Proteasome inhibitors and methods of use thereof

Abstract

The present disclosure provides proteasome inhibitors of Formula (I), useful in treating cancer, such as multiple myeloma and mantle cell lymphoma.

Description

[0001] Attorney Docket No.29618-0443WO1 PROTEASOME INHIBITORS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application Serial No.63 / 590,294, filed October 13, 2023; and U.S. Patent Application Serial No.63 / 690,762, filed September 4, 2024; each of which is incorporated by reference herein in its entirety. FIELD The present disclosure relates to proteasome inhibitors, useful in treating cancer, such as multiple myeloma and mantle cell lymphoma. BACKGROUND The proteasome is the protease responsible for most intracellular protein degradation. Unlike other proteases, the proteasome harbors three distinct active sites capable of cleaving after hydrophobic (β5), basic (β2), and acidic (β1) residues, respectively. Since each active site subunit is present twice, the proteasome comprises six individual proteases. Furthermore, the active sites are not exposed on the proteasome's surface but rather sequestered within the hollow cylindrical chamber of the central part of the proteasome, known as the core particle (CP). Substrates can only access this interior space through narrow regulated gates at either end of the CP. This arrangement protects cells by limiting proteolysis to only those substrates which have been selected and prepared for degradation by the proteasome. Proteasome inhibitors are widely used drugs, having been approved for the treatment of multiple myeloma and mantle cell lymphoma. All three approved drugs consist of small peptides with a C-terminal electrophile. Bortezomib is a modified Phe-Leu dipeptide with a boronic acid warhead. Carfilzomib is a related hydrophobic tetrapeptide with an epoxyketone warhead. Ixazomib is a second boronic acid peptide derivative but uses a prodrug mechanism to facilitate oral bioavailability. All three drugs operate similarly, and primarily target the β5 active site at physiologically relevant concentrations. There are no approved therapies that specifically target β2 or β1. In addition to these small molecule inhibitors, there is also an endogenous proteasome inhibitor known as PI31 (also known as Fub1 or PSMF1). Unlike the small Attorney Docket No.29618-0443WO1 molecules, this 31-kDa protein is capable of simultaneously inhibiting all three proteasome active sites. Despite having been discovered in 1992, PI31's inhibitory mechanism had remained a mystery until recently when a high-resolution cryo-EM structure of yeast Fub1 bound to the CP was obtained. This structure revealed an unprecedented mechanism whereby Fub1 entered the CP interior and then specifically interacted with all 6 proteasome active sites simultaneously (Fig.1A). By binding and filling each active site, Fub1 prevents access of substrates to the active sites. However, Fub1 itself evades degradation through different mechanisms at each active site. It is clear now that Fub1 / PI31 is among the most sophisticated protein inhibitors of a protease ever identified. A second PI31-CP structure was subsequently obtained from a microsporidian parasite, Vairimorpha necatrix, that primarily affects insects. This structure confirmed PI31's overall architecture and approach to proteasome inhibition (Fig. 1 B), suggesting that PI31's general mechanism of inhibition is evolutionarily conserved. However, there were interesting differences in some of the detailed interactions of PI31 with the active sites, suggesting that there may also be important species-specific differences. SUMMARY This disclosure reports a series of potent and specific β2 inhibitors that are cytotoxic to cancer cells, such as multiple myeloma cells, both as standalone agents and synergistically in combination with β5 inhibitors. In some embodiments, the present disclosure provides a compound of Formula (I): or a X, Y, each R1, R2, R3, R4, R5, R6, and R7are as described herein. In some embodiments, the present disclosure provides a compound of Formula (II): Attorney Docket No.29618-0443WO1 or a R2, R3, R4, R5, R6, R7, R8, and R9is as described herein. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is suitable for topical administration. In some embodiments, the present disclosure provides a method of preventing or treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the cancer is multiple myeloma or mantle cell lymphoma. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims. DESCRIPTION OF DRAWINGS FIG. 1 shows the structures of CP bound to Fub1 / PI31 from yeast and a microsporidian parasite. A: Structure of yeast CP (3.0 Å) with the Fub1 dimer present inside the CP's hollow barrel-shaped chamber. Note that only the C-terminal region of Fub1 was resolved at high-resolution (residues 127-229). Also note that this CP is from an α3Δ Attorney Docket No.29618-0443WO1 mutant. B: Structure of the microsporidian spore- stage 20S core-particle (2.8 Å) with comparable density also representing a dimer of the C-terminal domain of PI31. Yeast, PDB: 7TEO. Microsporidian, PDB: 8ADN.s. FIG.2 shows the identification of PI31 Residues Sufficient for Inhibition of the β2 Site. A: Enzymatic activity of the human β2 (CP at 10 nM) in the presence or absence of full-length PI31 (37.5-fold molar excess), or PI31 (232-251) peptide (varying concentrations), as determined using the fluorogenic β2 substrate Boc-LRR-AMC. Background fluorescence of Boc-LRR-AMC was subtracted. The IC50 of the PI31 (232- 251) peptide was <10 μM. B: Post-acidic (β1) activity assay of human CP (10 nM) in the presence or absence of PI31 (37.5-fold molar excess), or PI31 (232-251) peptide (10 μM), using Z-LLE-AMC as the fluorogenic substrate. C: Chymotryptic (β5) activity assay of human CP (10 nM) in the presence or absence of PI31 (37.5-fold molar excess), or PI31 (232-251) peptide (10uM), using suc-LLVY-AMC as the fluorogenic substrate. D: Sequence conservation of the yeast and human PI31 peptides. E: β2 activity assay comparing the inhibitory capacity of the yeast Fub1 (213-232) peptide (100 μM) and the human PI31 (232-251) peptide (100 μM) against human 20S CP (10nM). F: β2 activity assay with human 20S CP (10 nM) comparing the inhibitory capability of PI31 (232-251) peptide (50 μM) to a PI31-R242H (232-251) peptide (50 μM) that contains a mutation linked to late-onset Alzheimer’s disease patients. In panels a-c and e-f, error bars represent standard deviations from biological duplicates. FIG.3 shows the identification of PI31 Residues Sufficient for Inhibition of the β5 Site. A: Sequence alignment between yeast and human PI31. The P1 and P1’ residues of Fub1, as determined by structural analysis, are indicated. The putative P1 and P1' residues in human PI31 are also shown. B: Structure of yeast (left panel) and microsporidian (right panel) PI31 bound to the β5 active site pocket. Note that the P1 and P1' residues are separated into different polypeptides in yeast, thereby preventing proteolytic cleavage. In contrast, the P1 and P1' residues in microsporidian PI31 derive from the same polypeptide but are separated by intervening residues that loop away from the active site, again helping PI31 to evade proteolysis. Yeast, PDB: 7TEO. Microsporidian, PDB: 8ADN. Dashed lines represent unresolved residues. C: Enzymatic activity of the β5 active site, as determined using the fluorogenic substrate suc-LLVY-AMC with human 20S CP (10 nM) in the Attorney Docket No.29618-0443WO1 presence or absence of PI31 (37.5-fold molar excess), or PI31 (190-212) peptides at various concentrations. D: Enzymatic activity of the β1 active site, as determined using the fluorogenic substrate Z-LLE-AMC with human CP (10 nM) in the presence or absence of PI31 (37.5-fold molar excess) or PI31 (190-212) peptides (100 μM). E: Enzymatic activity of the β2 active site, as determined using the fluorogenic substrate Boc-LRR-AMC with human CP (10 nM) in the presence or absence of PI31 (37.5-fold molar excess) or PI31 (190-212) peptides (100 μM). FIG. 4 shows the selectivity of inhibition of the β2 active site. A: Human 20S proteasome (10 nM) enzymatic activity at the β2, β1, and β5 active sites in the absence or presence of PGARFL-Boro at varying concentrations. The three fluorogenic substrates used for each active site were Boc-LRR-AMC (β2), Z-LLE-AMC (β1), and suc-LLVY- AMC (β5). B: Human CP (10 nM) β2 enzymatic activity in presence or absence of various inhibitors (all at 100 nM), as measured using the Boc-LRR-AMC fluorogenic substrate. C: Enzymatic activity of human CP (10 nM) at all three active sites in the presence or absence of ARFL-boro at various concentrations. FIG.5 shows that the ARFL-Boro is Strongly Cytotoxic to Multiple Myeloma Cells in Culture, Both as a Standalone Agent and Synergistically with Bortezomib. A: MM.1S cells were treated with varying concentrations of ARFL-boro or bortezomib, incubated for 24 hours, and assayed for cell viability using the CellTiter-Glo method. Dose-response curves show the average percentage of metabolically active cells remaining relative to untreated controls. Error bars represent biological duplicates. B: MM.1S cells were treated with a combination of bortezomib (2 nM) and ARFL-boro (varying concentrations), incubated for 24 hours, and assayed for cell viability. Results were plotted as in panel a. Error bars represent biological duplicates. C: Accumulation of ubiquitin conjugates in treated MM.1S cells, as determined by SDS-PAGE and immunoblotting with anti-ubiquitin or GAPDH (loading control) antibodies. D: RPMI-8226 cells were treated with varying concentrations of ARFL-boro or bortezomib, incubated for 24 hours, and assayed for cell viability using the CellTiter-Glo method. Dose-response curves show the average percentage of metabolically active cells remaining relative to untreated controls. Error bars represent biological duplicates. Note that for panels a, b, and d, the standard deviations for Attorney Docket No.29618-0443WO1 some data points are too small to see in the graph. E: Combination Index plot of ARFL- boro and bortezomib. FIG. 6 shows a direct comparison of ARFL-Boro and Bortezomib. Enzymatic activity of human CP (5 nM) at the β2, β1, and β5 active sites after treatment with ARFL- Boro (panel A) or Bortezomib (panel B) at the indicated concentrations. FIG. 7 shows data from inhibition assays with ACanFL-boro, and ACitFL-boro. A: Human CP (5 nM) enzymatic activity at β2, β1, and β5 in the presence of ACanFL- boro. B: β2 activity of human CP (5 nM) in the presence of ACitFL-boro at varying concentrations. C: Direct comparison of the inhibitory effect of ARFL-boro, ACanFL- boro, and ACitFL-boro on human CP (5nM). D and E: MM.1S cells were treated with varying concentrations of ACanFL-boro or bortezomib and assayed for cell viability using the CellTiter-Glo method. Plotted is the percentage of metabolically active cells remaining relative to untreated controls. Error bars represent standard deviations from biological duplicates with some being too small to see in the graphs. FIG.8 shows the inhibition of ARFL-Epoxyketone Inhibitor of the β2 Active Site. Enzymatic activity of human CP (5 nM) at the β2, β1, and β5 active sites in the absence or presence of ARFL-epoxyketone at varying concentrations. The three fluorogenic substrates were Boc-LRR-AMC (β2), Z-LLE-AMC (β1), and suc-LLVY-AMC (β5). \ FIG. 9 shows that the ARFL-Boro is Strongly Cytotoxic to a Series of Human Cancer Cell Lines. A: Plot of IC50of ARFL-boro against human cancer cell lines. B: Plot of IC50of ARFL- boro against human cancer cell lines ARFL-boro is most active against. FIG. 10 shows the combination effect of vincristine and ARFL-boro on Molt-4 cells. A: Dose-response curve for ARFL-boro. B: Dose-response curve for ARFL-boro and vincristine. C: Dose-response matrix for ARFL-boro and vincristine. D: Bliss synergy score heatmap for ARFL-boro and vincristine. FIG.11 shows the combination effect of sorafenib and ARFL-boro on 786-O cells. A: Dose-response curve for ARFL-boro. B: Dose-response curve for ARFL-boro and sorafenib. C: Dose-response matrix for ARFL-boro and sorafenib. D: Bliss synergy score heatmap for ARFL-boro and sorafenib. FIG. 12 shows the combination effect of everolimus and ARFL-boro on 786-O cells. A: Dose-response curve for ARFL-boro. B: Dose-response curve for ARFL-boro Attorney Docket No.29618-0443WO1 and everolimus. C: Dose-response matrix for ARFL-boro and everolimus. D: Bliss synergy score heatmap for ARFL-boro and everolimus. FIG. 13 shows the combination effect of bortezomib and ARFL-boro on Molt-4 cells. A: Dose-response curve for ARFL-boro. B: Dose-response curve for ARFL-boro and bortezomib. C: Dose-response matrix for ARFL-boro and bortezomib. D: Bliss synergy score heatmap for ARFL-boro and bortezomib. FIG. 14 shows the combination effect of bortezomib and ARFL-boro on 786-O cells. A: Dose-response curve for ARFL-boro. B: Dose-response curve for ARFL-boro and bortezomib. C: Dose-response matrix for ARFL-boro and bortezomib. D: Bliss synergy score heatmap for ARFL-boro and bortezomib. FIG.15 shows the combination effect of bortezomib and ARFL-boro on A498 cells. A: Dose-response curve for ARFL-boro. B: Dose-response curve for ARFL-boro and bortezomib. C: Dose-response matrix for ARFL-boro and bortezomib. D: Bliss synergy score heatmap for ARFL-boro and bortezomib. FIG.16 is a plot of dose response curves of test articles on several cell lines. DETAILED DESCRIPTION Proteasome inhibitors are a multi-billion-dollar class of drugs approved for the treatment multiple myeloma. Despite their success, current inhibitors have limitations in the majority of patients, such as, for example, therapeutic resistance and severe dose- limiting side effects. There are three proteasome inhibitors: bortezomib, carfilzomib, and ixazomib. Furthermore, although the proteasome has three distinct active sites (β1, β2, β5), all three drugs target the same site (β5). Herein, an endogenous proteasome inhibitor, PI31, that simultaneously targets all three active sites (Fig.1B) was identified. A high-resolution structure of this protein bound to proteasome facilitated a rational approach to proteasome inhibitor design and the development of a series of potent and specific β2 inhibitors derived from PI31. Compounds In some embodiments, the present disclosure provides a compound of Formula (I): Attorney Docket No.29618-0443WO1 or a X, Y, each R1, R2, R3, R4, R5, R6, and R7are as described herein. In some embodiments, each R1is independently hydrogen or C1-C8 alkyl. In some embodiments, R2, R3, R4, R5, R6, and R7are selected from hydrogen, C1-C12alkyl, C3-C12alkenyl, C1-C12alkylOH, C1-C12alkylSH, C1- C4alkylSCH3, C1-C4alkylCONH2, C1-C4alkylCOOH, C1-C4alkylNH2, C1- C4 alkylNHC(NH)NH2, C1-C4 alkylONHC(NH)NH2, C1-C4 alkylNHC(O)NH2, C1-C4 alkyl (C3-C6cycloalkyl), C1-C4alkyl (3 to 10-membered heterocyclic), C1-C4alkyl (C6- C10aryl)RA, C1-C4alkyl ( 5 to 10-membered heteroaryl), and C1-C12alkyl)(W)C1-C12alkyl. In some embodiments, W is a heteroatom selected from N, S and O. In some embodiments, R2and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R3and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R4and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R5and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R6and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R7and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, RAis selected from H, OH, halo, (C1-C7alkyl), (C2-C7 alkenyl), OCF3, NO2, CN, NC, O(C1-C7 alkyl), CO2H, CO2(C1-C7 alkyl), NH2, aryl, and heteroaryl. In some embodiments, X is B , wherein Rxis selected from hydrogen and C1-C8 alkyl. In some selected from H, an amino acid, and a polypeptide. In some embodiments, the present disclosure provides a compound of Formula (I) Attorney Docket No.29618-0443WO1 or a each R1is R2, R3, R4, R5, R6, and R7are selected from hydrogen, C1-C12 alkyl, C3-C12 alkenyl, C1-C12alkylOH, C1-C12alkylSH, C1-C4alkylSCH3, C1-C4alkylCONH2, C1- C4 alkylCOOH, C1-C4 alkylNH2, C1-C4 alkylNHC(NH)NH2, C1-C4 alkylONHC(NH)NH2, C1-C4 alkylNHC(O)NH2, C1-C4 alkyl (C3-C6 cycloalkyl), C1-C4 alkyl (3 to 10-membered heterocyclic), C1-C4alkyl (C6-C10aryl)RA, C1-C4alkyl ( 5 to 10-membered heteroaryl), and C1-C12 alkyl)(W)C1-C12 alkyl; wherein W is a heteroatom selected from N, S and O; or R2and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R3and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; and / or R4and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R5and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; and / or R6and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R7and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; RAis selected from H, OH, halo, (C1-C7 alkyl), (C2-C7 alkenyl), OCF3, NO2, CN, NC, O(C1-C7 alkyl), CO2H, CO2(C1-C7 alkyl), NH2, aryl, and heteroaryl; X is B(OH)2 or , wherein Rxis selected from hydrogen and C1-C8 alkyl; Y is selected from H, an amino acid, and a polypeptide. In some embodiments, the present disclosure provides a compound of Formula (I) (I) Attorney Docket No.29618-0443WO1 or a pharmaceutically acceptable salt thereof, wherein: each R1is independently hydrogen or C1-C8 alkyl; R2, R3, R4, R5, R6, and R7are selected from hydrogen, C1-C12alkyl, C3-C12alkenyl, C1-C12 alkylOH, C1-C12 alkylSH, C1-C4 alkylSCH3, C1-C4 alkylCONH2, C1- C4 alkylCOOH, C1-C4 alkylNH2, C1-C4 alkylNHC(NH)NH2, C1-C4 alkylONHC(NH)NH2, C1-C4alkylNHC(O)NH2, C1-C4alkyl (C3-C6cycloalkyl), C1-C4alkyl (3 to 10-membered heterocyclic), C1-C4alkyl (C6-C10aryl)RA, C1-C4alkyl ( 5 to 10-membered heteroaryl), and (C1-C12 alkyl)(W)C1-C12 alkyl; wherein W is a heteroatom selected from N, S, and O; or R2and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R3and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; and / or R4and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R5and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; and / or R6and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R7and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; RAis selected from H, OH, halo, (C1-C7 alkyl), (C2-C7 alkenyl), OCF3, NO2, CN, NC, O(C1-C7alkyl), CO2H, CO2(C1-C7alkyl), NH2, aryl, and heteroaryl; X is B(OH)2or , wherein Rxis selected from hydrogen and C1-C8alkyl; Y is selected from H, an amino acid, and a polypeptide. In some embodiments, the present disclosure provides a compound of Formula (II): or a R2, R3, R4, R5, R6, R7, R8, and R9is as described herein. In some embodiments, R2, R3, R4, R5, R8, and R9are Attorney Docket No.29618-0443WO1 selected from hydrogen C2-C12 alkyl, C1-C4 alkylSCH3, C1-C4 alkyl(C6-C10 aryl)R7, and C1-C4(5 to 10-membered heteroaryl); R6and R7are selected from H, C2-C12alkylOH, C2-C12alkylSH, C1- C4 alkylCONH2, C1-C4 COOH, C1-C4 NH2, C1-C4 NHC(NH)NH2, C1- C4 alkylONHC(NH)NH2, C1-C4 alkylNHC(O)NH2, and C1-C4 (5 to 10-membered heteroaryl). In some embodiments, RAis selected from H, OH, halo, (C1-C7alkyl), (C2-C7alkenyl), OCF3, NO2, CN, NC, O(C1-C7alkyl), CO2H, CO2(C1-C7alkyl), NH2, aryl, and heteroaryl. In some embodiments, X is B(OH)2 or , wherein Rxis selected from hydrogen and C1-C8 alkyl. In some embodiments, Y is selected from H, an amino acid, or a polypeptide. In some embodiments, the present disclosure provides a compound of Formula (Ia) or a R2, R3, R4, R5, R6, R7, R8and R9are selected from hydrogen, C1-C12alkyl, C3- C12 alkenyl, C1-C12 alkylOH, C1-C12 alkylSH, C1-C4 alkylSCH3, C1-C4 alkylCONH2, C1- C4 alkylCOOH, C1-C4 alkylNH2, C1-C4 alkylNHC(NH)NH2, C1-C4 alkylONHC(NH)NH2, C1-C4alkylNHC(O)NH2, C1-C4alkyl (C3-C6cycloalkyl), C1-C4alkyl (3 to 10-membered heterocyclic), C1-C4alkyl (C6-C10aryl)RA, C1-C4alkyl (5 to 10-membered heteroaryl), and C1-C12 alkyl)(W)C1-C12 alkyl; wherein W is a heteroatom selected from N, S, and O; or R2and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R3and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; and / or R4and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R5and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; and / or Attorney Docket No.29618-0443WO1 R6and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R7and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; and / or R8and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R9and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; RAis selected from H, OH, halo, (C1-C7alkyl), (C2-C7alkenyl), OCF3, NO2, CN, NC, O(C1-C7 alkyl), CO2H, CO2(C1-C7 alkyl), NH2, aryl, and heteroaryl; X is B(OH)2 or , wherein Rxis selected from hydrogen and C1-C8 alkyl; Y is selected from H, an amino acid, and a polypeptide. In some embodiments, the present disclosure provides a compound of Formula (II) or a R2, R3, R4, R5, R8, and R9are selected from hydrogen, C1-C12alkyl, C1- C4 alkylSCH3, C1-C4 alkyl(C6-C10 aryl)R7, and C1-C4(5 to 10-membered heteroaryl); R6and R7are selected from H, C2-C12 alkylOH, C2-C12 alkylSH, C1- C4alkylCONH2, C1-C4COOH, C1-C4NH2, C1-C4NHC(NH)NH2, C1- C4alkylONHC(NH)NH2, C1-C4alkylNHC(O)NH2,and C1-C4(5 to 10-membered heteroaryl); RAis selected from H, OH, halo, (C1-C7alkyl), (C2-C7alkenyl), OCF3, NO2, CN, NC, O(C1-C7alkyl), CO2H, CO2(C1-C7alkyl), NH2, aryl, and heteroaryl; X is B(OH)2 or , wherein Rxis selected from hydrogen and C1-C8 alkyl; Y is selected from H, an amino acid, or a polypeptide. In some embodiments, the present disclosure provides a compound of Formula (IIa) Attorney Docket No.29618-0443WO1 or a R2, R3, and C1- C4alkyl(C6-C10aryl)R7; R6and R7are independently selected from H, C1-C4 NHC(NH)NH2, C1- C4alkylONHC(NH)NH2, and C1-C4alkylNHC(O)NH2; X is B(OH)2or , wherein Rxis selected from hydrogen and C1-C8alkyl; Y is selected from H, an amino acid, or a polypeptide. In some embodiments, the present disclosure provides a compound of Formula (IIb) or a R2and R3are selected from hydrogen and C1-C4 alkyl; R4and R5are selected from hydrogen and C1-C4 alkyl(C6-C10 aryl)R7; R6and R7are selected from H, C1-C4NHC(NH)NH2, C1-C4alkylONHC(NH)NH2, and C1-C4alkylNHC(O)NH2; R8and R9are selected from hydrogen and C1-C4 alkyl; X is B(OH)2 or , wherein Rxis selected from hydrogen and C1-C8 alkyl; Y is selected from H, an amino acid, or a polypeptide. In some embodiments, the present disclosure provides a compound of Formula (IIc) Attorney Docket No.29618-0443WO1 or a one of one of R4and R5is hydrogen and the other of R4and R5is –CH2-Ph; one of R6and R7is hydrogen and the other of R6and R7is selected from - CH2CH2CH2NHC(NH)NH2, -CH2CH2ONHC(NH)NH2, and -CH2CH2CH2NHC(O)NH2; one of R8and R9is hydrogen and the other of R8and R9is methyl; , wherein Rxis selected from hydrogen and C1-C8alkyl; amino acid, or a polypeptide. In some embodiments, the present disclosure provides a compound of Formula (IIc) or a one of R2and R3is hydrogen and the other of R2and R3is isobutyl; one of R4and R5is hydrogen and the other of R4and R5is –CH2-Ph; one of R6and R7is hydrogen and the other of R6and R7is selected from - CH2CH2CH2NHC(NH)NH2, -CH2CH2ONHC(NH)NH2, and -CH2CH2CH2NHC(O)NH2; one of R8and R9is hydrogen and the other of R8and R9is methyl; ; -Gly-Pro, -Gly-Pro-Pro, and -Gly-Pro-Pro-Val-Ala. In some embodiments, each R1is hydrogen. Attorney Docket No.29618-0443WO1 In some embodiments, the R1closest to X is hydrogen. In some embodiments, the R1closest to X is C1-C8 alkyl. In some embodiments, the R1closest to X is C1-C3 alkyl. In some embodiments, the R1closest to X is methyl. In some embodiments, the R1second closest to X is hydrogen. In some embodiments, the R1second closest to X is C1-C8 alkyl. In some embodiments, the R1second closest to X is C1-C3alkyl. In some embodiments, the R1second closest to X is methyl. In some embodiments, the R1third closest to X is hydrogen. In some embodiments, the R1third closest to X is C1-C8alkyl. In some embodiments, the R1third closest to X is C1-C3alkyl. In some embodiments, the R1third closest to X is methyl. In some embodiments, the R1fourth closest to X is hydrogen. In some embodiments, the R1fourth closest to X is C1-C8 alkyl. In some embodiments, the R1fourth closest to X is C1-C3alkyl. In some embodiments, the R1fourth closest to X is methyl. In some embodiments, R2and R3are independently selected from hydrogen, C1- C12alkyl, and C1-C4alkyl(C6-C10aryl)R7. In some embodiments, R2and R3are independently selected from hydrogen and C1-C12alkyl. In some embodiments, R2and R3are independently selected from hydrogen and C1-C4 alkyl. In some embodiments, R2and R3are independently selected from H, CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, CH2CH2SCH3, CH2(C6-aryl)RA, and CH2heteroaryl. In some embodiments, R2and R3are independently selected from H and CH2CH(CH3)2. In some embodiments, R4and R5are independently selected from hydrogen, C1- C12alkyl, and C1-C4alkyl(C6-C10aryl)R7. In some embodiments, R4and R5are independently selected from hydrogen and C1-C4 alkyl(C6-C10 aryl)R7. In some embodiments, R4and R5are independently selected from hydrogen and C1-C4 alkyl-Ph-R7. In some embodiments, R4and R5are independently selected from H, CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, CH2CH2SCH3, CH2(C6-aryl)RA, and CH2heteroaryl. In some embodiments, R4and R5are independently selected from H and CH2-phenyl. In some embodiments, R6and R7are independently selected from H, CH2(C0- C10alkyl)OH, CH2(C0-C10alkyl)SH, CH2(C0-C3alkyl)CONH2, CH2(C0-C3alkyl)COOH, CH2(C0-C3 alkyl)NH2, CH2(C0-C3 alkyl)NHC(NH)NH2, C1-C4 alkylONHC(NH)NH2, C1- Attorney Docket No.29618-0443WO1 C4 alkylNHC(O)NH2, and CH2(C1-C3 alkyl)(C3-C9 heteroaryl). In some embodiments, R6and R7are independently selected from H, CH2(C0-C3 alkyl)CONH2, CH2(C0- C3alkyl)COOH, CH2(C0-C3alkyl)NHC(NH)NH2, C1-C4alkylONHC(NH)NH2, and C1- C4 alkylNHC(O)NH2. In some embodiments, R6and R7are independently selected from H, CH2(C0-C3 alkyl)NHC(NH)NH2, C1-C4 alkylONHC(NH)NH2, and C1- C4alkylNHC(O)NH2. In some embodiments, R6and R7are independently selected from H, C1-C4NHC(NH)NH2, C1-C4alkylONHC(NH)NH2, and C1-C4alkylNHC(O)NH2In some embodiments, R6and R7are independently selected from H and (CH2)3NHC(NH)NH2. In some embodiments, R6and R7are independently selected from H and (CH2)3NHC(O)NH2. In some embodiments, R6and R7are independently selected from H and (CH2)2ONHC(NH)NH2. In some embodiments, R8and R9are independently selected from hydrogen and C1-C12alkyl. In some embodiments, R8and R9are independently selected from hydrogen and C1-C4 alkyl. In some embodiments, R8and R9are independently selected from H, CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, CH2CH2SCH3, CH2(C6-aryl)RA, and CH2heteroaryl. In some embodiments, R8and R9are independently selected from H and CH3. In some embodiments, R2and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R3and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R2and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R3and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R4and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R5and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R4and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R5and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R6and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R7and an R1on an adjacent N atom Attorney Docket No.29618-0443WO1 together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R6and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R7and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R8and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R9and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R8and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R9and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, R2is hydrogen. In some embodiments, R2is C1-C12 alkyl. In some embodiments, R2is C3-C12 alkenyl. In some embodiments, R2is C1-C12 alkylOH. In some embodiments, R2is C1-C12alkylSH. In some embodiments, R2is C1-C4alkylSCH3. In some embodiments, R2is C1-C4 alkylCONH2. In some embodiments, R2is C1- C4 alkylCOOH. In some embodiments, R2is C1-C4 alkylNH2. In some embodiments, R2is C1-C4alkylNHC(NH)NH2. In some embodiments, R2is C1-C4alkylONHC(NH)NH2. In some embodiments, R2is C1-C4alkylNHC(O)NH2. In some embodiments, R2is C1- C4 alkyl(C3-C6 cycloalkyl). In some embodiments, R2is C1-C4 alkyl(3 to 10-membered heterocyclic). In some embodiments, R2is C1-C4alkyl (C6-C10aryl)RA. In some embodiments, R2is C1-C4alkyl(5 to 10-membered heteroaryl). In some embodiments, R2is (C1-C12 alkyl)(W)C1-C12 alkyl. In some embodiments, R3is hydrogen. In some embodiments, R3is C1-C12alkyl. In some embodiments, R3is C3-C12alkenyl. In some embodiments, R3is C1-C12alkylOH. In some embodiments, R3is C1-C12 alkylSH. In some embodiments, R3is C1-C4 alkylSCH3. In some embodiments, R3is C1-C4 alkylCONH3. In some embodiments, R3is C1- C4alkylCOOH. In some embodiments, R3is C1-C4alkylNH3. In some embodiments, R3is C1-C4 alkylNHC(NH)NH3. In some embodiments, R3is C1-C4 alkylONHC(NH)NH3. In some embodiments, R3is C1-C4 alkylNHC(O)NH3. In some embodiments, R3is C1- C4alkyl(C3-C6cycloalkyl). In some embodiments, R3is C1-C4alkyl(3 to 10-membered heterocyclic). In some embodiments, R3is C1-C4alkyl (C6-C10aryl)RA. In some Attorney Docket No.29618-0443WO1 embodiments, R3is C1-C4 alkyl(5 to 10-membered heteroaryl). In some embodiments, R3is (C1-C12 alkyl)(W)C1-C12 alkyl. In some embodiments, R4is hydrogen. In some embodiments, R4is C1-C12alkyl. In some embodiments, R4is C3-C12 alkenyl. In some embodiments, R4is C1-C12 alkylOH. In some embodiments, R4is C1-C12 alkylSH. In some embodiments, R4is C1-C4 alkylSCH3. In some embodiments, R4is C1-C4alkylCONH4. In some embodiments, R4is C1- C4alkylCOOH. In some embodiments, R4is C1-C4alkylNH4. In some embodiments, R4is C1-C4 alkylNHC(NH)NH4. In some embodiments, R4is C1-C4 alkylONHC(NH)NH4. In some embodiments, R4is C1-C4alkylNHC(O)NH4. In some embodiments, R4is C1- C4alkyl(C3-C6cycloalkyl). In some embodiments, R4is C1-C4alkyl(3 to 10-membered heterocyclic). In some embodiments, R4is C1-C4 alkyl (C6-C10 aryl)RA. In some embodiments, R4is C1-C4 alkyl(5 to 10-membered heteroaryl). In some embodiments, R4is (C1-C12alkyl)(W)C1-C12alkyl. In some embodiments, R5is hydrogen. In some embodiments, R5is C1-C12 alkyl. In some embodiments, R5is C3-C12 alkenyl. In some embodiments, R5is C1-C12 alkylOH. In some embodiments, R5is C1-C12alkylSH. In some embodiments, R5is C1-C4alkylSCH3. In some embodiments, R5is C1-C4alkylCONH5. In some embodiments, R5is C1- C4 alkylCOOH. In some embodiments, R5is C1-C4 alkylNH5. In some embodiments, R5is C1-C4alkylNHC(NH)NH5. In some embodiments, R5is C1-C4alkylONHC(NH)NH5. In some embodiments, R5is C1-C4alkylNHC(O)NH5. In some embodiments, R5is C1- C4 alkyl(C3-C6 cycloalkyl). In some embodiments, R5is C1-C4 alkyl(3 to 10-membered heterocyclic). In some embodiments, R5is C1-C4alkyl (C6-C10aryl)RA. In some embodiments, R5is C1-C4alkyl(5 to 10-membered heteroaryl). In some embodiments, R5is (C1-C12 alkyl)(W)C1-C12 alkyl. In some embodiments, R6is hydrogen. In some embodiments, R6is C1-C12 alkyl. In some embodiments, R6is C3-C12alkenyl. In some embodiments, R6is C1-C12alkylOH. In some embodiments, R6is C1-C12 alkylSH. In some embodiments, R6is C1-C4 alkylSCH3. In some embodiments, R6is C1-C4 alkylCONH6. In some embodiments, R6is C1- C4alkylCOOH. In some embodiments, R6is C1-C4alkylNH6. In some embodiments, R6is C1-C4alkylNHC(NH)NH6. In some embodiments, R6is C1-C4alkylONHC(NH)NH6. In some embodiments, R6is C1-C4 alkylNHC(O)NH6. In some embodiments, R6is C1- Attorney Docket No.29618-0443WO1 C4 alkyl(C3-C6 cycloalkyl). In some embodiments, R6is C1-C4 alkyl(3 to 10-membered heterocyclic). In some embodiments, R6is C1-C4 alkyl (C6-C10 aryl)RA. In some embodiments, R6is C1-C4alkyl(6 to 10-membered heteroaryl). In some embodiments, R6is (C1-C12 alkyl)(W)C1-C12 alkyl. In some embodiments, R7is hydrogen. In some embodiments, R7is C1-C12 alkyl. In some embodiments, R7is C3-C12alkenyl. In some embodiments, R7is C1-C12alkylOH. In some embodiments, R7is C1-C12alkylSH. In some embodiments, R7is C1-C4alkylSCH3. In some embodiments, R7is C1-C4 alkylCONH7. In some embodiments, R7is C1- C4alkylCOOH. In some embodiments, R7is C1-C4alkylNH7. In some embodiments, R7is C1-C4alkylNHC(NH)NH7. In some embodiments, R7is C1-C4alkylONHC(NH)NH7. In some embodiments, R7is C1-C4 alkylNHC(O)NH7. In some embodiments, R7is C1- C4 alkyl(C3-C6 cycloalkyl). In some embodiments, R7is C1-C4 alkyl(3 to 10-membered heterocyclic). In some embodiments, R7is C1-C4alkyl (C6-C10aryl)RA. In some embodiments, R7is C1-C4 alkyl(7 to 10-membered heteroaryl). In some embodiments, R7is (C1-C12 alkyl)(W)C1-C12 alkyl. In some embodiments, R8is hydrogen. In some embodiments, R8is C1-C12alkyl. In some embodiments, R8is C3-C12alkenyl. In some embodiments, R8is C1-C12alkylOH. In some embodiments, R8is C1-C12 alkylSH. In some embodiments, R8is C1-C4 alkylSCH3. In some embodiments, R8is C1-C4alkylCONH8. In some embodiments, R8is C1- C4alkylCOOH. In some embodiments, R8is C1-C4alkylNH8. In some embodiments, R8is C1-C4 alkylNHC(NH)NH8. In some embodiments, R8is C1-C4 alkylONHC(NH)NH8. In some embodiments, R8is C1-C4alkylNHC(O)NH8. In some embodiments, R8is C1- C4alkyl(C3-C6cycloalkyl). In some embodiments, R8is C1-C4alkyl(3 to 10-membered heterocyclic). In some embodiments, R8is C1-C4 alkyl (C6-C10 aryl)RA. In some embodiments, R8is C1-C4 alkyl(8 to 10-membered heteroaryl). In some embodiments, R8is (C1-C12alkyl)(W)C1-C12alkyl. In some embodiments, R9is hydrogen. In some embodiments, R9is C1-C12 alkyl. In some embodiments, R9is C3-C12 alkenyl. In some embodiments, R9is C1-C12 alkylOH. In some embodiments, R9is C1-C12alkylSH. In some embodiments, R9is C1-C4alkylSCH3. In some embodiments, R9is C1-C4alkylCONH9. In some embodiments, R9is C1- C4 alkylCOOH. In some embodiments, R9is C1-C4 alkylNH9. In some embodiments, R9is Attorney Docket No.29618-0443WO1 C1-C4 alkylNHC(NH)NH9. In some embodiments, R9is C1-C4 alkylONHC(NH)NH9. In some embodiments, R9is C1-C4 alkylNHC(O)NH9. In some embodiments, R9is C1- C4alkyl(C3-C6cycloalkyl). In some embodiments, R9is C1-C4alkyl(3 to 10-membered heterocyclic). In some embodiments, R9is C1-C4 alkyl (C6-C10 aryl)RA. In some embodiments, R9is C1-C4 alkyl(9 to 10-membered heteroaryl). In some embodiments, R9is (C1-C12alkyl)(W)C1-C12alkyl. In some embodiments, W is a heteroatom selected from N, S, and O. In some embodiments, W is a heteroatom selected from N and S. In some embodiments, W is a heteroatom selected from N and O. In some embodiments, W is a heteroatom selected from N and O. In some embodiments, W is N. In some embodiments, W is S. In some embodiments, W is O. In some embodiments, RAis selected from H, OH, halo, (C1-C7 alkyl), (C2-C7 alkenyl), OCF3, NO2, CN, NC, O(C1-C7alkyl), CO2H, CO2(C1-C7alkyl), NH2, aryl, and heteroaryl. In some embodiments, RAis selected from H, OH, halo, (C1-C7 alkyl), OCF3, NO2, CN, O(C1-C7 alkyl), CO2H, CO2(C1-C7 alkyl), and NH2. In some embodiments, RAis selected from H and OH. In some embodiments, RAis selected from H. In some embodiments, RAis OH. In some embodiments, RAis halo. In some embodiments, RAis (C1-C7 alkyl). In some embodiments, RAis (C2-C7alkenyl). In some embodiments, RAis OCF3. In some embodiments, RAis NO2. In some embodiments, RAis CN. In some embodiments, RAis NC. In some embodiments, RAis O(C1-C7 alkyl). In some embodiments, RAis CO2H. In some embodiments, RAis CO2(C1-C7alkyl). In some embodiments, RAis NH2. In some embodiments, RAis aryl. In some embodiments, RAis heteroaryl. In some embodiments, Y is H. In some embodiments, Y is an amino acid. In some embodiments, Y is a polypeptide. In some embodiments, the polypeptide comprises 2 to 10 amino acid residues. In some embodiments, the polypeptide comprises 3 to 10 amino acid residues. In some embodiments, the polypeptide comprises 2 to 8 amino acid residues. In some embodiments, the polypeptide comprises 3 to 8 amino acid residues. In some embodiments, the polypeptide comprises 2 to 5 amino acid residues. In some embodiments, the polypeptide comprises 2 to 4 amino acid residues. In some embodiments, the polypeptide comprises 2 to 3 amino acid residues. In some Attorney Docket No.29618-0443WO1 embodiments, the polypeptide comprises 3 to 5 amino acid residues. In some embodiments, the polypeptide comprises 3 to 4 amino acid residues. In some embodiments, the polypeptide comprises 3 to 6 amino acid residues. In some embodiments, the polypeptide comprises 4 to 5 amino acid residues. In some embodiments, the polypeptide comprises 4 to 6 amino acid residues. In some embodiments, the polypeptide comprises 5 to 6 amino acid residues. In some embodiments, the polypeptide comprises 2 amino acid residues. In some embodiments, the polypeptide comprises 3 amino acid residues. In some embodiments, the polypeptide comprises 4 amino acid residues. In some embodiments, the polypeptide comprises 5 amino acid residues. In some embodiments, the polypeptide comprises 6 amino acid residues. In some embodiments, the polypeptide comprises 7 amino acid residues. In some embodiments, the polypeptide comprises 8 amino acid residues. In some embodiments, the polypeptide comprises 9 amino acid residues. In some embodiments, the polypeptide comprises 10 amino acid residues. In some embodiments, Y is -Gly. In some embodiments, Y is -Ala. In some embodiments, Y is -Ile. In some embodiments, Y is -Leu. In some embodiments, Y is -Pro. In some embodiments, Y is -Val. In some embodiments, Y is -Phe. In some embodiments, Y is -Trp. In some embodiments, Y is -Tyr. In some embodiments, Y is -Asp. In some embodiments, Y is -Glu. In some embodiments, Y is -Arg. In some embodiments, Y is - His. In some embodiments, Y is -Lys. In some embodiments, Y is -Ser. In some embodiments, Y is -Thr. In some embodiments, Y is -Cys. In some embodiments, Y is - Met. In some embodiments, Y is -Asn. In some embodiments, Y is -Gln. In some embodiments, Y is -Gly-Pro. In some embodiments, Y is -Gly-Pro-Pro. In some embodiments, Y is -Gly-Pro-Pro-Ala. In some embodiments, Y is -Gly-Pro-Pro-Val. In some embodiments, Y is -Gly-Pro-Pro-Val-Ala. In some embodiments, Y is -Ala-Gly. In some embodiments, Y is -Ala-Gly-Pro. In some embodiments, Y is -Ala-Gly-Pro-Pro. In some embodiments, Y is -Ala-Gly-Pro-Pro- Ala. In some embodiments, Y is -Ala-Gly-Pro-Pro-Val. In some embodiments, Y is -Ala- Gly-Pro-Pro-Val-Ala. In some embodiments, the amino acid is represented by Formula (A) below: Attorney Docket No.29618-0443WO1 R1Ais hydrogen or C 1-C8 R2Aand R3Aare independently selected from hydrogen, C1-C12 alkyl, C3- C12alkenyl, C1-C12alkylOH, C1-C12alkylSH, C1-C4alkylSCH3, C1-C4alkylCONH2, C1- C4 alkylCOOH, C1-C4 alkylNH2, C1-C4 alkylNHC(NH)NH2, C1-C4 alkylONHC(NH)NH2, C1-C4 alkylNHC(O)NH2, C1-C4 alkyl (C3-C6 cycloalkyl), C1-C4 alkyl (3 to 10-membered heterocyclic), C1-C4alkyl (C6-C10aryl)RA’, C1-C4alkyl ( 5 to 10-membered heteroaryl), and (C1-C12alkyl)(W’)C1-C12alkyl; wherein W’ is a heteroatom selected from N, S, and O; or R1Aand R2Atogether with the atoms to which they are attached form a pyrrolidine ring, or R1Aand an R3Atogether with the atoms to which they are attached form a pyrrolidine ring; and RA’is selected from H, OH, halo, (C1-C7 alkyl), (C2-C7 alkenyl), OCF3, NO2, CN, NC, O(C1-C7alkyl), CO2H, CO2(C1-C7alkyl), NH2, aryl, and heteroaryl. In some embodiments, R1Ais hydrogen. In some embodiments, R1Ais C1-C8 alkyl. In some embodiments, R1Ais C1-C3 alkyl. In some embodiments, R1Ais methyl. In some embodiments, R2Ais hydrogen. In some embodiments, R2Ais C1-C12alkyl. In some embodiments, R2Ais C2-C12alkenyl. In some embodiments, R2Ais C1- C12 alkylOH. In some embodiments, R2Ais C1-C12 alkylSH. In some embodiments, R2Ais C1-C4alkylSCH3. In some embodiments, R2Ais C1-C4alkylCONH2. In some embodiments, R2Ais C1-C4alkylCOOH. In some embodiments, R2Ais C1-C4alkylNH2. In some embodiments, R2Ais C1-C4 alkylNHC(NH)NH2. In some embodiments, R2Ais C1- C4 alkylONHC(NH)NH2. In some embodiments, R2Ais C1-C4 alkylNHC(O)NH2. In some embodiments, R2Ais C1-C4alkyl(C3-C6cycloalkyl). In some embodiments, R2Ais C1- C4 alkyl(3 to 10-membered heterocyclic). In some embodiments, R2Ais C1-C4 alkyl (C6- C10 aryl)RA. In some embodiments, R2Ais C1-C4 alkyl(5 to 10-membered heteroaryl). In some embodiments, R2Ais (C1-C12alkyl)(W)C1-C12alkyl. Attorney Docket No.29618-0443WO1 In some embodiments, R3Ais hydrogen. In some embodiments, R3Ais C1-C12 alkyl. In some embodiments, R3Ais C2-C12 alkenyl. In some embodiments, R3Ais C1- C12alkylOH. In some embodiments, R3Ais C1-C12alkylSH. In some embodiments, R3Ais C1-C4 alkylSCH3. In some embodiments, R3Ais C1-C4 alkylCONH2. In some embodiments, R3Ais C1-C4 alkylCOOH. In some embodiments, R3Ais C1-C4 alkylNH2. In some embodiments, R3Ais C1-C4alkylNHC(NH)NH2. In some embodiments, R3Ais C1- C4alkylONHC(NH)NH2. In some embodiments, R3Ais C1-C4alkylNHC(O)NH2. In some embodiments, R3Ais C1-C4 alkyl(C3-C6 cycloalkyl). In some embodiments, R3Ais C1- C4alkyl(3 to 10-membered heterocyclic). In some embodiments, R3Ais C1-C4alkyl (C6- C10aryl)RA. In some embodiments, R3Ais C1-C4alkyl(5 to 10-membered heteroaryl). In some embodiments, R3Ais (C1-C12 alkyl)(W)C1-C12 alkyl. In some embodiments, R1Aand R2Atogether with the atoms to which they are attached form a pyrrolidine ring, or R1Aand an R3Atogether with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, RA’is selected from H. In some embodiments, RA’is OH. In some embodiments, RA’is halo. In some embodiments, RA’is (C1-C7alkyl). In some embodiments, RA’is (C2-C7alkenyl). In some embodiments, RA’is OCF3. In some embodiments, RA’is NO2. In some embodiments, RA’is CN. In some embodiments, RA’is NC. In some embodiments, RA’is O(C1-C7alkyl). In some embodiments, RA’is CO2H. In some embodiments, RA’is CO2(C1-C7alkyl). In some embodiments, RA’is NH2. In some embodiments, RA’is aryl. In some embodiments, RA’is heteroaryl. In some embodiments, the polypeptide is represented by Formula (B) below: n is 2, 3, 4, 5, 6, 7, 8, each R1Bis independently selected from hydrogen or C1-C8alkyl; R1Cis hydrogen or C1-C8 alkyl; Attorney Docket No.29618-0443WO1 each R2Band R3Bis independently selected from hydrogen, C1-C12 alkyl, C3- C12 alkenyl, C1-C12 alkylOH, C1-C12 alkylSH, C1-C4 alkylSCH3, C1-C4 alkylCONH2, C1- C4alkylCOOH, C1-C4alkylNH2, C1-C4alkylNHC(NH)NH2, C1-C4alkylONHC(NH)NH2, C1-C4 alkylNHC(O)NH2, C1-C4 alkyl (C3-C6 cycloalkyl), C1-C4 alkyl (3 to 10-membered heterocyclic), C1-C4 alkyl (C6-C10 aryl)RA’’, C1-C4 alkyl ( 5 to 10-membered heteroaryl), and (C1-C12alkyl)(W’’)C1-C12alkyl; wherein each W’’ is independently selected from a heteroatom selected from N, S, and O; or R1Band an adjacent R2Btogether with the atoms to which they are attached form a pyrrolidine ring, or R1Band an adjacent R3Btogether with the atoms to which they are attached form a pyrrolidine ring; and RA’’is selected from H, OH, halo, (C1-C7 alkyl), (C2-C7 alkenyl), OCF3, NO2, CN, NC, O(C1-C7 alkyl), CO2H, CO2(C1-C7 alkyl), NH2, aryl, and heteroaryl. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 2 to 5. In some embodiments, n is 3 to 6. In some embodiments, n is 2 to 8. In some embodiments, at least one R1Bis hydrogen. In some embodiments, at least one R1Bis C1-C8alkyl. In some embodiments, at least one R1Bis C1-C3alkyl. In some embodiments, at least one R1Bis methyl. In some embodiments, at least one R2Bis hydrogen. In some embodiments, at least one R2Bis C1-C12alkyl. In some embodiments, at least one R2Bis C2-C12alkenyl. In some embodiments, at least one R2Bis C1-C12alkylOH. In some embodiments, at least one R2Bis C1-C12 alkylSH. In some embodiments, at least one R2Bis C1-C4 alkylSCH3. In some embodiments, at least one R2Bis C1-C4 alkylCONH2. In some embodiments, at least one R2Bis C1-C4alkylCOOH. In some embodiments, at least one R2Bis C1-C4alkylNH2. In some embodiments, at least one R2Bis C1-C4 alkylNHC(NH)NH2. In some embodiments, at least one R2Bis C1-C4 alkylONHC(NH)NH2. In some embodiments, at least one R2Bis C1-C4alkylNHC(O)NH2. In some embodiments, at least one R2Bis C1-C4alkyl(C3- C6cycloalkyl). In some embodiments, at least one R2Bis C1-C4alkyl(3 to 10-membered heterocyclic). In some embodiments, at least one R2Bis C1-C4 alkyl (C6-C10 aryl)RA. In Attorney Docket No.29618-0443WO1 some embodiments, at least one R2Bis C1-C4 alkyl(5 to 10-membered heteroaryl). In some embodiments, at least one R2Bis (C1-C12 alkyl)(W)C1-C12 alkyl. In some embodiments, at least one R3Bis hydrogen. In some embodiments, at least one R3Bis C1-C12 alkyl. In some embodiments, at least one R3Bis C2-C12 alkenyl. In some embodiments, at least one R3Bis C1-C12 alkylOH. In some embodiments, at least one R3Bis C1-C12alkylSH. In some embodiments, at least one R3Bis C1-C4alkylSCH3. In some embodiments, at least one R3Bis C1-C4alkylCONH2. In some embodiments, at least one R3Bis C1-C4 alkylCOOH. In some embodiments, at least one R3Bis C1-C4 alkylNH2. In some embodiments, at least one R3Bis C1-C4alkylNHC(NH)NH2. In some embodiments, at least one R3Bis C1-C4alkylONHC(NH)NH2. In some embodiments, at least one R3Bis C1-C4 alkylNHC(O)NH2. In some embodiments, at least one R3Bis C1-C4 alkyl(C3- C6 cycloalkyl). In some embodiments, at least one R3Bis C1-C4 alkyl(3 to 10-membered heterocyclic). In some embodiments, at least one R3Bis C1-C4alkyl (C6-C10aryl)RA. In some embodiments, at least one R3Bis C1-C4 alkyl(5 to 10-membered heteroaryl). In some embodiments, at least one R3Bis (C1-C12 alkyl)(W)C1-C12 alkyl. In some embodiments, R1Band an adjacent R2Btogether with the atoms to which they are attached form a pyrrolidine ring, or R1Band an adjacent R3Btogether with the atoms to which they are attached form a pyrrolidine ring. In some embodiments, at least one RA’’is selected from H. In some embodiments, at least one RA’’is OH. In some embodiments, at least one RA’’is halo. In some embodiments, at least one RA’’is (C1-C7 alkyl). In some embodiments, at least one RA’’is (C2-C7alkenyl). In some embodiments, at least one RA’’is OCF3. In some embodiments, at least one RA’’is NO2. In some embodiments, at least one RA’’is CN. In some embodiments, at least one RA’’is NC. In some embodiments, at least one RA’’is O(C1-C7 alkyl). In some embodiments, at least one RA’’is CO2H. In some embodiments, at least one RA’’is CO2(C1-C7alkyl). In some embodiments, at least one RA’’is NH2. In some embodiments, at least one RA’’is aryl. In some embodiments, at least one RA’’is heteroaryl. Attorney Docket No.29618-0443WO1 In some embodiments, X is B(OH)2. In some embodiments, X is . In some embodiments, X . In some embodiments, the absolute configuration of the carbon atom bonded to the –C(O)- group and the is (S). In some embodiments, the absolute configuration of the carbon –C(O)- group and the epoxide O in is (R). In some embodiments, the absolute configuration of the carbon atom bonded to the –C(O)- group and the epoxide O is (S). In some embodiments, the absolute configuration of the carbon atom the –C(O)- group and the epoxide O (R). In some embodiments, X is , wherein Rxis selected from hydrogen and C1-C3alkyl. In some embodiments, X , wherein Rxis selected from hydrogen and C1-C8alkyl. In some . In some compound is selected from the group consisting of: Attorney Docket No.29618-0443WO1 , , In some embodiments, the boro). Attorney Docket No.29618-0443WO1 Pharmaceutically acceptable salts In some embodiments, a salt of a compound of this disclosure is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. In some embodiments, the compound is a pharmaceutically acceptable acid addition salt. In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds of Formula (I) and Formula (II) include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- hydroxybutyrate, glycolate, maleate, tartrate, methanesu1fonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid. In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds of Formula (I) and Formula (II) include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, Attorney Docket No.29618-0443WO1 or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamine), such as N,N- dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D- glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. In some embodiments, the compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts thereof, are substantially pure (e.g., are at least 90% pure, at least 95% pure, at least 98% pure, at least 99% pure, or at least 99.5% pure). In some embodiments, the purity of the compound is measured using high-performance liquid chromatography by dividing the peak area of the compound by the combined peak areas. Pharmaceutical Compositions The present application also provides pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of the present disclosure (e.g., Formula (I) or Formula (II)) disclosed herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the composition. The present application also provides pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of the present disclosure (e.g., Formula (I) or Formula (II)) disclosed herein, or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; and a proteasome inhibitor. In some embodiments, the proteasome inhibitor is a β5 proteosome inhibitor. In some embodiments, the β5 proteosome inhibitor is selected from the group consisting of: bortezomib, carfilzomib, and ixazomib. In some embodiments, the β5 proteosome inhibitor is bortezomib. In some embodiments, the β5 proteosome inhibitor is carfilzomib. In some embodiments, the β5 proteosome inhibitor is ixazomib. Some embodiments provide a pharmaceutical composition comprising a compound of the present disclosure (e.g., Formula (I) or Formula (II)) disclosed herein, or a Attorney Docket No.29618-0443WO1 pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; and at least one of bortezomib, carfilzomib, and ixazomib. Some embodiments provide a pharmaceutical composition comprising a compound of the present disclosure (e.g., Formula (I) or Formula (II)) disclosed herein, or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; and bortezomib. Some embodiments provide a pharmaceutical composition comprising a compound of the present disclosure (e.g., Formula (I) or Formula (II)) disclosed herein, or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; and carfilzomib. Some embodiments provide a pharmaceutical composition comprising a compound of the present disclosure (e.g., Formula (I) or Formula (II)) disclosed herein, or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier; and ixazomib.

[0002] Attorney Docket No.29618-0443WO1 Methods of Use Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof is a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments of the methods described herein, compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof can be administered in combination with a β5 proteosome inhibitor. Examples of β5 proteosome inhibitors include, but are not limited to, bortezomib, carfilzomib, and ixazomib. In some embodiments, administration of a combination therapy comprising a compound of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof and a β5 proteosome inhibitor (such as those described herein) provide synergistic activity in the treatment of cancer, i.e., activity greater than the sum of activities of either agent when administered alone. Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (i) a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof; and (ii) a second therapeutic agent. In some embodiments, the cancer is a cancer of the immune system. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is a myeloma. Attorney Docket No.29618-0443WO1 In some embodiments, the cancer is multiple myeloma or mantle cell lymphoma. In some embodiments, the cancer is relapsed or refractory. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is non-Hodgkin lymphoma. In some embodiments, the cancer is mantle cell lymphoma. In some embodiments, the mantle cell lymphoma is classical mantle cell lymphoma. In some embodiments, the mantle cell lymphoma is leukemic non-nodal mantle cell lymphoma. In some embodiments, the mantle cell lymphoma is B cell lymphoma. In some embodiments, the multiple myeloma is relapsed or refractory. In some embodiments, the cancer is a blood cancer. In some embodiments, the cancer is leukemia. In some embodiments, the leukemia is acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). In some embodiments, the leukemia is acute lymphoblastic leukemia (ALL). In some embodiments, the leukemia is acute myelogenous leukemia (AML). In some embodiments, the AML is myeloid leukemia. In some embodiments, the AML is acute monocytic leukemia (AML-M5). In some embodiments, the AML is acute megakaryocytic leukemia (AMLK). In some embodiments, the AML is acute promyelocytic leukemia (APL). In some embodiments, the cancer is a kidney cancer. In some embodiments, the kidney cancer is renal cell carcinoma. In some embodiments, the renal cell carcinoma is clear (ccRCC). In some embodiments, the renal cell carcinoma is papillary renal cell carcinoma. In some embodiments, the renal cell carcinoma is chromophobe renal cell carcinoma. In some embodiments, the cancer is a stomach cancer. In some embodiments, the cancer is an adenocarcinoma. In some embodiments the adenocarcinoma is an intestinal adenocarcinoma. In some embodiments, the adenocarcinoma is a diffuse adenocarcinoma. In some embodiments, the cancer is multiple myeloma, mantle cell lymphoma, renal cell carcinoma, acute myelogenous leukemia, or acute lymphoblastic leukemia (AML). In some embodiments, the method further comprises administering a second therapeutic agent to the subject. Attorney Docket No.29618-0443WO1 In some embodiments, the second therapeutic agent is a proteasome inhibitor. In some embodiments, the proteasome inhibitor inhibits subunit β5. In some embodiments, the proteasome inhibitor inhibits subunit β5 selectively over subunit β2 and subunit β1. In some embodiments, the proteasome inhibitor inhibits subunit β2. In some embodiments, the proteasome inhibitor inhibits subunit β1. In some embodiments, the proteasome inhibitor inhibits subunit β5 and subunit β2. In some embodiments, the proteasome inhibitor inhibits subunit β1 and subunit β2. In some embodiments, the proteasome inhibitor inhibits subunit β5 and subunit β1. In some embodiments, the proteasome inhibitor inhibits subunit β5, subunit β1, and subunit β2. In some embodiments, the second therapeutic agent is selected from vincristine, sorafenib, everolimus, bortezomib, carfilzomib, ixazomib, and combinations thereof. In some embodiments, the second therapeutic agent is vincristine. In some embodiments, the second therapeutic agent is sorafenib. In some embodiments, the second therapeutic agent is everolimus. In some embodiments, the second therapeutic agent is bortezomib. In some embodiments, the second therapeutic agent is carfilzomib. In some embodiments, the second therapeutic agent is ixazomib. Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (i) a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof; and (ii) vincristine, sorafenib, everolimus, bortezomib, carfilzomib, ixazomib, or a combination thereof. Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (i) a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof; and (ii) bortezomib. Some embodiments provide a method of treating acute lymphoblastic leukemia or renal cell carcinoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (i) a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof; and (ii) bortezomib. Attorney Docket No.29618-0443WO1 Some embodiments provide a method of treating acute lymphoblastic leukemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (i) a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof; and (ii) bortezomib. Some embodiments provide a method of treating acute renal cell carcinoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (i) a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof; and (ii) bortezomib. Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (i) a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof; and (ii) carfilzomib. In some embodiments, the method comprises diagnosing the subject with cancer. Methods known in the art for diagnosing cancer include, but are not limited to, imaging techniques (e.g., computed tomography (CT), magnetic resonance imaging (MRI), radiographic testing (e.g., X-ray), nuclear medicine scanning, or ultrasound), blood tests, and analysis of a biopsy sample. In some embodiments, the method comprises determining that the cancer went into remission after the administering. In some embodiments, the remission is partial remission. In some embodiments, the method comprises reducing the number of cancer cells in the subject. In some embodiments, the method comprises measuring fewer cancer cells in the subject after the administering than before the administering. In some embodiments, the method comprises measuring at least 5% cells (e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%) fewer cancer in the subject after the administering than before the administering. In some embodiments, measuring fewer cancer cells in the subject comprises measuring fewer cancer cells in the subject according to an imaging technique, a blood test, or a biopsy analysis. In some embodiments, the imaging technique is selected from the group consisting of: computed tomography (CT), magnetic resonance imaging (MRI), radiographic testing (e.g., X-ray), nuclear medicine scanning, and ultrasound. In Attorney Docket No.29618-0443WO1 some embodiments, the imaging technique is CT. In some embodiments, the imaging technique is MRI. In some embodiments, the remission is complete remission. In some embodiments, the method comprises diagnosing or identifying the subject as having ALL. In some embodiments, diagnosing or identifying the subject as having ALL comprises obtaining a blood sample from the subject and measuring an abnormal number of white blood cells, red blood cells, or platelets in the blood sample; obtaining a bone marrow sample from the subject and detecting the presence of a leukemia cell in the bone marrow sample; obtaining a spinal fluid sample from the subject and detecting the presence of a leukemia cell in the spinal fluid sample; or a combination thereof. In this context, “abnormal number” refers to a value or range that is considered by a medical professional (e.g., a doctor (e.g., an oncologist), a scientist, a medical technician, a nurse, or a nurse practitioner) to fall outside the range found in a healthy subject at homeostasis. In some embodiments, an abnormal number of white blood cells is less than 4,000 white blood cells per ^L or greater than 11,000 white blood cells per ^L. In some embodiments, an abnormal number of red blood cells is less than 4,000,000 red blood cells per ^L or greater than 6,100,000 red blood cells per ^L. In some embodiments, an abnormal number of platelets is less than 150,000 platelets per ^L or greater than 400,000 platelets per ^L. In some embodiments, diagnosing or identifying the subject as having ALL comprises obtaining a blood sample from the subject and measuring an abnormal number of white blood cells, red blood cells, or platelets in the blood sample. In some embodiments, diagnosing or identifying the subject as having ALL comprises obtaining a bone marrow sample from the subject and detecting the presence of a leukemia cell in the bone marrow sample. In some embodiments, diagnosing or identifying the subject as having ALL comprises obtaining a spinal fluid sample from the subject and detecting the presence of a leukemia cell in the spinal fluid sample. In some embodiments, measuring an abnormal number of white blood cells, red blood cells, or platelets in the blood sample comprises measuring an abnormal number of white blood cells in the sample. In some embodiments, measuring an abnormal number of white blood cells, red blood cells, or platelets in the blood sample comprises measuring an abnormal number of red blood cells in the sample. In some embodiments, measuring an abnormal number of white blood cells, Attorney Docket No.29618-0443WO1 red blood cells, or platelets in the blood sample comprises measuring an abnormal number of platelets in the blood sample. In some embodiments, the method comprises measuring a white blood cell count in the subject that is about 4,000 to about 11,000 white blood cells per ^L after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject. In some embodiments, the method comprises measuring a white blood cell count in the subject that is about 4,000,000 to about 6,100,000 red blood cells per ^L after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject. In some embodiments, the method comprises measuring a white blood cell count in the subject that is about 150,000 to 400,000 platelets per ^L after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject. In some embodiments, the method comprises obtaining a bone marrow sample from the subject and detecting the absence of leukemia cells in the bone marrow sample after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject. In some embodiments, the method comprises obtaining a spinal fluid sample from the subject and detecting the absence of leukemia cells in the spinal fluid sample after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject. Some embodiments provide a method of reducing the number of leukemia cells in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In some embodiments, reducing the number of leukemia cells comprises reducing the number of leukemia cells in the bone marrow of the subject. In some embodiments, reducing the number of leukemia cells comprises reducing the number of leukemia cells in the spinal fluid of the subject. In some embodiments, the method comprises diagnosing or identifying the subject as having renal cell carcinoma. In some embodiments, diagnosing or identifying the subject as having renal cell carcinoma comprises detecting blood in the urine of the subject. In some embodiments, diagnosing or identifying the subject as having renal cell carcinoma comprises detecting cancer cells in the kidney of the subject. In some embodiments, detecting cancer cells in the kidney of the subject comprises detecting cancer cells in the Attorney Docket No.29618-0443WO1 kidney using an imaging technique or a biopsy analysis. In some embodiments, the imaging technique is selected from the group consisting of: computed tomography (CT), magnetic resonance imaging (MRI), radiographic testing (e.g., X-ray), nuclear medicine scanning, and ultrasound. In some embodiments, the method comprises measuring a lower concentration of blood in the urine of the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject than before the administering. In some embodiments, the method comprises measuring fewer cancer cells in a kidney of the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject than before the administering. In some embodiments, measuring fewer cancer cells in the kidney of the subject comprises measuring fewer cancer cells in the kidney of the subject using an imaging technique or a biopsy analysis. In some embodiments, the method comprises reducing pain in the flank of the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject than before the administering. In some embodiments, the method comprises reducing the frequency, severity, and / or duration of fever in the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject compared to before the administering. In some embodiments, the method comprises reducing the frequency, severity, and / or duration of nocturnal sweating in the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject compared to before the administering. In some embodiments, nocturnal sweating is sweating that occurs when the subject is sleeping. In some embodiments, nocturnal sweating is sweating that occurs between 9PM and 8AM (e.g., between 10PM and 7AM or between 12AM and 6AM) in the time zone that the subject is in. In some embodiments, the method comprises measuring a rate of weight change in the subject of less than 5 lb (e.g., less than 4 lb, less than 3 lb, less than 2 lb, or less than 1 lb) per month after administering the compound of Formula (I) or (II) or pharmaceutically Attorney Docket No.29618-0443WO1 acceptable salt thereof to the subject. In some embodiments, the weight change is weight loss. In some embodiments, the method comprises measuring a reduction in pain in the flank of the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject compared to before the administering. In some embodiments, the reduction in pain is measured using a visual analog scale (VAS). In some embodiments, the method comprises reducing the frequency, severity, and / or duration of dyspnea in the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject compared to before the administering. In some embodiments, the method comprises treating anemia in the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject. In some embodiments, the method comprises reducing the frequency, severity, and / or duration of fatigue in the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject compared to before the administering. Some embodiments provide a method of reducing the number of cancer cells in a kidney of a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In some embodiments, the method comprises diagnosing or identifying the subject as having multiple myeloma. In some embodiments, diagnosing or identifying the subject as having multiple myeloma comprises detecting the presence of an M protein or ^2- microglobulin in the subject. In some embodiments, diagnosing or identifying the subject as having multiple myeloma comprises detecting the presence of an M protein or ^2- microglobulin in the blood of the subject. In some embodiments, diagnosing or identifying the subject as having multiple myeloma comprises detecting the presence of an M protein in the urine of the subject. In some embodiments, diagnosing or identifying the subject as having multiple myeloma comprises detecting the presence of myeloma cells in the subject. Attorney Docket No.29618-0443WO1 In some embodiments, diagnosing or identifying the subject as having multiple myeloma comprises detecting the presence of myeloma cells in the bone marrow of the subject. In some embodiments, diagnosing or identifying the subject as having multiple myeloma comprises identifying a bone abnormality in the subject using an imaging technique. In some embodiments, the method comprises detecting the absence of myeloma cells in the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject. In some embodiments, the method comprises detecting the absence of myeloma cells in the bone marrow of the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject. In some embodiments, the method comprises detecting a reduction in M proteins in the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject compared to before the administering. In some embodiments, the method comprises detecting a reduction in M proteins in the urine or the blood of the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject compared to before the administering. In some embodiments, the method comprises detecting the absence of M proteins in the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject. In some embodiments, the method comprises detecting the absence of M proteins in the urine or the blood of the subject after administering the compound of Formula (I) or (II) or pharmaceutically acceptable salt thereof to the subject. Some embodiments provide a method of reducing M proteins in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Some embodiments provide a method of reducing myeloma cells in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Attorney Docket No.29618-0443WO1 In some embodiments, the method comprises diagnosing or identifying the subject as having mantle cell lymphoma. In some embodiments, diagnosing or identifying the subject as having mantle cell lymphoma comprises determining that the subject comprises CD5 positive cells, CD20 positive cells, CD positive cells, CD2 positive cells, CD10 negative cells, CD23 negative cells, cyclin D1 positive cells, cells that have 11;14 translocations, or any combination thereof. In some embodiments, diagnosing or identifying the subject as having mantle cell lymphoma comprises analyzing a biopsy sample from the subject and determining that the biopsy sample comprises CD5 positive cells, CD20 positive cells, CD positive cells, CD2 positive cells, CD10 negative cells, CD23 negative cells, cyclin D1 positive cells, cells that have 11;14 translocations, or any combination thereof. In some embodiments, diagnosing or identifying the subject as having mantle cell lymphoma comprises analyzing a biopsy sample from the subject and determining that the biopsy sample comprises CD positive cells, CD2 positive cells, CD10 negative cells, CD23 negative cells, or any combination thereof. In some embodiments, diagnosing or identifying the subject as having mantle cell lymphoma comprises analyzing a biopsy sample from the subject and determining that the biopsy sample comprises CD positive cells, CD2 positive cells, CD10 negative cells, and CD23 negative cells. In some embodiments, diagnosing or identifying the subject as having mantle cell lymphoma comprises determining that a lymph node of the subject has lymphadenopathy. In some embodiments, determining that the lymph node of the subject has lymphadenopathy is performed using positron emission tomography (PET). In some embodiments, diagnosing or identifying the subject as having mantle cell lymphoma comprises detecting lymphoma cells in the subject. In some embodiments, diagnosing or identifying the subject as having mantle cell lymphoma comprises detecting lymphoma cells in the spleen, a lymph node, the blood, the spinal fluid, or the bone marrow of the subject. In some embodiments, the method comprises treating anemia, thrombocytopenia, neutropenia, or any combination thereof in the subject. In some embodiments, the method comprises reducing swelling in a lymph node of the subject after the administering. In some embodiments, the method comprises reducing the volume of the spleen of the subject after the administering. In some embodiments, the method comprises reducing lymphoma cells in the subject after the administering. Attorney Docket No.29618-0443WO1 Some embodiments provide a method of treating anemia, thrombocytopenia, neutropenia, or any combination thereof in a subject diagnosed with mantle cell lymphoma. In some embodiments, the anemia, thrombocytopenia, neutropenia, or any combination thereof is anemia. In some embodiments, the anemia, thrombocytopenia, neutropenia, or any combination thereof is thrombocytopenia. In some embodiments, the anemia, thrombocytopenia, neutropenia, or any combination thereof is neutropenia. Some embodiments provide a method of reducing lymphoma cells in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In some embodiments, the method comprises reducing lymphoma cells in a lymph node in the subject. In some embodiments, the method comprises reducing lymphoma cells in a spleen of the subject. In some embodiments, the method comprises reducing lymphoma cells in the bone marrow of a subject. In some embodiments, the method comprises diagnosing or identifying the subject as having acute myelogenous leukemia (AML, also referred to herein as “acute myeloid leukemia”). In some embodiments, diagnosing or identifying the subject as having acute myelogenous leukemia comprises detecting myeloid cells in the subject. In some embodiments, detecting myeloid cells in the subject comprises detecting myeloid cells in the bone marrow, blood, or nervous system (e.g., central nervous system (e.g., brain or spinal cord)) of the subject. In some embodiments, detecting myeloid cells in the subject comprises detecting myeloid cells in the bone marrow of the subject. In some embodiments, detecting myeloid cells in the subject comprises detecting myeloid cells in the blood. In some embodiments, detecting myeloid cells in the subject comprises detecting myeloid cells in the nervous system (e.g., central nervous system (e.g., brain or spinal cord)) of the subject. In some embodiments, after the administering, the frequency, severity, and / or duration of one or more symptoms selected from the group consisting of dizziness, nosebleeds, fatigue, fever, nocturnal sweating, headache, loss of appetite, weight loss, pale Attorney Docket No.29618-0443WO1 skin, dyspnea, swollen lymph nodes, pain (e.g., bone pain, back pain, or abdominal pain), petechiae, sores, or any combination thereof in the subject are reduced. Some embodiments comprise reducing myeloid cells in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In some embodiments, the method comprises reducing myeloid cells in the bone marrow of the subject. In some embodiments, the method comprises reducing myeloid cells in the blood of the subject. In some embodiments, the method comprises reducing myeloid cells in the nervous system (e.g., central nervous system (e.g., brain or spinal cord)) of the subject. In some embodiments, after administering the compound of Formula (I) or Formula (II), the subject experiences gastrointestinal symptoms that are ameliorated by the consumption of food prior to administering the compound of Formula (I) or Formula (II). In some embodiments, the subject consumes food up to about 6 hours before administering the compound of Formula (I) or Formula (II). For example, the subject consumes food up to about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 30 minutes, about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, about 1 minute, about 30 seconds, or about 5 seconds before administering the compound of Formula (I) or Formula (II). For example, the subject consumes food concurrently with administering the compound of Formula (I) or Formula (II). Some embodiments provide a method of inhibiting mammalian cell proliferation, comprising contacting a mammalian cell with an effective amount of a compound of Formula (I) or Formula (II). In some embodiments, the contacting is performed in vivo. In some embodiments, the contacting is performed in a subject. In some embodiments, the contacting is performed ex vivo. In some embodiments, the contacting is performed in a tissue sample taken from the subject. In some embodiments, the tissue sample is a biopsy sample. In some embodiments, the inhibiting is performed in vitro. Attorney Docket No.29618-0443WO1 Definitions As used herein, the term "about" means "approximately" (e.g., plus or minus approximately 10% of the indicated value). The term “halo” or “halogen” refers to any radical of fluorine, chlorine, bromine or iodine. The term “alkyl” refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C6 alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. Any atom can be optionally substituted, e.g., by one or more substituents. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, and tert-butyl. The term “alkenyl” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds. Any atom can be optionally substituted, e.g., by one or more substituents. Alkenyl groups can include, e.g., vinyl, allyl, 1-butenyl, and 2-hexenyl. One of the double bond carbons can optionally be the point of attachment of the alkenyl substituent. The term “cycloalkyl” refers to a fully saturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon group. Any atom can be optionally substituted, e.g., by one or more substituents. A ring carbon serves as the point of attachment of a cycloalkyl group to another moiety. Cycloalkyl moieties can include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl (bicyclo[2.2.1]heptyl). The term “heterocyclyl” refers to a fully saturated monocyclic, bicyclic, tricyclic or other polycyclic ring system having one or more constituent heteroatom ring atoms independently selected from O, N (it is understood that one or two additional groups may be present to complete the nitrogen valence and / or form a salt), or S. The heteroatom (when valence allows) or ring carbon can be the point of attachment of the heterocyclyl substituent to another moiety. Any atom can be optionally substituted, e.g., by one or more substituents. Heterocyclyl groups can include groups such as tetrahydrofuryl, tetrahydropyranyl, piperidyl (piperidino), piperazinyl, morpholinyl (morpholino), pyrrolinyl, and pyrrolidinyl. By way of example, a phrase such as “heterocyclic ring containing from 5-6 ring atoms”, wherein from 1-2 of the ring atoms is independently Attorney Docket No.29618-0443WO1 selected from N, NH, N(C1-C6 alkyl), NC(O)(C1-C6 alkyl), O, and S; and wherein said heterocyclic ring is optionally substituted with from 1-3 independently selected Rawould include (but not be limited to) tetrahydrofuryl, tetrahydropyranyl, piperidyl (i.e., piperidino), piperazinyl, morpholinyl (i.e., morpholino), pyrrolinyl, and pyrrolidinyl. The term “aryl” refers to an aromatic monocyclic, bicyclic (2 fused rings), tricyclic (3 fused rings), or polycyclic (> 3 fused rings) hydrocarbon ring system, wherein one or more ring atoms are optionally substituted. Aryl moieties include groups such as, for example, phenyl and naphthyl. The term “heteroaryl” refers to an aromatic monocyclic, bicyclic (containing 2 fused rings), tricyclic (containing 3 fused rings), or polycyclic (containing > 3 fused rings) hydrocarbon group having one or more heteroatom ring atoms independently selected from O, N (it is understood that one or two additional groups may be present to complete the nitrogen valence and / or form a salt), or S. One or more ring atoms can be optionally substituted, e.g., by one or more substituents. Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, coumarinyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, and xanthenyl. The term “amino acid” refers to a naturally occurring or non-naturally occurring amino acid, an amino acid analog, or an amino acid mimetic that functions in a manner similar to that of a naturally occurring amino acid. When recited as part of a compound, it is understood that the amino acid is in the form of a univalent radical that bonds to the remainder of the compound from an atom having radical character resulting from the absence of an atom or a group normally present when the amino acid is in the form of a discrete molecule in which all valencies are full (for example, from the carbon atom of a carboxyl group after removal of a hydroxyl). In some embodiments, the amino acid is a naturally occurring or non-naturally occurring amino acid. Naturally occurring amino Attorney Docket No.29618-0443WO1 acids include the 20 common amino acids (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine) as well as amino acids that exist in some microorganisms (e.g., pyrrolysine and selenocysteine). An amino acid analog refers to a compound that has the same basic chemical structure as a naturally occurring amino acid, i.e., a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, such as, homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (such as norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acids include, for example, naturally occurring proteogenic L-amino acids; D-amino acids, chemically modified amino acids such as amino acid variants and derivatives; naturally occurring non- proteogenic amino acids such as β-alanine, ornithine, etc.; and chemically synthesized compounds having properties known in the art to be characteristic of amino acids. Examples of non-naturally occurring amino acids include, but are not limited to, α-methyl amino acids (e.g., α-methyl alanine), D-amino acids, histidine-like amino acids (e.g., 2- amino-histidine, β-hydroxy-histidine, homohistidine, α-fluoromethyl-histidine and α- methyl-histidine), amino acids having an extra methylene in the side chain (“homo” amino acids), and amino acids in which a carboxylic acid functional group in the side chain is replaced with a sulfonic acid group (e.g., cysteic acid). Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. The terms “polypeptide” and “peptide” are used interchangeably herein to refer to a polymer comprising (e.g., consisting of) residues of amino acids. When recited as part of a compound, it is understood that the polypeptide is in the form of a univalent radical that bonds to the remainder of the compound from an atom having radical character resulting from the absence of an atom or a group normally present when the polypeptide is in the form of a discrete molecule (for example, from the carbon atom of a carboxyl group after removal of a hydroxyl). The terms apply to polymers containing residues of naturally occurring amino acids as well as amino acid polymers in which one or more amino acid residues is a non-naturally occurring amino acid. As used herein, the terms encompass Attorney Docket No.29618-0443WO1 amino acid chains of any length, including full length proteins, wherein the amino acid residues are linked by covalent peptide bonds. The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated or synthesized as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R)-configuration. In some embodiments, the compound has the (S)- configuration. Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a Attorney Docket No.29618-0443WO1 cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal. As used herein, the term “subject” refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. In some embodiments, the subject is a human. As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (e.g., reversing the pathology and / or symptomatology). As used herein, the term “preventing” or “prevention” of a disease, condition or disorder refers to decreasing the risk of occurrence of the disease, condition or disorder in a subject or group of subjects (e.g., a subject or group of subjects predisposed to or susceptible to the disease, condition or disorder). In some embodiments, preventing a disease, condition or disorder refers to decreasing the probability of acquiring the disease, condition or disorder and / or its associated symptoms. In some embodiments, preventing a disease, condition or disorder refers to completely or almost completely stopping the disease, condition or disorder from occurring, wherein, for example, the subject is no longer diagnosed as having the disease, condition, or disorder.

[0003] Attorney Docket No.29618-0443WO1 EXAMPLES Example 1: Synthesis of ((6S,9S,12S,15R)-1-((S)-1-(L-alanyl-L-valyl-L- prolyl)pyrrolidin-2-yl)-12-benzyl-9-(3-guanidinopropyl)-6,17-dimethyl-1,4,7,10,13- pentaoxo-2,5,8,11,14-pentaazaoctadecan-15-yl)boronic acid: Peptide Synthesis: The peptide was synthesized using Fmoc chemistry. 1) Resin preparation: To the 2-CTC Resin (5.00 mmol, 1.00 eq) (Sub: 1.03 mmol / g) was added Fmoc-Phe-OH (5.00 mmol, 1.00 eq) and DIEA (20.0 mmol, 4.00 eq) in DCM (10.0 mL). The mixture was agitated with N2 for 2 hrs at 20 °C, then added MeOH (20.0 mL) and agitated with N2 for another 30.0 min. The resin was washed with DMF (70.0 mL * 5). Attorney Docket No.29618-0443WO1 2) Deprotection: 20% piperidine in DMF (60.0 mL) was added and agitated the resin with N2 for another 20.0 min. The resin was washed with DMF (60.0 mL * 5) and filtered to get the resin. 3) Coupling: A solution of Fmoc-Arg(Pbf)-OH (15.0 mmol, 3.00 eq) in DMF (20.0 mL) was added HBTU (14.3 mmol, 2.85 eq) and DIEA (30.0 mmol, 6.00 eq) to the resin and agitated with N2for 30.0 min at 20 °C. The resin was then washed with DMF (70.0 mL * 5). Repeat above step 2 to 3 for the coupling of following amino acids: # Materials Coupling reagents 1 Fmoc-Ala-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq) 2 Fmoc-Gly-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq) 3 Fmoc-Pro-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq) 4 Fmoc-Pro-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq) 5 Fmoc-Val-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq) 6 Fmoc-Ala-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq) A solution of Boc2O / DIEA / DMF= 10 / 5 / 85 was added to the resin and agitated with N2for 0.5 hr at 20 °C. The resin was then washed with DMF (70.0 mL * 5) Peptide Cleavage and Purification: The resin was washed with MeOH (50.0 mL * 3) and dried under vacuum to get 10.5 g peptide resin. Then 110 mL of cleavage buffer (20%HFIP / 80%DCM) was added to the flask containing the side chain protected peptide resin at 20 °C and the mixture was stirred for 20 min three times. Then the peptide was filtered and concentrated under reduced pressure to give a residue to get 3.71 g crude product. The crude peptide was purified by prep-HPLC (A: 0.05% TFA in H2O, B: ACN) to give the final product compound 1 (2.00 g, 1.43 mmol, 28.5% yield, 83.2% purity) as an off-white solid and confirmed by LCMS (Rt = 1.55 min, MS cal.: 1165.58, MS observed: [M+H]+= 1166.8) & HPLC (product: Rt = 15.5 min, purity: 83.2%). Attorney Docket No.29618-0443WO1 Step 2: To a solution of compound 1 (2.00 g, 1.71 mmol, 1.00 eq) and compound 1a (715 mg, 1.89 mmol, 1.10 eq, TFA) in DMF (10 mL) was added NMM (433 mg, 4.29 mmol, 471 μL, 2.50 eq) and HBTU (715 mg, 1.89 mmol, 1.10 eq) in DMF (10 mL). The mixture was stirred at 0 °C for 2 h. LCMS (EW35917-213-P1A1) showed was compound 1 was consumed and a desired Ms (Rt= 0.67 min) was detected. The reaction mixture was concentrated in vacuo (40 °C) to give a residue. The residue was purified by prep-HPLC (TFA condition) to give compound 2 (158 mg, 97.1 μmol, 5.66% yield, 86.9% purity) as a white solid which was indicated by LCMS (Rt= 0.67 min) and HPLC (Rt= 13.9 min). Step 3: To a solution compound 2 (148 mg, 91.0 μmol, 1.00 eq) in DCM (7.50 mL) was added Et3SiH (21.6 mg, 136 μmol, 28.0 μL, 1.50 eq) and TFA (10.0 g, 87.7 mmol, 6.52 mL, 964 eq) at 25 °C. The mixture was stirred at 25 °C for 3 h. LCMS (EW35917-216- P1B2) showed compound 2 was consumed and a desired Ms (Rt= 0.48 min) was detected. The reaction mixture was concentrated in vacuo to give a residue. The crude product was triturated with MTBE (30.0 mL) at 25 °C for 10.0 min to give compound 3 (100 mg, 66.7 Attorney Docket No.29618-0443WO1 μmol, 73.3% yield, 70.8% purity) as a white solid which was indicated by LCMS (Rt = 0.47 min) and HPLC (Rt = 2.06 min). Step 4: MTBE (1.00 mL) was added phenylboronic acid (14.6 mg, 120 μmol, 2.00 eq) then adjusted the pH = 2 with HCl (1.00 mol / L). The mixture was stirred at 25 °C for 3 h. LCMS (EW35917-219-P1A1) showed compound 3 was consumed and a desired Ms (Rt= 0.40 min) was detected. The mixture was extracted with MTBE (1.00 mL * 2) to give the aqueous phase as colorless liquid. The aqueous phase was purified by prep-HPLC to give AVPPGARFL-Boro (9.80 mg, 9.41 μmol, 15.7% yield, 100% purity, TFA) as a white solid which was indicated by LCMS (Rt = 0.61 min), HPLC (Rt = 1.61 mins) and1H NMR: EW35917-219-P1A, 400 MHz, D2O δ: 7.37 - 7.23 (m, 5H), 4.78 - 4.75 (m, 2H), 4.74 - 4.65 (m, 1H), 4.44 - 4.24 (m, 1H), 4.22 - 4.11 (m, 2H), 4.09 - 4.03 (m, 1H), 3.90 (s, 3H), 3.83 - 3.76 (m, 1H), 3.80 - 3.65 (m, 2H), 3.14 - 3.07 (m, 4H), 2.70 - 2.62 (m, 1H), 2.30 - 2.19 (m, 2H), 2.06 - 2.01 (m, 7H), 1.77 - 1.66 (m, 2H), 1.47 - 1.46 (m, 5H), 1.34 - 1.32 (m, 3H), 1.23 - 1.17 (m, 1H), 1.13 - 1.11 (m, 2H), 0.98 - 0.90 (m, 6H), 0.77 (t, J = 6.8 Hz, 6H).

[0004] Attorney Docket No.29618-0443WO1 Example 2: Synthesis of ((6S,9S,12S,15R)-1-((S)-1-(L-prolyl)pyrrolidin-2-yl)-12- benzyl-9-(3-guanidinopropyl)-6,17-dimethyl-1,4,7,10,13-pentaoxo-2,5,8,11,14- pentaazaoctadecan-15-yl)boronic acid

[0005] Attorney Docket No.29618-0443WO1 Peptide Synthesis: The peptide was synthesized using standard Fmoc chemistry. 1) Resin preparation: To the 2-CTC Resin (5.00 mmol, 1.00 eq) (Sub: 1.03 mmol / g) was added Fmoc-Phe-OH (5.00 mmol, 1.00 eq) and DIEA (20.0 mmol, 4.00 eq) in DCM (10.0 mL). The mixture was agitated with N2 for 2 hrs at 20 °C, then added MeOH (20.0 mL) and agitated with N2for another 30.0 min. The resin was washed with DMF (70.0 mL * 5). 2) Deprotection: 20% piperidine in DMF (60.0 mL) was added and agitated the resin with N2for another 20.0 min. The resin was washed with DMF (60.0 mL * 5) and filtered to get the resin. 3) Coupling: A solution of Fmoc-Arg(Pbf)-OH (15.0 mmol, 3.00 eq) in DMF (20.0 mL) was added HBTU (14.3 mmol, 2.85 eq) and DIEA (30.0 mmol, 6.00 eq) to the resin and agitated with N2for 30.0 min at 20 °C. The resin was then washed with DMF (70.0 mL * 5). Repeat above step 2 to 3 for the coupling of following amino acids: # Materials Coupling reagents 1 Fmoc-Ala-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq) 2 Fmoc-Gly-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq) 3 HBTU (2.85 eq) and DIEA (6.00 eq) 4 Fmoc-Pro-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq) A solution of Boc2O / DIEA / DMF= 10 / 5 / 85 was added to the resin and agitated with N2for 0.5 hr at 20 °C. The resin was then washed with DMF (70.0 mL * 5) Peptide Cleavage and Purification: The resin was washed with MeOH (50.0 mL * 3) and dried under vacuum to get 10.5 g peptide resin. Then 110 mL of cleavage buffer (20%HFIP / 80%DCM) was added to the flask containing the side chain protected peptide resin at 20 °C and the mixture was stirred for 20 min three times. Then the peptide was filtered and concentrated under reduced pressure to give a residue to get 3.45 g crude product. The crude peptide was purified by prep-HPLC (A: 0.05% TFA in H2O, B: ACN) to give the final product Attorney Docket No.29618-0443WO1 compound 4 (2.00 g, 1.71 mmol, 34.3% yield, 85.4% purity) as an off-white solid and confirmed by LCMS (EW34785-45-P1A1, Rt = 1.58 min, MS cal.: 995.5, MS observed: [M+H]+= 996.7) & HPLC (EW34785-45-P1B, product: Rt= 15.7 min, purity: 85.4%). Step 2: To a solution compound 4 (2.00 g, 2.01 mmol, 1.00 eq) and compound 1a (837 mg, 2.21 mmol, 1.10 eq, TFA) in DMF (10.0 mL) was added NMM (507 mg, 5.02 mmol, 552 μL, 2.50 eq) and HBTU (837 mg, 2.21 mmol, 1.10 eq) in DMF (10.0 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. LCMS (EW35917-212-P1A1) showed compound 4 was consumed and a desired Ms (Rt = 0.68 min) was detected. The reaction mixture was concentrated in vacuo (40 °C) to give a residue. The residue was purified by prep-HPLC (TFA condition) to give compound 5 (400 mg, 277 μmol, 13.8% yield, 86.3% purity) as a white solid which was indicated by LCMS (Rt = 0.68 min) and HPLC (Rt = 15.1 min). Step 3: To a solution of compound 5 (200 mg, 138 μmol, 1.00 eq) in DCM (10.0 mL) was added Et3SiH (33.0 mg, 208 μmol, 42.8 μL, 1.50 eq) and TFA (15.4 g, 134 mmol, 10.0 mL, 970 eq) at 25 °C, the mixture was stirred at 25 °C for 3 h. LCMS (EW35917-215-P1A1) showed compound 5 was consumed and a desired Ms (Rt = 0.47 min) was detected. The reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with MTBE (30.0 mL) at 25 °C for 10.0 min to give compound 6 (150 mg, 113 μmol, 81.3% Attorney Docket No.29618-0443WO1 yield, 67.0% purity) as a white solid which was indicated by LCMS (Rt = 0.47 min) and HPLC (Rt = 2.04 min). Step 4: MTBE (1.50 mL) was added phenylboronic acid (27.5 mg, 225 μmol, 2.00 eq), then adjusted the PH = 2 with HCl (1.00 mol / L). The mixture was stirred at 25 °C for 3 h. LCMS (EW35917-220-P1A1) showed compound 6 was consumed and a desired Ms (Rt= 0.40 min) was detected. The mixture was extracted with MTBE (1.00 mL * 2) to give the aqueous phase as colorless liquid. The aqueous phase was purified by prep-HPLC to give PPGARFL-Boro (10.0 mg, 11.5 μmol, 10.2% yield, 99.9% purity, TFA) as a white solid which was indicated by LCMS (Rt = 0.57 min), HPLC (Rt = 1.50 min) and1H NMR: EW35917-220-P1A, 400 MHz, D2O δ: 7.38 - 7.23 (m, 5H), 4.67 - 4.61 (m, 2H), 4.46 - 4.45 (m, 1H), 4.27 - 4.22 (m, 2H), 3.92 (s, 2H), 3.75 - 3.51 (m, 2H), 3.38 - 3.35 (m, 2H), 3.13 - 3.06 (m, 4H), 2.60 - 2.49 (m, 2H), 2.41 - 2.26 (m, 1H), 2.06 - 1.97 (m, 6H), 1.67 (d, J = 8.0 Hz, 2H), 1.51 - 1.40 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H), 1.32 - 1.10 (m, 3H), 0.77 (t, J = 6.4 Hz, 6H).

[0006] Attorney Docket No.29618-0443WO1 Example 3: Synthesis of ((R)-1-((S)-2-((S)-2-((S)-2-aminopropanamido)-5- guanidinopentanamido)-3-phenylpropanamido)-3-methylbutyl)boronic acid The peptide was synthesized using standard Fmoc chemistry. 1) Resin preparation: To the 2-CTC Resin (5.00 mmol, 1.00 eq) (Sub: 1.03 mmol / g) was added Fmoc-Phe-OH (5.00 mmol, 1.00 eq) and DIEA (20.0 mmol, 4.00 eq) in DCM (60.0 mL). The mixture was agitated with N2 for 2 hrs at 20 °C, then added MeOH (20.0 mL) and agitated with N2for another 30.0 min. The resin was washed with DMF (60.0 mL * 5). 2) Deprotection: 20% piperidine in DMF (60.0 mL) was added and agitated the resin with N2for another 20.0 min. The resin was washed with DMF (60.0 mL * 5) and filtered to get the resin. Attorney Docket No.29618-0443WO1 3) Coupling: A solution of Fmoc-Arg (Pbf) -OH (15.0 mmol, 3.00 eq) in DMF (60.0 mL) was added HBTU (14.3 mmol, 2.85 eq) and DIEA (30.0 mmol, 6.00 eq) to the resin and agitated with N2for 30.0 min at 20 °C. The resin was then washed with DMF (60.0 mL * 5). 4) Deprotection: 20% piperidine in DMF (60.0 mL) was added and agitated the resin with N2for another 20.0 min. The resin was washed with DMF (60.0 mL * 5) and filtered to get the resin. 5) Coupling: A solution of Fmoc-Ala-OH (15.0 mmol, 3.00 eq) in DMF (60.0 mL) was added HBTU (14.3 mmol, 2.85 eq) and DIEA (30.0 mmol, 6.00 eq) to the resin and agitated with N2for 30.0 min at 20 °C. The resin was then washed with DMF (60.0 mL * 5). 6) Deprotection: 20% piperidine in DMF (60.0 mL) was added and agitated the resin with N2for another 20.0 min. The resin was washed with DMF (60.0 mL * 5) and filtered to get the resin. 7) Coupling: A solution of (Boc)2O (15.0 mmol, 3.00 eq) in DMF (60.0 mL) agitated with N2for 15.0 min two times at 20 °C. The resin was then washed with DMF (60.0 mL * 5). Peptide Cleavage and Purification: The resin was washed with MeOH (60.0 mL * 3) and dried under vacuum to get 8.02 g peptide resin. Then 110 mL of cleavage buffer (20% HFIP / 80% DCM) was added to the flask containing the side chain protected peptide resin at 20 °C and the mixture was stirred for 20 min three times. Then the peptide was filtered and concentrated under reduced pressure to give a residue to get compound 7 (3.02 g, crude) product. LCMS (Rt= 1.58 min, MS cal.: 744.9, MS observed: [M+H]+=745.6 HPLC: product: Rt = 14.3 min, purity: 94.8%

[0007] Attorney Docket No.29618-0443WO1 Step 2: To a solution of compound 7 (1.30 g, 1.75 mmol, 1.00 eq) and compound 1a (728 mg, 1.92 mmol, 1.10 eq, TFA) in DMF (5.00 mL) was added NMM (441 mg, 4.36 mmol, 479 μL, 2.50 eq) and HBTU (728 mg, 1.92 mmol, 1.10 eq) in DMF (5.00 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. LCMS (EW35917-211-P1A1) showed compound 7 was consumed and a desired Ms (Rt= 0.70 min) was detected. The reaction mixture was concentrated in vacuo (40 °C) to give a residue. The residue was purified by prep-HPLC (TFA condition) to give compound 8 (210 mg, 210 μmol, 12.0% yield, 99.3% purity) as a white solid which was indicated by LCMS (Rt = 0.69 min) and HPLC (Rt = 15.9 min). Step 3: added Et3SiH (47.6 mg, 300 μmol, 61.7 μL, 1.50 eq) and TFA (15.2 g, 133 mmol, 9.90 mL, 665 eq) at 25 °C. The mixture was stirred at 25 °C for 3 h. LCMS (EW35917-217- P1B2) showed compound 8 was consumed and a desired Ms (Rt= 0.47 min) was detected. The reaction mixture was concentrated in vacuo to give a residue. The crude product was triturated with MTBE (30.0 mL) at 25 °C for 10.0 min to give compound 9 (150 mg, 169 Attorney Docket No.29618-0443WO1 μmol, 84.3% yield, 72.0% purity) as a white solid which was indicated by LCMS (Rt = 0.46 min). Step 4: MTBE (2 mL) was added phenylboronic acid (41.2 mg, 338 μmol, 2.00 eq) then adjusted the PH = 2 with HCl (1.00 mol / L). The mixture was stirred at 25 °C for 3 h. LCMS (EW35917-221-P1A1) showed compound 9 was consumed and desired Ms (Rt= 0.40 min) was detected. The mixture was extracted with MTBE (1.00 mL * 2) to give the aqueous phase as colorless liquid. The aqueous phase was purified by prep-HPLC to give ARFL-Boro (15.3 mg, 24.6 μmol, 14.5% yield, 99.4% purity, TFA) as a white solid which was indicated by LCMS (Rt = 0.61 min), HPLC (Rt= 0.89 min) and1H NMR: EW35917-220-P1A, 400 MHz, D2O δ: 7.37 - 7.23 (m, 5H), 4.63 (t, J = 8.4 Hz ,1H), 4.28 (t, J = 7.2 Hz ,1H), 4.04 (dd, J1 = 7.2 Hz, J2 = 14.4 Hz, 1H), 3.16 - 3.02 (m, 4H), 2.62 - 2.58 (m, 1H), 1.72 - 1.56 (m, 2H), 1.54 - 1.46 (m, 5H), 1.08 - 1.04 (m, 3H), 0.75 (t, J = 6.8 Hz ,6H)

[0008] Attorney Docket No.29618-0443WO1 Example 4: Synthesis of (S)-2-((S)-2-aminopropanamido)-5-guanidino-N-((S)-1- (((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3- phenylpropan-2-yl)pentanamide 1) Resin preparation: To the 2-CTC Resin (3.00 mmol, 1.00 eq) (Sub: 0.5 mmol / g) was added Fmoc-Phe-OH (3.00 mmol, 1.00 eq) and DIEA (12.0 mmol, 4.00 eq) in DCM (60.0 mL). The mixture was agitated with N2 for 2 hrs at 20 °C, then added MeOH (6.00 mL) and agitated with N2for another 30.0 min. The resin was washed with DMF (60.0 mL * 5). 2) Deprotection: 20% piperidine in DMF (60.0 mL) was added and agitated the resin with N2 for another 20.0 min. The resin was washed with DMF (60.0 mL * 5) and filtered to get the resin. Attorney Docket No.29618-0443WO1 3) Coupling: A solution of Fmoc-Arg (Pbf) -OH (9.00 mmol, 3.00 eq) in DMF (60.0 mL) was added HBTU (8.55 mmol, 2.85 eq) and DIEA (18.0 mmol, 6.00 eq) to the resin and agitated with N2for 30.0 min at 20 °C. The resin was then washed with DMF (60.0 mL * 5). 4) Deprotection: 20% piperidine in DMF (60.0 mL) was added and agitated the resin with N2for another 20.0 min. The resin was washed with DMF (60.0 mL * 5) and filtered to get the resin. 5) Coupling: A solution of Fmoc-Ala-OH (9.00 mmol, 3.00 eq) in DMF (60.0 mL) was added HBTU (8.55 mmol, 2.85 eq) and DIEA (18.0 mmol, 6.00 eq) to the resin and agitated with N2for 30.0 min at 20 °C. The resin was then washed with DMF (60.0 mL * 5). 6) Deprotection: 20% piperidine in DMF (60.0 mL) was added and agitated the resin with N2for another 20.0 min. The resin was washed with DMF (60.0 mL * 5) and filtered to get the resin. 7) Coupling: A solution of (Boc)2O (9.00 mmol, 3.00 eq) in DMF (60.0 mL) was added DIEA (9.00 mmol, 3.00 eq) to the resin and agitated with N2for 30.0 min at 20 °C. The resin was then washed with DMF (60.0 mL * 5). Peptide Cleavage and Purification: The resin was washed with MeOH (60.0 mL * 3) and dried under vacuum to get 8.50 g peptide resin. Then 110 mL of cleavage buffer (20% HFIP / 80% DCM) was added to the flask containing the side chain protected peptide resin at 20 °C and the mixture was stirred for 20 min three times. Then the peptide was filtered and concentrated under reduced pressure to give a residue to give 2.10 g crude. LCMS of monitoring: (EW41876-6-P1C1). The crude peptide was purified by prep-HPLC (A: 0.075% TFA in H2O, B: ACN) to give the final product compound 1 (300 mg, 40.3 μmol, 13.5% yield, 95.2% purity) as a white solid and confirmed by LCMS and HPLC. LCMS: Rt = 1.58 min, MS cal.: 744.9, MS observed: [M+H]+= 745.5. LCMS: Rt = 1.55 min, MS cal.: 744.9, MS observed: [M+H]+=745.5, Attorney Docket No.29618-0443WO1 Step 2: To a solution of compound 1 (300 mg, 0.40 mmol, 1.00 eq) and compound 1a (126 mg, 0.44 mmol, 1.10 eq, TFA) in DMF (1.00 mL) was added NMM (101 mg, 1.00 mmol, 110 μL, 2.50 eq) and HBTU (168 mg, 0.44 mmol, 1.10 eq) in DMF (1.00 mL), The mixture was stirred at 0 °C for 2 h. LCMS (EW34433-292-P1A) showed was compound 1 was consumed and desired mass (Rt = 0.67 min) was detected. The reaction mixture was concentrated in vacuo (40 °C) to give a residue. The residue was purified by prep-HPLC (TFA condition) to give compound 2 (260 mg, 289 μmol, 71.8% yield) as a white solid. LCMS: Rt = 0.67 min, MS cal.: 897.4, MS observed: [M+H]+= 898.6 Step 3: was added Et3SiH (68.7 mg, 434 μmol, 89.2 μL, 1.50 eq) and TFA (15.3 g, 134 mmol, 10.0 mL, 465 eq) at 25 °C. The mixture was stirred at 25 °C for 3 h. LCMS (EW34433-295- P1A1) showed compound 2 was consumed and desired mass (Rt= 0.48 min) was detected. The reaction mixture was concentrated in vacuo to give a residue. The aqueous phase was purified by prep-HPLC (TFA condition) to give ARFL-epoxyketon (32.0 mg, 57.1 μmol, 19.7% yield, 97.5% purity, TFA) as a white solid. LCMS: Rt= 0.48 min, MS Attorney Docket No.29618-0443WO1 cal.: 545.3, MS observed: [M+H]+= 546.4. LCMS: Rt = 0.48 min, MS cal.: 545.3, MS observed: [M+H]+= 546.4. HPLC: Rt = 1.24 min, purity: 97.4 %,1H NMR: EW34433- 295-P1C, 400 MHz, D2O δ: 7.25 - 7.13 (m, 5H), 4.66 - 4.65 (m, 1H), 4.51 - 4.45 (m, 1H), 4.23 - 4.21 (m, 1H), 3.98 - 3.96 (m, 1H), 3.09 - 3.05 (m, 2H), 3.00 (s, 2H), 2.96 - 2.94 (m, 2H), 1.64 - 1.60 (m, 2H), 1.52 - 1.47 (m, 2H), 1.45 (s, 9H), Example 5: Synthesis of ((6S,9S,12S,15R)-12-benzyl-2,2,6,17-tetramethyl-4,7,10,13- tetraoxo-9-(3-ureidopropyl)-3-oxa-5,8,11,14-tetraazaoctadecan-15-yl)boronic acid 1) Resin preparation: To the 2-CTC Resin (10.0 mmol, 1.00 eq, Sub: 0.50 mmol / g) was added Fmoc-Phe-OH (10.0 mmol, 1.00 eq.) and DIEA (40.0 mmol, 4.00 eq.) in DCM (500 mL). The mixture was agitated with N2 for 2.00 hrs at 20 °C, then added MeOH Attorney Docket No.29618-0443WO1 (20.0 mL) and agitated with N2 for another 30.0 min. The resin was washed with DMF (500 mL * 5). 2) Deprotection: 20% piperidine in DMF (500 mL) was added and agitated the resin with N2 for another 30.0 min. The resin was washed with DMF (500 mL * 5) and filtered to get the resin. 3) Coupling: A solution of Fmoc-Cit-OH (30.0 mmol, 3.00 eq) in DMF (500 mL) was added HBTU (28.5 mmol, 2.85 eq) and DIEA (60.0 mmol, 6.00 eq) to the resin and agitated with N2 for 2.00 h at 20 °C. The resin was then washed with DMF (500 mL * 5). 4) Deprotection: 20% piperidine in DMF (500 mL) was added and agitated the resin with N2 for another 30.0 min. The resin was washed with DMF (500 mL * 5) and filtered to get the resin. 5) Coupling: A solution of Boc-Ala-OH (30.0 mmol, 3.00 eq) and HBTU (28.5 mmol, 2.85 eq) in DMF (500 mL) was added DIEA (60.0 mmol, 6.00 eq) to the resin and agitated with N2 for 2.00 h at 20 °C. The resin was then washed with DMF (500 mL * 5). Peptide Cleavage and Purification: The resin was washed with MeOH (500 mL * 3) and dried under vacuum to get peptide resin. Then the peptide resin was treated with the cleavage cocktail (20% HFIP in DCM, 500 mL) for 20.0 min * 4, Filtered and concentrated under reduced pressure to give crude product (5.00 g). LCMS of monitoring (EW43799-25-P1C1, Rt = 1.33 min). The crude peptide was purified by prep-HPLC (A: 0.075% TFA in H2O, B: ACN) to give the final product compound 1 (2.00 g, 3.97 mmol, 39.1% yield, 98.1% purity, TFA) as white solid and confirmed by LCMS and HPLC. LCMS: Rt = 1.33 min, MS cal.: 493.3, MS observed: [M+H]+= 494.4 LCMS: Rt = 1.29 min, MS cal.: 493.3, MS observed: [M+H]+= 494.4 HPLC: Rt= 8.28 min, purity: 98.1%

[0009] Attorney Docket No.29618-0443WO1 Step 2: (768 mg, 2.03 mmol, 1.00 eq, TFA) in DMF (10.0 mL) was added HATU (924 mg, 2.43 mmol, 1.20 eq) and DIEA (288 mg, 2.23 mmol, 388 μL, 1.10 eq), then the mixture was stirred at 25 °C for 12 hrs. LCMS showed compound 1 was consumed completely and a new peak (Rt = 1.03 min) with desired mass was detected. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with water (20 mL * 2), dried over filtered and concentrated under reduced pressure to give residue. The residue was purified by prep-HPLC (TFA condition). Compound 2 was obtained as white solid, which was confirmed by LCMS and HPLC. LCMS: Rt= 1.03 min, MS cal.: 740.7, MS observed: [M+H]+= 741.3; LCMS: Rt = 1.02 min, MS cal.: 740.7, MS observed: [M+H]+= 741.4. Step 3: and MTBE (2.00 mL) was added phenylboronic acid (65.8 mg, 540 μmol, 2.00 eq) then adjusted the pH to 2 with HCl (1.00 mol / L). The mixture was stirred at 25 °C for 12 hrs. LCMS (EW35917-409-P1A5) showed compound 2 was consumed and desired mass (Rt= 0.40 min) was detected. The mixture was extracted with MTBE (3.00 mL * 2) to give the aqueous phase. The aqueous phase was purified by prep-HPLC (TFA condition) to Attorney Docket No.29618-0443WO1 give ACitFL-Boro (8.00 mg, 15.7 μmol, 5.83% yield, 99.7% purity) as white solid. LCMS: Rt = 0.68 min, MS cal.: 506.4, MS observed: [M-H2O+H]+= 489.3; LCMS: Rt = 0.67 min, MS cal.: 506.4, MS observed: [M-H2O+H]+= 489.3. HPLC: Rt= 1.30 min, purity: 99.7%.1H NMR: 400 MHz, D2O δ: 7.37 - 7.24 (m, 5H), 4.63 (t, J = 8.4 Hz, 1H), 4.28 (t, J = 7.2 Hz, 1H), 4.05 (dd, J1 = 7.2 Hz, J2 = 14.4 Hz, 1H), 3.14 - 3.03 (m, 4H), 2.61 (t, J = 7.2 Hz, 1H), 1.69 - 1.66 (m, 2H), 1.48 - 1.43 (m, 5H), 1.13 - 1.04 (m, 3H), 0.76 (t, J = 6.4 Hz, 6H). Example 6: Synthesis of ((6S,9S,12R)-1-amino-6-((S)-2-aminopropanamido)-9- benzyl-1-imino-14-methyl-7,10-dioxo-3-oxa-2,8,11-triazapentadecan-12-yl)boronic acid A. Synthesis of Fmoc L-canavanine

[0010] Attorney Docket No.29618-0443WO1 Step 1: To a solution of compound 1 (4.00 g, 15.8 mmol, 1.00 eq) in EtOH (160 mL) was added NaOH (632 mg, 15.8 mmol, 1.00 eq). The mixture was stirred at 25 °C for 12 hrs. TLC (Petroleum ether: ethyl acetate = 0: 1) showed compound 1 (Rf= 0.30) was consumed and a new spot (Rf= 0.05) was detected. The reaction mixture was concentrated under reduced pressure to obtain residue. Compound 2 (4.30 g, crude) was obtained as white solid. Step 2: To a solution of compound 2 (4.30 g, 15.6 mmol, 1.00 eq) in DMF (120 mL) was added BnBr (3.21 g, 18.7 mmol, 2.23 mL, 1.20 eq). The mixture was stirred at 25 °C for 12 hrs. LCMS (EW46031-23-P1A1) showed compound 2 was consumed completely and desired mass (Rt= 0.87 min) was detected. The reaction mixture was addition water (50.0 mL), and extracted with ethyl acetate (50.0 mL). The combined organic layers were washed with water (50.0 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. Compound 3 (6.30 g, crude) was obtained as yellow oil. LCMS: Rt= 0.87 min, MS cal.: 343.1, MS observed: [M+H]+= 344.1.

[0011] Attorney Docket No.29618-0443WO1 Step 3: To a mixture of compound 3 (6.3 g, 18.3 mmol, 1.00 eq) in DCM (60.0 mL) was added CBr4(9.13 g, 27.5 mmol, 1.50 eq) and PPh3(7.22 g, 27.5 mmol, 1.50 eq), then the mixture was stirred at 25 °C for 1 hr. TLC (Petroleum ether: ethyl acetate = 2: 1) indicated that compound 3 (Rf = 0.20) was consumed completely and new two spots (Rf = 0.10, Rf= 0.60) were formed. The reaction mixture was concentrated under reduced pressure to obtain residue. The residue was purified by column chromatography (SiO2, Petroleum ether: ethyl acetate = 10: 1 to 3: 1, petroleum ether: ethyl acetate = 2: 1, Rf = 0.60). Compound 4 (4.30 g, 10.6 mmol, 57.7% yield, 100% purity) was obtained white solid. LCMS: Rt= 0.95 min, MS cal.: 405.1, MS observed: [M +H]+= 406.0 Step 4: To a solution of K2CO3(4.39 g, 31.7 mmol, 3.00 eq) and BocNHOH (1.41 g, 10.6 mmol, 1.00 eq) in DMF (40.0 mL), then the resolution was added compound 4 (4.30 g, 10.6 mmol, 1.00 eq) at 25 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS (EW46031-32-P1C1) showed compound 4 was consumed and desired mass (Rt= 0.95 min) was detected. The reaction mixture was added H2O (100 mL), extracted with ethyl acetate (20.0 mL * 2), the combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to obtain residue. Compound 5 (2.56 g, 5.35 mmol, 50.6% yield, 95.9% purity) was obtained yellow oil. LCMS: Rt = 0.95 min, MS cal.: 458.2, MS Attorney Docket No.29618-0443WO1 observed: [M-Boc+H]+= 359.2. LCMS: Rt = 0.96 min, MS cal.: 458.2, MS observed: [M-Boc+H]+= 359.2. HPLC: Rt = 2.78 min, purity: 95.9% Step 5: To a solution of (25.0 mL) was added TFA (2.44 g, 21.4 mmol, 1.59 mL, 4.00 eq) at 25 °C for 12 hrs. LCMS (EW46031- 34-P1B5) showed compound 5 was consumed completely and desired mass (Rt= 0.78 min) was detected. The mixture solution was concentrated in vacuo to obtain residue. Compound 6 (2.50 g, 4.60 mmol, 86.0% yield, 87.0% purity, TFA) was obtained yellow oil. LCMS: Rt= 0.78 min, MS cal.: 358.1, MS observed: [M+H]+= 359.2. LCMS: Rt= 0.78 min, MS cal.: 358.1, MS observed: [M+H]+= 359.2. Step 6: To a solution of compound 6 (2.50 g, 6.07 mmol, 1.00 eq) in DMF (30.0 mL) was added DIEA (1.57 g, 12.1 mmol, 2.11 mL, 2.00 eq) and compound 6a (1.88 g, 6.07 mmol, 1.00 eq) at 25 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS (EW46031- 38-P1A4) showed compound 6 was consumed and desired mass (Rt = 1.04 min) was detected. The reaction mixture was added H2O (100 mL), extracted with ethyl acetate (20.0 mL * 2), the combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to obtain residue. The residue was purified by column Attorney Docket No.29618-0443WO1 chromatography (SiO2, Petroleum ether: ethyl acetate = 10: 1 to 5: 1, petroleum ether: ethyl acetate = 3: 1, Rf = 0.40). Compound 7 (2.20 g, 3.62 mmol, 59.6% yield, 98.8% purity) was obtained as white oil. LCMS: Rt= 1.04 min, MS cal.: 600.2, MS observed: [M+H]+= 601.4. LCMS: Rt = 1.04 min, MS cal.: 600.2, MS observed: [M+H]+= 601.7. Step 7: To a g, mL) and H2O (20.0 mL) was added Pd / C (0.20 g, 10.0% purity) under nitrogen atmosphere, the suspension was degassed and purged with H2 for three times. The reaction mixture was stirred under H2 (15 Psi) at 25 °C for 1 hr. LCMS (EW46031-41-P1A1) showed compound 7 was consumed and desired mass (Rt= 0.80 min) was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain residue. Compound 8 (1.30 g, crude) was obtained white oil. LCMS:Rt = 0.80 min, MS cal.: 376.2, MS observed: [M+H]+= 377.2. Step 8: To a solution of compound 8 (1.30 g, 3.45 mmol, 1.00 eq) in THF (20.0 mL) and H2O (20.0 mL) was added FmocOSu (1.17 g, 3.45 mmol, 1.00 eq), NaHCO3 (580 mg, 6.91 mmol, 269 μL, 2.00 eq), the reaction mixture was stirred at 25 °C for 12 hrs. LCMS Attorney Docket No.29618-0443WO1 (EW46031-42-P1A1) showed compound 8 was consumed completely and the desired mass (Rt = 1.05 min) was detected. The mixture was adjusted the pH to 6 with 1N HCl, then extracted with ethyl acetate (100 mL * 2). The combined organic layer was washed by NaCl (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain crude residue. The residue was purified by column chromatography (SiO2, Petroleum ether: ethyl acetate = 10: 1 to 2: 1, petroleum ether: ethyl acetate = 0: 1, Rf= 0.30). L-canavanine (2.00 g, 3.14 mmol, 90.8% yield, 93.9% purity) was obtained as white oil. LCMS: Rt = 1.05 min, MS cal.: 598.3, MS observed: [M+H]+= 599.2. LCMS: Rt= 1.03 min, MS cal.: 598.3, MS observed: [M+H]+= 599.2. HPLC: Rt= 2.93 min, purity: 93.9% B. Synthesis of ACanFL-Boro

[0012] Attorney Docket No.29618-0443WO1 Peptide Synthesis: 1) Resin preparation: To the 2-CTC Resin (1.00 mmol, 1.00 eq, Sub: 1.07 mmol / g) was added Fmoc-Phe-OH (1.00 mmol, 1.00 eq.) and DIEA (4.00 mmol, 4.00 eq.) in DCM (50.0 mL). The mixture was agitated with N2 for 2.00 hrs at 20 °C, then added MeOH (2.00 mL) and agitated with N2 for another 30.0 min. The resin was washed with DMF (50.0 mL * 5). 2) Deprotection: 20% piperidine in DMF (50.0 mL) was added and agitated the resin with N2 for another 30.0 min. The resin was washed with DMF (50.0 mL * 5) and filtered to get the resin. 3) Coupling: A solution of compound 8 (1.50 mmol, 1.50 eq) in DMF (500 mL) was added HATU (1.43 mmol, 1.43 eq) and DIEA (3.00 mmol, 3.00 eq) to the resin and agitated with N2 for 2.00 hrs at 20 °C. The resin was then washed with DMF (50.0 mL * 5). 4) Deprotection: 20% piperidine in DMF (50.0 mL) was added and agitated the resin with N2 for another 30.0 min. The resin was washed with DMF (50.0 mL * 5) and filtered to get the resin. 5) Coupling: A solution of Boc-Ala-OH (3.00 mmol, 3.00 eq) and HBTU (2.85 mmol, 2.85 eq) in DMF (50.0 mL) was added DIEA (6.00 mmol, 6.00 eq) to the resin and agitated with N2 for 2.00 h at 20 °C. The resin was then washed with DMF (50.0 mL * 5). Peptide Cleavage and Purification: The resin was washed with MeOH (50.0 mL * 3) and dried under vacuum to get peptide resin. Then the peptide resin was treated with the cleavage cocktail (20% HFIP in DCM, 50.0 mL) for 20.0 min * 4, Filtered and concentrated under reduced pressure to give crude product compound 9 (318 mg). LCMS: Rt = 1.61 min, MS cal.: 694.3, MS observed: [M+H]+= 695.5

[0013] Attorney Docket No.29618-0443WO1 Step 2: 1a (191 mg, eq, was mg, mmol, 126 μL, 2.50 eq) and HBTU (208 mg, 549 µmol, 1.20 eq) in DMF (3.00 mL). The mixture was stirred at 0 °C for 2 hrs. LCMS (EW35917-422-P1A1) showed compound 9 was consumed and desired mass (Rt = 1.18 min) was detected. The reaction mixture was concentrated in vacuo (40 °C) to give residue. The residue was purified by prep-HPLC (TFA condition) to give white solid. Compound 10 (272 mg, 289 μmol, 63.1% yield) was obtained as white solid. LCMS: Rt = 1.18 min, MS cal.: 941.9, MS observed: [M+H]+= 942.8. Step 3: was added triisopropylsilane (68.6 mg, 433 μmol, 89.0 μL, 1.50 eq) and TFA (658 mg, 5.78 mmol, 429 μL, 20.0 eq) at 25 °C. The mixture was stirred at 25 °C for 2 hrs. LCMS (EW35917-426-P1B1) showed compound 10 was consumed and desired mass (Rt=0.81 min) was detected. The reaction mixture was concentrated in vacuo to give residue. Compound 11 (218 mg, crude, TFA) was obtained as yellow solid. LCMS: Rt = 0.81 min, MS cal.: 641.6, MS observed: [M+H]+= 642.3. Attorney Docket No.29618-0443WO1 Step 4: mL) and MTBE (2.00 mL) was added phenylboronic acid (70.3 mg, 577 μmol, 2.00 eq) then adjusted the pH to 2 with HCl (1 M). The mixture was stirred at 25 °C for 2 hrs. LCMS (EW35917-427-P1A3) showed compound 11 was consumed and desired mass (Rt = 0.74 min) was detected. The mixture was extracted with MTBE (3.00 mL * 2) to give the aqueous phase. The aqueous phase was purified by prep-HPLC (TFA condition) to give ACanFL-Boro (9.00 mg, 17.6 μmol, 6.09% yield, 99.1% purity) as white solid. LCMS: Rt = 0.74 min, MS cal.: 507.4, MS observed: [M-H2O+H]+= 490.2. LCMS: Rt = 0.69 min, MS cal.: 507.4, MS observed: [M-H2O+H]+= 490.2. HPLC: Rt= 1.71 min, purity: 99.1%1H NMR: 400 MHz, D2O δ: 7.31 - 7.18 (m, 5H), 4.65 - 4.61 (m, 1H), 4.39 (t, J = 6.8 Hz, 1H), 4.00 - 3.97 (dd, J1 = 7.2 Hz, J2 = 14.4 Hz, 1H), 3.86 - 3.82 (m, 2H), 3.04 - 2.98 (m, 2H), 2.58 (d, J = 15.6 Hz, 1H), 2.05 - 1.97 (m, 2H), 1.41 (t, J = 6.8 Hz, 3H), 1.12 - 1.01 (m, 3H), 0.71 (d, J = 6.4 Hz, 6H). Example 7: In vitro Proteasome Activity Assays To identify the PI31 residues sufficient to inhibit the β2 active site, the yeast structure along with evolutionary sequence alignments were used to identify residues 232-251 as being responsible for inhibition of the β2 active site. As shown in Figure 2, this 20-residue peptide was synthesized and it was found that it was comparably effective at inhibiting human PI31, exhibiting an IC50<10 μM. The polypeptide was highly specific for β2 and showed little activity against β5 or β1 under the same conditions. The regions of Fub1 that target β2 and β5 are its most evolutionarily conserved. Interestingly, the yeast peptide showed little activity against human proteasome, which is perhaps Attorney Docket No.29618-0443WO1 surprising given the potency of the yeast peptide against yeast proteasomes. The β2- interacting peptides contain proline- and glycine-rich regions at either end which appear to kink the polypeptide, thereby presenting the central portion of the peptide to the active site, with the P1 residue being Asp224 in yeast and, by analogy, Asp244 in humans. The flanking proline-rich regions are more highly conserved than the central active site- interacting regions, suggesting that the sequence conservation reflects the structural requirement to present those central residues, which are themselves more variable, likely reflecting species-specific co-evolution with the proteasome. PI31 was a top hit in a study that identified genes linked to kindreds with late- onset Alzheimer's disease. Further supporting this association, loss of PI31 in mice resulted in a neurodegenerative phenotype. Interestingly, one of the mutations identified in human kindreds occurred directly within the β2-targeting sequences, R242H. The peptide was tested against β2 and the data indicated that there was a substantial decrease in β2 inhibition relative to the wild-type peptide. As shown in Figure 3, protease substrates can be described with respect to their scissile bond, with the residues on either side designated as P1 and P1'. In yeast, the P1 and P1' residues are far from each other since they are distributed into two separate Fub1 molecules that dimerize immediately in front of the active site. This arrangement explains how Fub1 evades degradation at this site since there is no scissile bond. In human PI31, the putative P1 and P1' residues were much closer to each other, being only 10 residues apart. It was postulated that a single peptide encompassing this region might be sufficient for inhibition. A 23-residue peptide (190-212) was synthesized and found to be sufficient to inhibit β5, although it was less potent than the β2 peptide (IC50~50 μM) (Fig.3C). The peptide was specific, although again less so than the β2 peptide. The β5 peptide showed little activity against β1. However, it did show some partial and reproducible inhibition at β2, the structural or mechanistic basis for which we do not yet understand. The greater separation of the P1 and P1' residues in Fub1 relative to PI31 is due to an insertion of 13 residues. Similar to human PI31, microsporidian PI31 also lacks this insertion and, interestingly, its mechanism of β5 inhibition is somewhat different from that seen in yeast. The P1 (Ala99) and P1' (Asp84) residues are still separated spatially, but instead of being split into two polypeptides, the intervening residues are looped away Attorney Docket No.29618-0443WO1 from the active site threonine, meaning that there is again no scissile bond between P1 and P1'. The ability of a single peptide to inhibit human CP is consistent with this arrangement. Next, human 20S CPs (10 nM) were pre-incubated for 20 minutes on ice in buffer (50 mM Tris pH 7.5, 1 mM EDTA, 5mM MgCl2, 10% glycerol, 0.02% SDS) with or without PI31 peptides or full-length PI31 (750nM). The small amount of SDS facilitates CP gate opening, allowing substrates to access the active sites. Immediately following pre-incubation, the fluorogenic substrates suc-LLVY-AMC (Bachem I-1395), Boc-LRR- AMC (Bachem I-1585), or z-LLE-AMC (Bachem I-1945) were added. Suc-LLVY-AMC (100 μM) was used to measure chymotryptic activity (β5) with a reaction time of 20 minutes at 30℃. Boc-LRR-AMC (300 μM) or z-LLE-AMC (300 μM) were used to measure tryptic (β2) or post-acidic (β1) activity, respectively, with a 45-minute reaction time at 30℃. Reactions were terminated by addition of 1% SDS. Fluorescence was measured using a VersaFluor fluorometer (Bio-Rad). PGARFL-boro showed strong dose-dependent inhibition of human β2 with an IC50 of 85 nM (Fig.4A). This molecule was highly specific for β2, showing little activity (greater than 1 μM) against β1 or β5 (Fig.4A). AVPPGARFL-boro and PPGARFL-boro exhibited strong potency against β2, but not as strong as PGARFL-boro (Fig.4B). ARFL-boro was more potent than the index compound, with an IC50of 45 nM (Fig.4C). Note that the CP in these assays was present at 10 nM, indicating that inhibition was approaching a stoichiometric level. ARFL-boro retained excellent specificity for β2, again with very little activity against the other two active sites (Fig.4 and 6). There was a limit to how short the peptide could be: an RFL-boro molecule showed lower activity than ARFL-boro, although it was still quite potent (Fig.4B). Thus, ARFL-boro appears to represent the optimal PI31-derived β2 inhibitor in vitro. ARFL-epoxyketone was also a potent inhibitor of β2 (Fig.8), although it was slightly less potent than ARFL-boro (IC50 of 81 nM versus 45 nM). ARFL-epoxyketone retained excellent specificity for β2 (Fig.8). These results indicate that the key feature imparting β2 specificity is the unique constellation of PI31-derived residues, and that multiple different electrophiles are compatible with in vitro efficacy. Attorney Docket No.29618-0443WO1 ACanFL-boro potently inhibited β2 whereas ACitFL-boro showed little inhibitory activity (Fig.7). ACanFL-boro was comparable in potency to ARFL-boro; it was slightly less specific, showing some activity against β5, but was still at least 20-fold more potent at β2. Example 8: In vitro IC50Assays in MM.1S and RPMI-8226 The ability of ARFL-boro to inhibit growth of the commonly used MM.1S multiple myeloma cell line was tested. Cell Culture Human multiple myeloma cells (MM.1S or RPMI-8226) were maintained in RPMI-1640 medium (Gibco) supplemented with 10% heat-inactivated fetal bovine serum (FBS; Excell) and 1% penicillin-streptomycin (P / S) solution (Hyclone). Cells used for viability assays were recovered from frozen low-passage stocks. Cell Viability Assays Cell viability assays were performed using CellTiter-Glo (Promega) which measures ATP-dependent generation of oxidized D-luciferin, resulting in a luminescence readout directly proportional to the amount of metabolically active cells.1×104MM.1S or RPMI-8226 cells were seeded in 90 μL of medium. The next day 10 μL of each tested condition were added. Controls lacking drug were used to establish baseline viability rates. ARFL-boro was tested with 8 doses in duplicate starting from 30 μM with 4-fold dilutions to a final concentration of 458 pM. Bortezomib was tested with 8 doses in duplicate starting from 200 nM with 4-fold dilutions to a final concentration of 3.1 pM. On day 3, a volume of CellTiter-Glo reagent equal to the volume of cell culture medium was added, the plate was then shaken at room temperature for 10 minutes, and luminescence was determined using an EnVision plate reader (Perkin Elmer). To analyze for a potential synergistic effect of ARFL-boro with bortezomib, the bortezomib concentration was held steady at 2 nM while varying concentrations of ARFL-boro were used (8 doses in duplicate starting from 10 μM and undergoing 2-fold serial dilutions to a final concentration of 3.9 nM). ARFL-boro was highly toxic to MM.1S with a half-maximal effective concentration (EC50) of 181 nM (Fig.5A). There was 100% growth inhibition at higher Attorney Docket No.29618-0443WO1 doses of the compound. For comparison, the β5-directed inhibitor bortezomib was significantly more potent than ARFL-boro, with an EC50 of 1.5 nM (Fig.5). The synergistic activity of bortezomib and ARFL-boro was tested. The assay was repeated with both drugs in combination. Bortezomib was held constant near its EC50 (2 nM), and ARFL-boro was added in increasing amounts. This resulted in enhanced toxicity to myeloma cells and reduced ARFL-boro’s EC50to 51 nM (Fig.5B). The two- drug combination was highly synergistic, as evidenced by the very low Combination Index (CI) scores (Fig.5E), where values of <1 indicate synergy. Different myeloma cell lines are characterized by different genetic drivers. To determine whether the anti-proliferative effect of ARFL-boro was specific to MM.1S, we a second widely used myeloma cell line, RPMI-8226 was tested. ARFL-boro again showed complete inhibition of growth with an EC50 of 318 nM (Fig.5). Note that bortezomib also showed a somewhat higher EC50in this cell line (3.9 nM) compared to MM.1S, and the relative strengths of bortezomib and ARFL-boro were comparable across both cell lines. Thus, ARFL-boro appears to be effective at inhibiting growth of myeloma cells in culture both as a standalone agent and as a combination therapy with bortezomib. In the MM.1S cell line, ACanFL-boro showed improved cytotoxicity over ARFL- boro, with an EC50 of 78 nM (Fig.7). Importantly, it showed complete growth inhibition at concentrations where it is expected to have little or no effect on β5 (Fig.7). Finally, ACanFl-boro showed strong synergistic effects in combination with bortezomib (Fig.7). The procedure for the assay is described below. Procedure: Day 1: Seed 10000 MM.1S cells in 90 uL medium (90% RPMI Medium 1640 and 10% FBS) to each well of assay plate, place at 5% CO2, 37°C overnight. Day 2: Prepare serial dilutions 1) 4-fold serial dilute Staurosporin to get 8 doses and transfer by MAP 10 uL of each concentration to the wells shown in the plate diagram below 2) 4-fold serial dilute Bortezomib to get 8 doses and transfer by MAP 10 uL of each concentration to the wells shown in the plate diagram below Attorney Docket No.29618-0443WO1 3) 4-fold serial dilute AcanFL-Boro to get 8 doses and transfer by MAP 10 uL of each concentration to the wells shown in the plate diagram below No. Compound IC50 (nM) %Inh_MaxDose Max Dose (nM) Ubiquitin Immunoblot Assays To monitor ubiquitin conjugates in whole cell extracts, MM.1S cells were treated with ARFL-boro (200 nM), bortezomib (1 nM), or a combination of the two for 16 hours. Cells were collected and lysed by sonication, and total protein concentrations were normalized by Bradford assay. The extracts were reconstituted in 5X Laemmli loading buffer, incubated at 70°C for 15 min, and analzyed by SDS-PAGE followed by immunoblotting with anti-ubiquitin (Santa Cruz, sc-8017) or anit-GAPDH antibodies (Sigma, G9545). A strong synergistic effect of the two-drug combination on the accumulation of high molecular weight ubiquitin conjugates was observed (Fig.5C). Example 9. In vitro IC50Assays in Human Cancer Cell Line Series The ability of ARFL-boro to inhibit growth of 158 human cancer cell lines was tested. Table 1 shows the IC50and % max inhibition of ARFL-boro and cisplatin against a panel of human cancer cell lines. Table 1. Cell IC50(μM) % Max inhibition Cell lines ARFL ARFL Attorney Docket No.29618-0443WO1 HT-1376 1.0488 5.2185 98.09% 90.98% JVM-3 0.4345 0.743 99.98% 99.89% K i1 7 2 417 4 7 Attorney Docket No.29618-0443WO1 KYSE-150 0.6276 5.7063 99.49% 95.29% KYSE-270 0.7129 4.5942 99.90% 99.96% LN22 1 7 2 Attorney Docket No.29618-0443WO1 NCI-H929 0.3332 2.8084 99.99% 99.99% NUGC-4 1.3909 4.1996 99.48% 87.86% ILY1 1 72 12 Attorney Docket No.29618-0443WO1 148 YCC-10 0.3733 2.0463 99.94% 95.37% 149 MKN45 3.2845 5.6819 99.35% 96.64% 1 7 P 11 7 422 2 . f cell lines, and Fig. 9B is an expanded view of the IC50 of ARFL-boro against cell lines it is most active against. All IC50values measured are less than 4 ^M, and the IC50values measured against myeloma cell lines (1), acute lymphoblastic leukemia cell lines (2), a mantle cell lymphoma cell line (3), renal cell carcinoma cell lines (4), stomach cancer cell lines (5), and acute myeloid leukemia cell lines (6) are in the nanomolar range (Fig.9B). Example 10. Combination Effect of ARFL-Boronic Acid and Anti-Cancer Drugs on Cancer Cell Lines Study Objectives ^ To measure the 50% inhibition concentrations (IC50) of test articles on the MM.1S cell line using a standard CTG assay. ^ To measure the compound synergy effect on the Molt-4, 786-O, and A498 cell lines using a standard CTG assay. Study Design IC50determination: MM.1S cell line was tested with 4 test articles for 1 day and incubated at a temperature of 37°C under an atmosphere including 5% CO2 and 95% humidity. Compound synergy effect determination: Molt-4, 786-O, and A498 cell lines were tested with the compound combinations below for 1 day and incubated at a temperature of 37°C, with 5% CO2 and 95% humidity. 1) Molt-4 with vincristine at 0.56 micromolar and ARFL-boro (dilution series) Attorney Docket No.29618-0443WO1 2) 786-O with sorafenib at 17 micromolar and ARFL-boro (dilution series) 3) 786-O with everolimus at 10 micromolar and ARFL-boro (dilution series) 4) Molt-4 with bortezomib at 4 nanomolar and ARFL-boro (dilution series) 5) 786-O with bortezomib at 5 nanomolar and ARFL-boro (dilution series) 6) A498 with bortezomib at 2 nanomolar and ARFL-boro (dilution series) Materials and Methods Table 2 lists the cell lines used in the experiments. Each cell line was cultured in the media listed and incubated at a temperature of 37°C, with 5% CO2and 95% humidity. Table 2. Cell lines No. Cell line Tissue Origin Culture Property Medium 1MM.1S Blood Adherent & Suspension RPMI-1640+10%FBS Materials and Reagents ^ 96-Well Flat Clear Bottom White Polystyrene TC-Treated Microplate (Cat.No.:3610, Corning) ^ CellTiter-Glo® Luminescent Cell Viability Assay (Cat. No.: G7572, Promega) ^ FBS (Cat. No.: FND500, ExCell) ^ DMSO (Cat. No.: D2650, Sigma) ^ RPMI1640 Medium (Cat# C22400500BT, Gibco) ^ MEM Medium (Cat# C11095500BT, Gibco) Equipment ^ Microplate Reader, SPARK, TECAN (Equipment ID: TAREA0070) ^ CO2 Water Jacketed Incubator, SANYO Electric Co., Ltd. (Japan). (Equipment ID: TAINC0530) ^ Microscope, Ts2-FL (Nikon P.R.China). (Equipment ID: TAMIC0360) Attorney Docket No.29618-0443WO1 ^ Vi-Cell XR. (Beckman Coulter) (Equipment ID: TAPUS0100) Table 3 lists the test articles used in the experiments. Table 3. Stock Storage after Subject Qty Purity (mg) (%) M.W. Solvent solution reconstitutio (mM) n p . Table 4. Subject Cat# Qty (mg) M.W. Solvent Storage Vendor rocedure or C50determ naton on t e . S ce ne Day -1 1. Harvested cells during the logarithmic growth period and counted cells. 2. Adjusted cell concentration with culture medium to proper concentration. 3. Added 90 µl cell suspensions to a 96-well plate according to the plate map with corresponding culture medium at a density of 10000 / well. Day 0 4. Prepared desired solution of test article using DMSO. Then, further diluted with culture medium to 10x working drug solution (see Test Articles Dilution). 5. Prepared 10x working drug solution of Cisplatin control (see Test Articles Dilution). 6. Dispensed 10 µl test article solution or Cisplatin (10×) separately to each well (triplicate for each concentration) (see appendix 2). Attorney Docket No.29618-0443WO1 7. Cultured the plates in a humidified incubator at 37°C with 5% CO2 for 1 day. Day 1 8. Determined the cell viability using CTG assay as following. 9. Equilibrated the plate and its contents at room temperature for approximately 30 minutes. 10. Added 100 µl of CellTiter-Glo® Reagent into the assay well. 11. Mixed contents for 10 minutes on an orbital shaker to induce cell lysis. 12. Allowed the plate to incubate at room temperature for 20 minutes to stabilize luminescent signal. 13. Recorded luminescence using Microplate Reader. Compound synergy effect determination Day -1 1. Harvested cells during the logarithmic growth period and counted cells. 2. Adjusted cell concentration with culture medium to proper concentration. 3. Added 80 µl cell suspensions to a 96-well plate according to the plate map with corresponding culture medium at a density of 10000 / well. Day 0 4. Prepared desired solution of test articles using DMSO. Then, further diluted with culture medium to 10x working drug solution (see Test Articles Dilution). 5. Dispensed 10 µl of dilution series of ARFL-boro separately to the desired wells of both single test and combo test (triplicate for each concentration) (see Plate Inoculation Map). 6. Dispensed 10 or 20 ul of culture medium containing 0.1% DMSO to the desired wells of single test (see Plate Inoculation Map). 7. Dispensed 10 ul of fixed dose solution of another test article to the desired wells of combo test (see Plate Inoculation Map). 8. Dispensed 10 or 20 ul of culture medium containing 0.1% DMSO to the desired wells of combo test (see Plate Inoculation Map). 9. Cultured the plates in a humidified incubator at 37°C with 5% CO2 for 1 day. Day 1 10. Determined the cell viability using CTG assay as following. 11. Equilibrated the plate and its contents at room temperature for approximately 30 minutes. 12. Added 100 µl of CellTiter-Glo® Reagent into the assay well. Attorney Docket No.29618-0443WO1 13. Mixed contents for 10 minutes on an orbital shaker to induce cell lysis. 14. Allowed the plate to incubate at room temperature for 20 minutes to stabilize luminescent signal. 15. Recorded luminescence using Microplate Reader. Data analysis The data was displayed graphically using Crownbio’s data portal. In order to calculate absolute IC50, a dose-response curve was fitted using nonlinear regression model with a sigmoidal dose response. The formula used for calculating surviving rate is shown below and the absolute IC50was calculated according to the dose-response curve generated by Crownbio’s data portal. The surviving rate (%) = (LumTest article-LumMedium control) / (LumNone treated-LumMedium control)×100%. The synergy score was Results Table 5 shows IC50values of test articles on the selected cell lines. Table 5. Cell Line Name Test Article IC50 (µM) Max Inhibition (%) . s a p o o ose espo se cu es o es a c es o se e a ce es. Test Articles Dilution Specifications IC50 determination Table 6 shows the final concentration of the test article and reference control. Table 6. Cpd Concentration (µM) Attorney Docket No.29618-0443WO1 Test article 30, 7.5, 1.875, 0.469, 0.117, 0.0293, 0.0073, 0.0018, 0.0005 Tables 7 and 8 (after 1:100 dilution 2µl + 198µl) show dilution tables for test articles. Table 7. 1000X Drug 4X Serial Dilution 100%DMSO Stock solution C1 C2 C3 C4 C5 C6 C7 C8 C9 O M l l Volume1: Volume of DMSO in the well before dilution Volume2: Volume of drug solution taken from the adjacent higher concentration to the next concentration Table 8. 10X Drug 1%DMSO C1-1 C2-1 C3-1 C4-1 C5-1 C6-1 C7-1 C8-1 C9-1 m M l Reference control of Cisplatin Attorney Docket No.29618-0443WO1 10mg Cisplatin (reference control) was dissolved into 10 ml PBS to obtain a 3.33mM stock solution, then diluted at 1:3 according to the specifications in Table 9. Table 9. 10X Cisplatin 3X Serial Dilution 100%PBS Stock solution C1 C2 C3 C4 C5 C6 C7 C8 C9 S M µl µl Table 10 shows the final concentration of test articles used in the fixed dose combination experiments. Table 10. Combination Concentration - L- - L- - Attorney Docket No.29618-0443WO1 Combo test: 30, 7.5, 1.875, 0.469, 0.117, 0.0293, 0.0073, 0.0018 (µM) ARFL- boro + 10 (µM) everolimus Single test: 30 75 1875 0469 0117 00293 00073 00018 (µM) ARFL- L- - L- - L- used in the fixed dose experiments. Table 11. 1000X Drug 4X Serial Dilution 100%DMSO Stock solution C1 C2 C3 C4 C5 C6 C7 C8 O M l l Not Vol Volume1: Volume of DMSO in the well before dilution Volume2: Volume of drug solution taken from the adjacent higher concentration to the next concentration Table 12. 10X Drug 1%DMSO Attorney Docket No.29618-0443WO1 C1-1 C2-1 C3-1 C4-1 C5-1 C6-1 C7-1 C8-1 m M l Med Plate Inoculation Maps used Table 13 shows a plate inoculation map used for IC50determination. Table 13. Row 1 2 3 4 5 6 7 8 9 10 11 12 A E E E E E E E E E E E E d12 V: Cells in Vehicle (0.1% DMSO or 10% PBS) Tables 14-19 show plate inoculation maps used for fixed dose combinations. Table 14. ARFL-boro and vincristine for Molt-4. Row 1 2 3 4 5 6 7 8 9 10 11 12o Attorney Docket No.29618-0443WO1 ARFL-boro G E C1* C2* C3* C4* C5* C6* C7* C8* F V E and vincristine g F: Fixed dose of vincristine only V: Cells in Vehicle (0.2% DMSO) Table 15. ARFL-boro and sorafenib for 786-O. Row 1 2 3 4 5 6 7 8 9 10 11 12A E E E E E E E E E E E Eo o ib C1*-C8* in green: 8 concentration levels of ARFL-boro and Fixed dose of sorafenib F: Fixed dose of sorafenib only V: Cells in Vehicle (0.2% DMSO) Table 16. ARFL-boro and everolimus for 786-O. Row 1 2 3 4 5 6 7 8 9 10 11 12o o s - e co ce a o e e s o - o o C1*-C8* in green: 8 concentration levels of ARFL-boro and Fixed dose of everolimus F: Fixed dose of everolimus only V: Cells in Vehicle (0.2% DMSO) Attorney Docket No.29618-0443WO1 Table 17. ARFL-boro and bortezomib for Molt-4. Row 1 2 3 4 5 6 7 8 9 10 11 12A E E E E E E E E E E E Eo o b C1 -C8 in green: 8 concentration levels of ARFL-boro and Fixed dose of bortezomib F: Fixed dose of everolimus only V: Cells in Vehicle (0.2% DMSO) Table 18. ARFL-boro and bortezomib for 786-O. Row 1 2 3 4 5 6 7 8 9 10 11 12A E E E E E E E E E E E Eo o b C1*-C8* in green: 8 concentration levels of ARFL-boro and Fixed dose of bortezomib F: Fixed dose of everolimus only V: Cells in Vehicle (0.2% DMSO) Table 19. ARFL-boro and bortezomib for A498. Row 1 2 3 4 5 6 7 8 9 10 11 12o Attorney Docket No.29618-0443WO1 ARFL-boro G E C1* C2* C3* C4* C5* C6* C7* C8* F V E and bortezomib g F: Fixed dose of everolimus only V: Cells in Vehicle (0.2% DMSO) Results The following results were obtained for combinations of (i) ARFL-boro and (ii) bortezomib, vincristine, sorafenib, or everolimus using the CrownSyn service: 1. Synergy scores calculated by Bliss independence model. A score higher than 5 indicates synergy, and a score less than -5 indicates antagonism. 2. Drug response curves for both single drug, combination, and drug inhibition heatmap. 3. Synergy plots heatmap. The Bliss independence model is expected to apply to non-interacting drugs that elicit their responses independently, e.g., by targeting separate pathways. Fixed dose combination results A total of 6 combination experiments were tested in 3 cell lines, shown in Table 2. Table 2. Model Drug 1 Drug 2 Bliss (Mean) Bliss (Median) M lt 4 i i ti ARFL b 311 224 1 4 7 5 7 FIG. 10A is a dose-response curve for ARFL-boro in Molt-4 cells. FIG. 10B is a dose- response curve for ARFL-boro and vincristine in Molt-4 cells. FIG.10C is a dose-response Attorney Docket No.29618-0443WO1 matrix for ARFL-boro and vincristine in Molt-4 cells. Table 3 shows synergy scores for the combination of vincristine and ARFL-boro in Molt-4 cells. Table 3. Synergy Scores table (Bliss) vincristine(μM) ARFL-boro(μM) Bliss_synergy 1 0.56 0.001831 -0.744909 . y gy p oro and vincristine in Molt-4 cells. FIGS 10A-10D show that ARFL-boro, alone or synergistically in combination with vincristine, inhibits the growth of Molt-4 cells and therefore has utility in, e.g., the treatment of acute lymphoblastic leukemia. FIG. 11A is a dose-response curve for ARFL-boro in 786-O cells. FIG. 11B is a dose- response curve for ARFL-boro and sorafenib in 786-O cells. FIG.11C is a dose-response matrix for ARFL-boro and sorafenib in 786-O cells. Table 4 shows synergy scores for the combination of sorafenib and ARFL-boro in 786-O cells. Table 4. sorafenib(μM) ARFL-boro(μM) Bliss_synergy 1 17 0001831 2625944 Attorney Docket No.29618-0443WO1 FIG.11D is a Bliss synergy score heatmap for ARFL-boro and sorafenib in 786-O cells. FIGS 11A-11D show that ARFL-boro inhibits the growth of 786-O cells and therefore has utility in, e.g., the treatment of renal cell carcinoma. FIG. 12A is a dose-response curve for ARFL-boro in 786-O cells. FIG. 12B is a dose- response curve for ARFL-boro and everolimus in 786-O cells. FIG.12C is a dose-response matrix for ARFL-boro and everolimus in 786-O cells. Table 5 shows synergy scores for the combination of everolimus and ARFL-boro in 786-O cells. Table 5. everolimus(μM) ARFL-boro(μM) Bliss_synergy 1 10 0.001831 2.161225 FIG.12D is a Bliss synergy score heatmap for ARFL-boro and everolimus in 786-O cells. FIGS 12A-12D show that ARFL-boro inhibits the growth of 786-O cells and therefore has utility in, e.g., the treatment of renal cell carcinoma. FIG. 13A is a dose-response curve for ARFL-boro in Molt-4 cells. FIG. 13B is a dose- response curve for ARFL-boro and bortezomib in Molt-4 cells. FIG.13C is a dose-response matrix for ARFL-boro and bortezomib in Molt-4 cells. Table 6 shows synergy scores for the combination of bortezomib and ARFL-boro in Molt-4 cells. Table 6. bortezomib(nM) ARFL-boro(μM) Bliss_synergy Attorney Docket No.29618-0443WO1 bortezomib(nM) ARFL-boro(μM) Bliss_synergy 4 4 0.117188 35.571938 ro and bortezomib in Molt-4 cells. FIGS 13A-13D show that ARFL-boro, alone or synergistically in combination with bortezomib, inhibits the growth of Molt-4 cells and therefore has utility in, e.g., the treatment of acute lymphoblastic leukemia. Particularly noteworthy is that at ARFL-boro concentrations of 0.117188 μM and 0.468750 μM, the Bliss synergy scores are an astoundingly high 35.571938 and 30.587023, demonstrating the surprisingly strong synergy of the ARFL-boro and bortezomib combination. FIG. 14A is a dose-response curve for ARFL-boro in 786-O cells. FIG. 14B is a dose- response curve for ARFL-boro and bortezomib in 786-O cells. FIG.14C is a dose-response matrix for ARFL-boro and bortezomib in 786-O cells. Table 7 shows synergy scores for the combination of bortezomib and ARFL-boro in 786-O cells. Table 7. bortezomib(nM) ARFL-boro(μM) Bliss_synergy 1 5 0001831 1136419 FIG.14D is a Bliss synergy score heatmap for ARFL-boro and bortezomib in 786-O cells. FIGS 14A-14D show that ARFL-boro, alone or synergistically in combination with bortezomib, inhibits the growth of 786-O cells and therefore has utility in, e.g., the treatment of renal cell carcinoma. Attorney Docket No.29618-0443WO1 FIG. 15A is a dose-response curve for ARFL-boro in A498 cells. FIG. 15B is a dose- response curve for ARFL-boro and bortezomib in A498 cells. FIG.15C is a dose-response matrix for ARFL-boro and bortezomib in A498 cells. Table 8 shows synergy scores for the combination of bortezomib and ARFL-boro in A498 cells. Table 8. bortezomib(nM) ARFL-boro(μM) Bliss_synergy 1 2 0.001831 -1.279408 . s a ss synergy score ea map or - oro and bortezomib in A498 cells. FIGS 15A-15D show that ARFL-boro inhibits the growth of A498 cells and therefore has utility in, e.g., the treatment of renal cell carcinoma. Summary ARFL-boronic acid, shows an in vitro half-maximal inhibitory concentration (IC50) of 45 nM against β2 with little activity against β5 or β1 (IC50> 4000 nM). ARFL-boro strongly inhibited growth of multiple myeloma cells in culture (IC50=105 nM), suggesting favorable cell permeability and establishing β2 as a therapeutic target in myeloma. Combining ARFL-boro with an approved β5 inhibitor, bortezomib, showed strongly synergistic activity against myeloma cells. Without wishing to be bound by theory, it is believed that such β2 / β5-targeting combination therapies might reduce therapeutic resistance and severe side effects. The efficacy of ARFL-boro against 158 cancer cell lines representing a broad spectrum of human malignancy were examined, and three other tumor types showing strong sensitivity to ARFL-boro were identified: acute lymphoblastic leukemia, acute myelogenous leukemia, and renal cell carcinoma. Attorney Docket No.29618-0443WO1 ARFL-boro exhibits significant synergy in combination with bortezomib against Molt-4 and 786-O and in combination with vincristine against Molt-4. ARFL-boro and bortezomib show dramatic synergy against Molt-4 cells at ARFL-boro concentrations of 0.117188 μM and 0.468750 μM. OTHER EMBODIMENTS It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

Attorney Docket No.29618-0443WO1 WHAT IS CLAIMED IS:

1. A compound of Formula (I) (I) or a 1each R is R2, R3, R4, R5, R6, and R7are selected from hydrogen, C1-C12 alkyl, C3- C12 alkenyl, C1-C12 alkylOH, C1-C12 alkylSH, C1-C4 alkylSCH3, C1-C4 alkylCONH2, C1- C4alkylCOOH, C1-C4alkylNH2, C1-C4alkylNHC(NH)NH2, C1-C4alkylONHC(NH)NH2, C1-C4 alkylNHC(O)NH2, C1-C4 alkyl (C3-C6 cycloalkyl), C1-C4 alkyl (3 to 10-membered heterocyclic), C1-C4 alkyl (C6-C10 aryl)RA, C1-C4 alkyl ( 5 to 10-membered heteroaryl), and C1-C12alkyl)(W)C1-C12alkyl; wherein W is a heteroatom selected from N, S, and O; or R2and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R3and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; and / or R4and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R5and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; and / or R6and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R7and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; RAis selected from H, OH, halo, (C1-C7alkyl), (C2-C7alkenyl), OCF3, NO2, CN, NC, O(C1-C7 alkyl), CO2H, CO2(C1-C7 alkyl), NH2, aryl, and heteroaryl; X is B2or , wherein Rxis selected from hydrogen and C1-C8alkyl;an amino acid, and a polypeptide.Attorney Docket No.29618-0443WO1 2. A compound of Formula (Ia) or a R2, R3, R4,alkyl, C3- C12 alkenyl, C1-C12 alkylOH, C1-C12 alkylSH, C1-C4 alkylSCH3, C1-C4 alkylCONH2, C1- C4 alkylCOOH, C1-C4 alkylNH2, C1-C4 alkylNHC(NH)NH2, C1-C4 alkylONHC(NH)NH2, C1-C4alkylNHC(O)NH2, C1-C4alkyl (C3-C6cycloalkyl), C1-C4alkyl (3 to 10-membered heterocyclic), C1-C4 alkyl (C6-C10 aryl)RA, C1-C4 alkyl (5 to 10-membered heteroaryl), and C1-C12 alkyl)(W)C1-C12 alkyl; wherein W is a heteroatom selected from N, S, and O; or R2and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R3and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; and / or R4and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R5and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; and / or R6and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R7and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; and / or R8and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring, or R9and an R1on an adjacent N atom together with the atoms to which they are attached form a pyrrolidine ring; RAis selected from H, OH, halo, (C1-C7alkyl), (C2-C7alkenyl), OCF3, NO2, CN, NC, O(C1-C7alkyl), CO2H, CO2(C1-C7alkyl), NH2, aryl, and heteroaryl; , wherein Rxis selected from hydrogen and C1-C8alkyl;amino acid, and a polypeptide.Attorney Docket No.29618-0443WO1 3. A compound of Formula (II) or a 23R , R , C4alkylSCH3, C1-C4alkyl(C6-C10aryl)R7, and C1-C4(5 to 10-membered heteroaryl); R6and R7are selected from H, C2-C12alkylOH, C2-C12alkylSH, C1- C4 alkylCONH2, C1-C4 COOH, C1-C4 NH2, C1-C4 NHC(NH)NH2, C1- C4 alkylONHC(NH)NH2, C1-C4 alkylNHC(O)NH2, and C1-C4 (5 to 10-membered heteroaryl); RAis selected from H, OH, halo, (C1-C7 alkyl), (C2-C7 alkenyl), OCF3, NO2, CN, NC, O(C1-C7 alkyl), CO2H, CO2(C1-C7 alkyl), NH2, aryl, and heteroaryl; , wherein Rxis selected from hydrogen and C1-C8 alkyl;amino acid, or a polypeptide. 4 The compound of any one of the preceding claims, wherein Y is H. 5 The compound of claim 2 or 3, wherein Y is -Gly. 6 The compound of claim 2 or 3, wherein Y is -Gly-Pro. 7 The compound of claim 2 or 3, wherein Y is -Gly-Pro-Pro. 8 The compound of claim 2 or 3, wherein Y is -Gly-Pro-Pro-Ala. 9 The compound of any one of the preceding claims, wherein X is B(OH)2.Attorney Docket No.29618-0443WO1 10. The compound of any of claims 1-8, wherein X is , wherein Rxis selected from hydrogen and C1-C8 alkyl.

11. The compound of claim 10, wherein X .

12. The compound of any one of the preceding claims, wherein R2and R3are independently selected from H, CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, CH2CH2SCH3, CH2(C6-aryl)RA, and CH2heteroaryl.

13. The compound of claim 12, wherein R2and R3are independently selected from H and CH2CH(CH3)2.

14. The compound of any one of the preceding claims, wherein R4and R5are independently selected from H, CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, CH2CH2SCH3, CH2(C6-aryl)RA, and CH2heteroaryl.

15. The compound of claim 14, wherein R4and R5are independently selected from H and CH2- phenyl.

16. The compound of any one of the preceding claims, wherein R6and R7are independently selected from H, CH2(C0-C10 alkyl)OH, CH2(C0-C10 alkyl)SH, CH2(C0-C3 alkyl)CONH2, CH2(C0-C3alkyl)COOH, CH2(C0-C3alkyl)NH2, CH2(C0-C3alkyl)NHC(NH)NH2, C1- C4 alkylONHC(NH)NH2, C1-C4 alkylNHC(O)NH2, and CH2(C1-C3 alkyl)(C3- C9 heteroaryl).Attorney Docket No.29618-0443WO1 17. The compound of claim 16, wherein R6and R7are independently selected from H and (CH2)3NHC(NH)NH2.

18. The compound of claim 16, wherein R6and R7are independently selected from H and (CH2)3NHC(O)NH2.

19. The compound of claim 16, wherein R6and R7are independently selected from H and (CH2)2ONHC(NH)NH2.

20. The compound of any one of claims 2-19, wherein R8and R9are independently selected from H, CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, CH2CH2SCH3, CH2(C6- aryl)RA, and CH2heteroaryl.

21. The compound of claim 20, wherein R8and R9are independently selected from H and CH3.

22. A compound selected from the group consisting of: , ,Attorney Docket No.29618-0443WO1or a pharmaceutically acceptable salt of any of the foregoing.

23. A compound that boro).

24. A pharmaceutical composition comprising a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24.

26. The method of claim 25, comprising administering a second therapeutic agent to the subject.Attorney Docket No.29618-0443WO1 27. The method of any one of claims 26-26, wherein the second therapeutic agent is vincristine, sorafenib, everolimus, bortezomib, carfilzomib, ixazomib, and combinations thereof.

28. The method of any one of claims 25-27, wherein the cancer is multiple myeloma, mantle cell lymphoma, renal cell carcinoma, acute myelogenous leukemia, or acute lymphoblastic leukemia (AML).

29. The method of claim 28, wherein the multiple myeloma is relapsed or refractory.

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