KR101126736B1

KR101126736B1 - Tyrosine kinase inhibitory compounds, isomers thereof or pharmaceutical acceptable salts thereof, and pharmaceutical composition comprising the same

Info

Publication number: KR101126736B1
Application number: KR1020080118850A
Authority: KR
Inventors: 양범석; 김선영; 조종운; 이향숙; 우성호; 박태교; 김용주; 김승태; 이홍범
Original assignee: 주식회사 레고켐 바이오사이언스; 한국과학기술연구원
Priority date: 2008-11-27
Filing date: 2008-11-27
Publication date: 2012-04-12
Also published as: KR20100060300A; WO2010062038A2; WO2010062038A3

Abstract

본 발명은 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염에 관한 것이다. 화학식 1의 화합물은 디스코이딘 도메인 리셉터 1 (DDR1)과 디스코이딘 도메인 리셉터 2(DDR2) 의 티로신 키나아제 활성을 억제할 수 있어, 폐 혹은 간 등 조직 섬유화증, 암, 동맥경화, 류마티스 관절염, 골 관절염등 디스코이딘 도메인 리셉터1, 혹은 디스코이딘 도메인 리셉터2 의 과다 활성화가 주요 원인으로 알려진 질환을 예방 또는 치료하는데 유용하게 사용될 수 있다.The present invention relates to a compound represented by the following formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof. Compounds of formula (1) can inhibit the tyrosine kinase activity of discoidin domain receptor 1 (DDR1) and discoidin domain receptor 2 (DDR2), resulting in tissue fibrosis such as lung or liver, cancer, arteriosclerosis, rheumatoid arthritis, osteoarthritis Over-activation of dorsal discodine domain receptor 1, or discodine domain receptor 2 may be usefully used to prevent or treat diseases known to be the main cause.

[화학식 1][Formula 1]

싸이에노피리미딘, 싸이에노피리딘, 싸이아졸로피리미딘, 티로신 키나아제 Thienopyrimidine, thienopyridine, thiazolopyrimidine, tyrosine kinase

Description

티로신 키나아제 저해 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염 및 이를 포함하는 약학적 조성물{TYROSINE KINASE INHIBITORY COMPOUNDS, ISOMERS THEREOF OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME}TYROSINE KINASE INHIBITORY COMPOUNDS, ISOMERS THEREOF OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME}

본 발명은 디스코이딘 도메인 리셉터 1(DDR1)과 디스코이딘 도메인 리셉터 2(DDR2)의 티로신 키나아제 활성을 억제할 수 있는 화학식 1로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 포함하는 약학적 조성물에 관한 것이다.The present invention provides a compound represented by formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof, the preparation thereof, capable of inhibiting the tyrosine kinase activity of discodine domain receptor 1 (DDR1) and discodine domain receptor 2 (DDR2). It relates to a method and a pharmaceutical composition comprising the same.

외부의 자극을 세포가 인지하는 방법 중의 하나는 세포막에 있는 수용체인 티로신 키나아제(tyrosine kinase)류를 통한 인지이다. 수용체 티로신 키나아제는 세포 밖에 노출된 세포 외 부분, 세포 내 사이토졸에 노출된 세포 내 부분 및 그 중간에 위치하는 원형질막을 통과하는 막 통과 부분으로 구성되어 있다. 수용체의 세포 외 부분은 특정 리간드가 결합하는 부분이며, 세포 내 부분은 리간드에 의해 활성화된 수용체의 활성 신호를 세포 내로 전달하는 기능을 수행한다. 티로신 키나아제 수용체는 세포 내 사이토졸에 노출된 C-말단 부위에 티로신 키나아제 활성을 가지는 도메인이 존재하여, 세포 외 부분에 특정 리간드가 부착되면 이 C-말단 도메인의 키나아제 효소가 활성화되어 자가 인산화 작용에 의해 C-말단의 티로신기를 인산화 시키는데, 이러한 티로신의 인산화 과정은 세포 외의 자극에 대한 신호를 세포 내로 전달하는 가장 중요한 과정이 된다. 이러한 기작을 가지고 세포 외 자극을 세포 내로 전달하는 티로신 키나아제 활성을 가지는 수용체는 많이 알려져 있다. 대표적인 것으로는 EGFR, PDGFR, IR, IGFR, c-fms, KDR, VEGFR등이 여기에 속한다. One of the ways cells recognize external stimuli is through tyrosine kinases, receptors on the cell membrane. Receptor tyrosine kinases consist of an extracellular part exposed outside the cell, an intracellular part exposed to the intracellular cytosol, and a membrane passing part passing through the plasma membrane located in between. The extracellular portion of the receptor is the portion to which a specific ligand binds, and the intracellular portion performs the function of delivering the activity signal of the receptor activated by the ligand into the cell. Tyrosine kinase receptors have a domain with tyrosine kinase activity at the C-terminal site exposed to intracellular cytosol, and when a specific ligand is attached to the extracellular domain, the kinase enzyme of this C-terminal domain is activated for autophosphorylation. Phosphorylation of C-terminal tyrosine groups by the phosphorylation of tyrosine is the most important process for transmitting signals for extracellular stimulation into cells. There are many known receptors with tyrosine kinase activity that transfer extracellular stimuli into cells with this mechanism. Typical examples include EGFR, PDGFR, IR, IGFR, c-fms, KDR, and VEGFR.

DDR(Discoidin Domain Receptor) 티로신 키나아제 수용체류 단백질도 이러한 티로신 키나아제 활성을 갖는 수용체들 중 하나이다. DDR은 세포 외 부위가 미생물에서 발견되는 렉틴에 부착하는 단백질인 디스코이딘과 유사성이 있는 관계로 이와 같이 명명되었다. 인간 등의 동물의 경우, DDR1 형과 DDR2 형의 아미노산 서열상 서로 유사성을 가진 단백질이 각각 서로 다른 유전자에 의해 코딩되면서 존재하는 것으로 알려져 있다. 인간의 경우 현재 5종의 DDR1 형이 알려져 있는데 이들은 같은 유전자에서 발현될 때 디퍼렌샬 스프라이싱(Differential splicing)에 의해 형성되지만 이들의 C-말단의 티로신 키나아제 도메인은 거의 동일하다. DDR2는 현재까지 한 가지 형태만 알려져 있다. 인간 DDR1과 DDR2의 C-말단 티로신 키나아제 도메인은 아미노산 서열에서 89% 이상 동일하다 (Vogel W, et al, Cellular Signalling 2006;18:11081). 인간에 있어서, DDR 티로신 키나아제 유전자의 존재는 1990년대 초에 알려져 있었지만, 상기 키나아제의 기능에 대한 연구는 1997년에 여기에 부착하는 리간드가 파이버 콜라젠이라는 사실이 처음 밝혀지며 본격적으로 시 작되었다.DDRid Domain Receptor (DDR) tyrosine kinase receptor proteins are also one of the receptors having such tyrosine kinase activity. DDR is so named because it has a similarity to discidine, a protein whose extracellular site is attached to lectins found in microorganisms. In animals such as humans, proteins having similarities in amino acid sequences of DDR1 type and DDR2 type are known to exist while being encoded by different genes. In humans, five DDR1 types are currently known, which are formed by differential splicing when expressed in the same gene, but their C-terminal tyrosine kinase domains are nearly identical. DDR2 has only been known to date. The C-terminal tyrosine kinase domains of human DDR1 and DDR2 are at least 89% identical in amino acid sequence (Vogel W, et al, Cellular Signaling 2006; 18: 11081). In humans, the presence of the DDR tyrosine kinase gene was known in the early 1990s, but studies of the function of the kinase began in earnest in 1997 when the first ligand to be attached to it was fiber collagen.

일반적으로, 유전적 변형이나 환경적 영향으로 특정 티로신 키나아제 수용체가 과다하게 발현되거나, 구조적 변화로 해당 리간드 존재 여부와 관계없이 지속적인 활성을 유지하거나, 해당 리간드의 과다 생성 등으로 그 활성 조절 기작이 손상되어 그 활성이 크게 증가되거나 또는 그 반대 경우로 활성이 감소하는 경우, 질병의 원인이 되는 경우가 많다. 가장 대표적으로는, EGFR 또는 VEGFR등과 같은 과잉 활성이 암의 중요한 요인 중 하나라는 것이 밝혀져 있으며, VEGFR의 활성 증가는 암 전이 및 악성화에 깊이 관련되어 있다. 최근에 여러 제약 회사에서 EGFR 특이적 저해 화합물이나 VEGFR 특이적 저해 화합물을 개발하여 항암제로 개발한 예가 있다. 이들 EGFR 및 VEGFR 특이적 저해제는 모두 이들 수용체 단백질의 C-말단에 있는 키나아제 활성을 저해하는 화합물들이며, 특히 이들의 키나아제 효소의 ATP 부착 부위에 대해서 ATP와 경쟁적으로 부착함으로써, 효소와 ATP의 결합을 방해하여 효소 활성을 저해한다. Generally, overexpression of a specific tyrosine kinase receptor due to genetic alteration or environmental influence, structural change impairs the activity regulating mechanisms due to sustained activity regardless of the presence of the ligand, or overproduction of the ligand. If the activity is greatly increased or vice versa, the activity is often the cause of the disease. Most typically, excess activity such as EGFR or VEGFR has been found to be one of the important factors of cancer, and increased activity of VEGFR is deeply involved in cancer metastasis and malignancy. Recently, several pharmaceutical companies have developed EGFR specific inhibitor compounds or VEGFR specific inhibitor compounds and developed them as anticancer agents. These EGFR and VEGFR specific inhibitors are both compounds that inhibit the kinase activity at the C-terminus of these receptor proteins, and in particular competitively attach ATP to the ATP attachment sites of their kinase enzymes, thereby binding the enzyme to ATP. Inhibits enzyme activity.

DDR1, 혹은 DDR2 수용체의 이상성이 난치성 인간 질병인 동맥경화, 폐경화, 간 경화증 및 류마티즘, 골관절염, 암 등과 연관이 있음이 증명되었다. 먼저 이전의 연구에서 DDR1과 DDR2 단백질의 과잉발현이 여러 암 세포주나 조직에서 관찰되었다 (Alves F, et al, Oncogene 1995;10:6091). DDR1과 DDR2의 세포내 작용중 하나로 밝혀진 것이 세포의 이동을 촉진하고 MMP 단백질의 발현을 촉진하는 것으로 미루어 암에서 과잉발현된 DDR1과 DDR2는 암세포 성장과 이동 전이를 촉진하는 것으로 제안되었다 (Olaso E et al, J Biol Chem 2002;277:3606-1; Vogel W et al, Cellular Signalling 2006, 18:11081). DDR1 유전자를 결손시킨 생쥐는 동맥경화나 레스테노시스(restenosis : 혈관재협착)의 진행이 현저히 저해됨이 확인되어 DDR1의 저해를 통해서 이들 질환을 치료 할 수 있음이 검증되었다 (Franco C et al, Circ Res. 2008 102(10):1202-11; Hou G et al, J Clin Invest. 2001, 107(6):727-3 ). 또한 DDR1과 DDR2의 비 이상적 과잉발현이 동맥경화증에서 크롯 (clot)의 평활근 세포에서 나타남이 확인 되어 이것이 동맥경화의 주 원인 중 하나임이 제안되었다 (Ferri N et al Am J Pathol. 2004. 164:1575-85). 또한 DDR1 유전자 결손 생쥐는 고혈압의 부작용으로 나타나는 신장손상에 안전함이 확인되어 DDR1 저해를 통해 고협압으로 인해 나타나는 신장병을 치료 할 수 있음을 보여 주었다 (Flamant M et al, J Am Soc Nephrol. 2006, 17(12):3374-81). DDR1 결손 생쥐는 폐 섬유화 생쥐 모델에서 섬유화 진행이나 염증 반응이 현저히 감소함이 보고되어 DDR1 저해 물질이 폐 섬유화 치료제로 쓰일 수 있음이 검증되었다 (Avivi-Green C et al, Am J Respir Crit Care Med. 2006, 174(4):420-7). 간 섬유화증은 간 조직에서 파이버 콜라겐이 과잉 생산되어 간에 축적되면서 질병이 야기되는 병변이다. 최근 들어, 현재 간 섬유화증 증상 유발의 주원인으로 지목되는 간 조직내의 간 성상 세포가 활성화되는 과정에서 DDR2의 발현과 그 키나아제 활성이 증가한다는 실험결과가 발표되었다 (Olaso E et al. J Clin Invest 2001,108:1369-78). 이는 DDR2의 발현증가가 간 성상 세포의 활성화에 중요한 역할을 하며, 간 섬유화증의 주요 발병 인자임을 의미하는 것이다. 류마티즘은 지속적으로 연골 부위에 면역 세포가 활성화되어 TNF-α와 같은 사이토카인(cytokine)의 분비량이 증가하면서, 콜라겐 분해 효소 인 매트릭스 메탈로 프로티아제 (Matrix metallo proteiase -1, MMP-1)의 활성이 매우 증가하여, 연골 조직이 크게 파괴되는 질병으로 알려져 있다. MMP-1 단백질을 주로 발현하는 연골 조직 내의 세포는 연골을 감싸고 있는 활막에 존재하는 활막 섬유아세포 (synovial fibroblast)이다. 일반적으로, 이러한 활막 섬유아세포는 정상적인 상황에서 증식과 활성이 잘 통제되어 있다. 최근 류마티스 환자의 연골 조직의 활막 섬유아세포에서 DDR2의 증가된 발현이 관찰되었고 이는 DDR2의 활성 증가에 의하여 MMP-1 유전자 발현이 증가함이 발표되어 졌다 (Wang J et al. J Autoimmun 2002;19:161-8). 이러한 사실은 DDR2의 활성 증가가 류마티즘 병변을 일으키는 주 원인임을 반증한다고 볼 수 있다. 골관절염을 유전적으로 일으키는 생쥐모델의 연골조직을 관찰한 결과 DDR2 발현이 현저히 증가되어 있고 이것이 직접적으로 MMP-13의 발현을 촉진하여 연골 파쇄를 촉진함이 보고되었다 (Xu L et al. J Biol Chem 2005;280:548-55). The abnormality of the DDR1 or DDR2 receptors has been shown to be associated with refractory human diseases such as atherosclerosis, menopause, liver cirrhosis and rheumatism, osteoarthritis and cancer. First, in previous studies, overexpression of DDR1 and DDR2 proteins was observed in several cancer cell lines or tissues (Alves F, et al, Oncogene 1995; 10: 6091). It has been suggested that one of the intracellular actions of DDR1 and DDR2 promotes cell migration and expression of MMP proteins, suggesting that overexpression of DDR1 and DDR2 in cancer promotes cancer cell growth and migration (Olaso E et. al, J Biol Chem 2002; 277: 3606-1; Vogel W et al, Cellular Signaling 2006, 18: 11081). Mice lacking the DDR1 gene have been shown to significantly inhibit the progression of atherosclerosis or restenosis (vascular restenosis), which has been shown to be able to treat these diseases through the inhibition of DDR1 (Franco C et al, Circ Res. 2008 102 (10): 1202-11; Hou G et al, J Clin Invest. 2001, 107 (6): 727-3). In addition, it was confirmed that non-ideal overexpression of DDR1 and DDR2 appeared in the smooth muscle cells of the clot in atherosclerosis, suggesting that this is one of the main causes of atherosclerosis (Ferri N et al Am J Pathol. 2004. 164: 1575 -85). In addition, DDR1 gene-deficient mice have been shown to be safe for kidney damage, which is a side effect of hypertension, suggesting that DDR1 inhibition can cure kidney disease caused by hyperstenosis (Flamant M et al, J Am Soc Nephrol. 2006, 17 ( 12): 3374-81). DDR1 deficient mice have been reported to have significantly reduced fibrosis progression or inflammatory responses in lung fibrotic mouse models, demonstrating that DDR1 inhibitors can be used as therapeutic agents for lung fibrosis (Avivi-Green C et al, Am J Respir Crit Care Med. 2006, 174 (4): 420-7). Liver fibrosis is a disease in which liver collagen causes excessive production of fiber collagen and builds up in the liver causing disease. Recently, experimental results have been reported to increase the expression of DDR2 and its kinase activity in the process of activating hepatic stellate cells in liver tissue, which is currently the main cause of liver fibrosis symptoms (Olaso E et al. J Clin Invest 2001). 108: 1369-78). This means that increased expression of DDR2 plays an important role in the activation of hepatic stellate cells and is a major pathogenesis factor of hepatic fibrosis. Rheumatism is continuously activated by immune cells in the cartilage area, increasing the secretion of cytokines such as TNF-α, and thus the collagen degrading enzyme matrix metallo proteiase-1 (MMP-1). It is known that the disease is very increased activity, cartilage tissue is greatly destroyed. The cells in the cartilage tissue that mainly express the MMP-1 protein are synovial fibroblasts present in the synovial membrane surrounding the cartilage. In general, these synovial fibroblasts are well controlled in proliferation and activity under normal circumstances. Recently, increased expression of DDR2 has been observed in synovial fibroblasts of cartilage tissue of rheumatoid patients, and it has been reported that MMP-1 gene expression is increased by increased activity of DDR2 (Wang J et al. J Autoimmun 2002; 19: 161-8). This fact proves that increased DDR2 activity is the main cause of rheumatic lesions. Observation of cartilage in a mouse model genetically causing osteoarthritis has shown that DDR2 expression is markedly increased, which directly promotes the expression of MMP-13 and promotes cartilage fracture (Xu L et al. J Biol Chem 2005). 280: 548-55).

조직의 섬유화증의 진행은 대부분 과도한 염증 반응과 함께 진행되어 병변현상을 더욱 심화 시킨다. DDR1의 활성이 대식세포의 부착과 활성화에 중요한 역할을 한다는 보고 (Matsuyama W et al, J Immunol. 2004, 172(4):2332-40)와 실제로 DDR1 활성을 유전자 결손이나 siRNA 기술을 이용하여 저해한 경우 동맥경화나 폐 섬유화증에서 대식세포의 활성이 크게 감소하였음이 관찰된 것에 미루어 DDR1의 저해는 병변의 주요 원인이 되는 과도한 염증반응을 억제 할 수 있음이 유추된다 (Matsuyama W et al, J Immunol. 2006, 176(3):1928-36). DDR2의 활성이 면역반응에 관여하는 세포인 덴드로사이트(Dendrocyte)의 활성화에 관여함이 보고된 적이 있다 (Lee JE et al, Biochem Biophys Res Commun. 2007, 352(1):244-5). The progression of tissue fibrosis is most often accompanied by an excessive inflammatory response, further exacerbating the lesion. Reported that DDR1 activity plays an important role in macrophage adhesion and activation (Matsuyama W et al, J Immunol. 2004, 172 (4): 2332-40) and indeed inhibits DDR1 activity using gene deletion or siRNA technology In one case, a significant decrease in the activity of macrophages in atherosclerosis or pulmonary fibrosis was observed, suggesting that inhibition of DDR1 could inhibit excessive inflammatory responses that are the major causes of lesions (Matsuyama W et al, J.). Immunol. 2006, 176 (3): 1928-36). It has been reported that the activity of DDR2 is involved in the activation of dendrocyte, a cell involved in the immune response (Lee JE et al, Biochem Biophys Res Commun. 2007, 352 (1): 244-5).

결론적으로 동맥경화, 페 섬유화증, 간섬유화증, 류마티즘 병변 발전의 주요한 원인이 병변 부위의 섬유아세포 형태의 파이브로틱 세포 (Fibrotic cell)의 비이상적 성장이며, 여기에는 또한 염증 반응이 수반되는 바 이러한 섬유아세포 계열 세포의 성장과 염증 반응 증가에 DDR 패밀리 단백질의 발현 및 활성화가 관여한다는 사실과 이 경우 DDR 패밀리 단백질의 키나아제 활성이 중심적으로 작용한다는 사실로부터 DDR1, DDR2 단백질의 티로신 키나아제 활성을 저해하는 물질이 동맥경화, 폐섬유화증, 간경화증이나 류마티즘, 골관절염, 암등의 DDR1 혹은 DDR2 활성이 증가함으로써 생기는 질환에 대한 치료제 표적이 됨이 확인되었다. In conclusion, the major cause of atherosclerosis, pulmonary fibrosis, hepatic fibrosis, and rheumatoid lesion development is the non-ideal growth of fibrotic cells in the form of fibroblasts in the lesion area, which also involves an inflammatory response. Inhibition of tyrosine kinase activity of DDR1 and DDR2 proteins is due to the fact that the expression and activation of DDR family proteins are involved in the growth and fibroblast growth and inflammatory response. The substance has been shown to be a therapeutic target for diseases caused by increased DDR1 or DDR2 activity, such as atherosclerosis, pulmonary fibrosis, liver cirrhosis, rheumatism, osteoarthritis, and cancer.

본 발명의 목적은 디스코이딘 도메인 리셉터 1(DDR1)과 디스코이딘 도메인 리셉터 2(DDR2)의 티로신 키나아제 활성을 억제할 수 있는 화학식 1로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 포함하는 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a compound represented by formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof, capable of inhibiting tyrosine kinase activity of discodine domain receptor 1 (DDR1) and discodine domain receptor 2 (DDR2), It provides a method for preparing the same and a pharmaceutical composition comprising the same.

상기와 같은 목적을 달성하기 위하여, 본 발명은 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 제공한다.In order to achieve the above object, the present invention provides a compound represented by the formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof.

또한 본 발명은 상기 화합물의 제조방법을 제공한다. The present invention also provides a method for preparing the compound.

나아가, 본 발명은 상기 화합물, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는 디스코이딘 도메인 리셉터1, 혹은 디스코이딘 도메인 리셉터2 의 과다 활성화가 주요 원인으로 알려진 질환의 예방 또는 치료용 약학적 조성물을 제공한다. Furthermore, the present invention is directed to the prevention or treatment of a disease in which the overactivation of discidine domain receptor 1 or discidine domain receptor 2 containing the compound, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient is known as a main cause. It provides a pharmaceutical composition.

본 발명의 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염은, DDR1과 DDR2 활성, 특히 이들의 티로신 키나제 활성 저해 물질을 발굴 후 이들의 생리 활성 기능을 확인함으로써 이 물질이 DDR1 이나 DDR2의 과잉 활성으로 초래되는 질환에 대한 치료제로 활용될 수 있다.Compounds represented by the general formula (1) of the present invention, isomers thereof, or pharmaceutically acceptable salts thereof can be prepared by identifying their physiologically active functions after excavation of DDR1 and DDR2 activity, in particular, their tyrosine kinase activity inhibitors. It can be used as a treatment for diseases caused by excessive activity of DDR1 or DDR2.

특히, 유전공학적으로 생산한 인간 DDR1 과 DDR2 유전자중 키나아제 활성을 가지는 세포질 노출부위의 C-말단 부위 단백질에 대하여 본 발명의 화합물의 DDR1, 혹은 DDR2 키나아제 활성 저해능을 측정되었으며, 본 발명의 화합물이 전장 DDR1 혹은 전장 DDR2 발현 벡터를 HEK293 세포에 트랜스펙션하여 이를 영구적으로 발현하는 세포주를 만든 후 이들 세포주를 제1형 콜라겐과 접촉시켜 DDR1 혹은 DDR2의 자가 인산화가 촉진되는 것을 저해한다. In particular, the C-terminal region protein of the cytoplasmic exposed site having kinase activity in the genetically produced human DDR1 and DDR2 genes was measured to inhibit the DDR1 or DDR2 kinase activity of the compound of the present invention, the compound of the present invention After transfecting a DDR1 or full-length DDR2 expression vector into HEK293 cells to create a cell line expressing it permanently, these cell lines are contacted with type 1 collagen to inhibit the promotion of autophosphorylation of DDR1 or DDR2.

또한, DDR1과 DDR2의 C-말단 티로신 키나아제 활성을 특이적으로 저해하는 화합물의 섬유화 병변에 대한 약리적 효과가 검증되었으며, 이는 간경화 병변 진행에 주요 원인으로 알려진 간 성상 세포 성장 억제능 및 콜라겐 생성 억제능, 류마티즘 병변에서 주요 역할을 하는 것으로 알려진 연골조직내 활막 섬유아세포 (Synovial fibroblast)의 성장 억제 및 MMP-1 발현 저해능, 동맥경화나 레스테노시스(restenosis)에서 주요 역할을 하는 혈관 평활근 세포 성장 억제 및 알파 스무쓰 머슬 액틴 (alpha smooth muscle actin) 단백질 발현 저해 효과를 검증하는 것으로 확인되었다.In addition, the pharmacological effects of fibrotic lesions of compounds that specifically inhibit the C-terminal tyrosine kinase activity of DDR1 and DDR2 have been verified, which is known to be a major cause of liver cirrhosis lesions, hepatic stellate cell growth inhibition and collagen production inhibition, rheumatism Inhibition of the growth of synovial fibroblasts in the cartilage and the inhibition of MMP-1 expression, inhibition of vascular smooth muscle cell growth and alpha smoothing that play a major role in atherosclerosis or restenosis. It has been shown to verify the effect of inhibiting alpha smooth muscle actin protein expression.

나아가, 대표적 전이성을 가지는 암 세포주인 MDA-MB-231 세포의 이동과 전이 억제능, 포칼 어드히젼 콤퓨렉스 (Focal adhesion) 형성 저해, 암세포 성장 억제, 루이스 렁 칼시노마 (Lewis lung carcinoma, LLC) 암세포를 이식한 생쥐 암 모델에서 종양의 성장을 억제하는 약리 효과가 검증되었는바, 본 발명의 화합물은 항암 약리기전이 있다.Furthermore, the ability to inhibit the migration and metastasis of MDA-MB-231 cells, a representative cancer cell line, to inhibit focal adhesion formation, inhibit cancer cell growth, and Lewis lung carcinoma, LLC cancer cells The pharmacological effect of inhibiting tumor growth has been demonstrated in transplanted mouse cancer models. The compounds of the present invention have anticancer pharmacological mechanisms.

이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.

본 발명은 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 제공한다. The present invention provides a compound represented by the following formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

상기 화학식 1에서 X¹ 과 Y는 독립적으로 N 또는 CH이고;X ¹ and Y in Formula 1 are independently N or CH;

R¹은 -OH, -OCH₃, -CF₂H 또는 -CF₃이고;R ¹ is —OH, —OCH ₃ , —CF ₂ H or —CF ₃ ;

R²는 -H, -OH, 할로겐, 나이트릴, 나이트로, C_1-6알킬 또는 C_1-6알콕시이고;R ² is —H, —OH, halogen, nitrile, nitro, C _1-6 alkyl or C _1-6 alkoxy;

Z는 R³로 치환된 C_6-10아릴, R³로 치환된 C_5-10헤테로아릴 또는 N-메틸피페라지닐이고;Z is a C _6-10 aryl substituted by R ^3, with R ³ is substituted C _5-10 heteroaryl, or N- methyl-piperazinyl and;

R³는 -(CH₂)_n-R⁴, -(CH₂)_n-C(O)-R⁴, 또는 -O(CH₂)_n-R⁴이고;R ³ is — (CH ₂ ) _n —R ⁴ , — (CH ₂ ) _n —C (O) —R ⁴ , or —O (CH ₂ ) _n —R ⁴ ;

R⁴는 -H, -CN, 할로겐, C_1-3알킬, C_1-3알콕시, 페닐, 피리디닐, 아미노 또는 -NR⁵R⁶ 이고;R ⁴ is —H, —CN, halogen, C _1-3 alkyl, C _1-3 alkoxy, phenyl, pyridinyl, amino or —NR ⁵ R ⁶ ;

R⁵ 및 R⁶는 각각 독립적으로 -H, C_1-3알킬, 하이드록시C_1-3알킬, 카르복시C_1-3알킬 또는 C_3-6사이클로알킬C_1-3알킬이거나, R ⁵ and R ⁶ are each independently —H, C _1-3 alkyl, hydroxyC _1-3 alkyl, carboxyC _1-3 alkyl or C _3-6 cycloalkylC _1-3 alkyl, or

또는 R⁵및 R⁶는 이들이 결합된 질소와 함께 추가적으로 N 또는 O를 m개 포함하는 5각 또는 6각 헤테로고리를 형성하고; 상기 5각 또는 6각 헤테로고리는 비치환되거나 하이드록시, 하이드록시C_1-3알킬, 카르복시, C_1-3알킬, 디C_1-3알킬 또는 C_1-4알콕시로 치환된 5각 또는 6각 헤테로고리이고;Or R ⁵ and R ⁶ together with the nitrogen to which they are attached form a five or six-membered heterocyclic ring containing m additional N or O; The 5- or 6-membered heterocyclic ring is 5 or 6 unsubstituted or substituted with hydroxy, hydroxyC _1-3 alkyl, carboxy, C _1-3 alkyl, diC _1-3 alkyl or C _1-4 alkoxy. Each heterocycle;

n은 0 내지 3의 정수이고;n is an integer from 0 to 3;

m은 0 또는 1이다. m is 0 or 1;

바람직하게는, 상기 X¹ 과 Y는 독립적으로 N 또는 CH이고;Preferably, X ¹ and Y are independently N or CH;

상기 R¹은 -OH, -OCH₃, -CF₂H 또는 -CF₃이고;R ¹ is —OH, —OCH ₃ , —CF ₂ H or —CF ₃ ;

상기 R²는 -H, -OH, 할로겐, 나이트릴, 나이트로, C_1-6알킬 또는 C_1-6알콕시이고;R ² is —H, —OH, halogen, nitrile, nitro, C _1-6 alkyl or C _1-6 alkoxy;

상기 Z는 R³로 치환된 C_6-10아릴, R³로 치환된 C_5-10헤테로아릴 또는 N-메틸피페라지닐이고;Wherein Z is substituted with R ³ C _6-10 aryl, substituted C _5-10 heteroaryl as R ^3, or N- methyl-piperazinyl and;

상기 R³는 -(CH₂)_n-R⁴, -(CH₂)_n-C(O)-R⁴, 또는 -O(CH₂)_n-R⁴이고;R ³ is — (CH ₂ ) _n —R ⁴ , — (CH ₂ ) _n —C (O) —R ⁴ , or —O (CH ₂ ) _n —R ⁴ ;

상기 R⁴는 -H, -CN, 할로겐, C_1-3알킬, C_1-3알콕시, 페닐, 피리디닐, 아미노, C_1-3알킬아미노, 디C_1-3알킬아미노, 하이드록시C_1-3알킬아미노, 카르복시C_1-3알킬아미노, C_3-6사이클로알킬C_1-3알킬아미노, 피롤리디닐, 하이드록시피롤리디닐, 하이드록시C_1-3알킬피롤리디닐, 카르복시피롤리디닐, 피페리디닐, C_1-3알킬피페리디닐, 디C_1-3알킬피페리디닐, 피페라지닐, C_1-3알킬피페라지닐, C_1-4알콕시카르보닐피페라지닐, 또는 모르포닐린이고;R ⁴ is —H, —CN, halogen, C _1-3 alkyl, C _1-3 alkoxy, phenyl, pyridinyl, amino, C _1-3 alkylamino, diC _1-3 alkylamino, hydroxyC _{1 -3} alkylamino, carboxyC _1-3 alkylamino, C _3-6 cycloalkylC _1-3 alkylamino, pyrrolidinyl, hydroxypyrrolidinyl, hydroxyC _1-3 alkylpyrrolidinyl, carboxypyrroli pyridinyl, piperidinyl, C _1-3 alkyl-piperidinyl, di-C _1-3 alkyl, piperidinyl, piperazinyl, C _1-3 alkyl, piperazinyl, C _1-4 alkoxy carbonyl nilpi piperazinyl, or Morphonyline;

상기 n은 0 내지 3의 정수이다. N is an integer of 0 to 3.

바람직하게는, 상기 R²는 -H, -OH 또는 할로겐인 것을 특징으로 하는 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 제공한다.Preferably, R ² provides -H, -OH, or a compound represented by the formula (1), or an isomer thereof or a pharmaceutically acceptable salt thereof, characterized in that the halogen.

바람직하게는, 상기 Z는,

,

또는 N-메틸피페라지닐인 것을 특징으로 하는 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 제공한다. Preferably, Z is

,

Or N-methylpiperazinyl. A compound represented by the formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof is provided.

바람직하게는, 상기 R⁴는 -H, -CN, 할로겐, C_1-3알킬, C_1-3알콕시, 페닐, 피리디닐, 아미노, 에틸아미노, 디에틸아미노, 피롤리디닐, 피페리디닐, 피페라지닐, 모르포닐린 또는 하기 구조식으로 이루어지는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 제공한다. Preferably, R ⁴ is —H, —CN, halogen, C _1-3 alkyl, C _1-3 alkoxy, phenyl, pyridinyl, amino, ethylamino, diethylamino, pyrrolidinyl, piperidinyl, Provided is a compound represented by the formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof, which is any one selected from the group consisting of piperazinyl, morphonyline, or the following structural formula.

,

,

및

.

,

And

.

또한 본 발명의 화학식 1의 화합물은 약학적으로 허용가능한 염을 형성할 수 있으며, 이러한 약학적으로 허용가능한 염에는 약학적으로 허용되는 음이온을 함유하는 무독성산부가염을 형성하는산, 예를 들면 염산, 황산, 질산, 인산, 브롬화수소산, 요오드화수소산등과 같은 무기산, 타타르산, 포름산, 시트르산, 아세트산, 트라이클로로아세트산, 트라이플루오로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산등과 같은 유기카본산, 메탄설폰산, 벤젠설폰산, p-톨루엔설폰산 또는 나프탈렌설폰산등과 같은 설폰산 등에 의해 형성된 산부가염이 포함된다. 바람직하게는 염산 또는 트라이플루오로아세트산과 약학적으로 허용되는 염을 형성할 수 있다. The compounds of formula 1 of the present invention may also form pharmaceutically acceptable salts, such pharmaceutically acceptable salts, which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as hydrochloric acid. Organic carbons such as inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrobromic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid Acid addition salts formed by sulfonic acids such as acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid and the like. Preferably, a pharmaceutically acceptable salt can be formed with hydrochloric acid or trifluoroacetic acid.

화학식 1로 표시되는 화합물 중 대표적인 화합물로는 다음과 같은 것을 들 수 있다. 괄호안의 명칭은 코드네임으로서 본 발명에서 화합물의 구분을 위하여 사용한다.Representative compounds among the compounds represented by the formula (1) include the following compounds. Names in parentheses are codenames used in the present invention to identify compounds.

N-(3-메톡시페닐)-6-페닐싸이에노[3,2-d]피리미딘-4-아민 (LCB03-0006),N- (3-methoxyphenyl) -6-phenylthieno [3,2-d] pyrimidin-4-amine (LCB03-0006),

(6-브로모-싸이에노[3,2-d]피리미딘-4-닐)-(3-메톡시-페닐)-아민 (LCB03-0007),(6-bromo-thieno [3,2-d] pyrimidin-4-yl)-(3-methoxy-phenyl) -amine (LCB03-0007),

3-(6-(페닐싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0008),3- (6- (phenylthieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0008),

4-(4-(3-메톡시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤조나이트릴 (LCB03-0009),4- (4- (3-methoxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzonitrile (LCB03-0009),

4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤조나이트릴 (LCB03-0013),4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzonitrile (LCB03-0013),

3-(6-브로모-싸이에노[3,2-d]피리미딘-4-닐아미노)-페놀 (LCB03-0015),3- (6-bromo-thieno [3,2-d] pyrimidin-4-ylamino) -phenol (LCB03-0015),

4-(4-(3-메톡시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페놀 (LCB03-0016),4- (4- (3-methoxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenol (LCB03-0016),

3-[6-(4-메톡시페닐)-싸이에노[3,2-d]피리미딘-4-닐아미노]-페놀 (LCB03-0017),3- [6- (4-methoxyphenyl) -thieno [3,2-d] pyrimidin-4-ylamino] -phenol (LCB03-0017),

N-(3-메톡시페닐)-6-(4-(2-모폴리노에톡시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (LCB03-0018),N- (3-methoxyphenyl) -6- (4- (2-morpholinoethoxy) phenyl) thieno [3,2-d] pyrimidin-4-amine (LCB03-0018),

3-(6-(4-클로로페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0019),3- (6- (4-chlorophenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0019),

3-(6-(4-(2-모폴리노에톡시)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0020),3- (6- (4- (2-morpholinoethoxy) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0020),

N-(3-메톡시페닐)-6-(4-페네톡시페닐)싸이에노[3,2-d]피리미딘-4-아민 (LCB03-0021),N- (3-methoxyphenyl) -6- (4-phenoxyphenyl) thieno [3,2-d] pyrimidin-4-amine (LCB03-0021),

N-(3-메톡시페닐)-6-(4-(2-(피리딘-2-일)에톡시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (LCB03-0022),N- (3-methoxyphenyl) -6- (4- (2- (pyridin-2-yl) ethoxy) phenyl) thieno [3,2-d] pyrimidin-4-amine (LCB03-0022 ),

(6-퓨란-2-일-싸이에노[3,2-d]피리미딘-4-일)-(3-메톡시페놀)-아민 (LCB03-0023),(6-furan-2-yl-thieno [3,2-d] pyrimidin-4-yl)-(3-methoxyphenol) -amine (LCB03-0023),

(6-퓨란-3-일-싸이에노[3,2-d]피리미딘-4-일)-(3-메톡시페놀)-아민 (LCB03-0024),(6-furan-3-yl-thieno [3,2-d] pyrimidin-4-yl)-(3-methoxyphenol) -amine (LCB03-0024),

터트-부틸 4-(2-(4-(3-메톡시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페녹시)에틸)피페라진-1-카복실레이트 (LCB03-0025),Tert-butyl 4- (2- (4- (3-methoxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenoxy) ethyl) piperazin-1-carboxylate (LCB03 -0025),

N-(3-메톡시페닐)-6-(4-(2-(피롤리딘-1-일)에톡시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (LCB03-0026),N- (3-methoxyphenyl) -6- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) thieno [3,2-d] pyrimidin-4-amine (LCB03 -0026),

N-(3-메톡시페닐)-6-(싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-아민 (LCB03-0027),N- (3-methoxyphenyl) -6- (thiophen-2-yl) thieno [3,2-d] pyrimidin-4-amine (LCB03-0027),

(3-메톡시페닐)-(6-싸이오펜-3-일-싸이에노[3,2-d]피리미딘-4-일)-아민 (LCB03-0028),(3-methoxyphenyl)-(6-thiophen-3-yl-thieno [3,2-d] pyrimidin-4-yl) -amine (LCB03-0028),

N-(3-메톡시페닐)-6-(4-(2-(피페라진-1-일)에톡시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (LCB03-0029),N- (3-methoxyphenyl) -6- (4- (2- (piperazin-1-yl) ethoxy) phenyl) thieno [3,2-d] pyrimidin-4-amine (LCB03- 0029),

(3-메톡시페닐)-(6-싸이오펜-2-일-싸이에노[3,2-d]피리미딘-4-일)-아민 (LCB03-0030),(3-methoxyphenyl)-(6-thiophen-2-yl-thieno [3,2-d] pyrimidin-4-yl) -amine (LCB03-0030),

3-(6-싸이오펜-3-일-싸이에노[3,2-d]피리미딘-4-일아미노)-페놀 (LCB03-0031),3- (6-thiophen-3-yl-thieno [3,2-d] pyrimidin-4-ylamino) -phenol (LCB03-0031),

3-(6-(4-(모폴리노메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0032),3- (6- (4- (morpholinomethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0032),

3-(6-(4-(피페라진-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0033),3- (6- (4- (piperazin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0033),

3-(6-(4-(피롤리딘-1-일메틸)페닐)사이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0034),3- (6- (4- (pyrrolidin-1-ylmethyl) phenyl) cyeno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0034),

3-(6-(4-(피페리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0035),3- (6- (4- (piperidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0035),

3-(6-(4-(4-메틸피페라진-1-일-메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0036),3- (6- (4- (4-methylpiperazin-1-yl-methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0036),

3-(6-(4-((다이에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0037),3- (6- (4-((diethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0037),

3-(6-(퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0038),3- (6- (furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0038),

3-(6-(퓨란-3-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0039),3- (6- (furan-3-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0039),

3-(6-(4-((사이클로프로필메틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0040),3- (6- (4-((cyclopropylmethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0040),

3-(6-(4-((아이소부틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0041),3- (6- (4-((isobutylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0041),

3-(6-(4-((에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0042),3- (6- (4-((ethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0042),

3-(6-(4-(2-(피롤리딘-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0043),3- (6- (4- (2- (pyrrolidin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0043),

3-(6-(4-(2-(피페리딘-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0044),3- (6- (4- (2- (piperidin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0044),

3-(6-(4-(2-(4-메틸피페라진-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0045),3- (6- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0045) ,

3-(6-(4-(2-모폴리노에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0046),3- (6- (4- (2-morpholinoethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0046),

2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)-1-(4-메틸피페라진-1-일)에타논 (LCB03-0047),2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) -1- (4-methylpiperazin-1-yl) eta Rice field (LCB03-0047),

삭제delete

2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)-1-(피롤리딘-1-일)에타논 (LCB03-0049),2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) -1- (pyrrolidin-1-yl) ethanone ( LCB03-0049),

N,N-다이에틸-2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)아세트아마이드 (LCB03-0050),N, N-diethyl-2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) acetamide (LCB03-0050),

3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤조산 (LCB03-0051),3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzoic acid (LCB03-0051),

(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)(4-메틸피페라진-1-일)메타논 (LCB03-0052),(4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone (LCB03-0052 ),

(3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐(피롤리딘-1-일)메타논 (LCB03-0053),(3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl (pyrrolidin-1-yl) methanone (LCB03-0053),

N,N-다이에틸-3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈아마이드 (LCB03-0054),N, N-diethyl-3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamide (LCB03-0054),

(3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐(4-메틸피페라진-1-일)메타논 (LCB03-0055),(3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl (4-methylpiperazin-1-yl) methanone (LCB03-0055) ,

메틸 1-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-2-카복실레이트 (LCB03-0056),Methyl 1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxylate (LCB03-0056),

3-(6-(4-((2-(하이드록시메틸)피롤리딘-1-일)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0057),3- (6- (4-((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03 -0057),

3-(6-(4-((4-메틸피페리딘-1-일)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0058),3- (6- (4-((4-methylpiperidin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0058),

3-(6-(4-(((2R,6S)-2,6-다이메틸피페리딘-1-일)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0059),3- (6- (4-(((2R, 6S) -2,6-dimethylpiperidin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-yl Amino) phenol (LCB03-0059),

3-(6-(3-(피페리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0060),3- (6- (3- (piperidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0060),

3-(6-(3-((4-메틸피페라진-1-일)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0061),3- (6- (3-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0061),

3-(6-(3-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0062),3- (6- (3- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0062),

3-(6-(3-((다이에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0063),3- (6- (3-((diethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0063),

3-(6-(3-(피페라진-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0064),3- (6- (3- (piperazin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0064),

3-(6-(3-((에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0065),3- (6- (3-((ethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0065),

3-(6-(3-(모폴리노메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0066),3- (6- (3- (morpholinomethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0066),

3-(6-(3-((아이소부틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0067),3- (6- (3-((isobutylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0067),

1-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-2-카복사마이드 (LCB03-0068),1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxamide (LCB03-0068),

1-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-2-카복실산 (LCB03-0069),1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxylic acid (LCB03-0069),

3-(6-(4-((2-하이드록시에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0070),3- (6- (4-((2-hydroxyethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0070),

메틸 2-(3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈아미도)프로파노에이트 (LCB03-0071),Methyl 2- (3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamido) propanoate (LCB03-0071),

1-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-3-올 (LCB03-0072),1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidin-3-ol (LCB03-0072),

3-(6-(4-(에톡시메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0073),3- (6- (4- (ethoxymethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0073),

4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)-N-(1-하이드록시프로판-2-일)벤즈아마이드 (LCB03-0074),4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) -N- (1-hydroxypropan-2-yl) benzamide (LCB03-0074 ),

2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈아미도)프로판산 (LCB03-0075),2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamido) propanoic acid (LCB03-0075),

3-(6-(3-(2-(피롤리딘-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0076),3- (6- (3- (2- (pyrrolidin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0076),

6-(4-(피롤리딘-1-일메틸)페닐)-N-(3-(트라이플로로메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (LCB03-0077),6- (4- (pyrrolidin-1-ylmethyl) phenyl) -N- (3- (trifluoromethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine (LCB03- 0077),

N-(3-(다이플로로메틸)페닐)-6-(4-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (LCB03-0078),N- (3- (difluoromethyl) phenyl) -6- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine (LCB03- 0078),

3-(6-(3-(2-(피페라진-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0079),3- (6- (3- (2- (piperazin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0079),

3-(2-(4-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 (LCB03-0080),3- (2- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol (LCB03-0080),

4-클로로-5-(6-(4-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0081),4-chloro-5- (6- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0081),

3-(6-(4-모폴리노페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0082),3- (6- (4-morpholinophenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0082),

3-(2-(4-(모폴리노메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 (LCB03-0083),3- (2- (4- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol (LCB03-0083),

3-(2-(4-((4-메틸피페라진-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 (LCB03-0084),3- (2- (4-((4-methylpiperazin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol (LCB03-0084),

3-(6-(5-(피롤리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0085),3- (6- (5- (pyrrolidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0085),

3-(6-(5-(피롤리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0086),3- (6- (5- (pyrrolidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0086),

3-(6-(5-((4-메틸피페라진-1-일)메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0087),3- (6- (5-((4-methylpiperazin-1-yl) methyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03- 0087),

3-(6-(5-(피페리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0088),3- (6- (5- (piperidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0088),

3-(6-(5-(모폴리노메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0089),3- (6- (5- (morpholinomethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0089),

3-(6-(5-(피페라진-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0090),3- (6- (5- (piperazin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0090),

3-(6-(5-((에틸아미노)메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0091),3- (6- (5-((ethylamino) methyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0091),

3-(6-(5-((4-메틸피페라진-1-일)메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0092),3- (6- (5-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03 -0092),

3-(6-(5-(피페리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0093),3- (6- (5- (piperidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0093),

3-(6-(5-(피페라진-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0094),3- (6- (5- (piperazin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0094),

3-(6-(5-((에틸아미노)메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0095),3- (6- (5-((ethylamino) methyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0095),

3-(6-(5-(모폴리노메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0096),3- (6- (5- (morpholinomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0096),

3-(2-(4-(피페리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 (LCB03-0097),3- (2- (4- (piperidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol (LCB03-0097),

3-(2-(4-(피페라진-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 (LCB03-0098),3- (2- (4- (piperazin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol (LCB03-0098),

3-(2-(4-((에틸아미노)메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 (LCB03-0099),3- (2- (4-((ethylamino) methyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol (LCB03-0099),

3-(2-(4-메틸피페라진-1-일)싸이아졸로[4,5-d]피리미딘-7-일아미노)페놀 (LCB03-0100),3- (2- (4-methylpiperazin-1-yl) thiazolo [4,5-d] pyrimidin-7-ylamino) phenol (LCB03-0100),

3-(6-(4-(피롤리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0101),3- (6- (4- (pyrrolidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0101),

3-(6-(4-((4-메틸피페라진-1-일)메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0102),3- (6- (4-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03 -0102),

3-(6-(4-(피페리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0103),3- (6- (4- (piperidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0103),

3-(6-(4-(모폴리노메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0104),3- (6- (4- (morpholinomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0104),

3-(6-(4-(피페라진-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0105),3- (6- (4- (piperazin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0105),

3-(6-(4-((에틸아미노메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0106),3- (6- (4-((ethylaminomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0106),

3-(2-(3-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 (LCB03-0107),3- (2- (3- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol (LCB03-0107),

3-(2-(3-((4-메틸피페라진-1-일)메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 (LCB03-0108),3- (2- (3-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol (LCB03-0108),

3-(2-(3-(피페리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 (LCB03-0109),3- (2- (3- (piperidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol (LCB03-0109),

3-(2-(3-(모폴리노메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 (LCB03-0110),3- (2- (3- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol (LCB03-0110),

3-(2-(3-(피페라진-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 (LCB03-0111),3- (2- (3- (piperazin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol (LCB03-0111),

3-(2-(3-((에틸아미노)메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 (LCB03-0112),3- (2- (3-((ethylamino) methyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol (LCB03-0112),

3-(6-(4-(피롤리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0113),3- (6- (4- (pyrrolidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0113),

3-(6-(4-((4-메틸피페라진-1-일)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0114), 및3- (6- (4-((4-methylpiperazin-1-yl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0114) , And

3-(6-(4-(피페리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (LCB03-0115).3- (6- (4- (piperidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (LCB03-0115).

또한 본 발명은 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는 항암용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for anticancer containing a compound represented by the formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

또한 본 발명은 화학식 1의 화합물, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는 동맥경화, 폐섬유화증 또는 간경화증의 예방 또는 치료용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for the prevention or treatment of atherosclerosis, pulmonary fibrosis or liver cirrhosis containing the compound of formula (1), isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient.

또한 본 발명은 화학식 1의 화합물, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는 류마티즘 또는 골관절염의 예방 또는 치료용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for the prevention or treatment of rheumatoid or osteoarthritis, containing a compound of formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

또한 본 발명은 화학식 1의 화합물, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는 혈관재협착의 예방 또는 치료용 약학적 조성물을 제공한다. In another aspect, the present invention provides a pharmaceutical composition for preventing or treating vascular restenosis, which contains a compound of Formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

또한 본 발명은 화학식 1의 화합물, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신장병의 예방 또는 치료용 약학적 조성물을 제공한다. In another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of kidney disease, containing a compound of formula (1), isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient.

본 발명의 조성물을 의약품으로 사용하는 경우, 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물은 임상투여 시에 다양한 하기의 경구 또는 비경구 투여 형태로 제제화되어 투여될 수 있으나, 이에 한정되는 것은 아니다.When the composition of the present invention is used as a medicine, the pharmaceutical composition containing the compound represented by the formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient may be used in various oral or parenteral forms as described below. It may be formulated in a dosage form and administered, but is not limited thereto.

경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/ 또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/ 또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 또한 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc. These formulations may contain, in addition to the active ingredients, diluents (e.g., lactose, dextrose). Rose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain additives such as starch, agar, alginic acid or its sodium salt A disintegrating or boiling mixture and / or an absorbent, a colorant, a flavoring agent, and a sweetening agent.

상기 화학식 1로 표시되는 화합물을 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. Pharmaceutical compositions comprising the compound represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1의 화합물, 이의 이성질체 또는 이의 약학적으로 허용되는 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.In this case, the compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, which is administered in ampoules or vials. It can be manufactured in a mold. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

또한, 본 발명의 화합물의 인체에 대한 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.1 ~ 1,000 ㎎/일이며, 바람직하게는 1 ~ 500 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.In addition, the dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.1-1,000 mg / day, Preferably it is 1-500 mg / day, It can also divide and administer once a day to several times at regular time intervals according to a decision of a doctor or a pharmacist.

본 발명의 화학식 1의 화합물의 제조방법을 도식화하여 나타내면 하기 반응식 1과 같다. 다만, 하기의 제조방법이 본 발명에 따른 화학식 1로 표시되는 화합물을 제조하는 방법을 한정하는 것은 아니며, 하기의 제조방법의 변형은 당업자에게 자명할 것이며, 달리 언급이 없는한 하기 반응식의 치환체의 정의는 상기 화학식 1에서의 정의와 동일하다.Scheme 1 shows a method for preparing a compound of Formula 1 according to the present invention. However, the following preparation method does not limit the method for preparing the compound represented by the formula (1) according to the present invention, modifications of the following preparation method will be apparent to those skilled in the art, and unless otherwise stated, The definition is the same as the definition in Formula 1.

화학식 1의 화합물은 싸이에노피리미디논, 싸이에노피리디논 또는 싸이아졸로피리미디논의 골격을 가지는 (I)의 화합물을 클로리네이션하여 7-클로로싸이에노피리미딘 또는 싸이에노피리딘 유도체 (II)를 합성하고, 브로미네이션하여 2-브로로-7-클로로싸이에노피리미딘 또는 싸이에토피리딘 유도체(III)을 합성한 다음, 아닐린 유도체 (IV)와 치환반응을 통해 (V)의 화합물을 합성 할 수 있다. 화합물 (V)는 스즈키 커플링(Suzuki coupling)을 통하여 각각의 화학식 1-1, 1-2, 1-3의 싸이에노피리미딘, 싸이에노피리딘 및 싸이아졸로피리미딘 골격을 갖는 화합물을 제조할 수 있다. The compound of formula (1) is a 7-chlorothienopyrimidine or thienopyridine by cloning a compound of (I) having a skeleton of thienopyrimidinone, thienopyridinone or thiazolopyrimidinone Synthesis of derivative (II), bromination to synthesize 2-bro-7-chlorothienopyrimidine or cytotopyridine derivative (III), and then through substitution reaction with aniline derivative (IV) ( The compound of V) can be synthesized. Compound (V) is a compound having a thienopyrimidine, thienopyridine and thiazolopyrimidine backbone of formulas 1-1, 1-2 and 1-3, respectively, via Suzuki coupling. It can manufacture.

[반응식 1] Scheme 1

상기 제조방법을 보다 구체화하여 본 발명의 화합물을 제조하기 위한 반응식을 도식화하면 하기 반응식 2와 같다. 하기 반응식 2에 기재되어 있는 화합물은 본 발명의 화합물을 제조하기 위한 출발물질로 사용될 수 있다. 다만, 하기 제조방법의 변형은 당업자에게 자명할 것이며, 달리 언급이 없는 한 하기 반응식의 치환체의 정의는 상기 화학식 1에서의 정의와 동일하다.When the above formulating method is more specifically, the scheme for preparing the compound of the present invention is shown in Scheme 2 below. The compounds described in Scheme 2 below can be used as starting materials for preparing compounds of the present invention. However, modifications of the following preparation methods will be apparent to those skilled in the art, and unless otherwise stated, the definitions of the substituents in the following reaction schemes are the same as those in the general formula (1).

[반응식 2]Scheme 2

이하, 본 발명을 더욱 상세하게 설명하기 위한 제조예 및 실시예를 제시한다. 그러나 하기의 제조예 및 실시예는 본 발명을 보다 쉽게 설명하기 위하여 제공되는 것일 뿐, 이에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preparation examples and examples for explaining the present invention in more detail. However, the following Preparation Examples and Examples are merely provided to more easily explain the present invention, thereby not limited to the content of the present invention.

각 화합물의 제조예를 다음에서 기술 하였다.Examples of preparation of each compound are described below.

[제조예 1][Production Example 1]

[제조예 1-1] 1-(4-(메톡시벤질옥시)-3-나이트로벤젠 (1-(4-methoxybenzyloxy)-3-nitrobenzene) 의 제조 Preparation Example 1-1 Preparation of 1- (4- (methoxybenzyloxy) -3-nitrobenzene (1- (4-methoxybenzyloxy) -3-nitrobenzene)

0 ℃ 에서 10 ml 탈기체화된 다이메틸포름아마이드에 소디움하이드라이드 (0.54g, 13.36 mmol)을 넣고 3-나이트로페놀 (1.69 g, 12.14 mmol)을 7 ml의 다이메틸포름아마이드에 녹여서 천천히 적가한 뒤, 파라-메톡시벤질클로라이드 (1.81 ml, 13.36 mmol)을 천천히 첨가하였다. 반응온도를 실온으로 올려서 2시간 교반 후 포화된 염화암모늄 100ml와 에틸아세테이트 100ml로 추출하였다. 유기층은 물 100 ml로 2회 반복하여 씻어준 후 무수 황산나트륨으로 건조한 뒤 감압농축하여 생긴 고체는 n-헥세인을 이용, 고체화하여 1-(4-methoxybenzyloxy)-3-nitrobenzene (2.85 g, 90 %)을 옅은 노란색 고체로 얻었다. Sodium hydride (0.54 g, 13.36 mmol) was added to 10 ml of degassed dimethylformamide at 0 ° C, and 3-nitrophenol (1.69 g, 12.14 mmol) was slowly added dropwise into 7 ml of dimethylformamide. Then para-methoxybenzylchloride (1.81 ml, 13.36 mmol) was added slowly. The reaction temperature was raised to room temperature and stirred for 2 hours, followed by extraction with 100 ml of saturated ammonium chloride and 100 ml of ethyl acetate. The organic layer was washed twice with 100 ml of water twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The solid was solidified using n-hexane to form 1- (4-methoxybenzyloxy) -3-nitrobenzene (2.85 g, 90% ) Was obtained as a pale yellow solid.

¹H-NMR (600 MHz, CDCl₃); δ 7.83-7.81 (m, 2H), 7.42 (t, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.28 (dd, J, 2.4, 8.4 Hz, 1H), 6.93 (d, J= 8.4 Hz, 2H), 5.06 (s, 2H), 3.82 (s, 3H) ¹ H-NMR (600 MHz, CDCl ₃ ); δ 7.83-7.81 (m, 2H), 7.42 (t, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.28 (dd, J, 2.4, 8.4 Hz, 1H), 6.93 ( d, J = 8.4 Hz, 2H), 5.06 (s, 2H), 3.82 (s, 3H)

[제조예 1-2] 3-(4-메톡시벤질옥시)아닐린 (3-(4-methoxybenzyloxy)aniline) 의 제조 Preparation Example 1-2 Preparation of 3- (4-methoxybenzyloxy) aniline (3- (4-methoxybenzyloxy) aniline)

철 (5.6g, 100.28 mmol)을 메탄올 : 물 (15 ml : 3 ml)와 혼합 후 30분간 환 류 교반하였다. 온도를 실온으로 낮춘 후 6ml의 메탄올 : 물 (5:1)에 녹인 1-(4-methoxybenzyloxy)-3-nitrobenzene (1.3 g, 5.01 mmol)을 첨가하고 15시간 환규교반하였다. 셀라이트를 이용하여 철을 제거하고 메탄올을 사용하여 씻어준 후 감압농축하에 용매를 제거하였다. 포화된 염화암모늄 100 ml에 다이클로로메테인 150 ml 를 넣고 추출한 뒤 유기층을 물로 다시 씻어주었다. 유기용매는 감압농축하고 표제 화합물 (1.14 g, 99 %)을 얻었다. Iron (5.6 g, 100.28 mmol) was mixed with methanol: water (15 ml: 3 ml) and stirred under reflux for 30 minutes. After the temperature was lowered to room temperature, 1- (4-methoxybenzyloxy) -3-nitrobenzene (1.3 g, 5.01 mmol) dissolved in 6 ml of methanol: water (5: 1) was added, and the mixture was stirred for 15 hours. Iron was removed using celite, washed with methanol, and the solvent was removed under reduced pressure. After diluting 150 ml of dichloromethane into 100 ml of saturated ammonium chloride, the organic layer was washed again with water. The organic solvent was concentrated under reduced pressure to obtain the title compound (1.14 g, 99%).

¹H-NMR (400 MHz, CDCl₃); δ 7.34 (d, J=7.2 Hz, 1H), 7.25 (s, 1H), 7.05-7.04 (m, 1H), 6.91-6.90 (m, 2H), 6.40-6.31 (m, 3H), 4.94 (s, 2H), 3.81 (s, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 7.34 (d, J = 7.2 Hz, 1H), 7.25 (s, 1H), 7.05-7.04 (m, 1H), 6.91-6.90 (m, 2H), 6.40-6.31 (m, 3H), 4.94 (s , 2H), 3.81 (s, 3H)

[제조예 2] 3-(터트-부틸다이메틸실릴옥시)아닐린 3-(tert-butyldimethylsilyloxy)aniline) 의 제조Preparation Example 2 Preparation of 3- (tert-butyldimethylsilyloxy) aniline 3- (tert-butyldimethylsilyloxy) aniline)

다이클로로메테인 200 ml에 3-아미노페놀 (6.64 g, 60.81 mmol), 아미다졸 (5.38 g, 79.10 mmol)을 넣고 클로로 터트-부틸다이메틸실란 (11 g, 72.98 mmol)을 첨가한 다음 실온에서 15시간 동안 교반하였다. 포화된 염화암모늄 200 ml와 다이클로로메테인 200 ml를 이용하여 추출하고 유기층은 다시 물 200 ml를 2회 반복하여 씻어주었다. 감압농축하여 표제화합물 (13.5 g, 99 %)을 얻었다. To 200 ml of dichloromethane, add 3-aminophenol (6.64 g, 60.81 mmol) and amidazole (5.38 g, 79.10 mmol), add chloro tert-butyldimethylsilane (11 g, 72.98 mmol), and then at room temperature Stir for 15 hours. 200 ml of saturated ammonium chloride and 200 ml of dichloromethane were extracted, and the organic layer was washed again with 200 ml of water twice. Concentration under reduced pressure afforded the title compound (13.5 g, 99%).

¹H-NMR (400 MHz, CDCl₃); δ 6.95 (t, J = 8.0 Hz, 1H), 6.27-6.18 (m, 2H), 6.16-6.15 (m, 1H), 3.56 (brs, 2H), 0.90 (s, 9H), 0.11 (s, 6H); LC-MS 224 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 6.95 (t, J = 8.0 Hz, 1H), 6.27-6.18 (m, 2H), 6.16-6.15 (m, 1H), 3.56 (brs, 2H), 0.90 (s, 9H), 0.11 (s, 6H ); LC-MS 224 (MH +)

[제조예 3][Manufacture example 3]

[제조예 3-1] 메틸 3-포름아미도사이오펜-2-카르복실레이트 (methyl 3-formamidothiophene-2-carboxylate) 의 제조 Preparation Example 3-1 Preparation of Methyl 3-formamidothiophene-2-carboxylate

메틸 3-아미노-2-사이오펜 카르복실레이트 (25 g, 159.04 mmol)에 포름산 125 ml와 암모늄 아세테이트 (15.9 g, 207 mmol)을 넣고 4시간 동안 환류교반한 뒤, 실온으로 온도를 내리고 이때 생성된 고체를 필터하여 물로 씻어주어 표제화합물 (29 g, 98%)을 얻었다. 125 ml of formic acid and ammonium acetate (15.9 g, 207 mmol) were added to methyl 3-amino-2-thiophene carboxylate (25 g, 159.04 mmol), and the mixture was stirred under reflux for 4 hours, and then cooled to room temperature. The solid was filtered and washed with water to obtain the title compound (29 g, 98%).

¹H-NMR (400 MHz, CDCl₃); δ 10.10 (br, 1H), 8.42 (s, 1H), 8.10 (d, J =5.6Hz, 1H), 7.49 (d, J =5.2Hz, 1H), 3.90 (s, 3H); LC-MS 186.20 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 10.10 (br, 1H), 8.42 (s, 1H), 8.10 (d, J = 5.6 Hz, 1H), 7.49 (d, J = 5.2 Hz, 1H), 3.90 (s, 3H); LC-MS 186.20 (MH +)

[제조예 3-2] 3H-싸이에노[3,2-d]피리미딘-4-온 (3H-Thieno[3,2-d]pyrimidin-4-one) 의 제조Preparation Example 3-2 Preparation of 3H-thieno [3,2-d] pyrimidin-4-one (3H-Thieno [3,2-d] pyrimidin-4-one)

제조예 3-1에서 합성한 화합물 (29 g, 156.6 mmol)와 암모늄 포메이트 (29.7 g, 469.8 mmol), 포름아마이드 (38 ml, 939.5 mmol)를 섞은 뒤 140 ℃에서 20시간 가열하였다. 반응액을 실온으로 내리고 생성된 고체를 물로 씻어주어 표제 화합물 (15.7 g, 66 %)을 황토색의 고체로 얻었다. Compound (29 g, 156.6 mmol) synthesized in Preparation Example 3-1, ammonium formate (29.7 g, 469.8 mmol), and formamide (38 ml, 939.5 mmol) were mixed and heated at 140 ° C. for 20 hours. The reaction solution was cooled to room temperature and the resulting solid was washed with water to obtain the title compound (15.7 g, 66%) as an ocher solid.

¹H-NMR (400 MHz, CDCl₃); δ 8.18 (d, J =5.2Hz, 1H), 8.15 (s, 1H), 7.40 (d, J =5.2Hz, 1H); LC-MS 153.0 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.18 (d, J = 5.2 Hz, 1H), 8.15 (s, 1H), 7.40 (d, J = 5.2 Hz, 1H); LC-MS 153.0 (MH +)

[제조예 3-3] 4-클로로-싸이에노[3,2-d]피리미딘 (4-chloro-thieno[3,2-d]pyrimidine) 의 제조Preparation Example 3-3 Preparation of 4-chloro-thieno [3,2-d] pyrimidine (4-chloro-thieno [3,2-d] pyrimidine)

다이클로로에테인 150 ml에 다이메틸포름아마이드 (15.4 ml, 197.13 mmol)를 넣고 0 ℃로 온도를 낮춘 후, 옥살릴 클로라이드 (25. 4 ml, 295.70 mmol)을 천천히 넣으면 흰색 젤형태가 생기기 시작할 때 3H-싸이에노[3,2-d]피리미딘-4-온 (15 g, 98.57 mmol)을 넣었다. 반응액을 2.5 시간 동안 환류교반한 뒤, 실온으로 온도를 내리고 물을 부은 다음 다이클로로메테인 (3×300 ml)로 추출하고 무수 황산 마그네슘을 이용하여 건조하고 감압농축 후 헥세인 200 ml로 트리터레이션(trituration)하여 표제화합물 (16.7 g, 99 %)을 황토색 고체로 얻었다. To 150 ml of dichloroethane, add dimethylformamide (15.4 ml, 197.13 mmol), lower the temperature to 0 ° C, and slowly add oxalyl chloride (25. 4 ml, 295.70 mmol) to form white gel. Thieno [3,2-d] pyrimidin-4-one (15 g, 98.57 mmol) was added. The reaction solution was stirred under reflux for 2.5 hours, cooled to room temperature, poured with water, extracted with dichloromethane (3 × 300 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then washed with 200 ml of hexane. Trituration gave the title compound (16.7 g, 99%) as an ocher solid.

¹H NMR (400MHz, DMSO-d₆); δ 9.06 (s, 1H), 8.61 (d, J =5.2Hz, 1H), 7.78 (d, J =5.2Hz, 1H); LC-MS 173.2 (MH+) ¹ H NMR (400 MHz, DMSO-d ₆ ); δ 9.06 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 5.2 Hz, 1H); LC-MS 173.2 (MH +)

[제조예 3-4] 6-브로모-4-클로로-싸이에노[3,2-d]피리미딘 (6-bromo-4-chloro-thieno[3,2-d]pyrimidine) 의 제조Preparation Example 3-4 Preparation of 6-bromo-4-chloro-thieno [3,2-d] pyrimidine (6-bromo-4-chloro-thieno [3,2-d] pyrimidine)

테트라하이드로퓨란 200 ml 에 리튬 다이아이소프로필아민 (25 ml, 61.54 mmol)을 넣고 -78 ℃로 온도를 낮춘 후, 50 ml의 테트라하이드로퓨란에 녹인 4-클로로-싸이에노[3,2-d]피리미딘 (5 g, 39.30 mmol)을 천천히 적가하였다. 20분 후에 1,2-다이브로로-1,1,2,2-테트라플루오로에테인 (11.45 g, 35.17 mmol)을 천천히 넣었다. -78 ℃에서 20분간 교반 후 실온으로 온도를 올려 2시간 동안 더 교반하고 반응액에 물을 부었다. 클로로포름 (3×300 ml)로 추출하고 무수 황산 마그네슘을 이용하여 건조하고 감압농축 후 n-헥세인 200 ml로 트리터레이션(trituration)하여 표제화합물 (6.5 g, 89.2 %)을 황토색 고체로 얻었다Lithium diisopropylamine (25 ml, 61.54 mmol) was added to 200 ml of tetrahydrofuran and the temperature was lowered to -78 ° C. 4-chloro-cyeno [3,2-d dissolved in 50 ml of tetrahydrofuran was added. ] Pyrimidine (5 g, 39.30 mmol) was added slowly dropwise. After 20 minutes slowly added 1,2-dibro-1,1,2,2-tetrafluoroethane (11.45 g, 35.17 mmol). After stirring at −78 ° C. for 20 minutes, the temperature was raised to room temperature, followed by further stirring for 2 hours, and water was added to the reaction solution. Extracted with chloroform (3 × 300 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and triturated with 200 ml of n-hexane to give the title compound (6.5 g, 89.2%) as an ocher solid.

¹H-NMR (400 MHz, CDCl₃); δ 8.94 (s, 1H), 7.62 (s, 1H); LC-MS: 249, 251(MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.94 (s, 1 H), 7.62 (s, 1 H); LC-MS: 249, 251 (MH < + >)

[제조예 4] 6-브로모-N-(3-(4-메톡시벤질옥시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (6-bromo-N-(3-(4-methoxybenzyloxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조Production Example 4 6-Bromo-N- (3- (4-methoxybenzyloxy) phenyl) thieno [3,2-d] pyrimidin-4-amine (6-bromo-N- (3 Preparation of-(4-methoxybenzyloxy) phenyl) thieno [3,2-d] pyrimidin-4-amine)

제조예 3-4에서 얻은 화합물 (0.18 g, 0.80 mmol)을 다이클로에테인 3 ml와 t-부탄올 3 ml에 녹여 sealed tube에 넣고 85 ℃에서 3일간 교반하였다. 실온으로 냉각 후 생성된 옅은 갈색 고체를 다이에틸 에테르를 이용하여 씻어주어 표제화합물 (0.25 g, 80%)을 잿빛의 고체로 수득하였다. The compound (0.18 g, 0.80 mmol) obtained in Preparation Example 3-4 was dissolved in 3 ml of dicloethane and 3 ml of t-butanol, and placed in a sealed tube and stirred at 85 ° C. for 3 days. The pale brown solid produced after cooling to room temperature was washed with diethyl ether to give the title compound (0.25 g, 80%) as a gray solid.

¹H-NMR (600MHz, DMSO-d₆); δ 10.52 (brs, 1H), 8.70 (s, 1H), 7.73 (s, 1H), 7.44-7.27 (m, 5H),6.95-6.88 (m, 3H), 5.04 (s, 2H), 3.75 (s, 3H); LC-MS: 443 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 10.52 (brs, 1H), 8.70 (s, 1H), 7.73 (s, 1H), 7.44-7.27 (m, 5H), 6.95-6.88 (m, 3H), 5.04 (s, 2H), 3.75 (s , 3H); LC-MS: 443 (MH < + >)

위와 유사한 방법으로 하기화합물을 합성하였다. The following compound was synthesize | combined by the method similar to the above.

[제조예 5] 6-브로로-N-(3-(터트-부틸다이메틸실릴옥시)페닐)싸이에토[3,2-d]피리미딘-4-아민 (6-bromo-N-(3-(tert-butyldimethylsilyloxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조Production Example 5 6-Bro-N- (3- (tert-butyldimethylsilyloxy) phenyl) cyeto [3,2-d] pyrimidin-4-amine (6-bromo-N- ( Preparation of 3- (tert-butyldimethylsilyloxy) phenyl) thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.62(s, 1H), 7.40(s, 1H), 7.30-7.26(m, 1H), 7.06-7.02(m, 2H), 6.87-6.82(m, 2H), 1.00(s, 9H), 0.23(s, 6H); LC-MS 439 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.62 (s, 1H), 7.40 (s, 1H), 7.30-7.26 (m, 1H), 7.06-7.02 (m, 2H), 6.87-6.82 (m, 2H), 1.00 (s, 9H), 0.23 (s, 6H); LC-MS 439 (MH +)

[제조예 6] 4-(4-(3-(터트-부틸다이메틸실릴옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈알데하이드 (4-(4-(3-(tert-butyldimethylsilyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)benzaldehyde) 의 제조Preparation Example 6 4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzaldehyde (4- (4- Preparation of (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzaldehyde)

제조예 5에서 합성한 화합물 (3.5 g, 8.02 mmol), 4-포밀페닐 보론산 (1.44 g, 9.62 mmol), 팔라듐 테트라키스트리페닐포스핀 (1.85 g, 1.60 mmol), 2N 탄산나트륨 (8 ml, 16.04 mmol)을 1,4-다이옥산 30 ml 에 넣고 3시간 동안 환류교반 시켰다. 반응액에 포화된 탄산수소나트륨 50 ml와 다이클로로메테인 150 ml를 이용하여 추출하고 유기층을 포화된 탄산수소나타륨 150 ml로 2회 더 추출한 후 무수 황산나트륨을 이용하여 건조하고 감압농축 후 관크로마토그래피 (에틸아세테이트/n-헥세인, 1/3)를 이용하여 표제 화합물 (2.1 g, 56.7 %)을 갈색 고체로 얻었다. Compound synthesized in Preparation Example 5 (3.5 g, 8.02 mmol), 4-formylphenyl boronic acid (1.44 g, 9.62 mmol), palladium tetrakistriphenylphosphine (1.85 g, 1.60 mmol), 2N sodium carbonate (8 ml, 16.04 mmol) was added to 30 ml of 1,4-dioxane and stirred under reflux for 3 hours. The reaction solution was extracted with 50 ml of saturated sodium bicarbonate and 150 ml of dichloromethane. The organic layer was extracted two more times with 150 ml of saturated sodium bicarbonate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography. (Ethyl acetate / n-hexane, 1/3) gave the title compound (2.1 g, 56.7%) as a brown solid.

¹H-NMR (600MHz, CDCl₃); δ 10.06 (s, 1H), 8.72 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 HZ, 2H), 7.17 (s, 1H), 7.30-7.28 (m, 1H), 7.18 (s, 1H), 7.16-7.14 (m, 1H), 6.93 (brs, 1H), 6.79 (d, J = 8.4 Hz, 1H), 0.96 (s, 9H), 0.21 (s, 6H); LC-MS: 462(MH+) ¹ H-NMR (600 MHz, CDCl ₃ ); δ 10.06 (s, 1H), 8.72 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 HZ, 2H), 7.17 (s, 1H), 7.30-7.28 ( m, 1H), 7.18 (s, 1H), 7.16-7.14 (m, 1H), 6.93 (brs, 1H), 6.79 (d, J = 8.4 Hz, 1H), 0.96 (s, 9H), 0.21 (s , 6H); LC-MS: 462 (MH < + >)

[제조예 7][Manufacture example 7]

[제조예 7-1] 1-(다이플루오로메틸)-3-나이트로벤젠 (1-(difluoromethyl)-3-nitrobenzene)의 제조 Preparation Example 7-1 Preparation of 1- (difluoromethyl) -3-nitrobenzene (1- (difluoromethyl) -3-nitrobenzene)

3-나이트로벤즈알데히드 (1 g, 6.61 mmol)을 20 ml의 다이클로로메테인에 녹인 후 -78 ℃하에서 5 ml의 다이클로로메테인에 희석된 다이에텔아미노설퍼 트리플루오라이드 (DAST, 20 ml, 13.23 mmol)을 천천히 적가한 후 15시간 실온에서 교반하였다. 물 100 ml를 넣고 100 ml의 다이클로로메테인으로 추출하여 유기층을 감압증류 후 관컬럼크로마토그래피 (에틸아세테이트/n-헥세인, 1/15)로 표제 화합물 (1.11 g, 97.3 %)을 갈색 오일로 얻었다. 3-nitrobenzaldehyde (1 g, 6.61 mmol) was dissolved in 20 ml of dichloromethane and then diethylaminosulfur trifluoride (DAST, 20 ml, diluted in 5 ml of dichloromethane at -78 ° C). 13.23 mmol) was slowly added dropwise and stirred at room temperature for 15 hours. 100 ml of water was added and extracted with 100 ml of dichloromethane. The organic layer was distilled under reduced pressure, and the title compound (1.11 g, 97.3%) was purified by column column chromatography (ethyl acetate / n-hexane, 1/15). Got it.

¹H-NMR (400 MHz, CDCl₃); δ 8.40 (s, 1H), 8.37-8.35 (m, 1H), 7.87 (d, J= 7.6 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 6.75 (t, J = 56.0 Hz, 1H) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.40 (s, 1H), 8.37-8.35 (m, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 6.75 (t, J = 56.0 Hz, 1H)

[제조예 7-2] 3-(다이플루오로메틸)아닐린 (3-(difluoromethyl)aniline) 의 제조 Preparation Example 7-2 Preparation of 3- (difluoromethyl) aniline (3- (difluoromethyl) aniline)

철 100 mg을 아세트산 3 ml에 넣고 15분동안 환류교반 후 실온으로 온도를 낮추고, 1-(difluoromethyl)-3-nitrobenzene (0.2 g, 1.15 mmol)을 넣고 다시 1시간 환류교반하였다. 에틸 아세테이트 20 ml를 첨가한 후 셀라이트로 부생성물들을 제거하고 유기층을 감압농축한 뒤 관크로마토그래피 (에틸아세테이트/n-헥세인, 1/15)를 이용하여 표제화합물 (0.16 g, 50 %)을 얻었다. 100 mg of iron was added to 3 ml of acetic acid, and the mixture was stirred under reflux for 15 minutes, and then cooled to room temperature. Then, 1- (difluoromethyl) -3-nitrobenzene (0.2 g, 1.15 mmol) was added thereto, and the mixture was stirred under reflux for 1 hour. 20 ml of ethyl acetate was added, the byproducts were removed by celite, and the organic layer was concentrated under reduced pressure, and then the title compound (0.16 g, 50%) was purified by column chromatography (ethyl acetate / n-hexane, 1/15). Got.

¹H-NMR (600 MHz, CDCl₃); δ 7.22 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.81 (s, 1H), 6.77-6.75 (m, 1H), 6.54 (t, J = 56 Hz, 1H), 3.91 (brs, 2H) ¹ H-NMR (600 MHz, CDCl ₃ ); δ 7.22 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.81 (s, 1H), 6.77-6.75 (m, 1H), 6.54 (t, J = 56 Hz, 1H), 3.91 (brs, 2H)

[제조예 8] 6-브로모-N-(3-(트라이플루오로메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (6-bromo-N-(3-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조Preparation Example 8 6-Bromo-N- (3- (trifluoromethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine (6-bromo-N- (3- ( Preparation of trifluoromethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine)

제조예 3-4에서 합성한 화합물 (0.1 g, 0.40 mmol)을 2 ml 다이클로로에테인과 2 ml t-부탄올 에 녹인 후 3-클루오로메틸 아닐린 (55 ㎕, 0.44 mmol)을 첨가한 후 20시간 환류교반하였다. 반응액을 감압농축 후 생성된 노란색 고체를 다이에틸 에테르를 사용하여 씻어주어 표제 화합물 (0.12 g, 100 %)을 얻었다. The compound synthesized in Preparation Example 3-4 (0.1 g, 0.40 mmol) was dissolved in 2 ml dichloroethane and 2 ml t-butanol, and 20 hours after 3-chloromethyl aniline (55 µl, 0.44 mmol) was added. The reflux was stirred. The reaction solution was concentrated under reduced pressure, and the resulting yellow solid was washed with diethyl ether to obtain the title compound (0.12 g, 100%).

¹H-NMR (400MHz, DMSO-d₆); δ 10.83 (brs, 1H), 8.76 (s, 1H), 8.20 (s, 1H), 8.09 (d, J= 8.0 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H); LC-MS: 323 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.83 (brs, 1H), 8.76 (s, 1H), 8.20 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H); LC-MS: 323 (MH +)

위와 유사한 방법으로 하기의 화합물들을 합성하였다. The following compounds were synthesized in a similar manner to the above.

[제조예 9] N-(3-(6-브로모싸이에노[3,2-d]피리미딘-4-일아미노)페닐)2,2,2-트라이플루오로마아세트아마이드 (N-(3-(6-bromothieno[3,2-d]pyrimidin-4-ylamino)phenyl)-2,2,2-trifluoroacetamide) 의 제조Preparation Example 9 N- (3- (6-bromocyeno [3,2-d] pyrimidin-4-ylamino) phenyl) 2,2,2-trifluoroamide acetamide (N- ( Preparation of 3- (6-bromothieno [3,2-d] pyrimidin-4-ylamino) phenyl) -2,2,2-trifluoroacetamide)

¹H-NMR (600MHz, DMSO-d₆) δ 11.40 (brs, 1H), 8.70 (s, 1H), 7.74 (s, 1H), 7.62-7.60 (m, 2H), 7.49-7.44 (m, 2H); LC-MS: 419 (MH+2) ¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 11.40 (brs, 1H), 8.70 (s, 1H), 7.74 (s, 1H), 7.62-7.60 (m, 2H), 7.49-7.44 (m, 2H ); LC-MS: 419 (MH + 2)

[제조예 10] 6-브로모-N-(3-(다이플루오로메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (6-bromo-N-(3-(difluoromethyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조 Preparation Example 10 6-Bromo-N- (3- (difluoromethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine (6-bromo-N- (3- ( Preparation of difluoromethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 10.75 (brs, 1H), 8.74 (s, 1H), 7.98 (s, 1H), 7.94-7.92 (m, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.57 (t, J = 8.0 HZ, 1H), 7.40 (d, J 8.0 HZ, 1H), 7.09 (t, J = 56 HZ, 1H) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 10.75 (brs, 1H), 8.74 (s, 1H), 7.98 (s, 1H), 7.94-7.92 (m, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.57 (t, J = 8.0 HZ, 1H), 7.40 (d, J 8.0 HZ, 1H), 7.09 (t, J = 56 HZ, 1H)

[제조예 11] 4-(4-(3-(트라이플루오로메틸)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈알데하이드 (4-(4-(3-(trifluoromethyl)phenylamino)thieno[3,2-d]pyrimidin-6-yl)benzaldehyde) 의 제조Preparation Example 11 4- (4- (3- (trifluoromethyl) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzaldehyde (4- (4- (3- Preparation of (trifluoromethyl) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzaldehyde)

제조예 8에서 합성한 화합물 (60 mg, 0.18 mmol)을 제조예 6과 유사한 방법으로 표제 화합물 (64 mg, 86 %)을 얻었다.Compound (60 mg, 0.18 mmol) synthesized in Preparation Example 8 was obtained in the same manner as in Preparation Example 6, to obtain the title compound (64 mg, 86%).

¹H-NMR (600 MHz, CDCl₃); δ 10.07 (s, 1H), 8.00-7.98 (m, 3H), 7.89-7.87 (m, 3H), 7.79 (s, 1H), 7.58-7.47 (m, 2H), 6.87 (brs, 1H) ¹ H-NMR (600 MHz, CDCl ₃ ); δ 10.07 (s, 1H), 8.00-7.98 (m, 3H), 7.89-7.87 (m, 3H), 7.79 (s, 1H), 7.58-7.47 (m, 2H), 6.87 (brs, 1H)

[제조예 12] 4-(4-(3-(다이플루오로메틸)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈알데하이드 (4-(4-(3-(difluoromethyl)phenylamino)thieno[3,2-d]pyrimidin-6-yl)benzaldehyde) 의 제조Preparation Example 12 4- (4- (3- (difluoromethyl) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzaldehyde (4- (4- (3- Preparation of (difluoromethyl) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzaldehyde)

¹H-NMR (400 MHz, CDCl₃); δ 10.07 (s, 1H), 8.77 (s, 1H), 7.99 (d, J= 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.99-7.78 (m, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.39 (d, J= 7.6 Hz, 1H), 6.84 (brs, 1H), 6.71 (t, J = 56 Hz, 1H) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 10.07 (s, 1H), 8.77 (s, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.99-7.78 (m, 2H), 7.53 ( t, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 6.84 (brs, 1H), 6.71 (t, J = 56 Hz, 1H)

[제조예 13]Production Example 13

¹H NMR (600Hz, CDCl₃); δ 10.06 (s, 1H), 8.72 (s, 1H), 7.96 (d J = 8.47 Hz, 2H), 7.83 (d, J = 8.47 Hz, 2H), 7.71 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.30-7.28 (m, 1H), 7.18 (s, 1H), 7.16-7.14 (m, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.93 (brs,1H), 5.03 (s, 2H), 3.82 (s, 3H); LC-MS 346 (MH+) ¹ H NMR (600 Hz, CDCl ₃ ); δ 10.06 (s, 1H), 8.72 (s, 1H), 7.96 (d J = 8.47 Hz, 2H), 7.83 (d, J = 8.47 Hz, 2H), 7.71 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.30-7.28 (m, 1H), 7.18 (s, 1H), 7.16-7.14 (m, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.93 (brs, 1H) , 5.03 (s, 2 H), 3.82 (s, 3 H); LC-MS 346 (MH +)

[제조예 14] 4-클로로-3-(4-메톡시벤질옥시)아닐린 (4-chloro-3-(4-methoxybenzyloxy)aniline) 의 제조Preparation Example 14 Preparation of 4-chloro-3- (4-methoxybenzyloxy) aniline (4-chloro-3- (4-methoxybenzyloxy) aniline)

1-아미노-5-나이트로페놀 (2 g, 12.97 mmol), 소디움나이트리트 (0.9 g, 12.97 mol)에 물 10 ml와 30 ml 48 % HBF4를 넣고 실온에서 30분 교반한 후 염화구리(I) (642 mg, 6.48 mmol)를 첨가하고 80 ℃에서 3시간 동안 가열하였다. 0 ℃하에서 얼음물을 첨가한 뒤 포화된 탄산수소나트륨 200 ml와 에틸아세테이트 200 ml로 추출, 무수 황산나트륨으로 건조, 여과 후 감압 농축하고 관크로마토그래피(n-헥세인/에틸아세테이트, 15/1)를 시행하여 2-클로로-5-나이트로페놀 (0.46 g, 23 %)을 수득하였다. 2-클로로-5-나이트로페놀 (0.36 g, 2.29 mmol)을 제조예 9와 유사한 방법으로 표제화합물 (0.167 g, 94 %)을 얻었다. 10 ml of water and 30 ml of 48% HBF4 were added to 1-amino-5-nitrophenol (2 g, 12.97 mmol) and sodium nitrite (0.9 g, 12.97 mol), followed by stirring at room temperature for 30 minutes. ) (642 mg, 6.48 mmol) was added and heated at 80 ° C for 3 h. Ice water was added at 0 ° C., extracted with saturated sodium hydrogencarbonate 200 ml and ethyl acetate 200 ml, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then chromatographed (n-hexane / ethyl acetate, 15/1). Trial to give 2-chloro-5-nitrophenol (0.46 g, 23%). 2-Chloro-5-nitrophenol (0.36 g, 2.29 mmol) was obtained in the same manner as in Preparation 9, to obtain the title compound (0.167 g, 94%).

¹H-NMR (400MHz, CDCl₃); δ 7.37 (d, J =8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 1H), 6.92 (d, J =10.8 Hz, 2H), 6.32 (d, J = 2.4 Hz, 1H), 6.23 (dd, J = 2.0, 8.4 Hz, 1H), 5.02 (s, 2H), 3.81 (s, 3H); LC-MS: 248 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 7.37 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 10.8 Hz, 2H), 6.32 (d, J = 2.4 Hz, 1H), 6.23 (dd, J = 2.0, 8.4 Hz, 1 H), 5.02 (s, 2 H), 3.81 (s, 3 H); LC-MS: 248 (MH < + >)

[제조예 15] 6-브로로-N-(4-클로로-3-(4-메톡시벤질옥시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (6-bromo-N-(4-chloro-3-(4-methoxybenzyloxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조Production Example 15 6-Broro-N- (4-chloro-3- (4-methoxybenzyloxy) phenyl) thieno [3,2-d] pyrimidin-4-amine (6-bromo- Preparation of N- (4-chloro-3- (4-methoxybenzyloxy) phenyl) thieno [3,2-d] pyrimidin-4-amine)

제조예 8과 유사한 방법으로 표제화합물을 얻었다. The title compound was obtained in a similar manner to Preparation Example 8.

¹H-NMR (400MHz, DMSO-d₆); δ 10.58 (brs, 1H), 8.72 (s, 1H), 7.75-7.73 (m, 2H), 7.43-7.38 (m, 4H), 6.97 (d, J= 8.0 Hz, 2H), 5.12 (s, 2H), 3.76 (s, 3H); LC-MS: 477 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.58 (brs, 1H), 8.72 (s, 1H), 7.75-7.73 (m, 2H), 7.43-7.38 (m, 4H), 6.97 (d, J = 8.0 Hz, 2H), 5.12 (s, 2H ), 3.76 (s, 3 H); LC-MS: 477 (MH < + >)

[제조예 16] 4-(4-(4-클로로-3-(4-메톡시벤질옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈알데하이드 (4-(4-(4-chloro-3-(4-methoxybenzyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)benzaldehyde) 의 제조Production Example 16 4- (4- (4-chloro-3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzaldehyde (4- Preparation of (4- (4-chloro-3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzaldehyde)

제조예 6과 유사한 방법으로 표제화합물을 얻었다. The title compound was obtained in a similar manner to Preparation Example 6.

¹H NMR (600MHz, CDCl₃); δ 10.05 (s, 1H), 8.62 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.76 (s, 1H), 7.49-7.48 (m, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.16 (dd, J = 1.8, 8.4 Hz, 1H), 6.94-6.90 (m, 4H), 5.13 (s, 2H), 3.79 (s, 3H); LC-MS 502 (MH+) ¹ H NMR (600 MHz, CDCl ₃ ); δ 10.05 (s, 1H), 8.62 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.76 (s, 1H), 7.49-7.48 ( m, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.16 (dd, J = 1.8, 8.4 Hz, 1H), 6.94-6.90 (m, 4H), 5.13 (s, 2H), 3.79 (s , 3H); LC-MS 502 (MH +)

[제조예 17] 3-(4-(3-(4-메톡시벤질옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈알데하이드 (3-(4-(3-(4-methoxybenzyloxy)phenylamino)thieno[3,2- d]pyrimidin-6-yl)benzaldehyde) 의 제조Production Example 17 3- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzaldehyde (3- (4- ( Preparation of 3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzaldehyde)

실시예 1에서 합성한 화합물 (500 mg, 0.89 mmol)과 3-포밀페닐보론산 (160 mg, 1.06 mmol), 팔라디움테트라키스트리페닐포스핀 (21.7 mg, 0.02 mmol)을 탈기체화된 다이메틸포름아마이드 5 ml에 순차적으로 넣고 2N 탄산나트륨 1.33 ml을 넣었다. 80 ℃에서 15시간 교반한 후 반응액에 다이클로로메테인 50 ml와 포화된 염화암모늄 50 ml을 넣고 추출하였다. 유기층을 포화된 염화암모늄 50 ml로 2회 더 추출한 후 황산나트륨을 이용하여 건조하고 감압농축 후 다이에틸에테르 10 ml로 트리터레이션(trituration)하여 표제화합물 (320 mg, 77 %)을 갈색 고체로 얻었다.Degassed dimethylform of the compound synthesized in Example 1 (500 mg, 0.89 mmol), 3-formylphenylboronic acid (160 mg, 1.06 mmol) and palladium tetrakistriphenylphosphine (21.7 mg, 0.02 mmol) 5 ml of amide were added sequentially and 1.33 ml of 2N sodium carbonate was added. After stirring at 80 ° C. for 15 hours, 50 ml of dichloromethane and 50 ml of saturated ammonium chloride were added to the reaction solution. The organic layer was extracted two more times with 50 ml of saturated ammonium chloride, dried over sodium sulfate, concentrated under reduced pressure and triturated with 10 ml of diethyl ether to obtain the title compound (320 mg, 77%) as a brown solid. .

¹H NMR (600MHz, CDCl₃); δ 10.09 (s, 1H), 8.73 (s, 1H), 8.17 (s, 1H), 7.94 (t, J = 9.0Hz, 1H), 7.69 (s, 1H), 7.65 (t, J = 7.8Hz, 1H), 7.37 (m, 3H), 7.33 (t, J = 7.8Hz , 3H), 7.11 (d, J = 5.4Hz, 1H), 6.90 (m, 3H), 6.79 (br, 1H), 5.04 (s, 2H), 3.80 (s, 3H); LC-MS 468(MH+) ¹ H NMR (600 MHz, CDCl ₃ ); δ 10.09 (s, 1H), 8.73 (s, 1H), 8.17 (s, 1H), 7.94 (t, J = 9.0 Hz, 1H), 7.69 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.37 (m, 3H), 7.33 (t, J = 7.8 Hz, 3H), 7.11 (d, J = 5.4 Hz, 1H), 6.90 (m, 3H), 6.79 (br, 1H), 5.04 ( s, 2H), 3.80 (s, 3H); LC-MS 468 (MH +)

[제조예 18][Production Example 18]

[제조예 18-1] 2-(5-브로모사이오펜-2-일)-1,3-다이옥솔레인 (2-(5-bromothiophen-2-yl)-1,3-dioxolane) 의 제조Production Example 18-1 Preparation of 2- (5-bromothiophen-2-yl) -1,3-dioxolane (2- (5-bromothiophen-2-yl) -1,3-dioxolane)

5-브로모사이오펜-2-카복시알데하이드 (2 g, 10.46 mmol)을 톨루엔 30 ml에 녹이고 파라-톨루엔설폰산 (60 mg, 0.31 mmol)과 에틸렌글라이콜 (0.75 ml, 13.61 mmol)을 투입한 후 dean stock 장치에서 130 ℃로 15시간 동안 교반하였다. 실온으로 냉각하고 물 20 ml을 가하고 포화된 탄산수소나트륨수용액으로 중화 후 다이에틸에테르 100 ml로 추출하였다. 유기층을 물 50 ml와 소금물 50 ml로 씻은 후 황산마그네슘을 이용해 건조, 여과후 감압 농축하여 표제화합물 (1.8 g, 73.1 %)을 갈색 오일로 얻었다.5-bromosiophen-2-carboxyaldehyde (2 g, 10.46 mmol) was dissolved in 30 ml of toluene, para-toluenesulfonic acid (60 mg, 0.31 mmol) and ethylene glycol (0.75 ml, 13.61 mmol) were added thereto. After stirring for 15 hours at 130 ℃ in a dean stock apparatus. After cooling to room temperature, 20 ml of water was added, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with 100 ml of diethyl ether. The organic layer was washed with 50 ml of water and 50 ml of brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (1.8 g, 73.1%) as a brown oil.

¹H NMR (600MHz, CDCl₃); δ 9.78 (s, 1H), 7.52 (d, J = 3.6 Hz, 1H) ¹ H NMR (600 MHz, CDCl ₃ ); δ 9.78 (s, 1 H), 7.52 (d, J = 3.6 Hz, 1 H)

[제조예 18-2] 6-(5-(1,3-다이옥솔레인-2-일)사이오펜-2-일)-N-(3-(4-메톡시벨질옥시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (6-(5-(1,3-dioxolan-2-yl)thiophen-2-yl)-N-(3-(4-methoxybenzyloxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조Production Example 18-2 6- (5- (1,3-dioxolane-2-yl) thiophen-2-yl) -N- (3- (4-methoxybellyloxy) phenyl) cye No [3,2-d] pyrimidin-4-amine (6- (5- (1,3-dioxolan-2-yl) thiophen-2-yl) -N- (3- (4-methoxybenzyloxy) phenyl) Preparation of thieno [3,2-d] pyrimidin-4-amine)

제조예 18-1에서 얻은 화합물 (0.1 g, 0.35 mmol)와 제조예 7에서 얻은 화합 물 (0.1 g, 0.22 mmol), PdCl2(dppf)2 (5 mg, 0.006 mmol)을 반응 용기에 넣고 질소로 충진 후, 탈기체화된 다이메틸포름아마이드 5 ml와 2N 탄산나트륨 (0.3 ml, 0.66 mmol)을 넣고 80 ℃에서 15시간 동안 교반하였다. 반응액에 다이클로로메테인 50 ml와 포화된 염화암모늄 수용액 50 ml을 넣고 추출하였다. 유기층을 포화된 염화암모늄 수용액 50 ml로 2회 더 추출한 후 황산나트륨을 이용하여 건조하고 감압농축 후 감압농축 후 관크로마토그래피 (에틸아세테이트/n-헥세인, 1/15)로 표제화합물 (39 mg, 34 %)의 갈색 고체로 얻었다. Compound (0.1 g, 0.35 mmol) obtained in Preparation Example 18-1, the compound obtained in Preparation Example 7 (0.1 g, 0.22 mmol), and PdCl 2 (dppf) 2 (5 mg, 0.006 mmol) were added to a reaction vessel, and the mixture was purged with nitrogen. After filling, 5 ml of degassed dimethylformamide and 2N sodium carbonate (0.3 ml, 0.66 mmol) were added and stirred at 80 ° C. for 15 hours. 50 ml of dichloromethane and 50 ml of saturated aqueous ammonium chloride solution were added to the reaction mixture, and extracted. The organic layer was extracted two more times with 50 ml of saturated aqueous ammonium chloride solution, dried over sodium sulfate, concentrated under reduced pressure, concentrated under reduced pressure, and then purified by column chromatography (ethyl acetate / n-hexane, 1/15) to obtain the title compound (39 mg, 34%) as a brown solid.

¹H NMR (600MHz, CDCl₃); δ 8.68 (s, 1H), 7.44 (s, 1H), 7.37 (d, J = 7.8 Hz, 2H), 7.32-7.31 (m, 2H), 7.23-7.22 (m, 1H), 7.12 (d, J = 3.0 Hz, 1H), 6.91 (d, J = 7.8 Hz, 2H), 6.88-6.87 (m, 1H), 6.79 (s, 1H), 5.03 (s, 2H), 4.17-4.15 (m, 2), 4.06-4.04 (m, 2H), 3.08 (s, 3H); LC-MS 518 (MH+) ¹ H NMR (600 MHz, CDCl ₃ ); δ 8.68 (s, 1H), 7.44 (s, 1H), 7.37 (d, J = 7.8 Hz, 2H), 7.32-7.31 (m, 2H), 7.23-7.22 (m, 1H), 7.12 (d, J = 3.0 Hz, 1H), 6.91 (d, J = 7.8 Hz, 2H), 6.88-6.87 (m, 1H), 6.79 (s, 1H), 5.03 (s, 2H), 4.17-4.15 (m, 2) , 4.06-4.04 (m, 2H), 3.08 (s, 3H); LC-MS 518 (MH +)

[제조예 18-3] 5-(4-(3-(4-메톡시벤질옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)사이오펜-2-카브알데하이드 (5-(4-(3-(4-methoxybenzyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)thiophene-2-carbaldehyde) 의 제조Production Example 18-3 5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) thiophene-2-carbaldehyde Preparation of (5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) thiophene-2-carbaldehyde)

제조예 18-2에서 얻은 화합물 (0.27 g, 0.52 mmol)을 Acetone 10 ml에 녹이고 파라-톨루엔설폰산 (49 mg, 0.26 mmol)을 가하고 실온에서 20시간 동안 교반하였다. 포화된 탄산수로나트륨 50 ml을 가하여 중화하여 감압농축하였다. 잔여물에 물 10 ml을 가하고 30분간 교반 후 여과하고 여과물을 다이클로로메테인 5 ml와 메탄올 1 ml에서 고체화하여 표제화합물 (240 mg, 85 %)을 노란색 고체로 얻었다.The compound (0.27 g, 0.52 mmol) obtained in Preparation Example 2-2 was dissolved in 10 ml of Acetone, para-toluenesulfonic acid (49 mg, 0.26 mmol) was added, and the mixture was stirred at room temperature for 20 hours. 50 ml of saturated sodium bicarbonate was added thereto, neutralized, and concentrated under reduced pressure. 10 ml of water was added to the residue, followed by stirring for 30 minutes, and the filtrate was solidified in 5 ml of dichloromethane and 1 ml of methanol to obtain the title compound (240 mg, 85%) as a yellow solid.

¹H NMR (600MHz, DMSO-d₆); δ 9.97 (brs, 1H), 8.63 (s, 1H), 8.23 (d, J = 3.6 Hz, 1H), 8.00 (s, 1H), 7.86 (d, J = 4.2 Hz, 1H), 7.59-7.58 (m, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.8 HZ, 1H), 7.27 (t, J = 8.4 HZ, 1H), 6.95 (d, J= 8.4 Hz, 2H), 6.78 (dd, J = 1.8, 8.4 Hz, 1H), 5.03 (s, 2H), 3.75 (s, 3H); LC-MS 474 (MH+) ¹ H NMR (600 MHz, DMSO-d ₆ ); δ 9.97 (brs, 1H), 8.63 (s, 1H), 8.23 (d, J = 3.6 Hz, 1H), 8.00 (s, 1H), 7.86 (d, J = 4.2 Hz, 1H), 7.59-7.58 ( m, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.8 HZ, 1H), 7.27 (t, J = 8.4 HZ, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.78 (dd, J = 1.8, 8.4 Hz, 1H), 5.03 (s, 2H), 3.75 (s, 3H); LC-MS 474 (MH +)

위와 유사한 방법으로 하기의 화합물을 합성하였다.The following compounds were synthesized in a similar manner as above.

[제조예 19] 5-(4-(3-(4-메톡시벤질옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)퓨란-2-카브알데하이드 (5-(4-(3-(4-methoxybenzyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)furan-2-carbaldehyde) 의 제조Production Example 19 5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) furan-2-carbaldehyde (5- Preparation of (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) furan-2-carbaldehyde)

[제조예 19-1] 2-(5-브로로퓨란-2-일)-1,3-다이옥솔레인 (2-(5-bromofuran-2-yl)-1,3-dioxolane) 의 제조Preparation Example 19-1 Preparation of 2- (5-brorofuran-2-yl) -1,3-dioxolane (2- (5-bromofuran-2-yl) -1,3-dioxolane)

¹H NMR (600MHz, CDCl₃); δ 6.41 (d, J = 2.4 Hz, 1H), 6.28 (d, J = 2.0 Hz, 1H), 5.87 (s, 1H), 4.15-4.10 (m, 2H), 4.03-4.00 (m, 2H) ¹ H NMR (600 MHz, CDCl ₃ ); δ 6.41 (d, J = 2.4 Hz, 1H), 6.28 (d, J = 2.0 Hz, 1H), 5.87 (s, 1H), 4.15-4.10 (m, 2H), 4.03-4.00 (m, 2H)

[제조예 19-2] 6-(5-(1,3-다이옥솔레인-2-일)퓨란-2-일)-N-(3-(4-메톡시벤질옥시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (6-(5-(1,3-dioxolan-2-yl)furan-2-yl)-N-(3-(4-methoxybenzyloxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조Production Example 19-2 6- (5- (1,3-dioxolane-2-yl) furan-2-yl) -N- (3- (4-methoxybenzyloxy) phenyl) cyeno [3,2-d] pyrimidin-4-amine (6- (5- (1,3-dioxolan-2-yl) furan-2-yl) -N- (3- (4-methoxybenzyloxy) phenyl) thieno Preparation of [3,2-d] pyrimidin-4-amine)

¹H NMR (600MHz, CDCl₃); δ 8.69 (s, 1H), 7.53 (s, 1H), 7.37 (d, J = 9.0 Hz, 2H), 7.34-7.33 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.08-7.07 (m, 1H), 6.91 (d, J= 9.0 Hz, 2H), 6.87-6.86 (m, 1H), 6.74 (brs, 1H), 6.71 (d, J = 3.6 Hz, 1H), 6.55 (d, J = 3.6 Hz, 1H), 5.99 (s, 1H), 5.03 (s, 2H), 4.17-4.15 (m, 2H), 4.07-4.04 (m, 3H), 3.80 (s, 4H); LC-MS 502 (MH+) ¹ H NMR (600 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.53 (s, 1H), 7.37 (d, J = 9.0 Hz, 2H), 7.34-7.33 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.08- 7.07 (m, 1H), 6.91 (d, J = 9.0 Hz, 2H), 6.87-6.86 (m, 1H), 6.74 (brs, 1H), 6.71 (d, J = 3.6 Hz, 1H), 6.55 (d , J = 3.6 Hz, 1H), 5.99 (s, 1H), 5.03 (s, 2H), 4.17-4.15 (m, 2H), 4.07-4.04 (m, 3H), 3.80 (s, 4H); LC-MS 502 (MH +)

[제조예 19-3] 5-(4-(3-(4-메톡시벤질옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)퓨란-2-카브알데하이드 (5-(4-(3-(4-methoxybenzyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)furan-2-carbaldehyde) 의 제조Production Example 19-3 5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) furan-2-carbaldehyde ( Preparation of 5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) furan-2-carbaldehyde)

¹H NMR (400MHz, DMSO-d₆); δ 9.80 (brs, 1H), 9.67 (s, 1H), 8.63 (s, 1H), 7.74 (d, J=4.0 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 4.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.38-7.36 (m, 1H), 7.28 (t, J = 8.0 HZ, 1H), 6.95 (d, J= 8.4 Hz, 2H), 6.79-6.78 (m, 1H), 5.03 (s, 2H), 3.75 (s, 3H); LC-MS 458 (MH+) ¹ H NMR (400 MHz, DMSO-d ₆ ); δ 9.80 (brs, 1H), 9.67 (s, 1H), 8.63 (s, 1H), 7.74 (d, J = 4.0 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 4.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.38-7.36 (m, 1H), 7.28 (t, J = 8.0 HZ, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.79- 6.78 (m, 1 H), 5.03 (s, 2 H), 3.75 (s, 3 H); LC-MS 458 (MH +)

[제조예 20][Production Example 20]

[제조예 20-1] 2-(5-브로모사이오펜-3-일)-1,3-다이옥솔레인 (2-(5-bromothiophen-3-yl)-1,3-dioxolane) 의 제조Preparation Example 20-1 Preparation of 2- (5-bromothiophen-3-yl) -1,3-dioxolane (2- (5-bromothiophen-3-yl) -1,3-dioxolane)

¹H-NMR (400 MHz, CDCl₃); δ 7.29 (d, J = 1.6 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 5.80 (s, 1H), 4.07-4.06 (m, 2H), 4.01-3.99 (m, 2H) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 7.29 (d, J = 1.6 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 5.80 (s, 1H), 4.07-4.06 (m, 2H), 4.01-3.99 (m, 2H)

[제조예 20-2] 6-(4-(1,3-다이옥솔레인-2-일)사이오펜-2-일)-N-(3-(4-메톡시벤질옥시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (6-(4-(1,3-dioxolan-2-yl)thiophen-2-yl)-N-(3-(4-methoxybenzyloxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조Production Example 20-2 6- (4- (1,3-dioxolane-2-yl) thiophen-2-yl) -N- (3- (4-methoxybenzyloxy) phenyl) No [3,2-d] pyrimidin-4-amine (6- (4- (1,3-dioxolan-2-yl) thiophen-2-yl) -N- (3- (4-methoxybenzyloxy) phenyl) Preparation of thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.68 (s, 1H), 7.45 (d, J = 4.4 Hz, 2H), 7.38 (m, 3H), 7.32 (s, 2H), 7.08 (d, J = 8.8 Hz, 1H), 6.87 (m, 4H); LC-MS 518 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.68 (s, 1H), 7.45 (d, J = 4.4 Hz, 2H), 7.38 (m, 3H), 7.32 (s, 2H), 7.08 (d, J = 8.8 Hz, 1H), 6.87 (m, 4H); LC-MS 518 (MH +)

[제조예 20-3] 5-(4-(3-(4-메톡시벤질옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)사이오펜-3-카브알데하이드 (5-(4-(3-(4-methoxybenzyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)thiophene-3-carbaldehyde) 의 제조Production Example 20-3 5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) thiophen-3-carbaldehyde Preparation of (5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) thiophene-3-carbaldehyde)

¹H-NMR (400 MHz, CDCl₃); δ 9.97 (s, 1H), 9.81 (s, 1H), 8.62 (s, 1H), 8.12 (d, J = 4.0 Hz, 1H), 8.00 (s, 1H), 7.86 (d, J = 4.0 Hz, 1H), 7.59 (s, 1H), 7.41 (d, J = 5.6 Hz, 2H), 7.30 (m, 1H), 7.27 (m, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.80 (m, 1H), 5.03 (s, 2H), 3.79 (s, 3H); LC-MS 474 (M+H+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 9.97 (s, 1H), 9.81 (s, 1H), 8.62 (s, 1H), 8.12 (d, J = 4.0 Hz, 1H), 8.00 (s, 1H), 7.86 (d, J = 4.0 Hz, 1H), 7.59 (s, 1H), 7.41 (d, J = 5.6 Hz, 2H), 7.30 (m, 1H), 7.27 (m, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.80 ( m, 1H), 5.03 (s, 2H), 3.79 (s, 3H); LC-MS 474 (M + H +)

[제조예 21][Production Example 21]

[제조예 21-1] 2-(5-브로모퓨란-3-일)-1,3-다이옥솔레인 (2-(5-bromofuran-3-yl)-1,3-dioxolane) 의 제조Preparation Example 21-1 Preparation of 2- (5-bromofuran-3-yl) -1,3-dioxolane (2- (5-bromofuran-3-yl) -1,3-dioxolane)

¹H-NMR (400 MHz, CDCl₃); δ 7.52(s, 1H), 6.39(s, 1H), 5.79(s, 1H), 4.11-4.04(m, 2H), 3.93-3.86(m, 2H) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 7.52 (s, 1H), 6.39 (s, 1H), 5.79 (s, 1H), 4.11-4.04 (m, 2H), 3.93-3.86 (m, 2H)

[제조예 21-2] 6-(4-(1,3-다이옥솔레인-2-일)퓨란-2-일)-N-(3-(4-메톡시벤질옥시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (6-(4-(1,3-dioxolan-2-yl)furan-2-yl)-N-(3-(4-methoxybenzyloxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조Production Example 21-2 6- (4- (1,3-dioxolane-2-yl) furan-2-yl) -N- (3- (4-methoxybenzyloxy) phenyl) cyeno [3,2-d] pyrimidin-4-amine (6- (4- (1,3-dioxolan-2-yl) furan-2-yl) -N- (3- (4-methoxybenzyloxy) phenyl) thieno Preparation of [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.66 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.37-7.26 (m, 6H), 7.08(d, J = 7.2Hz, 1H), 6.88 (m, 2H), 6.80 (s, 1H), 5.01 (s, 2H), 4.12-3.98 (m, 4H), 3.76 (s, 1H); LC-MS 502(MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.66 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.37-7.26 (m, 6H), 7.08 (d, J = 7.2 Hz, 1H), 6.88 (m, 2H), 6.80 (s, 1 H), 5.01 (s, 2 H), 4.12-3.98 (m, 4 H), 3.76 (s, 1 H); LC-MS 502 (MH +)

[제조예 21-3] 5-(4-(3-(4-메톡시벤질옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)퓨란-3-카브알데하이드 (5-(4-(3-(4-methoxybenzyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)furan-3-carbaldehyde) 의 제조Production Example 21-3 5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) furan-3-carbaldehyde ( Preparation of 5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) furan-3-carbaldehyde)

¹H-NMR (400 MHz, CDCl₃); δ 9.97 (s, 1H), 8.70 (s, 1H), 8.13 (s, 1H), 7.61 (s, 1H), 7.38-7.26 (m, 4H), 7.08 (m, 2H), 6.91 (m, 2H), 5.04 (s, 2H), 3.80 (s, 3H); LC MS 458 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 9.97 (s, 1H), 8.70 (s, 1H), 8.13 (s, 1H), 7.61 (s, 1H), 7.38-7.26 (m, 4H), 7.08 (m, 2H), 6.91 (m, 2H ), 5.04 (s, 2 H), 3.80 (s, 3 H); LC MS 458 (MH +)

[제조예 22] [Production Example 22]

[제조예 22-1] 사이오펜-3-아민 (thiophen-3-amine) 의 제조Production Example 22-1 Preparation of Thiophen-3-amine

메틸 3-아미노-2-사이오펜카르복실레이트 10 g (63.61mmol)을 60 ml 2N-소디움히드록사이드에 녹여 2시간 동안 환류교반 하였다. 반응용액을 0 ℃로 낮춘 다음 염산을 사용하여 pH 5로 맞추었다. 이때 생성된 베이지색 고체를 물로 씻어주고 acetone 40 ml에 녹인 후 황산 마그네슘으로 건조하였다. 여과후 감압 농축하고 50 ml 아이소프로필알코올과 옥살산 (6.3 g, 69.28 mmol)을 넣고 38 ℃에서 45분간 교반하였다. 반응혼합물을 0 ℃로 내리고 다이에틸에테르를 첨가한 뒤 생성된 침전물을 여과한 뒤 다이에틸에테르를 이용하여 씻어 주어 표제화합물 (2.54 g, 40.3 %)을 얻었다.10 g (63.61 mmol) of methyl 3-amino-2-thiophencarboxylate were dissolved in 60 ml 2N-sodium hydroxide and stirred under reflux for 2 hours. The reaction solution was lowered to 0 ° C. and then adjusted to pH 5 using hydrochloric acid. The beige solid produced was washed with water, dissolved in 40 ml of acetone, and dried over magnesium sulfate. After filtration and concentration under reduced pressure, 50 ml of isopropyl alcohol and oxalic acid (6.3 g, 69.28 mmol) were added thereto, and the mixture was stirred at 38 ° C. for 45 minutes. The reaction mixture was lowered to 0 ° C., diethyl ether was added, and the resulting precipitate was filtered and washed with diethyl ether to obtain the title compound (2.54 g, 40.3%).

¹H-NMR (400 MHz, CDCl₃); δ 7.13-7.11 (m, 1H), 6.65-6.63 (m,1H), 6.17-6.16 (m, 1H), 3.60 (brs, 2H) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 7.13-7.11 (m, 1H), 6.65-6.63 (m, 1H), 6.17-6.16 (m, 1H), 3.60 (brs, 2H)

[제조예 22-2] 4H-싸이에노[3,2-b]피리딘-7-온 (4H-Thieno[3,2-b]pyridine-7-one) 의 제조Preparation Example 22-2 Preparation of 4H-thieno [3,2-b] pyridin-7-one (4H-Thieno [3,2-b] pyridine-7-one)

다이메틸-[1,3]다이옥산-4,6-다이온 (4.61 g, 32.01 mmol)에 트리메틸올소포메이트 (14 ml, 128.07 mmol)을 넣고 30 ℃에서 1시간 정도 교반하였다. 반응물에 사이오펜-3-아민 (2.54 g, 25.61 mmol)을 실온에서 소량씩 첨가하면 백색의 침전물 이 생긴다. 이 반응혼합물을 85 ℃에서 15시간 교반 후, 실온으로 온도를 내리고 25 ml의 이소프르필 에테르를 첨가 한 뒤 실온에서 1시간 교반하였다. 이때 생성된 자주색 고체(중간체)는 아이소프로필 에테르를 이용하여 씻어주었다. 중간체를 다이클로로메테인과 탄산칼륨에 녹이고 30분간 교반시켰다. 고체는 여과하여 제거하고 용액을 농축하여 2,2-다이메틸-5-(사이오펜-3-일아미노에틸렌)-[1,3]다이오산-4,6-다이온을 얻었다. 259 ℃의 다이페닐 에테르 5 ml에 2,2-다이메틸-5-(사이오펜-3-일아미노에틸렌)-[1,3]다이오산-4,6-다이온을 소량씩 넣은 후 30분간 환류교반 하였다. 반응액을 실온으로 낮춘 후, 아이소프로필 에테르를 첨가한 뒤 1시간 교반하여 표제화합물을 옅은 갈색 고체 (2 g, 53 %)로 수득하였다. Trimethylol phosphomate (14 ml, 128.07 mmol) was added to dimethyl- [1,3] dioxane-4,6-dione (4.61 g, 32.01 mmol) and stirred at 30 ° C. for about 1 hour. A small amount of thiophen-3-amine (2.54 g, 25.61 mmol) is added to the reaction at room temperature to form a white precipitate. The reaction mixture was stirred at 85 ° C. for 15 hours, then cooled to room temperature, 25 ml of isopropyl ether was added, and stirred at room temperature for 1 hour. The produced purple solid (intermediate) was washed with isopropyl ether. The intermediate was dissolved in dichloromethane and potassium carbonate and stirred for 30 minutes. The solid was removed by filtration and the solution was concentrated to give 2,2-dimethyl-5- (thiophen-3-ylaminoethylene)-[1,3] dioic acid-4,6-dione. 30 ml of 2,2-dimethyl-5- (thiophen-3-ylaminoethylene)-[1,3] dioic acid-4,6-dione was added to 5 ml of diphenyl ether at 259 ° C. The reflux was stirred. After the reaction solution was cooled to room temperature, isopropyl ether was added, followed by stirring for 1 hour, thereby obtaining the title compound as a pale brown solid (2 g, 53%).

¹H-NMR (600MHz, DMSO-d₆); δ 12.15 (brs, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 10.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 6.01 (d, J = 10.8 Hz, 1H); LC-MS: 152 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 12.15 (brs, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 10.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 6.01 (d, J = 10.8 Hz, 1H); LC-MS: 152 (MH < + >)

[제조예 22-3] 7-클로로-싸이에노[3,2-b]피리딘 (7-chloro-thieno[3,2-b]pyridine) 의 제조Preparation Example 22-3 Preparation of 7-chloro-thieno [3,2-b] pyridine (7-chloro-thieno [3,2-b] pyridine)

250 ml 둥근 플라스트에 30 ml의 다클로로메테인과 20 ml의 디클로로에테인, 디메틸포름아미드(1.8 ml, 23.28 mmol)을 넣고 0 ℃ 에서 옥살릴클로라이드 (2.9 ml, 33.86 mmol)를 서서히 적가한 뒤, 4H-싸이에노[3,2-b]피리딘-7-온 (1.6 g, 10.58 mmol)을 첨가하고 6시간 동안 환류교반 하였다. 실온으로 온도를 내리면서 표제 화합물을 노란색 고체 (1.7 g, 90 %)로 얻었다. 30 ml of dichloromethane, 20 ml of dichloroethane and dimethylformamide (1.8 ml, 23.28 mmol) were added to a 250 ml round flask, and oxalyl chloride (2.9 ml, 33.86 mmol) was slowly added dropwise at 0 ° C. , 4H-thieno [3,2-b] pyridin-7-one (1.6 g, 10.58 mmol) was added and stirred under reflux for 6 hours. The title compound was obtained as a yellow solid (1.7 g, 90%) while lowering the temperature to room temperature.

¹H-NMR (400 MHz, CDCl₃); δ 8.61 (d, J = 5.2 Hz, 1H), 7.81 (d, J = 5.2 Hz, 1H), 7.30 (d, J = 4.8 Hz, 1H) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.61 (d, J = 5.2 Hz, 1H), 7.81 (d, J = 5.2 Hz, 1H), 7.30 (d, J = 4.8 Hz, 1H)

[제조예 22-4] 2-브로모-7-클로로싸이에노[3,2-b]피리딘 (2-bromo-7-chlorothieno[3,2-b]pyridine) 의 제조Preparation Example 22-4 Preparation of 2-bromo-7-chlorothieno [3,2-b] pyridine (2-bromo-7-chlorothieno [3,2-b] pyridine)

20 ml의 테트라히드로퓨란과 정제된 다이아이소프로필아민 (0.93 ml, 6.63 mmol)을 250 ml 둥근 플라스트에 넣은 후, 질소로 충전하고, -78 ℃ 에서 n-부틸리튬 (2.45 ml, 6.12 mmol)을 적가한 뒤 10분간 0 ℃에서 교반하고 이를 다시 -78 ℃로 내린 후, 10 ml 테트라히드로퓨란에 녹인 7-클로로-싸이에노[3,2-b]피리딘 (0.87 g, 5.1 mmol)을 캐뉼러(cannular)를 이용하여 첨가하였다. 반응혼합물을 10분간 교반 후 1,2-다이브로로-1,1,2,2-테트라플루오로메테인(2 g, 6.12 mmol)을 첨가하고 30분간 교반 후, 실온으로 서서히 온도를 올려준다. 1시간 후 반응 혼합물에 물을 붓고 에틸아세테이트로 추출하고 (30 ml x 2)로 추출하였다. 황산 마그네슘으로 건조하고 여과후 감압 농축하고, 관크로마토그래피 (n-헥세인/에틸아세테이트, 1/40) 를 시행하여 표제화합물 (1.12mg, 88 %)을 수득하였다. 20 ml of tetrahydrofuran and purified diisopropylamine (0.93 ml, 6.63 mmol) are placed in a 250 ml round flask, filled with nitrogen and n-butyllithium (2.45 ml, 6.12 mmol) at -78 ° C. Was added dropwise and stirred at 0 ° C. for 10 minutes and then lowered to −78 ° C., and then 7-chloro-thieno [3,2-b] pyridine (0.87 g, 5.1 mmol) dissolved in 10 ml tetrahydrofuran was added. It was added using a cannular. After stirring the reaction mixture for 10 minutes, 1,2-dibro-1,1,2,2-tetrafluoromethane (2 g, 6.12 mmol) is added, and after 30 minutes of stirring, the temperature is gradually raised to room temperature. . After 1 hour, water was added to the reaction mixture, followed by extraction with ethyl acetate (30 ml x 2). After drying over magnesium sulfate, filtration and concentration under reduced pressure, column chromatography (n-hexane / ethyl acetate, 1/40) was carried out to obtain the title compound (1.12 mg, 88%).

¹H-NMR (600MHz, DMSO-d₆); δ 8.64 (d, J = 5.2 Hz, 1H), 7.94 (s, 1H), 7.61 (d, J = 5.2 Hz, 1H) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 8.64 (d, J = 5.2 Hz, 1H), 7.94 (s, 1H), 7.61 (d, J = 5.2 Hz, 1H)

[제조예 23] 2-브로로-N-(3-(4-메톡시벤질옥시)페닐)싸이에노[3,2-b]피리딘-7-아민 (2-bromo-N-(3-(4-methoxybenzyloxy)phenyl)thieno[3,2-b]pyridin-7-amine) 의 제조Production Example 23 2-Bro-N- (3- (4-methoxybenzyloxy) phenyl) thieno [3,2-b] pyridin-7-amine (2-bromo-N- (3- Preparation of (4-methoxybenzyloxy) phenyl) thieno [3,2-b] pyridin-7-amine)

제조예 1에서 얻은 화합물 (0.18 g, 0.80 mmol)에 다이클로에테인 3 ml와 t-부탄올 3 ml에 녹여 sealed tube에 넣고 제조예 22-4에서 합성한 화합물 (198 mg, 0.80 mmol)을 첨가한 다음 85 ℃에서 3일간 교반하였다. 실온으로 냉각 후 생성된 옅은 갈색 고체를 다이에틸에테르를 이용하여 씻어주어 표제화합물 (0.25 g, 80%)을 잿빛의 고체로 수득하였다. To compound (0.18 g, 0.80 mmol) obtained in Preparation Example 1, 3 ml of dicloethane and 3 ml of t-butanol were dissolved in a sealed tube, and the compound (198 mg, 0.80 mmol) synthesized in Preparation Example 22-4 was added. Then stirred at 85 ° C. for 3 days. The pale brown solid produced after cooling to room temperature was washed with diethyl ether to give the title compound (0.25 g, 80%) as a gray solid.

¹H-NMR (400 MHz, CDCl₃); δ 8.32 (d, J = 5.2 Hz, 1H), 7.50 (s, 1H), 7.34 (d, J = 7.6 Hz, 2H), 7.29 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 7.6 Hz, 2H), 6.83-6.80 (m, 4H), 5.00 (s, 2H), 3.82 (s, 3H) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.32 (d, J = 5.2 Hz, 1H), 7.50 (s, 1H), 7.34 (d, J = 7.6 Hz, 2H), 7.29 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 7.6 Hz, 2H), 6.83-6.80 (m, 4H), 5.00 (s, 2H), 3.82 (s, 3H)

[제조예 24] 4-(7-(3-(4-메톡시벤질옥시)페닐아미노)싸이에노[3,2-b]피리딘-2-일)벤즈알데하이드 (4-(7-(3-(4-methoxybenzyloxy)phenylamino)thieno[3,2-b]pyridin-2-yl)benzaldehyde) 의 제조Production Example 24 4- (7- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-b] pyridin-2-yl) benzaldehyde (4- (7- (3 Preparation of-(4-methoxybenzyloxy) phenylamino) thieno [3,2-b] pyridin-2-yl) benzaldehyde)

제조예 22에서 얻은 화합물 (0.5 g, 0.89 mmol)와 4-포밀페닐보론산 (0.16 g, 1.06 mmol), PdCl2(dppf)2 (21 mg, 0.03 mmol)을 반응 용기에 넣고 질소로 충진 후, 탈기체화된 다이메틸포름아마이드 5 ml와 2N 탄산나트륨 (0.9 ml, 1.78 mmol)을 넣고 80 ℃에서 15시간 동안 교반하였다. 반응액에 다이클로로메테인 50 ml와 포화된 염화암모늄 수용액 50 ml을 넣고 추출하였다. 유기층을 포화된 염화암모늄 수용액 50mL로 2회 더 추출한 후 무수 황산나트륨을 이용하여 건조하고 감압농축 후 다이에틸에테르 10 ml로 트리터레이션(trituration)하여 표제화합물을 320mg (0.69mmol, 77%)의 갈색 고체로 얻었다. Compound (0.5 g, 0.89 mmol), 4-formylphenylboronic acid (0.16 g, 1.06 mmol) and PdCl2 (dppf) 2 (21 mg, 0.03 mmol) obtained in Preparation Example 22 were charged to a reaction vessel, and charged with nitrogen. 5 ml of degassed dimethylformamide and 2N sodium carbonate (0.9 ml, 1.78 mmol) were added and stirred at 80 ° C. for 15 hours. 50 ml of dichloromethane and 50 ml of saturated aqueous ammonium chloride solution were added to the reaction mixture, and extracted. The organic layer was extracted two more times with 50 mL of saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure and triturated with 10 ml of diethyl ether to give 320 mg (0.69 mmol, 77%) of the title compound as brown. Obtained as a solid.

¹H-NMR (400 MHz, CDCl₃); δ 10.06 (s, 1H), 8.39 (d, J =3.6Hz, 1H), 7.96 (d, J =5.2Hz, 2H), 7.89-7.7.86 (m, 3H), 7.35 (d, J =5.6Hz, 2H), 7.31 (t, J =5.2Hz, 1H), 6.94-6.90 (m, 4H), 6.86 (d, J =5.2Hz, 1H), 6.82 (d, J =5.2Hz, 1H), 6.09 (s, 1H), 5.01 (s, 2H), 3.82 (s, 3H); LC-MS 467.0 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 10.06 (s, 1H), 8.39 (d, J = 3.6 Hz, 1H), 7.96 (d, J = 5.2 Hz, 2H), 7.89-7.7.86 (m, 3H), 7.35 (d, J = 5.6 Hz, 2H), 7.31 (t, J = 5.2 Hz, 1H), 6.94-6.90 (m, 4H), 6.86 (d, J = 5.2 Hz, 1H), 6.82 (d, J = 5.2 Hz, 1H), 6.09 (s, 1 H), 5.01 (s, 2 H), 3.82 (s, 3 H); LC-MS 467.0 (MH +)

[제조예 25] 3-(7-(3-(4-메톡시벤질옥시)페닐아미노)싸이에노[3,2-b]피리딘-2-일)벤즈알데하이드 (3-(7-(3-(4-methoxybenzyloxy)phenylamino)thieno[3,2-b]pyridin-2-yl)benzaldehyde) 의 제조Production Example 25 3- (7- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-b] pyridin-2-yl) benzaldehyde (3- (7- (3 Preparation of-(4-methoxybenzyloxy) phenylamino) thieno [3,2-b] pyridin-2-yl) benzaldehyde)

제조예 23에서 얻은 화합물 (6.69 g, 15.63 mmol)와 3-포밀페닐보론산 (2.7 g, 18.76 mmol), PdCl2(dppf)2 (388 mg, 0.46 mmol)을 반응 용기에 넣고 질소로 충진 후, 탈기체화된 다이메틸포름아마이드 70 ml와 2N 탄산나트륨 (23 ml, 46.89 mmol)을 넣고 80 ℃에서 15시간 동안 교반하였다. 반응액에 다이클로로메테인 250 ml와 포화된 염화암모늄 수용액 250 ml을 넣고 추출하였다. 유기층을 포화된 염화암모늄 수용액 150mL로 2회 더 추출한 후 무수 황산나트륨을 이용하여 건조하고 감압농축 후 다이에틸에테르 10 ml로 트리터레이션(trituration)하여 표제화합물 (2.5 g, 36 %)을 갈색 고체로 얻었다. Compound (6.69 g, 15.63 mmol), 3-formylphenylboronic acid (2.7 g, 18.76 mmol) and PdCl 2 (dppf) 2 (388 mg, 0.46 mmol) obtained in Preparation Example 23 were placed in a reaction vessel, and charged with nitrogen. 70 ml of degassed dimethylformamide and 2N sodium carbonate (23 ml, 46.89 mmol) were added and stirred at 80 ° C. for 15 hours. 250 ml of dichloromethane and 250 ml of saturated aqueous ammonium chloride solution were added to the reaction mixture, and extracted. The organic layer was extracted two more times with 150 mL of saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure and triturated with 10 ml of diethyl ether to give the title compound (2.5 g, 36%) as a brown solid. Got it.

¹H-NMR (600MHz, DMSO-d₆); δ 10.11 (s, 1H), 8.92 (s, 1H), 8.32-8.31 (m, 2H), 8.19 (d, J=8.4Hz, 1H), 7.97 (s, 1H), 7.76 (d, J =7.8Hz, 1H), 7.75 (t, J =7.8Hz, 1H), 7.64-7.60 (m, 1H), 7.57-7.54 (m, 1H), 7.38 (d, J =8.4Hz, 2H), 6.95 (d, J =8.4Hz, 2H), 6.90-6.87 (m, 2H), 6.77 (dd, J =1.8Hz, 7.8Hz, 1H), 5.04 (s, 2H), 3.76 (s, 3H); LC-MS 467 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 10.11 (s, 1H), 8.92 (s, 1H), 8.32-8.31 (m, 2H), 8.19 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.64-7.60 (m, 1H), 7.57-7.54 (m, 1H), 7.38 (d, J = 8.4 Hz, 2H), 6.95 (d , J = 8.4 Hz, 2H), 6.90-6.87 (m, 2H), 6.77 (dd, J = 1.8 Hz, 7.8 Hz, 1H), 5.04 (s, 2H), 3.76 (s, 3H); LC-MS 467 (MH +)

[제조예 26]Production Example 26

[제조예 26-1] 메틸 2-(4-브로모페닐)아세테이트 (methyl 2-(4-bromophenyl)acetate) 의 제조Preparation Example 26-1 Preparation of Methyl 2- (4-bromophenyl) acetate

4-브로모페닐아세트산 (2g, 9.3 mmol)에 아세토나이트릴 20 ml를 넣고 0 ℃하에서 1,8-다이아자바이사이클로[5.4.0]운덱-2-엔 (1.7 g, 11.2 mmol)을 넣었다. 반응액에 아이오도 메테인 (1.98 g, 14.0 mmol)을 천천히 적가한 뒤 실온에서 2시간 동안 교반하였다. 반응완료 후 물(100 ml×2)과 다이클로로메테인 (100 ml)을 이용하여 추출하고 관크로마토그래피 (에틸아세테이트/n-헥세인, 1/15)를 이용하여 표제화합물 (1.7 g, 75 %)을 얻었다. 20 ml of acetonitrile were added to 4-bromophenylacetic acid (2 g, 9.3 mmol), and 1,8-diazabicyclo [5.4.0] undec-2-ene (1.7 g, 11.2 mmol) was added at 0 ° C. Iodine methane (1.98 g, 14.0 mmol) was slowly added dropwise to the reaction solution, followed by stirring at room temperature for 2 hours. After completion of the reaction, the mixture was extracted using water (100 ml × 2) and dichloromethane (100 ml), and the title compound (1.7 g, 75) was purified by column chromatography (ethyl acetate / n-hexane, 1/15). %) Was obtained.

¹H-NMR (600MHz, CDCl₃); δ 7.45 (d, J =12.6Hz, 2H), 7.15 (d, J =12.6Hz, 2H), 3.69 (s, 3H), 3.58 (2H), ¹ H-NMR (600 MHz, CDCl ₃ ); δ 7.45 (d, J = 12.6 Hz, 2H), 7.15 (d, J = 12.6 Hz, 2H), 3.69 (s, 3H), 3.58 (2H),

[제조예 26-2] 메틸 2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)아세테이트 (methyl 2-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)phenyl)acetate) 의 제조Preparation Example 26-2 Methyl 2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) acetate (methyl 2- (4 Preparation of-(4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) acetate)

비스(피나콜레이토)다이보레인 (1.95g, 7.68 mmol), PdCl2dppf (171 mg, 0.21 mmol), 포타슘아세테이트 (2.06 g, 7.68 mmol)을 반응용기에 넣고 진공건조하였다. 탈기체화된 다이메틸포름아마이드 5 ml에 제조예 18-1에서 합성한 화합물 (1.6 g, 7.0 mmol)을 녹여 반응용기에 옮긴 후 85 ℃에서 15시간 교반하였다. 반응액을 실온으로 냉각 하고 에틸아세테이트 50 ml와 포화된 염화암모늄 50 ml을 넣고 추출하였다. 유기층을 염화암모늄 50 ml로 2회 더 씻어준 후 무수 황산마그네슘을 이용하여 건조하고 감압농축하여 짙은 갈색 오일형태의 메틸 2-(4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤레인-2-일)페닐)아세테이트 (methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate)을 얻었다. 이 화합물과 제조예 5-2에서 합성한 화합물(1.8 g, 4.23 mmol), PdCl2dppf (80 mg, 0.10 mmol)을 탈기체화된 다이메틸포름아마이드 20 ml에 순차적으로 투입하고 2N 탄산나트륨 수용액 (2 ml, 6.52 mmol)을 투입하였다. 80 ℃에서 15시간 동안 교반 한 후 실온으로 냉각하고 에틸아세테이트 100 ml와 포화된 염화암모늄 100 ml로 추출하였다. 유기층을 포화된 염화암모늄 100 ml로 2회 더 씻어준 후 무수 황산 마그네슘을 이용해 건조하고 감압농축 후 관크로마토그래피(에틸아세테이트/헥세인, 1/2) 표제화합물(A) (0.51 g, 40 %)을 얻었다.Bis (pinacolato) diborane (1.95 g, 7.68 mmol), PdCl 2 dppf (171 mg, 0.21 mmol) and potassium acetate (2.06 g, 7.68 mmol) were added to the reaction vessel and vacuum dried. The compound (1.6 g, 7.0 mmol) synthesized in Preparation Example 18-1 was dissolved in 5 ml of degassed dimethylformamide, and then transferred to a reaction vessel. The mixture was stirred at 85 ° C. for 15 hours. The reaction solution was cooled to room temperature, 50 ml of ethyl acetate and 50 ml of saturated ammonium chloride were added and extracted. The organic layer was washed twice more with 50 ml of ammonium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain methyl 2- (4- (4,4,5,5-tetramethyl-1,3) as a dark brown oil. , 2-dioxaborole-2-yl) phenyl) acetate (methyl 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) acetate) Got it. This compound and the compound (1.8 g, 4.23 mmol) and PdCl2dppf (80 mg, 0.10 mmol) synthesized in Preparation Example 5-2 were sequentially added to 20 ml of degassed dimethylformamide, and an aqueous 2N sodium carbonate solution (2 ml, 6.52 mmol) was added. After stirring for 15 hours at 80 ℃ cooled to room temperature and extracted with 100 ml of ethyl acetate and 100 ml of saturated ammonium chloride. The organic layer was washed two more times with 100 ml of saturated ammonium chloride, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified by column chromatography (ethyl acetate / hexane, 1/2). The title compound (A) (0.51 g, 40% )

¹H-NMR (400MHz, DMSO-d₆); δ 9.61(brs, 1H), 9.43 (brs, 1H), 8.58 (s, 1H), 7.88 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.33-7.30 (m, 1H), 7.20-7.12 (m, 2H), 6.54-6.52 (m, 1H), 3.78 (s, 2H), 3.64 (s, 3H); LC-MS: 392 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.61 (brs, 1H), 9.43 (brs, 1H), 8.58 (s, 1H), 7.88 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.33-7.30 (m, 1H), 7.20-7.12 (m, 2H), 6.54-6.52 (m, 1H), 3.78 (s, 2H), 3.64 (s, 3H); LC-MS: 392 (MH < + >)

[제조예 27] methyl 2-(4-(4-(3-(터트-부틸다이메틸실릴옥시)페닐아미노)싸이에 노[3,2-d]피리미딘-6-일)페닐)아세테이트 (methyl 2-(4-(4-(3-(tert-butyldimethylsilyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)phenyl)acetate) 의 제조Production Example 27 methyl 2- (4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) cyeno [3,2-d] pyrimidin-6-yl) phenyl) acetate ( Preparation of methyl 2- (4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) acetate)

상시 제조예 26-2 에서 합성한 화합물 (0.51 g, 1.30 mmol)을 10 ml 다이클로로메테인과 5 ml 다이메틸포름아마이드에 녹인 후 이미다졸 (0.11 g, 1.69 mmol)과 tert-부틸클로로다이메틸실레인 (0.24 mg, 1.56 mmol)을 넣고 실온에서 10시간 교반하였다. 포화 암모늄 클로라이드 용액 (100 ml)에 반응 용액을 부은 후 에틸 아세테이트 (100 ml × 2)로 추출 한 후 유기층을 물 (100 ml × 2)로 씻어 주고 무수 황산 나트륨으로 건조하였다. 감압 농축 후 관크로마토그래피 (에틸아세테이트/n-헥세인, 1:2)로 분리하여 표제화합물 (0.49 g, 74.4 %)을 노란색 고체로 수득하였다.The compound synthesized in Preparation Example 26-2 (0.51 g, 1.30 mmol) was dissolved in 10 ml dichloromethane and 5 ml dimethylformamide, and then imidazole (0.11 g, 1.69 mmol) and tert-butylchlorodimethyl Silane (0.24 mg, 1.56 mmol) was added thereto, followed by stirring at room temperature for 10 hours. The reaction solution was poured into saturated ammonium chloride solution (100 ml), extracted with ethyl acetate (100 ml × 2), the organic layer was washed with water (100 ml × 2) and dried over anhydrous sodium sulfate. Concentration under reduced pressure and separation by column chromatography (ethyl acetate / n-hexane, 1: 2) gave the title compound (0.49 g, 74.4%) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃); δ 8.69 (s, 1H), 7.64 (d, J= 8.0 Hz, 2H), 7.59 (s, 1H), 7.36 (d, J= 8.0 Hz, 2H), 7.28-7.24 (m, 1H), 6.76 (brs, 1H), 7.19 (t, J= 2.2 Hz, 1H), 7.16-7.16 (m, 1H), 6.76 (brs, 1H), 6.75-6.74 (m, 1H), 3.68 (s, 2H), 1.00 (s, H), 0.24 (s, 6H) ; LC-MS: 506 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.28-7.24 (m, 1H), 6.76 ( brs, 1H), 7.19 (t, J = 2.2 Hz, 1H), 7.16-7.16 (m, 1H), 6.76 (brs, 1H), 6.75-6.74 (m, 1H), 3.68 (s, 2H), 1.00 (s, H), 0.24 (s, 6H); LC-MS: 506 (MH < + >)

[제조예 28] 4-(4-(3-(터트-부틸다이메틸실릴옥시)페닐아미노)싸이에노[3,2-d]피리 미딘-6-일)벤조산 (4-(4-(3-(tert-butyldimethylsilyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)benzoic acid) 의 제조Production Example 28 4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzoic acid (4- (4- ( Preparation of 3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzoic acid)

제조예 6에서 합성한 화합물 (0.2 g, 0.46 mmol)을 2 ml 아세톤에 녹인 후 물 0.4 ml와 아세톤2.5 ml에 녹인 포타슘 퍼망가네이트 (130 mg, 0.82 mmol)를 첨가한 다음 실온에서 3시간 교반하였다. 2N 염산 20 ml와 에틸 아세테이트 30 ml로 추출하고 물 30 ml로 두 번 더 씻었다. 황산나트륨으로 건조, 여과 후 감압농축하여 표제화합물 (0.2 g, 96 %)을 노란색 고체로 얻었다. Compound (0.2 g, 0.46 mmol) synthesized in Preparation Example 6 was dissolved in 2 ml of acetone, followed by addition of potassium permanganate (130 mg, 0.82 mmol) dissolved in 0.4 ml of water and 2.5 ml of acetone, followed by stirring at room temperature for 3 hours. It was. Extract with 20 ml of 2N hydrochloric acid and 30 ml of ethyl acetate and wash twice more with 30 ml of water. Drying with sodium sulfate, filtration and concentration under reduced pressure gave the title compound (0.2 g, 96%) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃); δ 10.44 (brs, 1H), 8.78 (s, 1H), 8.12 (t, J= 7.6 Hz, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.69-7.59 (m, 3H), 7.48 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.33 (t, J = 8.0 Hz, 1H), 6.74 (d, J= 8.4 Hz, 1H), 1.01 (s, 9H), 0.28 (s, 6H); LC-MS: 478 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 10.44 (brs, 1H), 8.78 (s, 1H), 8.12 (t, J = 7.6 Hz, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.69-7.59 (m, 3H), 7.48 ( d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.33 (t, J = 8.0 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 1.01 (s, 9H), 0.28 ( s, 6H); LC-MS: 478 (MH < + >)

[제조예 29] 2-(4-(4-(3-(터트-부틸다이메틸실릴옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)아세트산 (2-(4-(4-(3-(tert-butyldimethylsilyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)phenyl)acetic acid) 의 제조Production Example 29 2- (4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) acetic acid (2 Preparation of-(4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) acetic acid)

¹H-NMR (400 MHz, CDCl₃); δ 10.44 (br, 1H), 8.78 (s, 1H), 8.12 (t, J =7.6Hz, 1H), 8.05 (d, J =8.0Hz, 2H), 7.69-7.59 (m, 2H), 7.48 (d, J =8.0Hz, 1H), 7.43 (s, 1H), 7.33 (t, J =8.0Hz, 1H), 6.74 (d, J =8.4Hz, 1H), 3.60 (s, 2H), 1.01 (s, 9H), 0.28 (s, 6H); LC-MS 478 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 10.44 (br, 1H), 8.78 (s, 1H), 8.12 (t, J = 7.6 Hz, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.69-7.59 (m, 2H), 7.48 ( d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.33 (t, J = 8.0 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 3.60 (s, 2H), 1.01 ( s, 9H), 0.28 (s, 6H); LC-MS 478 (MH +)

[제조예 30] 1-브로모-4-(에톡시메틸)벤젠 (1-bromo-4-(ethoxymethyl)benzene) 의 제조 Preparation Example 30 Preparation of 1-bromo-4- (ethoxymethyl) benzene (1-bromo-4- (ethoxymethyl) benzene)

소디움하이드라이드 (0.1 g, 2.4 mmol)을 2 ml 탈기체화된 다이메틸포름아마이드에 넣고 4-브로모벨질알콜 (0.3 g, 1.6 mmol)을 서서히 넣었다. 실온에서 아이오도에테인 (0.14 ml, 1.76 mmol)을 첨가하고 2시간 교반한 후 2N 염산 50 ml를 가한 뒤, 에틸아세테이트 50 ml 로 추출한 뒤 물 50 ml로 2회 반복하여 유기층을 씻어주었다. 감압증류 후에 관크로마토그래피 (에틸아세테이트/n-헥세인, 1/10)로 표제 화합물 (0.17 g, 48 %)을 노란색 오일로 얻었다. Sodium hydride (0.1 g, 2.4 mmol) was added to 2 ml degassed dimethylformamide and 4-bromobelzyl alcohol (0.3 g, 1.6 mmol) was added slowly. After adding iodoethane (0.14 ml, 1.76 mmol) at room temperature and stirring for 2 hours, 50 ml of 2N hydrochloric acid was added thereto, extracted with 50 ml of ethyl acetate, and the organic layer was washed twice with 50 ml of water. After distillation under reduced pressure, the title compound (0.17 g, 48%) was obtained as a yellow oil by column chromatography (ethyl acetate / n-hexane, 1/10).

¹H-NMR (600MHz, CDCl₃); δ 7.46 (d, J = 8.4 Hz, 2H), 7.21 (d, J= 8.4 Hz, 2H), 4.45 (s, 2H), 3.55-3.51 (m, 2H), 1.28-1.23 (m, 3H) ¹ H-NMR (600 MHz, CDCl ₃ ); δ 7.46 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 4.45 (s, 2H), 3.55-3.51 (m, 2H), 1.28-1.23 (m, 3H)

[제조예 31] 에틸 4-아미노-2-(메틸사이오)사이아졸-5-카복실레이트 (ethyl 4-amino-2-(methylthio)thiazole-5-carboxylate) 의 제조Preparation Example 31 Preparation of ethyl 4-amino-2- (methylthio) thiazol-5-carboxylate (ethyl 4-amino-2- (methylthio) thiazole-5-carboxylate)

에틸 2-머켑토아세테이트 (50 g, 0.416 mol)를 다이메틸포름아마이드 500 ml에 녹이고 다이메틸 N-시아노다이사이오이미노 카보네이트 (67 g, 0.416 mol)과 다이아이소프로필아민 (112 ml, 0.624 mol)을 넣고 100 ℃에서 5시간 가열하고 포화된 염화암모늄 500 ml와 에틸아세테이트 500 ml를 사용하여 추출한 다음, 황산나트륨으로 건조, 여과하고 감압농축하여 생긴 고체를 n-헥세인으로 씻어주어 표제화합물 (90 g, 99 %)을 얻었다.Ethyl 2-mercetoacetate (50 g, 0.416 mol) was dissolved in 500 ml of dimethylformamide, and dimethyl N-cyanodithioimino carbonate (67 g, 0.416 mol) and diisopropylamine (112 ml, 0.624 mol) ), Heated at 100 ° C. for 5 hours, extracted with 500 ml of saturated ammonium chloride and 500 ml of ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure to wash the solid formed with n-hexane. g, 99%).

¹H-NMR (400 MHz, CDCl₃); δ 5.84 (brs, 2H), 4.26 (q, J = 7.2 Hz, 2H), 2.63 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H); LC-MS 219 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 5.84 (brs, 2H), 4.26 (q, J = 7.2 Hz, 2H), 2.63 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H); LC-MS 219 (MH +)

[제조예 32] [Production Example 32]

[제조예 32-1] 에틸 4-포름아미도-2-(메틸사이오)사이아졸-5-카복실레이트 (ethyl 4-formamido-2-(methylthio)thiazole-5-carboxylate) 의 제조Preparation Example 32-1 Preparation of ethyl 4-formamido-2- (methylthio) thiazol-5-carboxylate (ethyl 4-formamido-2- (methylthio) thiazole-5-carboxylate)

제조예 31에서 합성한 화합물 (30 g, 138.05 mol)와 암모늄아세테이트(13.8 g, 179.03 mol)을 200 ml의 포름산 (formic acid) 과 섞은 후 46시간 환류교반하였다. 감압농축하여 폼산을 제거하고 포화된 탄산수소나트륨 300 ml를 넣고 에틸아세테이트로 추출하고 황산나트륨으로 건조, 여과 후 유기층을 감압농축하여 표제화합물 (29.5 g, 87.3 %)를 노란색 고체로 얻었다. Compound (30 g, 138.05 mol) and ammonium acetate (13.8 g, 179.03 mol) synthesized in Preparation Example 31 were mixed with 200 ml of formic acid and stirred under reflux for 46 hours. Concentrated under reduced pressure to remove formic acid, 300 ml of saturated sodium hydrogen carbonate was added, extracted with ethyl acetate, dried over sodium sulfate, filtered and the organic layer was concentrated under reduced pressure to give the title compound (29.5 g, 87.3%) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃); δ 9.38 (s, 1H), 5.81 (brs, 1H), 4.32 (q, J= 6.8 Hz, 2H), 2.70 (s, 3H), 1.35 (t, J = 6.8 Hz, 3H); LC-MS 246 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 9.38 (s, 1H), 5.81 (brs, 1H), 4.32 (q, J = 6.8 Hz, 2H), 2.70 (s, 3H), 1.35 (t, J = 6.8 Hz, 3H); LC-MS 246 (MH +)

[제조예 32-2] 2-(메틸사이오)사이아졸로[4,5,-d]피리미딘-7(6H)-온 (2-(methylthio)thiazolo[4,5-d]pyrimidin-7(6H)-one) 의 제조Production Example 32-2 2- (methylthio) cyazolo [4,5, -d] pyrimidin-7 (6H) -one (2- (methylthio) thiazolo [4,5-d] pyrimidin- 7 (6H) -one)

제조예 32-1에서 합성한 화합물 (29.5 g, 0.12 mol), 암모늄 포메이트 (22.7 g, 0.36 mol), 포름아마이드 (28.7 ml, 0.72 mol)를 섞은 후 140 ℃에서 48 시간 가열한 후 100 ml의 물을 첨가하였다. 다이에틸에테르를 200 ml 첨가하여 실온에서 30분 정도 교반 후 생성된 고체를 n-헥세인을 이용하여 씻어주어 표제 화합물 (20.5 g, 85 %)을 옅은 노란색 고체로 얻었다. Compound (29.5 g, 0.12 mol), ammonium formate (22.7 g, 0.36 mol) and formamide (28.7 ml, 0.72 mol) synthesized in Preparation Example 32-1 were mixed, heated at 140 ° C. for 48 hours and then 100 ml Of water was added. After 200 ml of diethyl ether was added and stirred at room temperature for about 30 minutes, the resulting solid was washed with n-hexane to obtain the title compound (20.5 g, 85%) as a pale yellow solid.

¹H-NMR (400MHz, DMSO-d₆); δ 8.83 (s, 1H), 8.60 (s, 1H), 3.38 (s, 3H); LC-MS 202 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 8.83 (s, 1 H), 8.60 (s, 1 H), 3.38 (s, 3 H); LC-MS 202 (MH +)

[제조예 32-3] 7-클로로-2-(메틸사이오)사이아졸로[4,5-d]피리미딘 (7-chloro-2-(methylthio)thiazolo[4,5-d]pyrimidine) 의 제조Preparation Example 32-3 7-Chloro-2- (methylthio) thiazolo [4,5-d] pyrimidine (7-chloro-2- (methylthio) thiazolo [4,5-d] pyrimidine) Manufacture

제조예 32-2에서 합성한 화합물 (2 g, 9.93 mmol)과 포스포릴클로라이드 4 ml를 130 ℃에서 15시간 가열하였다. 감압농축하여 포스포릴클로라이드를 제거하고, 얼음물 100 ml를 넣고 20분간 교반하여 생성된 고체를 물 100 ml와 n-헥세인을 이용하여 씻어주어 표제 화합물 (0.88 g, 40.4 %)을 노란색 고체로 얻었다. The compound (2 g, 9.93 mmol) synthesized in Preparation Example 32-2 and 4 ml of phosphoryl chloride were heated at 130 ° C. for 15 hours. Concentrated under reduced pressure to remove the phosphoryl chloride, 100 ml of ice water was added and stirred for 20 minutes, and the resulting solid was washed with 100 ml of water and n-hexane to obtain the title compound (0.88 g, 40.4%) as a yellow solid. .

¹H-NMR (400 MHz, CDCl₃); δ 8.95 (s, 1H), 2.90 (s, 3H); LC-MS 220 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.95 (s, 1 H), 2.90 (s, 3 H); LC-MS 220 (MH +)

[제조예 33] N-(3-(4-메톡시벤질옥시)페닐)-2-(메틸사이오)사이아졸로[4,5-d]피리미딘-7-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-2-(methylthio)thiazolo[4,5-d]pyrimidin-7-amine) 의 제조Preparation Example 33 N- (3- (4-methoxybenzyloxy) phenyl) -2- (methylthio) thiazolo [4,5-d] pyrimidin-7-amine (N- (3- Preparation of (4-methoxybenzyloxy) phenyl) -2- (methylthio) thiazolo [4,5-d] pyrimidin-7-amine)

제조예 32-3에서 합성한 화합물 (0.2 g, 0.91 mmol)와 제조예 1에서 합성한 화합물 (0.23 g, 1.00 mmol), 다이아이소프로필아민 (0.2 ml, 1.09 mmol)을 2 ml 아이소프로필알코올과 혼합한 후 80 ℃에서 20시간 동안 가열하였다. 감압농축하여 아이소프로필알코올을 제거한 다음 다이클로로메테인 20 ml와 메탄올 2 ml를 넣고 다시 감압농축하여 유기용매를 제거한 후 n-헥세인과 다이에틸에테르를 이용 트리터레이션(trituration)하여 표제 화합물 (260 mg, 70 %)을 베이지색 고체로 얻었다. Compound (0.2 g, 0.91 mmol) synthesized in Preparation Example 32-3, Compound (0.23 g, 1.00 mmol) and Diisopropylamine (0.2 ml, 1.09 mmol) synthesized in Preparation Example 1 were mixed with 2 ml of isopropyl alcohol. After mixing, the mixture was heated at 80 ° C. for 20 hours. Concentrated under reduced pressure to remove isopropyl alcohol, 20 ml of dichloromethane and 2 ml of methanol were added thereto, and then concentrated under reduced pressure to remove the organic solvent, followed by trituration using n-hexane and diethyl ether to obtain the title compound ( 260 mg, 70%) was obtained as a beige solid.

¹H-NMR (400 MHz, CDCl₃); δ 8.65 (s, 1H), 7.36-7.30 (m, 3H), 7.07 (brs, 1H), 7.05-7.04 (m, 1H), 6.96-6.90 (m, 4H), 5.30 (s, 2H), 3.81 (s, 3H), 2.79 (s, 3H); LC-MS 412 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.65 (s, 1H), 7.36-7.30 (m, 3H), 7.07 (brs, 1H), 7.05-7.04 (m, 1H), 6.96-6.90 (m, 4H), 5.30 (s, 2H), 3.81 (s, 3H), 2.79 (s, 3H); LC-MS 412 (MH +)

상기 제조예에서 제조된 화합물을 이용하여 하기와 같이 실시예를 제시한다. Using the compound prepared in Preparation Example is given as follows.

[실시예 1] (6-브로모-싸이에노[3,2-d]피리미딘-4-닐)-(3-메톡시-페닐)-아민 ((6-Bromo-thieno[3,2-d]pyrimidin-4-yl)-(3-methoxy-phenyl)-amine) (LCB03-0007) 의 제조Example 1 (6-Bromo-thieno [3,2-d] pyrimidin-4-yl)-(3-methoxy-phenyl) -amine ((6-Bromo-thieno [3,2 Preparation of -d] pyrimidin-4-yl)-(3-methoxy-phenyl) -amine) (LCB03-0007)

제조예 3-4에서 합성한 화합물 (1 g, 4.00 mmol)과 다이아이소프로필에틸아민 0.9 ml, 메타아니시딘 0.56 ml을, 아이소프로필알콜 5 ml에 넣은 후 12시간 환류교반 한 후 감압 농축하였다. 반응물에 에틸아세테이트80 ml을 넣고 증류수 20 ml씩 2회 씻어주고 감압 농축 한 후 n-헥세인으로 3회 씻어주고 농축하여 표제화합 물 (1.05 g, 78 %)을 연한노란색 고체로 얻었다.The compound (1 g, 4.00 mmol) synthesized in Preparation Example 3-4, 0.9 ml of diisopropylethylamine, and 0.56 ml of metaanisidine were added to 5 ml of isopropyl alcohol, followed by stirring under reflux for 12 hours, and then concentrated under reduced pressure. 80 ml of ethyl acetate was added to the reaction mixture, washed twice with 20 ml of distilled water, concentrated under reduced pressure, washed three times with n-hexane, and concentrated to give the title compound (1.05 g, 78%) as a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃); δ 7.41(s, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.20 (s, 1H), 7.10 (dd, J = 2.0, 8.0 Hz, 1H), 7.03 (dd, J = 2.0, 8.0 Hz, 1H), 6.89 (dd, J = 2.4, 8.4 Hz, 1H), 3.85 (s, 3H); LC-MS 336, 338(M+, MH+2) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 7.41 (s, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.20 (s, 1H), 7.10 (dd, J = 2.0, 8.0 Hz, 1H), 7.03 (dd, J = 2.0, 8.0 Hz, 1H), 6.89 (dd, J = 2.4, 8.4 Hz, 1H), 3.85 (s, 3H); LC-MS 336, 338 (M +, MH + 2)

[실시예 2] 3-(6-브로모-싸이에노[3,2-d]피리미딘-4-닐아미노)-페놀 (3-(6-Bromo-thieno[3,2-d]pyrimidin-4-ylamino)-phenol) (LCB03-0015) 의 제조Example 2 3- (6-Bromo-thieno [3,2-d] pyrimidin-4-ylamino) -phenol (3- (6-Bromo-thieno [3,2-d] pyrimidin Preparation of -4-ylamino) -phenol) (LCB03-0015)

실시예 1에서 합성한 화합물 (150 mg, 0.45 mmol)을 다이클로로메테인 5 ml에 녹인 후 0 ℃에서 1M 보론트라이브로마이드 0.89 ml을 서서히 넣어준 후 상온에서 12시간 교반 후 다이클로로메테인 30 ml, 탄산수소나트륨 수용액 20 ml로 추출하였다. 감압 농축 후 관크로마토그래피 (다이클로로메테인/메탄올, 20/1)를 이용하여 표제화합물 (90 mg, 63 %)을 연한 노란색 고체로 수득하였다.The compound (150 mg, 0.45 mmol) synthesized in Example 1 was dissolved in 5 ml of dichloromethane, and 0.89 ml of 1M boron tribromide was added slowly at 0 ° C., followed by stirring at room temperature for 12 hours, followed by 30 ml of dichloromethane. It extracted with 20 ml of sodium hydrogencarbonate aqueous solution. After concentration under reduced pressure, the title compound (90 mg, 63%) was obtained as a pale yellow solid using tube chromatography (dichloromethane / methanol, 20/1).

¹H NMR (400 MHz, DMSO-d₆); δ 8.60 (s, 1H), 7.65 (s, 1H), 7.19-7.15 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 6.61 (d, J = 8.0 Hz, 1H), 3.83 (s, 3H); LC-MS 322, 324 (M+, MH+2) ¹ H NMR (400 MHz, DMSO-d ₆ ); δ 8.60 (s, 1H), 7.65 (s, 1H), 7.19-7.15 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 6.61 (d, J = 8.0 Hz, 1H), 3.83 (s, 3H); LC-MS 322, 324 (M +, MH + 2)

[실시예 3] 3-[6-(4-메톡시페닐)-싸이에노[3,2-d]피리미딘-4-닐아미노]-페놀 (3-[6-(4-Methoxy-phenyl)-thieno[3,2-d]pyrimidin-4-ylamino]-phenol) (LCB03-0017) 의 제조Example 3 3- [6- (4-methoxyphenyl) -thieno [3,2-d] pyrimidin-4-ylamino] -phenol (3- [6- (4-Methoxy-phenyl ) -thieno [3,2-d] pyrimidin-4-ylamino] -phenol) (LCB03-0017)

실시예 2에서 합성한 화합물 (45 mg, 0.14 mmol)과 4-메톡시페닐보론산 (22 mg, 0.15 mmol), 2M 탄산칼륨 (0.14 ml, 0.28 mmol), 팔라디움테트라키스트라이페닐포스핀 10 mg을 1,4-다이옥산 1 ml 에 넣은 후 3시간 환류교반 한 후 에틸아세테이트 20 ml을 넣고 탄산수소나트륨수용액 10 ml로 2회 씻어주고 감압 농축 한 후 관크로마토그래피 (다이클로로메테인/메탄올, 40/1)를 이용하여 표제화합물 (27 mg, 57 %)을 노란색고체로 수득하였다.Compound synthesized in Example 2 (45 mg, 0.14 mmol) and 4-methoxyphenylboronic acid (22 mg, 0.15 mmol), 2M potassium carbonate (0.14 ml, 0.28 mmol), palladium tetrakistriphenylphosphine 10 mg Was added to 1 ml of 1,4-dioxane, and the mixture was stirred under reflux for 3 hours. Then, 20 ml of ethyl acetate was added, washed twice with 10 ml of sodium bicarbonate solution, concentrated under reduced pressure, and then subjected to column chromatography (dichloromethane / methanol, 40 / 1) to give the title compound (27 mg, 57%) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃); δ 9.55 (s, 1H), 9.43 (s, 1H), 8.58 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.77 (s, 1H), 7.32 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.16 (m, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 8.0 Hz, 1H), 3.83 (s, 3H); LC-MS 350 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 9.55 (s, 1H), 9.43 (s, 1H), 8.58 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.77 (s, 1H), 7.32 (s, 1H), 7.19 ( d, J = 8.0 Hz, 1H), 7.16 (m, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 8.0 Hz, 1H), 3.83 (s, 3H); LC-MS 350 (MH +)

[실시예 4] (3-메톡시페닐)-(6-싸이오펜-2-일-싸이에노[3,2-d]피리미딘-4-일)-아민 ((3-Methoxyphenyl)-(6-thiophen-2-yl-thieno[3,2-d]pyrimidin-4-yl)-amine) (LCB03-0030) 의 제조Example 4 (3-methoxyphenyl)-(6-thiophen-2-yl-thieno [3,2-d] pyrimidin-4-yl) -amine ((3-Methoxyphenyl)-( Preparation of 6-thiophen-2-yl-thieno [3,2-d] pyrimidin-4-yl) -amine) (LCB03-0030)

실시예 1에서 합성한 화합물 (70 mg, 0.21 mmol)과 2-싸이오펜보론산 (20 mg, 0.23 mmol), 2M 탄산칼륨 (0.46 ml, 0.42 mmol), 팔라디움테트라키스트라이닐포스핀 10 mg을 1,4-다이옥산 1 ml 에 넣은 후 12시간 환류교반 한 후 에틸아세테이트 20 ml을 넣고 탄산수소나트륨수용액 10 ml로 2회 씻어주고 감압농축 한 후 관크로마토그래피 (에틸아세테이트/n-헥세인, 1/1)을 이용하여 표제화합물 (51 mg, 71 %)을 연한노란색의 고체로 수득하였다.A compound synthesized in Example 1 (70 mg, 0.21 mmol), 2-thiophenboronic acid (20 mg, 0.23 mmol), 2M potassium carbonate (0.46 ml, 0.42 mmol), and 10 mg of palladium tetrakistrinylphosphine 1 ml of 1,4-dioxane, and reflux agitating for 12 hours, add 20 ml of ethyl acetate, wash twice with 10 ml of sodium bicarbonate solution, concentrate under reduced pressure, and then vacuum chromatography (ethyl acetate / n-hexane, 1 / 1) to give the title compound (51 mg, 71%) as a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃); δ 8.69 (s, 1H), 7.46 (s, 1H), 7.40 (dd, J = 4.8, 0.8 Hz, 1H), 7.35 (dd, J = 4.8, 0.8 Hz, 1H), 7.33 (t, J = 8.0Hz, 1H), 7.25 (t, J = 2.4 Hz, 1H), 7.11-7.08 (m, 2H), 6.83-6.80 (m, 2H), 3.85 (s, 3H); LC-MS 340 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.46 (s, 1H), 7.40 (dd, J = 4.8, 0.8 Hz, 1H), 7.35 (dd, J = 4.8, 0.8 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.25 (t, J = 2.4 Hz, 1H), 7.11-7.08 (m, 2H), 6.83-6.80 (m, 2H), 3.85 (s, 3H); LC-MS 340 (MH +)

실시예 4와 유사한 방법으로 하기화합물을 합성하였다. The following compound was synthesize | combined by the method similar to Example 4.

[실시예 5] (3-메톡시페닐)-(6-싸이오펜-3-일-싸이에노[3,2-d]피리미딘-4-일)-아민 ((3-Methoxyphenyl)-(6-thiophen-3-yl-thieno[3,2-d]pyrimidin-4-yl)-amine) (LCB03-0028)의 제조Example 5 (3-methoxyphenyl)-(6-thiophen-3-yl-thieno [3,2-d] pyrimidin-4-yl) -amine ((3-Methoxyphenyl)-( Preparation of 6-thiophen-3-yl-thieno [3,2-d] pyrimidin-4-yl) -amine) (LCB03-0028)

¹H-NMR (400 MHz, CDCl₃); δ 8.70 (s, 1H), 7.61-7.60 (m, 1H), 7.49 (s, 1H), 7.44-7.39 (m, 2H), 7.33 (t, J = 8.0 Hz, 1H), 7.26-7.25 (m, 1H), 7.12-7.10 (m, 1H), 6.83-6.80 (m, 1H), 6.72 (s, 1H), 3.86 (s, 3H); LC-MS 340 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.70 (s, 1H), 7.61-7.60 (m, 1H), 7.49 (s, 1H), 7.44-7.39 (m, 2H), 7.33 (t, J = 8.0 Hz, 1H), 7.26-7.25 (m , 1H), 7.12-7.10 (m, 1H), 6.83-6.80 (m, 1H), 6.72 (s, 1H), 3.86 (s, 3H); LC-MS 340 (MH +)

[실시예 6] (6-퓨란-2-일-싸이에노[3,2-d]피리미딘-4-일)-(3-메톡시페놀)-아민 ((6-Furan-2-yl-thieno[3,2-d]pyrimidin-4-yl)-(3-methoxyphenyl)-amine) (LCB03-0023)의 제조Example 6 (6-furan-2-yl-thieno [3,2-d] pyrimidin-4-yl)-(3-methoxyphenol) -amine ((6-Furan-2-yl Preparation of -thieno [3,2-d] pyrimidin-4-yl)-(3-methoxyphenyl) -amine) (LCB03-0023)

¹H-NMR (400 MHz, CDCl₃); δ 8.70 (s, 1H), 7.52 (m, 2H), 7.40 (t, J = 8.0Hz, 1H), 7.25 (t, J = 2.4Hz, 1H), 7.11-7.08 (m, 1H), 6.84-6.81 (m, 1H), 6.78 (d, J = 7.6Hz, 1H), 6.73 (s, 1H), 6.53 (dd, J = 3.6, 2.4 Hz, 1H), 3.86 (s, 3H); LC-MS 324 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.70 (s, 1H), 7.52 (m, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.25 (t, J = 2.4 Hz, 1H), 7.11-7.08 (m, 1H), 6.84- 6.81 (m, 1 H), 6.78 (d, J = 7.6 Hz, 1 H), 6.73 (s, 1 H), 6.53 (dd, J = 3.6, 2.4 Hz, 1 H), 3.86 (s, 3H); LC-MS 324 (MH +)

[실시예 7] (6-퓨란-3-일-싸이에노[3,2-d]피리미딘-4-일)-(3-메톡시페놀)-아민 ((6-Furan-3-yl-thieno[3,2-d]pyrimidin-4-yl)-(3-methoxyphenyl)-amine) (LCB03-0024)의 제조Example 7 (6-Furan-3-yl-thieno [3,2-d] pyrimidin-4-yl)-(3-methoxyphenol) -amine ((6-Furan-3-yl Preparation of -thieno [3,2-d] pyrimidin-4-yl)-(3-methoxyphenyl) -amine) (LCB03-0024)

¹H-NMR (400 MHz, CDCl₃); δ 8.71 (s, 1H), 7.79 (s, 1H), 7.50 (t, J = 1.6 Hz, 1H), 7.40 (s, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.23 (t, J = 1.6Hz, 1H), 7.10-7.08 (m, 1H), 6.83-6.80 (m, 1H), 6.68 (dd, J = 1.6, 0.8 Hz, 1H), 3.84 (s, 3H); LC-MS 324 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.71 (s, 1H), 7.79 (s, 1H), 7.50 (t, J = 1.6 Hz, 1H), 7.40 (s, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.23 (t, J = 1.6 Hz, 1H), 7.10-7.08 (m, 1H), 6.83-6.80 (m, 1H), 6.68 (dd, J = 1.6, 0.8 Hz, 1H), 3.84 (s, 3H); LC-MS 324 (MH +)

[실시예 8] N-(3-메톡시페닐)-6-페닐싸이에노[3,2-d]피리미딘-4-아민 (N-(3-methoxyphenyl)-6-phenylthieno[3,2-d]pyrimidin-4-amine) (LCB03-0006)의 제조Example 8 N- (3-methoxyphenyl) -6-phenylthieno [3,2-d] pyrimidin-4-amine (N- (3-methoxyphenyl) -6-phenylthieno [3,2 -d] pyrimidin-4-amine) (LCB03-0006)

¹H-NMR (400 MHz, CDCl₃); δ 8.71 (s, 1H), 7.68 (d, J = 6.8 Hz, 2H), 7.60 (s, 1H), 5.46-7.41 (m, 4H), 7.34-7.30 (m, 2H), 7.13-7.11 (m, 1H), 7.03 (brs, 1H), 6.82-6.80 (m, 1H), 3.48 (s, 3H); LC-MS: 334 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.71 (s, 1H), 7.68 (d, J = 6.8 Hz, 2H), 7.60 (s, 1H), 5.46-7.41 (m, 4H), 7.34-7.30 (m, 2H), 7.13-7.11 (m , 1H), 7.03 (brs, 1H), 6.82-6.80 (m, 1H), 3.48 (s, 3H); LC-MS: 334 (MH < + >)

[실시예 9] 4-(4-(3-메톡시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페놀 (4-(4-(3-methoxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)phenol) (LCB03-0016)의 제조Example 9 4- (4- (3-methoxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenol (4- (4- (3-methoxyphenylamino) thieno [3 , 2-d] pyrimidin-6-yl) phenol) (LCB03-0016)

¹H-NMR (400 MHz, CDCl₃); δ 8.44 (s, 1H), 7.62 (d, J = 8.8 Hz, 2), 7.42 (s, 1H), 7.32 (t, J = 2.2 Hz, 1H), 7.25-7.19 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.74-6.71 (m, 1H), 3.79 (s, 3H); LC-MS 350 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.44 (s, 1H), 7.62 (d, J = 8.8 Hz, 2), 7.42 (s, 1H), 7.32 (t, J = 2.2 Hz, 1H), 7.25-7.19 (m, 2H), 6.85 ( d, J = 8.8 Hz, 2H), 6.74-6.71 (m, 1H), 3.79 (s, 3H); LC-MS 350 (MH +)

[실시예 10] 4-(4-(3-메톡시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤조나이트릴 (4-(4-(3-methoxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)benzonitrile) (LCB03-0009)의 제조Example 10 4- (4- (3-methoxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzonitrile (4- (4- (3-methoxyphenylamino) thieno Preparation of [3,2-d] pyrimidin-6-yl) benzonitrile) (LCB03-0009)

¹H-NMR (400 MHz, CDCl₃); δ 8.78 (s, 1H), 7.79-7.73 (m,4H), 7.70 (s, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.24-7.21 (m, 1H), 7.11-7.10 (m, 1H), 6.86-6.84 (m, 1H), 6.82 (brs, 1H), 3.86 (s, 3H); LC-MS 359 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.78 (s, 1H), 7.79-7.73 (m, 4H), 7.70 (s, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.24-7.21 (m, 1H), 7.11-7.10 (m , 1H), 6.86-6.84 (m, 1H), 6.82 (brs, 1H), 3.86 (s, 3H); LC-MS 359 (MH +)

[실시예 11] N-(3-메톡시페닐)-6-(싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-methoxyphenyl)-6-(thiophen-2-yl)thieno[3,2-d]pyrimidin-4-amine) (LCB03-0027) 의 제조Example 11 N- (3-methoxyphenyl) -6- (thiophen-2-yl) thieno [3,2-d] pyrimidin-4-amine (N- (3-methoxyphenyl)- Preparation of 6- (thiophen-2-yl) thieno [3,2-d] pyrimidin-4-amine) (LCB03-0027)

¹H-NMR (400 MHz, CDCl₃); δ 8.69 (s, 1H), 7.46 (s, 1H), 7.40 (dd, J = 4.8, 0.8 Hz, 1H), 7.35 (dd, J = 4.8, 0.8 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.25 (t, J = 2.4 Hz, 1H), 7.11-7.08 (m, 2H), 6.83-6.80 (m, 2H), 3.85 (s, 3H); LC-MS 340(MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.46 (s, 1H), 7.40 (dd, J = 4.8, 0.8 Hz, 1H), 7.35 (dd, J = 4.8, 0.8 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.25 (t, J = 2.4 Hz, 1H), 7.11-7.08 (m, 2H), 6.83-6.80 (m, 2H), 3.85 (s, 3H); LC-MS 340 (MH +)

[실시예 12] 3-(6-싸이오펜-2-일-싸이에노[3,2-d]피리미딘-4-일아미노)-페놀 (3-(6-Thiophen-2-yl-thieno[3,2-d]pyrimidin-4-ylamino)-phenol) 의 제조Example 12 3- (6-thiophen-2-yl-thieno [3,2-d] pyrimidin-4-ylamino) -phenol (3- (6-Thiophen-2-yl-thieno Preparation of [3,2-d] pyrimidin-4-ylamino) -phenol)

실시예 4에서 합성한 화합물 (40 mg, 0.12 mmol)을 다이클로로메테인 2 ml에 녹인 후 0 ℃에서 1M 보론 트라이브로마이드 0.3 ml을 서서히 넣은 후 상온에서 12시간 교반 후 증류수 20 ml, 에틸아세테이트 50 ml로 추출하고 감압농축한 다음 관크로마토그래피 (다이클로로메테인/메탄올, 20/1) 이용하여 표제화합물 (15 mg, 39 %)을 노란색고체로 수득하였다.The compound synthesized in Example 4 (40 mg, 0.12 mmol) was dissolved in 2 ml of dichloromethane, slowly added 0.3 ml of 1M boron tribromide at 0 ° C., and stirred at room temperature for 12 hours, followed by 20 ml of distilled water and 50 ethyl acetate. Extraction with ml, concentration under reduced pressure and the title compound (15 mg, 39%) were obtained as a yellow solid using column chromatography (dichloromethane / methanol, 20/1).

¹H-NMR (400 MHz,DMSO-d₆); δ 9.53 (s, 1H), 9.39 (s, 1H), 8.52 (s, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.63 (s, 1H), 7.61 (d, J = 1.2 Hz, 1H), 7.27 (s, 1H), 7.19-7.07 (m, 3H), 6.48-6.47 (m, 1H); LC-MS 326 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.53 (s, 1H), 9.39 (s, 1H), 8.52 (s, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.63 (s, 1H), 7.61 (d, J = 1.2 Hz, 1H), 7.27 (s, 1 H), 7.19-7.07 (m, 3 H), 6.48-6.47 (m, 1 H); LC-MS 326 (MH +)

실시예 12와 유사한 방법으로 하기의 화합물을 합성하였다. In the same manner as in Example 12, the following compounds were synthesized.

[실시예 13] 3-(6-싸이오펜-3-일-싸이에노[3,2-d]피리미딘-4-일아미노)-페놀 (3-(6-Thiophen-3-yl-thieno[3,2-d]pyrimidin-4-ylamino)-phenol) (LCB03-0031)의 제조Example 13 3- (6-thiophen-3-yl-thieno [3,2-d] pyrimidin-4-ylamino) -phenol (3- (6-Thiophen-3-yl-thieno Preparation of [3,2-d] pyrimidin-4-ylamino) -phenol) (LCB03-0031)

¹H-NMR (400 MHz,DMSO-d₆); δ 10.89 (s, 1H), 8.86 (s, 1H), 8.21 (t, J = 1.2 Hz, 1H), 7.76 (dd, J = 4.8, 2.4 Hz, 1H), 7.72 (s, 1H), 7.61 (d, J = 4.8Hz, 1H), 7.21 (t, J = 8.0Hz, 1H), 7.08 (s, 1H), 7.05 (d, J = 8.4Hz, 1H), 6.68 (d, J = 8.0Hz, 1H); LC-MS 326 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.89 (s, 1H), 8.86 (s, 1H), 8.21 (t, J = 1.2 Hz, 1H), 7.76 (dd, J = 4.8, 2.4 Hz, 1H), 7.72 (s, 1H), 7.61 ( d, J = 4.8 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.08 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H); LC-MS 326 (MH +)

[실시예 14] 3-(6-(페닐싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6- phenylthieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0008)의 제조Example 14 3- (6- (phenylthieno [3,2-d] pyrimidin-4-ylamino) phenol (3- (6-phenylthieno [3,2-d] pyrimidin-4-ylamino ) phenol) (LCB03-0008)

¹H-NMR (400 MHz,DMSO-d₆); δ 8.82 (s, 1H), 7.89-7.87 (m, 3H), 7.58-7.54 (m, 3H), 7.24 (t, J= 8.0 Hz, 1H), 7.16-7.11 (m, 2H), 6.71-6.69 (m, 1H); LC-MS 320 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 8.82 (s, 1H), 7.89-7.87 (m, 3H), 7.58-7.54 (m, 3H), 7.24 (t, J = 8.0 Hz, 1H), 7.16-7.11 (m, 2H), 6.71-6.69 (m, 1 H); LC-MS 320 (MH +)

[실시예 15] 4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤조나이트릴 (4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)benzonitrile) (LCB03-0013)의 제조Example 15 4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzonitrile (4- (4- (3-hydroxyphenylamino) thieno Preparation of [3,2-d] pyrimidin-6-yl) benzonitrile) (LCB03-0013)

¹H-NMR (400 MHz, MeOH-d₄); δ 8.43 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.71 (s, 1H), 7.16 (t, J = 2.0 Hz, 1H), 7.11 (t, J= 8.0 Hz, 1H), 7.01-6.99 (m, 1H), 6.57-6.55 (m, 1H); LC-MS 345 (MH+) ¹ H-NMR (400 MHz, MeOH-d ₄ ); δ 8.43 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.71 (s, 1H), 7.16 (t, J = 2.0 Hz, 1H) , 7.11 (t, J = 8.0 Hz, 1H), 7.01-6.99 (m, 1H), 6.57-6.55 (m, 1H); LC-MS 345 (MH +)

[실시예 16] 3-(6-(4-클로로페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6- (4-chlorophenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0019)의 제조Example 16 3- (6- (4-chlorophenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3- (6- (4-chlorophenyl) thieno [3, Preparation of 2-d] pyrimidin-4-ylamino) phenol) (LCB03-0019)

¹H-NMR (400 MHz,DMSO-d₆); δ 9.59 (s, 1H), 9.40 (s, 1H), 8.53 (s, 1H), 7.93 (s. 1H), 7.84 (d, J = 6.8 Hz, 2H), 7.52-7.49 (m, 1H), 7.26 (t, J = 2.0 Hz, 1H), 7.14-7.07 (m, 2H), 6.50-6.47 (m, 1H); LC-MS 354 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.59 (s, 1H), 9.40 (s, 1H), 8.53 (s, 1H), 7.93 (s. 1H), 7.84 (d, J = 6.8 Hz, 2H), 7.52-7.49 (m, 1H), 7.26 (t, J = 2.0 Hz, 1 H), 7.14-7.07 (m, 2 H), 6.50-6.47 (m, 1 H); LC-MS 354 (MH +)

[실시예 17] N-(3-메톡시페닐)-6-(4-(2-모폴리노에톡시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-methoxyphenyl)-6-(4-(2-morpholinoethoxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) (LCB03-0018)의 제조Example 17 N- (3-methoxyphenyl) -6- (4- (2-morpholinoethoxy) phenyl) thieno [3,2-d] pyrimidin-4-amine (N- Preparation of (3-methoxyphenyl) -6- (4- (2-morpholinoethoxy) phenyl) thieno [3,2-d] pyrimidin-4-amine) (LCB03-0018)

N-(3-메톡시페닐)-6-(4-브로모페닐)싸이에노[3,2-d]피리미딘-4-아민 (0.26 g, 0.76 mmol)을 5 ml의 탈기체화된 다이메틸폼아마이드에 녹이고 4-(2-하이드록시에틸)모폴린 (0.12 ml, 0.92 mmol)과 트라이페닐포스핀 (241 mg, 0.92 mmol)을 넣고 0 ℃에서 DIAD (0.18 ml, 0.92 mmol)를 첨가한 다음 실온에서 15시간 교반하였다. 포화된 탄산수소나트륨 50 ml와 에틸아세테이트 50 ml로 추출하고 유기층을 물 50 ml를 사용하여 2번 씻어준 후, 황산마그네슘을 이용하여 건조, 여과하였다. 감 압농축 후 관크로마토그래피 (다이클로로메테인/메탄올, 15/1)을 시행하여 표제 화합물 (100 mg, 29 %)을 상아색의 고체로 수득하였다. 5 ml of degassed die with N- (3-methoxyphenyl) -6- (4-bromophenyl) thieno [3,2-d] pyrimidin-4-amine (0.26 g, 0.76 mmol) Dissolve in methylformamide, add 4- (2-hydroxyethyl) morpholine (0.12 ml, 0.92 mmol) and triphenylphosphine (241 mg, 0.92 mmol) and add DIAD (0.18 ml, 0.92 mmol) at 0 ° C. Then stirred at room temperature for 15 hours. 50 ml of saturated sodium bicarbonate and 50 ml of ethyl acetate were extracted, and the organic layer was washed twice with 50 ml of water, dried over magnesium sulfate, and filtered. After concentration under reduced pressure, tube chromatography (dichloromethane / methanol, 15/1) was carried out to obtain the title compound (100 mg, 29%) as an ivory solid.

¹H-NMR (400 MHz, CDCl₃); δ 8.69 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.49 (s, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.26 (t, J = 2.0 Hz, 1H), 7.12-7.10 (m, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.86 (brs, 1H), 6.81-6.78 (m, 1H), 4.16 (t, J = 6.0 Hz, 2H), 3.76-3.73 (m, 4H), 2.83 (t, J = 5.6 Hz, 2H), 2.60-2.58 (m, 4H); LC-MS 463 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.49 (s, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.26 (t, J = 2.0 Hz, 1H) , 7.12-7.10 (m, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.86 (brs, 1H), 6.81-6.78 (m, 1H), 4.16 (t, J = 6.0 Hz, 2H), 3.76-3.73 (m, 4H), 2.83 (t, J = 5.6 Hz, 2H), 2.60-2.58 (m, 4H); LC-MS 463 (MH +)

실시예 17과 유사한 방법으로 하기의 화합물을 합성하였다. In the same manner as in Example 17, the following compound was synthesized.

[실시예 18] N-(3-메톡시페닐)-6-(4-(2-(피페라진-1-일)에톡시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-methoxyphenyl)-6-(4-(2-(piperazin-1-yl)ethoxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) (LCB03-0029)의 제조Example 18 N- (3-methoxyphenyl) -6- (4- (2- (piperazin-1-yl) ethoxy) phenyl) thieno [3,2-d] pyrimidine-4 Of -amine (N- (3-methoxyphenyl) -6- (4- (2- (piperazin-1-yl) ethoxy) phenyl) thieno [3,2-d] pyrimidin-4-amine) (LCB03-0029) Produce

¹H-NMR (400 MHz, DMSO-d₆); δ 9.64 (s, 1H), 8.58 (s, 1H), 7.82-7.79 (m, 3H), 7.48-7.42 (m, 2H), 7.27 (t, J= 8.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.70-6.82 (m, 1H), 4.16 (t, J = 5.6 Hz, 2H), 2.95-2.92 (m, 4H), 2.76 (t, J = 5.6 Hz, 2H), 2.59-2.51 (m, 4H); LC-MS 463 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.64 (s, 1H), 8.58 (s, 1H), 7.82-7.79 (m, 3H), 7.48-7.42 (m, 2H), 7.27 (t, J = 8.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.70-6.82 (m, 1H), 4.16 (t, J = 5.6 Hz, 2H), 2.95-2.92 (m, 4H), 2.76 (t, J = 5.6 Hz, 2H), 2.59 -2.51 (m, 4 H); LC-MS 463 (MH +)

[실시예 19] 터트-부틸 4-(2-(4-(3-메톡시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페녹시)에틸)피페라진-1-카복실레이트 (tert-butyl 4-(2-(4-(4-(3-methoxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)phenoxy)ethyl)piperazine-1-carboxylate) (LCB03-0025)의 제조Example 19 Tert-Butyl 4- (2- (4- (3-methoxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenoxy) ethyl) piperazine-1 -Carboxylate (tert-butyl 4- (2- (4- (4- (3-methoxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenoxy) ethyl) piperazine-1-carboxylate) (LCB03- 0025)

¹H-NMR (400 MHz, CDCl₃); δ 8.70 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.51 (s, 1H), 7.34-7.30 (m, 2H), 7.12-7.0 (m, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.81-6.78 (m, 1H), 6.70 (s, 1H), 4.16 (t, J= 5.6 Hz, 2H), 3.47-3.45 (m, 4H), 2.84 (t, J = 5.6 Hz, 2H), 2.55-2.50 (m, 4H), 1.55 (s, 9H); LC-MS 562 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.70 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.51 (s, 1H), 7.34-7.30 (m, 2H), 7.12-7.0 (m, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.81-6.78 (m, 1H), 6.70 (s, 1H), 4.16 (t, J = 5.6 Hz, 2H), 3.47-3.45 (m, 4H), 2.84 (t, J = 5.6 Hz, 2H), 2.55-2.50 (m, 4H), 1.55 (s, 9H); LC-MS 562 (MH +)

[실시예 20] N-(3-메톡시페닐)-6-(4-(2-(피롤리딘-1-일)에톡시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-methoxyphenyl)-6-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) (LCB03-0026)의 제조Example 20 N- (3-methoxyphenyl) -6- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) thieno [3,2-d] pyrimidine- 4-amine (N- (3-methoxyphenyl) -6- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) thieno [3,2-d] pyrimidin-4-amine) (LCB03-0026) Manufacture

¹H-NMR (400 MHz, CDCl₃); δ 8.69 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.49 (s, 1H), 7.34-7.28 (m, 2H), 7.12-7.10 (m, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.81-6.78 (m, 1H), 6.71 (brs 1H), 4.17 (t, J= 6.4 Hz, 2H), 2.96-2.95 (m, 3H), 2.67-2.66 (m, 2H), 2.07-2.02 (m, 1H), 1.83-1.80 (m, 2H), 1.65-1.63 (m, 2H); LC-MS 447 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.49 (s, 1H), 7.34-7.28 (m, 2H), 7.12-7.10 (m, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.81-6.78 (m, 1H), 6.71 (brs 1H), 4.17 (t, J = 6.4 Hz, 2H), 2.96-2.95 (m, 3H), 2.67-2.66 (m, 2H ), 2.07-2.02 (m, 1H), 1.83-1.80 (m, 2H), 1.65-1.63 (m, 2H); LC-MS 447 (MH +)

[실시예 21] N-(3-메톡시페닐)-6-(4-페네톡시페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-methoxyphenyl)-6-(4-phenethoxyphenyl)thieno[3,2-d]pyrimidin-4-amine) (LCB03-0021)의 제조Example 21 N- (3-methoxyphenyl) -6- (4-phenoxyphenyl) thieno [3,2-d] pyrimidin-4-amine (N- (3-methoxyphenyl) -6 Preparation of-(4-phenethoxyphenyl) thieno [3,2-d] pyrimidin-4-amine) (LCB03-0021)

¹H-NMR (400 MHz, CDCl₃); δ 8.69 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.49 (s, 1H), 7.35-7.30 (m, 8H), 7.12 7.10 (m, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.81-6.95 (m, 1H), 6.71 (brs, 1H), 4.23 (t, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.13 (t, J = 6.8 Hz, 2H); LC-MS 454 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.49 (s, 1H), 7.35-7.30 (m, 8H), 7.12 7.10 (m, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.81-6.95 (m, 1H), 6.71 (brs, 1H), 4.23 (t, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.13 (t, J = 6.8 Hz, 2H); LC-MS 454 (MH +)

[실시예 22] N-(3-메톡시페닐)-6-(4-(2-(피리딘-2-일)에톡시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-methoxyphenyl)-6-(4-(2-(pyridin-2- yl)ethoxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) (LCB03-0022)의 제조Example 22 N- (3-methoxyphenyl) -6- (4- (2- (pyridin-2-yl) ethoxy) phenyl) thieno [3,2-d] pyrimidine-4- Preparation of Amine (N- (3-methoxyphenyl) -6- (4- (2- (pyridin-2-yl) ethoxy) phenyl) thieno [3,2-d] pyrimidin-4-amine) (LCB03-0022)

¹H-NMR (400 MHz, CDCl₃); δ 10.07 (s, 1H), 9.65 (s, 1H), 8.58 (s, 1H), 7.72-7.70 (m, 4H), 7.48 (t, J = 2.0 Hz, 1H), 7.45-7.44 (m, 1H), 7.30-7.29 (m, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 7.6 Hz, 1H), 6.69 (dd, J = 2.0, 8.4 Hz, 1H), 3.76 (s, 3H), 3.72-3.71 (m, 2H), 3.20-3.17 (m, 2H); LC-MS 454 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 10.07 (s, 1H), 9.65 (s, 1H), 8.58 (s, 1H), 7.72-7.70 (m, 4H), 7.48 (t, J = 2.0 Hz, 1H), 7.45-7.44 (m, 1H ), 7.30-7.29 (m, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 7.6 Hz, 1H), 6.69 (dd, J = 2.0, 8.4 Hz, 1H), 3.76 (s, 3H), 3.72-3.71 (m, 2H), 3.20-3.17 (m, 2H); LC-MS 454 (MH +)

[실시예 23] 3-(6-(4-(2-모폴리노에톡시)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(4-(2-morpholinoethoxy)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0020) 의 제조Example 23 3- (6- (4- (2-morpholinoethoxy) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3- (6- ( Preparation of 4- (2-morpholinoethoxy) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol) (LCB03-0020)

실시예 17에서 합성한 화합물 (75 mg, 0.16mmol)을 다이클로로메테인 1 ml에 녹인 후 0 ℃에서 1M 보론트라이브로마이드 (0.73 ml, 0.64 mmol)을 서서히 넣어준 후 상온에서 12시간 교반 한 후 다이클로로메테인 30 ml, 탄산수소나트륨수용액 20 ml로 추출한 뒤, 감압 농축하고 관크로마토그래피 (다이클로로메테인/메탄올, 15/1)을 시행하여 표제 화합물 (22 mg, 30 %)을 연한 노란색고체로 수득하였다.After dissolving the compound (75 mg, 0.16 mmol) synthesized in Example 17 in 1 ml of dichloromethane, and slowly added 1M boron tribromide (0.73 ml, 0.64 mmol) at 0 ° C., and then stirred at room temperature for 12 hours. Extracted with 30 ml of dichloromethane and 20 ml of sodium bicarbonate solution, concentrated under reduced pressure and subjected to column chromatography (dichloromethane / methanol, 15/1) to give the title compound (22 mg, 30%) in pale yellow color. Obtained as a solid.

¹H-NMR (400 MHz, DMSO-d₆); δ 9.49 (brs, 1H), 9.38 (s, 1H), 8.50 (s, 1H), 7.73 (t, J = 8.0 Hz, 2H), 7.26 (s, 1H), 7.12-7.03 (m, 4H), 6.46 (d, J = 6.8 Hz, 1H), 4.13-4.11 (m, 2H), 3.53 (m, 4H), 3.12-3.10 (m, 4H), 2.67-2.66 (m, 2H); LC-MS449 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.49 (brs, 1H), 9.38 (s, 1H), 8.50 (s, 1H), 7.73 (t, J = 8.0 Hz, 2H), 7.26 (s, 1H), 7.12-7.03 (m, 4H), 6.46 (d, J = 6.8 Hz, 1H), 4.13-4.11 (m, 2H), 3.53 (m, 4H), 3.12-3.10 (m, 4H), 2.67-2.66 (m, 2H); LC-MS449 (MH +)

[실시예 24] 3-(6-(4-(모폴리노메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(4-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0032)의 제조Example 24 3- (6- (4- (morpholinomethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3- (6- (4- ( Preparation of morpholinomethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol) (LCB03-0032)

¹H-NMR (400 MHz, DMSO-d₆); δ 11.67 (br, 1H), 10.99 (br, 1H), 8.84 (s, 1H), 7.97-7.94 (m, 3H), 7.83 (d, J = 8.4Hz, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.17 (brs, 1H), 7.12 (d, J =8.0 Hz, 1H), 6.72 ( d, J= 7.6 Hz, 1H), 4.40 (s, 2H), 3.95-3.92 (m, 2H), 3.87-3.81 (m, 2H), 3.25-3.23 (m, 2H), 3.14-3.12 (m, 2H); LC-MS 419 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 11.67 (br, 1H), 10.99 (br, 1H), 8.84 (s, 1H), 7.97-7.94 (m, 3H), 7.83 (d, J = 8.4 Hz, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.17 (brs, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 4.40 (s, 2H), 3.95-3.92 (m, 2H ), 3.87-3.81 (m, 2H), 3.25-3.23 (m, 2H), 3.14-3.12 (m, 2H); LC-MS 419 (MH +)

[실시예 25] 3-(6-(4-(피페라진-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(4-(piperazin-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0033)의 제조Example 25 3- (6- (4- (piperazin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3- (6- ( Preparation of 4- (piperazin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol) (LCB03-0033)

¹H-NMR (400 MHz, DMSO-d₆); δ 9.59 (br, 2H), 8.80 (s, 1H), 7.97-7.95 (m, 3H), 7.83-7.81 (m, 2H), 7.23 (t, J= 7.6 Hz, 1H), 7.21 (s, 1H), 7.14-7.12 (m, 1H), 6.70 (d, J= 7.6 Hz, 1H), 4.43 (s, 2H), 3.57-3.37 (m, 4H), 3.36-3.30 (M, 2H), 2.53-2.50 (m, 2H); LC-MS 418 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.59 (br, 2H), 8.80 (s, 1H), 7.97-7.95 (m, 3H), 7.83-7.81 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.21 (s, 1H ), 7.14-7.12 (m, 1H), 6.70 (d, J = 7.6 Hz, 1H), 4.43 (s, 2H), 3.57-3.37 (m, 4H), 3.36-3.30 (M, 2H), 2.53- 2.50 (m, 2 H); LC-MS 418 (MH +)

[실시예 26] 3-(6-(4-(피페리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(4-(piperidin-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0035)의 제조Example 26 3- (6- (4- (piperidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3- (6- Preparation of (4- (piperidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol) (LCB03-0035)

i i

i i

¹H-NMR (400 MHz, DMSO-d₆); δ 10.99 (brs, 1H), 10.82 (brs, 1H), 8.82 (s, 1H), 7.97 (s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.22 (brs, 1H), 7.13 (d, J= 7.6 Hz, 1H), 6.71 (d, J= 8.0 Hz, 1H), 4.33 (s, 2H), 3.71-3.67 (m, 1H), 3.50-3.28 (m, 5H), 2.87-2.85 (m, 1H), 1.79-1.68 (m, 3H); LC-MS 417 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.99 (brs, 1H), 10.82 (brs, 1H), 8.82 (s, 1H), 7.97 (s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.22 (brs, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 4.33 (s, 2H), 3.71-3.67 (m, 1H), 3.50-3.28 (m, 5H), 2.87-2.85 (m, 1H), 1.79-1.68 (m, 3H); LC-MS 417 (MH +)

[실시예 27] 3-(6-(4-(4-메틸피페라진-1-일-메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(4-(4-methylpiperazin-1-yl)methyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0036)의 제조Example 27 3- (6- (4- (4-methylpiperazin-1-yl-methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3- Preparation of (6- (4- (4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol) (LCB03-0036)

¹H-NMR (400 MHz, DMSO-d₆); δ 11.03 (brs, 1H), 8.84 (s, 1H), 7.96 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.83-7.81 (m, 2H), 7.25 (t, J = 8.4 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.73 (d, J= 7.6 Hz, 1H), 4.39 (s, 2H), 3.73-3.34 (m, 6H), 3.26-3.24 (m, 2H), 2.89 (s, 3H); LC-MS 432 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 11.03 (brs, 1H), 8.84 (s, 1H), 7.96 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.83-7.81 (m, 2H), 7.25 (t, J = 8.4 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 4.39 (s, 2H), 3.73-3.34 (m, 6H ), 3.26-3.24 (m, 2 H), 2.89 (s, 3 H); LC-MS 432 (MH +)

[실시예 28] 3-(6-(4-((다이에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(4-((diethylamino)methyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0037)의 제조Example 28 3- (6- (4-((diethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3- (6- (4 Preparation of-((diethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol) (LCB03-0037)

¹H-NMR (400 MHz, DMSO-d₆); δ 10.86 (brs, 1H), 8.83 (s, 1H), 7.97 (s, 1H), 7.95 (d, J = 8. Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.24 (t, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 4.36 (d, J= 5.2 Hz, 2H), 3.07-3.04 (m, 4H), 1.27 (t, J = 7.2 Hz, 6H); LC-MS 405 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.86 (brs, 1H), 8.83 (s, 1H), 7.97 (s, 1H), 7.95 (d, J = 8. Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.24 (t , J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 4.36 (d, J = 5.2 Hz, 2H ), 3.07-3.04 (m, 4H), 1.27 (t, J = 7.2 Hz, 6H); LC-MS 405 (MH +)

[실시예 29] 3-(6-(4-((사이클로프로필메틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(4-((cyclopropylmethylamino)methyl)phenyl)thieno[3,2-d]pyrimidin-4-ylㅁ)methyl)pheamino)phenol) (LCB03-0040)의 제조Example 29 3- (6- (4-((cyclopropylmethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3- (6- ( Preparation of 4-((cyclopropylmethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-yl ㅁ) methyl) pheamino) phenol) (LCB03-0040)

¹H-NMR (400 MHz, DMSO-d₆); δ 9.50-9.48 (m, 2H), 8.77 (s, 1H), 7.95-7.93 (m, 3H), 7.73 (d, J = 8.0 Hz, 2H), 7.24-7.13 (m, 3 H), 6.67 (d, J = 7.6 Hz, 1H), 4.30 (s, 2H), 3.70-3.67 (m, 1H), 0.91-0.75 (m, 2H), 0.59-0.54 (m, 2H); LC-MS 389 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.50-9.48 (m, 2H), 8.77 (s, 1H), 7.95-7.93 (m, 3H), 7.73 (d, J = 8.0 Hz, 2H), 7.24-7.13 (m, 3H), 6.67 ( d, J = 7.6 Hz, 1H), 4.30 (s, 2H), 3.70-3.67 (m, 1H), 0.91-0.75 (m, 2H), 0.59-0.54 (m, 2H); LC-MS 389 (MH +)

[실시예 30] 3-(6-(4-((아이소부틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(4-((isobutylamino)methyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0041)의 제조Example 30 3- (6- (4-((isobutylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3- (6- (4 Preparation of-((isobutylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol) (LCB03-0041)

¹H-NMR (400 MHz, DMSO-d₆); δ 9.20 (brs, 2H), 8.78 (s, 1H), 7.95-7.93 (m, 3H), 7.75 (d, J = 8.0 Hz, 2H), 7.24-7.12 (m, 3H), 6.68 (d, J = 7.2 Hz, 1H), 4.21 (s, 2H), 2.75-2.74 (m, 2H), 2.08-2.02 (m, 1H), 0.95 (d, J = 6.8 Hz, 6H); LC-MS 405 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.20 (brs, 2H), 8.78 (s, 1H), 7.95-7.93 (m, 3H), 7.75 (d, J = 8.0 Hz, 2H), 7.24-7.12 (m, 3H), 6.68 (d, J = 7.2 Hz, 1H), 4.21 (s, 2H), 2.75-2.74 (m, 2H), 2.08-2.02 (m, 1H), 0.95 (d, J = 6.8 Hz, 6H); LC-MS 405 (MH +)

[실시예 31] 3-(6-(4-((에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 3-(6-(4-((ethylamino)methyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0042)의 제조Example 31 3- (6- (4-((ethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol 3- (6- (4- ( Preparation of (ethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol) (LCB03-0042)

i i

i i

¹H-NMR (400 MHz, DMSO-d₆); δ 9.11 (brs, 2H), 8.73 (s, 1H), 7.95-7.94 (m, 3H), 7.70 (d, J= 8.4 Hz, 2H), 7.22-7.13 (m, 3H), 6.64 (d, J = 7.2 Hz, 1H), 4.20 (s, 2H), 3.01-3.98 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H); LC-MS 377 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.11 (brs, 2H), 8.73 (s, 1H), 7.95-7.94 (m, 3H), 7.70 (d, J = 8.4 Hz, 2H), 7.22-7.13 (m, 3H), 6.64 (d, J = 7.2 Hz, 1H), 4.20 (s, 2H), 3.01-3.98 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H); LC-MS 377 (MH +)

[실시예 32] (3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐(피롤리딘-1-일)메타논 ((3-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)phenyl)(pyrrolidin-1-yl)methanone)) (LCB03-0053)의 제조Example 32 (3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl (pyrrolidin-1-yl) methanone (( Preparation of 3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) (pyrrolidin-1-yl) methanone)) (LCB03-0053)

¹H-NMR (600 MHz, DMSO-d₆); δ 11.09 (brs, 1H), 8.85 (s, 1H), 7.99-7.97 (m, 2H), 7.93 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.25 (t, J = 8.4 Hz, 1), 7.17 (s, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), 3.52-3.49 (m, 2H), 3.44-3.42 (m, 2H), 1.91-1.82 (m, 4H); LC-MS 417 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 11.09 (brs, 1H), 8.85 (s, 1H), 7.99-7.97 (m, 2H), 7.93 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.63 ( t, J = 7.8 Hz, 1H), 7.25 (t, J = 8.4 Hz, 1), 7.17 (s, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), 3.52-3.49 (m, 2H), 3.44-3.42 (m, 2H), 1.91-1.82 (m, 4H); LC-MS 417 (MH +)

[실시예 33] N,N-다이에틸-3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈아마이드 (N,N-diethyl-3-(4-(3-hydroxyphenylamino)thieno[3,2- d]pyrimidin-6-yl)benzamide)) (LCB03-0054)의 제조Example 33 N, N-diethyl-3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamide (N, N-diethyl Preparation of -3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamide)) (LCB03-0054)

¹H-NMR (600 MHz, DMSO-d₆); δ 8.82 (s, 1H), 7.99 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.50 (d, J= 7.2 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.70 (d, J= 7.2 Hz, 1H), 3.47-3.45 (m, 2H), 3.22-3.21 (m, 2H), 1.19-1.18 (m, 3H), 1.10-1.07 (m, 3H); LC-MS 419 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 8.82 (s, 1H), 7.99 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.70 (d, J = 7.2 Hz, 1H) , 3.47-3.45 (m, 2H), 3.22-3.21 (m, 2H), 1.19-1.18 (m, 3H), 1.10-1.07 (m, 3H); LC-MS 419 (MH +)

[실시예 34] (3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐(4-메틸피페라진-1-일)메타논 ((3-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone)) (LCB03-0055)의 제조Example 34 (3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl (4-methylpiperazin-1-yl) methanone Preparation of ((3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone)) (LCB03-0055)

¹H-NMR (600 MHz, DMSO-d₆); δ 9.70 (brs, 1H), 8.78 (s, 1H), 8.03-7.95 (m, 3H), 7.66-7.59 (m, 2H), 7.23-7.15 (m, 4H), 6.68 (s, 1H), 3.71-3.66 (m, 2H), 3.46-3.39 (m, 2H), 3.16-3.12 (m, 4H), 2.81 (s, 3H); LC-MS 482 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 9.70 (brs, 1H), 8.78 (s, 1H), 8.03-7.95 (m, 3H), 7.66-7.59 (m, 2H), 7.23-7.15 (m, 4H), 6.68 (s, 1H), 3.71 -3.66 (m, 2H), 3.46-3.39 (m, 2H), 3.16-3.12 (m, 4H), 2.81 (s, 3H); LC-MS 482 (MH +)

[실시예 35] 3-(6-(4-모폴리노페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0082)의 제조Example 35 3- (6- (4-morpholinophenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3- (6- (4-morpholinophenyl) thieno [ Preparation of 3,2-d] pyrimidin-4-ylamino) phenol) (LCB03-0082)

¹H-NMR (600 MHz, DMSO-d₆); δ 9.50(s, 1H), 8.53(s, 1H), 7.71(m, 3H), 7.32(s, 1H), 7.15(m, 2H), 7.06(d, J = 8.82 Hz, 1H), 6.52(d, J = 8.0 Hz, 1H), 3.76(t, J = 4.8 Hz, 4H), 3.23(t, J= 4.8 Hz, 4H); LC-MS 405 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 9.50 (s, 1H), 8.53 (s, 1H), 7.71 (m, 3H), 7.32 (s, 1H), 7.15 (m, 2H), 7.06 (d, J = 8.82 Hz, 1H), 6.52 ( d, J = 8.0 Hz, 1H), 3.76 (t, J = 4.8 Hz, 4H), 3.23 (t, J = 4.8 Hz, 4H); LC-MS 405 (MH +)

[실시예 36]Example 36

[단계 1] N-(3-(tert-부틸다이메틸실릴옥시)페닐)-6-(4-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(tert-butyldimethylsilyloxy)phenyl)-6-(4-(pyrrolidin-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidine Preparation of 4-amine (N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine)

제조예 6에서 합성한 화합물 (1.7 g, 3.68 mmol)과 피롤리딘 (0.46 ml, 5.52 mmol)을 다이클로로에탄 1 ml에 순차적으로 넣고 20분간 교반한 후 초산 나트륨 (0.44 g, 5.52 mmol)과 소디움트라이아세톡시보로하이드라이드 (1.56 g, 7.36 mmol)을 넣고 7시간 동안 실온에서 교반하였다. 반응완료 후 다이클로로메테인 130 ml와 포화된 염화암모늄 수용액 130 ml를 이용하여 추출하였다. 유기층을 황산나트륨으로 건조하고 감압농축 후, 관크로마토그래피 (다이클로로메테인/메탄올, 1/15)를 시행하여 표제화합물 (1.4 g, 73.7 %)을 수득하였다.Compound (1.7 g, 3.68 mmol) and pyrrolidine (0.46 ml, 5.52 mmol) synthesized in Preparation Example 6 were sequentially added to 1 ml of dichloroethane and stirred for 20 minutes, followed by sodium acetate (0.44 g, 5.52 mmol) and Sodium triacetoxyborohydride (1.56 g, 7.36 mmol) was added and stirred at room temperature for 7 hours. After completion of the reaction, extraction was performed using 130 ml of dichloromethane and 130 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (dichloromethane / methanol, 1/15) to obtain the title compound (1.4 g, 73.7%).

¹H-NMR (400 MHz, CDCl₃); δ 8.68 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.58 (s, 1H), 7.41 (d, J= 8.0 Hz, 2H), 7.28-7.24 (m, 1H), 7.17-7.14 (m, 1H), 7.20-7.19 (m, 1H), 6.99 (brs, 1H), 6.76-6.74 (m, 1H), 3.68 (s, 2H), 2.56 (m, 4H), 1.85-1.78 (m, 4H), 1.00 (s, 9H), 0.23 (s, 6H); LC-MS 517 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.68 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.58 (s, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.28-7.24 (m, 1H), 7.17- 7.14 (m, 1H), 7.20-7.19 (m, 1H), 6.99 (brs, 1H), 6.76-6.74 (m, 1H), 3.68 (s, 2H), 2.56 (m, 4H), 1.85-1.78 ( m, 4H), 1.00 (s, 9H), 0.23 (s, 6H); LC-MS 517 (MH +)

[단계 2] 3-(6-(4-(피롤리딘-1-일메틸)페닐)사이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(4-(pyrrolidin-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0034)의 제조[Step 2] 3- (6- (4- (pyrrolidin-1-ylmethyl) phenyl) cyeno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride (3- (6- Preparation of (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0034)

상기 단계 1에서 얻은 화합물 (15 mg, 0.03 mmol)을 디클로로메테인 1 ml에 녹인 후 4 M 염산/1,4-다이옥산 1 ml을 넣고 실온에서 15시간 동안 교반한 뒤 감압 농축하였다. 이를 다시 디클로로메테인과 메탄올, 디에틸에테르등을 이용하여 공비농축하고 진공건조하여 옅은 노란색고체의 표제화합물 (12 mg, 94 %)을 수득하였다. The compound (15 mg, 0.03 mmol) obtained in step 1 was dissolved in 1 ml of dichloromethane, 1 ml of 4 M hydrochloric acid / 1,4-dioxane was added thereto, stirred at room temperature for 15 hours, and then concentrated under reduced pressure. This was again azeotropically concentrated with dichloromethane, methanol, diethyl ether and the like and dried under vacuum to yield the title compound (12 mg, 94%) as a pale yellow solid.

¹H-NMR (400 MHz, DMSO-d₆); δ 11.29 (brs, 1H), 11.03 (brs, 1H), 8.84 (s, 1H), 7.96 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.25 (t, J = 8.0 Hz, 2H), 7.17 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), 4.42 (d, J= 6.0 Hz, 2H), 3.39-3.36 (m, 2H), 3.08-3.04 (m, 2H), 2.02-1.89 (m, 4H); LC-MS: 403 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 11.29 (brs, 1H), 11.03 (brs, 1H), 8.84 (s, 1H), 7.96 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.25 (t, J = 8.0 Hz, 2H), 7.17 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H), 3.39-3.36 (m, 2H), 3.08-3.04 (m, 2H), 2.02-1.89 (m, 4H); LC-MS: 403 (MH < + >)

상기 실시예 36과 유사한 방법으로 하기의 화합물을 합성하였다. In the same manner as in Example 36, the following compound was synthesized.

[실시예 37]Example 37

[단계 1] 메틸 1-(4-(4-(3-(tert-부틸다이메틸실릴옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-2-카복실레이트 (methyl 1-(4-(4-(3-(tert-butyldimethylsilyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)benzyl)pyrrolidine-2-carboxylate) 의 제조[Step 1] Methyl 1- (4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine Preparation of 2-carboxylate (methyl 1- (4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxylate)

¹H-NMR (600 MHz, CDCl₃); δ 8.67 (s, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.57 (s, 1H), 7.39 (d, J= 7.8 Hz, 2H), 7.24-7.23 (m, 2H), 7.17 (t, J = 2.4 Hz, 1H), 7.13-7.12 (m, 1H), 6.74-6.72 (m, 1H), 3.94 ( d, J = 7.2 Hz, 1H), 3.64 (s, 3H), 3.57 (d, J = 7.2 Hz, 1H), 3.28-3.25 (m, 1H), 3.05-3.02 (m, 1H), 2.37 (q, J = 8.4 Hz, 1H), 2.15-2.12 (m, 1H), 1.98-1.76 (m, 3H), 1.04 (s, 9H), 0.23 (s, 6H); LC-MS 575 (MH+) ¹ H-NMR (600 MHz, CDCl ₃ ); δ 8.67 (s, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.57 (s, 1H), 7.39 (d, J = 7.8 Hz, 2H), 7.24-7.23 (m, 2H), 7.17 ( t, J = 2.4 Hz, 1H), 7.13-7.12 (m, 1H), 6.74-6.72 (m, 1H), 3.94 (d, J = 7.2 Hz, 1H), 3.64 (s, 3H), 3.57 (d , J = 7.2 Hz, 1H), 3.28-3.25 (m, 1H), 3.05-3.02 (m, 1H), 2.37 (q, J = 8.4 Hz, 1H), 2.15-2.12 (m, 1H), 1.98- 1.76 (m, 3 H), 1.04 (s, 9 H), 0.23 (s, 6 H); LC-MS 575 (MH +)

[단계 2] 메틸 1-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-2-카복실레이트 염산염 (methyl 1-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)benzyl)pyrrolidine-2-carboxylate, HCl) (LCB03-0056)의 제조[Step 2] Methyl 1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxylate hydrochloride ( Preparation of methyl 1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxylate, HCl) (LCB03-0056)

¹H-NMR (600 MHz, DMSO-d₆); δ 10.75 (brs, 1H), 9.72 (brs, 1H), 8.79 (s, 1H), 7.94 (s, 1H), 7.92 (d, J = 7.8 Hz, 2H), 7.69 (d, J = 6.6 Hz, 2H), 7.20 (t, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.10 (d, J = 7.2 Hz, 1H), 6.78 (d, J= 7.2 Hz, 1H), 4.57-4.40 (m, 3H), 3.46-3.44 (m, 2H), 3.28-3.27 (m, 1H), 2.03-2.02 (m, 2H), 1.89-1.88 (m, 1H); LC-MS: 461 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 10.75 (brs, 1H), 9.72 (brs, 1H), 8.79 (s, 1H), 7.94 (s, 1H), 7.92 (d, J = 7.8 Hz, 2H), 7.69 (d, J = 6.6 Hz, 2H), 7.20 (t, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.10 (d, J = 7.2 Hz, 1H), 6.78 (d, J = 7.2 Hz, 1H), 4.57-4.40 ( m, 3H), 3.46-3.44 (m, 2H), 3.28-3.27 (m, 1H), 2.03-2.02 (m, 2H), 1.89-1.88 (m, 1H); LC-MS: 461 (MH < + >)

[실시예 38]Example 38

[단계 1] N-(3-(tert-부틸다이메틸실릴옥시)페닐)-6-(4-((4-메틸피페리딘-1-일)메틸)페닐싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(tert-butyldimethylsilyloxy)phenyl)-6-(4-((4-methylpiperidin-1-yl)methyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (4-((4-methylpiperidin-1-yl) methyl) phenylthieno [3,2- d] pyrimidin-4-amine (N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (4-((4-methylpiperidin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin Preparation of -4-amine)

¹H-NMR (600 MHz, CDCl₃); δ 7.63 (d, J = 7.8 Hz, 2H), 7.59 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.28 (t, J = 8.4 Hz, 1H), 7.20-7.19 (m, 2H), 7.16-7.15 (m, 1H), 6.75 (dd, J = 2.4, 8.4 Hz, 1H), 6.73 (brs, 1H), 3.52 (s, 2H), 2.86-2.84 (m, 2H), 2.10-1.94 (m, 3H), 1.62-1.60 (m, 4H), 1.00 (s, 9H), 0.93 (d, J = 7.2 Hz, 3H), 0.09 (s, 6H); LC-MS 545 (MH+) ¹ H-NMR (600 MHz, CDCl ₃ ); δ 7.63 (d, J = 7.8 Hz, 2H), 7.59 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.28 (t, J = 8.4 Hz, 1H), 7.20-7.19 (m, 2H), 7.16-7.15 (m, 1H), 6.75 (dd, J = 2.4, 8.4 Hz, 1H), 6.73 (brs, 1H), 3.52 (s, 2H), 2.86-2.84 (m, 2H), 2.10 -1.94 (m, 3H), 1.62-1.60 (m, 4H), 1.00 (s, 9H), 0.93 (d, J = 7.2 Hz, 3H), 0.09 (s, 6H); LC-MS 545 (MH +)

[단계 2] 3-(6-(4-((4-메틸피페리딘-1-일)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(4-((4-methylpiperidin-1-yl)methyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0058)의 제조[Step 2] 3- (6- (4-((4-methylpiperidin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride ( Preparation of 3- (6- (4-((4-methylpiperidin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0058)

¹H-NMR (600 MHz, DMSO-d₆); δ 8.79 (s, 1H), 8.00-7.95 (m, 3H), 7.78 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H),6.70-6.69 (m, 1H), 4.32 (d, J = 4.8 Hz, 2H), 3.32-3.31 (m, 1H), 2.93-2.88 (m, 1H), 1.80-1.76 (m, 2H), 1.49-1.43 (m, 2H), 1.10-1.09 (m, 1H), 0.91 (d, J = 6.0 Hz, 3H); LC-MS: 431 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 8.79 (s, 1H), 8.00-7.95 (m, 3H), 7.78 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.70-6.69 (m, 1H), 4.32 (d, J = 4.8 Hz, 2H), 3.32-3.31 (m, 1H), 2.93-2.88 (m, 1H), 1.80-1.76 (m, 2H), 1.49-1.43 (m, 2H), 1.10- 1.09 (m, 1 H), 0.91 (d, J = 6.0 Hz, 3H); LC-MS: 431 (MH < + >)

[실시예 39]Example 39

¹H-NMR (600 MHz, CDCl₃); δ 8.67 (s, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.59 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.28-7.23 (m, 1H), 7.20-7.19 (m, 1H), 7.18-7.17 (m, 1H), 7.15-7.13 (m, 1H), 6.76-6.75 (m, 1H), 3.83 (s, 2H), 2.51-2.50 (m, 2H), 2.04-2.02 (m, 1H), 1.67-1.65 (m, 1H), 1.60-1.58 (m, 2H), 1.35- 1.32 (m, 2H), 1.07 (d. J = 6.6 Hz, 6H), 1.00 (s, 9H), 0.23 (s, 6H); LC-MS 559 (MH+) ¹ H-NMR (600 MHz, CDCl ₃ ); δ 8.67 (s, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.59 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.28-7.23 (m, 1H), 7.20- 7.19 (m, 1H), 7.18-7.17 (m, 1H), 7.15-7.13 (m, 1H), 6.76-6.75 (m, 1H), 3.83 (s, 2H), 2.51-2.50 (m, 2H), 2.04-2.02 (m, 1H), 1.67-1.65 (m, 1H), 1.60-1.58 (m, 2H), 1.35- 1.32 (m, 2H), 1.07 (d. J = 6.6 Hz, 6H), 1.00 ( s, 9H), 0.23 (s, 6H); LC-MS 559 (MH +)

[단계 2] 3-(6-(4-(((2R,6S)-2,6-다이메틸피페리딘-1-일)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(4-(((2R,6S)-2,6-dimethylpiperidin-1-yl)methyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0059)의 제조[Step 2] 3- (6- (4-(((2R, 6S) -2,6-dimethylpiperidin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidine 4-ylamino) phenol hydrochloride (3- (6- (4-(((2R, 6S) -2,6-dimethylpiperidin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4 Preparation of -ylamino) phenol.HCl) (LCB03-0059)

¹H-NMR (600 MHz, DMSO-d₆); δ 8.78 (s, 1H), 7.99-7.93 (m, 3H), 7.78 (d, J = 8.4 Hz, 1H), 7.74 (d, J= 8.4 Hz, 1H), 7.24-7.21 (m, 2H), 7.14-7.13 (m, 1H), 6.89-6.88 (m, 1H), 4.56 (s, 1H), 4.39 (s, 1H), 3.38-3.36 (m, 2H), 3.09-3.08 (m, 1H), 1.85-1.82 (m, 1H), 1.76-1.70 (m, 3H), 1.68-1.60 (m, 1H), 1.56 (d, J = 6.0 Hz, 3H), 1.30 (d, J = 6.6 Hz, 3H); LC-MS: 445 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 8.78 (s, 1H), 7.99-7.93 (m, 3H), 7.78 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.24-7.21 (m, 2H), 7.14-7.13 (m, 1H), 6.89-6.88 (m, 1H), 4.56 (s, 1H), 4.39 (s, 1H), 3.38-3.36 (m, 2H), 3.09-3.08 (m, 1H), 1.85-1.82 (m, 1H), 1.76-1.70 (m, 3H), 1.68-1.60 (m, 1H), 1.56 (d, J = 6.0 Hz, 3H), 1.30 (d, J = 6.6 Hz, 3H) ; LC-MS: 445 (MH < + >)

[실시예 40]Example 40

[단계 1] 1-(4-(4-(3-(tert-부틸다이메틸실릴옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-2-카복사마이드 (1-(4-(4-(3-(tert- butyldimethylsilyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)benzyl)pyrrolidine-2-carboxamide) 의 제조[Step 1] 1- (4- (4- (3- (tert-Butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine- Preparation of 2-carboxamide (1- (4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxamide)

¹H-NMR (600 MHz, CDCl₃); δ 8.72 (s, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.60 (s, 1H), 7.38 (d, J = 7.8 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 7.20-7.15 (m, 2H), 6.87 (brs, 1H), 6.76 (dd, J = 2.4, 8.4 Hz, 1H), 5.40 (s, 1H), 3.98 (d, J = 13.8 Hz, 1H), 3.55 (d, J = 13.8 Hz, 1H), 3.22 (dd, J = 5.4, 10.2 Hz, 1H), 3.08-3.00 (m, 1H), 2.40-2.35 (m, 1H), 2.29-2.24 (m, 1H), 2.08-1.94 (m, 2H), 1.84-1.76 (m, 2H), 1.00 (s, 9H), 0.25 (s, 6H); LC-MS 560 (MH+) ¹ H-NMR (600 MHz, CDCl ₃ ); δ 8.72 (s, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.60 (s, 1H), 7.38 (d, J = 7.8 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H) , 7.20-7.15 (m, 2H), 6.87 (brs, 1H), 6.76 (dd, J = 2.4, 8.4 Hz, 1H), 5.40 (s, 1H), 3.98 (d, J = 13.8 Hz, 1H), 3.55 (d, J = 13.8 Hz, 1H), 3.22 (dd, J = 5.4, 10.2 Hz, 1H), 3.08-3.00 (m, 1H), 2.40-2.35 (m, 1H), 2.29-2.24 (m, 1H), 2.08-1.94 (m, 2H), 1.84-1.76 (m, 2H), 1.00 (s, 9H), 0.25 (s, 6H); LC-MS 560 (MH +)

[단계 2] 1-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-2-카복사마이드 염산염 (1-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)benzyl)pyrrolidine-2-carboxamide. HCl) (LCB03-0068)의 제조[Step 2] 1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxamide hydrochloride ( Preparation of 1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxamide.HCl) (LCB03-0068)

¹H-NMR (400 MHz, DMSO-d₆); δ 9.78 (brs, 1H), 8.81 (s, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.70-7.68 (m, 1H), 7.46 (brs, 1H), 7.25-7.10 (m, 3H), 6.70 (d, J = 8.0 Hz, 1H), 4.49-4.40 (m, 3H), 4.17 (br, 2H), 3.35-3.32 (m, 2H), 2.08-2.07 (m, 2H), 1.91-1.84 (m, 2H); LC-MS: 446 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.78 (brs, 1H), 8.81 (s, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.70-7.68 (m, 1H), 7.46 (brs, 1H), 7.25-7.10 (m, 3H), 6.70 (d, J = 8.0 Hz, 1H), 4.49-4.40 (m, 3H), 4.17 (br, 2H), 3.35-3.32 (m, 2H), 2.08-2.07 (m, 2H), 1.91-1.84 (m, 2H); LC-MS: 446 (MH < + >)

[실시예 41]Example 41

[단계 1] 2-(4-(4-(3-(tert-부틸다이메틸실릴옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벨질아미노)에탄올 (2-(4-(4-(3-(tert-butyldimethylsilyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)benzylamino)ethanol) 의 제조[Step 1] 2- (4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) belzylamino) ethanol (2 Preparation of-(4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzylamino) ethanol)

¹H-NMR (400 MHz, CDCl₃); δ 8.67 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.57 (s, 1H), 7.39 (d, J= 8.0 Hz, 2H), 7.26 (t, J= 8.0 Hz, 1H), 7.19-7.14 (m, 2H), 6.77-6.74 (m, 1H), 3.88 (s, 2H), 3.66-3.64 (m, 2H), 2.04-2.01 (m, 2H), 1.00 (s, 9H), 0.23 (s, 6H); LC-MS 507 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.67 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.57 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 8.0 Hz, 1H) , 7.19-7.14 (m, 2H), 6.77-6.74 (m, 1H), 3.88 (s, 2H), 3.66-3.64 (m, 2H), 2.04-2.01 (m, 2H), 1.00 (s, 9H) , 0.23 (s, 6 H); LC-MS 507 (MH +)

[단계 2] 3-(6-(4-((2-하이드록시에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘- 4-일아미노)페놀 염산염 (3-(6-(4-((2-hydroxyethylamino)methyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0070)의 제조[Step 2] 3- (6- (4-((2-hydroxyethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride (3- (6 Preparation of-(4-((2-hydroxyethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0070)

¹H-NMR (600 MHz, DMSO-d₆); δ 9.23 (brs, 2H), 8.77 (s, 1H), 7.95 (s, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.72 (d, J= 7.2 Hz, 2H), 7.23-7.20 (m, 2H), 7.14-7.13 (m, 1H), 6.67 -6.66 (m, 1H), 4.23 (t, J= 5.4 Hz, 2H), 3.72-3.67 (m, 2H), 2.99-2.98 (m, 2H); LC-MS 393 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 9.23 (brs, 2H), 8.77 (s, 1H), 7.95 (s, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.72 (d, J = 7.2 Hz, 2H), 7.23-7.20 ( m, 2H), 7.14-7.13 (m, 1H), 6.67 -6.66 (m, 1H), 4.23 (t, J = 5.4 Hz, 2H), 3.72-3.67 (m, 2H), 2.99-2.98 (m, 2H); LC-MS 393 (MH +)

[실시예 42] 6-(4-(피롤리딘-1-일메틸)페닐)-N-(3-(트라이플로로메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (6-(4-(pyrrolidin-1-ylmethyl)phenyl)-N-(3-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) (LCB03-0077)의 제조Example 42 6- (4- (pyrrolidin-1-ylmethyl) phenyl) -N- (3- (trifluoromethyl) phenyl) thieno [3,2-d] pyrimidine-4 Preparation of -amine (6- (4- (pyrrolidin-1-ylmethyl) phenyl) -N- (3- (trifluoromethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine) (LCB03-0077)

¹H-NMR (400 MHz, CDCl₃); δ 8.76 (s, 1H), 7.99 (s, 1H), 7.89 (d, J =8Hz, 1H), 7.66-7.63 (m, 3H), 7.53 (t, J=8Hz, 1H), 7.44 (m, 3H), 7.05 (br, 1H), 3.68 (s, 2H), 2.55 (s, 4H), 1.81 (s, 4H); LC-MS 454 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.76 (s, 1H), 7.99 (s, 1H), 7.89 (d, J = 8 Hz, 1H), 7.66-7.63 (m, 3H), 7.53 (t, J = 8 Hz, 1H), 7.44 (m, 3H), 7.05 (br, 1H), 3.68 (s, 2H), 2.55 (s, 4H), 1.81 (s, 4H); LC-MS 454 (MH +)

[실시예 43] N-(3-(다이플로로메틸)페닐)-6-(4-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(difluoromethyl)phenyl)-6-(4-(pyrrolidin-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) (LCB03-0078)의 제조Example 43 N- (3- (difluoromethyl) phenyl) -6- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidine-4 Preparation of -amine (N- (3- (difluoromethyl) phenyl) -6- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine) (LCB03-0078)

¹H-NMR (400 MHz, CDCl₃); δ 8.75 (s, 1H), 7.87 (s, 1H), 7.79 (d, J= 8.0 Hz, 1H), 7.69-7.63 (m, 3H), 7.51 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 6.90(brs, 1H), 6.70 (t, J = 56.4 Hz, 1H), 3.79 (s, 2H), 2.69 (s, 4H), 1.88 (s, 4H); LC-MS 436 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.75 (s, 1H), 7.87 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.69-7.63 (m, 3H), 7.51 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 6.90 (brs, 1H), 6.70 (t, J = 56.4 Hz, 1H), 3.79 (s, 2H), 2.69 (s, 4H), 1.88 (s, 4H); LC-MS 436 (MH +)

[실시예 44]Example 44

[단계 1] 1-(4-(4-(3-(터트-부틸다이메틸실릴옥시)페닐아미노)사이에토[3,2-d]피리미딘-6-일)벤질)피롤리딘-3-올 (1-(4-(4-(3-(tert-butyldimethylsilyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)benzyl)pyrrolidin-3-ol) 의 제조[Step 1] 1- (4- (4- (3- (tert-Butyldimethylsilyloxy) phenylamino) cyto [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine- Preparation of 3-ol (1- (4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidin-3-ol)

¹H-NMR (400 MHz, CDCl₃); δ 8.69 (s, 1H), 7.63 (d, J =5.2 Hz, 2H), 7.59 (s, 1H), 7.41 (d, J = 5.6 Hz, 2H), 7.28-7.25 (m, 1H), 7.19 (t, J= 1.6 Hz, 1H), 7.15 (d, J = 5.2 Hz, 1H), 6.18 (br, 1H), 6.75 (d, J = 5.2 Hz, 1H), 4.36-4.35 (m, 1H), 3.69 (s, 2H), 2.93-2.89 (m, 1H), 2.72 (d, J = 6.4 Hz, 1H), 2.59-2.56 (m, 1H), 2.36-2.33 (m, 1H), 2.25-2.19 (m, 1H), 2.04-2.02 (m, 1H), 1.80-1.76 (m, 1H), 1.00 (s, 9H), 0.24 (s, 6H); LC-MS 533.2 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.63 (d, J = 5.2 Hz, 2H), 7.59 (s, 1H), 7.41 (d, J = 5.6 Hz, 2H), 7.28-7.25 (m, 1H), 7.19 ( t, J = 1.6 Hz, 1H), 7.15 (d, J = 5.2 Hz, 1H), 6.18 (br, 1H), 6.75 (d, J = 5.2 Hz, 1H), 4.36-4.35 (m, 1H), 3.69 (s, 2H), 2.93-2.89 (m, 1H), 2.72 (d, J = 6.4 Hz, 1H), 2.59-2.56 (m, 1H), 2.36-2.33 (m, 1H), 2.25-2.19 ( m, 1H), 2.04-2.02 (m, 1H), 1.80-1.76 (m, 1H), 1.00 (s, 9H), 0.24 (s, 6H); LC-MS 533.2 (MH +)

[단계 2] 1-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-3-올 염산염 (1-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)benzyl)pyrrolidin-3-ol. HCl) (LCB03-0072)의 제조[Step 2] 1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidin-3-ol hydrochloride (1- Preparation of (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidin-3-ol.HCl) (LCB03-0072)

¹H-NMR (400 MHz, DMSO-d₆); δ 10.82 (br, 1H), 9.71 (br, 1H), 8.74 (s, 1H), 7.96 (m, 3H), 7.76 (m, 2H), 7.20 (m, 3H), 6.65 (d, J=8.4Hz, 1H), 4.45 (m, 4H), 3.71-3.43 (m, 3H), 2.40 (m, 1H), 2.13 (m, 1H), 2.02 (m, 1H) ); LC-MS 419.2 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.82 (br, 1H), 9.71 (br, 1H), 8.74 (s, 1H), 7.96 (m, 3H), 7.76 (m, 2H), 7.20 (m, 3H), 6.65 (d, J = 8.4 Hz, 1H), 4.45 (m, 4H), 3.71-3.43 (m, 3H), 2.40 (m, 1H), 2.13 (m, 1H), 2.02 (m, 1H)); LC-MS 419.2 (MH +)

[실시예 45] 3-(6-(4-((2-(하이드록시메틸)피롤리딘-1-일)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(4-((2-(hydroxymethyl)pyrrolidin-1-yl)methyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol, HCl) (LCB03-0057)의 제조Example 45 3- (6- (4-((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-yl Amino) phenol hydrochloride (3- (6- (4-((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol, HCl) (LCB03 Preparation of

¹H-NMR (400 MHz, DMSO-d₆); δ 8.89 (s, 1H), 8.02 (s, 1H), 8.17-7.98 (m, 2H), 7.77-7.76 (m, 2H), 7.30-7.27 (m, 1H), 7.26 (s, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.75 (d, J= 7.2 Hz, 1H), 4.69 (dd, J = 2.8, 8.8 Hz, 1H), 4.38 (dd, J = 4.4, 8.8 HZ, 1H), 3.75-3.64 (m, 3H), 3.32-3.31 (m, 1H), 3.21-3.17 (m, 1H), 2.18-2.13 (m, 1H), 2.02-2.00 (m, 1H), 1.91-1.80 (m, 2H); LC-MS: 433 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 8.89 (s, 1H), 8.02 (s, 1H), 8.17-7.98 (m, 2H), 7.77-7.76 (m, 2H), 7.30-7.27 (m, 1H), 7.26 (s, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 4.69 (dd, J = 2.8, 8.8 Hz, 1H), 4.38 (dd, J = 4.4, 8.8 HZ, 1H) , 3.75-3.64 (m, 3H), 3.32-3.31 (m, 1H), 3.21-3.17 (m, 1H), 2.18-2.13 (m, 1H), 2.02-2.00 (m, 1H), 1.91-1.80 ( m, 2H); LC-MS: 433 (MH < + >)

[실시예 46] 1-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-2-카복실산 염산염 (1-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)benzyl)pyrrolidine-2-carboxylic acid. HCl) (LCB03-0069)의 제 조Example 46 1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxylic acid hydrochloride (1 Preparation of-(4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxylic acid.HCl) (LCB03-0069)

¹H-NMR (400 MHz, DMSO-d₆); δ 8.65 (s, 1H), 7.98 (s, 1H), 7.96 (d, J= 8.4 Hz, 2H), 7.68 (d, J= 8.4 Hz, 2H), 7.27 (s, 1H), 7.18-7.17 (m, 2H), 6.59-6.58 (m, 1H), 4.55-4.39 (m, 2H), 3.45-3.40 (m, 3H), 2.51-2.49 (m, 2H); LC-MS: 447 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 8.65 (s, 1H), 7.98 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.27 (s, 1H), 7.18-7.17 ( m, 2H), 6.59-6.58 (m, 1H), 4.55-4.39 (m, 2H), 3.45-3.40 (m, 3H), 2.51-2.49 (m, 2H); LC-MS: 447 (MH < + >)

[실시예 47] 4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)-N-(1-하이드록시프로판-2-일)벤즈아마이드 염산염 (4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)-N-(1-hydroxypropan-2-yl)benzamide. HCl)) (LCB03-0074)의 제조Example 47 4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) -N- (1-hydroxypropan-2-yl) benz Amide hydrochloride (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) -N- (1-hydroxypropan-2-yl) benzamide.HCl)) (LCB03-0074) of Produce

¹H-NMR (400 MHz, DMSO-d₆); δ 10.65 (brs, 1H), 8.80 (s, 1H), 8.29 (d, J= 8.0 Hz, 1H), 8.04-7.95 (m, 4H),7.24 ( d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.07-4.02 (m, 1H), 3.52- 3.49 (m, 2H), 1.10 (d, J = 8.0 Hz, 3H); LC-MS 421 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.65 (brs, 1H), 8.80 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.04-7.95 (m, 4H), 7.24 (d, J = 8.0 Hz, 1H), 7.21 ( s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.07-4.02 (m, 1H), 3.52- 3.49 (m, 2H), 1.10 (d , J = 8.0 Hz, 3H); LC-MS 421 (MH +)

[실시예 48]Example 48

[단계 1] N-(3-(터트-부틸다이메틸실릴옥시)페닐)-6-(3-(피페리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(tert-butyldimethylsilyloxy)phenyl)-6-(3-(piperidin-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3- (piperidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidine Preparation of -4-amine (N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3- (piperidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.70 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.57-7.56 (m, 1H), 7.39-7.38 (m, 2H), 7.27-7.25 (m, 1H), 7.21 (m, 1H), 7.17-7.16 (m, 1H), 6.76-6.73 (m, 2H), 3.52 (s, 2H), 2.41-2.39 (m, 4H), 1.62-1.58 (m, 4H), 1.45-1.44 (m, 2H), 1.00 (s, 9H), 0.24 (s, 6H);LC-MS 531 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.70 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.57-7.56 (m, 1H), 7.39-7.38 (m, 2H), 7.27-7.25 (m, 1H), 7.21 (m, 1H), 7.17-7.16 (m, 1H), 6.76-6.73 (m, 2H), 3.52 (s, 2H), 2.41-2.39 (m, 4H), 1.62-1.58 (m, 4H), 1.45 -1.44 (m, 2H), 1.00 (s, 9H), 0.24 (s, 6H); LC-MS 531 (MH +)

[단계 2] 3-(6-(3-(피페리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(3-(piperidin-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0060)의 제조[Step 2] 3- (6- (3- (piperidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride (3- (6- Preparation of (3- (piperidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0060)

1H-NMR (400 MHz, DMSO-d₆); δ 10.54 (br, 1H), 9.65 (br, 1H), 8.76 (s, 1H), 8.23 (s, 1H), 7.95 (s,1H), 7.89 (m, 1H), 7.70-7.69 (m, 1H), 7.66-7.63 (t, J = 5.2 Hz, 1H), 7.21 (m, 2H), 7.14 (d, J = 4.8 Hz, 1H), 6.65 (m, 1H), 4.36 (s, 2H), 3.40-3.32 (m, 4H), 1.79 (m, 4H), 1.37 (m, 2H); LC-MS 417 (MH+)1 H-NMR (400 MHz, DMSO-d ₆ ); δ 10.54 (br, 1H), 9.65 (br, 1H), 8.76 (s, 1H), 8.23 (s, 1H), 7.95 (s, 1H), 7.89 (m, 1H), 7.70-7.69 (m, 1H ), 7.66-7.63 (t, J = 5.2 Hz, 1H), 7.21 (m, 2H), 7.14 (d, J = 4.8 Hz, 1H), 6.65 (m, 1H), 4.36 (s, 2H), 3.40 -3.32 (m, 4H), 1.79 (m, 4H), 1.37 (m, 2H); LC-MS 417 (MH +)

[실시예 49]Example 49

[단계 1] N-(3-(터트-부틸다이메틸실릴옥시)페닐)-6-(3-((4-메틸피페라진-1-일)메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(tert-butyldimethylsilyloxy)phenyl)-6-(3-((4-methylpiperazin-1-yl)methyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2- d] pyrimidin-4-amine (N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin Preparation of -4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.70 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.59-7.57 (m,1H), 7.40-7.37 (m, 2H), 7.27-7.25 (m, 1H), 7.22-7.21 (m, 1H), 7.18-7.16 (m, 1H), 6.78 (br, 1H), 6.76-6.73 (m, 1H), 3.64 (s, 2H), 2.65-2.64 (m, 4H), 2.44 (s, 3H), 1.47-1.45 (m, 4H), 1.00 (s, 9H), 0.24 (s, 6H);LC-MS 546.2 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.70 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.59-7.57 (m, 1H), 7.40-7.37 (m, 2H), 7.27-7.25 (m, 1H), 7.22 -7.21 (m, 1H), 7.18-7.16 (m, 1H), 6.78 (br, 1H), 6.76-6.73 (m, 1H), 3.64 (s, 2H), 2.65-2.64 (m, 4H), 2.44 (s, 3H), 1.47-1.45 (m, 4H), 1.00 (s, 9H), 0.24 (s, 6H); LC-MS 546.2 (MH +)

[단계 2] 3-(6-(3-((4-메틸피페라진-1-일)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(3-((4-methylpiperazin-1-yl)methyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0061)의 제조[Step 2] 3- (6- (3-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride (3 Preparation of-(6- (3-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0061)

¹H-NMR (400 MHz, DMSO-d₆); δ 10.54 (br, 1H), 9.65 (brs, 1H), 8.84 (s, 1H), 7.94 (s, 1H), 7.87 (m, 1H), 7.76 (m, 1H), 7.64 (t, J = 4.8 Hz, 1H), 7.26-7.23 (m, 2H), 7.18 (m, 1H), 7.14-7.12 (m, 1H), 6.72 (m, 1H), 3.76 (s, 2H), 2.81-2.80 (m, 4H), 2.47 (s, 3H), 1.41 (m, 4H); LC-MS 432 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.54 (br, 1H), 9.65 (brs, 1H), 8.84 (s, 1H), 7.94 (s, 1H), 7.87 (m, 1H), 7.76 (m, 1H), 7.64 (t, J = 4.8 Hz, 1H), 7.26-7.23 (m, 2H), 7.18 (m, 1H), 7.14-7.12 (m, 1H), 6.72 (m, 1H), 3.76 (s, 2H), 2.81-2.80 (m, 4H), 2.47 (s, 3H), 1.41 (m, 4H); LC-MS 432 (MH +)

[실시예 50]Example 50

[단계 1] N-(3-(터트-부틸다이메틸실릴옥시)페닐)-6-(3-(피롤리딘-1-일메틸)페닐 (사이에토[3,2-d]피리미딘-4-아민 (N-(3-(tert-butyldimethylsilyloxy)phenyl)-6- (3-(pyrrolidin-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3- (pyrrolidin-1-ylmethyl) phenyl (cyto [3,2-d] pyrimidine Preparation of 4-amine (N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.70 (s, 1H), 7.73 (s, 1H), 7.62-7.60 (m, 2H), 7.46-7.40 (m, 2H), 7.29-7.25 (m, 1H), 7.22 (m, 1H), 7.18-7.17 (m, 1H), 6.88 (br, 1H), 6.75-6.73 (m, 1H), 3.79 (s, 2H), 2.68-2.65 (m, 4H), 1.87-1.85 (m, 4H), 1.00 (s, 9H), 0.24 (s, 6H); LC-MS 518 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.70 (s, 1H), 7.73 (s, 1H), 7.62-7.60 (m, 2H), 7.46-7.40 (m, 2H), 7.29-7.25 (m, 1H), 7.22 (m, 1H), 7.18 -7.17 (m, 1H), 6.88 (br, 1H), 6.75-6.73 (m, 1H), 3.79 (s, 2H), 2.68-2.65 (m, 4H), 1.87-1.85 (m, 4H), 1.00 (s, 9H), 0.24 (s, 6H); LC-MS 518 (MH +)

[단계 2] 3-(6-(3-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(3-(pyrrolidin-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0062)의 제조[Step 2] 3- (6- (3- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride (3- (6- Preparation of (3- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0062)

¹H-NMR (400 MHz, DMSO-d₆); δ 11.22 (br, 1H), 9.65 (br, 1H), 8.81 (s, 1H), 8.27 (s, 1H), 7.96 (s, 1H), 7.86 (m, 1H), 7.75-7.73 (m, 1H), 7.64 (t, J = 4.8 Hz, 1H), 7.25-7.22 (m, 2H), 7.14-7.12 (m, 1H), 6.69 (m, 1H), 4.45 (d J = 4.0 Hz, 2H), 3.51-3.46 (m, 2H), 3.38-3.37 (m, 2H), 2.04 (m, 2H), 1.91 (m, 2H); LC-MS 403 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 11.22 (br, 1H), 9.65 (br, 1H), 8.81 (s, 1H), 8.27 (s, 1H), 7.96 (s, 1H), 7.86 (m, 1H), 7.75-7.73 (m, 1H ), 7.64 (t, J = 4.8 Hz, 1H), 7.25-7.22 (m, 2H), 7.14-7.12 (m, 1H), 6.69 (m, 1H), 4.45 (d J = 4.0 Hz, 2H), 3.51-3.46 (m, 2H), 3.38-3.37 (m, 2H), 2.04 (m, 2H), 1.91 (m, 2H); LC-MS 403 (MH +)

[실시예 51][Example 51]

[단계 1] N-(3-(터트-부틸다이메틸실릴옥시)페닐)-6-(3-((다이에틸아미노)메틸)페닐싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(tert-butyldimethylsilyloxy)phenyl)-6-(3-((diethylamino)methyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3-((diethylamino) methyl) phenylthieno [3,2-d] pyrimidine-4- Preparation of Amine (N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3-((diethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.68 (s, 1H), 7.67 (s, 1H), 7.62-7.58 (m, 2H), 7.47-7.39 (m, 2H), 7.28-7.24 (m,1H), 7.20-7.16 (m, 2H), 6.76-6.73 (m, 1H), 3.76 (s, 2H), 2.70-2.68 (m, 4H), 1.15 (t, J= 7.2 Hz, 6H), 0.99 (s, 9H), 0.24 (s, 6H); LC-MS 519.2 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.68 (s, 1H), 7.67 (s, 1H), 7.62-7.58 (m, 2H), 7.47-7.39 (m, 2H), 7.28-7.24 (m, 1H), 7.20-7.16 (m, 2H) , 6.76-6.73 (m, 1H), 3.76 (s, 2H), 2.70-2.68 (m, 4H), 1.15 (t, J = 7.2 Hz, 6H), 0.99 (s, 9H), 0.24 (s, 6H ); LC-MS 519.2 (MH < + >)

[단계 2] 3-(6-(3-((다이에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(3-((diethylamino)methyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0063)의 제조[Step 2] 3- (6- (3-((diethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride (3- (6- (3 Preparation of-((diethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0063)

¹H-NMR (400 MHz, DMSO-d₆); δ 10.86 (brs 1H), 9.79 (m, 1H), 8.81 (s, 1H), 8.32 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.21 (m, 2H), 7.14 (s, 1H),6.68 (s, 1H), 4.39 (s, 2H), 3.08 (m, 4H), 1.28 (s, 6H); LC-MS 405 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.86 (brs 1H), 9.79 (m, 1H), 8.81 (s, 1H), 8.32 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.21 (m, 2H), 7.14 (s, 1H), 6.68 (s, 1H), 4.39 (s, 2H), 3.08 (m, 4H), 1.28 (s, 6H); LC-MS 405 (MH +)

[실시예 52][Example 52]

[단계 1] 터트-부틸 4-(3-(4-(3-(터트-부틸다이메틸실릴옥시)페닐아미노)사이에토[3,2-d]피페라진-1-카복실레이트 (tert-butyl 4-(3-(4-(3-(tert-butyldimethylsilyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)benzyl)piperazine-1-carboxylate) 의 제조[Step 1] tert-butyl 4- (3- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) cyto [3,2-d] piperazine-1-carboxylate (tert- Preparation of butyl 4- (3- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) piperazine-1-carboxylate)

¹H-NMR (400 MHz, CDCl₃); δ 8.70 (s, 1H), 7.73 (s, 1H), 7.62-7.60 (m, 2H), 7.46-7.40 (m, 2H), 7.29-7.25 (m, 1H), 7.21 (m, 1H), 7.18-7.16 (m, 1H), 6.84 (br, 1H), 6.76-6.73 (m, 1H), 3.56 (d, J =3.6Hz, 2H), 3.45 (m, 4H), 2.42 (m, 4H), 1.46 (s, 9H), 1.00 (s, 9H), 0.24 (s, 6H); LC-MS 632.5 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.70 (s, 1H), 7.73 (s, 1H), 7.62-7.60 (m, 2H), 7.46-7.40 (m, 2H), 7.29-7.25 (m, 1H), 7.21 (m, 1H), 7.18 -7.16 (m, 1H), 6.84 (br, 1H), 6.76-6.73 (m, 1H), 3.56 (d, J = 3.6 Hz, 2H), 3.45 (m, 4H), 2.42 (m, 4H), 1.46 (s, 9H), 1.00 (s, 9H), 0.24 (s, 6H); LC-MS 632.5 (MH +)

[단계 2] 3-(6-(3-(피페라진-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(3-(piperazin-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0064)의 제조[Step 2] 3- (6- (3- (piperazin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride (3- (6- ( Preparation of 3- (piperazin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0064)

¹H-NMR (400 MHz, DMSO-d₆); δ 10.75 (br, 1H), 9.44 (br, 1H), 8.80 (s, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.89 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 4.4 Hz, 1H), 7.65 (t, J = 5.2 Hz, 1H), 7.23 (t, J= 5.6 Hz, 1H), 7.19 (s, 1H), 7.13 (d, J = 5.2 Hz, 1H), 6.69 (d, J = 5.2 Hz, 1H), 3.76 (s, 2H), 2.81-2.80 (m, 4H), 2.47 (m, 4H); LC-MS 418 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.75 (br, 1H), 9.44 (br, 1H), 8.80 (s, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.89 (d, J = 5.2 Hz, 1H), 7.74 ( d, J = 4.4 Hz, 1H), 7.65 (t, J = 5.2 Hz, 1H), 7.23 (t, J = 5.6 Hz, 1H), 7.19 (s, 1H), 7.13 (d, J = 5.2 Hz, 1H), 6.69 (d, J = 5.2 Hz, 1H), 3.76 (s, 2H), 2.81-2.80 (m, 4H), 2.47 (m, 4H); LC-MS 418 (MH +)

[실시예 53][Example 53]

[단계 1] N-(3-(터트-부틸다이메틸실릴옥시)페닐)-6-(3-((에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(tert-butyldimethylsilyloxy)phenyl)-6-(3-((ethylamino)methyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3-((ethylamino) methyl) phenyl) thieno [3,2-d] pyrimidine-4- Preparation of Amine (N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3-((ethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.70 (s, 1H), 7.67 (s, 1H), 7.62 (s,1H), 7.57-7.55 (m, 1H), 7.42-7.38 (m, 1H), 7.29-7.25 (m, 1H), 7.21 (t, J =1.2 Hz, 1H), 7.17 (m, 1H), 6.75-6.73 (m, 2H), 3.87 (s, 2H), 2.74 (q, J =4.8Hz, 2H), 1.18 (t, J=4.8Hz, 3H), 1.00 (s, 9H), 0.24 (s, 6H); LC-MS 491.2 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.70 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.57-7.55 (m, 1H), 7.42-7.38 (m, 1H), 7.29-7.25 (m, 1H), 7.21 (t, J = 1.2 Hz, 1H), 7.17 (m, 1H), 6.75-6.73 (m, 2H), 3.87 (s, 2H), 2.74 (q, J = 4.8 Hz, 2H), 1.18 (t, J = 4.8 Hz, 3H), 1.00 (s, 9H), 0.24 (s, 6H); LC-MS 491.2 (MH +)

[단계 2] 3-(6-(3-((에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(3-((ethylamino)methyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0065)의 제조[Step 2] 3- (6- (3-((ethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride (3- (6- (3- Preparation of ((ethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0065)

¹H-NMR (400 MHz, DMSO-d₆); δ 9.68 (br, 1H), 9.24 (br, 1H), 8.78 (s, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.88 (m, 1H), 7.67 (m, 1H), 7.63 (m, 1H), 7.22 (m, 2H), 7.14 (m, 1H), 6.68 (m, 1H), 4.23 (m, 2H), 3.01 (m, 2H), 1.25 (t, J = 4.8 Hz, 3H); LC-MS 377 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.68 (br, 1H), 9.24 (br, 1H), 8.78 (s, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.88 (m, 1H), 7.67 (m, 1H), 7.63 (m, 1H), 7.22 (m, 2H), 7.14 (m, 1H), 6.68 (m, 1H), 4.23 (m, 2H), 3.01 (m, 2H), 1.25 (t, J = 4.8 Hz , 3H); LC-MS 377 (MH +)

[실시예 54]Example 54

[단계 1] N-(3-(터트-부틸다이메틸실릴옥시)페닐)-6-(3-(모폴리노메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(tert-butyldimethylsilyloxy)phenyl)-6-(3-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3- (morpholinomethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine Preparation of (N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3- (morpholinomethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.69 (s, 1H), 7.73 (s, 1H), 7.62-7.60 (m, 2H), 7.46-7.40 (m, 2H), 7.29 (m, 1H), 7.25-7.24 (m, 2H), 7.21-7.19 (m, 1H), 6.73-6.71 (m, 1H), 3.73 (t, J =2.8 Hz, 4H), 3.55 (s, 2H), 2.48 (br, 4H), 0.99 (s, 9H), 0.24 (s, 6H); LC-MS 533.5 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.73 (s, 1H), 7.62-7.60 (m, 2H), 7.46-7.40 (m, 2H), 7.29 (m, 1H), 7.25-7.24 (m, 2H), 7.21 -7.19 (m, 1H), 6.73-6.71 (m, 1H), 3.73 (t, J = 2.8 Hz, 4H), 3.55 (s, 2H), 2.48 (br, 4H), 0.99 (s, 9H), 0.24 (s, 6 H); LC-MS 533.5 (MH +)

[단계 2] 3-(6-(3-(모폴리노메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(3-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0066)의 제조[Step 2] 3- (6- (3- (morpholinomethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride (3- (6- (3- ( Preparation of morpholinomethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0066)

¹H-NMR (400 MHz, DMSO-d₆); δ 10.86 (br, 1H), 9.80 (br, 1H), 8.81 (s, 1H), 8.28 (s,1H), 7.95 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.25-7.19 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 6.69 (d, J= 7.6 Hz, 1H), 4.44 (s, 2H), 3.93-3.85 (m, 3H), 3.82 (t, J = 12 Hz, 1H), 2.48 (br, 4H); LC-MS 419 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.86 (br, 1H), 9.80 (br, 1H), 8.81 (s, 1H), 8.28 (s, 1H), 7.95 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.73 ( d, J = 7.6 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.25-7.19 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 4.44 (s, 2H), 3.93-3.85 (m, 3H), 3.82 (t, J = 12 Hz, 1H), 2.48 (br, 4H); LC-MS 419 (MH +)

[실시예 55]Example 55

[단계 1] N-(3-(터트-부틸다이메티실릴옥시)페닐)-6-(3-((아이소부틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(tert-butyldimethylsilyloxy)phenyl)-6-(3-((isobutylamino)methyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3-((isobutylamino) methyl) phenyl) thieno [3,2-d] pyrimidine-4 Preparation of -amine (N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (3-((isobutylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.69 (s, 1H), 7.66 (s, 1H), 7.61 (s, 1H), 7.55 (d, J= 4.4 Hz, 1H), 7.40-7.38 (m, 2H), 7.26 (t, J = 5.2 Hz, 1H), 7.20 (t, J =1.2 Hz, 1H), 7.16 (d, J= 5.2 Hz, 1H), 7.08 (br, 1H), 6.75 (d, J = 4.4 Hz, 1H), 3.85 (s, 2H), 2.47 (d, J =4.8 Hz, 2H), 1.79 (m, 1H), 0.99 (s, 9H), 0.94 (d, J = 4.4 Hz, 6H), 0.24 (s, 6H); LC-MS 519 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.66 (s, 1H), 7.61 (s, 1H), 7.55 (d, J = 4.4 Hz, 1H), 7.40-7.38 (m, 2H), 7.26 (t, J = 5.2 Hz, 1H), 7.20 (t, J = 1.2 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 7.08 (br, 1H), 6.75 (d, J = 4.4 Hz, 1H), 3.85 ( s, 2H), 2.47 (d, J = 4.8 Hz, 2H), 1.79 (m, 1H), 0.99 (s, 9H), 0.94 (d, J = 4.4 Hz, 6H), 0.24 (s, 6H); LC-MS 519 (MH +)

[단계 2] 3-(6-(3-((아이소부틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(3-((isobutylamino)methyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0067)의 제조 [Step 2] 3- (6- (3-((isobutylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride (3- (6- (3 Preparation of-((isobutylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0067)

¹H-NMR (400 MHz, DMSO-d₆); δ 10.82 (br, 1H), 9.71 (br, 1H), 9.27 (br, 1H), 8.81 (s, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.25-7.19 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 6.70 (d, J= 8.8 Hz, 1H), 4.25 (s, 2H), 2.77-2.75 (m, 2H), 2.06-2.05(m, 1H), 0.96 (d, J = 6.4 Hz, 6H); LC-MS 405 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.82 (br, 1H), 9.71 (br, 1H), 9.27 (br, 1H), 8.81 (s, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.25-7.19 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 4.25 (s, 2H), 2.77-2.75 (m, 2H), 2.06-2.05 (m, 1H), 0.96 (d, J = 6.4 Hz, 6H); LC-MS 405 (MH +)

[실시예 56]Example 56

[단계 1] N-(3-(터트-부틸다이메틸실릴옥시)페닐)-6-(퓨란-2-일)싸이에노[3,2-d]피 리미딘-4-아민 (N-(3-(tert-butyldimethylsilyloxy)phenyl)-6-(furan-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (furan-2-yl) thieno [3,2-d] pyrimidin-4-amine (N- Preparation of (3- (tert-butyldimethylsilyloxy) phenyl) -6- (furan-2-yl) thieno [3,2-d] pyrimidin-4-amine)

제조예 5에서 합성한 화합물 (0.1 mg, 0.23 mmol), 2-퓨란보론산 (2-furanboronic acid) (33 mg, 0.27 mmol), 팔라듐 테트라키스트라이페닐포스핀 (53 mg, 0.04 mmol), 2N 탄산나트륨 (0.23 ml, 0.46 mmol)을 1,4-다이옥산 2 ml 에 넣고 2시간동안 환류교반 시켰다. 반응액에 포화된 탄산수소나트륨 50 ml와 다이클로로메테인 50 ml를 이용하여 추출하고 유기층을 포화된 탄산수소나타륨 50 ml로 2회 더 추출한 후 무수 황산나트륨을 이용하여 건조하고 감압농축 후 관크로마토그래피 (에틸아세테이트/n-헥세인, 1/3)를 이용하여 표제화합물 (76.3 mg, 78.9 %)을 노란색 고체로 수득하였다. Compound synthesized in Preparation Example 5 (0.1 mg, 0.23 mmol), 2-furanboronic acid (33 mg, 0.27 mmol), palladium tetrakistriphenylphosphine (53 mg, 0.04 mmol), 2N Sodium carbonate (0.23 ml, 0.46 mmol) was added to 2 ml of 1,4-dioxane and stirred under reflux for 2 hours. The reaction solution was extracted with 50 ml of saturated sodium bicarbonate and 50 ml of dichloromethane. The organic layer was extracted two more times with 50 ml of saturated sodium bicarbonate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography. (Ethyl acetate / n-hexane, 1/3) gave the title compound (76.3 mg, 78.9%) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃); δ 8.68 (s, 1H), 7.51-7.50 (m, 2H), 7.29-7.25 (m, 1H), 7.61-7.12 (m, 2H), 6.81 (brs, 1H), 6.78-6.75 (m, 2H), 6.52-6.51 (m, 1H), 1.00 (s, 9H), 0.23 (s, 6H); LC-MS 422 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.68 (s, 1H), 7.51-7.50 (m, 2H), 7.29-7.25 (m, 1H), 7.61-7.12 (m, 2H), 6.81 (brs, 1H), 6.78-6.75 (m, 2H) , 6.52-6.51 (m, 1H), 1.00 (s, 9H), 0.23 (s, 6H); LC-MS 422 (MH +)

[단계 2] 3-(6-(퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(furan-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0038)의 제조[Step 2] 3- (6- (furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride (3- (6- (furan-2-yl) thieno Preparation of [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0038)

¹H-NMR (400 MHz, DMSO-d₆); δ 11.10 (brs, 1H), 8.86 (s, 1H), 8.53 (s, 1H), 7.92 (t, J = 1.8 Hz, 1H), 7.71 (s, 1H), 7.24 (t, J= 8.0 Hz, 1H), 7.13 (s, 1H), 7.10-7.08 (m, 2H), 6.73 (dd, J = 1.6, 8.0 Hz, 1H); LC-MS 310 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 11.10 (brs, 1H), 8.86 (s, 1H), 8.53 (s, 1H), 7.92 (t, J = 1.8 Hz, 1H), 7.71 (s, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.10-7.08 (m, 2H), 6.73 (dd, J = 1.6, 8.0 Hz, 1H); LC-MS 310 (MH +)

상기 실시예 56과 유사한 방법으로 하기 화합물들을 합성하였다 The following compounds were synthesized in a similar manner to Example 56 above.

[실시예 57]Example 57

[단계 1] N-(3-(터트-부틸다이메틸실릴옥시)페닐)-6-(퓨란-3-일)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(tert-butyldimethylsilyloxy)phenyl)-6-(furan-3-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (furan-3-yl) thieno [3,2-d] pyrimidin-4-amine (N- ( Preparation of 3- (tert-butyldimethylsilyloxy) phenyl) -6- (furan-3-yl) thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.67 (s, 1H), 7.79 (s, 1H), 7.50 (t, J = 1.8 Hz, 1H), 7.37 (s. 1H), 7.28-7.24 (m, 1H), 7.15-7.11 (m, 2H), 6.79 (brs, 1H), 6.77-6.74 (m, 1H), 6.69-6.68 (m, 1H); LC-MS 422 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.67 (s, 1H), 7.79 (s, 1H), 7.50 (t, J = 1.8 Hz, 1H), 7.37 (s. 1H), 7.28-7.24 (m, 1H), 7.15-7.11 (m, 2H ), 6.79 (brs, 1 H), 6.77-6.74 (m, 1 H), 6.69-6.68 (m, 1 H); LC-MS 422 (MH +)

[단계 2] 3-(6-(퓨란-3-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(furan-3-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0039)의 제조[Step 2] 3- (6- (furan-3-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride (3- (6- (furan-3-yl) thieno Preparation of [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0039)

상기 단계 1에서 합성한 화합물 (63 mg, 0.15 mmol)을 다이클로로메테인 1 ml에 녹인 후 4M 염산/1,4-다이옥산 1mL과 메탄올 0.2 ml를 넣은 후, 실온에서 15시간 동안 교반 후 반응액을 감압농축하였다. 다이클로로메테인 2 ml, 메탄올 2 ml, 다이클로로메테인 2 ml과 다이에틸에테르 2 ml로 공비농축하고 진공건조하여 표제화합물 (42 mg, 90%)을 노란색의 고체로 수득하였다.The compound synthesized in step 1 (63 mg, 0.15 mmol) was dissolved in 1 ml of dichloromethane, 1 ml of 4M hydrochloric acid / 1,4-dioxane and 0.2 ml of methanol were added, followed by stirring at room temperature for 15 hours. Was concentrated under reduced pressure. Azeotropically concentrated with 2 ml of dichloromethane, 2 ml of methanol, 2 ml of dichloromethane and 2 ml of diethyl ether and dried under vacuum to afford the title compound (42 mg, 90%) as a yellow solid.

¹H-NMR (400 MHz, DMSO-d₆); δ 11.03 (brs, 1H), 8.84 (s, 1H), 7.94 (s, 1H), 7.72 (s, 1H), 7.39 (d, J = 3.6 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.78-6.74 (m, 2H); LC-MS 310 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 11.03 (brs, 1H), 8.84 (s, 1H), 7.94 (s, 1H), 7.72 (s, 1H), 7.39 (d, J = 3.6 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.78-6.74 (m, 2H); LC-MS 310 (MH +)

[실시예 58]Example 58

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(5-(피롤리딘-1-일메틸)싸이오펜-2-일) 싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(5-pyrrolidin-1-ylmethyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (5- (pyrrolidin-1-ylmethyl) thiophen-2-yl) thieno [3,2- d] pyrimidin-4-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (5-pyrrolidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4 -amine)

제조예 18에서 얻은 화합물 (24 mg, 0.05 mmol), 피롤리딘 (6.3 ㎕, 0.07 mmol)을 다이클로로에탄 1 ml에 순차적으로 넣고 20분간 교반한 후 초산 나트륨 (13 mg, 0.15 mmol)과 소디움트라이아세톡시보로하이드라이드 (64 mg, 0.30 mmol)을 넣고 7시간 동안 실온에서 교반하였다. 반응완료 후 다이클로로메테인 10 ml와 포화된 염화암모늄 수용액 10 ml를 이용하여 추출하였다. 유기층을 황산나트륨으로 건조하고 감압농축 후, 관크로마토그래피 (다이클로로메테인/메탄올, 40/1)를 시행하여 표제화합물 (21 mg, 78.6 %)을 노란색 고체로 수득하였다.Compound (24 mg, 0.05 mmol) and pyrrolidine (6.3 μl, 0.07 mmol) obtained in Preparation Example 18 were sequentially added to 1 ml of dichloroethane and stirred for 20 minutes, followed by sodium acetate (13 mg, 0.15 mmol) and sodium Triacetoxyborohydride (64 mg, 0.30 mmol) was added and stirred at room temperature for 7 hours. After completion of the reaction was extracted using 10 ml of dichloromethane and 10 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, followed by column chromatography (dichloromethane / methanol, 40/1) to give the title compound (21 mg, 78.6%) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃); δ 8.64 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.43 (s, 1H), 7.38-7.35 (m, 3H), 7.17 (d, J = 3.6 Hz, 1H), 6.89 (d, J = 8.8 HZ, 2H), 6.84-6.83 (m, 3H), 5.02 (s, 2H), 3.92 (s, 2H), 3.79 (s, 3H), 2.78-2.70 (m, 4H), 1.87-1.85 (m, 4H); LC-MS 529 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.64 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.43 (s, 1H), 7.38-7.35 (m, 3H), 7.17 (d, J = 3.6 Hz, 1H), 6.89 ( d, J = 8.8 HZ, 2H), 6.84-6.83 (m, 3H), 5.02 (s, 2H), 3.92 (s, 2H), 3.79 (s, 3H), 2.78-2.70 (m, 4H), 1.87 -1.85 (m, 4 H); LC-MS 529 (MH +)

[단계 2] 3-(6-(5-(피롤리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(5-(pyrrolidin-1- ylmethyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0085)의 제조[Step 2] 3- (6- (5- (pyrrolidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluor Preparation of Roacetic Acid (3- (6- (5- (pyrrolidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0085)

¹H-NMR (400 MHz, Acetone-d₆); δ 8.59 (s, 1H), 7.26-7.21 (m, 5H), 7.01 (d, J = 3.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 3.6 Hz, 1H), 6.75 (dd, J= 1.6, 8.4 Hz, 1H), 3.81 (s, 2H), 2.69-2.65(m, 4H), 2.04-2.02 (m, 4H); LC-MS 409 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 8.59 (s, 1H), 7.26-7.21 (m, 5H), 7.01 (d, J = 3.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 3.6 Hz, 1H), 6.75 (dd, J = 1.6, 8.4 Hz, 1H), 3.81 (s, 2H), 2.69-2.65 (m, 4H), 2.04-2.02 (m, 4H); LC-MS 409 (MH +)

상기 실시예 58과 유사한 방법으로 하기화합물을 합성하였다. In the same manner as in Example 58, the following compound was synthesized.

[실시예 59]Example 59

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(5-((4-메틸피페라진-1일)메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(5-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (5-((4-methylpiperazin-1 yl) methyl) thiophen-2-yl) thieno [3 , 2-d] pyrimidin-4-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (5-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) thieno [ 3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.67 (s, 1H), 7.39 (s, 1H), 7.37 (d, J= 8.8 Hz, 2H), 7.34-7.29 (m, 2H), 7.18 (d, J = 3.6 Hz, 1H), 7.09-7.07 (m, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.88 (d, J= 2.8 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.73 (brs, 1H), 5.03 (s, 2H), 3.81 (s, 3H), 3.71 (s, 2H), 2.50 (m, 4H), 2.20(s, 3H), 1.62 (m, 4H); LC-MS 558 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.67 (s, 1H), 7.39 (s, 1H), 7.37 (d, J = 8.8 Hz, 2H), 7.34-7.29 (m, 2H), 7.18 (d, J = 3.6 Hz, 1H), 7.09- 7.07 (m, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 2.8 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.73 (brs, 1H), 5.03 (s, 2H), 3.81 (s, 3H), 3.71 (s, 2H), 2.50 (m, 4H), 2.20 (s, 3H), 1.62 (m, 4H); LC-MS 558 (MH +)

[단계 2] 3-(6-(5-((4-메틸피페라진-1-일)메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(5-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0092)의 제조[Step 2] 3- (6- (5-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino ) Phenol trifluoroacetic acid (3- (6- (5-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA ) (LCB03-0092) Preparation

¹H-NMR (600 MHz, DMSO-d₆); δ 9.90 (brs, 1H), 8.62 (s, 1H), 7.61 (s, 1H), 7.53 (d, J= 3.6 Hz, 1H), 7.24 (s, 1H), 7.18-7.09 (m, 3H), 6.58 (d, J= 7.2 Hz, 1H), 3.86 (s, 2H), 3.47-3.46 (m, 4H), 3.05-3.03 (m, 4H), 2.80 (s, 3H); LC-MS 438 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 9.90 (brs, 1H), 8.62 (s, 1H), 7.61 (s, 1H), 7.53 (d, J = 3.6 Hz, 1H), 7.24 (s, 1H), 7.18-7.09 (m, 3H), 6.58 (d, J = 7.2 Hz, 1H), 3.86 (s, 2H), 3.47-3.46 (m, 4H), 3.05-3.03 (m, 4H), 2.80 (s, 3H); LC-MS 438 (MH +)

[실시예 60]Example 60

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(5-(피페리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(5-(piperidin-1-ylmethyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (5- (piperidin-1-ylmethyl) thiophen-2-yl) thieno [3,2- d] pyrimidin-4-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (5- (piperidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin- 4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.67 (s, 1H), 7.39 (s, 1H), 7.37 (d, J= 8.4 Hz, 2H), 7.34-7.29 (m, 2H), 7.19 (d, J = 3.6 Hz, 1H), 7.09-7.07 (m, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.88-6.86 (m, 2H),6.77 (brs, 1H), 5.03 (s, 2H), 3.81 (s, 3H), 3.68 (s, 2H), 2.46 (m, 4H), 1.62-1.60 (m, 4H), 1.47-1.45 (m, 2H); LC-MS 543 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.67 (s, 1H), 7.39 (s, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.34-7.29 (m, 2H), 7.19 (d, J = 3.6 Hz, 1H), 7.09- 7.07 (m, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.88-6.86 (m, 2H), 6.07 (brs, 1H), 5.03 (s, 2H), 3.81 (s, 3H), 3.68 (s, 2H), 2.46 (m, 4H), 1.62-1.60 (m, 4H), 1.47-1.45 (m, 2H); LC-MS 543 (MH +)

[단계 2] 3-(6-(5-(피페리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(5-(piperidin-1-ylmethyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0093)의 제조[Step 2] 3- (6- (5- (piperidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluor Preparation of Roacetic Acid (3- (6- (5- (piperidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0093)

¹H-NMR (600 MHz, DMSO-d₆); δ 9.97 (brs, 1H), 9.98 (brs, 1H), 8.61 (s, 1H), 7.75 (s, 1H), 7.66 (d, J = 3.6 Hz, 1H), 7.38 (d, J = 30 Hz, 1H), 7.25 (s, 1H), 7.18-7.14 (m, 2H), 6.38 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 3.73-3.70 (m, 2H), 2.93-2.91 (m, 2H), 1.86-1.84 (m, 2H), 1.70-1.62 (m, 3H), 1.38-1.36 (m, 1H); LC-MS 438 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 9.97 (brs, 1H), 9.98 (brs, 1H), 8.61 (s, 1H), 7.75 (s, 1H), 7.66 (d, J = 3.6 Hz, 1H), 7.38 (d, J = 30 Hz, 1H), 7.25 (s, 1H), 7.18-7.14 (m, 2H), 6.38 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 3.73-3.70 (m, 2H), 2.93-2.91 (m, 2H), 1.86-1.84 (m, 2H), 1.70-1.62 (m, 3H), 1.38-1.36 (m, 1H); LC-MS 438 (MH +)

[실시예 61]Example 61

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(5-(모폴리노메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(5-(morpholinomethyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (5- (morpholinomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidine Preparation of 4-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (5- (morpholinomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.68 (s, 1H), 7.49 (s, 1H), 7.38-7.31 (m, 4H), 7.08 (dd, J= 1.6, 7.6 Hz, 1H), 6.92 (brs, 1H), 6.90-6.85 (m, 3H), 6.70 (d, J = 3.2 Hz, 1H), 6.35 (d, J = 3.2 Hz, 1H), 5.03 (s, 2H), 3.80 (s, 3H), 3.74-3.72 (m, 4H), 3.62 (s, 2H), 2.56-2.53 (m, 4H); LC-MS 545 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.68 (s, 1H), 7.49 (s, 1H), 7.38-7.31 (m, 4H), 7.08 (dd, J = 1.6, 7.6 Hz, 1H), 6.92 (brs, 1H), 6.90-6.85 (m , 3H), 6.70 (d, J = 3.2 Hz, 1H), 6.35 (d, J = 3.2 Hz, 1H), 5.03 (s, 2H), 3.80 (s, 3H), 3.74-3.72 (m, 4H) , 3.62 (s, 2 H), 2.56-2.53 (m, 4 H); LC-MS 545 (MH +)

[단계 2] 3-(6-(5-(모폴리노메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(5-(morpholinomethyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0096)의 제조[Step 2] 3- (6- (5- (morpholinomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluoroacetic acid (3 Preparation of-(6- (5- (morpholinomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0096)

¹H-NMR (400 MHz, Acetone-d₆); δ 8.74 (s, 1H), 7.74 (s, 1H), 7.55-7.53 (m, 1H), 7.42-7.41 (m, 1H), 7.35-7.32 (m, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.20-7.18 (m, 1H), 6.83-6.82 (m, 1H), 4.67 (s, 2H), 3.96-3.94 (m, 4H), 3.35-3.33 (m, 4H); LC-MS 425 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 8.74 (s, 1H), 7.74 (s, 1H), 7.55-7.53 (m, 1H), 7.42-7.41 (m, 1H), 7.35-7.32 (m, 1H), 7.27 (t, J = 8.0 Hz , 1H), 7.20-7.18 (m, 1H), 6.83-6.82 (m, 1H), 4.67 (s, 2H), 3.96-3.94 (m, 4H), 3.35-3.33 (m, 4H); LC-MS 425 (MH +)

[실시예 62]Example 62

[단계 1] 터트-부틸 4-((5-(4-(3-(4-메톡시벤질옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)싸이오펜-2-일)메틸)피페라진-1-카복실레이트 (tert-butyl 4-((5-(4-(3-(4-methoxybenzyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)thiophen-2-yl)methyl)piperazine-1-carboxylate) 의 제조[Step 1] Tert-Butyl 4-((5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) thiophene- 2-yl) methyl) piperazin-1-carboxylate (tert-butyl 4-((5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) Preparation of thiophen-2-yl) methyl) piperazine-1-carboxylate)

¹H-NMR (400 MHz, CDCl₃); δ 8.68 (s, 1H), 7.40 (s, 1H), 7.38 (d, J= 8.4 Hz, 2H), 7.34-7.33 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 3.6 Hz, 1H),6.91 (d, J = 8.4 Hz, 2H), 6.88-6.86 (m, 3H), 6.77 (brs, 1H), 5.04 (s, 2H), 3.81 (s, 3H), 3.72 (s, 2H), 3.44-3.42 (m, 4H), 2.47-2.46 (m, 4H), 1.48 (s, 9H); LC-MS 644 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.68 (s, 1H), 7.40 (s, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.34-7.33 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.19 ( d, J = 3.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.88-6.86 (m, 3H), 6.77 (brs, 1H), 5.04 (s, 2H), 3.81 (s, 3H ), 3.72 (s, 2H), 3.44-3.42 (m, 4H), 2.47-2.46 (m, 4H), 1.48 (s, 9H); LC-MS 644 (MH +)

[단계 2] 3-(6-(5-(피페라진-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(5-(piperazin-1-ylmethyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0094)의 제조[Step 2] 3- (6- (5- (piperazin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluoro Preparation of acetic acid (3- (6- (5- (piperazin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0094)

¹H-NMR (400 MHz, Acetone-d₆); δ 8.71 (s, 1H), 7.67 (s, 1H), 7.46 (d, J= 3.6 Hz, 1H), 7.38 (s, 1H), 7.29-7.20 (m, 2H), 7.16-7.10(m, 1H), 6.84-6.78 (m, 1H), 4.04 (s, 2H), 3.51-3.43 (m, 4H), 3.05-3.04 (m, 4H); LC-MS 538 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 8.71 (s, 1H), 7.67 (s, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.38 (s, 1H), 7.29-7.20 (m, 2H), 7.16-7.10 (m, 1H) ), 6.84-6.78 (m, 1 H), 4.04 (s, 2 H), 3.51-3.43 (m, 4H), 3.05-3.04 (m, 4H); LC-MS 538 (MH +)

[실시예 63]Example 63

[단계 1] 6-(5-((에틸아미노)메틸)싸이오펜-2-일)-N-(3-(4-메톡시벤질옥시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (6-(5-((ethylamino)methyl)thiophen-2-yl)-N-(3-(4-methoxybenzyloxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] 6- (5-((ethylamino) methyl) thiophen-2-yl) -N- (3- (4-methoxybenzyloxy) phenyl) thieno [3,2-d] pyrid Midin-4-amine (6- (5-((ethylamino) methyl) thiophen-2-yl) -N- (3- (4-methoxybenzyloxy) phenyl) thieno [3,2-d] pyrimidin-4-amine) Manufacture

¹H-NMR (400 MHz, CDCl₃); δ 8.67 (s, 1H), 7.39 (s, 1H), 7.37 (d, J= 7.8 Hz, 2H), 7.34-7.29 (m, 2H), 7.20 (d, J = 3.6 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 7.2 Hz, 2H), 6.90 (d, J = 3.6 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.75 (brs, 1H), 5.03 (s, 1H), 4.00 (s, 2H), 3.81 (s, 3H), 2.74 (q, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H; LC-MS 503 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.67 (s, 1H), 7.39 (s, 1H), 7.37 (d, J = 7.8 Hz, 2H), 7.34-7.29 (m, 2H), 7.20 (d, J = 3.6 Hz, 1H), 7.07 ( d, J = 7.8 Hz, 1H), 6.91 (d, J = 7.2 Hz, 2H), 6.90 (d, J = 3.6 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.75 (brs, 1H), 5.03 (s, 1H), 4.00 (s, 2H), 3.81 (s, 3H), 2.74 (q, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H; LC-MS 503 (MH +)

[단계 2] 3-(6-(5-((에틸아미노)메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(5-((ethylamino)methyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0095)의 제조[Step 2] 3- (6- (5-((ethylamino) methyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluoroacetic acid ( Preparation of 3- (6- (5-((ethylamino) methyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0095)

¹H-NMR (600 MHz, Acetone-d₆); δ 8.65 (s, 1H), 7.60 (s, 1H), 7.47-7.42 (m, 3H), 7.23-7.21 (m, 3H), 6.74-6.73 (m, 1H), 4.64 (s, 2H), 3.32-3.30 (m, 2H), 1.39 (t, J = 6.4 Hz, 3H); LC-MS 383 (MH+) ¹ H-NMR (600 MHz, Acetone-d ₆ ); δ 8.65 (s, 1H), 7.60 (s, 1H), 7.47-7.42 (m, 3H), 7.23-7.21 (m, 3H), 6.74-6.73 (m, 1H), 4.64 (s, 2H), 3.32 -3.30 (m, 2H), 1.39 (t, J = 6.4 Hz, 3H); LC-MS 383 (MH +)

[실시예 64]Example 64

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(5-(피롤리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(5-(pyrrolidin-1-ylmethyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (5- (pyrrolidin-1-ylmethyl) furan-2-yl) thieno [3,2-d ] Pyrimidin-4-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (5- (pyrrolidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4 -amine)

¹H-NMR (600 MHz, Acetone-d₆); δ 8.74 (brs, 1H), 8.62 (s, 1H), 7.73 (s, 1H), 7.57 (s, 1H), 7.43 (d, J =8.4 Hz, 2H), 7.40 (d, J = 7.8 Hz, 1H), 7.27 (t, J = 8.4 Hz, 1H), 7.00 (d, J = 3.0 Hz, 1H), 6.95 (d, J= 8.4 Hz, 2H), 6.80-6.78 (m, 1H), 6.55 (s, 1H), 5.07 (s, 2H), 3.84 (s, 2H), 3.80 (s, 3H), 3.59-3.57 (m, 3H), 2.65 (brm 5H); LC-MS 513 (MH+) ¹ H-NMR (600 MHz, Acetone-d ₆ ); δ 8.74 (brs, 1H), 8.62 (s, 1H), 7.73 (s, 1H), 7.57 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 7.8 Hz, 1H), 7.27 (t, J = 8.4 Hz, 1H), 7.00 (d, J = 3.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.80-6.78 (m, 1H), 6.55 ( s, 1H), 5.07 (s, 2H), 3.84 (s, 2H), 3.80 (s, 3H), 3.59-3.57 (m, 3H), 2.65 (brm 5H); LC-MS 513 (MH +)

[단계 2] 3-(6-(5-(피롤리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(5-(pyrrolidin-1-ylmethyl)furan-2- yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0086)의 제조[Step 2] 3- (6- (5- (pyrrolidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluoro Preparation of acetic acid (3- (6- (5- (pyrrolidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0086)

¹H-NMR (600 MHz, CDCl₃); δ 8.60 (s, 1H), 7.31 (s, 1H), 7.27-7.26 (m, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.82 (brs, 1H), 6.69 (dd, J = 2.4, 8.4 Hz, 1H), 6.60 (d, J = 3.0 Hz, 1H), 6.31 (d, J= 3.0 Hz, 1H), 3.76 (s, 2H), 2.78-2.77 (m, 4H), 1.88-1.86 (m, 4H); LC-MS 330 (MH+) ¹ H-NMR (600 MHz, CDCl ₃ ); δ 8.60 (s, 1H), 7.31 (s, 1H), 7.27-7.26 (m, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.82 ( brs, 1H), 6.69 (dd, J = 2.4, 8.4 Hz, 1H), 6.60 (d, J = 3.0 Hz, 1H), 6.31 (d, J = 3.0 Hz, 1H), 3.76 (s, 2H), 2.78-2.77 (m, 4H), 1.88-1.86 (m, 4H); LC-MS 330 (MH +)

[실시예 65]Example 65

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(5-((4-메틸피페라진-1-일)메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (5-((4-methylpiperazin-1-yl) methyl) furan-2-yl) cyeno [3 , 2-d] pyrimidin-4-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (5-((4-methylpiperazin-1-yl) methyl) furan-2-yl) thieno [ 3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, Acetone-d₆); δ 8.72 (brs, 1H), 8.62 (s, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.55 (s, 1H), 7.44-7.40 (m, 3H), 7.27 (t, J = 8.0 Hz, 1H), 6.99 d, J = 3.2 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.79 (dd, J = 2.4, 8.4 Hz, 1H), 6.48 (d, J = 3.6 Hz, 1H), 5.07 (s, 2H), 3.80 (s, 3H), 3.61 (s, 2H), 2.51-2.21 (m, 8H), 2.20 (s, 3H); LC-MS 542 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 8.72 (brs, 1H), 8.62 (s, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.55 (s, 1H), 7.44-7.40 (m, 3H), 7.27 (t, J = 8.0 Hz, 1H), 6.99 d, J = 3.2 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.79 (dd, J = 2.4, 8.4 Hz, 1H), 6.48 (d, J = 3.6 Hz , 1H), 5.07 (s, 2H), 3.80 (s, 3H), 3.61 (s, 2H), 2.51-2.21 (m, 8H), 2.20 (s, 3H); LC-MS 542 (MH +)

[단계 2] 3-(6-(5-((4-메틸피페라진-1-일)메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0087)의 제조[Step 2] 3- (6- (5-((4-methylpiperazin-1-yl) methyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) Phenolic trifluoroacetic acid (3- (6- (5-((4-methylpiperazin-1-yl) methyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) Preparation of (LCB03-0087)

¹H-NMR (600 MHz, Acetone-d₆); δ 8.70 (brs, 1H), 8.61 (s, 1H), 7.58-7.53 (m, 2H), 7.28 (s, 1H), 7.21 (t, J = 8.4 H, 1H), 7.02 (s, 1H), 6.66 (d, J = 7.8 Hz, 1H), 6.55 (s, 1H), 3.72 (s, 2H), 2.88-2.86 (m, 4H), 2.60-2.58 (m, 4H), 2.27 (s, 3H); LC-MS 422 (MH+) ¹ H-NMR (600 MHz, Acetone-d ₆ ); δ 8.70 (brs, 1H), 8.61 (s, 1H), 7.58-7.53 (m, 2H), 7.28 (s, 1H), 7.21 (t, J = 8.4 H, 1H), 7.02 (s, 1H), 6.66 (d, J = 7.8 Hz, 1H), 6.55 (s, 1H), 3.72 (s, 2H), 2.88-2.86 (m, 4H), 2.60-2.58 (m, 4H), 2.27 (s, 3H) ; LC-MS 422 (MH +)

[실시예 66]Example 66

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(5-(피페리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(5-(piperidin- 1-ylmethyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (5- (piperidin-1-ylmethyl) furan-2-yl) thieno [3,2-d ] Pyrimidin-4-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (5- (piperidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4 -amine)

¹H-NMR (400 MHz, Acetone-d₆); δ 8.71 (brs, 1H), 8.62 (s, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.54 (s, 1H), 7.44-7.39 (m, 4H), 7.28 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.80-6.77 (m, 1H), 6.45 (d, J= 3.2 Hz, 1H), 5.07 (s, 2H), 3.80 (s, 3H), 3.57 (s, 2H), 2.46-2.45 (m, 4H), 1.59-1.53 (m, 4H), 1.42-1.41 (m, 2H); LC-MS 527 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 8.71 (brs, 1H), 8.62 (s, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.54 (s, 1H), 7.44-7.39 (m, 4H), 7.28 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.80-6.77 (m, 1H), 6.45 (d, J = 3.2 Hz, 1H), 5.07 (s, 2H), 3.80 (s, 3H), 3.57 (s, 2H), 2.46-2.45 (m, 4H), 1.59-1.53 (m, 4H), 1.42-1.41 (m, 2H); LC-MS 527 (MH +)

[단계 2] 3-(6-(5-(피페리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(5-(piperidin-1-ylmethyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0088)의 제조[Step 2] 3- (6- (5- (piperidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluoro Preparation of acetic acid (3- (6- (5- (piperidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0088)

¹H-NMR (400 MHz, Acetone-d₆); δ 8.66 (s, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.23-7.22 (m, 2H), 7.11 (d, J = 4.8 Hz, 1H), 6.93 (d, J= 4.8 Hz, 1H), 6.72-6.70 (m, 1H), 4.51 (s, 2H), 3.61 (brm, 6H), 1.93-1.91 (m, 4H); LC-MS 407 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 8.66 (s, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.23-7.22 (m, 2H), 7.11 (d, J = 4.8 Hz, 1H), 6.93 (d, J = 4.8 Hz, 1H), 6.72-6.70 (m, 1H), 4.51 (s, 2H), 3.61 (brm, 6H), 1.93-1.91 (m, 4H); LC-MS 407 (MH +)

[실시예 67]Example 67

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(5-(모폴리노메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(5-(morpholinomethyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (5- (morpholinomethyl) furan-2-yl) thieno [3,2-d] pyrimidine- Preparation of 4-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (5- (morpholinomethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.68 (s, 1H), 7.49 (s, 1H), 7.38-7.31 (m, 4H), 7.08 (dd, J = 1.6, 7.6 Hz, 1H), 6.92 (brs, 1H), 6.90-6.85 (m, 3H), 6.70 (d, J = 3.2 Hz, 1H), 6.35 (d, J = 3.2 Hz, 1H), 5.03 (s, 2H), 3.80 (s, 3H), 3.74-3.72 (m, 4H), 3.62 (s, 2H), 2.56-2.53 (m, 4H); LC-MS 529 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.68 (s, 1H), 7.49 (s, 1H), 7.38-7.31 (m, 4H), 7.08 (dd, J = 1.6, 7.6 Hz, 1H), 6.92 (brs, 1H), 6.90-6.85 (m , 3H), 6.70 (d, J = 3.2 Hz, 1H), 6.35 (d, J = 3.2 Hz, 1H), 5.03 (s, 2H), 3.80 (s, 3H), 3.74-3.72 (m, 4H) , 3.62 (s, 2 H), 2.56-2.53 (m, 4 H); LC-MS 529 (MH +)

[단계 2] 3-(6-(5-(모폴리노메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(5-(morpholinomethyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0089)의 제조[Step 2] 3- (6- (5- (morpholinomethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluoroacetic acid (3- Preparation of (6- (5- (morpholinomethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0089)

¹H-NMR (400 MHz, CDCl₃); δ 8.69 (s, 1H), 7.75 (s, 1H), 7.45 (s, 1H), 7.23 (d, J= 5.2 Hz, 2H), 7.09 (d, J = 3.2 H, 1H), 6.90 (d, J = 3.6 Hz, 1H), 6.76-6.71 (m, 1H), 4.48 (s, 2H), 3.94-3.93 (m, 4H), 3.34-3.31 (m, 4H); LC-MS 409 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.75 (s, 1H), 7.45 (s, 1H), 7.23 (d, J = 5.2 Hz, 2H), 7.09 (d, J = 3.2 H, 1H), 6.90 (d, J = 3.6 Hz, 1H), 6.76-6.71 (m, 1H), 4.48 (s, 2H), 3.94-3.93 (m, 4H), 3.34-3.31 (m, 4H); LC-MS 409 (MH +)

[실시예 68]Example 68

[단계 1] 터트-부틸 4-((5-(4-(3-(4-메톡시벤질옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)퓨란-2-일)메틸)피페라진-1-카복실레이트 (tert-butyl 4-((5-(4-(3-(4-methoxybenzyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)furan-2-yl)methyl)piperazine-1-carboxylate) 의 제조[Step 1] Tert-Butyl 4-((5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) furan-2 -Yl) methyl) piperazine-1-carboxylate (tert-butyl 4-((5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) furan -2-yl) methyl) piperazine-1-carboxylate)

¹H-NMR (400 MHz, CDCl₃); δ 8.67 (s, 1H), 7.47 (s, 1H), 7.37-7.34 (m, 4H), 7.28 (t, J = 8.0 Hz, 1H), 7.10-7.08 (m, 1H), 6.91-6.85 (m, 3H), 6.90 (d, J = 3.2 Hz, 1H), 6.33 (d, J = 3.6 Hz, 1H), 5.02 (s, 2H), 3.80 (s, 3H), 3.63 (s, 2H), 3.48-3.44 (m, 4H), 2.49-2.47 (m, 4H), 1.45 (s, 9H); LC-MS 628 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.67 (s, 1H), 7.47 (s, 1H), 7.37-7.34 (m, 4H), 7.28 (t, J = 8.0 Hz, 1H), 7.10-7.08 (m, 1H), 6.91-6.85 (m , 3H), 6.90 (d, J = 3.2 Hz, 1H), 6.33 (d, J = 3.6 Hz, 1H), 5.02 (s, 2H), 3.80 (s, 3H), 3.63 (s, 2H), 3.48 -3.44 (m, 4H), 2.49-2.47 (m, 4H), 1.45 (s, 9H); LC-MS 628 (MH +)

[단계 2] 3-(6-(5-(피페라진-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(5-(piperazin-1-ylmethyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0090)의 제조[Step 2] 3- (6- (5- (piperazin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluoroacetic acid Preparation of (3- (6- (5- (piperazin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0090)

¹H-NMR (400 MHz,Acetone-d₆); δ 8.76 (brs, 1H), 7.74 (s, 1H),7.37-7.36 (m, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.20-7.28 (m, 1H), 7.12-7.10 (m, 2H), 6.84-6.82 (m, 2H), 6.67 (d, J = 3.2 Hz, 1H), 3.95 (s, 2H), 3.53 (m, 4H), 3.14 (m, 4H); LC-MS 408 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 8.76 (brs, 1H), 7.74 (s, 1H), 7.37-7.36 (m, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.20-7.28 (m, 1H), 7.12-7.10 (m , 2H), 6.84-6.82 (m, 2H), 6.67 (d, J = 3.2 Hz, 1H), 3.95 (s, 2H), 3.53 (m, 4H), 3.14 (m, 4H); LC-MS 408 (MH +)

[실시예 69]Example 69

[단계 1] 6-(5-((에틸아미노)메틸)퓨란-2-일)-N-(3-(4-메톡시벤질옥시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (6-(5-((ethylamino)methyl)furan-2-yl)-N-(3-(4-methoxybenzyloxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] 6- (5-((ethylamino) methyl) furan-2-yl) -N- (3- (4-methoxybenzyloxy) phenyl) thieno [3,2-d] pyrimidine 4-amine (6- (5-((ethylamino) methyl) furan-2-yl) -N- (3- (4-methoxybenzyloxy) phenyl) thieno [3,2-d] pyrimidin-4-amine) Produce

¹H-NMR (400 MHz, CDCl₃); δ 8.67 (s, 1H), 7.46 (s, 1H), 7.38-7.28 (m, 4H), 7.08 (dd, J = 1.2, 8.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.86 (dd, J = 1.6, 7.6 Hz, 1H), 6.68 (d, J= 3.0 Hz, 1H), 6.32 (d, J = 3.2 Hz, 1H), 5.02 (s, 2H), 3.87 (s, 2H), 3.80 (s, 3H), 3.48 (q, J = 7.2 Hz, 2H), 2.74 (q, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H); LC-MS 487 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.67 (s, 1H), 7.46 (s, 1H), 7.38-7.28 (m, 4H), 7.08 (dd, J = 1.2, 8.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.86 (dd, J = 1.6, 7.6 Hz, 1H), 6.68 (d, J = 3.0 Hz, 1H), 6.32 (d, J = 3.2 Hz, 1H), 5.02 (s, 2H), 3.87 (s, 2H ), 3.80 (s, 3H), 3.48 (q, J = 7.2 Hz, 2H), 2.74 (q, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H); LC-MS 487 (MH +)

[단계 2] 3-(6-(5-((에틸아미노)메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(5-((ethylamino)methyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0091)의 제조[Step 2] 3- (6- (5-((ethylamino) methyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluoroacetic acid (3 Preparation of-(6- (5-((ethylamino) methyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0091)

¹H-NMR (400 MHz, CDCl₃); δ 8.67 (brs, 1H), 7.68 (s, 1H), 7.41 (s, 1H), 7.26-7.19 (m, 3H), 7.01 (d, J = 3.2 Hz, 1H), 6.86 (d, J= 3.2 Hz, 1H), 6.75-6.73 (m, 1H), 4.55 (s, 2H), 3.34 (q, J = 6.8 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H); LC-MS 367 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.67 (brs, 1 H), 7.68 (s, 1 H), 7.41 (s, 1 H), 7.26-7.19 (m, 3 H), 7.01 (d, J = 3.2 Hz, 1 H), 6.86 (d, J = 3.2 Hz, 1H), 6.75-6.73 (m, 1H), 4.55 (s, 2H), 3.34 (q, J = 6.8 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H); LC-MS 367 (MH +)

[실시예 70]Example 70

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(4-(모폴리노메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(4-(morpholinomethyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (4- (morpholinomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidine Preparation of 4-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (4- (morpholinomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.68 (s, 1H), 7.44 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.32 (m, 3H), 7.19 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.89 (m, 1H), 6.83 (br, 1H), 5.03 (s, 2H), 3.80 (s, 3H), 3.68 (m, 2H), 3.47-3.44 (m, 4H), 2.48 (m, 4H); LC-MS 423 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.68 (s, 1H), 7.44 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.32 (m, 3H), 7.19 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.89 (m, 1H), 6.83 (br, 1H), 5.03 (s, 2H), 3.80 (s, 3H), 3.68 (m, 2H), 3.47-3.44 (m, 4 H), 2.48 (m, 4 H); LC-MS 423 (MH +)

[단계 2] 3-(6-(4-(모폴리노메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(4-(morpholinomethyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0104)의 제조[Step 2] 3- (6- (4- (morpholinomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluoroacetic acid (3 Preparation of-(6- (4- (morpholinomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0104)

¹H-NMR (400 MHz, Acetone-d₆); δ 8.89 (s, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.42 (s, 1H), 7.28 (m, 2H), 7.15 (m, 1H), 6.87 (m, 1H), 6.79 (s, 1H), 4.51 (m, 2H), 3.77 (m, 2H), 3.45 (m, 2H), 1.15 (m, 4H); LC-MS 425 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 8.89 (s, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.42 (s, 1H), 7.28 (m, 2H), 7.15 (m, 1H), 6.87 (m, 1H), 6.79 (s, 1H), 4.51 (m, 2H), 3.77 (m, 2H), 3.45 (m, 2H), 1.15 (m, 4H); LC-MS 425 (MH +)

[실시예 71]Example 71

[단계 1] 터트-부틸 4-((5-(4-(3-(4-메톡시벤질옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)싸이오펜-3-일)메틸)피페라진-1-카복실레이트 (tert-butyl 4-((5-(4-(3-(4-methoxybenzyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)thiophen-3-yl)methyl)piperazine-1-carboxylate) 의 제조[Step 1] Tert-Butyl 4-((5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) thiophene- 3-yl) methyl) piperazin-1-carboxylate (tert-butyl 4-((5- (4- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) Preparation of thiophen-3-yl) methyl) piperazine-1-carboxylate)

¹H-NMR (400 MHz, CDCl₃); δ 8.68 (s, 1H),7.42 (s, 1H), 7.36 (d, J = 6.0 Hz, 2H), 7.33-7.31 (m, 3H), 7.19 (s,1H), 7.11 (d, J = 5.6 Hz, 1H), 6.68-6.66 (m, 3H), 5.02 (s,s 2H), 3.70 (s, 3H), 3.47-3.44 (m, 4H), 3.43 (s, 2H), 2.44-2.42 (m, 4H), 1.46 (s, 9H); LC-MS 524 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.68 (s, 1H), 7.42 (s, 1H), 7.36 (d, J = 6.0 Hz, 2H), 7.33-7.31 (m, 3H), 7.19 (s, 1H), 7.11 (d, J = 5.6 Hz, 1H), 6.68-6.66 (m, 3H), 5.02 (s, s 2H), 3.70 (s, 3H), 3.47-3.44 (m, 4H), 3.43 (s, 2H), 2.44-2.42 (m , 4H), 1.46 (s, 9H); LC-MS 524 (MH +)

[단계 2] 3-(6-(4-(피페라진-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4- 일아미노)페놀 트라이플루오로아세트산 (3-(6-(4-(piperazin-1-ylmethyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0105)의 제조[Step 2] 3- (6- (4- (piperazin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluoro Preparation of acetic acid (3- (6- (4- (piperazin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0105)

¹H-NMR (400 MHz, DMSO-d₆); δ 8.95 (s, 1H), 8.15(s, 1H), 7.40-7.37 (m, 2H), 7.32-7.27 (m, 1H), 7.13-7.11 (m, 2H), 6.93 (m, 1H), 6.86 (m, 1H), 4.29 (s, 2H), 3.75 (brm, 4H), 1.98-1.97 (m, 4H); LC-MS 422 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 8.95 (s, 1H), 8.15 (s, 1H), 7.40-7.37 (m, 2H), 7.32-7.27 (m, 1H), 7.13-7.11 (m, 2H), 6.93 (m, 1H), 6.86 (m, 1 H), 4.29 (s, 2 H), 3.75 (brm, 4 H), 1.98-1.97 (m, 4H); LC-MS 422 (MH +)

[실시예 72]Example 72

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(4-(피롤리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(4-(pyrrolidin-1-ylmethyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (4- (pyrrolidin-1-ylmethyl) thiophen-2-yl) thieno [3,2- d] pyrimidin-4-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (4- (pyrrolidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin- 4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.66 (s, 1H), 7.42 (s, 1H), 7.-7.36 (m, 3H), 7.66 (t, J = 1.6 Hz, 1H), 7.31 (d, J = 5.6 Hz, 1H), 7.25 (s, 1H), 7.10 (d, J = 3.6 Hz, 1H), 6.91 (d, J = 6.0 Hz, 2H), 6.87 (d, J = 5.6 Hz, 1H), 3.68 (s , 2H), 2.64 (m, 4H), 1.85 (m, 4H); LC-MS 409 (M+H+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.66 (s, 1H), 7.42 (s, 1H), 7.-7.36 (m, 3H), 7.66 (t, J = 1.6 Hz, 1H), 7.31 (d, J = 5.6 Hz, 1H), 7.25 (s, 1H), 7.10 (d, J = 3.6 Hz, 1H), 6.91 (d, J = 6.0 Hz, 2H), 6.87 (d, J = 5.6 Hz, 1H), 3.68 (s, 2H), 2.64 (m, 4H), 1. 85 (m, 4H); LC-MS 409 (M + H +)

[단계 2] 3-(6-(4-(피롤리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(4-(pyrrolidin-1-ylmethyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0101)의 제조[Step 2] 3- (6- (4- (pyrrolidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluor Preparation of Roacetic Acid (3- (6- (4- (pyrrolidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0101)

¹H-NMR (400 MHz, CDCl₃); δ 8.59 (s, 1H), 7.26-7.21 (m, 1H), 7.14-7.11 (m, 2H), 7.01 (d, J = 3.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 3.6 Hz, 1H), 6.75 (dd, J= 1.6, 8.4 Hz, 1H), 3.81 (s, 2H), 2.69 (brm, 4H), 2.04-2.02 (m, 4H); LC-MS 409 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.59 (s, 1H), 7.26-7.21 (m, 1H), 7.14-7.11 (m, 2H), 7.01 (d, J = 3.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 3.6 Hz, 1H), 6.75 (dd, J = 1.6, 8.4 Hz, 1H), 3.81 (s, 2H), 2.69 (brm, 4H), 2.04-2.02 (m, 4H); LC-MS 409 (MH +)

[실시예 73]Example 73

[단계 1] 6-(4-((에틸아미노)메틸)싸이오펜-2-일)-N-(3-(4-메톡시벤질옥시)페닐)싸이에노[3,2-d]피리미딘-4-아민 (6-(4-((ethylamino)methyl)thiophen-2-yl)-N-(3-(4-methoxybenzyloxy)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] 6- (4-((ethylamino) methyl) thiophen-2-yl) -N- (3- (4-methoxybenzyloxy) phenyl) thieno [3,2-d] pyrid Midin-4-amine (6- (4-((ethylamino) methyl) thiophen-2-yl) -N- (3- (4-methoxybenzyloxy) phenyl) thieno [3,2-d] pyrimidin-4-amine) Manufacture

¹H-NMR (600 MHz, CDCl₃); δ 8.68 (s, 1H), 7.42 (s, 1H), 7.38 (d, J = 6.0 Hz, 2H), 7.33 (m, 3H), 7.19 (s, 1H), 7.09 (d, J = 5.6 Hz, 1H), 6.68 (m, 3H), 3.80 (s, 2H), 2.71 (m, 2H), 1.06 (m, 3H); LC-MS 383 (MH+) ¹ H-NMR (600 MHz, CDCl ₃ ); δ 8.68 (s, 1H), 7.42 (s, 1H), 7.38 (d, J = 6.0 Hz, 2H), 7.33 (m, 3H), 7.19 (s, 1H), 7.09 (d, J = 5.6 Hz, 1H), 6.68 (m, 3H), 3.80 (s, 2H), 2.71 (m, 2H), 1.06 (m, 3H); LC-MS 383 (MH +)

[단계 2] 3-(6-(4-((에틸아미노메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(4-((ethylamino)methyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0106)의 제조[Step 2] 3- (6- (4-((ethylaminomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluoroacetic acid (3 Preparation of-(6- (4-((ethylamino) methyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0106)

[실시예 74]Example 74

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(4-(피롤리딘-1-일메틸)퓨란-2-일)싸이 에노[3,2-d]피리미딘-4-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(4-(pyrrolidin-1-ylmethyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (4- (pyrrolidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] Pyrimidin-4-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (4- (pyrrolidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4- Preparation of amine

¹H-NMR (400 MHz, CDCl₃); δ 8.96 (s, 1H), 8.73 (s, 1H), 8.17 (s, 1H), 7.41-7.36 (m, 2H), 7.32-7.26 (m, 2H), 7.14-7.10 (m, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.85 (m, 1H), 5.07 (s, 2H), 4.16 (s, 2H), 3.76 (s, 3H), 3.57 (m, 4H), 1.95 (m, 4H); LC-MS 393 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.96 (s, 1H), 8.73 (s, 1H), 8.17 (s, 1H), 7.41-7.36 (m, 2H), 7.32-7.26 (m, 2H), 7.14-7.10 (m, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.85 (m, 1H), 5.07 (s, 2H), 4.16 (s, 2H), 3.76 (s, 3H), 3.57 (m, 4H), 1.95 (m, 4H); LC-MS 393 (MH +)

[단계 2] 3-(6-(4-(피롤리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(4-(pyrrolidin-1-ylmethyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0113)의 제조[Step 2] 3- (6- (4- (pyrrolidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluoro Preparation of acetic acid (3- (6- (4- (pyrrolidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0113)

¹H-NMR (400 MHz, DMSO-d₆); δ 8.76 (s, 1H), 8.16 (s, 1H), 7.41-7.37 (m, 2H), 7.32-7.26 (m, 1H), 7.14-7.11(m, 2H), 6.93 (m, 1H), 6.86 (m, 1H), 4.50 (s, 2H), 2.48 (m, 4H), 1.72 (m, 4H); LC-MS 393 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 8.76 (s, 1H), 8.16 (s, 1H), 7.41-7.37 (m, 2H), 7.32-7.26 (m, 1H), 7.14-7.11 (m, 2H), 6.93 (m, 1H), 6.86 (m, 1 H), 4.50 (s, 2 H), 2.48 (m, 4 H), 1.72 (m, 4 H); LC-MS 393 (MH +)

[실시예 75]Example 75

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(4-((4-메틸피페라진-1-일)메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(4-((4-methylpiperazin-1-yl)methyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (4-((4-methylpiperazin-1-yl) methyl) furan-2-yl) cyeno [3 , 2-d] pyrimidin-4-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (4-((4-methylpiperazin-1-yl) methyl) furan-2-yl) thieno [ 3,2-d] pyrimidin-4-amine)

¹H-NMR (600 MHz, CDCl₃); δ 8.95 (s, 1H), 8.73 (s, 1H), 8.19 (s, 1H), 7.37-7.29 (m, 3H), 7.11 (d, J = 8.4 Hz, 2H), 6.92-6.86 (m, 3H), 6.79 (s, 1H), 5.02 (s, 2H), 3.74 (s, 3H), 3.45 (s, 2H), 3.57 (m, 4H), 1.95 (m, 4H), 2.27 (s, 3H); LC-MS 542 (MH+) ¹ H-NMR (600 MHz, CDCl ₃ ); δ 8.95 (s, 1H), 8.73 (s, 1H), 8.19 (s, 1H), 7.37-7.29 (m, 3H), 7.11 (d, J = 8.4 Hz, 2H), 6.92-6.86 (m, 3H ), 6.79 (s, 1H), 5.02 (s, 2H), 3.74 (s, 3H), 3.45 (s, 2H), 3.57 (m, 4H), 1.95 (m, 4H), 2.27 (s, 3H) ; LC-MS 542 (MH +)

[단계 2] 3-(6-(4-((4-메틸피페라진-1-일)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(4-((4-methylpiperazin-1-yl)methyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0114)의 제조[Step 2] 3- (6- (4-((4-methylpiperazin-1-yl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol tri Fluoroacetic acid (3- (6- (4-((4-methylpiperazin-1-yl) methyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03 Preparation of

¹H-NMR (400 MHz DMSO-d₆); δ 8.95 (s, 1H), 8.15 (s, 1H), 7.40-7.37 (m, 2H), 7.32-7.27 (m, 1H), 7.13-7.11 (m, 2H), 6.93 (m, 1H), 6.86 (m, 1H), 4.29 (s, 2H), 2.65-2.63 (m, 4H), 2.44 (s, 3H), 1.47-1.45 (m, 4H); LC-MS 422 (MH+) ¹ H-NMR (400 MHz DMSO-d ₆ ); δ 8.95 (s, 1H), 8.15 (s, 1H), 7.40-7.37 (m, 2H), 7.32-7.27 (m, 1H), 7.13-7.11 (m, 2H), 6.93 (m, 1H), 6.86 (m, 1H), 4.29 (s, 2H), 2.65-2.63 (m, 4H), 2.44 (s, 3H), 1.47-1.45 (m, 4H); LC-MS 422 (MH +)

[실시예 76]Example 76

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(4-(피페리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(4-(piperidin-1-ylmethyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (4- (piperidin-1-ylmethyl) furan-2-yl) thieno [3,2-d ] Pyrimidin-4-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (4- (piperidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4 -amine)

¹H-NMR (600 MHz, CDCl₃); δ 8.92 (s, 1H), 8.75 (s, 1H), 8.19 (s, 1H), 7.39-7.36 (m, 3H), 7.30 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz,1H), 6.80 (s, 1H), 5.02 (s, 2H), 4.19 (s, 2H), 3.81 (s, 3H), 3.43 (m, 4H) 1.64 (m, 6H); LC-MS 527 (MH+) ¹ H-NMR (600 MHz, CDCl ₃ ); δ 8.92 (s, 1H), 8.75 (s, 1H), 8.19 (s, 1H), 7.39-7.36 (m, 3H), 7.30 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (s, 1H), 5.02 (s, 2H), 4.19 (s, 2H), 3.81 (s, 3 H), 3.43 (m, 4 H) 1.64 (m, 6 H); LC-MS 527 (MH +)

[단계 2] 3-(6-(4-(피페리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(4-(piperidin-1-ylmethyl)furan-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0115) 의 제조[Step 2] 3- (6- (4- (piperidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3- Preparation of (6- (4- (piperidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol) (LCB03-0115)

¹H-NMR (400MHz, Acetone-d₆); δ 8.79 (brs, 1H), 7.74(s, 1H), 7.37-7.36(m, 1H), 7.28(t, J =7.6Hz, 1H), 7.20-7.18(m, 1H), 7.12-7.10(m, 2H), 6.84-6.82(m, 2H), 6.67(d, J=3.2Hz, 1H), 4.50(s, 2H), 2.48(m, 4H), 1.72(m, 4H), 1.37(m, 2H); LC-MS 407.0 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 8.79 (brs, 1H), 7.74 (s, 1H), 7.37-7.36 (m, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.20-7.18 (m, 1H), 7.12-7.10 (m , 2H), 6.84-6.82 (m, 2H), 6.67 (d, J = 3.2 Hz, 1H), 4.50 (s, 2H), 2.48 (m, 4H), 1.72 (m, 4H), 1.37 (m, 2H); LC-MS 407.0 (MH +)

[실시예 77] 3-(6-(4-(피페리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플루오로아세트산 (3-(6-(4-(piperidin-1-ylmethyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0103)의 제조Example 77 3- (6- (4- (piperidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol tri Preparation of fluoroacetic acid (3- (6- (4- (piperidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol. TFA) (LCB03-0103)

¹H-NMR (400 MHz, DMSO-d₆); δ 8.76 (s, 1H), 8.16 (s, 1H), 7.41-7.37 (m, 2H), 7.32-7.26 (m, 1H), 7.14-7.11 (m, 2H), 6.93 (m, 1H), 6.86 (m, 1H), 4.50 (s, 2H), 2.48 (m, 4H), 1.72 (m, 4H)1.56-1.54 (m, 2H); LC-MS 393 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 8.76 (s, 1H), 8.16 (s, 1H), 7.41-7.37 (m, 2H), 7.32-7.26 (m, 1H), 7.14-7.11 (m, 2H), 6.93 (m, 1H), 6.86 (m, 1H), 4.50 (s, 2H), 2.48 (m, 4H), 1.72 (m, 4H) 1.56-1.54 (m, 2H); LC-MS 393 (MH +)

[실시예 78] 3-(6-(4-((4-메틸피페라진-1-일)메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(4-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0102)의 제조Example 78 3- (6- (4-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-yl Amino) phenol (3- (6- (4-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol) (LCB03-0102 Manufacturing

¹H-NMR (400MHz, DMSO-d₆); δ 8.95 (s, 1H), 8.15(s, 1H), 7.40-7.37 (m, 2H), 7.32-7.27 (m, 1H), 7.13-7.11 (m, 2H), 6.93-6.92 (m, 1H), 6.86-6.85 (m, 1H), 2.81-2.80 (m, 4H), 2.47 (s, 3H), 1.41-1.39 (m, 4H); LC-MS 438 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 8.95 (s, 1H), 8.15 (s, 1H), 7.40-7.37 (m, 2H), 7.32-7.27 (m, 1H), 7.13-7.11 (m, 2H), 6.93-6.92 (m, 1H) , 6.86-6.85 (m, 1H), 2.81-2.80 (m, 4H), 2.47 (s, 3H), 1.41-1.39 (m, 4H); LC-MS 438 (MH +)

[실시예 79]Example 79

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-2-(4-(피페리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-2-(4-(piperidin-1-ylmethyl)phenyl)thieno[3,2-b]pyridin-7-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -2- (4- (piperidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridine-7 Preparation of -amine (N- (3- (4-methoxybenzyloxy) phenyl) -2- (4- (piperidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-amine)

제조예 24에서 얻은 화합물 (50 mg, 0.10 mmol)과 피페리딘 (92 mg, 1.07 mmol)을 다이클로로에테인 1 ml에 순차적으로 넣고 20분간 교반 후 초산나트륨 (26 mg, 0.32 mmol)과 소디움트라이아세톡시보로하이드라이드 (136 mg, 0.64 mmol)을 넣고 5시간 동안 실온에서 교반하였다. 반응완료 후 다이클로로메테인 30 ml와 포화된 염화암모늄 수용액 30 ml를 이용하여 추출하였다. 유기층을 황산나트륨으로 건조하고 감압농축 후, 관크로마토그래피 (다이클로로메테인/메탄올, 1/25)를 시행하여 표제화합물 (42mg, 73 %)을 수득하였다.Compound (50 mg, 0.10 mmol) and piperidine (92 mg, 1.07 mmol) obtained in Preparation Example 24 were sequentially added to 1 ml of dichloroethane, followed by stirring for 20 minutes, followed by sodium acetate (26 mg, 0.32 mmol) and sodium trichloride. Acetoxyborohydride (136 mg, 0.64 mmol) was added and stirred at room temperature for 5 hours. After completion of the reaction was extracted using 30 ml of dichloromethane and 30 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (dichloromethane / methanol, 1/25) to give the title compound (42 mg, 73%).

¹H-NMR (400 MHz, CDCl₃); δ 8.35 (d, J = 5.6 Hz, 1H), 7.74-7.72 (m, 1H), 7.62 (d, J = 5.6 Hz, 1H), 7.39-7.29 (m, 4H), 6.91-6.78 (m, 6H), 6.16 (s, 1H), 5.01 (s, 2H), 3.81 (s, 3H), 3.55 (s, 2H), 2.44 (m, 4H), 2.12 (m, 2H), 1.61 (m, 4H); LC-MS: 536 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.35 (d, J = 5.6 Hz, 1H), 7.74-7.72 (m, 1H), 7.62 (d, J = 5.6 Hz, 1H), 7.39-7.29 (m, 4H), 6.91-6.78 (m, 6H ), 6.16 (s, 1H), 5.01 (s, 2H), 3.81 (s, 3H), 3.55 (s, 2H), 2.44 (m, 4H), 2.12 (m, 2H), 1.61 (m, 4H) ; LC-MS: 536 (MH < + >)

[단계 2] 3-(2-(4-(피페리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 트라이플루오로아세트산 (3-(2-(4-(piperidin-1-ylmethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol. TFA) (LCB03-0097)의 제조[Step 2] 3- (2- (4- (piperidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamiphenol phenol trifluoroacetic acid (3- ( Preparation of 2- (4- (piperidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol.TFA) (LCB03-0097)

상기 단계 1에서 얻은 화합물 (15 mg, 0.03 mmol)을 다이클로로메테인 1 ml에 녹인 후 트라이플로로아세트산 1 ml와 아니솔 (40 mg, 0.38 mmol)을 넣고 실온에서 15시간 동안 교반한 뒤, 감압농축하였다. 이를 다시 다이클로로메테인과 메탄올, 다이에틸에테르등을 이용하여 공비농축하고 진공건조하여 옅은 노란색고체의 표제화합물 (14 mg, 99%)을 수득하였다. After dissolving the compound (15 mg, 0.03 mmol) obtained in step 1 in 1 ml of dichloromethane, 1 ml of trifluoroacetic acid and anisole (40 mg, 0.38 mmol) were added and stirred at room temperature for 15 hours. It concentrated under reduced pressure. This was again azeotropically concentrated with dichloromethane, methanol, diethyl ether and the like to obtain a pale yellow solid title compound (14 mg, 99%).

¹H-NMR (400 MHz, CDCl₃); δ 8.41-8.40 (m, 1H), 8.17 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.74 (d, J= 8.4 Hz, 2H), 7.34 (t, J = 8.4 Hzm 1H), 7.08-7.06 (m, 1H), 7.01-6.99 (m, 2H), 6.96-6.90 (m, 2H), 4.41 (s, 2H), 3.83-3.80 (m, 4H), 2.95-2.93 (m, 2H), 1.90-1.88 (m, 4H); LC-MS 416 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.41-8.40 (m, 1H), 8.17 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.34 (t, J = 8.4 Hzm 1H ), 7.08-7.06 (m, 1H), 7.01-6.99 (m, 2H), 6.96-6.90 (m, 2H), 4.41 (s, 2H), 3.83-3.80 (m, 4H), 2.95-2.93 (m , 2H), 1.90-1.88 (m, 4H); LC-MS 416 (MH +)

상기 실시예 79와 유사한 방법으로 하기화합물을 합성하였다. In the same manner as in Example 79, the following compound was synthesized.

[실시예 80]Example 80

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-2-(4-((4-메틸피페라진-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)thieno[3,2-b]pyridin-7-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -2- (4-((4-methylpiperazin-1-ylmethyl) phenyl) thieno [3,2-b] Pyridin-7-amine (N- (3- (4-methoxybenzyloxy) phenyl) -2- (4-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-b] pyridin-7- Preparation of amine

¹H-NMR (400 MHz, CDCl₃); δ 8.36 (d, J = 5.2 Hz, 1H), 7.70-7.68 (m, 3H), 7.41 (d, J = 7.2 Hz, 2H), 7.36 (d, J = 6.8 Hz, 2H), 7.31 (t, J = 8.4 Hz, 1H), 6.93 (d, J = 6.8 Hz, 2H), 6.89-6.84 (m, 3H), 6.80 (d, J = 7.6 Hz, 1H), 6.01 (s, 1H), 5.02 (s, 2H), 3.82 (s, 3H), 3,56 (s, 2H), 2.52 (m, 4H), 2.32 (s, 3H), 1.76 (m, 4H); LC-MS: 538 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.36 (d, J = 5.2 Hz, 1H), 7.70-7.68 (m, 3H), 7.41 (d, J = 7.2 Hz, 2H), 7.36 (d, J = 6.8 Hz, 2H), 7.31 (t, J = 8.4 Hz, 1H), 6.93 (d, J = 6.8 Hz, 2H), 6.89-6.84 (m, 3H), 6.80 (d, J = 7.6 Hz, 1H), 6.01 (s, 1H), 5.02 ( s, 2H), 3.82 (s, 3H), 3,56 (s, 2H), 2.52 (m, 4H), 2.32 (s, 3H), 1.76 (m, 4H); LC-MS: 538 (MH < + >)

[단계 2] 3-(2-(4-((4-메틸피페라진-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 트라이플루오로아세트산 (3-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol. TFA) (LCB03-0084)의 제조[Step 2] 3- (2- (4-((4-methylpiperazin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol trifluoroacetic acid ( Preparation of 3- (2- (4-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol.TFA) (LCB03-0084)

¹H-NMR (600 MHz, Acetone-d₆); δ 9.98 (brs, 1H), 8.41 (brs, 1H), 8.04 (s, 1H), 7.81 (d, J = 7.2 Hz, 2H), 7.69 (d, J = 7.2 Hz, 2H), 7.36 (t, J = 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.99 (s, 1H), 6.92-6.91 (m, 1H), 6.82 (d, J= 8.4 Hz, 2H), 4.40 (s, 2H), 3.75-3.74 (m, 4H), 3.66-3.65 (m, 4H), 3.00 (s, 3H); LC-MS: 431 (MH+) ¹ H-NMR (600 MHz, Acetone-d ₆ ); δ 9.98 (brs, 1H), 8.41 (brs, 1H), 8.04 (s, 1H), 7.81 (d, J = 7.2 Hz, 2H), 7.69 (d, J = 7.2 Hz, 2H), 7.36 (t, J = 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.99 (s, 1H), 6.92-6.91 (m, 1H), 6.82 (d, J = 8.4 Hz, 2H), 4.40 ( s, 2H), 3.75-3.74 (m, 4H), 3.66-3.65 (m, 4H), 3.00 (s, 3H); LC-MS: 431 (MH < + >)

[실시예 81]Example 81

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-2-(4-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-2-(4-(pyrrolidin-1-ylmethyl)phenyl)thieno[3,2-b]pyridin-7-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -2- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridine-7 Preparation of -amine (N- (3- (4-methoxybenzyloxy) phenyl) -2- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.36 (s, 1H), 7.75-7.73 (m, 1H), 7.66-7.65 (m, 1H), 7.41-7.29 (m, 5H), 6.93-6.79 (m, 6H), 6.14 (s, 1H), 5.05 (s, 2H), 3.82 (s, 3H), 3.76 (s, 2H), 2.62 (m, 4H), 1.83 (m, 4H); LC-MS: 523 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.36 (s, 1H), 7.75-7.73 (m, 1H), 7.66-7.65 (m, 1H), 7.41-7.29 (m, 5H), 6.93-6.79 (m, 6H), 6.14 (s, 1H) , 5.05 (s, 2H), 3.82 (s, 3H), 3.76 (s, 2H), 2.62 (m, 4H), 1.83 (m, 4H); LC-MS: 523 (MH < + >)

[단계 2] 3-(2-(4-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 트라이플루오로아세트산 (3-(2-(4-(pyrrolidin-1-ylmethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol. TFA) (LCB03-0080)의 제조[Step 2] 3- (2- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol trifluoroacetic acid (3- ( Preparation of 2- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol.TFA) (LCB03-0080)

¹H-NMR (400 MHz, Acetone-d₆); δ 8.41-8.40 (m, 1H), 8.17 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.34 (t, J = 8.4 Hz, 1H), 7.08-7.06 (m, 1H), 7.01-6.99 (m, 2H), 6.96-6.90 (m, 2H), 4.41 (s, 2H), 3.83-3.80 (m, 4H), 1.90-1.88 (m, 4H); LC-MS 402 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 8.41-8.40 (m, 1H), 8.17 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.34 (t, J = 8.4 Hz, 1H), 7.08-7.06 (m, 1H), 7.01-6.99 (m, 2H), 6.96-6.90 (m, 2H), 4.41 (s, 2H), 3.83-3.80 (m, 4H), 1.90-1.88 ( m, 4H); LC-MS 402 (MH +)

[실시예 82]Example 82

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-2-(4-(모폴리노메틸)페닐)싸이에노[3,2-b]피리딘-7-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-2-(4-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -2- (4- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-amine (N Preparation of-(3- (4-methoxybenzyloxy) phenyl) -2- (4- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.38 (d, J = 5.2 Hz, 1H), 7.72-7.70 (m, 3H), 7.44 (d, J= 7.2 Hz, 2H), 7.35 (d, J = 7.2 Hz, 2H), 7.32-7.29 (m, 1H), 6.94 (d, J = 6.8 Hz, 2H), 6.90-6.81 (m, 4H), 6.02 (s, 1H), 5.03 (s, 2H), 3.84 (s, 3H), 3.74-3.73 (m, 4H), 2.50-2.49 (m, 4H); LC-MS: 551 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.38 (d, J = 5.2 Hz, 1H), 7.72-7.70 (m, 3H), 7.44 (d, J = 7.2 Hz, 2H), 7.35 (d, J = 7.2 Hz, 2H), 7.32-7.29 ( m, 1H), 6.94 (d, J = 6.8 Hz, 2H), 6.90-6.81 (m, 4H), 6.02 (s, 1H), 5.03 (s, 2H), 3.84 (s, 3H), 3.74-3.73 (m, 4H), 2.50-2.49 (m, 4H); LC-MS: 551 (MH < + >)

[단계 2] 3-(2-(4-(모폴리노메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 트라이플루오로아세트산 (3-(2-(4-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol. TFA) (LCB03-0083)의 제조[Step 2] 3- (2- (4- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol trifluoroacetic acid (3- (2- (4 Preparation of-(morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol.TFA) (LCB03-0083)

¹H-NMR (600 MHz, Acetone-d₆); δ 10.61 (brs, 1H), 8.34 (brs, 1H), 8.00 (s, 1H), 7.77-7.70 (m, 3H), 7.33 (t, J= 8.4 Hz, 1H), 7.11 (d, J = 7.8 Hz, 2H), 6.99 (s, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 4.49 (s, 2H), 3.96-3.93 (m, 4H), 3.28-3.26 (m, 4H); LC-MS: 418 (MH+) ¹ H-NMR (600 MHz, Acetone-d ₆ ); δ 10.61 (brs, 1H), 8.34 (brs, 1H), 8.00 (s, 1H), 7.77-7.70 (m, 3H), 7.33 (t, J = 8.4 Hz, 1H), 7.11 (d, J = 7.8 Hz, 2H), 6.99 (s, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 4.49 (s, 2H), 3.96-3.93 (m, 4H ), 3.28-3.26 (m, 4 H); LC-MS: 418 (MH < + >)

[실시예 83]Example 83

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-2-(4-(피페라진-1-일메틸)페닐)싸이에 노[3,2-b]피리딘-7-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-2-(4-(piperazin-1-ylmethyl)phenyl)thieno[3,2-b]pyridin-7-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -2- (4- (piperazin-1-ylmethyl) phenyl) cyeno [3,2-b] pyridine-7- Preparation of Amine (N- (3- (4-methoxybenzyloxy) phenyl) -2- (4- (piperazin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-amine)

¹H-NMR (400 MHz, Acetone-d₆); δ 8.44 (d, J = 6.8 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.10 (m, 2H), 7.01 (m, 2H), 6.94 (m, 1H), 5.00 (s, 2H), 3.97 (s, 2H), 3.84 (s, 2H), 3.54-3.52 (m, 4H), 3.12-3.10 (m, 4H); LC-MS 537 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 8.44 (d, J = 6.8 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H) , 7.37 (t, J = 8.0 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.10 (m, 2H), 7.01 (m, 2H), 6.94 (m, 1H), 5.00 (s, 2H), 3.97 (s, 2H), 3.84 (s, 2H), 3.54-3.52 (m, 4H), 3.12-3.10 (m, 4H); LC-MS 537 (MH +)

[단계 2] 3-(2-(4-(피페라진-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 트라이플루오로아세트산 (3-(2-(4-(piperazin-1-ylmethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol. TFA) (LCB03-0098)의 제조[Step 2] 3- (2- (4- (piperazin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol trifluoroacetic acid (3- (2 Preparation of-(4- (piperazin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol.TFA) (LCB03-0098)

¹H-NMR (400 MHz, Acetone-d₆); δ 8.44 (d, J = 6.8 Hz, 1H), 8.15 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.10 (m, 2H), 7.01 (m, 2H), 6.94 (m, 1H), 3.97 (s, 2H), 3.54-3.52 (m, 4H), 3.12-3.10 (m, 4H); LC-MS 418 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 8.44 (d, J = 6.8 Hz, 1H), 8.15 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.10 (m, 2H), 7.01 (m, 2H), 6.94 (m, 1H), 3.97 (s, 2H), 3.54-3.52 (m, 4H), 3.12-3.10 (m, 4H ); LC-MS 418 (MH +)

[실시예 84]Example 84

[단계 1] 2-(4-((에틸아미노)메틸)페닐)-N-(3-(4-메톡시벤질옥시)페닐)싸이에노[3,2-b]피리딘-7-아민 (2-(4-((ethylamino)methyl)phenyl)-N-(3-(4-methoxybenzyloxy)phenyl)thieno[3,2-b]pyridin-7-amine) 의 제조[Step 1] 2- (4-((ethylamino) methyl) phenyl) -N- (3- (4-methoxybenzyloxy) phenyl) thieno [3,2-b] pyridin-7-amine ( Preparation of 2- (4-((ethylamino) methyl) phenyl) -N- (3- (4-methoxybenzyloxy) phenyl) thieno [3,2-b] pyridin-7-amine)

¹H-NMR (400 MHz, Acetone-d₆); δ 9.99 (brs, 1H), 8.36 (d, J = 6.8 Hz, 1H), 7.97 (s, 1H), 7.98 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.64 (t, J= 7.8 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.03 (m, 2H), 6.91 (m, 2H), 6.86-6.83 (m, 2H), 4.99 (s, 2H), 3.80 (s, 3H), 3.78 (s, 2H), 3.28 (q, J = 6.8 Hz, 2H), 1.38 (t, J = 6.8 Hz, 3H); LC-MS 496 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 9.99 (brs, 1H), 8.36 (d, J = 6.8 Hz, 1H), 7.97 (s, 1H), 7.98 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.64 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.03 (m, 2H), 6.91 (m, 2H), 6.86-6.83 ( m, 2H), 4.99 (s, 2H), 3.80 (s, 3H), 3.78 (s, 2H), 3.28 (q, J = 6.8 Hz, 2H), 1.38 (t, J = 6.8 Hz, 3H); LC-MS 496 (MH +)

[단계 2] 3-(2-(4-((에틸아미노)메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 트라이플루오로아세트산 (3-(2-(4-((ethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol. TFA) (LCB03-0099)의 제조[Step 2] 3- (2- (4-((ethylamino) methyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol trifluoroacetic acid (3- (2- ( Preparation of 4-((ethylamino) methyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol.TFA) (LCB03-0099)

¹H-NMR (400 MHz, Acetone-d₆); δ 8.36 (d, J = 6.8 Hz, 1H), 7.97 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 8.0 Hz, 1H), 7.03 (m, 2H), 6.91 (m, 2H), 4.37 (s, 2H), 3.28 (q, J = 6.8 Hz, 2H), 1.38 (t, J = 6.8 Hz, 3H); LC-MS 376 (MH+) ¹ H-NMR (400 MHz, Acetone-d ₆ ); δ 8.36 (d, J = 6.8 Hz, 1H), 7.97 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 8.0 Hz, 1H), 7.03 (m, 2H), 6.91 (m, 2H), 4.37 (s, 2H), 3.28 (q, J = 6.8 Hz, 2H), 1.38 (t, J = 6.8 Hz, 3H) ; LC-MS 376 (MH +)

[실시예 85]Example 85

[단계 1] N-(4-클로로-3-(4-메톡시벤질옥시)페닐)-6-(4-피롤리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(4-chloro-3-(4-methoxybenzyloxy)phenyl)-6-(4-(pyrrolidin-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (4-chloro-3- (4-methoxybenzyloxy) phenyl) -6- (4-pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] Pyrimidin-4-amine (N- (4-chloro-3- (4-methoxybenzyloxy) phenyl) -6- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4- Preparation of amine

¹H-NMR (400 MHz, CDCl₃); δ 8.69 (s, 1H), 7.63-7.59 (m, 3H), 7.53 (d, J= 2.0 Hz, 1H), 7.43-7.36 (m, 6H), 7.03 (dd, J =2.0, 8.4 Hz 1H), 6.89 (d, J = 8.8 Hz, 2H), 5.12 (s, 2H), 3.78 (s, 3H), 3.67 (s, 2H), 2.55 (m, 4H), 1.80 (m, 4H); LC-MS 558 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.63-7.59 (m, 3H), 7.53 (d, J = 2.0 Hz, 1H), 7.43-7.36 (m, 6H), 7.03 (dd, J = 2.0, 8.4 Hz 1H) , 6.89 (d, J = 8.8 Hz, 2H), 5.12 (s, 2H), 3.78 (s, 3H), 3.67 (s, 2H), 2.55 (m, 4H), 1.80 (m, 4H); LC-MS 558 (MH +)

[단계 2] 4-클로로-5-(6-(4-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 트라이플로로메탄술폰산 (2-chloro-5-(6-(4-(pyrrolidin-1-ylmethyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. TFA) (LCB03-0081)의 제조[Step 2] 4-Chloro-5- (6- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol trifluoro Preparation of methanesulfonic acid (2-chloro-5- (6- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.TFA) (LCB03-0081)

¹H-NMR (400 MHz, CDCl₃); δ 8.51 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 2.4 Hz, 1H), 7.25 (d, J= 8.8 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 4.80 (s, 1H), 4.09 (s, 2H), 3.01 (s, 4H), 1.97 (s, 4H); LC-MS 437 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.51 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 2.4 Hz, 1H) , 7.25 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 4.80 (s, 1H), 4.09 (s, 2H), 3.01 (s, 4H), 1.97 (s, 4H); LC-MS 437 (MH +)

[실시예 86]Example 86

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-2-(3-(피페리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-2-(3-(piperidin-1-ylmethyl)phenyl)thieno[3,2-b]pyridin-7-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -2- (3- (piperidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridine-7 Preparation of -amine (N- (3- (4-methoxybenzyloxy) phenyl) -2- (3- (piperidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-amine)

제조예 25에서 얻은 화합물 (30 mg, 0.06 mmol)과 피페리딘 (64 ㎕, 0.61 mmol)을 DCE 1 ml에 순차적으로 넣고 20분간 교반한 후 초산나트륨 (16 mg, 0.19 mmol)과 소디움트리아세톡시보로하이드라이드 (82 mg, 0.38 mmol)을 넣고 5시간 동안 실온에서 교반하였다. 반응완료 후 다이클로로메테인 30 ml와 포화된 염화암모늄 수용액 30 ml를 이용하여 추출하였다. 유기층을 무기 황산나트륨으로 건조하고 감압농축 후, 관크로마토그래피 (디클로로메테인/메탄올, 1/25)를 시행하여 표제화합물 (17 mg, 48 %)을 수득하였다.Compound (30 mg, 0.06 mmol) and piperidine (64 μl, 0.61 mmol) obtained in Preparation Example 25 were sequentially added to 1 ml of DCE, followed by stirring for 20 minutes, followed by sodium acetate (16 mg, 0.19 mmol) and sodium triacetoc Cheborohydride (82 mg, 0.38 mmol) was added and stirred at room temperature for 5 hours. After completion of the reaction was extracted using 30 ml of dichloromethane and 30 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over inorganic sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (dichloromethane / methanol, 1/25) to obtain the title compound (17 mg, 48%).

¹H-NMR (400 MHz, CDCl₃); δ 8.35 (d, J = 5.6 Hz, 1H), 7.72-7.70 (m, 1H), 7.62 (d, J = 5.6 Hz, 1H), 7.40-7.29 (m, 5H), 6.93-6.78 (m, 6H), 6.16 (s, 1H), 5.01 (s, 2H), 3.81 (s, 3H), 3.55 (s, 2H), 2.44 (m, 4H), 2.12 (m, 2H), 1.61 (m, 4H); LC-MS: 536 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.35 (d, J = 5.6 Hz, 1H), 7.72-7.70 (m, 1H), 7.62 (d, J = 5.6 Hz, 1H), 7.40-7.29 (m, 5H), 6.93-6.78 (m, 6H ), 6.16 (s, 1H), 5.01 (s, 2H), 3.81 (s, 3H), 3.55 (s, 2H), 2.44 (m, 4H), 2.12 (m, 2H), 1.61 (m, 4H) ; LC-MS: 536 (MH < + >)

[단계 2] 3-(2-(3-(피페리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 트라이플루오로아세트산 (3-(2-(3-(piperidin-1-ylmethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol.TFA) (LCB03-0109)의 제조[Step 2] 3- (2- (3- (piperidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol trifluoroacetic acid (3- ( Preparation of 2- (3- (piperidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol.TFA) (LCB03-0109)

¹H-NMR (600 MHz, Acetone-d₆); δ 8.32 (brs, 1H), 8.02 (brs, 1H), 7.99 (s, 1H), 7.71 (t, J= 7.2 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.31-7.26 (m, 2H), 7.03 (s, 1H), 6.98 (t, J = 6.6 Hz, 1H), 6.92-6.88 (m, 3H), 4.43 (s, 2H), 3.59-3.56 (m, 2H), 3.56-3.54 (m, 2H), 2.06-2.04 (m, 2H), 1.90-1.89 (m, 4H); LC-MS 416 (MH+) ¹ H-NMR (600 MHz, Acetone-d ₆ ); δ 8.32 (brs, 1H), 8.02 (brs, 1H), 7.99 (s, 1H), 7.71 (t, J = 7.2 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.31-7.26 ( m, 2H), 7.03 (s, 1H), 6.98 (t, J = 6.6 Hz, 1H), 6.92-6.88 (m, 3H), 4.43 (s, 2H), 3.59-3.56 (m, 2H), 3.56 -3.54 (m, 2H), 2.06-2.04 (m, 2H), 1.90-1.89 (m, 4H); LC-MS 416 (MH +)

상기 실시예 86과 유사한 방법으로 하기 화합물들을 합성하였다.In the same manner as in Example 86, the following compounds were synthesized.

[실시예 87]Example 87

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-2-(3-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-2-(3-(pyrrolidin-1-ylmethyl)phenyl)thieno[3,2-b]pyridin-7-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -2- (3- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridine-7 Preparation of -amine (N- (3- (4-methoxybenzyloxy) phenyl) -2- (3- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.36 (s, 1H), 7.73-7.72 (m, 1H), 7.64-7.63 (m, 1H), 7.41-7.29 (m, 5H), 6.93-6.79 (m, 6H), 6.14 (s, 1H), 5.01 (s, 2H), 3.82 (s, 3H), 3.74 (s, 2H), 2.62 (m, 4H), 1.83 (m, 4H); LC-MS: 523 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.36 (s, 1H), 7.73-7.72 (m, 1H), 7.64-7.63 (m, 1H), 7.41-7.29 (m, 5H), 6.93-6.79 (m, 6H), 6.14 (s, 1H) , 5.01 (s, 2H), 3.82 (s, 3H), 3.74 (s, 2H), 2.62 (m, 4H), 1.83 (m, 4H); LC-MS: 523 (MH < + >)

[단계 2] 3-(2-(3-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 트라이플루오로아세트산 (3-(2-(3-(pyrrolidin-1-ylmethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol. TFA) (LCB03-0107)의 제조[Step 2] 3- (2- (3- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol trifluoroacetic acid (3- ( Preparation of 2- (3- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol.TFA) (LCB03-0107)

¹H-NMR (600 MHz, Acetone-d₆); δ 10.07 (brs, 1H), 8.35-8.33 (m, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.73 (t, J = 8.4 Hz, 2H), 7.54 (t, J= 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.04 (s, 1H), 7.01 (t, J = 6.6 Hz, 1H), 6.93 (s, 1H), 6.92-6.89 (m, 2H), 4.55 (s, 2H), 3.66-3.64 (m, 2H), 3.29-3.28 (m, 2H), 2.16-2.14 (m, 4H); LC-MS: 402 (MH+) ¹ H-NMR (600 MHz, Acetone-d ₆ ); δ 10.07 (brs, 1H), 8.35-8.33 (m, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.73 (t, J = 8.4 Hz, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.04 (s, 1H), 7.01 (t, J = 6.6 Hz, 1H), 6.93 (s, 1H), 6.92-6.89 (m, 2H ), 4.55 (s, 2H), 3.66-3.64 (m, 2H), 3.29-3.28 (m, 2H), 2.16-2.14 (m, 4H); LC-MS: 402 (MH < + >)

[실시예 88]Example 88

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(3-((4-메틸피페라진-1-일)메틸)페닐)싸이에노[3,2-b]피리딘-7-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(3-((4-methylpiperazin-1-yl)methyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (3-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-b ] Pyridin-7-amine (N- (3- (4-methoxybenzyloxy) phenyl) -6- (3-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4 -amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.35 (d, J = 5.6 Hz, 1H), 7.72-7.71 (m, 2H), 7.62 (d, J= 7.2 Hz, 1H), 7.41-7.30 (m, 5H), 6.93-6.79 (m, 6H), 6.19 (s, 1H), 5.01 (s, 2H), 3.82 (s, 3H), 3.57 (s, 3H), 3.47-3.46 (m,2H), 2.63 (m, 4H), 2.09 (m, 4H); LC-MS: 523 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.35 (d, J = 5.6 Hz, 1H), 7.72-7.71 (m, 2H), 7.62 (d, J = 7.2 Hz, 1H), 7.41-7.30 (m, 5H), 6.93-6.79 (m, 6H ), 6.19 (s, 1H), 5.01 (s, 2H), 3.82 (s, 3H), 3.57 (s, 3H), 3.47-3.46 (m, 2H), 2.63 (m, 4H), 2.09 (m, 4H); LC-MS: 523 (MH < + >)

[단계 2] 3-(2-(3-((4-메틸피페라진-1-일)메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 트라이플루오로아세트산 (3-(2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol. TFA) (LCB03-0108)의 제조[Step 2] 3- (2- (3-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol trifluoroacetic acid Preparation of (3- (2- (3-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol.TFA) (LCB03-0108)

¹H-NMR (600 MHz, Acetone-d₆); δ 9.99 (brs, 1H), 8.39 (brs, 1H), 8.08 (s, 1H), 7.29 (s, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.35 (t, J= 7.8 Hz, 1H), 7.13-7.12 (m, 1H), 7.12- 7.10 (m, 2H), 6.96-6.92 (m, 2H), 6.83-6.82 (m, 1H), 4.03 (s, 2H), 3.86-3.85 (m, 2H), 3.74 (s, 3H), 3.62-3.61 (m, 3H), 3.19-3.18 (m, 3H), 2.09 (s, 3H); LC-MS: 431 (MH+) ¹ H-NMR (600 MHz, Acetone-d ₆ ); δ 9.99 (brs, 1H), 8.39 (brs, 1H), 8.08 (s, 1H), 7.29 (s, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.13-7.12 (m, 1H), 7.12- 7.10 (m, 2H), 6.96-6.92 (m , 2H), 6.83-6.82 (m, 1H), 4.03 (s, 2H), 3.86-3.85 (m, 2H), 3.74 (s, 3H), 3.62-3.61 (m, 3H), 3.19-3.18 (m , 3H), 2.09 (s, 3H); LC-MS: 431 (MH < + >)

[실시예 89]Example 89

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-6-(3-(모폴리노메틸)페닐)싸이에노[3,2-b]피리딘-7-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-6-(3-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -6- (3- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-amine (N Preparation of-(3- (4-methoxybenzyloxy) phenyl) -6- (3- (morpholinomethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.20 (d, J = 5.6 Hz, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.37-7.28 (m, 4H), 6.94-6.83 (m, 6H), 6.19 (s, 1H), 5.01 (s, 2H), 3.80 (s, 3H), 3.74-3.73 (m, 3H), 3.52-3.50 (m, 4H), 2.49-2.48 (m, 3H); LC-MS: 538 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.20 (d, J = 5.6 Hz, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.37-7.28 (m, 4H), 6.94-6.83 (m, 6H ), 6.19 (s, 1H), 5.01 (s, 2H), 3.80 (s, 3H), 3.74-3.73 (m, 3H), 3.52-3.50 (m, 4H), 2.49-2.48 (m, 3H); LC-MS: 538 (MH < + >)

[단계 2] 3-(2-(3-(모폴리노메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 트라이플루오로아세트산 (3-(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol. TFA) (LCB03-0110)의 제조[Step 2] 3- (2- (3- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol trifluoroacetic acid (3- (2- (3 Preparation of-(morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol.TFA) (LCB03-0110)

¹H-NMR (600 MHz, Acetone-d₆); δ 8.37 (d, J = 6.0 Hz, 1H), 8.08 (brs, 1H), 8.02 (s, 1H), 7.77-7.73 (m, 2H), 7.57 t, J = 7.8 Hz, 1H), 7.33 (t, J= 8.4 Hz, 1H), 7.29-7.26 (m, 1H), 7.02-7.01 (m, 1H), 6.93-6.91 (m, 3H), 4.52 (s, 2H), 4.07-4.03 (m, 4H), 3.59-3.55 (m, 4H); LC-MS: 418 (MH+) ¹ H-NMR (600 MHz, Acetone-d ₆ ); δ 8.37 (d, J = 6.0 Hz, 1H), 8.08 (brs, 1H), 8.02 (s, 1H), 7.77-7.73 (m, 2H), 7.57 t, J = 7.8 Hz, 1H), 7.33 (t , J = 8.4 Hz, 1H), 7.29-7.26 (m, 1H), 7.02-7.01 (m, 1H), 6.93-6.91 (m, 3H), 4.52 (s, 2H), 4.07-4.03 (m, 4H ), 3.59-3.55 (m, 4H); LC-MS: 418 (MH < + >)

[실시예 90]Example 90

[단계 1] 터트-부틸 4-(3-(7-(3-(4-메톡시벤질옥시)페닐아미노)싸이에노[3,2-b]피리딘-2-일)벤질)피페라진-1-카복실레이트 (tert-butyl 4-(3-(7-(3-(4-methoxybenzyloxy)phenylamino)thieno[3,2-b]pyridin-2-yl)benzyl)piperazine-1-carboxylate) 의 제조[Step 1] Tert-Butyl 4- (3- (7- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-b] pyridin-2-yl) benzyl) piperazine- Preparation of 1-carboxylate (tert-butyl 4- (3- (7- (3- (4-methoxybenzyloxy) phenylamino) thieno [3,2-b] pyridin-2-yl) benzyl) piperazine-1-carboxylate)

¹H-NMR (400 MHz, CDCl₃); δ 8.34 (d, J = 5.6 Hz, 1H), 7.72-7.63 (m, 3H), 7.56-7.53 (m, 1H), 7.48-7.46 (m, 1H), 7.41-7.27 (m, 4H), 6.93-6.85 (m, 4H), 6.80-6.78 (m, 1H), 6.48 (s, 1H), 5.00 (s, 2H), 3.81 (s, 3H), 3.40-3.38 (m, 2H), 2.47 (m, 4H), 2.20 (m, 4H), 1.49 (s, 9H); LC-MS 637 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.34 (d, J = 5.6 Hz, 1H), 7.72-7.63 (m, 3H), 7.56-7.53 (m, 1H), 7.48-7.46 (m, 1H), 7.41-7.27 (m, 4H), 6.93 -6.85 (m, 4H), 6.80-6.78 (m, 1H), 6.48 (s, 1H), 5.00 (s, 2H), 3.81 (s, 3H), 3.40-3.38 (m, 2H), 2.47 (m , 4H), 2.20 (m, 4H), 1.49 (s, 9H); LC-MS 637 (MH +)

[단계 2] 3-(2-(3-(피페라진-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 트라이플루오로아세트산 (3-(2-(3-(piperazin-1-ylmethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol. TFA) (LCB03-0111)의 제조[Step 2] 3- (2- (3- (piperazin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol trifluoroacetic acid (3- (2 Preparation of-(3- (piperazin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol.TFA) (LCB03-0111)

¹H-NMR (600 MHz, Acetone-d₆); δ 8.45 (d, J = 7.2 Hz, 1H), 8.12 (brs, 1H), 8.02 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.28-7.24 (m, 1H), 7.12 (d, J= 6.6 Hz, 1H), 6.98-6.95 (m, 1H), 6.92-6.60 (m, 3H), 4.61 (s, 2H), 3.94-3.87 (m, 4H), 3.72-3.52 (m, 4H); LC-MS: 417 (MH+) ¹ H-NMR (600 MHz, Acetone-d ₆ ); δ 8.45 (d, J = 7.2 Hz, 1H), 8.12 (brs, 1H), 8.02 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H) , 7.63 (t, J = 7.8 Hz, 1H), 7.28-7.24 (m, 1H), 7.12 (d, J = 6.6 Hz, 1H), 6.98-6.95 (m, 1H), 6.92-6.60 (m, 3H ), 4.61 (s, 2H), 3.94-3.87 (m, 4H), 3.72-3.52 (m, 4H); LC-MS: 417 (MH < + >)

[실시예 91]Example 91

[단계 1] 2-(3-((에틸아미노)메틸)페닐)-N-(3-(4-메톡시벤질옥시페닐)싸이에노[3,2-b]피리딘-7-아민 (2-(3-((ethylamino)methyl)phenyl)-N-(3-(4-methoxybenzyloxy)phenyl)thieno[3,2-b]pyridin-7-amine) 의 제조[Step 1] 2- (3-((ethylamino) methyl) phenyl) -N- (3- (4-methoxybenzyloxyphenyl) thieno [3,2-b] pyridin-7-amine (2 Preparation of-(3-((ethylamino) methyl) phenyl) -N- (3- (4-methoxybenzyloxy) phenyl) thieno [3,2-b] pyridin-7-amine)

¹H-NMR (400 MHz, CDCl₃); δ 8.31 (d, J= 5.6 Hz, 1H), 7.75-7.74 (m, 1H), 7.71 (s, 1H), 7.62-7.61 (m, 1H), 7.46-7.29 (m, 5H), 6.93-6.87 (m, 5H), 6.81-6.79 (m, 1H), 5.01 (s, 2H), 3.90 (s, 2H), 3.82 (s, 3H), 2.80 (q, J = 6.8 Hz, 2H), 1.24-1.22 (m, 3H); LC-MS 496 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.31 (d, J = 5.6 Hz, 1H), 7.75-7.74 (m, 1H), 7.71 (s, 1H), 7.62-7.61 (m, 1H), 7.46-7.29 (m, 5H), 6.93-6.87 (m, 5H), 6.81-6.79 (m, 1H), 5.01 (s, 2H), 3.90 (s, 2H), 3.82 (s, 3H), 2.80 (q, J = 6.8 Hz, 2H), 1.24- 1.22 (m, 3 H); LC-MS 496 (MH +)

[단계 2] 3-(2-(3-((에틸아미노)메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀 트라이플루오로아세트산 (3-(2-(3-((ethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol. TFA) (LCB03-0112)의 제조[Step 2] 3- (2- (3-((ethylamino) methyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol trifluoroacetic acid (3- (2- ( Preparation of 3-((ethylamino) methyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol.TFA) (LCB03-0112)

¹H-NMR (600 MHz, Acetone-d₆); δ 8.35 (d, J = 6.0 Hz, 1H), 8.09 (brs, 1H), 7.96 (s, 1H), 7.70 (t, J = 7.8 Hz, 2H), 7.51 (t, J = 7.8 Hz, 1H), 7.34 (t, J= 7.8 Hz, 1H), 7.29-7.26 (m, 1H), 7.05-6.94 (m, 2H), 6.92-6.89 (m, 3H), 4.43 (s, 2H), 3.41-3.40 (m, 2H), 1.40 (t, J= 7.2 Hz, 3H); LC-MS 376 (MH+) ¹ H-NMR (600 MHz, Acetone-d ₆ ); δ 8.35 (d, J = 6.0 Hz, 1H), 8.09 (brs, 1H), 7.96 (s, 1H), 7.70 (t, J = 7.8 Hz, 2H), 7.51 (t, J = 7.8 Hz, 1H) , 7.34 (t, J = 7.8 Hz, 1H), 7.29-7.26 (m, 1H), 7.05-6.94 (m, 2H), 6.92-6.89 (m, 3H), 4.43 (s, 2H), 3.41-3.40 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H); LC-MS 376 (MH +)

[실시예 92]Example 92

[단계 1] 2-(4-(4-(3-(터트-부틸다이메틸실릴옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)에탄올 (2-(4-(4-(3-(tert-butyldimethylsilyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)phenyl)ethanol) 의 제조[Step 1] 2- (4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) ethanol (2- Preparation of (4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) ethanol)

리튬알루미늄하이드라이드 (44 mg, 1.16 mmol)을 3 ml의 건조된 다이메틸포름아마이드에 넣고 질소로 충진된 상태에서 제조예 28에서 수득한 화합물 (0.49 mg, 0.96 mmol)을 건조된 테트라하이드로퓨란 7 ml에 녹여서 0 ℃하에서 천천히 적가하고 2시간동안 교반하였다. Lithium aluminum hydride (44 mg, 1.16 mmol) was added to 3 ml of dried dimethylformamide and charged with nitrogen, and the compound obtained in Preparation 28 (0.49 mg, 0.96 mmol) was dried with tetrahydrofuran 7 It was dissolved in ml and slowly added dropwise at 0 ° C and stirred for 2 hours.

물 44 ㎕와 15 % 수산화나트륨 44 ㎕, 132 ㎕의 물을 0 ℃하에서 천천히 순차적으로 넣어 준 후 무수 황산나트륨을 소량 넣고 건조한 다음 필터하여 다이클로로메테인으로 씻어주었다. 감압 농축 후 n-헥세인을 이용하여 트리터레이션(trituration)하여 표제화합물 (0.34 g, 76 %)을 옅은 노란색 고체로 수득하였다. 44 μl of water, 44 μl of 15% sodium hydroxide, and 132 μl of water were slowly added at 0 ° C., followed by a small amount of anhydrous sodium sulfate, followed by drying, followed by filtration and washing with dichloromethane. Trituration using n-hexane after concentration under reduced pressure gave the title compound (0.34 g, 76%) as a pale yellow solid.

¹H-NMR (400 MHz, DMSO-d₆); δ 9.64 (s, 1H), 8.58 (s, 1H), 7.86 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.50-7.48 (m, 1H), 7.44 (t, J = 2.0 Hz, 1H), 7.38 (d, J= 8.4 Hz, 2H), 6.60-6.58 (m, 1H), 4.70 (t, J = 5.2 Hz, 1H), 3.65 (q, J = 6.8 HZ, 2H), 2.79 (t, J= 7.2 HZ, 2H), 0.98 (s, 9H), 0.22 (s, 6H); LC-MS: 478 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.64 (s, 1H), 8.58 (s, 1H), 7.86 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.50-7.48 (m, 1H), 7.44 (t, J = 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 6.60-6.58 (m, 1H), 4.70 (t, J = 5.2 Hz, 1H), 3.65 (q, J = 6.8 HZ, 2H), 2.79 (t, J = 7.2 HZ, 2H), 0.98 (s, 9H), 0.22 (s, 6H); LC-MS: 478 (MH < + >)

[단계 2] 4-(4-(3-(터트-부틸다이메틸실릴옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페네틸메탄설포네이트 (4-(4-(3-(tert-butyldimethylsilyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)phenethyl methanesulfonate) 의 제조[Step 2] 4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) phenethylmethanesulfonate (4- ( Preparation of 4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) phenethyl methanesulfonate)

상기 단계 1에서 제조된 화합물 (0.33 g, 0.69 mmol)을 5 ml의 다이클로로메테인에 녹인 후 0 ℃에서 트라이에틸아민 (116 ㎕, 0.83 mmol), 클로로 메탄술폰산 (56 ㎕, 0.72 mmol)을 천천히 적가하였다. 30분간 0 ℃에서 교반 후, 실온에서 2시간 정도 더 교반하였다. 2 N 염산 (50 mL)를 반응 용액에 부은 후 에틸 아세테이트 (50 mL x 2)로 추출한 후 유기층을 물 (100 mL x 2)로 씻어 주고 무수 황산 나트륨으로 건조하였다. 감압 농축 후 관크로마토그래피 (에틸아세테이트/n-헥세인, 1:2)로 분리하여 표제화합물 (0.22 g, 57 %)을 노란색 고체로 수득하였다.The compound prepared in step 1 (0.33 g, 0.69 mmol) was dissolved in 5 ml of dichloromethane, and triethylamine (116 μl, 0.83 mmol) and chloromethanesulfonic acid (56 μl, 0.72 mmol) were added at 0 ° C. Slowly added dropwise. After 30 minutes of stirring at 0 ° C, the mixture was further stirred at room temperature for about 2 hours. 2 N hydrochloric acid (50 mL) was poured into the reaction solution, extracted with ethyl acetate (50 mL x 2), and the organic layer was washed with water (100 mL x 2) and dried over anhydrous sodium sulfate. Concentration under reduced pressure and separation by column chromatography (ethyl acetate / n-hexane, 1: 2) gave the title compound (0.22 g, 57%) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃); δ 8.53 (s, 1H), 7.73 (s, 1H), 7.58-7.52 (m, 2H), 7.32-7.14 (m, 5H), 6.89 (d, J = 6.0 Hz, 1H), 4.43 (brm, 2H), 3.08 (brm, 2H), 2.91 (s, 3H), 0.88 (s, 9H), 0.02 (s, 6H); LC-MS 556 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.53 (s, 1H), 7.73 (s, 1H), 7.58-7.52 (m, 2H), 7.32-7.14 (m, 5H), 6.89 (d, J = 6.0 Hz, 1H), 4.43 (brm, 2H ), 3.08 (brm, 2H), 2.91 (s, 3H), 0.88 (s, 9H), 0.02 (s, 6H); LC-MS 556 (MH +)

[단계 3] N-(3-(터트-부틸다이메틸실릴옥시)페닐)-6-(4-(2-모폴리노에틸)페닐)싸이에노[3,2-d]피리미딘-4-아민 (N-(3-(tert-butyldimethylsilyloxy)phenyl)-6-(4-(2-morpholinoethyl)phenyl)thieno[3,2-d]pyrimidin-4-amine) 의 제조[Step 3] N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (4- (2-morpholinoethyl) phenyl) thieno [3,2-d] pyrimidine-4 Preparation of -amine (N- (3- (tert-butyldimethylsilyloxy) phenyl) -6- (4- (2-morpholinoethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine)

상기 단계 2에서 제조된 화합물 (50 mg, 0.089 mmol)을 1 ml 톨루엔에 녹인 후 다이아이소프로필아민 (24 ㎕, 0.13 mmol), 모폴린 (12 ㎕, 0.13 mmol)을 반응액에 넣고 환류교반하였다. 감압 농축 후 관크로마토그래피 (에틸아세테이트/n-헥세인, 1:1)로 분리하여 표제화합물 (15 mg, 31 %)을 노란색 고체로 수득하였다.The compound prepared in step 2 (50 mg, 0.089 mmol) was dissolved in 1 ml toluene, and then diisopropylamine (24 μl, 0.13 mmol) and morpholine (12 μl, 0.13 mmol) were added to the reaction mixture and stirred under reflux. . Concentration under reduced pressure and separation by column chromatography (ethyl acetate / n-hexane, 1: 1) afforded the title compound (15 mg, 31%) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃); δ 8.69 (s, 1H), 7.61-7.57 (m, 3H), 7.30-7.24 (m, 3H), 7.19 (t, J = 2.0 Hz, 1H), 7.16-7.13 (m, 1H), 6.84 (br, 1H), 6.76-6.74 (m, 1H), 3.75 (t, J = 4.4 Hz, 2H), 2.87-2.83 (m, 2H), 2.64-2.60 (m, 4H), 2.55-2.54 (m, 4H), 0.99 (s, 9H), 0.24 (s, 6H); LC-MS: 547 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.61-7.57 (m, 3H), 7.30-7.24 (m, 3H), 7.19 (t, J = 2.0 Hz, 1H), 7.16-7.13 (m, 1H), 6.84 (br , 1H), 6.76-6.74 (m, 1H), 3.75 (t, J = 4.4 Hz, 2H), 2.87-2.83 (m, 2H), 2.64-2.60 (m, 4H), 2.55-2.54 (m, 4H ), 0.99 (s, 9H), 0.24 (s, 6H); LC-MS: 547 (MH < + >)

[단계 4] 3-(6-(4-(2-모폴리노에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(4-(2-morpholinoethyl)phenyl)thieno[3,2-d]pyrimidin-4- ylamino)phenol. HCl) (LCB03-0046)의 제조[Step 4] 3- (6- (4- (2-morpholinoethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride (3- (6- (4 Preparation of-(2-morpholinoethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0046)

상기 단계 3에서 제조된 화합물 (15 mg, 0.02 mmol)을 실시예 9와 유사한 방법으로 표제화합물 (12 mg, 93%)을 노란색의 고체로 수득하였다.The compound prepared in Step 3 (15 mg, 0.02 mmol) was obtained in the same manner as Example 9, to obtain the title compound (12 mg, 93%) as a yellow solid.

¹H-NMR (400 MHz, DMSO-d₆); δ 11.25 (brs, 1H), 8.80 (s, 1H), 7.89 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.25-7.11 (m, 3H), 6.69 (d, J = 7.6 Hz, 1H), 4.01-3.99 (m, 2H), 3.83-3.78 (m, 2H), 3.51-3.46 (m, 2H), 3.40-3.35 (m, 2H), 3.17-3.10 (m, 4H); LC-MS 433 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 11.25 (brs, 1H), 8.80 (s, 1H), 7.89 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.25-7.11 ( m, 3H), 6.69 (d, J = 7.6 Hz, 1H), 4.01-3.99 (m, 2H), 3.83-3.78 (m, 2H), 3.51-3.46 (m, 2H), 3.40-3.35 (m, 2H), 3.17-3.10 (m, 4H); LC-MS 433 (MH +)

상기 실시예 92와 유사한 방법으로 하기 화합물을 합성하였다. In the same manner as in Example 92, the following compound was synthesized.

[실시예 93] 3-(6-(4-(2-(피롤리딘-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-((6-(4-(2-(pyrrolidin-1-yl)ethyl)phenyl)thieno[3,2-d]pyrimidin-4-yl)methyl)phenol) (LCB03-0043)의 제조Example 93 3- (6- (4- (2- (pyrrolidin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3 Preparation of-((6- (4- (2- (pyrrolidin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-yl) methyl) phenol) (LCB03-0043)

¹H-NMR (400 MHz, DMSO-d₆); δ 7.87-7.85 (m, 3H), 7.49-7.47 (m, 2H), 7.22-7.15 (m, 4H), 6.66-6.65 (m, 1H), 3.55 (s, 2H), 3.17-3.11 (m, 4H), 2.34-2.32 (m, 2H), 2.01-1.89 (m, 4H); LC-MS 417 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 7.87-7.85 (m, 3H), 7.49-7.47 (m, 2H), 7.22-7.15 (m, 4H), 6.66-6.65 (m, 1H), 3.55 (s, 2H), 3.17-3.11 (m, 4H), 2.34-2.32 (m, 2H), 2.01-1.89 (m, 4H); LC-MS 417 (MH +)

[실시예 94] 3-(6-(4-(2-(피페리딘-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-((6-(4-(2-(piperidin-1-yl)ethyl)phenyl)thieno[3,2-d]pyrimidin-4-yl)methyl)phenol) (LCB03-0044)의 제조Example 94 3- (6- (4- (2- (piperidin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3 Preparation of-((6- (4- (2- (piperidin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-yl) methyl) phenol) (LCB03-0044)

¹H-NMR (400 MHz, DMSO-d₆); δ 10.44 (brs, 1H), 8.78 (s, 1H), 7.89-7.84 (m, 3H), 7.48-7.46 (m, 2H), 7.20-7.14 (m, 3H), 6.70-6.69 (m, 1H), 3.49 (s, 2H), 3.39-3.37 (m, 2H), 3.37-3.27 (m, 2H), 3.20-3.18 (m, 2H), 2.90-2.89 (m, 2H), 1.90-1.87 (m, 3H), 1.38-1.35 (m, 3H); LC-MS 431 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.44 (brs, 1H), 8.78 (s, 1H), 7.89-7.84 (m, 3H), 7.48-7.46 (m, 2H), 7.20-7.14 (m, 3H), 6.70-6.69 (m, 1H) , 3.49 (s, 2H), 3.39-3.37 (m, 2H), 3.37-3.27 (m, 2H), 3.20-3.18 (m, 2H), 2.90-2.89 (m, 2H), 1.90-1.87 (m, 3H), 1.38-1.35 (m, 3H); LC-MS 431 (MH +)

[실시예 95] 3-(6-(4-(2-(4-메틸피페라진-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0045)의 제조Example 95 3- (6- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol Preparation of (3- (6- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol) (LCB03-0045)

¹H-NMR (400 MHz, DMSO-d₆); δ 8.75 (s, 1H), 7.88 (S, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.48 (d, J = 7.6 Hz, 2H), 7.23-7.12 (m, 3H), 6.66 (d, J = 7.2 Hz, 1H), 3.72-3.68 (m, 2H), 3.51-3.47 (m, 2H), 3.44-3.37 (m, 4H), 3.16-3.12 (m, 4H), 2.83 (s, 3H); LC-MS 446 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 8.75 (s, 1H), 7.88 (S, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.48 (d, J = 7.6 Hz, 2H), 7.23-7.12 (m, 3H), 6.66 ( d, J = 7.2 Hz, 1H), 3.72-3.68 (m, 2H), 3.51-3.47 (m, 2H), 3.44-3.37 (m, 4H), 3.16-3.12 (m, 4H), 2.83 (s, 3H); LC-MS 446 (MH +)

[실시예 96] 3-(6-(3-(2-(피롤리딘-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 염산염 (3-(6-(3-(2-(pyrrolidin-1-yl)ethyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol. HCl) (LCB03-0076)의 제조Example 96 3- (6- (3- (2- (pyrrolidin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol hydrochloride ( Preparation of 3- (6- (3- (2- (pyrrolidin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol.HCl) (LCB03-0076)

¹H-NMR (400 MHz, CDCl₃); δ 8.53 (s, 1H), 7.72 (br, 1H), 7.58 (s, 1H), 7.34-7.26 (m, 3H), 7.22-7.12 (m, 3H), 6.88 (d, J =7.6Hz, 1H), 6.69 (d, J =8Hz, 1H), 2.89-2.87(m, 4H), 2.74-2.72 (m, 4H), 1.86 (s, 4H); LC-MS 417.2 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.53 (s, 1H), 7.72 (br, 1H), 7.58 (s, 1H), 7.34-7.26 (m, 3H), 7.22-7.12 (m, 3H), 6.88 (d, J = 7.6 Hz, 1H ), 6.69 (d, J = 8 Hz, 1H), 2.89-2.87 (m, 4H), 2.74-2.72 (m, 4H), 1.86 (s, 4H); LC-MS 417.2 (MH +)

[실시예 97] 3-(6-(3-(2-(피페라진-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(3-(2-(piperazin-1-yl)ethyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol) (LCB03-0079)의 제조Example 97 3- (6- (3- (2- (piperazin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3- Preparation of (6- (3- (2- (piperazin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol) (LCB03-0079)

¹H-NMR (400 MHz, DMSO-d₆); δ 9.83 (brs, 1H), 8.85 (s, 1H), 7.93 (s, 1H), 7.83-7.73 (m, 2H), 7.54-7.48 (m, 2H), 7.23-7.13 (m, 3H), 6.73 (s, 1H), 3.75-3.71 (m, 2H), 3.66-3.64 (m, 2H), 3.33-3.31 (m, 4H), 3.17-3.15 (m, 4H); LC-MS 432 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.83 (brs, 1H), 8.85 (s, 1H), 7.93 (s, 1H), 7.83-7.73 (m, 2H), 7.54-7.48 (m, 2H), 7.23-7.13 (m, 3H), 6.73 (s, 1H), 3.75-3.71 (m, 2H), 3.66-3.64 (m, 2H), 3.33-3.31 (m, 4H), 3.17-3.15 (m, 4H); LC-MS 432 (MH +)

[실시예 98]Example 98

[단계 1] 2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐아세트산 (2-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)phenyl)acetic acid) 의 제조[Step 1] 2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenylacetic acid (2- (4- (4- (3 Preparation of -hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) acetic acid)

제조예 27에서 합성한 화합물 (0.2 g, 0.39 mmol)을 테트라하이드로퓨란 1 ml와 메탄올 1 ml에 녹인 후 1 ml의 물에 녹인 리튬하이드록사이드 (166 mg, 3.95 mmol)을 0 ℃에서 적가하였다. 실온에서 15시간동안 교반한후 2N 염산을 이용하여 pH를 4로 맞추고 감압 증류하여 반응용매를 제거한 후 에틸아세테이트 (50 ml)와 물 (50 ml)을 이용하여 추출하였다. 유기용매를 감압증류하여 제거 한 후 표제 화합물 (0.13 mg, 87.2 %)을 수득하였다. The compound (0.2 g, 0.39 mmol) synthesized in Preparation Example 27 was dissolved in 1 ml of tetrahydrofuran and 1 ml of methanol, and lithium hydroxide (166 mg, 3.95 mmol) dissolved in 1 ml of water was added dropwise at 0 ° C. . After stirring at room temperature for 15 hours, the pH was adjusted to 4 using 2N hydrochloric acid, and the reaction solvent was removed by distillation under reduced pressure, and extracted with ethyl acetate (50 ml) and water (50 ml). After distilling off the organic solvent under reduced pressure, the title compound (0.13 mg, 87.2%) was obtained.

¹H-NMR (400 MHz, CDCl₃); δ 10.78 (brs, 1H), 9.69 (brs, 1H), 8.80 (s, 1H), 7.87 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.25 (t, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.14-7.12 (m, 1H), 6.71-6.68 (m, 1H), 3.68 (s, 2H; LC-MS 378 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 10.78 (brs, 1H), 9.69 (brs, 1H), 8.80 (s, 1H), 7.87 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.25 (t, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.14-7.12 (m, 1H), 6.71-6.68 (m, 1H), 3.68 (s, 2H; LC-MS 378 (MH +)

[단계 2] 2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)-1-(4-메틸피페라진-1-일)에타논 (2-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)phenyl)-1-(4-methylpiperazin-1-yl)ethanone)) (LCB03-0047)의 제조[Step 2] 2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) -1- (4-methylpiperazin-1 -Yl) ethanone (2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) -1- (4-methylpiperazin-1-yl) ethanone)) Preparation of (LCB03-0047)

상기 단계 1에서 제조된 화합물 (30 mg, 0.08 mmol)을 탈기체화된 다이메틸폼아마이드 2 ml에 녹인 후 (벤조트라이아졸-1-일옥시)트라이피롤리디노포스포니움 헥사플로로포스페이트 (62 mg, 0.12 mmol)을 첨가하고 N-메틸피페라진 (44 ㎕, 0.40 mmol)을 넣고 15시간 실온에서 교반하였다. 포화된 염화암모늄 50 ml 와 에틸 아세테이트 50 ml를 이용하여 추출하고 유기층을 물 50 ml로 두번 더 씻어준 후에 감압 증류하였다. 생성된 고체를 n-헥세인을 이용하여 고체화하여 표제화합물 (20 mg, 54.8 %)을 베이지색 고체로 수득하였다. The compound prepared in step 1 (30 mg, 0.08 mmol) was dissolved in 2 ml of degassed dimethylformamide (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (62 mg, 0.12 mmol) was added and N-methylpiperazine (44 μl, 0.40 mmol) was added and stirred at room temperature for 15 hours. Extracted with 50 ml of saturated ammonium chloride and 50 ml of ethyl acetate, the organic layer was washed twice with 50 ml of water and then distilled under reduced pressure. The resulting solid was solidified with n-hexane to afford the title compound (20 mg, 54.8%) as a beige solid.

¹H-NMR (400 MHz, DMSO-d₆); δ 8.87 (s, 1H), 7.88 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.41 (d, J= 8.0 Hz, 2H), 7.26 (t, J = 8.0 Hz, 1H), 7.14 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.76-6.74 (m, 1H), 3.60 (s, 2H), 3.54 (s, 3H), 3.49-3.39 (m, 6H), 2.77-2.76 (m, 2H); LC-MS: 460 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 8.87 (s, 1H), 7.88 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 8.0 Hz, 1H) , 7.14 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.76-6.74 (m, 1H), 3.60 (s, 2H), 3.54 (s, 3H), 3.49-3.39 (m, 6H ), 2.77-2.76 (m, 2 H); LC-MS: 460 (MH < + >)

상기 실시예 98과 유사한 방법으로 하기 화합물들을 합성하였다.In the same manner as in Example 98, the following compounds were synthesized.

[실시예 99] 2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)-1-(피롤리딘-1-일)에타논 (2-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)phenyl)-1-(pyrrolidin-1-yl)ethanone)) (LCB03-0049)의 제조Example 99 2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) -1- (pyrrolidine-1- Yl) ethanone (2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) -1- (pyrrolidin-1-yl) ethanone)) (LCB03- 0049)

¹H-NMR (400 MHz, DMSO-d₆); δ 9.61 (brs, 1H), 9.43 (s, 1H), 8.57 (s, 1H), 7.86 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.33 (s, 1H), 7.20-7.12 (m, 2H), 6.53-6.51 (m, 1H), 3.70 (s, 2H), 3.50 (t, J= 6.4 Hz, 2H), 3.40-3.29 (m, 2H), 1.89 (p, J = 7.0 Hz, 2H), 1.78 (p, J = 7.0 Hz, 2H); LC-MS: 431 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.61 (brs, 1H), 9.43 (s, 1H), 8.57 (s, 1H), 7.86 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.33 (s, 1H), 7.20-7.12 (m, 2H), 6.53-6.51 (m, 1H), 3.70 (s, 2H), 3.50 (t, J = 6.4 Hz, 2H), 3.40-3.29 (m, 2H), 1.89 (p, J = 7.0 Hz, 2H), 1.78 (p, J = 7.0 Hz, 2H); LC-MS: 431 (MH < + >)

[실시예 100] N,N-다이에틸-2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)아세트아마이드 (N,N-diethyl-2-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)phenyl)acetamide)) (LCB03-0050) 의 제조Example 100 N, N-diethyl-2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) acetamide ( Preparation of N, N-diethyl-2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) acetamide)) (LCB03-0050)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.72 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.54 (s, 1H), 7.31-7.28 (m, 3H), 6.93 (d, J = 8.4 Hz, 2H), 6.76 (dd, J = 2.0, 8.0 Hz, 1H), 3.91 (s, 2H), 3.42 (q, J = 7.2 HZ, 2H), 3.34 (q, J = 7.2 Hz, 2H), 1.13-1.10 (m, 6H); LC-MS 433 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.72 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.54 (s, 1H), 7.31-7.28 (m, 3H), 6.93 (d, J = 8.4 Hz, 2H), 6.76 (dd, J = 2.0, 8.0 Hz, 1H), 3.91 (s, 2H), 3.42 (q, J = 7.2 HZ, 2H), 3.34 (q, J = 7.2 Hz, 2H), 1.13-1.10 (m, 6H); LC-MS 433 (MH +)

[실시예 101]Example 101

[단계 1] (4-(4-(3-(터트-부틸다이메틸실릴옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)(4-메틸피페라진-1-일)메타논 ((4-(4-(3-(tert-butyldimethylsilyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)phenyl)(4- methylpiperazin-1-yl)methanone) 의 제조[Step 1] (4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) (4-methylpiperazin -1-yl) methanone ((4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone Manufacture of

¹H-NMR (400 MHz, CDCl₃); δ 7.71 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.64 (s, 1H), 7.49 (d, J= 8.0 Hz, 2H), 7.27 (t, J = 8.0 Hz, 2H), 7.19-7.15 (m, 2H), 6.85 (brs, 1H), 6.77 (dd, J = 2.4, 8.0 Hz, 1H), 3.82 (brm, 2H), 3.48 (brm, 2H), 3.44-3.33 (m, 1H), 2.50 (brm, 2H), 2.38-2.37 (m, 1H), 2.33 (s, 3H), 1.00 (s, 9H), 0.24 (s, 6H); LC-MS 560 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 7.71 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.64 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.27 (t, J = 8.0 Hz, 2H) , 7.19-7.15 (m, 2H), 6.85 (brs, 1H), 6.77 (dd, J = 2.4, 8.0 Hz, 1H), 3.82 (brm, 2H), 3.48 (brm, 2H), 3.44-3.33 (m , 1H), 2.50 (brm, 2H), 2.38-2.37 (m, 1H), 2.33 (s, 3H), 1.00 (s, 9H), 0.24 (s, 6H); LC-MS 560 (MH +)

[단계 2] (4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)(4-메틸피페라진-1-일)메타논 염산염 ((4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone. HCl)) (LCB03-0052)의 제조[Step 2] (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone Preparation of Hydrochloride ((4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone.HCl)) (LCB03-0052)

¹H-NMR (400 MHz, DMSO-d₆); δ 10.65 (brs, 1H), 9.68 (brs, 1H), 7.99 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.24-7.13 (m, 4H), 6.68 (d, J = 8.0 Hz, 1H), 3.50-3.39 (m, 4H), 3.33-3.32 (m, 2H), 3.11-3.08 (m, 2H), 2.78 (s, 3H); LC-MS 446 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 10.65 (brs, 1H), 9.68 (brs, 1H), 7.99 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.24-7.13 ( m, 4H), 6.68 (d, J = 8.0 Hz, 1H), 3.50-3.39 (m, 4H), 3.33-3.32 (m, 2H), 3.11-3.08 (m, 2H), 2.78 (s, 3H) ; LC-MS 446 (MH +)

[실시예 102]Example 102

[단계 1] 메틸 2-(4-(4-(3-(터트-부틸다이메틸실릴옥시)페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈아미도)프로파노에이트 (methyl 2-(4-(4-(3-(tert-butyldimethylsilyloxy)phenylamino)thieno[3,2-d]pyrimidin-6-yl)benzamido)propanoate) 의 제조[Step 1] Methyl 2- (4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamido) pro Preparation of Panoate (methyl 2- (4- (4- (3- (tert-butyldimethylsilyloxy) phenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamido) propanoate)

¹H-NMR (400 MHz, CDCl₃); δ 8.69 (s, 1H), 7.68-7.63 (m, 3H), 7.47-7.44 (m, 2H), 7.29-7.26 (m, 1H), 7.17-7.14 (m, 2H), 6.92 (d, J = 5.2 Hz, 1H), 6.77 (d, J= 3.6 Hz, 1H), 4.81 (m, 1H), 3.80 (s, 3H), 1.55 (d, J = 5.2 Hz, 3H), 0.99 (s, 9H), 0.23 (s, 6H); LC-MS 563 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1H), 7.68-7.63 (m, 3H), 7.47-7.44 (m, 2H), 7.29-7.26 (m, 1H), 7.17-7.14 (m, 2H), 6.92 (d, J = 5.2 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 4.81 (m, 1H), 3.80 (s, 3H), 1.55 (d, J = 5.2 Hz, 3H), 0.99 (s, 9H) , 0.23 (s, 6 H); LC-MS 563 (MH +)

[단계 2] 메틸 2-(3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈아미도)프로파노에이트 (methyl 2-(3-(4-(3-hydroxyphenylamino)thieno[3,2- d]pyrimidin-6-yl)benzamido)propanoate)) (LCB03-0071)의 제조[Step 2] Methyl 2- (3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamido) propanoate (methyl 2- ( Preparation of 3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamido) propanoate)) (LCB03-0071)

¹H-NMR (600 MHz, DMSO-d₆); δ 9.64 (brs, 1H), 8.91 (d, J = 6.6 Hz, 1H), 8.56 (s, 1H), 8.00-7.99 (m, 3H), 7.95 (d, J= 8.4 Hz, 2H), 7.29 (brs, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 4.48-4.46 (1H), 3.61 (s, 3H), 1.38 (d, J = 7.2 Ha, 3H); LC-MS 449 (MH+) ¹ H-NMR (600 MHz, DMSO-d ₆ ); δ 9.64 (brs, 1H), 8.91 (d, J = 6.6 Hz, 1H), 8.56 (s, 1H), 8.00-7.99 (m, 3H), 7.95 (d, J = 8.4 Hz, 2H), 7.29 ( brs, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 4.48-4.46 (1H), 3.61 ( s, 3H), 1.38 (d, J = 7.2 Ha, 3H); LC-MS 449 (MH +)

[실시예 103] 3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤조산 (3-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)benzoic acid)) (LCB03-0051) 의 제조Example 103 3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzoic acid (3- (4- (3-hydroxyphenylamino) thieno [3 , 2-d] pyrimidin-6-yl) benzoic acid)) (LCB03-0051)

¹H-NMR (400 MHz, DMSO-d₆); δ 9.70 (brs, 1H), 8.61 (s, 1H), 8.35 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.04-8.01 (m, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.45 (s, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H); LC-MS 364 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.70 (brs, 1H), 8.61 (s, 1H), 8.35 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.04-8.01 (m, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H); LC-MS 364 (MH +)

[실시예 104] 3-(6-(4-(에톡시메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀 (3-(6-(4-(ethoxymethyl)phenyl)thieno[3,2-d]pyrimidin-4-ylamino)phenol)) (LCB03-0073)의 제조Example 104 3- (6- (4- (ethoxymethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol (3- (6- (4- (ethoxymethyl ) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol)) (LCB03-0073)

비스(피나콜레이토)다이보레인 (0.16 g, 0.63 mmol), PdCl2dppf (13 mg, 0.015 mmol), 포타슘아세테이트 (0.15 g, 1.57 mmol)을 반응용기에 넣고 진공건조하였다. N2 로 탈기체화된 다이메틸포름아마이드 3 ml에 제조예 30에서 합성한 화합물 (0.11 g, 0.52 mmol)을 녹여 반응용기에 옮긴 후 85℃에서 15시간 교반하였다. 반응액을 실온으로 냉각 하고 에틸아세테이트 50 ml와 포화된 염화암모늄 50 ml을 넣고 추출하였다. 유기층을 염화암모늄 50 ml로 2회 더 씻어준 후 무수 황산나트륨을 이용하여 건조하고 감압농축하여 짙은 갈색 오일형태의 2-(4-(에톡시메틸)페닐)-4,4,5,5-테트라메틸-1,3,2-다이옥사보롤레인을 수득하였다. 이 화합물과 제조예 6 (50 mg, 0.11 mmol), PdCl2dppf (3 mg, 0.003 mmol)을 탈기체화된 다이메틸폼아마이드 20 ml에 순차적으로 투입하고 2N 탄산나트륨 수용액 (0.12 ml, 0.23 mmol)을 투입하였다. 80 ℃에서 5시간 동안 교반 한 후 실온으로 냉각하고 에틸아세테이트 100 ml와 포화된 염화암모늄 100 ml로 추출하였다. 유기층을 포화된 염화암모늄 100 ml로 2회 더 씻어준 후 황산나트륨을 이용해 건조하고 감압농축 후 관 크로마토그래피 (다이클로로메테인/메탄올, 20/1)로 표제화합물 (20 mg, 64 %)을 수득하였다.Bis (pinacolato) diborane (0.16 g, 0.63 mmol), PdCl2dppf (13 mg, 0.015 mmol) and potassium acetate (0.15 g, 1.57 mmol) were added to a reaction vessel and dried under vacuum. The compound (0.11 g, 0.52 mmol) synthesized in Preparation Example 30 was dissolved in 3 ml of dimethylformamide degassed with N 2, transferred to a reaction vessel, and stirred at 85 ° C. for 15 hours. The reaction solution was cooled to room temperature, 50 ml of ethyl acetate and 50 ml of saturated ammonium chloride were added and extracted. The organic layer was washed twice with 50 ml of ammonium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2- (4- (ethoxymethyl) phenyl) -4,4,5,5-tetra in the form of a dark brown oil. Methyl-1,3,2-dioxaborolane was obtained. This compound, Preparation Example 6 (50 mg, 0.11 mmol), and PdCl2dppf (3 mg, 0.003 mmol) were sequentially added to 20 ml of degassed dimethylformamide, followed by 2N aqueous sodium carbonate solution (0.12 ml, 0.23 mmol). . After stirring at 80 ° C. for 5 hours, the mixture was cooled to room temperature and extracted with 100 ml of ethyl acetate and 100 ml of saturated ammonium chloride. The organic layer was washed two more times with 100 ml of saturated ammonium chloride, dried over sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (dichloromethane / methanol, 20/1) to obtain the title compound (20 mg, 64%). It was.

¹H-NMR (400 MHz, DMSO-d₆); δ 9.60 (brs, 1H), 9.44 (brs, 1H), 8.58 (s, 1H), 7.88 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.33 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 2H), 6.52 (d, J = 7.6 Hz, 1H), 4.52 (s, 2H), 3.52 (q, J = 7.0 Hz, 2H), 1.18 (t, J= 6.8 Hz, 3H); LC-MS 378 (MH+) ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ 9.60 (brs, 1H), 9.44 (brs, 1H), 8.58 (s, 1H), 7.88 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.33 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 2H), 6.52 (d, J = 7.6 Hz, 1H), 4.52 (s, 2H), 3.52 (q, J = 7.0 Hz, 2H), 1.18 (t, J = 6.8 Hz, 3H); LC-MS 378 (MH +)

[실시예 105] 2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈아미도)프로판산 (2-(4-(4-(3-hydroxyphenylamino)thieno[3,2-d]pyrimidin-6-yl)benzamido)propanoic acid)) (LCB03-0075)의 제조Example 105 2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamido) propanoic acid (2- (4- Preparation of (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamido) propanoic acid)) (LCB03-0075)

실시예 102의 단계 1에서 제조된 화합물 (40 mg, 0.07 mmol)을 실시예 31과 유사한 방법으로 표제화합물 (18 mg, 60 %)을 수득하였다. The compound prepared in Step 1 of Example 102 (40 mg, 0.07 mmol) was obtained in the same manner as Example 31, to obtain the title compound (18 mg, 60%).

¹H-NMR (400 MHz, CDCl₃); δ 10.07 (brs, 1H), 9.53 (brs, 1H), 8.82 (d, J= 10.8 Hz, 1H), 8.67 (s, 1H), 8.05-7.97 (m, 4H), 7.28 (s, 1H), 7.18 (d, J = 7.2 Hz, 2H), 6.59-6.58 (m, 1H), 4.44 (p, J = 10.8 Hz, 1H), 1.49 (d, J = 10.8 Hz, 3H); LC-MS 435 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 10.07 (brs, 1H), 9.53 (brs, 1H), 8.82 (d, J = 10.8 Hz, 1H), 8.67 (s, 1H), 8.05-7.97 (m, 4H), 7.28 (s, 1H), 7.18 (d, J = 7.2 Hz, 2H), 6.59-6.58 (m, 1H), 4.44 (p, J = 10.8 Hz, 1H), 1.49 (d, J = 10.8 Hz, 3H); LC-MS 435 (MH +)

[실시예 106]Example 106

[단계 1] N-(3-(4-메톡시벤질옥시)페닐)-2-(4-메틸피페라진-1-일)싸이아졸로[4,5-d]피리미딘-7-아민 (N-(3-(4-methoxybenzyloxy)phenyl)-2-(4-methylpiperazin-1-yl)thiazolo[4,5-d]pyrimidin-7-amine) 의 제조[Step 1] N- (3- (4-methoxybenzyloxy) phenyl) -2- (4-methylpiperazin-1-yl) thiazolo [4,5-d] pyrimidin-7-amine ( Preparation of N- (3- (4-methoxybenzyloxy) phenyl) -2- (4-methylpiperazin-1-yl) thiazolo [4,5-d] pyrimidin-7-amine)

제조예 33에서 합성한 화합물 (100 mg, 0.24 mmol)을 2 ml의 N-메틸피롤리딘에 녹이고 N-메틸피페라진 (0.57 ml, 4.87 mmol)을 첨가하여 18시간동안 환류교반하였다. 물 40 ml와 에틸아세테이트 40 ml를 사용하여 추출하고 황산나트륨으로 건조, 여과후 감압농축한 다음 관크로마토그래피 (다이클로로메테인/메탄올, 20/1 → 15/1)를 이용하여 표제 화합물 (111 mg, 99 %)을 얻었다. The compound (100 mg, 0.24 mmol) synthesized in Preparation Example 33 was dissolved in 2 ml of N-methylpyrrolidine and stirred at reflux for 18 hours by adding N-methylpiperazine (0.57 ml, 4.87 mmol). Extracted with 40 ml of water and 40 ml of ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (dichloromethane / methanol, 20/1 → 15/1) to give the title compound (111 mg). , 99%).

¹H-NMR (400 MHz, CDCl₃); δ 8.52 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.29 (t, J= 8.0 Hz, 1H), 7.00-6.99 (m, 1H), 6.91-6.86 (m, 4H), 5.01 (s, 2H), 3.81 (s, 3H), 3.66 (m, 4H), 2.50-2.47 (m, 4H), 2.33 (s, 3H); LC-MS 463 (MH+) ¹ H-NMR (400 MHz, CDCl ₃ ); δ 8.52 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 8.0 Hz, 1H), 7.00-6.99 (m, 1H), 6.91-6.86 (m, 4H), 5.01 (s, 2H), 3.81 (s, 3H), 3.66 (m, 4H), 2.50-2.47 (m, 4H), 2.33 (s, 3H); LC-MS 463 (MH +)

[단계 2] 3-(2-(4-메틸피페라진-1-일)싸이아졸로[4,5-d]피리미딘-7-일아미노)페놀 트리플루오로아세트산 (3-(2-(4-methylpiperazin-1-yl)thiazolo[4,5-d]pyrimidin-7-ylamino)phenol. TFA)) (LCB03-0100)의 제조[Step 2] 3- (2- (4-methylpiperazin-1-yl) thiazolo [4,5-d] pyrimidin-7-ylamino) phenol trifluoroacetic acid (3- (2- ( Preparation of 4-methylpiperazin-1-yl) thiazolo [4,5-d] pyrimidin-7-ylamino) phenol.TFA)) (LCB03-0100)

상기 단계 1에서 제조된 화합물 (50 mg, 0.108 mmol)을 2 ml의 다이클로로메테인에 녹인 후크리플루오로아세트산 2 ml와 아니솔 (59 ㎕, 0.54 mmol)를 넣고 실온에서 10시간 교반하였다. 감압농축 후 다시 다이클로로메테인과 메탄올, 다이에틸에테르등을 이용하여 공비농축하여 표제화합물 (48 mg, 99 %)을 얻었다. The compound (50 mg, 0.108 mmol) prepared in step 1 was dissolved in 2 ml of dichloromethane, 2 ml of hookrifluoroacetic acid and anisole (59 μl, 0.54 mmol) were added thereto, and the mixture was stirred at room temperature for 10 hours. After concentration under reduced pressure, azeotropic concentration was again performed using dichloromethane, methanol, diethyl ether, etc. to obtain the title compound (48 mg, 99%).

¹H-NMR (600 MHz, Acetone-d₆); δ 8.69 (s, 1H), 7.31-7.28 (m, 1H), 7.15-7.13 (m, 1H), 7.02-6.98 (m, 1H), 6.87-6.84 (m, 1H), 4.13-4.10 (m, 4H), 3.59-3.58 (m, 4H), 3.02 (s, 3H); LC-MS 343 (MH+) ¹ H-NMR (600 MHz, Acetone-d ₆ ); δ 8.69 (s, 1H), 7.31-7.28 (m, 1H), 7.15-7.13 (m, 1H), 7.02-6.98 (m, 1H), 6.87-6.84 (m, 1H), 4.13-4.10 (m, 4H), 3.59-3.58 (m, 4H), 3.02 (s, 3H); LC-MS 343 (MH +)

[실험예 1] LCB 화합물의 in vitro DDR1과 DDR2 타이로신 카이네이즈 활성 저해능 측정Experimental Example 1 Measurement of Inhibition of In vitro DDR1 and DDR2 Tyrosine Kinase Activity of LCB Compounds

하기 표 1은, 상기 합성된 LCB 시리즈 화합물의 in vitro에서의 DDR1 및 DDR2 티로신 키나이제의 활성 저해능을 IC₅₀ 값 (50% 저해를 위해 필요한 각 화합물 농도값)으로 나타낸 것이다. in vitro상에서 DDR1이나 DDR2의 티로신 키나아제의 활성화를 측정하기 위해 sf21 세포로부터 발현 한 후 정제된 100 ng의 글루타치온 S 트랜스퍼레이즈에 융합한 재조합 DDR1이나 DDR2의 키아나제 도메인 단백질을 사용하여 20 mM Tris-HCl (pH 8.0), 5 mM MgCl₂, 0.5 mM dithiothreitol, 0.01 mM ATP, 0.2 μCi of 32P-ATP 그리고 펩티드 기질로서 4 μg of 히스톤 H2B (Sigma)이 포함된 20 ul의 반응화합물에서 반응을 실행하였다. 30 ℃에서 15분간 반응한 후 30% phosphoric acid을 부피의 절반을 넣어서 반응을 중지시키고 혼합물을 p81 paper (Millipore)에서 스포팅하였다. 스포팅된 paper는 0.1 M Tris-HCl (pH 8.0)에서 5번 세척하였고, BAS image analyzer(Fuji)를 사용하여서 스폿 각각의 방사능을 시각화하고 수치화하였다. Table 1 below shows the activity inhibitory activity of DDR1 and DDR2 tyrosine kinase in vitro of the synthesized LCB series of compounds by IC ₅₀ value (each compound concentration value required for 50% inhibition). To determine the activation of tyrosine kinase of DDR1 or DDR2 in vitro, 20 mM Tris- was expressed using recombinant DDR1 or DDR2 kinase domain proteins fused to purified 100 ng glutathione S transferase after expression from sf21 cells. The reaction was performed on 20 ul of reaction compound containing HCl (pH 8.0), 5 mM MgCl ₂ , 0.5 mM dithiothreitol, 0.01 mM ATP, 0.2 μCi of 32P-ATP and 4 μg of histone H2B (Sigma) as peptide substrate. . After reacting at 30 ° C. for 15 minutes, the reaction was stopped by adding half the volume of 30% phosphoric acid, and the mixture was spotted on p81 paper (Millipore). The spotted paper was washed five times in 0.1 M Tris-HCl (pH 8.0), and the radioactivity of each spot was visualized and quantified using a BAS image analyzer (Fuji).

화합물compound IC50 (μM) : DDR1 kinaseIC50 (μM): DDR1 kinase IC50 (μM) : DDR2 kinaseIC50 (μM): DDR2 kinase LCB030006LCB030006 2.192.19 1.281.28 LCB030007LCB030007 17.417.4 22.122.1 LCB030008LCB030008 0.0330.033 0.230.23 LCB030009LCB030009 10.510.5 8.18.1 LCB030013LCB030013 0.580.58 0.770.77 LCB030015LCB030015 3.143.14 2.692.69 LCB030016LCB030016 2.982.98 2.732.73 LCB030017LCB030017 0.190.19 0.210.21 LCB030018LCB030018 0.390.39 0.480.48 LCB030019LCB030019 0.470.47 0.320.32 LCB030020LCB030020 0.780.78 0.690.69 LCB030021LCB030021 29.929.9 33.133.1 LCB030022LCB030022 5.895.89 8.468.46 LCB030023LCB030023 0.270.27 0.570.57 LCB030024LCB030024 0.780.78 0.380.38 LCB030025LCB030025 N/DN / D N/DN / D LCB030026LCB030026 N/DN / D N/DN / D LCB030027LCB030027 0.390.39 0.370.37 LCB030028LCB030028 0.890.89 0.950.95 LCB030029LCB030029 N/DN / D N/DN / D LCB030030LCB030030 0.250.25 0.180.18 LCB030031LCB030031 0.180.18 0.140.14 LCB030032LCB030032 0.0570.057 0.080.08 LCB030033LCB030033 0.0360.036 0.0390.039 LCB030034LCB030034 0.0370.037 0.0370.037 LCB030035LCB030035 0.0820.082 0.0410.041 LCB030036LCB030036 0.0880.088 0.0440.044 LCB030037LCB030037 0.0790.079 0.0410.041 LCB030038LCB030038 0.490.49 0.320.32 LCB030039LCB030039 0.550.55 0.240.24 LCB030040LCB030040 0.0760.076 0.0870.087 LCB030041LCB030041 0.0450.045 0.0320.032 LCB030042LCB030042 0.0310.031 0.0190.019 LCB030043LCB030043 0.0480.048 0.0750.075 LCB030044LCB030044 0.0430.043 0.0380.038 LCB030045LCB030045 0.0550.055 0.030.03 LCB030046LCB030046 0.0590.059 0.060.06 LCB030047LCB030047 0.470.47 0.450.45 LCB030048LCB030048 >100> 100 >100> 100 LCB030049LCB030049 0.0570.057 0.0660.066 LCB030050LCB030050 0.0260.026 0.0520.052 LCB030051LCB030051 0.120.12 0.0670.067 LCB030052LCB030052 0.0480.048 0.0350.035 LCB030053LCB030053 0.0760.076 0.0890.089 LCB030054LCB030054 0.0480.048 0.0750.075 LCB030055LCB030055 0.0890.089 0.0920.092 LCB030056LCB030056 0.0780.078 0.0940.094 LCB030057LCB030057 0.0580.058 0.0450.045 LCB030058LCB030058 0.0510.051 0.0520.052 LCB030059LCB030059 0.0770.077 0.0690.069 LCB030060LCB030060 0.0350.035 0.0410.041 LCB030061LCB030061 0.0380.038 0.0240.024 LCB030062LCB030062 0.0620.062 0.0690.069 LCB030063LCB030063 0.0790.079 0.0710.071 LCB030064LCB030064 0.0480.048 0.0750.075 LCB030065LCB030065 0.0990.099 0.140.14 LCB030066LCB030066 0.0170.017 0.0280.028 LCB030067LCB030067 0.0920.092 0.0880.088 LCB030068LCB030068 0.0720.072 0.0750.075 LCB030069LCB030069 0.570.57 0.890.89 LCB030070LCB030070 0.0720.072 0.0820.082 LCB030071LCB030071 0.130.13 0.150.15 LCB030072LCB030072 0.0710.071 0.0620.062 LCB030073LCB030073 0.0690.069 0.0810.081 LCB030074LCB030074 0.0550.055 0.0780.078 LCB030075LCB030075 0.0710.071 0.0930.093 LCB030076LCB030076 0.0410.041 0.0460.046 LCB030077LCB030077 0.0590.059 0.0550.055 LCB030078LCB030078 0.0670.067 0.0790.079 LCB030079LCB030079 0.0390.039 0.0380.038 LCB030080LCB030080 0.0180.018 0.0210.021 LCB030081LCB030081 N/DN / D N/DN / D LCB030082LCB030082 N/DN / D N/DN / D LCB030083LCB030083 0.0110.011 0.0130.013 LCB030084LCB030084 0.0310.031 0.0250.025 LCB030085LCB030085 0.0670.067 0.0750.075 LCB030086LCB030086 0.0990.099 0.0970.097 LCB030087LCB030087 0.140.14 0.130.13 LCB030088LCB030088 0.0710.071 0.0880.088 LCB030089LCB030089 0.160.16 0.110.11 LCB030090LCB030090 0.0860.086 0.120.12 LCB030091LCB030091 0.0680.068 0.110.11 LCB030092LCB030092 0.0920.092 0.0760.076 LCB030093LCB030093 0.0790.079 0.0840.084 LCB030094LCB030094 0.0610.061 0.0740.074 LCB030095LCB030095 0.0640.064 0.0780.078 LCB030096LCB030096 0.0220.022 0.0370.037 LCB030097LCB030097 0.0820.082 0.0570.057 LCB030098LCB030098 0.0210.021 0.0180.018 LCB030099LCB030099 0.0330.033 0.0390.039 LCB030100LCB030100 0.0970.097 0.110.11 LCB030101LCB030101 0.240.24 0.190.19 LCB030102LCB030102 0.260.26 0.170.17 LCB030103LCB030103 0.170.17 0.150.15 LCB030104LCB030104 0.0940.094 0.0920.092 LCB030105LCB030105 0.120.12 0.110.11 LCB030106LCB030106 0.140.14 0.170.17 LCB030107LCB030107 0.0340.034 0.0640.064 LCB030108LCB030108 0.0280.028 0.0370.037 LCB030109LCB030109 0.0850.085 0.0950.095 LCB030110LCB030110 0.0090.009 0.0080.008 LCB030111LCB030111 0.0090.009 0.0090.009 LCB030112LCB030112 0.0450.045 0.0740.074 LCB030113LCB030113 0.130.13 0.170.17 LCB030114LCB030114 0.180.18 0.210.21 LCB030115LCB030115 0.150.15 0.190.19

[실험예 2] LCB 화합물의 세포내 DDR1, DDR2 의 콜라겐 처리에 의한 자가 인산화 활성 저해능 측정Experimental Example 2 Measurement of Inhibition of Autophosphorylation Activity by Intracellular DDR1 and DDR2 Collagen Treatment of LCB Compound

표 2는, 합성된 LCB 화합물의 세포 내에서 발현된 DDR1 및 DDR2가 제1형 콜라겐 단백질에 의해 활성화 될 때 증가하는 자가 인산화 활성에 대한 저해능을 IC₅₀ 값 (50% 저해를 위해 필요한 각 화합물 농도값)으로 나타낸 것이다. 즉 제 1형 콜라겐(200 μg/ml)이 코팅된 12 웰 배양접시에서 HA 꼬리표가 있는 DDR1이나 DDR2 유전자를 안정적으로 발현하는 5×10⁵ HEK293 세포를 각각 다른 농도의 화합물이 혼합된 혈청이 첨가되지 않은 DMEM 배지 1 ml에서 37℃, 5% 이산화탄소대기 상태에서 4시간 동안 배양한다. 배양 후에 세포를 150 ul 램리 버퍼를 넣어 용해하고 용해물을 5분 동안 끓인다. 자가 인산화 정도는 인산화된 티로신에 특이적으로 부착되는 p-Tyr-100 (Cell Signaling) 항체를 이용하여 웨스턴 브로팅 실험을 하여 나타나는 밴드를 덴시토메터를 사용하여 정량화 하였다. 대표적인 실험 예로 LCB030110을 처리시 보여준 DDR2 자가 인산화 활성 억제능 실험 결과를 도 1과 같이 나타내었다. Table 2 shows the inhibitory effects on the increased autophosphorylation activity of DDR1 and DDR2 expressed in cells of synthesized LCB compounds when activated by collagen protein type IC ₅₀ (each compound concentration required for 50% inhibition). Value). That is, 5 × 10 ⁵ HEK293 cells stably expressing the DDR1 or DDR2 genes with HA tag in the 12 well culture plate coated with type 1 collagen (200 μg / ml) were added with serum mixed with compounds of different concentrations. Incubate for 1 hour at 37 ℃, 5% carbon dioxide atmosphere in 1 ml of non-DMEM medium. After incubation, the cells are lysed in 150 ul Ramley buffer and the lysates are boiled for 5 minutes. The degree of autophosphorylation was quantified using a densitometer, the band appearing by Western brotting experiment using p-Tyr-100 (Cell Signaling) antibody that is specifically attached to phosphorylated tyrosine. As a representative experimental example, the results of experiments on the inhibition of DDR2 autophosphorylation activity showed by LCB030110 are shown in FIG. 1.

화합물compound IC50 (μM) : DDR1 kinaseIC50 (μM): DDR1 kinase IC50 (μM) : DDR2 kinaseIC50 (μM): DDR2 kinase LCB030034LCB030034 2.92.9 3.53.5 LCB030040LCB030040 1313 1515 LCB030041LCB030041 2.12.1 22 LCB030042LCB030042 0.090.09 1.11.1 LCB030043LCB030043 >15> 15 >15> 15 LCB030044LCB030044 >15> 15 >15> 15 LCB030045LCB030045 >15> 15 >15> 15 LCB030046LCB030046 >15> 15 >15> 15 LCB030047LCB030047 2.82.8 3.63.6 LCB030048LCB030048 >15> 15 >15> 15 LCB030049LCB030049 >15> 15 1515 LCB030050LCB030050 >15> 15 >15> 15 LCB030051LCB030051 >15> 15 >15> 15 LCB030052LCB030052 3.73.7 1.21.2 LCB030053LCB030053 1313 1515 LCB030054LCB030054 1414 1515 LCB030055LCB030055 >15> 15 >15> 15 LCB030056LCB030056 >15> 15 >15> 15 LCB030057LCB030057 2.92.9 3.63.6 LCB030058LCB030058 2.82.8 2.32.3 LCB030059LCB030059 5.35.3 3.63.6 LCB030060LCB030060 1.41.4 1.11.1 LCB030061LCB030061 0.910.91 0.840.84 LCB030062LCB030062 4.54.5 3.93.9 LCB030063LCB030063 9.19.1 1010 LCB030064LCB030064 0.770.77 0.860.86 LCB030065LCB030065 8.48.4 1010 LCB030066LCB030066 0.940.94 0.840.84 LCB030067LCB030067 1313 1010 LCB030068LCB030068 0.810.81 0.970.97 LCB030069LCB030069 >15> 15 >15> 15 LCB030070LCB030070 0.720.72 0.990.99 LCB030071LCB030071 >15> 15 >15> 15 LCB030072LCB030072 3.13.1 2.82.8 LCB030073LCB030073 >15> 15 >15> 15 LCB030074LCB030074 >15> 15 >15> 15 LCB030075LCB030075 >15> 15 >15> 15 LCB030076LCB030076 2.12.1 2.32.3 LCB030077LCB030077 >15> 15 >15> 15 LCB030078LCB030078 >15> 15 >15> 15 LCB030079LCB030079 4.64.6 2.82.8 LCB030080LCB030080 0.520.52 0.750.75 LCB030081LCB030081 N/DN / D N/DN / D LCB030082LCB030082 N/DN / D N/DN / D LCB030083LCB030083 0.330.33 0.350.35 LCB030084LCB030084 0.490.49 0.550.55 LCB030085LCB030085 1010 1010 LCB030086LCB030086 >20> 20 >20> 20 LCB030087LCB030087 >20> 20 >20> 20 LCB030088LCB030088 13.113.1 1616 LCB030089LCB030089 13.313.3 1010 LCB030090LCB030090 16.216.2 1010 LCB030091LCB030091 9.69.6 1010 LCB030092LCB030092 2.62.6 3.23.2 LCB030093LCB030093 5.25.2 8.18.1 LCB030094LCB030094 1.51.5 1.91.9 LCB030095LCB030095 3.33.3 4.24.2 LCB030096LCB030096 2.92.9 2.22.2 LCB030097LCB030097 0.950.95 0.910.91 LCB030098LCB030098 0.330.33 0.550.55 LCB030099LCB030099 0.760.76 0.910.91 LCB030100LCB030100 >10> 10 >10> 10 LCB030101LCB030101 >10> 10 >10> 10 LCB030102LCB030102 >10> 10 >10> 10 LCB030103LCB030103 >10> 10 >10> 10 LCB030104LCB030104 >10> 10 >10> 10 LCB030105LCB030105 >10> 10 >10> 10 LCB030106LCB030106 >10> 10 >10> 10 LCB030107LCB030107 3.93.9 4.34.3 LCB030108LCB030108 1.51.5 1.91.9 LCB030109LCB030109 6.76.7 8.38.3 LCB030110LCB030110 0.190.19 0.290.29 LCB030111LCB030111 0.280.28 0.350.35 LCB030112LCB030112 2.82.8 3.43.4 LCB030113LCB030113 >10> 10 >10> 10 LCB030114LCB030114 >10> 10 >10> 10 LCB030115LCB030115 >10> 10 >10> 10

하기 표 3에서, 합성된 LCB 화합물의 DDR1 및 DDR2 자가 인산화 활성 억제에 대한 특이성을 확인하기 위하여 세포내에서 다른 수용체 티로신 카나아제인 EGFR (epidermal growth factor receptor)과 IR (insulin receptor)를 발현하도록 조작된 HEK293 세포를 12웰 배양접시에서 키운 후 각 화합물을 여러 농도로 처리하고 30분 후에 EGF (1 ng/ml)을 10분 처리하거나 인슐린 (10 ng/ml)을 1분간 처리하였다. 처리 후 세포는 즉시 150 ul 램리 버퍼를 넣어 용해시키고 5분간 끓였다. 마지막으로 p-Tyr-100 (Cell Signaling) 항체를 사용하여서 immunoblot법을 수행하였다. 이를 덴시토미터로 정량화 한 후 각 수용체의 자가 인산화 억제능을 측정하여 IC₅₀ 값으로 나타내었다. In Table 3 below, the engineered LCB compounds were engineered to express different receptor tyrosine kinases, EGFR (epidermal growth factor receptor) and IR (insulin receptor), in order to confirm the specificity of inhibiting DDR1 and DDR2 autophosphorylation activity. HEK293 cells were grown in a 12-well culture dish and each compound was treated at various concentrations, and after 30 minutes, EGF (1 ng / ml) was treated for 10 minutes or insulin (10 ng / ml) for 1 minute. After treatment, cells were immediately lysed in 150 ul Lamley buffer and boiled for 5 minutes. Finally, immunoblot was performed using p-Tyr-100 (Cell Signaling) antibody. After quantification with a densitometer, the autophosphorylation inhibition of each receptor was measured and expressed as an IC ₅₀ value.

화합물compound IC50 : 세포내 DDR2IC50: Intracellular DDR2 IC50 : 세포내 EGFRIC50: Intracellular EGFR IC50 : 세포내 IRIC50: Intracellular IR 선택성 (DDR2 vs EGFR)Selectivity (DDR2 vs EGFR) 선택성 (DDR2 vs IR)Selectivity (DDR2 vs IR) LCB030034LCB030034 3.5 μM3.5 μM 100 nM100 nM 9 μM9 μM 0.030.03 2.62.6 LCB030042LCB030042 1.1 μM1.1 μM 100 nM100 nM 9 μM9 μM 0.090.09 8.28.2 LCB030052LCB030052 1.2 μM1.2 μM 300 nM300 nM 43 μM43 μM 0.250.25 3636 LCB030060LCB030060 1.1 μM1.1 μM N/DN / D N/DN / D N/DN / D N/DN / D LCB030061LCB030061 840 nM840 nM 300 nM300 nM >50 μM> 50 μM 2.82.8 >59> 59 LCB030066LCB030066 840 nM840 nM 100 nM100 nM >50 μM> 50 μM 8.48.4 >59> 59 LCB030080LCB030080 550 nM550 nM 10 μM10 μM 22 μM22 μM 1818 4040 LCB030088LCB030088 350 nM350 nM 2 μM2 μM 6 μM6 μM 5.75.7 1717 LCB030110LCB030110 290 nM290 nM 2 μM2 μM 7 μM7 μM 6.86.8 2424 LCB030111LCB030111 350 nM350 nM N/DN / D 10 μM10 μM N/DN / D 2828

[실험예 3] LCB 화합물에 의한 MDA-MB-231, SK-N-SH, Synovial fibroblast, HSC-T6 세포 성장 저해능 측정Experimental Example 3 Measurement of MDA-MB-231, SK-N-SH, Synovial Fibroblast, and HSC-T6 Cell Growth Inhibition by LCB Compounds

암 세포주이며 DDR2를 높게 발현하는 MDA-MB-231와 SK-N-SH와 류마티즘 환자에서 추출된 활성화된 연골조직의 파이브로틱 세포인 활막 섬유 아세포와 쥐의 동맥에서 추출한 혈관조직의 파이브로틱 세포인 평활근 세포, 그리고 간조직의 파이브로틱 세포인 HSC T6의 성장을 LCB03-0110 화합물이 억제하는 정도를 SRB 세포 성장 에세이를 통해 확인 후 이를 GI₅₀ 값 (50% 성장을 억제하는데 필요한 농도값) 으로 표 4에서 나타내었다. 간략하게, 3000개의 세포를 96 well plate에 깔고 밤새도록 배양하였다. 화합물 처리 전의 세포수를 측정하기 위해, 3개의 well을 4% 포르말린으로 고정하였다. 남은 well은 저해제 화합물을 다양한 농도로 처리하였고, 48시간동안 배양 후에 포르말린으로 고정하였다. 단지 살아있는 세포는 배양접시에 고정되는 반면에 죽은 세포는 분쇄되었거나 떠다닌다. 각 well을 물로 세척 후에, 1% acetic acid용액에 용해시킨 0.1% sulforhodamine B (SRB) (Sigma) 용액을 사용하여서 30분 동안 SRB 염색을 하였다. 1% acetic acid용액으로 염색된 세포를 세척하고 well당 0.1 M Tris-HCl (pH 8.0) 100 uL에서 10 분 동안 흔들어서 분리하였다. Microplate reader (Molecular Devices)를 사용하여서 520 nm에서 흡광도를 측정하였다. 모든 측정은 n=3 으로 행해졌다. 화합물 처리 없이 48 시간 동안 배양된 세포의 흡광도 값를 100% 하고, 화합물 처리를 시작한 시점의 세포들의 흡광도 값은 0%로서 할당하였다. GI₅₀ 값은 화합물 처리 후 48시간 동안에 성장을 50% 억제할 때의 처리한 화합물의 농도값으로하였다.Highly DDR2-expressing MDA-MB-231, SK-N-SH, and fibrotic cells of activated chondrocytes from rheumatoid patients and synovial fibroblasts from rat arteries and vascular tissues from rat arteries The SRB cell growth assay confirmed the degree of LCB03-0110 compound inhibition of the growth of smooth muscle cells and HSC T6, a hepatic fibrotic cell in liver tissues, and then the GI ₅₀ value (concentration required to inhibit 50% growth). ) Is shown in Table 4. Briefly, 3000 cells were plated in 96 well plates and incubated overnight. To measure the cell number before compound treatment, three wells were fixed with 4% formalin. The remaining wells were treated with various concentrations of inhibitor compounds and fixed in formalin after 48 hours of incubation. Only living cells are fixed in the culture dish while dead cells are crushed or floated. After washing each well with water, SRB staining was performed using 0.1% sulforhodamine B (SRB) (Sigma) solution dissolved in 1% acetic acid solution for 30 minutes. The cells stained with 1% acetic acid solution were washed and separated by shaking for 10 minutes at 100 uL of 0.1 M Tris-HCl (pH 8.0) per well. Absorbance was measured at 520 nm using a Microplate reader (Molecular Devices). All measurements were done with n = 3. The absorbance value of cells incubated for 48 hours without compound treatment was 100%, and the absorbance value of cells at the beginning of compound treatment was assigned as 0%. The GI ₅₀ value was taken as the concentration value of the treated compound when inhibiting growth by 50% for 48 hours after the compound treatment.

세포주Cell line GI50 (μM)GI50 (μM) MDA-MB-231MDA-MB-231 2.12.1 SK-N-SHSK-N-SH 1.51.5 Lewis Lung CarcinomaLewis Lung Carcinoma 1.11.1 Synovial fibroblastSynovial fibroblast 0.90.9 Vascular smooth muscle cellVascular smooth muscle cell 1.51.5 HSC T6HSC T6 0.70.7

[실험예 4] LCB 화합물에 의한 세포 이동 억제능 분석Experimental Example 4 Analysis of Cell Migration Inhibition by LCB Compound

DDR1 과 DDR2 활성은 파이브로틱 세포나 암세포의 이동과 관계가 있음이 제안되었다 (Hou et al, Circ Res. 2002 Jun 14;90(11):1147-9; Olaso E et al, J Biol Chem 2002;277:3606-1). 이에 본 발명자들은 합성된 DDR1과 DDR2 키나아제 저해제인 화합물 LCB03-0110 이 세포의 이동을 억제하는지를 확인하고자 하였다. MDA-MB-231 유방암 세포주는 전이성이 강하고 또한 DDR2를 다른 암 세포주에 비해 증가된 형태로 발현한다. MDA-MB-231세포를 제 1형 콜라겐이 배양접시 표면에 코딩되어있거나 있지 않은 12 웰 배양접시에 50% 정도 찰 만큼 플레이팅 한다. 하룻밤 동안 배양 후 단일 막으로 자란 세포층에 피펫 팁을 이용하여 일직선 상체를 내고 난 후 무혈청의 DMEM배지로 갈아주었다. 24시간 후에 광학현미경으로 세포사진을 찍었다. 이 때 MDA-MB-231 암세포는 제 1형 콜라겐이 코팅된 표면에서 세포 이동이 더욱 촉진됨을 도 2에서 확인하였다. 이 때 LCB 화합물 03-0110이 MDA-MB-231 유방암 세포주의 이동을 억제하는지를 측정하고자 LCB 화합물 03-0110을 5 μM 처리 시 이러한 콜라겐에 의해 촉진되는 세포 이동이 거의 모두 저해됨을 도 2에서 보여 주었다. 이는 LCB 화합물 03-0110이 MDA-MB-231 유방암 세포주에 많이 발현되는 DDR2 의 활성을 억제함으로써 콜라겐 표면에서 DDR2 활성화로 촉진된 세포이동을 억제함을 보여준다.DDR1 and DDR2 activity has been suggested to be related to migration of fibrotic or cancer cells (Hou et al, Circ Res. 2002 Jun 14; 90 (11): 1147-9; Olaso E et al, J Biol Chem 2002 277: 3606-1). Therefore, the present inventors tried to determine whether compound LCB03-0110, which is a synthesized DDR1 and DDR2 kinase inhibitors, inhibits the migration of cells. The MDA-MB-231 breast cancer cell line is highly metastatic and also expresses DDR2 in an increased form compared to other cancer cell lines. MDA-MB-231 cells are plated as much as 50% in a 12 well culture dish with or without collagen type 1 encoded on the culture dish surface. After overnight incubation, a pipette tip was used to pipe the cell layer grown into a single membrane, and the upper body was straightened and then transferred to a serum-free DMEM medium. After 24 hours, the cells were photographed with an optical microscope. At this time, it was confirmed in FIG. 2 that MDA-MB-231 cancer cells further promoted cell migration on the type 1 collagen-coated surface. In order to determine whether LCB compound 03-0110 inhibits migration of MDA-MB-231 breast cancer cell line, it was shown in FIG. 2 that 5 h of LCB compound 03-0110 inhibited almost all of these collagen-promoted cell migration. . This shows that LCB compound 03-0110 inhibits the cell migration promoted by DDR2 activation on the collagen surface by inhibiting the activity of DDR2, which is highly expressed in MDA-MB-231 breast cancer cell line.

[실험예 5] LCB 화합물의 암세포의 침윤성 세포 억제 분석Experimental Example 5 Invasive Cell Inhibition Assay of Cancer Cell by LCB Compound

SK-N-SH 뇌암 세포는 대표적인 전이성 암세포주로서 본 발명자들이 확인한 바로는 DDR2를 많이 발현한다. 이 세포의 매트리젤 (Matrigel) 침윤성이 본 발명의 화합물로 억제 되는지를 확인 하고자 하였다. 매트리젤 (Matrigel) 침윤 에세이는 BD biosciences에서 구입한 Matrigel invasion chamber를 이용하여 실험하였다. 간략하게 0.5 ml 무혈청 DMEM 배지에 있는 5×10⁴ 개의 MDA-MB-231세포를 chamber 위쪽에 넣고 다양한 농도의 화합물을 처리하였다. 이 chamber를 10% Fetal bovine serum이 들어있는 DMEM 0.75ml이 포함된 배양접시에 위에 장치한다. 22시간 동안 세포배양기에서 배양 후에 침윤이 되지 않은 세포는 매트리젤 멤브레인의 위쪽표면에서부터 면봉을 사용하여 조심스럽게 제거하였다. chamber 바닥 표면에 부착된 침윤된 세포는 100% 메탄올로 고정하고, 0.5% crystal violet으로 염색하고 건조하였다. 침윤된 세포는 광현미경 아래서 계수하였다. 도 3에서 보여준 바와 같이 LCB03-0110 화합물이 존재할 때 화합물 농도 양에 비례하여 SK-N-SH 뇌암 세포의 매트리젤 침윤성을 크게 억제한다. SK-N-SH brain cancer cells are a representative metastatic cancer cell line, and the inventors confirmed that they express a lot of DDR2. The purpose of this study was to determine whether the Matrigel invasiveness of these cells is inhibited with the compounds of the present invention. Matrigel infiltration assays were performed using a Matrigel invasion chamber purchased from BD biosciences. Briefly, 5 × 10 ⁴ MDA-MB-231 cells in 0.5 ml serum-free DMEM medium were placed above the chamber and treated with various concentrations of compounds. The chamber is placed on a culture plate containing 0.75 ml of DMEM containing 10% Fetal bovine serum. Cells that did not infiltrate after incubation in a cell culture for 22 hours were carefully removed using a cotton swab from the upper surface of the Matrigel membrane. Infiltrated cells attached to the chamber bottom surface were fixed with 100% methanol, stained with 0.5% crystal violet and dried. Infiltrated cells were counted under a light microscope. As shown in FIG. 3, LCB03-0110 compounds significantly inhibit Matrigel invasiveness of SK-N-SH brain cancer cells in proportion to the amount of compound concentration.

[실험예 6] LCB 화합물에 의한 MMP-1과 MMP-2 억제능 분석Experimental Example 6 Analysis of MMP-1 and MMP-2 Inhibitory Activity by LCB Compound

DDR1이나 DDR2가 활성화 되면 그 세포 내 신호전달의 결과로 MMP-1 혹은 MMP-2 발현을 촉진하는 기능을 가진 것으로 알려져 있으며 이것은 파이브로틱 세포 혹은 암세포의 성장과 침윤에 중요한 역할을 한다 (Olaso E et al, J Biol Chem 2002;277:3606-1;Vogel W et al, Mol Cell. 1997 Dec;1(1):13-23). MMP-1의 발현정도를 측정하기 위해서 활막 섬유아세포를 12 well 배양접시에서 꽉 찰 때까지 배양하였다. 각 well의 배지를 혈청이 없는 배지로 갈아주고 화합물 처리 후 37℃에서 16시간 동안 배양하였다. 각 well로 부터 배양배지를 수집하고 MMP-1 단백질의 정도를 R&D System에서 구입한 인간 MMP-1 ELISA 키트를 매뉴얼에 따라 실험하였다. MMP-2의 발현억제를 측정하기 위해서 MH7A 세포 대신 SK-N-SH 세포를 R&D system에서 구입한 MMP-2 ELISA 키트로 확인하였다. 본 발명의 LCB화합물을 이들 세포 배양에 처리 시 이들 화합물들이 MMP-1 혹은 MMP-2 생성을 억제하는 정도를 측정 후 EC₅₀ (50% 저해 효과를 내는데 필요한 농도) 값이나 % 저해 정도로 하기 표 5와 표 6 에서 각각 나타내었다.When DDR1 or DDR2 is activated, it is known to have a function of promoting MMP-1 or MMP-2 expression as a result of intracellular signaling, which plays an important role in the growth and infiltration of fibrotic or cancer cells (Olaso E et al, J Biol Chem 2002; 277: 3606-1; Vogel W et al, Mol Cell. 1997 Dec; 1 (1): 13-23). In order to measure the expression level of MMP-1, synovial fibroblasts were cultured in a 12 well culture dish until they were full. The medium of each well was changed to a medium without serum and incubated at 37 ° C. for 16 hours after compound treatment. Culture medium was collected from each well and the degree of MMP-1 protein was tested according to the manual of human MMP-1 ELISA kit purchased from R & D System. In order to measure the expression inhibition of MMP-2, SK-N-SH cells instead of MH7A cells were identified by the MMP-2 ELISA kit purchased from the R & D system. When the LCB compounds of the present invention were treated in these cell cultures, the levels of these compounds inhibiting the production of MMP-1 or MMP-2 were measured, followed by EC ₅₀ (concentration required to produce 50% inhibitory effect) or% inhibition. And in Table 6, respectively.

화합물compound MMP-1 생성 저해 EC50 (μM)MMP-1 production inhibition EC50 (μM) LCB030034LCB030034 4.64.6 LCB030042LCB030042 3.253.25 LCB030052LCB030052 8.78.7 LCB030057LCB030057 >10> 10 LCB030061LCB030061 6.26.2 LCB030064LCB030064 4.34.3 LCB030066LCB030066 2.22.2 LCB030076LCB030076 5.655.65 LCB030079LCB030079 13.613.6 LCB030080LCB030080 >10> 10 LCB030083LCB030083 >10> 10 LCB030084LCB030084 2.22.2 LCB030094LCB030094 7.67.6 LCB030095LCB030095 5.55.5 LCB030097LCB030097 >10> 10 LCB030098LCB030098 >10> 10 LCB030099LCB030099 >10> 10 LCB030110LCB030110 6.56.5

화합물compound 10μM에서의 MMP-2 생성 저해 (%)Inhibition of MMP-2 production at 10 μM (%) LCB030042LCB030042 50.350.3 LCB030083LCB030083 9090 LCB030098LCB030098 4848 LCB030107LCB030107 48.948.9 LCB030109LCB030109 68.268.2 LCB030110LCB030110 94.494.4 LCB030111LCB030111 75.175.1 LCB030112LCB030112 53.753.7

[실험예 7] LCB 화합물에 의한 alpha-smooth muscle actin 발현 억제능 분석Experimental Example 7 Analysis of Alpha-smooth Muscle Actin Expression Inhibition by LCB Compound

DDR1 이나 DDR2 발현은 파이브로틱 세포 (Fibrotic cell)의 활성화와 관련이 있음이 알려져 있다. 파이브로틱 세포가 활성화 될 때 보이는 바이오 마커중 하나는 alpha smooth muscle actin (alpha-SMA)의 발현의 증가이다. LCB 화합물을 쥐의 동맥 혈관에서 추출하여 배양한 혈관조직의 파이브로틱 세포인 혈관 평활근 세포에 처리 시 처리 농도에 따라 alpha smooth muscle actin 발현이 유의성 있게 감소함을 alpha smooth muscle actin 에 특이적인 항체를 이용한 웨스턴 브로팅을 통해 확인하여 도 4에서 보여주었다.DDR1 or DDR2 expression is known to be related to the activation of Fibrotic cells. One of the biomarkers seen when fibrotic cells are activated is the increased expression of alpha smooth muscle actin (alpha-SMA). When the LCB compound was extracted from the arterial blood vessels of rats and treated with vascular smooth muscle cells, which are fibrotic cells of vascular tissues, alpha smooth muscle actin expression was significantly decreased according to the treatment concentration. Confirmed through the Western broth used was shown in FIG.

[실험예 8] LCB 화합물에 의한 세포내 FAK 활성 저해 및 focal adhesion complex 형성 억제능 분석Experimental Example 8 Inhibition of Intracellular FAK Activity and Inhibition of Focal Adhesion Complex Formation by LCB Compound

세포의 이동과 전이에는 포칼 어드히젼 키나아제 (focal adhesion kinase, FAK)의 활성이 중요하며 포칼 어드히젼 복합체 (focal adhesion complex)의 형성이 필요하다. LCB03-0110화합물이 세포의 이동과 전이를 억제하는바 이 화합물을 MDA-MB-231 세포에 처리 시 포칼 어드히젼 키나아제에 미치는 영향을 포칼 어드히젼 키나아제에 특이적인 항체를 이용하여 웨스턴 브로팅으로 측정한 결과 처리 후 16시간 후에 포칼 어드히젼 키나아제 단백질이 손상을 입음을 확인하여 도 5에 나타내었다. 또한 LCB03-0110화합물이 포칼 어드히젼 복합체의 형성 정도를 억제하는지를 확인하기 위해 포칼 어드히젼 복합체를 염색하는 빈큐린 (vinculin) 항체와 이에 부착된 형광 물질 FITC를 이용하여 포칼 어드히젼 복합체를 영상화 한 결과 화합물 처리 후 24시간 후에 포칼 어드히젼 복합체가 거의 사라짐을 확인 하여 도 6에 나타내었다.The movement and migration of cells is important for the activity of focal adhesion kinase (FAK) and the formation of focal adhesion complexes. LCB03-0110 Compounds Inhibit Cell Migration and Metastasis. The effect of LCB03-0110 compounds on focal advice kinases when treated in MDA-MB-231 cells was measured by Western blotting using antibodies specific to focal advice kinases. As a result, it was confirmed that Focal Adduction Kinase protein was damaged after 16 hours after treatment, and is shown in FIG. 5. In addition, to confirm whether LCB03-0110 compound inhibits the formation of the focal advice complex, the focal advice complex was imaged using a vinculin antibody staining the focal advice complex and the fluorescent substance FITC attached thereto. After 24 hours after compound treatment, it was confirmed that the pocal advice complex was almost disappeared and is shown in FIG. 6.

[실험예 9] LCB 화합물에 의한 간성상 세포의 콜라겐 합성 억제능 분석Experimental Example 9 Analysis of Collagen Synthesis Inhibitory Activity of Hepatic Stellate Cells by LCB Compound

DDR1과 DDR2는 파이브로틱 세포의 기능을 활성화 하는 것으로 알려져 있다. 간 조직내의 파이브로틱 세포로 간성상 세포 (hepatic stellate cell)이 존재하며 이 세포는 활성화 되면 DDR2 활성이 증가하며 다량의 콜라겐을 생성한다. LCB03-0110 화합물이 활성화된 간성상 세포의 일종인 HSC T6 세포에 처리 후 이 세포에 의한 콜라겐 생성이 억제되는 지를 콜라겐 정량 실험을 통해 분석하였다. 즉 HSC-T6세포를 24 웰 배양접시에 5×10⁴ 개를 깔고 24시간동안 성장시켰다. 그리고 나서 신선한 배지로 갈아주고 각 웰에 ascorbic acid 50 ug/ml, 1uCi of [³H] proline 그리고 80 ug/ml amino propionitrile를 억제화합물과 같이 처리하고 24시간 동안 배양하였다. 배지를 수확한 후 0.33 M Tris-HCl (pH 7.5), 0.5 M CaCl₂와 50 mM NEM을 포함하는 10 × collagenase 반응 버퍼를 넣었다. 다시 배지는 동량의 부피로 나누고 나서 하나는 2 U/ul collagenase (Sigma)를 넣었고 다른 하나는 같은 양의 물을 넣은 후 세 시간 동안 37 ℃에서 배양하였다. 반응물은 10% BSA가 들어있는 50% TCA를 만들어 침전하였고 단백질을 펠렛으로 만들기 위해 원심기로 분리했다. 단백질 펠렛은 얼음에서 차게 한 10% TCA로 세척하였고 1N NaOH에서 용해시켰다. beta counter를 이용하여서 [³H]의 방사능을 측정하였다. 마지막으로, % 콜라겐 합성은 다음 방정식에 의해 계산되었다 : [( collagenase처리 안한 배지 샘플의 cpm + collagenase처리한 배지 샘플의 cpm )/(collagenase처리 안한 배지 샘플의 cpm)] × 100. LCB03-0110 화합물 처리 농도에 비례하여 콜라겐 생성이 억제됨을 도 7에서 나타내었다.DDR1 and DDR2 are known to activate the function of fibrotic cells. Hepatic stellate cells exist as liver fibrotic cells in the liver tissue, which when activated activate DDR2 activity and produce large amounts of collagen. It was analyzed by collagen quantitative experiment whether LCB03-0110 compound inhibited collagen production by HSC T6 cells, which is a kind of activated hepatic stellate cells. That is, HSC-T6 cells were grown in 24 well culture dishes for 5 hours with 5 × 10 ⁴ cells. Then, the mixture was changed to fresh medium, and treated with ascorbic acid 50 ug / ml, 1 uCi of [ ³ H] proline, and 80 ug / ml amino propionitrile in the wells and incubated for 24 hours. After harvesting the medium, 10 × collagenase reaction buffer containing 0.33 M Tris-HCl (pH 7.5), 0.5 M CaCl ₂ and 50 mM NEM was added. Again, the medium was divided into equal volumes, one containing 2 U / ul collagenase (Sigma) and the other containing the same amount of water, and then incubated at 37 ° C. for three hours. The reaction was precipitated by making 50% TCA containing 10% BSA and centrifuged to pellet the protein. Protein pellets were washed with 10% TCA chilled on ice and dissolved in 1N NaOH. The radioactivity of [ ³ H] was measured using a beta counter. Finally,% collagen synthesis was calculated by the following equation: [(cpm of collagenase-free media samples + cpm of collagenase-free media samples) / (cpm of collagenase-free media samples)] x 100. LCB03-0110 Compound It is shown in FIG. 7 that collagen production is inhibited in proportion to treatment concentration.

[실험예 10] LLC 암세포 이식 생쥐 모델에서의 종양 성장 억제능 분석 Experimental Example 10 Analysis of Tumor Growth Inhibition in the LLC Cancer Cell Mice Model

암세포를 이식한 마우스 모델에서 종양 성장억제를 측정하기위해 3백만개의 MDA-MB-231 세포주를 C57 BL/6 마우스의 오른쪽 엉덩이피하에 접종하였다. 종양이 보이기 시작하면, LCB03-0110과 대조 약물로 현재 임상적으로 사용되는 항암제이며 DNA 합성을 방해하는 항 대사 활성으로 인한 항암 활성을 보이는 5 FU (5-Fluorourasil)를 carrier 용액 (1:4:5 mixture of DMSO:PBS:PEG400)에 용해해서 동물 복강에 3주 동안 매일 ip 주사한다. 종양 부피는 몸무게와 함께 캘리퍼를 이용하여 매 2 ~ 3일마다 측정하였다. LCB03-0110을 ip로 매일 20 mpk 도즈로 주사하였을 때 몸무게 감소를 주지 않았지만 22일 후 약 35% 정도 종양 성장을 억제하였다 (도 8). 대조 약물로 쓴 항암제인 5 FU (5-Fluorourasil)는 20 mpk 도즈에서 몸무게 감소를 주지 않았고 약 70% 정도 종양 성장을 억제하였다 . Three million MDA-MB-231 cell lines were inoculated subcutaneously to the right hip of C57 BL / 6 mice to measure tumor growth inhibition in a mouse model of cancer cells. When tumors begin to appear, 5 FU (5-Fluorourasil) is a carrier solution (1: 4: 5 mixture of DMSO: PBS: PEG400) and injected ip into animal abdominal cavity for 3 weeks daily. Tumor volume was measured every two to three days using a caliper with weight. LCB03-0110 injected ip at 20 mpk dose daily did not reduce weight but inhibited tumor growth by about 35% after 22 days (FIG. 8). 5 FU (5-Fluorourasil), an anticancer drug used as a control drug, did not reduce weight at 20 mpk dose and inhibited tumor growth by about 70%.

이상의 실험 결과들로부터 본 발명에서 제시한 LCB 화합물은 세포 내 DDR1과 DDR2의 티로신 키나아제 활성을 저해함이 분명하다. 이러한 활성으로 첫째, DDR1 혹은 DDR2의 과잉발현이 관찰되는 암에서 암의 성장과 이동 및 전이, 포칼 어드히젼 키나아제 억제, MMP-1, MMP-2 등의 생성을 억제하여 항암 활성을 보이고 둘째로 합성된 LCB 화합물은 조직 내의 파이브로틱 세포로 알려진 활막 섬유 아세포, 혈관 평활근 세포, 간 성상 세포 등에 대한 실험에서 이들 세포의 성장을 억제하고 동시에 이들 세포의 활성화시의 특징인 alpha SMA, fiber collagen, MMP-1과 MMP-2 등의 증가된 발현을 억제함을 확인하여 LCB 화합물은 동맥경화, 간경화, 류마티즘의 주 원인인 조직 내의 파이브로틱 세포의 활성을 억제하여 이들 질환에 대해 약리 작용이 있음을 확인 하였다. From the above experimental results, it is clear that the LCB compound proposed in the present invention inhibits the tyrosine kinase activity of DDR1 and DDR2 in cells. In this activity, first, anticancer activity was inhibited by inhibiting the growth and migration and metastasis of cancer, inhibition of focal advance kinase, MMP-1, MMP-2, etc. in cancers where overexpression of DDR1 or DDR2 was observed. LCB compounds inhibit the growth of these cells in experiments on synovial fibroblasts, vascular smooth muscle cells, hepatic stellate cells, etc., known as fibrotic cells in tissues, and at the same time, alpha SMA, fiber collagen, MMP Inhibiting the increased expression of -1 and MMP-2, LCB compounds have a pharmacological action against these diseases by inhibiting the activity of fibrotic cells in tissues that are the main causes of atherosclerosis, cirrhosis and rheumatism. Confirmed.

위에 언급되었듯이 동맥경화에서 대식세포의 과다 활성화가 병리 현상에서 중요한 역할을 하고 DDR1의 결손이 이를 억제함이 보고되어 확인된 바 본 합성 화합물이 동맥경화나 레스테노시스에 대해 약리 효과를 보임은 더욱 분명하다(Franco C et al, Circ Res. 2008 102(10):1202-11; Hou G et al, J Clin Invest. 2001, 107(6):727-3). 비슷한 이유로 폐 조직의 경우 DDR1 발현 억제가 폐 섬유화를 억제함이 보고되어 확인 되었는바, 본 합성 화합물이 폐경화에 대해서도 약리 효과를 보임이 분명하다. 고혈압의 부작용으로 나타나는 신장경화에도 DDR1이 주요 원인임이 보고되었다 (Flamant M et al, J Am Soc Nephrol. 2006, 17(12):3374-81). 따라서 본 화합물은 파이브로틱 세포의 활성화로 야기되는 조직 섬유화 병변, 즉 폐, 혈관, 신장, 간 등의 경화증에 약리 효과를 줄 것으로 유추되며 마찬가지 이유로 피부의 켈로이드 증에 대한 치료제로 쓰일 수 있다 (Chin GS et al, Plast Reconstr Surg. 2000 Dec;106(7):1532-40). As mentioned above, it has been reported that overactivation of macrophages plays an important role in the pathogenesis of atherosclerosis, and the deficiency of DDR1 has been shown to have a pharmacological effect on atherosclerosis or resthesis. More clearly (Franco C et al, Circ Res. 2008 102 (10): 1202-11; Hou G et al, J Clin Invest. 2001, 107 (6): 727-3). For similar reasons, it has been reported that the suppression of DDR1 expression in lung tissues inhibits lung fibrosis, and it is clear that the synthetic compounds have a pharmacological effect on menopause. DDR1 has been reported to be a major cause of kidney hardening as a side effect of hypertension (Flamant M et al, J Am Soc Nephrol. 2006, 17 (12): 3374-81). Therefore, the compound is inferred to have a pharmacological effect on tissue fibrotic lesions caused by activation of fibrotic cells, namely, sclerosis of lungs, blood vessels, kidneys, liver, etc., and for the same reason, it may be used as a therapeutic agent for keloids of the skin ( Chin GS et al, Plast Reconstr Surg. 2000 Dec; 106 (7): 1532-40).

앞에서 언급되었듯이 골관절염의 경우 DDR2의 증가된 발현이 발견되며 이것은 MMP-13의 증가에 직접적인 원인이 됨이 알려진 바 본 발명의 화합물은 골관절염에서 DDR2 활성 저해를 통해 MMP-13의 발현을 억제하여 연골조직의 손상을 막는 약리 기전을 가질 수 있다 (Xu L et al. J Biol Chem 2005;280:548-55).As mentioned above, in the case of osteoarthritis, increased expression of DDR2 is found, which is known to be a direct cause of the increase of MMP-13. Compounds of the present invention inhibit cartilage by inhibiting the expression of MMP-13 through inhibition of DDR2 activity in osteoarthritis. Pharmacological mechanisms to prevent tissue damage (Xu L et al. J Biol Chem 2005; 280: 548-55).

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

<제제예 1> 정제(직접 가압)Preparation Example 1 Tablet (Direct Pressurization)

활성성분 5.0 ㎎을 체로 친 후, 락토스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 제조하였다.After sifting 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to prepare a tablet.

<제제예 2> 정제(습식 조립)Preparation Example 2 Tablet (Wet Assembly)

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

<제제예 3> 분말과 캡슐제Preparation Example 3 Powder and Capsule

활성성분 5.0 ㎎을 체로 친 후에, 락토스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 혼합하였다. 상기 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다.After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Filled in 5 gelatin capsules.

<제제예 4> 주사제<Example 4> Injection

활성성분으로서 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na₂HPO₄12H₂O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다.Injectables were prepared by containing 100 mg as active ingredient, as well as 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ 12H ₂ O and 2974 mg of distilled water.

도 1은 DDR2를 발현하도록 조작된 HEK293 세포를 제 1형 콜라겐에 접촉시키면서 동시에 합성된 화합물을 처리시 DDR2의 세포내 자가 인산화 활성 억제 정도를 인산화 티로신을 특이적으로 인식하는 항체를 이용한 웨스턴 브로팅 실험을 통해 알아본 결과의 예를 대표적으로 보여주는 것이다. 1 is a western brotting using an antibody that specifically recognizes phosphorylated tyrosine for inhibiting intracellular phosphorylation activity of DDR2 upon treatment of a compound synthesized simultaneously with contacting HEK293 cells engineered to express DDR2 with type 1 collagen. Representative examples of the results obtained through experiments are representative.

도 2는 정상적인 배양 접시 표면이나 혹은 파이브로넥틴이나 제 1형 콜라겐이 코팅된 배양접시 표면에서 혹은 제 1형 콜라겐이 코팅된 배양접시 표면에서 LCB03-0110 화합물 5 uM을 처리 할 때 MDA-MB-231 세포의 이동성을 관찰한 것이다.FIG. 2 shows MDA-MB- when treating 5 uM of LCB03-0110 compound on a normal culture dish surface or on a culture plate surface coated with fibronectin or type 1 collagen or on a culture plate surface coated with type 1 collagen. The mobility of 231 cells was observed.

도 3은 MDA-MB-231 세포의 매트리젤 침윤된 세포수가 LCB30066 혹은 LCB03-0110이 존재할 때 감소함을 보여준 것이고 각 처리 농도에서 침윤된 세포의 수를 정량하여 그래프로 나타낸 것이다.FIG. 3 shows that the number of Matrigel infiltrated cells of MDA-MB-231 cells decreased when LCB30066 or LCB03-0110 was present and is a graphical representation of the number of cells infiltrated at each treatment concentration.

도 4는 혈관 평활근 세포 배양에 LCB03-0110을 농도별로 처리시 알파-스무쓰 머슬액틴 단백질의 발현이 감소함을 웨스턴 브로팅으로 보인 것이다.Figure 4 shows Western blotting that the expression of alpha-smooth muscle actin protein is reduced when LCB03-0110 is treated by concentration in vascular smooth muscle cell culture.

도 5는 LCB03-0110을 MDA-MB-231 세포에 10 uM 농도로 처리 후 시간별로 Focal adhesion kinase 양 및 그 티로신 인산화 정도를 웨스턴 브로팅으로 보인 것이다.Figure 5 shows the amount of Focal adhesion kinase and its tyrosine phosphorylation by Western blotting after treatment with LCB03-0110 at 10 uM concentration in MDA-MB-231 cells.

도 6은 LCB03-0110을 MDA-MB-231 세포에 10 uM 농도로 처리 후 시간별로 세포내 빈큐린 단백질을 면역형광 이미지로 관찰하여 Focal adhesion complex의 변화를 관찰한 것이다.Figure 6 shows the change in Focal adhesion complex by observing intracellular Vincurin protein with immunofluorescence image after treatment with LCB03-0110 at 10 uM concentration in MDA-MB-231 cells.

도 7은 LCB03-0110을 HSC T6 세포에 여러 농도로 24시간이 처리시 세포내 콜라겐 생성이 저해됨을 보여준 것이다.7 shows that intracellular collagen production is inhibited when LCB03-0110 is treated in HSC T6 cells at various concentrations for 24 hours.

도 8은 LLC 암을 생쥐의 피하에 이식 후 LCB03-0110, 혹은 5FU을 20 mpk로 매일 ip 주사 할 때 LLC 종양의 크기와 동물의 몸무게 변화를 정량하여 보여준 것이다.FIG. 8 shows quantitative changes in the size of LLC tumors and animal body weight when LCB03-0110, or 5FU, at 20 mpk daily ip injection of LLC cancer subcutaneously.

Claims

삭제delete

N-(3-메톡시페닐)-6-페닐싸이에노[3,2-d]피리미딘-4-아민,N- (3-methoxyphenyl) -6-phenylthieno [3,2-d] pyrimidin-4-amine,

(6-브로모-싸이에노[3,2-d]피리미딘-4-닐)-(3-메톡시-페닐)-아민,(6-bromo-thieno [3,2-d] pyrimidin-4-yl)-(3-methoxy-phenyl) -amine,

3-(6-(페닐싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (phenylthieno [3,2-d] pyrimidin-4-ylamino) phenol,

4-(4-(3-메톡시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤조나이트릴,4- (4- (3-methoxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzonitrile,

4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤조나이트릴,4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzonitrile,

3-(6-브로모-싸이에노[3,2-d]피리미딘-4-닐아미노)-페놀,3- (6-bromo-thieno [3,2-d] pyrimidin-4-ylamino) -phenol,

4-(4-(3-메톡시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페놀,4- (4- (3-methoxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenol,

3-[6-(4-메톡시페닐)-싸이에노[3,2-d]피리미딘-4-닐아미노]-페놀,3- [6- (4-methoxyphenyl) -thieno [3,2-d] pyrimidin-4-ylamino] -phenol,

N-(3-메톡시페닐)-6-(4-(2-모폴리노에톡시)페닐)싸이에노[3,2-d]피리미딘-4-아민,N- (3-methoxyphenyl) -6- (4- (2-morpholinoethoxy) phenyl) thieno [3,2-d] pyrimidin-4-amine,

3-(6-(4-클로로페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4-chlorophenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-(2-모폴리노에톡시)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (2-morpholinoethoxy) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

N-(3-메톡시페닐)-6-(4-페네톡시페닐)싸이에노[3,2-d]피리미딘-4-아민,N- (3-methoxyphenyl) -6- (4-phenoxyphenyl) thieno [3,2-d] pyrimidin-4-amine,

N-(3-메톡시페닐)-6-(4-(2-(피리딘-2-일)에톡시)페닐)싸이에노[3,2-d]피리미딘-4-아민,N- (3-methoxyphenyl) -6- (4- (2- (pyridin-2-yl) ethoxy) phenyl) thieno [3,2-d] pyrimidin-4-amine,

(6-퓨란-2-일-싸이에노[3,2-d]피리미딘-4-일)-(3-메톡시페놀)-아민,(6-furan-2-yl-thieno [3,2-d] pyrimidin-4-yl)-(3-methoxyphenol) -amine,

(6-퓨란-3-일-싸이에노[3,2-d]피리미딘-4-일)-(3-메톡시페놀)-아민,(6-furan-3-yl-thieno [3,2-d] pyrimidin-4-yl)-(3-methoxyphenol) -amine,

터트-부틸 4-(2-(4-(3-메톡시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페녹시)에틸)피페라진-1-카복실레이트,Tert-butyl 4- (2- (4- (3-methoxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenoxy) ethyl) piperazin-1-carboxylate,

N-(3-메톡시페닐)-6-(4-(2-(피롤리딘-1-일)에톡시)페닐)싸이에노[3,2-d]피리미딘-4-아민,N- (3-methoxyphenyl) -6- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) thieno [3,2-d] pyrimidin-4-amine,

N-(3-메톡시페닐)-6-(싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-아민,N- (3-methoxyphenyl) -6- (thiophen-2-yl) thieno [3,2-d] pyrimidin-4-amine,

(3-메톡시페닐)-(6-싸이오펜-3-일-싸이에노[3,2-d]피리미딘-4-일)-아민,(3-methoxyphenyl)-(6-thiophen-3-yl-thieno [3,2-d] pyrimidin-4-yl) -amine,

N-(3-메톡시페닐)-6-(4-(2-(피페라진-1-일)에톡시)페닐)싸이에노[3,2-d]피리미딘-4-아민,N- (3-methoxyphenyl) -6- (4- (2- (piperazin-1-yl) ethoxy) phenyl) thieno [3,2-d] pyrimidin-4-amine,

(3-메톡시페닐)-(6-싸이오펜-2-일-싸이에노[3,2-d]피리미딘-4-일)-아민,(3-methoxyphenyl)-(6-thiophen-2-yl-thieno [3,2-d] pyrimidin-4-yl) -amine,

3-(6-싸이오펜-3-일-싸이에노[3,2-d]피리미딘-4-일아미노)-페놀,3- (6-thiophen-3-yl-thieno [3,2-d] pyrimidin-4-ylamino) -phenol,

3-(6-(4-(모폴리노메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (morpholinomethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-(피페라진-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (piperazin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-(피롤리딘-1-일메틸)페닐)사이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (pyrrolidin-1-ylmethyl) phenyl) cyeno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-(피페리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (piperidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-(4-메틸피페라진-1-일-메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (4-methylpiperazin-1-yl-methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-((다이에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4-((diethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(퓨란-3-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (furan-3-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-((사이클로프로필메틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4-((cyclopropylmethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-((아이소부틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4-((isobutylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-((에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4-((ethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-(2-(피롤리딘-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (2- (pyrrolidin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-(2-(피페리딘-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (2- (piperidin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-(2-(4-메틸피페라진-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-(2-모폴리노에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (2-morpholinoethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)-1-(4-메틸피페라진-1-일)에타논,2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) -1- (4-methylpiperazin-1-yl) eta Paddy Field,

2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)-1-(피롤리딘-1-일)에타논,2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) -1- (pyrrolidin-1-yl) ethanone,

N,N-다이에틸-2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)아세트아마이드,N, N-diethyl-2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) acetamide,

3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤조산,3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzoic acid,

(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐)(4-메틸피페라진-1-일)메타논,(4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl) (4-methylpiperazin-1-yl) methanone,

(3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐(피롤리딘-1-일)메타논,(3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl (pyrrolidin-1-yl) methanone,

N,N-다이에틸-3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈아마이드,N, N-diethyl-3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamide,

(3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)페닐(4-메틸피페라진-1-일)메타논,(3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) phenyl (4-methylpiperazin-1-yl) methanone,

메틸 1-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-2-카복실레이트,Methyl 1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxylate,

3-(6-(4-((2-(하이드록시메틸)피롤리딘-1-일)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4-((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-((4-메틸피페리딘-1-일)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4-((4-methylpiperidin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-(((2R,6S)-2,6-다이메틸피페리딘-1-일)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4-(((2R, 6S) -2,6-dimethylpiperidin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-yl Amino) phenol,

3-(6-(3-(피페리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (3- (piperidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(3-((4-메틸피페라진-1-일)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (3-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(3-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (3- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(3-((다이에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (3-((diethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(3-(피페라진-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (3- (piperazin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(3-((에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (3-((ethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(3-(모폴리노메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (3- (morpholinomethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(3-((아이소부틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (3-((isobutylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

1-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-2-카복사마이드,1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxamide,

1-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-2-카복실산,1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidine-2-carboxylic acid,

3-(6-(4-((2-하이드록시에틸아미노)메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4-((2-hydroxyethylamino) methyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

메틸 2-(3-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈아미도)프로파노에이트,Methyl 2- (3- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamido) propanoate,

1-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤질)피롤리딘-3-올,1- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzyl) pyrrolidin-3-ol,

3-(6-(4-(에톡시메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (ethoxymethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)-N-(1-하이드록시프로판-2-일)벤즈아마이드,4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) -N- (1-hydroxypropan-2-yl) benzamide,

2-(4-(4-(3-하이드록시페닐아미노)싸이에노[3,2-d]피리미딘-6-일)벤즈아미도)프로판산,2- (4- (4- (3-hydroxyphenylamino) thieno [3,2-d] pyrimidin-6-yl) benzamido) propanoic acid,

3-(6-(3-(2-(피롤리딘-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (3- (2- (pyrrolidin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

6-(4-(피롤리딘-1-일메틸)페닐)-N-(3-(트라이플로로메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민,6- (4- (pyrrolidin-1-ylmethyl) phenyl) -N- (3- (trifluoromethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine,

N-(3-(다이플로로메틸)페닐)-6-(4-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-아민,N- (3- (difluoromethyl) phenyl) -6- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-amine,

3-(6-(3-(2-(피페라진-1-일)에틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (3- (2- (piperazin-1-yl) ethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(2-(4-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀,3- (2- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol,

2-클로로-5-(6-(4-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,2-chloro-5- (6- (4- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-모폴리노페닐)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4-morpholinophenyl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(2-(4-(모폴리노메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀,3- (2- (4- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol,

3-(2-(4-((4-메틸피페라진-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀,3- (2- (4-((4-methylpiperazin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol,

3-(6-(5-(피롤리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (5- (pyrrolidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(5-(피롤리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (5- (pyrrolidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(5-((4-메틸피페라진-1-일)메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (5-((4-methylpiperazin-1-yl) methyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(5-(피페리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (5- (piperidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(5-(모폴리노메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (5- (morpholinomethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(5-(피페라진-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (5- (piperazin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(5-((에틸아미노)메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (5-((ethylamino) methyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(5-((4-메틸피페라진-1-일)메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (5-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(5-(피페리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (5- (piperidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(5-(피페라진-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (5- (piperazin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(5-((에틸아미노)메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (5-((ethylamino) methyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(5-(모폴리노메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (5- (morpholinomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(2-(4-(피페리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀,3- (2- (4- (piperidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol,

3-(2-(4-(피페라진-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀,3- (2- (4- (piperazin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol,

3-(2-(4-((에틸아미노)메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀,3- (2- (4-((ethylamino) methyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol,

3-(2-(4-메틸피페라진-1-일)싸이아졸로[4,5-d]피리미딘-7-일아미노)페놀,3- (2- (4-methylpiperazin-1-yl) thiazolo [4,5-d] pyrimidin-7-ylamino) phenol,

3-(6-(4-(피롤리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (pyrrolidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-((4-메틸피페라진-1-일)메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4-((4-methylpiperazin-1-yl) methyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-(피페리딘-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (piperidin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-(모폴리노메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (morpholinomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-(피페라진-1-일메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (piperazin-1-ylmethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-((에틸아미노메틸)싸이오펜-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4-((ethylaminomethyl) thiophen-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(2-(3-(피롤리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀,3- (2- (3- (pyrrolidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol,

3-(2-(3-((4-메틸피페라진-1-일)메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀,3- (2- (3-((4-methylpiperazin-1-yl) methyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol,

3-(2-(3-(피페리딘-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀,3- (2- (3- (piperidin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol,

3-(2-(3-(모폴리노메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀,3- (2- (3- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol,

3-(2-(3-(피페라진-1-일메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀,3- (2- (3- (piperazin-1-ylmethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol,

3-(2-(3-((에틸아미노)메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀,3- (2- (3-((ethylamino) methyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol,

3-(6-(4-(피롤리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀,3- (6- (4- (pyrrolidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol,

3-(6-(4-((4-메틸피페라진-1-일)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀, 및3- (6- (4-((4-methylpiperazin-1-yl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol, and

3-(6-(4-(피페리딘-1-일메틸)퓨란-2-일)싸이에노[3,2-d]피리미딘-4-일아미노)페놀로 이루어진 군으로부터 선택되는 어느 하나의 화합물, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염.Any selected from the group consisting of 3- (6- (4- (piperidin-1-ylmethyl) furan-2-yl) thieno [3,2-d] pyrimidin-4-ylamino) phenol One compound, an isomer thereof or a pharmaceutically acceptable salt thereof.

3-(2-(3-(모폴리노메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는 항암용 약학적 조성물,3- (2- (3- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Containing anticancer pharmaceutical composition,

3-(2-(3-(모폴리노메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는 동맥경화, 폐섬유화증 또는 간경화증의 예방 또는 치료용 약학적 조성물.3- (2- (3- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition for preventing or treating atherosclerosis, pulmonary fibrosis or cirrhosis containing.

3-(2-(3-(모폴리노메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는 류마티즘 또는 골관절염의 예방 또는 치료용 약학적 조성물.3- (2- (3- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition for preventing or treating rheumatoid or osteoarthritis containing.

3-(2-(3-(모폴리노메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는 혈관재협착의 예방 또는 치료용 약학적 조성물.3- (2- (3- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Pharmaceutical composition for preventing or treating vascular restenosis containing.

3-(2-(3-(모폴리노메틸)페닐)싸이에노[3,2-b]피리딘-7-일아미노)페놀, 이의 이성질체 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신장병의 예방 또는 치료용 약학적 조성물.3- (2- (3- (morpholinomethyl) phenyl) thieno [3,2-b] pyridin-7-ylamino) phenol, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition for preventing or treating kidney disease.