KR20050096574A - 2h-pyrimido[4,5-e][1,2,4]-triazin-3-ylidene-cyanamide derivatives and their preparation - Google Patents

2h-pyrimido[4,5-e][1,2,4]-triazin-3-ylidene-cyanamide derivatives and their preparation Download PDF

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KR20050096574A
KR20050096574A KR1020040021995A KR20040021995A KR20050096574A KR 20050096574 A KR20050096574 A KR 20050096574A KR 1020040021995 A KR1020040021995 A KR 1020040021995A KR 20040021995 A KR20040021995 A KR 20040021995A KR 20050096574 A KR20050096574 A KR 20050096574A
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phenyl
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dioxo
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ylidene
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공영대
이일영
김군도
공재양
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한국화학연구원
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Abstract

본 발명은 수용체 티로신 키나제(RTK)로서의 상피세포 성장인자 수용체(EGFR)와 혈관 내피세포 성장인자(VEGF)에 대해 우수한 억제활성을 가지고 있고, 다음 화학식 1로 표시되는 바와 같이 N-2, N-5, N-7번 위치가 치환된 2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 유도체 및 이의 제조방법에 관한 것이다.The present invention has excellent inhibitory activity against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) as receptor tyrosine kinase (RTK), as shown by the following formula (1) N-2, N- It relates to a 2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide derivative substituted with position 5, N-7 and a preparation method thereof.

상기 화학식 1 에서, R1, R2, 및 R3은 각각 발명의 상세한 설명에서 정의한 바와 같다.In Formula 1, R 1 , R 2 , and R 3 are each as defined in the detailed description of the invention.

Description

2Ｈ-피리도[4,5-ｅ][1,2,4]트리아진-3-일리덴-시안아마이드의 유도체 및 그의 제조방법 {2H-Pyrimido[4,5-e][1,2,4]-triazin-3-ylidene-cyanamide derivatives and their preparation}Derivatives of 2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide and preparation method thereof {2H-Pyrimido [4,5-e] [1,2, 4] -triazin-3-ylidene-cyanamide derivatives and their preparation}

본 발명은 신규 2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 유도체 및 그의 제조방법에 관한 것이다. 더욱 상세하게는 수용체 티로신 키나제(RTK)로서의 상피세포 성장인자 수용체(EGFR)와 혈관 내피세포 성장인자(VEGF)에 대한 우수한 억제활성을 나타내는 N-2, N-5, N-7번 위치가 치환된 2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 유도체와 이의 제조방법에 관한 것이다.The present invention relates to novel 2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide derivatives and methods for their preparation. More specifically, the positions N-2, N-5 and N-7, which show excellent inhibitory activity on epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) as receptor tyrosine kinase (RTK), are substituted. And 2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide derivatives and methods for their preparation.

[화학식 1][Formula 1]

상기 화학식 1에서, R1과 R2는 수소원자, 치환되거나 치환되지 않은 C1 -C10의 알킬기, 치환되거나 치환되지 않은 페닐기, 또는 치환되거나 치환되지 않은 벤질기를 나타내고; R3은 치환되거나 치환되지 않은 페닐기를 나타내고; 상기 치환기는 할로겐원자, 니트로기, C1-C10의 알킬기, C1-C10의 할로알킬기, C1-C10의 알콕시기, 및 C1-C10의 알킬술파닐기 중에서 선택된 하나 또는 둘 이상일 수 있다.In Formula 1, R 1 and R 2 represent a hydrogen atom, a substituted or unsubstituted C 1 -C 10 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group; R 3 represents a substituted or unsubstituted phenyl group; The substituent is one or two selected from halogen atom, nitro group, C 1 -C 10 alkyl group, C 1 -C 10 haloalkyl group, C 1 -C 10 alkoxy group, and C 1 -C 10 alkylsulfanyl group It may be abnormal.

수용체 티로신 키나제(RTK)는 표적 단백질을 인산화하여 세포증식 및 분화를 조절하는 작용을 한다. 수용체 티로신 키나제(RTK)의 대표적인 예로서 상피세포 성장인자 수용체(EGFR, Epidermal Growth Factor Receptor)와 관련된 이레사(Iressa, ZD1839, AstraZeneca)는 비소세포 폐암(NSCLC, Non-Small-Cell Lung Carcinoma) 치료제로서 일본(2002년 7월)과 미국(2003년 5월)에서 판매가 승인된 바도 있다. 그 외에도 여러 후보 물질들이 EGFR를 목표로 임상에 진행 중에 있고, 임상2상 이상에 있는 화합물로는 Cetuximab(IMCLONE사), R3(Center of Molecular Immunology), OSI-774(OSI/Genentech, Roche), GW2016(GlaxoSmithKline), CI-1033(Pfzer), PKI-166(Novatis), EMD-720000(Merck) 등이 있다. 수용체 티로신 키나제(RTK)의 다른 예로서 혈관 내피세포 성장인자(VEGF, vascular endothelial growth factor)와 관련된 ZD-6484(AstraZeneca)는 임상 2상에 있고, CP-547632(Pfizer)와 KRN633(Kirin)은 각각 임상 1 상에 있다.Receptor tyrosine kinases (RTKs) serve to regulate cell proliferation and differentiation by phosphorylating target proteins. As a representative example of receptor tyrosine kinase (RTK), Iressa (ZD1839, AstraZeneca), which is associated with Epidermal Growth Factor Receptor (EGFR), is a non-small cell lung cancer (NSCLC) treatment. It was approved for sale in Japan (July 2002) and the United States (May 2003). In addition, several candidates are in clinical trials targeting EGFR, and the compounds that are in phase 2 or higher are Cetuximab (IMCLONE), R3 (Center of Molecular Immunology), OSI-774 (OSI / Genentech, Roche), GW2016 (GlaxoSmithKline), CI-1033 (Pfzer), PKI-166 (Novatis), EMD-720000 (Merck), and the like. As another example of receptor tyrosine kinase (RTK), ZD-6484 (AstraZeneca), which is associated with vascular endothelial growth factor (VEGF), is in phase 2 clinical trials, and CP-547632 (Pfizer) and KRN633 (Kirin) Each is in phase 1 clinical trials.

6-아자프테리딘(6-azapteridine) 유도체는 항바이러스 활성을 보이는 것이 보고되어 있기는 하나, 이 화합물 계열의 유도체나 제법에 관한 연구는 극히 드물다 (Tayler, E. C., Martin, S. F., J. Org. Chem. 1970, 35, 3792. 2; Tayler, E. C., Sowinski, F. J., Am. Chem. Soc. 1968, 90, 1374). 이와 비슷한 구조로서 천연에서 분리된 7-아자프테리딘(7-Azapteridine) 유도체는 여러 곳에 약리 활성을 보이는 것으로 보고되어 있고, 그 중에서 항생제로서 넓은 약효를 보여 주고 있다. 대표적인 예로 toxoflavin(xanthothricin), reumycin, fervenulin(planomycin) MSD-92 등이 알려져 있다(Nagamatsu, T., Yamasaki, H., Yoneda, F., Heterocycles 1994, 37, 1147).Although 6-azapteridine derivatives have been reported to exhibit antiviral activity, very few studies have been conducted on derivatives or preparations of this compound family (Tayler, EC, Martin, SF, J. Org). Chem . 1970, 35 , 3792. 2; Tayler, EC, Sowinski, FJ, Am. Chem. Soc . 1968, 90 , 1374). In a similar structure, 7-Azapteridine derivatives isolated from nature have been reported to show pharmacological activity in various places, and among them, they have shown wide efficacy as antibiotics. Representative examples are toxoflavin (xanthothricin), reumycin, fervenulin (planomycin) MSD-92, etc. (Nagamatsu, T., Yamasaki, H., Yoneda, F., Heterocycles 1994, 37 , 1147).

또한, N-시안노-구아니딘 유도체 역시 다양한 약효를 보여 주고 있는데, 최근에 N-(5-하이드록시펜틸)-N'-시안노-N"-피리딜구아니딘 화합물은 항암효과를 보이는 것이 보고되었다(국제특허공개 WO 02/85857).In addition, N-cyano-guanidine derivatives also show various effects, and recently, N- (5-hydroxypentyl) -N'-cyano-N "-pyridylguanidine compounds have been reported to have anticancer effects. (International Patent Publication WO 02/85857).

또한, 토미나가(Tominaga) 등은 6-아미노-1,3-디메틸우라실 화합물에 S,S-디메틸-N-시안노디티오이미도카본에이트를 반응시킨 후에 중간체의 분리없이 연속해서 산(acid)을 가하여 5-아미노-1,3-디메틸-7-메틸설파닐-1H-피리도[4,5-d]피리미딘-2,4-디온을 제조하는 방법을 발표한 바 있다(Tominaga, Y. T. et al., Chem. Pharm. Bull. 1984, 32, 122).In addition, Tominaga et al. Reacted 6, amino-1,3-dimethyluracil compound with S, S-dimethyl-N-cyanodithioimidocarbonate and continuously added acid without separation of the intermediate. In addition, a method for preparing 5-amino-1,3-dimethyl-7-methylsulfanyl-1H-pyrido [4,5-d] pyrimidine-2,4-dione has been disclosed (Tominaga, YT et. al., Chem. Pharm. Bull . 1984, 32 , 122).

그러나, 본 발명이 특징으로 하는 상기 화학식 1로 표시되는 화합물 즉, N-시안노-구아니딘기를 갖는 6-아자프테리딘 유도체는 현재까지 문헌에 공개된 바 없는 신규 화합물이다.However, the compound represented by the formula (1) characterized by the present invention, that is, a 6-azapteridine derivative having an N-cyano-guanidine group, is a novel compound that has not been disclosed to date.

본 발명자들은 2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드를 기본골격으로 하면서 의약적으로 유용한 용도를 가지는 신규 화합물을 개발하고자 연구 노력하였다. 그 결과, 6-아미노-1,3-디치환우라실을 출발물질로 사용하고 이를 S,S-디메틸-N-시안노디티오이미도카본에이트와 반응시켜 신규 중간체 화합물을 합성하여 분리하였고, 상기한 신규 중간체 화합물에 디아조늄(R3N2 + )을 가하여 N-2, N-5, N-7번 위치에 다양한 치환기가 치환된 상기 화학식 1로 표시되는 신규 화합물을 합성함으로써 본 발명을 완성하게 되었다.The present inventors have tried to develop a novel compound having a medicinal useful use with 2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide as a basic skeleton. It was. As a result, 6-amino-1,3-disubstituted uracil was used as a starting material and reacted with S, S-dimethyl-N-cyanodithioimidocarbonate to synthesize and isolate a novel intermediate compound. The present invention was completed by adding diazonium (R 3 N 2 + ) to synthesize a novel compound represented by Chemical Formula 1 in which various substituents were substituted at positions N-2, N-5, and N-7.

따라서, 본 발명은 상기 화학식 1로 표시되는 2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 유도체를 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a 2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide derivative represented by Chemical Formula 1.

또한, 본 발명은 상기 화학식 1로 표시되는 화합물이 수용체 티로신 키나제(RTK)로서 상피세포 성장인자 수용체(EGFR)와 혈관 내피세포 성장인자(VEGF)에 대하여 우수한 생물활성을 가지므로, 상기 화학식 1로 표시되는 화합물을 항암제로 사용하는 용도를 제공하는데 다른 목적이 있다.In addition, the present invention is because the compound represented by the formula (1) has excellent biological activity against the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) as receptor tyrosine kinase (RTK), Another object is to provide the use of the compound represented by the anticancer agent.

또한, 본 발명은 상기 화학식 1로 표시되는 화합물 제조에 유용한 신규 중간체와, 이러한 중간체로부터 상기 화학식 1로 표시되는 화합물을 제조하는 방법을 제공하는데 또 다른 목적이 있다. Another object of the present invention is to provide a novel intermediate useful for preparing a compound represented by Chemical Formula 1 and a method for preparing the compound represented by Chemical Formula 1 from the intermediate.

본 발명은 수용체 티로신 키나제(RTK)에 대하여 억제활성을 가지는 다음 화학식 1로 표시되는 2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 유도체 및 이의 약제학적으로 허용 가능한 염을 그 특징으로 한다.The present invention provides 2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide derivatives having the inhibitory activity against receptor tyrosine kinase (RTK) And pharmaceutically acceptable salts thereof.

[화학식 1][Formula 1]

상기 화학식 1에서, R1과 R2는 수소원자, 치환되거나 치환되지 않은 C1 -C10의 알킬기, 치환되거나 치환되지 않은 페닐기, 또는 치환되거나 치환되지 않은 벤질기를 나타내고; R3은 치환되거나 치환되지 않은 페닐기를 나타내고; 상기 치환기는 할로겐원자, 니트로기, C1-C10의 알킬기, C1-C10의 할로알킬기, C1-C10의 알콕시기, 및 C1-C10의 알킬술파닐기 중에서 선택된 하나 또는 둘 이상이다.In Formula 1, R 1 and R 2 represent a hydrogen atom, a substituted or unsubstituted C 1 -C 10 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group; R 3 represents a substituted or unsubstituted phenyl group; The substituent is one or two selected from halogen atom, nitro group, C 1 -C 10 alkyl group, C 1 -C 10 haloalkyl group, C 1 -C 10 alkoxy group, and C 1 -C 10 alkylsulfanyl group That's it.

이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.

본 발명에 따른 상기 화학식 1로 표시되는 2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 유도체의 제조방법을 간략히 표시하면 다음 반응식 1로 나타낼 수 있다. The method for preparing 2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide derivative represented by Chemical Formula 1 according to the present invention is briefly shown in Scheme 1 below. Can be represented.

상기 반응식 1 에서, R1, R2, 및 R3은 각각 상기에서 정의한 바와 같다.In Reaction Scheme 1, R 1 , R 2 , and R 3 are each as defined above.

즉, 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법은That is, the preparation method of the compound represented by Formula 1 according to the present invention

상기 화학식 2로 표시되는 6-아미노-1,3-디치환우라실 화합물에 S,S-디메틸-N-시안노디티오이미도카본에이트를 반응시켜 상기 화학식 3으로 표시되는 1-시안노-3-(1,3-치환-2,6-디옥소-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아를 반응 중간체로 합성하는 과정, 및S-S-dimethyl-N-cyanodithioimidocarbonate is reacted with the 6-amino-1,3-disubstituted uracil compound represented by Formula 2 to form 1-cyano-3- ( Synthesizing 1,3-substituted-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2-methyl-isothiourea as a reaction intermediate, and

상기 화학식 3으로 표시되는 반응 중간체에 디아조늄(R3N2 +)을 가하여 상기 화학식 1로 표시되는 2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 유도체를 합성하는 과정으로 이루어진다.2H-pyrido [4,5-e] [1,2,4] triazine-3-yl represented by Formula 1 by adding diazonium (R 3 N 2 + ) to the reaction intermediate represented by Formula 3 It consists of synthesizing den-cyanamide derivatives.

상기 반응식 1에 따른 제조방법을 보다 구체적으로 설명하면 다음과 같다.Hereinafter, the preparation method according to Scheme 1 will be described in more detail.

본 발명에 따른 제조방법에서 출발물질로 사용하는 상기 화학식 2로 표시되는 6-아미노-1,3-디치환우라실은 공지 화합물로서 문헌(Papesch, V., Schroeder, E. F., J. Org. Chem. 1951, 16, 1879.)에 예시된 방법에 의해 용이하게 합성하여 사용할 수 있다.6-Amino-1,3-disubstituted uracil represented by the formula (2) used as a starting material in the preparation method according to the present invention as a known compound (Papesch, V., Schroeder, EF, J. Org. Chem . 1951, 16 , 1879.) can be easily synthesized by the method illustrated.

먼저, 상기 화학식 2로 표시되는 6-아미노-1,3-디치환우라실을 N,N-디메틸포름아마이드(DMF)와 같은 극성용매에 녹이고, 여기에 S,S-디메틸-N-시안노디티오이미도카본에이트를 가한 후 염기 존재 하에서 100 ℃ 내지 150 ℃ 온도범위에서 수 시간동안 가열하게 되면, 상기 화학식 3으로 표시되는 화합물이 반응 중간체로 합성된다. 본 반응에서 사용되는 S,S-디메틸-N-시안노디티오이미도카본에이트와 염기는 1.0 내지 1.5 당량 범위 내에서 사용한다. 또한, 염기로는 탄산칼륨과 같은 통상의 무기염기 또는 트리에틸아민과 같은 통상의 유기염기를 사용할 수 있다.First, 6-amino-1,3-disubstituted uracil represented by Chemical Formula 2 is dissolved in a polar solvent such as N, N-dimethylformamide (DMF), and S, S-dimethyl-N-cyanodithio 100 in the presence of base after addition of imidocarbonate ℃ 150 When heated for several hours in the ℃ temperature range, the compound represented by the formula (3) is synthesized as a reaction intermediate. S, S-dimethyl-N-cyanodithioimidocarbonate and the base used in this reaction are used within the range of 1.0 to 1.5 equivalents. In addition, as the base, a conventional inorganic base such as potassium carbonate or a conventional organic base such as triethylamine can be used.

그런 다음, 상기 반응으로부터 합성된 상기 화학식 3으로 표시되는 중간체를 N,N-디메틸포름아마이드(DMF)와 같은 극성용매에 녹이고, 여기에 디아조늄(R3N2 +)을 가하여 -10 ℃ 내지 상온 사이에서 반응을 수행하게 되면, 본 발명이 목적하는 상기 화학식 1로 표시되는 화합물을 합성할 수 있다. 본 반응에서 사용되는 디아조늄(R3N2 +)은 공지 화합물로서 이미 알려진 방법(Novinsom, T., Okabe, T. Robins, R. K., Matthews, T. R., J. Med. Chem. 1976, 19, 517.)에 의해 합성하여 사용할 수 있다. 상기 디아조늄(R3N2 +)은 2 내지 5 당량 범위 내에서 사용한다. 상기 반응은 한번에 하나씩 반응시키는 것이 일반적이지만, 필요에 따라 미니블록(miniblock, Bohdan사) 기기를 사용하여 용액 상에서 한번에 10개 이상의 화합물을 반응시켜 합성할 수도 있다.Then, the intermediate represented by Chemical Formula 3 synthesized from the reaction was dissolved in a polar solvent such as N, N-dimethylformamide (DMF), and diazonium (R 3 N 2 + ) was added thereto to add -10. When the reaction is carried out between ℃ and room temperature, it is possible to synthesize a compound represented by the formula (1) of the present invention. Diazonium (R 3 N 2 + ) used in this reaction is a known method (Novinsom, T., Okabe, T. Robins, RK, Matthews, TR, J. Med. Chem. 1976, 19 , 517). It can be used by synthesizing by. The diazonium (R 3 N 2 + ) is used in the range of 2 to 5 equivalents. The reaction is generally reacted one at a time, but if necessary, it may be synthesized by reacting 10 or more compounds at a time in a solution using a miniblock (Bohdan) company.

이상의 제조방법으로부터 합성한 상기 화학식 3으로 표시되는 반응 중간체 또는 상기 화학식 1로 표시되는 목적 화합물은 각각 크로마토그래피와 재결정화와 같은 통상적인 방법에 의하여 분리 및 정제될 수 있다.The reaction intermediate represented by Formula 3 or the target compound represented by Formula 1 may be separated and purified by conventional methods such as chromatography and recrystallization, respectively.

한편, 본 발명의 제조방법을 수행하는데 있어 반응 중간체로 합성되는 상기 화학식 3으로 표시되는 화합물은 신규 화합물인 바, 이에 본 발명은 상기 화학식 3으로 표시되는 신규 중간체를 포함한다. 본 발명이 특징으로 하는 상기 화학식 3으로 표시되는 화합물은 본 발명이 목적으로 하는 상기 화학식 1로 표시되는 화합물이외에도 다양한 고리 화합물을 합성하기 위한 중간체로서 유용하게 사용될 수 있다.On the other hand, in carrying out the preparation method of the present invention, the compound represented by Formula 3 synthesized as a reaction intermediate is a novel compound, and thus the present invention includes a novel intermediate represented by Formula 3. The compound represented by the formula (3) characterized by the present invention can be usefully used as an intermediate for synthesizing various ring compounds in addition to the compound represented by the formula (1) for the purpose of the present invention.

한편, 본 발명에 따른 상기 화학식 1로 표시되는 2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 유도체는 수용체 티로신 키나제(RTK) 구체적으로는 상피세포 성장인자 수용체(EGFR)와 혈관 내피세포 성장인자(VEGF)에 대해 우수한 억제활성을 나타내는 바, 이에 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용 가능한 염을 유효성분으로 함유하는 약제조성물을 포함한다.Meanwhile, the 2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide derivative represented by Formula 1 according to the present invention is specifically a receptor tyrosine kinase (RTK). Shows an excellent inhibitory activity against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), and thus the present invention provides a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. It contains a pharmaceutical composition containing.

본 발명에서 따른 약제학적으로 허용 가능한 염은 당해 기술분야에서 통상적인 방법에 의해 제조될 수 있는 것으로, 예를 들면, 염산, 브롬화수소, 황산, 황산수소나트륨, 인산, 탄산 등의 무기산과의 염 또는 개미산, 초산, 옥살산, 벤조산, 시트르산, 타르타르산, 글루콘산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산(아스피린)과 같은 유기산과 함께 약제학적으로 허용 가능한 이들의 산의 염을 형성하거나, 또는 나트륨, 칼륨 등의 알칼리금속이온과 반응하여 이들의 금속염을 형성하거나, 또는 암모늄 이온과 반응하여 또 다른 형태의 약제학적으로 허용 가능한 염을 형성할 수도 있다.Pharmaceutically acceptable salts according to the present invention can be prepared by conventional methods in the art, for example, salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid, and the like. Or pharmaceutically acceptable organic compounds, such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin) It is also possible to form salts of acids, or to react with alkali metal ions such as sodium and potassium to form their metal salts, or to react with ammonium ions to form another form of a pharmaceutically acceptable salt.

또한, 본 발명의 약제 조성물은 상기 화학식 1로 표시되는 화합물 또는 약제학적으로 허용 가능한 이들의 염에 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 경구투여용 제제 또는 비경구투여용 제제로 제제화할 수 있다. 경구투여에 적합한 제제는 정제, 분말제, 그래뉼제, 캡슐제 등의 고체형 제제; 용액제; 오일성 현탁제; 시럽, 엘릭시르 등과 같은 액제 등이다. 비경구 투여에 적합한 제제는 본 발명의 화합물을 수용성 또는 오일성 현탁액으로 제조하여 주사에 적합하도록 제제화한 것이다. 제제화함에 있어서는, 통상의 부형제, 결합제, 담체, 수용성 용매, 오일성 용매, 유화제, 현탁제 등이 사용될 수 있고, 그 밖에도 기타 첨가제 예를 들면 보존제, 안정제 등이 포함될 수 있다.In addition, the pharmaceutical composition of the present invention is conventional oral administration in the pharmaceutical field by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient to the compound represented by the formula (1) or pharmaceutically acceptable salts thereof It may be formulated as a formulation for parenteral or parenteral administration. Formulations suitable for oral administration include solid dosage forms such as tablets, powders, granules, capsules, and the like; Solution; Oily suspensions; Liquids such as syrups and elixirs. Formulations suitable for parenteral administration are those prepared by injection of the compounds of the invention into aqueous or oily suspensions. In formulating, conventional excipients, binders, carriers, water-soluble solvents, oily solvents, emulsifiers, suspending agents and the like can be used, and other additives such as preservatives, stabilizers and the like can be included.

또한, 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 전술한 바와 같은 질병의 치료 또는 예방을 목적으로 다양한 방법으로 투여할 수 있다. 실제적으로 투여량은 환자의 나이, 몸무게 및 기타 환자의 상태를 고려하여 결정하는 바, 일반적으로 성인남자를 기준으로 경구 투여 시에는 0.05 ∼ 1,000 ㎎/일(바람직하기로는 10 ∼ 1,000 ㎎/일)을 투여하고, 비경구 투여 시에는 0.01 ∼ 300 ㎎/일(바람직하기로는 0.05 ∼ 100 ㎎/일)을 투여한다. 또한, 투여는 하루에 한 번 또는 여러 회에 걸쳐서, 1회의 투여량 또는 여러 번의 투여량으로 복용된다.In addition, the compound represented by Formula 1 according to the present invention can be administered by various methods for the purpose of the treatment or prevention of diseases as described above. In practice, the dosage is determined in consideration of the patient's age, weight and other patient's condition. Generally, 0.05 to 1,000 mg / day (preferably 10 to 1,000 mg / day) for oral administration in adult men. In the case of parenteral administration, 0.01 to 300 mg / day (preferably 0.05 to 100 mg / day) is administered. In addition, the administration is administered in one dose or several doses, once or several times a day.

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.

다음 제조예 1의 방법에 의거하여 다음 표 1에 나타낸 바와 같은 화학식 3으로 표시되는 화합물을 각각 합성하였다.Based on the method of Preparation Example 1, the compound represented by the formula (3) as shown in Table 1 below was synthesized, respectively.

제조예 1. 1-시안노-3-(1,3-디메틸-2,6-디옥소-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 (화합물 3-1).Preparation Example 1 1-Cyano-3- (1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2-methyl-isothio Urea (compound 3-1).

디메틸포름아마이드 290 mL에 6-아미노-1,3-디메틸우라실(15 g, 97 mmol)과 S,S-디메틸-N-시안노이미도디티오카본에이트(19 g, 116 mmol), 탄산칼륨(20 g, 146 mmol)를 가하고 120 ℃에서 5시간 가열하였다. 이에 물 200 mL에 가하고 침전물을 여과하고 MeOH로 재결정하여 상기 표제화합물을 13 g(65%) 얻었다.6-amino-1,3-dimethyluracil (15 g, 97 mmol), S, S-dimethyl-N-cyanoimidodithiocarbonate (19 g, 116 mmol) in 290 mL of dimethylformamide, potassium carbonate ( 20 g, 146 mmol) was added and heated at 120 ° C. for 5 hours. To this was added 200 mL of water, the precipitate was filtered and recrystallized with MeOH to give 13 g (65%) of the title compound.

1H NMR(200 MHz, DMSO-d6) δ 7.95(s, 1H), 5.70(s, 1H), 3.27(s, 3H), 3.10(s, 3H), 2.35(s, 3H). 1 H NMR (200 MHz, DMSO-d 6 ) δ 7.95 (s, 1H), 5.70 (s, 1H), 3.27 (s, 3H), 3.10 (s, 3H), 2.35 (s, 3H).

제조예 2. 1-시안노-3-(1,3-디벤질-2,6-디옥소-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 (화합물 3-2).Preparation Example 2 1-Cyano-3- (1,3-dibenzyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2-methyl-iso Thiourea (Compound 3-2).

1H NMR(200 MHz, DMSO-d6) δ 7.15-7.32(m, 10H) 5.19(s, 2H), 4.95(s, 2H), 2.15(s, 3H). 1 H NMR (200 MHz, DMSO-d 6 ) δ 7.15-7.32 (m, 10H) 5.19 (s, 2H), 4.95 (s, 2H), 2.15 (s, 3H).

제조예 3. 1-시안노-3-(3-벤질-2,6-디옥소-1-메틸-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 (화합물 3-3).Preparation Example 3 1-Cyano-3- (3-benzyl-2,6-dioxo-1-methyl-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2-methyl- Isothiourea (Compound 3-3).

1H NMR(200 MHz, DMSO-d6) δ 7.12-7.38(m, 5H), 5.82(s, 2H), 5.17(s, 2H), 3.09(s, 3H), 2.11(s, 3H). 1 H NMR (200 MHz, DMSO-d 6 ) δ 7.12-7.38 (m, 5H), 5.82 (s, 2H), 5.17 (s, 2H), 3.09 (s, 3H), 2.11 (s, 3H).

제조예 4. 1-시안노-3-(3-벤질-2,6-디옥소-1,2,3,6-테트라하이드로-피리미딘-4- 일)-2-메틸-이소티오우레아 (화합물 3-4).Preparation Example 4 1-Cyano-3- (3-benzyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2-methyl-isothiourea ( Compound 3-4).

1H NMR(200 MHz, DMSO-d6) δ 10.48(s, 1H), 7.13-7.30(m, 5H), 5.63(s, 1H), 5.09(s, 2H), 2.10(s, 3H). 1 H NMR (200 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 7.13-7.30 (m, 5H), 5.63 (s, 1H), 5.09 (s, 2H), 2.10 (s, 3H).

제조예 5. 1-시안노-3-(3-메틸-2,6-디옥소-1,2,3,6-테트라하이드로-피리미딘-4- 일)-2-메틸-이소티오우레아 (화합물 3-5).Preparation Example 1 1-Cyano-3- (3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2-methyl-isothiourea ( Compound 3-5).

1H NMR(200 MHz, DMSO-d6) δ 10.45(s, 1H), 5.51(s 1H), 3.19(s, 3H), 2.34(s, 3H). 1 H NMR (200 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 5.51 (s 1H), 3.19 (s, 3H), 2.34 (s, 3H).

제조예 6. 1-시안노-3-(1-메틸-2,6-디옥소-3-페닐-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 (화합물 3-6).Preparation Example 6. 1-Cyano-3- (1-methyl-2,6-dioxo-3-phenyl-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2-methyl- Isothiourea (compound 3-6).

1H NMR(200 MHz, DMSO-d6) δ 7.21-7.42(m, 3H), 7.05-7.12(m, 2H), 5.99(s 1H), 3.11(s, 3H), 1.50(s, 3H). 1 H NMR (200 MHz, DMSO-d 6 ) δ 7.21-7.42 (m, 3H), 7.05-7.12 (m, 2H), 5.99 (s 1H), 3.11 (s, 3H), 1.50 (s, 3H) .

제조예 7. 1-시안노-3-(2,6-디옥소-3-(4-플르오로-페닐)-1-메틸-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 (화합물 3-7).Preparation Example 7 1-Cyano-3- (2,6-dioxo-3- (4-fluoro-phenyl) -1-methyl-1,2,3,6-tetrahydro-pyrimidine-4- Yl) -2-methyl-isothiourea (compound 3-7).

1H NMR(200 MHz, DMSO-d6) δ 7.20(s, 2H), 7.16(s, 2H), 5.99(s 1H), 3.10(s, 3H), 1.03(s, 3H). 1 H NMR (200 MHz, DMSO-d 6 ) δ 7.20 (s, 2H), 7.16 (s, 2H), 5.99 (s 1H), 3.10 (s, 3H), 1.03 (s, 3H).

제조예 8. 1-시안노-3-(2,6-디옥소-3-(2-플르오로-페닐)-1-메틸-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 (화합물 3-8).Preparation Example 8 1-Cyano-3- (2,6-dioxo-3- (2-fluoro-phenyl) -1-methyl-1,2,3,6-tetrahydro-pyrimidine-4- Yl) -2-methyl-isothiourea (compound 3-8).

1H NMR(200 MHz, DMSO-d6) δ 7.171-7.42(m, 5H), 6.14(s 1H), 3.13(s, 3H), 1.52(s, 3H). 1 H NMR (200 MHz, DMSO-d 6 ) δ 7.171-7.42 (m, 5H), 6.14 (s 1H), 3.13 (s, 3H), 1.52 (s, 3H).

다음 실시예 1의 방법에 의거하여 다음 표 2에 나타낸 바와 같은 화학식 1a로 표시되는 화합물을 각각 합성하였다.Based on the method of Example 1, the compounds represented by the formula (1a) as shown in Table 2 were synthesized, respectively.

실시예 1. 2-(3,5-디메틸-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 1)Example 1. 2- (3,5-Dimethyl-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 1)

미니브럭(Mini block)에 10개의 5 mL 용량의 바이알에 1-시안노-3-(1,3-디메틸-2,6-디옥소-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아(51mg, 0.2mmol)를 디메틸포름이미드 1 mL에 각각 녹이고 온도를 0 ℃로 한 후에 여기에 각기 다른 디아조늄(R3N2 +)을 점적하였다. 이를 상온에서 30분 저어 준 후 저압에서 감압증류하여 용매를 제거 후에 에틸아세테이트:헥산(1:1)으로 컬럼크로마토그라피로 분리하였다. 이때, 디아조늄(R3N2 +) 화합물로서 3,5-디메틸페닐디아조늄을 사용하였다. 상기 디아조늄 화합물은 공지방법(Novinsom, T., Okabe, T. Robins, R. K., Matthews, T. R., J. Med. Chem. 1976, 19, 517.)에 의해 합성하였는 바, 예를 들면 3,5-디메틸아닐린(50.9 μL, 0.4 mmol)을 에탄올(0.5 mL)에 녹이고 여기에 HCl(49 μL, 0.4 mmol)을 가하였다. 여기에 NaNO2(27.6 mg, 0.4 mL)를 물 0.2 mL에 녹여 점적하였다. 이때 생성된 3,5-디메틸페닐디아조늄을 정제 없이 사용하였다. 그 결과 상기 표제화합물을 35 mg (52%) 얻었다.In a 10-mL vial in a mini block 1-cyano-3- (1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine- Dissolve 4-yl) -2-methyl-isothiourea (51 mg, 0.2 mmol) in 1 mL of dimethylformimide, bring the temperature to 0 ° C, and add different diazonium (R 3 N 2 + ) to it. It was. After stirring for 30 minutes at room temperature and distilled under reduced pressure at low pressure to remove the solvent and then separated by column chromatography with ethyl acetate: hexane (1: 1). In this case, 3,5-dimethylphenyldiazonium was used as the diazonium (R 3 N 2 + ) compound. The diazonium compound was synthesized by a known method (Novinsom, T., Okabe, T. Robins, RK, Matthews, TR, J. Med. Chem. 1976, 19 , 517.), for example, 3,5 Dimethylaniline (50.9 μL, 0.4 mmol) was dissolved in ethanol (0.5 mL) and HCl (49 μL, 0.4 mmol) was added thereto. To this was dissolved NaNO 2 (27.6 mg, 0.4 mL) in 0.2 mL of water. The resulting 3,5-dimethylphenyldiazonium was used without purification. As a result, 35 mg (52%) of the title compound were obtained.

1H NMR(200 MHz, CDCl3) δ 7.27-7.53(m, 3H), 3.70(s, 3H), 3.50(s, 3H), 2.39(s, 6H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.27-7.53 (m, 3H), 3.70 (s, 3H), 3.50 (s, 3H), 2.39 (s, 6H).

실시예 2. 2-(3-플르오로-4-메틸-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 2).Example 2. 2- (3-Fluoro-4-methyl-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4, 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 2).

1H NMR(200 MHz, CDCl3) δ 7.30-7.39(m, 3H), 3.71(s, 3H), 3.51(s, 3H), 2.17(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.30-7.39 (m, 3H), 3.71 (s, 3H), 3.51 (s, 3H), 2.17 (s, 3H).

실시예 3. 2-(2-플르오로-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 3).Example 3. 2- (2-Fluoro-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 3).

1H NMR(200 MHz, CDCl3) δ 7.28-7.70(m, 4H), 3.73(s, 3H), 3.52(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.28-7.70 (m, 4H), 3.73 (s, 3H), 3.52 (s, 3H).

실시예 4. 5,7-디메틸-2-(4-메틸술파닐-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 4).Example 4. 5,7-Dimethyl-2- (4-methylsulfanyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 4).

1H NMR(200 MHz, CDCl3) δ 7.48(d, 2H, J=9.0Hz), 7.32(d, 2H, J=9.2Hz), 3.70(s, 3H), 3.50(s, 3H), 2.53(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.48 (d, 2H, J = 9.0 Hz), 7.32 (d, 2H, J = 9.2 Hz), 3.70 (s, 3H), 3.50 (s, 3H), 2.53 (s, 3 H).

실시예 5. 2-(2-브로모-4-메틸-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 5).Example 5. 2- (2-Bromo-4-methyl-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4, 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 5).

1H NMR(200 MHz, CDCl3) δ 7.57(s, 1H), 7.28-7.29(m, 2H), 3.73(s, 3H), 3.51(s, 3H), 2.44(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.57 (s, 1H), 7.28-7.29 (m, 2H), 3.73 (s, 3H), 3.51 (s, 3H), 2.44 (s, 3H).

실시예 6. 2-(4-브로모-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 6).Example 6. 2- (4-Bromo-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 6).

1H NMR(200 MHz, CDCl3) δ 7.67(d, 2H, J=8.9Hz), 7.46(d, 2H, J=8.9Hz), 3.71(s, 3H), 3.51(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.67 (d, 2H, J = 8.9 Hz), 7.46 (d, 2H, J = 8.9 Hz), 3.71 (s, 3H), 3.51 (s, 3H).

실시예 7. 2-(2,6-디플루오로-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 7).Example 7. 2- (2,6-Difluoro-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5 -e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 7).

1H NMR(200 MHz, CDCl3) δ 7.27-7.50(m, 1H), 6.81-6.90(m, 2H), 3.73(s, 3H), 3.51(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.27-7.50 (m, 1H), 6.81-6.90 (m, 2H), 3.73 (s, 3H), 3.51 (s, 3H).

실시예 8. 2-(3-에틸-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 8).Example 8. 2- (3-ethyl-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [ 1,2,4] triazine-3-ylidene-cyanamide (Compound No. 8).

1H NMR(200 MHz, CDCl3) δ 7.71-7.79(m, 1H), 7.30-7.42(m, 3H), 3.67(s, 3H), 3.48(s, 3H), 2.71-2.78(m, 2H), 1.23-1.37(m, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.71-7.79 (m, 1H), 7.30-7.42 (m, 3H), 3.67 (s, 3H), 3.48 (s, 3H), 2.71-2.78 (m, 2H ), 1.23-1.37 (m, 3 H).

실시예 9. 2-(4-플르오로-2-니트로-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 9).Example 9. 2- (4-Fluoro-2-nitro-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4, 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 9).

1H NMR(200 MHz, CDCl3) δ 7.76(d, 1H, J=2.6Hz), 7.31(d, 1H, J=2.8Hz), 7.26-7.28(m, 1H), 3.68(s, 3H), 3.48(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.76 (d, 1H, J = 2.6 Hz), 7.31 (d, 1H, J = 2.8 Hz), 7.26-7.28 (m, 1H), 3.68 (s, 3H) , 3.48 (s, 3 H).

실시예 10. 2-(4-플르오로-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 10).Example 10. 2- (4-Fluoro-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 10).

1H NMR(200 MHz, CDCl3) δ 7.50-7.57(m, 2H), 7.15-7.25(m, 2H), 3.66(s, 3H), 3.48(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.50-7.57 (m, 2H), 7.15-7.25 (m, 2H), 3.66 (s, 3H), 3.48 (s, 3H).

실시예 11. 5,7-디메틸-2-(2-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 11).Example 11. 5,7-dimethyl-2- (2-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [ 1,2,4] triazine-3-ylidene-cyanamide (Compound No. 11).

1H NMR(300 MHz, CDCl3) δ 8.33-8.36(m, 1H), 8.14-8.18(m, 1H), 7.79-7.90(m, 1H), 7.55-7.58(m, 1H), 3.73(s, 3H), 3.52(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.33-8.36 (m, 1H), 8.14-8.18 (m, 1H), 7.79-7.90 (m, 1H), 7.55-7.58 (m, 1H), 3.73 (s , 3H), 3.52 (s, 3H).

실시예 12. 5,7-디메틸-6,8-디옥소-2-(2,4,5-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 12)Example 12. 5,7-Dimethyl-6,8-dioxo-2- (2,4,5-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4, 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 12)

1H NMR(300 MHz, CDCl3) δ 7.70(s, 1H), 7.56(s, 1H), 3.66(s, 3H), 3.51(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.70 (s, 1H), 7.56 (s, 1H), 3.66 (s, 3H), 3.51 (s, 3H).

실시예 13. 5,7-디메틸-6,8-디옥소-2-(2,3,4-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 13).Example 13. 5,7-Dimethyl-6,8-dioxo-2- (2,3,4-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4, 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 13).

1H NMR(300 MHz, CDCl3) δ 7.53-7.61(m, 1H), 7.33-7.43(m, 1H), 3.73(s, 3H), 3.54(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.53-7.61 (m, 1H), 7.33-7.43 (m, 1H), 3.73 (s, 3H), 3.54 (s, 3H).

실시예 14. 5,7-디메틸-6,8-디옥소-2-(2,4,6-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 14).Example 14 5,7-Dimethyl-6,8-dioxo-2- (2,4,6-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4, 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 14).

1H NMR(300 MHz, CDCl3) δ 7.53(s, 1H), 7.27(s, 1H), 3.73(s, 3H), 3.51(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.53 (s, 1H), 7.27 (s, 1H), 3.73 (s, 3H), 3.51 (s, 3H).

실시예 15. 5,7-디메틸-6,8-디옥소-2-(4-니트로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 15).Example 15. 5,7-Dimethyl-6,8-dioxo-2- (4-nitro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [ 1,2,4] triazine-3-ylidene-cyanamide (Compound No. 15).

1H NMR(200 MHz, CDCl3) δ 8.41(d, J=10.0Hz, 2H), 7.85(d, J=10.0Hz, 2H), 3.73(s, 3H), 3.52(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 8.41 (d, J = 10.0 Hz, 2H), 7.85 (d, J = 10.0 Hz, 2H), 3.73 (s, 3H), 3.52 (s, 3H).

실시예 16. 5,7-디메틸-6,8-디옥소-2-(4-클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 16).Example 16. 5,7-Dimethyl-6,8-dioxo-2- (4-chloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [ 1,2,4] triazine-3-ylidene-cyanamide (Compound No. 16).

1H NMR(200 MHz, CDCl3) δ 7.51-7.59(m, 4H), 3.71(s, 3H), 3.51(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.51-7.59 (m, 4H), 3.71 (s, 3H), 3.51 (s, 3H).

실시예 17. 5,7-디메틸-6,8-디옥소-2-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 17).Example 17. 5,7-Dimethyl-6,8-dioxo-2-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] Triazine-3-ylidene-cyanamide (Compound No. 17).

1H NMR(200 MHz, CDCl3) δ 7.52(s, 5H), 3.67(s, 3H), 3.48(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.52 (s, 5H), 3.67 (s, 3H), 3.48 (s, 3H).

실시예 18. 5,7-디메틸-6,8-디옥소-2-(4-트리플르오로메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 18).Example 18. 5,7-Dimethyl-6,8-dioxo-2- (4-trifluoromethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5 -e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 18).

1H NMR(200 MHz, CDCl3) δ 7.60-7.67(d, J=10.2Hz, 2H), 7.37(d, J=10.1Hz, 2H), 3.66(s, 3H), 3.44(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.60-7.67 (d, J = 10.2 Hz, 2H), 7.37 (d, J = 10.1 Hz, 2H), 3.66 (s, 3H), 3.44 (s, 3H) .

실시예 19. 5,7-디메틸-6,8-디옥소-2-(3,4,5-트리메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 19).Example 19. 5,7-Dimethyl-6,8-dioxo-2- (3,4,5-trimethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4 , 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 19).

1H NMR(200 MHz, CDCl3) δ 6.73(s, 2H), 3.87(s, 9H), 3.69(s, 3H), 3.50(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 6.73 (s, 2H), 3.87 (s, 9H), 3.69 (s, 3H), 3.50 (s, 3H).

실시예 20. 5,7-디메틸-6,8-디옥소-2-p-톨릴-5,6,7,8-테트라하이드로-2H-피리도 [4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 20).Example 20. 5,7-Dimethyl-6,8-dioxo-2-p-tolyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2, 4] triazine-3-ylidene-cyanamide (Compound No. 20).

1H NMR(200 MHz, CDCl3) δ 7.26-7.45(m, 4H), 3.68(s, 3H), 3.49(s, 3H), 2.43(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.26-7.45 (m, 4H), 3.68 (s, 3H), 3.49 (s, 3H), 2.43 (s, 3H).

다음의 실시예 21 내지 38에서는 상기 실시예 1의 방법에 의해 수행하되, 1-시안노-3-(1,3-디벤질-2,6-디옥소-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아와, 다음 표 3에 나타낸 R3 치환기를 포함하는 디아조늄(R3N2 +) 화합물을 사용하여 각각의 표제화합물을 합성하였다.In Examples 21 to 38 which are carried out by the method of Example 1, 1-cyano-3- (1,3-dibenzyl-2,6-dioxo-1,2,3,6-tetra Each title compound was synthesized using hydropyrimidin-4-yl) -2-methyl-isothiourea and a diazonium (R 3 N 2 + ) compound comprising the R 3 substituents shown in Table 3 below. .

실시예 21. 5,7-디벤질-2-(4-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 21).Example 21. 5,7-Dibenzyl-2- (4-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 21).

1H NMR(200 MHz, CDCl3) δ 7.71(d, 2H, J=1.5Hz), 7.49(d, 2H, J=1.8Hz), 7.31-7.38(m, 10H), 5.44(s, 2H), 5.25(s, 2H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.71 (d, 2H, J = 1.5 Hz), 7.49 (d, 2H, J = 1.8 Hz), 7.31-7.38 (m, 10H), 5.44 (s, 2H) , 5.25 (s, 2 H).

실시예 22. 5,7-디벤질-6,8-디옥소-2-(3,4,5-트리메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 22).Example 22. 5,7-Dibenzyl-6,8-dioxo-2- (3,4,5-trimethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [ 4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 22).

1H NMR(300 MHz, CDCl3) δ 7.73-7.76(m, 2H), 7.49-7.52(m, 2H), 7.32-7.38(m, 6H), 6.72(s, 2H), 5.43(s, 2H), 5.24(s, 2H), 3.88(s, 3H), 3.85(s, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.73-7.76 (m, 2H), 7.49-7.52 (m, 2H), 7.32-7.38 (m, 6H), 6.72 (s, 2H), 5.43 (s, 2H ), 5.24 (s, 2H), 3.88 (s, 3H), 3.85 (s, 6H).

실시예 23. 5,7-디벤질-2-(4-브로모-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 23).Example 23. 5,7-Dibenzyl-2- (4-bromo-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 23).

1H NMR(300 MHz, CDCl3) δ 7.72(d, 2H, J=6.3Hz), 7.62(d, 2H, J=8.7Hz), 7.31-7.50(m, 10H), 5.40(s, 2H), 5.22(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.72 (d, 2H, J = 6.3 Hz), 7.62 (d, 2H, J = 8.7 Hz), 7.31-7.50 (m, 10H), 5.40 (s, 2H) , 5.22 (s, 2 H).

실시예 24. 5,7-디벤질-2-(4-클로로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 24).Example 24. 5,7-Dibenzyl-2- (4-chloro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 24).

1H NMR(300 MHz, CDCl3) δ 7.74(d, 2H, J=1.5Hz), 7.51(d, 2H, J=3.0Hz), 7.26-7.40(m, 10H), 5.41(s, 2H), 5.23(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.74 (d, 2H, J = 1.5 Hz), 7.51 (d, 2H, J = 3.0 Hz), 7.26-7.40 (m, 10H), 5.41 (s, 2H) , 5.23 (s, 2 H).

실시예 25. 5,7-디벤질-2-(2-플르오로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 25).Example 25. 5,7-Dibenzyl-2- (2-fluoro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 25).

1H NMR(300 MHz, CDCl3) δ 7.74-7.76(m, 2H), 7.50-7.55(m, 2H), 6.23-7.41(m, 10H), 5.43(s, 2H), 5.24(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.74-7.76 (m, 2H), 7.50-7.55 (m, 2H), 6.23-7.41 (m, 10H), 5.43 (s, 2H), 5.24 (s, 2H ).

실시예 26. 5,7-디벤질-2-(3-에틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 26).Example 26. 5,7-Dibenzyl-2- (3-ethyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 26).

1H NMR(300 MHz, CDCl3) δ 7.74-7.77(m, 2H), 7.49-7.52(m, 2H), 7.30-7.44(m, 10H), 5.43(s, 2H), 5.24(s, 2H), 2.71(m, 2H), 1.13(t, 3H, J=7.5Hz). 1 H NMR (300 MHz, CDCl 3 ) δ 7.74-7.77 (m, 2H), 7.49-7.52 (m, 2H), 7.30-7.44 (m, 10H), 5.43 (s, 2H), 5.24 (s, 2H ), 2.71 (m, 2H), 1.13 (t, 3H, J = 7.5 Hz).

실시예 27. 5,7-디벤질-2-(5-플르오로-2-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 27).Example 27. 5,7-Dibenzyl-2- (5-fluoro-2-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4 , 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 27).

1H NMR(300 MHz, CDCl3) δ 7.71-7.76(m, 3H), 7.49-7.52(m, 3H), 7.27-7.38(m, 7H), 5.42(s, 2H), 5.23(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.71-7.76 (m, 3H), 7.49-7.52 (m, 3H), 7.27-7.38 (m, 7H), 5.42 (s, 2H), 5.23 (s, 2H ).

실시예 28. 5,7-디벤질-2-(4-플르오로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 28).Example 28. 5,7-Dibenzyl-2- (4-fluoro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 28).

1H NMR(300 MHz, CDCl3) δ 7.72-7.74(m, 2H), 7.48-7.54(m, 4H), 7.31-7.37(m, 6H), 7.18-7.26(m, 2H), 5.41(s, 2H), 5.23(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.72-7.74 (m, 2H), 7.48-7.54 (m, 4H), 7.31-7.37 (m, 6H), 7.18-7.26 (m, 2H), 5.41 (s , 2H), 5.23 (s, 2H).

실시예 29. 5,7-디벤질-2-(2-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 29).Example 29. 5,7-Dibenzyl-2- (2-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 29).

1H NMR(300 MHz, CDCl3) δ 8.30-8.33(m, 1H), 7.71-7.86(m, 4H), 7.49-7.53(m, 3H), 7.33-7.38(m, 6H), 5.43(s, 2H), 5.23(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.30-8.33 (m, 1H), 7.71-7.86 (m, 4H), 7.49-7.53 (m, 3H), 7.33-7.38 (m, 6H), 5.43 (s , 2H), 5.23 (s, 2H).

실시예 30. 5,7-디벤질-6,8-디옥소-2-(2,4,5-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 30).Example 30. 5,7-Dibenzyl-6,8-dioxo-2- (2,4,5-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4 , 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 30).

1H NMR(300 MHz, CDCl3) δ 7.68-7.75(m, 2H), 7.50-7.58(m, 3H), 7.33-7.39(m, 7H), 5.43(s, 2H), 5.23(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.68-7.75 (m, 2H), 7.50-7.58 (m, 3H), 7.33-7.39 (m, 7H), 5.43 (s, 2H), 5.23 (s, 2H ).

실시예 31. 5,7-디벤질-6,8-디옥소-2-(2,3,4-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 31).Example 31. 5,7-Dibenzyl-6,8-dioxo-2- (2,3,4-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4 , 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 31).

1H NMR(300 MHz, CDCl3) δ 7.72-7.75(m, 2H), 7.50-7.58(m, 3H), 7.33-7.39(m, 7H), 5.45(s, 2H), 5.23(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.72-7.75 (m, 2H), 7.50-7.58 (m, 3H), 7.33-7.39 (m, 7H), 5.45 (s, 2H), 5.23 (s, 2H ).

실시예 32. 5,7-디벤질-6,8-디옥소-2-(4-트리플르오로메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 32).Example 32. 5,7-Dibenzyl-6,8-dioxo-2- (4-trifluoromethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4, 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 32).

1H NMR(300 MHz, CDCl3) δ 7.74(d, 2H, J=6.3Hz), 7.60(d, 2H, J=8.7Hz), 7.49-7.51(m, 2H), 7.32-7.38(m, 8H), 5.43(s, 2H), 5.24(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.74 (d, 2H, J = 6.3 Hz), 7.60 (d, 2H, J = 8.7 Hz), 7.49-7.51 (m, 2H), 7.32-7.38 (m, 8H), 5.43 (s, 2H), 5.24 (s, 2H).

실시예 33. 5,7-디벤질-2-(4-메톡시-2-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 33).Example 33. 5,7-Dibenzyl-2- (4-methoxy-2-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4 , 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 33).

1H NMR(300 MHz, CDCl3) δ 7.72-7.90(m, 3H), 7.42-7.65(m, 2H), 7.33-7.38(m, 8H), 5.42(s, 2H), 5.23(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.72-7.90 (m, 3H), 7.42-7.65 (m, 2H), 7.33-7.38 (m, 8H), 5.42 (s, 2H), 5.23 (s, 2H ).

실시예 34. 5,7-디벤질-2-(3,5-디메틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 34).Example 34. 5,7-Dibenzyl-2- (3,5-dimethyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 34).

1H NMR(300 MHz, CDCl3) δ 7.52-7.77(m, 2H), 7.34-7.44(m, 6H), 7.30-7.33(m, 3H), 6.99-7.26(m, 2H), 5.43(s, 2H), 5.24(s, 2H), 1.52(s, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.52-7.77 (m, 2H), 7.34-7.44 (m, 6H), 7.30-7.33 (m, 3H), 6.99-7.26 (m, 2H), 5.43 (s , 2H), 5.24 (s, 2H), 1.52 (s, 6H).

실시예 35. 5,7-디벤질-2-(3-플르오로-4-메틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 35).Example 35. 5,7-Dibenzyl-2- (3-fluoro-4-methyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4 , 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 35).

1H NMR(300 MHz, CDCl3) δ 7.72-7.75(m, 2H), 7.49-7.52(m, 2H), 7.26-7.38(m, 9H), 5.42(s, 2H), 5.24(s, 2H), 2.17(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.72-7.75 (m, 2H), 7.49-7.52 (m, 2H), 7.26-7.38 (m, 9H), 5.42 (s, 2H), 5.24 (s, 2H ), 2.17 (s, 3 H).

실시예 36. 5,7-디벤질-2-(4-메틸술파닐-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로 -2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 36).Example 36. 5,7-Dibenzyl-2- (4-methylsulfanyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 36).

1H NMR(300 MHz, CDCl3) δ 7.73(d, 2H, J=6.7Hz), 7.42-7.50(m, 6H), 7.26-7.39(m, 6H), 5.40(s, 2H), 5.21(s, 2H), 2.50(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.73 (d, 2H, J = 6.7 Hz), 7.42-7.50 (m, 6H), 7.26-7.39 (m, 6H), 5.40 (s, 2H), 5.21 ( s, 2H), 2.50 (s, 3H).

실시예 37. 5,7-디벤질-2-(2-브로모-6-메틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 37).Example 37. 5,7-Dibenzyl-2- (2-bromo-6-methyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4 , 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 37).

1H NMR(300 MHz, CDCl3) δ 7.74-7.77(m, 2H), 7.51-7.54(m, 3H), 7.35-7.41(m, 6H), 7.20-7.33(m, 2H), 5.45(s, 2H), 5.23(s, 2H), 2.42(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.74-7.77 (m, 2H), 7.51-7.54 (m, 3H), 7.35-7.41 (m, 6H), 7.20-7.33 (m, 2H), 5.45 (s , 2H), 5.23 (s, 2H), 2.42 (s, 3H).

실시예 38. 5,7-디벤질-2-(3,5-디플르오로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 38).Example 38. 5,7-Dibenzyl-2- (3,5-difluoro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4, 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 38).

1H NMR(300 MHz, CDCl3) δ 7.75(d, 2H, J=6,7Hz), 7.43-7.56(m, 3H), 7.33-7.42(m, 6H), 7.08-7.26(m, 2H), 5.44(s, 2H), 5.23(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.75 (d, 2H, J = 6,7 Hz), 7.43-7.56 (m, 3H), 7.33-7.42 (m, 6H), 7.08-7.26 (m, 2H) , 5.44 (s, 2 H), 5.23 (s, 2 H).

다음의 실시예 39 내지 58에서는 상기 실시예 1의 방법에 의해 수행하되, 1-시안노-3-(1-메틸-2,6-디옥소-3-페닐-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아와, 다음 표 4에 나타낸 R3 치환기를 포함하는 디아조늄(R3N 2 +) 화합물을 사용하여 각각의 표제화합물을 합성하였다.In Examples 39 to 58, which were carried out by the method of Example 1, except that 1-cyano-3- (1-methyl-2,6-dioxo-3-phenyl-1,2,3,6- Each title compound was synthesized using tetrahydro-pyrimidin-4-yl) -2-methyl-isothiourea and a diazonium (R 3 N 2 + ) compound comprising the R 3 substituent shown in Table 4 below. It was.

실시예 39. 7-메틸-6,8-디옥소-2,5-디페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 39).Example 39. 7-Methyl-6,8-dioxo-2,5-diphenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4 ] Triazine-3-ylidene-cyanamide (Compound No. 39).

1H NMR(300 MHz, CDCl3) δ 7.50-7.62(m, 6H), 7.29-7.32(m, 4H), 3.54(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.50-7.62 (m, 6H), 7.29-7.32 (m, 4H), 3.54 (s, 3H).

실시예 40. 7-메틸-2-(4-니트로-페닐)-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 40).Example 40. 7-Methyl-2- (4-nitro-phenyl) -6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 40).

1H NMR(300 MHz, CDCl3) δ 8.41(d, 2H, J=2.4Hz), 8.30(d, 2H, J=1.8Hz), 7.83-7,86(m, 2H), 7.56-7.61(m, 3H), 3.55(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.41 (d, 2H, J = 2.4 Hz), 8.30 (d, 2H, J = 1.8 Hz), 7.83-7,86 (m, 2H), 7.56-7.61 ( m, 3H), 3.55 (s, 3H).

실시예 41. 7-메틸-6,8-디옥소-5-페닐-2-(3,4,5-트리메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 41).Example 41. 7-Methyl-6,8-dioxo-5-phenyl-2- (3,4,5-trimethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 41).

1H NMR(300 MHz, CDCl3) δ 7.56-7.59(m, 3H), 7.27-7.30(m, 2H), 6.74(s, 2H), 3.95(s, 3H), 3.86(s, 6H), 3.53(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.56-7.59 (m, 3H), 7.27-7.30 (m, 2H), 6.74 (s, 2H), 3.95 (s, 3H), 3.86 (s, 6H), 3.53 (s, 3 H).

실시예 42. 2-(3,5-디메틸-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 42).Example 42. 2- (3,5-Dimethyl-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5 -e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 42).

1H NMR(300 MHz, CDCl3) δ 7.50-7.57(m, 6H), 7.11-7.13(m, 2H), 3.55(s, 3H), 2.34(s, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.50-7.57 (m, 6H), 7.11-7.13 (m, 2H), 3.55 (s, 3H), 2.34 (s, 6H).

실시예 43. 2-(3-플르오로-4-메틸-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 43).Example 43. 2- (3-Fluoro-4-methyl-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [ 4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 43).

1H NMR(300 MHz, CDCl3) δ 7.57(s, 4H), 7.29-7.33(m, 4H), 3.55(s, 3H), 2.35(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.57 (s, 4H), 7.29-7.33 (m, 4H), 3.55 (s, 3H), 2.35 (s, 3H).

실시예 44. 2-(2-플르오로-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 44).Example 44. 2- (2-Fluoro-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 44).

1H NMR(300 MHz, CDCl3) δ 7.54-7.60(m, 5H), 7.31-7.43(m, 4H), 3.55(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.54-7.60 (m, 5H), 7.31-7.43 (m, 4H), 3.55 (s, 3H).

실시예 45. 7-메틸-2-(4-메틸술파닐-페닐)-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 45).Example 45. 7-Methyl-2- (4-methylsulfanyl-phenyl) -6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5 -e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 45).

1H NMR(300 MHz, CDCl3) δ 7.47-7.59(m, 5H), 7.28-7.34(m, 4H), 3.55(s, 3H), 2.55(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.47-7.59 (m, 5H), 7.28-7.34 (m, 4H), 3.55 (s, 3H), 2.55 (s, 3H).

실시예 46. 2-(2-브로모-6-메틸-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 46).Example 46. 2- (2-Bromo-6-methyl-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [ 4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 46).

1H NMR(300 MHz, CDCl3) δ 7,52-7,62(m, 3H), 7.247.33(m, 5H), 3.54(s, 3H), 2.43(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7,52-7,62 (m, 3H), 7.247.33 (m, 5H), 3.54 (s, 3H), 2.43 (s, 3H).

실시예 47. 2-(4-브로모-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 47).Example 47. 2- (4-Bromo-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 47).

1H NMR(300 MHz, CDCl3) δ 7.57-7.68(m, 3H), 7.48-7.54(m, 6H), 3.55(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.57-7.68 (m, 3H), 7.48-7.54 (m, 6H), 3.55 (s, 3H).

실시예 48. 2-(4-클로로-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 48).Example 48. 2- (4-Chloro-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 48).

1H NMR(300 MHz, CDCl3) δ 7.51-7.60(m, 9H), 3.55(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.51-7.60 (m, 9H), 3.55 (s, 3H).

실시예 49. 2-(2,6-디플르오로-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 49).Example 49. 2- (2,6-Difluoro-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4 , 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 49).

1H NMR(300 MHz, CDCl3) δ 7.55-7.60(m, 3H), 7.39-7.45(m, 1H), 7.32-7.35(m, 2H), 6.84(t, 2H, J=8.6Hz), 3.54(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.55-7.60 (m, 3H), 7.39-7.45 (m, 1H), 7.32-7.35 (m, 2H), 6.84 (t, 2H, J = 8.6 Hz), 3.54 (s, 3 H).

실시예 50. 2-(2,6-디프로필-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 50).Example 50. 2- (2,6-Dipropyl-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4, 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 50).

1H NMR(300 MHz, CDCl3) δ 7.47-7.62(m, 6H), 7.29-7.35(m, 2H), 7.01-7.07(m, 4H) 3.57(s, 3H), 3.25(s, 3H), 2.67(s, 4H), 1.14-1.28(m, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.47-7.62 (m, 6H), 7.29-7.35 (m, 2H), 7.01-7.07 (m, 4H) 3.57 (s, 3H), 3.25 (s, 3H) , 2.67 (s, 4 H), 1.14-1.28 (m, 6 H).

실시예 51. 2-(3-에틸-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 51).Example 51. 2- (3-Ethyl-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 51).

1H NMR(300 MHz, CDCl3) δ 7.54-7.58(m, 3H), 7.28-7.35(m, 6H), 3.54(s, 3H), 2.73(q. 2H, J=7.6Hz), 1.23-1.29(m, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.54-7.58 (m, 3H), 7.28-7.35 (m, 6H), 3.54 (s, 3H), 2.73 (q. 2H, J = 7.6 Hz), 1.23- 1.29 (m, 3 H).

실시예 52. 2-(4-플르오로-2-니트로-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 52).Example 52. 2- (4-Fluoro-2-nitro-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [ 4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 52).

1H NMR(300 MHz, CDCl3) δ 7.74(s, 1H), 7.52-7.54(m, 3H), 7.29-7.39(m, 4H), 3.50(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.74 (s, 1H), 7.52-7.54 (m, 3H), 7.29-7.39 (m, 4H), 3.50 (s, 3H).

실시예 53. 2-(4-플르오로-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 53).Example 53. 2- (4-Fluoro-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 53).

1H NMR(300 MHz, CDCl3) δ 7.54-7.59(m, 6H), 7.18-7.31(m, 3H), 3.55(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.54-7.59 (m, 6H), 7.18-7.31 (m, 3H), 3.55 (s, 3H).

실시예 54. 7-메틸-2-(2-니트로-페닐)-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 54).Example 54. 7-Methyl-2- (2-nitro-phenyl) -6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 54).

1H NMR(300 MHz, CDCl3) δ 8.31-8.34(m, 1H), 7.77-7.88(m, 2H), 7.54-7.59(m, 4H), 7.30-7.33(m, 2H), 3.55(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.31-8.34 (m, 1H), 7.77-7.88 (m, 2H), 7.54-7.59 (m, 4H), 7.30-7.33 (m, 2H), 3.55 (s , 3H).

실시예 55. 7-메틸-6,8-디옥소-5-페닐-2-(2,4,5-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 55).Example 55. 7-Methyl-6,8-dioxo-5-phenyl-2- (2,4,5-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [ 4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 55).

1H NMR(300 MHz, CDCl3) δ 7.47-7.60(m, 5H), 7.29(s, 2H), 3.56(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.47-7.60 (m, 5H), 7.29 (s, 2H), 3.56 (s, 3H).

실시예 56. 7-메틸-6,8-디옥소-5-페닐-2-(2,3,4-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 56).Example 56. 7-Methyl-6,8-dioxo-5-phenyl-2- (2,3,4-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [ 4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 56).

1H NMR (300 MHz, CDCl3) δ 7.53-7.60(m, 3H), 7.39-7.42(m, 1H), 7.28-7.33(m, 3H), 3.55(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.53-7.60 (m, 3H), 7.39-7.42 (m, 1H), 7.28-7.33 (m, 3H), 3.55 (s, 3H).

실시예 57. 7-메틸-6,8-디옥소-5-페닐-2-(2,4,6-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드(화합물번호 57).Example 57. 7-Methyl-6,8-dioxo-5-phenyl-2- (2,4,6-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [ 4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 57).

1H NMR (300 MHz, CDCl3) δ 7.40-7.62(m, 5H), 7.29-7.32(m, 2H), 3.55(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.40-7.62 (m, 5H), 7.29-7.32 (m, 2H), 3.55 (s, 3H).

실시예 58. 7-메틸-6,8-디옥소-5-페닐-2-(4-트리플르오로메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드(화합물번호 58).Example 58. 7-Methyl-6,8-dioxo-5-phenyl-2- (4-trifluoromethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4 , 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 58).

1H NMR (300 MHz, CDCl3) δ 7.57-7.65(m, 6H), 7.37(d, 2H, J=9.0Hz), 7.31(d, 2H, J=2.1Hz), 3.55(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.57-7.65 (m, 6H), 7.37 (d, 2H, J = 9.0 Hz), 7.31 (d, 2H, J = 2.1 Hz), 3.55 (s, 3H) .

다음의 실시예 59 내지 72에서는 상기 실시예 1의 방법에 의해 수행하되, 1-시안노-3-(3-벤질-2,6-디옥소-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아와, 다음 표 5에 나타낸 R3 치환기를 포함하는 디아조늄(R3N2 +) 화합물을 사용하여 각각의 표제화합물을 합성하였다.In Examples 59 to 72 which are carried out by the method of Example 1, 1-cyano-3- (3-benzyl-2,6-dioxo-1,2,3,6-tetrahydro-pyri Each title compound was synthesized using a midin-4-yl) -2-methyl-isothiourea and a diazonium (R 3 N 2 + ) compound comprising an R 3 substituent shown in Table 5 below.

실시예 59. 5-벤질-2-(4-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드(화합물번호 59).Example 59. 5-benzyl-2- (4-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 59).

1H NMR (300 MHz, CDCl3) δ 8.38-8.41(m, 2H), 7.84-7.87(m,2H), 7.70-7.73(m, 2H), 7.35-7.40(m, 4H), 5.39(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.38-8.41 (m, 2H), 7.84-7.87 (m, 2H), 7.70-7.73 (m, 2H), 7.35-7.40 (m, 4H), 5.39 (s , 2H).

실시예 60. 5-벤질-2-(2-플르오로-4-메틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드(화합물번호 60).Example 60. 5-benzyl-2- (2-fluoro-4-methyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 60).

1H NMR (300 MHz, CDCl3) δ 7.73-7.75(m, 2H), 7.24-7.42(m, 5H), 6.37-6.40(m, 1H), 5.37(s, 2H), 2.21(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.73-7.75 (m, 2H), 7.24-7.42 (m, 5H), 6.37-6.40 (m, 1H), 5.37 (s, 2H), 2.21 (s, 3H ).

실시예 61. 5-벤질-2-(2-플르오로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드(화합물번호 61).Example 61. 5-benzyl-2- (2-fluoro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanide (Compound No. 61).

1H NMR (300 MHz, CDCl3) δ 7.48-7.76(d, 2H, J=6.6Hz), 7.24-7.43(m, 6H), 6.93-7.00(m, 2H), 5.38(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.48-7.76 (d, 2H, J = 6.6 Hz), 7.24-7.43 (m, 6H), 6.93-7.00 (m, 2H), 5.38 (s, 2H).

실시예 62. 5-벤질-2-(4-메틸술파닐-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드(화합물번호 62).Example 62. 5-benzyl-2- (4-methylsulfanyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [ 1,2,4] triazine-3-ylidene-cyanamide (Compound No. 62).

1H NMR (300 MHz, CDCl3) δ 7.48-7.74(m, 2H), 7.18-7.48(m, 6H), 6.66-6.69(m, 1H), 5.36(s, 2H), 2.48(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.48-7.74 (m, 2H), 7.18-7.48 (m, 6H), 6.66-6.69 (m, 1H), 5.36 (s, 2H), 2.48 (s, 3H ).

실시예 63. 5-벤질-2-(2-브로모-6-메틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드(화합물번호 63).Example 63. 5-benzyl-2- (2-bromo-6-methyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 63).

1H NMR (300 MHz, CDCl3) δ 8.03(s, 2H), 7.73-7.76 (m, 2H), 7.25-7.39(m, 4H), 5.37(s, 2H), 2.34(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.03 (s, 2H), 7.73-7.76 (m, 2H), 7.25-7.39 (m, 4H), 5.37 (s, 2H), 2.34 (s, 3H).

실시예 64. 5-벤질-2-(4-브로모-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드(화합물번호 64).Example 64. 5-benzyl-2- (4-bromo-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanamide (Compound No. 64).

1H NMR (300 MHz, CDCl3) δ 7.63-7.61(m, 1H), 7.61-7.75(m, 1H), 7.21-7.45(m, 5H), 6.55-6.57(m, 2H), 5.36(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.63-7.61 (m, 1H), 7.61-7.75 (m, 1H), 7.21-7.45 (m, 5H), 6.55-6.57 (m, 2H), 5.36 (s , 2H).

실시예 65. 5-벤질-2-(4-클로로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 65).Example 65. 5-benzyl-2- (4-chloro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanamide (Compound No. 65).

1H NMR(300 MHz, CDCl3) δ 7.73-7.75(d, 1H), 7.32-7.75(m, 4H), 7.07-7.11(m, 2H), 6.59-6.63(m, 2H), 5.38(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.73-7.75 (d, 1H), 7.32-7.75 (m, 4H), 7.07-7.11 (m, 2H), 6.59-6.63 (m, 2H), 5.38 (s , 2H).

실시예 66. 5-벤질-2-(3-에틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도 [4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 66).Example 66. 5-benzyl-2- (3-ethyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 66).

1H NMR(300 MHz, CDCl3) δ 7.66-8.02(m, 2H), 7.32-7.43(m, 7H), 5.38(s, 2H), 4.11-4.16(m, 2H), 1.20-1.35(m, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.66-8.02 (m, 2H), 7.32-7.43 (m, 7H), 5.38 (s, 2H), 4.11-4.16 (m, 2H), 1.20-1.35 (m , 3H).

실시예 67. 5-벤질-2-(4-플르오로-4-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 67).Example 67. 5-benzyl-2- (4-fluoro-4-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 67).

1H NMR(300 MHz, CDCl3) δ 7.48-7.73(m, 3H), 7.30-7.38(m, 5H), 5.40(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.48-7.73 (m, 3H), 7.30-7.38 (m, 5H), 5.40 (s, 2H).

실시예 68. 5-벤질-2-(4-플르오로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 68).Example 68. 5-benzyl-2- (4-fluoro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanamide (Compound No. 68).

1H NMR(300 MHz, CDCl3) δ 7.74-7.76(m, 2H), 7.53-7.57(m, 2H), 7.18-7.40(m, 5H), 5.41(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.74-7.76 (m, 2H), 7.53-7.57 (m, 2H), 7.18-7.40 (m, 5H), 5.41 (s, 2H).

실시예 69. 5-벤질-6,8-디옥소-2-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 69).Example 69. 5-benzyl-6,8-dioxo-2-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine -3-ylidene-cyanamide (Compound No. 69).

1H NMR(200 MHz, CDCl3) δ 7.50(m, 5H), 7.16-7.42(m, 5H), 5.36(s, 2H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.50 (m, 5H), 7.16-7.42 (m, 5H), 5.36 (s, 2H).

실시예 70. 5-벤질-2-(2-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 70).Example 70. 5-benzyl-2- (2-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanamide (Compound No. 70).

1H NMR(300 MHz, CDCl3) δ 8.19-8.23(m, 1H), 7.47-7.86(m, 5H), 7.24-7.27(m, 3H), 5.29(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.19-8.23 (m, 1H), 7.47-7.86 (m, 5H), 7.24-7.27 (m, 3H), 5.29 (s, 2H).

실시예 71. 5-벤질-6,8-디옥소-2-(2,4,5-트리클로로-페닐)-5,6,7,8-테트라하이드로 -2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 71).Example 71. 5-benzyl-6,8-dioxo-2- (2,4,5-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 71).

1H NMR(300 MHz, CDCl3) δ 7.69-7.78(m, 2H), 7.40-7.28(m, 5H), 5.41(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.69-7.78 (m, 2H), 7.40-7.28 (m, 5H), 5.41 (s, 2H).

실시예 72. 5-벤질-6,8-디옥소-2-(4-트리플르오로메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 72)Example 72. 5-benzyl-6,8-dioxo-2- (4-trifluoromethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 72)

1H NMR(300 MHz, CDCl3) δ 7.74-7.76(m, 1H), 7.61-7.64(m, 1H), 7.29-7.42(m, 5H), 6.63-6.99(m, 2H), 5.41(s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.74-7.76 (m, 1H), 7.61-7.64 (m, 1H), 7.29-7.42 (m, 5H), 6.63-6.99 (m, 2H), 5.41 (s , 2H).

다음의 실시예 73 내지 89에서는 상기 실시예 1의 방법에 의해 수행하되, 1-시안노-3-(3-벤질-2,6-디옥소-1-메틸-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아와, 다음 표 6에 나타낸 R3 치환기를 포함하는 디아조늄(R3N 2 +) 화합물을 사용하여 각각의 표제화합물을 합성하였다.In Examples 73 to 89, which were carried out by the method of Example 1, except that 1-cyano-3- (3-benzyl-2,6-dioxo-1-methyl-1,2,3,6- Each title compound was synthesized using a tetrahydro-pyrimidin-4-yl) -2-methyl-isothiourea and a diazonium (R 3 N 2 + ) compound comprising an R 3 substituent shown in Table 6 below. It was.

실시예 73. 5-벤질-7-메틸-6,8-디옥소-2-페닐-5,6,7,8-테트라하이드로-2H-피리도 [4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 73).Example 73. 5-benzyl-7-methyl-6,8-dioxo-2-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2, 4] triazine-3-ylidene-cyanamide (Compound No. 73).

1H NMR(300 MHz, CDCl3) δ 7.77(d, 2H, J=1.8Hz), 7.41-7.52(m, 5H), 7.28-7.39(m, 3H), 5.46(s, 2H), 3.50(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.77 (d, 2H, J = 1.8 Hz), 7.41-7.52 (m, 5H), 7.28-7.39 (m, 3H), 5.46 (s, 2H), 3.50 ( s, 3H).

실시예 74. 5-벤질-7-메틸-6,8-디옥소-2-(3,4,5-트리메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 74).Example 74. 5-benzyl-7-methyl-6,8-dioxo-2- (3,4,5-trimethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 74).

1H NMR(200 MHz, CDCl3) δ 7.74-7.78(m, 2H), 7.37-7.38(m, 3H), 6.72(s, 2H), 5.45(s, 2H), 3.87(s, 9H), 3.52(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.74-7.78 (m, 2H), 7.37-7.38 (m, 3H), 6.72 (s, 2H), 5.45 (s, 2H), 3.87 (s, 9H), 3.52 (s, 3 H).

실시예 75. 5-벤질-2-(2-프르오로-4-메틸-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 75).Example 75. 5-benzyl-2- (2-fluoro-4-methyl-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [ 4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 75).

1H NMR(200 MHz, CDCl3) δ 7.73-7.77(m, 2H), 7.23-7.40(m, 6H), 5.45(s, 2H), 3.52(s, 3H), 2.35(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.73-7.77 (m, 2H), 7.23-7.40 (m, 6H), 5.45 (s, 2H), 3.52 (s, 3H), 2.35 (s, 3H).

실시예 76. 5-벤질-2-(2-플르오로-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 76).Example 76. 5-benzyl-2- (2-fluoro-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 76).

1H NMR(200 MHz, CDCl3) δ 7.74-7.79(m, 2H), 7.24-7.56(m, 7H), 5.45(s, 2H), 3.51(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.74-7.79 (m, 2H), 7.24-7.56 (m, 7H), 5.45 (s, 2H), 3.51 (s, 3H).

실시예 77. 5-벤질-7-메틸-2-(4-메틸술파닐-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 77). Example 77. 5-benzyl-7-methyl-2- (4-methylsulfanyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5 -e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 77).

1H NMR(200, cdcl3) δ 7.52(s, 2H), 7.25-7.33(m, 7H), 5.47(s, 2H), 3.64(s, 3H), 3.54(s, 3H). 1 H NMR (200, cdcl3) δ 7.52 (s, 2H), 7.25-7.33 (m, 7H), 5.47 (s, 2H), 3.64 (s, 3H), 3.54 (s, 3H).

실시예 78. 5-벤질-2-(2-브로모-6-메틸-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 78).Example 78. 5-benzyl-2- (2-bromo-6-methyl-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [ 4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 78).

1H NMR(200 MHz, CDCl3) δ 7.78-7.80(m, 2H), 7.76(s, 1H), 7.38-7.56(m, 5H), 5.45(s, 2H), 3.52(s, 3H), 2.44(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.78-7.80 (m, 2H), 7.76 (s, 1H), 7.38-7.56 (m, 5H), 5.45 (s, 2H), 3.52 (s, 3H), 2.44 (s, 3 H).

실시예 79. 5-벤질-2-(4-브로모-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 79).Example 79. 5-benzyl-2- (4-bromo-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 79).

1H NMR(200 MHz, CDCl3) δ 7.66-7.77(m, 4H), 7.33-7.36(m, 5H), 5.43(s, 2H), 3.51(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.66-7.77 (m, 4H), 7.33-7.36 (m, 5H), 5.43 (s, 2H), 3.51 (s, 3H).

실시예 80. 5-벤질-2-(4-클로로-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 80).Example 80. 5-benzyl-2- (4-chloro-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 80).

1H NMR(200 MHz, CDCl3) δ 7.73-7.77(m, 2H), 7.25-7.55(m, 7H), 5.44(s, 2H), 3.52(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.73-7.77 (m, 2H), 7.25-7.55 (m, 7H), 5.44 (s, 2H), 3.52 (s, 3H).

실시예 81. 5-벤질-2-(2,6-디플르오로-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 81).Example 81. 5-benzyl-2- (2,6-difluoro-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4 , 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 81).

1H NMR(200 MHz, CDCl3) δ 7.79(d, 2H, J=6.3Hz), 7.30-7.45(m, 4H), 6.82(d, 2H, J=8.7Hz), 5.47(s, 2H), 3.53(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.79 (d, 2H, J = 6.3 Hz), 7.30-7.45 (m, 4H), 6.82 (d, 2H, J = 8.7 Hz), 5.47 (s, 2H) , 3.53 (s, 3 H).

실시예 82. 5-벤질-2-(2,6-디프로필-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 82).Example 82. 5-benzyl-2- (2,6-dipropyl-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4, 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 82).

1H NMR(200 MHz, CDCl3) δ 7.52-7.55(m, 2H), 7.28-7.38(m, 6H), 5.47(s, 2H), 4.09-4.13(m, 4H), 0.91-0.96(m, 6H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.52-7.55 (m, 2H), 7.28-7.38 (m, 6H), 5.47 (s, 2H), 4.09-4.13 (m, 4H), 0.91-0.96 (m , 6H).

실시예 83. 5-벤질-2-(2-에틸-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 83).Example 83. 5-benzyl-2- (2-ethyl-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 83).

1H NMR(300 MHz, CDCl3) δ 7.74-7.77(m, 2H), 7.31-7.42(m, 7H), 5.43(s, 2H), 3.51(s, 3H), 2.71(q, 2H, J=5.1Hz), 1.28(t, 3H, J=5.1Hz). 1 H NMR (300 MHz, CDCl 3 ) δ 7.74-7.77 (m, 2H), 7.31-7.42 (m, 7H), 5.43 (s, 2H), 3.51 (s, 3H), 2.71 (q, 2H, J = 5.1 Hz), 1.28 (t, 3H, J = 5.1 Hz).

실시예 84. 5-벤질-2-(4-플르오로-2-니트로-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 84).Example 84. 5-benzyl-2- (4-fluoro-2-nitro-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [ 4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 84).

1H NMR(300 MHz, CDCl3) δ 7.57-7.75(m, 3H), 7.25-7.42(m, 5H), 5.40(s, 2H), 3.48(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.57-7.75 (m, 3H), 7.25-7.42 (m, 5H), 5.40 (s, 2H), 3.48 (s, 3H).

실시예 85. 5-벤질-2-(4-플르오로-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 85).Example 85. 5-benzyl-2- (4-fluoro-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 85).

1H NMR(300 MHz, CDCl3) δ 7.76(d, 2H), J=7.8Hz), 7.53(d, 2H, J=7.2Hz), 7.18-7.38(m, 5H), 5.47(s, 2H), 3.53(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.76 (d, 2H), J = 7.8 Hz, 7.53 (d, 2H, J = 7.2 Hz), 7.18-7.38 (m, 5H), 5.47 (s, 2H ), 3.53 (s, 3 H).

실시예 86. 5-벤질-7-메틸-2-(2-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 86).Example 86. 5-benzyl-7-methyl-2- (2-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 86).

1H NMR(300 MHz, CDCl3) δ 7.52-7.55(m, 2H), 7.28-7.37(m, 7H), 5.47(s, 2H), 5.34(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.52-7.55 (m, 2H), 7.28-7.37 (m, 7H), 5.47 (s, 2H), 5.34 (s, 3H).

실시예 87. 5-벤질-7-메틸-6,8-디옥소-2-(2,4,5-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 87).Example 87. 5-benzyl-7-methyl-6,8-dioxo-2- (2,4,5-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [ 4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 87).

1H NMR(300 MHz, CDCl3) δ 7.72-7.78(m, 2H), 7.28-7.37(m, 5H), 5.47(s, 2H), 3.54(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.72-7.78 (m, 2H), 7.28-7.37 (m, 5H), 5.47 (s, 2H), 3.54 (s, 3H).

실시예 88. 5-벤질-7-메틸-6,8-디옥소-2-(2,3,4-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 88).Example 88. 5-benzyl-7-methyl-6,8-dioxo-2- (2,3,4-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [ 4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 88).

1H NMR(300 MHz, CDCl3) δ 7.73-7.76(m, 1H), 7.52-7.59(m, 1H), 7.27-7.40(m, 5H), 5.46(s,2 H), 3.53(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.73-7.76 (m, 1H), 7.52-7.59 (m, 1H), 7.27-7.40 (m, 5H), 5.46 (s, 2H), 3.53 (s, 3H).

실시예 89. 5-벤질-7-메틸-6,8-디옥소-2-(4-트리플르오로메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 89).Example 89. 5-benzyl-7-methyl-6,8-dioxo-2- (4-trifluoromethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4 , 5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 89).

1H NMR(300 MHz, CDCl3) δ 7.75(d, 2H, J=1.44Hz), 7.59-7.72(m, 2H), 7.24-7.50(m, 5H) 5.40(s, 2H), 3.48(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.75 (d, 2H, J = 1.44 Hz), 7.59-7.72 (m, 2H), 7.24-7.50 (m, 5H) 5.40 (s, 2H), 3.48 (s , 3H).

다음은 본 발명에 따른 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.The following are some examples of formulation methods containing the compound 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 the addition of 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O and 2974 mg of distilled water.

또한, 본 발명에 따른 화합물들의 수용체 티로신 키나제에 대한 활성을 알아보기 위하여, 다음과 같은 방법으로 상피세포 성장인자 수용체(EGFR)의 활성 억제율 확인 실험을 수행하였다.In addition, in order to determine the activity of the receptor tyrosine kinase of the compounds according to the present invention, the experiment to confirm the inhibition rate of the activity of epidermal growth factor receptor (EGFR) was carried out in the following manner.

[약효 시험예][Effective test example]

가) 상피세포 성장인자 수용체(EGFR)의 약효시험A) Efficacy test of epidermal growth factor receptor (EGFR)

상피세포 성장인자 수용체(EGFR)로는 Alpha ScreenTM P-Tyr-100 검색 장치(Packard BioScience 사)를 이용하였다. 이 검색은 수용체 비드에 인산화된 폴리펩타이드와 항포스포티로신 항체 P-Tyr-100사이의 결합을 기초로 한 poly[Glu:Tyr](4:1) 기질을 사용하였다. EGFR 효소는 Sf21로부터 만들었고, 곤충세포는 pBacPAK8-EFGR로 감염시켰고, 바이오틴화된 poly[Glu:Tyr](4:1)는 Packard BioScience사에서 구입하였다.As an epidermal growth factor receptor (EGFR), an Alpha Screen ™ P-Tyr-100 screening device (Packard BioScience) was used. This search used a poly [Glu: Tyr] (4: 1) substrate based on the binding between the phosphorylated polypeptide and the antiphosphotyrosine antibody P-Tyr-100 to the receptor beads. EGFR enzyme was made from Sf21, insect cells were infected with pBacPAK8-EFGR and biotinylated poly [Glu: Tyr] (4: 1) was purchased from Packard BioScience.

약효검색은 다음의 3 단계로 나눌 수 있다.Drug search can be divided into three steps.

1 단계 : 5 μL EGFR 효소(5 ng), Tyrphostin A51(Upstate Biotech 사) 또는 384-웰 플레이트(Griner Bioone)를 상온에서 15분 동안 배양하였다.Step 1: 5 μL EGFR enzyme (5 ng), Tyrphostin A51 (Upstate Biotech) or 384-well plate (Griner Bioone) were incubated at room temperature for 15 minutes.

2 단계 : 각 웰에 5 μL 비오틴화된 poly[Glu:Tyr](4:1)(5 nM)와 ATP(100 μM)를 가하고 1 시간 배양하였다. 사용된 키나제 반응 완충액은 50 mM Tris-HCl(pH 7.5), 5 mM MgCl2를 포함한다.Step 2: 5 μL biotinylated poly [Glu: Tyr] (4: 1) (5 nM) and ATP (100 μM) were added to each well and incubated for 1 hour. Kinase reaction buffers used included 50 mM Tris-HCl, pH 7.5, 5 mM MgCl 2 .

3 단계 : EDTA, 스트렙타비딘(Streptavdin, 20 μM) 공여체, P-Tyr-100 비드(20 μM) 수용체를 포함한 감지완충액(Capture buffer)을 첨가하였다. 상온에서 1시간 배양 후에 FusionTM microplate analyzer(PerkinElmer)를 이용하여 AlphaScreen 신호를 감지하였다.Step 3: Capture buffer containing EDTA, streptavidin (20 μM) donor, P-Tyr-100 bead (20 μM) receptor was added. After 1 hour incubation at room temperature the AlphaScreen signal was detected using a Fusion TM microplate analyzer (PerkinElmer).

나) 혈관 내피세포 성장인자(VEGF2)의 약효시험I) Drug efficacy test of vascular endothelial growth factor (VEGF2)

혈관 내피세포 성장인자(VEGFR2) 티로신 키나제(tyrosine kinase)의 활성도는 Alpha ScreenTM P-Tyr-100 분석방법(Packard BioScience사)을 이용하여 측정하였다. AlphaScreen이란 Amplified Luminescent Proximity Homogenous Assay를 의미하며, 발광 산소 라디칼 채널을 이용하는 면역측정 방법이다. 본 실험에서는 비오틴화된 poly[Glu:Tyr](4:1)(Packard BioScience사)를 반응효소에 대한 기질로 사용하였고, 이 기질들과 결합 할 수 있도록 스트렙타비딘(Streptavdin)이 코팅된 공여체 비드와 인산화된 기질을 인지하여 반응할 수 있는 항체(P-Tyr-100)가 결합된 수용체 비드를 효소 반응에 사용하였다. Sf21 곤충세포에서 과다 발현시킨 후 분리 정제된 VEFGR2 효소는 독일의 Proqinase사로부터 구입하였다. 분석은 희고 불투명한 384-웰 플레이트(Greiner Bio-One사)를 사용하여 각 웰의 전체 반응 부피가 25 mL 되도록 하는 조건에서 다음의 3과정을 통하여 진행되었다.Vascular endothelial growth factor (VEGFR2) tyrosine kinase activity was measured using Alpha Screen ™ P-Tyr-100 assay (Packard BioScience). AlphaScreen stands for Amplified Luminescent Proximity Homogenous Assay and is an immunoassay method using luminescent oxygen radical channels. In this experiment, biotinylated poly [Glu: Tyr] (4: 1) (Packard BioScience) was used as a substrate for the reaction enzyme, and a streptavidin-coated donor could bind to these substrates. Receptor beads to which the antibody (P-Tyr-100) that can recognize and react with the beads and the phosphorylated substrate were bound were used for the enzymatic reaction. After overexpression in Sf21 insect cells, purified VEFGR2 enzyme was purchased from Proqinase of Germany. The analysis was carried out using a white opaque 384-well plate (Greiner Bio-One) in three steps under the condition that the total reaction volume of each well was 25 mL.

1 단계: 5 mL의 VEGFR2 효소 (5 ng)를 5 mL(4 mL 반응완충액 + 1 mL DMSO에 용해된 화합물)의 알려진 표준 억제제인 CHIR200131 혹은 시험하고자 하는 화합물과 384-웰 플레이트의 각 웰에 첨가하여 15분 동안 상온에서 반응시켰다. Step 1: Add 5 mL of VEGFR2 enzyme (5 ng) to each well of a 384-well plate with CHIR200131, a known standard inhibitor of 5 mL (4 mL reaction buffer + compound dissolved in 1 mL DMSO), or the compound to be tested. The reaction was carried out at room temperature for 15 minutes.

2단계: 반응 15분 후, 각 웰에 비오틴화된 poly[Glu:Tyr](4:1)와 ATP를 각각 최종농도 5 nM과 100 mM로 함유한 반응완충액 5 mL를 첨가하여 1 시간 동안 상온에서 효소 반응을 진행시켰다. 이때 효소 반응에 사용된 반응완충액의 조성은 50 mM Tris-HCl (pH7.5), 5 mM MgCl2, 5 mM MnCl2, 2 mM DTT와 0.01 % Tween-20이다.Step 2: 15 minutes after the reaction, 5 mL of reaction buffer containing biotinylated poly [Glu: Tyr] (4: 1) and ATP at a final concentration of 5 nM and 100 mM, respectively, was added at room temperature for 1 hour. The enzyme reaction proceeded at. The composition of the reaction buffer used for the enzyme reaction was 50 mM Tris-HCl (pH7.5), 5 mM MgCl 2 , 5 mM MnCl 2 , 2 mM DTT and 0.01% Tween-20.

3단계: 1시간의 효소 반응 후, 여기에 공여체와 수용체 비드가 포함된 10 mL의 감지완충액을 첨가하여 1 시간 동안 상온에서 효소 반응을 추가 진행시켰다. 이 과정은 진행 중인 효소 반응을 중지시키면서 기질의 인산화 정도를 인지하도록 하는 과정으로 최종농도가 각각 20 mg/mL의 스트렙타비딘(Streptavdin) 공여체와 P-Tyr-100 비드 수용체, EDTA가 포함된 감지완충액을 사용하였다. 감지완충액의 조성(2.5배 농도)은 62.5 mM HEPES(pH 7.4), 250 mM NaCl, 100 mM EDTA 그리고 BSA 0.25 %이다. 반응 후, 효소의 활성도는 FusionTM microplate 분석장치 (PerkinElmer사)를 이용하여 AlphaScreen 신호를 측정함으로써 구할 수 있다.Step 3: After 1 hour of enzymatic reaction, 10 mL of the detection buffer containing donor and receptor beads was added thereto, and the enzyme reaction was further proceeded at room temperature for 1 hour. This process stops the enzymatic reaction in progress and recognizes the degree of phosphorylation of the substrate, and detects the final concentration of streptavidin donor, P-Tyr-100 bead receptor, and EDTA at 20 mg / mL, respectively. Buffer was used. The composition of the detection buffer (2.5-fold concentration) is 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 발명의 대표적인 화합물에 대한 약효시험 결과는 다음 표 7과 같다.Drug test results for the representative compounds of the present invention are shown in Table 7.

시험 화합물Test compound EGFR 약효(20 μM, n=3),% 억제율EGFR efficacy (20 μM, n = 3),% inhibition VEGFR 약효(20 μM, n=3),% 억제율VEGFR efficacy (20 μM, n = 3),% inhibition 화합물번호 8Compound number 8 5151 5858 화합물번호 21Compound number 21 4646 5151 화합물번호 29Compound number 29 6363 5959 화합물번호 30Compound number 30 6464 6161 화합물번호 34Compound number 34 8888 9191 화합물번호 36Compound number 36 6565 6868 화합물번호 38Compound number 38 7070 6969 화합물번호 43Compound number 43 6262 5858 화합물번호 59Compound number 59 9292 9696 화합물번호 66Compound number 66 5252 5555 화합물번호 74Compound number 74 6464 5858

이상에서 설명한 바와 같이, 본 발명에 따른 상기 화학식 1로 표시되는 신규 화합물은 수용체 티로신 키나제(RTK)로서의 상피세포 성장인자 수용체(EGFR)와 혈관 내피세포 성장인자(VEGF)에 대한 억제활성을 가지고 있으므로 항암제로서 유효하다.As described above, the novel compound represented by Formula 1 according to the present invention has an inhibitory activity on epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) as receptor tyrosine kinase (RTK). It is effective as an anticancer agent.

Claims (6)

다음 화학식 1로 표시되는 것임을 특징하는 2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 유도체 또는 이의 약제학적으로 허용 가능한 염 :2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide derivatives or pharmaceutically acceptable salts thereof, characterized by the formula: [화학식 1][Formula 1] 상기 화학식 1에서, R1과 R2는 수소원자, 치환되거나 치환되지 않은 C1 -C10의 알킬기, 치환되거나 치환되지 않은 페닐기, 또는 치환되거나 치환되지 않은 벤질기를 나타내고; R3은 치환되거나 치환되지 않은 페닐기를 나타내고; 상기 치환기는 할로겐원자, 니트로기, C1-C10의 알킬기, C1-C10의 할로알킬기, C1-C10의 알콕시기, 및 C1-C10의 알킬술파닐기 중에서 선택된 하나 또는 둘 이상이다.In Formula 1, R 1 and R 2 represent a hydrogen atom, a substituted or unsubstituted C 1 -C 10 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group; R 3 represents a substituted or unsubstituted phenyl group; The substituent is one or two selected from halogen atom, nitro group, C 1 -C 10 alkyl group, C 1 -C 10 haloalkyl group, C 1 -C 10 alkoxy group, and C 1 -C 10 alkylsulfanyl group That's it. 제 1 항에 있어서, 상기 화학식 1로 표시되는 화합물이 According to claim 1, wherein the compound represented by the formula (1) 2-(3,5-디메틸-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 1) ;2- (3,5-Dimethyl-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 1); 2-(3-플르오로-4-메틸-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 2) ;2- (3-fluoro-4-methyl-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 2); 2-(2-플르오로-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 3) ;2- (2-fluoro-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2 , 4] triazine-3-ylidene-cyanide (Compound No. 3); 5,7-디메틸-2-(4-메틸술파닐-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 4) ;5,7-dimethyl-2- (4-methylsulfanyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 4); 2-(2-브로모-4-메틸-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 5) ;2- (2-Bromo-4-methyl-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 5); 2-(4-브로모-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 6) ;2- (4-Bromo-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2 , 4] triazine-3-ylidene-cyanide (Compound No. 6); 2-(2,6-디플루오로-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 7) ;2- (2,6-difluoro-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [ 1,2,4] triazine-3-ylidene-cyanide (Compound No. 7); 2-(3-에틸-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 8) ;2- (3-ethyl-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2, 4] triazine-3-ylidene-cyanide (Compound No. 8); 2-(4-플르오로-2-니트로-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 9) ;2- (4-fluoro-2-nitro-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 9); 2-(4-플르오로-페닐)-5,7-디메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 10) ;2- (4-fluoro-phenyl) -5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2 , 4] triazine-3-ylidene-cyanide (Compound No. 10); 5,7-디메틸-2-(2-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 11) ;5,7-dimethyl-2- (2-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2, 4] triazine-3-ylidene-cyanide (Compound No. 11); 5,7-디메틸-6,8-디옥소-2-(2,4,5-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 12)5,7-dimethyl-6,8-dioxo-2- (2,4,5-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 12) 5,7-디메틸-6,8-디옥소-2-(2,3,4-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 13) ;5,7-dimethyl-6,8-dioxo-2- (2,3,4-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 13); 5,7-디메틸-6,8-디옥소-2-(2,4,6-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 14) ;5,7-dimethyl-6,8-dioxo-2- (2,4,6-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 14); 5,7-디메틸-6,8-디옥소-2-(4-니트로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 15) ;5,7-dimethyl-6,8-dioxo-2- (4-nitro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2, 4] triazine-3-ylidene-cyanide (Compound No. 15); 5,7-디메틸-6,8-디옥소-2-(4-클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 16) ;5,7-dimethyl-6,8-dioxo-2- (4-chloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2, 4] triazine-3-ylidene-cyanide (Compound No. 16); 5,7-디메틸-6,8-디옥소-2-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 17) ;5,7-dimethyl-6,8-dioxo-2-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3 -Ylidene-cyanide (Compound No. 17); 5,7-디메틸-6,8-디옥소-2-(4-트리플르오로메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 18) ;5,7-dimethyl-6,8-dioxo-2- (4-trifluoromethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [ 1,2,4] triazine-3-ylidene-cyanide (Compound No. 18); 5,7-디메틸-6,8-디옥소-2-(3,4,5-트리메톡시-페닐)-5,6,7,8-테트라하이드 (화합물 번호 19) ; 5,7-dimethyl-6,8-dioxo-2- (3,4,5-trimethoxy-phenyl) -5,6,7,8- tetrahydro (Compound No. 19); 5,7-디메틸-6,8-디옥소-2-p-톨릴-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 20) ; 5,7-dimethyl-6,8-dioxo-2-p-tolyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine -3-ylidene-cyanide (Compound No. 20); 5,7-디벤질-2-(4-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 21) ;5,7-dibenzyl-2- (4-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2 , 4] triazine-3-ylidene-cyanide (Compound No. 21); 5,7-디벤질-6,8-디옥소-2-(3,4,5-트리메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 22) ;5,7-dibenzyl-6,8-dioxo-2- (3,4,5-trimethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 22); 5,7-디벤질-2-(4-브로모-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 23) ;5,7-dibenzyl-2- (4-bromo-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 23); 5,7-디벤질-2-(4-클로로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 24) ;5,7-dibenzyl-2- (4-chloro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2 , 4] triazine-3-ylidene-cyanide (Compound No. 24); 5,7-디벤질-2-(2-플르오로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 25) ;5,7-dibenzyl-2- (2-fluoro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 25); 5,7-디벤질-2-(3-에틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 26) ;5,7-dibenzyl-2- (3-ethyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2 , 4] triazine-3-ylidene-cyanide (Compound No. 26); 5,7-디벤질-2-(5-플르오로-2-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 27) ;5,7-dibenzyl-2- (5-fluoro-2-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 27); 5,7-디벤질-2-(4-플르오로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 28) ;5,7-dibenzyl-2- (4-fluoro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 28); 5,7-디벤질-2-(2-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 29) ;5,7-dibenzyl-2- (2-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2 , 4] triazine-3-ylidene-cyanide (Compound No. 29); 5,7-디벤질-6,8-디옥소-2-(2,4,5-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 30) ;5,7-dibenzyl-6,8-dioxo-2- (2,4,5-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 30); 5,7-디벤질-6,8-디옥소-2-(2,3,4-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 31)5,7-dibenzyl-6,8-dioxo-2- (2,3,4-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 31) 5,7-디벤질-6,8-디옥소-2-(4-트리플르오로메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 32)5,7-dibenzyl-6,8-dioxo-2- (4-trifluoromethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 32) 5,7-디벤질-2-(4-메톡시-2-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 33) ;5,7-dibenzyl-2- (4-methoxy-2-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 33); 5,7-디벤질-2-(3,5-디메틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 34) ;5,7-dibenzyl-2- (3,5-dimethyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanide (Compound No. 34); 5,7-디벤질-2-(3-플르오로-4-메틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 35) ;5,7-dibenzyl-2- (3-fluoro-4-methyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 35); 5,7-디벤질-2-(4-메틸술파닐-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 36) ;5,7-dibenzyl-2- (4-methylsulfanyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanide (Compound No. 36); 5,7-디벤질-2-(2-브로모-6-메틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 37) ;5,7-dibenzyl-2- (2-bromo-6-methyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 37); 5,7-디벤질-2-(3,5-디플르오로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 38) ;5,7-dibenzyl-2- (3,5-difluoro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 38); 7-메틸-6,8-디옥소-2,5-디페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 39) ;7-methyl-6,8-dioxo-2,5-diphenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine- 3-ylidene-cyanide (Compound No. 39); 7-메틸-2-(4-니트로-페닐)-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 40)7-methyl-2- (4-nitro-phenyl) -6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 40) 7-메틸-6,8-디옥소-5-페닐-2-(3,4,5-트리메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 41)7-methyl-6,8-dioxo-5-phenyl-2- (3,4,5-trimethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5 -e] [1,2,4] triazine-3-ylidene-cyanamide (Compound No. 41) 2-(3,5-디메틸-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 42) ;2- (3,5-Dimethyl-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [ 1,2,4] triazine-3-ylidene-cyanide (Compound No. 42); 2-(3-플르오로-4-메틸-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 43) ;2- (3-fluoro-4-methyl-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 43); 2-(2-플르오로-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 44) ;2- (2-Fluoro-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanide (Compound No. 44); 7-메틸-2-(4-메틸술파닐-페닐)-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 45) ;7-methyl-2- (4-methylsulfanyl-phenyl) -6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [ 1,2,4] triazine-3-ylidene-cyanide (Compound No. 45); 2-(2-브로모-6-메틸-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 46) ;2- (2-Bromo-6-methyl-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 46); 2-(4-브로모-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 47) ;2- (4-Bromo-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanide (Compound No. 47); 2-(4-클로로-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 48) ;2- (4-chloro-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 48); 2-(2,6-디플르오로-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 49) ;2- (2,6-difluoro-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 49); 2-(2,6-디프로필-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 50) ;2- (2,6-Dipropyl-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 50); 2-(3-에틸-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 51) ;2- (3-ethyl-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 51); 2-(4-플르오로-2-니트로-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 52) ;2- (4-fluoro-2-nitro-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 52); 2-(4-플르오로-페닐)-7-메틸-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 53) ;2- (4-fluoro-phenyl) -7-methyl-6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanide (Compound No. 53); 7-메틸-2-(2-니트로-페닐)-6,8-디옥소-5-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 54) ;7-methyl-2- (2-nitro-phenyl) -6,8-dioxo-5-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 54); 7-메틸-6,8-디옥소-5-페닐-2-(2,4,5-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 55) ;7-methyl-6,8-dioxo-5-phenyl-2- (2,4,5-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 55); 7-메틸-6,8-디옥소-5-페닐-2-(2,3,4-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 56) ;7-methyl-6,8-dioxo-5-phenyl-2- (2,3,4-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 56); 7-메틸-6,8-디옥소-5-페닐-2-(2,4,6-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 57) ;7-methyl-6,8-dioxo-5-phenyl-2- (2,4,6-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 57); 7-메틸-6,8-디옥소-5-페닐-2-(4-트리플르오로메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 58) ;7-methyl-6,8-dioxo-5-phenyl-2- (4-trifluoromethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 58); 5-벤질-2-(4-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 59) ;5-benzyl-2- (4-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] Triazine-3-ylidene-cyanide (Compound No. 59); 5-벤질-2-(2-플르오로-4-메틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 60) ;5-benzyl-2- (2-fluoro-4-methyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanide (Compound No. 60); 5-벤질-2-(2-플르오로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 61) ;5-benzyl-2- (2-fluoro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4 ] Triazine-3-ylidene-cyanide (Compound No. 61); 5-벤질-2-(4-메틸술파닐-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 62) ;5-benzyl-2- (4-methylsulfanyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2, 4] triazine-3-ylidene-cyanide (Compound No. 62); 5-벤질-2-(2-브로모-6-메틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 63) ;5-benzyl-2- (2-bromo-6-methyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanide (Compound No. 63); 5-벤질-2-(4-브로모-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 64) ;5-benzyl-2- (4-bromo-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4 ] Triazine-3-ylidene-cyanide (Compound No. 64); 5-벤질-2-(4-클로로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 65) ;5-benzyl-2- (4-chloro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] Triazine-3-ylidene-cyanide (Compound No. 65); 5-벤질-2-(3-에틸-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 66) ;5-benzyl-2- (3-ethyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] Triazine-3-ylidene-cyanide (Compound No. 66); 5-벤질-2-(4-플르오로-4-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 67) ;5-benzyl-2- (4-fluoro-4-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanide (Compound No. 67); 5-벤질-2-(4-플르오로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 68) ;5-benzyl-2- (4-fluoro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4 ] Triazine-3-ylidene-cyanide (Compound No. 68); 5-벤질-6,8-디옥소-2-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 69) ;5-benzyl-6,8-dioxo-2-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-yl Den-cyanamide (Compound No. 69); 실시예 70. 5-벤질-2-(2-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 70) ;Example 70. 5-benzyl-2- (2-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 70); 5-벤질-6,8-디옥소-2-(2,4,5-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 71) ;5-benzyl-6,8-dioxo-2- (2,4,5-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanide (Compound No. 71); 5-벤질-6,8-디옥소-2-(4-트리플르오로메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 72)5-benzyl-6,8-dioxo-2- (4-trifluoromethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 72) 5-벤질-7-메틸-6,8-디옥소-2-페닐-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 73) ;5-benzyl-7-methyl-6,8-dioxo-2-phenyl-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine -3-ylidene-cyanide (Compound No. 73); 5-벤질-7-메틸-6,8-디옥소-2-(3,4,5-트리메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 74) ;5-benzyl-7-methyl-6,8-dioxo-2- (3,4,5-trimethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5 -e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 74); 5-벤질-2-(2-프르오로-4-메틸-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 75) ;5-benzyl-2- (2-fluoro-4-methyl-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 75); 5-벤질-2-(2-프르오로-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 76) ;5-benzyl-2- (2-fluoro-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanide (Compound No. 76); 5-벤질-7-메틸-2-(4-메틸술파닐-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 77) ; 5-benzyl-7-methyl-2- (4-methylsulfanyl-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [ 1,2,4] triazine-3-ylidene-cyanide (Compound No. 77); 5-벤질-2-(2-브로모-6-메틸-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 78) ;5-benzyl-2- (2-bromo-6-methyl-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 78); 5-벤질-2-(4-브로모-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 79) ;5-benzyl-2- (4-bromo-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanide (Compound No. 79); 5-벤질-2-(4-클로로-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 80) ;5-benzyl-2- (4-chloro-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 80); 5-벤질-2-(2,6-디플르오로-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 81) ;5-benzyl-2- (2,6-difluoro-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 81); 5-벤질-2-(2,6-디프로필-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 82) ;5-benzyl-2- (2,6-dipropyl-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 82); 5-벤질-2-(2-에틸-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 83) ;5-benzyl-2- (2-ethyl-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 83); 5-벤질-2-(4-플르오로-2-니트로-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 84) ;5-benzyl-2- (4-fluoro-2-nitro-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 84); 5-벤질-2-(4-플르오로-페닐)-7-메틸-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 85) ;5-benzyl-2- (4-fluoro-phenyl) -7-methyl-6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1 , 2,4] triazine-3-ylidene-cyanide (Compound No. 85); 5-벤질-7-메틸-2-(2-니트로-페닐)-6,8-디옥소-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 86) ;5-benzyl-7-methyl-2- (2-nitro-phenyl) -6,8-dioxo-5,6,7,8-tetrahydro-2H-pyrido [4,5-e] [1, 2,4] triazine-3-ylidene-cyanide (Compound No. 86); 5-벤질-7-메틸-6,8-디옥소-2-(2,4,5-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 87) ;5-benzyl-7-methyl-6,8-dioxo-2- (2,4,5-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 87); 5-벤질-7-메틸-6,8-디옥소-2-(2,3,4-트리클로로-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 88) ;5-benzyl-7-methyl-6,8-dioxo-2- (2,3,4-trichloro-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5- e] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 88); 5-벤질-7-메틸-6,8-디옥소-2-(4-트리플르오로메톡시-페닐)-5,6,7,8-테트라하이드로-2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 (화합물번호 89) ; 및 5-benzyl-7-methyl-6,8-dioxo-2- (4-trifluoromethoxy-phenyl) -5,6,7,8-tetrahydro-2H-pyrido [4,5-e ] [1,2,4] triazine-3-ylidene-cyanide (Compound No. 89); And 이의 약제학적으로 허용 가능한 염 중에서 선택된 것을 특징으로 하는 화합물.A compound characterized in that it is selected from pharmaceutically acceptable salts thereof. 다음 화학식 1로 표시되는 2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 유도체 또는 이의 약제학적으로 허용 가능한 염이 함유되어 있는 것임을 특징으로 하는 항암제용 약제조성물 :2H-pyrido [4,5-e] [1,2,4] triazine-3-ylidene-cyanamide derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof Anticancer drug composition: [화학식 1][Formula 1] 상기 화학식 1에서, R1과 R2는 수소원자, 치환되거나 치환되지 않은 C1 -C10의 알킬기, 치환되거나 치환되지 않은 페닐기, 또는 치환되거나 치환되지 않은 벤질기를 나타내고; R3은 치환되거나 치환되지 않은 페닐기를 나타내고; 상기 치환기는 할로겐원자, 니트로기, C1-C10의 알킬기, C1-C10의 할로알킬기, C1-C10의 알콕시기, 및 C1-C10의 알킬술파닐기 중에서 선택된 하나 또는 둘 이상이다.In Formula 1, R 1 and R 2 represent a hydrogen atom, a substituted or unsubstituted C 1 -C 10 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group; R 3 represents a substituted or unsubstituted phenyl group; The substituent is one or two selected from halogen atom, nitro group, C 1 -C 10 alkyl group, C 1 -C 10 haloalkyl group, C 1 -C 10 alkoxy group, and C 1 -C 10 alkylsulfanyl group That's it. 다음 화학식 3으로 표시되는 중간체 화합물 :Intermediate compound represented by the following formula (3): 상기 화학식 3에서, R1과 R2는 수소원자, 치환되거나 치환되지 않은 C1 -C10의 알킬기, 치환되거나 치환되지 않은 페닐기, 또는 치환되거나 치환되지 않은 벤질기를 나타내고, 상기 치환기는 할로겐원자, 니트로기, C1-C10의 알킬기, C1-C 10의 할로알킬기, C1-C10의 알콕시기, 및 C1-C10의 알킬술파닐기 중에서 선택된 하나 또는 둘 이상이다.In Formula 3, R 1 and R 2 represent a hydrogen atom, a substituted or unsubstituted C 1 -C 10 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group, the substituent is a halogen atom, At least one selected from a nitro group, a C 1 -C 10 alkyl group, a C 1 -C 10 haloalkyl group, a C 1 -C 10 alkoxy group, and a C 1 -C 10 alkylsulfanyl group. 제 4 항에 있어서, 상기 화학식 3으로 표시되는 화합물이According to claim 4, wherein the compound represented by the formula (3) 1-시안노-3-(1,3-디메틸-2,6-디옥소-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 ;1-cyano-3- (1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2-methyl-isothiourea; 1-시안노-3-(1,3-디벤질-2,6-디옥소-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 ;1-cyano-3- (1,3-dibenzyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2-methyl-isothiourea; 1-시안노-3-(3-벤질-2,6-디옥소-1-메틸-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 ;1-cyano-3- (3-benzyl-2,6-dioxo-1-methyl-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2-methyl-isothiourea; 1-시안노-3-(3-벤질-2,6-디옥소--1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 ;1-cyano-3- (3-benzyl-2,6-dioxo--1,2,3,6-tetrahydro-pyrimidin-4-yl) -2-methyl-isothiourea; 1-시안노-3-(3-메틸-2,6-디옥소-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 ;1-cyano-3- (3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2-methyl-isothiourea; 1-시안노-3-(1-메틸-2,6-디옥소-3-페닐-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 ;1-cyano-3- (1-methyl-2,6-dioxo-3-phenyl-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2-methyl-isothiourea; 1-시안노-3-(2,6-디옥소-3-(2-플르오로-페닐)-1-메틸-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 ; 및1-cyano-3- (2,6-dioxo-3- (2-fluoro-phenyl) -1-methyl-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2 -Methyl-isothiourea; And 1-시안노-3-(2,6-디옥소-3-(4-플르오로-페닐)-1-메틸-1,2,3,6-테트라하이드로-피리미딘-4-일)-2-메틸-이소티오우레아 1-cyano-3- (2,6-dioxo-3- (4-fluoro-phenyl) -1-methyl-1,2,3,6-tetrahydro-pyrimidin-4-yl) -2 -Methyl-isothiourea 중에서 선택된 것임을 특징으로 하는 중간체 화합물.Intermediate compound, characterized in that selected from. 다음 화학식 3으로 표시되는 중간체 화합물과 디아조늄(R3N2 +) 화합물을 반응시켜 제조하는 것을 특징으로 하는 다음 화학식 1로 표시되는 2H-피리도[4,5-e][1,2,4]트리아진-3-일리덴-시안아마이드 유도체의 제조방법 :Jonyum following dia and intermediate compounds represented by the following formula 3 (R 3 N 2 +), and then also 2H- pyrido represented by the general formula (1), characterized in that that produced by reacting the compound [4,5-e] [1,2, 4] Method of preparing triazine-3-ylidene-cyanide derivative: [화학식 3][Formula 3] [화학식 1][Formula 1] 상기 화학식 1에서, R1과 R2는 수소원자, 치환되거나 치환되지 않은 C1 -C10의 알킬기, 치환되거나 치환되지 않은 페닐기, 또는 치환되거나 치환되지 않은 벤질기를 나타내고; R3은 치환되거나 치환되지 않은 페닐기를 나타내고; 상기 치환기는 할로겐원자, 니트로기, C1-C10의 알킬기, C1-C10의 할로알킬기, C1-C10의 알콕시기, 및 C1-C10의 알킬술파닐기 중에서 선택된 하나 또는 둘 이상이다.In Formula 1, R 1 and R 2 represent a hydrogen atom, a substituted or unsubstituted C 1 -C 10 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group; R 3 represents a substituted or unsubstituted phenyl group; The substituent is one or two selected from halogen atom, nitro group, C 1 -C 10 alkyl group, C 1 -C 10 haloalkyl group, C 1 -C 10 alkoxy group, and C 1 -C 10 alkylsulfanyl group That's it.
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