Title - CONJUGATED COMPOUNDS OF PEG AND CARFILZOMIB

Abstract

This document discloses polymeric compounds of PEG and carfilzomib, and salts thereof suitable for pharmaceutical use, of formula (1), where R 1 , R 2 The compounds PEG, PEG, and nyo are as defined in this document. Methods for preparing and using these compounds to treat cancer, and in particular hematological malignancies, including multiple myeloma, are also disclosed.

Description

Cancer is one of the most common diseases and one of the leading causes of death worldwide. In the United States, cancer is the second leading cause of death, surpassed only by heart disease. Cancer is often characterized by dysregulation of normal cellular processes or unregulated cell proliferation. Multiple myeloma (MM) is a type of progressive, malignant neoplastic cancer that originates in plasma cells. It is characterized by an abnormal accumulation of malignant plasma cells within the bone marrow, and accounts for approximately 13% of all hematologic cancers (Palumbo and Anderson, 2011). In 2015, about 26,850 new cases of MM were expected to be diagnosed, and about 11,240 people were expected to die from the disease in the United States (ACS, 2015). The incidence of MM has been steadily increasing due to the increasing life expectancy of the general population in the United States (Warren et al., 2013). The disease most frequently affects the elderly population, with a mean age of incidence of around 69 years (Howlander et al., 2013, ACS, 2015). The therapeutic goals in the management of MM are to provide symptomatic relief, achieve disease control, and provide prolonged remissions (Kurtin, 2013). Conventionally, a combination of high-dose chemotherapeutic agents (melphalan, vincristine, cyclophosphamide, doxorubicin, liposomal doxorubicin, bendamamustine) followed by autologous stem cell transplantation (ASCT) has been used to treat young, treatment-naive, and healthy patients. of health (under 65 years of age) (Palumbo et al., 2011). Age, comorbid conditions, and geriatric evaluation are the main criteria for deciding the fitness of patients to tolerate high-dose therapy (HDT) followed by ASCT (Palumbo et al., 2014). For elderly patients unfit for HDT and ASCT, melphalan plus prednisone had been the standard therapy for several decades (Palumbo et al., 2011; Rodríguez et al., 2012). Over the past decade, the MM treatment algorithm has undergone a paradigm shift with the introduction of new immunomodulatory agents (such as thalidomide, lenalidomide, and pomalidomide) and targeted proteasome inhibitors (bortezomib and carfilzomib) (Richardson et al., 2007; Dmoszyñska, 2008 Gupta et al., 2013). Carfilzomib is an epoxy-ketone tetrapeptide proteasome inhibitor that selectively and irreversibly binds to the housekeeping and immunoproteasome proteasomes. More specifically, the electrophilic epoxyketone head binds to the catalytic threonine residue of the β5 subunit of the proteasome protein. CFZ is well tolerated with an acceptable toxicity profile. El carfílzomib, sus formas polimórfícas, métodos de fabricación, formulaciones, uso y otros atributos de carfílzomib se describen en las publicaciones US20050245435, US20140105921 y PCT W02006017842, W02009045497, W02014011695, W02006063154, W02014015016 y WO2010048298, cuyos contenidos se incorporan en su totalidad en la present specification by this reference. Carfilzomib has been shown to have an encouraging response rate in patients with recurrent and refractory MM and in newly diagnosed MM patients. To this end, carfilzomib was first approved (as Kyprolis®) in July 2012 for the treatment of patients with relapsed and refractory MM as single-agent therapy. More recently, Kyprolis in combination with lenalidomide and dexamethasone (July 2015) and in combination with dexamethasone (January 2016) was approved for the treatment of patients with relapsed and refractory MM who have received one to three lines of therapy. The approved treatment regimen for carfilzomib is to administer it to the patient by infusion, either over a short period of 10 minutes or over a slower, longer period of time of 30 minutes. This infusion must occur for 2 consecutive days per week for three consecutive weeks in a 28-day cycle. Therefore, to comply with this treatment schedule, patients must drive or be driven twice weekly on consecutive days to a licensed drug administration facility, such as a doctor's office, clinic, or hospital, where carfilzomib can be used. administered properly and safely. This may be inconvenient or impractical, or may simply be a burden for some patients, increasing the likelihood of reduced or diminished compliance or even complete non-compliance with the prescribed carfilzomib therapeutic regimen. Carfilzomib is rapidly metabolized and eliminated in humans. Carfilzomib, a small tetrapeptide compound, exhibits a short in vivo half-life of approximately 60 minutes or less in humans. One mechanism of elimination of carfiizomib is via the hepatic blood flow, which results in the relatively short half-life of carfilzomib. Pharmaceuticals that have short half-lives or rapid clearance generally tend to have reduced target coverage, leading to diminished and / or reduced inhibitory biological activity. To overcome such deficiencies, an additional amount of drug is typically administered to achieve more drug delivery and confer prolonged efficacy at the site of biologic action. Thus, both the rapid elimination and twice weekly dosing frequency of carfilzomib leave room for potential improvements in efficacy, active site drug availability, and / or patient compliance with the treatment schedule. Carfilzomib, as currently approved (Kyprolis®), is a sterile lyophilized formulation comprising sulfabutylether-beta-cyclodextrin (SBECD) and sodium citrate buffer. The lyophilisate is reconstituted with sterile water, and infused or injected into the patient. The excipient SBECD acts primarily as a solubilizing additive for carfilzomib, and forms a complex with carfilzomib, thus improving the water solubility of carfilzomib. History has revealed that attempts to solve the weaknesses of pharmaceuticals have led to the preparation of alternative forms of these medicinal compounds, including the production of prodrug versions, with the purpose of improving their pK and / or PD pharmacological properties. . For example, Greenwald et al. describe prodrugs of amine-containing compounds (J. Med. Chem., 1999, 42, 3657-3667). W02005063777 describes benzylphosphate and substituted benzylphosphate prodrugs for the treatment of lung inflammation. Document W020090152160 describes inhaled prodrugs of carbaprotacyclin and prostacyclin for the treatment of arterial hypertension. US Patent Publication 20040100225 describes acyloxymethyl prodrugs of imatinib (Gleevec®). Also, PCT publication WO2011084846 describes acyloxymethyl prodrugs of risperidone. These prodrug disclosures disclose alkylacyloxymethyl linked prodrugs. As another example, US patent application publication US20140105921 describes carfilzomib and other epoxyketone proteasome inhibitor prodrugs having an acyloxymethyl linker connecting the inhibitor to polyethylene glycol (PEG) units. However, these carfilzomib prodrug compounds have been found to release quinone methylide byproducts during metabolism in vivo, which may be potentially toxic and may present a safety risk. To this end, it would be desirable to identify alternative forms of carfilzomib and / or alternative ways of delivering the active pharmaceutical ingredient carfilzomib to patients, in such a way as to maintain or to the extent possible improve the efficacy and / or safety of carfilzomib treatments. currently approved. BRIEF DESCRIPTION OF THE INVENTION The present invention provides novel carfilzomib polymeric compounds, ie, modified carfilomib structures, which provide anti-cancer therapeutic benefits to the patient by maintaining comparable or longer plasma concentrations of carfilzomib and proteasome exposure. To this end, these polymeric carfilzomib compounds provide proteasome inhibitory activity comparable to that of the formulation for i.v. administration. of currently approved carfilzomib cyclodextrin. Particularly, the present invention provides conjugates of PEG and carfilzomib, which have improved water solubility, and which are useful for treating various types of cancer, including, but not limited to, multiple myeloma. More particularly, the PEG conjugate compounds disclosed herein maintain or exhibit adequate bioavailability and reduce or completely eliminate the need for excipients or solubilizing agents such as sulfobutylether-p-cyclodextrin. The present invention further provides a method of preparing the PEG and carfilzomib conjugate compounds, pharmaceutical compositions comprising the same, and methods of using the compounds and compositions to treat various forms of cancer, such as multiple myeloma. In one aspect of the invention, the PEG-carfilzomib conjugates described herein include one or more covalently attached PEG moieties that (i) may confer improvements in carfilzomib's solubility, permeability, and pharmacokinetic (pK) properties. and / or pharmacodynamics (PD) compared to the corresponding approved carfilzomib product that does not contain such polymeric moieties; and (ii) can be cleaved or eliminated in vivo after administration to a subject thereby further supplying free carfilzomib, which has proven capabilities of safety and efficacy to treat various types of cancer, including, but not limited to, cancer. multiple myeloma. The PEG and carfilzomib conjugates disclosed herein further provide potential benefits including, but not limited to, sustained release allowing for decreased dosing frequency, lower Cmax and possibly as a result reduced side effects compared to the product of currently approved carfilzomib. Higher aqueous solubility may also confer an improved safety profile to the compounds of the invention, which could facilitate alternative modes of administration to the currently approved infusion mode of administration, such as subcutaneous administration. A modified pK profile and / or biodistribution of the PEG and carfilzomib conjugates of the invention may result in improved efficacy in the treatment of certain types of cancer, including, but not limited to, multiple myeloma and solid tumors. In addition, the PEG and carfilzomib conjugates of the invention provide formulation options that potentially have better chemical and thermal stability, a smaller dosage volume, and the possibility of eliminating a lyophilization step, part of the currently approved product manufacturing process. of the drug carfilzomib. BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph of curves generated by conversion rates of several exemplified PEG compounds to free carfilzomib in human plasma (representative of human pKs); Figure 2 is a graph reflecting the pKs of exemplary PEG and carfilzomib conjugates in rat plasma; Figure 3 is a graphical illustration of the effects of carfilzomib and the compound of Example 1 on chymotrypsin-like proteasome activity in blood, and in adrenal gland, heart and liver tissues; Figure 4 is a graphical illustration of mean plasma carfilzomib concentrations over time for Examples 13, 26 and 34 of the invention; Figure 5 is a graph illustrating the efficacy of Example 13 versus the CFZcaptisol formulation in a xenograph [sic] mouse model of cancer; Figure 6 is a graphical illustration of the survival of mice in the study illustrated in Figure 5; Figure 7 is a graph illustrating a second efficacy study of Example 13 versus the CFZ-captisol formulation in a xenograph [sic] mouse model of cancer; Figure 8 is a figure of the NMR spectrum for Example 23; Figure 9 is a figure of CT-L cell activity for carfilzomib; Figure 10 is a figure of CT-L cell activity for the compound of Example 5; Figure 11 is a figure of CT-L cell activity for the compound of Example 35; Figure 12 is a figure of CT-L cell activity for the compound of Example 36; Figure 13 is a figure of CT-L cell activity for the compound of Example 37; Figure 14 is a figure of CT-L cell activity for the compound of Example 38; Y Figure 15 is a figure of in-vivo CT-L activity for the compounds of Examples 35 and 36. DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel conjugates of PEG and carfilzomib, pharmaceutical compositions comprising the compounds, methods of manufacturing the compounds, and uses of the compounds, and compositions containing the compounds for the treatment of cancer, including the treatment of neoplasms. hematological diseases such as multiple myeloma, lymphoma, leukemia, and the treatment of other types of cancer such as solid tumors. Specifically, the polymer units of carfilzomib bound to polyethylene glycol (PEG) possess several comparable or improved pharmacokinetic (pK) and / or pharmacodynamic (PD) properties relative to currently administered intravenously administered Kyprolis® (carfilzomib). Carfilzomib is an epoxy ketone protease inhibitor described in US Patent Nos. 7,417,042 and 7,737,112, among others. The PEG-carfilzomib conjugates described herein (i) generally confer improved solubility, permeability, pK and / or PD properties relative to free carfilzomib drug that does not contain such PEG moieties; and (ii) it can be cleaved in vivo thereby releasing the active drug carfilzomib in its free form. In embodiments presented by the invention, the N-terminal cap of carflizomib (eg, the morpholine cap) is converted to a quaternary salt (eg, by addition of an N-acyloxyphenylmethyl group). In some embodiments, the quaternary salt contains a PEG moiety. In some embodiments, the PEG-containing compounds are cleavable by pH change and / or enzymes such as, but not limited to, esterases, cytochrome P450, phosphodiesterase, phosphoamidase, phosphatase, and DT-diaphorase, or any combination thereof. In some embodiments, the PEG is a linear PEG. In some embodiments, the PEG is a bifunctional PEG, which can conjugate 1-2 compounds per PEG. In some embodiments, the PEG is a four-armed PEG that can conjugate 1-4 compounds per PEG. In some embodiments, the PEG is an eight-armed PEG with a hexaglycerin core that can conjugate 1-8 compounds per PEG. In some embodiments, the PEG is an eight-armed PEG with a tripentaerythritol core that can conjugate 1-8 PEG compounds. In some embodiments, the PEG is a two-armed branched PEG. In some embodiments, the PEG is a four-armed branched PEG. Furthermore, the compounds may further include solubilizers, permeation enhancers, masking agents, macromolecular carriers, target structures, and biologics to enhance half-life and disease specificity, which either bind directly to the compound or bind indirectly. to it through a spacer residue. The terms "appearance" and "embodiment" are used interchangeably herein. In aspect 1 of the invention, the invention provides a conjugate compound of PEG and carfilzomib having the structural formula I Formula I or a salt thereof suitable for pharmaceutical uses, where R1 is Ci-ioalkyl or C3.7cycloalkyl; each R2, taken independently, is Ci-ealkyl, -OCIE, or halogen; o is an integer to be selected from 0, 1,2 or 3; A linker is a molecule that has the structure of a where R3 is H or CH3; n is an integer to be selected from 1, 2, 3 or 4; p is an integer to be selected from 0, 1, 2, 3, or 4; q is an integer to be selected from 1,2, 3, 4, 5, 6, 7, 8 or 9; r is an integer to be selected from 0,1, 2, 3, 4, or 5; Y PEG is a polyethylene glycol polymeric molecule having a molecular weight in the range of about 500 to about 20,000. In the aspect of the invention, the invention provides a conjugate compound of PEG and carfilzomib having the structural formula I or a salt thereof suitable for pharmaceutical uses, where R1 is Ci-ioalkyl or C3-7CYcloalkyl; each R2, taken independently, is Ci-6alkyl, -OCH3, or halogen; o is an integer to be selected from 0, 1, 2, or 3; A linker is a molecule that has the structure of a where R3 is H or CH3; and p is an integer to be selected from 0, 1, 2, 3, or 4; n is an integer to be selected from 1, 2, 3 or 4; Y PEG is a polyethylene glycol polymeric molecule having a molecular weight in the range of about 500 to about 20,000. In aspect 2 of the invention, the invention provides the conjugate compound of PEG and carfilzomib of aspect 1 having the structural formula II where R1 is Ci-ioalkyl or C3-7CYcloalkyl; R2 is Ci-oalkyl, -OCH3 or halogen; A linker is a molecule that has the structure of a where R3 is H or CH3; n is an integer to be selected from 1, 2, 3 or 4; p is an integer to be selected from 0, 1, 2, 3, or 4; q is an integer to be selected from 1,2, 3, 4, 5, 6, 7, 8 or 9; r is an integer to be selected from 0, 1, 2, 3,4 or 5; X' is a salt of [sic] a counterion selected from a chloride, a bisulfate, a sulfate, a nitrate, a phosphate, an alkyl sulfonate or an aryl sulfonate; Y PEG is a polyethylene glycol polymer molecule having a molecular weight in the range of about 2,000 to about 20,000. In aspect 3 of the invention, the invention provides the compound according to aspects 1, 1 and 2 where R 1 is Ci-ioalkyl. In aspect 4 of the invention, the invention provides the compound of any one of aspects 1, la, 2 and 3 wherein each R2, considered independently, is H, CH3 or halogen. In aspect 5 of the invention, the invention provides the compound of any one of aspects 1, la, 2, 3 and 4 where each R2, considered independently, is H, CH3, Cl or F. In aspect 5a of the invention, the invention provides the compound of any one of aspects 1, la, 2, 3 and 4 where each R2, considered independently, is H, CH3 or F. In aspect 6 of the invention, the invention discloses the compound of any one of aspects 1, la, 2, 3, 4 and 5 where the linker is a molecule having the structure of where R3 is H or CEU; q is an integer to be selected from 1, 2, 3, 4, or 5; and r is an integer to be selected from 0, 1,2, 3, or 4. In aspect 6a of the invention, the invention discloses the compound of any one of aspects 1, la, 2, 3, 4 and 5 where the linker is a molecule having the structure of In aspect 7 of the invention, the invention provides the compound of any one of where R3 is H or CEE; q is 4; and r is 2. In aspect 7a of the invention, the invention provides the compound of any one of aspects 1, la, 2, 3, 4, 5 and 7 where the connector is where R3 is H or CH3. In aspect 8 of the invention, the invention provides the compound of any one of aspects 1, la, 2, 3, 4, 6, 6a, 7 and 7a where R3 is H. In aspect 9 of the invention, the invention provides the compound of any one of aspects 1-8 where R 1 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl or heptyl. In aspect 10 of the invention, the invention provides the compound of any one of aspects 1-9 wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl or heptyl; and the connector is In aspect 10a of the invention, the invention provides the compound of any one of aspects 1-9 where R 1 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl or heptyl; and the connector is It should be understood that in aspects 1, la, 2 and aspects 3-10 the term "or a salt thereof suitable for pharmaceutical uses" can include a salt of a counterion that neutralizes the cationic charge of the quaternary nitrogen, such as that is illustrated in Formula II of aspect 2, or those that are illustrated in aspects 11-24 below. Furthermore, the term "any one of Aspects 1-X" should also be understood to include all sub-aspects of 1-X disclosed herein, including, without limitation, sub-aspects la, 5a, 6a, 7a and 10a. In aspect 11 of the invention, the invention provides a conjugate compound of PEG and carfilzomib according to any one of aspects 1-10, which has the structure of PEG or VH or xPhHO xpeg. 5KV Ñ^R3 Rl JD. 0.2 ÍJJ O V H O %hH O X- J, *Ph ,nJI No. H'Ph where R' is Ci-ioalkyl; R2 is Ci-6alkyl, -0CH3 or halogen; R3 is H or CH3; X' is a counter anion selected from a chloride anion and an alkyl sulfonate anion; n is 4; Y PEG is a polyethylene glycol polymeric molecule having a molecular weight in the range of about 2,000 to about 20,000. In aspect 12 of the invention, the invention provides the compound of any one of aspects 1-11 wherein the compound is , where X' is a salt of [sic] a halide, sulfonate or alkyl sulfonate counterion. In aspect 12a of the invention, the invention provides the compound of any one of aspects 1-11 wherein the compound is , where X' is a salt of [sic] a halide, sulfonate or alkyl sulfonate counterion. In aspect 13 of the invention, the invention provides the compound of any one of aspects 1-11 wherein the compound is In aspect 14 of the invention, the invention provides the compound of any one of aspects 1-11 wherein the compound is In aspect 15 of the invention, the invention provides the compound of any one of aspects 1 and 2 wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl or heptyl; each R2, considered independently, is CH3 or halogen; A linker is a molecule that has the structure of a where R3 is H or CH3; Y PEG is a polyethylene glycol polymer molecule that has a molecular weight of 2,000, 3,000, 5,000, or 20,000. In aspect 16 of the invention, the invention provides the compound of aspect 15 wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, or heptyl; each R2, considered independently, is CH3; A linker is a molecule that has the structure of a where R3 is H; Y PEG is a polyethylene glycol polymer molecule that has a molecular weight of 3,000, 5,000, or 20,000. In aspect 17 of the invention, the invention provides the compound of any one of aspects 1-16 where the compound is an individual compound as represented in examples 1-34 described below in Table 2, or a salt thereof suitable for pharmaceutical uses. In aspect 18 of the invention, the invention provides the compound of any one of aspects 1-17 wherein the compound is PEG 2K. N-N H x Λ A °Y O 0 MS°- lh PEG3k. N-N VÑ PEGjk, PEG,, PEG„ Cl- ojj O-H Job N-N ^N Ύ° Οχ> MsO' PEGS Y ph Η θ f Η θ <;Ν^ιτΝγΛΝΛγΝγΛΝ N-N γ MsO' ph O / H O λΝ'γΝγΒ'Ν or H O cO O V H MsO' 1. ph Y! nJ<n -PhH N-N LN Λ° MsO' SH ph ph Y η O / H O COn'^n\nyAn O^> - = u = u PEG2kJ}NAV^N-N Οι PEGsK'o PEGjkJOPn-N EITHER or or a salt thereof suitable for pharmaceutical uses. In aspect 19 of the invention, the invention provides the compound of any one of aspects 1-18 wherein the compound is PEG; 3K. n'n On Ύ° Cl0. / J or V.H Ph H ? T H ? - u ü - L In aspect 19a of the invention, the invention provides the compound of any one of aspects 1-18 wherein the compound is In aspect 20 of the invention, the invention provides the compound of any one of aspects 1-18 wherein the compound is In aspect 21 of the invention, the invention provides the compound of any one of aspects 1-18 wherein the compound is In aspect 22 of the invention, the invention provides the compound of any one of aspects 1-18 wherein the compound is PEG5K MsO' cm or HO <^Ν^Νγ^Ν In aspect 23 of the invention, the invention provides the compound of any one of aspects 1-18 wherein the compound is In aspect 24 of the invention, the invention provides the compound of any one of aspects 1-18 wherein the compound is In aspect 25 of the invention, the invention provides the compound of any one of aspects 1-18 wherein the compound is 'Ά— / Ν-Ν ;ο ph In aspect 26 of the invention, the invention provides the compound of any one of aspects 1-18 wherein the compound is EITHER No. PEG3K I Ό P ph In aspect 27 of the invention, the invention provides the compound of any one of aspects 1-16 wherein the PEG has a weight within the range of about 2K to about 20K. In aspect 28 of the invention, the invention provides the compound of any one of aspects 1-16 wherein the PEG has a weight of 3K, 5K or 20K. In aspect 29 of the invention, the invention discloses the compound of any one of aspects 1-16 which is a pharmaceutically suitable salt comprising a counter anion selected from a chloride anion, a bisulfate anion, a sulfate anion, a nitrate anion, a phosphate anion, an alkyl sulfonate anion or an aryl sulfonate anion. In aspect 30 of the invention, the invention provides the compound of aspect 29 wherein the counterion is a chloride anion or an alkyl sulfonate anion. In aspect 31 of the invention, the invention provides the compound of aspect 29 wherein the counterion is a chloride anion or a methane sulfonate anion. In aspect 32 of the invention, the invention discloses a pharmaceutical composition comprising the compound according to any one of aspects 1-26 and an excipient, vehicle or diluent suitable for pharmaceutical uses. In aspect 33 of the invention, the invention provides the pharmaceutical composition of aspect 32 that is administered orally or parenterally, administrable by infusion or by injection. In aspect 34 of the invention, the invention provides the pharmaceutical composition according to any one of aspects 32-33 comprising one or more of the compounds according to any one [sic] of aspects 1-26 together with an excipient, vehicle or diluent suitable for pharmaceutical uses. In aspect 35 of the invention, the invention provides the pharmaceutical composition according to any one of aspects 32-34 comprising at least two of the compounds according to [one] any of aspects 1-28 together with an excipient, vehicle or diluent suitable for pharmaceutical uses. In aspect 36 of the invention, the invention discloses a method for treating multiple myeloma comprising administering, to a patient in need thereof, a therapeutically effective amount of the compound of any one of aspects 1-31 or the pharmaceutical composition of any one of aspects 32-35. In aspect 37 of the invention, the invention provides the method according to aspect 34 where the multiple myeloma is recurrent, resistant, or recurrent and resistant multiple myeloma. In aspect 38 of the invention, the invention provides the method according to aspect 36 where the multiple myeloma is newly diagnosed multiple myeloma. In aspect 39 of the invention, the invention discloses a process for making the compound according to any one of aspects 1-16, the process comprising the step of ;o peg-n3 Cu(ll) Ascorbic salt where X' is a salt of [sic] a counterion to be selected from the group consisting of a chloride anion, a bisulfate anion, a sulfate anion, a nitrate anion, a phosphate anion, an alkyl sulfonate anion, or an aryl sulfonate anion , and PEG has a weight in the range of about 2K to about 20K, to prepare a compound of Formula I. In aspect 40 of the invention, the invention discloses a process for making the compound of Formula I according to aspect 1, wherein the process comprises the step of where X' is a salt of [sic] a counterion, selected from a chloride anion, a bisulfate anion, a sulfate anion, a nitrate anion, a phosphate anion, an alkyl sulfonate anion or an aryl sulfonate anion; PEG has a weight in the range of about 2K to about 20K; Y R1, R2, R4 and or are as defined in aspect 1, to prepare a compound of Formula I. In other aspects, the invention provides compounds having the formula (SM)m-PEG, or a salt thereof suitable for pharmaceutical uses, in which each SM is a compound to be selected, independently, from Formula I or of Formula II as defined above and elsewhere herein and is attached to a PEG of a defined weight at a number of n positions, where n is 2-10 (eg, n = 4 in the compound of aspect 14; see also Table 1 below). In some embodiments, the nitrogen atom of the carfilzomib morpholine ring is substituted with the benzyl ester molecule as shown in Formulas I and II, thereby forming a quaternary nitrogen atom, with the associated positive charge with the secondary nitrogen atom is matched by an anion suitable for pharmaceutical uses, as defined herein under the representation X'. In some aspects of the invention, the compounds described herein themselves exhibit lower therapeutic activity compared to said corresponding epoxy ketone protease inhibitors and exhibit better solubility, permeability, and pharmacokinetic and / or pharmacodynamic properties in vivo. compared to said epoxy ketone protease inhibitors. In some aspects of the invention, the polymeric molecule or PEG molecule is separated from the active ingredient carfilzomib by a change in pH and / or enzymes such as, but not limited to, esterases, cytochrome P450, phosphodiesterase, phosphoamidase, phosphatase, and DT-diaphorase, or any combination thereof. In some aspects of the invention, the PEG is a linear PEG molecule. In some aspects of the invention, the PEG is a bifunctional PEG that can conjugate 1-2 compounds per PEG. In some aspects of the invention, the PEG is a four-armed PEG that can conjugate 1-4 compounds per PEG. In some aspects of the invention, the PEG is an eight-armed PEG with a hexaglycerin core that can conjugate 1-8 compounds per PEG. In some aspects of the invention, the PEG is an eight-armed PEG with a tripentaerythritol core that can conjugate 1-8 PEG compounds. In some aspects of the invention, the PEG is a branched two-armed PEG. In some aspects of the invention, the PEG is a branched four-armed PEG. Furthermore, compounds may also include solubilizers, permeation enhancers, masking agents, macromolecular carriers, targeting molecules, and biological techniques to enhance half-life and disease specificity, directly or indirectly linked to the compound. through a spacer molecule. Without being limited to any particular theory, it is possible that the compounds of the invention may transiently mask or partially mask protease inhibitory activity until the PEG-bound molecules have been cleaved to yield free carfilzaomib, an active pharmaceutical molecule. tested and regulatory approved, in the systemic circulation, allowing to reduce unwanted side effects, which could be associated with various routes of administration. For said purpose, the PEG-carfilzomib conjugates of the present invention can act as prodrugs of carfilzomib. Alternatively, the PEG molecule is attached near the morpholine end of the carilzomib tetrapeptide backbone. The compounds of the present invention, prior to PEG cleavage may possess inhibitory activity on active proteasomes. The beneficial properties of the compounds of the present invention may also facilitate subcutaneous administration and prolong the half-life of carfilzomib, eg, beyond 4 hours. In aspect 41 of the invention, the half-life in human plasma of the compounds of the invention is greater than 0.5 hr. In aspect 42 of the invention, the human plasma half-life of the compounds is between 0.5 and 5 hr. In aspect 43 of the invention, the human plasma half-life of the compound is greater than 5 hr. In aspect 44 of the invention, the human plasma half-life of the compound is between 5 and 100 hr. In aspect of the invention, the human plasma half-life of the compound is greater than 100 hr. In aspect 46 of the invention, the human plasma half-life of the compound is between 100 and 836 hr. In aspect 47 of the invention, the human plasma half-life of the compound is between 200 and 300 hr. In aspect 48 of the invention, the human plasma half-life of the compound is about 267 hr. In aspect 49 of the invention, the human plasma half-life of the compound is up to 836 hr. By virtue of prolonging the half-life of carfilzomib, the invention potentially improves dosing as well as convenience for the patient to be able to comply with carfilzomib treatment. In aspect 50 of the invention, the invention provides a pharmaceutical composition, which includes a conjugate of PEG and carfilzomib as disclosed herein and an excipient, vehicle or diluent suitable for pharmaceutical uses. In other aspects or embodiments of the invention, as described herein below, methods are provided for the treatment of a disease or condition selected from the group consisting of cancer, autoimmune diseases, related conditions with graft or transplantation, neurodegenerative disease, conditions associated with fibrosis, conditions related to ischemia, infection (viral, parasitic or prokaryotic), and diseases associated with bone loss, the method comprising administering to a patient a therapeutically effective amount of a compound as disclosed herein. In yet other aspects, the present invention provides methods of treating cancer (eg, multiple myeloma, eg, recurrent and / or refractory multiple myeloma) in a patient, the method comprising administering to a patient a therapeutically effectiveness of a compound as disclosed herein. Unless otherwise defined, all technical and scientific terms used herein have the meaning usually understood by an expert in the discipline to which this disclosure pertains. Methods and materials are described herein for use in the present disclosure, while other suitable methods and materials known in the art may also be used. The materials, methods, and examples are provided for illustrative purposes and are not to be construed as limiting the scope of the present invention. All publications, patent applications, patents, sequences, database records, and other references mentioned herein are incorporated herein in their entirety by reference, as if written herein. In the event of any disagreement, this report will prevail, including the definitions contained therein. Other features and advantages of the disclosure will be apparent from the following detailed description and from the claims. As used herein, the term "appearance" is used as a synonym for the term "embodiment." DEFINITIONS The following definitions will aid in understanding the terms as used herein and the scope of the invention as described herein. The term "Cx.yalkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight chain alkyl groups and branched chain alkyl groups containing x to y carbon atoms in the chain. The term "haloalkyl" refers to alkyl groups in which at least one hydrogen atom is replaced by a halogen (eg, fluoro, chloro, bromo, iodo), eg, CH2F, CHF2, trifluoromethyl, and 2,2, 2-trifluoroethyl. The terms "C2-yalkenyl" and "C2-yalkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups analogous to the alkyls described above in terms of length and possible substitutions, but containing at least one double or triple link, respectively. In some embodiments, the divalent alkenylene and alkynylene groups contain from 2 to 12 carbon atoms. In certain embodiments, alkylene and alkynylene contain from 2 to 10 carbon atoms. In certain embodiments, alkylene and alkynylene contain from 2 to 6 carbon atoms (eg, 2, 3, 4, 5, or 6 carbon atoms). The term "alkoxy" refers to an alkyl group having an oxygen attached thereto. Representative examples of alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. An "ether" is two hydrocarbons covalently linked through oxygen. Accordingly, the substituent on an alkyl that makes said alkyl an ether is or resembles an alkoxy. The term "C3-ycycloalkyl" as used herein refers to a fully saturated substituted or unsubstituted ring in which each ring atom is carbon and the ring is 3 to γ ​​carbon atoms in size. . For example, the term C3-7cycloalkyl is understood to mean a carbocyclic ring having a size of 3 to 7 carbon atoms. Examples of such rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl rings. These rings may also be substituted as specified. The terms cancer and cancerous when used herein refer to or describe the physiological condition of certain subjects which is typically characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, hematologic malignancies or forms of cancer that develop in the blood such as multiple myeloma and leukemia, and other forms of cancer such as carcinoma, lymphoma, sarcoma, and blastoma. More particular examples of such forms of cancer include squamous cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer. Although the term cancer as used herein is not limited to any specific form of the disease, it is believed that the methods of the invention will be particularly effective for forms of cancer which in certain subjects have become resistant to a certain degree. to treatment with anti-cancer agents, including, but not limited to, chemotherapeutic agents, antimitotic agents, anthracyclines and the like, and for forms of cancer that recur after treatment with such anti-cancer agents. The term comprising is understood in such a way that it has an open scope, in such a way that it includes the one or more components mentioned but does not exclude other elements. The term "for example" as used herein is understood to mean "example." The term "inhibitor" is understood to describe a compound that blocks or decreases an activity of an enzyme or system of enzymes, receptors, or other drug targets (for example, inhibition of proteolytic cleavage of standard fluorogenic peptide substrates such as suc-LLVY-AMC, Box-LLR-AMC and Z-LLE-AMC, inhibition of various catalytic activities of the 20S proteasome). An inhibitor can act with competitive, uncompetitive, or noncompetitive inhibition. An inhibitor can bind reversibly or irreversibly and therefore the term includes compounds that are "suicidal" substrates of an enzyme. An inhibitor can modify one or more sites at or near the active site of the enzyme, or it can cause a conformational change in any other part of the enzyme. The term inhibitor is used more broadly herein than in the specific literature, so as to encompass other classes of agents that possess pharmacological or therapeutic utility, such as agonists, antagonists, stimulants, co-factors, and the like. The terms "drug resistant" and "multi-drug resistant" when used herein refer to cancer cells that have developed resistance and / or are resistant to the drug. Among these are cancer cells that exhibit little or no efficacy or decreased efficacy relative to that which they exhibited at initiation of drug dosing. Cancer cells may be resistant to one drug or to multiple drugs of different chemical structures that are directed to act on different biological targets within cancer cells. The term "pharmaceutical grade salt" encompasses salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, as long as it is suitable for pharmaceutical uses. Pharmaceutical acid addition salts of the compound can be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acids. Examples of organic acids include, but are not limited to, the aliphatic, cycloaliphatic, aromatic, aryliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic , benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic, hexanoic, 2-hydroxyethanesulfonic, nicotinic, 2-naphthalenesulfonic, pectonic, pectonic, o , persulfuric, 2-phenylpropionic, picric, pivalic, propionic, succinic, t artharic, thiocyanic, mesylic, undecanoic, stearic, algenic, β-hydroxybutyric, salicylic, galactaric, and galacturonic. Base addition salts of the compound suitable for pharmaceutical uses include, but are not limited to, metal salts, such as salts containing aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or salts containing organic bases including primary, secondary and tertiary amines and substituted amines including cyclic amines such as caffeine, arginine, diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine. All salts contemplated herein can be prepared using conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. The term "proteasome" as used herein is understood to include immunological and housekeeping proteasomes. The term "resistant" when used herein is understood to refer to persistent, resistant or unresponsive to treatment, stimulus (therapy) or cure, including resistance to multiple therapeutic curative agents. "Resistant" when used herein in the context of characterizing a cancer or tumor is understood to mean that the cancer or tumor is unresponsive or has a resistant or decreased response to treatment with one or more more anticancer agents. Treatment is typically continued, prolonged, and / or repetitive for a period of time that results in the cancer or tumor recurring or developing resistance or becoming resistant to that same treatment. The term "subject" as used herein refers to any mammal, including humans, and animals such as cows, horses, dogs, and cats. Thus, the invention can be used in human patients as well as veterinary subjects and patients. In one embodiment of the invention, the compounds of the invention may be administered to a human subject. The phrase therapeutically effective or "therapeutically effective amount" is understood to quantify the amount of the compound of the invention that when administered as part of a desired dosage regimen (to a patient, eg, a human) alleviates a symptom. , improves a condition, or slows the onset of the conditions of the disease according to clinically acceptable standards for the disorder or condition being treated or for the cosmetic purpose, for example, to a risk-benefit ratio applicable to any medical treatment. Therefore, it is the amount of the compound of the invention that can treat cancer, whether it is multiple myeloma or another hematological malignancy or a solid tumor. The terms "treat" and treatment as used herein refer to therapy, including without limitation, curative therapy, prophylactic therapy, and preventative therapy, and generally include the reversal, lessening, or stopping of symptoms. , clinical signs and underlying pathology of a condition in such a way as to delay or stabilize a patient's condition. Prophylactic treatment generally constitutes either preventing the onset of the conditions or delaying the onset of an apparent pre-clinical stage of the disorders in individuals. The term "prophylactic or therapeutic treatment" is recognized in the art and includes administration to a subject of one or more of the compositions of the invention. If it is administered prior to the clinical manifestation of the undesired condition (for example, disease or other unwanted condition of the animal subject), or after the condition has abated, then the treatment is prophylactic (i.e., it protects the subject against the development of the unwanted condition), while if it is administered after the manifestation of the unwanted condition, then the treatment is therapeutic, (i.e. in such a way that it diminishes, improves or stabilizes the existing unwanted condition or its side effects). The term "substituted" refers to structures that have substituents that replace a hydrogen on one or more other than hydrogen atoms in the molecule. "Substitution" or "substituted with" is to be understood to include the implicit condition that said substitution satisfies the valency of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., that does not undergo spontaneous transformation such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is understood to include all permissible substituents on organic compounds. In a broad sense, among the permitted substituents are acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permitted substituents may be one or more and the same or different for the suitable organic compounds. For the purpose of the present disclosure, heteroatoms such as nitrogen may possess hydrogen substituents and / or any permitted substituent of the organic compounds described herein that satisfies the valence of the heteroatoms. Substituents include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic structure. It is to be understood that substituted structures in a hydrocarbon chain may themselves be substituted in the appropriate manner. The term PEG, as used herein, is understood in such a way that it has the meaning traditionally assigned to it. In particular, PEG is a structure formed by the repetition of polymeric units of poly(ethylene glycol), the precise number of units determining its molecular weight. For example, the PEG structure used in the present invention can possess any of the architectures disclosed herein as well as, for example, those illustrated in Formulas A-1 as shown in Table 1. The molecular weight unit it's the dalton Therefore, any reference to a molecular weight of PEG as used herein (the description, claims and abstract), for example, reference to "2K", "3K", "5K" is to be understood as ” and “20K” or “2000”, “3000”, “5000” or “20000” with respect to a given PEG means a PEG weight of 2000 daltons (or 2 kilodaltons), 3000 daltons (or 3 kilodaltons), 5000 dalton (or 5 kilodaltons), and 20,000 daltons (or 20 kilodaltons), respectively. Also, as used herein "KDa" means kilodalton. It should be understood that the carfilzomib compounds shown in Formulas A, B, C, D, E, F, G, H and I in Table 1 illustrate different PEG structures linked covalently via linkers as described and defined in the present memory. To help understand each Formula in Table 1, R-> or where R1 and R2 are as defined herein in Formulas I and II. The counter anion X' is as defined in Formulas I and II herein. For example, the counter anion X' can be Cl', HSOf, SO4'2, NO3', H2PO4, alkyl / aryl-SCb' such as a tosylate (tosylsulfonic acid), mesylate (methanesulfonic acid) or benzylate (benzylsulfonic acid) anion. ). The PEG portion of the carfilzomib compound typically has a molecular weight in the range of about 400 daltons to about 50,000 daltons. The linker portion of the compounds illustrated in Formulas A-I below are also defined herein in Formulas I and II. For example, the connector can be PEG O-N PEG, R3 or where R3 is H or Me. Table 1 Reference A B. PEG Molecule Type Carfilzomib linear 1 bifunctional arms 4 8-armed hexaglycerin nucleus E Y-Qinkerj^A-Zo' Nucleus of 8-armed tripentaeryth ritol η / η\ η> Y—{linker Y—Ilinker o— °A n\-c z 0^0^0< z °A 'n'-Q Z' 0»n Y—(linker r-T n \—i sz Zo oy °Za °A n \—c Branching of i arms Branching of i arms 4-branch branching branched or arms In embodiment 51, PEG has a molecular weight of more than lkDa. In embodiment 52, PEG has a molecular weight of about 1 kDa. In embodiment 53, PEG has a molecular weight of more than 2 kDa. In embodiment 54, PEG has a molecular weight of about 2 kDa. In embodiment 55, PEG has a molecular weight of more than 5 kDa. In embodiment 56, PEG has a molecular weight of about 5 kDa. In embodiment 57, PEG has a molecular weight of more than 10 kDa. In embodiment 58, PEG has a molecular weight of about 10 kDa. In embodiment 59, PEG has a molecular weight of more than 20 kDa. In embodiment 60, PEG has a molecular weight of about 20 kDa. In embodiment 61, PEG has a molecular weight of more than 30 kDa. In embodiment 62, PEG has a molecular weight of about 30 kDa. In embodiment 63, PEG has a molecular weight of more than 40 kDa. In embodiment 64, PEG has a molecular weight of about 40 kDa. In embodiment 65, PEG has a molecular weight of more than 50 kDa. In embodiment 66, prior to conjugation with the epoxy ketone protease inhibitors, PEG possesses a plurality of reactive functional groups (eg, azide groups). In some embodiments, prior to conjugation with the epoxy ketone protease inhibitors, PEG possesses 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 reactive functional groups (eg, azide groups). ). The PEG-carfilzomib conjugate compounds of the invention possess a polyethylene glycol (PEG) polymer chain conjugated to the active pharmaceutical ingredient carfilzomib (API). For said purpose, the invention discloses in aspect 67, a carfilzomib PEG compound of Formula I or Formula II where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In embodiment 68, n is 8. In embodiment 69, n is 4. In the form of embodiment 70, n is 2. In embodiment 71, n is 1. General Synthesis and Representative Examples of the Invention As described, the PEG and carfilzomib conjugates in Formulas I and II are polymeric PEG carriers of the active pharmaceutical ingredient carfilzomib (Formulas I and II) to which they are cleavedly linked, and release free carfilzomib in vivo. Polyethylene glycol (PEG) solubilizing polymeric supports of the desired size and / or weight are commercially available and can be purchased, for example, from ThermoFisher Scientific, SigmaAldrich and other commercial suppliers of polymeric materials. The PEG group can be attached to carfilzomib in the morpholine ring quaternary salt form of a variety of linkers, including an alkanoyloxy para-substituted benzyl autoimmolate linker, as disclosed herein. The linker contains a latent nucleophilic phenol group that becomes an electron donor after a biological or chemical trigger mechanism and then initiates an electron cascade that subsequently leads to the release of carfilzomib. The particular combination of a solubilizing polymeric support and the formation of a quaternary salt results in conjugates with extraordinarily high water solubility. Carfilzomib is released from the conjugate enzymatically via an esterase enzyme or chemically via hydroxide-catalyzed hydrolysis. It should be noted that this PEG conjugate in isolation / itself is active as a proteasome inhibitor and rapidly releases the most active pharmaceutical ingredient carfilzomib when the conjugate is exposed to an appropriate esterase enzyme or mildly basic environment. The rate of displacement can be varied within a time range by introducing one or more bulky groups that constitute a steric hindrance to enzyme access, and / or one or more electron density modulating groups at the R2 position in Formulas I and II. Abbreviations: The following abbreviations that are used throughout the general schemes as well as in the examples are to be understood according to the following meanings: DCM dichloromethane; methylene dichloride DMF dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate MeOH methanol Mpk milligrams per kilogram; mg / kg RT, rt room temperature NaCI sodium chloride tBuOH t-butanol; t-butyl alcohol El material de partida carfílzomib, utilizado para preparar los compuestos de la invención, se describe en las publicaciones PCT W02006017842, W02009045497, WO2014169897, WO2013169282, W02014011695, W02006063154, W02014015016, W02010048298 y US Patent Nos 7,714,042 y 7,737,112, cuyos contenidos se incorporan en su herein in its entirety by this reference. Scheme 1: Cleavage of the quaternary salt by benzyl elimination esterase or Chemical cleavage benzyl alcohol aids product remains attached to polymer Enzymatic and / or chemical hydrolysis of the phenyl ester gives rise to a carboxylic acid (II) and phenolate intermediate (I) that undergoes rapid elimination 1, 6 to give free carfilzomib and a methylide that remains covalently bound to the phenyl ester. solubilizing PEG polymer. Quinone methylides are known to be reactive Michael acceptors and are believed to present risks related to potential genotoxicity. In the present invention, permanent attachment of the quinone methylide linker (by-product) to the polymer can attenuate toxicity by preventing cellular access and decreasing reactivity against serum nucleophiles. The most likely fate of intermediate III in vivo is reaction with water to form a benzyl alcohol-polymer adduct that is rapidly eliminated from the body by excretion. Scheme 2: Cleavage of the carfilzomib-polymer conjugates described above PEG-<Ñ^^YvOv^i \_ θ / Α) H ° f H ° esterase or Chemical cleavage m vivo x.<\> O L H o =p|H o iZpCi Y = ch2, o, nh2 n = 0-6 χ.Ο S S * “ Yo. H 0 Ph υ Y=CH2 PEG—(ünker)^syOH Y= OH in vivo PEG—flinker^tyQH + Cq2 'n Y = NH2 PEG—(linker)^NH2 + COz free quinone nucleophile carfilzomib H0K(r2)c; Scheme 2 illustrates a metabolic pathway for the carfilzomib-polymer compounds described in WO2014011695. Herein, as illustrated above, the carfilzomib-polymer conjugates interact with an esterase enzyme or are subject to etching as shown by an arrow. This attack results in the release of a free quinone methylide (boxed in the figure above) upon ester hydrolysis. This methylide intermediate is free to react with cellular nucleophiles, which can lead to toxicity. The PEG and carfilzomib conjugates of the present invention avoid the potentially toxic side product, as described in Scheme 1. Scheme 3: Two-step procedure to conjugate the PEG polymer Yo The carfilzomib-PEG compounds disclosed herein are prepared following a two-step procedure, as shown in Scheme 3. Carfilzomib is first reacted with an appropriately substituted benzyl halide at the para position with a alkanoyloxy (1) to give rise to an intermediate compound that is a quaternary salt (2). The bromide or iodide anion of the quaternary salt can be exchanged with a pharmaceutically suitable anion such as bisulfate, sulfate, nitrate, monobasic phosphate, or alkyl / aryl sulfonate using an ion exchange resin to give intermediate (3). Conveniently, this intermediate is covalently linked with a suitable reactive group to react with a complementary function-containing polymeric reagent (4) to give the desired product 5. A number of PEG reagents exist and are commercially available. in a range of molecular weights, architectures, end group chemical structures, and with various reactive end groups (arms) (see Table 1). They may be directly compatible with the chemical structures of the linker described in the present disclosure or may require further chemical manipulation using known methods. Branched-chain, multi-arm PEGs may offer advantages over linear PEGs, including the potential for increased drug loading, increased stability, and / or viscosity of formulations. Scheme 4: Two-step polymer conjugation via azide / alkyne Click chemistry A4-1 A4-2 A4-3 A4-4 A4-5 Scheme 4 illustrates “Click” chemistries, such as Huisgen's l,3-dipolar azide / alkyne cycloaddition and aminooxy / aldehyde oximation, which are particularly suitable for PEG polymer and polymer linkages due to high chemical yields, the innocuousness of the secondary products, the great acting thermodynamic forces and the availability of the starting material. Huisgen's 1,3 dipolar azide / alkyne cycloaddition requires that the benzyl group be substituted with an alkyne group (A 1-(1-6)) capable of reacting with an azide-functional polymer support such as PEG-azide (-N3 ) to give rise to a conjugate linked to 1,2,3-triazole (A4-(16)). The alkyne moiety may be linked directly or indirectly via an alkyl spacer (Al-1), via an ether (Al-2,3), thioether, sulfoxide or sulfone (Al-4) bond, or may be linked via a amide (A 1-5.6). Many azido-substituted PEG reagents are commercially available in a wide variety of sizes and architectures, but they can also be prepared from any available PEG-alcohol by activation by mesylation or tosylation, followed by reaction with a salt. of azide. The cycloaddition reaction can be carried out using the available cuprous salt catalysts, but it proceeds more efficiently using a mixture of copper(II) (for example copper(II) sulfate, copper(II) methanesulfonate) and an agent. reductant (eg sodium ascorbate) to produce Cu(I) in situ. Since copper(I) is unstable in aqueous solution and in the presence of oxygen, stabilizing ligands such as tris-(benzyltriazolylmethyl)amine (TBTA), tris(3-hydroxy-propyltriazolylmethyl)amine (THPTA), sulfate 2-[4-({bis[(lyer-butyl-1H-1,2,3-triazoI-4-yl)methyl]amino}methyl)-1H-1,2,3-triazol-1-yl monobasic ]ethyl (BTTES) or 2-[4({bis[( 1 -er-butyl-1 Η-1,2,3-triazol-4-yl)methyl]amino}methyl)-1 Η-1,2 acid ,3-triazole-1 -i 1]acetic acid (BTTAA). The reaction can proceed at room temperature or at elevated temperature in a variety of solvents, and mixtures of water and a variety of miscible organic solvents including alcohols, DMSO, DMF, / BuOH, and acetone. The final product of PEG and carfilzomib (A4-(l-6)) can be conveniently redissolved by dilution of the reaction mixture with water or brine, extraction with an organic solvent such as DCM, and reprecipitation from isopropanol or mixtures. of ether / isopropanol until obtaining the product of the desired purity. Exposure of intermediates or products to anions during stripping procedures, such as chloride anions in brine, typically results in a mixture of anions in the final product, and a final treatment with exchange resin may be necessary. ammonium to ensure the homogeneity of the product salt. The intermediate halide (bromide or iodide, (A2-(l-6)) quaternary salt can be converted to an anion that does not precipitate with copper (I) catalyst such as methanesulfonate, bisulfate or sulfate (A3-(l-6 )) to achieve high reaction yields It may also be desirable to exchange the halide anion to prevent opening of the epoxide and the possible formation of bromohydrin or iodohydrin side products. Scheme 4A1-2 Synthesis of 4-(bromomethyl)-2-(prop-2-ynyloxy')phenyl acetate (intermediate A1-2 in Scheme 4) Step 1: 4-Hydroxy-3-(prop-2-ynyloxy)benzaldehyde (1) To a mixture of NaOtBu in DMF (150 mL) was added 3,4-dihydroxybenzaldehyde (10 g, 72.5 mmol) in DMF (50 mL) at 20 °C. The mixture was cooled in an ice bath and stirred while 3-bromoprop-l-yne (8.62 g, 72.5 mmol) was added in small portions, taking care to maintain the internal temperature between 15-20 °C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (300 mL) and extracted with EtOAc (200 mL><3). The combined organic layers were washed with water to remove DMF, dried over anhydrous Na2SO4, and concentrated to a brown solid. The residue was crystallized several times from DCM / petroleum ether (30 mL / 500 mL) to give compound 1. 'H NMR (CDC13, 300 MHz,): δ 9.87 (s, 1H), 7.54 (d , J = 1.2 Hz, 1H), 7.49 (dd, J1 = 1.5 Hz, J2 = 8.1 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 4.82 (m, 2H), 2.62 (m, 1H). Step 2: 4-formyl-2-(prop-2-ynyloxy)phenyl acetate (2) To a solution of compound 1 (10.00 g, 56.82 mmol) in DCM (150 mL) was added EthyN (11.48 g, 113.64 mmol) followed by acetyl chloride (5.35 g, 68.18 mmol) at 0 °C. The mixture of reaction was stirred at room temperature for 2 hours. The mixture was washed with 2N aqueous HCI saturated [sic] solution (100 mL) and water (50 mL), dried over anhydrous MgSOi, and concentrated to give compound 2, which was used in the next step without subsequent purification. Ή NMR (CDCh, 400 MHz): δ 9.96 (s, 1H), 7.63 (d, J= 1.6 Hz, 1H), 7.54 (dd, J\ = 1.6Hz, Λ = 8.0 Hz, 1H), 7.25 ( d, J= 8.0 Hz, 1H), 4.79 (d, 7= 2.4 Hz, 2H), 2.57 (t, J= 2.4 Hz, 1H), 2.35 (s, 3H). Step 3: 4-(Hydroxymethyl)-2-fprop-2-ynyloxy)phenyl acetate (3) To a solution of compound 2 (12.00 g, 55.05 mmol) in DCM / MeOH (150 mL / 15 mL) was added NaBHi (3.06 g, 82.57 mmol) in small portions at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with acetone (5 mL), and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 2:1) to give compound 3. Ή NMR (CDCh, 400 MHz): <5 7.16 (d, J = 1.6 Hz, 1H), 7.04 (d, 7 = 8.0 Hz, 1H), 6.98 (dd, 7, = 1.6 Hz, J2 = 8.0 Hz, 1H), 4.72 (d, J= 2.4 Hz, 2H), 4.69 (s, 2H ), 2.53 (t, J= 2.4 Hz, 1H), 2.32 (s, 3H). Step 4: 4-(bromomethyl)-2-(prop-2-ynyloxy)phenyl acetate (4) To a solution of compound 3 (11.50 g, 52.27 mmol) in DCM (150 mL) was added PPI13 (20.50 g, 78.41 mmol) and NBS (11.04 g, 62.73 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hour. Excess solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 20:1) to give compound 4 (7.82 g, 53% yield). Ή NMR (CDCh, 400 MHz): δ 7.14 (m, 1H), 7.02 (m, 2H), 4.73 (d, J= 2.4 Hz, 2H), 4.48 (s, 2H), 2.55 (t,7 = 2.4 Hz, 1H), 2.32 (s, 3H). Scheme 5: Quaternary salt anion exchange Amberlyst A26 (HO' fornjf j or equivalent ho^n; he HY or NH4+Y' Yo Ion exchange can be achieved by reacting the halide quaternary intermediate with a silver salt or more practically by passing it through an ion exchange resin, as shown in Scheme 5. The anion of the carfilzomib quaternary salt present in the Intermediates or final products can be efficiently converted to a different strong acid anion such as bisulfate, sulfate, monobasic phosphate, nitrate, or alkyl / aryl sulfonate using an anion exchange resin. An anion exchange resin such as Amberlyst A26 (OH form) is pretreated with the desired acid or ammonium salt / and then the halide quaternary salt is passed. Conjugates prepared from anions of weak acids such as acetate, formate, or lactate are unstable due to the increased basicity of the quaternary salt and incompatibility with the triggering ester group. Scheme 6: Two-step polymer conjugation via aminooxy / carbonyl chemistry X = Br, I R4 = H, Me carfilzomib z B2-(1-6) R5, Re = independently H or alkyl C-i.3 m = 0 - 4 n = 1 - 4 p = 0, 1,2 B1-1 B1-2 B1-3 B1-4 B1-S B1-6 Anion Exchange peg-onh3+.y-► B3-(1-6) β4-3 β4-4 β4-5 β4-6 Alternatively, the benzyl group (B 1-(1-6)) may be substituted with a carbonyl group (aldehyde or ketone) that is capable of reacting with aminooxy-functional polymeric supports such as PEG-aminooxy (-ONH2 ) to give rise to a stable conjugate bound to the oxime (B4-(l-6)). The carbonyl moiety can be attached directly or attached via an alkyl spacer (Bl-1), attached via an ether (B 1-2,3), thioether, sulfoxide, or sulfone bond (Bl4), or attached via a amide (Bl-5,6). Carfilzomib and the benzyl halide (B 1-(1-6)) are allowed to react at room temperature or at elevated temperature in a suitable organic solvent such as acetonitrile to give a quaternary intermediate (B2-(1-6) ) in the form of bromide or iodide salt. It is desirable to exchange this halide anion to prevent opening of the epoxide and the possible formation of bromohydrin or iodohydrin side products. Anion exchange can be carried out by reacting the quaternary halide intermediate with a silver salt or, more practically, by passing it through an ion exchange resin as described above (Scheme 5). The carfilzomib quaternary salt intermediate (B3-(1-6)) and PEG-ONH3+Y' polymer reagent are then allowed to react at room temperature or at elevated temperature in a suitable organic solvent such as DCM or a solvent aqueous and organic mix. Optionally oximation catalysts such as aniline, p-phenylenediamine, or 5-methoxyanthranilic acid may be added but are usually not required. It should be noted that the anion salts of the carfilzomib quaternary salt intermediate (B3-(1-6)) and the PEG-aminooxy reagent are identical to obviate the formation of a mixed anion salt end product and the need for of any subsequent manipulation of the anion. The final product of PEG and carfilzomib can be conveniently redissolved by evaporation of the reaction solvent and reprecipitation of the residue from isopropanol or ether / isopropanol mixtures to obtain the product of the desired purity. Scheme 7: Synthesis of the PEG-aminooxy reagents >LqAn.oh taask1 Η HX A. >Ο^°^Χ -► xO'SxO^O'N'|f'°YC X = halo,-OSO2R . . ° Anion ^Ο^Ο^θ.ΝΗ,'Χ- Exchange X = Cl-, RSO2O-, CF3CO2-, SO4-2 Y = RSO2O-, hso4-, SO42 Β. HX HO^o-NY°>< o o 1 coupling 'xo'S^°^n'Ux-on h3+xH Anion Exchange X = Cl', RSO2Q-, cf3co2-, so4 y = rso2o-, hso4-, SO4 PEG-aminooxy reagents are commercially available or can be readily prepared from mesyl- or tosyl-activated PEG-alcohols, PEG-halide (A), or PEG-amine (B) starting materials, as illustrated in Scheme 7. The ferr-butyloxycarbonyl-protected intermediate can be deprotected with a strong acid such as hydrogen chloride, methanesulfonic acid, trifluoroacetic acid, or sulfuric acid to give the PEG-aminooxy reagent in the chloride, trifluoroacetate, or sulfate salt form. . The anion of the reagent PEG-aminooxy can optionally be exchanged with a different anion using an anion exchange resin. Scheme 8: Isomers of the oxime Ketoxime (Z)-¡somer IO One skilled in the art will readily understand that oximes can exist as two geometric isomers: a syn (Z) isomer and an anti (E) isomer, as illustrated in Scheme 8. Many of the examples in the present disclosure are aromatic aldoximes and exist only as (£) isomers. The non-aromatic aldoximes and ketoximes can usually be completely separated and obtained as a (Z)-isomer and a (£j)-isomer. The non-aromatic aldoximes and PEG-conjugated ketoximes of the present invention can exist as (Z) and (E)-isomers. ) separately or as a mixture of (Z) and (E) isomers. Scheme 9: Direct conjugation with the polymer to form a quaternary salt Alternatively, the carfilzomib-polymer conjugates described herein can be prepared in a one-step reaction of carfilzomib and a para-substituted benzyl halide with an alkanoyloxy group previously attached to the desired polymer chain, as is shown in Scheme 9. The polymer chain can be linked via a wide variety of known chemical pathways or the alkyne / azide or carbonyl / aminooxy chemical pathways described above. This route may be less desirable due to the difficulty in separating PEG-containing products from unreacted PEG-conjugated starting materials. Representative Examples of the Invention The following PEG and carfilzomib conjugates are representative examples of the invention and should not be construed as limiting the scope of the present invention. PEG and carfilzomib conjugates were prepared using the following two general methods for PEG binding (A and B). Method A: Triazole PEG Linker A3-(1-6) PEG Intermediate carfilzomib A3-(l-6) quaternary salt (1.5 eq), PEG-azide(l eq) and (L)-ascorbic acid (0.75 eq) were mixed in DMF (50 mL / mmol PEG-azide ) to give rise to a cream-colored suspension. The mixture was stirred vigorously for 5 min and a solution of copper(II) sulfate pentahydrate (0.3 eq) in water (10 mL / mmol PEG-azide) was added rapidly dropwise. The reaction immediately darkened to a yellow-brown color and the suspension turned clear within 5 min. After 1 hour, a second portion of ascorbic acid (0.75 eq) was added and the reaction mixture was stirred for 60 minutes. A third portion of ascorbic acid (0.38 eq) was added and the reaction mixture was stirred overnight at room temperature. Water (100 mL / mmol PEG-azide) and NaCl (15 g / mmol PEG-azide) were added and the mixture stirred until the NaCl dissolved. The product was extracted with DCM (3 X 35 mL / mmol PEG-azide). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. under vacuum at 40 DC. The residue was dissolved in isopropanol (125 mL / mmol PEG-azide) at 40 µC. Once the solids were completely dissolved, diethyl ether (90mL / mmol PEGazide) was added and the solution cooled in an ice bath. The obtained solid was filtered and the filter cake was washed twice each with 2-propanol and diethyl ether. The filter cake was dissolved in DCM and concentrated in vacuo. The residue was dissolved in warm isopropanol (40DC) (200 mL / mmol PEG-azide) and then allowed to cool in an ice bath. The obtained solid was filtered and the filter cake was washed with 2-propanol and diethyl ether, each twice, and then dried under vacuum. Method B: Oxime PEG Linker The intermediate of carfilzomib B3-(l-6) quaternary salt (1 eq), PEG-ONH3+MsO' (0.8 eq) and 5-methoxyanthranilic acid (catalyst for oximation, 0.3 eq) in DCM (15 mL / mmol B3-(1-6))) were stirred at room temperature until complete consumption of the PEG reagent as determined by HPLC (ELS detector). The reaction mixture was evaporated to dryness and the residue was dissolved in isopropanol (15 mL / mmol B3-(1-6)) at 40 ÜC. The clear solution was cooled to room temperature and ether (5 mL / mmol B3-(1-6)) was added to induce crystallization. The mixture was cooled in an ice bath for 5-10 minutes and the solid formed was collected by filtration. Recrystallization from isopropanol / ether was repeated one to two more times until all unreacted carfilzomib B3-(1-6) quaternary salt intermediate was removed as detected by HPLC. The final solid was dried under vacuum at 30 µC. Typical yield: 6080%; Typical reaction time: 10-30 min for intermediates containing an aldehyde function, 24 h for intermediates with a ketone function. Examples of prepared PEG and carfilzomib conjugates, the PEG architecture and the PEG linker methodology are shown in Table 2. Table 2 also includes the size and weight (Daltons) of the PEG adduct and the method used to attach the PEG scaffold to the carfilzomib backbone. Table 2 Example Structure PEG Connector Arms PEG Size / Method 20K / 4 5K / 1A 5K / 1A 5K / 1A 5K / 1A 5K / 1A ;or 5K / 1A 5Κ / 1Α 5Κ / 1Α 5Κ / 1Α 20Κ / 4Α 20Κ / 4Α -Ν-Ν 4JÑ 20Κ. / 4 Α 20Κ / 4Α v. ΡΕ®5ΚΌ A. 5K / 1A 5K / 1B ΜβΟ Ph 5K / 1B 5K / 1B 5K / 1B%hH 5K / 1B 2K / 1B 2K / 1B 3Κ / 1Β 3Κ / 1Β 20Κ. / 4 Βρε<35ΚΌ 5Κ / 1Β 5Κ / 1Β 5Κ / 1Β 20Κ. / 4 Β 20Κ / 4Β 5K / 1B ΡΕ05Κ'φ 5K / 1B 5K / 1B PEG3k ¿h Ν-Ν vn Ό either 3K / 1A 3K / 1A ph PEG2Kx n–n y V' ς ««Η ΐΥ rS'YrSAn > 0 ph 2K / 1A - <5} » MsO Ο^χ1 O PE°3KS-n-n Í^N Y ph 3K / 1A -r>, i. MsO O,___J O 2K / 1A Example 1: 4-(4-acetoxy-3-(fl-(PEG20K-4-Arm)-lH-1,2,3-triazol-4-yl)methoxy)benzyl)-4-((4S,7S) methanesulfonate ,10S,13S)-10-benz¡l-7-isobutyl-15-methyl-13-((R)-2-methyloxyÍran-2carboniD-2,5,8,11 -tetraoxo-4-phenethyl-3,6 ,9,12-tetraazahexadecyl')morphblin-4-io (7) 4-Hydroxy-3-fprop-2-ynyloxy')benzaldehyde (1) To a mixture of NaH in DMSO (300 mL) was added 3,4-dihydroxybenzaldehyde (30 g, 217.39 mmol) in DMSO (50 mL) at 20 °C. The mixture was stirred for 30 min and 3-bromoprop-l-yne (25.87 g, 217.39 mmol) was added. The reaction mixture was stirred at room temperature for one hour. The mixture was poured into ice-water (800 mL) and the obtained solution was brought to pH = 2. The mixture was extracted with EtOAc (500 mL><3), dried over anhydrous MgSO4, and concentrated. The residue was crystallized several times from DCM / petroleum ether (30 mL / 500 mL) to give compound 1 (30 g, 78% yield); 'HNMR (CDCb, 300 MHz,): δ 9.87 (s, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.49 (dd, J, = 1.5 Hz, J2 = 8.1 Hz, 1H), 7.09 ( d, / =8.1 Hz, 1H), 4.82 (m, 2H), 2.62 (m, 1H). 4-Formyl-2-('prop-2-ynyloxy)phenyl(2) acetate To a solution of compound 1 (10.00 g, 56.82 mmol) in DCM (150 mL) was added Et3N (11.48 g, 113.64 mmol) followed by acetyl chloride (5.35 g, 68.18 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was washed with 2N aqueous saturated [sic] HCl solution (100 mL) and water (50 mL), dried over anhydrous MgSO4, and concentrated to give compound 2 (12 g, 97% yield) , which was used in the next step without further purification; 'H NMR (CDCb. 400 MHz): δ 9.96 (s, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.54 (dd, Chi = 1.6Hz, / 2 = 8.0 Hz, 1H), 7.25 ( d, J= 8.0 Hz, 1H), 4.79 (d, J= 2.4 Hz, 2H), 2.57 (t, J= 2.4 Hz, 1H), 2.35 (s, 3H) 4-(Hydroxymethyl)-2-(prop-2-ynyloxy)phenyl Í3] acetate To a solution of compound 2 (12.00 g, 55.05 mmol) in DCM / MeOH (150 mL / 15 mL) was added NaBH4 (3.06 g, 82.57 mmol) in small portions at 0 °C. The reaction mixture is stirred at room temperature for 30 min. The mixture was diluted with acetone (5 mL), and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 2:1) to give compound 3 (10.32 g, 85% yield); ’H NMR (CDCb, 400 MHz): δ 7.16 (d, 1.6 Hz, 1H), 7.04 (d, .7=8.0 Hz, 1H), 6.98 (dd, J, = 1.6 Hz, J2 = 8.0 Hz, 1H), 4.72 (d, J= 2.4 Hz, 2H), 4.69 (s, 2H), 2.53 (t, J= 2.4 Hz, 1H), 2.32 (s, 3H). 4-(Bromomethyl)-2-(prop-2-ynyloxy)phenyl acetate (4) To a solution of compound 3 (11.50 g, 52.27 mmol) in DCM (150 mL) was added PPlb (20.50 g, 78.41 mmol) and NBS (11.04 g, 62.73 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hour. Excess solvent [sic] was concentrated and the residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 20:1) to give compound 4 (7.82 g, 53% yield); 'H NMR (CDCb. 400 MHz): <5 7.14 (m, 1H), 7.02 (m, 2H), 4.73 (d, J= 2.4 Hz, 2H), 4.48 (s, 2H), 2.55 (t, J = 2.4 Hz, 1H), 2.32 (s, 3H). 4-(4-Acetoxy-3-(prop-2-yn-1-yloxy)benzyl)-4-((4S,7S,1OS,13S)-10-benzyl-7-isobutyl-15-methyl-13 methanesulfonate -((R)-2-methyloxiran-2-carbonyl)-2,5,8,l-tetraoxo-4-phenethyl-3,6.9,12tetraazahexadecyl)morpholin-4-ium (6) To a solution of compound 4 (5.85 g, 20.67 mmol) in MeCN (50 mL) was added (S)-4methyl-N-((S)-1 -(((S)-4-methyl-1 -(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)- 4-phenylbutanamido)pentanamide (4.96 g, 6.89 mmol). The reaction mixture was stirred at 45 °C for 2 days. An excess of solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (EtOAc / MeOH = 100:6) to give the desired compound 5, which was converted to the corresponding mesylate (3.2 g , 50% yield) by treatment with ion exchange resin; 'H NMR (CDCb, 400 MHz): δ 9.66 (m, 1H), 7.83 (m, 1H), 7.36 (m, 1H), 7.26-7.14 (m, 13H), 6.72 (m, 1H), 5.18 ( m, 1H), 4.90 (m, 2H), 4.77 (m, 2H), 4.53-4.36 (m, 4H), 4.26 (m, 3H), 4.08 (m, 1H), 3.92 (m, 2H), 3.74 (m, 1H), 3.46 (m, 1H), 3.35 (m, 1H), 3.13 (m, 1H), 3.04 (m, 2H), 2.81 (s, 3H), 2.75 (m, 2H), 2.62 ( m, 1H), 2.33 (m, 3H), 2.20 (m, 1H), 2.12 (m, 1H), 1.70-1.53 ​​(m, 3H), 1.50-1.33 (m, 5H), 1.25 (m, 2H) , 0.90-0.81 (m, 12H). Example 1 was prepared from compound 6 and PEG2ok(N3)4, following the technique for the preparation of PEG A derivatives; 'H NMR (500 MHz, relaxation time = 10 sec) DMSO-dó NMR: δ 9.50 (s, 4H), 8.50 (s, 4H), 8.39 (d, J= 8 Hz, 4H), 8.27 (d, J = 8 Hz, 4H), 8.11 (s, 4H), 8.05 (d, J = 8 Hz, 4H), 7.58 (s, 4H), 7.26-7.29 (m, 12H), 7.12-7.23 (m, 32H) ), 7.03-7.06 (m, 4H), 5.26 (m, 8H), 4.89-5.00 (m, 8H), 4.52-4.56 (m, 12H), 4.28-4.38 (m, 16H), 4.17-4.20 (m , 4H), 4.05 (m, 16H), 3.81 (t, J = 5.5 Hz, 8H), 3.63-3.66 (m, 8H), 3.50 (s, 2098H), 3.10 (d, J = 5 Hz, 4H) , 2.94-2.98 (m, 12Η), 2.72-2.78 (m, 4H), 2.50-2.65 (m, 8H), 2.24 (s, 12H), 1.90-1.98 (m, 4H), 1.78-1.88 (m, 4H), 1.58-1.66 ( m, 8H), 1.39 (s, 12H), 1.25-1.38 (m, 12H), 0.836-0.882 (m, 24H), 0.786-0.817 (m, 24H); Charge: 87%. Example 2: 4-(4-acetoxy-2-((1-PEG5K-1H-1,2.3-triazol-4yl)methoxy)benzyl)-4-((4S,7S,10S,13S') methanesulfonate -10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran-2carbonyl)-2,5,8.1 l-tetraoxo-4-phenethyl-3,6,9,12- tetraazahexadecyl)morpholin-4-¡o (9). to to 2-Hydroxy-4-(methoxymethoxy)benzaldehydeTl) To a solution of the compound 2,4-dihydroxybenzaldehyde (5.04 g, 36.24 mmol) in THF (100 mL) was added DIPEA (6.52 g, 54.35 mmol) and chloro(methoxy)methane (3.21 g, 39.86 mmol). The reaction mixture was stirred at room temperature overnight. Excess solvent [sic] was concentrated and the residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 15:1) to give compound 1 (3.96 g, 60% yield); Ή NMR (300 MHz, CDCb): <5 11.41 (s, 1H), 9.76 (s, 1H), 7.48 (dd, 71 = 2.7 Hz, 72 = 8.4 Hz, 1H), 6.67 (dd, 71 = 2.4 Hz , 72 = 8.7 Hz, 1H), 6.62 (d, 7= 2.1 Hz, 1H), 5.25 (d, 7= 2.7 Hz, 2H), 3.51 (d, 7= 3.0 Hz, 3H). 4-(Methoxymethoxy)-2-(prop-2-ynyloxy)benzaldehyde (2) To a mixture of NaH (900 mg, 21.252 mmol) in DMSO (100 mL) was added compound 1 (2.0 g, 10.63 mmol) in DMSO (50 mL) at 20 °C. The mixture was stirred at the same temperature for 30 min and then 3-bromoprop-l-yne (1.90 g, 15.94 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 4 hours and then poured into ice-water (100 mL). The obtained solution was brought to pH = 2-3 and EtOAc (100 mL) was added. The two phases were separated and the aqueous phase was extracted with EtOAc (100 mLx3). The combined organic phases were dried and concentrated. The residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 3:1) to give compound 2 (1.89 g, 80% yield); 'H NMR (300 MHz, CDCh): δ 10.34 (s, IH), 7.85 (d, J= 9.3 Hz, IH), 6.76 (m, 2H), 5.26 (s, 2H), 4.83 (d, J= 2.4 Hz, 2H), 3.52 (s, 3H), 2.60 (q, J= 2.4 Hz, IH). 4-Hydroxy-2-(prop-2-ynyloxy)benzaldehyde (3) To a solution of compound 2 (5.1 g, 23.18 mmol) in propan-2-ol (100 mL) was added CBr4 (760 mg, 2.32 mmol). The reaction mixture was refluxed overnight. An excess of solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 3:1) to give compound 3 (2.44 g, 60% yield); Ή NMR (400 MHz, DMSO-76): δ 10.76 (s, IH), 10.11 (s, IH), 7.60 (d, J= 8.8 Hz, IH), 6.59 (d, J= 2.0 Hz, IH), 6.52 (dd, 71 = 2.0 Hz, 72 = 8.8 Hz, IH), 4.92 (d, 7= 2.4 Hz, 2H), 3.70 (q, 7= 2.4 Hz, IH). 4-(Hydroxymethyl)-3-(prop-2-ynyloxy)phenol (4) To a solution of compound 3 (2.45 g, 13.92 mmol) in MeOH (40 mL) was added NaBH4 (618 mg, 16.698 mmol) in small portions at 0 °C. The reaction mixture was stirred at the same temperature for 1 hour and then diluted with water (1.5 mL). Excess solvent [sic] was concentrated and the residue redissolved in EtOAc (100 mL). The obtained solution was dried and concentrated to give compound 4 (1.80 g, 74% yield), which was used in the next step without further purification; Ή NMR (400 MHz, DMSO-76): δ 6.98 (d, 7 = 8.0 Hz, IH), 6.32 (s, IH), 6.26 (d, 7= 8.0 Hz, IH), 4.65 (d, 7= 2.0 Hz, 2H), 4.32 (s, 2H), 3.54 (m, IH). 4-(Hydroxymethyl)-3-(prop-2-ynyloxy)phenyl acetate (5) To a solution of compound 4 (1.20 g, 6.74 mmol) in DCM (30 mL) was added TEA (1.70 g, 16.85 mmol) followed by acetyl chloride (634 mg, 8 mmol) dropwise at 0 °C. The mixture of reaction was stirred at room temperature for 30 min. Excess solvent [sic] was concentrated and the residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 5:1) to give compound 5 (360 mg, 30% yield); Ή NMR (400 MHz, DMSO-76): δ 7.38 (d, 7 = 8.0 Hz, 1H), 6.79 (d, 7 = 2.0 Hz, 1H), 6.75 (dd, 71 = 2.0 Hz, 72 = 8.0 Hz, 1H), 5.09 (m, 7= 5.6 Hz, 1H), 4.82 (d, 7= 2.4 Hz, 1H), 4.46 (d, 7= 5.6 Hz, 2H), 3.60 (q, 7= 2.4 Hz, 1H) , 2.26 (s,3H). 4-(Bromomethyl)-3-(prop-2-ynyloxy')phenyl acetate (6) To a solution of compound 5 (360 mg, 1.64 mmol) in DCM (15 mL) was added PPh3 (515 mg, 1.96 mmol) followed by NBS (318 mg, 1.80 mmol) in small portions at 0 °C. The reaction mixture was stirred at the same temperature for 30 min. Excess solvent [sic] was concentrated and the residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 50:1) to give compound 6 (190 mg, 41% yield); Ή NMR (400 MHz, CDC13): <5 7.36 (d, 7= 8.4 Hz, 1H), 6.78 (d, 7= 2.0 Hz, 1H), 6.73 (dd, 71 = 2.0Hz, 72 = 8.4 Hz, 1H ), 4.77 (d, 7= 2.4 Hz, 2H), 4.54 (s, 2H), 2.56 (q, 7= 2.4 Hz, 1H), 2.31 (s, 3H). 4-(4-acetoxy-2-(prop-2-yn-l-yloxy)benzyl)-4-((4S,7S,10S,13S)-10-benzyl-7isobutyl-15-methyl-13 methanesulfonate -(YR)-2-methyloxiran-2-carbonyl)-2,5,8,11-tetraoxo-4-phenethyl-3,6,9,12tetraazahexadeciDmorpholin-4-ium (8) To a solution of compound 6 (190 mg, 0.67 mmol) in MeCN (10 mL) was added (S)-4-methyl-N-((S)-1-(((S)-4-methyl-1-(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (480 mg, 0.67 mmol). The reaction mixture was stirred at 45 °C overnight. Excess solvent [sic] was concentrated and the residue was purified by silica gel column flash chromatography (MeOH / EtOAc = 1:50) to give the desired compound 7, which was converted to the corresponding mesylate (340 mg , 74% yield) by treatment with ion exchange resin; Ή NMR (400 MHz, CDC13): δ 9.68 (m, 1H), 7.88 (m, 1H), 7.63 (m, 1H), 7.33-7.16 (m, 10H), 6.89 (m, 3H), 6.50 (m , 1H), 5.16 (m, 1H), 5.05 (m, 1H), 4.87 (m, 1H), 4.75 (m, 2H), 4.47 (m, 2H), 4.45-4.12 (m, 8H), 4.02 ( m, 3H), 3.72 (m, 1H), 3.54 (m, 1H), 3.38 (m, 1H), 3.20 (m, 1H), 3.06 (m, 2H), 2.80 (s, 3H), 2.74 (m , 2H), 2.63 (m, 2H), 2.40-2.08 (m, 5H), 1.64 (m, 2H), 1.47 (s, 3H), 0.85 (m, 12H). The compound of Example 2 was prepared from compound 8 and PEGskN3, following the technique for the preparation of PEG A derivatives. Example 3: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carboniD-2,5,8,11 methanesulfonate -tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(2-(( 1 -PEGsk- 1Hl,2,3-triazol-4-yl)methoxy')-4-(propionyloxy) benzyl)morpholin-4-io (9) 2-Hydroxy-4-(methoxymethoxy)benzaldehyde (1) To a solution of 2,4-dihydroxybenzaldehyde (5.0 g, 36.23 mmol) in THF was added DIPEA (6.52 g, 54.35 mmol) and chloro(methoxy)methane (3.21 g, 39.86 mmol). The reaction mixture was stirred overnight. Excess solvent [sic] was concentrated and the residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 15:1) to give compound 1 (3.96 g, 60% yield); 'H NMR (300 MHz, CDCb): δ 11.41 (s, 1H), 9.76 (s, 1H), 7.48 (dd, J\ = 2.7 Hz, 72 = 8.4 Hz, 1H), 6.67 (dd, 71 = 2.4 Hz, 72 = 8.7 Hz, 1H), 6.62 (d, 7 = 2.1 Hz, 1H), 5.25 (d,7=2.7Hz, 2H), 3.51 (d, 7= 3.0 Hz, 3H). 4-(Methoxymethoxy)-2-(prop-2-ynyloxyjbenzaldehyde (2) To a mixture of NaH (900 mg, 21.252 mmol) in DMSO (100 mL) was added compound 1 (2.0 g, 10.626 mmol) in DMSO (50 mL) at 20 °C. The mixture was stirred at the same temperature for 30 min and then 3-bromoprop-l-yne (1.90 g, 15.94 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 4 hours and then poured into ice-water (100 mL). The obtained solution was brought to pH = 2-3 and EtOAc (100 mL) was added. The two phases were separated and the aqueous phase was extracted with EtOAc (100 mL><3). The combined organic phases were dried and concentrated. The residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 3:1) to give compound 2 (1.89 g, 80% yield); 'H NMR (300 MHz, CDCb): <5 10.34 (s, 1H), 7.85 (d, 7= 9.3 Hz, 1H), 6.76 (m, 2H), 5.26 (s, 2H), 4.83 (d, 7 = 2.4 Hz, 2H), 3.52 (s, 3H), 2.60 (q, 7= 2.4 Hz, 1H). 4-Hydroxy-2-(prop-2-ynyloxy)benzaldehyde (3) To a solution of compound 2 (5.1 g, 23.18 mmol) in propan-2-ol (100 mL) was added CBr4 (760 mg, 2.318 mmol). The reaction mixture was refluxed overnight. An excess of solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 3:1) to give compound 3 (2.44 g, 60% yield); 'H NMR (400 MHz, DMSO-t / 6): δ 10.76 (s, 1H), 10.11 (s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 6.59 (d, J= 2.0 Hz, 1H), 6.52 (dd, J\ = 2.0 Hz, J2 = 8.8 Hz, 1H), 4.92 (d, J= 2.4 Hz, 2H), 3.70 (q,J=2.4 Hz, 1H). 4-(Hydroxymethyl)-3-(prop-2-ynyloxy)phenol (4) To a solution of compound 3 (2.45 g, 13.92 mmol) in MeOH (40 mL) was added NaBHt (618mg, 16.698mmol) in small portions at 0 °C. The reaction mixture was stirred at the same temperature for 1 hour and then diluted with water (1.5 mL). Excess solvent [sic] was concentrated and the residue redissolved in EtOAc (100 mL). The obtained solution was dried and concentrated to give compound 4 (1.80 g, 74% yield), which was used in the next step without further purification; 'H NMR (400 MHz, DMSO-t / 6): <5 6.98 (d, J = 8.0 Hz, 1H), 6.32 (s, 1H), 6.26 (d, J= 8.0 Hz, 1H), 4.65 (d , J= 2.0 Hz, 2H), 4.32 (s, 2H), 3.54 (m, 1H). 4-(Hydroxymethyl)-3-(prop-2-ynyloxy)phenyl propionate (5) To a solution of compound 4 (2.4 g, 13.5 mmol) in DCM / THF (30 mL / 5 mL) was added ΕίβΝ (3.41 g, 33.75 mmol) and propionic anhydride (1.93 g, 14.8 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight. Excess solvent [sic] was concentrated and the residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 3:1) to give compound 5 (850 mg, 30% yield); Ή NMR (400 MHz, DMSO-c / 6): δ 7.38 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 2.4 Hz, 1H), 6.74 (dd, J\ = 2.4 Hz, J2 = 8.4 Hz, 1H), 5.08 (br, s, 1H), 4.80 (d, J = 2.4 Hz, 1H), 4.46 (s, 2H), 3.60 (m, 1H), 2.20 (m, 2H), 1.16 ( m, 3H). 4-(Bromomethyl)-3-(prop-2-ynyloxy)phenyl propionate (6) To a solution of compound 5 (850 mg, 3.63 mmol) in DCM (40 mL) was added PPh3 (1.24 g, 4.72 mmol) and NBS (767.4 mg, 4.36 mmol) at room temperature. The reaction mixture was stirred for 30 min. Excess solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 3:1) to give compound 6 (780 mg, 73% yield); 'H NMR (400 MHz, CDCb): δ 7.34 (d, J = 8.0 Hz, 1H), 6.78 (d, J= 2.0 Hz, 1H), 6.73 (dd, J\ = 2.4 Hz, J2 = 8.4 Hz, 1H), 4.77 (d, J= 2.4 Hz, 1H), 4.54 (m, 1H), 2.60 (m, 2H), 2.56 (m, 1H), 1.27 (q, J= 7.6 Hz, 3H). 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran2-carbonyl)-2,5,8,11-tetraoxo methanesulfonate -4-phenethyl-3,6,9,12-tetraazahexadec¡l)-4-(2-(prop-2-yn-1 -yloxy)-4(propionyloxy)benzyl)morpholin-4-ium (8) To a solution of compound 6 (780 mg, 2.626 mmol) in MeCN (10 mL) was added (S)-4-methyl-N-((S)-l-(((S)-4-methyl-l-(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (945 mg, 1313 mmol). The reaction mixture was stirred at room temperature overnight. Excess solvent [sic] was concentrated and the residue was purified by silica gel column flash chromatography (EtOAc / MeOH = 100:3) to give the desired compound 7 (760 mg, 57% yield), which was converted to the corresponding mesylate (740 mg, 97% yield) by treatment with ion exchange resin; Ή NMR (400 MHz, CDCb): δ 9.64 (m, 1H), 7.88 (m, 1H), 7.63 (m, 1H), 7.26 (m, 10H), 6.92 (m, 1H), 6.89 (m, 2H), 6.50 (m, 1H), 5.16 (m, 1H) ), 5.05 (m, 1H), 4.87 (m, 1H), 4.78 (m, 2H), 4.47 (m, 2H), 4.45-4.12 (m, 8H), 3.72 (m, 1H), 3.54 (m, 1H), 3.38 (m, 1H), 3.20 (m, 1H), 3.06 (m, 2H), 2.84 (m, 1H), 2.80 (s, 3H), 2.74 (m, 2H), 2.63 (m, 3H) ), 2.40-2.08 (m, 5H), 1.64 (m, 2H), 1.47 (s, 3H), 1.24 (m, 3H), 0.85 (m, 12H). The PEG-carfilzomib conjugate of Example 3 was prepared from compound 8 and PEG5KN3, following the PEG A derivative preparation technique. Example 4: 4-((4S,7S,10S,13Sj-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8,l methanesulfonate l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(4-(isobutyryloxy)3-(((1 -PEGsk- 1 Η-1,2,3-triazol-4-ylmethylcarbamoyl )benzyl)morpholin-4-io (9) Ή or for-Butyl 5-formyl-2-hydroxybenzoate (1) To a solution of the compound 5-formyl-2-hydroxybenzoic acid (2.01 g, 12 mmol) in 2-methylpropan-2-ol (70 mL) was added DCC (2.3 g, 12 mmol) at room temperature. The reaction mixture was stirred under reflux for 3 hours. The solvent was concentrated and the residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 5:1) to give compound 1 (1.8 g, 75% yield). 'H NMR (300 MHz, CDCb): δ 11.76 (s, 1H), 9.91 (s, 1H), 8.33 (d, 7=2.1 Hz, 1H), 8.00 (dd, Chi = 1.8 Hz, 72 = 8.7 Hz , 1H), 7.11 (d, J= 8.4 Hz, 1H), 1.68 (s, 9H). er-Butyl 5-formyl-2-(isobutyryloxy)benzoate (2) To a solution of compound 1 (1.01 g, 4.5 mmol) in THF (20 mL) was added pyridine (1.07 g, 13.5 mmol) and isobutyric anhydride (1.423 g, 9 mmol) at room temperature. The reaction mixture was stirred for 3 hours. Excess solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 10:1) to give compound 2 (420 mg, 36% yield). Ή NMR (300 MHz, CDCb): δ 10.04 (s, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.04 (dd, 7i = 2.1 Hz, J2 = 8.4 Hz, 1H), 7.25 (m, 1H), 2.91 (m, 1H), 1.59 (s, 9H), 1.36 (d, J= 6.9 Hz, 6H) Zer-Butyl 5-(hydroxymethyl)-2-(isobutyryloxy)benzoate (3) To a solution of compound 2 (400 mg, 1.37 mmol) in THF (20 mL) was added NaBHt (57.3 mg, 1.5 mol) at room temperature. The reaction mixture was stirred for 1 hour and then diluted with acetone (1 mL). Excess solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 8:1) to give compound 3 (300 mg, 75% yield). Ή NMR (300 MHz, CDCb): δ 7.85 (m, 1H), 7.52 (d, J= 8.1 Hz, 1H), 7.06 (d, J= 8.1 Hz, 1H), 4.73 (s, 2H), 2.88 ( m, 1H), 1.57 (s, 9H), 1.30 (m, 6H). 5-(Hydroxymethyl)-2-(¡sobutyryloxy)benzoic acid (4) A solution of compound 3 (400 mg, 1.38 mmol) in TFA / DCM (v / v, 3 mL / 12 mL) was stirred at room temperature overnight. The mixture was poured into water and the aqueous solution brought to pH=3-4. The two phases were separated and the organic phase was dried over anhydrous MgSO4 and concentrated to give compound 4 (202 mg, 62% yield), which was used in the next step without further purification. 4-(Hydroxymethyl)-2-(prop-2-ynylcarbamoyl)phenyl isobutyrate (5) To a solution of compound 4 (202 mg, 0.85 mmol) in DCM (20 mL) was added DIPEA (219.3 mg, 1.7 mmol), HATU (969 mg, 2.55 mmol), and prop-2-yn-l-amine (93.5 mg, 1.7 mmol) at 0 °C. The reaction mixture was stirred for 30 min. Excess solvent [sic] was concentrated and the residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 5:1) to give compound 5 (130 mg, 60% yield); 'HNMR (300 MHz, CDCb): δ 7.83 (m, 1H), 7.52 (m, 1H), 7.10 (m, 1H), 4.65 (s, 2H), 4.24 (m, 2H), 2.87 (m, 1H ), 2.30 (m, 1H), 1.26 (m, 6H). 4-(Bromomethyl')-2-(prop-2-ynylcarbamoyl)phenyl isobutyrate (6) To a solution of compound 5 (130 mg, 0.5 mmol) in DCM (15 mL) was added PPh3 (170.3 mg, 0.65 mmol) and NBS (105.6 mg, 0.6 mmol) at 0 °C. The reaction mixture was stirred for 30 min and the solvent [sic] was concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 10:1) to give compound 6 (50 mg, 32% yield). 'HNMR (300 MHz, CDCb): δ 7.88 (m, 1H), 7.37 (m, 1H), 7.11 (m, 1H), 4.51 (s, 2H), 4.23 (m, 2H), 2.87 (m, 1H ), 2.31 (m, 1H), 1.37 (m, 6H). 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-(YR)-2-methyloxiran-2carboniD-2,5,8,1 l-tetraoxo- bromide 4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(4-(isobutryloxy)-3-(prop-2-yn-lylcarbamoyl)benzyl)morpholin-4-ium (8) To a solution of compound 6 (360 mg, 1.1 mmol) in MeCN (4 mL) was added (S)-4-methylN-((S)-1 -(((S)-4-methyl-1 -(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (720 mg, 1.0 mmol). The reaction mixture was stirred at 45 °C overnight. The solvent was concentrated and the residue was purified by silica gel flash column chromatography (EtOAc / MeOH = 50:1) to give the desired product 7, which was then converted to the corresponding mesylate (150 mg, 15% of yield) by treatment with ion exchange resin; Ή NMR (400 MHz, CDCb): δ 9.61 (m, 1H), 7.90 (m, 1H), 7.64 (m, 2H), 7.34-7.10 (m, 12H), 6.92 (m, 1H), 6.68 (m , 1H), 5.03 (m, 2H), 4.86 (m, 1H), 4.58-4.32 (m, 4H), 4.28-4.10 (m, 5H), 3.96 (m, 4H), 3.47-3.31 (m, 2H) ), 3.18 (m, 1H), 3.06-2.87 (m, 2H), 2.83 (s, 3H), 2.76 (m, 2H), 2.26 (m, 1H), 2.23-2.04 (m, 3H),1.66- 1.58 (m, 2H), 1.42 (m, 4H), 1.38-1.30 (m, 6H),1.27 (m, 4H), 0.90-0.84 (m, 12H). The PEG-carfilzomib conjugate of Example 4 was prepared from compound 8 and PEGskNí, following the PEG A derivative preparation technique. Example 5: 4-(4-acetoxy-3-(Yl-PEG5K-lH-l,2,3-triazole-4iDmethoxyjbenzylj-4-((4S,7S,10S,13S)-10-benzyl-7- methanesulfonate isobutyl-15-methyl-13-((R)-2-methyloxiran-2carbonyl-2,5,8,1 l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)morpholin-4-ium ( 7) 4-Hydroxy-3-(prop-2-ynyloxy)benzaldehyde (Ύ) To a mixture of NaH in DMSO (300 mL) was added 3,4-dihydroxybenzaldehyde (30 g, 217.39 mmol) in DMSO (50 mL) at 20 °C. The mixture was stirred for 30 min and 3-bromoprop-l-yne (25.87 g, 217.39 mmol) was added. The reaction mixture was stirred at room temperature for one hour. The mixture was poured into ice-water (800 mL) and the obtained solution was brought to pH = 2. The mixture was extracted with EtOAc (500 mL><3), dried over anhydrous MgSÜ4, and concentrated. The residue was crystallized several times from DCM / petroleum ether (30 mL / 500 mL) to give compound 1 (30 g, 78% yield); 'H NMR (CDCE, 300 MHz,): δ 9.87 (s, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.49 (dd, 7, = 1.5 Hz, 72 = 8.1 Hz, 1H), 7.09 (d, J= 8.1 Hz, 1H), 4.82 (m, 2H), 2.62 (m, 1H). 4-formyl-2-(prop-2-ynyloxy)phenyl acetate (2) To a solution of compound 1 (10.00 g, 56.82 mmol) in DCM (150 mL) was added Et3N (11.48 g, 113.64 mmol) followed by acetyl chloride (5.35 g, 68.18 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was washed with 2N HCI saturated [sic] aq. solution (100 mL) and water (50 mL), dried over anhydrous MgSCL, and concentrated to give compound 2 (12 g, 97% yield) , which was used in the next step without further purification; Ή NMR (CDCE. 400 MHz): δ 9.96 (s, 1H), 7.63 (d, 7= 1.6 Hz, 1H), 7.54 (dd, 7, = 1.6Hz, 72 = 8.0 Hz, 1H), 7.25 (d , 7 = 8.0 Hz, 1H), 4.79 (d, 7= 2.4 Hz, 2H), 2.57 (t, 7= 2.4 Hz, 1H), 2.35 (s, 3H). 4-(Hydroxymethyl)-2-(prop-2-ynyloxy)phenyl(3) acetate To a solution of compound 2 (12.00 g, 55.05 mmol) in DCM / MeOH (150 mL / 15 mL) was added NaBHi (3.06 g, 82.57 mmol) in small portions at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with acetone (5 mL), and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 2:1) to give compound 3 (10.32 g, 85% yield); Ή NMR (CDCE, 400 MHz): δ 7.16 (d, 7= 1.6 Hz, 1H), 7.04 (d, 7= 8.0 Hz, 1H), 6.98 (dd, 7, = 1.6 Hz, 72 = 8.0 Hz, 1H ), 4.72 (d, 7= 2.4 Hz, 2H), 4.69 (s, 2H), 2.53 (t, 7= 2.4 Hz, 1H), 2.32 (s, 3H). 4-(bromometiB-2-fprop-2-ynyloxy')phenyl acetate (4) To a solution of compound 3 (11.50 g, 52.27 mmol) in DCM (150 mL) was added PPh3 (20.50 g, 78.41 mmol) and NBS (11.04 g, 62.73 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hour. An excess of solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 20:1). to give compound 4 (7.82 g, 53% yield); Ή NMR (CDCh. 400 MHz): δ 7.14 (m, 1H), 7.02 (m, 2H), 4.73 (d, J= 2.4 Hz, 2H), 4.48 (s, 2H), 2.55 (t, J= 2.4 Hz, 1H), 2.32 (s, 3H). 4-(4-Acetoxy-3-(prop-2-yn-l-yloxy)benzyl)-4-('(4S,7S,10S,13S)-10-benzyl-7¡sobutyl-15-methyl methanesulfonate -13-(YR)-2-methyloxiran-2-carbonyl)-2,5,8,l-tetraoxo-4-phenethyl-3,6,9,12tetraazahexadecyl)morpholin-4-ium (6) To a solution of compound 4 (5.85 g, 20.67 mmol) in MeCN (50 mL) was added (S)-4methyl-N-((S)-1 -(((S)-4-methyl-1 -(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (4.96 g, 6.89 mmol). The reaction mixture was stirred at 45 °C for 2 days. An excess of solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (EtOAc / MeOH = 100:6) to give the desired compound 5, which was converted to the corresponding mesylate (3.2 g , 50% yield) by treatment with ion exchange resin; Ή NMR (CDCh, 400 MHz): δ 9.66 (m, 1H), 7.83 (m, 1H), 7.36 (m, 1H), 7.26-7.14 (m, 13H), 6.72 (m, 1H), 5.18 (m , 1H), 4.90 (m, 2H), 4.77 (m, 2H), 4.53-4.36 (m, 4H), 4.26 (m, 3H), 4.08 (m, 1H), 3.92 (m, 2H), 3.74 ( m, 1H), 3.46 (m, 1H), 3.35 (m, 1H), 3.13 (m, 1H), 3.04 (m, 2H), 2.81 (s, 3H), 2.75 (m, 2H), 2.62 (m , 1H), 2.33 (m, 3H), 2.20 (m, 1H), 2.12 (m, 1H), 1.70-1.53 ​​(m, 3H), 1.50-1.33 (m, 5H), 1.25 (m, 2H), 0.90-0.81 (m, 12H). The PEG-carfilzomib conjugate of Example 5 was prepared from compound 6 and PEG5KN3, following the PEG A derivative preparation technique. Example 6: 4-((4SJS,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8,11-methanesulfonate tetraoxo-4-phenethyl-3,6,9.12-tetraazahexadecyl)-4-(3-(( 1 -PEGsk- 1Hl,2,3-triazol-4-yl)methoxy)-4-Ípropionyloxy)benzyl)morpholin-4 -io (6) 4-Formyl-2-(prop-2-yn-l-yloxy)phenyl propionate (1) To a solution of 4-hydroxy-3-(prop-2-ynyloxy)benzaldehyde (2.64 g, 15 mmol) in DCM (30 mL) was added TEA (3 g, 30 mmol) and propionyl chloride (1.67 g, 18 mmol) at 0 °C. The reaction mixture was stirred at room temperature for one hour. Said mixture was diluted with water (50 mL) and the DCM layer was collected, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 10:1) to give compound 1 (2.4 g, 85% yield); Ή NMR (300 MHz, CDCb): δ 9.97 (s, IH), 7.64 (d, J= 1.5 Hz, IH), 7.55 (d, J\ = 1.5 Hz, J2 = 7.8 Hz, IH), 7.26 (d , J= 8.1 Hz, IH), 4.79 (d,J=2.1 Hz, IH), 2.68 (q,J = 7.5 Hz, 2H), 2.58 (t, J= 2.4 Hz, IH), 1.31 (t,J =7.5Hz, HI). 4-(Hydroxymethyl)-2-(prop-2-ynyloxy)phenyl propionate (2) To a solution of compound 1 (2.32 g, 0.01 mol) in THF (30 mL) was added NaBH4 (570 mg, 0.015 mol) at 0 °C in small portions. The reaction mixture was stirred at room temperature for 2 hours and then diluted with saturated NH4C1 solution (15 mL). The organic phase was collected and the aqueous phase was extracted with DCM (20 mL><3). The organic phases were combined, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 2:1) to give compound 2 (1.7 g, 73% yield); Ή NMR (400 MHz, CDCI3): δ 7.12-6.95 (m, 3H), 4.68 (m, 2H), 4.62 (m, 2H), 2.63 (m, 2H), 2.53 (m, IH), 1.27 (m , 3H). 4-(bromomethyl)-2-(prop-2-ynyloxy)phenyl propionate (3) To a solution of compound 2 (1.7 g, 7.26 mmol) in DCM (30 mL) was added PPh3 (2.28 g, 8.7 mmol) and DIPEA (1.12 g, 8.7 mmol) sequentially. The mixture was cooled to 0 °C and NBS (1.4 g, 7.78 mmol) was added in small portions. The reaction mixture was stirred at the same temperature for 20 min. Excess solvent [sic] was concentrated and the residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 10:1) to give compound 3 (400 mg, 19% yield). 4-((4S,7S,1OS,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran2-carbonyl)-2,5,8,l methanesulfonate -tetraoxo-4-phenethyl-3,6,9.12-tetraazahexadecyl)-4-(3-(prop-2-yn-l-yloxy)-4(propionyloxy)benzyl)morpholin-4-ium (5) To a solution of compound 3 (400 mg, 1.34 mmol) in MeCN (5 mL) was added the compound (S)-4-methyl-N-((S)-1 -(((S)-4-methyl- 1 -((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)l-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2 -morpholinoacetamido)-4-phenylbutanamido)pentanamide (484.8 mg, 0.67 mmol). The reaction mixture was heated at 45 °C overnight. Excess solvent [sic] was concentrated and the residue was purified by silica gel column flash chromatography to give the desired compound 4 (380 mg, 48% yield), which was converted to the corresponding mesylate (370 mg , quantitative) by treatment with ion exchange resin; Ή NMR (400 MHz, CDCb): δ 9.63 (m, 1H), 7.82 (m, 1H), 7.35-7.09 (m, 13H), 6.91 (m, 1H), 6.52 (m, 1H), 5.13 (m , 1H), 5.02-4.82 (m, 5H), 4.72 (m, 2H), 4.50-3.83 (m, 11H), 3.52-3.31 (m, 2H), 3.18-2.58 (m, 11H), 1.68-1.18 (m, 9H), 0.88 (m, 12H). The PEG-carfilzomib conjugate of Example 6 was prepared from compound 5 and PEG5KN3, following the PEG A derivative preparation technique. Example 7: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-inetyloxiran-2-carboniD-2,5,8'l methanesulfonate l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(4-(isobutyryloxy~)3-((1 -PEG5K-1 Η-1,2,3-triazol-4-yl )methoxy)benzyl)morpholin-4-io(6) 4-((4S,7S,1OS,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran2-carbonyl)-2,5,8,l methanesulfonate -tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(4-(isobutyryloxy)-3-(prop-2-ynl-yloxy)benzyl)morpholin-4-ium (5) To a solution of compound 3 (0.5 g, 1.6 mmol) in MeCN (9 mL) was added (S)-4-methyl-N((S)-l-(((S)-4-methyl-l-( (R)-2-methyloxiran-2-yl)-l-oxopentan-2-yl)amino)-l-oxo-3-phenylpropan-2-yl)2-((S)-2-(2-morpholinoacetamido) -4-phenylbutanamido)pentanamide (864 mg, 1.2 mmol). The reaction mixture was stirred at 45 °C for 20 hours. The solvent was concentrated and the residue was purified by flash chromatography on a silica gel column (EtOAc / MeOH = 100:6) to give the desired compound 4, which was then converted to the corresponding mesylate (500 mg, 44% of yield) by treatment with ion exchange resin; 'H NMR (400 MHz, CDCb): δ 9.67 (m, 1H), 7.82 (m, 1H), 7.27 (m, 16H), 6.85 (m, 1H), 6.47 (m, 1H), 5.13 (m, 1H), 5.02 (m, 1H), 4.85 (m, 1H), 4.70 (m, 2H), 4.45 (m, 2H), 4.37 (m, 2H), 4.23 (m, 4H), 3.92 (m, 2H) ), 3.84 (m, 1H), 3.46 (m, 1H), 3.35 (m, 1H), 3.15 (m, 1H), 3.03 (m, 1H), 2.92 (m, 1H), 2.80 (s, 3H) , 2.73 (m, 2H), 2.58 (m, 1H), 2.20 (m, 1H), 2.12 (m, 1H), 1.70 (m, 1H), 1.62 (m, 3H), 1.43 (m, 4H), 1.28 (m, 6H), 1.21 (m, 3H), 0.85 (m, 12H). Example 7 was prepared using methods analogous to those described in Examples 3 and 5, where intermediates were prepared in a similar manner, and compound 5 and PEG5KN3 were reacted, following the PEG A derivative preparation technique. Example 8: 4-((4S,7S,1OS,13Sb 10-benzyl-7-isobutyl-15-methyl 1-13-((R)-2methyloxiran-2-carbonylj-2,5,8,l methanesulfonate 1 -tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl')-4-(4-(butyrylox¡)-3((I-PEG5K-1 Η-1,2,3-triazole-4- yl)methoxy)benzyl)morpholin-4-io(6) 4-((4S,7S,1OS,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R')-2-methyloxiran2-carbonyl)-2,5,8,l methanesulfonate l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(4-(butyryloxy)-3-(prop-2-yn-lyloxy)benzyl)morpholin-4-ium (5) To a solution of compound 3 (0.7 g, 2.25 mmol) in MeCN (8 mL) was added (S)-4-methylN-((S)-l-(((S)-4-methyl-l-(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (0.8 g, 1.125 mmol). The reaction mixture was stirred at 45 °C overnight. An excess of solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (EtOAc / MeOH = 100 / 3) to give the desired compound 4 (500 mg, 23.3% yield), which was converted to the corresponding mesylate (460 mg, 92% yield) by treatment with ion exchange resin; Ή NMR (400 MHz, CDCh): δ 9.73 (m, IH), 7.76 (m, IH), 7.33-7.10 (m, 13H), 6.91 (m, IH), 6.52 (m, IH), 5.18 (m , HI), 5.08-4.85 (m, 2H), 4.72 (m, 2H), 4.50-3.78 (m, 1 HI), 3.52-3.31 (m, 2H), 3.18-2.58 (m, 1 HI), 2.18 (m, 2H), 1.68-1.24 (m, 12H), 0.84 (m, 12H). Example 8 was prepared using methods analogous to those described in Example 3, where intermediates were prepared in a similar fashion (using propanoyl chloride to generate intermediate 1 shown in Example 3), using compound 5 and PEG5KN3 were reacted, following the technique for the preparation of PEG A derivatives. Example 9: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8 methanesulfonate, l l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(4-(hexanoyloxy)3-((]-PEG5K-lH-],2,3-triazol-4-yl) methoxy)benzyl)morpholin-4-io(6) PEG-N3 Cu(ll) salt Ascorbic ai^[ PEG N-N ph 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran2-carbonyl)-2.5,8,ll-tetraoxo-4 methanesulfonate -phenethyl-3,6,9,12-tetraazahexadecyl')-4-(4-(hexanoyloxy)-3-(prop-2-inl-yloxy)benzyl)morpholin-4-ium (5) To a solution of compound 3 (1.41 g, 4.16 mmol) in MeCN (25 mL) was added (S)-4-methyl-N-((S)-l-(((S)-4-methyl-l-(( R)-2-methyloxiran-2-yl)-l-oxopentan-2-yl)amino)-l -oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (1.0 g, 1.39 mmol). The reaction mixture was heated at 40-45 °C overnight. An excess of solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (EtOAc / MeOH = 20:1) to give the desired compound 4, which was converted to the mesylate salt (570 mg, 41% yield) by treatment with ion exchange resin; Ή NMR (400 MHz, CDCh): δ 9.72 (m, IH), 7.82 (m, IH), 7.34-7.15 (m, 12H), 7.10 (m, IH), 6.82 (m, IH), 6.43 (m , IH), 5.15 (m, IH), 4.98 (m, IH), 4.76 (m, 2H), 4.46 (m, 2H), 4.38 (m, 2H), 4.25 (m, 3H), 4.12 (m, IH), 4.01 (m, 2H), 3.85 (m, 2H), 3.47 (m, IH), 3.36 (m, IH), 3.15 (m, IH), 3.01 (m, 2H), 2.80 (s, 3H), 2.72 (m, 2H), 2.60 (m, 2H), 2.51 (m, IH), 2.35-2.14 (m, 4H), 1.76 (m, 2H), 1.55 (m, 2H), 1.48 (m, 4H), 1.37 (m, 6H), 1.23 (m, 3H), 0.86 (m, 12H). Example 9 was prepared using methods analogous to those described in Example 3, where intermediates were prepared in a similar fashion (using pentanoyl chloride to generate intermediate 1 shown in Example 3), using compound 5 and PEG5kN3 were reacted, following the technique for the preparation of PEG A derivatives. Example 10: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8 methanesulfonate, 11 -tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(3-(( 1 -PEGsk- 1Hl,2,3-triazol-4-yl)methoxy)-4-(octanoyloxy) benzyl)morpholin-4-io (6) Example 10 was prepared using methods analogous to those described in Example 3, where the intermediates were prepared in a similar fashion (using heptanoyl chloride and trimethylamine to generate the aldehyde intermediate 1 shown in Example 3), using compound 5 and PEG5KN3 were reacted, following the technique of preparation of PEG A derivatives. 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran2-carbonyl)-2,5,8,l l- methanesulfonate tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(4-(octanoyloxy)-3-(prop-2-ynl-yloxy)benzyl)morpholin-4-ium (5) To a solution of compound 3 (1.53 g, 4.17 mmol) in MeCN (25 mL) was added (S)-4-methyl-N-((S)-l-(((S)-4-methyl-l-(( R)-2-methyloxiran-2-yl)-l-oxopentan-2-yl)amino)-l -oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (1.00 g, 1.39 mmol). The reaction mixture was stirred at 40-45 °C overnight. The solvent was concentrated and the residue was purified by silica gel flash column chromatography (EtOAc / MeOH = 100:5) to give the desired compound 4, which was then converted to the corresponding mesylate (620 mg, 44% of yield) by treatment with ion exchange resin; 'H NMR (400 MHz, CDCb): δ 9.69 (m, 1H), 7.82 (m, 1H), 7.34-7.15 (m, 12H), 7.10 (m, 1H), 6.88 (m, 1H), 6.51 ( m, 1H), 5.15 (m, 1H), 4.98 (m, 1H), 4.88 (m, 1H), 4.74 (m, 2H), 4.46 (m, 2H), 4.38 (m, 2H), 4.25 (m , 4H), 4.02 (m, 2H), 3.85 (m, 1H), 3.47 (m, 1H), 3.36 (m, 1H), 3.15 (m, 1H), 3.01 (m, 2H), 2.83 (s, 3H), 2.72 (m, 2H), 2.60 (m, 3H), 2.35-2.14 (m, 3H), 1.76 (m, 2H), 1.55 (m, 2H), 1.48-1.23 (15H), 0.92-0.78 (12 PM). Example 11: 4-('4-acetoxy-3-methyl-5-('('1-PEG5K-1H-1,2,3-triazol-4yl)methoxy)benzyl)-4-((4S, 7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran-2carbonyl)-2,5,8,11-tetraoxo-4-phenethyl-3,6 ,9,12-tetraazahexadecyl)morpholin-4-io(8) 3,4-Dihydroxy-5-methylbenzaldehyde (1) To a solution of the compound 4-hydroxy-3-methoxy¡-5-methyl-benzaldehyde (2.00 g, 12.04 mmol) in DCM (100 mL) was added BBn (3.02 g, 12.04 mmol) at -78 °C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with saturated NH4Cl solution (100 mL) at -20 °C. The two phases were separated and the aqueous solution was extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous MgSO4 and concentrated. The residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 10:1) to give compound 1 (1.56 g, 85% yield); 'H NMR (300 MHz, DMSO-76): δ 9.94 (s, 1H), 9.69 (s, 1H), 9.47 (s, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 2.02 ( s, 3H). 4-Hydroxy-3-methyl-5-(prop-2-ynyloxy)benzaldehyde (2) b To a mixture of NaH (489.12 mg, 20.38 mmol) in DMSO (30 mL) was added compound 1 (1.55 g, 10.19 mmol) in DMSO (10 mL) at 0 °C. The mixture was stirred for 30 min and then 3-bromoprop-l-yne (1.21 g, 10.19 mmol) was added at the same temperature. The reaction mixture was stirred for 30 min and diluted with water (100 mL). The obtained solution was brought to pH = 4-5 and extracted with EtOAc (400 mL><3). The combined EtOAc layers were washed with brine (50 mL), dried over anhydrous MgSO4, and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 10:1) to give compound 2 (1.7 g, 88% yield); 'H NMR (300 MHz, DMSO-76): δ 9.84 (s, 1H), 9.77 (s, 1H), 7.42 (m, 2H), 4.94 (d, J= 2.1Hz, 2H), 3.65 (m, 1H), 2.22 (s, 3H). 4-formyl-2-methyl-6-(prop-2-ynyloxy)phenyl acetate (3) To a solution of compound 2 (1.60 g, 8.41 mmol) in DCM was added pyridine (2.00 g, 25.23 mmol) followed by acetyl chloride (1.32 g, 16.82 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, then water (100 mL) was added. The two phases were separated and the organic phase was washed with dil. HCI (1 N, 50 mL), dried over anhydrous MgSCL, and concentrated to give compound 3 (2.0 g, quantitative), which was used in the next pass without further purification; 'H NMR (300 MHz, DMSO-76): <5 9.95 (s, 1H), 7.56 (m, 2H), 4.96 (m, 2H), 3.67 (m, 1H), 2.36 (m, 3H), 2.23 (s, 3H). 4-(Hydroxymethyl)-2-methyl-6-(prop-2-ynyloxy)phenyl(4) acetate To a solution of compound 3 (2.00 g, 8.61 mmol) in THF (50 mL) was added NaBH4 (325.80 mg, 8.61 mmol) in small portions at 0 °C. The reaction mixture was stirred at the same temperature for 1 hour and then diluted with water (1 mL). The mixture was diluted with DCM (100 mL), dried directly over anhydrous MgSCL, and concentrated. The residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 5:1) to give compound 4 (1.5 g, 74% yield); 'H NMR (300 MHz, DMSO-76): δ 7.00 (s, 1H), 6.86 (s, 1H), 5.26 (m, 1H),4.78 (d,7=2.4 Hz, 2H), 4.47 (m, 2H), 3.61 (m, 1H), 2.31 (s, 3H), 2.11 (s, 3H). 4-(Bromomethyl)-2-methyl-6-(prop-2-ynyloxy)phenyl acetate (5) To a solution of compound 4 (1.50 g, 6.46 mmol) in DCM (50 mL) was added PBr3 (1.75 g, 6.46 mmol) at 0 °C. The reaction mixture was stirred for 30 min and then diluted with water (50 mL). The two phases were separated and the organic phase was dried over anhydrous MgSO4 and concentrated. The residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 30:1) to give compound 5 (750 mg, 39% yield); Ή NMR (300 MHz, CDC13): <5 7.00 (s, 1H), 6.94 (s, 1H), 4.73 (d, J= 2.4 Hz, 2H), 4.47 (s, 2H), 2.57 (m, 1H) , 2.37 (s, 3H), 2.19 (s, 3H). 4-(4-acetoxy-3-methyl-5-(prop-2-yn-l-yloxy)benzyl)-4-((4S,7S,10S,13S)-10benzyl-7-isobutyl-15-methanesulfonate methyl-13-(YR)-2-methyloxiran-2-carbonyl)-2,5,8,11-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl~)morpholin-4-ium (7) To a solution of compound 5 (351.25 mg, 1.19 mmol) in MeCN (5 mL) was added (S)-4methyl-N-((S)-1 -(((S)-4-methyl-1 -(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (428.35 mg, 595.00 umol). The reaction mixture was stirred at 40-45 °C overnight. An excess of solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (EtOAc / MeOH = 100:1) to give the desired compound 6, which was converted to the corresponding mesylate (280 mg , 50% yield) by treatment with ion exchange resin; 'HNMR (300 MHz, CDCb): δ 9.68 (m, 1H), 7.82 (m, 1H), 7.26 (m, 11H), 7.00 (m, 2H), 6.60 (m, 1H), 5.17 (m, 1H ), 5.08 (m, 1H), 4.78 (m, 3H), 4.46 (m, 4H), 4.22 (m, 4H), 4.01 (m, 2H), 3.80 (m, 2H), 3.45 (m, 2H) , 3.18 (m, 1H), 3.05 (m, 2H), 2.80 (s, 3H), 2.73 (m, 2H), 2.60 (m, 1H), 2.43 (m, 3H), 2.20 (m, 3H), 1.58 (m, 2H), 1.46 (m, 6H), 1.32 (m, 3H), 0.88 (m, 12H). Example 11 was prepared from compound 7 and PEG5KN3 were reacted, following the PEG A derivative preparation technique. Example 12: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-(YR)-2-methyloxiran-2-carbonyl)-2,5,8,1 methanesulfonate l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-í3-((Yl -PEGsklH-l^J-triazol-d-immethyljcarbamoin-d-fpivaloyloxyjbenzinmorpholin-d-io (9) 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran2-carbonyl)-2,5,8,ll-tetraoxo methanesulfonate -4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(4-(pivaloyloxy)-3-(prop-2-inl-ylcarbamoyl)benzyl)morpholin-4-ium (8) To a solution of compound 6 (400 mg, 1.1 mmol) in MeCN (10 mL) was added (S)-4-methyl-N-((S)-l-(((S)-4-methyl-l-(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (720 mg, 0.1 mmol). The reaction mixture was stirred at 45 °C overnight. An excess of solvent [sic] was concentrated and the residue was crystallized several times from MeCN / Et20 (v / v, 1 / 5) to give the desired compound 7, which was converted to the corresponding mesylate (120 mg , 11.2% yield) by treatment with ion exchange resin; 'H NMR (400 MHz, CDCb): <5 9.63 (m, 1H), 7.82-7.55 (m, 4H), 7.33-7.08 (m, 11H), 6.85 (m, 1H), 6.62 (m, 1H) , 5.13-4.82 (m, 2H), 4.50-3.93 (m, 14H), 3.42-2.68 (m, 11H), 2.5-1.9 (m, 6H), 1.68-1.18 (m, 19H), 0.88 (m, 12 noon). Example 12 was prepared using methods analogous to those described in Example 4, where the intermediates were prepared in a similar fashion (using t-butanoyl chloride to generate intermediate 1 shown in Example 4), using the Compound 8 and PEG5KN3 were reacted, following the technique for the preparation of PEG A derivatives. Example 13: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R')-2methyloxiran^-carboniD^SAl l-tetraoxo-4- formate phenethyl-3,6,9,12-tetraazahexadecyl')-4-(3-((1-(PEG20K-4Arm)-1H-1,2,3-triazol-4-yl)methoxy)-4-(pivaloyloxy )benzyl)morpholin-4-io (7) 4-Hydroxy-3-(prop-2-ynyloxy')benzaldehyde (1) To a mixture of NaH in DMSO (300 mL) was added 3,4-dihydroxybenzaldehyde (30 g, 217.39 mmol) in DMSO (50 mL) at 20 °C. The mixture was stirred for 30 min and 3-bromoprop-l-yne (25.87 g, 217.39 mmol) was added. The reaction mixture was stirred at room temperature for one hour and then poured into ice-water. The obtained solution was brought to pH = 2 and then extracted with EtOAc (500 mL><3). The combined organic phases were dried over anhydrous MgSO4 and concentrated. The residue was crystallized several times from DCM / petroleum ether (30 mL / 500 mL) to give compound 1 (30 g, 78% yield); Ή NMR (CDCE, 300 MHz,): <5 9.89 (s, 1H), 7.54 (d, J= 1.2 Hz, 1H), 7.49 (dd, 7( = 1.5 Hz,72= 8.1 Hz, 1H), 7.09 (d, J= 8.1 Hz, 1H), 4.82 (m, 2H), 2.62 (m, 1H). 4-Formyl-2-(prop-2-ynyloxy')phenylpivalate (2) To a solution of compound 1 (3.0 g, 17 mmol) in DCM (120 mL) was added ΕίβΝ (3.45 g, 34 mmol) followed by pivaloyl chloride (2.34 g, 20.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was washed with saturated NaHCCb solution (20 mL) and water (20 mL), dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 50:1) to give compound 2 (2.10 g, 47% yield) as a white solid; 'H NMR (CDCE, 300 MHz): <5 9.99 (s, 1H), 7.61 (d,7 = 1.8 Hz, 1H), 7.55 (dd,7i = 1.8 Hz, 72 = 8.1 Hz, 1H), 7.26 ( d, 7=8.1 Hz, 1H), 4.77 (d, 7=2.4 Hz, 2H), 2.58 (t, 7= 2.4 Hz, 1H), 1.42 (s, 9H). 4-(Hydroxymethyl')-2-(prop-2-ynyloxy)phenylpivalate (3) To a solution of compound 2 (1.8 g, 6.9 mmol) in DCM / MeOH (100 mL / 10 mL) was added NaBHi (0.37 g, 10.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with acetone (3 mL) and the solvent was concentrated. The residue is purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 3:1) to give compound 3 (1.50 g, 83% yield); Ή NMR (CDCb, 300 MHz): δ 7.11 (m, 1H), 7.00 (m, 2H), 4.68 (m, 4H), 2.53 (m, 1H), 1.41 (s, 9H). 4ríBromometin-2-(prop-2-ynyloxy)phenylpivalate (4) To a solution of compound 3 (1.50 g, 5.7 mmol) in DCM (60 mL) was added PPlb (1.80 g, 6.8 mmol) and NBS (1.11 g, 6.3 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hour. Excess solvent [sic] was concentrated and the residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 50:1) to give compound 4 (1.34 g, 81% yield); Ή NMR (CDCb, 300 MHz): δ 7.12 (d, 7 = 1.5 Hz, 1H), 7.03 (m, 2H), 4.70 (d, 7= 2.4 Hz, 2H), 4.51 (d, 7= 3.9 Hz, 2H), 2.56 (t, 7= 2.4 Hz, 1H), 1.40 (s, 9H). 4-((4S,7S,1OS,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R')-2-methyloxiran2-carbonyl)-2,5,8, methanesulfonate ll-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(4-(pivaloyloxy)-3-(prop-2-ynl-yloxy)benzyl)morpholin-4-ium (6) To a solution of compound 4 (2.38 g, 7.3 mmol) in MeCN (30 mL) was added (S)-4-methyl-1-((S)-1-(((S)-4-methyl-1-(( R)-2-methyloxiran-2-yl)-l-oxopentan-2-yl)amino)-l-oxo-3-phenylpropan-2yl)-2-((S)-2-(2-morpholinoacetam¡do) -4-phenylbutanamido)pentanamide (2.64 g, 3.7 mmol). The reaction mixture was stirred at 45 °C overnight. An excess of solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (EtOAc / MeOH = 100:6) to give the desired compound 5, which was converted to the corresponding mesylate (1.23 g , 25% yield) by treatment with ion exchange resin; 'H NMR (CDCb, 300 MHz): ¿9.83 (m, 1H), 7.92 (m, 1H), 7.50-7.11 (m, 13H), 7.03 (m, 1H), 6.62 (m, 1H), 5.25 ( m, 1H), 5.15-4.90 (m, 2H), 4.88-4.75 (m, 2H), 4.70-4.20 (m, 7H), 4.20-3.90 (m, 3H), 3.70-3.40 (m, 4H), 3.26 (m, 1H), 3.15 (m, 2H), 2.90 (s, 3H), 2.85 (m, 2H), 2.40-2.10 (m, 2H), 1.87-1.63 (m, 5H), 1.55 (m, 3H), 1.41 (s, 9H), 1.38 (m, 2H), 0.89-1.05 (m, 12H). The compound of Example 13 was prepared from compound 6 and PEG2ok(N3)4, following the PEG A derivative preparation technique. The compound of Example 13 is also designated as OP-59381 in several of the figures illustrated in Figure present memory. Ή NMR (500 MHz, relaxation time = 10 sec, DMSO-dó) δ 8.47 (s, 4H), 8.42 (d, J = 8.5 Hz, 4H), 8.29 (d, 7= 7.5 Hz, 4H), 8.11 (s, 4H), 8.07 (d, J = 8 Hz, 4H), 7.53 (s, 4H), 7.26-7.29 (m, 4H), 7.11-7.19 (m, 32H), 7.05-7.06 (m, 4H ), 5.21 (s, 8H), 4.95 (dd, J = 12.5 Hz and 39.0 Hz, 8H), 4.52-4.54 (m, 12H), 4.284.38 (m, 16H), 4.17-4.20 (m, 4H) , 4.06 (m, 20H), 3.78 (t, 7= 5.5 Hz, 8H), 3.61-3.65 (m, 8H), 3.50 (s, 2133H), 3.35-3.37 (m, 8H), 3.10 (d, J = 5 Hz, 4H), 2.94-2.98 (m, 12H), 2.73-2.78 (m, 4H), 2.5079 2.65 (m, 8H), 1.90-1.98 (m, 4H), 1.78-1.88 (m, 4H), 1.51-1.68 (m, 8H), 1.39 (s, 12H), 1.25-1.38 (m, 16H), 1.18 (s, 36H), 0.833-0.881 (m, 24H), 0.782-0.815 (m, 24H); Charge: 86%. Example 14: 4-(í4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-f(R')-2methyloxiran-2-carboníl)-2,5 methanesulfonate, 8,l l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(4-(isobutyryloxy)3-(( 1 -PEG20K-4-Arm-1 Η-1,2,3 -triazol-4-yl)methoxy)benzyl)morpholin-4-yl (14) 4-((4S,7S,1OS,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran2-carbonyl)-2,5,8,l methanesulfonate -tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(4-(isobutyryloxy')-3-(prop-2-yn1-yloxy)benziDmorpholin-4-ium (5) To a solution of compound 3 (0.5 g, 1.6 mmol) in MeCN (9 mL) was added (S)-4-methyl-N((S)-1 -(((S)-4-methyl-1 -( (R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)2- ((S)-2-(2-morpholinoacetamido) -4-phenylbutanamido)pentanamide (864 mg, 1.2 mmol). The reaction mixture was stirred at 45 °C for 20 hours. The solvent was concentrated and the residue was purified by flash chromatography on a silica gel column (EtOAc / MeOH = 100:6) to give the desired compound 4, which was then converted to the corresponding mesylate (500 mg, 44% of yield) by treatment with ion exchange resin; Ή NMR (400 MHz, CDCb): <5 9.67 (m, 1H), 7.82 (m, 1H), 7.27 (m, 16H), 6.85 (m, 1H), 6.47 (m, 1H), 5.13 (m, 1H), 5.02 (m, 1H), 4.85 (m, 1H), 4.70 (m, 2H), 4.45 (m, 2H), 4.37 (m, 2H), 4.23 (m, 4H), 3.92 (m, 2H) ), 3.84 (m, 1H), 3.46 (m, 1H), 3.35 (m, 1H), 3.15 (m, 1H), 3.03 (m, 1H), 2.92 (m, 1H), 2.80 (s, 3H), 2.73 (m, 2H), 2.58 (m, 1H), 2.20 (m, 1H), 2.12 (m, 1H), 1.70 (m, 1H), 1.62 (m, 3H), 1.43 (m, 4H), 1.28 (m, 6H), 1.21 (m, 3H), 0.85 (m, 12H). Example 14 was prepared using methods analogous to those described in Example 3, 5 and 7 where intermediates were prepared in a similar fashion (using isopropanoyl chloride to generate intermediate 1 shown in Example 3), using compound 5 and PEG20KN3 were reacted, following the technique for the preparation of PEG A derivatives. Example 15: 4-(4-acetoxy-3-(2-(2-(2-((1-PEG5K-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethoxy)benzyl methanesulfonate )-4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8,l l- tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)morpholin-4-io(9) HO''—θ 2-(2-(2-(Prop-2-yn-1-yloxy)ethoxy)ethoxy)ethan-1-ol(1) To a mixture of NaH (3.47 g, 0.086 mol) in THF (320 mL) was added 2,2'-(ethan-1,2-diylbis(oxy))diethanol (20 g, 0.133 mol) at 0 °C. The mixture was stirred at the same temperature for 30 min and then 3-bromoprop-l-yne (7.93 g, 0.066 mol) was added. The reaction mixture was kept at 0 °C for 2 hours and then allowed to reach room temperature overnight. The mixture was diluted with water (4 mL) and the obtained solution was directly dried over anhydrous MgSC>4 and concentrated. The residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 1:1) to give compound 1 (10.12 g, 80% yield); Ή NMR (400 MHz, CDCb): δ 4.21 (d, J= 2.0 Hz, 2H), 3.75-3.68 (m, 10H), 3.62 (m, 2H), 2.44 (m, IH), 2.23 (s, IH ). 2-(2-(2-(Prop-2-yn-l-yloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2) To a solution of compound 1 (5 g, 26.6 mmol) in DCM (80 mL) was added TsCl (7.6 g, 39.89 mmol) at 0 °C followed by pyridine (25 mL). The reaction mixture was stirred at room temperature overnight. The DCM solution was washed with HC1 (3 N, 50 mL><4), dried, and concentrated to give compound 2 (7.89 g, 87% yield), which was used in the next step without further purification; 'H NMR (400 MHz, CDCb): <5 7.80 (d, J= 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.20 (m, 4H), 3.68 (m, 6H), 3.61 (m, 4H), 2.45 (m, 1H), 2.40 (m, 3H). 4-Hydroxy-3-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethoxy)benzaldehyde (3) To a mixture of NaH (0.82 g, 20.47 mmol) in DMSO (50 mL) was added a solution of 3,4-dihydroxybenzaldehyde (1.41 g, 10.23 mmol) in DMSO (5 mL) and a solution of compound 2 (3.5 g , 10.23 mmol) in DMSO (5 mL) at 20 °C sequentially. The reaction mixture was stirred at room temperature overnight. The mixture was poured into ice-water (500 mL) and said aqueous solution brought to pH = 2 by 2 N HC1. The obtained mixture was extracted with EtOAc (50 mL><3) and the combined EtOAc layers were dried over anhydrous MgSÜ4 and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc =1:1) to give compound 3 (579 mg, 18% yield); Ή NMR (400 MHz, CDCb): <5 9.80 (s, 1H), 7.46 (m, 2H), 7.03 (d, J= 7.6 Hz, 1H), 4.25 (m, 4H), 3.88 (m, 2H) , 3.70 (m, 8H), 2.45 (m, 1H). 4-Formyl-2-(2-('2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethoxy)phenyl (4) acetate To a solution of compound 3 (479 mg, 1.56 mmol) in THF (20 mL) was added TEA (471 mg, 4.67 mmol) and AC2O (238 mg, 2.33 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. Excess solvent [sic] was concentrated and the residue was dissolved in EtOAc (40 mL). The obtained solution was washed with water (50 mL), dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 2:1) to give compound 4 (400 mg, 74% yield); Ή NMR (400 MHz, CDCb): <5 9.94 (s, 1H), 7.52 (d, 7 = 1.6 Hz, 1H), 7.49 (dd, 7, = 1.6 Hz, 7- = 8.0 Hz, 1H), 7.22 (d, 7 = 8.0 Hz, 1H), 4.23 (m, 2H), 4.20 (m, 2H), 3.86 (m, 2H), 3.72 (m, 8H), 2.43 (m, 1H), 2.34 (s, 3H). 4-fHydroxymethyl)-2-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethoxy)phenyl acetate (5) To a solution of compound 4 (1.18 g, 3.38 mmol) in THF (50 mL) was added BH3 / THF solution (3.4 mL, 3.38 mmol) dropwise at 0 °C. The reaction mixture was stirred for 30 min and then diluted with MeOH (5 mL). The reaction solution was concentrated, and the residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc=1:1) to give compound 5 (700 mg, 59% yield); Ή NMR (300 MHz, CDCb): <5 7.09 (d, J = 1.8 Hz, 1H), 7.03 (d, 7 = 8.1 Hz, 1H), 6.94 (dd, 7, = 1.8 Hz, 72 = 8.1 Hz, 1H), 4.68 (s, 2H), 4.22 (m, 4H), 3.85 (m, 2H), 3.74 (m, 8H), 2.46 (m, 1H), 2.33 (s, 3H). 4-(Bromomethyl)-2-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethoxy)phenyl acetate (6) To a solution of compound 5 (680 mg, 1.93 mmol) in DCM (40 mL) was added PPh3 (607 mg, 2.32 mmol) followed by NBS (374 mg, 2.13 mmol) in small portions at 0 °C. Excess solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 3:1) to give compound 6 (430 mg, 54% yield); 'HNMR (400 MHz, CDCb): δ 7.03 (s, 1H), 6.99 (m, 2H), 4.46 (s, 2H), 4.20-4.16 (m, 4H), 3.83 (m, 2H), 3.68 (m , 8H), 2.43 (m, 1H), 2.29 (s, 3H). Compound 6 was converted to compound 8 using methods analogous to those described herein. 4-(4-acetoxy-3-(2-(2-(2-(prop-2-yn-l -iIoxy)ethoxy)ethoxy)ethoxy)benzyl)-4((4S,7S, 1OS, 13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran-2-carbonyl)-2,5,8,11 tetraoxo-4-phenethyl-3,6,9, 12-tetraazahexadecyl~)morpholin-4-io (8) To a solution of compound 6 (430 mg, 1.04 mmol) in MeCN (5 mL) was added compound (S)-4-methyl-N-((S)-l-(((S)-4-methyl-l -((R)-2-methyloxiran-2-yl)-l-oxopentan-2-yl)amino)-l -oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido )-4-phenylbutanamido)pentanamide (743 mg, 1.04 mmol). The reaction mixture was stirred at room temperature overnight. An excess of solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (EtOAc / MeOH = 10:1) to give the desired product 7 (160 mg, 14% yield), which then converted to the corresponding mesylate salt (135 mg, 85% yield) by treatment with ion exchange resin; Ή NMR (400 MHz, CDCb): δ 9.68 (m, 1H), 7.73 (m, 1H), 7.29-7.05 (m, 13H), 6.82 (m, 1H), 6.40 (m, 1H), 5.15 (m , 1H), 5.08 (m, 1H), 5.02 (m, 1H), 4.82 (m, 2H), 4.51 (m, 2H), 4.38 (m, 3H), 4.20 (m, 4H), 4.15 (m, 2H), 4.03 (m, 2H), 3.84 (m, 1H), 3.76 (m, 2H), 3.65 (m, 9H), 3.50 (m, 1H), 3.38 (m, 1H), 3.18 (m, 1H), 3.02 (m, 2H), 2.86 (m, 1H), 2.80 (s, 3H), 2.64 (m, 2H), 2.46 (m, 1H), 2.32 (m, 3H), 2.30-2.05 (m , 3H), 1.60 (m, 2H), 1.52 (m, 6H), 1.24 (m, 2H), 0.84 (12H). Example 15 was prepared from compound 8 and PEGskN3, following the technique for the preparation of PEG A derivatives. Example 16: 4-(4-acetoxy-3-(1-(PEG5K-imino)ethyljbenzyl')-4(Y4S,7S,IOS,13S)-10-benzyl-7-isobutyl-15-methyl-methanesulfonate 1 B-ffRO^-methyloxiran^-carbonin^-S-S, 11 tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadeciDmorpholin-4-io (5) Anion Exchange \zO Resin A, ph MsO 2-acetyl-4-methylphenyl acetate (1) To a solution of l-(2-hydroxy-5-methylphenyl)ethanone (1.5 g, 0.01 mol) in DCM (15 mL) was added TEA (1.5 g, 0.015 mol) and acetyl chloride (0.94 g, 0.012 mol). at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL). The DCM layer was collected, washed with brine (20 mL), dried over anhydrous MgSCb, and concentrated. The residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 3:1) to give compound 1 (0.9 g, 47% yield); Ή NMR (300 MHz, CDCb): δ 7.64 (m, 1H), 7.37 (m, 1H), 7.02 (d, 7= 8.1 Hz, 1H), 2.57 (s, 3H), 2.42 (s, 3H), 2.37 (s, 3H). 2-acetyl-4-(bromomethyl)phenyl acetate (2) To a solution of compound 1 (0.5 g, 2.6 mmol) in CCU (20 mL) was added NBS (573 mg, 3.25 mmol) and AIBN (42.6 mg, 0.26 mmol). The reaction mixture was heated under reflux overnight. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 10:1) to give compound 2 (160 mg, 23% yield); Ή NMR (300 MHz, DMSO84 d6): δ 8.02 (m, 1H), 7.73 (d, J= 8.1 Hz, 1H), 7.25 (d, J= 8.4 Hz, 1H), 4.81 (s, 2H), 2.53 (s, 3H), 2.32 (s, 3H). 4-(4-Acetoxy-3-acetylbenzyl)-4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15methyl-13-((R)-2-methyloxiran-2- methanesulfonate carbonyl)-2,5,8,l l-tetraoxo-4-phenethyl-3,6,9,12tetraazahexadecyl)morpholin-4-ium (4) To a solution of compound 2 (1.03 g, 3.7 mmol) in MeCN (10 mL) was added compound (S)-4-methyl-N-((S)-1 -(((S)-4-methyl-1 -((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido )-4-phenylbutanamido)pentanamide (884.7 mg, 1.23 mmol). The reaction mixture was heated at 45 °C overnight. An excess of solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (EtOAc / MeOH = 100:3) to give the desired compound 3, which was converted to the corresponding mesylate (260 mg , 21% yield) by treatment with ion exchange resin; 'H NMR (300 MHz, CDCb): δ 9.62 (m, 1H), 8.06 (m, 1H), 7.88-7.71 (m, 2H), 7.33-7.11 (m, 11H), 6.95 (m, 1H), 6.66 (m, 1H), 5.33-4.91 (m, 2H), 4.55-3.90 (m, 11H), 3.58-2.91 (m, 4H), 2.85 (s, 3H), 2.74 (m, 2H), 2.61 ( s, 3H), 2.40 (s, 3H), 2.31-1.94 (m, 7H), 1.72-1.18 (m, 8H), 0.88 (m, 12H). Example 16 was prepared from compound 4 and PEG5KONH3LMSO', following the technique for the preparation of PEG B derivatives. Example 17: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8 methanesulfonate, 1 l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl~)-4-(3-( 1 -(PEGskimino')ethyl)-4-(pivaloyloxy')benzyl)morpholin-4-io ( 51 4-(3-Acetyl-4-(pivaloyloxy)benzyl)-4-((4S,7S,1OS,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2- methanesulfonate methyloxiran-2-carbonyl)-2,5,8,11-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)morpholin-4-ium (4) To a solution of compound 2 (1.03 g, 3.2 mmol) in MeCN (10 mL) was added (S)-4-methylN-((S)-l-(((S)-4-methyl-l-(( R)-2-methyloxiran-2-yl)-l-oxopentan-2-yl)amino)-l-oxo-3-phenylpropan-285 yl)-2-((S)-2-(2-morpholinoacetamido)- 4-phenylbutanamido)pentanamide (766 mg, 1.06 mmol). The reaction mixture was stirred at 45 °C overnight. Excess solvent [sic] was concentrated and the residue was crystallized several times from EtOAc / Et2O (5 / 1, v / v) to give the desired compound 3, which was converted to the corresponding mesylate (300 mg , 32% yield) by treatment with ion exchange resin; 'H NMR (300 MHz, CDCE): δ 9.68 (m, 1H), 8.06 (m, 1H), 7.75 (m, 1H), 7.40-7.15 (m, 12H), 6.92 (m, 1H), 6.65 ( m, 1H), 5.28-4.96 (m, 2H), 4.55-4.42 (m, 4H), 4.38-4.18 (m, 4H), 4.07-3.90 (m, 3H), 3.60-3.30 (m, 2H), 3.17 (m, 2H), 3.04 (m, 2H), 2.85 (s, 3H), 2.80 (m, 2H), 2.63 (s, 3H), 2.44 (s, 3H), 2.28-2.12 (m, 2H), 2.04 (m, 3H), 1.76 (m, 3H), 1.50-1.40 (m, 6H), 1.30-1.18 (m, 4H), 0.92-0.84 (m, 12H). Example 17 was prepared using methods analogous to those described in Example 16, where intermediates were prepared in a similar fashion (using t-butanoyl chloride to generate intermediate 1 shown in Example 16), using compound 4 and PEG5kONH3+.MsO', following the technique for the preparation of PEG B derivatives. Example 18: 4-(3-acetoxy-4-('(PEG5K-imino)methylDbenzyl)-4((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13- methanesulfonate í(R)-2-methyloxiran-2-carbonyl)-2,5,8,l 1tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)morpholin-4-io (8) HO. AcOH O^H V O 5E> X = l Anion Exchange Resin, O^H ΟγΗ / uk h or k or H, V<BaY íu h q h¡ MSO^ 6 \H 6 PEG. '9 KKH PEG-ONH3+.MsO--—► ph 2-Hydroxy-5-(hydroxymethyl)benzaldehyde (1) To an aqueous formaldehyde solution (37%, 17 mL) was added 2-hydroxybenzaldehyde (10.3 g, 84.4 mmol) and concentrated HCI (42 mL). The reaction mixture was heated under reflux overnight. The mixture was cooled to room temperature and then extracted with EtOAc (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 3:1) to give compound 1 (1.97 g, 15% yield); 'H NMR (DMSO-úfe, 300 MHz): δ 10.61 (s, 1H), 10.26 (s, 1H), 7.60 (d, J= 2.1 Hz, 1H), 7.46 (dd, 7= 2.4, 8.7 Hz, 1H), 6.96 (d, 7=8.4 Hz, 1H), 5.18 (m, 1H), 4.42 (d, 7=3.3 Hz, 2H). 5-(((Zer-Butyldimethylsilyl)oxy)methyl)-2-hydroxybenzaldehyde (2) To a solution of compound 1 (2.01 g, 13.2 mmol) in DCM (60 mL) was added imidazole (1.43 g, 21 mmol). The solution was cooled to 0 °C and Zer-butylchloro dimethylsilane (2.57 g, 17.1mmol). The reaction mixture was stirred at room temperature for 3 h and then poured into water (50 mL). The two phases were separated and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 50:1) to give compound 2 (3.2 g, 91% yield); ’H NMR (CDCb, 400 MHz): δ 10.85 (br, s, 1H), 9.78 (s, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.35 (dd, J= 2.0, 8.4 Hz, 1H), 6.85 (d,7 = 8.4 Hz, 1H), 4.59 (s, 2H), 0.82 (s, 9H), 0.00 (s, 6H). 4-(( / er-Butyldimethylsilyloxy)methyl)-2-formylphenyl(3) acetate To a solution of compound 2 (25 g, 94 mmol) in DCM (500 mL) was added TEA (19.0 g, 188 mmol). The mixture was cooled to 0 °C and acetyl chloride (11.1 g, 141 mmol) was added. The reaction mixture was stirred at room temperature for 2h. The mixture was washed with water (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 100:1) to give compound 3 (19.7 g, 68% yield); Ή NMR (CDCb, 400 MHz): δ 9.98 (s, 1H), 7.70 (d, J= 2.0 Hz, 1H), 7.49 (dd, J= 2.4, 8.4 Hz, 1H), 7.03 (d, J= 2.4 Hz, 1H), 4.66 (s, 2H), 2.28 (s, 3H), 0.83 (s, 9H), 0.00 (s, 6H). 2-formyl-4-(hydroxymethyl)phenyl acetate (4) Compound 3 (3.6 g, 11.7 mmol) was dissolved in AcOH / THF / H2O (50 mL / 25 mL / 25 mL). The reaction mixture was stirred at 30 °C for 3 h. An excess [sic] of THF was removed and the obtained solution was brought to pH = 7-8 and then extracted with EtOAc (50 mLx3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 3:1) to give compound 4 (2.04 g, 90% yield); 'H NMR (DMSO-cfe, 400 MHz): δ 10.08 (s, 1H), 7.85 (d, J= 2.0 Hz, 1H), 7.67 (dd, 7= 2.4, 8.4 Hz, 1H), 7.26 (d, 7= 8.4 Hz, 1H), 4.57 (s, 2H), 2.35 (s, 3H). 4-(Bromomethyl)-2-formylphenyl acetate (5a) To a solution of compound 4 (2.03 g, 10.3 mmol) in DCM (80 mL) was added PBn (2.79 g, 10.3 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4h. The reaction was diluted by adding water (20 mL) and the obtained mixture was brought to pH = 7 with saturated NaHCCb aqueous solution. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 3:1) to give compound 5a (300 mg, 11% yield); 'H NMR (CDCb, 300 MHz): δ 10.12 (s, 1H), 7.92 (d, 7= 2.1 Hz, 1H), 7.68 (dd, 7= 2.4, 8.4 Hz, 1H), 7.22 (d, 7= 8.1 Hz, 1H), 4.54 (s, 2H), 2.42 (s, 3H). 4-(Iodomethyl)-2-formylphenyl acetate (5b) To a solution of compound 4 (5.0 g, 27.55 mmol) in DCM (300 mL) was added SOCk (6.13 g, 51.55 mmol) at 0 °C. The reaction mixture was heated under reflux overnight. The mixture was concentrated and the residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 10:1) to give the corresponding benzyl chloride (2.4 g, 44% yield); Ή NMR (CDCb, 300 MHz): δ 10.12 (s, 1H), 7.92 (d, J= 2.4 Hz, 1H), 7.68 (dd, J = 2.4, 8.4 Hz, 1H), 7.22 (d, J= 2.4 Hz, 1H), 4.64 (s, 2H), 2.42 (s, 3H). To a solution of benzyl chloride (2.4 g, 11.29 mmol) in acetone (160 mL) was added Nal (16.94 g, 112.94 mmol). The reaction mixture was stirred at 30 °C overnight. The mixture was concentrated and the residue was dissolved in DCM (100 mL). The obtained solution was washed with saturated aqueous Na2S2Cb solution (50 mL><3) and water (50 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 5b (2.1 g, 61% yield). , which was used in the next step without further purification. Ή NMR (CDCb, 300 MHz): δ 10.10 (s, 1H), 7.90 (d, 7 = 2.4 Hz, 1H), 7.66 (dd, J= 2.1, 8.4 Hz, 1H), 7.16 (d, J= 2.4 Hz, 1H),4.49 (s, 2H),2.41 (s, 3H). 4-(4-Acetoxy-3-formylbenzyl)-4-((4S,7S, 1 OS, 13SI-10-benzyl-7-isobutyl-15methyl-13-((R)-2-methyloxiran-2- carbonyl)-2,5,8,l l-tetraoxo^-phenethyl-SAO^ntetraazahexadeciQmorpholin^-io (71 To a solution of compound 5b (380 mg, 1.48 mmol) in MeCN (5 mL) was added (S)-4-methyl-N-((S)-1-(((S)-4-methyl-1-(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (532 mg, 0.74 mmol). The reaction mixture was stirred at 45 °C overnight. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column (DCM / MeOH = 10:1) to give the desired compound (6), which was then converted to the corresponding mesylate by treatment with ion exchange resin (280 mg, 39% yield); 'H NMR (CDCb, 400 MHz): δ 10.15 (s, 1H), 9.53 (br s, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.85 (m, 1H), 7.68 (br s, 1H), 7.37 (d, 7 = 8.0 Hz, 1H), 7.26-7.13 (m, 10H), 6.84 (br s, 1H), 6.52 (br s, 1H), 5.20 (m, 2H), 4.97 (m, 1H), 4.50-3.96 (m, 7H), 3.46-3.28 (m, 2H), 3.16 (m, 1H), 3.06-2.92 (m, 3H), 2.85-2.61 (m, 7H), 2.44 (s, 3H), 2.14 (m, 2H), 1.69-1.17 (m, 11H), 0.89-0.83 (m, 12H). Compound 5a could also be used for this reaction. Example 18 was prepared from compound 7 and PEGskONH3+.MsO', following the technique for the preparation of PEG A derivatives. Example 19: 4-(4-acetoxy-3-((E)-((2-(PEG5K-amino)-2oxoethoxy)imino)methyl)benzyl)-4-((4S,7S, 1OS, 13) methanesulfonate S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8,l-tetraoxo-4-phenethyl-3,6,9, 12-tetraazahexadecyl)morpholin-4-io(8) O^H HCVk TBSCI HO. ΟγΗ AcCI Ο^,Η ooh OTBS AcOH a) 1. SOCI2 2. Nal °or b) PBr3 x 5a X = Br 5b X = I ITBS ooh Anion Exchange Resin 2-Hydroxy-5-(hydroxymethyl)benzaldehyde (1) To an aqueous formaldehyde solution (37%, 17 mL) was added 2-hydroxybenzaldehyde (10.3 g, 84.4 mmol) and concentrated HC1 (42 mL). The reaction mixture was heated under reflux overnight. The mixture was cooled to room temperature and then extracted with EtOAc (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 3:1) to give compound 1 (1.97 g, 15% yield); Ή NMR (DMSO-c / ó, 300 MHz): δ 10.61 (s, 1H), 10.26 (s, 1H), 7.60 (d, J= 2.1 Hz, 1H), 7.46 (dd, 7= 2.4, 8.7 Hz , 1H), 6.96 (d,7= 8.4 Hz, 1H), 5.18 (m, 1H), 4.42 (d, 7=3.3 Hz, 2H). 5-((( / er-Butyldimethylsilyl)oxy)methyl)-2-hydroxybenzaldehyde (2) To a solution of compound 1 (2.01 g, 13.2 mmol) in DCM (60 mL) was added imidazole (1.43 g, 21 mmol). The solution was cooled to 0 °C and for-butylchloro dimethylsilane (2.57 g, 17.1mmol). The reaction mixture was stirred at room temperature for 3 h and then poured into water (50 mL). The two phases were separated and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 50:1) to give compound 2 (3.2 g, 91% yield); Ή NMR (CDCb, 400 MHz): δ 10.85 (br, s, 1H), 9.78 (s, 1H), 7.41 (d, J= 2.0 Hz, 1H), 7.35 (dd, 7= 2.0, 8.4 Hz, 1H ), 6.85 (d, 7= 8.4 Hz, 1H), 4.59 (s, 2H), 0.82 (s, 9H), 0.00 (s, 6H). 4-((For-butyldimethylsilyloxy)methyl)-2-formylphenyl(3) acetate To a solution of compound 2 (25 g, 94 mmol) in DCM (500 mL) was added TEA (19.0 g, 188 mmol). The mixture was cooled to 0 °C and acetyl chloride (1 Ll g, 141 mmol) was added. The reaction mixture was stirred at room temperature for 2h. The mixture was washed with water (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 100:1) to give compound 3 (19.7 g, 68% yield); 'H NMR (CDCb, 400 MHz): δ 9.98 (s, 1H), 7.70 (d, 7= 2.0 Hz, 1H), 7.49 (dd, 7= 2.4, 8.4 Hz, 1H), 7.03 (d, 7= 2.4 Hz, 1H), 4.66 (s, 2H), 2.28 (s, 3H), 0.83 (s, 9H), 0.00 (s, 6H). 2-formyl-4-(hydroxymethyl)phenyl acetate (4) Compound 3 (3.6 g, 11.7 mmol) was dissolved in AcOH / THF / H2O (50 mL / 25 mL / 25 mL). The reaction mixture was stirred at 30 °C for 3 h. An excess of [sic] THF was removed and the obtained solution was brought to pH = 7-8 and then extracted with EtOAc (50 mL><3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on a silica gel column (petroleum ether / EtOAc = 3:1) to give compound 4 (2.04 g, 90% yield); 'H NMR (DMSO-úfe, 400 MHz): δ 10.08 (s, 1H), 7.85 (d, 7= 2.0 Hz, 1H), 7.67 (dd, 7= 2.4, 8.4 Hz, 1H), 7.26 (d, 7= 8.4 Hz, 1H), 4.57 (s, 2H), 2.35 (s, 3H). 4-(Bromomethyl)-2-formylphenyl acetate (5a) To a solution of compound 4 (2.03 g, 10.3 mmol) in DCM (80 mL) was added ΡΒη (2.79 g, 10.3 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4h. The reaction was diluted by adding water (20 mL) and the obtained mixture was brought to pH = 7 with saturated NaHCCb aqueous solution. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on a silica gel column. (petroleum ether / EtOAc - 3:1) to give compound 5a (300 mg, 11% yield); 'H NMR (CDCb, 300 MHz): δ 10.12 (s, 1H), 7.92 (d, J= 2.1 Hz, 1H), 7.68 (dd, J= 2.4, 8.4 Hz, 1H), 7.22 (d, J= 8.1 Hz, 1H), 4.54 (s, 2H), 2.42 (s, 3H). 4-(Iodomethyl)-2-formylphenyl acetate (5b) To a solution of compound 4 (5.0 g, 27.55 mmol) in DCM (300 mL) was added SOCb (6.13 g, 51.55 mmol) at 0 °C. The reaction mixture was heated under reflux overnight. The mixture was concentrated and the residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 10:1) to give the corresponding benzyl chloride (2.4 g, 44% yield); 'H NMR (CDCb, 300 MHz): δ 10.12 (s, 1H), 7.92 (d, J= 2.4 Hz, 1H), 7.68 (dd, J = 2.4, 8.4 Hz, 1H), 7.22 (d, J= 2.4 Hz, 1H), 4.64 (s, 2H), 2.42 (s, 3H). To a solution of benzyl chloride (2.4 g, 11.29 mmol) in acetone (160 mL) was added Nal (16.94 g, 112.94 mmol). The reaction mixture was stirred at 30 °C overnight. The mixture was concentrated and the residue was dissolved in DCM (100 mL). The obtained solution was washed with saturated Na2S2Cb aqueous solution (50 mL*3) and water (50 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 5b (2.1 g, 61% yield), which was used in the next step without further purification. 'H NMR (CDCb, 300 MHz): δ 10.10 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.66 (dd, J= 2.1, 8.4 Hz, 1H), 7.16 (d, J= 2.4 Hz, 1H), 4.49 (s, 2H), 2.41 (s, 3H). 4-(4-Acetoxy-3-formylbenzyl)-4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15methyl-13-((R)-2-methyloxiran-2- methanesulfonate carbonyl)-2,5,8,l l-tetraoxo-4-phenethyl-3,6,9,12tetraazahexadecii)morpholin-4-io (7) To a solution of compound 5b (380 mg, 1.48 mmol) in MeCN (5 mL) was added (S)-4-methyl-N-((S)-1-(((S)-4-methyl-1-(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)- 4-phenylbutanamido)pentanamide (532 mg, 0.74 mmol). The reaction mixture was stirred at 45 °C overnight. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column (DCM / MeOH = 10:1) to give the desired compound (6), which was then converted to the corresponding mesylate by treatment with ion exchange resin (280 mg, 39% yield); 'H NMR (CDCb, 400 MHz): δ 10.15 (s, 1H), 9.53 (br s, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.85 (m, 1H), 7.68 (br s, 1H), 7.37 (d, / = 8.0 Hz, 1H), 7.26-7.13 (m, 10H), 6.84 (br s, 1H), 6.52 (br s, 1H), 5.20 (m, 2H), 4.97 (m, 1H), 4.50-3.96 (m, 7H), 3.46-3.28 (m, 2H), 3.16 (m, 1H), 3.06-2.92 (m, 3H), 2.85-2.61 (m, 7H), 2.44 (s, 3H), 2.14 (m, 2H), 1.69-1.17 (m, 11H), 0.89-0.83 (m, 12H). Compound 5a could also be used for this reaction. Example 19 was prepared from compound 7 and PEG5kNHC(O)CH2ONH2 (Creative PEGWorks, Chapel Hill, NC, US), following the PEG A derivative preparation technique. Example 20: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8 methanesulfonate, l l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(3-((PEG5KiminojmethylM-Ípropionyloxy'lbenzyl'lmorpholin^-io (7). 4-((4S,7S, IOS. 13 S)-10-benz¡l-7-isobutyl-1 5-methyl-13-((R)-2-methylox¡ran2-carbonyl)-2,5 methanesulfonate ,8,1 l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(3-formyl-4(propionyloxy)benzyl)morpholin-4-ium (6) To a solution of compound 4 (400 mg, 1.476 mmol) in MeCN (5 mL) was added (S)-4-methyl-N-((S)-1-(((S)-4-methyl-1-(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (318.8 mg, 0.442 mmol). The reaction mixture was stirred at 45 °C overnight. An excess of solvent [sic] was concentrated and the residue was crystallized several times from MeCN / Et2O (1 / 5, v / v) to give the desired compound 5, which was converted to the corresponding mesylate (200 mg , 15% yield) by treatment with ion exchange resin; Ή NMR (300 MHz, CDCb): δ 10.18 (s, 1H), 7.68 (br, s, IH), 8.03 (s, 1H), 7.88 (m, 1H), 7.72 (br, 1H), 7.38 (m , 1H), 7.30-7.15 (m, 10H), 6.74 (m, 1H), 6.37 (br, 1H), 5.25-5.01 (m, 3H), 4.50-3.90 (m, 12H), 3.47- 3.12 (m, 3H), 2.97 (m, 2H), 2.97-2.71 (m, 7H), 2.15 (m, 2H), 2.71-1.10 (m, 9H), 0.87 (m, 12 H). Example 20 was prepared using methods analogous to those described in Example 16, where intermediates were prepared in a similar fashion (using ethanoyl chloride to generate intermediate 1 shown in Example 16), using compound 6 and PEG5kONH3+.MsO', following the technique for the preparation of PEG B derivatives. Example 21: 4-(3-acetoxy-4-((PEG2K-imino)methyl)benzyl)-4ÍÍ4S,7S,1OS,13S)-10-benzyl-7-isobutyl-15-methyl-13-methanesulfonate ((R)-2-methyloxiran-2-carbonyl)-2,5,8,11 tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)morpholin-4-ium (8) ΡΕθ2κ-ο 4-(4-Acetoxy-3-formylbenzyl)-4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15methyl-13-((R)-2-methyloxiran-2- methanesulfonate carbonyl)-2,5,8,ll-tetraoxo-4-phenethyl-3,6,9,12tetraazahexadecyl)morpholin-4-io (7) To a solution of compound 5b (380 mg, 1.48 mmol) in MeCN (5 mL) was added (S)-4-methyl-N-((S)-1-(((S)-4-methyl-1-(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (532 mg, 0.74 mmol). The reaction mixture was stirred at 45 °C overnight. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column (DCM / MeOH = 10:1) to give the desired compound (6), which was then converted to the corresponding mesylate by treatment with ion exchange resin (280 mg, 39% yield); Ή NMR (CDCb, 400 MHz): δ 10.15 (s, 1H), 9.53 (br s, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.85 (m, 1H), 7.68 (br s, 1H ), 7.37 (d, J= 8.0 Hz, 1H), 7.26-7.13 (m, 10H), 6.84 (br s, 1H), 6.52 (br s, 1H), 5.20 (m, 2H), 4.97 (m, 1H), 4.50-3.96 (m, 7H), 3.46-3.28 (m, 2H), 3.16 (m, 1H), 3.06-2.92 (m, 3H), 2.85-2.61 (m, 7H), 2.44 (s, 3H), 2.14 (m, 2H), 1.69-1.17 (m, 11H), 0.89-0.83 (m, 12H). Example 21 was prepared from compound 7 and PEG2kONH3+.MsO', following the technique for the preparation of PEG A derivatives. Example 22: 4-(4-acetoxy-3-(l-(PEG2K-imino)ethyl)benzyl)-4((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl methanesulfonate -13-((R)-2-methyloxiran-2-carbonyl)-2,5,8,l 1-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)morpholin-4-ium (5) 2-acetyl-4-methylphenyl acetate (1) To a solution of l-(2-hydroxy-5-methylphenyl)ethanone (1.5 g, 0.01 mol) in DCM (15 mL) was added TEA (1.5 g, 0.015 mol) and acetyl chloride (0.94 g, 0.012 mol). at 0°C. The reaction mixture was stirred at room temperature overnight. Said mixture was diluted with water (20 mL). The DCM layer was collected, washed with brine (20 mL), dried over anhydrous MgSCT, and concentrated. The residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 3:1) to give compound 1 (0.9 g, 47% yield); Ή NMR (300 MHz, CDCb): δ 7.64 (m, 1H), 7.37 (m, 1H), 7.02 (d, J= 8.1 Hz, 1H), 2.57 (s, 3H), 2.42 (s, 3H), 2.37 (s, 3H). 2-acetyl-4-(bromomethyl)phenyl acetate (2) To a solution of compound 1 (0.5 g, 2.6 mmol) in CCU (20 mL) was added NBS (573 mg, 3.25 mmol) and AIBN (42.6 mg, 0.26 mmol). The reaction mixture was heated under reflux overnight. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 10:1) to give compound 2 (160 mg, 23% yield); 'H NMR (300 MHz, DMSO76): δ 8.02 (m, 1H), 7.73 (d, J= 8.1 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.81 (s, 2H), 2.53 (s, 3H), 2.32 (s, 3H). 4-(4-Acetoxy-3-acetylbenzyl)-4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15methyl-13-((R)-2-methyloxiran-2- methanesulfonate carbonyl)-2,5,8,l l-tetraoxo-4-phenethyl-3,6,9,12tetraazahexadecyl)morpholin-4-ium (4) To a solution of compound 2 (1.03 g, 3.7 mmol) in MeCN (10 mL) was added compound (S)-4-methyl-N-((S)-l -(((S)-4-methyl-l -((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1 -oxo-3phenylpropan-2-yl)-2-((S)-2-(2 -morpholinoacetamido)-4-phenylbutanamido)pentanamide (884.7 mg, 1.23 mmol). The reaction mixture was heated at 45 °C overnight. An excess of solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (EtOAc / MeOH = 100:3) to give the desired compound 3, which was converted to the corresponding mesylate (260 mg , 21% yield) by treatment with ion exchange resin; Ή NMR (300 MHz, CDCb): δ 9.62 (m, IH), 8.06 (m, IH), 7.88-7.71 (m, 2H), 7.33-7.11 (m, 1 IH), 6.95 (m, IH), 6.66 (m, HI), 5.33-4.91 (m, 2H), 4.55-3.90 (m, 1 HI), 3.58-2.91 (m, 4H), 2.85 (s, 3H), 2.74 (m, 2H), 2.61 (s, 3H), 2.40 (s, 3H), 2.31-1.94 (m, 7H), 1.72-1.18 (m, 8H), 0.88 (m, 12H). Example 22 was prepared from compound 4 and PEG2kONH3+.MsO', following the technique for the preparation of PEG B derivatives. Example 23: 4-(3-acetoxy-4-((PEG3K-imino)methyl)benzyl)-4((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13 methanesulfonate -((R)-2-methyloxiran-2-carbonyl)-2,5,8,1-1-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl~)morpholin-4-ium (8) 4-(4-Acetoxy-3-formylbenzyl)-4-((4S,7S,1OS,13S)-10-benzyl-7-isobutyl-15methyl-13-((R)-2-methyloxiran-2-methanesulfonate -carbonyl)-2,5,8,l l-tetraoxo-4-phenethyl-3,6,9,12tetraazahexadecyl)morpholin-4-io (7) To a solution of compound 5b (380 mg, 1.48 mmol) in MeCN (5 mL) was added (S)-4-methyl-N-((S)-l-(((S)-4-methyl-l-(( R)-2-methyloxiran-2-yl)-l-oxopentan-2-yl)amino)-l-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morphol¡noacetamido) -4-phenylbutanamido)pentanamide (532 mg, 0.74 mmol). The reaction mixture was stirred at 45 °C overnight. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column (DCM / MeOH = 10:1) to give the desired compound (6), which was then converted to the corresponding mesylate by treatment with ion exchange resin (280 mg, 39% yield); *H NMR (CDCh, 400 MHz): δ 10.15 (s, 1H), 9.53 (br s, 1H), 8.03 (d, 7-2.0 Hz, 1H), 7.85 (m, 1H), 7.68 (br s, 1H), 7.37 (d, 7= 8.0 Hz, 1H), 7.26-7.13 (m, 10H), 6.84 (br s, 1H), 6.52 (br s, 1H), 5.20 (m, 2H), 4.97 (m, 1H), 4.50-3.96 (m, 7H), 3.46-3.28 (m, 2H), 3.16 (m, 1H), 3.06-2.92 (m, 3H), 2.85-2.61 (m, 7H), 2.44 (s, 3H), 2.14 (m, 2H), 1.69-1.17 (m, 11H), 0.89-0.83 (m, 12H). Example 23 was prepared using methods analogous to those described in Example 16, where intermediates were prepared in a similar fashion (using acetyl chloride to generate intermediate 1 shown in Example 16), using compound 7 and PEG3kONH)+.MsO', following the technique for the preparation of PEG A derivatives. Example 24: 4-(4-acetoxy-3-(l-(PEG3K-imino)ethyl)benzyl)-4((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl methanesulfonate -13-((R)-2-methyloxiran-2-carbonyl)-2,5,8,l 1-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)morpholin-4-ium (5) 4-(4-Acetoxy-3-acetylbenzyl-D-4-((4S,7S,1OS,13S)-10-benzyl-7-isobutyl-15methyl-13-((R)-2-methyloxiran-2-methanesulfonate carbonyl)-2,5,8,ll-tetraoxo-4-phenethyl-3,6,9.12tetraazahexadecyl)morpholin-4-io (4) To a solution of compound 2 (1.03 g, 3.7 mmol) in MeCN (10 mL) was added compound (S)-4-methyl-N-((S)-1 -(((S)-4-methyl-1 -((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido )-4-phenylbutanamido)pentanamide (884.7 mg, 1.23 mmol). The reaction mixture was heated at 45 °C overnight. An excess of solvent [sic] was concentrated and the residue was purified by flash chromatography on a silica gel column (EtOAc / MeOH = 100:3) to give the desired compound 3, which was converted to the corresponding mesylate (260 mg , 21% yield) by treatment with ion exchange resin; Ή NMR (300 MHz, CDCh): δ 9.62 (m, 1H), 8.06 (m, 1H), 7.88-7.71 (m, 2H), 7.33-7.11 (m, 11Η), 6.95 (m, 1H), 6.66 (m, 1H), 5.33-4.91 (m, 2H), 4.55-3.90 (m, 11H), 3.58-2.91 (m, 4H), 2.85 (s, 3H) , 2.74 (m, 2H), 2.61 (s, 3H), 2.40 (s, 3H), 2.31-1.94 (m, 7H), 1.72-1.18 (m, 8H), 0.88 (m, 12H). Example 24 was prepared using methods analogous to those described in Example 22, where intermediates were prepared in a similar manner, and compound 4 and PEG3kONH3+.MsO, following the PEG B derivative preparation technique. Example 25: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8 methanesulfonate, l l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(3-(2-(PEG20K-4Arm-imino)ethoxy)-4-(pivaloyloxy)benzyl)morpholin-4-ium Example 25 was prepared using methods analogous to those described in Example 17, where the intermediates were prepared in a similar fashion, while using PEG2okONH3+. MsO' and the technique for the preparation of PEG B derivatives was followed. Example 26: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8 methanesulfonate, l l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(4-(isobutyryloxy)3-((PEG5K-imino)methyl)benzyl)morpholin-4-ium (6) 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran2-carbonyl')-2.5.8.1 l-tetraoxo-4 methanesulfonate -phenethyl-3,6,9,12-tetraazahexadecyl)-4-(3-formyl-4(isobutyryloxy)benzyl)morpholin-4-ium (5) To a solution of compound 3 (550 mg, 1.657 mmol) in MeCN (8 mL) was added (S)-4-methyl-N-((S)-l-(((S)-4-methyl-l-(( R)-2-methyloxiran-2-yl)-l-oxopentan-2-yl)amino)-l -oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (393 mg, 0.547 mmol). The reaction mixture was stirred at 40 °C overnight. Excess solvent [sic] was concentrated and the residue was crystallized several times from (EtOAc / Et2O =1:5) to give the desired compound 4, which was converted to the corresponding mesylate 5 (115 mg, 7.5 % of yield) by treatment with ion exchange resin; 'H NMR (400 MHz, CDCb): δ 10.18 (s, 1H), 9.68 (m, 1H), 8.04 (m, 1H), 7.89 (m, 1H), 7.81 (s, 1H), 7.35 (m, 1H), 7.30 (m, 1H), 7.11-7.29 (m, 9H), 6.79 (s, 1H), 6.44 (m, 1H), 5.18(m, 2H), 4.99 (m, 1H), 4.41 (m , 3H), 4.20 (m, 3H), 3.99 (m, 3H), 3.40 (m, 1H), 3.30 (m, 1H), 3.20 (m, 1H), 2.95 (m, 2H), 2.92 (m, 1H), 2.79 (m, 3H), 2.75 (m, 2H), 2.21 (m, 1H), 2.09 (m, 1H), 1.83 (m, 4H), 1.62 (m, 2H), 1.49 (m, 4H), 1.38 (m, 6H), 1.24 (m, 2H), 0.88 (m, 12H). Example 26 was prepared using methods analogous to those described in Example 16, where intermediates were prepared in a similar fashion (using isopropanoyl chloride to generate intermediate 1 shown in Example 16), using compound 5 and PEG5kONH3+.MsO', following the technique for the preparation of PEG B derivatives. Example 27: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8 methanesulfonate, 11-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl')-4-(3-((PEG5Kimino)methyl)-4-(pivaloyloxy)benzyl)morpholin-4-ium (6) 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran2-carbonylJ-2,5,8,l-tetraoxo methanesulfonate -4-phenethyl-3,6,9,12-tetraazahexadeciB-4-(3-formyl-4(pivaloyloxy)benzyl)morpholin-4-ium (5) To a solution of compound 3 (500 mg, 1.44 mmol) in MeCN (8 mL) was added (S)-4methyl-N-((S)-1 -(((S)-4-methyl-1 -(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (360 mg, 0.5 mmol). The reaction mixture was stirred at 40 °C overnight. Excess solvent [sic] was concentrated and the residue was crystallized several times from (EtOAc / Et2O = 1:5) to give the desired compound 4, which was converted to the corresponding mesylate 5 (130 mg, 12 % yield) by treatment with ion exchange resin; 'H NMR (400 MHz, CDCb): δ 10.17 (s, 1H), 9.74 (m, 1H), 8.01 (m, 1H), 7.90 (m, 1H), 7.74 (m, 1H), 7.36-7.12 ( m, 11Η), 6.78 (m, 1H), 6.41 (m, 1H), 5.22 (m, 1H), 5.14 (m, 2H), 4.58-4.35 (m, 3H), 4.28-4.10 (m, 3H) , 4.08-3.83 (m, 3H), 3.38 (m, 1H), 3.29 (m, 1H), 3.17 (m, 1H), 2.97 (m, 2H), 2.83 (s, 3H), 2.76 (m, 2H ), 2.30-2.20 (m, 2H), 1.70-1.58 (m, 2H),1.47 (m, 6H), 1.42 (s, 10H), 1.30-1.16 (m, 3H), 0.90-0.84 (m, 12H) ). Example 27 was prepared using methods analogous to those described in Example 16, where the intermediates were prepared in a similar fashion (using t-butanoyl chloride to generate intermediate 1 shown in Example 16), using compound 5 and PEGskONH3+.MsO', following the technique for the preparation of PEG B derivatives. Example 28: 4-(4-acetoxy-3-(l-(PEG5K-imino)ethyl)-5-methylbenzyl)-4((4S,7S,10S,13Sj-10-benzyl-7-isobutyl-15) methanesulfonate -methyl-13-((R)-2-methyloxiran-2-carbonyl)-2,5,8,l 1-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)morpholin-4-ium (7) 2-Hydroxy-5-(hydroxymethyl)-3-methylbenzaldehyde (1) To a mixture of 2-hydroxy-3-methylbenzaldehyde (5.01 g, 36.84 mmol) and formaldehyde (37%, 7.01 g, 86.45 mmol) was added concentrated HCl (30 mL) at room temperature. The reaction mixture was heated at 80 °C for 1 h. Water (90 mL) was added and the obtained mixture was extracted with EtOAc (100 mL><3). The combined organic phases were concentrated and the residue was treated with water (150 mL, 40 °C). The solid was filtered off and the filtrate was extracted with EtOAc (100 mL><3). The combined organic phases were dried over anhydrous MgSO4 and concentrated to 100 yield compound 1 (2.60 g, 43% yield); Ή NMR (400 MHz, CDCb): δ 11.26 (s, 1H), 9.88 (s, 1H), 7.41 (s, 2H), 4.66 (s, 2H), 2.28 (s, 3H). 5-(Y(7e / --Butyldimethylsilyl)oxy)methyl')-2-hydroxy-3-methylbenzaldehyde (2) To a solution of compound 1 (2.60 g, 15.66 mmol) in DCM (50 mL) was added imidazole (2.13 g, 31.33 mmol) at 0 °C. A solution of TBSC1 (3.54 g, 23.50 mmol) in DCM (5 mL) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated and the residue was purified by silica gel column flash chromatography (hexane / EtOAc = 200:1) to give compound 2 (3.90 g, 88.9% yield); Ή NMR (400 MHz, CDCb): δ 10.85 (br, s, 1H), 9.96 (s, 1H), 7.44 (d, J= 1.6 Hz, 1H), 7.33 (d, J = 1.2 Hz, 1H), 4.56 (s, 2H), 2.12 (s, 3H), 0.82 (s, 9H), 0.00 (s, 6H). 4-f((Zer-butyldimethylsilyl)oxy)methyl)-2-formyl-6-methylphenyl(3) acetate To a solution of compound 2 (1.70 g, 6.08 mmol) in DCM (50 mL) was added TEA (1.23 g, 12.14 mmol) and acetyl chloride (715 mg, 9.11 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 20 min. The mixture was diluted with DCM (50 mL) and then poured into water (100 mL). The two phases were separated and the organic phase was washed with brine (100 mL), dried over anhydrous MgSO4, and concentrated to give crude compound 3 (1.94 g, quantitative), which was used in the next step without further purification; 'H NMR (400 MHz, CDCb): δ 9.90 (s, 1H), 7.52 (d,J= 1.6 Hz, 1H), 7.35 (d, J= 1.2 Hz, 1H), 4.63 (s, 2H), 2.30 (s, 3H), 2.11 (s, 3H), 0.83 (s, 9H), 0.00 (s, 6H). 2-Formyl-4-(vodomethyl')-6-methylphenyl acetate (4) To a solution of Nal (4.66 g, 31.06 mmol) in MeCN (50 mL) was added compound 3 (2.01 g, 6.21 mmol) and SiCl4 (1.06 g, 6.21 mmol) at 0 °C. The reaction mixture was stirred for 15 min at room temperature. The mixture was concentrated and the residue was treated with DCM (100 mL). The obtained mixture was filtered, and the filtrate was washed with saturated Na2S2Ch solution (50 mL*2), dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column flash chromatography (hexane / EtOAc=15:1) to give compound 4 (803 mg, 41% yield); 'H NMR (400 MHz, CDCb): δ 10.00 (s, 1H), 7.70 (d, J= 2.4 Hz, 1H), 7.52 (d, J= 2.0 Hz, 1H), 4.44 (s, 2H), 2.42 (s, 3H), 2.22 (s, 3H). 4-(4-Acetoxy-3-acetyl-5-methylbenzyl)-4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R')-2 methanesulfonate -methyloxiran-2-carbonyl)-2,5,8,l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)morpholin-4-ium (6) 101 To a solution of compound 4 (803 mg, 1.57 mmol) in MeCN (5 mL) was added (S)-4-methyl-N-((S)-l-(((S)-4-methyl-l-(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (340 mg, 0.47 mmol). The reaction mixture was stirred at 40 °C overnight. An excess of solvent [sic] was concentrated and the residue was recrystallized three times from (EtOAc / Et2O = 1:5) to give the desired iodine salt 5, which was converted to the corresponding mesylate 6 (202 mg, 47% yield) by treatment with ion exchange resin; Ή NMR (400 MHz, CDCb): δ 10.05 (s, 1H), 9.55 (m, 1H), 7.86 (m, 1H), 7.74 (m, 2H), 7.13-7.29 (m, 10H), 6.85 (m , 1H), 6.51 (m, 1H), 5.23 (m, 1H), 5.05 (m, 2H), 4.45 (m, 5H), 4.22 (m, 5H), 4.00 (m, 4H), 3.30-3.52 ( m, 2H), 3.17 (m, 1H), 2.98 (m, 2H), 2.83 (s, 4H), 2.76 (m, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 2.082.25 (m, 2H), 1.48-1.69 (m, 4H), 1.45 (m, 2H), 1.38 (m, 2H), 1.25 (m, 2H), 0.88 (m, 12H). Example 28 was prepared from compound 6 and PEGskONHjLMsO', following the technique for the preparation of PEG B derivatives. Example 29: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8 methanesulfonate, l l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(3-((PEG2qk-4Arm-imino)methyl)-4-(pivaloyloxy)benzyl)morpholin-4-ium 4-((4S,7S,1OS,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran2-carbonyl)-2,5,8,11 methanesulfonate -tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadeci 1)-4-(3-formyl-4(pivaloyloxy)benzyl)morpholin-4-io(5) To a solution of compound 3 (500 mg, 1.44 mmol) in MeCN (8 mL) was added (S)-4methyl-N-((S)-1 -(((S)-4-methyl-1 -(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (360 mg, 0.5 mmol). The reaction mixture was stirred at 40 °C overnight. An excess of solvent [sic] was concentrated and the residue was crystallized several times from (EtOAc / Et2O =1:5) to give the desired compound 4, which was converted to the corresponding mesylate 5 (130 mg, 12 % yield) by treatment with ion exchange resin; 'H NMR (400 MHz, CDCb): δ 10.17 (s, 1H), 9.74 (m, 1H), 8.01 (m, 1H), 7.90 (m, 1H), 7.74 (m, 1H), 7.36-7.12 ( m, 102 11Η), 6.78 (m, 1H), 6.41 (m, 1H), 5.22 (m, 1H), 5.14 (m, 2H), 4.58-4.35 (m, 3H), 4.28-4.10 (m, 3H), 4.08 -3.83 (m, 3H), 3.38 (m, 1H), 3.29 (m, 1H), 3.17 (m, 1H), 2.97 (m, 2H), 2.83 (s, 3H), 2.76 (m, 2H), 2.30-2.20 (m, 2H), 1.70-1.58 (m, 2H), 1.47 (m, 6H), 1.42 (s, 10H), 1.30-1.16 (m, 3H), 0.90-0.84 (m, 12H). Example 29 was prepared using methods analogous to those described in Example 18, where the intermediates were prepared in a similar fashion (using t-butanoyl chloride to generate intermediate 1 shown in Example 18), using the compound 5 and PEG2ok-(ONH3+.MsO')4, following the technique for the preparation of PEG B derivatives. Example 30: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8 methanesulfonate, 11-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(3-(PEG2ok-4Arm-imino)methyl)-5-methyl-4-(pivaloyloxy)benzyl)morpholin-4-ium (6) 4-((4S,7S,1OS,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran2-carbonyl)-2,5,8,l methanesulfonate -tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(3-formyl-5-methyl-4(pivaloyloxy)benzyl)morpholin-4-ium (5) To a solution of compound 3 (900 mg, 2.60 mmol) in MeCN (8 mL) was added (S)-4-methyl-N-((S)-1-(((S)-4-methyl-1-(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (624 mg, 0.87 mmol). The reaction mixture was stirred at 40 °C overnight. Excess solvent [sic] was concentrated and the residue was crystallized several times from (EtOAc / Et2O = 1:5) to give the desired compound 4, which was converted to the corresponding mesylate 5 (222 mg, 9.0 % yield) by treatment with ion exchange resin; Ή NMR (400 MHz, CDCb): δ 10.05 (s, 1H), 9.66 (m, 1H), 7.82 (m, 3H), 7.12-7.30 (m, 10H), 6.84 (m, 1H), 6.47 (m , 1H), 5.19 (m, 1H), 5.01 (m, 2H), 4.47 (m, 5H), 4.20 (m, 4H), 3.98 (m, 4H), 3.40 (m, 1H), 3.28 (m, 1H), 3.17 (m, IH), 2.98 (m, 2H), 2.83 (m, 4H), 2.73 (m, 2H), 2.25 (m, 3H), 2.10 (m, 2H), 1.61 (m, 2H) ), 1.47 (m, 12H), 1.26 (m, 2H), 0.87 (m, 12H). 103 Example 30 was prepared using methods analogous to those described in Example 28, where intermediates were prepared in a similar fashion (using t-butanoyl chloride to generate intermediate 1 shown in Example 28), using compound 5 and PEG2ok(ONH3+.MsO')4, following the technique for the preparation of PEG B derivatives. Example 31: 4-(4-acetoxy-3-((4-(PEG5K-imino)methyl)benzyl)oxy)benzyl)-4Í(4S,7S,1OS,13S)-10-benzyl-7 methanesulfonate -isobutyl-15-methyl-13-((R)-2-methyloxiran-2-carbonyl)-2,5,8,11 tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)morpholin-4- i (8) -(Chloromethyl)-4-(dimethoxymethyl Dbenzene (1) To a solution of (4-(dimethoxymethyl)phenyl)methanol (200 mg, 1.1 mmol) in DCM (10 mL) was added TEA (365.6 mg, 3.62 mmol) and MsCl (207.6 mg, 1.813 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and then poured into saturated NaHCCb solution (10 mL). The two phases were separated, and the organic layer was dried over anhydrous Na2SC>4 and concentrated to give compound 1 (200 mg, 91%), which was used in the next step without further purification. 104 4-( 4-(Dimethoxymethyl)benzyloxy)-3-hydroxybenzaldehyde (2} To a solution of compound 1 (200 mg, 0.998 mmol) in DMSO (5 mL) was added NaH (37.4 mg, 1.1 mmol) at room temperature. After 30 min of reaction, a solution of 3,4-dihydroxybenzaldehyde (137.7 mg, 0.998 mmol) in DMSO (5 mL) was added and the reaction mixture was stirred at room temperature overnight. The mixture was poured into saturated NaHCO3 solution (10 mL) and the obtained mixture was extracted with DCM (10 mL><2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give compound 2 (300 mg, crude), which was used in the next step without further purification. 2-(4-(Dimethoxymethyl)benzyloxy)-4-formylphenyl acetate (3) To a solution of compound 2 (300 mg, 1 mmol) in DCM (10 mL) was added TEA (202 mg, 2 mmol) and AcCl (102 mg, 1.3 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and then poured into saturated NaHCCb solution (10 mL). The two phases were separated, and the organic layer was dried over anhydrous Na2SO4 and concentrated to give compound 3 (200 mg, crude), which was used in the next step without further purification. 2-(4-(Dimethoxymethyl)benzyloxy)-4-(hydroxymethyl)phenyl(4) acetate To a solution of compound 3 (200 mg, 0.58 mmol) in DCM / MeOH (10 mL / lmL), NaBHi (19.8 mg, 0.58 mmol) was added. The reaction mixture was stirred at 0 °C for 1 hour and then diluted with acetone (5 mL). The mixture was poured into saturated aqueous NaHCO3 solution (10 mL) and extracted with DCM (10 mLx2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give compound 4 (300 mg, crude), which was used in the next step without further purification. 4-(Bromomethyl)-2-(4-formylbenzyloxy)phenyl acetate (5) To a solution of compound 4 (1.8 g, 5.2 mmol) in DCM (50 mL) was added PBr3 (1.41 g, 5.2 mmol). The reaction mixture was stirred at room temperature for 5 hours and then diluted with saturated aqueous NaHCO3 solution (60 mL). The two layers were separated and the aqueous phase was extracted with DCM (50 mL><2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column flash chromatography (petroleum ether / EtOAc = 4:1) to give compound 5 (327 mg, 15% yield); Ή NMR (400 MHz, DMSO): <5 10.01 (s, 1H), 7.96-7.94 (m, 2H), 7.62-7.60 (m, 2H), 7.31 (m, 1H), 7.137.07 (m, 2H) ), 5.26 (s, 2H), 4.68 (s, 2H), 2.27 (s, 3H). 105 4-(4-Acetoxy-3-((4-formylbenzyl)oxy)benzyl)-4-((4S,7S,10S,13S)-10-benzyl7-isobutyl-15-methyl-13-((R) methanesulfonate )-2-methyloxiran-2-carbonyl)-2,5,8,l-tetraoxo-4-phenethyl-3,6,9,12tetraazahexadecyl)morpholin-4-io (7) To a solution of compound 5 (320 mg, 0.884 mmol) in MeCN (6 mL) was added (S)-4-methyl-N-((S)-l-(((S)-4-methyl-l-(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4 -phenylbutanamido)pentanamide (254 mg, 0.354 mmol). The reaction mixture was stirred at 45 °C for 48 hours. Excess solvent [sic] was evaporated and the residue was crystallized several times from MeCN / Et2O (1 / 5, v / v) to give the desired product 6, which was then converted to the corresponding mesylate compound 7 (180 mg, 47% yield) by treatment with ion exchange resin. A solution of compound 7 (500 mg, 0.46 mmol), 2-amino-5-methoxybenzoic acid (25.5 mg, 0.14 mmol) and PEG-O-NH2 (mesylate salt, 2.12 g, 0.41 mmol) in DCM was stirred at room temperature. environment for 2 h. The reaction mixture was then concentrated and the residue was dissolved in i-PrOW at 40 °C. The solution was cooled to room temperature and Et2O was added to induce crystallization. The mixture was kept in an ice bath for 10 min and then filtered. The filter cake was crystallized from i-PrOH / Et2O (5 / 2) to give 8 (2.10 g, 82% yield). Example 32: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carbonyl)-2,5,8 methanesulfonate, ll-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(4-(isobutyryloxy)3-((4-(PEG5K-imino)methyl)benzyl)oxy)benzyl)morpholin-4- i (8) 4-((45',7ó',105',135)-10-benzyl-7-isobutyl-15-methyl-13-((7?)-2-methyloxiran-2carboniD-2,5,8, methanesulfonate 1 l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(3-(4-formylbenzyloxy)-4(isobutyryloxy)benzyl)morpholin-4-ium (7) Yo 106 To a solution of compound 5 (310.4 mg, 0.80 mmol) in MeCN (2 mL) was added (S)-4methyl-N-((S)-1 -(((S)-4-methyl-1 -(( R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)- 4-phenylbutanamido)pentanamide (286 mg, 0.30 mmol). The reaction mixture was stirred at 45 °C for 48 hours. Excess solvent [sic] was evaporated and the residue was crystallized several times from MeCN / Et20 (1 / 5, v / v) to give the desired product 6, which was then converted to the corresponding mesylate compound 7 (280 mg, 83% yield) by treatment with ion exchange resin. A solution of compound 6 (280 mg, 0.25 mmol), 2-amino-5-methoxybenzoic acid (14.0 mg, 0.026 mmol), and PEG-O-NH2 (mesylate salt, 1.16 g, 0.227 mmol) in DCM (3 mL ) was stirred at room temperature for 2 h. The reaction mixture was then concentrated and the residue was dissolved in ζ-PrOH at 40 °C. The solution was cooled to room temperature and Et2O was added to induce crystallization. The mixture was kept in an ice bath for 10 min and the solid formed was collected by filtration. Recrystallization from ζ-PrOH / Et2Ü (5:2) was repeated twice until all 7 was removed to give 8 (1.0 g, 72% yield). Example 33: 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2methyloxiran-2-carboniD-2,5,8,l methanesulfonate l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)-4-(3-((4-(PEG5Kimino)methyl)benzyl)oxy)-4-(pivaloyloxy)benzyl)morpholin-4 -io (8) 4-((45,75,105,135)-10-benzyl-7-isobutyl-15-methyl-13-((7?)-2-methyloxiran-2carboniD-2,5,8,1 l-tetraoxo-4- phenethyl-3,6,9,12-tetraazahexadecyl)-4-(3-(4-formylbenzyloxy)-4(pivaloyloxy)benzyl)morpholin-4-ium (7) To a solution of compound 5 (analogue of t-butyl ester of compound 5 in example 31, 230 mg, 0.51 mmol) in MeCN (3 mL) was added (S)-4-methyl-N-((S)-l -(((S)-4-methyl-1-((R)-2methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2 -((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide (184 mg, 0.25 mmol). The reaction mixture 107 was stirred at 45 °C for 48 hours, an excess solvent [sic] was evaporated and the residue was crystallized several times from MeCN / Et2O (1 / 5, v / v) to give the desired product 6, which was then converted to the corresponding mesylate salt of compound 7 (170 mg, 71% yield) by treatment with ion exchange resin; Ή NMR (400 MHz, CDCb): <5 9.99 (s, 1H), 9.59 (m, 1H), 7.87-7.85 (m, 2H), 7.57-7.55 (m, 2H), 7.32 (m, 1H), 7.26-7.13 (m,llH), 7.03 (m, 1H), 6.89 (m, 1H), 6.44 (m, 1H), 5.18 (m, 2H), 5.05-5.03 (m, 1H), 4.92-4.88 ( m, 2H), 4.46-4.42 (m, 4H), 4.18-4.03 (m, 4H), 3.94-3.90 (m, 3H), 3.40-3.32 (m, 1H), 3.27-3.20 (m, 1H), 3.13 (m, 1H), 3.00-2.98 (m, 2H), 3.82-2.80 (m, 3H), 2.79 (m, 1H), 2.74-2.72 (m, 2H), 2.19 (m, 1H), 2.10- 1.97 (m, 4H), 1.64-1.55 (m, 2H), 1.48-1.44 (m, 5H), 1.29 (m, 6H), 0.88-0.81 (m, 12H). A solution of compound 7 (170 mg, 0.15 mmol), 2-amino-5-methoxybenzoic acid (28.2 mg, 0.016 mmol) and PEG-O-NH2 (mesylate salt, 614 mg, 0.12 mmol) in DCM was stirred at room temperature for 30 min. The reaction mixture was then concentrated and the residue was dissolved in z'-PrOH at 40 °C. The solution was cooled to room temperature and Et20 was added to induce crystallization. The mixture was kept in an ice bath for 10 min and then filtered. The filter cake was crystallized from i-PrOW / Et2O (5 / 2) to give 8 (580 mg, 77%). Representative examples of carfilzomib prodrugs of Examples 31-33 of the invention disclose oxime-linked conjugates with potentially improved chemical stability. In these examples the oxime linkage is spaced with an electron donating benzyloxy group to increase the overall stability of the PEG construct. Example 34: 4-í4-acetoxy-3-(yl-PEG3K-lH-l,2,3-triazol-4-yl)methoxy)benzyl)-4(Y4S,7S, 1OS, 13S)- chloride 10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran-2-carbonyl)-2,5,8,11 tetraoxo-4-phenethyl-3,6,9,12 -tetraazahexadecyl)morpholin-4-io Example 34 was prepared using a method analogous to that described in Examples 511 and Method A, but using the chloride salt intermediate having a chloride anion as a counterion. 108 Example 35: 4-(4-acetoxy-3-((1-PEG3K-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-4(Y4S,7S, 1OS, 13S) mesylate )-10-benzyl-7-isobutyl-15-methyl-13-(YR)-2-methyloxiran-2-carbonyl)-2,5,8,11 tetraoxo-4-phenethyl-3,6,9,12- tetraazahexadecyl)morpholin-4-io peg3I n-n y . i3^irNYS'SrNYI[iV<' MsO O___J O O Vph O ph Example 35 was prepared using a method analogous to that described in Examples 511 and method A using a PEG3kN3. Ή NMR (DMSO-d6, 400 MHz): δ 9.19 (Μ, 1H), 8.24 (m, 2H), 8.12 (m, 1H), 7.90 (m, 1H), 7.62 (m, 1H), 7.22 (m , 13H), 7.0 (m, 1H), 5.26 (m, 2H), 4.88 (m, 2H), 4.53 (m, 3H), 4.37 (br s, 4H), 4.05 (m, 5H), 3.81 ( m, 2H), 3.68 (m, 4H), 3.52 (br s, 339H), 3.30 (m, 4H), 3.24 (s, 4H), 2.94 (m, 2H), 2.75 (m, 1H), 2.63 ( m, 2H), 2.24 (s, 3H), 1.87 (m, 2H), 1.59 (m, 2H), 1.40 (m, 7H), 0.84 (m, 12H) Example 36: 4-(4-acetoxy-3-((1-PEG2K-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-4((4 S, 7 S, 1 OS) mesylate , 13 S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran-2-carbonyl)-2,5,8,11 tetraoxo-4-phenethyl-3,6, 9,12-tetraazahexadecyl)morpholin-4-io Example 36 was prepared using a method analogous to that described in Examples 511 and method A using a PEG2KN3. 'H NMR (DMSO-d6, 400 MHz): δ 9.44 (Μ, 1H), 8.26 (m, 2H), 8.16 (m, 1H), 8.00 (m, 1H), 7.62 (m, 1H), 7.22 ( m, 13H), 5.26 (m, 2H), 5.00 (m, 2H), 4.54 (m, 3H), 4.37 (m, 5H), 4.09 (m, 4H), 3.81 (m, 2H), 3.68 ( m, 2H), 3.50 (br s, 218H), 3.32 (m, 2H), 3.27 (s, 1H), 3.26 (s, 4H), 2.94 (m, 2H), 2.76 (m, 1H), 2.61 ( m, 2H), 2.24 (s, 3H), 1.90 (m, 2H), 1.62 (m, 2H), 1.40 (m, 7H), 0.82 (m, 12H) 109 Example 37: 4-(4-acetoxy-3-((1-(5-((2-PEG3K-ethyl)amino)-5-oxopentyl)-1H-1,2,3triazol-4-yl)methoxy mesylate )benzyl)-4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran2-carbonyl)-2,5,8.1 l- tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)morpholin-4-io Example 37 was prepared using a method analogous to that described in Examples 511 and method A using a PEG3K with a linker derived from 5-azidopentanoic acid. 'H NMR (DMSO-d6, 400 MHz): δ 9.26 (Μ, 1H), 8.25 (m, 2H), 8.17 (m, 1H), 7.98 (d, 1H), 7.87 (m, 1H), 7.62 ( m, 1H), 7.22 (m, 11H), 7.02 (m, 1H), 4.99 (m, 2H), 4.56 (m, 1H), 4.37 (br s, 6H), 4.11 (m, 3H), 3.71 (m, 3H), 3.52 (br s, 304H), 3.25 (br s, 7H), 2.75 (m, 1H), 2.61 (m, 2Η), 2.24 (s, 3H), 2.11 (m, 1H), 1.87 (m, 2H), 1.40 (m, 5H), 0.82 (m, 12H) Example 38: 4-(4-acetoxy-3-((1-(5-((2-PEG2K-ethyl)amino)-5-oxopentyl)-1H-1,2,3triazol-4-yl)methoxy mesylate )benzyl)-4-((4S,7S, 1OS, 13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxiran2-carbonyl)-2,5,8 ,l l-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecyl)morpholin-4-io or ph Example 38 was prepared using a method analogous to that described in Examples 511 and method A using a PEG2K with a linker derived from 5-azidopentanoic acid. 'H NMR (DMSO-d6, 400 MHz): δ 9.56 (Μ, 1H), 8.29 (m, 2H), 8.18 (m, 1H), 8.04 (m, 1H), 7.92 (m, 1H), 7.62 ( m, 1H), 7.22 (m, 11H), 7.0 (m, 1H), 5.38 (m, 2H), 4.99 (m, 2H), 4.56 (m, 1H), 4.37 (br s, 7H), 4.19 (m, 3H), 4.02 (m, 3H), 3.52 (br s, 179H), 3.25 (br s, 5H), 2.94 110 (m, 2H), 2.80 (m, 1H), 2.63 (m, 2H), 2.24 (s, 3H), 2.10 (m, 2H), 1.87 (m, 2H), 1.40 (m, 9H), 0.82 (m, 12H) The exemplary compounds of the present invention may be shown to be effective in the treatment of various types of cancer, including, but not limited to, multiple myeloma, by virtue of possessing adequate and sufficient pharmacokinetic and pharmacodynamic profiles to provide such treatment against cancer. The following exemplary descriptions and accompanying figures show some of these pharmacokinetic and pharmacodynamic profiles of a selection of representative compounds of the invention. Example 39: Conversion of the conjugate compound of PEG and carfilzomib human plasma Human plasma conversion protocol: A 1 millimolar (mM) stock solution of the desired test compound in DMSO was prepared. A 25 μΜ solution of the test compound in acetonitrile:water was prepared by diluting the 1 mM stock solution (ie, 2.5 pL of 1 mM stock solution was added to 97.5 pL of acetonitrile:water (50:50 )). Frozen human plasma (pooled from 5 male subjects, 2KEDTA anticoagulant) was thawed at room temperature and centrifuged at 1400 x RCF 4°C for 15 minutes. Approximately 90% of the clear supernatant fraction was transferred to a separate tube and used for assay. For samples of time 0 min, the plasma was inactivated by heat at 80 °C. To 72 pL of heat inactivated plasma was added 3 pL of the 25 pM working solution and 50 pL of sample was added with 200 pL of acetonitrile containing the internal reference. For the assay, a 1 pM incubation sample was prepared by adding 20 pL of the 25 pM working solution to 480 pL of plasma. Samples were incubated for 0, 5, 1, 2, 4, and 6 h at 37 °C in the water bath of a rocking shaker with gentle agitation. At each time point, 50 pL of sample was precipitated with 200 pL of acetonitrile containing the internal reference and centrifuged at 4000 x RCF, 4 °C for 20 min. 150 pL of supernatant was diluted with 150 pL of water and analyzed by LC-MS / MS. An 8-point calibration curve was generated using plasma with a higher concentration of 5 pM carfilzomib followed by dilution at a ratio of 2.5. The amount of carfilzomib released was quantified against the calibration curve and reported in pM. Figure 1 shows the rate of conversion of representative examples of the PEG-carfilzomib conjugates to the free, non-PEG-conjugated form of carfilzomib. As shown, the exemplary compounds of the invention provide plasma carfilzomib concentrations from time 0 which gradually increase, for most of the examples depicted, until reaching significant concentrations lasting up to 2 hours and, 111 in some cases, more than 2 hours. This figure shows that the projected half-life of the exemplary compounds of the present invention is less than 2 hours, and potentially longer in human plasma. Thus, Figure 1 illustrates that the PEG-carfilzomib conjugates of the present invention provide slow release of the active form of carfilzomib into blood plasma, potentially conferring longer lasting action on cellular proteosomal enzymes to carfilzomib, Therefore, it is expected that it will have a more prolonged inhibitory effect on the activity of the proteasome. Mean plasma concentration (μΜ) after intravenous administration of the PEG-carfilzomib conjugate to female Balb / c mice (n = 3). The indicated dose is expressed in mg / kg of PEG-carfilzomib conjugate. Example 40: pK of PEG and carfilzomib in mice PEG-carfilzomib conjugates were administered to mice (Balb / c, female, n=3 per dose group) in the form of an intravenous (iv) bolus at the specified dose (5 mL / kg dose volume) in a solution water containing 10% (w / v) ethanol. Blood samples were collected at the indicated times and carfilzomib plasma concentrations were measured in duplicate by LC / MS-MS. The control profile for comparison was a standard formulation of carfilzomib, i.e., a formulation in aqueous solution of 10% (w / v) sulfobutylether-β-cyclodextrin and 10 mmol / L sodium citrate (pH 3.5) for administration. (5mg / kg). This standard carfilzomib represents the currently approved formulation for carfilzomib for the treatment of multiple myeloma. The different doses administered to the mice for Examples 13, 16 and 18 reflect an amount of carfilzomib present and dosed and a calculated amount approximately equal to the amount of carfilzomib provided in the standard formulation of carfilzomib. As shown in Figure 2, while Example 18 exhibited a similar profile to control carfilzomib, Examples 13 and 16 exhibited extensions in their profiles. Particularly, Example 16 exhibited improved availability of free active carfilzomib for the same period of time as the control. However, Example 13 exhibited a release of carfilzomib over a much longer period of time than control carfilzomib, resulting in a significantly higher concentration of carfilzomib in plasma over that longer period of time. The plasma concentration for Example 13 was several times higher on a log scale than the control. 112 Example 41: Inhibition of the proteasome with the PEG conjugates and carfilzomib vs. carfilzomib PEG-carfilzomib Compound Example 1 was administered to mice (Balb / c, female, n=3 per dose group) in the form of an intravenous (iv) bolus at the specified dose (5 mL / kg dose volume) in a solution water containing 10% (w / v) ethanol. Standard carfilzomib was formulated in an aqueous solution of 10% (w / v) sulfobutyl-ether-p-cyclodextrin and 10 mmol / L sodium citrate (pH 3.5) for administration (5 mg / kg). At selected time points after i.v. of the drug, tissue samples (adrenal, heart, liver, and bone marrow) were obtained. Whole blood was collected by cardiac puncture into tubes containing sodium heparin. Blood: Approximately 0.4 mL of whole blood is collected using EDTA microcentrifuge tubes. Samples are immediately placed on ice and spun at maximum speed for 2 minutes in a microfuge at room temperature (RT). Cell pellets are stored on wet ice. Whole blood cell pellets are resuspended in 1 mL of phosphate-buffered saline (PBS) and centrifuged at maximum speed at 4 °C. The supernatants are removed and the pellets are washed a second time with PBS. Samples are resuspended in 2 volumes of lysis buffer (20 mM Tris, pH 8.0, 5 mM EDTA), then frozen and stored at -80 °C until analysis. Adrenal gland, heart and liver tissue: Tissues (adrenal glands, heart, and liver) were collected at specified graphical time points after dosing. Tissues were cut and placed in 15 mL tubes containing PBS at 4 °C. For tissues that were homogenized, samples were minced with scissors and ~0.1-0.2 mg portions were placed in 2 mL microcentrifuge tubes. Tissue slices were frozen and stored at -80 °C. Sample processing: All samples were thawed on ice. All individual cell pellets in lysis buffer (whole blood) were briefly vortexed and then centrifuged at 14,000 rpm in a microfuge at 4°C for 15 minutes. The supernatant was transferred in a ratio of 100 μΐ to 25 μΐ of 50% glycerol in a sample plate to obtain a final glycerol concentration of 10%. These samples were ready to test, or can be frozen at -80 °C. Approximately 2 volumes of lysis buffer and a stainless steel bead were added to the tissue parts. 113 thawed (adrenal glands, heart and liver). Samples were homogenized at 20 mHz for 60 seconds on each side and then spun at 14,000 rpm in a microcentrifuge at 4 °C for 15 minutes. The supernatant was transferred in a ratio of 100 μΐ to 25 μΐ of 50% glycerol in a sample plate to obtain a final glycerol concentration of 10%. Care was taken to avoid the upper lipid layer for tissues with high fat content (ie, adrenal). These were ready to test, or can be frozen at -80 °C. Samples frozen at this 10% glycerol / lysate stage should be thawed on ice before assaying. The protein concentration for each sample was measured by Bradford assay. Chymotrypsin-like activity of the proteasome (CT-L) was quantified by monitoring the release of free AMC from the fluorogenic peptide Suc-Leu-Leu-Val-Tyr-AMC (BostonBiochem). As shown in Figure 3, CT-L activity was comparable between standard carfilzomib and the conjugate of Example 1 in blood, as well as in adrenal gland, heart and liver tissues, in mice. Example 42: Mean carfilzomib plasma concentration - time profiles for Examples 13, 26 and 34, each of which was administered i.v. PEG-carfilzomib conjugates were administered to mice (Balb / c, male, n=9 per dose group) as an intravenous (i.v.) bolus at 5 mg / kg (equivalent to carfilzomib, dose volume 1 mL / kg). Blood samples were collected from each mouse at the indicated time points (0.5, 1, 2, 4, 6, 12, 16, and 24 hours post-dose) and 25 pL of the plasma samples were collected. Protein precipitation was extracted with 125 μΐ acetonitrile containing D10-CFZ as an internal reference and then centrifuged. Carfilzomib concentrations in the supernatant were measured by LC-MS / MS using a control with multiplex reaction in the positive electrospray ionization mode. The lower limit of quantification of the assay was 0.500 ng / mL. As shown in Figure 4, the standard formulation of carfilzomib (CFZ) cyclodextrin (5 mg / ml) used as a control in this study resulted in a decreased plasma concentration over a very short period of time. 3K-PEG CFZ (Example 34) is present in plasma for up to 20 to about 25 hours after the initial administration of the PEG conjugate. Similarly, 5K-PEG CFZ (Example 26) is present in plasma, as measured in Figure 5, at higher concentrations for virtually all of the time up to about 25 hours. Finally, the 20K-PEG (Example 114 13) is the curve above the 3K curves. and 5K-PEG, starting between them and revealing that this PEG conjugate releases carfilzomib into plasma over the 25 hour period measured, thereby delivering carfilzomib at significantly higher plasma concentrations over such a long period of time. Finally, as shown in Figure 4, the highest curve at baseline, corresponding to a formulation comprising a combination of carfilzomib 3K-PEG and 20K-PEG compounds exhibited a much higher plasma concentration as longer than that of 3K-PEG alone and comparable to that of the higher molecular weight carfilzomib compound 20K-PEG alone. Table 4 describes the results obtained when representative examples of the carfilzomib compound were compared with standard carfilzomib and all samples were dosed i.v. Table 4: pK measurements Example No. Cmax (ng / mL) AUCo-24 (ng.h / mL) Τι / z (h) CL / F (mL / kg / h) Volume of Distribution [sic] (Vdss; (mL / kg) CFZ -i.v. 46.7 153 10.9 29000 245000 34 1470 2230 6.09 2230 2110 26 472 847 8.51 5770 12800 13 616 3510 3.68 1400 6900 The PEG and carfilzomib formulations dosed in Examples 39-41 were generally prepared as follows: A desired amount of the PEG-CFZ compound was weighed into a sterile glass container using an analytical balance. A volume of diluent was calculated based on the weight of the material. 10 mM acetate diluent, pH 5.0, 9% sucrose, was added to the glass container to a final volume that resulted in 1 mg / mL, 5 mg / mL concentrations of the PEG-CFZ compounds. , 10 mg / mL or 20 mg / mL. Each PEG-CFZ sample was shaken for one hour at room temperature to allow complete dissolution of the material. Once the material was completely dissolved in the solution, a sample was taken to measure the pH, which was always in the desired range of 4.9-5.1. Therefore, no further pH adjustments were made. Osmolality measurements of the samples and endotoxin tests were performed. 115 for all samples and were found to always be within the acceptable osmolality range of 295 - 312 mOsm and < 1.0 EU / mL for endotoxin count. Immediately after dissolution, samples were aseptically filled into sterile 5 cc glass vials, capped, and capped. Samples were frozen at -70°C for a period of 1 day to 2.5 weeks prior to shipping and dosing in Examples 39-41 as described herein below. Example 43: Efficacy study of Example 13 and CFZ-captisol in the xenograph [sic] model of HT-29 human colorectal adenocarcinoma in Beige SCID mice (Figure 5) Procedure: Female Beige SCID (severe combined immunodeficiency) mice (60 plus refills) were purchased from Harlan Laboratories (Livermore, CA) at 6 to 7 weeks of age. Upon arrival, animals were weighed using an electronic scale (Ohaus SCOUT® PRO, Parsippany, NJ), clinically examined to ensure good condition, and housed 5 per cage (prior to placement). the dosage). Animals were maintained in a HEPA-filtered environment in a Micro-VENT fully ventilated rodent housing system (Allentown Caging Equipment Co., Allentown, NJ) that allowed at least 10 room air changes per hour. Animal room controls were adjusted to maintain temperature and relative humidity at 20 0 C ± 1° C and 50% ± 20%, respectively. The rooms in the house were kept on a 12:12 light / dark cycle. Cages were autoclaved, and SaniChip 7990.BG irradiated beds (Harlan Teklad, Hayward, CA) were placed for the animals. Water was autoclaved and supplied ad libitum to each cage via water bottles. Each cage was supplied ad libitum with irradiated 16% protein 2018 Teklad Global (Harian Teklad) rodent ration. Compound Formulation: Example 13 was prepared as generally described above. The carfilzomib compound used for comparison was prepared as CFZcaptisol (at 1 mg / ml). A powder sample from Example 13 was diluted to 30 mg / mL (Group 3) or 50 mg / mL (4th starting dose of Group 3) or 40 mg / mL (Group 4) in 10% ETOH / saline. Vehicle and CFZ-captisol were stored at 4 °C throughout the study. During the study, Example 13 was regularly inspected for possible changes in the quality of the suspension, without any being observed. Cell line: A human colorectal adenocarcinoma (CA) cancer cell line, NCI-HT29 (HT-29; ATCC® HTB-38™), was obtained from ATCC (Manassas, VA). Upon receipt at MGI, cells were cultured in the laboratory for 7 passages in RPMI 1640 and 10% 116 fetal bovine serum, and then used to generate frozen stocks. Cells were recovered from frozen stocks and cultured as above. After growth, cells were spun down and resuspended at a concentration of 5E07 cells / mL in serum-free medium with no additives, and then combined 1:1 with Matrigel™ (Trevigen, Gaithersburg, MD). At the time of implantation, the cells corresponded to MGI passage 7 (MGP7). Cell Implantation: Approximately 3 weeks prior to the projected staging day, mice were implanted by subcutaneous (SC) injection in the left lower abdominal flank with 200 μΐ (5.0E06 cells) per mouse of freshly prepared HT29 : Matrigel mixture. All procedures were carried out in HEPA-filtered laminar flow hoods. Study Design: The study design and treatments of all groups are shown in Table 1 (Efficacy). When tumors reached a mean volume of approximately 200 mm3 per mouse, forty animals with established tumors and moderate body weights were randomized into 4 treatment groups (n=10 mice per group). Starting on Day 0, animals were injected weekly (qw) with vehicle injection (Group 1) or twice weekly D1D2 (i.e., two adjacent days each week) with CFZ-captisol at 5 mpk (Group 2) or OP -59381 at 150 mg / kg (Groups 3). Starting with the fourth dose (ie, after three weeks), the dosage of Group 3 animals was increased to 250 mg / kg. Group 4 was dosed weekly injection (qw) with o [sic] OP-59381 (Example 13) at 200 mg / kg. All of these doses were administered as intravenous (i.v.) injections at dose volumes of 5 mL / kg. After i.v. by the seventh week (ie, after Day 42 for Groups 1-4), the efficacy of the tumor treatment appeared to decrease or cease altogether. Table 5 days 0-48 Experiment Group Agent Dose (mg / kg) Frequency 1 1 (n=10) Vehicle - QW x 7 weeks 1 2(n=10) CFZ-captisol 5 QD x 2 (D1D2) x 7 weeks 1 3(n=10) Example 13 150 / 250 QW x 7 weeks 1 4(n=10) Example 13 200 QW x 7 weeks 117 As seen in Figure 5, tumors in the vehicle group (Group 1) grew linearly over the i.v. dosing interval, with tumor sizes increasing to ~2.755% of initial size on Day 49. While on Day From 0 to Day 15 tumor sizes did not change from vehicle control in all three groups, tumor growth on Day 19 was significantly attenuated in animals treated with 200 mpk of Example 13 and those treated with 5 mpk CFZ -captisol. This significant attenuation continued until Day 29 when a level of significance was reached in all three experimental groups that continued until Day 40, demonstrating that the 3 doses were sufficient to provide antitumor activity. Example 44: Example 44 reflects the mouse survival data resulting from the study of Example 41, the data of which is tabulated in Table 6 and graphically illustrated in Figure 6. Table 6 Group

Claims

1. A conjugated compound of PEG and carfilzomib, of Structural Formula I or Structural Formula II (FORMULA I) (FORMULA II) or a pharmaceutically acceptable salt thereof, wherein R1 is C1-10alkyl or C3-7cycloalkyl; each R2, considered independently, is C1-6alkyl, -OCH3 or halogen; or is an integer selected from 0, 1, 2 or 3; linker is a molecule having the structure of (FORMULAS) wherein; R3 is H or CH3; n is an integer selected from 1, 2, 3 or 4; p is an integer selected from 0, 1, 2, 3 or 4; q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8 or 9; r is an integer selected from 0, 1, 2, 3, 4 or 5; X is a salt of a counterion selected from a chloride, a bisulfate, a sulfate, a nitrate, a phosphate, a C1-6 alkyl sulfonate or a C1-6 aryl sulfonate;and PEG is a polyethylene glycol polymer molecule having a molecular weight in the range of about 500 to about 20000, characterized in that said compound is selected from the group consisting of: (FORMULAS 1 to 38). Two claims follow;