Novel peptide and pharmaceutical composition for treating eye diseases containing the novel peptide as an active ingredient

Abstract

The present invention relates to a novel peptide and a pharmaceutical composition for treating eye diseases, which contains the novel peptide as an active ingredient. When the novel peptide of the present invention is applied to the eye, the amount of tear secretion is increased and the damaged cornea is healed, so the novel peptide can be effectively used as a therapeutic agent for eye diseases. [Selected Figure] Figure 1

Description

[Technical field]

[0001] The present invention relates to a novel peptide and a pharmaceutical composition for treating eye diseases containing the same as an active pharmaceutical ingredient. [Background technology]

[0002] Dry eye syndrome or keratoconjunctivitis sicca can be broadly defined as damage to the ocular surface due to impaired tear secretion (Joossen C et al., Exp. Eye Res., 146:172-8, 2016). Dry eye syndrome is known to result from a combination of various factors that cause impaired tear secretion and damage and discomfort to the eye. The onset of dry eye syndrome is closely related to age, but its incidence is increasing in younger age groups due to long-term exposure to dry environments such as the use of contact lenses, computers and smart devices (Stern ME et al., Int. Rev. Immunol., 32: 19-41, 2013).

[0003] Specifically, dry eye syndrome reduces mucus secretion from corneal and conjunctival epithelium, as well as mucus secretion from mucus-secreting goblet cells, resulting in a dramatic decrease in ocular lubrication. 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 via the Schirmer test using cobalt chloride paper. Furthermore, damage to the cornea that may accompany dry eye syndrome can be easily evaluated using common fluorescent dyes and a slit lamp fluorometer.

[0004] Meanwhile, most of the treatments for dry eye syndrome are limited to symptomatic therapy, whose therapeutic efficiency is often very low. Currently, artificial tears are the first choice for the treatment of dry eye syndrome. Since artificial tears as a representative symptomatic therapy only supplement insufficient tears, furthermore, they suffer from the disadvantage that they need to be administered to the eye frequently (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, synthetic compounds such as rebamipide (OPC-127959) and diquafosol sodium, which promote the secretion of tears and mucus, have been developed and used. However, the long-term use of these drugs may cause various side effects such as ocular hyperemia and corneal calcification (Bernauer W et al., Br. J. Ophthalmol., 90:285-8, 2006). Therefore, there is a demand for the development of a safe and effective therapeutic agent for treating dry eye syndrome. Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, the inventors have made efforts to develop a safe and effective therapeutic agent for treating eye diseases, and as a result, have completed the present invention by synthesizing new peptides, administering them to the eyes of rats with dry eye syndrome, and confirming the eye-protecting effects through Schirmer's test and fluorescent dye deposition test. [Means for solving the problem]

[0006] To achieve the objectives of the present invention, one aspect of the present invention provides a compound represented by formula 1:

[0007] Furthermore, another aspect of the present invention provides a peptide having the amino acid sequence represented by: HyP-Gly-Gln-Xaa-Gly-Leu-Ala-Gly-Pro-Lys.

[0008] Additionally, another aspect of the present invention provides a peptide having the amino acid sequence represented by: HyP-Gly-Gln-Asp-Xaa-Leu-Ala-Gly-Pro-Lys.

[0009] Furthermore, another aspect of the present invention provides a peptide having the amino acid sequence represented by: HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Xaa.

[0010] Additionally, another aspect of the present invention provides a peptide having the amino acid sequence represented by PD-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys.

[0011] Further, another aspect of the present invention is directed to Ala-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Ala-Lys, HyP-Gly-Gln-Leu-Gly-Leu-Ala, HyP-Gly-Gln-Glu-Gly-Leu-Gly, HyP-Gly-Gln-Leu-Gly-Leu, D- HyP(2R,4S)-Gly- D- Gln- D- Leu-Gly- D- Leu, HyP-Gly-Gln-Leu-Gly, HyP-Gly-Gln- D- Leu-Gly, and D- The present invention provides a peptide having any one of the amino acid sequences selected from the group consisting of HyP(2R,4S)-Gly-Gln-Leu-Gly.

[0012] Additionally, another aspect of the present invention provides a compound represented by formula 8:

[0013] Yet another aspect of the present invention provides a compound represented by formula 10:

[0014] Additionally, another aspect of the present invention provides a pharmaceutical composition for treating an ocular disease, comprising a compound or peptide as an active pharmaceutical ingredient.

[0015] Additionally, another aspect of the invention provides a method of treating an eye disease comprising administering to a subject a compound or peptide. Effect of the Invention

[0016] When the novel peptides of the present invention are administered to the eye, they increase the amount of tear secretion and promote the repair of damaged cornea. Therefore, they can be advantageously used as therapeutic agents for treating eye diseases. [Brief description of the drawings]

[0017] [Figure 1] FIG. 1 shows sequences and characteristics of peptides prepared according to embodiments of the present invention. [Diagram 2] FIG. 1 shows a process for synthesizing peptides prepared according to embodiments of the present invention. [Diagram 3] FIG. 1 shows the purification procedure of peptides prepared according to an embodiment of the present invention. [Figure 4] FIG. 1 confirms the purity of YDE-001 prepared according to an embodiment of the present invention via HPLC. [Diagram 5] FIG. 1 confirms the purity of YDE-002 prepared according to an embodiment of the present invention via HPLC. [Figure 6] FIG. 1 confirms the purity of YDE-003 prepared according to an embodiment of the present invention via HPLC. [Figure 7] FIG. 1 confirms the purity of YDE-004 prepared according to an embodiment of the present invention via HPLC. [Figure 8] FIG. 1 confirms the purity of YDE-005 prepared according to an embodiment of the present invention via HPLC. [Figure 9] FIG. 1 confirms the purity of YDE-006 prepared according to an embodiment of the present invention via HPLC. [Figure 10] FIG. 1 confirms the purity of YDE-007 prepared according to an embodiment of the present invention via HPLC. [Figure 11] FIG. 1 confirms the purity of YDE-008 prepared according to an embodiment of the present invention via HPLC. [Figure 12] FIG. 1 confirms the purity of YDE-009 prepared according to an embodiment of the present invention via HPLC. [Figure 13] FIG. 1 confirms the purity of YDE-010 prepared according to an embodiment of the present invention via HPLC. [Figure 14] FIG. 1 confirms the purity of YDE-011 prepared according to an embodiment of the present invention via HPLC. [Figure 15] FIG. 1 confirms the purity of YDE-012 prepared according to an embodiment of the present invention via HPLC. [Figure 16] FIG. 1 confirms the purity of YDE-013 prepared according to an embodiment of the present invention via HPLC. [Figure 17] FIG. 1 confirms the purity of YDE-014 prepared according to an embodiment of the present invention via HPLC. [Figure 18] FIG. 1 confirms the purity of YDE-015 prepared according to an embodiment of the present invention via HPLC. [Figure 19] FIG. 1 confirms the purity of YDE-016 prepared according to an embodiment of the present invention via HPLC. [Figure 20] FIG. 1 confirms the purity of YDE-017 prepared according to an embodiment of the present invention via HPLC. [Figure 21] FIG. 1 confirms the purity of YDE-018 prepared according to an embodiment of the present invention via HPLC. [Figure 22] FIG. 1 confirms the purity of YDE-019 prepared according to an embodiment of the present invention via HPLC. [Diagram 23]FIG. 1 confirms the purity of YDE-020 prepared according to an embodiment of the present invention via HPLC. [Figure 24] FIG. 1 confirms the purity of YDE-021 prepared according to an embodiment of the present invention via HPLC. [Diagram 25] FIG. 1 confirms the purity of YDE-022 prepared according to an embodiment of the present invention via HPLC. [Figure 26] FIG. 1 confirms the purity of YDE-023 prepared according to an embodiment of the present invention via HPLC. [Figure 27] FIG. 1 confirms the purity of YDE-024 prepared according to an embodiment of the present invention via HPLC. [Figure 28] FIG. 1 confirms the purity of YDE-025 prepared according to an embodiment of the present invention via HPLC. [Figure 29] FIG. 1 confirms the purity of YDE-026 prepared according to an embodiment of the present invention via HPLC. [Diagram 30] FIG. 1 confirms the purity of YDE-027 prepared according to an embodiment of the present invention via HPLC. [Diagram 31] FIG. 1 confirms the purity of YDE-028 prepared according to an embodiment of the present invention via HPLC. [Diagram 32] FIG. 1 confirms the purity of YDE-029 prepared according to an embodiment of the present invention via HPLC. [Diagram 33] FIG. 1 confirms the purity of YDE-030 prepared according to an embodiment of the present invention via HPLC. [Diagram 34] FIG. 1 confirms the purity of YDE-031 prepared according to an embodiment of the present invention via HPLC. [Diagram 35] FIG. 1 confirms the purity of YDE-032 prepared according to an embodiment of the present invention via HPLC. [Diagram 36] FIG. 1 confirms the purity of YDE-033 prepared according to an embodiment of the present invention via HPLC. [Figure 37] FIG. 1 confirms the purity of YDE-034 prepared according to an embodiment of the present invention via HPLC. [Figure 38] FIG. 1 confirms the purity of YDE-035 prepared according to an embodiment of the present invention via HPLC. [Figure 39] FIG. 1 confirms the purity of YDE-036 prepared according to an embodiment of the present invention via HPLC. [Diagram 40] FIG. 1 confirms the purity of YDE-037 prepared according to an embodiment of the present invention via HPLC. [Diagram 41] FIG. 1 confirms the purity of YDE-038 prepared according to an embodiment of the present invention via HPLC. [Diagram 42] FIG. 1 confirms the purity of YDE-039 prepared according to an embodiment of the present invention via HPLC. [Diagram 43] FIG. 1 confirms the purity of YDE-040 prepared according to an embodiment of the present invention via HPLC. [Diagram 44] FIG. 1 confirms the purity of YDE-041 prepared according to an embodiment of the present invention via HPLC. [Diagram 45] FIG. 1 confirms the purity of YDE-042 prepared according to an embodiment of the present invention via HPLC. [Diagram 46] FIG. 1 confirms the purity of YDE-043 prepared according to an embodiment of the present invention via HPLC. [Figure 47] FIG. 1 confirms the purity of YDE-044 prepared according to an embodiment of the present invention via HPLC. [Figure 48] FIG. 1 confirms the purity of YDE-045 prepared according to an embodiment of the present invention via HPLC. [Figure 49] FIG. 1 confirms the purity of YDE-047 prepared according to an embodiment of the present invention via HPLC. [Figure 50] FIG. 1 confirms the purity of YDE-048 prepared according to an embodiment of the present invention via HPLC. [Figure 51] FIG. 1 confirms the purity of YDE-049 prepared according to an embodiment of the present invention via HPLC. [Figure 52] FIG. 1 confirms the purity of YDE-050 prepared according to an embodiment of the present invention via HPLC. [Diagram 53] FIG. 1 confirms the purity of YDE-051 prepared according to an embodiment of the present invention via HPLC. [Figure 54] FIG. 1 confirms the purity of YDE-052 prepared according to an embodiment of the present invention via HPLC. [Figure 55] FIG. 1 confirms the purity of YDE-053 prepared according to an embodiment of the present invention via HPLC. [Figure 56] FIG. 1 confirms the purity of YDE-054 prepared according to an embodiment of the present invention via HPLC. [Figure 57] FIG. 1 confirms the purity of YDE-055 prepared according to an embodiment of the present invention via HPLC. [Figure 58] FIG. 1 confirms the purity of YDE-056 prepared according to an embodiment of the present invention via HPLC. [Figure 59] FIG. 1 confirms the purity of YDE-057 prepared according to an embodiment of the present invention via HPLC. [Figure 60] FIG. 1 confirms the purity of YDE-058 prepared according to an embodiment of the present invention via HPLC. [Figure 61] FIG. 1 confirms the purity of YDE-059 prepared according to an embodiment of the present invention via HPLC. [Figure 62] FIG. 1 confirms the purity of YDE-060 prepared according to an embodiment of the present invention via HPLC. [Figure 63] FIG. 1 confirms the purity of YDE-064 prepared according to an embodiment of the present invention via HPLC. [Figure 64]FIG. 1 confirms the purity of YDE-066 prepared according to an embodiment of the present invention via HPLC. [Figure 65] FIG. 1 confirms the purity of YDE-072 prepared according to an embodiment of the present invention via HPLC. [Figure 66] FIG. 1 confirms the purity of YDE-073 prepared according to an embodiment of the present invention via HPLC. [Figure 67] FIG. 1 confirms the purity of YDE-074 prepared according to an embodiment of the present invention via HPLC. [Figure 68] FIG. 1 confirms the purity of YDE-075 prepared according to an embodiment of the present invention via HPLC. [Figure 69] FIG. 1 confirms the molecular weight of YDE-001 prepared according to an embodiment of the present invention via ion-mass. [Figure 70] FIG. 1 confirms the molecular weight of YDE-002 prepared according to an embodiment of the present invention via ion-mass. [Figure 71] FIG. 1 confirms the molecular weight of YDE-003 prepared according to an embodiment of the present invention via ion-mass. [Figure 72] FIG. 1 confirms the molecular weight of YDE-004 prepared according to an embodiment of the present invention via ion-mass. [Figure 73] FIG. 1 confirms the molecular weight of YDE-005 prepared according to an embodiment of the present invention via ion-mass. [Figure 74] FIG. 1 confirms the molecular weight of YDE-006 prepared according to an embodiment of the present invention via ion-mass. [Figure 75] FIG. 1 confirms the molecular weight of YDE-007 prepared according to an embodiment of the present invention via ion-mass. [Figure 76] FIG. 1 confirms the molecular weight of YDE-008 prepared according to an embodiment of the present invention via ion-mass. [Figure 77]FIG. 1 confirms the molecular weight of YDE-009 prepared according to an embodiment of the present invention via ion-mass. [Figure 78] FIG. 1 confirms the molecular weight of YDE-010 prepared according to an embodiment of the present invention via ion-mass. [Figure 79] FIG. 1 confirms the molecular weight of YDE-011 prepared according to an embodiment of the present invention via ion-mass. [Figure 80] FIG. 1 confirms the molecular weight of YDE-012 prepared according to an embodiment of the present invention via ion-mass. [Figure 81] FIG. 1 confirms the molecular weight of YDE-013 prepared according to an embodiment of the present invention via ion-mass. [Figure 82] FIG. 1 confirms the molecular weight of YDE-014 prepared according to an embodiment of the present invention via ion-mass. [Figure 83] FIG. 1 confirms the molecular weight of YDE-015 prepared according to an embodiment of the present invention via ion-mass. [Figure 84] FIG. 1 confirms the molecular weight of YDE-016 prepared according to an embodiment of the present invention via ion-mass. [Figure 85] FIG. 1 confirms the molecular weight of YDE-017 prepared according to an embodiment of the present invention via ion-mass. [Figure 86] FIG. 1 confirms the molecular weight of YDE-018 prepared according to an embodiment of the present invention via ion-mass. [Figure 87] FIG. 1 confirms the molecular weight of YDE-019 prepared according to an embodiment of the present invention via ion-mass. [Figure 88] FIG. 1 confirms the molecular weight of YDE-020 prepared according to an embodiment of the present invention via ion-mass. [Figure 89] FIG. 1 confirms the molecular weight of YDE-021 prepared according to an embodiment of the present invention via ion-mass. [Figure 90]FIG. 1 confirms the molecular weight of YDE-022 prepared according to an embodiment of the present invention via ion-mass. [Figure 91] FIG. 1 confirms the molecular weight of YDE-023 prepared according to an embodiment of the present invention via ion-mass. [Figure 92] FIG. 1 confirms the molecular weight of YDE-024 prepared according to an embodiment of the present invention via ion-mass. [Figure 93] FIG. 1 confirms the molecular weight of YDE-025 prepared according to an embodiment of the present invention via ion-mass. [Figure 94] FIG. 1 confirms the molecular weight of YDE-026 prepared according to an embodiment of the present invention via ion-mass. [Figure 95] FIG. 1 confirms the molecular weight of YDE-027 prepared according to an embodiment of the present invention via ion-mass. [Figure 96] FIG. 1 confirms the molecular weight of YDE-028 prepared according to an embodiment of the present invention via ion-mass. [Figure 97] FIG. 1 confirms the molecular weight of YDE-029 prepared according to an embodiment of the present invention via ion-mass. [Figure 98] FIG. 1 confirms the molecular weight of YDE-030 prepared according to an embodiment of the present invention via ion-mass. [Figure 99] FIG. 1 confirms the molecular weight of YDE-031 prepared according to an embodiment of the present invention via ion-mass. [Figure 100] FIG. 1 confirms the molecular weight of YDE-032 prepared according to an embodiment of the present invention via ion-mass. [Figure 101] FIG. 1 confirms the molecular weight of YDE-033 prepared according to an embodiment of the present invention via ion-mass. [Figure 102] FIG. 1 confirms the molecular weight of YDE-034 prepared according to an embodiment of the present invention via ion-mass. [Figure 103]FIG. 1 confirms the molecular weight of YDE-035 prepared according to an embodiment of the present invention via ion-mass. [Figure 104] FIG. 1 confirms the molecular weight of YDE-036 prepared according to an embodiment of the present invention via ion-mass. [Figure 105] FIG. 1 confirms the molecular weight of YDE-037 prepared according to an embodiment of the present invention via ion-mass. [Figure 106] FIG. 1 confirms the molecular weight of YDE-038 prepared according to an embodiment of the present invention via ion-mass. [Figure 107] FIG. 1 confirms the molecular weight of YDE-039 prepared according to an embodiment of the present invention via ion-mass. [Figure 108] FIG. 1 confirms the molecular weight of YDE-040 prepared according to an embodiment of the present invention via ion-mass. [Fig. 109] FIG. 1 confirms the molecular weight of YDE-041 prepared according to an embodiment of the present invention via ion-mass. [Figure 110] FIG. 1 confirms the molecular weight of YDE-042 prepared according to an embodiment of the present invention via ion-mass. [Figure 111] FIG. 1 confirms the molecular weight of YDE-043 prepared according to an embodiment of the present invention via ion-mass. [Figure 112] FIG. 1 confirms the molecular weight of YDE-044 prepared according to an embodiment of the present invention via ion-mass. [Figure 113] FIG. 1 confirms the molecular weight of YDE-045 prepared according to an embodiment of the present invention via ion-mass. [Fig. 114] FIG. 1 confirms the molecular weight of YDE-047 prepared according to an embodiment of the present invention via ion-mass. [Figure 115] FIG. 1 confirms the molecular weight of YDE-048 prepared according to an embodiment of the present invention via ion-mass. [Fig. 116]FIG. 1 confirms the molecular weight of YDE-049 prepared according to an embodiment of the present invention via ion-mass. [Fig. 117] FIG. 1 confirms the molecular weight of YDE-050 prepared according to an embodiment of the present invention via ion-mass. [Fig. 118] FIG. 1 confirms the molecular weight of YDE-051 prepared according to an embodiment of the present invention via ion-mass. [Figure 119] FIG. 1 confirms the molecular weight of YDE-052 prepared according to an embodiment of the present invention via ion-mass. [Figure 120] FIG. 1 confirms the molecular weight of YDE-053 prepared according to an embodiment of the present invention via ion-mass. [Figure 121] FIG. 1 confirms the molecular weight of YDE-054 prepared according to an embodiment of the present invention via ion-mass. [Figure 122] FIG. 1 confirms the molecular weight of YDE-055 prepared according to an embodiment of the present invention via ion-mass. [Figure 123] FIG. 1 confirms the molecular weight of YDE-056 prepared according to an embodiment of the present invention via ion-mass. [Figure 124] FIG. 1 confirms the molecular weight of YDE-057 prepared according to an embodiment of the present invention via ion-mass. [Fig. 125] FIG. 1 confirms the molecular weight of YDE-058 prepared according to an embodiment of the present invention via ion-mass. [Fig. 126] FIG. 1 confirms the molecular weight of YDE-059 prepared according to an embodiment of the present invention via ion-mass. [Figure 127] FIG. 1 confirms the molecular weight of YDE-060 prepared according to an embodiment of the present invention via ion-mass. [Figure 128] FIG. 1 confirms the molecular weight of YDE-064 prepared according to an embodiment of the present invention via ion-mass. [Figure 129]FIG. 1 confirms the molecular weight of YDE-066 prepared according to an embodiment of the present invention via ion-mass. [Fig. 130] FIG. 1 confirms the molecular weight of YDE-072 prepared according to an embodiment of the present invention via ion-mass. [Fig. 131] FIG. 1 confirms the molecular weight of YDE-073 prepared according to an embodiment of the present invention via ion-mass. [Fig. 132] FIG. 1 confirms the molecular weight of YDE-074 prepared according to an embodiment of the present invention via ion-mass. [Fig. 133] FIG. 1 confirms the molecular weight of YDE-075 prepared according to an embodiment of the present invention via ion-mass. [Fig. 134] Photographs showing the procedure for extraorbital lacrimal gland resection. [Fig. 135] FIG. 1 shows changes in body weight in rat models administered YDE-001 to YDE-028 into the eye. [Fig. 136] FIG. 1 shows changes in body weight in rat models administered YDE-029 to YDE-043 into the eye. [Fig. 137] Photographs showing the procedure for administering drugs to the eye of a rat model. [Fig. 138] 1 is a photograph showing a procedure for measuring the amount of tear secretion in a rat model using cobalt chloride paper. [Fig. 139] 1 is a photograph showing the results of measuring, using cobalt chloride paper, the amount of tear secretion in rat models to which YDE-001 to YDE-028 were administered to the eyes. [Fig. 140] FIG. 1 shows changes in tear secretion in rat models administered YDE-001 to YDE-028 to the eye. [Fig. 141] 1 is a photograph showing the results of measuring, using cobalt chloride paper, the amount of tear secretion in rat models to which YDE-029 to YDE-043 were administered to the eyes. [Fig. 142] FIG. 1 shows changes in the amount of tear secretion in rat models administered YDE-029 to YDE-043 into the eye. [Fig. 143] Photographs showing the procedure for administering a fluorescent substance to the eye of a rat model and confirming the resulting corneal damage. [Fig. 144] 1 is a photograph showing the results of measuring, using a fluorescent substance, damage to the cornea of ​​rat models to which YDE-001 to YDE-028 were administered to the eyes. [Fig. 145] FIG. 1 shows the permeability of fluorescent dyes to confirm the recovery of corneal injury in rat models administered YDE-001 to YDE-028 into the eyes. [Fig. 146] Photographs showing the results of measuring, using a fluorescent substance, damage to the cornea of ​​rat models administered YDE-029 to YDE-043 into the eyes. [Fig. 147] FIG. 1 shows the permeability of fluorescent dyes to confirm the recovery of corneal injury in rat models administered YDE-029 to YDE-043 into the eye. [Fig. 148] FIG. 1 shows the cell growth rate 48 hours after treatment with hEGF on human corneal epithelial cells of plate No. 1. [Figure 149] FIG. 1 shows the cell growth rate 48 hours after treatment with hEGF on human corneal epithelial cells of plate No. 2. [Fig. 150] FIG. 1 shows the cell growth rate 48 hours after treatment with hEGF on human corneal epithelial cells of plate No. 3. [Fig. 151] FIG. 1 shows the cell growth rate 48 hours after treatment with hEGF on human corneal epithelial cells of plate No. 4. [Fig. 152] FIG. 1 shows the cell growth rate 72 hours after treatment with hEGF on human corneal epithelial cells of plate No. 1. [Fig. 153] FIG. 1 shows the cell growth rate 72 hours after treatment with hEGF on human corneal epithelial cells of plate No. 2. [Fig. 154] FIG. 1 shows the cell growth rate 72 hours after treatment with hEGF on human corneal epithelial cells of plate No. 3. [Fig. 155] FIG. 1 shows the cell growth rate 48 hours after treatment with hEGF on human corneal epithelial cells of plate No. 4. [Fig. 156] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YY-101 on human corneal epithelial cells. [Fig. 157] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YY-102 on human corneal epithelial cells. [Fig. 158] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-011 on human corneal epithelial cells. [Fig. 159] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-038 on human corneal epithelial cells. [Fig. 160] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-042 on human corneal epithelial cells. [Fig. 161] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-043 on human corneal epithelial cells. [Fig. 162] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-044 on human corneal epithelial cells. [Fig. 163] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-045 on human corneal epithelial cells. [Fig. 164] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-049 on human corneal epithelial cells. [Fig. 165] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-054 on human corneal epithelial cells. [Fig. 166] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-057 on human corneal epithelial cells. [Fig. 167] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-058 on human corneal epithelial cells. [Fig. 168]FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-059 on human corneal epithelial cells. [Fig. 169] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-060 on human corneal epithelial cells. [Fig. 170] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-072 on human corneal epithelial cells. [Fig. 171] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-073 on human corneal epithelial cells. [Fig. 172] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-074 on human corneal epithelial cells. [Fig. 173] FIG. 1 shows the cell growth rate after (a) 48 hours or (b) 72 hours of treatment with YDE-075 on human corneal epithelial cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The present invention will be described in detail below.

[0019] One aspect of the present invention provides compounds represented by formula 1:

[0020] [ka]

[0021] In the above formula, R 1 ~R 3 each independently represents hydrogen, a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 1~10 Alkoxy, substituted or unsubstituted C 1~10 Haloalkyl, substituted or unsubstituted C 2~10 Alkenyl, substituted or unsubstituted C 2~10 Alkynyl, substituted or unsubstituted C 1~10Alkylene, substituted or unsubstituted C 1~10 Alkenylene, substituted or unsubstituted C 1~10 Alkynylene, substituted or unsubstituted C 5~12 Aryl, substituted or unsubstituted C 7~12 Arylalkyl, substituted or unsubstituted C 5~14 Arylalkynyl, substituted or unsubstituted C 8~16 Arylalkenyl, substituted or unsubstituted C 3~10 Heteroalkyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl or substituted or unsubstituted C 5~12 heteroaryl, wherein said heteroalkyl, heterocycloalkyl or heteroaryl contains at least one of N, O and S; Substitution refers to substitution with one or more non-hydrogen substituents, each non-hydrogen substituent being -X 1 , -R a , -O - , =O, -OR a , -SR a , -S - , -N(R a ) 2 , -N + (R a ) 3 , =NR a , -C(X 1 ) 3 , -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO 2 , =N-OH, =N 2 , -N 3 , -NHC(=O)R a , -C(=O)R a , -C(=O)NR a R a , -S(=O) 2 O - , -S(=O) 2 OH, -S(=O) 2 R a , -OS(=O) 2 OR a , -S(=O) 2 NR a , -S(=O)R a,-OP(=O)(OR a ) 2 , -C(=O)R a , alkylene-C(=O)R a , -C(=S)R a , -C(=O)OR a , alkylene-C(=O)OR a , -C(=O)O - , alkylene-C(=O)O-, -C(=S)OR a , -C(=O)SR a , -C(=S)SR a , -C(=O)NR a R a , alkylene-C(=O)NR a R a , -C(=S)NR a R a and -C(-NR a )NR a R a Each X is selected from the group consisting of 1 is independently selected from F, Cl, Br, or I; a is hydrogen, C 1~6 Alkyl, C 5~12 Aryl, C 7~12 aryl, alkyl, or heterocyclic; R 4 and R 5 each independently represents hydrogen, a substituted or unsubstituted C 1~6 Alkyl, -X 2 , -R b , -O - , =O, -CH 2 OR b -OR b and X 2 is F, Cl, Br or I, R b is H, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 5~12 Aryl, substituted or unsubstituted C 7~12 arylalkyl, or a substituted or unsubstituted heterocycle; R 6 is hydrogen or a substituted or unsubstituted C 1~6 Alkyl, the substituent is -C(=O)NH 2and R 7 is hydrogen or C 1~6 is alkyl, R 8 and R 9 are each independently hydrogen or unsubstituted C 1~6 It is an alkyl.

[0022] R b In the definition of, substituted refers to substitution with a non-hydrogen substituent.

[0023] According to the convention used in the art, in the formulas herein

[0024] [ka] is used to indicate a bond where a moiety or substituent is attached to a core or backbone structure.

[0025] "Alkyl" is a hydrocarbon having primary, secondary, tertiary, and / or cyclic carbon atoms. For example, an alkyl group can be one having 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, i-propyl, -CH(CH 3 ) 2 ), 1-Butyl (n-Bu, n-Butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2CH(CH 3 ) 2 ), 2-Butyl (s-Bu, s-Butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-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 is not limited to these.

[0026] "Alkoxy" refers to a group having the formula -O-alkyl, where an alkyl group, as defined above, is attached to the parent compound through an oxygen atom. The alkyl portion of the alkoxy group can have 1 to 20 carbon atoms (i.e., C 1 ~C 20 alkoxy), 1 to 12 carbon atoms (i.e., C 1 ~C 12 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 3or -OEt), and t-butoxy (-OC(CH 3 ) 3 or -O-tBu), but are not limited to these.

[0027] "Haloalkyl" refers to an alkyl group, as defined above, in which at least one of the hydrogen atoms of the alkyl group is replaced by a halogen atom. The alkyl portion of the haloalkyl group has 1 to 20 carbon atoms (i.e., C 1 ~C 20 haloalkyl), 1 to 12 carbon atoms (i.e., C 1 ~C 12 haloalkyl), or 1 to 6 carbon atoms (i.e., C 1 ~C 6 haloalkyl). Examples of suitable haloalkyl groups include -CF 3 , -CHF 2 , -CFH 2 and -CH 2 CF 3 These include, but are not limited to:

[0028] "Alkenyl" refers to an alkyl group having primary, secondary, tertiary and / or cyclic carbon atoms and at least one area of ​​unsaturation, i.e., carbon-carbon sp 2 It is a hydrocarbon having a double bond. For example, an alkenyl group is a group having 2 to 20 carbon atoms (i.e., C 2 ~C 20 alkenyl), 2 to 12 carbon atoms (i.e., C 2 ~C 12 alkenyl), or 2 to 6 carbon atoms (i.e., C 2 ~C 6 An example of a suitable alkenyl group is 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=CH2 ), but is not limited to these.

[0029] "Alkynyl" is a hydrocarbon having primary, secondary, tertiary and / or cyclic carbon atoms and at least two sites of unsaturation, i.e., one carbon-carbon sp triple bond. For example, an alkynyl group can be any group having 2 to 20 carbon atoms (i.e., C 2 ~C 20 alkynyl), 2 to 12 carbon atoms (i.e., C 2 ~C 12 alkynyl), or 2 to 6 carbon atoms (i.e., C 2 ~C 6 Examples of suitable alkenyl groups include acetylene (-C≡CH) and propargyl (-CH 2 C≡CH), but is not limited to these.

[0030] "Alkylene" refers to a saturated hydrocarbon group, which may be branched, straight chain, or cyclic, and has two valencies derived by the removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent alkane. For example, an alkylene group can have from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. Examples of typical alkylene groups include methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 -), 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), and 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), but is not limited to these.

[0031] "Alkenylene" refers to an unsaturated hydrocarbon group, which may be branched, straight chain, and / or cyclic, and has two valencies derived by the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkene. For example, an alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of typical alkenylene groups include, but are not limited to, 1,2-ethylene (-CH=CH-).

[0032] "Alkynylene" refers to an unsaturated hydrocarbon group, branched, straight chain and / or cyclic, having two valencies derived by the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkyne. For example, an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of typical alkynylene groups include acetylenylene (-C≡C-), propargylene (-CH 2 C≡C-), and 4-pentynylene (-CH 2 CH 2 CH 2 C≡C-), but is not limited to these.

[0033] "Aryl" refers to an aromatic hydrocarbon group derived by the removal of one hydrogen atom from six carbon atoms of a parent aromatic ring system. For example, an aryl group can have from 6 to 20 carbon atoms, from 6 to 14 carbon atoms, or from 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 substituted or unsubstituted biphenyl.

[0034] "Arylalkyl" refers to an acyclic alkyl group in which one hydrogen atom bonded to a carbon atom, typically a terminal or other sp3 carbon atom, is replaced by an aryl group. Examples of typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, and 2-naphthophenylethan-1-yl, each of which is substituted or unsubstituted. An arylalkyl group can have 7 to 20 carbon atoms. For example, the alkyl portion can have 1 to 6 carbon atoms, and the aryl portion can have 6 to 14 carbon atoms.

[0035] "Arylalkenyl" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom although sp2 carbon atoms are also available, is replaced with an aryl group. The aryl portion of the arylalkenyl can be, for example, any aryl group described herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups described herein. The arylalkenyl group can have 8 to 20 carbon atoms. For example, the alkenyl portion can have 2 to 6 carbon atoms, and the aryl portion can have 6 to 14 carbon atoms.

[0036] "Cycloalkyl" refers to a saturated monocyclic or polycyclic ring containing only carbon atoms in the ring. Cycloalkyl groups can have 3 to 7 carbon atoms as monocyclic rings, 7 to 12 carbon atoms as bicyclic rings, and up to about 20 carbon atoms as polycyclic rings. Monocyclic cycloalkyls have 3 to 6 ring atoms, more typically 5 or 6 ring atoms. Bicyclic cycloalkyls can have 7 to 12 ring atoms arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system, or 9 to 10 ring atoms arranged in a bicyclo[5,6] or [6,6] system or in a spiro-connected ring. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which may be substituted or unsubstituted.

[0037] "Arylalkynyl" refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or other sp3 carbon atom, is replaced by an aryl group, although sp carbon atoms can also be used. The aryl portion of the arylalkynyl can be, for example, any aryl group described herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups described herein. The arylalkynyl group can have 8 to 20 carbon atoms. For example, the alkynyl portion can have 2 to 6 carbon atoms, and the aryl portion can have 6 to 14 carbon atoms.

[0038] The term "substituted" with respect to alkyl, alkylene, aryl, arylalkyl, heterocyclyl, etc., e.g., "substituted alkyl," "substituted alkylene," "substituted aryl," "substituted arylalkyl," "substituted heterocyclyl," and "substituted carbocyclyl (e.g., cycloalkyl)" means that at least one hydrogen atom of the alkyl, alkylene, aryl, arylalkyl, heterocyclyl, or carbocyclyl (e.g., cycloalkyl) is each independently replaced with a non-hydrogen substituent. Exemplary substituents include -X, -R, -O, -R ... -, =O, -OR, -SR, -S - , -NR 2 , -N + R 3 , =NR, -C(X) 3 , -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO 2 , =N-OH, =N 2 , -N 3 , -NHC(=O)R, -C(=O)R, -C(=O)NRR, -S(=O) 2 O - , -S(=O) 2 OH, -S(=O) 2 R, -OS(=O) 2 OR, -S(=O) 2 NR, -S(=O)R, -OP(=O)(OR) 2 , -C(=O)R, alkylene-C(=O)R, -C(S)R, -C(=O)OR, alkylene-C(=O)OR, -C(=O)O - Examples of alkylenes include, but are not limited to, alkylene-C(=O)O-, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, alkylene-C(=O)NRR, -C(=S)NRR and -C(-NR)NRR, where each X is independently a halogen such as F, Cl, Br or I, and R is independently H, alkyl, aryl, arylalkyl or heterocycle. Alkylene, alkenylene and alkynylene groups may be similarly substituted.

[0039] Those of skill in the art will understand that when moieties such as "alkyl", "aryl" and "heterocyclyl" are substituted with at least one substituent, they can be referred to as optionally "alkylene", "arylene", "heterocyclylene", 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 an "alkyl", "aryl" or "heterocyclyl" moiety is described herein or depicted in the drawings as being "substituted" (or is optionally substituted, e.g., the number of substituents is zero or a positive number), then the term "alkyl", "aryl" or "heterocyclyl" etc. should be understood to be interchangeable with "alkylene", "arylene" or "heterocyclylene", etc.

[0040] One of skill in the art will recognize that the substituents and other moieties of the compounds of formula 1 should be selected to provide compounds that are sufficiently stable as pharma- ceutically useful compounds that can be formulated into acceptably stable pharmaceutical compositions, and compounds of formula 1 having such stability should be understood to fall within the scope of the present invention.

[0041] "Heteroalkyl" refers to an alkyl group in which at least one carbon atom is replaced by a heteroatom such as O, N, or S. For example, if a carbon atom of an alkyl group that is attached to a parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group can be an alkoxy group (e.g., -OCH 3 ), amine groups (e.g., -NHCH 3 or -N(CH 3 ) 2 etc.), or thioalkyl groups (e.g., -SCH 3 If a non-terminal carbon atom of an alkyl group that is not attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group can be an alkyl ether (e.g., -CH 2CH 2 -O-CH 3 etc.), alkylamines (e.g., -CH 2 NHCH 3 or -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 can be a hydroxyalkyl group (e.g., -CH 2 CH 2 -OH), aminoalkyl groups (e.g., -CH 2 NH 2 ), or an alkylthiol group (e.g., -CH 2 CH 2 For example, the heteroalkyl group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. 1 ~C 6 Heteroalkyl refers to a heteroalkyl group having from 1 to 6 carbon atoms.

[0042] The term "heterocycle" or "heterocyclyl" as used herein includes, but is not limited to, those described in such publications as Paquette, Leo A., Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), in particular chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, 1950 to present), in particular volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. In certain embodiments of the present invention, "heterocycle" includes "carbocycle" as defined herein, in which at least one (e.g., 1, 2, 3, or 4) carbon atom is replaced by a heteroatom (e.g., O, N, or S). The term "heterocycle" or "heterocyclyl" includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Substituted heterocycles include heterocyclic rings substituted with any of the substituents disclosed herein, including, for example, a carbonyl group.

[0043] Examples of heterocyclic rings include pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-phenyl-2-phenylpropanedi ... -Pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl , pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, These include, but are not limited to, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isotinoyl, and bis-tetrahydrofuranyl, each of which may be substituted or unsubstituted.

[0044] By way of example, the carbon-bonded heterocycle may be bonded at the 2-, 3-, 4-, 5- or 6-position of pyrazine, at the 3-, 4-, 5- or 6-position of pyridazine, at the 2-, 4-, 5- or 6-position of pyrimidine, at the 2-, 3-, 5- or 6-position of pyrazine, at the 2-, 3-, 4- or 5-position of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, at the 2-, 4- or 5-position of oxazole, imidazole or thiazole, at the 3-, 4- or 5-position of isoxazole, pyrazole or isothiazole, at the 2- or 3-position of aziridine, at the 2-, 3- or 4-position of azetidine, at the 2-, 3-, 4-, 5-, 6-, 7- or 8-position of quinoline, or at the 1-, 3-, 4-, 5-, 6-, 7- or 8-position of isoquinoline, but this is not limited thereto. More typically, examples of carbon-linked 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.

[0045] By way of example, and not by way of limitation, the nitrogen-bonded heterocycle may be bonded at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline or 1H-indazole, at the 2-position of isoindole or isoindoline, at the 4-position of morpholine, and at the 9-position of carbazole or β-carboline (each of which may be substituted or unsubstituted).More typically, examples of nitrogen-bonded heterocycles include 1-aziridinyl, 1-azetidyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl (each of which may be substituted or unsubstituted).

[0046] "Heterocyclylalkyl" refers to an acyclic alkyl group in which one hydrogen atom bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced by a heterocyclyl group (i.e., a heterocyclyl-alkylene moiety). Exemplary heterocyclylalkyl groups include heterocyclyl-CH 2 -, and 2-(heterocyclyl)ethan-1-yl. As used herein, the "heterocyclyl" moiety includes any of the heterocyclyl groups described above and those described in references such as "Principles of Modern Heterocyclic Chemistry." One skilled in the art will appreciate that a heterocyclyl group can be attached to the alkyl portion of a heterocyclylalkyl via a carbon-carbon bond or a carbon-heteroatom bond, provided that the resulting group is chemically stable. A heterocyclylalkyl group can have 2 to 20 carbon atoms. For example, the alkyl portion of a heterocyclylalkyl group can have 1 to 6 carbon atoms, and the heterocyclyl portion can have 1 to 14 carbon atoms. Examples of heterocyclylalkyl include, but are not limited to, 5-membered heterocycles containing sulfur, oxygen and / or nitrogen, such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, and thiadiazolylmethyl; and 6-membered heterocycles containing sulfur, oxygen and / or nitrogen, such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridazylmethyl, pyrimidylmethyl, and pyrazinylmethyl, each of which may be substituted or unsubstituted.

[0047] "Heterocyclylalkenyl" refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom (although sp2 carbon atoms can also be used), is replaced by a heterocyclyl group (i.e., a heterocyclyl-alkenylene moiety). The heterocyclyl portion of the heterocyclylalkenyl group includes any of the heterocyclyl groups described in literature such as "Principles of Modern Heterocyclic Chemistry" and herein. The alkenyl portion of the heterocyclylalkenyl group includes any of the alkenyl groups described herein. One skilled in the art will appreciate that the heterocyclyl group can be bonded to the alkenyl portion of the heterocyclylalkenyl via a carbon-carbon bond or a carbon-heteroatom bond, provided that the resulting group is chemically stable. The heterocyclylalkenyl group can have 3 to 20 carbon atoms. For example, the alkenyl portion of a heterocyclylalkenyl group can have from 2 to 6 carbon atoms, and the heterocyclyl portion can have from 1 to 14 carbon atoms.

[0048] "Heterocyclylalkynyl" refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom (although sp carbon atoms can also be used), is replaced by a heterocyclyl group (i.e., a heterocyclyl-alkynylene moiety). The heterocyclyl portion of the heterocyclylalkynyl group includes any of the heterocyclyl groups described in literature such as "Principles of Modern Heterocyclic Chemistry" and herein. The alkynyl portion of the heterocyclylalkynyl group includes any of the alkynyl groups described herein. Those skilled in the art will appreciate that the heterocyclyl group can be bonded to the alkynyl portion of the heterocyclylalkynyl through a carbon-carbon bond or a carbon-heteroatom bond, provided that the resulting group is chemically stable. The heterocyclylalkynyl group can have 3 to 20 carbon atoms. For example, the alkynyl portion of a heterocyclylalkynyl group can have from 2 to 6 carbon atoms, and the heterocyclyl portion can have from 1 to 14 carbon atoms.

[0049] "Heteroaryl" refers to an aromatic heterocyclyl containing at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that can be contained in the aromatic ring include oxygen, sulfur and nitrogen. Non-limiting examples of heteroaryl rings include all of those listed in the definition of "heterocyclyl" herein, including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, and pyrazyl, each of which can be substituted or unsubstituted.

[0050] "Carbocycle" or "carbocyclyl" refers to a saturated, partially unsaturated, or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 6 ring atoms, more typically 5 or 6 ring atoms. Bicyclic carbocycles can have 7 to 12 ring atoms arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system, or 9 to 10 ring atoms arranged in a bicyclo[5,6] or [6,6] system. Examples of monocyclic or bicyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, and naphthyl, each of which may be substituted or unsubstituted.

[0051] "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), where the alkyl, carbocycle, or heterocycle moiety is as defined herein. A non-limiting example of "acyl" is -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 is substituted or unsubstituted), -C(=O)-cyclopropyl (which is substituted or unsubstituted), -C(=O)-cyclobutyl (which is substituted or unsubstituted), -C(=O)-cyclopentyl (which is substituted or unsubstituted), -C(=O)-cyclohexyl (which is substituted or unsubstituted), and -C(=O)-pyridyl (which is substituted or unsubstituted).

[0052] "Arylheteroalkyl" refers to a heteroalkyl, as defined herein, in which a hydrogen atom (which may be attached to either a carbon atom or a heteroatom) is replaced by an aryl group, as defined herein. The aryl group may be attached to a carbon atom of the heteroalkyl group or to a heteroatom of the heteroalkyl group, provided that the resulting group is chemically stable. 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, or -alkylene-S-alkylene-aryl. In addition, any alkylene moiety in the above formula may be further substituted with any of the substituents defined or exemplified herein.

[0053] "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 include -CH 2 -pyridinyl, -CH 2 -Pyrrolyl, -CH 2 -Oxazolyl, -CH 2 -Indolyl, -CH 2 -Isoindolyl, -CH 2 -Flynil, -CH 2 -Furanyl, -CH 2 -Thienyl, -CH 2 -benzofuranyl, -CH 2 -benzothiophenyl, -CH 2 -Carbazolyl, -CH 2 -Imidazolyl, -CH 2 -Thiazolyl, -CH 2 -Isoxazolyl, -CH 2 -Pyrazolyl, -CH 2 -isothiazolyl, -CH 2 -Quinolyl, -CH 2 -Isoquinolyl, -CH 2 -Pyridazyl, -CH 2-pyrimidyl, -CH 2 -Pyrazyl, -CH(CH 3 )-pyridinyl, -CH(CH 3 )-pyrrolyl, -CH(CH 3 )-Oxazolyl, -CH(CH 3 )-indolyl, -CH(CH 3 )-isoindolyl, -CH(CH 3 )-Furinyl, -CH(CH 3 )-furanyl, -CH(CH 3 )-Thienyl, -CH(CH 3 )-benzofuranyl, -CH(CH 3 )-benzothiophenyl, -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 )-Quinolyl, -CH(CH 3 )-isoquinolyl, -CH(CH 3 )-pyridazyl, -CH(CH 3 )-pyrimidyl and -CH(CH 3 )-pyrazyl.

[0054] "Silyloxy" is -O-SiR 3 "silyloxy" refers to the group, where R includes alkyl, aryl (which may be substituted or unsubstituted), heteroaryl (which may be substituted or unsubstituted), or combinations thereof. A non-limiting example of a silyloxy is -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 Examples include:

[0055] The term "optionally substituted" refers to certain moieties of a compound of Formula 1 that bear one, two or more substituents (eg, an optionally substituted aryl group).

[0056] The term "ester thereof" refers to any ester of a compound in which any -COOH functional group of the molecule is replaced with a -COOR functional group or any -OH functional group of the molecule is replaced with -C(=O)OR, where the R portion of the ester can be any carbon-containing group that forms a stable ester moiety, including but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, and substituted derivatives thereof. Examples of esters can also include esters of "tautomeric enols" as described below, such as those described above.

[0057] In the present invention, the compound represented by the above formula 1 may be the optical isomer L-form or D-form.

[0058] The compound represented by the above formula 1 is R 2 is H and R 3 but

[0059] [ka] and R 4 is -OH and R 5 is H and R 6 but

[0060] [ka] and R 7 but

[0061] [ka] and R 8 is H and R 9 is H. Furthermore, the compound represented by the following formula 1-1 may be an optical isomer L or D. [ka]

[0062] R 1 is a substituted or unsubstituted C 1~6 Alkyl,

[0063] [ka] TIFF0007680824000008.tif29141, where n may be an integer from 1 to 10, but is not limited thereto. a is hydrogen or C 1~6 It may be alkyl.

[0064] Specifically, R 1 teeth,

[0065] [ka] It may be one selected from the group consisting of:

[0066] More specifically, the compound may be a compound set forth in Table 1 below.

[0067] [Table 1] JPEG0007680824000011.jpg245130JPEG0007680824000012.jpg243132JPEG0007680824000013.jpg223134

[0068] The compound represented by the above formula 1 is R 1 but

[0069] [ka] and R 3 but

[0070] [ka] and R 4 is -OH and R 5 is H and R 6 but

[0071] [ka] and R 7 but

[0072] [ka] and R 8 is H and R 9 is H, it can be represented by formula 1-2. Furthermore, the compound represented by formula 1-2 below can be the optical isomer L or D.

[0073] [ka]

[0074] In addition, R 2 is hydrogen, substituted or unsubstituted C 1~6 Alkyl,

[0075] [ka] Here, n may be an integer from 1 to 10, but is not limited thereto. a is hydrogen or C 1~6 It may be alkyl.

[0076] Specifically, R 2 teeth,

[0077] [ka] More specifically, the compound may be a compound listed in Table 2 below. [Table 2] JPEG0007680824000022.jpg104130

[0078] The compound represented by the above formula 1 is R 3 but

[0079] [ka] and R 4 is -OH and R 5 is H and R 6 but

[0080] [ka] and R 7 but

[0081] [ka] and R 8 is H and R 9 is H, it can be represented by formula 1-3. Furthermore, the compounds represented by formula 1-3 below can be optical isomers L or D.

[0082] [ka]

[0083] R 1 is C 1~6 Specifically, R 1teeth,

[0084] [ka] It may be.

[0085] R 2 is C 1~6 Specifically, R 2 teeth,

[0086] [ka] It may be.

[0087] More specifically, the compound may be a compound set forth in Table 3 below.

[0088] [Table 3]

[0089] The compound represented by the above formula 1 is R 1 but

[0090] [ka] and R 2 is H and R 4 is -OH and R 5 is H and R 6 but

[0091] [ka] and R 7 but

[0092] [ka] and R 8 is H and R 9is H, it can be represented by formula 1-4. Furthermore, the compounds represented by formula 1-4 below can be optical isomers L or D.

[0093] [ka]

[0094] R 3 is a substituted or unsubstituted C 1~6 Alkyl,

[0095] [ka] Here, n may be an integer from 1 to 10, but is not limited thereto. a is hydrogen or C 1~6 It may be alkyl.

[0096] Specifically, R 3 teeth,

[0097] [ka] It may be one selected from the group consisting of:

[0098] More specifically, the compound may be a compound set forth in Table 4 below.

[0099] [Table 4] JPEG0007680824000037.jpg65135

[0100] The compound represented by the above formula 1 is R 1 but

[0101] [ka] and R 2is H and R 3 but

[0102] [ka] and R 6 but

[0103] [ka] and R 7 but

[0104] [ka] and R 8 is H and R 9 is H, it can be represented by formula 1-5. Furthermore, the compounds represented by formula 1-5 below can be optical isomers L or D.

[0105] [ka]

[0106] R 4 and R 5 each independently represents a substituted or unsubstituted C 1~6 Alkyl, -OR b , =O, -CH 2 OR b and -X 2 wherein X may be one selected from the group consisting of 2 may independently be a halogen, such as F, Cl, Br, or I. R b is hydrogen or C 1~6 It may be alkyl.

[0107] Specifically, R 4 are H, -OH, =O, -CH 2 OR b and F, in such an event, R 5 can be H. In addition, R 4CH 3 In such an event, R 5 CH 3 It could be.

[0108] More specifically, the compound may be a compound set forth in Table 5 below.

[0109] [Table 5] JPEG0007680824000044.jpg72133

[0110] The compound represented by the above formula 1 is R 2 is H and R 3 but

[0111] [ka] and R 4 is -OH and R 5 is H and R 7 but

[0112] [ka] and R 8 is H and R 9 is H, it can be represented by formula 1-6. Furthermore, the compounds represented by formula 1-6 below can be optical isomers L or D.

[0113] [ka]

[0114] R 1 is C 1~6 Specifically, R 1 teeth,

[0115] [ka] It may be.

[0116] R 6 is a substituted or unsubstituted C 1~6 alkyl, where the substituent is -C(=O)NH 2 Specifically, R 6 teeth,

[0117] [ka] It could be.

[0118] More specifically, the compound may be a compound set forth in Table 6 below.

[0119] [Table 6]

[0120] The compound represented by the above formula 1 is R 2 is H and R 3 but

[0121] [ka] and R 4 is -OH and R 5 is H and R 6 but

[0122] [ka] and R 8 is H and R 9 is H, it can be represented by formula 1-7. Furthermore, the compounds represented by formula 1-7 below can be optical isomers L or D.

[0123] [ka]

[0124] R1 is C 1~6 Specifically, R 1 teeth,

[0125] [ka] It could be.

[0126] R 7 is unsubstituted C 1~6 Specifically, R 7 teeth,

[0127] [ka] It could be TIFF0007680824000056.tif1430.

[0128] More specifically, the compound may be a compound set forth in Table 7 below.

[0129] [Table 7]

[0130] The compound represented by the above formula 1 is R 2 is H and R 3 but

[0131] [ka] and R 4 is -OH and R 5 is H and R 6 but

[0132] [ka] and R 7 but

[0133] [ka] and R 9 is H, it can be represented by formula 1-8. Furthermore, the compounds represented by formula 1-8 below can be optical isomers L or D.

[0134] [ka]

[0135] R 1 is C 1~6 Specifically, R 1 teeth,

[0136] [ka] It could be.

[0137] R 8 is hydrogen or C 1~6 Specifically, R 8 teeth,

[0138] [ka] It could be.

[0139] More specifically, the compound may be a compound set forth in Table 8 below.

[0140] [Table 8]

[0141] The compound represented by the above formula 1 is R 2 is H and R 3 but

[0142] [ka] and R 4 is -OH and R 5 is H and R6 but,

[0143] [ka] and R 7 but

[0144] [ka] and R 8 is H, it can be represented by formula 1-9. Additionally, the compounds represented by formula 1-9 below can be optical isomers L or D.

[0145] [ka]

[0146] R 1 is C 1~6 Specifically, R 1 teeth,

[0147] [ka] It could be.

[0148] R 9 is hydrogen or C 1~6 Specifically, R 9 teeth,

[0149] [ka] or

[0150] [ka] It could be.

[0151] More specifically, the compound may be a compound set forth in Table 9 below.

[0152] [Table 9]

[0153] The compound represented by the above formula 1 is R 2 is H and R 4 is -OH and R 5 is H and R 6 but

[0154] [ka] and R 7 but

[0155] [ka] and R 8 is H, it can be represented by formula 1-10. Furthermore, the compounds represented by formula 1-10 below can be optical isomers L or D.

[0156] [ka]

[0157] R 1 is C 1~6 Specifically, R 1 teeth,

[0158] [ka] It could be.

[0159] In such an event, R 3 is C 1~6 Specifically, R 3 teeth,

[0160] [ka] It could be.

[0161] In such an event, R 9 is C 1~6 Specifically, R 9 teeth,

[0162] [ka] It could be.

[0163] More specifically, the compound may be a compound set forth in Table 10 below.

[0164] [Table 10]

[0165] The compounds represented by the above formulas 1-1 to 1-10 are HyP-Gly-Gln-Glu-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asn-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Gln-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-His-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Lys-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Ser-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Thr-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Ala-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Val-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Ile-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Phe-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Tyr-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Trp-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Ser(homo)-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asp(Me)-Gly-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asn(Me)-Gly-Leu-Ala-Gly-Pro-Lys, D- HyP(2R,4S)-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, D- Hyp(2R,4S)-Gly- D- Gln- D- Leu-Gly- D- Leu- D- Ala-Gly- D- Pro- D- Lys, D- Hyp(2R,4R)-Gly- D- Gln- D- Leu-Gly- D- Leu-D- Ala-Gly- D- Pro- D- Lys、 HyP-Gly-Gln-Asp-Val-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Ile-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Leu-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Ala-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Phe-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Tyr-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Trp-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-His-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Ser-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asp-Thr-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Leu-Ala-Leu-Ala-Gly-Pro-Lys、 HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Tyr、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Leu、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Glu、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Gln、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Nle(6-OH)、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Ala、 D- HyP(2R,4S)-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Ala、 Hyp(2S,4S)-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (4-oxo)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (5-oxo)Pro- Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (4-hydroxyMe)Pro-Gly-Gln-Leu-Gl y-Leu-Ala-Gly-Pro-Lys, (4-fluoro)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (4-dimethyl)Pro-Gly-Gln-Leu-Gly-Leu-Ala -Gly-Pro-Lys, (4-Me)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (5-Me)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, Hyp-Gly-Ala-Leu-Gly-Leu-Ala-Gly-Pro-Lys, Hyp-Gly-Gln-Leu-Gly-Ala-Ala-Gly-Pro-Lys, Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Ala-Pro-Lys, Hyp-Ala-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, D- Hyp(2R,4S)-Ala-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys and D- It may be any one selected from the group consisting of Hyp(2R,4S)-Ala-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Ala.

[0166] Another aspect of the invention provides a peptide having an amino acid sequence represented by HyP-Gly-Gln-Xaa-Gly-Leu-Ala-Gly-Pro-Lys, where Xaa can be one selected from the group consisting of Glu, Asn, Gln, His, Lys, Ser, Thr, Ala, Val, Ile, Leu, Phe, Tyr, Trp, homoSer, Asp(Me) and Asn(Me).

[0167] The peptide may be a variant of a collagen type II α1 derived peptide.Collagen type II α1 can be isolated from the extracellular matrix derived from animal chondrocytes.

[0168] The term "peptide" as used in the present invention refers to a compound in which two or more amino acids are linked by peptide bonds. It is further classified into dipeptides, tripeptides, tetrapeptides, etc. according to the number of component amino acids. An oligopeptide has about 10 or less peptide bonds, and a polypeptide has multiple peptide bonds. In addition, the peptide in the present invention includes mutant peptides in which the amino acid residues are substituted.

[0169] The term "HyP" as used herein refers to an amino acid called hydroxyproline, in which a hydroxyl group (-OH) is attached to the carbon atom at the 4-position of proline. HyP is 5 H 9 NO 3 and can be represented by the following formula 2:

[0170] [ka]

[0171] HyP can include all isomers. In addition, HyP can be an isomer represented by the stereochemistry "2S,4R" unless otherwise specified.

[0172] The term "2S,4R" is represented by R and S, which indicate the stereochemical configuration of a chiral molecule. A typical chiral molecule has a chiral center, such as an asymmetric carbon atom. Since the chiral center has four different substituents (or substituting atoms), their priority is determined by a routine procedure. Once the order of the four substituents is determined by (1), (2), (3), and (4), the lowest order substituent (4) is placed furthest from the line of sight, and the remaining substituents are arranged from higher order to lower order. R (or rectus in Latin, right) indicates an arrangement in which the sequence of (1) to (2) to (3) rotates to the right. S (or sinister, left) indicates an arrangement in which this sequence rotates to the left.

[0173] The term "homoSer" as used in the present invention refers to an α-amino acid called homoserine, which has a hydroxyl group in the side chain. HomoSer is not a proteinogenic amino acid, but is an intermediate present in the biosynthesis of threonine and methionine in microbial organisms and plants. HomoSer can have the following formula 3:

[0174] [ka]

[0175] The term "Asp(Me)" as used herein means that the hydrogen atom of the hydroxyl group (OH) attached to the carbon atom at the 4-position of aspartic acid is substituted with a methyl group (CH 3 ) represents an amino acid that is substituted by Asp(Me). Asp(Me) can have the following formula 4:

[0176] [ka]

[0177] The term "Asn(Me)" as used herein refers to an amine group (NH 2 ) hydrogen atom is a methyl group (CH 3) represents an amino acid that is substituted by Asn(Me). Asn(Me) can have the following formula 5:

[0178] [ka]

[0179] Additionally, another aspect of the present invention provides a peptide having an amino acid sequence represented by HyP-Gly-Gln-Asp-Xaa-Leu-Ala-Gly-Pro-Lys, where Xaa can be one selected from the group consisting of Val, Ile, Leu, Ala, Phe, Tyr, Trp, Ser, Thr and (N-Me)Gly.

[0180] The term "(N-Me)Gly" as used herein refers to an amine group (NH 2 ) hydrogen atom is a methyl group (CH 3 (N-Me)Gly can have the following formula 6:

[0181] [ka]

[0182] Another aspect of the present invention provides a peptide having an amino acid sequence represented by HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Xaa, where Xaa can be one selected from the group consisting of Tyr, Leu, Glu, Gln, Ala and Nle(6-OH).

[0183] The term "Nle(6-OH)" as used herein refers to an amino acid in which a hydroxyl group (-OH) is attached to the carbon atom at the 6-position of norleucine. Nle(6-OH) is 5 H 11 NO 3 and can be represented by the following formula 7:

[0184] [ka]

[0185] Another aspect of the present invention provides a peptide having an amino acid sequence represented by PD-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, wherein PD can be any one selected from the group consisting of the following formulae:

[0186] [ka]

[0187] Yet another aspect of the invention is Ala-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys (SEQ ID NO: 54), Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Ala-Lys (SEQ ID NO: 55), HyP-Gly-Gln-Leu-Gly-Leu-Ala (SEQ ID NO: 56), HyP-Gly-Gln-Glu-Gly-Leu-Gly (SEQ ID NO: 57), HyP-Gly-Gln-Leu-Gly-Leu (SEQ ID NO: 58), D- HyP(2R,4S)-Gly- D- Gln- D- Leu-Gly- D- Leu (SEQ ID NO: 59), HyP-Gly-Gln-Leu-Gly (SEQ ID NO: 60), HyP-Gly-Gln- D- Leu-Gly (SEQ ID NO:61), and D- The present invention provides a peptide having any one of the amino acid sequences selected from the group consisting of HyP(2R,4S)-Gly-Gln-Leu-Gly (SEQ ID NO: 62).

[0188] Another aspect of the present invention provides compounds represented by formula 8:

[0189] [ka]

[0190] The compound represented by the above formula 8 indicates a compound in which Asp is modified to aspartimide by a dehydration condensation reaction of the hydroxyl group (-OH) bound to the carbon atom at the 4-position of Asp in the amino acid sequence represented by HyP-Gly-Gln-Asp-Gly-Leu-Ala-Gly-Pro-Lys having an Asp-Gly peptide bond.

[0191] The modified compound may be a compound represented by formula 9 below.

[0192] [ka]

[0193] Another aspect of the present invention provides compounds represented by formula 10:

[0194] [ka]

[0195] The compound represented by formula 10 may be a compound represented by the amino acid sequence of SEQ ID NO:31.

[0196] Furthermore, the present invention provides a pharmaceutical composition for treating an ocular disease, comprising the compound or peptide as an active pharmaceutical ingredient.

[0197] Specifically, the eye disease may be one selected from the group consisting of retinopathy, keratitis, dry macular degeneration, wet macular degeneration, dry eye syndrome, corneal and conjunctival epithelial disorder, proliferative vitreous retinopathy, pigmentary retinopathy, diabetic retinopathy, retinopathy of prematurity, retinopathy of immaturity, proliferative retinopathy, ischemic retinopathy, epidemic keratoconjunctivitis, atopic keratitis, superior limbal keratitis, pterygium keratitis dry, phlyctenular keratoconjunctivitis, scleritis, corneal graft rejection, choroidal neovascularization, neovascular glaucoma, ischemic optic neuropathy, retrolental fibroplasia, diabetic macula, neovascular iris disease, erythrochromia, myopia, von Hippel-Lindau syndrome, ocular histoplasmosis, central retinal vein occlusion, Sjogren's syndrome, and Stevens-Johnson syndrome. Preferably, the eye disease may be one selected from the group consisting of retinopathy, keratitis, macular degeneration, dry eye syndrome, and corneal and conjunctival epithelial disorders.

[0198] Corneal and conjunctival epithelial disorders may be due to post-operative surgery, medications, trauma, or contact lens wear.

[0199] Specifically, a composition for treating an eye disease, which contains a compound or peptide as an active pharmaceutical ingredient, may further contain at least one additive selected from the group consisting of a carrier, an excipient, a disintegrant, a sweetener, a coating agent, a swelling agent, a lubricant, a glidant, a flavor, an antioxidant, a buffer, a bacteriostatic agent, a diluent, a dispersant, a surfactant, and a binder. Specifically, a formulation for parenteral administration may be a sterile aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized preparation, or a suppository.

[0200] Yet another aspect of the invention provides a method of treating an eye disease comprising administering to a subject a compound or peptide.

[0201] The dosage of the compound or peptide can be adjusted depending on various factors such as the type of disease, the severity of the disease, the type and amount of the active pharmaceutical ingredient and other ingredients contained in the pharmaceutical composition, the type of formulation, the age, weight, general health condition, sex and diet of the patient, the time and route of administration, the duration of treatment and concurrently used drugs.

[0202] However, for the desired effect, the effective amount of the compound or peptide contained in the pharmaceutical composition may be 0.0001 μg / day to 100 μg / day. In such an event, administration may be performed once a day or divided into several doses. Specifically, the concentration of the compound or peptide contained in the pharmaceutical composition may be 1000 μM to 0.001 μM. Moreover, the concentration of the compound or peptide contained in the pharmaceutical composition may be 100 μM to 0.005 μM, or 50 μM to 0.02 μM.

[0203] In addition, if necessary, the concentration of the compound or peptide contained in the pharmaceutical composition may be 30 μM to 1 μM. Furthermore, the concentration of the compound or peptide contained in the pharmaceutical composition may be 0.01 μM to 1 μM.

[0204] In addition, the subject may be a mammal, particularly a human. The route of administration may be appropriately selected by those skilled in the art, taking into consideration the administration method, and the volume and viscosity of bodily fluids. Specifically, administration may be carried out via any one of the routes selected from the group consisting of application, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular and intradermal. In particular, it may be applied to the eye for use as an eye drop.

[0205] Another aspect of the invention provides the use of a compound or peptide for the treatment of an ocular disease.

[0206] Yet another aspect of the invention provides the use of a compound or peptide for the preparation of a pharmaceutical composition for treating an eye disease.

[0207] Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are intended to further illustrate the present invention. The scope of the present invention is not limited thereby. EXAMPLES

[0208] [Example 1] Preparation of YDE derivatives 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). Through the above protein analysis, proline-GQDGLAGPK (P-GQDGLAGPK), which is a part of the amino acid sequence of collagen type II α1 protein, was obtained. By replacing a part of the above peptide, YDE-001 to YDE-075 peptides were synthesized by ANYGEN (Gwangju, Korea) (Figure 1 and Table 11).

[0209] The process for synthesizing YDE-001 to YDE-075 peptides and their purification procedures performed by ANYGEN are illustrated in Figures 2 and 3.

[0210] [Table 11] JPEG0007680824000091.jpg220169JPEG0007680824000092.jpg222169JPEG0007680824000093.jpg222169JPEG0007680824000094.jpg148169

[0211] [Experimental Example 1] Analysis of YDE derivatives The YDE derivatives prepared in Example 1 were analyzed by HPLC. As a result, 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, Y DE-044, YDE-045, YDE-047, YDE-048, YDE-049, YDE-050, YDE-051, YDE-052, YDE-053, YDE-054, YDE-055, YDE-056, YDE-057, YDE-058, YDE-059, The purity of YDE-060, YDE-064, YDE-066, YDE-072, YDE-073, YDE-074 and YDE-075 was 99.7%, 99.7%, 99.7%, 99.5%, 98.9%, 98.0%, 98.8%, 98.1%, 99.0%, 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. The results were 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% and 96.3% (Figures 4-68).

[0212] In addition, the YDE derivatives prepared in Example 1 were analyzed by ion-mass. As a result, 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-045, YDE-047, YDE-048, YDE-049, YDE-050, YDE-051, YDE-052, YDE-053, YDE-054, YDE-055, YDE-056, YDE-057, YDE-058, YDE-059, YDE The molecular weights of YDE-060, YDE-064, YDE-066, YDE-072, YDE-073, YDE-074 and YDE-075 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 and 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 and 486.4 (Figures 69-133).

[0213] [Experimental Example 2] Evaluation of the ocular protective effect of YDE derivatives on dry eye syndrome [Experimental Example 2.1] Preparation of rats with dry eye syndrome To evaluate the ocular protective effect against dry eye syndrome by YDE-001 to YDE-028 prepared in Example 1, a total of 320 Sprague-Dawley male rats (OrientBio, Seungnam, Korea) were adapted for 7 days. Dry eye syndrome was then induced in 264 test rats via extraorbital lacrimal gland excision (hereinafter, ELGE). Eight test rats without eye anomalies were subjected to sham surgery as a control group.

[0214] The animals were anesthetized using a rodent anesthesia machine (Surgivet, Waukesha, Wis., USA) and a ventilator (Model 687, Harvard Apparatus, Cambridge, UK) with 2%–3% isoflurane (Hana Pharm. Co., Hwasung, Korea), 70% N 2 O and 28.6% O 2 The rats were put under general anesthesia by inhaling a mixed gas of 1000 mg / kg / day. Then, the extraorbital lacrimal glands located in the subcutaneous area above the masseter muscle and below the optic nerve were excised through a transverse incision with a size of 10 mm on the anterior part of the left tragus. The skin was sutured by a conventional method. The ELGE operation time did not exceed 5 minutes for each rat. Six days after the ELGE operation, confirmation was made through the Schirmer test by measuring the amount of tear secretion whether dry eye syndrome was induced. Meanwhile, each rat in the control group with sham operation was checked for the presence and location of the extraorbital lacrimal glands through a skin incision, and then the skin was sutured without excising the extraorbital lacrimal glands (Figure 134).

[0215] The mean body weight of the ELGE test group measured before ELGE surgery was 241.59 ± 13.56 g, and the mean body weight measured 6 days after ELGE surgery was 297.38 ± 34.02 g. The mean body weight of the control group measured before sham surgery was 240.13 ± 25.63 g, and the mean body weight measured 6 days after sham surgery was 297.38 ± 34.02 g (Figure 135).

[0216] The mean tear secretion volume in the control group was 8.34 ± 0.73 mm 3 The mean tear secretion volume in the ELGE study group was 3.55 ± 0.70 mm 3 Eight rats per group and a total of 32 groups were selected based on the average amount of tear production.

[0217] As a reference drug, 3% diquafosol sodium (Santen Pharmaceutical Co., Ltd. (Santen), Tokyo, Japan, hereafter referred to as DS), which is currently on the market, was used.

[0218] This animal study was conducted with prior approval from the Animal Experiment Ethics Committee of Daegu Haany University (approval number DHU2017-003, January 12, 2017). All test animals were fasted for 18 hours, except for water, prior to ELGE surgery and terminal sacrifice.

[0219] The 32 groups are summarized in Table 12.

[0220] [Table 12]

[0221] In addition, to evaluate the eye protection effect against dry eye syndrome by YDE-029 to YDE-043 prepared in Example 1, a total of 200 Sprague-Dawley male rats (OrientBio, Seungnam, Korea) were adapted for 7 days. Dry eye syndrome was induced in 165 test rats via ELGE. Eight test rats without eye deformity were subjected to sham surgery as a control group. ELGE was performed as described above.

[0222] The mean body weight of the ELGE test group measured before ELGE surgery was 264.09 ± 11.53 g, and the mean body weight measured 6 days after ELGE surgery was 316.13 ± 15.77 g. The mean body weight of the control group measured before sham surgery was 263.50 ± 9.24 g, and the mean body weight measured 6 days after sham surgery was 315.25 ± 10.85 g (Figure 136).

[0223] The mean tear secretion volume in the control group was 10.90 ± 1.69 mm 3 The mean tear secretion volume in the ELGE study group was 4.83 ± 0.99 mm 3 Eight rats per group and a total of 20 groups were selected based on the average amount of tear production.

[0224] As a reference drug, 3% DS, which is currently on the market, was used.

[0225] This animal study was conducted with prior approval from the Animal Experiment Ethics Committee of Daegu Haany University (approval number DHU2017-050, June 8, 2017). All test animals were fasted for 18 hours, except for water, prior to ELGE surgery and terminal sacrifice.

[0226] The 20 groups are summarized in Table 13.

[0227] [Table 13]

[0228] [Experimental Example 2.2] Administration of YDE derivatives 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 administered at a dose of 5 μl / eye at 9:30 am and 3:30 pm for 14 days after ELGE surgery for a total of 28 times. DS solution was dissolved in saline at a concentration of 30 mg / ml and administered at a dose of 5 μl / eye twice a day for 14 days after ELGE surgery for a total of 28 times. For the sham control and ELGE control groups, the same stimulation as administration was applied. To prevent excessive eye drying, the same volume of saline was applied in the same manner instead of the test substance.

[0229] In addition, for YDE-029 to YDE-043, YY-102 and 15 YDE series were each dissolved in physiological saline at a concentration of 3 mg / ml and administered at a dose of 5 μl / eye at 9:30 am and 3:30 pm for 14 days, 7 days after ELGE surgery, for a total of 28 times. DS solution was dissolved in physiological saline at a concentration of 30 mg / ml and administered at a dose of 5 μl / eye twice a day for 14 days, 7 days after ELGE surgery, for a total of 28 times. For the sham control and ELGE control groups, the same stimulation as the administration was applied. To prevent excessive eye drying, the same volume of physiological saline was applied in the same manner instead of the test substance (Figure 137).

[0230] [Test Example 2.3] Confirmation of changes in tear secretion volume by YDE derivatives Six days after ELGE surgery, changes in the amount of tear secretion were measured on days 7 and 14 after administration of YDE-001 to YDE-043. The amount of tear secretion was measured by the decrease in the distance traveled by tears absorbed by cobalt chloride paper of 1 × 15 mm size (Toyo Roshi Kaisha, Japan).

[0231] The cobalt chloride paper was placed in the lateral canthus of the rats for 60 seconds to absorb the tear fluid (Figure 139). The length of the absorbed area from the corner of the cobalt chloride paper was measured with an electronic digital caliper (Mitutoyo Corporation, Tokyo, Japan) (Figure 138).

[0232] FIG. 139 shows the results of the study, where A is for the sham control group, B is for the ELGE control group, C is for the DS reference group, D is for the YY-102 treatment group, and E-AF are for the YDE-001-YDE-028 treatment groups, respectively.

[0233] The results confirmed that the amount of tear secretion was decreased in the ELGE control group on the 7th and 14th days after application of physiological saline 6 days after the ELGE operation, compared to the sham control group. In the groups treated with YDE derivatives and the DS reference group, the amount of tear secretion was increased compared to the ELGE control group, except for the groups treated with YDE-9, YDE-10, YDE-17, YDE-19, YDE-20, YDE-21, YDE-22, YDE-25, YDE-27 and YDE-28 in 0.3% solution, which did not show any significant change in the amount of tear secretion after its administration for 14 days. In particular, the amount of tear secretion was increased by more than 20% in the groups treated with YDE-15, YDE-11, YDE-08, YDE-26, YDE-16, YDE-01, YDE-23 and YY-102 in 0.3% solution, compared to the DS reference group.

[0234] The specific amounts of tear secretion are shown in FIG.

[0235] [Table 14] JPEG0007680824000098.jpg16692

[0236] FIG. 141 shows the results of the study, where A is for the sham control group, B is for the ELGE control group, C is for the DS reference group, D is for the YY-102 treatment group, and E through S are for the YDE-029 through YDE-043 treatment groups, respectively.

[0237] The results confirmed that the amount of tear secretion was decreased in the ELGE control group on the 7th and 14th days after application of physiological saline 6 days after the ELGE operation, compared to the sham control group. In the groups treated with YDE derivatives and the DS reference group, the amount of tear secretion was increased compared to the ELGE control group, except for the groups treated with YDE-029, YDE-030, YDE-032, YDE-033, YDE-034, YDE-036 and YDE-41 in 0.3% solution, which did not show any significant change in the amount of tear secretion after its administration for 14 days. In particular, the amount of tear secretion was increased by more than 20% in the groups treated with YDE-040, YDE-043 and YDE-042 in 0.3% solution, in that order, compared to the DS reference group.

[0238] The specific amounts of tear secretion are shown in FIG.

[0239] [Table 15]

[0240] [Experimental Example 2.4] Confirmation of changes in corneal injury caused by YDE derivatives After administering YDE-001 to YDE-028 to each eye 14 times, changes in corneal permeability were checked.

[0241] To measure corneal permeability, the animal anesthetic Zolethyl 50™ (Virbac Lab., Carros, France) was injected intraperitoneally at a dose of 25 mg / kg. Then, 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 thus treated eye was closed and fixed with tape. After 1 hour, the remaining fluorescent solution was removed using a cotton swab (Figure 142). After 12 to 24 hours, the corneal permeability was measured using a table-top model biomicroscope (model SM-70N, Takaci Seiko Co., Nakano, Japan) with a blue light tungsten lamp and a slit lamp for eye drops (Figure 143).

[0242] FIG. 144 shows the results of the study, where A is for the sham control group, B is for the ELGE control group, C is for the DS reference group, D is for the YY-102 treatment group, and E through AF are for the YDE-001 through YDE-028 treatment groups, respectively.

[0243] As a result, the permeability of the fluorescent dye was increased in the ELGE control group compared to the sham control group. The permeability of the fluorescent dye was not decreased in the groups treated with 0.3% solutions of YDE-10, YDE-20, YDE-22, YDE-25, YDE-27 and YDE-28 compared to the ELGE control group on the 14th day after administration. In the groups treated with the YDE derivatives and the DS reference group, the corneal permeability of the fluorescent dye was decreased compared to the ELGE control group, except for the groups treated with 0.3% solutions of YDE-10, YDE-20, YDE-22, YDE-25, YDE-27 and YDE-28. Notably, fluorescent dye permeability was reduced by more than 20% in groups treated with 0.3% solutions of YDE-15, YDE-11, YDE-08, YDE-26, YDE-16, YDE-01, YDE-23 and YY-102 compared to the DS reference group.

[0244] Specific penetration properties of fluorescent dyes are shown in FIG. 145 and Table 16.

[0245] [Table 16] JPEG0007680824000101.jpg24097JPEG0007680824000102.jpg7999

[0246] In addition, YDE-029 to YDE-043 were administered to each eye 14 times, and then changes in corneal permeability were checked. Corneal permeability measurements were performed in the same manner as described above (Figure 146).

[0247] As a result, the permeability of the fluorescent dye was increased in the ELGE control group compared to the sham control group. The permeability of the fluorescent dye was not decreased in the groups treated with 0.3% solutions of YDE-29, YDE-32, YDE-33, YDE-36 and YDE-41 compared to the ELGE control group on the 14th day after administration. In the groups treated with YDE derivatives and the DS reference group, the corneal permeability of the fluorescent dye was decreased compared to the ELGE control group, except for the groups treated with 0.3% solutions of YDE-29, YDE-32, YDE-33, YDE-36 and YDE-41. In particular, the permeability of the fluorescent dye was decreased by more than 20% in the groups treated with 0.3% solutions of YDE-40, YDE-43 and YDE-42 compared to the DS reference group.

[0248] Specific penetration properties of fluorescent dyes are shown in FIG.

[0249] [Table 17] JPEG0007680824000104.jpg14094

[0250] [Experimental Example 3] Evaluation of the stability of YDE derivatives 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, which was then placed in a glass vial, capped 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 substances was evaluated by measuring the amount of related substances at 1 week, 2 weeks, 4 weeks, 8 weeks, and 12 weeks under long-term storage conditions.

[0251] As a result, 66.5% of related substances were generated in YY-101 after 2 weeks. In contrast, 1.1% to 30.6% of related substances were generated in YDE-001 to YDE-028 after 12 weeks. The specific amounts are shown in Table 18.

[0252] [Table 18] JPEG0007680824000106.jpg25092JPEG0007680824000107.jpg2390

[0253] [Test Example 4] Evaluation of corneal injury recovery by YDE derivatives To confirm whether the YDE derivatives could reverse corneal injury, the cell growth rate of human primary corneal epithelial cells was checked.

[0254] Specifically, 5 × 10 cells were cultured per well on 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). 3 The cells were seeded with primary corneal epithelial cells (ATCC, ATCC PCS-700-010) in an amount of 100 ml, and then incubated at 37° C. and 5% CO 2 The cells were cultured for 24 hours under the above conditions.

[0255] YDE-001 to YDE-075 were each dissolved in 100% DMSO (Sigma, D2660) to a concentration of 10 mM, which was then diluted with 100% DMSO to 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 medium so that the concentration of DMSO was diluted to 5%.

[0256] 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. The cells treated with YDE derivatives or hEGF were incubated at 37° C. and 5% CO 2 The cells were cultured for 48 and 72 hours under the above conditions (Figures 148 to 155).

[0257] The cultured cells were treated with CellTiter-Glo luminescence reagent (Promega, G7573) according to the manufacturer's instructions and reacted at room temperature for 30 minutes.Then, the fluorescent (or luminescent) signals were checked using an Envision 2014 multi-label plate reader.The measurements were normalized using the vehicle control (100% proliferating cells).

[0258] As a result, cell proliferation was observed 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 at concentrations of 0.3 μM or less. In particular, high cell proliferation rates were observed in YY-102, YDE-011, YDE-045, YDE-057 and YDE-060 (Figures 156 to 173). The following are examples of embodiments of the present invention. [Embodiment 1] Formula 1: [ka] (In the formula, R 1 ~R 3 each independently represents hydrogen, a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 1~10 Alkoxy, substituted or unsubstituted C 1~10 Haloalkyl, substituted or unsubstituted C 2~10 Alkenyl, substituted or unsubstituted C 2~10 Alkynyl, substituted or unsubstituted C 1~10 Alkylene, substituted or unsubstituted C 1~10 Alkenylene, substituted or unsubstituted C 1~10 Alkynylene, substituted or unsubstituted C 5~12 Aryl, substituted or unsubstituted C 7~12 Arylalkyl, substituted or unsubstituted C 5~14 Arylalkynyl, substituted or unsubstituted C 8~16 Arylalkenyl, substituted or unsubstituted C 3~10 Heteroalkyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl or substituted or unsubstituted C 5~12 heteroaryl, wherein said heteroalkyl, heterocycloalkyl or heteroaryl contains at least one of N, O and S; Substitution refers to substitution with a non-hydrogen substituent, said non-hydrogen substituent being -X 1 、-R a 、-O - , =O, -OR a , -SR a 、-S - , -N(R a ) 2 、-N + (R a ) 3 , =NR a , -C(X 1 ) 3 , -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO 2 , =N-OH, =N 2 、-N 3 , -NHC(=O)R a , -C(=O)R a , -C(=O)NR a R a , -S(=O) 2 O - , -S(=O) 2 OH, -S(=O) 2 R a , -OS(=O) 2 OR a , -S(=O) 2 NR a , -S(=O)R a ,-OP(=O)(OR a ) 2 , -C(=O)R a , alkylene-C(=O)R a , -C(=S)R a , -C(=O)OR a , alkylene-C(=O)OR a , -C(=O)O - , alkylene-C(=O)O-, -C(=S)OR a , -C(=O)SR a , -C(=S)SR a , -C(=O)NR a R a , alkylene-C(=O)NR a R a , -C(=S)NR a R a and -C(-NR a )NR a R a and X may be at least one selected from the group consisting of 1 is F, Cl, Br or I, R a is hydrogen, C 1~6 Alkyl, C 5~12 Aryl, C 7~12 arylalkyl or heterocycle; R 4 and R 5 each independently represents hydrogen, a substituted or unsubstituted C 1~6 Alkyl, -X 2 、-R b 、-O - , =O, -CH 2 OR b -OR b and X 2 is F, Cl, Br or I, R b is H, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 5~12 Aryl, substituted or unsubstituted C 7~12 arylalkyl, or a substituted or unsubstituted heterocycle; R 6 is hydrogen or a substituted or unsubstituted C 1~6 Alkyl, the substituent is -C(=O)NH 2 and R 7 is hydrogen or C 1~6 is alkyl, R 8 and R 9 is hydrogen or unsubstituted C 1~6 (It is alkyl) A compound represented by: [Embodiment 2] R 1 is substituted or unsubstituted C 1~6 Alkyl,

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Claims

1. Formula 1: 【Chemistry 1】 (In the formula, R 1 teeth, 【Chemistry 2】 is selected from R 2 teeth, 【Chemistry 3】 is selected from R 3 teeth, 【Chemistry 4】 is selected from R 4 is selected from substituted or unsubstituted C 1-6 alkyl, -OR b , ═O, -CH 2 OR b , and -X 2 ; R 5 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, -OR b , ═O, -CH 2 OR b , and -X 2 ; R b is hydrogen or C 1-6 alkyl; X 2 is F, Cl, Br or I, R 6 is -CH2CH2C(=O)NH2, R 7 is C 1～6 is alkyl, R 8 is H or -CH 3 , and R9 is H; If a group is substituted, the substituents may be selected from the group consisting of X, X , and X . 1 , -R j , -O - , =O, -OR j , -SR j , -S - , -N(R j ) 2 , -N + (R j ) 3 , =NR j , -C(X 1 ) 3 , -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO 2 , =N-OH, =N 2 , -N 3 , -NHC(=O)R j , -C(=O)R j , -C(=O)NR j R j , -S(=O) 2 O - , -S(=O) 2 OH, -S(=O) 2 R j , -OS(=O) 2 OR j , -S(=O) 2 NR j , -S(=O)R j ,-OP(=O)(OR j ) 2 , -C(=O)R j , alkylene-C(=O)R j , -C(=S)R j , -C(=O)OR j , alkylene-C(=O)OR j , -C(=O)O - , alkylene-C(=O)O-, -C(=S)OR j , -C(=O)SR j , -C(=S)SR j , -C(=O)NR j R j , alkylene-C(=O)NR j R j , -C(=S)NR j R j , and -C(-NR j )NR j R j is selected from X 1 is F, Cl, Br, or I, and R j Each occurrence of is a hydrogen, C 1-6 Alkyl, C 5-12 Aryl, C 7-12 aryl, alkyl, or heterocyclic (provided that the following compound: 【Chemistry 5】 (Except.

2. R 4 -OH and -CH 3 2. The compound of claim 1, selected from:

3. 2. The compound of claim 1, wherein the peptide is Hyp-Ala-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys.

4. 2. The compound of claim 1, wherein the peptide is Hyp(2S,4R)-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys.

5. The peptide is D- Hyp-(2R,4R)-Gly- D -Gln- D -Leu-Gly- D -Leu- D -Ala-Gly- D -Pro- D The compound of claim 1, wherein

6. HyP-Gly-Gln-Glu-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Asn-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Gln-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-His-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Lys-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Ser-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Thr-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Ala-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Phe-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Tyr-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Trp-Gly-Leu-Ala-Gly-Pro-Lys、HyP-Gly-Gln-Ser(ホモ)-Gly-Leu-Ala-Gly-Pro-Lys、 D- HyP(2R,4S)-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys、 D- Hyp(2R,4S)-Gly- D- Gln- D- Leu-Gly- D- Leu- D- Ala-Gly- D- Pro- D- Lys、 D- Hyp(2R,4R)-Gly- D- Gln- D- Leu-Gly- D- Leu- D- Ala-Gly- D- Pro- D- Lys、 HyP-Gly-Gln-Asp-Val-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asp-Ile-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asp-Ala-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asp-Ser-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asp-Thr-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Leu-Ala-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Glu、HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Ala、 D- HyP(2R,4S)-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Ala、 (4-Oxo)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (4-HydroxyMe)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (4-Fluoro)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-L ys, (4-dimethyl)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (4-Me)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, (5-Me)Pro-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, Hyp-Gly-Ala-Leu-Gly-Leu-Ala-Gly-Pro-Lys, Hyp-Gly-Gln-Leu-Gly-Ala-Ala-Gly-Pro-Lys, Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Ala-Pro-Lys, Hyp-Ala-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, D- Hyp(2R,4S)-Ala-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, and D- Hyp(2R,4S)-Ala-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Ala A compound selected from:

7. HyP-Gly-Gln-Xaa 1 A peptide having an amino acid sequence represented by the formula: 1 is selected from Glu, Asn, Gln, His, Lys, Ser, Thr, Ala, Val, Ile, Leu, Phe, Trp, and homoSer.

8. HyP-Gly-Gln-Asp-Xaa 2 A peptide having an amino acid sequence represented by Xaa-Leu-Ala-Gly-Pro-Lys, 2 is selected from Val, Ile, Leu, Ala, and Ser.

9. HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Xaa 3 A peptide consisting of an amino acid sequence represented by the formula: 3 is selected from Leu, Glu, Gln, Ala and Nle(6-OH).

10. A peptide consisting of an amino acid sequence represented by PD-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, wherein PD has the following formula: 【Chemistry 6】 A peptide selected from the group consisting of

11. A pharmaceutical composition for treating an eye disease comprising a compound according to any one of claims 1 to 6 or a peptide according to any one of claims 7 to 10.

12. The pharmaceutical composition according to claim 11, wherein 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.

13. 13. Use of a compound according to any one of claims 1 to 6 or a peptide according to any one of claims 7 to 10 in the manufacture of a medicament for treating an eye disease.

14. The use according to claim 13, wherein the eye disease is selected from retinopathy, keratitis, dry macular degeneration, wet macular degeneration, dry eye syndrome, keratoconjunctivitis sicca and keratoconjunctival epithelial disorder.

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