KR100546992B1

KR100546992B1 - 4,5-Diamino pyrimidine derivatives and methods for producing said compound

Info

Publication number: KR100546992B1
Application number: KR1019990012586A
Authority: KR
Inventors: 이정근; 서병철; 장명식; 김종훈
Original assignee: 씨제이 주식회사
Priority date: 1999-04-09
Filing date: 1999-04-09
Publication date: 2006-02-01
Also published as: KR20000065865A

Abstract

본 발명은 싸이클릭 구아노신 3',5'-모노포스페이트 포스포디에스터라제에 대한 억제작용을 갖는 하기 일반식(I)의 신규한 4,5-다이아미노 피리미딘 유도체 및 이의 생리학적으로 허용되는 염, 용매화물 또는 대사상 전환되기 쉬운 에스테르에 관한 것이다:The present invention provides novel 4,5-diamino pyrimidine derivatives of the following general formula (I) having inhibitory action against cyclic guanosine 3 ', 5'-monophosphate phosphodiesterase and physiologically acceptable thereof To esters that are susceptible to salts, solvates or metabolic conversions:

(I)

상기식에서, X는 결합, C_1-4알킬렌, C_1-4알킬렌옥시, C_1-4알콕시페닐 또는 페닐(C_1-4)알킬렌이고; Y는 결합 또는 C_1-2알킬이고; R¹는 (ⅰ) 할로겐, 니트로, 히드록시, C_1-6알킬 및 C_1-4알콕시로 이루어진 그룹중에서 선택된 하나 또는 두개의 기로 치환되거나 비치환된 페닐, (ⅱ) 할로겐, 니트로, 히드록시, C_1-6알킬 및 할로겐C_1-4알콕시로 이루어진 그룹중에서 선택된 하나 또는 두개의 기로 치환되고 질소 및 산소 중에서 선택된 하나 또는 두개의 원자를 함유하는 5 내지 15원의 측쇄사슬 또는 헤테로고리화합물, (ⅲ) C_4-10 카르보싸이클릭 고리화합물 또는 (ⅲ) 히드록시(C_1-4)알콕시이 고; R²는 (ⅰ) 히드록시, 할로겐, 니트로, 히드록시(C_1-5)알킬, C_1-6알킬, C_3-6알케닐 및 C_1-4알콕시로 이루어진 그룹 중에서 선택된 하나 또는 두개의 기로 치환되고 질소원자를 1 내지 4개 함유하는 5 내지 6 원의 헤테로 고리화합물 또는 (ⅱ) 히드록시, 할로겐, 니트로, 히드록시(C_1-5)알킬, C_1-6알킬, C_3-6알케닐 및 C_1-4알콕시로 이루어진 그룹 중에서 선택된 하나 또는 두개의 기로 치환되고 질소원자 하나를 함유하면서 산소 또는 황원자 하나를 선택적으로 함유하는 5 내지 15 원의 헤테로 고리화합물 이고; R³는 수소,

또는

이며; R⁴ 및 R⁵는 각각 독립적으로 (ⅰ) 아민, 할로겐, 카르복시, C_1-6알킬, 페닐, C_1-4알콕시 및 C_1-4알콕시카르보닐로 이루어진 그룹 중에서 선택된 하나 또는 두개의 기로 치환되고 질소원자를 2 내지 4개 함유하는 5 내지 6 원의 헤테로 고리화합물 또는 (ⅱ) 아민, 할로겐, 카르복시, C_1-6알킬, 페닐, C_1-4알콕시및 C_1-4알콕시카르보닐로 이루어진 그룹 중에서 선택된 하나 또는 두개의 기로 치환되고 질소, 산소 및 황 중에서 선택된 하나 또는 두개의 원자를 함유하는 5 내지 15 원의 헤테로 고리화합물이다. 또한 본 발명은 상기 화합물(I)의 제조방법에 관한 것이다.Wherein X is a bond, C _1-4 alkylene, C _1-4 alkyleneoxy, C _1-4 alkoxyphenyl or phenyl (C _1-4 ) alkylene; Y is a bond or C _1-2 alkyl; R ¹ is (iii) phenyl unsubstituted or substituted with one or two groups selected from the group consisting of halogen, nitro, hydroxy, C _1-6 alkyl and C _1-4 alkoxy, (ii) halogen, nitro, hydroxy , 5 to 15 membered side chain or heterocyclic compound substituted with one or two groups selected from the group consisting of C _1-6 alkyl and halogen C _1-4 alkoxy and containing one or two atoms selected from nitrogen and oxygen, (Iii) C _4-10 carbocyclic cyclic compounds or (iii) hydroxy (C _1-4 ) alkoxy; R ² is selected from the group consisting of (i) hydroxy, halogen, nitro, hydroxy (C _1-5 ) alkyl, C _1-6 alkyl, C _3-6 alkenyl and C _1-4 alkoxy 5- to 6-membered heterocyclic compounds substituted with groups and containing 1 to 4 nitrogen atoms or (ii) hydroxy, halogen, nitro, hydroxy (C _1-5 ) alkyl, C _1-6 alkyl, C _{3- A} 5-15 membered heterocyclic compound substituted with one or two groups selected from the group consisting of ₆ alkenyl and C _1-4 alkoxy and containing one nitrogen atom and optionally containing one oxygen or sulfur atom; R ³ is hydrogen,

or

Is; R ⁴ and R ⁵ are each independently substituted with one or two groups selected from the group consisting of amine, halogen, carboxy, C _1-6 alkyl, phenyl, C _1-4 alkoxy and C _1-4 alkoxycarbonyl And 5 to 6 membered heterocyclic compounds containing 2 to 4 nitrogen atoms or (ii) amine, halogen, carboxy, C _1-6 alkyl, phenyl, C _1-4 alkoxy and C _1-4 alkoxycarbonyl And a 5 to 15 membered heterocyclic compound substituted with one or two groups selected from the group consisting of and containing one or two atoms selected from nitrogen, oxygen and sulfur. The invention also relates to a process for the preparation of compound (I).

Description

4,5-다이아미노 피리미딘 유도체 및 이의 제조방법{4,5-Diamino pyrimidine derivatives and methods for producing said compound} 4,5-Diamino pyrimidine derivatives and methods for producing said compound}

본 발명의 목적은 싸이클릭 구아노신 3',5'-모노포스페이트 포스포디에스터라제(이하 약어로 "cGMP PDE" 라함)를 억제하여 순환기계 질환의 예방 또는 치료제에 유용할 수 있는 신규한 약물 및 이를 효율적으로 제조할 수 있는 방법을 제공하는데 있다. It is an object of the present invention to inhibit cyclic guanosine 3 ', 5'-monophosphate phosphodiesterase (hereinafter abbreviated as "cGMP PDE"), a novel drug that may be useful for the prevention or treatment of circulatory diseases. And to provide a method for producing this efficiently.

싸이클릭 구아노신 3',5'-모노포스페이트(이하 약어로 "CGMP" 라함)는 쥐의 신장에서 발견되어, 다양한 생리학적 활성, 즉 심장근육 또는 평활근의 이완을 유도하며 임파구의 세포증식에도 관여하는 물질로 알려졌다. 그러나, CGMP는 CGMP PDE에 의해서 비활성 상태인 5'GMP로 변형되어 생리학적 활성을 나타내지 못하는 것으로 보고되었다. 따라서, CGMP PDE의 억제 활성을 나타내는 물질은 CGMP의 수치를 유지 또는 높혀줌으로써 신진대사를 원활하게 하고 고혈압, 협심증, 동맥경화, 만성기관지 천식 또는 기관지 염증 등 다양한 순환기계 질환을 예방 또는 치료 제로 유용될 수 있다.Cyclic guanosine 3 ', 5'-monophosphate (hereinafter abbreviated as "CGMP") is found in the kidneys of mice, inducing various physiological activities, namely relaxation of heart muscle or smooth muscle, and also involved in cell proliferation of lymphocytes. It is known as a substance. However, it has been reported that CGMP is inactivated by CGMP PDE to 5'GMP which is inactive and does not exhibit physiological activity. Therefore, substances exhibiting inhibitory activity of CGMP PDE may be useful as agents for maintaining or increasing CGMP levels to facilitate metabolism and to prevent or treat various circulatory diseases such as hypertension, angina, arteriosclerosis, chronic bronchial asthma or bronchial inflammation. Can be.

CGMP PDE의 억제제로서 뉴질랜드 Berlex사의 미국특허 제5,318,975호에 하기 일반식(A)의 5-아미노피리미딘 유도체 화합물이 기술되어 있다:As an inhibitor of CGMP PDE, US Pat. No. 5,318,975 to Berlex, New Zealand, describes 5-aminopyrimidine derivative compounds of the general formula (A):

(A)

상기식에서, R₁은 수소 또는 저급 알킬로 치환된 이미다졸이고, R₃은 수소 또는 저급 알킬이며, R₄ 및 R₅는, 독립적으로, 저급 알킬로 치환된 이미다졸카르복사아미드 화합물이다.Wherein R ₁ is imidazole substituted with hydrogen or lower alkyl, R ₃ is hydrogen or lower alkyl, and R ₄ and R ₅ are independently imidazolecarboxamide compounds substituted with lower alkyl.

또 다른 CGMP PDE의 억제제가 일본 ONO사의 유럽특허공고 제640,599호에 기술되어 있는데 그 화합물(B)은 4-아미노 피리미딘 계열로 다음과 같다:Another inhibitor of CGMP PDE is described in European Patent Publication No. 640,599 to ONO of Japan, whose compound (B) is a 4-amino pyrimidine family:

(B)

상기식에서, B₁는 저급 알킬, 저급 알콕시, 할로겐 등으로 치환된 4 내지 15개의 헤테로싸이클릭 고리이고, B₂는 저급 알킬, 저급 알콕시, 할로겐, 니트로, 에스테르 등으로 치환된 4 내지 15개의 헤테로 싸이클릭 고리 또는 히드록시(저급알콕시)이며, B₃는 저급알킬, 저급 알콕시, 할로겐, 니트로, 술폰 등으로 치환된 4 내지 15개의 헤테로 고리 화합물이다.Wherein B ₁ is 4 to 15 heterocyclic rings substituted with lower alkyl, lower alkoxy, halogen, and the like, B ₂ is 4 to 15 hetero substituted with lower alkyl, lower alkoxy, halogen, nitro, ester and the like Cyclic ring or hydroxy (lower alkoxy), B ₃ is 4 to 15 heterocyclic compounds substituted with lower alkyl, lower alkoxy, halogen, nitro, sulfone and the like.

종래의 3',5'-모노포스페이트 포스포디에스터라제 억제제와 구조적으로 상이한 물질과 함께 그의 효율적인 제조방법의 개발이 요구된다.
There is a need for the development of efficient methods of preparation thereof with materials that are structurally different from conventional 3 ', 5'-monophosphate phosphodiesterase inhibitors.

(I)

상기식에서,In the above formula,

X는 결합, C_1-4알킬렌, C_1-4알킬렌옥시, C_1-4알콕시페닐 또는 페닐(C_1-4)알킬렌이고;X is a bond, C _1-4 alkylene, C _1-4 alkyleneoxy, C _1-4 alkoxyphenyl or phenyl (C _1-4 ) alkylene;

Y는 결합 또는 C_1-2알킬이고;Y is a bond or C _1-2 alkyl;

R¹는 (ⅰ) 할로겐, 니트로, 히드록시, C_1-6알킬 및 C_1-4알콕시로 이루어진 그룹중에서 선택된 하나 또는 두개의 기로 치환되거나 비치환된 페닐, (ⅱ) 할로겐, 니트로, 히드록시, C_1-6알킬 및 할로겐C_1-4알콕시로 이루어진 그룹중에서 선택된 하나 또는 두개의 기로 치환되고 질소 및 산소 중에서 선택된 하나 또는 두개의 원자를 함유하는 5 내지 15원의 측쇄사슬 또는 헤테로고리화합물, (ⅲ) C_4-10 카르보싸이클릭 고리화합물 또는 (ⅲ) 히드록시(C_1-4)알콕시이고;R ¹ is (iii) phenyl unsubstituted or substituted with one or two groups selected from the group consisting of halogen, nitro, hydroxy, C _1-6 alkyl and C _1-4 alkoxy, (ii) halogen, nitro, hydroxy , 5 to 15 membered side chain or heterocyclic compound substituted with one or two groups selected from the group consisting of C _1-6 alkyl and halogen C _1-4 alkoxy and containing one or two atoms selected from nitrogen and oxygen, (Iii) C _4-10 carbocyclic cyclic compounds or (iii) hydroxy (C _1-4 ) alkoxy;

R²는 (ⅰ) 히드록시, 할로겐, 니트로, 히드록시(C_1-5)알킬, C_1-6알킬, C _3-6알케닐 및 C_1-4알콕시로 이루어진 그룹 중에서 선택된 하나 또는 두개의 기로 치환되고 질소원자를 1 내지 4개 함유하는 5 내지 6 원의 헤테로 고리화합물 또는 (ⅱ) 히드록시, 할로겐, 니트로, 히드록시(C_1-5)알킬, C_1-6알킬, C_3-6알케닐 및 C_1-4알콕시로 이루어진 그룹 중에서 선택된 하나 또는 두개의 기로 치환되고 질소원자 하나를 함유하면서 산소 또는 황원자 하나를 선택적으로 함유하는 5 내지 15 원의 헤테로 고리화합물 이고;R ² is selected from the group consisting of (i) hydroxy, halogen, nitro, hydroxy (C _1-5 ) alkyl, C _1-6 alkyl, C _3-6 alkenyl and C _1-4 alkoxy 5- to 6-membered heterocyclic compounds substituted with groups and containing 1 to 4 nitrogen atoms or (ii) hydroxy, halogen, nitro, hydroxy (C _1-5 ) alkyl, C _1-6 alkyl, C _{3- A} 5-15 membered heterocyclic compound substituted with one or two groups selected from the group consisting of ₆ alkenyl and C _1-4 alkoxy and containing one nitrogen atom and optionally containing one oxygen or sulfur atom;

R³는 수소,

또는

이며;R ³ is hydrogen,

or

Is;

R⁴ 및 R⁵는 각각 독립적으로 (ⅰ) 아민, 할로겐, 카르복시, C_1-6알킬, 페닐, C_1-4알콕시 및 C_1-4알콕시카르보닐로 이루어진 그룹 중에서 선택된 하나 또는 두개의 기로 치환되고 질소원자를 2 내지 4개 함유하는 5 내지 6 원의 헤테로 고리화합물 또는 (ⅱ) 아민, 할로겐, 카르복시, C_1-6알킬, 페닐, C_1-4알콕시및 C_1-4알콕시카르보닐로 이루어진 그룹 중에서 선택된 하나 또는 두개의 기로 치환되고 질소, 산소 및 황 중에서 선택된 하나 또는 두개의 원자를 함유하는 5 내지 15 원의 헤테로 고리화합물이다.R ⁴ and R ⁵ are each independently substituted with one or two groups selected from the group consisting of amine, halogen, carboxy, C _1-6 alkyl, phenyl, C _1-4 alkoxy and C _1-4 alkoxycarbonyl And 5 to 6 membered heterocyclic compounds containing 2 to 4 nitrogen atoms or (ii) amine, halogen, carboxy, C _1-6 alkyl, phenyl, C _1-4 alkoxy and C _1-4 alkoxycarbonyl And a 5 to 15 membered heterocyclic compound substituted with one or two groups selected from the group consisting of and containing one or two atoms selected from nitrogen, oxygen and sulfur.

본 발명의 화합물(Ⅰ)은 광학 이성질체 또는 기하 이성질체의 형태로 존재할 수 있으며, 본 발명은 이들 이성질체 및 그의 혼합물을 포함한다.Compound (I) of the present invention may exist in the form of optical isomers or geometric isomers, and the present invention includes these isomers and mixtures thereof.

또한, 본 발명은 하기 일반식(III)의 화합물을 하기 일반식(III-1)의 화합물과 반응시키고, 생성된 하기 일반식(IV)의 화합물을 하기 일반식(IV-1)의 화합물과 반응시키고, 생성된 하기 일반식(V)의 화합물을 환원시키고, 생성된 하기 일반식(VI)의 화합물을 하기 일반식(VI-1) 또는 (VI-2)의 화합물과 반응시켜 각각 하기 일반식(I-A) 또는 하기일반식(I-B)의 화합물을 제조하는 방법에 관한 것이다.In addition, the present invention reacts a compound of the general formula (III) with a compound of the general formula (III-1), and the resulting compound of the general formula (IV) and a compound of the general formula (IV-1) React with each other, reducing the resulting compound of formula (V) and reacting the resulting compound of formula (VI) with the compound of formula (VI-1) or (VI-2), respectively It relates to a process for preparing a compound of formula (IA) or the following general formula (IB).

본 발명의 제법을 생성물을 기준으로 반응식으로 도시하면 다음과 같다:The formulation of the present invention is shown in the scheme on the basis of the product as follows:

상기식에서, R¹, R², R⁴, R⁵, X 및 Y는 상기 정의된 바와 같다.Wherein R ¹ , R ² , R ⁴ , R ⁵ , X and Y are as defined above.

상기 반응식에 따르면, 공지의 화합물(Ⅲ)(WO 9510506)은 화합물(Ⅱ)와 포스포러스 옥시클로라이드를 사용하여 염기의 존재하에서 반응을 진행시키는 것이 바람직하며, 염기로는 N,N-다이에틸-아닐린, N,N-다이메틸아닐린 또는 N,N-다이이소프로필에틸아민 등을 사용하여 환류 온도에서 반응을 수행하여 얻을 수 있다.According to the above reaction scheme, known compound (III) (WO 9510506) is preferably reacted in the presence of a base using compound (II) and phosphorus oxychloride, and the base is N, N-diethyl- It can be obtained by carrying out the reaction at reflux temperature using aniline, N, N-dimethylaniline or N, N-diisopropylethylamine or the like.

일반식(Ⅳ)의 화합물은 일반식(Ⅲ)의 화합물을, 바람직하게는 다이클로로메테인 또는 아세토나이트릴을 용매하에 피리딘 또는 트리에틸아민을 사용하여 0℃ 내지 실온에서 일반식(Ⅲ-1)의 화합물과 반응을 수행하여 제조할 수 있다(J. Med. Chem. 1994, 37, 2106):The compound of general formula (IV) is a compound of general formula (III-1) using pyridine or triethylamine in the solvent of the compound of general formula (III), preferably dichloromethane or acetonitrile Can be prepared by reaction with a compound of (J. Med. Chem. 1994, 37, 2106):

HN-X-R¹ (Ⅲ-1)HN-XR ¹ (III-1)

상기식에서, R¹는 상기 정의된 바와 같다.Wherein R ¹ is as defined above.

일반식(V)의 화합물은 일반식(Ⅳ)의 화합물을 극성 용매를 사용하여 용해한 후 0℃ 내지 환류 온도에서 일반식(Ⅳ-1)의 화합물과 반응을 수행하는데 통상적으로 아세토나이트릴, 에탄올 또는 아이소프로판을 등의 용매하에서 순수하게 결정으로 제조할 수 있다:The compound of formula (V) dissolves the compound of formula (IV) using a polar solvent and then reacts with the compound of formula (IV-1) at 0 ° C to reflux temperature, typically acetonitrile, ethanol Or isopropane can be prepared purely in crystals in a solvent such as:

Y-R² (Ⅳ-1)YR ² (Ⅳ-1)

상기식에서, R²는 상기 정의된 바와 같다.Wherein R ² is as defined above.

일반식(Ⅵ)의 화합물은 통상적인 방법으로 일반식(Ⅴ)의 화합물을 철과 산을 극성 용매에서 환류하여 반응을 진행시키거나(WO 9518097), 5％ 팔라디움 활성탄과 소듐보로하이드라이드를 사용하여 메탄올 또는 에탄올 등 용매하에 0℃ 내지 25℃에서 반응을 진행하여 제조하였다(Synthesis, 1994, 1437).The compound of formula (VI) is reacted by refluxing the compound of formula (V) by iron and acid in a polar solvent in a conventional manner (WO 9518097), or by using 5% palladium activated carbon and sodium borohydride. It was prepared by proceeding the reaction at 0 ℃ to 25 ℃ in a solvent such as methanol or ethanol (Synthesis, 1994, 1437).

일반식(Ⅵ)의 화합물과 일반식(Ⅵ-1)의 화합물인 카르복실산을 활성화시킨 화합물이나 애시드 클로라이드를 아세토나이트릴, 다이클로로메테인 또는 테트라하이드로퓨란 등 용매하에 피리딘, 트리에틸아민 또는 N,N-다이소프로필에틸아민 등 염기를 사용하여 0 내지 35℃ 온도에서 반응을 진행시켜 각각 일반식(Ⅰ-A)의 화합물을 제조하였다. 이때 카르복실산을 활성화시키는 방법으로 싸이오닐 클로라이드를 사용하여 애시드 클로라이드를 합성하거나 1-하이드록시트리아졸과 1,3-디싸이클로헥실다이이미드를 이용하여 활성화된 에스테르를 제조하는 방법을 인용하였다:Pyridine, triethylamine, or a compound obtained by activating a compound of formula (VI) and a carboxylic acid which is a compound of formula (VI-1) or an acid chloride in a solvent such as acetonitrile, dichloromethane or tetrahydrofuran Reaction was performed at 0-35 degreeC temperature using the base, such as N, N- diisopropyl ethylamine, and the compound of general formula (I-A) was respectively prepared. Here, the method of activating carboxylic acid is cited to synthesize acid chloride using thionyl chloride or to prepare activated ester using 1-hydroxytriazole and 1,3-dicyclohexyldiimid.

또는

(Ⅵ-1)

or

(VI-1)

(I-A)

(IA)

또한, 일반식(Ⅵ)의 화합물과 일반식(Ⅵ-2)의 화합물인 술폰일 클로라이드를 아세토나이트릴, 다이클로로메테인 또는 테트라하이드로퓨란 등 용매하에 피리딘 또는 N,N-다이이소프로필에틸아민 등 염기를 사용하여 0℃ 내지 35℃에서 반응을 진행시켜 각각 일반식(I-B)의 화합물을 제조하였다:In addition, the compound of formula (VI) and sulfonyl chloride, which is a compound of formula (VI-2), are pyridine or N, N-diisopropylethylamine in a solvent such as acetonitrile, dichloromethane or tetrahydrofuran. The reaction was carried out at 0 ° C. to 35 ° C. using isobases to prepare compounds of formula (IB), respectively:

(Ⅵ-2)

(VI-2)

(I-B)

(IB)

하기 실시예로 본 발명을 더욱 구체적으로 설명한다. 그러나, 이들 실시예로 본 발명을 한정하는 것으로 이해되어서는 안된다. The present invention is explained in more detail with reference to the following examples. However, these examples should not be understood as limiting the invention.

참고예 1Reference Example 1

2,4-디클로로-5-나이트로피리미딘2,4-dichloro-5-nitropyrimidine

5-니트로우라실 25gr을 포스포러스옥시 클로라이드 490ml에 10분간 현탁시킨 후 다이소프로필에틸아민을 실온에서 천천히 가한 다음 현탁용액을 130℃ 에서 3시간 동안 환류시킨다. 반응용액을 감압증류하여 부피가 100ml 정도의 반응용액을 얼음물 500ml에 천천히 적가하여 1시간 교반한 다음 다이에틸에테르 각 300ml로 5회 추출한다. 유기 용액층을 포화된 암모니움 클로라이드 500ml로 세척, 무수 황산마그네슘으로 탈수하고 감압증류한 다음 실리카젤 칼럼크로마토그라피(아세트산 에틸 : 헥산 = 1 : 5)로 분리하여 표제화합물 16.8gr을 얻었다.25 gr of 5-nitrouracil was suspended in 490 ml of phosphorusoxy chloride for 10 minutes, and then disopropylethylamine was slowly added at room temperature, and the suspension was refluxed at 130 ° C. for 3 hours. The reaction solution was distilled under reduced pressure, and a volume of about 100 ml was slowly added dropwise to 500 ml of ice water, stirred for 1 hour, and extracted five times with 300 ml of diethyl ether. The organic solution layer was washed with 500 ml of saturated ammonium chloride, dehydrated with anhydrous magnesium sulfate, distilled under reduced pressure, and separated by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to obtain the title compound (16.8gr).

NMR (CDCl₃, 400MHZ): δ = 8.82(1H,s)NMR (CDCl ₃ , 400MHZ): δ = 8.82 (1H, s)

참고예 2 Reference Example 2

4N-벤질-2-클로로-5-나이트로피리미딘아민4N-benzyl-2-chloro-5-nitropyrimidinamine

참고예1의 합성물질 5.0gr을 다이클로로메테인 75ml에 용해한 후 5℃에서 벤질아민 2.7ml을 투입하여 1시간 동안 교반한다. 5℃에서 트리에틸아민 3.6ml을 가하여 10분간 교반한 다음 포화 중탄산 나트륨 150ml로 세척, 무수 황산마그네슘으로 탈수하고 감압건조하여 표제화합물 6.6gr을 얻었다.After dissolving 5.0 gr of the synthetic material of Reference Example 1 in 75 ml of dichloromethane, 2.7 ml of benzylamine was added at 5 ° C. and stirred for 1 hour. 3.6 ml of triethylamine was added at 5 ° C, stirred for 10 minutes, washed with 150 ml of saturated sodium bicarbonate, dehydrated with anhydrous magnesium sulfate, and dried under reduced pressure to obtain 6.6 gr of the title compound.

NMR (CDC1₃, 400MHz): δ = 4.68(2H, d), 7.17(5H, m), 8.65(1H, t), 8.84(1H, s)NMR (CDC1 ₃ , 400 MHz): δ = 4.68 (2H, d), 7.17 (5H, m), 8.65 (1H, t), 8.84 (1H, s)

참고예 3Reference Example 3

2-클로로-4N-(1,3-디옥사인단-5-일)메틸-5-나이트로피리미딘아민2-chloro-4N- (1,3-dioxanedan-5-yl) methyl-5-nitropyrimidinamine

참고예1의 합성물질 5.0gr을 다이클로로메테인 75mml에 용해한 후 5℃에서 피페로닐아민 3.0ml을 투입하여 1시간동안 교반한다. 5℃에서 트리에틸아민 3.6ml을 가하여 10분간 교반한 다음 포화 중탄산 나트륨 150ml로 세척, 무수 황산마그네슘으로 탈수하고 감압건조하여 표제화합물 6.9gr을 얻었다.After dissolving 5.0 gr of the synthetic material of Reference Example 1 in 75mml of dichloromethane, 3.0 ml of piperonylamine was added at 5 ° C, and stirred for 1 hour. 3.6 ml of triethylamine was added at 5 ° C, stirred for 10 minutes, washed with 150 ml of saturated sodium bicarbonate, dehydrated with anhydrous magnesium sulfate, and dried under reduced pressure to obtain 6.9 gr of the title compound.

NMR (CDC1₃, 400MHz): δ = 4.60(2H, d), 5.95(2H, s), 6.86(1H, d), NMR (CDC1 ₃ , 400 MHz): δ = 4.60 (2H, d), 5.95 (2H, s), 6.86 (1H, d),

6.91(1H, d), 7.03(1H, d), 8.61(1H, t), 8.85(1H, s)6.91 (1H, d), 7.03 (1H, d), 8.61 (1H, t), 8.85 (1H, s)

참고예 4Reference Example 4

에틸 1-[4-벤질아미노-5-나이트로피리미딘-2-일)-4-피페리딘카르복실레이트Ethyl 1- [4-benzylamino-5-nitropyrimidin-2-yl) -4-piperidinecarboxylate

참고예2의 합성물질 1.0gr을 아세토나이트릴 35ml에 용해한 후 실온에서 에틸 아이소니페코테이트 3.5ml을 투입하여 일야 교반한다. 형성된 현탁액에 에탄올 35ml을 투입하고 5℃로 냉각한 다음 1시간 동안 교반한 후 여과하여 노란색의 표제화합물 0.91gr을 얻었다.1.0 g of the synthetic material of Reference Example 2 was dissolved in 35 ml of acetonitrile, and 3.5 ml of ethyl isonifate was added at room temperature and stirred overnight. 35 ml of ethanol was added to the formed suspension, cooled to 5 ° C., stirred for 1 hour, and filtered to obtain 0.91 gr of the title compound as a yellow color.

NMR (CDC1₃, 400MHz): δ = 1.06(3H, t), 1.51(2H, m), 1.79(2H, ABq),NMR (CDC1 ₃ , 400 MHz): δ = 1.06 (3H, t), 1.51 (2H, m), 1.79 (2H, ABq),

2.39(1H, m), 2.97(2H, m), 3.95(2H, q), 4.40(2H, d), 4.54(2H, d),2.39 (1H, m), 2.97 (2H, m), 3.95 (2H, q), 4.40 (2H, d), 4.54 (2H, d),

7.15(5H, m), 8.54(1H, t), 8.82(1H, s)7.15 (5H, m), 8.54 (1H, t), 8.82 (1H, s)

참고예 5Reference Example 5

4N-벤질-2-(4-에틸피페라지노)-5-나이트로-4-피리미딘아민4N-benzyl-2- (4-ethylpiperazino) -5-nitro-4-pyrimidinamine

참고예2의 합성물질 4N-벤질-2-클로로-5-나이트로피리미딘아민을 출발물질로 하여 표제화합물을 참고예4의 제조방법에 의거 제조하였다.Synthesis of Reference Example 2 The title compound was prepared according to the preparation method of Reference Example 4, using 4N-benzyl-2-chloro-5-nitropyrimidinamine as a starting material.

NMR (CDC1₃ , 400MHz): δ = 0.93(3H, t), 2.25(6H, m), 3.79(4H, m), NMR (CDC1 ₃ , 400 MHz): δ = 0.93 (3H, t), 2.25 (6H, m), 3.79 (4H, m),

4.55(2H, d), 7.16(5H, m), 8.58(1H, t), 8.81(1H, s)4.55 (2H, d), 7.16 (5H, m), 8.58 (1H, t), 8.81 (1H, s)

참고예 6Reference Example 6

4N-(1,3-디옥사인단-5-일)메틸-2-(2-에틸-4-메틸-1H-이미다졸-1-일)-5-나이트로피리미딘아민4N- (1,3-dioxanedan-5-yl) methyl-2- (2-ethyl-4-methyl-1H-imidazol-1-yl) -5-nitropyrimidinamine

참고예3의 합성물질 2-클로로-4N-(1,3-디옥사인단-5-일)메틸-5-나이트로피리미딘아민을 출발물질로 하여 표제화합물을 참고예4의 제조방법에 의거 제조하였다.Synthesis of Reference Example 3 Based on the preparation method of Reference Example 4, the title compound was prepared using 2-chloro-4N- (1,3-dioxanedan-5-yl) methyl-5-nitropyrimidinamine as starting material. Prepared.

NMR (CDC1₃, 400MHz): δ = 1.31(3H, t), 2.24(3H, s), 3.22(2H, q), NMR (CDC1 ₃ , 400 MHz): δ = 1.31 (3H, t), 2.24 (3H, s), 3.22 (2H, q),

4.78(2H, d), 6.00(2H, s), 6.94(3H, m), 7.58(1H, s), 8.72(1H, t),4.78 (2H, d), 6.00 (2H, s), 6.94 (3H, m), 7.58 (1H, s), 8.72 (1H, t),

9.25(1H, s)9.25 (1 H, s)

참고예 7Reference Example 7

4N-벤질-2-(1H-1,2,3-트리아졸-1-일)-5-나이트로피리미딘아민4N-benzyl-2- (1H-1,2,3-triazol-1-yl) -5-nitropyrimidinamine

NMR (CDC1₃, 400MHz): δ = 4.61(2H, d), 7.23(5H, m), 7.45(1H, s),NMR (CDC1 ₃ , 400 MHz): δ = 4.61 (2H, d), 7.23 (5H, m), 7.45 (1H, s),

7.69(1H, d), 7.69(1H, d), 8.24(1H, t), 8.47(1H, d)7.69 (1H, d), 7.69 (1H, d), 8.24 (1H, t), 8.47 (1H, d)

참고예 8Reference Example 8

4N-(1,3-디옥사인단-5-일)메틸-2-(1H-이미다졸-1-일)-5-나이트로피리미딘아민4N- (1,3-dioxanedan-5-yl) methyl-2- (1H-imidazol-1-yl) -5-nitropyrimidinamine

참고예3의 합성물질 2-클로로-4N-(1,3-디옥사인단-5-일)메틸-5-나이트로피리미딘아민 1.75gr을 아세토나이트릴 60ml에 용해한 후 실온에서 1H-이미다졸2.3gr 투입하여 일야교반한다. 형성된 현탁액을 감압증류한 후 형성된 고체를 물 : 에탄올 = 40 : 100ml에서 30분간 현탁시킨 후 여과, 건조하여 표제화합물 1.55gr을 얻었다.Synthesis Material of Reference Example 3 1.75 gr of 2-chloro-4N- (1,3-dioxayndan-5-yl) methyl-5-nitropyrimidinamine was dissolved in 60 ml of acetonitrile and then 1H-imidazole at room temperature. Put 2.3gr and stir overnight. The resulting suspension was distilled under reduced pressure, and then the formed solid was suspended in water: ethanol = 40: 100 ml for 30 minutes, filtered and dried to obtain 1.55 gr of the title compound.

NMR (CDC1₃, 400MHz): δ = 4.72(2H, d), 6.09(2H, s), 6.98(2H, d), 7.03(1H, s),NMR (CDC1 ₃ , 400 MHz): δ = 4.72 (2H, d), 6.09 (2H, s), 6.98 (2H, d), 7.03 (1H, s),

7.13(1H, s), 7.80(1H, s), 8.35(1H, t), 8.40(1H, s), 9.18(1H, s)7.13 (1H, s), 7.80 (1H, s), 8.35 (1H, t), 8.40 (1H, s), 9.18 (1H, s)

참고예 9Reference Example 9

4N-벤질-5-나이트로-2-(1H-테트라졸-1-일)피리미딘아민4N-benzyl-5-nitro-2- (1H-tetrazol-1-yl) pyrimidinamine

1H-테트라졸 3.0gr을 아세토나이트릴 120ml에 용해한 후 참고예2의 합성물질 4N-벤질-2-클로로-5-나이트로피리미딘아민 4.0gr을 가한 다음 트리에틸아민 2.5ml을 아세토나이트릴 45ml에 희석하여 천천히 적가한다. 실온에서 일야 교반한 후 용매를 감압 증류하여 형성된 고상물을 3N 수산화나트륨 용액에 1시간 동안 현탁시킨 후 여과, 건조하여 표제화합물 3.80gr을 얻었다.After dissolving 3.0 g of 1H-tetrazole in 120 ml of acetonitrile, 4.0 g of 4N-benzyl-2-chloro-5-nitropyrimidinamine (synthesis) of Reference Example 2 was added, followed by 2.5 ml of triethylamine and 45 ml of acetonitrile. Dilute to and slowly add dropwise. After stirring at room temperature overnight, the solvent was distilled under reduced pressure, and the solid formed was suspended in 3N sodium hydroxide solution for 1 hour, filtered and dried to obtain 3.80 gr of the title compound.

NMR (CDC1₃, 400MHz): δ = 4.99(2H, d), 7.44(5H, m), 8.79(1H, t), 9.32(1H, s),NMR (CDC1 ₃ , 400 MHz): δ = 4.99 (2H, d), 7.44 (5H, m), 8.79 (1H, t), 9.32 (1H, s),

9.48(1H, s)9.48 (1 H, s)

참고예 10Reference Example 10

에틸 1-(5-아미노-4-벤질아미노피리미딘-2-일)-4-피페리딘카르복실레이트Ethyl 1- (5-amino-4-benzylaminopyrimidin-2-yl) -4-piperidinecarboxylate

참고예4의 합성물질 에틸 1-[4-벤질아미노-5-나이트로피리미딘-2-일)-4-피페리딘카르복실레이트 0.90gr을 에탄올 50ml에 현탁시킨 후 초산 1.3ml, 증류수 1.3ml 그리고 철 1.40gr을 투입하고 현탁용액을 5시간 동안 환류시킨다. 진한 청색의 현탁용액을 여과하여 불용물을 제거한 후 감압증류하여 수득한 담황색의 유상물을 다이클로로메테인에 용해한 후 10％ 탄산나트륨 용액 50ml으로 2회 세척한다. 유기용액층을 무수 황산마그네슘으로 건조한 후 감압증류하여 유상물 0.57gr의 표제화합물을 얻었다.Synthesis of Reference Example 4 0.90 gr of ethyl 1- [4-benzylamino-5-nitropyrimidin-2-yl) -4-piperidinecarboxylate was suspended in 50 ml of ethanol, followed by 1.3 ml of acetic acid and 1.3 distilled water. Add ml and 1.40 gr of iron and reflux the suspension for 5 hours. The dark blue suspension solution is filtered to remove the insolubles, and the pale yellow oil obtained by distillation under reduced pressure is dissolved in dichloromethane and washed twice with 50 ml of 10% sodium carbonate solution. The organic solution layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain the title compound as an oil, 0.57 gr.

NMR (DMSO-d6, 400MHz): δ = 1.04(3H, t), 1.45(2H, m), 1.76(2H, m),NMR (DMSO-d6, 400 MHz): δ = 1.04 (3H, t), 1.45 (2H, m), 1.76 (2H, m),

2.41(1H, m), 2.91(2H, m), 3.93(2H, q), 4.40(2H, d), 4.48(2H, d),2.41 (1H, m), 2.91 (2H, m), 3.93 (2H, q), 4.40 (2H, d), 4.48 (2H, d),

5.31(2H, s), 7.20(5H, m), 7.54(1H, t), 7.62(1H, s).5.31 (2H, s), 7.20 (5H, m), 7.54 (1H, t), 7.62 (1H, s).

참고예 11Reference Example 11

4N-벤질-2-(4-에틸피페라지노)-5-피리미딘다이아민4N-benzyl-2- (4-ethylpiperazino) -5-pyrimidinediamine

참고예 5의 합성물질 4N-벤질-2-(4-에틸피페라지노)-5-나이트로-4-피리미딘아민을 출발물질로 하여 표제화합물을 참고예 10의 제조방법에 의거 제조하였다.Synthesis of Reference Example 5 The title compound was prepared according to the preparation method of Reference Example 10, using 4N-benzyl-2- (4-ethylpiperazino) -5-nitro-4-pyrimidinamine as a starting material.

NMR (CDC1₃, 400MHz): δ = 0.92(3H, t), 2.23(6H, m), 3.75(4H, m), 4.48(2H, d),NMR (CDC1 ₃ , 400 MHz): δ = 0.92 (3H, t), 2.23 (6H, m), 3.75 (4H, m), 4.48 (2H, d),

5.31(2H, s), 7.15(5H, m), 7.38(1H, t), 7.60(1H, s).5.31 (2H, s), 7.15 (5H, m), 7.38 (1H, t), 7.60 (1H, s).

참고예 12Reference Example 12

4N-(1,3-디옥사인단-5-일)메틸-2-(2-에틸-4-메틸-1H-이미다졸-1-일)-5-피리미딘다이아민4N- (1,3-dioxanedan-5-yl) methyl-2- (2-ethyl-4-methyl-1H-imidazol-1-yl) -5-pyrimidinediamine

참고예 6의 합성물질 4N-(1,3-디옥사인단-5-일)메틸-2-(2-에틸-4-메틸-1H-이미다졸-1-일)-5-나이트로피리미딘아민을 출발물질로 하여 표제화합물을 참고예10의 제조방법에 의거 제조하였다.Synthesis of Reference Example 6 4N- (1,3-dioxayndan-5-yl) methyl-2- (2-ethyl-4-methyl-1H-imidazol-1-yl) -5-nitropyrimidine Using the amine as a starting material, the title compound was prepared according to the preparation method of Reference Example 10.

NMR (DMSO-d6 , 400MHz): δ = 1.20(3H, t), 2.27(3H, s), 3.17(2H, q),NMR (DMSO-d6, 400 MHz): δ = 1.20 (3H, t), 2.27 (3H, s), 3.17 (2H, q),

4.55(2H, d), 5.33(2H, s), 5.98(2H, s), 6.86(2H, q), 6.93(1H, s),4.55 (2H, d), 5.33 (2H, s), 5.98 (2H, s), 6.86 (2H, q), 6.93 (1H, s),

7.60(1H, s), 7.77(1H, s), 7.93(1H, t).7.60 (1 H, s), 7.77 (1 H, s), 7.93 (1 H, t).

참고예 13Reference Example 13

4N-벤질-2-(1H-1,2,3-트리아졸-1-일)-5-나이트로피리미딘다이아민4N-benzyl-2- (1H-1,2,3-triazol-1-yl) -5-nitropyrimidinediamine

참고예 7의합성물질 4N-벤질-2-(1H-1,2,3-트리아졸-1-일)-5-나이트로피리미딘아민을 출발물질로 하여 표제화합물을 참고예 10의 제조방법에 의거 제조하였다.Synthesis of Reference Example 7 Preparation of Reference Example 10 using 4N-benzyl-2- (1H-1,2,3-triazol-1-yl) -5-nitropyrimidinamine as starting material It prepared according to.

NMR (CDC1₃, 400MHz): δ = 4.52(2H, d), 5.31(2H, s), 7.18(5H, m), 7.38(1H, s),NMR (CDC1 ₃ , 400 MHz): δ = 4.52 (2H, d), 5.31 (2H, s), 7.18 (5H, m), 7.38 (1H, s),

7.61(1H, d), 8.18(1H, t), 8.39(1H, d)7.61 (1H, d), 8.18 (1H, t), 8.39 (1H, d)

참고예 14Reference Example 14

4N-(1,3-디옥사인단-5-일) 메틸-2-(1H-이미다졸-1-일)-5-피리미딘다이아민4N- (1,3-dioxadindan-5-yl) methyl-2- (1H-imidazol-1-yl) -5-pyrimidinediamine

참고예8의 합성물질 4N-(1,3-디옥사인단-5-일)메틸-2-(1H-이미다졸-1-일)-5-나이트로피리미딘아민을 출발물질로 하여 표제화합물을 참고예10의 제조방법에 의거 제조하였다.Synthesis of Reference Example 8 Title compound with 4N- (1,3-dioxayndan-5-yl) methyl-2- (1H-imidazol-1-yl) -5-nitropyrimidinamine as starting material It was prepared according to the preparation method of Reference Example 10.

NMR (DMSO-d6 , 400MHz): δ = 4.68(2H, d), 5.38(2H, s), 6.05(2H, s),NMR (DMSO-d6, 400 MHz): δ = 4.68 (2H, d), 5.38 (2H, s), 6.05 (2H, s),

6.97(2H, d), 7.02(1H, s), 7.13(1H, s), 7.46(1H, t), 7.67(1H, s),6.97 (2H, d), 7.02 (1H, s), 7.13 (1H, s), 7.46 (1H, t), 7.67 (1H, s),

7.80(1H, s), .37(1H, s)7.80 (1 H, s), .37 (1 H, s)

참고예 15Reference Example 15

4N-벤질-2-(1H-테트라졸-1-일)-5-피리미딘다이아민4N-benzyl-2- (1H-tetrazol-1-yl) -5-pyrimidinediamine

참고예9의 합성물질 4N-벤질-5-나이트로-2-(1H-테트라졸-1-일)피리미딘아민을 출발물질로 하여 표제화합물을 참고예10의 제조방법에 의거 제조하였다.Synthesis of Reference Example 9 The title compound was prepared according to the preparation method of Reference Example 10, using 4N-benzyl-5-nitro-2- (1H-tetrazol-1-yl) pyrimidinamine as a starting material.

NMR (DMSO-d6 , 400MHz): δ = 4.72(2H, d), 5.36(2H, s), 7.28(1H, t), NMR (DMSO-d6, 400 MHz): δ = 4.72 (2H, d), 5.36 (2H, s), 7.28 (1H, t),

7.34(2H, t), 7.43(2H, t), 7.63(1H, s), 7.65(1H, t), 9.94(1H, s)7.34 (2H, t), 7.43 (2H, t), 7.63 (1H, s), 7.65 (1H, t), 9.94 (1H, s)

실시예 1 Example 1

5-(2-싸이엔일카르복스아미도)-4-(1,3-다이옥사인단-5-일)메틸아미노-2-(2-에틸-4-메틸-1H-이미다졸-1-일)피리미딘5- (2-thienylcarboxamido) -4- (1,3-dioxanedan-5-yl) methylamino-2- (2-ethyl-4-methyl-1H-imidazole-1- (Py) pyrimidine

4N-(1,3-다이옥사인단-5-일)메틸-2-(2-에틸-4-메틸-1H-이미다졸-1-일)피리미딘디아민 0.20gr(0.57mmole)을 다이클로로메테인 60ml에 용해한 후 2-싸이오펜카르보닐 클로라이드 0.073ml을 20~22℃에서 투입하고 10분간 교반한다. 반응용액에 피리딘 0.18ml을 주사기로 투입한 후 14시간 동안 20~22℃에서 교반하여 반응을 진행시키고 1.5N 수산화나트륨 용액 30ml, 1.5N염산용액 30ml, 증류수 60ml으로 세척한다. 유기층을 분리하고 무수 황산마그네슘으로 건조하고 감압증류하여 담황색의 유상물을 실리카젤 컬럼 크로마토그래피(에틸아세테이트:헥산=4:1(v/v))를 이용하여 백색의 표제화합물 0.21gr(80.0%)을 얻었다.4N- (1,3-dioxanedan-5-yl) methyl-2- (2-ethyl-4-methyl-1H-imidazol-1-yl) pyrimidinediamine 0.20gr (0.57mmole) in dichloromethane After dissolving in 60 ml of phosphorus, 0.073 ml of 2-thiophencarbonyl chloride was added at 20-22 ° C. and stirred for 10 minutes. 0.18ml of pyridine was added to the reaction solution with a syringe, followed by stirring at 20-22 ° C. for 14 hours. The reaction was then carried out and washed with 30ml of 1.5N sodium hydroxide solution, 30ml of 1.5N hydrochloric acid solution and 60ml of distilled water. The organic layer was separated, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to give a pale yellow oily substance by silica gel column chromatography (ethyl acetate: hexane = 4: 1 (v / v)). )

융점 : 143~145℃Melting Point: 143 ~ 145 ℃

NMR (DMSO-d6 , 400MHz): δ = 1.05(3H, t), 2.07(3H, d), 2.95(2H, q),NMR (DMSO-d6, 400 MHz): δ = 1.05 (3H, t), 2.07 (3H, d), 2.95 (2H, q),

4.53(2H, d), 5.96(2H, s), 6.84(2H, m), 6.94(1H, d), 7.24(1H, dd),4.53 (2H, d), 5.96 (2H, s), 6.84 (2H, m), 6.94 (1H, d), 7.24 (1H, dd),

7.43(1H, d), 7.87(1H, dd), 7.85(2H, m), 8.12(1H, t), 10.05(1H, s)7.43 (1H, d), 7.87 (1H, dd), 7.85 (2H, m), 8.12 (1H, t), 10.05 (1H, s)

실시예 2Example 2

5N-[4-(1,3-다이옥사인단-5-일)메틸아미노-2-(2-에틸-4-메틸-1H-1-이미다졸릴)-5-피리미딘일]-3-(2-클로로페닐)-4-메틸-5-아이소옥사졸카르복사아미드5N- [4- (1,3-dioxanedan-5-yl) methylamino-2- (2-ethyl-4-methyl-1H-1-imidazolyl) -5-pyrimidinyl] -3- (2-chlorophenyl) -4-methyl-5-isoxazolecarboxamide

4N-(1,3-다이옥사인단-5-일)메틸-2-(2-에틸-4-메틸-1H-이미다졸-1-일)피리미딘디아민 0.20gr(0.57mmole)을 다이클로로메테인60ml에 용해한 후 3-(2-클로로페닐)-5-메틸아이소옥사졸-4-카르보닐 클로라이드 0.18gr을 20~22℃에서 투입하고 10분간 교반한다. 반응용액에 피리딘 0.18ml을 주사기로 투입한 후 21시간 동안 20~22℃에서 교반하여 반응을 진행시키고 1.5N 수산화나트륨용액 30ml, 1.5N염산용액 30ml, 증류수 60ml으로 연속하여 세척한다. 유기층을 분리하고 무수 황산마그네슘으로 건조하고 감압증류하여 담황색의 유상물을 실리카젤 칼럼 크로마토그래피(에틸아세테이트:헥산=3:1(v/v))를 이용하여 백색의 표제화합물 0.28gr(86.2%)을 얻었다.4N- (1,3-dioxanedan-5-yl) methyl-2- (2-ethyl-4-methyl-1H-imidazol-1-yl) pyrimidinediamine 0.20gr (0.57mmole) in dichloromethane After dissolving in 60 ml of phosphorus, 0.18 gr of 3- (2-chlorophenyl) -5-methylisoxazole-4-carbonyl chloride was added at 20 to 22 ° C and stirred for 10 minutes. 0.18ml of pyridine was added to the reaction solution with a syringe, followed by stirring at 20-22 ° C. for 21 hours to proceed with reaction. The solution was washed successively with 30ml of 1.5N sodium hydroxide solution, 30ml of 1.5N hydrochloric acid solution and 60ml of distilled water. The organic layer was separated, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to give a pale yellow oily substance by silica gel column chromatography (ethyl acetate: hexane = 3: 1 (v / v)). )

융점 : 115~117℃Melting Point: 115 ~ 117 ℃

NMR (DMSO-d6 , 400MHz): δ = 1.09(3H, t), 2.06(3H, d), 2.77(3H, s),NMR (DMSO-d6, 400 MHz): δ = 1.09 (3H, t), 2.06 (3H, d), 2.77 (3H, s),

2.93(2H, q), 4.50(2H, d), 5.96(2H, s), 6.79(1H, dd), 6.84(2H, d),2.93 (2H, q), 4.50 (2H, d), 5.96 (2H, s), 6.79 (1H, dd), 6.84 (2H, d),

6.98(1H, d), 7.39(1H, d), 7.54(4H, m), 7.81(1H,brs), 8.08(1H, s),6.98 (1H, d), 7.39 (1H, d), 7.54 (4H, m), 7.81 (1H, brs), 8.08 (1H, s),

9.77(1H, brs)9.77 (1 H, brs)

실시예 3Example 3

4-(1,3-다이옥사인단-5-일)메틸아미노-2-(2-에틸-4-메틸-1H-1-이미다졸일)-5-(4-피리딜카르복스아미도)피리미딘4- (1,3-dioxanedan-5-yl) methylamino-2- (2-ethyl-4-methyl-1H-1-imidazolyl) -5- (4-pyridylcarboxamido) Pyrimidine

4N-(1,3-다이옥사인단-5-일)메틸-2-(2-에틸-4-메틸-1H-이미다졸-1-일)피리미딘디아민 0.20gr(0.57mmole)을 다이클로로메테인 60ml에 용해한 후 아이소니코틴일 클로라이드 염산염0.12gr을 20~22℃에서 투입하고 20분간 교반한다. 현탁용액에 피리딘 0.36ml을 주사기로 투입한 후 가온하여 35℃에서 20시간 동안 교반한다. 얻어진 반응용액을 1.5N 수산화나트륨 30ml, 1.5N염산용액 30ml, 증류수 60ml으로 세척한다. 유기층을 분리하고 무수 황산마그네슘으로 건조하고 감압증류하여 담황색의 유상물을 실리카젤 칼럼 크로마토그래피(에틸아세테이트:헥산=5:1(v/v))를 이용하여 백색의 표제화합물 0.22gr(84.7%)을 얻었다.4N- (1,3-dioxanedan-5-yl) methyl-2- (2-ethyl-4-methyl-1H-imidazol-1-yl) pyrimidinediamine 0.20gr (0.57mmole) in dichloromethane After dissolving in 60 ml of phosphorus, 0.12gr of isonicotinyl chloride hydrochloride was added at 20-22 ° C. and stirred for 20 minutes. 0.36 ml of pyridine was added to the suspension solution by a syringe, and then heated and stirred at 35 ° C. for 20 hours. The obtained reaction solution was washed with 30 ml of 1.5 N sodium hydroxide, 30 ml of 1.5 N hydrochloric acid solution and 60 ml of distilled water. The organic layer was separated, dried over anhydrous magnesium sulfate, and distilled under reduced pressure, and the pale yellow oily substance was purified by silica gel column chromatography (ethyl acetate: hexane = 5: 1 (v / v)) to give the title compound (0.22gr, 84.7%). )

융점 : 128~130℃Melting Point: 128 ~ 130 ℃

NMR (DMSO-d6 , 400MHz): δ =1.22(3H, t), 2.29(3H, d), 3.24(2H, q),NMR (DMSO-d6, 400 MHz): δ = 1.22 (3H, t), 2.29 (3H, d), 3.24 (2H, q),

4.57(2H, d), 5.97(2H, s), 6.87(2H, m), 6.96(1H, d), 7.93(1H, d),4.57 (2H, d), 5.97 (2H, s), 6.87 (2H, m), 6.96 (1H, d), 7.93 (1H, d),

8.00(2H, dd), 8.29(1H, d), 8.51(1H, t), 8.83(2H, dd), 10.46(1H, s)8.00 (2H, dd), 8.29 (1H, d), 8.51 (1H, t), 8.83 (2H, dd), 10.46 (1H, s)

실시예 4Example 4

에틸1-[4-벤질아미노-5-(4-피리딜카르복스아미도)-2-피리미딘일]-4-피페리딘카르복실레이트Ethyl 1- [4-benzylamino-5- (4-pyridylcarboxamido) -2-pyrimidinyl] -4-piperidinecarboxylate

에틸1-(5-아미노-4-벤질아미노피리미딘-2-일)-4-피페리딘카르복실레이트 0.20gr (0.56mmole)을 다이클로로메테인 60ml에 용해한 후 아이소니코틴일 클로라이드 염산염0.12gr을 20~22℃에서 투입하고 20분간 현탁 교반한다. 현탁용액에 피리딘 0.10ml을 주사기로 투입한 후 가온하여 35℃에서 20시간 동안 교반한다. 얻어진 반응용액을 1.5N 수산화나트륨 30ml, 1.5N염산용액 30ml, 증류수 60ml으로 세척한다. 유기층을 분리하고 무수 황산마그네슘으로 건조하고 감압증류하여 담황색의 유상물을 실리카젤 칼럼 크로마토그래피(에틸아세테이트:헥산=5:1(v/v))를 이용하여 백색의 표제화합물 0.21gr(81.0%)을 얻었다.Isonicotinyl chloride hydrochloride 0.12gr after dissolving 0.20gr (0.56mmole) of ethyl1- (5-amino-4-benzylaminopyrimidin-2-yl) -4-piperidinecarboxylate in 60ml of dichloromethane To 20 ~ 22 ℃ and stirred for 20 minutes. 0.10ml of pyridine was added to the suspension solution with a syringe, which was then heated and stirred at 35 ° C for 20 hours. The obtained reaction solution was washed with 30 ml of 1.5 N sodium hydroxide, 30 ml of 1.5 N hydrochloric acid solution and 60 ml of distilled water. The organic layer was separated, dried over anhydrous magnesium sulfate, and distilled under reduced pressure. The pale yellow oily substance was purified by silica gel column chromatography (ethyl acetate: hexane = 5: 1 (v / v)), and the title compound of white color was 0.21 gr (81.0%). )

융점 : 152~153℃Melting Point: 152 ~ 153 ℃

NMR (DMSO-d6, 400MHz): δ = 1.08(3H, t), 1.43(2H, m), 1.72(2H, m),NMR (DMSO-d6, 400 MHz): δ = 1.08 (3H, t), 1.43 (2H, m), 1.72 (2H, m),

2.40(1H, m), 2.91(2H, m), 3.93(2H, q), 4.34(2H, d), 4.44(2H, d),2.40 (1H, m), 2.91 (2H, m), 3.93 (2H, q), 4.34 (2H, d), 4.44 (2H, d),

7.20(5H, m), 7.54(1H, t), 8.00(2H, dd), 8.24(1H, s), 8.89(2H, dd)7.20 (5H, m), 7.54 (1H, t), 8.00 (2H, dd), 8.24 (1H, s), 8.89 (2H, dd)

실시예 5Example 5

1-[4-벤질아미노-5-(4-피리딜카르복스아미도)-2-피리미딘일]-4-피페리딘카르복실산1- [4-benzylamino-5- (4-pyridylcarboxamido) -2-pyrimidinyl] -4-piperidinecarboxylic acid

실시예4에서 합성한 에틸 1-[4-벤질아미노-5-(4-피리딜카르복스아미도)-2-피리미딘일]-4-피페리딘카르복실레이트 0.18gr(0.39mmole)을 메탄올 18ml에 용해하고 1.5N 수산화나트륨 10ml을 가한 후 20℃에서 30분간 교반하여 가수분해반응을 진행한다. 반응용액을 감압증류하여 유기용매를 제거한 후 수층 반응용액의 pH를 1.5N염산용액을 사용하여 pH3.5로 조정하여 30분간 교반한 후 석출된 결정을 여과하여 흰색 고상물 0.14gr(82.8%)의 표제화합물을 얻었다.0.18 gr (0.39 mmol) of ethyl 1- [4-benzylamino-5- (4-pyridylcarboxamido) -2-pyrimidinyl] -4-piperidinecarboxylate synthesized in Example 4 Dissolve in 18 ml of methanol, add 10 ml of 1.5N sodium hydroxide, and stir at 20 ° C. for 30 minutes to proceed with hydrolysis. The reaction solution was distilled under reduced pressure to remove the organic solvent. The pH of the aqueous layer was adjusted to pH 3.5 using 1.5 N hydrochloric acid, stirred for 30 minutes, and the precipitated crystals were filtered to give a white solid of 0.14 gr (82.8%). The title compound was obtained.

융점 : 138~139℃Melting Point: 138 ~ 139 ℃

NMR (DMSO-d6, 400MHz): δ = 1.41(2H, m), 1.71(2H, m), 2.39(1H, m),NMR (DMSO-d6, 400 MHz): δ = 1.41 (2H, m), 1.71 (2H, m), 2.39 (1H, m),

2.93(2H, m), 4.33(2H, d), 4.49(2H, d), 7.25(5H, m), 7.28(1H, t),2.93 (2H, m), 4.33 (2H, d), 4.49 (2H, d), 7.25 (5H, m), 7.28 (1H, t),

8.11(2H, dd), 8.50(1H, s), 8.89(2H, dd), 11.56(1H, s)8.11 (2H, dd), 8.50 (1H, s), 8.89 (2H, dd), 11.56 (1H, s)

실시예 6Example 6

5-(5-아미노-4H-1,2,4-트리아졸-3-일카르복사아미도)-4-(1,3-다이옥사인단-5-일)메틸아미노-2-(2-에틸-4-메틸-1H-1-이미다졸일)피리미딘5- (5-amino-4H-1,2,4-triazol-3-ylcarboxamido) -4- (1,3-dioxanedan-5-yl) methylamino-2- (2- Ethyl-4-methyl-1H-1-imidazolyl) pyrimidine

3-아미노-1,2,4-트리아졸-5-카르복실산 0.10gr을 N,N-디메틸포름아미드 30ml에 용해하고 1-하이드록시벤조트리아졸 0.092gr과 1,3-다이씨클로헥실카보다이이미 드 0.14gr을 투입한 후 1시간 동안 20~22℃에서 현탁시킨다. 현탁용액에 4N-(1,3-다이옥사인단-5-일)메틸-2-(2-에틸-4-메틸-1H-이미다졸-1-일)피리미딘디아민 0.20gr(0.57mmole)을 투입하고 30시간 동안 교반한다. 현탁용액을 감압증류하여 얻어진 고상물을 실리카젤 칼럼 크로마토그래피(다이클로로메탄:메탄올=75:15(v/v))를 이용하여 백색의 표제화합물 0.16gr(60.9%)을 얻었다.0.10 gr of 3-amino-1,2,4-triazole-5-carboxylic acid is dissolved in 30 ml of N, N-dimethylformamide, and 0.092 gr of 1-hydroxybenzotriazole and 1,3-dicyclohexylcarbo 0.14gr of diimide was added and then suspended at 20-22 ° C for 1 hour. 0.20 gr (0.57 mmol) of 4N- (1,3-dioxanedan-5-yl) methyl-2- (2-ethyl-4-methyl-1H-imidazol-1-yl) pyrimidinediamine was added to the suspension solution. Charge and stir for 30 hours. The solid obtained by distillation under reduced pressure of the suspension solution was purified by silica gel column chromatography (dichloromethane: methanol = 75: 15 (v / v)) to give 0.16 gr (60.9%) of the title compound as white.

융점 : 169~171℃Melting Point: 169 ~ 171 ℃

NMR (DMSO-d6 , 400MHz): δ = 1.11(3H, t), 2.07(3H, d), 2.95(2H, q),NMR (DMSO-d6, 400 MHz): δ = 1.11 (3H, t), 2.07 (3H, d), 2.95 (2H, q),

4.51(2H, d), 5.96(2H, s), 6.19(2H, s), 6.84(2H, m), 6.95(1H, d),4.51 (2H, d), 5.96 (2H, s), 6.19 (2H, s), 6.84 (2H, m), 6.95 (1H, d),

7.43(1H, d), 7.89(1H, t), 8.06(1H, d), 9.58(1H, s),7.43 (1H, d), 7.89 (1H, t), 8.06 (1H, d), 9.58 (1H, s),

12.61(1H, s)12.61 (1 H, s)

실시예 7Example 7

4-벤질아미노-2-(1H-1,2,3-트리아졸일)-5-(2-싸이엔일)술폰아미도피리미딘4-benzylamino-2- (1H-1,2,3-triazolyl) -5- (2-thienyl) sulfonamidopyrimidine

4N-벤질-2-(1H-12,3-트리아졸일)피리미딘디아민 0.20gr(0.75mmole)을 다이클로로메테인 100ml에 용해한 후 2-싸이오펜카르보닐 클로라이드 0.096ml을 20~22℃에서 투입하고 10분간 교반한다. 반응용액에 피리딘 0.18ml을 주사기로 투입한 후 14시간 동안 20~22℃에서 교반하여 반응을 진행시키고 1.5N 수산화나트륨 용액 70ml, 1.5N염산용액 70ml, 증류수 100ml으로 세척한다. 유기층을 분리하고 무수 황산마그네슘으로 건조하고 감압증류하여 담황색의 유상물을 실리카젤 컬럼 크로마토 그래피(다이클로로메탄:메탄올=80:20(v/v))를 이용하여 백색의 표제화합물 0.23gr(81.4%)을 얻었다.0.20gr (0.75 mmole) of 4N-benzyl-2- (1H-12,3-triazolyl) pyrimidinediamine was dissolved in 100 ml of dichloromethane, and then 0.096 ml of 2-thiophencarbonyl chloride was added at 20 to 22 ° C. And stir for 10 minutes. 0.18ml of pyridine was added to the reaction solution with a syringe, followed by stirring at 20-22 ° C. for 14 hours. The organic layer was separated, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to give a pale yellow oily substance by silica gel column chromatography (dichloromethane: methanol = 80: 20 (v / v)). %) Was obtained.

융점 : 161~163℃Melting Point: 161 ~ 163 ℃

NMR (DMSO-d6 , 400MHz): δ = 4.45(2H, s), 7.08(1H, s), 7.28(5H, m),NMR (DMSO-d6, 400 MHz): δ = 4.45 (2H, s), 7.08 (1H, s), 7.28 (5H, m),

7.35(1H, m), 7.82(1H, d), 7.85(1H, d), 7.91(1H, dd), 8.04(1H, t),7.35 (1H, m), 7.82 (1H, d), 7.85 (1H, d), 7.91 (1H, dd), 8.04 (1H, t),

8.13(1H, d), 9.58(1H, s)8.13 (1 H, d), 9.58 (1 H, s)

실시예 8Example 8

5-(5-브로모-3-피리딜카르복사아미도)-4-(1,3-디옥사인단-5-일)메틸아미노-2-(2-에틸-4-메틸-1H-1-이미다졸일)피리미딘5- (5-Bromo-3-pyridylcarboxamido) -4- (1,3-dioxanedan-5-yl) methylamino-2- (2-ethyl-4-methyl-1H-1 -Imidazolyl) pyrimidine

5-브로모니코틴익 에시드 0.18gr을 톨루엔에 현탁시키고 싸이오닐 클로라이드0.13ml를 투입한 후 반응용액을 120℃까지 가온하여 5시간 동안 질소조건하에서 환류시킨다. 용매를 감압증류하여 제거한 후 얻어진 유상물을 다이클로로메테인 100ml에 희석하고 피리딘 ml와 4N-(1,3-다이옥사인단-5-일)메틸-2-(2-에틸-4- 0.18 gr of 5-bromonicotic acid was suspended in toluene, 0.13 ml of thionyl chloride was added thereto, and the reaction solution was heated to 120 DEG C and refluxed under nitrogen for 5 hours. After distilling off the solvent under reduced pressure, the obtained oil was diluted in 100 ml of dichloromethane, and 4 ml of pyridine and 4N- (1,3-dioxanedan-5-yl) methyl-2- (2-ethyl-4-

메틸-1H-이미다졸-1-일)피리미딘디아민 0.37gr(mmole)을 반응용액에 투입하고 10시간 동안 20~22℃에서 교반하여 반응을 진행시킨다. 반응용액을 1.5N 수산화나트륨 용액 70ml, 1.5N염산용액 70ml, 증류수 100ml으로 세척한다. 유기층을 분리하고 무수 황산마그네슘으로 건조하고 감압증류하여 얻어진 담황색의 고상물을 실리카젤 컬럼 크로마토그래피(다이클로로메탄:메탄올=80:20(v/v))를 이용하여 백색의 표제 화합물 0.42gr(74.6%)을 얻었다.Methyl-1H-imidazol-1-yl) pyrimidinediamine 0.37gr (mmole) was added to the reaction solution and stirred at 20-22 ° C. for 10 hours to proceed with the reaction. The reaction solution is washed with 70 ml of 1.5 N sodium hydroxide solution, 70 ml of 1.5 N hydrochloric acid solution, and 100 ml of distilled water. The organic layer was separated, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to obtain a pale yellow solid obtained by silica gel column chromatography (dichloromethane: methanol = 80: 20 (v / v)) as a white title compound 0.42gr ( 74.6%).

융점 : 202~203℃Melting Point: 202 ~ 203 ℃

NMR (DMSO-d6 , 400MHz): δ = 1.23(3H, t), 2.29(3H, d), 3.24(2H, q),NMR (DMSO-d6, 400 MHz): δ = 1.23 (3H, t), 2.29 (3H, d), 3.24 (2H, q),

4.58(2H, d), 5.97(2H, s), 6.86(2H, m), 6.95(1H, d), 7.94(1H, d),4.58 (2H, d), 5.97 (2H, s), 6.86 (2H, m), 6.95 (1H, d), 7.94 (1H, d),

8.28(1H, t), 8.49(1H, t), 8.64(1H, dd), 8.95(1H, d), 9.16(1H, d),8.28 (1H, t), 8.49 (1H, t), 8.64 (1H, dd), 8.95 (1H, d), 9.16 (1H, d),

10.43(1H, s)10.43 (1H, s)

실시예 9Example 9

4-(1,3-디옥사인단-5-일)메틸아미노-2-(1H-1-이미다졸일)-5-(1-메틸-1H-이미다졸-4-일)술폰아미도피리미딘4- (1,3-dioxaindan-5-yl) methylamino-2- (1H-1-imidazolyl) -5- (1-methyl-1H-imidazol-4-yl) sulfonamidopyrimi Dean

4N-(1,3-디옥사인단-5-일)메틸-2-(1H-1-이미다졸일)-5-피리미딘디아민 0.30gr(0.97mmole)을 다이클로로메테인 100ml에 용해한 후 1-메틸이미다졸-4-술폰일 클로라이드 0.23gr을 20~22℃에서 투입하고 10분간 현탁 교반한다. 현탁용액에 피리딘 0.23ml을 주사기로 투입한 후 35℃에서 2시간 30분간 교반하여 맑은 용액이 되면 20~22℃ 15시간 동안 교반한다. 얻어진 반응용액을 0.5N 수산화나트륨용액 50ml을 투입하여 30분간 교반하여 추출한다. 분리된 수용액층을 1.0N염산용액으로 pH3.5까지 조정하여 석출된 결정을 여과, 건조하여 백색의 표제화합물 0.23gr(52.4%)을 얻었다.Dissolve 0.30gr (0.97mmole) of 4N- (1,3-dioxanedan-5-yl) methyl-2- (1H-1-imidazolyl) -5-pyrimidinediamine in 100 ml of dichloromethane, and then 1 0.23 gr of methylimidazole-4-sulfonyl chloride is added at 20-22 ° C., and the suspension is stirred for 10 minutes. 0.23ml of pyridine was added to the suspension solution with a syringe, followed by stirring at 35 ° C for 2 hours and 30 minutes. When the solution became clear, the solution was stirred for 20 hours to 22 ° C for 15 hours. 50 ml of 0.5 N sodium hydroxide solution was added to the obtained reaction solution, followed by stirring for 30 minutes to extract. The separated aqueous layer was adjusted to pH 3.5 with 1.0 N hydrochloric acid solution, and the precipitated crystals were filtered and dried to obtain 0.23 gr (52.4%) of the white title compound.

융점 : 220℃(분해)Melting Point: 220 ℃ (Decomposition)

NMR (DMSO-d6 , 400MHz): δ = 3.66(3H, s), 4.50(2H, d ), 5.97(2H, s),NMR (DMSO-d6, 400 MHz): δ = 3.66 (3H, s), 4.50 (2H, d), 5.97 (2H, s),

6.86(2H, d), 6.91(1H, s), 7.05(1H, s), 7.71(1H, s), 7.77(2H, dd),6.86 (2H, d), 6.91 (1H, s), 7.05 (1H, s), 7.71 (1H, s), 7.77 (2H, dd),

7.81(1H, d), 7.93(1H, t), 8.42(1H, s), 9.58(1H, brs)7.81 (1H, d), 7.93 (1H, t), 8.42 (1H, s), 9.58 (1H, brs)

실시예 10Example 10

4-벤질아미노-2-(1H-1-테트라졸일)-5-(1-메틸-1H-이미다졸-4-일)술폰아미도피리미딘4-benzylamino-2- (1H-1-tetrazolyl) -5- (1-methyl-1H-imidazol-4-yl) sulfonamidopyrimidine

4N-벤질-2-(1H-테트라졸-1-일)-5-피리미딘디아민 0.30gr(1.1mmole)을 다이클로로메테인 100ml에 현탁시킨 후 1-메틸이미다졸-4-술폰일 클로라이드 0.23gr을 20~22℃에서 투입하고 10분간 교반한다. 현탁용액에 피리딘 0.27ml을 주사기로 투입한 후 35℃에서 30분간 교반하여 맑은 용액이 되면 20~22℃ 15시간 동안 교반한다. 얻어진 반응용액을 0.5N 수산화나트륨용액 50ml을 투입하여 30분간 교반하여 추출한다. 분리된 수용액층을 1.0N염산용액으로 pH3.5까지 조정하여 석출된 결정을 여과, 건조하여 백색의 표제화합물 0.28gr(60.7%)을 얻었다.0.30 gr (1.1 mmol) of 4N-benzyl-2- (1H-tetrazol-1-yl) -5-pyrimidinediamine was suspended in 100 ml of dichloromethane and then 1-methylimidazole-4-sulfonyl chloride 0.23gr is added at 20-22 ° C and stirred for 10 minutes. 0.27ml of pyridine was added to the suspension solution with a syringe, and stirred at 35 ° C for 30 minutes. When the solution became clear, the solution was stirred for 20 hours at 22 ° C for 15 hours. 50 ml of 0.5 N sodium hydroxide solution was added to the obtained reaction solution, followed by stirring for 30 minutes to extract. The separated aqueous layer was adjusted to pH 3.5 with 1.0 N hydrochloric acid solution, and the precipitated crystals were filtered and dried to obtain 0.28 gr (60.7%) of the title compound as white.

융점 : 220℃(분해)Melting Point: 220 ℃ (Decomposition)

NMR (DMSO-d6 , 400MHz): δ = 3.64(3H, s), 4.73(2H, d ), 7.19(1H, s),NMR (DMSO-d6, 400 MHz): δ = 3.64 (3H, s), 4.73 (2H, d), 7.19 (1H, s),

7.25(1H, t), 7.34(2H, t), 7.49(2H, d), 7.68(1H, d), 7.81(1H, d),7.25 (1H, t), 7.34 (2H, t), 7.49 (2H, d), 7.68 (1H, d), 7.81 (1H, d),

7.98(1H, t), 9.92(1H, s), 10.21(1H, brs)7.98 (1 H, t), 9.92 (1 H, s), 10.21 (1 H, brs)

실시예 11Example 11

4-벤질아미노-2-(4-에틸피페라지노)-5-(2-카르복시-3-싸이엔일)술폰아미도피리미딘4-benzylamino-2- (4-ethylpiperazino) -5- (2-carboxy-3-thienyl) sulfonamidopyrimidine

4N-벤질-2-(4-에틸피페라지노)-5-피리미딘디아민 0.30gr(0.96mmole)을 다이클로로메테인 100ml에 현탁시키고 2-(메톡시카르보닐)싸이오펜-3-술폰일 클로라이드 0.30gr을 20~22℃에서 투입하고 10분간 교반한다. 현탁용액에 피리딘 0.23ml을 주사기로 투입한 후 35℃에서 1시간 30분간 교반하여 맑은 용액이 되면 20~22℃ 18시간 동안 교반한다. 얻어진 반응용액을 1.0N 수산화나트륨용액 50ml을 투입하여 1시간 교반하여 추출한다. 분리된 수용액층을 3.0N염산용액으로 pH3.5까지 조정하여 석출된 결정을 여과, 건조하여 백색의 표제화합물 0.30gr(67.0%)을 얻었다.0.30 gr (0.96 mmol) of 4N-benzyl-2- (4-ethylpiperazino) -5-pyrimidinediamine was suspended in 100 ml of dichloromethane and 2- (methoxycarbonyl) thiophen-3-sulfonyl 0.30 gr of chloride is added at 20-22 ° C. and stirred for 10 minutes. 0.23ml of pyridine was added to the suspension solution with a syringe, followed by stirring at 35 ° C for 1 hour and 30 minutes. When the solution became clear, the solution was stirred for 20 hours to 22 ° C for 18 hours. 50 ml of 1.0 N sodium hydroxide solution was added to the obtained reaction solution, followed by stirring for 1 hour. The separated aqueous layer was adjusted to pH 3.5 with 3.0 N hydrochloric acid solution, and the precipitated crystals were filtered and dried to obtain 0.30 gr (67.0%) of the title compound as white.

융점 : 225℃(분해)Melting Point: 225 ℃ (Decomposition)

NMR (DMSO-d6 , 400MHz): δ = 1.13(3H, t), 2.26(6H, m), 3.72(4H, m),NMR (DMSO-d6, 400 MHz): δ = 1.13 (3H, t), 2.26 (6H, m), 3.72 (4H, m),

4.65(2H, d), 7.13(1H, s), 7.26(5H, m), 7.30(1H, d), 7.84(1H, d),4.65 (2H, d), 7.13 (1H, s), 7.26 (5H, m), 7.30 (1H, d), 7.84 (1H, d),

7.99(1H, t), 9.94(1H, brs)7.99 (1 H, t), 9.94 (1 H, brs)

실시예 12Example 12

5-(2-카르복시-3-싸이엔일술폰아미도)-4-(1,3-디옥사인단-5-일)메틸아미노-2-(1H-1-이미다졸일)피리미딘5- (2-carboxy-3-thienylsulfonamido) -4- (1,3-dioxanedan-5-yl) methylamino-2- (1H-1-imidazolyl) pyrimidine

4N-(1,3-디옥사인단-5-일)메틸-2-(1H-1-이미다졸일)-5-피리미딘디아민 0.30gr(0.97mmole)을 다이클로로메테인 100ml에 용해한 후 2-(메톡시카르보닐)싸이오펜-3-술폰일 클로라이드 0.30gr을 20~22℃에서 투입하고 10분간 교반한다. 현탁용액에 피리딘 0.23ml을 주사기로 투입한 후 35℃에서 30분간 교반하여 맑은 용액이 되면 20~22℃ 18시간 동안 교반한다. 얻어진 반응용액을 1.0N 수산화나트륨용액 50ml을 투입하여 1시간 교반하여 추출한다. 분리된 수용액층을 3.0N염산용액으로 pH3.5까지 조정하여 석출된 결정을 여과, 건조하여 백색의 표제화합물 0.25gr(%)을 얻었다.4N- (1,3-dioxanedan-5-yl) methyl-2- (1H-1-imidazolyl) -5-pyrimidinediamine 0.30gr (0.97 mmoles) was dissolved in 100 ml of dichloromethane, followed by 2 0.30 gr of-(methoxycarbonyl) thiophen-3-sulfonyl chloride is added at 20-22 ° C. and stirred for 10 minutes. 0.23ml of pyridine was added to the suspension solution with a syringe, followed by stirring at 35 ° C for 30 minutes. When the solution became clear, the solution was stirred for 20 hours at 22 ° C for 18 hours. 50 ml of 1.0 N sodium hydroxide solution was added to the obtained reaction solution, followed by stirring for 1 hour. The separated aqueous layer was adjusted to pH 3.5 with 3.0 N hydrochloric acid solution, and the precipitated crystals were filtered and dried to yield 0.25 gr (%) of the title compound.

융점 : 222℃(분해)Melting Point: 222 ℃ (Decomposition)

NMR (DMSO-d6 , 400MHz): δ = 4.51(2H, d), 5.96(2H, s), 6.82(2H, d),NMR (DMSO-d6, 400 MHz): δ = 4.51 (2H, d), 5.96 (2H, s), 6.82 (2H, d),

6.91(1H, s), 7.19(1H, s), 7.31(1H, d), 7.59(1H, d), 7.80(1H, d),6.91 (1H, s), 7.19 (1H, s), 7.31 (1H, d), 7.59 (1H, d), 7.80 (1H, d),

7.84(1H, d), 8.10(1H, t), 8.64(1H, s)7.84 (1H, d), 8.10 (1H, t), 8.64 (1H, s)

본 발명의 4,5-다이아미노 피리미딘 유도체는 순환기계 질환의 예방 또는 치료제에 유용할수 있는 신규한 약물이다.

The 4,5-diamino pyrimidine derivatives of the present invention are novel drugs that may be useful for the prevention or treatment of circulatory diseases.

Claims

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5-(2-싸이엔일카르복스아미도)-4-(1,3-다이옥사인단-5-일)메틸아미노-2-(2-에틸-4-메틸-1H-이미다졸-1-일)피리미딘; 5- (2-thienylcarboxamido) -4- (1,3-dioxanedan-5-yl) methylamino-2- (2-ethyl-4-methyl-1H-imidazole-1- I) pyrimidine;

5N-[4-(1,3-다이옥사인단-5-일)메틸아미노-2-(2-에틸-4-메틸-1H-1-이미다졸릴)-5-피리미딘일]-3-(2-클로로페닐)-4-메틸-5-아이소옥사졸카르복사아미드; 5N- [4- (1,3-dioxanedan-5-yl) methylamino-2- (2-ethyl-4-methyl-1H-1-imidazolyl) -5-pyrimidinyl] -3- (2-chlorophenyl) -4-methyl-5-isoxazolecarboxamide;

4-(1,3-다이옥사인단-5-일)메틸아미노-2-(2-에틸-4-메틸-1H-1-이미다졸일)-5-(4-피리딜카르복스아미도)피리미딘; 4- (1,3-dioxanedan-5-yl) methylamino-2- (2-ethyl-4-methyl-1H-1-imidazolyl) -5- (4-pyridylcarboxamido) Pyrimidine;

에틸1-[4-벤질아미노-5-(4-피리딜카르복스아미도)-2-피리미딘일]-4-피페리딘카르복실레이트; Ethyl 1- [4-benzylamino-5- (4-pyridylcarboxamido) -2-pyrimidinyl] -4-piperidinecarboxylate;

1-[4-벤질아미노-5-(4-피리딜카르복스아미도)-2-피리미딘일]-4-피페리딘카르복실산; 1- [4-benzylamino-5- (4-pyridylcarboxamido) -2-pyrimidinyl] -4-piperidinecarboxylic acid;

5-(5-아미노-4H-1,2,4-트리아졸-3-일카르복사아미도)-4-(1,3-다이옥사인단-5-일)메틸아미노-2-(2-에틸-4-메틸-1H-1-이미다졸일)피리미딘; 5- (5-amino-4H-1,2,4-triazol-3-ylcarboxamido) -4- (1,3-dioxanedan-5-yl) methylamino-2- (2- Ethyl-4-methyl-1H-1-imidazolyl) pyrimidine;

4-벤질아미노-2-(1H-1-트리아졸일)-5-(2-싸이엔일)술폰아미도피리미딘; 4-benzylamino-2- (1H-1-triazolyl) -5- (2-thienyl) sulfonamidopyrimidine;

5-(5-브로모-3-피리딜카르복사아미도)-4-(1,3-디옥사인단-5-일)메틸아미노-2-(2-에틸-4-메틸-1H-1-이미다졸일)피리미딘; 5- (5-Bromo-3-pyridylcarboxamido) -4- (1,3-dioxanedan-5-yl) methylamino-2- (2-ethyl-4-methyl-1H-1 -Imidazolyl) pyrimidine;

4-(1,3-디옥사인단-5-일)메틸아미노-2-(1H-1-이미다졸일)-5-(1-메틸-1H-이미다졸-4-일)술폰아미도피리미딘; 4- (1,3-dioxaindan-5-yl) methylamino-2- (1H-1-imidazolyl) -5- (1-methyl-1H-imidazol-4-yl) sulfonamidopyrimi Dean;

4-벤질아미노-2-(1H-1-테트라졸일)-5-(1-메틸-1H-이미다졸-4-일)술폰아미도피리미딘;4-benzylamino-2- (1H-1-tetrazolyl) -5- (1-methyl-1H-imidazol-4-yl) sulfonamidopyrimidine;

4-벤질아미노-2-(4-에틸피페라지노)-5-(2-카르복시-3-싸이엔일)술폰아미도피리미딘; 및4-benzylamino-2- (4-ethylpiperazino) -5- (2-carboxy-3-thienyl) sulfonamidopyrimidine; And

5-(2-카르복시-3-싸이엔일술폰아미도)-4-(1,3-디옥사인단-5-일)메틸아미노-2-(1H-1-이미다졸일)피리미딘으로 이루어진 군에서 선택된 4,5-다이아미노 피리미딘 유도체 화합물.Consisting of 5- (2-carboxy-3-thienylsulfonamido) -4- (1,3-dioxanedan-5-yl) methylamino-2- (1H-1-imidazolyl) pyrimidine 4,5-diamino pyrimidine derivative compound selected from the group.

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