Peptides and pharmaceutical compositions for treating eye diseases

Abstract

The present invention relates to novel peptides and pharmaceutical compositions comprising the novel peptides. The peptide compounds and compositions disclosed herein can be used as therapeutic agents for treating eye diseases. When applied to the eyes, the peptide compounds and compositions disclosed herein increase tear secretion and promote the recovery of damaged corneas.

Description

[0001] Related applications

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62 / 767,180, filed on November 14, 2018; the contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to peptides and pharmaceutical compositions for treating eye diseases. Background Art

[0004] Dry eye syndrome or keratoconjunctivitis sicca can be broadly defined 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 of dry eye syndrome is increasing in younger age groups due to long-term exposure to dry environments, such as contact lenses, computers, and smart device use (Stern ME et al., Int. Rev. Immunol., 32: 19-41, 2013).

[0005] Specifically, dry eye syndrome reduces the mucus secretion of corneal and conjunctival epithelial and mucus secretion of goblet cells that secrete mucus, causing the lubrication of the eyeball to be sharply reduced. In addition, dry eye syndrome causes damage to the corneal surface, thereby increasing the penetration of fluorescein dye into the cornea. These symptoms of dry eye syndrome can be evaluated as changes in tear secretion by using the Schirmer test of cobalt chloride paper. In addition, the corneal damage that can be accompanied by dry eye syndrome can be easily evaluated using general fluorescent dyes and slit lamp fluorophotometers.

[0006] Meanwhile, most treatments for dry eye syndrome are limited to symptomatic therapy, and their therapeutic efficiency is usually very low. Currently, artificial tears are the first choice for treating dry eye syndrome. Artificial tears, as a representative symptomatic therapy, are merely a supplement to insufficient tears; in addition, their disadvantage is that they need to be frequently applied to the eyes (Kim CS et al., Nutrients 8.pii: E750, 2016). Sodium hyaluronate and eye drops derived from autologous serum have been developed and used for patients suffering from dry eye syndrome. In addition, such synthetic compounds as rebamipide (OPC-127959) and diquafosol sodium have been developed and used, and the synthetic compounds promote the secretion of tears and mucus. However, long-term use of these drugs can cause various side effects such as ocular congestion and corneal calcification (Bernauer W et al., Br. J. Ophthalmol., 90: 285-8, 2006). Therefore, it is necessary to develop a safe and effective therapeutic agent for treating dry eye syndrome. Summary of the invention

[0007] In certain aspects, the present invention provides a salt of a compound represented by formula (I):

[0008]

[0009] in:

[0010] R 1 , R 2 and R 3 each is independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl;

[0011] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0012] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0013] p is 0, 1, or 2;

[0014] R 6 is hydrogen or substituted or unsubstituted alkyl; and

[0015] R 7 , R 8 and R9 are each independently hydrogen or alkyl;

[0016] Wherein the compound is not:

[0017]

[0018] Preferably, wherein said compound comprises at least one D-amino acid residue.

[0019] In another aspect, the present invention provides a compound represented by formula (I):

[0020]

[0021] or a pharmaceutically acceptable salt thereof;

[0022] in:

[0023] R 1 , R 2 and R 3 each is independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl;

[0024] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0025] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0026] p is 0, 1, or 2;

[0027] R 6 is hydrogen or substituted or unsubstituted alkyl; and

[0028] R 7 , R 8 and R 9 are each independently hydrogen or alkyl;

[0029] At least one of the following:

[0030] (a)R 1 , R 2 and R 3 At least one of is substituted or unsubstituted (C 2 -C 10 ) haloalkyl;

[0031] (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 a 、-OR a 、-SR a 、-N(R a ) 2 、-N(R a ) 3 + , =NR a 、-NHC(=O)R c 、-C(=O)R c 、-C(=O)N(R a ) 2 、-S(=O) 2 R c 、-OS(=O) 2 OR a 、-S(=O) 2 OR a 、-S(=O) 2 N(R a ) 2 、-S(=O)R c ,-OP(=O)(OR a ) 2 , -(alkylene)-C(=O)R c 、-C(=S)R c 、-C(=O)OR a , -(alkylene)-C(=O)OR a 、-C(=S)OR a 、-C(=O)SR a 、-C(=S)SR a 、-(alkylene)-C(=O)N(R a ) 2 、-C(=S)N(R a ) 2 and -C(-NR a )N(R a ) 2 ;and

[0032] At least one occurrence of R a or R c is heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl;

[0033] (c) the compound comprises at least one D-amino acid residue; or

[0034] (d) At least two occurrences of R a ;

[0035] At least two occurrences of R c ;or

[0036] At least one occurrence of R a and at least one occurrence of R c ;and

[0037] At least one occurrence of R a and / or R c Unlike other occurrences; and

[0038] Wherein the compound is not:

[0039]

[0040]

[0041] In some aspects, the present invention provides a compound having the following structure: or a pharmaceutically acceptable salt thereof.

[0042] In another aspect, the present invention provides a compound represented by formula (V):

[0043]

[0044] or a pharmaceutically acceptable salt thereof;

[0045] in:

[0046] R 1 and R 2 each is independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl;

[0047] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0048] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0049] p is 0, 1, or 2;

[0050] R 6 is hydrogen or substituted or unsubstituted alkyl; and

[0051] R9 is hydrogen or alkyl;

[0052] Wherein the compound is not:

[0053]

[0054] In another aspect, the present invention provides a compound represented by formula (VI):

[0055]

[0056] or a pharmaceutically acceptable salt thereof;

[0057] in:

[0058] R 1 and R 2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl

[0059] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0060] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0061] p is 0, 1, or 2;

[0062] R 6 is hydrogen or substituted or unsubstituted alkyl;

[0063] R 7 is hydrogen or alkyl; and

[0064] R 9 is hydrogen or alkyl;

[0065] Wherein the compound is not:

[0066]

[0067] In another aspect, the present invention provides a compound represented by formula (VII):

[0068]

[0069] or a pharmaceutically acceptable salt thereof;

[0070] in:

[0071] R 1 and R 2 each is independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl;

[0072] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0073] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0074] p is 0, 1, or 2;

[0075] R 6 is hydrogen or substituted or unsubstituted alkyl;

[0076] R 7 is hydrogen or alkyl; and

[0077] R 9 is hydrogen or alkyl;

[0078] Wherein the compound is not:

[0079] In another aspect, the present invention provides a compound represented by formula (IX):

[0080]

[0081] or a pharmaceutically acceptable salt thereof;

[0082] in:

[0083] R 1 and R 2 each is independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl;

[0084] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0085] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0086] p is 0, 1, or 2;

[0087] R 6 is hydrogen or substituted or unsubstituted alkyl;

[0088] R 7 , R 8 and R 9 are each independently hydrogen or alkyl;

[0089] J is OH or -NR X R y ;and

[0090] R X and R y are each independently selected from H, optionally substituted alkyl, optionally substituted alkoxyalkyl, or R X and R y Together with the intervening nitrogen atom, they form a ring.

[0091] The present invention also provides a compound represented by formula (X-am):

[0092]

[0093] or a pharmaceutically acceptable salt thereof;

[0094] in:

[0095] R 1 , R 2 and R 3 each is independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl;

[0096] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0097] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0098] p is 0, 1, or 2;

[0099] R 6 is hydrogen or substituted or unsubstituted alkyl;

[0100] R 7 , R 8 and R 9 are each independently hydrogen or alkyl;

[0101] J is OH or -NR X R y ;and

[0102] R X and R y are each independently selected from H, optionally substituted alkyl, optionally substituted alkoxyalkyl, or R X and R y Together with the intervening nitrogen atom, they form a ring.

[0103] The present invention also provides salts of the following compounds:

[0104]

[0105] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound or salt of the present invention.

[0106] The present invention also provides a method for treating an eye disease, such as an eye disease selected from retinopathy, keratitis, dry macular degeneration, wet macular degeneration, dry eye syndrome, keratoconjunctivitis sicca, and corneal conjunctival epithelial disorders, by administering a compound or salt of the present invention or a pharmaceutical composition comprising the compound or salt. BRIEF DESCRIPTION OF THE DRAWINGS

[0107] Figure 1 is a diagram showing the sequence and characteristics of a peptide prepared according to one embodiment of the present invention.

[0108] Figure 2 is a diagram illustrating a method for synthesizing a peptide prepared according to one embodiment of the present invention.

[0109] Figure 3 is a diagram showing a purification procedure of a peptide prepared according to one embodiment of the present invention.

[0110] Figure 4 are photographs illustrating the procedure for extraorbital lacrimal gland resection.

[0111] Figure 5 It is a graph showing the changes in body weight of rat models to which YDE-001 to YDE-028 had been administered to their eyes.

[0112] Figure 6 It is a graph showing the changes in body weight of rat models to which YDE-029 to YDE-043 have been administered to their eyes.

[0113] Figure 7are photographs showing the procedure of administering the agent to the eye of a rat model.

[0114] Figure 8 are photographs showing the procedure of measuring the tear secretion amount of a rat model using cobalt chloride paper.

[0115] Fig. 9 are photographs showing the results of measuring the tear secretion amount of rat models to which YDE-001 to YDE-028 had been administered to their eyes using cobalt chloride paper.

[0116] Fig.10 It is a graph showing changes in tear secretion amount of rat models to which YDE-001 to YDE-028 have been administered to their eyes.

[0117] Fig.11 are photographs showing the results of measuring the tear secretion amount of rat models to which YDE-029 to YDE-043 had been administered to their eyes using cobalt chloride paper.

[0118] Fig.12 It is a graph showing changes in tear secretion amount of rat models to which YDE-029 to YDE-043 have been administered to their eyes.

[0119] Fig.13 are photographs showing a procedure for applying a fluorescent substance to the eyes of a rat model for confirming corneal damage thereof.

[0120] Fig.14 are photographs showing the results of measuring corneal damage using a fluorescent substance in rat models to which YDE-001 to YDE-028 had been administered to their eyes.

[0121] Fig.15 is a graph showing the penetration rate of fluorescent dye to confirm the recovery of corneal damage in rat models to which YDE-001 to YDE-028 had been administered to their eyes.

[0122] Fig.16 are photographs showing the results of measuring corneal damage using a fluorescent substance in a rat model to which YDE-029 to YDE-043 had been administered to the eyes.

[0123] Fig.17 is a graph showing the penetration rate of fluorescent dye to confirm the recovery of corneal damage in rat models to which YDE-029 to YDE-043 had been administered to their eyes.

[0124] Fig.18 It is a graph showing the cell growth rate after human corneal epithelial cells of plate No. 1 were treated with hEGF for 48 hours.

[0125] Fig.19It is a graph showing the cell growth rate after human corneal epithelial cells of plate No. 2 were treated with hEGF for 48 hours.

[0126] Fig. 20 It is a graph showing the cell growth rate after human corneal epithelial cells of plate No. 3 were treated with hEGF for 48 hours.

[0127] Fig.21 It is a graph showing the cell growth rate after human corneal epithelial cells of plate No. 4 were treated with hEGF for 48 hours.

[0128] Fig. 22 It is a graph showing the cell growth rate after human corneal epithelial cells of plate No. 1 were treated with hEGF for 72 hours.

[0129] Fig.23 It is a graph showing the cell growth rate after human corneal epithelial cells of plate No. 2 were treated with hEGF for 72 hours.

[0130] Fig.24 It is a graph showing the cell growth rate after human corneal epithelial cells of plate No. 3 were treated with hEGF for 72 hours.

[0131] Fig.25 It is a graph showing the cell growth rate after human corneal epithelial cells of plate No. 4 were treated with hEGF for 72 hours.

[0132] Fig.26 are graphs showing cell growth rates of human corneal epithelial cells after YY-101 treatment for (a) 48 hours or (b) 72 hours.

[0133] Fig. 27 are graphs showing cell growth rates of human corneal epithelial cells after YY-102 treatment for (a) 48 hours or (b) 72 hours.

[0134] Fig.28 Graphs showing cell growth rate after human corneal epithelial cells were treated with YDE-011 for (a) 48 hours or (b) 72 hours.

[0135] Fig.29 are graphs showing cell growth rates of human corneal epithelial cells after YDE-038 treatment for (a) 48 hours or (b) 72 hours.

[0136] Fig.30 Graphs showing cell growth rate of human corneal epithelial cells after YDE-042 treatment for (a) 48 hours or (b) 72 hours.

[0137] Fig.31Graphs showing cell growth rate after YDE-043 treatment of human corneal epithelial cells for (a) 48 hours or (b) 72 hours.

[0138] Fig.32 Graphs showing cell growth rate of human corneal epithelial cells after YDE-044 treatment for (a) 48 hours or (b) 72 hours.

[0139] Fig.33 Graphs showing cell growth rate of human corneal epithelial cells after YDE-045 treatment for (a) 48 hours or (b) 72 hours.

[0140] Fig.34 are graphs showing cell growth rates of human corneal epithelial cells after YDE-049 treatment for (a) 48 hours or (b) 72 hours.

[0141] Fig.35 are graphs showing cell growth rates of human corneal epithelial cells after YDE-054 treatment for (a) 48 hours or (b) 72 hours.

[0142] Fig.36 Graphs showing cell growth rate of human corneal epithelial cells after YDE-057 treatment for (a) 48 hours or (b) 72 hours.

[0143] Fig.37 are graphs showing cell growth rates of human corneal epithelial cells after YDE-058 treatment for (a) 48 hours or (b) 72 hours.

[0144] Fig.38 Graphs showing cell growth rate after YDE-059 treatment of human corneal epithelial cells for (a) 48 hours or (b) 72 hours.

[0145] Fig.39 Graphs showing cell growth rate of human corneal epithelial cells after YDE-060 treatment for (a) 48 hours or (b) 72 hours.

[0146] Fig.40 are graphs showing cell growth rates of human corneal epithelial cells after YDE-072 treatment for (a) 48 hours or (b) 72 hours.

[0147] Fig.41 Graphs showing cell growth rate of human corneal epithelial cells after YDE-073 treatment for (a) 48 hours or (b) 72 hours.

[0148] Fig.42Graphs showing cell growth rate after YDE-074 treatment of human corneal epithelial cells for (a) 48 hours or (b) 72 hours.

[0149] Fig.43 are graphs showing cell growth rates of human corneal epithelial cells after YDE-075 treatment for (a) 48 hours or (b) 72 hours.

[0150] Fig.44 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-078 treatment for 48 hours and 72 hours.

[0151] Fig.45 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-080 treatment for 48 hours and 72 hours.

[0152] Fig.46 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-081 treatment for 48 hours and 72 hours.

[0153] Fig.47 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-083 treatment for 48 hours and 72 hours.

[0154] Fig.48 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-084 treatment for 48 hours and 72 hours.

[0155] Fig.49 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-086 treatment for 48 hours and 72 hours.

[0156] Fig.50 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-001 treatment for 48 hours and 72 hours.

[0157] Fig.51 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-010 treatment for 48 hours and 72 hours.

[0158] Fig.52 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-029 treatment for 48 hours and 72 hours.

[0159] Fig.53 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-092 treatment for 48 hours and 72 hours.

[0160] Fig.54is a graph showing the cell growth rate of human corneal epithelial cells after YDE-053 treatment for 48 hours and 72 hours.

[0161] Fig.55 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-064 treatment for 48 hours and 72 hours.

[0162] Fig.56 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-066 treatment for 48 hours and 72 hours.

[0163] Fig.57 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-012 treatment for 48 hours and 72 hours.

[0164] Fig.58 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-019 treatment for 48 hours and 72 hours.

[0165] Fig.59 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-055 treatment for 48 hours and 72 hours.

[0166] Fig.60 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-085 treatment for 48 hours and 72 hours.

[0167] Fig.61 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-047 treatment for 48 hours and 72 hours.

[0168] Fig.62 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-048 treatment for 48 hours and 72 hours.

[0169] Fig.63 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-050 treatment for 48 hours and 72 hours.

[0170] Fig.64 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-051 treatment for 48 hours and 72 hours.

[0171] Fig.65 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-052 treatment for 48 hours and 72 hours.

[0172] Fig.66is a graph showing the cell growth rate of human corneal epithelial cells after YDE-056 treatment for 48 hours and 72 hours.

[0173] Fig.67 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-061 treatment for 48 hours and 72 hours.

[0174] Fig.68 is a graph showing the cell growth rate of human corneal epithelial cells after YDE-062 treatment for 48 hours and 72 hours. DETAILED DESCRIPTION

[0175] 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 by Schirmer test and fluorescent dye deposition test.

[0176] When the novel peptides of the present invention are applied to the eyes, they increase tear secretion and promote the recovery of damaged corneas. Therefore, these peptides can be advantageously used as therapeutic agents for treating eye diseases.

[0177] definition

[0178] According to the rules used in the art, Used to indicate a moiety or substituent "R" attached to the backbone structure.

[0179] "Alkyl" is a hydrocarbon having primary, secondary, tertiary and / or quaternary carbon atoms, and encompasses straight chain, branched chain and cyclic groups or combinations thereof. For example, an alkyl group may have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkyl), 1 to 10 carbon atoms (i.e., C 1 -C 10 alkyl) or 1 to 6 carbon atoms (i.e., C 1 -C 6 Examples of suitable alkyl groups include methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, isopropyl, -CH (CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH2 CH 3 ), 2-methyl-1-propyl (i-Bu, isobutyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, sec-butyl, -CH (CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 )、1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 )、3-hexyl(-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3))、2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ) and octyl (-(CH 2 ) 7 CH 3 ), but are not limited to them.

[0180] "Alkoxy" refers to a group having the formula -O-alkyl, wherein the alkyl group as defined above is attached to the parent compound via an oxygen atom. The alkyl portion of the alkoxy group may have, for example, 1 to 20 carbon atoms (i.e., C 1 -C 20 alkoxy), 1 to 12 carbon atoms (i.e., C 1 -C 12 alkoxy), 1 to 10 carbon atoms (i.e., C 1 -C 10 Alkoxy) or 1 to 6 carbon atoms (i.e., C 1 -C 6 Examples of suitable alkoxy groups include methoxy (—O—CH 3 or -OMe), ethoxy (-OCH 2 CH 3 or -OEt) and tert-butyloxy (-OC(CH 3 ) 3or -O-tBu), but not limited thereto.

[0181] "Haloalkyl" is an alkyl group in which at least one hydrogen atom of the alkyl group as defined above is replaced by a halogen atom. The alkyl portion of the haloalkyl group may have 1 to 20 carbon atoms (i.e., C 1 -C 20 haloalkyl), 1 to 12 carbon atoms (i.e., C 1 -C 12 haloalkyl), 1 to 10 carbon atoms (i.e., C 1 -C 10 haloalkyl) or 1 to 6 carbon atoms (i.e., C 1 -C 6 Examples of suitable haloalkyl groups include -CF 3 , -CHF 2 , -CFH 2 and -CH 2 CF 3 , but not limited to this.

[0182] "Alkenyl" is a hydrocarbon having primary, secondary, tertiary and / or quaternary carbon atoms, and encompasses straight chain, branched chain and cyclic groups or combinations thereof, and having at least one region of unsaturation, i.e., a carbon-carbon sp 2 For example, an alkenyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 20 alkenyl), 2 to 12 carbon atoms (i.e., C 2 -C 12 alkenyl), 2 to 10 carbon atoms (i.e., C 2 -C 10 alkenyl) or 2 to 6 carbon atoms (i.e., C 2 -C 6 Examples of suitable alkenyl groups include vinyl (—CH═CH 2 ), allyl (-CH 2 CH=CH 2 ), cyclopentenyl (-C 5 H 7 ) and 5-hexenyl (-CH 2 CH 2 CH 2 CH 2 CH=CH 2 ), but are not limited to them.

[0183] "Alkynyl" is a hydrocarbon having primary, secondary, tertiary and / or quaternary carbon atoms, and encompasses straight chain, branched chain and cyclic groups or combinations thereof, and has at least one carbon-carbon sp triple bond. For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C 2 -C20 alkynyl), 2 to 12 carbon atoms (i.e., C 2 -C 12 alkynyl), 2 to 10 carbon atoms (i.e., C 2 -C 10 Alkynyl) or 2 to 6 carbon atoms (i.e., C 2 -C 6 Examples of suitable alkynyl groups include ethynyl (—C≡CH) and propargyl (—CH 2 C≡CH), but is not limited thereto.

[0184] "Alkylene" refers to a saturated hydrocarbon group that can be branched, straight chain, or cyclic (or can have a combination of branched, straight chain, or cyclic moieties) and has two valences derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of typical alkylene groups include 1,2-ethylene (-CH 2 -CH 2 -), but not limited to this.

[0185] "Alkenylene" refers to an unsaturated hydrocarbon group that may be branched, straight chain or cyclic (or may have a combination of branched, straight chain or cyclic portions) and has a valence of two derived from the same carbon atom or two different carbon atoms of a parent olefin. For example, the alkenylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of typical alkenylene groups include 1,2-vinylene (-CH=CH-), but are not limited thereto.

[0186] "Alkynylene" refers to an unsaturated hydrocarbon group that may be branched, straight chain, or cyclic (or may have a combination of branched, straight chain, or cyclic portions) and has a valence of two derived by removing 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 typical alkynylene groups include ethynylene (-C≡C-), propargylene (-CH 2 C≡C-) and 4-pentynylene (-CH 2 CH 2 CH 2 C≡C-), but not limited to this.

[0187] "Aryl" refers to an aromatic hydrocarbon group. For example, the aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Examples of typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzene, substituted or unsubstituted naphthalene, substituted or unsubstituted anthracene, and the like.

[0188] "Arylalkyl" means a radical in which one of the radicals is bonded to a carbon atom (usually a terminal or other sp 3 The 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.

[0189] "Arylalkenyl" refers to a radical in which one of the radicals is bonded to a carbon atom (usually a terminal or other sp 3 Carbon atoms, but sp 2 The arylalkenyl group may have 8 to 20 carbon atoms. For example, the alkenyl group may have 2 to 6 carbon atoms, and the aryl group may have 6 to 14 carbon atoms.

[0190] "Arylalkynyl" refers to a group in which one of the radicals is bonded to a carbon atom (usually a terminal or other sp 3 The arylalkynyl group may be a non-cyclic alkynyl group in which the hydrogen atoms of the arylalkynyl group are replaced by aryl groups. The aryl moiety of the arylalkynyl group may be, for example, any aryl group described herein, and the alkynyl moiety of the arylalkynyl group may include, for example, any alkynyl group described herein. The 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.

[0191] "Cycloalkyl" refers to a saturated monocyclic or polycyclic ring containing only carbon atoms in the ring. Cycloalkyl can have 3 to 7 carbon atoms as a monocyclic ring, 7 to 12 carbon atoms as a bicyclic ring, and up to about 20 carbon atoms as a polycyclic ring. Monocyclic cycloalkyl has 3 to 7 ring atoms, more typically 5 or 6 ring atoms. Bicyclic cycloalkyl can have 7 to 12 ring atoms and can be a fused ring system, a spirocyclic ring system or a bridged ring system. In exemplary cycloalkyls, atoms can be arranged in a bicyclic [4,5], [5,5], [5,6] or [6,6] system. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl (each of which can be substituted or unsubstituted).

[0192] The term "substituted" with respect to alkyl, alkylene, aryl, arylalkyl, heterocyclyl, and the like, such as "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 independently replaced with a non-hydrogen substituent. Examples of typical substituents include halo, haloalkyl, oxo, -CN, -NO, -NH ... 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(=O) 2 R, -OS(=O) 2 OR, -S(=O) 2 OR, -S(=O) 2 N(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 heterocyclic, but is not limited thereto. Alkylene, alkenylene and alkynylene may also be substituted similarly.

[0193] Those skilled in the art will understand that when moieties such as "alkyl", "aryl", "heterocyclyl", etc. are substituted with at least one substituent, they may optionally be referred to as moieties of "alkylene", "arylene", "heterocyclyl", etc. (i.e., at least one hydrogen atom of the parent "alkyl", "aryl", or "heterocyclyl" moiety is replaced with a substituent as described herein). If moieties of "alkyl", "aryl", "heterocyclyl", etc. are described herein as "substituted" or depicted in the drawings as substituted (or optionally substituted, e.g., the number of substituents is 0 or a positive number), the terms "alkyl", "aryl", "heterocyclyl", etc. should be understood to be interchangeable with "alkylene", "arylene", "heterocyclyl", etc.

[0194] Those skilled in the art will recognize that the substituents and other moieties of the compounds of Formula I should be selected so as to provide sufficiently stable compounds as pharmaceutically useful compounds that can be formulated into acceptably stable pharmaceutical compositions. Compounds of Formula I having such stability should be understood to be within the scope of the present invention.

[0195] "Heteroalkyl" refers to an alkyl group in which at least one carbon atom is replaced with a heteroatom such as O, N or S. For example, if a carbon atom of an alkyl group attached to the parent molecule is replaced with a heteroatom (e.g., O, N or S), the resulting heteroalkyl group can be an alkoxy group (e.g., -OCH 3 ), amino groups (e.g., -NHCH 3 、-N(CH 3 ) 2 etc.) or thioalkyl (e.g., -SCH 3 If a non-terminal carbon atom of an alkyl group not attached to the parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group may be an alkyl ether (e.g., -CH 2 CH 2 -O-CH 3 etc.), alkylamines (e.g., -CH 2 NHCH 3 、-CH 2 N(CH 3 ) 2 etc.) or thioalkyl ethers (e.g., -CH 2 -S-CH 3 If the terminal carbon atom of an alkyl group is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group may be a hydroxyalkyl group (e.g., -CH 2 CH 2 -OH), aminoalkyl (e.g., -CH 2 NH 2 ) or an alkylthiol group (e.g., -CH 2 CH 2 -SH). For example, the heteroalkyl group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Preferably, the heteroalkyl group has 2 to 20, 2 to 10, or 2 to 6 total atoms (i.e., carbon atoms plus bound heteroatoms) in the chain. 1 -C 6 The heteroalkyl group refers to a heteroalkyl group having 1 to 6 carbon atoms.

[0196] As used herein, "heterocycle" or "heterocyclyl" includes those described in literature such as Paquette, Leo A., Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), specifically Chapter 1, Chapter 3, Chapter 4, Chapter 6, Chapter 7 and Chapter 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, 1950 to date), specifically Volume 13, Volume 14, Volume 16, Volume 19 and Volume 28; and J. Am. Chem. Soc. (1960) 82: 5566, but is not limited thereto. In a specific embodiment of the present invention, "heterocycle" includes carbocyclic rings as defined herein, wherein at least one (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., O, N or S). The term "heterocycle" or "heterocyclyl" includes saturated rings, partially unsaturated rings, and aromatic rings (ie, heteroaromatic rings). Substituted heterocycles include, for example, heterocycles substituted with any of the substituents disclosed herein, including carbonyl.

[0197] Exemplary heterocycles include pyridinyl, dihydropyridinyl, tetrahydropyridinyl (piperidinyl), thiazolyl, tetrahydrothiophenyl, thiooxytetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thiaindenyl, indolyl, indolene, quinolyl, isoquinolyl, benzimidazolyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydro furanyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, azocyclyl, triazine, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthene, phenoxathiophene, inyl), 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl (phenaziny l), 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 are not limited thereto.

[0198] As an example, the carbon-bonded heterocycle can be bonded to the 2, 3, 4, 5, or 6 position of pyrazine, the 3, 4, 5, or 6 position of pyridazine, the 2, 4, 5, or 6 position of pyrimidine, the 2, 3, 5, or 6 position of pyrazine, the 2, 3, 4, or 5 position of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, the 2, 4, or 5 position of oxazole, imidazole, or thiazole, the 3, 4, or 5 position of isoxazole, pyrazole, or isothiazole, the 2 or 3 position of aziridine, the 2, 3, or 4 position of azetidine, the 2, 3, 4, 5, 6, 7, or 8 position of quinoline, or the 1, 3, 4, 5, 6, 7, or 8 position of isoquinoline, but is not limited thereto. More typically, examples of carbon-bonded heterocycles 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).

[0199] As an example, the nitrogen-bonded heterocycle may be bonded to 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, the 2-position of isoindole or isoindoline, the 4-position of morpholine and the 9-position of carbazole or β-carboline (each of which may be substituted or unsubstituted), but is not limited thereto. More typically, examples of nitrogen-bonded heterocycles include 1-aziridinyl, 1-azetidinyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl (each of which may be substituted or unsubstituted).

[0200] "Heterocyclylalkyl" refers to a non-cyclic alkyl group (i.e., a heterocyclyl-alkylene moiety) in which one hydrogen atom bonded to a carbon atom (typically a terminal or spw carbon atom) is replaced with a heterocyclyl group. Examples of typical heterocyclylalkyl groups include heterocyclyl-CH 2 -, 2-(heterocyclyl) ethyl-1-yl, etc., but are not limited thereto. Its "heterocyclyl" part used herein includes those heterocyclyls described in the literature such as "Principles of Modern Heterocyclic Chemistry" and any heterocyclyl described above. It will be understood by those skilled in the art that if the resulting group is chemically stable, the heterocyclyl can be connected to the alkyl portion of the heterocyclylalkyl via a carbon-carbon bond or a carbon-heteroatom bond. The heterocyclylalkyl can have 2 to 20 carbon atoms. For example, the alkyl portion of the heterocyclylalkyl can have 1 to 6 carbon atoms, and its heterocyclyl moiety can have 2 to 14 carbon atoms. Examples of heterocyclylalkyl groups include 5-membered heterocyclic rings containing sulfur, oxygen and / or nitrogen, such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, and the like; and 6-membered heterocyclic rings containing sulfur, oxygen and / or nitrogen, such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, and the like (each of which may be substituted or unsubstituted), but are not limited thereto.

[0201] "Heterocyclylalkenyl" refers to a heterocyclyl radical in which one of the radicals is bonded to a carbon atom (usually a terminal or sp 3 Carbon atoms, but sp 2The non-cyclic alkenyl (i.e., heterocyclyl-alkenylene moiety) in which the hydrogen atom (carbon atom) of the heterocyclyl alkenyl group is replaced by a heterocyclyl group. The heterocyclyl moiety of the heterocyclyl alkenyl group includes those heterocyclyl groups described in the literature such as "Principles of Modern Heterocyclic Chemistry" and any heterocyclyl group described above. The alkenyl moiety of the heterocyclyl alkenyl group includes any alkenyl group described herein. It will be appreciated by those skilled in the art that if the resulting group is chemically stable, the heterocyclyl group can be connected to the alkenyl moiety of the heterocyclyl alkenyl group via a carbon-carbon bond or a carbon-heteroatom bond. The heterocyclyl alkenyl group can have 3 to 20 carbon atoms. For example, the alkenyl moiety of the heterocyclyl alkenyl group can have 2 to 6 carbon atoms, and its heterocyclyl moiety can have 2 to 14 carbon atoms.

[0202] "Heterocyclylalkynyl" refers to a group in which one of the radicals is bonded to a carbon atom (usually a terminal or sp 3 The non-cyclic alkynyl (i.e., heterocyclyl-alkynylene moiety) in which the hydrogen atom of the heterocyclyl alkynyl group is replaced by a heterocyclyl group (i.e., sp carbon atoms, but sp carbon atoms can also be used). The heterocyclyl moiety of the heterocyclyl alkynyl group includes those heterocyclyl groups described in the literature such as "Principles of Modem Heterocyclic Chemistry" and any heterocyclyl group described above. The alkynyl moiety of the heterocyclyl alkynyl group includes any alkynyl group described herein. It will be appreciated by those skilled in the art that if the resulting group is chemically stable, the heterocyclyl group can be connected to the alkynyl moiety of the heterocyclyl alkynyl group via a carbon-carbon bond or a carbon-heteroatom bond. The heterocyclyl alkynyl group can have 3 to 20 carbon atoms. For example, the alkynyl moiety of the heterocyclyl alkynyl group can have 2 to 6 carbon atoms, and its heterocyclyl moiety can have 2 to 14 carbon atoms.

[0203] "Heteroaryl" refers to an aromatic heterocyclic group containing at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that may be contained in the aromatic ring include oxygen, sulfur and nitrogen. Non-limiting examples of heteroaromatic rings include all those listed in the definition of "heterocyclic group" herein, including pyridyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, furyl, thienyl, benzofuranyl, benzothienyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazolyl, etc. (each of which may be substituted or unsubstituted).

[0204] "Carbocycle" or "carbocyclyl" refers to a saturated ring, partially unsaturated ring or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicyclic ring and up to about 20 carbon atoms as a polycyclic ring. Monocyclic carbocycles have 3 to 7 ring atoms, more typically 5 or 6 ring atoms. Bicyclic cycloalkyls may have 7 to 12 ring atoms and may be a fused ring system, a spirocyclic system or a bridged ring system. In exemplary cycloalkyls, atoms are arranged in a bicyclic [4,5], [5,5], [5,6] or [6,6] system. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl (each of which may be substituted or unsubstituted).

[0205] "Acyl" refers to -C(=O)-alkyl, -C(=O)-carbocycle (which may be substituted or unsubstituted), and -C(=O)-heterocycle (which may be substituted or unsubstituted), wherein the alkyl, carbocycle or heterocycle portion is as defined herein. Non-limiting examples of "acyl" include -C(=O)CH 3 、-C(=O)CH 2 CH 3 、-C(=O)CH(CH 3 ) 2 、-C(=O)C(CH 3 ) 3 , -C(=O)-phenyl (which may be substituted or unsubstituted), -C(=O)-cyclopropyl (which may be substituted or unsubstituted), -C(=O)-cyclobutyl (which may be substituted or unsubstituted), -C(=O)-cyclopentyl (which may be substituted or unsubstituted), -C(=O)-cyclohexyl (which may be substituted or unsubstituted) and -C(=O)-pyridinyl (which may be substituted or unsubstituted).

[0206] "Arylheteroalkyl" refers to a heteroalkyl group as defined herein in which a hydrogen atom (which may be attached to 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 a heteroatom of the heteroalkyl group. For example, an arylheteroalkyl group may have the formula: -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, etc. In addition, any alkylene moiety in the above formula may be further substituted by any of the substituents defined or exemplified herein.

[0207] "Heteroarylalkyl" refers to an alkyl group, as defined herein, in which a hydrogen atom is replaced by a heteroaryl group, as defined herein. Non-limiting examples of heteroarylalkyl groups include -CH 2 -pyridyl, -CH 2 -pyrrolyl, -CH 2 -oxazolyl, -CH2 -Indolyl, -CH 2 -isoindolyl, -CH 2 -furanyl, -CH 2 -thienyl, -CH 2 -Benzofuryl, -CH 2 -Benzothienyl, -CH 2 -Carbazolyl, -CH 2 -Imidazole, -CH 2 -thiazolyl, -CH 2 -isoxazolyl, -CH 2 -pyrazolyl, -CH 2 -isothiazolyl, -CH 2 -Quinolinyl, -CH 2 -isoquinolyl, -CH 2 -pyridazinyl, -CH 2 -pyrimidinyl, -CH 2 -pyrazolyl, -CH(CH 3 )-pyridyl, -CH(CH 3 )-pyrrolyl, -CH(CH 3 )-oxazolyl, -CH(CH 3 )-indolyl, -CH(CH 3 )-isoindolyl, -CH(CH 3 )-furanyl, -CH(CH 3 )-thienyl, -CH(CH 3 )-benzofuranyl, -CH(CH 3 )-benzothienyl, -CH(CH 3 )-carbazolyl, -CH(CH 3 )-imidazolyl, -CH(CH 3 )-thiazolyl, -CH(CH 3 )-isoxazolyl, -CH(CH 3 )-pyrazolyl, -CH(CH 3 )-isothiazolyl, -CH(CH 3 )-quinolinyl, -CH(CH 3 )-isoquinolinyl, -CH(CH 3 )-pyridazinyl, -CH(CH 3 )-pyrimidinyl, -CH(CH 3 )-pyrazolyl, etc.

[0208] "Siloxy" refers to the group -O-SiR 3 , wherein each R is independently an alkyl, aryl (which may be substituted or unsubstituted) or heteroaryl (which may be substituted or unsubstituted). Non-limiting examples of siloxy groups include -O-Si(CH 3 )3 、-O-Si(CH 3 ) 2 tBu, -O-Si(tBu) 2 CH 3 、-O-Si(tBu) 3 、-O-Si(CH 3 ) 2 Ph, -O-Si(Ph) 2 CH 3 and-O-Si(Ph) 3 .

[0209] The term "optionally substituted" refers to a particular moiety of a compound of Formula I (eg, optionally substituted aryl) optionally having one, two, or more substituents.

[0210] The term "ester thereof" refers to any ester of a compound in which any -COOH functional group of the molecule is modified to a -COOR functional group or any -OH functional group of the molecule is modified to -OC(=O)R. Here, the R portion of the ester can be any carbon-containing group that forms a stable ester portion, including but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl and substituted derivatives thereof. Examples of esters may also include esters of "tautomeric enols" as described below (such as those described above).

[0211] Compounds of the present invention

[0212] In certain embodiments, the present invention provides a salt of a compound represented by formula (I):

[0213]

[0214] in:

[0215] R 1 , R 2 and R 3 each is independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl;

[0216] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0217] R bis a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0218] p is 0, 1, or 2;

[0219] R 6 is hydrogen or substituted or unsubstituted alkyl; and

[0220] R 7 , R 8 and R 9 are each independently hydrogen or alkyl;

[0221] Wherein the compound is not:

[0222]

[0223] Preferably, wherein said compound comprises at least one D-amino acid residue.

[0224] In certain embodiments, R 1 , R 2 and R 3 are each independently H or substituted or unsubstituted alkyl, arylalkyl or heterocyclylalkyl;

[0225] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, oxo, hydroxy, -OR b , hydroxyalkyl, -CH 2 OR b and halogen groups;

[0226] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0227] R 6 is hydrogen or substituted or unsubstituted alkyl; and

[0228] R 7 , R 8 and R 9 Each is independently hydrogen or alkyl.

[0229] In some embodiments, when indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, haloalkyl, oxo, -CN, -NO, - 2 , =N-OH, -N 3 , -R a 、-OR a 、-SR a 、-N(R a ) 2、-N(R a ) 3 + , =NR a 、-NHC(=O)R c 、-C(=O)R c 、-C(=O)N(R a ) 2 、-S(=O) 2 R c 、-OS(=O) 2 OR a 、-S(=O) 2 OR a 、-S(=O) 2 N(R a ) 2 、-S(=O)R c ,-OP(=O)(OR a ) 2 , -(alkylene)-C(=O)R c 、-C(=S)R c 、-C(=O)OR a , -(alkylene)-C(=O)OR a 、-C(=S)OR a 、-C(=O)SR a 、-C(=S)SR a 、-(alkylene)-C(=O)N(R a ) 2 、-C(=S)N(R a ) 2 and -C(-NR a )N(R a ) 2 ;

[0230] R a is independently at each occurrence hydrogen or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl; and

[0231] R c is independently at each occurrence substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl.

[0232] In more specific embodiments, when indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, haloalkyl, oxo, -R a 、-OR a、-N(R a ) 2 、-N(R a ) 3 + 、-NHC(=O)R c 、-C(=O)R c 、-C(=O)N(R a ) 2 、-C(=O)OR a , -(alkylene)-C(=O)OR a and -(alkylene)-C(=O)N(R a ) 2 ;

[0233] R a is independently at each occurrence hydrogen or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl; and

[0234] R c is independently at each occurrence substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl.

[0235] In certain embodiments, R a is independently at each occurrence hydrogen, alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl; and R c is independently at each occurrence alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl.

[0236] In certain embodiments, the compound has the structure of Formula (I-10L):

[0237]

[0238] Alternatively, the compound may have the structure of Formula (I-10D):

[0239]

[0240] In certain embodiments, R 1 It is a substituted or unsubstituted alkyl group, arylalkyl group or heterocyclylalkyl group.

[0241] More specifically, R 1 can be selected from substituted or unsubstituted alkyl,

[0242] R a is hydrogen or alkyl; and

[0243] n is an integer of 1 to 10, preferably 1-5, more preferably 1-3.

[0244] Example R 1 Groups include

[0245] In some preferred embodiments, R 1 yes In an alternative preferred embodiment, R 1 yes

[0246] In certain embodiments, the compound has the structure of Formula (I-1L):

[0247]

[0248] Alternatively, the compound may have the structure of formula (I-1D)

[0249]

[0250] In certain embodiments, R 2 is H or substituted or unsubstituted alkyl, arylalkyl or heterocyclylalkyl.

[0251] In some embodiments, R 2 is selected from hydrogen, substituted or unsubstituted alkyl,

[0252]

[0253] R a is hydrogen or alkyl; and

[0254] n is an integer of 1 to 10, preferably 1-5, more preferably 1-3.

[0255] Example R 2 Groups include

[0256] Preferably, R 2 It's hydrogen.

[0257] In certain embodiments, the compound has the structure of Formula (I-2L):

[0258]

[0259] Alternatively, the compound may have the structure of Formula (I-2D):

[0260]

[0261] In certain embodiments, R 3 is a substituted or unsubstituted alkyl or arylalkyl group.

[0262] In some embodiments, R 3 is selected from substituted or unsubstituted alkyl,

[0263]

[0264] R a is hydrogen or alkyl; and

[0265] n is an integer of 1 to 10, preferably 1-5, more preferably 1-3.

[0266] Example R 3 Groups include Preferably, R 3 yes

[0267] In certain embodiments, the compound has the structure of Formula (I-3L):

[0268]

[0269] Alternatively, the compound may have the structure of Formula (I-3D):

[0270]

[0271] In certain embodiments, p is 1 or 2; and R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, -OR b 、-CH 2 OR b , halo, hydroxy and hydroxyalkyl.

[0272] In certain embodiments, p is 1 or 2; and R 4 is independently selected at each occurrence from -CH 3 , halo, hydroxy and hydroxyalkyl.

[0273] In certain preferred embodiments, R 4 In an alternative preferred embodiment, R 4 Yes-CH 3 .

[0274] In any of the above embodiments, p may be 1.

[0275] In certain embodiments, the compound has the structure of Formula (I-4Lg):

[0276]

[0277] In certain embodiments, the compound has the structure of Formula (I-4La):

[0278]

[0279] In certain embodiments, the compound has the structure of Formula (I-4Lb):

[0280]

[0281] In certain embodiments, the compound has the structure of Formula (I-4Lc):

[0282]

[0283] The prerequisite is R 4 Not hydroxyl.

[0284] In certain embodiments, the compound has the structure of Formula (I-4Dg):

[0285]

[0286] In certain embodiments, the compound has the structure of Formula (I-4Da):

[0287]

[0288] In certain embodiments, the compound has the structure of Formula (I-4Db):

[0289]

[0290] In certain embodiments, the compound has the structure of Formula (I-4Dc):

[0291]

[0292] The prerequisite is R 4 Not hydroxyl.

[0293] In certain embodiments, R 4 It is an oxo group.

[0294] In certain embodiments, the compound has the structure of Formula (I-4Ld):

[0295]

[0296] In certain embodiments, the compound has the structure of Formula (I-4Le):

[0297]

[0298] In certain embodiments, the compound has the structure of Formula (I-4Dd):

[0299]

[0300] In certain embodiments, the compound has the structure of Formula (I-4De):

[0301]

[0302] In certain embodiments, R 6 is hydrogen or alkyl, wherein the alkyl is optionally replaced by one occurrence of -C(=O)NH 2 In certain embodiments, wherein R 6 is optionally replaced by one occurrence of -C(=O)NH 2 Substituted alkyl. For example, R 6 Can be -CH 3 Or, R 6 Can be

[0303] In certain embodiments, the compound has the structure of Formula (I-6L):

[0304]

[0305] Alternatively, the compound may have the structure of Formula (I-6D):

[0306]

[0307] In certain embodiments, R 7 Yes (C 1 -C 10 ) alkyl, preferably

[0308] In certain embodiments, the compound has the structure of Formula (I-7L):

[0309]

[0310] Alternatively, the compound may have the structure of Formula (I-7D):

[0311]

[0312] In certain embodiments, the compound has the structure of Formula (I-11L):

[0313]

[0314] Alternatively, the compound may have the structure of Formula (I-11D):

[0315]

[0316] In certain embodiments, R 8 Yes-CH 3 or -H, preferably -H.

[0317] In certain embodiments, R 9 Yes-CH 3 or -H, preferably -H.

[0318] 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.

[0319] In certain embodiments, the present invention provides a salt of a compound of formula (I), wherein the compound is selected from:

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332] The present invention also provides a compound represented by formula (I):

[0333]

[0334] or a pharmaceutically acceptable salt thereof;

[0335] in:

[0336] R 1 , R 2 and R3 each is independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl;

[0337] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0338] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0339] p is 0, 1, or 2;

[0340] R 6 is hydrogen or substituted or unsubstituted alkyl; and

[0341] R 7 , R 8 and R 9 are each independently hydrogen or alkyl;

[0342] At least one of the following:

[0343] (a)R 1 , R 2 and R 3 At least one of is substituted or unsubstituted (C 2 -C 10 ) haloalkyl;

[0344] (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 a 、-OR a 、-SR a 、-N(R a ) 2 、-N(R a ) 3 + , =NR a 、-NHC(=O)R c 、-C(=O)R c 、-C(=O)N(R a ) 2 、-S(=O) 2 R c 、-OS(=O) 2 ORa 、-S(=O) 2 OR a 、-S(=O) 2 N(R a ) 2 、-S(=O)R c ,-OP(=O)(OR a ) 2 , -(alkylene)-C(=O)R c 、-C(=S)R c 、-C(=O)OR a , -(alkylene)-C(=O)OR a 、-C(=S)OR a 、-C(=O)SR a 、-C(=S)SR a 、-(alkylene)-C(=O)N(R a ) 2 、-C(=S)N(R a ) 2 and -C(-NR a )N(R a ) 2 ;and

[0345] At least one occurrence of R a or R c is heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl;

[0346] (c) the compound comprises at least one D-amino acid residue; or

[0347] (d) At least two occurrences of R a ;

[0348] At least two occurrences of R c ;or

[0349] At least one occurrence of R a and at least one occurrence of R c ;and

[0350] At least one occurrence of R a and / or R c Unlike other occurrences; and

[0351] Wherein the compound is not:

[0352]

[0353]

[0354] In certain embodiments, R 1 , R2 and R 3 At least one of is substituted or unsubstituted (C 2 -C 10 ) haloalkyl.

[0355] 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 a 、-OR a 、-SR a 、-N(R a ) 2 、-N(R a ) 3 + , =NR a 、-NHC(=O)R c 、-C(=O)R c 、-C(=O)N(R a ) 2 、-S(=O) 2 R c 、-OS(=O) 2 OR a 、-S(=O) 2 OR a 、-S(=O) 2 N(R a ) 2 、-S(=O)R c ,-OP(=O)(OR a ) 2 , -(alkylene)-C(=O)R c 、-C(=S)R c 、-C(=O)OR a , -(alkylene)-C(=O)OR a 、-C(=S)OR a 、-C(=O)SR a 、-C(=S)SR a 、-(alkylene)-C(=O)N(R a ) 2 、-C(=S)N(R a ) 2 and -C(-NR a )N(R a ) 2 ; and at least one occurrence of R a or R c It is heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl.

[0356] In certain embodiments, the compound comprises at least one D-amino acid residue.

[0357] In certain embodiments, the compound has:

[0358] At least two occurrences of R a ;

[0359] At least two occurrences of R c ;or

[0360] At least one occurrence of R a and at least one occurrence of R c ;and

[0361] At least one occurrence of R a and / or R c Different from other appearances.

[0362] In certain embodiments:

[0363] R 1 , R 2 and R 3 are each independently H or substituted or unsubstituted alkyl, arylalkyl or heterocyclylalkyl;

[0364] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, oxo, hydroxy, -OR b , hydroxyalkyl, -CH 2 OR b and halogen groups;

[0365] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0366] R 6 is hydrogen or substituted or unsubstituted alkyl; and

[0367] R 7 , R 8 and R 9 Each is independently hydrogen or alkyl.

[0368] In some embodiments, when indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, haloalkyl, oxo, -CN, -NO, - 2 , =N-OH, -N 3 , -R a 、-OR a 、-SR a 、-N(Ra ) 2 、-N(R a ) 3 + , =NR a 、-NHC(=O)R c 、-C(=O)R c 、-C(=O)N(R a ) 2 、-S(=O) 2 R c 、-OS(=O) 2 OR a 、-S(=O) 2 OR a 、-S(=O) 2 N(R a ) 2 、-S(=O)R c ,-OP(=O)(OR a ) 2 , -(alkylene)-C(=O)R c 、-C(=S)R c 、-C(=O)OR a , -(alkylene)-C(=O)OR a 、-C(=S)OR a 、-C(=O)SR a 、-C(=S)SR a 、-(alkylene)-C(=O)N(R a ) 2 、-C(=S)N(R a ) 2 and -C(-NR a )N(R a ) 2 ;

[0369] R a is independently at each occurrence hydrogen or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl; and

[0370] R c is independently at each occurrence substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl.

[0371] In more specific embodiments, when indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, haloalkyl, oxo, -Ra 、-OR a 、-N(R a ) 2 、-N(R a ) 3 + 、-NHC(=O)R c 、-C(=O)R c 、-C(=O)N(R a ) 2 、-C(=O)OR a , -(alkylene)-C(=O)OR a and -(alkylene)-C(=O)N(R a ) 2 ;

[0372] R a is independently at each occurrence hydrogen or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl; and

[0373] R c is independently at each occurrence substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl.

[0374] In certain embodiments, R a is independently at each occurrence hydrogen, alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl; and R c is independently at each occurrence alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl.

[0375] In certain embodiments, the compound has the structure of Formula (I-10L):

[0376]

[0377] Alternatively, the compound may have the structure of Formula (I-10D):

[0378]

[0379] In certain embodiments, R 1 is substituted or unsubstituted (C 2 -C 10 ) haloalkyl.

[0380] In certain embodiments, R 1 It is a substituted or unsubstituted alkyl group, arylalkyl group or heterocyclylalkyl group.

[0381] More specifically, R 1 can be selected from substituted or unsubstituted alkyl,

[0382]

[0383] R a is hydrogen or alkyl; and

[0384] n is an integer of 1 to 10, preferably 1-5, more preferably 1-3.

[0385] Example R 1 Groups include

[0386]

[0387] In certain embodiments, the compound has the structure of Formula (I-1L):

[0388]

[0389] Alternatively, the compound may have the structure of formula (I-1D)

[0390]

[0391] In certain embodiments, R 2 is substituted or unsubstituted (C 2 -C 10 ) haloalkyl.

[0392] In certain embodiments, R 2 is H or substituted or unsubstituted alkyl, arylalkyl or heterocyclylalkyl.

[0393] In some embodiments, R 2 is selected from hydrogen, substituted or unsubstituted alkyl,

[0394]

[0395] R a is hydrogen or alkyl; and

[0396] n is an integer of 1 to 10, preferably 1-5, more preferably 1-3.

[0397] Exemplary R2 groups include

[0398] Preferably, R 2 It's hydrogen.

[0399] In certain embodiments, the compound has the structure of Formula (I-2L):

[0400] Alternatively, the compound may have the structure of Formula (I-2D):

[0401]

[0402]

[0403] In certain embodiments, R 3 is substituted or unsubstituted (C 2 -C 10 ) haloalkyl.

[0404] In certain embodiments, R 3 is a substituted or unsubstituted alkyl or arylalkyl group.

[0405] In some embodiments, R 3 is selected from substituted or unsubstituted alkyl,

[0406]

[0407] R a is hydrogen or alkyl; and

[0408] n is an integer of 1 to 10, preferably 1-5, more preferably 1-3.

[0409] Example R 3 Groups include Preferably, R 3 yes

[0410] In certain embodiments, the compound has the structure of Formula (I-3L):

[0411]

[0412] Alternatively, the compound may have the structure of Formula (I-3D):

[0413]

[0414] In certain embodiments, p is 1 or 2; and R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, -OR b 、-CH 2 OR b , halo, hydroxy and hydroxyalkyl.

[0415] In certain embodiments, p is 1 or 2; and R4 is independently selected at each occurrence from -CH 3 , halo, hydroxy and hydroxyalkyl.

[0416] In certain preferred embodiments, R 4 In an alternative preferred embodiment, R 4 Yes-CH 3 .

[0417] In any of the above embodiments, p may be 1.

[0418] In certain embodiments, the compound has the structure of Formula (I-4Lg):

[0419]

[0420] In certain embodiments, the compound has the structure of Formula (I-4La):

[0421]

[0422] In certain embodiments, the compound has the structure of Formula (I-4Lb):

[0423]

[0424] In certain embodiments, the compound has the structure of Formula (I-4Lc):

[0425]

[0426]

[0427] The prerequisite is R 4 Not hydroxyl.

[0428] In certain embodiments, the compound has the structure of Formula (I-4Dg):

[0429]

[0430] In certain embodiments, the compound has the structure of Formula (I-4Da):

[0431]

[0432] In certain embodiments, the compound has the structure of Formula (I-4Db):

[0433]

[0434] In certain embodiments, the compound has the structure of Formula (I-4Dc):

[0435]

[0436] The prerequisite is R 4 Not hydroxyl.

[0437] In certain embodiments, R 4 It is an oxo group.

[0438] In certain embodiments, the compound has the structure of Formula (I-4Ld):

[0439] In certain embodiments, the compound has the structure of Formula (I-4Le):

[0440]

[0441] In certain embodiments, the compound has the structure of Formula (I-4Dd):

[0442]

[0443] In certain embodiments, the compound has the structure of Formula (I-4De):

[0444]

[0445] In certain embodiments, R 6 is hydrogen or alkyl, wherein the alkyl is optionally replaced by one occurrence of -C(=O)NH 2 In certain embodiments, wherein R 6 is optionally replaced by one occurrence of -C(=O)NH 2 Substituted alkyl. For example, R 6 Can be -CH 3 Or, R 6 Can be

[0446] In certain embodiments, the compound has the structure of Formula (I-6L):

[0447]

[0448] Alternatively, the compound may have the structure of Formula (I-6D):

[0449]

[0450] In certain embodiments, R 7 Yes (C 1 -C 10 ) alkyl, preferably

[0451] In certain embodiments, the compound has the structure of Formula (I-7L):

[0452]

[0453] Alternatively, the compound may have the structure of Formula (I-7D):

[0454]

[0455] In certain embodiments, the compound has the structure of Formula (I-11L):

[0456]

[0457] Alternatively, the compound may have the structure of Formula (I-11D):

[0458]

[0459] In certain embodiments, R 8 Yes-CH 3 or -H, preferably -H.

[0460] In certain embodiments, R 9 Yes-CH 3 or -H, preferably -H.

[0461] In certain embodiments, the compound is

[0462] or a pharmaceutically acceptable salt thereof.

[0463] 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;

[0464] or a pharmaceutically acceptable salt and / or stereoisomer thereof;

[0465] wherein Xaa is selected from the group consisting of Glu, Asn, Gln, His, Lys, Ser, Thr, Ala, Val, He, Leu, Phe, Tyr, Trp, HoSer, Asp(Me) and Asn(Me); and

[0466] At least one amino acid residue in the peptide is a D-amino acid residue.

[0467] In certain 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.

[0468] The peptide may be a variant of a peptide derived from type II collagen α1. Type II collagen α1 may be isolated from an extracellular matrix derived from animal chondrocytes.

[0469] The term "peptide" used in the present invention refers to a compound in which two or more amino acids are connected by a peptide bond. In addition, it is classified into dipeptides, tripeptides, tetrapeptides, etc. according to the number of constituent amino acids. Oligopeptides have about 10 or less peptide bonds, and polypeptides have multiple peptide bonds. In addition, the peptide in the present invention includes mutant peptides in which its amino acid residues are substituted.

[0470] 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 position 4 of proline. 5 H 9 NO 3 The structure of and can be depicted as follows: HyP may include all isomers. In addition, unless otherwise specified, HyP may be an isomer represented by a stereochemistry of "2S, 4R".

[0471] The term "homoSer" used in the present invention is called homoserine and refers to an α-amino acid having a hydroxyl group in the side chain. HomoSer is an intermediate present in the biosynthesis of threonine and methionine in microorganisms and plants. HomoSer can be depicted as follows:

[0472] The term "Asp(Me)" used in the present invention indicates that the hydrogen atom of the hydroxyl group (OH) bonded to the carbon atom at position 4 of aspartic acid is replaced by a methyl group (CH 3 ) substituted amino acid. Asp(Me) can be depicted as follows:

[0473] The term "Asn(Me)" used in the present invention refers to an amino group (NH 2 ) is replaced by a methyl group (CH 3 ) substituted amino acid. Asn(Me) can be depicted as follows:

[0474] The term "(N-Me)Gly" used in the present invention refers to an amino group (NH 2 ) is replaced by a methyl group (CH 3 ) substituted amino acid. (N-Me)Gly can be depicted as follows:

[0475] 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;

[0476] or a pharmaceutically acceptable salt and / or stereoisomer thereof;

[0477] wherein Xaa is selected from the group consisting of Val, He, Leu, Ala, Phe, Tyr, Trp, Ser, Thr, and (N-Me)Gly; and

[0478] At least one amino acid residue in the peptide is a D-amino acid residue.

[0479] In certain 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.

[0480] 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;

[0481] or a pharmaceutically acceptable salt and / or stereoisomer thereof;

[0482] wherein Xaa is selected from the group consisting of Tyr, Leu, Glu, Gln, Ala and Nle(6-OH); and

[0483] At least one amino acid residue in the peptide is a D-amino acid residue.

[0484] In certain 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.

[0485] 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;

[0486] or a pharmaceutically acceptable salt and / or stereoisomer thereof;

[0487] wherein Xaa is selected from:

[0488]

[0489] and

[0490] At least one amino acid residue in the peptide is a D-amino acid residue.

[0491] In certain 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.

[0492] In certain embodiments, the present invention provides a compound having the following structure: or a pharmaceutically acceptable salt thereof.

[0493] In certain embodiments, the present invention provides a compound represented by formula (V):

[0494]

[0495] or a pharmaceutically acceptable salt thereof;

[0496] in:

[0497] R 1 and R 2 each is independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl;

[0498] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0499] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0500] p is 0, 1, or 2;

[0501] R 6 is hydrogen or substituted or unsubstituted alkyl; and

[0502] R 9 is hydrogen or alkyl;

[0503] Wherein the compound is not:

[0504]

[0505] In certain embodiments, R 1 and R 2 are each independently H or substituted or unsubstituted alkyl;

[0506] R 4 In every occurrence it is hydroxyl;

[0507] p is 1;

[0508] R 6 is optionally replaced by one occurrence of -C(=O)NH 2 substituted alkyl; and

[0509] R 9 It's hydrogen.

[0510] In certain embodiments, R 1 is a substituted or unsubstituted alkyl group, such as

[0511] In certain embodiments, the compound has the structure of Formula (V-1L)

[0512]

[0513] Alternatively, the compound may have the structure of formula (V-1D)

[0514]

[0515] In certain embodiments, R 2 It's H.

[0516] In certain embodiments, p is 1 and R 4 It's a hydroxyl group.

[0517] In certain embodiments, the compound has the structure of Formula (V-4La):

[0518]

[0519] In certain embodiments, the compound has the structure of Formula (V-4Lb):

[0520]

[0521] In certain embodiments, the compound has the structure of Formula (V-4Da):

[0522]

[0523] In certain embodiments, the compound has the structure of Formula (V-4Db):

[0524]

[0525] In certain embodiments, R 6 is a single occurrence of -C(=O)NH 2 Substituted alkyl groups such as

[0526] In certain embodiments, the compound has the structure of Formula (V-6L):

[0527] Alternatively, the compound may have the structure of Formula (V-6D):

[0528]

[0529] In certain embodiments, R9 Yes -H.

[0530] In certain embodiments, the compound is selected from the group consisting of:

[0531]

[0532] or a pharmaceutically acceptable salt thereof.

[0533] In certain embodiments, the present invention provides a compound represented by formula (VI):

[0534]

[0535] or a pharmaceutically acceptable salt thereof;

[0536] in:

[0537] R 1 and R 2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl

[0538] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0539] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0540] p is 0, 1, or 2;

[0541] R 6 is hydrogen or substituted or unsubstituted alkyl;

[0542] R 7 is hydrogen or alkyl; and

[0543] R 9 is hydrogen or alkyl;

[0544] Wherein the compound is not:

[0545]

[0546] In certain embodiments:

[0547] R 1 and R 2 are each independently H or substituted or unsubstituted alkyl;

[0548] R 4 In every occurrence it is hydroxyl;

[0549] p is 1;

[0550] R 6 is optionally replaced by one occurrence of -C(=O)NH 2 substituted alkyl; and

[0551] R 9 It's hydrogen.

[0552] In certain embodiments, R 1 is a substituted or unsubstituted alkyl group, such as

[0553] In certain embodiments, the compound has the structure of Formula (VI-1L)

[0554] Alternatively, the compound may have the structure of formula (VI-1D)

[0555]

[0556] In certain embodiments, R 2 It's H.

[0557] In certain embodiments, p is 1 and R 4 It's a hydroxyl group.

[0558] In certain embodiments, the compound has the structure of Formula (VI-4La):

[0559]

[0560] In certain embodiments, the compound has the structure of Formula (VI-4Lb):

[0561]

[0562] In certain embodiments, the compound has the structure of Formula (VI-4Da):

[0563]

[0564] In certain embodiments, the compound has the structure of Formula (VI-4Db):

[0565]

[0566] In certain embodiments, R 6 is a single occurrence of -C(=O)NH 2 Substituted alkyl groups such as

[0567] In certain embodiments, the compound has the structure of Formula (VI-6L):

[0568] Alternatively, the compound may have the structure of Formula (VI-6D):

[0569]

[0570] In certain embodiments, R 9 Yes -H.

[0571] In certain embodiments, R 7 Yes (C 1 -C 10 ) alkyl groups, such as

[0572] In certain embodiments, the compound has the structure of Formula (VI-7L):

[0573]

[0574] Alternatively, the compound may have the structure of Formula (VI-7D):

[0575]

[0576] In certain embodiments, the present invention provides a compound represented by formula (VII):

[0577]

[0578] or a pharmaceutically acceptable salt thereof;

[0579] in:

[0580] R 1 and R 2 each is independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl;

[0581] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0582] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0583] p is 0, 1, or 2;

[0584] R 6 is hydrogen or substituted or unsubstituted alkyl;

[0585] R 7 is hydrogen or alkyl; and

[0586] R 9 is hydrogen or alkyl;

[0587] Wherein the compound is not:

[0588]

[0589] In certain embodiments:

[0590] R 1 and R 2 are each independently H or substituted or unsubstituted alkyl;

[0591] R 4 In every occurrence it is hydroxyl;

[0592] p is 1;

[0593] R 6 is optionally replaced by one occurrence of -C(=O)NH 2 substituted alkyl; and

[0594] R 9 It's hydrogen.

[0595] In certain embodiments, R 1 is a substituted or unsubstituted alkyl group, such as

[0596] In certain embodiments, the compound has the structure of Formula (VII-1L)

[0597]

[0598] Alternatively, the compound may have the structure of formula (VII-1D)

[0599]

[0600] In certain embodiments, R2 is H.

[0601] In certain embodiments, p is 1 and R4 is hydroxy.

[0602] In certain embodiments, the compound has the structure of Formula (VII-4La):

[0603]

[0604] In certain embodiments, the compound has the structure of Formula (VII-4Lb):

[0605]

[0606] In certain embodiments, the compound has the structure of Formula (VII-4Da):

[0607]

[0608] In certain embodiments, the compound has the structure of Formula (VII-4Db):

[0609]

[0610] In certain embodiments, R 6 is a single occurrence of -C(=O)NH 2 Substituted alkyl groups such as

[0611] In certain embodiments, the compound has the structure of Formula (VII-6L):

[0612] Alternatively, the compound may have the structure of Formula (VII-6D):

[0613]

[0614] In certain embodiments, R 9 Yes -H.

[0615] In certain embodiments, R 7 Yes (C 1 -C 10 ) alkyl groups, such as

[0616] In certain embodiments, the compound has the structure of Formula (VII-7L):

[0617]

[0618] Alternatively, the compound may have the structure of Formula (VII-7D):

[0619]

[0620] In certain embodiments, the compound has the structure of Formula (VII-10L):

[0621]

[0622] Alternatively, the compound may have the structure of Formula (VII-10D):

[0623]

[0624] The present invention also provides a compound represented by formula (IX):

[0625]

[0626] or a pharmaceutically acceptable salt thereof;

[0627] in:

[0628] R 1 and R 2 each is independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl;

[0629] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0630] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0631] p is 0, 1, or 2;

[0632] R 6 is hydrogen or substituted or unsubstituted alkyl;

[0633] R 7 , R 8 and R 9 are each independently hydrogen or alkyl;

[0634] J is OH or -NR x R y ;and

[0635] R X and R y are each independently selected from H, optionally substituted alkyl, optionally substituted alkoxyalkyl, or R X and R y Together with the intervening nitrogen atom, they form a ring.

[0636] Exemplary compounds of formula (IX) include YDE-100 to YDE-107.

[0637] In certain embodiments of the compound of formula (IX):

[0638] R1 and R 2 are each independently H or substituted or unsubstituted alkyl;

[0639] R 4 In every occurrence it is hydroxyl;

[0640] p is 1;

[0641] R 6 is optionally replaced by one occurrence of -C(=O)NH 2 substituted alkyl; and

[0642] R 9 It's hydrogen.

[0643] In certain embodiments of the compound of formula (IX), R 1 is a substituted or unsubstituted alkyl group, such as

[0644] In certain embodiments, the compound has the structure of Formula (IX-IL):

[0645]

[0646] Alternatively, in certain embodiments, the compound has the structure of Formula (IX-1D):

[0647]

[0648]

[0649] In certain embodiments, R 2 It's H.

[0650] In certain embodiments, p is 1 and R 4 In certain embodiments, the compound has the structure of formula (IX-4La):

[0651]

[0652] In certain embodiments, the compound has the structure of Formula (IX-4Lb):

[0653]

[0654] In certain embodiments, the compound has the structure of Formula (IX-4Da):

[0655]

[0656] In certain embodiments, the compound has the structure of Formula (IX-4Db):

[0657]

[0658] In certain embodiments, R 6 is a single occurrence of -C(=O)NH 2 Substituted alkyl, for example, R 6 Can be

[0659] In certain embodiments, the compound has the structure of Formula (IX-6L):

[0660]

[0661] In certain embodiments, the compound has the structure of Formula (IX-6D):

[0662]

[0663] In certain embodiments, R 9 Yes -H.

[0664] In certain embodiments, R 7 Yes (C 1 -C 10 ) alkyl. For example, R 7 Can be

[0665] In certain embodiments, the compound has the structure of Formula (IX-7L):

[0666]

[0667] In certain embodiments, the compound has the structure of Formula (IX-7D):

[0668]

[0669] In certain embodiments, the compound has the structure of Formula (IX-10L):

[0670]

[0671] In certain embodiments, the compound has the structure of Formula (IX-10D):

[0672]

[0673] In certain embodiments, the compound has the structure of Formula (IX-11L):

[0674]

[0675] In certain embodiments, the compound has the structure of Formula (IX-11D):

[0676]

[0677] In certain embodiments, R 8 Yes-CH 3 or -H, preferably -H.

[0678] In certain embodiments, J is OH. Alternatively, in other embodiments, J is -NR X R y In certain such embodiments, R X and R y are each independently an alkyl group. X and R y Together with the intervening nitrogen atom, they may form a ring.

[0679] In other embodiments, the present invention also provides a compound represented by formula (X-am):

[0680]

[0681] or a pharmaceutically acceptable salt thereof;

[0682] in:

[0683] R 1 , R 2 and R 3 each is independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl or heterocyclylalkyl;

[0684] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b 、-CH 2 OR b , halo, hydroxyl and hydroxyalkyl;

[0685] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0686] p is 0, 1, or 2;

[0687] R 6 is hydrogen or substituted or unsubstituted alkyl;

[0688] R 7 , R 8 and R 9 are each independently hydrogen or alkyl;

[0689] J is OH or -NR x R y ;and

[0690] R X and R y are each independently selected from H, optionally substituted alkyl, optionally substituted alkoxyalkyl, or R X and R y Together with the intervening nitrogen atom, they form a ring.

[0691] Exemplary compounds of formula (X-am) include YDE-93 and YDE-96.

[0692] In certain embodiments of compounds of formula (X-am):

[0693] R 1 , R 2 and R 3 are each independently H or substituted or unsubstituted alkyl, arylalkyl or heterocyclylalkyl;

[0694] R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, oxo, hydroxy, -OR b , hydroxyalkyl, -CH 2 OR b and halogen groups;

[0695] R b is a substituted or unsubstituted alkyl, aryl, arylalkyl or heterocyclic group;

[0696] R 6 is hydrogen or substituted or unsubstituted alkyl; and

[0697] R 7 , R 8 and R 9 Each is independently hydrogen or alkyl.

[0698] In certain embodiments, when indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, haloalkyl, oxo, -CN, -NO, - 2 , =N-OH, -N 3 , -R a 、-OR a 、-SR a 、-N(R a ) 2 、-N(R a ) 3 +, =NR a 、-NHC(=O)R c 、-C(=O)R c 、-C(=O)N(R a ) 2 、-S(=O) 2 R c 、-OS(=O) 2 OR a 、-S(=O) 2 OR a 、-S(=O) 2 N(R a ) 2 、-S(=O)R c ,-OP(=O)(OR a ) 2 , -(alkylene)-C(=O)R c 、-C(=S)R c 、-C(=O)OR a , -(alkylene)-C(=O)OR a 、-C(=S)OR a 、-C(=O)SR a 、-C(=S)SR a 、-(alkylene)-C(=O)N(R a ) 2 、-C(=S)N(R a ) 2 and -C(-NR a )N(R a ) 2 ;and

[0699] Ra is independently at each occurrence hydrogen or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl; and

[0700] R c is independently at each occurrence substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl.

[0701] In further embodiments, when indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, haloalkyl, oxo, -R a 、-OR a 、-N(R a ) 2 、-N(R a )3 + 、-NHC(=O)R c 、-C(=O)R c 、-C(=O)N(R a ) 2 、-C(=O)OR a , -(alkylene)-C(=O)OR a and -(alkylene)-C(=O)N(R a ) 2 ;and

[0702] R a is independently at each occurrence hydrogen or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl; and

[0703] R c is independently at each occurrence substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or (cycloalkyl)alkyl.

[0704] In another embodiment, R a is independently at each occurrence hydrogen, alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl; and

[0705] R c is independently at each occurrence alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl.

[0706] In certain embodiments, the compound has the structure of Formula (X-am-10L):

[0707]

[0708] In certain embodiments, the compound has the structure of Formula (X-am-10D):

[0709]

[0710] In certain embodiments, R 1 is substituted or unsubstituted (C 2 -C 10 ) haloalkyl. Or, R 1 It may be a substituted or unsubstituted alkyl group, an arylalkyl group or a heterocyclylalkyl group.

[0711] In another embodiment, R 1 is selected from substituted or unsubstituted alkyl,

[0712] Ra is hydrogen or alkyl; and

[0713] n is an integer of 1 to 10, preferably 1-5, more preferably 1-3.

[0714] In another embodiment, R 1 Selected from

[0715] Preferably, R 1 yes or R 1 yes

[0716] In certain embodiments, the compound has the structure of Formula (X-am-1L):

[0717]

[0718] In certain embodiments, the compound has the structure of Formula (X-am-1D):

[0719]

[0720] In certain embodiments, R 2 is substituted or unsubstituted (C 2 -C 10 ) haloalkyl. Or, R 2 It may be H or a substituted or unsubstituted alkyl, arylalkyl or heterocyclylalkyl group.

[0721] In another embodiment, R 2 is selected from hydrogen, substituted or unsubstituted alkyl, Where R a is hydrogen or an alkyl group; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

[0722] In other embodiments, R 2 Can be selected from

[0723] In some preferred embodiments, R 2 It's hydrogen.

[0724] In certain embodiments, the compound has the structure of Formula (X-am-2L):

[0725]

[0726] In certain embodiments, the compound has the structure of Formula (X-am-2D):

[0727]

[0728] In certain embodiments, R 3 is substituted or unsubstituted (C 2 -C 10 ) haloalkyl. Or, R 3 It may be a substituted or unsubstituted alkyl or arylalkyl group.

[0729] In certain embodiments, R 3 is selected from substituted or unsubstituted alkyl, R a is hydrogen or an alkyl group; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

[0730] In another embodiment, R 3 Selected from Preferably, R 3 yes

[0731] In certain embodiments, the compound has the structure of Formula (X-am-3L):

[0732]

[0733] In certain embodiments, the compound has the structure of Formula (X-am-3D):

[0734]

[0735] In certain embodiments, p is 1 or 2; and R 4 is independently selected at each occurrence from substituted or unsubstituted alkyl, -OR b 、-CH 2 OR b , halo, hydroxy and hydroxyalkyl.

[0736] In other embodiments, p is 1 or 2; and R 4 is independently selected at each occurrence from -CH 3 , halogen, hydroxyl and hydroxyalkyl. Preferably, R 4 is hydroxyl or R 4 Yes-CH 3 .

[0737] In certain embodiments, p is 1.

[0738] In certain embodiments, the compound has the structure of Formula (X-am-4Lg):

[0739]

[0740] In certain embodiments, the compound has the structure of Formula (X-am-4La):

[0741]

[0742] In certain embodiments, the compound has the structure of Formula (X-am-4Lb):

[0743]

[0744] In certain embodiments, the compound has the structure of Formula (X-am-4Lc):

[0745]

[0746] The prerequisite is R 4 Not hydroxyl.

[0747] In certain embodiments, the compound has the structure of Formula (X-am-4Dg):

[0748]

[0749] In certain embodiments, the compound has the structure of Formula (X-am-4Da):

[0750]

[0751] In certain embodiments, the compound has the structure of Formula (X-am-4Db):

[0752]

[0753] In certain embodiments, the compound has the structure of Formula (X-am-4Dc):

[0754]

[0755] The prerequisite is R 4 Not hydroxyl.

[0756] In certain embodiments, R 4 It is an oxo group.

[0757] In certain embodiments, the compound has the structure of Formula (X-am-4Ld):

[0758]

[0759] In certain embodiments, the compound has the structure of Formula (X-am-4Le):

[0760]

[0761] In certain embodiments, the compound has the structure of Formula (X-am-4Dd):

[0762]

[0763] In certain embodiments, the compound has the structure of Formula (X-am-4De):

[0764]

[0765] In certain embodiments, R 6 is hydrogen or alkyl, wherein the alkyl is optionally replaced by one occurrence of -C(=O)NH 2 Substituted; preferably, R 6 is optionally replaced by one occurrence of -C(=O)NH 2 Substituted alkyl. For example, R 6 Can be -CH 3 or R 6 Can be

[0766] In certain embodiments, the compound has the structure of Formula (X-am-6L):

[0767]

[0768] In certain embodiments, the compound has the structure of Formula (X-am-6D):

[0769]

[0770] In certain embodiments, R 7 Yes (C 1 -C1 0 ) alkyl. For example, R 7 Can be

[0771] In certain embodiments, the compound has the structure of Formula (X-am-7L):

[0772]

[0773] In certain embodiments, the compound has the structure of Formula (X-am-7D):

[0774]

[0775] In certain embodiments, the compound has the structure of Formula (X-am-11L):

[0776]

[0777] In certain embodiments, the compound has the structure of Formula (X-am-11D):

[0778]

[0779] In certain embodiments, R 8 Yes-CH 3 or -H, preferably -H.

[0780] In certain embodiments, R 9 Yes-CH 3 or -H, preferably -H.

[0781] In certain embodiments, R X and R y Each is independently an optionally substituted alkyl. X and R y Each is independently an optionally substituted alkoxyalkyl. In another alternative embodiment, R X and R y Together with the intervening nitrogen atom, they form a ring.

[0782] The present invention also provides a salt of a compound represented by Formula 8:

[0783]

[0784] Know

[0785] A salt of a compound represented by Formula 10:

[0786]

[0787] In certain embodiments, the compound can be a prodrug, for example, wherein a hydroxyl group in the parent compound is presented as an ester or 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 in vivo to an active parent compound (e.g., an ester is hydrolyzed to the corresponding hydroxyl group or carboxylic acid).

[0788] In certain embodiments, the compounds of the present invention may be racemic. In certain embodiments, the compounds of the present invention may be enriched in one enantiomer. For example, the compounds of the present 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.

[0789] The compounds of the present invention have more than one stereocenter. Therefore, the compounds of the present invention can be enriched in one or more diastereomers. For example, the compounds of the present invention can have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de or even 95% or more de. In certain embodiments, the compounds of the present invention have substantially one isomeric configuration at one or more stereocenters and multiple isomeric configurations at the remaining stereocenters.

[0790] 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 more.

[0791] As used herein, a single bond drawn without stereochemistry does not indicate the stereochemistry of the compound. Compounds of formula (I) provide examples of compounds with no stereochemistry indicated.

[0792] As used herein, hashed or bolded wedge bonds indicate absolute stereochemical configuration.

[0793] In certain embodiments, the therapeutic preparation of the compound of the present invention can be enriched to significantly provide one enantiomer of the compound. Enantiomer enriched mixtures can include, for example, at least 60 mol % of one enantiomer, or more preferably at least 75, 90, 95 or even 99 mol %. In certain embodiments, the compound enriched in one enantiomer is substantially free of another enantiomer, wherein substantially free means that compared with the amount of another enantiomer in, for example, a composition or a mixture of compounds, the material in question accounts for less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%. For example, if a composition or a mixture of compounds contains 98 grams of the first enantiomer and 2 grams of the second enantiomer, it will be referred to as containing 98 mol % of the first enantiomer and only 2% of the second enantiomer.

[0794] In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound of the invention. A diastereomerically enriched mixture may contain, for example, at least 60 mole % of one enantiomer, or more preferably at least 75, 90, 95 or even 99 mole %.

[0795] Pharmaceutical composition

[0796] In certain embodiments, the present invention provides a pharmaceutical composition comprising a salt or compound of the present invention, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0797] In certain embodiments, the pharmaceutical compositions are formulated for topical administration to the eye, for example, as eye drops.

[0798] In certain embodiments, at least 50%, 60%, 70%, 80% or 90% of the compound is present in salt form. Preferably, at least 95% of the compound is present in salt form. Even more preferably, at least 99% of the compound is present in salt form.

[0799] In certain embodiments, the present invention provides pharmaceutical preparations suitable for human patients, comprising any salt or compound of the present invention, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations can be used to treat or prevent an illness or disease as described herein. In certain embodiments, the pyrogenic activity of the pharmaceutical preparations is low enough to be suitable for human patients.

[0800] One embodiment of the invention provides a pharmaceutical kit comprising a salt or compound of the invention, or a pharmaceutically acceptable salt thereof, and optionally instructions on how to administer the compound.

[0801] The compositions and methods of the present invention can be used to treat individuals in need. In certain embodiments, the individual is a mammal, such as a human or non-human mammal. When applied to an animal such as a human, the composition or compound is preferably applied in the form of a pharmaceutical composition, which comprises, for example, a compound of the present 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 ethylene glycol, glycerol, oils such as olive oil or injectable organic esters. In certain preferred embodiments, when such pharmaceutical compositions are applied to humans, particularly for invasive routes of administration (i.e., routes of injection or implantation that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients (for example) may be selected to achieve delayed release of an agent or selectively target one or more cells, tissues or organs. Pharmaceutical compositions may be unit dosage forms, such as tablets, capsules (including dispersed capsules and gelatin capsules), granules, lyophilized materials for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition may also be presented in a transdermal delivery system, such as a skin patch. The composition may also be presented in a solution suitable for topical administration, such as eye drops.

[0802] A pharmaceutically acceptable carrier may contain a physiologically acceptable agent, which, for example, acts to stabilize a compound (such as a compound of the present invention), increase its solubility, or increase its absorption. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents, low molecular weight proteins, or other stabilizers or excipients. The selection 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 may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymer matrix, into which, for example, a compound of the present invention may be incorporated. For example, a liposome comprising a phospholipid or other lipid may be a relatively simple, non-toxic, physiologically acceptable, and metabolizable carrier to manufacture and administer.

[0803] The phrase "pharmaceutically acceptable" is used 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 humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0804] As used herein, the phrase "pharmaceutically acceptable carrier" 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 that can be used 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 carboxymethylcellulose, ethyl cellulose and cellulose acetate; (4) 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 starch, etc. oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0805] The pharmaceutical composition (preparation) can be administered to a subject by any of a variety of routes of administration, including, for example, oral (e.g., an infusion in water or non-aqueous solution or suspension for application to the tongue, tablets, capsules (including dispersible capsules and gelatin capsules), boluses, powders, granules, pastes); absorption through the oral mucosa (e.g., sublingual); anal, rectal or vaginal (e.g., as a pessary, cream or foam); parenteral (including, for example, as a sterile solution or suspension intramuscularly, intravenously, subcutaneously or intrathecally); nasal; intraperitoneal; subcutaneous; transdermal (e.g., as a patch applied to the skin); and topical administration (e.g., as a cream, ointment or spray applied to the skin, or as eye drops). The compound can also be formulated for inhalation. In certain embodiments, the compound can be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions useful therefor can be found, for example, in 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 and patents cited therein.

[0806] The formulation can be conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated, the specific 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 the amount of the compound that produces the therapeutic effect. Generally speaking, in percentage, this amount ranges from about 1% to 99% active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0807] The methods for preparing these formulations or compositions include the step of bringing into association the active compound (such as a compound of the present invention) with a 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.

[0808] Formulations of the invention suitable for oral administration may be in the form of capsules (including dispersible capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and gum arabic or tragacanth), lyophilisates, powders, granules, or in the form of a solution or suspension in an aqueous or non-aqueous liquid, or in the form of an oil-in-water or water-in-oil liquid emulsion, or in the form of an elixir or syrup, or in the form of a lozenge (using an inert base such as gelatin and glycerin, or sucrose and gum arabic) and / or in the form of a mouthwash, etc., each containing a predetermined amount of the compound of the invention as an active ingredient. The composition or compound may also be administered as a bolus, electuary or paste.

[0809] To prepare solid dosage forms for oral administration (capsules (including dispersible capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or calcium hydrogen phosphate and / or any of the following: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; (3) wetting agents such as glycerol. Oils; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution delay agents such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, 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 dispersible capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also contain a buffer. Solid compositions of a similar type may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose / milk sugar) and high molecular weight polyethylene glycols.

[0810] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant or a dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0811] Tablets and other solid dosage forms of pharmaceutical compositions such as dragees, capsules (including dispersible capsules and gelatin capsules), pills and granules may be optionally scored or prepared with coatings and shells, such as enteric coatings or other coatings well known in the art of pharmaceutical formulation. They may also be formulated to provide slow release or controlled release of the active ingredients contained therein using, for example, hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres in different proportions for providing the desired release characteristics. They may be sterilized by, for example, filtering through a filter membrane that retains bacteria or by immediately incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium before use. These compositions may also optionally contain an opacifier and may also be a composition that releases the active ingredient only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, with one or more of the above-mentioned excipients, where appropriate.

[0812] Liquid dosage forms suitable for oral administration include pharmaceutically acceptable emulsions, lyophilisates for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form can contain an inert diluent commonly used in the art, such as water or other solvents, cyclodextrins and derivatives thereof, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (specifically cottonseed oil, peanut oil, corn oil, germ oil (e.g., wheat germ), olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof.

[0813] Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0814] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0815] Formulations of pharmaceutical compositions for rectal, vaginal or transurethral administration may be presented in the form of suppositories which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate, and which are solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound.

[0816] The formulation of the pharmaceutical composition for administration to the oral cavity may be presented as a mouthwash or oral spray or oral ointment.

[0817] Alternatively or additionally, the composition may be formulated for delivery via a catheter, stent, guidewire or other intraluminal device. Delivery via such a device may be particularly suitable for delivery to the bladder, urethra, urinary catheter, rectum or intestine.

[0818] Formulations 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.

[0819] Dosage forms for 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 any preservatives, buffers, or propellants that may be required.

[0820] Ointments, pastes, creams and gels may contain, in addition to the active compounds, 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.

[0821] In addition to the active compound, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powders, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0822] Transdermal patches have the additional advantage of providing control of the delivery of the compounds of the invention to the body. Such dosage forms can be manufactured by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the transdermal flux of the compound. The rate of this flux can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0823] Ophthalmic formulations, eye ointments, powders, solutions, etc. are also encompassed within the scope of the present invention. Exemplary ophthalmic formulations are described in U.S. Patent 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 tears, waterproofing, or vitreous fluid or are compatible with such fluids. Preferably, the route of administration is topical (e.g., topical application, such as eye drops, or application via implant).

[0824] As used herein, the phrases "parenteral administration" and "administered parenterally" mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise a combination of one or more active compounds with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use, which combination may contain antioxidants, buffers, bacteriostats, solutes (to render the formulation isotonic with the blood of the intended recipient) or suspending or thickening agents.

[0825] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present 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 maintaining the desired particle size in the case of dispersions and by the use of surfactants.

[0826] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. The prevention of microbial action may be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. It may also be necessary to include isotonic agents, such as sugar, sodium chloride, etc. in the composition. In addition, delayed absorption of injectable drug forms may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0827] In some cases, in order to prolong the effect of the drug, it is necessary to slow down the absorption of the drug injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. The absorption rate of the drug depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, the delayed absorption of the drug form administered parenterally can be accomplished by dissolving or suspending the drug in an oil vehicle.

[0828] Injectable depot forms are prepared by forming a microencapsulated matrix of the subject compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the properties of the specific polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0829] For use in the methods of the invention, the active compound may be provided per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0830] The introduction method can also be provided by a refillable or biodegradable device. In recent years, various slow-release polymer devices have been developed and tested in vivo for controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers, including hydrogels, including both biodegradable and non-degradable polymers, can be used to form implants that continuously release compounds at specific target sites.

[0831] 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.

[0832] The selected dosage level will depend upon a variety of factors including the activity of the specific compound or combination of compounds employed, or the esters, salts or amides thereof, the route of administration, the time of administration, the rate of excretion of the specific compound employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the specific compound 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.

[0833] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe a therapeutically effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start a pharmaceutical composition or compound dosage at a level lower than the level required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. "Therapeutically effective amount" means a concentration of a compound sufficient to cause the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary according to the subject's weight, sex, age, and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the patient's illness, the condition being treated, the stability of the compound, and, if necessary, administering another type of therapeutic agent together with the compound of the present invention. A larger total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13th edition, 1814-1882, incorporated herein by reference).

[0834] In general, a suitable daily dose of the active compound used in the compositions and methods of the invention will be the amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above.

[0835] If desired, the effective daily dose of the active compound may optionally be administered in unit dosage form as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day. In certain embodiments of the invention, the active compound may be administered twice or three times a day. In a preferred embodiment, the active compound will be administered once a day.

[0836] Patients receiving such treatment are any animal in need thereof, including primates, particularly humans; other mammals such as horses, cattle, pigs, and sheep; and poultry and pets in general.

[0837] In certain embodiments, the compounds of the present invention can be used alone or in combination with another type of therapeutic agent. As used herein, the phrase "combined administration" refers to any form of administration of two or more different therapeutic compounds, so that the second compound is administered when the previously administered therapeutic compound is still effective in vivo (for example, the two compounds take effect simultaneously in the patient, which may include the synergistic effect of the two compounds). For example, different therapeutic compounds can be administered simultaneously or continuously with the same formulation or with a separate formulation. In certain embodiments, different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours or a week from each other. Therefore, individuals receiving such treatments can benefit from the combined effects of different therapeutic compounds.

[0838] In certain embodiments, the combined administration of a compound of the invention and one or more additional therapeutic agents provides an increased efficacy relative to each separate administration of a compound of the invention (e.g., a compound of Formula I, V, VI, or VII) or one or more additional therapeutic agents. In certain such embodiments, the combined administration provides an additive effect, wherein the additive effect refers to the sum of the effects of each of the separate administrations of a compound of the invention and one or more additional therapeutic agents.

[0839] The present invention includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. As used herein, the term "pharmaceutically acceptable salt" includes salts derived from inorganic or organic acids, including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, oxalic acid, mandelic acid and other acids. Pharmaceutically acceptable salt forms may include forms in which the molecular ratio of the salt is not 1:1. For example, the salt may contain more than one inorganic or organic acid molecule per base molecule, such as two hydrochloric acid molecules per compound molecule of Formula I, V, VI or VII. As another example, the salt may contain less than one inorganic or organic acid molecule per base molecule, such as two molecules of Formula I, V, VI or VII per tartaric acid molecule.

[0840] In other embodiments, the salts considered by the present invention include but are not limited to alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts. In certain embodiments, the salts considered by the present invention include but are not limited to L-arginine, phenethylbenzylamine, benzathine, betaine, calcium hydroxide, choline, diarno, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucosamine, haibamin, 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, the salts considered by the present invention include but are not limited to Na, Ca, K, Mg, Zn or other metal salts.

[0841] Pharmaceutically acceptable acid addition salts may also exist in the form of various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, which is inherent in the solvent of preparation or crystallization or adventitious to such solvent.

[0842] 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.

[0843] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0844] Treatment

[0845] The present invention also provides a method for treating an eye disease, comprising administering a salt of the present invention, a compound of the present invention, or a pharmaceutical composition comprising a salt or compound of the present invention to a subject in need thereof.

[0846] In particular, the eye disease can be selected from retinopathy, keratitis, dry macular degeneration, wet macular degeneration, dry eye syndrome, corneal conjunctival epithelial disorders, proliferative vitreoretinopathy, pigmentary retinopathy, diabetic retinopathy, retinopathy of prematurity, immature retinopathy, proliferative retinopathy, ischemic retinopathy, epidemic keratoconjunctivitis, atopic keratitis, superior marginal keratitis, pterygium dry keratitis, alveolar keratoconjunctivitis, scleritis, corneal transplant rejection, choroidal neovascularization, neovascular glaucoma, ischemic optic neuropathy, retrolental fibroplasia, diabetic macula, neovascular iris disease, erythroblastic tissue proliferation, 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 corneal conjunctival epithelial disorders.

[0847] In certain preferred embodiments, the eye disease is selected from retinopathy, keratitis, dry macular degeneration, wet macular degeneration, dry eye syndrome, keratoconjunctivitis sicca, and corneal and conjunctival epithelial disorders.

[0848] The pharmaceutical composition for treating ophthalmic diseases comprising the salt or compound of the present invention as an active pharmaceutical ingredient may further comprise at least one additive selected from the group consisting of: carriers, excipients, disintegrants, sweeteners, coating agents, swelling agents, lubricants, slip agents, flavoring agents, antioxidants, buffers, antibacterial agents, diluents, dispersants, surfactants and adhesives. Specifically, the formulation for parenteral administration may be a sterile aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized preparation, a suppository, etc.

[0849] The dosage of the salt or compound of the present invention administered to a subject can be adjusted according to various factors, such as the kind of disease, the severity of the disease, the kind and amount of active pharmaceutical ingredients and other ingredients contained in the pharmaceutical composition, the type of formulation, the age, weight, general health, sex and diet of the patient, the time and route of administration, the duration of treatment and concomitant drugs used.

[0850] However, for the desired effect, the effective amount of the salt or compound contained in the pharmaceutical composition can be 0.0001 micrograms / day to 100 micrograms / day. In such cases, administration can be performed once a day or divided into several doses. Specifically, the concentration of the salt or compound contained in the pharmaceutical composition can be 1000 μM to 0.001 μM. In addition, the concentration of the salt or compound contained in the pharmaceutical composition can be 100 μM to 0.005 μM or 50 μM to 0.02 μM.

[0851] In addition, if necessary, the concentration of the salt or compound contained in the pharmaceutical composition may be 30 μM to 1 μM. In addition, the concentration of the compound or peptide contained in the pharmaceutical composition may be 0.01 μM to 1 μM.

[0852] In addition, the subject can be a mammal, specifically a human being. Those skilled in the art can appropriately select the route of administration in consideration of the method of administration, the volume and viscosity of body fluids, etc. Specifically, administration can be carried out via any route selected from the group consisting of: coating, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular and intradermal. Preferably, administration includes topical administration to the eyes of the subject.

[0853] Specifically, it can be preferably applied to the eyes and used as eye drops.

[0854] Having generally described the invention, the invention will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0855] Example

[0856] Example 1: Preparation of YDE derivatives

[0857] Protein analysis of the extracellular matrix derived from animal chondrocytes was performed at Baek's group of Center of Biomedical Mass Spectrometry (Diatech Korea Co., Ltd., Seoul, Korea). Proline-GQDGLAGPK (P-GQDGLAGPK), which is part of the amino acid sequence of type II collagen α1 protein, was obtained through the above protein analysis.

[0858] The following is an exemplary protein synthesis of YDE-011. Other compounds of the invention (eg, YDE-001-YDE-086) were made via similar procedures, for example by substituting different amino acid building block reagents at the desired steps.

[0859]

[0860] Example Procedure of YDE-011

[0861] Solid phase synthesis

[0862] Fmoc-Pro-Lys(Boc)-Wang resin (1)

[0863] In the solid phase synthesis reactor equipped with filter membrane, DCM (30mL) containing Fmoc-Lys (Boc) -Wang resin (1.75g, 1 mmol) is added, then swelled for 30min, and then the resin is drained. A solution of piperidine (10mL) in DMF (40mL) is added to the resin and stirred for 5 minutes, and then the resin is drained. The resin is washed 6 times with DMF (50mL). A solution of Fmoc-Pro-OH (3.37g, 10 mmol) in DMF (25mL) and a solution of HBTU (3.8g, 10 mmol) and N-methylmorpholine (2.0g, 20 mmol) in DMF (25mL) are added to the resin respectively. The reaction mixture is stirred for 1h and the resin is drained. The resin is used for the next step without further purification.

[0864] Fmoc-Gly-Pro-Lys(Boc)-Wang resin (2)

[0865] To Fmoc-Pro-Lys (Boc) -Wang resin (1), piperidine (10 mL) was added in DMF (40 mL) and stirred for 5 minutes, then the resin was drained. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Gly-OH (3.0 g, 10 mmoles) in DMF (25 mL) and a solution of HBTU (3.8 g, 10 mmoles) and N-methylmorpholine (2.0 g, 20 mmoles) in DMF (25 mL) were added to the resin respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used for the next step without further purification.

[0866] Fmoc-Ala-Gly-Pro-Lys(Boc)-Wang resin (3)

[0867] To Fmoc-Gly-Pro-Lys(Boc)-Wang resin (2), piperidine (10 mL) was added in DMF (40 mL) and stirred for 5 minutes, then the resin was drained. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Ala-OH (3.1 g, 10 mmoles) in DMF (25 mL) and a solution of HBTU (3.8 g, 10 mmoles) and N-methylmorpholine (2.0 g, 20 mmoles) in DMF (25 mL) were added to the resin respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used for the next step without further purification.

[0868] Fmoc-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (4)

[0869] To Fmoc-Ala-Gly-Pro-Lys(Boc)-Wang resin (3), piperidine (10 mL) was added in DMF (40 mL) and stirred for 5 minutes, then the resin was drained. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Leu-OH (3.5 g, 10 mmoles) in DMF (25 mL) and a solution of HBTU (3.8 g, 10 mmoles) and N-methylmorpholine (2.0 g, 20 mmoles) in DMF (25 mL) were added to the resin respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used for the next step without further purification.

[0870] Fmoc-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (5)

[0871] Add 10mL piperidine solution in DMF (40mL) to Fmoc-Leu-Ala-Gly-Pro-Lys (Boc) -Wang resin (4) and stir for 5 minutes, then drain the resin. Wash the resin 6 times with DMF (50mL). Add Fmoc-Gly-OH (3.0g, 10 mmoles) in DMF (25mL) solution and HBTU (3.8g, 10 mmoles) and N-methylmorpholine (2.0g, 20 mmoles) in DMF (25mL) to the resin respectively. Stir the reaction mixture for 1h and drain the resin. The resin is used for the next step without further purification.

[0872] Fmoc-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (6)

[0873] To Fmoc-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (5), piperidine (10 mL) was added in DMF (40 mL) and stirred for 5 minutes, then the resin was drained. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Leu-OH (3.5 g, 10 mmoles) in DMF (25 mL) and a solution of HBTU (3.8 g, 10 mmoles) and N-methylmorpholine (2.0 g, 20 mmoles) in DMF (25 mL) were added to the resin respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used for the next step without further purification.

[0874] Fmoc-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (7)

[0875] To Fmoc-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (6), piperidine (10 mL) was added in DMF (40 mL) and stirred for 5 minutes, then the resin was drained. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Gln(Trt)-OH (6.1 g, 10 mmoles) in DMF (25 mL) and a solution of HBTU (3.8 g, 10 mmoles) and N-methylmorpholine (2.0 g, 20 mmoles) in DMF (25 mL, 10 equivalents) were added to the resin respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used for the next step without further purification.

[0876] Fmoc-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (8)

[0877] To Fmoc-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (7), piperidine (10 mL) was added in DMF (40 mL) and stirred for 5 minutes, then the resin was drained. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Gly-OH (3.0 g, 10 mmoles) in DMF (25 mL) and a solution of HBTU (3.8 g, 10 mmoles) and N-methylmorpholine (2.0 g, 20 mmoles) in DMF (25 mL) were added to the resin respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used for the next step without further purification.

[0878] H-Hyp(tBu)-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (9)

[0879] To Fmoc-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (8) was added a solution of piperidine (10 mL) in DMF (40 mL) and stirred for 5 minutes, then the resin was drained. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Hyp(tBu)-OH (4.2 g, 10 mmol) in DMF (25 mL) and a solution of HBTU (3.8 g, 10 mmol) and N-methylmorpholine (2.0 g, 20 mmol) in DMF (25 mL) were added to the resin and the reaction mixture was stirred for 1 h, and the resin was drained. To the Fmoc-Hyp(tBu)-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin was added a solution of piperidine (10 mL) in DMF (40 mL). The reaction mixture was stirred for 5 minutes and then the resin was drained. The resin was washed 6 times with DMF (50 mL).

[0880] Resin removal

[0881] H-Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys-OH TFA Salt (10)

[0882] To 1 mmol of H-Hyp(tBu)-Gly-Gln(Trt)-Leu-Gly-Leu-Ala-Gly-Pro-Lys(Boc)-Wang resin (9) was added 30 mL of a mixture solution (87.5% TFA / 2.5% 1,2-ethanedithiol / 2.5% H 2 0 / 5.0% thioanisole) and the reaction mixture was stirred for 2 h and the reaction mixture was monitored by HPLC. Cold ether (500 mL) was added to the filtered solution to precipitate the crude peptide. The precipitated peptide was filtered through a filtration apparatus and washed with 500 mL of ether. The crude peptide was dried under vacuum to give 105% (1 g).

[0883] Purification steps

[0884] H-Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys-OH TFA Salt (10)

[0885] The crude compound was purified by preparative HPLC system.

[0886] Salt exchange step

[0887] H-Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys-OH AcOH Salt (11)

[0888] The purified compound was exchanged from TFA salt to AcOH salt by ion exchange resin. The ion exchange peptide was dried by lyophilizer.

[0889] YDE-001 to YDE-092 peptides were prepared by ANYGEN (Gwangju, Korea) in a manner similar to the exemplary procedure shown above by substituting one or more different amino acid residues into the peptide proline-GQDGLAGPK ( Figure 1 and Table 1) to synthesize.

[0890] Figure 2 and 3 The synthesis method of YDE-001 to YDE-075 peptides and their purification procedures performed by ANYGEN are depicted in FIG.

[0891] [Table 1]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904] Analysis of YDE derivatives

[0905] The YDE derivatives prepared in Example 1 were analyzed through HPLC. The results showed that the synthesized 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-04 5, 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, The purity classification of 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 is 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%.

[0906] In addition, in general, the quality analysis example 1 is a systematic YDE biological organism. The results show that 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-0 45, 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 The molecular weight fractions of 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 are 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.

[0907] Example 2: Preparation of YDE derivatives with modified C-terminus

[0908] Preparation of YDE peptide

[0909] Derivatives of the amino acid sequence of the YDE peptides (YDE-093, YDE-096, and YDE-101 to YDE-107), YDE-011 were obtained by modifying the C-terminus of the YDE peptide such as YDE-011.

[0910] To prepare the C-terminal modified peptide, Fmoc solid phase peptide synthesis (SPPS) was performed based on the standard procedure described in WO 2018 / 225961 and further subjected to C-terminal amidation reaction.

[0911] The peptides of the invention are prepared via similar procedures, for example by substituting different amino acid building block reagents at the desired steps.

[0912] Exemplary preparation of YDE-093

[0913] To prepare the C-terminally amidated peptide YDE-093, the synthesis process was performed as depicted below in Scheme A. 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 WO2018 / 225961.

[0914] Based on the selected amino acid sequence, the chain reaction is carried out in the following order:

[0915] 1) Fmoc-Lys(Dde)-OH

[0916] 2) Fmoc-Pro-OH

[0917] 3) Fmoc-Gly-OH

[0918] 4) Fmoc-Ala-OH

[0919] 5) Fmoc-Leu-OH

[0920] 6) Fmoc-Gly-OH

[0921] 7) Fmoc-Leu-OH

[0922] 8) Fmoc-Gln(Trt)-OH

[0923] 9) Fmoc-Gly-OH

[0924] 10) Fmoc-Hyp(tBu)-OH

[0925] Process A:

[0926] Resin loading

[0927]

[0928] Coupling building blocks

[0929]

[0930] Resin pyrolysis

[0931]

[0932] C-terminal amidation and deprotection

[0933]

[0934] Salt exchange

[0935]

[0936] 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 (10 mL) at 0°C were added HOBt (76 mg, 0.56 mmol), EDCI (107 mg, 0.56 mmol) and i-Pr 2 The product of 4-nitro-1-yl pyrrolidone (20mL) and 4-nitro-1-yl pyrrolidone (20mL) was added into 4-nitro-1-yl pyrrolidone (20mL) and stirred at the same temperature for 1 hour. After 1 hour, the reaction mixture was warmed 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 (20mLx2). The combined organic layer was further washed with water (20mLx2) and concentrated in a vacuum. Residue was precipitated from ether to obtain the required Fmoc protected peptide (400mg, 71%) as a white solid.

[0937] Fmoc-Hyp-Gly-Gln-Leu-Gly-Ala-Leu-Gly-Pro-Lys(Dde)-PEG1-NHBoc (400mg, 0.26mmol) is put into a reaction vessel and a DMF solution (10mL) containing 4% hydrazine is added and stirred for 30min, followed by addition of ether (40mL) to induce precipitation. Thereafter, the precipitate is collected by filtration, then washed twice with excessive ether to obtain the crude peptide YDE-093 (quantitative yield) in the form of a white solid. Crude YDE-093 is purified by a preparative HPLC system. The purified peptide is exchanged from TFA salt to AcOH salt by an ion exchange resin. The ion exchange peptide is dried by a lyophilizer.

[0938] YDE-093, YDE-096, and YDE-101 to YDE-107 are depicted in Table 1A below.

[0939] Table 1A:

[0940]

[0941]

[0942] Analysis of YDE peptide

[0943] The YDE peptides prepared in Example 2 were analyzed by HPLC. The results confirmed that the purities of the synthesized YDE-093, YDE-096, YDE-101, YDE-102, YDE-103, YDE-105, YDE-106 and YDE-107 were 99.1%, 95.4%, 96.7%, 97.2%, 97.9%, 97.4%, 97.2% and 98.2%, respectively.

[0944] In addition, the YDE derivatives prepared in Example 2 were analyzed by ion-mass analysis. The results confirmed that the molecular weights of the synthesized YDE-093, YDE-096, YDE-101, YDE-102, YDE-103, YDE-105, YDE-106 and YDE-107 were 1139.0, 1173.6, 851.9, 880.1, 864.5, 866.1, 878.4 and 894.3, respectively.

[0945] Example 3: Evaluation of the eye protective effect of YDE derivatives on dry eye syndrome

[0946] Preparation of rats with dry eye syndrome

[0947] In order to evaluate the ocular protective effects of YDE-001 to YDE-028 prepared in Example 1 on dry eye syndrome, a total of 320 Sprague-Dawley-type male rats (OrientBio, Seungnam, Korea) were adapted for 7 days. Thereafter, dry eye was induced in 264 test rats by extraorbital lacrimal gland excision (hereinafter referred to as ELGE). Eight test rats without ocular abnormalities were subjected to sham surgery as a control group.

[0948] The patients were treated with inhalation of 2% to 3% isoflurane (Hana Pharm. Co., Hwasung, Korea), 70% N 2 O and 28.6% O 2 The rats were generally anesthetized with a mixed gas of , using a rodent anesthesia machine (Surgivet, Waukesha, Wis., USA) and a respirator (Model 687, Harvard Apparatus, Cambridge, UK). Thereafter, the extraorbital lacrimal gland located in the subcutaneous area above the masseter muscle and below the optic nerve was removed through a 10 mm transverse incision in the anterior part of the left tragus. The skin was sutured by a common method. The ELGE operation time for each rat did not exceed 5 minutes. Six days after the ELGE operation, the induction of dry eye syndrome was examined by measuring the tear secretion through the Schirmer test. At the same time, the presence and position of the extraorbital lacrimal gland of each rat in the sham-operated control group were examined through a skin incision, and then the skin was sutured without removing the extraorbital lacrimal gland ( Figure 4 ).

[0949] The average weight of the ELGE test group measured before ELGE surgery was 241.59 ± 13.56 g, while the average weight measured 6 days after ELGE surgery was 297.38 ± 34.02 g. The average weight of the control group measured before sham surgery was 240.13 ± 25.63 g, while the average weight measured 6 days after sham surgery was 297.38 ± 34.02 g ( Figure 5 ).

[0950] The average tear volume of the control group was 8.34±0.73mm 3 , while the average tear secretion of the ELGE test group was 3.55±0.70mm 3 Eight rats per group and 32 groups in total were selected based on the average amount of tear secretion.

[0951] As a reference drug, 3% diquafosol sodium (Santen, Tokyo, Japan; hereinafter referred to as DS) currently on the market was used.

[0952] The animal tests were performed with prior approval from the Animal Experimental Ethics Committee of Daegu Haany University, Korea (approval number DHU2017-003, January 12, 2017). All test animals were fasted for 18 hours, except for water, before ELGE surgery and final sacrifice.

[0953] The 32 groups are summarized in Table 2 .

[0954] [Table 2]

[0955]

[0956] In addition, to evaluate the ocular protective effects of YDE-029 to YDE-043 prepared in Example 1 on dry eye syndrome, a total of 200 Sprague-Dawley male rats (OrientBio, Seungnam, Korea) were adapted for 7 days. Dry eye was induced in 165 test rats by ELGE. Eight test rats without ocular abnormalities were subjected to sham surgery as a control group. ELGE was performed as described above.

[0957] The average weight of the ELGE test group measured before ELGE surgery was 264.09 ± 11.53 g, while the average weight measured 6 days after ELGE surgery was 316.13 ± 15.77 g. The average weight of the control group measured before sham surgery was 263.50 ± 9.24 g, while the average weight measured 6 days after sham surgery was 315.25 ± 10.85 g ( Figure 6 ).

[0958] The average tear volume of the control group was 10.90±1.69mm 3 , while the average tear secretion of the ELGE test group was 4.83±0.99mm 3 Eight rats per group and 20 groups in total were selected based on the average amount of tear secretion.

[0959] As a reference drug, 3% DS currently on the market was used.

[0960] The animal tests were performed with prior approval from the Animal Experiment Ethics Committee of Daegu University of Korean Medicine, Korea (approval number DHU2017-050, June 8, 2017). All test animals were fasted for 18 hours before ELGE surgery and final sacrifice, except for water.

[0961] The 20 groups are summarized in Table 3.

[0962] [Table 3]

[0963]

[0964] Administration of YDE derivatives

[0965] For YDE-001 to YDE-028, YY-102 and 28 YDE series were each dissolved in saline at a concentration of 3 mg / ml and applied at a dose of 5 μl / eye at 9:30 am and 3:30 pm every day for 14 days, for a total of 28 times after ELGE surgery. The DS solution was dissolved in saline at a concentration of 30 mg / ml and applied twice a day at a dose of 5 μl / eye 7 days after ELGE surgery for 14 days, for a total of 28 times. For the sham control group and ELGE control group, the same stimulus was applied. In order to prevent excessive dry eyes, the same volume of saline was applied in the same manner instead of the test substance.

[0966] In addition, for YDE-029 to YDE-043, YY-102 and 15 YDE series were each dissolved in saline at a concentration of 3 mg / ml and applied at a dose of 5 μl / eye every day at 9:30 am and 3:30 pm 7 days after ELGE surgery for 14 days, for a total of 28 times. The DS solution was dissolved in saline at a concentration of 30 mg / ml and applied twice a day at a dose of 5 μl / eye 7 days after ELGE surgery for 14 days, for a total of 28 times. For the sham control group and ELGE control group, the same stimulation as the application was applied. In order to prevent excessive dry eyes, the same volume of saline was applied in the same manner instead of the test substance ( Figure 7 ).

[0967] Confirmation of changes in tear secretion caused by YDE derivatives

[0968] The changes in tear secretion were measured 6 days after ELGE surgery and on days 7 and 14 after administration of YDE-001 to YDE-043. Tear secretion was measured by the decrease in the travel distance of tears absorbed by 1x15 mm sized cobalt chloride paper (Toyo Roshi Kaisha, Japan).

[0969] Cobalt chloride paper was placed at the outer corner of the rat's eye for 60 seconds to absorb tears ( Fig. 9 The length of the corner absorption area of ​​the cobalt chloride paper was measured using an electronic digital caliper (Mytutoyo, Tokyo, Japan). Figure 8 ).

[0970] Fig. 9The results of the test are shown, wherein A is a sham control group, B is an ELGE control group, C is a DS reference group, D is a YY-102-administered group, and E to AF are groups to which YDE-001 to YDE-028 were sequentially administered.

[0971] The results confirmed that the tear secretion volume decreased after 6 days of ELGE surgery, on the 7th and 14th days after the application of saline in the ELGE control group, compared with the sham control group. In the groups treated with YDE derivatives and the DS reference group, the tear secretion volume increased compared with the ELGE control group, except for the groups treated with 3% solutions 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 tear secretion volume after 14 days of its application. In particular, in the groups treated with 3% solutions of YDE-15, YDE-11, YDE-08, YDE-26, YDE-16, YDE-01, YDE-23 and YY-102, the tear secretion volume increased by more than 20% compared with the DS reference group.

[0972] The specific amount of tear secretion is shown in Fig.10 and Table 4.

[0973] [Table 4]

[0974]

[0975] Fig.11 The results of the test are shown, wherein A is a sham control group, B is an ELGE control group, C is a DS reference group, D is a YY-102-administered group, and E to S are groups to which YDE-029 to YDE-043 were sequentially administered.

[0976] The results confirmed that the tear secretion volume decreased 6 days after ELGE surgery, compared with the sham control group, on the 7th and 14th days after the application of saline in the ELGE control group. In the groups treated with YDE derivatives and the DS reference group, the tear secretion volume increased compared with the ELGE control group, except for the groups treated with 3% solutions of YDE-029, YDE-030, YDE-032, YDE-033, YDE-034, YDE-036 and YDE-41, which did not show any significant changes in tear secretion volume after 14 days of its application. In particular, in the groups treated with 3% solutions of YDE-040, YDE-043 and YDE-042, the tear secretion volume increased by more than 20% compared with the DS reference group.

[0977] The specific amount of tear secretion is shown in Fig.12 and Table 5.

[0978] [Table 5]

[0979]

[0980] Confirmation of corneal damage caused by YDE derivatives

[0981] After each of YDE-001 to YDE-028 was applied to the eye 14 times, changes in corneal permeability were examined.

[0982] To measure corneal permeability, animals were injected intraperitoneally with the anesthetic Zolethyl 50 at a dose of 25 mg / kg. TM (Virbac Lab., Carros, France). Thereafter, saline containing 1% (V / v) fluorescent solution (fluorescein sodium salt, Tokyo Kasei Kogyo Co., Tokyo, Japan) was applied to the eye at a dose of 5 μl / eye. The eye thus treated was closed and fixed with a strip. After 1 hour, the remaining fluorescent solution ( Fig.12 After 12 to 24 hours, corneal permeability was measured using a blue tungsten lamp and an ophthalmic slit lamp tabletop biological microscope (Model SM-70N; Takaci Seiko Co., Nakano, Japan). Fig.13 ).

[0983] Fig.14 The results of the test are shown, wherein A is a sham control group, B is an ELGE control group, C is a DS reference group, D is a YY-102-administered group, and E to AF are groups to which YDE-001 to YDE-028 were sequentially administered.

[0984] As a result, the penetration of the fluorescent dye in the ELGE control group increased compared with the sham control group. On the 14th day after application, the penetration of the fluorescent dye in the groups treated with the 3% solution of YDE-10, YDE-20, YDE-22, YDE-25, YDE-27 and YDE-28 did not decrease compared with the ELGE control group. In the groups treated with YDE derivatives and the DS reference group, the corneal penetration of the fluorescent dye decreased compared with the ELGE control group, except for the group treated with the 3% solution of YDE-10, YDE-20, YDE-22, YDE-25, YDE-27 and YDE-28. In particular, the penetration of the fluorescent dye in the groups treated with the 3% solution of YDE-15, YDE-11, YDE-08, YDE-26, YDE-16, YDE-01, YDE-23 and YY-102 decreased by more than 20% compared with the DS reference group.

[0985] The specific penetration of the fluorescent dye is shown in Fig.15 and Table 6.

[0986] [Table 6]

[0987]

[0988]

[0989] In addition, YDE-029 to YDE-043 were each applied to the eye 14 times, and then the change in corneal permeability was examined. The measurement of corneal permeability was performed in the same manner as described above ( Fig.16 ).

[0990] As a result, the penetration of the fluorescent dye increased in the ELGE control group compared with the sham control group. On day 14 after administration, the penetration of the fluorescent dye did not decrease in the groups treated with the 3% solution of YDE-29, YDE-32, YDE-33, YDE-36 and YDE-41 compared with the ELGE control group. In the groups treated with YDE derivatives and the DS reference group, the corneal penetration of the fluorescent dye decreased compared with the ELGE control group, except for the group treated with the 3% solution of YDE-29, YDE-32, YDE-33, YDE-36 and YDE-41. In particular, the penetration of the fluorescent dye decreased by more than 20% in the groups treated with the 3% solution of YDE-40, YDE-43 and YDE-42 compared with the DS reference group.

[0991] The specific penetration of the fluorescent dye is shown in Fig.17 and Table 7.

[0992] [Table 7]

[0993] serial number Fluorescent dye penetration (%) 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

[0994] Example 4: Evaluation of the stability of YDE derivatives

[0995] To confirm the stability of each test substance in aqueous solution, 10 mg of each sample was dissolved in 1 ml of water to a concentration of 1 mg / ml, then placed in a glass bottle, 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 the relevant substance at one, two, four, eight and twelve weeks under long-term storage conditions.

[0996] The results showed that after two weeks, YY-101 produced 66.5% of related substances. In contrast, after 12 weeks, YDE-001 to YDE-028 produced 1.1% to 30.6% of related substances. The specific amounts are shown in Table 8.

[0997] [Table 8]

[0998]

[0999]

[1000]

[1001] Example 5: Evaluation of the recovery of corneal damage caused by YDE derivatives

[1002] To confirm whether YDE derivatives can restore corneal damage, the cell growth rate of human primary corneal epithelial cells was examined.

[1003] Specifically, primary corneal epithelial cells (ATCC, ATCC PCS-700-010) were cultured at 5×10 3 The cells were seeded in a 96-well culture plate (Perkin Elmer, 6005680) containing corneal epithelial cell basal medium (ATCC, ATCC PCS-700-030) in a corneal epithelial cell growth kit (ATCC, ATCC PCS-700-040), and then incubated at 37°C and 5% CO. 2 The cells were cultured for 24 hours.

[1004] YDE-001 to YDE-075 were each dissolved in 100% DMSO (Sigma, D2660) to a concentration of 10 mM, and then diluted with 100% DMSO to compound concentrations of 6, 1.9, 0.6, 0.2, 0.06, 0.02, 0.006 and 0.002 mM. 20 μl of the diluted YDE derivatives were added to a 96-well microplate (Greiner Bio-One, 651201) containing 380 μl of corneal epithelial cell basal culture medium, so that the concentration of DMSO was diluted to 5%.

[1005] After 24 hours, 20 μl of each of the YDE derivatives diluted in a 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. Cells treated with YDE derivatives or hEGF were incubated at 37°C and 5% CO 2 48 h and 72 h ( Figures 18 to 25 ).

[1006] The cultured cells were treated with CellTiter-Glo luminescent reagent (Promega, G7573) according to the manufacturer's instructions and reacted at room temperature for 30 minutes. Thereafter, the fluorescent signal (or luminescent signal) was checked using an Envision 2014 multi-label plate reader. The measured values ​​were normalized using a vehicle control (100% proliferating cells).

[1007] As a result, cell proliferation was observed at a concentration of 0.3 μM 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. In particular, high cell proliferation rates ( Figure 26 to Figure 43 ).

[1008] Incorporated by Reference

[1009] All publications and patents mentioned herein are hereby incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the event of a conflict, the present application, including any definitions herein, will control.

[1010] Equivalent

[1011] Although specific embodiments of the present invention have been discussed, the above description is illustrative and not restrictive. After reading this specification and claims, many variations of the present invention will be apparent to those skilled in the art. The full scope of the present invention should be determined by reference to the claims together with the full scope of equivalents of the claims, and this specification together with these variations.

Claims

1. A composition comprising a salt of a compound selected from the following table At least 90% of the compound in the composition is in the form of a salt.

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

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

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

5. The composition of claim 1, wherein the compound has the following structure:

6. The composition of claim 1, wherein the compound has the following structure:

7. The composition of claim 1, wherein the compound has the following structure:

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

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

10. The composition of claim 1, wherein the compound has the following structure:

11. The composition of claim 1, wherein the composition is formulated for topical administration to the eye.

12. The composition of claim 1, wherein the composition is formulated as eye drops.

13. The composition of claim 1, wherein at least 95% of the compound is present in salt form.

14. The composition of claim 1, wherein at least 99% of the compound is present in salt form.

15. Use of the composition according to any one of claims 1 to 14 in the preparation of a medicament for treating dry eye syndrome.

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