KR101263263B1

KR101263263B1 - 2,4-Diaminoquinazoline compounds having anticancer activity

Info

Publication number: KR101263263B1
Application number: KR1020100097911A
Authority: KR
Inventors: 배애님; 남길수; 다나지 아튜트라오 또라트; 추현아; 조용서
Original assignee: 서울대학교산학협력단; 한국과학기술연구원
Priority date: 2010-10-07
Filing date: 2010-10-07
Publication date: 2013-05-10
Also published as: KR20120038034A

Abstract

본 발명은 항암활성을 가지는 2,4-다이아미노퀴나졸린 화합물 및 약제학적으로 허용 가능한 이의 염, 이들 화합물의 제조방법, 그리고 이들 화합물이 유효성분으로 함유된 약제조성물에 관한 것이다. The present invention relates to 2,4-diaminoquinazoline compounds having anticancer activity and pharmaceutically acceptable salts thereof, methods for preparing these compounds, and pharmaceutical compositions containing these compounds as active ingredients.

Description

2,4-Diaminoquinazoline compounds having anticancer activity

지난 수년 동안 분자표적 치료법 (molecular targeted therapies)은 항암제 개발 프로그램의 초점이 되어 왔다. 그러나 대부분의 암은 복수의 분자변이가 특징적으로 나타난다. 따라서 단지 하나의 분자변이를 표적으로 하는 것은 불충분할 수 있으며, 표적으로 삼는 단백질이 핵심역할을 하는 종양의 일부 부분집합(subset)에서만 의미 있는 효과를 나타낼 가능성이 있다. 이를 보완하기 위하여 암세포를 작동하게 하는 기구 (machinery)를 표적할 수 있다. 분자샤프론 (molecular chaperone)인 Hsp90 (Heat Shock Protein 90 inhibitors)은 이러한 기구의 핵심 구성요소로서, 암세포의 성장과 생존을 촉진하는 여러 가지 돌연변이성 또는 과다발현성 신호전달 단백질이 기능을 발휘하는 데 필요하다. 이는 Hsp90 저해제가 상당히 다양한 암에 대하여 효과를 가질 수 있음을 의미한다. 더욱이 Hsp90은 종양세포에서 특이적으로 활성화될 뿐 아니라 고친화적 형태로 존재하므로, Hsp90 저해제는 종양세포에 대해 높은 선택성을 나타낼 수 있다는 장점을 가진다. Molecular targeted therapies have been the focus of anti-cancer drug development programs over the past few years. However, most cancers are characterized by multiple molecular mutations. Thus, targeting only one molecular variation may be insufficient and it is possible that only a subset of tumors in which the targeting protein plays a key role will have a significant effect. To compensate for this, one can target machinery that makes cancer cells work. Molecular chaperone, Hsp90 (Heat Shock Protein 90 inhibitors), is a key component of these mechanisms, which are necessary for the function of several mutagenic or overexpressing signaling proteins that promote cancer cell growth and survival. Do. This means that Hsp90 inhibitors can be effective against a wide variety of cancers. Moreover, since Hsp90 is not only specifically activated in tumor cells but also exists in a high affinity form, Hsp90 inhibitors have the advantage of showing high selectivity for tumor cells.

Hsp90 샤프론은 진핵세포 내부에 가장 많이 존재하는 분자샤프론 중 하나로 세포성장, 분화, 생존에 관련된 다양한 단백질들의 안정화 및 활성 조절을 담당한다. 클라이언트 단백질(Client protein)로 불리는 Hsp90의 기질 단백질에는 50여 가지의 암을 유발하는 단백질들이 포함되어 있다. Hsp90 활성이 억제될 경우 Hsp90 클라이언트 단백질들은 프로테아좀에 의해 분해된다. [Pharmacol. Ther., 1998, 79(2), 129; Adv. Cancer Res., 2006, 95, 323] 따라서 Hsp90 활성 억제제는 다양한 암 유발 단백질을 동시에 감소시키는 효과를 나타낼 수 있으므로 폭넓은 종류의 암에 적용될 수 있는 항암제로 크게 주목 받고 있다. [Trends Biochem. Sci., 2006 31(3), 164-172] 암의 발생은 세포 성장 조절의 이상으로 인한 무한한 세포분열과 주변 세포로의 전이 등을 동반한다. 따라서 자가 성장 신호를 통한 세포 증식, 성장 억제 신호에 대한 반응성 저하, 세포사멸 과정으로부터의 회피, 무한 증식 능력의 획득, 지속적인 혈관 증식, 세포 침투와 전이 등이 암에서 나타나는 여섯 가지 특징으로 제시되고 있다. [Cell, 2000, 100(1), 57-70] Hsp90에 의해 그 안정성과 활성이 조절되는 많은 클라이언트 단백질들이 이러한 암세포로의 분화 과정에 관여하고 있다. [Curr. Top. Med. Chem., 2006, 6(11), 1163-1171] 또한 Hsp90은 불안정한 상태의 단백질을 보호함으로써 생물체의 진화를 유발함이 알려져 있다. [Nature, 2002, 417(6889), 618-624] 형질전환 과정에서 생겨난 v-Src, Bcr-Abl, p53 등의 불안정한 돌연변이 단백질들이 Hsp90에 의해 안정화됨으로써 암세포로의 분화가 촉진되는 결과를 초래하게 된다. 한편 암세포에서는 Hsp90의 발현 및 활성이 증가하는 현상이 관찰되는데, 이는 암세포 주변의 환경조건 (hypoxia, pH, 영양분의 고갈) 또는 암 유발 단백질을 활성화시키는 스트레스 조건에 의한 Hsp90의 발현 및 활성 유도에서 그 원인을 찾을 수 있다. [Int. J. Cancer, 1992, 51(4), 613-619] 세포의 비정상적인 증식이 일어나는 암세포에서는 분자샤프론 에 대한 필요성이 증가하게 되어 Hsp90의 발현 또는 활성이 높은 세포의 positive selection이 일어날 수 있다는 것도 암세포에서의 높은 Hsp90 활성을 설명하는 하나의 가설이다. 암세포의 Hsp90가 정상세포에 존재하는 Hsp90에 비해 활성이 높은 상태로 존재한다는 사실은 Hsp90 억제제를 실제 항암제로 사용할 수 있는 이유가 되기도 한다. 높은 활성을 가지는 암세포의 Hsp90가 Hsp90 억제제에 대한 강한 결합력을 보임으로써, Hsp90 억제제가 정상세포에는 비교적 적은 영향을 미치면서 선택적으로 암세포에 효과를 발휘할 수 있다는 사실이 알려져 있다. [Nature, 2003, 425(6956), 407-410] 특정 타겟에 작용하는 기존의 항암제에 비해 Hsp90 억제제는 다양한 암 유발 단백질들을 동시에 불안정화 함으로써 억제할 수 있어 다양한 암 종류에 적용이 가능하다는 점이 Hsp90의 억제제의 장점으로 부각되고 있다. 현재까지 가장 많이 개발된 Hsp90 억제제는 Hsp90 N-말단에 존재하는 ATP pocket에 결합하여 ATPase의 기능을 억제하는 물질들이다. Hsp90 억제제로 널리 알려진 겔다나마이신 (geldanamycin)은 1970년 스트렙토마이세스 (Streptomyces)속 균주로부터 제초제의 용도로 분리되었다. 이후 겔다나마이신의 항암 효과가 알려지고 그 결합 타겟이 Hsp90라는 사실이 1994년에 알려지게 되었다. 이후 겔다나마이신과 유사한 구조를 가진 벤조퀴논 안사마이신 (benzoquinone ansamycin) 계열의 물질인 17AAG가 Hsp90 억제 기능을 가짐이 알려졌다. [Cancer Chemother Pharmacol, 1998, 42(4), 273-279] 미국과 영국에서 흑색종, 전립선암, 유방암, 다발성 골수종 등을 대상으로 수행된 1단계 임상실험결과 성공적 항암 효과를 보여 그 가능성이 입증되었다. Hsp90 chaperone is one of the most common molecular chaperones in eukaryotic cells and is responsible for the stabilization and activity regulation of various proteins involved in cell growth, differentiation and survival. Hsp90's matrix protein, called the client protein, contains more than 50 cancer-causing proteins. When Hsp90 activity is inhibited, Hsp90 client proteins are degraded by proteasomes. Pharmacol. Ther., 1998 , 79 (2), 129; Adv. Cancer Res., 2006 , 95, 323] Hsp90 activity inhibitors are therefore attracting much attention as anticancer agents that can be applied to a wide range of cancers because they can reduce various cancer-causing proteins simultaneously. Trends Biochem. Sci., 2006 31 (3), 164-172] The development of cancer is accompanied by infinite cell division and metastasis to surrounding cells due to abnormal cell growth regulation. Therefore, the six characteristics of cancer are suggested by cancer cell growth through self-growth signal, decreased responsiveness to growth inhibition signal, avoidance of apoptosis process, acquisition of infinite proliferation capacity, continuous blood vessel proliferation, cell infiltration and metastasis. . [Cell, 2000 , 100 (1), 57-70] Many client proteins whose stability and activity are regulated by Hsp90 are involved in the differentiation of these cancer cells. Curr. Top. Med. Chem., 2006 , 6 (11), 1163-1171] It is also known that Hsp90 induces the evolution of organisms by protecting proteins in unstable states. [Nature, 2002 , 417 (6889), 618-624] Unstable mutant proteins, such as v-Src, Bcr-Abl, and p53, generated during the transformation process are stabilized by Hsp90, leading to differentiation into cancer cells. do. On the other hand, the expression and activity of Hsp90 is increased in cancer cells, which is induced in the expression and activity of Hsp90 by environmental conditions (hypoxia, pH, nutrient depletion) around cancer cells or stress conditions that activate cancer-causing proteins. Find the cause. Int. J. Cancer, 1992 , 51 (4), 613-619] In cancer cells where abnormal proliferation of cells occurs, the necessity for molecular chaperone is increased, which may result in positive selection of cells with high Hsp90 expression or activity. It is one hypothesis explaining the high Hsp90 activity. The fact that Hsp90 in cancer cells is more active than Hsp90 in normal cells may be a reason for using Hsp90 inhibitors as an anticancer drug. It is known that Hsp90 of a highly active cancer cell exhibits a strong binding force to the Hsp90 inhibitor, so that the Hsp90 inhibitor can selectively exert an effect on cancer cells with a relatively small effect on normal cells. [Nature, 2003 , 425 (6956), 407-410] Hsp90 inhibitors can be inhibited by simultaneously destabilizing a variety of cancer-causing proteins, compared to conventional anticancer agents that act on specific targets. It is emerging as an advantage of inhibitors. The most developed Hsp90 inhibitors to date are substances that bind to the ATP pocket at the Hsp90 N-terminus and inhibit the function of ATPase. Geldanamycin, widely known as an Hsp90 inhibitor, was isolated from the Streptomyces strain in 1970 for herbicide use. Later, the anticancer effect of geldanamycin was known and the binding target of Hsp90 became known in 1994. Later, it was known that 17AAG, a benzoquinone ansamycin-based substance having a structure similar to geldanamycin, has Hsp90 inhibitory function. [Cancer Chemother Pharmacol, 1998 , 42 (4), 273-279] Phase 1 clinical trials performed on melanoma, prostate cancer, breast cancer, and multiple myeloma in the United States and the United Kingdom demonstrated successful anticancer effects. It became.

17DMAG는 미국 국립 암연구소 (National Cancer Institute)와 Kosan Biosiences에서 17AAG의 문제점을 보완하여 만들어낸 물질로 현재 1차 임상실험 진행 중에 있다. [Drug Discov. Today, 2004, 9(20), 881-888; Cancer Chemother Pharmacol, 2002, 49(1), 7-19] 레디시콜 (Radicicol)의 경우 Hsp90 억제 효과는 있으나 혈청에서 불안정한 이유로 임상실험에는 부적합하다. 따라서 이 문제를 보완한 유도체 개발이 일본의 Kyowa Hakko Kogyo Co. 등에서 수행되었으나 임상실험은 진행되지 않고 있다. 한편 미국 Memorial Sloan-Kettering Cancer Center의 Chiosis 그룹에서 ATP 결합위치의 구조 분석을 이용해 퓨린-스캐폴드 (purine-scaffold)를 가진 PU3와 그 유도체 PU24FCl, PU-H58 등을 개발하였다. [J. Med. Chem., 2006, 49(1), 381-390] 이외에도 Workman group에서 고속탐색법 (HTS)을 통해 개발된 피라졸 유도체 (Bioorg. Med. Chem. Lett., 2005, 15(14), 3338-3343), 서바이빈-Hsp90 복합체의 억제제로 찾아진 펩티도미메틱 (peptidomimetic) 억제제인 셰퍼딘 (shepherdin) [Cancer Cell, 2005, 7(5), 457-468] 등이 ATP 결합 pocket에 결합하는 Hsp90 억제제에 해당한다. 한편 Hsp90의 C-말단에 존재하리라 생각되는 또 하나의 ATP 결합 위치에 결합하는 노보바이오신 (novobiocin)과 시스플라틴 (cisplatin)이 Hsp90 억제 효과가 있음이 알려져 있으나 그 기작은 아직 자세히 밝혀지지 않고 있다. [J. Biol. Chem., 2007, 277(9), 7066-7075] 현재 다양한 흑색종과 유방암 등을 대상으로 2차 임상실험이 진행 중이며, 다른 항생제와의 복합처방을 이용한 항암요법에 대한 임상실험도 함께 진행되고 있다. 겔다나마이신 및 겔다나마이신 유도체는 간독성을 유발하는 동일 구조를 포함하고 있다는 점에서 새로운 구조를 가진 억제제의 개발이 요구되고 있다. Hsp90 저해제 중에서 그 중, 최초로 임상시험을 거친 것은 천연항생물질인 겔다나마이신(geldanamycin)의 유도체인 17-알릴아미노-17-데메톡시겔다마이신 (17-AAG) 이다. 겔다나마이신은 스트렙토마이세스속 하이그로스코피커스 (Streptomyces sp. hygroscopicus)가 생성하는 천연물질로서, Hsp90의 ATP 결합부위에 대한 친화성이 높다. 겔다나마이신이 Hsp90에 결합하면 클라이언트 단백질이 안정성을 잃고 분해된다. 겔다나마이신은 이처럼 강력한 항암효과를 갖고 있음에도 불구하고 심각한 부작용 (예: 간독성) 때문에 17번 위치에 변형을 가한 17-AAG, 17-DMAG와 같은 유도체가 개발되었다. 그러나 Hsp90 억제제는 지금까지 천연생성물 또는 그 유도체에 머물고 있어 연구자들의 기대에 미치지 못해 왔다. 이러한 문제는 기본적으로 생체이용률, 용해도, 독성에서 기인하는데, 천연생성물의 구조적 복잡성도 관련 화합물에 대한 연구를 매우 어렵게 하는 요인이었다. 따라서 연구자들은 이러한 제한이 없는 새로운 Hsp90 억제제를 발굴하기 위하여 노력해 왔다. 17DMAG was developed by the National Cancer Institute and Kosan Biosiences to complement 17AAG's problems. Drug Discov. Today, 2004 , 9 (20), 881-888; Cancer Chemother Pharmacol, 2002 , 49 (1), 7-19] Radicicol inhibits Hsp90 but is unsuitable for clinical trials due to unstable serum. Therefore, the development of derivatives to solve this problem has been carried out by Kyowa Hakko Kogyo Co. Although it was performed on the back, clinical trials are not progressing. In the Chiosis group of the Memorial Sloan-Kettering Cancer Center in the US, the structure of ATP binding sites was used to develop PU3 with purine-scaffold and its derivatives PU24FCl and PU-H58. [J. Med. Chem., 2006 , 49 (1), 381-390], in addition to pyrazole derivatives developed by the HTS in the Workman group (Bioorg. Med. Chem. Lett., 2005 , 15 (14), 3338-). 3343), a peptidomimetic inhibitor found as an inhibitor of survivin-Hsp90 complex, shepherdin [Cancer Cell, 2005 , 7 (5), 457-468], binds to the ATP binding pocket. Corresponds to the Hsp90 inhibitor. Meanwhile, it is known that novobiocin and cisplatin, which bind to another ATP binding site, which are thought to be present at the C-terminus of Hsp90, have an inhibitory effect on Hsp90, but the mechanism has not yet been elucidated. [J. Biol. Chem., 2007 , 277 (9), 7066-7075] Currently, a second clinical trial is under way for various melanoma and breast cancer, and a clinical trial for anticancer therapy using a combination prescription with other antibiotics is also in progress. have. Geldanamycin and geldanamycin derivatives require the development of inhibitors with new structures in that they contain the same structures that cause hepatotoxicity. Among the Hsp90 inhibitors, the first clinical trials were 17-allylamino-17-demethoxygeldamycin (17-AAG), a derivative of the natural antibiotic geldanamycin. Geldanamycin is a natural substance produced by Streptomyces sp . Hygroscopicus and has a high affinity for the ATP binding site of Hsp90. When geldanamycin binds to Hsp90, the client protein loses its stability and degrades. Although geldanamycin has such potent anticancer effects, derivatives such as 17-AAG and 17-DMAG have been developed with modifications at position 17 due to serious side effects (eg hepatotoxicity). However, Hsp90 inhibitors have remained in natural products or derivatives until now, falling short of the researchers' expectations. These problems are primarily due to bioavailability, solubility, and toxicity. The structural complexity of natural products has also made research on related compounds very difficult. Therefore, researchers have been trying to find new Hsp90 inhibitors without this limitation.

최근에 Hsp90 저해제 계열에 속하는 새로운 합성 항암제로서 3,4-다이아릴피라졸 레조시놀 (CCT018159)이 발표되었다. 이 화합물은 Hsp90의 핵심부분에 ATP 대신 결합하는 것으로 알려졌다. CCT018159는 암세포를 장기간에 걸쳐 다발적으로 공격하여 자멸사하도록 유도하고, 암세포의 전파와 혈관신생을 막는다는 장점을 지니고 있다. [Cancer Res., 2007, 67, 2206] CCT018159는 암세포의 G1기 정체(G1 arrest)를 유발하고 세포자멸사를 초래하였으며, 또한 침윤과 혈관신생에 관여하는 상피세포 및 종양세포의 핵심적 기능을 저해하는 것으로 나타났다. Recently, 3,4-diarylpyrazole resorcinol (CCT018159) has been published as a new synthetic anticancer agent belonging to the Hsp90 inhibitor family. This compound is known to bind to the core of Hsp90 instead of ATP. CCT018159 induces apoptosis by proliferating and attacking cancer cells over a long period of time, and has the advantage of preventing cancer cell spread and angiogenesis. [Cancer Res., 2007 , 67, 2206] CCT018159 induced G1 arrest of cancer cells and resulted in apoptosis, and also inhibited the essential functions of epithelial and tumor cells involved in infiltration and angiogenesis. Appeared.

이외에도 새로운 Hsp90 ATPase 분석법을 이용한 고속탐색법 (HTS), 또는 구조 기반 가상 스크리닝 (virtual screening) 을 통해 새로운 선도 화합물을 찾기 위한 노력이 여러 그룹에서 진행되고 있고 [Bioorg. Med. Chem., Lett., 2007, 17(22), 6345-6349], 기존에 알려진 억제제의 구조를 기반으로 다양한 유도체를 합성하여 그 기능을 향상시키기 위한 시도가 계속되고 있다.
In addition, efforts have been made in several groups to find new lead compounds through high-speed search (HTS) using the new Hsp90 ATPase assay, or through structure-based virtual screening [Bioorg. Med. Chem., Lett., 2007 , 17 (22), 6345-6349], attempts to improve the function by synthesizing various derivatives based on the structure of known inhibitors.

본 발명은 신규 구조의 2,4-다이아미노퀴나졸린 화합물 및 약제학적으로 허용 가능한 이의 염을 제공하는데 그 목적이 있다.It is an object of the present invention to provide a 2,4-diaminoquinazoline compound of novel structure and a pharmaceutically acceptable salt thereof.

또한, 본 발명은 2-클로로-N-(퓨라닐메틸)퀴나졸린-4-아민 화합물과 다양한 아민화합물과 결합반응하여, 상기한 2,4-다이아미노퀴나졸린 화합물을 제조하는 방법을 제공하는데 다른 목적이 있다.In addition, the present invention provides a method for preparing the above-mentioned 2,4-diaminoquinazoline compound by combining a 2-chloro- N- (furanylmethyl) quinazolin-4-amine compound with various amine compounds. There is another purpose.

또한, 본 발명은 상기한 2,4-다이아미노퀴나졸린 화합물 및 약제학적으로 허용 가능한 이의 염이 유효성분으로 포함되어 있는 약제조성물을 제공하는데 또 다른 목적이 있다.It is another object of the present invention to provide a pharmaceutical composition containing the 2,4-diaminoquinazoline compound and a pharmaceutically acceptable salt thereof as an active ingredient.

또한, 본 발명은 상기한 2,4-다이아미노퀴나졸린 화합물 및 약제학적으로 허용 가능한 이의 염이 유효성분으로 포함되어 있는 항암제를 제공하는데 또 다른 목적이 있다.
It is another object of the present invention to provide an anticancer agent including the 2,4-diaminoquinazoline compound and a pharmaceutically acceptable salt thereof as an active ingredient.

상기의 목적을 실현하기 위하여, 본 발명은 항암활성을 가지는 하기 화학식 1로 표시되는 2,4-다이아미노퀴나졸린 화합물, 이 화합물의 제조방법, 이 화합물을 포함하는 약제조성물을 그 특징으로 한다.In order to realize the above object, the present invention is characterized by a 2,4-diaminoquinazoline compound represented by the following formula (1) having an anticancer activity, a method for preparing the compound, and a pharmaceutical composition comprising the compound.

상기 화학식 1에서,In Formula 1,

R₁은 수소원자 또는 할로겐원자를 나타내고;R ₁ represents a hydrogen atom or a halogen atom;

R₂는 수소원자, C₁-C₆ 알킬아미노기, 다이(C₁-C₆ 알킬)아미노기, C₆-C₁₅아릴기, C₁-C₆ 알콕시로 치환된 C₆-C₁₅아릴기, 또는 산소 및 질소 중에서 선택된 헤테로원자가 1 또는 2개 포함된 5 내지 10원자로 구성된 헤테로고리기를 나타내고, 이때 헤테로고리기는 할로, C₁-C₆ 알킬, 페닐, 및 할로 또는 C₁-C₆ 알킬로 치환된 페닐로 이루어진 군으로부터 선택된 치환체로 치환 또는 비치환될 수 있고;R ₂ is a hydrogen atom, a C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group, a C ₆ -C ₁₅ aryl group, a C ₆ -C ₁₅ aryl group substituted with C ₁ -C ₆ alkoxy, Or a heterocyclic group consisting of 5 to 10 atoms including 1 or 2 heteroatoms selected from oxygen and nitrogen, wherein the heterocyclic group is substituted with halo, C ₁ -C ₆ alkyl, phenyl, and halo or C ₁ -C ₆ alkyl Unsubstituted or substituted with a substituent selected from the group consisting of phenyl;

n은 0 내지 6의 정수를 나타낸다.
n represents the integer of 0-6.

본 발명에 따른 상기 화학식 1로 표시되는 2,4-다이아미노퀴나졸린 화합물은 항암제로서 유효한 효과를 가지고 있다.
The 2,4-diaminoquinazoline compound represented by Formula 1 according to the present invention has an effective effect as an anticancer agent.

본 발명에 따른 상기 화학식 1로 표시되는 2,4-다이아미노퀴나졸린 화합물은 당해 기술 분야에서 통상적인 방법에 의해 약제학적으로 허용 가능한 염을 형성할 수 있다. 예를 들면, 염산, 브롬산, 술폰산, 황산, 인산, 질산과 같은 무독성의 무기산, 또는 아세트산, 프로피온산, 숙신산, 글리콜산, 스테아르산, 젖산, 타르타르산, 시트르산, 파라톨루엔설폰산, 메탄설폰산과 같은 무독성의 유기산과 함께 약제학적으로 허용 가능한 이들의 산이 부가된 염을 형성할 수도 있다.The 2,4-diaminoquinazoline compound represented by Chemical Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. For example, non-toxic inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid, sulfuric acid, phosphoric acid, nitric acid, or acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, methanesulfonic acid It is also possible to form salts with non-toxic organic acids added with their pharmaceutically acceptable acids.

본 발명에 따른 상기 화학식 1로 표시되는 2,4-다이아미노퀴나졸린 화합물을 정의하기 위해 사용된 치환기를 좀 더 자세히 설명하면 다음과 같다. The substituents used to define the 2,4-diaminoquinazoline compound represented by Formula 1 according to the present invention will be described in more detail as follows.

'알킬기'는 1 내지 6개의 탄소원자를 가진 직쇄상, 분쇄상 및 고리상의 탄소사슬을 모두 포함하며, 선호하는 알킬기는 메틸, 에틸기, 노말프로필기, 아이소프로필기, 노말부틸기, 아이소부틸기, tert-부틸기, 시클로펜틸기, 시클로헥실기 등이 있다. '아릴기'는 탄소원자가 6 내지 15개인 방향족 고리기를 의미하는 것으로, 아릴은 최소한 6개의 원자를 가진 하나의 고리, 또는 최소한 10개의 원자를 가진 두 개의 고리나 인접 탄소 원자에 이중 결합으로 공명 안정화된 상태를 말하며, 아릴기로는 페닐기, 나프틸기 등이 포함될 수 있고, 상기한 아릴기는 할로겐원자, C₁-C₆알킬, C₁-C₆알콕시, 페녹시 등 중에서 선택된 치환체가 하나 이상 치환될 수도 있다. '헤테로고리기'는 질소원자(N) 또는 산소원자(O)의 헤테로원자가 1 내지 2개와 탄소원자로 구성되는 고리기로서 피롤리디닐, 몰포리닐, 피페리디닐, 피페라지닐 등이 포함될 수 있다. 상기한 헤테로고리기는 다른 치환기에 의해 치환될 수 있으며, 이때 치환기로는 클로로, 플루오로와 같은 할로겐원자, 상기에서 정의한 C₁-C₆ 알킬, 페닐, 또는 할로 또는 C₁-C₆ 알킬로 치환된 페닐로부터 선택되며, 이들 치환기는 1 내지 3개 치환될 수 있다.'Alkyl group' includes all linear, pulverized and cyclic carbon chains having 1 to 6 carbon atoms, and preferred alkyl groups are methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, tert- butyl group, cyclopentyl group, cyclohexyl group, and the like. 'Aryl group' means an aromatic ring group having 6 to 15 carbon atoms, and aryl is resonantly stabilized by a single ring having at least six atoms, or a double bond with two rings having at least 10 atoms or adjacent carbon atoms. The aryl group may include a phenyl group, a naphthyl group, and the like, and the aryl group may be substituted with one or more substituents selected from halogen atoms, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenoxy, and the like. It may be. 'Heterocyclic group' is a ring group composed of 1 to 2 heteroatoms of a nitrogen atom (N) or an oxygen atom (O) and a carbon atom, and may include pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and the like. have. The heterocyclic group may be substituted by other substituents, which may be substituted with a halogen atom such as chloro or fluoro, C ₁ -C ₆ alkyl, phenyl, or halo or C ₁ -C ₆ alkyl as defined above. Phenyl, and these substituents may be substituted with one to three.

상기 화학식 1로 표시되는 2,4-다이아미노퀴나졸린 화합물에 있어서, 바람직하기로는 상기 R₁은 수소원자, 플루오로원자, 또는 클로로원자를 나타내고; 상기 R₂는 수소원자, 메틸아미노기, 다이메틸아미노기, 다이에틸아미노기, 페닐기, 메톡시페닐기, 몰포리노기, 피페라진-1-일기, 4-(메틸)피페라진-1-일기, 4-(에틸)피페라진-1-일기, 4-(2-클로로페닐)피페라진-1-일기, 4-(3-클로로페닐)피페라진-1-일기, 4-(2,3-다이클로로페닐)피페라진-1-일기, 4-(2-메틸페닐)피페라진-1-일기, 4-(3-메틸페닐)피페라진-1-일기, 또는 4-(2,3-다이메틸페닐)피페라진-1-일기를 나타내고; 상기 n은 0 내지 6의 정수를 나타내는 화합물의 경우이다.In the 2,4-diaminoquinazoline compound represented by Formula 1, preferably, R ₁ represents a hydrogen atom, a fluoro atom, or a chloro atom; R ₂ is a hydrogen atom, methylamino group, dimethylamino group, diethylamino group, phenyl group, methoxyphenyl group, morpholino group, piperazin-1-yl group, 4- (methyl) piperazin-1-yl group, 4- ( Ethyl) piperazin-1-yl group, 4- (2-chlorophenyl) piperazin-1-yl group, 4- (3-chlorophenyl) piperazin-1-yl group, 4- (2,3-dichlorophenyl) Piperazin-1-yl, 4- (2-methylphenyl) piperazin-1-yl, 4- (3-methylphenyl) piperazin-1-yl, or 4- (2,3-dimethylphenyl) piperazin-1 -Represent diary; N is the case of the compound which shows the integer of 0-6.

특히 바람직한 상기 화학식 1로 표시되는 2,4-다이아미노퀴나졸린 화합물을 예시하면 하기와 같다:Particularly preferred examples of 2,4-diaminoquinazoline compounds represented by Formula 1 are as follows:

4N-(퓨란-2-일메틸)-2N-(4-메톡시페닐)퀴나졸린-2,4-다이아민 (화합물번호 1),4 N- (furan-2-ylmethyl) -2 N- (4-methoxyphenyl) quinazolin-2,4-diamine (Compound No. 1),

2N-(4-(4-(2,3-다이메틸페닐)피페라진-1-일)부틸)-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 2),2 N- (4- (4- (2,3-dimethylphenyl) piperazin-1-yl) butyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 2),

2N-(3-(4-(2,3-다이메틸페닐)피페라진-1-일)프로필)-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 3),2 N- (3- (4- (2,3-dimethylphenyl) piperazin-1-yl) propyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 3),

2N-(3-(4-(2,3-다이클로로페닐)피페라진-1-일)프로필)-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 4),2 N- (3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (compound Number 4),

2N-(4-(4-(2,3-다이클로로페닐)피페라진-1-일)부틸)-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 5),2 N- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (compound Number 5),

2N-(2-(다이메틸아미노)에틸)-4N-(퓨란-2일메틸)퀴나졸린-2,4-다이아민 (화합물번호 6),2 N- (2- (dimethylamino) ethyl) -4 N- (furan-2ylmethyl) quinazolin-2,4-diamine (Compound No. 6),

2N-(2-몰포리노에틸)-4N-(퓨란-2일메틸)퀴나졸린-2,4-다이아민 (화합물번호 7),2 N- (2-morpholinoethyl) -4 N- (furan-2ylmethyl) quinazolin-2,4-diamine (Compound No. 7),

4N-(퓨란-2일메틸)-2N-펜틸퀴나졸린-2,4-다이아민 (화합물번호 8),4 N- (furan-2ylmethyl) -2 N -pentylquinazolin-2,4-diamine (Compound No. 8),

4N-(퓨란-2일메틸)-2N-(3-몰포리노프로필)퀴나졸린-2,4-다이아민 (화합물번호 9),4 N- (furan-2ylmethyl) -2 N- (3-morpholinopropyl) quinazolin-2,4-diamine (Compound No. 9),

2N-(3-(다이메틸아미노)프로필)-4N-(퓨란-2-일메틸)퀴나졸린-2,4 다이아민 (화합물번호 10),2 N- (3- (dimethylamino) propyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4 diamine (Compound No. 10),

4N-(퓨란-2-일메틸)-2N-(3-(피롤리딘-1-일)프로필)퀴나졸린-2,4-다이아민 (화합물번호 11),4 N- (furan-2-ylmethyl) -2 N- (3- (pyrrolidin-1-yl) propyl) quinazolin-2,4-diamine (Compound No. 11),

2N-(2-(다이에틸아미노)에틸)-4N-(퓨라노-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 12),2 N- (2- (diethylamino) ethyl) -4 N- (furano-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 12),

2N-(3-(다이에틸아미노)프로필)-4N-(퓨라노-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 13),2 N- (3- (diethylamino) propyl) -4 N- (furano-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 13),

2N-부틸-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 14),2 N- butyl-4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 14),

4N-(퓨란-2-일메틸)-2N-(4-몰포리노부틸)퀴나졸린-2,4-다이아민 (화합물번호 15),4 N- (furan-2-ylmethyl) -2 N- (4-morpholinobutyl) quinazolin-2,4-diamine (Compound No. 15),

2N-(2-(4-(2,3-다이클로로페닐)피페라진-1-일)에틸)-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 16),2 N- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (compound Number 16),

6-플루오로-4N-(퓨란-2-일메틸)-2N-(3-몰포리노프로필)퀴나졸린-2,4-다이아민 (화합물번호 17),6-fluoro-4 N- (furan-2-ylmethyl) -2 N- (3-morpholinopropyl) quinazolin-2,4-diamine (Compound No. 17),

2N-부틸-6-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 18),2 N- butyl-6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 18),

6-플루오로-4N-(퓨란-2-일메틸)-2N-펜틸퀴나졸린-2,4-다이아민 (화합물번호 19),6-fluoro-4 N- (furan-2-ylmethyl) -2 N -pentylquinazolin-2,4-diamine (Compound No. 19),

6-플루오로-4N-(퓨란-2-일메틸)-2N-(4-메톡시페닐)퀴나졸린-2,4-다이아민 (화합물번호 20),6-fluoro-4 N- (furan-2-ylmethyl) -2 N- (4-methoxyphenyl) quinazolin-2,4-diamine (Compound No. 20),

2N-(4-(4-(2,3-다이클로로페닐)피페라진-1-일)부틸)-6-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 21),2 N- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl) -6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4 Diamine (compound number 21),

2N-(3-(4-(2,3-다이메틸페닐)피페라진-1-일)프로필)-6-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 22),2 N- (3- (4- (2,3-dimethylphenyl) piperazin-1-yl) propyl) -6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4- Diamine (Compound No. 22),

2N-(4-(4-(2,3-다이메틸페닐)피페라진-1-일)부틸)-6-플루오로-4N-(퓨라노-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 23),2 N- (4- (4- (2,3-dimethylphenyl) piperazin-1-yl) butyl) -6-fluoro-4 N- (furano-2-ylmethyl) quinazolin-2,4 Diamine (Compound No. 23),

2N-(3-(다이에틸아미노)-프로필)-6-플루오로-4N-(퓨란-2일메틸)퀴나졸린-2,4-다이아민 (화합물번호 24),2 N- (3- (diethylamino) -propyl) -6-fluoro-4 N- (furan-2ylmethyl) quinazolin-2,4-diamine (Compound No. 24),

2N-(2-(다이에틸아미노)에틸)-6-플루오로-4N-(퓨란-2일메틸)퀴나졸린-2,4-다이아민 (화합물번호 25),2 N- (2- (diethylamino) ethyl) -6-fluoro-4 N- (furan-2ylmethyl) quinazolin-2,4-diamine (Compound No. 25),

6-플루오로-4N-(퓨란-2-일메틸)-2N-(4-몰포리노부틸)퀴나졸린-2,4-다이아민 (화합물번호 26),6-fluoro-4 N- (furan-2-ylmethyl) -2 N- (4-morpholinobutyl) quinazolin-2,4-diamine (Compound No. 26),

6-플루오로-4N-(퓨란-2-일메틸)-2N-(2-몰포리노에틸)퀴나졸린-2,4-다이아민 (화합물번호 27),6-fluoro-4 N- (furan-2-ylmethyl) -2 N- (2-morpholinoethyl) quinazolin-2,4-diamine (Compound No. 27),

2N-(2-(4-(2,3-다이클로로페닐)피페라진-1-일)에틸)-6-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 28),2 N- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) -6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4 Diamine (compound number 28),

2N-(2-(4-(2,3-다이클로로페닐)피페라진-1-일)에틸)-8-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 29),2 N- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) -8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4 Diamine (Compound No. 29),

2N-(4-(4-(2,3-다이메틸페닐)피페라진-1-일)부틸)-8-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 30),2 N- (4- (4- (2,3-dimethylphenyl) piperazin-1-yl) butyl) -8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4- Diamine (Compound No. 30),

2N-(3-(4-(2,3-다이클로로페닐)피페라진-1-일)프로필)-8-플루오로-4N-(퓨란-2-일메틸l)퀴나졸린-2,4-다이아민 (화합물번호 31),2 N- (3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propyl) -8-fluoro-4 N- (furan-2-ylmethyll) quinazolin-2, 4-diamine (Compound No. 31),

2N-(4-(4-(2,3-다이클로로페닐)피페라진-1-일)부틸)-8-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 32),2 N- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl) -8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4 Diamine (compound number 32),

2N-부틸-8-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 33),2 N-butyl-N-8-fluoro -4 - (furan-2-ylmethyl) quinazoline-2,4-diamine (Compound No. 33),

8-플루오로-4N-(퓨란-2-일메틸)-2N-펜틸퀴나졸린-2,4-다이아민 (화합물번호 34),8-fluoro-4 N- (furan-2-ylmethyl) -2 N -pentylquinazolin-2,4-diamine (Compound No. 34),

2N-(3-(다이에틸아미노)프로필)-8-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 35),2 N- (3- (diethylamino) propyl) -8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 35),

2N-(2-(다이메틸아미노)에틸)-8-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 36),2 N- (2- (dimethylamino) ethyl) -8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 36),

8-플루오로-4N-(퓨란-2-일메틸)-2N-(2-몰포리노에틸)퀴나졸린-2,4-다이아민 (화합물번호 37),8-fluoro-4 N- (furan-2-ylmethyl) -2 N- (2-morpholinoethyl) quinazolin-2,4-diamine (Compound No. 37),

8-플루오로-4N-(퓨란-2-일메틸)-2N-(3-몰포리노프로필)퀴나졸린-2,4-다이아민 (화합물번호 38),8-fluoro-4 N- (furan-2-ylmethyl) -2 N- (3-morpholinopropyl) quinazolin-2,4-diamine (Compound No. 38),

8-플루오로-4N-(퓨란-2-일메틸)-2N-(4-메톡시페닐)퀴나졸린-2,4-다이아민 (화합물번호 39).
8-fluoro-4 N- (furan-2-ylmethyl) -2 N- (4-methoxyphenyl) quinazolin-2,4-diamine (Compound No. 39).

한편, 본 발명은 상기 화학식 1로 표시되는 2,4-다이아미노퀴나졸린 화합물의 제조방법을 포함한다.On the other hand, the present invention includes a method for producing a 2,4-diaminoquinazoline compound represented by the formula (1).

하기 반응식 1에 따른 하기 화학식 1로 표시되는 2,4-다이아미노퀴나졸린 화합물의 제조방법은, 하기 화학식 2로 표시되는 2-클로로-N-(퓨라닐메틸)퀴나졸린-4-아민 화합물과 하기 화학식 3으로 표시되는 아민화합물과 결합반응을 수행함으로써 이루어진다.Method for producing a 2,4-diaminoquinazoline compound represented by the following formula (1) according to Scheme 1, the 2-chloro- N- (furanylmethyl) quinazolin-4-amine compound represented by the formula (2) It is made by performing a coupling reaction with an amine compound represented by the following formula (3).

[반응식 1][Reaction Scheme 1]

상기 반응식 1에서, n, R₁, 및 R₂는 각각 상기에서 정의한 바와 같다.In Scheme 1, n, R ₁ , and R ₂ are each as defined above.

하기 반응식 1에 따른 결합반응은 메탄올, 에탄올 등의 알콜용매와 산 촉매를 사용하는 조건에서 수행한다. 이때 사용되는 산 촉매는 염산, 황산, 인산 등의 산의 수용액을 사용할 수 있으며, 좋기로는 염산 수용액을 사용하는 것이다. 반응온도는 사용된 알콜의 환류온도로서 구체적으로는 50℃ 내지 90℃ 온도를 유지한다.The coupling reaction according to Scheme 1 is carried out under conditions using an alcohol catalyst such as methanol and ethanol and an acid catalyst. At this time, the acid catalyst used may be an aqueous solution of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, preferably hydrochloric acid. The reaction temperature is a reflux temperature of the alcohol used, specifically, the temperature is maintained at 50 ℃ to 90 ℃.

또한, 상기 반응식 1에서 출발물질로 사용된 상기 화학식 2로 표시되는 2-클로로-N-(퓨라닐메틸)퀴나졸린-4-아민 화합물은 하기 반응식 2에 나타낸 합성방법에 의해 쉽게 제조하여 사용할 수 있다. In addition, the 2-chloro- N- (furanylmethyl) quinazolin-4-amine compound represented by Chemical Formula 2 used as a starting material in Scheme 1 can be easily prepared and used by the synthesis method shown in Scheme 2 below. have.

[반응식 2][Reaction Scheme 2]

상기 반응식 2에서, R₁은 상기에서 정의한 바와 같고, R은 수소원자 또는 C₁-C₆ 알킬기를 나타낸다.In Scheme 2, R ₁ is as defined above, R represents a hydrogen atom or a C ₁ -C ₆ alkyl group.

상기 반응식 2의 제조방법에서는, 먼저 상기 화학식 4로 표시되는 2-아미노벤조산, 우레아 및 페놀을 혼합하고 120℃ 내지 170℃ 온도로 가열 반응시켜 상기 화학식 5로 표시되는 퀴나졸린-2,4(1H,3H)-다이온을 제조한다. 그런 다음 상기 화학식 5로 표시되는 화합물과 포스포릴클로라이드 (POCl₃)를 아민 염기 존재하에서 100℃ 내지 130℃ 온도에서 환류가열 반응시켜 상기 화학식 6으로 표시되는 2,4-다이클로로퀴나졸린을 제조한다. 이때 사용되는 아민 염기는 트라이에틸아민 (TEA), N,N-다이아이소프로필에틸아민 (DIPEA), N,N-다이에틸아닐린 (DEA) 등을 사용할 수 있다. 그런 다음 상기 화학식 6으로 표시되는 화합물을 알콜용매에 용해시킨 후 퓨라닐메틸아민과 70℃ 내지 120℃ 온도에서 환류가열 반응시켜 상기 화학식 2로 표시되는 2-클로로-N-(퓨라닐메틸)퀴나졸린-4-아민 화합물을 제조한다. In the preparation method of Scheme 2, first, 2-aminobenzoic acid, urea, and phenol represented by Chemical Formula 4 are mixed, and heated and reacted at a temperature of 120 ° C. to 170 ° C. to quinazoline-2,4 (1). Prepare H , 3H ) -dione. Then, the compound represented by Chemical Formula 5 and phosphoryl chloride (POCl ₃ ) are heated under reflux at a temperature of 100 ° C. to 130 ° C. in the presence of an amine base to prepare 2,4-dichloroquinazolin represented by Chemical Formula 6. . The amine base used at this time may be triethylamine (TEA), N, N- diisopropylethylamine (DIPEA), N, N- diethylaniline (DEA) and the like. Then, the compound represented by Chemical Formula 6 is dissolved in an alcohol solvent, and then heated to reflux with furanylmethylamine at 70 ° C. to 120 ° C. to give 2-chloro- N- (furanylmethyl) quina represented by Chemical Formula 2 above. Prepare a zolin-4-amine compound.

또한, 상기 반응식 1에서 출발물질로 사용된 상기 화학식 3로 표시되는 다양한 아민 화합물은 하기 반응식 3에 나타낸 합성방법에 의해 쉽게 제조하여 사용할 수 있다. In addition, various amine compounds represented by Formula 3 used as starting materials in Scheme 1 can be easily prepared and used by the synthesis method shown in Scheme 3 below.

[반응식 3]Scheme 3

상기 반응식 3에서, n 및 R₂는 각각 상기에서 정의한 바와 같다.In Scheme 3, n and R ₂ are each as defined above.

상기 반응식 2의 제조방법에서는, 먼저 상기 화학식 7로 표시되는 2-브로모알킬아이소인돌린-1,3-다이온 화합물, R₂-H로 표시되는 화합물, 메틸 시아나이드(MeCN), 및 무기염기를 혼합하고, 70℃ 내지 120℃ 온도에서 환류가열 반응시켜 상기 화학식 8로 표시되는 R₂치환된 아이소인돌린-1,3-다이온 화합물을 제조한다. 그런 다음, 상기 화학식 8로 표시되는 화합물과 하이드라진을 알콜용매에서 70℃ 내지 120℃ 온도에서 환류가열 반응시켜 상기 화학식 3으로 표시되는 아민화합물을 제조한다.In the production method of Scheme 2, first, 2-bromoalkylisoindolin-1,3-dione compound represented by Chemical Formula 7, a compound represented by R ₂ -H, methyl cyanide (MeCN), and an inorganic compound The base is mixed and heated to reflux at 70 ° C. to 120 ° C. to prepare an R ₂ substituted isoindolin-1,3-dione compound represented by Chemical Formula 8. Thereafter, the compound represented by Chemical Formula 8 and the hydrazine are reflux heated at 70 ° C. to 120 ° C. in an alcohol solvent to prepare an amine compound represented by Chemical Formula 3.

상기에서 설명한 각 제조반응에서 합성된 화합물은 일반적인 분리 정제과정 예를 들면 유기 용매로 희석 및 세척한 후 유기층을 감압 농축할 수 있으며, 필요시 관 크로마토그래피로 정제할 수 있다.Compounds synthesized in each of the above-described preparation reactions may be diluted and washed with a general separation and purification process, for example, with an organic solvent, and the organic layer may be concentrated under reduced pressure, and, if necessary, purified by column chromatography.

또한, 본 발명은 상기 화학식 1로 표시되는 화합물의 약제학적으로 허용 가능한 염을 권리범위로 포함하는 바, 약제학적으로 허용 가능한 염의 제조방법은 공지된 문헌에 따른 통상적인 합성방법에 의하여 쉽게 제조될 수 있으며, 별다른 정제과정 없이도 순수하게 분리해 낼 수 있다. 다음에서는 염산염의 제조과정을 중심으로 상기 화학식 1로 표시되는 화합물의 약제학적으로 허용 가능한 염의 제조방법을 설명하고자 한다. 즉, 상기한 추출용매를 건조하고 증발시킨 다음, 잔여물을 에테르 소량에 녹이고, 여기에 염화수소의 에테르 용액을 약 1 내지 10 당량 정도 가하면 원하는 목표화합물의 염산염이 흰색 고체의 형태로 생성된다. 염화수소 용액을 제조하는데 사용 할 수 있는 유기용매는 클로로포름, 메틸렌클로리드, 에테르, 메탄올, 에틸아세테이트 또는 이들의 혼합용매를 사용할 수 있는데, 바람직하게는 에테르가 유용하다. 이때, 생성된 흰색 고체 형태로 얻어진 생성물은 원심 분리기나 간단한 솜을 사용한 용매 제거 장치를 사용하여 분리할 수 있다. 고체를 2 내지 3회에 걸쳐 에테르로 씻어 준 다음 잘 건조시키면 높은 순도의 염산염이 고체 상태로 얻어지게 된다.In addition, the present invention includes a pharmaceutically acceptable salt of the compound represented by the formula (1) as a right range, the method for preparing a pharmaceutically acceptable salt can be easily prepared by conventional synthetic methods according to known literature It can be separated purely without any purification process. Hereinafter, a method for preparing a pharmaceutically acceptable salt of the compound represented by the formula (1) will be described, focusing on the production process of the hydrochloride. That is, the extractant is dried and evaporated, and then the residue is dissolved in a small amount of ether, and about 1 to 10 equivalents of an ether solution of hydrogen chloride is added to form a hydrochloride of a desired target compound in the form of a white solid. The organic solvent that can be used to prepare the hydrogen chloride solution may be used chloroform, methylene chloride, ether, methanol, ethyl acetate or a mixed solvent thereof, preferably ether is useful. At this time, the product obtained in the form of a white solid can be separated using a centrifuge or a solvent removal device using a simple cotton. The solid is washed with ether two to three times and then dried well to obtain high purity hydrochloride in the solid state.

한편, 본 발명은 상기 화학식 1로 표시되는 2,4-다이아미노퀴나졸린 화합물 또는 약제학적 허용 가능한 이의 염을 치료상 유효성분으로 포함하는 약제조성물을 포함한다.On the other hand, the present invention includes a pharmaceutical composition comprising a 2,4-diaminoquinazoline compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as a therapeutically effective ingredient.

본 발명의 약제조성물은 상기 화학식 1로 표시되는 화합물 또는 약제학적 허용 가능한 이의 염과 함께 기타 통상적인 담체, 보조제 또는 희석제 등을 포함시켜 통상의 제제화 방법으로 제형화하여 경구투여 또는 비경구투여에 적합한 형태로 제조될 수 있다. 경구투여의 경우에는 정제, 캡슐제, 용액, 시럽제, 현탁제 등의 형태로 제조될 수 있고, 비경구투여의 경우에는 복강, 피하, 근육, 경피에 대한 주사제의 형태로 제조될 수 있다.The pharmaceutical composition of the present invention is suitable for oral or parenteral administration by formulating in a conventional formulation method including the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof and other conventional carriers, adjuvants or diluents and the like. It may be prepared in the form. In the case of oral administration, it may be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc., and in the case of parenteral administration, it may be prepared in the form of injections for intraperitoneal, subcutaneous, muscle, and transdermal.

본 발명의 약제조성물은 항암제로서 1일 유효투여량이 성인을 기준으로 0.01 내지 1000 mg/day이나, 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. The pharmaceutical composition of the present invention is an anticancer drug, and the effective daily dose is 0.01 to 1000 mg / day based on an adult, but the dosage may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. Depending on the judgment of the doctor or pharmacist, it may be administered once a day or divided into several times at regular intervals.

따라서, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 약제학적으로 허용 가능한 이들의 염 또는 이를 함유하는 약제학적 조성물을 암의 치료를 목적으로 사용하는 의약적 용도를 제공한다.Accordingly, the present invention provides a pharmaceutical use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same for the purpose of treating cancer.

상기한 바와 같은 본 발명은 다음의 실시예 및 실험예를 통하여 보다 상세히 설명하겠는 바, 본 발명이 이들 실시예 및 실험예에 의해 한정되는 것은 아니다.
The present invention as described above will be described in more detail through the following Examples and Experimental Examples, but the present invention is not limited to these Examples and Experimental Examples.

[참고실시예]
Reference Example

참고실시예 1. 퀴나졸린-2,4(1H,3H)-다이온 (화학식 5) 제조.Reference Example 1. Preparation of quinazoline-2,4 ( 1H , 3H ) -dione (Formula 5).

2-아미노벤조산 (0.1 mg, 0.72 mmol), 우레아 (0.22 mg, 3.72 mmol)와 페놀 (0.3 mg, 3.21 mmol)의 혼합 반응액을 150℃에서 10시간 가열하였다. 이 반응액을 100℃로 온도를 내렸다. 에틸알콜과 물(1:1)의 혼합액 5 mL를 첨가한 후, 반응액을 여과하고, 에틸알콜로 여러 번 세척한 후 목적화합물 0.096 mg (수율 82%)을 얻었다. The reaction mixture of 2-aminobenzoic acid (0.1 mg, 0.72 mmol), urea (0.22 mg, 3.72 mmol) and phenol (0.3 mg, 3.21 mmol) was heated at 150 ° C. for 10 hours. The reaction solution was cooled down to 100 ° C. After adding 5 mL of a mixture of ethyl alcohol and water (1: 1), the reaction solution was filtered, washed several times with ethyl alcohol to obtain 0.096 mg (yield 82%) of the title compound.

¹H NMR (300 MHz, DMSO-d ₆) δ 11.28 (s, 1H), 11.13 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.62 (quin, J = 7.7 Hz, 1H), 7.16 (t, J = 7.1 Hz, 2H)
¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.28 (s, 1H), 11.13 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.62 (quin, J = 7.7 Hz, 1H) , 7.16 (t, J = 7.1 Hz, 2H)

참고실시예 2. 2,4-다이클로로퀴나졸린 (화학식 6)의 제조Reference Example 2. Preparation of 2,4-dichloroquinazolin (Formula 6)

10℃에서 퀴나졸린-2,4(1H,3H)-다이온 (0.09 mg, 0.55 mmol)과 N,N-다이아이소프로필에틸아민 (DIPEA; 0.028 mL, 0.165 mmol)를 혼합한 용액에 포스포릴클로라이드 (POCl₃, 0.62 mL, 2.75 mmol)를 첨가한 후 14시간 동안 환류 가열하였다. 반응이 완료되면 0℃로 반응액의 온도를 내리고 1N NaOH 용액으로 중화하여 에틸 아세테이트로 추출하였다. 물로 유기용액을 씻어 준 후, 컬럼 크로마토그래피로 분리하여 목적화합물 0.053 mg (수율 48%)을 얻었다.To a solution of quinazoline-2,4 ( 1H , 3H ) -dione (0.09 mg, 0.55 mmol) and N, N -diisopropylethylamine (DIPEA; 0.028 mL, 0.165 mmol) at 10 ° C Phosphorylchloride (POCl ₃ , 0.62 mL, 2.75 mmol) was added and then heated to reflux for 14 hours. When the reaction was completed, the reaction solution was cooled to 0 ° C., neutralized with 1N NaOH solution, and extracted with ethyl acetate. The organic solution was washed with water and separated by column chromatography to obtain 0.053 mg (yield 48%) of the title compound.

¹H NMR (400 MHz, DMSO-d ₆) δ 8.32 (d, J = 0.7 Hz, 1H), 8.17 (quin, J = 1.4 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.91 (quin, J = 7.3 Hz, 1H)
¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.32 (d, J = 0.7 Hz, 1H), 8.17 (quin, J = 1.4 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.91 (quin, J = 7.3 Hz, 1H)

참고실시예 3. 2-클로로-N-(퓨란-2-일메틸)퀴나졸린-4-아민 (화학식 2)의 제조Reference Example 3. Preparation of 2-chloro- N- (furan-2-ylmethyl) quinazolin-4-amine (Formula 2)

에틸알콜 (1.2 mL)에 2,4-다이클로로퀴나졸린 (0.1 mg, 0.5 mmol)을 녹인 혼합액에 펄퍼릴아민 (0.046 mL, 0.5 mmol)을 첨가하여 16시간 동안 환류 가열하였다. 감압 농축하여 용매를 제거한 후 여액을 컬럼 크로마토그래피하여 목적화합물 0.028 mg (수율 44%)을 얻었다.To a mixture of 2,4-dichloroquinazoline (0.1 mg, 0.5 mmol) in ethyl alcohol (1.2 mL) was added perperylamine (0.046 mL, 0.5 mmol) and heated to reflux for 16 hours. After concentration under reduced pressure to remove the solvent, the filtrate was column chromatography to give 0.028 mg (yield 44%) of the title compound.

¹H NMR (400 MHz, CD₃OD) δ 8.21 (dd, J ₁ = 8.3 Hz, J ₂ = 0.78 Hz, 1H), 7.88 (t, J = 1.3 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 1.2 Hz, 1H), 7.55 (d, J = 1.2 Hz, 1H), 6.47 (d, J = 2.3 Hz, 2H), 4.88 (s,2H)
¹ H NMR (400 MHz, CD ₃ OD) δ 8.21 (dd, J ₁ = 8.3 Hz, J ₂ = 0.78 Hz, 1H), 7.88 (t, J = 1.3 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 1.2 Hz, 1H), 7.55 (d, J = 1.2 Hz, 1H), 6.47 (d, J = 2.3 Hz, 2H), 4.88 (s, 2H)

참고실시예 4. 2-(4-(4-(2,3-다이메틸페닐)피페라진-1-일)부틸)아이소인돌린-1,3-다이온 (화학식 8)의 제조 Reference Example 4. Preparation of 2- (4- (4- (2,3-dimethylphenyl) piperazin-1-yl) butyl) isoindolin-1,3-dione (Formula 8)

메틸시아나이드(2 mL)에 2-(4-브로모부틸)아이소인돌린-1,3-다이온 (0.12 mg, 0.43 mmol), 1-(2,3-다이메틸페닐피페라진) (0.1 mg, 0.52 mmol)과 K₂CO₃(0.06 mg, 0.43 mmol)를 첨가한 후, 환류 가열하였다. 반응이 완결되면 감압 농축하여 용매를 제거하고 물과 다이클로로메탄으로 여과한 후 무수 황산마그네슘으로 건조, 여과 및 농축시킨 다음, 컬럼 크로마토그래피로 분리하여 목적화합물 0.18 mg (수율 90%)을 얻었다.Methyl cyanide (2 mL) in 2- (4-bromobutyl) isoindolin-1,3-dione (0.12 mg, 0.43 mmol), 1- (2,3-dimethylphenylpiperazine) (0.1 mg , 0.52 mmol) and K ₂ CO ₃ (0.06 mg, 0.43 mmol) were added followed by heating to reflux. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, filtered with water and dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated, and then separated by column chromatography to obtain 0.18 mg (yield 90%) of the title compound.

¹H NMR (300 MHz, DMSO-d ₆) δ 7.88-7.81 (m, 4H), 7.01 (t, J = 7.7 Hz, 1H), 6.85 (d, J = 7.8 Hz, 2H), 3.59 (t, J = 6.8 Hz, 2H), 2.74 (s, 4H), 2.49 (s, 4H), 2.33 (t, J = 6.8 Hz, 2H), 2.18 (s, 3H), 2.11 (s, 3H), 1.62 (quin, J = 6.8 Hz, 2H), 1.47 (quin, J = 6.8 Hz, 2H)
¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.88-7.81 (m, 4H), 7.01 (t, J = 7.7 Hz, 1H), 6.85 (d, J = 7.8 Hz, 2H), 3.59 (t, J = 6.8 Hz, 2H), 2.74 (s, 4H), 2.49 (s, 4H), 2.33 (t, J = 6.8 Hz, 2H), 2.18 (s, 3H), 2.11 (s, 3H), 1.62 ( quin, J = 6.8 Hz, 2H), 1.47 (quin, J = 6.8 Hz, 2H)

참고실시예 5. 4-(4-(2,3-다이메틸페닐)피페라진-1-일)부탄-1-아민 (화학식 3)의 제조Reference Example 5. Preparation of 4- (4- (2,3-dimethylphenyl) piperazin-1-yl) butan-1-amine (Formula 3)

에틸알콜에 2-(4-(4-(2,3-다이메틸페닐)피페라진-1-일)부틸)아이소인돌린-1,3-다이온 (0.1 mg, 0.25 mmol)을 녹이고 하이드라진 (0.038 mL, 0.76 mmol)을 첨가한 후 환류 가열하였다. 반응이 완료되면 75%의 용매를 제거한 후 여과하여 고체를 제거하였고, 여액은 농축하여 목적화합물을 얻었다. Dissolve 2- (4- (4- (2,3-dimethylphenyl) piperazin-1-yl) butyl) isoindolin-1,3-dione (0.1 mg, 0.25 mmol) in ethyl alcohol and hydrazine (0.038) mL, 0.76 mmol) was added and then heated to reflux. After the reaction was completed, 75% of the solvent was removed and then filtered to remove the solid, the filtrate was concentrated to give the target compound.

¹H NMR (300 MHz, CD₃OD) δ 7.03 (t, J = 7.7 Hz, 1H), 6.90 (q, J = 7.9 Hz, 2H), 2.90 (d, J = 4.0 Hz, 4H), 2.74 (t, J = 7.0 Hz, 2H), 2.67 (s, 4H), 2.46 (t, J = 7.7 Hz, 2H), 2.25 (s, 3H), 2.22 (s, 3H), 1.64-1.56 (m, 4H)
¹ H NMR (300 MHz, CD ₃ OD) δ 7.03 (t, J = 7.7 Hz, 1H), 6.90 (q, J = 7.9 Hz, 2H), 2.90 (d, J = 4.0 Hz, 4H), 2.74 ( t, J = 7.0 Hz, 2H), 2.67 (s, 4H), 2.46 (t, J = 7.7 Hz, 2H), 2.25 (s, 3H), 2.22 (s, 3H), 1.64-1.56 (m, 4H )

참고실시예 6. 2N-(4-(4-(2,3-다이메틸페닐)피페라진-1-일)부틸)-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화학식 1)의 제조Reference Example 6. 2 N- (4- (4- (2,3-dimethylphenyl) piperazin-1-yl) butyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4- Preparation of Diamine (Formula 1)

에틸알콜 (2 mL)에 2-클로로-N-(퓨란-2-일메틸)퀴나졸린-4-아민 (0.03 mg, 0.11 mmol)녹이고, 4-(4-(2,3-다이메틸페닐)피페라진-1-일)부탄-1-아민 (0.034 mg, 0.132 mmol)과 촉매제로 농축된 HCl을 첨가하여 16시간 동안 환류 가열하였다. 용매를 감압 농축한 후, 여액을 물과 다이클로로메탄으로 추출하고 무수 황산마그네슘으로 건조하였다. 유기용매를 감압 농축한 후 컬럼 크로마토그래피하여 목적화합물 0.022 mg (수율 41%)을 얻었다.2-chloro- N- (furan-2-ylmethyl) quinazolin-4-amine (0.03 mg, 0.11 mmol) is dissolved in ethyl alcohol (2 mL), and 4- (4- (2,3-dimethylphenyl) pipe Rajin-1-yl) butan-1-amine (0.034 mg, 0.132 mmol) and HCl concentrated with catalyst were added and heated to reflux for 16 h. The solvent was concentrated under reduced pressure, and the filtrate was extracted with water and dichloromethane and dried over anhydrous magnesium sulfate. The organic solvent was concentrated under reduced pressure, and then column chromatography gave 0.022 mg (yield 41%) of the title compound.

¹H NMR (300 MHz, CD₃OD) δ 7.73 (dd, J ₁ = 9.5 Hz, J ₂ = 2.7 Hz, 1H), 7.51 (d, J = 1.0 Hz, 1H), 7.43 (dd, J ₁ = 7.8 Hz, J ₂ = 2.5 Hz, 2H), 7.11 (m, 1H), 6.97 (q, J = 7.3 Hz, 3H), 6.43 (q, J = 1.8 Hz, 1H), 6.38 (d, J = 2.7 Hz, 1H), 4.86 (s, 2H), 3.57 (t, J = 6.2 Hz, 2H), 2.96 (t, J = 4.8 Hz, 4H), 2.73 (s, 4H), 2.56 (t, J = 7.1 Hz, 4H), 2.32 (s, 3H), 2.28 (s, 3H), 1.76 (q, J = 3.0 Hz, 4H), ¹³C NMR (400 MHz, CD₃OD) δ 149.19, 148.90, 140.70, 136.17, 133.37, 129.32, 124.07, 123.71, 122.78, 121.77, 144.73, 108.63, 105.99, 55.72, 51.48, 49.04, 39.15, 36.35, 24.93, 20.94, 17.69, 11.03
¹ H NMR (300 MHz, CD ₃ OD) δ 7.73 (dd, J ₁ = 9.5 Hz, J ₂ = 2.7 Hz, 1H), 7.51 (d, J = 1.0 Hz, 1H), 7.43 (dd, J ₁ = 7.8 Hz, J ₂ = 2.5 Hz, 2H), 7.11 (m, 1H), 6.97 (q, J = 7.3 Hz, 3H), 6.43 (q, J = 1.8 Hz, 1H), 6.38 (d, J = 2.7 Hz, 1H), 4.86 (s, 2H), 3.57 (t, J = 6.2 Hz, 2H), 2.96 (t, J = 4.8 Hz, 4H), 2.73 (s, 4H), 2.56 (t, J = 7.1 Hz, 4H), 2.32 (s, 3H), 2.28 (s, 3H), 1.76 (q, J = 3.0 Hz, 4H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 149.19, 148.90, 140.70, 136.17 , 133.37, 129.32, 124.07, 123.71, 122.78, 121.77, 144.73, 108.63, 105.99, 55.72, 51.48, 49.04, 39.15, 36.35, 24.93, 20.94, 17.69, 11.03

[실시예][Example]

상기 참고실시예에 근거하여 본 발명의 화합물을 합성하였으며, 합성된 각 화합물의 구조 확인 데이터는 다음과 같다.
Compounds of the present invention were synthesized based on the above reference examples, and the structural confirmation data of each synthesized compound is as follows.

4N-(퓨란-2-일메틸)-2N-(4-메톡시페닐)퀴나졸린-2,4-다이아민 (화합물번호 1)4 N- (furan-2-ylmethyl) -2 N- (4-methoxyphenyl) quinazolin-2,4-diamine (Compound No. 1)

수율 41%, ¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, J = 8.2 Hz, 1H), 7.79 (t, J = 8.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.46 (t, J = 4.9 Hz, 2H), 7.43 (t, J = 4.2 Hz, 2H), 7.03 (d, J = 8.7 Hz, 1H), 6.36 (q, J = 1.8 Hz,1H), 6.25 (s, 1H), 4.82 (s, 2H), 3.82 (s, 3H), ¹³C NMR (400 MHz, CD₃OD) δ 160.64, 150.30, 142.27, 139.04, 135.17, 126.04, 124.96, 123.39, 117.05, 114.27, 110.33, 110.11, 107.91, 54.62, 37.90
Yield 41%, ¹ H NMR (400 MHz, CD ₃ OD) δ 8.15 (d, J = 8.2 Hz, 1H), 7.79 (t, J = 8.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H ), 7.46 (t, J = 4.9 Hz, 2H), 7.43 (t, J = 4.2 Hz, 2H), 7.03 (d, J = 8.7 Hz, 1H), 6.36 (q, J = 1.8 Hz, 1H), 6.25 (s, 1H), 4.82 (s, 2H), 3.82 (s, 3H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 160.64, 150.30, 142.27, 139.04, 135.17, 126.04, 124.96, 123.39, 117.05 , 114.27, 110.33, 110.11, 107.91, 54.62, 37.90

2N-(4-(4-(2,3-다이메틸페닐)피페라진-1-일)부틸)-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 2)2 N- (4- (4- (2,3-dimethylphenyl) piperazin-1-yl) butyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 2)

수율 41%, ¹H NMR (300 MHz, CD₃OD) δ 7.73 (dd, J ₁ = 9.5 Hz, J ₂ = 2.7 Hz, 1H), 7.51 (d, J = 1.0 Hz, 1H), 7.43 (dd, J ₁ = 7.8 Hz, J ₂ = 2.5 Hz, 2H), 7.11 (m, 1H), 6.97 (q, J = 7.3 Hz, 3H), 6.43 (q, J = 1.8 Hz, 1H), 6.38 (d, J = 2.7 Hz, 1H), 4.86 (s, 2H), 3.57 (t, J = 6.2 Hz, 2H), 2.96 (t, J = 4.8 Hz, 4H), 2.73 (s, 4H), 2.56 (t, J = 7.1 Hz, 4H), 2.32 (s, 3H), 2.28 (s, 3H), 1.76 (q, J = 3.0 Hz, 4H), ¹³C NMR (400 MHz, CD₃OD) δ 149.19, 148.90, 140.70, 136.17, 133.37, 129.32, 124.07, 123.71, 122.78, 121.77, 144.73, 108.63, 105.99, 55.72, 51.48, 49.04, 39.15, 36.35, 24.93, 20.94, 17.69, 11.03
Yield 41%, ¹ H NMR (300 MHz, CD ₃ OD) δ 7.73 (dd, J ₁ = 9.5 Hz, J ₂ = 2.7 Hz, 1H), 7.51 (d, J = 1.0 Hz, 1H), 7.43 (dd , J ₁ = 7.8 Hz, J ₂ = 2.5 Hz, 2H), 7.11 (m, 1H), 6.97 (q, J = 7.3 Hz, 3H), 6.43 (q, J = 1.8 Hz, 1H), 6.38 (d , J = 2.7 Hz, 1H), 4.86 (s, 2H), 3.57 (t, J = 6.2 Hz, 2H), 2.96 (t, J = 4.8 Hz, 4H), 2.73 (s, 4H), 2.56 (t , J = 7.1 Hz, 4H), 2.32 (s, 3H), 2.28 (s, 3H), 1.76 (q, J = 3.0 Hz, 4H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 149.19, 148.90 , 140.70, 136.17, 133.37, 129.32, 124.07, 123.71, 122.78, 121.77, 144.73, 108.63, 105.99, 55.72, 51.48, 49.04, 39.15, 36.35, 24.93, 20.94, 17.69, 11.03

2N-(3-(4-(2,3-다이메틸페닐)피페라진-1-일)프로필)-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 3)2 N- (3- (4- (2,3-dimethylphenyl) piperazin-1-yl) propyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 3)

수율 41% ¹H NMR (400 MHz, CD₃OD) δ 8.14 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.49 (s, 2H), 7.42 (t, J = 7.7 Hz, 1H), 7.04 (t, J = 7.7 Hz, 1H), 6.90 (t, J = 7.3 Hz, 2H), 6.42 (s, 2H), 4.92 (s, 2H), 3.68 (t, J = 6.2 Hz, 2H), 3.15 (s, 8H), 2.86 (t, J = 6.2 Hz, 2H), 2.26 (s, 3H), 2.23 (s, 3H), 2.07 (quin, J = 6.5 Hz, 2H), ¹³C NMR (400 MHz, CD₃OD) δ 149.20, 149.0, 140.71, 136.12, 129.30, 124.04, 123.62, 122.77, 121.79, 114.71, 108.64, 106.04, 53.65, 51.51, 49.21, 37.58, 36.33, 23.43, 17.69, 11.04
Yield 41% ¹ H NMR (400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.49 (s, 2H), 7.42 (t, J = 7.7 Hz, 1H), 7.04 (t, J = 7.7 Hz, 1H), 6.90 (t, J = 7.3 Hz, 2H), 6.42 (s, 2H), 4.92 (s, 2H), 3.68 (t, J = 6.2 Hz, 2H), 3.15 (s, 8H), 2.86 (t, J = 6.2 Hz, 2H), 2.26 (s, 3H), 2.23 (s, 3H), 2.07 (quin, J = 6.5 Hz, 2H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 149.20, 149.0, 140.71, 136.12, 129.30, 124.04, 123.62, 122.77, 121.79, 114.71, 108.64, 106.04, 53.65, 51.51, 49.21, 37.58, 36.33, 23.43 , 17.69, 11.04

2N-(3-(4-(2,3-다이클로로페닐)피페라진-1-일)프로필)-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 4)2 N- (3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (compound Number 4)

수율 41%, ¹H NMR (400 MHz, CD₃OD) δ 7.90 (d, J = 8.0 Hz,1H), 7.54 (t, J = 7.4 Hz, 1H), 7.41 (s, 1H), 7.36 (d, J = 7.3 Hz, 1H), 7.19 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.02 (dd, J ₁ = 6.0 Hz, J ₂ = 3.3 Hz, 1H), 6.34 (q, J = 1.9 Hz,1H), 6.29 (d, J = 3.3 Hz, 1H), 4.80 (s, 2H), 3.57 (t, J = 6.1 Hz, 2H), 3.03 (s, 4H), 2.64 (s, 4H), 2.54 (t, J = 7.1 Hz, 2H), 1.86 (t, J = 6.9 Hz,2H), ¹³C NMR (400 MHz, CD₃OD) δ 160.36, 158.78, 152.36, 151.17, 141.63, 133.45, 132.82, 127.61, 126.94, 14.36, 122.26, 121.5, 118.72, 110.01, 106.67, 56.09, 52.97, 50.70, 39.51, 37.26, 26.21
Yield 41%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.90 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.41 (s, 1H), 7.36 (d , J = 7.3 Hz, 1H), 7.19 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.02 (dd, J ₁ = 6.0 Hz, J ₂ = 3.3 Hz, 1H), 6.34 (q , J = 1.9 Hz, 1H), 6.29 (d, J = 3.3 Hz, 1H), 4.80 (s, 2H), 3.57 (t, J = 6.1 Hz, 2H), 3.03 (s, 4H), 2.64 (s , 4H), 2.54 (t, J = 7.1 Hz, 2H), 1.86 (t, J = 6.9 Hz, 2H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 160.36, 158.78, 152.36, 151.17, 141.63, 133.45, 132.82, 127.61, 126.94, 14.36, 122.26, 121.5, 118.72, 110.01, 106.67, 56.09, 52.97, 50.70, 39.51, 37.26, 26.21

2N-(4-(4-(2,3-다이클로로페닐)피페라진-1-일)부틸)-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 5)2 N- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (compound Number 5)

수율 41%, ¹H NMR (400 MHz, CD₃OD) δ 7.90 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 3.4 Hz, 1H), 7.42 (s, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.19 (m, 2H), 7.12 (t, J = 7.6 Hz, 1H), 7.04 (dd, J ₁ = 6.8 Hz, J ₂ = 2.6 Hz, 1H), 6.35 (q, J = 1.9 Hz, 1H), 6.30 (d, J = 3.0 Hz, 1H), 4.80 (s, 2H), 3.50 (t, J = 6.2 Hz, 2H), 3.13 (s, 4H), 2.64 (s, 4H), 2.47 (t, J = 7.2 Hz, 2H), 1.66 (q, J = 5.9 Hz, 4H), ¹³C NMR (400 MHz, CD₃OD) δ 152.21, 151.12, 141.67, 133.45, 133.05, 127.62, 126.93, 124.37, 122.34, 121.50, 118.72, 110.68, 110.01, 106.71, 57.97, 52.90, 50.58, 40.70, 37.32, 27.39, 23.48
Yield 41%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.90 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 3.4 Hz, 1H), 7.42 (s, 1H), 7.37 (d , J = 7.6 Hz, 1H), 7.19 (m, 2H), 7.12 (t, J = 7.6 Hz, 1H), 7.04 (dd, J ₁ = 6.8 Hz, J ₂ = 2.6 Hz, 1H), 6.35 (q , J = 1.9 Hz, 1H), 6.30 (d, J = 3.0 Hz, 1H), 4.80 (s, 2H), 3.50 (t, J = 6.2 Hz, 2H), 3.13 (s, 4H), 2.64 (s , 4H), 2.47 (t, J = 7.2 Hz, 2H), 1.66 (q, J = 5.9 Hz, 4H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 152.21, 151.12, 141.67, 133.45, 133.05, 127.62, 126.93, 124.37, 122.34, 121.50, 118.72, 110.68, 110.01, 106.71, 57.97, 52.90, 50.58, 40.70, 37.32, 27.39, 23.48

2N-(2-(다이메틸아미노)에틸)-4N-(퓨란-2일메틸)퀴나졸린-2,4-다이아민 (화합물번호 6) 2 N- (2- (dimethylamino) ethyl) -4 N- (furan-2ylmethyl) quinazolin-2,4-diamine (Compound No. 6)

수율 22%, ¹H NMR (400 MHz, CD₃OD) δ 7.95 (d, J = 7.6 Hz,1H), 7.63 (t, J = 7.3 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.2 (t, J = 7.3 Hz, 1H), 6.45 (d, J = 2.3 Hz, 1H), 6.38 (J = 3.1 Hz, 1H), 4.89 (s, 2H), 3.69 (t, J = 6.7 Hz,2H), 2.70 (t, J = 6.5 Hz, 2H), 2.41 (s, 6H), ¹³C NMR (400 MHz, CD₃OD) δ 162.97, 158.89, 151.11, 139.95, 130.89, 120.53, 119.27, 108.40, 104.83, 56.94, 42.61, 36.85, 35.60
Yield 22%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.95 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 7.3 Hz, 1H), 7.52 (s, 1H), 7.45 (d , J = 8.0 Hz, 1H), 7.2 (t, J = 7.3 Hz, 1H), 6.45 (d, J = 2.3 Hz, 1H), 6.38 ( J = 3.1 Hz, 1H), 4.89 (s, 2H), 3.69 (t, J = 6.7 Hz, 2H), 2.70 (t, J = 6.5 Hz, 2H), 2.41 (s, 6H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 162.97, 158.89, 151.11, 139.95 , 130.89, 120.53, 119.27, 108.40, 104.83, 56.94, 42.61, 36.85, 35.60

2N-(2-몰포리노에틸)-4N-(퓨란-2일메틸)퀴나졸린-2,4-다이아민 (화합물번호 7)2 N- (2-morpholinoethyl) -4 N- (furan-2ylmethyl) quinazolin-2,4-diamine (Compound No. 7)

수율 16%, ¹H NMR (400 MHz, CD₃OD) δ 7.90 (dd, J ₁ = 6.8 Hz, J ₂ = 0.8 Hz, 1H), 7.55 (m, 1H), 7.42 (0.68 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.13 (m, 1H), 6.34 (q, J = 1.8 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H), 4.84 (s, 2H), 3.68 (t, J = 4.5 Hz, 4H), 3.59 (t, J = 6.5 Hz, 2H), 2.59 (t, J = 6.5 Hz, 2H), 2.45(J = 6.5 Hz, 4H), ¹³C NMR (400 MHz, CD₃OD) δ 162.47, 160.45, 158.28, 152.18, 148.62, 141.68, 133.04, 122.35, 121.92, 121.58, 110.03, 106.71, 66.35, 57.55, 53.31, 37.51
Yield 16%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.90 (dd, J ₁ = 6.8 Hz, J ₂ = 0.8 Hz, 1H), 7.55 (m, 1H), 7.42 (0.68 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.13 (m, 1H), 6.34 (q, J = 1.8 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H), 4.84 (s, 2H), 3.68 (t, J = 4.5 Hz, 4H), 3.59 (t, J = 6.5 Hz, 2H), 2.59 (t, J = 6.5 Hz, 2H), 2.45 ( J = 6.5 Hz, 4H), ¹³ C NMR ( 400 MHz, CD ₃ OD) δ 162.47, 160.45, 158.28, 152.18, 148.62, 141.68, 133.04, 122.35, 121.92, 121.58, 110.03, 106.71, 66.35, 57.55, 53.31, 37.51

4N-(퓨란-2일메틸)-2N-펜틸퀴나졸린-2,4-다이아민 (화합물번호 8)4 N- (furan-2ylmethyl) -2 N -pentylquinazolin-2,4-diamine (Compound No. 8)

수율 16%, ¹H NMR (400 MHz, CD₃OD) δ 7.84 (dd, J ₁ = 8.2 Hz, J ₂ = 1.2 Hz, 1H), 7.48 (m, 1H), 7.39 (t, J = 0.6 Hz, 1H), 7.3 (d, J = 8.0 Hz, 1H), 7.04 (m, 1H), 6.32 (q, J = 1.9 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 4.81 (s, 2H), 3.4 (t, J = 6.7 Hz, 2H), 1.58 (quin, J = 6.9 Hz, 2H), 1.32 (q, J = 3.6 Hz, 4H), 0.90 (t, J = 5.0 Hz,3H), ¹³C NMR (400 MHz, CD₃OD) δ 160.31, 159.53, 152.57, 150.84, 141.50, 132.46, 123.03, 122.34, 122.05, 120.69, 110.87, 109.93, 106.50, 40.93, 37.14, 29.40, 28.99, 22.20, 13.08
Yield 16%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.84 (dd, J ₁ = 8.2 Hz, J ₂ = 1.2 Hz, 1H), 7.48 (m, 1H), 7.39 (t, J = 0.6 Hz , 1H), 7.3 (d, J = 8.0 Hz, 1H), 7.04 (m, 1H), 6.32 (q, J = 1.9 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 4.81 (s , 2H), 3.4 (t, J = 6.7 Hz, 2H), 1.58 (quin, J = 6.9 Hz, 2H), 1.32 (q, J = 3.6 Hz, 4H), 0.90 (t, J = 5.0 Hz, 3H ), ¹³ C NMR (400 MHz, CD ₃ OD) δ 160.31, 159.53, 152.57, 150.84, 141.50, 132.46, 123.03, 122.34, 122.05, 120.69, 110.87, 109.93, 106.50, 40.93, 37.14, 29.40, 28.99, 22.20, 13.08

4N-(퓨란-2일메틸)-2N-(3-몰포리노프로필)퀴나졸린-2,4-다이아민 (화합물번호 9)4 N- (furan-2ylmethyl) -2 N- (3-morpholinopropyl) quinazolin-2,4-diamine (Compound No. 9)

수율 17%, ¹H NMR (400 MHz, CD₃OD) δ 7.87 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 3.0 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J = 7.1 Hz, 1H), 7.1 (t, J = 7.2 Hz, 1H), 6.34 (d, J = 1.7 Hz, 1H), 6.29 (d, J = 0.9 Hz, 1H), 4.78 (s, 2H), 3.67 (t, J = 4.6 Hz, 4H), 3.48 (t, J = 4.0 Hz, 2H), 2.43 (d, J = 4.3 Hz, 6H), 1.83 (quin, J = 7.0 Hz, 2H), ¹³C NMR (400 MHz, CD₃OD) δ 160.38, 159.24, 152.51, 150.32, 141.57, 141.57, 132.62, 122.81, 122.10, 120.97, 110.85, 109.97, 106.52, 66.28, 56.49, 53.38, 39.36, 37.20, 26.02
Yield 17%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.87 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 3.0 Hz, 1H), 7.41 (s, 1H), 7.34 (d , J = 7.1 Hz, 1H), 7.1 (t, J = 7.2 Hz, 1H), 6.34 (d, J = 1.7 Hz, 1H), 6.29 (d, J = 0.9 Hz, 1H), 4.78 (s, 2H ), 3.67 (t, J = 4.6 Hz, 4H), 3.48 (t, J = 4.0 Hz, 2H), 2.43 (d, J = 4.3 Hz, 6H), 1.83 (quin, J = 7.0 Hz, 2H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 160.38, 159.24, 152.51, 150.32, 141.57, 141.57, 132.62, 122.81, 122.10, 120.97, 110.85, 109.97, 106.52, 66.28, 56.49, 53.38, 39.36, 37.20, 26.02

2N-(3-(다이메틸아미노)프로필)-4N-(퓨란-2-일메틸)퀴나졸린-2,4 다이아민 (화합물번호 10) 2 N- (3- (dimethylamino) propyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4 diamine (Compound No. 10)

수율 16% , ¹H NMR (300 MHz, CD₃OD) δ 7.85 (d, J = 7.3 Hz, 1H), 7.52 (t, J = 5.6 Hz, 1H), 7.42 (s, 1H), 7.34 (d, J = 8. Hz, 1H), 7.08 (t, J = 6.9 Hz, 1H), 6.34 (d, J = 1.2 Hz, 1H), 6.28 (J = 0.6 Hz, 1H), 4.78 (s, 2H), 3.47 (t, J = 6.8 Hz, 2H), 2.45 (t, J = 7.5 Hz, 2H), 2.26 (s, 6H), 1.82 (quin, J = 7.8 Hz, 2H), ¹³C NMR (300 MHz, CD₃OD) δ 160.40, 159.68, 152.62, 151.03, 141.51, 132.46, 123.22, 122.02, 120.75, 110.92, 109.94, 106.45, 56.85, 43.92, 39.0, 37.15, 27.24
Yield 16%, ¹ H NMR (300 MHz, CD ₃ OD) δ 7.85 (d, J = 7.3 Hz, 1H), 7.52 (t, J = 5.6 Hz, 1H), 7.42 (s, 1H), 7.34 (d , J = 8. Hz, 1H), 7.08 (t, J = 6.9 Hz, 1H), 6.34 (d, J = 1.2 Hz, 1H), 6.28 ( J = 0.6 Hz, 1H), 4.78 (s, 2H) , 3.47 (t, J = 6.8 Hz, 2H), 2.45 (t, J = 7.5 Hz, 2H), 2.26 (s, 6H), 1.82 (quin, J = 7.8 Hz, 2H), ¹³ C NMR (300 MHz , CD ₃ OD) δ 160.40, 159.68, 152.62, 151.03, 141.51, 132.46, 123.22, 122.02, 120.75, 110.92, 109.94, 106.45, 56.85, 43.92, 39.0, 37.15, 27.24

4N-(퓨란-2-일메틸)-2N-(3-(피롤리딘-1-일)프로필)퀴나졸린-2,4-다이아민 (화합물번호 11)4 N- (furan-2-ylmethyl) -2 N- (3- (pyrrolidin-1-yl) propyl) quinazolin-2,4-diamine (Compound No. 11)

수율 18%, ¹H NMR (400 MHz, CD₃OD) δ 7.85 (dd, J ₁ = 8.0 Hz, J ₂ = 1.1 Hz, 1H), 7.50 (m, 1H), 7.40 (t, J = 0.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.06 (m, 1H), 6.33 (q, J = 1.8 Hz, 1H), 6.27 (d, J = 0.5 Hz, 1H), 4.77 (s, 2H), 3.47 (t, J = 6.7 Hz, 2H), 2.51 (quin, J = 2.9 Hz, 6H), 1.85 (t, J = 8.0 Hz, 2H), 1.79 (quin, J = 3.9 Hz, 4H), ¹³C NMR (400 MHz, CD₃OD) δ 160.35, 159.75, 152.67, 151.30, 141.51, 132.41, 123.35, 122.01, 120.64, 110.92, 109.95, 106.47, 53.81, 53.60, 39.52, 39.20, 37.12, 28.69, 22.75
Yield 18%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.85 (dd, J ₁ = 8.0 Hz, J ₂ = 1.1 Hz, 1H), 7.50 (m, 1H), 7.40 (t, J = 0.8 Hz , 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.06 (m, 1H), 6.33 (q, J = 1.8 Hz, 1H), 6.27 (d, J = 0.5 Hz, 1H), 4.77 (s , 2H), 3.47 (t, J = 6.7 Hz, 2H), 2.51 (quin, J = 2.9 Hz, 6H), 1.85 (t, J = 8.0 Hz, 2H), 1.79 (quin, J = 3.9 Hz, 4H ), ¹³ C NMR (400 MHz, CD ₃ OD) δ 160.35, 159.75, 152.67, 151.30, 141.51, 132.41, 123.35, 122.01, 120.64, 110.92, 109.95, 106.47, 53.81, 53.60, 39.52, 39.20, 37.12, 28.69, 22.75

2N-(2-(다이에틸아미노)에틸)-4N-(퓨라노-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 12)2 N- (2- (diethylamino) ethyl) -4 N- (furano-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 12)

수율 17%, ¹H NMR (400 MHz, CD₃OD) δ 7.86-7.83 (m, 1H), 7.52-7.49 (m, 1H), 7.4 (t, J = 1.6 Hz, 1H), 7.3 (d, J = 8.2 Hz, 1H), 7.08-7.04 (m, 1H), 6.32 (dd, J = 1.7 Hz, 1H), 6.2 (d, J = 3.1 Hz, 1H), 4.78 (s, 2H), 3.54 (t, J = 6.6 Hz, 2H), 2.67 (q, J = 6.9 Hz, 2H), 2.61-2.56 (m, 4H), 1.07-0.98 (m, 6H), ¹³C NMR (400 MHz, CD₃OD) δ 162.43, 160.5, 159.7, 152.63, 151.34, 141.5, 132.42, 123.45, 122.01, 120.69, 110.95, 109.94, 106.4, 51.99, 38.33, 38.25, 10.29, 10.21
Yield 17%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.86-7.83 (m, 1H), 7.52-7.49 (m, 1H), 7.4 (t, J = 1.6 Hz, 1H), 7.3 (d, J = 8.2 Hz, 1H), 7.08-7.04 (m, 1H), 6.32 (dd, J = 1.7 Hz, 1H), 6.2 (d, J = 3.1 Hz, 1H), 4.78 (s, 2H), 3.54 ( t, J = 6.6 Hz, 2H), 2.67 (q, J = 6.9 Hz, 2H), 2.61-2.56 (m, 4H), 1.07-0.98 (m, 6H), ¹³ C NMR (400 MHz, CD ₃ OD δ 162.43, 160.5, 159.7, 152.63, 151.34, 141.5, 132.42, 123.45, 122.01, 120.69, 110.95, 109.94, 106.4, 51.99, 38.33, 38.25, 10.29, 10.21

2N-(3-(다이에틸아미노)프로필)-4N-(퓨라노-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 13) 2 N- (3- (diethylamino) propyl) -4 N- (furano-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 13)

수율 20%, ¹H NMR (400 MHz, CD₃OD) δ 8.1 (d, J = 8.1 Hz, 1H), 7.79 (t, J = 7.2 Hz, 1H), 7.49 (s, 2H), 7.40 (t, J = 7.3 Hz, 1H), 6.42 (s, 2H), 4.88 (s, 2H), 3.7 (t, J = 6.5 Hz, 2H), 3.2 (quin, J = 7.5 Hz, 6H), 2.1 (m, 2H), 1.35 (t, J = 5.9 Hz, 6H), ¹³C NMR (400 MHz, CD₃OD) δ 160.62, 153.57, 150.65, 142.31, 139.55, 135.1, 124.59, 123.45, 116.84, 110.25, 109.91, 107.64, 53.42, 38.17, 23.65, 7.8
Yield 20%, ¹ H NMR (400 MHz, CD ₃ OD) δ 8.1 (d, J = 8.1 Hz, 1H), 7.79 (t, J = 7.2 Hz, 1H), 7.49 (s, 2H), 7.40 (t , J = 7.3 Hz, 1H), 6.42 (s, 2H), 4.88 (s, 2H), 3.7 (t, J = 6.5 Hz, 2H), 3.2 (quin, J = 7.5 Hz, 6H), 2.1 (m , 2H), 1.35 (t, J = 5.9 Hz, 6H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 160.62, 153.57, 150.65, 142.31, 139.55, 135.1, 124.59, 123.45, 116.84, 110.25, 109.91, 107.64, 53.42, 38.17, 23.65, 7.8

2N-부틸-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 14) 2 N- butyl-4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 14)

수율 15%, ¹H NMR (400 MHz, CD₃OD) δ 7.92 (d, J = 8.2, 1H), 7.59 (t, J = 7.14 Hz, 1H), 7.4 (s,1H), 7.37 (d, J = 7.4 Hz, 1H), 7.2 (t, J = 7.2 Hz, 1H), 6.35 (d, J = 3.1 Hz, 1H), 6.3 (d, J = 2.9 Hz, 1H), 4.8 (s, 2H), 3.46 (t, J = 7.1 Hz, 2H), 1.6 (quin, J = 7.3 Hz, 2H), 1.45 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H), ¹³C NMR (400 MHz, CD₃OD) δ 160.31, 157.24, 151.85, 141.75, 133.38, 122.52, 122.06, 110.48, 109.98, 106.87, 40.74, 37.38, 31.51, 19.76, 12.82
Yield 15%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.92 (d, J = 8.2, 1H), 7.59 (t, J = 7.14 Hz, 1H), 7.4 (s, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.2 (t, J = 7.2 Hz, 1H), 6.35 (d, J = 3.1 Hz, 1H), 6.3 (d, J = 2.9 Hz, 1H), 4.8 (s, 2H) , 3.46 (t, J = 7.1 Hz, 2H), 1.6 (quin, J = 7.3 Hz, 2H), 1.45 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H), ¹³ C NMR (400 MHz , CD ₃ OD) δ 160.31, 157.24, 151.85, 141.75, 133.38, 122.52, 122.06, 110.48, 109.98, 106.87, 40.74, 37.38, 31.51, 19.76, 12.82

4N-(퓨란-2-일메틸)-2N-(4-몰포리노부틸)퀴나졸린-2,4-다이아민 (화합물번호 15) 4 N- (furan-2-ylmethyl) -2 N- (4-morpholinobutyl) quinazolin-2,4-diamine (Compound No. 15)

수율 17%, ¹H NMR (400 MHz, CD₃OD) δ 7.93 (d, J = 8.2 Hz, 1H), 7.59 (t, J = 7.1 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.35 (q, J = 1.5 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 4.80 (s, 2H), 3.67 (t, J = 4.4 Hz, 4H), 3.48 (t, J = 5.5 Hz, 2H), 2.41 (t, J = 4.3 Hz, 4H), 2.38 (t, J = 7.6 Hz, 2H), 1.64 (m, 4H), ¹³C NMR (400 MHz, CD₃OD) δ 160.33, 157.99, 152.11, 141.72, 133.12, 122.39, 121.67, 110.62, 110.02, 106.76, 66.16, 58.40, 53.31, 40.72, 37.34, 27.30, 23.20
Yield 17%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.93 (d, J = 8.2 Hz, 1H), 7.59 (t, J = 7.1 Hz, 1H), 7.44 (s, 1H), 7.38 (d , J = 7.8 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.35 (q, J = 1.5 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 4.80 (s, 2H ), 3.67 (t, J = 4.4 Hz, 4H), 3.48 (t, J = 5.5 Hz, 2H), 2.41 (t, J = 4.3 Hz, 4H), 2.38 (t, J = 7.6 Hz, 2H), 1.64 (m, 4H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 160.33, 157.99, 152.11, 141.72, 133.12, 122.39, 121.67, 110.62, 110.02, 106.76, 66.16, 58.40, 53.31, 40.72, 37.34, 27.30 , 23.20

2N-(2-(4-(2,3-다이클로로페닐)피페라진-1-일)에틸)-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 16) 2 N- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (compound Number 16)

수율 18%, ¹H NMR (300 MHz, CD₃OD) δ 8.02 (d, J = 7.5, 1H), 7.67 (t, J = 1.1 Hz, 1H), 7.45 (q, J = 0.8 Hz, 1H), 7.41 (d, 1H), 7.25 (m, 3H), 7.09 (dd, J ₁ = 6.7 Hz, J ₂ = 2.8 Hz, 1H), 6.37 (q, J = 1.9 Hz, 1H), 6.35 (J = 2.5 Hz, 1H), 4.86 (s, 2H), 3.7 (t, J = 6.4 Hz, 2H), 3.08 (s, 4H), 2.74 (t, J = 6.1 Hz, 6H), ¹³C NMR (400 MHz, CD₃OD) δ 160.48, 151.64, 151.14, 141.88, 133.74, 133.47, 131.95, 127.63, 16.94, 125.41, 124.39, 122.56, 118.73, 110.09, 107.01, 56. 91, 52.92, 50.75, 37.84, 37.56
Yield 18%, ¹ H NMR (300 MHz, CD ₃ OD) δ 8.02 (d, J = 7.5, 1H), 7.67 (t, J = 1.1 Hz, 1H), 7.45 (q, J = 0.8 Hz, 1H) , 7.41 (d, 1H), 7.25 (m, 3H), 7.09 (dd, J ₁ = 6.7 Hz, J ₂ = 2.8 Hz, 1H), 6.37 (q, J = 1.9 Hz, 1H), 6.35 ( J = 2.5 Hz, 1H), 4.86 (s, 2H), 3.7 (t, J = 6.4 Hz, 2H), 3.08 (s, 4H), 2.74 (t, J = 6.1 Hz, 6H), ¹³ C NMR (400 MHz , CD ₃ OD) δ 160.48, 151.64, 151.14, 141.88, 133.74, 133.47, 131.95, 127.63, 16.94, 125.41, 124.39, 122.56, 118.73, 110.09, 107.01, 56. 91, 52.92, 50.75, 37.84, 37.56

6-플루오로-4N-(퓨란-2-일메틸)-2N-(3-몰포리노프로필)퀴나졸린-2,4-다이아민 (화합물번호 17) 6-fluoro-4 N- (furan-2-ylmethyl) -2 N- (3-morpholinopropyl) quinazolin-2,4-diamine (Compound No. 17)

수율 18%, ¹H NMR (400 MHz, CD₃OD) δ 7.64 (tt, J ₁ = 9.6 Hz, J ₂ = 3.1 Hz, 1H), 7.41 (dd, J ₁ = 1.7 Hz, J ₂ = 0.7 Hz, 1H), 7.34 (dd, J ₁ = 7.7 Hz, J ₂ = 5.3 Hz, 2H), 6.34 (q, J = 1.9 Hz, 1H), 6.28 (d, J = 3.1 Hz, 1H), 4.7 (s, 2H), 3.68 (t, J = 4.7 Hz, 4H), 3.46 (t, J = 7.1 Hz, 2H), 2.45 (t, J = 7.3 Hz, 6H), 1.81 (quin, J = 6.8 Hz, 2H), ¹³C NMR (400 MHz, CD₃OD) δ 159.97, 159.57, 158.27, 155.89, 152.53, 148.03, 141.59, 125.31, 11.32, 121.08, 109.97, 106.58, 66.25, 56.54, 53.38, 39.34, 37.18, 26.58
Yield 18%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.64 (tt, J ₁ = 9.6 Hz, J ₂ = 3.1 Hz, 1H), 7.41 (dd, J ₁ = 1.7 Hz, J ₂ = 0.7 Hz , 1H), 7.34 (dd, J ₁ = 7.7 Hz, J ₂ = 5.3 Hz, 2H), 6.34 (q, J = 1.9 Hz, 1H), 6.28 (d, J = 3.1 Hz, 1H), 4.7 (s , 2H), 3.68 (t, J = 4.7 Hz, 4H), 3.46 (t, J = 7.1 Hz, 2H), 2.45 (t, J = 7.3 Hz, 6H), 1.81 (quin, J = 6.8 Hz, 2H ), ¹³ C NMR (400 MHz, CD ₃ OD) δ 159.97, 159.57, 158.27, 155.89, 152.53, 148.03, 141.59, 125.31, 11.32, 121.08, 109.97, 106.58, 66.25, 56.54, 53.38, 39.34, 37.18, 26.58

2N-부틸-6-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 18) 2 N- butyl-6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 18)

수율 18%, ¹H NMR (400 MHz, CD₃OD) δ 7.62 (dd, J ₁ = 8.6 Hz, J ₂ = 1.9 Hz, 1H), 7.41 (t, J = 0.9 Hz, 1H), 7.33 (dd, J ₁ = 7.7 Hz, J ₂ = 5.3 Hz, 2H), 6.34 (q, J = 1.9 Hz, 1H), 6.28 (d, J = 3.1 Hz, 1H), 4.7 (s, 2H), 3.41 (t, J = 7.1 Hz, 2H), 1.59 (quin, J = 7.0 Hz, 2H), 1.4 (q, J = 7.5 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H), ¹³C NMR (400 MHz, CD₃OD) δ 159.94, 159.49, 158.89, 152.40, 147.86, 141.56, 125.19, 121.30, 109.92, 106.58, 40.66, 37.17, 31.80, 23.84, 19.82, 12.87
Yield 18%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.62 (dd, J ₁ = 8.6 Hz, J ₂ = 1.9 Hz, 1H), 7.41 (t, J = 0.9 Hz, 1H), 7.33 (dd , J ₁ = 7.7 Hz, J ₂ = 5.3 Hz, 2H), 6.34 (q, J = 1.9 Hz, 1H), 6.28 (d, J = 3.1 Hz, 1H), 4.7 (s, 2H), 3.41 (t, J = 7.1 Hz, 2H), 1.59 (quin, J = 7.0 Hz, 2H), 1.4 (q, J = 7.5 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 159.94, 159.49, 158.89, 152.40, 147.86, 141.56, 125.19, 121.30, 109.92, 106.58, 40.66, 37.17, 31.80, 23.84, 19.82, 12.87

6-플루오로-4N-(퓨란-2-일메틸)-2N-펜틸퀴나졸린-2,4-다이아민 (화합물번호 19) 6-fluoro-4 N- (furan-2-ylmethyl) -2 N -pentylquinazolin-2,4-diamine (Compound No. 19)

수율 18%, ¹H NMR (400 MHz, CD₃OD) δ 7.63 (dd, J ₁ = 9.6 Hz, J ₂ = 3.1 Hz, 1H), 7.41 (t, J = 1.0 Hz, 1H), 7.33 (dd, J ₁ = 7.7 Hz, J ₂ = 5.3 Hz, 2H), 6.34 (q, J = 1.9 Hz, 1H), 6.28 (d, J = 3.1 Hz, 1H), 4.7 (s, 2H), 3.41 (t, J = 6.1 Hz, 2H), 1.62 (quin, J = 7.0 Hz, 2H), 1.37 (m, 4H), 0.94 (t, J = 7.3 Hz, 3H), ¹³C NMR (400 MHz, CD₃OD) δ 159.91, 159.60, 152.44, 148.08, 141.54, 125.24, 121.26, 121.02, 109.90, 106.64, 106.41, 40.91, 37.14, 29.35, 28.98, 22.18, 13.03
Yield 18%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.63 (dd, J ₁ = 9.6 Hz, J ₂ = 3.1 Hz, 1H), 7.41 (t, J = 1.0 Hz, 1H), 7.33 (dd , J ₁ = 7.7 Hz, J ₂ = 5.3 Hz, 2H), 6.34 (q, J = 1.9 Hz, 1H), 6.28 (d, J = 3.1 Hz, 1H), 4.7 (s, 2H), 3.41 (t , J = 6.1 Hz, 2H), 1.62 (quin, J = 7.0 Hz, 2H), 1.37 (m, 4H), 0.94 (t, J = 7.3 Hz, 3H), ¹³ C NMR (400 MHz, CD ₃ OD ) δ 159.91, 159.60, 152.44, 148.08, 141.54, 125.24, 121.26, 121.02, 109.90, 106.64, 106.41, 40.91, 37.14, 29.35, 28.98, 22.18, 13.03

6-플루오로-4N-(퓨란-2-일메틸)-2N-(4-메톡시페닐)퀴나졸린-2,4-다이아민 (화합물번호 20) 6-fluoro-4 N- (furan-2-ylmethyl) -2 N- (4-methoxyphenyl) quinazolin-2,4-diamine (Compound No. 20)

수율 20%, ¹H NMR (400 MHz, CD₃OD) δ 7.7 (dd, J ₁ = 9.4 Hz, J ₂ = 2.4 Hz, 1H), 7.51 (t, J = 6.8 Hz, 1H), 7.5 (t, J = 2.2 Hz, 1H), 7.43 (m, 3H), 6.88 (t, J = 3.4 Hz, 1H), 6.86(J = 3.2 Hz, 1H), 6.34 (q, J = 1.8 Hz, 1H), 6.26 (d, J = 3.1 Hz, 1H), 4.76 (s, 2H), 3.78 (s, 3H), ¹³C NMR (400 MHz, CD₃OD) δ 160.11, 157.11, 155.54, 152.09, 146.95, 141.69, 133.09, 125.86, 125.77, 122.16, 121.60, 121.35, 113.49, 111.40, 109.98, 106.81, 106.57, 54.52, 37.36
Yield 20%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.7 (dd, J ₁ = 9.4 Hz, J ₂ = 2.4 Hz, 1H), 7.51 (t, J = 6.8 Hz, 1H), 7.5 (t , J = 2.2 Hz, 1H), 7.43 (m, 3H), 6.88 (t, J = 3.4 Hz, 1H), 6.86 ( J = 3.2 Hz, 1H), 6.34 (q, J = 1.8 Hz, 1H), 6.26 (d, J = 3.1 Hz, 1H), 4.76 (s, 2H), 3.78 (s, 3H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 160.11, 157.11, 155.54, 152.09, 146.95, 141.69, 133.09, 125.86, 125.77, 122.16, 121.60, 121.35, 113.49, 111.40, 109.98, 106.81, 106.57, 54.52, 37.36

2N-(4-(4-(2,3-다이클로로페닐)피페라진-1-일)부틸)-6-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 21)2 N- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl) -6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4 -Diamine (compound number 21)

수율 12%, ¹H NMR (300 MHz, CD₃OD) δ 7.66 (dd, J ₁ = 9.5 Hz, J ₂ = 1.4 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.36 (dd, J ₁ = 7.2 Hz, J ₂ = 2.4 Hz, 2H), 7.20 (m, 2H), 7.05 (q, J = 3.2 Hz, 1H), 6.35 (q, J = 2.1 Hz, 1H), 6.30 (d, J = 3.1 Hz, 1H), 4.77 (s, 2H), 3.45 (t, J = 6.0 Hz, 2H), 3.03 (d, J = 6.0 Hz, 4H), 2.64 (s, 4H), 2.46 (t, J = 7.0 Hz, 2H), 1.67 (d, J = 3.2 Hz, 4H), ¹³C NMR (300 MHz, CD₃OD) δ 159.95, 159.46, 152.40, 151.12, 147.88, 141.80, 133.45, 127.60, 126.98, 124.86, 121.37, 121.07, 118.69, 109.98, 106.75, 106.61, 106.45, 58.08, 52.90, 50.57, 40.65, 37.20, 27.60, 23.52
Yield 12%, ¹ H NMR (300 MHz, CD ₃ OD) δ 7.66 (dd, J ₁ = 9.5 Hz, J ₂ = 1.4 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.36 (dd , J ₁ = 7.2 Hz, J ₂ = 2.4 Hz, 2H), 7.20 (m, 2H), 7.05 (q, J = 3.2 Hz, 1H), 6.35 (q, J = 2.1 Hz, 1H), 6.30 (d , J = 3.1 Hz, 1H), 4.77 (s, 2H), 3.45 (t, J = 6.0 Hz, 2H), 3.03 (d, J = 6.0 Hz, 4H), 2.64 (s, 4H), 2.46 (t , J = 7.0 Hz, 2H), 1.67 (d, J = 3.2 Hz, 4H), ¹³ C NMR (300 MHz, CD ₃ OD) δ 159.95, 159.46, 152.40, 151.12, 147.88, 141.80, 133.45, 127.60, 126.98 , 124.86, 121.37, 121.07, 118.69, 109.98, 106.75, 106.61, 106.45, 58.08, 52.90, 50.57, 40.65, 37.20, 27.60, 23.52

2N-(3-(4-(2,3-다이메틸페닐)피페라진-1-일)프로필)-6-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 22) 2 N- (3- (4- (2,3-dimethylphenyl) piperazin-1-yl) propyl) -6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4- Diamine (Compound No. 22)

수율 16%, ¹H NMR (300 MHz, CD₃OD) δ 7.67 (dd, J ₁ = 9.5 Hz, J ₂ = 3.1 Hz, 1H), 7.41 (s, 1H), 7.37 (dd, J ₁ = 7.0 Hz, J ₂ = 2.4 Hz, 2H), 6.98 (t, J = 7.5 Hz, 1H), 6.87 (t, J = 7.3 Hz, 2H), 6.35 (q, J= 1.9 Hz, 1H), 6.30 (d, J = 2.5 Hz, 1H), 4.82 (s, 2H), 3.52(J = 6.7 Hz, 2H), 2.89( (t, J = 3.3 Hz, 4H), 2.67 (s, 4H), 2.58 (t, J = 7.4 Hz, 2H), 2.24 (s, 3H), 2.20 (s, 3H), 1.91 (quin, J = 7.6 Hz, 2H), ¹³C NMR (300 MHz, CD₃OD) δ 152.27, 151.14, 147.26, 141.67, 137.43, 130.70, 125.49, 124.73, 116.18, 110.0, 106.88, 106.76, 106.65, 56.19, 53.39, 51.50, 39.47, 37.28, 26.18, 25.88, 19.30, 12.70
Yield 16%, ¹ H NMR (300 MHz, CD ₃ OD) δ 7.67 (dd, J ₁ = 9.5 Hz, J ₂ = 3.1 Hz, 1H), 7.41 (s, 1H), 7.37 (dd, J ₁ = 7.0 Hz, J ₂ = 2.4 Hz, 2H), 6.98 (t, J = 7.5 Hz, 1H), 6.87 (t, J = 7.3 Hz, 2H), 6.35 (q, J = 1.9 Hz, 1H), 6.30 (d , J = 2.5 Hz, 1H), 4.82 (s, 2H), 3.52 ( J = 6.7 Hz, 2H), 2.89 ((t, J = 3.3 Hz, 4H), 2.67 (s, 4H), 2.58 (t, J = 7.4 Hz, 2H), 2.24 (s, 3H), 2.20 (s, 3H), 1.91 (quin, J = 7.6 Hz, 2H), ¹³ C NMR (300 MHz, CD ₃ OD) δ 152.27, 151.14, 147.26, 141.67, 137.43, 130.70, 125.49, 124.73, 116.18, 110.0, 106.88, 106.76, 106.65, 56.19, 53.39, 51.50, 39.47, 37.28, 26.18, 25.88, 19.30, 12.70

2N-(4-(4-(2,3-다이메틸페닐)피페라진-1-일)부틸)-6-플루오로-4N-(퓨라노-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 23) 2 N- (4- (4- (2,3-dimethylphenyl) piperazin-1-yl) butyl) -6-fluoro-4 N- (furano-2-ylmethyl) quinazolin-2,4 Diamine (Compound No. 23)

수율 18%, ¹H NMR (400 MHz, CD₃OD) δ 7.62 (dd, J ₁ = 9.5 Hz, J ₂ = 3.1 Hz, 1H), 7.42 (s, 1H), 7.34 (dd, J ₁ = 7.8 Hz, J ₂ = 2.5 Hz, 1H), 7.0 (t, J = 7.5 Hz, 1H), 6.89 (t, J = 8.0 Hz, 2H), 6.34 (q, J = 1.9 Hz, 1H), 6.29 (d, J = 2.5 Hz, 1H), 4.84 (s, 2H), 3.47 (t, J = 6.7 Hz, 2H), 2.88( (t, J = 3.3 Hz, 4H), 2.65 (s, 4H), 2.47 (t, J = 7.0 Hz, 2H), 2.23 (s, 3H), 2.19 (s, 3H), 1.89 (quin, J = 7.6 Hz, 4H), ¹³C NMR (400 MHz, CD₃OD) δ 158.57, 158.14, 150.94, 149.66, 146.69, 140.03, 135.89, 129.17, 123.93, 123.15, 119.50, 114.64, 108.41, 105.11, 105.01, 104.88, 56.69, 51.85, 49.95, 39.11, 35.64, 26.08, 21.99, 17.71, 11.10
Yield 18%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.62 (dd, J ₁ = 9.5 Hz, J ₂ = 3.1 Hz, 1H), 7.42 (s, 1H), 7.34 (dd, J ₁ = 7.8 Hz, J ₂ = 2.5 Hz, 1H), 7.0 (t, J = 7.5 Hz, 1H), 6.89 (t, J = 8.0 Hz, 2H), 6.34 (q, J = 1.9 Hz, 1H), 6.29 (d , J = 2.5 Hz, 1H), 4.84 (s, 2H), 3.47 (t, J = 6.7 Hz, 2H), 2.88 ((t, J = 3.3 Hz, 4H), 2.65 (s, 4H), 2.47 ( t, J = 7.0 Hz, 2H), 2.23 (s, 3H), 2.19 (s, 3H), 1.89 (quin, J = 7.6 Hz, 4H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 158.57, 158.14, 150.94, 149.66, 146.69, 140.03, 135.89, 129.17, 123.93, 123.15, 119.50, 114.64, 108.41, 105.11, 105.01, 104.88, 56.69, 51.85, 49.95, 39.11, 35.64, 26.08, 21.99, 17.71, 17.71

2N-(3-(다이에틸아미노)-프로필)-6-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 24) 2 N- (3- (diethylamino) -propyl) -6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 24)

수율 17%, ¹H NMR (400 MHz, CD₃OD) δ 7.65 (dd, J ₁ = 9.5 Hz, J ₂ = 1.6 Hz, 1H), 7.41 (t, J = 1.0 Hz, 1H), 7.34 (dd, J ₁ = 7.7 Hz, J ₂ = 5.3 Hz, 2H), 6.33 (q, J = 1.9 Hz, 1H), 6.28 (d, J = 2.5 Hz, 1H), 4.76 (s, 2H), 3.45 (t, J = 6.8 Hz, 2H), 2.65 (m, 6H), 1.18 (quin, J = 6.7 Hz, 2H), 1.06 (t, J = 7.2 Hz, 6H), ¹³C NMR (400 MHz, CD₃OD) δ 160.09, 159.54, 158.30, 155.92, 152.40, 148.15, 141.58, 125.52, 121.36, 121.11, 109.95, 106.55, 51.96, 38.17, 37.20, 10.16
Yield 17%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.65 (dd, J ₁ = 9.5 Hz, J ₂ = 1.6 Hz, 1H), 7.41 (t, J = 1.0 Hz, 1H), 7.34 (dd , J ₁ = 7.7 Hz, J ₂ = 5.3 Hz, 2H), 6.33 (q, J = 1.9 Hz, 1H), 6.28 (d, J = 2.5 Hz, 1H), 4.76 (s, 2H), 3.45 (t , J = 6.8 Hz, 2H), 2.65 (m, 6H), 1.18 (quin, J = 6.7 Hz, 2H), 1.06 (t, J = 7.2 Hz, 6H), ¹³ C NMR (400 MHz, CD ₃ OD ) δ 160.09, 159.54, 158.30, 155.92, 152.40, 148.15, 141.58, 125.52, 121.36, 121.11, 109.95, 106.55, 51.96, 38.17, 37.20, 10.16

2N-(2-(다이에틸아미노)에틸-6-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 25)2 N- (2- (diethylamino) ethyl-6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 25)

수율 16%, ¹H NMR (400 MHz, CD₃OD) δ 7.65 (dd, J ₁ = 9.5 Hz, J ₂ = 1.6 Hz, 1H), 7.42 (t, J = 1.0 Hz, 1H), 7.35 (dd, J ₁ = 7.7 Hz, J ₂ = 5.3 Hz, 2H), 6.34 (q, J = 1.8 Hz, 1H), 6.28 (d, J = 2.5 Hz, 1H), 4.7 (s, 2H), 3.55 (t, J = 6.8 Hz, 2H), 2.74 (t, J = 6.9 Hz, 2H), 2.67 (q, J = 7.1 Hz, 4H), 1.12 (t, J = 7.3 Hz, 6H), ¹³C NMR (400 MHz, CD₃OD) δ 159.45, 158.30, 152.40, 146.53, 140.03, 123.87, 123.79, 119.77, 119.53, 108.40, 105.05, 48.31, 44.77, 37.58, 35.61, 24.23, 8.06
Yield 16%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.65 (dd, J ₁ = 9.5 Hz, J ₂ = 1.6 Hz, 1H), 7.42 (t, J = 1.0 Hz, 1H), 7.35 (dd , J ₁ = 7.7 Hz, J ₂ = 5.3 Hz, 2H), 6.34 (q, J = 1.8 Hz, 1H), 6.28 (d, J = 2.5 Hz, 1H), 4.7 (s, 2H), 3.55 (t , J = 6.8 Hz, 2H), 2.74 (t, J = 6.9 Hz, 2H), 2.67 (q, J = 7.1 Hz, 4H), 1.12 (t, J = 7.3 Hz, 6H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 159.45, 158.30, 152.40, 146.53, 140.03, 123.87, 123.79, 119.77, 119.53, 108.40, 105.05, 48.31, 44.77, 37.58, 35.61, 24.23, 8.06

6-플루오로-4N-(퓨란-2-일메틸)-2N-(4-몰포리노부틸)퀴나졸린-2,4-다이아민 (화합물번호 26) 6-fluoro-4 N- (furan-2-ylmethyl) -2 N- (4-morpholinobutyl) quinazolin-2,4-diamine (Compound No. 26)

수율 18%, ¹H NMR (400 MHz, CD₃OD) δ 7.64 (dd, J ₁ = 9.2 Hz, J ₂ = 1.8 Hz, 1H), 7.41 (t, J = 1.0 Hz, 1H), 7.34 (dd, J ₁ = 7.6 Hz, J ₂ = 2.3 Hz, 2H), 6.33 (q, J = 1.8 Hz, 1H), 6.28 (d, J = 3.1 Hz, 1H), 4.75 (s, 2H), 3.66 (t, J = 4.7 Hz, 4H), 3.43 (t, J = 6.2 Hz, 2H), 2.42 (s, 4H), 2.35 (t, J = 7.8 Hz, 2H), 1.59 (m, 4H), ¹³C NMR (300 MHz, CD₃OD) δ 159.64, 158.30, 152.47, 148.58, 141.56, 125.56, 125.48, 120.99, 114.30, 109.94, 106.67, 66.18, 58.48, 53.32, 40.64, 37.17, 27.47, 23.25
Yield 18%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.64 (dd, J ₁ = 9.2 Hz, J ₂ = 1.8 Hz, 1H), 7.41 (t, J = 1.0 Hz, 1H), 7.34 (dd , J ₁ = 7.6 Hz, J ₂ = 2.3 Hz, 2H), 6.33 (q, J = 1.8 Hz, 1H), 6.28 (d, J = 3.1 Hz, 1H), 4.75 (s, 2H), 3.66 (t , J = 4.7 Hz, 4H), 3.43 (t, J = 6.2 Hz, 2H), 2.42 (s, 4H), 2.35 (t, J = 7.8 Hz, 2H), 1.59 (m, 4H), ¹³ C NMR (300 MHz, CD ₃ OD) δ 159.64, 158.30, 152.47, 148.58, 141.56, 125.56, 125.48, 120.99, 114.30, 109.94, 106.67, 66.18, 58.48, 53.32, 40.64, 37.17, 27.47, 23.25

6-플루오로-4N-(퓨란-2-일메틸)-2N-(2-몰포리노에틸)퀴나졸린-2,4-다이아민 (화합물번호 27) 6-fluoro-4 N- (furan-2-ylmethyl) -2 N- (2-morpholinoethyl) quinazolin-2,4-diamine (Compound No. 27)

수율 17%, ¹H NMR (400 MHz, CD₃OD) δ 7.65 (td, J ₁ = 9.5 Hz, J ₂ = 1.6 Hz, 1H), 7.42 (t, J = 1.0 Hz, 1H), 7.35 (dd, J ₁ = 6.7 Hz, J ₂ = 1.4 Hz, 2H), 6.34 (q, J = 1.8 Hz, 1H), 6.28 (dd, J ₁ = 3.2 Hz, J ₂ = 0.6 Hz, 1H), 4.77 (s, 2H), 3.68 (t, J = 4.7 Hz, 4H), 3.57 (t, J = 6.6 Hz, 2H), 2.6 (t, J = 6.6 Hz, 2H), 2.51 (t, J = 4.2 Hz, 4H), ¹³C NMR (400 MHz, CD₃OD) δ 159.36, 158.78, 152.37, 147.83, 141.59, 125.39, 125.29, 121.47, 121.14, 109.96, 106.54, 66.35, 57.71, 53.34, 37.49, 37.24
Yield 17%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.65 (td, J ₁ = 9.5 Hz, J ₂ = 1.6 Hz, 1H), 7.42 (t, J = 1.0 Hz, 1H), 7.35 (dd , J ₁ = 6.7 Hz, J ₂ = 1.4 Hz, 2H), 6.34 (q, J = 1.8 Hz, 1H), 6.28 (dd, J ₁ = 3.2 Hz, J ₂ = 0.6 Hz, 1H), 4.77 (s , 2H), 3.68 (t, J = 4.7 Hz, 4H), 3.57 (t, J = 6.6 Hz, 2H), 2.6 (t, J = 6.6 Hz, 2H), 2.51 (t, J = 4.2 Hz, 4H ), ¹³ C NMR (400 MHz, CD ₃ OD) δ 159.36, 158.78, 152.37, 147.83, 141.59, 125.39, 125.29, 121.47, 121.14, 109.96, 106.54, 66.35, 57.71, 53.34, 37.49, 37.24

2N-(2-(4-(2,3-다이클로로페닐)피페라진-1-일)에틸)-6-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 28) 2 N- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) -6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4 -Diamine (compound number 28)

수율 18%, ¹H NMR (400 MHz, CD₃OD) δ 7.66 (tt, J ₁ = 9.5 Hz, J ₂ = 1.5 Hz, 1H), 7.43 (d, J = 0.9 Hz, 1H), 7.34 (d, J = 6.2 Hz, 1H), 7.19 (q, J = 2.8 Hz, 2H), 7.05 (dd, J ₁ = 6.4 Hz, J ₂ = 3.3 Hz, 2H), 6.35 (dd, J ₁ = 3.1 Hz, J ₂ = 1.9 Hz, 1H), 6.3 (d, J = 2.7 Hz, 1H), 4.78 (s, 2H), 3.62 (t, J = 6.6 Hz, 2H), 3.05 (s, 4H), 2.68 (t, J = 6.4 Hz, 6H), ¹³C NMR (400 MHz, CD₃OD) δ 157.10, 150.57, 149.65, 140.17, 131.94, 126.09, 122.85, 117.21, 108.46, 105.48, 105.18, 55.67, 51.42, 49.19, 36.22, 35.81
Yield 18%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.66 (tt, J ₁ = 9.5 Hz, J ₂ = 1.5 Hz, 1H), 7.43 (d, J = 0.9 Hz, 1H), 7.34 (d , J = 6.2 Hz, 1H), 7.19 (q, J = 2.8 Hz, 2H), 7.05 (dd, J ₁ = 6.4 Hz, J ₂ = 3.3 Hz, 2H), 6.35 (dd, J ₁ = 3.1 Hz, J ₂ = 1.9 Hz, 1H), 6.3 (d, J = 2.7 Hz, 1H), 4.78 (s, 2H), 3.62 (t, J = 6.6 Hz, 2H), 3.05 (s, 4H), 2.68 (t , J = 6.4 Hz, 6H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 157.10, 150.57, 149.65, 140.17, 131.94, 126.09, 122.85, 117.21, 108.46, 105.48, 105.18, 55.67, 51.42, 49.19, 36.22 , 35.81

2N-(2-(4-(2,3-다이클로로페닐)피페라진-1-일)에틸)-8-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 29) 2 N- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) -8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4 -Diamine (compound number 29)

수율 18%, ¹H NMR (400 MHz, CD₃OD) δ 8.03 (q, J = 6.1 Hz, 1H), 7.52 (s, 1H), 7.31 (m, 2H), 7.18 (d, J = 4.8 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.96 (td, J = 2.3 Hz, 1H), 6.45 (t, J = 0.9 Hz, 1H), 6.40 (d, J = 2.5 Hz, 1H), 4.89 (s, 2H), 3.74 (t, J = 6.5 Hz, 2H), 3.18 (s, 4H), 2.80 (t, J = 6.8 Hz, 6H), ¹³C NMR (400 MHz, CD₃OD) δ 163.0, 158.57, 150.89, 149.69, 140.06, 131.92, 126.07, 125.42, 123.35, 122.81, 117.21, 108.44, 108.0, 107.76, 104.99, 55.70, 51.42, 49.23, 36.15, 35.64
Yield 18%, ¹ H NMR (400 MHz, CD ₃ OD) δ 8.03 (q, J = 6.1 Hz, 1H), 7.52 (s, 1H), 7.31 (m, 2H), 7.18 (d, J = 4.8 Hz , 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.96 (td, J = 2.3 Hz, 1H), 6.45 (t, J = 0.9 Hz, 1H), 6.40 (d, J = 2.5 Hz, 1H ), 4.89 (s, 2H), 3.74 (t, J = 6.5 Hz, 2H), 3.18 (s, 4H), 2.80 (t, J = 6.8 Hz, 6H), ¹³ C NMR (400 MHz, CD ₃ OD ) δ 163.0, 158.57, 150.89, 149.69, 140.06, 131.92, 126.07, 125.42, 123.35, 122.81, 117.21, 108.44, 108.0, 107.76, 104.99, 55.70, 51.42, 49.23, 36.15, 35.64

2N-(4-(4-(2,3-다이메틸페닐)피페라진-1-일)부틸)-8-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 30) 2 N- (4- (4- (2,3-dimethylphenyl) piperazin-1-yl) butyl) -8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4- Diamine (Compound No. 30)

수율 18%, ¹H NMR (300 MHz, CD₃OD) δ 7.91 (q, J = 6.1 Hz, 1H), 7.41 (d, J = 1.5 Hz, 1H), 7.01 (m, 2H), 6.85 (m, 3H), 6.34 (t, J = 3.0 Hz, 1H), 6.29 (d, J = 3.1 Hz, 1H), 4.77 (s, 2H), 3.47 (t, J = 6.1 Hz, 2H), 2.86 (t, J = 4.4 Hz, 4H), 2.64 (s, 4H), 2.46 (t, J = 6.8 Hz, 2H), 2.23 (s, 3H), 2.18 (s, 3H), 1.58 (q, J = 3.2 Hz, 4H), ¹³C NMR (400 MHz, CD₃OD) δ 167.41, 164.11, 162.35, 160.11, 152.43, 1512.15, 141.60, 137.43, 137.43, 130.72, 125.48, 124.84, 116.19, 109.98, 109.46, 109.14, 106.61, 57.92, 53.34, 51.42, 40.64, 37.35, 23.46, 19.27, 12.67
Yield 18%, ¹ H NMR (300 MHz, CD ₃ OD) δ 7.91 (q, J = 6.1 Hz, 1H), 7.41 (d, J = 1.5 Hz, 1H), 7.01 (m, 2H), 6.85 (m , 3H), 6.34 (t, J = 3.0 Hz, 1H), 6.29 (d, J = 3.1 Hz, 1H), 4.77 (s, 2H), 3.47 (t, J = 6.1 Hz, 2H), 2.86 (t , J = 4.4 Hz, 4H), 2.64 (s, 4H), 2.46 (t, J = 6.8 Hz, 2H), 2.23 (s, 3H), 2.18 (s, 3H), 1.58 (q, J = 3.2 Hz , 4H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 167.41, 164.11, 162.35, 160.11, 152.43, 1512.15, 141.60, 137.43, 137.43, 130.72, 125.48, 124.84, 116.19, 109.98, 109.46, 109.14, 106.14, 106. 57.92, 53.34, 51.42, 40.64, 37.35, 23.46, 19.27, 12.67

2N-(3-(4-(2,3-다이클로로페닐)피페라진-1-일)프로필)-8-플루오로-4N-(퓨란-2-일메틸l)퀴나졸린-2,4-다이아민 (화합물번호 31) 2 N- (3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propyl) -8-fluoro-4 N- (furan-2-ylmethyll) quinazolin-2, 4-diamine (Compound No. 31)

수율 18%, ¹H NMR (400 MHz, CD₃OD) δ 8.15 (q, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.24 (m, 2H), 7.09 (m, 3H), 6.38 (s, 2H), 4.85 (s, 2H), 3.63 (s, 2H), 3.14 (s, 4H), 2.93 (s, 4H), 2.82 (s, 2H), 2.01 (quin, J = 7.4 Hz, 2H), ¹³C NMR (400 MHz, CD₃OD) δ 150.98, 150.54, 142.16, 133.56, 127.73, 127.03, 124.83, 118.84, 110.17, 107.48, 55.25, 52.65, 49.92, 39.19, 37.78
Yield 18%, ¹ H NMR (400 MHz, CD ₃ OD) δ 8.15 (q, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.24 (m, 2H), 7.09 (m, 3H), 6.38 (s, 2H), 4.85 (s, 2H), 3.63 (s, 2H), 3.14 (s, 4H), 2.93 (s, 4H), 2.82 (s, 2H), 2.01 (quin, J = 7.4 Hz, 2H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 150.98, 150.54, 142.16, 133.56, 127.73, 127.03, 124.83, 118.84, 110.17, 107.48, 55.25, 52.65, 49.92, 39.19, 37.78

2N-(4-(4-(2,3-다이클로로페닐)피페라진-1-일)부틸)-8-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 32) 2 N- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl) -8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4 -Diamine (compound number 32)

수율 17%, ¹H NMR (400 MHz, CD₃OD) δ 7.90 (q, J = 6.1 Hz, 1H), 7.41 (s, 1H), 7.18 (m, 2H), 7.05 (m, 1H), 6.94 (s, 1H), 6.83 (m, 1H), 6.34 (t, J = 2.9 Hz, 1H), 6.28 (d, J = 3.1 Hz, 1H), 4.79 (s, 2H), 3.46 (t, J = 6.0 Hz, 2H), 3.04 (s, 4H), 2.65 (s, 4H), 2.47 (t, J = 6.2 Hz, 2H), 1.66 (s, 4H), ¹³C NMR (400 MHz, CD₃OD) δ 166.95, 164.48, 160.27, 159.94, 152.46, 151.09, 141.60, 133.46, 127.57, 16.92, 124.81, 124.34, 118.65, 110.01, 109.08, 106.64, 58.0, 52.88, 50.57, 40.68, 37.17, 27.51, 23.57
Yield 17%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.90 (q, J = 6.1 Hz, 1H), 7.41 (s, 1H), 7.18 (m, 2H), 7.05 (m, 1H), 6.94 (s, 1H), 6.83 (m, 1H), 6.34 (t, J = 2.9 Hz, 1H), 6.28 (d, J = 3.1 Hz, 1H), 4.79 (s, 2H), 3.46 (t, J = 6.0 Hz, 2H), 3.04 (s, 4H), 2.65 (s, 4H), 2.47 (t, J = 6.2 Hz, 2H), 1.66 (s, 4H), ¹³ C NMR (400 MHz, CD ₃ OD) 166.95, 164.48, 160.27, 159.94, 152.46, 151.09, 141.60, 133.46, 127.57, 16.92, 124.81, 124.34, 118.65, 110.01, 109.08, 106.64, 58.0, 52.88, 50.57, 40.68, 37.17, 27.51, 27.51

2N-부틸-8-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 33) 2 N -butyl-8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 33)

수율 19%, ¹H NMR (400 MHz, CD₃OD) δ 7.89 (q, J = 6.1 Hz, 1H), 7.41 (d, J = 1.0 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.81 (td, J ₁ = 8.6 Hz, J ₂ = 2.5 Hz, 1H), 6.33 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.27 (d, J = 2.9 Hz, 1H), 4.75 (s, 2H), 3.41 (t, J = 7.1 Hz, 2H), 1.58 (quin, J = 7.3 Hz, 2H), 1.42 (quin, J = 7.5 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H), ¹³C NMR (400 MHz, CD₃OD) δ 165.38, 162.90, 158.71, 158.36, 151.71, 150.90, 139.97, 123.31, 108.35, 107.66, 107.42, 105.0, 39.03, 35.52, 30.20, 18.25, 11.32
Yield 19%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.89 (q, J = 6.1 Hz, 1H), 7.41 (d, J = 1.0 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H ), 6.81 (td, J ₁ = 8.6 Hz, J ₂ = 2.5 Hz, 1H), 6.33 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.27 (d, J = 2.9 Hz, 1H ), 4.75 (s, 2H), 3.41 (t, J = 7.1 Hz, 2H), 1.58 (quin, J = 7.3 Hz, 2H), 1.42 (quin, J = 7.5 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 165.38, 162.90, 158.71, 158.36, 151.71, 150.90, 139.97, 123.31, 108.35, 107.66, 107.42, 105.0, 39.03, 35.52, 30.20, 18.25 , 11.32

8-플루오로-4N-(퓨란-2-일메틸)-2N-펜틸퀴나졸린-2,4-다이아민 (화합물번호 34) 8-fluoro-4 N- (furan-2-ylmethyl) -2 N -pentylquinazolin-2,4-diamine (Compound No. 34)

수율 18%, ¹H NMR (400 MHz, CD₃OD) δ 7.88 (q, J = 6.1 Hz, 1H), 7.40 (d, J = 1.0 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.83 (td, J ₁ = 8.6 Hz, J ₂ = 2.5 Hz, 1H), 6.33 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.27 (d, J = 2.9 Hz, 1H), 4.74 (s, 2H), 3.40 (t, J = 7.1 Hz, 2H), 1.58 (quin, J = 6.9 Hz, 2H), 1.36 (t, J = 3.4 Hz, 4H), 0.91 (t, J = 6.8 Hz, 3H), ¹³C NMR (400 MHz, CD₃OD) δ 160.33, 157.99, 152.11, 141.72, 133.12, 122.39, 121.67, 110.62, 110.02, 106.76, 66.16, 58.40, 53.31, 40.72, 37.34, 27.30, 23.20
Yield 18%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.88 (q, J = 6.1 Hz, 1H), 7.40 (d, J = 1.0 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H ), 6.83 (td, J ₁ = 8.6 Hz, J ₂ = 2.5 Hz, 1H), 6.33 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.27 (d, J = 2.9 Hz, 1H ), 4.74 (s, 2H), 3.40 (t, J = 7.1 Hz, 2H), 1.58 (quin, J = 6.9 Hz, 2H), 1.36 (t, J = 3.4 Hz, 4H), 0.91 (t, J = 6.8 Hz, 3H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 160.33, 157.99, 152.11, 141.72, 133.12, 122.39, 121.67, 110.62, 110.02, 106.76, 66.16, 58.40, 53.31, 40.72, 37.34, 27.30 , 23.20

2N-(3-(다이에틸아미노)프로필)-8-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 35) 2 N- (3- (diethylamino) propyl) -8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 35)

수율 17%, ¹H NMR (400 MHz, CD₃OD) δ 7.89 (q, J = 6.2 Hz, 1H), 7.41 (d, J = 1.1 Hz, 1H), 6.80 (d, J = 7.1 Hz, 1H), 6.81 (td, J ₁ = 8.6 Hz, J ₂ = 2.5 Hz, 1H), 6.32 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.27 (d, J = 2.9 Hz, 1H), 4.80 (s, 2H), 3.58 (t, J = 6.2 Hz, 2H), 3.22 (q, J = 7.3 Hz, 6H), 2.07 (quin, J = 6.1 Hz, 2H), 1.28 (t, J = 7.2 Hz, 6H), ¹³C NMR (400 MHz, CD₃OD) δ 167.37, 164.07, 160.40, 160.01, 153.72, 153.54, 152.51, 141.55, 124.90, 109.95, 109.33, 109.01, 106.58, 50.03, 39.33, 37.12, 26.13, 10.09
Yield 17%, ¹ H NMR (400 MHz, CD ₃ OD) δ 7.89 (q, J = 6.2 Hz, 1H), 7.41 (d, J = 1.1 Hz, 1H), 6.80 (d, J = 7.1 Hz, 1H ), 6.81 (td, J ₁ = 8.6 Hz, J ₂ = 2.5 Hz, 1H), 6.32 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.27 (d, J = 2.9 Hz, 1H ), 4.80 (s, 2H), 3.58 (t, J = 6.2 Hz, 2H), 3.22 (q, J = 7.3 Hz, 6H), 2.07 (quin, J = 6.1 Hz, 2H), 1.28 (t, J = 7.2 Hz, 6H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 167.37, 164.07, 160.40, 160.01, 153.72, 153.54, 152.51, 141.55, 124.90, 109.95, 109.33, 109.01, 106.58, 50.03, 39.33, 37.12 , 26.13, 10.09

2N-(2-(다이메틸아미노)에틸)-8-플루오로-4N-(퓨란-2-일메틸)퀴나졸린-2,4-다이아민 (화합물번호 36) 2 N- (2- (dimethylamino) ethyl) -8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 36)

수율 18%, ¹H NMR (400 MHz, CD₃OD) δ 8.01 (q, J = 6.1 Hz, 1H), 7.5 (s, 1H), 7.01 (d, J = 9.7 Hz, 1H), 6.93 (td, J ₁ = 8.6 Hz, J ₂ = 2.5 Hz, 1H), 6.44 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.37 (d, J = 2.9 Hz, 1H), (4.86 (s, 2H), 3.65 (t, J = 6.2 Hz, 2H), 2.76 (t, J = 6.8 Hz, 2H), 2.61 (q, J = 7.4 Hz, 4H), 1.17 (t, J = 7.1 Hz, 6H), ¹³C NMR (400 MHz, CD₃OD) δ 165.45, 162.97, 158.81, 158.60, 152.02, 150.91, 140.03, 123.42, 108.41, 107.92, 107.68, 104.97, 50.44, 36.54, 35.58, 8.53
Yield 18%, ¹ H NMR (400 MHz, CD ₃ OD) δ 8.01 (q, J = 6.1 Hz, 1H), 7.5 (s, 1H), 7.01 (d, J = 9.7 Hz, 1H), 6.93 (td , J ₁ = 8.6 Hz, J ₂ = 2.5 Hz, 1H), 6.44 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.37 (d, J = 2.9 Hz, 1H), (4.86 ( s, 2H), 3.65 (t, J = 6.2 Hz, 2H), 2.76 (t, J = 6.8 Hz, 2H), 2.61 (q, J = 7.4 Hz, 4H), 1.17 (t, J = 7.1 Hz, 6H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 165.45, 162.97, 158.81, 158.60, 152.02, 150.91, 140.03, 123.42, 108.41, 107.92, 107.68, 104.97, 50.44, 36.54, 35.58, 8.53

8-플루오로-4N-(퓨란-2-일메틸)-2N-(2-몰포리노에틸)퀴나졸린-2,4-다이아민 (화합물번호 37) 8-fluoro-4 N- (furan-2-ylmethyl) -2 N- (2-morpholinoethyl) quinazolin-2,4-diamine (Compound No. 37)

수율 20%, ¹H NMR (400 MHz, CD₃OD) δ 8.0 (q, J = 6.1 Hz, 1H), 7.52 (d, J = 1.0 Hz, 1H), 7.0 (d, J = 7.2 Hz, 1H), 6.94(t J = 8.6 Hz, 1H), 6.44 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.38 (d, J = 2.9 Hz, 1H), 4.87 (s, 2H), 3.79 (t, J = 4.5 Hz, 4H), 3.69 (t, J = 7.1 Hz, 2H), 2.72 (t, J = 6.5 Hz, 2H), 2.62 (t, J = 7.1 Hz, 4H), ¹³C NMR (400 MHz, CD₃OD) δ 162.99, 158.75, 152.08, 140.03, 123.40, 123.29, 108.43, 107.91, 107.67, 104.94, 64.82, 59.32, 51.81, 35.89, 35.60
Yield 20%, ¹ H NMR (400 MHz, CD ₃ OD) δ 8.0 (q, J = 6.1 Hz, 1H), 7.52 (d, J = 1.0 Hz, 1H), 7.0 (d, J = 7.2 Hz, 1H ), 6.94 (t J = 8.6 Hz, 1H), 6.44 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.38 (d, J = 2.9 Hz, 1H), 4.87 (s, 2H), 3.79 (t, J = 4.5 Hz, 4H), 3.69 (t, J = 7.1 Hz, 2H), 2.72 (t, J = 6.5 Hz, 2H), 2.62 (t, J = 7.1 Hz, 4H), ¹³ C NMR (400 MHz, CD ₃ OD) δ 162.99, 158.75, 152.08, 140.03, 123.40, 123.29, 108.43, 107.91, 107.67, 104.94, 64.82, 59.32, 51.81, 35.89, 35.60

8-플루오로-4N-(퓨란-2-일메틸)-2N-(3-몰포리노프로필)퀴나졸린-2,4-다이아민 (화합물번호 38) 8-fluoro-4 N- (furan-2-ylmethyl) -2 N- (3-morpholinopropyl) quinazolin-2,4-diamine (Compound No. 38)

수율 17%, ¹H NMR (400 MHz, CD₃OD) δ 8.0 (q, J = 6.1 Hz, 1H), 7.51 (d, J = 1.0 Hz, 1H), 7.0 (d, J = 7.2 Hz, 1H), 6.91(t J ₁ = 8.5 Hz, J ₂ = 2.5 Hz, 1H), 6.43 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.37 (d, J = 3.1 Hz, 1H), 4.85 (s, 2H), 3.78 (t, J = 4.5 Hz, 4H), 3.66 (t, J = 5.0 Hz, 2H), 2.55 (m, 6H), 1.92 (quin, J = 6.7 Hz, 2H), ¹³C NMR (300 MHz, CD₃OD) δ 167.39, 164.09, 160.16, 159.99, 153.33, 152.45, 141.60, 124.95, 109.98, 109.44, 109.12, 106.59, 66.26, 56.50, 53.37, 39.33, 37.14, 25.97
Yield 17%, ¹ H NMR (400 MHz, CD ₃ OD) δ 8.0 (q, J = 6.1 Hz, 1H), 7.51 (d, J = 1.0 Hz, 1H), 7.0 (d, J = 7.2 Hz, 1H ), 6.91 (t J ₁ = 8.5 Hz, J ₂ = 2.5 Hz, 1H), 6.43 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.37 (d, J = 3.1 Hz, 1H) , 4.85 (s, 2H), 3.78 (t, J = 4.5 Hz, 4H), 3.66 (t, J = 5.0 Hz, 2H), 2.55 (m, 6H), 1.92 (quin, J = 6.7 Hz, 2H) , ¹³ C NMR (300 MHz, CD ₃ OD) δ 167.39, 164.09, 160.16, 159.99, 153.33, 152.45, 141.60, 124.95, 109.98, 109.44, 109.12, 106.59, 66.26, 56.50, 53.37, 39.33, 37.14, 25.97

실시예 39. 8-플루오로-4N-(퓨란-2-일메틸)-2N-(4-메톡시페닐)퀴나졸린-2,4-다이아민 (화합물번호 39) Example 39. 8-Fluoro-4 N- (furan-2-ylmethyl) -2 N- (4-methoxyphenyl) quinazolin-2,4-diamine (Compound No. 39)

수율 21%, ¹H NMR (400 MHz, CD₃OD) δ 8.21 (q, J = 6.2 Hz, 1H), 7.47 (d, J = 1.1 Hz, 1H), 7.39 (d, J = 8.6 Hz, 2H), 7.24 (m, 2H), 7.0 (d, J = 7.2 Hz, 1H), 6.43 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.37 (d, J = 3.1 Hz, 1H),4.80 (s, 2H), 3.82 (s, 3H), ¹³C NMR (300 MHz, CD₃OD) δ 160.07, 150.34, 142.27, 114.51, 114.32, 113.20, 112.88, 110.11, 107.92, 54.61, 37.85
Yield 21%, ¹ H NMR (400 MHz, CD ₃ OD) δ 8.21 (q, J = 6.2 Hz, 1H), 7.47 (d, J = 1.1 Hz, 1H), 7.39 (d, J = 8.6 Hz, 2H ), 7.24 (m, 2H), 7.0 (d, J = 7.2 Hz, 1H), 6.43 (dd, J ₁ = 3.1 Hz, J ₂ = 1.8 Hz, 1H), 6.37 (d, J = 3.1 Hz, 1H ), 4.80 (s, 2H), 3.82 (s, 3H), ¹³ C NMR (300 MHz, CD ₃ OD) δ 160.07, 150.34, 142.27, 114.51, 114.32, 113.20, 112.88, 110.11, 107.92, 54.61, 37.85

[제제예][Example]

한편, 본 발명에 따른 상기 화학식 1로 표시되는 신규 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 다음은 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.
On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following is a description of some formulations containing the compound of Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

제제 1. 정제(직접 가압) Formulation 1 . Tablet (direct pressurization)

활성성분 5.0 ㎎을 체로 친 후, 락토스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 만들었다.
After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

제제 2. 정제(습식 조립) Formulation 2 . Tablets (Wet Assembly)

활성성분 5.0 ㎎을 체로 친 후, 락토스 16.0 ㎎과 녹말 4.0 ㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 다이옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 만들었다.
After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

제제 3. 분말과 캡슐제 Formulation 3 . Powder and Capsule

활성성분 5.0 ㎎을 체로 친 후에, 락토스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 섞었다. 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다.
5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. Filled in 5 gelatin capsules.

제제 4. 주사제 Formulation 4 . Injection

활성성분으로서 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na₂HPO₄·12H₂O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다.
Injectables were prepared by containing 100 mg as the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

[실험예]
Experimental Example

본 발명의 화합물에 대한 항암활성을 측정하기 위하여 하기와 같이 실험을 실시하였다.In order to determine the anticancer activity for the compound of the present invention was carried out as follows.

본 실험에서는 암세포로서 전립선암 세포주로서 DU145 (Human prostate cancer cell line), 대장암 세포주로서 HT-29 (Human colon cancer cell line)와 HCT-116 (Human colon carcinoma cancer cell line), 흑색종 세포주로서 A375P (Human melanoma cancer cell line), 섬유아 세포주로 HS-27 (Human fibroblasts cell line), 유방암 세포주로서 MCF-7 (Human breast cancer cell line)를 사용하였다. 이들 암세포는 모두 인간 유래의 종양 세포주로서 한국 세포주 은행에서 분양받아 배양하였다. 배양액은 10% 우태아혈청을 포함한 RPMI-1640 배지를 사용하였으며, 항온항습 인큐베이터 (37℃, 5% CO₂)에서 배양하였다. 세포의 계대는 0.25% 트립신-1mM EDTA를 사용하여 3일에 1회씩 하였다.In this experiment, DU145 (Human prostate cancer cell line) as a prostate cancer cell line, human colon cancer cell line (HT-29) and HCT-116 (Human colon carcinoma cancer cell line) as a colorectal cancer cell line, and A375P as a melanoma cell line (Human melanoma cancer cell line), HS-27 (Human fibroblasts cell line) as a fibroblast cell line, and MCF-7 (Human breast cancer cell line) as a breast cancer cell line. These cancer cells were all human tumor cells and were cultured by the Korean Cell Line Bank. The culture medium was RPMI-1640 medium containing 10% fetal calf serum, and cultured in a constant temperature and humidity incubator (37 ℃, 5% CO ₂ ). Cell passage was performed once every 3 days using 0.25% trypsin-1 mM EDTA.

본 실험은 1989년 미국의 국립암연구소에서 약물의 생체외 (in vitro) 항암 활성을 측정하기 위하여 개발된 SRB분석법 (Sulforhodamine B assay method)을 사용하였다. 계대 중인 세포들을 실험에 사용하기 위하여 트립신-CDTA 용액을 이용하여 세포들을 착면으로부터 분리시키고, 배양중인 세포를 96웰 마이크로 플레이트에 각 웰(well)당 세포수가 5X10³되도록 분주하여 CO₂인큐베이터에서 24시간 배양하였다. 배지를 제거하고 4배 농도로 희석한 시험화합물 용액을 100 uL씩 넣어서 48시간 배양하였다. 포르말린 용액 100 uL씩을 가하여 세포를 고정시킨 후 증류수로 5회 세척하고 실온에서 건조시켰다. 0.4% SRB 용액을 100 uL씩 가하여 30분간 실온에서 방치한 후 1%아세트산으로 5회 세척하여 실온에서 건조시켰다. 각 웰(well)당 10 mM Tisma base pH 10.3을 200 uL씩 넣어 완전 용해시킨 후 520 nm에서 흡광도를 측정하였다.This study used the SRB assay (Sulforhodamine B assay method) developed in 1989 to measure the in vitro anticancer activity of the drug at the National Cancer Institute of the United States. Cells were separated from the implant using trypsin-CDTA solution for the passage of passaged cells for experiments, and the cells in culture were dispensed in 96-well microplates with 5 × 10 ³ cells per well in a CO ₂ incubator. Time incubation. The medium was removed and 100 uL of the test compound solution diluted to 4-fold concentration was added and incubated for 48 hours. 100 uL of formalin solution was added to fix the cells, and then washed five times with distilled water and dried at room temperature. 100% of 0.4% SRB solution was added thereto, and the mixture was left at room temperature for 30 minutes, washed five times with 1% acetic acid, and dried at room temperature. 200 mM of 10 mM Tisma base pH 10.3 was added to each well to completely dissolve the absorbance at 520 nm.

암 세포들에 대한 시험화합물의 약효를 계산하기 위하여, 하기 수학식 1 또는 2에 따라 GI₅₀을 계산하였다.In order to calculate the efficacy of the test compound on cancer cells, GI ₅₀ was calculated according to the following formula (1) or (2).

상기 수학식 1에서, T₀는 시험화합물을 첨가하기 이전의 세포 수이고, T₂는 시험화합물을 첨가하고 48시간 배양한 후의 세포 수이다.In Equation 1, T ₀ is the number of cells before adding the test compound, and T ₂ is the number of cells after incubation for 48 hours after adding the test compound.

상기 수학식 2에서, T₀는 시험화합물을 첨가하기 이전의 세포 수이고, T₂는 시험화합물을 첨가하고 48시간 배양한 후의 세포 수이고, C는 시험화합물을 첨가하지 않은 대조군을 48시간 배양한 후의 세포 수이다. In Equation 2, T ₀ is the number of cells before adding the test compound, T ₂ is the number of cells after incubation for 48 hours after adding the test compound, and C is 48 hours incubating the control group without adding the test compound. The number of cells after one.

또한, 상기 수학식 1에 의해 계산된 값들로부터 로터스 프로그램 (LOTUS program)에 의해 데이터 회귀 (data regression)를 이용하여 각 시험화합물이 암세포의 성장을 억제하는 정도 (%저해농도)를 구하였다. 또한 %저해농도로부터 IC₅₀값을 계산하였다.In addition, from the values calculated by Equation 1, the degree of inhibition (% inhibition) of each test compound by inhibiting the growth of cancer cells was determined by using data regression by the Lotus program. IC ₅₀ values were also calculated from the% inhibition concentrations.

시험화합물Test compound DU-145 (%저해농도, μM)DU-145 (% inhibition concentration, μM) HT-29 (%저해농도, μM)HT-29 (% inhibition concentration, μM) 100100 2525 1010 1One 100100 2525 1010 1One 화합물번호 1Compound number 1 94.3694.36 81.0081.00 94.6994.69 83.2483.24 화합물번호 2Compound number 2 94.7194.71 93.6393.63 94.7694.76 94.2194.21 화합물번호 3Compound number 3 94.5694.56 91.5291.52 96.4796.47 93.9993.99 화합물번호 4Compound number 4 93.6793.67 93.1693.16 93.4393.43 94.1094.10 화합물번호 5Compound number 5 94.4594.45 94.3294.32 95.0295.02 94.7594.75 화합물번호 6Compound number 6 20.0420.04 0.650.65 75.8775.87 21.6921.69 화합물번호 7Compound No. 7 24.6224.62 0.960.96 77.1377.13 21.0821.08 화합물번호 8Compound number 8 96.2296.22 95.9695.96 95.2395.23 94.5894.58 화합물번호 9Compound number 9 52.9252.92 10.8110.81 87.4287.42 70.4370.43 화합물번호 10Compound number 10 90.7890.78 40.0940.09 93.6493.64 83.5283.52 화합물번호 11Compound number 11 91.5591.55 40.0640.06 93.9293.92 87.4887.48 화합물번호 12Compound number 12 88.7388.73 30.2530.25 92.9492.94 75.1175.11 화합물번호 13Compound number 13 87.8987.89 28.4828.48 92.7692.76 80.0280.02 화합물번호 14Compound number 14 94.6094.60 89.9089.90 95.1895.18 92.2792.27 화합물번호 15Compound number 15 95.7295.72 52.2652.26 27.3527.35 96.5396.53 68.6868.68 26.9226.92 화합물번호 17Compound number 17 90.5790.57 26.7226.72 93.7293.72 83.0783.07 화합물번호 18Compound number 18 94.6194.61 75.3775.37 95.2495.24 88.0988.09 화합물번호 19Compound number 19 94.3994.39 83.5983.59 95.0095.00 화합물번호 20Compound number 20 94.2794.27 55.3855.38 94.8094.80 86.1986.19 화합물번호 21Compound number 21 95.4395.43 95.4895.48 -0.80-0.80 96.3296.32 96.3096.30 18.7318.73 화합물번호 22Compound number 22 95.8795.87 95.9395.93 -0.88-0.88 96.6096.60 96.6996.69 27.9627.96 화합물번호 23Compound number 23 95.7695.76 93.4093.40 10.5010.50 96.5596.55 96.1296.12 39.6139.61 화합물번호 24Compound number 24 88.2288.22 26.5926.59 9.359.35 90.9390.93 27.5227.52 -1.83-1.83 화합물번호 25Compound number 25 87.9087.90 32.3632.36 17.4717.47 90.3790.37 34.8334.83 0.360.36 화합물번호 26Compound number 26 95.7495.74 57.5757.57 21.3921.39 96.5396.53 76.7876.78 27.9127.91 화합물번호 27Compound number 27 59.6759.67 27.7627.76 20.2620.26 87.1187.11 9.689.68 -1.48-1.48

시험화합물Test compound HCT-116 (%저해농도, μM)HCT-116 (% inhibition concentration, μM) A375P (%저해농도, μM)A375P (% inhibition concentration, μM) 100100 1010 1One 100100 1010 1One 화합물번호 2Compound number 2 94.4294.42 94.3194.31 화합물번호 3Compound number 3 94.1694.16 93.2193.21 화합물번호 4Compound number 4 94.0394.03 94.4594.45 화합물번호 5Compound number 5 94.6394.63 94.7394.73 화합물번호 11Compound number 11 93.9893.98 67.5067.50 화합물번호 12Compound number 12 92.5592.55 62.5862.58 화합물번호 13Compound number 13 92.4892.48 50.2550.25 화합물번호 14Compound number 14 94.7794.77 94.7894.78 화합물번호 15Compound number 15 97.2597.25 79.7979.79 15.0015.00 97.4897.48 59.1959.19 37.9437.94 화합물번호 17Compound number 17 93.4693.46 52.0952.09 화합물번호 18Compound number 18 94.7994.79 87.7787.77 화합물번호 19Compound number 19 94.4794.47 94.1794.17 화합물번호 20Compound number 20 94.4094.40 73.9873.98 화합물번호 21Compound number 21 97.0897.08 97.0997.09 27.2127.21 97.3097.30 97.3597.35 11.5911.59 화합물번호 22Compound number 22 97.3097.30 97.3497.34 19.6819.68 97.5597.55 97.5997.59 12.0712.07 화합물번호 23Compound number 23 97.2797.27 97.3997.39 51.9951.99 97.4897.48 97.5597.55 11.4811.48 화합물번호 24Compound number 24 91.3891.38 26.3926.39 3.493.49 91.7591.75 7.677.67 5.705.70 화합물번호 25Compound number 25 90.7790.77 27.4427.44 0.050.05 91.6591.65 15.8415.84 12.9612.96 화합물번호 26Compound number 26 97.3097.30 81.9881.98 13.3113.31 97.4897.48 62.0062.00 36.6236.62 화합물번호 27Compound number 27 86.5186.51 12.7612.76 0.270.27 86.8486.84 28.5528.55 12.8012.80

시험화합물Test compound 암세포 주에 대한 IC₅₀(μM)IC ₅₀ (μM) for cancer cell lines DU-145DU-145 HT-29HT-29 HCT-116HCT-116 A375PA375P HS-27HS-27 화합물번호 1Compound number 1 35.01±3.2535.01 ± 3.25 12.19±1.9112.19 ± 1.91 화합물번호 2 Compound number 2 1.07±0.201.07 ± 0.20 0.86±0.050.86 ± 0.05 0.84±0.050.84 ± 0.05 3.90±0.483.90 ± 0.48 화합물번호 3Compound number 3 0.93±0.150.93 ± 0.15 0.84±0.100.84 ± 0.10 0.77±0.20.77 ± 0.2 3.04±0.643.04 ± 0.64 화합물번호 4Compound number 4 3.71±0.913.71 ± 0.91 3.37±0.453.37 ± 0.45 3.36±0.073.36 ± 0.07 3.36±0.273.36 ± 0.27 화합물번호 5Compound number 5 3.87±0.823.87 ± 0.82 3.37±0.293.37 ± 0.29 3.2±0.203.2 ± 0.20 3.75±0.223.75 ± 0.22 화합물번호 8Compound number 8 11.53±0.1511.53 ± 0.15 6.73±0.466.73 ± 0.46 화합물번호 9Compound number 9 79.91±5.1779.91 ± 5.17 23.93±0.5923.93 ± 0.59 화합물번호 10Compound number 10 51.03±9.2251.03 ± 9.22 4.45±0.244.45 ± 0.24 화합물번호 11Compound number 11 35.27±1.3235.27 ± 1.32 6.01±1.056.01 ± 1.05 16.12±1.2116.12 ± 1.21 19.39±1.0319.39 ± 1.03 화합물번호 12Compound number 12 >100> 100 11.26±2.1411.26 ± 2.14 26.14±9.7826.14 ± 9.78 >100> 100 화합물번호 13Compound number 13 >100> 100 10.29±0.8310.29 ± 0.83 25.91±10.6825.91 ± 10.68 34.88±12.3934.88 ± 12.39 화합물번호 14Compound number 14 4.99±1.324.99 ± 1.32 2.94±0.252.94 ± 0.25 5.47±0.045.47 ± 0.04 9.2±1.819.2 ± 1.81 화합물번호 15Compound number 15 6.249±1.26.249 ± 1.2 1.34±0.481.34 ± 0.48 2.103±0.382.103 ± 0.38 5.238±1.345.238 ± 1.34 1.6011.601 화합물번호 16Compound number 16 1.988±0.0711.988 ± 0.071 2.494±0.1632.494 ± 0.163 화합물번호 17Compound number 17 >100> 100 9.32±1.089.32 ± 1.08 25.28±10.3625.28 ± 10.36 22.51±2.0022.51 ± 2.00 화합물번호 18Compound number 18 5.91±2.485.91 ± 2.48 3.04±0.543.04 ± 0.54 4.31±1.394.31 ± 1.39 8.48±0.518.48 ± 0.51 화합물번호 19Compound number 19 7.24±0.767.24 ± 0.76 4.03±0.514.03 ± 0.51 4.1±0.924.1 ± 0.92 7.34±0.777.34 ± 0.77 화합물번호 20Compound number 20 11.63±0.1011.63 ± 0.10 4.34±0.864.34 ± 0.86 6.15±1.386.15 ± 1.38 7.66±1.477.66 ± 1.47 화합물번호 21Compound number 21 0.673±0.10.673 ± 0.1 0.396±0.040.396 ± 0.04 0.52±0.080.52 ± 0.08 2.655±0.372.655 ± 0.37 2.5752.575 화합물번호 22Compound number 22 2.665±0.162.665 ± 0.16 1.054±0.291.054 ± 0.29 1.148±0.081.148 ± 0.08 2.834±0.082.834 ± 0.08 2.5382.538 화합물번호 23Compound number 23 3.327±0.383.327 ± 0.38 1.831±0.451.831 ± 0.45 0.827±0.200.827 ± 0.20 3.281±0.103.281 ± 0.10 1.8011.801 화합물번호 26Compound number 26 6.468±0.716.468 ± 0.71 1.369±0.411.369 ± 0.41 2.141±0.332.141 ± 0.33 4.445±0.924.445 ± 0.92 1.2831.283 화합물번호 28Compound number 28 1.012±0.00851.012 ± 0.0085 2.421±0.2832.421 ± 0.283 화합물번호 29Compound number 29 2.054±0.0862.054 ± 0.086 2.418±0.2382.418 ± 0.238 화합물번호 30Compound number 30 0.31±0.0110.31 ± 0.011 2.55±0.2522.55 ± 0.252 화합물번호 31Compound number 31 2.096±0.1182.096 ± 0.118 2.547±0.1572.547 ± 0.157 화합물번호 32Compound number 32 1.198±0.1391.198 ± 0.139 2.63±0.2152.63 ± 0.215 화합물번호 33Compound number 33 1.336±0.1091.336 ± 0.109 1.829±0.1641.829 ± 0.164 화합물번호 34Compound number 34 1.359±0.0781.359 ± 0.078 1.665±0.1721.665 ± 0.172 화합물번호 35Compound number 35 3.43±0.1613.43 ± 0.161 3.667±0.1983.667 ± 0.198 화합물번호 36Compound number 36 12.597±1.22512.597 ± 1.225 22.05±1.98222.05 ± 1.982 화합물번호 37Compound number 37 24.943±1.09924.943 ± 1.099 20.997±0.87420.997 ± 0.874 화합물번호 38Compound number 38 21.94±1.09921.94 ± 1.099 20.997±0.87420.997 ± 0.874 화합물번호 39Compound number 39 6.122±0.4936.122 ± 0.493 12.24±0.81212.24 ± 0.812

시험화합물Test compound MCF-7 (%저해농도, μM)MCF-7 (% inhibition concentration, μM) IC₅₀(μM)IC ₅₀ ([mu] M) 100100 1010 1One AverageAverage STDEVSTDEV 화합물번호 1Compound number 1 95.8795.87 64.5564.55 25.0525.05 7.25E-067.25E-06 1.55E-061.55E-06 화합물번호 2Compound number 2 95.8195.81 95.7895.78 13.3213.32 3.14E-063.14E-06 2.54E-082.54E-08 화합물번호 3Compound number 3 95.7695.76 95.8695.86 9.159.15 3.31E-063.31E-06 2.01E-072.01E-07 화합물번호 4Compound number 4 95.7795.77 95.8595.85 13.6913.69 2.98E-062.98E-06 1.14E-071.14E-07 화합물번호 5Compound number 5 95.7695.76 95.8295.82 17.6317.63 2.97E-062.97E-06 2.05E-072.05E-07 화합물번호 8Compound number 8 95.8195.81 95.7595.75 41.2141.21 2.12E-062.12E-06 1.04E-071.04E-07 화합물번호 14Compound number 14 95.9095.90 66.7066.70 33.0633.06 5.64E-065.64E-06 9.05-079.05-07 화합물번호 19Compound number 19 95.6495.64 94.4294.42 33.6933.69 2.64E-062.64E-06 4.80E-074.80E-07 화합물번호 23Compound number 23 95.4995.49 95.6595.65 10.6710.67 3.13E-063.13E-06 2.05E-072.05E-07 화합물번호 28Compound number 28 95.4595.45 95.4895.48 16.2416.24 2.94E-062.94E-06 1.10E-071.10E-07 화합물번호 33Compound number 33 95.1995.19 86.9886.98 21.0621.06 3.09E-063.09E-06 4.65E-084.65E-08

상기 표 1 내지 4에서 확인되는 바와 같이, 본 발명에 따른 상기 화학식 1로 표시되는 2,4-다이아미노퀴나졸린 화합물은 다양한 암세포에 대한 세포 독성을 나타낸다.
As confirmed in Tables 1 to 4, the 2,4-diaminoquinazoline compound represented by Formula 1 according to the present invention shows cytotoxicity against various cancer cells.

본 발명에 따른 상기 화학식 1로 표시되는 2,4-다이아미노퀴나졸린 화합물 또는 이의 약제학적으로 허용 가능한 염은 암세포에 대한 세포독성을 가지고 있으므로, 항암제로서 유용하다.The 2,4-diaminoquinazoline compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention is useful as an anticancer agent because it has cytotoxicity against cancer cells.

Claims

Compounds characterized in that selected from 2,4-diaminoquinazoline compound represented by the formula (1) and a pharmaceutically acceptable salt:
[Formula 1]

In Chemical Formula 1,
R ₁ represents a hydrogen atom or a halogen atom;
R ₂ represents a hydrogen atom or a piperazin-1-yl group, wherein the piperazin-1-yl group is a halogen atom, a C ₁ -C ₆ alkyl group, a phenyl group, and a phenyl group substituted with halo or C ₁ -C ₆ alkyl May be substituted or unsubstituted with a substituent selected from the group consisting of:
n represents the integer of 2-6.

The method according to claim 1,
R ₁ represents a hydrogen atom, a fluoro atom, or a chloro atom;
R ₂ is a hydrogen atom, piperazin-1-yl group, 4- (methyl) piperazin-1-yl group, 4- (ethyl) piperazin-1-yl group, 4- (2-chlorophenyl) piperazin-1 -Group, 4- (3-chlorophenyl) piperazin-1-yl group, 4- (2,3-dichlorophenyl) piperazin-1-yl group, 4- (2-methylphenyl) piperazin-1-yl group, A 4- (3-methylphenyl) piperazin-1-yl group or a 4- (2,3-dimethylphenyl) piperazin-1-yl group;
N is an integer of 2 to 5, characterized in that the compound.

The method according to claim 1,
2 N- (4- (4- (2,3-dimethylphenyl) piperazin-1-yl) butyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 2),
2 N- (3- (4- (2,3-dimethylphenyl) piperazin-1-yl) propyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 3),
2 N- (3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (compound Number 4),
2 N- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (compound Number 5),
4 N- (furan-2ylmethyl) -2 N -pentylquinazolin-2,4-diamine (Compound No. 8),
2 N- butyl-4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 14),
2 N- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) -4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (compound Number 16),
2 N- butyl-6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4-diamine (Compound No. 18),
6-fluoro-4 N- (furan-2-ylmethyl) -2 N -pentylquinazolin-2,4-diamine (Compound No. 19),
2 N- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl) -6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4 Diamine (compound number 21),
2 N- (3- (4- (2,3-dimethylphenyl) piperazin-1-yl) propyl) -6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4- Diamine (Compound No. 22),
2 N- (4- (4- (2,3-dimethylphenyl) piperazin-1-yl) butyl) -6-fluoro-4 N- (furano-2-ylmethyl) quinazolin-2,4 Diamine (Compound No. 23),
2 N- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) -6-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4 Diamine (compound number 28),
2 N- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) -8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4 Diamine (Compound No. 29),
2 N- (4- (4- (2,3-dimethylphenyl) piperazin-1-yl) butyl) -8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4- Diamine (Compound No. 30),
2 N- (3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propyl) -8-fluoro-4 N- (furan-2-ylmethyll) quinazolin-2, 4-diamine (Compound No. 31),
2 N- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl) -8-fluoro-4 N- (furan-2-ylmethyl) quinazolin-2,4 Diamine (compound number 32),
2 N-butyl-N-8-fluoro -4 - (furan-2-ylmethyl) quinazoline-2,4-diamine (Compound No. 33),
8-fluoro-4 N- (furan-2-ylmethyl) -2 N -pentylquinazolin-2,4-diamine (Compound No. 34), and
A compound characterized in that it is selected from pharmaceutically acceptable salts thereof.

Anticancer pharmaceutical composition containing a compound of any one selected from claims 1 to 3.

delete