KR20070045063A - [1,2,4]-Triazolo[4,3-c]quinazoline derivatives having anticancer activity - Google Patents

[1,2,4]-Triazolo[4,3-c]quinazoline derivatives having anticancer activity Download PDF

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KR20070045063A
KR20070045063A KR1020050101516A KR20050101516A KR20070045063A KR 20070045063 A KR20070045063 A KR 20070045063A KR 1020050101516 A KR1020050101516 A KR 1020050101516A KR 20050101516 A KR20050101516 A KR 20050101516A KR 20070045063 A KR20070045063 A KR 20070045063A
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phenyl
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하재두
조성윤
조희영
공재양
최중권
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Abstract

본 발명은 항종양 활성을 갖는 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 유도체에 관한 것으로, 더욱 상세하게는 티로신 키나제에 대한 억제활성이 우수하여 비정상적인 키나제의 활성으로 야기되는 질환 예를 들면 암, 특히 결장직장암, 유방암, 폐암, 전립선암, 췌장암, 방광암, 신장암, 백혈병, 림프종과 같은 고증식성 질환 치료에 유효한 신규 구조의 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 유도체 및 이의 약학적으로 허용 가능한 염과, 이 화합물의 의약적 용도에 관한 것이다.The present invention relates to a [1,2,4] -triazolo [4,3-c] quinazolin derivative having antitumor activity, and more particularly, to an abnormal kinase activity due to its excellent inhibitory activity against tyrosine kinase. Diseases caused are novel structures of [1,2,4] -triazolo that are effective for treating hyperproliferative diseases such as cancer, in particular colorectal cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, bladder cancer, kidney cancer, leukemia, lymphoma [4,3-c] quinazolin derivatives and their pharmaceutically acceptable salts and medicinal uses of these compounds.

Description

항종양 활성을 갖는 〔1,2,4〕―트리아졸로〔4,3―ｃ〕퀴나졸린 유도체{[1,2,4]-Triazolo[4,3-c]quinazoline derivatives having anticancer activity}[1,2,4] -triazolo [4,3-c] quinazolin derivatives having anti-tumor activity {[1,2,4] -Triazolo [4,3-c] quinazoline derivatives having anticancer activity}

본 발명은 항종양 활성을 갖는 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 유도체에 관한 것으로, 더욱 상세하게는 티로신 키나제에 대한 억제활성이 우수하여 비정상적인 키나제의 활성으로 야기되는 질환 예를 들면 암, 특히 결장직장암, 유방암, 폐암, 전립선암, 췌장암, 방광암, 신장암, 백혈병, 림프종과 같은 고증식성 질환 치료에 유효한 신규 구조의 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 유도체 및 이의 약학적으로 허용 가능한 염과, 이 화합물의 의약적 용도에 관한 것이다. The present invention relates to a [1,2,4] -triazolo [4,3-c] quinazolin derivative having antitumor activity, and more particularly, to an abnormal kinase activity due to its excellent inhibitory activity against tyrosine kinase. Diseases caused are novel structures of [1,2,4] -triazolo that are effective for treating hyperproliferative diseases such as cancer, in particular colorectal cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, bladder cancer, kidney cancer, leukemia, lymphoma [4,3-c] quinazolin derivatives and their pharmaceutically acceptable salts and medicinal uses of these compounds.

암과 같은 고증식성 질환에 대한 현행 치료방법은 일반적으로 상당한 세포독성을 나타내는 항종양제가 주로 사용되며, 더욱이 이와 같은 방법은 암세포와 정상세포와의 낮은 선택성으로 환자들에게 많은 부작용을 초래하고 있는 실정이다. 이러한 세포독성 항종양제에 대한 부작용을 최소화시키는 진보된 방법이 세포 증식에 필요한 세포 신호전달 체계를 저해하는 억제제가 개발하는 것이며, 이러한 억제제는 종양세포에 대한 선택성을 나타나기 때문에 적은 부작용으로 효과적으로 고증식성 질환 치료제로서 사용이 가능하다. 암과 관련된 다양한 종류의 티로신 키나제 수용체 중 상피세포 성장인자 수용체(EGFR)는 암세포의 생존(survival)과 성장(proliferation)에 밀접한 관련을 가지고 있다. 즉, 상피세포 성장인자 수용체의 과도한 형성과 지나친 활성은 많은 종류의 암세포의 발달에 큰 영향을 주는 것으로 알려져 있다. Current treatments for hyperproliferative diseases such as cancer generally use anti-tumor agents that show significant cytotoxicity. Moreover, such methods have many side effects in patients with low selectivity between cancer cells and normal cells. to be. An advanced method of minimizing the side effects of these cytotoxic antitumor agents is the development of inhibitors that inhibit the cellular signaling system necessary for cell proliferation. It can be used as a disease treatment agent. Among the various types of tyrosine kinase receptors associated with cancer, epidermal growth factor receptor (EGFR) is closely related to the survival and proliferation of cancer cells. In other words, excessive formation and excessive activity of epidermal growth factor receptors are known to greatly influence the development of many types of cancer cells.

성장인자와 결합하는 수용체 티로신 키나제는 세포내 신호전달체계에 있어 가장 중요하게 작용하는 단백질이다. 단백질 티로신 키나제의 신호체계는 다양한 세포내 작용, 대표적으로 세포의 성장, 분화, 이동, 그리고 대사를 조절하게 된다. 그러나 신호전달체계가 비정상적으로 활성화됨으로써 암의 생성, 성장과 확산을 하게 된다. 수용체 티로신 키나제는 세포의 티로신 키나제 도메인과 연결된 세포외 리간드 결합도메인으로 이루어져 있다. 상피세포 성장인자 수용체(EGFR)는 다수의 아군(subfamily)을 포함하는데, 대표적으로 EGFR, HER2(ErbB2), HER3(ErbB3), 및 HER4(ErbB4)가 알려져 있다. 상피세포 성장인자(EGF)가 리간드 결합도메인의 수용체(EGFR)에 결합하게 되면 수용체 키나제는 동종 또는 이종의 이합체를 형성하게 된다. 동시에 ATP에 의한 티로신 잔기의 인산화가 이루어지게 됨으로써 키나제의 신호전달체계의 활성을 이루게 된다. 형성된 생물학적 신호전달은 다단계의 신호를 거쳐 결국에는 세포의 성장 및 분화를 조절하게 된다고 공지되어 있다 (EMBO J., 2000, 19, 3159). 따라서 이들 수용체 티로신 키나제 억제제는 포유동물의 암세포 증식의 선택적 억제제로 충분한 가치를 지니고 있는 것으로 공지되고 있다 (Oncogene, 2000, 19, 6550; Biophysica Acta, 1997, 133; Oncogene, 2000, 19, 5690).Receptor tyrosine kinases that bind to growth factors are the most important proteins in intracellular signaling. The signaling system of protein tyrosine kinases regulates a variety of intracellular actions, typically cell growth, differentiation, migration, and metabolism. However, abnormally activated signaling systems result in the generation, growth, and spread of cancer. Receptor tyrosine kinases consist of extracellular ligand binding domains linked to tyrosine kinase domains of cells. Epidermal growth factor receptor (EGFR) comprises a number of subfamily, representatively known as EGFR, HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). When epidermal growth factor (EGF) binds to the receptor of the ligand binding domain (EGFR), receptor kinases form homologous or heterologous dimers. At the same time, phosphorylation of tyrosine residues by ATP results in the activation of the kinase signaling system. It is known that the formed biological signaling results in a multistage signal that eventually regulates the growth and differentiation of cells (EMBO J., 2000, 19, 3159). These receptor tyrosine kinase inhibitors are therefore known to be of sufficient value as selective inhibitors of cancer cell proliferation in mammals (Oncogene, 2000, 19, 6550; Biophysica Acta, 1997, 133; Oncogene, 2000, 19, 5690).

지금까지 개발되었거나 개발이 진행중인 상피세포 성장인자(EGF)의 신호체계를 저해하는 퀴나졸린 계열 화합물들로서는 이레사(IressaTM)와 타르세바(TarcevaTM)가 현재 발매가 되고 있으며, 이들 화합물은 EGF RTK 억제 활동을 가지며, 암 조직의 증식 억제제로 공지되어 있다 (Iressa-국제특허출원공개공보 WO96/33980; Tarceva-국제특허출원공개공보 WO96/30347호). 또한 EKB-569, PKI-166, Lapatinib, 그리고 CI-1033 등이 현재 임상에서 개발이 진행되고 있으며, 대부분 상피세포 성장인자 수용체(EGFR)에 우수한 선택성을 보이고 있다. 이중에서 이레사(IressaTM)와 타르세바(Tarceva)는 비소세포성폐암 치료제로서, 비록 여러 가지 부작용을 나타내지만 말기 비소세포성폐암 환자군에 제한적으로 사용되고 있다.Or developed so far developed are as quinazolin-based compound to inhibit the signaling of an ongoing epidermal growth factor (EGF) is Iressa (Iressa TM) and Tarceva (Tarceva TM) is currently on sale, these compounds EGF RTK It has an inhibitory activity and is known as an inhibitor of proliferation of cancer tissues (Iressa-WO96 / 33980; Tarceva-WO96 / 30347). In addition, EKB-569, PKI-166, Lapatinib, and CI-1033 are currently being developed in the clinic, and most of them show excellent selectivity for epidermal growth factor receptor (EGFR). Iressa in double (Iressa TM) and Tarceva (Tarceva) is a non-small cell lung cancer treatment, although not indicate the end of a limited number of side-effects used in non-small cell lung cancer patients.

본 발명은 티로신 수용체 키나제 억제제 자체가 세포독성을 보유함으로써 암세포의 증식에 시너지 효과를 나타낼 수 있을 것이라는 생각과 함께 출발하였다. 고전적인 화학요법에서 많이 사용되는 세포독성을 나타내는 화합물은 많은 부작용을 나타내지만 수용체 키나제 억제제와 함께 사용할 때 효과의 극대화를 이루는 경우가 다수 보고 되어있다 (CHIR200131-abstract #3675, 4208; 93차 미국화학회 2002, 5월). 일반적으로 세포독성을 나타내는 화합물은 평면형의 다원환(multicyclic) 구조를 가지고 있는 바, 본 발명에서는 퀴나졸린 구조에 새로운 트리아졸 환을 부가시켜 삼환구조를 가지는 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 유도체를 합성한 것이다. The present invention starts with the idea that the tyrosine receptor kinase inhibitor itself may have a synergistic effect on the proliferation of cancer cells by retaining cytotoxicity. Cytotoxic compounds commonly used in classical chemotherapy have many side effects but have been reported to maximize their effectiveness when used in combination with receptor kinase inhibitors (CHIR200131-abstract # 3675, 4208; 93rd American Chemical Society May 2002). Generally, cytotoxic compounds have a planar multicyclic structure. In the present invention, a new triazole ring is added to a quinazoline structure to give a tricyclic structure [1,2,4] -triazolo [ 4,3-c] quinazoline derivatives are synthesized.

이에 본 발명자들은 다양한 암과 관련된 상피세포 수용체 티로신 키나제(EGFR)의 신호체계를 저해하는 우수한 활성을 보이는 삼환구조의 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 유도체를 합성하게 됨으로써 본 발명을 완성하게 되었다.The present inventors have identified a tricyclic [1,2,4] -triazolo [4,3-c] quinazolin derivative that exhibits excellent activity that inhibits the signaling system of epithelial cell receptor tyrosine kinase (EGFR) associated with various cancers. Synthesis made the present invention complete.

따라서, 본 발명은 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 유도체를 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a [1,2,4] -triazolo [4,3-c] quinazolin derivative.

또한, 본 발명은 상기한 신규 화합물이 대조약제와 비교하여 상피세포 성장인자 수용체(EGFR)에 우수한 활성을 나타내므로 비정상적인 티로신 키나제의 활성으로 야기되는 각종 질환 예를 들면, 암, 특히 결장직장, 유방, 폐, 전립선, 췌장 또는 방광 및 신장 암, 또는 백혈병 또는 림프종과 같은 고증식성 질환 치료용 약제로 사용하는 용도를 제공하는데 다른 목적이 있다.In addition, the present invention exhibits superior activity to epidermal growth factor receptor (EGFR) as compared to the reference drug, so that the various compounds caused by abnormal tyrosine kinase activity, such as cancer, especially colorectal, breast Another purpose is to provide a medicament for the treatment of hyperproliferative diseases such as lung, prostate, pancreas or bladder and kidney cancer, or leukemia or lymphoma.

본 발명은 티로신 키나제에 대하여 억제활성을 나타내는 다음 화학식 1로 표시되는 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 구조를 기본 골격으로 하고, 다양한 R1 및 R2 치환체가 도입된 신규 화합물, 이의 약학적으로 허용 가능한 염 및 이의 용매화물을 그 특징으로 한다.The present invention is based on the [1,2,4] -triazolo [4,3-c] quinazolin structure represented by the following formula (1) showing inhibitory activity against tyrosine kinase, and various R 1 and R 2 substituents. It is characterized by the novel compounds to which they are introduced, their pharmaceutically acceptable salts and their solvates.

상기 화학식 1에서, R1은 수소원자, 할로겐기, 히드록시기, 아민기, C1-4의 알콕시기, 또는 -NR3R4가 치환된 C1-4의 알콕시기를 나타내고; R2는 수소원자, C1-4의 알콕시기, 또는 -NR3R4가 치환된 C1-4의 알콕시기를 나타내고; R3 및 R4는 서로 같거나 다른 것으로, 각각 수소원자, C1-6의 알킬기, 또는 C1-4의 히드록시알킬기이거나, 또는 R3 및 R4이 결합된 질소원자 및 O, S, 및 NR5(이때, R5는 수소원자 또는 C1-6의 알킬기) 중에서 선택된 헤테로원자가 1 내지 3개 포함되어 고리로 연결된 5원 내지 7원의 헤테로 지방족 또는 방향족 시클릭기를 나타내고; 단, R1 및 R2가 동시에 수소원자인 경우는 제외한다.In Formula 1, R 1 represents a hydrogen atom, a halogen group, a hydroxy group, an amine group, a C 1-4 alkoxy group, or a C 1-4 alkoxy group substituted with —NR 3 R 4 ; R 2 represents a hydrogen atom, an alkoxy group of C 1-4 or a C 1-4 alkoxy group substituted with —NR 3 R 4 ; R 3 and R 4 are the same as or different from each other, and each is a hydrogen atom, an alkyl group of C 1-6 , or a hydroxyalkyl group of C 1-4 , or a nitrogen atom having R 3 and R 4 bonded thereto and O, S, And 5 to 7 membered heteroaliphatic or aromatic cyclic groups containing 1 to 3 heteroatoms selected from NR 5 (wherein R 5 is a hydrogen atom or an alkyl group of C 1-6 ) and is connected by a ring; Except that R 1 and R 2 are hydrogen atoms at the same time.

또한, 본 발명에 따른 상기 화학식 1로 표시되는 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 유도체는 약학적으로 허용 가능한 염의 형태로 사용될 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있다. 무기산으로는 염산, 브롬산, 황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 젖산, 주석산, 말레인산, 푸마린산, 글루콘산, 메탄설폰산, 글리콘산, 숙신산, 4-톨루엔설폰산, 글루투론산, 엠본산, 글루탐산, 또는 아스파트산 등을 사용할 수 있다.In addition, the [1,2,4] -triazolo [4,3-c] quinazolin derivative represented by Formula 1 according to the present invention may be used in the form of a pharmaceutically acceptable salt, and as a salt, Acid addition salts formed by acceptable free acids are useful. Inorganic acids and organic acids can be used as the free acid. Hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4-toluene Sulfonic acid, gluturonic acid, embonic acid, glutamic acid, aspartic acid and the like can be used.

또한, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 용매화물(예를 들면 수화물)의 형태로도 존재할 수 있다.In addition, the compound represented by Chemical Formula 1 according to the present invention may also exist in the form of a solvate (for example, a hydrate).

본 발명에 따른 상기 화학식 1로 표시되는 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 유도체에 있어서, 바람직하기로는 In the [1,2,4] -triazolo [4,3-c] quinazoline derivative represented by Formula 1 according to the present invention, Preferably,

R1은 수소원자, 할로겐기, 히드록시기, 아민기, 또는 -NR3R4가 치환된 C2-3의 알콕시기를 나타내고; R2는 수소원자, 메톡시기, 또는 -NR6R7가 치환된 C2-3의 알콕시기를 나타내고; R3 및 R4는 서로 같거나 다른 것으로, 각각 C1-2의 알킬기, 또는 C2-3의 히드록시알킬기이거나, 또는 R3 및 R4이 결합된 질소원자 및 O, S, 및 NR5(이때, R5는 수소원자 또는 C1-2의 알킬기) 중에서 선택된 헤테로원자가 1 내지 3개 포함되어 고리로 연결된 5원 내지 6원의 헤테로 지방족 또는 방향족 시클릭기를 나타내며, 단, R1 및 R2가 동시에 수소원자인 경우는 제외한다.R 1 represents a hydrogen atom, a halogen group, a hydroxy group, an amine group, or a C 2-3 alkoxy group substituted with —NR 3 R 4 ; R 2 represents a hydrogen atom, a methoxy group, or a C 2-3 alkoxy group substituted with —NR 6 R 7 ; R 3 and R 4 are the same as or different from each other, and are each an alkyl group of C 1-2 , or a hydroxyalkyl group of C 2-3 , or a nitrogen atom to which R 3 and R 4 are bonded and O, S, and NR 5 (Wherein R 5 represents a hydrogen atom or a C 1-2 alkyl group) represents a 5- to 6-membered heteroaliphatic or aromatic cyclic group linked by a ring containing 1 to 3 heteroatoms selected from R 1 and R Except when 2 is hydrogen atom at the same time.

본 발명에 따른 상기 화학식 1로 표시되는 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 유도체에 있어서, 더욱 바람직하기로는  In the [1,2,4] -triazolo [4,3-c] quinazoline derivative represented by Formula 1 according to the present invention, more preferably

R1은 수소원자, 브롬, 히드록시기, 몰폴린기, 또는 -NR3R4가 치환된 C2-3의 알콕시기를 나타내고; R2는 수소원자, 메톡시기, 또는 -NR6R7가 치환된 C2-3의 알콕시기를 나타내고; R3 및 R4는 서로 같거나 다른 것으로, 각각 메틸, 에틸, 또는 히드록시에틸기이거나, 또는 R3 및 R4이 고리로 연결되어 형성된 피롤, 피롤리딘기, 피페리딘기, 이미다졸기, 몰폴린기, 피페라진, 또는 N-메틸 피페라진기를 포함하며; 단, R1 및 R2가 동시에 수소원자인 경우는 제외한다.R 1 represents a hydrogen atom, bromine, a hydroxy group, a morpholine group, or a C 2-3 alkoxy group substituted with —NR 3 R 4 ; R 2 represents a hydrogen atom, a methoxy group, or a C 2-3 alkoxy group substituted with —NR 6 R 7 ; R 3 and R 4 are the same as or different from each other, and each is a methyl, ethyl, or hydroxyethyl group, or a pyrrole, pyrrolidine group, piperidine group, imidazole group, or mole formed when R 3 and R 4 are linked with a ring. A pollin group, a piperazine, or an N-methyl piperazine group; Except that R 1 and R 2 are hydrogen atoms at the same time.

본 발명에 따른 상기 화학식 1로 표시되는 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 구조의 퀴나졸린 유도체에 있어서 특히 바람직한 화합물을 예시하면 다음과 같다 :Particularly preferred compounds for the quinazoline derivatives of the [1,2,4] -triazolo [4,3-c] quinazolin structure represented by Formula 1 according to the present invention are as follows:

디메틸-[2-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-에틸]-아민 ;Dimethyl- [2- (4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenoxy) -ethyl] -amine;

디에틸-[2-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-에틸]-아민 ;Diethyl- [2- (4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenoxy) -ethyl] -amine;

3-[4-(2-피롤리딘-1-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline;

3-[4-(2-피페리딘-1-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (2-piperidin-1-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline;

3-[4-(2-몰폴린-4-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (2-morpholin-4-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline;

디에틸-[3-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-프로필]-아민 ;Diethyl- [3- (4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenoxy) -propyl] -amine;

3-[4-(3-피롤리딘-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (3-pyrrolidin-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazolin;

3-[4-(3-피페리딘-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (3-piperidin-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazolin;

3-[4-(2-몰폴린-4-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (2-morpholin-4-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline;

3-{4-[3-(4-메틸-피페라진-1-일)-프로폭시]-페닐}-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- {4- [3- (4-Methyl-piperazin-1-yl) -propoxy] -phenyl}-[1,2,4] triazolo [4,3-c] quinazoline;

2-{메틸-[3-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-프로필]-아미노}-에탄올 ;2- {methyl- [3- (4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenoxy) -propyl] -amino} -ethanol;

3-[4-(3-이미다졸-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (3-imidazol-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline;

3-[4-(3-피롤-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (3-pyrrole-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline;

8,9-디메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazoline;

4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페놀 ;4- (8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenol;

8,9-디메톡시-3-[4-(몰폴린-2-일-메톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- [4- (morpholin-2-yl-methoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline;

8,9-디메톡시-3-(4-몰폴린-4-일-페닐)-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- (4-morpholin-4-yl-phenyl)-[1,2,4] triazolo [4,3-c] quinazolin;

{2-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시]-에틸}-디에틸아민 ;{2- [4- (8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenoxy] -ethyl} -diethylamine;

8,9-디메톡시-3-[4-(2-몰폴린-4-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- [4- (2-morpholin-4-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline;

8,9-디메톡시-3-[4-(2-피페리딘-1-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline;

{3-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시]-프로필}-디에틸아민 ;{3- [4- (8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenoxy] -propyl} -diethylamine;

8,9-디메톡시-3-[4-(3-피롤리딘-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴놀린 ;8,9-dimethoxy-3- [4- (3-pyrrolidin-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinoline;

8,9-디메톡시-3-[4-(3-피페리딘-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- [4- (3-piperidin-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazolin;

8,9-디메톡시-3-[4-(3-몰폴린-4-일-프로폭시)-페닐]-[1,2,4]트리아졸[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- [4- (3-morpholin-4-yl-propoxy) -phenyl]-[1,2,4] triazole [4,3-c] quinazoline;

8,9-디메톡시-3-{4-[3-(4-메틸-피페라진-1-일)-프로폭시]-페닐}-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- {4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl}-[1,2,4] triazolo [4,3-c ] Quinazolin;

2-({3-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시]-프로필}-메틸아미노)-에탄올 ;2-({3- [4- (8,9-Dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenoxy] -propyl} -methylamino )-ethanol ;

3-[4-(3-이미다졸-1-일-프로폭시)-페닐]-8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (3-imidazol-1-yl-propoxy) -phenyl] -8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin;

9-메톡시-3-페닐-8-(2-피롤리딘-1-일-에톡시)-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-3-phenyl-8- (2-pyrrolidin-1-yl-ethoxy)-[1,2,4] triazolo [4,3-c] quinazolin;

9-메톡시-3-페닐-8-(2-피페리딘-1-일-에톡시)-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-3-phenyl-8- (2-piperidin-1-yl-ethoxy)-[1,2,4] triazolo [4,3-c] quinazoline;

9-메톡시-8-(2-몰폴린-4-일-에톡시)-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-8- (2-morpholin-4-yl-ethoxy) -3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin;

디에틸-[3-(9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린-8-일옥시)-프로필]-아민 ;Diethyl- [3- (9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin-8-yloxy) -propyl] -amine;

9-메톡시-3-페닐-8-(3-피롤리딘-1-일-프로폭시)-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-3-phenyl-8- (3-pyrrolidin-1-yl-propoxy)-[1,2,4] triazolo [4,3-c] quinazolin;

9-메톡시-3-페닐-8-(3-피페리딘-1-일-프로폭시)-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-3-phenyl-8- (3-piperidin-1-yl-propoxy)-[1,2,4] triazolo [4,3-c] quinazolin;

9-메톡시-8-(3-몰폴린-4-일-프로폭시)-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-8- (3-morpholin-4-yl-propoxy) -3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin;

9-메톡시-8-[3-(4-메틸-피페라진-1-일)-프로폭시]-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-8- [3- (4-methyl-piperazin-1-yl) -propoxy] -3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin;

2-{[3-(9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린-8-일옥시)-프로필]-메틸-아미노}-에탄올 ;2-{[3- (9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin-8-yloxy) -propyl] -methyl-amino} -ethanol ;

8-(3-이미다졸-1-일-프로폭시)-9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8- (3-imidazol-1-yl-propoxy) -9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin;

3-(4-브로모페닐)-8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- (4-bromophenyl) -8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazoline;

8,9-디메톡시-3-[4-(2-피롤리딘-1-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline;

{2-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시]-에틸}-디메틸아민 ;{2- [4- (8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenoxy] -ethyl} -dimethylamine;

그리고 상기 화합물들의 약학적으로 허용되는 염 및 용매화물(예를 들면 수화물) 등이다.And pharmaceutically acceptable salts and solvates (eg hydrates) of the compounds.

본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법은 다음 반응식 1에 나타낸 바와 같이, 다음 화학식 2로 표시되는 다양한 R2 치환체가 도입된 4-클로로퀴나졸린 화합물과 다음 화학식 3으로 표시되는 다양한 R1 치환체가 도입된 벤조산 하이드라자이드와 반응시켜 트리아졸 고리를 형성하는 과정으로 포함하여 이루어진다.Method for preparing a compound represented by the formula (1) according to the present invention is a 4-chloroquinazoline compound and a variety of represented by the following formula 3 is introduced into the various R 2 substituents represented by the following formula (2) And reacting with the benzoic acid hydrazide introduced with the R 1 substituent to form a triazole ring.

상기 반응식 1에서, R1 및 R2은 각각 상기 화학식 1에서 정의한 바와 같다.In Reaction Scheme 1, R 1 and R 2 are as defined in Formula 1, respectively.

본 발명에 따른 제조방법에서 출발물질로 사용되는 상기 화학식 2로 표시되는 4-클로로퀴나졸린 화합물은, 일반적인 많은 공지된 방법(J. Med. Chem. 1977, 20, 146; J. Med. Chem. 2002, 45, 3865; J. Med. Chem. 1996, 30, 267; Bioorg. Med. Chem. Lett. 1997, 7, 2723; Bioorg. Med. Chem. Lett. 2001, 11, 1911; U.S patent 5,770,599)에 의해 합성하여 사용될 수 있다.The 4-chloroquinazoline compound represented by the formula (2) used as a starting material in the preparation method according to the present invention, many known methods ( J. Med. Chem . 1977 , 20, 146; J. Med. Chem . 2002 , 45, 3865; J. Med. Chem . 1996 , 30, 267; Bioorg. Med. Chem. Lett . 1997 , 7, 2723; Bioorg. Med. Chem. Lett . 2001 , 11, 1911; US patent 5,770, 599) It can be used by synthesis.

상기 반응식 1에 따른 제조방법을 수행함에 있어, 트리아졸의 형성을 위한 반응은 다양한 유기아민 즉, 피리딘, 트리에틸아민, 2,6-루티딘, 디이소프로필에틸아민 같은 유기염기 또는 탄산나트륨, 탄산칼륨 또는 수산화나트륨 같은 무기염기의 존재 하에서 메탄올, 에탄올, 이소프로판올, n-부탄올, 테트라히드로퓨란, 1,2-디메톡시에탄, 다이옥산, 벤젠, 톨루엔, 자일렌과 같은 용매 중에서 가열 환류 하거나, 또는 가압용기를 사용하여 100 ℃ 내지 150 ℃에서 임의로 교반하여 수행한다.In carrying out the preparation method according to Scheme 1, the reaction for the formation of the triazole is organic base, such as pyridine, triethylamine, 2,6-lutidine, diisopropylethylamine or sodium carbonate, carbonic acid Heated to reflux or pressurized in a solvent such as methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, benzene, toluene, xylene in the presence of an inorganic base such as potassium or sodium hydroxide It is carried out by optionally stirring at 100 ° C. to 150 ° C. using the vessel.

또한, 치환기 R1 또는 R2가 아민기, 알콕시기 또는 아민기를 포함하는 알콕시기가 도입한 화합물은 다음 반응식 2와 3에 예시된 방법에 의해 제조될 수 있다.In addition, the compound in which the substituent R 1 or R 2 introduces an alkoxy group containing an amine group, an alkoxy group or an amine group can be prepared by the method illustrated in the following Schemes 2 and 3.

다음 반응식 2는 [1,2,4]트리아졸로[4,3-c]퀴나졸린의 C-3 위치 치환된 페닐고리 부분에 아민기 또는 알콕시아민기를 도입하는 일례이다.Scheme 2 below is an example of introducing an amine group or an alkoxyamine group to the C-3 position substituted phenyl ring portion of [1,2,4] triazolo [4,3-c] quinazolin.

상기 반응식 2에서, R1, R2, R3, 및 R4는 각각 상기 화학식 1에서 정의한 바와 같고, n은 1 내지 4의 정수이다.In Scheme 2, R 1 , R 2 , R 3 , and R 4 are each as defined in Chemical Formula 1, and n is an integer of 1 to 4.

상기 반응식 2에 따른 방법에 있어 R1=알콕시아민기가 치환된 상기 화학식 1c로 표시되는 화합물은, 다음과 같은 방법으로 합성할 수 있다. 즉, R1=히드록시가 치환된 상기 화학식 1a로 표시되는 화합물과 다양한 아민기가 치환된 상기 화학식 4로 표시되는 할로알킬아민을 탄산나트륨, 탄산칼륨 세슘카보네이트같은 무기염기의 존재 하에서 테트라하이드로퓨란, 다이옥산, 디메틸포름아마이드, 디메틸술폭사이드, N-메틸-2-피롤리돈 등과 같은 용매 중에서 10 ℃ 내지 150 ℃에서 임의로 반응시켜 제조한다.In the method according to Scheme 2, the compound represented by Formula 1c in which R 1 = alkoxyamine group is substituted may be synthesized by the following method. That is, the compound represented by the formula (1a) in which R 1 = hydroxy and the haloalkylamine represented by the formula (4) in which various amine groups are substituted are added to tetrahydrofuran and dioxane in the presence of inorganic bases such as sodium carbonate and potassium cesium carbonate. And dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone and the like at 10 ° C to 150 ° C.

또한, R1=알콕시아민기가 치환된 상기 화학식 1c로 표시되는 화합물은, 다음과 같은 또 다른 방법으로 합성이 가능하다. 즉, R1=히드록시가 치환된 상기 화학식 1a로 표시되는 화합물과 상기 화학식 5로 표시되는 디할로알칸을 탄산나트륨, 탄산칼륨 세슘카보네이트와 같은 무기염기의 존재 하에서 아세톤, 메틸에틸케톤, 테트라하이드로퓨란, 다이옥산, 디메틸포름아마이드, 디메틸술폭사이드, N-메틸-2-피롤리돈 등과 같은 용매 중에서 10 ℃ 내지 100 ℃에서 임의로 수행하여 이탈기로서 클로로알킬기가 치환된 상기 화학식 7로 표시되는 화합물을 얻은 후에, 상기 다양한 R3와 R4가 치환된 아민의 도입반응을 수행한다. 아민 도입반응은 무기 또는 유기염기(예를 들면 탄산나트륨, 수산화칼슘, 트리에틸아민, 피리딘, 디이소프로필에틸아민)의 존재 하에서 25 ℃ 내지 100 ℃의 온도에서 용매(예를 들면 디클로로메탄, 디옥산, N,N-디메틸포름아미드, 디메틸슬폭사이드, N-메틸피롤리돈)의 존재 하에서 임의의 다양한 아민 화합물을 사용하여 수행하거나, 용매나 염기의 사용함이 없이 R3와 R4가 치환된 아민 화합물만을 사용하여 반응을 수행할 수 있다. 이때 촉매량의 포타슘요오드, 소디움요오드를 사용할 수 있다.In addition, the compound represented by the formula (1c) in which R 1 = alkoxyamine group is substituted, can be synthesized by another method as follows. That is, the compound represented by the formula (1a) wherein R 1 = hydroxy is substituted and the dihaloalkane represented by the formula (5) are acetone, methyl ethyl ketone, tetrahydrofuran in the presence of an inorganic base such as sodium carbonate and potassium cesium carbonate. , Dioxane, dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and the like optionally carried out at 10 ℃ to 100 ℃ to obtain a compound represented by the formula (7) substituted with a chloroalkyl group as leaving group Subsequently, the introduction reaction of the amine substituted with the various R 3 and R 4 is performed. The amine introduction reaction is carried out at a temperature of 25 ° C. to 100 ° C. in the presence of an inorganic or organic base (eg sodium carbonate, calcium hydroxide, triethylamine, pyridine, diisopropylethylamine) (eg dichloromethane, dioxane, N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone) or an amine compound in which R 3 and R 4 are substituted without using a solvent or a base, using any of various amine compounds. The reaction can be carried out using only. At this time, catalytic amounts of potassium iodine and sodium iodine can be used.

상기 반응식 2에 따른 방법에 있어 R1=아민기가 치환된 상기 화학식 1d로 표시되는 화합물은, R1=Br으로 치환된 상기 화학식 1b로 표시되는 화합물로부터 팔라듐을 이용한 아민 치환반응을 통하여 얻을 수 있다. 이때 사용되는 아민은 디알킬아민이나, N이 포함된 고리화합물, 즉 피페리딘, 피롤리딘, 몰폴린, N-메틸 피페라진 등이 포함될 수 있다.In the method according to Scheme 2, the compound represented by Formula 1d in which R 1 = amine group is substituted may be obtained through an amine substitution reaction using palladium from the compound represented by Formula 1b substituted with R 1 = Br. . In this case, the amine used may include a dialkylamine or a cyclic compound containing N, that is, piperidine, pyrrolidine, morpholine, and N-methyl piperazine.

다음 반응식 3은 [1,2,4]트리아졸로[4,3-c]퀴나졸린의 C-9 위치에 알콕시아민기를 도입하는 일례이다.Scheme 3 below is an example of introducing an alkoxyamine group at the C-9 position of [1,2,4] triazolo [4,3-c] quinazolin.

상기 반응식 3에서, R1, R3, 및 R4는 각각 상기 화학식 1에서 정의한 바와 같고, n은 1 내지 4의 정수이다.In Reaction Scheme 3, R 1 , R 3 , and R 4 are each as defined in Chemical Formula 1, and n is an integer of 1 to 4.

상기 반응식 3에 따른 방법에서 출발물질로 사용되는 C-9 위치에 벤질옥시기가 치환된 상기 화학식 8로 표시되는 화합물은 공지된 방법(J. Med. Chem. 1999, 42, 5369; WO 2001/32651)에 의하여 제조하여 사용할 수 있다.Compound represented by the formula (8) in which the benzyloxy group is substituted in the C-9 position to be used as a starting material in the method according to Scheme 3 ( J. Med. Chem . 1999, 42, 5369; WO 2001/32651 Can be prepared and used).

상기 반응식 3에 따른 방법에 있어, 상기 화학식 8로 표시되는 화합물의 벤질 보호기의 탈보호는 문헌(Protective Groups in Organic Synthesis, T.W. Green and R.G.M. Wuts, 3rd Ed. Wiely)에서 잘 알려진 기법에 의해 수행할 수 있다. 구체적으로는 팔라듐착콜, 플라티늄옥사이드를 이용하는 수소화 반응, 또는 유기산(예를 들면, 트리플루오르아세트산 또는 메탄술포닐산)의 존재 하에서 용매가 없거나, 메틸렌클로라이드, 클로로포름, 벤젠 및 톨루엔과 같은 용매 중에서 20 ℃ 내지 120 ℃에서 임의로 수행하거나, 또는 루이스산(예를 들면, BBr3 또는 BCl3)의 존재 하에서 메틸렌클로라이드, 클로로포름, 1,2-디클로로에탄과 같은 용매 중에서 -20 ℃ 내지 50 ℃에서 임의로 수행할 수 있다.In the method according to Scheme 3, deprotection of the benzyl protecting group of the compound represented by Formula 8 may be performed by a technique well known in the literature ( Protective Groups in Organic Synthesis , TW Green and RGM Wuts, 3rd Ed. Wiely). Can be. Specifically, there is no solvent in the hydrogenation reaction using palladium complex call, platinum oxide, or in the presence of an organic acid (for example trifluoroacetic acid or methanesulfonyl acid), or in a solvent such as methylene chloride, chloroform, benzene and toluene Optionally at 120 ° C., or optionally at −20 ° C. to 50 ° C. in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane in the presence of Lewis acid (eg BBr 3 or BCl 3 ) have.

상기 화학식 9로 표시되는 히드록시트리아졸로 화합물로부터 상기 화학식 1f 및 화학식 1g로 표시되는 알콕시아민기가 치환된 화합물의 합성은 상기 반응식 2에서 언급한 동일한 방법에 의해 이루어 질 수 있다. Synthesis of the compound substituted with the alkoxyamine group represented by Formula 1f and Formula 1g from the hydroxytriazol compound represented by Formula 9 may be performed by the same method mentioned in Scheme 2.

이상의 제조방법을 수행하는데 있어 얻어지는 반응 중간체 화합물 또는 상기 화학식 1로 표시되는 목적 화합물은 크로마토그래피와 재결정화와 같은 통상적인 방법에 의하여 분리 및 정제될 수 있다.The reaction intermediate compound obtained in the above-mentioned preparation method or the target compound represented by Chemical Formula 1 may be separated and purified by conventional methods such as chromatography and recrystallization.

한편, 본 발명에 따른 화합물들은 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제로 제형화할 수 있다. 통상적인 제형이라 함은 예를 들면 경구(정제, 캡슐제, 분말제), 구강 내, 혀 밑, 직장 내, 질 내, 비강 내, 국소 또는 비경구(정맥 내, 해면체 내, 근육 내, 피하 및 관 내를 포함) 투여 제형을 일컫는다. 예를 들면, 본 발명에 따른 화합물은 전분 또는 락토오즈를 함유하는 정제 형태로, 또는 단독 또는 부형제를 함유하는 캡슐 형태로, 또는 맛을 내거나 색을 띄게 하는 화학 약품을 함유하는 엘릭시르 또는 현탁제 형태로 경구, 구강 내 또는 혀 밑 투여될 수 있다. 액체 제제는 현탁제(예를 들면, 메틸셀룰로오즈, 위텝솔(witepsol)과 같은 반합성 글리세라이드 또는 행인유(apricot kernel oil)와 PEG-6 에스테르의 혼합물 또는 PEG-8과 카프릴릭/카프릭 글리세라이드의 혼합물과 같은 글리세라이드 혼합물)와 같은 약제학적으로 허용 가능한 첨가제와 함께 제조된다. 또한, 비경구적으로 예를 들면, 정맥 내, 해면체 내, 근육 내, 피하 및 관내를 통하여 주사될 수 있다. 비경구 투여를 위해서는 무균의 수용액 형태로서 사용하는 것이 가장 바람직하며, 이때 상기 용액은 혈액과의 등장성을 갖기 위하여 다른 물질들(예를 들면 염(salt) 또는 만니톨, 글루코오스와 같은 단당류)를 함유할 수도 있다.On the other hand, the compounds according to the present invention can be formulated into a conventional formulation in the pharmaceutical field by the addition of conventional non-toxic pharmaceutically acceptable carriers, adjuvant and excipients. Conventional formulations include, for example, oral (tablets, capsules, powders), oral cavity, sublingual, intrarectal, intravaginal, intranasal, topical or parenteral (intravenous, cavernous, intramuscular, subcutaneous). And dosage forms). For example, the compounds according to the invention may be in the form of tablets containing starch or lactose, in the form of capsules alone or in the form of excipients, or in the form of elixirs or suspensions containing chemicals which flavor or color. It can be administered orally, orally or sublingually. Liquid formulations may be suspending agents (eg, methyl cellulose, semisynthetic glycerides such as witepsol or mixtures of apricot kernel oil with PEG-6 esters or PEG-8 with caprylic / capric glycerol). Pharmaceutically acceptable additives such as glyceride mixtures such as mixtures of lides). It can also be injected parenterally, for example, intravenously, intracavernosally, intramuscularly, subcutaneously and intratracheally. For parenteral administration, it is most preferred to use it in the form of a sterile aqueous solution, in which the solution contains other substances (e.g. salts or monosaccharides such as mannitol, glucose) to have isotonicity with the blood. You may.

또한, 상기 화학식 1로 표시되는 화합물의 인체에 대한 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환정도에 따라 달라질 수 있으며, 몸무게가 70 ㎏인 성인환자를 기준으로 할 때 일반적으로 0.01 내지 400 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. In addition, the dosage of the compound represented by Chemical Formula 1 to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is based on an adult patient having a weight of 70 kg. Generally, it is 0.01 to 400 mg / day, and may be dividedly administered once to several times a day at regular time intervals according to the judgment of a doctor or a pharmacist.

이상에서 설명한 바와 같은 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이에 한정되는 것은 아니다.The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

실시예 1. 4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페놀Example 1. 4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenol

4-클로로퀴나졸린 (1.50g, 8.92 mmol), 4-히드록시벤조산 히드라자이드 (1.49 g, 9.81 mmol) 그리고 트리에틸아민 (1.4 mL, 9.81 mmol)을 n-부탄올 (20 mL)에 녹이고 가압 용기 내에서 150 ℃에서 3일 동안 반응하였다. 반응 후 반응 혼합물을 농축하고 메탄올/디클로로메탄/에틸에테르의 혼합용매를 이용하여 고체화하고 여과하여 목적물을 얻었다. (0.57 g, 수율 24 %) 4-chloroquinazolin (1.50 g, 8.92 mmol), 4-hydroxybenzoic acid hydrazide (1.49 g, 9.81 mmol) and triethylamine (1.4 mL, 9.81 mmol) were dissolved in n-butanol (20 mL) and pressurized The reaction was carried out at 150 ° C. for 3 days. After the reaction, the reaction mixture was concentrated, solidified using a mixed solvent of methanol / dichloromethane / ethyl ether, and filtered to obtain the target product. (0.57 g, yield 24%)

1H NMR (300 MHz, DMSO-d 6 ) δ 10.04 (brs, 1H), 9.62 (s, 1H), 8.51 (d, J = 7.2 Hz, 1H), 8.12 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.1 Hz, 1H), 7.95 (m, 1H), 7.84 (m, 1H), 6.97 (d, J = 8.7 Hz, 2H); MS-ESI 262 (M+, 51), 111 (59), 84 (34), 75 (28), 65 (46), 40 (100). 1 H NMR (300 MHz, DMSO- d 6 ) δ 10.04 (brs, 1H), 9.62 (s, 1H), 8.51 (d, J = 7.2 Hz, 1H), 8.12 (d, J = 8.7 Hz, 2H) , 8.08 (d, J = 8.1 Hz, 1H), 7.95 (m, 1H), 7.84 (m, 1H), 6.97 (d, J = 8.7 Hz, 2H); MS-ESI 262 (M + , 51), 111 (59), 84 (34), 75 (28), 65 (46), 40 (100).

실시예 2. 디에틸-[2-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-에틸]-아민Example 2. Diethyl- [2- (4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenoxy) -ethyl] -amine

4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페놀 (20 mg, 0.076 mmol)을 DMF (1.5 mL)에 녹이고 (2-클로로에틸)-디에틸아민 염산 (14 mg, 0.084 mmol)과 세슘카보네이트 (74 mg, 0.23 mmol)를 가한 후 50 ℃에서 24시간 반응하였다. 반응 혼합물을 디클로로메탄으로 희석하고 소금물로 세척한 다음 소디움설페이트로 건조한 후 농축하여 목적화합물 디에틸-[2-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-에틸]-아민(7 mg, 수율 25 %)을 얻었다. 4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenol (20 mg, 0.076 mmol) was dissolved in DMF (1.5 mL) and (2-chloroethyl) -diethyl Amine hydrochloric acid (14 mg, 0.084 mmol) and cesium carbonate (74 mg, 0.23 mmol) were added, followed by reaction at 50 ° C. for 24 hours. The reaction mixture was diluted with dichloromethane, washed with brine, dried over sodium sulfate and concentrated to give the desired compound diethyl- [2- (4- [1,2,4] triazolo [4,3-c] quinazolin- 3-yl-phenoxy) -ethyl] -amine (7 mg, yield 25%) was obtained.

1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.1 Hz, 1H) 7.85 (m, 1H) 7.76 (m, 1H), 7.05 (d, J = 8.7 Hz, 2H), 4.15 (quin, J = 6.3 Hz, 2H), 2.93 (quin , J = 6 Hz, 2H), 2.72∼2.64 (m, 4H), 1.13∼1.07 (m, 6H); MS-ESI 361 (M+, 1), 261 (1), 245 (1), 86 (100), 45 (5). 1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.1 Hz , 1H) 7.85 (m, 1H) 7.76 (m, 1H), 7.05 (d, J = 8.7 Hz, 2H), 4.15 (quin, J = 6.3 Hz, 2H), 2.93 (quin, J = 6 Hz, 2H ), 2.72 to 2.64 (m, 4H), 1.13 to 1.07 (m, 6H); MS-ESI 361 (M + , 1), 261 (1), 245 (1), 86 (100), 45 (5).

실시예 3. 디메틸-[2-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-에틸]-아민Example 3. Dimethyl- [2- (4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenoxy) -ethyl] -amine

수율 45 %; 1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.1 Hz, 1H) 7.85 (m, 1H) 7.76 (m, 1H), 7.05 (d, J = 8.7 Hz, 2H), 4.17 (t, J = 5.7 Hz, 2H), 2.79 (t, J =5.7 Hz, 2H), 2.37 (s, 6H); MS-ESI 333 (M+, 1), 245 (1), 129 (1), 90 (2), 58 (100), 42 (6).Yield 45%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.1 Hz , 1H) 7.85 (m, 1H) 7.76 (m, 1H), 7.05 (d, J = 8.7 Hz, 2H), 4.17 (t, J = 5.7 Hz, 2H), 2.79 (t, J = 5.7 Hz, 2H ), 2.37 (s, 6 H); MS-ESI 333 (M + , 1), 245 (1), 129 (1), 90 (2), 58 (100), 42 (6).

실시예 4. 3-[4-(2-피롤리딘-1-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 4. 3- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline

수율 42 %; 1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.1 Hz, 1H) 7.85 (m, 1H) 7.76 (m, 1H), 7.05 (d, J = 8.7 Hz, 2H), 4.22 (t, J = 5.7 Hz, 2H), 2.98 (t, J = 5.7 Hz, 2H), 2.69 (s, 4H), 1.84 (s, 4H); MS-ESI 359 (M+, 1), 245 (1), 129 (2), 102 (2), 84 (100), 41 (21).Yield 42%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.1 Hz , 1H) 7.85 (m, 1H) 7.76 (m, 1H), 7.05 (d, J = 8.7 Hz, 2H), 4.22 (t, J = 5.7 Hz, 2H), 2.98 (t, J = 5.7 Hz, 2H ), 2.69 (s, 4H), 1.84 (s, 4H); MS-ESI 359 (M + , 1), 245 (1), 129 (2), 102 (2), 84 (100), 41 (21).

실시예 5. 3-[4-(2-피페리딘-1-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 5. 3- [4- (2-piperidin-1-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline

수율 21 %; 1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.1 Hz, 1H) 7.85 (m, 1H) 7.76 (m, 1H), 7.05 (d, J = 8.7 Hz, 2H), 4.21 (t, J = 5.88 Hz, 2H), 2.83 (t, J = 5.91 Hz, 2H), 2.55 (s, 2H), 1.65∼1.58 (m, 8H); MS-ESI 373 (M+, 1), 245 (2), 112 (1), 98 (100), 41 (24).Yield 21%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.1 Hz , 1H) 7.85 (m, 1H) 7.76 (m, 1H), 7.05 (d, J = 8.7 Hz, 2H), 4.21 (t, J = 5.88 Hz, 2H), 2.83 (t, J = 5.91 Hz, 2H ), 2.55 (s, 2H), 1.65-1.58 (m, 8H); MS-ESI 373 (M + , 1), 245 (2), 112 (1), 98 (100), 41 (24).

실시예 6. 3-[4-(2-몰폴린-4-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 6. 3- [4- (2-morpholin-4-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline

수율 52 %; 1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.1 Hz, 1H) 7.85 (m, 1H) 7.76 (m, 1H), 7.05 (d, J = 8.7 Hz, 2H), 4.21 (t, J = 5.7 Hz, 2H), 3.75 (t, J = 4.5 Hz, 4H), 2.85 (t, J = 5.7 Hz, 2H), 2.61 (t, J = 4.5 Hz, 4H); MS-ESI 375 (M+, 2), 245 (2), 114 (3), 100 (100), 42 (12).Yield 52%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.1 Hz , 1H) 7.85 (m, 1H) 7.76 (m, 1H), 7.05 (d, J = 8.7 Hz, 2H), 4.21 (t, J = 5.7 Hz, 2H), 3.75 (t, J = 4.5 Hz, 4H ), 2.85 (t, J = 5.7 Hz, 2H), 2.61 (t, J = 4.5 Hz, 4H); MS-ESI 375 (M + , 2), 245 (2), 114 (3), 100 (100), 42 (12).

실시예 7. 3-[4-(3-클로로프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 7. 3- [4- (3-chloropropoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline

4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페놀 (0.23 g, 0.87 mmol)을 디메틸포름아마이드 (10 mL)에 녹이고 1-브로모-3-클로로프로판 (0.44 mL, 4.35 mmol)과 포타슘카보네이트 (0.28 g, 2 mmol)를 가한 후 상온에서 5시간 동안 반응하였다. 반응 혼합물을 디클로로메탄으로 희석하고 소금물로 세척한 다음 소디움설페이트로 건조한 후 농축하여 목적화합물 3-[4-(3-클로로프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린(0.27 g, 91 %)을 얻었다. 4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenol (0.23 g, 0.87 mmol) is dissolved in dimethylformamide (10 mL) and 1-bromo-3- Chloropropane (0.44 mL, 4.35 mmol) and potassium carbonate (0.28 g, 2 mmol) were added, followed by reaction at room temperature for 5 hours. The reaction mixture was diluted with dichloromethane, washed with brine, dried over sodium sulfate and concentrated to give the title compound 3- [4- (3-chloropropoxy) -phenyl]-[1,2,4] triazolo [4, 3-c] quinazoline (0.27 g, 91%) was obtained.

1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.61 (d, J = 7.8Hz, 1H), 8.29 (d, J = 8.7Hz, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7Hz, 2H), 4.23∼4.19 (m, 2H) 3.80∼3.75 (m, 2H), 2.33∼2.25 (m, 2H); MS-ESI 338 (M+, 93), 262 (100), 233 (13), 161 (4), 129 (18), 102 (13), 62 (12), 41 (70). 1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 8.4 Hz , 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7 Hz, 2H), 4.23-4.19 (m, 2H) 3.80-3.75 (m, 2H), 2.33-2.25 (m, 2H); MS-ESI 338 (M + , 93), 262 (100), 233 (13), 161 (4), 129 (18), 102 (13), 62 (12), 41 (70).

실시예 8. 디에틸-[3-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-프로필]-아민Example 8. Diethyl- [3- (4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenoxy) -propyl] -amine

3-[4-(3-클롤로프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 (20 mg, 0.06 mmol)을 건조된 THF (3 mL)를 녹이고 디에틸아민 (0.06 mL, 0.06 mmol)과 포타슘요오드 (0.003 g, 0.018 mmol)을 가한 후 가압용기에서 80 ℃로 3일 동안 교반하였다. 반응 후 상온으로 식힌 후 휘발성 물질을 제거하여 디클로로메탄으로 희석하고 소금물로 세척 후 소디움설페이트로 건조한 뒤 농축하고 관크로마토그래피 (5% MeOH/CH2Cl2)로 정제하여 디에틸-[3-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-프로필]-아민(8 mg, 34%)을 얻었다.3- [4- (3-chloropropoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline (20 mg, 0.06 mmol) was dried THF (3 mL). Was dissolved, diethylamine (0.06 mL, 0.06 mmol) and potassium iodine (0.003 g, 0.018 mmol) were added, followed by stirring at 80 ° C. for 3 days in a pressure vessel. After the reaction, the mixture was cooled to room temperature, volatiles were removed, diluted with dichloromethane, washed with brine, dried over sodium sulfate, concentrated, and purified by tube chromatography (5% MeOH / CH 2 Cl 2 ) to obtain diethyl- [3- ( 4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenoxy) -propyl] -amine (8 mg, 34%) was obtained.

1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.61 (d, J = 7.8Hz, 1H), 8.29 (d, J = 8.7Hz, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7Hz, 2H), 4.17 (t, J = 5.58 Hz, 2H), 3.14∼2.96 (m, 6H), 2.03 (d, J = 5.55 Hz, 2H), 1.39∼1.25 (m, 6H); MS-ESI375 (M+, 2), 262 (1), 120 (3), 86 (100), 72 (20), 43 (10). 1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 8.4 Hz , 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7 Hz, 2H), 4.17 (t, J = 5.58 Hz, 2H), 3.14-2.96 (m, 6H) , 2.03 (d, J = 5.55 Hz, 2H), 1.39-1.25 (m, 6H); MS-ESI375 (M + , 2), 262 (1), 120 (3), 86 (100), 72 (20), 43 (10).

실시예 9. 3-{4-[3-(4-메틸-피페라진-1-일)-프로폭시]-페닐}-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 9. 3- {4- [3- (4-Methyl-piperazin-1-yl) -propoxy] -phenyl}-[1,2,4] triazolo [4,3-c] quinazoline

수율 78 %; 1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.61 (d, J = 7.8Hz, 1H), 8.29 (d, J = 8.7Hz, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7Hz, 2H), 4.11 (quin, J = 6.3 Hz, 2H), 2.59∼2.53 (m, 10H), 2.31 (s, 3H), 2.01 (quin, J = 6.3 Hz, 2H); MS-ESI 402 (M+, 2), 289 (2), 141 (2), 113 (29), 70 (30), 56 (10), 42 (100).Yield 78%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 8.4 Hz , 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7 Hz, 2H), 4.11 (quin, J = 6.3 Hz, 2H), 2.59-2.53 (m, 10H) , 2.31 (s, 3 H), 2.01 (quin, J = 6.3 Hz, 2H); MS-ESI 402 (M + , 2), 289 (2), 141 (2), 113 (29), 70 (30), 56 (10), 42 (100).

실시예 10. 3-[4-(3-피롤리딘-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 10. 3- [4- (3-Pyrrolidin-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline

수율 22 %; 1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.61 (d, J = 7.8Hz, 1H), 8.29 (d, J = 8.7Hz, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7Hz, 2H), 4.15∼4.10 (m, 2H), 2.74∼2.60 (m, 6H), 2.12∼2.03 (m, 2H), 1.61 (s, 4H); MS-ESI 373 (M+, 2), 364 (2), 233 (1), 129 (1), 112 (3), 84 (100), 41 (25).Yield 22%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 8.4 Hz , 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7 Hz, 2H), 4.15-4.10 (m, 2H), 2.74-2.60 (m, 6H), 2.12- 2.03 (m, 2 H), 1.61 (s, 4 H); MS-ESI 373 (M + , 2), 364 (2), 233 (1), 129 (1), 112 (3), 84 (100), 41 (25).

실시예 11. 3-[4-(3-피페리딘-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 11. 3- [4- (3-piperidin-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline

수율 60 %; 1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.61 (d, J = 7.8Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7 Hz, 2H), 4.12∼4.08 (m, 2H), 2.53∼2.42 (m, 6H), 2.05∼2.00 (m, 2H), 1.61∼1.57 (m, 6H); MS-ESI 387 (M+, 1), 261 (1), 177 (1), 126 (2), 98 (100), 41 (32).Yield 60%; 1 H NMR (300 MHz, CDCl 3) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7 Hz, 2H), 4.12-4.08 (m, 2H), 2.53-2.42 (m, 6H), 2.05-2.00 (m, 2H), 1.61-1.57 (m, 6H); MS-ESI 387 (M + , 1), 261 (1), 177 (1), 126 (2), 98 (100), 41 (32).

실시예 12. 3-[4-(3-몰폴린-4-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 Example 12. 3- [4- (3-morpholin-4-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline

수율 68 %; 1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.61 (d, J = 7.8Hz, 1H), 8.29 (d, J = 8.7Hz, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7Hz, 2H), 4.14∼4.10 (m, 2H), 3.74 (t, J = 4.8 Hz, 4H), 2.58∼2.49 (m, 6H), 2.02 (t, J = 7.5 Hz, 2H); MS-ESI 389 (M+, 3), 128 (9), 100 (100), 70 (15), 42 (54).Yield 68%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 8.4 Hz , 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7 Hz, 2H), 4.14-4.10 (m, 2H), 3.74 (t, J = 4.8 Hz, 4H) , 2.58-2.49 (m, 6H), 2.02 (t, J = 7.5 Hz, 2H); MS-ESI 389 (M + , 3), 128 (9), 100 (100), 70 (15), 42 (54).

실시예 13. 2-{메틸-[3-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-프로필]-아미노}-에탄올Example 13. 2- {methyl- [3- (4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenoxy) -propyl] -amino} -ethanol

수율 22 %; 1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.61 (d, J = 7.8Hz, 1H), 8.29 (d, J = 8.7Hz, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7Hz, 2H), 4.11 (t, J = 6.3Hz, 2H), 3.62 (t, J = 5.1 Hz, 2H), 2.68∼2.57 (m, 4H), 2.31 (s, 3H), 2.06∼1.99 (m, 2H); MS-ESI 377 (M+, 3), 368 (1), 3337 (10), 236 (1), 169 (3), 120 (8), 58 (100).Yield 22%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 8.4 Hz , 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7 Hz, 2H), 4.11 (t, J = 6.3 Hz, 2H), 3.62 (t, J = 5.1 Hz , 2H), 2.68 to 2.57 (m, 4H), 2.31 (s, 3H), 2.06 to 1.99 (m, 2H); MS-ESI 377 (M + , 3), 368 (1), 3337 (10), 236 (1), 169 (3), 120 (8), 58 (100).

실시예 14. 3-[4-(3-이미다졸-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 14. 3- [4- (3-imidazol-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline

소디움하이드라이드 (5 mg, 0.12 mmol)를 디메틸포름아마이드 (0.5 mL)에 가하고 0 ℃에서 10분간 교반 후, 이미다졸 (8 mg, 0.12 mmol)을 DMF (0.5 mL)에 녹인 용액을 천천히 가한 다음 5분간 교반 후 80 ℃에서 1시간 동안 교반한다. 다음 상온으로 식힌 후 디메틸포름아마이드 (1 mL)에 녹인 3-[4-(3-클로로-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 (20 mg, 0.06 mmol) 용액을 천천히 가한 후 상온에서 3시간동안 교반한다. 반응 후 CH2Cl2로 희석하고 소금물로 세척 후 소디움설페이트로 건조한 뒤 농축하고 관크로마토그래피 (5% MeOH/CH2Cl2)로 정제하여 3-[4-(3-이미다졸-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린을 얻었다.Sodium hydride (5 mg, 0.12 mmol) was added to dimethylformamide (0.5 mL), stirred at 0 ° C. for 10 minutes, and a solution of imidazole (8 mg, 0.12 mmol) in DMF (0.5 mL) was slowly added thereto. After stirring for 5 minutes, the mixture is stirred at 80 ° C. for 1 hour. Then cooled to room temperature and dissolved in dimethylformamide (1 mL) in 3- [4- (3-chloro-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazolin ( 20 mg, 0.06 mmol) was added slowly and stirred at room temperature for 3 hours. After the reaction, the mixture was diluted with CH 2 Cl 2 , washed with brine, dried over sodium sulfate, concentrated, and purified by tube chromatography (5% MeOH / CH 2 Cl 2 ) to give 3- [4- (3-imidazol-1-yl. -Propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline was obtained.

수율 25 %; 1H NMR (300 MHz, CDCl3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7Hz, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.51 (s, 1H), 7.08 (s, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.95 (s, 1H), 4.25∼4.20 (m, 2H,) 4.03∼3.98(m, 2H), 2.37∼2.24 (m, 2H); MS-ESI 370 (M+, 11), 109 (14), 81 (17), 40 (100).Yield 25%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 8.4 Hz , 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.51 (s, 1H), 7.08 (s, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.95 (s, 1H) , 4.25 to 4.20 (m, 2H,) 4.03 to 3.98 (m, 2H), 2.37 to 2.24 (m, 2H); MS-ESI 370 (M + , 11), 109 (14), 81 (17), 40 (100).

실시예 15. 3-[4-(3-피롤-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 15. 3- [4- (3-Pyrrole-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline

수율 42 %; 1H NMR (300 MHz, CDCl3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8Hz, 1H), 8.29 (d, J = 8.7Hz, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7Hz, 2H), 6.45 (m, 2H), 6.01 (m, 2H), 4.24 (m, 2H), 4.01(m, 2H), 2.26 (m, 2H); MS-ESI 370 (M+, 10.63) 109 (14.37) 81 (16.88) 40 (100).Yield 42%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 8.4 Hz , 1H), 7.86 (m, 1H), 7.76 (m, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.45 (m, 2H), 6.01 (m, 2H), 4.24 (m, 2H) , 4.01 (m, 2 H), 2.26 (m, 2 H); MS-ESI 370 (M + , 10.63) 109 (14.37) 81 (16.88) 40 (100).

실시예 16. 8,9-디메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 16. 8,9-Dimethoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazoline

실시예 1와 동일한 방법으로 진행한다.Proceed in the same manner as in Example 1.

수율 66 %; 1H NMR (300 MHz, DMSO-d 6 ) δ 9.53 (s, 1H), 8.26 (m, 2H), 7.75 (s, 1H), 7.59-7.55 (m, 3H), 7.51 (s, 1H).Yield 66%; 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.53 (s, 1H), 8.26 (m, 2H), 7.75 (s, 1H), 7.59-7.55 (m, 3H), 7.51 (s, 1H).

실시예 17. 4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페놀Example 17. 4- (8,9-Dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenol

실시예 1와 동일한 방법으로 진행한다.Proceed in the same manner as in Example 1.

수율 48 %; 1H NMR (300 MHz, CDCl3 ) δ 10.01 (brs, 1H), 9.54 (s, 1H), 8.15 (d, J = 8.7 Hz, 2H), 7.80 (s, 1H), 7.56 (s, 1H), 6.99 (d, J = 8.7 Hz, 2H).Yield 48%; 1 H NMR (300 MHz, CDCl 3 ) δ 10.01 (brs, 1H), 9.54 (s, 1H), 8.15 (d, J = 8.7 Hz, 2H), 7.80 (s, 1H), 7.56 (s, 1H) , 6.99 (d, J = 8.7 Hz, 2H).

실시예 18. 8,9-디메톡시-3-[4-(2-피롤리딘-1-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 18. 8,9-dimethoxy-3- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] Quinazoline

실시예 2와 동일한 방법으로 진행한다.Proceed in the same manner as in Example 2.

수율 54 %; 1H NMR (300 MHz, DMSO-d 6 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.21 (t, J = 5.94 Hz, 2H), 4.13 (s, 3H), 4.06 (s, 3H), 2.96 (t, J = 5.9 Hz, 2H), 2.67 (s, 4H), 1.84 (quin, J = 3.2 Hz, 4H); MS-ESI 419 (M+, 1), 322 (1), 98 (2), 84 (100), 42 (11).Yield 54%; 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.21 (t, J = 5.94 Hz, 2H), 4.13 (s, 3H), 4.06 (s, 3H), 2.96 (t, J = 5.9 Hz, 2H), 2.67 (s, 4H), 1.84 (quin, J = 3.2 Hz, 4H); MS-ESI 419 (M + , 1), 322 (1), 98 (2), 84 (100), 42 (11).

실시예 19. 8,9-디메톡시-3-[4-(2-피페리딘-1-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 19. 8,9-dimethoxy-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] Quinazoline

수율 58 %; 1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.18 (t, J = 6.2 Hz, 2H), 4.13 (s, 3H), 4.06 (s, 3H), 2.82 (t, J = 6.2 Hz, 2H), 2.54 (m, 4H), 1.62 (m, 4H) 1.48 (m, 2H); MS-ESI 433 (M+, 3), 98 (100), 70 (5), 55 (7), 42 (16).Yield 58%; 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s , 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.18 (t, J = 6.2 Hz, 2H), 4.13 (s, 3H), 4.06 (s, 3H), 2.82 (t, J = 6.2 Hz , 2H), 2.54 (m, 4H), 1.62 (m, 4H) 1.48 (m, 2H); MS-ESI 433 (M + , 3), 98 (100), 70 (5), 55 (7), 42 (16).

실시예 20. 8,9-디메톡시-3-[4-(2-몰폴린-4-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 20. 8,9-Dimethoxy-3- [4- (2-morpholin-4-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quina Sleepy

수율 74 %; 1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.20 (t, J = 5.7 Hz, 2H), 4.13 (s, 3H), 4.07 (s, 3H), 3.75 (t, J = 4.5 Hz, 4H), 2.85 (t, J = 5.7 Hz, 2H), 2.61 (t, J = 4.5 Hz, 4H); MS-ESI 435 (M+, 1), 305 (2), 289 (1), 114 (4), 100 (100), 70 (5), 56 (17), 42 (13).Yield 74%; 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s , 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.20 (t, J = 5.7 Hz, 2H), 4.13 (s, 3H), 4.07 (s, 3H), 3.75 (t, J = 4.5 Hz , 4H), 2.85 (t, J = 5.7 Hz, 2H), 2.61 (t, J = 4.5 Hz, 4H); MS-ESI 435 (M + , 1), 305 (2), 289 (1), 114 (4), 100 (100), 70 (5), 56 (17), 42 (13).

실시예 21. {2-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시]-에틸}-디메틸아민Example 21. {2- [4- (8,9-Dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenoxy] -ethyl} -dimethyl Amine

수율 52 %; 1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.14 (t, J = 5.7 Hz, 2H), 4.13 (s, 3H), 4.06 (s, 3H), 2.78 (t, J = 5.7 Hz, 2H), 2.37 (s, 6H); MS-ESI 393 (M+, 1), 90 (1), 72 (4), 58(100), 42 (2).Yield 52%; 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s , 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.14 (t, J = 5.7 Hz, 2H), 4.13 (s, 3H), 4.06 (s, 3H), 2.78 (t, J = 5.7 Hz , 2H), 2.37 (s, 6H); MS-ESI 393 (M + , 1), 90 (1), 72 (4), 58 (100), 42 (2).

실시예 22. {2-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시]-에틸}-디에틸아민Example 22. {2- [4- (8,9-Dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenoxy] -ethyl} -di Ethylamine

수율 38 %; 1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.15 (t, J = 6.3 Hz, 2H), 4.14 (s, 3H), 4.06 (s, 3H), 2.92 (t, J = 6.3 Hz, 2H), 2.67 (quin, J = 7.2 Hz, 4H), 1.09 (t, J = 6.9 Hz, 6H); MS-ESI 421 (M+, 1), 100 (4), 86 (100), 58 (6), 43 (9).Yield 38%; 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s , 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.15 (t, J = 6.3 Hz, 2H), 4.14 (s, 3H), 4.06 (s, 3H), 2.92 (t, J = 6.3 Hz , 2H), 2.67 (quin, J = 7.2 Hz, 4H), 1.09 (t, J = 6.9 Hz, 6H); MS-ESI 421 (M + , 1), 100 (4), 86 (100), 58 (6), 43 (9).

실시예 23. 3-[4-(3-클로로-프로폭시)-페닐]-8,9-다이메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 23. 3- [4- (3-Chloro-propoxy) -phenyl] -8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazoline

4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페놀 (0.25 g, 0.78 mmo)과 1-브로모-3-클로로프로판 (3.88 mL, 3.88 mmol)을 DMF (5 mL)에 녹인 후 K2CO3 (0.27 g, 1.95 mmol)을 가하고 상온에서 2시간 교반 하였다. 반응 혼합물을 CH2Cl2로 희석하고 소금물로 세척 후 소디움설페이트로 건조한 뒤 농축하고 에테르로 결정화하여 3-[4-(3-클로로프로폭시)-페닐]-8,9-다이메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린 (0.29 g, 수율 93 %)을 얻었다.4- (8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenol (0.25 g, 0.78 mmol) and 1-bromo-3- Chloropropane (3.88 mL, 3.88 mmol) was dissolved in DMF (5 mL), K 2 CO 3 (0.27 g, 1.95 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with CH 2 Cl 2 , washed with brine, dried over sodium sulfate, concentrated and crystallized with ether to give 3- [4- (3-chloropropoxy) -phenyl] -8,9-dimethoxy- [ 1,2,4] triazolo [4,3-c] quinazoline (0.29 g, yield 93%) was obtained.

1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.21 (t, J = 5.7 Hz, 2H), 4.13 (s, 3H), 4.06 (s, 3H), 3.78 (t, J = 6.6 Hz, 2H), 2.33∼2.25 (m, 2H); MS-ESI 398 (M+, 32), 322 (27), 279 (15), 161 (9), 105 (8), 62 (7), 40 (100). 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.21 (t, J = 5.7 Hz, 2H), 4.13 (s, 3H), 4.06 (s, 3H), 3.78 (t, J = 6.6 Hz, 2H), 2.33-2.25 (m, 2H); MS-ESI 398 (M + , 32), 322 (27), 279 (15), 161 (9), 105 (8), 62 (7), 40 (100).

실시예 24. 8,9-디메톡시-3-{4-[3-(4-메틸피페라진-1-일)-프로폭시]-페닐}-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 24. 8,9-Dimethoxy-3- {4- [3- (4-methylpiperazin-1-yl) -propoxy] -phenyl}-[1,2,4] triazolo [4, 3-c] quinazoline

3-[4-(3-클로로프로폭시)-페닐]-8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린(20 mg, 0.05 mmol)과 N-메틸피페라진 (0.056 mL, 0.5 mmol)과 KI (2.5 mg)를 건조된 THF (3 mL)를 녹인 후 밀봉된 튜브에 넣고 100 ℃에서 2일 동안 교반하였다. 반응 혼합물을 CH2Cl2로 희석하고 소금물로 세척 후 소디움설페이트로 건조한 뒤 농축하고 관크로마토그래피 (5% MeOH/CH2Cl2)로 정제하여 8,9-디메톡시-3-{4-[3-(4-메틸-피페라진-1-일)-프로폭시]-페닐}-[1,2,4]트리아졸로[4,3-c]퀴나졸린 (16 mg, 수율 68 %)을 얻었다.3- [4- (3-chloropropoxy) -phenyl] -8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin (20 mg, 0.05 mmol) and N Methylpiperazine (0.056 mL, 0.5 mmol) and KI (2.5 mg) were dissolved in dried THF (3 mL) and placed in a sealed tube and stirred at 100 ° C. for 2 days. The reaction mixture was diluted with CH 2 Cl 2 , washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography (5% MeOH / CH 2 Cl 2 ) to give 8,9-dimethoxy-3- {4- [ 3- (4-Methyl-piperazin-1-yl) -propoxy] -phenyl}-[1,2,4] triazolo [4,3-c] quinazolin (16 mg, yield 68%) was obtained. .

1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.13 (s. 3H), 4.09 (t, J = 6.3 Hz, 2H), 4.07 (s, 3H), 2.56 (d, J = 7.5 Hz, 10 H), 2.31 (s, 3H), 2.17 (t, J =7.5 Hz, 2H); MS-ESI 462 (M+, 12), 349 (5), 231 (2), 141 (6), 113 (84), 70 (53), 42 (100). 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.13 (s. 3H), 4.09 (t, J = 6.3 Hz, 2H), 4.07 (s, 3H), 2.56 (d, J = 7.5 Hz, 10H), 2.31 (s, 3H ), 2.17 (t, J = 7.5 Hz, 2H); MS-ESI 462 (M + , 12), 349 (5), 231 (2), 141 (6), 113 (84), 70 (53), 42 (100).

실시예 25. 8,9-디메톡시-3-[4-(3-피롤리딘-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 25. 8,9-dimethoxy-3- [4- (3-pyrrolidin-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] Quinazoline

수율 46 %; 1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.14 (s, 3H), 4.13 (t, J = 6.3 Hz, 2H), 4.07 (s, 3H), 2.71 (t, J = 7.2 Hz, 2H), 2.61 (s, 4H), 2.09 (t, J = 7.4 Hz, 2H), 1.83 (s, 4H); MS-ESI 433 (M+, 2), 112 (6), 97 (4), 84 (100), 42 (56).Yield 46%; 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s , 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.14 (s, 3H), 4.13 (t, J = 6.3 Hz, 2H), 4.07 (s, 3H), 2.71 (t, J = 7.2 Hz , 2H), 2.61 (s, 4H), 2.09 (t, J = 7.4 Hz, 2H), 1.83 (s, 4H); MS-ESI 433 (M + , 2), 112 (6), 97 (4), 84 (100), 42 (56).

실시예 26. 8,9-디메톡시-3-[4-(3-피페리딘-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 26. 8,9-dimethoxy-3- [4- (3-piperidin-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] Quinazoline

수율 53 %; 1H NMR (300 MHz, CDCl3 ) 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.134 (s, 3H), 4.11 (t, J = 6.9 Hz, 2H), 4.07 (s, 3H), 2.55 (t, J = 7.2 Hz, 2H), 2.47 (m, 4H), 2.10∼2.03 (m, 2H), 1.68∼1.62 (m, 6H); MS-ESI 447 (M+, 3), 98 (100), 85 (4), 55 (3), 42 (21).Yield 53%; 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s , 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.134 (s, 3H), 4.11 (t, J = 6.9 Hz, 2H), 4.07 (s, 3H), 2.55 (t, J = 7.2 Hz , 2H), 2.47 (m, 4H), 2.10 to 2.03 (m, 2H), 1.68 to 1.62 (m, 6H); MS-ESI 447 (M + , 3), 98 (100), 85 (4), 55 (3), 42 (21).

실시예 27. {3-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시]-프로필}-디에틸아민Example 27. {3- [4- (8,9-Dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenoxy] -propyl} -di Ethylamine

수율 45 %; 1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.13 (s, 3H), 4.11 (t, J = 6 Hz, 2H), 4.07 (s, 3H), 2.72∼2.58 (m, 6H), 2.01 (t, J = 7.8 Hz, 2H), 1.08 (t, J = 6.9 Hz, 6H); MS-ESI 435 (M+, 2), 321 (2), 293 (2), 98 (3), 86 (100), 72 (21), 42 (15).Yield 45%; 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s , 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.13 (s, 3H), 4.11 (t, J = 6 Hz, 2H), 4.07 (s, 3H), 2.72 to 2.58 (m, 6H) , 2.01 (t, J = 7.8 Hz, 2H), 1.08 (t, J = 6.9 Hz, 6H); MS-ESI 435 (M + , 2), 321 (2), 293 (2), 98 (3), 86 (100), 72 (21), 42 (15).

실시예 28. 8,9-디메톡시-3-[4-(3-몰폴린-4-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 28. 8,9-dimethoxy-3- [4- (3-morpholin-4-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quina Sleepy

수율 84 %; 1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.13 (s, 3H), 4.11 (t, J = 6.6 Hz, 2H), 4.07 (s, 3H), 3.74 (t, J = 4.5 Hz, 4H), 2.56 (t, J = 7.2 Hz, 2H), 2.49 (s, 4H), 2.02 (t, J = 6.6 Hz, 2H); MS-ESI 449 (M+, 4), 322 (7), 128 (13), 100 (100), 56 (16), 42 (32).Yield 84%; 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s , 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.13 (s, 3H), 4.11 (t, J = 6.6 Hz, 2H), 4.07 (s, 3H), 3.74 (t, J = 4.5 Hz , 4H), 2.56 (t, J = 7.2 Hz, 2H), 2.49 (s, 4H), 2.02 (t, J = 6.6 Hz, 2H); MS-ESI 449 (M + , 4), 322 (7), 128 (13), 100 (100), 56 (16), 42 (32).

실시예 29. 2-({3-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시]-프로필}-메틸아미노)-에탄올Example 29. 2-({3- [4- (8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenoxy] -propyl } -Methylamino) -ethanol

수율 45 %; 1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.13 (s, 3H), 4.11 (t, J = 6.3 Hz, 2H), 4.06 (s, 3H), 3.63 (t, J = 5.1 Hz, 2H), 2.67 (t, J = 6.9 Hz, 2H), 2.60 (t, J = 5.4 Hz, 2H), 2.33 (s, 3H), 2.08 (t, J = 6.9 Hz, 2H); MS-ESI 437 (M+, 8), 407 (5), 348 (4), 305 (3), 105 (2), 58 (100), 44 (38).Yield 45%; 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s , 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.13 (s, 3H), 4.11 (t, J = 6.3 Hz, 2H), 4.06 (s, 3H), 3.63 (t, J = 5.1 Hz , 2H), 2.67 (t, J = 6.9 Hz, 2H), 2.60 (t, J = 5.4 Hz, 2H), 2.33 (s, 3H), 2.08 (t, J = 6.9 Hz, 2H); MS-ESI 437 (M + , 8), 407 (5), 348 (4), 305 (3), 105 (2), 58 (100), 44 (38).

실시예 30. 3-[4-(3-이미다졸-1-일-프로폭시)-페닐]-8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 30. 3- [4- (3-imidazol-1-yl-propoxy) -phenyl] -8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quina Sleepy

실시예 14와 동일한 방법으로 진행한다. Proceed in the same manner as in Example 14.

수율 55 %; 1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.08 s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 6.97 (s, 1H), 4.23 (t, J = 6.6 Hz, 2H), 4.13 (s, 3H), 4.07 (s, 3H), 4.01 (t, J = 5.7 Hz, 2H), 2.26 (t, J = 6.3 Hz, 2H); MS-ESI 430 (M+, 42), 349 (14), 109 (66), 81 (98), 55 (33), 43 (100).Yield 55%; 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.51 (s , 1H), 7.44 (s, 1H), 7.08 s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 6.97 (s, 1H), 4.23 (t, J = 6.6 Hz, 2H), 4.13 ( s, 3H), 4.07 (s, 3H), 4.01 (t, J = 5.7 Hz, 2H), 2.26 (t, J = 6.3 Hz, 2H); MS-ESI 430 (M + , 42), 349 (14), 109 (66), 81 (98), 55 (33), 43 (100).

실시예 31. 8,9-디메톡시-3-[4-(몰폴린-2-일-메톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 31. 8,9-dimethoxy-3- [4- (morpholin-2-yl-methoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline

4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페놀 (60 mg, 0.19 mmol), 2-(톨루엔-4-술폰일옥시메틸)-몰폴린-4-카르복실산 t-부틸에스트 (76 mg, 0.2 mmol) 그리고 K2CO3 (52 mg, 0.38 mmol)을 DMF (3 mL)에 가하고 95 ℃에서 24시간 동안 교반 하였다. 반응 혼합물에 얼음물을 넣어 생성된 고형물체를 여과하여 2-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시메틸]-몰폴린-4-카르복실산 t-부틸에스트 (50 mg, 수율 50 %)를 얻었다.4- (8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenol (60 mg, 0.19 mmol), 2- (toluene-4- Sulfonyloxymethyl) -morpholine-4-carboxylic acid t-butylest (76 mg, 0.2 mmol) and K 2 CO 3 (52 mg, 0.38 mmol) were added to DMF (3 mL) and 24 h at 95 ° C. Was stirred. Ice water was added to the reaction mixture, and the resulting solid was filtered to give 2- [4- (8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl)- Phenoxymethyl] -morpholine-4-carboxylic acid t-butylest (50 mg, yield 50%) was obtained.

1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.16∼4.03 (m, 10H), 3.98∼3.82(m, 4H), 3.66~ 3.59(m, 1H), 1.48 (s, 9H); MS-ESI 521 (M+, 2), 322 (17), 144 (5), 57 (100), 40 (41). 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s , 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.16-4.03 (m, 10H), 3.98-3.82 (m, 4H), 3.66-3.59 (m, 1H), 1.48 (s, 9H); MS-ESI 521 (M + , 2), 322 (17), 144 (5), 57 (100), 40 (41).

2-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시메틸]-몰폴린-4-카르복실산 t-부틸에스트 (20mg, 0.038 mmol)를 CH2Cl2 (1 mL)에 녹인 후 CF3COOH(0.2 mL)을 가하고 상온에서 3시간 동안 교반한다. 반응 후 휘발성 물질을 제거하고 잔류물에 물을 가하고 2N-NaOH로 pH 10으로 조절 후 CH2Cl2로 추출하여 Na2SO4로 건조하고 농축하여 8,9-디메톡시-3-[4-(몰폴린-2-일-메톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린(10 mg, 수율 62 %)을 얻었다.2- [4- (8,9-Dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenoxymethyl] -morpholine-4-carboxylic acid t-Butyl ester (20 mg, 0.038 mmol) is dissolved in CH 2 Cl 2 (1 mL), CF 3 COOH (0.2 mL) is added, and the mixture is stirred at room temperature for 3 hours. After the reaction, the volatiles were removed, water was added to the residue, adjusted to pH 10 with 2N-NaOH, extracted with CH 2 Cl 2 , dried over Na 2 SO 4 and concentrated to give 8,9-dimethoxy-3- [4- (Morpholin-2-yl-methoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline (10 mg, yield 62%) was obtained.

1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.13 (s, 3H), 4.06 (s, 3H), 4.02∼3.95 (m, 2H), 3.74∼3.71 (m, 2H), 3.11∼3.07 (m, 1H), 2.96∼2.81 (m, 4H); MS-ESI 421 (M+, 15), 322 (100), 279 (5), 100 (15), 56 (73), 43 (42). 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.44 (s , 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.13 (s, 3H), 4.06 (s, 3H), 4.02-3.95 (m, 2H), 3.74-3.71 (m, 2H), 3.11- 3.07 (m, 1 H), 2.96 to 2.81 (m, 4H); MS-ESI 421 (M + , 15), 322 (100), 279 (5), 100 (15), 56 (73), 43 (42).

실시예 32. 8-벤질옥시-9-메톡시-6-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 32. 8-benzyloxy-9-methoxy-6-phenyl- [1,2,4] triazolo [4,3-c] quinazoline

실시예 1과 동일한 방법으로 치환반응 및 탈수반응하여 제조하였다.It was prepared by the substitution reaction and dehydration reaction in the same manner as in Example 1.

수율 59 %; 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.30 (d, J = 7.6 Hz, 2H), 7.91 (s, 1H), 7.55∼7.48 (m, 6H), 7.43∼7.34 (m, 3H), 5.33 (s, 2H), 4.13 (s, 3H); MS-ESI 382 (M+, 7), 291 (9), 104 (3), 91 (100), 65 (13).Yield 59%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.30 (d, J = 7.6 Hz, 2H), 7.91 (s, 1H), 7.55 to 7.48 (m, 6H), 7.43 to 7.74 ( m, 3H), 5.33 (s, 2H), 4.13 (s, 3H); MS-ESI 382 (M + , 7), 291 (9), 104 (3), 91 (100), 65 (13).

실시예 33. 9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린-8-올Example 33. 9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin-8-ol

8-벤질옥시-9-메톡시-6-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린 (0.4 g, 1.05 mmol)을 MeOH (40 mL)에 녹이고 10 % Pd/C (0.12 g)을 가한 뒤 수소 기류 하에서 2시간 동안 교반 하였다. 반응 혼합물을 셀라이트를 통하여 여과하고 농축하여 9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린-8-올 (0.27 g, 수율 87 %)을 얻었다. 8-benzyloxy-9-methoxy-6-phenyl- [1,2,4] triazolo [4,3-c] quinazolin (0.4 g, 1.05 mmol) is dissolved in MeOH (40 mL) and 10% Pd / C (0.12 g) was added followed by stirring for 2 hours under hydrogen stream. The reaction mixture was filtered through celite and concentrated to give 9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin-8-ol (0.27 g, 87% yield). Got.

1H NMR (300 MHz, DMSO-d 6 ) δ 9.47 (s, 1H), 8.28 (d, J = 7.6 Hz, 2H), 7.77 (s, 1H), 7.56 (m, 3H), 7.36 (s, 1H), 4.04 (s, 3H); MS-ESI 292 (M+, 100), 277 (60), 91 (25), 77 (32), 63 (24), 40 (51). 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.47 (s, 1H), 8.28 (d, J = 7.6 Hz, 2H), 7.77 (s, 1H), 7.56 (m, 3H), 7.36 (s, 1H), 4.04 (s, 3 H); MS-ESI 292 (M + , 100), 277 (60), 91 (25), 77 (32), 63 (24), 40 (51).

실시예 34. 8-(3-브로모프로폭시)-9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 34. 8- (3-Bromopropoxy) -9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazoline

9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린-8-올 (0.17 g, 0.58 mmol)을 디메틸포름아마이드 (15 mL)에 녹인 후 K2CO3 (0.1 g, 0.75 mmol)와 1,3-디브로모프로판 (0.3 mL)를 가하고 상온에서 4시간 동안 교반 하였다. 반응 혼합물을 CH2Cl2로 희석하고 소금물로 세척 후 소디움설페이트로 건조한 뒤 농축하고 8-(3-브로모프로폭시)-9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린 (0.16 g, 수율 68 %)을 얻었다9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin-8-ol (0.17 g, 0.58 mmol) was dissolved in dimethylformamide (15 mL) and K 2 CO 3 (0.1 g, 0.75 mmol) and 1,3-dibromopropane (0.3 mL) were added and stirred at room temperature for 4 hours. The reaction mixture was diluted with CH 2 Cl 2 , washed with brine, dried over sodium sulfate, concentrated and then 8- (3-bromopropoxy) -9-methoxy-3-phenyl- [1,2,4] triazole [4,3-c] quinazoline (0.16 g, yield 68%) was obtained.

1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.35 (t, J = 6 Hz, 2H), 4.11 (s, 3H), 3.68 (t, J = 6.3 Hz, 2H), 2.52∼2.44 (m, 2H); MS-ESI 413 (M+, 16), 292 (22), 277 (20), 77 (11), 62 (10). 1 H NMR (300 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.35 (t, J = 6 Hz, 2H), 4.11 (s, 3H), 3.68 (t, J = 6.3 Hz, 2H), 2.52-2.44 (m, 2H); MS-ESI 413 (M + , 16), 292 (22), 277 (20), 77 (11), 62 (10).

실시예 35. 9-메톡시-8-(3-몰폴린-4-일-프로폭시)-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 35. 9-methoxy-8- (3-morpholin-4-yl-propoxy) -3-phenyl- [1,2,4] triazolo [4,3-c] quinazoline

8-(3-브로모프로폭시)-9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸 (20 mg, 0.05 mmol)을 아세톤 (3 mL)에 녹이고 몰폴린 (0.013 mL, 0.15 mmol)과 포타슘카보네이트 (26 mg, 0.19 mmol), 소디움아이오다이드 (1 mg)을 넣어준 후 24시간 동안 환류 교반하였다. 휘발성 물질을 제거 후 CH2Cl2로 녹이고 소금물로 세척 후 소디움설페이트로 건조하여 관크로마토그래피 (5% MeOH/CH2Cl2)로 정제하여 9-메톡시-8-(3-몰폴린-4-일-프로폭시)-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린 (9mg, 45%)을 얻었다.8- (3-bromopropoxy) -9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazole (20 mg, 0.05 mmol) was diluted with acetone (3 mL ), Morpholine (0.013 mL, 0.15 mmol), potassium carbonate (26 mg, 0.19 mmol) and sodium iodide (1 mg) were added thereto, and the mixture was stirred under reflux for 24 hours. After removing volatiles, dissolved with CH 2 Cl 2 , washed with brine, dried over sodium sulfate, purified by tube chromatography (5% MeOH / CH 2 Cl 2 ), and purified by 9-methoxy-8- (3-morpholine-4 -Yl-propoxy) -3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin (9 mg, 45%) was obtained.

1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.29 (t, J = 6.6 Hz, 2H), 4.11 (s, 3H,) 3.74 (t, J = 4.4 Hz, 4H), 2.59 (t, J = 6.9 Hz, 2 Hz), 2.50 (m, 4H), 2.13 (quin, J = 6.6 Hz, 2H); MS-ESI 419 (M+, 3), 388 (12), 277 (3), 128 (9), 100 (100), 70 (14), 42 (43). 1 H NMR (300 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.29 (t, J = 6.6 Hz, 2H), 4.11 (s, 3H,) 3.74 (t, J = 4.4 Hz, 4H), 2.59 (t, J = 6.9 Hz, 2 Hz), 2.50 (m, 4H), 2.13 (quin , J = 6.6 Hz, 2H); MS-ESI 419 (M + , 3), 388 (12), 277 (3), 128 (9), 100 (100), 70 (14), 42 (43).

실시예 36. 9-메톡시-8-[3-(4-메틸-피페라진-1-일)-프로폭시]-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 36. 9-methoxy-8- [3- (4-methyl-piperazin-1-yl) -propoxy] -3-phenyl- [1,2,4] triazolo [4,3-c Quinazoline

수율 54 %; 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.27 (t, J = 6.6 Hz, 2H), 4.11 (s, 3H), 2.59 (t, J = 7.2 Hz, 2H), 2.48 (m, 8H), 2.30 (s, 3H), 2.14 (quin, J = 6.6 Hz, 2H); MS-ESI 432 (M+, 2), 362 (3), 113 (34), 70 (52), 42 (100).Yield 54%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.27 (t, J = 6.6 Hz, 2H), 4.11 (s, 3H), 2.59 (t, J = 7.2 Hz, 2H), 2.48 (m, 8H), 2.30 (s, 3H), 2.14 (quin, J = 6.6 Hz, 2H); MS-ESI 432 (M + , 2), 362 (3), 113 (34), 70 (52), 42 (100).

실시예 37. 9-메톡시-3-페닐-8-(3-피롤리딘-1-일-프로폭시)-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 37. 9-methoxy-3-phenyl-8- (3-pyrrolidin-1-yl-propoxy)-[1,2,4] triazolo [4,3-c] quinazoline

수율 45 %; 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.29 (t, J = 6.6 Hz, 2H), 4.11 (s, 3H), 2.73 (t, J = 7.2 Hz, 2H), 2.61 (s, 4H), 2.24∼2.15 (m, 2H), 1.88 (s, 4H); MS-ESI 403 (M+, 2), 111(2), 84 (100), 56 (5), 42 (41).Yield 45%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.29 (t, J = 6.6 Hz, 2H), 4.11 (s, 3H), 2.73 (t, J = 7.2 Hz, 2H), 2.61 (s, 4H), 2.24-2.15 (m, 2H), 1.88 (s, 4H); MS-ESI 403 (M + , 2), 111 (2), 84 (100), 56 (5), 42 (41).

실시예 38. 9-메톡시-3-페닐-8-(3-피페리딘-1-일-프로폭시)-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 38. 9-methoxy-3-phenyl-8- (3-piperidin-1-yl-propoxy)-[1,2,4] triazolo [4,3-c] quinazoline

수율 30 %; 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.27 (t, J = 6.6 Hz, 2H), 4.11 (s, 3H), 2.64∼2.53 (m, 6H), 2.21∼2.17 (m, 2H), 1.59 (m, 6H); MS-ESI 417 (M+, 5), 124 (6), 98 (100), 69 (7), 55 (11), 42 (19).Yield 30%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.27 (t, J = 6.6 Hz, 2H), 4.11 (s, 3H), 2.64-2.53 (m, 6H), 2.21-2.17 (m, 2H), 1.59 (m, 6H); MS-ESI 417 (M + , 5), 124 (6), 98 (100), 69 (7), 55 (11), 42 (19).

실시예 39. 디에틸-[3-(9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린-8-일옥시)-프로필]-아민Example 39. Diethyl- [3- (9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin-8-yloxy) -propyl] -amine

수율 41 %; 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.28 (t, J = 6.3 Hz, 2H), 4.10 (s, 3H), 2.92∼2.82 (m, 6H), 2.25∼2.17 (m, 2H), 1.23∼1.21 (m, 6H); MS-ESI 405 (M+, 3), 98 (4), 86 (100), 72 (17), 58 (12), 42 (15).Yield 41%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.28 (t, J = 6.3 Hz, 2H), 4.10 (s, 3H), 2.92-2.82 (m, 6H), 2.25-2.17 (m, 2H), 1.23-1.21 (m, 6H); MS-ESI 405 (M + , 3), 98 (4), 86 (100), 72 (17), 58 (12), 42 (15).

실시예 40. 2-{[3-(9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린-8-일옥시)-프로필]-메틸-아미노}-에탄올Example 40. 2-{[3- (9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin-8-yloxy) -propyl] -methyl- Amino} -ethanol

수율 41 %; 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.29 (t, J = 6.3 Hz, 2H), 4.11 (s, 3H), 3.69 (t, J = 5.4 Hz, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.68 (t, J = 5.1 Hz, 2H), 2.39 (s, 3H), 2.18 (t, J = 6.6 Hz, 2H), 2.02 (brs, 1H).Yield 41%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.29 (t, J = 6.3 Hz, 2H), 4.11 (s, 3H), 3.69 (t, J = 5.4 Hz, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.68 (t, J = 5.1 Hz, 2H) , 2.39 (s, 3H), 2.18 (t, J = 6.6 Hz, 2H), 2.02 (brs, 1H).

실시예 41. 8-(3-이미다졸-1-일-프로폭시)-9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 41. 8- (3-imidazol-1-yl-propoxy) -9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazoline

실시예 14와 동일한 방법으로 진행한다.Proceed in the same manner as in Example 14.

수율 73 %; 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.51 (s, 1H), 7.45 (s, 1H), 7.08 (s, 1H), 6.96 (s, 1H), 4.28 (t, J = 6.6 Hz, 2H), 4.14 (s, 5H), 2.43∼2.35 (m, 2H); MS-ESI 400 (M+, 91), 109 (90), 82 (100), 81 (90), 55 (33), 41 (57).Yield 73%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.51 (s, 1H), 7.45 (s, 1H), 7.08 (s, 1H), 6.96 (s, 1H), 4.28 (t, J = 6.6 Hz, 2H), 4.14 (s, 5H), 2.43-2.35 (m, 2H); MS-ESI 400 (M + , 91), 109 (90), 82 (100), 81 (90), 55 (33), 41 (57).

실시예 42. 9-메톡시-3-페닐-8-(2-피롤리딘-1-일-에톡시)-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 42. 9-methoxy-3-phenyl-8- (2-pyrrolidin-1-yl-ethoxy)-[1,2,4] triazolo [4,3-c] quinazoline

실시예 2와 동일한 방법으로 진행한다. Proceed in the same manner as in Example 2.

수율 56 %; 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.34 (t, J = 6.3 Hz, 2H) 4.11 (s, 3H) 3.06 (t, J = 6.3 Hz, 2H) 2.68 (d, J = 5.4 Hz, 4H) 1.86∼1.81 (m, 4H); MS-ESI 389 (M+, 2), 290 (1), 245 (1), 115 (1), 84 (100), 41 (18).Yield 56%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.34 (t, J = 6.3 Hz, 2H) 4.11 (s, 3H) 3.06 (t, J = 6.3 Hz, 2H) 2.68 (d, J = 5.4 Hz, 4H) 1.86-1.81 (m, 4H); MS-ESI 389 (M + , 2), 290 (1), 245 (1), 115 (1), 84 (100), 41 (18).

실시예 43. 9-메톡시-3-페닐-8-(2-피페리딘-1-일-에톡시)-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 43. 9-methoxy-3-phenyl-8- (2-piperidin-1-yl-ethoxy)-[1,2,4] triazolo [4,3-c] quinazoline

수율 32 %; 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.33 (t, J = 6.3 Hz, 2H), 4.11 (s, 3H), 2.92 (t, J = 6.3 Hz, 2H), 2.56 (t, J = 5.1 Hz, 4H), 1.63 (t, J = 5.7 Hz, 4H), 1.47 (d, J = 5.7 Hz, 2H); MS-ESI 403 (M+, 1), 272 (4), 149 (2), 98 (100), 80 (3), 41 (5).Yield 32%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.33 (t, J = 6.3 Hz, 2H), 4.11 (s, 3H), 2.92 (t, J = 6.3 Hz, 2H), 2.56 (t, J = 5.1 Hz, 4H), 1.63 (t, J = 5.7 Hz, 4H) , 1.47 (d, J = 5.7 Hz, 2H); MS-ESI 403 (M + , 1), 272 (4), 149 (2), 98 (100), 80 (3), 41 (5).

실시예 44. 9-메톡시-8-(2-몰폴린-4-일-에톡시)-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 44. 9-methoxy-8- (2-morpholin-4-yl-ethoxy) -3-phenyl- [1,2,4] triazolo [4,3-c] quinazoline

수율 57 %; 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.34 (t, J = 6 Hz, 2H), 4.11 (s, 3H), 3.76 (t, J = 4.8 Hz, 4H), 2.95 (t, J = 6 Hz, 2H), 2.65 (t, J = 4.8 Hz, 4H); MS-ESI 405 (M+, 2), 292 (2), 114 (5), 100 (100), 70 (4), 56 (20), 42 (9).Yield 57%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 4.34 (t, J = 6 Hz, 2H), 4.11 (s, 3H), 3.76 (t, J = 4.8 Hz, 4H), 2.95 (t, J = 6 Hz, 2H), 2.65 (t, J = 4.8 Hz, 4H) ; MS-ESI 405 (M + , 2), 292 (2), 114 (5), 100 (100), 70 (4), 56 (20), 42 (9).

실시예 45. 3-(4-브로모페닐)-8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 45. 3- (4-Bromophenyl) -8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazoline

실시예 1과 동일한 방법으로 치환반응 및 탈수반응하여 제조하였다.It was prepared by the substitution reaction and dehydration reaction in the same manner as in Example 1.

수율 62%; 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 7.44 (s, 1H), 4.13 (s, 3H), 4.06 (s, 3H).Yield 62%; 1 H NMR (300 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.34 (m, 2H), 7.89 (s, 1H), 7.55 (m, 3H), 7.46 (s, 1H), 7.44 (s, 1H), 4.13 (s, 3H), 4.06 (s, 3H).

실시예 46. 8,9-디메톡시-3-(4-몰폴린-4-일-페닐)-[1,2,4]트리아졸로[4,3-c]퀴나졸린Example 46. 8,9-Dimethoxy-3- (4-morpholin-4-yl-phenyl)-[1,2,4] triazolo [4,3-c] quinazoline

3-(4-브로모페닐)-8,9-다이메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린(0.1 g, 0.26 mmol), 몰폴린 (45 mg, 0.52 mmol), BINAP (16 mg, 0.05 mmol), Pd2(dba)3 (12 mg, 0.025 mmol) 그리고 Cs2CO3 (0.12g, 0.36 mmol)을 톨루엔 (3 mL)에 녹인 후 밀봉된 튜브에서 10시간 가열하였다. 반응 혼합물을 에틸아세트산에 희석시킨 후 소금물로 세척하고 소디움설페이트로 건조하여 관크로마토그래피 (5% MeOH/CH2Cl2)로 정제하여 8,9-디메톡시-3-(4-몰폴린-4-일-페닐)-[1,2,4]트리아졸로[4,3-c]퀴나졸린 (66 mg, 수율 65%)을 얻었다.3- (4-bromophenyl) -8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazoline (0.1 g, 0.26 mmol), morpholine (45 mg, 0.52 mmol), BINAP (16 mg, 0.05 mmol), Pd 2 (dba) 3 (12 mg, 0.025 mmol) and Cs 2 CO 3 (0.12 g, 0.36 mmol) in toluene (3 mL) and then sealed tube Heated at 10 h. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, purified by column chromatography (5% MeOH / CH 2 Cl 2 ), and 8,9-dimethoxy-3- (4-morpholine-4 -Yl-phenyl)-[1,2,4] triazolo [4,3-c] quinazolin (66 mg, yield 65%) was obtained.

1H NMR (300 MHz, CDCl3) δ 9.15 (s, 1H), 8.24 (d, J = 8.7 Hz, 2H), 7.89 (s, 1H), 7.44 (s, 1H), 8.03 (d, J = 8.7 Hz, 2H), 7.46 (s, 1H), 4.14 (s, 3H), 4.07 (s, 3H), 3.90 (m, 4H), 3.30 (m, 2H); MS-ESI 391 (M+, 100), 333 (61), 290 (15), 166 (49), 145(44), 43 (41). 1 H NMR (300 MHz, CDCl 3 ) δ 9.15 (s, 1H), 8.24 (d, J = 8.7 Hz, 2H), 7.89 (s, 1H), 7.44 (s, 1H), 8.03 (d, J = 8.7 Hz, 2H), 7.46 (s, 1H), 4.14 (s, 3H), 4.07 (s, 3H), 3.90 (m, 4H), 3.30 (m, 2H); MS-ESI 391 (M + , 100), 333 (61), 290 (15), 166 (49), 145 (44), 43 (41).

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 illustrates some formulation methods containing the compound represented by 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 pressure)

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 sifting 5.0 mg of active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to form a tablet.

제제 2 : 정제(습식 조립)Formulation 2: Tablet (Wet Granulation)

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 디옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 만들었다.After sifting 5.0 mg of the active ingredient, 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 then an appropriate amount of this solution was added and then atomized. 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 캡슐제Formulation 3: Powders and Capsules

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. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.

제제 4 : 주사제Formulation 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 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O and 2974 mg of distilled water.

실험예 1. EGFR 및 VEGFR 티로신 키나제 효능검색Experimental Example 1. Efficacy screening of EGFR and VEGFR tyrosine kinase

EGFR 및 VEGFR 티로신 키나제의 활성도는 Alpha Screen™ P-Tyr-100 분석법(Packard BioScience사)을 이용하여 측정하였다. Alpha Screen이란 Amplified Luminescent Proximity Homogenous Assay를 의미하며, Luminescent Oxygen Radical Channel을 이용하는 면역정량법(Immunoassay)이다. 본 실험에서는 비오틴화된 폴리[Glu:Tyr](4:1) (Packard BioScience 사)를 반응효소에 대한 기질로 사용하였고, 이 기질들과 결합할 수 있도록 스트렙타비딘(Streptavdin)이 코팅된 공여체 비드와 인산화된 기질을 인지하여 반응할 수 있는 항체(P-Tyr-100)가 결합된 수용체 비드가 효소 반응에 사용되었다. EGFR 티로신 키나제는 Sf21 곤충세포를 EFGR이 재조합된 pBacPAK8 곤충 발현 벡터(Clontech사)로 감염시켜 효소의 다량 발현을 유도하여 분리하였다. The activity of EGFR and VEGFR tyrosine kinases was measured using the Alpha Screen ™ P-Tyr-100 assay (Packard BioScience). Alpha Screen means Amplified Luminescent Proximity Homogenous Assay, and is an immunoassay using Luminescent Oxygen Radical Channel. In this experiment, biotinylated poly [Glu: Tyr] (4: 1) (Packard BioScience) was used as a substrate for the enzyme, and a streptavidin-coated donor could bind to these substrates. Receptor beads combined with an antibody (P-Tyr-100) capable of recognizing and reacting beads and phosphorylated substrates were used for the enzymatic reaction. EGFR tyrosine kinase was isolated from Sf21 insect cells by inducing high expression of the enzyme by infecting the EBGR pBacPAK8 insect expression vector (Clontech).

분석은 희고 불투명한 384-웰 플레이트(Greiner Bio-One사)를 사용하여 각 웰(well)의 전체 반응 부피가 25 μL 되도록 다음의 3 과정을 통하여 진행되었다.The analysis was carried out through the following three steps using a white and opaque 384-well plate (Greiner Bio-One) so that the total reaction volume of each well was 25 μL.

첫째, 5 μL의 EGFR 및 VEGFR 효소(5 ng)를 5 μL의 알려진 표준 억제제인 Tyrphostin A51(Upstate Biotech사) 혹은 시험하고자 하는 화합물과 384-웰 플레이트의 각 웰에 첨가하여 15분 동안 상온에서 반응하였다. 둘째, 반응 15분 후, 각 웰에 5 μL의 비오틴화된 폴리[Glu:Tyr] (4:1)와 ATP를 각각 최종농도가 5 nM과 100 μM이 되도록 첨가하여 1 시간 동안 상온에서 효소 반응을 진행하였다. 이때 효소 반응에 사용된 완충용액의 조성은 50 mM Tris-HCl(pH 7.5), 5 mM MgCl2, 5 mM MnCl2, 2 mM DTT와 0.01 % Tween-20이다. 셋째, 1시간의 효소 반응 후, 여기에 공여체 및 수용체 비드가 포함된 10 μL의 감지완충액(Capture buffer)을 첨가하여 1 시간 동안 상온에서 효소 반응을 추가 진행하였다. 이 과정은 진행 중인 효소 반응을 중지시키면서 기질의 인산화 정도를 인지하도록 최종농도가 각각 20 μg/mL인 스트렙타비딘(Streptavdin) 공여체와 P-Tyr-100 비드 수용체 및 EDTA가 포함된 감지완충액(Capture buffer)을 사용하였다. 감지완충액(Capture buffer)의 조성(2.5배 농도)은 62.5 mM HEPES(pH 7.4), 250 mM NaCl, 100 mM EDTA 및 BSA 0.25 % 이었다. 반응 후, 효소의 활성도는 Fusion™ microplate 분석장치(PerkinElmer사)를 이용하여 AlphaScreen 신호를 측정함으로써 구할 수 있다.First, add 5 μL of EGFR and VEGFR enzyme (5 ng) to each well of a 384-well plate with 5 μL of known standard inhibitor Tyrphostin A51 (Upstate Biotech) or the compound to be tested and react at room temperature for 15 minutes. It was. Second, after 15 minutes of reaction, 5 μL of biotinylated poly [Glu: Tyr] (4: 1) and ATP were added to each well so that the final concentration was 5 nM and 100 μM, respectively. Proceeded. The composition of the buffer used for the enzyme reaction is 50 mM Tris-HCl (pH 7.5), 5 mM MgCl 2 , 5 mM MnCl 2 , 2 mM DTT and 0.01% Tween-20. Third, after 1 hour of enzymatic reaction, 10 μL of capture buffer containing donor and receptor beads was added thereto, and the enzyme reaction was further performed at room temperature for 1 hour. This process captures a streptavidin donor with a final concentration of 20 μg / mL, a P-Tyr-100 bead receptor, and EDTA to stop the ongoing enzymatic reaction and recognize the degree of phosphorylation of the substrate. buffer) was used. The composition (2.5-fold concentration) of the capture buffer was 62.5 mM HEPES (pH 7.4), 250 mM NaCl, 100 mM EDTA and BSA 0.25%. After the reaction, the activity of the enzyme can be determined by measuring the AlphaScreen signal using a Fusion ™ microplate analyzer (PerkinElmer).

본 발명에 따른 화합물들에 대한 활성을 비교하기 위하여, 상피세포 성장인자 수용체(EGFR)에 대하여 아스트라제네카사의 ZD-1839(IressaTM) 화합물을 대조화합물로 사용하였다. 합성된 실시예 화합물과 대조화합물에 대한 활성 비교 결과는 다음 표 1에 나타내었다.In order to compare the activity of the compounds according to the present invention, AstraZeneca's ZD-1839 (Iressa ™ ) compound was used as a control compound for epidermal growth factor receptor (EGFR). The results of the activity comparison for the synthesized Example compound and the control compound are shown in Table 1 below.

EGFR 대한 저해효율(%저해율, 20 μM 농도에서)Inhibition efficiency against EGFR (% inhibition rate at 20 μM concentration) 시험화합물Test compound EGFREGFR 시험화합물Test compound EGFREGFR ZD-1839ZD-1839 7575 실시예 22Example 22 8181 실시예 2Example 2 4646 실시예 24Example 24 8282 실시예 3Example 3 7272 실시예 25Example 25 7373 실시예 4Example 4 5656 실시예 26Example 26 7272 실시예 5Example 5 7474 실시예 27Example 27 6666 실시예 6Example 6 7171 실시예 28Example 28 6767 실시예 8Example 8 5252 실시예 29Example 29 7474 실시예 9Example 9 7171 실시예 30Example 30 9999 실시예 10Example 10 7777 실시예 31Example 31 5252 실시예 11Example 11 5252 실시예 35Example 35 8282 실시예 12Example 12 5858 실시예 36Example 36 4545 실시예 13Example 13 6464 실시예 37Example 37 4646 실시예 14Example 14 4545 실시예 38Example 38 7777 실시예 15Example 15 5151 실시예 39Example 39 5252 실시예 16Example 16 5555 실시예 40Example 40 7878 실시예 17Example 17 5656 실시예 41Example 41 8787 실시예 18Example 18 8181 실시예 42Example 42 4141 실시예 19Example 19 6262 실시예 43Example 43 5656 실시예 20Example 20 7272 실시예 44Example 44 7272 실시예 21Example 21 4444 실시예 45Example 45 5555

EGFR에 대한 활성의 경우 실시예 18, 22, 24, 30, 35 및 41 화합물의 활성이 ZD-1839와 비교하여 비슷하거나 더 우수한 것으로 나타났으며, 특히 실시예 30 화합물은 99%의 가장 우수한 약효를 보이는 것으로 확인되었다. In terms of activity against EGFR, the activities of the compounds of Examples 18, 22, 24, 30, 35 and 41 were found to be comparable or better than those of ZD-1839. It was confirmed to show.

시험예 2 : 경구독성 시험Test Example 2: Oral Toxicity Test

본 발명에 따른 몇몇 화합물에 대해서는 랫트를 대상으로 급성독성 시험을 수행하였다. 그 결과 경구 투여량 10 mg/kg 까지는 목적에 반하는 심각한 독성의 증상이 없으며, 경구 투여량 100 mg/kg 까지는 사망이 전혀 없었다.Some compounds according to the invention were subjected to acute toxicity testing in rats. As a result, up to 10 mg / kg oral dose showed no serious toxicity symptoms, and up to 100 mg / kg oral dose did not cause any death.

이상에서 상세히 살펴 본 바와 같이, 본 발명에 따른 상기 화학식 1로 표시되는 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 구조를 기본 골격으로 R1과 R2 위치에 다양한 치환체를 도입한 신규 퀴나졸린 유도체는 티로신 키나제의 억제 활성이 우수하므로 비정상적인 키나제의 활성으로 야기되는 각종 질환의 치료제로서, 암, 특히 결장직장, 유방, 폐, 전립선, 췌장 또는 방광 및 신장 암, 또는 백혈병 또는 림프종과 같은 고증식성 질환 치료용 약제로 유용하게 사용될 수 있다.As described in detail above, the [1,2,4] -triazolo [4,3-c] quinazolin structure represented by Chemical Formula 1 according to the present invention has various structures at R 1 and R 2 positions as a basic skeleton. Novel quinazoline derivatives with substituents are used as therapeutic agents for various diseases caused by abnormal kinase activity because of their excellent inhibitory activity of tyrosine kinases, and cancers, particularly colorectal, breast, lung, prostate, pancreatic or bladder and kidney cancers, or It can be usefully used as a medicament for the treatment of hyperproliferative diseases such as leukemia or lymphoma.

Claims (8)

다음 화학식 1로 표시되는 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 유도체, 이의 약제학적 허용 가능한 염, 또는 이의 용매화물 :[1,2,4] -triazolo [4,3-c] quinazolin derivatives represented by Formula 1, pharmaceutically acceptable salts thereof, or solvates thereof: [화학식 1][Formula 1] 상기 화학식 1에서, R1은 수소원자, 할로겐기, 히드록시기, 아민기, C1-4의 알콕시기, 또는 -NR3R4가 치환된 C1-4의 알콕시기를 나타내고; R2는 수소원자, C1-4의 알콕시기, 또는 -NR3R4가 치환된 C1-4의 알콕시기를 나타내고; R3 및 R4는 서로 같거나 다른 것으로, 각각 수소원자, C1-6의 알킬기, 또는 C1-4의 히드록시알킬기이거나, 또는 R3 및 R4이 결합된 질소원자 및 O, S, 및 NR5(이때, R5는 수소원자 또는 C1-6의 알킬기) 중에서 선택된 헤테로원자가 1 내지 3개 포함되어 고리로 연결된 5원 내지 7원의 헤테로 지방족 또는 방향족 시클릭기를 나타내며; 단, R1 및 R2가 동시에 수소원자인 경우는 제외한다.In Formula 1, R 1 represents a hydrogen atom, a halogen group, a hydroxy group, an amine group, a C 1-4 alkoxy group, or a C 1-4 alkoxy group substituted with —NR 3 R 4 ; R 2 represents a hydrogen atom, an alkoxy group of C 1-4 or a C 1-4 alkoxy group substituted with —NR 3 R 4 ; R 3 and R 4 are the same as or different from each other, and each is a hydrogen atom, an alkyl group of C 1-6 , or a hydroxyalkyl group of C 1-4 , or a nitrogen atom having R 3 and R 4 bonded thereto and O, S, And 5 to 7 membered heteroaliphatic or aromatic cyclic groups containing 1 to 3 heteroatoms selected from NR 5 (wherein R 5 is a hydrogen atom or an alkyl group of C 1-6 ) and is connected by a ring; Except that R 1 and R 2 are hydrogen atoms at the same time. 제 1 항에 있어서, 상기 R1은 수소원자, 할로겐기, 히드록시기, 아민기 또는 -NR3R4가 치환된 C2-3의 알콕시기를 나타내고; R2는 수소원자, 메톡시기, 또는 -NR6R7가 치환된 C2-3의 알콕시기를 나타내고; R3 및 R4는 서로 같거나 다른 것으로, 각각 C1-2의 알킬기, 또는 C2-3의 히드록시알킬기이거나, 또는 R3 및 R4이 결합된 질소원자 및 O, S, 및 NR5(이때, R5는 수소원자 또는 C1-2의 알킬기) 중에서 선택된 헤테로원자가 1 내지 3개 포함되어 고리로 연결된 5원 내지 6원의 헤테로 지방족 또는 방향족 시클릭기를 나타내며; 단, R1 및 R2가 동시에 수소원자인 화합물은 제외된 것을 특징으로 하는 화합물.The compound of claim 1, wherein R 1 represents a hydrogen atom, a halogen group, a hydroxy group, an amine group or a C 2-3 alkoxy group substituted with —NR 3 R 4 ; R 2 represents a hydrogen atom, a methoxy group, or a C 2-3 alkoxy group substituted with —NR 6 R 7 ; R 3 and R 4 are the same as or different from each other, and are each an alkyl group of C 1-2 , or a hydroxyalkyl group of C 2-3 , or a nitrogen atom to which R 3 and R 4 are bonded and O, S, and NR 5 (Wherein R 5 represents a hydrogen atom or an alkyl group of C 1-2 ) containing 1 to 3 heteroatoms to represent a 5 to 6 membered heteroaliphatic or aromatic cyclic group linked by a ring; Provided that compounds wherein R 1 and R 2 are hydrogen atoms at the same time are excluded. 제 1 항에 있어서, 상기 R1은 수소원자, 브롬, 히드록시기, 몰폴린기, 또는 -NR3R4가 치환된 C2-3의 알콕시기를 나타내고; R2는 수소원자, 메톡시기, 또는 -NR6R7가 치환된 C2-3의 알콕시기를 나타내고; R3 및 R4는 서로 같거나 다른 것으로, 각각 메틸, 에틸, 또는 히드록시에틸기이거나, 또는 R3 및 R4이 고리로 연결되어 형성된 피롤기, 피롤리딘기, 피페리딘기, 이미다졸기, 몰폴린기, 피페라진, 또는 N-메틸 피페라진기를 나타내고; 단, R1 및 R2가 동시에 수소원자인 화합물은 제외된 것을 특징으로 하는 화합물.The compound of claim 1, wherein R 1 represents a hydrogen atom, a bromine, a hydroxy group, a morpholine group, or a C 2-3 alkoxy group substituted with —NR 3 R 4 ; R 2 represents a hydrogen atom, a methoxy group, or a C 2-3 alkoxy group substituted with —NR 6 R 7 ; R 3 and R 4 are the same as or different from each other, and each is a methyl, ethyl, or hydroxyethyl group, or a pyrrole group, a pyrrolidine group, a piperidine group, an imidazole group, formed by R 3 and R 4 being linked with a ring, Morpholine group, piperazine, or N-methyl piperazine group; Provided that compounds wherein R 1 and R 2 are hydrogen atoms at the same time are excluded. 제 1 항에 있어서, The method of claim 1, 디메틸-[2-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-에틸]-아민 ;Dimethyl- [2- (4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenoxy) -ethyl] -amine; 디에틸-[2-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-에틸]-아민 ;Diethyl- [2- (4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenoxy) -ethyl] -amine; 3-[4-(2-피롤리딘-1-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline; 3-[4-(2-피페리딘-1-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (2-piperidin-1-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline; 3-[4-(2-몰폴린-4-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (2-morpholin-4-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline; 디에틸-[3-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-프로필]-아민 ;Diethyl- [3- (4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenoxy) -propyl] -amine; 3-[4-(3-피롤리딘-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (3-pyrrolidin-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazolin; 3-[4-(3-피페리딘-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (3-piperidin-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazolin; 3-[4-(2-몰폴린-4-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (2-morpholin-4-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline; 3-{4-[3-(4-메틸-피페라진-1-일)-프로폭시]-페닐}-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- {4- [3- (4-Methyl-piperazin-1-yl) -propoxy] -phenyl}-[1,2,4] triazolo [4,3-c] quinazoline; 2-{메틸-[3-(4-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일-페녹시)-프로필]-아미노}-에탄올 ;2- {methyl- [3- (4- [1,2,4] triazolo [4,3-c] quinazolin-3-yl-phenoxy) -propyl] -amino} -ethanol; 3-[4-(3-이미다졸-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (3-imidazol-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline; 3-[4-(3-피롤-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (3-pyrrole-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline; 8,9-디메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazoline; 4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페놀 ;4- (8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenol; 8,9-디메톡시-3-[4-(몰폴린-2-일-메톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- [4- (morpholin-2-yl-methoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline; 8,9-디메톡시-3-(4-몰폴린-4-일-페닐)-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- (4-morpholin-4-yl-phenyl)-[1,2,4] triazolo [4,3-c] quinazolin; {2-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시]-에틸}-디에틸아민 ;{2- [4- (8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenoxy] -ethyl} -diethylamine; 8,9-디메톡시-3-[4-(2-몰폴린-4-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- [4- (2-morpholin-4-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline; 8,9-디메톡시-3-[4-(2-피페리딘-1-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazoline; {3-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시]-프로필}-디에틸아민 ;{3- [4- (8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenoxy] -propyl} -diethylamine; 8,9-디메톡시-3-[4-(3-피롤리딘-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴놀린 ;8,9-dimethoxy-3- [4- (3-pyrrolidin-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinoline; 8,9-디메톡시-3-[4-(3-피페리딘-1-일-프로폭시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- [4- (3-piperidin-1-yl-propoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazolin; 8,9-디메톡시-3-[4-(3-몰폴린-4-일-프로폭시)-페닐]-[1,2,4]트리아졸[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- [4- (3-morpholin-4-yl-propoxy) -phenyl]-[1,2,4] triazole [4,3-c] quinazoline; 8,9-디메톡시-3-{4-[3-(4-메틸-피페라진-1-일)-프로폭시]-페닐}-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8,9-dimethoxy-3- {4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl}-[1,2,4] triazolo [4,3-c ] Quinazolin; 2-({3-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시]-프로필}-메틸아미노)-에탄올 ;2-({3- [4- (8,9-Dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenoxy] -propyl} -methylamino )-ethanol ; 3-[4-(3-이미다졸-1-일-프로폭시)-페닐]-8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;3- [4- (3-imidazol-1-yl-propoxy) -phenyl] -8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin; 9-메톡시-3-페닐-8-(2-피롤리딘-1-일-에톡시)-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-3-phenyl-8- (2-pyrrolidin-1-yl-ethoxy)-[1,2,4] triazolo [4,3-c] quinazolin; 9-메톡시-3-페닐-8-(2-피페리딘-1-일-에톡시)-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-3-phenyl-8- (2-piperidin-1-yl-ethoxy)-[1,2,4] triazolo [4,3-c] quinazoline; 9-메톡시-8-(2-몰폴린-4-일-에톡시)-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-8- (2-morpholin-4-yl-ethoxy) -3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin; 디에틸-[3-(9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린-8-일옥시)-프로필]-아민 ;Diethyl- [3- (9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin-8-yloxy) -propyl] -amine; 9-메톡시-3-페닐-8-(3-피롤리딘-1-일-프로폭시)-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-3-phenyl-8- (3-pyrrolidin-1-yl-propoxy)-[1,2,4] triazolo [4,3-c] quinazolin; 9-메톡시-3-페닐-8-(3-피페리딘-1-일-프로폭시)-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-3-phenyl-8- (3-piperidin-1-yl-propoxy)-[1,2,4] triazolo [4,3-c] quinazolin; 9-메톡시-8-(3-몰폴린-4-일-프로폭시)-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-8- (3-morpholin-4-yl-propoxy) -3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin; 9-메톡시-8-[3-(4-메틸-피페라진-1-일)-프로폭시]-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;9-methoxy-8- [3- (4-methyl-piperazin-1-yl) -propoxy] -3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin; 2-{[3-(9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린-8-일옥시)-프로필]-메틸-아미노}-에탄올 ;2-{[3- (9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin-8-yloxy) -propyl] -methyl-amino} -ethanol ; 8-(3-이미다졸-1-일-프로폭시)-9-메톡시-3-페닐-[1,2,4]트리아졸로[4,3-c]퀴나졸린 ;8- (3-imidazol-1-yl-propoxy) -9-methoxy-3-phenyl- [1,2,4] triazolo [4,3-c] quinazolin; 3-(4-브로모페닐)-8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린;3- (4-bromophenyl) -8,9-dimethoxy- [1,2,4] triazolo [4,3-c] quinazoline; 8,9-디메톡시-3-[4-(2-피롤리딘-1-일-에톡시)-페닐]-[1,2,4]트리아졸로[4,3-c]퀴나졸린; 및8,9-dimethoxy-3- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl]-[1,2,4] triazolo [4,3-c] quinazolin; And {2-[4-(8,9-디메톡시-[1,2,4]트리아졸로[4,3-c]퀴나졸린-3-일)-페녹시]-에틸}-디메틸아민{2- [4- (8,9-Dimethoxy- [1,2,4] triazolo [4,3-c] quinazolin-3-yl) -phenoxy] -ethyl} -dimethylamine 중에서 선택된 것임을 특징으로 하는 화합물.The compound characterized in that it is selected from. 제 1 항에 있어서, 상기 약학적으로 허용 가능한 염이 유리산(free acid); 즉 구연산, 초산, 젖산, 주석산, 말레인산, 푸말리산, 글루콘산, 메탄설폰산, 글리콘산, 숙신산, 4-톨루엔설폰산, 글루투론산, 엠본산, 글루탐산 및 아스파트산 중에서 선택된 유기산이거나, 또는 브롬산, 황산 및 인산 중에서 선택된 무기산인 것임을 특징으로 하는 화합물.The method of claim 1, wherein the pharmaceutically acceptable salt is a free acid; I.e. an organic acid selected from citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid, gluturonic acid, embonic acid, glutamic acid and aspartic acid Or an inorganic acid selected from bromic acid, sulfuric acid and phosphoric acid. 다음 화학식 1로 표시되는 [1,2,4]-트리아졸로[4,3-c]퀴나졸린 유도체, 이의 약제학적 허용 가능한 염, 또는 이의 용매화물이 함유되어 있는 것임은 특징으로 하는 항종양제 조성물 :An anti-tumor agent characterized by containing [1,2,4] -triazolo [4,3-c] quinazolin derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof Composition: [화학식 1][Formula 1] 상기 화학식 1에서, R1, 및 R2는 각각 청구항 1에서 정의한 바와 같다.In Formula 1, R 1 and R 2 are as defined in claim 1, respectively. 제 6 항에 있어서, 결장직장암, 유방암, 폐암, 전립선암, 췌장암, 방광암, 신장암, 백혈병 또는 림프종 치료에 사용되는 것임을 특징으로 하는 조성물.The composition according to claim 6, which is used for treating colorectal cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, bladder cancer, kidney cancer, leukemia or lymphoma. 제 6 항에 있어서, 정제, 캡슐제, 분말제, 또는 주사제로 제형화된 것임을 특징으로 하는 조성물. The composition of claim 6 formulated as a tablet, capsule, powder, or injection.
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