KR20080061613A - 2-(methylthio)pyrimidine derivatives, method for preparing thereof and antiviral pharmaceutical composition comprising the same - Google Patents

2-(methylthio)pyrimidine derivatives, method for preparing thereof and antiviral pharmaceutical composition comprising the same Download PDF

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KR20080061613A
KR20080061613A KR1020060136537A KR20060136537A KR20080061613A KR 20080061613 A KR20080061613 A KR 20080061613A KR 1020060136537 A KR1020060136537 A KR 1020060136537A KR 20060136537 A KR20060136537 A KR 20060136537A KR 20080061613 A KR20080061613 A KR 20080061613A
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methylthio
pyrimidine
anilino
morpholino
acetyl
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김종우
이상욱
이근형
한재진
박상진
박을용
신중철
임종환
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(주) 비엔씨바이오팜
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings

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Abstract

2-(Methylthio)pyrimidine derivatives are provided to inhibit growth of hepatitis C virus and minimize toxicity and side effects, so that the compounds are useful for prevention and treatment of hepatitis C. The 2-(methylthio)pyrimidine derivatives represented by the formula(1) and pharmaceutically acceptable salts thereof inhibit growth of hepatitis C virus, wherein R1 is hydrogen, hydroxyl group, -N(R2)-(CH2)-R3 group, 4-(R4)-(Het)-1-yl group or -(CH2)n-R5 group; R2 is hydrogen or C1-C4 linear or branched alkyl group; R3 is hydrogen, halogen atom, hydroxyl group, isopropyl group, C2-C6 linear or branched dialkylamino group, C1-C4 linear or branched alkoxy group, C3-C6 cycloalkyl group or C3-C6 heterocyclic ring optionally substituted by C1-C4 linear or branched alkyl group; (Het) is piperidine or piperazine; R4 is hydrogen, hydroxyl group, carbamoyl group, acetyl group, acetamido group, C1-C4 linear or branched alkyl group, C1-C4 linear or branched hydroxyalkyl group, C1-C4 alkyl group substituted by C1-C4 alkoxy group, C1-C4 alkyl group substituted by morpholino group, phenyl group substituted by hydroxyl group, or C3-C6 heterocyclic ring containing nitrogen atom; R5 is C3-C6 heterocyclic group; and n is an integer from 0 to 4.

Description

2-(메틸티오)피리미딘 유도체, 그 제조방법 및 이를 포함하는 항바이러스용 약학적 조성물{2-(Methylthio)pyrimidine derivatives, method for preparing thereof and antiviral pharmaceutical composition comprising the same}2- (methylthio) pyrimidine derivative, method for preparing the same, and pharmaceutical composition for antiviral including same {2- (Methylthio) pyrimidine derivatives, method for preparing sweetie and antiviral pharmaceutical composition comprising the same}

본 발명은 항바이러스제로 유용한 2-(메틸티오)피리미딘 유도체에 관한 것으로, 보다 상세하게는 C형 간염 바이러스 (Hepatitis C virus; HCV)의 증식억제 효과가 뛰어난 하기 화학식 1로 표시되는 신규의 2-(메틸티오)피리미딘 유도체 및 그의 약학적으로 허용되는 염, 그의 제조방법과 상기 화합물을 유효성분으로 하는 항바이러스용 약학적 조성물에 관한 것이다.The present invention relates to a 2- (methylthio) pyrimidine derivative useful as an antiviral agent, and more particularly, a novel 2 represented by the following Chemical Formula 1 having an excellent antiproliferative effect of Hepatitis C virus (HCV). -(Methylthio) pyrimidine derivatives and pharmaceutically acceptable salts thereof, methods for preparing the same, and pharmaceutical compositions for antivirals comprising the compound as an active ingredient.

Figure 112006097710352-PAT00002
Figure 112006097710352-PAT00002

상기 화학식 1에서, R1 은 수소, 하이드록시기, -N(R2)-(CH2)n-R3 기, 4-(R4)- (Het)-1-일기 또는 -(CH2)n-R5 기를 나타내며, 상기 R1 을 나타내는 치환기에서, R2 는 수소, 또는 C1 - C4 의 직쇄 또는 분쇄상 알킬기를 나타내고, R3 는 수소, 할로겐 원자, 하이드록시기, 이소프로필기, C2 - C6 의 직쇄 또는 분쇄상 디알킬아미노기, C1 - C4 의 직쇄 또는 분쇄상 알콕시기, C3 - C6 의 사이클로알킬기 또는 치환기가 없거나 C1 - C4 의 직쇄 또는 분쇄상 알킬기가 치환된 C3 - C6 의 헤테로사이클릭 고리를 나타내며, (Het) 는 피페리딘 또는 피페라진을 나타내고, R4 는 수소, 하이드록시기, 카바모일기, 아세틸기, 아세트아미도기, C1 - C4 의 직쇄 또는 분쇄상 알킬기, C1 - C4 의 직쇄 또는 분쇄상 하이드록시알킬기, C1 - C4 의 알콕시기가 치환된 C1 - C4 의 알킬기, 모르포리노기가 치환된 C1 - C4 의 알킬기, 하이드록시기가 치환된 페닐기 또는 질소 원자를 포함하는 C3 - C6 의 헤테로사이클릭 고리를 나타내며, R5 는 치환기가 없는 C3 - C6 의 헤테로사이클릭 고리를 나타내고, n 은 0 내지 4 의 정수를 나타낸다.In Formula 1, R 1 Silver hydrogen, hydroxy group, -N (R 2 )-(CH 2 ) n -R 3 Group, 4- (R 4 )-(Het) -1-yl group or-(CH 2 ) n -R 5 Group, wherein R 1 In a substituent representing R 2 Is hydrogen, or C 1 -C 4 A linear or pulverized alkyl group of R 3 , R 3 is hydrogen, a halogen atom, a hydroxy group, isopropyl group, a C 2 -C 6 linear or pulverized dialkylamino group, C 1 -C 4 Straight or pulverized alkoxy groups of C 3 -C 6 cycloalkyl groups or substituents are absent or C 1 -C 4 A straight or branched chain the alkyl group is substituted by C 3 - represents a heterocyclic ring of C 6, (Het) is a piperidine or an piperazine, R 4 is hydrogen, a hydroxy group, a carbamoyl group, an acetyl group , acetic amido, C 1 - C 4 linear or grinding the alkyl group, C 1 - C 4 straight chain or branched a-hydroxy group, C 1 - C 4 a C 1 alkoxy group is substituted in the - group of C 4, do not know C 3 -C 6 heterocyclic ring containing a C 1 -C 4 alkyl group, a phenyl group substituted with a hydroxy group, or a nitrogen atom, in which a phosphorino group is substituted, R 5 represents a C 3 -C 6 group having no substituent Heterocyclic ring, n shows the integer of 0-4.

C형 간염 바이러스 (Hepatitis C virus, HCV: 이하 "HCV"라 함)는 비 A형, 비 B형 간염 (non-A, non-B viral hepatitis)의 주 인자로서, 주로 수혈 및 지역 특이적 감염 (community-acquired)에 의해 일어난다. HCV 에 감염되면, 그 징후가 나타나는 경우 약 80%는 만성 간염으로 진행되고 약 20% 정도가 간경화를 일으키는 급성 간염으로 진행되어 간암으로 전이된다. 최근의 보고에 의하면, 전 세계적으로 약 2억 명 이상이 HCV에 감염되어 있고, 미국 내에서도 4백 50만 명 이상이 HCV에 감염된 것으로 추정되며 (최대 천오백만 명까지 될 것으로 추정됨), 유럽에서만도 5백만 명 이상이 HCV 환자인 것으로 알려져 있다.Hepatitis C virus (HCV: hereinafter referred to as "HCV") is a major factor in non-A and non-B viral hepatitis, mainly transfusion and regionally specific infections. (community-acquired) When infected with HCV, about 80% of cases develop chronic hepatitis and about 20% progress to acute hepatitis, which causes cirrhosis and metastasize to liver cancer. According to recent reports, more than 200 million people are infected with HCV worldwide, and more than 4.5 million people are infected with HCV in the United States (up to 15 million), and only in Europe More than 5 million people are known to be HCV patients.

HCV는 플라비바이러스 (Flavivirus) 과에 속하는 막을 가진 바이러스이다.　 막 내에 약 9.5kb 크기의 (+)-RNA (single stranded positive-sense RNA)를 게놈으로 가지며, RNA 게놈은 5' 말단과 3' 말단의 비해석 부분과 하나의 긴 open reading frame (ORF) 으로 구성되어 있다. 이 ORF는 숙주세포의 효소에 의해 3,010 내지 3,040 개의 아미노산으로 이루어진 폴리프로테인 (polyprotein) 으로 발현되며, 숙주 세포와 바이러스 자신의 효소 (protease)에 의해 3가지의 구조 단백질 (structural protein)과 6 가지의 비구조 단백질 (nonstructural protein) 로 나눠진다. 게놈의 5' 말단과 3' 말단 부위에는 각각 동일하게 보존된 부분 (conserved region)이 존재하는데, 이 부분이 바이러스의 단백질 형성과 RNA 복제에 중요한 역할을 하는 것으로 생각된다.HCV is a virus with a membrane belonging to the Flavivirus family. The membrane contains about 9.5 kb of (+)-RNA (single stranded positive-sense RNA) into the genome, and the RNA genome is divided into a long open frame (ORF) and a non-fractionated portion at the 5 'and 3' ends. Consists of. The ORF is expressed as a polyprotein consisting of 3,010 to 3,040 amino acids by enzymes of the host cell, and three structural proteins and six kinds of proteins by the host cell and the virus's own protease. It is divided into nonstructural proteins. Conserved regions exist at the 5 'and 3' end of the genome, respectively, which are thought to play an important role in viral protein formation and RNA replication.

하나의 긴 ORF는 폴리프로테인으로 발현되며, 전사 단계 혹은 전사 후 과정 (posttranslational processing)을 통해 구조 단백질인 중심항원 단백질 (core), 표면항원 단백질 (E1, E2), 그리고 비구조 단백질인 NS2 (단백질 분해효소, protease), NS3 (세린계 단백질분해효소 serine protease, 헬리케이즈 helicase), NS4A (보조인자 serine protease cofactor), NS4B (protease cofactor, resistance 관련), NS5A, NS5B (RNA 중합효소 RdRp, RNA dependent RNA polymerase) 등으로 나 뉘어 각각 바이러스 증식에 작용하게 된다. 구조 단백질의 경우 숙주세포의 신호 펩티드 분해효소 (signal peptidase)에 의해 core, E1, E2의 부분으로 나뉘며, 비구조 단백질의 경우 바이러스 자신의 세린 단백질 분해효소 (serine protease, NS3)와 보조인자 (cofactor, NS2, NS4A, NS4B)에 의해 분리된다. 구조 단백질의 중심항원 단백질은 표면항원 단백질과 함께 바이러스의 캡시드 (capsid)를 구성하게 되며, NS3 와 NS5B 등의 비구조 단백질은 바이러스 RNA의 복제 (replication)에 중요한 역할을 하게 된다 (Bartenschlager, R., 1997, Molecular targets in inhibition of hepatitis C virus replication, Antivir. Chem. Chemother. 8: 281-301).One long ORF is expressed as a polyprotein and can be expressed through the transcriptional or posttranslational processing, which is the structural antigen core antigen protein (core), the surface antigen protein (E1, E2), and the nonstructural protein NS2 (protein). Degrading enzyme, protease), NS3 (serine protease serine protease, helicase helicase), NS4A (cofactor serine protease cofactor), NS4B (protease cofactor, resistance related), NS5A, NS5B (RNA polymerase RdRp, RNA dependent It is divided into RNA polymerase, etc., and each acts on virus growth. In the case of structural proteins, they are divided into parts of core, E1, and E2 by signal peptidase of the host cell, and in the case of non-structural proteins, the virus's own serine protease (NS3) and cofactor (cofactor) , NS2, NS4A, NS4B). The central antigenic protein of the structural protein together with the surface antigenic protein constitutes the capsid of the virus. Non-structural proteins such as NS3 and NS5B play an important role in the replication of viral RNA (Bartenschlager, R. , 1997, Molecular targets in inhibition of hepatitis C virus replication, Antivir. Chem. Chemother. 8: 281-301).

바이러스 RNA의 5' 및 3' 말단 부위에는 다른 플라비바이러스와 마찬가지로 동일하게 보존된 비해석 부분 (untranslational region, UTR)이 존재하며, 이 부분은 바이러스의 증식에 매우 중요한 역할을 하는 것으로 알려져 있다. 5' 말단에는 341 개의 뉴클레오타이드로 구성된 5'-UTR이 존재하는데, 이 부분은 4개의 스템 루프 (stem and loop) (Ⅰ,Ⅱ,Ⅲ,Ⅳ) 구조로 이루어져 있으며, 이 때문에 단백질 발현을 위한 전사 (translation) 과정에 필요한 리보솜 작용 개시 부위 (internal ribosome entry site, IRES) 로서 작용한다. 특히, 가장 크고 안정된 구조를 가지며 보존된 염기서열 (conserved sequence)이 존재하는 stem Ⅲ 가 리보솜 부착에 가장 필수적인 부분으로 보고되었다. 그리고, stem Ⅳ의 단일 RNA 부분에 존재하는 AUG 로부터 전사 과정이 개시되어 바이러스의 단백질이 발현되는 것으로 알려져 있다 (Stanley, M. Lemon and Masao Honda, 1997, Internal ribosome entry sites within the RNA genomes of hepatitis C virus and other Flaviviruses, Seminars in Virology 8:274-288).The 5 'and 3' terminal regions of the viral RNA, like other flaviviruses, contain the same conserved untranslational region (UTR), which is known to play a very important role in the propagation of the virus. At the 5 'end, there is a 5'-UTR consisting of 341 nucleotides, which consists of four stem and loop (I, II, III, IV) structures, which allow transcription for protein expression. It acts as an internal ribosome entry site (IRS) required for the translation process. In particular, stem III, which has the largest and most stable structure and has a conserved sequence, has been reported as the most essential part for the attachment of ribosomes. In addition, the transcription process is initiated from the AUG present in the single RNA region of stem IV and the protein of the virus is known to be expressed (Stanley, M. Lemon and Masao Honda, 1997, Internal ribosome entry sites within the RNA genomes of hepatitis C). virus and other Flaviviruses, Seminars in Virology 8: 274-288).

또한, 3' 말단에는 318 개의 뉴클레오타이드로 구성된 3'-UTR이 존재하는데, RNA 복제에 필수적인 효소인 NS5B의 부착 (binding)이 시작되는데 중요한 역할을 하는 것으로 알려져 있다. 이 부분은 염기 서열과 3차원적 구조에 따라 3가지의 다른 부분으로 나눌 수 있다. 즉, 5' 말단에서부터 98 뉴클레오타이드 (98nt.)로 구성된 -X-tail-5' 부분과 연속적으로 UTP가 존재하는 -poly(U)- 부분, 그리고,　3'-UTR-의 세 부분으로 나누어진다. X-tail-5' 은 매우 보존된 염기서열을 갖는 98 개의 뉴클레오타이드로 구성되어 있고, 3 개의 스템 루프 구조로 이루어져 안정적인 3차원적 구조를 가지므로 NS5B의 부착에 필수적인 부분으로 생각되어 진다. 또한, -poly(U)- 부분은 피리미딘 계열을 유도 (pyrimidine track)하여 RNA 중합효소의 작용을 용이하게 하는 것으로 보고되었다. 3' 말단 부위는 RNA 복제가 시작될 때 NS5B 의 부착에 필수적인 구조를 이루는 것으로 알려져 있다 (Yamada et al., 1996, Genetic organization and diversity of the hepatitis C virus genome, Virology 223:255-281).In addition, there is a 3'-UTR composed of 318 nucleotides at the 3 'end, which is known to play an important role in initiating the binding of NS5B, an enzyme essential for RNA replication. This part can be divided into three different parts depending on the nucleotide sequence and the three-dimensional structure. That is, it is divided into -X-tail-5 'portion consisting of 98 nucleotides (98nt.) From the 5' end, -poly (U)-portion continuously presenting UTP, and three portions of 3'-UTR-. . X-tail-5 'is composed of 98 nucleotides with very conserved nucleotide sequences, and consists of three stem loop structures and has a stable three-dimensional structure. In addition, the -poly (U)-moiety has been reported to facilitate the action of RNA polymerase by inducing pyrimidine tracks. The 3 'end region is known to form an essential structure for attachment of NS5B when RNA replication begins (Yamada et al ., 1996, Genetic organization and diversity of the hepatitis C virus genome, Virology 223: 255-281).

HCV의 다양한 효소들 중에서 NS5B 는 RNA 복제에 직접 작용하므로 매우 중요하다.　 NS5B는 591개의 아미노산으로 이루어져 있으며 68 kDa의 분자량을 갖는 효소이다. NS5B 효소 내에는 반응에 필요한 RNA의 부착에 필수적인 RBD (RNA-binding domain) 1, 2 의 두 부분의 영역이 존재한다. RBD1은 아미노산 83에서 194 번 사이에 존재하며, RBD2는 아미노산 196에서 298 번 사이에 존재한다. RNA 부착과 활성에 필수적으로 존재하는 (essential motif) 아미노산은 220번 Asp, 283번 Gly, 317번 Gly, 318번 Asp, 319번 Asp, 346번 Lys 등이다. 또한, 이 효소는 바이러스 자신의 RNA 주형 (template)이 존재할 때 다른 프라이머 (primer) 없이도 중합반응을 진행할 수 있다 (Lohmann, V. et al., 1997, Biochemical properties of hepatitis C virus NS5B RNA dependent RNA polymerase and identification of amino acid sequence motifs　 essential for enzymatic activity, J. Virol. 71:8416-8428).Among the various enzymes of HCV, NS5B is very important because it directly affects RNA replication. NS5B is an enzyme of 591 amino acids and has a molecular weight of 68 kDa. In the NS5B enzyme, there are two regions of the RBD (RNA-binding domain) 1 and 2 which are essential for the attachment of the RNA required for the reaction. RBD1 exists between amino acids 83 and 194 and RBD2 exists between amino acids 196 and 298. Essential amino acids essential for RNA attachment and activity are Asp 220, 283 Gly, 317 Gly, 318 Asp, 319 Asp, and 346 Lys. In addition, the enzyme can proceed polymerization without the presence of other primers in the presence of its own RNA template (Lohmann, V. et al ., 1997, Biochemical properties of hepatitis C virus NS5B RNA dependent RNA polymerase). and identification of amino acid sequence motifs essential for enzymatic activity, J. Virol. 71: 8416-8428).

HCV는 1989년 클로닝 (molecular cloning)에 의해 RNA 게놈 (genome)이 분리되었다 (Choo, Q-L, et al., 1989, Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359-362). 그 이후로 HCV에 대한 분자 생물학적 연구가 진행되어 왔지만 효과적인 세포 배양 시스템(cell culture system)과 동물 모델(animal model)의 부족으로 인해 제약이 있었다. 그러나 최근 안정하게 HCV의 복제 (replication)를 할 수 있는 간세포암 세포주 (hepatoma cell line)가 개발되어 이러한 문제들을 다소나마 해결할 수 있게 되었다 (Lohmann, V., F. Korner, J-O Koch, U. Herian, L. Theilmann, R. Bartenschlager, 1999, Replication of subgenomic hepatitis c virus RNAs in a hepatoma cell line. Science 285:110-113).HCV was isolated from the RNA genome by molecular cloning in 1989 (Choo, QL, et al. , 1989, Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis) genome.Science 244: 359-362). Since then, molecular and biological research on HCV has been underway, but there are limitations due to the lack of effective cell culture systems and animal models. Recently, however, a hepatoma cell line has been developed that can reliably replicate HCV. Some problems have been solved (Lohmann, V., F. Korner, JO Koch, U. Herian). , L. Theilmann, R. Bartenschlager, 1999, Replication of subgenomic hepatitis c virus RNAs in a hepatoma cell line.Science 285: 110-113).

현재까지 HCV에 대한 탁월한 백신이나 효과적인 치료제는 존재하지 않는다. 따라서 세계의 많은 제약회사와 연구소에서 HCV 치료제를 개발하고 있다.　 HCV는　 HBV와 비교하여 전 세계적으로 고른 분포를 보이고 있으며, 간경화와 간암으로 전 이되는 비율이 HBV 보다 월등히 높다. 그리고 만성 간염으로의 진행 비율이 높지만 이러한 감염기작에 대한 연구는 아직도 진행 중이다. 또한, C형 간염은 수혈을 통해서 뿐만 아니라 정맥주사를 통한 약물 사용이나 문신을 하는 것에 의해서도 감염이 가능하지만 주로 직접적인 혈액접촉 (blood contact)에 의해 감염된다. 그러나 아직도 40~50%의 경우 그 감염경로가 이미 알려진 요인들과 관계가 없어 이러한 경로로 HCV에 의해 간염이 발병하면 대부분의 환자가 만성으로 진행되며 다시 간경변증으로 진행되어 간암으로 발전하는데 큰 연관이 있을 것으로 생각된다. 따라서 효과적인 백신과 치료제의 개발이 절실한 상태이다. HCV는 균주 (strain)간에 그 유전형 (genotype)이 다양하고 돌연변이 (mutation)가 일어나는 경우가 많은데, HCV에 의한 만성간염이 된 경우 유전적 변이형 (genetic variants)에 의해 재감염 (reinfection), 동시감염 (coinfection) 등이 일어나기도 한다. 이 때문에 HCV의 효과적인 백신 개발은 성공하기가 어려웠다. 치료방법으로 알파 인터페론 (α-interferon)이 사용되고 있으나, HCV의 유전자형에 따라 그 효과도 다양하고 투여를 중단하면 대부분의 경우에 재발되므로 HCV가 복제하지 못하도록 HCV의 특정 단백질에만 결합하는 저해제 (inhibitor)를 개발하는 것이 그 치료방법 중 하나가 될 수 있다. 이러한 연구에서 가장 좋은 표적은 HCV의 NS3 단백질 분해효소/ 헬리케이즈와 NS5B RNA 중합효소이다. 이러한 효소는 자신의 증식에는 필수적이지만 숙주 세포에는 불필요하므로 일반적인 항바이러스제의 문제점인 부작용을 최소화하는데 유리한 것으로 판단된다. 따라서, HCV의 NS5B (RNA dependent RNA polymerase (replicase))와 NS3 (helicase)는　 HCV의 성장을 억제함으로써 C형 간염 치료제 개 발에 좋은 표적 (target)이 될 수 있을 것이다.To date, no excellent vaccine or effective treatment for HCV exists. Therefore, many pharmaceutical companies and research institutes around the world are developing HCV therapy. HCV is more evenly distributed worldwide than HBV, and the rate of liver cirrhosis and liver cancer is much higher than that of HBV. And although the rate of progression to chronic hepatitis is high, studies on these infection mechanisms are still ongoing. In addition, hepatitis C can be infected not only by transfusion but also by intravenous drug use or tattooing, but mainly by direct blood contact. However, in 40% to 50% of cases, the path of infection is not related to the known factors, and when hepatitis is developed by HCV through these pathways, most patients progress to chronic and then develop cirrhosis, which has a great involvement in developing liver cancer. I think there will be. Therefore, the development of effective vaccines and therapeutics is urgently needed. HCV has many genotypes and mutations among strains.In case of chronic hepatitis caused by HCV, reinfection and co-infection are caused by genetic variants. (coinfection) may occur. Because of this, the development of effective vaccines for HCV has been difficult. Although alpha-interferon is used as a treatment method, the effect varies depending on the genotype of HCV and in most cases recurs when discontinued, so it is an inhibitor that binds only to specific proteins of HCV to prevent HCV from replicating. Developing one could be one of the treatments. The best targets in this study are HCV NS3 protease / helicase and NS5B RNA polymerase. These enzymes are essential for their proliferation but are not necessary for the host cell, and thus, may be advantageous in minimizing side effects, which are a problem of general antiviral agents. Therefore, NS5B (RNA dependent RNA polymerase (replicase)) and NS3 (helicase) of HCV may be a good target for the development of hepatitis C therapeutics by inhibiting the growth of HCV.

현재까지의 연구에서는 백신을 이용한 예방이 어려우며, α-인터페론과 리바비린 (Ribavirin) 을 이용한 치료법이 시행되고 있으나 그 치료율이 낮고 부작용이 나타나므로 그 효과가 미약한 실정이다. 인터페론 요법의 경우 전혀 반응을 보이지 않는 경우가 약 25%이고, 일시적으로 반응하다가 재발하는 경우가 약 25% 정도이다. 나머지 약 50%의 환자에서는 치료 종료 후까지 에이엘티 (ALT)치가 정상으로 유지되고 HCV RNA가 음성이 되는데 그 중 50%정도는 치료 종료 후 3-6개월 내에 재발하므로 결국 25% 정도에서만 6개월 이상 치료효과가 유지되는 지속적 반응 (sustained response)을 보이는 셈이다. 또한, C형 간염 바이러스에는 6가지 유전자형 (subtype)이 존재하는데 우리나라에 가장 많은 1b형은 2, 3형에 비해 인터페론 치료에 좋은 반응을 보이지 않는다. 이러한 이유로 리바비린과의 병용요법을 사용하게 되었는데 이 경우 치료 효과가 2 배정도 높아지는 것으로 나타났으나, 리바비린만을 단독으로 사용하는 경우에는 효과가 거의 없고 적혈구가 파괴되어 빈혈 등의 부작용이 나타나므로, 주로 인터페론 치료에 반응이 없거나 재발한 경우에 처방하는 것으로 알려져 있다. 따라서 지금까지는 HCV에 특이적으로 작용하여 증식을 억제함으로써 C 형 간염을 치료하는 항바이러스제는 개발되지 못한 상태이다.Until now, it is difficult to prevent vaccines, and treatment with α-interferon and ribavirin has been performed. However, the treatment rate is low and the side effects appear. In the case of interferon therapy, there is about 25% of cases that do not respond at all, and about 25% of cases temporarily relapse. In about 50% of patients, ALT levels remain normal and HCV RNA becomes negative until the end of treatment. Of these, about 50% relapse within 3-6 months after the end of treatment. This is a sustained response that maintains the therapeutic effect. In addition, there are six genotypes (subtypes) in the hepatitis C virus, the most type 1b in Korea does not respond better to interferon treatment than type 2,3. For this reason, the combination therapy with ribavirin has been used, but the therapeutic effect has been shown to be about 2 times higher. However, the use of ribavirin alone alone has little effect, and red blood cells are destroyed, resulting in side effects such as anemia. It is known to prescribe it when there is no response or relapse in treatment. Therefore, until now, antiviral drugs for treating hepatitis C by specifically acting on HCV and inhibiting proliferation have not been developed.

이에 본 발명자들은 재조합 (recombinant) 발현된 HCV RNA 중합효소 (NS5B, RNA polymerase)의 활성을 저해하는 물질을 탐색함으로써, HCV에 대한 우수한 항바이러스 활성을 나타내고 독성과 부작용이 적은 비핵산계 (nonnucleoside) 화합물을 개발하기 위해 오랫동안 연구하여 왔다.Accordingly, the present inventors searched for substances that inhibit the activity of recombinant expressed HCV RNA polymerase (NS5B, RNA polymerase), thereby exhibiting excellent antiviral activity against HCV and non-nucleoside compounds having low toxicity and side effects. Has been researching for a long time.

이에 본 발명자들은 부작용 및 독성이 적고 내성 바이러스 출현이 낮은 새로운 C형 간염 치료제의 개발을 목적으로 HCV에 대해 우수한 항바이러스 활성을 나타내는 화합물을 개발하기 위해 노력한 결과, 상기 화학식 1로 표시되는 신규의　2-(메틸티오)피리미딘 유도체를 합성하였으며 이 물질이 HCV의 증식 억제 효과가 우수함을 밝힘으로써 본 발명을 완성하였다.Accordingly, the present inventors have tried to develop a compound exhibiting excellent antiviral activity against HCV for the purpose of developing a novel hepatitis C therapeutic agent with low side effects and toxicity, and low resistance virus appearance. A-(methylthio) pyrimidine derivative was synthesized and the present invention was completed by revealing that the substance was excellent in inhibiting the proliferation of HCV.

본 발명의 목적은 새로운 2-(메틸티오)피리미딘 유도체와 약학적으로 허용되는 그의 염 및 그의 제조방법을 제공하는 것이다.It is an object of the present invention to provide novel 2- (methylthio) pyrimidine derivatives, pharmaceutically acceptable salts thereof and methods for their preparation.

본 발명의 또 다른 목적은 상기 화합물을 유효성분으로 하며 부작용이 적고 경제적인, C형 간염의 치료 및 예방을 위한 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for the treatment and prevention of hepatitis C, the compound as an active ingredient and less side effects and economical.

상기 목적을 달성하기 위하여, 본 발명에서는 하기 화학식 1 로 표시되는 새로운 2-(메틸티오)피리미딘 유도체 및 약학적으로 허용되는 그의 염을 제공한다.In order to achieve the above object, the present invention provides a novel 2- (methylthio) pyrimidine derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

Figure 112006097710352-PAT00003
Figure 112006097710352-PAT00003

상기 화학식 1에서, R1 은 수소, 하이드록시기, -N(R2)-(CH2)n-R3 기, 4-(R4)-(Het)-1-일기 또는 -(CH2)n-R5 기를 나타내며, 상기 R1 을 나타내는 치환기에서, R2 는 수소, 또는 C1 - C4 의 직쇄 또는 분쇄상 알킬기를 나타내고, R3 는 수소, 할로겐 원자, 하이드록시기, 이소프로필기, C2 - C6 의 직쇄 또는 분쇄상 디알킬아미노기, C1 - C4 의 직쇄 또는 분쇄상 알콕시기, C3 - C6 의 사이클로알킬기 또는 치환기가 없거나 C1 - C4 의 직쇄 또는 분쇄상 알킬기가 치환된 C3 - C6 의 헤테로사이클릭 고리를 나타내며, (Het) 는 피페리딘 또는 피페라진을 나타내고, R4 는 수소, 하이드록시기, 카바모일기, 아세틸기, 아세트아미도기, C1 - C4 의 직쇄 또는 분쇄상 알킬기, C1 - C4 의 직쇄 또는 분쇄상 하이드록시알킬기, C1 - C4 의 알콕시기가 치환된 C1 - C4 의 알킬기, 모르포리노기가 치환된 C1 - C4 의 알킬기, 하이드록시기가 치환된 페닐기 또는 질소 원자를 포함하는 C3 - C6 의 헤테로사이클릭 고리를 나타내며, R5 는 치환기가 없는 C3 - C6 의 헤테로사이클릭 고리를 나타내고, n 은 0 내지 4 의 정수를 나타낸다.In Formula 1, ROne Silver hydrogen, hydroxy group, -N (R2)-(CH2)n-R3 Group, 4- (R4)-(Het) -1-yl or-(CH2)n-R5 Group, wherein ROne In the substituents2 Is hydrogen, or COne -C4 A linear or pulverized alkyl group of3 Is hydrogen, a halogen atom, a hydroxyl group, isopropyl group, C2 -C6 Straight or pulverized dialkylamino groups of C,One -C4 Straight or pulverized alkoxy groups of C,3 -C6 Without a cycloalkyl group or substituent of COne -C4 C having a linear or crushed alkyl group substituted for3 -C6 Heterocyclic ring of (Het) represents piperidine or piperazine, R4 Is hydrogen, a hydroxyl group, a carbamoyl group, an acetyl group, an acetamido group, COne -C4 Linear or pulverized alkyl groups of C,One -C4 Straight-chain or pulverized hydroxyalkyl groups of, COne -C4 C substituted by alkoxy groupOne -C4 Substituted with alkyl and morpholino groupsOne -C4 C containing an alkyl group, a phenyl group substituted with a hydroxy group or a nitrogen atom3 -C6 A heterocyclic ring of R5 Is C without substituent3 -C6 Represents a heterocyclic ring, and n represents an integer of 0 to 4.

한편, 상기 화학식 1의 화합물은 제조방법에 따라, 하기 화학식 1a 및 화학식 1b로 구분할 수 있다.On the other hand, the compound of Formula 1 can be divided into the following formula 1a and 1b according to the preparation method.

Figure 112006097710352-PAT00004
Figure 112006097710352-PAT00004

상기 화학식 1a에서, R1' 은 -N(R2)-(CH2)n-R3 기, 4-(R4)-(Het)-1-일기 또는 -(CH2)n-R5' 기를 나타내며, 상기 R1' 을 나타내는 치환기에서, R2 는 수소, 또는 C1 - C4 의 직쇄 또는 분쇄상 알킬기를 나타내고, R3 는 수소, 할로겐 원자, 하이드록시기, 이소프로필기, C2 - C6 의 직쇄 또는 분쇄상 디알킬아미노기, C1 - C4 의 직쇄 또는 분쇄상 알콕시기, C3 - C6 의 사이클로알킬기 또는 치환기가 없거나 C1 - C4 의 직쇄 또는 분쇄상 알킬기가 치환된 C3 - C6 의 헤테로사이클릭 고리를 나타내며, (Het) 는 피페리딘 또는 피페라진을 나타내고, R4 는 수소, 하이드록시기, 카바모일기, 아세틸기, 아세트아미도기, C1 - C4 의 직쇄 또는 분쇄상 알킬기, C1 - C4 의 직쇄 또는 분쇄상 하이드록시알킬기, C1 - C4 의 알콕시기가 치환된 C1 - C4 의 알킬기, 모르포리노기가 치환된 C1 - C4 의 알킬기, 하이드록시기가 치환된 페닐기 또는 질소 원자를 포함하는 C3 - C6 의 헤테로사이클릭 고리를 나타내며, R5' 는 치환기 가 없는 포화된 C3 - C6 의 헤테로사이클릭 고리를 나타내고, n 은 0 내지 4 의 정수를 나타낸다.In Formula 1a, R 1 ′ is -N (R 2 )-(CH 2 ) n -R 3 Group, 4- (R 4 )-(Het) -1-yl group or-(CH 2 ) n -R 5 ' Group, wherein R 1 ' In a substituent representing R 2 Is hydrogen, or C 1 -C 4 A linear or pulverized alkyl group of R 3 , R 3 is hydrogen, a halogen atom, a hydroxy group, isopropyl group, a C 2 -C 6 linear or pulverized dialkylamino group, C 1 -C 4 Straight or pulverized alkoxy groups of C 3 -C 6 cycloalkyl groups or substituents are absent or C 1 -C 4 A straight or branched chain the alkyl group is substituted by C 3 - represents a heterocyclic ring of C 6, (Het) is a piperidine or an piperazine, R 4 is hydrogen, a hydroxy group, a carbamoyl group, an acetyl group , acetic amido, C 1 - C 4 linear or grinding the alkyl group, C 1 - C 4 straight chain or branched a-hydroxy group, C 1 - C 4 a C 1 alkoxy group is substituted in the - group of C 4, do not know A C 3 -C 6 heterocyclic ring containing a C 1 -C 4 alkyl group, a phenyl group substituted with a hydroxy group, or a nitrogen atom, with a substituted phono group, R 5 ′ represents a saturated C 3- cyclic of C 6 heteroaryl represents a ring, n represents an integer of 0 to 4.

Figure 112006097710352-PAT00005
Figure 112006097710352-PAT00005

상기 화학식 1b에서, R1" 은 수소, 하이드록시기 또는 -(CH2)n-R5" 기를 나타내며, R5" 가 치환기가 없는 불포화된 C3 - C6 의 헤테로사이클릭 고리를 나타내고, n 은 0 내지 4 의 정수를 나타낸다.In Formula 1b, R 1 "is hydrogen, a hydroxyl group, or-(CH 2 ) n -R 5 " Group, R 5 " Represents an unsaturated C 3 -C 6 heterocyclic ring without substituents, and n represents an integer from 0 to 4.

본 발명의 화학식 1의 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산 (free acid) 에 의해 형성된 산 부가염이 유용하다. 화학식 1의 화합물은 당해 기술 분야에서 통상적인 방법에 따라 약제학적으로 허용되는 산 부가염을 형성할 수 있다.　 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산 (Citric acid), 초산, 젖산, 주석산 (Tartaric acid), 말레인산, 푸마르산 (Fumaric acid), 포름산, 프로피온산 (Propionic acid), 옥살산, 트리플루오로아세트산, 벤조산, 글루콘산, 메탄설폰산, 글리콜산, 숙신산 (Succinic acid), 4-톨루엔설폰산, 벤젠설폰산, 살리신산, 니코틴산, 이소니코틴산, 피콜린산, 글루탐산 또는 아스파르트산 등을 사용할 수 있다.The compound of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Compounds of formula (1) may form pharmaceutically acceptable acid addition salts according to methods conventional in the art. Organic acids and inorganic acids can be used as the free acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid can be used as the inorganic acid, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, Fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, benzenesulfonic acid, salicycin Acids, nicotinic acid, isnicotinic acid, picolinic acid, glutamic acid or aspartic acid, and the like.

또한 본 발명에서는 하기 반응식 1로 표시되는 화학식 1a의 2-(메틸티오)피리미딘 유도체의 제조방법을 제공한다.In addition, the present invention provides a method for preparing a 2- (methylthio) pyrimidine derivative represented by Chemical Formula 1a.

Figure 112006097710352-PAT00006
Figure 112006097710352-PAT00006

상기 반응식 1에서, R1' 은 -N(R2)-(CH2)n-R3 기, 4-(R4)-(Het)-1-일기 또는 -(CH2)n-R5' 기를 나타내며, 상기 R1' 을 나타내는 치환기에서, R2 는 수소, 또는 C1 - C4 의 직쇄 또는 분쇄상 알킬기를 나타내고, R3 는 수소, 할로겐 원자, 하이드록시기, 이소프로필기, C2 - C6 의 직쇄 또는 분쇄상 디알킬아미노기, C1 - C4 의 직쇄 또는 분쇄상 알콕시기, C3 - C6 의 사이클로알킬기 또는 치환기가 없거나 C1 - C4 의 직쇄 또는 분쇄상 알킬기가 치환된 C3 - C6 의 헤테로사이클릭 고리를 나타내며, (Het) 는 피페리딘 또는 피페라진을 나타내고, R4 는 수소, 하이드록시기, 카바모일 기, 아세틸기, 아세트아미도기, C1 - C4 의 직쇄 또는 분쇄상 알킬기, C1 - C4 의 직쇄 또는 분쇄상 하이드록시알킬기, C1 - C4 의 알콕시기가 치환된 C1 - C4 의 알킬기, 모르포리노기가 치환된 C1 - C4 의 알킬기, 하이드록시기가 치환된 페닐기 또는 질소 원자를 포함하는 C3 - C6 의 헤테로사이클릭 고리를 나타내며, R5' 는 치환기가 없는 포화된 C3 - C6 의 헤테로사이클릭 고리를 나타내고, n 은 0 내지 4 의 정수를 나타낸다.In Scheme 1, R 1 ′ is -N (R 2 )-(CH 2 ) n -R 3 Group, 4- (R 4 )-(Het) -1-yl group or-(CH 2 ) n -R 5 ' Group, wherein R 1 ' In a substituent representing R 2 Is hydrogen, or C 1 -C 4 A linear or pulverized alkyl group of R 3 , R 3 is hydrogen, a halogen atom, a hydroxy group, isopropyl group, a C 2 -C 6 linear or pulverized dialkylamino group, C 1 -C 4 Straight or pulverized alkoxy groups of C 3 -C 6 cycloalkyl groups or substituents are absent or C 1 -C 4 A straight or branched chain the alkyl group is substituted by C 3 - represents a heterocyclic ring of C 6, (Het) is a piperidine or an piperazine, R 4 is hydrogen, a hydroxyl group, a carbamoyl group, an acetyl group , acetic amido, C 1 - C 4 linear or grinding the alkyl group, C 1 - C 4 straight chain or branched a-hydroxy group, C 1 - C 4 a C 1 alkoxy group is substituted in the - group of C 4, do not know A C 3 -C 6 heterocyclic ring containing a C 1 -C 4 alkyl group, a phenyl group substituted with a hydroxy group, or a nitrogen atom, with a substituted purino group, and R 5 ′ represents a saturated C 3- cyclic of C 6 heteroaryl represents a ring, n represents an integer of 0 to 4.

상기 반응식 1에서 R1' 은 상기 화학식 1의 R1 이 수소 및 하이드록시기인 경우와, R1 을 나타내는 치환기 중에서 R5 가 치환기가 없는 불포화된 C3 - C6 의 헤테로사이클릭 고리인 경우를 제외한 것이다. 화학식 1의 R1 이 수소 및 하이드록시기인 경우와, R1 을 나타내는 치환기 중에서 R5 가 치환기가 없는 불포화된 C3 - C6 의 헤테로사이클릭 고리인 경우 즉, 화학식 1b에 대한 제조방법은 후술한다.In Formula 1, R 1 ′ is when R 1 of Formula 1 is hydrogen and a hydroxyl group, and R 1 R 5 in the substituents Except when is an unsaturated C 3 -C 6 heterocyclic ring without substituents. When R 1 in Formula 1 is hydrogen and a hydroxyl group, and R 1 R 5 in the substituents In the case where is an unsaturated C 3 -C 6 heterocyclic ring without substituent, that is, the preparation method for Formula 1b is described below.

본 발명의 제조방법은 상기 반응식 1에서 표시된 바와 같이,Production method of the present invention, as shown in Scheme 1,

상기 화학식 2의 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘을 상기 화학식 3의 H-R1' 로 표시되는 아민 화합물과 반응시켜서 상기 화학식 1a의 2-(메틸티오)피리미딘 유도체를 제조하는 방법이다.2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazin-1-yl] pyrimidine of Formula 2 may be substituted with HR 1 of Formula 3 It is a method of preparing the 2- (methylthio) pyrimidine derivative of Chemical Formula 1a by reacting with an amine compound represented by '.

상기 반응식 1에서 반응물질로 사용되는 상기 화학식 3의 H-R1' 으로 표시되는 아민 화합물은 상업적으로 시판되는 물질로서 용이하게 구입하여 사용할 수 있 다.The amine compound represented by HR 1 ′ of Formula 3 used as a reactant in Scheme 1 can be easily purchased and used as a commercially available material.

또한, 상기 반응식 1에서 사용되는 상기 화학식 3의 H-R1' 로 표시되는 아민 화합물은 상기 화학식 1a로 표시되는 목적화합물에 치환기를 도입하기 위한 물질로서, 치환기의 종류에 따라 적절한 시약을 선택할 수 있으며, 이는 당해 기술 분야에 속하는 통상의 지식을 가진 자라면 용이하게 선택하여 사용할 수 있다.In addition, the amine compound represented by HR 1 ′ of Formula 3 used in Scheme 1 is a substance for introducing a substituent into the target compound represented by Formula 1a, and an appropriate reagent may be selected according to the type of substituent. It can be easily selected and used by those of ordinary skill in the art.

상기 반응식 1의 제조방법을 좀 더 구체적으로 설명하면, 트리에틸아민, 트리벤질아민, N,N-디이소프로필에틸아민, 4-메틸모르포린, 4-에틸모르포린, 1-메틸피페리딘, 1-에틸피페리딘, 1,1,3,3-테트라메틸구아니딘, 피리딘, N,N-디메틸아닐린, N,N-디에틸아닐린, 2,6-루티딘, 2,4,6-콜리딘, 2,6-디-tert-부틸-4-메틸피리딘 등과 같은 유기염기 존재하에서 반응시키거나, 또는 유기염기를 사용하지 않고 상기 화학식 3의 H-R1' 로 표시되는 아민 화합물을 과량으로 사용하여 반응시킬 수도 있다.In more detail the preparation method of Scheme 1, triethylamine, tribenzylamine, N, N- diisopropylethylamine, 4-methylmorpholine, 4- ethylmorpholine , 1-methylpiperidine , 1-ethylpiperidine, 1,1,3,3-tetramethylguanidine, pyridine, N, N -dimethylaniline, N, N -diethylaniline, 2,6-lutidine, 2,4,6- Reacting in the presence of an organic base such as collidine, 2,6-di- tert -butyl-4-methylpyridine, or using an amine compound represented by HR 1 ′ of Formula 3 in an excess without using an organic base. It can also be made to react.

상기 반응은 디클로로메탄, 클로로포름, 아세토니트릴, N,N-디메틸포름아미드, N,N-디메틸아세트아미드, 디메틸설폭사이드, 1-메틸-2-피롤리디논, 에틸 에테르, 이소프로필 에테르, 테트라하이드로푸란, 1,4-디옥산, 아세톤, 메탄올, 에탄올, 이소프로판올, 부탄올 등과 같은 일반적인 용매의 단독 또는 혼합 용매 내에서 잘 진행된다.The reaction is dichloromethane, chloroform, acetonitrile, N, N -dimethylformamide, N, N -dimethylacetamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidinone, ethyl ether, isopropyl ether, tetrahydro It proceeds well in single or mixed solvents of common solvents such as furan, 1,4-dioxane, acetone, methanol, ethanol, isopropanol, butanol and the like.

상기 반응은 상기 화학식 3의 H-R1' 로 표시되는 선택된 아민 화합물의 화학적 반응성과 사용하는 유기염기 및 용매의 종류에 따라서, 0℃ - 80℃의 온도범위 내에서 1시간 내지 4일 이내에 잘 진행된다.The reaction proceeds well within 1 hour to 4 days within the temperature range of 0 ° C. to 80 ° C., depending on the chemical reactivity of the selected amine compound represented by HR 1 ′ in Formula 3 and the type of organic base and solvent used. .

그리고, 상기 반응식 1에서 출발물질로 사용되는 화학식 2의 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘은 다음 반응식 2로 표시되는 제조방법에 따라서 제조할 수 있다.And 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazin-1-yl of Chemical Formula 2 used as starting material in Scheme 1 above ] Pyrimidine can be manufactured according to the manufacturing method shown by following Reaction Formula 2.

Figure 112006097710352-PAT00007
Figure 112006097710352-PAT00007

상기 반응식 2의 제조방법을 간략하게 설명하면,Briefly describing the preparation method of Scheme 2,

(1) 상기 화학식 4의 4,6-디클로로-2-(메틸티오)피리미딘과 상기 화학식 5의 4-(4-모르포리노)아닐린을 반응시켜서 상기 화학식 6의　 2-메틸티오-6-[4-(4-모르 포리노)아닐리노]-4-클로로피리미딘 을 제조하는 단계 (단계 1);(1) reacting 4,6-dichloro-2- (methylthio) pyrimidine of formula 4 with 4- (4-morpholino) aniline of formula 5 to react 2-methylthio-6- of formula 6 Preparing [4- (4-morpholino) anilino] -4-chloropyrimidine (step 1);

(2) 상기 단계 1에서 제조된 상기 화학식 6의 합성 중간체를 상기 화학식 7의 피페라진과 반응시켜서 상기 화학식 8의 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-(피페라진-1-일)피리미딘을 제조하는 단계 (단계 2) ; 및(2) reacting the synthetic intermediate of Chemical Formula 6 prepared in Step 1 with piperazine of Chemical Formula 7 to 2-methylthio-6- [4- (4-morpholino) anilino]- Preparing 4- (piperazin-1-yl) pyrimidine (step 2); And

(3) 상기 단계 2에서 제조된 상기 화학식 8의 합성 중간체를 상기 화학식 9 의 클로로아세틸 클로라이드와 반응시켜서 상기 화학식 2의 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘, 또는 그의 염산염을 제조하는 단계 (단계 3)로 이루어진다.(3) reacting the synthetic intermediate of Chemical Formula 8 prepared in Step 2 with chloroacetyl chloride of Chemical Formula 9 to form 2-methylthio-6- [4- (4-morpholino) anilino] of Chemical Formula 2; It comprises the step of preparing -4- [4- (chloroacetyl) piperazin-1-yl] pyrimidine, or hydrochloride thereof (step 3).

상기 반응식 2에서 출발물질 및 반응물질로 사용되는 4,6-디클로로-2-(메틸티오)피리미딘, 4-(4-모르포리노)아닐린, 피페라진, 클로로아세틸 클로라이드 등은 상업적으로 시판되는 물질로서 용이하게 구입하여 사용할 수 있다.4,6-dichloro-2- (methylthio) pyrimidine, 4- (4-morpholino) aniline, piperazine, chloroacetyl chloride, etc. used as starting materials and reactants in Scheme 2 are commercially available. It can be easily purchased and used as a substance.

상기 반응식 2의 상세한 제조방법은 <제조예 1> 부터 <제조예 4> 까지 예시한다.Detailed manufacturing method of the reaction scheme 2 is illustrated in <Production Example 1> to <Production Example 4>.

상기 반응식 2의 제조방법 중에서 단계 1 <제조예 1>과 단계 2 <제조예 2>의 제조방법은, 본 출원인이 출원한 "6-(4-치환된-아닐리노)피리미딘 유도체, 그 제조방법 및 이를 포함하는 항바이러스용 약학적 조성물" <대한민국 특허 제 0516434호　(특허출원번호 ; 2002-18395)> 와, "6-(4-치환된-아닐리노)피리미딘 유도체, 그 제조방법 및 이를 포함하는 항바이러스용 약학적 조성물" <대한민국 특허출원번호 ; 2005-54885>의 명세서에도 기술되어 있다.Of the preparation method of Scheme 2, the preparation method of Step 1 <Preparation Example 1> and Step 2 <Preparation Example 2>, the "6- (4-substituted-anilino) pyrimidine derivatives filed by the applicant, the preparation Method and anti-viral pharmaceutical composition comprising the same "<Korean Patent No. 0516434 (patent application number; 2002-18395)>," 6- (4-substituted-anilino) pyrimidine derivatives, a method for preparing the same and Pharmaceutical composition for antiviral comprising the same "<Korea Patent Application No .; 2005-54885.

그리고 상기 반응식 1에서 출발물질로 사용되는 화학식 2의 2-메틸티오-6- [4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘을 제조하는 방법은 다음 <제조예 3> 과 <제조예 4>에서 상세히 기술한다. 즉, 유기염기를 사용하여 제조하는 방법인 <제조예 3>과 유기염기를 사용하지 않고 반응하여 염산염 상태로 직접 제조, 분리하여 사용하는 방법인 <제조예 4>의 방법을 선택하여 사용할 수 있다.And 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazin-1-yl] of Chemical Formula 2 used as starting material in Scheme 1 above. The method for producing pyrimidine is described in detail in Preparation Example 3 and Preparation Example 4 below. That is, it is possible to select and use <Production Example 3>, which is a method of manufacturing using organic base, and <Production Example 4>, which is a method of directly producing, separating and using a hydrochloride state by reacting without using an organic base. .

또한, 본 발명의 화학식 1로 표시되는 2-(메틸티오)피리미딘 유도체 중에서 R1 이 수소, 하이드록시기 등과 같은 간단한 치환기인 경우이거나, R1 을 나타내는 치환기 중에서 R5 가 치환되지 않은 불포화 C3 - C6 의 헤테로사이클릭 고리인 경우 즉, 화학식 1b인 경우에는, 상기 반응식 1의 제조방법 대신에 상기 반응식 2의 화학식 8로 표시되는 합성 중간체인 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-(피페라진-1-일)피리미딘으로부터 직접 제조할 수 있다.In addition, in the 2- (methylthio) pyrimidine derivative represented by the general formula (1) of the present invention, when R 1 is a simple substituent such as hydrogen or a hydroxy group, or unsaturated substituents in which R 5 is not substituted in the substituents representing R 1 3 -C 6 In the case of the heterocyclic ring, that is, in the case of formula (1b), instead of the preparation method of Scheme 1, 2-methylthio-6- [4- (4-morpho) which is a synthetic intermediate represented by the formula (8) It can be prepared directly from lino) anilino] -4- (piperazin-1-yl) pyrimidine.

또한 본 발명에서는 화학식 1의 2-(메틸티오)피리미딘 유도체 및/또는 약학적으로 허용되는 그의 염을 유효성분으로 포함하는, C형 간염의 치료제 또는 예방제용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for treating or preventing hepatitis C, comprising 2- (methylthio) pyrimidine derivative of Formula 1 and / or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명의 화학식 1의 화합물은 C형 간염의 치료제로서 임상 투여시에, 경구 또는 비경구로 투여가 가능하며 일반적인 의약품제제의 형태로 사용될 수 있다.　 즉, 본 발명의 화학식 1의 화합물은 실제 임상 투여시에 경구 및 비경구(바람직하게는 주사제로)의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다.　 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화학식 1의 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트 (Calcium carbonate), 수크로오스 (Sucrose) 또는 락토오스 (Lactose), 젤라틴 등을 섞어 조제된다.　 경구투여를 위한 액상제제로는 현탁제, 용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.　 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제 등이 포함된다.　 비수성용제, 현탁제로는 프로필렌 글리콜 (Propylene glycol), 폴리에틸렌 글리콜 (Polyethylene glycol), 올리브 오일과 같은 식물성 기름, 에틸 올레이트 와 같은 주사 가능한 에스테르 등이 사용될 수 있다.The compound of formula 1 of the present invention can be administered orally or parenterally during clinical administration as a therapeutic agent for hepatitis C, and can be used in the form of general pharmaceutical preparations. That is, the compound of formula 1 of the present invention may be administered in various dosage forms, orally and parenterally (preferably as an injection) during actual clinical administration, and when formulated, commonly used fillers, extenders, binders, wetting agents. And diluents or excipients such as disintegrants and surfactants. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate , Sucrose or lactose, gelatin, etc. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions and the like. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.

본 발명의 화학식 1의 화합물의 유효용량은 성별, 나이, 환자의 상태 등을 고려하여 적절히 선택될 수 있으나, 일반적으로 성인에게 20 - 2000 mg/일 이며, 하루에 1 - 3회 분할 투여할 수 있다.The effective dose of the compound of formula 1 of the present invention may be appropriately selected in consideration of sex, age, patient's condition, etc., but is generally 20-2000 mg / day to adults, and can be dividedly administered 1-3 times a day. have.

이하 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 단, 하기 실시예들은 본 발명을 예시하는 것으로 본 발명의 내용이 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are illustrative of the present invention, and the content of the present invention is not limited by the examples.

<< 제조예Production Example 1>　 2- 1> 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-]-4- 클로로피리미딘Chloropyrimidine 의 제조.Manufacturing.

메탄올 240 ml 에 4,6-디클로로-2-(메틸티오)피리미딘 17.55 g 과 4-(4-모르 포리노)아닐린 16.05 g , 그리고 트리에틸아민 15.0 ml 를 차례로 가하고, 가열하여 55℃ - 60℃ 에서 18시간 동안 반응시켰다. 20℃ 로 냉각하여 2시간 동안 교반한 후 여과하고 메탄올 75 ml 로 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조하여 26.37 g (수율 87 %)의 목적화합물을 얻었다.To 240 ml of methanol was added 17.55 g of 4,6-dichloro-2- (methylthio) pyrimidine, 16.05 g of 4- (4-morpholino) aniline, and 15.0 ml of triethylamine, followed by heating to 55 ° C.-60 The reaction was carried out at 18 ° C. for 18 hours. After cooling to 20 ° C., stirring for 2 hours, filtration and washing with 75 ml of methanol, the obtained crystals were dried in vacuo at 30 ° C.-40 ° C. to obtain 26.37 g (yield 87%) of the title compound.

m.p. : 159 - 161℃m.p. : 159-161 ℃

1H-NMR (CDCl3), ppm : δ　 2.51(s, 3H), 3.15(t, 4H), 3.86(t, 4H), 6.19(d, 1H), 6.76(s, 1H), 6.91(d, 2H), 7.16(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.51 (s, 3H), 3.15 (t, 4H), 3.86 (t, 4H), 6.19 (d, 1H), 6.76 (s, 1H), 6.91 (d , 2H), 7.16 (d, 2H)

<< 제조예Production Example 2>　2- 2> 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-(피페라진-1-일)피리미딘의 제조.] -4- (piperazin-1-yl) pyrimidine.

메탄올 320 ml 에 상기 제조예 1에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-클로로피리미딘 22.4 g 과 무수 피페라진 57.3 g, 그리고 트리에틸아민 10.2 ml 를 차례로 가하고, 가열하여 55℃ - 60℃ 에서 40시간 동안 반응시켰다. 20℃ 로 냉각하여 2시간 동안 교반한 후 여과하고 메탄올 100 ml 로 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조하여 24.68 g (수율 96 %)의 목적화합물을 얻었다.22.4 g of 2-methylthio-6- [4- (4-morpholino) anilino] -4-chloropyrimidine prepared in Preparation Example 1, 57.3 g of anhydrous piperazine, and triethylamine in 320 ml of methanol 10.2 ml were added sequentially, heated and reacted at 55 ° C.-60 ° C. for 40 hours. After cooling to 20 DEG C, stirring for 2 hours, filtration and washing with 100 ml of methanol, the obtained crystals were vacuum dried at 30 DEG C-40 DEG C to obtain 24.68 g (yield 96%) of the title compound.

m.p. : 232 - 234℃m.p. : 232-234 ℃

1H-NMR (DMSO-d6), ppm : δ　 2.39(d, 3H), 2.70(br s, 4H), 3.02(br s, 4H), 3.35(br s, 4H), 3.70(m, 4H), 5.53(s, 1H), 6.87(d, 2H), 7.34(d, 2H), 8.78(s, 1H) 1 H-NMR (DMSO-d 6 ), ppm: δ 2.39 (d, 3H), 2.70 (br s, 4H), 3.02 (br s, 4H), 3.35 (br s, 4H), 3.70 (m, 4H ), 5.53 (s, 1H), 6.87 (d, 2H), 7.34 (d, 2H), 8.78 (s, 1H)

<< 제조예Production Example 3>　 2- 3> 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-(] -4- [4- ( 클로로아세Chloroacetate 틸)피페라진-1-일]피리미딘의 제조.Til) piperazin-1-yl] pyrimidine.

디클로로메탄 200 ml 에 상기 제조예 2에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-(피페라진-1-일)피리미딘 17 g 과 트리에틸아민 9.2 ml 를 가하고 0℃ 로 냉각한 후, 클로로아세틸 클로라이드 5.5 g 을 디클로로메탄 50 ml 에 녹인 용액을 0℃ - 5℃ 에서 40분 동안 서서히 적하하였다. 반응용액을 0℃ - 5℃ 에서 1시간 동안 반응시킨 후, 감압농축하여 얻은 고체를 메탄올 300 ml 에 가하여 실온에서 4시간 동안 교반하였다. 여과하고 메탄올 30 ml 씩으로 2회 세척하여 얻은 결정을 에탄올 200 ml 와 디클로로메탄 200 ml 의 혼합용매에 완전히 녹인 후, 디클로로메탄을 감압농축하여 결정화시켰다. 결정이 석출된 에탄올 용액을 실온에서 4시간 동안 교반한 후, 여과하고 에탄올 30 ml 씩으로 2회 세척하여 얻어진 결정을 40℃ - 50℃ 에서 진공건조하여 13.5 g (수율 66 %)의 목적화합물을 얻었다.In 200 ml of dichloromethane, 17 g of 2-methylthio-6- [4- (4-morpholino) anilino] -4- (piperazin-1-yl) pyrimidine prepared in Preparation Example 2 and triethyl After adding 9.2 ml of amine and cooling to 0 ° C., a solution of 5.5 g of chloroacetyl chloride in 50 ml of dichloromethane was slowly added dropwise at 0 ° C.-5 ° C. for 40 minutes. The reaction solution was reacted at 0 ° C.-5 ° C. for 1 hour, and the solid obtained by concentration under reduced pressure was added to 300 ml of methanol and stirred at room temperature for 4 hours. The crystals obtained by filtration and washing twice with 30 ml of methanol were completely dissolved in a mixed solvent of 200 ml of ethanol and 200 ml of dichloromethane, and then dichloromethane was concentrated under reduced pressure to crystallize. The ethanol solution in which the crystals were precipitated was stirred at room temperature for 4 hours, filtered and washed twice with 30 ml of ethanol, and the resulting crystals were dried in vacuo at 40 ° C.-50 ° C. to obtain 13.5 g (yield 66%) of the title compound. .

m.p. : 204 - 207℃m.p. : 204-207 ℃

1H-NMR (DMSO-d6), ppm : δ　 2.41(s, 3H), 3.03(br s, 4H), 3.49 - 3.72(m, 12H), 4.42(s, 2H), 5.58(s, 1H), 6.88(d, 2H), 7.35(d, 2H), 8.89(s, 1H) 1 H-NMR (DMSO-d 6 ), ppm: δ 2.41 (s, 3H), 3.03 (br s, 4H), 3.49-3.72 (m, 12H), 4.42 (s, 2H), 5.58 (s, 1H ), 6.88 (d, 2H), 7.35 (d, 2H), 8.89 (s, 1H)

<< 제조예Production Example 4>　 2- 4> 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-(] -4- [4- ( 클로로아세Chloroacetate 틸)피페라진-1-일]피리미딘 염산염의 제조.Preparation of til) piperazin-1-yl] pyrimidine hydrochloride.

디클로로메탄 250 ml 에 상기 제조예 2에서 제조한 2-메틸티오-6-[4-(4-모르 포리노)아닐리노]-4-(피페라진-1-일)피리미딘 18 g 을 가하고 0℃ 로 냉각한 후, 클로로아세틸 클로라이드 5.8 g 을 디클로로메탄 50 ml 에 녹인 용액을 0℃ - 5℃ 에서 40분 동안 서서히 적하하였다. 반응용액을 0℃ - 5℃ 에서 1시간 동안 반응시킨 후, 서서히 가열하여 실온에서 에틸 에테르 300 ml 를 서서히 가하여 결정화시켰다. 실온에서 4시간 동안 교반한 후, 여과하고 에틸 에테르 50 ml 로 2회 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조하여 22.56 g (수율 97 %)의 목적화합물을 얻었다.18 g of 2-methylthio-6- [4- (4-morpholino) anilino] -4- (piperazin-1-yl) pyrimidine prepared in Preparation Example 2 was added to 250 ml of dichloromethane, and 0 After cooling to 캜, a solution of 5.8 g of chloroacetyl chloride in 50 ml of dichloromethane was slowly added dropwise at 0 캜 -5 캜 for 40 minutes. The reaction solution was reacted at 0 ° C.-5 ° C. for 1 hour, and then slowly heated to crystallize by slowly adding 300 ml of ethyl ether at room temperature. After stirring at room temperature for 4 hours, the crystals obtained by filtration and washing twice with 50 ml of ethyl ether were dried in vacuo at 30 ° C.-40 ° C. to obtain 22.56 g (yield 97%) of the title compound.

m.p. : 190 - 193℃m.p. : 190-193 ℃

1H-NMR (CDCl3), ppm : δ　 2.65(s, 3H), 3.23(t, 4H), 3.67 - 3.70(m, 8H), 3.93(t, 4H), 4.10(s, 2H), 5.35(s, 1H), 7.03(br d, 2H), 7.17(d, 2H), 10.01(s, 1H) 1 H-NMR (CDCl 3 ), ppm: δ 2.65 (s, 3H), 3.23 (t, 4H), 3.67-3.70 (m, 8H), 3.93 (t, 4H), 4.10 (s, 2H), 5.35 (s, 1H), 7.03 (br d, 2H), 7.17 (d, 2H), 10.01 (s, 1H)

<실시예 1>　 2-Example 1 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-(아세틸)피페라진-1-일]피리미딘의 제조.] -4- [4- (acetyl) piperazin-1-yl] pyrimidine.

디클로로메탄 20 ml 에 상기 제조예 2에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-(피페라진-1-일)피리미딘 0.2 g 과 트리에틸아민 0.09 ml 를 가하고 0℃ 로 냉각하였다. 0℃- 5℃ 에서 아세틸 클로라이드 45 mg 을 가하고 반응용액을 0℃ - 5℃ 에서 1시간 동안 반응시켰다. 반응 완결 후 감압농축하고, 잔사를 메탄올 10 ml 와 물 10 ml 로 결정화시켰다. 실온에서 4시간 동안 교반한 후 여과하고, 물 5 ml 로 세척하여 얻어진 결정을 40℃ - 50℃ 에서 진공건조하여 180 mg (수율 81 %)의 목적화합물을 얻었다.In 20 ml of dichloromethane, 0.2 g of 2-methylthio-6- [4- (4-morpholino) anilino] -4- (piperazin-1-yl) pyrimidine prepared in Preparation Example 2 and triethyl 0.09 ml of amine was added and cooled to 0 ° C. 45 mg of acetyl chloride was added at 0 ° C-5 ° C, and the reaction solution was reacted at 0 ° C-5 ° C for 1 hour. The reaction was concentrated under reduced pressure, and the residue was crystallized from 10 ml of methanol and 10 ml of water. After stirring for 4 hours at room temperature, filtered and washed with 5 ml of water, the obtained crystals were vacuum dried at 40 ℃-50 ℃ to give 180 mg (yield 81%) of the title compound.

m.p. : 217 - 219℃m.p. : 217-219 ℃

1H-NMR (CDCl3), ppm : δ　 2.11(s, 3H), 2.49(s, 3H), 3.15(br s, 4H), 3.44 - 3.52(m, 4H), 3.64 - 3.67(m, 4H), 3.87(t, 4H), 5.41(s, 1H), 6.58(s, 1H), 6.91(br s, 2H), 7.17(br s, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.11 (s, 3H), 2.49 (s, 3H), 3.15 (br s, 4H), 3.44-3.52 (m, 4H), 3.64-3.67 (m, 4H ), 3.87 (t, 4H), 5.41 (s, 1H), 6.58 (s, 1H), 6.91 (br s, 2H), 7.17 (br s, 2H)

<실시예 2>　 2-Example 2 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-(] -4- [4- ( 하이드록시Hydroxy 아세틸)피페라진-1-일]피리미딘의 제조.Preparation of Acetyl) piperazin-1-yl] pyrimidine.

디클로로메탄 20 ml 에 상기 제조예 2에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-(피페라진-1-일)피리미딘 0.3 g 과 트리에틸아민 0.12 ml 를 가하고 0℃ 로 냉각하였다. 0℃ - 5℃ 에서 아세톡시아세틸 클로라이드 0.09 ml 를 가하고 반응용액을 0℃ - 5℃ 에서 1시간 동안 반응시킨 후, 반응용액을 물 10 ml 로 세척하고 감압농축하였다. 잔사를 메탄올 10 ml 에 녹이고 탄산나트륨 0.25 g 과 물 15 ml 를 가한 후, 20℃ - 30℃ 에서 5시간 동안 반응시켰다. 반응 완결 후, 물 15 ml 를 더 가하고 디클로로메탄 30 ml 로 추출하였다. 유기층을 물 30 ml 로 세척하고 감압농축하여 얻은 잔사를, 디클로로메탄 3 ml 와 에틸 에테르 30 ml 로 결정화시켰다. 실온에서 4시간 동안 교반한 후 여과하고, 에틸 에테르 5 ml 로 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조하여 245 mg (수율 71 %)의 목적화합물을 얻었다.0.3 g of 2-methylthio-6- [4- (4-morpholino) anilino] -4- (piperazin-1-yl) pyrimidine prepared in Preparation Example 2 in 20 ml of dichloromethane and triethyl 0.12 ml of amine was added and cooled to 0 ° C. 0.09 ml of acetoxyacetyl chloride was added at 0 ° C-5 ° C, and the reaction solution was reacted at 0 ° C-5 ° C for 1 hour, and then the reaction solution was washed with 10 ml of water and concentrated under reduced pressure. The residue was dissolved in 10 ml of methanol, 0.25 g of sodium carbonate and 15 ml of water were added, followed by reaction at 20 ° C-30 ° C for 5 hours. After completion of the reaction, 15 ml of water was further added and extracted with 30 ml of dichloromethane. The organic layer was washed with 30 ml of water and concentrated under reduced pressure, and the residue was crystallized from 3 ml of dichloromethane and 30 ml of ethyl ether. After stirring at room temperature for 4 hours, the mixture was filtered, washed with 5 ml of ethyl ether, and the obtained crystals were dried in vacuo at 30 ° C.-40 ° C. to obtain 245 mg (yield 71%) of the title compound.

m.p. : 240 - 243℃m.p. : 240-243 ℃

1H-NMR (DMSO-d6), ppm : δ　 2.41(s, 3H), 3.03(t, 4H), 3.49(br s, 8H), 3.72(t, 4H), 4.11(s, 2H), 5.57(s, 1H), 6.87(d, 2H), 7.34(d, 2H), 8.86(s, 1H) 1 H-NMR (DMSO-d 6 ), ppm: δ 2.41 (s, 3H), 3.03 (t, 4H), 3.49 (br s, 8H), 3.72 (t, 4H), 4.11 (s, 2H), 5.57 (s, 1H), 6.87 (d, 2H), 7.34 (d, 2H), 8.86 (s, 1H)

<실시예 3>　 2-Example 3 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-(] -4- [4- ( 아미노아세Aminoace 틸)피페라진-1-일]피리미딘의 제조.Til) piperazin-1-yl] pyrimidine.

클로로포름 20 ml 에 상기 제조예 4에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 염산염 1 g 과 암모니아 (7N 메탄올 용액) 30 ml 를 가하고 20℃ - 30℃ 에서 4일 동안 반응시켰다. 반응 완결 후, 용액을 감압농축하고 잔사를 메탄올 30 ml 와 아세톤 10 ml 로 녹이고 물 20 ml 를 가한 후 실온에서 2시간 동안 교반하였다. 소량의 불용성 불순물을 여과하여 제거하고, 정제된 여액을 다시 감압농축하여 유기용매를 제거하였다. 수용액인 잔사에 물 50 ml 와 3N 수산화나트륨 수용액 5 ml 를 가하고 디클로로메탄 50 ml 로 추출하였다. 유기층을 물 50 ml 로 2회 세척하고 감압농축하여 얻은 잔사를, 디클로로메탄 10 ml 와 에틸 에테르 40 ml 로 결정화시켰다. 실온에서 5시간 동안 교반한 후 여과하고, 에틸 에테르 5 ml 로 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조하여 0.7 g (수율 79 %)의 목적화합물을 얻었다.2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazin-1-yl] pyrimidine prepared in Preparation Example 4 in 20 ml of chloroform. 1 g of hydrochloride and 30 ml of ammonia (7N methanol solution) were added and reacted at 20 ° C.-30 ° C. for 4 days. After completion of the reaction, the solution was concentrated under reduced pressure, the residue was dissolved in 30 ml of methanol and 10 ml of acetone, 20 ml of water was added thereto, and the mixture was stirred at room temperature for 2 hours. A small amount of insoluble impurities were filtered off and the purified filtrate was concentrated under reduced pressure again to remove the organic solvent. 50 ml of water and 5 ml of 3N sodium hydroxide solution were added to the residue, which was an aqueous solution, and extracted with 50 ml of dichloromethane. The organic layer was washed twice with 50 ml of water and concentrated under reduced pressure, and the residue was crystallized from 10 ml of dichloromethane and 40 ml of ethyl ether. After stirring at room temperature for 5 hours, the mixture was filtered and washed with 5 ml of ethyl ether to obtain 0.7 g (yield 79%) of the title compound by vacuum drying the obtained crystal at 30 ° C-40 ° C.

m.p. : 131 - 134℃m.p. : 131-134 ℃

1H-NMR (CDCl3), ppm : δ　 2.17(br s, 2H), 2.47(s, 3H), 3.14(t, 4H), 3.44 - 3.51(m, 6H), 3.61(br d, 4H), 3.86(t, 4H), 5.41(s, 1H), 6.50(s, 1H), 6.88(d, 2H), 7.16(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.17 (br s, 2H), 2.47 (s, 3H), 3.14 (t, 4H), 3.44-3.51 (m, 6H), 3.61 (br d, 4H) , 3.86 (t, 4H), 5.41 (s, 1H), 6.50 (s, 1H), 6.88 (d, 2H), 7.16 (d, 2H)

<실시예 4>　 2-Example 4 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[(] -4- [4-[( 메틸아미Methylami 노)아세틸]피페라진-1-일]피리미딘의 제조.No) acetyl] piperazin-1-yl] pyrimidine.

클로로포름 10 ml 에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.2 g 과 메틸아민 (40% 메탄올 용액) 10 ml 를 가하고 20℃ - 30℃ 에서 2시간 동안 반응시켰다. 반응 완결 후, 용액을 감압농축하고 얻은 잔사를 디클로로메탄 20 ml 에 녹였다. 유기층을 물 20 ml 로 2회 세척하고 감압농축하여 얻은 잔사를, 디클로로메탄 2 ml 에 녹이고 이소프로필 에테르 5 ml 와 헥산 10 ml 를 차례로 가하여 결정화시켰다. 실온에서 4시간 동안 교반한 후 여과하고, 헥산 3 ml 로 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조하여 165 mg (수율 84 %)의 목적화합물을 얻었다.2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazin-1-yl] pyrimidine prepared in Preparation Example 3 in 10 ml of chloroform. 0.2 g and 10 ml of methylamine (40% methanol solution) were added and reacted at 20 ° C-30 ° C for 2 hours. After completion of the reaction, the solution was concentrated under reduced pressure and the obtained residue was dissolved in 20 ml of dichloromethane. The organic layer was washed twice with 20 ml of water and concentrated under reduced pressure. The residue was dissolved in 2 ml of dichloromethane and crystallized by adding 5 ml of isopropyl ether and 10 ml of hexane in that order. After stirring at room temperature for 4 hours, the mixture was filtered and washed with 3 ml of hexane, and the obtained crystals were dried in vacuo at 30 ° C-40 ° C to obtain 165 mg (yield 84%) of the title compound.

m.p. : 153 - 155℃m.p. : 153-155 ℃

1H-NMR (CDCl3), ppm : δ　 2.48(m, 6H), 3.15(t, 4H), 3.47(br s, 6H), 3.58 - 3.67(m, 4H), 3.87(t, 4H), 5.41(s, 1H), 6.45(s, 1H), 6.89(d, 2H), 7.15(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.48 (m, 6H), 3.15 (t, 4H), 3.47 (br s, 6H), 3.58-3.67 (m, 4H), 3.87 (t, 4H), 5.41 (s, 1H), 6.45 (s, 1H), 6.89 (d, 2H), 7.15 (m, 2H)

<실시예 5>　 2-Example 5 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[(] -4- [4-[( 에틸아미Ethyl Army 노)아세틸]피페라진-1-일]피리미딘의 제조.No) acetyl] piperazin-1-yl] pyrimidine.

클로로포름 10 ml 에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.2 g 과 에틸아민 (2.0M 메탄올 용액) 10 ml 를 가하고 20℃ - 30℃ 에서 25시간 동안 반응시켰다. 반응 완결 후, 상기 실시예 4와 동일한 방법으로 반응후 처리와 정제 및 결정화를 실시하여 목적화합물을 얻었다.2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazin-1-yl] pyrimidine prepared in Preparation Example 3 in 10 ml of chloroform. 0.2 g and 10 ml of ethylamine (2.0 M methanol solution) were added and reacted at 20 ° C-30 ° C for 25 hours. After completion of the reaction, the reaction was carried out in the same manner as in Example 4, purification, and crystallization to obtain the target compound.

수율 : 71 %Yield: 71%

m.p. : 141 - 144℃m.p. : 141-144 ℃

1H-NMR (CDCl3), ppm : δ　 1.14(t, 3H), 2.48(s, 3H), 2.64(q, 2H), 3.14 - 3.17(m, 4H), 3.46(br s, 6H), 3.61 - 3.67(m, 4H), 3.85 - 3.88(m, 4H), 5.41(s, 1H), 6.41(s, 1H), 6.89 - 6.93(m, 2H), 7.14 - 7.18(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.14 (t, 3H), 2.48 (s, 3H), 2.64 (q, 2H), 3.14-3.17 (m, 4H), 3.46 (br s, 6H), 3.61-3.67 (m, 4H), 3.85-3.88 (m, 4H), 5.41 (s, 1H), 6.41 (s, 1H), 6.89-6.93 (m, 2H), 7.14-7.18 (m, 2H)

<실시예 6>　 2-Example 6 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[(] -4- [4-[( 이소프로Isopro 필아미노)아세틸]피페라진-1-일]피리미딘의 제조.Preparation of Philamino) acetyl] piperazin-1-yl] pyrimidine.

메탄올 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.2 g 과 이소프로필아민 2 ml 를 가하고 20℃ - 30℃ 에서 3일 동안 반응시켰다. 반응 완결 후, 상기 실시예 4와 동일한 방법으로 반응후 처리와 정제 및 결정화를 실시하여 목적화합물을 얻었다.To a mixed solvent of 10 ml of methanol and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazine prepared in Preparation Example 3 0.2 g of -1-yl] pyrimidine and 2 ml of isopropylamine were added and reacted at 20 ° C-30 ° C for 3 days. After completion of the reaction, the reaction was carried out in the same manner as in Example 4, purification, and crystallization to obtain the target compound.

수율 : 81 %Yield: 81%

m.p. : 185 - 188℃m.p. : 185-188 ℃

1H-NMR (CDCl3), ppm : δ　 1.08(d, 6H), 2.48(s, 3H), 2.71 - 2.84(m, 1H), 3.15(t, 4H), 3.45(br s, 6H), 3.62 - 3.68(m, 4H), 3.87(t, 4H), 5.41(s, 1H), 6.41(s, 1H), 6.90 - 6.94(m, 2H), 7.14 - 7.19(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.08 (d, 6H), 2.48 (s, 3H), 2.71-2.84 (m, 1H), 3.15 (t, 4H), 3.45 (br s, 6H), 3.62-3.68 (m, 4H), 3.87 (t, 4H), 5.41 (s, 1H), 6.41 (s, 1H), 6.90-6.94 (m, 2H), 7.14-7.19 (m, 2H)

<실시예 7>　 2-Example 7 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[(] -4- [4-[( 이소부틸Isobutyl 아미노)아세틸]피페라진-1-일]피리미딘의 제조.Preparation of amino) acetyl] piperazin-1-yl] pyrimidine.

메탄올 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.17 g 과 이소부틸아민 0.37 ml, 트리에틸아민 0.08 ml 를 가하고 서서히 가열하여 50℃ - 55℃ 에서 25시간 동안 반응시켰다. 반응 완결 후, 용액을 감압농축하고 잔사를 메탄올 20 ml 로 녹이고 물 10 ml 를 가한 후 실온에서 2시간 동안 교반하였다. 소량의 불용성 불순물을 여과하여 제거하고, 정제된 여액을 다시 감압농축하여 유기용매를 제거하였다. 수용액인 잔사를 디클로로메탄 20 ml 로 추출하였다. 유기층을 물 20 ml 로 2회 세척하고 감압농축하여 얻은 잔사를, 디클로로메탄 2 ml 에 녹이고 이소프로필 에테르 5 ml 와 헥산 10 ml 를 차례로 가하여 결정화시켰다. 실온에서 4시간 동안 교반한 후 여과하고, 헥산 3 ml 로 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조 하여 0.15 g (수율 82 %)의 목적화합물을 얻었다.To a mixed solvent of 10 ml of methanol and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazine prepared in Preparation Example 3 0.17 g of -1-yl] pyrimidine, 0.37 ml of isobutylamine and 0.08 ml of triethylamine were added thereto, and the resulting mixture was slowly heated to react at 50 ° C-55 ° C for 25 hours. After completion of the reaction, the solution was concentrated under reduced pressure, the residue was dissolved in 20 ml of methanol, 10 ml of water was added, and the mixture was stirred at room temperature for 2 hours. A small amount of insoluble impurities were filtered off and the purified filtrate was concentrated under reduced pressure again to remove the organic solvent. The residue, which was an aqueous solution, was extracted with 20 ml of dichloromethane. The organic layer was washed twice with 20 ml of water and concentrated under reduced pressure. The residue was dissolved in 2 ml of dichloromethane and crystallized by adding 5 ml of isopropyl ether and 10 ml of hexane in that order. After stirring at room temperature for 4 hours, the mixture was filtered, washed with 3 ml of hexane, and the obtained crystals were vacuum dried at 30 占 폚 to 40 占 폚 to obtain 0.15 g (yield 82%) of the title compound.

m.p. : 153 - 156℃m.p. : 153-156 ℃

1H-NMR (CDCl3), ppm : δ　 0.93(d, 6H), 1.71 - 1.84(m, 1H), 2.43 - 2.48(m, 5H), 3.15(t, 4H), 3.46(br d, 6H), 3.61 - 3.67(m, 4H), 3.87(t, 4H), 5.41(s, 1H), 6.41(s, 1H), 6.88 - 6.94(m, 2H), 7.14 - 7.19(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 0.93 (d, 6H), 1.71-1.84 (m, 1H), 2.43-2.48 (m, 5H), 3.15 (t, 4H), 3.46 (br d, 6H ), 3.61-3.67 (m, 4H), 3.87 (t, 4H), 5.41 (s, 1H), 6.41 (s, 1H), 6.88-6.94 (m, 2H), 7.14-7.19 (m, 2H)

<실시예 8>　 2-Example 8 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[(] -4- [4-[( 디에틸아Diethyla 미노)아세틸]피페라진-1-일]피리미딘의 제조.Preparation of Mino) acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.15 g 과 디에틸아민 36 mg, 트리에틸아민 0.09 ml 를 가하고 서서히 가열하여 55℃ - 60℃ 에서 2일 동안 반응시켰다. 반응 완결 후, 상기 실시예 4와 동일한 방법으로 반응후 처리와 정제 및 결정화를 실시하여 목적화합물을 얻었다.To a mixed solvent of 10 ml of acetonitrile and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) pipe prepared in Preparation Example 3 0.15 g of razin-1-yl] pyrimidine, 36 mg of diethylamine and 0.09 ml of triethylamine were added thereto, and the resulting mixture was slowly heated and reacted at 55 ° C.-60 ° C. for 2 days. After completion of the reaction, the reaction was carried out in the same manner as in Example 4, purification, and crystallization to obtain the target compound.

수율 : 56 %Yield: 56%

m.p. : 156 - 159℃m.p. : 156-159 ℃

1H-NMR (CDCl3), ppm : δ　 1.05(t, 6H), 2.49(s, 3H), 2.58(q, 4H), 3.16(t, 4H), 3.31(s, 2H), 3.46 - 3.70(m, 8H), 3.87(t, 4H), 5.42(s, 1H), 6.38(s, 1H), 6.90 - 6.93(m, 2H), 7.16 - 7.19(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.05 (t, 6H), 2.49 (s, 3H), 2.58 (q, 4H), 3.16 (t, 4H), 3.31 (s, 2H), 3.46-3.70 (m, 8H), 3.87 (t, 4H), 5.42 (s, 1H), 6.38 (s, 1H), 6.90-6.93 (m, 2H), 7.16-7.19 (m, 2H)

<실시예 9>　 2-Example 9 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -(2-하이드록시에틸)아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of-(2-hydroxyethyl) amino] acetyl] piperazin-1-yl] pyrimidine.

메탄올 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.3 g 과 에탄올아민 1 ml, 트리에틸아민 0.14 ml 를 가하고 20℃ - 30℃ 에서 2일 동안 반응시켰다. 반응 완결 후, 상기 실시예 7과 동일한 방법으로 반응후 처리와 정제 및 결정화를 실시하여 목적화합물을 얻었다.To a mixed solvent of 10 ml of methanol and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazine prepared in Preparation Example 3 0.3 g of -1-yl] pyrimidine, 1 ml of ethanolamine, and 0.14 ml of triethylamine were added thereto and reacted at 20 ° C-30 ° C for 2 days. After completion of the reaction, the reaction was carried out in the same manner as in Example 7, the purification and purification and crystallization to obtain the target compound.

수율 : 63 %Yield: 63%

m.p. : 128 - 131℃m.p. : 128-131 ℃

1H-NMR (DMSO-d6), ppm : δ　 2.41(s, 3H), 2.66(t, 2H), 3.03(t, 4H), 3.47 - 3.64(m, 12H), 3.72(t, 4H), 5.58(s, 1H), 6.87(d, 2H), 7.34(d, 2H), 8.89(s, 1H) 1 H-NMR (DMSO-d 6 ), ppm: δ 2.41 (s, 3H), 2.66 (t, 2H), 3.03 (t, 4H), 3.47-3.64 (m, 12H), 3.72 (t, 4H) , 5.58 (s, 1H), 6.87 (d, 2H), 7.34 (d, 2H), 8.89 (s, 1H)

<실시예 10>　 2-Example 10 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -- 메틸methyl -- NN -(2-하이드록시에틸)아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of-(2-hydroxyethyl) amino] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 20 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 4에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 염산염 0.4 g 과 2-(메틸아미노)에탄올 0.6 g, 트리에틸아민 0.28 ml 를 가하고 20℃ - 30℃ 에서 6시간 동안 반응시켰다. 반응 완결 후, 용액을 감압농축하여 얻은 잔사를 메탄올 20 ml 에 녹이고 물 60 ml 를 서서히 가하여 결정화시키고 실온에서 5시간 동안 교반하였다. 여과하고 물 10 ml 로 세척하여 얻어진 결정을 40℃ - 50℃ 에서 진공건조 하여 260 mg (수율 65 %)의 목적화합물을 얻었다.To a mixed solvent of 20 ml of acetonitrile and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) pipepe prepared in Preparation Example 4 0.4 g of razin-1-yl] pyrimidine hydrochloride, 0.6 g of 2- (methylamino) ethanol, and 0.28 ml of triethylamine were added and reacted at 20 占 폚-30 占 폚 for 6 hours. After completion of the reaction, the residue obtained by concentrating the solution under reduced pressure was dissolved in 20 ml of methanol, and 60 ml of water was gradually added to crystallize and stirred at room temperature for 5 hours. The crystals obtained by filtration and washing with 10 ml of water were dried in vacuo at 40 ° C-50 ° C to obtain 260 mg (yield 65%) of the title compound.

m.p. : 148 - 150℃m.p. : 148-150 ℃

1H-NMR (CDCl3), ppm : δ 2.45(s, 3H), 2.48(s, 3H), 2.73(t, 2H), 3.15(t, 4H), 3.42 - 3.67(m, 12H), 3.87(t, 4H), 5.41(s, 1H), 6.44(s, 1H), 6.89(d, 2H), 7.15(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.45 (s, 3H), 2.48 (s, 3H), 2.73 (t, 2H), 3.15 (t, 4H), 3.42-3.67 (m, 12H), 3.87 (t, 4H), 5.41 (s, 1H), 6.44 (s, 1H), 6.89 (d, 2H), 7.15 (d, 2H)

<실시예 11>　 2-Example 11 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -(2--(2- 클Cle 로로에틸)아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of Loroethyl) amino] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.15 g 과 2-클로로에틸아민 염산염 0.38 g, 트리에틸아민 0.54 ml 를 가하고 서서히 가열하여 55℃ - 60℃ 에서 15시간 동안 반응시켰다. 반응 완결 후 용액을 감압농축하고, 잔사를 디클로로메탄 20 ml 에 녹이고 물 20 ml 로 2 회 세척하였다. 분리된 유기층을 감압농축하고, 잔사를 칼럼크로마토그라피 (클로로포름 : 메탄올 = 8 : 1 (부피비)) 로 정제하였다. 정제된 분획을 감압농축하여 얻은 잔사를 디클로로메탄 2 ml 에 녹이고 에틸 에테르 10 ml 와 헥산 20 ml 를 차례로 가하여 결정화시켰다. 실온에서 4시간 동안 교반한 후 여과하고, 헥산 5 ml 로 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조하여 90 mg (수율 55 %)의 목적화합물을 얻었다.To a mixed solvent of 10 ml of acetonitrile and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) pipe prepared in Preparation Example 3 0.15 g of rajin-1-yl] pyrimidine, 0.38 g of 2-chloroethylamine hydrochloride and 0.54 ml of triethylamine were added thereto, and the resulting mixture was slowly heated to react at 55 ° C-60 ° C for 15 hours. After completion of the reaction, the solution was concentrated under reduced pressure, and the residue was dissolved in 20 ml of dichloromethane and washed twice with 20 ml of water. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol = 8: 1 (volume ratio)). The residue obtained by concentrating the purified fractions under reduced pressure was dissolved in 2 ml of dichloromethane and crystallized by sequentially adding 10 ml of ethyl ether and 20 ml of hexane. After stirring at room temperature for 4 hours, the mixture was filtered, washed with 5 ml of hexane, and the obtained crystals were dried in vacuo at 30 ° C to 40 ° C to obtain 90 mg (yield 55%) of the title compound.

m.p. : 191 - 194℃m.p. : 191-194 ℃

1H-NMR (CDCl3), ppm : δ　 2.48(s, 3H), 3.06(t, 2H), 3.16(t, 4H), 3.46(br s, 4H), 3.59 - 3.71(m, 8H), 3.87(t, 4H), 5.41(s, 1H), 6.51(s, 1H), 6.90(d, 2H), 7.16(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.48 (s, 3H), 3.06 (t, 2H), 3.16 (t, 4H), 3.46 (br s, 4H), 3.59-3.71 (m, 8H), 3.87 (t, 4H), 5.41 (s, 1H), 6.51 (s, 1H), 6.90 (d, 2H), 7.16 (d, 2H)

<실시예 12>　 2-Example 12 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[2-(디메 틸아미노)에틸]아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of [[2- (Dimethylamino) ethyl] amino] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 20 ml 에 상기 제조예 4에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 염산염 0.4 g 과 N,N-디메틸에틸렌디아민 0.7 g, 트리에틸아민 0.28 ml 를 가하고 20℃ - 30℃ 에서 6시간 동안 반응시켰다. 반응 완결 후, 용액을 감압농축하고 잔사를 메탄올 20 ml 로 녹이고 물 20 ml 를 가한 후 실온에서 3시간 동안 교반하였다. 소량의 불용성 불순물을 여과하여 제거하고, 정제된 여액을 다시 감압농축하여 유기용매를 제거하였다. 수용액인 잔사를 디클로로메탄 20 ml 로 추출하였다. 유기층을 물 20 ml 로 2회 세척하고 감압농축하여 얻은 잔사를, 디클로로메탄 3 ml 에 녹이고 에틸 에테르 30 ml 를 서서히 가하여 결정화시켰다. 실온에서 4시간 동안 교반한 후 여과하고, 에틸 에테르 3 ml 로 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조 하여 170 mg (수율 41 %)의 목적화합물을 얻었다.In 20 ml of acetonitrile, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazin-1-yl] pyridine prepared in Preparation Example 4 0.4 g of midine hydrochloride , 0.7 g of N, N -dimethylethylenediamine, and 0.28 ml of triethylamine were added and reacted at 20 ° C-30 ° C for 6 hours. After completion of the reaction, the solution was concentrated under reduced pressure, the residue was dissolved in 20 ml of methanol, 20 ml of water was added, and the mixture was stirred at room temperature for 3 hours. A small amount of insoluble impurities were filtered off and the purified filtrate was concentrated under reduced pressure again to remove the organic solvent. The residue, which was an aqueous solution, was extracted with 20 ml of dichloromethane. The organic layer was washed twice with 20 ml of water and concentrated under reduced pressure. The residue was dissolved in 3 ml of dichloromethane and crystallized by slowly adding 30 ml of ethyl ether. After stirring for 4 hours at room temperature, the mixture was filtered, washed with 3 ml of ethyl ether, and the obtained crystals were vacuum dried at 30 占 폚 to 40 占 폚 to obtain 170 mg (yield 41%) of the title compound.

m.p. : 172 - 174℃m.p. : 172-174 ℃

1H-NMR (DMSO-d6), ppm : δ　 2.42(s, 3H), 2.75(s, 6H), 3.03(t, 4H), 3.31 - 3.58(m, 12H), 3.72(t, 4H), 4.11(s, 2H), 5.64(s, 1H), 6.87(d, 2H), 7.37(d, 2H), 9.01(s, 1H) 1 H-NMR (DMSO-d 6 ), ppm: δ 2.42 (s, 3H), 2.75 (s, 6H), 3.03 (t, 4H), 3.31-3.58 (m, 12H), 3.72 (t, 4H) , 4.11 (s, 2H), 5.64 (s, 1H), 6.87 (d, 2H), 7.37 (d, 2H), 9.01 (s, 1H)

<실시예 13>　 2-Example 13 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[2-(-[2-( 디D 에틸아미노)에틸]아미노]아세틸]피페라진-1-일]피리미딘의 제조.Ethylamino) ethyl] amino] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 20 ml 에 상기 제조예 4에서 제조한 2-메틸티오-6-[4-(4-모르 포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 염산염 0.4 g 과 N,N-디에틸에틸렌디아민 0.93 g, 트리에틸아민 0.28 ml 를 가하고 20℃ - 30℃ 에서 6시간 동안 반응시켰다. 반응 완결 후, 용액을 감압농축하고 잔사를 메탄올 20 ml 로 녹이고 물 20 ml 를 가한 후 실온에서 3시간 동안 교반하였다. 소량의 불용성 불순물을 여과하여 제거하고, 정제된 여액을 다시 감압농축하여 유기용매를 제거하였다. 수용액인 잔사를 디클로로메탄 20 ml 로 추출하였다. 유기층을 물 20 ml 로 2회 세척하고 감압농축하여 얻은 잔사를, 디클로로메탄 3 ml 에 녹이고 에틸 에테르 10 ml 와 헥산 20 ml 를 차례로 가하여 결정화시켰다. 실온에서 4시간 동안 교반한 후 여과하고, 헥산 5 ml 로 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조 하여 225 mg (수율 52 %)의 목적화합물을 얻었다.In 20 ml of acetonitrile, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazin-1-yl] pyridine prepared in Preparation Example 4 0.4 g of midine hydrochloride , 0.93 g of N, N -diethylethylenediamine, and 0.28 ml of triethylamine were added and reacted at 20 ° C-30 ° C for 6 hours. After completion of the reaction, the solution was concentrated under reduced pressure, the residue was dissolved in 20 ml of methanol, 20 ml of water was added, and the mixture was stirred at room temperature for 3 hours. A small amount of insoluble impurities were filtered off and the purified filtrate was concentrated under reduced pressure again to remove the organic solvent. The residue, which was an aqueous solution, was extracted with 20 ml of dichloromethane. The organic layer was washed twice with 20 ml of water and concentrated under reduced pressure. The residue was dissolved in 3 ml of dichloromethane and crystallized by adding 10 ml of ethyl ether and 20 ml of hexane in order. After stirring at room temperature for 4 hours, the mixture was filtered, washed with 5 ml of hexane, and the obtained crystals were dried in vacuo at 30 ° C to 40 ° C to obtain 225 mg (yield 52%) of the title compound.

m.p. : 125 - 128℃m.p. : 125-128 ℃

1H-NMR (CDCl3), ppm : δ　 1.04(t, 6H), 2.48(s, 3H), 2.56 - 2.63(m, 6H), 2.73(t, 2H), 3.16(t, 4H), 3.47(br s, 6H), 3.62 - 3.67(m, 4H), 3.87(t, 4H), 5.41(s, 1H), 6.41(s, 1H), 6.90 - 6.94(m, 2H), 7.14 - 7.19(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.04 (t, 6H), 2.48 (s, 3H), 2.56-2.63 (m, 6H), 2.73 (t, 2H), 3.16 (t, 4H), 3.47 (br s, 6H), 3.62-3.67 (m, 4H), 3.87 (t, 4H), 5.41 (s, 1H), 6.41 (s, 1H), 6.90-6.94 (m, 2H), 7.14-7.19 ( m, 2H)

<실시예 14>　 2-Example 14 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[2-(-[2-( 디D 이소프로필아미노)에틸]아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of Isopropylamino) ethyl] amino] acetyl] piperazin-1-yl] pyrimidine.

N,N-디에틸에틸렌디아민 대신에 N,N-디이소프로필에틸렌디아민을 사용하여, 상기 실시예 13과 동일한 방법으로 실시하여 목적화합물을 얻었다. N, N - diethyl N, N in place of ethylenediamine-using diisopropyl ethylene diamine to give the object compound was carried out as Example 13.

수율 : 69 %Yield: 69%

m.p. : 124 - 127℃m.p. : 124-127 ℃

1H-NMR (CDCl3), ppm : δ　 1.04(d, 12H), 2.48(s, 3H), 2.62 - 2.69(m, 4H), 3.01 - 3.17(m, 6H), 3.44 - 3.51(m, 6H), 3.62 - 3.67(m, 4H), 3.87(t, 4H), 5.42(s, 1H), 6.44(s, 1H), 6.88 - 6.94(m, 2H), 7.15 - 7.19(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.04 (d, 12H), 2.48 (s, 3H), 2.62-2.69 (m, 4H), 3.01-3.17 (m, 6H), 3.44-3.51 (m, 6H), 3.62-3.67 (m, 4H), 3.87 (t, 4H), 5.42 (s, 1H), 6.44 (s, 1H), 6.88-6.94 (m, 2H), 7.15-7.19 (m, 2H)

<실시예 15>　 2-Example 15 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[2-(디메틸아미노)에틸]--[2- (dimethylamino) ethyl]- NN -- 메틸아미노Methylamino ]아세틸]피페라진-1-일]피리미딘의 제조.] Acetyl] piperazin-1-yl] pyrimidine.

메탄올 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.15 g 과 N,N,N'-트리메틸에틸렌디아민 0.33 mg, 트리에틸아민 0.07 ml 를 가하고 20℃ - 30℃ 에서 4일 동안 반응시켰다. 반응 완결 후, 상기 실시예 7과 동일한 방법으로 반응후 처리와 정제 및 결정화를 실시하여 목적화합물을 얻었다.To a mixed solvent of 10 ml of methanol and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazine prepared in Preparation Example 3 0.15 g of -1-yl] pyrimidine , 0.33 mg of N, N, N'- trimethylethylenediamine and 0.07 ml of triethylamine were added and reacted at 20 ° C-30 ° C for 4 days. After completion of the reaction, the reaction was carried out in the same manner as in Example 7, the purification and purification and crystallization to obtain the target compound.

수율 : 61 %Yield: 61%

m.p. : 137 - 140℃m.p. : 137-140 ℃

1H-NMR (CDCl3), ppm : δ　 2.25(s, 6H), 2.30(s, 3H), 2.41 - 2.49(m, 5H), 2.52 - 2.60(m, 2H), 3.16(t, 4H), 3.26(s, 2H), 3.46 - 3.69(m, 8H), 3.87(t, 4H), 5.42(s, 1H), 6.38(s, 1H), 6.90(d, 2H), 7.16(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.25 (s, 6H), 2.30 (s, 3H), 2.41-2.49 (m, 5H), 2.52-2.60 (m, 2H), 3.16 (t, 4H) , 3.26 (s, 2H), 3.46-3.69 (m, 8H), 3.87 (t, 4H), 5.42 (s, 1H), 6.38 (s, 1H), 6.90 (d, 2H), 7.16 (d, 2H )

<실시예 16>　 2-Example 16 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[2-(-[2-( 디D 에틸아미노)에틸]-Ethylamino) ethyl]- NN -- 메틸아미노Methylamino ]아세틸]피페라진-1-일]피리미딘의 제조.] Acetyl] piperazin-1-yl] pyrimidine.

N,N,N'-트리메틸에틸렌디아민 대신에 N,N-디에틸-N'-메틸에틸렌디아민을 사용하여, 상기 실시예 15와 동일한 방법으로 실시하여 목적화합물을 얻었다. N, N, N'- trimethylethylenediamine was used in place of N, N -diethyl- N' -methylethylenediamine in the same manner as in Example 15 to obtain the target compound.

수율 : 72 %Yield: 72%

m.p. : 110 - 112℃m.p. : 110-112 ℃

1H-NMR (CDCl3), ppm : δ　 1.03(t, 6H), 2.30(s, 3H), 2.49(s, 3H), 2.52 - 2.61(m, 8H), 3.15(t, 4H), 3.25(s, 2H), 3.46 - 3.69(m, 8H), 3.87(t, 4H), 5.42(s, 1H), 6.38(s, 1H), 6.89 - 6.94(m, 2H), 7.14 - 7.19(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.03 (t, 6H), 2.30 (s, 3H), 2.49 (s, 3H), 2.52-2.61 (m, 8H), 3.15 (t, 4H), 3.25 (s, 2H), 3.46-3.69 (m, 8H), 3.87 (t, 4H), 5.42 (s, 1H), 6.38 (s, 1H), 6.89-6.94 (m, 2H), 7.14-7.19 (m , 2H)

<실시예 17>　 2-Example 17 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -(사이클로펜틸)아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of-(cyclopentyl) amino] acetyl] piperazin-1-yl] pyrimidine.

N,N,N'-트리메틸에틸렌디아민 대신에 사이클로펜틸아민을 사용하여, 상기 실시예 15와 동일한 방법으로 실시하여 목적화합물을 얻었다.Cyclopentylamine was used instead of N, N, N'- trimethylethylenediamine to carry out the same method as in Example 15 to obtain the target compound.

수율 : 81 %Yield: 81%

m.p. : 173 - 176℃m.p. : 173-176 ℃

1H-NMR (CDCl3), ppm : δ　 1.36 - 1.85(m, 8H), 2.48(s, 3H), 3.02 - 3.11(m, 1H), 3.15(t, 4H), 3.44 - 3.47(m, 6H), 3.62 - 3.67(m, 4H), 3.87(t, 4H), 5.41(s, 1H), 6.39(s, 1H), 6.88 - 6.94(m, 2H), 7.14 - 7.19(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.36-1.85 (m, 8H), 2.48 (s, 3H), 3.02-3.11 (m, 1H), 3.15 (t, 4H), 3.44-3.47 (m, 6H), 3.62-3.67 (m, 4H), 3.87 (t, 4H), 5.41 (s, 1H), 6.39 (s, 1H), 6.88-6.94 (m, 2H), 7.14-7.19 (m, 2H)

<실시예 18>　 2-Example 18 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[(-[( 사이between 클로프로필)Chloropropyl) 메틸methyl ]아미노]아세틸]피페라진-1-일]피리미딘의 제조.] Amino] acetyl] piperazin-1-yl] pyrimidine.

이소부틸아민 대신에 아미노메틸사이클로프로판을 사용하여, 상기 실시예 7과 동일한 방법으로 실시하여 목적화합물을 얻었다.A target compound was obtained in the same manner as in Example 7 using aminomethylcyclopropane instead of isobutylamine.

수율 : 81 %Yield: 81%

m.p. : 142 - 145℃m.p. : 142-145 ℃

1H-NMR (CDCl3), ppm : δ　 0.13 - 0.18(m, 2H), 0.46 - 0.52(m, 2H), 0.92 - 1.00(m, 1H), 2.48 - 2.51(m, 5H), 3.15(t, 4H), 3.46 - 3.49(m, 6H), 3.63 - 3.67(m, 4H), 3.87(t, 4H), 5.41(s, 1H), 6.39(s, 1H), 6.90 - 6.93(m, 2H), 7.15 - 7.18(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 0.13-0.18 (m, 2H), 0.46-0.52 (m, 2H), 0.92-1.00 (m, 1H), 2.48-2.51 (m, 5H), 3.15 ( t, 4H), 3.46-3.49 (m, 6H), 3.63-3.67 (m, 4H), 3.87 (t, 4H), 5.41 (s, 1H), 6.39 (s, 1H), 6.90-6.93 (m, 2H), 7.15-7.18 (m, 2H)

<실시예 19>　 2-Example 19 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[2-(1-피롤리디닐)에틸]아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of [[2- (1-pyrrolidinyl) ethyl] amino] acetyl] piperazin-1-yl] pyrimidine.

N,N-디에틸에틸렌디아민 대신에 1-(2-아미노에틸)피롤리딘을 사용하여, 상기 실시예 13과 동일한 방법으로 실시하여 목적화합물을 얻었다.1- (2-aminoethyl) pyrrolidine was used in place of N, N -diethylethylenediamine, and the target compound was obtained in the same manner as in Example 13.

수율 : 51 %Yield: 51%

m.p. : 129 - 132℃m.p. : 129-132 ℃

1H-NMR (CDCl3), ppm : δ　 1.77 - 1.88(m, 4H), 2.48(s, 3H), 2.66 - 2.74(m, 4H), 2.81 - 2.85(m, 4H), 3.15(t, 4H), 3.46 - 3.48(m, 6H), 3.60 - 3.68(m, 4H), 3.87(t, 4H), 5.42(s, 1H), 6.46(s, 1H), 6.90 - 6.94(m, 2H), 7.15 - 7.19(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.77-1.88 (m, 4H), 2.48 (s, 3H), 2.66-2.74 (m, 4H), 2.81-2.85 (m, 4H), 3.15 (t, 4H), 3.46-3.48 (m, 6H), 3.60-3.68 (m, 4H), 3.87 (t, 4H), 5.42 (s, 1H), 6.46 (s, 1H), 6.90-6.94 (m, 2H) , 7.15-7.19 (m, 2H)

<실시예 20>　 2-Example 20 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[3-(1-피롤리디닐)프로필]아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of [[3- (1-pyrrolidinyl) propyl] amino] acetyl] piperazin-1-yl] pyrimidine.

N,N-디에틸에틸렌디아민 대신에 1-(3-아미노프로필)피롤리딘을 사용하여, 상기 실시예 13과 동일한 방법으로 실시하여 목적화합물을 얻었다.1- (3-aminopropyl) pyrrolidine was used in place of N, N -diethylethylenediamine, and the target compound was obtained in the same manner as in Example 13.

수율 : 50 %Yield: 50%

m.p. : 148 - 151℃m.p. : 148-151 ℃

1H-NMR (CDCl3), ppm : δ　 1.71 - 1.84(m, 6H), 2.48 - 2.59(m, 9H), 2.68(t, 2H), 3.14 - 3.17(m, 4H), 3.44 - 3.49(m, 6H), 3.60 - 3.68(m, 4H), 3.85 - 3.89(m, 4H), 5.42(s, 1H), 6.46(s, 1H), 6.88 - 6.94(m, 2H), 7.14 - 7.20(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.71-1.84 (m, 6H), 2.48-2.59 (m, 9H), 2.68 (t, 2H), 3.14-3.17 (m, 4H), 3.44-3.49 ( m, 6H), 3.60-3.68 (m, 4H), 3.85-3.89 (m, 4H), 5.42 (s, 1H), 6.46 (s, 1H), 6.88-6.94 (m, 2H), 7.14-7.20 ( m, 2H)

<실시예 21>　 2-Example 21 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[3-(4-모르포리노)프로필]아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of [[3- (4-morpholino) propyl] amino] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.15 g 과 4-(3-아미노프로필)모르포린 0.47 g, 트리에틸아민 0.07 ml 를 가하고 서서히 가열하여 55℃ - 60℃ 에서 15시간 동안 반응시켰다. 반응 완결 후, 상기 실시예 7과 동일한 방법으로 반응후 처리와 정제 및 결정화를 실시하여 목적화합물을 얻었다.To a mixed solvent of 10 ml of acetonitrile and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) pipe prepared in Preparation Example 3 0.15 g of razin-1-yl] pyrimidine, 0.47 g of 4- (3-aminopropyl) morpholine and 0.07 ml of triethylamine were added thereto, and the resulting mixture was slowly heated and reacted at 55 ° C-60 ° C for 15 hours. After completion of the reaction, the reaction was carried out in the same manner as in Example 7, the purification and purification and crystallization to obtain the target compound.

수율 : 81 %Yield: 81%

m.p. : 138 - 141℃m.p. : 138-141 ℃

1H-NMR (CDCl3), ppm : δ　 1.70(qn, 2H), 2.39 - 2.45(m, 6H), 2.48(s, 3H), 2.66(t, 2H), 3.15(t, 4H), 3.43 - 3.49(m, 6H), 3.63 - 3.72(m, 8H), 3.87(t, 4H), 5.41(s, 1H), 6.42(s, 1H), 6.88 - 6.94(m, 2H), 7.14 - 7.19(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.70 (qn, 2H), 2.39-2.45 (m, 6H), 2.48 (s, 3H), 2.66 (t, 2H), 3.15 (t, 4H), 3.43 -3.49 (m, 6H), 3.63-3.72 (m, 8H), 3.87 (t, 4H), 5.41 (s, 1H), 6.42 (s, 1H), 6.88-6.94 (m, 2H), 7.14-7.19 (m, 2H)

<실시예 22>　 2-Example 22 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[3-(-[3- ( 이this 미다졸-1-일)프로필]아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of midazol-1-yl) propyl] amino] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.15 g 과 1-(3-아미노프로필)이미다졸 0.41 g, 트리에틸아민 0.07 ml 를 가하고 서서히 가열하여 55℃ - 60℃ 에서 15시간 동안 반응시켰다. 반응 완결 후 용액을 감압농축하고, 잔사를 디클로로메탄 20 ml 에 녹이고 물 20 ml 로 2 회 세척하였다. 분리된 유기층을 감압농축하고, 잔사를 칼럼크로마토그라피 (클로로포름 : 메탄올 = 4 : 1 (부피비)) 로 정제하였다. 정제된 분획을 감압농축하여 얻은 잔사를 디클로로메탄 2 ml 에 녹이고 에틸 에테르 10 ml 와 헥산 20 ml 를 차례로 가하여 결정화시켰다. 실온에서 4시간 동안 교반한 후 여과하고, 헥산 5 ml 로 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조하여 95 mg (수율 53 %)의 목적화합물을 얻었다.To a mixed solvent of 10 ml of acetonitrile and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) pipe prepared in Preparation Example 3 0.15 g of rajin-1-yl] pyrimidine, 0.41 g of 1- (3-aminopropyl) imidazole and 0.07 ml of triethylamine were added thereto, and the resulting mixture was slowly heated to react at 55 ° C. to 60 ° C. for 15 hours. After completion of the reaction, the solution was concentrated under reduced pressure, and the residue was dissolved in 20 ml of dichloromethane and washed twice with 20 ml of water. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol = 4: 1 (volume ratio)). The residue obtained by concentrating the purified fractions under reduced pressure was dissolved in 2 ml of dichloromethane and crystallized by sequentially adding 10 ml of ethyl ether and 20 ml of hexane. After stirring at room temperature for 4 hours, the mixture was filtered, washed with 5 ml of hexane, and the obtained crystals were vacuum dried at 30 占 폚 to 40 占 폚 to give 95 mg (yield 53%) of the title compound.

m.p. : 152 - 155℃m.p. : 152-155 ℃

1H-NMR (CDCl3), ppm : δ 1.95(qn, 2H), 2.48(s, 3H), 2.56(t, 2H), 3.15(t, 4H), 3.39 - 3.49(m, 6H), 3.60 - 3.69(m, 4H), 3.87(t, 4H), 4.07(t, 2H), 5.41(s, 1H), 6.47(s, 1H), 6.88 - 6.94(m, 3H), 7.05(s, 1H), 7.14 - 7.19(m, 2H), 7.49(s, 1H) 1 H-NMR (CDCl 3 ), ppm: δ 1.95 (qn, 2H), 2.48 (s, 3H), 2.56 (t, 2H), 3.15 (t, 4H), 3.39-3.49 (m, 6H), 3.60 -3.69 (m, 4H), 3.87 (t, 4H), 4.07 (t, 2H), 5.41 (s, 1H), 6.47 (s, 1H), 6.88-6.94 (m, 3H), 7.05 (s, 1H ), 7.14-7.19 (m, 2H), 7.49 (s, 1H)

<실시예 23>　 2-Example 23 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[2-(2-피리딜)에틸]아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of [[2- (2-pyridyl) ethyl] amino] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.15 g 과 2-(2-아미노에틸)피리딘 0.4 g, 트리에틸아민 0.07 ml 를 가하고 서서히 가열하여 55℃ - 60℃ 에서 15시간 동안 반응시켰다. 반응 완결 후 용액을 감압농축하고, 잔사를 디클로로메탄 20 ml 에 녹이고 물 20 ml 로 2 회 세척하였다. 분리된 유기층을 감압농축하고, 잔사를 칼럼크로마토그라피 (클로로포름 : 메탄올 = 16 : 1 (부피비)) 로 정제하였다. 정제된 분획을 감압농축하여 얻은 잔사를 디클로로메탄 2 ml 에 녹이고 에틸 에테르 10 ml 와 헥산 20 ml 를 차례로 가하여 결정화시켰다. 실온에서 4시간 동안 교반한 후 여과하고, 헥산 5 ml 로 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조하여 0.11 g (수율 62 %)의 목적화합물을 얻었다.To a mixed solvent of 10 ml of acetonitrile and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) pipe prepared in Preparation Example 3 0.15 g of rajin-1-yl] pyrimidine, 0.4 g of 2- (2-aminoethyl) pyridine, and 0.07 ml of triethylamine were added thereto, and the resulting mixture was slowly heated to react at 55 ° C-60 ° C for 15 hours. After completion of the reaction, the solution was concentrated under reduced pressure, and the residue was dissolved in 20 ml of dichloromethane and washed twice with 20 ml of water. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol = 16: 1 (volume ratio)). The residue obtained by concentrating the purified fractions under reduced pressure was dissolved in 2 ml of dichloromethane and crystallized by sequentially adding 10 ml of ethyl ether and 20 ml of hexane. After stirring at room temperature for 4 hours, the mixture was filtered, washed with 5 ml of hexane, and the obtained crystals were vacuum dried at 30 占 폚 to 40 占 폚 to obtain 0.11 g (yield 62%) of the title compound.

m.p. : 164 - 167℃m.p. : 164-167 ℃

1H-NMR (CDCl3), ppm : δ 2.48(s, 3H), 2.97 - 3.09(m, 4H), 3.15(t, 4H), 3.43 - 3.48(m, 6H), 3.56 - 3.66(m, 4H), 3.87(t, 4H), 5.40(s, 1H), 6.43(s, 1H), 6.88 - 6.94(m, 2H), 7.09 - 7.20(m, 4H), 7.56 - 7.62(m, 1H), 8.51 - 8.53(m, 1H) 1 H-NMR (CDCl 3 ), ppm: δ 2.48 (s, 3H), 2.97-3.09 (m, 4H), 3.15 (t, 4H), 3.43-3.48 (m, 6H), 3.56-3.66 (m, 4H), 3.87 (t, 4H), 5.40 (s, 1H), 6.43 (s, 1H), 6.88-6.94 (m, 2H), 7.09-7.20 (m, 4H), 7.56-7.62 (m, 1H) , 8.51-8.53 (m, 1H)

<실시예 24>　 2-Example 24 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[2-(3-피리딜)에틸]아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of [[2- (3-pyridyl) ethyl] amino] acetyl] piperazin-1-yl] pyrimidine.

2-(2-아미노에틸)피리딘 대신에 3-(2-아미노에틸)피리딘을 사용하여, 상기 실시예 23과 동일한 방법으로 실시하여 목적화합물을 얻었다.Using the 3- (2-aminoethyl) pyridine instead of 2- (2-aminoethyl) pyridine, the same procedure as in Example 23 was carried out to obtain the target compound.

수율 : 51 %Yield: 51%

m.p. : 160 - 163℃m.p. : 160-163 ℃

1H-NMR (CDCl3), ppm : δ　 2.48(s, 3H), 2.80 - 2.94(m, 4H), 3.15(t, 4H), 3.43 - 3.47(m, 6H), 3.58 - 3.66(m, 4H), 3.87(t, 4H), 5.40(s, 1H), 6.43(s, 1H), 6.88 - 6.94(m, 2H), 7.14 - 7.23(m, 3H), 7.53 - 7.57(m, 1H), 8.44 - 8.48(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.48 (s, 3H), 2.80-2.94 (m, 4H), 3.15 (t, 4H), 3.43-3.47 (m, 6H), 3.58-3.66 (m, 4H), 3.87 (t, 4H), 5.40 (s, 1H), 6.43 (s, 1H), 6.88-6.94 (m, 2H), 7.14-7.23 (m, 3H), 7.53-7.57 (m, 1H) , 8.44-8.48 (m, 2H)

<실시예 25>　 2-Example 25 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[2-(4-피리딜)에틸]아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of [[2- (4-pyridyl) ethyl] amino] acetyl] piperazin-1-yl] pyrimidine.

2-(2-아미노에틸)피리딘 대신에 4-(2-아미노에틸)피리딘을 사용하여, 상기 실시예 23과 동일한 방법으로 실시하여 목적화합물을 얻었다.4- (2-aminoethyl) pyridine was used instead of 2- (2-aminoethyl) pyridine to carry out the same procedure as in Example 23 to obtain the target compound.

수율 : 56 %Yield: 56%

m.p. : 142 - 145℃m.p. : 142-145 ℃

1H-NMR (CDCl3), ppm : δ　 2.48(s, 3H), 2.80 - 2.94(m, 4H), 3.15(t, 4H), 3.45(br s, 6H), 3.61 - 3.66(m, 4H), 3.87(t, 4H), 5.40(s, 1H), 6.44(s, 1H), 6.89(d, 2H), 7.15 - 7.18(m, 4H), 8.49(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.48 (s, 3H), 2.80-2.94 (m, 4H), 3.15 (t, 4H), 3.45 (br s, 6H), 3.61-3.66 (m, 4H ), 3.87 (t, 4H), 5.40 (s, 1H), 6.44 (s, 1H), 6.89 (d, 2H), 7.15-7.18 (m, 4H), 8.49 (d, 2H)

<실시예 26>　 2-Example 26 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[(1-] -4- [4-[(1- 피롤리Pyrroly 디닐)아세틸]피페라진-1-일]피리미딘의 제조.Preparation of diyl) acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.15 g 과 피롤리딘 28 mg, 트리에틸아민 0.07 ml 를 가하고 서서히 가열하여 55℃ - 60℃ 에서 15시간 동안 반응시켰다. 반응 완결 후, 용액을 감압농축하여 얻은 잔사를 메탄올 10 ml 에 녹이고 물 20 ml 를 서서히 가하여 결정화시키고 실온에서 5시간 동안 교반하였다. 여과하고 물 5 ml 로 세척하여 얻어진 결정을 40℃ - 50℃ 에서 진공건조 하여 95 mg (수율 59 %)의 목적화합물을 얻었다.To a mixed solvent of 10 ml of acetonitrile and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) pipe prepared in Preparation Example 3 0.15 g of razin-1-yl] pyrimidine, 28 mg of pyrrolidine and 0.07 ml of triethylamine were added thereto, and the resulting mixture was slowly heated and reacted at 55 ° C.-60 ° C. for 15 hours. After completion of the reaction, the residue obtained by concentrating the solution under reduced pressure was dissolved in 10 ml of methanol, and 20 ml of water was slowly added to crystallize and stirred at room temperature for 5 hours. The crystals obtained by filtration and washing with 5 ml of water were vacuum dried at 40 캜-50 캜 to obtain 95 mg (yield 59%) of the title compound.

m.p. : 136 - 138℃m.p. : 136-138 ℃

1H-NMR (CDCl3), ppm : δ 1.77 - 1.80(m, 4H), 2.49(s, 3H), 2.58(br s, 4H), 3.15(t, 4H), 3.33(s, 2H), 3.46 - 3.64(m, 8H), 3.87(t, 4H), 5.42(s, 1H), 6.37(s, 1H), 6.90 - 6.93(m, 2H), 7.15 - 7.18(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.77-1.80 (m, 4H), 2.49 (s, 3H), 2.58 (br s, 4H), 3.15 (t, 4H), 3.33 (s, 2H), 3.46-3.64 (m, 8H), 3.87 (t, 4H), 5.42 (s, 1H), 6.37 (s, 1H), 6.90-6.93 (m, 2H), 7.15-7.18 (m, 2H)

<실시예 27>　 2-Example 27 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[(3-] -4- [4-[(3- 티아졸Thiazole 리디닐)아세틸]피페라진-1-일]피리미딘의 제조.Preparation of Ridinyl) acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.15 g 과 티아졸리딘 105 mg, 트리에틸아민 0.07 ml 를 가하고 서서히 가열하여 55℃ - 60℃ 에서 3일 동안 반응시켰다. 반응 완결 후 용액을 감압농축하고, 잔사를 디클로로메탄 20 ml 에 녹이고 물 20 ml 로 2 회 세척하였다. 분리된 유기층을 감압농축하고, 잔사를 칼럼크로마토그라피 (클로로포름 : 메탄올 = 30 : 1 (부피비)) 로 정제하였다. 정제된 분획을 감압농축하여 얻은 잔사를 디클로로메탄 2 ml 에 녹이고 이소프로필 에테르 5 ml 와 헥산 20 ml 를 차례로 가하여 결정화시켰다. 실온에서 4시간 동안 교반한 후 여과하고, 헥산 5 ml 로 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조하여 90 mg (수율 54 %)의 목적화합물을 얻었다.To a mixed solvent of 10 ml of acetonitrile and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) pipe prepared in Preparation Example 3 0.15 g of razin-1-yl] pyrimidine, 105 mg of thiazolidine and 0.07 ml of triethylamine were added thereto, and the resulting mixture was slowly heated and reacted at 55 ° C.-60 ° C. for 3 days. After completion of the reaction, the solution was concentrated under reduced pressure, and the residue was dissolved in 20 ml of dichloromethane and washed twice with 20 ml of water. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol = 30: 1 (volume ratio)). The residue obtained by concentrating the purified fractions under reduced pressure was dissolved in 2 ml of dichloromethane, and crystallized by adding 5 ml of isopropyl ether and 20 ml of hexane in that order. After stirring at room temperature for 4 hours, the mixture was filtered, washed with 5 ml of hexane, and the obtained crystals were dried in vacuo at 30 ° C to 40 ° C to obtain 90 mg (yield 54%) of the title compound.

m.p. : 149 - 152℃m.p. : 149-152 ℃

1H-NMR (CDCl3), ppm : δ 2.49(s, 3H), 2.93(t, 2H), 3.10 - 3.17(m, 6H), 3.27(s, 2H), 3.47(br d, 2H), 3.62 - 3.67(m, 6H), 3.87(t, 4H), 4.10(s, 2H), 5.41(s, 1H), 6.50(s, 1H), 6.90 - 6.94(m, 2H), 7.15 - 7.18(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.49 (s, 3H), 2.93 (t, 2H), 3.10-3.17 (m, 6H), 3.27 (s, 2H), 3.47 (br d, 2H), 3.62-3.67 (m, 6H), 3.87 (t, 4H), 4.10 (s, 2H), 5.41 (s, 1H), 6.50 (s, 1H), 6.90-6.94 (m, 2H), 7.15-7.18 ( m, 2H)

<실시예 28>　 2-Example 28 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[(1-] -4- [4-[(1- 피페리Piperi 디노)아세틸]피페라진-1-일]피리미딘의 제조.Preparation of Dino) acetyl] piperazin-1-yl] pyrimidine.

피롤리딘 대신에 피페리딘을 사용하여, 상기 실시예 26과 동일한 방법으로 실시하여 목적화합물을 얻었다.Using piperidine instead of pyrrolidine, it was carried out in the same manner as in Example 26 to obtain the target compound.

수율 : 60 %Yield: 60%

m.p. : 239 - 242℃m.p. : 239-242 ℃

1H-NMR (CDCl3), ppm : δ　 1.42(br d, 2H), 1.52 - 1.60(m, 4H), 2.42(br s, 4H), 2.49(s, 3H), 3.14 - 3.17(m, 6H), 3.44 - 3.47(m, 2H), 3.59 - 3.70(m, 6H), 3.87(t, 4H), 5.43(s, 1H), 6.41(s, 1H), 6.89 - 6.94(m, 2H), 7.15 - 7.20(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.42 (br d, 2H), 1.52-1.60 (m, 4H), 2.42 (br s, 4H), 2.49 (s, 3H), 3.14-3.17 (m, 6H), 3.44-3.47 (m, 2H), 3.59-3.70 (m, 6H), 3.87 (t, 4H), 5.43 (s, 1H), 6.41 (s, 1H), 6.89-6.94 (m, 2H) , 7.15-7.20 (m, 2H)

<실시예 29>　 2-Example 29 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[4-(] -4- [4-[[4- ( 하이Hi 드록시)피페리딘-1-일]아세틸]피페라진-1-일]피리미딘의 제조.Doxy) piperidin-1-yl] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.25 g 과 4-하이드록시피페리딘 60 mg, 트리에틸아민 0.12 ml 를 가하고 서서히 가열하여 55℃ - 60℃ 에서 15시간 동안 반응시켰다. 반응 완결 후, 용액을 감압농축하여 얻은 잔사를 메탄올 5 ml 에 녹이고 물 25 ml 를 서서히 가하여 결정화시키고 실온에서 5시간 동안 교반하였다. 여과하고 물 5 ml 로 세척하여 얻어진 결정을 40℃ - 50℃ 에서 진공건조 하여 185 mg (수율 65 %)의 목적화합물을 얻었다.To a mixed solvent of 10 ml of acetonitrile and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) pipe prepared in Preparation Example 3 0.25 g of rajin-1-yl] pyrimidine, 60 mg of 4-hydroxypiperidine and 0.12 ml of triethylamine were added thereto, and the resulting mixture was slowly heated and reacted at 55 ° C.-60 ° C. for 15 hours. After completion of the reaction, the residue obtained by concentrating the solution under reduced pressure was dissolved in 5 ml of methanol, and 25 ml of water was slowly added to crystallize and stirred at room temperature for 5 hours. The crystals obtained by filtration and washing with 5 ml of water were dried in vacuo at 40 ° C-50 ° C to obtain 185 mg (yield 65%) of the title compound.

m.p. : 176 - 179℃m.p. : 176-179 ℃

1H-NMR (CDCl3), ppm : δ 1.51 - 1.63(m, 2H), 1.86 - 1.92(m, 2H), 2.20 - 2.28(m, 2H), 2.49(s, 3H), 2.75 - 2.78(m, 2H), 3.14 - 3.18(m, 6H), 3.46 - 3.48(m, 2H), 3.58 - 3.73(m, 7H), 3.87(t, 4H), 5.42(s, 1H), 6.41(s, 1H), 6.90 - 6.93(m, 2H), 7.16 - 7.18(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.51-1.63 (m, 2H), 1.86-1.92 (m, 2H), 2.20-2.28 (m, 2H), 2.49 (s, 3H), 2.75-2.78 ( m, 2H), 3.14-3.18 (m, 6H), 3.46-3.48 (m, 2H), 3.58-3.73 (m, 7H), 3.87 (t, 4H), 5.42 (s, 1H), 6.41 (s, 1H), 6.90-6.93 (m, 2H), 7.16-7.18 (m, 2H)

<실시예 30>　 2-Example 30 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[4-(] -4- [4-[[4- ( 하이Hi 드록시메틸)피페리딘-1-일]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of hydroxymethyl) piperidin-1-yl] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.15 g 과 4-피페리딘메탄올 45 mg, 트리에틸아민 0.07 ml 를 가하고 서서히 가열하여 55℃ - 60℃ 에서 15시간 동안 반응시켰다. 반응 완결 후, 상기 실시예 4와 동일한 방법으로 반응후 처리와 정제 및 결정화를 실시하여 목적화합물을 얻었다.To a mixed solvent of 10 ml of acetonitrile and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) pipe prepared in Preparation Example 3 0.15 g of rajin-1-yl] pyrimidine, 45 mg of 4-piperidinmethanol and 0.07 ml of triethylamine were added thereto, and the resulting mixture was slowly heated and reacted at 55 ° C.-60 ° C. for 15 hours. After completion of the reaction, the reaction was carried out in the same manner as in Example 4, purification, and crystallization to obtain the target compound.

수율 : 57 %Yield: 57%

m.p. : 196 - 198℃m.p. : 196-198 ℃

1H-NMR (CDCl3), ppm : δ　 1.19 - 1.33(m, 2H), 1.46 - 1.55(m, 1H), 1.71(br d, 2H), 2.05 - 2.17(m, 2H), 2.49(s, 3H), 2.86(br d, 2H), 3.14 - 3.18(m, 6H), 3.45 - 3.50(m, 4H), 3.61 - 3.67(m, 6H), 3.85 - 3.89(m, 4H), 5.42(s, 1H), 6.41(s, 1H), 6.89 - 6.94(m, 2H), 7.15 - 7.20(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.19-1.33 (m, 2H), 1.46-1.55 (m, 1H), 1.71 (br d, 2H), 2.05-2.17 (m, 2H), 2.49 (s , 3H), 2.86 (br d, 2H), 3.14-3.18 (m, 6H), 3.45-3.50 (m, 4H), 3.61-3.67 (m, 6H), 3.85-3.89 (m, 4H), 5.42 ( s, 1H), 6.41 (s, 1H), 6.89-6.94 (m, 2H), 7.15-7.20 (m, 2H)

<실시예 31>　2-Example 31 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[4-(] -4- [4-[[4- ( 카바모일Cabamo )피페리딘-1-일]아세틸]피페라진-1-일]피리미딘의 제조.) Piperidin-1-yl] acetyl] piperazin-1-yl] pyrimidine.

피롤리딘 대신에 이소니페코트아미드를 사용하여, 상기 실시예 26과 동일한 방법으로 실시하여 목적화합물을 얻었다.Isonipecotamide was used instead of pyrrolidine and was carried out in the same manner as in Example 26 to obtain the target compound.

수율 : 72 %Yield: 72%

m.p. : 142 - 145℃m.p. : 142-145 ℃

1H-NMR (DMSO-d6), ppm : δ　 1.47 - 1.67(m, 4H), 1.93 - 2.01(m, 3H), 2.41(s, 3H), 2.80(br d, 2H), 3.03(t, 4H), 3.13(s, 2H), 3.46(br d, 6H), 3.63(br s, 2H), 3.72(t, 4H), 5.58(s, 1H), 6.71(s, 1H), 6.87(d, 2H), 7.21(s, 1H), 7.34(d, 2H), 8.85(s, 1H) 1 H-NMR (DMSO-d 6 ), ppm: δ 1.47-1.67 (m, 4H), 1.93-2.01 (m, 3H), 2.41 (s, 3H), 2.80 (br d, 2H), 3.03 (t , 4H), 3.13 (s, 2H), 3.46 (br d, 6H), 3.63 (br s, 2H), 3.72 (t, 4H), 5.58 (s, 1H), 6.71 (s, 1H), 6.87 ( d, 2H), 7.21 (s, 1H), 7.34 (d, 2H), 8.85 (s, 1H)

<실시예 32>　 2-Example 32 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[4-(1-] -4- [4-[[4- (1- 피blood 롤리디닐)피페리딘-1-일]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of Lolidinyl) piperidin-1-yl] acetyl] piperazin-1-yl] pyrimidine.

4-피페리딘메탄올 대신에 4-(1-피롤리디닐)피페리딘을 사용하여, 상기 실시예 30과 동일한 방법으로 실시하여 목적화합물을 얻었다.4- (1-pyrrolidinyl) piperidine was used in place of 4-piperidinmethanol, and the target compound was obtained in the same manner as in Example 30.

수율 : 51 %Yield: 51%

m.p. : 216 - 218℃m.p. : 216-218 ℃

1H-NMR (CDCl3), ppm : δ 1.71(br s, 2H), 1.88 - 1.96(m, 6H), 2.06 - 2.17(m, 3H), 2.49(s, 3H), 2.75(br s, 4H), 2.86(br d, 2H), 3.14 - 3.17(m, 6H), 3.53 - 3.70(m, 8H), 3.87(t, 4H), 5.47(s, 1H), 6.52(s, 1H), 6.90 - 6.95(m, 2H), 7.20 - 7.23(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.71 (br s, 2H), 1.88-1.96 (m, 6H), 2.06-2.17 (m, 3H), 2.49 (s, 3H), 2.75 (br s, 4H), 2.86 (br d, 2H), 3.14-3.17 (m, 6H), 3.53-3.70 (m, 8H), 3.87 (t, 4H), 5.47 (s, 1H), 6.52 (s, 1H), 6.90-6.95 (m, 2H), 7.20-7.23 (m, 2H)

<실시예 33>　 2-Example 33 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[4-(1-] -4- [4-[[4- (1- 피blood 페리디노)피페리딘-1-일]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of ferridino) piperidin-1-yl] acetyl] piperazin-1-yl] pyrimidine.

4-피페리딘메탄올 대신에 4-피페리디노피페리딘을 사용하여, 상기 실시예 30과 동일한 방법으로 실시하여 목적화합물을 얻었다.4-Piperidinopiperidine was used instead of 4-piperidinmethanol, and the target compound was obtained in the same manner as in Example 30.

수율 : 62 %Yield: 62%

m.p. : 225 - 228℃m.p. : 225-228 ℃

1H-NMR (CDCl3), ppm : δ 1.45 - 1.63(m, 8H), 1.84(br d, 2H), 2.06(t, 2H), 2.17(br s, 1H), 2.49(s, 3H), 2.54(br s, 4H), 2.90(br d, 2H), 3.14 - 3.18(m, 6H), 3.47 - 3.67(m, 8H), 3.87(t, 4H), 5.43(s, 1H), 6.41(s, 1H), 6.91 - 6.94(m, 2H), 7.16 - 7.19(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.45-1.63 (m, 8H), 1.84 (br d, 2H), 2.06 (t, 2H), 2.17 (br s, 1H), 2.49 (s, 3H) , 2.54 (br s, 4H), 2.90 (br d, 2H), 3.14-3.18 (m, 6H), 3.47-3.67 (m, 8H), 3.87 (t, 4H), 5.43 (s, 1H), 6.41 (s, 1H), 6.91-6.94 (m, 2H), 7.16-7.19 (m, 2H)

<실시예 34>　 2-Example 34 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[(1-] -4- [4-[(1- 피페라Pipera 지닐)아세틸]피페라진-1-일]피리미딘의 제조.Preparation of Genyl) acetyl] piperazin-1-yl] pyrimidine.

메탄올 10 ml 와 디클로로메탄 10 ml 의 혼합용매에 무수 피페라진 0.37 g 을 가하여 녹인 후, 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.2 g 과 트리에틸아민 0.07 ml 를 가하고 25℃ - 30℃ 에서 15시간 동안 반응시켰다. 반응 완결 후, 상기 실시예 4와 동일한 방법으로 반응후 처리와 정제 및 결정화를 실시하여 목적화합물을 얻었다.0.37 g of anhydrous piperazine was dissolved in a mixed solvent of 10 ml of methanol and 10 ml of dichloromethane, and then dissolved. 2-methylthio-6- [4- (4-morpholino) anilino]- 0.2 g of 4- [4- (chloroacetyl) piperazin-1-yl] pyrimidine and 0.07 ml of triethylamine were added and reacted at 25 ° C-30 ° C for 15 hours. After completion of the reaction, the reaction was carried out in the same manner as in Example 4, purification, and crystallization to obtain the target compound.

수율 : 81 %Yield: 81%

m.p. : 212 - 215℃m.p. : 212-215 ℃

1H-NMR (CDCl3), ppm : δ　 2.46 - 2.49(m, 7H), 2.88(t, 4H), 3.14 - 3.17(m, 6H), 3.43 - 3.47(m, 2H), 3.62 - 3.65(m, 6H), 3.85 - 3.89(m, 4H), 5.42(s, 1H), 6.41(s, 1H), 6.89 - 6.94(m, 2H), 7.14 - 7.20(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.46-2.49 (m, 7H), 2.88 (t, 4H), 3.14-3.17 (m, 6H), 3.43-3.47 (m, 2H), 3.62-3.65 ( m, 6H), 3.85-3.89 (m, 4H), 5.42 (s, 1H), 6.41 (s, 1H), 6.89-6.94 (m, 2H), 7.14-7.20 (m, 2H)

<실시예 35>　 2-Example 35 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[(4-] -4- [4-[(4- 메틸피Methyl blood 페라진-1-일)아세틸]피페라진-1-일]피리미딘의 제조.Preparation of Ferrazin-1-yl) acetyl] piperazin-1-yl] pyrimidine.

4-피페리딘메탄올 대신에 1-메틸피페라진을 사용하여, 상기 실시예 30과 동일한 방법으로 실시하여 목적화합물을 얻었다.Using the 1-methyl piperazine in place of 4-piperidinemethanol, it was carried out in the same manner as in Example 30 to obtain the target compound.

수율 : 66 %Yield: 66%

m.p. : 202 - 205℃m.p. : 202-205 ℃

1H-NMR (CDCl3), ppm : δ 2.29(s, 3H), 2.45 - 2.53(m, 11H), 3.14 - 3.19(m, 6H), 3.44 - 3.46(m, 2H), 3.63(br s, 6H), 3.87(t, 4H), 5.42(s, 1H), 6.35(s, 1H), 6.89 - 6.94(m, 2H), 7.15 - 7.19(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.29 (s, 3H), 2.45-2.53 (m, 11H), 3.14-3.19 (m, 6H), 3.44-3.46 (m, 2H), 3.63 (br s , 6H), 3.87 (t, 4H), 5.42 (s, 1H), 6.35 (s, 1H), 6.89-6.94 (m, 2H), 7.15-7.19 (m, 2H)

<실시예 36>　 2-Example 36 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[(4-] -4- [4-[(4- 에틸피Ethyl blood 페라진-1-일)아세틸]피페라진-1-일]피리미딘의 제조.Preparation of Ferrazin-1-yl) acetyl] piperazin-1-yl] pyrimidine.

4-피페리딘메탄올 대신에 1-에틸피페라진을 사용하여, 상기 실시예 30과 동 일한 방법으로 실시하여 목적화합물을 얻었다.1-ethyl piperazine was used instead of 4-piperidinemethanol, and the target compound was obtained in the same manner as in Example 30.

수율 : 60 %Yield: 60%

m.p. : 160 - 163℃m.p. : 160-163 ℃

1H-NMR (CDCl3), ppm : δ 1.09(t, 3H), 2.40 - 2.56(m, 13H), 3.14 - 3.19(m, 6H), 3.44 - 3.46(m, 2H), 3.62(br d, 6H), 3.85 - 3.89(m, 4H), 5.42(s, 1H), 6.38(s, 1H), 6.89 - 6.94(m, 2H), 7.14 - 7.20(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.09 (t, 3H), 2.40-2.56 (m, 13H), 3.14-3.19 (m, 6H), 3.44-3.46 (m, 2H), 3.62 (br d , 6H), 3.85-3.89 (m, 4H), 5.42 (s, 1H), 6.38 (s, 1H), 6.89-6.94 (m, 2H), 7.14-7.20 (m, 2H)

<실시예 37>　 2-Example 37 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[4-(아세틸)피페라진-1-일]아세틸]피페라진-1-일]피리미딘의 제조.] -4- [4-[[4- (acetyl) piperazin-1-yl] acetyl] piperazin-1-yl] pyrimidine.

디에틸아민 대신에 1-아세틸피페라진을 사용하여, 상기 실시예 8과 동일한 방법으로 실시하여 목적화합물을 얻었다.Using the 1-acetyl piperazine instead of diethylamine, it was carried out in the same manner as in Example 8 to obtain the target compound.

수율 : 67 %Yield: 67%

m.p. : 168 - 171℃m.p. : 168-171 ℃

1H-NMR (CDCl3), ppm : δ 2.08(s, 3H), 2.45 - 2.54(m, 7H), 3.15(t, 4H), 3.22(s, 2H), 3.45 - 3.48(m, 4H), 3.62(br d, 8H), 3.85 - 3.89(m, 4H), 5.42(s, 1H), 6.46(s, 1H), 6.90 - 6.94(m, 2H), 7.15 - 7.19(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.08 (s, 3H), 2.45-2.54 (m, 7H), 3.15 (t, 4H), 3.22 (s, 2H), 3.45-3.48 (m, 4H) , 3.62 (br d, 8H), 3.85-3.89 (m, 4H), 5.42 (s, 1H), 6.46 (s, 1H), 6.90-6.94 (m, 2H), 7.15-7.19 (m, 2H)

<실시예 38>　 2-Example 38 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[4-(2-하이드록시에틸)피페라진-1-일]아세틸]피페라진-1-일]피리미딘의 제조.] -4- [4-[[4- (2-hydroxyethyl) piperazin-1-yl] acetyl] piperazin-1-yl] pyrimidine.

4-피페리딘메탄올 대신에 1-(2-하이드록시에틸)피페라진을 사용하여, 상기 실시예 30과 동일한 방법으로 실시하여 목적화합물을 얻었다.Using the 1- (2-hydroxyethyl) piperazine in place of 4-piperidinemethanol, the target compound was obtained in the same manner as in Example 30.

수율 : 58 %Yield: 58%

m.p. : 137 - 140℃m.p. : 137-140 ℃

1H-NMR (CDCl3), ppm : δ 2.45 - 2.57(m, 13H), 3.14 - 3.20(m, 6H), 3.43 - 3.45(m, 2H), 3.60 - 3.63(m, 8H), 3.87(t, 4H), 5.42(s, 1H), 6.39(s, 1H), 6.89 - 6.94(m, 2H), 7.14 - 7.20(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.45-2.57 (m, 13H), 3.14-3.20 (m, 6H), 3.43-3.45 (m, 2H), 3.60-3.63 (m, 8H), 3.87 ( t, 4H), 5.42 (s, 1H), 6.39 (s, 1H), 6.89-6.94 (m, 2H), 7.14-7.20 (m, 2H)

<실시예 39>　 2-Example 39 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[4-(2-] -4- [4-[[4- (2- 메Me 톡시에틸)피페라진-1-일]아세틸]피페라진-1-일]피리미딘의 제조.Methoxyethyl) piperazin-1-yl] acetyl] piperazin-1-yl] pyrimidine.

4-피페리딘메탄올 대신에 1-(2-메톡시에틸)피페라진을 사용하여, 상기 실시예 30과 동일한 방법으로 실시하여 목적화합물을 얻었다.Using the 1- (2-methoxyethyl) piperazine in place of 4-piperidinmethanol, it was carried out in the same manner as in Example 30 to obtain the target compound.

수율 : 73 %Yield: 73%

m.p. : 134 - 137℃m.p. : 134-137 ℃

1H-NMR (CDCl3), ppm : δ 2.49 - 2.60(m, 13H), 3.14 - 3.18(m, 6H), 3.34(s, 3H), 3.44 - 3.46(m, 2H), 3.51(t, 2H), 3.61(br d, 6H), 3.87(t, 4H), 5.42(s, 1H), 6.38(s, 1H), 6.89 - 6.94(m, 2H), 7.14 - 7.20(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.49-2.60 (m, 13H), 3.14-3.18 (m, 6H), 3.34 (s, 3H), 3.44-3.46 (m, 2H), 3.51 (t, 2H), 3.61 (br d, 6H), 3.87 (t, 4H), 5.42 (s, 1H), 6.38 (s, 1H), 6.89-6.94 (m, 2H), 7.14-7.20 (m, 2H)

<실시예 40>　 2-Example 40 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[4-[2-(4-모르포리노)에틸]피페라진-1-일]아세틸]피페라진-1-일]피리미딘의 제조.] -4- [4-[[4- [2- (4-morpholino) ethyl] piperazin-1-yl] acetyl] piperazin-1-yl] pyrimidine.

4-피페리딘메탄올 대신에 1-[2-(모르포린-4-일)에틸]피페라진을 사용하여, 상기 실시예 30과 동일한 방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 30 using 1- [2- (morpholin-4-yl) ethyl] piperazin instead of 4-piperidinmethanol.

수율 : 72 %Yield: 72%

m.p. : 232 - 235℃m.p. : 232-235 ℃

1H-NMR (CDCl3), ppm : δ 2.46 - 2.51(m, 19H), 3.14 - 3.18(m, 6H), 3.43(br d, 2H), 3.63(br s, 6H), 3.70(t, 4H), 3.87(t, 4H), 5.42(s, 1H), 6.41(s, 1H), 6.89 - 6.94(m, 2H), 7.14 - 7.20(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.46-2.51 (m, 19H), 3.14-3.18 (m, 6H), 3.43 (br d, 2H), 3.63 (br s, 6H), 3.70 (t, 4H), 3.87 (t, 4H), 5.42 (s, 1H), 6.41 (s, 1H), 6.89-6.94 (m, 2H), 7.14-7.20 (m, 2H)

<실시예 41>　 2-Example 41 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[4-(2-] -4- [4-[[4- (2- 피blood 리미딜)피페라진-1-일]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of rimidyl) piperazin-1-yl] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.15 g 과 1-(2-피리미딜)피페라진 59 mg, 트리에틸아민 0.06 ml 를 가하고 서서히 가열하여 55℃ - 60℃ 에서 2일 동안 반응시켰다. 반응 완결 후, 용액을 감압농축하여 얻은 잔사를 메탄올 10 ml 에 녹이고 물 10 ml 를 서서히 가하여 결정화시키고 실온에서 5시간 동안 교반하였다. 여과하고 물 5 ml 로 세척하여 얻어진 결정을 40℃ - 50℃ 에서 진공건조 하여 145 mg (수율 76 %)의 목적화합물을 얻었다.To a mixed solvent of 10 ml of acetonitrile and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) pipe prepared in Preparation Example 3 0.15 g of razin-1-yl] pyrimidine, 59 mg of 1- (2-pyrimidyl) piperazine, and 0.06 ml of triethylamine were added thereto, and the resulting mixture was slowly heated to react at 55 ° C-60 ° C for 2 days. After completion of the reaction, the residue obtained by concentrating the solution under reduced pressure was dissolved in 10 ml of methanol, and 10 ml of water was slowly added to crystallize and stirred at room temperature for 5 hours. The crystals obtained by filtration and washing with 5 ml of water were dried in vacuo at 40 ° C-50 ° C to obtain 145 mg (yield 76%) of the title compound.

m.p. : 178 - 181℃m.p. : 178-181 ℃

1H-NMR (CDCl3), ppm : δ 2.49(s, 3H), 2.58(t, 4H), 3.15(br s, 4H), 3.25(s, 2H), 3.48(br s, 2H), 3.64(br d, 6H), 3.82 - 3.88(m, 8H), 5.42(s, 1H), 6.47 - 6.51(m, 2H), 6.89(br d, 2H), 7.15(br d, 2H), 8.29(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.49 (s, 3H), 2.58 (t, 4H), 3.15 (br s, 4H), 3.25 (s, 2H), 3.48 (br s, 2H), 3.64 (br d, 6H), 3.82-3.88 (m, 8H), 5.42 (s, 1H), 6.47-6.51 (m, 2H), 6.89 (br d, 2H), 7.15 (br d, 2H), 8.29 ( d, 2H)

<실시예 42>　 2-Example 42 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[4-(2-하이드록시페닐)피페라진-1-일]아세틸]피페라진-1-일]피리미딘의 제조.] -4- [4-[[4- (2-hydroxyphenyl) piperazin-1-yl] acetyl] piperazin-1-yl] pyrimidine.

메탄올 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 3에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 0.15 g 과 2-(1-피페라지노)페놀 70 mg, 트리에틸아민 0.06 ml 를 가하고 서서히 가열하여 55℃ - 60℃ 에서 2일 동안 반응시켰다. 반응 완결 후, 상기 실시예 41과 동일한 방법으로 반응후 처리와 정제 및 결정화를 실시하여 목적화합물을 얻었다.To a mixed solvent of 10 ml of methanol and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazine prepared in Preparation Example 3 0.15 g of -1-yl] pyrimidine, 70 mg of 2- (1-piperazino) phenol and 0.06 ml of triethylamine were added thereto, and the resulting mixture was slowly heated and reacted at 55 ° C-60 ° C for 2 days. After completion of the reaction, the reaction was carried out in the same manner as in Example 41, purification, and crystallization to obtain the target compound.

수율 : 64 %Yield: 64%

m.p. : 187 - 190℃m.p. : 187-190 ℃

1H-NMR (CDCl3), ppm : δ　 2.51(s, 3H), 2.74(br s, 4H), 2.92(t, 4H), 3.16(t, 4H), 3.31(s, 2H), 3.47(br s, 2H), 3.67(br s, 6H), 3.87(t, 4H), 5.43(s, 1H), 6.60(s, 1H), 6.83 - 6.96(m, 4H), 7.05 - 7.10(m, 1H), 7.14 - 7.19(m, 3H) 1 H-NMR (CDCl 3 ), ppm: δ 2.51 (s, 3H), 2.74 (br s, 4H), 2.92 (t, 4H), 3.16 (t, 4H), 3.31 (s, 2H), 3.47 ( br s, 2H), 3.67 (br s, 6H), 3.87 (t, 4H), 5.43 (s, 1H), 6.60 (s, 1H), 6.83-6.96 (m, 4H), 7.05-7.10 (m, 1H), 7.14-7.19 (m, 3H)

<실시예 43>　 2-Example 43 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[4-(4-하이드록시페닐)피페라진-1-일]아세틸]피페라진-1-일]피리미딘의 제조.] -4- [4-[[4- (4-hydroxyphenyl) piperazin-1-yl] acetyl] piperazin-1-yl] pyrimidine.

2-(1-피페라지노)페놀 대신에 4-(1-피페라지노)페놀을 사용하여, 상기 실시 예 42와 동일한 방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 42 using 4- (1-piperazino) phenol instead of 2- (1-piperazino) phenol.

수율 : 66 %Yield: 66%

m.p. : 234 - 237℃ (dec.)m.p. : 234-237 ℃ (dec.)

1H-NMR (CDCl3), ppm : δ 2.40(s, 3H), 2.55(br s, 4H), 2.95(br s, 4H), 3.02(t, 4H), 3.22(s, 2H), 3.47(br d, 6H), 3.65(br s, 2H), 3.72(t, 4H), 5.57(s, 1H), 6.61 - 6.66(m, 2H), 6.75(d, 2H), 6.86(d, 2H), 7.33(d, 2H), 8.79(s, 1H), 8.84(s, 1H) 1 H-NMR (CDCl 3 ), ppm: δ 2.40 (s, 3H), 2.55 (br s, 4H), 2.95 (br s, 4H), 3.02 (t, 4H), 3.22 (s, 2H), 3.47 (br d, 6H), 3.65 (br s, 2H), 3.72 (t, 4H), 5.57 (s, 1H), 6.61-6.66 (m, 2H), 6.75 (d, 2H), 6.86 (d, 2H ), 7.33 (d, 2H), 8.79 (s, 1H), 8.84 (s, 1H)

<실시예 44>　 2-Example 44 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -(2--(2- 메Me 톡시에틸)아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of methoxyethyl) amino] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 20 ml 에 상기 제조예 4에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 염산염 0.15 g 과 2-메톡시에틸아민 0.23 g, 트리에틸아민 0.11 ml 를 가하고 20℃ - 30℃ 에서 2일 동안 반응시켰다. 반응 완결 후, 용액을 감압농축하고 잔사를 메탄올 10 ml 로 녹이고 물 10 ml 를 가한 후 실온에서 3시간 동안 교반하였다. 소량의 불용성 불순물을 여과하여 제거하고, 정제된 여액을 다시 감압농축하여 유기용매를 제거하였다. 수용액인 잔사를 디클로로메탄 20 ml 로 추출하였다. 유기층을 물 20 ml 로 2회 세척하고 감압농축하여 얻은 잔사를, 디클로로메탄 2 ml 에 녹이고 에틸 에테르 5 ml 와 헥산 20 ml 를 차례로 가하여 결정화시켰다. 실온에서 4시간 동안 교반한 후 여과하고, 헥산 3 ml 로 세척하여 얻어진 결정을 30℃ - 40℃ 에서 진공건조 하 여 95 mg (수율 63 %)의 목적화합물을 얻었다.In 20 ml of acetonitrile, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazin-1-yl] pyridine prepared in Preparation Example 4 0.15 g of midine hydrochloride, 0.23 g of 2-methoxyethylamine, and 0.11 ml of triethylamine were added and reacted at 20 ° C-30 ° C for 2 days. After completion of the reaction, the solution was concentrated under reduced pressure, the residue was dissolved in 10 ml of methanol, 10 ml of water was added, and the mixture was stirred at room temperature for 3 hours. A small amount of insoluble impurities were filtered off and the purified filtrate was concentrated under reduced pressure again to remove the organic solvent. The residue, which was an aqueous solution, was extracted with 20 ml of dichloromethane. The organic layer was washed twice with 20 ml of water and concentrated under reduced pressure. The residue was dissolved in 2 ml of dichloromethane and crystallized by adding 5 ml of ethyl ether and 20 ml of hexane in order. After stirring at room temperature for 4 hours, the mixture was filtered, washed with 3 ml of hexane, and the obtained crystals were dried in vacuo at 30 ° C-40 ° C to obtain 95 mg (yield 63%) of the title compound.

m.p. : 122 - 125℃m.p. : 122-125 ℃

1H-NMR (CDCl3), ppm : δ　 2.17(s, 2H), 2.48(s, 3H), 2.82(t, 2H), 3.16(t, 4H), 3.36(s, 3H), 3.45 - 3.57(m, 7H), 3.57 - 3.69(m, 4H), 3.87(t, 4H), 5.41(s, 1H), 6.42(s, 1H), 6.90(d, 2H), 7.15(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.17 (s, 2H), 2.48 (s, 3H), 2.82 (t, 2H), 3.16 (t, 4H), 3.36 (s, 3H), 3.45-3.57 (m, 7H), 3.57-3.69 (m, 4H), 3.87 (t, 4H), 5.41 (s, 1H), 6.42 (s, 1H), 6.90 (d, 2H), 7.15 (d, 2H)

<실시예 45>　 2-Example 45 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -(3--(3- 하Ha 이드록시프로필)아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of Idroxypropyl) amino] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 20 ml 에 상기 제조예 4에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 염산염 0.15 g 과 3-아미노-1-프로판올 226 mg, 트리에틸아민 0.11 ml 를 가하고 20℃ - 30℃ 에서 24시간 동안 반응시켰다. 반응 완결 후, 상기 실시예 44와 동일한 방법으로 반응후 처리와 정제 및 결정화를 실시하여 목적화합물을 얻었다.In 20 ml of acetonitrile, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazin-1-yl] pyridine prepared in Preparation Example 4 0.15 g of midine hydrochloride, 226 mg of 3-amino-1-propanol, and 0.11 ml of triethylamine were added thereto, and reacted at 20 ° C-30 ° C for 24 hours. After completion of the reaction, the reaction was carried out in the same manner as in Example 44, purification, and crystallization to obtain the target compound.

수율 : 70 %Yield: 70%

m.p. : 114 - 117℃m.p. : 114-117 ℃

1H-NMR (CDCl3), ppm : δ　 1.74(qn, 2H), 2.48(s, 3H), 2.88(t, 2H), 3.04(br s, 2H), 3.15(t, 4H), 3.45 - 3.51(m, 6H), 3.57 - 3.66(m, 4H), 3.81(t, 2H), 3.87(t, 4H), 5.42(s, 1H), 6.52(s, 1H), 6.90(d, 2H), 7.16(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.74 (qn, 2H), 2.48 (s, 3H), 2.88 (t, 2H), 3.04 (br s, 2H), 3.15 (t, 4H), 3.45- 3.51 (m, 6H), 3.57-3.66 (m, 4H), 3.81 (t, 2H), 3.87 (t, 4H), 5.42 (s, 1H), 6.52 (s, 1H), 6.90 (d, 2H) , 7.16 (d, 2 H)

<실시예 46>　 2-Example 46 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -에틸--ethyl- NN - (2-하이드록시에틸)아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of (2-hydroxyethyl) amino] acetyl] piperazin-1-yl] pyrimidine.

2-메톡시에틸아민 대신에 2-(에틸아미노)에탄올을 사용하여, 상기 실시예 44와 동일한 방법으로 실시하여 목적화합물을 얻었다.2- (ethylamino) ethanol was used instead of 2-methoxyethylamine to carry out the same method as in Example 44 to obtain the target compound.

수율 : 65 %Yield: 65%

m.p. : 121 - 123℃m.p. : 121-123 ℃

1H-NMR (CDCl3), ppm : δ 1.70(t, 3H), 2.48(s, 3H), 2.69 - 2.75(m, 4H), 3.16(t, 4H), 3.40(s, 2H), 3.45 - 3.49(m, 2H), 3.54 - 3.63(m, 8H), 3.87(t, 4H), 5.42(s, 1H), 6.48(s, 1H), 6.90(d, 2H), 7.16(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.70 (t, 3H), 2.48 (s, 3H), 2.69-2.75 (m, 4H), 3.16 (t, 4H), 3.40 (s, 2H), 3.45 -3.49 (m, 2H), 3.54-3.63 (m, 8H), 3.87 (t, 4H), 5.42 (s, 1H), 6.48 (s, 1H), 6.90 (d, 2H), 7.16 (d, 2H) )

<실시예 47>　 2-Example 47 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[3-(디메틸아미노)프로필]아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of [[3- (dimethylamino) propyl] amino] acetyl] piperazin-1-yl] pyrimidine.

3-아미노-1-프로판올 대신에 N,N-디메틸-1,3-프로판디아민을 사용하여, 상기 실시예 45와 동일한 방법으로 실시하여 목적화합물을 얻었다. N, N -dimethyl-1,3-propanediamine was used instead of 3-amino-1-propanol to carry out the same procedure as in Example 45 to obtain the target compound.

수율 : 67 %Yield: 67%

m.p. : 140 - 143℃m.p. : 140-143 ℃

1H-NMR (CDCl3), ppm : δ 1.82(qn, 2H), 2.40(s, 6H), 2.48(s, 3H), 2.61(t, 2H), 2.78(t, 2H), 3.15(t, 4H), 3.38 - 3.66(m, 10H), 3.87(t, 4H), 5.44(s, 1H), 6.56(s, 1H), 6.90(d, 2H), 7.18(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.82 (qn, 2H), 2.40 (s, 6H), 2.48 (s, 3H), 2.61 (t, 2H), 2.78 (t, 2H), 3.15 (t , 4H), 3.38-3.66 (m, 10H), 3.87 (t, 4H), 5.44 (s, 1H), 6.56 (s, 1H), 6.90 (d, 2H), 7.18 (d, 2H)

<실시예 48>　 2-Example 48 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[3-(-[3- ( 디D 에 틸아미노)프로필]아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of ethylamino) propyl] amino] acetyl] piperazin-1-yl] pyrimidine.

3-아미노-1-프로판올 대신에 N,N-디에틸-1,3-프로판디아민을 사용하여, 상기 실시예 45와 동일한 방법으로 실시하여 목적화합물을 얻었다. N, N -diethyl-1,3-propanediamine was used instead of 3-amino-1-propanol to carry out the same procedure as in Example 45 to obtain the target compound.

수율 : 58 %Yield: 58%

m.p. : 126 - 129℃m.p. : 126-129 ℃

1H-NMR (CDCl3), ppm : δ 1.01(t, 6H), 1.67(qn, 2H), 2.47 - 2.56(m, 9H), 2.63(t, 2H), 3.16(t, 4H), 3.43 - 3.45(m, 6H), 3.62 - 3.67(m, 4H), 3.87(t, 4H), 5.41(s, 1H), 6.43(s, 1H), 6.90(d, 2H), 7.15(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.01 (t, 6H), 1.67 (qn, 2H), 2.47-2.56 (m, 9H), 2.63 (t, 2H), 3.16 (t, 4H), 3.43 -3.45 (m, 6H), 3.62-3.67 (m, 4H), 3.87 (t, 4H), 5.41 (s, 1H), 6.43 (s, 1H), 6.90 (d, 2H), 7.15 (d, 2H) )

<실시예 49>　 2-Example 49 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[(3-] -4- [4-[(3- 피리Pipe 딜)아세틸]피페라진-1-일]피리미딘의 제조.Dill) acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 10 ml 와 클로로포름 10 ml 의 혼합용매에 3-피리딜아세트산 염산염 108 mg 과 트리에틸아민 0.29 ml 를 차례로 가하여 녹이고, 3,5-디클로로-2-하이드록시벤젠설포닐 클로라이드 149 mg 을 가한 후 20℃ - 30℃에서 2시간 동안 반응시켰다. 반응 용액에 상기 제조예 2에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-(피페라진-1-일)피리미딘 0.2 g 을 가하고 25℃ - 30℃에서 15시간 동안 더 반응시켰다. 반응 완결 후 용액을 감압농축하고, 잔사를 디클로로메탄 20 ml 에 녹이고 물 20 ml, 0.5N 탄산수소나트륨 수용액 20 ml, 물 20 ml 로 차례로 세척하였다. 분리된 유기층을 감압농축하고, 잔사를 칼럼크로마토그라피 (클로로포름 : 메탄올 = 16 : 1 (부피비)) 로 정제하였다. 정제된 분획을 감압농축하여 얻은 잔사를 디클로로메탄 3 ml 에 녹이고 이소프로필 에테르 25 ml 를 서서히 가하여 결정화시켰다. 실온에서 4시간 동안 교반한 후 여과하고, 이소프로필 에테르 5 ml 로 세척하여 얻어진 결정을 30℃ - 40℃에서 진공건조하여 155 mg (수율 59 %)의 목적화합물을 얻었다.To a mixed solvent of 10 ml of acetonitrile and 10 ml of chloroform, 108 mg of 3-pyridylacetic acid hydrochloride and 0.29 ml of triethylamine were added sequentially, followed by addition of 149 mg of 3,5-dichloro-2-hydroxybenzenesulfonyl chloride. The reaction was carried out at 20 ° C.-30 ° C. for 2 hours. To the reaction solution, 0.2 g of 2-methylthio-6- [4- (4-morpholino) anilino] -4- (piperazin-1-yl) pyrimidine prepared in Preparation Example 2 was added thereto and 25 ° C- The reaction was further carried out at 30 ° C. for 15 hours. After completion of the reaction, the solution was concentrated under reduced pressure, and the residue was dissolved in 20 ml of dichloromethane, and washed sequentially with 20 ml of water, 20 ml of 0.5N sodium hydrogencarbonate aqueous solution and 20 ml of water. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol = 16: 1 (volume ratio)). The residue obtained by concentrating the purified fractions under reduced pressure was dissolved in 3 ml of dichloromethane and crystallized by slowly adding 25 ml of isopropyl ether. After stirring for 4 hours at room temperature, filtered, and washed with 5 ml of isopropyl ether, the crystals obtained were vacuum dried at 30-40 ℃ to give 155 mg (yield 59%) of the title compound.

m.p. : 201 - 203℃m.p. : 201-203 ℃

1H-NMR (CDCl3), ppm : δ 2.48(s, 3H), 3.15 - 3.17(m, 4H), 3.44 - 3.49(m, 2H), 3.53(s, 4H), 3.67 - 3.70(m, 2H), 3.73(s, 2H), 3.87(t, 4H), 5.39(s, 1H), 6.53(s, 1H), 6.89(d, 2H), 7.14(d, 2H), 7.25 - 7.29(m, 1H), 7.61(d, 1H), 8.48 - 8.52(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.48 (s, 3H), 3.15-3.17 (m, 4H), 3.44-3.49 (m, 2H), 3.53 (s, 4H), 3.67-3.70 (m, 2H), 3.73 (s, 2H), 3.87 (t, 4H), 5.39 (s, 1H), 6.53 (s, 1H), 6.89 (d, 2H), 7.14 (d, 2H), 7.25-7.29 (m) , 1H), 7.61 (d, 1H), 8.48-8.52 (m, 2H)

<실시예 50>　 2-Example 50 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[(2-] -4- [4-[(2- 피리Pipe 딜)아세틸]피페라진-1-일]피리미딘의 제조.Dill) acetyl] piperazin-1-yl] pyrimidine.

3-피리딜아세트산 염산염 대신에 2-피리딜아세트산 염산염을 사용하여, 상기 실시예 49와 동일한 방법으로 실시하여 목적화합물을 얻었다.2-pyridylacetic acid hydrochloride was used instead of 3-pyridylacetic acid hydrochloride, and the target compound was obtained in the same manner as in Example 49.

수율 : 56 %Yield: 56%

m.p. : 204 - 207℃m.p. : 204-207 ℃

1H-NMR (CDCl3), ppm : δ 2.47(s, 3H), 3.15(t, 4H), 3.42 - 3.49(m, 4H), 3.65(br d, 4H), 3.87(t, 4H), 3.94(s, 2H), 5.39(s, 1H), 6.51(s, 1H), 6.89(d, 2H), 7.14 - 7.20(m, 3H), 7.33(d, 1H), 7.62(td, 1H), 8.50(dt, 1H) 1 H-NMR (CDCl 3 ), ppm: δ 2.47 (s, 3H), 3.15 (t, 4H), 3.42-3.49 (m, 4H), 3.65 (br d, 4H), 3.87 (t, 4H), 3.94 (s, 2H), 5.39 (s, 1H), 6.51 (s, 1H), 6.89 (d, 2H), 7.14-7.20 (m, 3H), 7.33 (d, 1H), 7.62 (td, 1H) , 8.50 (dt, 1 H)

<실시예 51>　 2-Example 51 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[2-(3-] -4- [4-[[2- (3- 피blood 리딜)에틸]Ridyl) ethyl] 카보닐Carbonyl ]피페라진-1-일]피리미딘의 제조.] Piperazin-1-yl] pyrimidine.

아세토니트릴 10 ml 와 클로로포름 10 ml 의 혼합용매에 3-(3-피리딜)프로피온산 94 mg 과 트리에틸아민 0.18 ml 를 차례로 가하여 녹이고, 3,5-디클로로-2-하이드록시벤젠설포닐 클로라이드 149 mg 을 가한 후 20℃ - 30℃에서 1시간 동안 반응시켰다. 반응 용액에 상기 제조예 2에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-(피페라진-1-일)피리미딘 0.2 g 을 가하고 25℃ - 30℃에서 24시간 동안 더 반응시켰다. 반응 완결 후 용액을 감압농축하고, 잔사를 디클로로메탄 20 ml 에 녹여서 물 20 ml 로 2회 세척하였다. 분리된 유기층을 감압농축하여 얻은 잔사를 디클로로메탄 2 ml 에 녹이고 에틸 에테르 20 ml 를 서서히 가하여 결정화시켰다. 실온에서 3시간 동안 교반한 후 여과하고, 에틸 에테르 5 ml 로 세척하여 얻어진 결정을 30℃ - 40℃에서 진공건조하여 175 mg (수율 65 %)의 목적화합물을 얻었다.To a mixed solvent of 10 ml of acetonitrile and 10 ml of chloroform, 94 mg of 3- (3-pyridyl) propionic acid and 0.18 ml of triethylamine were added sequentially, followed by dissolving 149 mg of 3,5-dichloro-2-hydroxybenzenesulfonyl chloride. After the addition, the reaction was carried out at 20 ° C.-30 ° C. for 1 hour. To the reaction solution, 0.2 g of 2-methylthio-6- [4- (4-morpholino) anilino] -4- (piperazin-1-yl) pyrimidine prepared in Preparation Example 2 was added thereto and 25 ° C- The reaction was further reacted at 30 ° C. for 24 hours. After completion of the reaction, the solution was concentrated under reduced pressure, and the residue was dissolved in 20 ml of dichloromethane and washed twice with 20 ml of water. The residue obtained by concentrating the separated organic layer under reduced pressure was dissolved in 2 ml of dichloromethane and crystallized by slowly adding 20 ml of ethyl ether. After stirring for 3 hours at room temperature, filtered, and washed with 5 ml of ethyl ether, the crystals obtained were dried in vacuo at 30 ℃-40 ℃ to give 175 mg (yield 65%) of the title compound.

m.p. : 174 - 176℃m.p. : 174-176 ℃

1H-NMR (CDCl3), ppm : δ 2.48(s, 3H), 2.65(t, 2H), 3.00(t, 2H), 3.16(t, 4H), 3.44(br s, 4H), 3.55(br s, 2H), 3.65(m, 2H), 3.87(t, 4H), 5.40(s, 1H), 6.44(s, 1H), 6.90(d, 2H), 7.15 - 7.24(m, 3H), 7.55(d, 1H), 8.45 - 8.49(m, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 2.48 (s, 3H), 2.65 (t, 2H), 3.00 (t, 2H), 3.16 (t, 4H), 3.44 (br s, 4H), 3.55 ( br s, 2H), 3.65 (m, 2H), 3.87 (t, 4H), 5.40 (s, 1H), 6.44 (s, 1H), 6.90 (d, 2H), 7.15-7.24 (m, 3H), 7.55 (d, 1 H), 8.45-8.49 (m, 2 H)

<실시예 52>　 2-Example 52 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[4-(] -4- [4-[[4- ( 아세Ace 트아 미도)피페리딘-1-일]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of thamido) piperidin-1-yl] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 10 ml 와 클로로포름 10 ml 의 혼합용매에 상기 제조예 4에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 염산염 0.2 g 과 4-아세트아미도피페리딘 69 mg, 트리에틸아민 0.14 ml 를 가하고 서서히 가열하여 55℃ - 60℃ 에서 15시간 동안 반응시켰다. 반응 완결 후, 상기 실시예 51과 동일한 방법으로 반응후 처리와 정제 및 결정화를 실시하여 목적화합물을 얻었다.To a mixed solvent of 10 ml of acetonitrile and 10 ml of chloroform, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) pipe prepared in Preparation Example 4 0.2 g of razin-1-yl] pyrimidine hydrochloride, 69 mg of 4-acetamidopiperidine and 0.14 ml of triethylamine were added thereto, and the resulting mixture was slowly heated and reacted at 55 ° C.-60 ° C. for 15 hours. After completion of the reaction, the reaction was carried out in the same manner as in Example 51, and purification and crystallization were carried out to obtain the target compound.

수율 : 73 %Yield: 73%

m.p. : 213 - 215℃m.p. : 213-215 ℃

1H-NMR (CDCl3), ppm : δ　 1.44 - 1.47(m, 2H), 1.91 - 1.96(m, 5H), 2.24(t, 2H), 2.49(s, 3H), 2.83(br d, 2H), 3.14 - 3.20(m, 6H), 3.42(br s, 2H), 3.62(s, 6H), 3.81 - 3.89(m, 5H), 5.43 - 5.46(m, 2H), 6.44(s, 1H), 6.90(d, 2H), 7.16(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.44-1.47 (m, 2H), 1.91-1.96 (m, 5H), 2.24 (t, 2H), 2.49 (s, 3H), 2.83 (br d, 2H ), 3.14-3.20 (m, 6H), 3.42 (br s, 2H), 3.62 (s, 6H), 3.81-3.89 (m, 5H), 5.43-5.46 (m, 2H), 6.44 (s, 1H) , 6.90 (d, 2H), 7.16 (d, 2H)

<실시예 53>　 2-Example 53 2- 메틸티오Methylthio -6-[4-(4--6- [4- (4- 모르포리노Morphorino )) 아닐리노Anilino ]-4-[4-[[] -4- [4-[[ NN -[3-(4-메틸피페라진-1-일)프로필]아미노]아세틸]피페라진-1-일]피리미딘의 제조.Preparation of [[3- (4-methylpiperazin-1-yl) propyl] amino] acetyl] piperazin-1-yl] pyrimidine.

아세토니트릴 20 ml 에 상기 제조예 4에서 제조한 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘 염산염 0.2 g 과 1-(3-아미노프로필)-4-메틸피페라진 629 mg, 트리에틸아민 0.13 ml 를 가하고 20℃ - 30℃ 에서 15시간 동안 반응시켰다. 반응 완결 후, 상기 실시예 51과 동일한 방법 으로 반응후 처리와 정제 및 결정화를 실시하여 목적화합물을 얻었다.In 20 ml of acetonitrile, 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazin-1-yl] pyridine prepared in Preparation Example 4 0.2 g of midine hydrochloride, 629 mg of 1- (3-aminopropyl) -4-methylpiperazine, and 0.13 ml of triethylamine were added and reacted at 20 ° C.-30 ° C. for 15 hours. After completion of the reaction, the reaction was carried out in the same manner as in Example 51, and purification and crystallization were carried out to obtain the target compound.

수율 : 71 %Yield: 71%

m.p. : 167 - 169℃m.p. : 167-169 ℃

1H-NMR (CDCl3), ppm : δ　 1.70(qn, 2H), 2.23 - 2.28(m, 5H), 2.39 - 2.48(m, 11H), 2.65(t, 2H), 3.15(t, 4H), 3.43 - 3.45(m, 6H), 3.62 - 3.67(m, 4H), 3.87(t, 4H), 5.41(s, 1H), 6.48(s, 1H), 6.90(d, 2H), 7.15(d, 2H) 1 H-NMR (CDCl 3 ), ppm: δ 1.70 (qn, 2H), 2.23-2.28 (m, 5H), 2.39-2.48 (m, 11H), 2.65 (t, 2H), 3.15 (t, 4H) , 3.43-3.45 (m, 6H), 3.62-3.67 (m, 4H), 3.87 (t, 4H), 5.41 (s, 1H), 6.48 (s, 1H), 6.90 (d, 2H), 7.15 (d , 2H)

상기 제조예 1~4 및 실시예 1~53의 화합물의 구조식을 하기 표 1a 내지 표 1f에 나타낸다.Structural formulas of the compounds of Preparation Examples 1 to 4 and Examples 1 to 53 are shown in Tables 1A to 1F below.

Figure 112006097710352-PAT00008
Figure 112006097710352-PAT00008

Figure 112006097710352-PAT00009
Figure 112006097710352-PAT00009

Figure 112006097710352-PAT00010
Figure 112006097710352-PAT00010

Figure 112006097710352-PAT00011
Figure 112006097710352-PAT00011

Figure 112006097710352-PAT00012
Figure 112006097710352-PAT00012

Figure 112006097710352-PAT00013
Figure 112006097710352-PAT00013

<실험예 1 > Experimental Example 1 HCVHCV RNA 중합효소 (RNA 의존형 RNA 중합효소,  RNA polymerase (RNA dependent RNA polymerase, NS5BNS5B )에 대한 생체외 (In vitro () in vitroin vitro ) 저해활성 조사Inhibition activity investigation

본 발명의 화합물들의 HCV RNA 의존형 RNA 중합효소에 대한 활성 저해 효과를 알아보기 위하여 다음과 같은 생체외 실험을 실시하였다.In vitro experiments were performed to investigate the inhibitory effect of the compounds of the present invention on HCV RNA dependent RNA polymerase.

재조합 Recombination HCVHCV RNA 중합효소 제조 RNA polymerase preparation

HCV RNA 중합효소는 다음과 같은 방법으로 제조하였다. 먼저, HCV-1b 형 C 형 간염바이러스 환자의 혈액으로부터 cDNA를 얻어낸 다음 PCR을 이용하여 NS5B (1773bps)부위를 증폭하여 배큘로바이러스 (baculovirus) 전이벡터 pVLHIS에 삽입한 재조합 전이벡터를 제조하였다. 제조된 전이벡터를 wild-type AcNPV 벡터와 함께 곤충세포 (Sf 9 cell line)에 감염 (cotransfection)시켜 히스티딘 표지 (histidine tag) 된 재조합 벡터 pVLHIS-NS5B를 가진 재조합 배큘로바이러스를 만들었다. 이와 같이 제조된 재조합 배큘로바이러스를 충분히 배양된 곤충세포에 감염 (infection) 하고 10 % FBS 가 첨가된 Grace' medium에서 3-4일 간 배양한 다음 감염된 세포만을 원심분리 하여 얻어내었다.　　 얻어진 세포를 PBS 로 3차례 세척한 다음 초음파 분해 처리 (sonication)하고 NI-NTA His bind resin (Novagen 사)을 이용한 친화성 (affinity) 컬럼크로마토그래피 과정을 거쳐 순수한 NS5B 단백질을 제조하였다.HCV RNA polymerase was prepared by the following method. First, cDNA was obtained from the blood of HCV-1b hepatitis C virus patient, and then a recombinant transfer vector inserted into the baculovirus transition vector pVLHIS was prepared by amplifying the NS5B (1773bps) region by PCR. The prepared transfection vector was cotransfected with an insect cell (Sf 9 cell line) together with a wild-type AcNPV vector to produce a recombinant baculovirus with histidine tagged recombinant vector pVLHIS-NS5B. The recombinant baculovirus thus prepared was infected with sufficiently cultured insect cells, incubated for 3-4 days in Grace 'medium to which 10% FBS was added, and only infected cells were centrifuged. The obtained cells were washed three times with PBS, sonicated, and subjected to an affinity column chromatography using NI-NTA His bind resin (Novagen) to prepare pure NS5B protein.

HCVHCV 3' 말단 (3'- 3 'terminal (3'- UTRUTR )을 포함하는 RNA 주형 (RNA template) 제조RNA template preparation including

HCV 3'-UTR을 포함하는 RNA 주형은 다음과 같은 방법으로 제조하였다. 먼저 C형 간염환자의 혈액으로부터 얻어진 HCV RNA로부터 PCR 방법을 통해 cDNA를 얻어낸 다음 제한효소 Eco RⅠ을 이용하여 3'-UTR의 부위를 포함하는 DNA 절편을 얻어내었다. 이 DNA로부터 시험관내 전사 (in vitro transcription) 과정을 거쳐 3 -UTR을 포함하는 RNA를 제조하였다.RNA template containing HCV 3'-UTR was prepared by the following method. First, cDNA was obtained from the HCV RNA obtained from the blood of hepatitis C patients by PCR, and then DNA fragments containing the 3'-UTR region were obtained using restriction enzyme Eco Ri. RNA was prepared from the DNA by in vitro transcription.

재조합 Recombination HCVHCV RNA 중합효소에 대한 본 발명의 화합물들의  Of compounds of the invention for RNA polymerase 생체외In vitro 저해활성 측정 Inhibitory activity measurement

본 발명에 사용된　 HCV RNA 중합효소에 대한 본 발명의 화합물들의 생체외 저해활성 측정 방법은 다음과 같다. 측정하고자 하는 시료에 맞게 스트렙타비딘 (streptavidin)으로 코팅된 웰 (well)을 준비하고, 먼저, 각 웰에 2X 반응 완충액 [50mM Tris-Cl (pH 7.5), 100mM NaCl, 10mM MgCl2 , 20mM KCl, 1mM EDTA, 1mM DTT]을 25㎕ 씩 가하고, 분리정제 된 HCV RNA 중합효소 200ng을 10㎕ 씩 가한 후, 측정하고자 하는 시험 물질을 최종 농도가 각각 10, 1, 0.1, 0.01㎍/㎖ 이 되도록 하여　 5㎕ 씩 첨가한 다음, 마지막으로 RNA 주형인 HCV 3'-UTR RNA와 반응을 위한 뉴클레오타이드 로서 DIG-(digoxigenin)-UTP, biotin-UTP, ATP, CTP, GTP, UTP가 혼합된 반응 혼합액을 10㎕ 씩 가한 다음, 22 ℃에서 60분 간 반응시켰다. HCV 중합효소의 활성에 의해 RNA가 만들어지고 여기에는 바이오틴이 붙어있는 UTP가 포함되어 있으므로 새로운 RNA는 웰에 코팅되어 있는 스트렙타비딘과 결합한다. 반응이 끝난 후 반응하지 않고 남아있는 불순물을 제거하기 위해 각 웰 당 200㎕의 세척 완충액 (washing buffer, pH 7.0, Roche 사)을 가한 다음 3차례 반복하여 씻어 주었다. 그 다음 2차 항체인 항-DIG-POD (peroxidase, Roche 사)를 100㎕ 씩 가하고 37℃에서 1시간 동안 반응시킨 후　 다시 세척 완충액으로 각 웰을 씻어 주었다. 마지막으로 POD의 기질인 ABTSR (Roche 사)를 각각 100㎕씩 가하여 15-30 분간 반응시킨 다음 ELISA 판독기 (Bio-Tek instrument 사)를 이용하여 405nm에서 흡광도 (OD 값)를 측정하였다. 이때 시료를 넣지 않은 대조군 (positive control)과의 상대적인 흡광도 차이에 따라 HCV 중합효소에 대한 활성 억제 효과를 계산하였다.The method for measuring the in vitro inhibitory activity of the compounds of the present invention on the HCV RNA polymerase used in the present invention is as follows. Prepare wells coated with streptavidin for the sample to be measured, and firstly, in each well, 2X reaction buffer [50 mM Tris-Cl (pH 7.5), 100 mM NaCl, 10 mM MgCl 2 , 20 mM KCl , 1mM EDTA, 1mM DTT] were added thereto, and 200ng of the purified HCV RNA polymerase was added 10µl each. Then, the final test substance was measured to have a final concentration of 10, 1, 0.1, 0.01µg / ml, respectively. 5 μl each was added, and finally a reaction mixture of DIG- (digoxigenin) -UTP, biotin-UTP, ATP, CTP, GTP, and UTP was mixed as a nucleotide for reaction with HCV 3'-UTR RNA, an RNA template. 10 μl each was added, followed by reaction at 22 ° C. for 60 minutes. The RNA is produced by the activity of HCV polymerase, which contains UTP with biotin attached, so the new RNA binds to the well-coated streptavidin. After the reaction, 200 μl of washing buffer (washing buffer, pH 7.0, Roche) was added to each well to remove impurities remaining unreacted, and then washed three times. Then, 100 μl of a secondary antibody, anti-DIG-POD (peroxidase, Roche) was added thereto, reacted at 37 ° C. for 1 hour, and each well was washed again with a washing buffer. Finally, ABTS R , the substrate of POD 100 µl each of Roche was added and reacted for 15-30 minutes, and then the absorbance (OD value) was measured at 405 nm using an ELISA reader (Bio-Tek instrument). At this time, the inhibitory effect on the activity of HCV polymerase was calculated according to the difference in absorbance relative to the control without the sample (positive control).

그 결과를 다음 표 2에 나타내었다.The results are shown in Table 2 below.

화합물compound HCV RNA 중합효소의 활성 저해율 (%)Inhibition Rate of HCV RNA Polymerase Activity (%) 10 ㎍/㎖10 μg / ml 1 ㎍/㎖1 μg / ml 0.1 ㎍/㎖0.1 μg / ml 0.01 ㎍/㎖0.01 μg / ml 실시예 1Example 1 9393 7474 5353 2525 실시예 2Example 2 8888 7272 5050 1919 실시예 3Example 3 9090 7070 5151 2222 실시예 4Example 4 9292 6868 5454 2323 실시예 5Example 5 8787 7070 4747 1818 실시예 6Example 6 8585 6565 4242 55 실시예 7Example 7 8282 6666 3737 1818 실시예 8Example 8 7979 5555 3636 66 실시예 9Example 9 9393 7575 5555 3030 실시예 10Example 10 9090 7272 5353 1919 실시예 11Example 11 8080 6464 3333 1111 실시예 12Example 12 9292 7070 4848 1818 실시예 13Example 13 9292 7474 5454 2020 실시예 14Example 14 9595 7777 6060 3838 실시예 15Example 15 8383 6464 4242 1313 실시예 16Example 16 8181 6868 4040 1717 실시예 17Example 17 8080 6464 3838 1010 실시예 18Example 18 8686 6868 4848 2121 실시예 19Example 19 9393 7575 5555 2828 실시예 20Example 20 9494 7878 5757 3030 실시예 21Example 21 9090 7373 5151 1818 실시예 22Example 22 9090 7070 4848 1212 실시예 23Example 23 8484 6464 4040 1212 실시예 24Example 24 8686 6666 4242 2020 실시예 25Example 25 8989 6969 4343 1616 실시예 26Example 26 8383 6464 3939 1414 실시예 27Example 27 8787 7070 4141 2020 실시예 28Example 28 7979 5858 3636 1010 실시예 29Example 29 8282 6060 3737 1212 실시예 30Example 30 8686 6464 4242 88 실시예 31Example 31 8484 6262 4343 1313 실시예 32Example 32 8787 7070 4545 2121 실시예 33Example 33 8686 6969 4040 1313 실시예 34Example 34 9393 7575 5656 3030 실시예 35Example 35 8888 6464 4040 1010 실시예 36Example 36 8888 6767 4343 1717 실시예 37Example 37 8585 6565 4040 1212 실시예 38Example 38 9090 6868 4848 1919 실시예 39Example 39 8383 6262 3535 1515 실시예 40Example 40 8585 6464 3333 1010 실시예 41Example 41 8787 6565 3939 1616 실시예 42Example 42 9090 7272 4747 1818 실시예 43Example 43 9494 7575 5656 2828 실시예 44Example 44 9292 7171 5353 2020 실시예 45Example 45 9292 7272 5050 2323 실시예 46Example 46 9090 7070 4848 1717 실시예 47Example 47 9494 7676 5555 2121 실시예 48Example 48 9393 7474 5252 1515 실시예 49Example 49 8888 6464 3939 1515 실시예 50Example 50 8787 6363 3535 1010 실시예 51Example 51 9090 6969 4141 1818 실시예 52Example 52 9191 7070 4646 2020 실시예 53Example 53 9393 7474 5454 2121

이와 같이 본 발명의 화합물들은 HCV 의 복제에 중요한 역할을 하는 HCV RNA 중합효소의 활성을 저해하는 효과가 우수하므로 이를 기전으로 HCV 의 증식을 억제할 수 있으며, 따라서 C형 간염의 예방제 및 치료제로서 유용하게 사용될 수 있다.As described above, the compounds of the present invention have an excellent effect of inhibiting the activity of HCV RNA polymerase, which plays an important role in the replication of HCV. Therefore, the compounds of the present invention can suppress the proliferation of HCV and thus are useful as a prophylactic and therapeutic agent for hepatitis C. Can be used.

<실험예 2>　 세포독성 실험Experimental Example 2 Cytotoxicity Experiment

화학식 1의 화합물들이 세포독성 (Cytotoxicity)을 나타내는지 알아보기 위하여, Hep G2 세포를 이용하여 일반적으로 널리 알려진 MTT 분석방법으로 시험관내 (in vitro)실험을 실시하였다.　 그 결과, 실험에 사용된 화합물들은 CC50 값이 100 ㎍/㎖ 이상으로서, 세포에 대한 독성이 매우 적은 물질인 것으로 판명되었다.In order to determine whether the compounds of Formula 1 exhibit Cytotoxicity, in vitro experiments were performed using a well-known MTT assay using Hep G2 cells. As a result, the compounds used in the experiments were found to have a CC 50 value of 100 µg / ml or more, which is a very low toxicity to cells.

상기에서 살펴본 바와 같이, 본 발명에 의한 상기 화학식 1로 표시되는 신규의 2-(메틸티오)피리미딘 유도체는, C형 간염 바이러스 (HCV)의 증식을 억제하는 효과가 우수하고 독성도 적으므로, C형 간염의 예방제 및 치료제로서 유용하게 사용될 수 있다.As described above, the novel 2- (methylthio) pyrimidine derivative represented by Chemical Formula 1 according to the present invention has an excellent effect of inhibiting the proliferation of hepatitis C virus (HCV) and less toxicity, It can be usefully used as a prophylactic and therapeutic agent for hepatitis C.

Claims (4)

하기 화학식 1로 표시되는 2-(메틸티오)피리미딘 유도체 및 약학적으로 허용되는 그의 염.2- (methylthio) pyrimidine derivatives represented by the following formula (1) and pharmaceutically acceptable salts thereof. [화학식 1][Formula 1]
Figure 112006097710352-PAT00014
Figure 112006097710352-PAT00014
 상기 화학식 1에서, R1 은 수소, 하이드록시기, -N(R2)-(CH2)n-R3 기, 4-(R4)-(Het)-1-일기 또는 -(CH2)n-R5 기를 나타내며, 상기 R1 을 나타내는 치환기에서, R2 는 수소, 또는 C1 - C4 의 직쇄 또는 분쇄상 알킬기를 나타내고, R3 는 수소, 할로겐 원자, 하이드록시기, 이소프로필기, C2 - C6 의 직쇄 또는 분쇄상 디알킬아미노기, C1 - C4 의 직쇄 또는 분쇄상 알콕시기, C3 - C6 의 사이클로알킬기 또는 치환기가 없거나 C1 - C4 의 직쇄 또는 분쇄상 알킬기가 치환된 C3 - C6 의 헤테로사이클릭 고리를 나타내며, (Het) 는 피페리딘 또는 피페라진을 나타내고, R4 는 수소, 하이드록시기, 카바모일기, 아세틸기, 아세트아미도기, C1 - C4 의 직쇄 또는 분쇄상 알킬 기, C1 - C4 의 직쇄 또는 분쇄상 하이드록시알킬기, C1 - C4 의 알콕시기가 치환된 C1 - C4 의 알킬기, 모르포리노기가 치환된 C1 - C4 의 알킬기, 하이드록시기가 치환된 페닐기 또는 질소 원자를 포함하는 C3 - C6 의 헤테로사이클릭 고리를 나타내며, R5 는 치환기가 없는 C3 - C6 의 헤테로사이클릭 고리를 나타내고, n 은 0 내지 4 의 정수를 나타낸다.In Chemical Formula 1, R 1 is hydrogen, a hydroxyl group, -N (R 2 )-(CH 2 ) n -R 3 group, 4- (R 4 )-(Het) -1-yl group or-(CH 2 ) represents an n -R 5 group, and in the substituents representing R 1 , R 2 represents hydrogen or a C 1 -C 4 straight or crushed alkyl group, and R 3 represents hydrogen, a halogen atom, a hydroxy group, isopropyl group, C 2 - C 6 straight or branched chain a dialkylamino group, C 1 a - C straight or branched chain the alkoxy group of 4, C 3 - or a cycloalkyl group or a substituent of C 6 C 1 - straight or branched chain of C 4 A C 3 -C 6 heterocyclic ring substituted with an alkyl group, (Het) represents piperidine or piperazine, and R 4 represents hydrogen, a hydroxyl group, a carbamoyl group, an acetyl group, an acetamido group , C 1 - C 4 straight or branched chain of the alkyl group, C 1 - C 4 straight or branched chain of the hydroxyalkyl group, C 1 - C 4 alkoxy group substituted with C 1 a - C 4 alkyl group, Mo Poly group is substituted by C 1 - C a alkyl group, a hydroxy group of the C 4 comprises a substituted phenyl group or a nitrogen atom, 3 - represents a heterocyclic ring of C 6, R 5 is C 3 without the substituents of the C 6 Heterocyclic ring, n shows the integer of 0-4. 제 1항에 있어서,The method of claim 1, 상기 화학식 1의 2-(메틸티오)피리미딘 유도체는 하기 (1) - (53) 의 화합물로 구성된 군으로부터 선택된 것임을 특징으로 하는 화합물 및 약학적으로 허용되는 그의 염:2- (methylthio) pyrimidine derivative of Formula 1 is a compound and a pharmaceutically acceptable salt thereof, characterized in that selected from the group consisting of the following compounds (1) to (53): (1) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(아세틸)피페라진-1-일]피리미딘;(1) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (acetyl) piperazin-1-yl] pyrimidine; (2) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(하이드록시아세틸)피페라진-1-일]피리미딘;(2) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (hydroxyacetyl) piperazin-1-yl] pyrimidine; (3)　 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-(아미노아세틸)피페라진-1-일]피리미딘;(3) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (aminoacetyl) piperazin-1-yl] pyrimidine; (4) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[(메틸아미노)아세틸]피페라진-1-일]피리미딘;(4) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[(methylamino) acetyl] piperazin-1-yl] pyrimidine; (5)　2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[(에틸아미노)아세틸]피 페라진-1-일]피리미딘;(5) '2-Methylthio-6- [4- (4-morpholino) anilino] -4- [4-[(ethylamino) acetyl] piperazin-1-yl] pyrimidine; (6)　2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[(이소프로필아미노)아세틸]피페라진-1-일]피리미딘;(6) '2-Methylthio-6- [4- (4-morpholino) anilino] -4- [4-[(isopropylamino) acetyl] piperazin-1-yl] pyrimidine; (7)　2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[(이소부틸아미노)아세틸]피페라진-1-일]피리미딘;(7) '2-Methylthio-6- [4- (4-morpholino) anilino] -4- [4-[(isobutylamino) acetyl] piperazin-1-yl] pyrimidine; (8)　2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[(디에틸아미노)아세틸]피페라진-1-일]피리미딘;(8) '2-Methylthio-6- [4- (4-morpholino) anilino] -4- [4-[(diethylamino) acetyl] piperazin-1-yl] pyrimidine; (9)　2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-(2-하이드록시에틸)아미노]아세틸]피페라진-1-일]피리미딘;(9) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- (2-hydroxyethyl) amino] acetyl] piperazin-1-yl ] Pyrimidine; (10) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-메틸-N-(2-하이드록시에틸)아미노]아세틸]피페라진-1-일]피리미딘;(10) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N -methyl- N- (2-hydroxyethyl) amino] acetyl] piperazine -1-yl] pyrimidine; (11)　2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-(2-클로로에틸)아미노]아세틸]피페라진-1-일]피리미딘;(11) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- (2-chloroethyl) amino] acetyl] piperazin-1-yl] Pyrimidine; (12) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[2-(디메틸아미노)에틸]아미노]아세틸]피페라진-1-일]피리미딘;(12) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [2- (dimethylamino) ethyl] amino] acetyl] piperazine-1 -Yl] pyrimidine; (13) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[2-(디에틸아미노)에틸]아미노]아세틸]피페라진-1-일]피리미딘;(13) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [2- (diethylamino) ethyl] amino] acetyl] piperazine- 1-yl] pyrimidine; (14) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[2-(디이소프로필아미노)에틸]아미노]아세틸]피페라진-1-일]피리미딘;(14) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [2- (diisopropylamino) ethyl] amino] acetyl] piperazine -1-yl] pyrimidine; (15) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[2-(디메틸아미노) 에틸]- N-메틸아미노]아세틸]피페라진-1-일]피리미딘;(15) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [2- (dimethylamino) ethyl] -N -methylamino] acetyl] Piperazin-1-yl] pyrimidine; (16) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[2-(디에틸아미노)에틸]- N-메틸아미노]아세틸]피페라진-1-일]피리미딘;(16) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [2- (diethylamino) ethyl] -N -methylamino] acetyl ] Piperazin-1-yl] pyrimidine; (17) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-(사이클로펜틸)아미노]아세틸]피페라진-1-일]피리미딘;(17) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- (cyclopentyl) amino] acetyl] piperazin-1-yl] pyrimidine ; (18) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[(사이클로프로필)메틸]아미노]아세틸]피페라진-1-일]피리미딘;(18) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N -[(cyclopropyl) methyl] amino] acetyl] piperazin-1-yl ] Pyrimidine; (19) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[2-(1-피롤리디닐)에틸]아미노]아세틸]피페라진-1-일]피리미딘;(19) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [2- (1-pyrrolidinyl) ethyl] amino] acetyl] pipe Razin-1-yl] pyrimidine; (20) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[3-(1-피롤리디닐)프로필]아미노]아세틸]피페라진-1-일]피리미딘;(20) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [3- (1-pyrrolidinyl) propyl] amino] acetyl] pipe Razin-1-yl] pyrimidine; (21) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[3-(4-모르포리노)프로필]아미노]아세틸]피페라진-1-일]피리미딘;(21) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [3- (4-morpholino) propyl] amino] acetyl] pipe Razin-1-yl] pyrimidine; (22) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[3-(이미다졸-1-일)프로필]아미노]아세틸]피페라진-1-일]피리미딘;(22) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [3- (imidazol-1-yl) propyl] amino] acetyl] Piperazin-1-yl] pyrimidine; (23) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[2-(2-피리딜)에틸]아미노]아세틸]피페라진-1-일]피리미딘;(23) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [2- (2-pyridyl) ethyl] amino] acetyl] piperazine -1-yl] pyrimidine; (24) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[2-(3-피리딜)에틸]아미노]아세틸]피페라진-1-일]피리미딘;(24) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [2- (3-pyridyl) ethyl] amino] acetyl] piperazine -1-yl] pyrimidine; (25)　 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[2-(4-피리딜)에 틸]아미노]아세틸]피페라진-1-일]피리미딘;(25) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [2- (4-pyridyl) ethyl] amino] acetyl] pipe Razin-1-yl] pyrimidine; (26) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[(1-피롤리디닐)아세틸]피페라진-1-일]피리미딘;(26) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[(1-pyrrolidinyl) acetyl] piperazin-1-yl] pyrimidine; (27)　2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[(3-티아졸리디닐)아세틸]피페라진-1-일]피리미딘;(27) '2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[(3-thiazolidinyl) acetyl] piperazin-1-yl] pyrimidine; (28)　2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[(1-피페리디노)아세틸]피페라진-1-일]피리미딘;(28) '2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[(1-piperidino) acetyl] piperazin-1-yl] pyrimidine; (29)　2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[4-(하이드록시)피페리딘-1-일]아세틸]피페라진-1-일]피리미딘;(29) '2-Methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[4- (hydroxy) piperidin-1-yl] acetyl] piperazin- 1-yl] pyrimidine; (30)　2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[4-(하이드록시메틸)피페리딘-1-일]아세틸]피페라진-1-일]피리미딘;(30) '2-Methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[4- (hydroxymethyl) piperidin-1-yl] acetyl] piperazine -1-yl] pyrimidine; (31) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[4-(카바모일)피페리딘-1-일]아세틸]피페라진-1-일]피리미딘;(31) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[4- (carbamoyl) piperidin-1-yl] acetyl] piperazin- 1-yl] pyrimidine; (32) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[4-(1-피롤리디닐)피페리딘-1-일]아세틸]피페라진-1-일]피리미딘;(32) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[4- (1-pyrrolidinyl) piperidin-1-yl] acetyl] Piperazin-1-yl] pyrimidine; (33) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[4-(1-피페리디노)피페리딘-1-일]아세틸]피페라진-1-일]피리미딘;(33) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[4- (1-piperidino) piperidin-1-yl] acetyl] Piperazin-1-yl] pyrimidine; (34) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[(1-피페라지닐)아세틸]피페라진-1-일]피리미딘;(34) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[(1-piperazinyl) acetyl] piperazin-1-yl] pyrimidine; (35)　2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[(4-메틸피페라진-1- 일)아세틸]피페라진-1-일]피리미딘;(35) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[(4-methylpiperazin-1-yl) acetyl] piperazin-1-yl] Pyrimidine; (36)　2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[(4-에틸피페라진-1-일)아세틸]피페라진-1-일]피리미딘;(36) '2-Methylthio-6- [4- (4-morpholino) anilino] -4- [4-[(4-ethylpiperazin-1-yl) acetyl] piperazin-1-yl] Pyrimidine; (37) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[4-(아세틸)피페라진-1-일]아세틸]피페라진-1-일]피리미딘;(37) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[4- (acetyl) piperazin-1-yl] acetyl] piperazin-1- Il] pyrimidine; (38) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[4-(2-하이드록시에틸)피페라진-1-일]아세틸]피페라진-1-일]피리미딘;(38) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[4- (2-hydroxyethyl) piperazin-1-yl] acetyl] pipe Razin-1-yl] pyrimidine; (39) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[4-(2-메톡시에틸)피페라진-1-일]아세틸]피페라진-1-일]피리미딘;(39) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[4- (2-methoxyethyl) piperazin-1-yl] acetyl] pipe Razin-1-yl] pyrimidine; (40) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[4-[2-(4-모르포리노)에틸]피페라진-1-일]아세틸]피페라진-1-일]피리미딘;(40) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[4- [2- (4-morpholino) ethyl] piperazin-1- Yl] acetyl] piperazin-1-yl] pyrimidine; (41) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[4-(2-피리미딜)피페라진-1-일]아세틸]피페라진-1-일]피리미딘;(41) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[4- (2-pyrimidyl) piperazin-1-yl] acetyl] piperazine -1-yl] pyrimidine; (42) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[4-(2-하이드록시페닐)피페라진-1-일]아세틸]피페라진-1-일]피리미딘;(42) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[4- (2-hydroxyphenyl) piperazin-1-yl] acetyl] pipe Razin-1-yl] pyrimidine; (43) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[4-(4-하이드록시페닐)피페라진-1-일]아세틸]피페라진-1-일]피리미딘;(43) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[4- (4-hydroxyphenyl) piperazin-1-yl] acetyl] pipe Razin-1-yl] pyrimidine; (44) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-(2-메톡시에틸)아미노]아세틸]피페라진-1-일]피리미딘;(44) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- (2-methoxyethyl) amino] acetyl] piperazin-1-yl ] Pyrimidine; (45) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-(3-하이드록시프로 필)아미노]아세틸]피페라진-1-일]피리미딘;(45) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- (3-hydroxypropyl) amino] acetyl] piperazin-1- Il] pyrimidine; (46) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-에틸-N-(2-하이드록시에틸)아미노]아세틸]피페라진-1-일]피리미딘;(46) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N -ethyl- N- (2-hydroxyethyl) amino] acetyl] piperazine -1-yl] pyrimidine; (47) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[3-(디메틸아미노)프로필]아미노]아세틸]피페라진-1-일]피리미딘;(47) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [3- (dimethylamino) propyl] amino] acetyl] piperazine-1 -Yl] pyrimidine; (48) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[3-(디에틸아미노)프로필]아미노]아세틸]피페라진-1-일]피리미딘;(48) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [3- (diethylamino) propyl] amino] acetyl] piperazine- 1-yl] pyrimidine; (49) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[(3-피리딜)아세틸]피페라진-1-일]피리미딘;(49) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[(3-pyridyl) acetyl] piperazin-1-yl] pyrimidine; (50) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[(2-피리딜)아세틸]피페라진-1-일]피리미딘;(50) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[(2-pyridyl) acetyl] piperazin-1-yl] pyrimidine; (51) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[2-(3-피리딜)에틸]카보닐]피페라진-1-일]피리미딘;(51) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[2- (3-pyridyl) ethyl] carbonyl] piperazin-1-yl ] Pyrimidine; (52) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[4-(아세트아미도)피페리딘-1-일]아세틸]피페라진-1-일]피리미딘; 및(52) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[4- (acetamido) piperidin-1-yl] acetyl] piperazine -1-yl] pyrimidine; And (53) 2-메틸티오-6-[4-(4-모르포리노)아닐리노]-4-[4-[[N-[3-(4-메틸피페라진-1-일)프로필]아미노]아세틸]피페라진-1-일]피리미딘.(53) 2-methylthio-6- [4- (4-morpholino) anilino] -4- [4-[[ N- [3- (4-methylpiperazin-1-yl) propyl] amino ] Acetyl] piperazin-1-yl] pyrimidine. 하기 반응식 1에 나타내는 화학식 2의 2-메틸티오-6-[4-(4-모르포리노)아닐 리노]-4-[4-(클로로아세틸)피페라진-1-일]피리미딘을 화학식 3의 H-R1' 로 표시되는 아민 화합물과 반응시켜서 하기 화학식 1a의 2-(메틸티오)피리미딘 유도체를 제조하는 제 1항의 2-(메틸티오)피리미딘 유도체의 제조방법:2-methylthio-6- [4- (4-morpholino) anilino] -4- [4- (chloroacetyl) piperazin-1-yl] pyrimidine of the formula (2) shown in Scheme 1 below A method for preparing the 2- (methylthio) pyrimidine derivative of claim 1, wherein the 2- (methylthio) pyrimidine derivative of formula 1a is prepared by reacting with an amine compound represented by HR 1 ′ of [반응식 1]Scheme 1
Figure 112006097710352-PAT00015
Figure 112006097710352-PAT00015
 상기 반응식 1에서, R1' 은 -N(R2)-(CH2)n-R3 기, 4-(R4)-(Het)-1-일기 또는 -(CH2)n-R5' 기를 나타내며, 상기 R1' 을 나타내는 치환기에서, R2 는 수소, 또는 C1 - C4 의 직쇄 또는 분쇄상 알킬기를 나타내고, R3 는 수소, 할로겐 원자, 하이드록시기, 이소프로필기, C2 - C6 의 직쇄 또는 분쇄상 디알킬아미노기, C1 - C4 의 직쇄 또는 분쇄상 알콕시기, C3 - C6 의 사이클로알킬기 또는 치환기가 없거나 C1 - C4 의 직쇄 또는 분쇄상 알킬기가 치환된 C3 - C6 의 헤테로사이클릭 고리를 나타내며, (Het) 는 피페리딘 또는 피페라진을 나타내고, R4 는 수소, 하이드록시기, 카바모일기, 아세틸기, 아세트아미도기, C1 - C4 의 직쇄 또는 분쇄상 알킬기, C1 - C4 의 직 쇄 또는 분쇄상 하이드록시알킬기, C1 - C4 의 알콕시기가 치환된 C1 - C4 의 알킬기, 모르포리노기가 치환된 C1 - C4 의 알킬기, 하이드록시기가 치환된 페닐기 또는 질소 원자를 포함하는 C3 - C6 의 헤테로사이클릭 고리를 나타내며, R5' 는 치환기가 없는 포화된 C3 - C6 의 헤테로사이클릭 고리를 나타내고, n 은 0 내지 4 의 정수를 나타낸다.In Scheme 1, R 1 ′ is -N (R 2 )-(CH 2 ) n -R 3 Group, 4- (R 4 )-(Het) -1-yl group or-(CH 2 ) n -R 5 ' Group, wherein R 1 ' In a substituent representing R 2 Is hydrogen, or C 1 -C 4 Linear or pulverized alkyl group of R, R 3 is hydrogen, halogen atom, hydroxy group, isopropyl group, C 2 -C 6 linear or pulverized dialkylamino group, C 1 -C 4 linear or pulverized alkoxy Group, C 3 -C 6 cycloalkyl group or a C 3 -C 6 heterocyclic ring in which no substituent or C 1 -C 4 straight or crushed alkyl group is substituted, (Het) represents piperidine or pipe And R 4 represents hydrogen, a hydroxyl group, a carbamoyl group, an acetyl group, an acetamido group, a C 1 -C 4 straight or crushed alkyl group, a C 1 -C 4 straight or crushed hydroxyalkyl group , C 1 - C of the 4-alkoxy group is substituted C 1 - C 4 alkyl group, morpholino Poly group is substituted by C 1 - C 4 of the alkyl group, hydroxy C 3 a hydroxy group include a substituted phenyl group or a nitrogen atom - C 6 A heterocyclic ring of R 5 'is a saturated C 3- Cyclic of C 6 heteroaryl represents a ring, n represents an integer of 0 to 4. 제1항의 2-(메틸티오)피리미딘 유도체 또는 그의 약학적으로 허용가능한 염을 유효성분으로 함유하는, C형 간염의 치료 또는 예방용 약학적 조성물.A pharmaceutical composition for treating or preventing hepatitis C, comprising the 2- (methylthio) pyrimidine derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
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