KR100970670B1 - Benzamide derivative as an inhibitor of cell proliferation and a process for preparing the same - Google Patents

Benzamide derivative as an inhibitor of cell proliferation and a process for preparing the same Download PDF

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KR100970670B1
KR100970670B1 KR1020080036955A KR20080036955A KR100970670B1 KR 100970670 B1 KR100970670 B1 KR 100970670B1 KR 1020080036955 A KR1020080036955 A KR 1020080036955A KR 20080036955 A KR20080036955 A KR 20080036955A KR 100970670 B1 KR100970670 B1 KR 100970670B1
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benzamide
methyl
piperidin
benzoylamino
mmol
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KR20090111383A (en
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이진호
박종욱
이세희
백철수
이상효
박종원
홍지은
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계명대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton

Abstract

본 발명은 세포증식 억제활성을 갖는 하기 화학식 (I)의 벤즈아미드 유도체와 이의 제조방법, 약제학적으로 허용 가능한 그의 염, 그의 수화물, 그의 용매화물 또는 프로드럭, 그리고, 이를 함유하는 약제학적 조성물 및 치료제로서의 용도에 관한 것이다. The present invention provides a benzamide derivative of formula (I) having a cell proliferation inhibitory activity, a method for preparing the same, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate or a prodrug thereof, and a pharmaceutical composition containing the same, It relates to the use as a therapeutic agent.

Figure 112008028469180-pat00001
Figure 112008028469180-pat00001

상기 화학식 (I)에서 R1, R2, 및 R3는 각각 발명의 상세한 설명에서 정의하는 바와 같다. 상기 화학식의 화합물은 비정상적인 세포증식 억제활성이 우수하므로 암, 염증, 혈관 협착증 및 혈관 생성증 같은 비정상적인 세포증식과 관련된 질환에 치료제로서 유용하게 사용될 수 있다.R 1 , R 2 , and R 3 in the above formula (I) are as defined in the detailed description of the invention, respectively. Since the compound of the above formula has excellent abnormal cell proliferation inhibitory activity, it may be usefully used as a therapeutic agent in diseases related to abnormal cell proliferation such as cancer, inflammation, vascular stenosis and angiogenesis.

벤즈아미드 유도체, 세포증식, 세포성장 Benzamide Derivatives, Cell Proliferation, Cell Growth

Description

세포증식 억제제로서 유용한 벤즈아미드 유도체 및 그 제조방법{Benzamide derivative as an inhibitor of cell proliferation and a process for preparing the same}Benzamide derivative as an inhibitor of cell proliferation and a process for preparing the same

본 발명은 벤즈아미드 유도체와 이의 제조방법, 약제학적으로 허용 가능한 그의 염, 그의 수화물, 그의 용매화물, 이를 함유하는 약제학적 조성물 및 치료제로서의 용도에 관한 것이다. 본 발명은 세포증식 억제 활성을 갖는 벤즈아미드 유도체에 관한 것이다.The present invention relates to benzamide derivatives and methods for their preparation, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, pharmaceutical compositions containing them and use as therapeutic agents. The present invention relates to benzamide derivatives having cytostatic activity.

암은 역사적으로 인류의 주된 사망원인 이었으며, 산업과 기술의 발전에 따라 발생되는 암의 양상이 변화되어 왔다. 특히 수명연장과 생활형태의 변화가 발생되는 암의 종류와 발병률에 가장 많은 영향을 미쳤다. 즉 이번 세기에 들어서 일부 암들의 발병률은 현저하게 줄어들든 반면, 사회의 노령화에 따라 다른 암들의 발병은 늘어나고 있다. 연령이 증가 될수록 암의 발생률은 높아지며, 수명이 길어짐에 따라 개개인이 암에 걸릴 가능성도 증가된다고 보고되고 있다. (Rosemary C. Bonney, 2001, "Scrip's Guide to Cancer Therapies: A biotech revolution") Cancer has historically been the leading cause of death for humankind, and the pattern of cancer caused by industrial and technological developments has changed. In particular, life expectancy and lifestyle changes had the greatest impact on the type and incidence of cancer. In other words, the incidence of some cancers has declined significantly in this century, while the incidence of other cancers is increasing as society ages. It is reported that as the age increases, the incidence of cancer increases, and as the life span increases, the probability of the individual getting cancer increases. (Rosemary C. Bonney, 2001, "Scrip's Guide to Cancer Therapies: A biotech revolution")

암은 세계적으로 감염성 질환 및 심혈관계 질환에 이어서 3위의 사망원인을 차지하고, 서구사회에서는 심혈관계 질환에 이어 2위의 사망원인을 차지하고 있는 질환으로서 WHO의 World Health Report의 보고에 따르면 2001년에 총 사망자의 12.6%인 7,115,000명이 암으로 사망하였다. 또 식이, 환경의 변화 및 수명연장으로 인해 향후 25년 내에 암 발생인구가 매년 약 3천만 명으로 늘어나고 이중 2천만 명의 인구가 암으로 사망할 것으로 예상하고 있다. 2001년 한국의 암 사망자 수는 총 사망자 242,730명 중 24.8%인 60,086명으로 사망원인 1위를 차지하고 있다. 2000년도에 들어서면서부터 암으로 인한 사망이 순환기계 질환으로 인한 사망을 제치고 사망원인 1위의 질환이 되었다. 또 10년이나 20년 전에 비해 총 사망자 수는 큰 변동이 없으나 암으로 사망한 사람은 1.5배 및 2.3배로 각각 증가한 것을 알 수 있다. Cancer is the third leading cause of death worldwide following infectious and cardiovascular diseases, and Western society is the second leading cause of death after cardiovascular disease, according to a report by the World Health Report of WHO in 2001. 7,115,000 people, 12.6% of all deaths, died of cancer. In addition, due to changes in diet, the environment, and lifespan, the number of cancer-causing populations will increase to about 30 million every year within the next 25 years, of which 20 million will die of cancer. In 2001, the number of cancer deaths in South Korea was the number one cause of death, with 60,086, or 24.8% of the total 242,730 deaths. Since 2000, cancer deaths have become the number one cause of death, excluding deaths from circulatory diseases. In addition, the total number of deaths does not change much compared to 10 or 20 years ago, but the number of deaths from cancer increased 1.5 times and 2.3 times, respectively.

이처럼, 암은 파괴적인 질병이지만 많은 정도 예방이 가능한 질병이다. 암으로 인하여 초래되는 고통과 부담은 기초 연구와 치료 방법의 개선으로 줄일 수 있다고 보고되고 있다. 그동안의 많은 연구 결과 암 전체의 약 1/3 정도를 예방할 수 있다. 또한 암의 1/3정도는 수술, 방사선 치료, 항암요법 등의 효과적인 치료법을 통하여 치료될 수 있다. 따라서 기초 연구를 통한 암 발생 원인의 규명과 더불어 암을 효과적으로 치료할 수 있는 치료법의 발굴은 암의 예방과 치료 가능성을 높이게 된다.As such, cancer is a destructive disease, but to a large extent preventable disease. It is reported that pain and burden caused by cancer can be reduced by improvements in basic research and treatment. Many studies have prevented about one-third of all cancers. In addition, about one third of cancers can be treated through effective treatments such as surgery, radiation, and chemotherapy. Therefore, identifying the cause of cancer through basic research and discovering a treatment that can effectively treat cancer will increase the possibility of preventing and treating cancer.

암 환자의 치료는 여러 가지 방법이 사용되고 있으나 일반적으로 외과적 수 술(surgery), 방사선요법(radiotherapy), 화학요법(chemotherapy), 면역요법(immunotherapy), 호르몬요법(hormonaltherapy) 등이 많이 사용되고 있다. 일반적으로 외과적 수술은 다양한 암의 단계에서 적용될 수 있다. 초기단계의 암들은 대체로, 외과적 수술로 치료가 가능하지만, 암이 많이 진전되었거나, 전이가 일어난 경우에는 외과적 수술만으로는 치료가 어려워 다른 방법을 같이 사용하게 된다. 방사선 치료법은 외과적 수술이 곤란한 부위나 방사선에 특히 민감한 암의 치료에 사용되는데, 약물치료와 병행하거나, 외과적 수술 전후에 사용될 수도 있다. 약물치료는 항암제를 경구나 주사로 투여하여, 암세포의 증식에 필요한 DNA나 관련 enzyme을 파괴하거나 억제하는 방법이다. 방사선 치료나 외과적 수술과 비교하여, 약물치료가 가지는 장점은 몸의 어떤 부위에 생긴 암이라도 약물이 도달할 수 있고, 전이된 암을 치료할 수 있다는 것으로, 현재 약물치료는 전이성 암 치료에 표준 요법으로 사용되고 있다. 물론 약물요법으로 전이된 암을 완치시킬 수 있는 것은 아니지만 증상을 완화시켜 수명을 연장시켜주는 중요한 역할을 한다.There are many methods for the treatment of cancer patients, but generally surgical surgery, radiotherapy, chemotherapy, immunotherapy, hormonal therapy and the like are used. In general, surgical procedures can be applied at various stages of cancer. Early stage cancers can usually be treated with surgical procedures, but if the cancer is advanced or metastasized, surgical treatment alone is difficult to treat, so other methods are used together. Radiation therapy is used to treat areas that are difficult to operate in surgery or cancers that are particularly sensitive to radiation, which may be used in combination with medication or before or after surgery. Drug treatment is a method of destroying or inhibiting DNA or related enzymes necessary for the proliferation of cancer cells by administering oral or injection anticancer drugs. Compared to radiotherapy or surgical procedures, the advantages of drug therapy are that the drug can reach any cancer in any part of the body and can treat metastasized cancer. Currently, drug therapy is the standard therapy for treating metastatic cancer. Is being used. Of course, it is not possible to cure cancer metastasized by medication, but it plays an important role in relieving symptoms and extending lifespan.

화학요법제는 알킬화제(alkylating agent), 대사 길항제(antimetabolite), 항생제, 식물유래 알칼로이드(alkaloid) 및 호르몬제가 있으며, 생물요법제에는 면역치료제인 사이토카인(Cytokine) 및 재조합 단일클론 항체(Recombinant Monoclonal Antibody)가 있다. Chemotherapeutic agents include alkylating agents, metabolic antagonists, antibiotics, plant-derived alkaloids, and hormonal agents. Biotherapeutic agents include cytokines and recombinant monoclonal antibodies. There is).

대부분의 항암제들은 천연물로부터 추출되거나 인공적으로 합성된 생리활성 저분자 화합물 (bioactive small molecule)이다. 분자생물학의 발달에 따라, 1990년대 이후 신약 개발 과정은 주로 특정 분자 표적 (molecular target)에 대한 고효 율 스크리닝(high throughput screening; HTS)에 의해 이루어졌다. 초창기의 HTS는 대부분의 경우 정제된 단백질의 생화학적 활성을 측정하는 무세포 분석 (cell-free assay)에 의해 이루어졌다. Most anticancer agents are bioactive small molecules extracted from natural products or artificially synthesized. With the development of molecular biology, the development of new drugs since the 1990s has mainly been driven by high throughput screening (HTS) for specific molecular targets. Early HTS was done in most cases by cell-free assays that measured the biochemical activity of purified proteins.

그러나 최근에는 세포의 기능 변화 혹은 형질 변화를 분석하여 신약 후보 물질을 찾아내는 방법 (cell/phenotype-based screening; 세포/형질 기반 스크리닝)이 널리 사용되고 있다 (Hart, C. P. (2005) Finding the target after screening the phenotype. Drug Discov . Today 10, 513-519, Barberis, A. (2002) Cell-based high-throughput screens for drug discovery. Eur . Biopharm . Rev. Winter Issue). 형질 기반 스크리닝은 별도의 단백질 정제 과정이 필요 없고, 생리 조건과 유사한 환경을 이용한 기능 검색이 가능하며, 세포 독성이나 세포 투과성의 문제 등을 배제할 수 있는 등의 장점을 갖고 있다. Recently, however, cell / phenotype-based screening (Cell / Phenotype-based screening) has been widely used to analyze cell function or trait changes (Hart, CP (2005) Finding the target after screening the phenotype. Drug Discov . Today 10, 513-519, Barberis, A. (2002) Cell-based high-throughput screens for drug discovery. Eur . Biopharm . Rev. Winter Issue ). Trait-based screening does not require a separate protein purification process, it is possible to search for a function using a similar environment to physiological conditions, and has the advantage of eliminating the problems of cytotoxicity and cell permeability.

최근의 연구동향을 고려하여, 본 발명자들은 세포의 성장 및/또는 증식 기능에 기반을 두어 광범위한 연구와 수많은 실험을 행한 끝에, 비정상적 세포 증식을 억제할 수 있는, 기지의 벤즈아미드 화합물과는 전혀 다른 유도체를 합성하고, 그 저해능을 평가해 본 결과, 상기 화합물이 바람직하지 못한 세포성장으로 인한 질병들, 예를 들어, 암, 염증, 혈관 협착증 및 혈관 생성 등 비정상적 세포 증식에 관련된 질병들의 치료에 사용될 수 있음을 발견하고, 본 발명을 완성하였다. In view of recent research trends, the inventors have performed extensive studies and numerous experiments based on the growth and / or proliferation functions of cells, and thus are completely different from known benzamide compounds, which can suppress abnormal cell proliferation. By synthesizing derivatives and evaluating their inhibitory properties, the compounds can be used for the treatment of diseases associated with abnormal cell growth, such as cancer, inflammation, vascular stenosis and angiogenesis, such as undesirable cell growth. It has been found that the present invention has been completed.

본 발명은 비정상적 세포증식 억제제로서 효능이 우수한 신규 벤즈아미드 유도체, 이의 이성질체 또는 약제학적으로 허용가능한 이들의 염; 이들의 용매화물, 수화물 또는 프로드럭을 제공하는 것을 목적으로 한다.The present invention provides novel benzamide derivatives, isomers thereof having excellent efficacy as an abnormal cell proliferation inhibitor. Pharmaceutically acceptable salts thereof; It is an object to provide solvates, hydrates or prodrugs thereof.

또한, 본 발명의 다른 목적은 상기 벤즈아미드 유도체의 화합물의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing a compound of the benzamide derivative.

또한, 본 발명의 다른 목적은 상기 벤즈아미드 유도체, 이의 이성질체 또는 약제학적으로 허용 가능한 이들의 염; 이들의 용매화물, 수화물 또는 프로드럭을 유효성분으로 포함하는 약제학적 조성물을 제공하는 것이다.In addition, another object of the present invention is the benzamide derivative, an isomer thereof or Pharmaceutically acceptable salts thereof; It is to provide a pharmaceutical composition comprising these solvates, hydrates or prodrugs as an active ingredient.

상기 목적을 달성하기 위하여, 본 발명은 신규한 2, 5-디아미노벤즈아미드 유도체인 하기 화학식 (I)의 화합물, 이의 이성질체 또는 약제학적으로 허용가능한 이들의 염; 이들의 용매화물, 수화물 또는 프로드럭을 제공한다.In order to achieve the above object, the present invention provides a compound of formula (I), an isomer thereof or a novel 2,5-diaminobenzamide derivative Pharmaceutically acceptable salts thereof; These solvates, hydrates or prodrugs are provided.

[화학식 I][Formula I]

Figure 112008028469180-pat00002
Figure 112008028469180-pat00002

상기 식 중 R1과 R2는 각각 독립적으로 치환 또는 비치환 C1-C6 알킬; 치환 또는 비치환 아릴; 또는 치환 또는 비치환 아릴아민이고,Wherein R 1 and R 2 are each independently substituted or unsubstituted C 1 -C 6 Alkyl; Substituted or unsubstituted aryl; Or substituted or unsubstituted arylamine,

R3은 치환 또는 비치환 C1-C6 알킬아미드; 치환 또는 비치환 아릴아미드; 또는 치환 또는 비치환 유레아이다.R 3 is substituted or unsubstituted C 1 -C 6 Alkylamides; Substituted or unsubstituted arylamides; Or substituted or unsubstituted urea.

상기 화학식 (I)의 화합물은 비정상적 세포성장 또는 세포증식에 의한 질병의 치료 및/또는 예방에 유용하게 사용될 수 있다.The compound of formula (I) may be usefully used for the treatment and / or prevention of diseases caused by abnormal cell growth or cell proliferation.

이하 본 발명에 대하여 구체적으로 설명한다. Hereinafter, the present invention will be described in detail.

본 발명의 하나의 태양으로, 본 발명은 하기 화학식(I)로 나타내는 2,5-디아미노벤즈아미드 유도체 화합물에 관한 것이다.In one aspect of the present invention, the present invention relates to a 2,5-diaminobenzamide derivative compound represented by the following general formula (I).

Figure 112008028469180-pat00003
Figure 112008028469180-pat00003

상기 식 중 R1과 R2는 각각 독립적으로 치환 또는 비치환 C1-C6 알킬; 치환 또 는 비치환 아릴; 또는 치환 또는 비치환 아릴아민이고,Wherein R 1 and R 2 are each independently substituted or unsubstituted C 1 -C 6 Alkyl; Substituted or unsubstituted aryl; Or substituted or unsubstituted arylamine,

R3은 치환 또는 비치환 C1-C6 알킬아미드; 치환 또는 비치환 아릴아미드; 또는 치환 또는 비치환 유레아이다R 3 is substituted or unsubstituted C 1 -C 6 Alkylamides; Substituted or unsubstituted arylamides; Or substituted or unsubstituted urea

상기 화학식(I)에서, 상기 R1은 In formula (I), R 1 is

바람직하게는 Preferably

C1-C6 알킬 또는 아릴로 치환된 아민; C1-C6 알콕시, C1-C6 알킬 아미노, 몰포린, 피레리딘, 피롤리딘, 피페라진, 4-알킬피페라진 및 방향족 화합물로 구성된 군에서 선택된 하나 또는 그 이상의 치환기로 치환된 C1-C6 알킬 아민; 몰포린; 피레리딘; 피롤리딘; 피페라진; 또는 4-알킬피페라진이고, Amines substituted with C 1 -C 6 alkyl or aryl; Substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkyl amino, morpholine, pyreridine, pyrrolidine, piperazine, 4-alkylpiperazine and aromatic compounds C 1 -C 6 alkyl amines; Morpholine; Pyreridine; Pyrrolidine; Piperazine; Or 4-alkylpiperazine,

더욱 바람직하게는 More preferably

C1-C5 시클로알킬아민; 1-페닐에틸아민; 몰포린; 피페라진; 4-메틸피페라진; C 1 -C 5 cycloalkylamine; 1-phenylethylamine; Morpholine; Piperazine; 4-methylpiperazine;

피페리딘; 및 몰포린, 4-메틸피페라진, C1-C5 알킬아미노, 메톡시로 이루어진 군에서 선택된 하나 또는 그 이상의 치환기로 치환된 C1-C5 알킬아민이며, Piperidine; And morpholine, 4-methylpiperazine, and C 1 -C 5 alkyl, methoxy C 1 -C 5 alkylamine substituted with one or more substituents selected from the group consisting of,

가장 바람직하게는Most preferably

C1-C5 알킬아미노로 치환된 C1-C5 알킬아민이다. C 1 -C 5 alkylamine substituted with C 1 -C 5 alkylamino.

상기 화학식(I)에서, 상기 R2는 In Formula (I), R2 is

바람직하게는 Preferably

C1-C6 알킬아민, 시클로알킬 및 방향족 화합물로 이루어진 군에서 선택된 하나 이상의 치환기로 치환된 아민; 몰포린; 피레리딘; 알킬피페리딘; 피롤리딘; 피페라진; 4-알킬피페라진; 할로겐 및 C1-C6 알콕시로 치환된 아릴 피페라진; 퀴놀린; 이소퀴놀린이며, Amines substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkylamines, cycloalkyls and aromatic compounds; Morpholine; Pyreridine; Alkyl piperidine; Pyrrolidine; Piperazine; 4-alkylpiperazine; Aryl piperazine substituted with halogen and C 1 -C 6 alkoxy; Quinoline; Isoquinoline,

더욱 바람직하게는 More preferably

C1-C5 시클로알킬아민; 몰포린; 피페라진; 4-메틸피페라진; 피페리딘; 4-메틸피페리딘; 메톡시페닐 또는 페닐로 치환된 피페라진; 또는 메톡시페닐 또는 페닐로 치환된 이소퀴놀린이며, C 1 -C 5 cycloalkylamine; Morpholine; Piperazine; 4-methylpiperazine; Piperidine; 4-methylpiperidine; Piperazine substituted with methoxyphenyl or phenyl; Or isoquinoline substituted with methoxyphenyl or phenyl,

가장 바람직하게는Most preferably

4-메틸피페리딘; 또는 메톡시페닐 또는 페닐로 치환된 피페라진이다. 4-methylpiperidine; Or piperazine substituted with methoxyphenyl or phenyl.

상기 화학식(I)에서, 상기 R3는 In formula (I), R 3 is

바람직하게는 Preferably

C1-C6 알킬, 시클로알킬 및 방향족 화합물로 이루어진 군에서 선택된 하나 이상의 치환기로 치환된 아미드; Amides substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, cycloalkyl and aromatic compounds;

할로겐, C1-C6 알킬아민, 몰포린, 피레리딘, 피롤리딘, 피페라진 및 4-알킬피페라진으로 이루어진 군에서 선택된 하나 이상의 치환기로 치환된 C1-C6 알킬 아 미드; 또는Halogen, C 1 -C 6 alkyl amines, morpholine, Pirelli Dean, pyrrolidine, piperazine, and the C 1 -C 6 alkyl substituted imide Oh from the group consisting of 4-alkyl piperazine with one or more substituents selected; or

할로겐, C1-C6 알킬아민, 몰포린, 피레리딘, 피롤리딘, 피페라진, 4-알킬피페라진으로 이루어진 군에서 선택된 하나 이상의 치환기로 치환된 방향족 아미드이며,An aromatic amide substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 6 alkylamine, morpholine, pyreridine, pyrrolidine, piperazine, 4-alkylpiperazine,

더욱 바람직하게는 More preferably

C1-C5 알킬, C1-C5 시클로알킬, 플루오로, 클로로, 브로모, 트리플루오로메틸로 이루어진 군에서 선택된 하나 또는 그 이상의 치환기로 치환된 벤즈아미드; 수소, 클로로, C1-C5 알킬아미노로 이루어진 군에서 선택된 하나 또는 그 이상의 치환기로 치환된 C1-C5 알킬아미드; 4-메틸피페라진 유레아; 또는 C1-C5 알킬옥시카바네이트, C1-C5 알킬, 벤질로 이루어진 군에서 선택된 하나 또는 그 이상의 치환기로 치환된 이소니페코틱아미드이며,Benzamide substituted with one or more substituents selected from the group consisting of C 1 -C 5 alkyl, C 1 -C 5 cycloalkyl, fluoro, chloro, bromo, trifluoromethyl; A C 1 -C 5 alkyl amides substituted with hydrogen, chloro, one or more substituents selected from the group consisting of C 1 -C 5 alkylamino; 4-methylpiperazine urea; Or C 1 -C 5 and the iso you Chapeco tick amide substituted with alkyloxy cover carbonate, one or more substituents selected from the group consisting of C 1 -C 5 alkyl, benzyl,

가장 바람직하게는 Most preferably

C1-C5 알킬로 치환된 벤즈아미드; 또는 클로로로 치환된 C1-C5 알킬아미드이다.Benzamide substituted with C 1 -C 5 alkyl; Or C 1 -C 5 alkylamides substituted with chloro.

용어 "알킬(alkyl)"은 지방족 탄화수소 그룹을 의미한다. 알킬 부위는 어떠한 알켄이나 알킨 부위를 포함하고 있지 않음을 의미하는 "포화 알킬(saturated alkyl)" 그룹일 수 있다. 알킬 부위는 적어도 하나의 알켄 또는 알킨 부위를 포함 하고 있는 있음을 의미하는 "불포화 알킬(unsaturated alkyl)" 부위일 수도 있다. "알켄(alkene)" 부위는 적어도 두 개의 탄소원자가 적어도 하나의 탄소-탄소 이중 결합으로 이루어진 그룹을 의미하며, "알킨(alkyne)" 부위는 적어도 두 개의 탄소원자가 적어도 하나의 탄소-탄소 삼중 결합으로 이루어진 그룹을 의미한다. 포화이든 불포화이든 간에 알킬 부위는 분지형, 직쇄형 또는 환형일 수 있다.The term "alkyl" refers to an aliphatic hydrocarbon group. The alkyl moiety can be a "saturated alkyl" group, meaning that it does not contain any alkenes or alkyne moieties. The alkyl moiety may be an "unsaturated alkyl" moiety, meaning that it contains at least one alkene or alkyne moiety. "Alkene" moiety means a group of at least two carbon atoms consisting of at least one carbon-carbon double bond, and an "alkyne" moiety means at least two carbon atoms having at least one carbon-carbon triple bond Means a group. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain or cyclic.

알킬 그룹은 1 내지 20 개의 탄소원자를 가질 수 있다. 알킬 그룹은 1 내지 10 개의 탄소원자들을 가지는 중간 크기의 알킬일 수도 있으나, 바람직하게는 1 내지 6 개의 탄소원자들을 가지는 저급알킬이다. 예를 들어, C1-C4 알킬은 알킬쇄에 1 내지 4 개의 탄소원자, 즉, 알킬쇄는 메틸, 에틸, 프로필, 이소-프로필, n-부틸, 이소-부틸, sec-부틸 및 t-부틸로 이루어진 군에서 선택됨을 나타낸다.Alkyl groups may have from 1 to 20 carbon atoms. The alkyl group may be a medium sized alkyl having 1 to 10 carbon atoms, but is preferably lower alkyl having 1 to 6 carbon atoms. For example, C1-C4 alkyl is one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl Selected from the group consisting of:

상기 알킬 그룹은 임의적으로 치환 또는 비치환될 수도 있다. 치환된 경우, 치환 그룹은, 시클로알킬, 아릴, 헤테로아릴, 헤테로알리시클릭, 히드록시, 알콕시, 아릴옥시, 메르켑토, 알킬티오, 아릴티오, 시아노, 할로겐, 카르보닐, 티오카르보닐, O-카르바밀, N-카르바밀, O-티오카르바밀, N-티오카르바밀, C-아미도, N-아미도, S-술폰아미도, N-술폰아미도, C-카르복시, O-카르복시, 이소시아네이토, 티오시아네이토, 이소티오시아네이토, 니트로, 시릴, 트리할로메탄술포닐, 모노- 및 디-치환 아미노 그룹들을 포함한 아미노, 및 이들의 보호 유도체들로부터 개별적으로 그리고 독립적으로 선택된 하나 또는 그 이상의 그룹이다. 전형적인 알킬 그룹에는 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, 터셔리 부틸, 펜틸, 헥실, 에테닐, 프로페닐, 부테닐, 시클로프로필, 시클로부틸, 시클로펜틸, 시클로 헥실 등이 포함되지만, 이들만으로 한정되는 것은 아니다.The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, merceto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O- Individually from carboxy, isocyanato, thiocyanato, isothiocyanato, amino including nitro, cyryl, trihalomethanesulfonyl, mono- and di-substituted amino groups, and protective derivatives thereof And one or more groups independently selected. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. It is not limited only to these.

용어 "아릴(aryl)"은 공유 파이 전자계를 가지고 있는 적어도 하나의 링을 가지고 있고 카르보시클릭 아릴(예를 들어, 페닐)과 헤테로시클릭 아릴기(예를 들어, 피리딘)를 포함하는 아릴 그룹을 의미한다. 이 용어는 모노시클릭 또는 융합 링 폴리시클릭(즉, 탄소원자들의 인접한 쌍들을 나눠 가지는 링들) 그룹들을 포함한다. "헤테로 아릴(heteroaryl)"은 적어도 하나의 헤테로사이클릭 링을 포함하고 있는 아릴 그룹을 의미하고, 상기 "헤테로사이클(heterocycle)"은 환 탄소가 산소, 질소, 황 등으로 치환되어 있는 그룹으로서, 예를 들어, 퓨란, 티오펜, 피롤, 피롤린, 피롤리딘, 옥사졸, 티아졸, 이미다졸, 이미다졸린, 이미다졸리딘, 피라졸, 피라졸린, 피라졸리딘, 이소티아졸, 트리아졸, 티아디아졸, 피란, 피리딘, 피퍼리딘, 몰포린, 티오몰포린, 피리다진, 피리미딘, 피라진, 피퍼라진, 트리아진 등을 들 수 있지만, 이들만으로 한정되는 것은 아니다.The term "aryl" refers to an aryl group having at least one ring having a shared pi electron field and comprising a carbocyclic aryl (eg phenyl) and a heterocyclic aryl group (eg pyridine) Means. The term includes monocyclic or fused ring polycyclic (ie rings that divide adjacent pairs of carbon atoms) groups. "Heteroaryl" refers to an aryl group containing at least one heterocyclic ring, and "heterocycle" refers to a group in which ring carbon is replaced with oxygen, nitrogen, sulfur, or the like. For example, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isothiazole, Triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, and the like, but are not limited thereto.

상기 아릴 그룹은 임의적으로 치환 또는 비치환될 수도 있다. 치환된 경우, 치환 그룹은, 시클로알킬, 아릴, 헤테로아릴, 헤테로알리시클릭, 히드록시, 알콕시, 아릴옥시, 메르켑토, 알킬티오, 아릴티오, 시아노, 할로겐, 카르보닐, 티오카르보닐, O-카르바밀, N-카르바밀, O-티오카르바밀, N-티오카르바밀, C-아미도, N-아미도, S-술폰아미도, N-술폰아미도, C-카르복시, O-카르복시, 이소시아네이토, 티오시아네이토, 이소티오시아네이토, 니트로, 시릴, 트리할로메탄술포닐, 모노- 및 디-치환 아미노 그룹들을 포함한 아미노, 및 이들의 보호 유도체들로부터 개별 적으로 그리고 독립적으로 선택된 하나 또는 그 이상의 그룹이다. 대표적인 아릴기로, 벤젠에서 유도되는 페닐기, 축합고리방향족화합물에서 유도되는 안트릴기, 페난트릴기, 비페닐에서 유도되는 비페닐기 등이 있다. 방향족고리 2개가 직접 결합한 화합물을 비아릴이라고 한다.The aryl group may be optionally substituted or unsubstituted. When substituted, the substituents are cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, merceto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O- Separately from amino, including carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, cyryl, trihalomethanesulfonyl, mono- and di-substituted amino groups, and protective derivatives thereof And one or more groups selected independently. Typical aryl groups include a phenyl group derived from benzene, an anthryl group derived from a condensed ring aromatic compound, a phenanthryl group, and a biphenyl group derived from biphenyl. A compound in which two aromatic rings are directly bonded is called a biaryl.

별도로 설명되어 있지 않다면, 치환체가 "임의적으로 치환(optionally substituted)" 되어있다는 것은, 치환체가, 알킬, 시클로알킬, 알켄일, 시클로알켄일, 아릴, 헤테로아릴, 헤테로알리시클릭, 히드록시, 알콕시, 아릴옥시, 메르켑토, 알킬티오, 아릴티오, 옥소, 시아노, 할로겐, 카르보닐, 티오카르보닐, O-카르바밀, N-카르바밀, O-티오카르바밀, N-티오카르바밀, C-아미도, N-아미도, S-술폰아미도, N-술폰아미도, 임의적으로 치환된 술포닐, C-카르복시, O-카르복시, 이소시아네이토, 티오시아네이토, 이소티오시아네이토, 니트로, 시릴, 트리할로메탄술포닐, 피롤리디닐, 피페리디닐, 피페라지닐, 피리디닐, 몰포리닐, 퓨릴, 티아졸리딘, 이소옥사졸, 아제티디닐, 디옥솔란, 피라지닐, 티에닐, 아지리딘, 옥사졸리딘, 이미다졸, 알칸산(Alkanoic acid), 알카노에이트(Alkanoate), 모노- 및 디-치환 아미노 그룹들을 포함한 아미노, 및 이들의 보호 유도체들로부터 개별적으로 그리고 독립적으로 선택된 하나 또는 그 이상의 그룹으로 치환된 경우를 포함한다는 의미로 사용되고 있다. 경우에 따라서는, 이들 역시 임의적으로 치환될 수도 있다. Unless stated otherwise, when a substituent is "optionally substituted" means that the substituent is alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy , Aryloxy, merceto, alkylthio, arylthio, oxo, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C Amido, N-amido, S-sulfonamido, N-sulfonamido, optionally substituted sulfonyl, C-carboxy, O-carboxy, isocyanato, thiocyanate, isothiocyane Ito, nitro, cyryl, trihalomethanesulfonyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, morpholinyl, furyl, thiazolidine, isoxazole, azetidinyl, dioxolane, pyra Genyl, thienyl, aziridine, oxazolidine, imidazole, alkanoic acid, alkanoate e), amino including mono- and di-substituted amino groups, and substituted with one or more groups selected individually and independently from their protective derivatives. In some cases, these may also be optionally substituted.

"O-카르복시" 그룹은 RC(=O)O- 그룹을 의미하며, 상기 R 은 알킬, 시클로알킬, 아릴, 헤테로아릴(환 탄소를 통해 결합됨) 및 헤테로알리시클릭(환 탄소를 통 해 결합됨)로 이루어진 군에서 선택되는 치환기를 의미한다."O-carboxy" group refers to a RC (= O) O- group, wherein R is alkyl, cycloalkyl, aryl, heteroaryl (bonded via a ring carbon) and heteroalicyclic (via a ring carbon) Combined) means a substituent selected from the group consisting of:

"C-카르복시" 그룹은 -C(=O)OR 그룹을 의미하며, 상기 R 은 상기에서 정의된 바와 같다.A "C-carboxy" group refers to a -C (= 0) OR group, wherein R is as defined above.

"아세틸" 그룹은 -C(=O)CH3 그룹을 의미한다.An "acetyl" group refers to a -C (= 0) CH3 group.

"트리할로메탄 술포닐" 그룹은 Y3CS(=O)2- 그룹을 의미하며, 상기 Y 는 할로겐이다.A "trihalomethane sulfonyl" group refers to a Y3CS (= 0) 2- group, wherein Y is halogen.

"시아노" 그룹은 -CN 그룹을 의미한다."Cyano" group refers to a -CN group.

"이소시아네이토" 그룹은 -NCO 그룹을 의미한다."Isocyanato" group refers to the -NCO group.

"티오시아네이토" 그룹은 -CNS 그룹을 의미한다.A "thiocyanato" group refers to a -CNS group.

"이소티오시아네이토" 그룹은 -NCS 그룹을 의미한다."Isothiocyanato" group refers to a -NCS group.

"술피닐" 그룹은 -S(=O)-R 그룹을 의미하며, 상기 R 은 상기에서 정의된 바와 같다."Sulfinyl" group refers to the group -S (= 0) -R, wherein R is as defined above.

"S-술폰아미도" 그룹은 -S(=O)2NR 그룹을 의미하며, 상기 R 은 여기서 정의된 바와 같다."S-sulfonamido" group refers to the -S (= 0) 2NR group, wherein R is as defined herein.

"N-술폰아미도" 그룹은 RS(=O)2NH- 그룹을 의미하며, 상기 R 은 여기서 정의된 바와 같다."N-sulfonamido" group refers to the RS (= 0) 2NH- group, with R as defined herein.

"트리할로메탄술폰아미도" 그룹은 Y3CS(=O)2NR- 그룹을 의미하며, 상기 Y 및 R 은 여기서 정의된 바와 같다.Group refers to the Y3CS (= 0) 2NR- group, wherein Y and R are as defined herein.

"O-카르바밀" 그룹은 -OC(=O)-NR 그룹을 의미하며, 상기 R 은 여기서 정의된 바와 같다."O-carbamyl" group refers to an -OC (= 0) -NR group, wherein R is as defined herein.

"N-카르바밀" 그룹은 ROC(=O)NH- 그룹을 의미하며, 상기 R 은 여기서 정의된 바와 같다."N-carbamyl" group refers to the ROC (= 0) NH- group, with R as defined herein.

"O-티오카르바밀" 그룹은 -OC(=S)-NR 그룹을 의미하며, 상기 R 은 여기서 정의된 바와 같다."O-thiocarbamyl" group refers to the group -OC (= S) -NR, wherein R is as defined herein.

"N-티오카르바밀" 그룹은 ROC(=S)NH- 그룹을 의미하며, 상기 R 은 여기서 정의된 바와 같다."N-thiocarbamyl" group refers to the ROC (= S) NH- group, with R as defined herein.

"C-아미도" 그룹은 -C(=O)-NR2 그룹을 의미하며, 상기 R 은 여기서 정의된 바와 같다.A "C-amido" group refers to a -C (= 0) -NR 2 group, wherein R is as defined herein.

"N-아미도" 그룹은 RC(=O)NH- 그룹을의미하며, 상기 R 은 여기서 정의된 바와 같다.Group refers to a RC (= 0) NH- group, wherein R is as defined herein.

용어 "퍼할로알킬(perhaloalkyl)"은 모든 수소원자들이 할로겐원자들로 대체된 알킬 그룹을 의미한다.The term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms have been replaced with halogen atoms.

기타 용어들은 본발명이 속하는 분야에서 통상적으로 이해되는 의미로서 해석될 수 있다.Other terms may be interpreted as meanings commonly understood in the field of the present invention.

본 발명의 대표적인 화합물(I)로서는 하기 화합물들이 포함된다.Representative compound (I) of the present invention includes the following compounds.

1. 5-(2-클로로-아세틸아미노)-N-시클로프로필-2-(4-메틸-피페리딘-1-일)-벤즈아미드1. 5- (2-Chloro-acetylamino) -N-cyclopropyl-2- (4-methyl-piperidin-1-yl) -benzamide

2. 5-(4-tert-부틸l-벤조일아미노)-N-(2-디에틸아미노-에틸)-2-(4-메틸-피페리딘-1-일)-벤즈아미드2. 5- (4-tert-Butyll-benzoylamino) -N- (2-diethylamino-ethyl) -2- (4-methyl-piperidin-1-yl) -benzamide

3. N-(2-디에틸아미노-에틸)-5-(4-이소프로필-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-벤즈아미드3. N- (2-Diethylamino-ethyl) -5- (4-isopropyl-benzoylamino) -2- (4-methyl-piperidin-1-yl) -benzamide

4. N-(2-디에틸아미노-에틸)-5-(4-헥실-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-벤즈아미드4. N- (2-Diethylamino-ethyl) -5- (4-hexyl-benzoylamino) -2- (4-methyl-piperidin-1-yl) -benzamide

5. 5-(2-클로로-아세틸아미노)-N-(2-디에틸아미노-에틸)-2-(4-메틸-피페리딘-1-일)-벤즈아미드5. 5- (2-Chloro-acetylamino) -N- (2-diethylamino-ethyl) -2- (4-methyl-piperidin-1-yl) -benzamide

6. 5-(2-클로로-아세틸아미노)-2-(4-메틸-피페리딘-1-일)-N-(2-몰포린-4-일-에틸)-벤즈아미드6. 5- (2-Chloro-acetylamino) -2- (4-methyl-piperidin-1-yl) -N- (2-morpholin-4-yl-ethyl) -benzamide

7. 2-클로로-N-[4-(4-메틸-피페리딘-1-일)-3-(몰포린-4-카보닐)-페닐]-아세트아미드7. 2-Chloro-N- [4- (4-methyl-piperidin-1-yl) -3- (morpholin-4-carbonyl) -phenyl] -acetamide

8. 시클로프로판카복실산 [3-(4-메틸-피페라진-1-카보닐)-4-(4-메틸-피페리딘-1-일)-페닐]-아미드8. Cyclopropanecarboxylic acid [3- (4-methyl-piperazin-1-carbonyl) -4- (4-methyl-piperidin-1-yl) -phenyl] -amide

9. N-[3-(4-메틸-피페라진-1-카보닐)-4-(4-메틸-피페리딘-1-일)-페닐]-프로피온아미드9.N- [3- (4-Methyl-piperazin-1-carbonyl) -4- (4-methyl-piperidin-1-yl) -phenyl] -propionamide

10. 4-메톡시-N-[3-(4-메틸-피페라진-1-카보닐)-4-(4-메틸-피페리딘-1-일)-페닐]-벤즈아미드10. 4-methoxy-N- [3- (4-methyl-piperazin-1-carbonyl) -4- (4-methyl-piperidin-1-yl) -phenyl] -benzamide

11. 5-아세틸아미노-N-(3-디메틸아미노-프로필)-2-(4-메틸-피페리딘-1-일)-벤즈아미드11. 5-acetylamino-N- (3-dimethylamino-propyl) -2- (4-methyl-piperidin-1-yl) -benzamide

12. 5-(4-브로모-벤조일아미노)-N-(3-디메틸아미노-프로필)-2-(4-메틸-피페리딘-1-일)-벤즈아미드12. 5- (4-Bromo-benzoylamino) -N- (3-dimethylamino-propyl) -2- (4-methyl-piperidin-1-yl) -benzamide

13. 5-(3-브로모-벤조일아미노)-N-(3-디메틸아미노-프로필)-2-(4-메틸-피페리딘-1-일)-벤즈아미드13. 5- (3-Bromo-benzoylamino) -N- (3-dimethylamino-propyl) -2- (4-methyl-piperidin-1-yl) -benzamide

14. 5-(4-클로로-벤조일아미노)-N-(3-디메틸아미노-프로필)-2-(4-메틸-피페리딘-1-일)-벤즈아미드14. 5- (4-Chloro-benzoylamino) -N- (3-dimethylamino-propyl) -2- (4-methyl-piperidin-1-yl) -benzamide

15. N-(3-디메틸아미노-프로필)-5-(4-플루오로-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-벤즈아미드15.N- (3-Dimethylamino-propyl) -5- (4-fluoro-benzoylamino) -2- (4-methyl-piperidin-1-yl) -benzamide

16. N-(3-이소프로필-벤조일아미노)-5-(4-메틸-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-페닐]-벤즈아미드16. N- (3-Isopropyl-benzoylamino) -5- (4-methyl-benzoylamino) -2- (4-methyl-piperidin-1-yl) -phenyl] -benzamide

17. 5-(4-이소프로필-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-N-(2-피페리딘-1-일-에틸)-벤즈아미드17. 5- (4-Isopropyl-benzoylamino) -2- (4-methyl-piperidin-1-yl) -N- (2-piperidin-1-yl-ethyl) -benzamide

18. 5-(2-클로로-벤조일아미노)-N-(2-디에틸아미노-에틸)-2-(4-메틸-피페리딘-1-일)-벤즈아미드18. 5- (2-Chloro-benzoylamino) -N- (2-diethylamino-ethyl) -2- (4-methyl-piperidin-1-yl) -benzamide

19. N-(2-디에틸아미노-에틸)-5-(2-메틸-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-벤즈아미드19.N- (2-Diethylamino-ethyl) -5- (2-methyl-benzoylamino) -2- (4-methyl-piperidin-1-yl) -benzamide

20. N-(2-디에틸아미노-에틸)-5-(2-플루오로-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-벤즈아미드20.N- (2-Diethylamino-ethyl) -5- (2-fluoro-benzoylamino) -2- (4-methyl-piperidin-1-yl) -benzamide

21. N-(3-디메틸아미노-프로필)-5-(4-이소프로필-벤조일아미노)-2-몰포린-4-일-벤즈아미드21.N- (3-Dimethylamino-propyl) -5- (4-isopropyl-benzoylamino) -2-morpholin-4-yl-benzamide

22. N-(3-디메틸아미노-프로필)-2-(4-메틸-피페리딘-1-일)-5-(4-트리플루오로메-벤조일아미노)-벤즈아미드22.N- (3-Dimethylamino-propyl) -2- (4-methyl-piperidin-1-yl) -5- (4-trifluorome-benzoylamino) -benzamide

23. N-(2-디메틸아미노-에틸)-5-(4-이소프로필-벤조일아미노)-N-메틸-2-(4-메틸-피페리딘-1-일)-벤즈아미드23. N- (2-Dimethylamino-ethyl) -5- (4-isopropyl-benzoylamino) -N-methyl-2- (4-methyl-piperidin-1-yl) -benzamide

24. N-(3-디메틸아미노-프로필)-5-(4-이소프로필-벤조일아미노)-N-메틸-2-(4-메틸-피페리딘-1-일)-벤즈아미드24.N- (3-Dimethylamino-propyl) -5- (4-isopropyl-benzoylamino) -N-methyl-2- (4-methyl-piperidin-1-yl) -benzamide

25. 5-(4-tert-부틸-벤조일아미노)-N-(1-페닐l-에틸)-2-피롤리딘-1-일-벤즈아미드25. 5- (4-tert-Butyl-benzoylamino) -N- (1-phenyll-ethyl) -2-pyrrolidin-1-yl-benzamide

26. 5-(3-플루오로-벤조일아미노)-N-(1-페닐-에틸)-2-피롤리딘-1-일-벤즈아미드26. 5- (3-Fluoro-benzoylamino) -N- (1-phenyl-ethyl) -2-pyrrolidin-1-yl-benzamide

27. 5-(3-디에틸아미노-프로피오닐아미노)-N-(1-페닐-에틸)-2-피롤리딘-1-일-벤즈아미드27. 5- (3-Diethylamino-propionylamino) -N- (1-phenyl-ethyl) -2-pyrrolidin-1-yl-benzamide

28. 4-메틸-피페라진-1-카복실산 [3-(1-페닐-에틸카바모일)-4-피롤리딘-1-일-페닐]-아미드28. 4-Methyl-piperazin-1-carboxylic acid [3- (1-phenyl-ethylcarbamoyl) -4-pyrrolidin-1-yl-phenyl] -amide

29. 4-[3-(1-페닐-에틸카바모일)-4-피롤리딘-1-일-페닐카바모일]-피페리딘-1-카복시산 tert-부틸 에스터29. 4- [3- (1-phenyl-ethylcarbamoyl) -4-pyrrolidin-1-yl-phenylcarbamoyl] -piperidine-1-carboxylic acid tert-butyl ester

30. 1-벤질-피페리딘-4-카복실산 [3-(1-페닐-에틸카바모일)-4-피롤리딘-1-일-페닐]-아미드30. 1-benzyl-piperidine-4-carboxylic acid [3- (1-phenyl-ethylcarbamoyl) -4-pyrrolidin-1-yl-phenyl] -amide

31. 5-(2-클로로-아세틸아미노)-2-(3,4-디하이드로-1H-이소퀴놀린-2-일)-N-(3-메톡시-프로필)-벤즈아미드31. 5- (2-Chloro-acetylamino) -2- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methoxy-propyl) -benzamide

32. N-시클로헥실-2-(3,4-디하이드로-1H-이소퀴놀린-2-일)-5-이소부티릴아미노-벤즈아미드32.N-cyclohexyl-2- (3,4-dihydro-1H-isoquinolin-2-yl) -5-isobutyrylamino-benzamide

33. 2-(3,4-디하이드로-1H-이소퀴놀린-2-일)-N-(3-디메틸아미노-프로필)-5-이소부티릴아미노-N-메틸-벤즈아미드33. 2- (3,4-Dihydro-1H-isoquinolin-2-yl) -N- (3-dimethylamino-propyl) -5-isobutyrylamino-N-methyl-benzamide

34. N-(3-디메틸아미노-프로필)-5-(4-헥실-벤조일아미노)-2-피페리딘-1-일-벤즈아미드34. N- (3-Dimethylamino-propyl) -5- (4-hexyl-benzoylamino) -2-piperidin-1-yl-benzamide

35. 5-(4-부틸-벤조일아미노)-N-(3-디메틸아미노-프로필)-2-[4-(2-메톡시-페닐)-피페라진-1-일]-벤즈아미드35. 5- (4-Butyl-benzoylamino) -N- (3-dimethylamino-propyl) -2- [4- (2-methoxy-phenyl) -piperazin-1-yl] -benzamide

36. 4-부틸-N-[4-[4-(2-메톡시-페닐)-피페라진-1-일]-3-(피페리딘-1-카보닐l)-페닐]-벤즈아미드36. 4-Butyl-N- [4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -3- (piperidine-1-carbonyl) -phenyl] -benzamide

37. N-(3-디메틸아미노-프로필)-5-(4-이소프로필-벤조일아미노)-2-(4-페닐-피페라진-1-일)-벤즈아미드37.N- (3-Dimethylamino-propyl) -5- (4-isopropyl-benzoylamino) -2- (4-phenyl-piperazin-1-yl) -benzamide

특히 바람직하게는 이하의 화합물이 포함된다.Especially preferably, the following compounds are included.

N-(2-디에틸아미노-에틸)-5-(4-이소프로필-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,N- (2-Diethylamino-ethyl) -5- (4-isopropyl-benzoylamino) -2- (4-methyl-piperidin-1-yl) -benzamide,

N-(3-디메틸아미노-프로필)-2-(4-메틸-피페리딘-1-일)-5-(4-트리플루오로메-벤조일아미노)-벤즈아미드,N- (3-dimethylamino-propyl) -2- (4-methyl-piperidin-1-yl) -5- (4-trifluorome-benzoylamino) -benzamide,

5-(2-클로로-아세틸아미노)-2-(3,4-디하이드로-1H-이소퀴놀린-2-일)-N-(3-메톡시-프로필)-벤즈아미드,5- (2-Chloro-acetylamino) -2- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methoxy-propyl) -benzamide,

N-(3-디메틸아미노-프로필)-5-(4-헥실-벤조일아미노)-2-피페리딘-1-일-벤즈아미드,N- (3-dimethylamino-propyl) -5- (4-hexyl-benzoylamino) -2-piperidin-1-yl-benzamide,

5-(4-부틸-벤조일아미노)-N-(3-디메틸아미노-프로필)-2-[4-(2-메톡시-페닐)-피페라진-1-일]-벤즈아미드, 또는5- (4-Butyl-benzoylamino) -N- (3-dimethylamino-propyl) -2- [4- (2-methoxy-phenyl) -piperazin-1-yl] -benzamide, or

N-(3-디메틸아미노-프로필)-5-(4-이소프로필-벤조일아미노)-2-(4-페닐-피페라진-1-일)-벤즈아미드이다.N- (3-dimethylamino-propyl) -5- (4-isopropyl-benzoylamino) -2- (4-phenyl-piperazin-1-yl) -benzamide.

본 발명의 화합물은 용이하게 이용 가능한 출발 물질을 사용하여 당분야에 공지된 일반 기술을 이용하여 하기에 기술하는 바와 같은 반응 경로 및 합성 반응식을 이용하여 제조할 수 있다. The compounds of the present invention can be prepared using reaction routes and synthetic schemes as described below using general techniques known in the art using readily available starting materials.

따라서, 본 발명은 일 관점에서 상기 화학식 (I)의 화합물을 제조하는 방법에 관한 것이다. 이후 설명하는 제조예들과 실시예들에서도 알 수 있는 바와 같이, 본 발명에 따른 화합물의 제조방법은 매우 다양한 방법들에 의해 제조될 수 있다. Accordingly, the present invention relates to a process for preparing the compound of formula (I) in one aspect. As can be seen in the preparations and examples to be described later, the preparation method of a compound according to the present invention can be prepared by a wide variety of methods.

하기의 제조방법들은 그것의 예시적인 방법들에 지나지 않으며, 유기합성 분야의 기술에 근간한 다양한 방법들에 의해 제조될 수 있음은 물론이다. 따라서, 본 발명의 범주가 이들만으로 한정되는 것은 아니다. 예를 들면, 본 발명에 따른 비-예시된 화합물의 합성은, 당분야의 숙련가에게 명백한 변형에 의해, 예를 들면, 간섭 기를 적절히 보호하거나, 당분야에 공지된 다른 적당한 시약으로 교체하거나, 또는 반응 조건을 통상적으로 변화시킴으로써 성공적으로 수행될 수 있다. 또는, 본원에 개시되고 당분야에 일반적으로 공지되어 있는 다른 반응은 본 발명의 다른 화합물을 제조하기 위한 적응성을 갖는 것으로 인지될 것이다.The following preparation methods are merely exemplary methods thereof, and of course, may be prepared by various methods based on the art of organic synthesis. Therefore, the scope of the present invention is not limited only to these. For example, the synthesis of non-exemplified compounds according to the present invention may be carried out by modifications apparent to those skilled in the art, for example, by appropriate protection of the interfering groups, or by replacement with other suitable reagents known in the art, or It can be done successfully by changing the reaction conditions conventionally. Alternatively, it will be appreciated that other reactions disclosed herein and generally known in the art will have adaptability to prepare other compounds of the present invention.

본 발명의 화학식 (I)의 화합물은 하기 화학식(II)의 2-플루오로-5-니트로벤조산을 출발물질로 하여 제조할 수 있다. 일 관점에서, 본 발명은 화학식 II의 화 합물을 출발물질로 하여 화학식 (I)의 화합물을 제조하는 방법에 관한 것이다. The compound of formula (I) of the present invention can be prepared by using 2-fluoro-5-nitrobenzoic acid of formula (II) as a starting material. In one aspect, the present invention relates to a process for the preparation of the compound of formula (I), starting with the compound of formula (II).

[화학식 II][Formula II]

Figure 112008028469180-pat00004
Figure 112008028469180-pat00004

이에 대해 반응식을 이용하여 자세히 설명하면 다음과 같다.This will be described in detail using the reaction scheme as follows.

[반응식][Scheme]

Figure 112008028469180-pat00005
Figure 112008028469180-pat00005

[R1, R2 및 R3는 상기 정의한 바와 같다. Ra는

Figure 112008028469180-pat00006
또는
Figure 112008028469180-pat00007
이며, 이 때, R'은 치환 또는 비치환된 C1-C6 알킬, 시클로알킬, 유레아 또는 방향족 화합물이다] [R 1 , R 2 and R 3 are as defined above. Ra is
Figure 112008028469180-pat00006
or
Figure 112008028469180-pat00007
Wherein R 'is substituted or unsubstituted C 1 -C 6 alkyl, cycloalkyl, urea or aromatic compound;

출발물질인 화학식 (II)의 화합물에 (a) R2를 도입하는 단계, (b) R1을 도입하는 단계, (c) 니트로기를 환원하는 단계, 및 (d) Ra를 도입하는 단계를 거쳐 화학식 (I)의 화합물을 제조한다. 이 때, 상기 방법은 (a)단계, (c)단계, (d)단계 및 (b)단계의 순서로 수행되어도 무방하다. (A) introducing R 2 to the starting compound (II), (b) introducing R 1 , (c) reducing the nitro group, and (d) introducing Ra To prepare a compound of formula (I). At this time, the method may be performed in the order of (a), (c), (d) and (b).

본 발명이 속하는 분야에서 통상의 지식을 가진 자라면, 본 발명에 따른 화합물(I)의 제조를 위한 구체적인 반응조건 등을 추후 설명하는 제조예들과 실시예들을 통해 확인할 수 있으므로, 그에 대한 자세한 설명은 생략한다. Those skilled in the art to which the present invention pertains, specific reaction conditions for the preparation of the compound (I) according to the present invention can be confirmed through the preparation examples and examples which will be described later, a detailed description thereof Is omitted.

본 발명은 다른 관점에서, 상기 디아미노벤즈아미드 유도체인 하기 화학식 (I)의 화합물의 이성질체 또는 약제학적으로 허용 가능한 이들의 염; 이들의 용매화물 또는 이들의 수화물, 프로드럭에 관한 것이다.In another aspect, the present invention is an isomer of a compound of formula (I) Pharmaceutically acceptable salts thereof; And solvates thereof, hydrates thereof, and prodrugs thereof.

용어 "약제학적으로 허용되는 염"은, 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는, 화합물의 제형을 의미한다. 용어 "수화물", "용매화물" 및 "이성질체" 역시 상기와 같은 의미를 가진다. 상기 약제학적 염은, 본 발명의 화합물을, 염산, 브롬산, 황산, 질산, 인산 등의 무기산, 메탄술폰산, 에탄술폰산, p-톨루엔술폰산 등의 술폰산, 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산, 트리플루오로아세트 산, 카프릭산, 이소부탄산, 말론산, 석신산, 프탈산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산, 살리실산 등과 같은 유기 카본산과 반응시켜 얻어질 수 있다. 또한, 본 발명의 화합물을 염기와 반응시켜, 암모니움 염, 나트륨 또는 칼륨 염 등의 알칼리 금속염, 칼슘 또는 마그네슘 염 등의 알칼리 토금속염 등의 염, 디시클로헥실아민, N-메틸-D-글루카민, 트리스(히드록시메틸) 메틸아민 등의 유기염기들의 염, 및 아르기닌, 리신 등의 아미노산 염을 형성함으로써 얻어질 수도 있다.The term "pharmaceutically acceptable salt" means a formulation of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. The terms "hydrate", "solvate" and "isomer" also have the same meanings as above. The pharmaceutical salt is a compound of the present invention, such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, inorganic acids such as phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like, sulfonic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloro It can be obtained by reaction with organic carboxylic acids such as roacetic acid, trifluoroacetic acid, capric acid, isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like. In addition, the compound of the present invention is reacted with a base, and salts such as alkali metal salts such as ammonium salts, sodium or potassium salts, and alkaline earth metal salts such as calcium or magnesium salts, dicyclohexylamine, and N-methyl-D-glu It may be obtained by forming salts of organic bases such as carmine and tris (hydroxymethyl) methylamine, and amino acid salts such as arginine and lysine.

용어 "수화물(hydrate)"은 비공유적 분자간력(non-covalent intermolecular force)에 의해 결합된 화학양론적(stoichiometric) 또는 비화학양론적(non-stoichiometric) 량의 물을 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. The term "hydrate" includes a compound of the present invention comprising a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force. Or salts thereof.

용어 "용매화물(solvate)"은 비공유적 분자간력에 의해 결합된 화학양론적 또는 비화학양론적 량의 용매를 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 그에 관한 바람직한 용매들로는 휘발성, 비독성, 및/또는 인간에게 투여되기에 적합한 용매들이다. The term "solvate" refers to a compound of the present invention or a salt thereof comprising a stoichiometric or nonstoichiometric amount of solvent bound by noncovalent intermolecular forces. Preferred solvents therein are volatile, nontoxic, and / or solvents suitable for administration to humans.

용어 "이성질체(isomer)"는, 동일한 화학식 또는 분자식을 가지지만 광학적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 예를 들어, 본 발명의 화학식 1에 따른 화합물은 치환기들의 종류에 따라서는 입체생성 중심(asymmetric center, 비대칭 탄소 원자)을 가질 수 있는 바, 이 경우 화학식 1의 화합물은 거울상 이성질체 및 부분 입체 이성질체와 같은 광학 이성질체로서 존재할 수 있다. The term "isomer" means a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula, but which is optically or stereoscopically different. For example, the compound according to Formula 1 of the present invention may have an asymmetric center (asymmetric carbon atom) depending on the type of substituents, in which case the compound of Formula 1 is combined with enantiomers and diastereomers. May exist as the same optical isomer.

용어 "프로드럭(prodrug)"은 생체내에서 모 약제(parent drug)로 변형되는 물질을 의미한다. 프로드럭은, 몇몇 경우에 있어서, 모 약제보다 투여하기 쉽기 때문에 종종 사용된다. 예를 들어, 이들은 구강 투여에 의해 생활성을 얻을 수 있음에 반하여, 모 약제는 그렇지 못할수 있다. 프로드럭은 또한 모 약제보다 제약 조성물에서 향상된 용해도를 가질 수도 있다. 예를 들어, 프로드럭은, 수용해도가 이동성에 해가 되지만, 일단 수용해도가 이로운 세포에서는, 물질대사에 의해 활성체인 카르복실산으로 가수분해되는, 세포막의 통과를 용이하게 하는 에스테르("프로드럭")로서 투여되는 화합물일 것이다. 프로드럭의 또 다른 예는 펩티드가 활성 부위를 드러내도록 물질대사에 의해 변환되는 산기에 결합되어 있는 짧은 펩티드(폴리아미노 산)일 수 있다.The term "prodrug" refers to a substance that is transformed into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions than the parent drug. For example, prodrugs are esters that facilitate the passage of cell membranes, which are hydrolyzed to carboxylic acids, which are active by metabolism, once the water solubility is detrimental to mobility, but once the water solubility is beneficial. Drug "). Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group that is converted by metabolism to reveal the active site.

이하에서 별도의 설명이 없는 한, 용어 "본 발명에 따른 화합물" 또는 "화학식 (I)의 화합물"은, 화합물 그 자체, 약제학적으로 허용되는 그것의 염, 수화물, 용매화물, 이성질체 및 프로드럭을 모두 포함하는 개념으로 사용되고 있다.Unless stated otherwise, the terms "compound according to the invention" or "compound of formula (I)" refer to the compound itself, pharmaceutically acceptable salts, hydrates, solvates, isomers and prodrugs thereof. It is used as a concept that includes all of them.

본 발명에 따른 화합물들은 비정상적인 세포성장 및/또는 세포증식으로 인한 질병들의 치료 및 예방에 특히 유효하다. The compounds according to the invention are particularly effective for the treatment and prevention of diseases caused by abnormal cell growth and / or cell proliferation.

이러한 비정상적인 세포성장 및/또는 세포증식으로 인한 질병들의 예로는, 하기의 것으로 한정되는 것은 아니지만, 암, 염증, 혈관 협착증 및 혈관 생성증, 카포시 육종 등을 들 수 있다. Examples of diseases caused by such abnormal cell growth and / or cell proliferation include, but are not limited to, the following: cancer, inflammation, vascular stenosis and angiogenesis, Kaposi's sarcoma and the like.

따라서, 따라서 본 발명의 또 다른 관점에서, 본 발명은 환자에게 유효량의 화학식(I)의 화합물을 투여하여 세포의 비정상적 증식/성장을 감소시키거나 완화시키는 방법에 관한 것이다. 즉, 상기 화학식(I)의 화합물을 사용하여 비정상적 세포성장 및/또는 세포증식으로 인한 질병들의 치료 및 예방하는 방법을 제공한다.Thus, in yet another aspect of the invention, the invention relates to a method of administering to a patient an effective amount of a compound of formula (I) to reduce or alleviate abnormal proliferation / growth of cells. That is, the present invention provides a method of treating and preventing diseases caused by abnormal cell growth and / or cell proliferation using the compound of formula (I).

본 출원에서 "비정상적 세포성장(세포증식)" 이란 "과증식성 질환"이라는 용어로 상호교환적으로 사용될 수 있다. "비정상적 세포성장"은 정상 세포의 비정상 성장 및 비정상 세포의 성장을 포함하여, 정상 조절기작과 무관한 세포 성장(예를 들면, 접촉 억제의 상실)을 말한다. In the present application, the term "abnormal cell growth (cell proliferation)" may be used interchangeably with the term "hyperproliferative disease". “Abnormal cell growth” refers to cell growth that is independent of normal regulatory mechanisms, including abnormal growth of normal cells and growth of abnormal cells (eg, loss of contact inhibition).

상기 비정상 세포 성장에는 (1) 활성화된 Ras 종양유전자를 발현시키는, 양성 및 악성 둘 다의 종양 세포(종양); (2) 또 다른 유전자에서의 종양유전자 돌연변이 결과 종양 단백질이 활성화되는, 양성 및 악성 둘 다의 종양 세포; (3) 이상 Ras 및 종양 단백질의 활성화가 일어나는 다른 증식성 질환의 양성 및 악성 세포의비정상 성장이 포함되나, 이로 한정되지는 않는다. 상기 양성 증식성 질환의 예는 건선, 양성 전립선 비대증, 인간 파필로마 바이러스(HPV) 및 망막증이다. "비정상 세포 성장"은 또한 세포 신호전달 과정의 이상으로 야기되는 양성 및 악성 세포의 비정상 성장을 말하며 이를 포함한다.Such abnormal cell growth includes (1) both benign and malignant tumor cells (tumors) that express activated Ras oncogenes; (2) tumor cells of both benign and malignant in which oncogene mutation in another gene results in activation of the tumor protein; (3) Abnormal growth of benign and malignant cells of other proliferative diseases in which aberrant Ras and tumor protein activation occurs, but are not limited thereto. Examples of such benign proliferative diseases are psoriasis, benign prostatic hyperplasia, human papilloma virus (HPV) and retinopathy. "Abnormal cell growth" also refers to and includes abnormal growth of benign and malignant cells caused by abnormalities in cell signaling processes.

본원에서 사용된 바와 같이, "치료하는"이란 용어는, 달리 언급되지 않는 한, 상기 용어가 적용되는 질환 또는 질병, 또는 상기 질환 또는 질병의 하나 이상의 증상을 역전시키거나, 완화시키거나, 그 진행을 억제하거나, 또는 예방하는 것을 의미한다. 본원에서 사용된 바와 같이, "치료"란 용어는 "치료하는"이 상기와 같이 정의될 때 치료하는 행위를 말한다. As used herein, the term “treating”, unless stated otherwise, reverses, alleviates, or progresses the disease or condition to which the term applies, or one or more symptoms of the disease or condition. It means to inhibit or prevent. As used herein, the term "treatment" refers to the act of treating when "treating" is defined as above.

본 발명은 또 다른 태양에서, 약리학적 유효량의 본 발명의 화합물 (I) 및 약제학적으로 허용되는 담체를 포함하는 약제학적 조성물에 관한 것이다. 상기 조성물은 필요에 따라 희석제, 부형제 등을 추가로 더 포함할 수 있다. In another aspect, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound (I) of the present invention and a pharmaceutically acceptable carrier. The composition may further include a diluent, an excipient, and the like as needed.

용어 "약제학적 조성물(pharmaceutical composition)"은 본 발명의 화합물과 희석제 또는 담체와 같은 다른 화학 성분들의 혼합물을 의미한다. The term "pharmaceutical composition" means a mixture of a compound of the invention with other chemical components, such as diluents or carriers.

상기 약제 조성물은 생물체내로 화합물의 투여를 용이하게 한다. 화합물을 투여하는 다양한 기술들이 존재하며, 여기에는 경구, 주사, 에어로졸, 비경구, 및 국소 투여 등이 포함되지만, 이들만으로 한정되는 것은 아니다. 약제 조성물은 염산, 브롬산, 황산, 질산, 인산, 메탄술폰산, p-톨루엔술폰산, 살리실산 등과 같은 산 화합물들을 반응시켜서 얻어질 수도 있다.The pharmaceutical composition facilitates administration of the compound into the organism. There are a variety of techniques for administering compounds, including but not limited to oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions may also be obtained by reacting acid compounds such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

용어 "약리학적 유효량(therapeutically effective amount)"은 투여되는 화합물의 량이 치료하는 장애의 하나 또는 그 이상의 증상을 어느 정도 경감하는 것을 의미한다. 따라서, 약리학적 유효량은, (1) 질환의 진행 속도를 역전시키거나 또는 암의 경우에 종양의 크기를 줄이는 효과 (2) 질환의 그 이상의 진행을 어느 정도 금지시키고, 암의 경우에는 어느 정도 느리게 하는 것을 의미하며, 또는 바람직하게는 종양 전이를 중단하는 효과 및/또는 (3) 질환과 관련된 하나 또는 그 이상의 증상을 어느 정도 경감(바람직하게는, 제거)하는 효과를 가지는 량을 의미한다.The term “therapeutically effective amount” means that the amount of the compound administered to alleviate to some extent one or more symptoms of the disorder being treated. Thus, a pharmacologically effective amount may be (1) to reverse the rate of progression of the disease or to reduce the size of the tumor in the case of cancer; (2) to prohibit further progression of the disease to some extent; Or preferably a dose having the effect of stopping tumor metastasis and / or (3) alleviating (preferably eliminating) one or more symptoms associated with the disease.

용어 "담체(carrier)"는 세포 또는 조직 내로의 화합물의 부가를 용이하게 하는 화합물로 정의된다. 예를 들어, 디메틸술폭사이드(DMSO)는 생물체의 세포 또는 조직 내로의 많은 유기 화합물들의 투입을 용이하게 하는 통상 사용되는 담체이다.The term "carrier" is defined as a compound that facilitates the addition of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the incorporation of many organic compounds into cells or tissues of an organism.

용어 "희석제(diluent)"는 대상 화합물의 생물학적 활성 형태를 안정화시킬 뿐만 아니라, 화합물을 용해시키게 되는 물에서 희석되는 화합물로 정의된다. 버퍼 용액에 용해되어 있는 염은 당해 분야에서 희석제로 사용된다. 통상 사용되는 버퍼 용액은 포스페이트 버퍼 식염수이며, 이는 인간 용액의 염 상태를 모방하고 있기 때문이다. 버퍼 염은 낮은 농도에서 용액의 pH를 제어할 수 있기 때문에, 버퍼 희석제가 화합물의 생물학적 활성을 변형하는 일은 드물다.The term "diluent" is defined as a compound that not only stabilizes the biologically active form of the compound of interest, but also is diluted in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, because it mimics the salt state of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely modify the biological activity of a compound.

용어 "약리학적으로 허용되는(physiologically acceptable)"은 화합물의 생물학적 활성과 물성들을 손상시키지 않는 담체 또는 희석제로 정의된다.The term "physiologically acceptable" is defined as a carrier or diluent that does not impair the biological activity and the properties of the compound.

여기에 사용된 화합물들은 인간 환자에게 그 자체로서, 또는 결합 요법에서와 같이 다른 활성 성분들과 함께 또는 적당한 담체나 부형제와 함께 혼합된 약제 조성물로서, 투여될 수 있다. 본 응용에서의 화합물의 제형 및 투여에 관한 기술은 "Remington's Pharmaceutical Sciences,"Mack Publishing Co., 에틸아세테이트ston, PA, 18th edition, 1990에서 확인할 수 있다.The compounds used herein may be administered to human patients as such or as pharmaceutical compositions in combination with other active ingredients or with a suitable carrier or excipient, such as in a combination therapy. Techniques for formulation and administration of compounds in this application can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Ethyl acetateston, PA, 18th edition, 1990.

(a) 투여 경로(a) route of administration

적절한 투여 경로는, 예를 들어, 경구, 비강, 투과점막, 또는 장 투여 격막 내, 직접 심실내, 복강내, 또는 안내 주사뿐만 아니라, 근육내, 피하, 정맥, 골수 주사를 포함한 비경구 전달을 포함한다.Suitable routes of administration include parenteral delivery, including intramuscular, subcutaneous, intravenous, bone marrow injections, as well as intraoral, subcutaneous, intraperitoneal, or intraocular injections, eg, orally, nasal, permeable, or enteral septum. Include.

또한, 예를 들어, 종종 침적 또는 서방성 제형으로, 충실성 종양에 직접적으로 주사하는 것에 의해, 전신 방식보다는 국소 방식으로 화합물을 투여할 수도 있다. 또한, 약제를, 예를 들어, 종양-특이적 항체로 코팅된 리포좀으로, 표적화 약제 전달계로서 투여할 수도 있다. 리포좀은 종양으로 표적되고 그것에 의해 임의적으로 취해진다.In addition, the compounds may also be administered in a local rather than systemic manner, for example by direct injection into solid tumors, often in immersion or sustained release formulations. Agents may also be administered as targeted drug delivery systems, eg, in liposomes coated with tumor-specific antibodies. Liposomes are targeted to and taken arbitrarily by the tumor.

(b) 조성물/제형(b) Compositions / Formulations

본 발명의 약제 조성물은, 예를 들어, 통상적인 혼합, 용해, 과립화, 당제-제조, 분말화, 에멀션화, 캡슐화, 트래핑과 또는 동결건조 과정들의 수단에 의해, 공지 방식으로 제조될 수 있다.Pharmaceutical compositions of the invention can be prepared in a known manner, for example, by means of conventional mixing, dissolving, granulating, sugar-making, powdering, emulsifying, encapsulating, trapping and or lyophilizing processes. .

따라서, 본 발명에 따른 사용을 위한 약제 조성물은, 약제학적으로 사용될 수 있는 제형으로의 활성 화합물의 처리를 용이하게 하는 부형제들 또는 보조제들을 포함하는 것으로 구성되어 있는 하나 또는 그 이상의 약리학적으로 허용되는 담체를 사용하여 통상적인 방법으로 제조될 수도 있다. 적합한 제형은 선택된 투여 루트에 따라 좌우된다. 공지 기술들, 담체 및 부형제들 중의 어느 것이라도 적합하게, 그리고 당해 분야, 예를 들어, 앞서 설명한 Remingston's Pharmaceutical Sciences에서 이해되는 바와 같이 사용될 수 있다.Thus, pharmaceutical compositions for use according to the present invention comprise one or more pharmacologically acceptable compositions comprising excipients or auxiliaries which facilitate the treatment of the active compounds into formulations which can be used pharmaceutically. It may also be prepared by conventional methods using a carrier. Proper formulation is dependent upon the route of administration chosen. Any of the known techniques, carriers and excipients can be used suitably and as understood in the art, for example in Remingston's Pharmaceutical Sciences described above.

주사를 위해서, 본 발명의 성분들은 액상 용액으로, 바람직하게는 Hank 용 액, Ringer 용액, 또는 생리 식염수 버퍼와같은 약리학적으로 맞는 버퍼로 제형될 수 있다. 점막 투과 투여를 위해서, 통과할 배리어에 적합한 비침투성제가 제형에 사용된다. 그러한 비침투성제들은 당업계에 일반적으로 공지되어 있다.For injection, the components of the present invention may be formulated in liquid solutions, preferably in pharmacologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For mucosal permeation administration, noninvasive agents suitable for the barrier to pass through are used in the formulation. Such non-invasive agents are generally known in the art.

경구 투여를 위해서, 화합물들은 당업계에 공지된 약리학적으로 허용되는 담체들을 활성 화합물들과 조합함으로써 용이하게 제형될 수 있다. 이러한 담체들은 본발명의 화합물들이 정제, 알약, 당제, 캡슐, 액체, 겔, 시럽, 슬러리, 현탁액 등으로 제형화될 수 있도록 하여 준다. 경구 사용을 위한 약제 준비는 본 발명의 하나 또는 둘 이상의 화합물들과 하나 또는 둘 이상의 부형제를 혼합하고, 경우에 따라서는 이러한 혼합물을 분쇄하고, 필요하다면 적절한 보조제를 투과한 이후 과립의 혼합물을 처리하여 정제 또는 당체 코어를 얻을 수 있다. 적절한 부형제들은 락토스, 수크로즈, 만니톨, 또는 소르비톨과 같은 필러 옥수수 녹말, 밀 녹말, 쌀 녹말, 감자 녹말, 겔라틴, 검 트래거켄스, 메틸 셀룰로우즈, 히드록시프로필메틸-셀룰로우즈, 소듐 카르복시메틸 셀룰로우즈, 및/또는 폴리비닐피롤리돈 (PVP)와 같은 셀룰루오즈계 물질 등이다. 필요하다면, 가교 폴리비닐 피롤리돈, 우뭇가사리, 또는 알긴산 또는 알긴산 나트륨과 같은 그것의 염 등의 디스인터그레이팅 에이전트가 첨가될 수도 있다.For oral administration, the compounds can be formulated readily by combining the active compounds with pharmacologically acceptable carriers known in the art. Such carriers allow the compounds of the invention to be formulated into tablets, pills, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like. Pharmaceutical preparations for oral use may be achieved by mixing one or more compounds of the invention with one or more excipients, optionally grinding such mixtures and, if necessary, treating the mixture of granules after permeation of appropriate adjuvants. A tablet or sugar core can be obtained. Suitable excipients include filler corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragakens, methyl cellulose, hydroxypropylmethyl-cellulose, sodium such as lactose, sucrose, mannitol, or sorbitol Cellulose based materials such as carboxymethyl cellulose, and / or polyvinylpyrrolidone (PVP), and the like. If necessary, a disintergrating agent may be added, such as crosslinked polyvinyl pyrrolidone, butadiene, or salts thereof such as alginic acid or sodium alginate.

당제 코아는 적절히 코팅하여 공급한다. 이러한 목적을 위해, 경우에 따라서는 아라비드 검, 활석, 폴리비닐 피롤리돈, 카르보폴 겔, 폴리에틸렌 글리콜, 및/또는 이산화티탄, 락커 용액, 및 적합한 유기용매 또는 용매혼합물을 포함하기도 하는 농축 설탕 용액이 사용될 수 있다. 활성 화합물 용량의 확인 또는 이들의 다 른 조합을 특징지우기 위해 염료나 안료가 정제 또는 당제에 포함되기도 한다. Sugar cores are supplied by appropriate coating. For this purpose, concentrated sugars, which optionally include arabide gum, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures Solutions can be used. Dyestuffs or pigments may be included in the tablets or sugars to characterize the identity of the active compounds or to characterize other combinations thereof.

경구에 사용될 수 있는 제약 준비물은, 겔라틴 및 글리콜 또는 소르비톨과 같은 가소제로 만들어진 부드러운 밀봉 캡슐뿐만 아니라, 겔라틴으로 만들어진 밀어 고정하는 캡슐을 포함할 수도 있다. 밀어 고정하는 캡슐은 락토오스와 같은 필러, 녹말과 같은 바인더, 및/또는 활석 또는 마그네슘 스테아레이트와 같은 활제와의 혼합물로서, 활성 성분들을 포함할 수도 있다. 연질 캡슐에서, 활성 화합물들은 지방산, 액체 파라핀, 또는 액체 폴리에틸렌 글리콜과 같은 적합한 용체에 용해 또는 분산될 수도 있다. 또한, 안정화제가 포함될 수도 있다. 경구 투여를 위한 모든 조제들은 그러한 투여에 적합한 함량으로 되어 있어야 한다.Pharmaceutical preparations that can be used orally may include soft sealing capsules made of gelatin and plasticizers such as glycols or sorbitol, as well as pushable capsules made of gelatin. The push-fix capsule may contain the active ingredients, as a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate. In soft capsules, the active compounds may be dissolved or dispersed in suitable solvents such as fatty acids, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be included. All preparations for oral administration should be in amounts suitable for such administration.

협측 투여를 위해, 조성물들은 통상적인 방법에 따라 제형화된 정제 또는 마름모꼴 정제의 형태를 취할 수도 있다.For buccal administration, the compositions may take the form of tablets or lozenges formulated according to conventional methods.

흡입에 의한 투여를 위해, 본 발명에 따른 사용 화합물들은 통상적으로, 예를 들어, 디클로로디플루오로메탄, 트리클로로플루오로메탄, 디클로로테트라플루오로에탄, 이산화탄소 또는 다른 적절한 가스와 같은 적절한 추진제를 사용하여, 가압 팩 또는 네불라이절(nebulisher)로부터 에어졸 분사 제공의 형태로 전달될 수도 있다. 흡입제 또는 취분기에서의 사용을 위해, 화합물과 락토오스 또는 녹말과 같은 적절한 분말의 분말상 혼합물을 포함하는, 예를 들어, 겔라틴과 같은 캡슐 및 카트리지가 제형화될 수도 있다.For administration by inhalation, the compounds of use according to the invention typically use a suitable propellant such as, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Thus, it may be delivered in the form of aerosol injection provision from a pressurized pack or nebulisher. For use in inhalants or pulverulents, capsules and cartridges such as, for example, gelatin may be formulated comprising a powdered mixture of the compound and a suitable powder such as lactose or starch.

화합물들은, 주사에 의해, 예를 들어, 큰 환약 주사나 연속적인 주입에 의해, 비경구 투입용으로 제형화될 수도 있다. 주사용 제형은, 예를 들어, 방부제를 부가한 앰플 또는 멀티-도스 용기로서 단위 용량 형태로 제공될 수도 있다. 조성물은 유성 또는 액상 비히클상의 현탁액, 용액, 에멀션과 같은 형태를 취할 수도 있으며, 현탁제, 안정화제 및/또는 분산제와 같은 제형용 성분들을 포함할 수도 있다.The compounds may be formulated for parenteral administration by injection, eg, by large pill injection or continuous infusion. Injectable formulations may be presented in unit dose form, for example, as ampoules or multi-dos containers, with preservatives added. The compositions may take the form of suspensions, solutions, emulsions on oily or liquid vehicles, and may include components for formulation such as suspensions, stabilizers and / or dispersants.

비경구 투여용 액제 제형들은 수용성 형태로 활성화합물들의 액상 용액을 포함한다. 추가적으로, 활성 화합물의 현탁액은 적절한 유성 주사 현탁액으로 준비될 수도 있다. 적합한 친유성 용매 또는 비히클에는, 참기름과 같은 지방산, 에틸 올레이트 또는 트리글리세라이드와 같은 합성 지방산 에스테르, 또는 리포좀 등이 있다. 액상 주사 현탁액은 현탁액의 점도를 높이는 물질들, 예를 들어, 소듐 카르복시메틸 셀룰로우즈, 소르비톨, 또는 덱스트란 등을 포함할 수도 있다. 경우에 따라서는, 현탁액에 고농축 용액의 제조를 가능케 하도록 화합물의 용해도를 증가시키는 성분들이나 안정화제가 포함될 수도 있다.Liquid formulations for parenteral administration include liquid solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty acids such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, liposomes and the like. Liquid injection suspensions may include substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, dextran, and the like. In some cases, suspensions may contain components or stabilizers that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

또한, 활성 성분은, 사용 전에 멸균 무 발열물질의 물과 같은 적절한 비히클와 구성을 위해 분말의 형태일 수도 있다.The active ingredient may also be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

화합물들은, 예를 들어, 코코아 버터나 다른 글리세라이드와 같은 통상적인 좌약 기재를 포함하고 있는 좌약 또는 정체관장과 같은 직장 투여 조성물로 제형될 수도 있다.The compounds may also be formulated in rectal dosage compositions, such as suppositories or retention enemas, including, for example, conventional suppository bases such as cocoa butter or other glycerides.

상기 설명한 제형들 이외에, 화합물들은 침적체로서 제형될 수 있다. 그와 같이 오랫동안 활성을 나타내는 제형들은 이식(예를 들어 피하에 또는 근육내에) 또는 근육내 주입에 의해 투여될 수도 있다. 따라서, 화합물들은, 예를 들어, 적 절한 고분자 또는 소수성 물질(예를 들어 허용 가능한 오일내의 에멀션과 같이), 또는 이온 교환 수지를 가지고, 또는 예를 들어 저용해성 염과 같은 저용해성 유도체로서 제형될 수도 있다.In addition to the formulations described above, the compounds may be formulated as deposits. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular infusion. Thus, the compounds may be formulated, for example, with a suitable polymer or hydrophobic material (such as an emulsion in an acceptable oil), or with an ion exchange resin, or as a low soluble derivative, for example a low soluble salt. It may be.

본 발명의 소수성화합물용 제형 담체는 벤질 알코올, 비극성 계면활성제, 수-혼화성 유기 고분자, 및 액상으로 이루어진 공용매계이다. 공용매계는 V팔라듐 공용매계일 수도 있다. V팔라듐 공용매계는, 무수 에탄올에서 체적으로까지 만들어진, 벤질 알코올 3% w/v, 비극성 계면활성제 Polysorbate 80TM 85 w/v, 및 폴리에틸렌 글리콜 300 65% w/v의 용액이다. V팔라듐 공용매계(V팔라듐:D5W)는수용액에서 5% 테스트로오즈로 1:1 희석된 V팔라듐로 이루어져 있다. 이러한 공용매계는 소수성 화합물을 잘 용해시키고, 전신 투여시 저독성을 그 자체가 제공한다. 자연적으로, 공용매계의 비율은 그것의 용해도 및 독성 특성들을 저해하지 않으면서 상당히 변화될 수도 있다. 더욱이, 공용매 성분들의 확인은 변화될 수 있다: 예를 들어, 다른 저독성의 비극성 계면활성제가 Polysorbate 80대신에 사용될 수 있다 폴리에틸렌 글리콜의 분획 크기는 변화될 수 있다 다른 생체적합성 고분자들이 예를 들어 폴리비닐 피롤리돈과 같은 폴리에틸렌 글리콜을 대체할 수 있다 그리고 다른 당들과다당체들이 덱스트로스를 대신할 수 있다.The formulation carrier for the hydrophobic compound of the present invention is a cosolvent system composed of benzyl alcohol, nonpolar surfactant, water-miscible organic polymer, and liquid phase. The cosolvent system may be a V palladium cosolvent system. The V palladium cosolvent system is a solution of benzyl alcohol 3% w / v, nonpolar surfactant Polysorbate 80TM 85 w / v, and polyethylene glycol 300 65% w / v, made up to volume in anhydrous ethanol. The V palladium cosolvent system (V palladium: D5W) consists of V palladium diluted 1: 1 with 5% testrose in aqueous solution. This cosolvent system dissolves hydrophobic compounds well and provides itself with low toxicity upon systemic administration. Naturally, the proportion of cosolvent system may vary considerably without compromising its solubility and toxicological properties. Moreover, the identification of the cosolvent components can be varied: for example, other low-toxic nonpolar surfactants can be used instead of Polysorbate 80. The fraction size of polyethylene glycol can be varied. Other biocompatible polymers can be, for example, poly Polyethylene glycols such as vinyl pyrrolidone can be substituted and other sugars and polysaccharides can replace dextrose.

또한, 소수성 약제화합물용의 다른 전달계가 채용될 수도 있다. 리포좀과에멀션은 소수성 약제들용 전달 비히클의 공지 예들이다. 통상 더 높은 독성을 희생시킬지라도, 디메틸술폭사이드와 같은 임의의 유기 용매들이 채용될 수도 있다. 추가적으로, 치료 성분을 포함하고 있는 고상의 소수성 폴리머의 반투과성 매트릭 스와 같은 서방계를 사용하여 화합물이 전달될 수도 있다. 다양한 서방 물질들이 계발되어있고 당업자에게 공지되어 있다. 서방 캡슐은 그것의 화합물 특성에 따라 2 또는 3 주에서 100일까지 화합물을 방출할 수 있다. 치료제의 화학적 특성 및 생물학적 안정성에 따라, 단백질 안정을 위한 추가적인 전략이 채용될 수도 있다.In addition, other delivery systems for hydrophobic drug compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles for hydrophobic agents. Usually organic solvents such as dimethylsulfoxide may be employed, even at the expense of higher toxicity. In addition, the compound may be delivered using a sustained release system, such as a semipermeable matrix of a solid hydrophobic polymer containing a therapeutic ingredient. Various sustained release materials have been developed and are known to those skilled in the art. Sustained release capsules can release the compound from 2 or 3 weeks to 100 days depending on its compound properties. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for protein stability may be employed.

본 발명의 많은 화합물들은 약학적으로 허용되는 반대이온과의 염으로서 제공될 수도 있다. 약학적으로 허용되는 염은, 다음의 것으로 한정되지는 않지만, 염산, 황산, 아세트산, 젖산, 타르타르산, 말산, 숙신산 등을 포함한 많은 산에 의해 형성될 수 있다. 염은 그것에 대응하는 무산 또는 염기 형태보다도 수성 또는 양성자 용액에서 더 잘 용해되는 경향이 있다.Many compounds of the present invention may also be provided as salts with pharmaceutically acceptable counterions. Pharmaceutically acceptable salts may be formed with many acids including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to dissolve better in aqueous or proton solutions than their corresponding acid free or base forms.

(c) 유효량(c) effective amount

본 발명에서 사용에 적합한 약제 조성물에는, 활성 성분들이 그것의 의도된 목적을 달성하기에 유효한 량으로 함유되어 있는 조성물이 포함된다. 더욱 구체적으로, 치료적 유효량은 치료될 객체의 생존을 연장하거나, 질환의 증상을 방지, 경감 또는 완화시키는데 유효한 화합물의 량을 의미한다. 치료적 유효량의 결정은, 특히, 여기에 제공된 상세한 개시 내용 측면에서, 당업자의 능력 범위내에 있다. Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount of a compound effective to prolong the survival of the subject to be treated or to prevent, alleviate or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, in particular in terms of the detailed disclosure provided herein.

본 발명의 방법들에서 사용되는 임의의 화합물에 대한 치료적 유효량은 세포 배양 분석으로부터 초기에 측정될 수 있다. 예를 들어, 선량(dose)은 세포 배양에서 결정된 IC50를 포함하는 순환 농도 범위를 얻기 위하여 동물 모델에서 계산될 수 있다. 그러한 정보는 인간에서의 유용한 선량을 더욱 정확히 결정하는데 사용될 수 있다.A therapeutically effective amount for any compound used in the methods of the invention can be determined initially from cell culture assays. For example, the dose can be calculated in an animal model to obtain a range of circulating concentrations comprising an IC 50 determined in cell culture. Such information can be used to more accurately determine useful doses in humans.

여기에 기재되어 있는 화합물들의 독성과 치료 효율성은, 예를 들어, LD50(군집의 50%에 대한 치사량)과 ED50(군집의 50%에 대해 치료 효과를 갖는 선량)을 결정하기 위하여, 세포 배양 또는 실험동물에서의 표분 제약 과정들에 의해 산정될 수 있다. 독성과 치료 효과 간의 선량 비가 치료 지수이고 이것은 LD50과 ED50 간의 비율로서 표현될 수 있다. 높은 치료 지수를 보이는 화합물들이 바람직하다. 이들 세포 배양 분석에서 얻어진 데이터는 인간에 사용하는 선량의 범위를 산정하는데 사용될 수 있다. 그러한 화합물들의 투여량(dosage)은 바람직하게는 독성이 없거나 거의 없는 상태에서 ED50을 포함하는 순환 농도의 범위 내에 있다. 투여량은 채용된 투여 형태와 이용된 투여루트에 따라 상기범위에서 변화될 수 있다. 정확한 산정, 투여 루트 및 투여량은 환자의 상태를 고려하여 개개의 의사에 의해 선택될 수 있다(예를 들어, Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1 참조). 통상적으로, 환자에게 투여되는 조성물의 선량 범위는 환자 체중의 약 0.5 내지 1000 mg/kg 일 수 있다. 투여량은, 환자에게 요구되는 정도에 따라, 한번에 또는 하루 또는 그 이상의 과정으로 일련의 둘 또는 그 이상으로 제공될 수도 있다.Toxicity and therapeutic efficiency of the compounds described herein can be determined by, for example, cell culture or Estimates can be made by surface constraint procedures in laboratory animals. The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds showing high therapeutic indices are preferred. The data obtained from these cell culture assays can be used to estimate the range of doses used in humans. The dosage of such compounds is preferably in the range of circulating concentrations comprising ED50 in the absence or little toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact estimate, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition (eg, Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1 Reference). Typically, the dose range of the composition administered to the patient may be about 0.5 to 1000 mg / kg of the patient's body weight. Dosages may be given in a series of two or more, one at a time or in a day or more, depending on the extent required by the patient.

투여량과 간격은 키나아제 조절 효과 또는 최소 유효 농도(MEC)를 유지하기에 충분한 활성 부위의 혈장 수준을 제공하도록 개별적으로 조정될 수도 있다. MEC는 개개의 화합물에 따라 달라지지만, 예를 들어, 여기에 기재되어 있는 분석법 을 사용하여 키나아제의 50~90% 억제를 달성하는데 필요한 농도와 같이 생체외 데이터로부터 예측될 수도 있다. MEC를 달성하는데 필요한 투여량은 각자의 특성들과 투여 경로에 따라 달라지게 된다. 그러나, HPLC 정량 또는 생물학적 정량이 혈장 농도를 결정하는데 사용될 수 있다.Dosages and intervals may be individually adjusted to provide plasma levels of the active site sufficient to maintain a kinase modulating effect or minimal effective concentration (MEC). The MEC depends on the individual compound, but can also be predicted from ex vivo data, such as, for example, the concentration required to achieve 50-90% inhibition of kinases using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC or biological quantification can be used to determine plasma concentration.

투여 간격은 MEC 값을 사용하여 결정할 수도 있다. 화합물들은, 한번에 10~90%, 바람직하게는 30~90%, 특히 바람직하게는 50~90%로 되도록, 혈정 수준을 상기 MEC 이상으로 유지하는 투여 계획을 사용하여, 투여되어야 한다. Dosage intervals may be determined using MEC values. Compounds should be administered using a dosing regimen that maintains blood serum levels above the MEC, such that 10-90%, preferably 30-90%, particularly preferably 50-90%, at a time.

국소 투여 또는 선택적 업테이크의 경우에는, 약제의 유효 국소 농도가 혈장 농도와 관련되지 않을 수도 있다.In the case of topical administration or selective uptake, the effective local concentration of the medicament may not be related to the plasma concentration.

물론, 투여되는 조성물의 량은 치료될 개체에 따라, 객체의 체중에 따라, 통증의 심각에 따라, 투여 방식 및 의사의 판단에 따라 달라지게 된다.Of course, the amount of composition to be administered will depend on the subject to be treated, on the weight of the subject, on the severity of pain, on the manner of administration and on the judgment of the physician.

본 발명은 하기 실시예, 제조예 및 실험예에 의하여 더욱 상세히 설명되어진다. 그러나 본 발명의 범위가 하기 실시예 등에 국한되는 것은 아니다.The invention is illustrated in more detail by the following examples, preparations and experimental examples. However, the scope of the present invention is not limited to the following examples and the like.

하기에 기술하는 실시예에서는, 달리 언급하지 않는 한, 모든 온도는 섭씨로 나타낸 것이며, 모든 부와 퍼센트는 부피 및 중량 기준이다. 하기에 나타낸 반응들은 일반적으로 주변온도(달리 언급하지 않는 한)에서 아르곤 또는 질소의 양압하에서 또는 건조관을 사용하여 무수 용매 중에서 수행하였으며, 반응 플라스크에는 주사관을 통해 물질 및 시약을 도입하기 위한 고무 격막이 장착되었다. 유리 제품은 오븐 건조시키고/시키거나 열 건조시켰다. 반응은 TLC로 분석하였으며 출발 물질의 소모에 의해 판단되는 대로 종료하였다.In the examples described below, unless stated otherwise all temperatures are in degrees Celsius and all parts and percentages are by volume and weight. The reactions shown below were generally carried out in anhydrous solvent at ambient temperature (unless stated otherwise) under a positive pressure of argon or nitrogen or using a drying tube, and the reaction flask contained a rubber for introducing substances and reagents through a syringe tube. The diaphragm was mounted. Glass articles were oven dried and / or heat dried. The reaction was analyzed by TLC and ended as judged by the depletion of the starting material.

가수소분해는 실시예에 언급된 압력에서 또는 주위 압력에서 수행하였다. 1H-NMR 스펙트럼은 300 MHz에서 운전되는 브루커(Bruker) 기기상에서 기록하였으며, 13C-NMR 스펙트럼은 100 MHz에서 운전하는 기기상에서 기록하였다. NMR 스펙트럼은 기준물로서 클로로폼(7.25 ppm 및 77.00 ppm) 또는 CD3OD(3.4 및 4.8 ppm 및 49.3 ppm), 또는 경우에 따라 내부적으로 테트라메틸실레인(0.00 ppm)을 사용하여 CDCl3 용액(ppm으로 기록)으로서 수득하였다. 필요에 따라 다른 NMR 용매를 사용하였다.Hydrolysis was carried out at the pressure mentioned in the examples or at ambient pressure. 1 H-NMR spectra were recorded on a Bruker instrument operated at 300 MHz and 13 C-NMR spectra were recorded on an instrument operated at 100 MHz. NMR spectra were measured using CDCl 3 solution (chloroform (7.25 ppm and 77.00 ppm) or CD 3 OD (3.4 and 4.8 ppm and 49.3 ppm) as reference, or optionally internally tetramethylsilane (0.00 ppm). in ppm). Other NMR solvents were used as needed.

피크 다중성을 기록할 때, 다음의 약칭을 사용하였다: s(단일선), d(이중선), t(삼중선), m(다중선), br(광범위), dd(이중선의 이중선), dt(삼중선의 이중선). 커플링 상수는 주어지는 경우 헤르츠(Hz)로 기록하였다.When recording peak multiplicity, the following abbreviations were used: s (single line), d (double line), t (triple line), m (multiple line), br (wide range), dd (double line of double line), dt (Doublet of triplets). Coupling constants are reported in hertz (Hz), if given.

[[ 제조예Production Example 1] 2-(4- 1] 2- (4- 메틸methyl -피페리딘-1-일)-5-니트로-벤조산-Piperidin-1-yl) -5-nitro-benzoic acid

2-플루오르-5-니트로벤조산 7.0g(38mmol)을 200ml의 아세토니트릴에 녹인 후, 4-메틸피페리딘 6.7g(54mmol)을 가하고 12시간 동안 환류시키며 끓여주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 5% 시트르산 수용액으로 세척하였다. 마그네슘설페이트로 물을 제거한 다음 감압여과하고 에틸아세테이트를 감압증류로 제거하여 표제 화합물 9.6g을 96% 수율로 얻었다. 7.0 g (38 mmol) of 2-fluoro-5-nitrobenzoic acid was dissolved in 200 ml of acetonitrile, and 6.7 g (54 mmol) of 4-methylpiperidine was added thereto, and the mixture was boiled under reflux for 12 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added and the mixture was washed with 5% citric acid aqueous solution. Water was removed with magnesium sulfate, and the residue was filtered under reduced pressure and ethyl acetate was removed by distillation under reduced pressure to obtain 9.6 g of the titled compound in 96% yield.

1H NMR (CDCl3+CD3OD 400MHz): δ(ppm) 9.07(1H, d, J=2.39), 8.43(1H, dd J=8.82, 2.76), 7.65(1H, d, J=8.83), 3.20(2H, d, J=11.73), 3.03(2H, td, J=11.91, 2.14), 1.96(2H, dd, J=13.38, 1.68), 1.61(1H, m), 1.57(2H, qd, J=11.83, 3.86), 1.08(3H, d, J=6.47)1 H NMR (CDCl 3 + CD 3 OD 400 MHz): δ (ppm) 9.07 (1H, d, J = 2.39), 8.43 (1H, dd J = 8.82, 2.76), 7.65 (1H, d, J = 8.83), 3.20 (2H , d, J = 11.73), 3.03 (2H, td, J = 11.91, 2.14), 1.96 (2H, dd, J = 13.38, 1.68), 1.61 (1H, m), 1.57 (2H, qd, J = 11.83 , 3.86), 1.08 (3H, d, J = 6.47)

[[ 제조예Production Example 2] N- 2] N- 시클로프로필Cyclopropyl -2-(4--2- (4- 메틸methyl -피페리딘-1-일)-5-니트로--Piperidin-1-yl) -5-nitro- 벤즈아미드Benzamide

제조예 1 에서 얻은 화합물 0.25g(0.95mmol)을 15ml N,N-디메틸포름아미드에 녹인 후 시클로프로필아민 0.072ml(1.0mmol), EDC 0.25g(1.3mmol), HOBT 0.29g(2.2mmol)를 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 물, 탄산나트륨 포화 수용액, 5% 시트르산 수용액으로 각각 3번씩 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 헥세인:에틸아세테이트(3:1)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.17g을 61%의 수율로 얻었다. 0.25 g (0.95 mmol) of the compound obtained in Preparation Example 1 was dissolved in 15 ml N, N-dimethylformamide, followed by 0.072 ml (1.0 mmol) of cyclopropylamine, 0.25 g (1.3 mmol) of EDC, and 0.29 g (2.2 mmol) of HOBT. Put and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, and ethyl acetate was added thereto and washed three times with water, saturated aqueous sodium carbonate solution and 5% citric acid solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using hexane: ethyl acetate (3: 1) to obtain 0.17 g of the title compound in a yield of 61%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.69(1H, d, J=3.04), 8.63(1H, s), 8.14(1H, dd, J=8.92, 2.83), 7.15(1H, d, J=8.96), 3.32(2H, d), 2.26(1H, m), 2.82(2H, td, J=12.05, 2.05), 1.86(2H, d, J=11.42), 1.62(1H, m), 1.32(2H, qd, J=12.01, 3.08), 1.04(3H, d, J=6.52), 0.90(2H, q, J=5.62), 0.64(2H, q, J=4.18)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.69 (1H, d, J = 3.04), 8.63 (1H, s), 8.14 (1H, dd, J = 8.92, 2.83), 7.15 (1H, d, J = 8.96), 3.32 (2H, d), 2.26 (1H, m), 2.82 (2H, td, J = 12.05, 2.05), 1.86 (2H, d, J = 11.42), 1.62 (1H, m), 1.32 ( 2H, qd, J = 12.01, 3.08), 1.04 (3H, d, J = 6.52), 0.90 (2H, q, J = 5.62), 0.64 (2H, q, J = 4.18)

[[ 제조예Production Example 3] 5-아미노-N- 3] 5-amino-N- 시클로프로필Cyclopropyl -2-(4--2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 2 에서 얻은 화합물 0.17g(0.57mmol)을 30ml 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여표제 화합물 0.15g을 97%의 수율로 얻었다. 0.17 g (0.57 mmol) of the compound obtained in Preparation Example 2 was dissolved in 30 ml of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.15 g of the title compound in a yield of 97%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.9(1H, s), 7.58(1H, d, J=2.92), 7.03(1H, d, J=8.28), 6.71(1H, dd, J=8.43, 2.93), 2.99(1H, m), 2.95(2H, d, J=12.13), 2.67(2H, td, J=11.80, 2.22), 1.78(3H, d, J=12.78), 1.52(1H, m), 1.24(2H, qd, J=12.64, 3.58), 1.01(3H, d, J=6.31), 0.84(2H, q, J=5.44), 0.57(2H, q, J=5.02)1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.9 (1H, s), 7.58 (1H, d, J = 2.92), 7.03 (1H, d, J = 8.28), 6.71 (1H, dd, J = 8.43, 2.93), 2.99 (1H, m), 2.95 (2H, d, J = 12.13), 2.67 (2H, td, J = 11.80, 2.22), 1.78 (3H, d, J = 12.78), 1.52 (1H, m ), 1.24 (2H, qd, J = 12.64, 3.58), 1.01 (3H, d, J = 6.31), 0.84 (2H, q, J = 5.44), 0.57 (2H, q, J = 5.02)

[[ 실시예Example 1] 5-(2- 1] 5- (2- 클로로Chloro -- 아세틸아미노Acetylamino )-N-) -N- 시클로프로필Cyclopropyl -2-(4--2- (4- 메틸methyl -피페리딘-1-일)-벤즈아미드 -Piperidin-1-yl) -benzamide

제조예 3 에서 얻은 화합물 0.045g(0.16mmol)을 5ml 디클로로메테인에 녹인 후 피리딘 0.013ml(0.16mmol)을 넣고 10분간 교반해주었다. 클로로아세틸 클로라이드 0.013mll(0.16mmol)를 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 5% 시트르산 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 감압여과하고 에틸아세테이트를 감압증류로 제거하고 헥세인:에틸아세테이트(1:2)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.072g을 정량적으로 얻었다. 0.045g (0.16mmol) of the compound obtained in Preparation Example 3 was dissolved in 5ml dichloromethane, and 0.013ml (0.16mmol) of pyridine was added thereto, followed by stirring for 10 minutes. Add chloroacetyl chloride 0.013mll (0.16mmol) and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with 5% aqueous citric acid solution. Water was removed using magnesium sulfate, and the residue was filtered under reduced pressure, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using hexane: ethyl acetate (1: 2) to obtain 0.072 g of the title compound.

1H NMR (DMSO 400MHz): δ(ppm) 9.93(1H, s), 9.47(1H, d, J=4.30), 7.52(1H, d, J=2.68), 7.30(1H, dd, J=8.69, 2.70). 6.81(1H, d, J=8.72), 3.78(2H, s), 2.51(2H, d, J=11.52), 2.45(1H, m), 1.30(2H, d, J=11.35), 1.50(1H, m), 0.78(2H, qd, J=3.49), 0.51(3H, d, J=6.50), 0.32(2H, q, J=5.03), 0.07(2H, q, J=6.14). 13C NMR (CDCl3+DMSO 100MHz) : δ(ppm) 167.4, 165.1, 148.6, 135.2, 128.0, 123.8, 122.4, 122.2, 54.3, 43.6, 35.2, 32.1, 30.3, 29.9, 22.8, 22.2, 6.61 H NMR (DMSO 400 MHz): δ (ppm) 9.93 (1H, s), 9.47 (1H, d, J = 4.30), 7.52 (1H, d, J = 2.68), 7.30 (1H, dd, J = 8.69, 2.70). 6.81 (1H, d, J = 8.72), 3.78 (2H, s), 2.51 (2H, d, J = 11.52), 2.45 (1H, m), 1.30 (2H, d, J = 11.35), 1.50 (1H m), 0.78 (2H, qd, J = 3.49), 0.51 (3H, d, J = 6.50), 0.32 (2H, q, J = 5.03), 0.07 (2H, q, J = 6.14). 13C NMR (CDCl 3 + DMSO 100 MHz): δ (ppm) 167.4, 165.1, 148.6, 135.2, 128.0, 123.8, 122.4, 122.2, 54.3, 43.6, 35.2, 32.1, 30.3, 29.9, 22.8, 22.2, 6.6

[[ 제조예Production Example 4] N-(2- 4] N- (2- 디에틸아미노Diethylamino -에틸)-2-(4--Ethyl) -2- (4- 메틸methyl -피페리딘-1-일)-5-니트로--Piperidin-1-yl) -5-nitro- 벤즈아미드Benzamide

제조예 1 에서 얻은 화합물 0.20g(0.76mmol)을 15ml N,N-디메틸포름아미드에 녹인 후 N,N-디에틸에틸렌디아민 0.11ml(0.78mmol), EDC 0.15g(0.76mmol), HOBT 0.16g(1.2mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(7:93)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.12g을 43%의 수율로 얻었다. 0.20 g (0.76 mmol) of the compound obtained in Preparation Example 1 was dissolved in 15 ml N, N-dimethylformamide, and then 0.11 ml (0.78 mmol) of N, N-diethylethylenediamine, 0.15 g (0.76 mmol) of EDC, and 0.16 g of HOBT. (1.2 mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using methanol: dichloromethane (7:93) to obtain 0.12 g of the title compound in a yield of 43%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.73(1H, d, J=2.4), 8.42(1H, s), 8.18(1H, dd, J=9.2, 2.8), 7.15(1H, d, J=9.2), 3.57(2H, q, J=6), 3.36(2H, d, J=12.4), 2.84(2H, t, J=10.4), 2.68(2H, t, J=6.4), 2.62(4H, q. J=7.2), 1.81(2H, d, J=11.6), 1.60-1.55(1H, m), 1.40(2H, td, J=12.2, 3.6), 1.03(9H, t, J=7.6)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.73 (1H, d, J = 2.4), 8.42 (1H, s), 8.18 (1H, dd, J = 9.2, 2.8), 7.15 (1H, d, J = 9.2), 3.57 (2H, q, J = 6), 3.36 (2H, d, J = 12.4), 2.84 (2H, t, J = 10.4), 2.68 (2H, t, J = 6.4), 2.62 (4H , q.J = 7.2), 1.81 (2H, d, J = 11.6), 1.60-1.55 (1H, m), 1.40 (2H, td, J = 12.2, 3.6), 1.03 (9H, t, J = 7.6 )

[[ 제조예Production Example 5] 5-아미노-N-(2- 5] 5-amino-N- (2- 디에틸아미노Diethylamino -에틸)-2-(4--Ethyl) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 4 에서 얻은 화합물 0.45g(1.3mmol)을 20ml 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.41g을 98%의 수율로 얻었다. 0.45 g (1.3 mmol) of the compound obtained in Preparation Example 4 was dissolved in 20 ml of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.41 g of the title compound in a yield of 98%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.73(1H, s), 7.57(1H, s), 7.05(1H, d, J=8.4), 6.71(1H, d, J=8), 3.78(2H, s), 3.54(2H, q, J=6.4), 2.97(2H, d, J=11.2), 2.70-2.58(8H, m), 1.76(2H, d, J=12.8), 1.50(1H, m), 1.37(2H, q, J=12), 1.01(9H, m)1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.73 (1H, s), 7.57 (1H, s), 7.05 (1H, d, J = 8.4), 6.71 (1H, d, J = 8), 3.78 (2H , s), 3.54 (2H, q, J = 6.4), 2.97 (2H, d, J = 11.2), 2.70-2.58 (8H, m), 1.76 (2H, d, J = 12.8), 1.50 (1H, m), 1.37 (2H, q, J = 12), 1.01 (9H, m)

[[ 실시예2Example 2 ] 5-(4-5- (4- terttert -부틸-Butyl 벤조일아미노Benzoylamino )-N-(2-) -N- (2- 디에틸아미노Diethylamino -에틸)-2-(4--Ethyl) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 5 에서 얻은 화합물 0.10g(0.30mmol)을 5ml 디클로로메테인에 녹인 후 피리딘 0.032ml(0.34mmol), tert-부틸벤조일 클로라이드 0.050ml(0.30mmol)를 넣고 4시간 동안 교반해주었다. 용매는 감압증류로 제거한 다음 클로로포름:메탄올:암모니아 수용액(100:10:1)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.079g을 53%의 수율로 얻었다. 0.10 g (0.30 mmol) of the compound obtained in Preparation Example 5 was dissolved in 5 ml dichloromethane, and 0.032 ml (0.34 mmol) of pyridine and 0.050 ml (0.30 mmol) of tert-butylbenzoyl chloride were added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, and then purified by column chromatography using chloroform: methanol: ammonia aqueous solution (100: 10: 1) to obtain 0.079 g of the title compound in a yield of 53%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.3(1H, br s), 8.64(1H, s), 8.34(1H, dd, J=6. 2.7), 8.04(1H, d, J=2.7), 7.86(2H, d, J=8.5), 7.49(2H, d, J=8.5), 3.45(2H, q, J=6.1), 3.09(2H, br d, J=11.7), 2.76(2H, br t, J=9.9), 2.62(6H, p, J=6.5), 1.80(2H, br d, J=11.2), 1.44(12H, m), 1.02(9H, m). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.5, 166.1, 155.6, 148.6, 135.6, 132.3, 128.4, 127.5, 126.0, 124.1, 123.1, 122.0, 54.6, 52.1, 47.2, 37.8, 35.3, 35.2, 31.5, 30.7, 22.2, 11.71 H NMR (CDCl 3 400 MHz): δ (ppm) 10.3 (1H, br s), 8.64 (1H, s), 8.34 (1H, dd, J = 6.2.7), 8.04 (1H, d, J = 2.7), 7.86 (2H, d, J = 8.5), 7.49 (2H, d, J = 8.5), 3.45 (2H, q, J = 6.1), 3.09 (2H, br d, J = 11.7), 2.76 (2H, br t, J = 9.9), 2.62 (6H, p, J = 6.5), 1.80 (2H, br d, J = 11.2), 1.44 (12H, m), 1.02 (9H, m). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.5, 166.1, 155.6, 148.6, 135.6, 132.3, 128.4, 127.5, 126.0, 124.1, 123.1, 122.0, 54.6, 52.1, 47.2, 37.8, 35.3, 35.2, 31.5, 30.7 , 22.2, 11.7

[[ 실시예Example 3] N-(2- 3] N- (2- 디에틸아미노Diethylamino -에틸)-5-(4-이소프로필--Ethyl) -5- (4-isopropyl- 벤조일아미노Benzoylamino )-2-(4-) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 5 에서 얻은 화합물 0.10g(0.30mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, 4-이소프로필벤조산 0.049g(0.30mmol), EDC 0.058g(0.30mmol), HOBT 0.065g(0.48mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 포화 암모니 아 메탄올:디클로로메테인(5:95)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.016g을 11%의 수율로 얻었다. 0.10 g (0.30 mmol) of the compound obtained in Preparation Example 5 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.049 g (0.30 mmol) of 4-isopropylbenzoic acid, 0.058 g (0.30 mmol) of EDC, and 0.065 g of HOBT ( 0.48 mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using saturated ammonia methanol: dichloromethane (5:95) to obtain 0.016 g of the title compound in 11% yield.

1H NMR (CDCl3 400MHz): δ(ppm) 10.2(1H, br s), 8.59(1H, s), 8.39(1H, dd, J=6.1, 2.6), 8.08(1H, d, J=2.6), 7.85(2H, d, J=8.1), 7.33(2H, d, J=8.2), 3.44(2H, q, J=6.2), 3.09(2H, br d, J=11.6), 3.02(1H, m), 2.76(2H, br t, J=10.1), 2.60(6H, p, J=6.6), 1.80(2H, br d, J=11.3), 1.06(1H, m), 1.44(2H, m), 1.28(7H, d, J=6.9), 1.02(9H, m). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.5, 166.2, 153.4, 148.7, 135.5, 132.5, 128.5, 127.8, 127.1, 124.1, 123.0, 122.0, 54.6, 52.2, 47.2, 37.8, 35.2, 34.5, 30.7, 24.2, 22.2, 11.81 H NMR (CDCl 3 400 MHz): δ (ppm) 10.2 (1H, br s), 8.59 (1H, s), 8.39 (1H, dd, J = 6.1, 2.6), 8.08 (1H, d, J = 2.6), 7.85 (2H, d, J = 8.1), 7.33 (2H, d, J = 8.2), 3.44 (2H, q, J = 6.2), 3.09 (2H, br d, J = 11.6), 3.02 (1H, m ), 2.76 (2H, brt, J = 10.1), 2.60 (6H, p, J = 6.6), 1.80 (2H, br d, J = 11.3), 1.06 (1H, m), 1.44 (2H, m) , 1.28 (7H, d, J = 6.9), 1.02 (9H, m). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.5, 166.2, 153.4, 148.7, 135.5, 132.5, 128.5, 127.8, 127.1, 124.1, 123.0, 122.0, 54.6, 52.2, 47.2, 37.8, 35.2, 34.5, 30.7, 24.2 , 22.2, 11.8

[[ 실시예Example 4] N-(2- 4] N- (2- 디에틸아미노Diethylamino -에틸)-5-(4--Ethyl) -5- (4- 헥실Hexyl -- 벤조일아미노Benzoylamino )-2-(4-) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 5 에서 얻은 화합물 0.10g(0.30mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, 4-헥실벤조산 0.062g(0.30mmol), EDC 0.058g(0.30mmol), HOBT 0.065g(0.48mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 포화 암모니아 메탄올:디클로로메테인(5:95)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.026g을 17%의 수율로 얻었다.0.10 g (0.30 mmol) of the compound obtained in Preparation Example 5 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.062 g (0.30 mmol) of 4-hexylbenzoic acid, 0.058 g (0.30 mmol) of EDC, and 0.065 g (0.48 HOBT). mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using saturated ammonia methanol: dichloromethane (5:95) to obtain 0.026 g of the title compound in a yield of 17%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.3(1H, br t, J=5.04), 8.85(1H, s), 8.41(1H, dd, J=6.04, 2.67), 8.15(1H, d, J=2.72), 7.85(2H, d, J=8.23), 7.27(2H, m), 3.38(2H, q, J=6.26), 3.08(2H, br d, J=11.7), 2.76(2H, br t, J=9.86), 2.67(2H, t, J=7.60), 2.57(6H, m), 1.80(2H, br ｄ, J=11.1), 1.64(2H, m), 1.55(1H, m), 1.44(9H, m), 1.02(9H, m), 0.90(3H, m). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.5, 166.4, 148.6, 147.5, 135.7, 132.7, 129.0, 128.4, 127.8, 124.1, 123.2, 121.9, 56.1, 52.1, 47.1, 37.8, 36.3, 35.2, 32.1, 31.6, 30.7, 29.4, 23.0, 22.2, 14.5, 11.71 H NMR (CDCl 3 400 MHz): δ (ppm) 10.3 (1H, brt, J = 5.04), 8.85 (1H, s), 8.41 (1H, dd, J = 6.04, 2.67), 8.15 (1H, d, J = 2.72), 7.85 (2H, d, J = 8.23), 7.27 (2H, m), 3.38 (2H, q, J = 6.26), 3.08 (2H, br d, J = 11.7), 2.76 (2H, br t, J = 9.86), 2.67 (2H, t, J = 7.60), 2.57 (6H, m), 1.80 (2H, brd, J = 11.1), 1.64 (2H, m), 1.55 (1H, m) , 1.44 (9H, m), 1.02 (9H, m), 0.90 (3H, m). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.5, 166.4, 148.6, 147.5, 135.7, 132.7, 129.0, 128.4, 127.8, 124.1, 123.2, 121.9, 56.1, 52.1, 47.1, 37.8, 36.3, 35.2, 32.1, 31.6 , 30.7, 29.4, 23.0, 22.2, 14.5, 11.7

[[ 실시예Example 5] 5-(2- 5] 5- (2- 클로로Chloro -- 아세틸아미노Acetylamino )-N-(2-) -N- (2- 디에틸아미노Diethylamino -에틸)-2-(4--Ethyl) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 5 에서 얻은 화합물 0.050g(0.15mmol)을 5ml 디클로로메테인에 녹인 후 피리딘 0.012ml(0.15mmol), 클로로아세틸 클로라이드 0.013mll(0.16mmol)를 넣고 4시간 동안 교반해주었다. 용매는 감압증류로 제거한 다음 메탄올:디클로로메테인(7:93)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.046g을 75%의 수율로 얻었다. 0.050 g (0.15 mmol) of the compound obtained in Preparation Example 5 was dissolved in 5 ml dichloromethane, and pyridine 0.012 ml (0.15 mmol) and chloroacetyl chloride (0.016 mmol) were added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, and then purified by column chromatography using methanol: dichloromethane (7:93) to obtain 0.046 g of the title compound in a yield of 75%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.25(1H, s), 9.00.(1H, s), 8.11(1H, dd, J=8.6, 2.8), 7.97(1H, d, J=2.8), 7.23(1H, d, J=8.8), 4.20(2H, s), 3.59(2H, q, J=6), 3.07(2H, d, J=11.6), 2.75-2.62(8H, m), 1.80(2H, d, J=11.6), 1.54-1.50(1H, m), 1.40(2H, qd, J=12, 3.6), 1.06-1.03(9H, m). 13C NMR (CDCl3 100MHz) : δ(ppm)166.5, 164.8, 149.3, 134.2, 128.4, 123.1, 122.0, 54.6, 52.0, 47.2, 43.5, 37.7, 35.1, 30.6, 22.2, 11.4 1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.25 (1H, s), 9.00. (1H, s), 8.11 (1H, dd, J = 8.6, 2.8), 7.97 (1H, d, J = 2.8), 7.23 (1H, d, J = 8.8), 4.20 (2H, s), 3.59 (2H, q, J = 6), 3.07 (2H, d, J = 11.6), 2.75-2.62 (8H, m), 1.80 (2H, d, J = 11.6), 1.54-1.50 (1H, m), 1.40 (2H, qd, J = 12, 3.6), 1.06-1.03 (9H, m). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.5, 164.8, 149.3, 134.2, 128.4, 123.1, 122.0, 54.6, 52.0, 47.2, 43.5, 37.7, 35.1, 30.6, 22.2, 11.4

[[ 제조예Production Example 6] 2-(4- 6] 2- (4- 메틸methyl -피페리딘-1-일)-N-(2--Piperidin-1-yl) -N- (2- 몰포린Morpholine -4-일-에틸)-5-니트로--4-yl-ethyl) -5-nitro- 벤즈아미드Benzamide

제조예 1 에서 얻은 화합물 0.20g(0.76mmol)을 15ml N,N-디메틸포름아미드에 녹인 후 4-(2-아미노에틸)-몰포린 0.10ml(0.74mmol), EDC 0.15g(0.76mmol), HOBT 0.15g(1.1mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 헥세인:에틸아세테이트(1:4)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.19g을 66%의 수율로 얻었다. 0.20 g (0.76 mmol) of the compound obtained in Preparation Example 1 was dissolved in 15 ml N, N-dimethylformamide, and then 0.10 ml (0.74 mmol) of 4- (2-aminoethyl) -morpholine, 0.15 g (0.76 mmol) of EDC, 0.15 g (1.1 mmol) of HOBT was added thereto, followed by stirring for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure and purified by column chromatography using hexane: ethyl acetate (1: 4) to obtain 0.19 g of the title compound in a yield of 66%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.69(1H, d, J=2.4), 8.45(1H, s), 8.16(1H, dd, J=9, 2.8), 7.16(1H, d, J=8.8), 3.73(4H, t, J=4.4), 3.63(2H, q, J=4.8), 3.38(2H, d, J=12), 2.86(2H, t, J=10.8), 2.63(2H, t, J=6), 2.53(4H, s), 1.84(2H, d, J=12), 1.61-1.57(1H, m), 1.39(2H, td, J=12, 3.6), 1.02(3H, d, J=6.4) 1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.69 (1H, d, J = 2.4), 8.45 (1H, s), 8.16 (1H, dd, J = 9, 2.8), 7.16 (1H, d, J = 8.8), 3.73 (4H, t, J = 4.4), 3.63 (2H, q, J = 4.8), 3.38 (2H, d, J = 12), 2.86 (2H, t, J = 10.8), 2.63 (2H , t, J = 6), 2.53 (4H, s), 1.84 (2H, d, J = 12), 1.61-1.57 (1H, m), 1.39 (2H, td, J = 12, 3.6), 1.02 ( 3H, d, J = 6.4)

[[ 제조예Production Example 7] 5-아미노-2-(4- 7] 5-amino-2- (4- 메틸methyl -피페리딘-1-일)-N-(2--Piperidin-1-yl) -N- (2- 몰포린Morpholine -4-일-에틸)--4-yl-ethyl)- 벤즈아미드Benzamide

제조예 6에서 얻은 화합물 0.19g(0.50mmol)을 10ml 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.18g을 정량적으로 얻었다. 0.19 g (0.50 mmol) of the compound obtained in Preparation Example 6 was dissolved in 10 ml of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.18 g of the title compound quantitatively.

1H NMR (CDCl3 400MHz): δ(ppm) 10.80(1H, s), 7.56(1H, s), 7.07(1H, d, J=8.4), 6.74(1H, dd, J=8.2, 1.6), 3.76(4H, s), 3.64(2H, d, J=5.6), 2.99(2H, d, J=11.6), 2.70(4H, t, J=10.4), 2.60(4H, s), 1.79(2H, d, J=12.4), 1.52(1H, m), 1.37(2H, qd, J=9.6, 2.8), 1.00(3H, d, J=6.4)1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.80 (1H, s), 7.56 (1H, s), 7.07 (1H, d, J = 8.4), 6.74 (1H, dd, J = 8.2, 1.6), 3.76 (4H, s), 3.64 (2H, d, J = 5.6), 2.99 (2H, d, J = 11.6), 2.70 (4H, t, J = 10.4), 2.60 (4H, s), 1.79 (2H, d, J = 12.4), 1.52 (1H, m), 1.37 (2H, qd, J = 9.6, 2.8), 1.00 (3H, d, J = 6.4)

[[ 실시예Example 6] 5-(2- 6] 5- (2- 클로로Chloro -- 아세틸아미노Acetylamino )-2-(4-) -2- (4- 메틸methyl -피페리딘-1-일)-N-(2--Piperidin-1-yl) -N- (2- 몰포린Morpholine -4-일-에틸)--4-yl-ethyl)- 벤즈아미드Benzamide

제조예 7 에서 얻은 화합물 0.090g(0.26mmol)을 5ml 디클로로메테인에 녹인 후 피리딘 0.042ml(0.52mmol), 클로로아세틸 클로라이드 0.021ml(0.26mmol)를 넣고 4시간 동안 교반해주었다. 용매는 감압증류로 제거한 다음 메탄올:디클로로메테인(5:95)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.075g을 68%의 수율로 얻었다. 0.090 g (0.26 mmol) of the compound obtained in Preparation Example 7 was dissolved in 5 ml dichloromethane, and 0.042 ml (0.52 mmol) of pyridine and 0.021 ml (0.26 mmol) of chloroacetyl chloride were added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure and then purified by column chromatography using methanol: dichloromethane (5:95) to obtain 0.075 g of the title compound in a yield of 68%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.29(1H, s), 9.00(1H, s), 8.13(1H, dd, J=8.6, 2.4), 8.00(1H, d, J=2.4), 7.24(1H, d, J=8.8), 4.20(2H, s), 3.72(4H, t, J=4.4), 3.62(2H, q, J=6), 3.09(2H, d, J=11.6), 2.74(2H, t, J=10.4), 2.61(3H, t, J=6.4), 2.51(4H, s), 1.83(2H, d, J=11.6), 1.54(1H, m), 1.40(2H, qd, J=12, 3.6), 1.01(3H, d, J=6.4). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.5, 164.8, 149.3, 134.2, 128.3, 124.4, 123.3, 122.0, 67.2, 58.0, 54.5, 53.9, 43.4, 36.7, 35.3, 30.6, 22.21 H NMR (CDCl 3 400 MHz): δ (ppm) 10.29 (1H, s), 9.00 (1H, s), 8.13 (1H, dd, J = 8.6, 2.4), 8.00 (1H, d, J = 2.4), 7.24 (1H, d, J = 8.8), 4.20 (2H, s), 3.72 (4H, t, J = 4.4), 3.62 (2H, q, J = 6), 3.09 (2H, d, J = 11.6), 2.74 (2H, t, J = 10.4), 2.61 (3H, t, J = 6.4), 2.51 (4H, s), 1.83 (2H, d, J = 11.6), 1.54 (1H, m), 1.40 (2H , qd, J = 12, 3.6), 1.01 (3H, d, J = 6.4). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.5, 164.8, 149.3, 134.2, 128.3, 124.4, 123.3, 122.0, 67.2, 58.0, 54.5, 53.9, 43.4, 36.7, 35.3, 30.6, 22.2

[[ 제조예Production Example 8] [2-(4- 8] [2- (4- 메틸methyl -피페리딘-1-일)-5-니트로--Piperidin-1-yl) -5-nitro- 페닐Phenyl ]-]- 몰포린Morpholine -4-일--4- days- 메타논Metanon

제조예 1 에서 얻은 화합물 0.20g(0.76mmol)을 15ml N,N-디메틸포름아미드에 녹인 후 몰포린 0.080ml(0.91mmol), EDC 0.30g(1.6mmol), HOBT 0.26g(1.9mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 헥세인:에틸아세테이트(2:1)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.21g을 83%의 수율로 얻었다. 0.20 g (0.76 mmol) of the compound obtained in Preparation Example 1 was dissolved in 15 ml N, N-dimethylformamide, followed by 0.080 ml (0.91 mmol) of morpholine, 0.30 g (1.6 mmol) of EDC, and 0.26 g (1.9 mmol) of HOBT. Stir for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using hexane: ethyl acetate (2: 1) to obtain 0.21 g of the title compound in a yield of 83%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.14(2H, m), 6.96(1H, m), 4.04(1H, dt, J=14.8, 3.2), 3.86-3.81(1H, m), 3.76-3.66(3H, m), 3.63-3.50(2H, m), 3.45(1H, d, J=11.2), 3.37-3.31(1H, m), 3.16(1H, dt, J=13.2, 3.2(, 2.95(1H, td, J=12, 2.8), 2.81(1H, td, J=12.6, 2), 1.81(1H, d, J=13.2), 1.74(1H, d, J=12.8), 1.63-1.54(1H, m), 1.33-1.22(2H, m), 1.00(3H, d, J=6.4)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.14 (2H, m), 6.96 (1H, m), 4.04 (1H, dt, J = 14.8, 3.2), 3.86-3.81 (1H, m), 3.76-3.66 (3H, m), 3.63-3.50 (2H, m), 3.45 (1H, d, J = 11.2), 3.37-3.31 (1H, m), 3.16 (1H, dt, J = 13.2, 3.2 (, 2.95 ( 1H, td, J = 12, 2.8), 2.81 (1H, td, J = 12.6, 2), 1.81 (1H, d, J = 13.2), 1.74 (1H, d, J = 12.8), 1.63-1.54 ( 1H, m), 1.33-1.22 (2H, m), 1.00 (3H, d, J = 6.4)

[[ 제조예Production Example 9] [5-아미노-2-(4- 9] [5-amino-2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 페닐Phenyl ]-]- 몰포린Morpholine -4-일--4- days- 메타논Metanon

제조예 8 에서 얻은 화합물 0.21g(0.63mmol)을 10ml 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.21g을 정량적으로 얻었다. 0.21 g (0.63 mmol) of the compound obtained in Preparation Example 8 was dissolved in 10 ml of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.21 g of the title compound quantitatively.

1H NMR (CDCl3 400MHz): δ(ppm) 6.87(1H, d, J=8.8), 6.67-6.63(2H, m), 4.29(2H, s), 3.75(4H, s), 3.60(2H, s), 3.23(2H, s), 3.10(2H, s), 2.59(2H, s), 1.68(2H, d, J=11.6), 1.42(1H, m), 1.25(2H, qd, J=12, 4), 0.96(3H, d. J=6.4)1 H NMR (CDCl 3 400 MHz): δ (ppm) 6.87 (1H, d, J = 8.8), 6.67-6.63 (2H, m), 4.29 (2H, s), 3.75 (4H, s), 3.60 (2H, s ), 3.23 (2H, s), 3.10 (2H, s), 2.59 (2H, s), 1.68 (2H, d, J = 11.6), 1.42 (1H, m), 1.25 (2H, qd, J = 12 , 4), 0.96 (3H, d. J = 6.4)

[[ 실시예Example 7] 2- 7] 2- 클로로Chloro -N-[4-(4--N- [4- (4- 메틸methyl -피페리딘-1-일)-3-(-Piperidin-1-yl) -3- ( 몰포린Morpholine -4--4- 카보닐Carbonyl )-) - 페닐Phenyl ]-]- 아세트아미드Acetamide

제조예 9 에서 얻은 화합물 0.11g(0.35mmol)을 5ml 디클로로메테인에 녹인 후 피리딘 0.028ml(0.35mmol), 클로로아세틸 클로라이드 0.028ml(0.35mmol)를 넣고 4시간 동안 교반해주었다. 용매는 감압증류로 제거한 다음 디클로로메테인:에틸아세테이트(1:1)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.090g을 68%의 수율로 얻었다. 0.11 g (0.35 mmol) of the compound obtained in Preparation Example 9 was dissolved in 5 ml dichloromethane, and pyridine 0.028 ml (0.35 mmol) and chloroacetyl chloride 0.028 ml (0.35 mmol) were added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, and then purified by column chromatography using dichloromethane: ethyl acetate (1: 1) to obtain 0.090 g of the title compound in a yield of 68%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.54(1H, s), 7.66(1H, dd, J=8.8, 2.4), 7.29(1H, d, J=2.4), 6.98(1H, d, J=8.8), 4.15(2H, s), 3.95(1H, d, J=8), 3.73(4H, m), 3.51(1H, s), 3.37(2H, m), 3.13(2H, m), 2.84(1H, s), 2.48(1H, s), 1.72(2H, br d, J=34.4), 1.47(1H, m), 1.26(2H, m), 0.89(3H, d, J=6.4). 13C NMR (CDCl3 100MHz) : δ(ppm) 170.0, 164.6, 147.5, 132.3, 131.1, 122.9, 121.6, 119.5, 67.2, 67.1, 60.8, 55.6, 53.9, 51.1, 47.5, 43.3, 42.4, 35.4, 35.2, 30.9, 22.3, 21.4, 14.61 H NMR (CDCl 3 400 MHz): δ (ppm) 8.54 (1H, s), 7.66 (1H, dd, J = 8.8, 2.4), 7.29 (1H, d, J = 2.4), 6.98 (1H, d, J = 8.8), 4.15 (2H, s), 3.95 (1H, d, J = 8), 3.73 (4H, m), 3.51 (1H, s), 3.37 (2H, m), 3.13 (2H, m), 2.84 (1H, s), 2.48 (1H, s), 1.72 (2H, broad, J = 34.4), 1.47 (1H, m), 1.26 (2H, m), 0.89 (3H, d, J = 6.4). 13C NMR (CDCl3 100 MHz): δ (ppm) 170.0, 164.6, 147.5, 132.3, 131.1, 122.9, 121.6, 119.5, 67.2, 67.1, 60.8, 55.6, 53.9, 51.1, 47.5, 43.3, 42.4, 35.4, 35.2, 30.9 , 22.3, 21.4, 14.6

[[ 제조예Production Example 10] (4- 10] (4- 메틸methyl -피페라진-1-일)-[2-(4--Piperazin-1-yl)-[2- (4- 메틸methyl -피페리딘-1-일)-5-니트로--Piperidin-1-yl) -5-nitro- 페닐Phenyl ]-메타논] -Methanone

제조예 1 에서 얻은 화합물 0.20g(0.76mmol)을 15ml N,N-디메틸포름아미드에 녹인 후 1-메틸피페라진 0.10ml(0.91mmol), EDC 0.30g(1.6mmol), HOBT 0.27g(2.0mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(2:98)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.21g을 83%의 수율로 얻었다. 0.20 g (0.76 mmol) of the compound obtained in Preparation Example 1 was dissolved in 15 ml N, N-dimethylformamide, followed by 0.10 ml (0.91 mmol) of 1-methylpiperazine, 0.30 g (1.6 mmol) of EDC, and 0.27 g (2.0 mmol) of HOBT. ) Was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using methanol: dichloromethane (2:98) to obtain 0.21 g of the title compound in a yield of 83%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.14(2H, m), 6.96(1H, d, J=10), 4.15(1H, d, J=13.2), 3.69(1H, d, J=13.2), 3.53(1H, t, J=9.6), 3.46(1H, d, J=11.6), 3.35(1H, td, J=8.8, 2.4), 3.21(1H, dt, J=13.6, 4.4), 2.97(1H, td, J=11.2, 2.4), 2.80(1H, td, J=12.8, 2), 2.63(1H, m), 2.50(1H, m), 2.37(1H, td, J=10, 3.2), 2.33(3H, s), 2.17(1H, td, J=9.8, 2.8), 1.80(1H, d, J=12.8), 1.71(1H, d, J=12.8), 1.59-1.54(1H, m), 0.98(3H, d, J=6.8)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.14 (2H, m), 6.96 (1H, d, J = 10), 4.15 (1H, d, J = 13.2), 3.69 (1H, d, J = 13.2) , 3.53 (1H, t, J = 9.6), 3.46 (1H, d, J = 11.6), 3.35 (1H, td, J = 8.8, 2.4), 3.21 (1H, dt, J = 13.6, 4.4), 2.97 (1H, td, J = 11.2, 2.4), 2.80 (1H, td, J = 12.8, 2), 2.63 (1H, m), 2.50 (1H, m), 2.37 (1H, td, J = 10, 3.2 ), 2.33 (3H, s), 2.17 (1H, td, J = 9.8, 2.8), 1.80 (1H, d, J = 12.8), 1.71 (1H, d, J = 12.8), 1.59-1.54 (1H, m), 0.98 (3H, d, J = 6.8)

[[ 제조예Production Example 11] [5-아미노-2-(4- 11] [5-amino-2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 페닐Phenyl ]-(4-]-(4- 메틸methyl -피페라진-1-일)-메타논Piperazin-1-yl) -methanone

제조예 10 에서 얻은 화합물 0.21g(0.61mmol)을 10ml 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.22g을 정량적으로 얻었다. 0.21 g (0.61 mmol) of the compound obtained in Preparation Example 10 was dissolved in 10 ml of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.22 g of the title compound quantitatively.

1H NMR (CDCl3 400MHz): δ(ppm) 6.85(1H, d, J=8.8), 6.64(1H, dd,. J=8.4, 2.8), 6.58(1H, d, J=2.4), 4.05(1H, s), 3.71(1H, s). 3.40(1H, s), 3.27(2H, d, J=16.8), 2.94(1H, d, J=8), 2.80-2.71(3H, m), 2.66(1H, s), 2.42(3H, s), 2.35(2H, s), 1.71(1H, s), 1.61(1H, s), 1.41(1H, m), 1.25(2H, s), 0.94(3H, d, J=6.4)1 H NMR (CDCl 3 400 MHz): δ (ppm) 6.85 (1H, d, J = 8.8), 6.64 (1H, dd, .J = 8.4, 2.8), 6.58 (1H, d, J = 2.4), 4.05 (1H , s), 3.71 (1 H, s). 3.40 (1H, s), 3.27 (2H, d, J = 16.8), 2.94 (1H, d, J = 8), 2.80-2.71 (3H, m), 2.66 (1H, s), 2.42 (3H, s ), 2.35 (2H, s), 1.71 (1H, s), 1.61 (1H, s), 1.41 (1H, m), 1.25 (2H, s), 0.94 (3H, d, J = 6.4)

[[ 실시예Example 8]  8] 시클로프로판카복실산Cyclopropanecarboxylic acid [3-(4- [3- (4- 메틸methyl -피페라진-1-Piperazine-1- 카보닐Carbonyl )-4-(4-) -4- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 페닐Phenyl ]-아미드]-amides

제조예 11 에서 얻은 화합물 0.12g(0.37mmol)을 5ml 디클로로메테인에 녹인 후 피리딘 0.030ml(0.37mmol), 시클로프로페인카복실산 0.034ml(0.37mmol)를 넣고 4시간 동안 교반해주었다. 용매는 감압증류로 제거한 다음 메탄올:디클로로메테인(7:93)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.10g을 70%의 수율로 얻었다. 0.12 g (0.37 mmol) of the compound obtained in Preparation Example 11 was dissolved in 5 ml dichloromethane, and then pyridine 0.030 ml (0.37 mmol) and cyclopropanecarboxylic acid 0.034 ml (0.37 mmol) were added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure and then purified by column chromatography using methanol: dichloromethane (7:93) to give 0.10 g of the title compound in a yield of 70%.

1H NMR (CDCl3 400MHz): δ(ppm) 9.31(1H, s), 7.72(1H, dd, J=8.6, 2), 7.11(1H, d, J=2.4), 6.87(1H, d, J=8.8), 4.13(1H, d, J=13.2), 3.52(1H, t, J=9.6), 3.32(2H, td, J=6, 3.2), 3.17(1H, m), 3.02(1H, d, J=5.2), 2.80(2H, t, J=11.6), 2.63(1H, m), 2.51-2.42(2H, m), 2.31(4H, s) 2.09(1H, t, J=8.8), 1.74(1H, d, J=12), 1.67-1.58(2H, m), 1.43(1H, m). 1.31-1.16(2H, m), 0.99(2H, t, J=3.2), 0.94(3H, d, J=6.4), 0.77-0.68(2H, m). 13C NMR (CDCl3 100MHz) : δ(ppm) 172.8, 170.4, 146.2, 134.1, 131.0, 122.9, 120.6, 119.4, 55.6, 55.4, 55.0, 51.2, 47.1, 46.5, 41.9, 35.5, 35.2, 30.9, 22.3, 15.3, 8.0, 7.91 H NMR (CDCl 3 400 MHz): δ (ppm) 9.31 (1H, s), 7.72 (1H, dd, J = 8.6, 2), 7.11 (1H, d, J = 2.4), 6.87 (1H, d, J = 8.8), 4.13 (1H, d, J = 13.2), 3.52 (1H, t, J = 9.6), 3.32 (2H, td, J = 6, 3.2), 3.17 (1H, m), 3.02 (1H, d , J = 5.2), 2.80 (2H, t, J = 11.6), 2.63 (1H, m), 2.51-2.42 (2H, m), 2.31 (4H, s) 2.09 (1H, t, J = 8.8), 1.74 (1H, d, J = 12), 1.67-1.58 (2H, m), 1.43 (1H, m). 1.31-1.16 (2H, m), 0.99 (2H, t, J = 3.2), 0.94 (3H, d, J = 6.4), 0.77-0.68 (2H, m). 13C NMR (CDCl3 100 MHz): δ (ppm) 172.8, 170.4, 146.2, 134.1, 131.0, 122.9, 120.6, 119.4, 55.6, 55.4, 55.0, 51.2, 47.1, 46.5, 41.9, 35.5, 35.2, 30.9, 22.3, 15.3 , 8.0, 7.9

[[ 제조예Production Example 12] (4- 12] (4- 메틸methyl -피페라진-1-일)-[2-(4--Piperazin-1-yl)-[2- (4- 메틸methyl -피페리딘-1-일)-5-니트로--Piperidin-1-yl) -5-nitro- 페닐Phenyl ]-메타논] -Methanone

제조예 1 에서 얻은 화합물 1.0g(3.8mmol)을 30ml N,N-디메틸포름아미드에 녹인 후 1-메틸피페라진 0.50ml(4.5mmol), EDC 1.5g(7.6mmol), HOBT 1.3g(9.5mmol)을 넣고4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(5:95)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 1.2g을 89%의 수율로 얻었다. 1.0 g (3.8 mmol) of the compound obtained in Preparation Example 1 was dissolved in 30 ml N, N-dimethylformamide, followed by 0.50 ml (4.5 mmol) of 1-methylpiperazine, 1.5 g (7.6 mmol) of EDC, and 1.3 g (9.5 mmol) of HOBT. ) Was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using methanol: dichloromethane (5:95) to obtain 1.2 g of the title compound in a yield of 89%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.16-8.14(2H, m), 6.93(1H, d, J=9.6), 4.17(1H, br d, J=12.8), 3.67(1H, dd, J=13.2, 3.6), 2.96(1H, td, J=11.6, 2.4), 2.79(1H, td, J=12.6, 2.4), 2.65-2.62(1H, m), 2.50-2.47(1H, m), 2.40-2.36(1H, m), 2.33(3H, s), 2.17-2.12(1H, m), 1.79(1H, br d, J=13.2), 1.71(1H, br d, J=12.8), 1.57(1H, m), 1.34-1.19(2H, m), 0.98(3H, d, J=6.4)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.16-8.14 (2H, m), 6.93 (1H, d, J = 9.6), 4.17 (1H, br d, J = 12.8), 3.67 (1H, dd, J = 13.2, 3.6), 2.96 (1H, td, J = 11.6, 2.4), 2.79 (1H, td, J = 12.6, 2.4), 2.65-2.62 (1H, m), 2.50-2.47 (1H, m), 2.40-2.36 (1H, m), 2.33 (3H, s), 2.17-2.12 (1H, m), 1.79 (1H, br d, J = 13.2), 1.71 (1H, br d, J = 12.8), 1.57 (1H, m), 1.34-1.19 (2H, m), 0.98 (3H, d, J = 6.4)

[[ 제조예Production Example 13] [5-아미노-2-(4- 13] [5-amino-2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 페닐Phenyl ]-(4-]-(4- 메틸methyl -피페라진-1-일)-메타논Piperazin-1-yl) -methanone

제조예 12 에서 얻은 화합물 1.2g(3.4mmol)을 30ml 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 1.0g을 95%의 수율로 얻었다. 1H NMR (CDCl3 400MHz): δ(ppm) 6.90(1H, d, J=8.8), 6.68(1H, dd, J=8.6, 2.4), 6.58(1H, s), 3.55(4H, br d, J=32), 3.26(2H, s), 2.96-2.80(4H, m), 2.62(4H, s), 2.37(1H, t, J=10.8), 1.77(1H, d. J=11.2), 1.63(1H, d. J=11.2), 1.43(1H, m), 1.25-1.17(2H, m), 0.96(3H, d, J=6.4)1.2 g (3.4 mmol) of the compound obtained in Preparation Example 12 was dissolved in 30 ml of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 1.0 g of the title compound in a yield of 95%. 1 H NMR (CDCl 3 400 MHz): δ (ppm) 6.90 (1H, d, J = 8.8), 6.68 (1H, dd, J = 8.6, 2.4), 6.58 (1H, s), 3.55 (4H, br d, J = 32), 3.26 (2H, s), 2.96-2.80 (4H, m), 2.62 (4H, s), 2.37 (1H, t, J = 10.8), 1.77 (1H, d. J = 11.2), 1.63 (1H, d. J = 11.2), 1.43 (1H, m), 1.25-1.17 (2H, m), 0.96 (3H, d, J = 6.4)

[[ 실시예Example 9] N-[3-(4- 9] N- [3- (4- 메틸methyl -피페라진-1-Piperazine-1- 카보닐Carbonyl )-4-(4-) -4- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 페닐Phenyl ]-]- 프로피온아미드Propionamide

제조예 13 에서 얻은 화합물 0.10g(0.32mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, 프로피오닐산 0.028ml(0.38mmol), EDC 0.12g(0.63mmol), HOBT 0.086g(0.64mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(5:95)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.082g을 69%의 수율로 얻었다. 0.10 g (0.32 mmol) of the compound obtained in Preparation Example 13 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.028 ml (0.38 mmol) of propionyl acid, 0.12 g (0.63 mmol) of EDC, and 0.086 g (0.64 mmol) of HOBT. ) Was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using methanol: dichloromethane (5:95) to obtain 0.082 g of the title compound in a yield of 69%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.89(1H, s), 7.75(1H, dd. J=8.8, 2.4), 7.14(1H, d, J=2.8), 6.90(1H, d, J=8.8), 4.09(1H, d, J=12.8), 3.55(1H, m), 3.35-3.31(2H, m), 3.20-3.16(1H, m), 3.04(1H, d, J=10.8), 2.81(1H, td, J=10.2, 2), 2.65-2.62(1H, m), 2.53-2.41(2H, m), 2.36-2.27(6H, m), 2.14-2.10(1H, m), 1.74(1H, d, J=13.2), 1.61(1H, d, J=12), 1.44(1H, m), 1.33-1.21(2H, m), 1.17(3H, t, J=7.6), 0.95(3H, d, J=6.4). 13C NMR (CDCl3 100MHz) : δ(ppm) 172.7, 169.8, 146.1, 133.6, 130.8, 122.5, 120.4, 119.0, 55.3, 55.0, 54.7, 50.8, 46.7, 46.1, 41.5, 35.0, 34.8, 30.5, 21.9, 9.81 H NMR (CDCl 3 400 MHz): δ (ppm) 8.89 (1H, s), 7.75 (1H, dd.J = 8.8, 2.4), 7.14 (1H, d, J = 2.8), 6.90 (1H, d, J = 8.8), 4.09 (1H, d, J = 12.8), 3.55 (1H, m), 3.35-3.31 (2H, m), 3.20-3.16 (1H, m), 3.04 (1H, d, J = 10.8), 2.81 (1H, td, J = 10.2, 2), 2.65-2.62 (1H, m), 2.53-2.41 (2H, m), 2.36-2.27 (6H, m), 2.14-2.10 (1H, m), 1.74 (1H, d, J = 13.2), 1.61 (1H, d, J = 12), 1.44 (1H, m), 1.33-1.21 (2H, m), 1.17 (3H, t, J = 7.6), 0.95 ( 3H, d, J = 6.4). 13C NMR (CDCl3 100 MHz): δ (ppm) 172.7, 169.8, 146.1, 133.6, 130.8, 122.5, 120.4, 119.0, 55.3, 55.0, 54.7, 50.8, 46.7, 46.1, 41.5, 35.0, 34.8, 30.5, 21.9, 9.8

[[ 실시예Example 10] 4- 10] 4- 메톡시Methoxy -N-[3-(4--N- [3- (4- 메틸methyl -피페라진-1-Piperazine-1- 카보닐Carbonyl )-4-(4-) -4- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 페닐Phenyl ]-]- 벤즈아미드Benzamide

제조예 13 에서 얻은 화합물 0.12g(0.38mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, p-아니실산 0.071g(0.47mmol), EDC 0.15g(0.79mmol), HOBT 0.10g(0.74mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(5:95)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.091g을 53%의 수율로 얻었다. 0.12 g (0.38 mmol) of the compound obtained in Preparation Example 13 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.071 g (0.47 mmol) of p-anilic acid, 0.15 g (0.79 mmol) of EDC, and 0.10 g (0.74 of HOBT). mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using methanol: dichloromethane (5:95) to obtain 0.091 g of the title compound in a yield of 53%.

1H NMR (CDCl3 400MHz): δ(ppm) 9.42(1H, s), 8.02(1H, dd, J=2.4), 7.96(2H, d, J=8.8), 7.36(1H, d, J=2.4), 6.93(1H, d, J=8.8). 6.87(2H, d, J=7.6), 3.97(1H, br d, J=13.2), 3.13(3H, s), 3.44(1H, t, J=9.2), 3.36-3.25(2H, m), 3.18(1H, m), 3.05(1H, d, J=10.8)2.79(1H, t, J=11.2), 2.56-2.49(2H, m, 2.39(1H, t, J=12), 2,29-2.24(4H, m), 2.10(1H, m), 1.73(1H, d, J=12.4), 1.31-1.14(2H, m), 0.93(3H, d, J=6). 13C NMR (CDCl3 100MHz) : δ(ppm) 169.8, 165.6, 162.1, 146.1, 133.9, 130.7, 129.5, 127.2, 122.6, 120.9, 118.7, 113.4, 55.3, 55.2, 55.0, 54.6, 50.7, 46.7, 46.1, 41.5, 35.0, 34.8, 30.5, 21.91 H NMR (CDCl 3 400 MHz): δ (ppm) 9.42 (1H, s), 8.02 (1H, dd, J = 2.4), 7.96 (2H, d, J = 8.8), 7.36 (1H, d, J = 2.4) , 6.93 (1H, doublet, J = 8.8). 6.87 (2H, d, J = 7.6), 3.97 (1H, br d, J = 13.2), 3.13 (3H, s), 3.44 (1H, t, J = 9.2), 3.36-3.25 (2H, m), 3.18 (1H, m), 3.05 (1H, d, J = 10.8) 2.79 (1H, t, J = 11.2), 2.56-2.49 (2H, m, 2.39 (1H, t, J = 12), 2,29 -2.24 (4H, m), 2.10 (1H, m), 1.73 (1H, d, J = 12.4), 1.31-1.14 (2H, m), 0.93 (3H, d, J = 6) .13C NMR (CDCl3 100 MHz): δ (ppm) 169.8, 165.6, 162.1, 146.1, 133.9, 130.7, 129.5, 127.2, 122.6, 120.9, 118.7, 113.4, 55.3, 55.2, 55.0, 54.6, 50.7, 46.7, 46.1, 41.5, 35.0, 34.8 , 30.5, 21.9

[[ 제조예Production Example 14] N-(3-디메틸아미노-프로필)-2-(4- 14] N- (3-dimethylamino-propyl) -2- (4- 메틸methyl -피페리딘-1-일)-5-니트로--Piperidin-1-yl) -5-nitro- 벤즈아미드Benzamide

제조예 1 에서 얻은 화합물 1.5g(5.7mmol)을 30ml N,N-디메틸포름아미드에 녹인 후 3-디메틸아미노프로필아민 0.85ml(6.8mmol), EDC 2.1g(11mmol), HOBT 1.8g(13mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(5:95)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 1.4g을 80%의 수율로 얻었다. 1.5 g (5.7 mmol) of the compound obtained in Preparation Example 1 was dissolved in 30 ml N, N-dimethylformamide, followed by 0.85 ml (6.8 mmol) of 3-dimethylaminopropylamine, 2.1 g (11 mmol) of EDC, and 1.8 g (13 mmol) of HOBT. Was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using methanol: dichloromethane (5:95) to obtain 1.4 g of the title compound in a yield of 80%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.69(1H, d, J=2.8), 8.61(1H, s), 8.18(1H, dd, J=6.15, 2.81), 7.14(1H, d, J=8.99), 3.56(2H, q, J=6.73), 3.38(2H, d, J=12.2), 2.88(2H, dt, J=10.3, 1.67), 2.42(2H, t, J=6.92), 1.85(4H, m), 1.61(1H, m), 1.40(2H, m), 1.03(3H, d, J=6.5)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.69 (1H, d, J = 2.8), 8.61 (1H, s), 8.18 (1H, dd, J = 6.15, 2.81), 7.14 (1H, d, J = 8.99), 3.56 (2H, q, J = 6.73), 3.38 (2H, d, J = 12.2), 2.88 (2H, dt, J = 10.3, 1.67), 2.42 (2H, t, J = 6.92), 1.85 (4H, m), 1.61 (1H, m), 1.40 (2H, m), 1.03 (3H, d, J = 6.5)

[[ 제조예Production Example 15] 5-아미노-N-(3-디메틸아미노-프로필)-2-(4- 15] 5-amino-N- (3-dimethylamino-propyl) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 14 에서 얻은 화합물1.3g(3.9mmol)을 30ml 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 1.3g을 정량적으로 얻었다. 1.3 g (3.9 mmol) of the compound obtained in Preparation Example 14 was dissolved in 30 ml of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 1.3 g of the title compound quantitatively.

1H NMR (CDCl3 400MHz): δ(ppm) 10.8(1H, s), 7.58(1H, d, J=2.74), 7.07(1H, d, J=7.46), 6.73(1H, dd, J=5.50, 2.84), 3.50(2H, q, J=6.18), 2.99(2H, d, J=7.5), 2.72(2H, t, J=11.6), 2.39(2H, t, J=7.0), 1.84(4H, m), 1.53(1H, m), 1.35(2H, m), 1.01(4H, d, J=6.48)1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.8 (1H, s), 7.58 (1H, d, J = 2.74), 7.07 (1H, d, J = 7.46), 6.73 (1H, dd, J = 5.50, 2.84), 3.50 (2H, q, J = 6.18), 2.99 (2H, d, J = 7.5), 2.72 (2H, t, J = 11.6), 2.39 (2H, t, J = 7.0), 1.84 (4H , m), 1.53 (1H, m), 1.35 (2H, m), 1.01 (4H, d, J = 6.48)

[[ 실시예Example 11] 5- 11] 5- 아세틸아미노Acetylamino -N-(3-디메틸아미노-프로필)-2-(4--N- (3-dimethylamino-propyl) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 15 에서 얻은 화합물 0.091g(0.29mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, 아세트산 0.020ml(0.35mmol), EDC 0.11g(0.57mmol), HOBT 0.080g(0.59mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 클로로포름:메탄올:암모니아 수용액(100:10:1)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.070g을 68%의 수율로 얻었다. 0.091 g (0.29 mmol) of the compound obtained in Preparation Example 15 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.020 ml (0.35 mmol) of acetic acid, 0.11 g (0.57 mmol) of EDC, and 0.080 g (0.59 mmol) of HOBT. Put and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure and purified by column chromatography using chloroform: methanol: ammonia aqueous solution (100: 10: 1) to obtain 0.070 g of the title compound in a yield of 68%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.63(1H, s), 9.43(1H, s), 8.22(1H, dd, J=7.4, 2), 8.07(1H, s), 7.21(1H, d, J=8.8), 3.51(2H, q, J-6.4), 3.04(2H, d, J=11.2), 2.74(2H, t, J=11.2), 2.36(3H, t, J=7.2), 2.22(9H, m), 1.84-1.76(3H, m), 1.54(1H, m), 1.33(2H, q, J=9.2), 1.02(3H, d, J=6.4). 13C NMR (CDCl3 100MHz) : δ(ppm) 169.6, 166.7, 148.1, 136.2, 128.0, 124.6, 122.8, 122.1, 57.8, 54.6, 45.9, 38.3, 35.4, 30.6, 28.3, 24.7, 22.31 H NMR (CDCl 3 400 MHz): δ (ppm) 10.63 (1H, s), 9.43 (1H, s), 8.22 (1H, dd, J = 7.4, 2), 8.07 (1H, s), 7.21 (1H, d , J = 8.8), 3.51 (2H, q, J-6.4), 3.04 (2H, d, J = 11.2), 2.74 (2H, t, J = 11.2), 2.36 (3H, t, J = 7.2), 2.22 (9H, m), 1.84-1.76 (3H, m), 1.54 (1H, m), 1.33 (2H, q, J = 9.2), 1.02 (3H, d, J = 6.4). 13C NMR (CDCl3 100 MHz): δ (ppm) 169.6, 166.7, 148.1, 136.2, 128.0, 124.6, 122.8, 122.1, 57.8, 54.6, 45.9, 38.3, 35.4, 30.6, 28.3, 24.7, 22.3

[[ 실시예Example 12] 5-(4- 12] 5- (4- 브로모Bromo -- 벤조일아미노Benzoylamino )-N-(3-디메틸아미노-프로필)-2-(4-) -N- (3-dimethylamino-propyl) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 15 에서 얻은 화합물 0.084g(0.26mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, 4-브로모벤조산 0.066g(0.32mmol), EDC 0.10g(0.53mmol), HOBT 0.073g(0.55mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 클로로포름:메탄올:암모니아 수용액(80:10:1)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.077g을 58%의 수율로 얻었다. 0.084 g (0.26 mmol) of the compound obtained in Preparation Example 15 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.066 g (0.32 mmol) of 4-bromobenzoic acid, 0.10 g (0.53 mmol) of EDC, and 0.073 g of HOBT ( 0.55 mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using chloroform: methanol: ammonia aqueous solution (80: 10: 1) to obtain 0.077 g of the title compound in a yield of 58%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.48(1H, s), 9.82(1H, s), 8.38(1H, d, J=8.4), 8.33(1H, s), 7.87(2H, d, J=8.4), 7.55(2H, d, J=8), 7.24(1H, d, J=8.8), 3.12(2H, q, J=6.4), 3.02(2H, d, J=11.2), 2.74(2H, t, J=11.6), 2.17(8H, m), 1.82(2H, d, J=12.4), 1.65-1.54(3H, m), 1.30(2H, q, J=10.8), 1.01(3H, d, J=6). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.6, 165.9, 148.5, 136.1, 134.5, 132.0, 129.9, 128.1, 126.6, 124.7, 123.8, 122.2, 57.7, 54.6, 45.9, 38.2, 35.5, 30.6, 28.2, 22.31 H NMR (CDCl 3 400 MHz): δ (ppm) 10.48 (1H, s), 9.82 (1H, s), 8.38 (1H, d, J = 8.4), 8.33 (1H, s), 7.87 (2H, d, J = 8.4), 7.55 (2H, d, J = 8), 7.24 (1H, d, J = 8.8), 3.12 (2H, q, J = 6.4), 3.02 (2H, d, J = 11.2), 2.74 ( 2H, t, J = 11.6, 2.17 (8H, m), 1.82 (2H, d, J = 12.4), 1.65-1.54 (3H, m), 1.30 (2H, q, J = 10.8), 1.01 (3H , d, J = 6). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.6, 165.9, 148.5, 136.1, 134.5, 132.0, 129.9, 128.1, 126.6, 124.7, 123.8, 122.2, 57.7, 54.6, 45.9, 38.2, 35.5, 30.6, 28.2, 22.3

[[ 실시예Example 13] 5-(3- 13] 5- (3- 브로모Bromo -- 벤조일아미노Benzoylamino )-N-(3-디메틸아미노-프로필)-2-(4-) -N- (3-dimethylamino-propyl) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 15 에서 얻은 화합물 0.086g(0.27mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, 3-브로모벤조산 0.068g(0.33mmol), EDC 0.10g(0.54mmol), HOBT 0.072g(0.55mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 클로로포름:메탄올:암모니아 수용액(80:10:1)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.053g을 39%의 수율로 얻었다. 0.086 g (0.27 mmol) of the compound obtained in Preparation Example 15 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.068 g (0.33 mmol) of 3-bromobenzoic acid, 0.10 g (0.54 mmol), and HOBT 0.072 g ( 0.55 mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using chloroform: methanol: ammonia aqueous solution (80: 10: 1) to obtain 0.053 g of the title compound in 39% yield.

1H NMR (CDCl3 400MHz): δ(ppm) 10.44(1H, s), 9.47(1H, s), 8.39(1H, d, J=8.4), 8.27(1H, s), 8.14(1H, s), 7.90(1H, d, J=7.6), 7.64(1H, d, J=7.6), 7.33(1H, t, J=7.6), 7.26(1H, d, J=7.2), 3.19(2H, q, J=6.8), 3.07(2H, d, J=11.6), 2.76(2H, t, J-11.6), 2.21(8H, m), 1.82(2H, d, J=12.8), 16.8(2H, p, J=7.2), 1.55(1H, m), 1.30(2H, q, J=10.8), 1.02(3H, d, J=6.4). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.2, 164.9, 148.2, 137.3, 135.6, 134.4, 131.0, 129.9, 127.8, 126.4, 124.2, 123.5, 122.6, 121.5, 57.3, 54.2, 45.5, 37.7, 35.1, 30.2, 27.3, 21.91 H NMR (CDCl 3 400 MHz): δ (ppm) 10.44 (1H, s), 9.47 (1H, s), 8.39 (1H, d, J = 8.4), 8.27 (1H, s), 8.14 (1H, s), 7.90 (1H, d, J = 7.6), 7.64 (1H, d, J = 7.6), 7.33 (1H, t, J = 7.6), 7.26 (1H, d, J = 7.2), 3.19 (2H, q, J = 6.8), 3.07 (2H, d, J = 11.6), 2.76 (2H, t, J-11.6), 2.21 (8H, m), 1.82 (2H, d, J = 12.8), 16.8 (2H, p , J = 7.2), 1.55 (1H, m), 1.30 (2H, q, J = 10.8), 1.02 (3H, d, J = 6.4). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.2, 164.9, 148.2, 137.3, 135.6, 134.4, 131.0, 129.9, 127.8, 126.4, 124.2, 123.5, 122.6, 121.5, 57.3, 54.2, 45.5, 37.7, 35.1, 30.2 , 27.3, 21.9

[[ 실시예Example 14] 5-(4- 14] 5- (4- 클로로Chloro -- 벤조일아미노Benzoylamino )-N-(3-디메틸아미노-프로필)-2-(4-) -N- (3-dimethylamino-propyl) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 15 에서 얻은 화합물 0.10g(0.31mmol)을 5ml의 N,N-디메틸포름아미드 에 녹인 후, 4-클로로벤조산 0.061g(0.39mmol), EDC 0.12g(0.63mmol), HOBT 0.085g(0.63mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(2:98) 500ml에 7N 암모니아 메탄올 9ml 첨가한 용액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.062g을 43%의 수율로 얻었다. 0.10 g (0.31 mmol) of the compound obtained in Preparation Example 15 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.061 g (0.39 mmol) of 4-chlorobenzoic acid, 0.12 g (0.63 mmol) of EDC, and 0.085 g (0.63) of HOBT. mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using a solution of 9 ml of 7N ammonia methanol in 500 ml of methanol: dichloromethane (2:98) to obtain 0.062 g of the title compound (43%). Obtained in yield.

1H NMR (CDCl3 400MHz): δ(ppm) 10.49(1H, t, J=5.2), 9.77(1H, s), 8.39(1H, dd, J=8.6, 2.8), 8.31(1H, d, J=2.8), 7.95(2H, d, J=8.4), 7.40(2H, d, J=8.4), 7.24(1H, d, J=8.8), 3.14(2H, q, J=7.2), 3.02(2H, br d, J=11.2), 2.74(2H, td, J=10.8, 1.6), 2.19-.214(8H), 1.82(2H, br d, J=11.2), 1.65-1.52(3H, m), 1.30(2H, qd, J=12, 3.6), 1.01(3H, d, J=6.4). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.2, 165.4, 148.1, 137.7, 135.7, 133.6, 129.3, 128.6, 127.7, 124.3, 123.4, 121.8, 57.3, 54.2, 45.5, 37.8, 35.1, 30.2, 27.8, 21.91 H NMR (CDCl 3 400 MHz): δ (ppm) 10.49 (1H, t, J = 5.2), 9.77 (1H, s), 8.39 (1H, dd, J = 8.6, 2.8), 8.31 (1H, d, J = 2.8), 7.95 (2H, d, J = 8.4), 7.40 (2H, d, J = 8.4), 7.24 (1H, d, J = 8.8), 3.14 (2H, q, J = 7.2), 3.02 (2H , br d, J = 11.2, 2.74 (2H, td, J = 10.8, 1.6), 2.19-.214 (8H), 1.82 (2H, br d, J = 11.2), 1.65-1.52 (3H, m) , 1.30 (2H, qd, J = 12, 3.6), 1.01 (3H, d, J = 6.4). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.2, 165.4, 148.1, 137.7, 135.7, 133.6, 129.3, 128.6, 127.7, 124.3, 123.4, 121.8, 57.3, 54.2, 45.5, 37.8, 35.1, 30.2, 27.8, 21.9

[[ 실시예Example 15] N-(3-디메틸아미노-프로필)-5-(4- 15] N- (3-dimethylamino-propyl) -5- (4- 플루오로Fluoro -- 벤조일아미노Benzoylamino )-2-(4-) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 15 에서 얻은 화합물 0.10g(0.31mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, 4-플루오르벤조산 0.053g(0.37mmol), EDC 0.12g(0.63mmol), HOBT 0.085g(0.63mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(7:93) 250ml에 7N 암모니아 메탄올 1ml 첨가한 용액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.10g을 72%의 수율로 얻었다. 0.10 g (0.31 mmol) of the compound obtained in Preparation Example 15 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.053 g (0.37 mmol) of 4-fluorobenzoic acid, 0.12 g (0.63 mmol) of EDC, and 0.085 g (0.63) of HOBT. mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using 250 ml of methanol: dichloromethane (7:93) and 1 ml of 7N ammonia methanol. Obtained in yield.

1H NMR (CDCl3 400MHz): δ(ppm) 10.50(1H, t, J=5.6), 9.85(1H, s), 8.38(1H, dd, J=8.6, 2.8), 8.34(1H, d, J=2.8), 8.06-8.02(2H, m), 7.24)1H, d, J=8.8), 7.10(2H, t, J=8.4), 3.16(2H, q, J=6.8), 3.00(2H, br d, J=12), 2.73(2H, br t, J=10), 2.20-2.13(8H, m), 1.80(2H, br d, J=11.2), 1.62(2H, p, J=7.6), 1.55(1H, m), 1.30(2H, qd, J=12.2, 3.6), 1.01(3H, d, J=6.8). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.2, 166.0, 165.4, 163.5, 148.1, 135.8, 131.4, 131.3, 130.3, 130.2, 127.7, 124.4, 123.4, 121.7, 115.4, 115.2, 57.3, 54.2, 45.5, 37.7, 35.1, 30.2, 27.8, 21.9 1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.50 (1H, t, J = 5.6), 9.85 (1H, s), 8.38 (1H, dd, J = 8.6, 2.8), 8.34 (1H, d, J = 2.8), 8.06-8.02 (2H, m), 7.24) 1H, d, J = 8.8), 7.10 (2H, t, J = 8.4), 3.16 (2H, q, J = 6.8), 3.00 (2H, br d, J = 12), 2.73 (2H, brt, J = 10), 2.20-2.13 (8H, m), 1.80 (2H, brd, J = 11.2), 1.62 (2H, p, J = 7.6) , 1.55 (1H, m), 1.30 (2H, qd, J = 12.2, 3.6), 1.01 (3H, d, J = 6.8). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.2, 166.0, 165.4, 163.5, 148.1, 135.8, 131.4, 131.3, 130.3, 130.2, 127.7, 124.4, 123.4, 121.7, 115.4, 115.2, 57.3, 54.2, 45.5, 37.7 , 35.1, 30.2, 27.8, 21.9

[[ 실시예Example 16] N-(3-이소프로필- 16] N- (3-isopropyl- 벤조일아미노Benzoylamino )-5-(4-) -5- (4- 메틸methyl -- 벤조일아미노Benzoylamino )-2-(4-) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 페닐Phenyl ]-]- 벤즈아미드Benzamide

제조예 15 에서 얻은 화합물 0.084g(0.26mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, p-톨루익산 0.045g(0.32mmol), EDC 0.10g(0.52mmol), HOBT 0.07g(0.52mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘 설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(7:93)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.099g을 85%의 수율로 얻었다. 0.084 g (0.26 mmol) of the compound obtained in Preparation Example 15 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.045 g (0.32 mmol) of p-toluic acid, 0.10 g (0.52 mmol) of EDC, and 0.07 g (0.52) of HOBT. mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure and purified by column chromatography using methanol: dichloromethane (7:93) to obtain 0.099 g of the title compound in a yield of 85%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.48(1H, t, J=5.6), 9.24(1H, s), 8.38(1H, dd, J=8.8, 2.8), 8.22(1H, d, J=2.8), 7.86(2H, d, J=8.4), 7.24(3H, m), 3.25(2H, q, J=6.8), 3.12(2H, br d, J=11.6), 2.73(2H, td, J=11, 2), 2.40(3H, s), 2.27-2.22(8H, m), 1.81(2H, br d, J=11.6), 1.69(2H, p, J=7.6), 1.57-1.51(1H, m), 1.3(2H, qd, J=12, 3.6), 1.01(3H, d, J=6.4). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.2, 147.9, 142.0, 135.7, 132.2, 129.2, 127.8, 127.6, 124.0, 123.0, 121.8, 57.3, 54.2, 45.3, 37.6, 35.2, 30.2, 27.7, 21.9, 21.51 H NMR (CDCl 3 400 MHz): δ (ppm) 10.48 (1H, t, J = 5.6), 9.24 (1H, s), 8.38 (1H, dd, J = 8.8, 2.8), 8.22 (1H, d, J = 2.8), 7.86 (2H, d, J = 8.4), 7.24 (3H, m), 3.25 (2H, q, J = 6.8), 3.12 (2H, br d, J = 11.6), 2.73 (2H, td, J = 11, 2), 2.40 (3H, s), 2.27-2.22 (8H, m), 1.81 (2H, br d, J = 11.6), 1.69 (2H, p, J = 7.6), 1.57-1.51 ( 1H, m), 1.3 (2H, qd, J = 12, 3.6), 1.01 (3H, d, J = 6.4). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.2, 147.9, 142.0, 135.7, 132.2, 129.2, 127.8, 127.6, 124.0, 123.0, 121.8, 57.3, 54.2, 45.3, 37.6, 35.2, 30.2, 27.7, 21.9, 21.5

[[ 제조예Production Example 16] 2-(4- 16] 2- (4- 메틸methyl -피페리딘-1-일)-5-니트로-N-(2-피페리딘-1-일-에틸)--Piperidin-1-yl) -5-nitro-N- (2-piperidin-1-yl-ethyl)- 벤즈아미드Benzamide

제조예 1에서 얻은 화합물 0.10g(0.40mmol)을 5mL N,N-디메틸포름아미드에 녹인 후 1-(2-아미노에틸)피페리딘 0.068mL(0.48mmol), EDC 0.15g(0.81mmol), HOBT 0.11g(0.80mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(7:93) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.14g을 91%의 수율로 얻었다. 0.10 g (0.40 mmol) of the compound obtained in Preparation Example 1 was dissolved in 5 mL N, N-dimethylformamide, followed by 0.068 mL (0.48 mmol) of 1- (2-aminoethyl) piperidine, 0.15 g (0.81 mmol) of EDC, 0.11 g (0.80 mmol) of HOBT was added thereto, followed by stirring for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using methanol: dichloromethane (7:93) mixed solvent to obtain 0.14 g of the title compound in a yield of 91%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.76(1H, d, J=2.8), 8.33(1H, s), 8.20(1H, dd, J=9.0, 3.2), 7.14(1H, d, J=8.8), 3.60(2H, q, J=5.6), 3.57(2H, br d, 12.8), 2.84(2H, td, J=12.0, 2.0), 2.55(2H, t, J=6.0), 2.43(4H, br s), 181(2H, br d. J=11.2), 1.61~1.55(5H, m), 1.50~1.35(4H, m), 1.02(3H, d, J=6.8)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.76 (1H, d, J = 2.8), 8.33 (1H, s), 8.20 (1H, dd, J = 9.0, 3.2), 7.14 (1H, d, J = 8.8), 3.60 (2H, q, J = 5.6), 3.57 (2H, br d, 12.8), 2.84 (2H, td, J = 12.0, 2.0), 2.55 (2H, t, J = 6.0), 2.43 ( 4H, br s), 181 (2H, br d. J = 11.2), 1.61-1.55 (5H, m), 1.50-1.35 (4H, m), 1.02 (3H, d, J = 6.8)

[[ 제조예Production Example 17] 5-아미노-2-(4- 17] 5-amino-2- (4- 메틸methyl -피페리딘-1-일)-N-(2-피페리딘-1-일-에틸)--Piperidin-1-yl) -N- (2-piperidin-1-yl-ethyl)- 벤즈아미드Benzamide

제조예 16에서 얻은 화합물 0.14g(0.36mmol)을 10mL 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.12g을 정량적으로 얻었다. 0.14 g (0.36 mmol) of the compound obtained in Preparation Example 16 was dissolved in 10 mL methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.12 g of the title compound quantitatively.

1H NMR (CDCl3 400MHz): δ(ppm) 7.54(1H, d, J=2.8), 7.07(1H, d, J=8.8), 6.74(1H, dd, J=8.4, 2.8), 3.75~3,67(4H, m), 2.98(2H, br d, J=11.6), 2.71~2.60(8H, m), 1.78(2H, br d, J=12.8), 1.68(4H, br s), 1.52~1.48(3H, m), 1.38(2H, qd, J=12.2, 3.6), 1.01(3H, d, J=6.4)1 H NMR (CDCl 3 400 MHz): δ (ppm) 7.54 (1H, d, J = 2.8), 7.07 (1H, d, J = 8.8), 6.74 (1H, dd, J = 8.4, 2.8), 3.75-3, 67 (4H, m), 2.98 (2H, br d, J = 11.6), 2.71-2.60 (8H, m), 1.78 (2H, br d, J = 12.8), 1.68 (4H, br s), 1.52- 1.48 (3H, m), 1.38 (2H, qd, J = 12.2, 3.6), 1.01 (3H, d, J = 6.4)

[[ 실시예Example 17] 5-(4-이소프로필- 17] 5- (4-isopropyl- 벤조일아미노Benzoylamino )-2-(4-) -2- (4- 메틸methyl -피페리딘-1-일)-N-(2-피페리딘-1-일-에틸)--Piperidin-1-yl) -N- (2-piperidin-1-yl-ethyl)- 벤즈아미드Benzamide

제조예 17 에서 얻은 화합물 0.12g(0.35mmol)을 5mL N,N-디메틸포름아미드에 녹인 후 4-이소프로필벤조산 0.070mL(0.43mmol), EDC 0.15g(0.78mmol), HOBT 0.14g(1.0mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(5:95) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.14g을 91%의 수율로 얻었다.(NMR상에서 불순물이 있어 메탄올:디클로로메테인(3:97)혼합용액 300mL에 7N 암모니아 메탄올 용액 1mL를 첨가한 혼합용액으로 다시 정제하였으나 NMR상의 불순물은 여전히 존재하였다.0.12 g (0.35 mmol) of the compound obtained in Preparation Example 17 was dissolved in 5 mL N, N-dimethylformamide, followed by 0.070 mL (0.43 mmol) of 4-isopropylbenzoic acid, 0.15 g (0.78 mmol) of EDC, and 0.14 g (1.0 mmol) of HOBT. ) Was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using methanol: dichloromethane (5:95) mixed solvent to obtain 0.14 g of the title compound in a yield of 91%. There was an impurity, and the mixture was further purified with a mixed solution of 1 mL of 7N ammonia methanol in 300 mL of a methanol: dichloromethane (3:97) mixed solution, but impurities on the NMR were still present.

NMR (CDCl3 400MHz): δ(ppm) 10.22(1H, t, J=4.8), 9.11(1H, s), 8.41(1H, dd, J=8.6, 2.8), 8.20(1H, d, J=2.8), 7.88(2H, d, J=8.4), 7.30(2H, d, J=8.4), 7.24(1H, d, J=8.8), 3.36(2H, q, J=6.4), 3.08(2H, br d, J=11.6), 2.99~2.93(1H, m), 2.74(2H, t, J=10.0), 2.41(2H, t, J=6.4), 2.32(4H, br s), 1.81~1.76(2H, m), 1.55~1.52(5H, m), 1.44~1.39(4H, m), 1.27(6H, d, J=6.8), 1.01(3H, d, J=6.4). 13C NMR (CDCl3 100MHz): δ(ppm) 166.3, 166.1, 152.8, 148.2, 135.4, 132.6, 127.9, 127.6, 126.6, 123.9, 123.0, 121.4, 57.9, 54.4, 54.2, 36.7, 34.9, 34.1, 30.3, 25.8, 24.4, 23.8, 21.8NMR (CDCl 3 400 MHz): δ (ppm) 10.22 (1H, t, J = 4.8), 9.11 (1H, s), 8.41 (1H, dd, J = 8.6, 2.8), 8.20 (1H, d, J = 2.8 ), 7.88 (2H, d, J = 8.4), 7.30 (2H, d, J = 8.4), 7.24 (1H, d, J = 8.8), 3.36 (2H, q, J = 6.4), 3.08 (2H, br d, J = 11.6), 2.99-2.93 (1H, m), 2.74 (2H, t, J = 10.0), 2.41 (2H, t, J = 6.4), 2.32 (4H, br s), 1.81-1.76 (2H, m), 1.55-1.52 (5H, m), 1.44-1.39 (4H, m), 1.27 (6H, d, J = 6.8), 1.01 (3H, d, J = 6.4). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.3, 166.1, 152.8, 148.2, 135.4, 132.6, 127.9, 127.6, 126.6, 123.9, 123.0, 121.4, 57.9, 54.4, 54.2, 36.7, 34.9, 34.1, 30.3, 25.8 , 24.4, 23.8, 21.8

[[ 제조예Production Example 18] N-(2- 18] N- (2- 디에틸아미노Diethylamino -에틸)-2-(4--Ethyl) -2- (4- 메틸methyl -피페리딘-1-일)-5-니트로--Piperidin-1-yl) -5-nitro- 벤즈아 미드Benzamide

제조예 1 에서 얻은 화합물 0.20g(0.76mmol)을 15mL N,N-디메틸포름아미드에 녹인 후 N,N-디에틸에틸렌디아민 0.11mL(0.78mmol), EDC 0.15g(0.76mmol), HOBT 0.16g(1.2mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(7:93) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.12g을 43%의 수율로 얻었다. 0.20 g (0.76 mmol) of the compound obtained in Preparation Example 1 was dissolved in 15 mL N, N-dimethylformamide, and then 0.11 mL (0.78 mmol) of N, N-diethylethylenediamine, 0.15 g (0.76 mmol) of EDC, and 0.16 g of HOBT. (1.2 mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using methanol: dichloromethane (7:93) mixed solvent to obtain 0.12 g of the title compound in a yield of 43%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.73(1H, d, J=2.4 Hz), 8.42(1H, s), 8.18(1H, dd, J=9.2, 2.8 Hz), 7.15(1H, d, J=9.2 Hz), 3.57(2H, q, J=6.0 Hz), 3.36(2H, d, J=12.4 Hz), 2.84 (2H, t, J=10.4 Hz), 2.68(2H, t, J=6.4 Hz), 2.62(4H, q. J=7.2 Hz), 1.81(2H, d, J=11.6 Hz), 1.60-1.55(1H, m), 1.40(2H, td, J=12.2, 3.6 Hz), 1.03(9H, t, J=7.6 Hz)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.73 (1H, d, J = 2.4 Hz), 8.42 (1H, s), 8.18 (1H, dd, J = 9.2, 2.8 Hz), 7.15 (1H, d, J = 9.2 Hz), 3.57 (2H, q, J = 6.0 Hz), 3.36 (2H, d, J = 12.4 Hz), 2.84 (2H, t, J = 10.4 Hz), 2.68 (2H, t, J = 6.4 Hz), 2.62 (4H, q.J = 7.2 Hz), 1.81 (2H, d, J = 11.6 Hz), 1.60-1.55 (1H, m), 1.40 (2H, td, J = 12.2, 3.6 Hz) , 1.03 (9H, t, J = 7.6 Hz)

[[ 제조예Production Example 19]5-아미노-N-(2- 19] 5-amino-N- (2- 디에틸아미노Diethylamino -에틸)-2-(4--Ethyl) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 18 에서 얻은 화합물 0.45g(1.3mmol)을 20mL 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.41g을 98% 의 수율로 얻었다. 0.45 g (1.3 mmol) of the compound obtained in Preparation Example 18 was dissolved in 20 mL methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.41 g of the title compound in a yield of 98%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.73(1H, s), 7.57(1H, s), 7.05(1H, d, J=8.4 Hz), 6.71(1H, d, J=8.0 Hz), 3.78(2H, s), 3.54(2H, q, J=6.4 Hz), 2.97(2H, d, J=11.2 Hz), 2.70-2.58(8H, m), 1.76(2H, d, J=12.8 Hz), 1.50(1H, m), 1.37(2H, q, J=12.0 Hz), 1.01(9H, m)1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.73 (1H, s), 7.57 (1H, s), 7.05 (1H, d, J = 8.4 Hz), 6.71 (1H, d, J = 8.0 Hz), 3.78 (2H, s), 3.54 (2H, q, J = 6.4 Hz), 2.97 (2H, d, J = 11.2 Hz), 2.70-2.58 (8H, m), 1.76 (2H, d, J = 12.8 Hz) , 1.50 (1H, m), 1.37 (2H, q, J = 12.0 Hz), 1.01 (9H, m)

[[ 실시예Example 18] 5-(2- 18] 5- (2- 클로로Chloro -- 벤조일아미노Benzoylamino )-N-(2-) -N- (2- 디에틸아미노Diethylamino -에틸)-2-(4--Ethyl) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 19 에서 얻은 화합물 0.10g(0.30mmol)을 5mL N,N-디메틸포름아미드에 녹인 후 2-클로로벤조산 0.059mL(0.38mmol), EDC 0.086g(0.45mmol), HOBT 0.082g(0.61mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(7:93) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.14g을 99%의 수율로 얻었다. 0.10 g (0.30 mmol) of the compound obtained in Preparation Example 19 was dissolved in 5 mL N, N-dimethylformamide, followed by 0.059 mL (0.38 mmol) of 2-chlorobenzoic acid, 0.086 g (0.45 mmol) of EDC, and 0.082 g (0.61 mmol) of HOBT. Was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using methanol: dichloromethane (7:93) mixed solvent to obtain 0.14 g of the title compound in a yield of 99%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.15(1H, s), 9.55(1H, s), 8.40(1H, dd, J=8.8, 2.4 Hz), 8.39(1H, d, J=2.4 Hz), 7.62(1H, d, J=8.0 Hz), 7.39~7.27(3H, m), 7.22(1H, d, J=8.8 Hz), 3.03(4H, m), 2.71(2H, t, J=10.8 Hz), 2.59~2.50(6H, m), 1.77(2H, br d, J=11.6 Hz), 1.53~1.50(1H, m), 1.36(2H, qd, J=12.0, 3.6 Hz), 1.05~0.98(9H, m). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.3, 148.4, 136.3, 135.1, 131.2, 131.0, 130.0, 129.7, 126.9, 123.9, 123.0, 121.0, 54.2, 51.5, 46.7, 36.7, 34.7, 30.3, 21.8, 11.21 H NMR (CDCl 3 400 MHz): δ (ppm) 10.15 (1H, s), 9.55 (1H, s), 8.40 (1H, dd, J = 8.8, 2.4 Hz), 8.39 (1H, d, J = 2.4 Hz) , 7.62 (1H, d, J = 8.0 Hz), 7.39-7.27 (3H, m), 7.22 (1H, d, J = 8.8 Hz), 3.03 (4H, m), 2.71 (2H, t, J = 10.8 Hz), 2.59 to 2.50 (6H, m), 1.77 (2H, br d, J = 11.6 Hz), 1.53 to 1.50 (1H, m), 1.36 (2H, qd, J = 12.0, 3.6 Hz), 1.05 to 0.98 (9 H, m). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.3, 148.4, 136.3, 135.1, 131.2, 131.0, 130.0, 129.7, 126.9, 123.9, 123.0, 121.0, 54.2, 51.5, 46.7, 36.7, 34.7, 30.3, 21.8, 11.2

[[ 실시예Example 19] N-(2- 19] N- (2- 디에틸아미노Diethylamino -에틸)-5-(2--Ethyl) -5- (2- 메틸methyl -- 벤조일아미노Benzoylamino )-2-(4-) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 19 에서 얻은 화합물 0.10g(0.30mmol)을 5mL N,N-디메틸포름아미드에 녹인 후 o-톨루익산 0.050mL(0.38mmol), EDC 0.085g(0.44mmol), HOBT 0.081g(0.60mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(7:93) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.11g을 80%의 수율로 얻었다. 0.10 g (0.30 mmol) of the compound obtained in Preparation Example 19 was dissolved in 5 mL N, N-dimethylformamide, followed by 0.050 mL (0.38 mmol) of o-toluic acid, 0.085 g (0.44 mmol) of EDC, and 0.081 g (0.60 mmol) of HOBT. Was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure and purified by column chromatography using methanol: dichloromethane (7:93) mixed solvent to obtain 0.11 g of the title compound in a yield of 80%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.14(1H, s), 9.36(1H, s), 8.43(1H, dd, J=8.8, 2.4 Hz), 8.25(1H, d, J=2.4 Hz), 7.47(1H, d, J=7.6 Hz), 7.32(1H, t, J=6.4 Hz), 7.24~7.16(3H, m), 3.04~2.96(4H, m), 2.72(2H, t, J=10.4 Hz), 2.54(4H, q, J=6.8 Hz), 2.48~2.44(5H, m), 1.78(2H, br d, J=11.2 Hz), 1.54~1.52(1H, m), 1.37(2H, qd, J=12.0, 3.6 Hz), 1.02~0.97(9H, m). 13C NMR (CDCl3 100MHz) : δ(ppm) 168.6, 166.2, 148.2, 137.0, 136.3, 135.6, 130.9, 129.8, 127.9, 127.3, 125.6, 123.7, 122.9, 121.3, 54.2, 51.5, 46.6, 36.8, 34.8, 30.3, 21.8, 19.9, 11.21 H NMR (CDCl 3 400 MHz): δ (ppm) 10.14 (1H, s), 9.36 (1H, s), 8.43 (1H, dd, J = 8.8, 2.4 Hz), 8.25 (1H, d, J = 2.4 Hz) , 7.47 (1H, d, J = 7.6 Hz), 7.32 (1H, t, J = 6.4 Hz), 7.24-7.16 (3H, m), 3.04-2.96 (4H, m), 2.72 (2H, t, J = 10.4 Hz), 2.54 (4H, q, J = 6.8 Hz), 2.48-2.44 (5H, m), 1.78 (2H, br d, J = 11.2 Hz), 1.54-1.52 (1H, m), 1.37 ( 2H, qd, J = 12.0, 3.6 Hz), 1.02-0.97 (9H, m). 13C NMR (CDCl3 100 MHz): δ (ppm) 168.6, 166.2, 148.2, 137.0, 136.3, 135.6, 130.9, 129.8, 127.9, 127.3, 125.6, 123.7, 122.9, 121.3, 54.2, 51.5, 46.6, 36.8, 34.8, 30.3 , 21.8, 19.9, 11.2

[[ 실시예Example 20] N-(2- 20] N- (2- 디에틸아미노Diethylamino -에틸)-5-(2--Ethyl) -5- (2- 플루오로Fluoro -- 벤조일아미노Benzoylamino )-2-(4-) -2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 19 에서 얻은 화합물 0.10g(0.30mmol)을 5mL N,N-디메틸포름아미드에 녹인 후 2-플루오르벤조산 0.051mL(0.38mmol), EDC 0.085g(0.44mmol), HOBT 0.086g(0.64mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(7:93) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.12g을 91%의 수율로 얻었다. 0.10 g (0.30 mmol) of the compound obtained in Preparation Example 19 was dissolved in 5 mL N, N-dimethylformamide, followed by 0.051 mL (0.38 mmol) of 2-fluorobenzoic acid, 0.085 g (0.44 mmol) of EDC, and 0.086 g (0.64 mmol) of HOBT. Was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using methanol: dichloromethane (7:93) mixed solvent to obtain 0.12 g of the title compound in a yield of 91%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.23(1H, br s), 8.78(1H, d, J=13.6 Hz), 8.31(1H, dd, J=8.6, 2.8 Hz), 8.10(1H, td, J=8.0, 1.6 Hz), 8.01(1H, d, J=2.8 Hz), 7.53~7.47(1H, m), 7.30~7.24(2H, m), 7.18~7.13(1H, m), 3.51(2H, q, J=6.4 Hz), 3.09(2H, br d, J=12.0 Hz), 2.74(2H, t, J=10.0 Hz), 2.69~2.61(6H, m), 1.80(2H, br d, J=12.4 Hz), 1.55~1.51(1H, m), 1.40(2H, qd, J=12.2, 3.6 Hz), 1.06~1.01(9H, m). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.0, 131.6, 131.5, 159.1, 148.7, 134.5, 133.6, 133.5, 132.0, 131.9, 128.2, 124.93, 124.90, 124.1, 123.0, 121.6, 121.5, 116.3, 116.1, 54.2, 51.8, 46.9, 37.4, 34.8, 30.3, 21.8, 11.31 H NMR (CDCl 3 400 MHz): δ (ppm) 10.23 (1H, br s), 8.78 (1H, d, J = 13.6 Hz), 8.31 (1H, dd, J = 8.6, 2.8 Hz), 8.10 (1H, td , J = 8.0, 1.6 Hz), 8.01 (1H, d, J = 2.8 Hz), 7.53-7.47 (1H, m), 7.30-7.44 (2H, m), 7.18-7.13 (1H, m), 3.51 ( 2H, q, J = 6.4 Hz), 3.09 (2H, br d, J = 12.0 Hz), 2.74 (2H, t, J = 10.0 Hz), 2.69-2.61 (6H, m), 1.80 (2H, br d , J = 12.4 Hz), 1.55-1.51 (1H, m), 1.40 (2H, qd, J = 12.2, 3.6 Hz), 1.06-1.01 (9H, m). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.0, 131.6, 131.5, 159.1, 148.7, 134.5, 133.6, 133.5, 132.0, 131.9, 128.2, 124.93, 124.90, 124.1, 123.0, 121.6, 121.5, 116.3, 116.1, 54.2 , 51.8, 46.9, 37.4, 34.8, 30.3, 21.8, 11.3

[[ 제조예Production Example 20] 2- 20] 2- 몰포린Morpholine -4-일-5-니트로-벤조산-4-yl-5-nitro-benzoic acid

2-플루오르-5-니트로벤조산 0.10g(0.54mmol)을 15mL의 아세토니트릴에 녹인 후, 몰포린 0.071mL(0.81mmol)을 가하고 12시간 동안 환류시키며 끓여주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 1N 염화수소 수용액으로 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 감압여과하고 에틸아세테이트를 감압증류로 제거하여 표제 화합물 0.13g을 95%의 수율로 얻었다. 0.10 g (0.54 mmol) of 2-fluoro-5-nitrobenzoic acid was dissolved in 15 mL of acetonitrile, and 0.071 mL (0.81 mmol) of morpholine was added thereto, and the mixture was boiled under reflux for 12 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed with 1N aqueous hydrogen chloride solution. Water was removed with magnesium sulfate, and the residue was filtered under reduced pressure and ethyl acetate was removed by distillation under reduced pressure to obtain 0.13 g of the title compound in a yield of 95%.

1H NMR (CDCl3+CD3OD 400MHz): δ(ppm) 8.96(1H, d, J=2.8 Hz), 8.4(1H, dd, J=9.0, 2.8 Hz), 7.48(1H, d, J=9.2 Hz), 3.97(4H, t, J=4.4 Hz), 3.20(4H, t, J=4.4 Hz)1 H NMR (CDCl 3 + CD 3 OD 400 MHz): δ (ppm) 8.96 (1H, d, J = 2.8 Hz), 8.4 (1H, dd, J = 9.0, 2.8 Hz), 7.48 (1H, d, J = 9.2 Hz) , 3.97 (4H, t, J = 4.4 Hz), 3.20 (4H, t, J = 4.4 Hz)

[[ 제조예Production Example 21] N-(3-디메틸아미노-프로필)-2- 21] N- (3-dimethylamino-propyl) -2- 몰포린Morpholine -4-일-5-니트로--4-yl-5-nitro- 벤즈아미드Benzamide

제조예 20 에서 얻은 화합물 0.13g(0.51mmol)을 15mL N,N-디메틸포름아미드에 녹인 후 3-디메틸아미노프로필아민 0.078mL(0.62mmol), EDC 0.20g(1.0mmol), HOBT 0.14g(1.0mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그 네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 클로로포름:메탄올:암모니아 수용액(80:10:1) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.15g을 85%의 수율로 얻었다. 0.13 g (0.51 mmol) of the compound obtained in Preparation Example 20 was dissolved in 15 mL N, N-dimethylformamide, followed by 0.078 mL (0.62 mmol) of 3-dimethylaminopropylamine, 0.20 g (1.0 mmol), and HOBT 0.14 g (1.0). mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using a mixed solvent of chloroform: methanol: ammonia solution (80: 10: 1) to give 0.15 g of the title compound in a yield of 85%. .

1H NMR(CDCl3 400MHz): δ(ppm) 5.56(1H, d, J=2.8 Hz), 8.44(1H, t, J=4.8 Hz), 8.17(1H, dd, J=9.0, 2.4 Hz), 7.10(1H, d, J=8.8 Hz), 3.88(4H, t, J=4.4 Hz), 3.45(2H, q, J=6.4 Hz), 3.14(3H, t, J=4.4 Hz), 2.41(2H, t, J=6.8 Hz), 2.23(6H, s), 1.80(2H, p, J=6.8 Hz)1 H NMR (CDCl 3 400 MHz): δ (ppm) 5.56 (1H, d, J = 2.8 Hz), 8.44 (1H, t, J = 4.8 Hz), 8.17 (1H, dd, J = 9.0, 2.4 Hz), 7.10 (1H, d, J = 8.8 Hz), 3.88 (4H, t, J = 4.4 Hz), 3.45 (2H, q, J = 6.4 Hz), 3.14 (3H, t, J = 4.4 Hz), 2.41 (2H , t, J = 6.8 Hz), 2.23 (6H, s), 1.80 (2H, p, J = 6.8 Hz)

[[ 제조예Production Example 22] 5-아미노-N-(3-디메틸아미노-프로필)-2- 22] 5-amino-N- (3-dimethylamino-propyl) -2- 몰포린Morpholine -4-일--4- days- 벤즈아미드Benzamide

제조예 21 에서 얻은 화합물 0.15g(0.41mmol)을 10mL 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.14g을 정량적으로 얻었다. 0.15 g (0.41 mmol) of the compound obtained in Preparation Example 21 was dissolved in 10 mL of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to quantitatively obtain 0.14 g of the title compound.

1H NMR (CDCl3 400MHz): δ(ppm) 10.62(1H, s), 7.47(1H, s), 7.08(1H, d, J=8.4 Hz), 6.79(1H, d, J=8.4 Hz), 4.08(3H, s), 3.85(4H, s), 3.49(2H, m), 2.92(4H, s), 2.57(2H, t, J=6.8 Hz), 2.40(6H, s), 1.90(2H, p, J=7.2 Hz)1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.62 (1H, s), 7.47 (1H, s), 7.08 (1H, d, J = 8.4 Hz), 6.79 (1H, d, J = 8.4 Hz), 4.08 (3H, s), 3.85 (4H, s), 3.49 (2H, m), 2.92 (4H, s), 2.57 (2H, t, J = 6.8 Hz), 2.40 (6H, s), 1.90 (2H, p, J = 7.2 Hz)

[[ 실시예Example 21] N-(3-디메틸아미노-프로필)-5-(4-이소프로필- 21] N- (3-dimethylamino-propyl) -5- (4-isopropyl- 벤조일아미노Benzoylamino )-2-)-2- 몰포린Morpholine - 4-일--4-day- 벤즈아미드Benzamide

제조예 22 에서 얻은 화합물 0.14g(0.44mmol)을 5mL의 N,N-디메틸포름아미드에 녹인 후, 4-이소프로필벤조산 0.087g(0.53mmol), EDC 0.17g(0.88mmol), HOBT 0.12g(0.89mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 클로로포름:메탄올:암모니아 수용액(80:10:1) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.076g을 38%의 수율로 얻었다. 0.14 g (0.44 mmol) of the compound obtained in Preparation Example 22 was dissolved in 5 mL of N, N-dimethylformamide, followed by 0.087 g (0.53 mmol) of 4-isopropylbenzoic acid, 0.17 g (0.88 mmol) of EDC, and 0.12 g of HOBT ( 0.89 mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using a mixed solvent of chloroform: methanol: ammonia solution (80: 10: 1) to obtain 0.076 g of the title compound in a yield of 38%.

1H NMR (CDCl3 400MHz): δ(ppm) 9.96(1H, t, J=5.6 Hz), 9.12(1H, s), 8.40(1H, dd, J=8.6, 2.8 Hz), 8.15(1H, d, J=2.8 Hz), 7.88(2H, d, J=8.4 Hz), 7.29(2H, d, J=8.4 Hz), 7.23(1H, d, J=8.8 Hz), 3.84(4H, t, J=4 Hz), 3.29(2H, q, J=6.8 Hz), 2.96(5H, m), 2.24(2H, t, J=6.8 Hz), 2.18(6H, s), 1.68(2H, p, J=7.2 Hz), 1.26(6H, d, J=6.8 Hz). 13C NMR (CDCl3 100MHz): δ(ppm) 166.1, 166.0, 153.0, 146.4, 136.0, 132.4, 128.1, 127.6, 126.6, 124.1, 123.2, 121.4, 67.3, 57.4, 53.5, 45.5, 37.8, 34.1, 27.8, 23.81 H NMR (CDCl 3 400 MHz): δ (ppm) 9.96 (1H, t, J = 5.6 Hz), 9.12 (1H, s), 8.40 (1H, dd, J = 8.6, 2.8 Hz), 8.15 (1H, d, J = 2.8 Hz), 7.88 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.23 (1H, d, J = 8.8 Hz), 3.84 (4H, t, J = 4 Hz), 3.29 (2H, q, J = 6.8 Hz), 2.96 (5H, m), 2.24 (2H, t, J = 6.8 Hz), 2.18 (6H, s), 1.68 (2H, p, J = 7.2 Hz), 1.26 (6H, d, J = 6.8 Hz). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.1, 166.0, 153.0, 146.4, 136.0, 132.4, 128.1, 127.6, 126.6, 124.1, 123.2, 121.4, 67.3, 57.4, 53.5, 45.5, 37.8, 34.1, 27.8, 23.8

[[ 실시예Example 22] N-(3-디메틸아미노-프로필)-2-(4- 22] N- (3-dimethylamino-propyl) -2- (4- 메틸methyl -피페리딘-1-일)-5-(4--Piperidin-1-yl) -5- (4- 트리플루오로메틸Trifluoromethyl -- 벤조일아미노Benzoylamino )-) - 벤즈아미드Benzamide

제조예 15 에서 얻은 화합물 0.095g(0.30mmol)을 5mL의 N,N-디메틸포름아미 드에 녹인 후, α, α, α,-트리플루오르-p-톨루익산 0.12g(0.60mmol), EDC 0.13g(0.65mmol), HOBT 0.11g(0.81mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(2:98) 200mL에 7N 암모니아 메탄올 2mL 첨가한 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.096g을 74%의 수율로 얻었다. 1H NMR (CDCl3 400MHz): δ(ppm) 10.39(1H, t, J=5.6 Hz), 8.8((1H, s), 8.35(1H, dd, J=8.8, 2.4 Hz), 8.13(1H, d, J=2.8 Hz), 8.04(2H, d, J=8.0 Hz), 7.74(2H, d, J=8.4 Hz), 7.28(1H, d, J=8.8 Hz), 7.26(2H, td, J=11.0, 2.0 Hz), 3.30(2H, q, J=7.2 Hz), 3.07(2H, br d, J=12.0 Hz), 2.25(2H, q, J=5.6 Hz), 2.20(6H, s), 1.83(2H, br d, J=11.6 Hz), 1.74-1.67(6H, m), 1.58-1.53(1H, m), 1.37-1.28(2H, m), 1.02(3H, d, J=6.4 Hz). 13C NMR (CDCl3 100MHz): δ(ppm) 166.2, 165.2, 148.3, 138.6, 135.5, 133.5, 133.2, 132.9, 132.6, 128.3, 127.7, 125.4, 125.36, 125.33, 125.29, 124.4, 123.4, 121.8, 57.3, 54.2, 45.4, 37.7, 35.1, 30.1, 27.7, 21.80.095 g (0.30 mmol) of the compound obtained in Preparation Example 15 was dissolved in 5 mL of N, N-dimethylformamide, and then 0.12 g (0.60 mmol) of α, α, α, -trifluoro-p-toluic acid and 0.13 mmol of EDC. g (0.65 mmol) and HOBT 0.11 g (0.81 mmol) were added thereto, followed by stirring for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, purified by column chromatography using a mixed solvent in which 2 mL of 7N ammonia methanol was added to 200 mL of methanol: dichloromethane (2:98) to obtain 0.096 g of the title compound (74%). Obtained in the yield. 1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.39 (1H, t, J = 5.6 Hz), 8.8 ((1H, s), 8.35 (1H, dd, J = 8.8, 2.4 Hz), 8.13 (1H, d , J = 2.8 Hz), 8.04 (2H, d, J = 8.0 Hz), 7.74 (2H, d, J = 8.4 Hz), 7.28 (1H, d, J = 8.8 Hz), 7.26 (2H, td, J = 11.0, 2.0 Hz), 3.30 (2H, q, J = 7.2 Hz), 3.07 (2H, br d, J = 12.0 Hz), 2.25 (2H, q, J = 5.6 Hz), 2.20 (6H, s) , 1.83 (2H, broad, J = 11.6 Hz), 1.74-1.67 (6H, m), 1.58-1.53 (1H, m), 1.37-1.28 (2H, m), 1.02 (3H, d, J = 6.4 13 C NMR (CDCl3 100 MHz): δ (ppm) 166.2, 165.2, 148.3, 138.6, 135.5, 133.5, 133.2, 132.9, 132.6, 128.3, 127.7, 125.4, 125.36, 125.33, 125.29, 124.4, 123.4, 121.8, 57.3, 54.2, 45.4, 37.7, 35.1, 30.1, 27.7, 21.8

[[ 제조예Production Example 23] N-(2-디메틸아미노-에틸)-N- 23] N- (2-dimethylamino-ethyl) -N- 메틸methyl -2-(4--2- (4- 메틸methyl -피페리딘-1-일)-5-니트로-벤즈아미드-Piperidin-1-yl) -5-nitro-benzamide

제조예 1 에서 얻은 화합물 0.15g(0.57mmol)을 15mL N,N-디메틸포름아미드에 녹인 후 N,N,N'-트리메틸에틸렌디아민 0.091mL(0.70mmol), EDC 0.22g(1.1mmol), HOBT 0.15g(1.1mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(5:95) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.16g을 80%의 수율로 얻었다. 0.15 g (0.57 mmol) of the compound obtained in Preparation Example 1 was dissolved in 15 mL N, N-dimethylformamide, followed by 0.091 mL (0.70 mmol) of N, N, N'-trimethylethylenediamine, 0.22 g (1.1 mmol), and HOBT. 0.15 g (1.1 mmol) was added thereto and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using methanol: dichloromethane (5:95) mixed solvent to obtain 0.16 g of the title compound in a yield of 80%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.17-8.10(2H, m), 6.93(1H, dd, J=9, 3.6 Hz), 3.70(1H, m), 3.60(1H, m), 3.49(1H, br s), 3.12(1H, s), 3.11-2.91(3H, m), 2.82(1H, br q, J=12.8 Hz), 2.59(1H, m), 2.40-2.30(5H, m), 2.00(3H, s), 1.73(2H, m), 1.58 (1H, m), 1.29-1.13(2H, m), 0.98(3H, d, J=6.4 Hz)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.17-8.10 (2H, m), 6.93 (1H, dd, J = 9, 3.6 Hz), 3.70 (1H, m), 3.60 (1H, m), 3.49 ( 1H, br s), 3.12 (1H, s), 3.11-2.91 (3H, m), 2.82 (1H, br q, J = 12.8 Hz), 2.59 (1H, m), 2.40-2.30 (5H, m) , 2.00 (3H, s), 1.73 (2H, m), 1.58 (1H, m), 1.29-1.13 (2H, m), 0.98 (3H, d, J = 6.4 Hz)

[[ 제조예Production Example 24] 5-아미노-N-(2-디메틸아미노-에틸)-N- 24] 5-amino-N- (2-dimethylamino-ethyl) -N- 메틸methyl -2-(4--2- (4- 메틸methyl -피페리딘-1-일)-벤즈아미드-Piperidin-1-yl) -benzamide

제조예 23에서 얻은 화합물 0.16g(0.45mmol)을 10mL 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.14g을 99%의 수율로 얻었다. 0.16 g (0.45 mmol) of the compound obtained in Preparation Example 23 was dissolved in 10 mL methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.14 g of the title compound in a yield of 99%.

1H NMR (CDCl3 400MHz): δ(ppm) 6.91-6.85(1H, m), 6.68-6.64(1H, m),6.58(1H, dd, J=7.8, 2.4 Hz), 3.68(2H, m), 3.26-3.09(3H, m), 2.96(2H, m), 2.64(2H, t, J=7.2 Hz), 2.37(3H, s), 2.05(3H, s), 1.72-1.63(2H, m), 1.43(1H, m), 1.21(2H, qd, J=11.8, 4.0 Hz), 0.94(3H, d, J=6.4 Hz)1 H NMR (CDCl 3 400 MHz): δ (ppm) 6.91-6.85 (1H, m), 6.68-6.64 (1H, m), 6.58 (1H, dd, J = 7.8, 2.4 Hz), 3.68 (2H, m), 3.26-3.09 (3H, m), 2.96 (2H, m), 2.64 (2H, t, J = 7.2 Hz), 2.37 (3H, s), 2.05 (3H, s), 1.72-1.63 (2H, m) , 1.43 (1H, m), 1.21 (2H, qd, J = 11.8, 4.0 Hz), 0.94 (3H, d, J = 6.4 Hz)

[[ 실시예Example 23] N-(2-디메틸아미노-에틸)-5-(4-이소프로필- 23] N- (2-dimethylamino-ethyl) -5- (4-isopropyl- 벤조일아미노Benzoylamino )-N-) -N- 메틸methyl -2-(4-메틸-피페리딘-1-일)--2- (4-methyl-piperidin-1-yl)- 벤즈아미드Benzamide

제조예 24에서 얻은 화합물 0.14g(0.44mmol)을 5mL의 N,N-디메틸포름아미드에 녹인 후, 4-이소프로필벤조산 0.090g(0.53mmol), EDC 0.17g(0.88mmol), HOBT 0.12g(0.89mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 클로로포름:메탄올:암모니아 수용액(80:10:1) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.085g을 41%의 수율로 얻었다. 0.14 g (0.44 mmol) of the compound obtained in Preparation Example 24 was dissolved in 5 mL of N, N-dimethylformamide, followed by 0.090 g (0.53 mmol) of 4-isopropylbenzoic acid, 0.17 g (0.88 mmol) of EDC, and 0.12 g of HOBT ( 0.89 mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using a mixed solvent of chloroform: methanol: ammonia solution (80: 10: 1) to obtain 0.085 g of the title compound in a yield of 41%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.04-7.98(1H, m), 7.92(2H, d, J=7.6 Hz), 7.30-7.27(3H, m), 6.95(1H, d, J=9.2 Hz), 3.63(1H, m), 3.52(1H, m), 3.30(1H, m), 3.07(1H, m), 3.01(1H, s), 2.93(1H, p, J=6.8 Hz), 2.83-2.79(3H, m), 2.52(1H, m), 2.38(1H, m), 2.25(3H, s), 2.01(3H, s), 1.73(1H, br d, J=12.4 Hz), 1.48-1.40(2H, m), 1.28-1.26(6H, d, J=6.8 Hz), 1.24-1.16(3H, m), 0.93(3H, d, J=6.4 Hz). 13C NMR (CDCl3 100MHz): δ(ppm) 171.5, 171.3, 165.9, 165.7, 152.6, 152.5, 146.2, 145.8, 133.9, 133.7, 132.5, 132.0, 131.3 ,127.74, 127.71, 126.4, 122.4, 122.3, 120.9, 120.4, 119.3, 118.9, 57.4, 56.4, 55.2, 55.1, 51.0, 50.7, 48.8, 45.6, 45.5, 45.4, 36.8, 35.2, 35.0, 34.1, 33.2, 30.6, 30.5, 29.7, 23.8, 23.7, 22.0, 21.91 H NMR (CDCl 3 400 MHz): δ (ppm) 8.04-7.98 (1H, m), 7.92 (2H, d, J = 7.6 Hz), 7.30-7.27 (3H, m), 6.95 (1H, d, J = 9.2 Hz), 3.63 (1H, m), 3.52 (1H, m), 3.30 (1H, m), 3.07 (1H, m), 3.01 (1H, s), 2.93 (1H, p, J = 6.8 Hz), 2.83-2.79 (3H, m), 2.52 (1H, m), 2.38 (1H, m), 2.25 (3H, s), 2.01 (3H, s), 1.73 (1H, br d, J = 12.4 Hz), 1.48-1.40 (2H, m), 1.28-1.26 (6H, d, J = 6.8 Hz), 1.24-1.16 (3H, m), 0.93 (3H, d, J = 6.4 Hz). 13C NMR (CDCl3 100 MHz): δ (ppm) 171.5, 171.3, 165.9, 165.7, 152.6, 152.5, 146.2, 145.8, 133.9, 133.7, 132.5, 132.0, 131.3, 127.74, 127.71, 126.4, 122.4, 122.3, 120.9, 120.4 , 119.3, 118.9, 57.4, 56.4, 55.2, 55.1, 51.0, 50.7, 48.8, 45.6, 45.5, 45.4, 36.8, 35.2, 35.0, 34.1, 33.2, 30.6, 30.5, 29.7, 23.8, 23.7, 22.0, 21.9

[[ 제조예Production Example 25] N-(3-디메틸아미노-프로필)-N- 25] N- (3-dimethylamino-propyl) -N- 메틸methyl -2-(4--2- (4- 메틸methyl -피페리딘-1-일)-5-니트로--Piperidin-1-yl) -5-nitro- 벤즈아미드Benzamide

제조예 1에서 얻은 화합물 0.15g(0.57mmol)을 15mL N,N-디메틸포름아미드에 녹인 후 N,N,N'-트리메틸-1,3-프로페인디아민 0.10mL(0.71mmol), EDC 0.22g(1.1mmol), HOBT 0.16g(1.2mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(5:95) 혼합용매 250mL에 7N 암모니아 메탄올 1mL를 첨가한 용액을 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.19g을 91%의 수율로 얻었다. 0.15 g (0.57 mmol) of the compound obtained in Preparation Example 1 was dissolved in 15 mL N, N-dimethylformamide, and then 0.10 mL (0.71 mmol) of N, N, N'-trimethyl-1,3-propanediamine and 0.22 g of EDC. (1.1 mmol) and HOBT 0.16 g (1.2 mmol) were added thereto and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using a solution of 1 mL of 7N ammonia methanol in 250 mL of methanol: dichloromethane (5:95) mixed solvent, and purified by column chromatography to obtain 0.19 g of the title compound. Obtained at 91% yield.

1H NMR (CDCl3 400MHz): (ppm) 8.12(2H, m), 6.93(1H, m), 3.67(2H, m), 3.46(2H, m), 3.11(1H, s), 2.96(1H, t, J=9.6 Hz), 2.87-2.78(3H, m), 2.40(1H, t, J=1.6 Hz), 2.27(3H, s), 2.06(4H, m), 1.89-1.53(5H, m), 1.31-1.17(2H, m), 0.98(3H, d, J=6.4 Hz) 1 H NMR (CDCl3 400 MHz): (ppm) 8.12 (2H, m), 6.93 (1H, m), 3.67 (2H, m), 3.46 (2H, m), 3.11 (1H, s), 2.96 (1H, t , J = 9.6 Hz), 2.87-2.78 (3H, m), 2.40 (1H, t, J = 1.6 Hz), 2.27 (3H, s), 2.06 (4H, m), 1.89-1.53 (5H, m) , 1.31-1.17 (2H, m), 0.98 (3H, d, J = 6.4 Hz)

[[ 제조예Production Example 26] 5-아미노-N-(3-디메틸아미노-프로필)-N- 26] 5-amino-N- (3-dimethylamino-propyl) -N- 메틸methyl -2-(4--2- (4- 메틸methyl -피페리딘-1-일)--Piperidin-1-yl)- 벤즈아미드Benzamide

제조예 25에서 얻은 화합물 0.19g(0.51mmol)을 10mL 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.17g을 98%의 수율로 얻었다. 0.19 g (0.51 mmol) of the compound obtained in Preparation Example 25 was dissolved in 10 mL methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.17 g of the title compound in a yield of 98%.

1H NMR (CDCl3 400MHz): δ(ppm) 6.89-6.83(1H, m), 6.62(1H, br d, J=8.4 Hz), 6.56(1H, m), 3.60-3.47(1H, m), 3.26(1H, br t, J=14.4 Hz), 3.08(1H, s), 2.94(1H, br d, J=10.0 Hz), 2.81(3H, s), 2.50(1H, q, J=7.2 Hz), 2.36(1H, s), 1.91(1H, p, J=7.2 Hz), 1.70-1.64(2H, m), 1.59(1H, br d, J=12.0 Hz), 1.40(1H, m), 1.21-1.13(3H, m), 0.93(3H, d, J=6.4 Hz)1 H NMR (CDCl 3 400 MHz): δ (ppm) 6.89-6.83 (1H, m), 6.62 (1H, br d, J = 8.4 Hz), 6.56 (1H, m), 3.60-3.47 (1H, m), 3.26 (1H, brt, J = 14.4 Hz), 3.08 (1H, s), 2.94 (1H, br d, J = 10.0 Hz), 2.81 (3H, s), 2.50 (1H, q, J = 7.2 Hz) , 2.36 (1H, s), 1.91 (1H, p, J = 7.2 Hz), 1.70-1.64 (2H, m), 1.59 (1H, br d, J = 12.0 Hz), 1.40 (1H, m), 1.21 -1.13 (3H, m), 0.93 (3H, d, J = 6.4 Hz)

[[ 실시예Example 24] N-(3-디메틸아미노-프로필)-5-(4-이소프로필- 24] N- (3-dimethylamino-propyl) -5- (4-isopropyl- 벤조일아미노Benzoylamino )-N-) -N- 메틸methyl -2-(4-메틸-피페리딘-1-일)--2- (4-methyl-piperidin-1-yl)- 벤즈아미드Benzamide

제조예 26에서 얻은 화합물 0.17g(0.51mmol)을 5mL의 N,N-디메틸포름아미드에 녹인 후, 4-이소프로필벤조산 0.11g(0.67mmol), EDC 0.19g(1.0mmol), HOBT 0.14g(1.0mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 클로로포름:메 탄올:암모니아 수용액(100:10:1) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.074g을 31%의 수율로 얻었다. 0.17 g (0.51 mmol) of the compound obtained in Preparation Example 26 was dissolved in 5 mL of N, N-dimethylformamide, and then 0.11 g (0.67 mmol) of 4-isopropylbenzoic acid, 0.19 g (1.0 mmol) of EDC, and 0.14 g of HOBT ( 1.0 mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using a mixed solvent of chloroform: methanol: ammonia solution (100: 10: 1) to obtain 0.074 g of the title compound in a yield of 31%. .

1H NMR (CDCl3 400MHz): δ(ppm) 8.04(1H, dd, J=8.8, 2.4 Hz), 7.94(2H, t, J=8 Hz), 7.35(1H, d, J=2.4 Hz), 7.27(2H, d, J=8 Hz), 6.95(1H, m), 3.44-3.30(3H, m), 3.05(1H, m), 2.98-2.91(2H, m), 2.79(3H, s), 2.42(1H, m), 2.26(3H, s), 2.19(2H, s), 1.81-1.67(4H, m), 1.51-1.41(3H, m), 1.26(8H, d, J=6.8 Hz), 1.93-1.01(2H, m), 0.93(3H, d, J=2.4 Hz). 13C NMR (CDCl3 100MHz): δ(ppm) 171.4, 171.3, 168.9, 165.8, 152.7, 152.6, 146.1, 146.0, 133.9, 133.5, 132.5, 132.4, 132.0, 131.4, 127.8, 127.7, 126.5, 126.4, 122.7, 122.3, 121.1, 220.4, 119.3, 119.1, 56.7, 56.3, 55.2, 55.0, 50.9, 50.8, 48.8, 45.6, 45.0, 44.7, 36.4, 36.4, 35.2, 35.1, 35.0, 34.9, 34.1, 32.7, 30.54, 30.50, 25.7, 24.9, 23.8, 23.8, 22.01 H NMR (CDCl 3 400 MHz): δ (ppm) 8.04 (1H, dd, J = 8.8, 2.4 Hz), 7.94 (2H, t, J = 8 Hz), 7.35 (1H, d, J = 2.4 Hz), 7.27 (2H, d, J = 8 Hz), 6.95 (1H, m), 3.44-3.30 (3H, m), 3.05 (1H, m), 2.98-2.91 (2H, m), 2.79 (3H, s), 2.42 (1H, m), 2.26 (3H, s), 2.19 (2H, s), 1.81-1.67 (4H, m), 1.51-1.41 (3H, m), 1.26 (8H, d, J = 6.8 Hz) , 1.93-1.01 (2H, m), 0.93 (3H, d, J = 2.4 Hz). 13C NMR (CDCl3 100 MHz): δ (ppm) 171.4, 171.3, 168.9, 165.8, 152.7, 152.6, 146.1, 146.0, 133.9, 133.5, 132.5, 132.4, 132.0, 131.4, 127.8, 127.7, 126.5, 126.4, 122.7, 122.3 , 121.1, 220.4, 119.3, 119.1, 56.7, 56.3, 55.2, 55.0, 50.9, 50.8, 48.8, 45.6, 45.0, 44.7, 36.4, 36.4, 35.2, 35.1, 35.0, 34.9, 34.1, 32.7, 30.54, 30.50, 25.7 , 24.9, 23.8, 23.8, 22.0

[[ 제조예Production Example 27] 5-니트로-2- 27] 5-nitro-2- 피롤리딘Pyrrolidine -1-일-벤조산-1-yl-benzoic acid

2-플루오르-5-니트로벤조산 1.3g(7.0mmol)을 30ml의 아세토니트릴에 녹인 후, 피롤리딘 0.10ml(0.54mmol)을 가하고 12시간 동안 환류시키며 끓여주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 1N 염화수소 수용액으로 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 감압여과하고 에틸아세테이트를 감압증류로 제거하여 표제 화합물 0.13g을 정량적으로 얻었다. 1.3 g (7.0 mmol) of 2-fluoro-5-nitrobenzoic acid was dissolved in 30 ml of acetonitrile, and 0.10 ml (0.54 mmol) of pyrrolidine was added thereto, and the mixture was boiled under reflux for 12 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed with 1N aqueous hydrogen chloride solution. Water was removed with magnesium sulfate, and the residue was filtered under reduced pressure, and ethyl acetate was removed by distillation under reduced pressure to obtain 0.13 g of the title compound.

1H NMR (CDCl3+CD3OD 400MHz): δ(ppm) 8.59(1H, d, J=2.78), 8.14(1H, dd, J=9.43, 2.78), 6.75(1H, d, J=9.47), 3.41(4H, t, J=6.56), 2.03(4H, t, J=6.00)1 H NMR (CDCl 3 + CD 3 OD 400 MHz): δ (ppm) 8.59 (1H, d, J = 2.78), 8.14 (1H, dd, J = 9.43, 2.78), 6.75 (1H, d, J = 9.47), 3.41 ( 4H, t, J = 6.56), 2.03 (4H, t, J = 6.00)

[[ 제조예Production Example 28 ] 5-니트로-N-(1- 28] 5-nitro-N- (1- 페닐Phenyl -- 엘티Elti )-2-)-2- 피롤리딘Pyrrolidine -1-일--1 day- 벤즈아미드Benzamide

제조예 27 에서 얻은 화합물 1.2g(5.0mmol)을 30ml N,N-디메틸포름아미드에 녹인 후 메틸벤질아민 0.77ml(6.0mmol), EDC 1.9g(10mmol), HOBT 1.7g(13mmol)를 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 물, 탄산나트륨 포화 수용액, 5% 시트르산 수용액으로 각각 3번씩 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 헥세인:에틸아세테이트(2:1)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 1.2g을 70%의 수율로 얻었다. 1.2 g (5.0 mmol) of the compound obtained in Preparation Example 27 was dissolved in 30 ml N, N-dimethylformamide, and 0.77 ml (6.0 mmol) of methylbenzylamine, 1.9 g (10 mmol) of EDC, and 1.7 g (13 mmol) of HOBT were added thereto. Stir for hours. The solvent was removed by distillation under reduced pressure, and ethyl acetate was added thereto and washed three times with water, saturated aqueous sodium carbonate solution and 5% citric acid solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using hexane: ethyl acetate (2: 1) to obtain 1.2 g of the title compound in a yield of 70%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.03(1H, d, J=2.71), 7.92(1H, dd, J=9.38, 2.73), 7.39-7.32(3H, m), 7.29-7.26(1H, m), 6.73(1H, d, J=8.05), 6.49(1H, d, J=9.43), 5.23(1H, p, ), 3.23(4H, m), 1.86(4H, t), 1.59(3H, d, J=6.96)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.03 (1H, d, J = 2.71), 7.92 (1H, dd, J = 9.38, 2.73), 7.39-7.32 (3H, m), 7.29-7.26 (1H, m), 6.73 (1H, d, J = 8.05), 6.49 (1H, d, J = 9.43), 5.23 (1H, p,), 3.23 (4H, m), 1.86 (4H, t), 1.59 (3H , d, J = 6.96)

[[ 제조예Production Example 29] 5-아미노-N-(1- 29] 5-amino-N- (1- 페닐Phenyl -에틸)-2--Ethyl) -2- 피롤리딘Pyrrolidine -1-일--1 day- 벤즈아미드Benzamide

제조예 28 에서 얻은 화합물 0.90g(2.7mmol)을 30ml 메탄올에 녹인 후 팔라 듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.81g을 99%의 수율로 얻었다. 0.90 g (2.7 mmol) of the compound obtained in Preparation Example 28 was dissolved in 30 ml of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.81 g of the title compound in a yield of 99%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.73(1H, d, J=6.96), 7.54(1H, s), 7.37-7.29(4H, m), 7.23(1H, t, J=7.12), 7.04(1H, d, J=8.00), 6.73(1H, d, J=6.79), 5.26(1H, p, J=6.97), 2.94(4H, s), 1.79-1.71(4H, m), 1.55(3H, d, J=6.87)1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.73 (1H, d, J = 6.96), 7.54 (1H, s), 7.37-7.29 (4H, m), 7.23 (1H, t, J = 7.12), 7.04 (1H, d, J = 8.00), 6.73 (1H, d, J = 6.79), 5.26 (1H, p, J = 6.97), 2.94 (4H, s), 1.79-1.71 (4H, m), 1.55 ( 3H, d, J = 6.87)

[[ 실시예Example 25] 5-(4- 25] 5- (4- terttert -부틸-Butyl 벤조일아미노Benzoylamino )-N-(1-) -N- (1- 페닐Phenyl l-에틸)-2-l-ethyl) -2- 피롤리딘Pyrrolidine -1-일--1 day- 벤즈아미드Benzamide

제조예 29 에서 얻은 화합물 0.088g(0.28mmol)을 5ml 디클로로메테인에 녹인 후 피리딘 0.023ml(0.29mmol), 4-tert-부틸벤조일 클로라이드 0.056ml(0.29mmol)를 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 5% 시트르산 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 감압여과하고 에틸아세테이트를 감압증류로 제거하고 디클로로메테인:에틸아세테이트(4:1)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.083g을 62%의 수율로 얻었다. 0.088 g (0.28 mmol) of the compound obtained in Preparation Example 29 was dissolved in 5 ml dichloromethane, and 0.023 ml (0.29 mmol) of pyridine and 0.056 ml (0.29 mmol) of 4-tert-butylbenzoyl chloride were added thereto, followed by stirring for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with 5% aqueous citric acid solution. Water was removed with magnesium sulfate, and the residue was filtered under reduced pressure, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using dichloromethane: ethyl acetate (4: 1) to obtain 0.083 g of the title compound in a yield of 62%.

1H NMR (CDCl3 +CD3OD 400MHz): δ(ppm) 9.41(1H, s), 7.96(1H, s), 7.89(2H, d, J=8.15), 7.59(1H, d, J=2.29), 7.49(2H, d, J=8.21), 7.37-7.28(4H, m), 7.05(1H, d, J=8.59), 5.25(1H, p, J=6.74), 3.02(4H, s), 1.75(4H, m), 1.57(3H, d, J=6.85), 1.35(9H, s). 13C NMR (CDCl3+CD3OD 100MHz) : δ(ppm) 167.6, 155.6, 145.0, 143.5, 131.9, 129.0, 127.7, 127.5, 126.5, 126.2, 125.8, 125.2, 123.1, 119.4, 52.6, 35.2, 31.4, 30.0, 24.8, 22.11 H NMR (CDCl 3 + CD 3 OD 400 MHz): δ (ppm) 9.41 (1H, s), 7.96 (1H, s), 7.89 (2H, d, J = 8.15), 7.59 (1H, d, J = 2.29), 7.49 (2H, d, J = 8.21), 7.37-7.28 (4H, m), 7.05 (1H, d, J = 8.59), 5.25 (1H, p, J = 6.74), 3.02 (4H, s), 1.75 ( 4H, m), 1.57 (3H, d, J = 6.85), 1.35 (9H, s). 13C NMR (CDCl3 + CD3OD 100MHz): δ (ppm) 167.6, 155.6, 145.0, 143.5, 131.9, 129.0, 127.7, 127.5, 126.5, 126.2, 125.8, 125.2, 123.1, 119.4, 52.6, 35.2, 31.4, 30.0, 24.8 , 22.1

[[ 실시예Example 26] 5-(3- 26] 5- (3- 플루오로Fluoro -- 벤조일아미노Benzoylamino )-N-(1-) -N- (1- 페닐Phenyl -에틸)-2--Ethyl) -2- 피롤리딘Pyrrolidine -1-일--1 day- 벤즈아미드Benzamide

제조예 29에서 얻은 화합물 0.089g(0.29mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, 2-플루오르벤조산 0.049g(0.35mmol), EDC 0.11g(0.57mmol), HOBT 0. 77g(0.57mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 물, 탄산나트륨 포화 수용액, 5% 시트르산 수용액으로 각각 3번씩 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 디클로로메테인:에틸아세테이트(9:1)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.053g을 43%의 수율로 얻었다. 0.089 g (0.29 mmol) of the compound obtained in Preparation Example 29 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.049 g (0.35 mmol) of 2-fluorobenzoic acid, 0.11 g (0.57 mmol) of EDC, and HOBT 0.97 g ( 0.57 mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, and ethyl acetate was added thereto and washed three times with water, saturated aqueous sodium carbonate solution and 5% citric acid solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure and purified by column chromatography using dichloromethane: ethyl acetate (9: 1) to obtain 0.053 g of the title compound in a yield of 43%.

1H NMR (CDCl3 +CD3OD 400MHz): δ(ppm) 9.28(1H, d, J=6.94), 8.08(2H, d, J=5.86), 7.80(1H, d, J=2.67), 7.32(2H, m), 7.46(1H, m), 7.34(4H, d, J=4.36), 7.29-7.22(2H, m), 7.11(1H, d, J=8.82), 5.27(1H, m), 3.03(4H, q, J=7.17), 1.75(4H, m), 1.55(3H, d, J=6.88). 13C NMR (CDCl3 +CD3OD 100MHz) : δ(ppm) 166.5, 145.3, 143.6, 132.7, 130.8, 130.7, 129.1, 127.8, 127.4, 126.6, 124.5, 123.1, 122.9, 119.8, 119.3, 119.1, 115.2, 115.0, 52.9, 49.5, 30.1, 24.8, 22.3, 0.41 H NMR (CDCl 3 + CD 3 OD 400 MHz): δ (ppm) 9.28 (1H, d, J = 6.94), 8.08 (2H, d, J = 5.86), 7.80 (1H, d, J = 2.67), 7.32 (2H, m), 7.46 (1H, m), 7.34 (4H, d, J = 4.36), 7.29-7.22 (2H, m), 7.11 (1H, d, J = 8.82), 5.27 (1H, m), 3.03 ( 4H, q, J = 7.17), 1.75 (4H, m), 1.55 (3H, d, J = 6.88). 13C NMR (CDCl3 + CD3OD 100MHz): δ (ppm) 166.5, 145.3, 143.6, 132.7, 130.8, 130.7, 129.1, 127.8, 127.4, 126.6, 124.5, 123.1, 122.9, 119.8, 119.3, 119.1, 115.2, 115.0, 52.9 , 49.5, 30.1, 24.8, 22.3, 0.4

[[ 실시예Example 27] 5-(3- 27] 5- (3- 디에틸아미노Diethylamino -- 프로피오닐아미노Propionylamino )-N-(1-) -N- (1- 페닐Phenyl -에틸)-2--Ethyl) -2- 피롤리딘Pyrrolidine -1-일--1 day- 벤즈아미드Benzamide

제조예 29에서 얻은 화합물 0.088g(0.28mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, 3-(디에틸아미노)프로피오닐산 0.064g(0.35mmol), EDC 0.12g(0.63mmol), HOBT 0.098g(0.73mmol)을 넣고 8의 합성법과 같은 방법으로 실험하였다. 메탄올:디클로로메테인(7:93) 200ml에 7N 암모니아 메탄올 1ml 첨가한 용액을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.080g을 65%의 수율로 얻었다. 0.088 g (0.28 mmol) of the compound obtained in Preparation Example 29 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.064 g (0.35 mmol) of 3- (diethylamino) propionyl acid and 0.12 g (0.63 mmol) of EDC. , HOBT 0.098g (0.73mmol) was added and the same experiment as in Synthesis 8 was performed. Purification by column chromatography using a solution of 1 ml of 7N ammonia methanol in 200 ml of methanol: dichloromethane (7:93) gave 0.080 g of the title compound in a yield of 65%.

1H NMR (CDCl3 400MHz) : δ(ppm) 11.24(1H, s), 9.80(1H, d, J=7.6), 8.05(1H, dd, J=6, 2.8), 7.72(1H, d, J=2.4), 7.38-7.32(4H, m), 7.28-7.24(1H, m), 7.10(1H, d, J=8.8), 5.30(1H, p, J=7.2), 2.99(4H, h, J=6.8), 2.79(2H, t, J=5.6), 2.68(4H, q, J=7.2), 2.51(2H, t, J=6), 1.81-1.66(4H, m), 1.56(3H, d, J=6.8), 1.13(6H, t, J=7.2). 13C NMR (CDCl3 100MHz) : δ(ppm) 171.3, 166.1, 144.5, 144.0, 134.6, 129.0, 128.0, 127.7, 126.6, 123.9, 121.9, 120.6, 53.3, 49.4, 49.0, 46.4, 33.3, 24.6, 22.4, 11.71 H NMR (CDCl 3 400 MHz): δ (ppm) 11.24 (1H, s), 9.80 (1H, d, J = 7.6), 8.05 (1H, dd, J = 6, 2.8), 7.72 (1H, d, J = 2.4), 7.38-7.32 (4H, m), 7.28-7.24 (1H, m), 7.10 (1H, d, J = 8.8), 5.30 (1H, p, J = 7.2), 2.99 (4H, h, J = 6.8), 2.79 (2H, t, J = 5.6), 2.68 (4H, q, J = 7.2), 2.51 (2H, t, J = 6), 1.81-1.66 (4H, m), 1.56 (3H, d, J = 6.8), 1.13 (6H, t, J = 7.2). 13C NMR (CDCl3 100 MHz): δ (ppm) 171.3, 166.1, 144.5, 144.0, 134.6, 129.0, 128.0, 127.7, 126.6, 123.9, 121.9, 120.6, 53.3, 49.4, 49.0, 46.4, 33.3, 24.6, 22.4, 11.7

[[ 실시예Example 28] 4- 28] 4- 메틸methyl -피페라진-1-Piperazine-1- 카복실산Carboxylic acid [3-(1- [3- (1- 페닐Phenyl -- 에틸카바모일Ethylcarbamoyl )-4-)-4- 피롤리딘Pyrrolidine -1-일--1 day- 페닐Phenyl ]-아미드]-amides

제조예 29에서 얻은 화합물 0.096g(0.31mmol)을 4ml 디클로로메테인에 녹인 후 피리딘 0.025ml(0.31mmol)를 넣은 용액에 2ml 디클로로메테인에 트리포스젠 0.042g(0.14mmol)을 녹인 용액을 0℃에서 한방울씩 첨가하였다. 3시간 후 1-메틸피페라진 0.041ml(0.37mmol), 피리딘 0.021ml(0.26mmol)을 넣고 4시간 동안 교반해주었다. 용매는 감압증류로 제거한 다음 클로로포름:메탄올:암모니아 수용액(80:10:1)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.040g을 30%의 수율로 얻었다. 0.096 g (0.31 mmol) of the compound obtained in Preparation Example 29 was dissolved in 4 ml dichloromethane, and 0.042 g (0.14 mmol) of triphosphene was dissolved in 2 ml dichloromethane in a solution containing 0.025 ml (0.31 mmol) of pyridine. It was added dropwise at ℃. After 3 hours, 0.041ml (0.37mmol) of 1-methylpiperazine and 0.021ml (0.26mmol) of pyridine were added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, and then purified by column chromatography using chloroform: methanol: ammonia aqueous solution (80: 10: 1) to obtain 0.040 g of the title compound in a yield of 30%.

1H NMR (CDCl3 400MHz): δ(ppm) 9.85(1H, d, J=7.6), 7.74(1H, d, J=8.6, 2.4), 7.33-7.24(6H, m), 7.03(1H, d, J=8.8), 5.25(1H, p, J=6.8), 3.48(4H, t, J=4.8), 2.96(4H, h, J=6.4), 2.36(4H, t, J=4.8), 2.28(3H, s), 1.79-1.64(4H, m), 1.52(3H, d, J=6.8). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.4, 155.9, 144.0, 143.9, 135.1, 129.0, 127.7, 127.6, 126.6, 124.8, 122.8, 120.5, 55.1, 53.2, 49.4, 46.4, 44.3, 24.7, 22.51 H NMR (CDCl 3 400 MHz): δ (ppm) 9.85 (1H, d, J = 7.6), 7.74 (1H, d, J = 8.6, 2.4), 7.33-7.24 (6H, m), 7.03 (1H, d, J = 8.8), 5.25 (1H, p, J = 6.8), 3.48 (4H, t, J = 4.8), 2.96 (4H, h, J = 6.4), 2.36 (4H, t, J = 4.8), 2.28 (3H, s), 1.79-1.64 (4H, m), 1.52 (3H, d, J = 6.8). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.4, 155.9, 144.0, 143.9, 135.1, 129.0, 127.7, 127.6, 126.6, 124.8, 122.8, 120.5, 55.1, 53.2, 49.4, 46.4, 44.3, 24.7, 22.5

[ 실시예 29] 4-[3-(1- 페닐 - 에틸카바모일 )-4- 피롤리딘 -1-일- 페닐카바모일 ]-피페리딘-1-카 복시 산 tert -부틸 에스터 [Example 29] 4- [3- (1-phenyl-ethylcarbamoyl) -4-pyrrolidin-1-yl-phenylcarbamoyl] piperidine-1-car diplopia acid tert-butyl ester

제조예 29에서 얻은 화합물 0.36g(1.2mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, 피페리딘-1,4-디카복실산 모노-tert-부틸 에스터 0.27g(1.2mmol), EDC 0.46g(2.4mmol), HOBT 0.41g(3.0mmol)를 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 물, 탄산나트륨 포화 수용액, 5% 시트르산 수용액으로 각각 3번씩 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 헥세인:에틸아세테이트(1:1)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.23g을 37%의 수율로 얻었다. 0.36 g (1.2 mmol) of the compound obtained in Preparation Example 29 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.27 g (1.2 mmol) of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester and EDC. 0.46 g (2.4 mmol) and HOBT 0.41 g (3.0 mmol) were added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, and ethyl acetate was added thereto and washed three times with water, saturated aqueous sodium carbonate solution and 5% citric acid solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using hexane: ethyl acetate (1: 1) to obtain 0.23 g of the title compound in a yield of 37%.

1H NMR (CDCl3 400MHz): δ(ppm) 9.51(1H, d, J=7.6), 8.63(1H, s), 7.98(1H, dd, J=8.8, 2.4), 7.75(1H, d, J=2.8), 7.33-7.23(5H, m), 7.04(1H, d, J=8.8), 5.26(1H, p, J=7.2), 4.12(2H, s), 2.98(4H, q, J=6.4), 2.67(2H, s), 2.43(1H, m), 1.81-1.65(8H, m), 1.54(3H, d, J=6.8), 1.45(9H, s). 13C NMR (CDCl3 100MHz) : δ(ppm) 173.7, 166.7, 155.0, 144.8, 143.6, 133.7, 129.1, 127.9, 127.4, 126.6, 124.8, 122.8, 119.4, 80.0, 53.1, 49.6, 44.1, 28.9, 28.8, 24.8, 22.51 H NMR (CDCl 3 400 MHz): δ (ppm) 9.51 (1H, d, J = 7.6), 8.63 (1H, s), 7.98 (1H, dd, J = 8.8, 2.4), 7.75 (1H, d, J = 2.8), 7.33-7.23 (5H, m), 7.04 (1H, d, J = 8.8), 5.26 (1H, p, J = 7.2), 4.12 (2H, s), 2.98 (4H, q, J = 6.4 ), 2.67 (2H, s), 2.43 (1H, m), 1.81-1.65 (8H, m), 1.54 (3H, d, J = 6.8), 1.45 (9H, s). 13C NMR (CDCl3 100 MHz): δ (ppm) 173.7, 166.7, 155.0, 144.8, 143.6, 133.7, 129.1, 127.9, 127.4, 126.6, 124.8, 122.8, 119.4, 80.0, 53.1, 49.6, 44.1, 28.9, 28.8, 24.8 , 22.5

[[ 제조예Production Example 30] [3-(1-  30] [3- (1- 페닐Phenyl -- 에틸카바모일Ethylcarbamoyl )-4-)-4- 피롤리딘Pyrrolidine -1-일--1 day- 페닐Phenyl ]-아미드]-amides

실시예 29 에서 얻은 화합물 0.23g(0.28mmol)을 10ml 디클로로메테인에 녹인 후 트리플루오르아세트산 1ml를 넣고 2시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 감압여과하고 에틸아세테이트를 감압증 류로 제거하여 표제 화합물 0.19g을 정량적으로 얻었다. 0.23 g (0.28 mmol) of the compound obtained in Example 29 was dissolved in 10 ml dichloromethane, and 1 ml of trifluoroacetic acid was added thereto, followed by stirring for 2 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, and the residue was filtered under reduced pressure and ethyl acetate was removed by distillation under reduced pressure to obtain 0.19 g of the title compound.

1H NMR (CDCl3 400MHz): δ(ppm)(ppm) 9.84(2H, s), 8.52(1H, s), 7.87(1H, s), 7.80(1H, d, J=7.6), 7.29-7.21(5H, m), 7.00(1H, d, J=8.4), 5.15(1H, t, J=6.4), 3.24(2H, s), 2.96(4H, d, J=9.6), 2.76(2H, s), 2.61(1H, s), 1.90(4H, s), 1.73(4H, m), 1.50(3H, d, J=6.8)1 H NMR (CDCl 3 400 MHz): δ (ppm) (ppm) 9.84 (2H, s), 8.52 (1H, s), 7.87 (1H, s), 7.80 (1H, d, J = 7.6), 7.29-7.21 ( 5H, m), 7.00 (1H, d, J = 8.4), 5.15 (1H, t, J = 6.4), 3.24 (2H, s), 2.96 (4H, d, J = 9.6), 2.76 (2H, s ), 2.61 (1H, s), 1.90 (4H, s), 1.73 (4H, m), 1.50 (3H, d, J = 6.8)

[[ 실시예Example 30] 1-벤질-피페리딘-4- 30] 1-benzyl-piperidine-4- 카복실산Carboxylic acid [3-(1- [3- (1- 페닐Phenyl -- 에틸카바모일Ethylcarbamoyl )-4-)-4- 피롤리딘Pyrrolidine -1-일--1 day- 페닐Phenyl ]-아미드]-amides

제조예 30에서 얻은 화합물 0.063g(0.15mmol)을 5ml ethanol에 녹인 후 포타슘 카보네이트 0.020g(0.15mmol), 벤질 클로라이드 0.034ml(0.30mmol)을 넣고 24시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 메탄올:디클로로메테인(7:93)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.046g을 61%의 수율로 얻었다. 0.063 g (0.15 mmol) of the compound obtained in Preparation Example 30 was dissolved in 5 ml ethanol, and then 0.020 g (0.15 mmol) of potassium carbonate and 0.034 ml (0.30 mmol) of benzyl chloride were added and stirred for 24 hours. The solvent was removed by distillation under reduced pressure and then purified by column chromatography using methanol: dichloromethane (7:93) to obtain 0.046 g of the title compound in a yield of 61%.

1H NMR (CDCl3 400MHz): δ(ppm) 9.57(1H, d, J=7.6), 8.30(1H, s), 8.03(1H, dd, J=8.8, 2.4), 7.76(1H, d, J=2.8), 7.34-7.22(10H, m), 7.04(1H, d, J=8.8), 5.28(1H, p, J=7.2), 3.47(2H, s), 2.96(4H, q, J=5.2), 2.91(2H, d, J=11.2), 2.27(1H, p, J=7.6), 2.04-1.68(10H, m), 1.54(3H, d, J=6.8). 13C NMR (CDCl3 100MHz) : δ(ppm) 174.3, 166.6, 144.7, 143.7, 138.6, 133.9, 129.5, 129.1, 128.6, 127.8, 127.6, 127.4, 126.7, 124.6, 122.6, 120.1, 63.6, 52.4, 53.2, 49.5, 44.2, 29.2, 24.7, 22.51 H NMR (CDCl 3 400 MHz): δ (ppm) 9.57 (1H, d, J = 7.6), 8.30 (1H, s), 8.03 (1H, dd, J = 8.8, 2.4), 7.76 (1H, d, J = 2.8), 7.34-7.22 (10H, m), 7.04 (1H, d, J = 8.8), 5.28 (1H, p, J = 7.2), 3.47 (2H, s), 2.96 (4H, q, J = 5.2 ), 2.91 (2H, d, J = 11.2), 2.27 (1H, p, J = 7.6), 2.04-1.68 (10H, m), 1.54 (3H, d, J = 6.8). 13C NMR (CDCl3 100 MHz): δ (ppm) 174.3, 166.6, 144.7, 143.7, 138.6, 133.9, 129.5, 129.1, 128.6, 127.8, 127.6, 127.4, 126.7, 124.6, 122.6, 120.1, 63.6, 52.4, 53.2, 49.5 , 44.2, 29.2, 24.7, 22.5

[[ 제조예Production Example 31] 2-(3,4- 31] 2- (3,4- 디하이드로Dehydro -1H-이소퀴놀린-2-일)-5-니트로-벤조산-1H-isoquinolin-2-yl) -5-nitro-benzoic acid

2-플루오르-5-니트로벤조산 1.5g(8.1mmol)을 50ml의 아세토니트릴에 녹인 후, 1,2,3,4-테트라히드로이소퀴놀린 1.9ml(15mmol)을 가하고 12시간 동안 환류시키며 끓여주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 1N 염화수소 수용액으로 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 감압여과하고 에틸아세테이트를 감압증류로 제거하여 표제 화합물 2.6g을 정량적으로 얻었다. 1.5 g (8.1 mmol) of 2-fluoro-5-nitrobenzoic acid was dissolved in 50 ml of acetonitrile, and then 1.9 ml (15 mmol) of 1,2,3,4-tetrahydroisoquinoline was added thereto, and the mixture was boiled under reflux for 12 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed with 1N aqueous hydrogen chloride solution. Water was removed with magnesium sulfate, and the residue was filtered under reduced pressure and ethyl acetate was removed by distillation under reduced pressure to obtain 2.6 g of the title compound.

1H NMR (CDCl3+CD3OD 400MHz): δ(ppm) 8.91(1H, d, J=2.78), 8.33(1H, dd, J=9.07, 2.80), 7.34(1H, d, J=9.08), 7.23-7.18(3H, m), 7.09(1H, d, J=5.93), 4.36(2H, s), 3.54(2H, t, J=5.83), 3.10(2H, t, J=5.79) 1 H NMR (CDCl 3 + CD 3 OD 400 MHz): δ (ppm) 8.91 (1H, d, J = 2.78), 8.33 (1H, dd, J = 9.07, 2.80), 7.34 (1H, d, J = 9.08), 7.23- 7.18 (3H, m), 7.09 (1H, d, J = 5.93), 4.36 (2H, s), 3.54 (2H, t, J = 5.83), 3.10 (2H, t, J = 5.79)

[[ 제조예Production Example 32] 2-(3,4- 32] 2- (3,4- 디하이드로Dehydro -1H-이소퀴놀린-2-일)-N-(3--1H-isoquinolin-2-yl) -N- (3- 메톡시Methoxy -프로필)-5-니트로--Propyl) -5-nitro- 벤즈아미드Benzamide

제조예 31에서 얻은 화합물 0.14g(0.67mmol)을 15ml N,N-디메틸포름아미드에 녹인 후 3-메톡시프로필아민 0.068ml(1.3mmol), EDC 0.26g(1.4mmol), HOBT 0.27g(2.0mmol)를 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에 틸아세테이트를 가하고 물, 탄산나트륨 포화 수용액, 5% 시트르산 수용액으로 각각 3번씩 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 헥세인:에틸아세테이트(2:1)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.11g을 64%의 수율로 얻었다. 0.14 g (0.67 mmol) of the compound obtained in Preparation Example 31 was dissolved in 15 ml N, N-dimethylformamide, followed by 0.068 ml (1.3 mmol) of 3-methoxypropylamine, 0.26 g (1.4 mmol) of EDC, and 0.27 g (2.0BT) of HOBT. mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, and ethyl acetate was added thereto, and the mixture was washed three times with water, saturated aqueous sodium carbonate solution and 5% citric acid solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using hexane: ethyl acetate (2: 1) to obtain 0.11 g of the title compound in a yield of 64%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.64(1H, d, J=2.78), 8.17(1H, dd, J=8.95, 2.80), 8.08(1H, t, J=5.16), 7.23-7.17(3H, m), 7.14(1H, d, J=9.04), 7.10(1H, d, J=6.07), 4.34(2H, s), 3.54-3.49(4H, m), 3.36(2H, t, J=5.77), 3.17(3H, s), 3.02(2H, t, J=5.73), 1.71(2H, p, J=6.22)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.64 (1H, d, J = 2.78), 8.17 (1H, dd, J = 8.95, 2.80), 8.08 (1H, t, J = 5.16), 7.23-7.17 ( 3H, m), 7.14 (1H, d, J = 9.04), 7.10 (1H, d, J = 6.07), 4.34 (2H, s), 3.54-3.49 (4H, m), 3.36 (2H, t, J = 5.77), 3.17 (3H, s), 3.02 (2H, t, J = 5.73), 1.71 (2H, p, J = 6.22)

[[ 제조예Production Example 33] 5-아미노-2-(3,4- 33] 5-amino-2- (3,4- 디하이드로Dehydro -1H-이소퀴놀린-2-일)-N-(3--1H-isoquinolin-2-yl) -N- (3- 메톡시Methoxy -프로필)--profile)- 벤즈아미드Benzamide

제조예 32에서 얻은 화합물 0.11g(0.30mmol)을 10ml 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.10g을 99%의 수율로 얻었다. 0.11 g (0.30 mmol) of the compound obtained in Preparation Example 32 was dissolved in 10 ml of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.10 g of the title compound in a yield of 99%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.55(1H, t), 7.59(1H, d, J=2.54), 7.22-7.16(3H, m), 7.06(1H, d, J=8.45), 7.01(1H, d, J=4.09), 6.75(1H, dd, J=8.38, 2.74), 3.98(2H, s), 3.34(2H, t, J=5.80), 3.21(2H, t, J=5.90), 3.13(2H, t, J=5.90), 3.07(3H, s), 3.01(2H, t, J=6.22), 1.52(2H, p, J=6.47)1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.55 (1H, t), 7.59 (1H, d, J = 2.54), 7.22-7.16 (3H, m), 7.06 (1H, d, J = 8.45), 7.01 (1H, d, J = 4.09), 6.75 (1H, dd, J = 8.38, 2.74), 3.98 (2H, s), 3.34 (2H, t, J = 5.80), 3.21 (2H, t, J = 5.90 ), 3.13 (2H, t, J = 5.90), 3.07 (3H, s), 3.01 (2H, t, J = 6.22), 1.52 (2H, p, J = 6.47)

[[ 실시예Example 31] 5-(2- 31] 5- (2- 클로로Chloro -- 아세틸아미노Acetylamino )-2-(3,4-) -2- (3,4- 디하이드로Dehydro -1H-이소퀴놀린-2-일)-N-(3-메톡시-프로필)--1H-isoquinolin-2-yl) -N- (3-methoxy-propyl)- 벤즈아미드Benzamide

제조예 33에서 얻은 화합물 0.10g(0.30mmol)을 5ml 디클로로메테인에 녹인 후 피리딘 0.024ml(0.30mmol), 클로로아세틸 클로라이드 0.024mll(0.30mmol)를 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 5% 시트르산 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 감압여과하고 에틸아세테이트를 감압증류로 제거하고 헥세인:에틸아세테이트(1:1)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.072g을 정량적으로 얻었다. 0.10 g (0.30 mmol) of the compound obtained in Preparation Example 33 was dissolved in 5 ml of dichloromethane, and pyridine 0.024 ml (0.30 mmol) and chloroacetyl chloride 0.024 mmol (0.30 mmol) were added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with 5% aqueous citric acid solution. Water was removed with magnesium sulfate, and the residue was filtered under reduced pressure, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using hexane: ethyl acetate (1: 1) to obtain 0.072 g of the title compound.

1H NMR (CDCl3 400MHz): δ(ppm) 10.01(1H, t, J=4.92), 8.90(1H, s), 8.20(1H, dd, J=8.72, 2.72), 8.02(1H, d, J=2.68), 7.27(1H, d, J=8.92), 7.22-7.16(3H, m), 7.06(1H, d, J=6.84), 4.21(2H, s), 4.10(2H, s), 3.41(2H, q, J=6.73), 3.34(2H, t, J=5.81), 3.18(2H, t, J=6.11), 3.11(3H, s), 3.06(2H, t, J=5.58), 1.55(2H, p, J=6.47). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.1, 164.8, 148.0, 134.6, 134.2, 133.7, 129.4, 128.8, 127.3, 126.7, 126.6, 124.3, 123.3, 122.3, 70.6, 58.9, 56.8, 51.2, 43.4, 37.3, 29.7, 29.61 H NMR (CDCl 3 400 MHz): δ (ppm) 10.01 (1H, t, J = 4.92), 8.90 (1H, s), 8.20 (1H, dd, J = 8.72, 2.72), 8.02 (1H, d, J = 2.68), 7.27 (1H, d, J = 8.92), 7.22-7.16 (3H, m), 7.06 (1H, d, J = 6.84), 4.21 (2H, s), 4.10 (2H, s), 3.41 ( 2H, q, J = 6.73), 3.34 (2H, t, J = 5.81), 3.18 (2H, t, J = 6.11), 3.11 (3H, s), 3.06 (2H, t, J = 5.58), 1.55 (2H, p, J = 6.47). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.1, 164.8, 148.0, 134.6, 134.2, 133.7, 129.4, 128.8, 127.3, 126.7, 126.6, 124.3, 123.3, 122.3, 70.6, 58.9, 56.8, 51.2, 43.4, 37.3 , 29.7, 29.6

[[ 제조예Production Example 34] N- 34] N- 시클로헥실Cyclohexyl -2-(3,4--2- (3,4- 디하이드로Dehydro -1H-이소퀴놀린-2-일)-5-니트로--1H-isoquinolin-2-yl) -5-nitro- 벤즈아미드Benzamide

제조예 31 에서 얻은 화합물 0.28g(1.3mmol)을 15ml N,N-디메틸포름아미드에 녹인 후 시클로헥실아민 0.15ml(2.7mmol), EDC 0.26g(2.7mmol), HOBT 0.26g(2.9mmol)를 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 물, 탄산나트륨 포화 수용액, 5% 시트르산 수용액으로 각각 3번씩 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 헥세인:에틸아세테이트(5:1)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.18g을 53%의 수율로 얻었다. 0.28 g (1.3 mmol) of the compound obtained in Preparation Example 31 was dissolved in 15 ml N, N-dimethylformamide, and then 0.15 ml (2.7 mmol) of cyclohexylamine, 0.26 g (2.7 mmol) of EDC, and 0.26 g (2.9 mmol) of HOBT were added. Put and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, and ethyl acetate was added thereto and washed three times with water, saturated aqueous sodium carbonate solution and 5% citric acid solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using hexane: ethyl acetate (5: 1) to obtain 0.18 g of the title compound in a yield of 53%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.77(1H, d, J=2.79), 8.21(1H, dd, J=8.91, 2.80), 8.15(1H, d, J=7.47), 7.24-7.18(3H, m), 7.07(1H, d, J=7.06), 4.27(2H, s), 3.88(1H, m), 3.53(2H, t, J=5.86), 3.06(2H, t, J=5.68), 1.83(2H, d, J=5.68), 1.59-1.52(3H, m), 1.35-1.25(4H, m), 1.04-0.88(4H, m)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.77 (1H, d, J = 2.79), 8.21 (1H, dd, J = 8.91, 2.80), 8.15 (1H, d, J = 7.47), 7.24-7.18 ( 3H, m), 7.07 (1H, d, J = 7.06), 4.27 (2H, s), 3.88 (1H, m), 3.53 (2H, t, J = 5.86), 3.06 (2H, t, J = 5.68 ), 1.83 (2H, d, J = 5.68), 1.59-1.52 (3H, m), 1.35-1.25 (4H, m), 1.04-0.88 (4H, m)

[[ 제조예Production Example 35] 5-아미노-N- 35] 5-amino-N- 시클로헥실Cyclohexyl -2-(3,4--2- (3,4- 디하이드로Dehydro -1H-이소퀴놀린-2-일)--1H-isoquinolin-2-yl)- 벤즈아미드Benzamide

제조예 34에서 얻은 화합물 0.19g(0.50mmol)을 10ml 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.17g을 96% 의 수율로 얻었다. 0.19 g (0.50 mmol) of the compound obtained in Preparation Example 34 was dissolved in 10 ml of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.17 g of the title compound in a yield of 96%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.45(1H, d, J=7.72), 7.06(1H, d, J=2.48), 7.19-7.12(3H, m), 7.07(1H, d, J=8.40), 7.01(1H, d, J=7.19), 6.75(1H, dd, J=8.34, 2.68), 3.98(2H, s), 3.82(1H, m), 3.29(2H, t, J=5.84), 3.06(2H, t, J=5.60), 1.72(2H, d, J=8.52), 1.43(3H, d, J=5.38), 1.25-1.16(3H, m), 0.90-0.77(3H, m)1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.45 (1H, d, J = 7.72), 7.06 (1H, d, J = 2.48), 7.19-7.12 (3H, m), 7.07 (1H, d, J = 8.40), 7.01 (1H, d, J = 7.19), 6.75 (1H, dd, J = 8.34, 2.68), 3.98 (2H, s), 3.82 (1H, m), 3.29 (2H, t, J = 5.84 ), 3.06 (2H, t, J = 5.60), 1.72 (2H, d, J = 8.52), 1.43 (3H, d, J = 5.38), 1.25-1.16 (3H, m), 0.90-0.77 (3H, m)

[[ 실시예Example 32] N- 32] N- 시클로헥실Cyclohexyl -2-(3,4--2- (3,4- 디하이드로Dehydro -1H-이소퀴놀린-2-일)-5--1H-isoquinolin-2-yl) -5- 이소부티릴아미노Isobutyrylamino -- 벤즈아미드Benzamide

제조예 35에서 얻은 화합물 0.080g(0.23mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, 시클로헥실카복실산 0.033ml(0.26mmol), EDC 0.048g(0.25mmol), HOBT 0.065g(0.48mmol)를 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 물, 탄산나트륨 포화 수용액, 5% 시트르산 수용액으로 각각 3번씩 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 헥세인:에틸아세테이트(2:1)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.044g을 46%의 수율로 얻었다. 0.080 g (0.23 mmol) of the compound obtained in Preparation Example 35 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.033 ml (0.26 mmol) of cyclohexyl carboxylic acid, 0.048 g (0.25 mmol) of EDC, and 0.065 g (0.48 mmol) of HOBT. ) Was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, and ethyl acetate was added thereto and washed three times with water, saturated aqueous sodium carbonate solution and 5% citric acid solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using hexane: ethyl acetate (2: 1) to obtain 0.044 g of the title compound in a yield of 46%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.21(1H, d, J=7.72), 8.32(1H, dd, J=8.18, 2.68), 8.07(1H, s), 7.95(1H, d, J=2.68), 7.23-7.16(4H, m), 7.02(1H, d, J=7.28), 4.03(2H, s), 3.85(1H, m), 3.36(2H, t, J=5.88), 3.09(2H, t, J=5.65), 2.60(1H, m), 1.69(3H, m), 1.45(3H, m), 1.25(8H, d, J=6.85), 0.95-0.75(4H, m). 13C NMR (CDCl3 100MHz) : δ(ppm) 176.1, 164.9, 147.1, 136.2, 134.4, 133.7, 129.3, 128.7, 127.2, 126.8, 126.4, 124.2, 122.57, 122.55, 58.1, 50.2, 48.3, 36.8, 32.9, 30.0, 25.8, 24.9, 20.01 H NMR (CDCl 3 400 MHz): δ (ppm) 10.21 (1H, d, J = 7.72), 8.32 (1H, dd, J = 8.18, 2.68), 8.07 (1H, s), 7.95 (1H, d, J = 2.68), 7.23-7.16 (4H, m), 7.02 (1H, d, J = 7.28), 4.03 (2H, s), 3.85 (1H, m), 3.36 (2H, t, J = 5.88), 3.09 ( 2H, t, J = 5.65), 2.60 (1H, m), 1.69 (3H, m), 1.45 (3H, m), 1.25 (8H, d, J = 6.85), 0.95-0.75 (4H, m). 13C NMR (CDCl3 100 MHz): δ (ppm) 176.1, 164.9, 147.1, 136.2, 134.4, 133.7, 129.3, 128.7, 127.2, 126.8, 126.4, 124.2, 122.57, 122.55, 58.1, 50.2, 48.3, 36.8, 32.9, 30.0 , 25.8, 24.9, 20.0

[[ 제조예Production Example 36] 2-(3,4- 36] 2- (3,4- 디하이드로Dehydro -1H-이소퀴놀린-2-일)-N-(2-디메틸아미노-에틸)-N-메틸-5-니트로--1H-isoquinolin-2-yl) -N- (2-dimethylamino-ethyl) -N-methyl-5-nitro- 벤즈아미드Benzamide

제조예 31에서 얻은 화합물 0.20g(0.67mmol)을 5mL N,N-디메틸포름아미드에 녹인 후 N,N,N'-트리메틸에틸렌디아민 0.11mL(0.82mmol), EDC 0.26g(1.4mmol), HOBT 0.19g(1.4mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(5:95) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물을 정량적으로 얻었다. 0.20 g (0.67 mmol) of the compound obtained in Preparation Example 31 was dissolved in 5 mL N, N-dimethylformamide, and then 0.11 mL (0.82 mmol) of N, N, N'-trimethylethylenediamine, 0.26 g (1.4 mmol) of EDC, and HOBT. 0.19 g (1.4 mmol) was added thereto and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the title compound was quantitatively purified by column chromatography using methanol: dichloromethane (5:95) mixed solvent.

1H NMR (CDCl3 400MHz): δ(ppm) 8.18~8.12(2H, m), 7.22~7.17(3H, m), 7.13~7.11(1H, m), 7.02~6.98(1H, m), 4.52~4.40(2H, m), 3.75~3.54(2H, m), 3.12(2H, s), 2.98~2.93(2H, m), 2.92(3H, s), 2.54(2H, t, J=6.8), 1.95(3H, s)1 H NMR (CDCl3 400 MHz): δ (ppm) 8.18 to 8.12 (2H, m), 7.22 to 7.17 (3H, m), 7.13 to 7.71 (1H, m), 7.02 to 6.98 (1H, m), 4.52 to 4.40 (2H, m), 3.75-3.54 (2H, m), 3.12 (2H, s), 2.98-2.93 (2H, m), 2.92 (3H, s), 2.54 (2H, t, J = 6.8), 1.95 (3H, s)

[[ 제조예Production Example 37] 5-아미노-2-(3,4- 37] 5-amino-2- (3,4- 디하이드로Dehydro -1H-이소퀴놀린-2-일)-N-(2-디메틸아미노-에틸)-N--1H-isoquinolin-2-yl) -N- (2-dimethylamino-ethyl) -N- 메틸methyl -- 벤즈아미드Benzamide

제조에 36에서 얻은 화합물 0.25g(0.65mmol)을 10mL 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.22g을 96%의 수율로 얻었다. 0.25 g (0.65 mmol) of the compound obtained in Preparation 36 was dissolved in 10 mL of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.22 g of the title compound in a yield of 96%.

1H NMR (CDCl3 400MHz): δ(ppm) 7.14~7.11(3H, m), 7.05~7.01(1H, m), 6.95(1H, d, J=8.4), 6.68(1H, dd, =8.4, 2.8), 6.21~6.60(1H, m), 4.33~4.24(2H, m), 3.97~3.85(2H, m), 3.38~3.28(2H, m), 3.03(2H, s), 2.81(3H, s), 2.39(2H, t, J=7.6), 2.17(3H, s), 1.99(3H, s)1 H NMR (CDCl 3 400 MHz): δ (ppm) 7.14 to 7.11 (3H, m), 7.05 to 7.01 (1H, m), 6.95 (1H, d, J = 8.4), 6.68 (1H, dd, = 8.4, 2.8 ), 6.21-6.60 (1H, m), 4.33-4.24 (2H, m), 3.97-3.85 (2H, m), 3.38-3.28 (2H, m), 3.03 (2H, s), 2.81 (3H, s ), 2.39 (2H, t, J = 7.6), 2.17 (3H, s), 1.99 (3H, s)

[[ 실시예Example 33] 2-(3,4- 33] 2- (3,4- 디하이드로Dehydro -1H-이소퀴놀린-2-일)-N-(3-디메틸아미노-프로필)-5-이-1H-isoquinolin-2-yl) -N- (3-dimethylamino-propyl) -5-di 소부티릴아미Sobutyryl Army 노-N-No-N- 메틸methyl -- 벤즈아미드Benzamide

제조예 37에서 얻은 화합물 0.10g(0.27mmol)을 5mL N,N-디메틸포름아미드에 녹인 후 이소부틸릭산 0.033mL(0.37mmol), EDC 0.11g(0.59mmol), HOBT 0.081g(0.60mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(7:93) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.020g을 15%의 수율로 얻었다. 0.10 g (0.27 mmol) of the compound obtained in Preparation Example 37 was dissolved in 5 mL N, N-dimethylformamide, followed by 0.033 mL (0.37 mmol) of isobutyl acid, 0.11 g (0.59 mmol) of EDC, and 0.081 g (0.60 mmol) of HOBT. Put and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure and purified by column chromatography using methanol: dichloromethane (7:93) mixed solvent to obtain 0.020 g of the title compound in a yield of 15%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.35(1H, s), 8.17(1H, s), 7.84~7.79(1H, m), 7.24(1H, dd, J=11.6, 2.4), 7.17~7.13(3H, m), 7.08~7.01(2H, m), 4.38~4.32(1H, m), 4.06~3.96(1H, m), 3.42~3.28(2H, m), 3.04(2H, s), 2.93(2H, t, J=5.6), 2.81(3H, s), 2.61~2.55(1H, m), 2.34~2.26(2H, m), 2.13(3H, s), 1.94(3H, s), 1.23(6H, t, J=6.0). 13C NMR (CDCl3 100MHz) : δ(ppm) 175.7, 175.5, 171.2, 170.9, 145.0, 134.9, 134.7, 134.3, 134.2, 134.1, 133.7, 132.4, 131.6, 128.96, 128.92, 128.8, 126.5, 126.3, 126.28, 125.84, 128.82, 122.1, 121.8, 120.4, 119.9, 119.6, 118.9, 57.3, 56.0, 54.8, 53.5, 51.4, 50.4, 48.8, 45.5, 45.4, 36.9, 36.3, 36.2, 33.2, 29.7, 29.6, 19.73, 19.71, 19.61 H NMR (CDCl3 400 MHz): δ (ppm) 8.35 (1H, s), 8.17 (1H, s), 7.84-7.79 (1H, m), 7.24 (1H, dd, J = 11.6, 2.4), 7.17-7.13 (3H, m), 7.08-7.01 (2H, m), 4.38-4.32 (1H, m), 4.06-3.96 (1H, m), 3.42-3.28 (2H, m), 3.04 (2H, s), 2.93 (2H, t, J = 5.6), 2.81 (3H, s), 2.61-2.55 (1H, m), 2.34-2.26 (2H, m), 2.13 (3H, s), 1.94 (3H, s), 1.23 (6H, t, J = 6.0). 13C NMR (CDCl3 100 MHz): δ (ppm) 175.7, 175.5, 171.2, 170.9, 145.0, 134.9, 134.7, 134.3, 134.2, 134.1, 133.7, 132.4, 131.6, 128.96, 128.92, 128.8, 126.5, 126.3, 126.28, 125.84 , 128.82, 122.1, 121.8, 120.4, 119.9, 119.6, 118.9, 57.3, 56.0, 54.8, 53.5, 51.4, 50.4, 48.8, 45.5, 45.4, 36.9, 36.3, 36.2, 33.2, 29.7, 29.6, 19.73, 19.71, 19.6

[[ 제조예Production Example 38] 5-니트로-2-피페리딘-1-일-벤조산 38] 5-nitro-2-piperidin-1-yl-benzoic acid

2-플루오르-5-니트로벤조산 0.20g(1.1mmol)을 15ml의 아세토니트릴에 녹인 후, 피페리딘 0.2ml(2.0mmol)을 가하고 12시간 동안 환류시키며 끓여주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 1N 염화수소 수용액으로 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 감압여과하고 에틸아세테이트를 감압증류로 제거하여 표제 화합물 0.16g을 61%의 수율로 얻었다. 0.20 g (1.1 mmol) of 2-fluoro-5-nitrobenzoic acid was dissolved in 15 ml of acetonitrile, and then 0.2 ml (2.0 mmol) of piperidine was added and boiled under reflux for 12 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed with 1N aqueous hydrogen chloride solution. Water was removed with magnesium sulfate, and the residue was filtered under reduced pressure and ethyl acetate was removed by distillation under reduced pressure to obtain 0.16 g of the title compound in a yield of 61%.

1H NMR (CDCl3+CD3OD 400MHz) : δ(ppm) 9.00(1H, d, J=2.76), 8.40(1H, dd, J=8.89, 2.78), 7.55(1H, d, J=8.90), 3.14(4H, t, J=5.35), 1.89(4H, p, J=5.72), 1.73(2H, p, J=5.66)1 H NMR (CDCl 3 + CD 3 OD 400 MHz): δ (ppm) 9.00 (1H, d, J = 2.76), 8.40 (1H, dd, J = 8.89, 2.78), 7.55 (1H, d, J = 8.90), 3.14 ( 4H, t, J = 5.35), 1.89 (4H, p, J = 5.72), 1.73 (2H, p, J = 5.66)

[[ 제조예Production Example 39] N-(3-디메틸아미노-프로필)-5-니트로-2-피페리딘-1-일- 39] N- (3-dimethylamino-propyl) -5-nitro-2-piperidin-1-yl- 벤즈아미드Benzamide

제조예 38에서 얻은 화합물 0.16g(0.66mmol)을 15ml N,N-디메틸포름아미드에 녹인 후 3-디메틸아미노프로필아민 0.14ml(1.1mmol), EDC 0.27g(1.4mmol), HOBT 0.23g(1.7mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 클로로포름:메탄올:암모니아 수용액(80:10:1)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.20g을 90%의 수율로 얻었다. 0.16 g (0.66 mmol) of the compound obtained in Preparation Example 38 was dissolved in 15 ml N, N-dimethylformamide, followed by 0.14 ml (1.1 mmol) of 3-dimethylaminopropylamine, 0.27 g (1.4 mmol) of EDC, and 0.23 g (1.7 HOBT). mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure and purified by column chromatography using chloroform: methanol: ammonia aqueous solution (80: 10: 1) to obtain 0.20 g of the title compound in a yield of 90%.

1H NMR (CDCl3 400MHz) : δ(ppm) 8.71(1H, d, J=2.83), 8.68(1H, t), 8.17(1H, dd, J=8.95, 2.87), 7.14(1H, d, J=9.00), 3.54(2H, q, J=5.87), 3.09(4H, t, J=5.12), 2.39(4H, t, J=6.99), 2.24(6H, s), 1.82-1.73(6H, m), 1.64(2H, m)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.71 (1H, d, J = 2.83), 8.68 (1H, t), 8.17 (1H, dd, J = 8.95, 2.87), 7.14 (1H, d, J = 9.00), 3.54 (2H, q, J = 5.87), 3.09 (4H, t, J = 5.12), 2.39 (4H, t, J = 6.99), 2.24 (6H, s), 1.82-1.73 (6H, m ), 1.64 (2H, m)

[[ 제조예Production Example 40] 5-아미노-N-(3-디메틸아미노-프로필)-2-피페리딘-1-일- 40] 5-amino-N- (3-dimethylamino-propyl) -2-piperidin-1-yl- 벤즈아미드Benzamide

제조예 39에서 얻은 화합물 0.19g(0.58mmol)을 10ml 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.16g을 91%의 수율로 얻었다. 0.19 g (0.58 mmol) of the compound obtained in Preparation Example 39 was dissolved in 10 ml of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.16 g of the title compound in 91% yield.

1H NMR (CDCl3 400MHz): δ(ppm) 10.89(1H, s), 7.58(1H, d, J=3.2), 7.06(1H, d, J=8.4), 6.73(1H, dd, J=8.4, 2.8), 3.84(2H, br s), 3.48(2H, q, J=7.2), 2.82(4H, t, J=4.8), 2.40(2H, t, J=7.6), 2.26(6H, s), 1.83(2H, p, J=7.6), 1.71(4H, p, J=5.6), 1.58(2H, br s)1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.89 (1H, s), 7.58 (1H, d, J = 3.2), 7.06 (1H, d, J = 8.4), 6.73 (1H, dd, J = 8.4, 2.8), 3.84 (2H, br s), 3.48 (2H, q, J = 7.2), 2.82 (4H, t, J = 4.8), 2.40 (2H, t, J = 7.6), 2.26 (6H, s) , 1.83 (2H, p, J = 7.6), 1.71 (4H, p, J = 5.6), 1.58 (2H, br s)

[[ 실시예Example 34] N-(3-디메틸아미노-프로필)-5-(4- 34] N- (3-dimethylamino-propyl) -5- (4- 헥실Hexyl -- 벤조일아미노Benzoylamino )-2-피페리딘-1-일-벤) -2-piperidin-1-yl-bene 즈아미드Zamide

제조예 40에서 얻은 화합물 0.091g(0.30mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, 4-헥실벤조산 0.065ml(0.32mmol), EDC 0.15g(0.78mmol), HOBT 0.140g(1.0mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(5:95)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.053g을 36%의 수율로 얻었다. 0.091 g (0.30 mmol) of the compound obtained in Preparation Example 40 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.065 ml (0.32 mmol) of 4-hexylbenzoic acid, 0.15 g (0.78 mmol) of EDC, and 0.140 g (1.0 of HOBT). mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using methanol: dichloromethane (5:95) to obtain 0.053 g of the title compound in a yield of 36%.

1H NMR (CDCl3 400MHz) : δ(ppm) 10.54(1H, t, J=5.48), 9.06(1H, s), 8.40(1H, dd, J=8.70, 2.64), 8.18(1H, d, J=2.68), 7.87(1H, d, J=8.20), 7.26(3H, t, J=5.36), 3.26(2H, q, J=7.04), 2.88(4H, t, J=4.62), 2.65(2H, t, J=7.55), 2.25(2H, t, J=2.99), 2.20(6H, s), 1.73-1.66(6H, m), 1.63-1.60(4H, m), 1.33(6H, m), 0.88(3H, t, J=6.64). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.5, 166.4, 158.6, 147.5, 136.0, 132.7, 131.6, 129.0, 128.1, 127.9, 124.4, 123.2, 122.3, 57.7, 55.21, 45.8, 38.0, 36.2, 32.0, 31.6, 29.3, 28.2, 27.1, 24.0, 23.3, 14.51 H NMR (CDCl 3 400 MHz): δ (ppm) 10.54 (1H, t, J = 5.48), 9.06 (1H, s), 8.40 (1H, dd, J = 8.70, 2.64), 8.18 (1H, d, J = 2.68), 7.87 (1H, d, J = 8.20), 7.26 (3H, t, J = 5.36), 3.26 (2H, q, J = 7.04), 2.88 (4H, t, J = 4.62), 2.65 (2H , t, J = 7.55), 2.25 (2H, t, J = 2.99), 2.20 (6H, s), 1.73-1.66 (6H, m), 1.63-1.60 (4H, m), 1.33 (6H, m) , 0.88 (3H, t, J = 6.64). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.5, 166.4, 158.6, 147.5, 136.0, 132.7, 131.6, 129.0, 128.1, 127.9, 124.4, 123.2, 122.3, 57.7, 55.21, 45.8, 38.0, 36.2, 32.0, 31.6 , 29.3, 28.2, 27.1, 24.0, 23.3, 14.5

[[ 제조예Production Example 41] 2-[4-(2- 41] 2- [4- (2- 메톡시Methoxy -- 페닐Phenyl )-피페라진-1-일]-5-니트로-벤조산) -Piperazin-1-yl] -5-nitro-benzoic acid

2-플루오르-5-니트로벤조산 0.11g(0.53mmol)을 15ml의 아세토니트릴에 녹인 후, 1-(2-메톡시페닐)피페라진 0.15ml(0.85mmol)을 가하고 12시간 동안 환류시키며 끓여주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 5% 시트르산 수용액으로 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 감압여과하고 에틸아세테이트를 감압증류로 제거하여 표제 화합물 0.24g을 정량적으로 얻었다. 0.11 g (0.53 mmol) of 2-fluoro-5-nitrobenzoic acid was dissolved in 15 ml of acetonitrile, and then 0.15 ml (0.85 mmol) of 1- (2-methoxyphenyl) piperazine was added and boiled under reflux for 12 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed with 5% citric acid aqueous solution. Water was removed with magnesium sulfate, and the residue was filtered under reduced pressure and ethyl acetate was removed by distillation under reduced pressure to obtain 0.24 g of the title compound.

1H NMR (CDCl3+CD3OD 400MHz) : δ(ppm) 9.05(1H, d, J=2.76), 8.44(1H, dd, J=8.87, 2.79), 7.62(1H, d, J=8.87), 7.10(1H, td), 7.03-6.92(3H, m), 3.91(3H, s), 3.36(8H, s)1 H NMR (CDCl 3 + CD 3 OD 400 MHz): δ (ppm) 9.05 (1H, d, J = 2.76), 8.44 (1H, dd, J = 8.87, 2.79), 7.62 (1H, d, J = 8.87), 7.10 ( 1H, td), 7.03-6.92 (3H, m), 3.91 (3H, s), 3.36 (8H, s)

[[ 제조예Production Example 42] N-(3-디메틸아미노-프로필)-2-[4-(2- 42] N- (3-dimethylamino-propyl) -2- [4- (2- 메톡시Methoxy -- 페닐Phenyl )-피페라진-1-일]-5-니트로-) -Piperazin-1-yl] -5-nitro- 벤즈아미드Benzamide

제조예 41에서 얻은 화합물 0.24g(0.67mmol)을 15ml N,N-디메틸포름아미드에 녹인 후 3-디메틸아미노프로필아민 0.17ml(1.3mmol), EDC 0.26g(1.4mmol), HOBT 0.30g(2.2mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(7:93)를 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.23g을 77%의 수율로 얻었다. 0.24 g (0.67 mmol) of the compound obtained in Preparation Example 41 was dissolved in 15 ml N, N-dimethylformamide, followed by 0.17 ml (1.3 mmol) of 3-dimethylaminopropylamine, 0.26 g (1.4 mmol), and BT0 0.30 g (2.2). mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. After removing water with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using methanol: dichloromethane (7:93) to obtain 0.23 g of the title compound in a yield of 77%.

1H NMR (CDCl3 400MHz) : δ(ppm) 8.70(1H, d, J=2.78), 8.61(1H, t, J=5.42), 8.22(1H, dd, J=8.93, 2.77), 7.19(1H, d, J=8.97), 7.06(1H, td, J=6.19, 2.45), 6.99-6.90(3H, m), 3.90(3H, s), 3.33(2H, q, J=5.95), 3.37(4H, t, J=5.11), 3.26(4H, t, J=4.78), 2.41(2H, t, J=6.84), 2.23(6H, s), 1.80(2H, p, J=6.81)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.70 (1H, d, J = 2.78), 8.61 (1H, t, J = 5.42), 8.22 (1H, dd, J = 8.93, 2.77), 7.19 (1H, d, J = 8.97), 7.06 (1H, td, J = 6.19, 2.45), 6.99-6.90 (3H, m), 3.90 (3H, s), 3.33 (2H, q, J = 5.95), 3.37 (4H , t, J = 5.11), 3.26 (4H, t, J = 4.78), 2.41 (2H, t, J = 6.84), 2.23 (6H, s), 1.80 (2H, p, J = 6.81)

[[ 제조예Production Example 43] 5-아미노-N-(3-디메틸아미노-프로필)-2-[4-(2- 43] 5-amino-N- (3-dimethylamino-propyl) -2- [4- (2- 메톡시Methoxy -- 페닐Phenyl )-피페라진-1-일]-) -Piperazin-1-yl]- 벤즈아미드Benzamide

제조예 42에서 얻은 화합물 0.21g(0.48mmol)을 10ml 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.19g을 98%의 수율로 얻었다. 0.21 g (0.48 mmol) of the compound obtained in Preparation Example 42 was dissolved in 10 ml of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.19 g of the title compound in a yield of 98%.

1H NMR (CDCl3 400MHz) : δ(ppm) 10.76(1H, t, J=5.36), 7.57(1H, d, J=2.82), 7.16(1H, d, J=8.46), 7.07-6.93(3H, m), 6.90(1H, d, J=7.98), 6.76(1H, dd, J=8.42, 2.85), 3.88(3H, s), 3.49(2H, q, J=6.65), 3.22(4H, s), 3.11(4H, s), 2.52(2H, t, J=7.18), 2.33(6H, s), 1.89(2H, p, J=7.28) 3.22(4H, s), 3.11(4H, s), 2.52(2H, t), 2.33(6H, s), 1.89(2H, p)1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.76 (1H, t, J = 5.36), 7.57 (1H, d, J = 2.82), 7.16 (1H, d, J = 8.46), 7.07-6.93 (3H, m), 6.90 (1H, d, J = 7.98), 6.76 (1H, dd, J = 8.42, 2.85), 3.88 (3H, s), 3.49 (2H, q, J = 6.65), 3.22 (4H, s ), 3.11 (4H, s), 2.52 (2H, t, J = 7.18), 2.33 (6H, s), 1.89 (2H, p, J = 7.28) 3.22 (4H, s), 3.11 (4H, s) , 2.52 (2H, t), 2.33 (6H, s), 1.89 (2H, p)

[[ 실시예Example 35] 5-(4-부틸- 35] 5- (4-butyl- 벤조일아미노Benzoylamino )-N-(3-디메틸아미노-프로필)-2-[4-(2-) -N- (3-dimethylamino-propyl) -2- [4- (2- 메톡시Methoxy -페닐)-피페라진-1-일]--Phenyl) -piperazin-1-yl]- 벤즈아미드Benzamide

제조예 43에서 얻은 화합물 0.093g(0.47mmol)을 5ml의 N,N-디메틸포름아미드에 녹인 후, 4-부틸벤조산 0.085g(0.48mmol), EDC 0.24g(1.3mmol), HOBT 0.13g(1.4mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(5:95)을 이용한 컬럼크로마토그래피로 정제하여 표제 화합물 0.20g을 73%의 수율로 얻었다. 0.093 g (0.47 mmol) of the compound obtained in Preparation Example 43 was dissolved in 5 ml of N, N-dimethylformamide, followed by 0.085 g (0.48 mmol) of 4-butylbenzoic acid, 0.24 g (1.3 mmol) of EDC, and 0.13 g (1.4 of HOBT). mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using methanol: dichloromethane (5:95) to obtain 0.20 g of the title compound in a yield of 73%.

1H NMR (CDCl3 400MHz) : δ(ppm) 10.29(1H, t), 9.59(1H, s), 8.44(1H, dd, J=8.68, 2.60), 8.31(1H, d), 7.91(2H, d, J=8.08), 7.34(1H, d, J=8.76), 7.22(2H, d, J=8.08), 7.03(1H, td, J=7.12, 2.24), 6.97-6.88(3H, m), 3.89(3H, s), 3.22(6H, m), 3.14(4H, s), 2.63(2H, t, J=7.35), 2.19(2H, t, J=7.03), 2.15(6H, s), 1.64-1.59(4H, m), 1.34(2H, p, J=7.47), 0.91(3H, t, J=7.31). 13C NMR (CDCl3 100MHz) : δ(ppm) 166.7, 166.5, 152.5, 147.2, 147.1, 141.0, 136.6, 132.8, 128.8, 128.3, 128.1, 124.6 123.9, 123.7, 122.1, 121.4, 118.5, 111.7, 57.6, 55.8, 53.9, 51.7, 46.7, 45.4, 45.1, 44.9, 39.0, 35.8, 33.6, 30.7, 30.0, 29.3, 26.4, 24.1, 23.3, 22.7, 22.6, 15.1, 14.3 1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.29 (1H, t), 9.59 (1H, s), 8.44 (1H, dd, J = 8.68, 2.60), 8.31 (1H, d), 7.91 (2H, d , J = 8.08), 7.34 (1H, d, J = 8.76), 7.22 (2H, d, J = 8.08), 7.03 (1H, td, J = 7.12, 2.24), 6.97-6.88 (3H, m), 3.89 (3H, s), 3.22 (6H, m), 3.14 (4H, s), 2.63 (2H, t, J = 7.35), 2.19 (2H, t, J = 7.03), 2.15 (6H, s), 1.64-1.59 (4H, m), 1.34 (2H, p, J = 7.47), 0.91 (3H, t, J = 7.31). 13C NMR (CDCl3 100 MHz): δ (ppm) 166.7, 166.5, 152.5, 147.2, 147.1, 141.0, 136.6, 132.8, 128.8, 128.3, 128.1, 124.6 123.9, 123.7, 122.1, 121.4, 118.5, 111.7, 57.6, 55.8, 53.9, 51.7, 46.7, 45.4, 45.1, 44.9, 39.0, 35.8, 33.6, 30.7, 30.0, 29.3, 26.4, 24.1, 23.3, 22.7, 22.6, 15.1, 14.3

[[ 제조예44Preparation Example 44 ] {2-[4-(2-] {2- [4- (2- 메톡시Methoxy -- 페닐Phenyl )-피페라진-1-일]-5-니트로-) -Piperazin-1-yl] -5-nitro- 페닐Phenyl }-피페라진-1-일-} -Piperazin-1-yl- 메타논Metanon

제조예 41에서 얻은 화합물 0.10g(0.28mmol)을 5mL N,N-디메틸포름아미드에 녹인 후 피페리딘 0.033mL(0.33mmol), EDC 0.11g(0.56mmol), HOBT 0.083g(0.61mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 헥세인:에틸아세테이트(1:1) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.12g을 99%의 수율로 얻었다. 0.10 g (0.28 mmol) of the compound obtained in Preparation Example 41 was dissolved in 5 mL N, N-dimethylformamide, followed by 0.033 mL (0.33 mmol) of piperidine, 0.11 g (0.56 mmol) of EDC, and 0.083 g (0.61 mmol) of HOBT. Put and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using hexane: ethyl acetate (1: 1) mixed solvent to obtain 0.12 g of the title compound in a yield of 99%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.19(1H, dd, J=8.8, 2.8), 8.15(1H, d, J=2.8), 7.08~6.98(2H, m), 6.96(2H, d, J=4.0), 6.90(1H, d, J=8.0), 3.97~3.84(1H, m), 3.89(3H, s), 3.63~3.50(3H, m), 3.35~3.30(2H, m), 3.22~3.14(6H, m), 1.72~1.62(6H, m)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.19 (1H, dd, J = 8.8, 2.8), 8.15 (1H, d, J = 2.8), 7.08-6.98 (2H, m), 6.96 (2H, d, J = 4.0), 6.90 (1H, d, J = 8.0), 3.97-3.84 (1H, m), 3.89 (3H, s), 3.63-3.50 (3H, m), 3.35-3.30 (2H, m), 3.22-3.14 (6H, m), 1.72-1.62 (6H, m)

[[ 제조예Production Example 45] {5-아미노-2-[4-(2- 45] {5-amino-2- [4- (2- 메톡시Methoxy -- 페닐Phenyl )-피페라진-1-일]-) -Piperazin-1-yl]- 페닐Phenyl }-피페리딘-1-일-메} -Piperidin-1-yl-meth 타논Thanon

제조예 44에서 얻은 화합물 0.11g(0.26mmol)을 10mL 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물을 정량적으로 얻었다. 1H NMR (CDCl3 400MHz): δ(ppm) 7.01~7.02(2H, m), 6.98~6.93(2H, m), 6.88(1H, d, J=8.0), 6.77(1H, d, J=8.4), 6.72(1H, s), 3.87(3H, s), 3.71(2H, br s), 3.18(8H, br s), 1.64(8H, br s)0.11 g (0.26 mmol) of the compound obtained in Preparation Example 44 was dissolved in 10 mL methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain the title compound quantitatively. 1 H NMR (CDCl 3 400 MHz): δ (ppm) 7.01 to 7.02 (2H, m), 6.98 to 6.63 (2H, m), 6.88 (1H, d, J = 8.0), 6.77 (1H, d, J = 8.4) , 6.72 (1H, s), 3.87 (3H, s), 3.71 (2H, br s), 3.18 (8H, br s), 1.64 (8H, br s)

[[ 실시예Example 36] 4-부틸-N-[4-[4-(2- 36] 4-butyl-N- [4- [4- (2- 메톡시Methoxy -- 페닐Phenyl )-피페라진-1-일]-3-(피페리딘-1-) -Piperazin-1-yl] -3- (piperidin-1- 카보닐Carbonyl )-) - 페닐Phenyl ]-]- 벤즈아미드Benzamide

제조예 45에서 얻은 화합물 0.11g(0.13mmol)을 5mL 디클로로메테인에 녹인 후 피리딘 0.027mL(0.51mmol)을 넣고 10분간 교반해주었다. 531번 화합물(4-부틱벤조일 클로라이드)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 헥세인:에틸아세테이트(1:1) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.073g을 51%의 수율로 얻었다. 0.11 g (0.13 mmol) of the compound obtained in Preparation Example 45 was dissolved in 5 mL dichloromethane, and then pyridine 0.027 mL (0.51 mmol) was added and stirred for 10 minutes. Compound 531 (4-butybenzoyl chloride) was added thereto, followed by stirring for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using hexane: ethyl acetate (1: 1) mixed solvent to obtain 0.073 g of the title compound in a yield of 51%.

1H NMR (CDCl3 400MHz): δ(ppm) 9.15(1H, s), 8.00(1H, dd, J=8.8, 2.8), 7.90(2H, d, J=8.0), 6.96~6.88(3H, m), 3.88(3H, s), 3.81~3.78(1H, m), 3.54~3.51(1H, m), 3.34~.30(2H,m), 3.25~3.11(4H, m), 3.00~2.93(4H, m), 2.63(2H, t, J=7.6), 1.61~1.54(8H, m), 1.34~1.24(2H, m), 0.90(3H, t, J=7.2). 13C NMR (CDCl3 100MHz): δ(ppm) 169.4, 165.9, 152.3, 146.9, 145.2, 141.1, 134.1, 132.3,131.8, 128.4, 127.6, 123.1, 122.4, 120.9, 120.7, 119.1, 118.0, 111.3, 55.4, 52.4, 52.1, 48.1, 42.6, 35.6, 33.4, 26.2, 25.7, 24.5, 22.4, 13.91 H NMR (CDCl 3 400 MHz): δ (ppm) 9.15 (1H, s), 8.00 (1H, dd, J = 8.8, 2.8), 7.90 (2H, d, J = 8.0), 6.96-6.88 (3H, m) , 3.88 (3H, s), 3.81 ~ 3.78 (1H, m), 3.54 ~ 3.51 (1H, m), 3.34 ~ .30 (2H, m), 3.25 ~ 3.11 (4H, m), 3.00 ~ 2.93 (4H , m), 2.63 (2H, t, J = 7.6), 1.61-1.54 (8H, m), 1.34-1.24 (2H, m), 0.90 (3H, t, J = 7.2). 13C NMR (CDCl3 100 MHz): δ (ppm) 169.4, 165.9, 152.3, 146.9, 145.2, 141.1, 134.1, 132.3, 131.8, 128.4, 127.6, 123.1, 122.4, 120.9, 120.7, 119.1, 118.0, 111.3, 55.4, 52.4 , 52.1, 48.1, 42.6, 35.6, 33.4, 26.2, 25.7, 24.5, 22.4, 13.9

[[ 제조예Production Example 46] 3-니트로-6-(4- 46] 3-nitro-6- (4- 페닐Phenyl -피페라진-1-일)-Piperazin-1-yl) 시클로헥사Cyclohexa -2,4--2,4- 디엔카복실산Dienecarboxylic acid

2-플루오르-5-니트로벤조산 0.10g(0.54mmol)을 15mL의 아세토니트릴에 녹인 후, 1-페닐피페라진 0.12mL(0.81mmol)을 가하고 12시간 동안 환류시키며 끓여주었다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 1N 염화수소 수용액으로 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 감압여과하고 에틸아세테이트를 감압증류로 제거하여 표제 화합물 0.16g을 89%의 수율로 얻었다. 0.10 g (0.54 mmol) of 2-fluoro-5-nitrobenzoic acid was dissolved in 15 mL of acetonitrile, and then 0.12 mL (0.81 mmol) of 1-phenylpiperazine was added and boiled under reflux for 12 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed with 1N aqueous hydrogen chloride solution. Water was removed with magnesium sulfate, and the residue was filtered under reduced pressure and ethyl acetate was removed by distillation under reduced pressure to obtain 0.16 g of the title compound in a yield of 89%.

1H NMR(CDCl3+CD3OD 400MHz): δ(ppm) 9.03(1H, d, J=2.8 Hz), 8.42(1H, dd, J=8.8, 2.8 Hz), 7.52(1H, d, J=9.2 Hz), 7.34(2H, t, J=8.0 Hz), 7.03-6.97(3H, m), 3.46(4H, d, J=4.8 Hz), 3.36(4H, br s)1 H NMR (CDCl 3 + CD 3 OD 400 MHz): δ (ppm) 9.03 (1H, d, J = 2.8 Hz), 8.42 (1H, dd, J = 8.8, 2.8 Hz), 7.52 (1H, d, J = 9.2 Hz) , 7.34 (2H, t, J = 8.0 Hz), 7.03-6.97 (3H, m), 3.46 (4H, d, J = 4.8 Hz), 3.36 (4H, br s)

[[ 제조예Production Example 47] 3-니트로-6-(4- 47] 3-nitro-6- (4- 페닐Phenyl -피페라진-1-일)-Piperazin-1-yl) 시클로헥사Cyclohexa -2,4--2,4- 디엔카복실산Dienecarboxylic acid (3- 디메틸아미노-프로필)-아미드(3-dimethylamino-propyl) -amide

제조예 46에서 얻은 화합물 0.16g(0.48mmol)을 15mL N,N-디메틸포름아미드에 녹인 후 3-디메틸아미노프로필아민 0.072mL(0.57mmol), EDC 0.19g(0.99mmol), HOBT 0.15g(1.1mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 메탄올:디클로로메테인(5:95) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.084g을 43%의 수율로 얻었다. 0.16 g (0.48 mmol) of the compound obtained in Preparation Example 46 was dissolved in 15 mL N, N-dimethylformamide, followed by 0.072 mL (0.57 mmol) of 3-dimethylaminopropylamine, 0.19 g (0.99 mmol), and HOBT 0.15 g (1.1). mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography using methanol: dichloromethane (5:95) mixed solvent to obtain 0.084 g of the title compound in a yield of 43%.

1H NMR (CDCl3 400MHz): δ(ppm) 8.67(1H, d, J=2.8 Hz), 8.48(1H, t, J=5.2 Hz), 8.21(1H, dd, J=8.8, 2.8 Hz), 7.31(2H, t, J=8.4 Hz), 7.15(1H, d, J=8.8 Hz), 6.98-6,91(3H, m), 3.54(2H, q, J=6.4 Hz), 3.47-3.32(8H, m), 2.37(2H, t, J=6.8 Hz), 2.19(6H, s), 1.77(2H, p, J=6.4 Hz)1 H NMR (CDCl 3 400 MHz): δ (ppm) 8.67 (1H, d, J = 2.8 Hz), 8.48 (1H, t, J = 5.2 Hz), 8.21 (1H, dd, J = 8.8, 2.8 Hz), 7.31 (2H, t, J = 8.4 Hz), 7.15 (1H, d, J = 8.8 Hz), 6.98-6,91 (3H, m), 3.54 (2H, q, J = 6.4 Hz), 3.47-3.32 ( 8H, m), 2.37 (2H, t, J = 6.8 Hz), 2.19 (6H, s), 1.77 (2H, p, J = 6.4 Hz)

[[ 제조예Production Example 48] 3-아미노-6-(4- 48] 3-amino-6- (4- 페닐Phenyl -피페라진-1-일)-Piperazin-1-yl) 시클로헥사Cyclohexa -2,4--2,4- 디엔카복실산Dienecarboxylic acid (3-디메틸아미노-프로필)-아미드(3-dimethylamino-propyl) -amide

제조예 47에서 얻은 화합물 0.21g(0.48mmol)을 10mL 메탄올에 녹인 후 팔라듐 촉매를 넣고 수소공기 하에서 1시간 동안 교반하여 주었다. 셀라이트를 이용한 감압여과로 고체를 제거하고 용매를 감압증류로 제거하여 표제 화합물 0.19g을 98%의 수율로 얻었다. 0.21 g (0.48 mmol) of the compound obtained in Preparation Example 47 was dissolved in 10 mL of methanol, and a palladium catalyst was added thereto, followed by stirring for 1 hour under hydrogen air. The solid was removed by vacuum filtration using celite and the solvent was removed by distillation under reduced pressure to obtain 0.19 g of the title compound in a yield of 98%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.54(1H, t, J=5.6 Hz), 7.56(1H, d, J=2.8 Hz), 7.32-7.29(2H, m), 7.12(1H, d, J=8.4 Hz), 6.99(2H, d, J=8.4 Hz), 6.92(1H, t, J=7.2 Hz), 6.77(1H, dd, J=8.6, 2.8 Hz), 3.78(2H, br s), 3.48(2H, q, J=6.8 Hz), 3.34(4H, t, J=4.4 Hz), 3.09(4H, t, J=5.2 Hz), 2.55(2H, t, J=7.2 Hz), 2.35(6H, s), 1.89(2H, p, J=7.2 Hz)1 H NMR (CDCl 3 400 MHz): δ (ppm) 10.54 (1H, t, J = 5.6 Hz), 7.56 (1H, d, J = 2.8 Hz), 7.32-7.29 (2H, m), 7.12 (1H, d, J = 8.4 Hz), 6.99 (2H, d, J = 8.4 Hz), 6.92 (1H, t, J = 7.2 Hz), 6.77 (1H, dd, J = 8.6, 2.8 Hz), 3.78 (2H, br s ), 3.48 (2H, q, J = 6.8 Hz), 3.34 (4H, t, J = 4.4 Hz), 3.09 (4H, t, J = 5.2 Hz), 2.55 (2H, t, J = 7.2 Hz), 2.35 (6H, s), 1.89 (2H, p, J = 7.2 Hz)

[[ 실시예Example 37] N-(3-디메틸아미노-프로필)-5-(4-이소프로필- 37] N- (3-dimethylamino-propyl) -5- (4-isopropyl- 벤조일아미노Benzoylamino )-2-(4-) -2- (4- 페닐Phenyl -피페라진-1-일)-Piperazin-1-yl) 벤즈아미드Benzamide

제조예 48에서 얻은 화합물 0.081g(0.21mmol)을 5mL의 N,N-디메틸포름아미드에 녹인 후, 4-이소프로필벤조산 0.045g(0.27mmol), EDC 0.11g(0.56mmol), HOBT 0.080g(0.59mmol)을 넣고 4시간 동안 교반하였다. 용매를 감압증류로 제거한 다음 에틸아세테이트를 가하고 탄산나트륨 포화 수용액으로 세 번 씻어주었다. 마그네슘설페이트로 물을 제거한 다음 에틸아세테이트를 감압증류로 제거하고 클로로포름:메탄올:암모니아 수용액(100:10:1) 혼합용매를 이용한 칼럼크로마토그래피로 정제하여 표제 화합물 0.025g을 23%의 수율로 얻었다. 0.081 g (0.21 mmol) of the compound obtained in Preparation Example 48 was dissolved in 5 mL of N, N-dimethylformamide, followed by 0.045 g (0.27 mmol) of 4-isopropylbenzoic acid, 0.11 g (0.56 mmol) of EDC, and 0.080 g of HOBT ( 0.59 mmol) was added and stirred for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed three times with a saturated aqueous sodium carbonate solution. Water was removed with magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using a mixed solvent of chloroform: methanol: ammonia solution (100: 10: 1) to obtain 0.025 g of the title compound in a yield of 23%.

1H NMR (CDCl3 400MHz): δ(ppm) 10.07(1H, t, J=5.6 Hz), 8.64(1H, s), 8.40(1H, dd, J=8.8, 2.8 Hz), 8.08(1H, d, J=2.8 Hz), 7.86(3H, d, J=8.4 Hz), 7.34-7.29(5H, m), 6.98(2H, d, J=8 Hz), 6.93(1H, t, J=7.2 Hz), 3.39-3.33(6H, m), 3.14(4H, m), 3.03-2.90(1H, m), 2.26(2H, t, J=7.2 Hz), 2.16(6H, s), 1.70(2H, t, J=7.2 Hz), 1.28(6H, d, J=6.8 Hz). 13C NMR (CDCl3 100MHz): δ(ppm) 165.93, 165.91, 153.2, 150.8, 146.7, 135.8, 132.3, 129.3, 128.2, 127.5, 126.8, 124.0, 122.9, 121.6, 120.5, 116.4, 57.4, 53.4, 50.0, 45.5, 37.8, 34.2, 28.0, 23.81 H NMR (CDCl 3 400 MHz): δ (ppm) 10.07 (1H, t, J = 5.6 Hz), 8.64 (1H, s), 8.40 (1H, dd, J = 8.8, 2.8 Hz), 8.08 (1H, d, J = 2.8 Hz), 7.86 (3H, d, J = 8.4 Hz), 7.34-7.29 (5H, m), 6.98 (2H, d, J = 8 Hz), 6.93 (1H, t, J = 7.2 Hz) , 3.39-3.33 (6H, m), 3.14 (4H, m), 3.03-2.90 (1H, m), 2.26 (2H, t, J = 7.2 Hz), 2.16 (6H, s), 1.70 (2H, t , J = 7.2 Hz), 1.28 (6H, d, J = 6.8 Hz). 13C NMR (CDCl3 100 MHz): δ (ppm) 165.93, 165.91, 153.2, 150.8, 146.7, 135.8, 132.3, 129.3, 128.2, 127.5, 126.8, 124.0, 122.9, 121.6, 120.5, 116.4, 57.4, 53.4, 50.0, 45.5 , 37.8, 34.2, 28.0, 23.8

생물학적 활성시험Biological Activity Test

[실험예] 본 발명에 따른 화합물들의 암세포 성장 억제 효능 실험Experimental Example Experiments for Inhibiting Cancer Cell Growth of Compounds According to the Present Invention

HN4 (현대 아산 병원, 한국), Caki (ATCC HTB46/ATCC HTB-47) 및 HepG2 (ATCC, HB-8065) 종양세포는 10% heat-inactivated fetal bovine serum, 100 U/ml penicillin, 100 mg/ml streptomycin이 함유된 Dulbecco's modified Eagle's medium을 이용해 배양하였다. A549 (ATCC CCL 185) 종양세포는 10% heat-inactivated fetal bovine serum, 100 U/ml penicillin, 100 mg/ml streptomycin이 함유된 RPMI 1640 medium을 이용하여 배양하였다. HN4 (Hyundai Asan Hospital, Korea), Caki (ATCC HTB46 / ATCC HTB-47) And HepG2 (ATCC, HB-8065) tumor cells were cultured using Dulbecco's modified Eagle's medium containing 10% heat-inactivated fetal bovine serum, 100 U / ml penicillin, and 100 mg / ml streptomycin. A549 (ATCC CCL 185) Tumor cells were cultured using RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum, 100 U / ml penicillin, and 100 mg / ml streptomycin.

화합물의 종양세포 성장억제 효능을 측정하기 위하여 먼저 각 종양 세포를 상기배지에 2.5-3 x 103 cell /100 ul 농도로 부유시킨 후 96-Well plates에 100 ul 씩 분주하고, 24시간 배양하여 세포를 안정화 시켰다. In order to measure the tumor cell growth inhibition effect of the compound, each tumor cell was first suspended in the medium at a concentration of 2.5-3 x 10 3 cells / 100 ul, and then divided into 100-ul in 96-Well plates and cultured for 24 hours. Stabilized.

여기에 합성된 각종 화합물을 최종 10 uM 농도로 첨가하여 72시간 배양하였으며, 첨가한 화합물이 각종 종양세포 성장에 미치는 영향은 2,3-Bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt (XTT) assay를 이용하여 측정하였다. Various synthesized compounds were added to the final 10 uM concentration and incubated for 72 hours. The effect of the added compounds on the growth of various tumor cells was 2,3-Bis (2-methoxy-4-nitro-5-sulfophenyl)- 2H-tetrazolium-5-carboxanilide inner salt (XTT) assay was used.

간기하면 XTT 시약 1 ml와 phenazine methosulfate 시약 20 ul를 혼합한 후, 이 혼합물을 세포가 든 각 well에 20 ul 씩 첨가하였으며, 37℃, 5% CO2 배양기 속에서 4시간 동안 반응시킨 후 spectrophotometer를 이용하여 450 nm의 파장에서 흡광도(OD)를 측정하였다. 또 화합물이 첨가되지 않고 동일한 조건으로 배양한 세포를 대조군으로 하여 XTT assay를 실시하고 OD를 측정하였다. In brief, 1 ml of XTT reagent and 20 ul of phenazine methosulfate reagent were mixed, and then the mixture was added to each well containing 20 ul of cells at 37 ° C. and 5% CO 2. After reacting for 4 hours in the incubator, the absorbance (OD) was measured at a wavelength of 450 nm using a spectrophotometer. In addition, the cells were cultured under the same conditions without addition of the compound as a control group was subjected to XTT assay and OD was measured.

화합물의 % 저해능 값은 다음의 공식에 의해 구하였다. The% inhibitory value of the compound was determined by the following formula.


% % 저해능Inhibition 값 = ( Value = ( 실험군Experimental group ODOD /대조군 / Control ODOD ) X 100 ) X 100

화학식 1의 대표적인 화합물들과 그들의 암세포들에 대해 측정된 성장억제능력을 화합물 농도 10 uM에서 % 저해능 값으로 나타낸 결과를 하기 표 1에 나타내었다. Table 1 shows the results of the growth inhibitory capacity measured for the representative compounds of Formula 1 and their cancer cells as a% inhibitory value at the compound concentration of 10 uM.

A549A549 HepG2HepG2 CakiCaki HN4HN4 1One 5757 5656 9191 8787 22 1212 7070 2424 2525 33 9595 9090 9090 7676 44 7474 6161 4343 2222 55 3939 7575 9292 7171 66 4040 5151 8686 7373 77 4141 1414 9090 7070 88 1One 1818 1515 22 99 22 22 22 6969 1010 77 nana 1One 1111 2727 nana 00 00 1212 nana 3535 1818 4242 1313 44 3333 2323 00 1414 1616 3030 55 3232 1515 1111 2222 22 2020 1616 00 nana 44 2323 1717 4242 1010 2222 5252 1818 55 00 00 3131 1919 44 00 33 2828 2020 44 00 33 2727 2121 44 nana 22 00 2222 4040 2929 7676 5656 2323 44 88 00 3737 2424 1919 2020 5151 6363 2525 88 3333 1313 88 2626 1515 1313 44 44 2727 66 1818 1616 1One 2828 22 1313 1111 00 2929 88 3333 1313 88 3030 2929 2727 22 1010 3131 2727 6969 8989 7979 3232 2525 5050 5454 6262 3333 55 66 00 3535 3434 9696 9090 9393 9191 3535 9696 9090 9393 9292 3636 1414 1111 00 4141 3737 9595 nana 6565 9393

* na는 측정하지 않은 것을 의미한다. * na means not measured.

상기의 결과에서 나타낸 바와 같이 본 발명의 화합물(I)은 비정상적 세포성장(세포증식)질환의 대표적인 암에 있어서, 암세포의 성장 억제에 매우 효과적임을 확인할 수 있다.As shown in the above results, the compound (I) of the present invention can be found to be very effective in inhibiting the growth of cancer cells in typical cancers of abnormal cell growth (cell proliferation) diseases.

특히, 그 중에서도 화합물 3의 N-(2-디에틸아미노-에틸)-5-(4-이소프로필-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-벤즈아미드; 화합물 22의 N-(3-디메틸아미노-프로필)-5-(4-이소프로필-벤조일아미노)-2-몰포린-4-일-벤즈아미드; 화합물 31 5-(2-클로로-아세틸아미노)-2-(3,4-디하이드로-1H-이소퀴놀린-2-일)-N-(3-메톡시-프로필)-벤즈아미드; 화합물 34의 N-(3-디메틸아미노-프로필)-5-(4-헥실-벤조일아미노)-2-피페리딘-1-일-벤즈아미드; 화합물 35의 5-(4-부틸-벤조일아미노)-N-(3-디메틸아미노-프로필)-2-[4-(2-메톡시-페닐)-피페라진-1-일]-벤즈아미드, 및 화합물 37의 N-(3-디메틸아미노-프로필)-5-(4-이소프로필-벤조일아미노)-2-(4-페닐-피페라진-1-일)-벤즈아미드의 암세포 성장 억제 효능이 우수함을 확인할 수 있다.In particular, N- (2-diethylamino-ethyl) -5- (4-isopropyl-benzoylamino) -2- (4-methyl-piperidin-1-yl) -benzamide of compound 3; N- (3-dimethylamino-propyl) -5- (4-isopropyl-benzoylamino) -2-morpholin-4-yl-benzamide of compound 22; Compound 31 5- (2-chloro-acetylamino) -2- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methoxy-propyl) -benzamide; N- (3-dimethylamino-propyl) -5- (4-hexyl-benzoylamino) -2-piperidin-1-yl-benzamide of compound 34; 5- (4-Butyl-benzoylamino) -N- (3-dimethylamino-propyl) -2- [4- (2-methoxy-phenyl) -piperazin-1-yl] -benzamide of compound 35, And the cancer cell growth inhibitory effect of N- (3-dimethylamino-propyl) -5- (4-isopropyl-benzoylamino) -2- (4-phenyl-piperazin-1-yl) -benzamide of compound 37 It can be confirmed that excellent.

Claims (10)

하기 화학식 (I)의 세포 증식 억제용 화합물 또는 약제학적으로 허용 가능한 이들의 염:A compound for inhibiting cell proliferation of formula (I) or Pharmaceutically acceptable salts thereof:
Figure 112010012127862-PAT00008
Figure 112010012127862-PAT00008
 상기 식 중 R1은 C1-C6 알킬 또는 아릴로 치환된 아민; C1-C6 알콕시, C1-C6 알킬 아미노, 몰포린, 피레리딘, 피롤리딘, 피페라진, 4-알킬피페라진 및 방향족 화합물로 구성된 군에서 선택된 하나 또는 그 이상의 치환기로 치환된 C1-C6 알킬 아민; 몰포린; 피레리딘; 피롤리딘; 피페라진; 및 4-알킬피페라진으로 구성된 군에서 선택되고,R 1 is an amine substituted with C 1 -C 6 alkyl or aryl; Substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkyl amino, morpholine, pyreridine, pyrrolidine, piperazine, 4-alkylpiperazine and aromatic compounds C 1 -C 6 alkyl amines; Morpholine; Pyreridine; Pyrrolidine; Piperazine; And 4-alkylpiperazine, R2는 C1-C6 알킬아민, 시클로알킬 및 방향족 화합물로 이루어진 군에서 선택된 하나 이상의 치환기로 치환된 아민; 몰포린; 피레리딘; 알킬피페리딘; 피롤리딘; 피페라진; 4-알킬피페라진; 할로겐 및 C1-C6 알콕시로 치환된 아릴 피페라진; 퀴놀린; 및 이소퀴놀린으로 구성된 군에서 선택되며,R 2 is an amine substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkylamines, cycloalkyls and aromatic compounds; Morpholine; Pyreridine; Alkyl piperidine; Pyrrolidine; Piperazine; 4-alkylpiperazine; Aryl piperazine substituted with halogen and C 1 -C 6 alkoxy; Quinoline; And isoquinoline, R3은 비치환 C1-C6 알킬아미드, 비치환 아릴아미드, 비치환 유레아; C1-C6 알킬, 시클로알킬 및 방향족 화합물로 이루어진 군에서 선택된 하나 이상의 치환기로 치환된 아미드; 할로겐, C1-C6 알킬아민, 몰포린, 피레리딘, 피롤리딘, 피페라진 및 4-알킬피페라진으로 이루어진 군에서 선택된 하나 이상의 치환기로 치환된 C1-C6 알킬 아미드; 및 할로겐, C1-C6 알킬아민, 몰포린, 피레리딘, 피롤리딘, 피페라진, 4-알킬피페라진으로 이루어진 군에서 선택된 하나 이상의 치환기로 치환된 방향족 아미드로 구성된 군에서 선택된다.R 3 is unsubstituted C 1 -C 6 alkylamide, unsubstituted arylamide, unsubstituted urea; Amides substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, cycloalkyl and aromatic compounds; C 1 -C 6 alkyl amide substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 6 alkylamine, morpholine, pyreridine, pyrrolidine, piperazine and 4-alkylpiperazine; And aromatic amides substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 6 alkylamine, morpholine, pyreridine, pyrrolidine, piperazine, 4-alkylpiperazine. 삭제delete 삭제delete 삭제delete 제 1 항에 있어서, The method of claim 1, 5-(2-클로로-아세틸아미노)-N-시클로프로필-2-(4-메틸-피페리딘-1-일)-벤즈아미드,5- (2-Chloro-acetylamino) -N-cyclopropyl-2- (4-methyl-piperidin-1-yl) -benzamide, 5-(4-tert-부틸l-벤조일아미노)-N-(2-디에틸아미노-에틸)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,5- (4-tert-butyll-benzoylamino) -N- (2-diethylamino-ethyl) -2- (4-methyl-piperidin-1-yl) -benzamide, N-(2-디에틸아미노-에틸)-5-(4-이소프로필-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,N- (2-Diethylamino-ethyl) -5- (4-isopropyl-benzoylamino) -2- (4-methyl-piperidin-1-yl) -benzamide, N-(2-디에틸아미노-에틸)-5-(4-헥실-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,N- (2-Diethylamino-ethyl) -5- (4-hexyl-benzoylamino) -2- (4-methyl-piperidin-1-yl) -benzamide, 5-(2-클로로-아세틸아미노)-N-(2-디에틸아미노-에틸)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,5- (2-Chloro-acetylamino) -N- (2-diethylamino-ethyl) -2- (4-methyl-piperidin-1-yl) -benzamide, 5-(2-클로로-아세틸아미노)-2-(4-메틸-피페리딘-1-일)-N-(2-몰포린-4-일-에틸)-벤즈아미드,5- (2-Chloro-acetylamino) -2- (4-methyl-piperidin-1-yl) -N- (2-morpholin-4-yl-ethyl) -benzamide, 2-클로로-N-[4-(4-메틸-피페리딘-1-일)-3-(몰포린-4-카보닐)-페닐]-아세트아미드,2-chloro-N- [4- (4-methyl-piperidin-1-yl) -3- (morpholin-4-carbonyl) -phenyl] -acetamide, 시클로프로판카복실산 [3-(4-메틸-피페라진-1-카보닐)-4-(4-메틸-피페리딘-1-일)-페닐]-아미드,Cyclopropanecarboxylic acid [3- (4-methyl-piperazin-1-carbonyl) -4- (4-methyl-piperidin-1-yl) -phenyl] -amide, N-[3-(4-메틸-피페라진-1-카보닐)-4-(4-메틸-피페리딘-1-일)-페닐]-프로피온아미드,N- [3- (4-Methyl-piperazin-1-carbonyl) -4- (4-methyl-piperidin-1-yl) -phenyl] -propionamide, 4-메톡시-N-[3-(4-메틸-피페라진-1-카보닐)-4-(4-메틸-피페리딘-1-일)-페닐]-벤즈아미드,4-methoxy-N- [3- (4-methyl-piperazin-1-carbonyl) -4- (4-methyl-piperidin-1-yl) -phenyl] -benzamide, 5-아세틸아미노-N-(3-디메틸아미노-프로필)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,5-acetylamino-N- (3-dimethylamino-propyl) -2- (4-methyl-piperidin-1-yl) -benzamide, 5-(4-브로모-벤조일아미노)-N-(3-디메틸아미노-프로필)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,5- (4-Bromo-benzoylamino) -N- (3-dimethylamino-propyl) -2- (4-methyl-piperidin-1-yl) -benzamide, 5-(3-브로모-벤조일아미노)-N-(3-디메틸아미노-프로필)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,5- (3-Bromo-benzoylamino) -N- (3-dimethylamino-propyl) -2- (4-methyl-piperidin-1-yl) -benzamide, 5-(4-클로로-벤조일아미노)-N-(3-디메틸아미노-프로필)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,5- (4-Chloro-benzoylamino) -N- (3-dimethylamino-propyl) -2- (4-methyl-piperidin-1-yl) -benzamide, N-(3-디메틸아미노-프로필)-5-(4-플루오로-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,N- (3-dimethylamino-propyl) -5- (4-fluoro-benzoylamino) -2- (4-methyl-piperidin-1-yl) -benzamide, N-(3-이소프로필-벤조일아미노)-5-(4-메틸-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-페닐]-벤즈아미드,N- (3-Isopropyl-benzoylamino) -5- (4-methyl-benzoylamino) -2- (4-methyl-piperidin-1-yl) -phenyl] -benzamide, 5-(4-이소프로필-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-N-(2-피페리딘-1-일-에틸)-벤즈아미드,5- (4-isopropyl-benzoylamino) -2- (4-methyl-piperidin-1-yl) -N- (2-piperidin-1-yl-ethyl) -benzamide, 5-(2-클로로-벤조일아미노)-N-(2-디에틸아미노-에틸)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,5- (2-Chloro-benzoylamino) -N- (2-diethylamino-ethyl) -2- (4-methyl-piperidin-1-yl) -benzamide, N-(2-디에틸아미노-에틸)-5-(2-메틸-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,N- (2-Diethylamino-ethyl) -5- (2-methyl-benzoylamino) -2- (4-methyl-piperidin-1-yl) -benzamide, N-(2-디에틸아미노-에틸)-5-(2-플루오로-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,N- (2-Diethylamino-ethyl) -5- (2-fluoro-benzoylamino) -2- (4-methyl-piperidin-1-yl) -benzamide, N-(3-디메틸아미노-프로필)-5-(4-이소프로필-벤조일아미노)-2-몰포린-4-일-벤즈아미드,N- (3-dimethylamino-propyl) -5- (4-isopropyl-benzoylamino) -2-morpholin-4-yl-benzamide, N-(3-디메틸아미노-프로필)-2-(4-메틸-피페리딘-1-일)-5-(4-트리플루오로메-벤조일아미노)-벤즈아미드,N- (3-dimethylamino-propyl) -2- (4-methyl-piperidin-1-yl) -5- (4-trifluorome-benzoylamino) -benzamide, N-(2-디메틸아미노-에틸)-5-(4-이소프로필-벤조일아미노)-N-메틸-2-(4-메틸-피페리딘-1-일)-벤즈아미드,N- (2-dimethylamino-ethyl) -5- (4-isopropyl-benzoylamino) -N-methyl-2- (4-methyl-piperidin-1-yl) -benzamide, N-(3-디메틸아미노-프로필)-5-(4-이소프로필-벤조일아미노)-N-메틸-2-(4-메틸-피페리딘-1-일)-벤즈아미드,N- (3-dimethylamino-propyl) -5- (4-isopropyl-benzoylamino) -N-methyl-2- (4-methyl-piperidin-1-yl) -benzamide, 5-(4-tert-부틸-벤조일아미노)-N-(1-페닐l-에틸)-2-피롤리딘-1-일-벤즈아미드,5- (4-tert-butyl-benzoylamino) -N- (1-phenyll-ethyl) -2-pyrrolidin-1-yl-benzamide, 5-(3-플루오로-벤조일아미노)-N-(1-페닐-에틸)-2-피롤리딘-1-일-벤즈아미드,5- (3-fluoro-benzoylamino) -N- (1-phenyl-ethyl) -2-pyrrolidin-1-yl-benzamide, 5-(3-디에틸아미노-프로피오닐아미노)-N-(1-페닐-에틸)-2-피롤리딘-1-일-벤즈아미드,5- (3-Diethylamino-propionylamino) -N- (1-phenyl-ethyl) -2-pyrrolidin-1-yl-benzamide, 4-메틸-피페라진-1-카복실산 [3-(1-페닐-에틸카바모일)-4-피롤리딘-1-일-페닐]-아미드,4-Methyl-piperazin-1-carboxylic acid [3- (1-phenyl-ethylcarbamoyl) -4-pyrrolidin-1-yl-phenyl] -amide, 4-[3-(1-페닐-에틸카바모일)-4-피롤리딘-1-일-페닐카바모일]-피페리딘-1-카복시산 tert-부틸 에스터,4- [3- (1-phenyl-ethylcarbamoyl) -4-pyrrolidin-1-yl-phenylcarbamoyl] -piperidine-1-carboxylic acid tert-butyl ester, 1-벤질-피페리딘-4-카복실산 [3-(1-페닐-에틸카바모일)-4-피롤리딘-1-일-페닐]-아미드,1-benzyl-piperidine-4-carboxylic acid [3- (1-phenyl-ethylcarbamoyl) -4-pyrrolidin-1-yl-phenyl] -amide, 5-(2-클로로-아세틸아미노)-2-(3,4-디하이드로-1H-이소퀴놀린-2-일)-N-(3-메톡시-프로필)-벤즈아미드,5- (2-Chloro-acetylamino) -2- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methoxy-propyl) -benzamide, N-시클로헥실-2-(3,4-디하이드로-1H-이소퀴놀린-2-일)-5-이소부티릴아미노-벤즈아미드,N-cyclohexyl-2- (3,4-dihydro-1H-isoquinolin-2-yl) -5-isobutyrylamino-benzamide, 2-(3,4-디하이드로-1H-이소퀴놀린-2-일)-N-(3-디메틸아미노-프로필)-5-이소부티릴아미노-N-메틸-벤즈아미드,2- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-dimethylamino-propyl) -5-isobutyrylamino-N-methyl-benzamide, N-(3-디메틸아미노-프로필)-5-(4-헥실-벤조일아미노)-2-피페리딘-1-일-벤즈아미드,N- (3-dimethylamino-propyl) -5- (4-hexyl-benzoylamino) -2-piperidin-1-yl-benzamide, 5-(4-부틸-벤조일아미노)-N-(3-디메틸아미노-프로필)-2-[4-(2-메톡시-페닐)-피페라진-1-일]-벤즈아미드,5- (4-Butyl-benzoylamino) -N- (3-dimethylamino-propyl) -2- [4- (2-methoxy-phenyl) -piperazin-1-yl] -benzamide, 4-부틸-N-[4-[4-(2-메톡시-페닐)-피페라진-1-일]-3-(피페리딘-1-카보닐l)-페닐]-벤즈아미드,4-butyl-N- [4- [4- (2-methoxy-phenyl) -piperazin-1-yl] -3- (piperidine-1-carbonyl) -phenyl] -benzamide, N-(3-디메틸아미노-프로필)-5-(4-이소프로필-벤조일아미노)-2-(4-페닐-피페라진-1-일)-벤즈아미드N- (3-Dimethylamino-propyl) -5- (4-isopropyl-benzoylamino) -2- (4-phenyl-piperazin-1-yl) -benzamide 로 이루어진 군으로부터 선택되는 화학식 (I)의 화합물 또는 약제학적으로 허용가능한 이들의 염.Selected from the group consisting of Compounds of formula (I) or pharmaceutically acceptable salts thereof. 제5항에 있어서, The method of claim 5, N-(2-디에틸아미노-에틸)-5-(4-이소프로필-벤조일아미노)-2-(4-메틸-피페리딘-1-일)-벤즈아미드,N- (2-Diethylamino-ethyl) -5- (4-isopropyl-benzoylamino) -2- (4-methyl-piperidin-1-yl) -benzamide, N-(3-디메틸아미노-프로필)-2-(4-메틸-피페리딘-1-일)-5-(4-트리플루오로메-벤조일아미노)-벤즈아미드,N- (3-dimethylamino-propyl) -2- (4-methyl-piperidin-1-yl) -5- (4-trifluorome-benzoylamino) -benzamide, 5-(2-클로로-아세틸아미노)-2-(3,4-디하이드로-1H-이소퀴놀린-2-일)-N-(3-메톡시-프로필)-벤즈아미드,5- (2-Chloro-acetylamino) -2- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methoxy-propyl) -benzamide, N-(3-디메틸아미노-프로필)-5-(4-헥실-벤조일아미노)-2-피페리딘-1-일-벤즈아미드,N- (3-dimethylamino-propyl) -5- (4-hexyl-benzoylamino) -2-piperidin-1-yl-benzamide, 5-(4-부틸-벤조일아미노)-N-(3-디메틸아미노-프로필)-2-[4-(2-메톡시-페닐)-피페라진-1-일]-벤즈아미드, 및5- (4-Butyl-benzoylamino) -N- (3-dimethylamino-propyl) -2- [4- (2-methoxy-phenyl) -piperazin-1-yl] -benzamide, and N-(3-디메틸아미노-프로필)-5-(4-이소프로필-벤조일아미노)-2-(4-페닐-피페라진-1-일)-벤즈아미드로 이루어진 군으로부터 선택되는 화학식 (I)의 화합물 또는 약제학적으로 허용가능한 이들의 염.N- (3-dimethylamino-propyl) -5- (4-isopropyl-benzoylamino) -2- (4-phenyl-piperazin-1-yl) -benzamide Compounds of formula (I) or pharmaceutically acceptable salts thereof. 다음의 단계를 포함하는 제 1항의 화학식 (I)의 화합물을 제조하는 방법:A process for preparing a compound of formula (I) according to claim 1 comprising the following steps: 하기의 화학식(II)의 화합물에To a compound of formula (II) (a) R2를 도입하는 단계,(a) introducing R 2 , (b) R1을 도입하는 단계,(b) introducing R 1 , (c) 니트로기를 환원하는 단계, 및(c) reducing the nitro group, and (d) Ra를 도입하는 단계, Ra는
Figure 112010012127862-PAT00009
또는
Figure 112010012127862-PAT00010
이며, 이 때, R'은 비치환된 C1-C6 알킬, 시클로알킬, 유레아 또는 방향족 화합물; 할로겐, C1-C6 알킬아민, 몰포린, 피레리딘, 피롤리딘, 피페라진 및 4-알킬피페라진으로 이루어진 군에서 선택된 하나 이상의 치환기로 치환된 C1-C6 알킬; 및 할로겐, C1-C6 알킬아민, 몰포린, 피레리딘, 피롤리딘, 피페라진, 4-알킬피페라진으로 이루어진 군에서 선택된 하나 이상의 치환기로 치환된 방향족 화합물(d) introducing Ra, where Ra is
Figure 112010012127862-PAT00009
or
Figure 112010012127862-PAT00010
Wherein R 'is unsubstituted C 1 -C 6 alkyl, cycloalkyl, urea or aromatic compound; Halogen, C 1 -C 6 alkyl amines, morpholine, Pirelli Dean, pyrrolidine, piperazine, and 4-a C 1 -C 6 alkyl substituted with one or more substituents selected from the group consisting of alkyl piperazine; And an aromatic compound substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 6 alkylamine, morpholine, pyreridine, pyrrolidine, piperazine, 4-alkylpiperazine 로 이루어진 군에서 선택되는 화합물이다.It is a compound selected from the group consisting of.
Figure 112010012127862-PAT00011
Figure 112010012127862-PAT00011
 제1항, 제5항 또는 제6항 중 어느 한 항의 화합물 및 약제학적으로 허용 가능한 담체를 포함하는, 세포의 비정상적 증식에 의한 암, 염증, 혈관 협착증 및 혈관 생성증으로 구성된 군에서 선택되는 질병 치료 및/또는 예방용 약제학적 조성물.A disease selected from the group consisting of cancer, inflammation, vascular stenosis and angiogenesis caused by abnormal proliferation of cells, comprising the compound of any one of claims 1, 5 or 6 and a pharmaceutically acceptable carrier. Pharmaceutical compositions for treatment and / or prophylaxis. 삭제delete 삭제delete
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