WO2019213620A1

WO2019213620A1 - Epha4 cyclic peptide antagonists and methods of use thereof

Info

Publication number: WO2019213620A1
Application number: PCT/US2019/030739
Authority: WO
Inventors: Christopher Ronald Smith; Justin Chapman
Original assignee: Iron Horse Therapeutics Inc
Current assignee: Iron Horse Therapeutics Inc
Priority date: 2018-05-04
Filing date: 2019-05-03
Publication date: 2019-11-07
Anticipated expiration: 2020-11-04

Abstract

Disclosed herein are compounds and methods of use thereof for the modulation of EphA4 receptor activity. In an aspect, is provided a method of treating or preventing a disease or disorder mediated by EphA4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein, including certain embodiments, or the structural Formula (I), (l-A), (II), (III), (IV), (IV-1), (V), (Vl-A), (Vl-B), (VII-1), (VII-2), (VIII-1), or (VIII-2), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

Description

EPHA4 CYCLIC PEPTIDE ANTAGONISTS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Applciation No.62/667,313, filed on May 4, 2018; U.S. Provisional Application No.62/742,224, filed on October 5, 2018; and U.S. Provisional Application No.62/808,539, filed on February 21, 2019. The disclosure of each of the prior applications is considered part of and is incorporated by reference in the disclosure of this application.

BACKGROUND

[0002] Eph receptors (Eph receptors) are a group of receptors that are activated in response to binding with Eph receptor-interacting proteins (Ephrins). Ephs form the largest known subfamily of receptor tyrosine kinases (RTKs). Both Eph receptors and their corresponding ephrin ligands are membrane- bound proteins that require direct cell-cell interactions for Eph receptor activation. Eph/ephrin signaling has been implicated in the regulation of a host of processes critical to embryonic development including axon guidance, formation of tissue boundaries, cell migration, and segmentation. Additionally,

Eph/ephrin signaling has recently been identified to play an important role in the maintenance of several processes during adulthood including long-term potentiation, angiogenesis, and stem cell differentiation and cancer.

[0003] The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Ephrin type-A receptor 4 (EphA4) belongs belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family.

Through activation by the cell surface-anchored ephrin ligands, EphA4 plays physiological roles in axon guidance during development as well as in the structural remodeling of synaptic connections and modulation of synapatic transmission in the adult brain. The identification of compounds that modulate EphA4 function is an ongoing challenge. Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY

[0004] In an aspect provided herein, is a compound having structural Formula (I):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:

X¹ is CR⁹R¹⁰ or S;

X² is CR¹¹R¹² or S;

X³ is–NH– or–C(O)NH–,

z1 is an integer from 0 to 2;

z2 is an integer from 0 to 5;

n1, n2, n3, n5, n6, n7, n8, n9, n10, n11, and n12 are independently an integer from 0 to 4;

m1, m2, m5, m6, m7, m8, m9, m10, m11, m12, v1, v2, v3, v5, v6, v7, v8, v9, v10, v11, and v12 are independently 1 or 2;

L¹ and L² are independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

L³ is a bond,–O–,–S–,–NR^3L–,–C(O)–, -C(O)O–,–S(O)–,–S(O)₂–, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R¹ is hydrogen, halogen,–CX^1.1

3, -CHX1.1

2, -CH₂X^1.1,–CN,–N₃,–SO_n1R^1A,–SO_v1NR^1BR^1C,

-NHNR^1BR^1C, -ONR^1BR^1C, -NHC(O)NHNR^1BR^1C, -NHC(O)NR^1BR^1C,–N(O)_m1,–NR^1BR^1C,– C(O)R^1D,–C(O)OR^1D,–C(O)NR^1BR^1C,–OR^1A, -NR^1BSO₂R^1A, -NR^1BC(O)R^1D, -NR^1BC(O)OR^1D,– NR^1BOR^1D,–OCX^1.1

3,–OCHX1.1

2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R² is hydrogen, halogen,–CX^2.1

3, -CHX2.1

2, -CH₂X^2.1,–CN,–N₃,–SO_n2R^2A,–SO_v2NR^2BR^2C,

-NHNR^2BR^2C, -ONR^2BR^2C, -NHC(O)NHNR^2BR^2C, -NHC(O)NR^2BR^2C,–N(O)_m2,–NR^2BR^2C,– C(O)R^2D,–C(O)OR^2D,–C(O)NR^2BR^2C,–OR^2A, -NR^2BSO₂R^2A, -NR^2BC(O)R^2D, -NR^2BC(O)OR^2D,– NR^2BOR^2D,–OCX^2.1

3,–OCHX2.1

R³ is hydrogen,–SO_n3R^3A,–SO_v3NR^3BR^3C,–C(O)R^3D,–C(O)OR^3D,–C(O)NR^3BR^3C,–C=NHNR^3B,

substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁴ is hydrogen, halogen,–CX^4.1

3, -CHX4.1

2, -CH₂X^4.1,–NR^4BR^4C,–C(O)R^4D,–C(O)NR^4BR^4C,–OR^4A, - NR^4BSO₂R^4A, -NR^4BC(O)R^4D, -NR^4BC(O)OR^4D,–NR^4BOR^4D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁵ is hydrogen, halogen, oxo,–CX^5.1

3, -CHX5.1

2, -CH₂X^5.1,–CN,–N₃,–SO_n5R^5A,–SO_v5NR^5BR^5C, -NHNR^5BR^5C, -ONR^5BR^5C, -NHC(O)NHNR^5BR^5C, -NHC(O)NR^5BR^5C,–N(O)_m5,–NR^5BR^5C,– C(O)R^5D,–C(O)OR^5D,–C(O)NR^5BR^5C,–OR^5A, -NR^5BSO₂R^5A, -NR^5BC(O)R^5D, -NR^5BC(O)OR^5D,– NR^5BOR^5D,–OCX^5.1

3,–OCHX5.1

R⁶ is hydrogen, halogen,–CX^6.1

3, -CHX6.1

2, -CH₂X^6.1,–CN,–N₃,–SO_n6R^6A,–SO_v6NR^6BR^6C,

-NHNR^6BR^6C, -ONR^6BR^6C, -NHC(O)NHNR^6BR^6C, -NHC(O)NR^6BR^6C,–N(O)_m6,–NR^6BR^6C,– C(O)R^6D,–C(O)OR^6D,–C(O)NR^6BR^6C,–OR^6A, -NR^6BSO₂R^6A, -NR^6BC(O)R^6D, -NR^6BC(O)OR^6D,– NR^6BOR^6D,–OCX^6.1

3,–OCHX6.1

R⁷ is hydrogen, halogen,–CX^7.1

3, -CHX7.1

2, -CH₂X^7.1,–CN,–N₃,–SO_n7R^7A,–SO_v7NR^7BR^7C,

-NHNR^7BR^7C, -ONR^7BR^7C, -NHC(O)NHNR^7BR^7C, -NHC(O)NR^7BR^7C,–N(O)_m7,–NR^7BR^7C,– C(O)R^7D,–C(O)OR^7D,–C(O)NR^7BR^7C,–OR^7A, -NR^7BSO₂R^7A, -NR^7BC(O)R^7D, -NR^7BC(O)OR^7D,– NR^7BOR^7D,–OCX^7.1

3,–OCHX7.1

2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁸ is independently hydrogen, halogen,–CX^8.1

3, -CHX8.1

2, -CH₂X^8.1,–CN,–N₃,–SO_n8R^8A,–

SO_v8NR^8BR^8C, -NHNR^8BR^8C, -ONR^8BR^8C, -NHC(O)NHNR^8BR^8C, -NHC(O)NR^8BR^8C,–N(O)_m8,– NR^8BR^8C,–C(O)R^8D,–C(O)OR^8D,–C(O)NR^8BR^8C,–OR^8A, -NR^8BSO₂R^8A, -NR^8BC(O)R^8D, - NR^8BC(O)OR^8D,–NR^8BOR^8D,–OCX^8.1

3,–OCHX8.1

R⁹ is hydrogen, halogen,–CX^9.1

3, -CHX9.1

2, -CH₂X^9.1,–CN,–N₃,–SO_n9R^9A,–SO_v9NR^9BR^9C,

-NHNR^9BR^9C, -ONR^9BR^9C, -NHC(O)NHNR^9BR^9C, -NHC(O)NR^9BR^9C,–N(O)_m9,–NR^9BR^9C,– C(O)R^9D,–C(O)OR^9D,–C(O)NR^9BR^9C,–OR^9A, -NR^9BSO₂R^9A, -NR^9BC(O)R^9D, -NR^9BC(O)OR^9D,– NR^9BOR^9D,–OCX^9.1

3,–OCHX9.1

R¹⁰ is hydrogen, halogen,–CX^10.1

3, -CHX10.1

2, -CH₂X^10.1,–CN,–N₃,–SO_n10R^10A,–SO_v10NR^10BR^10C, -NHNR^10BR^10C, -ONR^10BR^10C, -NHC(O)NHNR^10BR^10C, -NHC(O)NR^10BR^10C,–N(O)_m10,– NR^10BR^10C,–C(O)R^10D,–C(O)OR^10D,–C(O)NR^10BR^10C,–OR^10A, -NR^10BSO₂R^10A, -NR^10BC(O)R^10D, - NR^10BC(O)OR^10D,–NR^10BOR^10D,–OCX^10.1

3,–OCHX10.1

R¹¹ is hydrogen, halogen,–CX^11.1

3, -CHX11.1

2, -CH₂X^11.1,–CN,–N₃,–SO_n11R^11A,–SO_v11NR^11BR^11C, -NHNR^11BR^11C, -ONR^11BR^11C, -NHC(O)NHNR^11BR^11C, -NHC(O)NR^11BR^11C,–N(O)_m11,– NR^11BR^11C,–C(O)R^11D,–C(O)OR^11D,–C(O)NR^11BR^11C,–OR^11A, -NR^11BSO₂R^11A, -NR^11BC(O)R^11D, - NR^11BC(O)OR^11D,–NR^11BOR^11D,–OCX^11.1

3,–OCHX11.1

R¹² is hydrogen, halogen,–CX^12.1

3, -CHX12.1

2, -CH₂X^12.1,–CN,–N₃,–SO_n12R^12A,–SO_v12NR^12BR^12C, -NHNR^12BR^12C, -ONR^12BR^12C, -NHC(O)NHNR^12BR^12C, -NHC(O)NR^12BR^12C,–N(O)_m12,– NR^12BR^12C,–C(O)R^12D,–C(O)OR^12D,–C(O)NR^12BR^12C,–OR^12A, -NR^12BSO₂R^12A, -NR^12BC(O)R^12D, - NR^12BC(O)OR^12D,–NR^12BOR^12D,–OCX^12.1

3,–OCHX12.1

R¹⁵ is -C(O)NR^15AR^15B, -C(O)OR^15A, substituted or unsubstituted heteroalkyl, or substituted or

unsubstituted heteroaryl; R¹⁶ is -OR^16A, -C(O)OR^16A, or substituted or unsubstituted heteroalkyl; or R³ and R¹⁶ may optionally be joined to form substituted or unsubstituted heteroalkyl;

R^1A, R^1B, R^1C, R^1D, R^2A, R^2B, R^2C, R^2D, R^3A, R^3B, R^3C, R^3D, R^3L, R^4A, R^4B, R^4C, R^4D, R^5A, R^5B, R^5C, R^5D, R^6A, R^6B, R^6C, R^6D, R^7A, R^7B, R^7C, R^7D, R^8A, R^8B, R^8C, R^8D, R^9A, R^9B, R^9C, R^9D, R^10A, R^10B, R^10C, R^10D, R^11A, R^11B, R^11C, R^11D, R^12A, R^12B, R^12C, R^12D, R^15A, R^15B, and R^16A are independently hydrogen, halogen,– CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^1B and R^1C; R^2B and R^2C; R^3B and R^3C; R^4B and R^4C; R^5B and R^5C; R^6B and R^6C; R^7B and R^7C; R^8B and R^8C; R^9B and R^9C; R^10B and R^10C; R^11B and R^11C; or R^12B and R^12C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and

X^1.1, X^2.1, X^4.1, X^5.1, X^6.1, X^7.1, X^8.1, X^9.1, X^10.1, X^11.1, and X^12.1 are independently–Cl,–Br,–I, or–F.

[0005] In certain embodiments, the compound is not 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H- indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20-(3-guanidinopropyl)-23-(4- hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontan-7-yl)propanoic acid.

[0006] In certain embodiments, the compound is not 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H- indol-3-yl)methyl)-7-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20-(3-guanidinopropyl)-23-(4- hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontan-13-yl)propanoic acid.

[0007] In certain embodiments, the compound is not 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H- indol-3-yl)methyl)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4- hydroxyphenyl)propanamido)-4-carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13- diyl)dipropionic acid.

[0008] In an aspect is provided a pharmaceutical composition, including a compound as described herein, including certain embodiments, or the structural Formula (I), (I-A), (II), (III), (IV), (IV-1), (V), (VI-A), (VI-B), (VII-1), (VII-2), (VIII-1), or (VIII-2) , and a pharmaceutically acceptable excipient.

[0009] In another aspect is provided a method of inhibiting ephrin type-A receptor 4 (EphA4), the method comprising contacting EphA4 with a compound as described herein, including certain embodiments, or the structural Formula (I), (I-A), (II), (III), (IV), (IV-1), (V), (VI-A), (VI-B), (VII-1), (VII-2), (VIII-1), or (VIII-2), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. [0010] In an aspect, is provided a method of treating or preventing a disease or disorder mediated by EphA4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein, including certain embodiments, or the structural Formula (I), (I-A), (II), (III), (IV), (IV-1), (V), (VI-A), (VI-B), (VII-1), (VII-2), (VIII-1), or (VIII-2), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a

pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0011] In another aspect, provided herein is a kit including a compound described herein (e.g., an EphA4 inhibitor) or pharmaceutical compositions thereof. The kits are generally in the form of a physical structure housing various components, as described below, and may be utilized, for example, in practicing the methods described above.

INCORPORATION BY REFERENCE

[0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIGS.1A-1B are graphical representations of the results of Growth Cone Collapse assay of Example 121 (1A) and Example 62 (1B). E15 mouse cortical neuronal culture was pre-treated for 30 minutes with Examples 121 or 62 and stimulated for 15 minutes with 1 µg/mL clustered Fc-Ephrin A5 (~20 nM).

DETAILED DESCRIPTION

I. Definitions

[0014] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0015] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH₂O- is equivalent to -OCH₂-.

[0016] The term“alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals, having the number of carbon atoms designated (i.e., C₁-C₁₀ means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).

[0017] The term“alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH₂CH₂CH₂CH₂-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A“lower alkyl” or“lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term“alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0018] The term“heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH₂-CH₂-O-CH₃, -CH₂-CH₂-NH-CH₃, -CH₂-CH₂-N(CH₃)- CH₃, -CH₂-S-CH₂-CH₃, -CH₂-CH₂, -S(O)-CH₃, -CH₂-CH₂-S(O)₂-CH₃, -CH=CH-O-CH₃, -Si(CH₃)₃, -CH₂- CH=N-OCH₃, -CH=CH-N(CH₃)-CH₃, -O-CH₃, -O-CH₂-CH₃, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH₂-NH-OCH₃ and -CH₂-O-Si(CH₃)₃. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).

[0019] Similarly, the term“heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH₂- CH₂-S-CH₂-CH₂- and -CH₂-S-CH₂-CH₂-NH-CH₂-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino,

alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)₂R'- represents both -C(O)₂R'- and -R'C(O)₂-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO₂R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term“heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. [0020] The terms“cycloalkyl” and“heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of“alkyl” and“heteroalkyl,” respectively.

Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1- cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1- piperazinyl, 2-piperazinyl, and the like. A“cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.“Cycloalkyl” is also meant to refer to bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

[0021] The terms“halo” or“halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as“haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobutyl, 3-bromopropyl, and the like.

[0022] The term“acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0023] The term“aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term“heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term“heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl- 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5- quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An“arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0024] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or

unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.

[0025] The symbol“ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0026] The term“oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0027] The term“alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In certain embodiments, the alkylarylene group has the formula: or .

[0028] An alkylarylene moiety may be substituted (e.g. with a substituent group) on the alkylene moiety or the arylene linker (e.g. at carbons 2, 3, 4, or 6) with halogen, oxo, -N₃, -CF₃, -CCl₃, -CBr₃, -CI₃, -CN, - CHO, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO₂CH₃ -SO₃H, -OSO₃H, -SO₂NH₂, -NHNH₂, -ONH₂, -NHC(O)NHNH₂, substituted or unsubstituted C₁-C₅ alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In certain embodiments, the alkylarylene is unsubstituted. [0029] Each of the above terms (e.g.,“alkyl,”“heteroalkyl,”“cycloalkyl,”“heterocycloalkyl,”“aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0030] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO₂R', -CONR'R'', - OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)₂R', -NR-C(NR'R''R''')=NR'''', -NR- C(NR'R'')=NR''', -S(O)R', -S(O)₂R', -S(O)₂NR'R'', -NRSO₂R', -NR'NR''R''', -ONR'R'',

-NR'C(O)NR''NR'''R'''', -CN, -NO₂, -NR'SO₂R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF₃ and -CH₂CF₃) and acyl (e.g., -C(O)CH₃, -C(O)CF₃, -C(O)CH₂OCH₃, and the like).

[0031] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R'', -SR', -halogen, -SiR'R''R''', - OC(O)R', -C(O)R', -CO₂R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)₂R', - NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)₂R', -S(O)₂NR'R'', -NRSO₂R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO₂, -R', -N₃, -CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁- C₄)alkyl, -NR'SO₂R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' groups when more than one of these groups is present. [0032] Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.

[0033] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0034] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')_q-U-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH₂)_r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, -S(O)₂-, -S(O)₂NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')_s-X'- (C''R''R''')_d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, - S(O)₂-, or -S(O)₂NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0035] As used herein, the terms“heteroatom” or“ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0036] A“substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO₃H, -SO₄H, -SO₂NH₂, -NHNH₂, -ONH₂, -NHC=(O)NHNH₂, -NHC=(O) NH₂, -NHSO₂H, -NHC= (O)H, -NHC(O)- OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:

(i) oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO₃H, -SO₄H, -SO₂NH₂, -NHNH₂, -ONH₂, -NHC=(O)NHNH₂, -NHC=(O) NH₂, -NHSO₂H, -NHC= (O)H, -NHC(O)- OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:

(a) oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO₃H, -SO₄H, -SO₂NH₂, -NHNH₂, -ONH₂, -NHC=(O)NHNH₂, -NHC=(O) NH₂, -NHSO₂H, -NHC= (O)H, -NHC(O)- OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CF₃, -CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO₃H, - SO₄H, -SO₂NH₂, -NHNH₂, -ONH₂, -NHC=(O)NHNH₂, -NHC=(O) NH₂, -NHSO₂H, -NHC= (O)H, - NHC(O)-OH, -NHOH, -OCF₃, -OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

[0037] A“size-limited substituent” or“ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0038] A“lower substituent” or“ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₇ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.

[0039] In some certain embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some certain embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other certain embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other certain embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0040] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈ cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0041] In some certain embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₇ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆- C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some certain embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇ cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered

heteroarylene. In some certain embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0042] Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those that are known in art to be too unstable to synthesize and/or isolate. The present invention is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0043] As used herein, the term“isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

[0044] The term“tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0045] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.

[0046] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0047] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. [0048] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I), or carbon- 14 (¹⁴C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0049] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.

[0050]“Analog” or“analogue” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

[0051] The terms“a” or“an,” as used in herein means one or more. In addition, the phrase“substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is“substituted with an unsubstituted C₁-C₂₀ alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0052] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R¹³ substituents are present, each R¹³ substituent may be distinguished as R^13A, R^13B, R^13C, R^13D, etc., wherein each of R^13A, R^13B, R^13C, R^13D, etc. is defined within the scope of the definition of R¹³ and optionally differently.

[0053] A“detectable moiety” as used herein refers to a moiety that can be covalently or noncovalently attached to a compound or biomolecule that can be detected for instance, using techniques known in the art. In certain embodiments, the detectable moiety is covalently attached. The detectable moiety may provide for imaging of the attached compound or biomolecule. The detectable moiety may indicate the contacting between two compounds. Exemplary detectable moieties are fluorophores, antibodies, reactive dies, radio-labeled moieties, magnetic contrast agents, and quantum dots. Exemplary fluorophores include fluorescein, rhodamine, GFP, coumarin, FITC, Alexa fluor, Cy3, Cy5, BODIPY, and cyanine dyes. Exemplary radionuclides include Fluorine-18, Gallium-68, and Copper-64. Exemplary magnetic contrast agents include gadolinium, iron oxide and iron platinum, and manganese.

[0054] Descriptions of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0055] The term“pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.

Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,

monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al.,“Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0056] Thus, the compounds of the present invention may exist as salts, such as with pharmaceutically acceptable acids. The present invention includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art. [0057] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In certain embodiments, compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compounds differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but, unless specifically indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present invention.

[0058] In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.

[0059] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0060]“Pharmaceutically acceptable excipient” and“pharmaceutically acceptable carrier” refer to a substance that aids the administration of a compound to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0061] The term“preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0062] A“EPHA4 inhibitor” refers to a compound (e.g., compounds described herein) that reduces the activity of EPHA4 when compared to a control, such as absence of the compound or a compound with known inactivity.

[0063] The terms“polypeptide,”“peptide” and“protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer. In certain embodiments, the terms“polypeptide,”“peptide,” and“protein”, used interchangeably herein, refer to a polymeric form of amino acids of any length, which can include genetically coded and non-genetically coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified polypeptide backbones. The terms include fusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence; fusion proteins with heterologous and homologous leader sequences, with or without N-terminus methionine residues; immunologically tagged proteins; and the like.

[0064] A polypeptide, or a cell is“recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g. non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide.

Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.

[0065]“Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture.

[0066] The term“contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway (e.g., MAP kinase pathway).

[0067] As defined herein, the term“activation”,“activate”,“activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.

[0068] The terms“agonist,”“activator,”“upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5- fold, 10-fold or higher than the expression or activity in the absence of the agonist. In certain

embodiments, an agonist is a molecule that interacts with a target to cause or promote an increase in the activation of the target. In certain embodiments, activators are molecules that increase, activate, facilitate, enhance activation, sensitize, or up-regulate, e.g., a gene, protein, ligand, receptor, or cell.

[0069] As defined herein, the term“inhibition,”“inhibit,”“inhibiting,” and the like, in reference to a protein-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments inhibition refers to reduction of a disease or symptoms of disease. In certain embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In certain embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In certain embodiments, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g. an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).

[0070] The terms“inhibitor,”“repressor” or“antagonist” or“downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist. An antagonist prevents, reduces, inhibits, or neutralizes the activity of an agonist, and an antagonist can also prevent, inhibit, or reduce constitutive activity of a target, e.g., a target receptor, even where there is no identified agonist. In certain embodiments, inhibitors are molecules that decrease, block, prevent, delay activation, inactivate, desensitize, or down-regulate, e.g., a gene, protein, ligand, receptor, or cell. An inhibitor may also be defined as a molecule that reduces, blocks, or inactivates a constitutive activity. An“antagonist” is a molecule that opposes the action(s) of an agonist.

[0071] The terms“EPH receptor A4,”“ephrin type-A receptor 4,” and“EphA4” refer to a protein (including homologs, isoforms, and functional fragments thereof) that belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. The terms include any recombinant or naturally- occurring form of EphA4 variants thereof that maintain EphA4 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype EphA4). The terms include any mutant form of EphA4 variants (e.g., frameshift mutations) thereof that maintain EphA4 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype EphA4). Ephrins (also known as ephrin ligands or Eph family receptor interacting proteins) are a family of proteins that serve as the ligands of the eph receptor. Eph receptors in turn compose the largest known subfamily of receptor protein-tyrosine kinases (RTKs).

[0072] Since ephrin ligands (ephrins) and Eph receptors (Ephs) are both membrane-bound proteins, binding and activation of Eph/ephrin intracellular signaling pathways occurs via direct cell-cell interaction. Eph/ephrin signaling regulates a variety of biological processes during embryonic development including the guidance of axon growth cones, formation of tissue boundaries, cell migration, and segmentation. Additionally, Eph/ephrin signaling has been identified to play a role in the maintenance of several processes during adulthood including long-term potentiation, angiogenesis, and stem cell differentiation.

[0073] In certain embodiments, the EphA4 protein encoded by the EPHA4 gene has the amino acid sequence set forth in or corresponding UniProt P54764. In certain embodiments, the EPHA4 gene has the nucleic acid sequence set forth in EMBL (mRNA) AK300772. In certain embodiments, the EPHA4 gene has the nucleic acid sequence set forth in GenBank (mRNA) AK312380. In certain embodiments, the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application. In certain embodiments, the sequence corresponds to AC010899.

[0074] The term“expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0075] The terms“disease” or“condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. The disease may be a cancer. The disease may be an autoimmune disease. The disease may be an inflammatory disease. The disease may be an infectious disease. In some further instances,“cancer” refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin’s lymphomas (e.g., Burkitt’s, Small Cell, and Large Cell lymphomas), Hodgkin’s lymphoma, leukemia (including MDS, AML, ALL, ATLL and CML), or multiple myeloma. [0076] As used herein, the term“inflammatory disease” refers to a disease or condition characterized by aberrant inflammation (e.g. an increased level of inflammation compared to a control such as a healthy person not suffering from a disease). Examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain- Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren’s syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet’s disease, Crohn’s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison’s disease, Vitiligo,asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis. Such conditions are frequently inextricably intertwined with other diseases, disorders and conditions. A non-limiting list of inflammatory-related diseases, disorders and conditions which may, for example, be caused by inflammatory cytokines, include, arthritis, kidney failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., where inflammatory cytokines prevent healing), anemia, and fibromyalgia. Other diseases and disorders which may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation and multiple sclerosis. Some of the aforementioned diseases, disorders and conditions for which a compound (e.g., EPHA4 inhibitor) of the present invention may be particularly efficacious (due to, for example, limitations of current therapies) are described in more detail hereafter.

[0077] As used herein, the term“cancer” refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and cancer of the head. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, pancreatic cancer. Additional examples include, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer,

hepatocellular carcinoma, or prostate cancer.

[0078] The term“leukemia” refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid

(myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia,

lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0079] The term“sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0080] The term“melanoma” is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

[0081] The term“carcinoma” refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, thyroid carcinoma,

cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare,

mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma

telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

[0082] As used herein, the term“autoimmune disease” refers to a disease or condition in which a subject’s immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy subject. Examples of autoimmune diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison’s disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria, Axonal or neuronal neuropathies, Balo disease, Behcet’s disease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricial pemphigoid/benign mucosal pemphigoid, Crohn’s disease, Cogans syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST disease, Essential mixed cryoglobulinemia, Demyelinating neuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic’s disease (neuromyelitis optica), Discoid lupus, Dressler’s syndrome, Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Experimental allergic encephalomyelitis, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with Polyangiitis (GPA) (formerly called Wegener’s

Granulomatosis), Graves’ disease, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease,

Immunoregulatory lipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome,

Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere’s disease, Microscopic polyangiitis, Mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic’s), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS (Pediatric Autoimmune

Neuropsychiatric Disorders Associated with Streptococcus), Paraneoplastic cerebellar degeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis), Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Type I, II, & III autoimmune polyglandular syndromes, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome,

Postpericardiotomy syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia, Raynauds phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Reiter’s syndrome, Relapsing polychondritis, Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren’s syndrome, Sperm & testicular autoimmunity, Stiff person syndrome, Subacute bacterial endocarditis (SBE), Susac’s syndrome, Sympathetic ophthalmia, Takayasu’s arteritis, Temporal arteritis/Giant cell arteritis,

Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, Transverse myelitis, Type 1 diabetes, Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis,

Vesiculobullous dermatosis, Vitiligo, or Wegener’s granulomatosis (i.e., Granulomatosis with

Polyangiitis (GPA).

[0083] As used herein, the term“inflammatory disease” refers to a disease or condition characterized by aberrant inflammation (e.g. an increased level of inflammation compared to a control such as a healthy person not suffering from a disease). Examples of inflammatory diseases include traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain- Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren’s syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet’s disease, Crohn’s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison’s disease, Vitiligo,asthma, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0084] As used herein, the terms“neurodegeneration“ and/or“neurodegenerative disease” refer to a disease or condition involving the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases– including but not limited to amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, Huntington's, traumatic brain injury (TBI), and spinal cord injury– occur as a result of neurodegenerative processes. Such diseases result in progressive degeneration and/or death of neuron cells. Neurodegeneration can be found in many different levels of neuronal circuitry ranging from molecular to systemic

[0085] The terms“treating” or“treatment” refer to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term“treating” and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In certain embodiments, treating is preventing. In certain embodiments, treating does not include preventing.

[0086]“Treating” or“treatment” as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease’s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, “treatment” as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms (e.g., ocular pain, seeing halos around lights, red eye, very high intraocular pressure), fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things.

[0087]“Treating” and“treatment” as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of a compound described herein. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.

[0088] The term“prevent” refers to a decrease in the occurrence of disease symptoms in a patient. As indicated above, the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment. In certain embodiments, prevent refers to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state.

[0089] “Patient” or“subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some certain embodiments, a patient is human.

[0090] An“effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an“effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a“therapeutically effective amount.” A“reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An“activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A“function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). The therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject’s condition, and the like. By way of example, measurement of the serum level of an EphA4 inhibitor (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been administered.

[0091] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

[0092] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan. Adjusting the dose to achieve maximal therapeutic window efficacy or toxicity in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0093] The term“therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as“-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. [0094] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0095] As used herein, the term“administering” means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By“co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g. anti-cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease). The compound of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. The compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed.7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res.12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol.49:669-674, 1997). In another embodiment, the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul.13:293-306, 1996; Chonn, Curr. Opin. Biotechnol.6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989). The compositions of the present invention can also be delivered as nanoparticles.

[0096] By“co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). The compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0097] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

[0098] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0099] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. [0100] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0101] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.

[0102] The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating cancer (e.g., colon cancer), cardiovascular disease, metabolic disease, immune or inflammatory disease or disorder.

[0103] In some certain embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week or 1 month of a second active agent. Co- administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some certain embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other certain embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another. In some certain embodiments, the compounds described herein may be combined with treatments for cancer (e.g., colon cancer), cardiovascular disease, metabolic disease, immune or inflammatory disease or disorder.

[0104]“Cardiovascular agent” is used in accordance with its plain ordinary meaning and refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator) used in any way to treat conditions of the heart or the circulatory or vascular system. In some certain embodiments, a cardiovascular agent is an agent identified herein having utility in methods of treating cardiovascular disease or disorder. In some certain embodiments, a cardiovascular agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cardiovascular disease or disorder.

[0105]“Anti-inflammatory agent” is used in accordance with its plain ordinary meaning and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) used in any way to reduce inlfammation or swelling. In some certain embodiments, an anti-inflammatory agent is an agent identified herein having utility in methods of treating an inflammatory disease or disorder. In some certain embodiments, an anti-inflammatory agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for reducing swelling and inflammation.

[0106] The compounds described herein can be administered to treat a neurodegenerative disease or disorder and/or cancer. In this regard, the compounds disclosed herein may be administered either alone to treat such diseases or disorders or may be co-administered with another therapeutic agent to treat such diseases or disorders.

[0107] The compounds disclosed herein may be co-administered with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signaling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as analcinra; tumour necrosis factor alpha (TNF-.alpha.) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.

[0108] The compounds disclosed herein may be co-administered with an anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol, a non-steroidal anti- inflammatory agent (hereinafter NSAID) including non-selective cyclo-oxygenase COX-1/COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs);

glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

[0109] The compounds disclosed herein may be co-administered with a calcium channel blocker, a beta- adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.

[0110]“Anti-cancer agent” is used in accordance with its plain ordinary meaning and refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. In some certain embodiments, an anti-cancer agent is a chemotherapeutic. In certain embodiments, an anti-cancer agent is an agent identified herein having utility in methods of treating cancer. In some certain embodiments, an anti-cancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer. Examples of anti-cancer agents include, but are not limited to, MEK (e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518, CI-1040, PD035901, selumetinib/ AZD6244, GSK1120212/ trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin), triazenes (decarbazine)), anti-metabolites (e.g., 5- azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis- inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamycin, 17-N-Allylamino-17- Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;

acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;

andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C;

camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;

carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox;

diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists;

estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin;

ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine;

mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;

molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid

A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;

phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim;

placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds;

platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone;

prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;

saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate;

solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine;

splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista;

suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin;

thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;

bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin;

carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin

hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole;

etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine;

gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin I1 (including recombinant interleukin II, or rlL.sub.2), interferon alfa-2a; interferon alfa-2b; interferon alfa- n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;

mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie;

nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate;

perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin

hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine;

simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone

hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa;

tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate;

trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;

vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride, agents that arrest cells in the G2-M phases and/or modulate the formation or stability of microtubules, (e.g. Taxol.TM (i.e. paclitaxel), Taxotere.TM, compounds comprising the taxane skeleton, Erbulozole (i.e. R-55104), Dolastatin 10 (i.e. DLS-10 and NSC-376128), Mivobulin isethionate (i.e. as CI-980), Vincristine, NSC-639829, Discodermolide (i.e. as NVP-XX-A-296), ABT-751 (Abbott, i.e. E-7010), Altorhyrtins (e.g. Altorhyrtin A and Altorhyrtin C), Spongistatins (e.g. Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (i.e. LU- 103793 and NSC-D-669356), Epothilones (e.g. Epothilone A, Epothilone B, Epothilone C (i.e.

desoxyepothilone A or dEpoA), Epothilone D (i.e. KOS-862, dEpoB, and desoxyepothilone B),

Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21- aminoepothilone B (i.e. BMS-310705), 21-hydroxyepothilone D (i.e. Desoxyepothilone F and dEpoF), 26-fluoroepothilone, Auristatin PE (i.e. NSC-654663), Soblidotin (i.e. TZT-1027), LS-4559-P

(Pharmacia, i.e. LS-4577), LS-4578 (Pharmacia, i.e. LS-477-P), LS-4477 (Pharmacia), LS-4559

(Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e. WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF- 223651 (BASF, i.e. ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970

(Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (i.e. LY-355703), AC-7739 (Ajinomoto, i.e. AVE-8063A and CS- 39.HCl), AC-7700 (Ajinomoto, i.e. AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (i.e. NSC-106969), T-138067 (Tularik, i.e. T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, i.e. DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (i.e. BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e. SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972

(Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (i.e. NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e. T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (i.e. NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, i.e. D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e. SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g.,

hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette- Guérin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti- CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992, CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK- 285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, or the like.

[0111]“Chemotherapeutic” or“chemotherapeutic agent” is used in accordance with its plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.

[0112] Additionally, the compounds described herein can be co-administered with conventional immunotherapeutic agents including, but not limited to, immunostimulants (e.g., Bacillus Calmette- Guérin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti- CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I, etc.).

[0113] The compounds disclosed herein may be co-administered with an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent; an

antimetabolite; an antitumor antibiotic; an antimitotic agent; or a topoisomerase inhibitor; a cytostatic agent such as an antioestrogen, an oestrogen receptor down regulator, a LHRH antagonist or LHRH agonist, a progestogen, an aromatase inhibitor or an inhibitor of 5a-reductase such as finasteride; an agent which inhibits cancer cell invasion; an inhibitor of growth factor function, for example: a growth factor antibody, a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family, an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family; an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor, or a compound that works by another; a vascular damaging agent; an agent used in antisense therapy; an agent used in a gene therapy approach; or an agent used in an immunotherapeutic approach.

[0114] In a further embodiment, the compounds described herein can be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as ⁴⁷Sc, ⁶⁴Cu, ⁶⁷Cu, ⁸⁹Sr, ⁸⁶Y, ⁸⁷Y, ⁹⁰Y, ¹⁰⁵Rh, ¹¹¹Ag, ¹¹¹In, ^117mSn, ¹⁴⁹Pm, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁸⁶Re, ¹⁸⁸Re, ²¹¹At, and ²¹²Bi, optionally conjugated to antibodies directed against tumor antigens.

[0115] In addition, an EphA4 inhibitor may be combined with the therapeutic administration of immune cells, sometimes referred to as adoptive cell transfer. These cells may be cells from the patient, a genetically related or unrelated donor, they may be genetically modified (e.g., CAR-T cells, NK cells, etc), cell lines, genetically modified cell lines and live or dead versions of the above. EPHA4 inhibitors may also be combined with vaccines of any kind (e.g. protein/peptide, viral, bacterial, cellular) to stimulate immune responses to cancer.

[0116] The EPHA4 inhibitors disclosed herein can be administered by any acceptable route, such oral, intraadiposal, intraarterial, intraarticular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocularal, intrapericardial, intraperitoneal, intrapleural, intraprostatical, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenousl, intravesicullar, intravitreal, liposomal, local, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, transbuccal, transdermal, vaginal, in cremes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, via localized perfusion, bathing target cells directly, or any combination thereof.

[0117] The EPHA4 inhibitors disclosed herein may be administered once daily until study reached endpoint. The immune modulator disclosed herein may be administered at least three times but in some studies four or more times depending on the length of the study and/or the design of the study. [0118] The methods disclosed herein may be used in combination with additional cancer therapy. In some certain embodiments, the distinct cancer therapy comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy. In some certain embodiments, the cancer is a chemotherapy-resistant or radio-resistant cancer.

[0119] A“cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.

[0120]“Control” or“control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some certain embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).

[0121] The term“modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule. In some certain embodiments, an EphA4 associated disease modulator is a compound that reduces the severity of one or more symptoms of a disease associated with EphA4 (e.g., neurodegenerative disease, a hearing loss, a promotion of nerve regeneration, a promotion of neuroprotection, or a cancer). An EphA4 modulator is a compound that increases or decreases the activity or function or level of activity or level of function of EphA4. A modulator may act alone, or it may use a cofactor, e.g., a protein, metal ion, or small molecule. Examples of modulators include small molecule compounds and other bioorganic molecules. Numerous libraries of small molecule compounds (e.g., combinatorial libraries) are commercially available and can serve as a starting point for identifying a modulator. The skilled artisan is able to develop one or more assays (e.g., biochemical or cell-based assays) in which such compound libraries can be screened in order to identify one or more compounds having the desired properties; thereafter, the skilled medicinal chemist is able to optimize such one or more compounds by, for example, synthesizing and evaluating analogs and derivatives thereof. Synthetic and/or molecular modeling studies can also be utilized in the identification of an activator

[0122] The term“modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties.“Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. In certain embodiments, the terms“modulate”,“modulation” and the like refer to the ability of a molecule (e.g., an activator or an inhibitor) to increase or decrease the function or activity of EphA4, either directly or indirectly, relative to the absence of the molecule.

[0123] The term“associated” or“associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a protein associated disease, a cancer associated with EphA4 activity, EphA4 associated cancer, EphA4 associated disease (e.g., neurodegenerative disease, a hearing loss, a promotion of nerve regeneration, a promotion of neuroprotection, or a cancer) means that the disease (e.g. neurodegenerative disease, a hearing loss, a promotion of nerve regeneration, a promotion of neuroprotection, or a cancer) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function. For example, a cancer associated with EphA4 activity or function may be a cancer that results (entirely or partially) from aberrant EphA4 function (e.g., enzyme activity, protein-protein interaction, signaling pathway) or a cancer wherein a particular symptom of the disease is caused (entirely or partially) by aberrant EphA4 activity or function. As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. For example, a cancer associated with EphA4 activity or function or an EphA4 associated disease (e.g., neurodegenerative disease, a hearing loss, a promotion of nerve regeneration, a promotion of neuroprotection, or a cancer), may be treated with a compound described herein (e.g., EphA4 modulator or EphA4 inhibitor), in the instance where increased EphA4 activity or function (e.g., signaling pathway activity) causes the disease (e.g., neurodegenerative disease, a hearing loss, a promotion of nerve regeneration, a promotion of neuroprotection, or a cancer). For example, an inflammatory disease associated with EphA4 activity or function or an EphA4 associated inflammatory disease, may be treated with an EphA4 modulator or EphA4 inhibitor, in the instance where increased EphA4 activity or function (e.g., signaling pathway activity) causes the disease.

[0124] The term“aberrant” as used herein refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non- disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0125] The term“signaling pathway” as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propogated to other signaling pathway components. For example, binding of an EphA4 with a compound as described herein may reduce the level of a product of the EphA4 catalyzed reaction or the level of a downstream derivative of the product or binding may reduce the interactions between the EphA4 or a reaction product and downstream effectors or signaling pathway components (e.g., Ephexin-1 pathway), resulting in changes in cell growth, proliferation, or survival.

[0126] As used herein, the terms“EphA4 inhibitor,”“EphA4 antagonist,”“HEK8 inhibitor,”“SEK inhibitor,”“TYRO1 inhibitor,”“ephrin type-A receptor 4 antagonist” and all other related art-accepted terms, many of which are set forth below, refer to a compound capable of modulating, either directly or indirectly, the EphA4 receptor in an in vitro assay, an in vivo model, and/or other means indicative of therapeutic efficacy. The terms also refer to a compound that exhibits at least some therapeutic benefit in a human subject.

[0127] The phrase“in a sufficient amount to effect a change” means that there is a detectable difference between a level of an indicator measured before (e.g., a baseline level) and after administration of a particular therapy. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., a subject’s feeling of well-being).

[0128] The“activity” of a molecule may describe or refer to the binding of the molecule to a ligand or to a receptor; to catalytic activity; to the ability to stimulate gene expression or cell signaling,

differentiation, or maturation; to antigenic activity; to the modulation of activities of other molecules; and the like. The term“proliferative activity” encompasses an activity that promotes, that is necessary for, or that is specifically associated with, for example, normal cell division, as well as cancer, tumors, dysplasia, cell transformation, metastasis, and angiogenesis.

[0129]“Substantially pure” indicates that a component makes up greater than about 50% of the total content of the composition, and typically greater than about 60% of the total polypeptide content. More typically,“substantially pure” refers to compositions in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. In some cases, the polypeptide will make up greater than about 90%, or greater than about 95% of the total content of the composition (percentage in a weight per weight basis).

[0130] The terms“specifically binds” and“selectively binds,” when referring to a ligand/receptor, antibody/antigen, or other binding pair, indicate a binding reaction which is determinative of the presence of the protein in a heterogeneous population of proteins and other biologics. Thus, under designated conditions, a specified ligand binds to a particular receptor and does not bind in a significant amount to other proteins present in the sample. The antibody, or binding composition derived from the antigen- binding site of an antibody, of the contemplated method binds to its antigen, or a variant or mutein thereof, with an affinity that is at least two-fold greater, at least 10-times greater, at least 20-times greater, or at least 100-times greater than the affinity with any other antibody, or binding composition derived therefrom. In certain embodiments, the antibody will have an affinity that is greater than about 10⁹ liters/mol, as determined by, e.g., Scatchard analysis (Munsen, et al. (1980) Analyt. Biochem.

107:220-239).

II. Compounds

[0131] In an aspect provided herein, is a compound having structural Formula (I):

X¹ is CR⁹R¹⁰ or S;

X² is CR¹¹R¹² or S;

X³ is–NH– or–C(O)NH–,

z1 is an integer from 0 to 2;

z2 is an integer from 0 to 5;

R¹ is hydrogen, halogen,–CX^1.1

3, -CHX1.1

2, -CH₂X^1.1,–CN,–N₃,–SO_n1R^1A,–SO_v1NR^1BR^1C,

3,–OCHX1.1

R² is hydrogen, halogen,–CX^2.1

3, -CHX2.1

2, -CH₂X^2.1,–CN,–N₃,–SO_n2R^2A,–SO_v2NR^2BR^2C,

3,–OCHX2.1

R⁴ is hydrogen, halogen,–CX^4.1

3, -CHX4.1

R⁵ is hydrogen, halogen, oxo,–CX^5.1

3, -CHX5.1

3,–OCHX5.1

R⁶ is hydrogen, halogen,–CX^6.1

3, -CHX6.1

2, -CH₂X^6.1,–CN,–N₃,–SO_n6R^6A,–SO_v6NR^6BR^6C,

3,–OCHX6.1

R⁷ is hydrogen, halogen,–CX^7.1

3, -CHX7.1

2, -CH₂X^7.1,–CN,–N₃,–SO_n7R^7A,–SO_v7NR^7BR^7C,

3,–OCHX7.1

3, -CHX8.1

2, -CH₂X^8.1,–CN,–N₃,–SO_n8R^8A,–

3,–OCHX8.1

R⁹ is hydrogen, halogen,–CX^9.1

3, -CHX9.1

2, -CH₂X^9.1,–CN,–N₃,–SO_n9R^9A,–SO_v9NR^9BR^9C,

3,–OCHX9.1

R¹⁰ is hydrogen, halogen,–CX^10.1

3, -CHX10.1

3,–OCHX10.1

R¹¹ is hydrogen, halogen,–CX^11.1

3, -CHX11.1

3,–OCHX11.1

R¹² is hydrogen, halogen,–CX^12.1

3, -CHX12.1

3,–OCHX12.1

[0132] In certain embodiments, the compound is not 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H- indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20-(3-guanidinopropyl)-23-(4- hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontan-7-yl)propanoic acid.

[0133] In certain embodiments, the compound is not 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H- indol-3-yl)methyl)-7-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20-(3-guanidinopropyl)-23-(4- hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontan-13-yl)propanoic acid.

[0134] In certain embodiments, the compound is not 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H- indol-3-yl)methyl)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4- hydroxyphenyl)propanamido)-4-carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13- diyl)dipropionic acid.

[0135] In certain embodiments, the compound has structural Formula (I-A):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. X¹, X², z1, z2, L¹, L², L³, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as described herein, including embodiments.

[0136] In certain embodiments, the compound has structural Formula (II):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. X¹, X², z2, L¹, L², L³, R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are as described herein, including embodiments.

[0137] In certain embodiments, the compound has structural Formula (III):

[0138] In certain embodiments, the compound has structural Formula (IV):

( ),

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. X¹, X², z1, z2, L¹, L², L³, R¹, R², R³, R⁵, R⁶, R⁷, and R⁸ are as described herein, including embodiments. R¹³ is independently hydrogen, halogen,–CX^13.1 3.1 ^13B

3, -CHX1

2, -CH₂X^13.1,–CN,–N₃,–SO_n13R^13A,–SO_v13NR R^13C,

-NHNR^13BR^13C, -ONR^13BR^13C, -NHC(O)NHNR^13BR^13C, -NHC(O)NR^13BR^13C,–N(O)_m13,–NR^13BR^13C,– C(O)R^13D,–C(O)OR^13D,–C(O)NR^13BR^13C,–OR^13A, -NR^13BSO₂R^13A, -NR^13BC(O)R^13D, -NR^13BC(O)OR^13D, –NR^13BOR^13D,–OCX^13.1

3,–OCHX13.1

2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R^13A, R^13B, R^13C, and R^13D are independently hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R^13B and R^13C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X^13.1 is–Cl,–Br,–I, or–F. The symbol z3 is an integer from 0 to 5. The symbol n13 is an integer from 0 to 4. The symbols m13 and v13 are independently 1 or 2.

[0139] In certain embodiments, R⁴ is a substituted or unsubstituted naturally occurring or non-naturally occurring amino acid. In certain embodiments, R⁴ is substituted or unsubstituted A, substituted or unsubstituted R, substituted or unsubstituted N, substituted or unsubstituted D, substituted or unsubstituted C, substituted or unsubstituted E, substituted or unsubstituted Q, substituted or unsubstituted G, substituted or unsubstituted H, substituted or unsubstituted I, substituted or

unsubstituted L, substituted or unsubstituted K, substituted or unsubstituted M, substituted or unsubstituted F, substituted or unsubstituted P, substituted or unsubstituted S, substituted or unsubstituted T, substituted or unsubstituted W, substituted or unsubstituted Y, or substituted or unsubstituted V.

[0140] In certain embodiments, R⁴ is a unsubstituted naturally occurring or non-naturally occurring amino acid. In certain embodiments, R⁴ is unsubstituted A, unsubstituted R, unsubstituted N, unsubstituted D, unsubstituted C, unsubstituted E, unsubstituted Q, unsubstituted G, unsubstituted H, unsubstituted I, unsubstituted L, unsubstituted K, unsubstituted M, unsubstituted F, unsubstituted P, unsubstituted S, unsubstituted T, unsubstituted W, unsubstituted Y, or unsubstituted V.

[0141] In certain embodiments, R⁴ is R⁶⁰-substituted naturally occurring or non-naturally occurring amino acid. In certain embodiments, R⁴ is R⁶⁰-substituted A, R⁶⁰-substituted R, R⁶⁰-substituted N, R⁶⁰- substituted D, R⁶⁰-substituted C, R⁶⁰-substituted E, R⁶⁰-substituted Q, R⁶⁰-substituted G, R⁶⁰-substituted H, R⁶⁰-substituted I, R⁶⁰-substituted L R⁶⁰-substituted K, R⁶⁰-substituted M, R⁶⁰-substituted F, R⁶⁰- substituted P, R⁶⁰-substituted S, R⁶⁰-substituted T, R⁶⁰-substituted W, R⁶⁰-substituted Y, or R⁶⁰- substituted V.

[0142] In certain embodiments, R⁵ is a substituted or unsubstituted naturally occurring or non-naturally occurring amino acid. In certain embodiments, R⁵ is substituted or unsubstituted A, substituted or unsubstituted R, substituted or unsubstituted N, substituted or unsubstituted D, substituted or unsubstituted C, substituted or unsubstituted E, substituted or unsubstituted Q, substituted or unsubstituted G, substituted or unsubstituted H, substituted or unsubstituted I, substituted or

[0143] In certain embodiments, R⁵ is a unsubstituted naturally occurring or non-naturally occurring amino acid. In certain embodiments, R⁵ is unsubstituted A, unsubstituted R, unsubstituted N, unsubstituted D, unsubstituted C, unsubstituted E, unsubstituted Q, unsubstituted G, unsubstituted H, unsubstituted I, unsubstituted L, unsubstituted K, unsubstituted M, unsubstituted F, unsubstituted P, unsubstituted S, unsubstituted T, unsubstituted W, unsubstituted Y, or unsubstituted V.

[0144] In certain embodiments, R⁵ is R⁶⁰-substituted naturally occurring or non-naturally occurring amino acid. In certain embodiments, R⁵ is R⁶⁰-substituted A, R⁶⁰-substituted R, R⁶⁰-substituted N, R⁶⁰- substituted D, R⁶⁰-substituted C, R⁶⁰-substituted E, R⁶⁰-substituted Q, R⁶⁰-substituted G, R⁶⁰-substituted H, R⁶⁰-substituted I, R⁶⁰-substituted L R⁶⁰-substituted K, R⁶⁰-substituted M, R⁶⁰-substituted F, R⁶⁰- substituted P, R⁶⁰-substituted S, R⁶⁰-substituted T, R⁶⁰-substituted W, R⁶⁰-substituted Y, or R⁶⁰- substituted V.

[0145] In certain embodiments, R⁶ is a substituted or unsubstituted naturally occurring or non-naturally occurring amino acid. In certain embodiments, R⁶ is substituted or unsubstituted A, substituted or unsubstituted R, substituted or unsubstituted N, substituted or unsubstituted D, substituted or unsubstituted C, substituted or unsubstituted E, substituted or unsubstituted Q, substituted or unsubstituted G, substituted or unsubstituted H, substituted or unsubstituted I, substituted or

[0146] In certain embodiments, R⁶ is a unsubstituted naturally occurring or non-naturally occurring amino acid. In certain embodiments, R⁶ is unsubstituted A, unsubstituted R, unsubstituted N, unsubstituted D, unsubstituted C, unsubstituted E, unsubstituted Q, unsubstituted G, unsubstituted H, unsubstituted I, unsubstituted L, unsubstituted K, unsubstituted M, unsubstituted F, unsubstituted P, unsubstituted S, unsubstituted T, unsubstituted W, unsubstituted Y, or unsubstituted V.

[0147] In certain embodiments, R⁶ is R⁶⁰-substituted naturally occurring or non-naturally occurring amino acid. In certain embodiments, R⁶ is R⁶⁰-substituted A, R⁶⁰-substituted R, R⁶⁰-substituted N, R⁶⁰- substituted D, R⁶⁰-substituted C, R⁶⁰-substituted E, R⁶⁰-substituted Q, R⁶⁰-substituted G, R⁶⁰-substituted H, R⁶⁰-substituted I, R⁶⁰-substituted L R⁶⁰-substituted K, R⁶⁰-substituted M, R⁶⁰-substituted F, R⁶⁰- substituted P, R⁶⁰-substituted S, R⁶⁰-substituted T, R⁶⁰-substituted W, R⁶⁰-substituted Y, or R⁶⁰- substituted V.

[0148] In certain embodiments, R⁷ is a substituted or unsubstituted naturally occurring or non-naturally occurring amino acid. In certain embodiments, R⁷ is substituted or unsubstituted A, substituted or unsubstituted R, substituted or unsubstituted N, substituted or unsubstituted D, substituted or unsubstituted C, substituted or unsubstituted E, substituted or unsubstituted Q, substituted or unsubstituted G, substituted or unsubstituted H, substituted or unsubstituted I, substituted or unsubstituted L, substituted or unsubstituted K, substituted or unsubstituted M, substituted or unsubstituted F, substituted or unsubstituted P, substituted or unsubstituted S, substituted or unsubstituted T, substituted or unsubstituted W, substituted or unsubstituted Y, or substituted or unsubstituted V.

[0149] In certain embodiments, R⁷ is a unsubstituted naturally occurring or non-naturally occurring amino acid. In certain embodiments, R⁷ is unsubstituted A, unsubstituted R, unsubstituted N, unsubstituted D, unsubstituted C, unsubstituted E, unsubstituted Q, unsubstituted G, unsubstituted H, unsubstituted I, unsubstituted L, unsubstituted K, unsubstituted M, unsubstituted F, unsubstituted P, unsubstituted S, unsubstituted T, unsubstituted W, unsubstituted Y, or unsubstituted V.

[0150] In certain embodiments, R⁷ is R⁶⁰-substituted naturally occurring or non-naturally occurring amino acid. In certain embodiments, R⁷ is R⁶⁰-substituted A, R⁶⁰-substituted R, R⁶⁰-substituted N, R⁶⁰- substituted D, R⁶⁰-substituted C, R⁶⁰-substituted E, R⁶⁰-substituted Q, R⁶⁰-substituted G, R⁶⁰-substituted H, R⁶⁰-substituted I, R⁶⁰-substituted L R⁶⁰-substituted K, R⁶⁰-substituted M, R⁶⁰-substituted F, R⁶⁰- substituted P, R⁶⁰-substituted S, R⁶⁰-substituted T, R⁶⁰-substituted W, R⁶⁰-substituted Y, or R⁶⁰- substituted V.

[0151] In certain embodiments, R¹³ is independently hydrogen, halogen, or–OH. In certain

embodiments, R¹³ is independently hydrogen or halogen. In certain embodiments, R¹³ is independently halogen.

[0152] In certain embodiments, the compound has structural Formula (IV-1):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. X¹, X², z1, z2, z3, L¹, L², L³, R¹, R², R³, R⁵, R⁶, R⁷, and R⁸ are as described herein, including embodiments. R^13.1 is

independently hydrogen, halogen,–CX^{13.1A 1A}

3, -CHX13.1A

2, -CH₂X^13. ,–CN,–N ^3.1A

3,–SO_n13.1R¹ ,– SO_v13.1NR^13.1BR^13.1C, -NHNR^13.1BR^13.1C, -ONR^13.1BR^13.1C, -NHC(O)NHNR^13.1BR^13.1C,

-NHC(O)NR^13.1BR^13.1C,–N(O)_m13.1,–NR^13.1BR^13.1C,–C(O)R^13.1D,–C(O)OR^13.1D,–C(O)NR^13.1BR^13.1C,– OR^13.1A, -NR^13.1BSO₂R^13.1A, -NR^13.1BC(O)R^13.1D, -NR^13.1BC(O)OR^13.1D,–NR^13.1BOR^13.1D,–OCX^13.1A

3,– OCHX^13.1A

2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R^13.2 is independently hydrogen, halogen,–CX^13.2A

3, - CHX^{13.2A 13.2A}

2, -CH₂X^13.2A,–CN,–N₃,–SO_n13.2R ,–SO_v13.2NR^13.2BR^13.2C, -NHNR^13.2BR^13.2C,

-ONR^13.2BR^13.2C, -NHC(O)NHNR^13.2BR^13.2C, -NHC(O)NR^13.2BR^13.2C,–N(O)_m13.2,–NR^13.2BR^13.2C,– C(O)R^13.2D,–C(O)OR^13.2D,–C(O)NR^13.2BR^13.2C,–OR^13.2A, -NR^13.2BSO₂R^13.2A, -NR^13.2BC(O)R^13.2D, - NR^13.2BC(O)OR^13.2D,–NR^13.2BOR^13.2D,–OCX^13.2A 2A

3,–OCHX13.

2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R^13.1A, R^13.1B, R^13.1C, R^13.1D, R^13.2A, R^13.2B, R^13.2C, and R^13.2D are independently hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^13B and R^13C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X^13.1A and X^13.2A are independently–Cl,–Br,–I or–F. The symbols n13.1 and n13.2 are independently an integer from 0 to 4. The symbols m13.1, m13.2, v13.1, and v13.2 are independently 1 or 2.

[0153] In certain embodiments, R^13.1 is independently hydrogen or halogen. In certain embodiments, R^13.2 is independently hydrogen or halogen. In certain embodiments, both R^13.1 and R^13.2 are halogen.

[0154] In certain embodiments, the compound has structural Formula (V):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. X¹, X², z1, z2, L¹, L², L³, R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are as described herein, including embodiments.

[0155] In certain embodiments, the compound has structural Formula (VI-A) or (VI-B):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. X¹, X², z1, z2, L¹, L², L³, R¹, R², R⁴, R⁵, R⁷, and R⁸ are as described herein, including embodiments. R¹⁴ is hydrogen, halogen,– CX^14.1

3, -CHX^14.14, -CH₂X^14.1,–CN,–N₃,–SO_n14R^14A,–SO_v14NR^14BR^14C, -NHNR^14BR^14C, -ONR^14BR^14C, -NHC(O)NHNR^14BR^14C, -NHC(O)NR^14BR^14C,–N(O)_m14,–NR^14BR^14C,–C(O)R^14D,–C(O)OR^14D,– C(O)NR^14BR^14C,–OR^14A, -NR^14BSO₂R^14A, -NR^14BC(O)R^14D, -NR^14BC(O)OR^14D,–NR^14BOR^14D,–OCX^14.1

3, –OCHX^14.1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R^14A, R^14B, R^14C, and R^14D are independently hydrogen, halogen, –CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R^14B and R^14C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X^14.1 is–Cl,–Br,–I, or–F. The symbol n14 is an integer from 0 to 4. The symbols m14 and v14 are independently 1 or 2.

[0156] In certain embodiments, the compound has structural Formula (VI-A), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0157] In certain embodiments, the compound has structural Formula (VI-B), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0158] In certain embodiments, R¹⁴ is hydrogen,–C(O)R^14D,–C(O)OR^14D,–C(O)NR^14BR^14C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In certain embodiments, R¹⁴ is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalky. In certain embodiments, R¹⁴ is -C(O)R^14D,–C(O)OR^14D, or–C(O)NR^14BR^14C. In certain embodiments, R¹⁴ is -C(O)R^14D.

[0159] In certain embodiments, z1 is 0. In certain embodiments, z1 is 1. In certain embodiments, z1 is 2.

[0160] In certain embodiments, z2 is 0. In certain embodiments, z2 is 1. In certain embodiments, z2 is 2. In certain embodiments, z2 is 3. In certain embodiments, z2 is 4. In certain embodiments, z2 is 5.

[0161] In certain embodiments, z3 is 0. In certain embodiments, z3 is 1. In certain embodiments, z3 is 2. In certain embodiments, z3 is 3. In certain embodiments, z3 is 4. In certain embodiments, z3 is 5.

[0162] In certain embodiments, m1, m2, m4, m5, m7, m8, m9, m10, m11, m12, v1, v2, v3, v4, v5, v6, v7, v8, v9, v10, v11, and v12 are independently 1. In certain embodiments, m1, m2, m4, m5, m7, m8, m9, m10, m11, m12, v1, v2, v3, v4, v5, v6, v7, v8, v9, v10, v11, and v12 are independently 2.

[0163] In certain embodiments, n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, and n12 are independently 0. In certain embodiments, n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, and n12 are independently 1. In certain embodiments, n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, and n12 are independently 2. In certain embodiments, n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, and n12 are independently 3. In certain embodiments, n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, and n12 are independently 4.

[0164] In certain embodiments, X¹ is CR⁹R¹⁰. In certain embodiments, X¹ is S. In certain embodiments, X² is CR¹¹R¹². In certain embodiments, X² is S.

[0165] In certain embodiments, L¹ is R⁵⁷-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In certain embodiments, L¹ is R⁵⁷-substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In certain embodiments, L¹ is an unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).

[0166] In certain embodiments, L¹ is R⁵⁷-substituted or unsubstituted cycloalkylene (e.g., C₁-C₈ cycloalkylene, C₁-C₆ cycloalkylene, or C₅-C₆ cycloalkylene). In certain embodiments, L¹ is R⁵⁷- substituted cycloalkylene (e.g., C₁-C₈ cycloalkylene, C₁-C₆ cycloalkylene, or C₅-C₆ cycloalkylene). In certain embodiments, L¹ is an unsubstituted cycloalkylene (e.g., C₁-C₈ cycloalkylene, C₁-C₆ cycloalkylene, or C₅-C₆ cycloalkylene).

[0167] In certain embodiments, L¹ is R⁵⁷-substituted or unsubstituted heterocycloalkylene (e.g., 1 to 8 membered heterocycloalkylene, 1 to 6 membered heterocycloalkylene, or 5 to 6 membered

heterocycloalkylene). In certain embodiments, L¹ is R⁵⁷-substituted heterocycloalkylene (e.g., 1 to 8 membered heterocycloalkylene, 1 to 6 membered heterocycloalkylene, or 5 to 6 membered

heterocycloalkylene). In certain embodiments, L¹ is an unsubstituted heterocycloalkylene (e.g., 1 to 8 membered heterocycloalkylene, 1 to 6 membered heterocycloalkylene, or 5 to 6 membered

heterocycloalkylene).

[0168] In certain embodiments, L¹ is R⁵⁷-substituted or unsubstituted arylene (e.g., C₆-C₁₀ arylene, C₁₀ arylene, or phenylene). In certain embodiments, L¹ is R⁵⁷-substituted arylene (e.g., C₆-C₁₀ arylene, C₁₀ arylene, or phenylene). In certain embodiments, L¹ is an unsubstituted arylene (e.g., C₆-C₁₀ arylene, C₁₀ arylene, or phenylene).

[0169] In certain embodiments, L¹ is R⁵⁷-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In certain embodiments, L¹ is R⁵⁷-substituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In certain embodiments, L¹ is an unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).

[0170] In certain embodiments, L² is R⁵⁸-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In certain embodiments, L² is R⁵⁸-substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In certain embodiments, L² is an unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).

[0171] In certain embodiments, L² is R⁵⁸-substituted or unsubstituted cycloalkylene (e.g., C₂-C₈ cycloalkylene, C₂-C₆ cycloalkylene, or C₅-C₆ cycloalkylene). In certain embodiments, L² is R⁵⁸- substituted cycloalkylene (e.g., C₂-C₈ cycloalkylene, C₂-C₆ cycloalkylene, or C₅-C₆ cycloalkylene). In certain embodiments, L² is an unsubstituted cycloalkylene (e.g., C₂-C₈ cycloalkylene, C₂-C₆ cycloalkylene, or C₅-C₆ cycloalkylene).

[0172] In certain embodiments, L² is R⁵⁸-substituted or unsubstituted heterocycloalkylene (e.g., 2 to 8 membered heterocycloalkylene, 2 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene). In certain embodiments, L² is R⁵⁸-substituted heterocycloalkylene (e.g., 2 to 8 membered heterocycloalkylene, 2 to 6 membered heterocycloalkylene, or 5 to 6 membered

heterocycloalkylene). In certain embodiments, L² is an unsubstituted heterocycloalkylene (e.g., 2 to 8 membered heterocycloalkylene, 2 to 6 membered heterocycloalkylene, or 5 to 6 membered

heterocycloalkylene).

[0173] In certain embodiments, L² is R⁵⁸-substituted or unsubstituted arylene (e.g., C₆-C₁₀ arylene, C₁₀ arylene, or phenylene). In certain embodiments, L² is R⁵⁸-substituted arylene (e.g., C₆-C₁₀ arylene, C₁₀ arylene, or phenylene). In certain embodiments, L² is an unsubstituted arylene (e.g., C₆-C₁₀ arylene, C₁₀ arylene, or phenylene).

[0174] In certain embodiments, L² is R⁵⁸-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In certain embodiments, L² is R⁵⁸-substituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In certain embodiments, L² is an unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).

[0175] In certain embodiments, L³ is a bond,–O–,–S–,–NR^3L–,–C(O)–, -C(O)O–,–S(O)–,–S(O)₂–, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0176] In certain embodiments, L³ is a bond,–O–,–S–,–NR^3L–,–C(O)–, -C(O)O–,–S(O)–,–S(O)₂–, substituted or unsubstituted alkylene (e.g., C₁-C₈ alkylene, C₁-C₆ alkylene, or C₁-C₄ alkylene), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), substituted or unsubstituted cycloalkylene (e.g., C₃-C₈

cycloalkylene, C₃-C₆ cycloalkylene, or C₅-C₆ cycloalkylene), substituted or unsubstituted

heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), substituted or unsubstituted arylene (e.g., C₆-C₁₀ arylene, C₁₀ arylene, or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).

[0177] In certain embodiments, L³ is a bond,–O–,–S–,–NR^3L–,–C(O)–, -C(O)O–,–S(O)–,–S(O)₂–, R⁵⁹-substituted or unsubstituted alkylene (e.g., C₁-C₈ alkylene, C₁-C₆ alkylene, or C₁-C₄ alkylene), R⁵⁹- substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R⁵⁹-substituted or unsubstituted cycloalkylene (e.g., C₃-C₈ cycloalkylene, C₃-C₆ cycloalkylene, or C₅-C₆ cycloalkylene), R⁵⁹-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), R⁵⁹-substituted or unsubstituted arylene (e.g., C₆-C₁₀ arylene, C₁₀ arylene, or phenylene), or R⁵⁹-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In certain embodiments, L³ is a bond.

[0178] In certain embodiments, L³ is R⁵⁹-substituted or unsubstituted alkylene (e.g., C₁-C₈ alkylene, C₁- C₆ alkylene, or C₁-C₄ alkylene). In certain embodiments, L³ is R⁵⁹-substituted alkylene (e.g., C₁-C₈ alkylene, C₁-C₆ alkylene, or C₁-C₄ alkylene). In certain embodiments, L³ is an unsubstituted alkylene (e.g., C₁-C₈ alkylene, C₁-C₆ alkylene, or C₁-C₄ alkylene).

[0179] In certain embodiments, L³ is R⁵⁹-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In certain embodiments, L³ is R⁵⁹-substituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In certain embodiments, L³ is an unsubstituted heteroalkylene (e.g., 2 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).

[0180] In certain embodiments, L³ is R⁵⁹-substituted or unsubstituted cycloalkylene (e.g., C₃-C₈ cycloalkylene, C₃-C₆ cycloalkylene, or C₅-C₆ cycloalkylene). In certain embodiments, L³ is R⁵⁹- substituted cycloalkylene (e.g., C₃-C₈ cycloalkylene, C₃-C₆ cycloalkylene, or C₅-C₆ cycloalkylene). In certain embodiments, L³ is an unsubstituted cycloalkylene (e.g., C₃-C₈ cycloalkylene, C₃-C₆

cycloalkylene, or C₅-C₆ cycloalkylene).

[0181] In certain embodiments, L³ is R⁵⁹-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered

heterocycloalkylene). In certain embodiments, L³ is R⁵⁹-substituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered

heterocycloalkylene). In certain embodiments, L³ is an unsubstituted heterocycloalkylene (e.g., 3 to 8 membered heterocycloalkylene, 3 to 6 membered heterocycloalkylene, or 5 to 6 membered

heterocycloalkylene).

[0182] In certain embodiments, L³ is R⁵⁹-substituted or unsubstituted arylene (e.g., C₆-C₁₀ arylene, C₁₀ arylene, or phenylene). In certain embodiments, L³ is R⁵⁹-substituted arylene (e.g., C₆-C₁₀ arylene, C₁₀ arylene, or phenylene). In certain embodiments, L³ is an unsubstituted arylene (e.g., C₆-C₁₀ arylene, C₁₀ arylene, or phenylene).

[0183] In certain embodiments, L³ is R⁵⁹-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In certain embodiments, L³ is R⁵⁹-substituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In certain embodiments, L³ is an unsubstituted heteroarylene (e.g., 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).

[0184] In certain embodiments, R¹ is hydrogen, halogen,–CX^1.1

3, -CHX1.1

2, -CH₂X^1.1,–CN,–SO_n1R^1A,– SO_v1NR^1BR^1C, -NHNR^1BR^1C, -ONR^1BR^1C, -NHC(O)NHNR^1BR^1C, -NHC(O)NR^1BR^1C,–N(O)_m1,– NR^1BR^1C,–C(O)R^1D,–C(O)OR^1D,–C(O)NR^1BR^1C,–OR^1A, -NR^1BSO₂R^1A, -NR^1BC(O)R^1D, - NR^1BC(O)OR^1D,–NR^1BOR^1D,–OCX^1.1

3,–OCHX1.1

2, R¹⁵-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R¹⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R¹⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R¹⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R¹⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R¹⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0185] In certain embodiments, R¹ is R¹⁵-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹ is R¹⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0186] In certain embodiments, R¹ is R¹⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹ is R¹⁵-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0187] In certain embodiments, R¹ is R¹⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹ is R¹⁵-substituted cycloalkyl (e.g., C₃- C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0188] In certain embodiments, R¹ is R¹⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹ is R¹⁵-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0189] In certain embodiments, R¹ is R¹⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹ is R¹⁵-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0190] In certain embodiments, R¹ is R¹⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹ is R¹⁵-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0191] In certain embodiments, R² is hydrogen, halogen,–CX^2.1

3, -CHX2.1

2, -CH₂X^2.1,–CN,–SO_n1R^2A,– SO_v1NR^2BR^2C, -NHNR^2BR^2C, -ONR^2BR^2C, -NHC(O)NHNR^2BR^2C, -NHC(O)NR^2BR^2C,–N(O)_m1,– NR^2BR^2C,–C(O)R^2D,–C(O)OR^2D,–C(O)NR^2BR^2C,–OR^2A, -NR^2BSO₂R^2A, -NR^2BC(O)R^2D, - NR^2BC(O)OR^2D,–NR^2BOR^2D,–OCX^2.1

3,–OCHX2.1

2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0192] In certain embodiments, R² is halogen,–CX^2.1

3, -CHX2.1

2, -CH₂X^2.1,–CN,–SO_n2R^2A,–

SO_v2NR^2BR^2C, -NHNR^2BR^2C, -ONR^2BR^2C, -NHC(O)NHNR^2BR^2C, -NHC(O)NR^2BR^2C,–N(O)_m2,– NR^2BR^2C,–C(O)R^2D,–C(O)OR^2D,–C(O)NR^2BR^2C,–OR^2A, -NR^2BSO₂R^2A, -NR^2BC(O)R^2D, - NR^2BC(O)OR^2D,–NR^2BOR^2D,–OCX^2.1

3,–OCHX2.1

2, R¹⁸-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R¹⁸-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R¹⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R¹⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R¹⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R¹⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0193] In certain embodiments, R² is R¹⁸-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R² is R¹⁸-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R² is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0194] In certain embodiments, R² is R¹⁸-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R² is R¹⁸-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R² is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0195] In certain embodiments, R² is R¹⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R² is R¹⁸-substituted cycloalkyl (e.g., C₃- C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R² is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0196] In certain embodiments, R² is R¹⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R² is R¹⁸-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R² is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0197] In certain embodiments, R² is R¹⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R² is R¹⁸-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R² is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). [0198] In certain embodiments, R² is R¹⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R² is R¹⁸-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R² is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0199] In certain embodiments, R³ is hydrogen, halogen,–CX^3.1

3, -CHX3.1

2, -CH₂X^3.1,–CN,–SO_n3R^3A,– SO_v3NR^3BR^3C, -NHNR^3BR^3C, -ONR^3BR^3C, -NHC(O)NHNR^3BR^3C, -NHC(O)NR^3BR^3C,–N(O)_m3,– NR^3BR^3C,–C(O)R^3D,–C(O)OR^3D,–C(O)NR^3BR^3C,–OR^3A, -NR^3BSO₂R^3A, -NR^3BC(O)R^3D, - NR^3BC(O)OR^3D,–NR^3BOR^3D,–OCX^3.1

3,–OCHX3.1

2,–C=NHNR^3B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0200] In certain embodiments, R³ is halogen,–CX^3.1

3, -CHX3.1

2, -CH₂X^3.1,–CN,–SO_n3R^3A,–

SO_v3NR^3BR^3C, -NHNR^3BR^3C, -ONR^3BR^3C, -NHC(O)NHNR^3BR^3C, -NHC(O)NR^3BR^3C,–N(O)_m3,– NR^3BR^3C,–C(O)R^3D,–C(O)OR^3D,–C(O)NR^3BR^3C,–OR^3A, -NR^3BSO₂R^3A, -NR^3BC(O)R^3D, - NR^3BC(O)OR^3D,–NR^3BOR^3D,–OCX^3.1

3,–OCHX3.1

2, R²¹-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²¹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²¹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²¹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²¹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R²¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0201] In certain embodiments, R³ is R²¹-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³ is R²¹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0202] In certain embodiments, R³ is R²¹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³ is R²¹-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0203] In certain embodiments, R³ is R²¹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³ is R²¹-substituted cycloalkyl (e.g., C₃- C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). [0204] In certain embodiments, R³ is R²¹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³ is R²¹-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0205] In certain embodiments, R³ is R²¹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³ is R²¹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0206] In certain embodiments, R³ is R²¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³ is R²¹-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0207] In certain embodiments, R⁴ is hydrogen, halogen,–CX^4.1

3, -CHX4.1

2, -CH₂X^4.1,–CN,–SO_n4R^4A,– SO_v4NR^4BR^4C, -NHNR^4BR^4C, -ONR^4BR^4C, -NHC(O)NHNR^4BR^4C, -NHC(O)NR^4BR^4C,–N(O)_m4,– NR^4BR^4C,–C(O)R^4D,–C(O)OR^4D,–C(O)NR^4BR^4C,–OR^4A, -NR^4BSO₂R^4A, -NR^4BC(O)R^4D, - NR^4BC(O)OR^4D,–NR^4BOR^4D,–OCX^4.1

3,–OCHX4.1

2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0208] In certain embodiments, R⁴ is halogen,–CX^4.1

3, -CHX4.1

2, -CH₂X^4.1,–CN,–SO_n4R^4A,–

SO_v4NR^4BR^4C, -NHNR^4BR^4C, -ONR^4BR^4C, -NHC(O)NHNR^4BR^4C, -NHC(O)NR^4BR^4C,–N(O)_m4,– NR^4BR^4C,–C(O)R^4D,–C(O)OR^4D,–C(O)NR^4BR^4C,–OR^4A, -NR^4BSO₂R^4A, -NR^4BC(O)R^4D, - NR^4BC(O)OR^4D,–NR^4BOR^4D,–OCX^4.1

3,–OCHX4.1

2, R²⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁴-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R²⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0209] In certain embodiments, R⁴ is R²⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴ is R²⁴-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0210] In certain embodiments, R⁴ is R²⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴ is R²⁴-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0211] In certain embodiments, R⁴ is R²⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴ is R²⁴-substituted cycloalkyl (e.g., C₃- C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0212] In certain embodiments, R⁴ is R²⁴-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴ is R²⁴-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0213] In certain embodiments, R⁴ is R²⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴ is R²⁴-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0214] In certain embodiments, R⁴ is R²⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴ is R²⁴-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0215] In certain embodiments, R⁵ is hydrogen, halogen, oxo,–CX^5.1

3, -CHX5.1

2, -CH₂X^5.1,–CN,– SO_n5R^5A,–SO_v5NR^5BR^5C, -NHNR^5BR^5C, -ONR^5BR^5C, -NHC(O)NHNR^5BR^5C, -NHC(O)NR^5BR^5C,– N(O)_m5,–NR^5BR^5C,–C(O)R^5D,–C(O)OR^5D,–C(O)NR^5BR^5C,–OR^5A, -NR^5BSO₂R^5A, -NR^5BC(O)R^5D, - NR^5BC(O)OR^5D,–NR^5BOR^5D,–OCX^5.1

3,–OCHX5.1

[0216] In certain embodiments, R⁵ is halogen,–CX^5.1

3, -CHX5.1

2, -CH₂X^5.1,–CN,–SO_n5R^5A, –SO_v5NR^5BR^5C, -NHNR^5BR^5C, -ONR^5BR^5C, -NHC(O)NHNR^5BR^5C, -NHC(O)NR^5BR^5C,–N(O)_m5,– NR^5BR^5C,–C(O)R^5D,–C(O)OR^5D,–C(O)NR^5BR^5C,–OR^5A, -NR^5BSO₂R^5A, -NR^5BC(O)R^5D, - NR^5BC(O)OR^5D,–NR^5BOR^5D,–OCX^5.1

3,–OCHX5.1

2, R²⁷-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁷-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁷-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁷-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁷-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R²⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0217] In certain embodiments, R⁵ is R²⁷-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁵ is R²⁷-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁵ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0218] In certain embodiments, R⁵ is R²⁷-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁵ is R²⁷-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁵ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0219] In certain embodiments, R⁵ is R²⁷-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁵ is R²⁷-substituted cycloalkyl (e.g., C₃- C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁵ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0220] In certain embodiments, R⁵ is R²⁷-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁵ is R²⁷-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁵ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0221] In certain embodiments, R⁵ is R²⁷-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁵ is R²⁷-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁵ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0222] In certain embodiments, R⁵ is R²⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁵ is R²⁷-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁵ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0223] In certain embodiments, R⁶ is hydrogen, halogen, oxo,–CX^6.1

3, -CHX6.1

2, -CH₂X^6.1,–CN,– SO_n6R^6A,–SO_v6NR^6BR^6C, -NHNR^6BR^6C, -ONR^6BR^6C, -NHC(O)NHNR^6BR^6C, -NHC(O)NR^6BR^6C,– N(O)_m6,–NR^6BR^6C,–C(O)R^6D,–C(O)OR^6D,–C(O)NR^6BR^6C,–OR^6A, -NR^6BSO₂R^6A, -NR^6BC(O)R^6D, - NR^6BC(O)OR^6D,–NR^6BOR^6D,–OCX^6.1

3,–OCHX6.1

[0224] In certain embodiments, R⁶ is halogen,–CX^6.1

3, -CHX6.1

2, -CH₂X^6.1,–CN,–SO_n6R^6A,–

SO_v6NR^6BR^6C, -NHNR^6BR^6C, -ONR^6BR^6C, -NHC(O)NHNR^6BR^6C, -NHC(O)NR^6BR^6C,–N(O)_m6,– NR^6BR^6C,–C(O)R^6D,–C(O)OR^6D,–C(O)NR^6BR^6C,–OR^6A, -NR^6BSO₂R^6A, -NR^6BC(O)R^6D, - NR^6BC(O)OR^6D,–NR^6BOR^6D,–OCX^6.1

3,–OCHX6.1

2, R³⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁰-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁰-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R³⁰-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0225] In certain embodiments, R⁶ is R³⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁶ is R³⁰-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁶ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0226] In certain embodiments, R⁶ is R³⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁶ is R³⁰-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁶ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0227] In certain embodiments, R⁶ is R³⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁶ is R³⁰-substituted cycloalkyl (e.g., C₃- C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁶ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0228] In certain embodiments, R⁶ is R³⁰-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁶ is R³⁰-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁶ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0229] In certain embodiments, R⁶ is R³⁰-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁶ is R³⁰-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁶ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0230] In certain embodiments, R⁶ is R³⁰-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁶ is R³⁰-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁶ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0231] In certain embodiments, R⁷ is hydrogen, halogen,–CX^7.1

3, -CHX7.1

2, -CH₂X^7.1,–CN,–SO_n7R^7A,– SO_v7NR^7BR^7C, -NHNR^7BR^7C, -ONR^7BR^7C, -NHC(O)NHNR^7BR^7C, -NHC(O)NR^7BR^7C,–N(O)_m7,– NR^7BR^7C,–C(O)R^7D,–C(O)OR^7D,–C(O)NR^7BR^7C,–OR^7A, -NR^7BSO₂R^7A, -NR^7BC(O)R^7D, - NR^7BC(O)OR^7D,–NR^7BOR^7D,–OCX^7.1

3,–OCHX7.1

[0232] In certain embodiments, R⁷ is halogen,–CX^7.1

3, -CHX7.1

2, -CH₂X^7.1,–CN,–SO_n7R^7A,–

SO_v7NR^7BR^7C, -NHNR^7BR^7C, -ONR^7BR^7C, -NHC(O)NHNR^7BR^7C, -NHC(O)NR^7BR^7C,–N(O)_m7,– NR^7BR^7C,–C(O)R^7D,–C(O)OR^7D,–C(O)NR^7BR^7C,–OR^7A, -NR^7BSO₂R^7A, -NR^7BC(O)R^7D, - NR^7BC(O)OR^7D,–NR^7BOR^7D,–OCX^7.1

3,–OCHX7.1

2, R³³-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³³-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³³-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R³³-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0233] In certain embodiments, R⁷ is R³³-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁷ is R³³-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁷ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0234] In certain embodiments, R⁷ is R³³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁷ is R³³-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁷ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0235] In certain embodiments, R⁷ is R³³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁷ is R³³-substituted cycloalkyl (e.g., C₃- C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁷ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0236] In certain embodiments, R⁷ is R³³-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁷ is R³³-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁷ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). [0237] In certain embodiments, R⁷ is R³³-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁷ is R³³-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁷ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0238] In certain embodiments, R⁷ is R³³-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁷ is R³³-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁷ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0239] In certain embodiments, R⁸ is hydrogen, halogen,–CX^8.1

3, -CHX8.1

2, -CH₂X^8.1,–CN,–SO_n8R^8A,– SO_v8NR^8BR^8C, -NHNR^8BR^8C, -ONR^8BR^8C, -NHC(O)NHNR^8BR^8C, -NHC(O)NR^8BR^8C,–N(O)_m8,– NR^8BR^8C,–C(O)R^8D,–C(O)OR^8D,–C(O)NR^8BR^8C,–OR^8A, -NR^8BSO₂R^8A, -NR^8BC(O)R^8D, - NR^8BC(O)OR^8D,–NR^8BOR^8D,–OCX^8.1

3,–OCHX8.1

[0240] In certain embodiments, R⁸ is halogen,–CX^8.1

3, -CHX8.1

2, -CH₂X^8.1,–CN,–SO_n8R^8A,–

3,–OCHX8.1

2, R³⁶-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁶-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁶-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁶-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁶-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R³⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0241] In certain embodiments, R⁸ is R³⁶-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁸ is R³⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁸ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0242] In certain embodiments, R⁸ is R³⁶-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁸ is R³⁶-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁸ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0243] In certain embodiments, R⁸ is R³⁶-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁸ is R³⁶-substituted cycloalkyl (e.g., C₃- C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁸ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0244] In certain embodiments, R⁸ is R³⁶-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁸ is R³⁶-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁸ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0245] In certain embodiments, R⁸ is R³⁶-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁸ is R³⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁸ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0246] In certain embodiments, R⁸ is R³⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁸ is R³⁶-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁸ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0247] In certain embodiments, R⁹ is hydrogen, halogen,–CX^9.1

3, -CHX9.1

2, -CH₂X^9.1,–CN,–SO_n9R^9A,– SO_v9NR^9BR^9C, -NHNR^9BR^9C, -ONR^9BR^9C, -NHC(O)NHNR^9BR^9C, -NHC(O)NR^9BR^9C,–N(O)_m9,– NR^9BR^9C,–C(O)R^9D,–C(O)OR^9D,–C(O)NR^9BR^9C,–OR^9A, -NR^9BSO₂R^9A, -NR^9BC(O)R^9D, - NR^9BC(O)OR^9D,–NR^9BOR^9D,–OCX^9.1

3,–OCHX9.1

[0248] In certain embodiments, R⁹ is halogen,–CX^9.1

3, -CHX9.1

2, -CH₂X^9.1,–CN,–SO_n9R^9A,–

SO_v9NR^9BR^9C, -NHNR^9BR^9C, -ONR^9BR^9C, -NHC(O)NHNR^9BR^9C, -NHC(O)NR^9BR^9C,–N(O)_m9,– NR^9BR^9C,–C(O)R^9D,–C(O)OR^9D,–C(O)NR^9BR^9C,–OR^9A, -NR^9BSO₂R^9A, -NR^9BC(O)R^9D, - NR^9BC(O)OR^9D,–NR^9BOR^9D,–OCX^9.1

3,–OCHX9.1

2, R³⁹-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R³⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0249] In certain embodiments, R⁹ is R³⁹-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁹ is R³⁹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). [0250] In certain embodiments, R⁹ is R³⁹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁹ is R³⁹-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁹ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0251] In certain embodiments, R⁹ is R³⁹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁹ is R³⁹-substituted cycloalkyl (e.g., C₃- C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁹ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0252] In certain embodiments, R⁹ is R³⁹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁹ is R³⁹-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁹ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0253] In certain embodiments, R⁹ is R³⁹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁹ is R³⁹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0254] In certain embodiments, R⁹ is R³⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁹ is R³⁹-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁹ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0255] In certain embodiments, R¹⁰ is hydrogen, halogen,–CX^10.1

3, -CHX10.1

2, -CH₂X^10.1,–CN,– SO_n10R^10A,–SO_v10NR^10BR^10C, -NHNR^10BR^10C, -ONR^10BR^10C, -NHC(O)NHNR^10BR^10C,

-NHC(O)NR^10BR^10C,–N(O)_m10,–NR^10BR^10C,–C(O)R^10D,–C(O)OR^10D,–C(O)NR^10BR^10C,–OR^10A, - NR^10BSO₂R^10A, -NR^10BC(O)R^10D, -NR^10BC(O)OR^10D,–NR^10BOR^10D,–OCX^10.1

3,–OCHX10.1

[0256] In certain embodiments, R¹⁰ is halogen,–CX^10.1

3, -CHX10.1

2, -CH₂X^10.1,–CN,–SO_n10R^10A,– SO_v10NR^10BR^10C, -NHNR^10BR^10C, -ONR^10BR^10C, -NHC(O)NHNR^10BR^10C, -NHC(O)NR^10BR^10C,– N(O)_m10,–NR^10BR^10C,–C(O)R^10D,–C(O)OR^10D,–C(O)NR^10BR^10C,–OR^10A, -NR^10BSO₂R^10A, - NR^10BC(O)R^10D, -NR^10BC(O)OR^10D,–NR^10BOR^10D,–OCX^10.1

3,–OCHX10.1

2, R⁴²-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅- C₆ cycloalkyl), R⁴²-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴²-substituted or

unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁴²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0257] In certain embodiments, R¹⁰ is R⁴²-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹⁰ is R⁴²-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹⁰ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0258] In certain embodiments, R¹⁰ is R⁴²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹⁰ is R⁴²-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹⁰ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0259] In certain embodiments, R¹⁰ is R⁴²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹⁰ is R⁴²-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹⁰ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0260] In certain embodiments, R¹⁰ is R⁴²-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹⁰ is R⁴²-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹⁰ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0261] In certain embodiments, R¹⁰ is R⁴²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹⁰ is R⁴²-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹⁰ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0262] In certain embodiments, R¹⁰ is R⁴²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹⁰ is R⁴²-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹⁰ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0263] In certain embodiments, R¹¹ is hydrogen, halogen,–CX^11.1

3, -CHX11.1

2, -CH₂X^11.1,–CN,– SO_n11R^11A,–SO_v11NR^11BR^11C, -NHNR^11BR^11C, -ONR^11BR^11C, -NHC(O)NHNR^11BR^11C,

-NHC(O)NR^11BR^11C,–N(O)_m11,–NR^11BR^11C,–C(O)R^11D,–C(O)OR^11D,–C(O)NR^11BR^11C,–OR^11A, - NR^11BSO₂R^11A, -NR^11BC(O)R^11D, -NR^11BC(O)OR^11D,–NR^11BOR^11D,–OCX^11.1

3,–OCHX11.1

[0264] In certain embodiments, R¹¹ is halogen,–CX^11.1

3, -CHX11.1

2, -CH₂X^11.1,–CN,–SO_n11R^11A,– SO_v11NR^11BR^11C, -NHNR^11BR^11C, -ONR^11BR^11C, -NHC(O)NHNR^11BR^11C, -NHC(O)NR^11BR^11C,– N(O)_m11,–NR^11BR^11C,–C(O)R^11D,–C(O)OR^11D,–C(O)NR^11BR^11C,–OR^11A, -NR^11BSO₂R^11A, - NR^11BC(O)R^11D, -NR^11BC(O)OR^11D,–NR^11BOR^11D,–OCX^11.1

3,–OCHX11.1

2, R⁴⁵-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅- C₆ cycloalkyl), R⁴⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴⁵-substituted or

unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁴⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0265] In certain embodiments, R¹¹ is R⁴⁵-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹¹ is R⁴⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹¹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0266] In certain embodiments, R¹¹ is R⁴⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹¹ is R⁴⁵-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹¹ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0267] In certain embodiments, R¹¹ is R⁴⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹¹ is R⁴⁵-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹¹ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0268] In certain embodiments, R¹¹ is R⁴⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹¹ is R⁴⁵-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹¹ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0269] In certain embodiments, R¹¹ is R⁴⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹¹ is R⁴⁵-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹¹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0270] In certain embodiments, R¹¹ is R⁴⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹¹ is R⁴⁵-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹¹ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0271] In certain embodiments, R¹² is hydrogen, halogen,–CX^12.1

3, -CHX12.1

2, -CH₂X^12.1,–CN,– SO_n12R^12A,–SO_v12NR^12BR^12C, -NHNR^12BR^12C, -ONR^12BR^12C, -NHC(O)NHNR^12BR^12C,

-NHC(O)NR^12BR^12C,–N(O)_m12,–NR^12BR^12C,–C(O)R^12D,–C(O)OR^12D,–C(O)NR^12BR^12C,–OR^12A, - NR^12BSO₂R^12A, -NR^12BC(O)R^12D, -NR^12BC(O)OR^12D,–NR^12BOR^12D,–OCX^12.1

3,–OCHX12.1

[0272] In certain embodiments, R¹² is halogen,–CX^12.1

3, -CHX12.1

2, -CH₂X^12.1,–CN,–SO_n12R^12A,– SO_v12NR^12BR^12C, -NHNR^12BR^12C, -ONR^12BR^12C, -NHC(O)NHNR^12BR^12C, -NHC(O)NR^12BR^12C,– N(O)_m12,–NR^12BR^12C,–C(O)R^12D,–C(O)OR^12D,–C(O)NR^12BR^12C,–OR^12A, -NR^12BSO₂R^12A, - NR^12BC(O)R^12D, -NR^12BC(O)OR^12D,–NR^12BOR^12D,–OCX^12.1

3,–OCHX12.1

2, R⁴⁸-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴⁸-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅- C₆ cycloalkyl), R⁴⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴⁸-substituted or

unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁴⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 12 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0273] In certain embodiments, R¹² is R⁴⁸-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹² is R⁴⁸-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹² is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0274] In certain embodiments, R¹² is R⁴⁸-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹² is R⁴⁸-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹² is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0275] In certain embodiments, R¹² is R⁴⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹² is R⁴⁸-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹² is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0276] In certain embodiments, R¹² is R⁴⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹² is R⁴⁸-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹² is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0277] In certain embodiments, R¹² is R⁴⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹² is R⁴⁸-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹² is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0278] In certain embodiments, R¹² is R⁴⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 12 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹² is R⁴⁸-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 12 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹² is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 12 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0279] In certain embodiments, R¹³ is hydrogen, halogen,–CX^13.1

3, -CHX13.1

2, -CH₂X^13.1,–CN,– SO_n13R^13A,–SO_v13NR^13BR^13C, -NHNR^13BR^13C, -ONR^13BR^13C, -NHC(O)NHNR^13BR^13C,

-NHC(O)NR^13BR^13C,–N(O)_m13,–NR^13BR^13C,–C(O)R^13D,–C(O)OR^13D,–C(O)NR^13BR^13C,–OR^13A, - NR^13BSO₂R^13A, -NR^13BC(O)R^13D, -NR^13BC(O)OR^13D,–NR^13BOR^13D,–OCX^13.1

3,–OCHX13.1

[0280] In certain embodiments, R¹³ is halogen,–CX^13.1

3, -CHX13.1

2, -CH₂X^13.1,–CN,–SO_n13R^13A,– SO_v13NR^13BR^13C, -NHNR^13BR^13C, -ONR^13BR^13C, -NHC(O)NHNR^13BR^13C, -NHC(O)NR^13BR^13C,– N(O)_m13,–NR^13BR^13C,–C(O)R^13D,–C(O)OR^13D,–C(O)NR^13BR^13C,–OR^13A, -NR^13BSO₂R^13A, - NR^13BC(O)R^13D, -NR^13BC(O)OR^13D,–NR^13BOR^13D,–OCX^13.1

3,–OCHX13.1

2, R⁵¹-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵¹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁵¹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅- C₆ cycloalkyl), R⁵¹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵¹-substituted or

unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁵¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 13 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0281] In certain embodiments, R¹³ is R⁵¹-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹³ is R⁵¹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹³ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0282] In certain embodiments, R¹³ is R⁵¹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹³ is R⁵¹-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹³ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0283] In certain embodiments, R¹³ is R⁵¹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹³ is R⁵¹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹³ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0284] In certain embodiments, R¹³ is R⁵¹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹³ is R⁵¹-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹³ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0285] In certain embodiments, R¹³ is R⁵¹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹³ is R⁵¹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹³ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0286] In certain embodiments, R¹³ is R⁵¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 13 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹³ is R⁵¹-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 13 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹³ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 13 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0287] In certain embodiments, R¹⁴ is hydrogen, halogen,–CX^14.1

3, -CHX14.1

2, -CH₂X^14.1,–CN,– SO_n14R^14A,–SO_v14NR^14BR^14C, -NHNR^14BR^14C, -ONR^14BR^14C, -NHC(O)NHNR^14BR^14C,

-NHC(O)NR^14BR^14C,–N(O)_m14,–NR^14BR^14C,–C(O)R^14D,–C(O)OR^14D,–C(O)NR^14BR^14C,–OR^14A, - NR^14BSO₂R^14A, -NR^14BC(O)R^14D, -NR^14BC(O)OR^14D,–NR^14BOR^14D,–OCX^14.1

3,–OCHX14.1

[0288] In certain embodiments, R¹⁴ is halogen,–CX^14.1

3, -CHX14.1

2, -CH₂X^14.1,–CN,–SO_n14R^14A,– SO_v14NR^14BR^14C, -NHNR^14BR^14C, -ONR^14BR^14C, -NHC(O)NHNR^14BR^14C, -NHC(O)NR^14BR^14C,– N(O)_m14,–NR^14BR^14C,–C(O)R^14D,–C(O)OR^14D,–C(O)NR^14BR^14C,–OR^14A, -NR^14BSO₂R^14A, - NR^14BC(O)R^14D, -NR^14BC(O)OR^14D,–NR^14BOR^14D,–OCX^14.1

3,–OCHX14.1

2, R⁵⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁵⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅- C₆ cycloalkyl), R⁵⁴-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁵⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 14 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0289] In certain embodiments, R¹⁴ is R⁵⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹⁴ is R⁵⁴-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹⁴ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0290] In certain embodiments, R¹⁴ is R⁵⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹⁴ is R⁵⁴-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹⁴ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0291] In certain embodiments, R¹⁴ is R⁵⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹⁴ is R⁵⁴-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹⁴ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0292] In certain embodiments, R¹⁴ is R⁵⁴-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹⁴ is R⁵⁴-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹⁴ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0293] In certain embodiments, R¹⁴ is R⁵⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹⁴ is R⁵⁴-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹⁴ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0294] In certain embodiments, R¹⁴ is R⁵⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 14 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹⁴ is R⁵⁴-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 14 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹⁴ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 14 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0295] In certain embodiments, R^1A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^15A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^15A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^15A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^15A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^15A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^15A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0296] In certain embodiments, R^2A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^18A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^18A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^18A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^18A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^18A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^18A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0297] In certain embodiments, R^3A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^21A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^21A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^21A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^21A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^21A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^21A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0298] In certain embodiments, R^4A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^24A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^24A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^24A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^24A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^24A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^24A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0299] In certain embodiments, R^5A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^27A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^27A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^27A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^27A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^27A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^27A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0300] In certain embodiments, R^6A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^30A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^30A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^30A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^30A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^30A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^30A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0301] In certain embodiments, R^7A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^33A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^33A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^33A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^33A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^33A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^33A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0302] In certain embodiments, R^8A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^36A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^36A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^36A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^36A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^36A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^36A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0303] In certain embodiments, R^9A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^39A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^39A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^39A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^39A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^39A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^39A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0304] In certain embodiments, R^10A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^42A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^42A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^42A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^42A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^42A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^42A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0305] In certain embodiments, R^11A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^45A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^45A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^45A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^45A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^45A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^45A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0306] In certain embodiments, R^12A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^48A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^48A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^48A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^48A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^48A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^48A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0307] In certain embodiments, R^13A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^51A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^51A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^51A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^51A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^51A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^51A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0308] In certain embodiments, R^14A is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^54A-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^54A-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^54A-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^54A-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^54A-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^54A-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0309] In certain embodiments, R^1B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^15B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^15B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^15B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^15B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^15B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^15B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^1B and R^1C substituents bonded to the same nitrogen atom may optionally be joined to form a R^15B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^15B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0310] In certain embodiments, R^2B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^18B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^18B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^18B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^18B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^18B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^18B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^2B and R^2C substituents bonded to the same nitrogen atom may optionally be joined to form a R^18B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^18B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0311] In certain embodiments, R^3B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^21B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^21B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^21B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^21B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^21B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^21B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^3B and R^3C substituents bonded to the same nitrogen atom may optionally be joined to form a R^21B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^21B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0312] In certain embodiments, R^4B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^24B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^24B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^24B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^24B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^24B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^24B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^4B and R^4C substituents bonded to the same nitrogen atom may optionally be joined to form a R^24B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^24B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0313] In certain embodiments, R^5B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^27B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^27B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^27B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^27B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^27B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^27B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^5B and R^5C substituents bonded to the same nitrogen atom may optionally be joined to form a R^27B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^27B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0314] In certain embodiments, R^6B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^30B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^30B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^30B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^30B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^30B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^30B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^6B and R^6C substituents bonded to the same nitrogen atom may optionally be joined to form a R^30B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^30B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0315] In certain embodiments, R^7B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^33B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^33B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^33B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^33B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^33B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^33B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^7B and R^7C substituents bonded to the same nitrogen atom may optionally be joined to form a R^33B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^33B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0316] In certain embodiments, R^8B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^36B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^36B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^36B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^36B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^36B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^36B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^8B and R^8C substituents bonded to the same nitrogen atom may optionally be joined to form a R^36B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^36B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0317] In certain embodiments, R^9B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^39B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^39B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^39B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^39B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^39B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^39B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^9B and R^9C substituents bonded to the same nitrogen atom may optionally be joined to form a R^39B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^39B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0318] In certain embodiments, R^10B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^42B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^42B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^42B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^42B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^42B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^42B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^10B and R^10C substituents bonded to the same nitrogen atom may optionally be joined to form a R^42B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^42B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0319] In certain embodiments, R^11B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^45B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^45B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^45B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^45B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^45B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^45B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^11B and R^11C substituents bonded to the same nitrogen atom may optionally be joined to form a R^45B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^45B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^11B and R^11C substituents bonded to the same nitrogen atom may optionally be joined to form a R^45B-substituted or unsubstituted

heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^45B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0320] In certain embodiments, R^12B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^48B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^48B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^48B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^48B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^48B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^48B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^12B and R^12C substituents bonded to the same nitrogen atom may optionally be joined to form a R^48B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^48B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0321] In certain embodiments, R^13B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^51B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^51B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^51B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^51B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^51B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^51B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^13B and R^13C substituents bonded to the same nitrogen atom may optionally be joined to form a R^51B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^51B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0322] In certain embodiments, R^14B is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^54B-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^54B-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^54B-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^54B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^54B-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^54B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^14B and R^14C substituents bonded to the same nitrogen atom may optionally be joined to form a R^54B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^54B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0323] In certain embodiments, R^1C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^15C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^15C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^15C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^15C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^15C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^15C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^1B and R^1C substituents bonded to the same nitrogen atom may optionally be joined to form a R^15C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^15C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0324] In certain embodiments, R^2C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^18C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^18C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^18C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^18C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^18C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^18C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^2B and R^2C substituents bonded to the same nitrogen atom may optionally be joined to form a R^18C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^18C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0325] In certain embodiments, R^3C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^21C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^21C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^21C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^21C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^21C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^21C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^3B and R^3C substituents bonded to the same nitrogen atom may optionally be joined to form a R^21C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^21C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0326] In certain embodiments, R^4C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^24C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^24C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^24C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^24C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^24C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^24C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^4B and R^4C substituents bonded to the same nitrogen atom may optionally be joined to form a R^24C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^24C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0327] In certain embodiments, R^5C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^27C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^27C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^27C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^27C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^27C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^27C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^5B and R^5C substituents bonded to the same nitrogen atom may optionally be joined to form a R^27C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^27C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0328] In certain embodiments, R^6C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^30C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^30C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^30C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^30C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^30C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^30C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^6B and R^6C substituents bonded to the same nitrogen atom may optionally be joined to form a R^30C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^30C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0329] In certain embodiments, R^7C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^33C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^33C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^33C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^33C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^33C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^33C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^7B and R^7C substituents bonded to the same nitrogen atom may optionally be joined to form a R^33C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^33C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0330] In certain embodiments, R^8C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^36C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^36C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^36C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^36C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^36C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^36C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^8B and R^8C substituents bonded to the same nitrogen atom may optionally be joined to form a R^36C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^36C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0331] In certain embodiments, R^9C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^39C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^39C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^39C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^39C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^39C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^39C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^9B and R^9C substituents bonded to the same nitrogen atom may optionally be joined to form a R^39C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^39C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0332] In certain embodiments, R^10C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^42C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^42C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^42C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^42C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^42C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^42C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^10B and R^10C substituents bonded to the same nitrogen atom may optionally be joined to form a R^42B-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^42B-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0333] In certain embodiments, R^11C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^45C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^45C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^45C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^45C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^45C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^45C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^11B and R^11C substituents bonded to the same nitrogen atom may optionally be joined to form a R^45C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^45C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0334] In certain embodiments, R^12C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^48C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^48C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^48C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^48C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^48C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^48C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^12B and R^12C substituents bonded to the same nitrogen atom may optionally be joined to form a R^48C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^48C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0335] In certain embodiments, R^13C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^51C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^51C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^51C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^51C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^51C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^51C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^13B and R^13C substituents bonded to the same nitrogen atom may optionally be joined to form a R^51C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^51C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0336] In certain embodiments, R^14C is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^54C-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^54C-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^54C-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^54C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^54C-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^54C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R^14B and R^14C substituents bonded to the same nitrogen atom may optionally be joined to form a R^54C-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) or R^54C-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0337] In certain embodiments, R^1D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^15D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^15D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^15D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^15D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^15D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^15D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0338] In certain embodiments, R^2D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^18D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^18D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^18D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^18D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^18D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^18D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0339] In certain embodiments, R^3D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^21D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^21D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^21D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^21D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^21D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^21D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0340] In certain embodiments, R^4D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^24D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^24D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^24D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^24D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^24D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^24D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0341] In certain embodiments, R^5D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^27D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^27D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^27D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^27D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^27D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^27D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0342] In certain embodiments, R^6D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^30D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^30D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^30D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^30D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^30D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^30D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0343] In certain embodiments, R^7D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^33D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^33D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^33D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^33D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^33D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^33D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0344] In certain embodiments, R^8D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^36D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^36D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^36D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^36D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^36D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^36D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0345] In certain embodiments, R^9D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^39D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^39D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^39D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^39D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^39D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^39D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0346] In certain embodiments, R^10D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^42D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^42D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^42D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^42D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^42D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^42D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0347] In certain embodiments, R^11D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^45D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^45D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^45D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^45D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^45D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^45D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0348] In certain embodiments, R^12D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^48D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^48D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^48D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^48D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^48D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^48D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0349] In certain embodiments, R^13D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^51D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^51D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^51D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^51D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^51D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^51D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0350] In certain embodiments, R^14D is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^54D-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^54D-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^54D-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^54D-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^54D-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^54D-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0351] In certain embodiments, R^3L is hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, R^59L-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^59L-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^59L-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^59L-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R^59L-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^59L-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0352] In certain embodiments, R¹⁵ is independently oxo,

halogen, -CCl₃, -CBr₃, -CF₃, -CI₃,-CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO₃H, -SO₄H, -SO₂N H₂, -NHNH₂, -ONH₂, -NHC(O)NHNH₂, -NHC(O)NH₂, -NHSO₂H, -NHC(O)H,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R¹⁶- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R¹⁶-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R¹⁶-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R¹⁶-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R¹⁶- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R¹⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0353] In certain embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹⁵ is R¹⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹⁵ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0354] In certain embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹⁵ is R¹⁶-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹⁵ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0355] In certain embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹⁵ is R¹⁶-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹⁵ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0356] In certain embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹⁵ is R¹⁶-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹⁵ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0357] In certain embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹⁵ is R¹⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹⁵ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0358] In certain embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹⁵ is R¹⁶-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹⁵ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0359] In certain embodiments, R¹⁶ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF, R¹⁷- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R¹⁷-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R¹⁷-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R¹⁷-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R¹⁷- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R¹⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0360] In certain embodiments, R¹⁶ is R¹⁷-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹⁶ is R¹⁷-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹⁶ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0361] In certain embodiments, R¹⁶ is R¹⁷-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹⁶ is R¹⁷-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹⁶ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0362] In certain embodiments, R¹⁶ is R¹⁷-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹⁶ is R¹⁷-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹⁶ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0363] In certain embodiments, R¹⁶ is R¹⁷-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹⁶ is R¹⁷-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹⁶ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0364] In certain embodiments, R¹⁶ is R¹⁷-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹⁶ is R¹⁷-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹⁶ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). [0365] In certain embodiments, R¹⁶ is R¹⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹⁶ is R¹⁷-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹⁶ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0366] In certain embodiments, R¹⁸ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R¹⁹- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R¹⁹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R¹⁹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R¹⁹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R¹⁹- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R¹⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0367] In certain embodiments, R¹⁸ is R¹⁹-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹⁸ is R¹⁹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹⁸ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0368] In certain embodiments, R¹⁸ is R¹⁹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹⁸ is R¹⁹-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹⁸ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0369] In certain embodiments, R¹⁸ is R¹⁹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹⁸ is R¹⁹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹⁸ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0370] In certain embodiments, R¹⁸ is R¹⁹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹⁸ is R¹⁹-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹⁸ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). [0371] In certain embodiments, R¹⁸ is R¹⁹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹⁸ is R¹⁹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹⁸ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0372] In certain embodiments, R¹⁸ is R¹⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹⁸ is R¹⁹-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹⁸ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0373] In certain embodiments, R¹⁹ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R²⁰- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁰-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁰- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R²⁰-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0374] In certain embodiments, R¹⁹ is R²⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹⁹ is R²⁰-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R¹⁹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0375] In certain embodiments, R¹⁹ is R²⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹⁹ is R²⁰-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R¹⁹ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0376] In certain embodiments, R¹⁹ is R²⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹⁹ is R²⁰-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R¹⁹ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0377] In certain embodiments, R¹⁹ is R²⁰-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹⁹ is R²⁰-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R¹⁹ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0378] In certain embodiments, R¹⁹ is R²⁰-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹⁹ is R²⁰-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R¹⁹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0379] In certain embodiments, R¹⁹ is R²⁰-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹⁹ is R²⁰-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R¹⁹ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0380] In certain embodiments, R²¹ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R²²- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²²-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²²- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0381] In certain embodiments, R²¹ is R²²-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R²¹ is R²²-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R²¹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0382] In certain embodiments, R²¹ is R²²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R²¹ is R²²-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R²¹ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0383] In certain embodiments, R²¹ is R²²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R²¹ is R²²-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R²¹ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0384] In certain embodiments, R²¹ is R²²-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R²¹ is R²²-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R²¹ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0385] In certain embodiments, R²¹ is R²²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R²¹ is R²²-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R²¹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0386] In certain embodiments, R²¹ is R²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R²¹ is R²²-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R²¹ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0387] In certain embodiments, R²² is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R²³- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²³-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²³- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R²³-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0388] In certain embodiments, R²² is R²³-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R²² is R²³-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R²² is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0389] In certain embodiments, R²² is R²³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R²² is R²³-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R²² is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0390] In certain embodiments, R²² is R²³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R²² is R²³-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R²² is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). [0391] In certain embodiments, R²² is R²³-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R²² is R²³-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R²² is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0392] In certain embodiments, R²² is R²³-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R²² is R²³-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R²² is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0393] In certain embodiments, R²² is R²³-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R²² is R²³-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R²² is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0394] In certain embodiments, R²⁴ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R²⁵- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁵- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R²⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0395] In certain embodiments, R²⁴ is R²⁵-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R²⁴ is R²⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R²⁴ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0396] In certain embodiments, R²⁴ is R²⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R²⁴ is R²⁵-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R²⁴ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0397] In certain embodiments, R²⁴ is R²⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R²⁴ is R²⁵-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R²⁴ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0398] In certain embodiments, R²⁴ is R²⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R²⁴ is R²⁵-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R²⁴ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0399] In certain embodiments, R²⁴ is R²⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R²⁴ is R²⁵-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R²⁴ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0400] In certain embodiments, R²⁴ is R²⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R²⁴ is R²⁵-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R²⁴ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0401] In certain embodiments, R²⁵ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R²⁶- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁶-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁶-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁶-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁶- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R²⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0402] In certain embodiments, R²⁵ is R²⁶-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R²⁵ is R²⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R²⁵ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0403] In certain embodiments, R²⁵ is R²⁶-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R²⁵ is R²⁶-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R²⁵ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). [0404] In certain embodiments, R²⁵ is R²⁶-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R²⁵ is R²⁶-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R²⁵ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0405] In certain embodiments, R²⁵ is R²⁶-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R²⁵ is R²⁶-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R²⁵ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0406] In certain embodiments, R²⁵ is R²⁶-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R²⁵ is R²⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R²⁵ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0407] In certain embodiments, R²⁵ is R²⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R²⁵ is R²⁶-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R²⁵ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0408] In certain embodiments, R²⁷ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R²⁸- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁸-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁸- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0409] In certain embodiments, R²⁷ is R²⁸-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R²⁷ is R²⁸-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R²⁷ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0410] In certain embodiments, R²⁷ is R²⁸-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R²⁷ is R²⁸-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R²⁷ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0411] In certain embodiments, R²⁷ is R²⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R²⁷ is R²⁸-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R²⁷ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0412] In certain embodiments, R²⁷ is R²⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R²⁷ is R²⁸-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R²⁷ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0413] In certain embodiments, R²⁷ is R²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R²⁷ is R²⁸-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R²⁷ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0414] In certain embodiments, R²⁷ is R²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R²⁷ is R²⁸-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R²⁷ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0415] In certain embodiments, R²⁸ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R²⁹- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁹- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R²⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0416] In certain embodiments, R²⁸ is R²⁹-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R²⁸ is R²⁹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R²⁸ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). [0417] In certain embodiments, R²⁸ is R²⁹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R²⁸ is R²⁹-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R²⁸ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0418] In certain embodiments, R²⁸ is R²⁹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R²⁸ is R²⁹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R²⁸ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0419] In certain embodiments, R²⁸ is R²⁹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R²⁸ is R²⁹-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R²⁸ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0420] In certain embodiments, R²⁸ is R²⁹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R²⁸ is R²⁹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R²⁸ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0421] In certain embodiments, R²⁸ is R²⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R²⁸ is R²⁹-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R²⁸ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0422] In certain embodiments, R³⁰ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R³¹- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³¹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³¹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³¹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³¹- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R³¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0423] In certain embodiments, R³⁰ is R³¹-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³⁰ is R³¹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³⁰ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0424] In certain embodiments, R³⁰ is R³¹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³⁰ is R³¹-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³⁰ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0425] In certain embodiments, R³⁰ is R³¹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³⁰ is R³¹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³⁰ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0426] In certain embodiments, R³⁰ is R³¹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³⁰ is R³¹-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³⁰ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0427] In certain embodiments, R³⁰ is R³¹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³⁰ is R³¹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³⁰ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0428] In certain embodiments, R³⁰ is R³¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³⁰ is R³¹-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³⁰ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0429] In certain embodiments, R³¹ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R³²- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³²-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³²- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R³²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0430] In certain embodiments, R³¹ is R³²-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³¹ is R³²-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³¹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0431] In certain embodiments, R³¹ is R³²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³¹ is R³²-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³¹ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0432] In certain embodiments, R³¹ is R³²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³¹ is R³²-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³¹ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0433] In certain embodiments, R³¹ is R³²-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³¹ is R³²-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³¹ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0434] In certain embodiments, R³¹ is R³²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³¹ is R³²-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³¹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0435] In certain embodiments, R³¹ is R³²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³¹ is R³²-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³¹ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0436] In certain embodiments, R³³ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R³⁴- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁴-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁴- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R³⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0437] In certain embodiments, R³³ is R³⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³³ is R³⁴-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³³ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0438] In certain embodiments, R³³ is R³⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³³ is R³⁴-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³³ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0439] In certain embodiments, R³³ is R³⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³³ is R³⁴-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³³ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0440] In certain embodiments, R³³ is R³⁴-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³³ is R³⁴-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³³ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0441] In certain embodiments, R³³ is R³⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³³ is R³⁴-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³³ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0442] In certain embodiments, R³³ is R³⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³³ is R³⁴-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³³ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0443] In certain embodiments, R³⁴ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R³⁵- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁵- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R³⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0444] In certain embodiments, R³⁴ is R³⁵-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³⁴ is R³⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³⁴ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0445] In certain embodiments, R³⁴ is R³⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³⁴ is R³⁵-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³⁴ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0446] In certain embodiments, R³⁴ is R³⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³⁴ is R³⁵-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³⁴ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0447] In certain embodiments, R³⁴ is R³⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³⁴ is R³⁵-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³⁴ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0448] In certain embodiments, R³⁴ is R³⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³⁴ is R³⁵-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³⁴ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0449] In certain embodiments, R³⁴ is R³⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³⁴ is R³⁵-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³⁴ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0450] In certain embodiments, R³⁶ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R³⁷- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁷-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁷-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁷-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁷- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R³⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0451] In certain embodiments, R³⁶ is R³⁷-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³⁶ is R³⁷-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³⁶ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0452] In certain embodiments, R³⁶ is R³⁷-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³⁶ is R³⁷-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³⁶ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0453] In certain embodiments, R³⁶ is R³⁷-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³⁶ is R³⁷-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³⁶ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0454] In certain embodiments, R³⁶ is R³⁷-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³⁶ is R³⁷-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³⁶ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0455] In certain embodiments, R³⁶ is R³⁷-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³⁶ is R³⁷-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³⁶ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0456] In certain embodiments, R³⁶ is R³⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³⁶ is R³⁷-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³⁶ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0457] In certain embodiments, R³⁷ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R³⁸- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁸-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁸- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R³⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0458] In certain embodiments, R³⁷ is R³⁸-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³⁷ is R³⁸-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³⁷ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0459] In certain embodiments, R³⁷ is R³⁸-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³⁷ is R³⁸-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³⁷ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0460] In certain embodiments, R³⁷ is R³⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³⁷ is R³⁸-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³⁷ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0461] In certain embodiments, R³⁷ is R³⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³⁷ is R³⁸-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³⁷ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0462] In certain embodiments, R³⁷ is R³⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³⁷ is R³⁸-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³⁷ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0463] In certain embodiments, R³⁷ is R³⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³⁷ is R³⁸-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³⁷ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0464] In certain embodiments, R³⁹ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R⁴⁰- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁰-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴⁰- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁴⁰-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0465] In certain embodiments, R³⁹ is R⁴⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³⁹ is R⁴⁰-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R³⁹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0466] In certain embodiments, R³⁹ is R⁴⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³⁹ is R⁴⁰-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R³⁹ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0467] In certain embodiments, R³⁹ is R⁴⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³⁹ is R⁴⁰-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R³⁹ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0468] In certain embodiments, R³⁹ is R⁴⁰-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³⁹ is R⁴⁰-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R³⁹ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0469] In certain embodiments, R³⁹ is R⁴⁰-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³⁹ is R⁴⁰-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R³⁹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0470] In certain embodiments, R³⁹ is R⁴⁰-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³⁹ is R⁴⁰-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R³⁹ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0471] In certain embodiments, R⁴⁰ is independently, oxo, halogen,

-CCl₃, -CBr₃, -CF₃, -CI₃,-CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO₃H, -SO₄H, -SO₂NH₂, -N HNH₂, -ONH₂, -NHC(O)NHNH₂, -NHC(O)NH₂, -NHSO₂H, -NHC(O)H,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R⁴¹- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴¹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴¹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴¹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴¹- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁴¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0472] In certain embodiments, R⁴⁰ is R⁴¹-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴⁰ is R⁴¹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴⁰ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0473] In certain embodiments, R⁴⁰ is R⁴¹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴⁰ is R⁴¹-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴⁰ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0474] In certain embodiments, R⁴⁰ is R⁴¹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴⁰ is R⁴¹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴⁰ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0475] In certain embodiments, R⁴⁰ is R⁴¹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴⁰ is R⁴¹-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴⁰ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0476] In certain embodiments, R⁴⁰ is R⁴¹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴⁰ is R⁴¹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴⁰ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0477] In certain embodiments, R⁴⁰ is R⁴¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴⁰ is R⁴¹-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴⁰ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0478] In certain embodiments, R⁴² is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R⁴³- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴³-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴³- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁴³-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0479] In certain embodiments, R⁴² is R⁴³-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴² is R⁴³-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴² is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0480] In certain embodiments, R⁴² is R⁴³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴² is R⁴³-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴² is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0481] In certain embodiments, R⁴² is R⁴³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴² is R⁴³-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴² is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0482] In certain embodiments, R⁴² is R⁴³-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴² is R⁴³-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴² is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0483] In certain embodiments, R⁴² is R⁴³-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴² is R⁴³-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴² is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). [0484] In certain embodiments, R⁴² is R⁴³-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴² is R⁴³-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴² is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0485] In certain embodiments, R⁴³ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R⁴⁴- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁴-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴⁴- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁴⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0486] In certain embodiments, R⁴³ is R⁴⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴³ is R⁴⁴-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴³ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0487] In certain embodiments, R⁴³ is R⁴⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴³ is R⁴⁴-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴³ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0488] In certain embodiments, R⁴³ is R⁴⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴³ is R⁴⁴-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴³ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0489] In certain embodiments, R⁴³ is R⁴⁴-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴³ is R⁴⁴-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴³ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). [0490] In certain embodiments, R⁴³ is R⁴⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴³ is R⁴⁴-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴³ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0491] In certain embodiments, R⁴³ is R⁴⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴³ is R⁴⁴-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴³ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0492] In certain embodiments, R⁴⁵ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R⁴⁶- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴⁶-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴⁶-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁶-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴⁶- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁴⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0493] In certain embodiments, R⁴⁵ is R⁴⁶-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴⁵ is R⁴⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴⁵ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0494] In certain embodiments, R⁴⁵ is R⁴⁶-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴⁵ is R⁴⁶-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴⁵ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0495] In certain embodiments, R⁴⁵ is R⁴⁶-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴⁵ is R⁴⁶-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴⁵ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0496] In certain embodiments, R⁴⁵ is R⁴⁶-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴⁵ is R⁴⁶-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴⁵ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0497] In certain embodiments, R⁴⁵ is R⁴⁶-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴⁵ is R⁴⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴⁵ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0498] In certain embodiments, R⁴⁵ is R⁴⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴⁵ is R⁴⁶-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴⁵ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0499] In certain embodiments, R⁴⁶ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R⁴⁷- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴⁷-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴⁷-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁷-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴⁷- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁴⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0500] In certain embodiments, R⁴⁶ is R⁴⁷-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴⁶ is R⁴⁷-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴⁶ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0501] In certain embodiments, R⁴⁶ is R⁴⁷-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴⁶ is R⁴⁷-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴⁶ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0502] In certain embodiments, R⁴⁶ is R⁴⁷-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴⁶ is R⁴⁷-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴⁶ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0503] In certain embodiments, R⁴⁶ is R⁴⁷-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴⁶ is R⁴⁷-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴⁶ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0504] In certain embodiments, R⁴⁶ is R⁴⁷-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴⁶ is R⁴⁷-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴⁶ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0505] In certain embodiments, R⁴⁶ is R⁴⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴⁶ is R⁴⁷-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴⁶ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0506] In certain embodiments, R⁴⁸ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R⁴⁹- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴⁹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁴⁹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴⁹- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁴⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0507] In certain embodiments, R⁴⁸ is R⁴⁹-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴⁸ is R⁴⁹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴⁸ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0508] In certain embodiments, R⁴⁸ is R⁴⁹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴⁸ is R⁴⁹-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴⁸ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0509] In certain embodiments, R⁴⁸ is R⁴⁹-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴⁸ is R⁴⁹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴⁸ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). [0510] In certain embodiments, R⁴⁸ is R⁴⁹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴⁸ is R⁴⁹-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴⁸ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0511] In certain embodiments, R⁴⁸ is R⁴⁹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴⁸ is R⁴⁹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴⁸ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0512] In certain embodiments, R⁴⁸ is R⁴⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴⁸ is R⁴⁹-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴⁸ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0513] In certain embodiments, R⁴⁹ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R⁵⁰- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁵⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁰-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵⁰- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁵⁰-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0514] In certain embodiments, R⁴⁹ is R⁵⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴⁹ is R⁵⁰-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁴⁹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0515] In certain embodiments, R⁴⁹ is R⁵⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴⁹ is R⁵⁰-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁴⁹ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0516] In certain embodiments, R⁴⁹ is R⁵⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴⁹ is R⁵⁰-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁴⁹ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0517] In certain embodiments, R⁴⁹ is R⁵⁰-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴⁹ is R⁵⁰-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁴⁹ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0518] In certain embodiments, R⁴⁹ is R⁵⁰-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴⁹ is R⁵⁰-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁴⁹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0519] In certain embodiments, R⁴⁹ is R⁵⁰-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴⁹ is R⁵⁰-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁴⁹ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0520] In certain embodiments, R⁵¹ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R⁵²- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁵²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵²-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵²- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁵²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0521] In certain embodiments, R⁵¹ is R⁵²-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁵¹ is R⁵²-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁵¹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0522] In certain embodiments, R⁵¹ is R⁵²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁵¹ is R⁵²-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁵¹ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). [0523] In certain embodiments, R⁵¹ is R⁵²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁵¹ is R⁵²-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁵¹ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0524] In certain embodiments, R⁵¹ is R⁵²-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁵¹ is R⁵²-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁵¹ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0525] In certain embodiments, R⁵¹ is R⁵²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁵¹ is R⁵²-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁵¹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0526] In certain embodiments, R⁵¹ is R⁵²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁵¹ is R⁵²-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁵¹ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0527] In certain embodiments, R⁵² is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R⁵³- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁵³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵³-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵³- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁵³-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0528] In certain embodiments, R⁵² is R⁵³-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁵² is R⁵³-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁵² is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0529] In certain embodiments, R⁵² is R⁵³-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁵² is R⁵³-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁵² is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0530] In certain embodiments, R⁵² is R⁵³-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁵² is R⁵³-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁵² is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0531] In certain embodiments, R⁵² is R⁵³-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁵² is R⁵³-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁵² is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0532] In certain embodiments, R⁵² is R⁵³-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁵² is R⁵³-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁵² is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0533] In certain embodiments, R⁵² is R⁵³-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁵² is R⁵³-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁵² is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0534] In certain embodiments, R⁵⁴ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R⁵⁵- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁵⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵⁵- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁵⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0535] In certain embodiments, R⁵⁴ is R⁵⁵-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁵⁴ is R⁵⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁵⁴ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). [0536] In certain embodiments, R⁵⁴ is R⁵⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁵⁴ is R⁵⁵-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁵⁴ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0537] In certain embodiments, R⁵⁴ is R⁵⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁵⁴ is R⁵⁵-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁵⁴ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0538] In certain embodiments, R⁵⁴ is R⁵⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁵⁴ is R⁵⁵-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁵⁴ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0539] In certain embodiments, R⁵⁴ is R⁵⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁵⁴ is R⁵⁵-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁵⁴ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0540] In certain embodiments, R⁵⁴ is R⁵⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁵⁴ is R⁵⁵-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁵⁴ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0541] In certain embodiments, R⁵⁵ is independently oxo,

-NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, R⁵⁶- substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵⁶-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R⁵⁶-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁶-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵⁶- substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R⁵⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0542] In certain embodiments, R⁵⁵ is R⁵⁶-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁵⁵ is R⁵⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In certain embodiments, R⁵⁵ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

[0543] In certain embodiments, R⁵⁵ is R⁵⁶-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁵⁵ is R⁵⁶-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In certain embodiments, R⁵⁵ is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).

[0544] In certain embodiments, R⁵⁵ is R⁵⁶-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁵⁵ is R⁵⁶-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In certain embodiments, R⁵⁵ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl).

[0545] In certain embodiments, R⁵⁵ is R⁵⁶-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁵⁵ is R⁵⁶-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In certain embodiments, R⁵⁵ is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered

heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

[0546] In certain embodiments, R⁵⁵ is R⁵⁶-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁵⁵ is R⁵⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In certain embodiments, R⁵⁵ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

[0547] In certain embodiments, R⁵⁵ is R⁵⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁵⁵ is R⁵⁶-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In certain embodiments, R⁵⁵ is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0548] In certain embodiments, X^1.1, X^2.1, X^3.1, X^4.1, X^5.1, X^6.1, X^7.1, X^8.1, X^9.1, X^10.1, X^11.1, X^12.1, X^13.1, and X^14.1 are independently–Cl. In certain embodiments, X^1.1, X^2.1, X^3.1, X^4.1, X^5.1, X^6.1, X^7.1, X^8.1, X^9.1, X^10.1, X^11.1, X^12.1, X^13.1, and X^14.1 are independently–Br. In certain embodiments, X^1.1, X^2.1, X^3.1, X^4.1, X^5.1, X^6.1, X^7.1, X^8.1, X^9.1, X^10.1, X^11.1, X^12.1, X^13.1, and X^14.1 are independently–I. In certain embodiments, X^1.1, X^2.1, X^3.1, X^4.1, X^5.1, X^6.1, X^7.1, X^8.1, X^9.1, X^10.1, X^11.1, X^12.1, X^13.1, and X^14.1 are independently–F.

[0549] In certain embodiments, X¹ and X² are S.

[0550] In certain embodiments, L¹ is substituted or unsubstituted alkylene. In certain embodiments, L¹ is unsubstituted alkylene. In certain embodiments, L¹ is–CH₂–.

[0551] In certain embodiments, L² is substituted or unsubstituted alkylene. In certain embodiments, L² is unsubstituted alkylene. In certain embodiments, L² is–CH₂–.

[0552] In certain embodiments, L³ is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. [0553] In certain embodiments, the compound has structural Formula (VII-1).

( ),

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0554] R⁴, R⁵, R⁶, and R⁷ are as described herein, including embodiments. In certain embodiments, R¹⁷ is–NH₂ or–OH. In certain embodiments, R¹⁷ is–NH₂. In certain embodiments, R¹⁷ is–OH.

[0555] In certain embodiments, the compound has structural Formula (VII-2):

[0556] R⁴, R⁵, R⁶, and R⁷ are as described herein, including embodiments.

[0557] In certain embodiments, the compound has structural Formula (VIII-1):

[0558] R⁴, R⁵, R⁶, and R⁷ are as described herein, including embodiments. In certain embodiments, R¹⁷ is–NH₂,or–OH. In certain embodiments, R¹⁷ is–NH₂. In certain embodiments, R¹⁷ is–OH.

[0559] In certain embodiments, the compound has structural Formula (VIII-2):

[0560] R⁴, R⁵, R⁶, and R⁷ are as described herein, including embodiments.

[0561] In certain embodiments, R¹⁴ is hydrogen, halogen,–CN,–SO_n14R^14A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0562] In certain embodiments, R⁸ is hydrogen, halogen, or alkyl. In certain embodiments, R⁸ is hydrogen or halogen. In certain embodiments, R⁸ is halogen. In certain embodiments, R⁸ is hydrogen.

[0563] In certain embodiments, R⁵ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. [0564] In certain embodiments, R⁵ is methyl, 2-butyl, propyl, (CH₂CH₂SCH₃),

, ,

, , , , , , , , ,

In certain embodiments, R⁵ is methy, 2-butyl, propyl,

In certain embodiments, R⁵ is propyl, or

. In certain embodiments, R⁵ is propyl. In certain embodiments, R⁵ is

[0565] In certain embodiments, R⁶ is substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroaryl. In certain embodiments, R⁶ is

certain embodiments, R⁶ is

. In certain embodiments, R⁶ is

In certain embodiments, R⁶ is In certain embodiments, R⁶

is

[0566] In certain embodiments, R¹⁴ is substituted or unsubstituted heteroalkyl or substituted or unsubstituted heteroaryl. In certain embodiments, R¹⁴ is

In certain embodiments, R¹⁴ is

. In certain embodiments, R¹⁴ is

[0567] In certain embodiments, R⁷ is substituted aryl.

[0568] In certain embodiments, R⁴ is substituted aryl. [0569] R^15A, R^15B, R^15C, R^15D, R¹⁷, R^18A, R^18B, R^18C, R^18D, R²⁰, R^21A, R^21B, R^21C, R^21D, R²³, R^24A, R^24B, R^24C, R^24D, R²⁶, R^27A, R^27B, R^27C, R^27D, R²⁹, R^30A, R^30B, R^30C, R^30D, R³², R^33A, R^33B, R^33C, R^33D, R³⁵, R^36A, R^36B, R^36C, R^36D, R³⁹, R^39A, R^39B, R^39C, R^39D, R⁴¹, R^42A, R^42B, R^42C, R^42D, R⁴⁴, R^45A, R^45B, R^45C, R^45D, R⁴⁷, R^48A, R^48B, R^48C, R^48D, R⁵⁰, R^51A, R^51B, R^51C, R^51D, R⁵³, R^54A, R^54B, R^54C, R^54D, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R^59L, and R⁶⁰ are independently hydrogen, oxo,

halogen, -CCl₃, -CBr₃, -CF₃, -CI₃,-CN, -OH, -NH₂, -COOH, -CONH₂, -NO₂, -SH, -SO₃H,

-SO₄H, -SO₂NH₂, -NHNH₂, -ONH₂, -NHC(O)NHNH₂, ^NHC(O)NH₂, -NHSO₂H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl₃, -OCF₃, -OCBr₃, -OCI₃,-OCHCl₂, -OCHBr₂, -OCHI₂, -OCHF₂, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0570] In some embodiments, the compound is selected from the compounds in Table 8.

[0571] In certain embodiments, the compound is:

enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

III. Pharmaceutical Compositions

[0572] In an aspect, there is provided a pharmaceutical composition, including a compound as described herein, including certain embodiments, or the structural Formula (I), (I-A), (II), (III), (IV), (IV-1), (V), (VI-A), (VI-B), (VII-1), (VII-2), (VIII-1), or (VIII-2), and at least one pharmaceutically acceptable excipient. [0573] The compounds (e.g., EphA4 inhibitors) of the present disclosure may be in the form of compositions suitable for administration to a subject. In general, such compositions are“pharmaceutical compositions” comprising a compound (e.g., EphA4 inhibitor(s)) and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients. In certain certain embodiments, the compound (e.g., AphA4 inhibitor) are present in a therapeutically acceptable amount. The pharmaceutical compositions may be used in the methods of the present disclosure; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic and prophylactic methods and uses described herein.

[0574] The pharmaceutical compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein.

[0575] The pharmaceutical compositions containing the active ingredient (e.g., an inhibitor of EphA4 function) may be in a form suitable for oral use, for example, as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets, capsules and the like contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture thereof. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.

[0576] The tablets, capsules and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinylacetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide/glycolide copolymers, polylactide/glycolide copolymers, or

ethylenevinylacetate copolymers in order to control delivery of an administered composition. For example, the oral agent can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, by the use of hydroxymethylcellulose or gelatin-microcapsules or poly(methylmethacrolate) microcapsules, respectively, or in a colloid drug delivery system. Colloidal dispersion systems include macromolecule complexes, nano-capsules, microspheres, microbeads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for the preparation of the above-mentioned formulations will be apparent to those skilled in the art.

[0577] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0578] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture thereof. Such excipients can be suspending agents, for example sodium

carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl- pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example a naturally- occurring phosphatide (e.g., lecithin), or condensation products of an alkylene oxide with fatty acids (e.g., polyoxy-ethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., for heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more

preservatives.

[0579] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.

[0580] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, and optionally one or more suspending agents and/or preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0581] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.

[0582] The pharmaceutical compositions typically comprise a therapeutically effective amount of an EphA4 inhibitor contemplated by the present disclosure and one or more pharmaceutically and physiologically acceptable formulation agents. Suitable pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p- hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants. For example, a suitable vehicle may be physiological saline solution or citrate-buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize a variety of buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, a Tris buffer; N- (2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES); 2-(N-Morpholino)ethanesulfonic acid (MES); 2-(N-Morpholino)ethanesulfonic acid sodium salt (MES); 3-(N-Morpholino)propanesulfonic acid (MOPS); and N-tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0583] After a pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form. In some certain embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampule, syringe, or autoinjector (similar to, e.g., an EpiPen®)), whereas a multi-use container (e.g., a multi-use vial) is provided in other embodiments.

[0584] Formulations can also include carriers to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, including liposomes, hydrogels, prodrugs and microencapsulated delivery systems. For example, a time-delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed. Any drug delivery apparatus may be used to deliver an EphA4 inhibitor, including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are well known to the skilled artisan.

[0585] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Acceptable diluents, solvents and dispersion media that may be employed include water, Ringer's solution, isotonic sodium chloride solution, Cremophor^® EL (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium; for this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. Moreover, fatty acids, such as oleic acid, find use in the preparation of injectables. Prolonged absorption of particular injectable formulations can be achieved by including an agent that delays absorption (e.g., aluminum monostearate or gelatin).

[0586] In certain embodiments, the pharmaceutical composition is formulated for administration by injection. In certain embodiments, the pharmaceutical composition is adminisered by intraveous, intramuscular, subcutaneous, intradermal, or intrathecal injection. In certain embodiments, the pharmaceutical composition is administered by intraveous injection. In certain embodiments, the pharmaceutical composition is administerd by intrathecal injection.

[0587] In certain embodiments, the pharmaceutical composition is formulated for administration by injection with a a pump or mini-pump. In certain embodiments, the pharmaceutical composition is administered by an implantable pump. In certain embodiments, an intrathecal pump is used. In certain embodiments, an intraveous (IV) pump is used.

[0588] The compound (e.g., EphA4 inhibitor) contemplated by the present disclosure may be in the form of any other suitable pharmaceutical composition (e.g., sprays for nasal or inhalation use) currently known or developed in the future. IV. Methods of Use

[0589] In another aspect, there is provided a method of inhibiting Ephrin type-A receptor 4 (EphA4), the method including contacting EphA4 with a compound as described herein, including certain embodiments, or the structural Formula (I), (I-A), (II), (III), (IV), (IV-1), (V), (VI-A), (VI-B), (VII-1), (VII-2), (VIII-1), or (VIII-2), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0590] In an aspect, there is provided a method of treating or preventing a disease or disorder associated with EphA4 in a subject in need thereof, wherein the administration reduces at least one symptom associated with the EphA4-associated disease or disorder, the method including administering to a subject in need thereof a therapeutically effective amount of a compound as described herein, including certain embodiments, or the Formula (I), (I-A), (II), (III), (IV), (IV-1), (V), (VI-A), (VI-B), (VII-1), (VII- 2), (VIII-1), or (VIII-2), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0591] In certain embodiments, the disease or disorder comprises a condition, a disease, a disorder and/or pathology where a pathophysiology effect is due to dysregulation of EphA4 signaling in a manner that causes EphA4 signaling hyperactivity in cells or spatially or temporally aberrant EphA4 signaling.

[0592] In certain embodiments, the disease or disorder is a neurodegenerative disease, a hearing loss, a promotion of nerve regeneration, a promotion of neuroprotection, or a cancer. [0593] In certain embodiments, the neurodegenerative disease or disorder is an Alexander disease, an Alper's disease, Alzheimer's disease, an amyotrophic lateral sclerosis, an ataxia telangiectasia, a Canavan disease, a Cockayne syndrome, a corticobasal degeneration, a Creutzfeldt- Jakob disease, a Guillain- Barre Syndrome a HIV-induced neurodegeneration, a Huntington disease, a Kennedy's disease, a Krabbe disease, a Lewy body dementia, a Machado- Joseph disease, a multiple sclerosis, a Parkinson's disease, a Pelizaeus-Merzbacher disease, a Pick's disease, a primary lateral sclerosis, a Refsum's disease, a Sandhoff disease, a Schilder's disease, a spinal cord injury, a Steele-Richardson-Olszewski disease, a stroke, a tabes dorsalis and/or a traumatic brain injury.

[0594] In certain embodiments, the cancer is a glioblastoma, a gastric cancer, a pancreatic cancer, a prostate cancer, a breast cancer, a liver cancer, a leukemia or a Sezary syndrome.

[0595] In certain embodiments, the at least one symptom includes abnormal movement, abnormal sensation, limb grasping, muscle weakness, atrophy, paralysis, abnormal inhibition of axon growth, abnormal axonal transport, aberrant synaptic function, synaptic transmission loss, impaired synaptic plasticity, synaptic loss, neuronal degeneration, motor neuron degeneration, motor neuron loss, poor neuronal survival, memory loss, impaired learning, dementia, b-amyloid plaque deposits, aberrant neurofilament accumulation, reactive astroglia and/or reactive microglia.

[0596] In certain embodiments, the methods of treating a cancer disclosed herein further include co- administering an anti-cancer agent in combination with a compound of structural Formula (I), (I-A), (II), (III), (IV), (IV-1), (V), (VI-A), (VI-B), (VII-1), (VII-2), (VIII-1), or (VIII-2), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a

pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0597] It is frequently beneficial to improve one of more physical properties of the treatment modalities disclosed herein and/or the manner in which they are administered. Improvements of physical properties include, for example, methods of increasing water solubility, bioavailability, serum half-life, and/or therapeutic half-life; and/or modulating biological activity. Modifications known in the art include pegylation, Fc-fusion and albumin fusion. Although generally associated with large molecule agents (e.g., polypeptides), such modifications have recently been evaluated with particular small molecules. By way of example, Chiang, M. et al. (J. Am. Chem. Soc., 2014, 136(9):3370-73) describe a small molecule agonist of the adenosine 2a receptor conjugated to the immunoglobulin Fc domain. The small molecule- Fc conjugate retained potent Fc receptor and adenosine 2a receptor interactions and showed superior properties compared to the unconjugated small molecule. Covalent attachment of PEG molecules to small molecule therapeutics has also been described (Li, W. et al., Progress in Polymer Science, 2013 38:421-44).

[0598] In an embodiment, a method of treating or preventing an EphA4-based disease, disorder or pathology, comprises administering one or more EphA4 antagonists, like one or more compounds disclosed herein, or a pharmaceutical composition disclosed herein to an individual in need thereof in an amount sufficient to reduce one or more physiological conditions or symptom associated with an EphA4- based disease, disorder or pathology, thereby treating the EphA4-based disease, disorder or pathology. In aspects of this embodiment, an EphA4-based disease, disorder or pathology includes, without limitation, a neurodegenerative disease, a hearing loss, promotion of nerve regeneration, promotion of

neuroprotection, and a cancer.

[0599] In certain embodiments, compounds of the present disclosure are effective in the treatment and prevention of neurodegenerative diseases (e.g., ALS, Alzheimer’s disease, multiple sclerosis, stroke, traumatic brain injury). Neurodegenerative diseases are conditions that affect brain or peripheral nerve function. They result from the deterioration of neurons and they are characterized by progressive central or peripheral nervous dysfunction. They are divided into two groups: conditions causing problems with movement or sensation and conditions affecting memory or related to dementia. EphA4 signaling activity has important functions in both categories. For example, increased expression of EphA4 and its activation by ephrin ligands contribute to the pathogenesis of ALS, Alzheimer's disease, multiple sclerosis, stroke and traumatic brain injury and other neurodegenerative disease because EphA4 signaling leads to abnormal inhibition of axon growth, aberrant synaptic function and poor neuronal survival. Thus, a modified EphA4 antagonist, like a compound disclosed herein, or a pharmaceutical composition disclosed herein can be useful in treating any neurodegenerative disease expressing high EphA4 levels because the compounds disclosed herein inhibit EphA4 signaling. A neurodegenerative disease includes, without limitation, an Alexander disease, an Alper's disease, Alzheimer's disease, an amyotrophic lateral sclerosis, an ataxia telangiectasia, a Canavan disease, a Cockayne syndrome, a corticobasal degeneration, a Creutzfeldt- Jakob disease, a Guillain-Barre Syndrome, a HIV-induced neurodegeneration, a

Huntington disease, a Kennedy's disease, a Krabbe disease, a Lewy body dementia, a Machado-Joseph disease, a multiple sclerosis, a Parkinson's disease, a Pelizaeus-Merzbacher disease, a Pick's disease, a primary lateral sclerosis, a Refsum's disease, a Sandhoff disease, a Schilder's disease, a spinal cord injury, a Steele- Richardson-Olszewski disease, a stroke, a tabes dorsalis and/or a traumatic brain injury. Symptoms associated with a neurodegenerative disease include, without limitation, abnormal movement, abnormal sensation, limb grasping, muscle weakness, atrophy, paralysis, abnormal inhibition of axon growth, abnormal axonal transport, aberrant synaptic function, synaptic transmission loss, impaired synaptic plasticity, synaptic loss, neuronal degeneration, motor neuron degeneration, motor neuron loss, poor neuronal survival, memory loss, impaired learning, dementia, b-amyloid plaque deposits, aberrant neurofilament accumulation, reactive astroglia and/or reactive microglia.

[0600] The compounds of the present disclosure can be used to to reduce one or more physiological conditions or symptom associated with a neurodegenerative disease, thereby treating the

neurodegenerative disease.

[0601] Oncology-related Disorders. Originally identified as axon guidance molecules, ephrins and Eph receptors are now known to be involved in a vast array of cell communication events. Many A- and B- class receptors were shown to be overexpressed in a wide variety of tumors, including malignant melanoma, glioma, prostate cancer, breast cancer, small cell lung cancer, endometrial cancer, esophageal cancer, gastric cancer, and colorectal cancer. Subsequent work has shown the Eph receptors regulate critical steps of blood vessel formation (vasculogenesis) and remodeling (angiogenesis) and hence tumor growth. Increasing evidence has implicated EphA4 in various types of cancer, including glioblastoma, gastric cancer, pancreatic cancer, prostate cancer and breast cancer. For example, EphA4 downregulation studies have suggested a role for EphA4 in leukemia, prostate cancer, pancreatic cancer and gastric cancer cell growth and in liver cancer metastasis. High EphA4 expression has also been correlated with shorter survival in breast and gastric cancer patients, although the opposite correlation was found in lung cancer patients. EphA4 is also highly upregulated in Sezary syndrome, a leukemic variant of cutaneous T-cell lymphomas. Finally, EphA4 can enhance the oncogenic effects of fibroblast growth factor receptor 1 in glioblastoma cells. Hence, inhibiting EphA4-ephrin interaction could be useful for promoting axon regeneration and neural repair, providing neuroprotection and regulating synaptic plasticity in the nervous system as well as inhibiting the progression of cancer.

[0602] In accordance with the present disclosure, a compound or pharmaceutical salt thereof can be used to treat or prevent a proliferative condition or disorder, including a cancer, for example, cancer of the uterus, cervix, breast, prostate, testes, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestines, colon, or rectum), kidney, renal cell, bladder, bone, bone marrow, skin, head or neck, liver, gall bladder, heart, lung, pancreas, salivary gland, adrenal gland, thyroid, brain (e.g., gliomas), ganglia, central nervous system (CNS) and peripheral nervous system (PNS), and cancers of the hematopoietic system and the immune system (e.g., spleen or thymus). The present disclosure also provides methods of treating or preventing other cancer-related diseases, disorders or conditions, including, for example, immunogenic tumors, non-immunogenic tumors, dormant tumors, virus-induced cancers (e.g., epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and

papillomavirus), adenocarcinomas, lymphomas, carcinomas, melanomas, leukemias, myelomas, sarcomas, teratocarcinomas, chemically-induced cancers, metastasis, and angiogenesis. The disclosure contemplates reducing tolerance to a tumor cell or cancer cell antigen, e.g., by modulating activity of a regulatory T-cell and/or a CD8+ T-cell (see, e.g., Ramirez-Montagut, et al. (2003) Oncogene 22:3180-87; and Sawaya, et al. (2003) New Engl. J. Med.349:1501-09). In some certain embodiments, the tumor or cancer is colon cancer, ovarian cancer, breast cancer, melanoma, lung cancer, glioblastoma, or leukemia. In particular certain embodiments, the cancer is gastric cancer. The use of the term(s) cancer-related diseases, disorders and conditions is meant to refer broadly to conditions that are associated, directly or indirectly, with cancer, and includes, e.g., angiogenesis and precancerous conditions such as dysplasia. In certain embodiments, the cancer is glioblastoma, a gastric cancer, a pancreatic cancer, a prostate cancer, a breast cancer, a liver cancer, a leukemia and Sezary syndrome, a leukemic variant of cutaneous T-cell lymphomas, thyroid carcinoma, cholangiocarcinoma, pancreatic cancer pancreatic adenocarcinoma, skin cutaneous melanoma, colon cancer, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma. [0603] In certain embodiments, a cancer may be metastatic or at risk of becoming metastatic, or may occur in a diffuse tissue, including cancers of the blood or bone marrow (e.g., leukemia). In some further certain embodiments, the compounds of the disclosure can be used to overcome T-cell tolerance.

[0604] In some certain embodiments, the present disclosure provides methods for treating and/or preventing a proliferative condition, cancer, tumor, or precancerous condition with a compound described herein and at least one additional therapeutic or diagnostic agent, examples of which are set forth elsewhere herein.

[0605] The present disclosure provides methods for treating and/or preventing a proliferative condition, cancer, tumor, or precancerous disease, disorder or condition with a compound described herein.

[0606] In embodiments drawn to methods of treating cancer, the administration of a therapeutically effective amount of a compound described herein results in a cancer survival rate greater than the cancer survival rate observed by administering either agent alone. In further embodiments drawn to methods of treating cancer, the administration of a therapeutically effective amount of a compound described herein (e.g., EphA4 inhibitor) results in a reduction of tumor size or a slowing of tumor growth greater than reduction of tumor size or tumor growth observed following administration of either agent alone. In certain embodiments, the methods of treating cancer disclosed herein further include administering a chemotherapeutic agent or anticancer agent in combination with a compound of structural Formula (I), (I-A), (II), (III), (IV), (IV-1), (V), (VI-A), (VI-B), (VII-1), (VII-2), (VIII-1), or (VIII-2), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the chemotherapeutic agent or anticancer agent is an antiproliferative/antineoplastic drug, an antimetabolite, an antitumor antibiotic, an antimitotic agent, a topoisomerase inhibitor, a cytostatic agent, an oestrogen receptor down regulator, an antiandrogen, a LHRH antagonist or LHRH agonist, a progestogen, an aromatase inhibitor, an inhibitor of 5.alpha.-reductase, an agent which inhibits cancer cell invasion, an inhibitor of growth factor function, a farnesyl transferase inhibitor, a tyrosine kinase inhibitor, a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family, an inhibitor of the platelet-derived growth factor family, an inhibitor of the hepatocyte growth factor family; an

antiangiogenic agent, a vascular damaging agent, an agent used in antisense therapy, an anti-ras antisense, an agent used in a gene therapy, an immunotherapeutic agent, oran antibody.

[0607] CNS-related and Neurological Disorders. Inhibition of EphA4 activity may also represent an important strategy for the treatment or prevention of neurological, neuropsychiatric, neurodegenerative or other diseases, disorders and conditions having some association with the central nervous system, including disorders associated with impairment of cognitive function and/or motor function. Many of these diseases, disorders and conditions comprise an immune and/or inflammatory component. In certain embodiments, the disease or disorder is Parkinson's disease, extra pyramidal syndrome (EPS), dystonia, akathisia, tardive dyskinesia, restless leg syndrome, epilepsy, periodic limb movement in sleep, attention deficit disorders, depression, anxiety, dementia, Alzheimer's disease, Huntington's disease, multiple sclerosis, cerebral ischemia, hemorrhagic stroke, subarachnoid hemorrhage, or traumatic brain injury. In certain embodiments, the methods of treating or preventing a neurological disorder disclosed herein further include administering an anti-neurodegenertive thereapy in combination with a compound of structural Formula (I), (I-A), (II), (III), (IV), (IV-1), (V), (VI-A), (VI-B), (VII-1), (VII-2), (VIII-1), or (VIII-2), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0608] Other Disorders. Cochlear hair cells are the primary sensory receptors of both the auditory system and the vestibular system in all vertebrates. Through mechanotransduction, hair cells detect movement in their environment (i.e., sound) and are responsible for the sense of hearing. Hair cell damage results in decreased hearing sensitivity, i.e. sensorineural hearing loss. Such damage can occur due to hereditary and/or environmental causes. For example, hair cell degenerate and/or death can be caused by lack of essential growth factors, exogenous toxins (such as ototoxic drugs), overstimulation by noise or sound, viral or bacterial infections, autoimmune conditions or hereditary disease. Since human cochlear hair cells are incapable of regeneration, damaged cells cannot be replaced, and as such, their loss leads to permanent hearing loss. Symptoms associated with a neurodegenerative disease include, without limitation, decreased hearing sensitivity and/or sensorineural hearing loss. It is now known that EpHA4 signaling prevents the generation of new cochlear hair cells suggesting that inhibition of EpHA4 activity could be an effective therapy in the treatment of hearing loss.

[0609] In another embodiment, a method of treating an EphA4-based disease, disorder or pathology includes a method of treating a hearing loss. In an aspect of this embodiment, a method of treating a hearing loss comprises administering one or more EphA4 antagonists, like one or more compounds disclosed herein, or a pharmaceutical composition disclosed herein to an individual in need thereof in an amount sufficient to reduce one or more physiological conditions or symptom associated with a hearing loss, thereby treating the hearing loss. In an aspect of this embodiment, administration of one or more EphA4 antagonists, like one or compounds disclosed herein, or a pharmaceutical composition disclosed herein promotes the generation of cochlear sensory hair cells. In an aspect of this embodiment, administration is by injection to the ear region.

[0610] Nerve regeneration or neuroregeneration, refers to the regrowth or repair of nervous tissues, cells or cell products. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Although neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms that control axon regrowth, both are influenced by EphA4 signaling which contribute to the inhibition of axon regeneration following injury. Thus, a modified EphA4 antagonist, like the compounds disclosed herein, or a pharmaceutical composition disclosed herein can be useful in promoting neuroregeneration by inhibiting the activity of EphA4 signaling. Symptoms associated with a lack of nerve regeneration include, without limitation, abnormal movement, abnormal sensation, limb grasping, muscle weakness, atrophy, paralysis, loss of neuronal function, loss of motor neuron function, loss of sensory neuron function, inhibited neuronal growth, inhibited axon growth, inhibited synaptic plasticity, synaptic loss, astrocytic gliosis and/or glial scaring.

[0611] The present disclosure contemplates the administration of the compounds described herein, and compositions (e.g., pharmaceutical salts, pharmaceutical composition) thereof, in any appropriate manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intraarticular, intraperitoneal, intracerebral (intraparenchymal) and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal and inhalation. Depot injections, which are generally administered subcutaneously or intramuscularly, may also be utilized to release the compounds disclosed herein over a defined period of time. In certain embodiments, the administration is oral administration.

[0612] Metabolic and Cardiovascular Diseases. The present disclosure provides methods for treating and/or preventing certain cardiovascular- and/or metabolic-related diseases, disorders and conditions, as well as disorders associated therewith, with a compound described herein.

[0613] The compounds of the present disclosure may be administered to a subject in an amount that is dependent upon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof. The dosing regimen may also take into consideration the existence, nature, and extent of any adverse effects associated with the agent(s) being administered. Effective dosage amounts and dosage regimens can readily be determined from, for example, safety and dose-escalation trials, in vivo studies (e.g., animal models), and other methods known to the skilled artisan.

[0614] In general, dosing parameters dictate that the dosage amount be less than an amount that could be irreversibly toxic to the subject (the maximum tolerated dose (MTD)) and not less than an amount required to produce a measurable effect on the subject. Such amounts are determined by, for example, the pharmacokinetic and pharmacodynamic parameters associated with ADME, taking into consideration the route of administration and other factors.

[0615] An effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the subjects taking it. The“median effective dose” or ED50 of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50% of the population to which it is administered. Although the ED50 is commonly used as a measure of reasonable expectance of an agent’s effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration all relevant factors. Thus, in some situations the effective amount is more than the calculated ED50, in other situations the effective amount is less than the calculated ED50, and in still other situations the effective amount is the same as the calculated ED50.

[0616] In addition, an effective dose of the compounds of the present disclosure may be an amount that, when administered in one or more doses to a subject, produces a desired result relative to a healthy subject. For example, for a subject experiencing a particular disorder, an effective dose may be one that improves a diagnostic parameter, measure, marker and the like of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, where 100% is defined as the diagnostic parameter, measure, marker and the like exhibited by a normal subject.

[0617] In certain embodiments, in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level of a compound of Formula (I), (I-A), (II), (III), (IV), (IV-1), (V), (VI-A), (VI-B), (VII-1), (VII-2), (VIII-1), or (VIII-2), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof generally is ranging from about 1 to 2,000 mg, from about 1 to about 1000 mg, from about 1 to about 500 mg, from about 5 to about 500 mg, from about 5 to about 200 mg, from about 5 to about 250 mg, or from about 10 to about 150 mg, which can be administered in single or multiple doses.

[0618] In certain embodiments, the compound of Formula (I), (I-A), (II), (III), (IV), (IV-1), (V), (VI-A), (VI-B), (VII-1), (VII-2), (VIII-1), or (VIII-2), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 1,000 mg, or 2,000 mg. The pharmaceutical compositions can be administered on a regimen of one or more times per day, including once, twice, three times, four times, or more per day. The pharmaceutical compositions can be administered continually through the day (for example, by a pump).

[0619] In the methods of treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level of a compound described herein (e.g., an EphA4 inhibitor) generally is ranging from about 1 to 2,000 milligrams per day, per week, per month, or every two months. For example, 100, 500, or 1,000 milligrams once or multiple times per month may be effective to obtain the desired results.

[0620] In certain embodiments, the compounds contemplated by the present disclosure may be administered (e.g., IV infusion) at dosage levels of about 0.01 mg/kg to about 50 mg/kg, or about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one, two, three, four or more times a day, to obtain the desired therapeutic effect. For administration of an IV infusion, the compositions can be provided in the form of an aqueous solution containing from 0.05 to 1000 milligrams of the active ingredient, particularly 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 125.0, 150.0, 175.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient. A pharmaceutically acceptable carrier(s), diluent(s) and/or excipient(s) may be present in an amount of from about 0.1 g to about 2.0 g. [0621] In certain embodiments, the dosage of the desired compound is contained in a“unit dosage form.” The phrase“unit dosage form” refers to physically discrete units, each unit including a predetermined amount of the compound (e.g., EphA4 inhibitor), sufficient to produce the desired effect. It will be appreciated that the parameters of a unit dosage form will depend on the particular agent and the effect to be achieved.

[0622] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

V. Examples

[0623] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0624] The present disclosure relates to compounds that inhibit ephrin type-A receptor 4 (EphA4) activity, and compositions (e.g., pharmaceutical compositions) comprising the compounds. Such compounds, including methods of their synthesis, and compositions are described in detail herein. The present disclosure also relates to the use of such compounds and compositions for the treatment and/or prevention of diseases, disorders and conditions mediated, in whole or in part, by EphA4.

[0625] Identification of EphA4 antagonists

[0626] In certain embodiments, compounds described herein possess at least one property or characteristic that is of therapeutic relevance. Candidate antagonists may be identified by using, for example, an art-accepted assay or model. The Example section describes assay(s) that were used to determine the EphA4 activity of the compounds described herein, as well as assays that could be used to evaluate one or more characteristics of the compounds; the skilled artisan is aware of other procedures, assay formats, and the like that can be employed to generate data and information useful to assess the EphA4 antagonists described herein.

[0627] After identification, candidate antagonists can be further evaluated by using techniques that provide data regarding characteristics of the antagonists (e.g., pharmacokinetic parameters). Comparisons of the candidate antagonists to a reference standard (which may the“best-of-class” of current antagonists) are indicative of the potential viability of such candidates. Other means of analyzing candidate inhibitors will be apparent to the skilled artisan.

[0628] Synthesis details [0629] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as their disclosure, nor are they intended to represent that the experiments below were performed or that they are all of the experiments that may be performed. It is to be understood that exemplary descriptions written in the present tense were not necessarily performed, but rather that the descriptions can be performed to generate data, and the like, of a nature described therein. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental errors and deviations should be accounted for.

[0630] Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius (°C), and pressure is at or near atmospheric. Standard abbreviations are used, including the following: wt = wildtype; bp = base pair(s); kb = kilobase(s); nt = nucleotides(s); aa = amino acid(s); s or sec = second(s); min = minute(s); h or hr = hour(s); ng = nanogram; mg = microgram; mg = milligram; g = gram; kg = kilogram; dl or dL = deciliter; ml or mL = microliter; ml or mL = milliliter; l or L = liter; mM = micromolar; mM = millimolar; M = molar; kDa = kilodalton; i.m. = intramuscular(ly); i.p. = intraperitoneal(ly); SC or SQ = subcutaneous(ly); QD = daily; BID = twice daily; QW = weekly; QM = monthly; psi = pounds per square inch; HPLC = high performance liquid chromatography; BW = body weight; U = unit; ns = not statistically significant; MBTE = methyl t-butyl ether; DCM = dichloromethane; PBS = phosphate-buffered saline; IHC = immunohistochemistry; DMEM = Dulbeco’s Modification of Eagle’s Medium; EDTA =

ethylenediaminetetraacetic acid.

[0631] Exemplary compounds EXAMPLES 1A-1B

[0632] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indazol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid and 3- ((4R,7S,10R,13S,20S,23S,26S,29R)-10-((1H-indazol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-29-((S)-2- ((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl- 20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared as follows.

[0633] Scheme 1

[0634] Step A. A solution of 15 g (0.0926 mol, 1 eq) 2H-indazole-3-carboxylic acid (1) and 0.5 ml (9.387 mmol, 0.1 eq) concentrated sulfuric acid in 300 mL of methanol were heated at reflux for 16 hours. The reaction mixture was concentrated in vacuo and then partitioned between ethyl acetate (300 mL) and water (300 mL), washed with aq. saturated sodium bicarbonate solution (100 mL x 2), the aqueous phase extracted with ethyl acetate (150 mL x 3), the combined organic layers were washed with brine (200 mL), dried (magnesium sulfate) and concentrated to give 15 g of 2 (92 % yield).

[0635] Step B. A solution of compound 2 (15 g, 0.0852 mol, 1 eq) in 150 mL of THF was added dropwise to suspension of LiAlH₄ (3.3 g, 0.0868 mol, 1.02 eq) in 120 mL THF at room temperature. The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was cooled to 0 °C and quenched with 3.3 mL of water, 3.3 ml 15% of aq. KOH and 10 ml of water sequentially. The resulting mixture was warmed to room temperature, stirred for 30 min and filtered. The filtrate was evaporated and the residue was dissolved in 200 mL of ethyl acetate. The resulting solution was dried over magnesium sulfate and concentrated to give 11 g of white solid 3 (87% yield).

[0636] Step C. Sodium hydrocarbonate (16.6 g, 0.197 mol, 2.66 eq), DMAP (0.15 g, 1.23 mmol, 0.017 eq) were added to solution of 3 (11 g, 0.074 mol, 1 eq) in 240 mL of CH₂Cl₂. To this mixture, Boc₂O (16.6 g, 0.076 mol, 1.03 eq) in 25 ml of CH₂Cl₂ was added dropwise at room temperature.11 g of compound 3 was dissolved in 240 mL of dry DCM. The reaction mixture was stirred for 12 hours, washed with water (300 mL x 3) and dried over sodium sulphate. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica-gel flash chromatography (CH₂Cl₂/MeOH = 98:2) to give 15.5 g of the product 4 (84% yield).¹H NMR (400 MHz, CDCl3) d 8.09 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 4.75 (s, 2H), 1.68 (s, 9H). ¹³C NMR (126 MHz, CDCl3) d 148.91 (s), 147.18 (s), 140.72 (s), 129.24 (s), 124.05 (s), 123.71 (s), 120.66 (s), 114.88 (s), 85.28 (s), 28.16 (s), 22.87 (s).

[0637] Step D. NBS (11.1 g, 0.062 mol, 1 eq) was added portion wise to solution of 4 (15.5 g, 0.062 mol, 1 eq) and PPh₃ (17.3 g, 0.066 mol, 1.05 eq) in 150 mL of CH₂Cl₂ at -10°C under an argon atmosphere. Then, the mixture was stirred at room temperature for 12 hours. The resulting mixture was evaporated and the residue was dissolved in CCl₄ (500 mL). The solids were removed by filtration and the filtrate was evaporated. The residue was purified by silica-gel flash chromatography (Hex/MTBE = 85:15) to give 4.65 g of the product 5 (24 % yield).

[0638] Step E. Diethyl acetamidomalonate (3.25 g, 0.015 mol, 1 eq) in ethanol (100 mL) was added to solution of sodium ethoxide (prepared by dissolving 0.35 g, 0.015 mol, 1 eq of sodium in 80 mL ethanol) and the resulting mixture was stirred at for a few minutes (until the mixture becomes slightly yellow). To the solution being formed, 5 (4.65 g, 0.015 mol, 1 eq) in 100 mL of absolute ethanol was added and the resulting mixture was stirred at 70°C for 12 hours. Then, the mixture was cooled to room temperature and concentrated in vacuo to dryness. The residue was taken up in dichloromethane (200 mL), and washed with water (200 mL x 2). The organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. To the resulting yellow solid 70 ml of water, 30 ml of ethanol and solid sodium hydroxide (10.8 g, 0.27 mol, 18 eq) were added sequentially. The mixture was heated at reflux for 4 hours. Then, the mixture was cooled to room temperature and 135 mL of conc. hydrochloric acid was added. The resulting reaction mixture was heated at reflux for an additional 68 hours. The solvent was removed in vacuo, and the residue was extracted with boiling ethanol (~ 2.8 L). The combined organic extracts were

concentrated in vacuo to give hydrochloride of 7 (2.5 g) as a white hydroscopic solid (69 % yield).¹H NMR (400 MHz, DMSO-d₆) d 8.64 (brs, 3H), 7.79 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 4.37– 4.21 (m, 1H), 3.54 (ddd, J = 30.5, 15.5, 6.0 Hz, 1H). MS (m/z, ES-API): 206.2 [M+1]⁺.

[0639] Step F. To a suspension of hydrochloride of 7 (0.85 g, 3.52 mmol, 1 eq) in CH₂Cl₂ (15 mL), ethyl diisopropylamine (2.44 mL, 14.08 mmol, 4 eq.) was added followed by trimethylsilyl chloride (0.888 mL, 7.04 mmol, 2 eq.). The resulting mixture was stirred at reflux for 1 hour. The resulting mixture was cooled to 0 °C and FmocCl (1.00 g, 3.87 mmol, 1.1 eq) was added in one portion under stirring, and then the mixture was left under argon atmosphere for 2 hours at a room temperature. Next, the mixture was diluted with CH₂Cl₂ (10 mL), washed with 10% aqueous citric acid (2 × 20 mL) and brine (10 mL), dried over Na₂SO₄, and evaporated in vacuo. The residue after evaporation was purified by HPLC (acetonitrile:water + 0.1% HCOOH ) to give 0.418 g of pure 8 (27 % yield).¹H NMR (400 MHz, DMSO-d6+CCl₄) d 12.64 (s, 1H), 7.76 (d, J = 7.4 Hz, 2H), 7.61 (d, J = 6.9 Hz, 1.5H), 7.46– 7.20 (m, 5.5H), 7.02 (t, J = 7.6 Hz, 1H), 4.50 (q, J = 5.9 Hz, 1H), 4.23– 4.06 (m, 2H), 3.45– 3.31 (s, 1H). MS (m/z, ES-API): 428 [M+1]⁺.

[0640] Scheme 2

[0641] To 9H-fluoren-9-ylmethyl carbamate (acquired from Rink Amide Resin ChemPep Inc.) (0.125 g, 0.1 mmol, 1 eq) was added 20% piperidine/DMF (5 mL). The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (5 mL) was added to it and the mixture was bubbled for 5 min, filtered, washed with DMF (5 mL). The procedure was repeated for 4 times. A solution of Na- Fmoc-S-trityl-L-cysteine 9 (0.234 g, 0.40 mmol, 4 eq), HATU (0.152 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) in DMF (10 mL) was added to the resin. The mixture was bubbled for 30 min at 25 °C. Coupling with of N-(9-Fluorenylmethoxycarbonyl)-S-trityl-L-cysteine 9 was repeated again. The coupling of Fmoc-L-glutamic acid 5-tert-butyl ester 10 (0.17 g, 0.40 mmol, 4 eq), amino acid 8 (0.17 g, 0.17 mmol, 4 eq ), Na-Fmoc-Nd-trityl-L-glutamine 11 (0.24 g, 0.40 mmol, 4 eq), Fmoc-b- alanine 12 (0.125 g, 0.40 mmol, 4 eq), Na-Fmoc-Nw-(2,2,4,6,7-pentamethyldihydrobenzofuran-5- sulfonyl)-L-arginine 13 (0.26 g, 0.40 mmol, 4 eq), Fmoc-O-tert-butyl-L-tyrosine 6 (0.18 g, 0.40 mmol, 4 eq), Fmoc-L-valine 15 (0.14 g, 0.40 mmol, 4 eq), Na-Fmoc-S-trityl-L-cysteine 9 (0.234 g, 0.40 mmol, 4 eq), O-tert-butyl-L-tyrosine 14 (0.18 g, 0.40 mmol, 4 eq), Fmoc-L-proline 18 (0.14 g, 0.40 mmol, 4 eq), Boc-b-alanine 19 was performed as for the first amino acid (Na-Fmoc-S-trityl-L-cysteine - 9). The last amino acid was not de-protected. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C).

[0642] The resin was dispersed in TFA (7.5 mL,), TIS (0.2 mL), EDT (0.2 ml) and H₂O (2.6 mL), then stirred for 5 hours at 25 °C. The resulting mixture was filtered and concentrated under reduced pressure to give crude linear peptide which was used directly without further purification.

[0643] The crude linear peptide was dissolved in AcOH-H₂O (1:1, the final concentration was 1 mg/ml). Iodine (0.254 g, 1 mmol, 10 eq) was added in one portion to the resulting solution. The reaction mixture was stirred for 90 min at 25 °C (the progress of the cyclization was monitored by HPLC). Upon completion, the reaction mixture was diluted with water (50 mL) and the residual iodine was extracted with CCl₄ (5-6 x 25 mL)_. The crude product was purified by prep-HPLC to give two separate

diastereomers.

[0644] HPLC was performed on a Agilent Infinity 1260, with a XBridge Peptide BEH C18300A 5 mm, 2.1х50 mm column at a flowrate of 1 mL/min. Preparative HPLC was performed on a Agilent Infinity 1260 using a XBridge Peptide BEH C18300A 5 mm, 19х150 mm at a flow rate of 40mL/min; solvent A – 0.01% aqueous TFA; solvent B– 90% CH₃CN, 0.01% TFA.1A: (13 mg, 7.6% yield); M.S. (m/z, ES- API): 1487.6 [M+2]⁺.1B: (8.3 mg, 4.8% yield); M.S. (m/z, ES-API): 1488.2 [M+3]⁺.

EXAMPLE 2

[0645] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-26-isopropyl-23-(4-methoxybenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared as follows.

[0646] Scheme 3

[0647] Step A. (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoate (20) (3.00 g, 0.0101 mol, 1 eq) was dissolved in acetone (75 mL) and K₂CO₃ (2.79 g, 2 eq) was added portion wise to the solution. Dimethyl sulfate (0.6363 g, 0.005 mol, 0.5 eq) was added to the reaction mixture portion wise. The resulting mixture was stirred for 12 hours at room temperature, and then the reaction solution was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (200 mL), washed with 10% sodium bicarbonate solution (200 mL x 3) and then with saturated brine (100 mL x 2). The final organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product. The crude product was subjected to silica gel column chromatography to yield compound 21 (2.4 g, 80% yield) as a colorless oil.¹H NMR (400 MHz, DMSO-d6) d 7.20 (d, J = 7.7 Hz, 1H), 7.14 (d, J = 8.3 Hz, 2H), 6.83 (d, J = 8.3 Hz, 2H), 4.15– 4.07 (m, 1H), 3.71 (s, 3H), 3.60 (s, 3H), 2.94– 2.85 (m, 1H), 2.82– 2.70 (m, 1H), 1.33 (s, 9H). MS (m/z, ES-API): 210 [M– C(O)OtBu]⁺.

[0648] Step B. To a solution of compound 21 (1.2 g, 3.9 mmol, 1 eq) in THF/H₂O (4:1, 50 mL) was added LiOH▪H₂O (226 mg, 5.4 mmol, 1.38 eq) at 0 °C. After stirring at 0 °C for 1 h, the organic solvents were evaporated. Then the residue was treated with 15% aqueous citric acid to pH = 3, and the whole resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na₂SO₄, and filtered. The crude material was dissolved in ethyl acetate (50 mL) and then HCI (40 mL of a 4.0M solution in dioxane) was added to the solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness to afford compound 23 as white solid (0.9 g, 98%).¹H NMR (500 MHz, D₂O) d 7.15 (d, J = 7.4 Hz, 2H), 6.89 (d, J = 7.3 Hz, 2H), 4.16 (t, J = 6.0 Hz, 1H), 3.72 (d, J = 1.0 Hz, 3H), 3.18 (dd, J = 14.6, 5.1 Hz, 1H), 3.06 (dd, J = 14.6, 7.6 Hz, 1H).

[0649] Step C. Compound 24 was synthesized analogously to 8 (using step F of Scheme 1 of

EXAMPLE 1). Compound 24 (1.1 g, 87% yield) was obtained from 0.7 g of compound 23 (3.03 mmol). ¹H NMR (400 MHz, DMSO-d6) d 12.74 (s, 1H), 7.87 (d, J = 7.4 Hz, 2H), 7.72– 7.59 (m, 3H), 7.40 (t, J = 7.1 Hz, 2H), 7.30 (dt, J = 15.3, 7.6 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 4.26– 4.06 (m, 4H), 3.01 (dd, J = 13.7, 3.9 Hz, 1H), 2.87– 2.74 (m, 1H).

[0650] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-26-isopropyl-23-(4-methoxybenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to the general procedure of EXAMPLE 1 with N-a-Fmoc-N-in-t-Boc-L-tryptophan in lieu of compound 8 and (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid in lieu of Fmoc-O-tert-butyl-L-tyrosine (14). The synthesis was initiated from (0.125 g, 0.10 mmol) of 9H-fluoren- 9-ylmethyl carbamate Rink Amide Resin ChemPep Inc.. HPLC was performed on a Agilent Infinity 1260, with a XBridge Peptide BEH C18300A 5 mm, 2.1х50 mm column at a flowrate of 1 mL/min. Preparative HPLC was performed on a Agilent Infinity 1260 using a XBridge Peptide BEH C18300A 5 mm, 19х150 mm at a flow rate of 40mL/min; solvent A– 0.01% aqueous TFA; solvent B– 90% CH₃CN, 0.01% TFA. (29.8 mg, 17.3% yield); M.S. (m/z, ES-API): 1499.2 [M+1]⁺. EXAMPLE 3

[0651] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-26-isopropyl-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to the general procedure of EXAMPLE 1 with N-a-Fmoc-N-in-t-Boc-L-tryptophan in lieu of compound 8 and Fmoc-4-methyl-L-phenylalanine (acquired from Leap Labchem Co., Ltd) in lieu of Fmoc-O-tert- butyl-L-tyrosine (14). The synthesis was initiated from (0.125 g, 0.10 mmol) of 9H-fluoren-9-ylmethyl carbamate Rink Amide Resin ChemPep Inc.. HPLC was performed on a Agilent Infinity 1260, with a XBridge Peptide BEH C18300A 5 mm, 2.1х50 mm column at a flowrate of 1 mL/min. Preparative HPLC was performed on a Agilent Infinity 1260 using a XBridge Peptide BEH C18300A 5 mm, 19х150 mm at a flow rate of 40mL/min; solvent A– 0.01% aqueous TFA; solvent B– 90% CH₃CN, 0.01% TFA. (34.9 mg, 20% yield); M.S. (m/z, ES-API): 1481.8 [M]⁺.

EXAMPLE 4

[0652] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-23- (4-bromobenzyl)-4-carbamoyl-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to the general procedure of EXAMPLE 1 with N-a-Fmoc-N-in-t-Boc-L-tryptophan in lieu of compound 8 and Fmoc-4-bromo-L-phenylalanine (acquired from Ark Pharm, Inc.) in lieu of Fmoc-O-tert-butyl-L-tyrosine (14). The synthesis was initiated from (0.125 g, 0.10 mmol) of 9H-fluoren-9-ylmethyl carbamate (Rink Amide Resin ChemPep Inc.). HPLC was performed on a Agilent Infinity 1260, with a XBridge Peptide BEH C18300A 5 mm, 2.1х50 mm column at a flowrate of 1 mL/min. Preparative HPLC was performed on a Agilent Infinity 1260 using a XBridge Peptide BEH C18300A 5 mm, 19х150 mm at a flow rate of 40mL/min; solvent A– 0.01% aqueous TFA; solvent B– 90% CH₃CN, 0.01% TFA. (12.5 mg, 7.8% yield); M.S. (m/z, ES-API): 1547.4 [M+1]⁺.

EXAMPLE 5

[0653] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-29-((S)-2-((S)-1-ethylpyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-20-(3- guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (2xTFA) was prepared according to Schemes 4-7 and as follows. (20.5 mg, 12.3% yield); M.S. (m/z, ES-API): 1444.6 [M+2]⁺.

[0654] Scheme 4

[0655] Step A. The hydrochloride salt of proline methyl ester (25) (29.7 g, 0.179 mol, 1 eq) was dissolved in dry DMF (186 mL) under argon atmosphere. To this, triethylamine (50 mL, 0.358 mol, 2 eq) and DMAP (0.218 g, 1.79 mmol, 0.01 eq) were added and the reaction mixture was stirred for 30 min at room temperature. Ethyl methanesulfonate (24.4 g, 0.197 mol, 1.1 eq) dissolved in dry DMF (111 mL) was added drop-wise to mixture and the resulting reaction mixture was heated at 60 °C for 3 h. The cooled mixture was poured into ice, extracted with ethyl acetate (500 mL), then washed with water (50 mL x 2), brine (50 mL) and dried over Na₂SO₄. The organic extracts were concentrated. The crude product subjected to silica gel column chromatography to give compound 26 (9.2 g, 33% yield).

[0656] Step B. Sodium metal (1.288 g, 0.056 mol, 1 eq) was slowly added to methanol (180 mL). Water was added to the resulting mixture (20 mL). Then compound 26 (8.75 g, 0.056 mol, 1 eq) was added and the resulting mixture was stirred for 12 hours. The pH of the mixture was adjusted to 7 by 10 % aqueous solution of NaHSO₄ and the mixture was then placed in fridge (+ 4 °C) for 12 hours. The precipitate was formed during this time. The precipitate was filtered and dried to give the final product 27 (7.9 g, 98% yield).¹H NMR (400 MHz, D₂O) d 3.06– 3.03 (m, 1H), 2.96– 2.90 (m, 1H), 2.74– 2.60 (m, 1H), 2.36– 2.30 (m, 1H), 2.27 (q, J = 8.8 Hz), 2.10– 2.07 (m, 1H), 1.80– 1.75 (m, 3H), 1.05 (t, J = 8.8 Hz, 3H).

[0657] Scheme 5

[0658] To 9H-fluoren-9-ylmethyl carbamate Rink Amide Resin ChemPep Inc. (0.575 g, 0.5mmol, 1 eq) was added 20% piperidine/DMF (10 mL). The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (10 mL) was added to it and the mixture was bubbled for 5 min, filtered, washed with DMF (10 mL). The procedure was repeated 4 times. A solution of Na-Fmoc-S-trityl-L- cysteine 9 (1.17 g, 2.0 mmol, 4 eq), HATU (0.76 g, 2.00 mmol, 4 eq) and DIPEA (0.5 g, 4.00 mmol, 0.69 mL, 8 eq) in DMF (12 mL) was added to the resin.

[0659] The mixture was bubbled for 30 min at 25 °C. Coupling with of N-(9- Fluorenylmethoxycarbonyl)-S-trityl-L-cysteine 9 was repeated again. The coupling of Fmoc-L-glutamic acid 5-tert-butyl ester 10 (0.85 g, 2.00 mmol, 4 eq), Na-Fmoc-N(in)-Boc-L-tryptophan 18 (0.85 g, 2.00 mmol, 4 eq ), Na-Fmoc-Nd-trityl-L-glutamine 11 (1.2 g, 2.0 mmol, 4 eq), Fmoc-b-alanine 12 (0.625 g, 2.00 mmol, 4 eq), Na-Fmoc-Nw-(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl)-L-arginine 13 (1.3 g, 2.0 mmol, 4 eq), Fmoc-O-tert-butyl-L-tyrosine 14 (0.9 g, 2.0 mmol, 4eq), Fmoc-L-valine 15 (0.7 g, 2.0 mmol, 4eq), Na-Fmoc-S-trityl-L-cysteine 9 (1.17 g, 2.00 mmol, 4 eq),O-tert-butyl-L-tyrosine 14 (0.9 g, 2.0 mmol, 4eq). The last amino acid was not de-protected. Each step was monitored with Kaiser reagent (the naked amine with kaiser became purple under 115 °C).

[0660] Scheme 6

[0661] To intermediate peptide A from previous step (0.22 g, 0.1 mmol, 1 eq), 20% piperidine/DMF (5 mL) was added. The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (5 mL) was added and the resulting mixture was bubbled for 5 min, filtered, washed with DMF (5 mL). The procedure was repeated for 4 times giving N-de-protected peptide on resin.

[0662] A solution of acid 27 (57.2 mg, 0.40 mmol, 4 eq), DIC (0.05 g, 0.40 mmol, 4 eq), oxima (CAS 3849-21-6) (0.06 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) in DMF (5 mL) was added to the resin. The mixture was bubbled for 30 min at 25 °C, then filtered and DMF (15 mL) was added. The mixture was bubbled for 5 min, filtered, washed with DMF (15 mL). The procedure was repeated for 4 times giving intermediate peptides B. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C). [0663] Scheme 7

[0664] The resins with intermediate peptides B were dispersed in TFA (7.5 mL,), TIS (0.2 mL), EDT (0.2 ml) and H₂O (2.6 mL), then stirred for 5 hours at 25 °C. The resulting mixtures were filtered and concentrated under reduced pressure to give crude linear peptides (intermediate peptides C) which were used directly without further purification.

[0665] The crude intermediate peptides C were dissolved in AcOH-H₂O (1:1, the final concentration was 1 mg/ml). Iodine (0.254 g, 1 mmol, 10 eq) was added in one portion to the each solution. The reaction mixtures were stirred for 90 min at 25 °C (the progress of the cyclization was monitored by HPLC). Upon completion, the reaction mixtures were diluted with water (50 ml) and the residual iodine was extracted with CCl₄ (5-6 x 25_mL)_. The crude products were purified by prep-HPLC.

[0666] HPLC was performed on a Agilent Infinity 1260, with a XBridge Peptide BEH C18300A 5 mm, 2.1х50 mm column at a flowrate of 1 mL/min. Preparative HPLC was performed on a Agilent Infinity 1260 using a XBridge Peptide BEH C18300A 5 mm, 19х150 mm at a flow rate of 40mL/min; solvent A – 0.01% aqueous TFA; solvent B– 90% CH₃CN, 0.01% TFA.

EXAMPLE 6

[0667] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-3-(4-hydroxyphenyl)-2-((S)-1-(2,2,2- trifluoroethyl)pyrrolidine-2-carboxamido)propanamido)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (2xTFA) was prepared according to Schemes 5-8 and as follows. (23.7 mg, 13.7% yield); M.S. (m/z, ES-API): 1495.2 [M]⁺.

[0668] Scheme 8

[0669] Step A. tert-butyl (2S)-pyrrolidine-2-carboxylate hydrochloride (28) (1.26 g, 6.08 mmol, 1 eq.), 2,2,2-trifluoroethyl trifluoromethanesulfonate (29) (2.82 g, 12.16 mmol, 2 eq) and potassium carbonate (2.5 g, 18.11 mmol, 3 eq) were mixed in acetonitrile (30 mL). The resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was then filtered and evaporated. The residue was dissolved in ethyl acetate (100 mL) and the organic solution was washed with water (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo affording sufficiently pure 30 (1.46 g, 85% yield).¹H NMR (400 MHz, DMSO-d6) d 3.49– 3.34 (m, 3H), 3.11– 2.99 (m, 1H), 2.73 (dd, J = 15.2, 7.4 Hz, 1H), 2.07– 1.93 (m, 1H), 1.85– 1.70 (m, 3H), 1.40 (s, 9H).

[0670] Step B. Compound 30 (1 g, 3.94 mmol, 1 eq) was placed in the round bottom flask (100 mL).6N aqueous HCl (30 mL) was added. The resulting mixture was stirred for 12 hours at room temperature and then evaporated to dryness. The residue was carefully dried in vacuo for 24 hours affording pure hydrochloride salt of 31 as highly hydroscopic solid (0.92 g, 99% yield).¹H NMR (400 MHz, D₂O) d 3.43– 3.26 (m, 1H), 3.25– 3.03 (m, 3H), 2.55 (q, J = 8.0 Hz, 1H), 2.11– 1.96 (m, 1H), 1.79– 1.56 (m, 3H).¹⁹F NMR (376 MHz, D₂O) d -69.25 (s).

[0671] A solution of acid 31 (78.8 mg, 0.40 mmol, 4 eq), DIC (0.05 g, 0.40 mmol, 4 eq), oxima (CAS 3849-21-6) (0.06 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) in DMF (5 mL) was added to the resin. The mixture was bubbled for 30 min at 25 °C, then filtered and DMF (15 mL) was added. The mixture was bubbled for 5 min, filtered, washed with DMF (15 mL). The procedure was repeated for 4 times giving intermediate peptides B. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C). The title compound was then prepared from intermediate B as described in the general procedure above.

EXAMPLE 7

[0672] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-2-((S)-1-(2-hydroxyethyl)pyrrolidine- 2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (2xTFA) was prepared according to Schemes 5-7, 9, and as follows. (5.8 mg, 11.9% yield); M.S. (m/z, ES-API): 1459.4 [M+2]⁺. [0673] Scheme 9

[0674] Step A. Compound 32 was synthesized analogously to compound 26 (step A).32 (0.98 g) was obtained from 2.14 g of hydrochloride salt of proline methyl ester (25) (0.013 mol) in 29% yield.¹H NMR (400 MHz, CDCl₃) d 4.66– 4.45 (m, 1H), 3.90– 3.73 (m, 2H), 3.67 (s, 3H), 3.58– 3.39 (m, 2H), 3.32– 3.22 (m, 1H), 3.22– 3.10 (m, 1H), 2.90– 2.77 (m, 1H), 2.77– 2.66 (m, 1H), 2.53– 2.39 (m, 1H), 2.17– 1.96 (m, 1H), 1.92– 1.82 (m, 2H), 1.76 (d, J = 2.7 Hz, 2H), 1.69– 1.60 (m, 1H), 1.58– 1.39 (m, 4H).

[0675] Step B. Sodium metal (85 mg, 3.67 mmol, 1.05 eq) was slowly added to methanol (5 mL). Water (3.5 mL) was added to the mixture. Then compound 32 (0.90 g, 3.5 mmol, 1 eq) was added and the resulting mixture was stirred for 12 hours. The mixture was concentrated to dryness and the residue was dried in vacuo to give the sodium salt of the final product 33 (0.88 g, 95% yield).¹H NMR (400 MHz, D₂O) d 4.58 (brs, 1H), 3.78– 3.71 (m, 2H), 3.53– 3.40 (m, 2H), 2.98– 2.90 (m, 1H), 2.89 (t, 1H, J = 8.3 Hz), 2.84– 2.80 (m, 1H), 2.45 (sext, 1H, J = 6.4 Hz), 2.30– 2.20 (m, 1H), 2.07– 1.93 (m, 1H), 1.75– 1.55 (m, 5H), 1.55– 1.30 (m, 4H).

[0676] A solution of acid 33 (106 mg, 0.40 mmol, 4 eq), DIC (0.05 g, 0.40 mmol, 4 eq), oxima (CAS 3849-21-6) (0.06 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) in DMF (5 mL) was added to the resin. The mixture was bubbled for 30 min at 25 °C, then filtered and DMF (15 mL) was added. The mixture was bubbled for 5 min, filtered, washed with DMF (15 mL). The procedure was repeated for 4 times giving intermediate peptides B. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C).

[0677] The title compound was then prepared from intermediate B as described in the general procedure above. EXAMPLE 8

[0678] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-3-(4-hydroxyphenyl)-2-((S)-1-(3- hydroxypropanoyl)pyrrolidine-2-carboxamido)propanamido)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (1xTFA) was prepared according to Schemes 5, 10, 11, and as follows. (19.9 mg, 12.4% yield); M.S. (m/z, ES-API): 1486.8 [M+1]⁺.

[0679] Scheme 10

[0680] Step A. Pyridinium p-toluenesulfonate (7.65 g, 30.45 mmol) was added to a clear solution of methyl 3-hydroxypropanoate (6.34 g, 0.0609 mol) (38) and 3,4-dihydro-2H-pyran (7.8 mL, 0.0852 mol) in dichloromethane (65 mL) at room temperature under nitrogen to give a cloudy solution. The mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was washed with water (25 mL) and brine (25 mL) before drying (MgSO₄) and evaporating to obtain an oil. This crude product was purified by flash silica chromatography, elution gradient 15 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 39 (6.8 g, 59 % yield) as a colorless oil.¹H NMR (400 MHz, CDCl₃) d 4.63 (s, 1H), 4.01 (dt, J = 10.1, 6.4 Hz, 1H), 3.86 (t, J = 10.1 Hz, 1H), 3.80– 3.60 (m, 4H), 3.56 – 3.46 (m, 1H), 2.63 (t, J = 6.4 Hz, 2H), 1.95– 1.44 (m, 6H).

[0681] Step B. Sodium metal (0.6 g, 0.0249 mol, 1.05 eq) was slowly added to methanol (30 mL). Water (8.5 mL) was added to the mixture. Then compound 39 (4.5 g, 0.0237 mol, 1 eq) was added and the resulting mixture was stirred for 12 hours. The mixture was concentrated to dryness and the residue was dried in vacuo to give the final product 40 (4 g, 96% yield).¹H NMR (400 MHz, D₂O) d 4.58 (s, 1H), 3.93– 3.66 (m, 2H), 3.66– 3.57 (m, 1H), 3.51– 3.36 (m, 1H), 2.43– 2.25 (m, 2H), 1.76– 1.53 (m, 2H), 1.52– 1.21 (m, 4H).

[0682] To intermediate peptide A according to Scheme 11 (0.22 g, 0.1 mmol, 1 eq) was added 20% piperidine/DMF (5 mL). The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (5 mL) was added and the resulting mixture was bubbled for 5 min, filtered, washed with DMF (5 mL). The procedure was repeated 4 times. Then, the next acids were coupled as follows.

[0683] Scheme 11

[0684] A solution of Fmoc -L-proline 17 (0.14 g, 0.40 mmol, 4 eq), HATU (0.152 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) in DMF (10 mL) was added to the resin. The mixture was bubbled for 30 min at 25 °C. The mixture was filtered, then DMF (5 mL) was added and the resulting mixture was bubbled for 5 min, filtered, washed with DMF (5 mL). Coupling with of Fmoc -L-proline 17 was repeated again. After coupling, Fmoc de-protection was carried out as for intermediate peptide A. Then, the next amino acid was introduced as described below.

[0685] A solution of 40 (0.40 mmol, 4 eq), DIC (0.05 g, 0.40 mmol, 4 eq), oxima (CAS 3849-21-6) (0.06 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) in DMF (5 mL) was added to the resin. The mixture was bubbled for 30 min at 25 °C, then filtered and DMF (15 mL) was added. The mixture was bubbled for 5 min, filtered, washed with DMF (15 mL). The procedure was repeated for 4 times giving intermediate peptide B. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C). The title compound was then prepared as described in the general procedure above. The title compound was then prepared from intermediate B as described in the general procedure above.

EXAMPLE 9

[0686] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropyl)-5-oxopyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (2xTFA) was prepared according to Schemes 5-7, 12 and as follows. (34.4 mg, 20% yield); M.S. (m/z, ES-API): 1486.6 [M+2]⁺.

[0687] Scheme 12

[0688] Step A. (S)-methyl 5-oxopyrrolidine-2-carboxylate (5.0 g, 35 mmol, 1 eq) (34) was dissolved in 100 ml of dry DMF then obtained solution was cooled on ice-bath and 1.5 g of NaH (60% suspension, 37.5 mmol, 1.05 eq.) was added portion wise. Obtained mixture was stirred at ambient temperature for 30 min. Then 8.7 g (37.5 mmol, 1.07 eq) of bromide (35) was added. The resulting mixture was stirred at ambient temperature for 12 hours, and then poured in cold water (200 mL). The product was extracted two times with ethyl acetate (100 mL x 2). Combined organic fractions were washed with 100 mL of 10% solution of citric acid, 100 mL of saturated solution of NaHCO₃ and 100 mL of saturated solution of NaCl, dried over Na₂SO₄ and evaporated in vacuo to give 8.6 g of crude product 36. This material was used in the next step without further purification. Yield: 82%.

[0689] Step B.8.6 g (29 mmol, 1 eq) of 36 was dissolved in 100 mL of MeOH. Solution of KOH (2.4 g, 43 mmol, 1.5 eq) in 10 mL of water was added to the solution of 36. The resulting mixture was gently heated to boiling point and then stirred at ambient temperature for 1 hour. Volatiles were removed and residue was partitioned between 100 mL of water and 100 mL of MTBE. Organic layer was discarded, water layer was washed one more time with MTBE then acidified with 10% aqueous NaHSO₄ solution to pH » 2 and extracted twice with ethyl acetate (70 mL x 2). Combined organic fractions were washed with 50 mL of saturated solution of NaCl, dried over Na₂SO₄ and evaporated in vacuo to give 3.5 g of 37 as a mixture of two enantiomers– stereocenter should not be drawn then? (55:45– S:R). LCMS: m/z [M-1]- 285.1.¹H NMR (400 MHz, DMSO-d6): d 12.9 (br., 0.5H), 6.76 (s, 1H), 4.18 (br., s.1H), 3.46 (m, 1H), 2.85 (m, 3H), 2.23 (m, 3H), 1.93 (m, 1H), 1.56 (m, 1H), 1.47 (m, 1H), 1.36 (s, 9H). Yield: 43%.

[0690] A solution of acid 37 (114 mg, 0.40 mmol, 4 eq), DIC (0.05 g, 0.40 mmol, 4 eq), oxima (CAS 3849-21-6) (0.06 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) in DMF (5 mL) was added to the resin. The mixture was bubbled for 30 min at 25 °C, then filtered and DMF (15 mL) was added. The mixture was bubbled for 5 min, filtered, washed with DMF (15 mL). The procedure was repeated for 4 times giving intermediate peptides B. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C). The title compound was then prepared from intermediate B as described in the general procedure above.

EXAMPLE 10

[0691] 2-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20-(3- guanidinopropyl)-23-(4-hydroxybenzyl)-7-(hydroxymethyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-13-yl)acetic acid (2xTFA) was prepared according to Schemes 13-14 and as follows. (5.3 mg, 3.2% yield); M.S. (m/z, ES-API): 1416.3 [M]⁺.

[0692] Scheme 13

[0693] Step A. Compound 41 was synthesized analogously to 26 (step A).41 (49.6 g) was obtained from 45.6 g of hydrochloride salt of proline methyl ester (25) (0.275 mol) in 63% yield.

[0694] Step B. Compound 42 was synthesized analogously to 27 (step B).42 (14.4 g) was obtained from 15.93 g of 41 (0.275 mol) in 95% yield.¹H NMR (400 MHz, D₂O) d 3.06– 2.90 (m, 3H), 2.84 (t, J = 7.8 Hz, 1H), 2.58– 2.51 (m, 1H), 2.27– 2.11 (m, 2H), 2.05– 1.93 (m, 1H), 1.75– 1.64 (m, 3H), 1.62– 1.43 (m, 2H), 1.32 (s, 9H).

[0695] Scheme 14

[0696] To 9H-fluoren-9-ylmethyl carbamate (Rink Amide Resin ChemPep Inc.) (0.125 g, 0.1 mmol, 1 eq) was added 20% piperidine/DMF (5 mL). The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (5 mL) was added to it and the mixture was bubbled for 5 min, filtered, washed with DMF (5 mL). The procedure was repeated for 4 times. A solution of Na-Fmoc-S-trityl-L- cysteine 9 (0.234 g, 0.40 mmol, 4 eq), HATU (0.152 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) in DMF (10 mL) was added to the resin. The mixture was bubbled for 30 min at 25 °C. Coupling with of N-(9-Fluorenylmethoxycarbonyl)-S-trityl-L-cysteine 9 was repeated again. The coupling of Fmoc-O-tert-butyl-L-serine 16 (0.15 g, 0.40 mmol, 4 eq), a-Fmoc-N-in-t-Boc-L-tryptophan (0.21 g, 0.4 mmol, 4 eq ) 18, a-Fmoc-L-Aspartic acid beta-tert-butyl ester 80 (0.16 g, 0.40 mmol, 4 eq), Fmoc-b-alanine 12 (0.125 g, 0.40 mmol, 4 eq), Na-Fmoc-Nw-(2,2,4,6,7-pentamethyldihydrobenzofuran- 5-sulfonyl)-L-arginine 13 (0.26 g, 0.40 mmol, 4 eq), Fmoc-O-tert-butyl-L-tyrosine 14 (0.18 g, 0.40 mmol, 4 eq), Fmoc-L-valine 15 (0.14 g, 0.40 mmol, 4 eq), Na-Fmoc-S-trityl-L-cysteine 9 (0.234 g, 0.40 mmol, 4 eq), O-tert-butyl-L-tyrosine 14 (0.18 g, 0.40 mmol, 4 eq) and 42 (0.11 g, 0.40 mmol, 4 eq) or 44 (0.10 g, 0.40 mmol, 4 eq) was performed as for the first amino acid (Na-Fmoc-S-trityl-L-cysteine - 9). The last amino acid was not de-protected. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C).

[0697] The resin was dispersed in TFA (7.5 mL,), TIS (0.2 mL), EDT (0.2 ml) and H₂O (2.6 mL), then stirred for 5 hours at 25 °C. The resulting mixture was filtered and concentrated under reduced pressure to give crude linear peptides which were used directly without further purification.

[0698] Each crude linear peptide was dissolved in AcOH-H₂O (1:1, the final concentration was 1 mg/ml). Iodine (0.254 g, 1 mmol, 10 eq) was added in one portion to the resulting solution. The reaction mixture was stirred for 90 min at 25 °C (the progress of the cyclization was monitored by HPLC). Upon completion, the reaction mixture was diluted with water (50 mL) and the residual iodine was extracted with CCl₄ (5-6 x 25 mL)_. The crude product was purified by prep-HPLC to give the pure peptides of EXAMPLE 10 or EXAMPLE 11.

[0699] HPLC was performed on a Agilent Infinity 1260, with a XBridge Peptide BEH C18300A 5 mm, 2.1х50 mm column at a flowrate of 1 mL/min. Preparative HPLC was performed on a Agilent Infinity 1260 using a XBridge Peptide BEH C18300A 5 mm, 19х150 mm at a flow rate of 40mL/min; solvent A – 0.01% aqueous TFA; solvent B– 90% CH₃CN, 0.01% TFA.

EXAMPLE 11

[0700] 2-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(2- aminoethyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20-(3- guanidinopropyl)-23-(4-hydroxybenzyl)-7-(hydroxymethyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-13-yl)acetic acid (2xTFA) was prepared according to Schemes 14-15 and as follows. (5 mg, 3.1% yield); M.S. (m/z, ES-API): 1402.0 [M]⁺.

[0701] Scheme 15

[0702] Step A. Compound 43 was synthesized analogously to 26 (step A).43 (1.44 g) was obtained from 8.78 g of hydrochloride salt of proline methyl ester (25) (0.053 mol) in 10% yield.

[0703] Step B. Compound 44 was synthesized analogously to 27 (step B).44 (1.070 g) was obtained from 1.20 g of 43 (4.411 mmol) in 94% yield.¹H NMR (500 MHz, D₂O) d 3.22– 1.95 (m, 2H), 3.11– 3.07 (t, J = 7.8 Hz, 1H), 2.99 (t, J = 8.0 Hz, 1H), 2.80– 2.76 (m, 1H), 2.51– 2.45 (m, 1H), 2.36 (q, J = 8.5, 1H), 2.17– 2.11 (m, 1H), 1.85– 1.75 (m, 3H) 1.32 (s, 9H). The title compound was then prepared as described in EXAMPLE 10. EXAMPLE 12

[0704] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-29-((S)-2-(cyclopentanecarboxamido)-3-(4-hydroxyphenyl)propanamido)-20-(3- guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (1xTFA) was prepared according to the general procedure in Schemes 5, 16 (procedure A), 17 and as follows. (16.9 mg, 11.1% yield); M.S. (m/z, ES-API): 1413.2 [M+1]⁺.

EXAMPLE 13

[0705] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-29-((S)-2-(cyclohexanecarboxamido)-3-(4-hydroxyphenyl)propanamido)-20-(3- guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (1xTFA) was prepared according to the general procedure in Schemes 5, 16 (procedure A), 17 and as follows. (5.2 mg, 3.4% yield); M.S. (m/z, ES-API): 1429.7 [M+2]⁺.

EXAMPLE 14

[0706] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-29-((S)-2-(2,3-dihydro-1H-indene-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-20-(3- guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (1xTFA) was prepared according to the general procedure in Schemes 5, 16 (procedure A), 17 and as follows. (12.8 mg, 8.1% yield); M.S. (m/z, ES-API): 1462.4 [M+2]⁺.

EXAMPLE 15

[0707] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-3-(4-hydroxyphenyl)-2- pivalamidopropanamido)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontan-7-yl)propanoic acid (1xTFA) was prepared according to the general procedure in Schemes 5, 16 (procedure A), 17 and as follows. (25 mg, 16.5% yield); M.S. (m/z, ES-API): 1402.4 [M+1]⁺.

EXAMPLE 16

[0708] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-3-(4-hydroxyphenyl)-2- isobutyramidopropanamido)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (1xTFA) was prepared according to the general procedure in Schemes 5, 16 (procedure A), 17 and as follows. (3.5 mg, 2.3% yield); M.S. (m/z, ES-API): 1388.6 [M+1]⁺.

EXAMPLE 17

[0709] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-20-(3-guanidinopropyl)-29-((S)-2-(2-hydroxyacetamido)-3-(4-hydroxyphenyl)propanamido)- 23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontan-7-yl)propanoic acid (1xTFA) was prepared according to the general procedure in Schemes 5, 16 (procedure A), 17 and as follows. (7.3 mg, 4.9% yield); M.S. (m/z, ES-API): 1374.2 [M+1]⁺.

EXAMPLE 18

[0710] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-3-(4-hydroxyphenyl)-2-(3- hydroxypropanamido)propanamido)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (1xTFA) was prepared according to the general procedure in Schemes 5, 16 (procedure A), 17 and as follows. (28.3 mg, 18.8% yield); M.S. (m/z, ES-API): 1389.2 [M+1]⁺.

[0711] Intermediate peptide A was prepared according to Scheme 5 as follows. To 9H-fluoren-9- ylmethyl carbamate Rink Amide Resin ChemPep Inc. (1.375 g, 1.1 mmol, 1 eq) was added 20% piperidine/DMF (15 mL). The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (15 mL) was added to it and the mixture was bubbled for 5 min, filtered, washed with DMF (15 mL). The procedure was repeated for 4 times. A solution of Na-Fmoc-S-trityl-L-cysteine 9 (2.57 g, 4.40 mmol, 4 eq), HATU (1.67 g, 4.40 mmol, 4 eq) and DIPEA (1.1 g, 8.80 mmol, 1.529 mL, 8 eq) in DMF (30 mL)was added to the resin. The mixture was bubbled for 30 min at 25 °C. Coupling with of N- (9-Fluorenylmethoxycarbonyl)-S-trityl-L-cysteine 9 was repeated again. The coupling of Fmoc-L- glutamic acid 5-tert-butyl ester 10 (1.87 g, 4.40 mmol, 4 eq), Na-Fmoc-N(in)-Boc-L-tryptophan 18 (1.87 g, 4.40 mmol, 4 eq ), Na-Fmoc-Nd-trityl-L-glutamine 11 (2.64 g, 4.40 mmol, 4 eq), Fmoc-b-alanine 12 (1.375 g, 4.40 mmol, 4 eq), Na-Fmoc-Nw-(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl)-L- arginine 13 (2.86 g, 4.40 mmol, 4eq), Fmoc-O-tert-butyl-L-tyrosine 14 (1.98 g, 4.40 mmol, 4eq),Fmoc- L-valine 15 (1.54 g, 4.40 mmol, 4eq), Na-Fmoc-S-trityl-L-cysteine 9 (2.57 g, 4.40 mmol, 4 eq), O-tert- butyl-L-tyrosine 14 (1.98 g, 4.40 mmol, 4 eq) was performed as for the first amino acid (Na-Fmoc-S- trityl-L-cysteine - 9). The last amino acid was not de-protected. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C).

[0712] Scheme 16

[0713] To intermediate peptide A (0.22 g, 0.1 mmol, 1 eq) was added 20% piperidine/DMF (5 mL). The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (5 mL) was added and the resulting mixture was bubbled for 5 min, filtered, washed with DMF (5 mL). The procedure was repeated for 4 times giving intermediate peptide B.

[0714] Procedure A (for EXAMPLES 12-18) - Synthesis of intermediate peptides C

[0715] The corresponding acid (0.40 mmol, 4 eq) was dissolved in 5 mL of DMF. The amounts for each corresponding acid is given in Table 1 following.

[0716] Table 1

[0717] To solutions of the acids, DIC (0.05 g, 0.40 mmol, 4 eq), DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) and oxima (CAS 3849-21-6) (0.06 g, 0.40 mmol, 4 eq) were added sequentially. The resulting solutions were added to intermediate peptide B (0.1 mmol, 1 eq). The mixtures were bubbled for 30 min at 25 °C, then filtered and DMF (15 mL) was added. The mixtures were bubbled for 5 min again, filtered, washed with DMF (15 mL). The procedure was repeated 4 times to afford intermediate peptides C.

EXAMPLE 19

[0718] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-3-(4-hydroxyphenyl)-2- (methylsulfonamido)propanamido)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (1xTFA) was prepared according to the general procedure in Schemes 5, 16 (procedure B), 17 and as follows. (11.6 mg, 7.7% yield); M.S. (m/z, ES-API): 1395.2 [M]⁺.

EXAMPLE 20

[0719] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-3-(4-hydroxyphenyl)-2- (phenylsulfonamido)propanamido)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (1xTFA) was prepared according to the general procedure in Schemes 5, 16 (procedure B), 17 and as follows. (24.8 mg, 15.8% yield); M.S. (m/z, ES-API): 1457.6 [M]⁺.

EXAMPLE 21

[0720] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-3-(4-hydroxyphenyl)-2-((N- methylsulfamoyl)amino)propanamido)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (1xTFA) was prepared according to the general procedure in Schemes 5, 16 (procedure B), 17 and as follows. (16.3 mg, 10.7% yield); M.S. (m/z, ES-API): 1409.0 [M]⁺.

EXAMPLE 22

[0721] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-3-(4-hydroxyphenyl)-2-((N- isopropylsulfamoyl)amino)propanamido)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (1xTFA) was prepared according to the general procedure in Schemes 5, 16 (procedure B), 17 and as follows. (11.9 mg, 7.7% yield); M.S. (m/z, ES-API): 1438.2 [M+1]⁺.

[0722] Procedure B (for EXAMPLES 19-22).

[0723] The corresponding sulfonyl chloride (0.40 mmol, 4 eq) was dissolved in 5 mL of pyridine at 0 °C. The amounts are given in Table 2 following.

[0724] Table 2

[0725] The resulting solutions were added to the intermediate peptide B (0.1 mmol, 1 eq, each) at 0 °C. The mixtures were bubbled for 30 min at 0 °C, then filtered and DMF (15 mL) was added to each resin. The mixtures were bubbled for 5 min again, filtered, washed with DMF (15 mL). The procedure was repeated for 4 times giving intermediate peptides C.

[0726] Scheme 17: General Procedure for cleavage and cyclization for EXAMPLES 12-21

[0727] The intermediate peptides C were dispersed in mixture of TFA (7.5 mL), TIS (0.2 mL), EDT (0.2 ml) and H₂O (2.6 mL). The mixtures were shaken for 5 hours at 25 °C. The resulting mixtures were filtered and concentrated under reduced pressure to give crude linear peptides (intermediate peptides D) which were used directly without further purification. The crude intermediate peptides D were dissolved in AcOH-H₂O (1:1, the final concentration was 1 mg/ml). Iodine (0.254 g, 1 mmol, 10 eq) was added in one portion to each solution. The reaction mixtures were stirred for 90 min at 25 °C (the progress of the cyclization was monitored by HPLC). Upon completion, the reaction mixtures were diluted with water (50 ml) and the residual iodine was extracted with CCl₄ (5-6 x 25 mL). The crude products were purified by prep-HPLC.

[0728] HPLC was performed on a Agilent Infinity 1260, with a XBridge Peptide BEH C18300A 5 mm, 2.1х50 mm column at a flowrate of 1 mL/min. Preparative HPLC was performed on a Agilent Infinity 1260 using a XBridge Peptide BEH C18300A 5 mm, 19х150 mm at a flow rate of 40mL/min; solvent A – 0.01% aqueous TFA; solvent B– 90% CH3CN, 0.01% TFA.

EXAMPLE 23

[0729] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-(aminomethyl)-1,2,4-thiadiazole-5-carbonyl)pyrrolidine-2-carboxamido)-3-(4- hydroxyphenyl)propanamido)-4-carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (2xTFA) was prepared according to the general procedure in Schemes 18-21 (procedure B) and as follows. (18.9 mg, 10.6% yield); M.S. (m/z, ES-API): 1557.7 [M+3]⁺. [0730] Scheme 18

[0731] Step A. Ester 45 (1.00 g, 4.5 mmol, 1 eq) and TEA (0.91 g, 9 mmol, 2 eq) were dissolved in CH₂Cl₂ (25 mL). Boc₂O (1.09 g, 5 mmol 1.1 eq) was added to the reaction solution. The resulting mixture was stirred for 12 hours at room temperature, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and the organic solution was washed sequentially with 10% sodium bicarbonate solution (3x100 mL), saturated brine (3x100 mL). The final organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 1.0 g of sufficiently pure 46 (76 % yield).¹H NMR (400 MHz, CDCl₃) d 5.15 (d, J = 6.1 Hz, 1H), 4.74 (d, J = 6.1 Hz, 2H), 4.49 (q, J = 6.8 Hz, 2H), 1.57– 1.32 (m, 12H).

[0732] Step B. Sodium metal (0.019 g, 0.841 mmol, 1.05 eq) was slowly added to methanol (10 mL). Water was added to the resulting solution (0.3 mL). Then ethyl ester 46 (0.23 g, 0.801 mmol, 1 eq) was added and the resulting mixture was stirred for 12 hours. The reaction solution was concentrated under reduced pressure to give 47 (0.2 g, 95% yield) which was used directly without further purification.¹H NMR (500 MHz, D₂O) d 9 (s, 9H), 2 (d, J = 29.2 Hz, 2H). The title compound was then prepared according to the general procedures of Schemes 19-21 described below.

EXAMPLES 24A-24B

[0733] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (2xTFA) and 3- ((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-29-((S)-2- ((S)-1-((S)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (2xTFA) were prepared according to the general procedure in Schemes 19-21 (procedure A) described below. (5.4 mg, 3.1% yield); M.S. (m/z, ES-API): 1498.6 [M]⁺. (3.0 mg, 1.7% yield); M.S. (m/z, ES-API): 1499.6 [M+1]⁺.

EXAMPLE 25

[0734] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-3-(4-hydroxyphenyl)-2-((S)-1-(3- (methylamino)propanoyl)pyrrolidine-2-carboxamido)propanamido)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (1xTFA) was prepared according to the general procedure in Schemes 19-21 (procedure A) described below. (34.8 mg, 20.1% yield); M.S. (m/z, ES-API): 1498.6 [M]⁺.

EXAMPLE 26

[0735] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((2S)-2-((2S)-1-(3-amino- 2-methylpropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-13-(3-amino-3- oxopropyl)-4-carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to the general procedure in Schemes 19-21 (procedure A) described below. (8.2 mg, 4.7% yield); M.S. (m/z, ES-API): 1500.7 [M+1]⁺.

[0736] Scheme 19

[0737] To 9H-fluoren-9-ylmethyl carbamate Rink Amide Resin ChemPep Inc. (0.575 g, 0.5 mmol, 1 eq) was added 20% piperidine/DMF (10 mL). The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (10 mL) was added to it and the mixture was bubbled for 5 min, filtered, washed with DMF (10 mL). The procedure was repeated for 4 times. A solution of Na-Fmoc-S-trityl-L- cysteine 9 (1.17 g, 2.0 mmol, 4 eq), HATU (0.76 g, 2.00 mmol, 4 eq) and DIPEA (0.5 g, 4.00 mmol, 0.69 mL, 8 eq) in DMF (12 mL)was added to the resin. The mixture was bubbled for 30 min at 25 °C.

Coupling with of N-(9-Fluorenylmethoxycarbonyl)-S-trityl-L-cysteine 9 was repeated again. The coupling of Fmoc-L-glutamic acid 5-tert-butyl ester 10 (0.85 g, 2.00 mmol, 4 eq), Na-Fmoc-N(in)-Boc- L-tryptophan 18 (0.85 g, 2.00 mmol, 4 eq ), Na-Fmoc-Nd-trityl-L-glutamine 11 (1.2 g, 2.0 mmol, 4 eq), Fmoc-b-alanine 12 (0.625 g, 2.00 mmol, 4 eq), Na-Fmoc-Nw-(2,2,4,6,7-pentamethyldihydrobenzofuran- 5-sulfonyl)-L-arginine 13 (1.3 g, 2.0 mmol, 4 eq), Fmoc-O-tert-butyl-L-tyrosine 15 (0.9 g, 2.0 mmol, 4eq), Fmoc-L-valine 15 (0.7 g, 2.0 mmol, 4eq), Na-Fmoc-S-trityl-L-cysteine 9 (1.17 g, 2.00 mmol, 4 eq),O-tert-butyl-L-tyrosine 14 (0.9 g, 2.0 mmol, 4eq), Fmoc-L-proline 17 (0.7 g, 2.0 mmol, 4eq). The last amino acid was not de-protected. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C).

[0738] Scheme 20

[0739] To intermediate peptide A (0.22 g, 0.1 mmol, 1 eq) was added 20% piperidine/DMF (5 mL). The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (5 mL) was added and the resulting mixture was bubbled for 5 min, filtered, washed with DMF (5 mL). The procedure was repeated for 4 times giving intermediate peptide B.

[0740] General coupling procedure for EXAMPLES 24-26 (procedure A)

[0741] Corresponding acids (0.40 mmol, 4 eq) were dissolved in 5 mL of DMF. The amounts are given in Table 3 below.

[0742] Table 3

[0743] To the solutions, DIC (0.05 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) were added sequentially. Intermediate peptide B (0.1 mmol, 1 eq) was added to each solution. The mixtures were bubbled for 30 min at 25 °C, then filtered and DMF (15 mL) were added to each resin. The mixtures were bubbled for 5 min, filtered, washed with DMF (15 mL). The procedure was repeated for 4 times giving intermediate peptides C.

[0744] General coupling procedure for EXAMPLES 23 and 27 (procedure B)

[0745] A solution of salt amino acid 47 or 50 (0.40 mmol, 4 eq, 99.2 mg of 50 and 112 mg of 47), DIC (0.05 g, 0.40 mmol, 4 eq), oxima (CAS 3849-21-6) (0.06 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) in DMF (5 mL) was added to the intermediate peptide B (0.1 mmol, 1 eq, each). The mixture was bubbled for 30 min at 25 °C, then filtered and DMF (15 mL) was added. The mixture was bubbled for 5 min, filtered, washed with DMF (15 mL). The procedure was repeated 4 times giving intermediate peptides C.

[0746] Scheme 21: General Procedure for cleavage and cyclization for EXAMPLES 23-27

[0747] The intermediate peptides C were dispersed in mixture of TFA (7.5 mL), TIS (0.2 mL), EDT (0.2 ml) and H₂O (2.6 mL). The mixtures were shaken for 5 hours at 25 °C. The resulting mixtures were filtered and concentrated under reduced pressure to give crude linear peptides (intermediate peptides D) which were used directly without further purification. The intermediate peptides D (0.1 mmol, 1 eq) were dissolved in AcOH-H₂O (1:1, the final concentration was 1 mg/ml). Iodine (0.254 g, 1 mmol, 10 eq) was added in one portion to each solution. The reaction mixtures were stirred for 90 min at 25 °C (the progress of the cyclization was monitored by HPLC). Upon completion, the mixtures were diluted with water (50 ml) and the residual iodine was extracted with CCl₄ (5-6 x 25 mL). The crude products were purified by prep-HPLC.

[0748] HPLC was performed on a Agilent Infinity 1260, with a XBridge Peptide BEH C18300A 5 mm, 2.1х50 mm column at a flowrate of 1 mL/min. Preparative HPLC was performed on a Agilent Infinity 1260 using a XBridge Peptide BEH C18300A 5 mm, 19х150 mm at a flow rate of 40mL/min; solvent A – 0.01% aqueous TFA; solvent B– 90% CH₃CN, 0.01% TFA.

EXAMPLE 27

[0749] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(5-(aminomethyl)-1H-1,2,4-triazole-3-carbonyl)pyrrolidine-2-carboxamido)-3-(4- hydroxyphenyl)propanamido)-4-carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to the general procedure in Schemes 19-22 (procedure B) described above and as follows. (11.2 mg, 4.9% yield); M.S. (m/z, ES-API): 1539.6 [M+2]⁺.

[0750] Scheme 22

[0751] Step A.49 was synthesized analogously to 46 (step A).49 (2.8 g) was obtained from 3.00 g (14.5 mmol) of starting material (EN300-157183) in 71% yield.¹H NMR (400 MHz, CDCl₃) d 5.82 (s, 1H), 4.53 (d, J = 5.9 Hz, 2H), 4.46 (q, J = 7.1 Hz, 2H), 1.44– 1.33 (s, 12H).

[0752] Step B. Lithium hydroxide monohydrate (0.25 g, 6.00 mmol, 2 eq) was dissolved in H₂O (10 mL). The solution of ester 49 (1.00 g, 3.7 mmol, 1 eq) in THF (25 mL) was added. The resulting mixture was stirred for 14 hours and then concentrated under reduced pressure to give 0.97 g of 50 (100% yield). ¹H NMR (500 MHz, D₂O) d 4.18 (d, J = 5.2 Hz, 2H), 1.31 (s, 9H).

EXAMPLE 28

[0753] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- methylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-20-(4-aminobutyl)-4-carbamoyl-23- (4-hydroxybenzyl)-26-isopropyl-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) was prepared as described below. (31.1 mg, 19.7% yield); M.S. (m/z, ES-API): 1344.2 [M]⁺.

EXAMPLE 29

[0754] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- ethylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-20-(4-aminobutyl)-4-carbamoyl-23-(4- hydroxybenzyl)-26-isopropyl-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) was prepared as described below. (33.6 mg, 21.2% yield); M.S. (m/z, ES-API): 1359.2 [M+1]⁺.

EXAMPLE 30

[0755] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- isopropylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-20-(4-aminobutyl)-4-carbamoyl- 23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) was prepared as described below. (32.9 mg, 20.5% yield); M.S. (m/z, ES-API): 1372.2 [M]⁺.

EXAMPLE 31

[0756] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-20-(4-aminobutyl)-4- carbamoyl-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) was prepared as described below. (12.0 mg, 7.4% yield); M.S. (m/z, ES-API): 1399.2 [M+1]⁺.

[0757] EXAMPLES 28-32 were prepared according to the general procedure in Schemes 23-24 described below and as follows.

[0758] Scheme 23: Synthesis of intermediate peptide A for EXAMPLES 28-32

[0759] To 9H-fluoren-9-ylmethyl carbamate Rink Amide Resin ChemPep Inc. (0.575 g, 0.5mmol, 1 eq) was added 20% piperidine/DMF (10 mL). The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (10 mL) was added to it and the mixture was bubbled for 5 min, filtered, washed with DMF (10 mL). The procedure was repeated for 4 times. A solution of Na-Fmoc-S-trityl-L- cysteine 9 (1.17 g, 2.0 mmol, 4 eq), HATU (0.76 g, 2.00 mmol, 4 eq) and DIPEA (0.5 g, 4.00 mmol, 0.69 mL, 8 eq) in DMF (12 mL) was added to the resin. The mixture was bubbled for 30 min at 25 °C.

Coupling with of N-(9-Fluorenylmethoxycarbonyl)-S-trityl-L-cysteine 9 was repeated again. The coupling of Fmoc-L-glutamic acid 5-tert-butyl ester 10 (0.85 g, 2.00 mmol, 4 eq), Na-Fmoc-N(in)-Boc- L-tryptophan 18 (0.85 g, 2.00 mmol, 4 eq ), 56 (0.7 g, 2.0 mmol, 4 eq), Nb-Fmoc-Nv-Boc-L-b-lysine 57 (0.9 g, 2.00 mmol, 4 eq), Fmoc-O-tert-butyl-L-tyrosine 14 (0.9 g, 2.0 mmol, 4eq), Fmoc-L-valine 15 (0.7 g, 2.0 mmol, 4eq), Na-Fmoc-S-trityl-L-cysteine 9 (1.17 g, 2.00 mmol, 4 eq),O-tert-butyl-L-tyrosine 14 (0.9 g, 2.0 mmol, 4 eq). The last amino acid was not de-protected. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C).

[0760] Scheme 24: Synthesis of EXAMPLES 28-31 from intermediate peptide A

[0761] To intermediate peptide A (0.22 g, 0.1 mmol, 1 eq) was added 20% piperidine/DMF (5 mL). The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (5 mL) was added to it and the mixture was bubbled for 5 min, filtered, washed with DMF (5 mL). A solution of corresponding Fmoc-Glycine analogue, HATU (0.152 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) in DMF (10 mL) was added to the resin. The amounts of Fmoc-Glycine analogues are given in Table 4 below:

[0762] Table 4

[0763] The mixtures were bubbled for 30 min at 25 °C. The mixtures were filtered, then DMF (5 mL) was added. The mixtures were bubbled for 5 min, filtered, washed with DMF (5 mL). Coupling with Fmoc-Glycine analogs 51-54 was repeated again. After coupling, 20% piperidine/DMF (5 mL) was added. The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (5 mL) was added. The mixture was bubbled for 5 min, filtered, washed with DMF (5 mL). A solution of Fmoc- b-alanine (0.15 g, 0.40 mmol, 4 eq), DIC (0.05 g, 0.40 mmol, 4 eq), oxima (0.06 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) in DMF (5 mL) was added to the resin. The mixture was bubbled for 30 min at 25 °C. The mixture was filtered and DMF (15 mL) was added. The mixture was bubbled for 5 min, filtered, washed with DMF (15 mL). The procedure was repeated for 4 times. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C).

[0764] After coupling steps, the resins were dispersed in TFA (7.5 mL,), TIS (0.2 mL), EDT (0.2 ml) and H₂O (2.6 mL), then stirred for 5 hours at 25 °C. The resulting mixtures were filtered and

concentrated under reduced pressure to give crude linear peptides (intermediate peptides B) which were used directly without further purification.

[0765] The intermediate peptides B were dissolved in AcOH-H₂O (1:1, the final concentration was 1 mg/ml). Iodine (0.254 g, 1 mmol, 10 eq) was added in one portion to the each resulting solution. The reaction mixtures were stirred for 90 min at 25 °C (the progress of the cyclization was monitored by HPLC). Upon completion, the reaction mixtures were diluted with water (50 ml) and the residual iodine was extracted with CCl₄ (5-6 x 25 mL). The crude products were purified by prep-HPLC.

[0766] HPLC was performed on a Agilent Infinity 1260, with a XBridge Peptide BEH C18300A 5 mm, 2.1х50 mm column at a flowrate of 1 mL/min. Preparative HPLC was performed on a Agilent Infinity 1260 using a XBridge Peptide BEH C18300A 5 mm, 19х150 mm at a flow rate of 40mL/min; solvent A – 0.01% aqueous TFA; solvent B– 90% CH3CN, 0.01% TFA. EXAMPLE 32

[0767] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((2S)-2-(2-(3-amino-N- (pyrrolidin-3-yl)propanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-20-(4-aminobutyl)-4- carbamoyl-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (3xTFA) was prepared according to the general procedure in Scheme 23 described above and as follows. (2.7 mg, 0.15% yield); M.S. (m/z, ES- API): 1399.2 [M]⁺.

[0768] Scheme 25: Synthesis of EXAMPLE 32 from intermediate peptide A

[0769] To intermediate peptide A (0.22 g, 0.1 mmol, 1 eq) was added 20% piperidine/DMF (5 mL). The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, and then DMF (5 mL) was added. The mixture was bubbled for 5 min, filtered, washed with DMF (5 mL). A solution of Fmoc- Boc-amino acid 55 (0.186 g, 0.40 mmol, 4 eq), HATU (0.152 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) in DMF (10 mL) was added to the resin. The mixture was bubbled for 30 min at 25 °C. Coupling with Fmoc-Boc-amino acid 55 was repeated again. After coupling, the mixture was filtered, then DMF (15 mL) was added. The mixture was bubbled for 5 min, filtered, washed with DMF (15 mL). The procedure was repeated for 4 times. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C).

[0770] The resin was dispersed in TFA (7.5 mL,), TIS (0.2 mL), EDT (0.2 ml) and H₂O (2.6 mL), then stirred for 5 hours at 25 °C. The resulting mixture was filtered and concentrated under reduced pressure to give crude linear peptide which was used directly without further purification.

[0771] The crude linear peptide was dissolved in AcOH-H₂O (1:1, the final concentration was 1 mg/ml). Iodine (0.254 g, 1 mmol, 10 eq) was added in one portion to the resulting solution. The reaction mixture was stirred for 90 min at 25 °C (the progress of the cyclization was monitored by HPLC). Upon completion, the reaction mixture was diluted with water (50 ml) and the residual iodine was extracted with CCl₄ (5-6 x 25 mL). The crude products were purified by prep-HPLC.

[0772] HPLC was performed on a Agilent Infinity 1260, with a XBridge Peptide BEH C18300A 5 mm, 2.1х50 mm column at a flowrate of 1 mL/min. Preparative HPLC was performed on a Agilent Infinity 1260 using a XBridge Peptide BEH C18300A 5 mm, 19х150 mm at a flow rate of 40mL/min; solvent A – 0.01% aqueous TFA; solvent B– 90% CH3CN, 0.01% TFA.

EXAMPLES 33A-33B

[0773] 3-((4R,7S,10S,20S,23S,26R,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopropyl-23-(4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) and 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H- indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)- 3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclopropyl-23-(4-hydroxybenzyl)- 6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) were prepared according to the general procedures in Schemes 30-31 described below. A: (19.4 mg, 12.1% yield); M.S. (m/z, ES-API): 1369.2 [M+1]⁺. B: (15.9 mg, 10.0% yield); M.S. (m/z, ES-API): 1369.2 [M+1]⁺. EXAMPLES 34A-34B

[0774] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23- (4-hydroxybenzyl)-26-(2-methoxy-2-methylpropyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) and 3- ((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(4- hydroxybenzyl)-26-(2-methoxy-2-methylpropyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) were prepared according to the general procedure in Schemes 30-31 described below. A: (15.8 mg, 9.6% yield); M.S. (m/z, ES-API): 1416.2 [M+2]⁺. B: (17.1 mg, 10.4% yield); M.S. (m/z, ES-API): 1415.0 [M+1]⁺.

EXAMPLES 35A-35B

[0775] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclohexyl-23-(4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) and 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H- indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)- 3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclohexyl-23-(4-hydroxybenzyl)- 6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) were prepared according to the general procedure in Schemes 30-31 described below and as follows. A: (21.9 mg, 13.4% yield); M.S. (m/z, ES-API): 1412.0 [M+2]⁺. B: (18.5 mg, 11.3% yield); M.S. (m/z, ES-API): 1411.2 [M+1]⁺.

[0776] Scheme 27

[0777] Compound 64 was synthesized analogously to 8 (step F of Scheme 1 of EXAMPLE 1): (2.19 g) was obtained from 1 g of starting material (EN300-51752) (6.37 mmol) in 91% yield.¹H NMR (400 MHz, DMSO d6): d 7.89 (d, J = 7.6 Hz, 2H), 7.75 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.32 (m, 2H), 4.24 (m, 3H), 3.89 (m, 1H), 1.68 (m, 3H), 1.60 (m, 3H), 1.14 (m, 5H). EXAMPLES 36A-36B

[0778] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23- (4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-26-(tetrahydro-2H-pyran-4-yl)-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) and 3- ((4R,7S,10S,20S,23S,26R,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(4- hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-26-(tetrahydro-2H-pyran-4-yl)-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) were prepared according to the general procedure in Schemes 30-31 described below and as follows. A: (12.7 mg, 7.7% yield); M.S. (m/z, ES-API): 1415.0 [M+3]⁺. B: (6.7 mg, 4.1% yield); M.S. (m/z, ES-API): 1412.2 [M]⁺.

[0779] Scheme 28

[0780] Compound 66 was synthesized analogously to 8 (step F of Scheme 1 of EXAMPLE 1): (2.01 g) was obtained from 1 g of starting material (EN300-69837) (6.29 mmol) in 84% yield.¹H NMR (400 MHz, CDCl₃) d (COOH is not visible) 7.76 (d, J = 7.3 Hz, 2H), 7.59 (d, J = 7.1 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.32 (d, J = 7.0 Hz, 2H), 6.08 (s, 0.4H), 5.93 (brs, 0.6H),5.37 (d, J = 8.2 Hz, 1H), 4.56– 4.27 (m, 3H), 4.21 (t, J = 5.9 Hz, 1H), 4.02 (d, J = 9.3 Hz, 2H), 3.46– 3.29 (m, 2H), 2.10 (s, 1H), 1.61- 1.38 (m, 3H).

EXAMPLES 37A-37B

[0781] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclobutyl-23-(4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) and 3-((4R,7S,10S,20S,23S,26R,29R)-10-((1H- indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)- 3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclobutyl-23-(4-hydroxybenzyl)- 6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) were prepared according to the general procedure in Schemes 30-31 described below. A: (16.6 mg, 10.3% yield); M.S. (m/z, ES-API): 1384.2 [M+3]⁺. B: (17.8 mg, 11.1% yield); M.S. (m/z, ES-API): 1383.0 [M+1]⁺. EXAMPLES 38A-38B

[0782] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23- (4-hydroxybenzyl)-26-(1-methoxycyclobutyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) and 3- ((4R,7S,10S,20S,23S,26R,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(4- hydroxybenzyl)-26-(1-methoxycyclobutyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) were prepared according to the general procedure in Schemes 30-31 described below. A: (11.3 mg, 6.9% yield); M.S. (m/z, ES-API): 1412.2 [M]⁺. B: (10.6 mg, 6.5% yield); M.S. (m/z, ES-API): 1412.0 [M]⁺.

EXAMPLES 39A-39B

[0783] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23- (4-hydroxybenzyl)-26-(3-methoxypropyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) and 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H- indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)- 3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-26- (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,2-dithia-5,8,11,18,21,24,27-heptaazacyclotriacontan-7- yl)propanoic acid (2xTFA) were prepared according to the general procedure in Schemes 30-31 described below. A: (15.1 mg, 9.3% yield); M.S. (m/z, ES-API): 1400.2 [M]⁺. B: (17.7 mg, 10.9% yield); M.S. (m/z, ES-API): 1400.4 [M]⁺.

EXAMPLE 40

[0784] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- (ethoxymethyl)-23-(4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) was prepared according to the general procedure in Schemes 30-31 described below and as follows. (6.8 mg, 4.2% yield); M.S. (m/z, ES-API): 1386.2 [M]⁺.

[0785] Scheme 29

[0786] Compound 68 was synthesized analogously to 8 (step F of Scheme 1 of EXAMPLE 1): (1.72 g) was obtained from 1 g of starting material (67) (7.52 mmol) in 90% yield.¹H NMR (400 MHz, DMSO- d6) d 12.77 (s, 1H), 7.89 (d, J = 7.4 Hz, 2H), 7.75 (d, J = 7.3 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 7.3 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 4.28 (d, J = 6.2 Hz, 2H), 4.25– 4.14 (m, 2H), 3.69– 3.57 (m, 2H), 3.53– 3.38 (m, 2H), 1.09 (t, J = 6.9 Hz, 3H).

EXAMPLES 41A-41B

[0787] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23- (4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-26-(3,3,3-trifluoropropyl)-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) and 3-((4R,7S,10S,20S,23S,26R,29R)-10-((1H- indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)- 3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-26- (3,3,3-trifluoropropyl)-1,2-dithia-5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) were prepared according to the general procedure in Schemes 30-31 described below. A: (7.1 mg, 4.3% yield); M.S. (m/z, ES-API): 1425.2 [M+1]⁺. B: (12.5 mg, 7.6% yield); M.S. (m/z, ES-API): 1425.0 [M+1]⁺.

EXAMPLES 42A-42B

[0788] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23- (4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-26-(1-(trifluoromethyl)cyclopropyl)-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) and 3- ((4R,7S,10S,20S,23S,26R,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(4- hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-26-(1-(trifluoromethyl)cyclopropyl)-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) were prepared according to the general procedure in Schemes 30-31 described below. A: (13.7 mg, 8.2% yield); M.S. (m/z, ES-API): 1437.2 [M+1]⁺. B: (10.4 mg, 6.3% yield); M.S. (m/z, ES-API): 1437.2 [M+1]⁺. EXAMPLE 43

[0789] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23- (4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-26-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,2- dithia-5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid (2xTFA) was prepared according to the general procedure in Schemes 30-31 described below. (34.1 mg, 20.2% yield); M.S. (m/z, ES- API): 1464.0 [M+2]⁺.

EXAMPLE 44

[0790] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid (2xTFA) was prepared according to the general procedures in Schemes 30-31 described below and as follows. (15.0 mg, 9.2% yield); M.S. (m/z, ES-API): 1411.0 [M+1]⁺.

[0791] Scheme 30

[0792] Step A. To a solution of 7.78 g (0.046 mol, 1 eq) 6-aminohexanoic acid hydrochloride (58) in 500 mL acetone/water (1:1), 15.65 g (0.046 mol, 1 eq) N-(9-Fluorenylmethoxycarbonyloxy)succinimide (59) and 77.3 g (0.92 mol, 2 eq) NaHCO₃ were added. The suspension was stirred at room temperature for 3 hours. Acetone was removed at reduced pressure and 300 mL of CH₂Cl₂ was added to the residue. The precipitated solid was removed by filtration. The organic phase was washed with 1000 mL of 0.1 M HCl 3 times and 200 mL of water. The solution was dried over Na₂SO₄, the solvent removed at reduced pressure and the residue was dried in vacuo, yielding of 11.53 g (71 % yield) 60 as colorless solid.

[0793] Scheme 31: General peptide synthesis for EXAMPLES 33-44

[0794] To 9H-fluoren-9-ylmethyl carbamate Rink Amide Resin ChemPep Inc. (0.125 g, 0.1 mmol, 1 eq) was added 20% piperidine/DMF (5 mL). The mixture was bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (5 mL) was added to it and the mixture was bubbled for 5 min, filtered, washed with DMF (5 mL). The procedure was repeated for 4 times. A solution of Na-Fmoc-S-trityl-L- cysteine 9 (0.234 g, 0.40 mmol, 4 eq), HATU (0.152 g, 0.40 mmol, 4 eq) and DIPEA (0.1 g, 0.80 mmol, 0.139 mL, 8 eq) in DMF (10 mL) was added to the resin. The mixture was bubbled for 30 min at 25 °C. Coupling with of N-(9-Fluorenylmethoxycarbonyl)-S-trityl-L-cysteine 9 was repeated again. The coupling of Fmoc-L-glutamic acid 5-tert-butyl ester 10 (0.17 g, 0.40 mmol, 4 eq), Na-Fmoc-N(in)-Boc- L-tryptophan 18 (1.87 g, 4.40 mmol, 4 eq ), Fmoc-6-aminohexanoic acid 60 (0.14 g, 0.40 mmol, 4 eq), Na-Fmoc-Ne-Boc-L-lysine 61 (0.19 g, 0.40 mmol, 4 eq), Fmoc-O-tert-butyl-L-tyrosine 14 (0.18 g, 0.40 mmol, 4 eq), Fmoc protected Valine analogue (0.40 mmol, 4 eq), Na-Fmoc-S-trityl-L-cysteine 9 (0.234 g, 0.40 mmol, 4 eq), O-tert-butyl-L-tyrosine 14 (0.18 g, 0.40 mmol, 4eq),Fmoc-L-proline 17 (0.14 g, 0.40 mmol, 4eq), Boc-b-alanine 62 was performed as for the first amino acid (Na-Fmoc-S-trityl-L-cysteine - 9). The amounts of each Fmoc protected valine analogue are given in Table 5 below.

[0795] Table 5

[0796] The last amino acid was not de-protected. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C).

[0797] The resin was dispersed in the solution of TFA (7.5 mL,), TIS (0.2 mL), EDT (0.2 ml) and H₂O (2.6 mL). The mixture was shaken for 5 hours at 25 °C. The resulting mixture was filtered and concentrated under reduced pressure to give crude linear peptides which were used directly without further purification.

[0798] The crude linear peptides were dissolved in AcOH-H₂O (1:1, the final concentration was 1 mg/ml). Iodine (0.254 g, 1 mmol, 10 eq) was added in one portion to each solution. The reaction mixture was stirred for 90 min at 25 °C (the progress of the cyclization was monitored by HPLC). Upon completion, the reaction mixture was diluted with water (50 ml) and the residual iodine was extracted with CCl₄ (5-6 x 25 mL)_. The crude products were purified by prep-HPLC.

[0799] HPLC was performed on a Agilent Infinity 1260, with a XBridge Peptide BEH C18300A 5 mm, 2.1х50 mm column at a flowrate of 1 mL/min. Preparative HPLC was performed on a Agilent Infinity 1260 using a XBridge Peptide BEH C18300A 5 mm, 19х150 mm at a flow rate of 40mL/min; solvent A – 0.01% aqueous TFA; solvent B– 90% CH₃CN, 0.01% TFA.

[0800] Scheme 32: Synthesis of peptide intermediate for EXAMPLES 45-48

[0801] General procedure for the synthesis of intermediate peptide D:

[0802] To 9H-fluoren-9-ylmethyl carbamate (10.36 g, 5 mmol, 1 eq) was added 20% piperidine/DMF (75 mL), bubbled with N₂ for 5 min at 25 °C. The mixture was filtered, then DMF (80 mL) was added and the resulting mixture was bubbled for 5 min, filtered, washed with DMF (80 mL)– this procedure was repeated four (4) times. A solution of (2R)-3-(acetamidomethyl sulfanyl)-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid 78 (4.14 g, 10.00 mmol, 2 eq), HATU (3.80 g, 10.00 mmol, 2 eq) and DIEA (1.94 g, 15.00 mmol, 2.61 mL, 3 eq) was added to the compound with resin, bubbled for 30 min at 25 °C. The mixture was filtered and washed with DMF (80 mL x 3). The Fmoc group de- protected using 20% piperidine/DMF, then washed with DMF (80 mL x 5). The remaining amino acids ((2S)-3-tert-butoxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid 79 (3.83 g, 10.00 mmol,2 eq), (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(1H-indol-3-yl) propanoic acid 18 (4.26 g, 10.00 mmol, 2 eq), (2S)-3-tert-butoxy-2-(9H-fluoren-9-ylmethoxy carbonylamino)propanoic acid 80 (3.83 g, 10.00 mmol, 2 eq), 3-(9H-fluoren-9-ylmethoxy carbonylamino)propanoic acid 12 (3.11 g, 10.00 mmol, 2 eq), (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-[[N-[(2,2,4,6,7-pentamethyl-3H-benzofuran-5- yl)sulfonyl]carbamimidoyl]amino]pentanoic acid 81 (6.49 g, 10.00 mmol, 2 eq)) were added according to the procedure for the first amino acid. The last amino acid was not de-protected. Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C). The crude product 9H-fluoren-9-ylmethylN-[(1S)-1-[[3-[[(1S)-2-[[(1S)-2-[[(1S)-2-[[(1R)-1 - (acetamidomethylsulfanylmethyl)-2-amino-2-oxo-ethyl]amino]-1-(tert-butoxymethyl)-2-oxo- ethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]amino]-1-(tertbutoxymethyl)-2-oxo-ethyl]amino]-3- oxo-propyl]carbamoyl]-4-[[N-[(2,2,4,6,7-pentamethyl-3H-benzofuran-5- yl)sulfonyl]carbamimidoyl]amino]butyl]carbamate with resin (Intermediate Peptide D) (23 g, 4.99 mmol, 99.70% yield, 29.6% purity) was used in the next step without further purification.

[0803] Table 6

[0804] (4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-23-(2-cyanobenzyl)-20- (3-guanidinopropyl)-7,13-bis(hydroxymethyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-4-carboxamide.¹H NMR: MeOD-d₄ (400 MHz): d 8.55 (s, 2H), 7.52-7.50 (m, 1H), 7.39-7.37 (m, 2H), 7.32 (s, 2H), 7.21-6.98 (m, 6H), 6.78-6.68 (m, 2H), 5.50 (s, 2H), 5.21 (s, 1H), 4.67-4.62 (m, 4H), 4.50-4.43 (m, 1H), 4.32-4.18 (m, 2H), 3.90 (s, 2H), 3.80-3.69 (m, 2H), 3.64-3.48 (m, 3H), 3.25-2.97 (m, 13H), 2.78-2.75 (m, 1H), 2.67-2.64 (mz, 1H), 2.31 (s, 2H), 2.22-1.83 (m, 7H), 1.73-1.54 (m, 3H), 1.52-1.40 (m, 1H), 1.02-0.95 (m, 6H). LCMS: Rt=2.282, m/z 1411.6 [M+1]⁺.

[0805] Scheme 33

[0806] To 9H-fluoren-9-ylmethylN-[(1S)-1-[[3-[[(1S)-2-[[(1S)-2-[[(1S)-2-[[(1R)-1-(acetamido methylsulfanylmethyl)-2-amino-2-oxo-ethyl]amino]-1-(tert-butoxymethyl)-2-oxo-ethyl]amino]-1-(1H- indol-3-ylmethyl)-2-oxo-ethyl]amino]-1-(tert-butoxymethyl)-2-oxo-ethyl]amino]-3-oxo- propyl]carbamoyl]-4-[[N-[(2,2,4,6,7-pentamethyl-3H-benzofuran-5- yl)sulfonyl]carbamimidoyl]amino]butyl]carbamate with resin (2.30 g, 498.51 µmol, 1 eq) was added 20% piperidine/DMF (35 mL) and the ensuing mixture was agitated for 5 min. The mixture was filtered, and washed with DMF (50 mL x 5). A solution of ((2S)-3-(2-cyanophenyl)-2-(9H-fluoren- 9- ylmethoxycarbonylamino)propanoic acid 82 (411.21 mg, 997.02 µmol, 2 eq), HATU (379.10 mg, 997.02 µmol, 2 eq) and DIEA (193.29 mg, 1.50 mmol, 260.50 µL, 3 eq) in DMF (20 mL) was added to the compound with resin and agitated for 20 min. The mixture was filtered and washed with DMF (50 mL x 3). The Fmoc group deprotected using 20% piperidine/DMF (35 mL), then washed with DMF (50 mL x 5). The remaining amino acids 14, 15, 17, 19, and 78 were reacted with the substrate peptide according to the procedure for first amino acid 82. The last amino acid was not deprotected. I₂ (253.05 mg, 997.02 µmol, 200.83 µL, 2 eq) was added into the mixture after the last amino acid 8 condensed. Then the mixture was agitated for 2 hours with N₂. The mixture was filtered and washed with DMF (50 mL x 3). The resin was dispersed in TFA (30.80 g, 270.12 mmol, 20 mL, 541.86 eq) and H₂O (5.00 g, 277.54 mmol, 5 mL, 556.74 eq), then stirred for 10 hours at 25 °C. The mixture in TFA and water was filtered and concentrated under reduced pressure to afford crude product. Each condensation and deprotection step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C). The amounts of HATU and DIEA used for each condensation step were the same. The amounts of each amino acid are provided in Table 7 below. The crude product was purified by prep-HPLC (Instrument: Gilson GX-281; column: Phenomenex Synergi C18150*25*10um; mobile phase: [water (0.1%TFA)- ACN];B%: 5%-35%,10min, and then further purified by prep-HPLC (Instrument: Gilson GX-281, column: Phenomenex Synergi C18150*25*10um; mobile phase: [water (0.225%FA)-ACN]; B%: 1%- 30%, 10 min) to afford the title compound (43.62 mg, 5.82% yield, 2 formic acid (FA) salt) as a white solid.

[0807] Table 7

EXAMPLE 46

[0808] (4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-20-(3- guanidinopropyl)-7,13-bis(hydroxymethyl)-26-isopropyl-23-(4-(methylthio)benzyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-4-carboxamide was prepared according to Scheme 33 (EXAMPLE 45) except (2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-(3-thienyl)propanoic acid 83 was used in lieu of 82.¹H NMR: MeOD-d₄ (400MHz) d 7.40-7.30 (m, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.15-6.91 (m, 6H), 6.77-6.62 (m, 2H), 6.22-6.08 (m, 2H), 5.73-5.46 (m, 2H), 5.26-5.18 (m, 1H), 4.83-4.80 (m, 1H), 4.70-4.41 (m, 4H), 4.29-4.18 (m, 1H), 4.12-4.00 (m, 1H), 3.92-3.66 (m, 4H), 3.62-3.42 (m, 3H), 3.23-2.94 (m, 12H), 2.91-2.67 (m, 3H), 2.44 (s, 3H), 2.41-2.30 (m, 2H), 2.22-1.87 (m, 7H), 1.70-1.35 (m, 4H), 0.97 (t, J=7.6 Hz, 6H). LCMS: Rt=2.344, m/z 717.0 [1/2M+H]⁺.

[0809] To a solid of 9H-fluoren-9-ylmethyl N-[(1S)-1-[[3-[[(1S)-2-[[(1S)-2-[[(1S)-2-[[(1R)-1- (acetamidomethylsulfanylmethyl)-2-amino-2-oxo-ethyl]amino]-1-(tert-butoxymethyl)-2-oxo- ethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]amino]-1-(tert-butoxymethyl)-2-oxo-ethyl]amino]-3- oxo-propyl]carbamoyl]-4-[[N-[(2,2,4,6,7-pentamethyl-3H-benzofuran-5- yl)sulfonyl]carbamimidoyl]amino]butyl]carbamate with resin (4.6 g, 997.76 µmol, 1 eq) was added a solution of piperidine in DMF (25 mL, 20%, v/v) and the resulting mixture was bubbled with nitrogen for 5 min at 20 °C, then filtered and washed with DMF (20 mL x 5). A solution of (2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-(4-methylsulfanylphenyl) propanoic acid 83 (865.10 mg, 2.00 mmol, 2 eq), HATU (758.76 mg, 2.00 mmol, 2 eq), DIPEA (386.85 mg, 2.99 mmol, 521.37 µL, 3 eq) in 20 mL DMF was added to the compound with resin, bubbled with nitrogen for 30 min at 20 °C. The mixture was filtered and washed with DMF (20 mL x 3). The Fmoc group was deprotected using a solution of piperidine in DMF (25 mL, 20%, v/v), then washed with DMF (20 mL x 5). The other five amino acids (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl-butanoic acid 15 (677.25 mg, 2.00 mmol, 2 eq), (2R)-3-(acetamidomethylsulfanyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino) propanoic acid 78 (827.10 mg, 2.00 mmol, 2 eq), (2S)-3-(4-tert-butoxyphenyl)-2-(9H-fluoren -9- ylmethoxycarbonylamino)propanoic acid 14 (917.01 mg, 2.00 mmol, 2 eq), (2S)-1-(9H-fluoren-9- ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid 17 (673.23 mg, 2.00 mmol, 2 eq),3-(tert- butoxycarbonylamino)propanoic acid 19 (377.57 mg, 2.00 mmol, 2 eq) were added in sequence according to the same procedure used for the first amino acid above. The last Boc protected amino acid was not deprotected. Then I₂ (506.48 mg, 2.00 mmol, 401.97 µL, 2 eq) in DMF (150 mL) was added in the compound with resin and bubbled with nitrogen for 1.5h at 20 °C. The mixture was filtered and washed with DMF (20 mL x 5). Then TFA (47.5 mL), H₂O (1.25 mL), anisole (1.25 mL) was added into the compound with resin and bubbled with nitrogen for 5h at 20 °C. (Each step was monitored with kaiser reagent (the naked amine with kaiser became purple under 115 °C). The last step was monitored by LCMS (EW4106-733-P1C). The mixture was filtered and the filter cake was washed with DMF (50 mL x 2). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (Instrument: Gilson, GX-281, column: Phenomenex Synergi C18150 x 25 x 10um; mobile phase: [water (0.1%TFA)-ACN]; B%: 10%-40%, 10 min), then purified by Prep-HPLC

(Instrument: Gilson, GX-281, column: Luna C18150 x 25 x 5um; mobile phase: [water (0.225%FA)- ACN]; B%: 22%-43%, 10 min). The title compound (13.11 mg, 0.906% yield) was obtained as a white solid.

EXAMPLE 47

[0810] (4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-23-(4-chlorobenzyl)- 20-(3-guanidinopropyl)-7,13-bis(hydroxymethyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-4-carboxamide was prepared according to Scheme 33 (EXAMPLE 45) except (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(3-thienyl)propanoic acid 84 was used in lieu of 82.¹H NMR: (MeOD-d₄) 400MHz d 8.55 (br s, 2H), 7.38-7.35 (m, 2H), 7.25-7.23 (m, 1H), 7.12-6.98 (m, 6H), 6.76-6.70 (m, 2H), 6.21-6.14 (m, 2H), 5.67-5.51 (m, 2H), 5.27-5.19 (m, 1H), 4.67-4.61 (m, 4H), 4.48-4.46 (m, 1H), 4.24-4.21 (m, 1H), 4.09-4.06 (m, 1H), 3.94-3.84 (m, 2H), 3.80- 3.69 (m, 2H), 3.62-3.50 (m, 3H), 3.19-2.99 (m, 11H), 2.76-2.73 (m, 2H), 2.48-2.30 (m, 3H), 2.16-1.93 (m, 7H), 1.66-1.30 (m, 5H), 1.01-0.96 (m, 6H). LCMS: Rt=2.284, m/z 1421.3 [M+H]⁺.

[0811] To 9H-fluoren-9-ylmethyl N-[(1S)-1-[[3-[[(1S)-2-[[(1S)-2-[[(1S)-2-[[(1R)-1 - (acetamidomethylsulfanylmethyl)-2-amino-2-oxoethyl]amino]-1-(tert-butoxymethyl)-2-oxo- ethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]amino]-1-(tert-butoxymethyl)-2-oxo-ethyl]amino]-3- oxo-propyl]carbamoyl]-4-[[N-[(2,2,4,6,7-pentamethyl-3H-benzofuran-5- yl)sulfonyl]carbamimidoyl]amino]butyl]carbamate with resin (2.3 g, 498.88 µmol, 1 eq) was added 20% piperidine/DMF and the ensuing mixture was bubbled with N₂ for 5 min then washed with DMF (20 mL x 5). A solution of (2S)-3-(4-chlorophenyl)-2-(9Hfluoren-9-ylmethoxycarbonylamino) propanoic acid 84 (420.93 mg, 997.76 µmol, 2 eq), HATU (379.38 mg, 997.76 µmol, 2 eq) and DIEA (193.43 mg, 1.50 mmol, 260.69 µL, 3 eq) in DMF (20 mL) was added to the compound with resin and the mixture was bubbled for 30 min. The mixture was then filtered and washed with DMF (20 mL x 3). The Fmoc group was de-protected using 20% piperidine/DMF then washed with DMF (20 mL x 5). The remaining amino acids ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3 -methylbutanoic acid 15 (338.63 mg, 997.76 mmol, 2 eq), (2R)-3-(acetamidomethylsulfanyl)-2 -(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid 78 (413.55 mg, 997.76 mmol, 2 eq), (2S)-3-(4-tert-butoxyphenyl)-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid 14 (458.51 mg, 997.76 µmol, 2 eq), (2S)-1-(9H-fluoren-9- ylmethoxycarbonyl)pyrrolidine-2 -carboxylic acid 17 (336.61 mg, 997.76 mmol, 2 eq) were added in sequence according to the procedure for the first amino acid. The last amino acid (3-(tert- butoxycarbonylamino)propanoic acid 19 (188.79 mmol, 997.76 mmol, 2 eq) was repeated according to the procedure for the first amino acid and the group Boc was not de-protected. A solution of I₂ (253.24 mg, 997.76 µmol, 200.98 µL, 2 eq) in DMF (20 mL) was added to the amino acid with resin, then bubbled with N₂ for 1 h. The mixture was filtered and washed with DMF (20 mL x 3). The mixture with resin was added to H₂O (2 mL) and TFA (20 mL), then stirred at 25 °C for 3 h. Each step was monitored with kaiser reagent (the naked amine with kaiser reagent became purple under 115 °C). The resin was filtered through a sintered funnel, washed with DCM/MeOH (10/1, 40 mL x 3) and mother liquor was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC

(Instrument: Gilson, GX-281; Column: Boston pH-lex 150*2510 um; mobile phase: [water

(0.1%TFA)-ACN]; B%: 5%-41%, 12min), then the compound was purified further by prep-HPLC (Instrument: Gilson, GX-281; Column: Phenomenex Synergi C18150*25*10 um;mobile phase: [water (0.225%FA)-ACN];B%: 1%-30%,10min) to give the title compound (26.2 mg, 3.4% yield, 2FA) as a white solid. EXAMPLE 48

[0812] (4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-20-(3- guanidinopropyl)-7,13-bis(hydroxymethyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-23-(thiophen-3- ylmethyl)-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-4-carboxamide was prepared according to Scheme 33 (EXAMPLE 45) except (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(3- thienyl)propanoic acid 85 was used in lieu of 82.¹H NMR: MeOD-d₄ (400MHz) d 8.50 (br s, 1H), 7.36- 7.31 (m, 2H), 7.24 (d, J=8.0 Hz, 1H), 7.21-6.93 (m, 6H), 6.75-6.67 (m, 2H), 6.48 (br s, 1H), 5.65 (br s, 1H), 5.54 (d, J=10.8 Hz, 1H), 5.22-5.08 (m, 1H), 4.70-4.61 (m, 4H), 4.45 (dd, J=3.6, 8.4 Hz, 1H), 4.24 (dd, J=3.6, 10.8 Hz, 1H), 4.01 (dd, J=4.8, 11.6 Hz, 1H), 3.92-3.76 (m, 3H), 3.74-3.67 (m, 1H), 3.62-3.48 (m, 3H), 3.20-3.05 (m, 9H), 3.02-2.88 (m, 4H), 2.80-2.70 (m, 1H), 2.58 (t, J=12.4 Hz, 1H), 2.46-2.23 (m, 2H), 2.17-1.89 (m, 7H), 1.71-1.54 (m, 2H), 1.45 (td, J=7.2, 14.0 Hz, 1H), 1.31 (br s, 1H), 0.97 (t, J=7.6 Hz, 6H). LCMS: Rt=2.239, m/z 696.7 [M/2+H]⁺.

[0813] To a mixture of 9H-fluoren-9-ylmethylN-[(1S)-1-[[3-[[(1S)-2-[[(1S)-2-[[(1S)-2-[[(1R)-1- (acetamidomethylsulfanylmethyl)-2-amino-2-oxo-ethyl]amino]-1-(tert-butoxymethyl)-2-oxo- ethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]amino]-1-(tertbutoxymethyl)-2-oxo-ethyl]amino]-3- oxo-propyl]carbamoyl]-4-[[N-[(2,2,4,6,7-pentamethyl-3H-benzofuran-5- yl)sulfonyl]carbamimidoyl]amino]butyl]carbamate with resin (2.3 g, 498.88 µmol, 1 eq) with resin was added a solution of piperidine in DMF (10 mL, 20%, v/v) and the resulting mixture was bubbled with N₂ for 5 min. Then, the mixture was filtered and washed with DMF (40 mL for each time) (bubbled and filtered) 5 times. To a mixture of the resin in DMF (20 mL) was added (2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-(3-thienyl)propanoic acid 85 (392.58 mg, 997.76 µmol, 2 eq), HATU (398.35 mg, 1.05 mmol, 2.1 eq) and DIPEA (193.43 mg, 1.50 mmol, 260.69 µL, 3 eq), the mixture was bubbled with N₂ for 30 min. Then, the mixture was filtered and washed with DMF (40 mL for each time) (bubbled and filtered) for 5 times. The remaining amino acids [(2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-methyl-butanoic acid 15 (338.63 mg, 997.76 µmol, 2 eq), (2R)-3- (acetamidomethylsulfanyl)-2-(9Hfluoren-9- ylmethoxycarbonylamino)propanoic acid 78 (413.55 mg, 997.76 µmol, 2 eq), (2S)-3-(4-tert-butoxyphenyl)-2-(9Hfluoren-9-ylmethoxycarbonylamino)propanoic acid 14 (458.51 mg, 997.76 µmol, 2 eq), (2S)-1-(9H-fluoren-9- ylmethoxycarbonyl)pyrrolidine-2- carboxylic acid 17 (336.61 mg, 997.76 µmol, 2 eq), 3-(tert-butoxycarbonylamino)propanoic acid 19 (188.79 mg, 997.76 µmol, 2 eq)] were linked in sequence with the same procedure as amino acid 85. The last amino acid 19 was not de-protected after linking. Then to the residue which was linked with resin was added a solution of I₂ (379.86 mg, 1.50 mmol, 301.48 µL, 3 eq) in DMF (20 mL). The mixture was bubbled with N₂ for 60 min, filtered and washed with DMF (40 mL for each time) (bubbled and filtered) for 5 times. The residue (resin) was transferred to a flask which was filled with TFA (20 mL) and H₂O (0.5 mL). The mixture was stirred at 25 °C for 4 h. Each step of condensation reaction and de-protection was monitored with Kaiser reagent(the naked amine became purple at 115 °C). The mixture was concentrated under reduced pressure to remove TFA and H₂O. Then the residue was diluted with DMF (20 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Instrument: Gilson GX-281; column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225%FA)-ACN]; B%: 15%-45%, 10 min) to give the title compound (42.15 mg, 5.63% yield, FA) as a white solid.

EXAMPLE 49

[0814] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid. LCMS: Rt=2.238, m/z 755.3 [M/2+H]⁺.¹H NMR: DMSO-d₆ (400 MHz) d 10.79 (br s, 1H), 9.12-9.04 (m, 1H), 8.99-8.92 (m, 2H), 8.84-8.77 (m, 1H), 8.75-8.70 (m, 1H), 8.42-8.30 (m, 5H), 8.05-7.84 (m, 1H), 7.76-7.65 (m, 1H), 7.57-7.50 (m, 4H), 7.45-7.37 (m, 3H), 7.34-7.25 (m, 3H), 7.16-6.92 (m, 7H), 6.84 (t, J=7.2 Hz, 2H), 6.76-6.71 (m, 3H), 6.65 (dd, J=8.4, 11.2 Hz, 3H), 5.92-5.68 (m, 3H), 5.55-5.35 (m, 2H), 5.20-5.10 (m, 1H), 4.94 (br s, 1H), 4.71-4.61 (m, 2H), 4.54-4.48 (m, 1H), 4.35-4.25 (m, 1H), 3.50-3.46 (m, 2H), 3.39- 3.33 (m, 2H), 3.29-3.24 (m, 2H), 3.01-2.90 (m, 10H), 2.64-2.60 (m, 1H), 2.19 (s, 3H), 2.15-2.02 (m, 8H), 1.92-1.76 (m, 10H), 1.60-1.50 (m, 6H), 1.46-1.38 (m, 3H), 1.31-1.23 (m, 1H), 1.00-0.80 (m, 1H).

[0815] Scheme 34: Preparation of Intermediate E for the synthesis of EXAMPLE 49

[0816] General procedure for the synthesis of Intermediate E:

[0817] Step 1. De-protection of Fmoc group: To a mixture of 9H-fluoren-9-ylmethyl carbamate (6.01 g, 3 mmol, 1 eq) with resin (MBHA, CAS: 431041-83-7, 0.5 mmol/g) was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0818] Step 2. Condensation reaction: To a mixture of the resin in DMF (50 mL) was added (2R)-3- (acetamidomethylsulfanyl)-2-(9Hfluoren-9-ylmethoxycarbonylamino)propanoic acid (2.49 g, 6.00 mmol, 2 eq), HATU (2.40 g, 6.30 mmol, 2.1 eq) and DIPEA (1.16 g, 9.00 mmol, 1.57 mL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0819] Step 3. De-protection of Fmoc group: To a mixture of the resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0820] Step 4. Condensation reaction: To a mixture of the resin in DMF (50 mL) was added (2S)-5-tert- butoxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxo-pentanoic acid (2.55 g, 6.00 mmol, 2 eq), HATU (2.40 g, 6.30 mmol, 2.1 eq) and DIPEA (1.16 g, 9.00 mmol, 1.57 mL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0821] Step 5. De-protection of Fmoc group: To a mixture of the resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0822] Step 6. Condensation reaction: To a mixture of the resin in DMF (50 mL) was added (2S)-2-(9H- fluoren-9-ylmethoxycarbonylamino)-3-(1H-indol-3-yl)propanoic acid (2.56 g, 6.00 mmol, 2 eq), HATU (2.40 g, 6.30 mmol, 2.1 eq) and DIPEA (1.16 g, 9.00 mmol, 1.57 mL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0823] Step 7. De-protection of Fmoc: To a mixture of the resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0824] Step 8. Condensation reaction: To a mixture of the resin in DMF (50 mL) was added (2S)-2-(9H- fluoren-9-ylmethoxycarbonylamino)-5-oxo-5-(tritylamino)pentanoic acid (3.66 g, 6.00 mmol, 2 eq), HATU (2.40 g, 6.30 mmol, 2.1 eq) and DIPEA (1.16 g, 9.00 mmol, 1.57 mL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0825] Step 9. De-protection of Fmoc: To a mixture of the resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0826] Step 10. Condensation reaction: To a mixture of the resin in DMF (50 mL) was added 3-(9H- fluoren-9-ylmethoxycarbonylamino)propanoic acid (1.87 g, 6.00 mmol, 2 eq), HATU (2.40 g, 6.30 mmol, 2.1 eq) and DIPEA (1.16 g, 9.00 mmol, 1.57 mL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0827] Step 11. De-protection of Fmoc: To a mixture of the resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0828] Step 12. Condensation reaction: To a mixture of the resin in DMF (50 mL) was added (2S)-2- (9H-fluoren-9-ylmethoxycarbonylamino)-5-[[N-[(2,2,4,6,7-pentamethyl-3H-benzofuran-5- yl)sulfonyl]carbamimidoyl]amino]pentanoic acid (3.89 g, 6.00 mmol, 2 eq), HATU (2.40 g, 6.30 mmol, 2.1 eq) and DIPEA (1.16 g, 9.00 mmol, 1.57 mL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times to give tert-butyl (4S)-5-[[(1R)-1-(acetamidomethylsulfanylmethyl)-2-amino-2-oxo- ethyl]amino]-4-[[(2S)-2-[[(2S)-2-[3-[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-[[N-[(2,2,4,6,7- pentamethyl-3H-benzofuran-5-yl)sulfonyl]carbamimidoyl]amino]pentanoyl]amino]propanoylamino]-5- oxo-5-(tritylamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-oxo-pentanoate

Intermediate E (12.0 g, 100% yield) (linked with resin) as a yellow solid. [0829] Scheme 35: Preparation of Intermediate F for the synthesis of EXAMPLE 49

[0830] General procedure for the synthesis of Intermediate F:

[0831] Step 1. De-protection of Fmoc group: To a mixture of tert-butyl (4S)-5-[[(1R)-1- (acetamidomethylsulfanylmethyl)-2-amino-2-oxoethyl]amino]-4-[[(2S)-2-[[(2S)-2-[3-[[(2S)-2-(9H- fluoren-9-ylmethoxycarbonylamino)-5-[[N-[(2,2,4,6,7-pentamethyl-3Hbenzofuran-5- yl)sulfonyl]carbamimidoyl]amino]pentanoyl]amino]propanoylamino]-5-oxo-5- (tritylamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-oxo-pentanoate (3 g, 750.03 µmol, 1 eq) with resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0832] Step 2. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added (2S)-2-(9H- fluoren-9-ylmethoxycarbonylamino)-3-(p-tolyl)propanoic acid (602.20 mg, 1.50 mmol, 2 eq), HATU (598.88 mg, 1.58 mmol, 2.1 eq) and DIPEA (290.80 mg, 2.25 mmol, 391.91 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0833] Step 3. De-protection of Fmoc group: To a mixture of the resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0834] Step 4. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added (2S)-2- cyclopentyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)acetic acid (548.15 mg, 1.50 mmol, 2 eq), HATU (598.88 mg, 1.58 mmol, 2.1 eq) and DIPEA (290.80 mg, 2.25 mmol, 391.91 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0835] Step 5. De-protection of Fmoc group: To a mixture of the resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0836] Step 6. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added (2R)-3- (acetamidomethylsulfanyl)-2-(9Hfluoren-9-ylmethoxycarbonylamino)propanoic acid (621.73 mg, 1.50 mmol, 2 eq), HATU (598.88 mg, 1.58 mmol, 2.1 eq) and DIPEA (290.80 mg, 2.25 mmol, 391.91 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0837] Step 7. De-protection of Fmoc group: To a mixture of the resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0838] Step 8. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added (2S)-3-(4- tert-butoxyphenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (689.32 mg, 1.50 mmol, 2 eq), HATU (598.88 mg, 1.58 mmol, 2.1 eq) and DIPEA (290.80 mg, 2.25 mmol, 391.91 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0839] Step 9. De-protection of Fmoc group: To a mixture of the resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0840] Step 10. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added (2S)-1- (9H-fluoren-9- ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid (506.07 mg, 1.50 µmol, 2 eq), HATU (598.88 mg, 1.58 mmol, 2.1 eq) and DIPEA (290.80 mg, 2.25 mmol, 391.91 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times to give 9H-fluoren-9-ylmethyl (2S)-2-[[(1S)-2-[[(1R)-1- (acetamidomethylsulfanylmethyl) -2-[[(1S)-2-[[(1S)-2-[[(1S)-1-[[3-[[(1S)-1-[[(1S)-2-[[(1S)-1-[[(1R)-1- (acetamidomethylsulfanylmethyl)-2-amino-2-oxo-ethyl]carbamoyl]-4-tert-butoxy-4-oxobutyl]amino]-1- (1H-indol-3-ylmethyl)-2-oxo-ethyl]carbamoyl]-4-oxo-4-(tritylamino)butyl]amino]-3-oxo- propyl]carbamoyl]-4-[[N-[(2,2,4,6,7-pentamethyl-3H-benzofuran-5- yl)sulfonyl]carbamimidoyl]amino]butyl]amino]-2-oxo-1-(ptolylmethyl)ethyl]amino]-1-cyclopentyl-2- oxo-ethyl]amino]-2-oxo-ethyl]amino]-1-[(4-tert-butoxyphenyl)methyl]-2- oxoethyl]carbamoyl]pyrrolidine-1-carboxylate Intermediate F (4 g, 100% yield) (linked with resin) as a yellow solid.

[0841] Scheme 36: Preparation of Intermediate F for the synthesis of EXAMPLE 49

[0842] Procedure for the synthesis of EXAMPLE 49:

Step 1. De-protection of Fmoc group: To a mixture of 9H-fluoren-9-ylmethyl (2S)-2-[[(1S)-2-[[(1R)-1- (acetamidomethylsulfanylmethyl)-2-[[(1S)-2-[[(1S)-2-[[(1S)-1-[[3-[[(1S)-1-[[(1S)-2-[[(1S)-1-[[(1R)-1- (acetamidomethylsulfanylmethyl)-2-amino-2-oxo-ethyl]carbamoyl]-4-tert-butoxy-4-oxo-butyl]amino]-1- (1H-indol-3-ylmethyl)-2-oxo-ethyl]carbamoyl]-4-oxo-4-(tritylamino)butyl]amino]-3-oxo- propyl]carbamoyl]-4-[[N-[(2,2,4,6,7-pentamethyl-3Hbenzofuran-5- yl)sulfonyl]carbamimidoyl]amino]butyl]amino]-2-oxo-1-(p-tolylmethyl)ethyl]amino]-1-cyclopentyl-2- oxoethyl]amino]-2-oxo-ethyl]amino]-1-[(4-tert-butoxyphenyl)methyl]-2-oxo- ethyl]carbamoyl]pyrrolidine-1-carboxylate (2 g, 374.97 µmol, 1 eq) (linked with resin) was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0843] Step 2. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added 3-(tert- butoxycarbonylamino)propanoic acid (141.89 mg, 749.94 µmol, 2 eq), HATU (299.41 mg, 787.43 µmol, 2.1 eq) and DIPEA (145.39 mg, 1.12 mmol, 195.94 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0844] Step 3. Cyclization reaction: To a mixture of the resin in DMF (30 mL) was added I₂ (285.51 mg, 1.12 mmol, 226.60 µL, 3 eq), the mixture was bubbled with N₂ for 120 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0845] Step 4. Desorption from the resin: To the resin was added TFA (20 mL), H₂O (0.5 mL) and anisole (0.5 mL), the mixture was stirred at 25 °C for 240 min. The mixture was filtered and washed with TFA (5 mL). Then the filtrate was concentrated under reduced pressure to remove TFA. Then the residue was poured into cold MTBE (20 mL) and filtered to give the filter cake. LC-MS (EW4597-750-P1A1) showed ~13% of desired m/z was detected. The residue was purified by prep-HPLC (Instrument: Gilson GX-281; column: Phenomenex Synergi C18150*25*10um; mobile phase: [water (0.225%FA)-ACN]; B%: 4%-40%,10min) to give the title compound (59.2 mg, 9.63% yield, 2FA) as a white solid.

EXAMPLE 50

[0846] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((2S)-2-((2S)-1-(3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-26-isopropyl-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid. LCMS: Rt=2.240, m/z 749.3 [M/2+H]⁺.¹H NMR: DMSO-d₆ (400 MHz) d 10.84 (br s, 1H), 9.15-9.05 (m, 1H), 8.97-8.85 (m, 2H), 8.84-8.70 (m, 2H), 8.56-8.24 (m, 1H), 8.09-7.93 (m, 4H), 7.46-7.31 (m, 7H), 7.28-7.13 (m, 6H), 7.10-6.93 (m, 6H), 6.88-6.82 (m, 2H), 6.77-6.70 (m, 3H), 6.69-6.60 (m, 3H), 5.90-5.75 (m, 2H), 5.55- 5.40 (m, 1H), 5.30-5.15 (m, 1H), 4.95-5.85 (m, 1H), 4.78-4.32 (m, 5H), 3.92-3.86 (m, 3H), 3.54-3.35 (m, 3H), 3.32-3.25 (m, 1H), 3.11-3.04 (m, 1H), 3.00-2.82 (m, 10H), 2.23-2.10 (m, 11H), 1.95-1.85 (m, 4H), 1.83-1.73 (m, 5H), 1.59-1.50 (m, 1H), 1.46-1.36 (m, 1H), 1.23 (br dd, J=3.6, 6.0 Hz, 3H), 1.16-1.10 (m, 1H), 0.90-0.80 (m, 6H).

[0847] Scheme 37: Preparation of Intermediate G for the synthesis of EXAMPLE 50

[0848] General procedure for the synthesis of Intermediate G:

[0849] Step 1. De-protection of Fmoc group: To a mixture of tert-butyl (4S)-5-[[(1R)-1- (acetamidomethylsulfanylmethyl)-2-amino-2-oxoethyl]amino]-4-[[(2S)-2-[[(2S)-2-[3-[[(2S)-2-(9H- fluoren-9-ylmethoxycarbonylamino)-5-[[N-[(2,2,4,6,7-pentamethyl-3Hbenzofuran-5- yl)sulfonyl]carbamimidoyl]amino]pentanoyl]amino]propanoylamino]-5-oxo-5- (tritylamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-oxo-pentanoate (3 g, 750.03 µmol, 1 eq) with resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0850] Step 2. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added (2S)-2-(9H- fluoren-9-ylmethoxycarbonylamino)-3-(p-tolyl)propanoic acid (602.20 mg, 1.50 mmol, 2 eq), HATU (598.88 mg, 1.58 mmol, 2.1 eq) and DIPEA (290.80 mg, 2.25 mmol, 391.91 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0851] Step 3. De-protection of Fmoc group: To a mixture of the resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0852] Step 4. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added (2S)-2-(9H- fluoren-9- ylmethoxycarbonylamino)-3-methyl-butanoic acid (509.10 mg, 1.50 mmol, 2 eq), HATU (598.88 mg, 1.58 mmol, 2.1 eq) and DIPEA (290.80 mg, 2.25 mmol, 391.91 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0853] Step 5. De-protection of Fmoc group: To a mixture of the resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0854] Step 6. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added (2R)-3- (acetamidomethylsulfanyl)-2-(9Hfluoren-9-ylmethoxycarbonylamino)propanoic acid (621.73 mg, 1.50 mmol, 2 eq), HATU (598.88 mg, 1.58 mmol, 2.1 eq) and DIPEA (290.80 mg, 2.25 mmol, 391.91 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0855] Step 7. De-protection of Fmoc group: To a mixture of the resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0856] Step 8. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added (2S)-3-(4- tert-butoxyphenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (689.32 mg, 1.50 mmol, 2 eq), HATU (598.88 mg, 1.58 mmol, 2.1 eq) and DIPEA (290.80 mg, 2.25 mmol, 391.91 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0857] Step 9. De-protection of Fmoc group: To a mixture of the resin was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0858] Step 10. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added (2S)-1- (9H-fluoren-9- ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid (506.07 mg, 1.50 µmol, 2 eq), HATU (598.88 mg, 1.58 mmol, 2.1 eq) and DIPEA (290.80 mg, 2.25 mmol, 391.91 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times to give 9H-fluoren-9-ylmethyl(2S)-2-[[(1S)-2-[[(1R)-1- (acetamidomethylsulfanylmethyl)-2- [[(1S)-1-[[(1S)-2-[[(1S)-1-[[3-[[(1S)-1-[[(1S)-2-[[(1S)-1-[[(1R)-1- (acetamidomethylsulfanylmethyl)-2-amino-2-oxo-ethyl]carbamoyl]-4-tert-butoxy-4-oxobutyl]amino]-1- (1H-indol-3-ylmethyl)-2-oxo-ethyl]carbamoyl]-4-oxo-4-(tritylamino)butyl]amino]-3-oxo- propyl]carbamoyl]-4-[[N-[(2,2,4,6,7-pentamethyl-3H-benzofuran-5- yl)sulfonyl]carbamimidoyl]amino]butyl]amino]-2-oxo-1-(ptolylmethyl)ethyl]carbamoyl]-2-methyl- propyl]amino]-2-oxo-ethyl]amino]-1-[(4-tert-butoxyphenyl)methyl]-2-oxoethyl]carbamoyl]pyrrolidine- 1-carboxylate Intermediate G (3.2 g, 749.74 µmol, 99.96% yield, 55.9% purity) (linked with resin) as a yellow solid.

[0859] Procedure for the synthesis of EXAMPLE 50:

[0860] Step 1. De-protection of Fmoc group: To a mixture of 9H-fluoren-9-ylmethyl (2S)-2-[[(1S)-2- [[(1R)-1-(acetamidomethylsulfanylmethyl)-2-[[(1S)-1-[[(1S)-2-[[(1S)-1-[[3-[[(1S)-1-[[(1S)-2-[[(1S)-1- [[(1R)-1-(acetamidomethylsulfanylmethyl)-2-amino-2-oxo-ethyl]carbamoyl]-4-tert-butoxy-4-oxo- butyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]carbamoyl]-4-oxo-4-(tritylamino)butyl]amino]-3- oxo-propyl]carbamoyl]-4-[[N-[(2,2,4,6,7-pentamethyl-3Hbenzofuran-5- yl)sulfonyl]carbamimidoyl]amino]butyl]amino]-2-oxo-1-(p-tolylmethyl)ethyl]carbamoyl]-2- methylpropyl]amino]-2-oxo-ethyl]amino]-1-[(4-tert-butoxyphenyl)methyl]-2-oxo- ethyl]carbamoyl]pyrrolidine-1-carboxylate (1.6 g, 374.87 µmol, 1 eq) (linked with resin) was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0861] Step 2. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added 3-(tert- butoxycarbonylamino)butanoic acid (152.37 mg, 749.74 µmol, 2 eq), HATU (299.33 mg, 787.23 µmol, 2.1 eq) and DIPEA (145.34 mg, 1.12 mmol, 195.88 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0862] Step 3. Cyclization reaction: To a mixture of the resin in DMF (30 mL) was added I₂ (285.44 mg, 1.12 mmol, 226.54 µL, 3 eq), the mixture was bubbled with N₂ for 120 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0863] Step 4. Desorption from the resin: To the resin was added TFA (20 mL), H₂O (0.5 mL) and anisole (0.5 mL), the mixture was stirred at 25 °C for 240 min. The mixture was filtered and washed with TFA (5 mL). Then the filtrate was concentrated under reduced pressure to remove TFA. Then the residue was poured into cold MTBE (20 mL) and filtered to give the filter cake. LC-MS showed ~16% of desired m/z was detected. The residue was purified by prep-HPLC twice (Instrument: Gilson GX-281; column: Phenomenex Synergi C18150*25*10um; mobile phase: first by [water(0.225%FA)-ACN]; B%: 2%- 38%,10min, then by [water(0.05%HCl)-ACN]; B%: 10%-25%,10min) to give the title compound (2HCl) (17.47 mg, 2.96% yield) as a brown solid.

EXAMPLE 51

[0864] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-methylbenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid. LCMS: Rt=2.457, m/z 712.4 [M/2+H]⁺. ¹H NMR: MeOD-d₄ (400 MHz) d 8.44 (s, 3H), 7.39-7.37 (m, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.18-6.98 (m, 6H), 6.77-6.71 (m, 4H), 6.02-5.85 (m, 2H), 5.80-5.70 (m, 1H), 5.62-5.40 (m, 1H), 5.10- 5.15 (m, 1H), 4.80-4.75 (m, 4H), 4.72-4.65 (m, 1H), 4.52-4.44 (m, 1H), 4.26-4.22 (m, 1H), 4.00-3.96 (m, 1H), 3.65-3.43 (m, 2H), 3.20-3.13 (m, 5H), 3.12-3.07 (m, 4H), 3.05-2.97 (m, 5H), 2.78-2.67 (m, 2H), 2.61-2.53 (m, 1H), 2.40-2.25 (m, 6H), 2.21 (s, 3H), 2.06-1.92 (m, 1H), 1.80-1.68 (m, 1H), 1.65-1.55 (m, 7H), 1.50-1.40 (m, 1H), 1.20- 1.05 (m, 5H).

[0865] Scheme 38: Preparation of Intermediate H for the synthesis of EXAMPLE 51

[0866] General procedure for the synthesis of Intermediate H:

[0867] Step 1. Deprotection of Fmoc: To rink amide MBHA resin (6.06 g, 3 mmol, 1 eq, 0.5 mmol/g, CAS: 431041-83-7) was added 20% piperidine/DMF (50 mL, volume fraction), agitated with N₂ for 10 min at 25°C. The mixture was filtered to give resin. The resin was washed with DMF until piperidine was not detected by the kaiser reagent.

[0868] Step 2. Condensation: A solution of (2R)-3-(acetamidomethylsulfanyl)-2-(9H-fluoren-9- ylmethoxy carbonylamino)propanoic acid (2.49 g, 6.00 mmol, 2 eq), HATU (2.28 g, 6.00 mmol, 2 eq) and DIEA (775.46 mg, 6.00 mmol, 1.05 mL, 2 eq) in DMF (50 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0869] Step 3. Deprotection of Fmoc: This step was repeated with the Step 1.

[0870] Step 4.Condensation: A solution of (2S)-5-tert-butoxy-2-(9H-fluoren-9- ylmethoxycarbonylamino) -5-oxo-pentanoic acid (2.55 g, 6.00 mmol, 2 eq), HATU (2.28 g, 6.00 mmol, 2 eq) and DIEA (775.46 mg, 6.00 mmol, 1.05 mL, 2 eq) in DMF (50 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0871] Step 5. Deprotection of Fmoc: This step was repeated with the Step 1. [0872] Step 6.Condensation: A solution of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3- (1H- indol-3-yl)propanoic acid (2.56 g, 6.00 mmol, 2 eq), HATU (2.28 g, 6.00 mmol, 2 eq) and DIEA (775.46 mg, 6.00 mmol, 1.05 mL, 2 eq) in DMF (50 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0873] Step 7. Deprotection of Fmoc: This step was repeated with the Step 1.

[0874] Step 8. Condensation: A solution of 6-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid (2.12 g, 6.00 mmol, 2 eq), HATU (2.28 g, 6.00 mmol, 2 eq) and DIEA (775.46 mg, 6.00 mmol, 1.05 mL, 2 eq) in DMF (50 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0875] Step 9. Deprotection of Fmoc: This step was repeated with the Step 1.

[0876] Step 10.Condensation: A solution of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5- [(N- methylcarbamimidoyl)amino]pentanoic acid (2.44 g, 6 mmol, 2 eq), HATU (2.28 g, 6.00 mmol, 2 eq) and DIEA (775.46 mg, 6.00 mmol, 1.05 mL, 2 eq) in DMF (50 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3). LCMS: Rt=2.342, m/z 1250.0 [M+H]⁺.

[0877] Scheme 39: Preparation of Intermediate I for the synthesis of EXAMPLE 51

[0878] General procedure for the synthesis of Intermediate H:

[0879] Step 1. Deprotection of Fmoc: To the peptide with resin (3 g, 746.79 µmol, 1 eq) was added 20% piperidine/DMF (30 mL, volume fraction), agitated with N₂ for 10 min at 25°C. The mixture was filtered, then DMF (50 mL) was added to it and was agitated with N₂ for 5 min, filtered. The wash operation was repeated until piperidine was not detected by the kaiser reagent.

[0880] Step 2.Condensation: A solution of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(p-tolyl) propanoic acid (599.61 mg, 1.49 mmol, 2 eq), HATU (567.91 mg, 1.49 mmol, 2 eq) and DIEA (193.03 mg, 1.49 mmol, 260.15 µL, 2 eq) in DMF (20 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3). [0881] Step 3. Deprotection of Fmoc: This step was repeated with the Step 1.

[0882] Step 4 Condensation: A solution of (2S)-2-cyclopentyl-2-(9H-fluoren-9- ylmethoxycarbonylamino) acetic acid (545.79 mg, 1.49 mmol, 2 eq), HATU (567.91 mg, 1.49 mmol, 2 eq) and DIEA (193.03 mg, 1.49 mmol, 260.15 µL, 2 eq) in DMF (20 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0883] Step 5. Deprotection of Fmoc: This step was repeated with the Step 1.

[0884] Step 6.Condensation: A solution of (2R)-3-(acetamidomethylsulfanyl)-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid (619.05 mg, 1.49 mmol, 2 eq), HATU (567.91 mg, 1.49 mmol, 2 eq) and DIEA (193.03 mg, 1.49 mmol, 260.15 µL, 2 eq) in DMF (20 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0885] Step 7. Deprotection of Fmoc: This step was repeated with the Step 1.

[0886] Step 8.Condensation: A solution of (2S)-3-(4-tert-butoxyphenyl)-2-(9H-fluoren-9-ylmethoxy carbonylamino)propanoic acid (686.35 mg, 1.49 mmol, 2 eq), HATU (567.91 mg, 1.49 mmol, 2 eq) and DIEA (193.03 mg, 1.49 mmol, 260.15 µL, 2 eq) in DMF (20 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0887] Step 9. Deprotection of Fmoc: This step was repeated with the Step 1.

[0888] Step 10.Condensation: A solution of (2S)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2- carboxylic acid (503.89 mg, 1.49 mmol, 2 eq), HATU (567.91 mg, 1.49 mmol, 2 eq) and DIEA (193.03 mg, 1.49 mmol, 260.15 µL, 2 eq) in DMF (20 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0889] Procedure for the synthesis of EXAMPLE 51:

[0890] Step 1. Deprotection of Fmoc: To Intermediate I with resin (1.6 g, 362.63 µmol, 1 eq) was added 20% piperidine/DMF (30 mL, volume fraction), agitated with N₂ for 10 min at 25°C. The mixture was filtered, then DMF (50 mL) was added to it and was agitated with N₂, filtered. The wash operation was repeated until piperidine was not detected by the kaiser reagent.

[0891] Step 2. Condensation: A solution of 3-(tert-butoxycarbonylamino)propanoic acid (137.23 mg, 725.26 µmol, 2 eq), HATU (275.77 mg, 725.26 µmol, 2 eq) and DIEA (93.73 mg, 725.26 µmol, 126.32 µL, 2 eq) in DMF (10 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0892] Step 3. Cyclization: The peptide with resin was dispersed in DMF (100 mL). Then a solution of I₂ (276.12 mg, 1.09 mmol, 219.14 µL, 3 eq)/DMF (5 mL) was added at 25°C. The resulting mixture was agitated with N₂ for 2 hours at 25 °C. The mixture was filtered after the cyclization. Then the resin was washed with DMF (50 mL x 3).

[0893] Step 4. Cleavage of resin: The peptide with resin was dispersed in TFA (15.40 g, 135.06 mmol, 10 mL, 372.46 eq) and H₂O (500.00 mg, 27.75 mmol, 0.5 mL, 76.52 eq) in a round flask. The resulting mixture was stirred at 25 °C for 4 hours. The mixture (obtained from the cleavage of resin operation) was concentrated under reduced pressure to remove TFA. Then the residue was dispersed in cold MTBE (15 mL). Some solid was precipitated, then filtered to give crude product. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10um;mobile phase: [water(0.225%FA)- ACN];B%: 9%-45%,10min Instrument: Gilson GX-281, FA condition) to give the title compound (7.18 mg, 1.15% yield, 3FA) as a brown solid.

EXAMPLE 52

[0894] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((2S)-2-((2S)-1-(3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid. LCMS: Rt=1.954, m/z 762.4 [M/2+H]⁺.¹H NMR: MeOD-d₄ (400 MHz) d 8.43 (s, 2H), 7.90-7.60 (m, 1H), 7.41 (s, 1H), 7.35- 7.28 (m, 1H), 7.23-7.17 (m, 1H), 7.17-6.93 (m, 5H), 6.82 (br d, J=7.6 Hz, 2H), 6.74-6.67 (m, 2H), 5.96- 5.74 (m, 3H), 5.68-5.50 (m, 1H), 5.01 (d, J=10.4 Hz, 2H), 4.81-4.65 (m, 2H), 4.56-4.44 (m, 1H), 4.26- 4.15 (m, 1H), 4.01-3.90 (m, 1H), 3.59-3.43 (m, 3H), 3.21-2.95 (m, 10H), 2.79-2.55 (m, 2H), 2.43-2.14 (m, 15H), 2.01-1.88 (m, 6H), 1.75-1.65 (m, 3H), 1.62-1.56 (m, 5H), 1.48-1.40 (m, 2H), 1.33 (d, J=6.8 Hz, 3H), 1.22 (dd, J=2.8, 6.7 Hz, 1H), 1.12-1.00 (m, 1H).

[0895] Procedure for the synthesis of EXAMPLE 51:

[0896] Step 1. De-protection of Fmoc group: To a mixture of 9H-fluoren-9-ylmethyl (2S)-2-[[(1S)-2- [[(1R)-1-(acetamidomethylsulfanylmethyl)-2-[[(1S)-2-[[(1S)-2-[[(1S)-1-[[3-[[(1S)-1-[[(1S)-2-[[(1S)-1- [[(1R)-1-(acetamidomethylsulfanylmethyl)-2-amino-2-oxo-ethyl]carbamoyl]-4-tert-butoxy-4-oxo- butyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]carbamoyl]-4-oxo-4-(tritylamino)butyl]amino]-3- oxo-propyl]carbamoyl]-4-[[N-[(2,2,4,6,7-pentamethyl-3Hbenzofuran-5- yl)sulfonyl]carbamimidoyl]amino]butyl]amino]-2-oxo-1-(p-tolylmethyl)ethyl]amino]-1-cyclopentyl-2- oxoethyl]amino]-2-oxo-ethyl]amino]-1-[(4-tert-butoxyphenyl)methyl]-2-oxo- ethyl]carbamoyl]pyrrolidine-1-carboxylate (2 g, 374.97 µmol, 1 eq) (linked with resin) (Intermediate F of EXAMPLE 49) was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0897] Step 2. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added 3-(tert- butoxycarbonylamino)butanoic acid (152.41 mg, 749.94 µmol, 2 eq), HATU (299.41 mg, 787.43 µmol, 2.1 eq) and DIPEA (145.39 mg, 1.12 mmol, 195.94 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0898] Step 3. Cyclization reaction: To a mixture of the resin in DMF (30 mL) was added I₂ (285.51 mg, 1.12 mmol, 226.60 µL, 3 eq), the mixture was bubbled with N₂ for 120 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0899] Step 4. Desorption from the resin: To the resin was added TFA (20 mL), H₂O (0.5 mL) and anisole (0.5 mL), the mixture was stirred at 25 °C for 240 min. The mixture was filtered and washed with TFA (5 mL). Then the filtrate was concentrated under reduced pressure to remove TFA. Then the residue was poured into cold MTBE (20 mL) and filtered to give the filter cake. LC-MS showed ~14% of desired m/z was detected. The residue was purified by prep-HPLC (Instrument: Gilson GX-281; column: Phenomenex Synergi C18150*25*10um; mobile phase: [water(0.225%FA)-ACN];B%: 6%- 42%,10min) to give the title compound (42.91 mg, 7.0% yield, 2FA) as a white solid. EXAMPLE 53

[0900] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((2S)-2-((2S)-1-(3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-methylbenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid. LCMS: Rt=2.471, m/z 719.4 [M/2+H]⁺. ¹H NMR DMSO-d₆ (400 MHz) d 10.90 (s, 1H), 9.25-8.75 (m, 3H), 8.48 (s, 1H), 8.37 (d, J=10.8 Hz, 3H), 7.58-7.22 (m, 11H), 7.10-6.86 (m, 6H), 6.72-6.61 (m, 4H), 4.70-4.35 (m, 5H), 4.32 (s, 2H), 4.20-3.98 (m, 5H), 3.05-2.95 (m, 8H), 2.53 (s, 3H), 2.20-1.75 (m, 20H), 1.74-1.49 (m, 7H), 1.46-1.22 (m, 12H), 1.18- 0.97 (m, 6H).

[0901] Scheme 40: Synthesis of EXAMPLE 53

[0902] Procedure for the synthesis of EXAMPLE 53:

[0903] Step 1. Deprotection of Fmoc: To rink amide MBHA resin (1 g, 0.5 mmol, 1 eq, 0.5 mmol/g, CAS: 431041-83-7) was added 20% piperidine/DMF (50 mL, volume fraction), agitated with N₂ for 10 min at 25°C. The mixture was filtered to give resin. The resin was washed with DMF until piperidine was not detected by the kaiser reagent.

[0904] Step 2. Condensation: A solution of (2R)-3-(acetamidomethylsulfanyl)-2-(9H-fluoren-9- ylmethoxy carbonylamino)propanoic acid (414.37 mg, 999.74 µmol, 2 eq), HATU (380.13 mg, 999.74 µmol, 2 eq) and DIEA (129.21 mg, 999.74 µmol, 174.13 µL, 2 eq) in DMF (25 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0905] Step 3. Deprotection of Fmoc: This step was repeated with the Step 1.

[0906] Step 4. Condensation: A solution of (2S)-5-tert-butoxy-2-(9H-fluoren-9- ylmethoxycarbonylamino) -5-oxo-pentanoic acid (425.36 mg, 999.74 µmol, 2 eq), HATU (380.13 mg, 999.74 µmol, 2 eq) and DIEA (129.21 mg, 999.74 µmol, 174.13 µL, 2 eq) in DMF (25 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0907] Step 5. Deprotection of Fmoc: This step was repeated with the Step 1.

[0908] Step 6. Condensation: A solution of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3- (1H- indol-3-yl)propanoic acid (426.35 mg, 999.74 µmol, 2 eq), HATU (380.13 mg, 999.74 µmol, 2 eq) and DIEA (129.21 mg, 999.74 µmol, 174.13 µL, 2 eq) in DMF (25 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0909] Step 7. Deprotection of Fmoc: This step was repeated with the Step 1.

[0910] Step 8. Condensation: A solution of 6-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid (353.32 mg, 999.74 µmol, 2 eq), HATU (380.13 mg, 999.74 µmol, 2 eq) and DIEA (129.21 mg, 999.74 µmol, 174.13 µL, 2 eq) in DMF (25 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0911] Step 9. Deprotection of Fmoc: This step was repeated with the Step 1.

[0912] Step 10.Condensation: A solution of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-[[N- [(2,2,4,6,7-pentamethyl-3H-benzofuran-5-yl)sulfonyl]carbamimidoyl]amino]pentanoic acid (648.60 mg, 999.74 mmol, 2 eq), HATU (380.13 mg, 999.74 µmol, 2 eq) and DIEA (129.21 mg, 999.74 µmol, 174.13 µL, 2 eq) in DMF (25 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0913] Step 11. Deprotection of Fmoc: This step was repeated with the Step 1.

[0914] Step 12. Condensation: A solution of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(p- tolyl) propanoic acid(401.35 mg, 999.74 mmol, 2 eq), HATU (380.13 mg, 999.74 µmol, 2 eq) and DIEA (129.21 mg, 999.74 µmol, 174.13 µL, 2 eq) in DMF (25 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25°C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0915] Step 13. Deprotection of Fmoc: This step was repeated with the Step 1.

[0916] Step 14. Condensation: A solution of (2S)-2-cyclopentyl-2-(9H-fluoren-9- ylmethoxycarbonylamino) acetic acid (365.33 mg, 999.74 mmol, 2 eq), HATU (380.13 mg, 999.74 µmol, 2 eq) and DIEA (129.21 mg, 999.74 µmol, 174.13 µL, 2 eq) in DMF (25 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0917] Step 15. Deprotection of Fmoc: This step was repeated with the Step 1.

[0918] Step 16. Condensation: A solution of (2R)-3-(acetamidomethylsulfanyl)-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid(414.37 mg, 999.74 mmol, 2 eq), HATU (380.13 mg, 999.74 µmol, 2 eq) and DIEA (129.21 mg, 999.74 µmol, 174.13 µL, 2 eq) in DMF (25 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0919] Step 17. Deprotection of Fmoc: This step was repeated with the Step 1.

[0920] Step 18. Condensation: A solution of (2S)-3-(4-tert-butoxyphenyl)-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid(459.41 mg, 999.74 mmol, 2 eq), HATU (380.13 mg, 999.74 µmol, 2 eq) and DIEA (129.21 mg, 999.74 µmol, 174.13 µL, 2 eq) in DMF (25 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0921] Step 19. Deprotection of Fmoc: This step was repeated with the Step 1.

[0922] Step 20. Condensation: A solution of (2S)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine -2- carboxylic acid(337.28 mg, 999.74 mmol, 2 eq), HATU (380.13 mg, 999.74 µmol, 2 eq) and DIEA (129.21 mg, 999.74 µmol, 174.13 µL, 2 eq) in DMF (25 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0923] Step 21. Deprotection of Fmoc: This step was repeated with the Step 1.

[0924] Step 22. Condensation: A solution of 3-(tert-butoxycarbonylamino)butanoic acid(203.18 mg, 999.74 mmol, 2 eq), HATU (380.13 mg, 999.74 µmol, 2 eq) and DIEA (129.21 mg, 999.74 µmol, 174.13 µL, 2 eq) in DMF (25 mL) was added to the compound with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3). [0925] Step 23. Cyclization: The peptide with resin was dispersed in DMF (100 mL). Then a solution of I₂ (380.61 mg, 1.50 mmol, 302.07 µL, 3 eq) / DMF (5 mL) was added at 25 °C. The resulting mixture was agitated with N₂ for 2 hours at 25 °C. The mixture was filtered after the cyclization. Then the resin was washed with DMF (50 mL x 3).

[0926] Step 24. Cleavage of resin: The peptide with resin was dispersed in TFA (15.40 g, 135.06 mmol, 10 mL, 270.19 eq) and H₂O (500.00 mg, 27.75 mmol, 0.5 mL, 55.52 eq) in a round flask. The resulting mixture was stirred at 25 °C for 4 hours. The mixture (obtained from the cleavage of resin operation) was concentrated under reduced pressure to remove TFA. Then the residue was dispersed in cold MTBE (30 mL). Some solid was precipitated, then filtered to give crude product. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10um; mobile phase: [water (0.225%FA)- ACN];B%: 6%-38%,10min, Instrument: Gilson GX-281, FA condition) to give the title compound (105.89 mg, 14.2% yield, FA) as a pink solid.

EXAMPLE 54

[0927] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((2S)-2-((2S)-1-(3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20-(3- guanidinopropyl)-26-isopropyl-23-(4-methylbenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid. LCMS: Rt=2.449, m/z 706.3 [M/2+H]⁺. ¹H NMR: DMSO-d₆ (400 MHz) d 10.92 (s, 1H), 9.30-8.70 (m, 3H), 8.48 (s, 1H), 8.45-8.35 (m, 3H), 7.75-7.17 (m, 11H), 7.15-6.82 (m, 6H), 6.79-6.58 (m, 4H), 5.17-4.39 (m, 7H), 4.33 (s, 3H), 4.00 (s, 2H), 3.20-2.80 (m, 8H), 2.53 (s, 3H), 2.23-1.68 (m, 20H), 1.52-1.23 (m, 7H), 1.22-0.88 (m, 10H), 0.83 (s, 6H).

[0928] General procedure for the synthesis of Intermediate J:

[0929] Step 1. Deprotection of Fmoc: To Intermediate H (of EXAMPLE 51) with resin (3 g, 746.79 µmol, 1 eq) was added 20% piperidine/DMF (30 mL, volume fraction), agitated with N₂ for 10 min at 25°C. The mixture was filtered, then DMF (50 mL) was added to it and was agitated with N₂ for 5 min, filtered. The wash operation was repeated until piperidine was not detected by the kaiser reagent.

[0930] Step 2. Condensation: A solution of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(p-tolyl) propanoic acid (599.61 mg, 1.49 mmol, 2 eq), HATU (567.91 mg, 1.49 mmol, 2 eq) and DIEA (193.03 mg, 1.49 mmol, 260.15 µL, 2 eq) in DMF (20 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0931] Step 3. Deprotection of Fmoc: This step was repeated with the Step 1.

[0932] Step 4. Condensation: A solution of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl- butanoic acid (506.90 mg, 1.49 mmol, 2 eq), HATU (567.91 mg, 1.49 mmol, 2 eq) and DIEA (193.03 mg, 1.49 mmol, 260.15 µL, 2 eq) in DMF (20 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0933] Step 5. Deprotection of Fmoc: This step was repeated with the Step 1.

[0934] Step 6. Condensation: A solution of (2R)-3-(acetamidomethylsulfanyl)-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid (619.05 mg, 1.49 mmol, 2 eq), HATU (567.91 mg, 1.49 mmol, 2 eq) and DIEA (193.03 mg, 1.49 mmol, 260.15 µL, 2 eq) in DMF (20 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0935] Step 7. Deprotection of Fmoc: This step was repeated with the Step 1.

[0936] Step 8. Condensation: A solution of (2S)-3-(4-tert-butoxyphenyl)-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid (686.35 mg, 1.49 mmol, 2 eq), HATU (567.91 mg, 1.49 mmol, 2 eq) and DIEA (193.03 mg, 1.49 mmol, 260.15 µL, 2 eq) in DMF (20 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3).

[0937] Step 9. Deprotection of Fmoc: This step was repeated with the Step 1.

[0938] Step 10. Condensation: A solution of (2S)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2- carboxylic acid (503.89 mg, 1.49 mmol, 2eq), HATU (567.91 mg, 1.49 mmol, 2 eq) and DIEA (193.03 mg, 1.49 mmol, 260.15 µL, 2 eq) in DMF (20 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3). The peptide with resin (Intermediate J) (3.2 g) was obtained as a yellow solid and it was used for the next step directly.

[0939] Scheme 41: Synthesis of EXAMPLE 54

[0940] Procedure for the synthesis of EXAMPLE 54

[0941] Step 1. Deprotection of Fmoc: To the peptide with resin (1.6 g, 372.67µmol, 1 eq) was added 20% piperidine/DMF (20 mL, volume fraction), agitated with N₂ for 10 min at 25 °C. The mixture was filtered, then DMF (30 mL) was added to it and was agitated with N₂ for 5 min, filtered. The wash operation was repeated until piperidine was not detected by the kaiser reagent.

[0942] Step 2. Condensation: A solution of 3-(tert-butoxycarbonylamino)butanoic acid (151.48 mg, 745.34 µmol, 2 eq), HATU (283.40 mg, 745.34 µmol, 2 eq) and DIEA (96.33 mg, 745.34 µmol, 129.82 µL, 2 eq) in DMF (15 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 25 °C. The resin was detected with the kaiser reagent to ensure the condensation was completed. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (30 mL x 3).

[0943] Step 3. Cyclization: The peptide with resin was dispersed in DMF (100 mL). Then a solution of I₂ (283.76 mg, 1.12 mmol, 225.20 µL, 3 eq)/DMF (5 mL) was added at 25 °C. The resulting mixture was agitated with N₂ for 2 hours at 25 °C. The mixture was filtered after the cyclization. Then the resin was washed with DMF (50 mL x 3). [0944] Step 4. Cleavage of resin: The peptide with resin was dispersed in TFA (15.40 g, 135.06 mmol, 10.00 mL, 362.42 eq) and H₂O (500 mg, 27.75 mmol, 0.5 mL, 74.47 eq) in a round flask. The resulting mixture was stirred at 25 °C for 4 hours. The mixture (obtained from the cleavage of resin operation) was concentrated under reduced pressure to remove TFA. Then the residue was dispersed in cold MTBE (30 mL). Some solid was precipitated, then filtered to give crude product. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10um;mobile phase: [water(0.225%FA)- ACN];B%: 5%-37%,10 min, Instrument: Gilson GX-281, FA condition) to give the title compound (25.68 mg, 4.3% yield, FA) as a white solid.

EXAMPLE 55

[0945] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-26-isopropyl-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid. LCMS: Rt=2.223, m/z 742.5 [M/2+H]⁺.¹H NMR: DMSO-d₆ (400 MHz) d 10.84 (s, 1H), 9.15-9.05 (m, 1H), 9.02-8.72 (m, 3H), 8.46-8.31 (m, 1H), 8.10-7.72 (m, 4H), 7.49-7.11 (m, 11H), 7.09-6.94 (m, 4H), 6.90-6.82 (m, 2H), 6.74 (d, J=7.2 Hz, 2H), 6.66 (dd, J=8.0, 14.4 Hz, 2H), 5.87-5.80 (m, 1H), 5.56-5.40 (m, 1H), 5.30-5.10 (m, 1H), 4.98-4.40 (m, 5H), 4.38-4.21 (m, 1H), 4.10-3.75 (m, 2H), 3.38-3.32 (m, 4H), 3.17-2.74 (m, 14H), 2.26- 2.03 (m, 12H), 1.99-1.68 (m, 8H), 1.60-1.38 (m, 2H), 1.31-1.17 (m, 1H), 0.90-0.80 (m, 6H).

[0946] Procedure for the synthesis of EXAMPLE 55

[0947] Step 1. De-protection of Fmoc group: To a mixture of 9H-fluoren-9-ylmethyl (2S)-2-[[(1S)-2- [[(1R)-1-(acetamidomethylsulfanylmethyl)-2-[[(1S)-1-[[(1S)-2-[[(1S)-1-[[3-[[(1S)-1-[[(1S)-2-[[(1S)-1- [[(1R)-1-(acetamidomethylsulfanylmethyl)-2-amino-2-oxo-ethyl]carbamoyl]-4-tert-butoxy-4-oxo- butyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]carbamoyl]-4-oxo-4-(tritylamino)butyl]amino]-3- oxo-propyl]carbamoyl]-4-[[N-[(2,2,4,6,7-pentamethyl-3Hbenzofuran-5- yl)sulfonyl]carbamimidoyl]amino]butyl]amino]-2-oxo-1-(p-tolylmethyl)ethyl]carbamoyl]-2- methylpropyl]amino]-2-oxo-ethyl]amino]-1-[(4-tert-butoxyphenyl)methyl]-2-oxo- ethyl]carbamoyl]pyrrolidine-1-carboxylate (Intermediate G of EXAMPLE 50) (1.6 g, 374.87 µmol, 1 eq) (linked with resin) was added a solution of piperidine in DMF (30 mL, 20%, v/v), and bubbled with N₂ for 10 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0948] Step 2. Condensation reaction: To a mixture of the resin in DMF (30 mL) was added 3-(tert- butoxycarbonylamino)propanoic acid (141.86 mg, 749.74 µmol, 2 eq), HATU (299.33 mg, 787.23 µmol, 2.1 eq) and DIPEA (145.34 mg, 1.12 mmol, 195.88 µL, 3 eq), the mixture was bubbled with N₂ for 30 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0949] Step 3. Cyclization reaction: To a mixture of the resin in DMF (30 mL) was added I₂ (285.44 mg, 1.12 mmol, 226.54 µL, 3 eq), the mixture was bubbled with N₂ for 120 min at 25 °C. Then the mixture was filtered and washed with DMF (50 mL for each time) (bubbled and filtered) for 5 times.

[0950] Step 4. Desorption from the resin: To the resin was added TFA (20 mL), H₂O (0.5 mL) and anisole (0.5 mL), the mixture was stirred at 25 °C for 240 min. The mixture was filtered and washed with TFA (5 mL). Then the filtrate was concentrated under reduced pressure to remove TFA. Then the residue was poured into cold MTBE (20 mL) and filtered to give the filter cake. LC-MS showed ~25% of desired m/z was detected. The residue was purified by prep-HPLC twice (Instrument: Gilson GX-281; column: Phenomenex Synergi C18150*25*10um; mobile phase: first by [water(0.225%FA)-ACN];B%: 3%- 39%,10 min, then by [water(0.05%HCl)-ACN];B%: 10%-30%,7.8 min) to give the title compound (8.08 mg, 1.4% yield, 2HCl) as a brown solid.

EXAMPLE 56

[0951] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-((R)-3-amino-N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(3-chloro-2-fluorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was was prepared according to Scheme 42 with amino acids 92 and 15; followed by Scheme 43 utilizing 90 to give the crude product. A second purificiation was conducted by prep-HPCL: HOAc condition [(A:

water(0.5%AcOH); B: AcONH₄: 1-60%] to give a white solid (39.53 mg, 23.4% yield, 99.9% purity with 2HOAC). LCMS: Rt=2.381, m/z 782.7 [M/2+H]⁺. ¹H NMR: DMSO-d₆, 400MHz d10.66 (br s, 1H), 9.69 - 9.09 (m, 1H), 9.08 - 8.84 (m, 3H), 8.83 - 8.39 (m, 1H), 8.22 - 7.69 (m, 3H), 7.66 - 7.36 (m, 3H), 7.28 (br s, 2H), 7.21 - 7.07 (m, 1H), 7.06 - 6.91 (m, 3H), 6.89 - 6.77 (m, 1H), 6.73 (br s, 1H), 6.62 (t, J = 8.2 Hz, 1H), 5.62 - 4.96 (m, 2H), 4.77 - 4.42 (m, 4H), 4.33 - 4.07 (m, 1H), 3.97 - 3.78 (m, 4H), 3.65 (br d, J = 17.4 Hz, 21H), 3.30 - 3.09 (m, 9H), 3.07 - 2.71 (m, 8H), 2.30 - 1.98 (m, 5H), 1.96 - 1.87 (m, 3H), 1.84 (br d, J = 11.7 Hz, 6H), 1.69 - 1.16 (m, 9H), 1.15 - 0.93 (m, 3H), 0.92 - 0.69 (m, 6H).

[0952] Procedure for the synthesis of EXAMPLE 56

[0953] Scheme 42

[0954] Step 1. To 9H-fluoren-9-ylmethyl carbamate Rink Amide Resin ChemPep Inc. (0.575 g, 0.5mmol, 1 eq) was added 20% piperidine/DMF (3 mL). The mixture was bubbled with N₂ for 30 min at 20 °, filtered and DMF (10 mL) was added. The procedure was repeated 5 times.

[0955] Step 2. Condensation: A solution of Na-Fmoc-S-trityl-L-cysteine 9 (175 mg, 300 µmol, 3 eq), HBTU (108 mg, 285 µmol, 2.85 eq) and DIEA (77.5 mg, 600 µmol, 105 µL, 6 eq) in DMF (3 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 20 °C. The mixture was filtered. Then the resin was washed with DMF (50 mL x 3).

[0956] Step 3. Deprotection of Fmoc: To the peptide with resin was added 20% piperidine/DMF (30 mL, volume fraction), agitated with N₂ for 20 min at 20 °C. The mixture was filtered, then DMF (50 mL) was added to it and was agitated with N₂ for 5 min, filtered. The wash operation was repeated until piperidine was not detected by the kaiser reagent.

[0957] Steps 2 and 3 repeated. The coupling of Fmoc-L-glutamic acid 5-tert-butyl ester 10 (3 eq), Na- Fmoc-N(in)-Boc-L-tryptophan 18 (3 eq ), Na-Fmoc-Nd-trityl-L-glutamine 11 (3 eq), Fmoc-b-alanine 12 (3 eq), Na-Fmoc-Nw-(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl)-L-arginine 13 (3 eq), (S)-2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-2-fluorophenyl)propanoic acid 92 (3 eq), Fmoc-L-valine 15 (3 eq), Na-Fmoc-S-trityl-L-cysteine 9 (3 eq),O-tert-butyl-L-tyrosine 14 (3 eq) ws accomplished by repeating steps 1 and 2 with each amino acid addition. The last amino acid was not de- protected to yield Intermediate peptide K.

[0958] Scheme 43

[0959] Intermediate peptide K was Fmoc deprotected in a similar manner to Scheme 42 Step 3 to yeild the de-protected peptide on resin.

[0960] Step 4. Condensation: A solution of 2-bromoacetic acid (139 mg, 1.0 mmol, 72 µL, 10 eq) and DIC (126 mg, 1.0 mmol, 155 µL, 10 eq) in DMF (3 mL) was added to the resin. The mixture was bubbled with N₂ for 20 min at 20 °C. The resin was then washed with DMF (50 mL x 3). Next a solution of cyclopentanamine (25.6 mg, 0.3 mmol, 29.6 µL, 3 eq) in DMF (3 mL) was added. The mixture was bubbled for 20 min at 20 °C and then the resin was then washed with DMF (50 mL x 3). Lastly, a solution of (3R)-(tertbutoxycarbonylamino)butanoic acid 90 (60.9 mg, 0.3 mmol, 3 eq), DIEA (77.5 mg, 0.6 mmol, 105 µL, 6 eq) and HATU (108 mg, 0.285 mmol, 2.85 eq) in DMF (3 mL) was added to the resin. The mixture was bubbled for 20 min at 20 °C and the resin was then washed with DMF (3 mL x 3).

[0961] Step 5. Cleavage of resin: The peptide with resin was washed with MeOH (30 mL x 3) and dried under vacuum. Next 7 mL of cleavage buffer was added (90% TFA, 2.5% EDT, 2.5% TIS, 2.5% H2) and 2.5% methylsulfanylbenzene). The resulting mixture was stirred at 20 °C for 2.5 hours. The residue was dispered in cold MTBE (50 mL), centrifuged (3 min at 3000 rpm) and dried under vacuum.

[0962] Step 6. Cyclization: To the crude peptide (130 mg) in water (30 mL) and CH₃CN (20 mL) was added a solution of I₂ in MeOH (0.1 M, 3 eq) dropwise at 20 °C until the yellow color persisted. Then the mixture was stirred at 20 °C for 2 min. The sodium thiosulfate (0.1 M in water) was added dropwise until the yellow color disappears. The mixture was lyophilized to give the crude powder. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10µm; mobile phase: TFA conditions [A: water(0.10-0.25%TFA); B: Acetonirile: 10-90%]. Instrument: Gilson (GX-281).

EXAMPLE 57

[0963] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(3-chloro-2-fluorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was was prepared according to Scheme 42 with amino acids 92 and 89; followed by Scheme 43 utilizing 19 to give a white solid (26.99 mg, 15.83 µmol, 15.8% yield, 99.5% purity, 2HOAC). LCMS: Rt=2.399, m/z 788.5

[M/2+H]⁺.¹H NMR:DMSO-d₆, 400MHz d 10.64 (br s, 1H), 8.92 (br s, 5H), 8.36 - 7.68 (m, 3H), 7.61 - 7.23 (m, 6H), 7.17 (br d, J = 7.0 Hz, 1H), 7.10 - 6.91 (m, 3H), 6.82 (br d, J = 7.5 Hz, 1H), 6.72 (br s, 1H), 6.68 - 6.59 (m, 1H), 5.48 - 4.95 (m, 2H), 4.75 - 4.39 (m, 5H), 4.17 (br s, 1H), 3.92 - 3.71 (m, 9H), 3.25 - 3.10 (m, 6H), 3.09 - 2.92 (m, 7H), 2.90 - 2.70 (m, 5H), 2.30 - 1.96 (m, 9H), 1.95 - 1.86 (m, 4H), 1.83 (br d, J = 5.3 Hz, 6H), 1.74 - 1.47 (m, 11H), 1.47 - 1.02 (m, 15H). EXAMPLE 58

[0964] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-23-(3-chloro-2-fluorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 92 and 89; followed by Scheme 44 utilizing 90 to give a white solid (12.28 mg, 7.22 µmol, 7.22% yield, 98.9% purity, 2HOAC). LCMS: Rt=2.361, m/z 781.5 [M/2+H]⁺.¹H NMR:DMSO-d₆, 400 MHz d 10.63 (br s, 1H), 9.55 (br s, 1H), 9.14 - 8.68 (m, 5H), 8.49 (br s, 1H), 8.26 (br d, J = 7.1 Hz, 1H), 7.99 (br s, 1H), 7.90 - 7.67 (m, 2H), 7.54 - 7.38 (m, 1H), 7.54 - 7.38 (m, 1H), 7.33 - 7.11 (m, 6H), 7.05 (br d, J = 8.3 Hz, 1H), 7.00 (br d, J = 8.3 Hz, 2H), 6.92 (br t, J = 7.3 Hz, 1H), 6.87 - 6.77 (m, 2H), 6.71 (br s, 1H), 6.66 - 6.59 (m, 2H), 5.48 - 4.94 (m, 5H), 4.72 - 4.41 (m, 4H), 4.30 (br d, J = 8.2 Hz, 1H), 4.15 (br s, 1H), 3.81 (br s, 1H), 3.23 - 3.10 (m, 7H), 3.08 - 2.90 (m, 9H), 2.89 - 2.71 (m, 5H), 2.30 - 1.99 (m, 10H), 1.98 - 1.86 (m, 5H), 1.82 (s, 6H), 1.80 - 1.71 (m, 2H), 1.69 - 1.48 (m, 6H), 1.46 - 1.23 (m, 7H), 1.03 - 0.93 (m, 3H).

[0965] Procedure for the synthesis of EXAMPLE 58

[0966] Scheme 44

[0967] Intermediate peptide K was Fmoc deprotected in a similar manner to Scheme 42 Step 3 to yield the de-protected peptide on resin.

[0968] Step 4. Condensation: A solution of (2S)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2- carboxylic acid 17 (3 eq), HBTU (2.85 eq) and DIEA (6 eq) in DMF (20 mL) was added to the peptide with resin, agitated for 20 min with N₂ at 20 °C. The mixture was filtered after the condensation was completed. Then the resin was washed with DMF (50 mL x 3). Next a solution of (3R)-3- (tertbutoxycarbonylamino)butanoic acid 90 (60.97 mg, 0.3 mmol, 3 eq), DIEA(77.5 mg, 0.60 mmol, 105 µL, 6 eq) and HATU (108 mg, 0.285 mmol, 2.85 eq) in DMF (3 mL) was added to the resin and agitated with N₂ for 20 min at 20 °C. The resin was then washed with DMF (50 mL x 3).

[0969] Step 5. Cleavage of resin: The peptide with resin was washed with MeOH (30 mL x 3) and dried under vacuum. Next 7 mL of cleavage buffer was added (90% TFA, 2.5% EDT, 2.5% TIS, 2.5% H2) and 2.5% methylsulfanylbenzene). The resulting mixture was stirred at 20 °C for 2.5 hours. The residue was dispered in cold MTBE (50 mL), centrifuged (3 min at 3000 rpm) and dried under vacuum.

[0970] Step 6. Cyclization: To the crude peptide (130 mg) in water (30 mL) and CH₃CN (20 mL) was added a solution of I₂ in MeOH (0.1 M, 3 eq) dropwise at 20 °C until the yellow color persisted. Then the mixture was stirred at 20 °C for 2 min. The sodium thiosulfate (0.1 M in water) was added dropwise until the yellow color disappears. The mixture was lyophilized to give the crude powder. The residue was purified by prep-HPLC twice (Instrument: Gilson GX-281; column: Phenomenex Synergi C18 150*25*10um; mobile phase: first by TFA conditions [water(0.225%TFA)-Acetonitrile];B%: 3%-39%, then by HOAc condition [water(0.05%AcOH)-ACN];B%: 10%-30%). EXAMPLE 59

[0971] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 82 and 89; followed by Scheme 43 with 19 to give a white solid (25.0 mg, 14.95 µmol, 33.12% yield, 99.81% purity, 2HOAC). LCMS: Rt=2.297, m/z 774.9 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d10.56 (br s, 1H), 9.73 (br s, 1H), 9.10 - 8.88 (m, 3H), 8.80 (br s, 1H), 8.60 - 8.40 (m, 1H), 8.10 (br s, 1H), 7.87 - 7.68 (m, 2H), 7.55 - 7.09 (m, 9H), 7.07 - 6.95 (m, 2H), 6.88 (br s, 2H), 6.81 (br s, 1H), 6.71 (br s, 1H), 6.62 (br t, J=8.2 Hz, 2H), 5.42 (br s, 2H), 5.10 (br s, 2H), 4.70 - 4.49 (m, 4H), 4.27 - 4.13 (m, 1H), 3.91 - 3.63 (m, 2H), 3.21 - 2.92 (m, 11H), 2.91 - 2.67 (m, 4H), 2.30 - 2.09 (m, 10H), 2.06 - 1.92 (m, 5H), 1.90 (br s, 2H), 1.85 (s, 6H), 1.77 - 1.04 (m, 27H).

EXAMPLE 60

[0972] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(3-chloro-2-fluorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 92 and 89; followed by Scheme 44 with 19 to give a white solid (30.22 mg, 18.07 µmol, 12.05% yield, 99.74% purity, 2HOAC). LCMS: Rt=2.328, m/z 774.5

[M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.65 (br s, 1H), 9.47 (br s, 1H), 9.18 - 8.65 (m, 6H), 8.58 - 8.18 (m, 2H), 8.05 - 7.67 (m, 3H), 7.45 (br d, J=8.8 Hz, 1H), 7.37 - 7.11 (m, 7H), 7.09 - 6.89 (m, 5H), 6.82 (br d, J=7.8 Hz, 2H), 6.73 (br s, 1H), 6.64 (br t, J=7.8 Hz, 2H), 5.51 - 4.91 (m, 7H), 4.71 - 4.44 (m, 6H), 4.35 - 4.07 (m, 2H), 3.81 (br s, 1H), 3.13 - 2.72 (m, 19H), 2.29 - 1.99 (m, 10H), 1.83 (s, 6H), 1.70 - 1.18 (m, 16H).

EXAMPLE 61

[0973] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-((R)-3-amino-N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-chlorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids (2S)-3-(2-chlorophenyl)-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid 93 and 15; followed by Scheme 43 with 90 to give a white solid (27 mg, 16.81 µmol, 52.05% yield, 100% purity, HOAC). LCMS: Rt=2.332, m/z 773.7 [M/2+H]⁺. ¹H NMR: DMSO-d₆, 400 MHz d 10.58 (br s, 1H), 9.41 (br s, 1H), 8.91 (br d, J=8.6 Hz, 2H), 8.67 (br s, 1H), 8.58 - 8.37 (m, 1H), 8.15 (br s, 1H), 8.00 - 7.65 (m, 4H), 7.59 - 7.34 (m, 3H), 7.33 - 7.21 (m, 3H), 7.17 - 6.95 (m, 4H), 6.65 - 6.59 (m, 1H), 5.85 (br s, 1H), 5.42 (br s, 2H), 5.20 - 4.96 (m, 1H), 4.73 - 4.48 (m, 5H), 4.34 - 4.12 (m, 2H), 4.02 - 3.72 (m, 4H), 3.71 - 3.45 (m, 6H), 3.29 - 2.69 (m, 20H), 2.48 - 2.37 (m, 2H), 2.28 - 2.10 (m, 3H), 2.09 - 1.88 (m, 4H), 1.87 (s, 3H), 1.85 (br s, 3H), 1.69 (br s, 2H), 1.56 (br d, J=7.6 Hz, 3H), 1.48 - 1.36 (m, 3H), 1.36 - 1.16 (m, 4H), 1.08 - 0.96 (m, 3H), 0.90 - 0.74 (m, 7H). EXAMPLE 62

[0974] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-((R)-3-amino-N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 93 and 89; followed by Scheme 43 with 90 to yield a white solid (20 mg, 12.16 µmol, 38.31% yield, 99.30% purity, HOAC).¹H NMR: DMSO-d₆, 400 MHz d 10.58 (br s, 1H), 9.40 (br s, 1H), 9.11 - 8.75 (m, 4H), 8.72 - 8.33 (m, 2H), 7.70 (br d, J=7.6 Hz, 3H), 7.40 (br t, J=17.6 Hz, 3H), 7.31 - 7.17 (m, 4H), 7.14 (br d, J=7.2 Hz, 1H), 7.06 - 6.93 (m, 6H), 6.90 (br t, J=7.4 Hz, 2H), 6.81 (br t, J=6.8 Hz, 1H), 6.73 (br s, 1H), 6.65 - 6.57 (m, 3H), 5.83 (br s, 1H), 5.32 (br s, 1H), 5.02 (br s, 2H), 4.68 - 4.40 (m, 5H), 4.22 (br dd, J=8.2, 17.2 Hz, 2H), 3.94 - 3.69 (m, 3H), 3.01 - 2.85 (m, 8H), 2.25 - 1.98 (m, 10H), 1.84 (s, 6H), 1.77 - 1.14 (m, 30H), 1.07 - 0.92 (m, 5H). LCMS: Rt=2.369, m/z 786.5 [M/2+H]⁺.

EXAMPLE 63

[0975] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-chlorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 93 and 15; followed by Scheme 43 with 19 to yield a white solid (23 mg, 13.92 µmol, 42.71% yield, 100% purity, 2HOAC).¹H NMR: DMSO-d₆, 400 MHz, d 10.60 (br s, 1H), 9.28 (br s, 1H), 9.16 - 8.85 (m, 5H), 8.80 - 8.40 (m, 1H), 8.17 (br s, 1H), 7.90 (br s, 1H), 7.71 (br d, J=7.8 Hz, 3H), 7.57 - 7.21 (m, 8H), 7.21 - 7.10 (m, 1H), 7.09 - 6.89 (m, 5H), 6.88 - 6.71 (m, 1H), 6.69 - 6.58 (m, 1H), 5.84 (br s, 1H), 5.48 - 5.24 (m, 1H), 5.16 - 4.94 (m, 1H), 4.70 - 4.44 (m, 4H), 4.32 - 4.11 (m, 2H), 3.97 - 3.73 (m, 4H), 3.67 (br d, J=16.6 Hz, 4H), 3.15 - 2.71 (m, 16H), 2.27 - 2.10 (m, 4H), 2.02 (br d, J=7.6 Hz, 2H), 1.98 - 1.87 (m, 4H), 1.84 (s, 6H), 1.81 - 1.64 (m, 8H), 1.54 (m, 4H), 1.41 (br d, J=7.6 Hz, 4H), 1.34 - 1.01 (m, 5H), 0.88 - 0.81 (m, 6H). LCMS: Rt=2.304, m/z 766.5 [M/2+H]⁺.

EXAMPLE 64

[0976] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 93 and 89; followed by Scheme 43 with 19 to yield a white solid (22 mg, 12.91 µmol, 40.29% yield, 98.49% purity, 2HOAC).¹H NMR: DMSO-d₆, 400 MHz d 10.57 (br s, 1H), 9.53 (br s, 1H), 8.93 (br s, 5H), 8.66 (br s, 1H), 8.57 - 8.39 (m, 1H), 8.16 (br s, 1H), 7.90 (br s, 1H), 7.71 (br d, J=8.2 Hz, 3H), 7.48 - 7.33 (m, 2H), 7.30 - 7.11 (m, 7H), 7.06 - 6.94 (m, 8H), 6.90 (br t, J=7.2 Hz, 2H), 6.81 (br t, J=7.0 Hz, 2H), 6.74 (br s, 1H), 6.62 (br t, J=7.6 Hz, 3H), 5.82 (br s, 1H), 5.26 (br s, 2H), 5.01 (br s, 2H), 4.70 - 4.42 (m, 6H), 4.34 - 4.07 (m, 2H), 3.95 - 3.63 (m, 3H), 2.96 (br s, 6H), 2.17 (br s, 7H), 1.89 (s, 6H), 1.75 - 0.96 (m, 31H). LCMS: Rt=2.344, m/z 779.6 [M/2+H]⁺. EXAMPLE 65

[0977] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-23-(2-chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 93 and 89; followed by Scheme 44 with 90 to give the crude product. A second purification was preformed to yield the title compound as a white solid (27 mg, 16.76 µmol, 16.20% yield, 99.60% purity, HOAC). LCMS: Rt= 2.282, m/z 772.3 [M/2+H]⁺.¹H NMR: DMSO- d₆, 400 MHz, d ppm 10.59 (br s, 1 H) 8.80 - 9.30 (m, 4 H) 8.44 - 8.72 (m, 1 H) 8.29 (br d, J=8.50 Hz, 1 H) 7.63 - 7.96 (m, 3 H) 7.34 - 7.54 (m, 4 H) 7.19 - 7.33 (m, 3 H) 6.87 - 7.17 (m, 8 H) 6.71 - 6.84 (m, 2 H) 6.58 - 6.68 (m, 2 H) 5.84 (br s, 1 H) 4.94 - 5.52 (m, 3 H) 4.42 - 4.70 (m, 5 H) 4.17 - 4.35 (m, 3 H) 2.64 - 3.23 (m, 17 H) 1.85 - 2.45 (m, 16 H) 1.82 - 1.83 (m, 1 H) 1.83 (s, 3 H) 1.66 - 1.82 (m, 4 H) 1.15 - 1.66 (m, 14 H) 1.01 (dd, J=16.45, 6.44 Hz, 3 H).

EXAMPLE 66

[0978] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-((R)-3-amino-N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2- fluorophenyl)propanoic acid 94 and 15; followed by Scheme 43 with 90 to yield a white solid (200.76 mg, 126.28 µmol, 15.78% yield, 100% purity, HOAc).¹H NMR: DMSO-d₆, 400 MHz, d 10.67 (br s, 1H), 9.32-8.39 (m, 8H), 8.18 (br s, 1H), 7.99-7.25 (m, 13H), 7.13-6.91 (m, 5H), 6.90-6.78 (m, 3H), 6.73 (s, 1H), 6.68-6.59 (m, 2H), 5.60 - 5.32 (m, 2H), 5.24 - 4.93 (m, 3H), 4.73 - 4.49 (m, 6H), 4.28 - 4.04 (m, 2H), 3.95 - 3.66 (m, 12H), 3.27 - 2.82 (m, 8H), 2.81 - 2.68 (m, 1H), 2.28 - 1.98 (m, 5H), 1.98 - 1.85 (m, 4H), 1.83 (s, 3H), 1.81 - 1.15 (m, 11H), 1.07 - 0.97 (m, 3H), 0.85 (br d, J=6.8 Hz, 6H). LCMS: Rt=2.311, m/z 765.5 [M/2+H]⁺.

EXAMPLE 67

[0979] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-((R)-3-amino-N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 94 and 89; followed by Scheme 43 with 90 to give a white solid (314.27 mg, 194.49 µmol, 24.31% yield, 100% purity, HOAC).¹H NMR: DMSO-d₆, 400 MHz, d10.67 (br s, 1H), 9.30-8.35 (m, 7H), 8.18 (br s, 1H), 7.94-7.55 (m, 3H), 7.48-7.23 (m, 7H), 7.08-6.76 (m, 9H), 6.73 (br s, 1H), 6.62 (br t, J=7.8 Hz, 2H), 5.64-5.24 (m, 2H), 5.01 (br s, 2H), 4.67-4.41 (m, 5H), 4.25-4.03 (m, 1H), 3.96-3.61 (m, 2H), 3.27-2.81 (m, 18H), 2.75 (br dd, J=8.7, 13.6 Hz, 2H), 2.29 - 1.85 (m, 12H), 1.83 (s, 3H), 1.79-1.17 (m, 21H), 1.08-0.99 (m, 3H). LCMS: Rt=2.346, m/z 778.5 [M/2+H]⁺. EXAMPLE 68

[0980] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 94 and 89; (HOBt (3 eq) and DIC (3 eq) were used in place of HBTU and DIEA in this synthesis). This was followed by Scheme 43 with 19 to give the crude product. The crude peptide was purified twice via prep-HPLC to yield a white solid (27.03 mg).¹H NMR: DMSO-d₆, 400 MHz d ppm 10.66 (br s, 1 H) 9.49 (s, 1 H) 8.47 - 9.05 (m, 6 H) 8.41 (br s, 1 H) 7.91 (br s, 1 H) 7.14 - 7.78 (m, 10 H) 6.76 - 7.11 (m, 9 H) 6.71 (br s, 1 H) 6.63 (br t, J=7.83 Hz, 2 H) 5.22 - 5.63 (m, 2 H) 5.03 (br s, 2 H) 4.37 - 4.72 (m, 4 H) 4.20 (br s, 2 H) 3.60 - 3.98 (m, 3 H) 2.92 - 3.25 (m, 18 H) 2.67 - 2.89 (m, 5 H) 1.98 - 2.26 (m, 5 H) 1.88 (br s, 4 H) 1.84 (s, 6 H) 1.05 - 1.76 (m, 21 H). LCMS: Rt=2.330min, m/z 771.5 [M/2+H]⁺.

EXAMPLE 69

[0981] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-23-(2,5-dichlorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2,5- dichlorophenyl)propanoic acid 95 and 89; followed by Scheme 44 with 19 to yield a white solid (30 mg, 17.76 µmol, 18.52% yield, 99.72% purity, 2HOAC). LCMS: Rt=2.343, m/z 782.5 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.73 (br s, 1H), 9.07 - 8.64 (m, 3H), 8.57 - 8.08 (m, 3H), 7.77 (br s, 3H), 7.51 - 7.08 (m, 11H), 7.07 - 6.89 (m, 5H), 6.84 (br s, 1H), 6.77 (br s, 1H), 6.63 (br d, J=7.0 Hz, 3H), 4.89 (br s, 1H), 4.66 - 4.33 (m, 4H), 4.32 - 4.21 (m, 1H), 4.02 (br s, 1H), 3.11 - 2.69 (m, 13H), 2.25 - 1.90 (m, 16H), 1.85 (s, 6H), 1.81 - 1.12 (m, 25H).

EXAMPLE 70

[0982] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(5-chloro-2-fluorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5- chloro-2-fluorophenyl)propanoic acid 96 and 89; followed by Scheme 44 with 19 to yield a white solid (36.93 mg, 22.12 µmol, 14.75% yield, 99.92% purity, 2HOAC). LCMS: Rt=2.345, m/z 774.5[M/2+H]⁺. ¹H NMR: DMSO-d₆, 400MHz, d10.77 (br s, 1H), 9.37 (br s, 1H), 9.12 - 8.15 (m, 4H), 8.12 - 7.08 (m, 16H), 7.07 - 6.82 (m, 6H), 6.75 (br s, 1H), 6.64 (br dd, J=2.4, 8.4 Hz, 3H), 4.88 (br s, 1H), 4.65 - 4.21 (m, 4H), 4.06 (br s, 1H), 3.32 - 2.69 (m, 22H), 2.29 - 1.87 (m, 13H), 1.82 (s, 6H), 1.79 - 1.07 (m, 19H).

EXAMPLE 71

[0983] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-23-(2,3-dichlorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2,3- dichlorophenyl)propanoic acid 97 and 89; followed by Scheme 44 with 19 to give a white solid (45 mg, 26.21 µmol, 27.34% yield, 98.14% purity, 2HOAC). LCMS: Rt=2.345, m/z 782.4[M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.50 (br s, 1H), 9.66 (br s, 1H), 9.13 - 8.68 (m, 6H), 8.27 (br d, J=8.6 Hz, 1H), 8.07 (br s, 1H), 7.90 (br s, 2H), 7.75 (br d, J=7.6 Hz, 1H), 7.54 - 7.39 (m, 1H), 7.36 - 7.13 (m, 6H), 7.10 - 6.97 (m, 4H), 6.88 (br s, 2H), 6.77 (br s, 1H), 6.72 (br s, 1H), 6.64 (t, J=7.6 Hz, 3H), 5.89 - 5.29 (m, 2H), 5.07 (br s, 2H), 4.71 - 4.42 (m, 4H), 4.34 - 4.18 (m, 3H), 3.80 (br s, 1H), 3.15 - 2.73 (m, 19H), 2.27 - 1.92 (m, 12H), 1.87 - 1.83 (m, 6H), 1.72 - 1.14 (m, 19H). EXAMPLE 72

[0984] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-((R)-3-amino- N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 93 and 89; followed by Scheme 46 with 90 to give a white solid (20 mg, 12.16 µmol, 38.31% yield, 99.30% purity, HOAC) as a white solid.¹H NMR: DMSO-d₆, 400 MHz d 10.57 (br s, 1H), 8.92 (br s, 3H), 8.78 - 8.50 (m, 3H), 8.42 (br d, J=16.8 Hz, 2H), 7.78 (br s, 1H), 7.39 (br s, 3H), 7.29 - 7.10 (m, 5H), 7.08 - 6.94 (m, 7H), 6.94 - 6.86 (m, 2H), 6.80 (br s, 1H), 6.62 (br t, J=7.0 Hz, 3H), 5.79 (br s, 1H), 5.28 (br s, 1H), 5.04 (br s, 1H), 4.70 - 4.48 (m, 4H), 4.37 - 4.08 (m, 2H), 3.99 - 3.74 (m, 2H), 3.05 - 2.78 (m, 12H), 2.14 (br s, 9H), 1.88 (s, 3H), 1.76 - 1.17 (m, 29H), 1.16 - 1.02 (m, 6H). LCMS: Rt=2.395, m/z 786.9 [M/2+H]⁺.

[0985] Procedure towards the synthesis of EXAMPLE 72

[0986] Scheme 45

[0987] Steps 1, 2 and 3 are the same as in General Scheme 42.

[0988] Steps 2 and 3 repeated. The coupling of Fmoc-L-glutamic acid 5-tert-butyl ester 10 (3 eq), Na- Fmoc-N(in)-Boc-L-tryptophan 18 (3 eq ), Fmoc-L-glutamic acid 5-tert-butyl ester 10, (3 eq), Fmoc-b- alanine 11 (3 eq), Na-Fmoc-Nw-(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl)-L-arginine 13 (3 eq), (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-2-fluorophenyl)propanoic acid 92 (3 eq), (2S)-2-cyclopentyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)acetic acid 89 (3 eq), Na-Fmoc-S- trityl-L-cysteine 9 (3 eq),O-tert-butyl-L-tyrosine 14 (3 eq) was accomplished by repeating steps 1 and 2 with each amino acid addition. The last amino acid was not de-protected to yield Intermediate peptide L. [0989] Scheme 46

[0990] From protected Intermediate peptide L, the product was synthesized in a manner similar to General Scheme 43. Upon cyclization, the crude mixture was lyophilized. The crude product was then purified by prep-HPLC twice (column: Phenomenex Synergi C18150*25*10µm; mobile phase:

[water(0.075%TFA)-ACN];B%: 9%-39%. (Instrument: Gilson GX-281) for the first purification and [water(0.5%HOAc)-ACN];B%: %-60% for the second purification.

EXAMPLE 73

[0991] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 93 and 89; followed by Scheme 47 with 90 to give a white solid (48 mg, 29.88 µmol, 28.02% yield, 99.94% purity, HOAC). LCMS: Rt=2.308, m/z 772.9 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400 MHz, d ppm 10.61 (br s, 1 H) 8.02 - 9.21 (m, 10 H) 7.11 - 7.95 (m, 12 H) 6.87 - 7.10 (m, 7 H) 6.81 (br s, 1 H) 6.57 - 6.69 (m, 2 H) 4.84 - 6.03 (m, 3 H) 4.41 - 4.81 (m, 3 H) 4.31 (br s, 4 H) 2.64 - 3.16 (m, 16 H) 1.98 - 2.47 (m, 12 H) 1.14 - 1.97 (m, 25 H) 0.89 - 1.10 (m, 4 H). [0992] Procedure towards the synthesis of EXAMPLE 73

[0993] Scheme 47

[0994] From protected Intermediate peptide L (General Scheme 45), the product was synthesized in a manner similar to General Scheme 44. Upon cyclization, the crude mixture was lyophilized. The crude product was then purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10µm; mobile phase: [water(0.075%TFA)-ACN];B%: 8%-38%. (Instrument: Gilson GX-281). Second purification [water(0.5%HOAc)-ACN];B%: 1%-60%.

EXAMPLE 74

[0995] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 93 and 89; followed by Scheme 46 with 19 to give a white solid (16 mg, 9.38 µmol, 29.29% yield, 98.45% purity, 2HOAC).¹H NMR: DMSO-d₆, 400 MHz d 10.61 (br s, 1H), 9.23 - 8.30 (m, 9H), 8.25 - 7.66 (m, 2H), 7.57 - 6.76 (m, 21H), 6.62 (br d, J=6.0 Hz, 3H), 5.78 (br s, 1H), 5.03 (br s, 2H), 4.74 - 4.05 (m, 10H), 4.00 - 3.59 (m, 2H), 2.99 (br s, 14H), 2.29 - 1.97 (m, 10H), 1.87 (s, 6H), 1.78 - 0.98 (m, 21H). LCMS: Rt=2.350, m/z 779.9 [M/2+H]⁺. EXAMPLE 75

[0996] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 94 and 89; followed by Scheme 47 with 19 to give a white solid (35 mg, 22.2 µmol, 21.0% yield, 99.9% purity, HOAC). LCMS: Rt=2.262, m/z 758.1 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d ppm 10.70 (br s, 1 H) 8.12 - 9.49 (m, 7 H) 7.16 - 8.09 (m, 8 H) 6.75 - 7.15 (m, 7 H) 6.64 (br t, J=7.88 Hz, 2 H) 4.95 - 5.91 (m, 5 H) 4.40 - 4.93 (m, 5 H) 2.59 - 4.37 (m, 33 H) 1.87 - 2.47 (m, 10 H) 1.84 (s, 3 H) 0.50 - 1.81 (m, 14 H).

EXAMPLE 76

[0997] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 94 and 89; followed by Scheme 47 with 90 to give a white solid (30 mg, 18.40 µmol, 17.61% yield, 97.46% purity, HOAC). LCMS: Rt=2.299, m/z 765.0 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d ppm 10.68 (br s, 1 H) 8.84 (br s, 3 H) 8.07 - 8.61 (m, 2 H) 7.65 - 7.96 (m, 1 H) 7.22 - 7.55 (m, 6 H) 6.76 - 7.10 (m, 9 H) 6.59 - 6.67 (m, 2 H) 4.84 - 5.59 (m, 2 H) 4.38 - 4.74 (m, 3 H) 4.07 - 4.35 (m, 2 H) 3.86 (br s, 1 H) 2.64 - 3.16 (m, 19 H) 1.88 - 2.43 (m, 17 H) 1.85 (s, 3 H) 1.63 - 1.83 (m, 6 H) 1.17 - 1.62 (m, 16 H) 0.71 - 1.11 (m, 4 H).

EXAMPLE 77

[0998] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclopentyl- 23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 94 and 89; followed by Scheme 46 with 19 to give a white solid (232.31 mg, 144.66 µmol, 18.08% yield, 99.81% purity, HOAC).¹H NMR: DMSO-d₆, 400MHz d10.69 (br s, 1H), 9.19 - 8.15 (m, 7H), 7.77 (br s, 1H), 7.55 - 7.26 (m, 6H), 7.17 - 6.81 (m, 7H), 6.68 - 6.60 (m, 2H), 5.39 - 4.88 (m, 2H), 4.59 (br dd, J=8.4, 16.8 Hz, 5H), 4.23 - 4.10 (m, 2H), 3.91 - 3.69 (m, 13H), 3.19 - 2.88 (m, 12H), 2.88 - 2.69 (m, 4H), 2.29 - 1.98 (m, 7H), 1.89 (br s, 2H), 1.85 (s, 3H), 1.69 (br s, 3H), 1.62 - 1.02 (m, 22H). LCMS: Rt=2.344, m/z 772.3 [M/2+H]⁺. EXAMPLE 78

[0999] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-((R)-3-amino- N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclopentyl- 23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 94 and 89; followed by Scheme 46 with 90 to give a white solid (290.5 mg, 179.67 µmol, 22.46% yield, 100% purity, HOAC).¹H NMR: DMSO-d₆, 400MHz d 10.68 (br s, 1H), 9.20 - 8.09 (m, 8H), 7.77 (br s, 1H), 7.65 - 7.15 (m, 7H), 7.13 - 6.78 (m, 7H), 6.62 (dd, J=5.4, 8.2 Hz, 2H), 5.73 - 4.84 (m, 3H), 4.69 - 4.47 (m, 3H), 4.25 - 4.13 (m, 1H), 3.95 - 3.67 (m, 5H), 3.21 - 2.84 (m, 18H), 2.75 (br dd, J=7.3, 13.2 Hz, 3H), 2.32 - 1.97 (m, 10H), 1.89 (br s, 2H), 1.86 (s, 3H), 1.83 - 1.15 (m, 24H), 1.05 (br dd, J=6.4, 18.2 Hz, 3H). LCMS: Rt=2.375, m/z 779.0 [M/2+H]⁺.

EXAMPLE 79

[1000] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2,3- dichlorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2,3- dichlorophenyl)propanoic acid 97 and 15; followed by Scheme 47 with 19 to give a white solid (24.88 mg, 15.48 µmol, 15.48% yield, 99.52% purity, 1HOAC).¹H NMR: DMSO-d₆, 400 MHz, d 10.53 (br s, 1H), 9.34-7.73 (m, 9H), 7.44 (m, 3H), 7.34-7.13 (m, 4H), 7.12-6.97 (m, 3H), 6.91 (m, 2H), 6.77 (m, 1H), 6.88-6.57 (m, 2H), 5.96-4.93 (m, 2H), 4.74-4.15 (m, 5H), 3.85 (m, 1H), 3.22-2.86 (m, 18H), 2.85-2.68 (m, 5H), 2.28-1.85 (m, 14H), 1.84-1.80 (m, 3H), 1.78-1.48 (m, 7H), 1.46-0.95 (m, 6H), 0.83 (m, 6H). LCMS: Rt=2.339, m/z 770.8 [M/2+H]⁺.

EXAMPLE 80

[1001] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-23-(2,3-dichlorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 97 and 89; followed by Scheme 47 with 90 to give a white solid (13.03 mg, 8.24 µmol, 8.24% yield, 99.84% purity, 1 CH3COOH).¹H NMR: DMSO-d₆, 400 MHz, d 10.43 (br s, 1H), 8.90 (m, 3H), 8.75 (m, 2H), 8.22 (m, 1H), 7.81-7.79 (m, 2H), 7.72 (m, 6H), 7.24-7.19 (m, 2H), 7.17- 7.10 (m, 2H), 7.00-6.98 (m, 2H), 6.58-6.56 (m, 1H), 6.54 (m, 2H), 5.68-5.49 (m, 1H), 5.26-5.24 (m, 2H), 4.54-4.44 (m, 4H), 4.25-4.23 (m, 3H), 3.75 (m, 1H), 3.38-3.36 (m, 6H), 2.95-2.94 (m, 5H), 2.92 (m, 10H), 2.30 (m, 9H), 2.06 (m, 3H), 1.83-1.81 (m, 3H), 1.77-1.75 (m, 4H), 1.47 (m, 7H), 1.36 (m, 5H), 1.28-1.00 (m, 5H), 0.98-0.92 (m, 4H). LCMS: Rt=2.384, m/z 790.8 [M/2+H]⁺. EXAMPLE 81

[1002] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-23-(2,3-dichlorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 97 and 15; followed by Scheme 47 with 19 to give a white solid (39.54 mg, 24.23 µmol, 24.23% yield, 99.63% purity, 1 HOAC).¹H NMR: DMSO-d₆, 400 MHz, d 10.53 (br s, 1H), 9.17-8.39 (m, 7H), 8.34-8.07 (m, 1H), 8.03-7.65 (m, 2H), 7.43 (m, 4H), 7.33-7.14 (m, 5H), 7.12-6.96 (m, 4H), 6.90 (m, 2H), 6.79 (m, 1H), 6.67-6.54 (m, 3H), 5.44-4.85 (m, 2H), 4.74-4.39 (m, 4H), 4.35-4.14 (m, 2H), 3.84 (m, 1H), 3.05-2.87 (m, 13H), 2.84-2.69 (m, 5H), 2.25-2.01 (m, 6H), 1.92 (m, 5H), 1.84 (m, 3H), 1.67 (m, 5H), 1.60-1.09 (m, 18H). LCMS: Rt=2.385, m/z 783.8 [M/2+H]⁺.

EXAMPLE 82

[1003] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclopentyl- 23-(2,3-dichlorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 97 and 89; followed by Scheme 46 with 19 to give a white solid (32.0mg, 19.4 µmol, 19.4% yield, 100% purity, HOAC) as a white solid.¹H NMR: DMSO-d₆, 400 MHz, d ppm 10.56 (br s, 1 H) 8.11 - 9.33 (m, 9 H) 7.17 - 8.08 (m, 15 H) 6.58 - 7.15 (m, 4 H) 4.08 - 5.56 (m, 13 H) 2.71 - 3.06 (m, 11 H) 1.90 - 2.32 (m, 12 H) 1.86 (s, 6 H) 0.96 - 1.77 (m, 30 H). LCMS: Rt=2.449, 797.5 [M/2+H]⁺.

EXAMPLE 83

[1004] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-((R)-3-amino- N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2,3- dichlorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 97 and 15; followed by Scheme 46 with 90 to give a white solid (29.0 mg, 17.7 µmol, 17.7% yield, 100% purity, HOAC).¹H NMR: DMSO-d₆, 400 MHz, d ppm 10.52 (br s, 1 H) 8.37 - 9.11 (m, 7 H) 7.76 - 8.26 (m, 2 H) 7.14 - 7.73 (m, 9 H) 6.71 - 7.12 (m, 6 H) 6.62 (t, J=7.64 Hz, 2 H) 4.92 - 5.88 (m, 3 H) 4.44 - 4.80 (m, 4 H) 4.20 (br dd, J=17.30, 8.38 Hz, 4 H) 3.71 - 4.04 (m, 10 H) 2.69 - 3.11 (m, 14 H) 1.87 - 2.30 (m, 10 H) 1.85 (s, 3 H) 1.21 - 1.79 (m, 13 H) 1.14 (br s, 1 H) 0.97 - 1.12 (m, 1 H) 1.04 (br dd, J=19.81, 6.36). LCMS: Rt=2.426, 791.8 [M/2+H]⁺. EXAMPLE 84

[1005] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2,3- dichlorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 97 and 15; followed by Scheme 46 with 19 to give a white solid (29.8 mg, 18.2 µmol, 18.2% yield, 99.7% purity, HOAC).¹H NMR: DMSO-d₆, 400 MHz, d ppm 10.53 (br s, 1 H) 8.35 - 9.28 (m, 7 H) 7.15 - 8.28 (m, 10 H) 6.86 - 7.14 (m, 4 H) 6.59 - 6.84 (m, 2 H) 4.88 - 5.95 (m, 3 H) 3.70 - 4.78 (m, 18 H) 2.69 - 3.23 (m, 19 H) 1.88 - 2.31 (m, 9 H) 1.85 (s, 3 H) 1.62 - 1.82 (m, 3 H) 0.99 - 1.61 (m, 11 H) 0.72 - 0.92 (m, 6 H). LCMS: Rt=2.402, 783.8 [M/2+H]⁺.

[1006] Procedure for the synthesis of EXAMPLE 85

[1007] Scheme 48

[1008] Intermediate peptide M was synthesized in a manner similar to Intermediate peptide K via General Scheme 42 (Steps 1 through 3).

[1009] Steps 2 and 3 repeated. The coupling of Fmoc-L-glutamic acid 5-tert-butyl ester 10 (3 eq), (S)- 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(tert-butoxycarbonyl)-5-fluoro-1H-indol-3- yl)propanoic acid 18, Na-Fmoc-Nd-trityl-L-glutamine 11 (3 eq), Fmoc-b-alanine 12 (3 eq), Na-Fmoc- Nw-(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl)-L-arginine 13 (3 eq), (S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(3-fluoro-2-fluorophenyl)propanoic acid 92 (3 eq), Fmoc-L-valine 15 (3 eq), Na-Fmoc-S-trityl-L-cysteine 9 (3 eq),O-tert-butyl-L-tyrosine 14 (3 eq) was accomplished by repeating steps 1 and 2 with each amino acid addition. The last amino acid was not de-protected to yeild Intermediate peptide M. [1010] Scheme 49

[1011] From protected Intermediate peptide M (Scheme 48), the cyclized product was synthesized in a manner similar to General Scheme 43. Upon cyclization, the crude mixture was lyophilized. The crude product was then purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10µm; mobile phase: TFA conditions [water(0.075%TFA)-ACN];B%: 8%-38%. (Instrument: Gilson GX-281). This was followed by a second HPLC purification: HOAc conditions [water(0.5% HOAc)-ACN];B%: 1%- 44%.

EXAMPLE 85

[1012] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-10-((5-fluoro-1H- indol-3-yl)methyl)-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 94 and 15. This followed by Scheme 49 with 19 to give a white solid (22.0 mg, 13.2 µmol, 13.2% yield, 99.6% purity, 2HOAC) as a white solid.¹H NMR: DMSO- d₆, 400 MHz, d 10.81 (br s, 1H), 8.35-9.57 (m, 5H), 7.19-8.26 (m, 9H), 6.31-7.12 (m, 12H), 4.80-5.81 (m, 4H), 4.11-4.72 (m, 6H), 3.48-4.04 (m, 12H), 2.61-3.11 (m, 15H), 2.09-2.40 (m, 6H), 1.75-2.06 (m, 12H), 0.94-1.72 (m, 14H), 0.81 (d, J=5.75 Hz, 6H). LCMS: Rt=2.325, m/z 767.5 [M/2+H]⁺.

EXAMPLE 86

[1013] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-10-((5-fluoro-1H-indol-3-yl)methyl)-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 94 and 89; followed by Scheme 50 with 90 to give a white solid (35.9 mg, 21.34 µmol, 21.34% yield, 99.02% purity, 2HOAC). LCMS: Rt=2.298, m/z 773.5 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.80 (br s, 1H), 9.53 (br s, 1H), 9.11 - 8.46 (m, 5H), 8.28 (br d, J=8.8 Hz, 1H), 8.09 - 7.63 (m, 4H), 7.55 - 7.36 (m, 2H), 7.30 (br s, 3H), 7.10 - 6.95 (m, 5H), 6.93 - 6.68 (m, 4H), 6.67 - 6.58 (m, 2H), 5.73 - 4.95 (m, 4H), 4.67 - 4.26 (m, 6H), 3.87 (br s, 1H), 3.26 - 2.74 (m, 22H), 2.28 - 1.88 (m, 13H), 1.82 (s, 6H), 1.78 - 1.12 (m, 17H), 0.99 (dd, J=6.4, 19.2 Hz, 3H).

[1014] Scheme 50

[1015] From protected Intermediate peptide M (General Scheme 48), the product was synthesized in a manner similar to General Scheme 44. Upon cyclization, the crude mixture was lyophilized. The crude product was then purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10µm; mobile phase: TFA conditions [water(0.075%TFA)-ACN;B%: 6%-36%]. (Instrument: Gilson GX-281). This was followed by a second HPLC purification: HOAc conditions [water(0.5%HOAc)-ACN; B%: 1%- 44%].

EXAMPLE 87

[1016] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-10-((5-fluoro-1H-indol-3-yl)methyl)-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 94 and 89; followed by Scheme 50 with 19 to give a white solid (26.69 mg, 16.07 µmol, 16.07% yield, 99.46% purity, 2HOAC). LCMS: Rt=2.278, m/z 766.5 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.80 (br s, 1H), 9.62 (br s, 1H), 9.04 - 8.64 (m, 4H), 8.51 - 8.16 (m, 1H), 8.11 - 7.68 (m, 5H), 7.52 - 7.19 (m, 3H), 7.12 - 6.96 (m, 5H), 6.95 - 6.68 (m, 5H), 6.63 (br t, J=7.4 Hz, 2H), 5.75 - 4.93 (m, 5H), 4.73 - 4.23 (m, 6H), 4.00 - 3.76 (m, 1H), 3.10 - 2.93 (m, 11H), 2.89 (s, 6H), 2.80 - 2.74 (m, 4H), 2.73 (s, 4H), 2.27 - 1.88 (m, 12H), 1.77 (s, 6H), 1.73 - 1.22 (m, 16H). EXAMPLE 88

[1017] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- chlorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 93 and 15; followed by Scheme 49 with 19. The crude product was purified by prep-HPLC (A: 0.01M NH₄HCO₃ in H₂O, B: ACN) and then by prep- HPLC, HOAc conditions (A: 0.5% HOAC in H₂O, B: ACN) to give a white solid (14.0 mg, 8.34 µmol, 8.34% yield, 99.4% purity, 2HOAC) as a white solid.¹H NMR: DMSO-d₆, 400MHz, d 10.72 (br s, 1H), 9.56 (br s, 1H), 8.38-9.11 (m, 7H), 7.61-8.25 (m, 6H), 7.14-7.48 (m, 7H), 6.55-7.09 (m, 10H), 4.89-6.10 (m, 7H), 4.36-4.76 (m, 7H), 3.63-4.02 (m, 2H), 2.69-3.13 (m, 16H), 2.15 (d, J=5.75 Hz, 4H), 1.73-2.06 (m, 14H), 1.21-1.73 (m, 13H), 0.81 (d, J=5.87 Hz, 6H). LCMS: Rt=2.365, m/z 775.4 [M/2+H]⁺.

EXAMPLE 89

[1018] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-23-benzyl-4-carbamoyl-10-((5- fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 82 and 15; followed by Scheme 49 with 19 to give a white solid (17.0 mg, 10.3 µmol, 10.3% yield, 99.5% purity, 2HOAC).¹H NMR: DMSO-d₆, 400MHz, d 10.90 (br s, 1H), 8.10- 9.50 (m, 6H), 7.25-8.08 (m, 9H), 6.51-7.19 (m, 11H), 5.36-6.41 (m, 4H), 4.39-5.32 (m, 6H), 4.05-4.33 (m, 2H), 3.65-4.02 (m, 2H), 2.54-3.34 (m, 20H), 1.86-2.46 (m, 13H), 1.83 (s, 9H), 1.01-1.60 (m, 10H), 0.82 (d, J=6.36 Hz, 6H). LCMS: Rt=2.296, m/z 758.3 [M/2+H]⁺.

EXAMPLE 90

[1019] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-10-((5-fluoro-1H- indol-3-yl)methyl)-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 94 and 15. This was followed by Scheme 52 with 19 (HOBT and DIC was used in place of HATU and DIEA) to give a white solid (21.0 mg, 12.6 µmol, 12.6% yield, 99.5% purity, 2HOAC).¹H NMR: DMSO-d₆, 400MHz, d 10.75-10.86 (m, 1H), 8.34-9.10 (m, 9H), 7.18-8.27 (m, 6H), 6.94-7.17 (m, 6H), 6.56-6.93 (m, 6H), 4.07-6.02 (m, 8H), 3.75-3.98 (m, 7 H), 2.55-3.13 (m, 22H), 1.97-2.42 (m, 9H), 1.86 (s, 10H), 1.02-1.62 (m, 11H), 0.45-1.00 (m, 6H). LCMS: Rt=2.347, m/z 767.8 [M/2+H]⁺.

[1020] Procedure for the synthesis of EXAMPLE 90 [1021] Scheme 51

[1022] Steps 1, 2 and 3 are the same as General Scheme 48.

[1023] Steps 2 and 3 are repeated with Fmoc-L-glutamic acid 5-tert-butyl ester 10 (3 eq), in place of Na-Fmoc-Nd-trityl-L-glutamine 11 (fouth amino acid added). The last amino acid was not de-protected to yield Intermediate peptide N.

[1024] Scheme 52

[1025] From protected Intermediate peptide N (General Scheme 51), the product was synthesized in a manner similar to General Scheme 43. Upon cyclization, the crude mixture was lyophilized. The crude product was then purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10µm; mobile phase: TFA conditions [water(0.075%TFA)-ACN];B%: 8%-38%. This was followed by a second HPLC purification: HOAc conditions [water(0.5%HOAc)-ACN];B%: 1%-44%. (Instrument: Gilson GX-281).

EXAMPLE 91

[1026] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclopentyl-10-((5-fluoro-1H-indol-3- yl)methyl)-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 94 and 89; followed by Scheme 53 with 90 to give a white solid (23.38 mg, 14.42 µmol, 14.42% yield, 99.13% purity, HOAC).¹H NMR: DMSO-d₆, 400MHz, d 10.80 (br s, 1H), 9.07 - 8.13 (m, 7H), 7.87 (br s, 2H), 7.66 - 7.18 (m, 6H), 7.15 - 6.96 (m, 5H), 6.88 (br d, J=10.6 Hz, 2H), 6.75 (br s, 1H), 6.68 - 6.58 (m, 2H), 5.68 - 4.91 (m, 4H), 4.75 - 4.26 (m, 7H), 3.89 (br s, 5H), 3.15 - 2.68 (m, 20H), 2.31 - 1.91 (m, 10H), 1.88 (s, 3H), 1.86 - 1.60 (m, 6H), 1.59 - 1.13 (m, 12H), 1.09 - 0.94 (m, 3H). LCMS: Rt=2.329, m/z 774.0 [M/2+H]⁺.

[1027] Procedure for the synthesis of EXAMPLE 91

[1028] Scheme 53

[1029] From protected Intermediate peptide N (General Scheme 51), the product was synthesized in a manner similar to General Scheme 44. Upon cyclization, the crude mixture was lyophilized. The crude product was then purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10µm; mobile phase: TFA conditions[water(0.225%TFA)-ACN];B%: 6%-36% for the first purificationa and then HOAc conditions [water(0.075%HOAc)-ACN];B%: 1%-44% ; (Instrument: Gilson GX-281).

EXAMPLE 92

[1030] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclopentyl-10-((5-fluoro-1H-indol-3- yl)methyl)-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 94 and 89; followed by Scheme 53 with 90 to give a white solid (19.87 mg, 12.45 µmol, 12.45% yield, 99.82% purity, HOAC). LCMS: Rt=2.298, m/z 766.9 [M/2+H]⁺. ¹H NMR: DMSO-d₆, 400MHz, d10.81 (br s, 1H), 8.83 (br s, 4H), 8.58 - 7.72 (m, 5H), 7.63 - 7.21 (m, 4H), 7.16 - 6.97 (m, 6H), 6.97 - 6.96 (m, 1H), 6.88 (br s, 2H), 6.75 (br s, 1H), 6.68 - 6.57 (m, 2H), 5.87 - 4.86 (m, 5H), 4.74 - 4.34 (m, 6H), 4.32 - 4.22 (m, 1H), 3.90 (br s, 3H), 3.12 - 2.86 (m, 17H), 2.85 - 2.69 (m, 6H), 2.09 (br s, 9H), 1.86 (s, 3H), 1.81 - 1.14 (m, 19H).

EXAMPLE 93

[1031] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-10-((5-fluoro-1H-indol-3-yl)methyl)-23- (2-fluorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 94 and 15; followed by Scheme 53 with 19 to give a white solid (28.58 mg, 18.01 µmol, 18.01% yield, 98.71% purity, HOAC). LCMS: Rt=2.269, m/z 753.8 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d10.80 (br s, 1H), 9.08 - 8.09 (m, 7H), 7.95 (s, 4H), 7.68 - 7.18 (m, 4H), 7.11 - 6.95 (m, 5H), 6.87 (br s, 2H), 6.75 (br s, 1H), 6.63 (t, J=7.8 Hz, 2H), 4.73 - 4.34 (m, 7H), 4.33 - 4.23 (m, 1H), 3.91 (br s, 2H), 3.12 - 2.95 (m, 12H), 2.89 (s, 5H), 2.86 - 2.75 (m, 5H), 2.73 (s, 5H), 2.07 (br s, 9H), 1.86 (s, 3H), 1.84 - 1.18 (m, 11H), 0.80 (br s, 6H).

EXAMPLE 94

[1032] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-23-benzyl-4-carbamoyl-10-((5- fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids (((9H-fluoren-9-yl)methoxy)carbonyl)-L-phenylalanine and 15; followed by Scheme 52 with 19. The crude product was lyphilized and purified by prep-HPLC to give a white solid (22.0 mg, 13.9 µmol, 13.9% yield, 99.7% purity, HOAC). LCMS: Rt=2.313, m/z 758.9

[M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.90 (br s, 1H), 7.67-9.18 (m, 8H), 6.88-7.51 (m, 15H), 6.55-6.81 (m, 3H), 4.90-6.34 (m, 8H), 3.71-4.82 (m, 17H), 2.71-3.09 (m, 15H), 1.94-2.30 (m, 8H), 1.85 (s, 4H), 1.07-1.68 (m, 13H), 0.82 (br s, 6H).

EXAMPLE 95

[1033] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclopentyl-23-(2,3-dichlorobenzyl)- 10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 97 and 89; followed by Scheme 53 with 19 to give a white solid (12.6 mg, 7.67 µmol, 7.67% yield, 100% purity, HOAC). LCMS: Rt=2.393, m/z 792.78 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d ppm 10.66 (br s, 1 H) 7.67 - 9.31 (m, 11 H) 7.17 - 7.58 (m, 6 H) 6.81 - 7.14 (m, 6 H) 6.59 - 6.74 (m, 4 H) 5.07 (br s, 1 H) 4.19 - 4.81 (m, 9 H) 3.87 (br s, 1 H) 2.75 - 3.07 (m, 16 H) 1.91 - 2.27 (m, 13 H) 1.87 (s, 3 H) 1.07 - 1.80 (m, 22 H). EXAMPLE 96

[1034] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclopentyl-23-(2,3-dichlorobenzyl)- 10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 97 and 89; followed by Scheme 53 with 90 to yield a white solid (20.9 mg, 12.6 µmol, 12.6% yield, 100% purity, HOAC). LCMS: Rt=2.416, m/z 799.5 [M/2+H]⁺.¹H NMR:

DMSO-d₆, 400MHz, d ppm 10.66 (br s, 1 H) 8.84 (br s, 5 H) 7.75 - 8.38 (m, 2 H) 7.17 - 7.60 (m, 7 H) 6.85 - 7.12 (m, 6 H) 6.59 - 6.73 (m, 4 H) 4.21 - 5.51 (m, 8 H) 2.70 - 3.14 (m, 19 H) 1.88 - 2.30 (m, 15 H) 1.86 (s, 3 H) 1.15 - 1.82 (m, 22 H) 0.92 - 1.11 (m, 3 H).

EXAMPLE 97

[1035] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- chlorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13- diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 93 and 15; followed by Scheme 52 with 19 to yeild a white solid (19.0 mg, 11.3 µmol, 11.3% yield, 99.5% purity, 2HOAC). LCMS: Rt=2.359, m/z 776.1 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.73 (br s, 1H), 7.99-9.20 (m, 9H), 7.12-7.91 (m, 9H), 6.55-7.08 (m, 8H), 4.92-6.13 (m, 4H), 3.60-4.81 (m, 13H), 2.55-3.20 (m, 22H), 1.73-2.35 (m, 17H), 1.01-1.69 (m, 12H), 0.82 (br s, 6H).

EXAMPLE 98

[1036] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was was prepared according to Scheme 42 with amino acids Fmoc-L-2-cyanophenylalanine 82 and 89; followed by Scheme 44 utilizing 19. The crude product was purified twice by prep-HPCL. First by the TFA method and second by: HCl method [A: H₂O (0.05% HCl in H₂O); B: ACN 0-33%] to give a white solid (32 mg, 20.41 µmol, 25.90% yield, 99.31% purity, HCl). LCMS: Rt=2.221, m/z 761.0 [M/2+H]⁺.¹H NMR: MeOD-d₄, 400MHz, d 7.75 - 7.85 (m, 1 H) 7.48 (br d, J=7.70 Hz, 1 H) 7.25 - 7.42 (m, 4 H) 6.93 - 7.22 (m, 5 H) 6.61 - 6.79 (m, 2 H) 5.35 - 5.73 (m, 3 H) 5.05 (br s, 1 H) 4.27 - 4.73 (m, 3 H) 3.86 - 4.24 (m, 2 H) 3.45 - 3.66 (m, 3 H) 2.81 - 3.25 (m, 14 H) 2.69 - 2.80 (m, 1 H) 1.88 - 2.64 (m, 17 H) 1.24 - 1.86 (m, 13 H). EXAMPLE 99A

[1037] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-((S)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-23-(2-cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was was prepared according to Scheme 42 with amino acids Fmoc-L-2-cyanophenylalanine 82 and 89; followed by Scheme 44 and (S)-N-Boc-3-aminobutyric acid. The product was purified twice with prep-HPLC. The first purification was by the TFA method followed by a second HPLC by the HCl method; A: H₂O [(0.05% HCl in H₂O); B: ACN 0-35%] to give a white solid (32.1 mg, 19.62 µmol, 23.20% yield, 96.05% purity, HCl). LCMS: Rt=2.237, m/z 768.0 [M/2+H]⁺.¹H NMR: MeOD-d₄, 400MHz; d 7.80 (br d, J=9.17 Hz, 1 H) 7.49 (d, J=7.70 Hz, 1 H) 7.23 - 7.40 (m, 4 H) 6.93 - 7.20 (m, 5 H) 6.67 - 6.78 (m, 2 H) 5.37 - 5.74 (m, 3 H) 5.05 (br d, J=5.26 Hz, 1 H) 4.61 - 4.73 (m, 2 H) 4.46 (br d, J=6.12 Hz, 1 H) 4.00 - 4.27 (m, 2 H) 3.43 - 3.76 (m, 4 H) 2.85 - 3.23 (m, 11 H) 2.57 - 2.80 (m, 2 H) 1.87 - 2.51 (m, 17 H) 1.12 - 1.76 (m, 16 H).

EXAMPLE 99B

[1038] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-23-(2-cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was was prepared according to Scheme 42 with amino acids Fmoc-L-2-cyanophenylalanine 82 and 89; followed by Scheme 44 utilizing 90. The resulting compound was purified twice by prep-HPLC. First by the TFA method, followed by the HOAc method, to give a white solid (216.3 mg, 130.29 µmol, 16.02% Yield, 99.68% Purity, 2HOAC). LCMS: Rt=2.233, m/z 768.0 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d ppm 9.49 (br s, 1 H) 8.66 - 8.71 (m, 1 H) 8.47 - 9.18 (m, 4 H) 8.30 (br d, J=8.68 Hz, 1 H) 8.05 (br s, 1 H) 7.76 - 7.91 (m, 2 H) 7.70 (br d, J=7.70 Hz, 1 H) 7.16 - 7.63 (m, 9 H) 6.69 - 7.10 (m, 5 H) 6.51 - 6.69 (m, 2 H) 5.41 (br s, 2 H) 5.11 (br s, 2 H) 4.44 - 4.83 (m, 5 H) 4.07 - 4.38 (m, 2 H) 3.75 (br s, 1 H) 2.73 - 3.42 (m, 26 H) 2.59 - 2.70 (m, 1 H) 1.88 - 2.45 (m, 12 H) 1.84 (s, 6 H) 1.79 - 1.80 (m, 1 H) 0.88 - 1.13 (m, 3 H) 0.78 - 1.78 (m, 6 H).

EXAMPLE 100

[1039] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((R)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with 56 substitued for 12 and amino acids 82 and 89; followed by Scheme 44 utilizing 19. The crude product was purified twice by prep-HPCL. First by the TFA mehtod and second by the HCl method: [A: H₂O (0.05% HCl in H₂O); B: ACN 0-33%] to give a white solid (15.0 mg, 10.2 µmol, 22.65% yield, 99.73% purity, HCl). LCMS: Rt=2.415, m/z 718.3 [M/2+H]⁺.¹H NMR: MeOD-d₄, 400MHz, d 7.54 - 7.49 (m, 1H), 7.38 (br d, J=7.2 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.21 (s, 1H), 7.18 - 7.02 (m, 5H), 6.76 - 6.68 (m, 2H), 5.82 - 5.41 (m, 3H), 5.19 - 5.06 (m, 1H), 4.73 (br d, J=7.2 Hz, 3H), 4.66 - 4.58 (m, 1H), 4.46 - 4.39 (m, 1H), 4.34 - 4.23 (m, 1H), 4.22 - 4.12 (m, 1H), 3.70 - 3.45 (m, 4H), 3.22 - 2.96 (m, 11H), 2.79 - 2.70 (m, 1H), 2.57 (br s, 1H), 2.43 - 2.25 (m, 5H), 2.22 - 2.02 (m, 3H), 2.02 - 1.84 (m, 4H), 1.80 - 1.38 (m, 14H), 1.36 - 1.00 (m, 5H). EXAMPLE 101A

3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((S)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with 56 substitued for 12 and amino acids 82 and 89; followed by Scheme 44 utilizing (3S)-3-(tert- butoxycarbonylamino)butanoic acid. The crude product was purified by prep-HPLC (TFA condition: [A:0.075% TFA in H₂O], B:CH₃CN, 3-33%) and then by (HCl condition: [A:0.05% HCl in H₂O], B:CH₃CN, 0-60%) to give a white solid (18.0 mg, 12.1 µmol, 19.45% yield, 99.55% purity, HCl).

LCMS: Rt=2.432, m/z 724.9 [M/2+H]⁺.¹H NMR: MeOD-d₄, 400MHz; d 7.54 - 7.49 (m, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.21 (s, 1H), 7.17 - 7.01 (m, 5H), 6.74 - 6.68 (m, 2H), 5.76 - 5.42 (m, 3H), 5.17 - 5.07 (m, 1H), 4.81 - 4.63 (m, 3H), 4.60 (t, J=7.2 Hz, 1H), 4.45 - 4.40 (m, 1H), 4.27 (dt, J=5.0, 9.2 Hz, 1H), 4.18 (br s, 1H), 3.71 - 3.46 (m, 4H), 3.19 - 2.96 (m, 11H), 2.79 - 2.61 (m, 1H), 2.56 (br s, 1H), 2.44 - 2.23 (m, 5H), 2.22 - 2.03 (m, 3H), 2.01 - 1.87 (m, 3H), 1.84 - 1.38 (m, 14H), 1.38 - 1.10 (m, 8H).

EXAMPLE 101B

[1040] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with the 56 substitued for 12 and amino acids 82 and 89; followed by Scheme 44 utilizing (3R)-3-(tert- butoxycarbonylamino)butanoic acid. The crude product was purified by prep-HPLC (TFA condition: [A:0.075% TFA in H₂O], B:ACN, 3-33%) and then by (HCl condition: [A:0.05% HCl in H₂O], B:ACN, 0-60%) to give a white solid (15.0 mg, 10.1 µmol, 18.32% yield, 100% purity, HCl). LCMS: Rt=2.432, m/z 725.0 [M/2+H]⁺.¹H NMR: MeOD-d₄, 400MHz; d 7.54 - 7.49 (m, 1H), 7.38 (br d, J=7.6 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.21 (s, 1H), 7.18 - 7.02 (m, 5H), 6.75 - 6.68 (m, 2H), 5.80 - 5.41 (m, 3H), 5.18 - 5.07 (m, 1H), 4.76 - 4.70 (m, 3H), 4.65 - 4.61 (m, 1H), 4.44 (dd, J=3.6, 8.4 Hz, 1H), 4.27 (br dd, J=4.6, 8.9 Hz, 1H), 4.19 (br dd, J=4.3, 10.8 Hz, 1H), 3.64 - 3.44 (m, 4H), 3.16 - 2.96 (m, 11H), 2.75 (dd, J=4.0, 17.3 Hz, 1H), 2.56 (br dd, J=9.1, 17.3 Hz, 2H), 2.45 - 2.25 (m, 6H), 2.17 - 2.05 (m, 3H), 1.99 - 1.90 (m, 3H), 1.79 - 1.38 (m, 15H), 1.34 (d, J=6.7 Hz, 3H), 1.20 (br d, J=6.7 Hz, 2H).

EXAMPLE 102

[1041] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-((S)-3-amino-N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 82 and 89; followed by Scheme 43 with (3S)-3-(tert- butoxycarbonylamino)butanoic acid to yield the crude procude. Purification was by prep-HPLC; first by the TFA method followed by HOAc method to yield a white solid (30 mg, 17.59 µmol, 34.41% yield, 98.69% purity, 2HOAC). LCMS: Rt=2.320, m/z 782.0 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d10.56 (br s, 1H), 9.77 (br s, 1H), 9.10 - 8.78 (m, 5H), 8.11 (br s, 1H), 7.87 - 7.68 (m, 3H), 7.53 - 6.97 (m, 12H), 6.88 (br s, 2H), 6.81 (br s, 1H), 6.71 (br s, 1H), 6.62 (t, J=7.8 Hz, 2H), 5.54 - 5.27 (m, 3H), 5.11 (br s, 2H), 4.67 - 4.53 (m, 4H), 4.22 (br s, 1H), 3.83 - 3.68 (m, 2H), 3.18 (br d, J=13.2 Hz, 5H), 3.09 - 2.71 (m, 5H), 2.25 - 1.93 (m, 19H), 1.89 (br s, 3H), 1.86 (s, 6H), 1.66 - 1.29 (m, 23H), 1.04 - 0.91 (m, 3H).

EXAMPLE 103

[1042] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 82 and 89; followed by Scheme 47 with 19 to yield a white solid (16.5 mg, 10.26 µmol, 15.32% yield, 98.31% purity, HOAC). LCMS: Rt=2.245, m/z 761.5 [M/2+H]⁺.¹H NMR: MeOD-d₄, 400MHz, d ppm 7.45 (d, J=7.34 Hz, 1 H) 7.20 - 7.39 (m, 4 H) 6.93 - 7.17 (m, 5 H) 6.67 - 6.77 (m, 2 H) 5.78 (s, 1 H) 5.49 (br s, 2 H) 5.10 (br s, 2 H) 4.37 - 4.67 (m, 5 H) 4.04 - 4.35 (m, 1 H) 3.69 (d, J=1.59 Hz, 3 H) 2.54 - 3.06 (m, 11 H) 1.98 - 2.52 (m, 13 H) 1.92 (s, 6 H) 0.58 - 1.85 (m, 20 H).

EXAMPLE 104

[1043] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((S)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 82 and 89; followed by Scheme 47 with (3S)-3-(tert- butoxycarbonylamino)butanoic acid to yield the crude product. Purification was accomplished by prep- HPLC; first by the TFA method followed by the HOAc method to yield a white solid (10 mg, 6.20 µmol, 9.26% yield, 98.97% purity, HOAC). LCMS: Rt=2.261, m/z 768.4 [M/2+H]⁺.¹H NMR: MeOD-d₄, 400MHz, d ppm 7.46 (br d, J=7.09 Hz, 1 H) 7.22 - 7.39 (m, 4 H) 6.92 - 7.15 (m, 5 H) 6.65 - 6.78 (m, 2 H) 5.73 (br s, 1 H) 5.46 (br s, 2 H) 5.09 (br s, 1 H) 4.24 - 4.76 (m, 6 H) 4.13 (br s, 2 H) 3.47 - 3.84 (m, 5 H) 2.85 - 3.15 (m, 6 H) 2.53 - 2.83 (m, 2 H) 1.96 - 2.51 (m, 14 H) 1.94 (s, 3 H) 0.70 - 1.89 (m, 21 H).

EXAMPLE 105

[1044] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 82 and 89; followed by Scheme 47 with (3R)-3-(tert- butoxycarbonylamino)butanoic acid. The crude product was purified twice by prep-HPLC; first by the TFA method followed by the HOAc methos to yield a white solid (15 mg, 9.36 µmol, 13.97% yield, 99.55% purity, HOAC). LCMS: Rt=2.268, m/z 768.3 [M/2+H]⁺.¹H NMR: DMSO-d_6, 400MHz, d ppm 10.56 (br s, 1 H) 8.21 - 9.17 (m, 7 H) 7.66 - 7.93 (m, 1 H) 7.11 - 7.58 (m, 11 H) 6.96 - 7.11 (m, 3 H) 6.71 - 6.95 (m, 2 H) 6.58 - 6.68 (m, 2 H) 5.04 - 5.56 (m, 2 H) 4.41 - 4.78 (m, 3 H) 4.14 - 4.34 (m, 2 H) 3.78 (br s, 1 H) 3.11 - 3.22 (m, 5 H) 2.81 - 3.04 (m, 8 H) 2.03 - 2.28 (m, 15 H) 1.89 (s, 3 H) 1.82 (br s, 5 H) 1.20 - 1.69 (m, 21 H) 0.91 - 1.03 (m, 5 H). EXAMPLE 106

[1045] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 82 and 89; followed by Scheme 46 with 19. The crude product was purified twice by prep-HPLC; first by the TFA method followed by the HOAc method to yield a white solid (28.0 mg, 16.61 µmol, 33.05% yield, 99.08% purity, 2 HOAC). LCMS: Rt=2.234, m/z 775.3 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d10.57 (br s, 1H), 9.21 - 8.39 (m, 8H), 7.75 (br s, 1H), 7.58 - 7.13 (m, 9H), 7.09 - 6.95 (m, 3H), 6.91 (br s, 3H), 6.68 - 6.58 (m, 2H), 5.65 - 4.88 (m, 3H), 4.74 - 4.47 (m, 4H), 4.19 (br dd, J=9.2, 17.4 Hz, 2H), 3.93 - 3.71 (m, 4H), 3.67 (br d, J=16.6 Hz, 2H), 2.99 (br d, J=14.4 Hz, 12H), 2.82 - 2.71 (m, 9H), 2.26 (br s, 5H), 2.12 (br s, 5H), 1.94 - 1.90 (m, 2H), 1.87 (s, 6H), 1.75 - 0.96 (m, 21H).

[1046] Procedure for the synthesis of Compound 99

[1047] Scheme 54

[1048] Step 1. To a solution of (S)-proline tert-butyl ester hydrochloride (550 mg, 2.8 mmol) in dry CH₂Cl₂ (30 mL), sulfonyl chloride (777 mg, 2.8 mmol), triethylamine (1.2 mL, 8.4 mmol) and catalytic DMAP (10mg) were consecutively added at 0 °C. The mixture was stirred at room temperature overnight and then washed with water (2 x 20 mL). The organic layer was separated, dried over Na₂SO₄ and concentrated. Purification by column chromatography on silica gel (EtOAc: Hex 1:1) afforded 99A as a light yellow oil (850 mg, 74%).¹H NMR (400 MHz, CDCl₃) ^ 1.44 (s, 9H), 1.91 (m, 3H), 2.22 (m, 1H), 3.22 (m, 2H), 3.34 (m, 1H), 3.48 (m, 1H), 3.57 (m, 1H), 3.74 (m, 1H), 4.40 (m, 1H), 5.10 (m, 2H), 6.19 (br. s, 1H), 7.32 (m, 5H).

[1049] Step 2. To 850 mg (2.1 mmol) of 99A was dissolved in 70 ml of THF and 85mg (10 % mass) of Pd/C (10%) was added. The mixture was purged with hydrogen at intense stirring for 18h. Then catalyst was filtered off and solvent was evaporated under reduced pressure. The residue was dissolved in Et₂O and solution of dioxane/HCl was added. The obtained precipitate was filtered, washed with Et₂O, dried to give 99B as a white solid (520mg, 78%).¹H NMR (400 MHz, DMSO-d₆) ^ 1.42 (s, 9H), 1.66 (m, 0.7H, rot), 1.90 (m, 2.6H, rot), 2.26 (m, 0.7H, rot), 2.95 (m, 0.7H, rot), 3.16 (m, 1H), 3.40 (m, 2.6H, rot), 3.53 (m, 1H), 3.63 (m, 0.6H, rot), 4.24 (m, 0.7H, rot), 8.20 - 8.18 (m, 3Н).

[1050] Step 3. Intermediate 99B 520mg (1.65 mmol) of was heated to 75 °C in the mixture of dioxane (30ml) and 10N aqueous HCl (5ml) for 6 h. Then cooled and volatiles were removed at reduced pressure. Obtained residue was coevaporated with 10 ml of toluene twice, stirred for 45 min with 50ml of Et₂O and filtered to give 410mg (96% yield) of intermediate 99C as a white powder.¹H NMR (400 MHz, DMSO- d₆) ^ 1.46 (m, 0.4H, rot), 1.67 (m, 0.6H, rot), 1.93 (m, 2.3H, rot), 2.27 (m, 0.7H, rot), 2.95 (m, 0.6H, rot), 3.17 (m, 1H), 3.27 (m, 0.7H, rot), 3.4 (m, 2.4H, rot), 3.66 (m, 0.7H,rot), 4.32 (m, 1H), 8.23,9.22 (m, 3H), (H of COOH group was not detected).

[1051] Step 4. To a suspension of 99C (410mg, 1.58 mmol) and di-tert-butyl dicarbonate (800 mg, 3.67 mmol) in CH₂Cl₂ (50 mL) was added triethylamine (2.5 mL, 19.3 mmol) slowly at 0 °C. The reaction mixture was then allowed to warm to room temperature and stirred overnight. Then diluted with CH₂Cl₂ (50 ml), washed with water (30 ml) and brine (30 ml), dried over Na₂SO₄, filtrated and concentrated to yield 370mg of crude product as a slightly yellow oil (the mixture of two rotomers). Purification by HPLC afforded 109mg of 99 as a white solid.¹H NMR (400 MHz, DMSO-d₆) d 1.38 (s, 9H), 1.86 (m, 3H), 2.2 (m, 11.9 Hz, 1H), 3.24 (m, 9.2 Hz, 6H), 4.24 (d, 1H), 6.95 (t, 1H), 12.66 (s, 1H).

EXAMPLE 107

[1052] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-((2-aminoethyl)sulfonyl)pyrrolidine-2-carboxamido)-3-(4- hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(4- hydroxybenzyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan- 7-yl)propanoic acid was synthesized using General Scheme 14 with the amino acids 9, 10, 18, 11, 12, 13, 14, 89, and 99 (substituted at as the last amino acid added). All reagents, equivalents and steps are the same as Scheme 14. The crude peptide was purified by prep-HPLC: (TFA conditions; Instrument: Agilent Infinity 1260; Column: XBridge Peptide BEH C18300A 5 µM, 19x150mm) to yield a white solid (31.3 mg, 17.6% yield, 2TFA). LCMS: (m/z ES-API) 1548.2 [M+2]⁺.

Procedure for the synthesis of Compound 100

[1053] Scheme 55

[1054] Step 1. To a stirred solution of aminoether (1.25 g, 1.1 eq) and Et₃N (1.5 mL, 1.5 eq) in CH₂Cl₂ (25 mL), sulfochloride (2 g in 10 mL CH₂Cl₂) was added dropwise at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into 0.1 N HCl and extracted with CH₂Cl₂. The combined organic layers were washed with aq NaHCO₃, brine, and dried over Na₂SO₄, filtered and concentrated to obtain 2.55 g of intermediate 100A.¹H NMR (500 MHz, CDCl₃) d 7.41-7.33 (m, 5H), 5.80 (br s, 1H), 5.06 (s, 2H), 4.01 (s 23), 3.77– 3.65 (m, 5H), 3.42– 3.36 (m, 2H), 1.96– 1.85 (m, 2H), 1.73– 1.30 (m, 6H). [1055] Step 2. Intermediate 100A (2.35 g), Boc₂O (1.55 g, 1.2 eq) and Pd/C (250 mg, 10% on activated carbon) was suspended in 30 mL of MeOH. The resulting suspension was bubbled with H₂ for 6 h (monitored by TLC). After the reaction was completed, Pd/C was filtered and MeOH was evaporated. The residue was subjected to column chromatography to give 1.6 g of 100B.¹H NMR (400 MHz, CDCl₃) d 5.48 (s, 1H), 4.10– 3.94 (m, 3H), 3.74 (s, 3H), 3.61 (br s, 2H), 3.40– 3.30 (m, 2H), 1.92 (s, 2H), 1.71– 1.50 (m, 5H), 1.48– 1.35 (m, 10H).

[1056] Step 3. Intermediate 100B (1.5 g) was dissolved in 15 mL of THF and a solution of LiOH (345 mg, 2 eq) in 45 mL of H₂O was added. The resulting mixture was stirred overnight and diluted with water, acidified with 10% aq NaHSO₄ and extracted with EtOAc (2x50 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated to obtain 100 (780 mg).¹H NMR (400 MHz, CDCl₃) d 6.92 (br s, 1H), 5.57 (br s, 1H), 4.22– 3.89 (m, 3H), 3.76 - 3.56 (d, J = 32.8 Hz, 2H), 3.40 (br s, 2H), 1.92 (br s, 2H), 1.73– 1.34 (m, 14H).

EXAMPLE 108

[1057] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-((2-amino-N-cyclopentylethyl)sulfonamido)acetamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was synthesized according to General Scheme 14 with the following amino acid sequence: 9, 10, 18, 11, 12, 13, 14, 89, and 100 (substituted as the last amino acid added). All the steps, equivalents, and reagents remain the same. The crude peptide was purified by prep-HPLC: (TFA conditions; Instrument: Agilent Infinity 1260; Column: XBridge Peptide BEH C18300A 5 µM, 19x150mm) to yield a white solid (35.2 mg, 19.4% yield, 2TFA). LCMS: (m/z ES-API) 1576.6 [M+2]⁺. EXAMPLE 109

[1058] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20-(3- guanidinopropyl)-26-isopropyl-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 5 with amino acids 88 substitued for 14; followed by cyclization and cleavage from resin following Scheme 16 to yield the crude product. The crude peptide was purified by prep-HPLC: (TFA conditions; Instrument: Agilent Infinity 1260; Column: XBridge Peptide BEH C18300A 5 µM, 2.1x50mm) to yield a white solid (14.1 mg, 8.1% yield, 2TFA)

EXAMPLE 110

[1059] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-23-benzyl-4-carbamoyl-20-(3- guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 5 with amino acids Fmoc-L-phenylalanine in place of 14; followed by Scheme 16. The crude peptide was purified by prep-HPLC: (TFA conditions; Instrument: Agilent Infinity 1260; Column: XBridge Peptide BEH C18 300A 5 µM, 2.1x50mm) to yield a white solid (46.2 mg, 26.7% yield, 2TFA).

EXAMPLE 111

[1060] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20-(3- guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 5 with 10 substitued for 14; followed by Scheme 16. The crude peptide was purified by prep- HPLC: (TFA conditions; Instrument: Agilent Infinity 1260; column: XBridge Peptide BEH C18300A 5 µM, 2.1x50mm) to yield a white solid (26.3 mg, 15.1% yield, 2TFA).

EXAMPLE 112

[1061] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-23- benzyl-4-carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids Fmoc-L-phenylalanine and 89; followed by Scheme 44 with 19. The crude product was purified by prep-HPLC (HOAc method), to yeild a white solid (199.8 mg, 127.98 µmol, 17.11% yield, 99.65% purity, HOAC). LCMS: Rt=2.189, m/z 748.5[M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d ppm 10.78 (br s, 1 H) 8.58 - 9.20 (m, 5 H) 8.12 - 8.54 (m, 1 H) 7.70 - 8.06 (m, 1 H) 7.22 - 7.62 (m, 8 H) 6.79 - 7.14 (m, 8 H) 6.50 - 6.75 (m, 4 H) 5.90 (br s, 2 H) 4.86 - 5.54 (m, 3 H) 4.19 - 4.79 (m, 4 H) 3.75 - 4.08 (m, 2 H) 2.65 - 3.66 (m, 8 H) 0.81 - 2.38 (m, 51 H).

EXAMPLE 113A

[1062] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((S)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-23-benzyl-4-carbamoyl- 26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with 6-(9H-fluoren- 9-ylmethoxycarbonylamino)hexanoic acid 56 substituted for 12 and amino acids Fmoc-L-phenylalanine and 89; followed by Scheme 44 with (3S)-3-(tert-butoxycarbonylamino)butanoic acid. The crude product was purified twice by prep-HPLC; first by the TFA method folled by the HCl method: [(A: 0.05% HCl in water), B: CH₃CN], to yeild a white solid (13 mg, 8.90 µmol, 9.76% yield, 100% purity, HCl). LCMS: Rt=2.453, m/z 712.4 [M/2+H]⁺.¹H NMR: MeOD-d₄, 400MHz, d 7.29-7.38 (m, 2H), 7.25 (s, 1H), 7.01-7.18 (m, 5H), 6.91-7.00 (m, 2H), 6.67-6.76 (m, 2H), 6.07 (d, J=6.5 Hz, 2H), 5.66 (d, J=11.1 Hz, 1H), 5.54 (t, J=7.6 Hz, 1H), 5.05 (d, J=9.8 Hz, 1H), 4.77 (d, J=8.1 Hz, 1H), 4.62 (t, J=7.1 Hz, 1H), 4.36-4.49 (m, 1H), 4.27 (s, 1H), 3.96 (d, J=5.6 Hz, 1H), 3.41-3.71 (m, 4H), 2.93-3.18 (m, 10H), 2.53- 2.81 (m, 3H), 1.90-2.52 (m, 12H), 1.39-1.85 (m, 14H), 1.33 (d, J=6.7 Hz, 3H), 0.94-1.26 (m, 6H). EXAMPLE 113B

[1063] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-23-benzyl-4-carbamoyl- 26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with 6-(9H-fluoren- 9-ylmethoxycarbonylamino)hexanoic acid 56 in place of 12 and amino acids Fmoc-L-phenylalanine and 89; followed by Scheme 44 with (3R)-3-(tert-butoxycarbonylamino)butanoic acid. The crude product was purified twice by prep-HPLC; first by the TFA method folled by the HCl method: [(A: 0.05% HCl in water), B: CH₃CN], to yeild a white solid (13 mg, 8.87 µmol, 9.73% yield, 99.67% purity, HCl). LCMS: Rt=2.494, m/z 712.4 [M/2+H]⁺.¹H NMR: MeOD-d₄, 400MHz, d 7.30-7.41 (m, 2H), 7.25 (s, 1H), 7.01-7.19 (m, 5H), 6.95 (t, J=7.4 Hz, 2H), 6.65-6.77 (m, 2H), 5.89-6.19 (m, 2H), 5.67 (d, J=12.1 Hz, 1H), 5.46-5.60 (m, 1H), 5.05 (d, J=12.1 Hz, 1H), 4.77 (s, 1H), 4.64 (t, J=6.7 Hz, 1H), 4.46 (dd, J=8.2, 3.6 Hz, 1H), 4.26 (d, J=4.5 Hz, 1H), 3.96 (d, J=7.5 Hz, 1H), 3.42-3.70 (m, 4H), 2.92-3.19 (m, 10H), 2.68- 2.80 (m, 1H), 1.85-2.66 (m, 14H), 1.39-1.85 (m, 14H), 1.26-1.38 (m, 3H), 0.94-1.25 (m, 6H).

EXAMPLE 114A

[1064] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((S)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-methoxybenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with 6-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid 56 substitued for 12 and amino acids (S)- 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 3-(4-methoxyphenyl)propanoic acid 24 and 89; followed by Scheme 44 with (3S)-3-(tert- butoxycarbonylamino)butanoic acid. The crude product was purified twice by prep-HPLC; first by the TFA method folled by the HCl method: [(A: 0.05% HCl in water), B: CH₃CN], to yield a white solid (10.48 mg, 7.03 µmol, 9.31% yield, 100% purity, HCl). LCMS: Rt=2.418, m/z 727.8 [M/2+H]⁺.¹H NMR: MeOD-d₄, 400MHz, d ppm 7.34 (d, J=7.95 Hz, 2 H) 7.25 (s, 1 H) 6.96 - 7.17 (m, 4 H) 6.63 - 6.76 (m, 2 H) 6.48 (d, J=8.19 Hz, 2 H) 5.86 - 6.11 (m, 2 H) 5.44 - 5.72 (m, 2 H) 5.05 (s, 1 H) 4.70 - 4.77 (m, 1 H) 4.62 (t, J=6.60 Hz, 1 H) 4.36 - 4.49 (m, 1 H) 4.28 (s, 1 H) 3.91 (s, 1 H) 3.67 (s, 3 H) 3.34 - 3.63 (m, 3 H) 2.92 - 3.25 (m, 11 H) 1.89 - 2.81 (m, 15 H) 0.97 - 1.80 (m, 23 H).

EXAMPLE 114B

[1065] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-methoxybenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with 6-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid 56 substitued for 12 and with amino acids 24 and 89; followed by Scheme 44 with (3R)-3-(tert-butoxycarbonylamino) butanoic acid. The crude product was purified twice by prep-HPLC; first by the TFA method folled by HCl method: [(A: 0.05% HCl in water), B: CH₃CN], to yield a white solid (10.12 mg, 6.79 µmol, 8.99% yield, 100% purity, HCl). LCMS: Rt=2.419, m/z 727.5 [M/2+H]⁺.¹H NMR: MeOD-d₄, 400MHz, d ppm 7.34 (d, J=8.07 Hz, 2 H) 7.25 (s, 1 H) 7.01 - 7.18 (m, 4 H) 6.66 - 6.76 (m, 2 H) 6.49 (d, J=8.31 Hz, 2 H) 5.92 - 6.09 (m, 2 H) 5.68 (d, J=9.90 Hz, 1 H) 5.49 - 5.59 (m, 1 H) 4.99 - 5.10 (m, 1 H) 5.04 (d, J=10.51 Hz, 1 H) 4.73 - 4.78 (m, 1 H) 4.64 (t, J=6.79 Hz, 1 H) 4.35 - 4.50 (m, 1 H) 4.28 (s, 1 H) 3.84 - 3.98 (m, 1 H) 3.68 (s, 3 H) 3.45 - 3.62 (m, 3 H) 2.95 - 3.19 (m, 10 H) 2.74 (dd, J=17.36, 3.67 Hz, 1 H) 2.04 - 2.63 (m, 11 H) 1.37 - 2.02 (m, 19 H) 1.34 (d, J=6.60 Hz, 2 H) 0.93 - 1.26 (m, 6 H).

EXAMPLE 115

[1066] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(4-methoxybenzyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 25 and 89; followed by Scheme 44 with 19. The crude product was purified by prep-HPLC (HOAc method), to give a white solid (185 mg, 112.03 µmol, 14.15% Yield, 99.67% Purity, 2HOAC). LCMS: Rt=2.216, m/z 763.5[M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d ppm 10.78 (br s, 1 H) 8.83 - 9.16 (m, 3 H) 8.37 - 8.79 (m, 2 H) 7.81 - 8.33 (m, 2 H) 7.37 - 7.74 (m, 4 H) 7.32 (br d, J=11.98 Hz, 5 H) 6.89 - 7.15 (m, 4 H) 6.67 - 6.87 (m, 2 H) 6.57 - 6.67 (m, 2 H) 6.48 (br d, J=7.95 Hz, 2 H) 5.83 (br s, 2 H) 4.74 - 5.26 (m, 2 H) 4.39 - 4.69 (m, 3 H) 4.21 - 4.36 (m, 1 H) 3.83 - 4.05 (m, 1 H) 3.73 (s, 3 H) 3.49 (br d, J=9.78 Hz, 2 H) 2.63 - 3.26 (m, 11 H) 1.89 - 2.40 (m, 21 H) 1.86 (s, 6 H) 1.64 - 1.80 (m, 6 H) 0.88 - 1.61 (m, 17 H).

EXAMPLE 116

[1067] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-2-(3-aminopropanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)-3-(4- hydroxyphenyl)propanamido)-4-carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-methyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 117

[1068] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 118

[1069] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-23-(prop-2-yn-1-yl)- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 119

[1070] (4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-20-(3- guanidinopropyl)-7,13-bis(hydroxymethyl)-26-isopropyl-23-(4-(methylthio)benzyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-4-carboxamide was prepared according to Schemes 2-55. EXAMPLE 120

[1071] 3-((4R,7S,10S,13S,21S,24S,27S,30R)-10-((1H-indol-3-yl)methyl)-21-(4-aminobutyl)-30-((S)-2- ((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl- 24-(4-hydroxybenzyl)-13-(hydroxymethyl)-27-isopropyl-6,9,12,15,20,23,26,29-octaoxo-1,2-dithia- 5,8,11,14,19,22,25,28-octaazacyclohentriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 121

[1072] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2- 55. EXAMPLE 122

[1073] (4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-23-(4-chlorobenzyl)- 20-(3-guanidinopropyl)-7,13-bis(hydroxymethyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-4-carboxamide was prepared according to Schemes 2-55.

EXAMPLE 123

[1074] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((R)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-23-(prop-2-yn-1-yl)-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 124

[1075] (4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-23-(4- hydroxybenzyl)-7,13-bis(hydroxymethyl)-29-((S)-3-(4-hydroxyphenyl)-2-((S)-1-(piperidin-4- yl)pyrrolidine-2-carboxamido)propanamido)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-4-carboxamide was prepared according to Schemes 2-55.

EXAMPLE 125

[1076] 2-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)acetic acid was prepared according to Schemes 2-55. EXAMPLE 126

[1077] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23- (4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-26-(2,2,2-trifluoroethyl)-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 127

[1078] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23- (4-hydroxybenzyl)-26-(2-(methylthio)ethyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 128

[1079] (4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2- ((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-7- (carboxymethyl)-23-(4-hydroxybenzyl)-13-(hydroxymethyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-4-carboxylic acid was prepared according to Schemes 2-55.

EXAMPLE 129

[1080] 3-((4R,7S,10S,20S,23S,26R,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23- (4-hydroxybenzyl)-26-(3-methoxypropyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 130

[1081] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-23-(4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 131

[1082] (4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-23-benzyl-20-(3- guanidinopropyl)-7,13-bis(hydroxymethyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-4-carboxamide was prepared according to Schemes 2-55. EXAMPLE 132

[1083] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-26-(sec-butyl)-4- carbamoyl-23-(4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 133

[1084] 2-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((S)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-23-(4-hydroxybenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)acetic acid was prepared according to Schemes 2-55. EXAMPLE 134

[1085] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-20-(4-aminobutyl)-29-((S)-2-((R)- 1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23- (4-hydroxybenzyl)-26-isopropyl-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 135

[1086] 3-((4R,7S,10S,13S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((R)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-13- (carboxymethyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,22,25,28-heptaoxo-1,2-dithia- 5,8,11,14,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2- 55. EXAMPLE 136

[1087] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 137

[1088] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-7-(3-amino-3-oxopropyl)-29- ((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-13-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 138

[1089] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20-(3- guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55.

EXAMPLE 139

[1090] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-6,9,12,15,19,22,25,28-octaoxo-26-phenyl-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 140

3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-29-((S)-2- ((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 94 and 89; followed by Scheme 44 with (3S)- (tertbutoxycarbonylamino)butanoic acid to give a white solid (37 mg, 21.77 µmol, 20.81% yield, 96.95% purity, 2HOAC). LCMS: Rt=;2.289, m/z 764.3 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d ppm 10.68 (br s, 1 H) 8.49 - 9.30 (m, 7 H) 8.30 (br d, J=8.25 Hz, 1 H) 7.88 (br d, J=6.13 Hz, 1 H) 7.36 - 7.73 (m, 7 H) 7.23 - 7.35 (m, 3 H) 6.77 - 7.14 (m, 9 H) 6.74 (br s, 1 H) 6.59 - 6.67 (m, 2 H) 4.97 - 5.54 (m, 5 H) 4.44 - 4.75 (m, 5 H) 4.31 (br d, J=5.00 Hz, 1 H) 4.11 (br s, 1 H) 2.62 - 3.26 (m, 17 H) 1.87 - 2.44 (m, 14 H) 1.82 (s, 6 H) 1.65 - 1.79 (m, 3 H) 1.18 - 1.64 (m, 13 H) 0.80 - 1.08 (m, 4 H).

EXAMPLE 141

[1091] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-((R)-3-amino-N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2,3-dichlorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 97 and 15; followed by Scheme 43 with 90 to give a white solid (33.5 mg, 20.3 µmol, 20.3% yield, 99.7% purity, HOAC). LCMS: Rt=2.391, m/z 791.2 [M/2+H]⁺.¹H NMR (400 MHz, DMSO-d₆) d ppm 8.43 - 9.70 (m, 6 H) 7.71 - 8.23 (m, 4 H) 7.35 - 7.56 (m, 2 H) 7.11 - 7.32 (m, 5 H) 6.83 - 7.09 (m, 6 H) 6.74 (br d, J=9.05 Hz, 2 H) 6.61 (br t, J=8.31 Hz, 2 H) 4.91 - 5.83 (m, 6 H) 4.10 - 4.85 (m, 6 H) 2.79 - 3.07 (m, 17 H) 1.85 - 2.30 (m, 14 H) 1.84 (br d, J=3.55 Hz, 3 H) 0.92 - 1.80 (m, 21 H) 0.74 - 0.91 (m, 5 H).

EXAMPLE 142

[1092] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2,3- dichlorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13- diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 97 and 15; followed by Scheme 47 with 19 to give a white solid (296.2 mg, 179.54 µmol, 22.44% yield, 99.75% purity, HOAC). LCMS: Rt=2.406, m/z 793.8 [M/2+H]⁺.¹H NMR (400 MHz, DMSO-d₆) d ppm 10.68 (br s, 1 H) 7.17 - 9.76 (m, 17 H) 6.80 - 7.15 (m, 3 H) 6.58 - 6.78 (m, 2 H) 4.88 - 6.31 (m, 3 H) 4.58 (dt, J=17.79, 9.08 Hz, 6 H) 3.80 - 4.21 (m, 8 H) 2.56 - 3.37 (m, 24 H) 1.88 - 2.42 (m, 9 H) 1.84 (s, 3 H) 1.01 - 1.79 (m, 13 H) 0.83 (br s, 6 H). EXAMPLE 143

[1093] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-(2-((R)-3-amino-N- cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2,3- dichlorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13- diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 97 and 15; followed by Scheme 52 with 90 to yield a white solid (18.47 mg, 11.03 µmol, 11.03% yield, 99.15% purity, HOAC). LCMS: Rt=2.456, 800.8 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.66 (br s, 1H), 9.25 - 8.31 (m, 6H), 8.17 (br s, 1H), 7.88 (br s, 1H), 7.69 - 7.14 (m, 8H), 7.13 - 6.76 (m, 6H), 6.76 - 6.56 (m, 3H), 6.09 - 4.89 (m, 4H), 4.74 - 4.37 (m, 5H), 4.28 - 4.13 (m, 1H), 3.95 - 3.67 (m, 5H), 3.16 - 2.83 (m, 14H), 2.82 - 2.68 (m, 2H), 2.29 - 1.87 (m, 12H), 1.85 (s, 3H), 1.75 - 1.16 (m, 16H), 1.08 - 0.99 (m, 3H), 0.83 (br s, 6H).

EXAMPLE 144

[1094] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-23-(2,3-dichlorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 145

[1095] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-23-(2,3-dichlorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 97 and 89; followed by Scheme 44 with (3S)-(tertbutoxycarbonylamino)butanoic acid to give a white solid (24.8 mg, 14.6 µmol, 14.6% yield, 100% purity, 2HOAC). LCMS: Rt=2.362, m/z 792.3 [M/2+H]⁺.¹H NMR (400 MHz, DMSO-d₆) d ppm 10.64 (br s, 1 H) 9.72 (br s, 1 H) 8.64 - 9.24 (m, 5 H) 7.73 - 8.54 (m, 4 H) 6.78 - 7.54 (m, 10 H) 6.58 - 6.76 (m, 4 H) 4.94 - 6.15 (m, 5 H) 4.20 - 4.76 (m, 7 H) 2.57 - 3.24 (m, 21 H) 1.87 - 2.44 (m, 15 H) 1.82 (s, 6 H) 1.08 - 1.77 (m, 18 H).

EXAMPLE 146

[1096] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2,3-dichlorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 97 and 15; followed by Scheme 43 with 19 to give a white solid (24.3 mg, 14.9 µmol, 14.9% yield, 99.5% purity, HOAC). LCMS: Rt=2.391, m/z 794.9 [M/2+H]⁺.¹H NMR (400 MHz, DMSO-d₆) d ppm 8.31 - 9.72 (m, 4 H) 7.68 - 8.26 (m, 3 H) 7.10 - 7.63 (m, 6 H) 6.83 - 7.09 (m, 4 H) 6.54 - 6.82 (m, 3 H) 4.91 - 5.86 (m, 2 H) 4.08 - 4.73 (m, 3 H) 3.63 - 4.01 (m, 2 H) 2.69 - 3.15 (m, 23 H) 1.84 - 2.31 (m, 18 H) 1.83 (s, 3 H) 0.96 - 1.81 (m, 20 H) 0.73 - 0.95 (m, 6 H).

EXAMPLE 147

[1097] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3- chloro-2-fluorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 92 and 15; followed by Scheme 47 with 19 to give a white solid (22.26 mg, 14.03 µmol, 14.0% yield, 99.8% purity, HOAC). LCMS: Rt=2.322, m/z 761.9 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.65 (br s, 1H), 8.90 (br s, 5H), 8.58 (br s, 2H), 8.36 - 8.14 (m, 1H), 7.99 - 7.72 (m, 1H), 7.47 (br s, 1H), 7.37 - 7.13 (m, 5H), 7.11 - 6.97 (m, 3H), 6.96 - 6.85 (m, 2H), 6.79 (br s, 1H), 6.63 (br t, J = 7.9 Hz, 2H), 5.48 - 5.00 (m, 3H), 4.76 - 4.41 (m, 3H), 4.37 - 4.06 (m, 2H), 3.82 (br s, 5H), 3.18 - 2.88 (m, 20H), 2.86 - 2.69 (m, 5H), 2.28 - 1.99 (m, 11H), 1.97 - 1.73 (m, 4H), 1.71 - 1.48 (m, 5H), 1.43 - 1.13 (m, 4H), 0.84 (br s, 6H).

EXAMPLE 148

[1098] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclopentyl- 23-(2,3-dichlorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 149

[1099] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(3-chloro-2-fluorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 92 and 15; followed by Scheme 44 with 19 to give a white solid (29.23 mg, 17.80 µmol, 17.8% yield, 100% purity, 2HOAC). LCMS: Rt=2.275, m/z 761.5

[M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.66 (br s, 1H), 9.32 - 8.65 (m, 5H), 8.48 (br s, 1H), 8.31 (br s, 1H), 7.94 (br s, 1H), 7.84 - 7.67 (m, 2H), 7.65 - 7.35 (m, 4H), 7.28 (br s, 3H), 7.17 (br t, J = 7.4 Hz, 1H), 7.11 - 6.98 (m, 3H), 6.94 (br t, J = 7.3 Hz, 1H), 6.88 - 6.77 (m, 2H), 6.74 (br s, 1H), 6.69 - 6.60 (m, 2H), 5.64 - 4.90 (m, 4H), 4.70 - 4.47 (m, 4H), 4.37 - 4.00 (m, 4H), 3.83 - 3.68 (m, 6H), 3.41 (br d, J = 7.5 Hz, 12H), 3.22 - 2.69 (m, 9H), 2.26 - 2.01 (m, 6H), 1.98 - 1.86 (m, 5H), 1.83 (br s, 6H), 1.67 (br d, J = 4.3 Hz, 2H), 1.62 - 1.16 (m, 4H), 0.92 - 0.74 (m, 6H).

EXAMPLE 150

[1100] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3- chloro-2-fluorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 92 and 89; followed by Scheme 47 with (3S)- (tertbutoxycarbonylamino)butanoic acid to give a white solid (36.32 mg, 21.43 µmol, 21.4% yield, 99.3% purity, 2HOAC). LCMS: Rt=2.369, m/z 782.0 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.67 (br s, 1H), 9.18 - 8.82 (m, 5H), 8.74 - 8.26 (m, 2H), 7.97 - 7.84 (m, 1H), 7.79 (br s, 1H), 7.49 (br s, 5H), 7.34 - 7.24 (m, 3H), 7.19 (br s, 1H), 7.11 - 6.99 (m, 3H), 6.97 - 6.79 (m, 2H), 6.70 - 6.61 (m, 2H), 5.37 (br s, 1H), 5.07 (br s, 2H), 4.80 - 4.39 (m, 6H), 4.37 - 4.04 (m, 2H), 3.43 (br d, J = 6.0 Hz, 8H), 3.18 - 2.89 (m, 12H), 2.91 - 2.72 (m, 3H), 2.27 - 2.00 (m, 8H), 1.89 (br d, J = 19.1 Hz, 5H), 1.84 (br d, J = 4.3 Hz, 6H), 1.26 (br d, J = 18.5 Hz, 4H), 1.70 - 1.19 (m, 12H), 1.07 (br d, J = 6.2 Hz, 4H).

EXAMPLE 151

[1101] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3- chloro-2-fluorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 92 and 89; followed by Scheme 47 with 19 to give a white solid (22.11 mg, 13.18 µmol, 13.2% yield, 99.5% purity, 2HOAC). LCMS: Rt=2.346, m/z 775.0 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.65 (br s, 1H), 9.04 - 8.54 (m, 4H), 8.53 - 8.01 (m, 2H), 7.95 - 7.51 (m, 1H), 7.46 - 7.14 (m, 6H), 7.09 - 6.70 (m, 8H), 6.67 - 6.54 (m, 3H), 5.33 (br s, 1H), 5.52 - 5.17 (m, 1H), 5.04 (br s, 1H), 4.69 - 4.25 (m, 4H), 4.17 (br s, 2H), 3.84 (br s, 1H), 3.54 - 3.45 (m, 12H), 3.04 - 2.78 (m, 14H), 2.11 (br s, 9H), 1.97 - 1.76 (m, 11H), 1.69 - 1.20 (m, 16H). EXAMPLE 152

[1102] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(3-chloro-2-fluorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 92 and 15; followed by Scheme 43 with 19 to give a white solid (43.48 mg, 25.6 µmol, 25.6% yield, 98.5% purity, 2HOAC). LCMS: Rt=2.352, m/z 775.7

[M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.65 (br s, 1H), 9.20 - 8.71 (m, 4H), 8.64 - 8.12 (m, 1H), 8.09 - 7.68 (m, 3H), 7.48 (br s, 2H), 7.39 (br d, J = 18.7 Hz, 1H), 7.27 (br s, 2H), 7.17 (br t, J = 7.1 Hz, 1H), 7.12 - 6.89 (m, 3H), 6.88 - 6.70 (m, 2H), 6.69 - 6.55 (m, 1H), 5.57 - 5.21 (m, 1H), 5.19 - 4.95 (m, 1H), 4.74 - 4.40 (m, 4H), 4.15 (br s, 1H), 3.88 - 3.75 (m, 5H), 3.68 (br d, J = 17.2 Hz, 18H), 3.16 (br s, 5H), 3.12 - 2.70 (m, 12H), 2.65 - 2.53 (m, 2H), 2.30 - 2.09 (m, 4H), 2.09 - 1.90 (m, 4H), 1.86 (br d, J = 3.4 Hz, 6H), 1.70 (br s, 2H), 1.56 (br s, 3H), 1.48 - 1.18 (m, 5H), 0.94 - 0.70 (m, 6H).

EXAMPLE 153

[1103] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3-chloro-2- fluorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 92 and 89; followed by Scheme 46 with 19 to give a white solid (40.43 mg, 23.75 µmol, 23.7% yield, 99.7% purity, 2HOAC). LCMS: Rt=2.429, m/z 788.8 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.66 (br s, 1H), 9.08 - 8.06 (m, 13H), 7.89 - 7.15 (m, 9H), 7.10 - 6.77 (m, 7H), 6.72 - 6.57 (m, 2H), 5.66 - 4.87 (m, 8H), 4.72 - 4.46 (m, 3H), 4.18 (br s, 1H), 3.95 - 3.78 (m, 7H), 3.76 - 3.66 (m, 5H), 2.98 (br s, 10H), 2.79 (br s, 4H), 2.11 (br s, 3H), 1.96 - 1.79 (m, 7H), 1.69 (br s, 2H), 1.54 (br s, 7H), 1.43 (br s, 6H), 1.34 - 1.20 (m, 4H), 1.34 - 1.20 (m, 1H), 1.12 (br d, J = 18.1 Hz, 1H).

EXAMPLE 154

[1104] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-((R)-3-amino- N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3-chloro-2- fluorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 92 and 15; followed by Scheme 46 with 90 to give a white solid (36.09 mg, 21.2 µmol, 21.2% yield, 99.2% purity, 2HOAC). LCMS: Rt=2.410, m/z 783.3 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.65 (br s, 1H), 8.91 (br s, 4H), 8.73 - 8.39 (m, 2H), 7.82 (br s, 1H), 7.64 - 7.13 (m, 7H), 7.08 - 6.72 (m, 5H), 6.62 (t, J = 7.6 Hz, 2H), 5.79 - 4.83 (m, 4H), 4.76 - 4.46 (m, 4H), 4.19 (br s, 3H), 4.04 - 3.73 (m, 9H), 3.66 (br d, J = 17.0 Hz, 10H), 3.17 - 2.86 (m, 13H), 2.76 (br d, J = 6.8 Hz, 2H), 2.30 - 1.97 (m, 6H), 1.95 - 1.83 (m, 6H), 1.81 - 1.61 (m, 3H), 1.60 - 1.18 (m, 9H), 1.17 - 0.96 (m, 4H), 0.85 (br s, 6H). EXAMPLE 155

[1105] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3-chloro-2- fluorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 92 and 15; followed by Scheme 46 with 19 to give a white solid (32.53 mg, 19.39 µmol, 19.39% yield, 99.6% purity, 2HOAC). LCMS: Rt=2.386, m/z 775.8 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.65 (br s, 1H), 9.41 - 8.37 (m, 9H), 8.02 - 7.25 (m, 9H), 7.19 (br s, 1H), 7.01 (br dd, J = 8.1, 19.4 Hz, 4H), 6.69 - 6.59 (m, 1H), 5.67 - 4.92 (m, 3H), 4.82 - 4.48 (m, 4H), 4.20 (br s, 1H), 3.93 - 3.74 (m, 12H), 3.19 - 2.85 (m, 17H), 2.77 (br s, 5H), 2.30 - 2.00 (m, 10H), 1.95 - 1.83 (m, 7H), 1.69 (br s, 3H), 1.59 - 1.35 (m, 8H), 1.36 - 1.17 (m, 4H), 1.16 - 1.05 (m, 1H), 0.85 (br s, 6H).

EXAMPLE 156

[1106] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2,3-dichlorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 97 and 15; followed by Scheme 44 with 19 to give a white solid (17.86 mg, 10.74 µmol, 10.74% yield, 99.75% purity, 1HOAC). LCMS: Rt=2.306, m/z 770.3 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.54 (br s, 1H), 9.39-8.57 (m, 6H), 8.52-8.10 (m, 1H), 8.06-7.68 (m, 3H), 7.64- 7.11 (m, 8H), 7.08-6.49 (m, 9H), 5.75-4.87 (m, 5H), 4.70-4.37 (m, 2H), 4.34-4.04 (m, 2H), 3.83 (m, 1H), 3.20-2.85 (m, 19H), 2.83-2.73 (m, 4H), 2.08-1.85 (m, 10H), 1.79 (m, 6H), 1.72-1.18 (m, 11H), 1.08 (m, 2H), 0.88-0.77 (m, 6H).

EXAMPLE 157

[1107] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-26-cyclopentyl-23-(2,3-dichlorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 97 and 89; followed by Scheme 44 with (3S)- (tertbutoxycarbonylamino)butanoic acid to give a white solid (44.62 mg, 26.19 µmol, 26.19% yield, 99.69% purity, 2HOAC). LCMS: Rt=2.371, m/z 790.5 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.51 (br s, 1H), 9.46 (m, 1H), 9.10-8.43 (m, 5H), 8.34-7.96 (m, 1H), 7.94-7.58 (m, 3H), 7.56-7.10 (m, 7H), 7.07-6.47 (m, 10H), 5.88-4.92 (m, 4H), 4.72-4.10 (m, 6H), 3.80 (m, 2H), 3.24-2.73 (m, 21H), 2.28- 1.85 (m, 15H), 1.84-1.75 (m, 6H), 1.71-1.18 (m, 15H), 1.01-0.96 (m, 3H). EXAMPLE 158

[1108] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-23-(2,3-dichlorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 97 and 89; followed by Scheme 43 with 19 to give a white solid (24.88 mg, 15.48 µmol, 15.48% yield, 99.52% purity, 1HOAC). LCMS: Rt=2.339, m/z 770.8

[M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.53 (br s, 1H), 9.34-7.73 (m, 9H), 7.44 (m, 3H), 7.34- 7.13 (m, 4H), 7.12-6.97 (m, 3H), 6.91 (m, 2H), 6.77 (m, 1H), 6.88-6.57 (m, 2H), 5.96-4.93 (m, 2H), 4.74- 4.15 (m, 5H), 3.85 (m, 1H), 3.22-2.86 (m, 18H), 2.85-2.68 (m, 5H), 2.28-1.85 (m, 14H), 1.84-1.80 (m, 3H), 1.78-1.48 (m, 7H), 1.46-0.95 (m, 6H), 0.83 (m, 6H).

EXAMPLE 159

[1109] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2,3- dichlorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 97 and 15; followed by Scheme 50 with 19 to give a white solid (14.0 mg, 8.64 µmol, 8.64% yield, 100% purity, HOAC). LCMS: Rt=2.322, m/z 778.9 [M/2+H]⁺.¹H NMR (400 MHz, DMSO-d₆) d ppm 10.65 (br s, 1 H) 9.52 (br s, 1 H) 8.61 - 9.13 (m, 4 H) 7.78 - 8.56 (m, 5 H) 7.12 - 7.73 (m, 7 H) 6.80 - 7.09 (m, 5 H) 6.53 - 6.75 (m, 4 H) 4.95 - 6.01 (m, 5 H) 4.23 - 4.73 (m, 7 H) 3.86 (br s, 1 H) 2.55 - 3.26 (m, 18 H) 1.83 - 2.47 (m, 15 H) 1.81 (s, 3 H) 1.02 - 1.80 (m, 10 H) 0.82 (br d, J=5.50 Hz, 6 H).

EXAMPLE 160

[1110] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2,3-dichlorobenzyl)-10-((5-fluoro- 1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 97 and 15; followed by Scheme 53 with 19 to give a white solid (11.6 mg, 6.94 µmol, 6.94% yield, 96.9% purity, HOAC). LCMS: Rt=2.352, m/z 779.9 [M/2+H]⁺.¹H NMR (400 MHz, DMSO-d₆) d ppm 10.65 (br s, 1 H) 7.74 - 9.55 (m, 10 H) 6.76 - 7.71 (m, 4 H) 6.55 - 6.76 (m, 3 H) 4.99 - 6.10 (m, 4 H) 4.11 - 4.86 (m, 7 H) 3.87 (br s, 1 H) 2.68 - 3.19 (m, 20 H) 1.88 - 2.30 (m, 12 H) 1.86 (s, 3 H) 1.08 - 1.81 (m, 11 H) 0.83 (br s, 6 H). EXAMPLE 161

[1111] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-(2-((R)-3-amino-N- cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2,3- dichlorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 162

[1112] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2,3- dichlorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 163

[1113] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclopentyl- 23-(2,3-dichlorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13- diyl)dipropionic acid was prepared according to Schemes 2-55.

EXAMPLE 164

[1114] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- cyanobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 165

[1115] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- cyanobenzyl)-26-cyclopentyl-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 166

[1116] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2-cyanobenzyl)-26-cyclopentyl-10- ((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55. EXAMPLE 167

[1117] 3,3'-((4R,7S,10S,13S,20S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3- fluorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55.

EXAMPLE 168

[1118] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- cyanobenzyl)-26-cyclopentyl-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 169

[1119] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2-cyanobenzyl)-10-((5-fluoro-1H- indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55.

EXAMPLE 170

[1120] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2-cyanobenzyl)-26-cyclopentyl-10- ((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55. EXAMPLE 171

[1121] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-10-((5- fluoro-1H-indol-3-yl)methyl)-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 94 and 15; followed by Scheme 50 with 19 to give a white solid (35.83 mg, 22.01 µmol, 22.01% yield, 99.86% purity, 2HOAc). LCMS:Rt=2.245, m/z 753.4 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d10.79 (br s, 1H), 9.37 (br s, 1H), 8.91 (br s, 2H), 8.73 (br d, J=8.0 Hz, 1H), 8.49 - 8.17 (m, 2H), 8.06 - 7.86 (m, 1H), 7.84 - 7.60 (m, 3H), 7.56 - 7.38 (m, 1H), 7.36 - 7.17 (m, 4H), 7.10 - 6.94 (m, 6H), 6.92 - 6.68 (m, 5H), 6.62 (t, J=8.8 Hz, 2H), 5.70 - 4.96 (m, 5H), 4.70 - 4.44 (m, 3H), 4.42 - 4.23 (m, 3H), 3.89 (br s, 1H), 3.09 - 2.70 (m, 19H), 2.26 - 1.87 (m, 13H), 1.83 (s, 6H), 1.79 - 1.12 (m, 11H), 0.79 (br d, J=5.2 Hz, 6H).

EXAMPLE 172

[1122] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- chlorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 93 and 15; followed by Scheme 50 with 19 to give a white solid (17.0 mg, 10.1 µmol, 10.1% yield, 99.6% purity, 2HOAc). LCMS: Rt=2.257, m/z 761.3 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.72 (br s, 1H), 8.26-9.58 (m, 7H), 7.77-8.13 (m, 3H), 7.14-7.54 (m, 5H), 6.91-7.10 (m, 6H), 6.59-6.75 (m, 4H), 5.17-5.74 (m, 1H), 5.17-5.74 (m, 1H), 4.94-6.19 (m, 2H), 4.16-4.74 (m, 6H), 3.28-3.89 (m, 22H), 2.53-3.23 (m, 14H), 1.21-2.20 (m, 20H), 0.81 (d, J=5.01 Hz, 6H).

EXAMPLE 173

[1123] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- chlorobenzyl)-26-cyclopentyl-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 93 and 89; followed by Scheme 50 with (3S)-(tertbutoxycarbonylamino)butanoic acid to give a white solid (26.0 mg, 15.4 µmol, 15.4% yield, 99.6% purity, 2HOAC). LCMS: Rt=2.309, m/z 782.3 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.71 (br s, 1H), 7.72-9.65 (m, 10H), 7.14-7.60 (m, 6H), 6.85-7.12 (m, 6H), 6.52-6.78 (m, 4H), 4.26-6.19 (m, 12H), 3.17-3.95 (m, 19H), 2.61-3.14 (m, 16H), 1.73-2.47 (m, 16H), 1.22-1.73 (m, 8H), 1.20-1.69 (m, 1H), 0.89-1.15 (m, 3H). EXAMPLE 174

[1124] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- chlorobenzyl)-26-cyclopentyl-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 93 and 89; followed by Scheme 50 with 19 to give a white solid (30.0 mg, 18.5 µmol, 18.5% yield, 99.3% purity, HOAC). LCMS: Rt=2.293, m/z 774.4 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.72 (br s, 1H), 8.39-9.78 (m, 5H), 7.37-8.36 (m, 6H), 6.94-7.37 (m, 8H), 6.56-6.78 (m, 3H), 4.13-6.17 (m, 9H), 3.23-4.10 (m, 18H), 2.80-3.21 (m, 11H), 2.57-4.11 (m, 7H), 2.23-2.46 (m, 4H), 0.59-2.22 (m, 28H).

EXAMPLE 175

[1125] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2-chlorobenzyl)-10-((5-fluoro-1H- indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 93 and 15; followed by Scheme 53 with 19 to give a white solid (31.0 mg, 18.3 µmol, 18.3% yield, 98.7% purity, 2HOAC). LCMS: Rt=2.285, m/z 761.8 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.73 (br s, 1H), 7.78-9.13 (m, 9H), 7.15-7.71 (m, 6H), 6.90-7.13 (m, 6H), 6.53- 6.76 (m, 3H), 4.92-6.25 (m, 2H), 4.18-4.88 (m, 7H), 3.26-4.10 (m, 20H), 2.75-3.10 (m, 15H), 1.97-2.39 (m, 9H), 1.77-1.97 (m, 10H), 1.19-1.73 (m, 3H), 0.82 (br s, 6H).

EXAMPLE 176

[1126] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2-chlorobenzyl)-26-cyclopentyl-10- ((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 93 and 89; followed by Scheme 53 with 90 to give a white solid (11.0 mg, 6.73 µmol, 6.73% yield, 99.2% purity, HOAC). LCMS: Rt=2.342, m/z 781.8 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.73 (br s, 1H), 7.38-9.11 (m, 9H), 6.44-7.34 (m, 13H), 3.77-6.17 (m, 12H), 2.65-3.21 (m, 20H), 1.90-2.49 (m, 18H), 1.74-1.88 (m, 7H), 1.17-1.70 (m, 14H), 0.94-1.16 (m, 3H).

EXAMPLE 177

[1127] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2-chlorobenzyl)-26-cyclopentyl-10- ((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 93 and 89; followed by Scheme 53 with 19 to give a white solid (28.0 mg, 16.7 µmol, 16.7% yield, 99.7% purity, 2HOAC). LCMS: Rt=2.316, m/z 774.9 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.74 (br s, 1H), 7.81-9.15 (m, 9H), 7.12-7.68 (m, 7H), 6.79-7.10 (m, 6H), 6.59- 6.78 (m, 3H), 5.06 (br s, 3H), 4.15-4.78 (m, 6H), 4.11-4.78 (m, 1H), 3.30-4.03 (m, 16H), 2.58-3.26 (m, 16H), 1.96-2.45 (m, 10 H), 1.77-1.94 (m, 1H), 1.75-1.95 (m, 8H), 1.06-1.75 (m, 14H).

EXAMPLE 178

[1128] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(3-methoxybenzyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 179

[1129] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 94 and 15; followed by Scheme 43 with 19 to give a white solid (23.37 mg, 99.07% purity). LCMS: Rt=2.294min, m/z 758.6 [M/2+H]⁺. ¹H NMR: (400 MHz, DMSO-d₆) d ppm 10.68 (br s, 1 H) 9.31 (br s, 1 H) 8.45 - 9.09 (m, 6 H) 8.18 (br s, 1 H) 7.89 - 8.05 (m, 1 H) 7.95 (s, 1 H) 7.53 - 7.78 (m, 4 H) 7.23 - 7.50 (m, 6 H) 6.88 - 7.11 (m, 6 H) 6.52 - 6.84 (m, 6 H) 5.41 (br s, 1 H) 4.91 - 5.19 (m, 3 H) 4.43 - 4.71 (m, 5 H) 4.04 - 4.25 (m, 1 H) 3.58 - 3.95 (m, 2 H) 2.93 - 3.07 (m, 7 H) 2.82 - 2.91 (m, 4 H) 2.64 - 2.79 (m, 6 H) 2.33 (dt, J=3.60, 1.77 Hz, 2 H) 2.15 (br d, J=13.63 Hz, 5 H) 1.81 - 2.05 (m, 9 H) 1.50 - 1.63 (m, 5 H) 1.37 - 1.46 (m, 3 H) 1.30 (br s, 2 H) 0.72 - 0.91 (m, 7 H).

EXAMPLE 180

[1130] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55.

EXAMPLE 181

[1131] 3,3'-((4R,7S,10S,13S,20S,23R,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55. EXAMPLE 182

[1132] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55.

EXAMPLE 183

[1133] 3,3'-((4R,7S,10S,13S,20S,23R,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55. EXAMPLE 184

[1134] 3-((4R,7S,10S,13S,20S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-29- ((S)-2-(2-(3-amino-N-cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 185

[1135] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-20- (3-guanidinopropyl)-23-(4-hydroxybenzyl)-4-(hydroxymethyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 186

[1136] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((S)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55.

EXAMPLE 187

[1137] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclopentyl- 20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55. EXAMPLE 188

[1138] 3-((7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-29- ((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-20-(3- guanidinopropyl)-23-(4-hydroxybenzyl)-4-(hydroxymethyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 189

[1139] 3-((3S,6S,9S,16S,19S,22S,25S,31S,E)-6-((1H-indol-3-yl)methyl)-9-(3-amino-3-oxopropyl)-25- ((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-31- carbamoyl-16-(3-guanidinopropyl)-19-(4-hydroxybenzyl)-22-isopropyl-2,5,8,11,15,18,21,24-octaoxo- 1,4,7,10,14,17,20,23-octaazacyclohentriacont-27-en-3-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 190

[1140] 3-((3S,6S,9S,16S,19S,22S,25S,30S,E)-6-((1H-indol-3-yl)methyl)-9-(3-amino-3-oxopropyl)-25- ((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-30- carbamoyl-16-(3-guanidinopropyl)-19-(4-hydroxybenzyl)-22-isopropyl-2,5,8,11,15,18,21,24-octaoxo- 1,4,7,10,14,17,20,23-octaazacyclotriacont-27-en-3-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 191

[1141] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55. EXAMPLE 192

[1142] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-((S)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 193

[1143] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 194

[1144] 3-((4R,7S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-10-((5- fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was synthesized according to Scheme 48 with amino acids 14 and 15; followed by Scheme 50 with 19 to yield a white solid (29.7 mg, 17.0% yield).

EXAMPLE 195

[1145] 3-((4R,7S,10R,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-10-((5- chloro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was synthesized according to Scheme 48 with amino acids 14 and 15 [((R)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(5-chloro-1H-indol-3-yl)propanoic acid was used in place of (R)-2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1H-indol-3-yl)propanoic acid in coupling step 3 of the synthesis]; followed by Scheme 50 with 19 to yield a white solid (7.7 mg, 4.4% yield).

EXAMPLE 196

3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-((S)-3-amino-N- cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 82 and 89; followed by Scheme 46 with 90 to give a white solid (17.0 mg, 10.45 µmol, 20.21% yield, 99.85% purity, HOAC). LCMS: Rt=2.340, m/z 782.5 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.56 (br s, 1H), 9.13 - 8.33 (m, 8H), 7.81 - 7.15 (m, 12H), 7.07 - 6.77 (m, 6H), 6.62 (br dd, J=5.0, 7.8 Hz, 3H), 5.58 - 4.92 (m, 4H), 4.59 (br dd, J=8.2, 16.8 Hz, 4H), 4.22 (br d, J=8.2 Hz, 1H), 3.92 - 3.63 (m, 2H), 3.20 (br s, 6H), 3.06 - 2.89 (m, 7H), 2.30 - 2.06 (m, 15H), 1.90 (br s, 3H), 1.87 (s, 3H), 1.58 - 1.25 (m, 22H), 1.06 - 0.97 (m, 4H).

EXAMPLE 197

[1146] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-((R)-3-amino-N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 82 and 89; followed by Scheme 43 with 90 to give a white solid (15.0 mg, 8.90 µmol, 18.32% yield, 99.84% purity, 2HOAC). LCMS: Rt=2.319, m/z 782.0 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.56 (br s, 1H), 9.80 (br s, 1H), 9.11 - 8.78 (m, 6H), 8.12 (br s, 1H), 7.82 (br s, 2H), 7.72 (br s, 1H), 7.54 - 7.13 (m, 10H), 7.13 - 6.96 (m, 4H), 6.94 - 6.77 (m, 3H), 6.71 (br s, 1H), 6.62 (t, J=7.8 Hz, 2H), 5.43 (br s, 2H), 5.12 (br s, 2H), 4.71 - 4.52 (m, 5H), 4.22 (br s, 1H), 3.93 - 3.61 (m, 3H), 3.25 - 2.93 (m, 6H), 2.91 - 2.79 (m, 1H), 2.28 - 2.06 (m, 14H), 2.05 - 1.88 (m, 9H), 1.85 (s, 6H), 1.60 - 1.32 (m, 21H), 1.02 - 0.92 (m, 3H).

EXAMPLE 198

[1147] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-((R)-3-amino- N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- cyanobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 82 and 89; followed by Scheme 46 with 90 to give a white solid (29.0 mg, 17.13 µmol, 36.75% yield, 99.48% purity, 2HOAC). LCMS: Rt=2.350, m/z 782.6 [M/2+H]⁺.¹H NMR: (DMSO-d₆, 400MHz), d 10.57 (br s, 1H), 9.13 - 8.82 (m, 4H), 8.74 - 8.34 (m, 2H), 7.89 - 7.68 (m, 1H), 7.56 - 7.16 (m, 9H), 7.15 - 6.95 (m, 3H), 6.95 - 6.78 (m, 3H), 6.62 (br t, J=7.2 Hz, 2H), 5.57 - 4.98 (m, 3H), 4.59 (br dd, J=8.2, 17.0 Hz, 3H), 4.22 (br d, J=8.8 Hz, 1H), 3.94 - 3.61 (m, 2H), 3.23 - 3.06 (m, 9H), 3.05 - 2.73 (m, 7H), 2.30 - 2.05 (m, 13H), 2.02 (br d, J=14.8 Hz, 3H), 1.88 (m, 8H), 1.74 - 1.08 (m, 26H), 1.06 - 0.94 (m, 4H).

EXAMPLE 199

[1148] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 200

[1149] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-23-benzyl-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55.

EXAMPLE 201

[1150] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26-cyclopentyl- 20-(3-guanidinopropyl)-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55. EXAMPLE 202

[1151] 3-((4R,7S,10S,13S,20S,23R,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(3-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 203

[1152] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(3-chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 204

[1153] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-23-(pyridin-2- ylmethyl)-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 205

[1154] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(2-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 206

[1155] 3-((4R,7S,10S,13S,20S,23R,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 207

[1156] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-phenylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 208

[1157] 3-((4R,7S,10S,20S,23S,26S,29R,E)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20-(3- guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacont-14-en-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 209

[1158] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-10-((5- chloro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was synthesized according to Scheme 48 with amino acids 14 and 15 [((R)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(5-chloro-1H-indol-3-yl)propanoic acid was used in place of (R)-2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1H-indol-3-yl)propanoic acid in coupling step 3 of the synthesis]; followed by Scheme 50 with amino acid 19 to yield a white solid (11.9 mg, 6.7% yield).

EXAMPLE 210

[1159] dinitrogen 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20-(3- formimidamidopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-10-((5-methyl-1H-indol-3-yl)methyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoate was synthesized according to Scheme 48 with amino acids 14 and 15 [((R)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(5-methyl-1H-indol-3-yl)propanoic acid was used in place of (R)-2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1H-indol-3-yl)propanoic acid in coupling step 3 of the synthesis]; followed by Scheme 50 with amino acid 19 to yield a white solid (29.5 mg, 17.0% yield).

EXAMPLE 211

[1160] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-3-methyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 212

[1161] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(3-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 213

[1162] 3-((4R,7S,10S,13S,20S,23R,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(2-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 214

[1163] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 215

[1164] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-23-(2-fluorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 216

[1165] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55.

EXAMPLE 217

[1166] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(4-methoxybenzyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids 14 and 89; followed by Scheme 44 with 90 to give a white solid (52 mg, 32.99 µmol, 32.14% yield, 100% purity, HCl)). LCMS: Rt=2.257, m/z 770.5 [M/2+H]⁺.¹H NMR: (MeOD-d₄, 400MHz), d 8.10-8.28 (m, 1H), 7.67-7.78 (m, 1H), 7.43 (s, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.12-7.21 (m, 1 H), 6.96-7.09 (m, 3H), 6.67-6.76 (m, 2H), 6.60 (d, J=8.4 Hz, 2H), 5.99 (s, 2 H), 5.46-5.76 (m, 2H), 4.99 (d, J=4.2 Hz, 1H), 4.52-4.68 (m, 2H), 4.36-4.50 (m, 1H), 4.16-4.29 (m, 1H), 3.88 (d, J=4.8 Hz, 1H), 3.78 (s, 3H), 3.36-3.67 (m, 4H), 2.93-3.21 (m, 10H), 1.78- 2.79 (m, 19H), 1.10-1.76 (m, 16H).

EXAMPLE 218

[1167] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-((S)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(4-methoxybenzyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 219

[1168] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55.

EXAMPLE 220

[1169] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-methylbenzyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55. EXAMPLE 221

[1170] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-cyclohexylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 222

[1171] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-(2-hydroxyethyl)propanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 223

[1172] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((2S)-2-(2-(3-amino-N-cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 224

[1173] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-propylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 225

[1174] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-butylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 226

[1175] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-benzylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 227

[1176] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-(2-aminoethyl)propanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 228

[1177] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-30-methyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 229

[1178] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- (dimethylcarbamoyl)-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 230

[1179] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(1H-indazol-5-yl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 231

[1180] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((R)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(1H-indazol-5-yl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 232

[1181] 3-((4R,7S,10S,13R,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-13-methyl-6,9,12,19,22,25,28-heptaoxo-1,2- dithia-5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 233

[1182] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-13-(hydroxymethyl)-6,9,12,19,22,25,28- heptaoxo-1,2-dithia-5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 234

[1183] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-4-carbamoyl-20-(3- guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-3-(4-hydroxyphenyl)-2-((S)-1-(pyridin-2-yl)pyrrolidine- 2-carboxamido)propanamido)-26-isopropyl-6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 235

[1184] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-20- (3-guanidinopropyl)-23-(4-hydroxybenzyl)-4-(1H-imidazol-2-yl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 236

[1185] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)- 23-benzyl-4-carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids Fmoc-phenylalanine and 89; followed by Scheme 44 with 90 to give a white solid (25.0 mg, 16.2 µmol, 26.57% yield, 100% purity, HCl). LCMS: Rt=2.214, m/z 755.5

[M/2+H]⁺.¹H NMR: (MeOD-d₄, 400MHz), d 7.61 (br d, J=9.6 Hz, 1H), 7.45 (s, 1H), 7.31 (br d, J=8.0 Hz, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.17 - 6.97 (m, 7H), 6.77 - 6.67 (m, 2H), 6.01 (br s, 2H), 5.71 (br d, J=9.8 Hz, 1H), 5.59 - 5.51 (m, 1H), 4.95 (br d, J=4.4 Hz, 1H), 4.69 - 4.62 (m, 2H), 4.47 (dd, J=3.6, 8.2 Hz, 1H), 4.25 - 4.17 (m, 1H), 3.92 (br d, J=4.2 Hz, 1H), 3.63 - 3.44 (m, 4H), 3.16 - 2.97 (m, 9H), 2.62 - 1.89 (m, 20H), 1.74 - 1.38 (m, 12H), 1.34 (d, J=6.8 Hz, 3H), 1.20 (d, J=6.6 Hz, 1H), 1.11 (br d, J=8.8 Hz, 1H).

EXAMPLE 237

[1186] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-((S)-3-aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)- 23-benzyl-4-carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 42 with amino acids Fmoc phenylalanine and 89; followed by Scheme 44 with (3S)- (tertbutoxycarbonylamino)butanoic acid to give a white solid (20.0 mg, 12.9 µmol, 20.58% yield, 99.40% purity, HCl). LCMS: Rt=2.227, m/z 756.0 [M/2+H]⁺.¹H NMR: (MeOD-d₄, 400MHz), d 7.62 (br d, J=9.8 Hz, 1H), 7.45 (s, 1H), 7.31 (br d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.16 - 6.96 (m, 7H), 6.75 - 6.68 (m, 2H), 6.00 (br d, J=7.4 Hz, 2H), 5.70 (br d, J=11.0 Hz, 1H), 5.55 (br t, J=7.4 Hz, 1H), 4.95 (br d, J=4.2 Hz, 1H), 4.69 - 4.59 (m, 2H), 4.48 - 4.43 (m, 1H), 4.25 - 4.16 (m, 1H), 3.92 (br d, J=5.4 Hz, 1H), 3.70 - 3.40 (m, 4H), 3.14 - 2.95 (m, 9H), 2.63 - 1.86 (m, 20H), 1.74 - 1.38 (m, 12H), 1.33 (d, J=6.6 Hz, 3H), 1.21 (d, J=6.6 Hz, 1H), 1.10 (br d, J=9.4 Hz, 1H). EXAMPLE 238

[1187] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-20-(3-guanidinopropyl)-23-(4-methoxybenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2- 55.

EXAMPLE 239

[1188] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-23-benzyl-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2- 55. EXAMPLE 240

[1189] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2- cyanobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2- 55.

EXAMPLE 241

[1190] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 242

[1191] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 243

[1192] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-6,9,12,15,19,22,25,28-octaoxo-26-(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7- yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 244

[1193] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-6,9,12,15,19,22,25,28-octaoxo-26-(1- (trifluoromethyl)cyclopropyl)-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 245

[1194] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclobutyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 246

[1195] 3-((3R,6S,9S,12S,19S,22S,25S,28S)-9-((1H-indol-3-yl)methyl)-12-(3-amino-3-oxopropyl)-28- ((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-3- carbamoyl-19-(3-guanidinopropyl)-22-(4-hydroxybenzyl)-25-isopropyl-5,8,11,14,18,21,24,27-octaoxo- 1-thia-4,7,10,13,17,20,23,26-octaazacyclotriacontan-6-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 247

[1196] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-4-carbamoyl-20-(3- guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-3-(4-hydroxyphenyl)-2-((S)-1-(pyrimidin-2- yl)pyrrolidine-2-carboxamido)propanamido)-26-isopropyl-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2- 55. EXAMPLE 248

[1197] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-4-carbamoyl-20-(3- guanidinopropyl)-23-(4-hydroxybenzyl)-29-((S)-3-(4-hydroxyphenyl)-2-((S)-1-(pyrimidin-4- yl)pyrrolidine-2-carboxamido)propanamido)-26-isopropyl-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2- 55.

EXAMPLE 249

[1198] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-20- (3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-4-(methylcarbamoyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55. EXAMPLE 250

[1199] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2-cyanobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 251

[1200] 3-((4R,7S,10S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20-(3- guanidinopropyl)-26-isopropyl-23-(4-methoxybenzyl)-6,9,12,19,22,25,28-heptaoxo-1,2-dithia- 5,8,11,18,21,24,27-heptaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2- 55. EXAMPLE 252

[1201] 3-((1S,4S,7S,10R,15R,18S,21S,24S)-21-((1H-indol-3-yl)methyl)-10-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-15-carbamoyl-4-(4- hydroxybenzyl)-7-isopropyl-3,6,9,17,20,23,26,30,36-nonaoxo-12,13-dithia-2,5,8,16,19,22,25,29,35- nonaazabicyclo[16.12.8]octatriacontan-24-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 253

[1202] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3-chloro-2-fluorobenzyl)-26- cyclopentyl-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 92 and 89; followed by Scheme 53 with 19 to give a white solid (47.0 mg, 28.7 µmol, 28.7% yield, 99.6% purity, HOAC). LCMS: R_t=2.365, m/z 784.1 [M/2+H]⁺. ¹H NMR: DMSO-d₆, 400MHz d 10.78 (br s, 1H), 8.06-9.32 (m, 6H), 7.16-8.04 (m, 6H), 6.69-7.16 (m, 6H), 6.55-6.69 (m, 2H), 4.89-5.94 (m, 4H), 3.67-4.80 (m, 13H), 2.62-3.27 (m, 23H), 1.74-2.48 (m, 18H), 1.11-1.73 (m, 14H). EXAMPLE 254

[1203] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-((R)-3-aminobutanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3-chloro-2-fluorobenzyl)-26- cyclopentyl-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 92 and 89; followed by Scheme 53 with 90 to give a white solid (42.0 mg, 25.5 µmol, 25.5% yield, 99.6% purity, HOAc). LCMS: Rt=2.387, m/z 790.9 [M/2+H]⁺. ¹H NMR: DMSO-d₆, 400MHz, d 10.78 (br s, 1H), 8.08-9.71 (m, 7H), 6.72-7.97 (m, 13H), 6.45-6.69 (m, 2H), 4.82-6.06 (m, 4H), 3.55-4.80 (m, 16H), 2.59-3.22 (m, 18H), 1.74-2.48 (m, 18H), 1.11-1.73 (m, 13H), 0.91-1.10 (m, 3H).

EXAMPLE 255

[1204] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-((S)-1-(3-aminopropanoyl)pyrrolidine-2- carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3-chloro-2-fluorobenzyl)-10-((5- fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2- dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 92 and 15; followed by Scheme 53 with 19 to give a white solid (25.0 mg, 15.5 µmol, 15.5% yield, 99.7% purity, HOAc). LCMS: Rt=2.323, m/z 771.4 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.77 (br s, 1H), 8.09-9.29 (m, 7H), 6.71-7.98 (m, 15H), 6.57-6.68 (m, 1H), 6.57- 6.69 (m, 1H), 4.97-5.84 (m, 4H), 3.66-4.86 (m, 16H), 2.54-3.10 (m, 17H), 1.85 (s, 4H), 2.32 (m, 2H), 0.81 (br s, 6H).

EXAMPLE 256

[1205] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3-chloro-2- fluorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13- diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 92 and 15; followed by Scheme 52 with 19 to give a white solid.

EXAMPLE 257

[1206] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3- chloro-2-fluorobenzyl)-26-cyclopentyl-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 92 and 89; followed by Scheme 50 with 19 to give a white solid (39.0 mg, 23.9 µmol, 23.9% yield, 99.6% purity, HOAc). LCMS: Rt=2.343, m/z 783.5 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.77 (br s, 1H), 7.63-9.88 (m, 8H), 6.68-7.55 (m, 11H), 6.55-6.68 (m, 2H), 4.79-6.15 (m, 4H), 4.01-4.74 (m, 4H), 3.82 (br s, 3H), 2.57-3.25 (m, 23H), 2.56-3.19 (m, 1H), 1.72-2.48 (m, 22H), 0.87-1.69 (m, 16H).

EXAMPLE 258

[1207] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-((R)-3- aminobutanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3- chloro-2-fluorobenzyl)-26-cyclopentyl-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 92 and 89; followed by Scheme 50 with 90 to give a white solid (41.0 mg, 24.9 µmol, 24.9% yield, 99.7% purity, HOAc). LCMS: Rt=2.363, m/z 790.4 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.78 (br s, 1H), 7.48-9.82 (m, 9H), 6.68-7.46 (m, 10H), 6.56-6.67 (m, 2H), 4.83-5.83 (m, 4H), 3.49-4.74 (m, 8H), 2.55-3.30 (m, 24H), 1.71-2.45 (m, 21H), 0.77-1.70 (m, 18 H). EXAMPLE 259

[1208] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3- chloro-2-fluorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 92 and 15; followed by Scheme 50 with 19 to give a white solid (31.0 mg, 19.2 µmol, 19.2% yield, 99.1% purity, HOAc). LCMS: Rt=2.301, m/z 770.3 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.78 (br s, 1H), 7.75-10.18 (m, 9H), 7.13-7.58 (m, 6H), 6.59-7.10 (m, 8H), 4.93-5.68 (m, 4H), 4.19-4.79 (m, 6H), 3.85 (br s, 2H), 2.57-3.27 (m, 24H), 1.74- 2.48 (m, 20H), 1.08-1.73 (m, 7H), 0.81 (d, J = 5.2 Hz, 5H), 0.63-0.93 (m, 1H).

EXAMPLE 260

[1209] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-(2-((R)-3-amino-N- cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3-chloro-2- fluorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13- diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 92 and 15; followed by Scheme 52 with 90 to give a white solid 2 (44.0 mg, 26.5 µmol, 26.5% yield, 99.2% purity, HOAc). LCMS: Rt=2.433, m/z 792.9 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.78 (br s, 1H), 8.45-9.24 (m, 6H), 7.14-8.36 (m, 9H), 6.67-7.13 (m, 6H), 6.62 (t, J = 8.0 Hz, 2H), 4.68-5.84 (m, 4H), 3.58-4.65 (m, 15H), 2.51-3.21 (m, 19H), 1.76-2.34 (m, 14H) ,0.94-1.71 (m, 16H), 0.82 (br s, 6H).

EXAMPLE 261

[1210] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3-chloro-2- fluorobenzyl)-26-cyclopentyl-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13- diyl)dipropionic acid was prepared according to Scheme 51 with amino acids 92 and 89; followed by Scheme 52 with 19 to give a white solid (32.0 mg, 19.2 µmol, 19.2% yield, 99.5% purity, HOAc).

LCMS: Rt=2.448, m/z 798.2[M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.80 (br s, 1H), 8.04-9.71 (m, 6H), 6.70-8.00 (m, 15H), 6.62 (m, 2H), 4.86-5.96 (m, 4H), 3.71-4.82 (m, 16H), 2.53-3.15 (m, 20H), 1.78- 2.36 (m, 15H), 0.94-1.76 (m, 18H).

EXAMPLE 262

[1211] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3-chloro-2- fluorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 92 and 15; followed by Scheme 49 with 19 to give a white solid (36.0 mg, 21.1 µmol, 21.1% yield, 99.3% purity, 2HOAc). LCMS: Rt=2.377, m/z 784.4 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.78 (br s, 1H), 8.34-9.76 (m, 6H), 6.90-8.28 (m, 13H), 6.67-6.88 (m, 3H), 6.62 (m, 2 H), 4.89-5.57 (m, 4H), 3.55-4.74 (m, 17H), 2.61-3.15 (m, 17H), 1.77-2.35 (m, 18H), 1.01-1.76 (m, 14H), 0.82 (d, J = 6.25 Hz, 6H).

EXAMPLE 263

[1212] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-(2-((R)-3-amino-N- cyclopentylbutanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3-chloro-2- fluorobenzyl)-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 92 and 15; followed by Scheme 49 with 90 to give a white solid (19.0 mg, 11.5 µmol, 11.5% yield, 99.7% purity, HOAc). LCMS: Rt=2.409, m/z 792.0 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.78 (br s, 1H), 7.95-9.66 (m, 6H), 6.65-7.91 (m, 15H), 6.51-6.65 (m, 2H), 4.74-5.53 (m, 4H), 3.51-4.69 (m, 8H), 2.61-3.10 (m, 18H), 1.79-2.43 (m, 20H), 0.92-1.74 (m, 19H), 0.82 (d, J = 5.6 Hz, 6H).

EXAMPLE 264

[1213] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-13-(3-amino-3-oxopropyl)-29-((S)-2-(2-(3-amino-N- cyclopentylpropanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(3-chloro-2- fluorobenzyl)-26-cyclopentyl-10-((5-fluoro-1H-indol-3-yl)methyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 48 with amino acids 92 and 89; followed by Scheme 49 with 19 to give a white solid (20.0 mg, 12.0 µmol, 12.0% yield, 99.6% purity, HOAc). LCMS: Rt=2.415, m/z 797.3[M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.78 (br s, 1H), 7.86-9.92 (m, 6H), 6.67-7.82 (m, 13H), 6.62 (t, J = 9.0 Hz, 2H), 4.72-5.89 (m, 4 H), 3.56-4.69 (m, 10H), 2.62-3.23 (m, 23H), 1.73-2.47 (m, 19H), 0.97-1.71 (m, 21H).

EXAMPLE 265

[1214] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- (2-aminoethyl)propanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2,3- dichlorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 45 with amino acids 97 and 15; followed Scheme 24 to give a white solid (56.0 mg, 34.0 µmol, 34.0% yield, 97.5% purity, HOAc). LCMS: Rt=2.198, m/z 772.3 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.53 (br s, 1H), 8.19-9.38 (m, 16H), 6.48-8.07 (m, 14H), 4.86-5.88 (m, 10H), 3.89-4.59 (m, 13H), 2.72-3.26 (m, 19H), 1.26-2.31 (m, 18H), 0.85 (br s, 6H).

EXAMPLE 266

[1215] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-(2-aminoethyl)propanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-23-(2,3-dichlorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 43 with amino acids 97 and 15; followed by Scheme 24 with 19 to give a white solid (40.0 mg, 23.8 µmol, 23.8% yield, 95.3% purity, HOAc). LCMS: Rt=2.173, m/z 771.6 [M/2+H]⁺.¹H NMR:

DMSO-d₆, 400MHz, d 10.53 (br s, 1H), 7.67-9.68 (m, 9H), 6.52-7.47 (m, 18H), 4.99-5.90 (m, 8H), 4.00- 4.76 (m, 10H), 2.68-3.15 (m, 17H), 1.27-2.29 (m, 25 H), 0.73-0.95 (m, 6H).

EXAMPLE 267

[1216] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((S)-2-(2-(3-amino-N-(2-aminoethyl)propanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-26-cyclopentyl-23-(2,3-dichlorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Scheme 43 with amino acids 97 and 89; followed by Scheme 24 with 19 to give a white solid (23.0 mg, 13.4 µmol, 13.4% yield, 95.1% purity, HOAC). LCMS: Rt=2.207, m/z 783.8 [M/2+H]⁺. ¹H NMR: DMSO-d₆, 400MHz, d 10.51 (br s, 1H), 8.29-9.90 (m, 7H), 7.11-8.21 (m, 12H), 6.53-7.09 (m, 8H), 4.95-6.00 (m, 4H), 3.83-4.78 (m, 8H), 2.60-3.23 (m, 23H), 1.80-2.37 (m, 22H), 1.00-1.76 (m, 12H).

EXAMPLE 268

[1217] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- (2-aminoethyl)propanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-26- cyclopentyl-23-(2,3-dichlorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Scheme 43 with amino acids 97 and 89; followed by Scheme 24 with 19 to give a white solid (21.0 mg, 12.4 µmol, 12.4% yield, 96.4% purity, HOAC). LCMS: Rt=2.237, m/z 785.5 [M/2+H]⁺.¹H NMR: DMSO-d₆, 400MHz, d 10.51 (br s, 1H), 8.29-9.90 (m, 8H), 6.95-8.21 (m, 18H), 6.59-6.65 (m, 2H), 4.27- 5.75 (m, 6H), 2.66-3.27 (m, 27H), 1.83-2.66 (m, 14H), 1.75 (s, 3H), 0.85-1.54 (m, 16H).

EXAMPLE 269

[1218] 3,3'-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-(2-(3-amino-N- (2-hydroxyethyl)propanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-23-(2,3- dichlorobenzyl)-20-(3-guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid was prepared according to Schemes 2-55.

EXAMPLE 270

[1219] 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)- 29-((2S)-2-(2-(3-amino-N-(pyrrolidin-3-yl)propanamido)acetamido)-3-(4-hydroxyphenyl)propanamido)- 4-carbamoyl-26-cyclopentyl-23-(2,3-dichlorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid was prepared according to Schemes 2-55.

EXAMPLE 271

[1220] Biological Samples and Assays

[1221] EphA4 LANCE TR-FRET assay:

[1222] Ligand Binding Domain solution was prepared by combining 50nM His-tagged human EphA4 LBD (GSK, La Jolla, CA, USA) with 10nM APC-anti-6XHis (Perkin Elmer, Waltham, MA, USA) in LANCE Detection buffer (Perkin Elmer, Waltham, MA, USA) and incubated in the dark for 30 minutes at room temperature. Receptor Binding Domain solution was prepared by combining 6.25nM human EphrinA5 RBD-hFc (COI Pharmaceuticals, La Jolla, CA, USA) with 2nM Eu-W1024 anti-human IgG (Perkin Elmer, Waltham, MA, USA) in LANCE Detection buffer (Perkin Elmer, Waltham, MA, USA) and incubated in the dark for 30 min at room temperature. Dilution series of compounds were added to the prepared Ligand Binding Domain solution in 50 ml final volume and incubated for 30 min at room temperature in white 384-well plates. After the compound incubation, 50 ml Receptor Binding Domain solution was added followed by a 1 hour incubation in the dark at room temperature. The plate was then read on a Victor 3 plate reader (Perkin Elmer, Waltham, MA, USA) for TR-FRET signal with 340 nm excitation and 615nm/665nm emission. The IC50 was determined by fitting the 665nm TR-FRET data into a Sigmoidal dose-response (variable slope) non-linear regression model.

[1223] EphA4 phosphorylation/SH2 recruitment cellular assay:

[1224] Inhibition of cellular EphA4 activation was determined with the PathHunter enzyme fragment complementation system from DiscoverX (San Diego, CA, 92130). Briefly U2OS cells stably expressing EphA4 were plated at 1x10⁴ cells in 20 ml/well into a 384 well plate and incubated overnight. Compounds were prepared in a 9-point serial dilution and 5 ml of the compound dilutions were added to the plate and incubated at 37 ^C for 60 minutes in a 5% CO₂ incubator.5 ml of EphrinA4 (R&D Systems, Minneapolis, MN, USA) (20 nM final concentration) was added to the plate and then incubated at room temperature for 180 minutes. PathHunter detection solution was added to the wells and incubated at room temperature in the dark for 1 hour. The resulting luminescence was then read on a Victor 3 plate reader (Perkin Elmer, Waltham, MA, USA). The IC50 was determined by fitting the luminescence data into a Sigmoidal dose-response (variable slope) non-linear regression model.

[1225] EphA4 Growth Cone Collapse Functional Assay:

[1226] Inhibition of Ephrin ligand-induced growth cone collapse was determined with neonatal mouse primary cortical neurons. Cortical neurons from E19 C57Bl/6 mouse embryos were isolated by trypsin digestion in Neurobasal medium (Gibco). After straining through a 70 ^m strainer, cells were plated on 12mm round coverslips coated with poly-D-lysine/mouse laminin (Corning BioCoat Cellware) at 75,000 cells per well in 24-well plates in Neuronal Culture Medium (Neurobasal medium +

Antibiotic/antimycotic + GlutaMax + B-27 supplement). After overnight culture, cells were pre-treated with inhibitor compound for 30 minutes followed by 30 minute stimulation with 1 ^g/ml preclustered Fc- EphrinA5 (R&D Systems). Cells were then fixed in 4% paraformaldehyde for 30 minutes at 37C. After fixation, cells were permeabilized for 20 minutes in a solution containing 0.3% Triton X-100, 5% normal goat serum and 5% bovine serum albumin. Cells were then stained for 20 min with Alexa546-Phalloidin (Thermo-Fisher) (1:100 diluted in 0.3% Triton X-100, 5% Normal Goat Serum, 5% BSA). After washing, slides were sealed with Vectashield plus DAPI. Growth cones were identified by fluorescence microscopy and the number of collapsed axonal growth cones was determined relative to the total number of axonal growth cones.

[1227] Using the assays described herein, the activity for several compounds disclosed herein was determined. The potency levels are set forth in Table 8, wherein IC₅₀: A < 0.1 µM; B = 0.1-0.5 µM; and C > 0.5 µM.

Table 8

guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontan-7-yl)propanoic acid

20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontan-7-yl)propanoic acid

23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,19,22,25,28- heptaoxo-1,2-dithia-5,8,11,18,21,24,27-heptaazacyclotriacontan- 7-yl)propanoic acid

(trifluoromethyl)cyclopropyl)-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacontan-7-yl)propanoic acid

chlorobenzyl)-26-cyclopentyl-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontan-7-yl)propanoic acid

(2,5-dichlorobenzyl)-20-(3-guanidinopropyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontan-7-yl)propanoic acid

5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13- diyl)dipropionic acid

octaazacyclotriacontane-7,13-diyl)dipropionic acid

guanidinopropyl)-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13- diyl)dipropionic acid

octaazacyclotriacontan-7-yl)propanoic acid

octaazacyclohentriacontan-7-yl)propanoic acid

octaazacyclotriacontan-7-yl)propanoic acid

guanidinopropyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13- diyl)dipropionic acid

6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontan-7-yl)propanoic acid

6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontane-7,13-diyl)dipropionic acid

octaazacyclotriacontane-7,13-diyl)dipropionic acid

hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo- 1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-7- yl)propanoic acid

6,9,12,19,22,25,28-heptaoxo-1,2-dithia-5,8,11,18,21,24,27- heptaazacyclotriacont-14-en-7-yl)propanoic acid

(2-fluorobenzyl)-20-(3-guanidinopropyl)-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontan-7-yl)propanoic acid

hydroxybenzyl)-26-isopropyl-4-(methylcarbamoyl)- 6,9,12,15,19,22,25,28-octaoxo-1,2-dithia-5,8,11,14,18,21,24,27- octaazacyclotriacontan-7-yl)propanoic acid

1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13- diyl)dipropionic acid

y y )p p

1 ND = Not determined

[1228] EXAMPLE 121 was investigated in the growth cone assay (FIG.1A). Five groups were investigated: a no stimulation group, a vehicle group and three concentrations of Example 121 (100, 300 and 1000 nM). EXAMPLE 121 blocked ephrin-induced growth cone collapse with complete inhibition observed at 1000 ^nM.

[1229] EXAMPLE 63 was investigated in the growth cone assay (FIG.1B). Five groups were investigated: a no stimulation group, a vehicle group and three concentrations of Example 64 (100, 300 and 1000 nM). EXAMPLE 63 blocked ephrin-induced growth cone collapse with complete inhibition observed at 300 ^nM.

[1230] EXAMPLE 272: This study seeks to evaluate the efficacy and safety of EXAMPLE 63 and EXAMPLE 121 in subjects with mild cognitive impairment due to Alzheimer's Disease.

[1231] Primary Outcome Measures:

[1232] Change from baseline in Clinical Dementia Rating Scale- Sum of Boxes (CDR-SB) score at Week 24 [ Time Frame: Week 24 ]

[1233] To study to the change from baseline in the Clinical Dementia Rating scale-Sum of Boxes (CDR- SB) score at Week 2 and Week 24.

[1234] The CDR-SB is obtained through interviews of patients and informants, and cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The CDR-SOB score is obtained by summing each of the domain box scores, with scores ranging from 0 to 18 with the higher values represent worse outcome. [1235] Secondary Outcome Measures :

[1236] Mean difference between the last (Week 24) and first (Week 2) postdose using Clinical

[1237] Dementia Rating Scale- Sum of Boxes (CDR-SB) assessment [ Time Frame: Week 24 ]

[1238] To assess the Clinical Dementia Rating Scale- Sum of Boxes (CDR-SB) mean difference between the

[1239] Week 2 and Week 24

[1240] The CDR-SB is obtained through interviews of patients and informants, and cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The CDR-SOB score is obtained by summing each of the domain box scores, with scores ranging from 0 to 18, with the higher values represent worse outcome.Assess the change from baseline in ADCS-ADL MCI at Week 24.

[1241] Time Frame Week 24

[1242] Change from baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version) (ADCS-ADL MCI) at Week 24.

[1243] The Galasko method for Alzheimer Disease Cooperative Study (ADCS) will be used, which contains 23 items covering physical and mental functioning and independence in self-care. For Activities of Daily Living (ADLs), the scoring used was the following: 0 = no impairment, 1 = problem performing but no supervision or assistance needed, 2 = problem requiring supervision, 3 = problem with assistance needed, and 4 = unable to perform.

[1244] The scores range from 0 to 78, with higher values indicating greater disability. Change from baseline in Clinical Dementia Rating Scale- Sum of Boxes (CDR-SB) score at Week 24 [ Time Frame: Week 24 ] To study to the change from baseline in the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score at Week 2 and Week 24. The CDR-SB is obtained through Current Primary interviews of patients and informants, and cognitive functioning is rated in 6 domains Outcome of functioning: memory, orientation, judgment and problem solving, community Measures affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The CDR-SOB score is obtained by summing each of the domain box scores, with scores ranging from 0 to 18 with the higher values represent worse outcome. Change from baseline in CDR-SB score at Week 24

Original Primary

Outcome [ Time Frame: Baseline and Week 24 ] [ Time Frame: Week 24 ]

Measures

To study to the change from baseline in the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score at 24

^ 1. Mean difference between the last (Week 24) and first (Week 2) postdose using Clinical Dementia Rating Scale- Sum of Boxes (CDR-SB) assessment

[ Time Frame: Week 24 ]

To assess the Clinical Dementia Rating Scale- Sum of Boxes (CDR-SB) mean difference between the Week 2 and Week 24. The CDR-SB is obtained through interviews of patients and informants, and cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating Current

available). The CDR-SOB score is obtained by summing each of the domain box Secondary

scores, with scores ranging from 0 to 18, with the higher values represent worse Outcome

outcome.

Measures

^ Assess the change from baseline in ADCS-ADL MCI at Week 24

[ Time Frame: Week 24 ]

Change from baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version) (ADCS-ADL MCI) at Week 24. The Galasko method for Alzheimer Disease Cooperative Study (ADCS) will be used, which contains 23 items covering physical and mental functioning and independence in self-care. For Activities of Daily Living (ADLs), the scoring used was the following: 0 = no impairment, 1 = problem performing but no supervision or assistance needed, 2 = problem requiring supervision, 3 = problem with assistance needed, and 4 = unable to perform. The scores range from 0 to 78, with higher values indicates greater disability.

Original ^ 1. Mean difference between the last (Week 24) and first (Week 2) postdose CDR- Secondary SB assessment [ Time Frame: Weeks 2 and 24 ] [ Time Frame: Week 24 ] Outcome

To assess the CDR-SB mean difference between the Week 2 and Week 24 Measures Assess the change from baseline in ADCS-ADL MCI at Week 24

[ Time Frame: Week 24 ]

Change from baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version) (ADCS-ADL MCI) at Week 24

Descriptive Information

A Double-Blind, Placebo-Controlled Safety and Efficacy Study of EXAMPLE 63 and Brief Title

EXAMPLE 121

A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Official Title Tolerability, and Efficacy of EXAMPLE 63 and EXAMPLE 121 in Alzheimer

Patients With Mild Cognitive Impairment

This study seeks to evaluate the efficacy and safety of EXAMPLE 63 and EXAMPLE Brief Summary

121 in subjects with mild cognitive impairment due to Alzheimer's Disease

Mild cognitive impairment ("MCI") is defined as the "symptomatic pre-dementia stage" on the continuum of cognitive decline. Currently, no medications have proven Detailed

effective for MCI. This study seeks to evaluate the efficacy and safety of EXAMPLE Description

63 and EXAMPLE 121 in 126 subjects with mild cognitive impairment due to Alzheimer's Disease

Study Type Interventional

Study Phase Phase 2

Allocation: Randomized

Intervention Model: Parallel Assignment

Study Design

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) Primary Purpose: Other

Mild Cognitive Impairment

Alzheimer Disease

Alzheimer Dementia

Dementia, Vascular

Condition Dementia With Lewy Bodies

Cognitive Impairment

Tauopathies

Neurodegenerative Diseases

Neurocognitive Disorders

Cognitive Disorder ^ Drug: EXAMPLE 63 or EXAMPLE 12110 mg QD

Administration of 10 mg of EXAMPLE 63 or EXAMPLE 121 QD for 24 weeks ^ Drug: EXAMPLE 63 or EXAMPLE 12120 mg QD

Administration of 20 mg of EXAMPLE 63 or EXAMPLE 121 QD for 24 weeks Intervention ^ Drug: EXAMPLE 63 or EXAMPLE 12140 mg QD

Administration of 40 mg of EXAMPLE 63 or EXAMPLE 121 QD or for 24 weeks

^ Drug: Placebo QD

Administration of placebo QD or 24 weeks ^ Experimental: Low-dose EXAMPLE 63 and EXAMPLE 12110 mg QD Administration of 10 mg of EXAMPLE 63 or EXAMPLE 121 per day for 24 weeks

Intervention: Drug: EXAMPLE 63 and EXAMPLE 12110 mg QD ^ Experimental: Medium-dose EXAMPLE 63 or EXAMPLE 12120 mg QD

Administration of 20 mg of EXAMPLE 63 OR EXAMPLE 121 QD for 24 weeks Study Arms Intervention: Drug: EXAMPLE 63 or EXAMPLE 12120 mg QD

^ Experimental: High-dose EXAMPLE 63 or EXAMPLE 121- 40 mg QD Administration of 40 mg of EXAMPLE 63 or EXAMPLE 121 QD for 24 weeks Intervention: Drug: EXAMPLE 63 or EXAMPLE 12140 mg QD ^ Placebo Comparator: Placebo

Administration of placebo per day for 24 weeks

Intervention: Drug: Placebo QD

[1245] The structure of EXAMPLE 121 is:

[1246] The structure of EXAMPLE 63 is:

[1247] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of structural Formula (I):

(I),

X¹ is CR⁹R¹⁰ or S;

X² is CR¹¹R¹² or S;

X³ is–NH– or–C(O)NH–,

z1 is an integer from 0 to 2;

z2 is an integer from 0 to 5;

R¹ is hydrogen, halogen,–CX^1.1

3, -CHX1.1

2, -CH₂X^1.1,–CN,–N₃,–SO_n1R^1A,–SO_v1NR^1BR^1C,

-NHNR^1BR^1C, -ONR^1BR^1C, -NHC(O)NHNR^1BR^1C, -NHC(O)NR^1BR^1C,–N(O) ^C m₁,–NR^1BR¹ ,– C(O)R^1D,–C(O)OR^1D,–C(O)NR^1BR^1C,–OR^1A, -NR^1BSO ^1B

2R^1A, -NR C(O)R^1D, -NR^1BC(O)OR^1D,– NR^1BOR^1D,–OCX^1.1

3,–OCHX1.1

R² is hydrogen, halogen,–CX^2.1

3, -CHX2.1

2, -CH₂X^2.1,–CN,–N₃,–SO_n2R^2A,–SO_v2NR^2BR^2C,

3,–OCHX2.1

R⁴ is hydrogen, halogen,–CX^4.1

3, -CHX4.1

R⁵ is hydrogen, halogen, oxo,–CX^5.1

3, -CHX5.1

3,–OCHX5.1

R⁶ is hydrogen, halogen,–CX^6.1

3, -CHX6.1

2, -CH₂X^6.1,–CN,–N₃,–SO_n6R^6A,–SO_v6NR^6BR^6C,

3,–OCHX6.1

R⁷ is hydrogen, halogen,–CX^7.1

3, -CHX7.1

2, -CH₂X^7.1,–CN,–N₃,–SO_n7R^7A,–SO_v7NR^7BR^7C,

3,–OCHX7.1

3, -CHX8.1

2, -CH₂X^8.1,–CN,–N₃,–SO_n8R^8A,–

3,–OCHX8.1

R⁹ is hydrogen, halogen,–CX^9.1

3, -CHX9.1

2, -CH₂X^9.1,–CN,–N₃,–SO_n9R^9A,–SO_v9NR^9BR^9C,

3,–OCHX9.1

R¹⁰ is hydrogen, halogen,–CX^10.1

3, -CHX10.1

3,–OCHX10.1

R¹¹ is hydrogen, halogen,–CX^11.1

3, -CHX11.1

3,–OCHX11.1

R¹² is hydrogen, halogen,–CX^12.1

3, -CHX12.1

3,–OCHX12.1

2. The compound of claim 1, wherein the compound is not 3-((4R,7S,10S,13S,20S,23S,26S,29R)-10- ((1H-indol-3-yl)methyl)-13-(3-amino-3-oxopropyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20- (3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontan-7-yl)propanoic acid; 3- ((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-7-(3-amino-3-oxopropyl)-29-((S)- 2-((S)-1-(3-aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4- carbamoyl-20-(3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28- octaoxo-1,2-dithia-5,8,11,14,18,21,24,27-octaazacyclotriacontan-13-yl)propanoic acid; or 3,3'- ((4R,7S,10S,13S,20S,23S,26S,29R)-10-((1H-indol-3-yl)methyl)-29-((S)-2-((S)-1-(3- aminopropanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-4-carbamoyl-20- (3-guanidinopropyl)-23-(4-hydroxybenzyl)-26-isopropyl-6,9,12,15,19,22,25,28-octaoxo-1,2-dithia- 5,8,11,14,18,21,24,27-octaazacyclotriacontane-7,13-diyl)dipropionic acid.

3. The compound of claim 1 or 2, wherein the compound has structural Formula (II):

4. The compound of any one of claims 1-3, wherein the compound has structural Formula (III):

( ), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

5. The compound of any one of claims 1-4, wherein the compound has structural Formula (IV):

( ),

z3 is an integer from 0 to 5;

n13 is an integer from 0 to 4;

m13 and v13 are independently 1 or 2;

R¹³ is independently hydrogen, halogen,–CX^13.1

3, -CHX13.1

2, -CH₂X^13.1,–CN,–N₃,–SO_n13R^13A,– SO_v13NR^13BR^13C, -NHNR^13BR^13C, -ONR^13BR^13C, -NHC(O)NHNR^13BR^13C, -NHC(O)NR^13BR^13C,– N(O)_m13,–NR^13BR^13C,–C(O)R^13D,–C(O)OR^13D,–C(O)NR^13BR^13C,–OR^13A, -NR^13BSO₂R^13A, - NR^13BC(O)R^13D, -NR^13BC(O)OR^13D,–NR^13BOR^13D,–OCX^13.1

3,–OCHX13.1

R^13A, R^13B, R^13C, and R^13D are independently hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,– CONH₂, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^13B and R^13C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and

X^13.1 is–Cl,–Br,–I, or–F.

6. The compound of claim 5, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R¹³ is independently hydrogen, halogen, or–OH.

7. The compound of claim 5 or 6, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R¹³ is independently hydrogen or halogen.

8. The compound of any one of claims 5-7, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein z3 is 1 or 2.

9. The compound of claim 1, wherein the compound has structural Formula (IV-1):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic

variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:

n13.1 and n13.2 are independently an integer from 0 to 4;

m13.1, m13.2, v13.1, and v13.2 are independently 1 or 2;

R^13.1 is hydrogen, halogen,–CX^{13.1A .1A}

3, -CHX13.1A

2, -CH₂X^13.1A,–CN,–N₃,–SO_n13.1R¹³ ,–

SO_v13.1NR^13.1BR^13.1C, -NHNR^13.1BR^13.1C, -ONR^13.1BR^13.1C, -NHC(O)NHNR^13.1BR^13.1C,

-NHC(O)NR^13.1BR^13.1C,–N(O) ^D

m_13.1,–NR^13.1BR^13.1C,–C(O)R^13.1 ,–C(O)OR^13.1D,–C(O)NR^13.1BR^13.1C, –OR^13.1A, -NR^13.1BSO ^1D

2R^13.1A, -NR^13.1BC(O)R^13.1D, -NR^13.1BC(O)OR^13. ,–NR^13.1BOR^13.1D,–

OCX^13.1A 1A

3,–OCHX13.

R^13.2 is hydrogen, halogen,–CX^13.2A

3, -CHX13.2A

2, -CH₂X^13.2A,–CN,–N₃,–SO_n13.2R^13.2A,–

SO ^.2B

v_13.2NR^13.2BR^13.2C, -NHNR^13.2BR^13.2C, -ONR¹³ R^13.2C, -NHC(O)NHNR^13.2BR^13.2C,

-NHC(O)NR^13.2BR^13.2C,–N(O) ^13.2B

m_13.2,–NR R^13.2C,–C(O)R^13.2D,–C(O)OR^13.2D,–C(O)NR^13.2BR^13.2C, –OR^13.2A, -NR^13.2BSO ^.2A, -NR^13.2BC(O)R^13.2D, -NR^13.2B

2R¹³ C(O)OR^13.2D,–NR^13.2BOR^13.2D,– OCX^13.2A 13.2A

3,–OCHX ₂, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^13.1A, R^13.1B, R^13.1C, R^13.1D, R^13.2A, R^13.2B, R^13.2C, and R^13.2D are independently hydrogen, halogen,–CF₃,– CCl₃,–CBr₃,–CI₃,–COOH,–CONH₂, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^13B and R^13C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl; and X^13.1A and X^13.2A are independently–Cl,–Br,–I, or–F.

10. The compound of claim 9, wherein each of R^13.1 and R^13.2 is independently hydrogen or halogen.

11. The compound of claim 1, wherein the compound has structural Formula (V):

12. The compound of claim 1, wherein the compound has structural Formula (VI-A):

n14 is an integer from 0 to 4;

m14 and v14 are independently 1 or 2;

R¹⁴ is hydrogen, halogen,–CX^{14.1 B}

3, -CHX^14.14, -CH₂X^14.1,–CN,–N ^4A

3,–SO_n14R¹ ,–SO_v14NR¹⁴ R^14C, -NHNR^14BR^14C, -ONR^14BR^14C, -NHC(O)NHNR^14BR^14C, -NHC(O)NR^14BR^14C,–N(O)_m14,– NR^14BR^14C,–C(O)R^14D,–C(O)OR^14D,–C(O)NR^14BR^14C,–OR^14A, -NR^14BSO ^D

2R^14A, -NR^14BC(O)R¹⁴ , - NR^14BC(O)OR^14D,–NR^14BOR^14D,–OCX^14.1

3,–OCHX^14.1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^14A, R^14B, R^14C, and R^14D are independently hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,– CONH₂, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or

R^14B and R^14C substituents bonded to the same nitrogen atom may optionally be joined to form a

substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X^14.1 is–Cl,–Br,–I, or–F.

13. The compound of claim 1, wherein the compound has structural Formula (VI-B):

n14 is an integer from 0 to 4;

m14 and v14 are independently 1 or 2;

R¹⁴ is hydrogen, halogen,–CX^14.1

3, -CHX^14.14, -CH₂X^14.1,–CN,–N₃,–SO_n14R^14A,–SO_v14NR^14BR^14C, -NHNR^14BR^14C, -ONR^14BR^14C, -NHC(O)NHNR^14BR^14C, -NHC(O)NR^14BR^14C,–N(O)_m14,– NR^14BR^14C,–C(O)R^14D,–C(O)OR^14D,–C(O)NR^14BR^14C,–OR^14A, -NR^14BSO ^4B

2R^14A, -NR¹ C(O)R^14D, - NR^14BC(O)OR^14D,–NR^14BOR^14D,–OCX^14.1

14. The compound of any one of claims 1 or 3-12, or an enantiomer, a mixture of enantiomers, a

mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R³ is hydrogen or–C=NHNH₂.

15. The compound of any one of claims 1 or 3-14, or an enantiomer, a mixture of enantiomers, a

mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R⁸ is hydrogen, halogen, or alkyl.

16. The compound of any one of claims 1 or 2-15, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R⁸ is hydrogen or halogen.

17. The compound of any one of claims 1 or 3-16, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein z2 is 1.

18. The compound of any one of claims 1 or 3-17, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X¹ is S.

19. The compound of any one of claims 1 or 3-18, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X² is S.

20. The compound of any one of claims 1 or 3-19, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein L¹ is substituted or unsubstituted alkylene.

21. The compound of any one of claims 1 or 3-20, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein L¹ is unsubstituted alkylene.

22. The compound of any one of claims 1 or 3-21, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein L¹ is–CH₂–.

23. The compound of any one of claims 1 or 3-22, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein L² is substituted or unsubstituted alkylene.

24. The compound of any one of claims 1 or 3-23, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein L² is unsubstituted alkylene.

25. The compound of any one of claims 1 or 3-24, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein L² is–CH₂–.

26. The compound of any one of claims 1 or 3-25, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein L³ is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

27. The compound of claim 1, wherein the compound has structural Formula (VII-1) or Formula (VII- 2):

( ),

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R¹⁷ is–NH₂ or–OH.

28. The compound of claim 1, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the compound has structural Formula (VIII-1) or Formula (VIII-2):

( ),

variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein

R¹⁷ is–NH₂ or–OH.29.

29. The compound of any one of claims 1 or 3-28, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R⁵ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

30. The compound of any one of claims 1 or 3-29, or an enantiomer, a mixture of enantiomers, a

mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R⁵ is methyl, 2-butyl, propyl, (CH₂CH₂SCH₃),

, ,

31. The compound of any one of claims 1 or 3-30, or an enantiomer, a mixture of enantiomers, a

mixture of two or more diasteroemers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R⁵ is propyl or

32. The compound of any one of claims 1 or 3-31, or an enantiomer, a mixture of enantiomers, a

mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R⁶ is substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroaryl.

33. The compound of any one of claims 1 or 3-32, or an enantiomer, a mixture of enantiomers, a

mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R⁶ is:

wherein:

n14 is an integer from 0 to 4;

m14 and v14 are independently 1 or 2;

R¹⁴ is hydrogen, halogen,–CX^{14.1 4C}

3, -CHX14.1

2, -CH₂X^14.1,–CN,–N₃,–SO_n14R^14A,–SO_v14NR^14BR¹ , -NHNR^14BR^14C, -ONR^14BR^14C, -NHC(O)NHNR^14BR^14C, -NHC(O)NR^14BR^14C,–N(O)_m14,– NR^14BR^14C,–C(O)R^14D,–C(O)OR^14D,–C(O)NR^14BR^14C,–OR^14A, -NR^14BSO₂R^14A, -NR^14BC(O)R^14D, - NR^14BC(O)OR^14D,–NR^14BOR^14D,–OCX^14.1

3,–OCHX14.1

R^14A, R^14B, R^14C, and R^14D are independently hydrogen, halogen,–CF₃,–CCl₃,–CBr₃,–CI₃,–COOH,– CONH₂, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^14B and R^14C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and

X^14.1 is–Cl,–Br,–I, or–F.

34. The compound of any one of claims 1 or 3-33, or an enantiomer, a mixture of enantiomers, a

35. The compound of claim 33 or 34, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R¹⁴ is hydrogen, halogen,–CN,–SO_n14R^14A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

36. The compound of any one of claims 32-35 , or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R¹⁴ is substituted or unsubstituted heteroalkyl or substituted or unsubstituted heteroaryl.

37. The compound of any one of claims 32-36, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R¹⁴ is

, , , , , , ,

38. The compound of any one of claims 1 or 3-37, or an enantiomer, a mixture of enantiomers, a

mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R⁷ is substituted aryl.

39. The compound of any one of claims 1 or 3-38, or an enantiomer, a mixture of enantiomers, a

mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R⁴ is substituted aryl.

40. The compound of claim 1, wherein the compound has structural Formula (I-A):

41. The compound of claim 1, wherein the compound is:

variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

42. A pharmaceutical composition, comprising a compound of any one of claims 1-41, or an

enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a

pharmaceutically acceptable excipient.

43 A method of inhibiting Ephrin type-A receptor 4 (EphA4), comprising contacting EphA4 with a compound of any one of claims 1-41, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or the pharmaceutical composition of claim 42.

44. A method of treating a disease or disorder associated with EphA4 in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1-41 or the

pharmaceutical composition of claim 42, wherein the administration reduces at least one symptom associated with the EphA4-associated disease or disorder.

45. A method of preventing a disease or disorder associated with EphA4 in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1-41 or the pharmaceutical composition of claim 42, wherein the administration reduces at least one symptom associated with the EphA4-associated disease or disorder.

46. The method of claim 45, wherein the disease or disorder comprises a condition, a disease, a

disorder and/or pathology where a pathophysiology effect is due to dysregulation of EphA4 signaling in a manner that causes EphA4 signaling hyperactivity in cells or spatially or temporally aberrant EphA4 signaling.

47. The method of claim 45, wherein the disease or disorder is a neurodegenerative disease, a hearing loss, a promotion of nerve regeneration, a promotion of neuroprotection, or a cancer.

48. The method of claim 47, wherein the neurodegenerative disease or disorder is an Alexander

disease, an Alper's disease, Alzheimer's disease, an amyotrophic lateral sclerosis, an ataxia telangiectasia, a Canavan disease, a Cockayne syndrome, a corticobasal degeneration, a

Creutzfeldt- Jakob disease, a Guillain-Barre Syndrome, a HIV-induced neurodegeneration, a Huntington disease, a Kennedy's disease, a Krabbe disease, a Lewy body dementia, a Machado- Joseph disease, a multiple sclerosis, a Parkinson's disease, a Pelizaeus-Merzbacher disease, a Pick's disease, a primary lateral sclerosis, a Refsum's disease, a Sandhoff disease, a Schilder's disease, a spinal cord injury, a Steele-Richardson-Olszewski disease, a stroke, a tabes dorsalis, and/or a traumatic brain injury.

49. The method of claim 47, wherein the neurodegenerative disease or disorder is Alzheimer's disease.

50. The method of claim 47, wherein the cancer is a glioblastoma, a gastric cancer, a pancreatic cancer, a prostate cancer, a breast cancer, a liver cancer, a leukemia, or a Sezary syndrome.

51. The method of any one of claims 45-50, wherein the at least one symptom includes abnormal movement, abnormal sensation, limb grasping, muscle weakness, atrophy, paralysis, abnormal inhibition of axon growth, abnormal axonal transport, aberrant synaptic function, synaptic transmission loss, impaired synaptic plasticity, synaptic loss, neuronal degeneration, motor neuron degeneration, motor neuron loss, poor neuronal survival, memory loss, impaired learning, dementia, b-amyloid plaque deposits, aberrant neurofilament accumulation, reactive astroglia, and/or reactive microglia.

52. The method of any one of claims 45-51, wherein the method furhter comprises administering to a subject in need thereof, a second therapy.

53.The method of claim 52, wherein the second therapy is an anti-cancer therapy.

54. The method of claim 52, wherein the second therapy is an anti-inflammatory therapy.

55.The method of claim 52, wherein the second therapy is an anti-neurodegeneration therapy.