JP2022507404A - Peptides and pharmaceutical compositions for the treatment of eye diseases - Google Patents

Abstract

The present invention relates to novel peptides and pharmaceutical compositions containing them. The peptide compounds and compositions disclosed herein are useful as therapeutic agents for treating eye diseases. When administered to the eye, the peptide compounds and compositions disclosed herein increase tear secretion and promote recovery of the damaged cornea. [Selection diagram] None

Description

This application claims the priority of US Provisional Patent Application No. 62 / 767,180 filed November 14, 2018. Its contents are incorporated herein by reference.

The present invention relates to peptides and pharmaceutical compositions for the treatment of eye diseases.

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 cause tear secretion disorders and to cause eye damage and discomfort due to a combination of various factors. Although the onset of dry eye syndrome is closely related to age, its incidence is increasing in the younger age group, which is due to the long-term use of contact lenses, computers, and information terminals in a dry environment. The cause is exposure (Stern ME et al., Int. Rev. Immunol., 32: 19-41, 2013).

Specifically, dry eye syndrome reduces mucus secretion in the corneal epithelium and conjunctival epithelium as well as in mucus-secreting goblet cells, resulting in a sharp decrease in eye lubricity. Dry eye syndrome also causes damage to the corneal surface, thereby increasing fluorescein pigment penetration into the cornea. These symptoms of dry eye syndrome can be assessed as changes in tear secretion by Schirmer's test using cobalt chloride paper. In addition, corneal damage that may be associated with dry eye syndrome can be readily assessed using common fluorescent dyes and slit lamp fluorometers.

On the other hand, most treatments for dry eye syndrome are limited to symptomatic treatments, and their therapeutic efficiency is often very low. At present, artificial tears are the first-line treatment for dry eye syndrome. Artificial tears as a typical symptomatic treatment only replenish the deficient tears. Moreover, artificial tears have the disadvantage that they need to be administered frequently to the eye (Kim CS et al., Nutrients 8. pii: E750, 2016). Eye drops derived from sodium hyaluronate and autologous serum have been developed and have been used in patients suffering from dry eye syndrome. In addition, synthetic compounds such as rebamipide (OPC-127959) and sodium diquafosol have been developed and used to promote the secretion of tears and mucus. However, long-term use of these drugs can cause various side effects such as red eye and corneal calcification (Bernauer Wet al., Br. J. Opthalmol., 90: 285-8, 2006). Therefore, there is a need for the development of safe and effective therapeutic agents for the treatment of dry eye syndrome.

で表される化合物の塩を提供し、
式中：
Ｒ^１、Ｒ^２、及びＲ^３は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、もしくはヘテロシクリルアルキルであり；
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；ならびに
Ｒ^７、Ｒ^８、及びＲ^９は、それぞれ独立して、水素またはアルキルであり；
ただし、化合物は、以下のものではなく：

好ましくは、化合物は少なくとも１つのＤ－アミノ酸残基を有する。 In certain embodiments, the present invention relates to formula (I) :.

Provides a salt of the compound represented by,
During the ceremony:
R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, respectively. , Heterocyclyl, or heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl;
However, the compounds are not:

Preferably, the compound has at least one D-amino acid residue.

で表される化合物またはその薬学上許容される塩を提供し、
式中：
Ｒ^１、Ｒ^２、及びＲ^３は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、もしくはヘテロシクリルアルキルであり；
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；ならびに
Ｒ^７、Ｒ^８、及びＲ^９は、それぞれ独立して、水素またはアルキルであり；
ただし、以下：
（ａ）Ｒ^１、Ｒ^２、及びＲ^３の少なくとも１つは、置換または無置換の（Ｃ_２－Ｃ_１０）ハロアルキルである；
（ｂ）アルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、またはヘテロシクリルアルキルのうち少なくとも１つは、－Ｒ^ａ、－ＯＲ^ａ、－ＳＲ^ａ、－Ｎ（Ｒ^ａ）_２、－Ｎ（Ｒ^ａ）_３ ^＋、＝ＮＲ^ａ、－ＮＨＣ（＝Ｏ）Ｒ^ｃ、－Ｃ（＝Ｏ）Ｒ^ｃ、－Ｃ（＝Ｏ）Ｎ（Ｒ^ａ）_２、－Ｓ（＝Ｏ）_２Ｒ^ｃ、－ＯＳ（＝Ｏ）_２ＯＲ^ａ、－Ｓ（＝Ｏ）_２ＯＲ^ａ、－Ｓ（＝Ｏ）_２Ｎ（Ｒ^ａ）_２、－Ｓ（＝Ｏ）Ｒ^ｃ、－ＯＰ（＝Ｏ）（ＯＲ^ａ）_２、－（アルキレン）－Ｃ（＝Ｏ）Ｒ^ｃ、－Ｃ（＝Ｓ）Ｒ^ｃ、－Ｃ（＝Ｏ）ＯＲ^ａ、－（アルキレン）－Ｃ（＝Ｏ）ＯＲ^ａ、－Ｃ（＝Ｓ）ＯＲ^ａ、－Ｃ（＝Ｏ）ＳＲ^ａ、－Ｃ（＝Ｓ）ＳＲ^ａ、－（アルキレン）－Ｃ（＝Ｏ）Ｎ（Ｒ^ａ）_２、－Ｃ（＝Ｓ）Ｎ（Ｒ^ａ）_２、及び－Ｃ（－ＮＲ^ａ）Ｎ（Ｒ^ａ）_２から選択される１つまたは複数の置換基で置換され；かつ
少なくとも１つ存在するＲ^ａまたはＲ^ｃは、ヘテロシクリルアルキル、シクロアルキル、または（シクロアルキル）アルキルである；
（ｃ）化合物は、少なくとも１つのＤ－アミノ酸残基を有する；あるいは
（ｄ）少なくとも２つのＲ^ａが存在し；
少なくとも２つのＲ^ｃが存在し；または
少なくとも１つのＲ^ａ及び少なくとも１つのＲ^ｃが存在し；かつ
存在するこれらＲ^ａ及び／またはＲ^ｃとは異なるＲ^ａ及び／またはＲ^ｃが少なくとも１つ存在する
のうちの少なくとも１つのとおりであり；ならびに
ただし、化合物は以下のものではない：

。 In a further aspect, the present invention relates to formula (I) :.

Provided is a compound represented by the above or a pharmaceutically acceptable salt thereof.
During the ceremony:
R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, respectively. , Heterocyclyl, or heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl;
However, the following:
(A) At least one of R ¹ , R ² , and R ³ is a substituted or unsubstituted (C2 _- C ₁₀ ) haloalkyl;
(B) At least one of alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is -R ^a , -OR ^a , -SR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , = NR ^a , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) N (R ^a ) ₂ , -S (= O) ₂ R ^c , -OS (= O) ₂ OR ^a , -S (= O) ₂ OR ^a , -S (= O) ₂ N (R ^a ) ₂ , -S (= O) R ^c , -OP (= O) (OR ^a ) ₂ ,-(alkylene) -C (= O) R ^c , -C (= S) R ^c , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , -C (= S) OR ^a , -C (= O) SR ^a , -C (= S) SR ^a ,-(alkylene) -C (= O) Substituted with one or more substituents selected from N (R ^a ) ₂ , -C (= S) N (R ^a ) ₂ , and -C (-NR ^a ) N (R ^a ) ₂ . And at least one Ra or R ^c is heterocyclylalkyl, cycloalkyl, or ⁽ cycloalkyl) alkyl;
(C) The compound has at least one D-amino acid residue; or ( ^d ) at least two Ra are present;
At least two R ^cs are present; or at least one R ^a and at least one R ^c are present; and at least one R ^a and / or R ^c different from these R ^a and / or R ^c is present. At least one of them is present; as well as the compounds are not:

..

を有する化合物、またはその薬学上許容される塩を提供する。 Depending on the embodiment, the present invention has the following structure:

Provided is a compound having the above, or a pharmaceutically acceptable salt thereof.

で表される化合物またはその薬学上許容される塩を提供し、
式中：
Ｒ^１及びＲ^２は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、もしくはヘテロシクリルアルキルであり；
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；ならびに
Ｒ^９は、水素またはアルキルであり；
ただし、化合物は、以下のものではない：

。 In a further aspect, the present invention has the formula (V) :.

Provided is a compound represented by the above or a pharmaceutically acceptable salt thereof.
During the ceremony:
R ¹ and R ² are independently H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or Heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁹ is hydrogen or alkyl;
However, the compounds are not:

..

で表される化合物またはその薬学上許容される塩を提供し、
式中：
Ｒ^１及びＲ^２は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、またはヘテロシクリルアルキルであり
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；
Ｒ^７は、水素またはアルキルであり；ならびに
Ｒ^９は、水素またはアルキルであり；
ただし、化合物は、以下のものではない：

。 In a further aspect, the invention is based on formula (VI) :.

Provided is a compound represented by the above or a pharmaceutically acceptable salt thereof.
During the ceremony:
R ¹ and R ² are independently H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or Heterocyclylalkyl, ^R4 , is independent of its presence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl. Selected;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
^R6 is hydrogen, or substituted or unsubstituted alkyl;
R ⁷ is hydrogen or alkyl; and R ⁹ is hydrogen or alkyl;
However, the compounds are not:

..

で表される化合物またはその薬学上許容される塩を提供し、
式中：
Ｒ^１及びＲ^２は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、もしくはヘテロシクリルアルキルであり；
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；
Ｒ^７は、水素またはアルキルであり；ならびに
Ｒ^９は、水素またはアルキルであり；
ただし、化合物は、以下のものではない：

。 In still further embodiments, the present invention relates to formula (VII) :.

Provided is a compound represented by the above or a pharmaceutically acceptable salt thereof.
During the ceremony:
R ¹ and R ² are independently H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or Heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
^R6 is hydrogen, or substituted or unsubstituted alkyl;
R ⁷ is hydrogen or alkyl; and R ⁹ is hydrogen or alkyl;
However, the compounds are not:

..

で表される化合物またはその薬学上許容される塩を提供し、
式中：
Ｒ^１及びＲ^２は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、もしくはヘテロシクリルアルキルであり；
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；
Ｒ^７、Ｒ^８、及びＲ^９は、それぞれ独立して、水素またはアルキルであり；
Ｊは、ＯＨまたは－ＮＲ^ｘＲ^ｙであり；ならびに
Ｒ^ｘ及びＲ^ｙは、それぞれ独立して、Ｈ、任意選択で置換されたアルキル、任意選択で置換されたアルコキシルアルキルから選択されるか、あるいはＲ^ｘ及びＲ^ｙは介在する窒素原子と一緒になって環を形成する。 In still further embodiments, the present invention relates to formula (IX) :.

Provided is a compound represented by the above or a pharmaceutically acceptable salt thereof.
During the ceremony:
R ¹ and R ² are independently H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or Heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
^R6 is hydrogen, or substituted or unsubstituted alkyl;
R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl;
J is OH or -NR ^x R ^y ; and R ^x and R ^y are independently selected from H, optionally substituted alkyl, optionally substituted alkoxyl alkyl, respectively. Alternatively, R ^x and R ^y form a ring together with the intervening nitrogen atom.

で表される化合物またはその薬学上許容される塩も提供し；
式中：
Ｒ^１、Ｒ^２、及びＲ^３は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、もしくはヘテロシクリルアルキルであり；
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；
Ｒ^７、Ｒ^８、及びＲ^９は、それぞれ独立して、水素またはアルキルであり；
Ｊは、ＯＨまたは－ＮＲ^ｘＲ^ｙであり；ならびに
Ｒ^ｘ及びＲ^ｙは、それぞれ独立して、Ｈ、任意選択で置換されたアルキル、任意選択で置換されたアルコキシルアルキルから選択されるか、あるいはＲ^ｘ及びＲ^ｙは介在する窒素原子と一緒になって環を形成する。 The present invention also has the formula (X-am) :.

Also provided is a compound represented by or a pharmaceutically acceptable salt thereof;
During the ceremony:
R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, respectively. , Heterocyclyl, or heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
^R6 is hydrogen, or substituted or unsubstituted alkyl;
R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl;
J is OH or -NR ^x R ^y ; and R ^x and R ^y are independently selected from H, optionally substituted alkyl, optionally substituted alkoxyl alkyl, respectively. Alternatively, R ^x and R ^y form a ring together with the intervening nitrogen atom.

。 The invention also provides salts of the following compounds:

..

Also provided by the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or salt of the present invention.

The present invention also provides a method for treating an eye disease by administering the compound or salt of the present invention or a pharmaceutical composition containing the same, wherein the eye disease is, for example, retinopathy, keratitis, dry macular degeneration. , Wet macular degeneration, dry eye syndrome, keratitis sicca, and keratoconjunctival epithelial disorder.

It is a table which shows the sequence and property of a peptide prepared according to embodiment of this invention. It is a figure which shows the synthetic process of the peptide prepared according to the embodiment of this invention. It is a figure which shows the purification procedure of the peptide prepared according to the embodiment of this invention. It is a photograph showing the procedure of extraorbital lacrimal gland resection. It is a table which shows the body weight change of the rat model which administered YDE-001 to YDE-028 to the eye. It is a table which shows the body weight change of the rat model which administered YDE-029 to YDE-043 to the eye. It is a photograph showing the procedure of administering an agent to the eyes of a rat model. It is a photograph showing the procedure for measuring the tear secretion amount of a rat model using cobalt chloride paper. It is a photograph which shows the result of having measured the tear secretion amount of the rat model which administered YDE-001 to YDE-028 to the eye using cobalt chloride paper. It is a table which shows the change of the tear secretion amount of the rat model which administered YDE-001 to YDE-028 to the eye. It is a photograph showing the result of measuring the tear secretion amount of a rat model to which YDE-029 to YDE-043 was administered to the eyes using cobalt chloride paper. It is a table which shows the change of the tear secretion amount of the rat model which administered YDE-029 to YDE-043 to the eye. It is a photograph showing the procedure of administering a fluorescent substance to the eye of a rat model to confirm the corneal damage. It is a photograph which shows the result of having measured the corneal damage of the rat model which administered YDE-001 to YDE-028 to the eye using a fluorescent substance. It is a table which shows the transmittance of the fluorescent dye for confirming the recovery of the corneal damage of the rat model which administered YDE-001 to YDE-028 to the eye. It is a photograph which shows the result of having measured the corneal damage of the rat model which administered YDE-029 to YDE-043 to the eye using a fluorescent substance. It is a table which shows the transmittance of the fluorescent dye for confirming the recovery of the corneal damage of the rat model which administered YDE-029 to YDE-043 to the eye. It is a figure which shows the cell proliferation rate 48 hours after hEGF treatment with the human corneal epithelial cell of plate number 1. It is a figure which shows the cell proliferation rate 48 hours after hEGF treatment with the human corneal epithelial cell of plate number 2. It is a figure which shows the cell proliferation rate 48 hours after hEGF treatment with the human corneal epithelial cell of plate number 3. It is a figure which shows the cell proliferation rate 48 hours after hEGF treatment with the human corneal epithelial cell of plate number 4. It is a figure which shows the cell proliferation rate 72 hours after hEGF treatment with the human corneal epithelial cell of plate number 1. It is a figure which shows the cell proliferation rate 72 hours after hEGF treatment with the human corneal epithelial cell of plate number 2. It is a figure which shows the cell proliferation rate 72 hours after hEGF treatment with the human corneal epithelial cell of plate number 3. It is a chart showing the cell proliferation rate 72 hours after hEGF treatment with the human corneal epithelial cells of plate No. 4. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YY-101 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YY-102 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-011 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-038 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after the treatment with YDE-042 with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after the treatment with YDE-043 with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-044 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-045 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-049 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-054 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-057 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-058 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-059 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-060 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-072 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-073 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-074 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate after (a) 48 hours or (b) 72 hours after YDE-075 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-078 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after the treatment with YDE-080 with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-081 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-083 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-084 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-086 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-001 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-010 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after the treatment with YDE-029 with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-092 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after the treatment with YDE-053 with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-064 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after the treatment with YDE-066 with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-012 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after the treatment with YDE-019 with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-055 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-085 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-047 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-048 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-050 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after the treatment with YDE-051 with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after the treatment with YDE-052 with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-056 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-061 treatment with human corneal epithelial cells. It is a figure which shows the cell proliferation rate 48 hours and 72 hours after YDE-062 treatment with human corneal epithelial cells.

The present invention is based on the surprising discovery of therapeutic agents for treating eye diseases such as dry eye syndrome. The efficacy of this agonist was demonstrated by synthesizing the peptides, administering them to the eyes of rats with dry eye syndrome, and confirming the protective effect of the eyes through Schirmer's test and fluorescent pigmentation test. ..

When administered to the eye, the novel peptides of the invention increase tear secretion and promote recovery of damaged cornea. Therefore, they can be advantageously used as therapeutic agents for the treatment of eye diseases.

は、部分または置換基「Ｒ」が、骨格構造に結合していることを示すのに使用される。 Definitions In the formulas herein, according to the conventions used in the art.

Is used to indicate that the moiety or substituent "R" is attached to the skeletal structure.

An "alkyl" is a hydrocarbon having a primary, secondary, tertiary, and / or quaternary carbon atom, which is a straight chain, branched chain, and cyclic group, or a combination thereof. Including. For example, an alkyl group has 1 to 20 carbon atoms (ie, C1-C ₂₀ alkyl) and ₁ to _{10 carbon atoms (ie, C1-C 10 alkyl} ). Alternatively, it can have ₁ to ₆ carbon atoms (ie, a C1-C6 alkyl). Examples of suitable alkyl groups are 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 ₂ CH (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 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- Hexil (-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 (-CH (CH 3) CH 2 CH (CH 3) 2) -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 (-CH) 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 ). However, it is not limited to these.

“Alkoxy” refers to a group having the formula —O-alkyl, where the alkyl group as defined above binds to the parent compound via an oxygen atom. The alkyl moiety of the alkoxy group has, for example, 1 to 20 carbon atoms (ie, C ₁ -C ₂₀ alkoxy) and 1 to 12 carbon atoms (ie, C ₁ -C ₁₂ alkoxy). It can have 1 to _{10 carbon atoms (ie, C1-C 10 alkoxy} ), or it can have 1 to 6 carbon atoms (ie, C1 _- C ₆ alkoxy). .. Examples of suitable alkoxy groups are methoxy (-O-CH ₃ or -OME), ethoxy (-OCH ₂ CH ₃ or -OEt), and t-butoxy (-OC (CH ₃ ) ₃ or -O-tBu). However, it is not limited to these.

A "haloalkyl" is an alkyl group in which at least one of the hydrogen atoms of the alkyl group as defined above is replaced with a halogen atom. The alkyl moiety of a haloalkyl group has 1 to 20 carbon atoms (ie, C ₁ -C ₂₀ haloalkyl) and 1 to 12 carbon atoms (ie, C ₁ -C ₁₂ haloalkyl). It can have 1 to 10 carbon atoms (ie, C1-C ₁₀ haloalkyl) or ₁ to 6 carbon atoms (ie, C1 _- C ₆ haloalkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF ₃ , -CHF ₂ , -CFH ₂ , and -CH ₂ CF ₃ .

"Alkenyl" is a hydrocarbon having primary, secondary, tertiary, and / or quaternary carbon atoms, including linear, branched, and cyclic groups, or combinations thereof. And it has at least one unsaturated region, i.e., a carbon-carbon sp2 ^double bond. For example, an alkenyl group has 2 to 20 carbon atoms (ie, C2 _- C ₂₀ alkenyl) and has 2 to 12 carbon atoms (ie, C2 _- C ₁₂ alkenyl). It can have 2 to 10 carbon atoms (ie, C2 _- C ₁₀ alkenyl) or 2 to 6 carbon atoms (ie, C2 _- C ₆ alkenyl). Examples of suitable alkenyl groups are vinyl (-CH = CH ₂ ), allyl (-CH ₂ CH = CH ₂ ), cyclopentenyl (-C ₅ H ₇ ), and 5-hexenyl (-CH ₂ CH ₂ CH ₂ ). CH ₂ CH = CH ₂ ), but is not limited to these.

"Alkynyl" is a hydrocarbon having primary, secondary, tertiary, and / or quaternary carbon atoms, including linear, branched, and cyclic groups, or combinations thereof. And has at least one carbon-carbon sp triple bond. For example, an alkynyl group has 2 to 20 carbon atoms (ie, C2 _- C ₂₀ alkynyl) and has 2 to 12 carbon atoms (ie, C2 _- C ₁₂ alkynyl). It can have _2-10 carbon atoms (ie, C2 _- C10 alkynyl) or _2-6 carbon atoms (ie, C2 _- C6 alkynyl). Examples of suitable alkenyl groups include, but are not limited to, ethynyl (-C≡CH) and propargyl (-CH ₂ C≡CH).

"Alkylene" refers to a saturated hydrocarbon group, which can be branched, linear, or cyclic (or can have a combination of branched, linear, or cyclic groups) and. , Has a divalence derived from removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of typical alkylene groups include, but are not limited to, 1,2-ethylene ( _{-CH2 -} CH2-).

"Alkenylene" refers to an unsaturated hydrocarbon group, which can be branched, linear, or cyclic (or can have a combination of branched, linear, or cyclic groups). Moreover, it has a divalence derived from removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the 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-ethenylene (-CH = CH-).

"Alkynylene" refers to an unsaturated hydrocarbon group, which can be branched, linear, or cyclic (or can have a combination of branched, linear, or cyclic groups). Moreover, it has a divalence derived from removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the 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 radicals are ethynylene (-C≡C-), 2-propinylene (-CH ₂ C≡C-), and 4-pentinylene (-CH ₂ CH ₂ CH ₂ C≡C-). However, it is not limited to these.

"Aryl" indicates an aromatic hydrocarbon group. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Examples of typical aryl groups include, but are not limited to, radicals derived from benzene (eg, phenyl), substituted benzene, substituted or unsubstituted naphthalene, substituted or unsubstituted anthracene, and the like.

"Arylalkyl" refers to an acyclic alkyl group in which one hydrogen atom attached to a carbon atom ^, typically a terminal or other sp3 carbon atom, has been replaced with an aryl group. Examples of typical arylalkyl groups include benzyl, 2-phenylethane-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, naphthobenzyl, 2-naphthophenylethane-1-yl, etc. (each of which). , Substitutable or non-substitutable), but is not limited thereto. Arylalkyl groups can have 7 to 20 carbon atoms. For example, the alkyl moiety of an arylalkyl group can have 1-6 carbon atoms and the aryl moiety of an arylalkyl group can have 6-14 carbon atoms.

An "arylalkenyl" is one hydrogen atom attached to a carbon atom, typically a terminal or other ^sp3 carbon atom (though it could be an ^sp2 carbon atom), replaced with an aryl group. Indicates an acyclic alkenyl group. The aryl moiety of an arylalkenyl may be, for example, any of the aryl groups described herein, and the alkenyl moiety of an arylalkenyl may include, for example, any of the alkenyl groups described herein. Arylalkenyl groups can have 8 to 20 carbon atoms. For example, the alkenyl moiety of an arylalkenyl group can have 2-6 carbon atoms and the aryl moiety of an arylalkenyl group can have 6-14 carbon atoms.

"Aryl alkynyl" is a carbon atom, typically one hydrogen atom attached to a terminal or other sp ³ carbon atom (which may be an sp carbon atom), replaced with an aryl group. , Shows an acyclic alkynyl group. The aryl moiety of the aryl alkynyl may be, for example, any of the aryl groups described herein, and the alkynyl moiety of the aryl alkynyl may include, for example, any of the alkynyl groups described herein. Arylalkynyl groups can have 8 to 20 carbon atoms. For example, the alkynyl moiety of an aryl alkynyl group can have 2-6 carbon atoms and the aryl moiety of an aryl alkynyl group can have 6-14 carbon atoms.

"Cycloalkyl" refers to a saturated monocyclic or compound ring having only a carbon atom in the ring. The cycloalkyl group can have 3 to 7 carbon atoms as a monocycle, can have 7 to 12 carbon atoms as a bicycle, and can have a maximum of about 20 carbon atoms as a polycycle. Can be done. The monocyclic cycloalkyl has 3 to 7 ring atoms, more typically 5 or 6 ring atoms. Bicyclic cycloalkyls can have 7-12 ring atoms and can be fused ring systems, spiro ring systems, or crosslinked ring systems. In the example of cycloalkyl groups, the atoms may be located in a bicyclo [4,5], [5,5], [5,6], or [6,6] system. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl (which may be substituted or unsubstituted, respectively).

The term "substituted" refers to alkyl, alkylene, aryl, arylalkyl, heterocyclyl and the like, eg, "substituted alkyl", "substituted alkylene", "substituted aryl", "substituted arylalkyl", "substituted heterocyclyl". , And in "substituted carbocyclyl (eg, substituted cycloalkyl)", at least one hydrogen atom of the alkyl, alkylene, aryl, arylalkyl, heterocyclyl, or carbocyclyl (eg, cycloalkyl) is independent of each other. It means that it has been replaced by a non-hydrogen substituent. Examples of typical substituents are halo, haloalkyl, oxo, -CN, -NO ₂ , = N-OH, -N ₃ , -R, -OR, -SR, -N (R) ₂ , -N ( R) ₃ ⁺ , = NR, -NHC (= O) R, -C (= O) R, -C (= O) N (R) ₂ , -S (= O) ₂ R, -OS (= O) ) ₂ OR, -S (= O) ₂ OR, -S (= O) ₂ N (R) ₂ , -S (= O) R, -OP (= O) (OR) ₂ ,-(alkylene)- C (= O) R, -C (= S) R, -C (= O) OR,-(alkylene) -C (= O) OR, -C (= S) OR, -C (= O) SR , -C (= S) SR,-(alkylene) -C (= O) N (R) ₂ , -C (= S) N (R) ₂ , and -C (-NR) N (R) ₂ However, but not limited to these, R is independently H, alkyl, aryl, arylalkyl, or heterocyclyl. The alkylene group, the alkenylene group, and the alkynylene group can be substituted in the same manner.

Of course to those skilled in the art, if moieties such as "alkyl", "aryl", "heterocyclyl" are substituted with at least one substituent, they are optionally "alkylene", "allylen". , "Heterocyclylene" and the like (ie, at least one hydrogen atom of the parent "alkyl", "aryl", or "heterocyclyl" moiety is substituted as described herein. Replaced by the group). Parts such as "alkyl," "aryl," and "heterocyclyl" are described herein as "replaced" or substituted in the drawings (or optionally substituted, eg,). Of course, terms such as "alkyl," "aryl," and "heterocyclyl" are referred to as "alkylene," "allylen," and "heterocyclyl," when the number of substituents is described as (0 or a positive number). It is interchangeable with terms such as "ren".

As will be appreciated by those skilled in the art, substituents and other moieties of the compounds of Formula I are sufficiently stable as pharmaceutically useful compounds that can be incorporated into acceptable stable pharmaceutical compositions. Should be selected to provide. Compounds of formula I having such stability are, of course, included within the scope of the present invention.

"Heteroalkyl" refers to an alkyl group in which at least one carbon atom is replaced by a heteroatom such as O, N, or S. For example, if the carbon atom attached to the parent molecule in the alkyl group is replaced by a heteroatom (eg, O, N, or S), the resulting heteroalkyl groups will each be an alkoxy group (eg, eg). -OCH ₃ ), an amine group (eg, -NHCH ₃ , -N (CH ₃ ) ₂ , etc.), or a thioalkyl group (eg, -SCH ₃ ). If the non-terminal carbon atom in the alkyl group that is not attached to the parent molecule is replaced by a heteroatom (eg, O, N, or S), the resulting heteroalkyl group will each be an alkyl ether (eg, O, N, or S). , -CH ₂ CH ₂ -O-CH ₃ , etc.), Alkyl amines (eg, -CH ₂ NHCH ₃ , -CH ₂ N (CH ₃ ) ₂ , etc.), or thioalkyl ethers (eg, -CH ₂ -S-). It can be CH ₃ ). When the terminal carbon atom of the alkyl group is replaced by a heteroatom (eg, O, N, or S), the resulting heteroalkyl groups are hydroxyalkyl groups (eg, -CH ₂ CH ₂ -OH), respectively. It can be an aminoalkyl group (eg, -CH ₂ NH ₂ ) or an alkylthiol group (eg, -CH ₂ CH ₂ -SH). For example, a heteroalkyl group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Preferably, the heteroalkyl group has a total of 2 to 20, 2 to 10 or 2 to 6 atoms in the chain (ie, carbon atoms and heteroatoms combined). The C1-C6 heteroalkyl group represents a heteroalkyl group having ₁ to ₆ carbon atoms.

As used herein, the term "heterocycle" or "heterocyclyl" is used in the following documents, such as Paquette, Leo A. et al. , Principles of Heterocyclic Chemistry (WA Benjamin, New York, 1968), specifically Chapters 1, 3, 4, 6, 7, and 9; The Chemistry Wiley & Sons, New York, from 1950 to the present), specifically Volumes 13, 14, 16, 19, and 28; and J. Mol. Am. Chem. Soc. (1960), but is not limited to those described in 82: 5566 and the like. In certain embodiments of the invention, a "heterocycle" is a carbon ring as defined herein, of at least one (eg, 1, 2, 3, or 4) in the ring. Includes carbon atoms replaced with heteroatoms (eg, O, N, or S). The term "heterocycle" or "heterocyclyl" includes saturated rings, partially unsaturated rings, and aromatic rings (ie, heteroaromatic rings). Substituted heterocycles include, for example, heterocycles substituted with any of the substituents disclosed herein, the substituents comprising a carbonyl group.

Examples of heterocycles are pyridyl, dihydropyridyl, tetrahydropyranid (piperidyl), thiazolyl, tetrahydrothiophenyl, tetrahydrothiophenyl sulfur oxide, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaftenyl, indolyl, indolinyl. , Kinolinyl, Isoquinolinyl, Benzimidazolyl, Piperidinyl, 4-Piperidinyl, Pyrrolidinyl, 2-Pyrrolidonyl, Pyrrolinyl, Tetrahydropyranyl, Tetrahydroquinolinyl, Tetrahydroisoquinolinyl, Decahydroquinolinyl, Octahydroisoquinolinyl, Azocinyl, Triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thiantrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxadinyl, 2H-pyrrolyl, isothiazolyl, isooxazolyl, pyrazinyl, pyridadinyl , Indridinyl, Isoindrill, 3H-Indrill, 1H-Indazolyl, Prinyl, 4H-Kinoridinyl, Tetrahydropyran, Naftyridinyl, Kinoxalinyl, Kinazolinyl, Synnolinyl, Pteridinyl, 4aH-Carbazolyl, Carbazolyl, β-Carborinyl, Phenantridinyl, Acridinyl, Pyridinyl. Phenanthrolinyl, phenazinyl, phenothiazine, frazanyl, phenoxadinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinucridinyl, morpholinyl, oxazolidinyl, benzotrizyl Examples include, but are not limited to, indrill and benzooxazolinyl, which may be substituted or unsubstituted, respectively.

As an example, a carbon-bonded heterocycle is at the 2, 3, 4, 5, or 6 position of pyrazine, at the 3, 4, 5, or 6 position of pyridazine and at the 2, 4, 5, or 6 position of pyrimidine. And at the 2, 3, 5, or 6 position of pyrazine, furan, tetrahydrofuran, thiofuran, thiophene, pyrrol, or at the 2, 3, 4, or 5 position of tetrahydropyrazole, oxazole, imidazole, or thiazole 2, At position 4, or 5, isoxazole, pyrazole, or isothiazole at position 3, 4, or 5, with aziridin at position 2 or 3, with azetidine at position 2, 3, or 4, with quinoline 2, 3, It is possible, but not limited to, bound at positions 4, 5, 6, 7, or 8 or at positions 1, 3, 4, 5, 6, 7, or 8 of isoquinoline. More typically, examples of carbon-bonded heterocycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-. Pyridadinyl, 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). It may be substituted or non-substituted).

As an example, nitrogen-bound heterocycles include aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazolin, 3-imidazolin, pyrazole, pyrazoline, 2-pyrazoline, 3-. Pyrazoline, piperidine, piperazin, indol, isoindoline, or 1H-indazole 1-position, isoindole or isoindoline 2-position, morpholin 4-position, and carbazole or β-carbolin 9-position (these are each) Substitution or non-substitution) is possible, but not limited to these. More typically, examples of nitrogen-bound heterocycles are 1-aziridinyl, 1-azetidinyl, 1-pyrrolid, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl, which may be substituted or unsubstituted, respectively. ).

A "heterocyclylalkyl" is an acyclic alkyl radical (ie, a heterocyclyl-alkylene moiety) in which a carbon atom, typically a single hydrogen atom attached to a terminal or sp3 carbon atom ^, is replaced by a heterocyclyl radical. Is shown. Examples of typical heterocyclylalkyl groups include, but are not limited to, heterocyclyl-CH _2- , 2- (heterocyclyl) ethane-1-yl, and the like. The "heterocyclyl" portion of the heterocyclylalkyl used herein includes those described in documents such as "Principles of Modern Chemistry" and any of the above heterocyclic groups. Of course to those skilled in the art, if the resulting group is chemically stable, the heterocyclyl group can be attached to the alkyl moiety of the heterocyclylalkyl either through a carbon-carbon bond or a carbon-heteroatom bond. .. The heterocyclylalkyl group can have 2 to 20 carbon atoms. For example, the alkyl moiety of a heterocyclyl alkyl group can have 1 to 6 carbon atoms and the heterocyclyl moiety of a heterocyclyl alkyl group can have 2 to 14 carbon atoms. Examples of heterocyclylalkyls include five-membered heterocycles containing sulfur, oxygen, and / or nitrogen, such as thiazolylmethyl, 2-thiazolylethane-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl; and sulfur. Six-membered heterocycles containing oxygen and / or nitrogen, such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridadylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc. (each of which may be substituted or unsubstituted) However, but not limited to these.

A "heterocyclyl alkenyl" is one in which one of the hydrogen atoms attached to a carbon atom, typically a terminal or sp ³ carbon atom (though it could be a sp ² carbon atom), is replaced by a heterocyclyl radical. It shows an acyclic alkenyl radical (ie, a heterocyclyl alkenylene moiety). Heterocyclyl The heterocyclyl moiety of an alkenyl group includes those described in documents such as "Principles of Modern Chemistry" and any of the heterocyclyl groups described herein. The alkenyl portion of the heterocyclylalkenyl group comprises any of the alkenyl groups described herein. Of course to those skilled in the art, if the resulting group is chemically stable, the heterocyclyl group can be attached to the alkenyl moiety of the heterocyclylalkenyl, either through a carbon-carbon bond or a carbon-heteroatom bond. .. The heterocyclylalkenyl group can have 3 to 20 carbon atoms. For example, the alkenyl moiety of a heterocyclylalkenyl group can have 2-6 carbon atoms and the heterocyclyl moiety of a heterocyclylalkenyl group can have 2-14 carbon atoms.

A "heterocyclyl alkynyl" is one in which one of the hydrogen atoms attached to a carbon atom, typically a terminal or sp ³ carbon atom (though it could be a sp carbon atom), is replaced by a heterocyclyl radical. It shows a cyclic alkynyl radical (ie, a heterocyclyl alkynylene moiety). Heterocyclyl The heterocyclyl moiety of the alkynyl group includes those described in documents such as "Principles of Modern Chemistry" and any of the heterocyclyl groups described herein. The alkynyl moiety of a heterocyclyl alkynyl group comprises any of the alkynyl groups described herein. Of course to those skilled in the art, if the resulting group is chemically stable, the heterocyclyl group can be attached to the alkynyl moiety of the heterocyclyl alkynyl either through a carbon carbon bond or a carbon heteroatom bond. .. The heterocyclyl alkynyl group can have 3 to 20 carbon atoms. For example, the alkynyl moiety of a heterocyclyl alkynyl group can have 2 to 6 carbon atoms and the heterocyclyl moiety of a heterocyclyl alkynyl group can have 2 to 14 carbon atoms.

"Heteroaryl" refers to an aromatic heterocyclyl containing at least one heteroatom in the ring. Examples of non-limiting examples of suitable heteroatoms that may be contained in aromatic rings include oxygen, sulfur, and nitrogen. As an example, but not a limitation of the heteroaryl ring, all of those listed in the definition of "heterocyclyl" herein include pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindrill, furanyl, thienyl, benzofuranyl, Includes benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isooxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridadyl, pyrimidyl, pyrazil, etc. (each of which may be substituted or unsubstituted).

A "carbon ring" or "carbocyclyl" is a saturated, partially unsaturated or aromatic ring, one having 3 to 7 carbon atoms as a monocycle, one having 7 to 12 carbon atoms as a bicycle, And those having a maximum of about 20 carbon atoms as polycycles are shown. The monocyclic carbon ring has 3 to 7 carbon atoms, and more typically 5 or 6 ring atoms. Bicyclic cycloalkyls can have 7-12 carbon atoms and can be fused ring systems, spiro ring systems, or crosslinked ring systems. In the example of cycloalkyl groups, the atoms may be located in a bicyclo [4,5], [5,5], [5,6], or [6,6] system. Examples of non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl (which may be substituted or unsubstituted, respectively).

"Acyl" is -C (= O) -alkyl, -C (= O) -carbon ring (which is substituted or unsubstituted), and -C (= O) -heterocycle (which is substituted). Or unsubstituted), the alkyl, carbocyclic, or heterocyclic moieties in the formula are as defined herein. Not limited to "acyl", but as an example, -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).

An "aryl heteroalkyl" is a heteroalkyl as defined herein, wherein a hydrogen atom (which may be attached to either a carbon atom or a heteroatom) is present herein. Shown are those replaced by aryl groups as defined in the medium. If the resulting group is chemically stable, the aryl group can be attached to the carbon atom of the heteroalkyl group or to the heteroatom of the heteroalkyl group. For example, the aryl heteroalkyl group is -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-. It can have a formula such as S-alkylene-aryl. Also, any alkylene moiety in the above formula can be further substituted with any of the substituents defined or exemplified herein.

"Heteroarylalkyl" refers to an alkyl group as defined herein in which a hydrogen atom has been replaced by a heteroaryl group as defined herein. Not limited to heteroarylalkyl, but as an example, -CH ₂ -pyridinyl, -CH ₂ -pyrrolyl, -CH ₂ -oxazolyl, -CH ₂ -indolyl, -CH ₂ -isoindolyl, -CH ₂ -furanyl, -CH _2- Thienyl, -CH ₂ -benzofuranyl, -CH ₂ -benzothiophenyl, -CH ₂ -carbazolyl, -CH ₂ -imidazolyl, -CH ₂ -thiazolyl, -CH ₂ -isooxazolyl, -CH ₂ -pyrazolyl, -CH _2- Isothiazolyl, -CH ₂ -quinolyl, -CH ₂ -isoquinolyl, -CH ₂ -pyridazole, -CH ₂ -pyrimidyl, -CH ₂ -pyrazyl, -CH (CH ₃ ) -pyridinyl, -CH (CH ₃ ) -pyrrolyl, -CH (CH ₃ ) -oxazolyl, -CH (CH ₃ ) -indrill, -CH (CH ₃ ) -isoindrill, -CH (CH _{3) -furanyl, -CH (CH 3 )} -thienyl, -CH (CH ₃ ) ) -Benzophenyl, -CH (CH ₃ ) -benzothiophenyl, -CH (CH ₃ ) -carbazolyl, -CH (CH ₃ ) -imidazolyl, -CH (CH ₃ ) -thiazolyl, -CH (CH ₃ ) -isooxazolyl , -CH (CH ₃ ) -pyrazolyl, -CH (CH ₃ ) -isothiazolyl, -CH (CH ₃ ) -quinolyl, -CH (CH ₃ ) -isoquinolyl, -CH (CH ₃ ) -pyridazole, -CH (CH) ₃ ) -Pyrimidyl, -CH (CH ₃ ) -Pyrazyl and the like can be mentioned.

"Cyriloxy" represents the group -O-SiR ₃ , in which each R is independently alkyl, aryl (which is substituted or unsubstituted), or heteroaryl (which is substituted or unsubstituted). It is a substitution). Not limited to silyloxy, but as an example, -O-Si (CH ₃ ) ₃ , -O-Si (CH ₃ ) ₂ tBu, -O-Si (tBu) ₂ CH ₃ , -O-Si (tBu) ₃ ,- Examples thereof include O-Si (CH ₃ ) ₂ Ph, -O-Si (Ph) ₂ CH ₃ , and -O-Si (Ph) ₃ .

The term "optionally substituted" means that a particular moiety of a compound of formula I (eg, an optionally substituted aryl group) has one, two, or more optional substituents. Show that.

The term "the ester" means that any of the -COOH functional groups in the molecule is modified to be a -COOR functional group, or any of the -OH functional groups in the molecule is -OC (= O). ) Indicates any ester of the compound that has been modified to be R. As used herein, the R moiety of the ester can be any carbon-containing group that forms a stable ester moiety, such as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aryl. Examples include, but are not limited to, alkyls, heterocyclyls, heterocyclylalkyls, and their substituted derivatives. Examples of esters can also include the above esters for "tautomer enols" as described below.

で表される化合物の塩を提供し、
式中：
Ｒ^１、Ｒ^２、及びＲ^３は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、もしくはヘテロシクリルアルキルであり；
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；ならびに
Ｒ^７、Ｒ^８、及びＲ^９は、それぞれ独立して、水素またはアルキルであり；
ただし、化合物は、以下のものではなく：

好ましくは、化合物は、少なくとも１つのＤ－アミノ酸残基を有する。 Compounds of the Invention In certain embodiments, the present invention relates to formula (I) :.

Provides a salt of the compound represented by,
During the ceremony:
R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, respectively. , Heterocyclyl, or heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl;
However, the compounds are not:

Preferably, the compound has at least one D-amino acid residue.

In certain embodiments, R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl, respectively;
^R4 is independently selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -OR ^b , hydroxyalkyl, -CH ₂ OR ^b , and halo in each presence;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl, respectively.

In some embodiments, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl are unsubstituted or unsubstituted, as specified. Alternatively, halo, haloalkyl, oxo, -CN, -NO ₂ , = N-OH, -N ₃ , -R ^a , -OR ^a , -SR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , = NR ^a , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) N (R ^a ) ₂ , -S (= O) ₂ R ^c , -OS ( = O) ₂ OR ^a , -S (= O) ₂ OR ^a , -S (= O) ₂ N (R ^a ) ₂ , -S (= O) R ^c , -OP (= O) (OR ^a ) ₂ ,-(alkylene) -C (= O) R ^c , -C (= S) R ^c , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , -C (= S) OR ^a , -C (= O) SR ^a , -C (= S) SR ^a ,-(alkylene) -C (= O) N (R ^a ) ₂ , -C (= S) N (R ^a ) ) ₂ and -C (-NR ^a ) N (R ^a ) ₂ substituted with one or more substituents selected from;
R ^a is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl, independently of each presence; and R ^c is present. Independently, substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl.

Further in certain embodiments, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl are unsubstituted, as specified. Or halo, haloalkyl, oxo, -R ^a , -OR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) N (R ^a ) ₂ , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , and-(alkylene) -C (= O) N ( ^Ra ) Substituted with one or more substituents selected from ₂ ;
R ^a is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl, independently of each presence; and R ^c is present. Independently, substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl.

In certain cases of such embodiments, Ra is independently hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl each ^{time it is present; and R c is} each time it is present. Independently, it is alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl.

。 In certain embodiments, the compound has a structure of formula (I-10L):

..

。 Alternatively, the compound may have a structure of (I-10D):

..

In certain embodiments, R ¹ is a substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl.

から選択することができ；
Ｒ^ａは、水素またはアルキルであり；ならびに
ｎは、１～１０、好ましくは１～５、より好ましくは１～３の整数である。 More specifically, R ¹ is a substituted or unsubstituted alkyl,

You can choose from;
Ra is hydrogen or alkyl; and n is an ^integer of 1-10, preferably 1-5, more preferably 1-3.

が挙げられる。 As an example of ^one R

Can be mentioned.

である。代替の好適な実施形態において、Ｒ^１は、

である。 In some preferred embodiments, R ¹ is

Is. In a preferred embodiment of the alternative, R ¹

Is.

。 In certain embodiments, the compound has a structure of formula (I-1L):

..

。 Alternatively, the compound may have a structure of formula (I-1D).

..

In certain embodiments, R ² is H, or a substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl.

から選択され；
Ｒ^ａは、水素またはアルキルであり；ならびに
ｎは、１～１０、好ましくは１～５、より好ましくは１～３の整数である。 In some embodiments, R ² is hydrogen, substituted or unsubstituted alkyl,

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

が挙げられる。 As an example of ^two R units

Can be mentioned.

Preferably, R ² is hydrogen.

。 In certain embodiments, the compound has a structure of formula (I-2L):

..

。 Alternatively, the compound may have a structure of formula (I-2D):

..

^In certain embodiments, R3 is a substituted or unsubstituted alkyl or arylalkyl.

から選択され；
Ｒ^ａは、水素またはアルキルであり；ならびに
ｎは、１～１０、好ましくは１～５、より好ましくは１～３の整数である。 ^In some embodiments, R3 is a substituted or unsubstituted alkyl,

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

が挙げられる。好ましくは、Ｒ^３は、

である。 As an example of ³ R units

Can be mentioned. Preferably, R ³ is

Is.

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

..

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

..

In certain embodiments, p is 1 or 2; and ^R4 is a substituted or unsubstituted alkyl, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, each present independently. , And hydroxyalkyl.

In certain embodiments, p is 1 or 2; and ^R4 is independently selected from -CH ₃ , halo, hydroxyl, and hydroxyalkyl each time it is present.

In certain preferred embodiments, ^R4 is a hydroxyl group. In a preferred embodiment of the alternative, R ⁴ is -CH ₃ .

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

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

..

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

..

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

..

ただし、Ｒ^４はヒドロキシルではない。 In certain embodiments, the compound has a structure of formula (I-4Lc):

However, R ⁴ is not a hydroxyl group.

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

..

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

..

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

..

ただし、Ｒ^４はヒドロキシルではない。 In certain embodiments, the compound has a structure of formula (I-4Dc):

However, R ⁴ is not a hydroxyl group.

In certain embodiments, ^R4 is oxo.

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

..

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

..

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

..

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

..

の場合がある。 In certain embodiments, R ⁶ is hydrogen or alkyl, where alkyl is optionally replaced by the presence of one of -C (= O) NH ₂ . In certain embodiments, R6 is an alkyl substituted with the presence of _{one of -C (= O) NH 2} ^at the option. For example, R ⁶ may be -CH ₃ . Alternatively, R ⁶ is

In some cases.

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

..

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

..

である。 In certain embodiments, R ⁷ is (C1 _{-C 10 )} alkyl, preferably

Is.

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

..

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

..

。 In certain embodiments, the compound has a structure of formula (I-11L):

..

。 Alternatively, the compound may have a structure of formula (I-11D):

..

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

In certain embodiments, R ⁹ is —CH ₃ or —H, preferably —H.

In certain embodiments, the compound has at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 D-amino acid residues.

。 In certain embodiments, the invention provides a salt of a compound of formula (I), the compound being selected from:

..

で表される化合物またはその薬学上許容される塩も提供し；
式中：
Ｒ^１、Ｒ^２、及びＲ^３は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、もしくはヘテロシクリルアルキルであり；
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；ならびに
Ｒ^７、Ｒ^８、及びＲ^９は、それぞれ独立して、水素またはアルキルであり；
ただし、以下：
（ａ）Ｒ^１、Ｒ^２、及びＲ^３の少なくとも１つは、置換または無置換の（Ｃ_２－Ｃ_１０）ハロアルキルである；
（ｂ）アルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、またはヘテロシクリルアルキルのうち少なくとも１つは、－Ｒ^ａ、－ＯＲ^ａ、－ＳＲ^ａ、－Ｎ（Ｒ^ａ）_２、－Ｎ（Ｒ^ａ）_３ ^＋、＝ＮＲ^ａ、－ＮＨＣ（＝Ｏ）Ｒ^ｃ、－Ｃ（＝Ｏ）Ｒ^ｃ、－Ｃ（＝Ｏ）Ｎ（Ｒ^ａ）_２、－Ｓ（＝Ｏ）_２Ｒ^ｃ、－ＯＳ（＝Ｏ）_２ＯＲ^ａ、－Ｓ（＝Ｏ）_２ＯＲ^ａ、－Ｓ（＝Ｏ）_２Ｎ（Ｒ^ａ）_２、－Ｓ（＝Ｏ）Ｒ^ｃ、－ＯＰ（＝Ｏ）（ＯＲ^ａ）_２、－（アルキレン）－Ｃ（＝Ｏ）Ｒ^ｃ、－Ｃ（＝Ｓ）Ｒ^ｃ、－Ｃ（＝Ｏ）ＯＲ^ａ、－（アルキレン）－Ｃ（＝Ｏ）ＯＲ^ａ、－Ｃ（＝Ｓ）ＯＲ^ａ、－Ｃ（＝Ｏ）ＳＲ^ａ、－Ｃ（＝Ｓ）ＳＲ^ａ、－（アルキレン）－Ｃ（＝Ｏ）Ｎ（Ｒ^ａ）_２、－Ｃ（＝Ｓ）Ｎ（Ｒ^ａ）_２、及び－Ｃ（－ＮＲ^ａ）Ｎ（Ｒ^ａ）_２から選択される１つまたは複数の置換基で置換され；かつ
少なくとも１つ存在するＲ^ａまたはＲ^ｃは、ヘテロシクリルアルキル、シクロアルキル、または（シクロアルキル）アルキルである；
（ｃ）化合物は、少なくとも１つのＤ－アミノ酸残基を有する；あるいは
（ｄ）少なくとも２つのＲ^ａが存在し；
少なくとも２つのＲ^ｃが存在し；または
少なくとも１つのＲ^ａ及び少なくとも１つのＲ^ｃが存在し；かつ
存在するこれらＲ^ａ及び／またはＲ^ｃとは異なるＲ^ａ及び／またはＲ^ｃが少なくとも１つ存在する
のうちの少なくとも１つのとおりであり；ならびに
ただし、化合物は以下のものではない：

。 The present invention has the formula (I) :.

Also provided is a compound represented by or a pharmaceutically acceptable salt thereof;
During the ceremony:
R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, respectively. , Heterocyclyl, or heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl;
However, the following:
(A) At least one of R ¹ , R ² , and R ³ is a substituted or unsubstituted (C2 _- C ₁₀ ) haloalkyl;
(B) At least one of alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is -R ^a , -OR ^a , -SR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , = NR ^a , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) N (R ^a ) ₂ , -S (= O) ₂ R ^c , -OS (= O) ₂ OR ^a , -S (= O) ₂ OR ^a , -S (= O) ₂ N (R ^a ) ₂ , -S (= O) R ^c , -OP (= O) (OR ^a ) ₂ ,-(alkylene) -C (= O) R ^c , -C (= S) R ^c , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , -C (= S) OR ^a , -C (= O) SR ^a , -C (= S) SR ^a ,-(alkylene) -C (= O) Substituted with one or more substituents selected from N (R ^a ) ₂ , -C (= S) N (R ^a ) ₂ , and -C (-NR ^a ) N (R ^a ) ₂ . And at least one Ra or R ^c is heterocyclylalkyl, cycloalkyl, or ⁽ cycloalkyl) alkyl;
(C) The compound has at least one D-amino acid residue; or ( ^d ) at least two Ra are present;
At least two R ^cs are present; or at least one R ^a and at least one R ^c are present; and at least one R ^a and / or R ^c different from these R ^a and / or R ^c is present. At least one of them is present; as well as the compounds are not:

..

In certain embodiments, at least one of R ¹ , R ² , and R ³ is a substituted or unsubstituted (C2 _- C ₁₀ ) haloalkyl.

In certain embodiments, at least one of alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is ^-Ra ,. -OR ^a , -SR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , = NR ^a , -NHC (= O) R ^c , -C (= O) R ^c , -C ( = O) N (R ^a ) ₂ , -S (= O) ₂ R ^c , -OS (= O) ₂ OR ^a , -S (= O) ₂ OR ^a , -S (= O) ₂ N (R) ^a ) ₂ , -S (= O) R ^c , -OP (= O) (OR ^a ) ₂ ,-(alkylene) -C (= O) R ^c , -C (= S) R ^c , -C ( = O) OR ^a ,-(alkylene) -C (= O) OR ^a , -C (= S) OR ^a , -C (= O) SR ^a , -C (= S) SR ^a ,-(alkylene) One or more substitutions selected from -C (= O) N (R ^a ) ₂ , -C (= S) N (R ^a ) ₂ , and -C (-NR ^a ) N (R ^a ) ₂ . The Ra or R ^c substituted with a group; and at least one present is a heterocyclylalkyl, cycloalkyl, or ⁽ cycloalkyl) alkyl.

In certain embodiments, the compound has at least one D-amino acid residue.

In certain embodiments, the compound meets the following:
There are at least two ^Ra ;
At least two R ^cs are present; or at least one R ^a and at least one R ^c are present; and at least one R ^a and / or R ^c different from these R ^a and / or R ^cs present. exist.

In certain embodiments:
R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl, respectively;
^R4 is independently selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -OR ^b , hydroxyalkyl, -CH ₂ OR ^b , and halo in each presence;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl, respectively.

In some embodiments, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl are unsubstituted or unsubstituted, as specified. Alternatively, halo, haloalkyl, oxo, -CN, -NO ₂ , = N-OH, -N ₃ , -R ^a , -OR ^a , -SR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , = NR ^a , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) N (R ^a ) ₂ , -S (= O) ₂ R ^c , -OS ( = O) ₂ OR ^a , -S (= O) ₂ OR ^a , -S (= O) ₂ N (R ^a ) ₂ , -S (= O) R ^c , -OP (= O) (OR ^a ) ₂ ,-(alkylene) -C (= O) R ^c , -C (= S) R ^c , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , -C (= S) OR ^a , -C (= O) SR ^a , -C (= S) SR ^a ,-(alkylene) -C (= O) N (R ^a ) ₂ , -C (= S) N (R ^a ) ) ₂ and -C (-NR ^a ) N (R ^a ) ₂ substituted with one or more substituents selected from;
R ^a is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl, independently of each presence; and R ^c is present. Independently, substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl.

Further in certain embodiments, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl are unsubstituted, as specified. Or halo, haloalkyl, oxo, -R ^a , -OR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) N (R ^a ) ₂ , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , and-(alkylene) -C (= O) N ( ^Ra ) Substituted with one or more substituents selected from ₂ ;
R ^a is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl, independently of each presence; and R ^c is present. Independently, substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl.

In certain cases of such embodiments, Ra is independently hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl each ^{time it is present; and R c is} every presence. Independently, it is alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl.

。 In certain embodiments, the compound has a structure of formula (I-10L):

..

。 Alternatively, the compound may have a structure of formula (I-10D):

..

_In certain embodiments, R ¹ is a substituted or unsubstituted (C2 _- C10) haloalkyl.

In certain embodiments, R ¹ is a substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl.

から選択することができ；
Ｒ^ａは、水素またはアルキルであり；ならびに
ｎは、１～１０、好ましくは１～５、より好ましくは１～３の整数である。 More specifically, R ¹ is a substituted or unsubstituted alkyl,

You can choose from;
Ra is hydrogen or alkyl; and n is an ^integer of 1-10, preferably 1-5, more preferably 1-3.

が挙げられる。 As an example of ^one R unit

Can be mentioned.

である。代替の好適な実施形態において、Ｒ^１は、

である。 In some preferred embodiments, R ¹ is

Is. In a preferred embodiment of the alternative, R ¹

Is.

。 In certain embodiments, the compound has a structure of formula (I-1L):

..

。 Alternatively, the compound may have a structure of formula (I-1D).

..

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

In certain embodiments, R ² is H, or a substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl.

から選択され；
Ｒ^ａは、水素またはアルキルであり；ならびに
ｎは、１～１０、好ましくは１～５、より好ましくは１～３の整数である。 In some embodiments, R ² is hydrogen, substituted or unsubstituted alkyl,

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

が挙げられる。 As an example of ^two R units

Can be mentioned.

Preferably, R ² is hydrogen.

。 In certain embodiments, the compound has a structure of formula (I-2L):

..

。 Alternatively, the compound may have a structure of formula (I-2D):

..

_In certain embodiments, R ³ is a substituted or unsubstituted (C2 _- C10) haloalkyl.

^In certain embodiments, R3 is a substituted or unsubstituted alkyl or arylalkyl.

から選択され；
Ｒ^ａは、水素またはアルキルであり；ならびに
ｎは、１～１０、好ましくは１～５、より好ましくは１～３の整数である。 ^In some embodiments, R3 is a substituted or unsubstituted alkyl,

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

が挙げられる。好ましくは、Ｒ^３は、

である。 As an example of ³ R units

Can be mentioned. Preferably, R ³ is

Is.

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

..

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

..

In certain embodiments, p is 1 or 2; and ^R4 is a substituted or unsubstituted alkyl, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, each present independently. , And hydroxyalkyl.

In certain embodiments, p is 1 or 2; and ^R4 is independently selected from -CH ₃ , halo, hydroxyl, and hydroxyalkyl each time it is present.

In certain preferred embodiments, ^R4 is a hydroxyl group. In a preferred embodiment of the alternative, R ⁴ is -CH ₃ .

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

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

..

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

..

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

..

ただし、Ｒ^４はヒドロキシルではない。 In certain embodiments, the compound has a structure of formula (I-4Lc):

However, R ⁴ is not a hydroxyl group.

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

..

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

..

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

..

ただし、Ｒ^４はヒドロキシルではない。 In certain embodiments, the compound has a structure of formula (I-4Dc):

However, R ⁴ is not a hydroxyl group.

In certain embodiments, ^R4 is oxo.

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

..

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

..

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

..

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

..

の場合がある。 In certain embodiments, R ⁶ is hydrogen or alkyl, which optionally is replaced by the presence of one of -C (= O) NH ₂ . In certain embodiments, R6 is an alkyl substituted with the presence of _{one of -C (= O) NH 2} ^at the option. For example, R ⁶ may be -CH ₃ . Alternatively, R ⁶ is

In some cases.

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

..

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

..

である。 In certain embodiments, R ⁷ is (C1 _{-C 10 )} alkyl, preferably

Is.

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

..

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

..

。 In certain embodiments, the compound has a structure of formula (I-11L):

..

。 Alternatively, the compound may have a structure of formula (I-11D):

..

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

In certain embodiments, R ⁹ is —CH ₃ or —H, preferably —H.

またはその薬学上許容される塩である。 In certain embodiments, the compound is

Or the pharmaceutically acceptable salt.

In certain embodiments, the compound is
A peptide having an amino acid sequence represented by HyP-Gly-Gln-Xaa-Gly-Leu-Ala-Gly-Pro-Lys;
Or its pharmaceutically acceptable salt and / or stereoisomer;
In the formula, Xaa is Glu, Asn, Gln, His, Lys, Ser, Thr, Ala, Val, Ile, Leu, Phe, Tyr, Trp, homo-Ser, Asp (Me), and Asn (Me). ); And at least one amino acid residue in the peptide is a D-amino acid residue.

In certain cases of such embodiments, at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 amino acid residues in the peptide are D-amino acid residues. be.

The peptide may be a variant of a peptide derived from collagen IIα1 type. Collagen IIα1 type may be isolated from extracellular matrix derived from animal chondrocytes.

As used in the present invention, the term "peptide" refers to a compound in which two or more amino acids are linked by a peptide bond. Further, peptides are classified into dipeptides, tripeptides, tetrapeptides and the like according to the number of constituent amino acids. Oligopeptides have about 10 or less peptide bonds and polypeptides have multiple peptide bonds. In addition, the peptide of the present invention includes a mutant peptide in which amino acid residues are substituted.

。
ＨｙＰには、全ての異性体を含めることができる。また、ＨｙＰは、特に記載がない限り、「２Ｓ，４Ｒ」の立体化学で表される異性体であることもできる。 The term "HyP" used in the present invention refers to an amino acid called hydroxyproline, in which the hydroxyl group (-OH) is attached to a carbon atom at the 4-position of proline. HyP has the formula C ₅ H ₉ NO ₃ and can be expressed as:

..
HyP can include all isomers. Further, HyP can also be an isomer represented by the stereochemistry of "2S, 4R" unless otherwise specified.

。 The term "homo-Ser" used in the present invention is read as homoserine and refers to an α-amino acid having a hydroxyl group in the side chain. Homo-Ser is an intermediate present in the biosynthesis of threonine and methionine in microorganisms and plants. Homo-Ser can be expressed as:

..

。 As used in the present invention, the term "Asp (Me)" means that the hydrogen atom of the hydroxyl group (OH) bonded to the carbon atom at the 4-position of aspartic acid is replaced with a methyl group (CH ₃ ). Indicates an amino acid. Asp (Me) can be expressed as:

..

。 As used in the present invention, the term "Asn (Me)" means that the hydrogen atom of an amine group (NH ₂ ) bonded to a carbon atom at the 4-position of asparagine is replaced with a methyl group (CH ₃ ). Indicates an amino acid. Asn (Me) can be expressed as:

..

。 As used in the present invention, the term "(N-Me) Gly" is used in which the hydrogen atom of the amine group (NH ₂ ) bonded to the carbon atom at the 2-position of glycine is replaced with a methyl group (CH ₃ ). Indicates the amino acid that is present. (N-Me) Gly can be expressed as:

..

In certain embodiments, the compound is
A peptide having an amino acid sequence represented by HyP-Gly-Gln-Asp-Xaa-Leu-Ala-Gly-Pro-Lys;
Or its pharmaceutically acceptable salt and / or stereoisomer;
In the formula, Xaa is selected from Val, Ile, Leu, Ala, Phe, Tyr, Trp, Ser, Thr, and (N-Me) Gly; and at least one amino acid residue in the peptide is. It is a D-amino acid residue.

In certain cases of such embodiments, at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 amino acid residues in the peptide are D-amino acid residues. be.

In certain embodiments, the compound is
A peptide having an amino acid sequence represented by HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Xaa;
Or its pharmaceutically acceptable salt and / or stereoisomer;
In the formula, Xaa is selected from Tyr, Leu, Glu, Gln, Ala, and Nle (6-OH); and at least one amino acid residue in the peptide is a D-amino acid residue.

In certain cases of such embodiments, at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 amino acid residues in the peptide are D-amino acid residues. be.

から選択され；ならびに
ペプチド中の少なくとも１つのアミノ酸残基は、Ｄ－アミノ酸残基である。 In certain embodiments, the compound is
A peptide having an amino acid sequence represented by Xaa-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys;
Or its pharmaceutically acceptable salt and / or stereoisomer;
In the formula, Xaa is:

Selected from; as well as at least one amino acid residue in the peptide is a D-amino acid residue.

In certain cases of such embodiments, at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 amino acid residues in the peptide are D-amino acid residues. be.

を有する化合物またはその薬学上許容される塩を提供する。 In certain embodiments, the present invention has the following structure:

Provided is a compound having the above or a pharmaceutically acceptable salt thereof.

で表される化合物またはその薬学上許容される塩を提供し、
式中：
Ｒ^１及びＲ^２は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、もしくはヘテロシクリルアルキルであり；
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；ならびに
Ｒ^９は、水素またはアルキルであり；
ただし、化合物は、以下のものではない：

。 In certain embodiments, the present invention relates to formula (V) :.

Provided is a compound represented by the above or a pharmaceutically acceptable salt thereof.
During the ceremony:
R ¹ and R ² are independently H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or Heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁹ is hydrogen or alkyl;
However, the compounds are not:

..

In certain embodiments, R ¹ and R ² are H, or substituted or unsubstituted alkyl, respectively;
^R4 is a hydroxyl, if any,;
p is 1;
R ⁶ is an alkyl optionally substituted with the presence of one of -C (= O) NH ₂ ; and R ⁹ is hydrogen.

である。 In certain embodiments, R ¹ is a substituted or unsubstituted alkyl, eg,

Is.

。 In certain embodiments, the compound has a structure of formula (V-1L).

..

。 Alternatively, the compound may have a structure of formula (V-1D).

..

In certain embodiments, R ² is H.

In certain embodiments, p is 1 and ^R4 is hydroxyl.

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

..

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

..

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

..

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

..

である。 In certain embodiments, R ⁶ is an alkyl substituted with the presence of one of -C (= O) NH ₂ , eg,

Is.

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

..

。 Alternatively, the compound may have a structure of formula (V-6D):

..

In certain embodiments, R ⁹ is —H.

、またはそれらの薬学上許容される塩から選択される。 In certain embodiments, the compound is:

, Or their pharmaceutically acceptable salts.

で表される化合物またはその薬学上許容される塩を提供し、
式中：
Ｒ^１及びＲ^２は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、もしくはヘテロシクリルアルキルであり
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；
Ｒ^７は、水素またはアルキルであり；ならびに
Ｒ^９は、水素またはアルキルであり；
ただし、化合物は、以下のものではない：

。 In certain embodiments, the present invention relates to formula (VI) :.

Provided is a compound represented by the above or a pharmaceutically acceptable salt thereof.
During the ceremony:
R ¹ and R ² are independently H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or Heterocyclylalkyl, ^R4 , is independent of each presence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl. Selected;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
^R6 is hydrogen, or substituted or unsubstituted alkyl;
R ⁷ is hydrogen or alkyl; and R ⁹ is hydrogen or alkyl;
However, the compounds are not:

..

In certain embodiments:
R ¹ and R ² are H, or substituted or unsubstituted alkyl, respectively;
^R4 is a hydroxyl, if any,;
p is 1;
R ⁶ is an alkyl optionally substituted with the presence of one of -C (= O) NH ₂ ; and R ⁹ is hydrogen.

である。 In certain embodiments, R ¹ is a substituted or unsubstituted alkyl, eg,

Is.

。 In certain embodiments, the compound has the structure of formula (VI-1L).

..

。 Alternatively, the compound may have a structure of formula (VI-1D).

..

In certain embodiments, R ² is H.

In certain embodiments, p is 1 and ^R4 is hydroxyl.

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

..

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

..

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

..

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

..

である。 In certain embodiments, R ⁶ is an alkyl substituted with the presence of one of -C (= O) NH ₂ , eg,

Is.

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

..

。 Alternatively, the compound may have a structure of formula (VI-6D):

..

In certain embodiments, R ⁹ is —H.

である。 In certain embodiments, the R ⁷ is a (C1 _{-C 10 )} alkyl, eg,

Is.

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

..

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

..

で表される化合物またはその薬学上許容される塩を提供し、
式中：
Ｒ^１及びＲ^２は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、もしくはヘテロシクリルアルキルであり；
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；
Ｒ^７は、水素またはアルキルであり；ならびに
Ｒ^９は、水素またはアルキルであり；
ただし、化合物は以下のものではない：

。 In certain embodiments, the present invention relates to formula (VII) :.

Provided is a compound represented by the above or a pharmaceutically acceptable salt thereof.
During the ceremony:
R ¹ and R ² are independently H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or Heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
^R6 is hydrogen, or substituted or unsubstituted alkyl;
R ⁷ is hydrogen or alkyl; and R ⁹ is hydrogen or alkyl;
However, the compounds are not:

..

In certain embodiments:
R ¹ and R ² are H, or substituted or unsubstituted alkyl, respectively;
^R4 is a hydroxyl, if any,;
p is 1;
R ⁶ is an alkyl optionally substituted with the presence of one of -C (= O) NH ₂ ; and R ⁹ is hydrogen.

である。 In certain embodiments, R ¹ is a substituted or unsubstituted alkyl, eg,

Is.

。 In certain embodiments, the compound has a structure of formula (VII-1L).

..

。 Alternatively, the compound may have a structure of formula (VII-1D).

..

In certain embodiments, R ² is H.

In certain embodiments, p is 1 and ^R4 is hydroxyl.

。 In certain embodiments, the compound has a structure of formula (VII-4La):

..

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

..

。 In certain embodiments, the compound has a structure of formula (VII-4Da):

..

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

..

である。 In certain embodiments, R ⁶ is an alkyl substituted with the presence of one of -C (= O) NH ₂ , eg,

Is.

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

..

。 Alternatively, the compound may have a structure of formula (VII-6D):

..

In certain embodiments, R ⁹ is —H.

である。 In certain embodiments, the R ⁷ is a (C1 _{-C 10 )} alkyl, eg,

Is.

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

..

。 Alternatively, the compound may have a structure of formula (VII-7D):

..

。 In certain embodiments, the compound has a structure of formula (VII-10L):

..

。 Alternatively, the compound may have a structure of formula (VII-10D):

..

で表される化合物またはその薬学上許容される塩も提供し；
式中：
Ｒ^１及びＲ^２は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、もしくはヘテロシクリルアルキルであり；
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；
Ｒ^７、Ｒ^８、及びＲ^９は、それぞれ独立して、水素またはアルキルであり；
Ｊは、ＯＨまたは－ＮＲ^ｘＲ^ｙであり；ならびに
Ｒ^ｘ及びＲ^ｙは、それぞれ独立して、Ｈ、任意選択で置換されたアルキル、任意選択で置換されたアルコキシルアルキルから選択されるか、またはＲ^ｘ及びＲ^ｙは介在する窒素原子と一緒になって環を形成する。 The present invention has the formula (IX) :.

Also provided is a compound represented by or a pharmaceutically acceptable salt thereof;
During the ceremony:
R ¹ and R ² are independently H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or Heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
^R6 is hydrogen, or substituted or unsubstituted alkyl;
R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl;
J is OH or -NR ^x R ^y ; and R ^x and R ^y are independently selected from H, optionally substituted alkyl, optionally substituted alkoxyl alkyl, respectively. Alternatively, R ^x and R ^y form a ring together with the intervening nitrogen atom.

Examples of the compound of the formula (IX) include YDE-100 to YDE-107.

In certain embodiments of the compounds of formula (IX):
R ¹ and R ² are H, or substituted or unsubstituted alkyl, respectively;
^R4 is a hydroxyl, if any,;
p is 1;
R ⁶ is an alkyl optionally substituted with the presence of one of -C (= O) NH ₂ ; and R ⁹ is hydrogen.

である。 In certain embodiments of the compounds of formula (IX), R ¹ is a substituted or unsubstituted alkyl, eg,

Is.

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

..

。 Alternatively, in certain embodiments, the compound has the structure of formula (IX-1D):

..

In certain embodiments, R ² is H.

。 In certain embodiments, p is 1 and ^R4 is hydroxyl. In certain embodiments, the compound has the structure of formula (IX-4La):

..

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

..

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

..

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

..

の場合がある。 In certain embodiments, R ⁶ is an alkyl substituted with the presence of one of -C (= O) NH ₂ , eg, R ⁶ is.

In some cases.

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

..

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

..

In certain embodiments, R ⁹ is —H.

である場合がある。 In certain embodiments, R ⁷ is (C1 _{-C 10 )} alkyl. For example, R ⁷ is

May be.

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

..

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

..

。 In certain embodiments, the compound has a structure of formula (IX-10L):

..

。 In certain embodiments, the compound has the structure of formula (IX-10D):

..

。 In certain embodiments, the compound has the structure of formula (IX-11L):

..

。 In certain embodiments, the compound has the structure of formula (IX-11D):

..

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

In certain embodiments, J is OH. Alternatively, in another embodiment, J is −NR ^x R ^y . In certain cases of such embodiments, R ^x and R ^y are each independently alkyl. Alternatively, R ^x and R ^y may form a ring together with the intervening nitrogen atoms.

で表される化合物またはその薬学上許容される塩も提供し；
式中：
Ｒ^１、Ｒ^２、及びＲ^３は、それぞれ独立して、Ｈ、あるいは置換または無置換のアルキル、アルコキシ、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、アリールアルキニル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、もしくはヘテロシクリルアルキルであり；
Ｒ^４は、存在するごとに独立して、置換または無置換のアルキル、アリール、アリールアルキル、ヘテロシクリル、オキソ、－ＯＲ^ｂ、－ＣＨ_２ＯＲ^ｂ、ハロ、ヒドロキシル、及びヒドロキシアルキルから選択され；
Ｒ^ｂは、置換または無置換のアルキル、アリール、アリールアルキル、もしくはヘテロシクリルであり；
ｐは、０、１、または２であり；
Ｒ^６は、水素、あるいは置換または無置換のアルキルであり；
Ｒ^７、Ｒ^８、及びＲ^９は、それぞれ独立して、水素またはアルキルであり；
Ｊは、ＯＨまたは－ＮＲ^ｘＲ^ｙであり；ならびに
Ｒ^ｘ及びＲ^ｙは、それぞれ独立して、Ｈ、任意選択で置換されたアルキル、任意選択で置換されたアルコキシルアルキルから選択されるか、またはＲ^ｘ及びＲ^ｙは介在する窒素原子と一緒になって環を形成する。 In another embodiment, the present invention has the formula (X-am) :.

Also provided is a compound represented by or a pharmaceutically acceptable salt thereof;
During the ceremony:
R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, respectively. , Heterocyclyl, or heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
^R6 is hydrogen, or substituted or unsubstituted alkyl;
R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl;
J is OH or -NR ^x R ^y ; and R ^x and R ^y are independently selected from H, optionally substituted alkyl, optionally substituted alkoxyl alkyl, respectively. Alternatively, R ^x and R ^y form a ring together with the intervening nitrogen atom.

Examples of compounds of formula (X-am) include YDE-93 and YDE-96.

In certain embodiments of the compounds of formula (X-am):
R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl, respectively;
^R4 is independently selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -OR ^b , hydroxyalkyl, -CH ₂ OR ^b , and halo in each presence;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl, respectively.

In certain embodiments, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl are unsubstituted, as specified. Or halo, haloalkyl, oxo, -CN, -NO ₂ , = N-OH, -N ₃ , -R ^a , -OR ^a , -SR ^a , -N (R ^a ) ₂ , -N (R ^a ). ) ₃ ⁺ , = NR ^a , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) N (R ^a ) ₂ , -S (= O) ₂ R ^c ,- OS (= O) ₂ OR ^a , -S (= O) ₂ OR ^a , -S (= O) ₂ N (R ^a ) ₂ , -S (= O) R ^c , -OP (= O) (OR) ^a ) ₂ ,-(alkylene) -C (= O) R ^c , -C (= S) R ^c , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , -C (= S) OR ^a , -C (= O) SR ^a , -C (= S) SR ^a ,-(alkylene) -C (= O) N (R ^a ) ₂ , -C (= S) N ( Replaced with one or more substituents selected from R ^a ) ₂ and -C (-NR ^a ) N (R ^a ) ₂ ; and R ^a is independently hydrogen, or, in each presence. Substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl; and ^Rc is an independently substituted or unsubstituted alkyl, aryl, as it exists. , Arylalkyl, Heterocyclyl, Heterocyclylalkyl, Cycloalkyl, or (Cycloalkyl) Alkyl.

In a further embodiment, if specified, the alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or unsubstituted. Alternatively, halo, haloalkyl, oxo, -R ^a , -OR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) N (R ^a ) ₂ , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , and-(alkylene) -C (= O) N (R ^a ) ) Substituent with one or more substituents selected from ₂ ; as well as ^Ra , in each presence, hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, It is a cycloalkyl, or (cycloalkyl) alkyl; as well as ^Rc , each present independently, substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl). It is alkyl.

In still further embodiments, Ra is independent of hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl in the ^{presence; and R c is} the alkyl, independent of the presence. Aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl.

。 In certain embodiments, the compound has a structure of formula (X-am-10L):

..

。 In certain embodiments, the compound has a structure of formula (X-am-10D):

..

_In certain embodiments, R ¹ is a substituted or unsubstituted (C2 _- C10) haloalkyl. Alternatively, R ¹ may be substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl.

から選択され；
Ｒ^ａは、水素またはアルキルであり；ならびに
ｎは、１～１０の整数、好ましくは１～５、より好ましくは１～３である。 In a further embodiment, R ¹ is a substituted or unsubstituted alkyl,

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

から選択される。好ましくは、Ｒ^１は、

であるか、またはＲ^１は、

である。 In a further embodiment, R ¹ is

Is selected from. Preferably, R ¹ is

Or R ¹ is

Is.

。 In certain embodiments, the compound has a structure of formula (X-am-1L):

..

。 In certain embodiments, the compound has a structure of formula (X-am-1D):

..

In certain embodiments, R ² is a substituted or unsubstituted (C ₂ -C ₁₀ ) haloalkyl. Alternatively, R ² may be H, or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl.

から選択され；式中、Ｒ^ａは、水素またはアルキルであり；ならびに、ｎは、１～１０、好ましくは１～５、より好ましくは１～３の整数である。 In a further embodiment, R ² is a hydrogen, substituted or unsubstituted alkyl,

In the formula, Ra is hydrogen or alkyl; and n is an ^integer of 1-10, preferably 1-5, more preferably 1-3.

から選択される場合がある。一部の好適な実施形態において、Ｒ^２は、水素である。 In other embodiments, R ² is

May be selected from. In some preferred embodiments, R ² is hydrogen.

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

..

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

..

_In certain embodiments, R ³ is a substituted or unsubstituted (C2 _- C10) haloalkyl. Alternatively, R ³ may be a substituted or unsubstituted alkyl or arylalkyl.

から選択され；Ｒ^ａは、水素またはアルキルであり；ならびに、ｎは、１～１０、好ましくは１～５、より好ましくは１～３の整数である。 ^In certain embodiments, R3 is a substituted or unsubstituted alkyl,

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

から選択され；好ましくは、Ｒ^３は、

である。 In a further embodiment, the R ³ is

Selected from; preferably, R ³

Is.

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

..

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

..

In certain embodiments, p is 1 or 2; and ^R4 is a substituted or unsubstituted alkyl, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, each present independently. , And hydroxyalkyl.

In a further embodiment, p is 1 or 2; and ^R4 is independently selected from -CH ₃ , halo, hydroxyl, and hydroxyalkyl each time it is present. Preferably, R ⁴ is hydroxyl or R ⁴ is -CH ₃ .

In certain embodiments, p is 1.

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

..

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

..

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

..

ただし、Ｒ^４はヒドロキシルではない。 In certain embodiments, the compound has a structure of formula (X-am-4Lc):

However, R ⁴ is not a hydroxyl group.

。 In certain embodiments, the compound has a structure of formula (X-am-4Dg):

..

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

..

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

..

ただし、Ｒ^４はヒドロキシルではない。 In certain embodiments, the compound has a structure of formula (X-am-4Dc):

However, R ⁴ is not a hydroxyl group.

In certain embodiments, ^R4 is oxo.

。 In certain embodiments, the compound has a structure of formula (X-am-4Ld):

..

。 In certain embodiments, the compound has a structure of formula (X-am-4Le):

..

。 In certain embodiments, the compound has a structure of formula (X-am-4Dd):

..

。 In certain embodiments, the compound has a structure of formula (X-am-4De):

..

である場合がある。 In certain embodiments, R ⁶ is hydrogen or alkyl, where alkyl is optionally substituted with the presence of one of -C (= O) NH ₂ ; preferably R ⁶ is optional. -C (= O) An alkyl substituted with one presence of NH ₂ . For example, R ⁶ may be -CH ₃ , or R ⁶ may be.

May be.

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

..

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

..

である場合がある。 In certain embodiments, R ⁷ is (C1 _{-C 10 )} alkyl. For example, R ⁷ is

May be.

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

..

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

..

。 In certain embodiments, the compound has a structure of formula (X-am-11L):

..

。 In certain embodiments, the compound has a structure of formula (X-am-11D):

..

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

In certain embodiments, R ⁹ is —CH ₃ or —H, preferably —H.

In certain embodiments, R ^x and R ^y are independently substituted alkyls, respectively. In an alternative embodiment, R ^x and R ^y are each independently and optionally substituted alkoxylalkyl. In a further alternative embodiment, R ^x and R ^y form a ring together with the intervening nitrogen atom.

で表される化合物の塩、及び
式１０：

で表される化合物の塩、も提供する。 The present invention is based on Equation 8:

The salt of the compound represented by, and the formula 10:

Also provided are salts of compounds represented by.

In certain embodiments, the compound may be a prodrug, for example, in which case the hydroxyl of the parent compound is present as an ester or carbonate group and the carboxylic acid present in the parent compound is present as an ester. , Or the amino group exists as an amide. In certain cases of such embodiments, the prodrug is metabolized in vivo to the active parent compound (eg, the ester is hydrolyzed to the corresponding hydroxyl or carboxylic acid).

In certain embodiments, the compounds of the invention may be racemic. In certain embodiments, the compounds of the invention may be rich in one enantiomer. For example, the compounds of the invention may have 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or more ee.

The compounds of the present invention have more than one asymmetric center. Therefore, the compounds of the present invention may be rich in one or more diastereomers. For example, the compounds of the invention may have 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or more de. In certain embodiments, the compounds of the invention have substantially one isomer configuration at one or more asymmetric centers and a plurality of isomer configurations at the remaining asymmetric centers.

In certain embodiments, the enantiomeric excess of a given asymmetric center in the compound is at least 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, 92%. ee, 94% ee, 95% ee, 96% ee, 98% ee, or more.

As used herein, a single bond drawn without showing stereochemistry does not show the stereochemistry of the compound. The compound of formula (I) is an example of a compound for which stereochemistry has not been shown.

As used herein, dashed or filled wedge-shaped bonds indicate an absolute stereochemical arrangement.

In certain embodiments, the therapeutic formulations of the compounds of the invention can be enriched primarily to provide one enantiomer of the compound. A mixture enriched with certain enantiomers may contain, for example, at least 60 mol percent, or more preferably at least 75, 90, 95, or even 99 mol percent of one enantiomer. In certain embodiments, a compound enriched with one enantiomer is substantially free of, in this case, substantially free of the other enantiomers. It accounts for less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% when compared to, for example, the amount of other enantiomers in the substance or compound mixture. Means not. For example, if the composition or compound mixture contains 98 grams of the first enantiomer and 2 grams of the second enantiomer, it contains 98 mol% of the first enantiomer and the second enantiomer. It can be said that it contains only 2%.

In certain embodiments, the therapeutic formulation can be enriched primarily to provide one diastereomer of the compounds of the invention. A mixture enriched with certain diastereomers may contain, for example, at least 60 mol percent, or more preferably at least 75, 90, 95, or even 99 mol percent of one diastereomer.

Pharmaceutical Compositions In certain embodiments, the invention provides a pharmaceutical composition comprising a salt or compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical composition is formulated for external administration to the eye, eg, as an eye drop.

In certain embodiments, at least 50%, 60%, 70%, 80%, or 90% of the compound is present as a salt. Preferably, at least 95% of the compound is present as a salt. Even more preferably, at least 99% of the compounds are present as salts.

In certain embodiments, the present invention provides a pharmaceutical formulation suitable for use in a human patient, wherein the pharmaceutical formulation is one or more pharmaceutically acceptable of any of the salts or compounds of the invention. Contains excipients. In certain embodiments, the pharmaceutical formulation may be intended for use in the treatment or prevention of symptoms or disorders as described herein. In certain embodiments, the pharmaceutical product has a pyrogen activity that is low enough to be suitable for use in human patients.

One embodiment of the invention provides a pharmaceutical kit comprising the salts or compounds of the invention, or pharmaceutically acceptable salts thereof, and optionally instructions on how to administer the compounds.

The compositions and methods of the invention can be utilized to treat individuals in need of treatment. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to animals such as humans, the composition or compound is preferably administered as a pharmaceutical composition, the pharmaceutical composition comprising, for example, the compounds of the invention and pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers are well known in the art and are, for example, aqueous solutions such as water or physiological buffered saline, or other solvents, or vehicles, such as oils such as glycols, glycerol, olive oil, or for injection. Examples include organic esters. In certain preferred embodiments, such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (ie, routes that avoid transport or diffusion through epithelial barriers, such as injections or transplants). If the aqueous solution is pyrogen-free, or substantially free of pyrogen. Excipients can be selected, for example, to achieve sustained release of the agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition is in the form of tablets, capsules (including sprinkle capsules and gelatin capsules), granules, freeze-drying agents for reconstruction, powders, liquids, syrups, suppositories, injections and the like. It is possible to be. The composition can also be present in a transdermal delivery system, eg, a skin patch. The composition can also be, for example, an eye drop, which is present in a liquid preparation suitable for external administration.

A pharmaceutically acceptable carrier comprises a physiologically acceptable agent that acts to act to, for example, stabilize, enhance its solubility, or enhance its absorption of a compound, such as a compound of the invention. Can be done. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other. Stabilizers, excipients and the like can be mentioned. Pharmaceutically acceptable carriers, including physiologically acceptable agents, are selected, for example, depending on the route of administration of the composition. The pharmaceutical or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) can also be, for example, a liposome or other polymer matrix capable of incorporating the compound of the present invention into the pharmaceutical composition (formulation). Liposomes, such as those containing phospholipids or other lipids, are nontoxic, physiologically acceptable, metabolic carriers that are relatively easy to make and administer.

The phrase "pharmaceutically acceptable" is suitable herein for use in contact with human and animal tissues, to the extent of medically correct judgment, and is excessively toxic, irritating, allergic, or otherwise. It is used to indicate a compound, material, composition, and / or dosage form that is commensurate with a reasonable risk-to-effect ratio without any problems or complications.

The phrase "pharmaceutically acceptable carrier" as used herein is a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent. , Or an encapsulating material. Each carrier must be "acceptable" in that it is compatible with the other ingredients of the formulation and is not harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose, (2) starches such as corn starch and potato starch. Etc. (3) Cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate, (4) powdered tragacant, (5) malt, (6) gelatin, (7) talc, (8) excipients, etc. , Such as cocoa butter and suppository wax, (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, (10) glycols such as propylene glycol, etc. (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers such as magnesium hydroxide. And aluminum hydroxide, etc., (15) alginic acid, (16) starch-free water, (17) isotonic physiological saline, (18) ringer solution, (19) ethyl alcohol, (20) phosphate buffer, etc. And (21) other non-toxic compatible substances used in pharmaceutical formulations.

The pharmaceutical composition (formulation) can be administered to a subject by any of a plurality of routes of administration, and such a route of administration includes, for example, an oral (for example, an aqueous or non-aqueous solution or suspension). Drench, tablets, capsules (including sprinkle capsules and gelatin capsules), bolus, powders, granules, pastes for application to the tongue, etc.; absorption through the oral mucosa (eg, sublingual) Through the anus, rectum, or vagina (eg, as a pessary, cream, or foam); parenteral (including intramuscular, intravenous, subcutaneous, or submucosal space, eg, sterile solution or suspension). As); nasal; intraperitoneal; subcutaneous; transdermal (eg, as a patch applied to the skin); and external use (eg, as a cream, ointment, or spray applied to the skin, or as an eye drop) Can be mentioned. The compounds may also be formulated for inhalation. In certain embodiments, the compound may simply be dissolved or suspended in sterile water. For more information on the appropriate route of administration and suitable compositions thereof, see, for example, US Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541. , 231 and 5,427,798, 5,358,970, and 4,172,896, and the patents cited therein.

The formulations can conveniently be present in unit dosage forms and can be prepared by any method well known in the art of pharmaceuticals. The amount of active ingredient that can be mixed with the carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be mixed with the carrier material to produce a single dosage form is generally the amount of compound that provides a therapeutic effect. Generally, this amount ranges from about 1 percent to about 99 percent, preferably about 5 percent to about 70 percent, and particularly preferably about 10 percent to about 30 percent, of the 100 percent active ingredient.

The method for preparing such a formulation or composition comprises integrating an active compound, eg, a compound of the invention, with a carrier and optionally with one or more accessory components. In general, formulations are prepared by uniformly and closely integrating the compounds of the invention with liquid carriers, / or finely ground solid carriers, and then molding the product, if necessary. Will be done.

The formulations of the present invention suitable for oral administration include capsules (including sprinkle capsules and gelatin capsules), cashews, pills, tablets, lozenges (flavor base material, usually sucrose and acacia rubber or tragacant). (Use), as a lyophile, powder, pill, or solution or suspension contained in an aqueous or non-aqueous solution, or as an oil or water-in-oil liquid emulsion, or an elixir or syrup. Or as a lozenge (using an inert substrate such as gelatin and glycerin, or a capsule and acacia rubber), and / or a mouthwash, etc., respectively, as the active ingredient of the present invention. Contains the compound in a predetermined amount. The composition or compound can also be administered as a bolus, licking agent, or paste.

One or more active ingredients to prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, rounds, draggers, powders, granules, etc.) Mix with pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and / or any of the following: (1) Fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, And / or silicates and the like, (2) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia rubber, (3) moisturizers, such as glycerol, etc., (4) disintegration. Agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retarding agents, such as paraffin, (6) promoting absorption. Agents such as quaternary ammonium compounds, (7) wetting agents such as cetyl alcohol and glycerol monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as. (10) Complexing agents such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, such as modified or unmodified cyclodextrin, and (11) colorants. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical composition can also include a buffer. The same type of solid composition can also be used as a filler to be filled in soft and hard gelatin capsules using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycol and the like.

Tablets can optionally be made by compression or molding with one or more accessory components. Compressed tablets are binders (eg gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (eg sodium starch glycolate or crosslinked sodium carboxymethyl cellulose), surfactants, or dispersants. Can be prepared using. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent with a suitable machine.

Tablets and other solid dosage forms of the pharmaceutical composition, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, are optionally coated and shelled, eg, It can be surface-treated or prepared using enteric coatings and other coatings well known in the pharmaceutical manufacturing field. Such dosage forms can also be formulated to result in sustained release or controlled release of the active ingredient in the dosage form, eg, hydroxypropylmethylcellulose is used in various proportions to provide the desired release profile, and others. Polymer matrix, liposomes, and / or microspheres are used. These dosage forms are sterile, for example, by filtration through a bacterial collection filter or by incorporating the sterile agent in the form of a sterile solid composition that is soluble in sterile water or some other sterile injection medium immediately before use. can do. Such compositions may optionally also contain an opaque agent, releasing only the active ingredient (s), or preferentially, in a particular portion of the gastrointestinal tract, in an optional, delayed manner. It can also be a composition to be released. Examples of usable embedding compositions include polymer substances and waxes. The active ingredient can also be in microencapsulated form, optionally with one or more of the above excipients.

Liquid dosage forms that are easy to use for oral administration include pharmaceutically acceptable emulsions, lyophilizers for reconstruction, microemulsions, liquids, suspensions, syrups, and elixirs. The liquid dosage form, in addition to the active ingredient, is an inert diluent commonly used in the art, such as water or other solvents, cyclodextrins and derivatives thereof, solubilizers and emulsifiers, such as ethyl alcohol. Isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (specifically, cottonseed oil, peanut oil, corn oil, germ oil (eg, wheat germ), olive oil. , Hima oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof.

In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, flavoring agents, and preservatives.

In addition to active compounds, suspending agents include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, crystalline cellulose, aluminum metahydroxydo, bentonite, agar and tragacant, and them. Can contain a mixture of.

Formulations of pharmaceutical compositions for rectal, vaginal, or urinary administration may be present as suppositories, which are one or more active compounds with one or more suitable non-irritating excipients. It can be prepared by mixing with a form or carrier, the excipient or carrier containing, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate, although it is solid at room temperature. At body temperature, it becomes liquid and therefore melts in the rectum or vaginal cavity to release the active compound.

Formulations of pharmaceutical compositions for oral administration can be present as mouthwashes, or oral sprays, or oral ointments.

Alternatively or additionally, the composition can be formulated to be delivered via a catheter, stent, wire, or other intraluminal device. Delivery via such a device may be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

Formulations suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations, which appropriately contain carriers known in the art.

Dosage forms for external or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, liquids, patches, and inhalants. The active compound can be mixed with pharmaceutically acceptable carriers under sterile conditions and with any preservatives, buffers or, if necessary, propellants.

Ointments, pastes, creams, and gels are, in addition to active compounds, excipients such as animal and vegetable fats and oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc. , And zinc oxide, or mixtures thereof.

In addition to active compounds, powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. The spray can additionally contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Transdermal patches have the additional advantage of being able to control and deliver the compounds of the invention to the body. The dosage form can be made by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. Such a flow rate can be controlled either by providing a rate control membrane or by dispersing the compound in a polymer matrix or gel.

It is also contemplated that eye formulations, eye ointments, eye drop powders, eye drops and the like are within the scope of the present invention. Examples of ocular formulations are described in US Publications 2005/00830056, 2005/0059744, 2005/0031697, and 2005/004074, and US Pat. No. 6,583,124. These contents are incorporated herein by reference. If desired, the liquid eye formulation has properties similar to those of tear fluid, aqueous humor, or vitreous fluid, or is compatible with such fluids. A suitable route of administration is topical administration (eg, external administration such as eye drops, or administration via a graft).

The terms "parenteral administration" and "administered parenterally", as used herein, mean administration modalities other than enteric and external administration, usually by injection, as such. The administration is not particularly limited, and is intravenous, intramuscular, intraarterial, intrathecal, intra-articular, intraocular, intracardiac, intracutaneous, intraperitoneal, transtracheal, subcutaneous, subepithelial, intra-articular, sac. Injections and infusions include inferior, submucosal, intraspinal, and intrathoracic bones. Pharmaceutical compositions suitable for parenteral administration include one or more active compounds in one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or milks. Containing in combination with turbid liquids or sterile powders, the sterile powders can be reconstituted immediately prior to use into sterile injections or dispersants, and pharmaceutical compositions are antioxidants, buffers, bacteriostatic agents. , Solutes that make the formulation isotonic with the blood of the recipient of interest, or suspensions or thickeners can be included.

Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, olive oil, and the like. Examples include vegetable oils and organic esters for injection such as ethyl oleate. Proper fluidity can be maintained, for example, by using a coating material such as lecithin, by maintaining the required particle size in the case of dispersants, and by using surfactants. can.

Such compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersants and the like. Microbial activity can be reliably inhibited by the inclusion of various antibacterial and antifungal agents such as parabens, chlorobutanol, phenolsorbic acid and the like. It may be desirable to include isotonic agents such as sugars, sodium chloride and the like in the composition. In addition, long-term absorption of the pharmaceutical formulation for injection may be brought about by including an absorption retarding agent such as aluminum monostearate and gelatin.

In some cases, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection for the purpose of prolonging the effect of the drug. This can be achieved by using a liquid suspending agent of crystalline or amorphous material with poor water solubility. In that case, the rate of absorption of the drug depends on the rate of dissolution and therefore may depend on crystal size and crystal form. Alternatively, delayed absorption of the dosage form administered parenterally is achieved by dissolving or suspending the drug in an oily vehicle.

The injectable depot form is made by forming a microencapsulation matrix in which the compound of interest is contained in a biodegradable polymer such as polylactide-polyglycolide. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Examples of other biodegradable polymers include poly (orthoester) and poly (anhydride). Depot injection formulations are also prepared by trapping the drug in liposomes or microemulsions that are compatible with body tissue.

When used in the methods of the invention, the active compound is a carrier that is pharmaceutically acceptable as such or, for example, 0.1-99.5% (more preferably 0.5-90%) of the active ingredient. It can be administered as a pharmaceutical composition contained in combination with.

Introductory methods using refillable or biodegradable devices can also be provided. In recent years, various sustained release polymer devices including protein biologics have been developed for controlled delivery of drugs and are being tested in vivo. Various biocompatible polymers (including hydrogels), including both biodegradable and non-biodegradable polymers, can be used to form grafts that release the compound slowly at a particular target site.

The actual dosage level of the active ingredient in the pharmaceutical composition provides an amount of the active ingredient that is effective in achieving the desired therapeutic response in a particular patient, composition, and mode of administration but is not toxic to the patient. It can be changed as follows.

The dosage level selected will depend on a variety of factors, such as the activity, route of administration, duration of administration of the particular compound used or its esters, salts, or amides or combinations thereof. , Emission rate of the specific compound (s) used, duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound (s) used, age, gender, weight of the patient being treated. , Symptoms, general health, and previous medical history, as well as similar factors well known in the pharmaceutical field.

A physician or veterinarian in the art can readily determine and prescribe a therapeutically effective amount of the required pharmaceutical composition. For example, a physician or veterinarian may start dosing a pharmaceutical composition or compound at a level lower than the level required to achieve the desired therapeutic effect and gradually dose until the desired effect is achieved. Can be increased. "Therapeutically effective amount" means the concentration of a compound sufficient to elicit the desired therapeutic effect. As is generally the case, the effective amount of the compound will vary depending on the subject's weight, gender, age, and medical history. Other factors that affect the effective dose include the severity of the patient's symptoms, the disorder being treated, the stability of the compound, and, if desired, another therapeutic agent administered with the compound of the invention. However, it is not limited to these. If the total dose is high, it can be delivered by multiple doses of the agent. Methods of determining efficacy and dosage are known to those of skill in the art (Isselbacher et al. (1996) Harrison's Principles of International Medicine 13 ed., 1814-1882, which is incorporated herein by reference. ).

In general, an appropriate daily dose of the active compound used in the compositions and methods of the invention will be the amount of the compound which is the lowest effective amount to bring about a therapeutic effect. Such effective amounts will generally depend on the factors mentioned above.

If desired, the effective daily dose of the active compound may be in divided doses of once, twice, three times, four times, five times, six times, or more, separately at appropriate intervals throughout the day. Optionally, it can be administered in a unit dosage form. In certain embodiments of the invention, the active compound can be administered twice or three times daily. In a preferred embodiment, the active compound is administered once daily.

Patients receiving this treatment are any animals in need of treatment, such as primates, in particular humans, and other mammals such as horses, cows, pigs, and sheep, as well. , Poultry and common pets.

In certain embodiments, the compounds of the invention may be used alone or co-administered with another therapeutic agent. As used herein, the phrase "co-administration" means that for two or more different therapeutic compounds, the second compound is administered while the previously administered therapeutic compound is still effective in the body. (For example, two compounds are effective simultaneously in a patient, which may include synergistic effects of the two compounds), indicating any mode of administration. For example, different therapeutic compounds can be administered in the same formulation or in separate formulations either simultaneously or sequentially. In certain embodiments, the different therapeutic compounds can be administered to each other within 1 hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or 1 week. That is, individuals receiving such treatment can benefit from the combined effects of different therapeutic compounds.

In certain embodiments, co-administration of a compound of the invention with one or more additional therapeutic agents (s) is a compound of the invention (eg, a compound of formula I, V, VI, or VII) or 1 Species or multiple additional therapies (s) result in improved efficacy compared to individual doses of each. In certain cases of such embodiments, co-administration provides an additive effect, which is the effect of individual administration of the compound of the invention and one or more additional therapeutic agents (s), respectively. Shows the total of.

The invention includes the use of pharmaceutically acceptable salts of the compounds of the invention in the compositions and methods of the invention. The term "pharmaceutically acceptable salt" as used herein includes salts derived from inorganic or organic acids, such acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc. Nitrate, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoro Included are acetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, oxalic acid, mandelic acid, and other acids. Pharmaceutically acceptable salt forms can include forms in which the molecular ratios that make up the salt are not 1: 1. For example, the salt can contain more than one molecule of inorganic or organic acid per molecule of base, such as two molecules of hydrochloric acid per molecule of compound of formula I, V, VI, or VII. As another example, the salt can contain less than one inorganic or organic acid molecule per molecule of base, eg, two compounds of the formula I, V, VI, or VII per molecule of tartrate acid.

In a further embodiment, the intended salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, the intended salts of the invention include L-arginine, venetamine, benzatin, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethanolamine, ethylenediamine, N-Methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4- (2-hydroxyethyl) morpholine, piperazine, potassium, 1- (2-hydroxyethyl) pyrrolidine, sodium, triethanolamine, Examples include, but are not limited to, tromethamine and zinc salts. In certain embodiments, the intended salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.

The pharmaceutically acceptable acid addition salt can also exist as a solvate with various solvates such as water, methanol, ethanol, dimethylformamide and the like. A mixture of such solvates can also be prepared. The source of such solvates can be derived from the crystallization solvent and may be specific to the solvent of preparation or crystallization, or accidental with such a solvent.

Wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, mold release agents, coating agents, sweeteners, flavors, and fragrances, preservatives, and antioxidants are also composed. Can be present in things.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bicarbonate, sodium metabisulfite, sodium sulfite, etc. (2). ) Oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl citrate, alpha-tocopherol, and (3) metal chelating agents such as. , Citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

Therapeutic method The present invention also provides a method for treating an eye disease, and the present invention provides a pharmaceutical composition containing the salt of the present invention, the compound of the present invention, or the salt or compound of the present invention to a subject in need of treatment. Including administration.

Specifically, eye diseases include retinopathy, keratitis, dry-type retinal degeneration, wet-type retinal degeneration, dry eye syndrome, keratoconjunctival epithelial disorder, proliferative vitreous retinopathy, pigmented retinopathy, and diabetic. Retinopathy, retinopathy of prematurity, retinopathy of retinopathy, proliferative retinopathy, ischemic retinopathy, epidemic keratoconjunctivitis, atopic keratitis, upper ring keratitis, wing-like Hemidry keratitis, frictenic keratoconjunctivitis, cankeritis, corneal transplant rejection, choroidal angiogenesis, angiogenic glaucoma, ischemic optic nerve neuropathy, posterior crystalline fibroproliferative disorder, diabetic retinopathy, angiogenic iris disease, retinopathy, myopia , Von Hippel-Lindau's disease, ocular histoplasmosis, central retinal vein occlusion, Schegren's syndrome, and Stevens-Johnson's syndrome. Preferably, the eye disease can be selected from retinopathy, keratitis, macular degeneration, dry eye syndrome, and corneal conjunctival epithelial disorders.

In certain preferred embodiments, the eye disease is selected from retinopathy, keratitis, dry macular degeneration, wet macular degeneration, dry eye syndrome, keratoconjunctivitis sicca, and keratoconjunctival epithelial disorder.

Pharmaceutical compositions for the treatment of eye disorders include the salts or compounds of the invention as active pharmaceutical ingredients, as well as carriers, excipients, disintegrants, sweeteners, coatings, swelling agents, lubricants, slip agents, flavors. It can contain at least one additive selected from the group consisting of agents, antioxidants, buffers, bacteriostatic agents, diluents, dispersants, surfactants, and binders. Specifically, the formulation for parenteral administration can be a sterilized aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized preparation, a suppository, or the like.

The dose of the salt or compound of the invention administered to a subject is the type of disease, the severity of the disease, the type and amount of active pharmaceutical ingredient and other ingredients contained in the pharmaceutical composition, the type of formulation, the patient. It can be adjusted according to various factors such as age, weight, general health, gender, and diet, time and route of administration, duration of treatment, and concomitant medications.

However, with respect to the desired effect, the effective amount of salt or compound contained in the pharmaceutical composition may be 0.0001 μg / day to 100 μg / day. In such cases, administration can be done once daily or divided into multiple doses. Specifically, the concentration of the salt or compound contained in the pharmaceutical composition may be 1000 μM to 0.001 μM. Similarly, the concentration of the salt or compound contained in the pharmaceutical composition may be 100 μM to 0.005 μM or 50 μM to 0.02 μM.

If necessary, the concentration of the salt or compound contained in the pharmaceutical composition may be 30 μM to 1 μM. Further, the concentration of the compound or peptide contained in the pharmaceutical composition may be 0.01 μM to 1 μM.

The subject may be a mammal, more specifically a human. The administration route can be appropriately selected by those skilled in the art in consideration of the administration method, the volume and viscosity of the body fluid, and the like. Specifically, administration is from the group consisting of application, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, percutaneous, intranasal, inhalation, external, rectal, oral, intraocular, and intradermal. It can be done through any one route selected. Preferably, the administration comprises external administration to the subject's eye.

In particular, the administration can be preferably administered to the eye as it is used as eye drops.

The present invention has been described in its entirety so far, but may be more easily understood by reference to the following examples. The examples are included solely for the purpose of exemplifying certain embodiments and embodiments of the invention and are not intended to limit the invention.

Example 1: Preparation of YDE Derivatives Protein analysis of extracellular matrix derived from animal chondrocytes was performed by the group of Beak at the Medical Mass Spectrometry Center (Diatech Korea Co., Ltd., Seoul, Korea). Proline-GQDGLAGPK (P-GQDGLAGPK), which is part of the amino acid sequence of collagen IIα1 type protein, was obtained through the above protein analysis.

Examples of protein synthesis of YDE-011 are as follows. Other compounds of the invention (eg, YDE-001 to YDE-086) are made through similar procedures, eg, by replacing them with different amino acid component reagents in a desired step.

Example of procedure of YDE-011 Solid-phase synthesis Fmoc-Pro-Lys (Boc) -Wang resin (1)
To a solid-phase synthesis reactor equipped with a filtration membrane, Fmoc-Lys (Boc) -Wang resin (1.75 g, 1 mmol) added to DCM (30 mL) was added, then swollen for 30 minutes, and then the resin to the liquid phase. Was separated. A solution of piperidine (10 mL) in DMF (40 mL) was added to the resin and stirred for 5 minutes, then the liquid phase was separated from the resin. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Pro-OH (3.37 g, 10 mmol) in DMF (25 mL) and a solution of HBTU (3.8 g, 10 mmol) and N-methylmorpholine (2.0 g, 20 mmol) in DMF (25 mL) were added to the resin. , Added respectively. The reaction mixture was stirred for 1 hour to separate the liquid phase from the resin. The resin was used in the next step without further purification.

Fmoc-Gly-Pro-Lys (Boc) -Wang resin (2)
A solution of piperidine (10 mL) in DMF (40 mL) was added to Fmoc-Pro-Lys (Boc) -Wang resin (1), and the mixture was stirred for 5 minutes, and then the liquid phase was separated from the resin. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Gly-OH (3.0 g, 10 mmol) in DMF (25 mL) and a solution of HBTU (3.8 g, 10 mmol) and N-methylmorpholine (2.0 g, 20 mmol) in DMF (25 mL) were added to the resin. , Added respectively. The reaction mixture was stirred for 1 hour to separate the liquid phase from the resin. The resin was used in the next step without further purification.

Fmoc-Ala-Gly-Pro-Lys (Boc) -Wang resin (3)
A solution of piperidine (10 mL) in DMF (40 mL) was added to Fmoc-Gly-Pro-Lys (Boc) -Wang resin (2), and the mixture was stirred for 5 minutes, and then the liquid phase was separated from the resin. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Ala-OH (3.1 g, 10 mmol) in DMF (25 mL) and a solution of HBTU (3.8 g, 10 mmol) and N-methylmorpholine (2.0 g, 20 mmol) in DMF (25 mL) were added to the resin. , Added respectively. The reaction mixture was stirred for 1 hour to separate the liquid phase from the resin. The resin was used in the next step without further purification.

Fmoc-Leu-Ala-Gly-Pro-Lys (Boc) -Wang resin (4)
A solution of piperidine (10 mL) in DMF (40 mL) was added to Fmoc-Ala-Gly-Pro-Lys (Boc) -Wang resin (3), and the mixture was stirred for 5 minutes, and then the liquid phase was separated from the resin. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Leu-OH (3.5 g, 10 mmol) in DMF (25 mL) and a solution of HBTU (3.8 g, 10 mmol) and N-methylmorpholine (2.0 g, 20 mmol) in DMF (25 mL) were added to the resin. , Added respectively. The reaction mixture was stirred for 1 hour to separate the liquid phase from the resin. The resin was used in the next step without further purification.

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

Fmoc-Leu-Gly-Leu-Ala-Gly-Pro-Lys (Boc) -Wang resin (6)
To Fmoc-Gly-Leu-Ala-Gly-Pro-Lys (Boc) -Wang resin (5), add a DMF (40 mL) solution of piperidine (10 mL), stir for 5 minutes, and then separate the liquid phase from the resin. did. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Leu-OH (3.5 g, 10 mmol) in DMF (25 mL) and a solution of HBTU (3.8 g, 10 mmol) and N-methylmorpholine (2.0 g, 20 mmol) in DMF (25 mL) were added to the resin. , Added respectively. The reaction mixture was stirred for 1 hour to separate the liquid phase from the resin. The resin was used in the next step without further purification.

Fmoc-Gln (Trt) -Leu-Gly-Leu-Ala-Gly-Pro-Lys (Boc) -Wang resin (7)
To Fmoc-Leu-Gly-Leu-Ala-Gly-Pro-Lys (Boc) -Wang resin (6), add a solution of piperidine (10 mL) in DMF (40 mL), stir for 5 minutes, and then the liquid phase from the resin. Was separated. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Gln (Trt) -OH (6.1 g, 10 mmol) in DMF (25 mL) and HBTU (3.8 g, 10 mmol) and N-methylmorpholine (2.0 g, 20 mmol) in DMF (25 mL) are added to the resin. 10 equivalents) solution was added respectively. The reaction mixture was stirred for 1 hour to separate the liquid phase from the resin. The resin was used in the next step without further purification.

Fmoc-Gly-Gln (Trt) -Leu-Gly-Leu-Ala-Gly-Pro-Lys (Boc) -Wang resin (8)
To Fmoc-Gln (Trt) -Leu-Gly-Leu-Ala-Gly-Pro-Lys (Boc) -Wang resin (7), add a solution of piperidine (10 mL) in DMF (40 mL), stir for 5 minutes, and then stir. , The liquid phase was separated from the resin. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Gly-OH (3.0 g, 10 mmol) in DMF (25 mL) and a solution of HBTU (3.8 g, 10 mmol) and N-methylmorpholine (2.0 g, 20 mmol) in DMF (25 mL) were added to the resin. , Added respectively. The reaction mixture was stirred for 1 hour to separate the liquid phase from the resin. The resin was used in the next step without further purification.

H-Hyp (tBu) -Gly-Gln (Trt) -Leu-Gly-Leu-Ala-Gly-Pro-Lys (Boc) -Wang resin (9)
To Fmoc-Gly-Gln (Trt) -Leu-Gly-Leu-Ala-Gly-Pro-Lys (Boc) -Wang resin (8), add a solution of piperidine (10 mL) in DMF (40 mL) and stir for 5 minutes. Then, the liquid phase was separated from the resin. The resin was washed 6 times with DMF (50 mL). A solution of Fmoc-Hyp (tBu) -OH (4.2 g, 10 mmol) in DMF (25 mL) and HBTU (3.8 g, 10 mmol) and N-methylmorpholine (2.0 g, 20 mmol) in DMF (25 mL) are added to the resin. ) The solution was added and the reaction mixture was stirred for 1 hour to separate the liquid phase from the resin. A solution of piperidine (10 mL) in DMF (40 mL) was added to Fmoc-Hyp (tBu) -Gly-Gln (Trt) -Leu-Gly-Leu-Ala-Gly-Pro-Lys (Boc) -Wang resin. The reaction mixture was stirred for 5 minutes and then the liquid phase was separated from the resin. The resin was washed 6 times with DMF (50 mL).

Removal from Resin H-Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys-OH TFA Salt (10)
H-Hyp (tBu) -Gly-Gln (Trt) -Leu-Gly-Leu-Ala-Gly-Pro-Lys (Boc) -Wang resin (9) 1 mmol of cocktail solution (87.5% TFA / 2) 30 mL of 1.5% 1,2-ethanedithiol / 2.5% _H2O / 5.0% thioanisole) was added, the reaction mixture was stirred for 2 hours and the reaction mixture was monitored by HPLC. Cold diethyl ether (500 mL) was added to the filtered solution to precipitate the crude peptide. The precipitated peptide was filtered through a filtration device and washed with 500 mL of diethyl ether. The crude peptide was vacuum dried to give 105% (1 g).

Purification Step TFA salt of H-Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys-OH (10)
The crude compound was purified by a preparative HPLC system.

Salt exchange step H-Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys-OH AcOH salt (11)
The purified compound was exchanged from a TFA salt to an AcOH salt with an ion exchange resin. The ion-exchanged peptide was dried by a freeze-dryer.

The peptides of YDE-001 to YDE-092 are introduced into the peptide, proline-GQDGLAGPK, by substituting one or more different amino acid residues in a manner similar to the above exemplary procedure (FIGS. 1 and 1). , ANYGEN (Gwangju, Korea) synthesized.

The process of synthesizing the peptides of YDE-001 to YDE-075 performed by ANYGEN and the purification procedure thereof are shown in FIGS. 2 and 3.

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-09, YDE-010, YDE-011, YDE -012, YDE-013, YDE-014, YDE-015, YDE-016, YDE-017, YDE-018, YDE-019, YDE-020, YDE-021, YDE-022, YDE-023, YDE-024 , YDE-025, YDE-026, YDE-027, YDE-028, YDE-029, YDE-030, YDE-031, YDE-032, YDE-033, YDE-034, YDE-035, YDE-036, YDE -037, YDE-038, YDE-039, YDE-040, YDE-041, YDE-042, YDE-043, YDE-044, YDE-045, YDE-047, YDE-048, YDE-049, YDE-050 , YDE-051, YDE-052, YDE-053, YDE-054, YDE-055, YDE-056, YDE-057, YDE-058, YDE-059, YDE-060, YDE-064, YDE-066, YDE -072, YDE-073, YDE-074, YDE-075, YDE-078, YDE-080, YDE-081, YDE-083, YDE-084, YDE-085, YDE-086, YDE-092, YDE-094. , And YDE-100 have 98.3%, 98.9%, 98.7%, 98.5%, 99.1%, 99.4%, 98.0%, and 99.6%, respectively. , 99.6%, 99.2%, 98.1%, 98.3%, 96.1%, 98.9%, 95.1%, 98.6%, 96.9%, 99.5% , 98.0%, 98.1%, 98.8%, 98.2%, 97.2%, 98.6%, 98.8%, 98.7%, 99.2%, 98.7% , 98.1%, 97.5%, 96.5%, 97.4%, 98.7%, 97.8%, 95.5%, 97.5%, 97.2%, 96.9% , 99.3%, 98.0%, 99.4%, 96.4%, 95.1%, 98.6%, 97.4%, 98.8%, 97.4%, 95.8% , 98.9%, 96.9%, 98.8%, 97.7%, 95.0%, 97.9%, 96.3%, 97.8%, 99.2%, 98.6% , 95.9%, 99.2%, 99.0%, 95.1%, 95.0%, 97 It was confirmed that it was 0.4% and 98.7%.

Moreover, the YDE derivative prepared in Example 1 was analyzed by ion mass spectrometry. As a result, the synthesized YDE-001, YDE-002, YDE-003, YDE-004, YDE-005, YDE-006, YDE-007, YDE-008, YDE-09, YDE-010, YDE-011, YDE -012, YDE-013, YDE-014, YDE-015, YDE-016, YDE-017, YDE-018, YDE-019, YDE-020, YDE-021, YDE-022, YDE-023, YDE-024 , YDE-025, YDE-026, YDE-027, YDE-028, YDE-029, YDE-030, YDE-031, YDE-032, YDE-033, YDE-034, YDE-035, YDE-036, YDE -037, YDE-038, YDE-039, YDE-040, YDE-041, YDE-042, YDE-043, YDE-044, YDE-045, YDE-047, YDE-048, YDE-049, YDE-050 , YDE-051, YDE-052, YDE-053, YDE-054, YDE-055, YDE-056, YDE-057, YDE-058, YDE-059, YDE-060, YDE-064, YDE-066, YDE -072, YDE-073, YDE-074, YDE-075, YDE-078, YDE-080, YDE-081, YDE-083, YDE-084, YDE-085, YDE-086, YDE-092, YDE-094. , And YDE-100 have molecular weights of 969.6, 954.8, 967.7, 977.1, 968.1, 926.9, 941.1, 910.7, 939.7, 953.0, respectively. , 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 9.9, 999.1, 969.7, 942.0, 937.6, 967.3, 988.1, 960.6, 954.2, 991.1, 954.4, 990.7, 950.9 , 937.6, 968.1, 955.4, 966.0, 709.3, 622.2, 486.8, 951.3, 951.3, 911.4, 967.5, 896.5, 911 .0, 967.3, 911.2, 953.2, 967.2, 927.4, 896.4, 952.8, 953.4, 670.1, 953.3, 599.7, 486.5 , 966.1, 895.8 , 909.1, 486.4, 995.1, 953.1, 486.5, 486.5, 486.5, 486.5, 486.5, 486.5, 673.2, and 823.9. I confirmed that there was.

Example 2: Preparation of YDE derivative having modified C-terminal Preparation of YDE peptide YDE peptide (YDE-093, YDE-096, and YDE-101 to YDE-107) which is a derivative of the amino acid sequence of YDE-011 is used as YDE. Obtained by C-terminal modification of YDE peptide such as -011.

For the purpose of preparing a C-terminal modified peptide, Fmoc solid phase peptide synthesis (SPPS) was performed according to the standard procedure described in WO2018 / 225961, and a C-terminal amidation reaction was further performed.

The peptides of the invention are made through similar procedures, eg, by substituting different amino acid component reagents in a desired step.

Preparation Example of YDE-093 In order to prepare the C-terminal amidated peptide YDE-093, a synthetic process as shown in Scheme A below was performed. Fmoc-protected dimeric peptides (Fmoc-Hyp-H-Gly-Gln-Leu-Gly-Ala-Leu-Gly-Pro-Pro-Lys (Dde) -OH) were prepared according to the procedure described in WO2018 / 225961.

Based on the selected amino acid sequence, the chain reaction was performed in the following order:
1) Fmoc-Lys (Dde) -OH
2) Fmoc-Pro-OH
3) Fmoc-Gly-OH
4) Fmoc-Ala-OH
5) Fmoc-Leu-OH
6) Fmoc-Gly-OH
7) Fmoc-Leu-OH
8) Fmoc-Gln (Trt) -OH
9) Fmoc-Gly-OH
10) Fmoc-Hyp (tBu) -OH
Scheme A:

Fmoc-Hyp-Gly-Gln-Leu-Gly-Ala-Leu-Gly-Pro-Lys (Dde) -OH (500 mg, 0.37 mmol) and tert-butyl (2- (2-aminoethoxy) ethyl) carbamate ( HOBt (76 mg, 0.56 mmol), EDCI (107 mg, 0.56 mmol), and i-Pr ₂ EtN (24 μL, 0. 136 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. After 1 hour, the reaction mixture was heated to room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with DCM (20 mL x 2). The organic layers were combined into one, washed with water (20 mL × 2), and concentrated under reduced pressure. Diethyl ether was added to the residue to precipitate, and the desired Fmoc-protected peptide (400 mg, 71%) was obtained as a white solid.

Fmoc-Hyp-Gly-Gln-Leu-Gly-Ala-Leu-Gly-Pro-Lys (Dde) -PEG1-NHBoc (400 mg, 0.26 mmol) was placed in a reaction vessel, and a DMF solution of 4% hydrazine (10 mL) was added. ) Was added, the mixture was stirred for 30 minutes, and then diethyl ether (40 mL) was added for precipitation. The precipitate was then filtered and collected and then washed twice with a large amount of ether to give the crude peptide YDE-093 (quantitative yield) as a white solid. Crude YDE-093 was purified by preparative HPLC system. The purified peptide was converted from a TFA salt to an AcOH salt with an ion exchange resin. The ion-exchanged peptide was dried by a freeze-dryer.

YDE-093, YDE-096, and YDE-101 to YDE-107 are shown in Table 1A below.

Analysis of YDE peptide The YDE peptide prepared in Example 2 was analyzed by HPLC. As a result, the purity of the synthesized YDE-093, YDE-096, YDE-101, YDE-102, YDE-103, YDE-105, YDE-106, and YDE-107 was 99.1% and 95. It was confirmed that it was 4%, 96.7%, 97.2%, 97.9%, 97.4%, 97.2%, and 98.2%.

Moreover, the YDE derivative prepared in Example 2 was analyzed by ion mass spectrometry. As a result, the molecular weights of the synthesized YDE-093, YDE-096, YDE-101, YDE-102, YDE-103, YDE-105, YDE-106, and YDE-107 were 1139.0 and 1173.6, respectively. , 851.9, 880.1, 864.5, 866.1, 878.4, and 894.3.

Example 3: Evaluation of Eye Protective Effect of YDE Derivative for Dry Eye Syndrome Preparation of Rats with Dry Eye Syndrome The purpose of evaluating the eye protective effect of YDE-001 to YDE-028 prepared in Example 1 for dry eye syndrome. A total of 320 Sprague-Dawley type male rats (Orient Bio, Syndrome, Korea) were acclimatized for 7 days. Then, 264 test rats were induced to have dry eye syndrome by extraorbital lacrimal gland resection (hereinafter referred to as ELGE in the present specification). Eight test rats with no abnormalities in the eyes underwent sham surgery as a control group.

2% to 3% isoflurane (Hana Pharma. Co., Hwasung, K ), 70% N2O, and _28.6 % _O2 mixed gas was inhaled to give the rats general anesthesia. The extraorbital lacrimal gland, located in the subcutaneous region above the masseter muscle and below the optic nerve, was then resected through a 10 mm sized transverse incision in the anterior part of the left tragus. The skin was sutured by the standard method. ELGE surgery time did not exceed 5 minutes for each rat. Six days after ELGE surgery, the Schirmer test was used to measure tear secretion to confirm whether dry eye syndrome was induced. On the other hand, each rat in the control group that underwent sham surgery confirmed the presence and location of the extraorbital lacrimal gland by skin incision, and then sutured the skin without excising the extraorbital lacrimal gland (Fig. 4).

The average body weight of the ELGE test group measured before the ELGE operation was 241.59 ± 13.56 g, and the average body weight measured 6 days after the ELGE operation was 297.38 ± 34.02 g. The average body weight of the control group measured before the sham operation was 240.13 ± 25.63 g, and the average body weight measured 6 days after the sham operation was 297.38 ± 34.02 g (FIG. 5).

The average tear secretion in the control group was 8.34 ± 0.73 mm ³ , and the average tear secretion in the ELGE test group was 3.55 ± 0.70 mm ³ . A total of 32 groups were selected with 8 rats per group based on the average tear secretion.

As a reference drug, 3% diquafosol sodium (Santen, Tokyo, Japan; DS in the present specification) currently on the market was used.

This animal experiment was conducted with the prior approval of the Animal Experiment Ethics Committee of Daegu Haany University (Approval No. DHU2017-003, January 12, 2017). All test animals were fasted except for water supply for 18 hours prior to ELGE surgery and final sabotage.

The groups of 32 were as summarized in Table 2.

In addition, for YDE-029 to YDE-043 prepared in Example 1, a total of 200 Assessment-Dawley type male rats (OrientBio, Seungnam, Korea) were adapted for 7 days for the purpose of evaluating the eye protection effect against dry eye syndrome. I let you. Dry eye syndrome was induced in 165 test rats by ELGE. Eight test rats with no abnormalities in the eyes underwent sham surgery as a control group. ELGE was performed as described above.

The average body weight of the ELGE test group measured before the ELGE operation was 264.09 ± 11.53 g, and the average body weight measured 6 days after the ELGE operation was 316.13 ± 15.77 g. The average body weight of the control group measured before the sham operation was 263.50 ± 9.24 g, and the average body weight measured 6 days after the sham operation was 315.25 ± 10.85 g (FIG. 6).

The average tear secretion in the control group was 10.90 ± 1.69 mm ³ , and the average tear secretion in the ELGE test group was 4.83 ± 0.99 mm ³ . A total of 20 groups were selected with 8 rats per group based on the average tear secretion.

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

This animal experiment was conducted with the prior approval of the Animal Experiment Ethics Committee of Daegu Haany University (Approval No. DHU2017-050, June 8, 2017). All test animals were fasted except for water supply for 18 hours prior to ELGE surgery and final sabotage.

The 20 groups were as summarized in Table 3.

Administration of YDE Derivatives For YDE-001 to YDE-028, YY-102 and 28 YDE-series were dissolved in physiological saline at a concentration of 3 mg / ml, respectively, and 9 days after ELGE surgery for 14 days every day. A total of 28 doses of 30 am and 3:30 pm were administered at a dose of 5 μl / eye. The 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 a total of 28 times from 7 days after the ELGE operation for 14 days. The same administration stimulus was given to the sham surgery control group and the ELGE control group. To prevent excessive dry eye, the same volume of saline was administered in the same manner instead of the study drug.

Furthermore, for YDE-029 to YDE-043, YY-102 and 15 YDE series were dissolved in physiological saline at a concentration of 3 mg / ml, respectively, and 9:30 am daily for 14 days from 7 days after ELGE surgery. A total of 28 doses of 3:30 pm were administered at a dose of 5 μl / eye. The 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 a total of 28 times from 7 days after the ELGE operation for 14 days. The same administration stimulus was given to the sham surgery control group and the ELGE control group. In order to prevent excessive dry eye, the same volume of saline was administered in the same manner instead of the study drug (Fig. 7).

Confirmation of changes in tear secretion due to YDE derivatives Changes in tear secretion were measured 6 days after ELGE surgery, and 7 and 14 days after the start of administration of YDE-001 to YDE-043. The amount of tear secretion was measured by a decrease in the distance traveled by tears absorbed by cobalt chloride paper (Toyo Roshi Kaisha, Japan) having a size of 1 × 15 mm.

Cobalt chloride paper was placed in the external eye angle of the rat for 60 seconds to absorb tears (Fig. 9). The length of the absorption area was measured from the corners of cobalt chloride paper with an electronic digital caliper (Mytutoyo, Tokyo, Japan) (FIG. 8).

FIG. 9 shows the test results. In the figure, A is a false control group, B is an ELGE control group, C is a DS reference group, D is a YY-102 administration group, and E to AF are YDE-001 to YDE, respectively. It is from the -028 administration group.

As a result, it was confirmed that the tear secretion amount of the ELGE control group was reduced as compared with the sham control group on the 7th and 14th days after the start of the administration of the physiological saline solution 6 days after the ELGE operation. Was done. In the group treated with the YDE derivative and the DS reference group, the amount of tear secretion was increased when compared with the ELGE control group, except that YDE-9, YDE-10, YDE-17, and YDE-19. , YDE-20, YDE-21, YDE-22, YDE-25, YDE-27, and YDE-28, with the exception of the group treated with a 3% solution, which were tears after 14 days of administration. No significant change was shown in the amount of fluid secretion. In particular, tear secretion was higher in YDE-15, YDE-11, YDE-08, YDE-26, YDE-16, YDE-01, YDE-23, and YY-102 when compared to the DS reference group. There was an increase of more than 20% in the group treated with the 3% solution.

Specific tear secretions are shown in FIGS. 10 and 4.

FIG. 11 shows the test results. In the figure, A is a false control group, B is an ELGE control group, C is a DS reference group, D is a YY-102 administration group, and E to S are YDE-029 to YDE, respectively. It is from the -043 administration group.

As a result, it was confirmed that the tear secretion amount of the ELGE control group was reduced as compared with the sham control group on the 7th and 14th days after the start of the physiological saline administration 6 days after the ELGE operation. rice field. In the group treated with the YDE derivative and the DS reference group, the amount of tear secretion was increased when compared with the ELGE control group, except that YDE-029, YDE-030, YDE-032, and YDE-033. , YDE-034, YDE-036, and YDE-41 treated with a 3% solution, with the exception of these, which show any significant change in tear production after 14 days of administration. I didn't. In particular, tear secretion increased by more than 20% in the group treated with the 3% solution of YDE-040, YDE-043, and YDE-042, in order, when compared to the DS reference group.

Specific tear secretions are shown in FIGS. 12 and 5.

Confirmation of changes in corneal damage caused by YDE derivatives After 14 doses of YDE-001 to YDE-028 were administered to each eye, changes in corneal transmittance were checked.

For the purpose of measuring corneal permeability, Zolethyl 50 ™ (Virbac Lab., Carros, France), an anesthesia for animals, was injected intraperitoneally at a dose of 25 mg / kg. Then, a saline solution containing a 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 eyes treated in this way were closed and taped. After 1 hour, the remaining fluorescent solution was removed with a cotton swab (FIG. 12). After 12 to 24 hours, the corneal transmittance was measured using a blue light tungsten lamp and a tabletop slit lamp biomicroscope (model SM-70N; Takaci Seiko Co., Nakano, Japan) (FIG. 13). ..

FIG. 14 shows the test results. In the figure, A is a false control group, B is an ELGE control group, C is a DS reference group, D is a YY-102 administration group, and E to AF are YDE-001 to YDE, respectively. It is from the -028 administration group.

As a result, the transmittance of the fluorescent dye was increased in the ELGE control group when compared with the false control group. The transmittance of the fluorescent dye was 3% of YDE-10, YDE-20, YDE-22, YDE-25, YDE-27, and YDE-28 on the 14th day after the start of administration when compared with the ELGE control group. There was no reduction in the solution-treated group. In the group treated with the YDE derivative and the DS reference group, the corneal permeability of the fluorescent dye was lower when compared with the ELGE control group, except that YDE-10, YDE-20, YDE-22, YDE- The exception was the group treated with a 3% solution of 25, YDE-27, and YDE-28. In particular, the transmittance of the fluorescent dye was YDE-15, YDE-11, YDE-08, YDE-26, YDE-16, YDE-01, YDE-23, and YY-102 when compared with the DS reference group. There was a decrease of more than 20% in the group treated with the 3% solution of.

Specific fluorescent dye transmittances are shown in FIGS. 15 and 6.

In addition, YDE-029 to YDE-043 were administered to the eyes 14 times each, and then changes in corneal transmittance were checked. The measurement of corneal transmittance was performed in the same manner as described above (FIG. 16).

As a result, the transmittance of the fluorescent dye was increased in the ELGE control group when compared with the false control group. The transmittance of the fluorescent dye was treated with a 3% solution of YDE-29, YDE-32, YDE-33, YDE-36, and YDE-41 on the 14th day after the start of administration when compared with the ELGE control group. It did not decrease in the group. In the group treated with the YDE derivative and the DS reference group, the corneal permeability of the fluorescent dye was lower when compared with the ELGE control group, except that YDE-29, YDE-32, YDE-33, YDE- The group treated with a 3% solution of 36 and YDE-41 was an exception. In particular, the transmittance of the fluorescent dye was reduced by more than 20% in the group treated with a 3% solution of YDE-40, YDE-43, and YDE-42 when compared with the DS reference group.

Specific fluorescent dye transmittances are shown in FIGS. 17 and 7.

Example 4: Evaluation of Stability of YDE Derivatives For the purpose of confirming the stability of each test substance in an aqueous solution, 10 mg of each sample was dissolved in 1 ml of water to a concentration of 1 mg / ml, which was then placed in a glass vial. , Covered with a rubber stopper, sealed with an aluminum cap, and stored under long-term storage conditions (25 ° C., 75% RH). Test material stability was assessed by measuring the amount of relevant material at 1 week, 2 weeks, 4 weeks, 8 weeks, and 12 weeks under long-term storage conditions.

As a result, 66.5% of related substances were produced in YY-101 after 2 weeks. In contrast, in YDE-001 to YDE-028, 1.1% to 30.6% of related substances were produced after 12 weeks. The specific amounts are shown in Table 8.

Example 5: Evaluation of recovery of corneal damage by YDE derivative The cell proliferation rate of human primary corneal epithelial cells was checked for the purpose of confirming whether the YDE derivative has the potential to recover corneal damage.

Specifically, the primary corneal epithelial cells (ATCC, ATCC PCS-700-010) are used as the corneal epithelial cell basal medium (ATCC, ATCC PCS-700-) of the corneal epithelial cell proliferation kit (ATCC, ATCC PCS-700-040). A 96-well culture plate (Perkin Elmer, 6005680) containing 030) was seeded in an amount of 5 × 10 ³ cells per well, which was then cultured for 24 hours under 37 ° C. and 5% CO ₂ conditions.

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

After 24 hours, 20 μl of each YDE derivative diluted in 96-well microplates was added to 96-well culture plates containing cells. As a control group, hEGF (Sigma, E9644) was treated at the same concentration as the YDE derivative. Cells treated with the YDE derivative or hEGF were cultured for 48 and 72 hours under 37 ° C. and 5% CO ₂ conditions (FIGS. 18-25).

Cultured cells were treated with CellTiter-Glo luminescent reagent (Promega, G7573) according to the manufacturer's instructions and reacted at room temperature for 30 minutes. The fluorescence signal (ie, emission signal) was then checked using an Envision 2014 Multi-label plate reader. The measured values were normalized using a vehicle control (100% proliferating cells).

As a result, 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 showed cell proliferation at concentrations of 0.3 μM or less. In particular, YY-102, YDE-011, YDE-045, YDE-057, and YDE-060 showed high cell proliferation rates (FIGS. 26-43).

Reference Incorporation All publications and patents referred to herein are herein in their entirety, as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. Incorporated as a reference by the book. In the event of a conflict, this application will prevail, including all definitions herein.

Equivalents Although specific embodiments of the present invention have been studied, the above specification is an example and is not limited thereto. Many modifications of the invention will be apparent to those skilled in the art by examining the specification and the following claims. The entire scope of the invention should be determined by reference to the claims and their equivalents, as well as the specification and such modifications.

Claims (318)

The following formula (I):

It is a salt of the compound represented by
During the ceremony:
R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, respectively. , Heterocyclyl, or heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl;
However, the compound is not:

Preferably, the compound has at least one D-amino acid residue.
The salt. R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl, respectively;
^R4 is independently selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -OR ^b , hydroxyalkyl, -CH ₂ OR ^b , and halo in each presence;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl, respectively.
The salt according to claim 1. If specified, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or halo, haloalkyl, Oxo, -CN, -NO ₂ , = N-OH, -N ₃ , -R ^a , -OR ^a , -SR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , = NR ^a , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) N (R ^a ) ₂ , -S (= O) ₂ R ^c , -OS (= O) ₂ OR ^a , -S (= O) ₂ OR ^a , -S (= O) ₂ N (R ^a ) ₂ , -S (= O) R ^c , -OP (= O) (OR ^a ) ₂ ,-(alkylene) ) -C (= O) R ^c , -C (= S) R ^c , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , -C (= S) OR ^a , -C (= O) SR ^a , -C (= S) SR ^a ,-(alkylene) -C (= O) N (R ^a ) ₂ , -C (= S) N (R ^a ) ₂ , and- Substituted with one or more substituents selected from C (-NR ^a ) N (R ^a ) ₂ ;
R ^a is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl, independently of each presence; and R ^c is present. The salt according to claim 1 or 2, which is a substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl independently of each other. If specified, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl are unsubstituted or halo, haloalkyl, Oxo, -R ^a , -OR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) ) N (R ^a ) ₂ , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , and-(alkylene) -C (= O) N (R ^a ) ₂ . Substituted with one or more substituents;
R ^a is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl, independently of each presence; and R ^c is present. The salt according to any one of claims 1 to 3, which is a substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl independently of each other. .. R ^a is hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl independently as it is present; and R ^c is alkyl, aryl, arylalkyl, heterocyclyl, independently as it is present. , Or the salt according to claim 4, which is heterocyclylalkyl. The compound is of the formula (I-10L) :.

The salt according to any one of claims 1 to 5, which has the structure of. The following formula (I-10D):

The salt according to any one of claims 1 to 5, which has the structure of. The salt according to any one of claims 1 to 7, wherein R ¹ is a substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl. R ¹ is a substituted or unsubstituted alkyl,

Selected from;
Ra is hydrogen or alkyl; and n is an ^integer of 1-10, preferably 1-5, more preferably 1-3.
The salt according to any one of claims 1 to 8. R ¹ is

The salt according to any one of claims 1 to 9, which is selected from. R ¹ is

The salt according to any one of claims 1 to 10. R ¹ is

The salt according to any one of claims 1 to 10. The compound is of the formula (I-1L).

The salt according to any one of claims 1 to 12, which has the structure of. The compound is of the formula (I-1D).

The salt according to any one of claims 1 to 12, which has the structure of. The salt according to any one of claims 1 to 14, wherein ^R2 is H, or a substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl. R ² is hydrogen, substituted or unsubstituted alkyl,

Selected from;
Ra is hydrogen or alkyl; and n is an ^integer of 1-10, preferably 1-5, more preferably 1-3.
The salt according to any one of claims 1 to 15. R ² is

The salt according to any one of claims 1 to 16, which is selected from. The salt according to any one of claims 1 to 17, wherein R ² is hydrogen. The compound is of formula (I-2L) :.

The salt according to any one of claims 1 to 18, which has the structure of. The compound is of formula (I-2D) :.

The salt according to any one of claims 1 to 18, which has the structure of. The salt according to any one of claims 1 to ²⁰ , wherein R3 is a substituted or unsubstituted alkyl or arylalkyl. R ³ is a substituted or unsubstituted alkyl,

Selected from;
Ra is hydrogen or alkyl; and n is an ^integer of 1-10, preferably 1-5, more preferably 1-3.
The salt according to any one of claims 1 to 21. R ³ is

The salt according to any one of claims 1 to 24, which is selected from. R ³ is

The salt according to any one of claims 1 to 23. The compound is of formula (I-3L) :.

The salt according to any one of claims 1 to 24, which has the structure of. The compound is of formula (I-3D) :.

The salt according to any one of claims 1 to 24, which has the structure of. p is 1 or 2; and ^R4 is independently selected from substituted or unsubstituted alkyl, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl each time it is present. ,
The salt according to any one of claims 1 to 26. p is 1 or 2; and ^R4 is independently selected from -CH ₃ , halo, hydroxyl, and hydroxyalkyl each time it is present.
The salt according to any one of claims 1 to 27. 28. The salt of claim 28, wherein ^R4 is a hydroxyl group. 28. The salt according to claim 28, wherein R ⁴ is −CH ₃ . The salt according to any one of claims 27 to 30, wherein p is 1. The compound is of the formula (I-4Lg):

The salt according to any one of claims 1 to 31, which has the structure of. The compound is of the formula (I-4La) :.

The salt according to any one of claims 1 to 32, which has the structure of. The compound is of the formula (I-4Lb):

The salt according to any one of claims 1 to 32, which has the structure of. The compound is of the formula (I-4Lc):

Has the structure of;
However, the salt according to any one of claims 1 to 28, 30, and 31, wherein ^R4 is not a hydroxyl group. The compound is of the formula (I-4Dg):

The salt according to any one of claims 1 to 31, which has the structure of. The compound is of the formula (I-4Da):

The salt according to any one of claims 1 to 31 and 36, which has the structure of. The compound is of the formula (I-4Db):

The salt according to any one of claims 1 to 31 and 36, which has the structure of. The compound is of the formula (I-4Dc):

Has the structure of;
However, the salt according to any one of claims 1 to 28, 30, 31, and 36, wherein R ⁴ is not a hydroxyl group. The salt according to any one of claims 1 to 26, wherein ^R4 is oxo. The compound is of the formula (I-4Ld):

40. The salt according to claim 40, which has the structure of. The compound is of the formula (I-4Le):

40. The salt according to claim 40, which has the structure of. The compound is of the formula (I-4Dd):

40. The salt according to claim 40, which has the structure of. The compound is of the formula (I-4De):

40. The salt according to claim 40, which has the structure of. The salt according to any one of claims 1 to 44, wherein R ⁶ is hydrogen or an alkyl, wherein the alkyl is optionally substituted with the presence of one of -C (= O) NH ₂ . The salt according to any one of claims 1 to 45, wherein R ⁶ is an alkyl optionally substituted with the presence of one of -C (= O) NH ₂ . The salt according to any one of claims 1 to 46, wherein R ⁶ is −CH ₃ . ^R6 is

The salt according to any one of claims 1 to 46. The compound is of formula (I-6L) :.

The salt according to any one of claims 1 to 48, which has the structure of. The compound is of formula (I-6D) :.

The salt according to any one of claims 1 to 48, which has the structure of. The salt according to any one of claims 1 to 50, wherein R ⁷ is (C ₁ -C ₁₀ ) alkyl. R ⁷ is

The salt according to any one of claims 1 to 51. R ⁷ is

The salt according to any one of claims 1 to 51. The compound is of formula (I-7L) :.

The salt according to any one of claims 1 to 53, which has the structure of. The compound is of formula (I-7D) :.

The salt according to any one of claims 1 to 53, which has the structure of. The compound is of the formula (I-11L):

The salt according to any one of claims 1 to 55, which has the structure of. The compound is of the formula (I-11D) :.

The salt according to any one of claims 1 to 55, which has the structure of. The salt according to any one of claims 1 to 57, wherein R ⁸ is —CH ₃ or —H. The salt according to any one of claims 1 to 58, wherein R ⁸ is −H. The salt according to any one of claims 1 to 59, wherein R ⁹ is —CH ₃ or —H. The salt according to any one of claims 1 to 60, wherein R ⁹ is −H. Any one of claims 1 to 61, wherein the compound comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 D-amino acid residues. The salt described in. The compound is as follows:

The salt of claim 1, which is selected from. The compound is as follows:

The salt of claim 1, which is selected from. The compound is as follows:

The salt of claim 1, which is selected from. The compound is as follows:

The salt of claim 1, which is selected from. The compound is as follows:

The salt of claim 1, which is selected from. The following formula (I):

Compound represented by;
During the ceremony:
R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, respectively. , Heterocyclyl, or heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl;
However, the following:
(A) At least one of R ¹ , R ² , and R ³ is a substituted or unsubstituted (C2 _- C ₁₀ ) haloalkyl;
(B) At least one of alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is -R ^a , -OR ^a ,-. SR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , = NR ^a , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) N ( R ^a ) ₂ , -S (= O) ₂ R ^c , -OS (= O) ₂ OR ^a , -S (= O) ₂ OR ^a , -S (= O) ₂ N (R ^a ) ₂ ,- S (= O) R ^c , -OP (= O) (OR ^a ) ₂ ,-(alkylene) -C (= O) R ^c , -C (= S) R ^c , -C (= O) OR ^a ,-(Alkylene) -C (= O) OR ^a , -C (= S) OR ^a , -C (= O) SR ^a , -C (= S) SR ^a ,-(alkylene) -C (= O) ) N (R ^a ) ₂ , -C (= S) N (R ^a ) ₂ , and -C (-NR ^a ) N (R ^a ) ₂ substituted with one or more substituents selected from; And at least one Ra or R ^c is heterocyclylalkyl, cycloalkyl, or ⁽ cycloalkyl) alkyl;
(C) The compound has at least one D-amino acid residue; or ( ^d ) at least two Ra are present;
At least two R ^cs are present; or at least one R ^a and at least one R ^c are present; and at least one R ^a and / or R ^c different from these existing R ^a and / or R ^c is present. At least one of the two is present; as well, the compound is:

Not the compound, or a pharmaceutically acceptable salt thereof. 28. The compound of claim 68, wherein at least one of R ¹ , R ² , and R ³ is a substituted or unsubstituted (C2 _- C ₁₀ ) haloalkyl. At least one of alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is -R ^a , -OR ^a , -SR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , = NR ^a , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) N (R ^a ) ₂ , -S (= O) ₂ R ^c , -OS (= O) ₂ OR ^a , -S (= O) ₂ OR ^a , -S (= O) ₂ N (R ^a ) ₂ , -S (= O) R ^c , -OP (= O) (OR ^a ) ₂ ,-(alkylene) -C (= O) R ^c , -C (= S) R ^c , -C (= O) OR ^a ,-( Alkylene) -C (= O) OR ^a , -C (= S) OR ^a , -C (= O) SR ^a , -C (= S) SR ^a ,-(alkylene) -C (= O) N ( Replaced with one or more substituents selected from R ^a ) ₂ , -C (= S) N (R ^a ) ₂ , and -C (-NR ^a ) N (R ^a ) ₂ ; and at least 1. The existing R ^a or R ^c are heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl.
The compound according to claim 68 or 69. The compound according to any one of claims 68 to 70, wherein the compound contains at least one D-amino acid residue. The compound is as follows:
There are at least two ^Ra ;
At least two R ^cs are present; or at least one R ^a and at least one R ^c are present; and at least one R ^a and / or R ^c different from these existing R ^a and / or R ^c is present. The compound according to any one of claims 68 to 71, which satisfies the above conditions. R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl, respectively;
^R4 is independently selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -OR ^b , hydroxyalkyl, -CH ₂ OR ^b , and halo in each presence;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl, respectively.
The compound according to any one of claims 68 to 72. If specified, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or halo, haloalkyl, Oxo, -CN, -NO ₂ , = N-OH, -N ₃ , -R ^a , -OR ^a , -SR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , = NR ^a , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) N (R ^a ) ₂ , -S (= O) ₂ R ^c , -OS (= O) ₂ OR ^a , -S (= O) ₂ OR ^a , -S (= O) ₂ N (R ^a ) ₂ , -S (= O) R ^c , -OP (= O) (OR ^a ) ₂ ,-(alkylene) ) -C (= O) R ^c , -C (= S) R ^c , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , -C (= S) OR ^a , -C (= O) SR ^a , -C (= S) SR ^a ,-(alkylene) -C (= O) N (R ^a ) ₂ , -C (= S) N (R ^a ) ₂ , and- Substituted with one or more substituents selected from C (-NR ^a ) N ( ^Ra ) ₂ ; and ^Ra is an independent, hydrogen, or substituted or unsubstituted alkyl, each present. Aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl; as well as R ^c , each present independently, substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclyl. Alkyl, cycloalkyl, or (cycloalkyl) alkyl,
The compound according to any one of claims 68 to 73. If specified, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or halo, haloalkyl, Oxo, -R ^a , -OR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) ) N (R ^a ) ₂ , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , and-(alkylene) -C (= O) N (R ^a ) ₂ . Substituted with one or more substituents; as well as ^Ra , each present independently, hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or ( Cycloalkyl) alkyl; as well as ^Rc , each present independently, is a substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl.
The compound according to any one of claims 68 to 74. R ^a is hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl independently as it is present; and R ^c is alkyl, aryl, arylalkyl, heterocyclyl, independently as it is present. , Or the compound according to claim 75, which is a heterocyclylalkyl. The following formula (I-10L):

The compound according to any one of claims 68 to 76, which has the structure of. The following formula (I-10D):

The compound according to any one of claims 68 to 76, which has the structure of. The compound according to any one of claims 68 to 78, wherein ^R1 is a substituted or unsubstituted (C2 _{- C10} ) haloalkyl. The compound according to any one of claims 68 to 78, wherein R ¹ is a substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl. R ¹ is a substituted or unsubstituted alkyl,

Selected from;
Ra is hydrogen or alkyl; and n is an ^integer of 1-10, preferably 1-5, more preferably 1-3.
The compound according to any one of claims 68 to 78. R ¹ is

The compound according to any one of claims 68 to 78, which is selected from the above. R ¹ is

The compound according to any one of claims 68 to 78. R ¹ is

The compound according to any one of claims 68 to 78. The following formula (I-1L)

The compound according to any one of claims 68 to 84, which has the structure of. The following formula (I-1D)

The compound according to any one of claims 68 to 84, which has the structure of. The compound according to any one of claims 68 to 86, wherein R ² is a substituted or unsubstituted (C ₂ -C ₁₀ ) haloalkyl. The compound according to any one of claims 68 to 86, wherein R ² is H, or a substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl. R ² is hydrogen, substituted or unsubstituted alkyl,

Selected from;
Ra is hydrogen or alkyl; and n is an ^integer of 1-10, preferably 1-5, more preferably 1-3.
The compound according to any one of claims 68 to 86. R ² is

The compound according to any one of claims 68 to 86, which is selected from. The compound according to any one of claims 68 to 86, wherein R ² is hydrogen. The following formula (I-2L):

The compound according to any one of claims 68 to 90, which has the structure of. The following formula (I-2D):

The compound according to any one of claims 68 to 90, which has the structure of. The compound according to any one of claims 68 to 93, wherein R ³ is a substituted or unsubstituted (C2 _- C ₁₀ ) haloalkyl. The compound according to any one of claims 68 to 93, wherein R ³ is a substituted or unsubstituted alkyl or aryl alkyl. R ³ is a substituted or unsubstituted alkyl,

Selected from;
Ra is hydrogen or alkyl; and n is an ^integer of 1-10, preferably 1-5, more preferably 1-3.
The compound according to any one of claims 68 to 93. R ³ is

The compound according to any one of claims 68 to 93, which is selected from the above. R ³ is

The compound according to any one of claims 68 to 93. The following formula (I-3L):

The compound according to any one of claims 68 to 98, which has the structure of. The following formula (I-3D):

The compound according to any one of claims 68 to 98, which has the structure of. p is 1 or 2; and ^R4 is independently selected from substituted or unsubstituted alkyl, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl each time it is present. ,
The compound according to any one of claims 68 to 100. p is 1 or 2; and ^R4 is independently selected from -CH ₃ , halo, hydroxyl, and hydroxyalkyl each time it is present.
The compound according to any one of claims 68 to 100. The compound according to claim 102, wherein ^R4 is a hydroxyl group. The compound according to claim 102, wherein R ⁴ is −CH ₃ . The compound according to any one of claims 101 to 104, wherein p is 1. The following formula (I-4Lg):

The compound according to any one of claims 68 to 105, which has the structure of. The following formula (I-4La):

The compound according to any one of claims 68 to 106, which has the structure of. The following formula (I-4Lb):

The compound according to any one of claims 68 to 106, which has the structure of. The following formula (I-4Lc):

Has the structure of;
However, the compound according to any one of claims 68 to 102 and 104 to 106, wherein R ⁴ is not a hydroxyl group. The following formula (I-4Dg):

The compound according to any one of claims 68 to 105, which has the structure of. The following formula (I-4Da):

The compound according to any one of claims 68 to 105 and 110, which has the structure of. The following formula (I-4Db):

The compound according to any one of claims 68 to 105 and 110, which has the structure of. The following formula (I-4Dc):

Has the structure of;
However, the compound according to any one of claims 68 to 102, 104 to 106, and 110, wherein R ⁴ is not a hydroxyl group. The compound according to any one of claims 68 to 98, wherein ^R4 is oxo. The following formula (I-4Ld):

The compound according to claim 114, which has the structure of. The following formula (I-4Le):

The compound according to claim 114, which has the structure of. The following formula (I-4Dd):

The compound according to claim 114, which has the structure of. The following formula (I-4De):

The compound according to claim 114, which has the structure of. The compound according to any one of claims 68 to 118, wherein R ⁶ is hydrogen or an alkyl, wherein the alkyl is optionally substituted with the presence of one of -C (= O) NH ₂ . The compound according to any one of claims 68 to 119, wherein R ⁶ is an alkyl optionally substituted with the presence of one of -C (= O) NH ₂ . The compound according to any one of claims 68 to 120, wherein R ⁶ is −CH ₃ . ^R6 is

The compound according to any one of claims 68 to 120. The following formula (I-6L):

The compound according to any one of claims 68 to 122, which has the structure of. The following formula (I-6D):

The compound according to any one of claims 68 to 122, which has the structure of. The compound according to any one of claims 68 to 124, wherein R ⁷ is (C ₁ -C ₁₀ ) alkyl. R ⁷ is

The compound according to any one of claims 68 to 125. R ⁷ is

The compound according to any one of claims 68 to 125. The following formula (I-7L):

The compound according to any one of claims 68 to 127, which has the structure of. The following formula (I-7D):

The compound according to any one of claims 68 to 127, which has the structure of. The following formula (I-11L):

The compound according to any one of claims 68 to 129, which has the structure of. The following formula (I-11D):

The compound according to any one of claims 68 to 129, which has the structure of. The compound according to any one of claims 68 to 131, wherein R ⁸ is —CH ₃ or —H. The compound according to any one of claims 68 to 131, wherein R ⁸ is −H. The compound according to any one of claims 68 to 133, wherein R ⁹ is —CH ₃ or —H. The compound according to any one of claims 68 to 133, wherein R ⁹ is −H. Less than:

The compound according to claim 68, or a pharmaceutically acceptable salt thereof. A peptide having an amino acid sequence represented by HyP-Gly-Gln-Xaa-Gly-Leu-Ala-Gly-Pro-Lys;
In the formula, Xaa is selected from Glu, Asn, Gln, His, Lys, Ser, Thr, Ala, Val, Ile, Leu, Phe, Tyr, Trp, homo-Ser, Asp (Me), and Asn (Me). And at least one amino acid residue in the peptide is a D-amino acid residue.
The compound according to claim 68, or a pharmaceutically acceptable salt and / or stereoisomer thereof. The compound according to claim 137, wherein at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 amino acid residues in the peptide are D-amino acid residues. A peptide having an amino acid sequence represented by HyP-Gly-Gln-Asp-Xaa-Leu-Ala-Gly-Pro-Lys;
In the formula, Xaa is selected from Val, Ile, Leu, Ala, Phe, Tyr, Trp, Ser, Thr, and (N-Me) Gly; and at least one amino acid residue in the peptide is D-. Amino acid residue,
The compound according to claim 68, or a pharmaceutically acceptable salt and / or stereoisomer thereof. The compound according to claim 139, wherein at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 amino acid residues in the peptide are D-amino acid residues. A peptide having an amino acid sequence represented by HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Xaa;
In the formula, Xaa is selected from Tyr, Leu, Glu, Gln, Ala, and Nle (6-OH); and at least one amino acid residue in the peptide is a D-amino acid residue.
The compound according to claim 68, or a pharmaceutically acceptable salt and / or stereoisomer thereof. The compound according to claim 141, wherein at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 amino acid residues in the peptide are D-amino acid residues. A peptide having an amino acid sequence represented by Xaa-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys;
In the formula, Xaa is as follows:

Selected from; and at least one amino acid residue in the peptide is a D-amino acid residue.
The compound according to claim 68, or a pharmaceutically acceptable salt and / or stereoisomer thereof. The compound according to claim 143, wherein at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 amino acid residues in the peptide are D-amino acid residues. The following formula:

A compound having, or a pharmaceutically acceptable salt thereof. The following formula (V):

It is a compound represented by
During the ceremony:
R ¹ and R ² are independently H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or Heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁹ is hydrogen or alkyl;
However, the compound is as follows:

is not it,
The compound, or a pharmaceutically acceptable salt thereof. R ¹ and R ² are H, or substituted or unsubstituted alkyl, respectively;
^R4 is a hydroxyl, if any,;
p is 1;
R ⁶ is an alkyl optionally substituted with the presence of one of -C (= O) NH ₂ ; and R ⁹ is hydrogen.
The compound according to claim 146. The compound according to claim 146 or 147, wherein ^R1 is a substituted or unsubstituted alkyl. R ¹ is

The compound according to any one of claims 146 to 148. The following formula (V-1L)

The compound according to any one of claims 146 to 149, which has the structure of. The following formula (V-1D)

The compound according to any one of claims 146 to 149, which has the structure of. The compound according to any one of claims 146 to 151, wherein R ² is H. The compound according to any one of claims 146 to 152, wherein p is 1 and ^R4 is a hydroxyl. The following formula (V-4La):

The compound according to any one of claims 146 to 153, which has the structure of. The following formula (V-4Lb):

The compound according to any one of claims 146 to 153, which has the structure of. The following formula (V-4Da):

The compound according to any one of claims 146 to 153, which has the structure of. The following formula (V-4Db):

The compound according to any one of claims 146 to 153, which has the structure of. The compound according to any one of claims 146 to 157, wherein R ⁶ is an alkyl substituted with the presence of one of -C (= O) NH ₂ . ^R6 is

The compound according to any one of claims 146 to 158. The following formula (V-6L):

The compound according to any one of claims 146 to 159, which has the structure of. The following formula (V-6D):

The compound according to any one of claims 146 to 159, which has the structure of. The compound according to any one of claims 146 to 161 in which ^R9 is −H. Less than:

The compound according to claim 146, or a pharmaceutically acceptable salt thereof, which is selected from the above. The following formula (VI):

It is a compound represented by
During the ceremony:
R ¹ and R ² are independently H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or Heterocyclylalkyl, ^R4 , is independent of each presence from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl. Selected;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
^R6 is hydrogen, or substituted or unsubstituted alkyl;
R ⁷ is hydrogen or alkyl; and R ⁹ is hydrogen or alkyl;
However, the compound is as follows:

is not it,
The compound, or a pharmaceutically acceptable salt thereof. R ¹ and R ² are H, or substituted or unsubstituted alkyl, respectively;
^R4 is a hydroxyl, if any,;
p is 1;
R ⁶ is an alkyl optionally substituted with the presence of one of -C (= O) NH ₂ ; and R ⁹ is hydrogen.
The compound according to claim 164. The compound according to claim 164 or 165, wherein ^R1 is a substituted or unsubstituted alkyl. R ¹ is

The compound according to any one of claims 164 to 166. The following formula (VI-1L)

The compound according to any one of claims 164 to 167, which has the structure of. The following equation (VI-1D)

The compound according to any one of claims 164 to 167, which has the structure of. The compound according to any one of claims 164 to 169, wherein R ² is H. The compound according to any one of claims 164 to 170, wherein p is 1 and ^R4 is a hydroxyl. The following formula (VI-4La):

The compound according to any one of claims 164 to 171 having the structure of. The following formula (VI-4Lb):

The compound according to any one of claims 164 to 171 having the structure of. The following formula (VI-4Da):

The compound according to any one of claims 164 to 171 having the structure of. The following formula (VI-4Db):

The compound according to any one of claims 164 to 171 having the structure of. The compound according to any one of claims 164 to 175, wherein R ⁶ is an alkyl substituted with the presence of one of -C (= O) NH ₂ . ^R6 is

The compound according to any one of claims 164 to 176. The following formula (VI-6L):

The compound according to any one of claims 164 to 177, which has the structure of. The following formula (VI-6D):

The compound according to any one of claims 164 to 177, which has the structure of. The compound according to any one of claims 164 to 179, wherein R ⁹ is −H. The compound according to any one of claims 164 to 180, wherein R ⁷ is (C ₁ -C ₁₀ ) alkyl. R ⁷ is

The compound according to any one of claims 164 to 180. R ⁷ is

The compound according to any one of claims 164 to 180. The following formula (VI-7L):

The compound according to any one of claims 164 to 183, which has the structure of. The following formula (VI-7D):

The compound according to any one of claims 164 to 183, which has the structure of. The following formula (VII):

It is a compound represented by
During the ceremony:
R ¹ and R ² are independently H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or Heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
^R6 is hydrogen, or substituted or unsubstituted alkyl;
R ⁷ is hydrogen or alkyl; and R ⁹ is hydrogen or alkyl;
However, the compound is as follows:

is not it,
The compound, or a pharmaceutically acceptable salt thereof. R ¹ and R ² are H, or substituted or unsubstituted alkyl, respectively;
^R4 is a hydroxyl, if any,;
p is 1;
R ⁶ is an alkyl optionally substituted with the presence of one of -C (= O) NH ₂ ; and R ⁹ is hydrogen.
The compound according to claim 186. The compound according to claim 186 or 187, wherein ^R1 is a substituted or unsubstituted alkyl. R ¹ is

The compound according to any one of claims 186 to 188. The following formula (VII-1L)

The compound according to any one of claims 186 to 189, which has the structure of. The following equation (VII-1D)

The compound according to any one of claims 186 to 189, which has the structure of. The compound according to any one of claims 186 to 191 in which ^R2 is H. The compound according to any one of claims 186 to 192, wherein p is 1 and ^R4 is a hydroxyl. The following formula (VII-4La):

The compound according to any one of claims 186 to 193, which has the structure of. The following formula (VII-4Lb):

The compound according to any one of claims 186 to 193, which has the structure of. The following formula (VII-4Da):

The compound according to any one of claims 186 to 193, which has the structure of. The following formula (VII-4Db):

The compound according to any one of claims 186 to 193, which has the structure of. The compound according to any one of claims 186 to 197, wherein R ⁶ is an alkyl substituted with the presence of one of -C (= O) NH ₂ . ^R6 is

The compound according to any one of claims 186 to 198. The following formula (VII-6L):

The compound according to any one of claims 186 to 199, which has the structure of. The following formula (VII-6D):

The compound according to any one of claims 186 to 199, which has the structure of. The compound according to any one of claims 186 to 201, wherein R ⁹ is −H. The compound according to any one of claims 186 to 202, wherein R ⁷ is (C ₁ -C ₁₀ ) alkyl. R ⁷ is

The compound according to any one of claims 186 to 203. R ⁷ is

The compound according to any one of claims 186 to 203. The following formula (VII-7L):

The compound according to any one of claims 186 to 205, which has the structure of. The following formula (VII-7D):

The compound according to any one of claims 186 to 205, which has the structure of. The following formula (VII-10L):

The compound according to any one of claims 186 to 207, which has the structure of. The following formula (VII-10D):

The compound according to any one of claims 186 to 207, which has the structure of. The following formula (IX):

It is a compound represented by;
During the ceremony:
R ¹ and R ² are independently H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or Heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
^R6 is hydrogen, or substituted or unsubstituted alkyl;
R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl;
J is OH or -NR ^x R ^y ; and R ^x and R ^y are independently selected from H, optionally substituted alkyl, optionally substituted alkoxyl alkyl, respectively. Alternatively, R ^x and R ^y form a ring together with the intervening nitrogen atoms.
The compound, or a pharmaceutically acceptable salt thereof. R ¹ and R ² are H, or substituted or unsubstituted alkyl, respectively;
^R4 is a hydroxyl, if any,;
p is 1;
R ⁶ is an alkyl optionally substituted with the presence of one of -C (= O) NH ₂ ; and R ⁹ is hydrogen.
The compound according to claim 210. The compound according to claim 210 or 211, wherein ^R1 is a substituted or unsubstituted alkyl. R ¹ is

The compound according to any one of claims 210 to 212. The following formula (IX-1L):

The compound according to any one of claims 210 to 213, which has the structure of. The following formula (IX-1D):

The compound according to any one of claims 210 to 213, which has the structure of. The compound according to any one of claims 210 to 215, wherein R ² is H. The compound according to any one of claims 210 to 216, wherein p is 1 and ^R4 is a hydroxyl. The following formula (IX-4La):

The compound according to any one of claims 210 to 217, which has the structure of. The following formula (IX-4Lb):

The compound according to any one of claims 210 to 217, which has the structure of. The following formula (IX-4Da):

The compound according to any one of claims 210 to 217, which has the structure of. The following formula (IX-4Db):

The compound according to any one of claims 210 to 217, which has the structure of. The compound according to any one of claims 210 to 221, wherein R ⁶ is an alkyl substituted with the presence of one of -C (= O) NH ₂ . ^R6 is

The compound according to any one of claims 210 to 222. The following formula (IX-6L):

The compound according to any one of claims 210 to 223, which has the structure of. The following formula (IX-6D):

The compound according to any one of claims 210 to 223, which has the structure of. The compound according to any one of claims 210 to 225, wherein R ⁹ is −H. The compound according to any one of claims 210 to 226, wherein R ⁷ is (C ₁ -C ₁₀ ) alkyl. R ⁷ is

The compound according to any one of claims 210 to 227. R ⁷ is

The compound according to any one of claims 210 to 227. The following formula (IX-7L):

The compound according to any one of claims 210 to 229, which has the structure of. The following formula (IX-7D):

The compound according to any one of claims 210 to 229, which has the structure of. The following formula (IX-10L):

The compound according to any one of claims 210 to 231 having the structure of. The following formula (IX-10D):

The compound according to any one of claims 210 to 231 having the structure of. The following formula (IX-11L):

The compound according to any one of claims 210 to 233, which has the structure of. The following formula (IX-11D):

The compound according to any one of claims 210 to 233, which has the structure of. The compound according to any one of claims 210 to 235, wherein R ⁸ is —CH ₃ or —H. The compound according to any one of claims 210 to 236, wherein R ⁸ is −H. The compound according to any one of claims 210 to 237, wherein J is OH. The compound according to any one of claims 210 to 237, wherein J is −NR ^x R ^y . The compound according to claim 239, wherein R ^x and R ^y are each independently alkyl. The compound according to claim 239, wherein R ^x and R ^y form a ring together with an intervening nitrogen atom. The following formula (X-am):

It is a compound represented by
During the ceremony:
R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, respectively. , Heterocyclyl, or heterocyclylalkyl;
^R4 is independently selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
p is 0, 1, or 2;
^R6 is hydrogen, or substituted or unsubstituted alkyl;
R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl;
J is OH or -NR ^x R ^y ; and R ^x and R ^y are independently selected from H, optionally substituted alkyl, optionally substituted alkoxyl alkyl, respectively. Alternatively, R ^x and R ^y form a ring together with the intervening nitrogen atoms.
The compound, or a pharmaceutically acceptable salt thereof. R ¹ , R ² , and R ³ are H, or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl, respectively;
^R4 is independently selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -OR ^b , hydroxyalkyl, -CH ₂ OR ^b , and halo in each presence;
^Rb is a substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
R ⁶ is hydrogen, or substituted or unsubstituted alkyl; and R ⁷ , R ⁸ and R ⁹ are independently hydrogen or alkyl, respectively.
The compound according to claim 242. If specified, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or halo, haloalkyl, Oxo, -CN, -NO ₂ , = N-OH, -N ₃ , -R ^a , -OR ^a , -SR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , = NR ^a , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) N (R ^a ) ₂ , -S (= O) ₂ R ^c , -OS (= O) ₂ OR ^a , -S (= O) ₂ OR ^a , -S (= O) ₂ N (R ^a ) ₂ , -S (= O) R ^c , -OP (= O) (OR ^a ) ₂ ,-(alkylene) ) -C (= O) R ^c , -C (= S) R ^c , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , -C (= S) OR ^a , -C (= O) SR ^a , -C (= S) SR ^a ,-(alkylene) -C (= O) N (R ^a ) ₂ , -C (= S) N (R ^a ) ₂ , and- Substituted with one or more substituents selected from C (-NR ^a ) N ( ^Ra ) ₂ ; and ^Ra is an independent, hydrogen, or substituted or unsubstituted alkyl, each present. Aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl; as well as R ^c , each present independently, substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclyl. Alkyl, cycloalkyl, or (cycloalkyl) alkyl,
The compound according to claim 242 or 243. If specified, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or halo, haloalkyl, Oxo, -R ^a , -OR ^a , -N (R ^a ) ₂ , -N (R ^a ) ₃ ⁺ , -NHC (= O) R ^c , -C (= O) R ^c , -C (= O) ) N (R ^a ) ₂ , -C (= O) OR ^a ,-(alkylene) -C (= O) OR ^a , and-(alkylene) -C (= O) N (R ^a ) ₂ . Substituted with one or more substituents; as well as ^Ra , each present independently, hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or ( Cycloalkyl) alkyl; as well as ^Rc , each present independently, is a substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl) alkyl, claim. Item 6. The compound according to any one of Items 242 to 244. R ^a is hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl independently as it is present; and R ^c is alkyl, aryl, arylalkyl, heterocyclyl, independently as it is present. , Or the compound of claim 245, which is heterocyclylalkyl. The following formula (X-am-10L):

The compound according to any one of claims 242 to 246, which has the structure of. The following formula (X-am-10D):

The compound according to any one of claims 242 to 246, which has the structure of. The compound according to any one of claims 242 to 248, wherein R ¹ is a substituted or unsubstituted (C2 _- C ₁₀ ) haloalkyl. The compound according to any one of claims 242 to 248, wherein R ¹ is a substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl. R ¹ is a substituted or unsubstituted alkyl,

Selected from;
Ra is hydrogen or alkyl; and n is an ^integer of 1-10, preferably 1-5, more preferably 1-3.
The compound according to any one of claims 242 to 248. R ¹ is

The compound according to any one of claims 242 to 248, which is selected from. R ¹ is

The compound according to any one of claims 242 to 248. R ¹ is

The compound according to any one of claims 242 to 248. The following formula (X-am-1L)

The compound according to any one of claims 242 to 254, which has the structure of. The following formula (X-am-1D)

The compound according to any one of claims 242 to 254, which has the structure of. The compound according to any one of claims 242 to 256, wherein R ² is a substituted or unsubstituted (C ₂ -C ₁₀ ) haloalkyl. The compound according to any one of claims 242 to 256, wherein R ² is H, or a substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl. R ² is hydrogen, substituted or unsubstituted alkyl,

Selected from;
Ra is hydrogen or alkyl; and n is an ^integer of 1-10, preferably 1-5, more preferably 1-3.
The compound according to any one of claims 242 to 256. R ² is

The compound according to any one of claims 242 to 256, which is selected from the above. The compound according to any one of claims 242 to 256, wherein R ² is hydrogen. The following formula (X-am-2L):

The compound according to any one of claims 242 to 260, which has the structure of. The following formula (X-am-2D):

The compound according to any one of claims 242 to 260, which has the structure of. The compound according to any one of claims 242 to 263, wherein R ³ is a substituted or unsubstituted (C2 _- C ₁₀ ) haloalkyl. The compound according to any one of claims 242 to 263, wherein R ³ is a substituted or unsubstituted alkyl or aryl alkyl. R ³ is a substituted or unsubstituted alkyl,

Selected from;
Ra is hydrogen or alkyl; and n is an ^integer of 1-10, preferably 1-5, more preferably 1-3.
The compound according to any one of claims 242 to 263. R ³ is

The compound according to any one of claims 242 to 263, which is selected from the above. R ³ is

The compound according to any one of claims 242 to 263. The following formula (X-am-3L):

The compound according to any one of claims 242 to 268, which has the structure of. The following formula (X-am-3D):

The compound according to any one of claims 242 to 268, which has the structure of. p is 1 or 2; and ^R4 is independently selected from substituted or unsubstituted alkyl, -OR ^b , -CH ₂ OR ^b , halo, hydroxyl, and hydroxyalkyl each time it is present. ,
The compound according to any one of claims 242 to 270. p is 1 or 2; and ^R4 is independently selected from -CH ₃ , halo, hydroxyl, and hydroxyalkyl each time it is present.
The compound according to any one of claims 242 to 270. The compound according to claim 272, wherein ^R4 is a hydroxyl group. The compound according to claim 272, wherein R ⁴ is −CH ₃ . The compound according to any one of claims 271 to 274, wherein p is 1. The following formula (X-am-4Lg):

The compound according to any one of claims 242 to 275, which has the structure of. The following formula (X-am-4La):

The compound according to any one of claims 242 to 276, which has the structure of. The following formula (X-am-4Lb):

The compound according to any one of claims 242 to 276, which has the structure of. The following formula (X-am-4Lc):

Has the structure of;
However, the compound according to any one of claims 242 to 272 and 274 to 276, wherein R ⁴ is not a hydroxyl group. The following formula (X-am-4Dg):

The compound according to any one of claims 242 to 275, which has the structure of. The following formula (X-am-4Da):

The compound according to any one of claims 242 to 275 and 280, which has the structure of. The following formula (X-am-4Db):

The compound according to any one of claims 242 to 275 and 280, which has the structure of. The following formula (X-am-4Dc):

Has the structure of;
However, the compound according to any one of claims 242 to 272, 274 to 276, and 280, wherein R ⁴ is not a hydroxyl group. The compound according to any one of claims 242 to 268, wherein ^R4 is oxo. The following formula (X-am-4Ld):

284. The compound according to claim 284. The following formula (X-am-4Le):

284. The compound according to claim 284. The following formula (X-am-4Dd):

284. The compound according to claim 284. The following formula (X-am-4De):

284. The compound according to claim 284. The compound according to any one of claims 242 to 288, wherein R ⁶ is hydrogen or an alkyl, wherein the alkyl is optionally substituted with the presence of one of -C (= O) NH ₂ . The compound according to any one of claims 242 to 289, wherein R ⁶ is an alkyl optionally substituted with the presence of one of -C (= O) NH ₂ . The compound according to any one of claims 242 to 290, wherein R ⁶ is −CH ₃ . ^R6 is

The compound according to any one of claims 242 to 290. The following formula (X-am-6L):

The compound according to any one of claims 242 to 292, which has the structure of. The following formula (X-am-6D):

The compound according to any one of claims 242 to 292, which has the structure of. The compound according to any one of claims 242 to 294, wherein R ⁷ is (C ₁ -C ₁₀ ) alkyl. R ⁷ is

The compound according to any one of claims 242 to 295. R ⁷ is

The compound according to any one of claims 242 to 295. The following formula (X-am-7L):

The compound according to any one of claims 242 to 297, which has the structure of. The following formula (X-am-7D):

The compound according to any one of claims 242 to 297, which has the structure of. The following formula (X-am-11L):

The compound according to any one of claims 242 to 299, which has the structure of. The following formula (X-am-11D):

The compound according to any one of claims 242 to 299, which has the structure of. The compound according to any one of claims 242 to 301, wherein R ⁸ is —CH ₃ or —H. The compound according to any one of claims 242 to 301, wherein R ⁸ is −H. The compound according to any one of claims 242 to 303, wherein R ⁹ is —CH ₃ or —H. The compound according to any one of claims 242 to 303, wherein R ⁹ is −H. The compound according to any one of claims 242 to 305, wherein R ^x and R ^y are independently substituted alkyls, respectively. The compound according to any one of claims 242 to 305, wherein R ^x and R ^y are each independently and optionally substituted alkoxylalkyl. The compound according to any one of claims 242 to 305, wherein R ^x and R ^y form a ring together with an intervening nitrogen atom. Equation 8:

A salt of a compound represented by. Equation 10:

A salt of a compound represented by. A pharmaceutical composition comprising the salt according to any one of claims 1 to 67, 309, and 310 or the compound according to any one of claims 68 to 308, and a pharmaceutically acceptable carrier. .. The pharmaceutical composition according to claim 311, which is formulated, for example, as an eye drop for external administration to the eye. 13. Pharmaceutical composition. The pharmaceutical composition according to claim 313, wherein at least 95% of the compound is present as a salt. The pharmaceutical composition according to claim 314, wherein at least 99% of the compound is present as a salt. The salt according to any one of claims 1 to 67, 309, and 310 or the salt according to any one of claims 68 to 308, which is a method for treating an eye disease and is in need of treatment. The method described above comprising administering the compound or the pharmaceutical composition according to any one of claims 311 to 315. 316. The method of claim 316, wherein the eye disease is selected from retinopathy, keratitis, dry macular degeneration, wet macular degeneration, dry eye syndrome, keratoconjunctivitis sicca, and keratoconjunctival epithelial disorder. The method of claim 316 or 317, wherein administration of the compound or composition comprises administration to the eye of the subject for external use.

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