1.15 eq) at 25 °C. The mixture was stirred at 25 °C for 12 hr. LCMS showed desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 80 mL / min, Petroleum ether : Ethyl acetate = 20 : 1) to give N,N-dibenzyl-1-[tert- butyl(dimethyl)silyl]oxy-3-iodo-propan-2-amine (1 g, crude) as a colorless oil. Data:1H NMR (400 MHz, CHLOROFORM-d) δ = 7.41 - 7.36 (m, 4H), 7.36 - 7.28 (m, 5H), 7.26- 7.22 (m, 1H), 4.14 - 4.06 (m, 1H), 3.79 (dd, J = 4.1, 5.3 Hz, 2H), 3.70 - 3.63 (m, 2H),3.60 - 3.54 (m, 2H), 2.88 (d, J = 7.3 Hz, 2H), 0.88 (s, 9H), 0.06 - 0.03 (m, 6H)3. General procedure for preparation of tert-butyl 3-[3-[tert-butyl(dimethyl)silyl]oxy-2-(dibenzylamino)propoxy]azetidine-1-carboxylate： To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (0.39 g, 2.25 mmol, 1 eq) in THF (20 mL) was added NaH (117.08 mg, 2.93 mmol, 60% purity, 1.3 eq) at 0 °C under N2atmosphere, the mixture was stirred at 0 °C for 0.5 h, then a solution of N,N-dibenzyl- 1-[tert-butyl(dimethyl)silyl]oxy-3-iodo-propan-2-amine (1.00 g, 2.03 mmol, 0.9 eq) in THF (5 mL) was added into the above mixture at 0 °C. The mixture was stirred at 70 °C for 12 h under N2atmosphere. The reaction mixture was added into ice sat. NH4Cl solution (50 mL) slowly and then extracted with EtOAc (40 mL * 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 100 mL / min, Petroleum ether : Ethyl acetate = 5 : 1) to give tert-butyl 3-[3- [tert-butyl(dimethyl)silyl]oxy-2-(dibenzylamino)propoxy]azetidine-1-carboxylate (0.8 g, 1.48 mmol, 65.70% yield) as a yellow oil. Data: LCMS (ESI+): m / z 541.4 (M+H)+1H NMR (400 MHz, CHLOROFORM-d) δ = 7.40 - 7.35 (m, 4H), 7.29 (t, J = 7.5 Hz, 4H),7.24 - 7.18 (m, 2H), 4.18 - 4.11 (m, 1H), 4.07 - 4.01 (m, 2H), 3.83 - 3.74 (m, 8H), 3.54(d, J = 5.9 Hz, 2H), 2.95 (quin, J = 5.7 Hz, 1H), 1.45 (s, 9H), 0.89 (s, 9H), 0.03 (d, J = 6.5Hz, 6H)4. General procedure for preparation of tert-butyl 3-[2-amino-3-[tert-butyl(dimethyl)silyl]oxy-propoxy]azetidine-1-carboxylate： To a solution of tert-butyl 3-[3-[tert-butyl(dimethyl)silyl]oxy-2- (dibenzylamino)propoxy]azetidine-1-carboxylate (380 mg, 702.65 μmol, 1 eq) in EtOAc (25 mL) was added Pd / C (0.1 g, 10% purity) and NH3.H2O (147.75 mg, 1.05 mmol, 162.36 μL, 25% purity, 1.5 eq) at 25 °C. Then the mixture was degassed and purged with H2three times. The mixture was stirred at 25 °C for 12 hr under H2atmosphere (15 psi). The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give tert-butyl 3-[2-amino-3-[tert-butyl(dimethyl)silyl]oxy-propoxy]azetidine- 1-carboxylate (260 mg, crude) as a colorless oil. Data:1H NMR (400 MHz, CHLOROFORM-d) δ = 4.26 - 4.18 (m, 1H), 4.07 (dd, J = 6.6, 9.2 Hz,2H), 3.84 (dd, J = 4.2, 9.5 Hz, 2H), 3.65 - 3.53 (m, 2H), 3.45 - 3.27 (m, 2H), 3.05 (quin,J = 5.5 Hz, 1H), 1.44 (s, 9H), 0.90 (s, 9H), 0.07 (s, 6H)5. General procedure for preparation of tert-butyl 3-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[2-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl- pentyl]carbamoyl]-2-pyridyl]oxy]phenoxy]acetyl]amino]propoxy]azetidine-1- carboxylate： To a solution of 2-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl-pentyl]carbamoyl]-2- pyridyl]oxy]phenoxy]acetic acid (200 mg, 358.10 μmol, 1 eq, TFA) and tert-butyl 3-[2- amino-3-[tert-butyl(dimethyl)silyl]oxy-propoxy]azetidine-1-carboxylate (167.85 mg, 465.53 μmol, 1.3 eq) in DMF (5 mL) was added HATU (177.01 mg, 465.53 μmol, 1.3 eq) and DIEA (138.85 mg, 1.07 mmol, 187.12 μL, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered to give the filtrate. The filtrate was purified by reversed-phase HPLC (column: C1820-35 μm 100A 80 g; mobile phase: [water-ACN]; B%: 0%-95% @ 90 mL / min) to give tert-butyl 3-[3-[tert- butyl(dimethyl)silyl]oxy-2-[[2-[3-[[5-[[(1S)-1-methoxycarbonyl-4,4-dimethyl- pentyl]carbamoyl]-2-pyridyl]oxy]phenoxy]acetyl]amino]propoxy]azetidine-1-carboxylate (160 mg, crude) as a light yellow solid. Data: LCMS (ESI+): m / z 787.6 (M+H)+6. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[[1-(azetidin-3-yloxymethyl)-2-hydroxy-ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of tert-butyl 3-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[2-[3-[[5-[[(1S)-1- methoxycarbonyl-4,4-dimethyl-pentyl]carbamoyl]-2-pyridyl]oxy]phenoxy]acetyl]amino] propoxy]azetidine-1-carboxylate (160 mg, 203.30 μmol, 1 eq) in DCM (2 mL) was added TFA (0.4 mL) at 25 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-[[6-[3-[2-[[1-(azetidin-3- yloxymethyl)-2-hydroxy-ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]- 5,5-dimethyl-hexanoate (140 mg, crude, TFA) as a yellow oil. Data: LCMS (ESI+): m / z 573.4 (M+H)+7. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[[1-(hydroxymethyl)-2-[1-(2-prop-2-ynoxyacetyl)azetidin-3-yl]oxy-ethyl]amino]-2- oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-2-[[6-[3-[2-[[1-(azetidin-3-yloxymethyl)-2-hydroxy- ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (140 mg, 203.88 μmol, 1 eq, TFA) and 2-prop-2-ynoxyacetic acid (25.59 mg, 224.27 μmol, 1.1 eq) in DMF (2.5 mL) was added HATU (100.78 mg, 265.05 μmol, 1.3 eq) and DIEA (79.05 mg, 611.65 μmol, 106.54 μL, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hr. The reaction mixture was filtered to give the filtrate. The filtrate was purified by reversed-phase HPLC (column: C1820-35 μm 100A 120 g; mobile phase: [water- ACN]; B%: 0%-55% @ 90 mL / min) to give methyl (2S)-2-[[6-[3-[2-[[1-(hydroxymethyl)-2- [1-(2-prop-2-ynoxyacetyl)azetidin-3-yl]oxy-ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine- 3-carbonyl]amino]-5,5-dimethyl-hexanoate (98 mg, crude) as a white solid. Data: LCMS (ESI+): m / z 669.5 (M+H)+1H NMR (400 MHz, CHLOROFORM-d) δ = 8.66 - 8.59 (m, 1H), 8.21 - 8.16 (m, 1H), 7.37(t, J = 8.1 Hz, 1H), 7.08 - 7.00 (m, 2H), 6.95 - 6.87 (m, 1H), 6.83 (br t, J = 7.2 Hz, 2H),6.77 (br dd, J = 2.3, 4.6 Hz, 1H), 4.82 - 4.74 (m, 1H), 4.55 (s, 2H), 4.47 - 4.39 (m, 1H),4.32 - 4.24 (m, 1H), 4.23 (br s, 3H), 4.16 (br dd, J = 4.3, 8.4 Hz, 1H), 4.13 - 4.04 (m, 3H),3.92 - 3.81 (m, 2H), 3.79 (s, 3H), 3.73 - 3.67 (m, 1H), 3.64 - 3.58 (m, 1H), 3.56 - 3.50 (m,1H), 2.49 (br d, J = 2.2 Hz, 1H), 2.00 - 1.91 (m, 1H), 1.32 - 1.16 (m, 3H), 0.88 (s, 9H)8. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[[1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-hydroxy-ethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-2-[[6-[3-[2-[[1-(hydroxymethyl)-2-[1-(2-prop-2- ynoxyacetyl)azetidin-3-yl]oxy-ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (30 mg, 44.86 μmol, 1 eq) and 2-[3-[(2- azidoacetyl)amino]propyl]-N-[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]anilino]-2-oxo-ethyl]pyrazole-3-carboxamide (34.69 mg, 49.35 μmol, 1.1 eq) in t-BuOH (1 mL) and H2O (1 mL) was added CuSO4.5H2O (5.60 mg, 22.43 μmol, 0.5 eq) and sodium;(2R)-2-[(1S)-1,2- dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (8.89 mg, 44.86 μmol, 1 eq) at 25 °C. The mixture was stirred at 50 °C for 1 h. The reaction mixture was filtered to give the filtrate. The filtrate was purified by reversed-phase HPLC (column: C1820-35 μm 100A 40 g; mobile phase: [water-ACN]; B%: 0%-78% @ 65 mL / min) to give methyl (2S)-2-[[6- [3-[2-[[1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl) pyrazol-4-yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo- ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-hydroxy-ethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (37 mg, crude) as a white solid. Data: LCMS (ESI+): m / z 1371.8 (M+H)+9. General procedure for preparation of methyl (2S)-2-[[6-[3-[2-[[1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2- oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-hydroxy-ethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of methyl (2S)-2-[[6-[3-[2-[[1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-hydroxy-ethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (37 mg, 26.97 μmol, 1 eq) in DCM (1.2 mL) was added TFA (0.4 mL) at 25 °C. The mixture was stirred at 25 °C for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-[[6-[3-[2-[[1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5- dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2- oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-hydroxy-ethyl]amino]-2- oxo-ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (36 mg, crude, TFA) as a colorless oil. Data: LCMS (ESI+): m / z 1241.7 (M+H)+10. General procedure for preparation of (2S)-2-[[6-[3-[2-[[1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo- ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4- yl]methoxy]acetyl]azetidin-3-yl]oxymethyl]-2-hydroxy-ethyl]amino]-2-oxo- ethoxy]phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid： To a solution of methyl (2S)-2-[[6-[3-[2-[[1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl] pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3- yl]oxymethyl]-2-hydroxy-ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (36 mg, 26.56 μmol, 1 eq, TFA) in THF (1 mL) and H2O (0.5 mL) was added LiOH.H2O (3.34 mg, 79.68 μmol, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The residue was concentrated under the reduced pressure to remove THF and the residue was adjusted pH~5 by using formic acid to give a solution. The residue was purified by prep-HPLC (neutral condition; column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:25%-55% B over 8.0 min) to give (2S)-2-[[6-[3-[2-[[1-[[1-[2-[[1-[2-[3-[5-[[(1S)-1- (dicyclopropylmethyl)-2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl] pyrazol-1-yl]propylamino]-2-oxo-ethyl]triazol-4-yl]methoxy]acetyl]azetidin-3- yl]oxymethyl]-2-hydroxy-ethyl]amino]-2-oxo-ethoxy]phenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoic acid (11.1 mg, 8.90 μmol, 33.52% yield, 98.453% purity) as a white solid. Data: LCMS (ESI+): m / z 1227.6 (M+H)+1H NMR (400 MHz, METHANOL-d4) δ = 8.62 (d, J = 2.1 Hz, 1H), 8.26 - 8.19 (m, 1H),8.02 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 1.8 Hz, 1H), 7.34 (t, J = 8.2Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.81 (s,1H), 6.77 (br d, J = 8.3 Hz, 1H), 5.11 (s, 2H), 4.70 - 4.54 (m, 6H), 4.54 - 4.46 (m, 2H),4.38 - 4.31 (m, 1H), 4.27 (br d, J = 4.2 Hz, 1H), 4.18 - 4.09 (m, 2H), 4.06 - 3.98 (m, 3H),3.82 - 3.73 (m, 1H), 3.67 - 3.56 (m, 2H), 3.55 - 3.44 (m, 2H), 3.23 - 3.11 (m, 2H), 2.22 (s,6H), 2.08 - 2.00 (m, 2H), 1.99 - 1.91 (m, 1H), 1.87 - 1.75 (m, 1H), 1.38 - 1.29 (m, 2H),0.90 (s, 10H), 0.87 - 0.76 (m, 2H), 0.60 - 0.52 (m, 1H), 0.52 - 0.43 (m, 2H), 0.42 - 0.35(m, 2H), 0.33 - 0.23 (m, 3H)X-093: (2S)-2-[[6-[3-[1-[[3-amino-2-[2-[[1-[2-[3-[5-[[(1S)-1-(dicyclopropylmethyl)-2-[4-(3,5- dimethyl-1H-pyrazol-4-yl)anilino]-2-oxo-ethyl]carbamoyl]pyrazol-1-yl]propylamino]-2- oxo-ethyl]triazol-4-yl]methoxy]ethoxymethyl]-3-oxo-propyl]carbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoic acid1. General procedure for preparation of methyl 2-(2-prop-2-ynoxyethoxymethyl)prop-2-enoate： To a solution of 2-prop-2-ynoxyethanol (3 g, 29.97 mmol, 1 eq) in DMF (80 mL) was added NaH (1.56 g, 38.96 mmol, 60% purity, 1.3 eq) at 0 °C, the mixture was stirred at 0 °C for 0.5 h, then a solution of methyl 2-(bromomethyl)prop-2-enoate (6.17 g, 34.46 mmol, 1.15 eq) in DMF (3 mL) was added into the above mixture at 0 °C. The mixture was stirred at 25 °C for 2.5 h. The reaction mixture was added into ice sat.NH4Cl solution (100 mL) slowly and then extracted with EtOAc (50 mL * 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 85 mL / min, Petroleum ether : Ethyl acetate = 5 : 1) to give methyl 2-(2- prop-2-ynoxyethoxymethyl)prop-2-enoate (1.34 g, crude) as a colorless oil. Data:1H NMR (400 MHz, CHLOROFORM-d) δ = 6.32 (d, J = 1.3 Hz, 1H), 5.92 (d, J = 1.6 Hz,1H), 4.26 (t, J = 1.4 Hz, 2H), 4.23 - 4.21 (m, 2H), 3.77 (s, 3H), 3.75 - 3.72 (m, 2H), 3.71- 3.68 (m, 2H), 2.44 (t, J = 2.4 Hz, 1H)2. General procedure for preparation of 2-(aminomethyl)-3-(2-prop-2-ynoxyethoxy)propanamide： The reaction was set up in 5 parallel batches. A mixture of methyl 2-(2-prop-2-ynoxyethoxymethyl)prop-2-enoate (400 mg, 2.02 mmol, 1 eq) in NH3 / MeOH (8 mL) (7M) was stirred at 70 °C for 36 h. The combined reaction mixture was concentrated under reduced pressure to give 2-(aminomethyl)-3-(2-prop-2- ynoxyethoxy)propanamide (2 g, crude) as an off white solid.3. General procedure for preparation of tert-butyl N-[3-amino-3-oxo-2-(2-prop-2-ynoxyethoxymethyl)propyl]carbamate： To a solution of 2-(aminomethyl)-3-(2-prop-2-ynoxyethoxy)propanamide (2 g, 9.99 mmol, 1 eq) in DCM (50 mL) was added Boc2O (2.62 g, 11.99 mmol, 2.75 mL, 1.2 eq) and TEA (2.02 g, 19.98 mmol, 2.78 mL, 2 eq) and DMAP (122.02 mg, 998.83 μmol, 0.1 eq) at 25 °C. The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether to 0~3% Methanol / Ethyl acetate gradient @ 100 mL / min, Petroleum ether : Ethyl acetate = 0 : 1) to give tert-butyl N-[3-amino-3-oxo- 2-(2-prop-2-ynoxyethoxymethyl)propyl]carbamate (310 mg, crude) as a colorless oil. Data: LCMS (ESI+): m / z 301.2 (M+H)+1H NMR (400 MHz, CHLOROFORM-d) δ = 4.20 (d, J = 2.3 Hz, 2H), 3.73 - 3.64 (m, 6H),3.45 - 3.31 (m, 2H), 2.73 (br d, J = 7.0 Hz, 1H), 2.46 (t, J = 2.3 Hz, 1H), 1.43 (s, 9H)4. General procedure for preparation of 2-(aminomethyl)-3-(2-prop-2-ynoxyethoxy)propanamide： To a solution of tert-butyl N-[3-amino-3-oxo-2-(2-prop-2- ynoxyethoxymethyl)propyl]carbamate (280 mg, 932.25 μmol, 1 eq) in DCM (3 mL) was added TFA (0.6 mL) at 25 °C. The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give 2-(aminomethyl)-3-(2-prop-2- ynoxyethoxy)propanamide (290 mg, crude, TFA) as a colorless oil.5. General procedure for preparation of N-[3-amino-3-oxo-2-(2-prop-2-ynoxyethoxymethyl)propyl]imidazole-1-carboxamide： To a solution of 2-(aminomethyl)-3-(2-prop-2-ynoxyethoxy)propanamide (290 mg, 922.81 μmol, 1 eq, TFA) in ACN (5 mL) was added CDI (157.11 mg, 968.95 μmol, 1.05 eq) and TEA (280.13 mg, 2.77 mmol, 385.33 μL, 3 eq) at 25 °C. The mixture was stirred at 25 °C for 1.5 h. Then the reaction was stirred at 25 °C for 2 h. The crude product N- [3-amino-3-oxo-2-(2-prop-2-ynoxyethoxymethyl)propyl]imidazole-1-carboxamide (270 mg, crude) in solvent ACN (5mL) as a yellow solution was used into the next step directly. Data: LCMS (ESI+): m / z 295.3 (M+H)6. General procedure for preparation of methyl (2S)-2-[[6-[3-[1-[[3-amino-3-oxo-2-(2-prop-2-ynoxyethoxymethyl)propyl]carbamoyl]azetidin-3- yl]oxyphenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate： To a solution of N-[3-amino-3-oxo-2-(2-prop-2-ynoxyethoxymethyl)propyl]imidazole-1- carboxamide (264.88 mg, 900.02 μmol, 2.5 eq) in ACN (5 mL) was added methyl (2S)- 2-[[6-[3-(azetidin-3-yloxy)phenoxy]pyridine-3-carbonyl]amino]-5,5-dimethyl-hexanoate (200 mg, 360.01 μmol, 1 eq, TFA) and TEA (109.29 mg, 1.08 mmol, 150.33 μL, 3 eq) at 25 °C. The mixture was stirred at 60 °C for 3 hr. The reaction mixture was filtered to give the filtrate. The filtrate was purified by reversed-phase HPLC (column: C1820- 35μm 100A 120g; mobile phase: [water-ACN]; B%: 0%-65% @ 85 mL / min) to give methyl (2S)-2-[[6-[3-[1-[[3-amino-3-oxo-2-(2-prop-2- ynoxyethoxymethyl)propyl]carbamoyl]azetidin-3-yl]oxyphenoxy]pyridine-3- carbonyl]amino]-5,5-dimethyl-hexanoate (68 mg, crude) as a white solid. Data: LCMS (ESI+): m / z 668.4 (M+H)+7...

Claims

Claims1. A bifunctional compound according to Formula (I):wherein SL is a moiety that binds to Sortilin according to formula A-Iformula (A-I), wherein RLdenotes the attachment with LI; LIis a linker or a bond; and TLis a moiety that binds an extracellular target molecule, or a pharmaceutically acceptable salt thereof.

2. The bifunctional compound according to claim 1, wherein SL is according to formula(A-Ia):, wherein RLdenotes the attachment with LI.

3. The bifunctional compound according to any one of the preceding claims, whereinSLis according to formula (A-Ib):formula (A-Ib), wherein RLdenotes the attachment with LI.

4. The bifunctional compound according to any one of the preceding claims, whereinthe linker is according to formula (II):Formula (II) wherein * denotes the attachment to either TLor SL; L1 and L2 are each independently selected from the group consisting of a bond, -C(H2)- , -O- , -N(H)-, a functional group selected from carbonyl, ester, amide,carbamate, thiourea, urea, sulphonamide and triazole; and a C1-C3 hydrocarbon chain wherein one or more methylene groups are individually and optionally replaced with a carbonyl, ester, amide, carbamate, thiourea, urea, sulphonamide and triazole; Z is selected from the group consisting of: a bivalent, saturated or unsaturated, straight or branched, C1-C30 hydrocarbon chain wherein one or more methylene groups are individually and optionally replaced by one or more of the groups selected from: -O-, –N(H)-, -N(RL1)-, -OC(=O)-, -C(=O)O-, -C(=O)-, -N(H)C(=O)- , -N(RL1)C(=O)-, -C(=O)N(H)-, -NHC(O)NH-, -NHC(O)O- -C(=O)N(RL1)-, -S-, - S(=O)-, -S(=O)2-, -N(RL1)S(=O)2-, -S(=O)2N(RL1)-; an optionally substituted aromatic group; an optionally substituted carbocycle; an optionally substitutedheterocycle; an optionally substituted aromatic heterocycle; ;, , ,, -C(RL2)H- and -N(RL2)-;RL1 is selected from the group consisting of C1-5 alkyl; RL2 is –(CH2)L-RX; Rx is -OH, or -C(=O)NH2; L is an Integer from 0 to 3; n and w each individually integers from 1 to 9.

5. The bifunctional compound according to any one of the preceding claims,wherein the C1-C30hydrocarbon chain is C5-C30hydrocarbon chain, such as aC8-C30hydrocarbon chain, such as a C10-C30hydrocarbon chain, such as a C12- C30hydrocarbon chain .

6. The bifunctional compound according to any one of the preceding claims,wherein the C1-C30hydrocarbon chain is a C10-C25hydrocarbon chain, such as a C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24or C25hydrocarbon chain.

7. The bifunctional compound according to any one of the preceding claims,wherein the C1-C30hydrocarbon chain is a C14-C20hydrocarbon chain.

8. The bifunctional compound according to any one of the preceding claims, theC1-C30hydrocarbon chain is a C7-C13hydrocarbon chain.

9. The bifunctional compound according to any one of the preceding claims,wherein one or more methylene groups, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 methylene groups of the hydrocarbon chain in Z are individually and optionally replaced by one or more of the groups selected from-O-, –N(H)-, -N(RL1)-, - OC(=O)-, -C(=O)O-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -C(=O)N(H)-, - C(=O)N(RL1)-, -S-, -S(=O)-, -S(=O)2-, -N(RL1)S(=O)2-, -S(=O)2N(RL1)-, -CH2-CH2- O-, an optionally substituted carbocycle; an optionally substituted heterocycle and a triazole; and RL1is C1-5 alkyl.

10. The bifunctional compound according to any one of the preceding claims,wherein Z comprises one or more groups –NH-SO2- groups.

11. The bifunctional compound according to any one of the preceding claims,wherein Z comprises one or more triazole groups.

12. The bifunctional compound according to any one of the preceding claims,wherein Z comprises one or more groups selected from: an optionally substituted carbocycle group(s) and an optionally substituted heterocycle group(s).

13. The bifunctional compound according to any one of the preceding claims,wherein Z comprises two groups each individually selected from: a triazole, an optionally substituted carbocycle group(s) and an optionally substituted heterocycle group(s).

14. The bifunctional compound according to any one of the preceding claims,wherein Z, comprises three groups each individually selected from: a triazole, an optionally substituted carbocycle group(s) and an optionally substituted heterocycle group(s).

15. The bifunctional compound according to any one of the preceding claims,wherein the carbocyle is according to, wherein n is an integerselected from 0, 1, 2 or 3.

16. The bifunctional compound according to any one of the preceding claims,wherein Z comprises one or more heterocycle groups.

17. The bifunctional compound according to any one of the preceding claims,wherein the heterocycle group may be an optionally substituted 3 to 6 membered ring wherein one or two carbon atoms of the ring have been replaced by N.

18. The bifunctional compound according to any one of the preceding claims,wherein the heterocycle group is according to, wherein n is an integer selected from 0, 1, 2 or 3.

19. The bifunctional compound according to any one of the preceding claims,wherein Z comprises one, two or three groups each individually selected from..

20. The bifunctional compound according to any one of the preceding claims,wherein Z comprises one or two groups each individually selected from,,,wherein n and / or n’ are each individually integers from 1 to 10 and t, t’ and / or w are each individually integers from 1 to 20..

21. The bifunctional compound according to any one of the preceding claims,wherein Z comprises, wherein n is an integer from 1 to 10.

22. The bifunctional compound according to any one of the preceding claims,wherein Z comprises, wherein n is an integer from 1 to 10 and t or w is an integer from 1 to 20.

23. The bifunctional compound according to any one of the preceding claims,wherein Z comprises , wherein n is an integer from 1 to 10 and each of t and t’ is individually an integer from 1 to 20.

24. The bifunctional compound according to any one of the preceding claims,wherein Z comprises , wherein each of n and n’ is individually an integer from 1 to 10 and t is an integer from 1 to 20.

25. The bifunctional compound according to any one of the preceding claims,wherein Z comprises one or more, such as one, two or three branches bearingpolar groups, said branch(es) being each independently -C(RL2)H- or -N(RL2)-;wherein RL2 is -(CH2)L-RX; Rx is -OH, or -C(=O)NH2; and L is an integer from 0 to3.

26. The bifunctional compound according to any one of the preceding claims,wherein Z comprises one branch bearing polar groups, said branch being -C(RL2)H-, or -N(RL2)-; wherein RL2 is -(CH2)L-RX; Rx is -OH, or -C(=O)NH2;and L is an integer from 0 to 3.

27. The bifunctional compound according to any one of the preceding claims,wherein Z comprises,28. The bifunctional compound according to any one of the preceding claims,,o .

29. The bifunctional compound according to any one of the preceding claims,wherein Z comprises.

30. The bifunctional compound according to any one of the preceding claims,wherein L1or L2are a triazole group.

31. The bifunctional compound according to any one of the preceding claims,wherein L1and L2are a triazole group.

32. The bifunctional compound according to any one of the preceding claims,wherein L1or L2are –O-.

33. The bifunctional compound according to any one of the preceding claims,wherein L1and L2are –O-.

34. The bifunctional compound according to any one of the preceding claims,wherein L1or L2are –NH-.

35. The bifunctional compound according to any one of the preceding claims,wherein L1and L2are –NH-.

36. The bifunctional compound according to any one of the preceding claims,wherein L1or L2are –S(=O)2-.

37. The bifunctional compound according to any one of the preceding claims,wherein L1and L2are –S(=O)2-.

38. The bifunctional compound according to any one of the preceding claims,wherein L1or L2are.

39. The bifunctional compound according to any one of the preceding claims,.

40. The bifunctional compound according to any one of the preceding claims,12wherein L or L are .

41. The bifunctional compound according to any one of the preceding claims,12wherein L and L are .

42. The bifunctional compound according to any one of the preceding claims,.

43. The bifunctional compound according to any one of the preceding claims,.

44. The bifunctional compound according to any one of the preceding claims,12wherein L and / or L are , wherein X is an atom selected from N or O.

45. The bifunctional compound according to any one of the preceding claims,wherein L1and / or L2are, wherein X is an atom selected from N or O.

46. The bifunctional compound according to any one of the preceding claims,wherein L1and L2are different groups.

47. The bifunctional compound according to any one of the preceding claims,wherein L1and L2are identical.

48. The bifunctional compound according to any one of the preceding claims,wherein linker LI is according to any one of formulas II-1 to II-98:

49. The bifunctional compound according to any one of the preceding claims,wherein the target molecule is a protein.

50. The bifunctional compound according to any of the preceding claims, whereinsaid compound is able to form a ternary complex between sortilin and the target protein.

51. The bifunctional compound according to any of the preceding claims, wherein thecompound is able to bind to bind to sortilin and the target protein at the same time.

52. The bifunctional compound according to any of the preceding claims wherein thedissociation constant of the binding of SLto sortilin is of less than 50 µM, such as less than 2 µM, such as less than 0.5 µM, preferably less than 0.1 µM and the dissociation constant of the binding of TLto its target is of less than 100 µM, such as less than 0.5 µM, such as less than 0.1 µM.

53. The bifunctional compound according to any of the preceding claims, wherein thecompound is able to bind to sortilin at the cell surface.

54. The bifunctional compound according to any of the preceding claims, whereinupon binding of SL to sortilin located on the cell surface and binding of TL to the target protein, the target protein is internalized into said cell.

55. The bifunctional compound according to any of the preceding claims, wherein thetarget protein is degraded after internalization into the cell.

56. The bifunctional compound according to any one of the preceding claims,wherein TL is according to any one of formulas B-I or B-II:Formula (B-II) Formula (B-I) wherein RLdenotes the attachment with LI .

57. The bifunctional compound according to any one of the preceding claims,wherein the target protein is selected from the group consisting of: PCSK9, TNF-^, ANGPTL-3, an antibody light chain, IgG, IgE, IgA IL-1, IL-2 , IL-6, IFN-^,VEGF, TFG-^1, IL-21, IL-22, IL-5, IL-10, IL-8, cholinestearase,human CCL2, carboxypeptidase B-2, neutrophil elastase, Factor Xa, Factor XI, Factor XIa, Factor XII, Factor XIII, prothrombin, coagulation factor VII, coagulation factor IX, fibroblast growth factor 1, FGF-2, fibronectin 1, kallikrein-1, lipoprotein lipase, human matrix metallopeptidase 1, macrophage migration inhibitory factor, transformin growth factor-p (TGF-p), thrombospondin-1 (TSP-T), CD40 ligand, urokinase-type plasminogen activator, plasminogen activator tissue type (TPA), Plasminogen (PLG), Plasminogen Activator Inhibitor-1, Placenta Growth Factor, Phospholipase A2 Group IB, Phospholipase A2 Group IIA, Complement factor B, Complement factor D, complement factor H, Complement Component 5 and complement C1s.

58. The bifunctional compound according to any one of the preceding claims,wherein the target protein is TNF-^^59. The bifunctional compound according to any one of the preceding claims,wherein TL is according to any one of formulas (B-III-1) to (B-III-8):Formula (B-III-3)Formula (B-III-6) Formula (B-III-7)Formula (B-III-8) wherein RL denotes attachment with LI.

60. The bifunctional compound according to any one of the preceding claims, thecompound is according to any one of formulas IV-B1 to IV-B8 :

61. The bifunctional compound according to any one of the preceding claims, thecompound is according to any one of formulas V-B1 to V-B8 :

62. The bifunctional compound according to any one of the preceding claims,wherein the compound is according to formula IV-B7.

63. The bifunctional compound according to any one of the preceding claims,wherein the compound is according to formula V-B7.

64. The compound according to any one of claims 60 to 63, wherein LI is as definedin any one of claims 4 to 48.

65. The bifunctional compound according to any one of claims 60 to 63, wherein LIis as defined claim 48.

66. The bifunctional compound according to any one of the preceding claims,wherein said compound is able to form a ternary complex between sortilin and TNF-^.

67. The bifunctional compound according to any one of the preceding claims,wherein the compound is able to bind to sortilin and TNFα at the same time.

68. The bifunctional compound according to any one of the preceding claims,wherein upon binding of SLto sortilin located on the cell surface and binding of TL TNF-^, TNF-^ is internalized into said cell.

69. The bifunctional compound according to any one of the preceding claims,wherein TNF-^ is degraded after internalization into the cell.

70. The bifunctional compound according to any one of the preceding claimswherein the bifunctional compound isor a pharmaceutically acceptable salt thereof.

71. A pharmaceutical composition comprising a bifunctional compound according toany one of the preceding claims.

72. A bifunctional compound according to any one of the preceding claims for useas a medicament.

73. A bifunctional compound according to any one of the preceding claims for usein the treatment of a disorder or condition in a subject in need thereof.

74. The bifunctional compound for use according to claim 73, wherein the disorderor condition is mediated by an extracellular protein.

75. The bifunctional compound for use according to any one of the preceding claims,wherein the extracellular protein is selected form the group consisting of: PCSK9, TNF-^, ANGPTL-3, an antibody light chain, IgG, IgE, IgA IL-1, IL-2 , IL-6, IFN-^, VEGF, TFG-^1, IL-21, IL-22, IL-5, IL-10, IL-8, cholinestearase,human CCL2,carboxypeptidase B-2, neutrophil elastase, Factor Xa, Factor XI, Factor XIa, Factor XII, Factor XIII, prothrombin, coagulation factor VII, coagulation factor IX, fibroblast growth factor 1, FGF-2, fibronectin 1, kallikrein-1, lipoprotein lipase, human matrix metallopeptidase 1, macrophage migration inhibitory factor, transformin growth factor-p (TGF-p), thrombospondin-1 (TSP-T), CD40 ligand, urokinase-type plasminogen actVator, plasminogen actVator tissue type (TPA), Plasminogen (PLG), Plasminogen ActVator Inhibitor-1, Placenta Growth Factor, Phospholipase A2 Group IB, Phospholipase A2 Group IIA, Complement factor B, Complement factor D, complement factor H, Complement Component 5 and complement C1s.

76. The bifunctional compound for use according to any one of the preceding claims,wherein the extracellular protein is TNF-^.

77. The bifunctional compound for use according to any one of the preceding claims,wherein the disorder or condition is an inflammatory disease.

78. The bifunctional compound for use according to any one of the preceding claims,wherein the disorder or condition is an autoimmune disease.

79. The bifunctional compound for use according to any one of the preceding claims,wherein the disorder or condition is a cancer.

80. The bifunctional compound for use according to any one of the preceding claims,wherein the subject is a mammal.

81. The bifunctional compound for use according to any one of the preceding claims,wherein the mammal is a human.

82. A method of targeted lysosomal degradation of an extracellular protein,comprising administering an effective amount of the bifunctional compound according to any one of claims 1 to 70.

83. A method of removal of an extracellular target protein from the plasma of a patientor subject in need thereof, comprising administering a bifunctional compound according to any one of claims 1 to 70.

84. Use of a bifunctional compound according to any one of the preceding claims,for the manufacture of a medicament for the treatment of a disease or condition.

85. A method of treatment of a disease or condition comprising administering abifunctional compound according to any one of claims any one of claims 1 to 70 to a subject in need thereof.

86. Use of a bifunctional compound according to any one of claims 1 to 70 for themanufacture of a medicament for the treatment of a disorder or condition mediated by an extracellular protein.

87. A method of treatment of a disorder or condition mediated by an extracellularprotein, comprising administering a bifunctional compound according to any one of claims 1 to 70 to a subject in need thereof.

88. A compound according to formula (A-II):formula (A-II), or a pharmaceutically acceptable salt thereof, or an enantiomer thereof or a mixture thereof; wherein R1 is H, halogen, alkoxy, -CF3, or an optionally substituted C1-5 hydrocarbonchain, wherein one or more carbon groups of the C1-C5 hydrocarbon chain areoptionally individually replaced by one or more of the groups consisting of – O-, -NH-, -C(O)-, ester, amide, carbamate, thiourea, sulphonamide, urea,,carbocycle; an optionally substituted heterocycle and ; wherein X isNH or O.

89. The compound according to claim 88, wherein the compound is according toformula (A-IIa)-IIa), or a pharmaceutically acceptable salt thereof.

90. The compound according to any one of claims 88 to 89, wherein the compoundis according to formula (A-II-1):pharmaceutically acceptable salt thereof.

91. The compound according to any one of claims 88 to 90, R1 is H.

92. The compound according to any one of claims 88 to 90, R1 is selected fromhalogen or –CF3.

93. The compound according to any one of claims 88 to 90, R1 is an optionallysubstituted C1-C5alkyl, wherein one or more methylene group(s) of the C1-5alkyl are optionally individually replaced by one or more of the groups consisting of – O-, -NH-, -C(O)-, ester, amide, carbamate, thiourea and.

94. The compound according to any one of claims 88 to 90, wherein the compoundisacceptable salt thereof.

95. A composition comprising the compound according to any one of claims 88 to94.

96. The compound according to any one of claims 88 to 94, or the compositionaccording to claim 95 for use as a medicament.

97. A bifunctional compound according to formula (X):TA-L– LI – SA-L (X)wherein, SA-Lis a moiety that binds to Sortilin; LIis a linker or a bond; and TA-Lis a moiety that binds interleukin 17-A (IL-17A), or a pharmaceutically acceptable salt thereof.

98. The bifunctional compound according to claim 97, wherein SA-L is according toformula X-III:formula X-III, or a pharmaceutically acceptable salt thereof; wherein LIis a linker or a bond; and TA-Lis a moiety that binds interleukin 17-A (IL-17A).

99. The bifunctional compound according to claim 98, wherein the bifunctionalcompound is according to any one of formulas X-III-B1 to X-III-D4:

100. The bifunctional compound according to claim 97, wherein SA-L is according toformula X-IV:acceptable salt thereof; wherein LIis a linker or a bond; and TA-Lis a moiety that binds interleukin 17-A (IL-17A).

101. The bifunctional compound according to claim 100, wherein the bifunctionalcompound is according to any one of formulas X-IV-B1 to X-IV-D4:

102. The bifunctional compound according to claim 97, wherein SA-L isaccording to formula X-V:pharmaceutically acceptable salt thereof; wherein LIis a linker or a bond; and TA-Lis a moiety that binds interleukin 17-A (IL-17A).

103. The bifunctional compound according to claim 102, wherein thebifunctional compound is according to any one of formulas X-V-B1 to X-V-D4:

104. The bifunctional compound according to any one of claims 97 to 103, whereinthe linker (LI) is as defined in any one of claims 4 to 48.

105. The bifunctional compound according to any one of claims 97 to 104, whereinthe linker (LI) is as defined in claim 48.

106. The bifunctional compound according to any one of claims 97 to 105, whereinthe bifunctional compound is any one of the compounds X-001 to X-098, or apharmaceutically acceptable salt thereof:

107. The bifunctional compound according to any one of claims 97 to 106, whereinthe compound is able to form a ternary complex with sortilin and IL-17A.

108. The bifunctional compound according to any one of claims 97 to 106, whereinthe compound is able to bind to bind to sortilin and IL17-A at the same time.

109. The bifunctional compound according to any one of claims 97 to 108, whereinthe compound is able to induce internalization of IL-17A into cells expressing sortilin.

110. The bifunctional compound according to any one of claims 97 to 109, whereinupon binding of SA-Lto sortilin located on the cell surface and binding of TA-Lto the IL-17A, IL-17A is internalized into said cell.

111. The bifunctional compound according to any one of claims 97 to 110, whereinIL17-A is degraded after internalization into the cell112. The bifunctional compound according to any one of claims 97 to 111, whereinthe dissociation constant (KD) of the binding of TA-L to IL 17-A is lower than 500nM, such as lower than 250 nM, such as lower than 100 nM, such as lower than 50 nM.

113. The bifunctional compound according to any one of claims 97 to 112, whereinthe dissociation constant (KD) of the binding of SA-Lto sortilin is of less than 50 µM, such as less than 2 µM, such as less than 0.5 µM, preferably less than 0.1 µM and the dissociation constant of the binding of TA-Lto its target is of less than 100 µM, such as less than 0.5 µM, such as less than 0.1 µM.

114. A composition comprising the bifunctional compound according to any one ofclaims 97 to 113 and a pharmaceutically acceptable excipient.

115. A bifunctional compound according to any one of claims 97 to 113, or acomposition according to claim 114, for use in a method of removing IL-17A from the blood plasma of a subject in need thereof, the method comprising administering to the subject an effective amount of the bifunctional compound.

116. A bifunctional compound according to any one of claims 97 to 113, or acomposition according to claim 114, for use in a method of treatment orprevention of inflammation or an inflammatory condition, the method comprising administering to the subject an effective amount of the bifunctional compound.

117. The bifunctional compound, or the composition, for use according to claim116, wherein the inflammation or inflammatory condition is characterized by high levels of IL-17A or overexpression of IL-17A.

118. The bifunctional compound, or the composition, for use according to claim117, wherein condition is psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis.

119. A compound selected from:,,,thereof.

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