WO2018164549A1 - Novel compound having malate dehydrogenase inhibitory activity and pharmaceutical composition for preventing or treating cancer comprising same as active ingredient - Google Patents

Abstract

The present invention relates to a compound exhibiting inhibitory activity of at least one of malate dehydrogenases 1 (MDH1) and malate dehydrogenases 2 (MDH2), and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient. The inventors of the present invention have experimentally confirmed that the compound exhibiting the MDH1 and/or MDH2 inhibitory activity has an inhibitory effect on mitochondrial respiration in cancer cells, an excellent inhibitory effect on cancer cell growth, etc.. Thus, the compound of the present invention is expected to be effectively used as a pharmaceutical composition for treating cancer.

Description

Novel compound having maleic acid dehydrogenase inhibitory activity and pharmaceutical composition for cancer prevention or treatment comprising the same as an active ingredient

The present invention relates to a novel compound having inhibitory activity of MDH1 (malate dehydrogenases 1) or MDH2 (malate dehydrogenases 2) and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient.

This application claims the priority based on Korean Patent Application No. 10-2017-0029916, filed March 9, 2017 and Korean Patent Application No. 10-2018-0027397, filed March 8, 2018, All content disclosed in the specification and drawings of an application is incorporated in this application.

Compared to normal cells, cancer cells exhibit various changes in metabolism such as aerobic glycolysis, increased fatty acid synthesis, and rapid glutamine metabolism. In particular, activation of glycolysis causes changes in ATP production, biosynthesis of biomaterials, and redox regulation. The malic acid-asphalic acid shuttle is a mechanism that plays an important role in delivering NADH to the mitochondria in the cytoplasm generated during glycolysis. The malic acid-asphalic acid shuttle is made by malic dehydrogenases (MDHs) and glutamate oxaloacetate transaminases (GOTs) present in the cytoplasm and mitochondria. Aminooxyacetic acid (AOA), an inhibitor of the maleic acid-asphalic acid shuttle, inhibits the proliferation of breast cancer cells by preventing glucose from becoming a product of the tricarboxylic acid cycle. In addition, it has been reported that acetylation of GOT2 (Mitochondrial GOT2) present in mitochondria in pancreatic cancer promotes the migration of NADH through malic acid-asphalic acid and is involved in the production of ATP necessary for the proliferation of cancer cells.

Meanwhile, MDH1 and MDH2 isozymes produced by different MDH genes are present in the cytoplasm and mitochondrial matrix. MDH1 and MDH2 reversibly serve to convert malate and oxaloacetate (OAA) using the NAD / NADH cofactor system. MDH1 in the cytoplasm oxidizes NADH to NAD ⁺ by reducing oxalic acid to malic acid. In the malic acid-asphalic acid shuttle, malic acid is transported into the mitochondria and oxidized back to oxalic acid by mitochondrial MDH2 to produce NADH. The generated NADH generates ATP through an electron transport system. In addition, MDH2 involved in the TCA cycle is involved in ATP production through respiration.

Recently, cancer-related associations of MDH1 and MDH2 have been reported, and glutamine metabolism reprogramming in glutamine-dependent pancreatic ductaladenocarcinoma (PDAC) cells is used to maintain intracellular redox state. It has been reported that it requires MDH1. As a result of knocking down MDH1, it was observed that PDAC cells were killed and also inhibited proliferation of ERBB2 (Erb-B2 receptor tyrosine kinase 2) -positive BT474 breast cancer cells by inhibiting fatty acid synthesis. In addition, prostate cancer cells expressing MDH2 are reported to be anti-cancer drug resistant and have a short relapse-free survival period. When knocking down MDH2 in these prostate cancer cell lines, induction of metabolism of cancer cell lines leads to inefficiency of the cells. It was confirmed that the proliferation and sensitivity to docetaxel (docetaxel) is increased. At present, various attempts have been made to treat cancer (Korean Patent Laid-Open Publication No. 10-2010-0126924), but there is a problem of having side effects such as resistance, and studies on cancer-related effects of MDH1 and MDH2 have been reported, but anticancer drugs Attempts to develop MDH1 and MDH2 inhibitors have not been made.

Accordingly, the present inventors while continuing to research to develop a more effective cancer treatment material, in order to solve the conventional problems as described above, the substrate binding site and active site structure of MDH1 and MDH2 is very similar to that of MDH1 and MDH2 In anticipation of the possibility of developing MDH1 / 2 dualinhibitors that simultaneously inhibit activity, a compound was prepared that simultaneously inhibits the activities of MDH1 and MDH2, and a cancer therapeutic agent containing the compound was first devised to complete the present invention.

The present invention has been made to solve the above problems, the present inventors have confirmed the cancer preventive or therapeutic effect of the compound that inhibits the activity of MDH1 and / or MDH2 to complete the present invention based on this.

It is therefore an object of the present invention to provide compounds, isomers thereof or pharmaceutically acceptable salts thereof which exhibit MDH1 and / or MDH2 inhibitory activity.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, which comprises as an active ingredient a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, which exhibits MDH1 and / or MDH2 inhibitory activity.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.

In order to achieve the object of the present invention as described above, the present invention provides a compound represented by the following formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof.

[Formula 1]

At this time, in the formula (1),

X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene;

R ₁ is a nitro group, trifluoromethyl group, C ₁ -C ₂₀ alkyl or C ₁ -C ₂₀ cycloalkyl; And

R ₂ is

,

,

,

,

,

,

,

,

or

ego;

R ₂ is

when,

R ₃ is methyl or 2-propynyl; And

R ₄ is methyl, hydrogen, hydroxy, methoxy, 2-propynyl,

,

,

,

,

, or

ego;

R ₂ is

when,

R ₅ is

,

or

ego,

R ₂ is

when,

R ₆ is methyl or hydroxy; And

R ₂ is

when,

R ₇ may be C or N.

In one embodiment of the present invention, R ₁ may be substituted with adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl.

In addition, in one embodiment of the present invention, R ₁ is adamantyl;

X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene; And

R ₂ is

ego,

R ₄ is methyl, hydrogen, hydroxy,

,

,

or

And

R ₃ may be methyl.

In addition, as an embodiment of the present invention, the compound may be a compound represented by the following formula (2).

[Formula 2]

At this time, in the formula (2),

R ₁ is adamantyl or tert -butyl; And

R ₂ is

,

or

ego,

R ₂ is

when,

R ₃ is methyl or 2-propynyl;

R ₄ is methyl, hydrogen or hydroxy;

R ₂ is

when,

R ₆ is methyl or hydroxy; And

R ₂ is

when,

R ₇ may be C or N.

In addition, as an embodiment of the present invention, the compound may be a compound represented by the following formula (3).

[Formula 3]

At this time, in the formula (3),

R ₁ is a nitro group, trifluoromethyl group, adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl;

R ₂ is

,

,

,

,

, or

ego;

R ₂ is

when,

R ₃ is methyl or 2-propynyl; And

R ₄ is methyl, hydrogen, hydroxy, methoxy, 2-propynyl,

,

,

,

,

, or

Can be.

In another embodiment of the present invention, the compound may be any one or more selected from the group consisting of:

(1) Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate (Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate);

(2) methyl 3- (2- (4-trifluoromethyl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (trifluoromethyl) phenoxy) acetamido) benzoate);

(3) methyl 3- (2- (4-tert-butylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-tert-butylphenoxy) acetamido) benzoate);

(4) Methyl 3- (2- (p-tolyloxy) acetamido) benzoate (Methyl 3- (2- (p-tolyloxy) acetamido) benzoate);

(5) methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate);

(6) methyl 3- (2- (4-propylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-propylphenoxy) acetamido) benzoate);

(7) methyl 3- (2- (4-butyl phenoxy) acetamido) benzoate;

(8) methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate);

(9) methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate);

(10) methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate);

(11) Methyl 3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(12) Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-hydroxy-3- ( 2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(13) N- (4- (trifluoromethyl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide (N- (4- (trifluoromethyl ) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);

(14) N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide (N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);

(15) 1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) Ethanone (1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone);

(16) 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) ethanone ( 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone);

(17) Prop-2-ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Prop-2 -ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(18) N- (3-hydroxy-adamantane-1-yl) -2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamide (N- (3 -hydroxy-adamantan-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);

(19) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) benzoate );

(20) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido 4-hydroxybenzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate);

(21) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate (Methyl 3- (2 -(4-adamantan-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate);

(22) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate (Methyl 3 -(2- (4-adamantan-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate);

(23) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate (Methyl 3- (2- (4 -adamantan-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate);

(24) Methyl 4-methoxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-methoxy-3- ( 2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(25) Methyl 4- (2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4 -(2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(26) Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(27) Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(28) Methyl 4- (4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4 -(4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(29) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) -2-methylpropaneamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy ) -2-methylpropanamido) benzoate);

(30) Methyl 3- (2-methyl-2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (2-methyl-2 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(31) Methyl-4-hydroxy-3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy -3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(32) Methyl 3- [4- (4-adamantane-1-yl-phenoxy) butanamido] benzoate (Methyl 3- [4- (4-adamantan-1-yl-phenoxy) butanamido] benzoate );

(33) Methyl 3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 3- (4- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate);

(34) Methyl 4-hydroxy-3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 4-hydroxy-3- ( 4- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate);

(35) (E) -3- [3- (4-adamantane-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester ((E) -3- [3- (4- Adamantan-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester);

(36) (E) -3- {3- [4- (2,4,4-trimethylpentan-2-yl) phenoxy] acrylamido} benzoic acid methyl ester ((E) -3- {3 -[4- (2,4,4-Trimethylpentan-2-yl) phenoxy] acrylamido} benzoic acid methyl ester);

(37) (E) -methyl4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 4 -methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

(38) (E) -methyl2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2 -methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

(39) (E) -methyl2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

(40) (E) -isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -isopropyl 3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

(41) (E) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

(42) (E) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy Acrylate ((E) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy ) acrylate);

(43) (E) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate ((E) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate);

(44) (E) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

(45) Methyl 3- [3- (4-adamantane-1-yl-phenoxy) propanamido] benzoate (Methyl 3- (3- (4- (adamantan-1-yl) phenoxy) propanamido) benzoate);

(46) Methyl 3- (3- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (3- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(47) Methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy-3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(48) methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(49) Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(50) Methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-hydroxy-5- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(51) Isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Isopropyl 3- (3- (4- (2,4 , 4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(52) methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) nicotinate; (Methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) nicotinate)

(53) N- (3- (morpholin-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamide (N- (3- (Morpholine-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamide);

(54) ethyl 2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) acetate (Ethyl 2- (3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) acetate); or

(55) (S) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) butano Ate ((S) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) butanoate).

The present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the composition may inhibit the activity of malate dehydrogenases 1 (MDH1) and / or malate dehydrogenases 2 (MDH2).

In one embodiment of the invention, the composition may simultaneously inhibit the activity of MDH1 (malate dehydrogenases 1) and MDH2 (malate dehydrogenases 2).

The present invention provides a method for preventing or treating cancer, comprising administering the pharmaceutical composition to a subject.

The present invention provides a cancer prevention or treatment of the composition comprising the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention relates to a compound exhibiting inhibitory activity of MDH1 (malate dehydrogenases 1) and / or MDH2 (malate dehydrogenases 2) and a pharmaceutical composition for preventing or treating cancer, comprising the same as an active ingredient. The present inventors have experimentally confirmed the mitochondrial respiratory inhibitory effect and excellent cancer cell growth inhibitory effect in cancer cells of the compound showing MDH1 and / or MDH2 inhibitory activity, the compound of the present invention is useful as a pharmaceutical composition for treating cancer It is expected to be used.

1 is a schematic diagram illustrating the synthesis of 55 compounds of the present invention (compounds 3-1 to 3-34, compounds 6-1 to 6-10 and compounds 9-1 to 9-11).

Figure 2 shows the overexpressed recombinant MDH2 protein isolated and purified in the present invention.

Figure 3 is the result of measuring the enzyme kinetics (enzyme kinetics) of MDH1 and MDH2 according to the change of NADH concentration of the compound of the present invention.

4 is a result of confirming the HIF-1α inhibitory activity of the compounds of the present invention using immunoblot analysis (immunoblot analysis).

5 is a result of measuring the oxygen consumption rate (OCR) of mitochondria in cancer cells of the compound of the present invention.

6 is a result of confirming the increase in the oxygen concentration in the cell by inhibiting the oxygen consumption rate of the mitochondria of the compound of the present invention using an oxygen-sensitive fluorescent probe.

Figures 7a and 7b is a result of confirming that the tumor size or volume after administration of the compound of the present invention.

Figure 7c is a result confirming that the weight of the tumor after administration of the compound of the present invention.

The present inventors, when treated with the compound prepared in Example, exhibits the inhibitory activity of MDH1 / 2 expression, HIF-1α expression inhibitory activity, mitochondrial respiratory inhibitory effect in cancer cells and excellent cancer cell growth The inhibitory effect etc. were confirmed specifically, and this invention was completed based on this.

Hereinafter, the present invention will be described in detail.

The present invention provides a compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

At this time, in the formula (1),

X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene;

R ₁ is a nitro group, trifluoromethyl group, C ₁ -C ₂₀ alkyl or C ₁ -C ₂₀ cycloalkyl; And

R ₂ is

,

,

,

,

,

,

,

,

or

Can be.

In addition, R ₂ is

when,

R ₃ is methyl or 2-propynyl; And

R ₄ is methyl, hydrogen, hydroxy, methoxy, 2-propynyl,

,

,

,

,

, or

Can be.

R ₂ is

when,

R ₅ is

,

or

Can be.

R ₂ is

when,

R ₆ may be methyl or hydroxy.

R ₂ is

when,

R ₇ may be C or N.

More preferably, in Formula 1, R ₁ is adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl.

More preferably, in Chemical Formula 1, R ₁ is adamantyl;

X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene; And

R ₂ is

ego,

R ₄ is methyl, hydrogen, hydroxy,

,

, or

And

R ₃ may be methyl.

More preferably, the compound may be a compound represented by the following formula (2).

[Formula 2]

At this time, in the formula (2),

R ₁ is adamantyl or tert -butyl; And

R ₂ is

,

or

ego,

R ₂ is

when,

R ₃ is methyl or 2-propynyl;

R ₄ is methyl, hydrogen or hydroxy;

R ₂ is

when,

R ₆ is methyl or hydroxy; And

R ₂ is

when,

R ₇ is C or N.

More preferably, the compound may be a compound represented by the following formula (3).

[Formula 3]

At this time, in the formula (3),

R ₁ is a nitro group, trifluoromethyl group, adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl;

R ₂ is

,

,

,

,

, or

ego;

R ₂ is

when,

R ₃ is methyl or 2-propynyl; And

R ₄ is methyl, hydrogen, hydroxy, methoxy, 2-propynyl,

,

,

,

,

, or

Can be.

The following describes the definition of the various substituents for preparing the compounds according to the invention.

The term "C ₁ -C ₂₀ alkyl" as used herein refers to a monovalent alkyl group having 1 to 20 carbon atoms. The term is exemplified by functional groups such as methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, tert -butyl, n -hexyl and the like.

As used herein, the term “C ₁ -C ₂₀ cycloalkyl” refers to a saturated hydrocarbon ring compound having a single ring (eg cyclohexyl) or multiple condensed ring (eg norbornyl), cyclopentyl, Cyclohexyl, norbornyl, adamantane and the like.

The term "methylene group" used in the present invention means a bond in the form of-(CH ₂ )-, and means a form when one carbon is bonded to X in the general formula (1) of the present invention. N is 1 or 2.

The term "ethane group" used in the present invention means a bond in the form of-(C ₂ H ₄ )-, and refers to a form when two carbons are bonded to X in Formula 1 of the present invention.

The term "ethylene group" used in the present invention means a bond in the form of-(C ₂ H ₂ )-, and means the form when two carbons are bonded to X in the general formula (1) of the present invention.

The term " n -propylene group" used in the present invention means a bond in the form of-(C ₃ H ₆ )-, and in the formula (1) of the present invention means a form when three carbons are bonded to the X in a straight chain form. do.

As used herein, the term "isopropylene group" refers to a bond in the form of-(C ₃ H ₆ )-, wherein in the formula (1) of the present invention, when X is combined with three carbons in a crushed or branched form, it means.

As used herein, the term "2-propynyl" refers to -CH ₂ C≡CH, and means a linear hydrocarbon group of three carbon atoms, including unsaturated carbon bonded to the triple bond at the end.

Substituents comprising alkyl and other alkyl moieties described in the present invention include both straight and pulverized forms.

Preferred examples of the compound represented by Formula 1 according to the present invention are as follows:

(1) Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate (Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate);

(2) methyl 3- (2- (4-trifluoromethyl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (trifluoromethyl) phenoxy) acetamido) benzoate);

(3) methyl 3- (2- (4-tert-butylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-tert-butylphenoxy) acetamido) benzoate);

(4) Methyl 3- (2- (p-tolyloxy) acetamido) benzoate (Methyl 3- (2- (p-tolyloxy) acetamido) benzoate);

(5) methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate);

(6) methyl 3- (2- (4-propylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-propylphenoxy) acetamido) benzoate);

(7) methyl 3- (2- (4-butyl phenoxy) acetamido) benzoate;

(8) methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate);

(9) methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate);

(10) methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate);

(11) Methyl 3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(12) Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-hydroxy-3- ( 2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(13) N- (4- (trifluoromethyl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide (N- (4- (trifluoromethyl ) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);

(14) N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide (N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);

(15) 1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) Ethanone (1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone);

(16) 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) ethanone ( 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone);

(17) Prop-2-ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Prop-2 -ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(18) N- (3-hydroxy-adamantane-1-yl) -2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamide (N- (3 -hydroxy-adamantan-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);

(19) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) benzoate );

(20) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido 4-hydroxybenzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate);

(21) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate (Methyl 3- (2 -(4-adamantan-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate);

(22) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate (Methyl 3 -(2- (4-adamantan-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate);

(23) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate (Methyl 3- (2- (4 -adamantan-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate);

(24) Methyl 4-methoxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-methoxy-3- ( 2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(25) Methyl 4- (2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4 -(2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(26) Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(27) Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(28) Methyl 4- (4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4 -(4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

(29) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) -2-methylpropaneamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy ) -2-methylpropanamido) benzoate);

(30) Methyl 3- (2-methyl-2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (2-methyl-2 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(31) Methyl-4-hydroxy-3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy -3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(32) Methyl 3- [4- (4-adamantane-1-yl-phenoxy) butanamido] benzoate (Methyl 3- [4- (4-adamantan-1-yl-phenoxy) butanamido] benzoate );

(33) Methyl 3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 3- (4- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate);

(34) Methyl 4-hydroxy-3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 4-hydroxy-3- ( 4- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate);

(35) (E) -3- [3- (4-adamantane-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester ((E) -3- [3- (4- Adamantan-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester);

(36) (E) -3- {3- [4- (2,4,4-trimethylpentan-2-yl) phenoxy] acrylamido} benzoic acid methyl ester ((E) -3- {3 -[4- (2,4,4-Trimethylpentan-2-yl) phenoxy] acrylamido} benzoic acid methyl ester);

(37) (E) -methyl4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 4 -methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

(38) (E) -methyl2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2 -methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

(39) (E) -methyl2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

(40) (E) -isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -isopropyl 3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

(41) (E) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

(42) (E) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy Acrylate ((E) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy ) acrylate);

(43) (E) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate ((E) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate);

(44) (E) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

(45) Methyl 3- [3- (4-adamantane-1-yl-phenoxy) propanamido] benzoate (Methyl 3- (3- (4- (adamantan-1-yl) phenoxy) propanamido) benzoate);

(46) Methyl 3- (3- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (3- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(47) Methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy-3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(48) methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(49) Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(50) Methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-hydroxy-5- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(51) Isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Isopropyl 3- (3- (4- (2,4 , 4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

(52) methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) nicotinate; (Methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) nicotinate)

(53) N- (3- (morpholin-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamide (N- (3- (Morpholine-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamide);

(54) ethyl 2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) acetate (Ethyl 2- (3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) acetate); or

(55) (S) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) butano Ate ((S) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) butanoate).

As used herein, the term "pharmaceutically acceptable" is suitable for use in contact with the tissues of a subject (eg, a human being) because the benefit / risk ratio is reasonable without excessive toxicity, irritation, allergic reactions or other problems or complications. A compound or composition is within the scope of sound medical judgment.

As used herein, the term "salt" is useful for acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.

The acid addition salt according to the present invention is dissolved in a conventional method, for example, the compound represented by Formula 1 of the present invention in an excess of an aqueous acid solution, and the salt is mixed with a water miscible organic solvent such as methanol, ethanol, It can be prepared by precipitation with acetone or acetonitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).

In one embodiment of the present invention to prepare a compound according to the formula (1) of the present invention was analyzed and confirmed the structure by NMR or Mass spectrum (see Example 1).

In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. .

In addition, the composition of the present invention includes a pharmaceutical and nutraceutical composition.

As used herein, the term "prevention" means any action that inhibits cancer or delays the onset by administration of a pharmaceutical composition according to the invention.

As used herein, the term "treatment" means any action that improves or beneficially alters the symptoms of cancer by administration of a pharmaceutical composition according to the present invention.

"Cancer", a disease to be prevented and treated by the composition of the present invention, is classified into a disease in which normal tissue cells proliferate unlimitedly for any cause and continue to develop rapidly regardless of the living phenomenon of the living body or the surrounding tissue state. Cancer "includes, but is not limited to, dysplasia, hyperplasia, solid tumors, and hematopoietic stem cell cancer, and includes various cancer types known in the art. Other cancers may include, but are not limited to, cancers of the following organs or organs: brain, heart, lung, stomach, large intestine, genitourinary tract, liver, bone, nervous system, gynecology, blood, skin, breast and adrenal gland. It doesn't work. Other types of cancer cells include glioma (Schwannoma, glioblastoma, astrocytoma), neuroblastoma, pheochromocytoma, adrenal ganglia, meningioma, adrenal cortex, medulloblastoma, rhabdomyosarcoma, kidney cancer, various types of cancer Vascular cancer, osteoblastic osteocarcinoma, prostate cancer, ovarian cancer, uterine myoma, salivary gland cancer, choroid plexus cancer, breast cancer, pancreatic cancer, colon cancer, colon cancer and megakaryocyte leukemia; And sarcomas, such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, hemangioma, cutaneous fibroma, keloid, fibrosarcoma or angiosarcoma, and melanoma Includes skin cancer, including.

In addition, the cancer of the present invention may be a disease due to overexpression of MDH1 and / or MDH2. More specifically, MDH1 or MDH2 of the present invention are isoenzymes produced by different MDH genes, where MDH is present in the cytoplasm and mitochondrial matrix. More specifically, MDH1 and MDH2 reversibly serve to convert malate and oxaloacetate (OAA) using a NAD / NADH cofactor system. MDH1 in the cytoplasm oxidizes NADH to NAD ⁺ by reducing oxalic acid to malic acid. In the malic acid-asphalic acid shuttle, malic acid is transported into the mitochondria and oxidized back to oxalic acid by mitochondrial MDH2 to produce NADH. The generated NADH generates ATP through an electron transport system. In addition, MDH2 involved in the TCA cycle is involved in ATP production through respiration.

Therefore, the composition of the present invention can inhibit the activity of MDH1 (malate dehydrogenases 1) and / or MDH2 (malate dehydrogenases 2), and in particular can inhibit the activity of MDH1 and MDH2 simultaneously.

As used herein, the term "inhibition" means inhibiting any step of transcription, mRNA processing, translation, translocation, and maturation of a gene, or inhibition of protein-to-protein binding, activation of a protein, or signaling through it. .

In one embodiment of the present invention, the inhibitory activity of MDH1 and MDH2 by the compound treatment synthesized according to the preparation method of the present invention was confirmed (see Experimental Example 1). In addition, MDH inhibition mechanism was confirmed using the compound of the present invention (see Experimental Example 2), HIF-1α inhibitory activity was confirmed using the compound of the present invention (see Experimental Example 3), and mitochondria in cancer cells. The respiratory inhibitory effect was confirmed (see Experimental Example 4), and cancer cell transplantation mouse model was used to specifically confirm the effect of reducing tumor weight and size (see Experimental Example 5) as a pharmaceutical composition for cancer prevention or treatment. It was confirmed that it can be used very usefully.

Therefore, the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof according to the present invention may be usefully used as a pharmaceutical composition for preventing, ameliorating or treating cancer including the same as an active ingredient.

The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. At this time, the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , Polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like. In addition to the above components, it may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.

The pharmaceutical compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, Depending on the extent, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level refers to the type of disease, the severity, the activity of the drug, It may be determined according to the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the drug used concurrently and other factors well known in the medical field. The pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, the drug used in general 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day. However, since the dose may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention by any method.

The present invention also provides a method for preventing, controlling or treating cancer comprising administering the pharmaceutical composition to a subject. As used herein, "individual" means a subject in need of treatment for a disease, and more specifically, a mammal, such as a primate, mouse, dog, cat, horse and cow, which is human or non-human. .

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.

EXAMPLE

Example  One. MDH1  And MDH2  Synthesis of Compounds with Inhibitory Activity

As the MDH inhibitor according to the present invention, examples of the non-limiting compound used as an active ingredient of the pharmaceutical composition include the following compounds, isomers thereof and pharmaceutically acceptable salts thereof. The reactants and / or starting materials of known methods were appropriately modified to synthesize the following compounds according to the present invention.

First, the synthesis process of the following compounds according to the present invention is as described in Figure 1, the reagents and conditions used in each process is described below.

Reagents and conditions: a) (i) K ₂ CO ₃ , methyl-4-bromobutanoate or methyl-2-bromo-2-methylpropanoate (Methyl 2-bromo-2 -methylpropanoate), DMF; (ii) LiOH, THF / H ₂ O; b) EDC.HCl, HOBT, DIPEA, DMF, NH ₂ -R ₂ ; c) PPh ₃ , Methylpropiolate, Toluene; d, g) LiOH, THF / H ₂ O; e) EDC.HCl, HOBT, DIPEA, DMF, NH ₂ -R _{2 or} HATU, DIPEA, DMF, NH ₂ -R ₂ ; f) Pd / C, H ₂ , MeOH; h) EDC.HCl, HOBT, DIPEA, DMF, NH ₂ -R _{2 or} HATU, DIPEA, DMF / THF, NH ₂ -R _{2 or} i) CDI, THF; ii) NH ₂ -R ₂ , imidazole, THF.

In addition, specific synthetic procedures of the compounds obtained as MDH inhibitors according to the present invention and their yields and NMR measurement results are described below.

1-1. Synthesis of Compound 3-1 to Compound 3-34

Compounds 3-1 to 3-34 were synthesized through Compound 2 as an intermediate as Compound 1 as a starting material, as shown in FIG.

First, the synthesis process of compound 2 is as follows.

Synthesis process of compound 2: compound 1 (1.0 equiv), anhydrous potassium carbonate (2.0 equiv) and methyl 4-bromobutanoate or methyl alpha-bromoisobutyrate A mixture of (methyl α-bromoisobutyrate) (2.0 equiv) was stirred overnight at room temperature in DMF. The reaction mixture was diluted with EtOAc and then washed with aqueous sodium bicarbonate, brine and water. The organic layer was collected and water was removed with anhydrous magnesium sulfate (anhydrous MgSO ₄ ). The solvent was filtered and evaporated under reduced pressure so that the crude dry matter purified by silica gel column chromatography became an ester compound. An ester compound suspension (1.0 equiv) in THF / H ₂ O (1: 1) was added to lithium hydroxide monohydrate (3.0 equiv) and stirred overnight at room temperature. The reaction mixture was neutralized with 10% HCl, diluted with EtOAc and subsequently washed with water soluble sodium bicarbonatenet, brine and water. The organic layer was collected and water was removed with anhydrous magnesium sulfate (anhydrous MgSO ₄ ). The solvent was filtered and evaporated under reduced pressure to give a crude dried product which was purified by silica gel column chromatography.

Compound 3-1. : Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate (Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate)

2- (4-nitrophenoxy) acetic acid (1.0 equiv), and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF (dimethylformamide) and EDCHCl ( N- (3-dimethylaminopropyl) -N `-ethylcarbonate hydrochloride) (1.2 equiv), HOBT (1-hydroxybenzotriazole) (1.2 equiv) and DIPEA ( N, N- diisopropylethylamine) (2.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate (white solid, 0.21 g, 64.2% yield).

¹ H-NMR (400 MHz, DMSO) δ 10.5 (brs, 1H), 8.33 (t, J = 1.8 Hz, 1H), 8.25 (d, J = 9.4 Hz, 2H), 7.89 (m, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 9.0 Hz, 2H), 4.95 (s, 2H), 3.86 (s, 3H); ¹³ C-NMR (100 MHz, DMSO) δ 166.4, 163.5, 141.7, 139.1, 130.6, 129.7, 126.3, 124.8, 124.5, 120.5, 115.7, 67.6, 52.7; HRMS [M + H] calcd [ C 16 H 15 N 2 O 6]: 329.0852, Found: 329.0676; Purity 97.3% (as determined by RP-HPLC, method A, tR = 14.62 min).

Compound 3-2. : Methyl 3- (2- (4-trifluoromethyl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (trifluoromethyl) phenoxy) acetamido) benzoate)

2- (4- (trifluoromethyl) phenoxy) acetic acid (1.0 equiv), and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) )). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4-trifluoromethyl) phenoxy) acetamido) benzoate (white solid, 0.01 g, 40.8% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 4.68 (s, 2H), 3.93 (s, 3H), 1.62 (s, 2 H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.5, 159.1, 136.8, 131.0, 129.4, 127.5, 127.4, 127.4, 126.1, 124.6, 120.9, 114.9, 67.4, 52.3; HRMS [M + H] calcd [C ₁₇ H ₁₅ F ₃ NO ₄ ]: 354.0875, found: 354.0929; Purity 99.9% (as determined by RP-HPLC, method A, tR = 17.70 min).

Compound 3-3. : Methyl 3- (2- (4- tert -Butylphenoxy) acetamido) benzoate (Methyl 3- (2- (4- tert -butylphenoxy) acetamido) benzoate)

The 2- (4- tert -butylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) to a mixture of DMF in this EDC · HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) Added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4- tert -butylphenoxy) acetamido) benzoate (white solid, 0.11 g, 61.3% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 12.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 4.61 (s, 2H), 3.92 (s, 3H), 1.31 (s, 9 H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.7,166.6, 154.8, 145.5, 137.1, 131.1, 129.3, 126.8, 125.9, 124.5, 120.9, 114.4, 67.8, 52.3, 34.2, 31.5; HRMS [M + H] calcd [C ₂₀ H ₂₄ NO ₄ ]: 342.1705, Found: 342.1705; Purity 100% (as determined by RP-HPLC, method A, tR = 18.66 min).

Compound 3-4. Methyl 3- (2- ( p -Tolyoxy) acetamido) benzoate (Methyl 3- (2- ( p -tolyloxy) acetamido) benzoate)

2- ( p -tolyloxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and added to EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- ( p -tolyloxy) acetamido) benzoate (white solid, 0.10 g, 40.4% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.51 (s, 1H), 8.09 (t, J = 8.0 Hz, 1H), 7.99 (m, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.2 Hz, 2H), 6.87 (m, 2H), 4.56 (s, 2H), 3.89 (s, 3H), 2.29 (s, 3H ); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.7, 166.5, 154.9, 137.2, 131.8, 130.9, 130.3, 129.2, 125.8, 124.5, 120.9, 114.6, 67.7, 52.3, 20.5; HRMS [M + H] calcd [C ₁₇ H ₁₈ NO ₄ ]: 300.1158, Found: 300.1232; Purity 100% (as determined by RP-HPLC, method A, tR = 16.29 min).

Compound 3-5. Methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate)

2- (4-ethylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and added to EDC.HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate (white solid, 0.34 g, 97.2% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.48 (brs, 1H), 8.00 (m, 1H), 7.81 (m, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.91 (m, 2H), 4.59 (s, 2H), 3.90 (s, 3H), 2.61 (q, J = 7.4 Hz, 2H), 1.23 (m, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.7, 166.5, 155.0, 138.3, 137.1, 13.9, 129.2, 129.1, 125.8, 124.5, 120.9, 114.7, 67.7, 52.2, 28.0, 15.8; HRMS [M + H] calcd [ C 18 H 20 NO 4]: 314.1314, Found: 314.1379; Purity 100% (as determined by RP-HPLC, method A, tR = 18.06 min).

Compound 3-6. Methyl 3- (2- (4-propylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-propylphenoxy) acetamido) benzoate)

2- (4-propylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and added to EDC.HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-propylphenoxy) acetamido) benzoate (white solid, 0.31 g, 90.5% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.46 (brs, 1H), 8.09 (t, J = 1.8 Hz, 1H), 8.00 (dd, J = 8.2 Hz, 1H), 7.82 (dd, J = 7.8 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.6 Hz, 2H), 6.90 (m, 2H), 4.59 (s, 2H), 3.91 (s, 3H), 2.54 (m, 2H), 1.61 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.7, 166.6, 155.0, 137.1, 136.8, 131.0, 129.7, 129.2, 125.8, 124.5, 120.9, 114.6, 67.7, 52.3, 37.1, 24.7, 13.7; HRMS [M + H] calcd [C ₁₉ H ₂₂ NO ₄ ]: 328.2471, Found: 328.1546; Purity 100% (as determined by RP-HPLC, method A, tR = 19.92 min).

Compound 3-7. : Methyl 3- (2- (4-butylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-Butylphenoxy) acetamido) benzoate)

2- (4-butylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and added to EDC.HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO 4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-butyl phenoxy) acetamido) benzoate (white solid, 0.32 g, 98.4% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.52 (brs, 1H), 8.10 (s, 1H), 7.99 (dd, J = 8.2, 1.2 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H ), 7.40 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.57 (s, 2H), 3.89 (s, 3H ), 2.56 (t, J = 7.6 Hz, 2H), 1.56 (m, 2H), 1.34 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.8, 166.5, 155.0, 137.2, 137.0, 130.9, 129.6, 129.2, 125.8, 124.5, 120.9, 114.6, 67.7, 52.2, 34.7, 33.8, 22.3, 14.0; HRMS [M + H] calcd [ C 20 H 24 NO 4] 342.1627, found 342.1694; Purity 100% (as determined by RP-HPLC, method A, tR = 21.59 min).

Compound 3-8. : Methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate)

2- (4-pentylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and added to EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate (yellow solid, 0.13 g, 81.2% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 12.0 Hz , 1H), 7.15 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 4.60 (s, 2H), 3.92 (s, 3H), 2.56 (t, J = 8.0 Hz, 2H), 1.61-1.57 (m, 2H), 1.34-1.29 (m, 4H), 0.89 (t, J = 4.0 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.7, 166.6, 155.0, 137.2, 137.1, 131.1, 129.7, 129.3, 125.9, 124.5, 120.9, 114.7,67.8, 52.3, 35.0, 31.4, 31.3, 22.5, 14.0; HRMS [M + H] calcd [C ₂₁ H ₂₆ NO ₄ ]: 356.1862, Found: 356.1862; Purity 100% (as determined by RP-HPLC, method A, tR = 23.53 min).

Compound 3-9. : Methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate)

2- (4-cyclopentylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and added to EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate (yellow solid, 0.10 g, 62.5% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 12.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 4.61 (s, 2H), 3.93 (s, 3H), 2.98-2.94 (m, 1H), 2.06-2.05 (m, 2H), 1.82-1.77 (m, 2H), 1.70-1.67 (m, 2H), 1.57-1.52 (m, 4H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.7, 166.6, 155.1, 140.8, 137.1, 131.1, 129.3, 128.4, 125.9, 124.5, 120.9, 114.7, 67.9, 52.3, 45.2, 34.7, 25.4; HRMS [M + H] calcd [C ₂₁ H ₂₄ NO ₄ ]: 354.1705, Found: 354.1705; Purity 100% (as determined by RP-HPLC, method A, tR = 22.03 min).

Compound 3-10. : Methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate)

2- (4-cyclohexylphenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed in DMF and added to EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). . The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate (yellow solid, 0.11 g, 70.5% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 8.07 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 12.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 4.60 (s, 2H), 3.92 (s, 3H), 2.50-2.46 (m, 1H), 1.84-1.76 (m, 4H), 1.73-1.58 (m, 2H), 1.44 (m, 4H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.7, 166.6, 155.1, 142.4, 137.1, 131.1, 129.3, 128.1, 125.9, 124.5, 120.9, 114.7, 67.8, 52.3, 43.3, 34.6, 26.9, 26.1; HRMS [M + H] calcd [C ₂₂ H ₂₆ NO ₄ ]: 368.1862, Found: 368.1862; Purity 100% (as determined by RP-HPLC, method A, tR = 23.62 min).

Compound 3-11. : Methyl 3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (2,4,4) -trimethylpentan-2-yl) phenoxy) acetamido) benzoate)

2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (white solid, 0.10 g, 64.1% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 8.08 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.44-7.32 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 4.60 (s, 2H), 3.91 (s, 3H) 1.71 (s, 2H), 1.35 (s, 6H), 0.71 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.7, 166.6, 154.6, 144.3, 137.1, 131.0, 129.3, 127.5, 125.8, 124.5, 120.9, 114.0, 67.6, 56.9, 52.3, 30.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C ₂₄ H ₃₂ NO ₄ ]: 398.2331, Found: 398.2331; Purity 100% (as determined by RP-HPLC, method A, tR = 26.11 min).

Compound 3-12. : Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)

2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and methyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (White solid, 1.00 g, 64.1% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.75 (s, 1H), 8.60 (s, 1H), 7.85-7.83 (m, 1H), 7.73 (s, 1H), 7.38-7.34 (m, 2H) , 7.06 (d, J = 8.0 Hz, 1H), 6.94-6.90 (m, 2H), 4.68 (s, 2H), 3.89 (s, 3H), 1.73 (s, 2H), 1.36 (s, 6H), 0.72 (s, 9 H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.2, 166.7, 154.5, 147.2, 144.6, 129.2, 128.0, 127.6, 122.3, 121.3, 119.5, 114.2, 67.5, 57.0, 52.3, 38.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C ₂₄ H ₃₂ NO ₅ ]: 414.2280, Found: 414.2280; Purity 100% (as determined by RP-HPLC, method A, tR = 24.95 min).

Compound 3-13. : N -(4- (trifluoromethyl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide ( N -(4- (trifluoromethyl) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide)

2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and 4- (trifluoromethyl) aniline (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv). , HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain N- (4- (trifluoromethyl) phenyl) -2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamide. Obtained (white solid, 0.11 g, 71.5% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 6.4 Hz, 2H), 6.91 (d, J = 6.8 Hz, 2H), 4.62 (s, 2H), 1.72 (s, 2H), 1.36 (s, 6H), 0.71 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.8, 154.5, 144.5, 139.9, 127.6, 126.8, 126.4, 126.3, 120.0, 114.1, 67.6, 56.9, 38.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C ₂₃ H ₂₉ F ₃ NO ₂ ]: 408.2150, Found: 408.2150; Purity 100% (as determined by RP-HPLC, method A, tR = 28.40 min).

Compound 3-14. : N -(4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamide ( N -(4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide)

2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and 4- (4-methylpiperazin-1-yl) aniline (1.0 equiv) were mixed with DMF and EDC HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy Acetamide was obtained (white solid, 0.12 g, 72.7% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.17 (s, 1H), 7.45 (d, J = 9.2 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 6.92-6.88 (m, 4H ), 4.58 (s, 2H), 3.25-3.23 (m, 4H), 2.68-2.67 (m, 4H), 2.42 (s, 3H), 1.71 (s, 2H), 1.31 (s, 6H), 0.71 ( s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.2, 154.7, 148.7, 144.1, 129.2, 127.5, 121.6, 116.6, 114.0, 67.7, 57.0, 55.1, 49.4, 46.1, 38.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C ₂₇ H ₄₀ N ₃ 0 ₂ ]: 438.3121, Found: 438.3121; Purity 100% (as determined by RP-HPLC, method A, tR = 12.56 min).

Compound 3-15. : 1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) ethanone (1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone)

2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and 1- (4- (trifluoromethyl) benzyl) piperazine (1.0 equiv) were mixed with DMF and mixed with EDC. HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane- 2-yl) phenoxy) ethanone was obtained (white solid, 0.15 g, 81.0% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.58 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.6 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.85 ( d, J = 8.8 Hz, 2H ), 4.66 (s, 2H), 3.63-3.59 (m, 4H), 3.56 (s, 2H), 2.40-2.39 (m, 4H), 1.70 (s, 2H), 1.38 (s, 6H), 0.71 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.6, 155.4, 143.2, 142.0, 129.4, 129.1, 127.2, 125.3, 125.2, 113.8, 67.9, 62.2, 57.0, 53.2, 52.7, 45.4, 42.1, 38.0, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C ₂₈ H ₃₈ F ₃ N ₂ O ₂ ]: 491.2885, Found: 491.2885; Purity 100% (as determined by RP-HPLC, method A, t R = 14.31 min).

Compound 3-16. : 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) ethanone (1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone)

2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and 1- (prop-2-ynyl) piperazine (1.0 equiv) were mixed with DMF and EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl Phenoxy) ethanone was obtained (white solid, 0.11 g, 78.5% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.30 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 4.67 (s, 2H), 3.68-3.63 (m, 4H ), 3.29 (t, J = 4.0 Hz, 2H), 2.56-2.51 (m, 4H), 2.25 (t, J = 4.0 Hz, 1H), 1.69 (s, 2H), 1.33 (s, 6H), 0.70 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.6, 155.4, 143.3, 127.2, 113.8, 78.1, 73.6, 67.9, 57.0, 51.9, 51.6, 46.8, 45.2, 41.9, 38.0, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C ₂₃ H ₃₅ N ₂ O ₂ ]: 371.2699, Found: 371.2699; Purity 100% (as determined by RP-HPLC, method A, tR = 11.38 min).

Compound 3-17. : Prop-2-ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Prop-2-ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)

2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and prop-2-ynyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF and EDC HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give prop-2-ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido ) Benzoate was obtained (white solid, 0.10 g, 60.6% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.84 (s, 1H), 8.63 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 4.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 4.91 (d, J = 4.0 Hz, 2H), 4.69 ( s, 2H), 2.51 (t, J = 4.0 Hz, 1H), 1.72 (s, 2H), 1.36 (s, 6H), 0.72 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.0, 164.9, 154.2, 153.7, 144.8, 129.6, 127.7, 124.6, 124.5, 121.6, 120.2, 114.1, 77.7, 75.1, 67.1, 56.9, 52.4, 38.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [ C 26 H 32 NO 5]: 438.2280, Found: 438.2280; Purity 100% (as determined by RP-HPLC, method A, tR = 24.56 min).

Compound 3-18. : N -(3-hydroxy-adamantane-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamide ( N -(3-hydroxy-adamantan-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide)

2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetic acid (1.0 equiv) and 3-hydroxy-adamantan-1-yl-amine (1.0 equiv) were mixed with DMF and mixed with EDC. HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain N- (3-hydroxy-adamantane-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) Acetamide was obtained (white solid, 0.12 g, 76.9% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.31 (d, J = 4.0 Hz, 2H), 6.81 (d, J = 12.0 Hz, 2H), 6.31 (s, 1H), 4.36 (s, 2H), 2.28 (s, 2H), 2.02 (s, 2H), 1.99 (s, 4H), 1.70 (s, 6H), 1.58 (s, 2H), 1.34 (s, 6H), 0.70 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 167.4, 154.7, 143.7, 127.4, 113.9, 69.0, 67.6, 57.0, 54.2, 48.9, 44.0, 40.2, 38.0, 34.8, 32.3, 31.7, 31.6, 30.6; HRMS [M + H] calcd [C ₂₆ H ₄₀ NO ₃ ]: 414.3008, Found: 414.3008; Purity 100% (as determined by RP-HPLC, method A, tR = 23.33 min).

Compound 3-19. : Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) benzoate)

(4-adamantan-1-yl-phenoxy) acetic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF, which was then mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). ) Was added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc (Ethyl Acetate) and washed with water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) benzoate (white solid, 0.12 g, 82.2% yield) .

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 8.07 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 4.61 (s, 2H), 3.92 (s, 3H), 2.09 (brs, 3 H), 1.82-1.81 (m, 6 H), 1.77-1.72 (m, 6 H); ^{13 C-NMR (100 MHz,} CDCl 3) δ 166.7, 166.6, 154.8, 145.8, 137.1, 131.1, 129.3, 126.3, 125.9, 124.5, 120.9, 114.4, 67.8, 52.3, 43.3, 36.8, 35.7, 29.0; HRMS [M + H] calcd [C ₂₆ H ₃₀ NO ₄ ]: 420.2175, Found: 420.2175; Purity 100% (as determined by RP-HPLC, method A, tR = 26.99 min).

Compound 3-20. : Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido 4-hydroxybenzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate)

2- (4- (adamantan-1-yl) phenoxy) acetic acid (1.0 equiv) and methyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc (Ethyl Acetate) and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido 4-hydroxybenzoate.

¹ H-NMR (300 MHz, DMSO) δ 11.10 (s, 1H), 9.24 (s, 1H), 8.69 (m, 1H), 7.60-7.64 (m, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.94-6.99 (m, 3H), 4.74 (s, 2H), 3.79 (s, 3H), 2.04 (m, 3H), 1.83 (m, 6H), 1.72 (m, 6H); MS (ESI) m / z 434 (M ⁻ H) ⁻ ; HRMS (ESI) m / z calcd for C ₂₆ H ₂₉ O ₅ NNa [(M + Na) ⁺ ] 458.1943, found: 458.1942.

Compound 3-21. : Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate (Methyl 3- (2- ( 4-adamantan-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate)

Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and ethyl chloroacetate (2.0 equiv) are mixed in DMF and at room temperature After stirring overnight, the mixture was concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with sodium bicarbonate, water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzo Obtain was obtained (white solid, 0.09 g, 75.0% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 9.06 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H), 4.71 (s, 2H), 4.64 (s, 2H), 4.28 (q, J = 8.0 Hz, 2H), 3.90 (s, 3H), 2.09 (brs, 3H), 1.89-1.88 (m, 6H), 1.77-1.75 (m, 6H), 1.28 (t, J = 12.0 Hz, 3H); ^{13 C-NMR (100 MHz,} CDCl 3) δ 166.7, 166.7, 155.0, 150.3, 145.4, 127.3, 126.6, 126.1, 124.4, 121.7, 114.5, 111.3, 67.8, 66.2, 61.8, 52.1, 43.3, 36.7, 35.7, 28.9, 14.2; HRMS [M + H] calcd [C ₃₀ H ₃₆ NO ₇ ]: 522.2492, Found: 522.2492; Purity> 96.0% (as determined by RP-HPLC, method A, tR = 28.66 min).

Compound 3-22. : Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate (Methyl 3- ( 2- (4-adamantan-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate)

Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and 1- (2-chloroethyl) pyrrolidine (2.0 equiv) The mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with sodium bicarbonate, water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) Oxy) benzoate was obtained (white solid, 0.09 g, 75.0% yield).

^{1 H-NMR (400 MHz,} CDCl 3) δ 9.06 (s, 1H), 9.02 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.95-6.91 (m, 3H), 4.62 (s, 2H), 4.22 (t, J = 4.0 Hz, 2H), 3.89 (s, 3H), 2.92 (t, J = 4.0 Hz, 2H), 2.64-2.62 (m, 4H), 2.09 (brs, 3H), 1.89-1.88 (m, 6H), 1.77-1.72 (m, 10H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 114.4, 110.6, 68.3, 68.0, 54.8, 54.7, 52.0, 43.4, 36.7, 35.7, 28.9, 23.6; HRMS [M + H] calcd [C ₃₂ H ₄₁ N ₂ O ₅ ]: 533.3015, Found: 533.3015; Purity 100% (as determined by RP-HPLC, method A, tR = 13.39 min).

Compound 3-23. : Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate (Methyl 3- (2- (4-adamantan -1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate)

Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and 4- (3-chloropropyl) morpholine (2.0 equiv) The mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with sodium bicarbonate, water and brine. The organic layers were combined, dried over anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate. (White solid, 0.09 g, 69.7% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.05 (s, 1H), 9.04 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.94-6.92 (m, 3H), 4.62 (s, 2H), 4.16 (t, J = 4.0 Hz, 2H), 3.90 (s, 3H), 3.69-3.68 (m, 4H), 2.53 (t, J = 4.0 Hz, 2H), 2.42-2.40 (m, 4H), 2.09 (brs, 3H), 2.02 (t, J = 4.0 Hz, 2H), 1.89-1.88 (m, 6H), 1.77-1.72 (m, 6H ); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.8, 166.3, 154.9, 151.1, 145.7, 126.7, 126.5, 126.3, 123.0, 120.9, 114.4, 110.3, 68.0, 66.9, 55.2, 53.7, 52.0, 43.4, 36.7, 35.7, 28.9; HRMS [M + H] calcd [C ₃₃ H ₄₃ N ₂ O ₆ ]: 563.3121, Found: 563.3121; Purity 100% (as determined by RP-HPLC, method A, tR = 13.38 min).

Compound 3-24. : Methyl 4-methoxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-methoxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)

Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and methyl iodide (2.0 equiv) The mixture was mixed with DMF and stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc, washed with sodium bicarbonate, water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4-methoxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (White solid, 0.08 g, 77.6% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.03 (s, 1H), 8.97 (s, 1H), 7.85-7.83 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.93-6.90 (m, 3H), 4.63 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.71 (s, 2H), 1.35 (s, 6H), 0.71 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.7, 166.5, 154.8, 151.9, 144.1, 127.5, 126.8, 126.5, 123.1, 121.1, 114.1, 109.6, 67.9, 56.9, 56.1, 52.0, 38.1, 32.3, 31.8, 31.7; HRMS [M + H] calcd [C ₂₅ H ₃₄ NO ₅ ]: 428.2437, Found: 428.2437; Purity 100% (as determined by RP-HPLC, method A, tR = 27.91 min).

Compound 3-25. : Methyl 4- (2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4- ( 2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)

Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and 1-chloro-2- The methoxyethane (2.0 equiv) was mixed with DMF, stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc, washed with sodium bicarbonate, water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 4- (2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetami Benzoate was obtained (white solid, 0.10 g, 87.7% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.15 (s, 1H), 9.06 (s, 1H), 7.83-7.80 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.94-6.90 (m, 3H), 4.62 (s, 2H), 4.23 (t, J = 4.0 Hz, 2H), 3.89 (s, 3H), 3.78 (t, J = 4.0 Hz, 2H), 3.44 (s, 3H) , 1.71 (s, 2 H), 1.34 (s, 6 H), 0.70 (s, 9 H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.7, 166.4, 154.8, 151.0, 144.0, 127.4, 126.9, 126.6, 123.4, 121.0, 114.0, 110.7, 70.7, 68.4, 67.0, 59.2, 57.0, 52.0, 38.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C ₂₇ H ₃₈ NO ₆ ]: 472.2699, Found: 472.2699; Purity 100% (as determined by RP-HPLC, method A, tR = 27.57 min).

Compound 3-26. : Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)

Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and 4- (2-chloroethyl ) morpholine (2.0 equiv) was mixed with DMF, stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc, washed with sodium bicarbonate, water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetate. Amido) benzoate was obtained (white solid, 0.09 g, 70.8% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.06 (s, 1H), 9.04 (s, 1H), 7.84-7.81 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.93-6.88 (m, 3H), 4.62 (s, 2H), 4.21 (t, J = 4.0 Hz, 2H), 3.90 (s, 3H), 3.69-3.66 (m, 4H), 2.83 (t, J = 4.0 Hz, 2H), 2.56-2.54 (m, 4H), 1.71 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.7, 166.4, 154.8, 151.0, 144.3, 127.5, 126.7, 123.3, 121.1, 114.1, 110.6, 68.1, 66.9, 66.8, 57.5, 56.9, 54.0, 52.1, 38.1, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C ₃₀ H ₄₃ N ₂ O ₆ ]: 527.3121, Found: 527.3121; Purity 100% (as determined by RP-HPLC, method A, tR = 12.9 min).

Compound 3-27. : Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)

Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and propargyl bromide (2.0 equiv) The mixture was mixed with DMF and stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc, washed with sodium bicarbonate, water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetate. Amido) benzoate was obtained (white solid, 0.10 g, 91.7% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.06 (s, 1H), 9.02 (s, 1H), 7.85-7.83 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.04 (d , J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 4.81 (s, 2H), 4.63 (s, 2H), 3.90 (s, 3H), 2.60 (t, J = 4.0 Hz , 2H), 1.71 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.6, 166.4, 154.8, 149.8, 144.1, 127.4, 127.0, 126.5, 124.1, 121.4, 114.1, 111.1, 67.8, 57.0, 56.8, 52.1, 38.1, 32.3, 31.9, 31.8, 31.6; HRMS [M + H] calcd [C ₂₇ H ₃₄ NO ₅ ]: 452.2437, Found: 452.2437; Purity 100% (as determined by RP-HPLC, method A, tR = 27.33 min).

Compound 3-28. : Methyl 4- (4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamido) benzoate (Methyl 4- ( 4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate)

Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate (1.0 equiv), anhydrous potassium carbonate (3.0 equiv) and p -methoxy benzyl chloride ( 2.0 equiv) was mixed with DMF, stirred at room temperature overnight, concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with sodium bicarbonate, water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 4- (4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetami Benzoate was obtained (white solid, 0.11 g, 85.2% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.20 (s, 1H), 9.09 (s, 1H), 7.86-7.83 (m, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.21 (d , J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 8.0 Hz, 2H), 5.08 (s, 2H ), 4.54 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 1.71 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 166.8, 166.2, 160.0, 154.6, 151.0, 143.9, 129.9, 129.8, 127.6, 127.2, 126.9, 126.6, 123.3, 120.6, 114.3, 113.9, 110.6, 70.9, 67.5, 57.0, 55.3, 52.0, 38.0, 32.3, 31.8, 31.6; HRMS [M + H] calcd [C ₃₂ H ₄₀ NO ₆ ]: 534.2856, Found: 534.2856; Purity 100% (as determined by RP-HPLC, method A, tR = 30.37 min).

Compound 3-29. : Methyl 3- (2- (4-adamantane-1-yl-phenoxy) -2-methylpropaneamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy)- 2-methylpropanamido) benzoate)

2- (4-adamantan-1-yl-phenoxy) -2-methylpropanoic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv) and HOBT (1.2 equiv). And DIPEA (2.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (2- (4-adamantane-1-yl-phenoxy) -2-methylpropaneamido) benzoate (white solid, 0.12 g, 84.5% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.74 (s, 1H) 8.14 (t, J = 2.0 Hz, 1H), 7.95-7.92 (m, 1H), 7.82-7.79 (m, 1H), 7.43 ( t, J = 8.0 Hz, 1H), 7.27 (d, J = 9.2 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 3.91 (s, 3H), 2.09 (brs, 3H), 1.88- 1.86 (m, 6H), 1.76-1.74 (m, 6H), 1.57 (s, 6H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 173.5, 166.7, 151.3, 147.2, 137.8, 131.0, 129.2, 125.8, 125.4, 124.1, 121.5, 120.6, 81.8, 52.2, 43.3, 36.7, 35.8, 28.9, 25.0; HRMS (EI) m / z [M + H] calcd [C ₂₈ H ₃₄ NO]: 4448.2488, found: 448.2488; Purity 100% (as determined by RP-HPLC, method A, tR = 29.60 min).

Compound 3-30. : Methyl 3- (2-methyl-2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (2-methyl-2- ( 4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate)

2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (2-methyl-2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate. (White solid, 0.11 g, 75.8% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.79 (s, 1H), 8.14 (t, J = 2.0 Hz, 1H), 7.96-7.93 (m, 1H), 7.82-7.80 (m, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H), 3.91 (s, 3H), 1.71 (s, 2H), 1.55 (s, 6H), 1.35 (s, 6H), 0.70 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 173.4, 166.6, 151.1, 145.8, 137.8, 130.9, 129.1, 127.1, 125.4, 124.1, 121.4, 120.7, 81.8, 57.1, 52.1, 38.1, 32.3, 31.7, 31.6, 24.9; HRMS (EI) m / z [M + H] calcd [C ₂₆ H ₃₆ NO ₄ ]: 426.2644, found: 426.2644; Purity 100% (as determined by RP-HPLC, method A, tR = 28.88 min).

Compound 3-31. : Methyl-4-hydroxy-3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy-3 -(2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate)

2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF and EDC HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to prepare methyl-4-hydroxy-3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) Obtained benzoate (white solid, 0.03 g, 83.2% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.1 (s, 1H), 9.09 (s, 1H), 7.82 (dd, J = 8.6 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 3.87 (s, 3H), 1.72 (s, 2H), 1.57 (s, 6H), 1.37 (s, 6H), 0.71 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 175.7, 166.3, 153.2, 150.5, 146.5, 128.9, 127.2, 124.9, 124.2, 122.2, 122.0, 119.7, 81.7, 57.1, 52.0, 38.2, 32.3, 31.7, 31.5, 24.9; HRMS [M + H] calcd [C ₂₆ H ₃₆ NO ₅ ]: 442.2515, Found: 442.2576; Purity 100% (as determined by RP-HPLC, method A, tR = 16.29 min).

Compound 3-32. : Methyl 3- [4- (4-adamantane-1-yl-phenoxy) butanamido] benzoate (Methyl 3- [4- (4-adamantan-1-yl-phenoxy) butanamido] benzoate)

4- (4- (adamantan-1-yl) phenoxy) butanoic acid (1.0 equiv), methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) was added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- [4- (4-adamantane-1-yl-phenoxy) butanamido] benzoate (white solid, 0.11 g, 77.5% yield). .

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.4 (d, J = 8.0 Hz, 2H), 7.28 (s, 1H), 6.86 (d, J = 8.8 Hz, 2H), 4.06 (t, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.60 (t, J = 7.2 Hz, 2H), 2.18-2.24 (m, 2H), 2.08 (brs, 3H), 1.88-1.86 (m, 6H), 1.76-1.74 (m, 6H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.9, 166.7, 156.4, 144.1, 138.1, 130.9, 129.2, 125.8, 125.3, 124.2, 120.6, 114.0, 66.8, 52.2, 43.4, 36.8, 35.6, 34.2, 30.9, 29.0, 25.1; HRMS (EI) m / z [M + H] calcd [C ₂₈ H ₃₃ NO ₄ ]: 448.2488, found: 448.2478; Purity 100% (as determined by RP-HPLC, method A, tR = 27.50 min).

Compound 3-33. : Methyl 3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butaneamido) benzoate (Methyl 3- (4- (4- (2,4,4) -trimethylpentan-2-yl) phenoxy) butanamido) benzoate)

4- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) butanoic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv) and HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- (4- (4- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) butanamido) benzoate (white solid, 0.12 g, 82.7% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 4.04 (t, J = 6.6 Hz, 4H), 3.91 ( s, 3H), 2.61 (t, J = 7.2 Hz, 2H), 2.26-2.19 (m, 2H), 1.70 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.5, 166.9, 156.3, 142.4, 138.4, 130.6, 129.0, 127.0, 125.1, 124.5, 120.8, 113.6, 66.8, 56.9, 52.2, 37.9, 34.0, 32.7, 31.7, 31.6, 25.1; HRMS (EI) m / z [M + H] calcd [C ₂₆ H ₃₆ NO ₄ ]: 426.2644, found: 426.2644; Purity 100% (as determined by RP-HPLC, method A, tR = 26.93 min).

Compound 3-34. : Methyl 4-hydroxy-3- (4- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 4-hydroxy-3- (4- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate)

4- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) butanoic acid (1.0 equiv) and methyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF and added to EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4-hydroxy-3- (4- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (White solid, 0.10 g, 66.2% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.80 (dd, J = 2.0, 6.4 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H), 4.06 (t, J = 5.6 Hz, 2H), 3.86 (s, 3H), 2.72 (t, J = 7.2 Hz, 6.8 Hz, 2H), 2.24-2.21 (m, 2H), 1.69 (s, 2H), 1.33 (s, 6H), 0.70 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 173.8, 166.8, 156.1, 153.4, 142.8, 128.7, 127.1, 125.8, 124.3, 121.9, 119.6, 113.6 66.7, 56.9, 52.2, 38.0, 33.6, 32.3, 31.8, 31.6 , 25.2; HRMS (EI) m / z [M + H] calcd [C ₂₆ H ₃₆ NO ₅ ]: 442.2593, found: 442.2593; Purity 100% (as determined by RP-HPLC, method A, tR = 25.63 min).

1-2. Synthesis of Compound 6-1 to Compound 6-9

Compounds 6-1 to 6-9 were synthesized through Compound 4 and Compound 5 as intermediates, using Compound 1 as a starting material as described in FIG.

First, the synthesis process of compound 4 and compound 5 is as follows.

Compound 4 Synthesis Process : A mixture in toluene of compound 1 (1.0 equiv) and methyl propiolate (2.0 equiv) was added to Ph ₃ P (1.0 equiiv) at −10 ^° C. The mixture was heated to 115 ^° C. and stirred for 2 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography.

Compound 5 Synthesis Process: A suspension of ester compound 4 (1.0 equiv) in THF / H ₂ O (1: 1) was added to lithium hydroxide monohydrate (3.0 equiv) and stirred overnight at room temperature. The reaction mixture was neutralized with 10% HCl, diluted with EtOA and washed successively with aqueous sodium bicarbonate, brine and water. The organic layer was collected and water was removed with anhydrous magnesium sulfate (anhydrous MgSO ₄ ). The solvent was filtered off, evaporated under reduced pressure and purified by silica gel column chromatography to give a crude dry matter.

Compound 6-1. : ( E ) -3- [3- (4-adamantane-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester (( E ) -3- [3- (4-Adamantan-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester)

( E ) -3- (4- (adamantan-1-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and added to EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( E ) -3- [3- (4-Adamantan-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester (white solid, 0.23 g, 88.5%). yield).

¹ H-NMR (CDCl ₃ , 300 MHz) δ 8.06 (s, 1H), 7.89-7.95 (m, 2H), 7.77 (d, J = 7.5 Hz, 1H), 7.33-7.42 (m, 3H), 7.02 ( d, J = 8.7 Hz, 2H), 5.68 (d, J = 11.7 Hz, 1H), 3.90 (s, 3H), 2.11 (m, 3H), 1.90 (m, 6H), 1.77 (m, 6H); HRMS (EI) m / z calcd for C ₂₇ H ₂₉ NO ₄ [M + H] 431. 2097, found: 431.2101.

Compound 6-2. :( E ) -3-3- [4- (2,4,4-trimethylpentan-2-yl) phenoxy] acrylamidobenzoic acid methyl ester (( E ) -3-3- [4- (2,4,4-Trimethylpentan-2-yl) phenoxy] acrylamidobenzoic acid methyl ester)

( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF to give EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( E ) -3-3- [4- (2,4,4-trimethylpentan-2-yl) phenoxy] acrylamidobenzoic acid methyl ester ( White solid, 0.07 g, 62.8% yield).

¹ H-NMR (DMSO, 300 MHz) δ 8.05 (m, 1H), 7.89-7.93 (m, 2H), 7.78 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H) , 7.37 (d, J = 8.4 Hz, 2H), 7.11 (s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 5.66 (d, J = 11.4 Hz, 1H), 3.91 (s, 3H) , 1.73 (s, 2 H), 1.37 (s, 6 H), 0.72 (s, 9 H); HRMS (EI) m / z calcd for C ₂₅ H ₃₁ NO ₄ [M ⁺ ] 409.2253, found: 409.2256.

Compound 6-3. : ( E ) -Methyl4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate (( E ) -methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate)

( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 3-amino-4-methylbenzoate (1.0 equiv) were mixed with DMF and HATU (1.2 equiv) and DIPEA (0.7 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( E ) -methyl4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate Obtained (white solid, 0.04 g, 40.2% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.93 (d, J = 11.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.29 ( s, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.80 (s, 1H), 5.69 (d, J = 10.8, 1H), 3.90 (s, 3H), 2.33 (s, 3H), 1.72 (s, 2H), 1.36 (s, 6H), 0.70 (s, 9H); Purity 99.9% (as determined by RP-HPLC, method A, tR = 26.11 min).

Compound 6-4. ( E ) -Methyl2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate (( E ) -methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate)

( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 5-amino-2-methylbenzoate (1.0 equiv) were mixed with DMF and HATU (1.2 equiv) and DIPEA (0.7 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrated solution was purified by silica gel column chromatography ( E ) -methyl2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate Obtained (white solid, 0.04 g, 40.2% yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.03 (s, 1H), 7.89 (d, J = 11.6 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 7.53 (s, 1H) , 7.34 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 5.71 (d, J = 12.0 Hz, 1H), 3.84 (s, 3H), 2.54 (s, 3H), 1.71 (s, 2H), 1.35 (s, 6H), 0.70 (s, 9H); Purity 99.9% (as determined by RP-HPLC, method A, tR = 27.35 min).

Compound 6-5. : ( E ) -Methyl2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate (( E ) -methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate)

( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 5-amino-2-hydroxybenzoate (1.0 equiv) were mixed with DMF and HATU (1.2 equiv) and DIPEA (0.7 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrated solution was purified by silica gel column chromatography to give ( E ) -methyl2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzo Obtain was obtained (white solid, 0.03 g, 29.9% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.63 (s, 1H), 8.13 (s, 1H), 7.88 (d, J = 11.6 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.35-7.33 (m, 3H), 6.97 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.8 Hz, 1H), 5.68 (d, J = 12.0 Hz, 1H), 3.90 (s, 3H ), 1.71 (s, 2H), 1.35 (s, 6H), 0.70 (s, 9H); Purity 99.9% (as determined by RP-HPLC, method A, tR = 26.40 min).

Compound 6-6. : ( E ) -Isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate (( E ) -isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate)

( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and isopropyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and HATU (1.2 equiv) And DIPEA (0.7 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( E ) -isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate (White solid, 0.05 g, 48.2% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.99 (brs, 2H), 7.92 (d, J = 11.6 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.42-7.35 (m, 3H ), 7.31 (s, 1H), 7.00 (d, J = 9.2 Hz, 2H), 5.70 (d, J = 11.6 Hz, 1H), 5.28-5.21 (m, 1H), 1.72 (s, 2H), 1.37 -1.35 (m, 12H), 0.70 (s, 9H); Purity 99.99% (as determined by RP-HPLC, method A, tR = 28.62 min).

Compound 6-7. : ( E ) -Methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate (( E ) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate)

( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 5-amino-2,4-dimethylbenzoate (1.0 equiv) were mixed with DMF It was added HATU (1.2 equiv) and DIPEA (0.7 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( E ) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido ) Benzoate was obtained (white solid, 0.07 g, 57.3% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 7.91 (d, J = 11.6 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.06 (s, 1H), 6.99 (d, J = 8.4, 2H), 6.91 (s, 1H), 5.70 (brs, 1H), 3.85 (s, 3H), 2.54 (s, 3H), 2.25 (s, 3H), 1.72 (s, 2H), 1.35 (s, 6H), 0.70 (s, 9H); Purity 99.9% (as determined by RP-HPLC, method A, tR = 27.02 min).

Compound 6-8. : ( E ) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate ( ( E ) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate)

( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 5-aminothiophene-2-carboxylate (1.0 equiv) were mixed with DMF and HATU (1.2 equiv) and DIPEA (0.7 equiv) were added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography ( E ) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethyl Pentan-2-yl) phenoxy) acrylate was obtained (white solid, 0.05 g, 44.6% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.74 (d, J = 4.4 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 12.0 Hz, 1H), 7.46- 7.41 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 5.83 (d, J = 12.0 Hz, 1H), 1.75 (s, 2H), 1.37 (s, 6H), 0.71 (s, 9H ).

Compound 6-9. : ( E ) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate (( E ) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate)

( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 2-aminoisonicotinate (1.0 equiv) were mixed with DMF and HATU (1.2 equiv) And DIPEA (0.7 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( E ) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2- I) phenoxy) acrylate was obtained (white solid, 0.05 g, 54.0% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.25 (d, J = 13.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 4.0 Hz, 2H), 7.56- 7.52 (m, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 13.6 Hz, 1H), 1.74 (s, 2H), 1.38 (s, 6 H), 0.73 (s, 9 H).

Compound 6-10. : ( E ) -Methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate (( E ) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate)

( E ) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylic acid (1.0 equiv) and methyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF to give EDC HCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv) were added. The reaction mixture was stirred at room temperature overnight under nitrogen, then concentrated under reduced pressure, and the obtained residue was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrated solution was purified by silica gel column chromatography ( E ) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzo A was obtained (white solid, 0.01 g, 56.2% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.47 (s, 1H), 7.97 (d, J = 11.2 Hz, 1H), 7.80 (dd, J = 2.0, 9.0 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.00-7.02 (m, 3H), 5.73 (d, J = 11.2 Hz, 1H), 3.88 (s, 3H), 1.74 (s , 2H), 1.37 (s, 6H), 0.72 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 167.0, 166.7, 160.2, 153.8, 153.5, 147.3, 128.8, 127.7, 125.9, 124.2, 121.8, 120.0, 117.1, 101.8, 56.9, 52.1, 38.3, 32.3, 31.7, 31.6; HRMS (EI) m / z calcd for C ₂₅ H ₃₂ NO ₅ [M + H] 426.2202, found: 426.2286; Purity 99.9% (as determined by RP-HPLC, method A, tR = 26.18 min).

1-3. Synthesis of Compound 9-1 and Compound 9-11

Compounds 9-1 to 9-11 were synthesized through Compound 8 as an intermediate as Compound 1 as a starting material, as shown in FIG. 1.

First, the synthesis process of compound 8 is as follows.

Synthesis Process of Compound 8: A methanol solution of acrylic acid methyl ester compound 4 (1.0 equiv) was treated with 10% Pd / C (10% w / w). The reaction was hydrogenated at 1 atm hydrogen atmosphere at room temperature and the reaction mixture was stirred overnight. After completion of the reaction, the mixture was filtered through Celite pad and concentrated. The result was purified via silica gel column chromatography. A THF / H ₂ O (1: 1) suspension of methyl ester compound 7 was added to lithium hydroxy monohydrate (4.0equiv) and stirred at room temperature overnight. The reaction mixture was neutralized with 10% HCl, diluted with EtOA and subsequently washed with water soluble sodium bicarbonate, brine and water. The organic layer was collected and dried over anhydrous magnesium sulfate. The solvent was filtered off, evaporated under reduced pressure and purified using silica gel column chromatography to give a crude dry matter.

Compound 9-1. Methyl 3- (3- (4- (adamantan-1-yl) phenoxy) propanamido) benzoate): Methyl 3- [3- (4-adamantane-1-yl-phenoxy) propanamido] benzoate

3- (4-adamantan-1-yl-phenoxy) -propanoic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA. (2.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 3- [3- (4-adamantane-1-yl-phenoxy) propanamido] benzoate (white solid, 0.12 g, 83.3% yield) .

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 7.79-7.82 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H ), 6.91 (d, J = 8.8 Hz, 2H), 4.32 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 2.65 (t, J = 7.2 Hz, 2H), 2.02 (brs, 3H ), 1.99-1.97 (m, 6H), 1.77-1.71 (m, 6H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.2, 166.7, 155.7, 144.9, 138.0, 130.9, 129.1, 126.1, 125.4, 124.4, 120.8, 114.2, 64.2, 52.2, 43.4, 36.8, 35.6, 29.6, 28.8; HRMS (EI) m / z [M + H] calcd [C ₂₇ H ₃₁ NO ₄ ]: 433.2253. Found: 433.2257; Purity 100% (as determined by RP-HPLC, method A, tR = 26.80 min).

Compound 9-2. : Methyl 3- (3- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (3- (4- (2,4,4) -trimethylpentan-2-yl) phenoxy) propanamido) benzoate)

3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 3-aminobenzoate (1.0 equiv) were mixed with DMF and mixed with EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 3- (3- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (white solid, 0.13 g, 88.4% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.18 (s, 1H), 8.07 (t, J = 1.6 Hz, 1H), 7.88-7.86 (m, 1H), 7.77 (d, J = 8.0 Hz, 1H ), 7.38 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H), 4.32 (t, J = 4.0 Hz, 2H), 3.89 (s, 3H), 2.85 (t, J = 4.0 Hz, 2H), 1.70 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.2, 166.7, 155.6, 143.4, 138.0, 130.9, 129.2, 127.3, 125.4, 124.4, 120.8, 113.8, 64.1, 56.9, 52.2, 38.0, 37.8, 32.3, 31.8, 31.6, 29.7; HRMS (EI) m / z [M + H] calcd [C ₂₅ H ₃₄ NO ₄ ]: 412.2488, found 412.2488; Purity 100% (as determined by RP-HPLC, method A, tR = 26.00 min).

Compound 9-3. : Methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy-3- (3- ( 4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate)

3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 3-amino-4-hydroxybenzoate (1.0 equiv) were mixed with DMF to give EDCHCl (1.2 equiv), HOBT (1.2 equiv) and DIPEA (2.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate. (White solid, 0.01 g, 75.0% yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.74 (s, 1H), 8.36 (s, 1H), 7.81 (dd, J = 2.0 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 4.35 (t, J = 5.4 Hz, 2H), 3.88 (s , 3H), 2.94 (t, J = 5.6 Hz, 2H), 1.71 (s, 2H), 1.34 (s, 6H), 0.71 (s, 9H); ¹³ CNMR (100 MHz, CDCl ₃ ) δ 171.7, 166.4, 155.3, 153.2, 143.7, 128.9, 127.3, 125.5, 124.2, 122.1, 119.7, 113.9, 63.8, 56.9, 52.1, 38.0, 36.8, 32.3, 31.7, 31.6; HRMS (EI) m / z calcd for C ₂₅ H ₃₄ NO ₅ [M + H] 428.2359, found: 428.2431; Purity 99.9% (as determined by RP-HPLC, method A, tR = 24.09 min).

Compound 9-4. : methyl  4- methyl -3- (3- (4- (2,4,4- Trimethylpentane -2 days) Phenoxy ) Pro Panamido) benzoate (Methyl 4-methyl-3- (3- (4- (2,4,4- trimethylpentan -2-yl) phenoxy) propanamido) benzoate)

3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 3-amino-4-methylbenzoate (1.2 equiv) were mixed with THF and HATU (1.5 equiv) And DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate ( White solid, 0.02 g, 28.2% yield).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 7.98 (s, 1H), 7.75-7.77 (m, 1H), 7.31 (d, J = 9.0 Hz, 2H), 7.24 (d , J = 8.5 Hz, 1H), 6.88 (d, J = 9.0 Hz, 2H), 4.35 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 2.92 (t, J = 5.5 Hz, 2H ), 2.28 (s, 3H), 1.72 (s, 2H), 1.36 (s, 6H), 0.72 (s, 9H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 169.4, 166.8, 155.5, 143.4, 135.9, 134.3, 130.5, 128.8, 127.4, 126.2, 123.9, 113.6, 64.1, 57.0, 52.1, 38.0, 37.7, 32.3, 31.8, 31.7, 18.2.

Compound 9-5. : Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-methyl-5- (3- (4 -(2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate)

3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 5-amino-2-methylbenzoate (1.2 equiv) were mixed with DMF and HATU (1.5 equiv) And DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate ( Yellow solid, 0.05 g, 61.0% yield).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.65-7.67 (m, 1H), 7.30 (d, J = 8.5 Hz, 2H ), 7.19 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 4.32 (t, J = 6.0 Hz, 2H), 3.87 (s, 3H), 2.84 (t, J = 5.0 Hz, 2H), 2.55 (s, 3H), 1.72 (s, 2H), 1.35 (s, 6H), 0.72 (s, 9H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 169.2, 167.6, 155.7, 143.3, 136.1, 135.6, 132.3, 129.8, 127.3, 123.7, 121.9, 113.8, 64.1, 56.9, 52.0, 38.0, 37.7, 32.3, 31.8, 31.7, 21.2.

Compound 9-6. : Methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-hydroxy-5- (3- ( 4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate)

Some solution of CDI (1,1-Carbonyldiimidazole) (1.0 equiv) in THF was added and stirred at room temperature for 45 minutes. In another flask, imidazole (1.1 equiv) was added to a solution of methyl 5-amino-2-hydroxybenzoate (0.9 equiv) in THF. The acid / CDI mixture was added to the aniline-imidazole solution and stirred overnight under argon. The solvent was evaporated under vacuum and the result was purified by silica gel column chromatography (white solid, 0.08 g, 33.4% yield).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 10.64 (s, 1H), 8.10 (d, J = 3.0 Hz, 1H,), 7.89 (brs, 1H), 7.47 (dd, J = 3.0, 8.5 Hz, 1H), 7.31 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 9.0 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 4.33 (t, J = 6.0 Hz, 2H) , 3.93 (s, 3H), 2.83 (t, J = 6.0 Hz, 2H), 1.72 (s, 2H), 1.35 (s, 6H), 0.72 (s, 9H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.2, 169.1, 158.5, 155.6, 143.3, 129.4, 128.7, 127.3, 121.6, 117.9, 113.8, 112.1, 64.1, 56.9, 52.4, 38.0, 37.5, 32.3, 31.8, 31.7.

Compound 9-7. : Isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Isopropyl 3- (3- (4- (2,4,4) -trimethylpentan-2-yl) phenoxy) propanamido) benzoate)

3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and isopropyl 3-aminobenzoate (1.2 equiv) were mixed with DMF to form HATU (1.5 equiv) and DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (clear liquid, 0.06 g, 26.5% yield).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.99 (brs, 2H), 7.93 (d, J = 7.0 Hz, 1H), 7.79 (d, J = 7.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 5.25 (m, 1H), 4.35 (t, J = 6.0 Hz, 2H), 2.87 ( t, J = 6.0 Hz, 2H), 1.72 (s, 2H), 1.38 (d, J = 6.5 Hz, 6H), 1.36 (s, 6H), 0.72 (s, 9H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 169.2, 165.7, 155.6, 143.4, 137.9, 131.6, 129.1, 127.3, 125.3, 124.3, 120.6, 113.8, 68.6, 64.1, 56.9, 38.0, 37.8, 32.3, 31.8, 31.7, 21.9.

Compound 9-8. : Methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) nicotinate (Methyl 5- (3- (4- (2,4,4) -trimethylpentan-2-yl) phenoxy) propanamido) nicotinate)

3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and methyl 5-aminonicotinate (1.2 equiv) were mixed with THF and EDCHCl (1.5 equiv), HOBT (1.5 equiv) and DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) nicotinate (white solid, 0.06 g, 40.3% yield).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.97 (d, J = 1.5 Hz, 1H), 8.84 (d, J = 2.5 Hz, 1H), 8.64 (t, J = 2.0 Hz, 1H), 8.27 ( s, 1H), 7.32 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.35 (t, J = 5.0 Hz, 2H), 3.95 (s, 3H), 2.91 ( t, J = 5.5 Hz, 2H), 2.72 (s, 2H), 1.35 (s, 6H), 0.72 (s, 9H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 169.7, 165.5, 155.4, 146.3, 144.8, 143.7, 127.7, 127.4, 113.8, 63.9, 56.9, 52.6, 38.0, 37.6, 32.3, 31.8, 31.7.

Compound 9-9. :  N -(3- (morpholin-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamide ( N -(3- (Morpholine-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamide)

3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and (3-aminophenyl) (morpholino) methanone (1.2 equiv) were mixed with THF and EDC-HCl ( 1.5 equiv), HOBT (1.5 equiv) and DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain N- (3- (morpholine-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propane Amide was obtained (white solid, 0.08 g, 53.0% yield).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.56 (s, 1H), 7.57-7.60 (m, 2H), 7.27-7.33 (m, 3H), 7.10 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 4.30 (t, J = 5.5 Hz, 2H), 3.46-3.77 (m, 8H), 2.81 (t, J = 5.5 Hz, 2H), 1.71 (s, 2H) , 1.35 (s, 6 H), 0.72 (s, 9 H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.1, 169.3, 155.7, 143.2, 138.3, 135.7, 129.3, 127.3, 122.5, 121.4, 118.7, 113.7, 66.9, 64.0, 56.9, 38.0, 37.6, 32.3, 31.8, 31.7, 22.7, 14.2.

Compound 9-10. : Ethyl 2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) acetate (Ethyl 2- (3- (3- ( 4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) acetate)

3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and ethyl 2- (3-aminobenzamido) acetate (1.2 equiv) were mixed with THF to give EDCHCl ( 1.5 equiv), HOBT (1.5 equiv) and DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. After collection of the organic layer was removed, the dried over anhydrous magnesium sulfate (anhydrous MgSO _4), and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ethyl 2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) acetate (White solid, 0.14 g, 64.4% yield).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.47 (s, 1H), 7.86 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.28-7.34 (m, 3H), 6.99 (s, 1H), 6.86 (d, J = 8.5 Hz, 2H), 4.32 (t, J = 5.5 Hz, 2H), 4.20-4.26 (m, 4H), 2.85 (d, J = 5.0 Hz, 2H), 1.70 (s, 2H), 1.34 (s, 6H), 1.30 (t, J = 7.0 Hz, 3H), 0.71 (s, 9H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.2, 169.4, 167.4, 155.7, 143.2, 138.4, 134.2, 129.3, 127.3, 123.2, 122.6, 118.4, 113.8, 64.0, 61.7, 56.9, 41.9, 38.0, 37.6, 32.3, 31.8, 31.7, 14.2.

Compound 9-11. : ( S )- methyl  3- methyl -2- (3- (3- (4- (2,4,4- Trimethylpentane -2 days) Phenoxy Propane amido benz amido butanoate S ) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) butanoate)

3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanoic acid (1.0 equiv) and ( S ) -methyl 2- (3-aminobenzamido) -3-methylbutanoate (1.2 equiv) in THF It was mixed and added to EDC.HCl (1.5 equiv), HOBT (1.5 equiv) and DIPEA (1.5 equiv). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue obtained was diluted with EtOAc and washed with water and brine. The organic layers were combined, water was removed with anhydrous magnesium sulfate (anhydrous MgSO ₄ ), and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give ( S ) -methyl3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido ) Benzamido) butanoate was obtained (white solid, 0.15 g, 73.3% yield).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.60 (s, 1H), 7.90 (s, 1H), 7.89 (s, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 9.0 Hz, 2H), 6.81-6.86 (m, 3H), 4.72-4.75 (m, 1H), 4.31 (t, J = 5.5 Hz, 2H), 3.75 (s, 3H), 2.85 (t, J = 5.5 Hz, 2H), 2.33-2.30 (m, 1H), 1.70 (s, 2H), 1.34 (s, 6H), 0.99 (t, J = 6.5 Hz, 6H), 0.71 (s, 9H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 172.6, 169.4, 167.3, 155.8, 143.0, 138.6, 134.7, 129.3, 127.2, 123.2, 122.4, 118.5, 113.8, 64.0, 57.8, 56.9, 52.3, 38.0, 37.6, 32.3, 31.8, 31.7, 31.4, 19.1, 18.1.

Experimental Example

Experimental Example 1. Confirmation of MDH inhibitory activity of the prepared compound

1-1. Gene Cloning and Recombinant Protein Isolation and Purification of MDH2

In order to confirm the MDH2 inhibitory activity of the compound prepared according to Example 1, an MDH2 recombinant protein was prepared. The MDH2 gene was purchased from the Korea Human Genetics Bank (Korean Human GeneBank, KUGI, NM_005918), and amplified by PCR and cloned into the pET28a vector (Merck, Germany). Thereafter, the plasmid vector was introduced into E. coli Rosetta 2 (DE3), followed by IPTG treatment to overexpress MDH2 recombinant protein.

As a result, as shown in FIG. 2, the overexpressed recombinant MDH2 protein was purified by Ni-NTA affinity chromatography, TEV enzyme cleavage, and size-exclusion chromatography.

1-2. Of the prepared compound MDH1  And MDH2  Confirmation of inhibitory activity (in vitro)

The inhibitory activity of the compounds against MDH1 and MDH2 recombinant proteins produced in Experimental Examples 1-1, 1-2, 1-3 and 1-4 were measured. More specifically, 0.25 nM MDH1 recombinant protein (Biovision) or MDH2 recombinant protein was prepared using 200 μM oxaloacetate, nicotinamide adenine dinucleotide (NADH), the compound prepared in Example 1, and MDH assay buffer (100 mM potassium phosphate, pH 7.4) for 30 minutes. Thereafter, the change in NADH concentration in the solution by oxidation of NADH (NAD ⁺ ) by MDH1 or MDH2 enzyme was measured at absorbance 340 nm.

As a result, as shown in Table 1 below, SAR results of 55 compounds described in Example 1 were confirmed.

Comp. No.	MDH1IC 50 (μM)	MDH2IC 50 (μM)
3-1	+	+
3-2	+	+
3-3	+	+
3-4	+	+
3-5	+	+
3-6	+	+
3-7	++	+
3-8	++	+
3-9	+	+
3-10	+	+
3-11	++	++
3-12	+++	+++
3-13	+++	+++
3-14	+++	+++
3-15	+++	++
3-16	+	+
3-17	+++	++
3-18	+	+
3-19	+	+
3-20	+++	++
3-21	+	+
3-22	+	+
3-23	+	+
3-24	+++	+
3-25	+	+
3-26	+	+
3-27	+++	+++
3-28	+++	+++
3-29	+++	+++
3-30	+++	+++
3-31	+++	+
3-32	+++	+++
3-33	+++	+++
3-34	++	+++
6-1	+	+++
6-2	+++	+++
6-3	++	++
6-4	+	+
6-5	+	+
6-6	+	+
6-7	++	+
6-8	++	++
6-9	+	+
6-10	+++	+++
9-1	+++	++
9-2	+++	+++
9-3	+++	+++
9-4	++	++
9-5	+	+
9-6	+	+
9-7	+	+
9-8	++	++
9-9	+	+
9-10	+	+
9-11	+	+

1 to 5 μM: +++, 5 to 10 μM: ++,> 10 μM: +

Experimental Example 2. Confirmation of MDH inhibition mechanism of the prepared compound 9-2

MDH of compound 9-2 prepared in Example 1-3, ie, methyl 3- (3- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate The inhibition mechanism was confirmed. More specifically, as described in Experimental Example 1-2, enzyme kinetics using various concentrations of nicotinamide adenine dinucleotide (60, 75, 100, 150 and 300 μM) and 600 μM oxaloacetic acid ) Experiments were performed. In addition, the maximum velocity (Vmax) and the Michaelis constant (Km) were measured through the Lineweaver-Burk plot method.

As a result, as shown in FIG. 3, lines from three different concentrations of compound 9-2 in the MDH1 and MDH2 enzymatic reactions crossed the x-axis, and as the NADH concentration changed, the V _max value did not change. The binding affinity (Km) value decreased in a concentration dependent manner. Thus, compound 9-2 was found to bind to the same binding site as NADH competitively MDH inhibitors.

Experimental Example 3. Confirmation of HIF-1α inhibitory activity of the prepared compound 9-2

The HIF-1α inhibitory activity of the compound 9-2 prepared in Example 1-3 was confirmed. HIF-1α (hypoxia-inducible factor-1α) affects radiation resistance and anticancer drug resistance in solid cancers and is a factor influencing cancer malignancy. More specifically, the HCT-116 colon cancer cell line was suspended in DMEM medium containing 5% fetal calf serum (FBS) and transferred to 6 well plates (5 × 10 ⁵ cells / well) at 37 ° C. to maintain 5% carbon dioxide. The cells were incubated for 24 hours in a cell incubator. Cells were incubated for 6 hours at 1% oxygen, 94% nitrogen and 5% carbon dioxide conditions to induce accumulation of HIF-1α protein by hypoxia. After cell disruption was obtained by disrupting HCT-116 cells using radioimmuno precipitation assay buffer (RIPA buffer, Millipore), 10 μg of each cell extract was developed on SDS-PAGE, and then separated. Transferred to a PVDF membrane (polyvinylidene fluoride membrane), HIF-1α antibody (BD Science), HIF-1β antibody (BD Science), β-Actin (Santa Cruz) and horseradish peroxidase (HRP) labeled secondary antibody (Santa Cruz) G) were sequentially combined to confirm protein expression.

As a result, as shown in FIG. 4, it was confirmed that Compound 9-2 inhibited HIF-1α protein accumulation in a concentration-dependent manner without affecting HIF-1β protein expression at 2.5, 5, and 10 μM.

Experimental Example 4. Confirmation of mitochondrial respiration inhibition of compound 9-2

4-1. Confirmation of Inhibition of Oxygen Consumption of Compound 9-2

In order to examine the inhibitory activity on mitochondrial respiration of compound 9-2 described in Example 1-3, the change in oxygen consumption rate was measured. More specifically, the oxygen consumption rate (OCR) of the mitochondria was measured using an XF24 extracellular flux analyzer (Seaholes). After HCT-116 cells (1 × 10 ⁵ cells) were incubated for 24 hours in a measuring plate (XF24 cell cultureplate), the culture medium was exchanged with XF measuring medium and incubated for 1 hour in a cell incubator without carbon dioxide. The oxygen consumption rate of mitochondria was measured three times in non-drug cells, three times after administration of the ATP synthesis inhibitor oligomycin (1 μM), and three times after administration of the chemical decoupling agent carbonyl cyanide p -trifluoromethoxyphenylhydrazone (0.5 μM). Oxygen consumption was measured three times after administration of rotenone (1 μM) and antimycin A (1 μM).

As a result, as shown in Figure 5, Compound 9-2 suppressed the oxygen consumption rate of mitochondria in cancer cells, it was confirmed that the basal respiratory rate and the maximum respiratory rate decreases in a concentration-dependent manner.

4-1. Confirmation of Increased Intracellular Oxygen by Compound 9-2

In order to confirm the increase in the intracellular oxygen concentration by inhibiting the oxygen consumption rate of the mitochondria of the compound 9-2 described in Example 1-3, an experiment using an oxygen-sensitive fluorescent probe was performed. More specifically, HCT-116 cells (1 × 10 ⁵ cells) were treated with compound 9-2 and hypoxic specific sensitive fluorescent probe MAR (Gray, 0.5 μM), and then incubated for 6 hours in a cell incubator under hypoxic conditions. Thereafter, changes in intracellular fluorescence intensity due to hypoxia were measured and quantified by a real-time cell observation analysis system (Incusite, Essen).

As a result, as shown in Figure 6, it was confirmed that the oxygen concentration in the cell is increased by the compound 9-2.

Experimental Example 5. Confirmation of antitumor effect of compound 9-2

In order to confirm the effect of inhibiting cancer cell growth of compound 9-2 in vivo, experiments were carried out using a cancer cell transplant mouse model. More specifically, plate culture HCT-116 colon cancer cell line was obtained by trypsin treatment, and then washed with serum-free medium and diluted to 2.5 × 10 ⁷ cells / ml. Subsequently, the diluted cells of the 6-week-old female nude mice (SLC-Central Animal Co., South Korea), which are specific pathogen free (SPF) mice of the Balb / c strain, were 5 × 10 ⁶ cells. / 200 μl was injected by subcutaneous injection, respectively. After tumor growth was about 100 mm 3, compound 9-2 was orally administered once daily at a concentration of 20 mg / kg, and 3, 5, 7, 10, 12, 14, 17, 19, 21, and 24 days Body weight and tumor size of the nude mouse were measured using Equation 1 below. Mice were sacrificed 24 days after Compound 9-2 administration to determine the weight and size of the extracted tumor.

As a result, as shown in Table 2, after the tumor was transplanted, there was no significant change in the body weight of the mouse, as shown in Figure 7a, 7b and Table 3, in vivo term of the compound 9-2 As a result of confirming the tumor efficacy, it was confirmed that the degree of tumor formation (size or volume) was reduced by 76.4% in the compound 9-2 administration mice, and as shown in FIG. 163.0 ± 117.5 mg, which was 67.0% less than the tumor weight of 493.5 ± 216.5 mg of non-administered mice.

Hours (days)	Body weight (g)
	Vehicle	Compound 9-2
0	21.2 ± 0.9	21.2 ± 0.6
3	21.7 ± 0.8	21.5 ± 0.8
5	21.9 ± 0.7	21.8 ± 0.7
7	21.9 ± 0.9	21.6 ± 1.1
10	22.4 ± 0.9	22.2 ± 1.0
12	22.9 ± 0.9	22.7 ± 0.7
14	22.9 ± 1.0	22.7 ± 1.0
17	23.0 ± 1.0	22.6 ± 0.8
19	22.6 ± 0.9	22.4 ± 0.5
21	23.0 ± 0.9	22.5 ± 0.7
24	22.7 ± 0.7	22.3 ± 0.8

Hours (days)	Tumor size (㎣)
	Vehicle	Compound 9-2
0	102.5 ± 11.0	94.1 ± 11.0
3	138.9 ± 38.9	97.3 ± 9.8
5	151.7 ± 32.8	101.6 ± 15.7
7	177.9 ± 49.2	119.9 ± 29.3
10	248.5 ± 82.2	111.0 ± 19.0
12	308.7 ± 94.7	124.2 ± 35.5
14	351.3 ± 186.4	159.9 ± 44.6
17	432.3 ± 248.9	187.9 ± 78.5
19	631.8 ± 394.3	241.4 ± 162.8
21	822.1 ± 484.1	258.3 ± 195.7
24	1175.1 ± 630.5	277.5 ± 216.0

The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.

Experimental Example 6. Confirmation of cell proliferation inhibitory activity of compound 9-2

The cell proliferation inhibitory activity of the compound 9-2 prepared according to the above Example was confirmed. The cell lines used in the experiment were lung cancer cell lines A549 and H1703, colorectal cancer cell lines HCT116 and HT29, liver cancer (liver). cancer cell lines Hep3B and HepG2, gastric or stomach cancer cell lines NUGC-3 and AGS, kidney and renal cancer cell lines 786-O and Caki-1, breast cancer cell lines MCF-7 and MDA -MB-231, prostate cancer cell line PC3, pancreatic cancer cell line MIA-PaCa-2, cervical cancer cell line HeLa, normal cell WI-38 and CCD-32Lu cell lines. Specifically, the cell line was suspended in DMEM medium containing 5% fetal bovine serum (FBS), and then transferred to a 96 well plate (3 × 10 ³ cells / well) for 24 hours in a 37 ° C. cell incubator maintaining 5% carbon dioxide. It was. Compound 9-2 was treated at various concentrations, incubated for 72 hours, and the cells were fixed with an aqueous 10% formalin solution, followed by staining with 0.5% methylene blue solution. Thereafter, the concentration change of methylene blue extracted with an aqueous 0.5% hydrochloric acid solution was measured at an absorbance of 600 nm.

As a result, as shown in Table 4, Compound 9-2 inhibited the proliferation of various cancer cell lines that are normal cell lines, and showed a particularly strong inhibitory effect in A549, HCT116, HepG2 cells. Compound 9-2 was found to have no effect on the proliferation of normal cell lines in a concentration range that inhibits cancer cell proliferation.

Cells	Viability GI50 ( μM )
A549	+++
H1703	++
HCT116	+++
HT29	++
Hep3B	+
HepG2	+++
NUGC-3	++
AGS	+
786-O	+
Caki-1	+
MCF-7	+
MDA-MB-231	+
PC3	+
MIA PaCa-2	++
HeLa	+
WI-38	-
CCD-32Lu	-

1 to 5 μM: +++, 5 to 10 μM: ++, 10 to 20 μM: +,> 20 μM:-

Claims (11)

1. A compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof:

   [Formula 1]

   

   (In the above formula 1,

   X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene;

   R ₁ is a nitro group, trifluoromethyl group, C ₁ -C ₂₀ alkyl or C ₁ -C ₂₀ cycloalkyl; And

   R ₂ is

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   ,

   

   or

   

   ego;

   R ₂ is

   

   when,

   R ₃ is methyl or 2-propynyl;

   R ₄ is methyl, hydrogen, hydroxy, methoxy, 2-propynyl,

   

   ,

   

   ,

   

   ,

   

   ,

   

   , or

   

   ego;

   R ₂ is

   

   when,

   R ₅ is

   

   ,

   

   ,or

   

   ego,

   R ₂ is

   

   when,

   R ₆ is methyl or hydroxy; And

   R ₂ is

   

   when,

   R ₇ is C or N.
2. The method of claim 1,

   R ₁ is a nitro group, trifluoromethyl group, adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl, a compound thereof, Isomers or pharmaceutically acceptable salts thereof.
3. The method of claim 1,

   R ₁ is adamantyl;

   X is methylene group, ethane group, ethylene group, n -propylene group or isopropylene; And

   R ₂ is

   

   ego,

   R ₄ is methyl, hydrogen, hydroxy,

   

   ,

   

   ,or

   

   And

   R ₃ is methyl, a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
4. The compound, isomer thereof or pharmaceutically acceptable salt thereof, characterized in that the compound is represented by the following formula (2).

   [Formula 2]

   

   (In the above formula 2,

   R ₁ is adamantyl or tert -butyl; And

   R ₂ is

   

   ,

   

   or

   

   ego,

   R ₂ is

   

   when,

   R ₃ is methyl or 2-propynyl;

   R ₄ is methyl, hydrogen or hydroxy;

   R ₂ is

   

   when,

   R ₆ is methyl or hydroxy; And

   R ₂ is

   

   when,

   R ₇ is C or N).
5. The compound, isomer thereof or pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is a compound represented by the following Chemical Formula 3.

   [Formula 3]

   

   (In Formula 3,

   R ₁ is a nitro group, trifluoromethyl group, adamantyl, tert -butyl, pentyl, cyclopentyl, cyclohexyl, or 2,4,4-trimethylpentin-2-yl;

   R ₂ is

   

   ,

   

   ,

   

   ,

   

   ,

   

   , or

   

   ego;

   R ₂ is

   

   when,

   R ₃ is methyl or 2-propynyl; And

   R ₄ is methyl, hydrogen, hydroxy, methoxy, 2-propynyl,

   

   ,

   

   ,

   

   ,

   

   ,

   

   , or

   

   Compound, isomer thereof or pharmaceutically acceptable salt thereof, characterized in that.
6. The method of claim 1,

   The compound represented by Formula 1 is any one selected from the group consisting of the following compounds, isomers thereof or pharmaceutically acceptable salts thereof:

   (1) Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate (Methyl 3- (2- (4-nitrophenoxy) acetamido) benzoate);

   (2) methyl 3- (2- (4-trifluoromethyl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (trifluoromethyl) phenoxy) acetamido) benzoate);

   (3) methyl 3- (2- (4-tert-butylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-tert-butylphenoxy) acetamido) benzoate);

   (4) Methyl 3- (2- (p-tolyloxy) acetamido) benzoate (Methyl 3- (2- (p-tolyloxy) acetamido) benzoate);

   (5) methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-ethylphenoxy) acetamido) benzoate);

   (6) methyl 3- (2- (4-propylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-propylphenoxy) acetamido) benzoate);

   (7) methyl 3- (2- (4-butyl phenoxy) acetamido) benzoate;

   (8) methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-pentylphenoxy) acetamido) benzoate);

   (9) methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclopentylphenoxy) acetamido) benzoate);

   (10) methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate (Methyl 3- (2- (4-cyclohexylphenoxy) acetamido) benzoate);

   (11) Methyl 3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 3- (2- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

   (12) Methyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-hydroxy-3- ( 2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

   (13) N- (4- (trifluoromethyl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide (N- (4- (trifluoromethyl ) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);

   (14) N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentin-2-yl) phenoxy) acetamide (N- (4- (4-methylpiperazin-1-yl) phenyl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);

   (15) 1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) Ethanone (1- (4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone);

   (16) 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) ethanone ( 1- (4- (prop-2-ynyl) piperazin-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) ethanone);

   (17) Prop-2-ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Prop-2 -ynyl 4-hydroxy-3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

   (18) N- (3-hydroxy-adamantane-1-yl) -2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamide (N- (3 -hydroxy-adamantan-1-yl) -2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamide);

   (19) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) benzoate );

   (20) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido 4-hydroxybenzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy) acetamido) -4-hydroxybenzoate);

   (21) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate (Methyl 3- (2 -(4-adamantan-1-yl-phenoxy) acetamido) -4- (2-ethoxy-2-oxoethoxy) benzoate);

   (22) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate (Methyl 3 -(2- (4-adamantan-1-yl-phenoxy) acetamido) -4- (2- (pyrrolidin-1-yl) ethoxy) benzoate);

   (23) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate (Methyl 3- (2- (4 -adamantan-1-yl-phenoxy) acetamido) -4- (3-morpholinopropoxy) benzoate);

   (24) Methyl 4-methoxy-3- (2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) acetamido) benzoate (Methyl 4-methoxy-3- ( 2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

   (25) Methyl 4- (2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4 -(2-methoxyethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

   (26) Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (2-morpholinoethoxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

   (27) Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4- (prop-2-ynyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

   (28) Methyl 4- (4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentane-2-yl) phenoxy) acetamido) benzoate (Methyl 4 -(4-methoxybenzyloxy) -3- (2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acetamido) benzoate);

   (29) Methyl 3- (2- (4-adamantane-1-yl-phenoxy) -2-methylpropaneamido) benzoate (Methyl 3- (2- (4-adamantan-1-yl-phenoxy ) -2-methylpropanamido) benzoate);

   (30) Methyl 3- (2-methyl-2- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (2-methyl-2 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

   (31) Methyl-4-hydroxy-3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy -3- (2-methyl-2- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

   (32) Methyl 3- [4- (4-adamantane-1-yl-phenoxy) butanamido] benzoate (Methyl 3- [4- (4-adamantan-1-yl-phenoxy) butanamido] benzoate );

   (33) Methyl 3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 3- (4- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate);

   (34) Methyl 4-hydroxy-3- (4- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) butanamido) benzoate (Methyl 4-hydroxy-3- ( 4- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) butanamido) benzoate);

   (35) (E) -3- [3- (4-adamantane-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester ((E) -3- [3- (4- Adamantan-1-yl-phenoxy) -acryloylamino] -benzoic acid methyl ester);

   (36) (E) -3- {3- [4- (2,4,4-trimethylpentan-2-yl) phenoxy] acrylamido} benzoic acid methyl ester ((E) -3- {3 -[4- (2,4,4-Trimethylpentan-2-yl) phenoxy] acrylamido} benzoic acid methyl ester);

   (37) (E) -methyl4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 4 -methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

   (38) (E) -methyl2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2 -methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

   (39) (E) -methyl2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

   (40) (E) -isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -isopropyl 3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

   (41) (E) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 2,4-dimethyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

   (42) (E) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy Acrylate ((E) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy ) acrylate);

   (43) (E) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate ((E) -1H-benzo [d] [1,2,3] triazol-1-yl 3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylate);

   (44) (E) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate ((E) -methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) acrylamido) benzoate);

   (45) Methyl 3- [3- (4-adamantane-1-yl-phenoxy) propanamido] benzoate (Methyl 3- (3- (4- (adamantan-1-yl) phenoxy) propanamido) benzoate);

   (46) Methyl 3- (3- (4- (2,4,4-trimethylpenten-2-yl) phenoxy) propaneamido) benzoate (Methyl 3- (3- (4- (2,4) , 4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

   (47) Methyl 4-hydroxy-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-hydroxy-3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

   (48) methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 4-methyl-3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

   (49) Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-methyl-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

   (50) Methyl 2-hydroxy-5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Methyl 2-hydroxy-5- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

   (51) Isopropyl 3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzoate (Isopropyl 3- (3- (4- (2,4 , 4-trimethylpentan-2-yl) phenoxy) propanamido) benzoate);

   (52) methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) nicotinate; (Methyl 5- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) nicotinate)

   (53) N- (3- (morpholin-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamide (N- (3- (Morpholine-4-carbonyl) phenyl) -3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamide);

   (54) ethyl 2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) acetate (Ethyl 2- (3- (3 -(4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) acetate); or

   (55) (S) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propaneamido) benzamido) butano Ate ((S) -methyl 3-methyl-2- (3- (3- (4- (2,4,4-trimethylpentan-2-yl) phenoxy) propanamido) benzamido) butanoate).
7. The compound of any one of claims 1 to 6, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, cancer prevention or treatment pharmaceutical composition.
8. The method of claim 7, wherein

   The composition is characterized in that simultaneously inhibiting the activity of any one or more of MDH1 (malate dehydrogenases 1) and MDH2 (malate dehydrogenases 2), cancer prevention or treatment pharmaceutical composition.
9. The method of claim 7, wherein the cancer is carcinoma, lymphoma, blastoma, sarcoma, liposarcoma, neuroendocrine tumor, mesothelioma, neurocholia ( schwanoma, meningioma, adenocarcinoma, melanoma, melanoma, leukemia, lymphoidmalignancy, squamous cell cancer, squamous cell cancer, epithelial squamous cell cancer, Lung cancer, small-cell lungcancer, non-small cell lungcancer, adenocarcinoma of the lung, squamous carcinoma of the lung, peritoneal tumor of the peritoneum, hepatocellular cancer, gastric or stomach cancer, gastrointestinal cancer, pancreatic cancer, brain cancer, glioblastoma, cervical cancer cancer, ovarian cancer, liver cancer ancer, bladder cancer, hepatoma, breast cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, Salivary gland carcinoma, kidney and renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatocarcinoma, anal carcinoma Selected from the group consisting of penile carcinoma, testicular cancer, esophageal cancer, biliary tract, colorectal cancer and head and neck cancer Characterized in that the pharmaceutical composition for preventing or treating cancer.
10. A cancer treatment comprising administering to a subject a pharmaceutical composition for preventing or treating cancer, comprising the compound of any one of claims 1 to 6, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. Way.
11. Use of the compound of any one of claims 1 to 6, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, cancer prevention or treatment of cancer of the pharmaceutical composition for preventing or treating cancer.

Images