KR20180134675A - Cyclopropylamine derivative compound and use thereof - Google Patents

Abstract

According to an embodiment of the present invention, provided is a compound represented by chemical formula 1, an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, which has inhibitory activities against lysine-specific demethylase-1 (LSD1) and is effective in preventing or treating diseases caused by abnormal activation of LSD1.

Description

Cyclopropylamine derivative compounds and their use {Cyclopropylamine derivative compound and use thereof}

The present invention relates to cyclopropylamine derivatives and their use, and more particularly, to cyclopropylamine derivatives having cyclosporinic acid derivatives having an inhibitory activity on lysine-specific histone demethylase-1 (LSD1) which is histone demethylase Derivatives and pharmaceutical compositions containing them.

Cancer stem cells or cancer-initiating cells have some pluripotent stem cell characteristics that contribute to the heterogeneity of cancer cells. This feature can make cancer cells more resistant to traditional therapies, such as chemotherapy or radiotherapy, and then cause recurrence after treatment. Therefore, efforts are being made to develop chemotherapeutic drugs that are more advanced than conventional chemotherapy or radiotherapy.

Epigenetics is a study of the phenomenon that gene expression pattern and activity are changed without genetic alteration of DNA sequence and that it is inherited to the next generation. These epigenetic studies are centered on mechanisms such as DNA methylation, histone modification, and chromatin remodeling. Post sexual variability has been found to be a major cause of the development of various diseases. The initiation and maintenance of posterior sexual changes include DNA methylation, histone modification, and genetic modification associated with noncoding RNA (ncRNA), and many posterior regulatory genes are often mutated or their expression is abnormal in many cancers .

On the other hand, lysine-specific demethylase-1 (LSD1) (also called KDM1A) removes methyl groups and regulates the expression of several genes important for cancer progression and cell proliferation. (Shi, Y., et al., Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 2004. 119 (7): 941-53). In addition, LSD1 was associated with cancer formation and vascular inflammation. Overexpression of LSD1 was detected in bladder cancer, pemphigus (non-small cell lung cancer, small cell lung cancer), breast cancer, ovarian cancer, glioma, colorectal cancer, , Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma), neuroblastoma, prostate cancer, esophageal squamous cell carcinoma, and papillary thyroid carcinoma. Accordingly, research on cancer treatment using compounds capable of inhibiting LSD1 is underway (Patent Document 1).

However, the conventional inhibitors of LSD1 do not exhibit sufficient inhibitory activity against LSD1, and there are side effects such as resistance to drugs or toxicity to normal cells, and thus they can not be effectively used in the treatment of cancer and neoplastic diseases have.

WO2010043721

Cell, 2004. 119 (7): p. 941-53

One aspect of the present invention is to provide a novel compound having a sufficient inhibitory activity against histone demethylase-1 (Lysine-specific histone demethylase-1: LSD1).

Another aspect of the present invention is the use of the novel compounds for the prophylaxis or treatment of diseases caused by abnormal activation of lysine-specific demethylase-1 (LSD1).

One aspect of the present invention is

There is provided a compound of formula (I) or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

Another aspect of the present invention is a lysine-specific dehydrogenase inhibitor comprising the cyclopropylamine derivative of the formula (1) or an optical isomer thereof or a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, There is provided a pharmaceutical composition for preventing or treating diseases caused by abnormal activation of methylase-1 (LSD1).

Another aspect of the present invention is a method for the treatment or prevention of diseases caused by abnormal activation of LSD1 comprising administering to a subject a therapeutically effective amount of a compound of formula 1, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof. Thereby providing a method of treating the disease.

According to one aspect of the present invention, there is provided a compound of formula (I) or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the lysine-specific histone demethylase-1 (LSD1) To prevent or treat diseases caused by abnormal activation of LSD1.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. Also, the numerical values set forth herein are considered to include the meaning of " about " unless explicitly stated. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

The present inventors have made intensive efforts to develop a novel anticancer drug by using lysine-specific demethylase-1 (LSD1) as an important target for cancer therapy. As a result, the present inventors have found that transcription of several genes important for cancer progression and cell proliferation (LSD1) involved in the lysine-specific demethylase-1 (LSD1).

An aspect of the present invention is to provide a cyclopropylamine derivative compound represented by the following formula (1), an optical isomer thereof or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

Wherein A is aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted or unsubstituted with one to three R < ^{5 &} gt ;; k is an integer from 0 to 2; m and n are each independently an integer of 0 to 3, but not simultaneously 0; W is _{-CH 2-, -C (O) -} , -C (O) NR 6 -, -S (O) -, and -S (O) ₂ - is selected from the group consisting of; l is an integer from 0 to 4; R ¹ and R ² are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, Alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be unsubstituted or substituted with one to five R ⁷ ; R ¹ and R ² together with the nitrogen atom to which they are attached may form a heterocycloalkyl ring compound or a heteroaryl ring compound wherein the heterocycloalkyl ring compound or the heteroaryl ring compound is substituted with 1 to 5 R ⁷ Or unsubstituted; R ³ is the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, heterocycloalkyl alkyl, aryl, arylalkyl, heteroaryl, and heteroaryl-alkoxy Wherein the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkylalkoxy, heterocycloalkyl, heterocycloalkylalkoxy, aryl, arylalkoxy, heteroaryl, and heteroarylalkoxy 1 to 5 R < ⁷ > or -NR < ⁸ > R < ⁹ >; R < ⁴ > is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl; R ⁵ is selected from the group consisting of halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, and -NR ¹⁰ R ¹¹ ; R ⁶ , R ¹⁰ , R ¹¹ , and R ¹² are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, and alkynyl; R ⁷ is selected from the group consisting of halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR ¹¹ R ¹² , cycloalkyl, cycloalkylalkoxy, heterocycloalkyl, heterocycloalkylalkoxy, , heteroaryl, ^{heteroaryl-alkoxy, C (O) R 6,} S (O) 2 R 6, NHS (O) 2 R 6, NHS (O) 2 NHR 6, NHCOR 6, NHCONHR 6, CONHR 6, and CONR ¹⁰ R < ^{11 &} gt ;; R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl ring compounds, The alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl ring compounds may be unsubstituted or substituted with one to five R ⁷ .

The term " halogen ", as used herein, unless otherwise indicated, means fluorine, chlorine, bromine or iodine.

As used herein, the term " alkyl " means a linear or branched hydrocarbon residue, which may be substituted or unsubstituted, unless otherwise indicated. The alkyl group may be, for example, C ₁ -C _30, C ₁ -C ₂₀ alkyl, C ₁ -C ₁₅ alkyl, C ₁ -C ₁₀ alkyl, or C ₁ -C ₆ alkyl, Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl or all possible isomers thereof.

The term " cycloalkyl ", as used herein, unless otherwise indicated, refers to a cyclic alkyl which may be substituted or unsubstituted. The cycloalkyl group may be, for example, C ₃ -C ₃₀ cycloalkyl, C ₃ -C ₂₀ cycloalkyl, or C ₃ -C ₁₀ cycloalkyl, for example, mono- or bicycloaliphatic . Cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, bicyclo [2.2.2] 2-oxocyclo [2.2.1] hept-1-yl, or any of the possible isomers thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof. Without limitation.

The term " heterocycloalkyl ", as used herein, unless otherwise indicated, refers to a monocyclic or bicyclic moiety containing one or more, preferably one to four, heteroatoms selected from O, N, Or cyclic alkyl, which may be unsubstituted. Examples of monoheterocycloalkyl include, but are not limited to, piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl, and similar groups no.

The term "aryl" herein, unless otherwise noted, refers to an aromatic group which may be substituted or unsubstituted, e.g., C _6- C ₃₀ aryl, C _6- C ₂₀ aryl, or C _6- C ₁₀ aryl, including And the double bonds alternate (resonate) between adjacent carbon atoms or suitable heteroatoms. For example, phenyl, biphenyl, naphthyl, tolyl, naphthalenyl, anthracenyl, or all possible isomers thereof.

The term " heteroaryl ", as used herein, unless otherwise indicated, refers to a monocyclic or bicyclic moiety containing one or more, preferably one to four, heteroatoms selected from O, N and S, Aromatic group in which at least one of the carbons forming the ring is replaced by C = O. Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridine Pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups, but are not limited thereto. Examples of bicyclic heteroaryl include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, iso But are not limited to, quinolinyl, purine, furopyridinyl, oxochromene, dioxoisoindoline, and similar groups.

In the present specification, the numerical range indicated by using the terms " to " refers to a range including the numerical values described before and after the terms " lower limit " and " upper limit ", respectively.

The term " isomer " as used herein refers to different compounds having the same molecular formula. The term " optical isomer " as used herein refers to various stereoisomers and geometric isomers that may exist for the compounds according to the present invention. The compounds of formula (1) according to the present invention may have asymmetric carbon centers (absent carbon) and thus may exist as optical isomers ( R or S isomers), racemates, diastereoisomers, or any mixture thereof, Isomers and mixtures are included within the scope of the present invention. The optically active ( R ) - and ( S ) -isomers can be resolved using conventional techniques or can be prepared using chiral synthons or chiral reagents. When the compound contains a double bond, the substituent may be in E or Z form. When the compound contains a disubstituted cycloalkyl, it may be in the cis- or trans form. All tautomeric forms may also be included.

In addition, solvate forms of the compounds of formula (1) are also included within the scope of the present invention. The term " solvate " may include a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules, for example, ethanol or water. The complex in which the solvent molecule is water is also referred to as " hydrate ".

The term " derivative " as used herein refers to a compound obtained by substituting a part of the structure of the above compound with another atom or atomic group.

In addition, the compounds according to the invention can also form pharmaceutically acceptable salts. Such a pharmaceutically acceptable salt is not particularly limited as long as it is an acid which forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion. The acid addition salts include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like; Organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid and maleic acid; Methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like.

In one embodiment, there is provided a cyclopropylamine derivative compound represented by the following formula (1), an optical isomer thereof or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

A is C ₆ -C ₂₀ aryl or C ₁ -C ₂₀ heteroaryl, wherein the aryl or heteroaryl can be substituted or unsubstituted with one to three R ⁵ ;

k is an integer from 0 to 2;

m and n are each independently an integer of 0 to 3, but not simultaneously 0;

W is _{-CH 2-, -C (O) -} , -C (O) NR 6 -, -S (O) -, and -S (O) ₂ - is selected from the group consisting of;

l is an integer from 0 to 4;

R ¹ and R ² are each independently selected from the group consisting of hydrogen, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₂₀ alkenyl, C ₂ -C ₂₀ alkynyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₂₀ heterocycloalkyl, C ₆ -C ₂₀ aryl, and C ₁ -C ₂₀ heteroaryl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo Alkyl, aryl, and heteroaryl may be substituted or unsubstituted with one to five R < ⁷ >;

R ¹ and R ² together with the nitrogen atom to which they are attached may form a heterocycloalkyl ring compound or a heteroaryl ring compound wherein the heterocycloalkyl ring compound or the heteroaryl ring compound is substituted with 1 to 5 R ⁷ Or unsubstituted;

R ³ is selected from the group consisting of C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₂₀ alkenyl, C ₂ -C ₂₀ alkynyl, C ₁ -C ₂₀ alkoxy, C ₁ -C ₂₀ haloalkoxy, C C ₃ -C ₂₀ cycloalkyl, C ₄ -C ₂₀ cycloalkylalkoxy, C ₁ -C ₂₀ heterocycloalkyl, C ₁ -C ₂₀ heterocycloalkylalkoxy, C ₆ -C ₂₀ aryl, C ₇ -C ₂₀ arylalkoxy, C ₁ -C ₂₀ heteroaryl, and C ₁ -C ₂₀ heteroarylalkoxy, wherein the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkylalkoxy, heterocyclo Alkyl, heterocycloalkylalkoxy, aryl, arylalkoxy, heteroaryl, and heteroarylalkoxy may be unsubstituted or substituted with one to five R ⁷ or -NR ⁸ R ⁹ ;

R ⁴ is selected from the group consisting of hydrogen, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₂₀ alkenyl, C ₂ -C ₂₀ alkynyl;

R ⁵ is halogen, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₂₀ alkenyl, C ₂ -C ₂₀ alkynyl, C ₁ -C ₂₀ alkoxy, C ₁ -C ₂₀ haloalkoxy, , And -NR < ¹⁰ > R < ^{11 &} gt ;;

R ⁶ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from the group consisting of hydrogen, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₂₀ alkenyl, and C ₂ -C ₂₀ alkynyl ≪ / RTI >

R ⁷ is halogen, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₂₀ alkenyl, C ₂ -C ₂₀ alkynyl, C ₁ -C ₂₀ alkoxy, C ₁ -C ₂₀ haloalkoxy, , _{^{cyano, -NR 11 R 12, C 3}} -C 20 cycloalkyl, C ₄ -C ₂₀ cycloalkyl, alkoxy, C ₁ -C ₂₀ heterocycloalkyl, C ₁ -C ₂₀ heterocycloalkyl-alkoxy, C ₆ -C ₂₀ aryl, C ₇ -C ₂₀ arylalkyl, C ₁ -C ₂₀ heteroaryl, C ₁ -C ₂₀ heteroaryl, ^{alkoxy, C (O) R 6,} S (O) 2 R 6, NHS (O) 2 R 6 , NHS (O) ₂ NHR ⁶ , NHCOR ⁶ , NHCONHR ⁶ , CONHR ⁶ , and CONR ¹⁰ R ¹¹ ;

R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₂₀ alkenyl, C ₂ -C ₂₀ alkynyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₂₀ heterocycloalkyl, C ₆ -C ₂₀ aryl, and C ₁ -C ₂₀ heteroaryl ring compounds, wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo The alkyl, aryl, and heteroaryl ring compounds may be unsubstituted or substituted with 1 to 5 R < ⁷ >.

In one embodiment, the compound of formula 1 may be, for example, aryl substituted or unsubstituted with one to three R < ⁵ >;

k may be an integer from 0 to 1;

m and n each independently represent an integer of 0 to 2,

Not;

R ⁴ can be hydrogen; And / or R < ⁵ > is hydrogen or halogen.

In one embodiment, Formula 1 may have the structure of Formula 1a:

[Formula 1a]

Wherein W, R ¹ , R ² , R ³ , R ⁴ _, n, m and l are as defined in the above formula (1).

In one embodiment, the compound of formula 1 is

m and n each independently may be an integer of 1 or 2;

W is -CH _2-, or -C (O) - may be; And / or

l may be a 0 or 1 compound.

In one embodiment, the compounds of formula 1 are those wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₂₀ alkenyl, C ₂ -C ₂₀ Alkynyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₂₀ heterocycloalkyl, C ₆ -C ₂₀ aryl, or C ₁ -C ₂₀ heteroaryl; And / or

R ¹ and R ² together with the nitrogen atom to which they are attached may form a heterocycloalkyl ring compound wherein the heterocycloalkyl ring compound may be substituted or unsubstituted with one to three R ⁷ ;

R ⁷ is halogen, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₂₀ alkenyl, C ₂ -C ₂₀ alkynyl, C ₁ -C ₂₀ alkoxy, C ₁ -C ₂₀ haloalkoxy, , _{^{cyano, -NR 11 R 12, C 3}} -C 20 cycloalkyl, C ₄ -C ₂₀ cycloalkyl, alkoxy, C ₁ -C ₂₀ heterocycloalkyl, C ₁ -C ₂₀ heterocycloalkyl-alkoxy, C ₆ -C ₂₀ aryl, C ₇ -C ₂₀ arylalkyl, C ₁ -C ₂₀ heteroaryl, C ₁ -C ₂₀ heteroaryl, ^{alkoxy, C (O) R 6,} S (O) 2 R 6, NHS (O) 2 R 6 , NHS (O) ₂ NHR ⁶ , NHCOR ⁶ , NHCONHR ⁶ , CONHR ⁶ , and CONR ¹⁰ R ¹¹ .

In one embodiment of the present invention, specific examples of the compound of the formula (1) are as follows, and the scope of the present invention includes an isomer comprising an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof :

1) oxo-3- (4 - (((1R, 2S) -2-phenylcyclopropyl) -N- ((S) -1- Amino) piperidin-1-yl) propan-2-yl) - [1,1'-biphenyl] -4-carboxamide;

2) N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1- Amino) piperidin-1-yl) propan-2-yl) benzamide;

3) Preparation of N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) Amino) piperidin-1-yl) propan-2-yl) cyclohexanecarboxamide;

4) Synthesis of N - ((S) -1-oxo-1- (phenylamino) -3- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- Yl) - [1,1'-biphenyl] -4-carboxamide;

5) Preparation of N - ((S) -1-oxo-1- (phenylamino) -3- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- -2-yl) benzamide;

6) Synthesis of N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1,4-dioxo-4- Cyclopropyl) amino)

Piperidin-1-yl) butan-2-yl) - [1,1'-biphenyl] -4-carboxamide;

7) Synthesis of N - ((2S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1,4- Cyclopropyl) amino) pyrrolidin-1-yl) butan-2-yl) - [1,1'-biphenyl] -4-carboxamide;

8) N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1,4- Cyclopropyl) amino) azetidin-1-yl) butan-2-yl) - [1,1'-biphenyl] -4-carboxamide;

9) Synthesis of N - ((S) -1- (cyclohexylamino) -1,4-dioxo-4- (4- (((1R, 2S) -2- phenylcyclopropyl) amino) Yl) butan-2-yl) benzamide;

10) N - ((S) -1,4-dioxo-4- (4 - (((1R, 2S) -2-phenylcyclopropyl)

Amino) piperidin-1-yl) -1- (piperidin-1-yl) butan-2-yl) benzamide;

11) Synthesis of N - ((S) -1 - ((4-chlorophenyl) amino) -1,4-dioxo-4- 1-yl) butan-2-yl) benzamide;

12) 4-Methoxy-N - ((S) -1- (4-methylpiperazin- Phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide;

13) 3-Methoxy-N - ((S) -1- (4-methylpiperidin- 1 -yl) -Phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide;

14) 3- (Dimethylamino) -N - ((S) -1- (4-methylpiperazin-1-yl) 2-phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide;

15) 4-Flo -N - ((S) -1- ( 4- methylpiperazin-1-yl) -1,4-dioxo -4- (4 - (((1 R, 2 S) - 2-phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide;

16) 4-chloro -N - ((S) -1- ( 4- methylpiperazin-1-yl) -1,4-dioxo -4- (4 - (((1 R, 2 S) -2 -Phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide;

17) N - ((S) -1,4-dioxo-1- (phenylamino) -4- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- Yl) butan-2-yl) benzamide;

18) N- ((S) -1,4-dioxo-1- (phenylamino) -4- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- Yl) butan-2-yl) - [1,1'-biphenyl] -4-carboxamide;

19) N- ((S) -1,4-dioxo-1- (phenylamino) -4- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- Yl) butan-2-yl) cyclohexanecarboxamide;

Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, Lt; RTI ID = 0.0 > of LSD1) < / RTI >

Lysine-specific demethylase-1 (LSD1) can be involved in important histone modifications, and is an enzyme that plays a key role in transcriptional regulators from a phylogenetic point of view. LSD1 contains the N-terminal SWRIM domain (Swi3p, Rsc8p and Moira), and there are two transcription variants of LSDl made by selective splicing, including polyamine oxidases and monoamine oxidase oxidase: MAO) and amino acid identity / homology. LSDl can also demethylate H3K9 to demethylate H3K4 and inhibit transcription while at the same time activating gene expression in nuclear hormone receptor complexes (e.g., androgen receptors). This suggests that the substrate specificity of LSDl is determined by factors involved and that it is possible to control alternative gene expression in a context-dependent manner.

In addition, cancer cells rapidly divide and grow, resulting in a hypoxic environment due to lack of blood vessels in solid tumors. Hypoxia induced factor-1 (HIF-1) protein, which is known to promote cancer development and metastasis in this hypoxic condition Expression can be regulated by methylation by LSD1. LSD1 may also be involved in the activation of some proteins such as E2F, STAT3, Tat and myosin phosphatase target subset 1 (MYPT1), which are not histones, such as p53 and DNMTl, which play an important role in cancer. This suggests a tumorigenic mechanism due to lysine-specific demethylase-1 (LSD1) or higher in modulating chromatin remodeling. In addition, LSDl can increase activity with respect to other post-regulators, such as DNA methyltransferase 1 (DNMTl) and histone deacetylase (HDAC) complexes. It can also contribute to a variety of biological processes including cell proliferation, epithelial mesenchymal transition (EMT), and stem cell biology (embryonic and cancer stem cell) or cell regeneration of self-renewing and somatic cells.

In addition, since LSDl contributes to tumorigenesis by altering prognostic markers on histone and non-histone proteins, abnormal activation of LSDl can result in a variety of cancers.

In the present specification, according to the results of Test Example 1, the compound of Formula 1 showed excellent inhibitory effect of LSD1 on lysine-specific demethylase-1 (LSD1).

In addition, as described above, LSD1 contributes to tumorigenesis by altering prognostic markers on histone and non-histone proteins, and LSDl inhibitory activity induces differentiation programs into mature cell types by normalizing gene expression and decreases cell proliferation And is known to promote apoptosis in cancer cells, the compound of Formula 1 can be used for the prevention or treatment of various diseases caused by abnormal activation of LSD1.

The diseases caused by abnormal activation of LSD1 include gastric cancer, lung cancer, liver cancer, small bowel cancer, small bowel cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, cervical adenoma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, Atherosclerosis, autoimmune disease, autoimmune disease, autoimmune disease, autoimmune disease, autoimmune disease, autoimmune disease, autoimmune disease, autoimmune disease, Asthma, neurodegenerative diseases, acute infections, or ocular diseases caused by angiogenesis, but the present invention is not limited thereto, and the pharmaceutical composition of the present invention may exhibit a preventive or therapeutic effect on the diseases.

The pharmaceutical compositions of the present invention are particularly useful for the treatment of acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), neuroblastoma, small blue cell tumors, Compounds and compositions useful for the treatment or prevention of cancer such as cancer, breast cancer, bladder cancer, lung cancer or melanoma can be provided.

In one embodiment, the pharmaceutical composition is used alone or in combination with additional other pharmaceutically acceptable agents for use in the prevention or treatment of diseases caused by abnormal activation of lysine-specific demethylase-1 (LSD1) And can be used in combination with other agents such as cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, growth factor inhibitors, inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological reaction modifiers, antihormonal agents, antiandrogen, cell differentiation / proliferation, / Cell survival inhibitors, cell differentiation / proliferation / survival inhibitors, apoptosis inhibitors, inflammation inhibitors, P-glycoprotein inhibitors. When the pharmaceutical composition of the present invention is formulated, it may be used in combination with the above-mentioned additional medicines or may be compounded.

In one embodiment, the abnormal cell growth diseases for which the pharmaceutical composition has an efficacy include gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, melanoma, breast cancer, cystic adenoma, uterine cancer, , Cancer of the head and neck, cancer of the esophagus, cancer of the thyroid, pituitary cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, leukemia, multiple myeloma, blood cancer, lymphoma, fibroadenoma, inflammation, diabetes, obesity, psoriasis, rheumatoid arthritis, , Acute or chronic kidney disease, coronary artery restenosis, autoimmune disease, asthma, neurodegenerative disease, acute infection, or ocular disease due to vascular breakdown.

In one embodiment, the pharmaceutical composition may comprise conventional pharmaceutically acceptable carriers, excipients or additives. The pharmaceutical composition of the present invention may be formulated according to a conventional method and may be formulated into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions or parenteral administration such as intramuscular, intravenous or subcutaneous administration Can be prepared in a dosage form.

When the pharmaceutical composition of the present invention is prepared in the form of an oral dosage form, examples of the additives or carriers to be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, Calcium stearate, gelatin, talc, a surfactant, a suspending agent, an emulsifying agent and a diluent. When the pharmaceutical composition of the present invention is prepared in the form of an injectable preparation, the additive or carrier includes water, saline solution, aqueous glucose solution, pseudosugar solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid, fatty acid ester , Glyceride, a surfactant, a suspending agent, and an emulsifying agent.

The dosage of the pharmaceutical composition is an amount effective for treating or preventing an individual or a patient, and may be orally or parenterally administered as desired, and may be 0.01 to 1000 mg per kg of body weight per day kg, more specifically 0.1 to 300 mg per kg of body weight per day, based on the active ingredient, per parenteral administration, in an amount of 0.01 to 100 mg, more specifically 0.1 to 50 mg per kg of body weight per day 1 to several times a day. The dosage for a particular individual or patient should be determined in light of various relevant factors such as the patient's weight, age, sex, health condition, diet, time of administration, method of administration, severity of the disease, And the dose is not intended to limit the scope of the invention in any way.

Another aspect of the present invention provides a method of treating a disease caused by abnormal activation of LSD1 comprising administering to a subject or a patient a compound of formula 1, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, Prevention or treatment of cancer.

The details of the method for preventing or treating the above can be applied to the above description of the pharmaceutical composition according to one aspect of the present invention.

In addition, the dosage for use in the above-mentioned method for preventing or treating can be applied as an amount effective for treating or preventing an individual or a patient, and the description of the dosage of the pharmaceutical composition may be applied as it is.

As used herein, the term " treating " or " treating " refers to inhibiting a disease, for example a disease, condition or disorder, Preventing or ameliorating a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of a disease, condition or disorder, i.e., preventing the disease, condition or disorder from occurring, Reversing pathology and / or signs, such as reducing the severity of the disease.

As used herein, the term " preventing " or " prevention " refers to the prevention of a disease, for example a disease, condition or disorder in a subject that may be predisposed to the disease, To prevent a condition or disorder.

The term "individual" or "patient" as used herein refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and humans .

Hereinafter, a method for producing the compound according to the present invention will be described in detail.

The abbreviations used in the following production examples, production methods and examples mean respectively the following.

HATU: 2- (1H-9-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate

HOBt: N-hydroxybenzotriazole

EDCI: 1-ethyl-3- (3-dimethylaminopropyl) carbodiamide

NaBH ₄ : Sodium borohydride

DIPEA: N, N-diisopropylethylamine

THF; Tetrahydrofuran

ClCH ₂ CH ₂ Cl: dichloroethane

DMSO: dimethylsulfoxide, EA: ethyl acetate

1,4-Dioxane: 1,4-dioxane

CH ₂ Cl ₂ : dichloromethane, EtOAc; Ethyl acetate

Na ₂ SO ₄ : anhydrous sodium sulfate

The cyclopropylamine derivative of the present invention can be synthesized using intermediates prepared in the following Reaction Scheme 1 or Reaction Scheme 2 or commercially available intermediates, and the mass spectrometric analysis of the obtained cyclopropylamine derivatives can be carried out by using Waters'Lt; / RTI > MicroMass ZQ ^TM .

The pharmaceutical composition comprising as an active ingredient the compound of the formula (I) synthesized by this production method, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, is characterized in that lysine- Lt; RTI ID = 0.0 > LSD1). ≪ / RTI >

In one embodiment, the process for preparing a compound of formula

Reacting a compound of formula (2) with an azodicarboxylate compound in an organic solvent to obtain a compound of formula (3);

Reacting a compound of formula (3) in an amine-based cyclic compound in an organic solvent to obtain a compound of formula (4);

Reacting a compound of formula 4 in an amine compound (R ₁ R ₂ NH) in an organic solvent to obtain a compound of formula 5;

Reacting a compound of formula (5) with an aryl or heteroaryl substituted cyclopropylamine derivative compound in an organic solvent to obtain a compound of formula (6); And

Removing the amine protecting group of the compound of formula 6 to obtain the compound of formula 1.

As the azodicarboxylate compound, for example, diethyl azodicarboxylate, diisopropyl azodicarboxylate and the like can be used. One of them or a mixture of two or more of them can be used .

The process for preparing the compound of formula (1) according to one embodiment of the present invention can be represented by the following reaction formula (1).

[Reaction Scheme 1]

Wherein A, W, R ¹ , R ² , R ³ , R ⁴ _, R ⁵ , n, m and l are as defined in Formula 1. In the above Reaction Scheme 1, the protecting group (PG) may be a butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), a 9-fluorenylmethoxycarbonyl group (Fmoc), an acetyl group, a benzoyl group or a tosyl group.

The manufacturing method according to the above description will be described in more detail as follows.

Step 1)

2 (1 to 1.5 eq.) Was dissolved in tetrahydrofuran and cooled to -80 < 0 > C to -78 < 0 > C. Diethyl azodicarboxylate (1 to 1.5 equivalents) was added, the temperature was raised to room temperature, and the mixture was stirred for 30 minutes to 2 hours. The reaction mixture was cooled to -80 ° C to -78 ° C and reacted at room temperature for 2 hours to 5 hours after addition of the compound of Formula 2 (1 equivalent, standard equivalent). After completion of the reaction, the product was purified by column chromatography to obtain the target compound.

Step 2)

The cyclic compound derivative (1 to 1.5 equivalents) containing amine was dissolved in acetonitrile, and the solution was added dropwise over 1 to 3 hours. The reaction was completed at room temperature for 12 hours to 24 hours, and then purified by column chromatography to obtain the desired compound.

Step 3)

HATU (1 to 2 equivalents) or EDCI (1 to 2 equivalents), HOBt, DIPEA (1 to 1.5 equivalents) were added to dissolve the compound of Formula 4 (1 equivalent, standard equivalent) in dichloromethane. The reaction mixture was stirred at room temperature for 30 to 2 hours and R ₁ R ₂ NH material (1 to 3 equivalents) was added. The reaction was completed at room temperature for 12 hours to 24 hours, and then purified by column chromatography to obtain the desired compound.

Step 4)

5 (1 eq., Standard equivalent) was dissolved in dichloroethane and cooled to -50 to 0. Sodium hydride (2 to 3 equivalents) and acetic acid (2-3 equivalents) are added and A A solution of the substituted cyclopropylamine derivative (1-2 equivalents) in dichloroethane was slowly added dropwise. The internal temperature was raised and reacted for 2 to 6 hours. After completion of the reaction, the product was purified by column chromatography to obtain the target compound.

Step 5)

Formula 6 after treatment under acidic condition (1 eq, based on eq.), R ₃ substituted materials (1 to 1.5 eq), HATU (2 to 3 equivalents) or EDCI (2 to 3 eq.), HOBt, DIPEA (2 To 3 equivalents) was added and reacted at room temperature for 12 to 24 hours. After completion of the reaction, the desired compound was obtained by column chromatography.

In another embodiment, the process for preparing a compound of formula

Removing the amine protecting group of the compound of formula 8 and reacting it with an amine compound (R ₁ R ₂ NH) in an organic solvent to obtain a compound of formula 9;

Oxidizing the compound of formula (9) in an organic solvent to obtain a compound of formula (10);

Removing the amine protecting group of the compound of formula 10 to obtain the compound of formula 11;

Reacting a compound of formula (11) with an amine-based cyclic compound in an organic solvent to obtain a compound of formula (12); And

And reacting the compound of formula (12) with an aryl or heteroaryl substituted cyclopropylamine derivative compound in an organic solvent to obtain the compound of formula (1).

The process for preparing the compound of formula (1) according to one embodiment of the present invention can be represented by the following reaction formula (2).

[Reaction Scheme 2]

Wherein A, W, R ¹ , R ² , R ³ , R ⁴ _, R ⁵ , n, m and l are as defined in Formula 1. In the protecting group (PG or PG ') in the above Reaction Scheme 2, the amine protecting group (PG) includes a butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), a 9-fluorenylmethoxycarbonyl group (Fmoc) An acetyl group, a benzoyl group, or a tosyl group.

The manufacturing method according to the above description will be described in more detail as follows.

Step 1)

HATU (1-2 equivalents), DIPEA (2-3 equivalents) was added to the solution of formula 8 (1 equiv., Standard equivalent) in dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes to 1 hour, and was added to the R ₁ R ₂ NH material (1 to 1.5 eq.). And reacted at room temperature for 12 to 24 hours. After the reaction was completed, dichloromethane and water were added to the reaction mixture, and the organic layer was separated. Washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained objective compound was dissolved in dichloromethane and an organic base (10 to 20 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours. When the reaction was completed, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to obtain the target compound.

Step 2)

R ₃ is dissolved substituted material (1 to 2 equivalents) in 25 mL dichloromethane HATU or EDCI (1 to 1.5 eq), HOBt (0.1 to 0.5 eq), DIPEA (3 to 4 eq) was added and 30 minutes at room temperature And stirred for 2 hours. (9 equivalents, standard equivalent) was added and the mixture was stirred at room temperature for 12 hours to 24 hours. After completion of the reaction, the product was purified by column chromatography to obtain the desired compound.

Step 3)

10 (1 eq., Standard equivalent) was dissolved in 1,4-dioxane, 4N hydrochloric acid 1,4-dioxane solution was added, and the mixture was stirred at room temperature for 3 hours to 5 hours. When the reaction was completed, the solvent was concentrated under reduced pressure, and the resulting solid was filtered and washed with hexane to obtain the desired compound.

Step 4)

HATU or EDCI (1 to 1.5 equivalents) and DIPEA (2-3 equivalents) were added to the compound of Formula 11 (1 equiv., Standard equivalent) in dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes to 2 hours and a cyclic compound derivative containing amine (1 to 1.5 equivalents) was added. And the mixture was stirred at room temperature for 12 hours to 24 hours. After completion of the reaction, the product was purified by column chromatography to obtain the target compound.

Step 5)

The compound of formula 12 (1 eq., Reference material) was dissolved in dichloroethane and cooled to -50 ° C to -30 ° C. Sodium hydride (1 to 2 equivalents) and acetic acid (1 to 2 equivalents) are added and A A solution of the substituted cyclopropylamine derivative (1 to 1.5 equivalents) in dichloroethane was slowly added dropwise. The internal temperature was raised and stirred for 2 to 6 hours. After completion of the reaction, the product was purified by column chromatography to obtain the target compound.

The method for preparing the compound of formula (1) is not limited to those described in the present specification, and those skilled in the art of organic chemistry can produce it by any method using known techniques. In addition, although the production method of the above-mentioned chemical formula 1 has been described by way of specific examples, the specific reaction conditions such as the amount of the reaction solvent, the base and the amount of the reaction material are not limited to those described in the present specification, And can not be construed as limiting the scope of the invention.

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, these examples and experimental examples are provided to aid understanding of the present invention, and the scope of the present invention is not limited thereto in any sense.

Example 1: Synthesis of N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) Propylamino) piperidin-1-yl) propan-2-yl) - [1,1'-biphenyl] -4-carboxamide

Step 1) Preparation of N- (tert-butoxycarbonyl) -L-serine beta-lactone

Triphenylphosphine (17.9 g, 68.2 mmol) was dissolved in 630 mL of tetrahydrofuran and cooled to -78 < 0 > C. Diethyl azodicarboxylate (10.7 mL, 68.2 mmol) was added, the temperature was raised to room temperature and stirred for 30 min. The temperature was cooled to -78 ° C and N-tert-butoxycarbonyl-L-serine was diluted in 105 mL of tetrahydrofuran and added dropwise for 20 minutes. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and solidified with ethyl acetate: hexane (1: 1, 200 mL) and filtered. The filtrate was concentrated and the resulting residue was purified by column chromatography (ethyl acetate: hexane = 1: 1 (v / v)) to obtain the desired compound (5.2 g, 41%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.47 (s, 9H), 4.45 (m, 2H), δ 5.10 (m, 1H), 5.22 (m, 1H)

Step 2) Preparation of (S) -2 - ((tert-butoxycarbonyl) amino) -3- (4-oxopiperidin-1-yl) propanoic acid

(1 g, 5.34 mmol) was dissolved in 20 mL of acetonitrile, and 4-piperidinone (0.53 g, 5.34 mmol) was diluted in 30 mL of acetonitrile And added dropwise for 1 hour. The mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure. The residue was purified by column chromatography to give the desired compound (100 mg, 6.5%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.42 (s, 9H), 2.59 (m, 2H), 2.92 (m, 1H) 3.23 (m, 3H), 4.23 (m, 1H)

Step 3) Synthesis of tert-butyl (S) - (1- (4- (methylsulfonyl) piperazin-1-yl) -1-oxo-3- (4-oxopiperidin- - yl) carbamate

(40 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL) and a solution of (S) -2 - ((tert- butoxycarbonyl) amino) -3- HATU (64 mg, 0.17 mmol), DIPEA (0.24 mL, 1.4 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes and 1- (methylsulfonyl) piperazine (55 mg, 0.209 mmol) was added. And the mixture was stirred at room temperature for 12 hours. After the reaction was completed, dichloromethane and water were added to the reaction mixture, and the organic layer was separated. Washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1 (v / v)) to obtain the desired compound (11 mg, 18%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.45 (s, 9H), 2.44 (m, 4H), 2.72 (m, 2H), 2.81 (s, 3H), 2.84 (m, 3H), 3.26 ( (m, 2H), 3.27 (m, 2H), 3.59 (m, 2H), 3.84

Step 4) Synthesis of tert-butyl ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) Propyl) amino) piperidin-1-yl) propan-2-yl) carbamate

(S) - (1- (4- (methylsulfonyl) piperazin- 1 -yl) -1-oxo-3- (4-oxopiperidin- Carbamate (360 mg, 0.996 mmol) was dissolved in 6 mL of dichloroethane and the temperature was cooled to -35. (1R) -1-amino-2-phenylcyclopropane (133 mg, 0.996 mmol) was diluted with 2 mL of dichloroethane to which was added sodium hydrogen sulphate (528 mg, 2.49 mmol) and acetic acid The solution was slowly added dropwise. The temperature of the reaction mixture was raised to 0 and stirred for 2 hours. After the reaction was completed, water and ethyl acetate were added to the reaction mixture and the organic layer was separated. Washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1 (v / v)) to obtain the desired compound (200 mg, 37%).

¹ H-NMR (300 MHz, CDCl ₃ ):? 1.06 (m, 2H), 1.44 (s, 9H), 1.85-1.78 (m, 3H), 2.31-2.18 2H), 7.18 (m, 2H), 2.81 (s, 3H), 2.93 (m, 1H), < / RTI > 7.27 (m, 2H)

Step 5) Synthesis of N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1- ) Amino) piperidin-1-yl) propan-2-yl) - [1,1'-biphenyl] -4-carboxamide

3- (4 - (((1R, 2S) -2-phenylcyclopropyl) amino-1-oxo- ) Piperidin-1-yl) propan-2-yl) carbamate To 1 mL of dichloromethane, add 1 mL of TFA and stir at room temperature for 2 hours. The residue obtained by concentration under reduced pressure was used for next support without purification.

(21 mg, 0.109 mmol), HOBt (2.5 mg, 0.018 mmol) and DIPEA (0.031 mL, 0.182 mmol) were dissolved in dichloromethane And the mixture was stirred at room temperature for 30 minutes. The obtained residue was diluted with 1 mL of dichloromethane, added dropwise to the reaction mixture, and stirred at room temperature for 12 hours. After the reaction was completed, dichloromethane and water were added to the reaction mixture, and the organic layer was separated. Washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1 (v / v)) to obtain the desired compound (20 mg, 35%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.09 (m, 2H), 1.42 (m, 2H), 1.64 (m, 1H), 2.30-1.90 (m, 8H), 2.80 (s, 3H), 2H), 3.75-3.56 (m, 2H), 4.05-3.90 (m, 2H), 5.18 (m, (m, 2H), 7.17 (m, 1H), 7.48-7.36 (m, 4H), 7.66-7.58

^{MS (ESI +): [M} + H] + m / z 630.3

Example 2: Synthesis of N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) Propyl) amino) piperidin-1-yl) propan-2-yl) benzamide

The procedure of Example 1 was repeated except that benzoic acid was used instead of biphenyl-4-carboxylic acid in step 5) of Example 1 to obtain the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.04 (m, 2H), 1.88 (m, 2H), 2.19-1.91 (m, 3H), 2.30 (m, 2H), 2.73 (m, 2H), (M, 2H), 3.63 (m, 2H), 2.63 (s, 3H) , 6.69 (m, IH), 7.15 (m, IH), 7.32-7.25 (m, 4H), 7.52-7.40

^{MS (ESI +): [M} + H] + m / z 554.3

Example 3: Synthesis of N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) Propyl) amino) piperidin-1-yl) propan-2-yl) cyclohexanecarboxamide

The procedure of Example 1 was repeated except that cyclohexylcarboxylic acid was used instead of biphenyl-4-carboxylic acid in step 5) of Example 1 to obtain the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.11 (m, 2H), 1.46 (m, 8H), 1.93 (m, 8H), 2.17 (m, 2H), 2.21 (m, 1H), 2.69 ( 2H), 3.99 (m, IH), 4.05 (m, IH), 5.01 (m, IH) 2H), 7.24 (m, 2H), 7.34 (m, 2H)

^{MS (ESI +): [M} + H] + m / z 560.3

Example 4: Synthesis of N - ((S) -1- oxo-1- (phenylamino) -3- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- ) Propan-2-yl) - [1,1'-biphenyl] -4-carboxamide

The procedure of Example 1 was repeated except that aniline was used instead of 1- (methylsulfonyl) piperazine in the step 3) of Example 1 to obtain the target compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.15 (m, 2H), 1.59 (m, 2H), 1.93 (m, 1H), 2.06 (m, 2H), 2.10 (m, 2H), 2.35 ( 2H), 2.38 (m, IH), 2.64 (m, IH), 2.82 (m, IH), 3.03 , 7.06 (m, 2H), 7.24 (m, 2H), 7.27 (m, 1H), 7.38 m, 2H), 7.92-7.69 (m, 4H), 7.94 (d, 2H), 10.88

^{MS (ESI +): [M} + H] + m / z 559.3

Example 5: Synthesis of N - ((S) -1- oxo-1- (phenylamino) -3- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- ) Propan-2-yl) benzamide

Step 3) of Example 1 was repeated except that aniline was used instead of 1- (methylsulfonyl) piperazine in Example 1, step 3) was repeated except that benzylic acid , The procedure of Example 1 was repeated to give the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.11 (m, 2H), 1.61 (m, 3H), 1.92 (m, 1H), 2.09 (m, 2H), 2.36 (m, 2H), 2.47 ( (m, 1H), 2.65 (m, 1H), 2.80 (m, 1H), 2.94 2H), 7.18-7.13 (m, 2H), 7.55-7.25 (m, 9H), 7.87

^{MS (ESI +): [M} + H] + m / z 483.3

Example 6: Synthesis of N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1,4- - phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) - [1,1'-biphenyl] -4-carboxamide

Step 1) Preparation of tert-butyl (S) -3-amino-4- (4- (methylsulfonyl) piperazin-1-yl) -4-oxobutanoate

HATU (4.6 g, 12.07 mmol) and DIPEA (3.5 mL, 20.1 mmol) were added to dissolve Fmoc-Asp (OtBu) -OH (4.1 g, 10.06 mmol) in 40 mL of dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes and 1- (methylsulfonyl) piperazine (1.8 g, 11.07 mmol) was added. And the mixture was stirred at room temperature for 12 hours. After the reaction was completed, dichloromethane and water were added to the reaction mixture, and the organic layer was separated. Washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The desired compound was used in the next reaction without further purification.

The obtained target compound (5.6 g, 10.06 mmol) was dissolved in 50 mL of dichloromethane, and piperidine (9.9 mL, 100.6 mmol) was added. The mixture was stirred at room temperature for 2 hours, and when the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: hexane = 0: 100 (v / v) -> 50:50 (v / v), dichloromethane: methanol = 10: 1 (v / v) 2.5 g, 74%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.44 (s, 9H), 2.81 (s, 3H), 3.79-3.29 (m, 7H), 3.81 (m, 2H), 3.95 (m, 1H), 4.24 (m, 1 H)

Step 2) Synthesis of tert-butyl (S) -3 - ([1,1'-biphenyl] -4-carboxamido) -4- (4- (methylsulfonyl) piperazin- -Oxobutanoate < / RTI >

(1.7 g, 8.94 mmol), HOBT (0.2 mg, 1.47 mmol) and DIPEA (2.9 mL, 22.63 mmol) were dissolved in 25 mL of dichloromethane and the mixture was stirred at room temperature Lt; / RTI > for 30 minutes. 4-oxobutanoate (2.5 g, 7.45 mmol) was added and the mixture was stirred at room temperature for 12 hours. Respectively. After completion of the reaction, the reaction was completed, dichloromethane and water were added to the reaction mixture, and the organic layer was separated. Washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1 (v / v)) to obtain the desired compound (3 g, 79%).

¹ H-NMR (300 MHz, CDCl ₃ ):? 1.49 (s, 9H), 2.83 (s, 3H), 3.23-3.18 (m, 6H), 3.82-3.31 ), 7.50 (m, 2H), 7.60 (m, 2H)

Step 3) Synthesis of (S) -3 - ([1,1'-biphenyl] -4-carboxamido) -4- (4- (methylsulfonyl) piperazin- Manufacture of Noik Mountain

(S) -3 - ([1,1'-biphenyl] -4-carboxamido) -4- (4- (methylsulfonyl) piperazin- (3 g, 5.81 mmol) was dissolved in 15 mL of 1,4-dioxane and 15 mL of a 4N solution of 1,4-dioxane hydrochloride was added. After stirring at room temperature for 4 hours, the solvent was concentrated under reduced pressure when the reaction was completed. The resulting solid was filtered and washed with hexane to give the desired compound (1.4 g, 53%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 2.98 (s, 1H), 3.69-3.31 (m, 9H), 3.78 (m, 1H), 4.88 (m, 1H), 7.44 (m, 1H), 2H), 7.56 (m, 2H), 7.76 (m, 2H), 7.83

Step 4) Synthesis of (S) -N- (1- (4- (methylsulfonyl) piperazin-1-yl) -1,4-dioxo-4- -2-yl) - [1,1'-biphenyl] -4-carboxamide

(S) -3 - ([1,1'-biphenyl] -4-carboxamido) -4- (4- (methylsulfonyl) piperazin- 1 -yl) -4-oxobutanoic acid 100 mg, 0.218 mmol) was dissolved in 2 mL of dichloromethane, and HATU (120 mg, 0.261 mmol) and DIPEA (0.38 mL, 0.6528 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes and 4-piperidinone (43 mg, 0.218 mmol) was added. And the mixture was stirred at room temperature for 12 hours. After the reaction was completed, dichloromethane and water were added to the reaction mixture, and the organic layer was separated. Washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1 (v / v)) to obtain the desired compound (75 mg, 64%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 2.80 (s, 3H), 2.82 (m, 1H), 3.26-3.19 (m, 8H), 3.64 (m, 4H), 3.88 (m, 4H), 2H), 7.51-7.27 (m, 3H), 7.71-7.61 (m, 4H), 7.90 (d, 2H)

Step 5) Synthesis of N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1,4- Phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) - [1,1'- biphenyl] -4-carboxamide

(S) -N- (1- (4- (methylsulfonyl) piperazin-1-yl) -1,4-dioxo-4- (4-oxopiperidin- Yl) - [1,1'-biphenyl] -4-carboxamide (75 mg, 0.139 mmol) was dissolved in 2 mL of dichloroethane and the temperature was cooled to -35 ° C. (1R) -1-amino-2-phenylcyclopropane (18.5 mg, 0.139 mmol) was diluted with 1 mL of dichloroethane and the reaction mixture was diluted with dichloromethane The solution was slowly added dropwise. The temperature of the reaction mixture was raised to 0 캜 and stirred for 2 hours. After the reaction was completed, water and ethyl acetate were added to the reaction mixture and the organic layer was separated. Washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10: 1 (v / v)) to obtain the desired compound (9 mg, 10%).

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.06 (m, 2H), 1.97-1.86 (m, 4H), 2.17 (m, 1H), 2.75 (s, 3H), 2.86 (m, 4H), (M, 2H), 3.64 (m, 1H), 3.82 (m, 1H), 4.40 (M, 3H), 7.49-7.42 (m, 3H), 7.67-7.60 (m, 4H), 7.89

^{MS (ESI +): [M} + H] + m / z 658.3

Example 7: Preparation of N - ((2S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1,4- - phenylcyclopropyl) amino) pyrrolidin-1-yl) butan-2-yl) - [1,1'-biphenyl] -4-carboxamide

The procedure of Example 6 was repeated except that 3-pyrrolidinone was used instead of 4-piperidinone in the step 4) of Example 6 to obtain the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.13 (m, 2H), 1.87 (m, 1H), 2.17-1.96 (m, 1H), 2.32 (m, 1H), 2.76 (s, 3H), 2H), 7.17 (m, 2H), 2.39 (m, 2H), 2.39 (m, , 7.26 (m, 2H), 7.49-7.39 (m, 3H), 7.88-7.59 (m, 3H), 7.90

^{MS (ESI +): [M} + H] + m / z 644.3

Example 8: Preparation of N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1,4- - phenylcyclopropyl) amino) azetidin- 1 -yl) butan-2-yl) - [1,1'-biphenyl] -4-carboxamide

The procedure of Example 6 was repeated except that 3-azetidinone was used instead of 4-piperidinone in step 4) of Example 6 to obtain the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.07 (m, 2H), 1.93 (m, 1H), 2.29 (m, 1H), 2.79 (s, 3H), 3.29-3.27 (m, 3H), 1H), 7.09 (m, 2H), 7.28-7. 15 (m, 1H) m, 3H), 7.51-7.41 (m, 3H), 7.88-7.61 (m, 4H), 7.91

^{MS (ESI +): [M} + H] + m / z 630.3

Example 9: Synthesis of N - ((S) -1- (cyclohexylamino) -1,4-dioxo-4- (4- (((1R, 2S) -2- phenylcyclopropyl) amino) piperidine -1-yl) butan-2-yl) benzamide

Except using cyclohexylamine instead of l- (methylsulfonyl) piperazine in step 1 of Example 6 and using benzoic acid instead of [l, l'-biphenyl] -4-carboxylic acid in step 2) The procedure of Example 6 was repeated to give the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.08 (m, 2H), 1.38 (m, 4H), 1.68 (m, 4H), 1.88-1.85 (m, 6H), 2.01 (m, 1H), 2H), 3.99 (m, 1H), 3.99 (m, 1H), 3.99 (m, (m, 2H), 7.19 (m, 2H), 7.27 (m, IH), 7.56-7.44

^{MS (ESI +): [M} + H] + m / z 517.3

Example 10: Synthesis of N - ((S) -1,4-dioxo-4- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- (Piperidin-1-yl) butan-2-yl) benzamide

Except that piperidine was used instead of 1- (methylsulfonyl) piperazine in step 1) of Example 6 and benzoic acid was used instead of [l, l'-biphenyl] -4-carboxylic acid in step 2) The procedure of Example 6 was repeated to give the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.06 (m, 2H), 1.58 (m, 4H), 1.87 (m, 3H), 2.18 (m, 2H), 2.89-2.71 (m, 4H), 2H), 7.29-7. 18 (m, 3H), 7.51-7. 42 (m, 1H) m, 3 H), 7.84 (m, 2 H)

^{MS (ESI +): [M} + H] + m / z 503.3

Example 11: Synthesis of N - ((S) -1- (4-chlorophenyl) amino) -1,4-dioxo-4- (4- ) Piperidin-1-yl) butan-2-yl) benzamide

Except that 4-chloroaniline was used instead of 1- (methylsulfonyl) piperazine in step 1 of Example 6 and benzoic acid was used instead of [1,1'-biphenyl] -4-carboxylic acid in step 2) And the procedure of Example 6 was repeated to give the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.04 (m, 2H), 1.46-1.25 (m, 4H), 2.01 (m, 2H), 2.19 (m, 1H), 2.30 (m, 1H), 1H), 7.17 (m, 1H), 7.24 (m, 1H), 2.74 (m, 2H), 8.34 (m, IH), 9.73 (m, IH), 7.54 (m,

^{MS (ESI +): [M} + H] + m / z 545.2

Example 12: Preparation of 4-methoxy-N - ((S) -1- (4-methylpiperazin-1-yl) 2-phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide

Except that 1-methylpiperazine was used instead of 1- (methylsulfonyl) piperazine in step 1 of Example 6 and 4-methoxypyridine was used instead of [1,1'-biphenyl] -4-carboxylic acid in step 2) Benzoic acid was used, the procedure of Example 6 was repeated to give the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.06 (m, 2H), 1.68-1.63 (m, 4H), 1.95-1.84 (m, 4H), 2.28 (s, 3H), 2.42 (m, 4H ), 2.88-2.84 (m, 3H), 3.09 (m, IH), 3.77-3.48 (m, 4H), 3.84 2H), 7.01 (m, 2H), 7.17 (m, IH), 7.26 (m, IH), 7.36

MS (ESI ⁺ ): [M + H] < ⁺ >

Example 13: Preparation of 3-methoxy-N - ((S) -1- (4-methylpiperidin- Phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide

Except that 1-methylpiperazine was used instead of 1- (methylsulfonyl) piperazine in step 1 of Example 6 and 3-methoxypyridine was used instead of [1,1'-biphenyl] -4-carboxylic acid in step 2) Benzoic acid was used, the procedure of Example 6 was repeated to give the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.03 (m, 2H), 1.63 (m, 4H), 1.91-1.82 (m, 4H), 2.28 (s, 3H), 2.47-2.42 (m, 4H 1H), 7.03 (m, IH), 3.90 (m, IH) 2H), 7.17 (m, 1H), 7.42-7.22 (m, 5H), 7.58

MS (ESI ⁺ ): [M + H] < ⁺ >

Example 14: Preparation of 3- (dimethylamino) -N- (S) -1- (4-methylpiperazin-1-yl) -1,4-dioxo-4- (4- ) -2-phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide

Except that 1-methylpiperazine was used instead of 1- (methylsulfonyl) piperazine in step 1) of Example 6 and 3- (dimethyl Amino) benzoic acid was used as a starting material, the procedure of Example 6 was repeated to give the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 1.06 (m, 2H), 1.68 (m, 4H), 1.19-1.82 (m, 4H), 2.28 (s, 3H), 2.33 (m, 4H), (M, 1H), 6.85 (m, 1H), 7.01-6.99 (m, 1H) 3H), 7.31-7.18 (m, 5H), 7.48 (m, IH)

^{MS (ESI +): [M} + H] + m / z 561.4

Example 15: 4-Fluoro- N - (( S ) -1- (4-methylpiperazin-1-yl) -1,4-dioxo-4- (4 - (((1 R ,2 S ) -2-phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide

Except that 1-methylpiperazine was used instead of 1- (methylsulfonyl) piperazine in step 1) of Example 6 and 4-fluorobenzene was used instead of [1,1'-biphenyl] -4-carboxylic acid in step 2) Benzoic acid was used, the procedure of Example 6 was repeated to give the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 7.83-7.79 (m, 2H), 7.68-7.50 (m, 1H), 7.28-7.23 (m, 2H), 7.19-7.08 (m, 3H), 7.00 (d, 2H), 5.47-5.42 (m, IH), 4.43-4.37 (m, IH), 3.82-3.70 (m, 5H), 3.09 -2.29 (m, 8H), 1.91-1.82 (m, 4H), 1.33-1.18 (m, 2H), 1.07-0.99 (m, 2H).

^{MS (ESI +): [M} + H] + m / z 536.3

Example 16: 4-Chloro- N - (( S ) -1- (4-methylpiperazin-1-yl) -1,4-dioxo-4- (4 - (((1 R ,2 S ) -2-phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide

Except that 1-methylpiperazine was used instead of 1- (methylsulfonyl) piperazine in step 1) of Example 6 and 4-chlorobenzoic acid was used instead of [1,1'-biphenyl] -4-carboxylic acid in step 2) , The procedure of Example 6 was repeated to give the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 7.81-7.66 (m, 3H), 7.40 (d, 2H), 7.27-7.22 (m, 2H), 7.15 (t, 1H), 6.99 (d, 2H ), 5.50-5.46 (m, IH), 4.38 (t, IH), 3.79-3.67 (m, 5H), 3.09 (m, IH), 2.88-2.80 (m, 4H), 2.50-2.18 ), 1.90-1.86 (m, 4H), 1.25-1.21 (m, 2H), 1.03-1.00 (m, 2H).

^{MS (ESI +): [M} + H] + m / z 552.3

Example 17: Synthesis of N - ((S) -1,4-dioxo-1- (phenylamino) -4- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidine- Yl) butan-2-yl) benzamide

The procedure of Example 6 was repeated except for using aniline instead of 1- (methylsulfonyl) piperazine in step 6) and using benzoic acid instead of [1,1'-biphenyl] -4-carboxylic acid in step 2) 6 was repeated to obtain the target compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 9.63 (d, 1H), 8.33 (dd, 1H), 7.88 (d, 2H), 7.55-7.45 (m, 5H), 7.33-7.22 (m, 4H ), 7.15-7.09 (m, 2H), 7.02-6.99 (m, 2H), 5.18-5.13 (m, IH), 4.43 2H), 2.67-2.65 (m, 1H), 2.31-2.30 (m, 1H), 1.96-1.78 (m, 4H), 1.28-1.21 (m, , ≪ / RTI > 2H), 1.08-0.99 (m, 2H).

^{MS (ESI +): [M} + H] + m / z 511.3

Example 18: Synthesis of N - ((S) -1,4-dioxo-1- (phenylamino) -4- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidine- Yl) butan-2-yl) - [1,1'-biphenyl] -4-carboxamide

The procedure of Example 6 was repeated except that aniline was used instead of 1- (methylsulfonyl) piperazine in the step 1) of Example 6 to obtain the target compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 9.64 (d, 1H), 8.36 (dd, 1H), 7.95 (d, 2H), 7.67 (d, 2H), 7.62 (d, 2H), 7.55 ( 2H), 7.31-7.23 (m, 4H), 7.20-7.05 (m, 2H), 7.03-7.00 2H), 2.69-2.63 (m, 1H), 2.32-2.30 (m, 1H), 3.44 (m, 2.30 (m, 1H), 1.97-1.77 (m, 4H), 1.33-1.25 (m, 2H), 1.08-0.99 (m, 2H).

^{MS (ESI +): [M} + H] + m / z 587.3

Example 19: Synthesis of N - ((S) -1,4-dioxo-1- (phenylamino) -4- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidine- 1-yl) butan-2-yl) cyclohexanecarboxamide

Except that aniline was used instead of 1- (methylsulfonyl) piperazine in step 1 of Example 6 and cyclohexanecarboxylic acid was used instead of [1,1'-biphenyl] -4-carboxylic acid in step 2) And the procedure of Example 6 was repeated to give the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 9.41 (d, 1H), 7.50 (d, 3H), 7.32-7.23 (m, 4H), 7.16 (d, 1H), 7.08 (t, 1H), (M, 2H), 3.94-3. 75 (m, 2H), 4.97-4.92 ), 2.57-2.50 (m, IH), 2.31-2.30 (m, IH), 2.19-2.16 (m, IH), 1.92-1.75 (m, 4H), 1.07 - 0.99 (m, 2H).

^{MS (ESI +): [M} + H] + m / z 517.3

The structural formulas of the compounds obtained in Examples 1 to 19 are shown in Table 1 below.

Example Name rescue One Amino) -3-methyl-N - ((S) -1- (4- (methylsulfonyl) piperazin- Piperidin-1-yl) propan-2-yl) - [1,1'-biphenyl] -4- carboxamide

2 Amino) -3-methyl-N - ((S) -1- (4- (methylsulfonyl) piperazin- Piperidin-1-yl) propan-2-yl) benzamide

3 Amino) -3-methyl-N - ((S) -1- (4- (methylsulfonyl) piperazin- Piperidin-1-yl) propan-2-yl) cyclohexanecarboxamide

4 2-phenylcyclopropyl) amino) piperidin-1-yl) propane-2 (2S) - yl) - [1,1'-biphenyl] -4-
Carboxamide

5 2-phenylcyclopropyl) amino) piperidin-1-yl) propane-2 (2S) Yl) benzamide

6 N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1,4-dioxo-4- ) Amino) piperidin-1-yl) butan-2-yl) - [1,1'-biphenyl] -4- carboxamide

7 4 - (3 - (((1R, 2S) -2-phenylcyclopropyl) -N- (2S) -1- (4-methylsulfonyl) piperazin- Amino) pyrrolidin-1-yl) butan-2-yl) - [1,1'-biphenyl] -4- carboxamide

8 4-dioxo-4- (3 - (((1R, 2S) -2-phenylcyclopropyl) -1,2- ) Amino) azetidin-1-yl) butan-2-yl) - [1,1'-biphenyl] -4- carboxamide

9 Amino] piperidin-1-yl} -1- (cyclohexylamino) -1,4-dioxo-4- (4- (((1R, 2S) -2- phenylcyclopropyl) amino) ) Butan-2-yl) benzamide

10 N - ((S) -1,4-dioxo-4- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- -1-yl) butan-2-yl) benzamide

11 4 - (4 - (((1R, 2S) -2-phenylcyclopropyl) amino) piperidine -1-yl) butan-2-yl) benzamide

12 4- (4 - (((1R, 2S) -2-phenylcyclohexyl) -1 H-pyrrolo [
Propyl) amino) piperidin-1-yl) butan-2-yl) benzamide

13 4 - (4 - (((1R, 2S) -2-Phenylsulfanyl) Cyclo
Propyl) amino) piperidin-1-yl) butan-2-yl) benzamide

14 4- (4 - (((1R, 2S) -2- (4-methylpiperazin-1 -yl) Phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide

15 4-Flo - N - ((S) -1- (4- methylpiperazin-1-yl) -1,4-dioxo -4- (4 - (((1 R, 2 S) -2- Phenylcyclo
Propyl) amino) piperidin-1-yl) butan-2-yl) benzamide

16 4- (4 - ((( 1R , 2S ) -2-Phenyl) -4-chloro- N - (( S ) -1- Cyclo
Propyl) amino) piperidin-1-yl) butan-2-yl) benzamide

17 N - ((S) -1,4-dioxo-1- (phenylamino) -4- (4-
(((1R, 2S) -2-phenylcyclopropyl) amino) piperidin-1-yl) butan-

18 N - ((S) -1,4-dioxo-1- (phenylamino) -4- (4-
(1R, 2S) -2-phenylcyclopropyl) amino) piperidin-1-yl) butan-

19 N - ((S) -1,4-dioxo-1- (phenylamino) -4- (4-
(((1R, 2S) -2-phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) cyclohexanecarboxamide

The compounds prepared in the above Examples were subjected to the bioassay test as follows.

Test Example  One: LSD1  Histone Demethylase  Biochemical analysis

The inhibitory activity of the synthetic compound against biochemical lysine-specific demethylase-1 (LSD1) was measured. As a control group, RG6016 was used. Activity measurements were performed on a Reaction Biology (Malvern, USA). Reaction Biology (Malvern, USA) has detected the H ₂ O ₂ produced during the demethylation of the histone H3K4 residue by lysine-specific demethylase-1 (LSD1) and detected the fluorescent resorpine- (Resorufin) to determine demethylation. Table 2 below shows the inhibition of the activity of the compounds against lysine-specific demethylase-1 (LSD1), where the results are expressed as A 50 nM, 50 nM < B 500 nM and C 500 nM.

Example LSD1
(IC ₅₀ , nM) Control group A One A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 A 10 B 11 A 12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A

Claims (15)

Claims 1. A compound of the general formula (1), or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In Formula 1,
A is aryl or heteroaryl, wherein aryl or heteroaryl may be substituted or unsubstituted with one to three R &lt; ^{5 &} gt ;;
k is an integer from 0 to 2;
m and n are each independently an integer of 0 to 3, but not simultaneously 0;
W is _{-CH 2-, -C (O) -} , -C (O) NR 6 -, -S (O) -, and -S (O) ₂ - is selected from the group consisting of;
l is an integer from 0 to 4;
R ¹ and R ² are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, Alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be unsubstituted or substituted with one to five R ⁷ ;
R ¹ and R ² together with the nitrogen atom to which they are attached may form a heterocycloalkyl ring compound or a heteroaryl ring compound wherein the heterocycloalkyl ring compound or the heteroaryl ring compound is substituted with 1 to 5 R ⁷ Or unsubstituted;
R ³ is the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, heterocycloalkyl alkyl, aryl, arylalkyl, heteroaryl, and heteroaryl-alkoxy Wherein the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkylalkoxy, heterocycloalkyl, heterocycloalkylalkoxy, aryl, arylalkoxy, heteroaryl, and heteroarylalkoxy 1 to 5 R &lt; ⁷ &gt; or -NR &lt; ⁸ &gt; R &lt; ⁹ &gt;;
R &lt; ⁴ &gt; is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl;
R ⁵ is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, and -NR ¹⁰ R ¹¹ ;
R ⁶ , R ¹⁰ , R ¹¹ , and R ¹² are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, and alkynyl;
R ⁷ is selected from the group consisting of halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR ¹¹ R ¹² , cycloalkyl, cycloalkylalkoxy, heterocycloalkyl, heterocycloalkylalkoxy, , heteroaryl, ^{heteroaryl-alkoxy, C (O) R 6,} S (O) 2 R 6, NHS (O) 2 R 6, NHS (O) 2 NHR 6, NHCOR 6, NHCONHR 6, CONHR 6, and CONR ¹⁰ R &lt; ^{11 &} gt ;;
R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl ring compounds, The alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl ring compounds may be unsubstituted or substituted with one to five R ⁷ . The method according to claim 1,
A is aryl substituted or unsubstituted with one to three R &lt; ^{5 &} gt ;. The method according to claim 1,
and k is 0 or 1. The method according to claim 1,
m and n each independently represents an integer of 0 to 2, and is not 0 at the same time. The method according to claim 1,
R &lt; ⁴ &gt; is hydrogen. The method according to claim 1,
And R &lt; ⁵ &gt; is hydrogen or halogen. The method according to claim 1,
m and n are each independently an integer of 1 or 2;
W is -CH _2- or -C (O) -;
and l is 0 or 1. 8. The method of claim 7,
R ¹ and R ² are each independently selected from the group consisting of hydrogen, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₂₀ alkenyl, C ₂ -C ₂₀ alkynyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₂₀ heterocycloalkyl, C ₆ -C ₂₀ aryl, or C ₁ -C ₂₀ heteroaryl. 9. The method of claim 8,
R ¹ and R ² together with the nitrogen atom to which they are attached may form a heterocycloalkyl ring compound wherein the heterocycloalkyl ring compound may be substituted or unsubstituted with one to three R ⁷ ;
R ⁷ is halogen, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₂₀ alkenyl, C ₂ -C ₂₀ alkynyl, C ₁ -C ₂₀ alkoxy, C ₁ -C ₂₀ haloalkoxy, , _{^{cyano, -NR 11 R 12, C 3}} -C 20 cycloalkyl, C ₄ -C ₂₀ cycloalkyl, alkoxy, C ₁ -C ₂₀ heterocycloalkyl, C ₁ -C ₂₀ heterocycloalkyl-alkoxy, C ₆ -C ₂₀ aryl, C ₇ -C ₂₀ arylalkyl, C ₁ -C ₂₀ heteroaryl, C ₁ -C ₂₀ heteroaryl, ^{alkoxy, C (O) R 6,} S (O) 2 R 6, NHS (O) 2 R 6 , NHS (O) ₂ NHR ⁶ , NHCOR ⁶ , NHCONHR ⁶ , CONHR ⁶ , and CONR ¹⁰ R ¹¹ . The method according to claim 1,
A compound selected from the group consisting of the following compounds 1) to 19) or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof:
1) oxo-3- (4 - (((1R, 2S) -2-phenylcyclopropyl) -N- ((S) -1- Amino) piperidin-1-yl) propan-2-yl) - [1,1'-biphenyl] -4-carboxamide;
2) N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1- Amino) piperidin-1-yl) propan-2-yl) benzamide;
3) Preparation of N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) Amino) piperidin-1-yl) propan-2-yl) cyclohexanecarboxamide;
4) Synthesis of N - ((S) -1-oxo-1- (phenylamino) -3- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- Yl) - [1,1'-biphenyl] -4-carboxamide;
5) Preparation of N - ((S) -1-oxo-1- (phenylamino) -3- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- -2-yl) benzamide;
6) Synthesis of N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1,4-dioxo-4- Cyclopropyl) amino) piperidin-1-yl) butan-2-yl) - [1,1'-biphenyl] -4-carboxamide;
7) Synthesis of N - ((2S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1,4- Cyclopropyl) amino) pyrrolidin-1-yl) butan-2-yl) - [1,1'-biphenyl] -4-carboxamide;
8) N - ((S) -1- (4- (methylsulfonyl) piperazin-1-yl) -1,4- Cyclopropyl) amino) azetidin-1-yl) butan-2-yl) - [1,1'-biphenyl] -4-carboxamide;
9) Synthesis of N - ((S) -1- (cyclohexylamino) -1,4-dioxo-4- (4- (((1R, 2S) -2- phenylcyclopropyl) amino) Yl) butan-2-yl) benzamide;
10) N - ((S) -1,4-dioxo-4- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- 1-yl) butan-2-yl) benzamide;
11) Synthesis of N - ((S) -1 - ((4-chlorophenyl) amino) -1,4-dioxo-4- 1-yl) butan-2-yl) benzamide;
12) 4-Methoxy-N - ((S) -1- (4-methylpiperazin- Phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide;
13) 3-Methoxy-N - ((S) -1- (4-methylpiperidin- 1 -yl) -Phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide;
14) 3- (Dimethylamino) -N - ((S) -1- (4-methylpiperazin-1-yl) 2-phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide;
15) 4-Flo -N - ((S) -1- ( 4- methylpiperazin-1-yl) -1,4-dioxo -4- (4 - (((1 R, 2 S) - 2-phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide;
16) 4-chloro -N - ((S) -1- ( 4- methylpiperazin-1-yl) -1,4-dioxo -4- (4 - (((1 R, 2 S) -2 -Phenylcyclopropyl) amino) piperidin-1-yl) butan-2-yl) benzamide;
17) N - ((S) -1,4-dioxo-1- (phenylamino) -4- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- Yl) butan-2-yl) benzamide;
18) N- ((S) -1,4-dioxo-1- (phenylamino) -4- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- Yl) butan-2-yl) - [1,1'-biphenyl] -4-carboxamide; And
19) N- ((S) -1,4-dioxo-1- (phenylamino) -4- (4 - (((1R, 2S) -2- phenylcyclopropyl) amino) piperidin- Yl) butan-2-yl) cyclohexanecarboxamide. 10. A method for preventing or treating a disease caused by abnormal activation of lysine-specific demethylase-1 (LSD1) comprising a compound according to any one of claims 1 to 10 as an active ingredient and a pharmaceutically acceptable carrier &Lt; / RTI &gt; 12. The method of claim 11,
Wherein the disease caused by the abnormal activation is cancer or a neoplastic disease. 13. The method of claim 12,
The diseases caused by the abnormal activation include gastric cancer, lung cancer, liver cancer, colon cancer, small bowel cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, cystic adenoma, uterine cancer, cervical cancer, head and neck cancer, esophagus cancer, The present invention relates to a method of treating or preventing a disease selected from the group consisting of cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer, lymphoma, fibroadenoma, inflammation, diabetes, obesity, psoriasis, rheumatoid arthritis, angioma, acute or chronic nephropathy, A neurodegenerative disease, an acute infection, or an ocular disease caused by angiogenesis. 12. The method of claim 11,
A pharmaceutical composition for use in combination with an additional pharmaceutical agent for use in the prevention or treatment of diseases caused by abnormal activation of lysine-specific demethylase-1 (LSD1). 15. The method of claim 14,
Wherein the pharmaceutical composition is formulated in a pharmaceutically acceptable form, including tablets, pills, powders, capsules, syrups, emulsions or microemulsions.