AU2019378162B2 - Peptides and pharmaceutical compositions for treating eye diseases - Google Patents

Abstract

The present invention relates to novel peptides and a pharmaceutical compositions comprising the same. The peptide compounds and compositions disclosed herein are useful as therapeutic agents for treating eye diseases. When administered to the eyes, the peptide compounds and compositions disclosed herein increase the amount of tear secretion and promotes recovery of a damaged cornea.

Description

Peptides and Pharmaceutical Compositions for Treating Eye Diseases

Related Applications This application claims the benefit of priority to United States Provisional Patent Application serial number 62/767,180, filed November 14, 2018; the contents of which are hereby incorporated by reference.

Technical Field The present invention relates to peptides and pharmaceutical compositions for treating eye diseases. Background Dry eye syndrome or keratoconjunctivitis sicca may be defined, in a broad sense, as damage to the ocular surface due to tear secretion disorders (Joossen C et al., Exp. Eye Res., 146:172-8, 2016). Dry eye syndrome is known to cause tear secretion disorders and damage and discomfort to the eyeball due to a combination of various factors. Although the onset of dry eye syndrome is closely related to age, the incidence thereof is increasing in younger age groups due to a long-term exposure to a dry environment as the use of contact lenses, computers, and smart devices (Stern ME et al., Int. Rev. Immunol., 32: 19-41, 2013). Specifically, dry eye syndrome reduces the mucus secretion of the corneal and conjunctival epithelia and that of the mucus-secreting goblet cells, resulting in a sharp decrease in the lubrication of the eyeball. In addition, dry eye syndrome causes damage to the corneal surface, thereby increasing the penetration of a fluorescein dye into the cornea. These symptoms of dry eye syndrome can be evaluated as changes in the tear secretion through the Schirmer test, which uses cobalt chloride paper. Further, the damage to the cornea that may accompany dry eye syndrome can be easily evaluated using a general fluorescent dye and a slit-lamp fluorophotometer. In the meantime, most of the treatments for dry eye syndrome are confined to symptom therapies, the treatment efficiency of which is often very low. Currently, artificial tears are the first choice for the treatment of dry eye syndrome. Artificial tears as a representative symptom therapy merely supplement the insufficient tears; moreover, they suffer from the disadvantage that they need to be administered to the eyes frequently (Kim CS et al., Nutrients 8. pii: E750, 2016). Sodium hyaluronate and eye drops derived from autologous serum have been developed and used in patients suffering from dry eye syndrome. In addition, such synthetic compounds as rebamipide (OPC-127959) and diquafosol sodium, which promote the secretion of tears and mucus, have been developed and used. Long-term use of these drugs, however, may give rise to various side effects such as ocular hyperemia and corneal calcification (Bernauer W et al., Br. J Ophthalmol., 90:285-8, 2006). Therefore, there has been a demand for the development of a safe and effective therapeutic agent for treating dry eye syndrome.

Summary of Invention In certain aspects, the present invention provides a composition comprising a pharmaceutically acceptable salt of a compound represented by Formula (I): (R4)p H R O R2 OH CH3 0 H N N NH N' N N N N H": 88 N"j OH H _ H H H R

(I)

wherein: R4, independently for each occurrence, is selected from -CH 3 , -OR, -CH 2OR, halo, hydroxyl, and hydroxy(Ci-6)alkyl; Rb is unsubstitutedC1-6alkyl; p is 1 or 2; R6 is hydrogen or substitutedC 1 -6alkyl, wherein theC1 -6alkyl is optionally substituted with one occurrence of -C(=O)NH 2 ; and R 7, R 8, and R9 are each independently hydrogen orC1 -6alkyl;

0 o 0H

R' is selected from H HO 0 H 2 , H 2N NH 2

HNH CH 3 H 3C OH H 3C OH CH 3 H 3C CH 3 H3 H3

and H

CH 3 CH 3 H H3 C CH 3 CH 3 CH 3 CH 3 <OH

R2 is selected from ,and H 3C OH

Sand

H 3C

R3 is selected from NH H3 HO Oand wherein the compound is not: H 2N 0 HO O 0 H O0 H CH3H H H 0 H 0 0 N N N N NQ N NOH HH NA-OH

N 2 ,or

H 2N 0 HO O 0 H0 0 0 H H H z HH N N H NN N N N OH

NH 2 Hyp Gly Gin Ile Gly Leu Ala Gly Pro Lys (2S,4R) and

at least 90% of the compound in the composition is present as the salt; and wherein the salt is selected from a hydrochloride, hydrobromide, sulfate, nitrate, perchlorate, phosphate, formate, acetate, lactate, malate, fumarate, succinate, tartrate,

glycolate, salicylate, citrate, methanesulfonate, benzenesulfonate, benzoate, malonate, trichloroacetate, naphthalene-2-sulfonate, oxalate, mandelate, alkylammonium, dialkylammonium, trialkylammonium, tetra-alkyl ammonium, L-arginine, benethamine,

benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2 (diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, calcium, magnesium, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salt.

In further aspects, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above composition and a pharmaceutically acceptable carrier. In yet further aspects, the present invention provides a method of treating dry eye syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of the above composition or the above pharmaceutical composition. In still further aspects, the present invention provides a use of the above composition or the above pharmaceutical composition in the manufacture of a medicament for the treatment of dry eye syndrome. In further aspects, the present invention provides an ophthalmic formulation comprising the above composition or the above pharmaceutical composition, and a pharmaceutically acceptable excipient or carrier. In yet further aspects, the present invention provides a kit comprising: (1) the above composition or the above pharmaceutical composition; and (2) instructions for administration of the composition.

Brief Description of the Drawings Fig. 1 is a diagram showing the sequence and characteristics of the peptides prepared according to an embodiment of the present invention. Fig. 2 is a diagram showing a process for synthesizing the peptides prepared according to an embodiment of the present invention. Fig. 3 is a diagram showing a purification procedure of the peptides prepared according to an embodiment of the present invention. Fig. 4 is a photograph showing a procedure of extraorbital lacrimal gland excision. Fig. 5 is a diagram showing a change in the body weight of a rat model whose eyes have been administered with YDE-001 to YDE-028. Fig. 6 is a diagram showing a change in the body weight of a rat model whose eyes have been administered with YDE-029 to YDE-043. Fig. 7 is a photograph showing a procedure of administering an agent to the eyes of a rat model. Fig. 8 is a photograph showing a procedure of measuring the amount of tear secretion of a rat model using cobalt chloride paper.

Fig. 9 is a photograph showing the results of measuring the amount of tear secretion of a rat model whose eyes have been administered with YDE-001 to YDE-028 using cobalt chloride paper. Fig. 10 is a diagram showing the changes in the amount of tear secretion of a rat model whose eyes have been administered with YDE-001 to YDE-028. Fig. 11 is a photograph showing the results of measuring the amount of tear secretion of a rat model whose eyes have been administered with YDE-029 to YDE-043 using cobalt chloride paper. Fig. 12 is a diagram showing the changes in the amount of tear secretion of a rat model whose eyes have been administered with YDE-029 to YDE-043. Fig. 13 is a photograph showing a procedure of administering a fluorescent substance to the eyes of a rat model for confirming damage to the comea thereof. Fig. 14 is a photograph showing the results of measuring damage to the comea of a rat model whose eyes have been administered with YDE-001 to YDE-028 using a fluorescent substance. Fig. 15 is a diagram showing the permeability of a fluorescence dye to confirm the recovery of corneal damage of a rat model whose eyes have been administered with YDE 001 to YDE-028. Fig. 16 is a photograph showing the results of measuring damage to the comea of a rat model whose eyes have been administered with YDE-029 to YDE-043 using a fluorescent substance. Fig. 17 is a diagram showing the permeability of a fluorescence dye to confirm the recovery of corneal damage of a rat model whose eyes have been administered with YDE 029 to YDE-043. FIG. 18 is a diagram showing the cell growth rate after 48 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 1. FIG. 19 is a diagram showing the cell growth rate after 48 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 2. FIG. 20 is a diagram showing the cell growth rate after 48 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 3. FIG. 21 is a diagram showing the cell growth rate after 48 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 4.

FIG. 22 is a diagram showing the cell growth rate after 72 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 1. FIG. 23 is a diagram showing the cell growth rate after 72 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 2. FIG. 24 is a diagram showing the cell growth rate after 72 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 3. FIG. 25 is a diagram showing the cell growth rate after 72 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 4. FIG. 26 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YY-101 on human corneal epithelial cells. FIG. 27 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YY-102 on human corneal epithelial cells. FIG. 28 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-011 on human corneal epithelial cells. FIG. 29 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-038 on human corneal epithelial cells. FIG. 30 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-042 on human corneal epithelial cells. FIG. 31 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-043 on human corneal epithelial cells. FIG. 32 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-044 on human corneal epithelial cells. FIG. 33 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-045 on human corneal epithelial cells. FIG. 34 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-049 on human corneal epithelial cells. FIG. 35 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-054 on human corneal epithelial cells. FIG. 36 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-057 on human corneal epithelial cells. FIG. 37 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-058 on human corneal epithelial cells.

FIG. 38 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-059 on human comeal epithelial cells. FIG. 39 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-060 on human comeal epithelial cells. FIG. 40 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-072 on human comeal epithelial cells. FIG. 41 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-073 on human comeal epithelial cells. FIG. 42 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-074 on human comeal epithelial cells. FIG. 43 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-075 on human comeal epithelial cells. FIG. 44 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-078 on human corneal epithelial cells. FIG. 45 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-080 on human corneal epithelial cells. FIG. 46 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-081 on human corneal epithelial cells. FIG. 47 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-083 on human corneal epithelial cells. FIG. 48 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-084 on human corneal epithelial cells. FIG. 49 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-086 on human corneal epithelial cells. FIG. 50 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-001 on human corneal epithelial cells. FIG. 51 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-010 on human corneal epithelial cells. FIG. 52 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-029 on human corneal epithelial cells. FIG. 53 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-092 on human corneal epithelial cells.

FIG. 54 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-053 on human comeal epithelial cells. FIG. 55 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-064 on human comeal epithelial cells. FIG. 56 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-066 on human comeal epithelial cells. FIG. 57 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-012 on human comeal epithelial cells. FIG. 58 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-019 on human comeal epithelial cells. FIG. 59 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-055 on human comeal epithelial cells. FIG. 60 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-085 on human comeal epithelial cells. FIG. 61 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-047 on human comeal epithelial cells. FIG. 62 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-048 on human comeal epithelial cells. FIG. 63 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-050 on human comeal epithelial cells. FIG. 64 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-051 on human comeal epithelial cells. FIG. 65 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-052 on human comeal epithelial cells. FIG. 66 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-056 on human comeal epithelial cells. FIG. 67 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-061 on human corneal epithelial cells. FIG. 68 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-062 on human corneal epithelial cells.

Detailed Description of the Invention

The present invention is based on the surprising discovery of therapeutic agents for treating eye diseases such as dry eye syndrome. The effectiveness of the agents has been demonstrated by synthesizing these peptides, administering them to the eyes of rats with dry eye syndrome, and confirming the eye protection effect through the Schirmer test and the fluorescent dye deposition test. When the novel peptide of the present invention is administered to the eye, it increases the amount of tear secretion and promotes recovery of the damaged cornea. Hence, they can be advantageously used as therapeutic agents for treating eye diseases.

Definitions

According to the convention used in the art, " R "in the formulae herein is used to indicate that a moiety or substituent "R" is attached to a backbone structure. "Alkyl" is a hydrocarbon having primary, secondary, tertiary, and/or quaternary carbon atoms, and encompasses straight, branched, and cyclic groups, or a combination thereof. For example, an alkyl group may have 1 to 20 carbon atoms (i.e., C1-C2 alkyl), 1 to 10 carbon atoms (i.e., CI-C10 alkyl), or 1 to 6 carbon atoms (i.e., Ci-C alkyl). Examples of a suitable alkyl group include methyl (Me, -CH 3), ethyl (Et, -CH 2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH 2CH 3), 2-propyl (i-Pr, i-propyl, -CH(CH 3)2 ), 1-butyl (n-Bu, n-butyl, -CH 2CH2 CH2CH3 ), 2-methyl-1-propyl (i-Bu, i-butyl, CH 2CH(CH 3) 2), 2-butyl (s-Bu, s-butyl, -CH(CH 3)CH 2CH 3), 2-methyl-2-propyl (t-Bu, t butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH2 CH2CH2 CH2CH 3), 2-pentyl (-CH(CH 3)CH 2CH 2CH 3), 3-pentyl (-CH(CH 2CH3 )2), 2-methyl-2-butyl (-C(CH 3) 2CH 2CH3), 3-methyl-2-butyl (-CH(CH 3)CH(CH 3) 2), 3-methyl-I-butyl (-CH 2CH 2CH(CH 3) 2), 2-methyl-I-butyl (-CH 2 CH(CH 3)CH 2CH3), 1-hexyl (-CH 2CH 2CH2 CH2CH 2CH3), 2-hexyl (-CH(CH 3)CH 2CH 2CH2 CH3), 3-hexyl (-CH(CH 2 CH3)(CH 2CH2 CH3)), 2-methyl-2-pentyl (-C(CH 3) 2 CH2CH2 CH3), 3-methyl-2 pentyl (-CH(CH 3 )CH(CH 3)CH 2CH3), 4-methyl-2-pentyl (-CH(CH 3)CH2 CH(CH 3) 2), 3 methyl-3-pentyl (-C(CH 3)(CH 2CH 3)2 ), 2-methyl-3-pentyl (-CH(CH 2 CH3)CH(CH 3) 2), 2,3-dimethyl-2-butyl (-C(CH 3) 2CH(CH 3) 2), 3,3-dimethyl-2 butyl (-CH(CH 3)C(CH 3) 3), and octyl (-(CH 2) 7CH 3), but it is not limited thereto. "Alkoxy" refers to a group having the formula -0-alkyl, wherein the alkyl group as defined above is attached to the parent compound via an oxygen atom. The alkyl moiety of the alkoxy group may have, for example, 1 to 20 carbon atoms (i.e., C1-C2o alkoxy), 1 to 12 carbon atoms (i.e., C1-C12 alkoxy), 1 to 10 carbon atoms (i.e., CI-C10 alkoxy), or 1 to 6 carbon atoms (i.e., Ci-C 6 alkoxy). Examples of a suitable alkoxy group include methoxy( O-CH 3 or -OMe), ethoxy (-OCH 2CH 3 or -OEt), and t-butoxy (-OC(CH 3) 3 or -O-tBu), but it is not limited thereto. "Haloalkyl" is an alkyl group in which at least one of the hydrogen atoms of the alkyl group as defined above is replaced by a halogen atom. The alkyl moiety of the haloalkyl group may have 1 to 20 carbon atoms (i.e., C1-C2o haloalkyl), 1 to 12 carbon atoms (i.e., C1 C 12 haloalkyl), 1 to 10 carbon atoms (i.e., CI-C10 haloalkyl), or 1 to 6 carbon atoms (i.e.,

C 1-C 6 haloalkyl). Examples of a suitable haloalkyl group include -CF 3, -CHF 2 , -CFH 2 , and -CH 2 CF3 , but it is not limited thereto. "Alkenyl" is a hydrocarbon having primary, secondary, tertiary, and/or quaternary carbon atoms, and encompasses straight, branched, and cyclic groups, or a combination thereof, and having at least one unsaturated region, i.e., a carbon-carbon sp2 double bond. For example, an alkenyl group may have 2 to 20 carbon atoms (i.e., C2-C20 alkenyl), 2 to 12 carbon atoms (i.e., C2-C 12 alkenyl), 2 to 10 carbon atoms (i.e., C2-C10 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C 6 alkenyl). Examples of a suitable alkenyl group include vinyl( CH=CH 2), allyl (-CH 2 CH=CH2), cyclopentenyl (-C 5 H 7), and 5-hexenyl( CH 2CH 2CH2CH 2CH=CH 2), but it is not limited thereto. "Alkynyl" is a hydrocarbon having primary, secondary, tertiary, and/or quaternary carbon atoms, and encompasses straight, branched, and cyclic groups, or a combination thereof, and having at least one carbon-carbon sp triple bond. For example, an alkynyl group may have 2 to 20 carbon atoms (i.e., C2-C20 alkynyl), 2 to 12 carbon atoms (i.e., C2 C 12 alkynyl), 2 to 10 carbon atoms (i.e., C2-C10 alkynyl), or 2 to 6 carbon atoms (i.e., C2-C alkynyl). Examples of a suitable alkenyl group include acetylenic (-C--CH) and propargyl( CH 2C--CH), but it is not limited thereto. "Alkylene" refers to a saturated hydrocarbon group that may be branched, straight, or cyclic (or may have a combination of branched, straight, or cyclic moeities) and has two valencies derived by a removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. For example, an alkylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of a typical alkylene group include 1,2-ethylene (-CH 2-CH2 -), but it is not limited thereto. "Alkenylene" refers to an unsaturated hydrocarbon group that may be branched, straight, or cyclic (or may have a combination of branched, straight, or cyclic moeities) and has two valencies derived by a removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkene. For example, an alkenylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of a typical alkenylene group include 1,2-ethenylene (-CH=CH-), but it is not limited thereto. "Alkynylene" refers to an unsaturated hydrocarbon group that may be branched, straight, or cyclic (or may have a combination of branched, straight, or cyclic moeities) and has two valencies derived by a removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkyne. For example, an alkynylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of a typical alkynylene radical include acetylenylene (-C-C-), propargylene (-CH 2C-C-), and 4 pentynylene (-CH 2 CH2CH 2C-C-), but it is not limited thereto. "Aryl" refers to an aromatic hydrocarbon group. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Examples of a typical aryl group include a radical derived from benzene (e.g., phenyl), substituted benzene, substituted or unsubstituted naphthalene, substituted or unsubstituted anthracene, and the like, but it is not limited thereto. "Arylalkyl" refers to an acyclic alkyl group in which one hydrogen atom bonded to a carbon atom, typically a terminal or other sp3 carbon atom, is replaced by an aryl group. Examples of a typical arylalkyl group include benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like (each of which may be substituted or unsubstituted), but it is not limited thereto. An arylalkyl group may have 7 to 20 carbon atoms. For example, the alkyl moiety thereof may have 1 to 6 carbon atoms, and the aryl moiety thereof may have 6 to 14 carbon atoms. "Arylalkenyl" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or other sp3 carbon atom, although an sp2 carbon atom may also be used, is replaced by an aryl group. The aryl moiety of the arylalkenyl may be, for example, any aryl group described herein, and the alkenyl moiety of the arylalkenyl may comprise, for example, any of the alkenyl groups described herein. An arylalkenyl group may have 8 to 20 carbon atoms. For example, the alkenyl moiety thereof may have 2 to 6 carbon atoms, and the aryl moiety thereof may have 6 to 14 carbon atoms. "Arylalkynyl" refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or other sp3 carbon atom, although an sp carbon atom may also be used, is replaced by an aryl group. The aryl moiety of the arylalkynyl may be, for example, any aryl group described herein, and the alkynyl moiety of the arylalkynyl may comprise, for example, any of the alkynyl groups described herein. An arylalkynyl group may have 8 to 20 carbon atoms. For example, the alkynyl moiety thereof may have 2 to 6 carbon atoms, and the aryl moiety thereof may have 6 to 14 carbon atoms. "Cycloalkyl" refers to a saturated monocycle or polycycle that comprises only carbon atoms in the ring. A cycloalkyl group may have 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. A monocyclic cycloalkyl has 3 to 7 ring atoms, more typically 5 or 6 ring atoms. A bicyclic cycloalkyl may have 7 to 12 ring atoms and may be a fused ring system, a spirocyclic ring system, or a bridged ring system. In exemplary cycloalkyl groups, the atoms may be arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Non-limiting examples of a monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl (each of which may be substituted or unsubstituted). The term "substituted" with respect to alkyl, alkylene, aryl, arylalkyl, heterocyclyl, and the like, for example, "substituted alkyl," "substituted alkylene," "substituted aryl," "substituted arylalkyl," "substituted heterocyclyl," and "substituted carbocyclyl (e.g., substituted cycloalkyl)," means that at least one hydrogen atom of the alkyl, alkylene, aryl, arylalkyl, heterocyclyl, or carbocyclyl (e.g., cycloalkyl) is each independently replaced by a non-hydrogen substituent. Examples of the typical substituent include halo, haloalkyl, oxo, -CN, -NO 2 , =N-OH, -N 3, -R, -OR, -SR, -N(R) 2, -N(R)3*, =NR, -NHC(=O)R, -C(=O)R, C(=O)N(R) 2 , -S(=0) 2R, -OS(=0) 2 OR, -S(=0) 2OR, -S(=0)2N(R) 2 , -S(=O)R, OP(=O)(OR) 2, -(alkylene)-C(=O)R, -C(=S)R, -C(=O)OR, -(alkylene)-C(=O)OR, C(=S)OR, -C(=O)SR, -C(=S)SR, -(alkylene)-C(=O)N(R)2, -C(=S)N(R) 2 , and -C( NR)N(R) 2 , and R is independently H, alkyl, aryl, arylalkyl, or heterocyclyl, but it is not limited thereto. The alkylene, alkenylene, and alkynylene groups may also be similarly substituted. Those skilled in the art will understand that when a moiety such as "alkyl," "aryl," "heterocyclyl," and the like is substituted with at least one substituent, they may optionally be referred to as a moiety of "alkylene," "arylene," "heterocyclylene," or the like (that is, at least one hydrogen atom of the parent "alkyl," "aryl," or "heterocyclyl" moiety is replaced by the substituent as described herein). If the moiety of "alkyl," "aryl," "heterocyclyl," or the like is described herein as "substituted" or depicted in the drawings as substituted (or optionally substituted, for example, the number of substituents is 0 or a positive number), the term "alkyl," "aryl," "heterocyclyl," or the like should be understood to be interchangeable with "alkylene," "arylene," "heterocyclylene," or the like. Those skilled in the art will recognize that the substituents and other moieties of the compound of Formula I should be selected so as to provide a compound that is sufficiently stable as a pharmaceutically useful compound that can be formulated into an acceptably stable pharmaceutical composition. The compound of Formula I having such stability is to be understood to fall within the scope of the present invention.

"Heteroalkyl" refers to an alkyl group in which at least one carbon atom is replaced by a heteroatom such as 0, N, or S. For example, if a carbon atom of the alkyl group attached to a parent molecule is replaced by a heteroatom (e.g., 0, N, or S), the resulting heteroalkyl group may be an alkoxy group (e.g., -OCH 3), an amine group (e.g., -NHCH3 , N(CH 3 ) 2 , or the like), or a thioalkyl group (e.g., -SCH 3), respectively. If a non-terminal carbon atom of the alkyl group that is not attached to a parent molecule is replaced by a heteroatom (e.g., 0, N, or S), the resulting heteroalkyl group may be an alkyl ether (e.g., CH 2CH 2-0-CH 3 or the like), an alkylamine (e.g., -CH2NHCH 3 , -CH 2N(CH 3 ) 2 , or the like), or a thioalkyl ether (e.g., -CH 2-S-CH 3), respectively. If the terminal carbon atom of the alkyl group is replaced by a heteroatom (for example, 0, N, or S), the resulting heteroalkyl group may be a hydroxyalkyl group (e.g., -CH2 CH2-OH), an aminoalkyl group (e.g., CH 2 NH 2 ), or an alkylthiol group (e.g., -CH 2 CH2 -SH), respectively. For example, a heteroalkyl group may have 1to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Preferably, a heteroalkyl group has from 2 to 20, 2 to 10, or 2 to 6 total atoms in the chain (i.e., carbon atoms plus heteroatoms combined). A Ci-C6 heteroalkyl group refers to a heteroalkyl group having 1 to 6 carbon atoms. The term "heterocycle" or "heterocyclyl" used herein includes those described in the documents such as Paquette, Leo A., Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968), specifically Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, from 1950 to the present), specifically Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566, but it is not limited thereto. In a specific embodiment of the present invention, "heterocycle" includes carbocycle as defined herein in which at least one (e.g., 1, 2, 3, or 4) carbon atom is replaced by a heteroatom (e.g., 0, N, or S). The term "heterocycle" or "heterocyclyl" includes saturated, partially unsaturated, and aromatic rings (i.e., a heteroaromatic ring). Substituted heterocycle, for example, includes a heterocyclic ring substituted with any of the substituents disclosed herein, inclusive of a carbonyl group. Exemplary heterocycles include pyridyl, dihydropyridyl, tetrahydropyridyl(piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocynyl, triazinyl,

6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phtheridinyl, 4aH carbazolyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, and benzoxazolinyl (each of which may be substituted or unsubstituted), but it is not limited thereto. As an example, a carbon-bonded heterocycle may be bonded at the 2, 3, 4, 5, or 6 position of pyrazine, at the 3, 4, 5, or 6-position of pyridazine, at the 2, 4, 5, or 6-position of pyrimidine, at the 2, 3, 5, or 6-position of pyrazine, at the 2, 3, 4, or 5-position of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, at the 2, 4, or 5-position of oxazole, imidazole, or thiazole, at the 3, 4, or 5-position of isoxazole, pyrazole, or isothiazole, at the 2 or 3-position of aziridine, at the 2, 3, or 4-position of azetidine, at the 2, 3, 4, 5, 6, 7, or 8-position of quinoline, or at the 1, 3, 4, 5, 6, 7, or 8-position of isoquinoline, but it is not limited thereto. More typically, examples of a carbon-bonded heterocycle include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4 pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6 pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl (each of which may be substituted or unsubstituted). As an example, a nitrogen-bonded heterocycle may be bonded at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, or 1H-indazole, at the 2-position of isoindole or isoindoline, at the 4-position of morpholine, and at the 9-position of carbazole or p-carboline (each of which may be substituted or unsubstituted), but it is not limited thereto. More typically, examples of a nitrogen-bonded heterocycle include 1-aziridinyl, 1-azetidyl, 1-pyrrolyl, 1 imidazolyl, 1-pyrazolyl, and 1-piperidinyl (each of which may be substituted or unsubstituted). "Heterocyclylalkyl" refers to an acyclic alkyl radical in which one hydrogen atom bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced by a heterocyclyl radical (i.e., a heterocyclyl-alkylene moiety). Examples of a typical heterocyclylalkyl group include heterocyclyl-CH2-, 2-(heterocyclyl)ethan-1-yl, and the like, but it is not limited thereto. The "heterocyclyl" moiety thereof used herein includes those described in the document such as "Principles of Modem Heterocyclic Chemistry" and any heterocyclyl group described above. Those skilled in the art will understand that if the resulting group is chemically stable, the heterocyclyl group may be attached to the alkyl moiety of the heterocyclylalkyl through a carbon-to-carbon bond or a carbon-to-heteroatom bond. A heterocyclylalkyl group may have 2 to 20 carbon atoms. For example, the alkyl moiety of the heterocyclylalkyl group may have 1 to 6 carbon atoms, and the heterocyclyl moiety thereof may have 2 to 14 carbon atoms. Examples of the heterocyclylalkyl include a 5-membered heterocycle containing sulfur, oxygen, and/or nitrogen such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, and the like; and a 6-membered heterocycle containing sulfur, oxygen, and/or nitrogen such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridazylmethyl, pyrimidylmethyl, pyrazinylmethyl, and the like (each of which may be substituted or unsubstituted), but it is not limited thereto. "Heterocyclylalkenyl" refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom although an sp2 carbon atom may also be used, is replaced by a heterocyclyl radical (i.e., a heterocyclyl-alkenylene moiety). The heterocyclyl moiety of the heterocyclylalkenyl group includes those described in the document such as "Principles of Modern Heterocyclic Chemistry" and any heterocyclyl group described herein. The alkenyl moiety of the heterocyclylalkenyl group includes any alkenyl group described herein. Those skilled in the art will understand that if the resulting group is chemically stable, the heterocyclyl group may be attached to the alkenyl moiety of the heterocyclylalkenyl via a carbon-to-carbon bond or a carbon-to-heteroatom bond. A heterocyclylalkenyl group may have 3 to 20 carbon atoms. For example, the alkenyl moiety of the heterocyclylalkenyl group may have 2 to 6 carbon atoms, and the heterocyclyl moiety thereof may have 2 to 14 carbon atoms. "Heterocyclylalkynyl" refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom although an sp carbon atom may also be used, is replaced by a heterocyclyl radical (i.e., a heterocyclyl-alkynylene moiety). The heterocyclyl moiety of the heterocyclylalkynyl group includes those described in the document such as "Principles of Modern Heterocyclic

Chemistry" and any heterocyclyl group described herein. The alkynyl moiety of the heterocyclylalkynyl group includes any alkynyl group described herein. Those skilled in the art will understand that if the resulting group is chemically stable, the heterocyclyl group may be attached to the alkynyl moiety of the heterocyclylalkynyl via a carbon-to-carbon bond or a carbon-to-heteroatom bond. A heterocyclylalkynyl group may have 3 to 20 carbon atoms. For example, the alkynyl moiety of the heterocyclylalkynyl group may have 2 to 6 carbon atoms, and the heterocyclyl moiety thereof may have 2 to 14 carbon atoms. "Heteroaryl" refers to an aromatic heterocyclyl containing at least one heteroatom in the ring. Non-limiting examples of a suitable heteroatom that may be contained in the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of a heteroaryl ring include all of those enumerated in the definition of "heterocyclyl" herein, inclusive of pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, and the like (each of which may be substituted or unsubstituted). "Carbocycle" or "carbocyclyl" refers to a saturated, partially unsaturated, or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. A monocyclic carbocycle has 3 to 7 ring atoms, more typically 5 or 6 ring atoms. A bicyclic cycloalkyl may have 7 to 12 ring atoms and may be a fused ring system, a spirocyclic ring system, or a bridged ring system. In exemplary cycloalkyl groups, the atoms are arranged in a bicyclo[4,5], [5,5], [5,6], or

[6,6] system. Non-limiting examples of a monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl (each of which may be substituted or unsubstituted). "Acyl" refers to -C(=O)-alkyl, -C(=O)-carbocycle (which is substituted or unsubstituted), and -C(=O)-heterocycle (which is substituted or unsubstituted), wherein the alkyl, carbocycle, or heterocycle moiety is as defined herein. Non-limiting examples of "acyl" include -C(=0)CH 3 , -C(=O)CH 2 CH3 , -C(=0)CH(CH 3) 2, -C(=0)C(CH 3) 3, -C(=0)

phenyl (which is substituted or unsubstituted), -C(=O)-cyclopropyl (which is substituted or unsubstituted), -C(=O)-cyclobutyl (which is substituted or unsubstituted), -C(=O) cyclopentyl (which is substituted or unsubstituted), -C(=O)-cyclohexyl (which is substituted or unsubstituted), and -C(=O)-pyridyl (which is substituted or unsubstituted).

"Arylheteroalkyl" refers to a heteroalkyl as defined herein, wherein a hydrogen atom (which may be attached to either a carbon atom or a heteroatom) is replaced by an aryl group as defined herein. If the resulting group is chemically stable, the aryl group may be attached to a carbon atom of the heteroalkyl group or the heteroatom of the heteroalkyl group. For example, an arylheteroalkyl group may have a formula of -alkylene-O-aryl, alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, or the like. In addition, any alkylene moiety in the above formulae may be further substituted with any of the substituents defined or exemplified herein. "Heteroarylalkyl" refers to an alkyl group as defined herein, wherein a hydrogen atom is replaced by a heteroaryl group as defined herein. Non-limiting examples of heteroarylalkyl include -CH2-pyridinyl, -CH2-pyrrolyl, -CH2-oxazolyl, -CH2-indolyl, -CH 2 isoindolyl, -CH2-furanyl, -CH2-thienyl, -CH2-benzofuranyl, -CH2-benzothiophenyl, -CH 2 carbazolyl, -CH2-imidazolyl, -CH2-thiazolyl, -CH2-isoxazolyl, -CH2-pyrazolyl, -CH 2 isothiazolyl, -CH2-quinolyl, -CH2-isoquinolyl, -CH2-pyridazyl, -CH2-pyrimidyl, -CH2 pyrazyl, -CH(CH3)-pyridinyl, -CH(CH3)-pyrrolyl, -CH(CH3)-oxazolyl, -CH(CH3)-indolyl, CH(CH3)-isoindolyl, -CH(CH3)-furanyl, -CH(CH3)-thienyl, -CH(CH3)-benzofuranyl, CH(CH3)-benzothiophenyl, -CH(CH3)-carbazolyl, -CH(CH3)-imidazolyl, -CH(CH3 ) thiazolyl, -CH(CH3)-isoxazolyl, -CH(CH3)-pyrazolyl, -CH(CH3)-isothiazolyl, -CH(CH3 ) quinolyl, -CH(CH3)-isoquinolyl, -CH(CH3)-pyridazyl, -CH(CH3)-pyrimidyl, -CH(CH3 ) pyrazyl, and the like. "Silyloxy" refers to the group -0-SiR3 , wherein each R independently is alkyl, aryl (which is substituted or unsubstituted), or heteroaryl (which is substituted or unsubstituted). Non-limiting examples of silyloxy include -O-Si(CH3) 3, -O-Si(CH3)2tBu, -O-Si(tBu)2CH3, O-Si(tBu)3, -O-Si(CH 3) 2Ph, -O-Si(Ph)2CH 3 , and -O-Si(Ph)3 .

The term "optionally substituted" refers to a particular moiety (e.g., an optionally substituted aryl group) of the compound of Formula I that optionally has one, two, or more substituents. The term "ester thereof' refers to any ester of a compound wherein any -COOH functional group of the molecule is modified to be a -COOR functional group or any -OH functional group of the molecule is modified to be a -OC(=O)R. Here, the R moiety of the ester may be any carbon-containing group that forms a stable ester moiety, which includes, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, and substituted derivatives thereof. Examples of the ester may also include an ester such as those described above of a "tautomeric enol" as described below.

Compounds of the Invention In certain embodiments, the invention provides a salt of a compound represented by Formula (I):

(R')p H R H R2 H CH3 O H N N N N OH 8 H H HH R3 (I

wherein: R, R2 , and R3 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl; R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR, -CH 2ORb, halo, hydroxyl, and hydroxyalkyl; Rb is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2; R' is hydrogen or substituted or unsubstituted alkyl; and R 7, R 8, and R9 are each independently hydrogen or alkyl; wherein the compound is not: H2N 0 HO 0 H H H 0 H? OH 3 H 0 N N N N N -N N N --OH H H N c

NN N OH N- NH

H2 ;

preferably wherein the compound comprises at least one D-amino acid residue. In certain embodiments, R, R2, and R3 are each independently H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl; R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -ORb, hydroxyalkyl, -CH 2ORb, and halo; Rb is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; R' is hydrogen or substituted or unsubstituted alkyl; and

R7 , R 8, and R9 are each independently hydrogen or alkyl.

In some embodiments, where indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or is substituted with one or more substituents selected from halo, haloalkyl, oxo, -CN, -NO 2, =N-OH, -N3 , -R, -ORa, -SRa, -N(Ra) 2 , -N(Ra), =NRa, -NHC(=O)R, -C(=O)Rc, -C(=O)N(Ra) 2 , -S(=0) 2R°, -OS(=0)ORa, 2 -S(=0) 2 ORa, _ S(=0) 2N(Ra)2 , -S(=o)R, -OP(=0)(ORa) 2 , -(alkylene)-C(=O)R°, -C(=S)R, -C(=O)ORa, (alkylene)-C(=O)ORa, -C(=S)ORa, -C(=O)SRa, -C(=S)SRa, -(alkylene)-C(=O)N(Ra)2, C(=S)N(Ra) 2, and -C(-NRa)N(Ra) 2; R, independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; and R°, independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.

In more particular embodiments, where indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or is substituted with one or more substituents selected from halo, haloalkyl, oxo, -Ra, -ORa, -N(R) 2 , -N(Ra)3, -NHC(=O)R, -C(=O)R°, C(=O)N(Ra) 2, -C(=)ORa, -(alkylene)-C(=O)ORa, and -(alkylene)-C(=O)N(Ra)2; R, independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; and R, independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl. In certain such embodiments, R, independently for each occurrence, is hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl; and R, independently for each occurrence, is alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl. In certain embodiments, the compound has the structure of formula (I-OL): (R')p H O R H R2 H 0 CH3H 0 H 0 N 1 N N XN N N H N N N OH (I-10L).

Alternatively, the compound may have the structure of formula (I-IOD): (R')p O R6 O R2 0 CH3H 0 H 0 N N N N N N N N NOH H R9' H H Y H 8 RR_ R (101)D).

In certain embodiments, R is substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl. More specifically, R may be selected from substituted or unsubstituted alkyl,

H n n nH R OR nH~ R a rO a a H a, O

NH

Ra Ra is hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

H HO 0 H H2N O Exemplary R groups include H, 0 2

NH 2 OH tt H 3C OH cH 3 H 3C CH 3 CH3 H H3

INH 0 0

HN OH H 'CH3, and H3

H 3C

In some preferred embodiments, R is H3 . In alternative preferred

0

embodiments, R is UH In certain embodiments, the compound has the structure of formula (I-IL): (R')p H 0 R6 0 R2 0 CH3 O O N N '-AN N OH H R9H i H 7H 3 8R (Ii.

Alternatively, the compound may have the structure of formula (I-ID)

(RH)p 0 R6 0 R2 0 CH3 O O N N NT N N N-10H HHH (I-1D).

In certain embodiments, R2 is H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl. In some embodiments, R2 is selected from hydrogen, substituted or unsubstituted Ra

~Ra P ORa H N a OH n H n NR H an alkyl, O H , and nO Ra is hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3. CH3 CH 3

H 3C,,CH 3 OH 3 CH3 OH 3 2H Exemplary R2 groups include H CHH3

OH N OHH OH H3 C OH N HI ,and r Preferably, R2 is hydrogen. In certain embodiments, the compound has the structure of formula (I-2L): (R 4 )p O R6 O R2 H CH3 0 0 N N N N -N N jN N 0H N N N OH H R9 H H H (I

2L). Alternatively, the compound may have the structure of formula (I-2D): (R')p H R O R2 OH CH3H 0 0 1N N N N OH HH 1H H83 R 9 RR7 (I

2D). In certain embodiments, R3 is substituted or unsubstituted alkyl or arylalkyl. In some embodiments, R3 is selected from substituted or unsubstituted alkyl,

nQ (n a, RNHR O H Ra, and NHRa

Ra is hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

1~ H3C

Exemplary R3 groups include NH 2 OH H3 HO 0

H 2N H3 , and H.Preferably,Ris NH 2

In certain embodiments, the compound has the structure of formula (I-3L):

(RH)p O R6 O R2 O CH3H O H NNN N N N N - OH H R9 H R1H R7 H 8 R R3 (1-3L).

Alternatively, the compound may have the structure of formula (I-3D):

(R')p(RpH 0 R6 H 0 R2 H O CH CHH O H O N N N N N N N N OH H R9 H N'H 7H (I3)

In certain embodiments, p is 1 or 2; and R, independently for each occurrence, is selected from substituted or unsubstituted alkyl, -OR, -CH 2ORb, halo, hydroxyl, and hydroxyalkyl. In certain embodiments, p is 1 or 2; and R, independently for each occurrence, is selected from -CH 3, halo, hydroxyl, and hydroxyalkyl. In certain preferred embodiments, R4 is hydroxyl. In alternative preferred embodiments, R4 is -CH 3 .

In any of the above embodiments, p may be 1. In certain embodiments, the compound has the structure of formula (I-4Lg):

(R4)p H 0 R6 H 0 R2 H 0 CH 3 H 0 H 0 N N N AN N 'A IN N O N N N OH H H9 H H R8 R(I

4Lg). In certain embodiments, the compound has the structure of formula (I-4La):

O R6 0 R2 0 H N N N O(INN-4N) H R9HN N H R7H N RR3 OH (I-4La).

In certain embodiments, the compound has the structure of formula (I-4Lb):

H O R O R2 H H CH3 O H N)-N NJ N N N N N 0H 0 OH 0 H 8 R R2 0 HRH 4D(-4Lb). In certain embodiments, the compound has the structure of formula (I-4Lc):

- H4 H 0 OH3 00 RH H O NN 15 0 R2 H N N OH H H9R R8 R (I N N N N OH 4Lc); provided that R4 is not hydroxyl. In certain embodiments, the compound has the structure of formula (I-4Dg):

H HH 0 NN N N NN N N '-N N '__N - N N N N OH Y3 'OH H Y H Y H Y-H R

4Dg). In certain embodiments, the compound has the structure of formula (-4Da):

H 0 R H 0 R H CH3H 0 H N N N N N Y NN N N O H H H H H R 8 R3 (1

4Da). In certain embodiments, the compound has the structure of formula (1-4Db):

H O H R6 0 R2 H 0 CH H 00 0 H N L N N Ni N XN N ''OH H H H- H R8 R 15R9R7R3 (1

4Db). In certain embodiments, the compound has the structure of formula (-4Dc):

HR 0 R2 0 CH3 R 0 R4H 6 0 H 3 H H N( N N N N N R4 N N N N OH H H )R H7H 83 H R R (I

4Dc);

provided that R4 is not hydroxyl. In certain embodiments, R4 is oxo. In certain embodiments, the compound has the structure of formula (I-4Ld): 0 O R6 O R2 H CH3 0 H N N_ N N N N N N N N J 0H OH H 9H H H (I

4Ld).

In certain embodiments, the compound has the structure of formula (I-4Le): 0 R0 O R2 0 CH H O N N N N ,N N 0H N N N OH HR H HR7H R3 H H R8 R (I

4Le). In certain embodiments, the compound has the structure of formula (I-4Dd): 0

H O R6 O R2 O HC3 CH3 O H O N N N NOH N 11N N N -I 8OH H H H H R(I

4Dd).

In certain embodiments, the compound has the structure of formula (I-4De): O R6 R2 O CH3 0_H R H 0 H CHH HOHJ O ON N N N N N N N N OH H 'r'H H 7H3 R9R1RR (I 4De).

In certain embodiments, R6 is hydrogen or alkyl, wherein the alkyl is optionally substituted with one occurrence of -C(=O)NH 2 . In certain embodiments, wherein R' is alkyl optionally substituted with one occurrence of -C(=O)NH 2 . For example, R6 may be H 2N 0

CH 3 . Alternatively, R6 may be .

In certain embodiments, the compound has the structure of formula (I-6L): (R)p H O R H 0N R2 H CH 3 0 0 N N N _1N -A 'IN NT O N N N OH H H H R H R (I

6L). Alternatively, the compound may have the structure of formula (I-6D): (R')p(RpH O R6 - H 0 R2 H O 0 CH3 OH O 00 O N - N __N N N N N N N OH H H H H 8 3

(I-6D).

H3 C

In certain embodiments, R7 is (C-Co)alkyl, preferably 3 or H3

In certain embodiments, the compound has the structure of formula (I-7L): (R')p H O R O 0 R2 0 CH3 H 0 H 0 N N N N N N N N N OH H H H 8 3 (I

7L). Alternatively, the compound may have the structure of formula (I-7D): (R')p H R6 0 R2 O CH3 H O IH H 0 H 0 N1 -N N N N NN N N jN' N N" OH H AH H H R8

(I-7D). In certain embodiments, the compound has the structure of formula (I-11L): (R0)p(RpH R R HRO R2 H H CH 3 O H O 0 N N N N N' jIN 1 ,N 0H 15 N N N OH 15H H9 H H R8 R3 (I

I1L). Alternatively, the compound may have the structure of formula (I-IID): (R')p 0 R6 0 R2 0 CH 3 0 O HH H3HH N N N OH H ' H 3 1 SH R R (I

I1D).

In certain embodiments, R 8 is -CH 3 or -H, preferably -H.

In certain embodiments, R9 is -CH 3 or -H, preferably -H. In certain embodiments, the compound comprises at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight D-amino acid residues. In certain embodiments, the invention provides a salt of a compound of formula (I), wherein the compound is selected from the following: H2N 0 HO

N HN N N N )N N ~ N OH

H OH NH2 Hyp Gly Gln Glu Gly Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO

N N N J N N R.N NAOH HH HH

NH2 Hyp Gly Gln Asn Gly Leu Ala Gly Pro Lys (2S,4R)

H2 N 0 HO

H 0 H 0 H 0 HR H N N ,AN N JINN NN N OH H H H H

O NH 2 NH, Hyp Gly Gln Gln Gly Leu Ala Gly Pro Lys (2S,4R)

H2N 0 HO 0 0 0 0' 0 H H H H H N N N N -N N - N N J4 N Q OH H H = H = H=

HN_//

NH2 Hyp Gly Gln His Gly Leu Ala Gly Pro Lys (2S,4R)

H2N 0 HO

H0H 0 H0 HjOI H N N N N OH H H H H

NH2 NH2 Hyp Gly Gln Lys Gly Leu Ala Gly Pro Lys (2S,4R)

H2N 0 HO HO 0 H0 0 o_ 0 N HH N N H N H H OH~A H HH

NH 2 Hyp Gly Gln Ser Gly Leu Ala Gly Pro Lys (2S, 4R)

H2N 0 HO

H H 0H H H HN N N-N"') N N N -OH HHH

NH2 Hyp Gly Gln Thr Gly Leu Ala Gly Pro Lys (2S,4R)

H2 N 0 HO

H 0 H 0 H 0 H H0 HN N N ,N N ' N N N IJAOH H

H2 Hyp Gly Gln Ala Gly Leu Ala Gly Pro Lys (2S, 4R)

H2 N 0 HO

H0 H0 0 H H0 HN N N NOHN NNIN.N H zH H NJO

NH 2 Hyp Gly Gln Val Gly Leu Ala Gly Pro Lys (2S,4R)

HN 0 HO

H 0H 0 H 0 H? H 0 'N N N N N NJ NJ4 N 1 0 H H H H

NH, Hyp Gly Gin Ilie Giy Leu Aia Giy Pro Lys (2S,4R?)

HN 0 HO 0 0 0 0 0 H H H H H N N~N N N N 1- N NJJ NJL -OH H H £H H=

NH, Hyp Gly Gin Leu Gly Leu Ala Gly Pro Lys (2S,4R)

HN 0 HO0

H 0 H 0 H 0 H H 0 N H N,_ N N N N -'U'N N ~ N --OH HHH

NH, Hyp Gly Gin Phe Gly Leu Ala Gly Pro Lys (2S,4R)

HN 0 HO O 0 0 0NN H H H H H H HH

OH NH, Hyp Gly Gin Tyr Gly Leu Ala Gly Pro Lys (2S,4/?)

HN 0 HO HO 0 0 0j 0 'N H Nl N H N __ N N KN N ~ N OH H H NH

NH, Hyp Gly Gin Trp Gly Leu Ala Gly Pro Lys (2S,4R)

HN 0 HO HO 0 H0 0, 0 N N' N .RN N .. N NN1 O H H N~H -H

"'T 0H "- '*'N H, Hyp Gly Gin Asp Val Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO

H 0 H 0 H 0 H H N N-1j' N .. N N )<N N N--- <OH H H OH H

0NHH

Hyp Gly Gin Asp Ilie Leu Ala Gly Pro Lys (2S,4R)

H2 N 0 HO

H H H HH N ~ N N)N N.JN N ~L. N)tH H H K~H H

0NHH

Hyp Gly Gin Asp Leu Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO0 O 0 0 0 H H H H H N N -- 'N N )N N N N>L--O H H H HH

Hyp Gly Gin Asp Ala Leu Ala Gly Pro Lys (2S,4R)

H2 N 0 HO O 0 0 H O H 0 H H H H H 0HH

Hyp Gly Gin Asp Phe Leu Ala Gly Pro Lys (2S,4R)

HN 0 OH HO 0 000 H H 0 H N N)N N~LN N '.J N NN - O H H N~H -H

Hyp Gly Gin Asp Tyr Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO H 0 H0 0 0 N N>N N N N ~ N~O H OHH

Hyp Gly Gin Asp Trp Leu Ala Gly Pro Lys (2S,4R)

HO H 2N 0N H O 0 N0 0 H H HHH N NN N~LN JN N>L N&LO H H H H

Hyp Gly Gin Asp His Leu Ala Gly Pro Lys (2S,4R)

H2 N 0 HO

HHH? XH H0 N- N N >-N - NN N ' OH H H H H 4XOH

Hyp Gly Gin Asp Ser Leu Ala Gly Pro Lys (2S,4R)

H2 N 0 HO

H 0 0 H H HH0fH 0 0H N N N N,_,lN N N N N " OH HH OH H

ONH

Hyp Gly Gin Asp Thr Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO

HH H H N N N N N N N .KOH H H H

Hyp Gly Gln Homo-Ser Gly Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO 0 0 H0H H H ~Hj H N- N N N OH H H £H -H

NH 2 Hyp Gly Gln Asp(Me) Gly Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO

H 0 H 0 H 0 H H N N ,N N NN N UN N N OH H H :H H

HN

NH 2 Hyp Gly Gln Asn(Me) Gly Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO

HN N N',N N N OH OH

Hyp Gly Gln Leu Gly Leu Ala Gly Pro Tyr (2S,4R)

H2N 0 HO

H 0 H 0 H 0 H H0 NN N N N NJ N NOH H HHH

Hyp Gly Gln Leu Gly Leu Ala Gly Pro Leu (2S,4R)

HN 0 HO H O 0 H 0 0 0 HH H H

Hyp Gly Gin Leu Gly Leu Ala Gly Pro Glu (2S,4R)

HN 0 HO 0 0 0 0 J 0 H H H Hj N N-A"N N JN N.LN NN - O H H H H

0 INH2

Hyp Gly Gin Leu Gly Leu Ala Gly Pro Gin (2S,4R)

H 2N 0 HO0

H H H Hj 'N N- ' N N N 1 -OH HH H

H Hyp Gly Gin Leu Gly Leu Ala Gly Pro Nie(6-OH) (2S,4R)

H2 N 0 HO

H 0 H 0 H 0 HjH N N N NN NN " N - N O H H H H

"NH 2 Hyp Gly Gin Leu Gly Leu Ala Gly Pro Lys (28,48)

H 2N 0 0

H 0 H 0 H 0 01H 0 Nl- N, N N' N, N N N 1kO1H H H H

-NH 2 (4-oxo)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys

HN 0

H0H 0 H? 0HH 0 0N N,J N NIAWN N '>KAN N ~.t N 11-1O H H H H

-N H, (5-oxo)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys

H2 N 0

H 0 H 0 H 0 Hj ( XH N N ,N N N N N N N~ 1-OH H H H z

H NH

Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys 2

H 2N 0 H0-. 0 H0 H H H H 0 N N NN N- -N Nj N _I 1 OH

(4-hydroxyMe)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys (4R)

H 2N 0

H0 H0 H0 0 H 0 N N~.JN N 'AW.N ')kN N - O H' H H J~ H

(4-Fluoro)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys (4R)

H2 N 0

0 H 0 H0 H0 Hj l 0 N N JtN N'AW.N N KN N N --- O H H H

NH-2 (4-Dimethyi)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys

HN 0

0 H 0 0 0 0 H j 0 N N.LN N. )N N 1)t.N\ N)t N 0H H H H

(4-Me)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys 2 (4R)

HN 0

0 jI 0 N N-N N-1JkN" N - ' N -, OH H H H H

(5-Me)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys NH (5R)

HN 0 HO

H 0 H 0 H 0 H H0 N H N )N N ~tN N ~tN N t.O N --

NH, Hyp Ala Gin Leu Gly Leu Ala Gly Pro Lys (2S,4R)

HO HH H0H 0 H0 0 Nj N 1J<N\ N .)N N..)kN N N 1 N>,)KH H H H

Hyp Gly Ala Leu Gly Leu Ala Gly Pro Lys (2S,4R)

HN 0 HO H 0 H 0 H 0 H 01 IN N N ,I N N I N NA INN'OH H H z H H

NH, Hyp Gly Gin Ala Gly Leu Ala Gly Pro Lys (2S,4R)

HN 0 HO H 0 H 0 H 0 H 0 H 0 N IN IN IN - N IN - N IN IN IOH H H z H = H

NH, Hyp Gly Gin Leu Ala Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO

H 0 H 0 H 0 H 0 -1 H 0 IN '- N IN IN N NAN IN ),IN O H H H H~H

NH2 Hyp Gly Gin Leu Gly Ala Ala Gly Pro Lys (2S,4R)

HN 0 HO

H 0 H 0 H 0 H 0/-I H 0 IN I> N I 1 N IN N N" IN -)I.OH H H H H

NH, Hyp Gly Gin Leu Gly Leu Ala Ala Pro Lys (2S,4R)

H 2N 0 HO

H 0 H 0 H 0 H H 0 N IN I I I N ~N IN IN IN-- N 0O H H H

Hyp Gly Gin Leu Gly Leu Ala Gly Pro Ala (2S,4R)

H 2N 0 HO H0 H0 jH0 0H 0 H H H H c

0-Hyp Gly Gin Leu Gly Leu Ala Gly Pro Lys 2

(2R,4S)

H 2N 0 HO

- _N_ HN N N 0 N` 11 'NOH H H

D-Hyp Gly D-Gln D-Leu Gly D-Leu D-Ala Gly D-Pro D-Lys NH2 (2R,4S)

H2N 0 HO;

H 0 H0 H 0 H 1 ~ H0 N NN N N N~ OH OHO

D-Hyp Gly D-Gln D-Leu Gly D-Leu D-Ala Gly D-Pro D-Lys NH2 (2R,4R)

H2N 0 HO H0-H0 H0 0 0 N N N N N -'N -' I>N -OH HH H H

NH2 D-Hyp Ala Gln Leu Gly Leu Ala Gly Pro Lys 2

(2R,4S)

H 2N 0 HO = H0 H 0 H 0 0j j 0 N N N N O H H Nz)HOH

D-Hyp Gly Gln Leu Gly Leu Ala Gly Pro Ala (2R, 4S)

H2N 0 HO

N N N 0 O H H- H

D-Hyp Ala Gln Leu Gly Leu Ala Gly Pro Ala

(2R,4S)

H2 N 0 HO H0 H0 H0 H0 H0 H'H H H N N N ~ N ~<N H N~L ~ IOH

HN 0

Hyp Gly Gln Leu Gly Leu Ala Gly Pro Lys(Ac) (2S, 4R) and H2N 0 HO

H 0 H 0 H 0 H 0 H 0 N N )JN N, N, HN H H ~ H

NH 2 Hyp Gly Gln D-Leu Gly D-Leu D-Ala Gly Pro Lys (2S,4R)

The present invention also provides a compound represented by Formula (I): (R')p 0 R6 0 R2 O CH3 CH O H O (R - H H H NI N ' NJ N j N' N N N 0H OH N N 5 N H R9H N H R7H I R 8 R3 (I

or a pharmaceutically acceptable salt thereof; wherein: R', R2 , and R3 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl; R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR, -CH 2ORb, halo, hydroxyl, and hydroxyalkyl; Rb is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2; R' is hydrogen or substituted or unsubstituted alkyl; and R 7, R 8, and R9 are each independently hydrogen or alkyl; wherein at least one of: (a) at least one of R, R2, and R 3 is substituted or unsubstituted(C 2 Cio)haloalkyl; (b) at least one of alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is substituted with one or more substituents selected from -R-', -SRa, -N(R)2, -N(Ra)g+ =NRa, -NHC(=o)R, -C(=O)R, -C(=)N(Ra)2 , -S(=0) 2R°, -OS(=0) 2 ORa, -S(=0) 2 ORa, _ S(=0) 2 N(Ra)2 , -S(=o)R, -OP(=O)(ORa) 2 , -(alkylene)-C(=O)R°, -C(=S)R, -C(=O)ORa, (alkylene)-C(=)ORa, -C(=S)ORa, -C(=0)SRa, -C(=S)SRa, -(alkylene)-C(=O)N(Ra)2, C(=S)N(Ra) 2, and -C(-NRa)N(Ra) 2; and at least one occurrence of Ra or R° is heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; (c) the compound comprises at least one D-amino acid residue; or (d) at least two occurrences of Ra; at least two occurrences of R°; or at least one occurrence of Ra and at least one occurrence of R°; and at least one occurrence of Ra and/or R° differs from the other occurrences; and wherein the compound is not: H2N 0 HO H0 H0 ' H0 0X 0 N N N N NN"kN NN H H H H.. OH

NH2 D-Hyp Gly Gln Leu Gly Leu Ala Gly Pro Lys 2

(2R,4S)

H 2N 0 HO

HHH 0 ~~N~~<N N N >N XN O H H~

N OH

D-Hyp Gly D-Gln D-Leu Gly D-Leu D-Ala Gly D-Pro D-Lys NH2 (2R,4S)

H2N 0 HOH

NH

D-Hyp Gly D-Gln D-Leu Gly D-Leu D-Ala Gly D-Pro D-Lys NH2 (2R,4R)

H2N 0 HO H0 0_ 0 NH0 H0 HH N-~N o N H N H OH

NH2 D-Hyp Ala Gln Leu Gly Leu Ala Gly Pro Lys 2

(2R,4S)

H 2N 0 HO H0 H0 H0 0 0 N N N NO H H HH

D-Hyp Gly Gln Leu Gly Leu Ala Gly Pro Ala (2R,4S) or H2N 0 HO

N N NN OH H H H H )H

D-Hyp Ala Gln Leu Gly Leu Ala Gly Pro Ala (2R,4S)

In certain embodiments, at least one of R, R 2, and R3 is substituted or unsubstituted (C 2 -Cio)haloalkyl. In certain embodiments, at least one of alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is substituted with one or more substituents selected from -R, -ORa, -SRa -N(Ra)2 , -N(Ra)3, =NRa, -NHC(=)R°, -C(=)R, -C(=)N(Ra) 2 , -S(=0) 2 R°,

OS(=0) 2 ORa, -S(=0) 2 ORa, -S(=0) 2N(Ra)2, -S(=0)R°, -OP(=0)(ORa) 2 , -(alkylene) C(=O)RC, -C(=S)R°, -C(=O)ORa, -(alkylene)-C(=)ORa, -C(=S)ORa, -C(=O)SRa, C(=S)SRa, -(alkylene)-C(=O)N(Ra)2, -C(=S)N(Ra) 2, and -C(-NRa)N(Ra)2 ; and at least one occurrence of Ra or R° is heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl. In certain embodiments, the compound comprises at least one D-amino acid residue. In certain embodiments, the compound has: at least two occurrences of Ra; at least two occurrences of R°; or at least one occurrence of Ra and at least one occurrence of R°; and at least one occurrence of Ra and/or R° differs from the other occurrences. In certain embodiments: R 1, R2 , and R3 are each independently H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl; R 4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -ORb, hydroxyalkyl, -CH 2ORb, and halo; Rb is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; R' is hydrogen or substituted or unsubstituted alkyl; and R 7, R 8, and R9 are each independently hydrogen or alkyl.

In some embodiments, where indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or is substituted with one or more substituents selected from halo, haloalkyl, oxo, -CN, -NO2, =N-OH, -N3 , -R, -OR', -SRa, -N(Ra) 2 , -N(Ra),

=NRa, -NHC(=O)R, -C(=O)Rc, -C(=O)N(Ra) 2 , -S(=0) 2 R°, -OS(=0)ORa, 2 -S(=0) 2 ORa, _

S(=0) 2 N(Ra)2 , -S(=o)R, -OP(=0)(ORa) 2 , -(alkylene)-C(=O)R°, -C(=S)R, -C(=O)ORa, (alkylene)-C(=O)ORa, -C(=S)ORa, -C(=O)SRa, -C(=S)SRa, -(alkylene)-C(=O)N(Ra)2, C(=S)N(Ra) 2, and -C(-NRa)N(Ra) 2; Ra, independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; and R, independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.

In more particular embodiments, where indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or is substituted with one or more substituents selected from halo, haloalkyl, oxo, -Ra, -ORa, -N(R) 2 , -N(Ra)+, -NHC(=O)R, -C(=O)Rc, C(=O)N(Ra) 2, -C(=)ORa, -(alkylene)-C(=O)ORa, and -(alkylene)-C(=O)N(Ra)2; R, independently for each occurrence, is hydrogen, or substituted or unsubstituted

alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; and R°, independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl. In certain such embodiments, R, independently for each occurrence, is hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl; and R°, independently for each occurrence, is alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl.

In certain embodiments, the compound has the structure of formula (I-OL): (R')p O R H R2 H O CH3H 0 H N- N N N N N - O HY H Y H8 N9 N N O (I-OL). Alternatively, the compound may have the structure of formula (I-OD): (R')p H O R H R2 H 0 CH3H 0 H 0 N N N N OH H ,HH H R9 RRR (101)D). In certain embodiments, R is substituted or unsubstituted (C2-Co)haloalkyl. In certain embodiments, R is substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl. More specifically, R may be selected from substituted or unsubstituted alkyl,

R NHRa NHaR,~ OH ,and (H n

NH R.

Sishydrogenor alkyl; and n isan integer from 1to 10, preferably 1-5, more preferably 1-3.

H HO 0 H H2N 0 Exemplary R groups include H,,,

NH2 OH H 3C OH OH3 H 3C OH3 H 3 C3HC H3

~NH 0 0 HN OH /H 'CH3,and CH3

H 3C

In some preferred embodiments, R is H3 . In alternative preferred

0

embodiments, R is H In certain embodiments, the compound has the structure of formula (I-IL): (R')p H 0 R6 0 R2 0 CH3 O O N N '-A N N 3 OH H R9H P1 H 7H 8R (Ii)

Alternatively, the compound may have the structure of formula (I-ID) (R 4 )p H 0 R6 0 R2 0 CH3 O O N N N N N 0H H9 H H H7RHOR 3 (I-ID). In certain embodiments, R2 is substituted or unsubstituted (C2-Co)haloalkyl. In certain embodiments, R2 is H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl. In some embodiments, R2 is selected from hydrogen, substituted or unsubstituted Ra

~R Oa N

(R H ~Ra OH

alkylO H , and

Ra is hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3. CH3 CH 3 H H 3C CH3 CH3 CH 3 CH 3 Exemplary R2 groups include

N pOH 1 , OH H3 C OH HN

Preferably, R2 is hydrogen.

In certain embodiments, the compound has the structure of formula (I-2L): (R 4 )p H O R6 O R2 H CH3H 0 H 0 NjN N N 8N N N N N OH H R9 H HR H R

( 2L). Alternatively, the compound may have the structure of formula (I-2D): (R')p H R H R2 H CH3 0 0 N N - N N N SN N N N OH 8 5H R9 H R1H R H R

( 2D). In certain embodiments, R3 is substituted or unsubstituted(C2-Co)haloalkyl. In certain embodiments, R3 is substituted or unsubstituted alkyl or arylalkyl. In some embodiments, R3 is selected from substituted or unsubstituted alkyl,

aNH a N Oa (no ( o OR OH Rand NHRa Ra is hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

H 3C

Exemplary R3 groups include NH 2 OH H3 HO 0

H2N H, , and H.Preferably,Ris NH 2

In certain embodiments, the compound has the structure of formula (I-3L): 2 (R4)p H HH R6 0 R H 0 CHH3 H O H O

NN N , N N N .J NAN) N N AO HR 9 HR R7 N HR3 OH(I3) H - (1-3L).

Alternatively, the compound may have the structure of formula (I-3D): (R')p(RpH 0 R6 H 0 R2 H O CHH3 H O u H O

N N N N OH H R H H H (

In certain embodiments, p is 1 or 2; and R, independently for each occurrence, is selected from substituted or unsubstituted alkyl, -OR, -CH 2ORb, halo, hydroxyl, and hydroxyalkyl. In certain embodiments, p is 1 or 2; and R, independently for each occurrence, is selected from -CH 3, halo, hydroxyl, and hydroxyalkyl. In certain preferred embodiments, R4 is hydroxyl. In alternative preferred embodiments, R4 is -CH 3 . In any of the above embodiments, p may be 1. In certain embodiments, the compound has the structure of formula (I-4Lg):

(R4)p H 0 R6 H 0 R2 H 0 CH 3 H 0 H 0 N N N N N' IN N 0H HN H N OH 10N 1HN H H9R HR8 R3 (I 4Lg). In certain embodiments, the compound has the structure of formula (I-4La): R4

O R6 0 R2 0 CH3 O O H H H CHH~H N -- N -- ' N N -N N 0H H H H H R8 3 I4L)

In certain embodiments, the compound has the structure of formula (I-4Lb):

15 N7 N8 NR (I-4Lb). O H 0 6H 0 2H 0 CH3H 0 H 0 N N N j N N N N N N N OH H H Y H HI 15R4Lc R O 0 R2 0 H In certain embodiments, the compound has the structure of formula (I-4Lc):

(R4) O R6 0N R 2 O CH H O N N"N _ N NN ,

N N N OH H 'A AH7H 3 9 HR 8 R R (I

4Lc); provided that R 4is not hydroxyl. In certain embodiments, the compound has the structure of formula (-4Dg): R 4p 0 R6 R H 0 OH 3 00 0 HR)~ ~ H H H 8 H N N '__N N N N -- N N -N Y 'OH HR7 H9 H H R3 (I

4Dg).

In certain embodiments, the compound has the structure of formula (I-4Da): R4 O R6 O R2 0 CH3 O H IN .-- N _1 N N N N N N N OH H R H H R7H R (I

4Da). In certain embodiments, the compound has the structure of formula (-4Db): R4

O H R6 0 R2 0 CH O H O H H C3H H N1 11 NOH H 9H H - H R8 R

4Db). In certain embodiments, the compound has the structure of formula (I-4Dc): O R6 0 O CHR2 H O N N N N N N N N N N OH H 'T1H7H 3 H HR R8(I

4Dc); provided that R4 is not hydroxyl. In certain embodiments, R4 is oxo. In certain embodiments, the compound has the structure of formula (I-4Ld): 0 O R H R2 H CH3 0 O SN NN N OH H H R H H (I 4Ld). In certain embodiments, the compound has the structure of formula (I-4Le): 0 R0 O R2 0 CH H O 0 N N N 1 N N N N N N OH H9H1HR H R3 H H R8 R (I 4Le). In certain embodiments, the compound has the structure of formula (I-4Dd):

O R H O R2 CH3 O H N XN N N N N N N N OH SH H (I

4Dd). In certain embodiments, the compound has the structure of formula (I-4De): O RS O R2 O CH3 0_H R H 0 H CHH HOHJ O N N N NO N N-' N N OH HH H H (I

4De).

In certain embodiments, R6 is hydrogen or alkyl, wherein the alkyl is optionally substituted with one occurrence of -C(=O)NH 2 . In certain embodiments, wherein R' is alkyl optionally substituted with one occurrence of -C(=O)NH 2 . For example, R6 may be H 2N 0

CH 3 . Alternatively, R6 may be .

In certain embodiments, the compound has the structure of formula (I-6L):

(R4)p H 0 R6 H 0 R2 H 0 CH 3 H 0UH 0 N N NN , N' IN N O N N N 8 3 OH HN H H 7H (I

6L). Alternatively, the compound may have the structure of formula (I-6D):

(R4)p H R6 0 R2 O CH3 H O N N N N OH

(I-6D).

H3 C

In certain embodiments, R7 is (Ci-Cio)alkyl, preferably 3 or H3

In certain embodiments, the compound has the structure of formula (I-7L):

(R4)p O R H O R2 H O CH H 0 H O 3 N N N N N N N N N OH H HRH H R (I

7L).

Alternatively, the compound may have the structure of formula (I-7D):

(R')p H R6 0 R2 O CH3 H O , H H 0 H 0 N1 -N N N N NN N N j N 8 N 0H OH H H H H 3

(I-7D). In certain embodiments, the compound has the structure of formula (I-11L):

(R0)p(RpH R R H O RR2 H CH 3 H O H 0O N N N AN N 'A IN NTO 5NN N N OH 5H H9 H H R8 R3

( I1L). Alternatively, the compound may have the structure of formula (I-IID):

(R')p 0 R6 0 R2 0 CH 3 0 HH H3HH N N N OH H ' H 3 H9 H1 R RI

I1D). In certain embodiments, R 8 is -CH 3 or -H, preferably -H. In certain embodiments, R9 is -CH 3 or -H, preferably -H. In certain embodiments, the compound is H2N 0 HO

H 0 H 0 H 0 H 0 H N NN N, N, H' H H ~ H

NH 2 Hyp Gly Gin D-Leu Gly D-Leu D-Ala Gly Pro Lys (2S,4R) , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a peptide having an amino acid sequence represented by HyP-Gly-Gln-Xaa-Gly-Leu-Ala-Gly-Pro-Lys; or a pharmaceutically acceptable salt and/or stereoisomer thereof; wherein Xaa is selected from Glu, Asn, Gln, His, Lys, Ser, Thr, Ala, Val, Ile, Leu, Phe, Tyr, Trp, homo-Ser, Asp(Me), and Asn(Me); and at least one amino acid residue in the peptide is a D-amino acid residue. In certain such embodiments, at least two, at least three, at least four, at least five, at least six, or at least seven amino acid residues in the peptide are D-amino acid residues.

The peptide may be a variant of a collagen typeII al-derived peptide. The collagen type II al may be isolated from the extracellular matrix derived from animal chondrocytes. The term "peptide" used in the present invention refers to a compound in which two or more amino acids are linked by a peptide bond. Further, it is classified into dipeptide, tripeptide, tetrapeptide, and the like according to the number of constituent amino acids. An oligopeptide has about 10 or fewer peptide bonds, and a polypeptide has a plurality of peptide bonds. In addition, a peptide in the present invention includes a mutated peptide in which its amino acid residue is substituted. The term "HyP" used in the present invention refers to an amino acid called hydroxyproline, in which a hydroxyl group (-OH) is bonded to the carbon atom at the 4 position of proline. HyP has a structure of CH9 N03 and may be depicted as follows: HO

N H HyP may include all isomers. In addition, HyP may be an isomer represented by the stereochemistry of "2S,4R" unless otherwise specified. The term "homo-Ser" used in the present invention is called homoserine and refers to an a-amino acid having a hydroxyl group in the side chain. Homo-Ser is an intermediate present in the biosynthesis of threonine and methionine in microorganisms and plants. HO

N H Homo-Ser may be depicted as follows: The term "Asp(Me)" used in the present invention indicates an amino acid in which the hydrogen atom of the hydroxyl group (OH) bonded to the carbon atom at the 4-position of aspartic acid is substituted by a methyl group (CH 3). Asp(Me) may be depicted as OCH3

ON H follows: The term "Asn(Me)" used in the present invention indicates an amino acid in which the hydrogen atom of the amine group (NH 2) bonded to the carbon atom at the 4-position of asparagine is substituted by a methyl group (CH 3). Asn(Me) may be depicted as follows: 3 HN'CH

.

The term "(N-Me)Gly" used in the present invention indicates an amino acid in which the hydrogen atom of the amine group (NH 2) bonded to the carbon atom at the 2-position of glycine is replaced by a methyl group (CH3 ). (N-Me)Gly may be depicted as follows:

In certain embodiments, the compound is a peptide having an amino acid sequence represented by HyP-Gly-Gln-Asp-Xaa-Leu-Ala-Gly-Pro-Lys; or a pharmaceutically acceptable salt and/or stereoisomer thereof; wherein Xaa is selected from Val, Ile, Leu, Ala, Phe, Tyr, Trp, Ser, Thr, and (N-Me)Gly; and at least one amino acid residue in the peptide is a D-amino acid residue. In certain such embodiments, at least two, at least three, at least four, at least five, at least six, or at least seven amino acid residues in the peptide are D-amino acid residues. In certain embodiments, the compound is a peptide having an amino acid sequence represented by HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Xaa; or a pharmaceutically acceptable salt and/or stereoisomer thereof; wherein Xaa is selected from Tyr, Leu, Glu, Gln, Ala, and Nle(6-OH); and at least one amino acid residue in the peptide is a D-amino acid residue. In certain such embodiments, at least two, at least three, at least four, at least five, at least six, or at least seven amino acid residues in the peptide are D-amino acid residues. In certain embodiments, the compound is a peptide having an amino acid sequence represented by Xaa-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys; or a pharmaceutically acceptable salt and/or stereoisomer thereof; wherein Xaa is selected from:

HO 0 HO-.

N N N HHH H Ht

H 3 1,

N H3 C' N N , ,and ;and at least one amino acid residue in the peptide is a D-amino acid residue.

In certain such embodiments, at least two, at least three, at least four, at least five, at least six, or at least seven amino acid residues in the peptide are D-amino acid residues. In certain embodiments, the invention provides a compound having the following H2 N 0 HO H0 H0 H0 H0 H 0 N N N N OH H H £H H1

H 0

Hyp Gly Gln Leu Gly Leu Ala Gly Pro Lys(Ac) structure: (2S,4R) or a pharmaceutically acceptable salt thereof. In certain embodiments, the invention provides a compound represented by Formula (V): (R')p H O R6 H O R2 N N OH H R9H-' H M

or a pharmaceutically acceptable salt thereof; wherein: R' and R2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl; R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR, -CH 2ORb, halo, hydroxyl, and hydroxyalkyl; Rb is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2; R' is hydrogen or substituted or unsubstituted alkyl; and R9 is hydrogen or alkyl; wherein the compound is not:

HO H2 N 0 HO H 0 H 00 0 N, N OH H H N N OHH N OH HH H NH"r0 N H H

Hyp Gly Gin Leu Gly Hyp Gly Gln D-Leu Gly (2S,4R) (2S,4R) ;or

H2N 0 HO

N N N OH H H H

D-Hyp Gly Gin Leu Gly (2R,4S)

In certain embodiments, R and R2 are each independently H or substituted or unsubstituted alkyl; R4 for each occurrence is hydroxyl; p is 1; R' is alkyl optionally substituted with one occurrence of -C(=0)NH 2; and R9 is hydrogen.

H 3C

In certain embodiments, R is substituted or unsubstituted alkyl, such as 3

In certain embodiments, the compound has the structure of formula (V-IL) (R4 )p H 0 R6 H 0 R2 N N OH H'I R H I1H (V-IL). Alternatively, the compound may have the structure of formula (V-ID) (R4 )p H 0 R6 H 0 R2 N N N OH HN H H H R9 (V- ID). In certain embodiments, R2 is H. In certain embodiments, p is 1 and R4 is hydroxyl. In certain embodiments, the compound has the structure of formula (V-4La): R4

0 R6 0 R2 N N OH HN H 'A H R R (V-4La). In certain embodiments, the compound has the structure of formula(V-4Lb):

R4

O R6 0 R2

N OH R R (V-4Lb).

In certain embodiments, the compound has the structure of formula (V-4Da): R4

O R6 0 R2 N N OH N N N H H- - H R R1 (V-4Da). In certain embodiments, the compound has the structure of formula (V-4Db): R4

0 R6 0 R2 N N OH N N N H H - H RR1(V-4Db). In certain embodiments, R 6 is alkyl substituted with one occurrence of -C(=0)NH 2

, H 2N 0

such as .

In certain embodiments, the compound has the structure of formula (V-6L):

(R4 )p H 0 R6 H 0 R2 N N N OH HN H H R9 R(V-6L). Alternatively, the compound may have the structure of formula (V-6D):

(R4 )p H 0 R6 H 0 R2 N NN OH 6D). HHH R9 H R1(V-61)).

In certain embodiments, R9 is -H. In certain embodiments, the compound is selected from the following:

HN 0 H HN 0 HO HO HNOH

N N OH N N OH H N ~ O H H

D-Hyp Gly D-Gln D-Leu Gly Hyp Gly D-Gln Leu Gly (2R, 4S) (2S,4R)

HO H 2N 0 H 2N 0 H 0HO N N1 ,OH HH NN OH HH H~H H

D-Hyp Gly D-Gin Leu Gly D-Hyp Gly Gin D-Leu Gly (2R,4S) (2R,4S) and H 2N 0 HO H N NN N, OH H H H

Hyp Gly D-Gln D-Leu Gly (2S,4R) , or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention provides a compound represented by Formula (VI): (R')p H R6 O R2 H NIN' jN N ' N N N N OH H H H (VI);

or a pharmaceutically acceptable salt thereof; wherein: R' and R2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR, -CH 2ORb, halo, hydroxyl, and hydroxyalkyl; Rb is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2; R' is hydrogen or substituted or unsubstituted alkyl; R 7 is hydrogen or alkyl; and R9 is hydrogen or alkyl; wherein the compound is not:

H2 N 0 HO H 2N 0 HO:-H 0 0 O H 0 H H 0 HO H N H N N OH H N N N OH

Hyp Gly Gin Leu Gly Leu D-Hyp Gly D-Gln D-Leu Gly D-Leu (2S,4R) or (2R,4S)

In certain embodiments: R and R2 are each independently H or substituted or unsubstituted alkyl; R4 for each occurrence is hydroxyl; p is 1; R' is alkyl optionally substituted with one occurrence of -C(=O)NH 2; and R9 is hydrogen.

H 3C

In certain embodiments, R is substituted or unsubstituted alkyl, such as 3

In certain embodiments, the compound has the structure of formula (VI-IL)

(R')p H R O R2 N N _ N N 'NN N _, T;OH 9 H H (VI-IL). Alternatively, the compound may have the structure of formula (VI-ID)

(Ro)p HR)'_H O R6 H 0 R2 H N N N ' -N 0H H H H (VI-1D).

In certain embodiments, R2 is H. In certain embodiments, p is 1 and R4 is hydroxyl. In certain embodiments, the compound has the structure of formula (VI-4La): R4 O R6 0 R2 0 H _ H H N N NT N' - NN)O H NN N'O R9 H H (VI-4La). In certain embodiments, the compound has the structure of formula(VI-4Lb):

R4

O R6 0 R2 0 jH H H N N N N OH H H-1 HT Y R HR R (VI-4Lb). In certain embodiments, the compound has the structure of formula (VI-4Da): R4

O R6 0 R2 0 N _1 N N N N N O'0H H H H -1X N9 N(VI-4Da).

In certain embodiments, the compound has the structure of formula (VI-4Db):

O R6 0 R2 0 N N jN N N O,0H H Y H H N N N O (VI-4Db). In certain embodiments, R 6 is alkyl substituted with one occurrence of -C(=0)NH 2

, H 2N 0

such as .

In certain embodiments, the compound has the structure of formula (VI-6L):

(R04)p p HH HR R6 0 R2 H O

NN N' OH H H HO (VI-6L). Alternatively, the compound may have the structure of formula (VI-6D):

(R')p H 0 R6 0 R2 0 N N N- N N N 0H N N OH H R R R (VI-6D). In certain embodiments, R9 is -H.

H 3C

In certain embodiments, R7 is (Ci-Cio)alkyl, such as 3 or 3

In certain embodiments, the compound has the structure of formula (VI-7L):

(R')p H R6 O R2 H

N N N OH RH R (VI-7L).

Alternatively, the compound may have the structure of formula (VI-7D):

(R)p H R6 O R2 H N N NN NN H I N O0H H H H (VI-7D).

In certain embodiments, the invention provides a compound represented by Formula (VII):

(R')p H O R6 H O R2 H O CH 3 N1 N NN N N OH H H H H (VII); or a pharmaceutically acceptable salt thereof; wherein: R' and R2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl; R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR, -CH 2ORb, halo, hydroxyl, and hydroxyalkyl; Rb is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2; R' is hydrogen or substituted or unsubstituted alkyl; R7 is hydrogen or alkyl; and R9 is hydrogen or alkyl; wherein the compound is not:

H 2N 0 HO H0 H0 H0 N N N N OH H H H H

Hyp Gly Gln Leu Gly Leu Ala (2S,4R) or H2N 0 HO 0 H 0H 0 H N N N NYN NYN OH H H H H

O OH

Hyp Gly Gln Glu Gly Leu Gly (2S,4R)

In certain embodiments: R and R2 are each independently H or substituted or unsubstituted alkyl; R4 for each occurrence is hydroxyl; p is 1; R' is alkyl optionally substituted with one occurrence of -C(=O)NH 2; and R9 is hydrogen.

H3 C

In certain embodiments, R is substituted or unsubstituted alkyl, such as H3

In certain embodiments, the compound has the structure of formula (VII-IL)

(R)p H O R6 H 0 R2 H O CH 3 N N HHN N H9 H I1 H H OH (I-I) (VII-IlIL). Alternatively, the compound may have the structure of formula (VII-1D) (R')p H R H O R2 H O CH 3 N N N , N N J OH HN N H H N9 N H OH (VII-ID).

In certain embodiments, R2 is H. In certain embodiments, p is 1 and R4 is hydroxyl. In certain embodiments, the compound has the structure of formula (VII-4La):

R4

H0 R6 H 0 R' 0 CH 3 N N N OH H HHH (VII-4La). In certain embodiments, the compound has the structure of formula(VII-4Lb):

H O R H R2 H O CH 3 N N N N N OH N R N H H H R4 R 7 (VII-4Lb). In certain embodiments, the compound has the structure of formula (VII-4Da):

H R6 0 R2 0 CH3 N N OH(VII4Db) N R4 H R9 H H H H (VII-4Da). In certain embodiments, the compound has the structure of formula (VII-4Db):

HN H O NR H O R2 H O CH 3 N N N OH NN N N H H OH R2 OH NN N OH(VII-4Db). In certain embodiments, R' is alkylsubstitutedwithoneoccurrenceof-C(=O)NH 2

, H 2N 0

such as 7 In certain embodiments, the compound has the structure of formula (VII-6L): (R4)p H 0 R6 0 H 0 CH 3 N N N XN XOH HN N H __XH N N H XH H R9 R(VII-6L).

Alternatively, the compound may have the structure of formula (VII-6D): (R4)p - H 0 R6 H 0 R2 H 0 OH 3 N11 N N NT N N N OH -Y HH 7(VII-6D)).

In certain embodiments, R9is -H.

H 3C

In certain embodiments, R7 is (Ci-Cio)alkyl, such as 3 or 3

. In certain embodiments, the compound has the structure of formula (VII-7L): (R')p H O R6 H O R2 H O CH 3 N N N OH H H H H H H 59 N N7 N O(VII-7L).

Alternatively,thecompound may have the structure of formula (VII-7D): (R')p H O R H O R2 H O 3CH N N OHN OH N H - H - H H (VII-7D)). Incertainembodiments,th compound has the structure of formula (VII-OL):

(R)p HO R6 H 0 R2 0 CH3 H H

R R R (VII-1IOL). N N Alternatively,thecompound may N have the structureof formulaVII- OD): N OH I-0) (R')p (R1O 0 RH 9p, 1 O H _I H R OH O2 CH3O 'N N N N OH N N N N H H 7H H R9 (VII- IOD). The present invention also provides acompound represented by Formula (IX):

(R 4 )p 0 R

N N N N N

or a pharmaceutically acceptable salt thereof; wherein: R' and R2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl; R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR, -CH 2ORb, halo, hydroxyl, and hydroxyalkyl; Rb is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2;

R is hydrogen or substituted or unsubstituted alkyl; R7 , R 8, and R9 are each independently hydrogen or alkyl; J is OH or -NRRY; and R' and R are each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or R' and R taken together with the intervening nitrogen atom form a ring. Exemplary compounds of Formula (IX) include YDE-100 through YDE-107.

In certain embodiments of the compounds of formula (IX): R' and R2 are each independently H or substituted or unsubstituted alkyl; R for each occurrence is hydroxyl; pis 1; R is alkyl optionally substituted with one occurrence of -C(=O)NH 2; and R9 is hydrogen.

In certain embodiments of the compounds of formula (IX), R is substituted or

H 3C

unsubstituted alkyl, for example 3

In certain embodiments, the compound has the structure of formula (IX-IL):

(R 4 )p O R O 0~ R2 H 0 OH 3H H H H N N N NJ N N N HN' H _IH"NH H (IX-IL).

Alternatively, in certain embodiments, the compound has the structure of formula (IX-ID):

(R 4 )p O RN O R2 O CH3 O N N N N HN' N H, N Y[N' Y.H H (IX-ID).

In certain embodiments, R2 is H. In certain embodiments, p is 1 and R4 is hydroxyl.In certain embodiments, the compound has the structure of formula (IX-4La): o R6 0 R2 0 H

R4

H 0 6H 0 2H 0 CH3H 0 In certain N embodiments, XN the)compound NN has the structure N of formula J (IX-4Lb): N N NN

R (IX-4La). H H H

o R6 0 R2 0 H In J - certain embodiments, NN the compound N has the IN structure N J (IX-4Db): of formula NA N N' N

H RH R2 CH3 0

H9 H HR R8 (IX-4LD). o R6 0 R2 0 H In Ncertain embodiments, N the compound N has the structure N J (IX-4D): of formula N N N N'

H 0 R6 0 R2 CH3 0 H H9 H1 H R8 (IX-4Db).

H 0 R H0 H20 H3 H0 N N N NJ IJN N "j N NJ H HR 1R H 8 'T (IX-6Lb). H Y 'H

In certain embodiments, th compound hasthestructure offormula(IX-):

R4 ~In certain embodiments, the compound has the structure of formula (IX-6D):

(R4pH 0 R6 0 R2 H 0 OH 3 H 0 KN N N__X N N "T N' NJ HN -T H - H 7H H 9R R8 (IX-6D).

In certain embodiments,R sh . opudhstesrctr ffrua(X6

(R 4)p H0 R6 H 0 2H 0 3H 0

In certain embodiments, R7 is (Ci-Cio)alkyl. For example, R7 may be 3 or

H 3C

1H 3

In certain embodiments, the compound has the structure of formula (IX-7L):

(RH)p O R H O H 0 CH 3 H 0 N N N ~N N HN H - H 7H R8 (IX-7L).

In certain embodiments, the compound has the structure of formula (IX-7D):

(R')p O RS 0 R2 H 0 CH 3 N K N N _I N H N N NUW NJ H-j H H H R8 (IX-7D).

In certain embodiments, the compound has the structure of formula (IX-1OL):

(R)p H 0 R6 0 R2 H 0 CH 3 H 0 H H Hj -AH (IX-OL). In certain embodiments, the compound has the structure of formula (IX-OD):

(RR)p R H O R2 H CH 3 H 0 K. NN N N NN N N J HN H H HH H (IX-OD). In certain embodiments, the compound has the structure of formula (IX-1IL):

(R4 )p O R. O R2 CH3 O H N K N N _, N AN NNJ ' N' H H ' H 1H 7H R8 (IX-1IL).

In certain embodiments, the compound has the structure of formula (IX-1ID):

(R 4 )p H 0 R6 0 R2 H 0 CH 3 NN N Nj N N N QJ HT H - H 7H 8 R (IX-1ID). In certain embodiments, R 8 is -CH 3 or -H, preferably -H. In certain embodiments, J is OH. Alternatively, in other embodiments, J is-NRxRy. In certain such embodiments, Rx and R are each independently alkyl. Alternatively, R' and R may be taken together with the intervening nitrogen atom form a ring.

In other embodiments, the present invention also provides a compound compound represented by Formula (X-am): (R 4)pH 0 R6 0 R2 0 CH3 O O NN N N NR R (X N N N N xR H R9 H H7 R 71R8R (X

am); or a pharmaceutically acceptable salt thereof; wherein: R, R 2, and R3 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl; R, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR, -CH 2ORb, halo, hydroxyl, and hydroxyalkyl; Rb is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2; R' is hydrogen or substituted or unsubstituted alkyl; R 7, R 8, and R9 are each independently hydrogen or alkyl; J is OH or -NRxRY; and Rx and R are each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or R' and R taken together with the intervening nitrogen atom form a ring. Exemplary compounds of Formula (X-am) include YDE-93 and YDE-96. In certain embodiments of the compound of Formula (X-am): R', R2 , and R3 are each independently H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl; R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -ORb, hydroxyalkyl, -CH 2ORb, and halo; Rb is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; R6 is hydrogen or substituted or unsubstituted alkyl; and R 7, R 8, and R9 are each independently hydrogen or alkyl. In certain embodiments, where indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or is substituted with one or more substituents selected from halo, haloalkyl, oxo, -CN, -NO2, =N-OH, -N3 , -R, -ORa, -SR, -N(Ra) 2 , -N(Ra), =NRa, -NHC(=O)R, -C(=O)Rc, -C(=O)N(Ra) 2 , -S(=0) 2R°, -OS(=0)ORa, 2 -S(=0) 2 ORa, _ S(=0) 2N(Ra)2 , -S(=o)R, -OP(=0)(ORa) 2 , -(alkylene)-C(=O)R°, -C(=S)R, -C(=O)ORa, (alkylene)-C(=O)ORa, -C(=S)ORa, -C(=O)SRa, -C(=S)SRa, -(alkylene)-C(=O)N(Ra)2, C(=S)N(Ra) 2, and -C(-NRa)N(Ra) 2; and Ra, independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; and R°, independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl. In further embodiments, where indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or is substituted with one or more substituents selected from halo, haloalkyl, oxo, -Ra, -ORa, -N(R) 2, -N(Ra)3, -NHC(=O)R, -C(=O)R°, C(=O)N(Ra) 2, -C(=)ORa, -(alkylene)-C(=)ORa, and -(alkylene)-C(=O)N(Ra)2; and R, independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; and R°, independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl. In still further embodiments, R, independently for each occurrence, is hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl; and R°, independently for each occurrence, is alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl. In certain embodiments, the compound has the structure of formula (X-am-1OL):

(R 4)p H o R6 0 R2 0 CH3 O O H H CHH u H 0 N K N N N N N N N _N NRR NRxRY H' '1 9 H H H R R 71RR (X

am-OL). In certain embodiments, the compound has the structure of formula (X-am-1OD):

(R 4)p H o R6 H 0 R2 H 0 CH3 CHH O H O 0 'NNK NN N N N 'J XN N NRxRY H'j " 9 H " NHH NNRR(X R R1R 7 8 HR_ R3(X

am-10D). In certain embodiments, R1 is substituted or unsubstituted (C2-Co)haloalkyl. Alternatively, R 1 may be substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl.

In still further embodiments, R' is selected from substituted or unsubstituted alkyl,

R NHRa HR H, and

(n NH

Ra

Ra is hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

O 0

In still further embodiments, R is selected from H HO 0 NH 2

'_H N CH3 H2 N NH 2 OH H3C OH H3 H3 C CH3 H3

H3 C NH 0 0 HN H3 OH H CH 3 andH3

H 3C

Preferably, R is 3 or R is H In certain embodiments, the compound has the structure of formula (X-am-1L): (R4 )p H o R6 H 0 R2 H 0 CH3 CHH O U H O 0 NN N NI NRN N N -"N N N NRxRY H H -7 H R9 R R (X

am-IL). In certain embodiments, the compound has the structure of formula (X-am-ID): (R4 )p H 0 R6 H 0 R2 H 0 CH3 CHH O U H O 0 K N N N N N N N N NRR NRIRN (X 'N 9H H 7H R R 71RR (X

am-ID).

In certain embodiments, R2 is substituted or unsubstituted (C2-Co)haloalkyl. Alternatively, R 2 may be H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl. In further embodiments, R2 is selected from hydrogen, substituted or unsubstituted Ra

~Ra ~ ORa .. nN H ROH alkyl, , , , , and ;wherein Ra is hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3. CH 3 H H3 C CH 3 CH 3

In other embodiments, R2 may be selected from

CH 3 OH . N

CH 3 H3 HH O a ,and H3 C OH

. In some preferred embodiments, R2 is hydrogen. In certain embodiments, the compound has the structure of formula (X-am-2L): O (RH)p O R6 O R2 O CH 3 H H N N NRxRY 8 H A H H H 3

(X-am-2L). In certain embodiments, the compound has the structure of formula (X-am-2D):

(R 4 )p R6 0 R2 0 H0 H CH3 H H CjHH 0H 0 'N N 9 N N N N NNRR N 8 N NRxRY H-' NN R H N H H

(X-am-2D). In certain embodiments, R3 is substituted or unsubstituted (C2-Co)haloalkyl. Alternatively, R 3 may be substituted or unsubstituted alkyl or arylalkyl.

In certain embodiments, R' is selected from substituted or unsubstituted alkyl,

no (no NH Ra RRa , OnH ' R , and ; Ra is hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

H 3C

In further embodiments, R' is selected from NH 2 , OH H3

HO 0 H2N H3, and H; preferably R3 is NH 2

In certain embodiments, the compound has the structure of formula (X-am-3L):

(R')p O R6 O R2 0 CH3 0 H 'j H H,8 N. NN N N N N - NR NN N N NRRY H R9 H HR R

(X-am-3L). In certain embodiments, the compound has the structure of formula (X-am-3D):

(R 4)ps H R6 H R2 O CH 3 H H

'r- HN'" N N NNRY N.J 8 N NRxRY N N H H R 10 H H 10RRRR (X-am-3D). In certain embodiments, p is 1 or 2; and R, independently for each occurrence, is selected from substituted or unsubstituted alkyl, -OR, -CH 2ORb, halo, hydroxyl, and hydroxyalkyl. In further embodiments, p is 1 or 2; and R, independently for each occurrence, is selected from -CH 3, halo, hydroxyl, and hydroxyalkyl. Preferably, R4 is hydroxyl or R4 is CH 3 .

In certain embodiments, p is 1. In certain embodiments, the compound has the structure of formula (X-am-4Lg):

(RH)p O R6 0 R2 0 CH3 O H H ) H HHH N N C:N N rXR N N N N NRxRY HR 9 H1 H H

(X-am-4Lg). In certain embodiments, the compound has the structure of formula (X-am-4La):

H o 0 R6 R6H 0 0 2 RR2H 0 0 H H CH3 0 H N N N NRRY HR H H H R R3

(X-am-4La). In certain embodiments, the compound has the structure of formula (X-am-4Lb): R4

H0 R6H 0 R2H O H3 H 0H 0

N N N NRxRY 8 HR H H H R

(X-am-4Lb). In certain embodiments, the compound has the structure of formula (X-am-4Lc):

H O R6 0 R2 0 CH3 0 H N HH N N N NRxRy H H 8 ' R 10HR9RRR (X-am-4Lc); provided that R4 is not hydroxyl. In certain embodiments, the compound has the structure of formula (X-am-4Dg):

(R 4 )p H 0 R6 0 R2 O CH H 0 H H 0 H 0 N N N N H9 H1 H H RR3

(X-am-4Dg). In certain embodiments, the compound has the structure of formula (X-am-4Da): R4

o R O R2 O CH3 H O N N Y' N 3 NRXRY H H H H HR R8 1

(X-am-4Da). In certain embodiments, the compound has the structure of formula (X-am-4Db):

H R OR2 H CH3 0 O N Nj N , N N N N N N H H H H R8 A NRxRY

(X-am-4Db). In certain embodiments, the compound has the structure of formula (X-am-4Dc):

O R6 0 R2 0 CH3 O H R4HH H R XN N N NRRY H R9 H H 7H R8 3

(X-am-4Dc); provided that R4 is not hydroxyl. In certain embodiments, R4 is oxo. In certain embodiments, the compound has the structure of formula (X-am-4Ld): 0 H 0 6H 0 2H 0 CH3 H 0 H 0 N N N 3 NRxRY H H H H 8

(X-am-4Ld). In certain embodiments, the compound has the structure of formula (X-am-4Le): O R6 0 R2 0 CH3 O H 0H"j H HHH oN N N N N jN NNRR N-1 NA NRxRy H 'A H H HR

(X-am-4Le). In certain embodiments, the compound has the structure of formula (X-am-4Dd): 0 O R6 0 R2 H 0 CH 3 H H N"N N XN N N) N N N NRxRY N 0 R1T (X-am-4Dd). In certain embodiments, the compound has the structure of formula (X-am-4De): H 0 R6 0 R2 0 CH3H H N N N N N NRxRY H R9H 1H H R

(X-am-4De).

In certain embodiments, R6 is hydrogen or alkyl, wherein the alkyl is optionally substituted with one occurrence of -C(=O)NH 2 ; preferably R' is alkyl optionally substituted H 2N 0

with one occurrence of -C(=O)NH 2 . For example, R6 may be -CH3 or R6 may be

In certain embodiments, the compound has the structure of formula (X-am-6L):

2 (RR)p 0ROR 0 CH3H O H NY I N N 11 N N N NRY N N N R8 R3 NRRY H R9 H H H

(X-am-6L). In certain embodiments, the compound has the structure of formula (X-am-6D):

2 (RR)p 0ROR 0 CH3H H 'NNK NN N NN N N N NRxRY N H-R 9 H H Y1HNNRR R8 A

(X-am-6D).

In certain embodiments, R7 is (Ci-Cio)alkyl. For example, R7 may be 3 or

H 3C

1H 3

In certain embodiments, the compound has the structure of formula (X-am-7L):

(RR)p 0 R O R2O CH3 H 0 _, H H8 0NH N N N N N j N N NRxRY H)Hj H H 7

(X-am-7L). In certain embodiments, the compound has the structure of formula (X-am-7D):

(R 4)p H O R6 0 R2 0 CH3H 0 H 0 NN H N H NNRR HR 9 H H H7 R3

(X-am-7D). In certain embodiments, the compound has the structure of formula (X-am-1IL):

(RH)p O R6 0 R2 0 CH3 O H H j H HHH N'XN NN N N -Nj N N N NNRR N NRxRY H Y H Y.'H Y-H 8

(X-am-1IL). In certain embodiments, the compound has the structure of formula (X-am-1ID):

(R 4)p O R 0 R2 0 CH3 H O N N N NN -N -N R8 N RNR NRRY 3 R7

(X-am-11D). In certain embodiments, R 8 is -CH 3 or -H, preferably -H. In certain embodiments, R9 is -CH 3 or -H, preferably -H. In certain embodiments, RX and R are each independently optionally substituted alkyl. In alternative embodiments, RX and RY are each independently optionally substituted alkoxylalkyl. In further alternative embodiments, Rx and R taken together with the intervening nitrogen atom form a ring. The invention also provides a salt of a compound represented by Formula 8: HZN HQ

( ~'A H Jj?~?H N N o Ho

0i

Gin Aspatimide Gly Leu Ala Gly Pro Lys NH2 Hyp Gly (2S.R) [Formula 8]; and a salt of a compound represented by Formula 10: 1-11,1 0 HHz

HDD H 0 H 0 H C 0

NH

Hyp Gly Gin Asp (N-Me)Gly Lau Ala Gly Pro Lys NH2 (2S,4R) [Formula 10]. In certain embodiments, the compound may be a prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, a carboxylic acid present in the parent compound is presented as an ester, or an amino group is presented as an amide.

In certain such embodiments, the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl or carboxylic acid). In certain embodiments, compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee. The compounds of the invention have more than one stereocenter. Accordingly, the compounds of the invention may be enriched in one or more diastereomers. For example, a compound of the invention may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de. In certain embodiments, the compounds of the invention have substantially one isomeric configuration at one or more stereogenic centers, and have multiple isomeric configutations at the remaining stereogenic centers. In certain embodiments, the enantiomeric excess of a given stereocenter in the compound is at least 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, 92% ee, 94% ee, 95% ee, 96% ee, 98% ee or greater ee. As used herein, single bonds drawn without stereochemistry do not indicate the stereochemistry of the compound. The compound of formula (I) provides an example of a compound for which no stereochemistry is indicated. As used herein, hashed or bolded wedge bonds indicate absolute stereochemical configuration. In certain embodiments, a therapeutic preparation of the compound of the invention may be enriched to provide predominantly one enantiomer of a compound. An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer. In certain embodiments, a therapeutic preparation may be enriched to provide predominantly one diastereomer of the compound of the invention. A diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.

PharmaceuticalCompositions In certain embodiments, the invention provides a pharmaceutical composition comprising a salt or compound of the invention, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition is formulated for topical administration to the eye, e.g., as eye drops.

In certain embodiments at least 50%, 60%, 70%, 80%, or 90% of the compound is present as a salt. Preferably, at least 95% of the compound is present as a salt. Even more preferably, at least 99% of the compound is present as a salt. In certain embodiments, the present invention provides a pharmaceutical preparation suitable for use in a human patient, comprising any salt or compound of the invention, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical preparations have a low enough pyrogen activity to be suitable for use in a human patient. One embodiment of the present invention provides a pharmaceutical kit comprising a salt or compound of the invention, or a pharmaceutically acceptable salt thereof, and optionally directions on how to administer the compound. The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In certain preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop. A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste. To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ (e.g., wheat germ), olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment. Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine. Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatable with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant). The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue. For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier. Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference). In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily. The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general. In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase "conjoint administration" refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds. In certain embodiments, conjoint administration of compounds of the invention with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the compound of the invention (e.g., a compound of formula I, V, VI, or VII) or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the invention and the one or more additional therapeutic agent(s). This invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. The term "pharmaceutically acceptable salt" as used herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, oxalic, mandelic and other acids. Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1:1. For example, the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound of Formula I, V, VI, or VII. As another example, the salt may comprise less than one inorganic or organic acid molecule per molecule of base, such as two molecules of compound of Formula I, V, VI, or VII per molecule of tartaric acid. In further embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2 hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Methods of Treatment The present invention also provides methods of treating eye disease, comprising administering to a subject in need thereof salt of the invention, a compound of the invention, or a pharmaceutical composition comprising a salt or compound of the invention. Specifically, the eye disease may be selected from retinopathy, keratitis, dry macular degeneration, wet-macular degeneration, dry eye syndrome, keratoconjunctival epithelium disorder, proliferative vitreoretinopathy, pigmentary retinopathy, diabetic retinopathy, retinopathy of prematurity, retinopathy of immaturity, proliferative retinopathy, ischemic retinopathy, epidemic keratoconjunctivitis, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, phlyctenular keratoconjunctivitis, scleritis, comeal transplant rejection, choroidal neovascularization, neovascular glaucoma, ischemic optic neuropathy, retrolental fibroplasias, diabetic macula, neovascular iris disease, erythrosis, myopia, Von Hippel-Lindau syndrome, ocular histoplasmosis, central retinal vein occlusion, Sjogren syndrome and Stevens-Johnson syndrome. Preferably, the eye disease may be selected from retinopathy, keratitis, macular degeneration, dry eye syndrome and keratoconjunctival epithelium disorder. In certain preferred embodiments, the eye disease is selected from retinopathy, keratitis, dry-macular degeneration, wet-macular degeneration, dry eye syndrome, heratoconjunctivitis sicca and keratoconjunctival epithelium disorder. The pharmaceutical composition for treating an eye disease, which comprises a salt or compound of the invention as an active pharmaceutical ingredient, may further comprise at least one additive selected from the group consisting of a carrier, an excipient, a disintegrant, a sweetener, a coating agent, a swelling agent, a lubricant, a slip agent, a flavor, an antioxidant, a buffer, a bacteriostat, a diluent, a dispersant, a surfactant, and a binder. Specifically, a formulation for parenteral administration may be a sterilized aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized preparation, a suppository, or the like. The dose of the salt or compound of the invention that is administered to the subject may be adjusted depending on such various factors as the kind of the disease, the severity of the disease, the kinds and amounts of the active pharmaceutical ingredient and other ingredients contained in the pharmaceutical composition, the type of the formulation, the age, body weight, general health condition, sex, and diet of the patient, the time and the route of administration, the duration of treatment, and the drugs concurrently used.

However, for the desired effect, the effective amount of the salt or compound contained in the pharmaceutical composition may be 0.0001 g/day to 100 [g/day. In such event, the administration may be carried out once a day, or divided into several doses. Specifically, the concentration of the salt or compound contained in the pharmaceutical composition may be 1000 M to 0.001 jM. Also, the concentration of the salt or compound contained in the pharmaceutical composition may be 100 M to 0.005 M or 50 M to 0.02 jaM. In addition, if necessary, the concentration of the salt or compound contained in the pharmaceutical composition may be 30 M to 1 M. Further, the concentration of the compound or the peptide contained in the pharmaceutical composition may be 0.01 M to 1 jaM. In addition, the subject may be a mammal, particularly a human. The administration route may be appropriately selected by a person skilled in the art in consideration of the administration method, the volume and viscosity of the body fluid, and the like. Specifically, the administration may be carried out through any one route selected from the group consisting of an application, intravenous, intraarterial, intraperitoneal, intramuscular, intrastemal, percutaneous, intranasal, inhalation, topical, rectal, oral, intraocular, and intradermal. Preferably, the administration comprises topical administration to the eye of the subject. In particular, it may preferably be applied to the eye for use as an eye drop. The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

Examples

Example 1: Preparation of YDE derivatives A protein analysis of the extracellular matrix derived from animal chondrocytes was performed in Baek's group of Center of Biomedical Mass Spectrometry (Diatech Korea Co., Ltd., Seoul, Korea). Proline-GQDGLAGPK (P-GQDGLAGPK), which is a part of the amino acid sequence of the collagen type II al protein, was obtained through the above protein analysis.

An exemplary protein synthesis for YDE-011 follows. The other compounds of the invention (e.g., YDE-001 - YDE-086) are made through an analogous procedure by, e.g., substituting in a different amino acid building block reagent in a desired step. 1. 20% piperidine/DMF 1. 20% piperidine/DMF Fmoc-Lys(Boc) 2 Fmoc-Pro-Lys(Boc)- Fmoc-Gly-Pro-Lys(Boc) Wang resin 2. 19,iQV0DMF 1 2

1. 20% piperidine/DMF 1. 20% piperidine/DMF S Fmoc-Ala-Gly-Pro-Lys(Boc Fmoc-Leu-Ala-Gly-Pro-Lys(Boc)-- 2. fNi9? , DMF 3 2$ DMF 4

1. 20% piperidine/DMF 1. 20% piperidine/DMF Fmoc-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-- 2 2. Ji9A&, DMF 52 -$% DMF 5

1. 20% piperidine/DMF Fmoc-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)--- 1d Fmoc-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-- 2. 7ggggW-t) 67

1. 20% piperidine/DMF 1. 20% piperidine/DMF ,p e Fmoc-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc) 2. PY,9 -DMF 8 2 3. 20% piperidine/DMF

1. Cleavage step H-Hyp(tBu)-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-- 2. Prep HPLC step

9

H-Hyp-Gly-GIn-Leu-Gly-Leu-Ala-Gly-Pro-Lys-OH 1.Ion exchange step H-Hyp-GIy-GIn-Leu-Gly-Leu-Ala-Gly-Pro-Lys-OH TEA salt 2. Lyophizer AcOH salt 10

Exemplary procedure for YDE-011

Solid Phase Synthesis

Fmoc-Pro-Lys(Boc)- Wang Resin (1)

To a solid phase synthesis reactor equipped with filtration membrane was added Fmoc Lys(Boc)-Wang Resin (1.75 g, 1 mmole) in DCM (30 mL) then swelled for 30 min then the resin was drained. To the resin, a solution of piperidine (10 mL) in DMF (40mL) was added and stirred for 5 minutes then the resin was drained. The resin was washed 6 times with DMF (50 mL). To the resin, a solution of Fmoc-Pro-OH (3.37 g, 10 mmole) in DMF (25mL) and a solution of HBTU (3.8g, 10 mmole) and N-Methylmorpholine (2.Og, 20 mmole) in DMF (25mL) were added respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used to next step without further purification.

Fmoc-Gly-Pro-Lys(Boc)- Wang Resin (2)

To Fmoc-Pro-Lys(Boc)-Wang resin (1), a solution of piperidine (10 mL) in DMF (40mL) was added and stirred for 5 minutes then the resin was drained. The resin was washed 6 times with DMF (50 mL). To the resin, a solution of Fmoc-Gly-OH (3.0g, 10 mmole) in DMF (25 mL) and a solution of HBTU(3.8g, 10 mmole) and N-Methylmorpholine(2.0g, 20 mmole) in DMF (25mL) were added respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used to next step without further purification.

Fmoc-Ala-Gly-Pro-Lys(Boc)-Wang Resin (3)

To Fmoc-Gly-Pro-Lys(Boc)-Wang resin (2), a solution of piperidine (10 mL) in DMF (40mL) was added and stirred for 5 minutes then the resin was drained. The resin was washed 6 times with DMF (50 mL). To the resin, a solution of Fmoc-Ala-OH (3.1g, 10 mmole.) in DMF (25 mL) and a solution of HBTU (3.8g, 10 mmole) and N Methylmorpholine (2.0g, 20 mmole) in DMF (25mL) were added respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used to next step without further purification.

Fmoc-Leu-Ala-Gly-Pro-Lys(Boc)-Wang Resin (4)

To Fmoc-Ala-Gly-Pro-Lys(Boc)-Wang resin (3), a solution of piperidine (10 mL) in DMF (40mL) was added and stirred for 5 minutes then the resin was drained. The resin was washed 6 times with DMF (50 mL). To the resin, a solution of Fmoc-Leu-OH (3.5g, 10 mmole) in DMF (25 mL) and a solution of HBTU (3.8g, 10 mmole) and N Methylmorpholine (2.0g, 20 mmole) in DMF (25mL) were respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used to next step without further purification.

Fmoc-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang Resin (5)

To Fmoc-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (4), 10 mL piperidine in DMF(40 mL) was added and stirred for 5 minutes then the resin was drained. The resin was washed 6 times with DMF (50 mL). To the resin, a solution of Fmoc-Gly-OH (3.0g, 10 mmole) in DMF (25 mL) and a solution of HBTU (3.8g, 10 mmole) and N-Methylmorpholine (2.0g, 20 mmole) in DMF (25mL) were respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used to next step without further purification.

Fmoc-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang Resin (6)

To Fmoc-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (5), a solution of piperidine (10 mL) in DMF (40mL) was added and stirred for 5 minutes then the resin was drained. The resin was washed 6 times with DMF (50 mL). To the resin, a solution of Fmoc-Leu-OH (3.5g, 10 mmole) in DMF (25 mL) and a solution of HBTU (3.8g, 10 mmole) and N Methylmorpholine (2.0g, 20 mmole) in DMF (25mL) were respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used to next step without further purification.

Fmoc-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang Resin (7)

To Fmoc-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (6), a solution of piperidine (10 mL) in DMF (40mL) was added and stirred for 5 minutes then the resin was drained. The resin was washed 6 times with DMF (50 mL). To the resin, a solution of Fmoc-Gln(Trt) OH (6.1g, 10 mmole) in DMF (25 mL) and a solution of HBTU(3.8g, 10 mmole) and N Methylmorpholine (2.0g, 20 mmole) in DMF (25mL, 10eq) were respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used to next step without further purification.

Fmoc-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang Resin (8)

To Fmoc-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (7), a solution of piperidine (10 mL) in DMF (40mL) was added and stirred for 5 minutes then the resin was drained. The resin was washed 6 times with DMF (50 mL). To the resin, a solution of Fmoc-Gly-OH (3.0g, 10 mmole) in DMF (25 mL) and a solution of HBTU (3.8g, 10 mmole) and N-Methylmorpholine (2.0g, 20 mmole) in DMF (25mL) were added respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used to next step without further purification.

H-Hyp(tBu)-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang Resin (9)

To Fmoc-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (8), a solution of piperidine (10 mL) in DMF (40mL) was added and stirred for 5 minutes then the resin was drained The resin was washed for 6 times with DMF (50 mL). To the resin, a solution of Fmoc-Hyp(tBu)-OH(4.2g, 10 mmole) in DMF (25 mL) and a solution of HBTU (3.8g, 10 mmole) and N-Methylmorpholine (2.0g, 20 mmole) in DMF (25mL) were added and the reaction mixture was stirred for 1 h and the resin was drained. To Fmoc-Hyp(tBu)-Gly

Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin, a solution of piperidine (10 mL) in DMF (40mL) was added. The reaction mixture was stirred for 5 minutes then the resin was drained. The resin was washed 6 times with DMF (50 mL).

Removal from Resin

H-Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys-OH TFA salt (10)

To the 1 mmole H-Hyp(tBu)-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang Resin (9), 30 mL of cocktail solution (87.5% TFA/2.5% 1,2-ethandithiol/2.5% H 20/5.0% thioanisole) were added and the reaction mixture was stirred for 2 h and monitored the reaction mixture by HPLC. To filtered solution was added cold diethyl ether (500 mL) to precipitate crude peptide. The precipitated peptide was filtered through a filtration apparatus and washed with 500 mL of diethyl ether. The crude peptide was dried under vacuum to give 105% (Ig).

Purification step

H-Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys-OH TFA salt(10)

The crude compound was purified by Prep HPLC system

Salt exchange step

H-Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys-OH AcOH salt (11)

The Purified compound was exchanged from TFA salt to AcOH salt by Ion Exchange resin. The Ion exchanged peptide was dried by lyophilizer.

YDE-001 to YDE-092 peptides were synthesized by ANYGEN (Gwangju, Korea) in a manner analogous to the exemplary procedure shown above, by substituting one or more different amino acid residues into the peptide Proline-GQDGLAGPK (Fig. 1 and Table 1). The process for synthesizing the YDE-001 to YDE-075 peptides and the purification procedure thereof conducted by ANYGEN are depicted in Figs. 2 and 3.

[Table 1] SEQ ID NO. No. Chemical structure

HO HN 0SEQ ID NO: H H H H H 201 NH N N N N LAN OH HH H YY-101 N.OHH

Gly Gin Asp Gly Lau Ala Gly Pro Lys NH Hyp (2S,4R) H 2N 0 SEQ ID NO: HO

H AO H 0 H 0 H 0/-hH022 Nj N ~)~ N -LN N '-L-N N")L N '-L-01H YY-102 HH

Hyp Gly Gin Aspatimide Gly Leu Ala Gly Pro Lys I1 (2S,4R) H 2N 0 HO

H H H H H)N N N ,N N JNI N SEQNDNO: YDE-001 H H H HH8ZH QI O 0 0H Hyp Gly Gin Glu Gly Leu Ala Gly Pro Lys I1 (2S,4R) H 2N 0 HO0

H H H H N N-" 0 NH NjN N N 1)koH H H H H --r - SQDO YDE-002 HN NH2 2ED O

Hyp Gly Gin Asn Gly Leu Ala Gly Pro Lys I1 (2S,4R) H 2N 0 HO

H 0 H 0 H H " H ' ~LNH I~ ~N N JLH N)OH H H H -SEQ ID NO: YDE-003 0 N-23

Hyp Gly Gin Gin Gly Leu Ala Gly Pro Lys I1 (2S,4R) H 2N 0 HO0 H0 H0 0 0 H0 Nj N , N N -N HN NN N N OH ,

H HHH-SQDO YDE-004 4EQI O

Hyp Gly Gin His Gly Leu Ala Gly Pro Lys H ___________ (2S,4R)

HN 0 HO

H H 0 H H H 0 IN N N NNNIN I N N IN )L YE05 H H z H -SE ID NO: 5 NH, NH,

Hyp Gly Gin Lys Gly Leu Ala Gly Pro Lys (2S,4R) HN 0 HO

N N H HO HO HO N _ NNH N,)NH YDE-006 H0- H 6H-SQDO

Hyp Gly Gin Ser Gly Leu Ala Gly Pro Lys (2S,4R) H 2N 0 HO0

H H H? H NN NNN NN NA) NH H H 'NzH H -SEQ IDNO: YDE-007 --- OH -r7 NH 2 Hyp Gly Gin Thr Gly Leu Ala Gly Pro Lys (2S, 4R) H 2N 0 HO

H 0 H 0 H 0 _ H 0 -6 H 0 N N N N - N OH \ "tX 0 YE08 H H =H Z H -SEQ ID NO:

Hyp Gly Gin Ala Gly Lau Ala Gly Pro Lys (2S,4R) HN 0 HO0

H 0 H 0 H 0 H 0 H 0

H N --NN H N N" H N 3 H i o N-UO SEQ)D NO YDE-009 H- 9EIDO

NH, Hyp Gly Gin Val Gly Leu Ala Gly Pro Lys (2S,4R) H 2N 0 HO

N - N _>U, N N Nl,< H N). 01 H H H ~H - SEQ ID NO: YDE-010 10

NH-2 Hyp Gly Gin Ilie Gly Leu Ala Gly Pro Lys (2S,4R)

HN 0 HO

H 0 H 0 H H H,0 N N NIN I N INiSE YE01 H H H H QID NO:

NH, Hyp Gly Gin Lou Gly Lou Ala Gly Pro Lys (2S,4R) HN 0 HO H0 H0 0 0/-H 0 IN IN NH N IN IN IN IN N IN OH

, HYHE-0H2 H -SEQ ID NO: YDE-01212

NH, Hyp Gly Gin Phe Gly Leu Ala Gly Pro Lys (2S,4R) HN 0 HO0 H O H 0 H 0 H 0 /-v H 0

N N N N N N IN N-SEQ ID NO: YDE-013 OH -T 113 NH, Hyp Gly Gin Tyr Gly Leu Ala Gly Pro Lys (2S,4R) HN 0

IN IN IN.N )II0 jI H H H SEQ ID NO: YDE-014 NH N 2 14

Hyp Gly Gin Trp Gly Leu Ala Gly Pro Lys (2S,4R) HN 0 HO

, XHO YE05 H H - - - SEQ ID NO: YDE-15 O Ir15

NH, Hyp Gly Gin Asp Val Leu Ala Gly Pro Lys (2S,4R) HN 0 HO H0 H0 H0 H0/-H 0

H HH H H HE D O H0 H YDE-01616

NH, Hyp Gly Gin Asp Ilie Leu Ala Gly Pro Lys (2S,4R)

HN 0 HO

H H 0 H 0_H 0 H0 N I N IN N1).'N ININ ININ - OH YE07 H H 0H H - SEQ ID NO: YDE-17 - -OH17

NH, Hyp Gly Gin Asp Leu Leu Ala Gly Pro Lys (2S,4R) H 2N 0 HO

H HH H 0/1 H 0 IN N IN N N N IN IN& N-JIOH H H HHSQI O YDE-018 )0H H8

NH 2 Hyp Gly Gin Asp Ala Leu Ala Gly Pro Lys (2S,4R) HN 0

0H 0 0 H 0 H H HNH " H IN N NiL NHH NIN _ )I - OH £H - SEQ ID NO: YDE-019 NOH 19

NH, Hyp Gly Gin Asp Phe Leu Ala Gly Pro Lys (2S,4R) H 2N 0 OH HO

H0 H 0 0 N N N" ZN>JOH H H HN z~JNA H SEQ IDNO: YDE-020 H 'OH 20

NH 2 Hyp Gly Gin Asp Tyr Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO H H H 0 H 0 0 IN N-N -N NNJNNA N)KH SEQ ID NO: YDE-021 H H H5 0H -21

NH 2 Hyp Gly Gin Asp Trp Leu Ala Gly Pro Lys (2S,4R) H 2N 0 I HO; .- H 0 H H H / H N ~ ~ )N N~ H.I. .L ~K SEQ ID NO: YDE-022 Hr H yOH r H2

NH 2 Hyp Gly Gin Asp His Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO OH

HH H? H H O

HD-03H 0H I NO: SEQ 23

NH 2 Hyp Gly Gin Asp Ser Leu Ala Gly Pro Lys (2S,4R) H 2N 0 HO

H0 H0 0 'H 0 HJ0/1- H0 N N ,A,N N N N N NA N 1il10H H H'HHI SEQ ID NO: YDE-024 )~OH 24 NH 2 Hyp Gly Gin Asp Thr Leu Ala Gly Pro Lys (2S,4R)

HO HN0SQDO

H 0 0 H 25 N N N N)t 1 NL. NIL _NJLH H YDE-025 HH KOH

Hyp Gly Gin Asp (Me)Gly Leu Ala Gly Pro Lys NH2 (2S, 4R) H 21N 0 HO0 HO 0 H0 H0/-H 0 HH H H H H HD-2 H SEQ ID NO: YDE-06 ~H26

NH 2 Hyp Gly Gin Homo-Ser Gly Leu Ala Gly Pro Lys (2S,4R) HN 0 HO

H H

N<H,

Hyp Gly Gin Asp(Me) Gly Leu Ala Gly Pro Lys (2S,4R) H 21N 0 HO

H 0 H 0 H 0 H 0-6H0 I IN ,kI INN NI k IN IN O Hz SEQ ID NO: YDE-028 >"-o 28 HIN NH 2 Hyp Gly Gin Asn(Me) Gly Leu Ala Gly Pro Lys (2S,4R) H 2N 0 HO H0 H 0 _ H 0 _H 0 /-b H 0 N ,L N N ,L N 1 ' NA ,N"

YDE-029 H H - -H- SEQ ID NO: -r "a OH29

Hyp Gly Gin Leu Gly Leu Ala Gly Pro Tyr (2S,4R)

HN 0 HO

H0 H 0 _ H 0 HJ0'- H0 INt , N IN N N1 'N '-N 1, N N OHH HD-3 H H H - SEQ ID NO: YDE-030"- 30

Hyp Gly Gin Leu Gly Leu Ala Gly Pro Leu (2S,4R) H 2N 0 HO 0/10-0 0 HH HH INJJ IN1 N NjX O HN HNN NO SEQ ID NO: YDE03 H HH 31

Hyp Gly Gin Leu Gly Leu Ala Gly Pro Glu (2S,4R) H2N 0 HO 0 0 H 0 H H H /-b NINN IN i I N INO 'IIN '-N

YDE-032 H H -H H AN 2 SEQ IDNO:

Hyp Gly Gin Leu Gly Leu Ala Gly Pro Gin (2S,4R)

HO

N INLN INIA.N INIA NA I -UO YDE-033 H H - SEQ IDNO: ,-r 'Ir 33 Hyp Gly Gin Leu Gly Leu Ala Gly Pro Nie(6-OH) (2S,4R) H 2N 0 HO 0 0 0 H H H H /1VH0 N N '"N NINNIN IN IN ' OH 034 HHli HDH - SEQ IDNO: YDE-03434 NH2 Hyp Gly Gin Leu Gly Leu Ala Gly Pro Lys (2S,4S) H 2N 0

35H NH HE03 H H 0 H

NH 2 (4-oxo)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys

0 H 0 H 0/1- H 0 0, H 0 IINI 1NIN1 IN NA~ IN N>-OH SEQ ID NO: YDE-036 H H H -H36

NH 2 ________ (5-oxo)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys

H 2N 0

H0 H 0 __ H 0 H 0/1 H H H H YDE-037 HHH

Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys NH 2 H 2N 0 HO 0 0 H0 H __H0 H 0/1tH I - IN I N ,1'N I N N A N1> H YDE-038 H H H HSEQ ID NO: 38 NH 2 (4-hydroxyMe)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys (4R) H2N 0

H H HN NH NO SEQ IDNO: YDE-039 -39

NH 2 (4-Fluoro)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys (4R) H 2N 0

',AN NiNitN N - O YDE-040 HHH40 N ~N ~ N~ OH SEQ ID NO:

NH 2 (4-Dimethyl)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys HO HN 0 SEQ ID NO: 0 0 041 C IN I IN I IN NO0H

YDE-041

Hyp Gly Gin Leu Gly Leu Ala (2S,4R)

H0 H2N 0 SEQ ID NO: HO 42

N IN N IN N ", I OH11 YDE-042 HH

Hyp Gly Gin Leu Gly Leu (2S,4R?)

HO HN 0 SEQ ID NO: 43 H?0 H 0 CN N IN N ,, H

YDE-043

Hyp Gly Gin Leu Gly I (2S,4R) HN 0

H0 H 0 H 0 0/1 , H H N H N, NN IN NIN _&KN A)[ NNJH "X SQDO YDE-044 H H HHSQI O 44

(4-Me)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys (4R) HN 0

H 0 H 0 H 0 H /1%H0 N N I 1)' I NL NiLN i N )N il.O H HN zH ID NO: YDE-045 H45 6 6

(5-Me)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys NH, (5R) HN 0 SEQ ID NO: H H0H H 47 HN N , N IN IN1XN- I NA N 1 YDE-047 H2~g H N'-N - OH

Ala Gly Gin Leu Gly Leu Ala Gly Pro Ly NH,

HO HN 0 SEQ ID NO: H0 HJ0__ H 0 jHO01- H 0 48

YDE-048 H-~ ~ .LO

NH, Hyp Ala Gin Leu Gly Leu Ala Gly Pro Lys (2S,4R) HO SEQ ID NO: H0 0 0 0 /-- 0 49 H H H H H

YDE-049 NH, Hyp Gly Ala Leu Gly Leu Ala Gly Pro Lys (2S,4R) HO HN 0 SEQ ID NO: HA H 0 H 0 H o 8 IN N I I IN , N N IN ,_ H HHH YDE-050 - O

Hyp Gly Gln Ala Gly Leu Ala Gly Pro Lys NH (2S,4R)

HO H 2N O SEQ ID NO: 0 0 0 H0051 H H 0 IH H N NiNN N ~% N ~~ Nj.N NtH H H H YDE-051 N N

NH 2 Hyp Gly Gin Leu Ala Leu Ala Gly Pro Lys (2S,4R)

H H 2N O SEQ ID NO: O O O O O 52 N HI NH NN HU:HN N H1110 N OH

YDE-052

NH 2 Hyp Gly Gin Leu Gly Ala Ala Gly Pro Lys (2S,4R) H2 N O SEQ ID NO: N0 W0~Kr 0 11

YDE-053 H pV, 0 0

NH2 Hyp Gly Gin Leu Gly teu Ala Gly Pro Lys H 2N 0 HO 0 0 0 0 0 H H H H NH N NJL-N N ,N )QN N NIAOH H SEQ ID NO: YDE-054 H H H 0 H54

Hyp Gly Gin Leu Gly Leu Ala Ala Pro Lys (2S,4R)

HO ID NO: 0 0 0 0 0 ..-H H H2N H OSEQ H H H 5 N N rN 'AN N OaH YDE-055 NH2

Hyp Gly Gin Leu Gly Leu Ala Gly Ala Lys (2S,4R)

HO H 2N 0 SEQ ID NO: 0 0 0 H O 56 N N N N N

YDE-056 Ho

Hyp Gly Gin Leu Gly Leu Ala Gly Pro Ala (2S,4R) HOH 2N0 0 A 0 0 H 2 H _ H H 0 H 0 N N \' N N N YDE-057 H H -H - H SEQ ID NO: YD-5 H57

D-Hyp Gly Gin Leu Gly Leu Ala Gly Pro Lys NH 2 (2R,4S)

H 2N 0 HO

ALN-,,N, ,, N, N_ N \N N-- INIkN X, ~ HSE YDE-058 H0 H SEV INO: 58

D-Hyp Gly D-Gln D-Leu Gly D-Leu D-Ala Gly D-Pro D-Lys NH2 (2R,4S) HO H 2N 0 SEQ ID NO: 00 0 59 N N N, N ,OH

YDE-059 H Hyp Gly Gin Glu Gly Lys Gly (2S,4R) a.midebond_ H 21N 0 SEQ ID NO: HO 0 6 H0 H0H 0 H / H 6

YDE-060 H~ H~ r~ \N O

D-Hyp Gly D-Gln D-Leu Gly D-Leu D-Ala Gly D-Pro D-Lys H (2R,4R) H 2N 0 SEQ ID NO: H O' 0 64 N N '>'kN _,_N_"' N OH H H HA YDE-064

D-Hyp Gly D-Gln D-Leu Gly D-Leu (2R,4S)

HO H 21N 0 SEQ ID NO: HO0 66 I IN fOH C NIAIN H H HJ YDE-066

Hyp Gly Gin D-Leu Gly (2S,4R) H 2N 0 HO

7H0H 0 H 0 Hj01- H 0 %) , k N IN IUN N 1N N IN '-OH HDE-H72 H YDE-72- H SEQ ID NO: -r72

D-Hyp Ala Gin Leu Gly Leu Ala Gly Pro Lys H (2R,4S)

HO HN 0 SEQ ID NO: /~ HA H 0 H 0 H o'-.H 07 \ IN IN IN 'N- N"JN, NI~N N OH H H HA H YDE-073 -r u

D-Hyp Gly Gin Leu Gly Leu Ala Gly Pro Ala (2R,4S)

HO HN 0 SEQ ID NO:

H H H 7 YDE-074

D-Hyp Ala Gin Leu Gly Leu Ala Gly Pro Ala (2R,4S) H0 HN 0 SEQ ID NO: 0 0 75 IN N N O H ~HH YDE-075 r

D-Hyp Gly Gin Leu Gly (2R, 4S)

HO H 2 1N 0 SEQ ID NO: 0 0 o oP, o 78 INNN-N IN IIN N.N N N-j-OH H H z H z H YDE-078

Leu Ala Gly Pro Lys(Ac) HN' Hyp Gly Gin Leu Gly (2S,4R)

HO H2N 0 SEQ ID NO: H AO H 0 H 0 H 0t H 0 80 N NN N, N,

YDE-080 H H

NH 2 Hyp Gly Gin D-Leu Gly D-Leu D-Ala Gly Pro Lys (2S,4R)

YDE-081 HO H2N 0 SEQ ID NO: HO 81 H OH H H H

D-Hyp Gly D-Gln D-Leu Gly (2R,4S)

HO HN, 0 SEQ ID NO: 0 0 83 N' N }LZ1\ N1 NjOH YDE-083 H H H H zH

Hyp Gly D-Gln Lau Gly (2S,4R)

YDE-084 HN2 > 0 SEQ IDNO: HOK 0 84 >HJ N N H N1N ,OH HH z H

D-Hyp Gly D-Gln Leu Gly (2R,4S)

YDE-085 HO H2 N 0 SEQ ID NO: OH0 85

D-Hyp Gly Gin D-Leu Gly (2R,4S) H2 N 0 SEQ ID NO: HO 86 H N N 1, \ N,,,OH Y-086 HN 'I

Hyp Gly D-Gln D-Leu Gly (2S,4R)

HO H2 N 0 SEQ ID NO: HO 92

N N~N N 1N>1\ ,OH YDE-9 H HH

Hyp Gly Gin Ilie Giy (2S,4R)

HO H2 N 0 SEQ ID NO: H H 0 H 09 N N N~ OH 0 H H H IHL YDE-094 '

OH 0

Hyp Gly Gin Asp Gly Lau Ala (2S,4R) H 2 0 AHN SEQ ID NO: H 0 H 0 H 0, H o'. 0

YDE-100 H H~ N H H~

Hyp Gly Gin Leu Gly Leu Ala Gly Pro (2S,4R)

Analysis of YDE derivatives

The YDE derivatives prepared in Example 1 were analyzed by HPLC. As a result, it was confirmed that the purities of YDE-001, YDE-002, YDE-003, YDE-004, YDE-005, YDE-006, YDE-007, YDE-008, YDE-009, YDE-010, YDE-011, YDE-012, YDE-013, YDE-014, YDE-015, YDE-016, YDE-017, YDE-018, YDE-019, YDE-020, YDE-021, YDE-022, YDE-023, YDE-024, YDE-025, YDE-026, YDE-027, YDE-028, YDE-029, YDE-030, YDE-031, YDE-032, YDE-033, YDE-034, YDE-035, YDE-036, YDE-037, YDE-038, YDE-039, YDE-040, YDE-041, YDE-042, YDE-043, YDE-044, YDE-045, YDE-047, YDE-048, YDE-049, YDE-050, YDE-051, YDE-052, YDE-053, YDE-054, YDE-055, YDE-056, YDE-057, YDE-058, YDE-059, YDE-060, YDE-064, YDE-066, YDE-072, YDE-073, YDE-074, YDE-075, YDE-078, YDE-080, YDE-081, YDE-083, YDE-084, YDE-085, YDE-086, YDE-092, YDE-094, and YDE-100 synthesized were 98.3%, 98.9%, 98.7%, 98.5%, 99.1%, 99.4%, 98.0%, 99.6%, 99.6%, 99.2%, 98.1%, 98.3%, 96.1%, 98.9%, 95.1%, 98.6%, 96.9%, 99.5%, 98.0%, 98.1%, 98.8%, 98.2%, 97.2%, 98.6%, 98.8%, 98.7%, 99.2%, 98.7%, 98.1%, 97.5%, 96.5%, 97.4%, 98.7%, 97.8%, 95.5%, 97.5%, 97.2%, 96.9%, 99.3%, 98.0%, 99.4%, 96.4%, 95.1%, 98.6%, 97.4%, 98.8%, 97.4%, 95.8%, 98.9%, 96.9%, 98.8%, 97.7%, 95.0%, 97.9%, 96.3%, 97.8%, 99.2%, 98.6%, 95.9%, 99.2%, 99.0%, 95.1%, 95.0%, 97.4%, and 98.7%, respectively. In addition, the YDE derivatives prepared in Example 1 were analyzed by Ion-Mass. As a result, it was confirmed that the molecular weights of YDE-001, YDE-002, YDE-003, YDE-004, YDE-005, YDE-006, YDE-007, YDE-008, YDE-009, YDE-010, YDE-011, YDE-012, YDE-013, YDE-014, YDE-015, YDE-016, YDE-017, YDE-018, YDE-019, YDE-020, YDE-021, YDE-022, YDE-023, YDE-024, YDE-025, YDE-026, YDE-027, YDE-028, YDE-029, YDE-030, YDE-031, YDE-032, YDE-033, YDE-034, YDE-035, YDE-036, YDE-037, YDE-038, YDE-039, YDE-040, YDE-041, YDE-042, YDE-043, YDE-044, YDE-045, YDE-047, YDE-048, YDE-049, YDE-050, YDE-051, YDE-052, YDE-053, YDE-054, YDE-055, YDE-056, YDE-057, YDE-058, YDE-059, YDE-060, YDE-064, YDE-066, YDE-072, YDE-073, YDE-074, YDE-075, YDE-078, YDE-080, YDE-081, YDE-083, YDE-084, YDE-085, YDE-086, YDE-092, YDE-094, and YDE-100 synthesized were 969.6, 954.8, 967.7, 977.1, 968.1, 926.9, 941.1, 910.7, 939.7, 953.0, 953.7, 987.8, 1003.8, 1025.9, 996.7, 1011.0, 1011.4, 968.7, 1044.4, 1061.4, 1084.5, 1035.0, 984.9, 999.1, 969.7, 942.0, 937.6, 967.3, 988.1, 960.6, 954.2, 991.1, 954.4, 990.7, 950.9, 937.6, 968.1, 955.4, 966.0, 709.3, 622.2, 486.8, 951.3, 951.3, 911.4, 967.5, 896.5, 911.0, 967.3, 911.2, 953.2, 967.2, 927.4, 896.4, 952.8, 953.4, 670.1, 953.3, 599.7, 486.5, 966.1,

895.8, 909.1, 486.4, 995.1, 953.1, 486.5, 486.5, 486.5, 486.5, 486.5, 486.5, 673.2, and 823.9, respectively.

Example 2: Preparation of YDE derivatives with modified C-terminus Preparation of YDEpeptides YDE peptides (YDE-093, YDE-096, and YDE-101 through YDE-107), derivatives of the amino acid sequence of the YDE-011, were obtained through the C-terminal modification of a YDE peptide such as YDE-011. In order to prepare C-terminal modified peptide, Fmoc solid-phase peptide synthesis (SPPS) was conducted, based on a standard procedure described in WO 2018/225961 and further a C-terminal amidation reaction was carried out. The peptides of the invention are made through an analogous procedure by, e.g., substituting in a different amino acid building block reagent in a desired step. Exemplary Preparation of YDE-093 To prepare C-terminal amidated peptide YDE-093, a synthetic process was conducted as depicted in Scheme A, below. The Fmoc protected 10-mer peptide (Fmoc-Hyp-H-Gly Gln-Leu-Gly-Ala-Leu-Gly-Pro-Lys(Dde)-OH) was prepared according to the procedure described in WO 2018/225961. Based on the selected amino acid sequence, a chain reaction was conducted in this order as below: 1) Fmoc-Lys(Dde)-OH 2) Fmoc-Pro-OH 3) Fmoc-Gly-OH 4) Fmoc-Ala-OH 5) Fmoc-Leu-OH 6) Fmoc-Gly-OH 7) Fmoc-Leu-OH 8) Fmoc-Gln(Trt)-OH 9) Fmoc-Gly-OH 10) Fmoc-Hyp(tBu)-OH Scheme A:

Resin Loading

1) i-Pr2EtN / DCM Fmoc-Lys(Dde)-OH + CI)P t D Fmoc-Lys(Dde)--a CTC resin 2) DCM/MeOH/i-Pr2EtN

Coupling the Building Blocks 1) Deprotection 1) Deprotection Fmoc-Lys(Dde--Q - p Fmoc-Pro-Lys(Dde)C 2) Coupling 2) Coupling o H Fm-Gly-OH

1) Deprotection 1) Deprotection Fmoc-Gly-Pro-Lys(Dde --o Fmoc-Aa-Gy-Pro-Lys(Dde)- 2C l 'W 2) Coupling 2) Coupling

Fmoc-Ala-OH FeuO

1) Deprotection Fmoc-Leu-Ala-Gly-Pro-Lys(Dde)-Q 2)Coupling Fmoc-Gly-Leu-Ala-Gly-Pro-Lys(Dde)--Q

1) Deprotection 2) Coplin Fmoc-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Dde)-- resin 2) Coupling Deprotection = 20% piperidine /DMF

1) Deprotection Fmoc-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Dde)--- Coupling= HBTU, NMM, DMF

2) Coupling

1)Deprotection Fmoc-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Dde)-- FmGln(t)OH 2) Coupling 1) Deprotection

i Fmoc-Hyp(tBu)-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Dde)--

2) Coupling

Fmoc-Hyp(tBu)-OH

Resin Cleavage Cleavage

solution , Fmoc-Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Dde)-OH Fmc-yp(tBu)-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Dde)-

C-terminal Amidation & Deprotection 0 H 2N-- -- INHBoc Fmoc-Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Dde)-OH EDC, HOBt, i-Pr 2EtN, DMF

1) 4% Hydrazine / DMF Fmoc-Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Dde)-PEG1-NHBoc 2) Prep LC purification

Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys-PEG1-NHBoc TFA salt

Salt Exchange

Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys-PEG1-NHBoc Hyp-Gly-Gn-Leu-Gly-Leu-Ala-Gly-Pro-Lys-PEG1-NHBoc TFA salt 2) Lyophilize AcOH salt

To a solution of Fmoc-Hyp-Gly-Gln-Leu-Gly-Ala-Leu-Gly-Pro-Lys(Dde)-OH (500 mg, 0.37 mmol) and tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (91 mg, 0.44 mmol) in DMF (10mL) was

added HOBt (76 mg, 0.56 mmol), EDCI (107 mg, 0.56 mmol) and i-Pr2EtN (24 pL, 0.136 mmol) at

0°C and stirred for 1 hour at same temperature. After 1 hour, the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After the reaction was completed, the reaction mixture was poured into water (20mL) and extracted with DCM (20mL x 2). The combined organic layers were further washed with water (20mL x 2) and concentrated in vacuo. The residue was precipitation from diethyl ether to afford a desired Fmoc-protected peptide (400 mg, 71%) as a white solid. Fmoc-Hyp-Gly-Gln-Leu-Gly-Ala-Leu-Gly-Pro-Lys(Dde)-PEG1-NHBoc (400 mg, 0.26 mmol) was put into a reaction vessel and 4% Hydrazine in DMF solution (10 mL) was added and stirred for 30 min, then diethyl ether (40 mL) was added to induce precipitation. Thereafter, the precipitates were collected by filtration, followed by washing twice with excess ether to afford the crude peptide YDE-093 (quantitative yield) as a white solid. The crude YDE-093 was purified by Preparative HPLC system. The purified peptide was exchanged from TFA salt to AcOH salt by ion exchange resin. The ion exchanged peptide was dried bylyophilizer. YDE-093, YDE-096, and YDE-101 through YDE-107 are depicted in Table IA below. Table IA: SEQ ID NO. No. Chemical structure

H H2N 0 SEQ ID NO: N NNHBo 93 ~H N H N H + ~ g 0 H

YDE-093 Y Y A0H H2 Hyp Gly Gin Leu Gly Leu Ala Gly Pro Lys-NH-PEG-NHBoc (2S,4R)

HO H2N O SEQ ID NO: N HN NNHHbz 96 YDE-096 Y Y AcOH H2 Hyp Gly Gln Leu Gly Leu Ala Gly Pro Lys-NH-PEG1-NHCbz (2S,4R)

HOH 2N O HO 0 0 H 0 _ H , H H N SEQ ID NO: YDE-101 N "I"-O H H101

Hyp Gly Gin Leu Gly Leu Ala Gly Pro (dimethyl) (2S,4R)

H2 N O HO 0 0 H 0 H

/ H H YDE-103 H N&, SEQ ID NO: -102

Hyp Gly Gln Leu Gly Leu Ala Gly Pro (daethyi) (2S,4R)

HO O, 0 __ 0 ' / YD-0 NN NNN NSEQ ID NO: YDE-103 N NH~N H N 2 0 HN H103

Hyp Gly Gn Le Gly Le Ala Gly Pro (aetdne) (2S,4R)

HO HO 0 0 H NE1 H N H - SEQ ID NO: NO: YDE-105 N H 2N 0 £H H-' H~ 105 Hyp Gly Gln Leu Gly Leu Ala Gly Pro (pethylethyl) (2S,4R)

H2 N 0 HO

H H 0 H 0 IH 0/

YDE-106 NE N -1 SEQ ID NO: H HY 106~N< Hyp Gly Gn Le Gly Le Ala Gly Pro (pyrm ldne) (2S,4R)

0 0 0 106 HO

H 0_ H _H0 NHA N N-.-'N' N '' AY SEQ ID NO: YDE-107 H H H O~ 107 Hyp Gly Glrn Leu Gly Leu Ala Gly Pro (isopropyle~hy) (2S,4R)

Analysis of YDEpeptides The YDE peptides prepared in Example 2 were analyzed by HPLC. As a result, it was confirmed that the purities of YDE-093, YDE-096, YDE-101, YDE-102, YDE-103, YDE-105, YDE-106 and YDE-107 synthesized were 99.1%, 95.4%,96.7%,97.2%,97.9%, 97.4%, 97.2% and 98.2%, respectively. In addition, the YDE derivatives prepared in Example 2 were analyzed by Ion-Mass. As a result, it was confirmed that the molecular weights of YDE-093, YDE-096, YDE-101, YDE-102, YDE-103, YDE-105, YDE-106 and YDE-107 synthesized were 1139.0, 1173.6, 851.9, 880.1, 864.5, 866.1, 878.4 and 894.3, respectively.

Example 3: Evaluation of the eyeprotection effect on dry eye syndrome by the YDE derivatives Preparation of rats with dry eye syndrome In order to evaluate the eye protection effect on dry eye syndrome by YDE-001 to YDE-028 prepared in Example 1, a total of 320 Sprague-Dawley-type male rats (OrientBio,

Seungnam, Korea) were adapted for 7 days. Thereafter, dry eye syndrome was induced in 264 test rats through extraorbital lacrimal gland excision (hereinafter, ELGE). 8 test rats without the eye abnormality were subjected to a sham operation as a control group. The rat was systemically anesthetized by inhaling a mixed gas of 2% to 3% of isoflurane (Hana Pharm. Co., Hwasung, Korea), 70% Oof N 2 0, and 28.6% of 02 using a rodent anesthesia machine (Surgivet, Waukesha, Wis., USA) and a ventilator (Model 687, Harvard Apparatus, Cambridge, UK). Thereafter, the extraorbital lacrimal gland located in the subdermal area above the masseter muscle and under the optic nerve was excised through a transverse incision in a size of 10 mm on the anterior part of the left ear tragus. The skin was sutured by a general method. The ELGE operation time did not exceed 5 minutes for each rat. After 6 days from the ELGE operation, it was checked through the Schirmer test by measuring the amount of tear secretion whether dry eye syndrome had been induced. Meanwhile, each rat of the control group with the sham operation was checked for the presence and location of the extraorbital lacrimal gland through a skin incision, and the skin was then sutured without the excision thereof (Fig. 4). The average weight of the ELGE test group measured before the ELGE operation was 241.59 13.56 g, and the average weight measured after 6 days from the ELGE operation was 297.38 34.02 g. The average weight of the control group measured before the sham operation was 240.1325.63 g, and the average weight measured after 6 days from the sham operation was 297.38+34.02 g (Fig. 5). The average amount of tear secretion of the control group was 8.34 0.73 mm3 , and the average amount of tear secretion of the ELGE test group was 3.55 0.70 mm3 . 8 rats per group and a total of 32 groups were selected based on the average amount of tear secretion. As a reference drug, 3% diquafosol sodium (Santen, Tokyo, Japan; hereinafter, DS), which is currently on the market, was used. The present animal tests were conducted with a prior approval of the Animal Experimental Ethics Committee of Daegu Haany University (Approval No. DHU2017-003, January 12, 2017). All test animals were fasted for 18 hours before the ELGE operation and final sacrifice except for feeding water. The 32 groups were summarized in Table 2.

[Table 2] Group classification 32 groups in total; 8 rats per group Sham control group Group administered with physiological saline after the sham operation ELGE control group Group administered with physiological saline after the ELGE operation Reference Group administered with DS after the ELGE operation YY-102 Group administered with a 0.3% YY-102 solution after the ELGE operation YDE series Group administered with any of 0.3% YDE 01 to YDE-28 solutions (28 groups in total)

In addition, in order to evaluate the eye protection effect on dry eye syndrome by YDE-029 to YDE-043 prepared in Example 1, a total of 200 Sprague-Dawley-type male rats (OrientBio, Seungnam, Korea) were adapted for 7 days. Dry eye syndrome was induced in 165 test rats through the ELGE. 8 test rats without the eye abnormality were subjected to the sham operation as a control group. The ELGE was carried out as described above. The average weight of the ELGE test group measured before the ELGE operation was 264.0911.53 g, and the average weight measured after 6 days from the ELGE operation was 316.13+15.77 g. The average weight of the control group measured before the sham operation was 263.509.24 g, and the average weight measured after 6 days from the sham operation was 315.25+10.85 g (Fig. 6). The average amount of tear secretion of the control group was 10.901.69 mm3 , and the average amount of tear secretion of the ELGE test group was 4.83+0.99 mm3 . 8 rats per group and a total of 20 groups were selected based on the average amount of tear secretion. As a reference drug, 3% DS, which is currently on the market, was used. The present animal tests were conducted with a prior approval of the Animal Experimental Ethics Committee of Daegu Haany University (Approval No. DHU2017-050, June 08, 2017). All test animals were fasted for 18 hours before the ELGE operation and final sacrifice except for feeding water. The 20 groups were summarized in Table 3.

[Table 3] Group classification 20 groups in total; 8 rats per group Sham control group Group administered with physiological saline after the sham operation ELGE control group Group administered with physiological saline after the ELGE operation Reference Group administered with DS after the ELGE operation YY-101 Group administered with a 0.3% YY-101 solution after the ELGE operation YY-102 Group administered with a 0.3% YY-102 solution after the ELGE operation YDE series Group administered with any of 0.3% YDE 01 to YDE-28 solutions (15 groups in total)

Administration of the YDE derivatives For YDE-001 to YDE-028, YY-102 and the 28 YDE-series were each dissolved in physiological saline at a concentration of 3 mg/ml and administered at a dose of 5 l/eye at 9:30 am and 3:30 pm daily for 14 days after 7 days from the ELGE operation for a total of 28 times. The DS solution was dissolved in physiological saline at a concentration of 30 mg/ml and administered at a dose of 5 l/eye twice a day for 14 days after 7 days from the ELGE operation for a total of 28 times. For the sham control and the ELGE control groups, the same stimulation as the administration was applied. In order to prevent excessive eye dryness, the same volume of physiological saline was applied in the same manner in place of the test substances. Further, for YDE-029 to YDE-043, YY-102 and the 15 YDE-series were each dissolved in physiological saline at a concentration of 3 mg/ml and administered at a dose of 5 l/eye at 9:30 am and 3:30 pm daily for 14 days after 7 days from the ELGE operation for a total of 28 times. The DS solution was dissolved in physiological saline at a concentration of 30 mg/ml and administered at a dose of 5 l/eye twice a day for 14 days after 7 days from the ELGE operation for a total of 28 times. For the sham control and the ELGE control groups, the same stimulation as the administration was applied. In order to prevent excessive eye dryness, the same volume of physiological saline was applied in the same manner in place of the test substances (Fig. 7).

Confirmation of the changes in the amount of tear secretion by the YDE derivatives After 6 days from the ELGE surgery, the changes in the amount of tear secretion were measured at day 7 and day 14 after the administration of YDE-001 to YDE-043. The amount of tear secretion was measured by the decrease in the travel distance of tears absorbed by cobalt chloride paper in a size of 1 x 15 mm (Toyo Roshi Kaisha, Japan). The cobalt chloride paper was placed in the lateral canthus of a rat for 60 seconds to absorb tears (Fig. 9). The length of the area absorbed from the comer of the cobalt chloride paper was measured with an electronic digital caliper (Mytutoyo, Tokyo, Japan) (Fig. 8). Fig. 9 shows the results of the test, wherein A is for the sham control group, B is for the ELGE control group, C is for the DS reference group, D is for the YY-102 administered group, and E to AF are for the YDE-001 to YDE-028 administered groups in order. As a result, it was confirmed that the amount of tear secretion was decreased after 6 days from the ELGE operation at days 7 and 14 after the application of physiological saline in the ELGE control group as compared with the sham control group. In the groups treated with YDE derivatives and the DS reference group, the amount of tear secretion was increased as compared with the ELGE control group, except for the groups treated with a 3% solution of YDE-9, YDE-10, YDE-17, YDE-19, YDE-20, YDE-21, YDE-22, YDE-25, YDE-27, and YDE-28, which did not show any significant changes in the amount of tear secretion after the administration thereof for 14 days. Especially, the amount of tear secretion was increased by more than 20% in the groups treated with a 3% solution of YDE-15, YDE-11, YDE-08, YDE-26, YDE-16, YDE-01, YDE-23, and YY-102 as compared with the DS reference group. The specific amounts of tear secretion are shown in Fig. 10 and Table 4.

[Table 4] No. Tear Volumes (mm 3 )

Day 7 Day 14 YY-101 7.66+0.61 6.00+0.69 YY-102 4.59+1.43 5.77+1.99 YDE-001 4.88+1.62 5.92+2.19

YDE-002 3.84+1.16 5.01+1.67 YDE-003 4.13+1.76 4.88+1.57 YDE-004 3.42+1.06 5.19+1.84 YDE-005 3.85+0.93 5.08+1.91 YDE-006 3.44+1.69 5.35+1.68 YDE-007 3.91+1.28 5.45+1.26 YDE-008 4.57+1.25 6.10+2.36 YDE-009 3.76+1.21 4.54+1.11 YDE-010 3.42+1.31 4.35+1.36 YDE-011 4.22+1.45 6.16+2.16 YDE-012 3.68+0.99 5.67+1.86 YDE-013 5.27±1.50 5.49+1.92 YDE-014 3.81+1.21 5.62+1.85 YDE-015 4.03+2.19 6.65+2.13 YDE-016 4.59+1.13 5.98+2.27 YDE-017 4.00+1.22 4.89+1.50 YDE-018 3.75+1.54 4.99+1.60 YDE-019 4.84+1.39 4.52+1.07 YDE-020 3.41+1.47 4.20+1.35 YDE-021 4.08+1.33 4.90+1.13 YDE-022 3.19+0.67 4.10+0.95 YDE-023 5.32+2.30 5.78+2.23 YDE-024 3.85+1.30 5.72+1.36 YDE-025 3.21+0.72 4.72+2.19 YDE-026 4.32+1.47 6.01+1.83 YDE-027 2.82+0.86 3.95+1.52 YDE-028 4.04+0.99 4.73+1.18

Fig. 11 shows the results of the test, wherein A is for the sham control group, B is for the ELGE control group, C is for the DS reference group, D is for the YY-102 administered group, and E to S are for the YDE-029 to YDE-043 administered groups in order.

As a result, it was confirmed that the amount of tear secretion was decreased after 6 days from the ELGE operation at days 7 and 14 after the application of physiological saline in the ELGE control group as compared with the sham control group. In the groups treated with YDE derivatives and the DS reference group, the amount of tear secretion was increased as compared with the ELGE control group, except for the groups treated with a 3% solution of YDE-029, YDE-030, YDE-032, YDE-033, YDE-034, YDE-036, and YDE 41, which did not show any significant changes in the amount of tear secretion after the administration thereof for 14 days. Especially, the amount of tear secretion was increased by more than 20% in the groups treated with a 3% solution of YDE-040, YDE-043, and YDE-042 in order as compared with the DS reference group. The specific amounts of tear secretion are shown in Fig. 12 and Table 5.

[Table 5] Tear Volumes (mm 3 No. ) Day 7 Day 14 YY-101 5.36+0.68 6.25+0.68 YY-102 5.77+1.01 6.60+0.64 YDE-029 5.33+1.43 6.03+1.71 YDE-030 5.69+1.79 6.65+2.17 YDE-031 5.63+1.97 5.91+0.85 YDE-032 5.58+0.80 5.03+0.93 YDE-033 4.99+1.20 4.54+1.16 YDE-034 6.16+1.01 6.43+1.86 YDE-035 4.96+0.96 6.25+0.79 YDE-036 4.95+1.05 5.13+1.03 YDE-037 4.98+0.66 5.80+0.90 YDE-039 6.04+1.01 6.44+1.96 YDE-040 5.77+1.05 8.63+1.53 YDE-041 5.01+1.26 6.25+2.15 YDE-042 6.30+1.08 7.97+1.48 YDE-043 5.90+1.06 8.16+1.42

Confirmation of the changes in the corneal damage by the YDE derivatives After YDE-001 to YDE-028 were each administered to the eyes 14 times, the changes in the comeal permeability were checked. In order to measure the comeal permeability, Zolethyl 50 TM (Virbac Lab., Carros, France), an animal anesthetic, was intraperitoneally injected at a dose of 25 mg/kg. Thereafter, saline containing a 1% (v/v) fluorescent solution (fluorescein sodium salt, Tokyo Kasei Kogyo Co., Tokyo, Japan) was applied to the eyes at a dose of 5 l/eye. The eyes thus treated were closed and fixed with a tape. After1 hour, the remaining fluorescent solution was removed using a cotton swab (Fig. 12). After 12 hours to 24 hours, the comeal permeability was measured using a blue light tungsten lamp and an ophthalmic slit lamp table top model biomicroscope (Model SM-70N; Takaci Seiko Co., Nakano, Japan) (Fig. 13). Fig. 14 shows the results of the test, wherein A is for the sham control group, B is for the ELGE control group, C is for the DS reference group, D is for the YY-102 administered group, and E to AF are for the YDE-001 to YDE-028 administered groups in order. As a result, the permeability of the fluorescent dye was increased in the ELGE control group as compared with the sham control group. The permeability of the fluorescent dye was not decreased in the groups treated with a 3% solution of YDE-10, YDE-20, YDE-22, YDE-25, YDE-27, and YDE-28 as compared with the ELGE control group at day 14 after the administration. In the groups treated with YDE derivatives and the DS reference group, the corneal permeability of the fluorescent dye was decreased as compared with the ELGE control group, except for the groups treated with a 3% solution of YDE-10, YDE-20, YDE 22, YDE-25, YDE-27, and YDE-28. Especially, the permeability of the fluorescent dye was decreased by more than 20% in the groups treated with a 3% solution of YDE-15, YDE-11, YDE-08, YDE-26, YDE-16, YDE-01, YDE-23, and YY-102, as compared with the DS reference group. The specific permeabilities of the fluorescent dye are shown in Fig. 15 and Table 6.

[Table 6] No. Permeability of fluorescent dye(%) YY-101 27.53+5.62 YY-102 27.48+14.37 YDE-001 25.49+11.62 YDE-002 38.26+11.25 YDE-003 40.45+6.46 YDE-004 35.05+11.74 YDE-005 37.98+11.53 YDE-006 33.23+13.26 YDE-007 32.79+10.77 YDE-008 20.32+11.87 YDE-009 41.50+7.86 YDE-010 49.29+12.06 YDE-011 18.11+11.61 YDE-012 31.01+11.38 YDE-013 32.24±7.84 YDE-014 31.15+10.87 YDE-015 15.95+6.48 YDE-016 24.57+10.34 YDE-017 39.76+7.42 YDE-018 38.19+10.96 YDE-019 40.39+12.57 YDE-020 47.84+13.47 YDE-021 37.00+10.49 YDE-022 47.82±10.01 YDE-023 26.51+8.18 YDE-024 30.63+10.41 YDE-025 47.10+11.45 YDE-026 22.63+11.23 YDE-027 50.24+11.94 YDE-028 41.17+10.25

In addition, YDE-029 to YDE-043 were each administered to the eyes 14 times, and the changes in the comeal permeability were then checked. The measurement of the corneal permeability was carried out in the same manner as described above (Fig. 16). As a result, the permeability of the fluorescent dye was increased in the ELGE control group as compared with the sham control group. The permeability of the fluorescent dye was not decreased in the groups treated with a 3% solution of YDE-29, YDE-32, YDE-33, YDE-36, and YDE-41 as compared with the ELGE control group at day 14 after the administration. In the groups treated with YDE derivatives and the DS reference group, the corneal permeability of the fluorescent dye was decreased as compared with the ELGE control group, except for the groups treated with a 3% solution of YDE-29, YDE-32, YDE 33, YDE-36, and YDE-41. Especially, the permeability of the fluorescent dye was decreased by more than 20% in the groups treated with a 3% solution of YDE-40, YDE-43, and YDE-42, as compared with the DS reference group. The specific permeabilities of the fluorescent dye are shown in Fig. 17 and Table 7.

[Table 7] No. Permeability of fluorescent dye (%) YY-101 33.80+11.11 YY-102 27.89+7.10 YDE-029 63.45+11.57 YDE-030 30.60+13.61 YDE-031 33.35+11.01 YDE-032 58.90+19.81 YDE-033 60.55+21.22 YDE-034 32.17+12.94 YDE-035 27.62+6.51 YDE-036 57.87+22.91 YDE-037 36.30+9.75 YDE-039 29.94+11.40 YDE-040 18.33+9.41 YDE-041 46.38+26.65 YDE-042 20.72+11.37 YDE-043 19.04+7.36

Example 4: Evaluation of the stability of the YDE derivatives In order to confirm the stability of each test substance in an aqueous solution, 10 mg of each sample was dissolved in 1 ml of water to a concentration of 1 mg/ml, which was then charged to a glass vial, plugged with a rubber cap, sealed with an aluminum cap, and stored under long-term storage conditions (25°C, 75% RH). The stability of the test substance was evaluated by measuring the amount of related substances at the time of one week, two weeks, four weeks, eight weeks, and twelve weeks under the long-term storage conditions. As a result, 66.5% of related substances was generated in YY-101 after two weeks. In contrast, 1.1% to 30.6% of related substances was generated in YDE-001 to YDE-028 after 12 weeks. The specific amounts are shown in Table 8.

[Table 8] No. Amount of related substances (%; after 12 weeks) YY-101 66.51 (after 2 weeks) YDE-001 3.92 YDE-002 4.93 YDE-003 6.86 YDE-004 2.11 YDE-005 2.97 YDE-006 3.67 YDE-007 3.76 YDE-008 4.42 YDE-009 4.71 YDE-010 4.39 YDE-011 3.83 YDE-012 3.57 YDE-013 5.92 YDE-014 6.72 YDE-015 13.05 YDE-016 11.33 YDE-017 11.88

YDE-018 25.39 YDE-019 13.43 YDE-020 21.54 YDE-021 21.33 YDE-022 19.23 YDE-023 30.66 YDE-024 20.59 YDE-025 5.17 YDE-026 10.15 YDE-027 12.74 YDE-028 1.15 YDE-029 2.77 YDE-030 2.74 YDE-031 34.82 YDE-032 6.16 YDE-033 5.6 YDE-034 1.25 YDE-035 3.89 YDE-036 8.77 YDE-037 2.88 YDE-039 2.19 YDE-040 3.58 YDE-041 3.04 YDE-042 3.98 YDE-043 3.43

Example 5: Evaluation of recovery of corneal damage by the YDE derivatives In order to confirm whether the YDE derivatives could recover corneal damage, the cellular growth rate of human primary corneal epithelial cells was checked. Specifically, primary corneal epithelial cells (ATCC, ATCC PCS-700-010) were seeded on a 96-well culture plate (Perkin Elmer, 6005680) containing the Comeal Epithelial Cell Basal Medium (ATCC, ATCC PCS-700-030) in the Corneal Epithelial Cell

Growth Kit (ATCC, ATCC PCS-700-040) in an amount of 5x103 cells per well, which was then cultured for 24 hours under the conditions of 37C and 5% Co 2

. YDE-001 to YDE-075 were each dissolved in 100% DMSO (Sigma, D2660) to a concentration of 10 mM, which was then diluted with 100% DMSO to a concentration of the compound of 6, 1.9, 0.6, 0.2, 0.06, 0.02, 0.006, and 0.002 mM. 20 pl of the diluted YDE derivative was added to a 96-well microplate (Greiner Bio-One, 651201) containing 380 pl of the Corneal Epithelial Cell Basal Medium such that the concentration of DMSO was diluted to 5%. After 24 hours, 20 pl of each of the YDE derivatives diluted in the 96-well microplate was added to the 96-well culture plate containing the cells. As a control group, hEGF (Sigma, E9644) was treated at the same concentration as the YDE derivatives. The cells treated with the YDE-derivatives or hEGF were cultured for 48 hours and 72 hours under the conditions of 37C and 5% C02 (Figs. 18 to 25). The cultured cells were treated with the CellTiter-Glo luminescent reagent (Promega, G7573) according to the manufacturer's instructions and reacted for 30 minutes at room temperature. Thereafter, the fluorescent signal (or luminescence signal) was checked using an Envision 2014 Multi-label plate reader. The measured values were normalized using a vehicle control (100% proliferation cell). As a result, the cell proliferation was observed at concentrations of 0.3 M or less in YY-101, YY-102, YDE-011, YDE-038, YDE-042, YDE-043, YDE-044, YDE-045, YDE 049, YDE-054, YDE-057, YDE-058, YDE-059, and YDE-060. Especially, a high cell proliferation rate was shown in YY-102, YDE-011, YDE-045, YDE-057, and YDE-060 (Figs. 26 to 43).

Incorporation by Reference

All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Equivalents

While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

The term "comprise" and variants of the term such as "comprises" or "comprising" are used herein to denote the inclusion of a stated integer or stated integers but not to exclude any other integer or any other integers, unless in the context or usage an exclusive interpretation of the term is required.

Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

Claims (3)

The claims defining the invention are as follows:

1. A composition comprising a pharmaceutically acceptable salt of a compound represented by Formula (I):

(R4)p(RpH 0 R6 H 0 R2 H O CH3 CHH~H O O N , N , N N N N N N N OH H A H H H 8 3

(I)

wherein: R4, independently for each occurrence, is selected from -CH3, -OR, -CH 2OR, halo, hydroxyl, and hydroxy(C-6)alkyl; Rb is unsubstituted C1-6 alkyl;

p is 1 or 2; R6 is hydrogen or substituted C1-6 alkyl, wherein the CI-6 alkyl is optionally substituted with one occurrence of -C(=O)NH2; and R7 , R 8, and R 9 are each independently hydrogen or C-6 alkyl;

0 0 N R1 is selected from H HO 0 NH 2 H2N 0 NH 2

NH CH 3 H 3C OH H 3C OH CH 3 H3 C CH 3 H3 H3

and H.

CH 3 CH 3 H H3 C CH 3 CH 3 CH 3 CH 3 OH

R2 is selected from 4 , , , , , ,and H 3C OH ; and

H 3C

R3 isselectedfrom NH 2 H3 HO 0 , and 3

wherein the compound is not: H 2N 0 HO

H 0 H 0 H 0 CH3H H N N N N NN NQ N N N 0OH H HH ' OH

N 2 ,or

H 2N 0 HO O 0 H0 0 0 H H H H H NN N N N N N OH

NH 2 Hyp Gly Gin Ile Gly Leu Ala Gly Pro Lys (2S,4R) and

at least 90% of the compound in the composition is present as the salt; and wherein the salt is selected from a hydrochloride, hydrobromide, sulfate, nitrate, perchlorate, phosphate, formate, acetate, lactate, malate, fumarate, succinate, tartrate,

glycolate, salicylate, citrate, methanesulfonate, benzenesulfonate, benzoate, malonate, trichloroacetate, naphthalene-2-sulfonate, oxalate, mandelate, alkylammonium, dialkylammonium, trialkylammonium, tetra-alkyl ammonium, L-arginine, benethamine,

benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2 (diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, calcium, magnesium, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salt.

H

2. The composition of claim 1, wherein R2 is.

3. The composition of claim 1 or 2, wherein R3 is NH 2

, 4. The composition of any one of claims 1-3, wherein p is 1 or 2; and R4, independently for each occurrence, is selected from -CH3, halo, hydroxyl, and hydroxyalkyl.

H 2N 0

5. The composition of any one of claims 1-4, wherein R' is -CH3 or

. 6. The composition of any one of claims 1-5, wherein R7 is (CI-C6)alkyl.

7. The composition of any one of claims 1-6, wherein R' is -CH3 or -H.

8. The composition of any one of claims 1-7, wherein R9 is -CH3 or -H.

9. The composition of any one of claims 1-8, wherein the compound comprises at least one D-amino acid residue.

10. The composition of any one of claims 1-9, wherein the compound comprises at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight D amino acid residues.

11. The composition of claim 1, wherein the compound is selected from the following: H2N 0 HO

H 0 H 0 H 0 Hj H0 N N&N N1jl.NN Njl.N N 01 N OH H HHH

O OH

Hyp Gly Gln Glu Gly Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO

N H NH N H N H N N~k »OH H HH

NH 2 NH Hyp Gly Gln Asn Gly Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO s. H 0 H 0 H 0 0

NN NN N H H £H 1 H

0 NH 2 NH 2 Hyp Gly Gln Gln Gly Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO

N N N IN N NN 1 N NIN OH HH HN

NH 2 Hyp Gly Gln His Gly Leu Ala Gly Pro Lys (2S,4R)

H2N 0 HO H0 H0 H0 0 0 NN NN H N OH H H

NH2 NH2 Hyp Gly Gln Lys Gly Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO

N IN N IN N-IN OH H HHH

NH 2 Hyp Gly Gln Ser Gly Leu Ala Gly Pro Lys (2S,4R)

H2N 0 HO H0 0j 0 0 (X H N N N N }LN N OH

NOH H

NH, Hyp Gly Gln Thr Gly Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO

H 0 H 0 0 H H0 N N N N N OH H HHH

NH 2 Hyp Gly Gln Ala Gly Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO

H 0 0 0 H H0 H N N N N H HHH

NH 2 Hyp Gly Gln Leu Gly Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO

NNNNN OH

NH 2 Hyp Gly Gln Phe Gly Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO

H 0 H 0 H 0 H H 0

HN N N N -N N NN OH H £ H NH NNH

Hyp Gly Gln Trp Gly Leu Ala Gly Pro Lys (2S,4R) and

H2N 0 HO H O 0 H 0 0 0 N N N OH H H H H H H H...-.HHH

Hyp Gly Gin Asp Val Leu Ala Gly Pro Lys (2S,4R)

12. The composition of claim 1, wherein the compound is selected from the following:

H2N 0 HO 0 0 0 0 X 0 H H H Hj I NN N N - OH H H OH A H,

OH NH 2 Hyp Gly Gin Asp Ile Leu Ala Gly Pro Lys (2S,4R)

H2N 0 HO

H 0 H 0 H H H 0 N N N N N NJIN N N -I-OH HH

NH, Hyp Gly Gin Asp Ala Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO OH H 0 H 0f H 0 H H 0 N N ,N.U N N N N N >-'N - OH HH z H H 4,OH

NH 2 Hyp Gly Gin Asp Ser Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO 0 H H 0 H 0N 0 HH 0 ) H 0 N N N N N N N N>'- OH H OH H

Hyp Gly Gln Asp Thr Leu Ala Gly Pro Lys (2S,4R)

H2N 0 HO

H HH H 0 Hj H N N N N N N QKN N N OH H H H H

I rNH 2 Hyp Gly Gln Homo-Ser Gly Leu Ala Gly Pro Lys (2S,4R) and

H2N 0 HO 0 0 0 0 J 0 H H H Hj N N- - N N J N NN OH H H H H

0 OH

Hyp Gly Gln Leu Gly Leu Ala Gly Pro Glu (2S,4R)

13. The composition of claim 1, wherein the compound is selected from the following:

H2N 0 HO. 0 0 0 0 0 H H H H H N N,,N N "N >N N N - OH H H H z H

NH 2 (4-hydroxyMe)Pro Gly Gln Leu Gly Leu Ala Gly Pro Lys (4R)

HN 0 F

H 0 H 0 H0 j I 0 N N, A N N'-i N -N N N)<N-O H H H Hj

(4-Fluoro)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys (4R)

HN 0

H 0 H0 H0 Hj 0 l 0 N N N NI-AN N N N~ N >YOH1 H HHH

NH, (4-Dimethyl)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys

HN 0

0 0 H0 0J HH H H N N. N N N N N N N -, OH H H H H

"-r -r -N H, (4-Me)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys 2 (4R)

HN 0

0H 0 o o 0 H H H H jo

-r "r 'NH, (5-Me)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys 2 (5R)

HN 0 HO

H 0 ^ H H0 N N 1L1-N N 1'N NIN Nj _ NAH H H H ~i H).

NH, Hyp Ala Gin Leu Gly Leu Ala Gly Pro Lys (2S,4R)

HO H 0 H? H? H? 0 N N )KN NI)N N ,> _ N NKN OH H H :HH

NH2 Hyp Gly Ala Leu Gly Leu Ala Gly Pro Lys (2S,4R)

H 2N 0 HO O 0 H0 H0/1hH0 H N H N H N H NOH

NH 2 Hyp Gly Gln Ala Gly Leu Ala Gly Pro Lys (2S,4R) and H 2N 0 HO

N' - N >-' N >- N - OH H HHH

NH 2 Hyp Gly Gln Leu Ala Leu Ala Gly Pro Lys (2S,4R)

14. The composition of claim 1, wherein the compound is selected from the following: H 2N 0 HO 0 s.- H 0 H H0 H0/- 0 H

H H H H~O N N N N OH~k

NH 2 Hyp Gly Gin Leu Gly Ala Ala Gly Pro Lys (2S,4R)

H 2N 0 HO HO 0 H0 0 /-. 0 H NNN H H NNN H H OH

NH2 Hyp Gly Gin Leu Gly Leu Ala Ala Pro Lys (2S,4R)

H 2N 0 HO 0 0 H 0 H 0 H HH

HN HHH N N N OH

Hyp Gly Gln Leu Gly Leu Ala Gly Pro Ala (2S,4R)

H 2N 0 HO 0 0 H0 H H^Jl 0 H N N N N NJJ-OH H 2

D-Hyp Gly Gln Leu Gly Leu Ala Gly Pro Lys (2R,4S)

H 2N 0 HO

~HO H H Hj/> H N _=N N_1A. N-I N H~N N,,j N O0H N OH

D-Hyp Gly D-Gln D-Leu Gly D-Leu D-Ala Gly D-Pro D-Lys NH2 (2R,4S)

H 2N 0 HO 0 0 0 H 0 H H - H ( H N N N N OH

D-Hyp Gly D-Gln D-Leu Gly D-Leu D-Ala Gly D-Pro D-Lys NH2 (2R,4R)

H 2N 0 HO 0 H0 -H H H0 H N N N N N H H £H NH O

H2 D-Hyp Ala Gln Leu Gly Leu Ala Gly Pro Lys 2

(2R, 4S)

H 2N 0 HO 0 0 0 0 0 N N N 'N N N N N 0OH H H H H

D-Hyp Gly Gln Leu Gly Leu Ala Gly Pro Ala (2R,4S) and H2N 0 HO H 0 H 0 H 0 H H N N N NOH H H H ~ -H

D-Hyp Ala Gln Leu Gly Leu Ala Gly Pro Ala (2R,4S)

15. The composition of claim 1, wherein the compound is H2N 0 HO

NO N "'N N NXNN_, N -- O H H H ~ H ~ ~

Hyp Gly Gln D-Leu Gly D-Leu D-Ala Gly Pro Lys (2S,4R)

16. A pharmaceutical composition comprising a therapeutically effective amount of a composition of any one of claims 1, 6-8, and 10-15 and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is formulated for topical administration to the eye, e.g., as eye drops.

18. The pharmaceutical composition of claim 16 or 17, wherein at least 95% of the compound of formula (I) in the composition is present as the salt.

19. The pharmaceutical composition of claim 18, wherein at least 99% of the compound of formula (I) in the composition is present as the salt.

20. A method of treating dry eye syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a composition of any one of claims 1, 6 8, and 10-15 or a pharmaceutical composition of any one of claims 16-18.

21. The method of claim 20, wherein administering the composition comprises topical administration to the eye of the subject.

22. Use of a composition of any one of claims 1, 6-8, and 10-15 or a pharmaceutical composition of any one of claims 16-18 in the manufacture of a medicament for the treatment of dry eye syndrome.

23. An ophthalmic formulation comprising a composition of any one of claims 1, 6-8, and 10-15 or a pharmaceutical composition of any one of claims 16-18, and a pharmaceutically acceptable excipient or carrier.

24. The ophthalmic formulation according to claim 23, wherein the ophthalmic formulation is an eye drop.

25. A kit comprising: (1) a composition of any one of claims 1, 6-8, and 10-15 or a pharmaceutical composition of any one of claims 16-18; and (2) instructions for administration of the composition.

26. A kit comprising an ophthalmic formulation according to claim 24 or 25; and instructions for administration of the ophthalmic formulation.

Purity Solubility Amount No that Number Pepticle Name Sequence M.W. (%) (mg) (0.5mg/ml)

Stining $ VOS-001 OGQEGLAGPK (0 >99.7% Water 10.0mg

Siting 2 8161390 VOE-002 OSQNGLAGP% (D) 954.0 -99.7% Water 10.0mg

K163391 VESS-003 (2) 599.7% 5.0mg Water 3 9683 30.0mg

K263393 YOE-004 (o) 977.3 -99.7% 5.0mg Water & 10.0mg

$ 82561393 YOEIDOS OGORGLAGAK (D) Hydroapprofine} 968.1 >99.5% 5.0mg Water 10.0mg

8281394 YDE-008 927.0 $98.93 5.0mg § OGQSGLAGPK D Wash

> 8261395 YDE-007 OGQTGLAGPE (C) 941.0 5.0mg Water

K361395 YDE-008 OGOAGLAGPK (o Hydrosyprotine) 921.0 $98.8% 5.0mg Water a 30.0km

K361397 YES-009 OCOWSLAGPK (a Hydrosyptoline) 5.0mg Water S 9391 x9818 10.0mg

K161398 YOF-020 DEGIGLAGPS to : Hydromyprofise) 953.1 S.0mg Water 10 10.0mg

K161399 YOE-013 OGQLGLAGPK is -98,998 Sting Water 11 9531 300mg 987.1 Siding 12 2161400 YOF-012 OGQFGLAGPK to >98.9% Water 10.0mg

8163401 1000.1 -98.2% Stong Water 13 OGQYGLAGPK RD 10.0mg

14 8365402 VOE-014 >98.98 Writes DGOWGLAGPY (c) 10262 10:0mg

is 8261408 vos-ors OSQOVLAGPK (i) Hydrospositives 997.7 >99.1% Weige 10.0mg SiDing 16 8261408 VOS-016 OCODILAGPS (O.: Hychoxyprofine) 1011.1 500.0% Would 19.0mg

$7 8151405 VOE-017 OGQOLLAGPK to : 1915.1 $60mg Water 19:0mg

$8

to 8151406

8161407 YOS 018

VOE-019 OSQUALAGPK in

OCCDRAGPR (O): Hydroxypmines 969.1

15852 - 5.0mg

10.0mg

5.0mg Water

Wister

10.0mg

30 8261408 VOE-020 16883 $98.28 5.0mg Water OGODYLAGPR ID: 10.0mg

21 VOI-021 1084.2 5.0mg Water GGGDWLAGPK to

22 YOU-022 1035.1 >98.3% 5:0mg Wister OGODBLAGF% (0 10.0mg

as SESTERS YOE-023 OGQESLAGPY ID Hydroapproline} 985.1 >98.3% 5.0mg Water

200g 24 K161412 OGQDILAGPK (C Hydroxyprofine) -98.0% 5.0mg Water 9931 10.0mg

(Sex medicity) to Hydrosyptoline} Siting 25 X161413 VOH-025 9693 SRINK Water 10.0mg

36 KIEIGIA YOU-026 (2) home-Ser (c) 981.1 Sting Water **** 10.0mg

27 X161415 YOU-022 OGGUFGLAGPK (EPA) D(OMe)) to 5.0mg 9831 >39% water 30.0mg

28 K261416 YOU-028 968.1 3.0mg Water OGQN"GLAGFR (N° N(NMe) & AREX 3000mg

Fig. 1

1/60

Finoc-AA-Wang resin

Swell Resin (DMF) & 20% Pip.

Drain a Wash Resin(DMF)

Add Amino acid Mixture to Resin A.A. and DIC/HOB: Washes Y

After Coupling, Ninhydrin Test A Washes Pass

Fail Ninhydrin Test B Finoc Deprotection (Piperidine)

Fail Pass

Pass

Recoupling of Capping

Peptide on Resin

TFA mixture Global cleavage from the Resin

Filter & Dry

Crude Product

Fig. 2

2/60

Crude Peptide TFA 0.1% TFA/Purified water

Dissolve in H.O. Acetonitrile 0.1% TFA/Acetonitrile

Prep. By HPLC

Quality Spec In

Concentration

Product as Solution Status

0.2um Filter

Freeze Dryer

OC HPLC, MASS Product Released Product

Fig. 3

Sprague-Dawley Rat m Left ELGE Surgery

General ELG skin suture 7 days after ELGE surgery

Year volume & been measurement CORES By Schirmer test

Step 1 Step 2 Step 3 Step 4 Step 5

Surgery steps

Fig. 4

3/60

Body weights at Items Body weight gains First test material 24 hrs after last Groups ELGE surgery* [B-A] topical eye drop (A) treatment [B]*

Control

Sham 213.63+21.04 305.50433.53 340.50438.46 35.00.11.19 ELGE 215.50.16.10 302.63420.42 339.13=20.01 36.50+9.97 Reference DS 220.5028.70 304.50=13.11 340.63410.20 36.13.5.38 Test materials (0.3% solutions)

YY-102 211 88 12 89 302.00=20.70 337.75425.95 35.7526.84 YDE-01 212.63+11.30 302.25:24.57 341 00+24.98 38.75=9.50 YDE-02 210.38+10.89 302.00+15.96 338.00.22.39 36.00412.29 YDE-03 212.50+14.84 301.00+20.63 339 38+22.93 38.38+7.74 YDE-04 217.50+16.25 302.50419.66 338.50+21.44 36.00+10.97 YDE-05 212.50+16.75 303.50e17.77 341.50=17.53 38.00+3.12 YDE-06 212.38419.00 306.38425.21 345.13=21.06 38.75.6.14 YDE-07 219.1324.73 310.5049.99 349.88.12.28 39.3824.53 YDE-08 213.38413.99 307.00e13.73 845.63e17.87 38:63:7.01 YDE-09 215.63=13.69 304.25.18.58 341.38425.47 37.13410.34 YDE-10 216.00+12.99 305.25+13.82 343.63416.36 38.38=6.44 YDE-11 219.88.13.42 309.13+20.36 347.00-27.91 37.88+13.66 YDE-12 222.1319.98 311.00.15.57 349.88+21.70 38.88+9.08 YDE-13 217.6344.69 305.13+7.66 343.25+11.44 38.13+7.20 YDE-14 216.75915.53 301.25420.11 339.75=26.99 38.50=9.94 YDE-15 214.88=14.74 302.19e16.57 340.00.16.44 37.88+12.69 YDE-16 213.50=18.31 299.50#16.42 337.38.20.50 37.88+7.57 YDE-17 214.63.11.81 306.63417.54 346.25=19.26 39.63+10.51 YDE-18 213.88+13.24 307.88+13.27 347.38923.02 39.50+14.68 YDE-19 218.88+11.29 307.25.12.85 345.38.21.71 38.1329.83 YDE-20 217.88+9.61 300.75+16.79 339.25+15.68 38.50+5.71 YDE-21 216.38.15.31 301.38+20.89 340.13+21.53 38.75+8.14 YDE-22 219.38=10.85 304.13.14.56 343.50+21.37 39.38+9.30 YDE-23 219.00.12.54 308.25215.64 346.00e15.26 37.75+6.94 YDE-24 212.13.18.41 298.38+25.85 334.00.31.75 35.63410.29 YDE-25 213.13413.39 303.63+21.87 342.50=19.82 38.8825.84 YDE-26 213.63414.71 305.75423.07 343.25=29.09 37.50+9.38 YDE-27 214.75413.73 306.63425.44 345.38=26.40 38.75=10.02 YDE-28 212.75.13.36 297.63421.12 336.38=22.02 38.75+7.63

Fig. 5

4/60

Body weights at Body weight Items First test 24 hrs after last gains Groups ELGE surgery* material topical treatment [B]* [B-A] eye drop [A]

Control

Sham 242.38+7.73 320.25+9.91 363.38+27.21 43.13+19.71 ELGE 243.88+3.83 329.25+18.90 367.50+19.89 38.25+11.40 Reference

DS 246.63+15.68 330.50+23.33 369.63+37.46 39.13+25.56 YY-101 241.25+4.37 318.88-10.91 356.25.18.16 37.38+7.82 YY-102 242.38+11.46 318.75+15.20 361.25+23.56 42.50+9.41 Test materials (0.3% solutions)

YDE-029 242.25+16.63 327.38+18.75 373.75+28.50 46.38+12.49 YDE-030 243.25+10.26 315.88+14.96 355.50+29.68 39.63+16.61 YDE-031 241.00+15.82 316.75+27.58 359.00+39.87 42.25+14.96 YDE-032 242.75+9.32 324.25+14.59 365.38+16.16 41.13+10.12 YDE-033 243.50+11.96 327.50+17.57 377.13+26.59 49.63+16.27 YDE-034 243.88+8.68 322.63+17.15 361.63+19.08 39.00+4.99 YDE-035 240.88+11.29 321.00+22.17 358.50+29.18 37.50+20.36 YDE-036 242.25+14.01 329.38+21.07 378.38+24.20 49.00+10.81 YDE-037 244.50+10.94 324.88+17.36 369.13+21.43 44.25+8.83 YDE-039 242.88+7.14 325.25+15.51 363.25+28.35 38.00+15.41 YDE-040 241.13+13.39 319.25+14.10 357.00+27.93 37.75+19.37 YDE-041 244.75.14.49 322.88+22.47 366.13+37.43 43.25+16.97 YDE-042 239.13+8.29 323.38+8.28 372.38+19.46 49.00+13.54 YDE-043 246.25+7.92 324.00+14.31 361.25+19.20 37.25+13.63

Fig. 6

Sprague-Dawley Rat m Left Eye

$ ul/eye

See drop

Step 1 Step 2 Step 3 Step 4

Treatment steps

Fig. 7

5/60

Sprague-Dawley Rat w Left Eye

60 sec 60 sec

Lateral

canthus

Before After

Step 1 Step 2 Step 3

Schirmer tear test steps

Fig. 8

BEFORE 3) & Y IS V X AS AS AR AD & AF

DAYDAFTER EYE DROP 83 A C $ Y $$ > x Z AA AB so AD AR AR 84 DAYSAFTER EYE DROP A C a E $ G 338 X R 3. N N o & $ MTEYIY

Fig. 9

6/60

Items Tear volumes (mm) after test material topical eyedrop Groups -1 day 7 davs 14 days Control Sham 8.34.0.73 8.5620.76 8.63=0.93

ELGE 3.54:0.78 2.65:0.85* 3.27:1.06* Reference

DS 3.53z0.66 4.101.07* 4.80:0.94 Test materials (0.3% solutions)

YY-102 3.5820,93* 4.59+1.43 5.77+1.99 YDE-01 3.55=0.934 4.88=1.62* 5.92+2.19*

YDE-02 3.590.754 3.8421.16 5.01:11.67 YDE-03 3.5620.74 4.1321.76 4.88=1.57 YDE-04 3.57+0.55 3.42=1.06 5.19+1.84 YDE-05 3.56:0.86 3.85:0.93 5.08:21.91

YDE-06 3.5620.65 3.44+1.694 5:35:1:68 YDE-07 3.53+0.68 3.91=1.28 5.45+1.26 YDE-08 3.5420.82 4.5721.25 6.10+236 YDE-09 3.5620.78 3.76=1.21 4.54:41.11"

YDE-10 3.5240.61 3.42:131 439136 YDE-11 3.5640.884 4.22+1.45* 6.16=2.16 YDE-12 3.5520.71 3.68=0.99 5.6721.86 YDE-13 3.5520.498 5.27z1.50 5.491.92* YDE-14 3.55%0.66 5.62+1.85 YDE-15 3.5420.73 4.00-279 YDE-16 3.5620.93 #.5921.13 5.98=2.27 YDE-17 3.5420.91 4.00-1.22 4.89+1.50 YDE-18 3.58=0.68 3.75e1.54 4.99e1.60 YDE-19 3.5820.635 4.8421.39* 4.52+1.07 YDE-20 3.56:0.86 3.4121.47 4.20e1.35 YDE-21 3.5520.72 4.0821.33 4.90z1.13 YDE-22 3.5020.79 3.19+0.674 4.10+0.99 YDE-23 3.5120.72 5.32=2.30* 5.78=2.23*

YDE-24 3.5320.63 3.85=1.30 5.72+1.36 YDE-25 3.5620.75 3.21:0.72 4.72=2.19 YDE-26 3.57.0.57 4.32+1.47 6.01+1.83 YDE-27 3.57:0.64 2.82:0.86 3.95+1.52 YDE-28 3.5620.91 4.04.0.99 4.7321.18

Fig. 10

7/60

BEFORE A S

8 C D F GHIJKLMOPQR

DAYDAFTEREYE DROP

ABCDEFGHIIKLMNOPQRS 14 DAYS AFTER I EYE DROP

ABCDEFGHIIKLMNOPR Fig. 11

8/60

Items Tear volumes (mm) after test material topical eye drop -1 - day 7 days 14 days Groups Control

Sham 10.90+1.69 10.38+1.08 10.28+0.69

ELGE 4.81+1.09 4.37+0.83k 4.70+0.65b Reference

DS 4.74+1.30 5.72+1.28be 6.56+1.15bc

YY-101 4.86+1.08 5.36+0.68be 6.25+0.68bd

YY-102 4.94+0.71ª 5.77+1.01be 6.60+0.64bd Test materials (0.3% solutions)

YDE-029 4.72+1.05a 5.33+1.43b 6.03+1.71°

YDE-030 4.93+1.15 5.69+1.79b 6.65+2.17b

YDE-031 4.70+0.69a 5.63+1.97b 5.91+0.85be

YDE-032 4.94+1.04a 5.58+0.80be 5.03+0.93b

YDE-033 4.77+1.32ª 4.99+1.20b 4.54+1.16b

YDE-034 4.88+1.07 6.16+1.01bd 6.43*1.86b

YDE-035 4.92+1.18ª 4.96+0.96b 6.25+0.79bd

YDE-036 4.83+1.07ª 4.95+1.05b 5.13+1.03b

YDE-037 4.68+0.83 4.98+0.66b 5.80+0.96be

YDF-039 4.81+1,27 6.04+1.01bc 6.44+1.96be

YDE-040 4.77+0.91ª 5.77+1.05be 8.63+1.53cc

YDE-041 4.87+1.19a 5.01+1.26b 6.25+2.15b

YDE-042 4.83+0.84 6.30+1.08bd 7.97+1.48b

YDE-043 4.86+0.81 5.90+1.06bd 8.16+1.42bd

Fig. 12

Sprague-Dawley Rat - Left Eye

Photographed using Sub/eye large biomicroscon

I the

Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Step 7

Fluorescein staining steps

Fig. 13

9/60

-A- -D- B. &

-E- -F- -G- -B-

-3- -K- 4-

-O- p. 3/

-R- -S- -To

Q

-0- St. it V

-Yo AB- Ad- Z

AD- -AE- AF- AC-

Fig. 14

10/60

Items Fluorescent stained

Groups cornea areas (%) Control

Sham 2.62+1.71

ELGE 57.34=12.83 Reference DS 35.40#13.32 Test materials (0.3%solutions)

YY-102 27.48:14.37 YDE-01 25.49=11.62 YDE-02 38.26:11.25* YDE-03 40.4526.46 YDE-04 35.05211.74 YDE-05 37.98+11.53 YDE-06 33.23=13.26* YDE-07 32.79.10.77 YDE-08 20.32+11.87 YDE-09 41.50:7.86 YDE-10 49.29+12.06 YDE-11 18.11=11.61

YDE-12 31.01+11.38 YDE-13 32.24+7.84 YDE-14 31.15#10.87 YDE-15 15.95=6.48 YDE-16 24.57:10.34 YDE-17 39.767.42° YDE-18 38.19.10.96 YDE-19 40.39+12.57 YDE-20 47.84=13.47 YDE-21 37.00=10.49 YDE-22 47.82=10.01*

YDE-23 26.51:88.18"

YDE-24 30.63=10.41* YDE-25 47.10=11.454

YDE-26 22.63211.23 YDE-27 50.24=11.94 YDE-28 41.17=10.25*

Fig. 15

11/60

-B- .C. -D-

-E- -F- -H-

-1. -X- -L-

M. -O-

-R-

Fig. 16

12/60

Items Fluorescent stained

Groups cornea areas (%) Control

Sham 1.53+0.65

ELGE 66.71+10.02b

Reference DS 30.03+10.97bd

YY-101 33.80+11.11bd

YY-102 27.89+7.10bd

Test materials (0.3% solutions)

YDE-029 63.45+11.57b

YDE-030 30.60+13.61bd 33.35+11.01bd YDE-031 YDE-032 58.90+19.81° 60.55+21.226 YDE-033 YDE-034 32.17+12.94bd

YDE-035 27.62+6.516d

YDE-036 57.87+22.91°

YDE-037 36.30+9.75bd 29 94+11 40 bd YDF-039 18.33+9.41bd YDE-040 YDE-041 46.38+26.65b

YDE-042 20.72+11.37bo 19.04+7.36bd YDE-043

Fig. 17

13/60

Dose Response of hEGF(48hrs)

50 Plate 1

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

Concentration, uM

Fig. 18

Dose Response of hEGF(48hrs) Plate 2 50

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

Concentration, uM

Fig. 19

14/60

Dose Response of hEGF(48hrs) 50 Plate 3

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

Concentration, uM

Fig. 20

Dose Response of hEGF(48hrs) 50 Plate 4

40

30

20

10

o 30 10 3 1 0.3 0.1 0.03 0.01

Concentration,

Fig. 21

15/60

Dose Response of hEGF(72hrs) Plate 1 50

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

Concentration, uM

Fig. 22

Dose Response of hEGF(72hrs) Plate 2 50

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

Concentration, uM

Fig. 23

16/60

Dose Response of hEGF(72hrs) Plate 3 50

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

Concentration, uM

Fig. 24

Dose Response of hEGF(72hrs) Plate 4 50

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

Concentration, um

Fig. 25

17/60

(a) Dose Response YY-101 7 (48hrs) 40

30

20

10

0 an so $ 1 0.3 0.1 0.03 0.01

-10

-20 Concentration, uM

(b) Dose Response of YY-101 (72hrs) 45

40

35

30

25

20

15

10

5

0 30 10 3 1 0.3 0.1 0.03 0.01 -5 Concentration, um

Fig. 26

18/60

(a) YY-102 40

30

I 20

10

0 10 3 1 0.3 0.1 0.03 0.01

-10

-20 Concentration, pM

(b) YY-102

45

I 35

25

15

x 5

30 10 3 1 0.3 0.1 0.03 0.01 S Concentration, uM

Fig. 27

19/60

(a) YDE-011 so

70 person 60

SAND 50

40

30

20

10

x 0 0.3 0.03 0.01 30 10 1 0.1 -10

-20 Concentration, uM

(b) YDE-011 70

60 perce so

10/05 40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01 -10

20 Concentration, uM

Fig. 28

20/60

(a) YDE-038 50

40

I 30 12/10

20

10

0 all 0.3 0.1 0.03 0.01

-10

-20 Concentration, pM

(b) YDE-038 50

40

I 2010 30

20

10

0 30 10 0.3 0.1 0.08 0.01

-10 Concentration, uM

Fig. 29

21/60

(a) YDE-042 40

30 based

INVO 20

10

0 30 10 0.3 0.1 0.03 0.01

x -10

-20 Concentration, uM

(b) YDE-042 40

30

I 20

10

0 30 10 $ 1 0.3 0.1 0.03 0.01

*10

-20 Concentration, pM

Fig. 30

22/60

(a) YDE-043 40

30 issue

20 serv

10

0 <08 to 0.3 0.1 0.03 0.01

-10

x -20

-30 Concentration, uM

(b) YDE-043 40

30 pass

SAME 20

10

0 10 3 0.3 0.1 0.03 0.01 of 10

-20 Concentration, uM

Fig. 31

23/60

(a) YDE-044 so

40 1 and 30

20

10

a 0 as 10 3 1 0.3 0.1 0.03 0.01

>10 Concentration, pM

(b) YDE-044 so

passed 40

and 30

20

10

x 0 30 10 0.3 0.1 0.03 0.01

-10 Concentration, uM

Fig. 32

24/60

(a) YDE-045 50

40

I 30

20

10

& 0 30 10 1 0.3 0.1 0.03 0.01

-10 Concentration, uM

(b) YDE-045 so

40 pase

SAME 30

20

10

& 0 30 10 3 1 0.3 0.1 0.03 0.01

-10 Concentration, uM

Fig. 33

25/60

(a) YDE-049 40

30

pass 20

adidas 10

0 <00 0.1 to 0.3 0.03 0.01 -10

-20

-30

x 40 -50

-60 Concentration, pM

(b) YDE-049 50

40

I 30

20

10

all

0 30 10 0.3 0.1 0.03 0.01

-10 Concentration, pM

Fig. 34

26/60

(a) YDE-054 40

30

20

10

0 the 0.3 0.1 0.03 0.01

-10

-20 Concentration, uM

(b) YDE-054 $0

40

30

20

10

0 30 10 $ 0.3 0.1 0.03 0.01

-10 Concentration, uM

Fig. 35

27/60

(a) YDE-057 70

60 (see

so

40

30

20

10

0 30 10 $ 0.3 0.1 0.03 0.01 -10 Concentration, uM

(b) YDE-057 60

50 1 40

30

20

10

0 30 10 1 0.3 0.1 0.03 0.01

Concentration, pM

Fig. 36

28/60

(a) YDE-058 40

30 pass

GOVE 20

10

0 0.3 0.1 0.03 0.01

-10

-20 Concentration, uM

(b) YDE-058 40

35

30 1 25

20

15

10

$ of 0 30 10 3 0.3 0.1 0.03 0.01 -$

-10 Concentration, uM

Fig. 37

29/60

(a) YDE-059 40

30 I 20

10

0 AND 0.3 0.1 0.03 0.01 10 1 x -10

-20 Concentration, uM

(b) YDE-059 50

40

1 QUAL 30

20

10

& 0 30 10 1 0.3 0.1 0.03 0.01

-10 Concentration, uM

Fig. 38

30/60

(a) YDE-060 70

60 based

50

40

30

20

10

0 10 3 1 0.3 0.1 0.03 0.01 -10 Concentration, uM

(b) YDE-060 60

pass 50

sout

40

30

20

10

0 30 10 1 0.3 0.1 0.03 0.01

Concentration, uM

Fig. 39

31/60

(a) YDE-072 40

30

20

10

0 30 to 0.3 0.1 0.03 0.01

-10

-20 Concentration, uM

(b) YDE-072 40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

-10

-20 Concentration, uM

Fig. 40

32/60

(a) YDE-073 40

30

20

10

0 30 TO 1 0.3 0.1 0.03 0.01

-10

-20 Concentration, uM

(b) YDE-073 40

30

20

10

0 St 10 1 0.3 0.1 0.03 0.01

-10

-20 Concentration, uM

Fig. 41

33/60

(a) YDE-074 40

30

(see 20

10

0 30 to 3 $ 0.03 0.01 as -10 a -20

& -30

-40

-50 Concentration, pM

(b) YDE-074 40

30

20

10

0 .........

30 10 3 1 0.3 0.1 0.03 0.01

-10

-20 Concentration, UM

Fig. 42

34/60

(a) YDE-075 40

30

20

10

0 30 to $ 1 and our 0.03 0.01

-10

% -20

-30 Concentration, uM

(b) YDE-075 50

40 based

30

20

10

0 30 10 a 1 0.3 0.1 0.03 0.01 & -10

-20 Concentration, uM

Fig. 43

35/60

Dose Response of YDE-078 (48hrs)

50

40

30

20

10

0 10 $ 1 0.3 0.1 0.03 0.01

-10

-20 Concentration, uM

Dose Response of YDE-078 (72hrs)

so

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

-10

-20 Concentration, uM

Fig. 44

36/60

Dose Response of YDE-080 (48hrs)

50

40

30

20

10

0 10 3 1 0.3 0.1 0.03 0.01 30 -10

-20 Concentration, um

Dose Response of YDE-080 (72hrs)

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

-10

-20 Concentration, uM

Fig. 45

37/60

Dose Response of YDE-081 (48hrs)

50

40

30

20

10

0 30 10 1 0.3 0.1 0.03 0.01 & -10

-20 Concentration, pm

Dose Response of YDE-081 (72hrs)

40

30

20

10

0 30 10 3 I 0.3 0.1 0.03 0.01

-10

-20 Concentration, uM

Fig. 46

38/60

Dose Response of YDE-083 (48hrs)

40

30

20

10

0 0.3 0.1 0.03 0.01

-10

-20

~30 Concentration, uM

Dose Response of YDE-083 (72hrs)

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

-10 Concentration,

Fig. 47

39/60

Dose Response of YDE-084 (48hrs)

50

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

-10

-20 Concentration, UM

Dose Response of YDE-084 (72hrs)

40

35

30

25

20

15

10

S

0 30 10 3 % 0.3 0.1 0.03 0.01 -S

.10 Concentration, pM

Fig. 48

40/60

Dose Response of YDE-086 (48hrs) 40

30

20

10

0 30 10 $ 1 0.3 0.1 0.03 0.01

-10

-20 Concentration, uM

Dose Response of YDE-086 (72hrs) 50

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

-10 Concentration, pM

Fig. 49

41/60

Dose Response of YDE-001 (48hrs)

50

40

30 y 20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

-30

-20 Concentration, UM

Dose Response of YDE-001 (72hrs)

50

40

30

20

10

0 so 10 3 3 0.3 0.1 0.09 0.01

-10 Concentration, UM

Fig. 50

42/60

Dose Response of YDE-010 (48hrs) so

40

so

20

10 >>>

0 30 10 3 1 0.3 0.1 0.03 0.01 -10

~20 Concentration, UM

Dose Response of YDE-010 (72hrs) 50

so

30

20

10

0 30 10 3 1 0.3 0.3 0.08 0.01

-10 Concentration, uM

Fig. 51

43/60

Dose Response of YDE-029 (48hrs)

50

40

30

20

10

0 $ 1 0.3 0.1 0.03 0.01

-10

-20 Concentration, uM

Dose Response of YDE-029 (72hrs)

50

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

>10 Concentration, pM

Fig. 52

44/60

Dose Response of YDE-092 (48hrs) 50

40

30

20

10

0 20 to S 1 0.3 0.1 0.03 0.01 -10

-20

-30 Concentration, uM

Dose Response of YDE-092 (72hrs) 50

40

30

20

10

0 30 10 3 1 0.3 0.1 0.03 0.01

-10 Concentration, uM

Fig. 53

45/60

Dose Response of YDE-053 (48hrs)

80

60

40

20

0 0.01 0.03 0.1 0.3 1 3 10 30 -20 Concentration, uM

Dose Response of YDE-053 (72hrs)

60

40

20

o 0.01 0.03 0.1 0.3 1 3 10 30 -20 Concentration,

Fig. 54

46/60

Dose Response of YDE-064 (48hrs)

40

30

20

10

o 0.01 0.03 0.1 0.3 1 3 10 30 -10

-20 Concentration, uM

Dose Response of YDE-064 (72hrs)

40

30

20

10

o 0.01 0.03 0.1 0.3 1 3 10 30 -10 Concentration, M

Fig. 55

47/60

Dose Response of YDE-066 (48hrs)

40

30

20

10

0 0.01 0.03 0.1 0.3 1 3 10 30 -10

-20 Concentration, uM

Dose Response of YDE-066 (72hrs)

40

30

20

10

o 0.01 0.03 0.1 0.3 1 3 10 30 -10

-20 Concentration, M

Fig. 56

48/60

Dose Response of YDE-012 (48hrs)

50

40 30

20

10

0 0.01 0.03 0.1 0.3 1 10 30 -10

-20 Concentration, M

Dose Response of YDE-012 (72hrs)

50

40

30

20

10

0 0.01 0.03 0.1 0.3 1 10 30 -10 Concentration, uM

Fig. 57

49/60

Dose Response of YDE-019 (48hrs)

50 40 30

20 10

0 0.01 0.03 0.1 0.3 1 10 30 -10

-20 Concentration, uM

Dose Response of YDE-019 (72hrs)

60

40

20

0 0.01 0.03 0.1 0.3 1 3 10 30 -20

-40 Concentration, M

Fig. 58

50/60

Dose Response of YDE-055 (48hrs)

50 40 30 20 10

0 0.01 0.03 0.1 0.3 1 3 10 30 -10

-20 Concentration, M

Dose Response of YDE-055 (72hrs)

70

50

30

10

-10 0.01 0.03 0.1 0.3 1 3 10 30 Concentration, uM

Fig. 59

51/60

Dose Response of YDE-085 (48hrs)

40

30 20

10

o 0.01 0.03 0.1 0.3 1 3 10 30 -10

-20 Concentration, M

Dose Response of YDE-085 (72hrs)

40

30

20

10

o 0.01 0.03 0.1 0.3 1 3 10 30 -10 Concentration, uM

Fig. 60

52/60

Dose Response of YDE-047 (48hrs)

40 30

20

10

0 0.01 0.03 0.1 0.3 1 3 10 30 -10

-20 Concentration, uM

Dose Response of YDE-047 (72hrs)

40

30

20

10

o 0.01 0.03 0.1 0.3 1 3 10 30 Concentration, M

Fig. 61

53/60

Dose Response of YDE-048 (48hrs)

40

30

20

10

o 0.01 0.03 0.1 0.3 1 3 10 30 -10

-20 Concentration, M

Dose Response of YDE-048 (72hrs)

70

50

30

10

-10 0.01 0.03 0.1 0.3 1 3 10 30 Concentration, M

Fig. 62

54/60

Dose Response of YDE-050 (48hrs)

40

30

20

10

0 0.01 0.03 0.1 0.3 3 10 30 -10 I

-20 Concentration, uM

Dose Response of YDE-050 (72hrs)

40

30

20

10

o 0.01 0.03 0.1 0.3 1 3 10 30 -10 Concentration, M

Fig. 63

55/60

Dose Response of YDE-051 (48hrs)

40

30

20 10

0 0.01 0.03 0.1 0.3 1 3 10 30 -10

-20 Concentration, uM

Dose Response of YDE-051 (72hrs)

40

30

20 10

o 0.01 0.03 0.1 0.3 1 3 10 30 -10

-20 Concentration, uM

Fig. 64

56/60

Dose Response of YDE-052 (48hrs)

40

30

20

10

o 0.01 0.03 0.1 0.3 1 3 -10 10 30 -20 Concentration, uM

Dose Response of YDE-052 (72hrs)

40 30 20 10

o 0.01 0.03 0.1 0.3 1 3 10 30 -10

-20

-30 Concentration, uM

Fig. 65

Dose Response of YDE056 (48hrs)

70

50

30

10

-10 0.01 0.03 0.1 0.31 3 10 30 Concentration, uM

Dose Response of YDE056 (72hrs)

70

50

30

10

-10 0.01 0.03 0.1 0.3 3 10 30 Concentration, M

Fig. 66

58/60

Dose Response of YDE-061 (48hrs)

70

50

30

10

-10 0.01 0.03 0.1 0.3 1 3 10 30 Concentration, M

Dose Response of YDE-061 (72hrs)

70

50

30

10

-10 0.01 0.03 0.1 0.3 1 3 10 30 Concentration, uM

Fig. 67

59/60

Dose Response of YDE-062 (48hrs)

60

40

20

0 0.01 0.03 0.1 0.3 1 3 10 30 -20 Concentration, uM

Dose Response of YDE-062 (72hrs)

50

30

10

-10 0.01 0.03 0.1 0.3 1 3 10 30

-30 Concentration, M

Fig. 68

60/60