KR20210076857A - Novel indole derivatives and its use - Google Patents

Abstract

The present invention relates to a novel indole derivative and uses thereof. Since the novel indole derivative of the present invention captures methylglyoxal (MGO), a major precursor of a final glycation product, and has an excellent cytoprotective effect, it can be usefully used for the prevention or treatment of diseases related to the final glycation product.

Description

Novel indole derivatives and uses thereof

The present invention relates to novel indole derivatives and uses thereof. Since the novel indole derivative of the present invention captures methylglyoxal (MGO), a major precursor of the final glycated product, it can be usefully used for the prevention or treatment of diseases related to the final glycated product.

Diabetes mellitus is a metabolic disease in which high blood sugar levels persist for a long time due to insufficient insulin secretion or insulin resistance. As the blood sugar level in the body continues for a long time, chronic complications occur as glycation products invade the retina, kidneys, nerves, or large and small blood vessels throughout the body. Since diabetes is more dangerous than diabetes itself, the biggest goal in diabetes treatment today is to suppress the occurrence or progression of diabetes complications. Typical complications of diabetes include diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic heart disease, diabetic osteoporosis, diabetic atherosclerosis, and the like.

Mechanisms that induce these complications of diabetes are largely oxidative stress caused by free radicals, non-enzymatic glycation of protein, and osmotic pressure caused by a change in the mechanism of the polyol pathway. stress, etc.

Oxidative stress, the cause of diabetes complications, refers to a reaction caused by a decrease in the ability to remove free radicals generated in the body or a rapid increase in the production of active oxygen due to environmental factors. In diabetic patients, it is known that oxidative stress rises due to high blood sugar, which increases insulin resistance and damages cells such as blood vessels, kidneys, and retina. In addition, advanced glycation end products (AGEs) produced by oxidative stress are a major cause of diabetic complications. The glycation reaction is a non-enzymatic reaction between the aldehyde group of sugars present in blood or cell fluid and the free amino group of proteins inside and outside the cell. It refers to a series of reactions that cross-link with other proteins after rearrangement to produce final glycosylation products. Since this reaction occurs almost spontaneously without energy supply in the reaction initiation stage, it occurs in food or our body, and has irreversible characteristics after a certain stage. Therefore, once the final glycation product is generated, it is not decomposed even when blood sugar is restored to normal, but accumulates in the tissue during the protein survival period, abnormally changing the structure and function of the tissue. As such, glycosylation occurs in proteins such as basement membrane, plasma albumin, lens protein, fibrin, and collagen by non-enzymatic protein glycation, and the resulting final glycation product abnormally changes the structure and function of the tissue, causing chronic diabetes complications. .

Therefore, in order to delay, prevent, or treat the onset of diabetic complications, it is important to prevent oxidative stress or to inhibit the production of final glycated products or to have a decomposition effect.

It was recently found that the final glycation product is related to nonalcoholic steatohepatitis (NASH) disease in addition to diabetic complications. Although the pathogenesis of nonalcoholic steatohepatitis is not fully elucidated, it is widely accepted that it is at least closely related to insulin resistance. When insulin resistance increases due to the complex action of lifestyle-related environmental factors such as diet and exercise along with genetic factors, excess free fatty acid (FAA) is produced in the liver. Free fatty acids are converted into non-toxic triglycerides (TG) in hepatocytes, primarily resulting in simple steatosis (Hepatology, 2007 Jun:45(6):1366-74; Hepatology, 2004 Jul:40(1)) :185-94). Thereafter, as various oxidative stresses are added, hepatocyte damage and inflammatory reaction occur due to fat peroxidation and overproduction of inflammatory cytokines, which develops into nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis is often accompanied by type 2 diabetes, another insulin resistance-related disease.

Methylglyoxal (MGO) is a major precursor of the final glycosylation product that causes complications due to diabetes. Experimental results have shown that MGO formation by cellular metabolism is increased at high glucose concentrations in vitro, and the abnormal accumulation of MGO affects the occurrence of diabetic complications in various tissues and organs. In addition, there are experimental results showing that increasing MGO levels induced obesity and hyperglycemia in fruit flies. MGO is produced through several pathways, including as a by-product of glycolysis, and several mechanisms may influence MGO detoxification. MGO increased due to detoxification disorders within the organism is directly toxic to tissues and leads to the gradual development of obesity, hyperglycemia and insulin resistance. This suggests that an increase in MGO may result in and cause insulin resistance and hyperlipidemia, creating a potential vicious cycle (Moraru et al., 2018).

Therefore, if the production of the final glycated product is suppressed by trapping the MGO before the final glycated product is produced, the resulting diabetic complications can be prevented. In type 2 diabetes patients, obesity and coronary artery disease act as risk factors, so treatment of hyperglycemia and treatment of these diseases can be performed at the same time to prevent the progression of complications. Capture is also expected to help manage obesity in people with type 2 diabetes.

Accordingly, the present inventors developed a novel material capable of capturing MGO and completed the present invention.

Yamaguchi K, et al., Hepatology. 2007 Jun;45(6):1366-74 Feldstein AE et al., Hepatology. 2004 Jul;40(1):185-94 Moraru et al., Cell Metabolism 27, 926-934, April 3, 2018

An object of the present invention is to provide a novel compound having excellent capture ability of methylglyoxal (MGO).

The present invention also seeks to provide a composition comprising the novel compound.

The present invention also intends to provide a composition for improving, preventing or treating diseases related to final glycation products comprising the novel compound.

The composition may be a pharmaceutical composition, a food composition, or a feed composition for animals.

The present invention provides a compound of the following formula (I) (hereinafter also referred to as 'indole derivative' or 'compound of formula (I)') or a pharmaceutically acceptable salt thereof.

[Formula I]

In the above formula,

R ₁ is hydrogen, halo, alkyl, alkenyl, or alkynyl,

R ₂ is hydrogen; -N(Ra)(Rb) unsubstituted or substituted alkyl; or - aryl unsubstituted or substituted with N(Ra)(Rb) or alkyl;

Ra or Rb is each independently hydrogen or alkyl,

R ₃ is hydrogen; -(CH ₂ )nC(Rc)(N(Rd)(Re))(COORf); or -(CH ₂ )nC(Rc)(N(Rd)(Re))(C(=O)Rf),

Rc is hydrogen or alkyl,

Rd or Re is each independently hydrogen, -C(=O)alkyl _, -C(=O)alkyl-O-alkyl, -C(=O)alkyl-cycloalkyl, -C(=O)alkyl-alkenyl , -C(=O)O-alkyl, or -NH-alkyl-NH-alkyl-NH ₂ ,

Rf is hydrogen; alkyl unsubstituted or substituted with an aryl group; or —NH-alkyl-NH-alkyl-NH ₂ ,

R ₄ is hydrogen, halo, alkyl, alkenyl, or alkynyl;

R ₅ is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or - OC(=O)(CH ₂ )aS(CH2)bCH(Rg)(Rh),

Rk is hydrogen; alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH ₂ NHC(=O)CH(CH ₂ SH),

Rg or Rh is each independently hydrogen, alkyl, heterocycloalkyl, -S(=O)alkyl,

,

,

, 또는 -NH(CH₂)mNH₂이고,

,

,

, or —NH(CH ₂ )mNH ₂ ,

R ₆ or R ₇ are each independently hydrogen, halo, alkyl, alkenyl, alkynyl, —OH or —Oalkyl,

a, b, n or m is an integer from 1 to 10;

The present invention provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably a composition for preventing, ameliorating, or treating a disease related to a final glycated product.

The composition may be a pharmaceutical composition, a food composition, or a feed composition for animals.

In one embodiment, the final glycation product-related disease is aging, diabetes, diabetic complications, hyperlipidemia, hyperglycemia, cardiovascular disease, degenerative brain disease, autism spectrum disorder, arteriosclerosis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, skin fibrosis, lung It may be selected from the group consisting of fibrosis, renal fibrosis, and cardiac fibrosis. Preferably, it is diabetes (particularly preferably type 2 diabetes) or a diabetic complication.

In one embodiment, the diabetic complications are diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, diabetic osteoporosis, diabetic sarcopenia. And it may be selected from the group consisting of obesity.

In one embodiment, the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia, It may be selected from the group consisting of progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, early-stage dementia, temporal lobe epilepsy, and stroke.

The present invention relates to a novel indole derivative or a pharmaceutically acceptable salt thereof. The indole derivative according to the present invention exhibits an effect of capturing methylglyoxal, a major precursor of the final glycation product, and an excellent cytoprotective effect. It can be usefully used as a pharmaceutical composition for preventing or treating diseases related to glycation products.

The novel indole derivative of the present invention is particularly useful for preventing or treating type 2 diabetes and diabetic complications resulting therefrom.

1 and 2 show the results of analyzing the free methylglyoxal (MGO) concentration on days 1 and 7 by high-performance liquid chromatography (HPLC) after methylglyoxal (MGO) is treated with the compound of the present invention and cultured. .
Figure 3 shows the results of analyzing the cytoprotective activity according to the concentration of the compound 10 in the N2a cell line after treatment with methylglyoxal (MGO) and the compound 10 of the present invention.
4 shows the results of analyzing the cytoprotective activity according to the concentration of the compound 10 in the N2a cell line after treatment with methylglyoxal (MGO) and the compound 11 of the present invention.
5 shows the results of analysis of cytoprotective activity according to the concentration of compound 10 in SH-SY5Y cell line after treatment with methylglyoxal (MGO) and compound 10 of the present invention.
6 shows the results of analyzing the cytoprotective activity according to the concentration of the compound 10 in the SH-SY5Y cell line after treatment with methylglyoxal (MGO) and the compound 11 of the present invention.
7 shows the results of analyzing the LDH production in the group pretreated with compounds 10 and 11.
8 shows the results of analysis of LDH production in the post-treatment group with compounds 10 and 11.
9 shows the results of analyzing the cytoprotective activity after pretreatment of the compounds 10 and 11 of the present invention using the BrdU primary antibody.
10 shows the results of analysis of cytoprotective activity after post-treatment of compounds 10 and 11 of the present invention using the BrdU primary antibody.
11 shows the results of analyzing the cytoprotective activity of the compound 10 of the present invention with respect to cytotoxicity caused by free L-DOPA treatment.
12 shows the results of analyzing the cytoprotective activity of compound 11 of the present invention with respect to cytotoxicity caused by silver-free L-DOPA treatment.
13 shows the results of analyzing the cytoprotective activity of the compound 10 of the present invention with respect to cytotoxicity caused by MGO + L-DOPA treatment.
Figure 14 shows the results of analyzing the cytoprotective activity of the compound 11 of the present invention with respect to the cytotoxicity caused by MGO + L-DOPA treatment.
15 shows the results of measuring the levels of MGO-induced inflammatory cytokines after treatment with compounds 10 and 11 of the present invention.

Hereinafter, with reference to the accompanying drawings, embodiments and examples of the present invention will be described in detail so that those of ordinary skill in the art to which the present invention pertains can easily carry out. However, the present application may be embodied in various forms and is not limited to the embodiments and examples described herein.

Throughout this specification, when a part "includes" a certain component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.

The present invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof.

[Formula I]

In the above formula,

R ₁ is hydrogen, halo, alkyl, alkenyl, or alkynyl,

R ₂ is hydrogen; -N(Ra)(Rb) unsubstituted or substituted alkyl; or - aryl unsubstituted or substituted with N(Ra)(Rb) or alkyl;

Ra or Rb is each independently hydrogen or alkyl,

R ₃ is hydrogen; -(CH ₂ )nC(Rc)(N(Rd)(Re))(COORf); or -(CH ₂ )nC(Rc)(N(Rd)(Re))(C(=O)Rf),

Rc is hydrogen or alkyl,

Rd or Re are each independently hydrogen, -C(=O)alkyl _, -C(=O)alkyl-O-alkyl, C(=O)alkyl-cycloalkyl, C(=O)alkyl-alkenyl, - C(=O)O-alkyl, or -NH-alkyl-NH-alkyl-NH ₂ ,

Rf is hydrogen; alkyl unsubstituted or substituted with an aryl group; or —NH-alkyl-NH-alkyl-NH ₂ ,

R ₄ is hydrogen, halo, alkyl, alkenyl, or alkynyl;

R ₅ is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or - OC(=O)(CH ₂ )aS(CH2)bCH(Rg)(Rh),

Rk is hydrogen; alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH ₂ NHC(=O)CH(CH ₂ SH),

Rg or Rh is each independently hydrogen, alkyl, heterocycloalkyl, -S(=O)alkyl,

,

,

, 또는 -NH(CH₂)mNH₂이고,

,

,

, or —NH(CH ₂ )mNH ₂ ,

R ₆ or R ₇ are each independently hydrogen, halo, alkyl, alkenyl, alkynyl, —OH or —Oalkyl,

a, b, n or m is an integer from 1 to 10;

In a preferred embodiment,

R ₁ is hydrogen, or C ₁ -C ₆ alkyl,

R ₂ is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with —N(Ra)(Rb); or - aryl unsubstituted or substituted with N(Ra)(Rb) or C ₁ -C _{6 alkyl,}

Ra or Rb is each independently hydrogen or C ₁ -C ₆ alkyl,

R ₃ is hydrogen; -(CH ₂ )nC(Rc)(N(Rd)(Re))(COORf); or -(CH ₂ )nC(Rc)(N(Rd)(Re))(C(=O)Rf),

Rc is hydrogen or C ₁ -C ₆ alkyl,

Rd or Re are each independently hydrogen, -C(=O)C ₁ -C ₆ alkyl _, -C(=O)C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₆ alkyl-C ₃ -C ₇ cycloalkyl, -C(=O)C ₁ -C ₆ alkyl-C ₂ -C ₆ alkenyl, -C(=O)OC ₁ -C ₆ alkyl, or -NH -C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl-NH ₂ and

Rf is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with an aryl group; or -NH-C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl-NH ₂ ,

R ₄ is hydrogen or C ₁ -C ₆ alkyl,

R ₅ is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or - OC(=O)(CH ₂ )aS(CH2)bCH(Rg)(Rh),

Rk is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH ₂ NHC(=O)CH(CH ₂ SH),

Rg or Rh are each independently hydrogen; C ₁ -C ₆ alkyl; _{C 3} -C ₁₀ heterocycloalkyl having a heteroatom selected from N, O, or S; -S(=O)C ₁ -C ₆ alkyl;

;

;

; 또는 -NH(CH₂)mNH₂이고

;

;

; or -NH(CH ₂ )mNH ₂ and

R ₆ or R ₇ are each independently hydrogen, C ₁ -C ₆ alkyl, —OH or —OC ₁ -C ₆ alkyl,

a, b, n or m may be an integer from 1 to 5.

In another preferred embodiment,

R ₁ is hydrogen,

R ₂ is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with NH _{2 ;} or aryl unsubstituted or substituted with _{NH 2} or C ₁ -C _{6 alkyl,}

R ₃ is hydrogen; -(CH ₂ )n-CH(N(Rd)(Re))(COORf); or -(CH ₂ )n-CH(N(Rd)(Re))(C(=O)Rf),

Rd or Re are each independently hydrogen, -C(=O)C ₁ -C ₆ alkyl _, -C(=O)C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₆ alkyl-C ₃ -C ₇ cycloalkyl, -C(=O)C ₁ -C ₆ alkyl-C ₂ -C ₆ alkenyl, -C(=O)OC ₁ -C ₆ alkyl, or -NH -C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl-NH ₂ and

Rf is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with an aryl group; or -NH-C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl-NH ₂ ,

R ₄ is hydrogen or C ₁ -C ₆ alkyl,

이고,R ₅ is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or

ego,

Rk is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH ₂ NHC(=O)CH(CH ₂ SH),

;

;

; 또는 -NH(CH₂)mNH₂이고Rg or Rh are each independently hydrogen; C ₁ -C ₆ alkyl; _{C 3} -C ₇ heterocycloalkyl having a heteroatom selected from S; -S(=O)C ₁ -C ₆ alkyl;

;

;

; or -NH(CH ₂ )mNH ₂ and

R ₆ or R ₇ are each independently hydrogen, C ₁ -C ₆ alkyl, —OH or —OC ₁ -C ₆ alkyl,

n or m may be an integer from 1 to 5.

In another preferred embodiment,

R ₁ is hydrogen,

R ₂ is hydrogen; -C ₁ -C ₆ alkyl-NH ₂ ; Or NH ₂ substituted or unsubstituted phenyl,

R ₃ is hydrogen; -(CH ₂ )n-CH(N(Rd)(Re))(COORf); or -(CH ₂ )n-CH(N(Rd)(Re))(C(=O)Rf),

Rd or Re are each independently hydrogen, -C(=O)C ₁ -C ₆ alkyl _, -C(=O)C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₆ alkyl-C ₃ -C ₇ cycloalkyl, -C(=O)C ₁ -C ₆ alkyl-C ₂ -C ₆ alkenyl, -C(=O)OC ₁ -C ₆ alkyl, or -NH -C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl-NH ₂ and

Rf is hydrogen, C ₁ -C ₆ alkyl, benzyl or —NH-C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl-NH ₂ ,

R ₄ is hydrogen,

이고,R ₅ is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or

ego,

Rk is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH ₂ NHC(=O)CH(CH ₂ SH),

;

;

; 또는 -NH(CH₂)mNH₂이고Rg or Rh are each independently hydrogen; C ₁ -C ₆ alkyl; _{C 3} -C ₇ heterocycloalkyl having a heteroatom selected from S; -S(=O)C ₁ -C ₆ alkyl;

;

;

; or -NH(CH ₂ )mNH ₂ and

R ₆ is hydrogen, —OH or —OC ₁ -C ₆ alkyl

R ₇ is hydrogen,

n or m may be an integer from 1 to 5.

In another preferred embodiment,

R ₁ is hydrogen,

R ₂ is hydrogen, —CH ₂ NH ₂ , or phenyl substituted with _{NH 2 ,}

,

,

,

,

,

,

,

,

,

,

또는

이고, R ₃ is hydrogen,

,

,

,

,

,

,

,

,

,

,

or

ego,

R ₄ is hydrogen,

,

,

,

,

,

,

,

, 또는

이고, R ₅ is hydrogen, -OH, -OCH ₃ ,

,

,

,

,

,

,

,

, or

ego,

R ₆ is hydrogen, -OH, -OCH ₃

R ₇ is hydrogen,

However, R ₂ and R ₃ may not be hydrogen at the same time.

The present invention also provides a compound selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof.

The present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention is suitable not only for human medical use, but also for veterinary use in animals. Preferably, the animal is a mammal, warm-blooded animals including companion animals (eg, dogs, cats, horses, etc.), and guinea pigs, mice, rats, gerbils, cattle, goats, sheep, monkeys, pigs, rodents, rabbits, primates, and the like.

Preferably, the pharmaceutical composition of the present invention can be used for the prevention or treatment of diseases related to final glycation products.

In one embodiment, the pharmaceutical composition may further include conventional pharmaceutically acceptable additives, such as excipients, binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or extenders.

In one embodiment, the final glycation product-related disease is aging, diabetes, diabetic complications, hyperlipidemia, hyperglycemia, cardiovascular disease, degenerative brain disease, autism spectrum disorder, arteriosclerosis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, skin fibrosis, lung It may be selected from the group consisting of fibrosis, renal fibrosis, and cardiac fibrosis. Preferably, it is diabetes (particularly preferably type 2 diabetes) or a diabetic complication.

In one embodiment, the diabetic complications are diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, diabetic osteoporosis, diabetic sarcopenia. And it may be selected from the group consisting of obesity.

In one embodiment, the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia, It may be selected from the group consisting of progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, early-stage dementia, temporal lobe epilepsy, and stroke.

The present invention provides a food composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably, a food composition for preventing or ameliorating diseases related to final glycated products.

In one embodiment, the food composition may be a health functional food, dairy product, fermented product or food additive.

In one embodiment, the food composition comprises various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and It may further include salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.

The present invention provides a feed composition for animals comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, preferably, a feed composition for animals for preventing or improving diseases related to final glycated products.

In one embodiment, the animal feed composition may further include one or more carriers, excipients, diluents, fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifying agents or preservatives.

Justice

Unless defined otherwise, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Moreover, numerical values recited herein are intended to include the meaning of “about” unless explicitly stated otherwise. Definitions of residues and substituents as used herein are provided below. Unless otherwise specified, each residue has the following definitions and is used in the sense commonly understood by one of ordinary skill in the art.

"은 잔기 또는 치환기 "R"이 골격 구조에 부착되어 있는 것을 나타내는데 사용된다.In accordance with the convention used in the art, "" is used in the formulas herein.

"A" is used to indicate that a moiety or substituent "R" is attached to the backbone structure.

"Alkyl" as used herein is a hydrocarbon having primary, secondary, tertiary and/or quaternary carbon atoms, substituted or unsubstituted, and saturated aliphatic, which may be straight chain, branched, cyclic, or combinations thereof. includes the group. For example, an alkyl group may have 1 to 20 carbon atoms (ie, C ₁ -C ₂₀ alkyl), 1 to 10 carbon atoms (ie, C ₁ -C ₁₀ alkyl), or 1 to 6 carbon atoms (ie, C 1 -C 10 alkyl). C ₁ -C ₆ alkyl). Unless otherwise defined, in a preferred embodiment, alkyl refers to _{C 1} -C _{6 alkyl.} Examples of suitable alkyl groups include methyl (Me, —CH ₃ ), ethyl (Et, —CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, —CH ₂ CH ₂ CH ₃ ), 2-propyl (i-Pr, i-propyl, -CH(CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (i -Bu, i-butyl, -CH 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 _{3 )} )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl ( -CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (- CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C (CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C( CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), and octyl (-(CH ₂ ) ₇ CH ₃ ). may be, but is not limited thereto.

Moreover, the term “alkyl” as used throughout the specification, examples and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which are trifluoromethyl and 2,2,2-tri refers to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as fluoroethyl, and the like.

The term "C _xy " or "C _x -C _y ", when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, refers to a group containing x to y carbons in the chain. considered to include For example, a (C ₁ -C ₆ )alkyl group contains 1 to 6 carbon atoms in the chain.

"Alkenyl" has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and includes one or more regions of unsaturation, i.e., carbon- It is a hydrocarbon with a carbon sp ^{2 double bond.} For example, an alkenyl group has 2 to 20 carbon atoms (ie, C ₂ -C ₂₀ alkenyl), 2 to 12 carbon atoms (ie, C ₂ -C ₁₂ alkenyl), 2 to 10 carbon atoms ( ie, C ₂ -C ₁₀ alkenyl), or 2 to 6 carbon atoms (ie, C ₂ -C ₆ alkenyl). Examples of suitable alkenyl groups include vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), cyclopentenyl (-C ₅ H ₇ ), and 5-hexenyl (-CH ₂ CH ₂ CH). ₂ CH ₂ CH=CH ₂ ), but is not limited thereto.

"Alkynyl" has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and contains one or more carbon-carbon sp triple bonds. hydrocarbons with For example, an alkynyl group has 2 to 20 carbon atoms (ie, C ₂ -C ₂₀ alkynyl), 2 to 12 carbon atoms (ie, C ₂ -C ₁₂ alkynyl), 2 to 10 carbon atoms ( ie, C ₂ -C ₁₀ alkynyl), or 2 to 6 carbon atoms (ie, C ₂ -C ₆ alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic _{(-C≡CH) and propargyl (-CH 2 C≡CH).}

"Cycloalkyl," as used herein, refers to a monovalent or divalent, saturated or partially saturated non-aromatic ring, which may be monocyclic, bicyclic or polycyclic, substituted or unsubstituted, and wherein each atom of the ring is carbon. . A “cycloalkyl” may also have 3 to 7 carbon atoms when monocyclic, 7 to 12 carbon atoms when bicyclic, and up to about 20 carbon atoms when polycyclic. Bicyclic or polycyclic ring systems may be fused, bridged, or spiro ring systems.

As used herein, "heterocycloalkyl" refers to monocyclic, bicyclic or containing one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms in the ring. polycyclic, substituted or unsubstituted monovalent or divalent, saturated or partially saturated non-aromatic ring. Also "heterocycloalkyl" is a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is heterocyclic, and at the other The click ring can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl. Bicyclic or polycyclic ring systems may be fused, bridged, or spiro ring systems. “Heterocycloalkyl” includes, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like, each of which may be substituted or unsubstituted.

As used herein, “halo” means halogen and includes chloro, fluoro, bromo, and iodo.

As used herein, the term “aryl” includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups wherein each atom of the ring is carbon, monocyclic, bicyclic or polycyclic. "Aryl" is a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is aromatic and the other cyclic rings are, for example, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl. “Aryl” can be, for example, benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, aniline, and the like, each of which may be substituted or unsubstituted.

As used herein, the term “Bn” refers to benzyl (—CH ₂ C ₆ H ₅ ) and “Boc” refers to tert -butyloxycarbonyl (—C(=O)OC(CH ₃ ) ₃ ) .

As used herein, the term “substituted” refers to a particular moiety of a compound of the present invention having one or more substituents. The term "substituted" with respect to alkyl, heterocycloalkyl, etc., for example "substituted alkyl" or "substituted heterocycloalkyl" means that one or more hydrogen atoms of the alkyl or heterocycloalkyl are each independently replaced by a non-hydrogen substituent. meant to be replaced.

As used herein, the term "pharmaceutically acceptable salt" is used herein to refer to an acid or base addition salt suitable or compatible with the treatment of a patient. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di- and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid acids, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, as well as sulfonic acids such as p-toluene sulfonic acid and methanesulfonic acid. Monoacid or diacid salts may be formed, and such salts may exist in hydrated, solvated or substantially anhydrous form. In general, acid addition salts of compounds of the present invention are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base form. The selection of an appropriate salt is known to the person skilled in the art.

As used herein, the term “diabetes mellitus (DM, or diabetes)” refers to a group of metabolic diseases in which high blood sugar levels persist for a long time. Diabetes can be caused by the pancreas not making enough insulin or the body's cells not responding properly to the insulin made. Diabetes is largely divided into type 1 diabetes, which is caused by not producing enough insulin, type 2 diabetes, which results from insulin resistance in which cells do not respond properly to insulin, and gestational diabetes.

As used herein, the term “diabetic complications” refers to symptoms caused when diabetes persists for a long time. "Diabetic complications" is evaluated by criteria different from the criteria for the onset and judgment of diabetes.

As used herein, the term "Autism Spectrum Disorder (ASD)" includes a class of neurodevelopmental disorders characterized by a deficit in social communication and interaction or a restricted or repetitive pattern of behaviors, interests or activities. Autism spectrum disorders include, but are not limited to, autism, Asperger's Syndrome, Pervasive Developmental Disorder Not Elsewhere Classified (PDD-NOS), Childhood Disintegrative Disorder, Rett's Syndrome, and Fragile X Syndrome.

The present invention will be described in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

All starting materials and reagents were obtained from commercial suppliers and used without further purification. The reaction sensitive to air and moisture was carried out under a nitrogen atmosphere. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck) with the indicated solvents. Thin layer chromatography (TLC) was performed using a 0.25 mm silica gel plate (Merck). ¹ H and ¹³ C{ ¹ H} NMR spectra were recorded on a Bruker 600 MHz as solutions _{in CDCl 3} or DMSO-d _{6 .} ¹ H NMR data were recorded in the order of chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet and/or multiple resonance), number of protons and binding constant ( J ; Hz).

[Example 1]

methyl ( S )-2-amino-3-(5-hydroxy-1 H -Indol-3-yl)propanoate (KST-11001)

A solution of 5-hydroxy tryptophan (0.66 g, 3.0 mmol) in methanol (10 mL) was cooled to 0 °C. Thionyl chloride (0.44 mL, 6.0 mmol) _{was added dropwise to the solution under N 2} and stirred at 40 °C overnight. The reaction mixture was concentrated under reduced pressure. The residue was added to ethyl acetate (10 mL) and stirred at room temperature for 3 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure, methyl ( S )-2-amino-3-(5-hydroxy-1 H -indol-3-yl)propanoate (2) (0.70 g, 99) %) was obtained.

¹ H NMR (600 MHz, DMSO-d6) δ 10.83 (d, 1H, J = 1.6 Hz), 8.66 (s, 3H), 7.15 (m, 2H), 6.78 (d, 1H, J = 2.1 Hz), 6.63 (m, 1H), 4.13 (s, 1H), 3.65 (s, 3H), 3.22 (m, 2H). ¹³ C{ ¹ H} NMR (150 MHz, DMSO-d6) δ 169.8, 150.6, 130.7, 127.6, 125.4, 111.9, 111.6, 105.3, 101.9, 52.7, 52.5, 26.3.

[Example 2]

( S )-3-(5-hydroxy-1 H -Indol-3-yl)-2-(3-methylbutanamido)propanoic acid (KST-11002)

To a solution of isovaleric acid (0.06 mL, 0.5 mmol) and HOBT (0.07 g, 0.5 mmol) in dichloromethane (3 mL) at 0 °C was added EDCI (0.1 g, 0.5 mmol) and stirred for 30 min. Then, 5-hydroxy-tryptophan (1) (0.11 g, 0.5 mmol) and trimethyl amine (0.2 mL, 1.5 mmol) were added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/CH ₂ Cl ₂ =1 : 20) (S )-3-(5-hydroxy-1 H -indol-3-yl)-2-(3) -Methylbutanamido)propanoic acid (0.03 g, 22%) was obtained.

¹ H NMR (600 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.49 (d, 1H, J = 1.8 Hz), 8.60 (s, 1H), 8.02 (d, 1H, J = 7.8 Hz), 7.11 (d, 1H, J = 8.6 Hz), 7.02 (d, 1H, J = 2.3 Hz), 6.83 (d, 1H, J = 2.2 Hz), 6.58 (m, 1H), 4.42 (m, 1H), 3.05 (m, 1H), 2.88 (m, 1H), 1.93 (m, 3H), 0.82 (d, 3H, J = 6.4 Hz), 0.78 (d, 3H, J = 6.4 Hz). ¹³ C{1H} NMR (150 MHz, DMSO-d6) δ 173.8, 171.6, 150.3, 130.7, 127.8, 124.0, 111.7, 111.2, 109.0, 102.1, 52.6, 44.4, 27.2, 25.6, 22.3, 22.2.

[Example 3]

methyl ( S )-2-(3-ethoxypropanamido)-3-(5-hydroxy-1 H -Indol-3-yl)propanoate (KST-11003)

Methyl ( S )-2-amino-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.07 g, 0.3 mmol), 3-ethoxypropanoic acid ( To a solution of 0.037 mL, 0.33 mmol) and HBTU (0.13 g, 0.33 mmol) at 0 °C was added DIPEA (0.16 mL, 0.9 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/CH ₂ Cl ₂ =1 : 50) to give the title compound (0.05 g, 47%).

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.19 (d, 1H, J = 8.7 Hz), 7.03 (d, 1H, J = 2.3 Hz), 6.90 (d, 1H, J = 2.3 Hz), 6.78 (m, 1H), 6.54 (d, 1H, J = 7.8 Hz), 6.02 (s, 1H), 5.00 (m, 1H), 3.83 (m, 1H), 3.70 (m, 4H) , 3.55 (m, 2H), 3.39 (m, 1H), 3.22 (m, 1H), 2.44 (m, 2H), 1.19 (t, 3H, J = 7.0 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 172.2, 170.7, 150.4, 131.2, 128.9, 123.5, 112.2, 112.0, 109.9, 103.9, 67.1, 66.2, 53.7, 52.4, 36.8, 27.9, 15.0.

[Example 4]

methyl ( S )-2-(2-cyclopentylacetamido)-3-(5-hydroxy-1 H -Indol-3-yl)propanoate (KST-11004)

Methyl (S )-2-amino-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.06 g, 0.25) in dry DMF/CH ₂ Cl ₂ (1/6, 1 mL) mmol), cyclopentyl acetic acid (0.03 mL, 0.28 mmol) and HBTU (0.10 g, 0.28 mmol) at 0 °C was added DIPEA (0.13 mL, 0.75 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1:1) to methyl ( S )-2-(2-cyclopentylacetamido)-3-(5-hydroxy- 1H -indole) -3-yl)propanoate (0.06 g, 64%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 7.20 (d, 1H, J = 8.6 Hz), 6.99 (d, 1H, J = 2.3 Hz), 6.93 (d, 1H, J = 2.4 Hz), 6.79 (m, 1H), 6.03 (d, 1H, J = 7.7 Hz), 5.69 (s, 1H), 4.95 (m, 1H), 3.70 (s, 3H), 3.24 (m, 2H) , 2.18 (m, 3H), 1.74 (m, 2H), 1.57 (m, 2H), 1.49 (m, 2H), 1.07 (m, 2H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 172.9, 172.8, 150.3, 131.4, 128.6, 123.7, 112.4, 112.0, 109.7, 103.1, 60.6, 52.5, 42.9, 37.1, 32.7, 32.6, 28.0, 25.1 , 14.3.

[Example 5]

methyl ( S )-2-butyramido-3-(5-hydroxy-1 H -Indol-3-yl)propanoate (KST-11005)

Methyl (S )-2-amino-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.06 g, 0.25) in dry DMF/CH ₂ Cl ₂ (1/6, 1 mL) mmol), butyric acid (0.03 mL, 0.28 mmol) and HBTU (0.10 g, 0.28 mmol) at 0 °C was added DIPEA (0.13 mL, 0.75 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1:1) to methyl ( S )-2-butyramido-3-(5-hydroxy-1 H -indol-3-yl) Propanoate (0.05 g, 62%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 7.20 (d, 1H, J = 8.6 Hz), 6.97 (d, 1H, J = 2.4 Hz), 6.93 (d, 1H, J = 2.4 Hz), 6.79 (m, 1H), 6.02 (d, 1H, J = 7.7 Hz), 5.59 (s, 1H), 4.95 (m, 1H), 3.70 (s, 3H), 3.24 (m, 2H) , 2.15 (m, 2H), 1.62 (m, 2H), 0.89 (t, 3H, J = 7.4 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 173.1, 172.7, 150.2, 131.4, 128.7, 123.7, 112.4, 112.0, 109.7, 103.1, 60.6, 52.5, 38.6, 27.9, 19.1, 13.8.

[Example 6]

methyl ( S )-2-hexanamido-3-(5-hydroxyl-1 H -Indol-3-yl)propanoate (KST-11006)

Methyl (S )-2-amino-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.06 g, 0.25) in dry DMF/CH ₂ Cl ₂ (1/6, 1 mL) mmol), hexanoic acid (0.03 mL, 0.28 mmol) and HBTU (0.10 g, 0.28 mmol) at 0 °C was added DIPEA (0.13 mL, 0.75 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1:1) to methyl ( S )-2-hexanamido-3-(5-hydroxy- 1H -indol-3-yl)pro Fanoate (0.08 g, 99%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.14 (d, 1H, J = 8.6 Hz), 6.98 (s, 1H), 6.94 (s, 1H), 6.87 (s, 1H) , 6.78 (d, 1H, J = 8.6 Hz), 6.21 (d, 1H, J = 7.7 Hz), 4.92 (m, 1H), 3.20 (m, 2H), 2.14 (m, 2H), 1.53 (m, 2H), 1.18 (m, 4H), 0.80 (t, 3H, J = 7.0 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 173.8, 172.9, 150.5, 131.3, 128.5, 123.8, 112.4, 112.1, 109.2, 102.9, 60.6, 52.5, 36.6, 31.4, 27.8, 25.3, 22.4, 14.0 .

[Example 7]

methyl ( S )-2-(but-3-enamido)-3-(5-hydroxy-1 H -Indol-3-yl)propanoate (KST-11007)

Methyl (S )-2-amino-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.06 g, 0.25) in dry DMF/CH ₂ Cl ₂ (1/6, 1 mL) mmol), 3-butenoic acid (0.02 mL, 0.28 mmol) and HBTU (0.10 g, 0.28 mmol) at 0 °C was added DIPEA (0.13 mL, 0.75 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (10 mL) and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1:1) to methyl ( S )-2-(but-3-enamido)-3-(5-hydroxy-1 H -indole) -3-yl)propanoate (0.05 g, 66%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.21 (d, 1H, J = 8.6 Hz), 6.93 (m, 1H), 6.78 (m, 1H), 6.15 (d, 1H, J = 7.5 Hz), 5.84 (m, 1H), 5.15 (m, 2H), 5.06 (s, 1H), 4.92 (m, 1H), 3.70 (d, 3H, J = 5.1 Hz), 3.28 (m, 1H), 3.23 (m, 1H), 2.99 (m, 2H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 172.4, 170.5, 150.0, 131.0, 128.7, 123.8, 120.2, 112.3, 112.0, 109.7, 103.3, 53.2, 52.6, 41.6, 27.8, 21.2.

[Example 8]

2-Amino-3-(5-((butylcarbamoyl)oxy)-1 H -Indol-3-yl)propanoic acid (KST-11008)

2-((((9 H -fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-hydroxy-1 H -indol-3-yl)propanoic acid in CH ₂ Cl _{2 (} 0.09 g, 0.20 mmol) was added dropwise butyl isocyanate (0.02 mL, 0.22 mmol) and TEA (0.08 mL, 0.60 mmol) in methanol (1 mL) at 0 °C. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and purified by C18 reverse phase column chromatography (H ₂ O/MeOH as eluent) to 2-((((9 H -fluoren-9-yl)methoxy)carbonyl)amino)-3 - (5 - ((butyl-carbamoyl) oxy) -1 H-indol-3-yl) propanoic acid (22 mg, 20%) was obtained. Proanoic acid (0.01 g, 0.02 mmol) was dissolved in 20% piperidine in DMF (0.5 mL). The mixture was then stirred for 20 min and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/CH ₂ Cl _{2 /} TFA = 1 : 7 : 0.1) to 2-amino-3-(5-((butylcarbamoyl)oxy)-1 H -indole -3-yl)propanoic acid (5.5 mg, 71%) was obtained.

¹ H NMR (600 MHz, DMSO- d6 ) δ 13.87 (s, 1H), 11.09 (s, 1H), 8.19 (s, 2H), 7.58 (t, 1H, J = 5.7 Hz), 7.32 (d, 1H) , J = 8.7 Hz), 7.25 (s, 1H), 6.81 (dd, 1H, J = 8.7, 2.2 Hz), 4.13 (d, 1H, J = 5.0 Hz), 3.20 (m, 2H), 3.06 (m) , 2H), 1.46 (m, 2H), 1.33 (m, 2H), 0.90 (t, 3H, J = 7.3 Hz).

[Example 9]

( S )-1-(benzyloxy)-3-(5-(butyryloxy)-1 H -Indol-3-yl)-1-oxopropane-2-aminium 2,2,2-trifluoroacetate (KST-11009)

A dichloromethane solution of benzyl ( S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy- 1H -indol-3-yl)propanoate (0.08 g, 0.20 mmol) in dichloromethane To (1 mL) was added butyric acid (0.02 mL, 0.23 mmol), EDCI (0.06 g, 0.29 mmol) and DMAP (2.3 mg, 0.02 mmol). After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine _{, dried over MgSO 4} and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1 : 2) to ( S )-3-(3-(benzyloxy)-2-(( tert -butoxycarbonyl)amino)-3 - to give the indol-5-yl butyrate (0.08 g, 81%) - oxopropyl) -1 H. _{To a CH 2} Cl ₂ solution (2 mL) of indol-5-yl butyrate (0.02 g, 0.03 mmol) at 0 °C was added TFA (0.5 mL). After stirring for 2.5 hours at room temperature, The reaction mixture was concentrated under reduced pressure to give (S) -1- (benzyloxy) -3- (5- (butyryl-oxy) -1 H - indol-3-yl) -1 Oxopropane-2-aminium 2,2,2-trifluoroacetate (0.05 g, quantitative) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.09 (bs, 1H), 7.34 (m, 3H), 7.28 (m, 3H), 7.22 (d, 1H, J = 1.8 Hz), 6.90 (d, 1H, J = 9 Hz), 6.80 (s, 1H), 5.12 (m, 3H), 4.68 (d, 1H, J = 7.8 Hz), 3.25 (d, 2H, J = 5.4 Hz), 2.56 (t, 2H, J = 7.8 Hz), 1.82 (q, 2H, J = 7.2 Hz), 1.42 (s, 9H), 1.08 (t, 3H, J = 7.8 Hz); ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 173.0, 172.0, 155.2, 144.4, 135.4, 133.9, 128.5, 128.4, 128.3, 128.1, 124.2, 116.5, 111.6, 110.9, 110.4, 79.9, 67.1, 54.3 , 36.3, 28.3, 28.0, 18.6, 13.8.

[Example 10]

( S )-2-(5-(butyryloxy)-1 H -Indol-3-yl)-1-carboxyethane-1-aminium 2,2,2-trifluoroacetate (KST-11010)

(S) -2 - ((tert - butoxycarbonyl) amino) - CH ₂ of the (indol-3-yl 5- (butyryl-oxy) -1 H) propanoic acid (0.02 g, 0.05 mmol), 3- To a Cl ₂ solution (2 mL) at 0 °C was added TFA (0.5 mL). After stirring for 2.5 hours at room temperature, The reaction mixture was concentrated under reduced pressure to give (S) -2- (5- (butyryl-oxy) -1 H - indol-3-yl) -1-carboxy-1-aminium ethane 2,2,2-trifluoroacetate (20 mg, quantitative) was obtained.

¹ H NMR (600 MHz, DMSO- d6 ) δ 11.18 (d, 1H, J = 1.8 Hz), 8.24 (s, 3H), 7.37 (d, 1H, J = 8.7 Hz), 7.28 (m, 2H), 6.83 (m, 1H), 5.75 (s, 2H), 4.13 (d, 1H, J = 5.0 Hz), 3.21 (m, 2H), 2.55 (t, 2H, J = 7.3 Hz), 1.68 (m, 2H) ), 0.99 (t, 3H, J = 7.4 Hz). ¹³ C{ ¹ H} NMR (150 MHz, DMSO- d6 ) δ 172.4, 170.9, 143.6, 134.1, 127.2, 126.5, 115.8, 111.9, 110.4, 107.1, 54.9, 52.6, 35.4, 26.1, 18.1, 13.5.

[Example 11]

( S )-1-(benzyloxy)-3-(5-(butyryloxy)-1 H -Indol-3-yl)-1-oxopropane-2-aminium 2,2,2-trifluoroacetate (KST-11011)

(S) 3-CH of indol-5-yl butyrate (0.04 g, 0.09 mmol) - (2 - ((tert - butoxycarbonyl) amino) -3-methoxy-3-oxopropyl) -1 H _{To a 2} Cl ₂ solution (2 mL) at 0 °C was added TFA (0.5 mL). After stirring at room temperature for 2.5 hours, the reaction mixture was concentrated under reduced pressure to give the title compound (48 mg, quantitative).

¹ H NMR (600 MHz, DMSO- d6 ) δ 11.22 (s, 1H), 8.47 (s, 3H), 7.37 (d, 1H, J = 8.6 Hz), 7.26 (d, 1H, J = 21.9 Hz), 7.19 (s, 1H), 6.83 (m, 1H), 4.26 (s, 1H), 3.66 (s, 3H), 3.23 (m, 2H), 2.55 (t, 2H, J = 7.2 Hz), 1.68 (m) , 2H), 0.99 (t, 3H, J = 7.4 Hz). ¹³ C{ ¹ H} NMR (150 MHz, DMSO- d6 ) δ 172.4, 169.8, 143.6, 134.1, 127.0, 126.5, 115.7, 112.0, 110.2, 106.6, 52.6, 35.4, 26.1, 18.0, 13.4.

[Example 12]

(2 S )-3-(5-((5-(1,2-dithiolan-3-yl)pentanoyl)oxy)-1 H -Indol-3-yl)-1-(benzyloxy)-1-oxopropane-2-aminium chloride (KST-11012)

Benzyl ( S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.10 g, 0.24 mmol) was added α- D,L -lipoic acid (0.06 g, 0.29 mmol), EDCI (0.07 g, 0.36 mmol) and DMAP (2 mg, 0.01 mmol). After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine _{, dried over MgSO 4} and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1 : 2) to 3-(( S )-3-(benzyloxy)-2-(( tert -butoxycarbonyl)amino)-3 - to give the indol-5-yl 5- (1,2-dithiol olran-3-yl) pentanoate-oxopropyl) -1 H. To a solution (2 mL) of indol-5-yl 5-(1,2-dithiolan-3-yl)pentanoate (0.02 g, 0.03 mmol) in CH ₂ Cl _{2 at 0 °C 4N HCl in dioxane} (0.5 mL) was added. After stirring at room temperature for 2.5 h, the reaction mixture was concentrated under reduced pressure to (2 S )-3-(5-((5-(1,2-dithiolan-3-yl)pentanoyl)oxy)-1 H Obtained -indol-3-yl)-1-(benzyloxy)-1-oxopropan-2-aminium chloride (5 mg, 35%).

¹ H NMR (600 MHz, DMSO- d6 ) δ 11.24 (s, 1H), 7.29 (m, 8H), 6.83 (m, 1H), 5.14 (m, 1H), 5.05 (m, 1H), 4.24 (m , 1H), 3.63 (m, 1H), 3.26 (m, 4H), 3.11 (m, 1H), 2.56 (t, 2H, J = 7.3 Hz) 2.42 (m, 1H), 1.87 (m, 1H), 1.59 (m, 8H). ¹³ C{ ¹ H} NMR (150 MHz, DMSO- d6 ) δ 172.4, 169.3, 150.6, 143.6, 134.9, 134.0, 130.8, 128.4, 128.3, 128.1, 128.0, 127.0, 126.6, 115.7, 112.0, 110.2, 106.7, 67.0, 56.1, 52.6, 38.1, 34.1, 33.4, 28.1, 24.2.

[Example 13]

(2 S )-3-(5-((5-(1,2-dithiolan-3-yl)pentanoyl)oxy)-1 H -Indol-3-yl)-1-methoxy-1-oxopropane-2-aminium chloride (KST-11013)

methyl ( S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.06 g, 0.18 mmol) was added α- D,L -lipoic acid (0.05 g, 0.22 mmol), EDCI (0.05 g, 0.27 mmol) and DMAP (2 mg, 0.01 mmol). After stirring for 17 hours, the reaction mixture was diluted with dichloromethane, washed with water and brine _{, dried over MgSO 4} and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane = 1 : 2) to 3-(( S )-2-(( tert -butoxycarbonyl)amino)-3-methoxy-3-oxo to give the indol-5-yl 5- (1,2-dithiol olran-3-yl) pentanoate-propyl) -1 H. Indol-5-yl 5-(1,2-dithiolan-3-yl)pentanoate (16.6 mg, 0.03 mmol) in a CH ₂ Cl ₂ solution (2 mL) at 0 °C in 4N HCl in dioxane ( 0.5 mL) was added. After stirring at room temperature for 2.5 h, the reaction mixture was concentrated under reduced pressure to (2 S )-3-(5-((5-(1,2-dithiolan-3-yl)pentanoyl)oxy)-1 H -Indol-3-yl)-1-methoxy-1-oxopropan-2-aminium chloride (5 mg, 25%) was obtained.

¹ H NMR (600 MHz, DMSO- d6 ) δ 11.25 (s, 1H), 7.25 (m, 3H), 6.72 (m, 2H), 4.17 (m, 1H), 3.65 (m, 4H), 3.19 (m) , 4H), 2.59 (t, 2H, J = 7.3 Hz), 2.41 (m, 1H), 2.21 (t, 1H, J = 7.3 Hz), 1.75 (m, 8H). ¹³ C{ ¹ H} NMR (150 MHz, DMSO- d6 ) δ 172.4, 150.6, 143.6, 134.0, 127.0, 126.6, 125.4, 112.0, 110.2, 106.6, 105.2, 101.9, 56.1, 52.6, 38.2, 34.1, 33.4, 28.1, 24.3.

[Example 14]

(5-Methoxy-1 H -Indol-2-yl)methanamine (KST-41001)

To a solution of 5-methoxy-2-carboxylic acid (0.05 g, 0.26 mmol) in THF (2 mL) was added CDI (0.09 mg, 0.52 mmol). After the reaction mixture was stirred for 2 h, NH ₄ OH (28-30% aqueous solution, 0.5 mL) was added. The reaction mixture was then stirred for 2 h, _{then quenched with H 2} O (5 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 Х 10 mL). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was dissolved in THF (5 mL) and cooled to 0 °C. LiAlH ₄ (14 mg, 0.38 mmol) was added slowly and the reaction mixture was warmed to room temperature, heated to reflux, and stirred for 2 hours. The reaction mixture was then _{quenched with H 2} O (100 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 Х 100 mL). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH 10% NH ₄ OH/CH ₂ Cl ₂ , 0:1 to 1:9 gradient run) (5-methoxy-1 H -indol-2-yl) Methanamine (11 mg, 43%) was obtained in the form of a white solid.

¹ H NMR (600 MHz, DMSO- d6 ) δ 10.81 (s, 1H), 7.20 (d, 1H, J = 8.7 Hz), 6.95 (d, 1H, J = 2.4 Hz), 6.66 (m, 1H), 6.20 (s, 1H), 3.87 (s, 2H), 3.72 (s, 3H). ¹³ C{ ¹ H} NMR (150 MHz, DMSO- d6 ) δ 153.2, 140.4, 131.1, 128.4, 111.5, 110.4, 101.6, 98.5, 55.2, 38.5.

[Example 15]

(6-methoxy-1 H -Indol-2-yl)methanamine (KST-41002)

To a solution of 6-methoxy-2-carboxylic acid (0.05 g, 0.26 mmol) in THF (5 mL) was added CDI (0.09 g, 0.52 mmol). The reaction mixture was stirred for 2 h before NH ₄ OH (28-30% aqueous solution, 0.5 mL) was added. The reaction mixture was then stirred for 2 h and then _{quenched with H 2} O (5 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 Х 10 mL). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was dissolved in THF (5 mL) and cooled to 0 °C. LiAlH ₄ (0.01 g, 0.38 mmol) was added slowly, and the reaction mixture was warmed to room temperature, heated to reflux, and stirred for 2 hours. The reaction mixture was then _{quenched with H 2} O (10 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 Х 10 mL). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH 10% NH ₄ OH/CH ₂ Cl ₂ , 0:1 to 1:9 gradient run) (6-methoxy-1 H -indol-2-yl) Methanamine (7.5 mg, 28%) was obtained in the form of a white solid.

¹ H NMR (600 MHz, DMSO- d6 ) δ 10.74 (d, 2H, J = 12.9 Hz), 7.28 (m, 1H), 6.82 (m, 1H), 6.58 (m, 1H), 6.11 (d, 1H) , J = 0.7 Hz), 4.43 (s, 1H), 3.78 (s, 2H), 3.73 (s, 3H).

[Example 16]

benzyl (2 S )-2-(( tert -Butoxycarbonyl)amino)-3-(5-(((4-(methylsulfinyl)butyl)carbamothioyl)oxy)-1 H -Indol-3-yl)propanoate

Benzyl (S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.2 g, 0.34) in THF (3 mL) mmol) was added sulforaphane (0.06 g, 0.34 mmol) and potassium t-butoxide (0.08 mg, 0.68 mmol). After stirring for 1 hour, the reaction mixture was diluted with dichloromethane, washed with water and brine _{, dried over MgSO 4} and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ /CH ₃ OH= 20 : 1) to benzyl (2 S )-2-(( tert -butoxycarbonyl)amino)-3-(5) - (((4- (methyl sulfinyl) butyl) cover motif oil) oxy) -1 H-indole-3-yl) propanoate (0.08 g, 35%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.95 (d, 1H, J = 42.2 Hz), 7.67 (m, 2H), 7.31 (d, 3H, J = 6.5 Hz), 6.89 (s, 1H), 6.71 (d, 1H, J = 8.7 Hz), 5.08 (d, 2H, J = 7.9 Hz), 4.62 (m, 1H), 3.80 (s, 2H), 3.05 (m, 2H), 2.68 (s, 2H) , 2.50 (d, 3H, J = 5.9 Hz), 1.88 (s, 4H), 1.39 (d, 9H, J = 2.7 Hz). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 171.9, 155.4, 152.3, 152.3, 135.1, 128.6, 128.4, 128.4, 114.2, 113.2, 104.8, 80.3, 67.4, 53.7, 53.1, 53.0, 45.2, 38.2 , 38.1, 28.3, 28.0, 27.9, 20.3, 20.2. LRMS (ESI) m/z: [M + Na] ^{+ Calcd} for C ₂₉ H ₃₇ N ₃ NaO ₆ S ₂ 610.2; found 610.2.

[Example 17]

(2 S )-1-(benzyloxy)-3-(5-(((4-(methylsulfinyl)butyl)carbamothioyl)oxy)-1 H -Indol-3-yl)-1-oxopropan-2-aminium 2,2,2-trifluoroacetate

Benzyl 2 - ((tert-butoxycarbonyl) amino) -3- (5 - (((4- (methyl sulfinyl) butyl) cover motif oil) oxy) -1 H-indol-3-yl) propanoate _{To a CH 2} Cl ₂ solution (3 mL) of ate (0.05 g, 0.08 mmol) at 0 °C was added TFA (0.1 mL). After stirring at room temperature for 3 h, the reaction mixture was diluted with dichloromethane, washed with water and brine _{, dried over MgSO 4} and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ /CH ₃ OH= 15 : 1 to 7 : 1) to (2 S )-1-(benzyloxy)-3-(5-(((( 4- (methyl sulfinyl) butyl) cover motif oil) oxy) -1 H - indol-3-yl) -1-oxo-propane-2-aminium 2,2,2-trifluoro-acetate (25 mg, 52 %) was obtained.

¹ H NMR (600 MHz, DMSO- d6 ) δ 9.66 (t, 1H, J = 5.2 Hz), 9.29 (s, 1H), 8.10 (bs, 2H), 8.06 (d, 1H, J = 9.0 Hz), 7.72 (s, 1H), 7.34 (m, 3H), 7.25 (m, 2H), 6.89 (d, 1H, J = 2.4 Hz), 6.79 (m, 1H), 5.13 (m, 2H), 4.28 (t) , 1H, J = 6.7 Hz), 3.72 (m, 2H), 3.16 (d, 2H, J = 7.2 Hz), 2.83 (m, 1H), 2.71 (m, 1H), 2.53 (s, 3H), 1.83 (m, 2H), 1.75 (m, 2H). ¹³ C{ ¹ H} NMR (150 MHz, DMSO- d6 ) δ 178.2, 169.7, 153.0, 134.9, 131.1, 129.1, 128.5, 128.3, 128.2, 127.6, 115.3, 112.8, 111.4, 103.4, 67.2, 52.8, 52.2, 48.6, 45.0, 38.0, 26.8, 26.3, 19.7.; LRMS (ESI) m/z: [M + Na] ^{+ Calcd} for C ₂₄ H ₂₉ N ₃ NaO ₄ S ₂ 510.2; found 510.2.

[Example 18]

methyl (2 S )-2-(( tert -Butoxycarbonyl)amino)-3-(5-(((4-(methylsulfinyl)butyl)carbamothioyl)oxy)-1 H -Indol-3-yl)propanoate

Methyl (S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy-1 H -indol-3-yl)propanoate (0.08 g, 0.16) in THF (3 mL) mmol) was added sulforaphane (0.03 g, 0.16 mmol) and potassium t-butoxide (0.04 g, 0.32 mmol). After stirring for 1 hour, the reaction mixture was diluted with dichloromethane, washed with water and brine _{, dried over MgSO 4} and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ /CH ₃ OH= 20 : 1) to methyl (2 S )-2-(( tert -butoxycarbonyl)amino)-3-(5) - (((4- (methyl sulfinyl) butyl) cover motif oil) oxy) -1 H-indole-3-yl) propanoate (0.03 g, 36%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.13 (d, 1H, J = 21.6 Hz), 7.65 (m, 2H), 6.87 (s, 1H), 6.71 (s, 1H), 5.34 (m, 1H) , 3.79 (s, 2H), 3.67 (s, 3H), 3.04 (m, 2H), 2.68 (s, 2H), 2.51 (s, 2H), 2.16 (s, 3H), 1.86 (s, 4H), 1.39 (s, 9H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 207.3, 179.5, 172.5, 155.4, 152.4, 132.4, 129.0, 127.9, 114.2, 113.2, 104.7, 80.3, 53.5, 53.1, 52.5, 45.2, 38.1, 31.0 , 28.3, 20.2. LRMS (ESI) m/z: [M + Na] ^{+ Calcd} for C ₂₃ H ₃₃ N ₃ NaO ₆ S ₂ 534.2; found 534.3.

[Example 19]

(2 S )-1-methoxy-3-(5-(((4-(methylsulfinyl)butyl)carbamothioyl)oxy)-1 H -Indol-3-yl)-1-oxopropan-2-aminium 2,2,2-trifluoroacetate

Methyl (2 S) -2 - ((tert-butoxycarbonyl) amino) -3- (5 - (((4- (methyl sulfinyl) butyl) cover motif oil) oxy) -1 H-indol -3 _{To a CH 2} Cl ₂ solution (3 mL) of -yl)propanoate (0.03 g, 0.06 mmol) at 0 °C was added TFA (0.1 mL). After stirring at room temperature for 3 h, the reaction mixture was diluted with dichloromethane, washed with water and brine _{, dried over MgSO 4} and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ /CH ₃ OH= 15 : 1 to 7 : 1) (2 S )-1-methoxy-3-(5-(((4- (methyl sulfinyl) butyl) cover motif oil) oxy) -1 H - indol-3-yl) acetate (14 mg, 44% propan-2-oxo-1-aminium 2,2,2-trifluoroethyl) was obtained.

¹ H NMR (600 MHz, DMSO- d6 ) δ 9.72 (s, 1H), 9.32 (d, 1H, J = 2.9 Hz), 8.11 (bs, 2H) 8.01 (d, 2H, J = 9.0 Hz), 7.72 (s, 1H), 6.84 (d, 1H, J = 2.3 Hz), 6.77 (m, 1H), 4.21 (t, 1H, J = 6.3 Hz), 3.71 (d, 2H, J = 6.0 Hz), 3.67 (s, 3H), 3.14 (d, 2H, J = 6.0 Hz), 2.83 (m, 1H), 2.71 (m, 1H), 2.53 (s, 3H), 1.83 (m, 2H), 1.74 (m, 2H). ¹³ C{ ¹ H} NMR (150 MHz, DMSO- d6 ) δ 178.3, 158.2, 158.0, 153.0, 131.1, 129.0, 127.8, 115.2, 112.8, 103.3, 52.8, 52.7, 52.2, 45.0, 38.0, 30.7, 26.8, 19.7.; LRMS (ESI) m/z: [M + Na] ^{+ Calcd} for C ₁₈ H ₂₅ N ₃ NaO ₄ S ₂ 434.1; found 434.2.

[Example 20]

2-amino- N -(3-((4-aminobutyl)amino)propyl)-3-(5-hydroxy-1 H -Indol-3-yl)propanamide

Stage 1: tert -Butyl ( S )-(3-(2-(( tert -Butoxycarbonyl)amino)-3-(5-hydroxy-1 H -indol-3-yl)propanamido)propyl)(4-(( tert Preparation of -butoxycarbonyl)amino)butyl)carbamate

_{CH 2} Cl ₂ solution of ( S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy-1 H -indol-3-yl)propanoic acid (0.13 g, 0.4 mmol) To N1, N5-bis-boc spermidine (0.17 g, 0.5 mmol) and N-methylmorpholine (NMM) (0.13 mL, 0.4 mmol) were added. After stirring at 0 °C for 30 minutes, EDCI and HOBt were added and stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane, washed with water and brine _{, dried over Na 2} SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH ₃ OH = 1: 2: 0.1) to tert -butyl( S )-(3-(2-(( tert -butoxycarbonyl)amino )-3-(5-hydroxy- 1H -indol-3-yl)propanamido)propyl)(4-(( tert -butoxycarbonyl)amino)butyl)carbamate (0.17 g, 51%) was obtained.

¹ H NMR (600 MHz, MeOD) δ 7.15 (d, 1H, J = 8.6 Hz), 7.03 (s, 1H), 6.95 (d, 1H, J = 2.3 Hz), 6.66 (m, 1H), 4.24 ( s, 1H), 3.11 (d, 4H, J = 10.4 Hz), 2.98 (m, 6H), 1.49 (s, 4H), 1.42 (m, 27H), 1.29 (m, 2H). ¹³ C{ ¹ H} NMR (150 MHz, MeOD) δ 173.0, 158.6, 157.6, 151.4, 133.0, 129.5, 125.3, 112.7, 112.5, 110.2, 103.7, 80.9, 80.7, 79.9, 61.5, 57.3, 41.2, 28.8, 28.8, 28.7, 20.9, 14.4.

Step 2: N1-(3-(2-ammonio-3-(5-hydroxy-1) H -Indol-3-yl)propanamido)propyl)butane-1,4-diaminium chloride

tert -Butyl( S )-(3-(2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy- 1H -indol-3-yl)propanamido)propyl)(4 -(( tert -butoxycarbonyl)amino)butyl)carbamate (0.04 g, 0.06 mmol) was dissolved in 4.0 M HCl in dioxane (2 mL) and stirred at room temperature for 2 hours. After removing the reaction solvent, it was diluted with diethyl ether and stirred for 2 hours to obtain a precipitated solid. (0.03 g, 98%)

¹ H NMR (600 MHz, MeOD) δ 7.23 (d, 1H, J = 8.6 Hz), 7.19 (s, 1H), 7.02 (d, 1H, J = 2.3 Hz), 6.72 (m, 1H), 4.11 ( t, 1H, J = 7.3 Hz), 3.25 (m, 4H), 3.00 (d, 2H, J = 6.7 Hz), 2.93 (t, 2H, J = 6.7 Hz), 2.75 (m, 2H), 1.78 ( m, 6H). ¹³ C{ ¹ H} NMR (150 MHz, MeOD) δ 170.8, 151.7, 132.9, 129.2, 126.3, 113.1, 113.0, 107.3, 103.5, 55.1, 48.2, 46.2, 40.0, 37.3, 28.7, 27.0, 25.5, 24.3.

[Example 21]

2-amino-3-(5-(((3-((4-aminobutyl)amino)propyl)carbamoyl)oxy)-1 H -Indol-3-yl)propanoic acid

Step 1: Benzyl ( S )-3-(5-(((3-(( tert -butoxycarbonyl) (4-(( tert -Butoxycarbonyl)amino)butyl)amino)propyl)carbamoyl)oxy)-1 H -Indol-3-yl)-2-(( tert -Preparation of butoxycarbonyl)amino)propanoate

_{CH 2} Cl of benzyl ( S )-2-(( tert -butoxycarbonyl)amino)-3-(5-hydroxy- 1H -indol-3-yl)propanoate (0.15 g, 0.4 mmol) _{2 To the} solution were added triphosgene (0.05 g, 0.2 mmol) and pyridine (0.03 mL, 0.4 mmol). After stirring at room temperature for 30 min, N1, N5-bis-boc spermidine (0.13 g, 0.4 mmol) and pyridine (0.04 mL, 0.4 mmol) were added at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was quenched with water. Diluted with dichloromethane, washed with water and brine _{, dried over Na 2} SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH ₃ OH = 1:3:0.1) to benzyl ( S )-3-(5-(((3-(( tert -butoxycarbonyl) ) (4 - ((tert - butoxycarbonyl) amino) butyl) amino) propyl) carbamoyl) oxy) -1 H - indol-3-yl) -2 - ((tert - butoxycarbonyl) amino ) propanoate (0.16 g, 55%) was obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.31 (m, 3H), 7.23 (m, 4H), 6.92 (m, 1H), 6.77 (d, 1H, J = 2.0 Hz), 5.08 (d, 2H, J = 11.1 Hz), 4.64 (d, 1H, J = 7.0 Hz), 3.33 (s, 2H), 3.24 (s, 2H), 3.21 (d, 1H, J = 5.4 Hz), 3.16 (s, 2H) , 3.13 (t, 2H, J = 6.9 Hz), 1.73 (m, 2H), 1.55 (m, 2H), 1.47 (s, 9H), 1.43 (d, 18H, J = 14.0 Hz), 1.37 (s, 1H), 1.31 (m, 1H). ¹³ C{ ¹ H} NMR (150 MHz, CDCl ₃ ) δ 172.2, 156.2, 155.3, 135.5, 128.7, 128.6, 128.6, 128.4, 128.1, 111.6, 111.2, 110.3, 80.0, 67.3, 67.2, 60.5, 54.4, 46.7 , 31.7, 28.6, 28.6, 28.4, 28.1, 27.6, 21.2, 14.3, 14.3.

Step 2: 3-(5-(((3-(( tert -butoxycarbonyl) (4-(( tert -Butoxycarbonyl)amino)butyl)amino)propyl)carbamoyl)oxy)-1 H -Indol-3-yl)-2-(( tert Preparation of -butoxycarbonyl)amino)propanoic acid (intermediate)

benzyl ( S )-3-(5-(((3-(( tert -butoxycarbonyl)(4-(( tert -butoxycarbonyl)amino)butyl)amino)propyl)carbamoyl)oxy) -1 H -indol-3-yl)-2-(( tert -butoxycarbonyl)amino)propanoate (0.16 g, 0.2 mmol) in ethyl acetate solution and 10% dry Pd/C (4 mg, 0.04) mmol) was reacted under a hydrogen atmosphere. After stirring for 2 hours, the reaction mixture was diluted with methyl alcohol, filtered through a celite pad, and concentrated under reduced pressure. The residue was purified by MPLC (20-100% CH ₃ CN/H ₂ O over 1 h) to obtain the target compound (0.07 g, 47%).

¹ H NMR (600 MHz, MeOD) δ 7.28 (m, 2H), 7.12 (s, 1H), 6.84 (d, 1H, J = 8.7 Hz), 4.38 (m, 1H), 3.23 (m, 7H), 3.13 (d, 1H, J = 7.2 Hz), 3.06 (t, 2H, J = 6.9 Hz), 1.79 (s, 2H), 1.56 (d, 2H, J = 14.4 Hz), 1.49 (m, 9H), 1.42 (d, 18H, J = 16.1 Hz), 1.24 (s, 2H). ¹³ C{ ¹ H} NMR (150 MHz, MeOD) δ 158.6, 158.4, 157.7, 145.6, 135.6, 129.3, 126.0, 116.9, 112.4, 111.9, 111.6, 81.0, 80.5, 79.9, 56.2, 41.0, 28.8, 28.8, 28.7, 28.4.

Step 3: 2-Amino-3-(5-(((3-((4-aminobutyl)amino)propyl)carbamoyl)oxy)-1 H -Indol-3-yl)propanoic acid

3- (5 - (((3 - ((tert - butoxycarbonyl) (4 - ((tert - butoxycarbonyl) amino) butyl) amino) propyl) carbamoyl) oxy) -1 H - indole -3-yl)-2-(( tert -butoxycarbonyl)amino)propanoic acid (0.05 g, 0.08 mmol) was dissolved in 4.0 M HCl in dioxane (3 mL) and stirred at room temperature for 3 hours. After removing the reaction solvent, it was diluted with diethyl ether and stirred for 2 hours to obtain a precipitated solid. (0.03 g, quantitative)

¹ H NMR (600 MHz, MeOD) δ 7.38 (m, 2H), 7.29 (s, 1H), 6.91 (m, 1H), 4.27 (m, 1H), 3.46 (m, 1H), 3.33 (d, 3H) , J = 5.8 Hz), 3.11 (d, 4H, J = 23.5 Hz), 2.98 (t, 2H, J = 6.6 Hz), 2.02 (m, 2H), 1.81 (d, 4H, J = 27.6 Hz). ¹³ C{ ¹ H} NMR (150 MHz, MeOD) δ 171.5, 158.8, 145.8, 135.9, 128.5, 127.3, 117.4, 113.0, 111.6, 108.1, 54.6, 48.4, 46.8, 40.1, 38.9, 27.8, 27.3, 25.6, 24.3.

Examples compounds 22 to 51 of Table 1 were synthesized in a manner similar to Examples 1 to 21 above.

[Experimental Example 1]

Analysis of methylglyoxal (MGO) capture ability (1): analysis of fluorescence intensity

Methylglyoxal (MGO) is a major precursor of the final glycation product that causes complications due to diabetes. When methylglyoxal (MGO) is successfully trapped, it can inhibit the production of the final glycation product. have. Therefore, in this example, it was attempted to confirm whether the compound of the present invention has the ability to capture methylglyoxal (MGO), a precursor before the formation of the final glycation product.

Methylglyoxal (MGO) was added to phosphate buffered saline (PBS, Cat no. 10010023, pH 7.4) to prepare a mixture. The mixture (MGO+PBS) was treated with the compound of each of Examples at a concentration of 1.0 mM, and then cultured at 37°C for 7 days. On days 1 and 7 after incubation, the fluorescence intensity of the reaction product was measured at an excitation wavelength of 355 nm and an emission wavelength of 460 nm using a ^{VICTOR TM X3 multilabel plate reader.} The fluorescence intensity obtained for each compound is shown in Table 2.

The reaction product produced by the reaction of the compound with methylglyoxal exhibits fluorescence. The higher the fluorescence intensity measured from the reaction product, the higher the ability of the compound to trap methylglyoxal. In addition, in this example, when the fluorescence intensity is 10 X 10 ³ or more, it was determined that the compound has the ability to capture methylglyoxal.

As shown in Table 2, the compounds of the present invention were confirmed to have excellent methylglyoxal capture ability.

division Day 1 fluorescence intensity (Х 10 ³ ) Day 7 fluorescence intensity (Х 10 ³ ) PBS 3.12±0.69 3.50±0.52 MGO+PBS 3.75±0.92 5.20±1.23 Example compound 1 137.78±0.59 137.82±1.20 Example compound 2 3.94±0.18 24.46±0.15 Example compound 3 4.21±0.38 24.18±0.16 Example compound 4 4.46±0.06 33.01±0.95 Example compound 5 3.76±0.10 29.00±0.52 Example compound 6 4.91±0.04 28.90±1.09 Example compound 7 5.41±0.18 27.06±0.16 Example compound 8 8.19±0.17 22.89±0.23 Example compound 9 5.00±0.05 15.20±0.23 Example compound 10 29.04±0.08 98.42±0.59 Example compound 11 59.72±0.26 120.22±1.57 Example compound 12 7.34±0.13 13.79±0.23 Example compound 13 5.71±0.02 13.68±0.20 Example compound 14 41.91±0.41 40.04±1.09 Example compound 15 688.24±1.10 642.98±32.82

[Experimental Example 2]

Analysis of methylglyoxal (MGO) capture capacity (2): HPLC analysis

In this example, by analyzing the free methylglyoxal (MGO) concentration by high-performance liquid chromatography (HPLC), it was attempted to confirm the methylglyoxal (MGO) capture ability of the compound of the present invention.

Specifically, methylglyoxal (MGO) was added to phosphate buffered saline (PBS, Cat no. 10010023, pH 7.4) to prepare a mixture. Each compound of Examples was added to the mixture (MGO+PBS) at a concentration of 1:1 with methylglyoxal (MGO) to react with each other, and then cultured at 37°C for 7 days. On days 1 and 7 after culture, the concentration of free methylglyoxal (free MGO) unreacted with the example compound was measured by HPLC. The results are shown in FIGS. 1 and 2 .

1 and 2, the compound of the present invention was confirmed to reduce the concentration of free methylglyoxal (free MGO) by almost half or less as compared to the control (N: PBS + MGO). In particular, when the compound of Example 9 was treated, the concentration of free methylglyoxal on the 7th day after culture was reduced to about 10% to 15% of the control group, and about 4% when the compound of Example 13 was treated was reduced to

[Experimental Example 3]

In the N2a cell line caused by methylglyoxal (MGO) treatment Measurement of cytotoxic protective effect

In this example, by inducing cytotoxicity due to free methylglyoxal (MGO) treatment, it was attempted to confirm the methylglyoxal (MGO) protective ability of the compound of the present invention.

Specifically, N2a cells were seeded in a 96-well plate at ^{2 x 10 4 cells/well.} Each cell line was pretreated with 500 nM of the compound for 1 hour, followed by post-treatment with 500 μM MGO and cultured for 24 hours. After removing the medium, 0.5 mg/ml 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution was treated for 1 hour, and the reduced formazan was dissolved in 150 μl of DMSO to 570 nm Cell viability was measured with a microspectrophotometer at wavelength. Cell viability in the case of treatment with each substance was evaluated by setting the cell viability of the normal control untreated to 100%. The results are shown in Table 3, Figures 3 and 4 below.

division cell viability PBS 100±0.84 MGO+PBS 50.20±4.49 Example compound 10 79.28±4.76 Example compound 11 80.00±4.49

As shown in Table 3, FIGS. 3 and 4, it was confirmed that the cell viability in the groups treated with Examples Compounds 10 and 11 was higher than that of the control group (MGO+PBS).

In particular, the cell viability was significantly decreased in the group treated with 500 μM MGO in each cell line compared to that of the normal control group (Control). In contrast, in the group pretreated with Examples 10 and 11, the cell viability increased in a concentration-dependent manner. Therefore, it can be seen that Example compounds 10 and 11 have excellent protective efficacy against MGO.

[Experimental Example 4]

Measurement of cytoprotective effect in SH-SY5Y cell line caused by methylglyoxal (MGO) treatment

In this example, by inducing cytotoxicity due to free methylglyoxal (MGO) treatment, it was attempted to confirm the methylglyoxal (MGO) protective ability of the compound of the present invention.

Specifically, SH-SY5Y cells were seeded in a 96-well plate at ^{2 x 10 4 cells/well.} Each cell line was pretreated with 500 nM of the compound for 1 hour, followed by post-treatment with 500 μM MGO and cultured for 24 hours. After removing the medium, 0.5 mg/ml 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution was treated for 1 hour, and the reduced formazan was dissolved in 150 μl of DMSO to 570 nm Cell viability was measured with a microspectrophotometer at wavelength. Cell viability in the case of treatment with each substance was evaluated by setting the cell viability of the normal control untreated to 100%. The results are shown in Table 4, FIGS. 5 and 6 .

division cell viability PBS 100.00±2.37 MGO+PBS 57.16±3.07 Example compound 4 78.97±1.36 Example compound 5 78.28±1.57 Example compound 10 80.13±1.17 Example compound 11 78.40±3.65 Example compound 13 79.18±3.13

As shown in Table 4, FIGS. 5 and 6, the cell viability in the treatment groups of Example compounds 4, 5, 10, 11 and 13 was confirmed to be higher than that of the control group (500 μM MGO).

In particular, the cell viability was significantly decreased in the group treated with 500 μM MGO in each cell line compared to that of the normal control group (Control). In contrast, in the group pretreated with Examples 10 and 11, the cell viability increased in a concentration-dependent manner. Therefore, it can be seen that the compound of the present invention has excellent protective efficacy against MGO.

[Experimental Example 5]

Measurement of LDH production by methylglyoxal (MGO) treatment

In this example, cytotoxicity was induced due to free methylglyoxal (MGO) treatment, and the methylglyoxal (MGO) protective ability of the compound of the present invention was confirmed using CyQUANT™ LDH Cytotoxicity Assay kit (Invitrogen).

Specifically, SH-SY5Y cells were ^{seeded in a 96-well plate at 2 x 10 4} cells/well and stabilized for 24 hours. Thereafter, cells were pre/post-treated with Example Compounds 10 and 11 at a concentration of 500 nM for 1 hour, followed by pre/post-treatment with 500 μM MGO and cultured for 24 hours. 50 μL of the medium was mixed with the substrate mix solution in the same amount and reacted for 30 minutes in the dark at room temperature, 50 μL stop solution was added, and absorbance was measured at 490 nm. The change in LDH content according to each sample treatment was calculated by setting the LDH content of the normal control untreated to 100%. The results are shown in FIGS. 7 and 8 below.

7 and 8 , it was confirmed that the LDH production level in the compound 10 and 11 treatment groups was low compared to the control group (500 μM MGO). In particular, in each cell line, the cell viability was significantly increased in the groups pre-treated and post-treated with 500 μM MGO compared to the normal control group. On the other hand, LDH production was decreased in the pre- and post-treatment groups with compounds 10 and 11.

[Experimental Example 6]

BrdU measurement with methylglyoxal (MGO) treatment

In this example, cell proliferation inhibition was induced due to free methylglyoxal (MGO) treatment, and the protective ability of the compound of the present invention to methylglyoxal (MGO) was confirmed using the BrdU cell proliferation assay kit (Cell signalin). .

Specifically, SH-SY5Y cells were ^{seeded in a 96-well plate at 2 x 10 4} cells/well and stabilized for 24 hours. Thereafter, cells were pre/post-treated with compounds 10 and 11 at a concentration of 500 nM for 1 hour, followed by pre/post-treatment with 500 μM MGO and cultured for 24 hours. After 24 hours, 200 μL of the fixing solution was treated and reacted at room temperature for 30 minutes. After washing 3 times with washing buffer, the BrdU primary antibody was treated and reacted for 1 hour. After washing with washing buffer, TMB peroxidase substrate was added and reacted for 30 minutes. After 30 minutes, the reaction was stopped using a stop solution. Absorbance was measured at 450/550 nm with a microspectrophotometer. With the cell proliferation rate of the normal control untreated as 100%, the change in cell proliferation according to each sample treatment was calculated, and the results are shown in FIGS. 9 and 10 .

As shown in FIGS. 9 and 10 , it was confirmed that the cell proliferation rate in the compound 10 and 11 treatment groups was higher than that of the control group (500 μM MGO).

In particular, the cell proliferation rate was significantly decreased in the group treated with 500 μM MGO in each cell line compared to the normal group (control). In contrast, in the group treated with compounds 10 and 11, the cell proliferation rate was increased.

[Experimental Example 7]

_L -Measurement of cytotoxic protective effect due to DOPA treatment

In this example, _{by inducing cytotoxicity due to free L-} DOPA treatment, it was attempted to confirm _{the L-} DOPA protective ability of the compound of the present invention.

Specifically, SH-SY5Y cells were seeded in a 96-well plate at 2 x 104 cells/well and stabilized for 24 hours. Thereafter, the cells were pre/post-treated with compounds 10 and 11 at concentrations of 1, 5, and 10 μM for 1 hour, and then treated with 100 μM _L- DOPA before/after and cultured for 24 hours. After removing the medium, 0.5 mg/ml MTT solution was treated for 1 hour after removing the medium, and the reduced formazan was dissolved in 150 μl of DMSO to measure cell viability with a microspectrophotometer at 570 nm wavelength. did. A change in cell protection according to each sample treatment was measured with the cell viability of the normal control untreated as 100%, and the results are shown in FIGS. 11 and 12 .

As shown in FIGS. 11 and 12 , it was confirmed that the cytotoxicity level in the compound 10 and 11 treatment groups was lower than that of the control group (500 μM MGO).

In particular, in _{the group treated with 100 μM L-} DOPA in each cell line, the cell proliferation rate was significantly reduced compared to that of the normal group (control). In contrast, the cell viability was significantly increased in the compounds 10 and 11 treatment groups.

[Experimental Example 8]

MGO+ _L -Measurement of cytotoxic protective effect due to DOPA treatment

In this example, free MGO + _L -DOPA treatment was induced to induce cytotoxicity, to confirm the MGO + _L -DOPA protective ability of the compound of the present invention.

SH-SY5Y cells were ^{seeded in a 96-well plate at 2 x 10 4} cells/well and stabilized for 24 hours. Thereafter, cells were pre/post-treated with compounds 10 and 11 at a concentration of 500 nM for 30 minutes, followed by pre/post-treatment with 500 μM MGO and cultured for 24 hours. After removing the medium, 0.5 mg/ml MTT solution was treated for 1 hour after removing the medium, and the reduced formazan was dissolved in 150 μl of DMSO and cell viability was measured with a microspectrophotometer at a wavelength of 570 nm. did. The cell viability of the untreated normal control group (Control) was set to 100%, and the cell viability when treated with MGO was measured and shown in FIGS. 13 and 14 .

13 and 14 , it was confirmed that the cell proliferation rate in the compound 10 and 11 treatment groups was higher than that of the control group (MGO + L-DOPA).

In particular, in each cell line, in the group treated with MGO + L-DOPA, the cell proliferation rate was significantly reduced compared to that of the normal group (control). In contrast, cell viability increased in a concentration-dependent manner in the groups treated with compounds 10 and 11 of the present invention.

[Experimental Example 9]

Measurement of inflammatory cytokines due to MGO treatment

In this example, by inducing cytotoxicity due to free MGO treatment, it was attempted to confirm the MGO protective ability of the compound of the present invention.

To compare the expression levels of CD14 and CD68 in monocyte THP-1 cells, reverse transcription polymerase chain reaction (RTPCR) was performed. RNA was isolated from liver and adipose tissue using Trizol (Invitrogen), and cDNA was synthesized using rimeScript™ RT Master Mix synthesis kit (Takara). Real-time PCR was performed in triplicate using TB Green® Premix Ex Taq™ II (Takara) on Mx3000/Mx3005P Real-Time PCR System (Agilent). The expression of the target gene was proportionally measured using the delta cycle threshold method for the expression of the endogenous standard gene actin, and the results are shown in FIG. 15 .

As shown in FIG. 15 , it was confirmed that the levels of inflammatory cytokines in the compounds 10 and 11 treated groups were lower than in the control group (MGO).

Claims (19)

A compound of formula (I): or a pharmaceutically acceptable salt thereof:
[Formula I]

In the above formula,
R ₁ is hydrogen, halo, alkyl, alkenyl, or alkynyl,
R ₂ is hydrogen; -N(Ra)(Rb) unsubstituted or substituted alkyl; or - aryl unsubstituted or substituted with N(Ra)(Rb) or alkyl;
Ra or Rb is each independently hydrogen or alkyl,
R ₃ is hydrogen; -(CH ₂ )nC(Rc)(N(Rd)(Re))(COORf); or -(CH ₂ )nC(Rc)(N(Rd)(Re))(C(=O)Rf),
Rc is hydrogen or alkyl,
Rd or Re is each independently hydrogen, -C(=O)alkyl _, -C(=O)alkyl-O-alkyl, -C(=O)alkyl-cycloalkyl, -C(=O)alkyl-alkenyl , -C(=O)O-alkyl, or -NH-alkyl-NH-alkyl-NH ₂ ,
Rf is hydrogen; alkyl unsubstituted or substituted with an aryl group; or —NH-alkyl-NH-alkyl-NH ₂ ,
R ₄ is hydrogen, halo, alkyl, alkenyl, or alkynyl;
R ₅ is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or - OC(=O)(CH ₂ )aS(CH2)bCH(Rg)(Rh),
Rk is hydrogen; alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH ₂ NHC(=O)CH(CH ₂ SH),
Rg or Rh is each independently hydrogen, alkyl, heterocycloalkyl, -S(=O)alkyl,

,

,

, or —NH(CH ₂ )mNH ₂ ,
R ₆ or R ₇ are each independently hydrogen, halo, alkyl, alkenyl, alkynyl, —OH or —Oalkyl,
a, b, n or m is an integer from 1 to 10;
According to claim 1,
R ₁ is hydrogen, or C ₁ -C ₆ alkyl,
R ₂ is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with —N(Ra)(Rb); or - aryl unsubstituted or substituted with N(Ra)(Rb) or C ₁ -C _{6 alkyl,}
Ra or Rb is each independently hydrogen or C ₁ -C ₆ alkyl,
R ₃ is hydrogen; -(CH ₂ )nC(Rc)(N(Rd)(Re))(COORf); or -(CH ₂ )nC(Rc)(N(Rd)(Re))(C(=O)Rf),
Rc is hydrogen or C ₁ -C ₆ alkyl,
Rd or Re are each independently hydrogen, -C(=O)C ₁ -C ₆ alkyl _, -C(=O)C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₆ alkyl-C ₃ -C ₇ cycloalkyl, -C(=O)C ₁ -C ₆ alkyl-C ₂ -C ₆ alkenyl, -C(=O)OC ₁ -C ₆ alkyl, or -NH -C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl-NH ₂ and
Rf is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with an aryl group; or -NH-C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl-NH ₂ ,
R ₄ is hydrogen or C ₁ -C ₆ alkyl,
R ₅ is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or - OC(=O)(CH ₂ )aS(CH2)bCH(Rg)(Rh),
Rk is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH ₂ NHC(=O)CH(CH ₂ SH),
Rg or Rh are each independently hydrogen; C ₁ -C ₆ alkyl; _{C 3} -C ₁₀ heterocycloalkyl having a heteroatom selected from N, O, or S; -S(=O)C ₁ -C ₆ alkyl;

;

;

; or -NH(CH ₂ )mNH ₂ and
R ₆ or R ₇ are each independently hydrogen, C ₁ -C ₆ alkyl, —OH or —OC ₁ -C ₆ alkyl,
a, b, n or m is an integer from 1 to 5;
A compound of formula (I) or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ₁ is hydrogen,
R ₂ is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with NH _{2 ;} or aryl unsubstituted or substituted with _{NH 2} or C ₁ -C _{6 alkyl,}
R ₃ is hydrogen; -(CH ₂ )n-CH(N(Rd)(Re))(COORf); or -(CH ₂ )n-CH(N(Rd)(Re))(C(=O)Rf),
Rd or Re are each independently hydrogen, -C(=O)C ₁ -C ₆ alkyl _, -C(=O)C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₆ alkyl-C ₃ -C ₇ cycloalkyl, -C(=O)C ₁ -C ₆ alkyl-C ₂ -C ₆ alkenyl, -C(=O)OC ₁ -C ₆ alkyl, or -NH -C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl-NH ₂ and
Rf is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with an aryl group; or -NH-C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl-NH ₂ ,
R ₄ is hydrogen or C ₁ -C ₆ alkyl,
R ₅ is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or

ego,
Rk is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH ₂ NHC(=O)CH(CH ₂ SH),
Rg or Rh are each independently hydrogen; C ₁ -C ₆ alkyl; _{C 3} -C ₇ heterocycloalkyl having a heteroatom selected from S; -S(=O)C ₁ -C ₆ alkyl;

;

;

; or -NH(CH ₂ )mNH ₂ and
R ₆ or R ₇ are each independently hydrogen, C ₁ -C ₆ alkyl, —OH or —OC ₁ -C ₆ alkyl,
n or m is an integer from 1 to 5;
A compound of formula (I) or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ₁ is hydrogen,
R ₂ is hydrogen; -C ₁ -C ₆ alkyl-NH ₂ ; Or NH ₂ substituted or unsubstituted phenyl,
R ₃ is hydrogen; -(CH ₂ )n-CH(N(Rd)(Re))(COORf); or -(CH ₂ )n-CH(N(Rd)(Re))(C(=O)Rf),
Rd or Re are each independently hydrogen, -C(=O)C ₁ -C ₆ alkyl _, -C(=O)C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₆ alkyl-C ₃ -C ₇ cycloalkyl, -C(=O)C ₁ -C ₆ alkyl-C ₂ -C ₆ alkenyl, -C(=O)OC ₁ -C ₆ alkyl, or -NH -C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl-NH ₂ and
Rf is hydrogen, C ₁ -C ₆ alkyl, benzyl or —NH-C ₁ -C ₆ alkyl-NH-C ₁ -C ₆ alkyl-NH ₂ ,
R ₄ is hydrogen,
R ₅ is hydrogen, -ORk, -OC(=O)Rk-Rg, -OC(=O)NHRk-Rg, -OC(=S)Rk-Rg, -OC(=S)NHRk-Rg, or

ego,
Rk is hydrogen; _{C 1} -C ₆ alkyl unsubstituted or substituted with an amino group or a carboxyl group; or -CH ₂ NHC(=O)CH(CH ₂ SH),
Rg or Rh are each independently hydrogen; C ₁ -C ₆ alkyl; _{C 3} -C ₇ heterocycloalkyl having a heteroatom selected from S; -S(=O)C ₁ -C ₆ alkyl;

;

;

; or -NH(CH ₂ )mNH ₂ and
R ₆ is hydrogen, —OH or —OC ₁ -C ₆ alkyl
R ₇ is hydrogen,
n or m is an integer from 1 to 5;
A compound of formula (I) or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ₁ is hydrogen,
R ₂ is hydrogen, —CH ₂ NH ₂ , or phenyl substituted with _{NH 2 ,}
R ₃ is hydrogen,

,

,

,

,

,

,

,

,

,

,

or

ego,

R ₄ is hydrogen,
R ₅ is hydrogen, -OH, -OCH ₃ ,

,

,

,

,

,

,

,

, or

ego,
R ₆ is hydrogen, -OH, -OCH ₃
R ₇ is hydrogen,
with the proviso that R ₂ and R ₃ are not hydrogen at the same time,
A compound of formula (I) or a pharmaceutically acceptable salt thereof.
A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof:

A pharmaceutical composition for the prophylaxis or treatment of diseases related to final glycation products, comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
The method of claim 7, wherein the final glycation product-related disease is aging, diabetes, diabetic complications, hyperlipidemia, hyperglycemia, cardiovascular disease, degenerative brain disease, autism spectrum disorder, arteriosclerosis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, skin fibrosis, A pharmaceutical composition, characterized in that it is selected from the group consisting of pulmonary fibrosis, renal fibrosis, and cardiac fibrosis.
The pharmaceutical composition according to claim 7, wherein the final glycation product-related disease is diabetes or a diabetic complication.
The pharmaceutical composition according to claim 9, wherein the diabetes is second diabetes.
10. The method of claim 9, wherein the diabetic complications are diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, diabetic osteoporosis, diabetic muscle. A pharmaceutical composition, characterized in that it is selected from the group consisting of hypothyroidism, and obesity.
The method of claim 8, wherein the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph disease, dystonia , progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, senile dementia, temporal lobe epilepsy, and a pharmaceutical composition, characterized in that selected from the group consisting of stroke.
A food composition for preventing or ameliorating a disease related to the final glycation product, comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
The method of claim 13, wherein the final glycation product-related disease is aging, diabetes, diabetic complications, hyperlipidemia, hyperglycemia, cardiovascular disease, degenerative brain disease, autism spectrum disorder, arteriosclerosis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, skin fibrosis, A food composition, characterized in that it is selected from the group consisting of pulmonary fibrosis, renal fibrosis, and cardiac fibrosis.
[Claim 14] The food composition for preventing or improving end-glycated product-related disease according to claim 13, wherein the end-glycated product-related disease is diabetes or a diabetic complication.
The food composition according to claim 15, wherein the diabetes is second diabetes.
16. The method of claim 15, wherein the diabetic complications are diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, diabetic osteoporosis, diabetic muscle. A food composition for the prevention or improvement of diseases related to final glycation products, characterized in that it is selected from the group consisting of atrophy and obesity.
15. The method of claim 14, wherein the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia , progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, senile dementia, temporal lobe epilepsy, and stroke. Food composition for the prevention or improvement of.
A feed composition for animals for preventing or improving diseases related to final glycation products, comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

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