KR100979439B1 - Novel 4-pyrazol-2-benzoxazole-pyridine derivatives or pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition for the prevention and treatment of abnormal cell growth diseases containing the same as an active ingredient - Google Patents

Novel 4-pyrazol-2-benzoxazole-pyridine derivatives or pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition for the prevention and treatment of abnormal cell growth diseases containing the same as an active ingredient Download PDF

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KR100979439B1
KR100979439B1 KR1020080033282A KR20080033282A KR100979439B1 KR 100979439 B1 KR100979439 B1 KR 100979439B1 KR 1020080033282 A KR1020080033282 A KR 1020080033282A KR 20080033282 A KR20080033282 A KR 20080033282A KR 100979439 B1 KR100979439 B1 KR 100979439B1
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pyridin
pyrazol
piperidin
amine
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고종성
이종국
조성윤
한선영
이정옥
류재욱
박경찬
한동초
하재두
박성규
정희정
권병목
유경호
심태보
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한국화학연구원
한국생명공학연구원
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Abstract

본 발명은 하기 화학식 1로 표시되는 신규 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염 및 이의 제조방법 및 이를 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물에 관한 것으로, 이상 세포 성장질환의 치료에 유용한 다양한 단백질 키나아제, 예를 들면 c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, Aurora-A 등에 대하여 우수한 억제효과를 나타내므로, 이상 세포 성장 질환의 예방 및 치료에 유용하게 사용될 수 있다.The present invention is a pyridine derivative substituted by novel pyrazole and benzoxazole represented by the following formula (1) or a pharmaceutically acceptable salt thereof and a method for preparing the same and a pharmaceutical for preventing and treating aberrant cell growth disease containing the same as an active ingredient The composition relates to a variety of protein kinases useful for the treatment of aberrant cell growth diseases such as c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, Aurora-A, etc. Since it shows an inhibitory effect, it can be usefully used for the prevention and treatment of abnormal cell growth diseases.

[화학식 1][Formula 1]

Figure 112008025718184-pat00001
Figure 112008025718184-pat00001

(상기 화학식 1에서, R1, R2, R3 및 A는 본 명세서에서 정의된 바와 같다)(In Formula 1, R 1 , R 2 , R 3 and A are as defined herein)

피라졸, 벤즈옥사졸, 피리딘, 단백질 키나아제, 억제제 Pyrazole, benzoxazole, pyridine, protein kinase, inhibitor

Description

신규 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물{Novel 4-pyrazol-2-benzoxazole-pyridine derivatives or pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition for the prevention and treatment of abnormal cell growth diseases containing the same as an active ingredient}Novel pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for preventing and treating aberrant cell growth disease containing the same as an active ingredient Novel 4-pyrazol-2- benzoxazole-pyridine derivatives or pharmaceutically acceptable salts, preparation method according to the formula and the prevention and treatment of abnormal cell growth diseases containing the same as an active ingredient

본 발명은 신규 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물에 관한 것이다.The present invention relates to novel pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutically acceptable salts thereof, methods for preparing the same, and pharmaceutical compositions for preventing and treating aberrant cell growth diseases containing the same as an active ingredient.

단백질 키나아제(PK)는 단백질의 티로신, 세린 및 트레오닌 잔사 상의 하이드록시 그룹의 인산화를 촉매하는 효소이다. 상기 단백질 키나아제는 세포 성장, 분화 및 증식을 야기하는 성장 인자 신호 전달에 중요한 역할을 하고, 따라서 단백질 키나아제의 활성은 세포 생명의 거의 모든 양태에 영향을 미친다. Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The protein kinases play an important role in the growth factor signal transduction that causes cell growth, differentiation and proliferation, and thus the activity of protein kinases affects almost all aspects of cell life.

단백질 키나아제의 돌연변이나 과발현에 의한 세포신호전달체계의 이상은 건선과 같이 비교적 생명에 위협적이지 않은 질환에서부터 암과 같은 독성(병원성) 질환에 걸친 기질(stroma) 질환에 밀접한 영향을 미친다.Aberrations in cellular signaling systems due to mutation or overexpression of protein kinases have a close effect on stroma diseases ranging from relatively non-life threatening diseases such as psoriasis to toxic (pathogenic) diseases such as cancer.

단백질 키나아제는 티로신 키나아제(TK) 및 세린-트레오닌 키나아제(STK)로 분류할 수 있다. Protein kinases can be classified into tyrosine kinases (TK) and serine-threonine kinases (STK).

티로신 키나아제의 활성의 주요 양태들 중의 하나는 이것이 성장 인자 수용체와 관련이 있다는 것이다. 성장 인자 수용체는 세포 표면 단백질로서, 성장 인자 리간드에 결합된 경우에는 성장 인자 수용체가 활성 형태로 전환되어 세포막의 내부 표면상의 단백질과 상호 작용하여, 상기 수용체와 기타 단백질의 티로신 잔사 상에서 인산화가 유발되고, 세포 내부에 각종 세포질성 시그널링 분자와의 복합체가 형성되어 궁극적으로는 수많은 세포 반응, 예를 들면, 세포 성장, 분화 및 증식, 세포외 미소환경에 대한 대사성 효과 발현 등이 나타난다(Schleessinger and Ullrich, Neuron. 1992 9, 303-391). One of the major aspects of the activity of tyrosine kinases is that it is associated with growth factor receptors. Growth factor receptors are cell surface proteins that, when bound to growth factor ligands, convert the growth factor receptors into active form and interact with proteins on the inner surface of the cell membrane, causing phosphorylation on tyrosine residues of these receptors and other proteins. In addition, complexes with various cytoplasmic signaling molecules are formed inside cells, resulting in numerous cellular reactions such as cell growth, differentiation and proliferation, and expression of metabolic effects on extracellular microenvironments (Schleessinger and Ullrich, Neuron. 1992 9, 303-391).

티로신 키나아제의 활성을 지닌 성장 인자 수용체는 수용체 티로신 키나아제(Receptor tyrosine kinase, RTK)로서 알려져 있다. 상기 수용체 티로신 키나아제는 다양한 생물학적 활성을 나타내는 큰 계열의 막관통(transmembrane)수용체를 포함한다. Growth factor receptors with tyrosine kinase activity are known as receptor tyrosine kinase (RTK). The receptor tyrosine kinases contain a large family of transmembrane receptors that exhibit a variety of biological activities.

종래에 19개 이상의 "HER RTK"로 명명되는 것과 같은 아계열의 수용체 티로 신 키나아제가 알려져 있고, 상기 HER RTK에는 상피 성장 인자 수용체(EGFR), HER2, HER3, HER4 등이 포함된다. 상기 수용체 티로신 키나아제는 세포외 글리코실화리간드 결합성 도메인, 막관통 도메인 및 단백질 상의 티로신 잔사를 인산화시킬 수 있는 세포내 세포질성 도메인으로 이루어진다. Subtype receptor tyrosine kinases such as those previously termed 19 or more "HER RTKs" are known, and the HER RTKs include epidermal growth factor receptors (EGFR), HER2, HER3, HER4 and the like. The receptor tyrosine kinase consists of an extracellular glycosylated ligand binding domain, a transmembrane domain and an intracellular cytoplasmic domain capable of phosphorylating tyrosine residues on proteins.

또한, 수용체 티로신 키나아제 아계열은 인슐린 수용체(IR), 인슐린 유사 성장 I 수용체(IGF-1R) 및 인슐린 수용체 관련 수용체(IRR)로 이루어진다. IR 및 IGF-IR은 인슐린, IGF-I 및IGF-II와 상호 작용하여, 세포막을 가로지르고 키나아제 도메인을 함유하는 2개의 β소단위체와 2개의 완전하게 세포외 글리코실화된 α소단위체의 이종사량체(heterotetramer)를 형성한다.The receptor tyrosine kinase subfamily also consists of insulin receptor (IR), insulin like growth I receptor (IGF-1R) and insulin receptor related receptor (IRR). IR and IGF-IR interact with insulin, IGF-I and IGF-II, resulting in heterologous doses of two β subunits and two completely extracellular glycosylated α subunits that cross the cell membrane and contain a kinase domain Forms a heterotetramer.

또한, 수용체 티로신 키나아제 아계열은 혈소판 유도된 성장 인자 수용체(PDGFR)로서 명명되는 PDGFRα, PDGFRβ, CSFIR, c-Kit 및 c-Fms을 포함한다. 상기 수용체는 가변수의 면역글로블린 유사 루프와 세포내 도메인으로 구성된 글리코실화 세포외 도메인으로 이루어진다. PDGFR 아계열과의 유사성으로 인해 상기 PDGFR 그룹에 포함되는 태아 간 키나아제(Flk) 수용체 아계열이 알려져 있다. 상기 Flk 아계열은 키나아제 삽입물 도메인-수용체 태아 간 키나아제-1(KDR/Flk-1), Flk-1R, Flk-1, Fms-유사 티로신 키나아제 1 또는 3(Flt-1 또는 Flt-3) 등으로 이루어진다.In addition, the receptor tyrosine kinase subfamily includes PDGFRα, PDGFRβ, CSFIR, c-Kit and c-Fms, which are termed platelet induced growth factor receptors (PDGFR). The receptor consists of a glycosylated extracellular domain consisting of a variable immunoglobulin-like loop and an intracellular domain. Due to its similarity to the PDGFR subfamily, fetal liver kinase (Flk) receptor subfamily belonging to the PDGFR group is known. The Flk subfamily is a kinase insert domain-receptor fetal liver kinase-1 (KDR / Flk-1), Flk-1R, Flk-1, Fms-like tyrosine kinase 1 or 3 (Flt-1 or Flt-3) and the like. Is done.

티로신 키나아제 성장 인자 수용체 계열로서 MET은 c-Met으로서 명명되고 사람 간세포 성장 인자 수용체 티로신 키나아제(hHGFR)로서 1차적 종양 성장 및 전이에 일정 역할을 하는 것으로 여겨지고 있다(Plowman et al.,DN&P, 1994, 7, 6, 334-339).As a family of tyrosine kinase growth factor receptors, MET is named c-Met and is believed to play a role in primary tumor growth and metastasis as human hepatocyte growth factor receptor tyrosine kinase (hHGFR) (Plowman et al., DN & P, 1994, 7, 6, 334-339).

수용체 티로신 키나아제 이외에도, 비수용체 티로신 키나아제 또는 세포성 티로신 키나아제(CTK)로 불리우는 특정 계열의 완전한 세포내 TK가 존재한다. 상기 비수용체 티로신 키나아제는 세포외 도메인과 막관통 도메인을 함유하지 않고, Src, Frk, Btk, Csk Abl, Zap70, Fes, Fak, Jak 및 Ack 아계열로 이루어진다. 이중 Src 아계열은 Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1(Aurora-B), AUR2(Aurora-A), AUR3(Aurora-C), Yrk 등을 포함한다(Bolen, Oncogene. 1993, 8, 2025-2031).In addition to receptor tyrosine kinases, there is a specific family of complete intracellular TKs called nonreceptor tyrosine kinases or cellular tyrosine kinases (CTKs). The non-receptor tyrosine kinase contains no extracellular and transmembrane domains and consists of the Src, Frk, Btk, Csk Abl, Zap70, Fes, Fak, Jak and Ack subfamily. Src subfamily includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1 (Aurora-B), AUR2 (Aurora-A), AUR3 (Aurora-C), Yrk, etc. (Bolen, Oncogene. 1993, 8, 2025-2031).

수용체 티로신 키나아제 및 비수용체 티로신 키나아제와 관련된 병원성 질환은 건선, 간경변, 당뇨병, 혈관형성, 재발 협착증, 안과질환, 류마티스성 관절염, 자가면역 질환, 죽상경화증, 신장 장애 등이 포함된다.Pathogenic diseases associated with receptor tyrosine kinases and non-receptor tyrosine kinases include psoriasis, cirrhosis, diabetes, angiogenesis, recurrent stenosis, ophthalmic diseases, rheumatoid arthritis, autoimmune diseases, atherosclerosis, kidney disorders and the like.

상기에서 살펴본 PK 중에서 Bcr-Abl, EGFR, VEGFR 등의 수용체 티로신 키나아제는 좋은 항암제 타겟으로 많이 연구되어 왔으며, 글리벡, 이레사 등의 항암제가 개발되어 시판되고 있다. Among the PKs described above, receptor tyrosine kinases such as Bcr-Abl, EGFR, and VEGFR have been studied as a good anticancer target, and anticancer agents such as Gleevec and Iresa have been developed and marketed.

또한, 항암제 타겟으로 연구되고 있는 RTK 중에서도 간세포 성장인자(Hepatocyte Growth Factor/Scatter Factor, HGF/SF) 수용체인 c-Met(Hepatocyte Growth Factor Receptor: HGFR)을 타겟으로 하는 항암제가 많이 개발되고 있다(J. G. Christensen, J. Burrows et al., Cancer Letters, 2005, 225, 1-26; WO 2004/076412; WO 2006/021881 A; WO 2006/021886; WO 2007/064797). In addition, among the RTKs being studied as anticancer agents, many anticancer agents targeting c-Met (Hepatocyte Growth Factor Receptor (HGFR)), a hepatocyte growth factor / scatter factor (HGF / SF) receptor, have been developed (JG). Christensen, J. Burrows et al., Cancer Letters, 2005, 225, 1-26; WO 2004/076412; WO 2006/021881 A; WO 2006/021886; WO 2007/064797).

c-Met은 종양 형성, 증대된 세포 운동성 및 침입성 하에서의 종양 진행, 및 전이에 수반되는 폐암, 위암, 피부암, 신장암, 직장암, 췌장암 등의 많은 인간 암에서 과발현 또는 활성화되어 있다(J. G. Christensen et al., Cancer Letters, 2005, 225, 1-26; W. G. Jiang et al., Critical Reviews in Oncology/Hematology, 2005, 53, 35-69). c-MET 및 이의 리간드인 HGF는 많은 조직에서 발현되지만, 정상적으로는 주로 상피 및 간엽 기원의 세포 각각으로 한정되어 발현된다. c-MET 및 HGF/SF는 정상적인 포유동물의 발육에 필요하며, 세포 전이, 세포 증식 및 생존, 형태 형성성 분화 및 3-차원적 관상 구조물(신 세뇨관 세포, 선 형성 등)의 조직화에서 중요한 것으로 밝혀졌다. HGF/SF는 신생혈관생성 인자이며, 상피 세포에서의 c-MET 신호전달은 신생혈관생성에 필수적인 세포 반응(증식, 운동성, 침입성 등)을 유도한다. c-Met is overexpressed or activated in many human cancers, including lung cancer, gastric cancer, skin cancer, kidney cancer, rectal cancer, and pancreatic cancer, accompanied by tumor formation, increased cell motility and invasive tumor progression, and metastasis (JG Christensen et. al., Cancer Letters, 2005, 225, 1-26; WG Jiang et al., Critical Reviews in Oncology / Hematology, 2005, 53, 35-69). c-MET and its ligand, HGF, are expressed in many tissues, but are normally limited to cells of epithelial and mesenchymal origin, respectively. c-MET and HGF / SF are necessary for the development of normal mammals and are important for cell metastasis, cell proliferation and survival, morphogenic differentiation and organization of three-dimensional coronary structures (neotubule cells, glandogenesis, etc.). Turned out. HGF / SF is an angiogenesis factor and c-MET signaling in epithelial cells induces cellular responses (proliferation, motility, invasiveness, etc.) that are essential for angiogenesis.

또한 c-Met 및 이의 리간드인 HGF는 다양한 인간 암에서 증가된 수준으로 공-발현되는 것으로 밝혀졌다. 그러나, 수용체 및 리간드는 통상적으로 상이한 세포 유형에 의해 발현되기 때문에, c-Met 신호전달은 대부분 보편적으로 종양-기질 (tumor-stroma) 상호작용에 의해 조절된다.It has also been found that c-Met and its ligand, HGF, are co-expressed at increased levels in various human cancers. However, because receptors and ligands are usually expressed by different cell types, c-Met signaling is most commonly regulated by tumor-stroma interactions.

또한, c-Met의 유전자 증폭, 돌연변이 및 재배열이 다양한 인간 암에서 관찰되었다. c-Met 키나아제를 활성화시키는 생식계 돌연변이를 갖는 부류는 다중 신 장 종양 및 다른 조직의 종양에 걸리기 쉽다.In addition, gene amplification, mutations and rearrangements of c-Met have been observed in various human cancers. Classes with germline mutations that activate c-Met kinase are susceptible to multiple kidney tumors and tumors of other tissues.

c-Met 및/또는 HGF/SF의 발현은 상이한 유형의 암(폐, 결장, 유방, 전립선, 간, 췌장, 뇌, 신장, 난소, 위, 피부, 뼈 등의 암)의 질환 진행 상태와 연관되어 있으며, c-Met 또는 HGF/SF의 과발현은 폐, 간, 위 및 유방을 포함한 많은 주요 인간 암에서 나쁜 예후 및 질환 결과와 상관되는 것으로 밝혀졌다. 또한, c-Met은 췌장암, 신경교종 및 간세포암과 같은 성공적인 치료법이 없는 암에 직접 관련되어 있다고 보고되었으며, c-Met이 과발현되면서 ERBB3 신호전달체계 활성화로 야기된 폐암이 게피티니브(Gefitinib; 이레사(상품명:Irresa))에 내성을 갖게 된다고 보고되었다 (J. A. Engelman, K. Zejnullahu et. al. Science, 2007, 316, 1039-1043). Expression of c-Met and / or HGF / SF is associated with disease progression in different types of cancer (lungs, colon, breast, prostate, liver, pancreas, brain, kidney, ovary, stomach, skin, bone, etc.) Overexpression of c-Met or HGF / SF has been found to correlate with poor prognosis and disease outcome in many major human cancers including lung, liver, stomach and breast. In addition, c-Met has been reported to be directly related to cancers without successful treatment such as pancreatic cancer, glioma and hepatocellular carcinoma, and lung cancer caused by ERBB3 signaling system activation due to overexpression of c-Met is Gefitinib (Gefitinib; It has been reported to be resistant to Irresa (JA Engelman, K. Zejnullahu et. Al. Science, 2007, 316, 1039-1043).

HGF/SF는 c-Met의 세포외 도메인에 결합하여 c-Met을 활성화시키며, c-Met의 활성화는 각각 Gab1 및 Grb2 매개된 PI3-키나제 및 Ras/MAPK 활성화를 통한 티로신 포스포릴화 및 다운스트림 시그널화를 이끌어, 세포 운동성 및 증식을 유도한다. HGF / SF binds to the extracellular domain of c-Met to activate c-Met, and activation of c-Met is tyrosine phosphorylation and downstream via Gab1 and Grb2-mediated PI3-kinase and Ras / MAPK activation, respectively. Signaling to induce cell motility and proliferation.

c-Met은 수용체 활성화, 형질전환 및 침습을 이끄는 다른 단백질과 상호작용하는 것으로 밝혀졌고, 또한 c-Met은 초점부착(focal adhesion)을 형성하는 α6β4 인테그린(Integrin:라미닌과 같은 세포외 기질(ECM) 성분에 대한 수용체)과 상호작용하여 HGF/SF 의존적 침습적 성장을 촉진하는 것으로 보고되었다. c-Met has been shown to interact with other proteins leading to receptor activation, transformation and invasion, and c-Met also has an extracellular matrix (ECM) such as α6β4 integrin (laminin) that forms focal adhesion. Has been reported to promote HGF / SF dependent invasive growth.

이에, 본 발명자들은 단백질 키나아제 억제제를 개발하기 위한 연구를 수행 하 던 중, 단백질 키나아제에 대한 우수한 저해 활성을 갖는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체가 이상 세포 성장의 치료에 유용한 c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, Aurora-A 등과 같은 단백질 키나아제에 대한 억제효과를 나타내므로, 이상 세포 성장 질환의 예방 및 치료에 유용하게 사용될 수 있음을 알아내고 본 발명을 완성하였다.Accordingly, the present inventors, while conducting research to develop protein kinase inhibitors, pyridine derivatives substituted with pyrazole and benzoxazole having excellent inhibitory activity against protein kinases are useful for the treatment of abnormal cell growth, Inhibits protein kinases such as Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, Aurora-A, etc., and therefore can be usefully used for the prevention and treatment of abnormal cell growth diseases. It was found and completed the present invention.

본 발명의 목적은 신규 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 제공하는 데 있다. It is an object of the present invention to provide novel pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutically acceptable salts thereof.

본 발명의 다른 목적은 신규 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법을 제공하는 데 있다.Another object of the present invention is to provide a method for preparing novel pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutically acceptable salts thereof.

본 발명의 또 다른 목적은 신규 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물을 제공하는 데 있다.Still another object of the present invention is to provide a pharmaceutical composition for preventing and treating aberrant cell growth disease, which contains a novel pyrazole and benzoxazole substituted pyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

상기 목적을 달성하기 위하여, 본 발명은 신규 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a novel pyrazole and benzoxazole-substituted pyridine derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical for preventing and treating aberrant cell growth disease containing the same as an active ingredient. To provide a composition.

본 발명에 따른 신규 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염은 단백질 키나아제에 대한 우수한 저해 활성을 나타내는바, 이상 세포 성장질환의 치료에 유용한 다양한 단백질 키나아제, 예를들면 c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, Aurora-A 등에 대하여 우수한 억제효과를 나타내므로, 이상 세포 성장 질환의 예방 및 치료에 유용하게 사용될 수 있다.The pyridine derivatives or pharmaceutically acceptable salts thereof substituted with the novel pyrazoles and benzoxazoles according to the present invention exhibit excellent inhibitory activity against protein kinases, which are useful for the treatment of aberrant cell growth diseases, for example It has excellent inhibitory effect on c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, Aurora-A, etc., and thus can be usefully used for the prevention and treatment of abnormal cell growth diseases. .

이하, 본 발명을 상세하게 설명한다.EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

본 발명은 하기 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a pyridine derivative or a pharmaceutically acceptable salt thereof substituted with pyrazole and benzoxazole represented by the following formula (1).

Figure 112008025718184-pat00002
Figure 112008025718184-pat00002

상기 화학식 1에서, In Chemical Formula 1,

R1은 수소 또는 NHR4이고, 여기서, 상기 R4는 수소, C1-C4의 직쇄 또는 측쇄 알킬 또는 벤질이고;R 1 is hydrogen or NHR 4 , wherein R 4 is hydrogen, C 1 -C 4 straight or branched chain alkyl or benzyl;

R2는 수소, 할로겐, C1-C4의 직쇄 또는 측쇄 알킬, -NHR5, -NR6R7, OR5, -CN, -NHC(O)R6, -SO2R6, -OS(O)2R6, 피롤리딘, 피페리딘 및 모폴린 중에서 선택되되 상기 벤즈옥사졸 고리의 5번 또는 6번 위치에 치환되는 어느 하나 또는 상기 벤즈옥사졸 고리의 5번 및 6번 위치에 접합되는 C6-C12의 아릴이고, 여기서, 상기 R5는 수소, C1-C6의 직쇄 또는 측쇄 알킬, C1-C4의 직쇄 또는 측쇄 알키닐, C1-C4의 직쇄 또는 측쇄 알케닐, C6-C12의 아릴, 할로겐으로 치환된 C6-C12의 아릴 또는 트리할로겐메틸로 치환된 C6-C12의 아릴이고, 상기 R6은 C1-C4의 직쇄 또는 측쇄 알킬이고, R7는 C1-C4의 직쇄 또는 측쇄 알킬 또는 C6-C12의 아릴이고;R 2 is hydrogen, halogen, C 1 -C 4 straight or branched chain alkyl, -NHR 5 , -NR 6 R 7 , OR 5 , -CN, -NHC (O) R 6 , -SO 2 R 6 , -OS (O) any one selected from 2 R 6 , pyrrolidine, piperidine and morpholine, substituted in positions 5 or 6 of the benzoxazole ring or in positions 5 and 6 of the benzoxazole ring C 6 -C 12 aryl, wherein R 5 is hydrogen, C 1 -C 6 straight or branched chain alkyl, C 1 -C 4 straight or branched chain alkynyl, C 1 -C 4 straight chain or branched chain alkenyl, aryl of C 6 a C 6 -C 12 aryl substituted with halogen or tri-methyl substituted with a C 6 -C 12 aryl, halogen, -C 12, wherein R 6 is a C 1 -C 4 Straight or branched alkyl, R 7 is C 1 -C 4 straight or branched alkyl or C 6 -C 12 aryl;

R3는 수소, C1-C4의 직쇄 또는 측쇄 알킬, 4-피페리딘이며;R 3 is hydrogen, C 1 -C 4 straight or branched chain alkyl, 4-piperidine;

A는 탄소 또는 질소이다.A is carbon or nitrogen.

바람직하게는 상기 R1은 수소 또는 -NHR4이고, 여기서 R4는 수소, 메틸 또는 벤질이고;Preferably said R 1 is hydrogen or —NHR 4 , wherein R 4 is hydrogen, methyl or benzyl;

상기 R2는 수소, 불소, 염소, 메틸, -CN, -NHR5, -NR6R7, OR5, -CN, -NHC(O)R6, -SO2R6, -OS(O)2R6, 피롤리딘, 피페리딘 및 모폴린 중에서 선택되되 상기 벤즈옥사졸 고리의 5번 또는 6번 위치에 치환되는 어느 하나 또는 상기 벤즈옥사졸 고리의 5번 및 6번 위치에 접합되는 벤젠이고, 여기서 R5는 수소, 메틸, 에틸, 프로필, 이소프로필, 부틸, 페닐, 4-플루오로페닐, 2,6-디플루오로페닐, 3,5-디플루오로페닐 또는 3,5-디트리플루오로메틸이고, R6는 메틸 또는 에틸이고, R7은 메틸 또는 페닐이고;R 2 is hydrogen, fluorine, chlorine, methyl, -CN, -NHR 5 , -NR 6 R 7 , OR 5 , -CN, -NHC (O) R 6 , -SO 2 R 6 , -OS (O) 2 R 6 , pyrrolidine, piperidine and morpholine, either substituted at position 5 or 6 of the benzoxazole ring or conjugated at positions 5 and 6 of the benzoxazole ring Benzene, where R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, phenyl, 4-fluorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl or 3,5- Ditrifluoromethyl, R 6 is methyl or ethyl, R 7 is methyl or phenyl;

상기 R3는 수소, 메틸 또는 4-피페리딘이며;R 3 is hydrogen, methyl or 4-piperidine;

상기 A는 탄소 또는 질소이다.A is carbon or nitrogen.

본 발명의 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체의 구체적인 화합물은 하기와 같다.Specific compounds of the pyridine derivatives substituted with pyrazole and benzoxazole represented by the general formula (1) of the present invention are as follows.

1) 3-(5-클로로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;1) 3- (5-chlorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine;

2) 3-(벤즈[d]옥사졸-2일)-N-메틸-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;2) 3- (benz [d] oxazol-2yl) -N-methyl-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine;

3) 3-(벤즈[d]옥사졸-2일)-N-벤질-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;3) 3- (benz [d] oxazol-2yl) -N-benzyl-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine;

4) 3-(벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;4) 3- (benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine;

5) 3-(5-(에틸설포닐)벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;5) 3- (5- (ethylsulfonyl) benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine- 2-amine;

6) 3-(5-(에틸설포닐)벤즈[d]옥사졸-2-일)-N-메틸-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;6) 3- (5- (ethylsulfonyl) benz [d] oxazol-2-yl) -N-methyl-5- (1- (piperidin-4-yl) -1H-pyrazole-4- Yl) pyridin-2-amine;

7) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-5-카보나이트릴;7) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-5-carbonitrile ;

8) 3-(5-(클로로벤즈[d]옥사졸-2-일)-N-메틸-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;8) 3- (5- (chlorobenz [d] oxazol-2-yl) -N-methyl-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine 2-amine;

9) 3-(6-메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;9) 3- (6-methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine;

10) 3-(6-클로로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;10) 3- (6-chlorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine;

11) 3-(6-플루오로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;11) 3- (6-fluorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ;

12) 3-(5-(메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;12) 3- (5- (methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ;

13) 3-(나프토[2,3-d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;13) 3- (naphtho [2,3-d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2- Amines;

14) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-프로필벤즈[d]옥사졸-5-아민;14) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-propylbenz [d] oxazole- 5-amine;

15) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-메틸벤즈[d]옥사졸-5-아민;15) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-methylbenz [d] oxazole- 5-amine;

16) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-에틸벤즈[d]옥사졸-5-아민;16) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-ethylbenz [d] oxazole- 5-amine;

17) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소프로필벤즈[d]옥사졸-5-아민;17) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-isopropylbenz [d] oxazole -5-amine;

18) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-부틸벤즈[d]옥사졸-5-아민;18) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-butylbenz [d] oxazole- 5-amine;

19) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N,N-디메틸벤즈[d]옥사졸-5-아민;19) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N, N-dimethylbenz [d] oxa Sol-5-amine;

20) 5-(1-(피페리딘-4-일)-1H-피라졸-4-일)-3-(5-(피롤리딘-1-일)벤즈[d]옥사졸-2-일)피리딘-2-아민;20) 5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3- (5- (pyrrolidin-1-yl) benz [d] oxazole-2- Yl) pyridin-2-amine;

21) 3-(5-(피페리딘-1-일)벤즈[d]옥사졸-2일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;21) 3- (5- (piperidin-1-yl) benz [d] oxazol-2yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl ) Pyridin-2-amine;

22) 3-(5-모폴리노벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;22) 3- (5-morpholinobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine-2- Amines;

23) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-페닐벤즈[d]옥사졸-5-아민;23) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-phenylbenz [d] oxazole- 5-amine;

24) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-메틸-N-페닐벤즈[d]옥사졸-5-아민;24) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-methyl-N-phenylbenz [d ] Oxazole-5-amine;

25) N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-5-일)아세트아마이드;25) N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-5 -Yl) acetamide;

26) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소프로필벤즈[d]옥사졸-6-아민;26) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-isopropylbenz [d] oxazole -6-amine;

27) 5-(1-(피페리딘-4-일)-1H-피라졸-4-일)-3-(6-(피롤리딘-1-일)벤즈[d]옥사졸-2-일)피리딘-2-아민;27) 5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3- (6- (pyrrolidin-1-yl) benz [d] oxazole-2- Yl) pyridin-2-amine;

28) 3-(6-(피페리딘-1-일)벤즈[d]옥사졸-2일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;28) 3- (6- (piperidin-1-yl) benz [d] oxazol-2yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl ) Pyridin-2-amine;

29) 3-(6-모폴리노벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;29) 3- (6-morpholinobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine-2- Amines;

30) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-페닐벤즈[d]옥사졸-6-아민;30) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-phenylbenz [d] oxazole- 6-amine;

31) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-메틸-N-페닐벤즈[d]옥사졸-6-아민;31) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-methyl-N-phenylbenz [d ] Oxazole-6-amine;

32) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(4-플루오로페닐)벤즈[d]옥사졸-6-아민;32) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N- (4-fluorophenyl) benz [d] oxazol-6-amine;

33) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(2,6-디플루오로페닐)벤즈[d]옥사졸-6-아민;33) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N- (2,6-difluoro Phenyl) benz [d] oxazol-6-amine;

34) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(3,5-디플루오로페닐)벤즈[d]옥사졸-6-아민;34) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N- (3,5-difluoro Phenyl) benz [d] oxazol-6-amine;

35) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(3,5-비스(트리플루오로메틸)페닐)벤즈[d]옥사졸-6-아민;35) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N- (3,5-bis (tri Fluoromethyl) phenyl) benz [d] oxazol-6-amine;

36) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-5-아민;36) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazol-5-amine;

37) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-벤즈[d]옥사졸-6-아민;37) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -benz [d] oxazol-6-amine ;

38) 3-(5-에톡시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;38) 3- (5-ethoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ;

39) 3-(5-메톡시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;39) 3- (5-methoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ;

40) 3-(6-메톡시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;40) 3- (6-methoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ;

41) 3-(6-에톡시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;41) 3- (6-ethoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ;

42) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-일 메탄설포네이트;42) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [ d ] oxazol-6-yl methane Sulfonates;

43) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-5-올;43) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazol-5-ol;

44) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-올;44) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazol-6-ol;

45) 3-(벤즈[d]옥사졸-2-일)-5-(1-메틸-1H-피라졸-4-일)피리딘-2-아민;45) 3- (benz [d] oxazol-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine;

46) 3-(벤즈[d]옥사졸-2일)-N-메틸-5-(1메틸-1H-피라졸-4-일)피리딘-2-아민;46) 3- (benz [d] oxazol-2yl) -N-methyl-5- (1methyl-1H-pyrazol-4-yl) pyridin-2-amine;

47) 3-(6-클로로벤즈[d]옥사졸-2-일)-5-(1-메틸-1H-피라졸-4-일)피리딘-2-아민;47) 3- (6-chlorobenz [d] oxazol-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine;

48) 3-(벤즈[d]옥사졸-2-일)-5-(1H-피라졸-4-일)피리딘-2-아민;48) 3- (benz [d] oxazol-2-yl) -5- (1H-pyrazol-4-yl) pyridin-2-amine;

49) 5-(1-메틸-1H-피라졸-4-일)-3-(옥사졸로[4,5-c]피리딘-2-일)피리딘-2-아민;49) 5- (1-methyl-1H-pyrazol-4-yl) -3- (oxazolo [4,5-c] pyridin-2-yl) pyridin-2-amine;

50) 3-(옥사졸로[4,5-c]피리딘-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;50) 3- (oxazolo [4,5-c] pyridin-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ;

51) 5-(1-메틸-1H-피라졸-4-일)- 3-(옥사졸로[4,5-c]피리딘-2-일)피리딘-2-아민; 또는51) 5- (1-methyl-1H-pyrazol-4-yl) -3 (oxazolo [4,5-c] pyridin-2-yl) pyridin-2-amine; or

52) 2-(5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸.52) 2- (5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole.

본 발명의 상기 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체는 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 약학적으로 허용가능한 염이란 표현은 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1의 염기 화합물의 이로운 효능을 떨어뜨리지 않는 화학식 1의 염기 화합물의 어떠한 유기 또는 무기 부가염을 의미한다. 이들 염은 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 질산, 황산, 과염소산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 젖산, 말레산, 푸마린산, 글루콘산, 메탄설폰산, 글리콘산, 숙신산, 타타르산, 갈룩투론산, 엠본산, 글루탐산, 아스파르트산, 옥살산, (D) 또는 (L) 말산, 메테인설폰산, 에테인설폰산, 4-톨루엔술폰산, 살리실산, 시트르산, 벤조산, 말론산 등을 사용할 수 있다. 또한, 이들 염은 알칼리 금속염(나트륨염, 칼륨염 등) 및 알칼리 토금속염(칼슘염, 마그네슘염 등) 등을 포함한다. 예를들면, 산부가염으로는 아세테이트, 아스파테이트, 벤즈에이트, 베실레이트, 바이카보네이트/카보네이트, 바이설페이트/설페이트, 보레이트, 캄실레이트, 시트레이트, 에디실레이트, 에실레이트, 포메이트, 퓨마레이트, 글루셉테이트, 글루코네이트, 글루큐로네이트, 헥사플루오로포스페이트, 하이벤제이트, 하이드로클로라이드/클로라이드, 하이드로브로마이드/브로마이드, 하이드로요오디드/요오디드, 이세티오네이트, 락테이트, 말레이트, 말리에이트, 말로네이트, 메실레이트, 메틸설페이트, 나프틸레이트, 2-나프실레이트, 니코티네이트, 나이트레이트, 오로테이트, 옥살레이트, 팔미테이트, 파모에이트, 포스페이트/수소 포스페이트/이수소 포스페이트, 사카레이트, 스테아레이트, 석시네이트, 타르트레이트, 토실레이트, 트리플루오로아세테이트, 알루미늄, 알기닌, 벤자틴, 칼슘, 콜린, 디에틸아민, 디올아민, 글라이신, 라이신, 마그네슘, 메글루민, 올아민, 칼륨, 나트륨, 트로메타민, 아연염 등이 포함될 수 있으며, 이들 중 하이드로클로라이드 또는 트리플루오로아세테이트가 바람직하다.The pyridine derivatives substituted with pyrazole and benzoxazole represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid moiety formed by a pharmaceutically acceptable free acid. Salting is useful. The expression pharmaceutically acceptable salt is a concentration that has a relatively nontoxic and harmless effect on the patient and that any side effects due to the salt do not degrade the beneficial efficacy of the base compound of formula 1, or Means inorganic addition salts. These salts may include inorganic acids and organic acids as free acids, hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, and the like, and citric acid, acetic acid, lactic acid, maleic acid, and fumarine as organic acids. Acids, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, tartaric acid, galluxuronic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, methanesulfonic acid, ethanesulfonic acid, 4 Toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, malonic acid and the like can be used. These salts also include alkali metal salts (sodium salts, potassium salts, and the like), alkaline earth metal salts (calcium salts, magnesium salts, and the like) and the like. For example, acid addition salts include acetates, aspartates, benzates, besylates, bicarbonates / carbonates, bisulfates / sulfates, borates, camsylates, citrates, edisylates, ecylates, formates, fumarates, Gluceptate, Gluconate, Glucuronate, Hexafluorophosphate, Hibenzate, Hydrochloride / Chloride, Hydrobromide / Bromide, Hydroiodide / Iodide, Isetionate, Lactate, Maleate, Mali Eate, malonate, mesylate, methylsulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccha Laterate, stearate, succinate, tartrate, tosylate, trifluoroacete , Aluminum, arginine, benzatin, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salts, and the like. Heavy hydrochloride or trifluoroacetate are preferred.

또한, 본 발명의 상기 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체는 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물 및 용매화물을 모두 포함한다.In addition, the pyridine derivatives substituted with pyrazole and benzoxazole represented by Formula 1 of the present invention include not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods. do.

본 발명에 따른 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 과량의 유기산을 가하거나 무기산의 산 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 이어서 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 in a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an inorganic acid. It can be prepared by adding an acidic aqueous solution of and then precipitating or crystallizing. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.

또한, 본 발명은 상기 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법을 제공한다. In another aspect, the present invention provides a method for preparing a pyridine derivative or a pharmaceutically acceptable salt thereof substituted with pyrazole and benzoxazole represented by the formula (1).

본 발명에 따른 상기 화학식 1의 화합물은 하기 반응식 1~6에 나타낸 바와 같은 방법으로 제조될 수 있다. The compound of Formula 1 according to the present invention may be prepared by the method as shown in Schemes 1-6.

이하, 상기 제조방법을 반응식을 이용하여 설명한다.Hereinafter, the above production method will be described using the reaction scheme.

제조방법 1Manufacturing Method 1

하기 반응식 1로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은 As represented by the following Scheme 1, the derivative of Formula 1 or a pharmaceutically acceptable salt thereof

출발물질인 화학식 2의 화합물을 브롬화반응시켜 화학식 3의 화합물을 제조하는 단계(단계 1);Preparing a compound of Chemical Formula 3 by bromination of a compound of Chemical Formula 2 as a starting material (Step 1);

상기 단계 1에서 제조된 화학식 3의 화합물을 염소화반응시켜 화학식 4의 화 합물을 제조하는 단계(단계 2);Preparing a compound of formula 4 by chlorination of the compound of formula 3 prepared in step 1 (step 2);

상기 단계 2에서 제조된 화학식 4의 화합물을 화학식 5의 화합물을 치환반응시켜 화학식 6의 화합물을 제조하는 단계(단계 3);Preparing a compound of formula 6 by replacing the compound of formula 4 with the compound of formula 5 prepared in step 2 (step 3);

상기 단계 3에서 제조된 화학식 6의 화합물을 고리화반응시켜 화학식 7의 화합물을 제조하는 단계(단계 4);Preparing a compound of formula 7 by cyclizing the compound of formula 6 prepared in step 3 (step 4);

상기 단계 4에서 제조된 화학식 7의 화합물과 아민화합물(R4NH2)을 치환반응시켜 화학식 8의 화합물을 제조하는 단계(단계 5);Preparing a compound of Chemical Formula 8 by performing a substitution reaction between the compound of Chemical Formula 7 and an amine compound (R 4 NH 2 ) prepared in Step 4 (Step 5);

상기 단계 5에서 제조된 화학식 8의 화합물과 화학식 9의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 10의 화합물을 제조하는 단계(단계 6); 및Preparing a compound of Formula 10 by performing a Suzuki coupling reaction between the compound of Formula 8 and the compound of Formula 9 prepared in Step 5 (Step 6); And

상기 단계 6에서 제조된 화학식 10의 화합물을 탈보호반응시켜 화학식 1a의 화합물을 제조하는 단계(단계 7)를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다.It may be prepared by a manufacturing method comprising the step (step 7) of preparing a compound of Formula 1a by the deprotection reaction of the compound of Formula 10 prepared in step 6.

Figure 112008025718184-pat00003
Figure 112008025718184-pat00003

(상기 반응식 1에서,(In Scheme 1,

R2, R4 및 A는 화학식 1에서 정의한 바와 같고, R4'는 수소 또는 R4이고, n은 1-3의 정수이고, 화학식 1a는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이며, NBS: N-브로모숙신이미드, NaOBr: 나트륨하이포브로마이드 PPTS: 파라톨루엔설폰산-피리딘 염, Pd(dppf)Cl2:1,1`-비스(디페닐포스피노)페로센디클로로 팔라듐, Pd(Ph3P)2Cl2: 비스트리페닐포스핀디클로로팔라듐, TFA: 트리플루오로아세트산, Boc: 3급-부톡시카보닐을 의미한다)R 2 , R 4 And A is as defined in Formula 1, R 4 ' is hydrogen or R 4 , n is an integer of 1-3, Formula 1a is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, NBS: N- Bromosuccinimide, NaOBr: sodium hypobromide PPTS: paratoluenesulfonic acid-pyridine salt, Pd (dppf) Cl 2 : 1,1′-bis (diphenylphosphino) ferrocenedichloro palladium, Pd (Ph 3 P) 2 Cl 2 : bistriphenylphosphinedichloropalladium, TFA: trifluoroacetic acid, Boc: tert-butoxycarbonyl)

제조방법 2Manufacturing Method 2

하기 반응식 2로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은As represented by Scheme 2 below, the derivative of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof

화학식 11의 화합물과 아민화합물(NH2R4 또는 NHR6R7)을 치환반응시켜 화학식 12의 화합물을 제조하는 단계(단계 1); 및Preparing a compound of Chemical Formula 12 by performing a substitution reaction between the compound of Chemical Formula 11 and an amine compound (NH 2 R 4 or NHR 6 R 7 ); And

상기 단계 1에서 제조된 화학식 12의 화합물을 탈보호반응시켜 화학식 1b의 화합물을 제조하는 단계(단계 2)를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다.Deprotection of the compound of Chemical Formula 12 prepared in Step 1 may be prepared by a manufacturing method comprising the step of preparing a compound of Chemical Formula 1b (Step 2).

Figure 112008025718184-pat00004
Figure 112008025718184-pat00004

(상기 반응식 2에서,(In Scheme 2,

R4, R6 및 R7은 화학식 1에서 정의한 바와 같고, R8은 -NHR4 또는 -NR6R7이고, n은 1-3의 정수이며, 화학식 1b는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이다)R 4 , R 6 and R 7 are as defined in Formula 1, R 8 is -NHR 4 or -NR 6 R 7 , n is an integer of 1-3, Formula 1b is a derivative of Formula 1 or a pharmaceutical thereof Is an acceptable salt)

제조방법 3Manufacturing Method 3

하기 반응식 3으로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은As represented by Scheme 3 below, the derivative of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof

화학식 11의 화합물을 염기성 처리시켜 화학식 13의 화합물을 제조하는 단계(단계 1);Basic treating the compound of Formula 11 to prepare a compound of Formula 13 (step 1);

상기 단계 1에서 제조된 화학식 13을 알킬화반응시켜 화학식 14의 화합물을 제조하는 단계(단계 2); 및Preparing a compound of Chemical Formula 14 by alkylating the Chemical Formula 13 prepared in Step 1 (Step 2); And

상기 단계 2에서 제조된 화학식 14의 화합물을 탈보호반응시켜 화학식 1c의 화합물을 제조하는 단계(단계 3)를 포함하여 이루어지거나 또는Or deprotecting the compound of Formula 14 prepared in Step 2 to prepare a compound of Formula 1c (Step 3), or

상기 단계 1에서 제조된 화학식 13의 화합물을 탈보호반응시켜 화학식 1d의 화합물을 제조하는 단계(단계 4)를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다.Deprotection of the compound of Chemical Formula 13 prepared in Step 1 may be prepared by a preparation method comprising the step of preparing a compound of Chemical Formula 1d (Step 4).

Figure 112008025718184-pat00005
Figure 112008025718184-pat00005

(상기 반응식 3에서,(In Scheme 3,

R5 및 R6는 화학식 1에서 정의한 바와 같고, X는 할로겐이고, n은 1-3의 정수이고, R9은 -R5 또는 -SO2R6이며, 화학식 1c 및 1d는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이다)R 5 and R 6 are as defined in Formula 1, X is halogen, n is an integer of 1-3, R 9 is -R 5 or -SO 2 R 6 , Formula 1c and 1d are derivatives of Formula 1 Or a pharmaceutically acceptable salt thereof)

제조방법 4Manufacturing Method 4

하기 반응식 4로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은As represented by Scheme 4 below, the derivative of Formula 1 or a pharmaceutically acceptable salt thereof

화학식 8의 화합물과 화학식 15의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 16의 화합물을 제조하는 단계(단계 1); 및Preparing a compound of Formula 16 by performing a Suzuki coupling reaction between a compound of Formula 8 and a compound of Formula 15 (step 1); And

상기 단계 1에서 제조된 화학식 16의 화합물을 탈보호반응시켜 화학식 1e의 화합물을 제조하는 단계(단계 2)를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다.It may be prepared by a manufacturing method comprising the step (step 2) of preparing a compound of Formula 1e by deprotection reaction of the compound of Formula 16 prepared in Step 1.

Figure 112008025718184-pat00006
Figure 112008025718184-pat00006

(상기 반응식 4에서,(In Scheme 4,

R2, R3, R4 및 A는 화학식 1에서 정의한 바와 같고, R4'는 수소 또는 R4이고, n은 1-3의 정수이고, 화학식 1e는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이며, A는 탄소 또는 질소이다)R 2 , R 3 , R 4 And A is as defined in Formula 1, R 4 ' is hydrogen or R 4 , n is an integer of 1-3, Formula 1e is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, and A is carbon or Nitrogen)

제조방법 5Manufacturing Method 5

하기 반응식 5로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은As represented by Scheme 5, the derivative of Formula 1 or a pharmaceutically acceptable salt thereof

출발물질인 화학식 17의 화합물을 염소화반응시켜 화학식 18의 화합물을 제 조하는 단계(단계 1);Preparing a compound of Chemical Formula 18 by chlorination of a compound of Chemical Formula 17 as a starting material (Step 1);

상기 단계 1에서 제조된 화학식 18의 화합물과 화학식 5의 화합물을 치환반응시켜 화학식 19의 화합물을 제조하는 단계(단계 2);Preparing a compound of Formula 19 by performing a substitution reaction of the compound of Formula 18 and the compound of Formula 5 prepared in Step 1 (step 2);

상기 단계 2에서 제조된 화학식 19의 화합물을 고리화반응시켜 화학식 20의 화합물을 제조하는 단계(단계 3);Preparing a compound of formula 20 by cyclization of the compound of formula 19 prepared in step 2 (step 3);

상기 단계 3에서 제조된 화학식 20의 화합물과 화학식 9의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 21의 화합물을 제조하는 단계(단계 4); 및Preparing a compound of Formula 21 by performing a Suzuki coupling reaction between the compound of Formula 20 and the compound of Formula 9 prepared in Step 3 (Step 4); And

상기 단계 4에서 제조된 화학식 21의 화합물을 탈보호반응시켜 화학식 1f의 화합물을 제조하는 단계(단계 5)를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다.Deprotection of the compound of Chemical Formula 21 prepared in Step 4 may be prepared by a manufacturing method comprising the step of preparing a compound of Chemical Formula 1f (Step 5).

Figure 112008025718184-pat00007
Figure 112008025718184-pat00007

(상기 반응식 5에서,(In Scheme 5,

R2 및 A는 화학식 1에서 정의한 바와 같고, n은 1-3의 정수이고, 화학식 1f는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이다)R 2 And A is as defined in Formula 1, n is an integer of 1-3 and Formula 1f is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof)

제조방법 6Manufacturing Method 6

하기 반응식 6으로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은As represented by Scheme 6, the derivative of Formula 1 or a pharmaceutically acceptable salt thereof

화학식 22의 화합물과 화학식 15의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 1g의 화합물을 제조하는 단계를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다.The compound of Formula 22 and the compound of Formula 15 may be prepared by a preparation method comprising the step of preparing a compound of Formula 1g by performing a Suzuki coupling reaction.

Figure 112008025718184-pat00008
Figure 112008025718184-pat00008

(상기 반응식 6에서,(In Scheme 6,

R2, R3 및 A는 화학식 1에서 정의한 바와 같고, 화학식 1g는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이다)R 2 , R 3 And A is as defined in Formula 1, where Formula 1g is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof)

또한, 본 발명은 상기 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for the prevention and treatment of aberrant cell growth diseases containing a pyridine derivative substituted with pyrazole and benzoxazole represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. .

이때, 상기 이상세포 성장 질환은 폐암, 뼈암, 췌장암, 피부암, 두경부암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 항문 주위 암, 위암, 결장암, 유방암, 자궁암, 나팔관 암, 자궁내막 암, 자궁경부암, 질암, 외음부암, 호지킨병, 식도암, 소장암, 내분비계암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신세포암, 신우암, 중추 신경계(CNS) 종양, 1차 CNS 림프종, 척수 종양, 뇌간 신경교종, 뇌하수체 선종 등이 바람직하다. At this time, the abnormal cell growth disease is lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, perianal cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrium Cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocyte lymphoma, Bladder cancer, kidney or ureter cancer, renal cell cancer, renal cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, and the like are preferred.

또한, 상기 이상세포 성장 질환은 건선, 양성 전립선 비대 또는 망막증인 것이 바람직하다.In addition, the abnormal cell growth disease is preferably psoriasis, benign prostatic hypertrophy or retinopathy.

나아가, 상기 이상세포 성장 질환은 양성 증식성 질환인 것이 바람직하며, 상기 양성 증식성 질환은 섬유선종, 경화성 선질환, 유두종 등이 바람직하다. Further, the abnormal cell growth disease is preferably a benign proliferative disease, the benign proliferative disease is preferably fibroadenoma, sclerotic gland disease, papilloma and the like.

상기 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염, 용매화물 및 수화물은 c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, Aurora-A 등의 단백질 키나아제를 억제할 수 있다. Pyridine derivatives or pharmaceutically acceptable salts, solvates and hydrates thereof substituted with pyrazole and benzoxazole represented by Formula 1 are c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, protein kinases such as b-Raf and Aurora-A can be inhibited.

상기 단백질 키나아제 중 c-Met은 항암제 타겟으로 연구되고 있는 간세포 성장인자(HGF/SF) 수용체로서, 이를 타겟으로 하는 항암제가 많이 보고되어 있다(J. G. Christensen, J. Burrows et al., Cancer Letters, 2005, 225, 1-26; WO 2004/076412; WO 2006/021881 A; WO 2006/021886; WO 2007/064797). Among the protein kinases, c-Met is a hepatocyte growth factor (HGF / SF) receptor that is being studied as an anticancer agent, and many anticancer agents targeting it have been reported (JG Christensen, J. Burrows et al., Cancer Letters, 2005). , 225, 1-26; WO 2004/076412; WO 2006/021881 A; WO 2006/021886; WO 2007/064797).

c-Met은 종양 형성, 증대된 세포 운동성 및 침입성 하에서의 종양 진행, 및 전이에 수반되는 폐암, 위암, 피부암, 신장암, 직장암, 췌장암 등의 많은 인간 암에서 과발현 또는 활성화되어 있다(J. G. Christensen et al., Cancer Letters, 2005, 225, 1-26; W. G. Jiang et al., Critical Reviews in Oncology/Hematology, 2005, 53, 35-69). c-MET 및 이의 리간드인 HGF는 많은 조직에서 발현되지만, 정 상적으로는 주로 상피 및 간엽 기원의 세포 각각으로 한정되어 발현된다. c-MET 및 HGF/SF는 정상적인 포유동물의 발육에 필요하며, 세포 전이, 세포 증식 및 생존, 형태 형성성 분화 및 3-차원적 관상 구조물(신 세뇨관 세포, 선 형성 등)의 조직화에서 중요한 것으로 밝혀졌다. HGF/SF는 신생혈관생성 인자이며, 상피 세포에서의 c-MET 신호전달은 신생혈관생성에 필수적인 세포 반응(증식, 운동성, 침입성 등)을 유도한다. c-Met is overexpressed or activated in many human cancers, including lung cancer, gastric cancer, skin cancer, kidney cancer, rectal cancer, and pancreatic cancer, accompanied by tumor formation, increased cell motility and invasive tumor progression, and metastasis (JG Christensen et. al., Cancer Letters, 2005, 225, 1-26; WG Jiang et al., Critical Reviews in Oncology / Hematology, 2005, 53, 35-69). c-MET and its ligand, HGF, are expressed in many tissues, but are normally expressed mainly limited to cells of epithelial and mesenchymal origin, respectively. c-MET and HGF / SF are necessary for the development of normal mammals and are important for cell metastasis, cell proliferation and survival, morphogenic differentiation and organization of three-dimensional coronary structures (neotubule cells, glandogenesis, etc.). Turned out. HGF / SF is an angiogenesis factor and c-MET signaling in epithelial cells induces cellular responses (proliferation, motility, invasiveness, etc.) that are essential for angiogenesis.

또한 c-Met 및 이의 리간드인 HGF는 다양한 인간 암에서 증가된 수준으로 공-발현되는 것으로 밝혀졌다. 그러나, 수용체 및 리간드는 통상적으로 상이한 세포 유형에 의해 발현되기 때문에, c-Met 신호전달은 대부분 보편적으로 종양-기질(tumor-stroma) 상호작용에 의해 조절된다.It has also been found that c-Met and its ligand, HGF, are co-expressed at increased levels in various human cancers. However, because receptors and ligands are usually expressed by different cell types, c-Met signaling is most commonly regulated by tumor-stroma interactions.

또한, c-Met은 유전자 증폭, 돌연변이 및 재배열이 다양한 인간 암에서 관찰되었다. c-Met 키나아제를 활성화시키는 생식계 돌연변이를 갖는 부류는 다중 신장 종양 및 다른 조직의 종양에 걸리기 쉽다.In addition, c-Met has been observed in various human cancers with gene amplification, mutations and rearrangements. Classes with germline mutations that activate c-Met kinase are susceptible to multiple kidney tumors and tumors of other tissues.

c-Met 및/또는 HGF/SF의 발현은 상이한 유형의 암(폐, 결장, 유방, 전립선, 간, 췌장, 뇌, 신장, 난소, 위, 피부, 뼈 등의 암)의 질환 진행 상태와 연관되어 있으며, c-Met 또는 HGF/SF의 과발현은 폐, 간, 위 및 유방을 포함한 많은 주요 인간 암에서 나쁜 예후 및 질환 결과와 상관되는 것으로 밝혀졌다. 또한, c-Met은 췌장암, 신경교종 및 간세포암과 같은 성공적인 치료법이 없는 암에 직접 관련되어 있다고 보고되었으며, c-Met이 과발현되면서 ERBB3 신호전달체계 활성화로 야기된 폐암이 게피티니브(Gefitinib; 이레사(상품명:Irresa))에 내성을 갖게 된다고 보고되었다 (J. A. Engelman, K. Zejnullahu et. al. Science, 2007, 316, 1039-043).Expression of c-Met and / or HGF / SF is associated with disease progression in different types of cancer (lungs, colon, breast, prostate, liver, pancreas, brain, kidney, ovary, stomach, skin, bone, etc.) Overexpression of c-Met or HGF / SF has been found to correlate with poor prognosis and disease outcome in many major human cancers including lung, liver, stomach and breast. In addition, c-Met has been reported to be directly related to cancers without successful treatment such as pancreatic cancer, glioma and hepatocellular carcinoma, and lung cancer caused by ERBB3 signaling system activation due to overexpression of c-Met is Gefitinib (Gefitinib; It has been reported to be resistant to Irresa (JA Engelman, K. Zejnullahu et. Al. Science, 2007, 316, 1039-043).

본 발명에 따른 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은 c-Met 키나아제 활성 실험에서 IC50가 20 μM 이하의 c-Met 키나아제 저해 활성을 갖는 결과를 나타내었다.The derivative of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof showed the result that the IC 50 had a c-Met kinase inhibitory activity of 20 μM or less in the c-Met kinase activity experiment.

또한, 본 발명에 따른 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은 암세포 증식억제 실험에서 GI50가 HT-29, A549 및 SK-MEL-28에 대해서 100 μM 이하의 암세포 증식억제 활성을 갖는 결과를 나타내었다. In addition, the derivative of Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof has GI 50 having a cancer cell proliferation inhibitory activity of 100 μM or less against HT-29, A549 and SK-MEL-28 in cancer cell proliferation experiments. The results are shown.

따라서, 본 발명에 따른 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 또는 이의 약학적인 염을 유효성분으로 함유하는 약학적 조성물은 c-Met의 발현으로부터 유도되는 상술한 각종 암을 치료하는데 유용하게 사용될 수 있다. Therefore, the pharmaceutical composition containing pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutical salts thereof according to the present invention as an active ingredient can be usefully used to treat various cancers described above derived from the expression of c-Met. have.

본 발명의 화합물은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있으며, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다. The compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. Are manufactured.

경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 하나 이상의 본 발명의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose) 또는 락토오 스(lactose) 또는 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.

비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

또한, 본 발명의 화합물의 인체에 대한 효과적인 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 일반적으로 약 0.001-100 mg/kg/일이며, 바람직하게는 0.01-35 mg/kg/일이다. 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.07-7000 mg/일이며, 바람직하게는 0.7-2500 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.In addition, the effective 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 is generally about 0.001-100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals according to the judgment of the doctor or pharmacist. Multiple doses may be administered.

이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기의 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기의 실시예에 의해 한정되는 것은 아니다. Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.

하기 실시예에서, "Et"는 에틸을 의미하고, "Me"는 메틸을 의미하고, "t-Bu"는 3급-부틸을 의미하고, "Boc"는 3급-부톡시카보닐을 의미하고, "EtOAc"는 에틸 아세테이트를 의미하고, "NEt3" 또는 "Et3N"은 트리에틸아민을 의미하고, "Et2O"는 디에틸에테르를 의미하고, "MeOH"는 메탄올을 의미하고, "DMSO"는 디메틸설폭사이드를 의미하고, "CDCl3"는 중수소화 클로로폼을 의미하고, "CH2Cl2"는 메틸렌클로라이드(이염화탄소)를 의미하고, "DMF"는 디메틸 폼아마이드를 의미하고, "SOCl2"는 티오닐클로라이드를 의미하고, "MsCl"는 메탄설포닐클로라이드를 의미하고, "PPTS"는 파라톨루엔설폰산-피리딘 염을 의미하고, "TFA"는 트리플루오로아세트산을 의미하고, "X-Phos"는 2-디사이클로헥실포스피노-2',4',6'-트리아이소프로필바이페닐을 의미하고, "t-Butyl X-Phos"는 2-디-3급-부틸포스피노-2',4',6'-트리아이소프로필바이페닐을 의미하고, "Pd(Ph3P)2Cl2"는 비스트리페닐포스핀디클로로팔라듐을 의미하고, "Pd2(dba)3"는 트리스(디벤질리딘아세톤)디팔라듐을 의미하고, "Pd(dppf)Cl2"는 1,1'-비스(디페닐포스피노페로센)디클로팔라듐을 의미하고, "t-BuONa"는 나트륨3급-부톡사이드를 의미하고, "Na2CO3"는 탄산나트륨를 의미하고, "K2CO3"는 탄산칼륨을 의미하고, "KI"는 요오드화칼륨을 의미하고, "MgSO4"는 황산마그네슘을 의미하고, "KOH"는 수산화칼륨을 의미한다.In the examples below, "Et" means ethyl, "Me" means methyl, " t -Bu" means tert-butyl, and "Boc" means tert-butoxycarbonyl "EtOAc" means ethyl acetate, "NEt 3 " or "Et 3 N" means triethylamine, "Et 2 O" means diethyl ether, and "MeOH" means methanol "DMSO" means dimethylsulfoxide, "CDCl 3 " means deuterated chloroform, "CH 2 Cl 2 " means methylene chloride (carbon dichloride), and "DMF" means dimethyl formamide "SOCl 2 " means thionylchloride, "MsCl" means methanesulfonylchloride, "PPTS" means paratoluenesulfonic acid-pyridine salt, and "TFA" means trifluoro Acetic acid, "X-Phos" means 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, and " t- Butyl X-Phos" means 2-di- Tert-butyl Phosphino-2 ', 4', 6'-triisopropylbiphenyl;"Pd (Ph 3 P) 2 Cl 2 " means bistriphenylphosphinedichloropalladium, "Pd 2 (dba) 3 "means tris (dibenzylidineacetone) dipalladium," Pd (dppf) Cl 2 "means 1,1'-bis (diphenylphosphinoferrocene) dichloropalladium and" t -BuONa " Means sodium tert-butoxide, “Na 2 CO 3 ” means sodium carbonate, “K 2 CO 3 ” means potassium carbonate, “KI” means potassium iodide, and “MgSO 4 ” Magnesium sulfate, and "KOH" means potassium hydroxide.

<< 실시예Example 1> 3-(5- 1> 3- (5- 클로로벤즈[d]옥사졸Chlorobenz [d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피라Fira 졸-4-일)피리딘-2-아민의 Of zol-4-yl) pyridin-2-amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

단계 1: 5-Step 1: 5- 브로모Bromo -2-옥소-1,2-디2-oxo-1,2-di 하이드로피리딘Hydropyridine -3--3- 카복실산의Carboxylic acid 제조 Produce

Figure 112008025718184-pat00009
Figure 112008025718184-pat00009

2-옥소-1,2-디하이드로피리딘-3-카르복실산으로부터 참조문헌에 나와 있는 방법으로 목적화합물(5-브로모-2-옥소-1,2-디하이드로피리딘-3-카복실산)을 얻었다(참조문헌: A. D. Cale, Jr., T. W. Gero et. al. J. Med. Chem. 1989, 32, 2178-2199; 미국특허 등록번호 5,034,531). From the 2-oxo-1,2-dihydropyridine-3-carboxylic acid, the target compound (5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid) was prepared by the method described in the reference. Obtained by reference (AD Cale, Jr., TW Gero et. Al. J. Med. Chem. 1989, 32, 2178-2199; US Pat. No. 5,034,531).

단계 2: 5-Step 2: 5- 브로모Bromo -2--2- 클로로니코티노일Chloronicotinoyl 클로라이드의 제조 Preparation of Chloride

Figure 112008025718184-pat00010
Figure 112008025718184-pat00010

반응용기에 5-브로모-2-옥소-1,2-디하이드로피리딘-3-카복실산(20.0 g, 91.7 mmol), 티오닐클로라이드(SOCl2, 91.7 mL)와 DMF(1.4 mL)를 차례로 넣은 후, 70-80 ℃에서 4시간 동안 교반하였다. 반응물의 온도를 실온으로 낮추고 반응물을 감압농축하여 주황색 고체의 목적화합물(5-브로모-2-클로로니코티노일 클로라이드)을 얻었다(22.7 g 97%). 상기 화합물을 더 이상의 정제 없이 다음 반응에 사용하였 다.To the reaction vessel, 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (20.0 g, 91.7 mmol), thionyl chloride (SOCl 2 , 91.7 mL) and DMF (1.4 mL) were added sequentially. Then stirred at 70-80 ° C. for 4 h. The temperature of the reaction was lowered to room temperature and the reaction was concentrated under reduced pressure to obtain the target compound (5-bromo-2-chloronicotinoyl chloride) as an orange solid (22.7 g 97%). The compound was used for the next reaction without further purification.

단계 3: 5-Step 3: 5- 브로모Bromo -2--2- 클로로Chloro -N-(5--N- (5- 클로로Chloro -2--2- 하이드록시페닐Hydroxyphenyl )) 니코틴아마이드의Nicotinamide 제조 Produce

Figure 112008025718184-pat00011
Figure 112008025718184-pat00011

2-아미노-4-클로로페놀(14.5 g)과 트리에틸아민(12.8 mL)이 용해되어 있는 메틸렌클로라이드 용액에 5-브로모-2-클로로니코티노일 클로라이드(22.7 g, 89.1 mmol)를 얼음중탕을 이용하여 0 ℃에서 천천히 넣었다. 반응물의 온도를 실온으로 높이고 질소분위기 하에서 2시간 동안 교반하였다. 반응물을 물에 넣고 30분 동안 교반한 후 유기층을 분리하고, 수층을 메틸렌클로라이드를 이용하여 추출하였다. 혼합한 유기층을 무수 황산마그네슘을 이용하여 건조시키고, 감압농축하였다. 상기 농축물에 에틸에테르를 넣고 30분 동안 교반한 후, 여과하여 갈색 고체의 목적화합물(5-브로모-2-클로로-N-(5-클로로-2-하이드록시페닐)니코틴아마이드)을 얻었다(16.5 g, 51%). 상기 화합물은 더 이상의 정제 없이 다음 반응에 사용하였다.5-bromo-2-chloronicotinoyl chloride (22.7 g, 89.1 mmol) was immersed in a methylene chloride solution containing 2-amino-4-chlorophenol (14.5 g) and triethylamine (12.8 mL). Was slowly added at 0 ° C. The temperature of the reaction was raised to room temperature and stirred for 2 hours under nitrogen atmosphere. The reaction was poured into water, stirred for 30 minutes, the organic layer was separated, and the aqueous layer was extracted with methylene chloride. The mixed organic layer was dried using anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl ether was added to the concentrate, followed by stirring for 30 minutes, followed by filtration to obtain the title compound (5-bromo-2-chloro-N- (5-chloro-2-hydroxyphenyl) nicotinamide) as a brown solid. (16.5 g, 51%). The compound was used for the next reaction without further purification.

단계 4: 2-(5-Step 4: 2- (5- 브로모Bromo -2--2- 클로로피리딘Chloropyridine -3-일)-5--3-yl) -5- 클로로벤즈[d]옥사졸의Of chlorobenz [d] oxazole 제조 Produce

Figure 112008025718184-pat00012
Figure 112008025718184-pat00012

반응용기에 5-브로모-2-클로로-N-(5-클로로-2-하이드록시페닐)니코틴아미드(16.5 g), 파라톨루엔설폰산 피리딘염(2.9 g) 및 크실렌(xylene, 228 mL)을 넣고, 150~170 ℃에서 24시간 동안 교반하였다. 반응물의 온도를 약 100 ℃ 로 낮추고 반응 중 생성된 타르가 흘러나오지 않게 반응물을 여과하고, 뜨거운 크실렌으로 생성된 타르를 여러 번 씻고 여과하였다. 여액을 감압농축하고, 에틸에테르에 농축물을 넣고 30분 동안 교반하였다. 에틸에테르에 용해되지 않은 고체를 여과하고, 차가운 에틸아세테이트로 씻어 준 후 건조하여 갈색 고체의 목적화합물(2-(5-브로모-2-클로로피리딘-3-일)-5-클로로벤즈[d]옥사졸)을 얻었다(7.2 g, 45%).5-bromo-2-chloro-N- (5-chloro-2-hydroxyphenyl) nicotinamide (16.5 g), paratoluenesulfonic acid pyridine salt (2.9 g) and xylene (xylene, 228 mL) in the reaction vessel Was added and stirred for 24 hours at 150 ~ 170 ℃. The temperature of the reaction was lowered to about 100 ° C. and the reaction was filtered so that no tar was generated during the reaction, and the tar generated with hot xylene was washed several times and filtered. The filtrate was concentrated under reduced pressure, the concentrate was added to ethyl ether and stirred for 30 minutes. The solid which was not dissolved in ethyl ether was filtered, washed with cold ethyl acetate and dried to give the title compound as a brown solid (2- (5-bromo-2-chloropyridin-3-yl) -5-chlorobenz [d ] Oxazole) was obtained (7.2 g, 45%).

1H NMR (300 MHz, CDCl3) 8.66-8.62 (m, 2H), 7.85 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.44 (dd, J = 8.7, 2.1 Hz, 1H). 1 H NMR (300 MHz, CDCl 3 ) 8.66-8.62 (m, 2H), 7.85 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.44 (dd, J = 8.7 , 2.1 Hz, 1H).

단계 5: 5-Step 5: 5- 브로모Bromo -N-3급-N-3 class 부틸Butyl -3-(5--3- (5- 클로로벤즈[d]옥사졸Chlorobenz [d] oxazole -2-일)피리딘-2--2-yl) pyridine-2- 아민Amine 의 제조Manufacture

Figure 112008025718184-pat00013
Figure 112008025718184-pat00013

고압반응용기(sealed tube)에 2-(5-브로모-2-클로로피리딘-3-일)-5-클로로벤즈[d]옥사졸(8.1 g), 3급 부틸아민(50.4 mL) 및 디메틸폼아마이드(60 mL)를 넣고 마개를 막아 밀봉하였다. 반응물을 50-70 ℃에서 65시간 동안 교반한 후 감압농축하였다. 고체 농축물에 에틸에테르를 넣고 40-50 ℃에서 30분 동안 교반한 후, 얼음 중탕을 이용하여 냉각시켰다. 생성된 고체를 여과하고 차가운 에틸에테르로 씻어주어 등황색 고체의 목적화합물(5-브로모-N-3급-부틸-3-(5-클로로벤즈[d]옥사졸-2-일)피리딘-2-아민)을 얻었다(5.2 g, 57%).2- (5-bromo-2-chloropyridin-3-yl) -5-chlorobenz [d] oxazole (8.1 g), tert-butylamine (50.4 mL) and dimethyl in a sealed tube Foamamide (60 mL) was added and the plug was sealed. The reaction was stirred at 50-70 ° C. for 65 hours and then concentrated under reduced pressure. Ethyl ether was added to the solid concentrate, stirred at 40-50 ° C. for 30 minutes, and then cooled using an ice bath. The resulting solid was filtered and washed with cold ethyl ether to give the title compound (5-bromo-N-tert-butyl-3- (5-chlorobenz [d] oxazol-2-yl) pyridine-2 as an orange solid. -Amine) was obtained (5.2 g, 57%).

1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 7.72 (s, 1H), 7.47 (d, J= 8.7 Hz, 1H), 7.33 (d, J= 8.4 Hz, 1H), 1.57 (s, 9H); GC-MS (EI) m/z calcd for C16H15NBrClN3O(M+) 381.0, 379.0, found 380.9. 1 H NMR (300 MHz, CDCl 3 ) δ 8.64 (s, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 7.72 (s, 1H), 7.47 (d, J = 8.7 Hz, 1H) , 7.33 (d, J = 8.4 Hz, 1H), 1.57 (s, 9H); GC-MS (EI) m / z calcd for C 16 H 15 NBrClN 3 O (M + ) 381.0, 379.0, found 380.9.

단계 6: 3급-Step 6: Level 3 부틸Butyl 4-(4-(6-(3급- 4- (4- (6- (tertiary- 부틸아미노Butylamino )-5-(5-) -5- (5- 클로로벤즈[d]옥사졸Chlorobenz [d] oxazole -2-일)피리딘-3-일)-1H--2-yl) pyridin-3-yl) -1H- 피라졸Pyrazole -1-일)피페리딘-1--1-yl) piperidine-1- 카복실레이트의Carboxylate 제조 Produce

Figure 112008025718184-pat00014
Figure 112008025718184-pat00014

반응용기에 5-브로모-N-3급-부틸-3-(5-클로로벤즈[d]옥사졸-2-일)피리딘-2-아민(3.5 g, 9.3 mmol), 3급-부틸 4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-피라졸-1-일)-피페리딘-1-카복실레이트(4.6 g), Pd(Ph3P)2Cl2(330 mg) 및 1,4-디옥산(30 mL)을 넣고 질소분위기 및 실온에서 30분 동안 교반하였다. 반응물에 1 M 탄산나트륨 수용액(27.9 mL)을 넣고 2시간 동안 110 ℃에서 교반하였다. 실온으로 냉각한 후 반응물을 셀라이트를 이용하여 여과하고 여액을 농축하였다. 농축물에 물을 넣어 주고 메틸렌클로라이드로 여러 번 추출하였다. 혼합한 유층을 황산마그네슘으로 건조하고 감압농축하였다. 농축물에 에틸에테르를 넣고 10분 동안 교반하고 여과하여 초록색 고체의 목적화합물(3급-부틸-4-(4-(6-(3급-부틸아미노)-5-(5-클로로벤즈[d]옥사졸-2-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트)을 얻었다(4.3 g, 84%). 5-bromo-N-tert-butyl-3- (5-chlorobenz [d] oxazol-2-yl) pyridin-2-amine (3.5 g, 9.3 mmol), tert-butyl 4 -(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) -piperidine-1-carboxylate (4.6 g), Pd (Ph 3 P) 2 Cl 2 (330 mg) and 1,4-dioxane (30 mL) were added thereto, and the mixture was stirred for 30 minutes at a nitrogen atmosphere and room temperature. 1 M aqueous sodium carbonate solution (27.9 mL) was added to the reaction and the mixture was stirred at 110 ° C. for 2 hours. After cooling to room temperature the reaction was filtered through celite and the filtrate was concentrated. Water was added to the concentrate and extracted several times with methylene chloride. The mixed oil layer was dried over magnesium sulfate and concentrated under reduced pressure. Ethyl ether was added to the concentrate, followed by stirring for 10 minutes, followed by filtration to give the title compound as a green solid (tert-butyl-4- (4- (6- (tert-butylamino) -5- (5-chlorobenz [d] ] Oxazol-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate) was obtained (4.3 g, 84%).

1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 8.45 (d, J= 2.5 Hz, 1H), 8.30 (d, J= 2.5 Hz, 1H), 7.77(s, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.48 (d, J= 8.6 Hz, 1H), 7.32 (dd, J= 8.6, 2.0 Hz, 1H), 4.35-4.26 (m, 3H), 2.92 (t, J= 12.1 Hz, 2H), 2.20-2.17 (m, 2H), 2.05-1.90 (m, 2H), 1.60 (d, J= 3.7 Hz, 9H), 1.48 (s, 9H) ; GC-MS (EI) m/z calcd for C29H35ClN6O3 (M+) 550.3, found 550.2. 1 H NMR (300 MHz, CDCl 3 ) δ 8.63 (s, 1H), 8.45 (d, J = 2.5 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 7.77 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.32 (dd, J = 8.6, 2.0 Hz, 1H), 4.35-4.26 (m, 3H), 2.92 (t, J = 12.1 Hz, 2H), 2.20-2.17 (m, 2H), 2.05-1.90 (m, 2H), 1.60 (d, J = 3.7 Hz, 9H), 1.48 (s, 9H); GC-MS (EI) m / z calcd for C 29 H 35 ClN 6 O 3 (M + ) 550.3, found 550.2.

여기서 사용된 3급-부틸 4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-피라졸-1-일)-피페리딘-1-카복실레이트는 참고문헌에 나와 있는 방법으로 제조하였다(참고문헌: WO 2006/021881).Tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl)-as used herein- Piperidine-1-carboxylate was prepared by the method described in the reference (WO 2006/021881).

Figure 112008025718184-pat00015
Figure 112008025718184-pat00015

단계 7: 3-(5-Step 7: 3- (5- 클로로벤즈[d]옥사졸Chlorobenz [d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00016
Figure 112008025718184-pat00016

3급-부틸-4-(4-(6-(3급-부틸아미노)-5-(5-클로로벤즈[d]옥사졸-2-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트(1.5 g, 2.7 mmol) 및 트리플루오로아세트산(10 mL) 반응물을 60 ℃에서 24시간 동안 교반하였다. 반응물의 온도를 실온으로 낮추고 감압농축하였다. 농축물에 에틸에테르를 넣고 30분 동안 교반한 후 여과하여 연두색 고체의 목적화합물(3-(5-클로로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(1.8 g, 85%).Tert-butyl-4- (4- (6- (tert-butylamino) -5- (5-chlorobenz [d] oxazol-2-yl) -1H-pyrazol-1-yl) piperi Dean-1 -carboxylate (1.5 g, 2.7 mmol) and trifluoroacetic acid (10 mL) were stirred for 24 hours at 60 ° C. The temperature of the reaction was lowered to room temperature and concentrated under reduced pressure. The mixture was stirred for 30 minutes, and then filtered to give the title compound as a light green solid (3- (5-chlorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- Ditrifluoroacetic acid salt of pyrazol-4-yl) pyridin-2-amine) (1.8 g, 85%).

1H NMR (300 MHz, CD3OD) δ 8.78 (d, J= 1.8 Hz, 1H), 8.41 (d, J= 2.1 Hz, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.86 (d, J= 1.5 Hz, 1H), 7.72 (d, J= 8.7 Hz, 1H), 7.49 (dd, J= 8.7, 1.8 Hz, 1H), 4.64-4.56 (m, 1H), 3.62-3.57 (m, 2H), 3.24-3.21 (m, 2H), 2.36-2.26 (m, 4H) ; GC-MS (EI) m/z calcd for C20H19ClN6O(M+) 394.1, found 394.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.78 (d, J = 1.8 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.49 (dd, J = 8.7, 1.8 Hz, 1H), 4.64-4.56 (m, 1H), 3.62-3.57 (m, 2H), 3.24-3.21 (m, 2H), 2.36-2.26 (m, 4H); GC-MS (EI) m / z calcd for C 20 H 19 ClN 6 O (M + ) 394.1, found 394.1.

<< 실시예Example 2> 3-( 2> 3- ( 벤즈[d]옥사졸Mercedes-Benz [d] oxazole -2일)-N--2 days) -N- 메틸methyl -5-(1-(피페리딘-4-일)-1H--5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00017
Figure 112008025718184-pat00017

실시예 1에서 사용한 t-부틸아민과 2-아미노-4-클로로페놀 대신 메틸아민과 2-아미노페놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 7과 동일한 방법으로 수행하여 연두색 고체의 목적화합물(3-(벤즈[d]옥사졸-2일)-N-메틸-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(38.8 mg, 65%). Except for using t-butylamine and 2-amino-4-chlorophenol used in Example 1, except that methylamine and 2-aminophenol were used in the same manner as in Step 1 to Step 7 of Example 1 Target compound (3- (benz [d] oxazol-2yl) -N-methyl-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine Ditrifluoroacetic acid salt) was obtained (38.8 mg, 65%).

1H NMR (300 MHz, CD3OD) δ 8.73 (d, J= 1.9 Hz, 1H), 8.33 (d, J= 1.9 Hz, 1H), 8.18 (s, 1H), 7.94 (s, 1H), 7.78 (d, J= 8.1 Hz, 1H), 7.66 (d, J= 7.4 Hz, 1H), 7.44-7.40 (m, 2H), 4.57-4.52 (m, 1H), 3.56-3.52 (m, 2H), 3.31-3.15 (m, 5H), 2.31-2.24 (m, 4H); GC-MS (EI) m/z calcd for C21H22N6O(M+) 374.2, found 374.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.73 (d, J = 1.9 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.18 (s, 1H), 7.94 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.44-7.40 (m, 2H), 4.57-4.52 (m, 1H), 3.56-3.52 (m, 2H) , 3.31-3.15 (m, 5H), 2.31-2.24 (m, 4H); GC-MS (EI) m / z calcd for C 21 H 22 N 6 O (M + ) 374.2, found 374.1.

<< 실시예Example 3> 3-( 3> 3- ( 벤즈[d]옥사졸Mercedes-Benz [d] oxazole -2일)-N-벤질-5-(1-(피페리딘-4-일)-1H--2 days) -N-benzyl-5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00018
Figure 112008025718184-pat00018

실시예 1에서 사용한 t-부틸아민과 2-아미노-4-클로로페놀 대신 벤질아민과 2-아미노페놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 7과 동일한 방법으로 수행하여 연두색 고체의 목적화합물(3-(벤즈[d]옥사졸-2일)-N-벤질-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(8.6 mg, 25%). Except for using t-butylamine and 2-amino-4-chlorophenol used in Example 1, except that benzylamine and 2-aminophenol were used in the same manner as in Step 1 to Step 7 of Example 1 Target compound (3- (benz [d] oxazol-2yl) -N-benzyl-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine Ditrifluoroacetic acid salt) was obtained (8.6 mg, 25%).

1H NMR (300 MHz, CD3OD) δ 8.56 (d, J= 2.4 Hz, 1H), 8.44 (d, J= 2.1 Hz, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.73-7.66 (m, 2H), 7.42-7.26 (m, 7H), 4.60-4.55 (m, 1H), 3.61-3.57 (m, 2H), 3.24-3.21 (m, 2H), 2.42-2.22 (m, 4H); GC-MS (EI) m/z calcd for C27H26N6O(M+) 450.2, found 450.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.56 (d, J = 2.4 Hz, 1H), 8.44 (d, J = 2.1 Hz, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.73-7.66 (m, 2H), 7.42-7.26 (m, 7H), 4.60-4.55 (m, 1H), 3.61-3.57 (m, 2H), 3.24-3.21 (m, 2H), 2.42-2.22 (m , 4H); GC-MS (EI) m / z calcd for C 27 H 26 N 6 O (M + ) 450.2, found 450.1.

<< 실시예Example 4> 3-( 4> 3- ( 벤즈[d]옥사졸Mercedes-Benz [d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00019
Figure 112008025718184-pat00019

실시예 1에서 사용한 2-아미노-4-클로로페놀 대신 대신 2-아미노페놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 7과 동일한 방법으로 수행하여 고체의 목적화합물(3-(벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(52 mg, 63%).Except for using 2-amino-4-chlorophenol instead of 2-amino-4-chlorophenol used in Example 1, the same procedure as in Step 1 to Step 7 of Example 1 was carried out to obtain the target compound (3- (benz [ d] oxazol-2-yl) -5- (1-trifluoroacetic acid salt of 1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine) was obtained ( 52 mg, 63%).

1H NMR (300 MHz, CD3OD) δ 8.76 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.83 (d, J= 7.5Hz, 1H), 7.72 (d, J= 7.2 Hz, 1H), 7.51-7.45 (m, 2H), 4.65-4.60 (m, 1H), 3.62-3.53 (m, 2H), 3.06-2.90 (m, 2H), 2.40-2.29 (m, 4H); GC-MS (EI) m/z calcd for C20H20N6O2 (M+) 360.2, found 360.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.76 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.83 (d, J = 7.5 Hz, 1H ), 7.72 (d, J = 7.2 Hz, 1H), 7.51-7.45 (m, 2H), 4.65-4.60 (m, 1H), 3.62-3.53 (m, 2H), 3.06-2.90 (m, 2H), 2.40-2.29 (m, 4 H); GC-MS (EI) m / z calcd for C 20 H 20 N 6 O 2 (M + ) 360.2, found 360.1.

<< 실시예Example 5> 3-(5-( 5> 3- (5- ( 에틸설포닐Ethylsulfonyl )) 벤즈Mercedes Benz [d][d] 옥사졸Oxazole -2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2--2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00020
Figure 112008025718184-pat00020

실시예 1에서 사용한 2-아미노-4-클로로페놀 대신 2-아미노-4-에틸설포닐페놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 7과 동일한 방법으로 수행하여 고체의 목적화합물(3-(5-(에틸설포닐)벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(19 mg, 57%).Except for using 2-amino-4-ethylsulfonylphenol instead of 2-amino-4-chlorophenol used in Example 1, the procedure was carried out in the same manner as in Step 1 to Step 7 of Example 1 to obtain a solid target compound ( 3- (5- (ethylsulfonyl) benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine-2- Ditrifluoroacetic acid salt of amine) (19 mg, 57%).

1H NMR (300 MHz, CD3OD) δ 8.76 (s, 1H), 8.44 (s, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 8.05-7.95 (m, 3H), 4.66-4.55 (m, 1H), 3.62-3.57 (m, 2H), 3.30-3.21 (m, 2H), 2.36-2.29 (m, 5H), 1.35-1.17 (m, 4H); GC-MS (EI) m/z calcd for C22H24N6O3S (M+) 452.2, found 452.2. 1 H NMR (300 MHz, CD 3 OD) δ 8.76 (s, 1H), 8.44 (s, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 8.05-7.95 (m, 3H), 4.66 -4.55 (m, 1H), 3.62-3.57 (m, 2H), 3.30-3.21 (m, 2H), 2.36-2.29 (m, 5H), 1.35-1.17 (m, 4H); GC-MS (EI) m / z calcd for C 22 H 24 N 6 O 3 S (M + ) 452.2, found 452.2.

<< 실시예Example 6> 3-(5-( 6> 3- (5- ( 에틸설포닐Ethylsulfonyl )) 벤즈Mercedes Benz [d][d] 옥사졸Oxazole -2-일)-N-2-yl) -N- 메틸methyl -5-(1-(피페리딘-4-일)-1H--5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00021
Figure 112008025718184-pat00021

실시예 1에서 사용한 t-부틸아민과 2-아미노-4-클로로페놀 대신 메틸아민과 2-아미노-4-에틸설포닐페놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 7과 동일한 방법으로 수행하여 고체의 목적화합물(3-(5-(에틸설포닐)벤즈[d]옥사졸-2-일)-N-메틸-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(20 mg, 58%).The same method as in Step 1 to Step 7 of Example 1, except that methylamine and 2-amino-4-ethylsulfonylphenol were used instead of the t-butylamine and 2-amino-4-chlorophenol used in Example 1 Solid as the target compound (3- (5- (ethylsulfonyl) benz [d] oxazol-2-yl) -N-methyl-5- (1- (piperidin-4-yl) -1H Ditrifluoroacetic acid salt of -pyrazol-4-yl) pyridin-2-amine) (20 mg, 58%).

1H NMR (300 MHz, CD3OD) δ 8.55 (s, 1H), 8.48 (d, J= 2.1 Hz, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.96 (m, 3H), 4.70-4.50 (m, 1H), 3.62-3.58 (m, 2H), 3.26-3.20 (m, 5H), 2.36-2.29 (m, 6H), 1.26 (t, J= 7.4 Hz, 3H); GC-MS (EI) m/z calcd for C23H26N6O3S (M+) 466.2, found 466.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.55 (s, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.96 (m, 3H ), 4.70-4.50 (m, 1H), 3.62-3.58 (m, 2H), 3.26-3.20 (m, 5H), 2.36-2.29 (m, 6H), 1.26 (t, J = 7.4 Hz, 3H); GC-MS (EI) m / z calcd for C 23 H 26 N 6 O 3 S (M + ) 466.2, found 466.1.

<< 실시예Example 7> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 7> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)벤즈[-4-yl) pyridin-3-yl) benz [ d]옥사졸d] oxazole -5--5- 카보나이트릴의Carbonitrile 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00022
Figure 112008025718184-pat00022

실시예 1에서 사용한 2-아미노-4-클로로페놀 대신 2-아미노-4-시아노페놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 7과 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-5-카보나이트릴의 이트리플루오로아세트산 염)을 얻었다(16 mg, 91%).Except for using 2-amino-4-cyanophenol instead of 2-amino-4-chlorophenol used in Example 1, the procedure was carried out in the same manner as in Step 1 to Step 7 of Example 1 to obtain a solid target compound (2 Itri of-(2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-5-carbonitrile Fluoroacetic acid salt) was obtained (16 mg, 91%).

1H NMR (300 MHz, CD3OD) δ 8.75 (d, J= 2.3 Hz, 1H), 8.47 (d, J= 2.3 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7.91 (d, J= 7.9 Hz, 1H), 7.86 (dd, J= 1.6, 8.5 Hz, 1H), 4.65-4.55 (m, 1H), 3.63-3.50 (m, 4H), 3.39-2.30 (m, 4H); LC/MS m/z calcd for C21H20N7O (MH+) 386.2, found 385.9. 1 H NMR (300 MHz, CD 3 OD) δ 8.75 (d, J = 2.3 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 1.6, 8.5 Hz, 1H), 4.65-4.55 (m, 1H), 3.63-3.50 (m, 4H) , 3.39-2.30 (m, 4 H); LC / MS mlz calcd for C 21 H 20 N 7 O (MH + ) 386.2, found 385.9.

<< 실시예Example 8> 3-(5-( 8> 3- (5- ( 클로로벤즈[d]옥사졸Chlorobenz [d] oxazole -2-일)-N-2-yl) -N- 메틸methyl -5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2--5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00023
Figure 112008025718184-pat00023

실시예 1에서 사용한 t-부틸아민 대신 메틸아민을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 7과 동일한 방법으로 수행하여 고체의 목적화합물(3-(5-(클로로벤즈[d]옥사졸-2-일)-N-메틸-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(6 mg, 24%).Except for using methylamine instead of t-butylamine used in Example 1, the procedure was carried out in the same manner as in Step 1 to Step 7 of Example 1 to obtain the target compound (3- (5- (chlorobenz [d] oxa) Zol-2-yl) -N-methyl-5- (ditrifluoroacetic acid salt of 1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine) was obtained. (6 mg, 24%).

1H NMR (300 MHz, DMSO-d 6 ) δ 8.64 (d, J= 2.4 Hz, 1H), 8.44 (d, J= 2.4 Hz, 1H), 8.30 (s, 1H), 7.98 (s, 1H), 7.93 (d, J= 2.1 Hz, 1H), 7.81 (d, J= 8.7 Hz, 1H), 7.49 (dd, J= 8.7, 2.1 Hz, 1H), 4.58-4.40 (m, 1H), 3.44-3.40 (m, 2H), 3.20-3.00 (m, 5H), 2.26-1.97 (m, 4H); GC-MS (EI) m/z calcd for C21H21N6O (M+) 408.2, found 408.1. 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.64 (d, J = 2.4 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.30 (s, 1H), 7.98 (s, 1H) , 7.93 (d, J = 2.1 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.49 (dd, J = 8.7, 2.1 Hz, 1H), 4.58-4.40 (m, 1H), 3.44- 3.40 (m, 2 H), 3.20-3.00 (m, 5 H), 2.26-1.97 (m, 4H); GC-MS (EI) m / z calcd for C 21 H 21 N 6 O (M + ) 408.2, found 408.1.

<< 실시예Example 9> 3-(6- 9> 3- (6- 메틸벤즈[d]옥사졸Methyl benz [d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00024
Figure 112008025718184-pat00024

실시예 1에서 사용한 2-아미노-4-클로로페놀 대신 2-아미노-5-메틸페놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 7과 동일한 방법으로 수행하여 고체의 목적화합물(3-(6-메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(105 mg, 69%).Except for using 2-amino-5-methylphenol instead of 2-amino-4-chlorophenol used in Example 1, the procedure was carried out in the same manner as in Step 1 to Step 7 of Example 1 to obtain a solid target compound (3- Itrifluoro of (6-methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine Acetic acid salt) (105 mg, 69%).

1H NMR (300 MHz, CD3OD) δ 8.52 (d, J= 2.1 Hz, 1H), 8.44 (d, J= 2.4 Hz, 1H), 8.33 (s, 1H), 7.99 (s, 1H), 7.70 (d, J= 8.1 Hz, 1H), 7.51 (s, 1H), 7.33 (d, J= 8.1 Hz, 1H), 4.49-4.46 (m, 1H), 3.43-3.39 (m, 2H), 3.12-3.09 (m, 2H), 2.49 (s, 3H), 2.26-2.14 (m, 4H); LC/MS m/z calcd for C21H23N6O (MH+) 375.2, found 375.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.52 (d, J = 2.1 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.33 (s, 1H), 7.99 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.51 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 4.49-4.46 (m, 1H), 3.43-3.39 (m, 2H), 3.12 -3.09 (m, 2H), 2.49 (s, 3H), 2.26-2.14 (m, 4H); LC / MS mlz calcd for C 21 H 23 N 6 O (MH + ) 375.2, found 375.1.

<실시예 10> 3-(6-클로로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-Example 10 3- (6-chlorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine-2 - 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00025
Figure 112008025718184-pat00025

실시예 1에서 사용한 2-아미노-4-클로로페놀 대신 2-아미노-5-클로로페놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 7과 동일한 방법으로 수행하여 고체의 목적화합물(3-(6-클로로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(25 mg, 45%).Except for using 2-amino-4-chlorophenol used in Example 1, except that 2-amino-5-chlorophenol was used in the same manner as in Step 1 to Step 7 of Example 1 to obtain a solid target compound (3- Itrifluoro of (6-chlorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine Acetic acid salt) (25 mg, 45%).

1H NMR (300 MHz, DMSO-d 6 ) δ 8.56 (d, J= 2.4 Hz, 1H), 8.44 (d, J= 2.3 Hz, 1H), 8.31 (s, 1H), 7.99 (s, 1H), 7.96 (d, J= 1.8 Hz, 1H), 7.86 (d, J= 8.5 Hz, 1H), 7.5 (dd, J= 2.0, 8.5 Hz, 1H), 4.55-4.48 (m, 1H), 3.46-3.37 (m, 2H), 3.18-3.07 (m, 2H), 2.28-1.99 (m, 4H); LC/MS m/z calcd for C20H20ClN6O (MH+) 395.1, found 395.5. 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.56 (d, J = 2.4 Hz, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.31 (s, 1H), 7.99 (s, 1H) , 7.96 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.5 (dd, J = 2.0, 8.5 Hz, 1H), 4.55-4.48 (m, 1H), 3.46- 3.37 (m, 2 H), 3.18-3.07 (m, 2 H), 2.28-1.99 (m, 4H); LC / MS mlz calcd for C 20 H 20 ClN 6 O (MH + ) 395.1, found 395.5.

<< 실시예Example 11> 3-(6- 11> 3- (6- 플루오로벤즈[d]옥사졸Fluorobenz [d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피blood 라졸-4-일)피리딘-2-Razol-4-yl) pyridine-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00026
Figure 112008025718184-pat00026

실시예 1에서 사용한 2-아미노-4-클로로페놀 대신 2-아미노-5-플루오로페놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 7과 동일한 방법으로 수행하여 고체의 목적화합물(3-(6-플루오로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(9 mg, 41%).Except for using 2-amino-5-fluorophenol instead of 2-amino-4-chlorophenol used in Example 1, the procedure was carried out in the same manner as in Step 1 to Step 7 of Example 1 to obtain a solid target compound (3 Ytri of-(6-fluorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine Fluoroacetic acid salt) was obtained (9 mg, 41%).

1H NMR (300 MHz, CD3OD) d 8.78 (d, J= 2.4 Hz, 1H), 8.4 (d, J= 2.1 Hz, 1H), 8.21 (s, 1H), 8.05 (s, 1H), 7.85-7.81 (m, 1H), 7.56 (dd, J= 2.7, 7.8 Hz, 1H), 7.27-7.24 (m, 1H), 4.63-4.58 (m, 1H), 3.62-3.57 (m, 2H), 3.24-3.21 (m, 2H), 2.36-2.30 (m, 4H); LC/MS m/z calcd for C20H20FN6O (MH+) 379.2, found 379.1. 1 H NMR (300 MHz, CD 3 OD) d 8.78 (d, J = 2.4 Hz, 1H), 8.4 (d, J = 2.1 Hz, 1H), 8.21 (s, 1H), 8.05 (s, 1H), 7.85-7.81 (m, 1H), 7.56 (dd, J = 2.7, 7.8 Hz, 1H), 7.27-7.24 (m, 1H), 4.63-4.58 (m, 1H), 3.62-3.57 (m, 2H), 3.24-3.21 (m, 2 H), 2.36-2.30 (m, 4H); LC / MS mlz calcd for C 20 H 20 FN 6 O (MH + ) 379.2, found 379.1.

<< 실시예Example 12> 3-(5-( 12> 3- (5- ( 메틸벤즈[d]옥사졸Methyl benz [d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피라Fira 졸-4-일)피리딘-2-Zol-4-yl) pyridin-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00027
Figure 112008025718184-pat00027

실시예 1에서 사용한 2-아미노-4-클로로페놀 대신 2-아미노-4-메틸페놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 7과 동일한 방법으로 수행하여 고체의 목적화합물(3-(5-(메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(24 mg, 33%).Except for using 2-amino-4-methylphenol instead of 2-amino-4-chlorophenol used in Example 1, the procedure was carried out in the same manner as in Step 1 to Step 7 of Example 1 to obtain a solid target compound (3- Itrifluoro of (5- (methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine Roacetic acid salt) was obtained (24 mg, 33%).

1H NMR (300 MHz, CD3OD) δ 8.83 (d, J= 2.1 Hz, 1H), 8.38 (d, J= 2.1 Hz, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.64-7.53 (m, 2H), 7.33 (d, J= 9.9 Hz, 1H), 4.61-4.58 (m, 1H), 3.60-3.52 (m, 2H), 3.29-3.21 (m, 2H), 2.51 (s, 3H), 2.36-2.30 (m, 4H); LC/MS m/z calcd for C21H23N6O (MH+) 375.2, found 375.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.83 (d, J = 2.1 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.64-7.53 (m, 2H), 7.33 (d, J = 9.9 Hz, 1H), 4.61-4.58 (m, 1H), 3.60-3.52 (m, 2H), 3.29-3.21 (m, 2H), 2.51 ( s, 3H), 2.36-2.30 (m, 4H); LC / MS mlz calcd for C 21 H 23 N 6 O (MH + ) 375.2, found 375.1.

<< 실시예Example 13> 3-( 13> 3- ( 나프토[2,3-d]옥사졸Naphtho [2,3-d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00028
Figure 112008025718184-pat00028

실시예 1에서 사용한 2-아미노-4-클로로페놀 대신 2-아미노-나프탈레놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 7과 동일한 방법으로 수행하여 고체의 목적화합물(3-(나프토[2,3-d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(22 mg, 44%).Except for using 2-amino-naphthalenol instead of 2-amino-4-chlorophenol used in Example 1, the procedure was carried out in the same manner as in Step 1 to Step 7 of Example 1 to obtain a solid target compound (3- ( Itrifluoro of naphtho [2,3-d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine Roacetic acid salt) (22 mg, 44%).

1H NMR (300 MHz, CD3OD) δ 8.84 (d, J= 1.96 Hz, 1H), 8.43 (d, J= 1.8 Hz, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 8.08-8.01 (m, 3H), 7.60-7.52 (m, 2H), 4.62-4.59 (m, 1H), 3.62-3.56 (m, 2H), 3.24-3.18 (m, 2H), 2.40-2.28 (m, 4H); LC/MS m/z calcd for C24H23N6O (MH+) 411.2, found 411.0. 1 H NMR (300 MHz, CD 3 OD) δ 8.84 (d, J = 1.96 Hz, 1H), 8.43 (d, J = 1.8 Hz, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 8.08-8.01 (m, 3H), 7.60-7.52 (m, 2H), 4.62-4.59 (m, 1H), 3.62-3.56 (m, 2H), 3.24-3.18 (m, 2H ), 2.40-2.28 (m, 4 H); LC / MS mlz calcd for C 24 H 23 N 6 O (MH + ) 411.2, found 411.0.

<< 실시예Example 14> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 14> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)-N--4-yl) pyridin-3-yl) -N- 프로필벤즈[d]옥사졸Propyl benz [d] oxazole -5--5- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

단계 1: 3급-부틸-4-(4-(6-(3급-Step 1: tert-butyl-4- (4- (6- (tert- 부틸아미노Butylamino )-5-(5-() -5- (5- ( 프로필아미노Propylamino )) 벤즈Mercedes Benz [d][d] 옥사졸Oxazole -2-일)피리딘-3-일)-1H--2-yl) pyridin-3-yl) -1H- 피라졸Pyrazole -1-일)피페리딘-1--1-yl) piperidine-1- 카복실레이트의Carboxylate 제조 Produce

Figure 112008025718184-pat00029
Figure 112008025718184-pat00029

고압반응용기에 3급-부틸-4-(4-(6-(3급-부틸아미노)-5-(5-클로로벤즈[d]옥사졸-2-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트(198 mg, 0.36 mmol), 트리스(디벤질리딘아세톤)디팔라듐(66 mg), 나트륨-3급-부톡사이드(104 mg), 2-디-3급-부틸포스피노-2',3',6'-트리아이소프로필바이페닐(61 mg), 프로필아민(0.3 mL) 및 톨루엔(1.2 mL)을 넣고 질소로 반응용기의 공기를 치환한 후 밀봉하였다. 반응물을 110 ℃에서 24시간 동안 교반하고, 실온으로 냉각시킨 후 메틸렌클로라이드로 희석하고 셀라이트를 이용하여 여과하였다. 여액을 농축하고 농축물을 관크로마토그래피로 정제하여 연두색 고체의 목적화합물(3급-부틸-4-(4-(6-(3급-부틸아미노)-5-(5-(프로필아미노)벤즈[d]옥사졸-2-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트)을 얻었다(99 mg, 48%).Tert-butyl-4- (4- (6- (tert-butylamino) -5- (5-chlorobenz [d] oxazol-2-yl) -1H-pyrazol-1- I) piperidine-1-carboxylate (198 mg, 0.36 mmol), tris (dibenzylideneacetone) dipalladium (66 mg), sodium tert-butoxide (104 mg), 2-di-tert-third -Butylphosphino-2 ', 3', 6'-triisopropylbiphenyl (61 mg), propylamine (0.3 mL) and toluene (1.2 mL) were added, and the reaction vessel was replaced with nitrogen and sealed. The reaction was stirred at 110 ° C. for 24 hours, cooled to room temperature, diluted with methylene chloride and filtered using celite, the filtrate was concentrated and the concentrate was purified by column chromatography to give the title compound as a light green solid (3). Tert-butyl-4- (4- (6- (tert-butylamino) -5- (5- (propylamino) benz [d] oxazol-2-yl) -1H-pyrazol-1-yl) Piperidine-1-carboxylate) was obtained (99 mg, 48%).

1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.41 (d, J= 2.5Hz, 1H), 8.28 (d, J= 2.5 Hz, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.33 (d, J= 8.7 Hz, 1H), 6.90 (d, J= 2.1 Hz, 1H), 6.63 (dd, J= 8.7, 2.3 Hz, 1H), 4.32-4.26 (m, 3H), 3.70 (s, 1H), 3.14 (t, J= 7.1 Hz, 2H), 2.92 (t, J= 12.2 Hz, 2H), 2.20-2.17 (m, 2H), 1.99-1.94 (m, 2H), 1.73-1.67 (m, 2H), 1.61 (s, 9H), 1.49 (s, 9H), 1.04 (t, J= 7.4 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.76 (s, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.28 (d, J = 2.5 Hz, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.33 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 2.1 Hz, 1H), 6.63 (dd, J = 8.7, 2.3 Hz, 1H), 4.32-4.26 (m, 3H), 3.70 (s, 1H), 3.14 (t, J = 7.1 Hz, 2H), 2.92 (t, J = 12.2 Hz, 2H), 2.20-2.17 (m, 2H), 1.99-1.94 (m, 2H ), 1.73-1.67 (m, 2H), 1.61 (s, 9H), 1.49 (s, 9H), 1.04 (t, J = 7.4 Hz, 3H).

단계 2: 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-Step 2: 2- (2-amino-5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-3-일)-N-프로필벤즈[-4-yl) pyridin-3-yl) -N-propylbenz [ d]옥사졸d] oxazole -5--5- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00030
Figure 112008025718184-pat00030

반응용기에 3급-부틸-4-(4-(6-(3급-부틸아미노)-5-(5-(프로필아미노)벤즈[d]옥사졸-2-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트(99 mg, 0.17 mmol) 및 트리플루오로아세트산(2 mL)을 넣고, 반응물을 60 ℃에서 24시간 동안 교반하였다. 반응물의 온도를 실온으로 낮추고, 감압농축하였다. 농축물에 에틸에테르를 넣고 30분 동안 교반한 후 여과하여 연두색 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-프로필벤즈[d]옥사졸-5-아민의 삼트리플루오로아세트산 염)을 얻었다(105 mg, 81%).Tert-butyl-4- (4- (6- (tert-butylamino) -5- (5- (propylamino) benz [d] oxazol-2-yl) -1H-pyrazole- in the reaction vessel 1-yl) piperidine-1-carboxylate (99 mg, 0.17 mmol) and trifluoroacetic acid (2 mL) were added and the reaction stirred for 24 hours at 60 ° C. The temperature of the reaction was lowered to room temperature, Ethyl ether was added to the concentrate, followed by stirring for 30 minutes, followed by filtration. Zol-4-yl) pyridin-3-yl) -N-propylbenz [d] oxazol-5-amine tritrifluoroacetic acid salt) was obtained (105 mg, 81%).

1H NMR (300 MHz, CD3OD) δ 8.89 (d, J= 2.1 Hz, 1H), 8.41 (d, J= 2.1 Hz, 1H), 8.29 (s, 1H), 8.01 (s, 1H), 7.78 (d, J= 8.8 Hz, 1H), 7.65 (d, J= 2.1 Hz, 1H), 7.36 (dd, J= 8.8, 2.2 Hz, 1H), 4.68-4.58 (m, 1H), 3.63-3.56 (m, 2H), 3.35-3.20 (m, 4H), 2.41-2.27 (m, 4H), 1.83-1.71 (m, 2H), 1.06 (t, J= 7.4 Hz, 3H); GC-MS (EI) m/z calcd for C23H27N7O(M+) 417.2, found 417.2. 1 H NMR (300 MHz, CD 3 OD) δ 8.89 (d, J = 2.1 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.29 (s, 1H), 8.01 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.36 (dd, J = 8.8, 2.2 Hz, 1H), 4.68-4.58 (m, 1H), 3.63-3.56 (m, 2H), 3.35-3.20 (m, 4H), 2.41-2.27 (m, 4H), 1.83-1.71 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H); GC-MS (EI) m / z calcd for C 23 H 27 N 7 O (M + ) 417.2, found 417.2.

<< 실시예Example 15> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 15> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)-N--4-yl) pyridin-3-yl) -N- 메틸벤즈[d]옥사졸Methyl benz [d] oxazole -5--5- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00031
Figure 112008025718184-pat00031

실시예 14에서 사용한 프로필아민 대신 메틸아민을 사용한 것을 제외하고는 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-메틸벤즈[d]옥사졸-5-아민의 삼트리플루오로아세트산 염)을 얻었다(6 mg, 83%).Except for using methylamine in place of the propylamine used in Example 14, the procedure was carried out in the same manner as in Step 1 and Step 2 of Example 14 to obtain a solid target compound (2- (2-amino-5- (1- (P Tridine-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-methylbenz [d] oxazol-5-amine tritrifluoroacetic acid salt) was obtained (6 mg , 83%).

1H NMR (300 MHz, CD3OD) δ 8.83 (d, J= 2.1 Hz, 1H), 8.39 (d, J= 2.1 Hz, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.67 (d, J= 8.7 Hz, 1H), 7.38 (d, J= 2.1 Hz, 1H), 7.16 (dd, J= 8.7, 2.4 Hz, 1H), 4.65-4.56 (m, 1H), 3.59 (d, J= 13.5 Hz, 2H), 3.22 (dd, J= 12.6, 3.6 Hz, 2H), 2.98 (s, 3H), 2.40-2.25 (m, 4H); GC-MS (EI) m/z calcd for C21H23N7O (M+) 389.2, found 389.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.83 (d, J = 2.1 Hz, 1H), 8.39 (d, J = 2.1 Hz, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.16 (dd, J = 8.7, 2.4 Hz, 1H), 4.65-4.56 (m, 1H), 3.59 (d , J = 13.5 Hz, 2H), 3.22 (dd, J = 12.6, 3.6 Hz, 2H), 2.98 (s, 3H), 2.40-2.25 (m, 4H); GC-MS (EI) m / z calcd for C 21 H 23 N 7 O (M + ) 389.2, found 389.1.

<< 실시예Example 16> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 16> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)-N--4-yl) pyridin-3-yl) -N- 에틸벤즈[d]옥사졸Ethyl benz [d] oxazole -5--5- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00032
Figure 112008025718184-pat00032

실시예 14에서 사용한 프로필아민 대신 에틸아민을 사용한 것을 제외하고는 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-에틸벤즈[d]옥사졸-5-아민의 삼트리플루오로아세트산 염)을 얻었다(3 mg, 48%).Except for using ethylamine instead of the propylamine used in Example 14, it was carried out in the same manner as in Step 1 and Step 2 of Example 14 to give a solid target compound (2- (2-amino-5- (1- (P Tritrifluoroacetic acid salt of ferridin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-ethylbenz [d] oxazol-5-amine) was obtained (3 mg). , 48%).

1H NMR (300 MHz, CD3OD) δ 8.77 (s, 1H), 8.42 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.73 (d, J= 11.7 Hz, 1H), 7.59 (s, 1H), 7.31 (d, J= 11.7 Hz, 1H), 4.65-4.56 (m, 1H), 3.59 (d, J= 13.2 Hz, 2H), 3.24 (d, J= 13.2 Hz, 2H), 2.42-2.22 (m, 4H); GC-MS (EI) m/z calcd for C22H25N7O (M+) 403.2, found 403.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.77 (s, 1H), 8.42 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.73 (d, J = 11.7 Hz, 1H ), 7.59 (s, 1H), 7.31 (d, J = 11.7 Hz, 1H), 4.65-4.56 (m, 1H), 3.59 (d, J = 13.2 Hz, 2H), 3.24 (d, J = 13.2 Hz , 2H), 2.42-2.22 (m, 4H); GC-MS (EI) m / z calcd for C 22 H 25 N 7 O (M + ) 403.2, found 403.1.

<< 실시예Example 17> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 17> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)-N--4-yl) pyridin-3-yl) -N- 이소프로필벤즈[d]옥사졸Isopropyl benz [d] oxazole -5--5- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00033
Figure 112008025718184-pat00033

실시예 14에서 사용한 프로필아민 대신 이소프로필아민을 사용한 것을 제외하고는 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소프로필벤즈[d]옥사졸-5-아민의 삼트리플루오로아세트산 염)을 얻었다(9 mg, 41%).Except for using isopropylamine in place of the propylamine used in Example 14, it was carried out in the same manner as in Step 1 and Step 2 of Example 14 to obtain a solid target compound (2- (2-amino-5- (1- ( Piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-isopropylbenz [d] oxazol-5-amine tritrifluoroacetic acid salt) 9 mg, 41%).

1H NMR (300 MHz, CD3OD) δ 8.65 (d, J= 2.3 Hz, 1H), 8.43 (d, J= 2.3 Hz, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.76 (d, J= 8.7 Hz, 1H), 7.60 (d, J= 2.1 Hz, 1H), 7.30 (dd, J= 8.7, 2.2 Hz, 1H), 4.65-4.59 (m, 1H), 3.85-3.77 (m, 1H), 3.63-3.59 (m, 2H), 3.27-3.22 (m, 2H), 2.43-2.31 (m, 4H), 1.36 (d, J= 6.5 Hz, 6H); GC-MS (EI) m/z calcd for C23H27N7O (M+) 417.2, found 417.2. 1 H NMR (300 MHz, CD 3 OD) δ 8.65 (d, J = 2.3 Hz, 1H), 8.43 (d, J = 2.3 Hz, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.30 (dd, J = 8.7, 2.2 Hz, 1H), 4.65-4.59 (m, 1H), 3.85-3.77 (m, 1H), 3.63-3.59 (m, 2H), 3.27-3.22 (m, 2H), 2.43-2.31 (m, 4H), 1.36 (d, J = 6.5 Hz, 6H); GC-MS (EI) m / z calcd for C 23 H 27 N 7 O (M + ) 417.2, found 417.2.

<< 실시예Example 18> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 18> 2- (2-amino-5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-3-일)-N--4-yl) pyridin-3-yl) -N- 부틸벤즈[d]옥사졸Butyl benz [d] oxazole -5--5- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00034
Figure 112008025718184-pat00034

실시예 14에서 사용한 프로필아민 대신 부틸아민을 사용한 것을 제외하고는 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-부틸벤즈[d]옥사졸-5-아민의 삼트리플루오로아세트산 염)을 얻었다(13 mg, 85%).Except for using butylamine instead of propylamine used in Example 14, the same procedure as in Step 1 and Step 2 of Example 14 was carried out to yield the target compound as a solid (2- (2-amino-5- (1- (P Tritrifluoroacetic acid salt of ferridin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-butylbenz [d] oxazol-5-amine) was obtained (13 mg). , 85%).

1H NMR (300 MHz, CD3OD) δ 8.82 (d, J= 2.1 Hz, 1H), 8.40 (d, J= 2.1 Hz, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.72 (d, J= 8.7 Hz, 1H), 7.53 (d, J= 2.1 Hz, 1H), 7.27 (dd, J= 8.7, 2.1 Hz, 1H), 4.65-4.56 (m, 1H), 3.54 (d, J= 15.6 Hz, 2H), 3.23 (d, J= 13.8 Hz, 2H), 2.40-2.30 (m, 4H), 1.79-1.64 (m, 2H), 1.56-1.40 (m, 2H), 1.38-1.24 (m, 2H), 0.99 (t, J= 7.4 Hz, 3H); GC-MS (EI) m/z calcd for C24H29N7O (M+) 431.2, found 431.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.82 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.27 (dd, J = 8.7, 2.1 Hz, 1H), 4.65-4.56 (m, 1H), 3.54 (d, J = 15.6 Hz, 2H), 3.23 (d, J = 13.8 Hz, 2H), 2.40-2.30 (m, 4H ), 1.79-1.64 (m, 2H), 1.56-1.40 (m, 2H), 1.38-1.24 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); GC-MS (EI) m / z calcd for C 24 H 29 N 7 O (M + ) 431.2, found 431.1.

<실시예 19> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N,N-Example 19 2- (2-amino-5- (1- (piperidin-4-yl) -1 H-pyrazol-4-yl) pyridin-3-yl) -N, N- 디메틸벤즈[d]옥사졸Dimethyl benz [d] oxazole -5--5- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00035
Figure 112008025718184-pat00035

실시예 14에서 사용한 프로필아민 대신 디메틸아민을 사용한 것을 제외하고는 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N,N-디메틸벤즈[d]옥사졸-5-아민의 삼트리플루오로아세트산 염)을 얻었다(92 mg, 76%).Except that dimethylamine was used instead of propylamine used in Example 14, the same procedure as in Step 1 and Step 2 of Example 14 was carried out to obtain the target compound as a solid (2- (2-amino-5- (1- (P Tridinfluoroyl) -1H-pyrazol-4-yl) pyridin-3-yl) -N, N-dimethylbenz [d] oxazol-5-amine) 92 mg, 76%).

1H NMR (300 MHz, CD3OD) δ 8.81 (d, J= 2.2 Hz, 1H), 8.38 (d, J= 2.2 Hz, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.68 (d, J= 9.0 Hz, 1H), 7.44 (d, J= 2.3 Hz, 1H), 7.25 (dd, J= 9.0, 2.5 Hz, 1H), 4.63 (m, 1H), 3.62 (dd, J= 9.8, 3.6 Hz, 2H), 3.25 (dd, J= 12.1, 3.3 Hz, 2H), 2.42-2.32 (m, 4H); GC-MS (EI) m/z calcd for C22H25N7O (M+) 403.2, found 403.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.81 (d, J = 2.2 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 9.0, 2.5 Hz, 1H), 4.63 (m, 1H), 3.62 (dd, J = 9.8, 3.6 Hz, 2H), 3.25 (dd, J = 12.1, 3.3 Hz, 2H), 2.42-2.32 (m, 4H); GC-MS (EI) m / z calcd for C 22 H 25 N 7 O (M + ) 403.2, found 403.1.

<< 실시예Example 20> 5-(1-(피페리딘-4-일)-1H- 20> 5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)-3-(5-(-4-yl) -3- (5- ( 피롤리딘Pyrrolidine -1-일)-1 day) 벤Ben 즈[Zu [ d]옥사졸d] oxazole -2-일)피리딘-2--2-yl) pyridine-2- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00036
Figure 112008025718184-pat00036

실시예 14에서 사용한 프로필아민 대신 피롤리딘을 사용한 것을 제외하고는 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(5-(1-(피페리딘-4-일)-1H-피라졸-4-일)-3-(5-(피롤리딘-1-일)벤즈[d]옥사졸-2-일)피리딘-2-아민의 삼트리플루오로아세트산 염)을 얻었다(4 mg, 59%).A solid target compound (5- (1- (piperidin-4-yl) was prepared by the same method as Step 1 and Step 2 of Example 14, except that pyrrolidin was used instead of the propylamine used in Example 14. ) -1H-pyrazol-4-yl) -3- (tritriacetic acid salt of 5- (pyrrolidin-1-yl) benz [d] oxazol-2-yl) pyridin-2-amine) Was obtained (4 mg, 59%).

1H NMR (300MHz, CD3OD) δ 8.65 (d, J= 2.2 Hz, 1H), 8.24 (d, J= 2.2 Hz, 1H), 8.13 (s, 1H), 7.89 (s, 1H), 7.41 (d, J= 8.9 Hz, 1H), 6.80 (d, J= 2.2 Hz, 1H), 6.69 (dd, J= 9.0, 2.4 Hz, 1H), 4.53-4.48 (m, 1H), 3.55-3.44 (m, 2H), 3.26-3.10 (m, 6H), 2.31-2.20 (m, 4H), 2.00-1.91 (m, 4H); GC-MS (EI) m/z calcd for C24H27N7O (M+) 429.2, found 429.2. 1 H NMR (300MHz, CD 3 OD) δ 8.65 (d, J = 2.2 Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.13 (s, 1H), 7.89 (s, 1H), 7.41 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 6.69 (dd, J = 9.0, 2.4 Hz, 1H), 4.53-4.48 (m, 1H), 3.55-3.44 ( m, 2H), 3.26-3.10 (m, 6H), 2.31-2.20 (m, 4H), 2.00-1.91 (m, 4H); GC-MS (EI) m / z calcd for C 24 H 27 N 7 O (M + ) 429.2, found 429.2.

<< 실시예Example 21> 3-(5-(피페리딘-1-일) 21> 3- (5- (piperidin-1-yl) 벤즈Mercedes Benz [d][d] 옥사졸Oxazole -2일)-5-(1-(피페리딘-4-일)-1H--2 days) -5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00037
Figure 112008025718184-pat00037

실시예 14에서 사용한 프로필아민 대신 피페리딘을 사용한 것을 제외하고는 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(3-(5-(피페리딘-1-일)벤즈[d]옥사졸-2일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 삼트리플루오로아세트산 염)을 얻었다(14 mg, 49%).A solid target compound (3- (5- (piperidin-1-yl) was prepared by the same method as Step 1 and Step 2 of Example 14, except that piperidine was used instead of propylamine. Benz [d] oxazol-2yl) -5- (trifluoroacetic acid salt of 1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine) Obtained (14 mg, 49%).

1H NMR (300 MHz, CD3OD) δ 8.64 (d, J= 2.1 Hz, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.90 (s, 1H), 7.81 (d, J= 8.7 Hz, 1H), 7.56 (d, J= 7.8 Hz, 1H), 4.64-4.58 (m, 1H), 3.62-3.48 (m, 6H), 3.26-3.20 (m, 2H), 2.36-2.29 (m, 4H), 2.20-1.96 (m, 4H), 1.84-1.72 (m, 2H); GC-MS (EI) m/z calcd for C25H29N7O (M+) 443.2, found 443.2. 1 H NMR (300 MHz, CD 3 OD) δ 8.64 (d, J = 2.1 Hz, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.90 (s, 1H ), 7.81 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 4.64-4.58 (m, 1H), 3.62-3.48 (m, 6H), 3.26-3.20 (m, 2H), 2.36-2.29 (m, 4H), 2.20-1.96 (m, 4H), 1.84-1.72 (m, 2H); GC-MS (EI) m / z calcd for C 25 H 29 N 7 O (M + ) 443.2, found 443.2.

<< 실시예Example 22> 3-(5- 22> 3- (5- 모폴리노벤즈[d]옥사졸Morpholinobenz [d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피blood 라졸-4-일)피리딘-2-Razol-4-yl) pyridine-2- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00038
Figure 112008025718184-pat00038

실시예 14에서 사용한 프로필아민 대신 모폴린을 사용한 것을 제외하고는 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(3-(5-모폴리노벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 삼트리플루오로아세트산 염)을 얻었다(10 mg, 62%).Except for using morpholine instead of propylamine used in Example 14, it was carried out in the same manner as in Step 1 and Step 2 of Example 14 to obtain a solid target compound (3- (5-morpholinobenz [d] oxazole -2-yl) -5- (trifluoroacetic acid salt of 1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine) was obtained (10 mg, 62 %).

1H NMR (300 MHz, CD3OD) δ 8.84 (d, J= 1.8 Hz, 1H), 8.36 (s, 1H), 8.26(s, 1H), 8.01 (s, 1H), 7.61 (d, J= 9.0 Hz, 1H), 7.36 (s, 1H), 7.23 (dd, J= 9.0, 2.0 Hz, 1H), 4.66-4.59 (m, 1H), 3.88 (t, J= 4.4 Hz, 4H), 3.63-3.58 (m, 2H), 3.35-3.19 (m, 6H), 2.41-2.31 (m, 4H); GC-MS (EI) m/z calcd for C24H27N7O2 (M+) 445.2, found 445.2. 1 H NMR (300 MHz, CD 3 OD) δ 8.84 (d, J = 1.8 Hz, 1H), 8.36 (s, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.36 (s, 1H), 7.23 (dd, J = 9.0, 2.0 Hz, 1H), 4.66-4.59 (m, 1H), 3.88 (t, J = 4.4 Hz, 4H), 3.63 -3.58 (m, 2H), 3.35-3.19 (m, 6H), 2.41-2.31 (m, 4H); GC-MS (EI) m / z calcd for C 24 H 27 N 7 O 2 (M + ) 445.2, found 445.2.

<< 실시예Example 23> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 23> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)-N--4-yl) pyridin-3-yl) -N- 페닐벤즈[d]옥사졸Phenylbenz [d] oxazole -5--5- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00039
Figure 112008025718184-pat00039

실시예 14에서 사용한 프로필아민 대신 아닐린을 사용한 것을 제외하고는 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-페닐벤즈[d]옥사졸-5-아민의 삼트리플루오로아세트산 염)을 얻었다(7 mg, 76%).Except for using aniline in place of the propylamine used in Example 14, it was carried out in the same manner as in Step 1 and Step 2 of Example 14 to obtain a solid target compound (2- (2-amino-5- (1- (piperi) Ditrifluoroacetic acid salt of di-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-phenylbenz [d] oxazol-5-amine) (7 mg, 76%).

1H NMR (300 MHz, CD3OD) δ 8.80 (d, J= 1.8 Hz, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.57 (d, J= 8.7 Hz, 1H), 7.49 (d, J= 1.8 Hz, 1H), 7.28-7.18 (m, 3H), 7.13-7.11 (m, 2H), 6.88 (t, J= 7.4 Hz, 1H), 4.64-4.58 (m, 1H), 3.64-3.57 (m, 2H), 3.24-3.20 (m, 2H), 2.40-2.29 (m, 4H); GC-MS (EI) m/z calcd for C26H25N7O (M+) 451.2, found 451.2. 1 H NMR (300 MHz, CD 3 OD) δ 8.80 (d, J = 1.8 Hz, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.28-7.18 (m, 3H), 7.13-7.11 (m, 2H), 6.88 (t, J = 7.4 Hz, 1H), 4.64 -4.58 (m, 1 H), 3.64-3.57 (m, 2H), 3.24-3.20 (m, 2H), 2.40-2.29 (m, 4H); GC-MS (EI) m / z calcd for C 26 H 25 N 7 O (M + ) 451.2, found 451.2.

<< 실시예Example 24> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 24> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)-N--4-yl) pyridin-3-yl) -N- 메틸methyl -N--N- 페닐벤즈[d]옥사졸Phenylbenz [d] oxazole -5--5- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00040
Figure 112008025718184-pat00040

실시예 14에서 사용한 프로필아민 대신 N-메틸아닐린을 사용한 것을 제외하고는 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-메틸-N-페닐벤즈[d]옥사졸-5-아민의 삼트리플루오로아세트산 염)을 얻었다(61 mg, 47%).Except for using N-methylaniline in place of the propylamine used in Example 14, it was carried out in the same manner as in Step 1 and Step 2 of Example 14 to give the target compound (2- (2-amino-5- (1- Tritrifluoroacetic acid salt of (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-methyl-N-phenylbenz [d] oxazol-5-amine ) (61 mg, 47%).

1H NMR (300 MHz, CD3OD) δ 8.84 (s, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 7.61 (d, J= 8.7 Hz, 1H), 7.44 (s, 1H), 7.29 (t, J= 7.8 Hz, 2H), 7.17 (d, J= 7.2 Hz, 1H), 7.04-6.95 (m, 3H), 4.64-4.61 (m, 1H), 3.63-3.58 (m, 2H), 3.37 (s, 3H), 3.25-3.22 (m, 2H), 2.38-2.30 (m, 4H); GC-MS (EI) m/z calcd for C27H27N7O (M+) 465.2, found 465.2. 1 H NMR (300 MHz, CD 3 OD) δ 8.84 (s, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H ), 7.44 (s, 1H), 7.29 (t, J = 7.8 Hz, 2H), 7.17 (d, J = 7.2 Hz, 1H), 7.04-6.95 (m, 3H), 4.64-4.61 (m, 1H) , 3.63-3.58 (m, 2H), 3.37 (s, 3H), 3.25-3.22 (m, 2H), 2.38-2.30 (m, 4H); GC-MS (EI) m / z calcd for C 27 H 27 N 7 O (M + ) 465.2, found 465.2.

<< 실시예Example 25> N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 25> N- (2- (2-amino-5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-3-일)-4-yl) pyridin-3-yl) 벤즈Mercedes Benz [d][d] 옥사졸Oxazole -5-일)-5 days) 아세트아마이드의Acetamide 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00041
Figure 112008025718184-pat00041

실시예 14에서 사용한 프로필아민 대신 아세트아미드를 사용한 것을 제외하고는 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-5-일)아세트아마이드의 이트리플루오로아세트산 염)을 얻었다(13 mg, 90%).Except for using acetamide in place of the propylamine used in Example 14, it was carried out in the same manner as in Step 1 and Step 2 of Example 14 to obtain a solid target compound (N- (2- (2-amino-5- (1 Ditriacetic acid salt of-(piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazol-5-yl) acetamide) 13 mg, 90%).

1H NMR (300 MHz, CD3OD) δ 8.85 (d, J= 2.1 Hz, 1H), 8.38 (d, J= 2.4 Hz, 1H), 8.25 (s, 1H), 8.21 (d, J= 2.1 Hz, 1H), 8.01 (s, 1H), 7.67 (d, J= 8.7 Hz, 1H), 7.53 (dd, J= 8.9, 2.0 Hz, 1H), 4.67-4.58 (m, 1H), 3.62-3.56 (m, 2H), 3.25-3.19 (m, 2H), 2.41-2.27 (m, 4H), 2.17 (s, 3H); GC-MS (EI) m/z calcd for C22H23N7O2 (M+) 417.2, found 417.2. 1 H NMR (300 MHz, CD 3 OD) δ 8.85 (d, J = 2.1 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.25 (s, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.01 (s, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.53 (dd, J = 8.9, 2.0 Hz, 1H), 4.67-4.58 (m, 1H), 3.62-3.56 (m, 2H), 3.25-3.19 (m, 2H), 2.41-2.27 (m, 4H), 2.17 (s, 3H); GC-MS (EI) m / z calcd for C 22 H 23 N 7 O 2 (M + ) 417.2, found 417.2.

<< 실시예Example 26> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 26> 2- (2-amino-5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-3-일)-N--4-yl) pyridin-3-yl) -N- 이소프로필벤즈[d]옥사졸Isopropyl benz [d] oxazole -6--6- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00042
Figure 112008025718184-pat00042

실시예 1에서 사용한 2-아미노-4-클로로페놀과 실시예 14에서 사용한 프로필아민 대신 2-아미노-5-클로로페놀과 이소프로필아민을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소프로필벤즈[d]옥사졸-6-아민의 삼트리플루오로아세트산 염)을 얻었다(8 mg, 99%).Example 1 steps 1 to 6 and except that 2-amino-5-chlorophenol and isopropylamine were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14. In the same manner as in Step 1 and Step 2 of Example 14, the target compound (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) as a solid was obtained. Tripyridine-3-yl) -N-isopropylbenz [d] oxazol-6-amine tritrifluoroacetic acid salt) was obtained (8 mg, 99%).

1H NMR (300 MHz, CD3OD) δ 8.84 (d, J= 2.2 Hz, 1H), 8.34 (d, J= 2.2 Hz, 1H), 8.27 (s, 1H), 8.04 (s, 1H), 7.67 (d, J= 8.7 Hz, 1H), 7.14 (d, J= 1.8 Hz, 1H), 6.99 (dd, J= 2.1, 8.7 Hz, 1H), 4.65-4.60 (m, 1H), 3.64-3.6 (m, 2H), 3.27-3.22 (m, 2H), 2.39-2.36 (m, 4H), 1.31 (d, J= 6.4 Hz, 6H); LC/MS m/z calcd for C23H28N7O (MH+) 418.2, found 418.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.84 (d, J = 2.2 Hz, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.27 (s, 1H), 8.04 (s, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 6.99 (dd, J = 2.1, 8.7 Hz, 1H), 4.65-4.60 (m, 1H), 3.64-3.6 (m, 2H), 3.27-3.22 (m, 2H), 2.39-2.36 (m, 4H), 1.31 (d, J = 6.4 Hz, 6H); LC / MS mlz calcd for C 23 H 28 N 7 O (MH + ) 418.2, found 418.1.

<< 실시예Example 27> 5-(1-(피페리딘-4-일)-1H- 27> 5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)-3-(6-(-4-yl) -3- (6- ( 피롤리딘Pyrrolidine -1-일)-1 day) 벤Ben 즈[Zu [ d]옥사졸d] oxazole -2-일)피리딘-2--2-yl) pyridine-2- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00043
Figure 112008025718184-pat00043

실시예 1에서 사용한 2-아미노-4-클로로페놀과 실시예 14에서 사용한 프로필아민 대신 2-아미노-5-클로로페놀과 피롤리딘을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(5-(1-(피페리딘-4-일)-1H-피라졸-4-일)-3-(6-(피롤리딘-1-일)벤즈[d]옥사졸-2-일)피리딘-2-아민의 삼트리플루오로아세트산 염)을 얻었다(15 mg, 23%).Example 1 steps 1 to 6 and except that 2-amino-5-chlorophenol and pyrrolidine were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14. In the same manner as in Step 1 and Step 2 of Example 14, the target compound (5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3- (6- Tritrifluoroacetic acid salt of (pyrrolidin-1-yl) benz [d] oxazol-2-yl) pyridin-2-amine) (15 mg, 23%).

1H NMR (300 MHz, CD3OD) δ 8.76 (d, J= 2.2 Hz, 1H), 8.31 (d, J= 2.2 Hz, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.61 (d, J= 8.8 Hz, 1H), 6.81 (d, J= 1.9 Hz, 1H), 6.77 (dd, J= 2.3, 8.8 Hz, 1H), 4.65-4.60 (m, 1H), 3.64-3.62 (m, 2H), 3.42-3.38 (m, 4H), 3.27-3.22 (m, 2H), 2.45-2.30 (m, 4H), 2.15-2.05 (m, 4H); LC/MS m/z calcd for C24H28N7O (MH+) 430.2, found 430.3. 1 H NMR (300 MHz, CD 3 OD) δ 8.76 (d, J = 2.2 Hz, 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 1.9 Hz, 1H), 6.77 (dd, J = 2.3, 8.8 Hz, 1H), 4.65-4.60 (m, 1H), 3.64-3.62 (m, 2H), 3.42-3.38 (m, 4H), 3.27-3.22 (m, 2H), 2.45-2.30 (m, 4H), 2.15-2.05 (m, 4H); LC / MS mlz calcd for C 24 H 28 N 7 O (MH + ) 430.2, found 430.3.

<< 실시예Example 28> 3-(6-(피페리딘-1-일) 28> 3- (6- (piperidin-1-yl) 벤즈Mercedes Benz [d][d] 옥사졸Oxazole -2일)-5-(1-(피페리딘-4-일)-1H--2 days) -5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00044
Figure 112008025718184-pat00044

실시예 1에서 사용한 2-아미노-4-클로로페놀과 실시예 14에서 사용한 프로필아민 대신 2-아미노-5-클로로페놀과 피페리딘을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(3-(6-(피페리딘-1-일)벤즈[d]옥사졸-2일)-5-(1-(피페리딘- 4-일)-1H-피라졸-4-일)피리딘-2-아민의 삼트리플루오로아세트산 염)을 얻얻었다(16 mg, 30%).Steps 1 to 6 of Example 1 except that 2-amino-5-chlorophenol and piperidine were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14. In the same manner as in Step 1 and Step 2 of Example 14, the target compound (3- (6- (piperidin-1-yl) benz [d] oxazol-2yl) -5- (1- Tritrifluoroacetic acid salt of (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine) (16 mg, 30%).

1H NMR (300 MHz, DMSO-d 6 ) δ 8.49 (s, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 7.98 (s, 1H), 7.64 (d, J= 8.7 Hz, 1H), 7.27 (s, 1H), 7.12 (d, J= 9.0 Hz, 1H), 4.60-4.50 (m, 1H), 3.46-3.41 (m, 2H), 3.25-3.11 (m, 6H), 2.28-2.12 (m, 4H), 1.70-1.60 (m, 6H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.49 (s, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 7.98 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.27 (s, 1H), 7.12 (d, J = 9.0 Hz, 1H), 4.60-4.50 (m, 1H), 3.46-3.41 (m, 2H), 3.25-3.11 (m, 6H), 2.28 -2.12 (m, 4H), 1.70-1.60 (m, 6H).

<< 실시예Example 29> 3-(6- 29> 3- (6- 모폴리노벤즈[d]옥사졸Morpholinobenz [d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피blood 라졸-4-일)피리딘-2-Razol-4-yl) pyridine-2- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00045
Figure 112008025718184-pat00045

실시예 1에서 사용한 2-아미노-4-클로로페놀과 실시예 14에서 사용한 프로필아민 대신 2-아미노-5-클로로페놀과 모폴린을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(3-(6-모폴리노벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 삼트리플루오로아세트산 염)을 얻었다(33 mg, 52%).Steps 1 to 6 and of Example 1, except that 2-amino-5-chlorophenol and morpholine were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14 The target compound (3- (6-morpholinobenz [d] oxazol-2-yl) -5- (1- (piperidin-4) as a solid was carried out in the same manner as in Step 1 and Step 2 of Example 14. Triylfluoroacetic acid salt of -yl) -1H-pyrazol-4-yl) pyridin-2-amine) (33 mg, 52%).

1H NMR (300 MHz, CD3OD) δ 8.84 (d, J= 2.2 Hz, 1H), 8.35 (d, J= 2.2 Hz, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 8.21 (d, J= 8.9 Hz, 1H), 7.79 (d, J= 2.2 Hz, 1H), 7.21 (dd, J= 2.3, 8.1Hz, 1H), 4.66-4.63 (m, 1H), 3.90-3.84 (m, 4H), 3.64-3.54 (m, 2H), 3.30-3.10 (m, 6H), 2.40-2.30 (m, 4H); LC/MS m/z calcd for C24H28N7O2 (MH+) 446.2, found 446.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.84 (d, J = 2.2 Hz, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 2.2 Hz, 1H), 7.21 (dd, J = 2.3, 8.1 Hz, 1H), 4.66-4.63 (m, 1H), 3.90-3.84 (m, 4H), 3.64-3.54 (m, 2H), 3.30-3.10 (m, 6H), 2.40-2.30 (m, 4H); LC / MS mlz calcd for C 24 H 28 N 7 O 2 (MH + ) 446.2, found 446.1.

<< 실시예Example 30> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 30> 2- (2-amino-5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-3-일)-N--4-yl) pyridin-3-yl) -N- 페닐벤즈[d]옥사졸Phenylbenz [d] oxazole -6--6- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00046
Figure 112008025718184-pat00046

실시예 1에서 사용한 2-아미노-4-클로로페놀과 실시예 14에서 사용한 프로필아민 대신 2-아미노-5-클로로페놀과 아닐린을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-페닐벤즈[d]옥사졸-6-아민의 삼트리플루오로아세트산 염)을 얻었다(46 mg, 65%).Steps 1 to 6 and Example of Example 1, except that 2-amino-5-chlorophenol and aniline were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14 The desired compound as a solid was prepared in the same manner as in Steps 1 and 2 of 14 (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine 3-triyl) -trifluoroacetic acid salt of N-phenylbenz [d] oxazol-6-amine) was obtained (46 mg, 65%).

1H NMR (300 MHz, CD3OD) δ 8.86 (d, J= 2.2 Hz, 1H), 8.33 (d, J= 2.2 Hz, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.66 (d, J= 8.7 Hz, 1H), 7.41 (d, J= 1.8 Hz, 1H), 7.35-7.30 (m, 2H), 7.23-7.14 (m, 3H), 7.01-6.96 (m, 1H), 5.00-4.67 (m, 1H), 3.63-3.56 (m, 2H), 3.26-3.21 (m, 2H), 2.38-2.31 (m, 4H); LC/MS m/z calcd for C26H26N7O (MH+) 452.2, found 452.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.86 (d, J = 2.2 Hz, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.35-7.30 (m, 2H), 7.23-7.14 (m, 3H), 7.01-6.96 (m, 1H) , 5.00-4.67 (m, 1H), 3.63-3.56 (m, 2H), 3.26-3.21 (m, 2H), 2.38-2.31 (m, 4H); LC / MS mlz calcd for C 26 H 26 N 7 O (MH + ) 452.2, found 452.1.

<< 실시예Example 31> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 31> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)-N--4-yl) pyridin-3-yl) -N- 메틸methyl -N--N- 페닐벤즈[d]옥사졸Phenylbenz [d] oxazole -6--6- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00047
Figure 112008025718184-pat00047

실시예 1에서 사용한 2-아미노-4-클로로페놀과 실시예 14에서 사용한 프로필아민 대신 2-아미노-5-클로로페놀과 N-메틸아닐린을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피 리딘-3-일)-N-메틸-N-페닐벤즈[d]옥사졸-6-아민의 삼트리플루오로아세트산 염)을 얻었다(40 mg, 41%).Steps 1 to 6 of Example 1, except that 2-amino-5-chlorophenol and N-methylaniline were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14 And the desired compound as a solid (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazole-4- in the same manner as in Step 1 and Step 2 of Example 14). 1) pyridin-3-yl) -N-methyl-N-phenylbenz [d] oxazol-6-amine tritrifluoroacetic acid salt) was obtained (40 mg, 41%).

1H NMR (300 MHz, DMSO-d 6 ) δ 8.51 (d, J= 2.1 Hz, 1H), 8.43 (d, J= 2.1 Hz, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.38-7.33 (m, 2H), 7.27 (d, J= 1.8 Hz, 1H), 7.15-7.00 (m, 4H), 4.53-4.46 (m, 1H), 3.54-3.40 (m, 2H), 3.36 (s, 3H), 3.13-3.10 (m, 2H), 2.23-2.00 (m, 4H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.51 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.32 (s, 1H), 7.99 (s, 1H) , 7.68 (d, J = 8.4 Hz, 1H), 7.38-7.33 (m, 2H), 7.27 (d, J = 1.8 Hz, 1H), 7.15-7.00 (m, 4H), 4.53-4.46 (m, 1H ), 3.54-3.40 (m, 2H), 3.36 (s, 3H), 3.13-3.10 (m, 2H), 2.23-2.00 (m, 4H).

<< 실시예Example 32> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 32> 2- (2-amino-5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-3-일)-N-(4--4-yl) pyridin-3-yl) -N- (4- 플루오로페닐Fluorophenyl )) 벤즈Mercedes Benz [d][d] 옥사졸Oxazole -6--6- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00048
Figure 112008025718184-pat00048

실시예 1에서 사용한 2-아미노-4-클로로페놀과 실시예 14에서 사용한 프로필아민 대신 2-아미노-5-클로로페놀과 4-플루오로아닐린을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(4-플루오로페닐)벤즈[d]옥사졸-6-아민의 삼트리플루오로아세트 산 염)을 얻었다(26 mg, 50%).Steps 1 to 1 of Example 1, except that 2-amino-5-chlorophenol and 4-fluoroaniline were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14 6 and the same procedure as in Step 1 and Step 2 of Example 14 to give the target compound of the solid (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazole-4 -Yl) pyridin-3-yl) -N- (4-fluorophenyl) benz [d] oxazol-6-amine tritrifluoroacetic acid salt) was obtained (26 mg, 50%).

1H NMR (300 MHz, CD3OD) δ 8.82 (s, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 8.02 (s, 1H), 7.63 (d, J= 9.0 Hz, 1H), 7.29 (s, 1H), 7.23-7.18 (m, 2H), 7.09-7.03 (m, 3H), 4.63-4.59 (m, 1H), 3.61-3.57 (m, 2H), 3.24-3.21 (m, 2H), 2.36-2.28 (m, 4H); LC/MS m/z calcd for C26H25FN7O (MH+) 470.2, found 470.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.82 (s, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 8.02 (s, 1H), 7.63 (d, J = 9.0 Hz, 1H ), 7.29 (s, 1H), 7.23-7.18 (m, 2H), 7.09-7.03 (m, 3H), 4.63-4.59 (m, 1H), 3.61-3.57 (m, 2H), 3.24-3.21 (m , 2H), 2.36-2.28 (m, 4H); LC / MS mlz calcd for C 26 H 25 FN 7 O (MH + ) 470.2, found 470.1.

<< 실시예Example 33> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 33> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)-N-(2,6--4-yl) pyridin-3-yl) -N- (2,6- 디플루오로페닐Difluorophenyl )) 벤즈Mercedes Benz [d][d] 옥사졸Oxazole -6--6- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 Salt 제조Produce

Figure 112008025718184-pat00049
Figure 112008025718184-pat00049

실시예 1에서 사용한 2-아미노-4-클로로페놀과 실시예 14에서 사용한 프로필아민 대신 2-아미노-5-클로로페놀과 2,6-디플루오로아닐린을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸- 4-일)피리딘-3-일)-N-(2,6-디플루오로페닐)벤즈[d]옥사졸-6-아민의 삼트리플루오로아세트산 염)을 얻었다(18 mg, 23%).The steps of Example 1, except that 2-amino-5-chlorophenol and 2,6-difluoroaniline were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14. 1 to 6 and the same procedure as in Step 1 and Step 2 of Example 14 to give a solid target compound (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyra) Sol-4-yl) pyridin-3-yl) -N- (2,6-difluorophenyl) benz [d] oxazol-6-amine tritrifluoroacetic acid salt) was obtained (18 mg, 23 %).

1H NMR (300 MHz, CD3OD) δ 8.74 (s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.63 (d, J= 9.1 Hz, 1H), 7.18 (m, 1H), 6.92 (m, 2H), 6.74 (m, 2H), 4.59 (m, 1H), 3.60 (m, 2H), 3.20 (m, 2H), 2.35 (m, 4H); LC/MS m/z calcd for C26H24F2N7O (MH+) 488.2, found 488.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.74 (s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.63 (d, J = 9.1 Hz, 1H ), 7.18 (m, 1H), 6.92 (m, 2H), 6.74 (m, 2H), 4.59 (m, 1H), 3.60 (m, 2H), 3.20 (m, 2H), 2.35 (m, 4H) ; LC / MS mlz calcd for C 26 H 24 F 2 N 7 O (MH + ) 488.2, found 488.1.

<< 실시예Example 34> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 34> 2- (2-amino-5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-3-일)-N-(3,5--4-yl) pyridin-3-yl) -N- (3,5- 디플루오로페닐Difluorophenyl )) 벤즈Mercedes Benz [d][d] 옥사졸Oxazole -6--6- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 Salt 제조Produce

Figure 112008025718184-pat00050
Figure 112008025718184-pat00050

실시예 1에서 사용한 2-아미노-4-클로로페놀과 실시예 14에서 사용한 프로필아민 대신 2-아미노-5-클로로페놀과 3,5-디플루오로아닐린을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 14의 단계 1 및 단계 2와 동일한 방 법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(3,5-디플루오로페닐)벤즈[d]옥사졸-6-아민의 삼트리플루오로아세트산 염)을 얻었다(56 mg, 73%).The steps of Example 1, except that 2-amino-5-chlorophenol and 3,5-difluoroaniline were used in place of the 2-amino-4-chlorophenol used in Example 1 and the propylamine used in Example 14 1 to 6 and the same procedure as in Step 1 and Step 2 of Example 14 was carried out in the same manner as the target compound of solid (2- (2-amino-5- (1- (piperidin-4-yl) -1H- Pyrazol-4-yl) pyridin-3-yl) -N- (3,5-difluorophenyl) benz [d] oxazol-6-amine tritrifluoroacetic acid salt) was obtained (56 mg, 73%).

1H NMR (300 MHz, CD3OD) δ 8.74 (s, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.81 (s, 1H), 7.63 (d, J= 9.0 Hz, 1H), 7.42 (s, 1H), 7.10 (d, J= 8.4 Hz, 1H), 6.58 (d, J= 9.9 Hz, 2H), 6.36 (m, 1H), 4.59 (m, 1H), 3.58 (m, 2H), 3.20 (m, 2H), 2.32 (m, 4H); LC/MS m/z calcd for C26H24F2N7O (MH+) 488.2, found 488.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.74 (s, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.81 (s, 1H), 7.63 (d, J = 9.0 Hz, 1H ), 7.42 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 9.9 Hz, 2H), 6.36 (m, 1H), 4.59 (m, 1H), 3.58 (m , 2H), 3.20 (m, 2H), 2.32 (m, 4H); LC / MS mlz calcd for C 26 H 24 F 2 N 7 O (MH + ) 488.2, found 488.1.

<< 실시예Example 35> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 35> 2- (2-amino-5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-3-일)-N-(3,5--4-yl) pyridin-3-yl) -N- (3,5- 비스(트라이플루오로메틸)페닐Bis (trifluoromethyl) phenyl )) 벤즈Mercedes Benz [d][d] 옥사졸Oxazole -6--6- 아민의Amine 삼트리플루오로Tritrifluoro 아세트산 Acetic acid 염의Salt 제조 Produce

Figure 112008025718184-pat00051
Figure 112008025718184-pat00051

실시예 1에서 사용한 2-아미노-4-클로로페놀과 실시예 14에서 사용한 프로필아민 대신 2-아미노-5-클로로페놀과 3,5-디(트리플루오로메틸)아닐린을 사용한 것 을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(3,5-비스(트라이플루오로메틸)페닐)벤즈[d]옥사졸-6-아민의 삼트리플루오로아세트산 염)을 얻었다(51 mg, 58%).Except for using 2-amino-5-chlorophenol and 3,5-di (trifluoromethyl) aniline instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14 In the same manner as in Step 1 to Step 6 of Example 1 and Step 1 and Step 2 of Example 14, the target compound (2- (2-amino-5- (1- (piperidin-4-yl) Samtrifluoroacetic acid of) -1H-pyrazol-4-yl) pyridin-3-yl) -N- (3,5-bis (trifluoromethyl) phenyl) benz [d] oxazol-6-amine Salt) was obtained (51 mg, 58%).

1H NMR (300 MHz, CD3OD) δ 8.79 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.79 (d, J= 8.4 Hz, 1H), 7.57 (s, 3H), 7.35 (s, 1H), 7.25 (d, J= 9.0 Hz, 1H), 4.64-4.57 (m, 1H), 3.61-3.57 (m, 2H), 3.24-3.21 (m, 2H), 2.36-2.28 (m, 4H); LC/MS m/z calcd for C28H24F6N7O (MH+) 588.2, found 588.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.79 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H ), 7.57 (s, 3H), 7.35 (s, 1H), 7.25 (d, J = 9.0 Hz, 1H), 4.64-4.57 (m, 1H), 3.61-3.57 (m, 2H), 3.24-3.21 ( m, 2H), 2.36-2.28 (m, 4H); LC / MS mlz calcd for C 28 H 24 F 6 N 7 O (MH + ) 588.2, found 588.1.

<< 실시예Example 36> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 36> 2- (2-amino-5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-3-일)-4-yl) pyridin-3-yl) 벤즈Mercedes Benz [d][d] 옥사졸Oxazole -5--5- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00052
Figure 112008025718184-pat00052

실시예 14에서 사용한 프로필아민 대신 2,4-디메톡시페닐메틸아민을 사용한 것을 제외하고는 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-5-아민의 삼트리플루오로아세트산 염)을 얻었다(55 mg, 93%).Except for using 2,4-dimethoxyphenylmethylamine in place of the propylamine used in Example 14, the procedure was carried out in the same manner as in Step 1 and Step 2 of Example 14 to obtain the target compound as a solid (2- (2-amino- 5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazol-5-amine tritrifluoroacetic acid salt) was obtained. (55 mg, 93%).

1H NMR (300 MHz, CD3OD) δ 8.76 (d, J= 1.8 Hz, 1H), 8.43 (d, J= 2.4 Hz, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.77 (d, J= 8.7 Hz, 1H), 7.64 (d, J= 2.1 Hz, 1H), 7.32 (dd, J= 8.7, 2.1 Hz, 1H), 4.64-4.58 (m, 1H), 3.60 (d, J= 13.5 Hz, 2H), 3.23 (d, J= 9.0 Hz, 2H), 2.42-2.30 (m, 4H); GC-MS (EI) m/z calcd for C20H21N7 (M+) 375.2, found 375.2. 1 H NMR (300 MHz, CD 3 OD) δ 8.76 (d, J = 1.8 Hz, 1H), 8.43 (d, J = 2.4 Hz, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 8.7, 2.1 Hz, 1H), 4.64-4.58 (m, 1H), 3.60 (d , J = 13.5 Hz, 2H), 3.23 (d, J = 9.0 Hz, 2H), 2.42-2.30 (m, 4H); GC-MS (EI) m / z calcd for C 20 H 21 N 7 (M + ) 375.2, found 375.2.

<< 실시예Example 37> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 37> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)--4-yl) pyridin-3-yl)- 벤즈[d]옥사졸Mercedes-Benz [d] oxazole -6--6- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00053
Figure 112008025718184-pat00053

실시예 1에서 사용한 2-아미노-4-클로로페놀과 실시예 14에서 사용한 프로필아민 대신 2-아미노-5-클로로페놀과 2,4-디메톡시페닐메틸아민을 사용한 것을 제외 하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 14의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-벤즈[d]옥사졸-6-아민의 삼트리플루오로아세트산 염)을 얻었다(8 mg, 95%).Example 2 except that 2-amino-5-chlorophenol and 2,4-dimethoxyphenylmethylamine were used instead of 2-amino-4-chlorophenol used in Example 1 and propylamine used in Example 14. Performing the same procedure as in Step 1 to Step 6 and Step 1 and Step 2 of Example 14 to give the target compound (2- (2-amino-5- (1- (piperidin-4-yl) -1H-) as a solid Pyrazol-4-yl) pyridin-3-yl) -benz [d] oxazol-6-amine) tritrifluoroacetic acid salt) (8 mg, 95%).

1H NMR (300 MHz, CD3OD) δ 8.68 (d, J= 2.2 Hz, 1H), 8.33 (d, J= 2.2 Hz, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.57 (d, J= 8.6 Hz, 1H), 7.01 (d, J= 2.0 Hz, 1H), 6.94 (dd, J= 2.0, 8.6 Hz, 1H), 4.64-4.62 (m, 1H), 3.64-3.55 (m, 2H), 3.30-3.20 (m, 2H), 2.40-2.31 (m, 4H); LC/MS m/z calcd for C20H22N7O (MH+) 376.2, found 376.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.68 (d, J = 2.2 Hz, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 2.0, 8.6 Hz, 1H), 4.64-4.62 (m, 1H), 3.64-3.55 (m, 2H), 3.30-3.20 (m, 2H), 2.40-2.31 (m, 4H); LC / MS mlz calcd for C 20 H 22 N 7 O (MH + ) 376.2, found 376.1.

<< 실시예Example 38> 3-(5- 38> 3- (5- 에톡시벤즈[d]옥사졸Ethoxybenz [d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피라Fira 졸-4-일)피리딘-2-Zol-4-yl) pyridin-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

단계 1: 3급-부틸-4-(4-(6-(3급-Step 1: tert-butyl-4- (4- (6- (tert- 부틸아미노Butylamino )-5-(5-) -5- (5- 하이드록시벤즈[d]옥사졸Hydroxybenz [d] oxazole -2-일)피리딘-3-일)-1H--2-yl) pyridin-3-yl) -1H- 피라졸Pyrazole -1-일)피페리딘-1--1-yl) piperidine-1- 카복실레이트의Carboxylate 제조 Produce

Figure 112008025718184-pat00054
Figure 112008025718184-pat00054

고압반응용기에 3급-부틸-4-(4-(6-(3급-부틸아미노)-5-(5-클로로벤즈[d]옥사졸-2-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트(1.0 g, 1.8 mmol), 수산화칼륨(310 mg), 트리스(디벤질리딘아세톤)디팔라듐(339 mg), 2-디-3급-부틸포스피노-2',4,'6'-트리이소프로필바이페닐(314 mg) 및 증류수/1,4-디옥산(1/1, 5.5 mL)를 넣고 질소로 반응용기의 공기를 치환한 후 밀봉하였다. 반응물을 105 ℃에서 24시간 동안 교반하고, 반응물의 온도를 실온으로 냉각시킨 후 메틸렌클로라이드로 희석하고 셀라이트를 이용하여 여과하였다. 여액을 농축하고 농축물을 관크로마토그래피로 정제하여 연두색 고체의 목적화합물(3급-부틸-4-(4-(6-(3급-부틸아미노)-5-(5-하이드록시벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트)을 얻었다(291 mg, 30%).Tert-butyl-4- (4- (6- (tert-butylamino) -5- (5-chlorobenz [d] oxazol-2-yl) -1H-pyrazol-1- 1) piperidine-1-carboxylate (1.0 g, 1.8 mmol), potassium hydroxide (310 mg), tris (dibenzylideneacetone) dipalladium (339 mg), 2-di-tert-butylphosphino- 2 ', 4,' 6'-triisopropylbiphenyl (314 mg) and distilled water / 1,4-dioxane (1/1, 5.5 mL) were added thereto, the air of the reaction vessel was replaced with nitrogen, and sealed. The reaction was stirred at 105 ° C. for 24 hours, the temperature of the reaction was cooled to room temperature, diluted with methylene chloride and filtered using Celite. Compound (tert-butyl-4- (4- (6- (tert-butylamino) -5- (5-hydroxybenz [d] oxazol-2-yl) pyridin-3-yl) -1H- Pyrazol-1-yl) piperidine-1-carboxylate) (291 mg, 30%).

1H NMR (300 MHz, CDCl3) δ 8.70 (s, 1H), 8.83 (d, J= 2.5 Hz, 1H), 8.22 (d, J= 2.5 Hz, 1H), 7.79 (s, 1H), 7.64 (s, 1H), 7.38 (d, J= 8.7 Hz, 1H), 7.18 (d, J= 2.4 Hz, 1H), 6.91 (dd, J= 8.7, 2.4 Hz, 1H), 4.38-4.29 (m, 3H), 2.92 (t, J= 12.2 Hz, 2H), 2.22-2.18 (m, 2H), 2.01-1.96 (m, 2H), 1.58 (s, 9H), 1.50 (s, 9H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.70 (s, 1H), 8.83 (d, J = 2.5 Hz, 1H), 8.22 (d, J = 2.5 Hz, 1H), 7.79 (s, 1H), 7.64 (s, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.91 (dd, J = 8.7, 2.4 Hz, 1H), 4.38-4.29 (m, 3H), 2.92 (t, J = 12.2 Hz, 2H), 2.22-2.18 (m, 2H), 2.01-1.96 (m, 2H), 1.58 (s, 9H), 1.50 (s, 9H).

단계 2: 3급-부틸-4-(4-(6-(3급-Step 2: tert-butyl-4- (4- (6- (tert- 부틸아미노Butylamino )-5-(5-) -5- (5- 하이드록시벤즈[d]옥사졸Hydroxybenz [d] oxazole -2-일)피리딘-3-일)-1H--2-yl) pyridin-3-yl) -1H- 피라졸Pyrazole -1-일)피페리딘-1--1-yl) piperidine-1- 카복실레이트의Carboxylate 제조 Produce

Figure 112008025718184-pat00055
Figure 112008025718184-pat00055

고압반응용기에 3급-부틸 4-(4-(6-(3급-부틸아미노)-5-(5-하이드록시벤즈[d]옥사졸-2-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트(27 mg, 0.051 mmol), 탄산칼륨(28 mg), 요오드화칼륨(2 mg), 에틸 요오드(0.008 mL)와 디메틸포름아미드(0.5 mL)를 넣고 밀봉하였다. 반응물을 실온에서 48시간 동안 교반한 후, 물을 넣고 에틸 아세테이트로 추출하였다. 유기층을 무수 황산마그네슘으로 건조하고 감압농축하였다. 농축물을 관크로마토그래피로 정제하여 연두색 고체의 목적화합물(3급-부틸-4-(4-(6-(3급-부틸아미노)-5-(5-에톡시벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트)을 얻었다(12 mg, 43%).Tert-butyl 4- (4- (6- (tert-butylamino) -5- (5-hydroxybenz [d] oxazol-2-yl) -1H-pyrazole-1- in a high pressure reaction vessel (1) Piperidine-1-carboxylate (27 mg, 0.051 mmol), potassium carbonate (28 mg), potassium iodide (2 mg), ethyl iodine (0.008 mL) and dimethylformamide (0.5 mL) were added and sealed. After the reaction was stirred for 48 hours at room temperature, water was added, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. -Butyl-4- (4- (6- (tert-butylamino) -5- (5-ethoxybenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazole-1 -Yl) piperidine-1-carboxylate) (12 mg, 43%).

1H NMR (300 MHz, CDCl3) δ 8.72 (s, 1H), 8.42 (d, J= 2.5 Hz, 1H), 8.30 (d, J= 2.5 Hz, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.43 (d, J= 8.8 Hz, 1H), 7.20 (d, J= 2.4 Hz, 1H), 6.94 (dd, J= 8.9, 2.5 Hz, 1H), 4.36-4.27 (m, 3H), 4.11 (q, J= 7.0 Hz, 2H), 2.92 (t, J= 12.0 Hz, 2H), 2.20-2.12 (m, 2H), 2.04-1.90 (m, 2H), 1.61 (s, 9H), 1.49-1.44 (m, 12H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.72 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.9, 2.5 Hz, 1H), 4.36-4.27 (m, 3H), 4.11 (q, J = 7.0 Hz, 2H), 2.92 (t, J = 12.0 Hz, 2H), 2.20-2.12 (m, 2H), 2.04-1.90 (m, 2H), 1.61 (s, 9H ), 1.49-1.44 (m, 12H).

단계 3: 3-(5-Step 3: 3- (5- 에톡시벤즈[d]옥사졸Ethoxybenz [d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00056
Figure 112008025718184-pat00056

반응용기에 3급-부틸-4-(4-(6-(3급-부틸아미노)-5-(5-에톡시벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트(12 mg, 0.021 mmol) 및 트리플루오로아세트산(1 mL)을 넣고 60 ℃에서 24시간 동안 교반하였다. 반응물의 온도를 실온으로 낮추고, 감압농축하였다. 농축물에 에틸에테르를 넣고 30분 동안 교반한 후 여과하여 연두색 고체의 목적화합물(3-(5-에톡시벤즈[d]옥사졸-2- 일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(7 mg, 54%).Tert-butyl-4- (4- (6- (tert-butylamino) -5- (5-ethoxybenz [d] oxazol-2-yl) pyridin-3-yl) -1H in the reaction vessel Pyrazol-1-yl) piperidine-1-carboxylate (12 mg, 0.021 mmol) and trifluoroacetic acid (1 mL) were added and stirred at 60 ° C. for 24 hours. The temperature of the reaction was lowered to room temperature and concentrated under reduced pressure. Ethyl ether was added to the concentrate, followed by stirring for 30 minutes, followed by filtration to give the title compound (3- (5-ethoxybenz [d] oxazol-2-yl) -5- (1- (piperidine-) as a light green solid. 4-tri) -1H-pyrazol-4-yl) pyrifluoroacetic acid salt) was obtained (7 mg, 54%).

1H NMR (300 MHz, CD3OD) δ 8.78 (d, J= 1.8 Hz, 1H), 8.35 (d, J= 1.8 Hz, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.58 (d, J= 9.0 Hz, 1H), 7.30 (d, J= .2.4 Hz, 1H), 7.06 (dd, J= 8.9, 2.6 Hz, 1H), 4.63-4.60 (m, 1H), 4.09 (q, J= 7.2 Hz, 2H), 3.62-3.57 (m, 2H), 3.25-3.20 (m, 2H), 2.37-2.29 (m, 4H), 1.43 (t, J= 6.9 Hz, 3H); GC-MS (EI) m/z calcd for C22H24N6O2(M+) 404.2, found 404.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.78 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.30 (d, J = .2.4 Hz, 1H), 7.06 (dd, J = 8.9, 2.6 Hz, 1H), 4.63-4.60 (m, 1H), 4.09 ( q, J = 7.2 Hz, 2H), 3.62-3.57 (m, 2H), 3.25-3.20 (m, 2H), 2.37-2.29 (m, 4H), 1.43 (t, J = 6.9 Hz, 3H); GC-MS (EI) m / z calcd for C 22 H 24 N 6 O 2 (M + ) 404.2, found 404.1.

<< 실시예Example 39> 3-(5- 39> 3- (5- 메톡시벤즈[d]옥사졸Methoxy benz [d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피라Fira 졸-4-일)피리딘-2-Zol-4-yl) pyridin-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00057
Figure 112008025718184-pat00057

실시예 38에서 사용한 에틸요오드 대신 메틸요오드를 사용한 것을 제외하고는 실시예 38의 단계 1 내지 단계 3의 동일한 방법으로 수행하여 고체의 목적화합물(3-(5-메톡시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘- 2-아민의 이트리플루오로아세트산 염)을 얻었다(15 mg, 81%).The target compound (3- (5-methoxybenz [d] oxazole-) was prepared by the same method as in Step 1 to Step 3 of Example 38, except that methyl iodine was used instead of ethyl iodine used in Example 38. 2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine trifluoroacetic acid salt) was obtained (15 mg, 81% ).

1H NMR (300 MHz, CD3OD) δ 8.80 (d, J= 2.1 Hz, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 8.00 (s. 1H), 7.60 (d, J= 8.9 Hz, 1H), 7.33 (d, J= 2.3 Hz, 1H), 7.08 (dd, J= 9.0, 2.5 Hz, 1H), 4.66-4.59 (m, 1H), 3.88 (s, 3H), 3.63-3.59 (m, 2H), 3.26-3.23 (m, 2H), 2.38-2.31 (m, 4H); GC-MS (EI) m/z calcd for C21H22N6O2 (M+) 390.2, found 391.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.80 (d, J = 2.1 Hz, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 8.00 (s. 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.08 (dd, J = 9.0, 2.5 Hz, 1H), 4.66-4.59 (m, 1H), 3.88 (s, 3H), 3.63 -3.59 (m, 2H), 3.26-3.23 (m, 2H), 2.38-2.31 (m, 4H); GC-MS (EI) m / z calcd for C 21 H 22 N 6 O 2 (M + ) 390.2, found 391.1.

<< 실시예Example 40> 3-(6- 40> 3- (6- 메톡시벤즈[d]옥사졸Methoxy benz [d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피라Fira 졸-4-일)피리딘-2-Zol-4-yl) pyridin-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00058
Figure 112008025718184-pat00058

실시예 1에서 사용한 2-아미노-4-클로로페놀과 실시예 38에서 사용한 에틸요오드 대신 2-아미노-5-클로로페놀과 메틸요오드를 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 38의 단계 1 내지 단계 3과 동일한 방법으로 수행하여 고체의 목적화합물(3-(6-메톡시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)- 1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(10 mg, 46%).Steps 1 to 6 and of Example 1, except that 2-amino-5-chlorophenol and methyliodine were used instead of the 2-amino-4-chlorophenol used in Example 1 and the ethyl iodine used in Example 38 The desired compound (3- (6-methoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-) as a solid was carried out in the same manner as in steps 1 to 3 of Example 38. 1)-1H-pyrazol-4-yl) pyrifluoroacetic acid salt) of (i mg, 46%).

1H NMR (300 MHz, CD3OD) δ 8.71 (s, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.69 (d, J= 8.7 Hz, 1H), 7.30 (s, 1H), 7.06, J= 7.5 Hz, 1H), 4.75-4.60 (m, 3H),　3.91 (s, 3H), 3.62-3.57 (m, 2H), 2.50-2.36 (m, 4H); LC/MS m/z calcd for C21H23N6O2 (MH+) 391.2, found (M++1) 391.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.71 (s, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H ), 7.30 (s, 1H), 7.06, J = 7.5 Hz, 1H), 4.75-4.60 (m, 3H), 3.91 (s, 3H), 3.62-3.57 (m, 2H), 2.50-2.36 (m, 4H); LC / MS mlz calcd for C 21 H 23 N 6 O 2 (MH + ) 391.2, found (M + +1) 391.1.

<< 실시예Example 41> 3-(6- 41> 3- (6- 에톡시벤즈[d]옥사졸Ethoxybenz [d] oxazole -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피라Fira 졸-4-일)피리딘-2-Zol-4-yl) pyridin-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00059
Figure 112008025718184-pat00059

실시예 1에서 사용한 2-아미노-4-클로로페놀 대신 2-아미노-5-클로로페놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 38의 단계 1 내지 단계 3과 동일한 방법으로 수행하여 고체의 목적화합물(3-(6-에톡시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아 세트산 염)을 얻었다(19 mg, 89%).The same method as Steps 1 to 6 of Example 1 and Steps 1 to 3 of Example 38, except that 2-amino-5-chlorophenol was used instead of 2-amino-4-chlorophenol used in Example 1 Solid as the target compound (3- (6-ethoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl Ditrifluoroacetic acid salt of pyridin-2-amine) (19 mg, 89%).

1H NMR (300 MHz, CD3OD) δ 8.82 (d, J= 2.2 Hz, 1H), 8.37 (d, J= 2.2 Hz, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.72 (d, J= 8.8 Hz, 1H), 7.31 (d, J= 2.2 Hz, 1H), 7.08 (dd, J= 2.4, 8.8 Hz, 1H), 4.70-4.60 (m, 1H), 4.16 (q, J= 6.9 Hz, 1H), 3.64-3.59 (m, 2H), 3.30-3.20 (m, 2H), 2.39-2.36 (m, 4H), 1.47 (t,　J= 6.0 Hz, 3H); LC/MS m/z calcd for C22H25N6O2 (MH+) 405.2, found 405.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.82 (d, J = 2.2 Hz, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.31 (d , J = 2.2 Hz, 1H), 7.08 (dd, J = 2.4, 8.8 Hz, 1H), 4.70-4.60 (m, 1H), 4.16 (q , J = 6.9 Hz, 1H), 3.64-3.59 (m, 2H), 3.30-3.20 (m, 2H), 2.39-2.36 (m, 4H), 1.47 (t, J = 6.0 Hz, 3H); LC / MS mlz calcd for C 22 H 25 N 6 O 2 (MH + ) 405.2, found 405.1.

<< 실시예Example 42> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 42> 2- (2-amino-5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-3-일)-4-yl) pyridin-3-yl) 벤즈Mercedes Benz [[ dd ]] 옥사졸Oxazole -6-일 -6- days 메탄설포네이트의Methanesulfonate 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00060
Figure 112008025718184-pat00060

실시예 1에서 사용한 2-아미노-4-클로로페놀과 실시예 38에서 사용한 에틸요오드 대신 2-아미노-5-클로로페놀과 메탄설포닐클로라이드를 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 38의 단계 1 내지 단계 3과 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라 졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-일 메탄설포네이트의 이트리플루오로아세트산 염)을 얻었다(19 mg, 87%).Steps 1 through 6 of Example 1, except that 2-amino-5-chlorophenol and methanesulfonylchloride were used instead of 2-amino-4-chlorophenol used in Example 1 and ethyl iodine used in Example 38 And the desired compound as a solid (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazole-4-) in the same manner as in steps 1 to 3 of Example 38. 1) pyridin-3-yl) benz [ d ] ditrifluoroacetic acid salt of oxazol-6-yl methanesulfonate) was obtained (19 mg, 87%).

1H NMR (300 MHz, CD3OD) d 8.64 (d, J= 2.4 Hz, 1H), 8.57 (d, J= 2.4 Hz, 1H), 8.44 (s, 1H), 7.99 (s, 1H), 7.92 (d, J= 8.7 Hz, 1H), 3.07 (m, 2H), 7.45 (dd, J= 8.6, 1.8 Hz, 1H), 4.52 (m, 1H), 3.45 (s, 3H), 3.35 (m, 2H), 3.10 (m, 1H), 2.21 (m, 4H); LC/MS m/z calcd for C21H22N6O4S (MH+) 454.1, found 454.5. 1 H NMR (300 MHz, CD 3 OD) d 8.64 (d, J = 2.4 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.44 (s, 1H), 7.99 (s, 1H), 7.92 (d, J = 8.7 Hz, 1H), 3.07 (m, 2H), 7.45 (dd, J = 8.6, 1.8 Hz, 1H), 4.52 (m, 1H), 3.45 (s, 3H), 3.35 (m , 2H), 3.10 (m, 1 H), 2.21 (m, 4 H); LC / MS mlz calcd for C 21 H 22 N 6 O 4 S (MH + ) 454.1, found 454.5.

<< 실시예Example 43> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 43> 2- (2-amino-5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-3-일)-4-yl) pyridin-3-yl) 벤즈Mercedes Benz [d][d] 옥사졸Oxazole -5-올의 -5-all 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00061
Figure 112008025718184-pat00061

실시예 38의 단계 1과 동일한 방법으로 수행한 뒤 다음과 같은 단계 4를 수행하였다.Step 4 was carried out in the same manner as in Step 1 of Example 38, and then Step 4 was performed.

반응용기에 3급-부틸-4-(4-(6-(3급-부틸아미노)-5-(5-하이드록시벤즈[d]옥사졸-2-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트(11 mg, 0.021 mmol) 및 트리플 루오로아세트산(1 mL)을 넣고 60 ℃에서 24시간 동안 교반하였다. 반응물의 온도를 실온으로 낮추고, 감압농축하였다. 농축물에 에틸에테르를 넣고 30분 동안 교반한 후 여과하여 연두색 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-5-올의 이트리플루오로아세트산 염)을 얻었다(12 mg, 92%). Tert-butyl-4- (4- (6- (tert-butylamino) -5- (5-hydroxybenz [d] oxazol-2-yl) -1H-pyrazol-1- I) piperidine-1-carboxylate (11 mg, 0.021 mmol) and triple luoroacetic acid (1 mL) were added and stirred for 24 hours at 60 ° C. The reaction was cooled to room temperature and concentrated under reduced pressure. Ethyl ether was added to the water and stirred for 30 minutes, followed by filtration to obtain the title compound as a light green solid (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl). ) Pyridin-3-yl) benz [d] oxazol-5-ol ditrifluoroacetic acid salt) (12 mg, 92%).

1H NMR (300 MHz, CD3OD) δ 8.82 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.00 (s, 1H), 7.52 (d, J= 9.0 Hz, 1H), 7.15 (s, 1H), 6.95 (dd, J= 8.7, 1.8 Hz, 1H), 4.62-4.58 (m, 1H), 3.60 (d, J= 13.5 Hz, 2H), 3.24 (d, J= 9.0 Hz, 2H), 2.40-2.24 (m, 4H); GC-MS (EI) m/z calcd for C20H20N6O2 (M+) 376.2, found 376.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.82 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.00 (s, 1H), 7.52 (d, J = 9.0 Hz, 1H ), 7.15 (s, 1H), 6.95 (dd, J = 8.7, 1.8 Hz, 1H), 4.62-4.58 (m, 1H), 3.60 (d, J = 13.5 Hz, 2H), 3.24 (d, J = 9.0 Hz, 2H), 2.40-2.24 (m, 4H); GC-MS (EI) m / z calcd for C 20 H 20 N 6 O 2 (M + ) 376.2, found 376.1.

<< 실시예Example 44> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 44> 2- (2-amino-5- (1- (piperidin-4-yl) -1 H- 피라졸Pyrazole -4-일)피리딘-3-일)-4-yl) pyridin-3-yl) 벤즈Mercedes Benz [d][d] 옥사졸Oxazole -6-올의 6-ol 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00062
Figure 112008025718184-pat00062

실시예 44를 얻기 위해, 실시예 1에서 사용한 2-아미노-4-클로로페놀 대신 2-아미노-5-클로로페놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 6 및 실시예 43과 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-올의 이트리플루오로아세트산 염)을 얻었다(20 mg, 78%).To obtain Example 44, the same as in Example 1 Step 1 to Step 6 and Example 43, except that 2-amino-5-chlorophenol was used instead of the 2-amino-4-chlorophenol used in Example 1 The desired compound as a solid (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] Ditrifluoroacetic acid salt of oxazole-6-ol) (20 mg, 78%).

1H NMR (300 MHz, CD3OD) δ 8.81 (d, J= 2.1Hz, 1H), 8.35 (d, J= 2.2 Hz, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 7.64 (d, J= 8.7 Hz, 1H), 7.12 (d, J= 2.1 Hz, 1H), 6.96 (dd, J= 2.1, 8.5 Hz, 1H), 4.67-4.60 (m, 1H), 3.64-3.56 (m, 2H), 3.30-3.20 (m, 2H), 2.40-2.30 (m, 4H); LC/MS m/z calcd for C20H21N6O2 (MH+) 377.2, found 377.1. 1 H NMR (300 MHz, CD 3 OD) δ 8.81 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.96 (dd, J = 2.1, 8.5 Hz, 1H), 4.67-4.60 (m, 1H), 3.64-3.56 (m, 2H), 3.30-3.20 (m, 2H), 2.40-2.30 (m, 4H); LC / MS mlz calcd for C 20 H 21 N 6 O 2 (MH + ) 377.2, found 377.1.

<< 실시예Example 45> 3-( 45> 3- ( 벤즈[d]옥사졸Mercedes-Benz [d] oxazole -2-일)-5-(1--2-yl) -5- (1- 메틸methyl -1H--1H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 제조 Produce

단계 1: 3-(Step 1: 3- ( 벤즈[d]옥사졸Mercedes-Benz [d] oxazole -2일)-N-3급-부틸-5-(-2 days) -N-tert-butyl-5- ( 1메틸1 methyl -1H--1H- 피라졸Pyrazole -4-일)피리딘-2-아민의 제조Preparation of -4-yl) pyridin-2-amine

Figure 112008025718184-pat00063
Figure 112008025718184-pat00063

반응용기에 5-브로모-N-3급-부틸-3-(벤즈[d]옥사졸-2-일)피리딘-2-아민(20 mg, 0.058 mmol), 1-메틸피라졸-4-보론산 피나콜에스테르(36 mg), 비스트리페닐포스핀디클로로팔라듐(2 mg) 및 1,4-디옥산(30 mL)을 넣고 질소분위기 및 실온에서 30분 동안 교반하였다. 반응물에 1 M 탄산나트륨 수용액(0.17 mL)을 넣고 2시간 동안 100 ℃에서 교반하였다. 실온으로 냉각한 후 반응물을 셀라이트를 이용하여 여과시키고 메틸렌클로라이드로 씻어주었다. 여액을 농축하고, 농축물을 관크로마토그래피로 정제하여 연두색 고체의 목적화합물(3-(벤즈[d]옥사졸-2일)-N-3급-부틸-5-(1메틸-1H-피라졸-4-일)피리딘-2-아민)을 얻었다(16 mg, 80%).5-bromo-N-tert-butyl-3- (benz [d] oxazol-2-yl) pyridin-2-amine (20 mg, 0.058 mmol), 1-methylpyrazole-4- in the reaction vessel Boronic acid pinacol ester (36 mg), bistriphenylphosphinedichloropalladium (2 mg), and 1,4-dioxane (30 mL) were added thereto, and the mixture was stirred at a nitrogen atmosphere and room temperature for 30 minutes. 1 M aqueous sodium carbonate solution (0.17 mL) was added to the reaction and stirred at 100 ° C. for 2 hours. After cooling to room temperature, the reaction was filtered through celite and washed with methylene chloride. The filtrate was concentrated and the concentrate was purified by column chromatography to give the title compound (3- (benz [d] oxazol-2yl) -N-tert-butyl-5- (1methyl-1H-pyra) as a light green solid. Zol-4-yl) pyridin-2-amine) (16 mg, 80%).

1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.43 (d, J= 2.5 Hz, 1H), 8.34 (d, J= 2.5 Hz, 1H), 7.76-7.71 (m, 2H), 7.60-7.56 (m, 2H), 7.38-7.33 (m, 2H), 3.96 (d, J= 6.5 Hz, 3H), 1.61 (d, J= 2.2 Hz, 9H); GC-MS (EI) m/z calcd for C20H21N5O (M+) 347.2, found 347.1. 1 H NMR (300 MHz, CDCl 3 ) δ 8.74 (s, 1H), 8.43 (d, J = 2.5 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H), 7.76-7.71 (m, 2H) , 7.60-7.56 (m, 2H), 7.38-7.33 (m, 2H), 3.96 (d, J = 6.5 Hz, 3H), 1.61 (d, J = 2.2 Hz, 9H); GC-MS (EI) m / z calcd for C 20 H 21 N 5 O (M + ) 347.2, found 347.1.

단계 2: 3-(Step 2: 3- ( 벤즈[d]옥사졸Mercedes-Benz [d] oxazole -2-일)-5-(1--2-yl) -5- (1- 메틸methyl -1H--1H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 제조 Produce

Figure 112008025718184-pat00064
Figure 112008025718184-pat00064

반응용기에 3-(벤즈[d]옥사졸-2일)-N-3급-부틸-5-(1메틸-1H-피라졸-4-일)피리딘-2-아민(10.0 mg, 0.029 mmol) 및 트리플루오로아세트산(1 mL)을 넣고 60 ℃에서 24시간 동안 교반하였다. 반응물의 온도를 실온으로 낮추고, 감압농축하였다. 농축물을 관크로마토그래피로 정제하여 연두색 고체의 목적화합물(3-(벤즈[d]옥사졸-2-일)-5-(1-메틸-1H-피라졸-4-일)피리딘-2-아민)을 얻었다(7.5 mg, 89%).3- (benz [d] oxazol-2yl) -N-tert-butyl-5- (1methyl-1H-pyrazol-4-yl) pyridin-2-amine (10.0 mg, 0.029 mmol) ) And trifluoroacetic acid (1 mL) were added and stirred at 60 ° C. for 24 hours. The temperature of the reaction was lowered to room temperature and concentrated under reduced pressure. The concentrate was purified by column chromatography to give the title compound (3- (benz [d] oxazol-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyridine-2- as a pale green solid. Amine) (7.5 mg, 89%).

1H NMR (300 MHz, CDCl3) δ 9.00 (d, J= 2.2 Hz, 1H), 8.38 (d, J= 2.2 Hz, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.88 (d, J= 7.4 Hz, 1H), 7.79 (d, J= 8.0 Hz, 1H) 7.58-7.50 (m, 2H), 3.99 (s, 3H); GC-MS (EI) m/z calcd for C16H13N5O (M+) 291.1, found 291.1. 1 H NMR (300 MHz, CDCl 3 ) δ 9.00 (d, J = 2.2 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H) 7.58-7.50 (m, 2H), 3.99 (s, 3H); GC-MS (EI) m / z calcd for C 16 H 13 N 5 O (M + ) 291.1, found 291.1.

<< 실시예Example 46> 3-( 46> 3- ( 벤즈[d]옥사졸Mercedes-Benz [d] oxazole -2일)-N--2 days) -N- 메틸methyl -5-(-5- ( 1메틸1 methyl -1H--1H- 피라졸Pyrazole -4-일)피리딘-2-아민의 제조Preparation of -4-yl) pyridin-2-amine

Figure 112008025718184-pat00065
Figure 112008025718184-pat00065

실시예 45에서 사용한 t-부틸아민 대신 메틸아민을 사용한 것을 제외하고는 실시예 45의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(3-(벤즈[d]옥사졸-2일)-N-메틸-5-(1메틸-1H-피라졸-4-일)피리딘-2-아민)을 얻었다(6 mg, 38%).A solid target compound (3- (benz [d] oxazol-2yl) was prepared in the same manner as in Step 1 and Step 2 of Example 45, except that methylamine was used instead of t-butylamine used in Example 45. ) -N-methyl-5- (1methyl-1H-pyrazol-4-yl) pyridin-2-amine) was obtained (6 mg, 38%).

1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.47 (d, J= 2.1 Hz, 1H), 8.36 (d, J= 1.8 Hz, 1H), 7.76-7.70 (m, 2H), 7.61-7.57 (m, 2H), 7.40-7.35 (m, 2H), 3.97 (s, 3H), 3.27-3.23 (m, 3H); GC-MS (EI) m/z calcd for C17H15N5O (M+) 305.1, found 305.1. 1 H NMR (300 MHz, CDCl 3 ) δ 8.56 (s, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 1.8 Hz, 1H), 7.76-7.70 (m, 2H) , 7.61-7.57 (m, 2H), 7.40-7.35 (m, 2H), 3.97 (s, 3H), 3.27-3.23 (m, 3H); GC-MS (EI) m / z calcd for C 17 H 15 N 5 O (M + ) 305.1, found 305.1.

<< 실시예Example 47> 3-(6- 47> 3- (6- 클로로벤즈[d]옥사졸Chlorobenz [d] oxazole -2-일)-5-(1--2-yl) -5- (1- 메틸methyl -1H--1H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00066
Figure 112008025718184-pat00066

실시예 1에서 사용한 2-아미노-4-클로로페놀 대신 2-아미노-5-클로로페놀을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 5 및 실시예 45의 단계 2에서 농축물을 관크로마토그래피를 이용하여 정제하는 대신 에틸에테르를 이용하여 고체화를 실시한 것을 제외하고는 실시예 45의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(3-(6-클로로벤즈[d]옥사졸-2-일)-5-(1-메틸-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(10 mg, 73%).The concentrate was subjected to tube chromatography in steps 1 to 5 of Example 1 and step 2 of Example 45, except that 2-amino-5-chlorophenol was used instead of 2-amino-4-chlorophenol used in Example 1. A solid target compound (3- (6-chlorobenz [d] oxa) was prepared in the same manner as in Step 1 and Step 2 of Example 45, except that the solidification was performed using ethyl ether instead of the purification by chromatography. Itrifluoroacetic acid salt of zol-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine) (10 mg, 73%).

1H NMR (300 MHz, DMSO-d 6 ) δ 8.66 (s, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.90 (d, J= 8.4 Hz, 1H), 7.54 (d, J= 8.7Hz, 1H), 3.89 (s, 3H). 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.66 (s, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.90 ( d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 3.89 (s, 3H).

<< 실시예Example 48> 3-( 48> 3- ( 벤즈[d]옥사졸Mercedes-Benz [d] oxazole -2-일)-5-(1H--2-yl) -5- (1H- 피라졸Pyrazole -4-일)피리딘-2--4-yl) pyridine-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00067
Figure 112008025718184-pat00067

실시예 45에서 사용한 1-메틸피라졸-4-보론산 피나콜에스테르 대신 피라졸-4-보론산 피나콜에스테르를 사용한 것과 실시예 45의 단계 2에서 농축물을 관크로마토그래피를 이용하여 정제하는 대신 에틸에테르를 이용하여 고체화를 실시한 것을 제외하고는 실시예 45의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(3-(벤즈[d]옥사졸-2-일)-5-(1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(13 mg, 49%).Purification of the concentrate in the step 2 of Example 45 using pyrazole-4-boronic acid pinacol ester instead of 1-methylpyrazole-4-boronic acid pinacol ester used in Example 45 Instead, the solid was subjected to the same method as in Step 1 and Step 2 of Example 45, except that the solidification was performed using ethyl ether (3- (benz [d] oxazol-2-yl) -5- Ditrifluoroacetic acid salt of (1H-pyrazol-4-yl) pyridin-2-amine) (13 mg, 49%).

1H NMR (200 MHz, DMSO-d 6 ) δ 8.54 (s, 2H), 8.14 (s, 2H), 7.89-7.69 (m, 2H), 7.64-7.51 (m, 2H); GC-MS (EI) m/z calcd for C15H11N5O (M+) 277.1, found 277.1. 1 H NMR (200 MHz, DMSO- d 6 ) δ 8.54 (s, 2H), 8.14 (s, 2H), 7.89-7.69 (m, 2H), 7.64-7.51 (m, 2H); GC-MS (EI) m / z calcd for C 15 H 11 N 5 O (M + ) 277.1, found 277.1.

<< 실시예Example 49> 5-(1- 49> 5- (1- 메틸methyl -1H--1H- 피라졸Pyrazole -4-일)- 3-(-4-yl)-3- ( 옥사졸로[4,5-c]피리딘Oxazolo [4,5-c] pyridine -2-일)피리딘-2--2-yl) pyridine-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00068
Figure 112008025718184-pat00068

실시예 1에서 사용한 2-아미노-4-클로로페놀 대신 3-아미노-피리딘-4-올을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 5 및 실시예 45의 단계 2에서 농축물을 관크로마토그래피를 이용하여 정제하는 대신 에틸에테르를 이용하여 고체화를 실시한 것을 제외하고는 실시예 45의 단계 1 및 단계 2와 동일한 방법으로 수행하여 고체의 목적화합물(5-(1-메틸-1H-피라졸-4-일)- 3-(옥사졸로[4,5-c]피리딘-2-일)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(25 mg, 40%).Concentrate the concentrate from steps 1 to 5 of Example 1 and step 2 of Example 45 except that 3-amino-pyridin-4-ol was used instead of 2-amino-4-chlorophenol used in Example 1 A solid target compound (5- (1-methyl-1H-pyra) was prepared in the same manner as in Step 1 and Step 2 of Example 45, except that the solidification was performed using ethyl ether instead of purification using chromatography. Zol-4-yl)-(trifluoroacetic acid salt of 3- (oxazolo [4,5-c] pyridin-2-yl) pyridin-2-amine) was obtained (25 mg, 40%).

1H NMR (300 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 8.62 (d, J= 5.5 Hz 1H), 8.55 (d, J= 1.9 Hz, 1H), 8.42(d, J= 1.7 Hz, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.88 (s, 1H), 7.66 (brs, 2H), 3.88 (s, 3H); GC-MS(EI)m/z calcd for C15H12N6O (M+) 292.0 found 292.0. 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.13 (s, 1H), 8.62 (d, J = 5.5 Hz 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.42 (d, J = 1.7 Hz, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.88 (s, 1H), 7.66 (brs, 2H), 3.88 (s, 3H); GC-MS (EI) m / z calcd for C 15 H 12 N 6 O (M + ) 292.0 found 292.0.

<< 실시예Example 50> 3-( 50> 3- ( 옥사졸로[4,5-c]피리딘Oxazolo [4,5-c] pyridine -2-일)-5-(1-(피페리딘-4-일)-1H--2-yl) -5- (1- (piperidin-4-yl) -1 H- 피라Fira 졸-4-일)피리딘-2-Zol-4-yl) pyridin-2- 아민의Amine 삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00069
Figure 112008025718184-pat00069

실시예 1에서 사용한 2-아미노-4-클로로페놀 대신 3-아미노-피리딘-4-올을 사용한 것을 제외하고는 실시예 1의 단계 1 내지 단계 7과 동일한 방법으로 수행하여 고체의 목적화합물(3-(옥사졸로[4,5-c]피리딘-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 삼트리플루오로아세트산 염)을 얻었다(33 mg, 48%).Except for using 3-amino-pyridin-4-ol instead of 2-amino-4-chlorophenol used in Example 1, the procedure was carried out in the same manner as in Step 1 to Step 7 of Example 1 to obtain a solid target compound (3 Samtri of-(oxazolo [4,5-c] pyridin-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine Fluoroacetic acid salt) was obtained (33 mg, 48%).

1H NMR (300 MHz, DMSO-d 6 ) δ 9.21 (s, 1H), 8.73 (brs, 1H), 8.68 (d, J= 5.6 Hz, 1H), 8.61 (d, J= 2.4 Hz, 1H), 8.51 (d, J= 2.4 Hz, 1H), 8.50 (brs, 1H), 8.34 (s, 1H), 8.01 (s, 1H), 7.98 (t, J= 9.9 Hz, 1H), 4.52-4.47 (m, 1H), 3.42-3.33 (m, 2H), 3.15-3.07 (m, 2H), 2.29-2.08 (m, 4H); GC-MS(EI)m/z calcd for C19H19N7O (M+) 361.2 found 361.1. 1 H NMR (300 MHz, DMSO- d 6 ) δ 9.21 (s, 1H), 8.73 (brs, 1H), 8.68 (d, J = 5.6 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H) , 8.51 (d, J = 2.4 Hz, 1H), 8.50 (brs, 1H), 8.34 (s, 1H), 8.01 (s, 1H), 7.98 (t, J = 9.9 Hz, 1H), 4.52-4.47 ( m, 1H), 3.42-3.33 (m, 2H), 3.15-3.07 (m, 2H), 2.29-2.08 (m, 4H); GC-MS (EI) m / z calcd for C 19 H 19 N 7 O (M + ) 361.2 found 361.1.

<< 실시예Example 51> 5-(1- 51> 5- (1- 메틸methyl -1H--1H- 피라졸Pyrazole -4-일)- 3-(-4-yl)-3- ( 옥사졸로[4,5-c]피리딘Oxazolo [4,5-c] pyridine -2-일)피리딘-2--2-yl) pyridine-2- 아민의Amine 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

단계 1: 5-Step 1: 5- 브로모니코티노일Bromonicotinoyl 클로라이드의 제조 Preparation of Chloride

Figure 112008025718184-pat00070
Figure 112008025718184-pat00070

반응용기에 5-브로모니코틴산(2.0 g, 10.0 mmol), 티오닐클로라이드(SOCl2, 10 mL) 및 디메틸포름아미드(0.15 mL)를 넣고, 70-80 ℃에서 4시간 동안 교반하였다. 반응물의 온도를 실온으로 낮추고, 감압 농축하여 주황색 고체의 목적화합물(5-브로모니코티노일 클로라이드)을 얻었다(2.1 g, 97%). 상기 화합물은 더 이상의 정제없이 다음 반응에 사용하였다.5-bromonicotinic acid (2.0 g, 10.0 mmol), thionyl chloride (SOCl 2 , 10 mL) and dimethylformamide (0.15 mL) were added to the reaction vessel, and the mixture was stirred at 70-80 ° C. for 4 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give the title compound (5-bromonicotinoyl chloride) as an orange solid (2.1 g, 97%). The compound was used for the next reaction without further purification.

단계 2 및 단계 3: 2-(5-Step 2 and Step 3: 2- (5- 브로모피리딘Bromopyridine -3-일)-3 days) 벤즈Mercedes Benz [d][d] 옥사졸의Oxazole 제조 Produce

Figure 112008025718184-pat00071
Figure 112008025718184-pat00071

반응용기에 2-아미노페놀(982 mg), 트리에틸아민(1.4 mL), 파라톨루엔설폰산 피리딘염(628 mg) 및 크실렌(100 mL) 혼합물에 5-브로모니코티노일 클로라이드(2.1 g, 9.5 mmol)를 얼음중탕을 이용하여 0 ℃에서 천천히 넣었다. 반응물의 온도를 상온으로 높이고, 질소분위기 하에서 2시간 동안 교반한 후, 150~170 ℃에서 24시간 동안 교반하였다. 반응물을 약 100 ℃로 낮추고, 생성된 타르를 여과하였다. 여액을 감압농축하고, 에틸에테르에 농축물을 넣고 30분간 동안 교반하였다. 에틸 에테르에 용해되지 않은 고체를 여과하고, 차가운 에틸아세테이트로 씻어 준 후 건조하여 갈색 고체의 목적화합물(2-(5-브로모피리딘-3-일)벤즈[d]옥사졸)을 얻었다(1.2 g, 46%). 5-bromonicotinoyl chloride (2.1 g, 9.5) in a mixture of 2-aminophenol (982 mg), triethylamine (1.4 mL), paratoluenesulfonic acid pyridine salt (628 mg) and xylene (100 mL). mmol) was slowly added at 0 ° C. using an ice bath. The temperature of the reaction was raised to room temperature, stirred for 2 hours under a nitrogen atmosphere, and then stirred for 24 hours at 150 ~ 170 ℃. The reaction was lowered to about 100 ° C and the resulting tar was filtered off. The filtrate was concentrated under reduced pressure, the concentrate was added to ethyl ether and stirred for 30 minutes. The solid which was not dissolved in ethyl ether was filtered, washed with cold ethyl acetate and dried to obtain the target compound (2- (5-bromopyridin-3-yl) benz [d] oxazole) as a brown solid (1.2). g, 46%).

1H NMR (300 MHz, CDCl3) δ 9.38 (s, 1H), 8.82 (d, J= 2.2 Hz, 1H), 8.68 (t, J= 2.0 Hz, 1H), 7.83-7.78 (m, 1H), 7.64-7.60 (m, 1H), 7.46-7.26 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 9.38 (s, 1H), 8.82 (d, J = 2.2 Hz, 1H), 8.68 (t, J = 2.0 Hz, 1H), 7.83-7.78 (m, 1H) , 7.64-7.60 (m, 1 H), 7.46-7.26 (m, 2 H).

단계 4 및 단계 5: 2-(5-(1-(피페리딘-4-일)-1H-Step 4 and Step 5: 2- (5- (1- (piperidin-4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)-4-yl) pyridin-3-yl) 벤Ben 즈[Zu [ d]옥사졸의d] oxazole 이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt

Figure 112008025718184-pat00072
Figure 112008025718184-pat00072

반응용기에 2-(5-브로모피리딘-3-일)벤즈[d]옥사졸 (100 mg, 0.36 mmol), 3급-부틸-4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-피라졸-1-일)-피페리딘-1-카복실레이트(407 mg), 비스트리페닐포스핀디클로로팔라듐(13 mg) 및 1,4-디옥산(1.2 mL)을 넣고 질소분위기 및 실온에서 30분 동안 교반하였다. 반응물에 1 M 탄산나트륨 수용액(1.1 mL)을 넣고 2시간 동안 110 ℃에서 교반하였다. 반응물의 온도를 실온으로 낮추고, 셀라이트를 이용하여 여과시키고 메틸렌클로라 이드로 씻어주었다. 여액을 농축한 후 관크로마토그래피로 정제하여 초록색 고체의 3급-부틸-4-(4-(5-(벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트를 얻었다(130 mg). 2- (5-bromopyridin-3-yl) benz [d] oxazole (100 mg, 0.36 mmol), tert-butyl-4- (4- (4,4,5,5-tetra) in the reaction vessel Methyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) -piperidine-1-carboxylate (407 mg), bistriphenylphosphinedichloropalladium (13 mg) and 1,4-dioxane (1.2 mL) were added and stirred for 30 minutes at nitrogen atmosphere and room temperature. 1 M aqueous sodium carbonate solution (1.1 mL) was added to the reaction and stirred for 2 hours at 110 ° C. The temperature of the reaction was lowered to room temperature, filtered through celite and washed with methylene chloride. The filtrate was concentrated and purified by column chromatography to give tert-butyl-4- (4- (5- (benz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazole as a green solid. -1-yl) piperidine-1-carboxylate was obtained (130 mg).

반응용기에 상기 3급-부틸-4-(4-(5-(벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트(130 mg)을 에틸아세테이트(3 mL)에 용해시키고, 여기에 4 N HCl/1,4-디옥산 용액(1 mL)을 넣어 주었다. 실온에서 3시간 동안 교반한 후 생성된 고체 침전물을 여과하였다. 여과물을 메탄올에 녹이고 에틸에테르를 천천히 가하여 고체가 생성되도록 하고, 생성된 고체를 다시 여과 및 건조하여 연두색 고체의 목적화합물(2-(5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸의 이트리플루오로아세트산 염)을 얻었다(111 mg, 74%). The tert-butyl-4- (4- (5- (benz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1 in the reaction vessel Carboxylate (130 mg) was dissolved in ethyl acetate (3 mL), and 4N HCl / 1,4-dioxane solution (1 mL) was added thereto. After stirring for 3 hours at room temperature the resulting solid precipitate was filtered off. The filtrate was dissolved in methanol and ethyl ether was slowly added to form a solid, and the resulting solid was filtered and dried again to give the title compound as a light green solid (2- (5- (1- (piperidin-4-yl)-). 1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole ditrifluoroacetic acid salt) was obtained (111 mg, 74%).

1H NMR (300 MHz, CDCl3) δ 9.38 (s, 1H), 9.24 (t, J= 1.8 Hz, 1H), 8.61 (s, 1H), 8.28 (s, 1H), 7.89 (d, J= 7.2 Hz, 1H), 7.81 (d, J= 6.9 Hz, 1H), 7.59-7.51 (m, 2H), 4.83-4.70 (m, 1H), 3.65-3.60 (m, 2H), 3.40-3.31 (m, 2H), 2.44-2.31 (m, 4H); GC-MS (EI) m/z calcd for C20H19N5O (M+) 345.2, found 345.1. 1 H NMR (300 MHz, CDCl 3 ) δ 9.38 (s, 1H), 9.24 (t, J = 1.8 Hz, 1H), 8.61 (s, 1H), 8.28 (s, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 6.9 Hz, 1H), 7.59-7.51 (m, 2H), 4.83-4.70 (m, 1H), 3.65-3.60 (m, 2H), 3.40-3.31 (m , 2H), 2.44-2.31 (m, 4H); GC-MS (EI) m / z calcd for C 20 H 19 N 5 O (M + ) 345.2, found 345.1.

<< 실시예Example 52> 2-(5-(1- 52> 2- (5- (1- 메틸methyl -1H--1H- 피라졸Pyrazole -4-일)피리딘-3-일)-4-yl) pyridin-3-yl) 벤즈Mercedes Benz [d][d] 옥사졸의Oxazole 제조 Produce

Figure 112008025718184-pat00073
Figure 112008025718184-pat00073

반응용기에 2-(5-브로모피리딘-3-일)벤즈[d]옥사졸(100 mg, 0.36 mmol), 1-메틸피라졸-4-보론산 피나콜에스테르 (150 mg), 비스트리페닐포스핀디클로로팔라듐(13 mg) 및 1,4-디옥산(1.2 mL)을 넣고 질소분위기 및 실온에서 30분 동안 교반하였다. 반응물에 1 M 탄산나트륨 수용액(1.1 mL)을 넣고 2시간 동안 110 ℃에서 교반하였다. 반응물의 온도를 실온으로 낮추고, 셀라이트를 이용하여 여과시키고 메틸렌클로라이드로 씻어주었다. 여액을 농축한 후 관크로마토그래피로로 1차 정제하여 80% 이상 순수한 초록색 고체를 얻었다. 상기 고체에 에틸에테르를 넣고 1시간 동안 교반한 후 여과 및 건조하여 밝은 갈색 고체의 목적화합물(2-(5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸)을 얻었다(33 mg, 33%).2- (5-bromopyridin-3-yl) benz [d] oxazole (100 mg, 0.36 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (150 mg), bistri Phenylphosphinedichloropalladium (13 mg) and 1,4-dioxane (1.2 mL) were added thereto, and the mixture was stirred at a nitrogen atmosphere and at room temperature for 30 minutes. 1 M aqueous sodium carbonate solution (1.1 mL) was added to the reaction and stirred for 2 hours at 110 ° C. The temperature of the reaction was lowered to room temperature, filtered through celite and washed with methylene chloride. The filtrate was concentrated and purified first by column chromatography to obtain a green solid at least 80%. Ethyl ether was added to the solid, stirred for 1 hour, filtered and dried to give the title compound (2- (5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) benz as a light brown solid. [d] oxazole) was obtained (33 mg, 33%).

1H NMR (300 MHz, CDCl3) δ 9.30 (d, J= 2.0 Hz, 1H), 8.89 (d, J= 2.2 Hz, 1H), 8.57 (t, J= 2.1 Hz, 1H), 7.92 (s, 1H), 7.84-7.81 (m, 2H), 7.66-7.63 (m, 1H), 7.43-7.26 (m, 2H), 4.01 (s, 3H); GC-MS (EI) m/z calcd for C16H12N4O (M+) 276.1, found 276.1. 1 H NMR (300 MHz, CDCl 3 ) δ 9.30 (d, J = 2.0 Hz, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.57 (t, J = 2.1 Hz, 1H), 7.92 (s , 1H), 7.84-7.81 (m, 2H), 7.66-7.63 (m, 1H), 7.43-7.26 (m, 2H), 4.01 (s, 3H); GC-MS (EI) m / z calcd for C 16 H 12 N 4 O (M + ) 276.1, found 276.1.

<< 실험예Experimental Example 1> c- 1> c- MetMet 키나아제Kinase 억제활성 실험 Inhibitory activity test

본 발명에 따른 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 이상세포의 증식억제활성을 세포단계에서 측정하기 위하여 하기와 같은 실험을 수행하였다.In order to determine the proliferation inhibitory activity of the abnormal cells of the pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutically acceptable salts thereof according to the present invention, the following experiments were performed.

c-Met 키나아제에 대한 저해활성을 시간분해형광도(Time-resolved fluorescence, TRF)의 일종인 분리 증강된 란탄족플루오로 면역 분석(Dissociation Enhanced Lanthanide Fluoro Immuno Assay, DELFIA; Perkin Elmer)을 이용하여 분석하였다. Inhibitory activity against c-Met kinase was analyzed using Dissociation Enhanced Lanthanide Fluoro Immuno Assay (DELFIA; Perkin Elmer), a type of time-resolved fluorescence (TRF). It was.

그레이너 96웰 V형 바닥 플레이트에 실시예 1, 4, 5, 7, 9~45 및 47~50(10 mL)을 가하고 c-Met 효소를 섞은 티로신 키나아제 버퍼(20 μL)를 가한 후, 상기 효소 및 실시예 1, 4, 5, 7, 9~45 및 47~50 혼합물을 15분 동안 혼합하여 배양하였다. 여기에 ATP용액(10 μL)을 가하여 상온에서 30분 동안 키나아제 반응을 시킨후, 50 mM 에틸렌다이아민테트라아세트산 용액(EDTA, 40 μL)을 가하여 반응을 중지시켰다. 스트렙트아비딘이 코팅된 플레이트에 반응물을 옮기고 진탕하에 배양하고 2시간 후 PBS-T 완충액(PBS 0.05% 트윈20)으로 3회 세척하였다.Example 1, 4, 5, 7, 9-45, and 47-50 (10 mL) were added to a Grainer 96-well V-type bottom plate, followed by addition of tyrosine kinase buffer (20 μL) mixed with c-Met enzyme. Enzyme and Example 1, 4, 5, 7, 9-45 and 47-50 mixtures were incubated for 15 minutes by mixing. ATP solution (10 μL) was added thereto, followed by kinase reaction at room temperature for 30 minutes, and then 50 mM ethylenediaminetetraacetic acid solution (EDTA, 40 μL) was added to stop the reaction. The reactions were transferred to streptavidin-coated plates, incubated under shaking and washed three times with PBS-T buffer (PBS 0.05% Tween20) after 2 hours.

유로퓸이 붙은 항-포스포타이로신 항체를 1:2,500으로 희석시켜 웰 당 100 ml씩 가하고 진탕하에 배양하고 1시간 후, PBS-T 완충액(PBS 0.05% 트윈20)으로 5회 세척하였다.Europium-containing anti-phosphotyrosine antibody was diluted 1: 2,500, added 100 ml per well, incubated under shaking, and washed 1 time with PBS-T buffer (PBS 0.05% Tween20).

개선제(enhancement solution, 100 mL)을 가하고 5분 동안 진탕배양한 후, 왈락 인비전 2103(Wallac Envision 2103) 기기로 615/665 nm의 파장 범위에서 판독하였다.Enhancement solution (100 mL) was added and shaken for 5 minutes, then read in a wavelength range of 615/665 nm with a Wallac Envision 2103 instrument.

상기 실험을 수행한 실시예 1, 4, 5, 7, 9~45 및 47~50 화합물의 IC50는 2개씩의 데이터 세트로 결정하였고 프리즘(버전 5.01, 그래프패드) 소프트웨어를 이용하여 구하였다. The IC 50 of the compounds of Examples 1, 4, 5, 7, 9-45 and 47-50 that performed the experiments were determined in two data sets and obtained using Prism (version 5.01, GraphPad) software.

c-Met 키나아제 효소활성을 50%로 감소시키는 상기 화합물의 IC50는 하기 표 2에 나타내었다.The IC 50 of this compound which reduces c-Met kinase enzyme activity by 50% is shown in Table 2 below.

c-c- MetMet 키나아제에Kinase 대한 저해활성분석[IC Inhibitory Activity Analysis [IC 5050 (μM)](μM)] 실시예Example c-Metc-Met 실시예Example c-Metc-Met 실시예Example c-Metc-Met 1One <20<20 2020 <20<20 3535 <20<20 44 <20<20 2121 <20<20 3636 <20<20 55 <20<20 2222 <20<20 3737 <20<20 77 <20<20 2323 <20<20 3838 <20<20 99 <20<20 2424 <20<20 3939 <20<20 1010 <20<20 2525 <20<20 4040 <20<20 1111 <20<20 2626 <20<20 4141 <20<20 1212 <20<20 2727 <20<20 4242 <20<20 1313 <20<20 2828 <20<20 4343 <20<20 1414 <20<20 2929 <20<20 4444 <20<20 1515 <20<20 3030 <20<20 4545 <20<20 1616 <20<20 3131 <20<20 4747 <20<20 1717 <20<20 3232 <20<20 4848 <20<20 1818 <20<20 3333 <20<20 4949 <20<20 1919 <20<20 3434 <20<20 5050 <20<20

표 2의 결과로부터, 실시예 1, 4, 5, 7, 9~45 및 47~50 화합물의 IC50가 20 μM 이하로 측정되었으며, 이로부터 본 발명에 따른 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염은 c-Met 키나아제에 대한 우수한 억제효과가 있음을 알 수 있다. From the results in Table 2, the IC 50 of the compounds of Examples 1, 4, 5, 7, 9-45 and 47-50 were determined to be 20 μM or less, from which pyrazole and benzoxazole substituted pyridine according to the invention It can be seen that the derivative or pharmaceutically acceptable salt thereof has an excellent inhibitory effect on c-Met kinase.

<< 실험예Experimental Example 2> 암세포 증식억제 실험 2> Cancer Cell Proliferation Inhibition Experiment

본 발명에 따른 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 암세포 증식 억제능을 알아보기 위해 하기와 같은 실험을 수행하였다.In order to determine the cancer cell proliferation inhibitory effect of pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutically acceptable salts thereof according to the present invention, the following experiments were performed.

1) 실험 재료1) experimental material

가. 시약end. reagent

세포배양액인 RPMI 1640 배지, FBS(fetal bovine serum) 및 트립신은 Gibco 사(Grand Island, NY)로부터 구입하였으며, 탄산수소나트륨, 암포테리신 B 및　겐타마이신은 시그마케미컬 제품을 사용하였다. Cell culture medium RPMI 1640 medium, fetal bovine serum (FBS) and trypsin were purchased from Gibco (Grand Island, NY), and sodium hydrogen carbonate, amphotericin B and gentogenycin were used as sig-chemical products.

또한, 세포독성 측정 실험에 사용한 시약인 SRB(sulforhodamine) B, 트리스마 염기(trisma base), 트리클로로아세트산(TCA)등의 시약은 시그마케미컬사로부터 구입하였다. In addition, reagents such as SRB (sulforhodamine) B, trisma base, and trichloroacetic acid (TCA), which are reagents used in cytotoxicity measurement experiments, were purchased from Sigma Chemical.

또한, 세포배양을 위해 사용한 T-25 배양용기,　96-웰(well) 플레이트 및 기타 세포배양에 사용한 일회용 초자류는 팔콘사(Lincoln Park, NJ) 제품을 사용하였다.In addition, T-25 culture vessels used for cell culture, 96-well plate, and other disposable supernatants used for cell culture were manufactured by Lincoln Park (NJ).

나. I. 사용기기Device used

세포독성 측정을 위한 엘라이자 리더기(microplate reader)는 Molecular Devices사(Sunnyvale, CA)의 E-max 기종을 사용하였다. As a microplate reader for cytotoxicity measurement, the E-max model of Molecular Devices (Sunnyvale, CA) was used.

2) 실험방법2) Experiment Method

가. 실험약물의 조제end. Preparation of Experimental Drugs

실험에 사용한 약물은　시험에 원하는 농도까지 실험용 배지로서 희석하여　사용하였고, 최종 다이메틸설폭사이드 농도는 0.5% 이하가 되도록 하였다.The drug used in the experiment was diluted as an experimental medium to the desired concentration in the test, and the final dimethyl sulfoxide concentration was adjusted to 0.5% or less.

나. 세포배양I. Cell culture

실험에 사용한 암세포주는 모두 인체기원 암세포주들로서, 비소세포폐암 세포주인 A549,　피부암 세포주인 SK-MEL-28,　및 대장암세포주인 HT-29를 사용하였다.The cancer cell lines used in the experiment were all human-derived cancer cell lines, including A549, a non-small cell lung cancer cell line, SK-MEL-28, a skin cancer cell line, and HT-29, a colon cancer cell line.

배양액으로는 5% FBS(fetal bovine serum)가 첨가된 RPMI 1640 배지를 사용하여 37 ℃ 및 5% 이산화탄소 인큐베이터에서 배양하였고, 3~4일에 한번씩 계대 유지하였다.　 The culture medium was incubated in 37 ° C and 5% carbon dioxide incubator using RPMI 1640 medium to which 5% FBS (fetal bovine serum) was added, and maintained once every 3 to 4 days.

다. 세포독성 실험All. Cytotoxicity Experiment

　96 웰(well) 평평한 바닥 마이크로플레이트(flat-bottom microplate)의 각 웰(well)에 A549는 5×103 cells을 분주하고, SKMEL-28 및 HT-29는 1×104 cells를 분주하고, 세포가 바닥면에 부착하도록 24시간 동안 배양한 후, 배양액을 제거하고, 여기에 실시예 1, 4, 5, 7, 9~45 및 47~50 화합물이 각각 포함된 배양액을 가하고 72시간 동안 배양하였다. 상기 화합물과의 배양이 종료된 후, 세포독성의 측정은 단백질 염색 시약인 SRB를 이용하여 측정하였다. In each well of a 96 well flat-bottom microplate, A549 dispenses 5 × 10 3 cells, SKMEL-28 and HT-29 dispense 1 × 10 4 cells, After culturing for 24 hours to allow the cells to adhere to the bottom surface, the culture solution was removed, and the culture solution containing the compounds of Examples 1, 4, 5, 7, 9 to 45, and 47 to 50 was added thereto and cultured for 72 hours. It was. After incubation with the compound was terminated, cytotoxicity was measured using SRB, a protein staining reagent.

구체적으로, 실시예 1, 4, 5, 7, 9~45 및 47~50 화합물과의 배양이 종료된 후, 배양액을 제거하고 각 웰(well)에 차가운 TCA 용액을 처리하고 4 ℃에서 1시간 동안 방치하여 세포들을 고정시켰다. 상기 TCA 용액을 제거하고 실온에서 건조시킨 후, 1% 아세트산 용액에 0.4% SRB를 녹인 염색용액을 가하여 실온에서 30분 동안 방치하여 세포를 염색하였다. 세포와 결합하지 않은 여분의 SRB를 1% 아세트산 용액으로 세척하여 제거하고, 염색된 세포들에 pH 10.3~10.5의 10 mM 트리스 완충용액(Trisma base; unbuffered)을 가하여 SRB를 용출시켰다. 각 웰(well)의 흡광도는 엘라이자 리더기(microplate reader)를 이용하여 520 nm의 파장 범위에서 측정하였다.Specifically, after incubation with the compounds of Examples 1, 4, 5, 7, 9-45, and 47-50, the culture solution was removed, each well was treated with cold TCA solution, and then treated at 4 ° C. for 1 hour. The cells were fixed by standing for a while. After removing the TCA solution and drying at room temperature, a dye solution in which 0.4% SRB was dissolved in 1% acetic acid solution was added and left at room temperature for 30 minutes to stain cells. Extra SRB that did not bind to cells was removed by washing with 1% acetic acid solution, and SRB was eluted by adding 10 mM Trisma buffer (unbuffered) at pH 10.3-10.5 to the stained cells. The absorbance of each well was measured in a wavelength range of 520 nm using a microplate reader.

약물을 가하지 않은 웰(well)(C)과 약물을 가한 각 웰(well)(T) 및 약물을 처음 가할 때의 웰(well)(Tz)의 OD값으로부터,From the OD values of the well (C) without the drug, each well (T) with the drug and the well (Tz) when the drug is first applied,

Tz=T인 경우에는 [(T-Tz)/(C-Tz)]×100의 수식으로; 또는When Tz = T, the formula [(T-Tz) / (C-Tz)] × 100; or

Tz＞T인 경우에는 [(T-Tz)/(Tz)×100 의 수식으로 약물의 세포독성을 계산하였다. In the case of Tz> T, the cytotoxicity of the drug was calculated by the formula [(T-Tz) / (Tz) × 100.

암세포(HT-29, A549 및 SK-MEL-28) 증식을 50%로 억제하는 상기 화합물의 GI50는 하기 표 3에 나타내었다.GI 50 of the compound that inhibits cancer cell (HT-29, A549 and SK-MEL-28) proliferation by 50% is shown in Table 3 below.

암세포(Cancer cells HTHT -29, A549 및 SK-MEL-28) 증식 억제 분석[GI-29, A549 and SK-MEL-28) proliferation inhibition assay [GI 5050 (μM)](μM)] 실시예Example HT-29HT-29 A549A549 SK-MEL-28SK-MEL-28 실시예Example HT-29HT-29 A549A549 SK-MEL-28SK-MEL-28 1One <100<100 <100<100 <100<100 2828 <100<100 <100<100 <100<100 44 <100<100 <100<100 <100<100 2929 <100<100 <100<100 <100<100 55 <100<100 <100<100 <100<100 3030 <100<100 <100<100 <100<100 77 <100<100 <100<100 <100<100 3131 <100<100 <100<100 <100<100 99 <100<100 <100<100 <100<100 3232 <100<100 <100<100 <100<100 1010 <100<100 <100<100 <100<100 3333 <100<100 <100<100 <100<100 1111 <100<100 <100<100 <100<100 3434 <100<100 <100<100 <100<100 1212 <100<100 <100<100 <100<100 3535 <100<100 <100<100 <100<100 1313 <100<100 <100<100 <100<100 3636 <100<100 <100<100 <100<100 1414 <100<100 <100<100 <100<100 3737 <100<100 <100<100 <100<100 1515 <100<100 <100<100 <100<100 3838 <100<100 <100<100 <100<100 1616 <100<100 <100<100 <100<100 3939 <100<100 <100<100 <100<100 1717 <100<100 <100<100 <100<100 4040 <100<100 <100<100 <100<100 1818 <100<100 <100<100 <100<100 4141 <100<100 <100<100 <100<100 1919 <100<100 <100<100 <100<100 4242 <100<100 <100<100 <100<100 2020 <100<100 <100<100 <100<100 4343 <100<100 <100<100 <100<100 2121 <100<100 <100<100 <100<100 4444 <100<100 <100<100 <100<100 2222 <100<100 <100<100 <100<100 4545 <100<100 <100<100 <100<100 2323 <100<100 <100<100 <100<100 4747 <100<100 <100<100 <100<100 2424 <100<100 <100<100 <100<100 4848 <100<100 <100<100 <100<100 2525 <100<100 <100<100 <100<100 4949 <100<100 <100<100 <100<100 2626 <100<100 <100<100 <100<100 5050 <100<100 <100<100 <100<100 2727 <100<100 <100<100 <100<100

표 3의 결과로부터, 실시예 1, 4, 5, 7, 9~45 및 47~50 화합물의 암세포(HT-29, A549 및 SK-MEL-28)에 대한 GI50가 모두 100 μM 이하로 측정되었으며, 이로부터 본 발명에 따른 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염은 암세포 등의 이상세포 증식을 억제하는 우수한 효과가 있음을 알 수 있다. From the results in Table 3, the GI 50 for cancer cells (HT-29, A549 and SK-MEL-28) of the compounds of Examples 1, 4, 5, 7, 9-45 and 47-50 were all measured to be 100 μM or less. From this, it can be seen that the pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutically acceptable salts thereof according to the present invention have an excellent effect of inhibiting abnormal cell proliferation such as cancer cells.

<< 실험예Experimental Example 3>  3> BaBa /F3 c-/ F3 c- MetMet 세포주에 대한 c- C- for cell lines MetMet 키나아제Kinase 저해활성 실험 Inhibitory activity test

c-Met 키나아제 억제제들의 c-Met 특이적 억제활성을 평가하기 위해 노바티스사에서 키나아제 프로파일링(kinase profilng)을 위해 사용한 Ba/F3 세포 시스템을 이용하였다. Ba/F3 세포는 인터루킨-3(IL-3)가 매질(media)에 있을 경우에만 증식할 수 있는 IL-3 의존적 pro-B cell 세포주이나, 티로신 키나아제들에 의해 형질변환이 일어나는 경우, IL-3 비의존적 증식을 할 수 있다. 이에, 활성화 된 c-Met을 발현하는 벡터를 제작하고 c-Met 활성에 의한 IL-3의 비의존적 성장이 가능한 Ba/F3 c-Met 세포주를 제작하였다. To evaluate c-Met specific inhibitory activity of c-Met kinase inhibitors, the Ba / F3 cell system used for kinase profilng at Novartis was used. Ba / F3 cells are IL-3 dependent pro-B cell lines that can only proliferate if interleukin-3 (IL-3) is in the media, but IL- when transduced by tyrosine kinases 3 Independent proliferation is possible. Thus, a vector expressing the activated c-Met was prepared and a Ba / F3 c-Met cell line capable of independent growth of IL-3 by c-Met activity was prepared.

c-c- MetMet 발현벡터 제작 Expression vector production

1. IL-3 비의존적 성장이 가능한 Ba/F3_c-Met 세포주를 제작하기 위해 항상 활성을 지닌 c-Met을 발현할 수 있는 벡터를 제작하였다(도 1). pcDNA3.0 벡터를 모(母)벡터로 선택하였으며 제작될 벡터의 전체 크기를 줄이기 위해 불필요한 부위인 네오(Neor) 유전자부분을 SmaI/BstBI 제한효소들을 이용하여 제거하였다1. To produce a Ba / F3_c-Met cell line capable of IL-3 independent growth, a vector capable of expressing c-Met that is always active was constructed ( FIG. 1 ). The pcDNA3.0 vector was selected as the parent vector and the neo r gene region, which is unnecessary, was removed using SmaI / BstBI restriction enzymes to reduce the overall size of the vector to be produced.

2. 세포의 증식을 측정하기 위한 표지자로 루시페라제(luciferase)를 이용하였으며 루시페라제가 세포에서 c-Met 키나아제와 항상 함께 발현되도록 IRES(internal ribosome entry site)를 이용하였다. IRES는 전진프라이머(forward primer; 5'-CTCATCTCAGAAGAGGATCTGAATTAGCAATTCCTCGACGACTGC-3')와 역전사프라이머(reverse primer; 5'-TTTTTCTAGAAGTGGCCATTATCATCGTG-3')를 이용하여 스트라테이진(Stratagene; pShuttle-IRES-hrGFP-1) 벡터로부터 얻었으며, 이때 카이나제의 탄소 말단에 myc 항원결정기(epitope)를 붙이기 위해 myc 항원결정기 시퀀스(epitope sequence)를 포함하는 IRES 2nd 전진프라이머(5'-TTTTCTCGAGGAACAAAAACTCATCTCAGAAGAGGATCTG-3')와 상기한 IRES 역전사프라아머로 2nd PCR을 수행하여 IRES 시퀀스를 얻었다. 한편 전진프라이머(5'-TTTTTCTAGAACCATGACCGAGTACAAGCC-3')와 역전사프라이머(5'-TTTTTCTAGAGCTAGCGGCACCGGGCTTGCGGGTC-3')를 이용하여 푸로마이신 저항(Puror; puromycin resistant) 유전자를, 전진프라이머(5'-TTTTGCTAGCATGGAAGACGCCAAAAACATA-3')와 역전사프라이머(5'-TTTTGCTAGCATTACACGGCGATCTTTCCG-3')를 이용하여 pGL3 벡터로부터 루시페라제 유전자를 얻어서 Puror와 루시퍼라제가 결합한 형태의 단백질로 발현되는 pcDNA-myc-IRES-Puror-Luc(pcDNA-Luc)벡터를 제작하였다. 2. Luciferase was used as a marker for measuring cell proliferation, and an internal ribosome entry site (IRS) was used to always express luciferase with c-Met kinase in cells. IRES is composed of stratagene (Stratagene; pShuttle-IRES-hrGFP) using forward primer (5'-CTCATCTCAGAAGAGGATCTGAATTAGCAATTCCTCGACGACTGC-3 ') and reverse primer (5'- TTTT TCTAGA AGTGGCCATTATCATCGTG-3'). Obtained from the vector, wherein the IRES 2 nd forward primer (5'- TTTT CTCGAG GAACAAAAACTCATCTCAGAAGAGGATCTG-3 ') containing the myc epitope sequence was attached to attach the myc epitope to the carbon end of the kinase. by performing a 2 nd PCR as the one IRES reverse transcription to obtain a plastic armor IRES sequence. The forward primer (5'-TTTT ACCATGACCGAGTACAAGCC TCTAGA-3 ') and reverse primer (5'-TTTT TCTAGAGCTAGC GGCACCGGGCTTGCGGGTC-3 ') using the neomycin resistance furo (Puro r; puromycin resistant) gene, the forward primer (5 ' TTTT GCTAGC ATGGAAGACGCCAAAAACATA-3 ') and reverse transcriptase (5'- TTTT GCTAGC ATTACACGGCGATCTTTCCG-3') were used to obtain luciferase gene from pGL3 vector and to express the protein expressed as Puro r and luciferase-binding protein. An IRES-Puro r -Luc (pcDNA-Luc) vector was constructed.

3. c-Met 키나아제 활성에 필요한 막 위치화(membrane localization)과 키나아제 이합체화(dimerization)을 위해 우선 N-말단에 Src의 미리스틸화(myristoylation) 시퀀스(myr)를 포함하는 Tel 유전자의 N-말단 도메인을 PCR을 통해 얻은 후 pShuttle-IRES-hrGFP-1 벡터에 클로닝(cloning)한 후, c-Met 키나아제 도메인의 N-말단에 myr-Tel이 퓨전(fusion)되고 C-말단에 myc 항원결정기가 붙도록 PCR로 얻은 c-Met 키나아제 도메인을 넣어 pShuttle-myrTel-Met 벡터를 제작하였다. 본 발명에 사용한 프라이머는 하기에 나타내었다. 3. For the membrane localization and kinase dimerization required for c-Met kinase activity, the N- of the Tel gene containing the myristoylation sequence (myr) of Src at the N-terminus first. The terminal domain was obtained by PCR and then cloned into the pShuttle-IRES-hrGFP-1 vector, followed by fusion of myr-Tel to the N-terminus of the c-Met kinase domain and determination of myc antigen at the C-terminus. P-Shuttle-myrTel-Met vector was prepared by adding c-Met kinase domain obtained by PCR to attach a group. Primers used in the present invention are shown below.

가. end. TelTel PCRPCR

전진프라이머(5'-GAGACATGTCTGAGACTCCTGCTCAG-3')Forward Primer (5'-GAGACATGTCTGAGACTCCTGCTCAG-3 ')

역전사프라이머(5'-AAGCAGTCTACAGTCTGCTATTCTCCC-3') Reverse transcription primer (5'-AAGCAGTCTACAGTCTGCTATTCTCCC-3 ')

나. I. myrTelmyrTel PCRPCR

전진프라이머(5'-GCAACAAGAGCAAGCCCAAGGATGCCATGTCTGAGACTCCTGC-3'(1stPCR)/ 5'-TTTTGCGGCCGCACCATGGGTAGCAACAAGAGCAAGCCCAAG-3'(2nd PCR))Forward primer (5'-GCAACAAGAGCAAGCCCAAGGATGCCATGTCTGAGACTCCTGC-3 '(1 st PCR) / 5'-TTTT GCGGCCGC ACCATGGGTAGCAACAAGAGCAAGCCCAAG-3' (2 nd PCR))

역전사프라이머(5'-TTTTACTAGTAAGCAGTCTACAGTCTGCTA-3')Reverse transcription primer (5'- TTTT ACTAGT AAGCAGTCTACAGTCTGCTA-3 ')

다. c-All. c- MetMet 키나아제Kinase 도메인  domain PCRPCR

전진프라이머(5'-TTTTACTAGTGCAGTGCAGCATGTAGTG-3')Forward Primer (5'- TTTT ACTAGT GCAGTGCAGCATGTAGTG-3 ')

역전사프라이머(5'-TTTTGTCGACTCACATGGACATAGTGCTCC-3') Reverse transcription primer (5'- TTTT GTCGAC TCACATGGACATAGTGCTCC-3 ')

pShuttle-myrTel-Met 벡터로부터 myrTel-Met 부분을 NotI/SalI으로 잘라내어 NoI/XhoI이 처리된 pcDNA-Luc 벡터에 넣어서 myr-Tel-cMet-myc과 Puror-Luc 두 fusion 단백질들이 하나의 mRNA로부터 발현되도록 하는 pcMet-Luc 발현벡터를 제작하였다. Two fusion proteins, myr-Tel-cMet-myc and Puro r -Luc, were expressed from one mRNA by cutting the myrTel-Met portion from the pShuttle-myrTel-Met vector into NotI / SalI and inserting it into a NoI / XhoI-treated pcDNA-Luc vector. A pcMet-Luc expression vector was prepared.

4. 상기의 pcMet-Luc 벡터를 Ba/F3 세포주에 주입하고 1 mg/mL 의 푸로마이신(puromycin)을 이용하여 선택한 Ba/F3 c-Met 세포주를 IL-3를 첨가하지 않은 매질(media)로 배양하여 c-Met 활성 의존적으로 IL-3 없이 증식 가능한 c-Met 키나아제 억제제 활성 평가용 Ba/F3 c-Met 세포주를 제작하였다.4. The above-mentioned pcMet-Luc vector was injected into Ba / F3 cell line, and Ba / F3 c-Met cell line selected using 1 mg / mL puromycin was added to the medium without IL-3. Can be cultured without IL-3 depending on c-Met activity A Ba / F3 c-Met cell line for the evaluation of c-Met kinase inhibitor activity was constructed.

상기와 같이 제작된 Ba/F3 c-Met 세포주에 대하여 c-Met 키나아제에 대한 저해활성분석을 수행하였고 이를 하기 표 4에 나타내었다. Inhibition activity assay for c-Met kinase was performed on the Ba / F3 c-Met cell line prepared as described above.

BaBa /F3 c-/ F3 c- MetMet 세포주를 이용한 c- C- using cell line MetMet 키나아제에Kinase 대한 저해활성분석[IC Inhibitory Activity Analysis [IC 5050 (μM)](μM)] 실시예Example c-Metc-Met 실시예Example c-Metc-Met 실시예Example c-Metc-Met 1One <50<50 2020 <50<50 3535 <50<50 44 <50<50 2121 <50<50 3636 <50<50 55 <50<50 2222 <50<50 3737 <50<50 77 <50<50 2323 <50<50 3838 <50<50 99 <50<50 2424 <50<50 3939 <50<50 1010 <50<50 2525 <50<50 4040 <50<50 1111 <50<50 2626 <50<50 4141 <50<50 1212 <50<50 2727 <50<50 4242 <50<50 1313 <50<50 2828 <50<50 4343 <50<50 1414 <50<50 2929 <50<50 4444 <50<50 1515 <50<50 3030 <50<50 4545 <50<50 1616 <50<50 3131 <50<50 4747 <50<50 1717 <50<50 3232 <50<50 4848 <50<50 1818 <50<50 3333 <50<50 4949 <50<50 1919 <50<50 3434 <50<50 5050 <50<50

표 4에 나타낸 바와 같이, Ba/F3 c-Met 세포주를 이용한 c-Met 키나아제에 대한 저해활성분석 실험에서 실시예 1, 4, 5, 7, 9~45 및 47~50 화합물의 IC50가 모두 20 μM 이하로 측정되었으며, 이로부터 본 발명에 따른 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염이 c-Met 키나아제에 대한 우수한 억제효과가 있음을 알 수 있다. As shown in Table 4, in the inhibitory activity assay for c-Met kinase using Ba / F3 c-Met cell line, the IC 50 of the compounds of Examples 1, 4, 5, 7, 9-45 and 47-50 were all It was measured to be 20 μM or less, from which it can be seen that the pyrazole and benzoxazole substituted pyridine derivatives or pharmaceutically acceptable salts thereof according to the present invention have an excellent inhibitory effect on c-Met kinase.

하기에 본 발명의 조성물을 위한 제제예를 예시한다.Examples of formulations for the composition of the present invention are illustrated below.

<< 제제예Formulation example 1> 약학적 제제의 제조 1> Preparation of Pharmaceutical Formulations

<1-1> 산제의 제조 <1-1> Preparation of powders

화학식 1의 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 2 g2 g of pyrazole and benzoxazole substituted pyridine derivatives of Formula 1

유당 1 g1 g lactose

상기의 성분을 혼합한 후, 기밀포에 충진하여 산제를 제조하였다.After mixing the above components, the airtight cloth was filled to prepare a powder.

<1-2> 정제의 제조 <1-2> Preparation of Tablet

화학식 1의 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 100 ㎎100 mg of pyrazole and benzoxazole substituted pyridine derivatives of formula 1

옥수수전분 100 ㎎Corn starch 100 mg

유 당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎2 mg magnesium stearate

상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

<1-3> 캡슐제의 제조 <1-3> Preparation of Capsule

화학식 1의 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 100 ㎎100 mg of pyrazole and benzoxazole substituted pyridine derivatives of formula 1

옥수수전분 100 ㎎Corn starch 100 mg

유 당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎2 mg magnesium stearate

상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

<1-4> 주사액제의 제조 <1-4> Preparation of Injection Solution

화학식 1의 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체 10 ㎍/㎖10 μg / ml of pyrazole and benzoxazole substituted pyridine derivatives of formula (I)

묽은 염산 BP pH 3.5로 될 때까지Dilute hydrochloric acid BP until pH 3.5

주사용 염화나트륨 BP 최대 1 ㎖Injectable sodium chloride BP up to 1 ml

적당한 용적의 주사용 염화나트륨 BP 중에 본 발명에 따른 화학식 1의 피라졸 및 벤즈옥사졸 치환된 피리딘 유도체를 용해시키고, 생성된 용액의 pH를 묽은 염산 BP를 사용하여 pH 3.5로 조절하고, 주사용 염화나트륨 BP를 사용하여 용적을 조절하고 충분히 혼합하였다. 용액을 투명 유리로 된 5 ㎖ 타입 I 앰플 중에 충전시키고, 유리를 용해시킴으로써 공기의 상부 격자하에 봉입시키고, 120 ℃에서 15 분 이상 오토클래이브시켜 살균하여 주사액제를 제조하였다.Dissolve the pyrazole and benzoxazole substituted pyridine derivatives of formula 1 according to the invention in an appropriate volume of sodium chloride BP for injection, adjust the pH of the resulting solution to pH 3.5 with dilute hydrochloric acid BP, and The volume was adjusted using BP and mixed well. The solution was filled into a 5 ml Type I ampoule made of clear glass, encapsulated under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

도 1은 본 발명에 따른 활성 c-Met과 루시페라아제(Luciferase) 발현벡터를 나타내는 모식도이다. Figure 1 is a schematic diagram showing the active c-Met and luciferase (Luciferase) expression vector according to the present invention.

Claims (16)

하기 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염:A pyridine derivative substituted with pyrazole and benzoxazole represented by the following formula (1) or a pharmaceutically acceptable salt thereof: <화학식 1><Formula 1>
Figure 112008025718184-pat00074
.
Figure 112008025718184-pat00074
. (상기 화학식 1에서, (In the formula 1, R1은 수소 또는 NHR4이고, 여기서, 상기 R4는 수소, C1-C4의 직쇄 또는 측쇄 알킬 또는 벤질이고;R 1 is hydrogen or NHR 4 , wherein R 4 is hydrogen, C 1 -C 4 straight or branched chain alkyl or benzyl; R2는 수소, 할로겐, C1-C4의 직쇄 또는 측쇄 알킬, -NHR5, -NR6R7, OR5, -CN, -NHC(O)R6, -SO2R6, -OS(O)2R6, 피롤리딘, 피페리딘 및 모폴린 중에서 선택되되 상기 벤즈옥사졸 고리의 5번 또는 6번 위치에 치환되는 어느 하나 또는 상기 벤즈옥사졸 고리의 5번 및 6번 위치에 접합되는 C6-C12의 아릴이고, 여기서, 상기 R5는 수소, C1-C6의 직쇄 또는 측쇄 알킬, C1-C4의 직쇄 또는 측쇄 알키닐, C1-C4의 직쇄 또는 측 쇄 알케닐, C6-C12의 아릴, 할로겐으로 치환된 C6-C12의 아릴 또는 트리할로겐메틸로 치환된 C6-C12의 아릴이고, 상기 R6은 C1-C4의 직쇄 또는 측쇄 알킬이고, R7는 C1-C4의 직쇄 또는 측쇄 알킬 또는 C6-C12의 아릴이고;R 2 is hydrogen, halogen, C 1 -C 4 straight or branched chain alkyl, -NHR 5 , -NR 6 R 7 , OR 5 , -CN, -NHC (O) R 6 , -SO 2 R 6 , -OS (O) any one selected from 2 R 6 , pyrrolidine, piperidine and morpholine, substituted in positions 5 or 6 of the benzoxazole ring or in positions 5 and 6 of the benzoxazole ring C 6 -C 12 aryl, wherein R 5 is hydrogen, C 1 -C 6 straight or branched chain alkyl, C 1 -C 4 straight or branched chain alkynyl, C 1 -C 4 straight chain or branched alkenyl, and aryl of C 6 a C 6 -C 12 aryl substituted with halogen or tri-methyl substituted with a C 6 -C 12 aryl, halogen, -C 12, wherein R 6 is C 1 -C 4 Is linear or branched alkyl of R 7 is C 1 -C 4 straight or branched alkyl or C 6 -C 12 aryl; R3는 수소, C1-C4의 직쇄 또는 측쇄 알킬, 4-피페리딘이며;R 3 is hydrogen, C 1 -C 4 straight or branched chain alkyl, 4-piperidine; A는 탄소 또는 질소이다)A is carbon or nitrogen) 제1항에 있어서, The method of claim 1, 상기 R1은 수소 또는 -NHR4이고, 여기서 R4는 수소, 메틸 또는 벤질이고;R 1 is hydrogen or —NHR 4 , wherein R 4 is hydrogen, methyl or benzyl; 상기 R2는 수소, 불소, 염소, 메틸, -CN, -NHR5, -NR6R7, OR5, -CN, -NHC(O)R6, -SO2R6, -OS(O)2R6, 피롤리딘, 피페리딘 및 모폴린 중에서 선택되되 상기 벤즈옥사졸 고리의 5번 또는 6번 위치에 치환되는 어느 하나 또는 상기 벤즈옥사졸 고리의 5번 및 6번 위치에 접합되는 벤젠이고, 여기서 R5는 수소, 메틸, 에틸, 프로필, 이소프로필, 부틸, 페닐, 4-플루오로페닐, 2,6-디플루오로페닐, 3,5-디플루오로페닐 또는 3,5-디트리플루오로메틸이고, R6는 메틸 또는 에틸이고, R7은 메틸 또는 페닐이고;R 2 is hydrogen, fluorine, chlorine, methyl, -CN, -NHR 5 , -NR 6 R 7 , OR 5 , -CN, -NHC (O) R 6 , -SO 2 R 6 , -OS (O) 2 R 6 , pyrrolidine, piperidine and morpholine, either substituted at position 5 or 6 of the benzoxazole ring or conjugated at positions 5 and 6 of the benzoxazole ring Benzene, where R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, phenyl, 4-fluorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl or 3,5- Ditrifluoromethyl, R 6 is methyl or ethyl, R 7 is methyl or phenyl; 상기 R3는 수소, 메틸 또는 4-피페리딘이며;R 3 is hydrogen, methyl or 4-piperidine; 상기 A는 탄소 또는 질소인 것을 특징으로 하는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염.Wherein A is carbon or nitrogen, and pyridine derivatives substituted with pyrazole and benzoxazole or pharmaceutically acceptable salts thereof. 제1항에 있어서, 상기 화학식 1로 표시되는 피리딘 유도체는 According to claim 1, wherein the pyridine derivative represented by Formula 1 1) 3-(5-클로로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;1) 3- (5-chlorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine; 2) 3-(벤즈[d]옥사졸-2일)-N-메틸-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;2) 3- (benz [d] oxazol-2yl) -N-methyl-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine; 3) 3-(벤즈[d]옥사졸-2일)-N-벤질-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;3) 3- (benz [d] oxazol-2yl) -N-benzyl-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine; 4) 3-(벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;4) 3- (benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine; 5) 3-(5-(에틸설포닐)벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;5) 3- (5- (ethylsulfonyl) benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine- 2-amine; 6) 3-(5-(에틸설포닐)벤즈[d]옥사졸-2-일)-N-메틸-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;6) 3- (5- (ethylsulfonyl) benz [d] oxazol-2-yl) -N-methyl-5- (1- (piperidin-4-yl) -1H-pyrazole-4- Yl) pyridin-2-amine; 7) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d] 옥사졸-5-카보나이트릴;7) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-5-carbonitrile ; 8) 3-(5-(클로로벤즈[d]옥사졸-2-일)-N-메틸-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;8) 3- (5- (chlorobenz [d] oxazol-2-yl) -N-methyl-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine 2-amine; 9) 3-(6-메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;9) 3- (6-methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine; 10) 3-(6-클로로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;10) 3- (6-chlorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine; 11) 3-(6-플루오로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;11) 3- (6-fluorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ; 12) 3-(5-(메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;12) 3- (5- (methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ; 13) 3-(나프토[2,3-d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;13) 3- (naphtho [2,3-d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2- Amines; 14) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-프로필벤즈[d]옥사졸-5-아민; 14) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-propylbenz [d] oxazole- 5-amine; 15) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-메틸벤즈[d]옥사졸-5-아민;15) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-methylbenz [d] oxazole- 5-amine; 16) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-에틸벤즈[d]옥사졸-5-아민;16) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-ethylbenz [d] oxazole- 5-amine; 17) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소 프로필벤즈[d]옥사졸-5-아민;17) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-isopropylbenz [d] oxazole -5-amine; 18) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-부틸벤즈[d]옥사졸-5-아민;18) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-butylbenz [d] oxazole- 5-amine; 19) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N,N-디메틸벤즈[d]옥사졸-5-아민;19) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N, N-dimethylbenz [d] oxa Sol-5-amine; 20) 5-(1-(피페리딘-4-일)-1H-피라졸-4-일)-3-(5-(피롤리딘-1-일)벤즈[d]옥사졸-2-일)피리딘-2-아민;20) 5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3- (5- (pyrrolidin-1-yl) benz [d] oxazole-2- Yl) pyridin-2-amine; 21) 3-(5-(피페리딘-1-일)벤즈[d]옥사졸-2일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;21) 3- (5- (piperidin-1-yl) benz [d] oxazol-2yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl ) Pyridin-2-amine; 22) 3-(5-모폴리노벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;22) 3- (5-morpholinobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine-2- Amines; 23) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-페닐벤즈[d]옥사졸-5-아민;23) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-phenylbenz [d] oxazole- 5-amine; 24) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-메틸-N-페닐벤즈[d]옥사졸-5-아민;24) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-methyl-N-phenylbenz [d ] Oxazole-5-amine; 25) N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-5-일)아세트아마이드;25) N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-5 -Yl) acetamide; 26) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소프로필벤즈[d]옥사졸-6-아민;26) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-isopropylbenz [d] oxazole -6-amine; 27) 5-(1-(피페리딘-4-일)-1H-피라졸-4-일)-3-(6-(피롤리딘-1-일)벤즈[d]옥 사졸-2-일)피리딘-2-아민;27) 5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3- (6- (pyrrolidin-1-yl) benz [d] oxazol-2- Yl) pyridin-2-amine; 28) 3-(6-(피페리딘-1-일)벤즈[d]옥사졸-2일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;28) 3- (6- (piperidin-1-yl) benz [d] oxazol-2yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl ) Pyridin-2-amine; 29) 3-(6-모폴리노벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;29) 3- (6-morpholinobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine-2- Amines; 30) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-페닐벤즈[d]옥사졸-6-아민;30) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-phenylbenz [d] oxazole- 6-amine; 31) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-메틸-N-페닐벤즈[d]옥사졸-6-아민;31) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N-methyl-N-phenylbenz [d ] Oxazole-6-amine; 32) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(4-플루오로페닐)벤즈[d]옥사졸-6-아민;32) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N- (4-fluorophenyl) benz [d] oxazol-6-amine; 33) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(2,6-디플루오로페닐)벤즈[d]옥사졸-6-아민;33) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N- (2,6-difluoro Phenyl) benz [d] oxazol-6-amine; 34) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(3,5-디플루오로페닐)벤즈[d]옥사졸-6-아민;34) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N- (3,5-difluoro Phenyl) benz [d] oxazol-6-amine; 35) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(3,5-비스(트리플루오로메틸)페닐)벤즈[d]옥사졸-6-아민;35) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N- (3,5-bis (tri Fluoromethyl) phenyl) benz [d] oxazol-6-amine; 36) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-5-아민;36) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazol-5-amine; 37) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-벤 즈[d]옥사졸-6-아민;37) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -benz [d] oxazole-6- Amines; 38) 3-(5-에톡시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;38) 3- (5-ethoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ; 39) 3-(5-메톡시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;39) 3- (5-methoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ; 40) 3-(6-메톡시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;40) 3- (6-methoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ; 41) 3-(6-에톡시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;41) 3- (6-ethoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ; 42) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-일 메탄설포네이트;42) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [ d ] oxazol-6-yl methane Sulfonates; 43) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-5-올;43) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazol-5-ol; 44) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-올;44) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazol-6-ol; 45) 3-(벤즈[d]옥사졸-2-일)-5-(1-메틸-1H-피라졸-4-일)피리딘-2-아민;45) 3- (benz [d] oxazol-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine; 46) 3-(벤즈[d]옥사졸-2일)-N-메틸-5-(1메틸-1H-피라졸-4-일)피리딘-2-아민;46) 3- (benz [d] oxazol-2yl) -N-methyl-5- (1methyl-1H-pyrazol-4-yl) pyridin-2-amine; 47) 3-(6-클로로벤즈[d]옥사졸-2-일)-5-(1-메틸-1H-피라졸-4-일)피리딘-2-아민;47) 3- (6-chlorobenz [d] oxazol-2-yl) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine; 48) 3-(벤즈[d]옥사졸-2-일)-5-(1H-피라졸-4-일)피리딘-2-아민;48) 3- (benz [d] oxazol-2-yl) -5- (1H-pyrazol-4-yl) pyridin-2-amine; 49) 5-(1-메틸-1H-피라졸-4-일)-3-(옥사졸로[4,5-c]피리딘-2-일)피리딘-2-아민;49) 5- (1-methyl-1H-pyrazol-4-yl) -3- (oxazolo [4,5-c] pyridin-2-yl) pyridin-2-amine; 50) 3-(옥사졸로[4,5-c]피리딘-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;50) 3- (oxazolo [4,5-c] pyridin-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine ; 51) 5-(1-메틸-1H-피라졸-4-일)- 3-(옥사졸로[4,5-c]피리딘-2-일)피리딘-2-아민; 또는51) 5- (1-methyl-1H-pyrazol-4-yl) -3 (oxazolo [4,5-c] pyridin-2-yl) pyridin-2-amine; or 52) 2-(5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염.52) substituted with pyrazole and benzoxazole, characterized in that it is selected from the group consisting of 2- (5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole. Pyridine derivatives or pharmaceutically acceptable salts thereof. 하기 반응식 1로 표시되는 바와 같이, As represented by Scheme 1 below, 출발물질인 화학식 2의 화합물을 브롬화반응시켜 화학식 3의 화합물을 제조하는 단계(단계 1);Preparing a compound of Chemical Formula 3 by bromination of a compound of Chemical Formula 2 as a starting material (Step 1); 상기 단계 1에서 제조된 화학식 3의 화합물을 염소화반응시켜 화학식 4의 화합물을 제조하는 단계(단계 2);Preparing a compound of formula 4 by chlorination of the compound of formula 3 prepared in step 1 (step 2); 상기 단계 2에서 제조된 화학식 4의 화합물을 화학식 5의 화합물을 치환반응시켜 화학식 6의 화합물을 제조하는 단계(단계 3);Preparing a compound of formula 6 by replacing the compound of formula 4 with the compound of formula 5 prepared in step 2 (step 3); 상기 단계 3에서 제조된 화학식 6의 화합물을 고리화반응시켜 화학식 7의 화합물을 제조하는 단계(단계 4);Preparing a compound of formula 7 by cyclizing the compound of formula 6 prepared in step 3 (step 4); 상기 단계 4에서 제조된 화학식 7의 화합물과 아민화합물(R4NH2)을 치환반응시켜 화학식 8의 화합물을 제조하는 단계(단계 5);Preparing a compound of Chemical Formula 8 by performing a substitution reaction between the compound of Chemical Formula 7 and an amine compound (R 4 NH 2 ) prepared in Step 4 (Step 5); 상기 단계 5에서 제조된 화학식 8의 화합물과 화학식 9의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 10의 화합물을 제조하는 단계(단계 6); 및Preparing a compound of Formula 10 by performing a Suzuki coupling reaction between the compound of Formula 8 and the compound of Formula 9 prepared in Step 5 (Step 6); And 상기 단계 6에서 제조된 화학식 10의 화합물을 탈보호반응시켜 화학식 1a의 화합물을 제조하는 단계(단계 7)를 포함하여 이루어지는 제1항의 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.A pyridine derivative substituted with pyrazole and benzoxazole represented by Formula 1 of claim 1 comprising the step (7) of preparing a compound of Formula 1a by deprotecting the compound of Formula 10 prepared in Step 6; Method for preparing a pharmaceutically acceptable salt thereof. <반응식 1><Scheme 1>
Figure 112008025718184-pat00075
Figure 112008025718184-pat00075
 (상기 반응식 1에서,(In Scheme 1, R2, R4 및 A는 화학식 1에서 정의한 바와 같고, R4'는 수소 또는 R4이고, n은 1-3의 정수이고, 화학식 1a는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이며, NBS: N-브로모숙신이미드, NaOBr: 나트륨하이포브로마이드 PPTS: 파라톨루엔설폰산-피리딘 염, Pd(dppf)Cl2:1,1`-비스(디페닐포스피노)페로센디클로로 팔라듐, Pd(Ph3P)2Cl2: 비스트리페닐포스핀디클로로팔라듐, TFA: 트리플루오로아세트산, Boc: 3급-부톡시카보닐을 의미한다)R 2 , R 4 And A is as defined in Formula 1, R 4 ' is hydrogen or R 4 , n is an integer of 1-3, Formula 1a is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, NBS: N- Bromosuccinimide, NaOBr: sodium hypobromide PPTS: paratoluenesulfonic acid-pyridine salt, Pd (dppf) Cl 2 : 1,1′-bis (diphenylphosphino) ferrocenedichloro palladium, Pd (Ph 3 P) 2 Cl 2 : bistriphenylphosphinedichloropalladium, TFA: trifluoroacetic acid, Boc: tert-butoxycarbonyl) 하기 반응식 2로 표시되는 바와 같이,As represented by Scheme 2 below, 화학식 11의 화합물과 아민화합물(NH2R5 또는 NHR6R7)을 치환반응시켜 화학식 12의 화합물을 제조하는 단계(단계 1); 및Preparing a compound of Chemical Formula 12 by performing a substitution reaction between the compound of Chemical Formula 11 and an amine compound (NH 2 R 5 or NHR 6 R 7 ) (step 1); And 상기 단계 1에서 제조된 화학식 12의 화합물을 탈보호반응시켜 화학식 1b의 화합물을 제조하는 단계(단계 2)를 포함하여 이루어지는 제1항의 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.A pyridine derivative substituted with pyrazole and benzoxazole represented by Chemical Formula 1 of claim 1 comprising the step of deprotecting the compound of Chemical Formula 12 prepared in Step 1 to prepare a compound of Chemical Formula 1b (Step 2); Method for preparing a pharmaceutically acceptable salt thereof. <반응식 2><Scheme 2>
Figure 112010053734322-pat00082
Figure 112010053734322-pat00082
 (상기 반응식 2에서,(In Scheme 2, R5, R6 및 R7은 화학식 1에서 정의한 바와 같고, R8은 -NHR5 또는 -NR6R7이고, n은 1-3의 정수이며, 화학식 1b는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이다)R 5 , R 6 and R 7 are as defined in Formula 1, R 8 is -NHR 5 or -NR 6 R 7 , n is an integer of 1-3, Formula 1b is a derivative of Formula 1 or a pharmaceutical thereof Is an acceptable salt) 하기 반응식 3으로 표시되는 바와 같이,As represented by Scheme 3 below, 화학식 11의 화합물을 염기성 처리시켜 화학식 13의 화합물을 제조하는 단계(단계 1);Basic treating the compound of Formula 11 to prepare a compound of Formula 13 (step 1); 상기 단계 1에서 제조된 화학식 13을 알킬화반응시켜 화학식 14의 화합물을 제조하는 단계(단계 2); 및Preparing a compound of Chemical Formula 14 by alkylating the Chemical Formula 13 prepared in Step 1 (Step 2); And 상기 단계 2에서 제조된 화학식 14의 화합물을 탈보호반응시켜 화학식 1c의 화합물을 제조하는 단계(단계 3)를 포함하여 이루어지거나 또는Or deprotecting the compound of Formula 14 prepared in Step 2 to prepare a compound of Formula 1c (Step 3), or 상기 단계 1에서 제조된 화학식 13의 화합물을 탈보호반응시켜 화학식 1d의 화합물을 제조하는 단계(단계 4)를 포함하여 이루어지는 제1항의 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.A pyridine derivative substituted with pyrazole and benzoxazole represented by Chemical Formula 1 of claim 1 comprising the step (4) of preparing a compound of Chemical Formula 1d by deprotecting the compound of Chemical Formula 13 prepared in Step 1; Method for preparing a pharmaceutically acceptable salt thereof. <반응식 3><Scheme 3>
Figure 112008025718184-pat00077
Figure 112008025718184-pat00077
 (상기 반응식 3에서,(In Scheme 3, R5 및 R6는 화학식 1에서 정의한 바와 같고, X는 할로겐이고, n은 1-3의 정수이고, R9은 -R5 또는 -SO2R6이며, 화학식 1c 및 1d는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이다)R 5 and R 6 are as defined in Formula 1, X is halogen, n is an integer of 1-3, R 9 is -R 5 or -SO 2 R 6 , Formula 1c and 1d are derivatives of Formula 1 Or a pharmaceutically acceptable salt thereof) 하기 반응식 4로 표시되는 바와 같이,As represented by Scheme 4 below, 화학식 8의 화합물과 화학식 15의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 16의 화합물을 제조하는 단계(단계 1); 및Preparing a compound of Formula 16 by performing a Suzuki coupling reaction between a compound of Formula 8 and a compound of Formula 15 (step 1); And 상기 단계 1에서 제조된 화학식 16의 화합물을 탈보호반응시켜 화학식 1e의 화합물을 제조하는 단계(단계 2)를 포함하여 이루어지는 제1항의 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.A pyridine derivative substituted with pyrazole and benzoxazole represented by Chemical Formula 1 of claim 1 comprising the step of deprotecting the compound of Chemical Formula 16 prepared in Step 1 to prepare a compound of Chemical Formula 1e (Step 2); Method for preparing a pharmaceutically acceptable salt thereof. <반응식 4><Scheme 4>
Figure 112008025718184-pat00078
Figure 112008025718184-pat00078
 (상기 반응식 4에서,(In Scheme 4, R2, R3, R4 및 A는 화학식 1에서 정의한 바와 같고, R4'는 수소 또는 R4이고, n은 1-3의 정수이고, 화학식 1e는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이며, A는 탄소 또는 질소이다)R 2 , R 3 , R 4 And A is as defined in Formula 1, R 4 ' is hydrogen or R 4 , n is an integer of 1-3, Formula 1e is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, and A is carbon or Nitrogen) 하기 반응식 5로 표시되는 바와 같이, As represented by Scheme 5 below, 출발물질인 화학식 17의 화합물을 염소화반응시켜 화학식 18의 화합물을 제조하는 단계(단계 1);Preparing a compound of Chemical Formula 18 by chlorination of a compound of Chemical Formula 17 as a starting material (Step 1); 상기 단계 1에서 제조된 화학식 18의 화합물과 화학식 5의 화합물을 치환반응시켜 화학식 19의 화합물을 제조하는 단계(단계 2);Preparing a compound of Formula 19 by performing a substitution reaction of the compound of Formula 18 and the compound of Formula 5 prepared in Step 1 (step 2); 상기 단계 2에서 제조된 화학식 19의 화합물을 고리화반응시켜 화학식 20의 화합물을 제조하는 단계(단계 3);Preparing a compound of formula 20 by cyclization of the compound of formula 19 prepared in step 2 (step 3); 상기 단계 3에서 제조된 화학식 20의 화합물과 화학식 9의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 21의 화합물을 제조하는 단계(단계 4); 및Preparing a compound of Formula 21 by performing a Suzuki coupling reaction between the compound of Formula 20 and the compound of Formula 9 prepared in Step 3 (Step 4); And 상기 단계 4에서 제조된 화학식 21의 화합물을 탈보호반응시켜 화학식 1f의 화합물을 제조하는 단계(단계 5)를 포함하여 이루어지는 제1항의 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.A pyridine derivative substituted with pyrazole and benzoxazole represented by Formula 1 of claim 1 comprising the step (step 5) of preparing a compound of Formula 1f by deprotecting the compound of Formula 21 prepared in Step 4; Method for preparing a pharmaceutically acceptable salt thereof. <반응식 5>Scheme 5
Figure 112008025718184-pat00079
Figure 112008025718184-pat00079
 (상기 반응식 5에서,(In Scheme 5, R2 및 A는 화학식 1에서 정의한 바와 같고, n은 1-3의 정수이고, 화학식 1f는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이다)R 2 And A is as defined in Formula 1, n is an integer of 1-3 and Formula 1f is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof) 하기 반응식 6으로 표시되는 바와 같이, As represented by Scheme 6 below, 화학식 22의 화합물과 화학식 15의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 1g의 화합물을 제조하는 단계를 포함하여 이루어지는 제1항의 화학식 1로 표시되는 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염 또는 이의 약학적으로 허용가능한 염 의 제조방법.Substituting the pyrazole and benzoxazole represented by the formula (1) of claim 1 comprising the step of preparing a compound of formula 1g by performing a Suzuki coupling reaction of the compound of formula 22 and the compound of formula 15 A method for preparing a pyridine derivative or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. <반응식 6><Scheme 6>
Figure 112008025718184-pat00080
Figure 112008025718184-pat00080
 (상기 반응식 6에서,(In Scheme 6, R2, R3 및 A는 화학식 1에서 정의한 바와 같고, 화학식 1g는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이다)R 2 , R 3 And A is as defined in Formula 1, where Formula 1g is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof) 제1항의 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물.A pharmaceutical composition for preventing and treating aberrant cell growth diseases, comprising a pyridine derivative substituted with pyrazole and benzoxazole of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 제10항에 있어서, 상기 피라졸 및 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염은 단백질 키나아제를 억제하여 세포의 증식을 억제하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물.The pharmaceutical composition for preventing and treating aberrant cell growth disease according to claim 10, wherein the pyridine derivatives substituted with pyrazole and benzoxazole or pharmaceutically acceptable salts thereof inhibit protein kinase to inhibit cell proliferation. 제11항에 있어서, 단백질 키나아제는 c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf 및 Aurora-A로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물.12. The aberrant cell growth disease of claim 11, wherein the protein kinase is selected from the group consisting of c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf and Aurora-A. Pharmaceutical composition for the prevention and treatment of. 제11항에 있어서, 상기 이상세포 성장 질환은 폐암, 뼈암, 췌장암, 피부암, 두경부암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 항문 주위 암, 위암, 결장암, 유방암, 자궁암, 나팔관 암, 자궁내막 암, 자궁경부암, 질암, 외음부암, 호지킨병, 식도암, 소장암, 내분비계암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신세포암, 신우암, 중추 신경계(CNS) 종양, 1차 CNS 림프종, 척수 종양, 뇌간 신경교종 및 뇌하수체 선종으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물.The method of claim 11, wherein the abnormal cell growth disease is lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, perianal cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tubes Cancer, Endometrial Cancer, Cervical Cancer, Vaginal Cancer, Vulvar Cancer, Hodgkin's Disease, Esophageal Cancer, Small Intestine Cancer, Endocrine Cancer, Thyroid Cancer, Parathyroid Cancer, Adrenal Cancer, Soft Tissue Sarcoma, Urethral Cancer, Penis Cancer, Prostate Cancer, Chronic or Acute Leukemia Abnormal cells, characterized in that selected from the group consisting of lymphocyte lymphoma, bladder cancer, kidney or ureter cancer, renal cell cancer, renal cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma and pituitary adenoma Pharmaceutical compositions for the prevention and treatment of growth diseases. 제10항에 있어서, 상기 이상세포 성장질환은 건선, 양성 전립선 비대 또는 망막증인 것을 특징으로 하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물.The pharmaceutical composition of claim 10, wherein the abnormal cell growth disease is psoriasis, benign prostatic hypertrophy or retinopathy. 제10항에 있어서, 상기 이상세포 성장질환은 양성 증식성 질환인 것을 특징으로 하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물.The pharmaceutical composition for preventing and treating aberrant cell growth disease according to claim 10, wherein the aberrant cell growth disease is a benign proliferative disease. 제15항에 있어서, 양성 증식성 질환은 섬유선종, 경화성 선질환 또는 유두종인 것을 특징으로 하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물.The pharmaceutical composition for preventing and treating aberrant cell growth disease according to claim 15, wherein the benign proliferative disease is fibroadenoma, sclerotic gland disease or papilloma.
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