KR101245559B1 - Novel pyridine derivatives substituted with multiple substituted benzoxazole 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 pyridine derivatives substituted with multiple substituted benzoxazole 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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KR101245559B1
KR101245559B1 KR1020120070944A KR20120070944A KR101245559B1 KR 101245559 B1 KR101245559 B1 KR 101245559B1 KR 1020120070944 A KR1020120070944 A KR 1020120070944A KR 20120070944 A KR20120070944 A KR 20120070944A KR 101245559 B1 KR101245559 B1 KR 101245559B1
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pyrazol
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김형래
이정옥
류재욱
하재두
조성윤
정희정
한선영
이종국
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한국화학연구원
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems

Abstract

본 발명은 하기 화학식 1로 표시되는 신규 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물에 관한 것으로, 본 발명에 따르면 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.
[화학식 1]

Figure 112012052254195-pat00096

(상기 화학식 1에서, R1~R4는 본 명세서에서 정의된 바와 같다.)The present invention provides a pyridine derivative substituted with a novel multi-substituted benzoxazole represented by Formula 1 or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for preventing and treating aberrant cell growth disease containing the same as an active ingredient. According to the present invention, various protein kinases useful for the treatment of aberrant cell growth diseases, for example c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, Aurora-A Since it shows an excellent inhibitory effect, etc., it can be usefully used for the prevention and treatment of abnormal cell growth diseases.
[Formula 1]
Figure 112012052254195-pat00096

(In Chemical Formula 1, R 1 to R 4 are as defined herein.)

Description

신규 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물{Novel pyridine derivatives substituted with multiple substituted benzoxazole 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 pyridine derivatives substituted with multiple substituted benzoxazoles, pyridine derivatives substituted with novel multi-substituted benzoxazoles, or pharmaceutically acceptable salts thereof, preparation methods thereof, and methods for preventing and treating abnormal cell growth disorders containing the same as active ingredients or pharmaceutically acceptable acceptable salts, preparation method, and pharmaceutical composition for the prevention and treatment of abnormal cell growth diseases containing the same as an active ingredient}

본 발명은 신규 다중치환 벤즈옥사졸로 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 a pyridine derivative substituted with a novel multi-substituted benzoxazole or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition 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 히드록시 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 티로신 키나아제가 알려져 있고, 상기 HER RTK에는 상피 성장 인자 수용체(EGFR), HER2, HER3, HER4 등이 포함된다. 상기 수용체 티로신 키나아제는 세포외 글리코실화리간드 결제조 도메인, 막관통 도메인 및 단백질 상의 티로신 잔사를 인산화시킬 수 있는 세포내 세포질성 도메인으로 이루어진다. Subsequent receptor tyrosine kinases such as those previously termed 19 or more "HER RTKs" are known, and such HER RTKs include epidermal growth factor receptors (EGFR), HER2, HER3, HER4 and the like. The receptor tyrosine kinase consists of an extracellular glycosylated ligand pool, 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 studied as anticancer drugs, many anticancer drugs 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 신장 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 수행하 던 중, 단백질 키나아제에 대한 우수한 저해 활성을 갖는 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.
Therefore, the inventors of the present invention, while conducting research to develop a protein kinase inhibitor, a benzoxazole-substituted pyridine derivative having excellent inhibitory activity against protein kinase is useful for the treatment of abnormal cell growth, c-Met, Ron, KDR. Inhibition of protein kinases such as, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, Aurora-A, etc., thus finding out that it can be useful for the prevention and treatment of abnormal cell growth diseases. The invention was completed.

본 발명의 목적은 신규 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 제공하는 데 있다. It is an object of the present invention to provide pyridine derivatives or pharmaceutically acceptable salts thereof substituted with novel polysubstituted benzoxazoles.

본 발명의 다른 목적은 신규 다중치환 벤즈옥사졸로 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 a pyridine derivative or a pharmaceutically acceptable salt thereof substituted with a novel multi-substituted benzoxazole.

본 발명의 또 다른 목적은 신규 다중치환 벤즈옥사졸로 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 pyridine derivative substituted with a novel multi-substituted benzoxazole or a pharmaceutically acceptable salt thereof as an active ingredient.

상기 목적을 달성하기 위하여, 본 발명은 신규 다중치환 벤즈옥사졸로 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 pyridine derivative substituted with a novel multi-substituted benzoxazole or a pharmaceutically acceptable salt thereof, a method for preparing the same 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 다중치환 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 novel polysubstituted benzoxazole-substituted pyridine derivatives or pharmaceutically acceptable salts thereof exhibit excellent inhibitory activity against protein kinases and are therefore useful for treating various cell kinases, e.g. c -Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b-Raf, Aurora-A, etc. shows an excellent inhibitory effect, can be useful for the prevention and treatment of abnormal cell growth diseases.

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

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

Figure 112012052254195-pat00001
Figure 112012052254195-pat00001

(상기 화학식 1에서, (In the formula 1,

R1은 수소; C1~C3 직쇄 또는 측쇄 알킬; 니트로; 아미노; 또는 -NHCONHR5이고, 이때, R5는 C1~C3 직쇄 또는 측쇄 알킬; 또는 C6~C12 아릴이고,R 1 is hydrogen; C 1 -C 3 straight or branched alkyl; Nitro; Amino; Or -NHCONHR 5, wherein R 5 is C 1 -C 3 straight or branched alkyl; Or C 6 -C 12 aryl,

R2 및 R3은 각각 수소; 히드록시; C1~C4의 할로알킬; C1~C4의 직쇄 또는 측쇄 알킬; C6~C12 아릴; C5~C12 헤테로아릴; -NHR6; -NHCONHR6; -CONHR6; -NHCONHSO2R6; -OR7; -NHC(O)R7; -NHSO2R7; -OS(O)2R7이고, 이때, 상기 R6는 C1~C4의 직쇄 또는 측쇄 알킬; 또는 C6~C12 아릴이고, 상기 R7은 C1~C4의 직쇄 또는 측쇄 알킬; C6~C12의 아릴; C6~C12의 헤테로아릴; 또는 벤질이고,R 2 And R 3 is each hydrogen; Hydroxy; Haloalkyl of C 1 to C 4 ; C 1 -C 4 straight or branched alkyl; C 6 ~ C 12 Aryl; C 5 ~ C 12 Heteroaryl; -NHR 6 ; -NHCONHR 6 ; -CONHR 6 ; -NHCONHSO 2 R 6 ; -OR 7 ; -NHC (O) R 7 ; -NHSO 2 R 7 ; -OS (O) 2 R 7 , wherein R 6 is C 1 -C 4 straight or branched alkyl; Or C 6 -C 12 aryl, wherein R 7 is C 1 -C 4 straight or branched alkyl; C 6 -C 12 aryl; C 6 -C 12 heteroaryl; Or benzyl,

R4는 수소; 히드록시; -NHR8; -NH(CH2)nNR8; 또는 -NH(CH2)nNR9이고, 이때, R8은 수소; C1~C4의 직쇄 또는 측쇄 알킬; C3~C8의 사이클로알킬; C6~C12의 아릴; 또는 C5~C12의 헤테로아릴이고, n은 1-5이고, R9은 C3~C8의 사이클로알킬 아민, C5~C12의 아릴 또는 C5~C12의 헤테로아릴이다.)
R 4 is hydrogen; Hydroxy; -NHR 8 ; -NH (CH 2 ) n NR 8 ; Or —NH (CH 2 ) n NR 9, wherein R 8 is hydrogen; C 1 -C 4 straight or branched alkyl; C 3 -C 8 cycloalkyl; C 6 -C 12 aryl; Or C 5 -C 12 heteroaryl, n is 1-5, R 9 is C 3 -C 8 cycloalkyl amine, C 5 -C 12 aryl or C 5 -C 12 heteroaryl.)

바람직하게 상기 R1은 수소; 니트로; 아미노; 또는 -NHCONHR5이고, 이때, R5는 4-메톡시페닐이고,Preferably R 1 is hydrogen; Nitro; Amino; Or -NHCONHR 5, wherein R 5 is 4-methoxyphenyl,

상기 R2 및 R3은 각각 수소; 히드록시; 메틸; 페닐; 4-메톡시페닐; 이미다졸릴; 피리딜; 피라졸릴; -OR6; -NHR6; -NHCONHR6; NHC(O)R6; -NHCONHSO2R6; -CONHR7; -NHSO2R7; 또는 -OS(O)2R7이고, 이때, 상기 R6는 메틸; 이소프로필; 페닐; 4-플루오로페닐; 4-트리플루오로페닐; 2,4-다이클로로페닐; p-톨릴; 4-메톡시페닐; 벤질; 6-인다졸릴; 피리딜; 2,5-피리미딜; 2,4-피리미딜; 5-클로로피리딜; 4-시아노피리딜; 또는 7-페닐피리다지닐이고, 상기 R7은 메틸; 이소프로필; 4-메톡시페닐; 4-플루오로페닐; 2,5-다이클로로페닐; C6~C12의 헤테로아릴; 또는 벤질이고,R 2 And R 3 is each hydrogen; Hydroxy; methyl; Phenyl; 4-methoxyphenyl; Imidazolyl; Pyridyl; Pyrazolyl; -OR 6 ; -NHR 6 ; -NHCONHR 6 ; NHC (O) R 6 ; -NHCONHSO 2 R 6 ; -CONHR 7 ; -NHSO 2 R 7 ; Or -OS (O) 2 R 7 , wherein R 6 is methyl; Isopropyl; Phenyl; 4-fluorophenyl; 4-trifluorophenyl; 2,4-dichlorophenyl; p-tolyl; 4-methoxyphenyl; benzyl; 6-indazolyl; Pyridyl; 2,5-pyrimidyl; 2,4-pyrimidyl; 5-chloropyridyl; 4-cyanopyridyl; Or 7-phenylpyridazinyl, wherein R 7 is methyl; Isopropyl; 4-methoxyphenyl; 4-fluorophenyl; 2,5-dichlorophenyl; C 6 -C 12 heteroaryl; Or benzyl,

상기 R4는 수소; 메틸; 히드록시; 할로겐; N-피롤리디닐; -OR8; -OSO2R8; -NHR8; -NH(CH2)nNR8; 또는 -NH(CH2)nNR9이고, 이때 R8은 수소; 에틸; 이소프로필; 3-벤질옥시페닐; 3-티오페닐메틸; N,N-디메틸프로필; N-메틸-피페라지닐; 모폴리닐; 또는 4-메틸피페리디닐이고, n은 1-5이고, R9은 C3~C8의 사이클로알킬 아민; 페닐; 6-인다졸릴; 2-피리딜; 2,5-피리미디닐이다.
R 4 is hydrogen; methyl; Hydroxy; halogen; N-pyrrolidinyl; -OR 8 ; -OSO 2 R 8 ; -NHR 8 ; -NH (CH 2 ) n NR 8 ; Or —NH (CH 2 ) n NR 9, wherein R 8 is hydrogen; ethyl; Isopropyl; 3-benzyloxyphenyl; 3-thiophenylmethyl; N, N-dimethylpropyl; N-methyl-piperazinyl; Morpholinyl; Or 4-methylpiperidinyl, n is 1-5, R 9 is C 3 -C 8 cycloalkyl amine; Phenyl; 6-indazolyl; 2-pyridyl; 2,5-pyrimidinyl.

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

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

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

3) N-2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-7-일)-N,N-다이메틸프로판-1,3-다이아민;3) N-2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-7- Yl) -N, N-dimethylpropane-1,3-diamine;

4) 5-(1-(피페리딘-4-일)-1H-피라졸-4-일)-3-(7-(피롤리딘-1-일)벤즈[d]옥사졸-2-일)피리딘-2-아민;4) 5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3- (7- (pyrrolidin-1-yl) benz [d] oxazol-2- Yl) pyridin-2-amine;

5) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-4-일)-N-(싸이오펜-2-일메틸)벤즈[d]옥사졸-7-아민;5) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-4-yl) -N- (thiophen-2-ylmethyl ) Benz [d] oxazol-7-amine;

6) 3-(7-(4-메틸피페라진-1-일)벤즈[d]옥사졸-2일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;6) 3- (7- (4-methylpiperazin-1-yl) benz [d] oxazol-2yl) -5- (1- (piperidin-4-yl) -1H-pyrazole-4 -Yl) pyridin-2-amine;

7) 3-(7-모폴리노벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;7) 3- (7-morpholinobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2- Amines;

8) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(피페리딘-4-일메틸)벤즈[d]옥사졸-7-아민;8) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N- (piperidin-4-yl Methyl) benz [d] oxazol-7-amine;

9) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(3-(벤질옥시)페닐)벤즈[d]옥사졸-7-아민; 9) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N- (3- (benzyloxy) phenyl ) Benz [d] oxazol-7-amine;

10) N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-4-일)메탄설폰아마이드;10) N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-4 -Yl) methanesulfonamide;

11) 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-4-일)-3-(4-메톡시페닐)우레아;11) 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-4 -Yl) -3- (4-methoxyphenyl) urea;

12) 3-(6-(4-메톡시페닐)벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;12) 3- (6- (4-methoxyphenyl) benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) Pyridin-2-amine;

13) 3-(6-페닐벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;13) 3- (6-phenylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine;

14) 5-(1-(피페리딘-4-일)-1H-피라졸-4-일)-3-(6-(피리딘-3-일)벤즈[d]옥사졸-2-일)피리딘-2-아민;14) 5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3- (6- (pyridin-3-yl) benz [d] oxazol-2-yl) Pyridin-2-amine;

15) 3-(6-(1H-피라졸-5-일)벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;15) 3- (6- (1H-pyrazol-5-yl) benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazole-4 -Yl) pyridin-2-amine;

16) 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-3-(4-플루오로페닐)우레아;16) 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-6 -Yl) -3- (4-fluorophenyl) urea;

17) 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-3-(2,4-다이클로로페닐)우레아;17) 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-6 -Yl) -3- (2,4-dichlorophenyl) urea;

18) 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-3-페닐우레아;18) 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-3-yl) benz [d] oxazole-6 -Yl) -3-phenylurea;

19) N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-3-일)벤즈[d]옥사졸-6-일카바모일-4-메틸벤젠설폰아마이드;19) N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-3-yl) benz [d] oxazole-6 -Ylcarbamoyl-4-methylbenzenesulfonamide;

20) N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-3-일)벤즈[d]옥사졸-6-일)메탄설폰아마이드;20) N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-3-yl) benz [d] oxazole-6 -Yl) methanesulfonamide;

21) N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-4-메톡시벤젠설폰아마이드;21) N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-3-yl) benz [d] oxazole-6 -Yl) -4-methoxybenzenesulfonamide;

22) N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-4-플루오로벤젠설폰아마이드;22) N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-6 -Yl) -4-fluorobenzenesulfonamide;

23) N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-2,5-다이클로로벤젠설폰아마이드;23) N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-3-yl) benz [d] oxazole-6 -Yl) -2,5-dichlorobenzenesulfonamide;

24) 5-(1-(피페리딘-4-일)-1H-피라졸-3-일)-3-(4,5,7-트리클로로벤즈[d]옥사졸-2-일)피리딘-2-아민;24) 5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) -3- (4,5,7-trichlorobenz [d] oxazol-2-yl) pyridine 2-amine;

25) 3-(5,7-다이클로로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-2-아민;25) 3- (5,7-dichlorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridine-2 Amines;

26) 3-(7-클로로-5-플루오로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-2-아민;26) 3- (7-chloro-5-fluorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridine 2-amine;

27) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-3-일)-5-플루오로벤즈[d]옥사졸-7-올;27) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-3-yl) -5-fluorobenz [d] oxazole -7-ol;

28) 3-(5-클로로-7-플루오로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-2-아민;28) 3- (5-chloro-7-fluorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridine 2-amine;

29) 3-(5-클로로-6-플루오로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-2-아민;29) 3- (5-chloro-6-fluorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridine 2-amine;

30) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일) 피리딘-3-일)-6-클로로-N-이소프로필벤즈[d]옥사졸-5-카르복스아마이드;30) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -6-chloro-N-isopropylbenz [ d] oxazole-5-carboxamide;

31) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일) 피리딘-3-일)-6-히드록시-N-이소프로필벤즈[d]옥사졸-5-카르복스아마이드;
31) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -6-hydroxy-N-isopropylbenz [d] oxazole-5-carboxamide;

*32) 3-(5-히드록시-6-메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;* 32) 3- (5-hydroxy-6-methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) Pyridin-2-amine;

33) 3-(6-히드록시-5-메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;33) 3- (6-hydroxy-5-methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine 2-amine;

34) 3-(5-히드록시-6-에틸벤즈[d]옥사졸-2-일)-5-(1-(피페리-4-일)-1H-피라졸-4-일)피리딘-2-아민;34) 3- (5-hydroxy-6-ethylbenz [d] oxazol-2-yl) -5- (1- (piperid-4-yl) -1H-pyrazol-4-yl) pyridine- 2-amine;

35) 3-(3,5-디메틸-6-히드록시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;35) 3- (3,5-dimethyl-6-hydroxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl ) Pyridin-2-amine;

36) 3-(6-히드록시-7-메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;36) 3- (6-hydroxy-7-methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine 2-amine;

37) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-7-(1H-인돌-6-일)벤즈[d]옥사졸-6-올;37) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -7- (1H-indol-6-yl ) Benz [d] oxazol-6-ol;

38) 3-(7-(1H-인돌-6-일)-6-메톡시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;38) 3- (7- (1H-indol-6-yl) -6-methoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- Pyrazol-4-yl) pyridin-2-amine;

39) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-7-페닐벤즈[d]옥사졸-6-올; 및39) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -7-phenylbenz [d] oxazole- 6-ol; And

40) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-7-(4-메톡시페닐)벤즈[d]옥사졸-6-올.
40) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -7- (4-methoxyphenyl) benz [d] oxazole-6-ol.

본 발명의 상기 화학식 1로 표시되는 다중치환 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, 말레산, 메테인설폰산, 에테인설폰산, 4-톨루엔술폰산, 살리실산, 시트르산, 벤조산 또는 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 derivative substituted with the polysubstituted benzoxazole represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and the salt may be an acid addition salt formed by a pharmaceutically acceptable free acid. This is useful. The term pharmaceutically acceptable salt means a concentration that is relatively non-toxic to a patient and has a beneficial effect that is harmless to the patient, such that the side effects caused by the salt are any organic or inorganic salt of the base compound of Formula 1 that does not impair the beneficial effects of the base compound of Formula An inorganic addition salt. Examples of the inorganic acid include hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid and phosphoric acid. Examples of the organic acid include citric acid, acetic acid, lactic acid, maleic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, succinic acid, tartaric acid, galacturonic acid, embic acid, glutamic acid, aspartic acid, oxalic acid, P-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid. These salts also include alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.). 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 다중치환 벤즈옥사졸로 치환된 피리딘 유도체는 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 이성질체, 수화물, 용매화물을 모두 포함한다.In addition, the pyridine derivative substituted with a polysubstituted benzoxazole represented by the formula (1) of the present invention is not only a pharmaceutically acceptable salt, but also all salts, isomers, hydrates, and solvates that can be prepared by conventional methods. Include.

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 Chemical Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile, etc., And then precipitating or crystallizing the acid solution. 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.

본 명세서에서 이성질체는 동일한 화학식 또는 분자식을 가지지만 광학적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미하며, 상기 이성질체 및 이들의 혼합물 역시 본 발명의 범위에 포함된다.
Isomers herein means compounds of the present invention or salts thereof having the same chemical formula or molecular formula, but which are optically or sterically different, and such isomers and mixtures thereof are also included within the scope of the present invention.

또한, 본 발명은 상기 화학식 1로 표시되는 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법을 제공한다.In addition, the present invention provides a method for preparing a pyridine derivative or a pharmaceutically acceptable salt thereof substituted with a polysubstituted benzoxazole represented by Chemical Formula 1.

본 발명에 따른 상기 화학식 1의 화합물은 하기 반응식 1~9에 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 the following Schemes 1-9.

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 치환반응시켜 화학식 4의 화합물을 제조하는 단계(단계 1);Preparing a compound of Chemical Formula 4 by substituting a compound of Chemical Formula 2 as a starting material (Step 1);

상기 단계 1에서 제조된 화학식 4의 화합물을 고리화반응시켜 화학식 5의 화합물을 제조하는 단계(단계 2);Preparing a compound of formula 5 by cyclization of the compound of formula 4 prepared in step 1 (step 2);

상기 단계 2에서 제조된 화학식 5의 화합물과 아민화합물을 치환반응시켜 화학식 6의 화합물을 제조하는 단계(단계 3);Preparing a compound of Chemical Formula 6 by performing a substitution reaction between the compound of Chemical Formula 5 and an amine compound prepared in Step 2 (Step 3);

상기 단계 3에서 제조된 화학식 6의 화합물과 화학식 7의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 8의 화합물을 제조하는 단계(단계 4); Preparing a compound of Chemical Formula 8 by performing a Suzuki coupling reaction between the compound of Chemical Formula 6 and the compound of Chemical Formula 7 prepared in Step 3 (Step 4);

상기 단계 4에서 제조된 화학식 8의 화합물을 수소화반응시켜 화학식 9의 화합물을 제조하는 단계(단계 5); Preparing a compound of formula 9 by hydrogenating the compound of formula 8 prepared in step 4 (step 5);

상기 단계 5에서 제조된 화학식 9의 화합물을 화학식 10의 화합물과 부가반응시켜 화학식 11의 화합물을 제조하는 단계(단계 6); 및 Preparing a compound of formula 11 by adding a compound of formula 9 prepared in step 5 with a compound of formula 10 (step 6); And

상기 단계 6에서 제조된 화학식 11의 화합물을 탈보호반응시켜 화학식 1a의 화합물을 제조하는 단계(단계 7)를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다.Deprotection of the compound of Chemical Formula 11 prepared in Step 6 may be prepared by a manufacturing method comprising the step of preparing a compound of Chemical Formula 1a (Step 7).

<반응식 1<Scheme 1

Figure 112012052254195-pat00002
Figure 112012052254195-pat00002

(상기 반응식 1에서, 화학식 1a는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, n은 1~3의 정수이며, Ar은 화학식 1에서 정의한 R5 또는 R7이고, Et3N는 트리에틸아민, PPTS는 파라톨루엔 피리디늄염, Pd(dppf)Cl2는 1,1`-비스(디페닐포스피노)페로센다이클로로 팔라듐, Pd(Ph3P)2Cl2는 비스트리페닐포스핀다이클로로팔라듐, NCO는 이소시아네이트, TFA는 트리플루오로아세트산, Boc는 t-부톡시카보닐이다.)
(In Scheme 1, Formula 1a is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, n is an integer of 1 to 3, Ar is R 5 or R 7 defined in Formula 1, Et 3 N is a tree Ethylamine, PPTS is paratoluene pyridinium salt, Pd (dppf) Cl 2 is 1,1`-bis (diphenylphosphino) ferrocenedichloro palladium, Pd (Ph 3 P) 2 Cl 2 is bistriphenylphosphinedi Chloropalladium, NCO is isocyanate, TFA is trifluoroacetic acid, Boc is t-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 9의 화합물을 화학식 13으로 표시되는 아릴설포닐이소시아네이트와 부가반응시켜 화학식 14의 화합물을 제조하는 단계(단계 1);Reacting the compound of Formula 9 with an arylsulfonyl isocyanate represented by Formula 13 to prepare a compound of Formula 14 (step 1);

상기 단계 1에서 제조된 화학식 14의 화합물을 탈보호반응시켜 화학식 1c의 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 1c by deprotection reaction of the compound of Formula 14 prepared in Step 1.

<반응식 2><Reaction Scheme 2>

Figure 112012052254195-pat00003
Figure 112012052254195-pat00003

(상기 반응식 2에서, 화학식 1c는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, n은 1~3의 정수이며, Ar은 화학식 1에서 정의한 R5 또는 R7이고, ArSO2NCO는 아릴설포닐이소시아네이트이다.)
(In Scheme 2, Formula 1c is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, n is an integer of 1 to 3, Ar is R 5 as defined in Formula 1 Or R 7 and ArSO 2 NCO is arylsulfonylisocyanate.)

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 9의 화합물을 화학식 15로 표시되는 아릴설포닐클로라이드 혹은 알킬설포닐 클로라이드와 부가반응시켜 화학식 16의 화합물을 제조하는 단계(단계 1);Reacting the compound of Formula 9 with arylsulfonyl chloride or alkylsulfonyl chloride represented by Formula 15 to prepare a compound of Formula 16 (step 1);

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

<반응식 3><Reaction Scheme 3>

Figure 112012052254195-pat00004
Figure 112012052254195-pat00004

(상기 반응식 3에서, 화학식 1d는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, n은 1~3의 정수이며, Ar(또는 R)은 화학식 1에서 정의한 R5 또는 R7이고, ArSO2Cl는 아릴설포닐클로라이드이다.)
(In Scheme 3, Formula 1d is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, n is an integer of 1 to 3, Ar (or R) is R 5 as defined in Formula 1 Or R 7 and ArSO 2 Cl is arylsulfonylchloride.)

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 2의 화합물을 화학식 17의 화합물과 반응시켜 화학식 18의 화합물을 제조하는 단계(단계 1);Reacting a compound of Formula 2 with a compound of Formula 17 to prepare a compound of Formula 18 (step 1);

상기 단계 1에서 제조된 화학식 18의 화합물을 고리화반응시켜 화학식 19의 화합물을 제조하는 단계(단계 2);Preparing a compound of formula 19 by cyclization of the compound of formula 18 prepared in step 1 (step 2);

상기 단계 2에서 제조된 화학식 19의 화합물과 아민화합물을 치환반응시켜 화학식 20의 화합물을 제조하는 단계(단계 3);Preparing a compound of Chemical Formula 20 by performing a substitution reaction between the compound of Chemical Formula 19 and an amine compound prepared in Step 2 (Step 3);

상기 단계 3에서 제조된 화학식 20의 화합물과 화학식 6의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 21의 화합물을 제조하는 단계(단계 4); Preparing a compound of Chemical Formula 21 by performing a Suzuki coupling reaction between the compound of Chemical Formula 20 and the compound of Chemical Formula 6 prepared in Step 3 (Step 4);

상기 단계 4에서 제조된 화학식 21의 화합물을 수산화칼륨과 스즈키 커플링 (Suzuki coupling reaction)을 수행하여 화학식 22의 화합물을 제조하는 단계(단계 5); Preparing a compound of Chemical Formula 22 by performing a Suzuki coupling reaction with potassium hydroxide on the compound of Chemical Formula 21 prepared in Step 4 (Step 5);

상기 단계 5에서 제조된 화학식 22의 화합물을 탈보호반응시켜 화학식 1e의 화합물을 제조하는 단계(단계 6)를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다.Deprotection of the compound of Chemical Formula 22 prepared in Step 5 may be prepared by a manufacturing method comprising the step of preparing a compound of Chemical Formula 1e (Step 6).

<반응식 4><Reaction Scheme 4>

Figure 112012052254195-pat00005
Figure 112012052254195-pat00005

(상기 반응식 4에서, 화학식 1e는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, n은 1~3의 정수이며, R1은 화학식 1에서 정의한 바와 같다.)
(In Scheme 4, Formula 1e is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, n is an integer of 1 to 3, R 1 is as defined in Formula 1.)

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

화학식 22의 화합물을 화학식 23 화합물에 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 24의 화합물을 제조하는 단계(단계 1); Preparing a compound of Chemical Formula 24 by performing a Suzuki coupling reaction on a compound of Chemical Formula 22 to a compound of Chemical Formula 23 (step 1);

단계 1에서 제조된 화학식 24의 화합물을 탈보호반응시켜 화학식 1f의 화합물을 제조하는 단계(단계 2)를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다.Deprotection of the compound of Chemical Formula 24 prepared in Step 1 to prepare a compound of Chemical Formula 1f (Step 2) can be prepared by the production method comprising a.

<반응식 5>Scheme 5

Figure 112012052254195-pat00006
Figure 112012052254195-pat00006

(상기 반응식 5에서, 화학식 1f는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, n은 1~3의 정수이며, Ar은 화학식 1에서 정의한 R7이고, ArBr은 브로모아렌, X-Phos는 디사이클로헥실포스피노-2',4',6'-트리이소프로필바이페닐, K3PO4는 삼인산포스페이트이다.)
(In Scheme 5, Formula 1f is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, n is an integer of 1 to 3, Ar is R 7 as defined in Formula 1, ArBr is bromoarene, X- Phos is dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, K 3 PO 4 is triphosphate.)

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 25의 화합물을 염화알킬과 반응시켜 화학식 26의 화합물을 제조하는 단계(단계 1); Reacting a compound of formula 25 with alkyl chloride to produce a compound of formula 26 (step 1);

단계 1에서 제조된 화학식 26의 화합물을 탈보호반응시켜 화학식 1h의 화합물을 제조하는 단계(단계 2)를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다.Deprotection of the compound of formula 26 prepared in step 1 to prepare a compound of formula (1h) can be prepared by the preparation method comprising the step (step 2).

<반응식 6><Reaction Scheme 6>

Figure 112012052254195-pat00007
Figure 112012052254195-pat00007

(상기 반응식 6에서, 화학식 1h는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, n은 1~3의 정수이며, Ar은 화학식 1에서 정의한 R4 중 비치환 또는 C1~C4 직쇄 또는 측쇄 알킬이나 C1~C4 알콕시로 치환된 C6~C12 아릴; 또는 비치환 또는 C1~C4 직쇄 또는 측쇄 알킬이나 C1~C4 알콕시로 치환된 C5~C12 헤테로아릴이고, R은 C1~C4 직쇄 또는 측쇄 알킬이고, DMF는 N,N-디메틸포름아마이드이다.)
(In Scheme 6, Formula 1h is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, n is an integer of 1 to 3, Ar is an unsubstituted or C 1 ~ C 4 straight chain in R 4 as defined in Formula 1 or a C 6 ~ C 12 substituted with a branched alkyl or C 1 ~ C 4 alkoxy aryl, or unsubstituted or C 1 ~ C 4 linear or branched alkyl or C 1 ~ C 4 alkoxy-substituted C 5 ~ C 12 heteroaryl group as R is C 1 -C 4 straight or branched alkyl, and DMF is N, N -dimethylformamide.)

제조방법 7Manufacturing Method 7

하기 반응식 7로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은As represented by the following Scheme 7, the derivative of Formula 1 or a pharmaceutically acceptable salt thereof

화학식 21의 화합물을 아릴보론산과 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 27의 화합물을 제조하는 단계(단계 1); Preparing a compound of Formula 27 by performing a Suzuki coupling reaction with an arylboronic acid with a compound of Formula 21 (step 1);

단계 1에서 제조된 화학식 27의 화합물을 탈보호반응시켜 화학식 1i의 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 1i by deprotection reaction of the compound of formula 27 prepared in step 1.

<반응식 7><Reaction Scheme 7>

Figure 112012052254195-pat00008
Figure 112012052254195-pat00008

(상기 반응식 7에서, 화학식 1i는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, n은 1~3의 정수이며, Ar은 화학식 1에서 정의한 R4 중 비치환 또는 C1~C4 직쇄 또는 측쇄 알킬이나 C1~C4 알콕시로 치환된 C6~C12 아릴; 또는 비치환 또는 C1~C4 직쇄 또는 측쇄 알킬이나 C1~C4 알콕시로 치환된 C5~C12 헤테로아릴이다.)
(In Scheme 7, Formula 1i is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, n is an integer of 1 to 3, Ar is unsubstituted or C 1 ~ C 4 straight chain in R 4 as defined in Formula 1 or a C 6 ~ C 12 substituted with a branched alkyl or C 1 ~ C 4 alkoxy aryl, or unsubstituted or C 1 ~ C 4 linear or branched alkyl or C 1 ~ C 4 alkoxy-substituted C 5 ~ C 12 heteroaryl group as to be.)

제조방법 8Manufacturing Method 8

하기 반응식 8로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은As represented by Scheme 8, the derivative of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof

화학식 28의 화합물을 염화반응과 부가반응을 수행하여 화학식 29의 화합물을 제조하는 단계(단계 1); Preparing a compound of Chemical Formula 29 by performing a chloride reaction and an addition reaction of the compound of Chemical Formula 28 (step 1);

단계 1에서 제조된 화학식 29의 화합물을 니트로화을 수행하여 화학식 30의 화합물을 제조하는 단계(단계 2);Preparing a compound of Chemical Formula 30 by performing nitration of the compound of Chemical Formula 29 prepared in Step 1 (Step 2);

상기 단계 2에서 제조된 화학식 30의 화합물을 수소화 반응을 수행하여 화학식 31의 화합물을 제조하는 단계(단계 3);Preparing a compound of Chemical Formula 31 by performing a hydrogenation reaction of the compound of Chemical Formula 30 prepared in Step 2 (step 3);

상기 단계 3에서 제조된 화학식 31의 화합물과 아민화합물을 치환반응시켜 화학식 32의 화합물을 제조하는 단계(단계 4);Preparing a compound of Chemical Formula 32 by performing a substitution reaction between the compound of Chemical Formula 31 and an amine compound prepared in Step 3 (Step 4);

상기 단계 4에서 제조된 화학식 32의 화합물을 고리화반응을 수행하여 화학식 33의 화합물을 제조하는 단계(단계 5);Preparing a compound of Chemical Formula 33 by performing a cyclization reaction on the compound of Chemical Formula 32 prepared in Step 4 (step 5);

상기 단계 5에서 제조된 화학식 33의 화합물을 아민의 부가반응을 수행하여 화학식 34의 화합물을 제조하는 단계(단계 6);Preparing a compound of Chemical Formula 34 by performing an addition reaction of an amine with the compound of Chemical Formula 33 prepared in step 5 (step 6);

상기 단계 6에서 제조된 화학식 34의 화합물과 화학식 6의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 35의 화합물을 제조하는 단계(단계 7); Preparing a compound of Chemical Formula 35 by performing a Suzuki coupling reaction between the compound of Chemical Formula 34 and the compound of Chemical Formula 6 prepared in Step 6 (Step 7);

단계 7에서 제조된 화학식 35의 화합물을 탈보호반응시켜 화학식 1j의 화합물을 제조하는 단계(단계 8)를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다.It may be prepared by a manufacturing method comprising the step (step 8) of preparing a compound of formula 1j by deprotection reaction of the compound of formula 35 prepared in step 7.

<반응식 8><Reaction Scheme 8>

Figure 112012052254195-pat00009
Figure 112012052254195-pat00009

(상기 반응식 8에서, 화학식 1j는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, n은 1~3의 정수이며, R은 이소프로필이고, DEE는 다이에톡시에틸에테르이다.)
(In Scheme 8, Formula 1j is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, n is an integer from 1 to 3, R is isopropyl, and DEE is diethoxyethyl ether.)

제조방법 9Manufacturing Method 9

하기 반응식 9로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은As represented by Scheme 9, the derivative of Formula 1 or a pharmaceutically acceptable salt thereof

화학식 35의 화합물을 수산화칼륨과 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 36의 화합물을 제조하는 단계(단계 1); Preparing a compound of Chemical Formula 36 by performing a Suzuki coupling reaction with potassium hydroxide to a compound of Chemical Formula 35 (step 1);

단계 1에서 제조된 화학식 36의 화합물을 탈보호반응시켜 화학식 1k의 화합물을 제조하는 단계(단계 2)를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다.Deprotection of the compound of Chemical Formula 36 prepared in Step 1 to prepare a compound of Chemical Formula 1k (Step 2) can be prepared by the production method comprising a.

<반응식 9><Reaction Scheme 9>

Figure 112012052254195-pat00010
Figure 112012052254195-pat00010

(상기 반응식 9에서, 화학식 1k는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, n은 1~3의 정수이며, R은 이소프로필이다.)
(In Scheme 9, Formula 1k is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, n is an integer of 1 to 3, R is isopropyl.)

나아가, 본 발명은 상기 화학식 1로 표시되는 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물을 제공한다. Furthermore, the present invention provides a pharmaceutical composition for preventing and treating aberrant cell growth diseases containing a pyridine derivative substituted with polysubstituted 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 다중치환 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 multi-substituted benzoxazoles represented by Formula 1 are c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, TrkA, TrkB, b Can inhibit protein kinases such as Raf and Aurora-A.

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, 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-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 10 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 10 μM or less in the c-Met kinase activity experiment.

따라서, 본 발명에 따른 신규 다중치환 벤즈옥사졸로 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 a pyridine derivative substituted with a novel multi-substituted benzoxazole according to the present invention or a pharmaceutical salt thereof 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 락토오스(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 stearate 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. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. 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 to 100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient with a weight of 70 kg, it is generally 0.07 ~ 7000 mg / day, preferably 0.7 ~ 2500 mg / day, once a day at regular intervals depending on 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 t-부틸을 의미하고, "Boc"는 t-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-t-부틸포스피노-2',4',6'-트리아이소프로필바이페닐을 의미하고, "Pd(Ph3P)2Cl2"는 비스트리페닐포스핀다이클로로팔라듐을 의미하고, "Pd2(dba)3"는 트리스(디벤질리딘아세톤)디팔라듐을 의미하고, "Pd(dppf)Cl2"는 1,1'-비스(디페닐포스피노페로센)디클로팔라듐을 의미하고, "t-BuONa"는 나트륨t-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 t-butyl, "Boc" means t-butoxycarbonyl, "EtOAc" means ethyl acetate, "NEt 3 " or "Et 3 N" means triethylamine, "Et 2 O" means diethyl ether, "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 trifluoroacetic acid "X-Phos" means 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, and " t- Butyl X-Phos" means 2-di-t- Butylphospho No-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 t-butoxide, “Na 2 CO 3 ” means sodium carbonate, “K 2 CO 3 ” means potassium carbonate, “KI” means potassium iodide, and “MgSO 4 ” magnesium sulfate "KOH" means potassium hydroxide.

< 제조예 1> t-부틸-4-(4-(4,4,5,5- 테트라메틸 -1,3,2- 디옥사보롤란 -2-일)-1H-피라졸-1-일)-피페리딘-1-카복실레이트의 제조 <Production Example 1> t- butyl-4 (4- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) -1H- pyrazol-1-yl Preparation of) -piperidine-1-carboxylate

Figure 112012052254195-pat00011
Figure 112012052254195-pat00011

문헌(WO 2006/021881)에 기재된 방법을 이용하여 제조하였다.
It was prepared using the method described in WO 2006/021881.

< 실시예 1> 3-(4- 니트로벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H- 피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 <Example 1> 3- (4-nitro-benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-2 Preparation of Ditrifluoroacetic Acid of Amine

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

Figure 112012052254195-pat00012
Figure 112012052254195-pat00012

2-옥소-1,2-디하이드로피리딘-3-카르복실산으로부터 문헌(A. D. Cale, Jr., T. W. Gero et. al. J. Med. Chem. 1989, 32, 2178-2199; 미국특허 등록번호 5,034,531)에 개시된 방법으로 목적화합물을 얻었다.
From 2-oxo-1,2-dihydropyridine-3-carboxylic acid (AD Cale, Jr., TW Gero et. Al. J. Med. Chem. 1989, 32, 2178-2199; US Pat. 5,034,531) gave the target compound.

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

Figure 112012052254195-pat00013
Figure 112012052254195-pat00013

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 사용하였다.
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- 브로모 -2- 클로로 -N-(6-니트로-2- 히드록시페닐 ) 니코틴아마이드의 제조 Step 3: 5- Bromo- 2- chloro- N- (6-nitro-2 -hydroxyphenyl ) nicotinamide Produce

Figure 112012052254195-pat00014
Figure 112012052254195-pat00014

2-아미노-3-니트로페놀(3.3 g, 21.4 mmol))과 트리에틸아민(3.0 mL, 21.5 mmol)이 용해되어 있는 이염화탄소용액에 5-브로모-2-클로로니코티노일 클로라이드(5.0 g, 19.6 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-(6-니트로-2-히드록시페닐)니코틴아마이드)을 얻었다(7.3 g, 99%). 상기 화합물은 더 이상의 정제 없이 다음 반응에 사용하였다.
5-bromo-2-chloronicotinoyl chloride (5.0 g) in a carbon dichloride solution containing 2-amino-3-nitrophenol (3.3 g, 21.4 mmol) and triethylamine (3.0 mL, 21.5 mmol). , 19.6 mmol) was slowly added at 0 ° C. using an ice bath. 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- (6-nitro-2-hydroxyphenyl) nicotinamide) as a brown solid. (7.3 g, 99%). 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)-4-Yl) -4- 니트로벤즈[d]옥사졸의Of nitrobenz [d] oxazole 제조 Produce

Figure 112012052254195-pat00015
Figure 112012052254195-pat00015

반응용기에 5-브로모-2-클로로-N-(6-니트로-2-히드록시페닐) 니코틴아마이드(7.3 g, 20.6 mmol), 파라톨루엔설폰산 피리딘염(10.7 g, 39.8 mmol) 및 크실렌(xylene, 150 mL)을 넣고, 150-170 ℃에서 18시간 동안 교반하였다. 반응물의 온도를 약 80 ℃ 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 노란색 고체의 목적화합물(2-(5-브로모-2-클로로피리딘-3-일)-4-니트로벤즈[d]옥사졸)을 얻었다(6.9 g, 98%).5-bromo-2-chloro-N- (6-nitro-2-hydroxyphenyl) nicotinamide (7.3 g, 20.6 mmol), paratoluenesulfonic acid pyridine salt (10.7 g, 39.8 mmol) and xylene (xylene, 150 mL) was added and stirred at 150-170 ° C. for 18 hours. The temperature of the reaction was lowered to about 80 ° C. and the reaction was filtered so that no tar was generated during the reaction, and the tar produced with hot xylene was washed and filtered several times. The filtrate was concentrated under reduced pressure, the concentrate was added to ethyl ether and stirred for 30 minutes. The solid not dissolved in ethyl ether was filtered, washed with cold ethyl acetate and dried to give the title compound as a yellow solid (2- (5-bromo-2-chloropyridin-3-yl) -4-nitrobenz [d ] Oxazole) was obtained (6.9 g, 98%).

1H NMR (300 MHz, CDCl3) δ 8.70 (s, 1H), 8.45 (s, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.51 (m, 1H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.70 (s, 1H), 8.45 (s, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.51 (m, 1 H).

단계 5: 5- 브로모 -N-t-부틸-3-(4- 니트로벤즈[d]옥사졸 -2-일) 피리딘-2- 아민 의 제조 Step 5: Preparation of 5- bromo- Nt-butyl-3- (4- nitrobenz [d] oxazol -2-yl) pyridin-2- amine

Figure 112012052254195-pat00016
Figure 112012052254195-pat00016

고압반응용기(sealed tube)에 2-(5-브로모-2-클로로피리딘-3-일)-4-니트로벤즈[d]옥사졸(6.9 g), t-부틸아민(20.1 mL) 및 디메틸포름아마이드(60 mL)를 넣고 마개를 막아 밀봉하였다. 반응물을 50-70 ℃에서 18시간 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 노란색 고체의 목적화합물(5-브로모-N-t-부틸-3-(4-니트로벤즈[d]옥사졸-2-일)피리딘-2-아민)을 얻었다(3.5 g, 46%).2- (5-Bromo-2-chloropyridin-3-yl) -4-nitrobenz [d] oxazole (6.9 g), t-butylamine (20.1 mL) and dimethyl in a sealed tube Formamide (60 mL) was added and the cap was sealed. The reaction was stirred at 50-70 ° C for 18 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-Nt-butyl-3- (4-nitrobenz [d] oxazol-2-yl) pyridin-2-amine) as a yellow solid. Was obtained (3.5 g, 46%).

1H NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 8.57 (s, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.25 (d , J = 2.4 Hz, 1H), 7.51 (m, 1H), 1.51 (s, 9H); GC-MS (EI) m/z calcd for C16H15NBrN4O3(M+) 391.0, found 391.2.
 1 H NMR (300 MHz, CDCl 3 ) δ 8.75 (s, 1H), 8.57 (s, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.51 (m, 1 H), 1.51 (s, 9 H); GC-MS (EI) m / z calcd for C 16 H 15 NBrN 4 O 3 (M + ) 391.0, found 391.2.

단계 6: t-부틸-4-(4-(6-(t- 부틸아미노 )-5-(4- 니트로벤즈[d]옥사졸 -2-일)피 리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트의 제조 Step 6: t-butyl-4- (4- (6- (t- butylamino ) -5- (4- nitrobenz [d] oxazol- 2 -yl) pyridin-3-yl) -1H-pyra Preparation of zol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00017
Figure 112012052254195-pat00017

반응용기에 5-브로모-N-t-부틸-3-(4-니트로벤즈[d]옥사졸-2-일) 피리딘-2-아민(648 mg, 1.66 mmol), t-부틸-4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-피라졸-1-일)-피페리딘-1-카복실레이트(939 mg), Pd(Ph3P)2Cl2(58 mg) 및 1,4-다이옥산(4 mL)을 넣고 질소분위기 및 실온에서 30분 동안 교반하였다. 반응물에 1 M 탄산나트륨 수용액(4.98 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(t-부틸-4-(4-(6-(t-부틸아미노)-5-(4-니트로벤즈[d]옥사졸-2-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트)을 얻었다(445 mg, 54%). 5-bromo-Nt-butyl-3- (4-nitrobenz [d] oxazol-2-yl) pyridin-2-amine (648 mg, 1.66 mmol), t-butyl-4- (4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) -piperidine-1-carboxylate (939 mg ), Pd (Ph 3 P) 2 Cl 2 (58 mg) and 1,4-dioxane (4 mL) were added and stirred for 30 minutes at a nitrogen atmosphere and room temperature. 1 M aqueous sodium carbonate solution (4.98 mL) was added to the reaction and 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 (t-butyl-4- (4- (6- (t-butylamino) -5- (4-nitrobenz [d] oxa). Zol-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate) (445 mg, 54%).

1H NMR (300 MHz, CDCl3) δ 7.94 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.57(s, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.20 (dd, J = 7.4, 1.6 Hz, 1H), 7.10 (t, J = 6.2, 1H), 4.22-4.31 (m, 3H), 2.83 (m, 2H), 1.91-2.01 (m, 2H), 1.76-1.87 (m, 2H), 1.38 (d, J= 2.8 Hz, 9H), 1.21 (s, 9H) ; GC-MS (EI) m/z calcd for C29H35N7O5 (M+) 561.4, found 561.6.
 1 H NMR (300 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.57 (s, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.20 (dd, J = 7.4, 1.6 Hz, 1H), 7.10 (t, J = 6.2, 1H), 4.22-4.31 (m, 3H), 2.83 (m, 2H ), 1.91-2.01 (m, 2H), 1.76-1.87 (m, 2H), 1.38 (d, J = 2.8 Hz, 9H), 1.21 (s, 9H); GC-MS (EI) m / z calcd for C 29 H 35 N 7 O 5 (M + ) 561.4, found 561.6.

단계 7: 3-(4- 니트로벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H- 피라졸 - 4-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 Step 7: 3- (4- nitrobenz [d] oxazol- 2 -yl ) -5- (1- (piperidin-4-yl) -1H- pyrazol - 4-yl) pyridin-2-amine Of ditrifluoroacetic acid salts

Figure 112012052254195-pat00018
Figure 112012052254195-pat00018

t-부틸-4-(4-(6-(t-부틸아미노)-5-(4-니트로벤즈[d]옥사졸-2-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트(59 mg, 0.11 mmol) 및 트리플루오로아세트산(4 mL) 반응물을 60 ℃에서 18시간 동안 교반하였다. 반응물의 온도를 실온으로 낮추고 감압농축하였다. 농축물에 에틸에테르를 넣고 30분 동안 교반한 후 여과하여 연두색 고체의 목적화합물(3-(4-니트로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산염)을 얻었다(44 mg, 63%).t-butyl-4- (4- (6- (t-butylamino) -5- (4-nitrobenz [d] oxazol-2-yl) -1H-pyrazol-1-yl) piperidine- 1-carboxylate (59 mg, 0.11 mmol) and trifluoroacetic acid (4 mL) were stirred for 18 h at 60 ° C. The reaction was cooled to room temperature and concentrated under reduced pressure. After stirring for minutes, the resultant was filtered to give the title compound (3- (4-nitrobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazole as a light green solid). Ditrifluoroacetic acid salt of -4-yl) pyridin-2-amine) was obtained (44 mg, 63%).

1H NMR (300 MHz, CD3OD) δ 7.96 (s, 1H), 7.77 (s, 1H), 7.45 (d, J = 1.2 Hz, 2H), 7.12 (dd, J = 2.4, 1.2 Hz, 2H), 7.08 (dd, J = 4.2, 1.2 Hz, 1H), 4.41-4.50 (m, 1H), 3.47-3.51 (m, 2H), 3.12-3.17 (m, 2H), 2.12-2.28 (m, 4H) ; GC-MS (EI) m/z calcd for C20H19N7O3(M+) 405.5, found 405.4.
 1 H NMR (300 MHz, CD3OD) δ 7.96 (s, 1H), 7.77 (s, 1H), 7.45 (d, J = 1.2 Hz, 2H), 7.12 (dd, J = 2.4, 1.2 Hz, 2H), 7.08 (dd, J = 4.2, 1.2 Hz, 1H), 4.41-4.50 (m, 1H), 3.47-3.51 (m, 2H), 3.12-3.17 (m, 2H), 2.12-2.28 (m, 4H); GC-MS (EI) m / z calcd for C 20 H 19 N 7 O 3 (M + ) 405.5, found 405.4.

< 실시예 2> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)벤즈[d]옥사졸-4-아민의 삼트리플루오로아세트산염의 제조 <Example 2> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) -4 benz [d] oxazole Preparation of Tritrifluoroacetic Acid of Amine

Figure 112012052254195-pat00019
Figure 112012052254195-pat00019

실시예 1에서 사용한 t-부틸아민 대신 2,4-다이메톡시페닐메틸아민을 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-4-아민의 삼트리플루오로아세트산염)을 얻었다(38 mg, 89%).Except for using 2,4-dimethoxyphenylmethylamine 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 a solid target compound (2- (2 Tritrifluoroacetic acid salt of -amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazol-4-amine ) (38 mg, 89%).

1H NMR (300 MHz, CD3OD) δ 8.68 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.76 (s, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.07 (t, J = 8.1, 8.0 Hz, 1H), 4.30-4.36 (m, 1H), 3.25 (d, J = 1.5 Hz, 2H), 2.91 (d, J = 10.3 Hz, 2H), 1.96-2.07 (m, 4H); GC-MS (EI) m/z calcd for C20H21N7 (M+) 375.2, found 375.4.
 1 H NMR (300 MHz, CD 3 OD) δ 8.68 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.76 (s, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.07 (t, J = 8.1, 8.0 Hz, 1H), 4.30-4.36 (m, 1H), 3.25 (d, J = 1.5 Hz , 2H), 2.91 (d, J = 10.3 Hz, 2H), 1.96-2.07 (m, 4H); GC-MS (EI) m / z calcd for C 20 H 21 N 7 (M + ) 375.2, found 375.4.

< 실시예 3> N-2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)벤즈[d]옥사졸-7-일)-N,N-다이메틸프로판-1,3-다이아민의 사트리플루오로아세트산염의 제조 <Example 3> N-2- (2- amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole Preparation of Satrifluoroacetic Acid of -7-yl) -N, N-dimethylpropane-1,3-diamine

Figure 112012052254195-pat00020
Figure 112012052254195-pat00020

2,4-다이메톡시아민 대신 다이메틸프로판다이아민을 사용한 것을 제외하고는 실시예 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-7-일)-N,N-다이메틸프로판-1,3-다이아민의 사트리플루오로아세트산염)을 얻었다(16 mg, 45%).Except that dimethylpropanediamine was used instead of 2,4-dimethoxyamine, the reaction was carried out in the same manner as in Example 2 to obtain a solid target compound (N-2- (2-amino-5- (1- (P Ferridin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazol-7-yl) -N, N-dimethylpropane-1,3-diamine Trifluoroacetic acid salt) was obtained (16 mg, 45%).

1H NMR (300 MHz, CD3OD) δ 8.38 (dd, J = 12.6, 2.4 Hz, 2H), 7.91 (s, 1H), 7.74 (s, 1H), 7.06 (t, J = 15.9, 7.9 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 6.55 (d, J = 7.4 Hz, 1H), 4.20-4.26 (m, 1H), 4.10 (d, J = 13.3 Hz, 2H), 3.28 (t, J = 13.6, 6.8 Hz, 1H), 3.19 (s, 4H), 2.61-2.66 (m, 2H), 2.35 (s, 6H), 1.81-1.84 (m, 5H); GC-MS (EI) m/z calcd for C25H32N8O (M+) 460.5, found 460.5.
 1 H NMR (300 MHz, CD 3 OD) δ 8.38 (dd, J = 12.6, 2.4 Hz, 2H), 7.91 (s, 1H), 7.74 (s, 1H), 7.06 (t, J = 15.9, 7.9 Hz , 1H), 6.89 (d, J = 7.2 Hz, 1H), 6.55 (d, J = 7.4 Hz, 1H), 4.20-4.26 (m, 1H), 4.10 (d, J = 13.3 Hz, 2H), 3.28 (t, J = 13.6, 6.8 Hz, 1H), 3.19 (s, 4H), 2.61-2.66 (m, 2H), 2.35 (s, 6H), 1.81-1.84 (m, 5H); GC-MS (EI) m / z calcd for C 25 H 32 N 8 O (M + ) 460.5, found 460.5.

< 실시예 4> 5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)-3-(7-( 피롤리딘 -1-일) 벤즈[d]옥사졸-2-일)피리딘-2-아민의 삼트리플루오로아세트산염의 제조 <Example 4> 5- (l- (piperidin-4-yl) -1H- pyrazol-4-yl) -3- (7- (pyrrolidin-1-yl) ben's [d] oxazole Preparation of tritrifluoroacetic acid salt of zol-2-yl) pyridin-2-amine

Figure 112012052254195-pat00021
Figure 112012052254195-pat00021

2,4-다이메톡시아민 대신 피롤리딘을 사용한 것을 제외하고는 실시예 2와 동일한 방법으로 수행하여 고체의 목적화합물(5-(1-(피페리딘-4-일)-1H-피라졸-4-일)-3-(7-(피롤리딘-1-일)벤즈[d]옥사졸-2-일)피리딘-2-아민의 삼트리플루오로아세트산염)을 얻었다(37 mg, 73%).Except for using pyrrolidine in place of 2,4-dimethoxyamine, it was carried out in the same manner as in Example 2 to obtain the target compound as a solid (5- (1- (piperidin-4-yl) -1H-pyra Zol-4-yl) -3- (trifluoroacetic acid salt of 7- (pyrrolidin-1-yl) benz [d] oxazol-2-yl) pyridin-2-amine) was obtained (37 mg). , 73%).

1H NMR (300MHz, CD3OD) δ 8.64 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 5.9 Hz, 1H), 7.45 (dd, J = 5.2, 1.6 Hz, 1H), 4.51-4.61 (m, 1H), 3.55-3.64 (m, 2H), 3.20-3.26 (m, 6H), 2.28-2.39 (m, 4H), 2.01-2.08 (m, 4H); GC-MS (EI) m/z calcd for C24H27N7O (M+) 429.5, found 429.2.
 1 H NMR (300MHz, CD 3 OD) δ 8.64 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 5.9 Hz, 1H), 7.45 (dd, J = 5.2, 1.6 Hz, 1H), 4.51-4.61 (m, 1H), 3.55-3.64 ( m, 2H), 3.20-3.26 (m, 6H), 2.28-2.39 (m, 4H), 2.01-2.08 (m, 4H); GC-MS (EI) m / z calcd for C 24 H 27 N 7 O (M + ) 429.5, found 429.2.

< 실시예 5> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-4-일)-N-(싸이오펜-2-일메틸)벤즈[d]옥사졸-7-아민의 삼트리플루오로아세트산염의 제조 <Example 5> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-4-yl) -N- (thiophen -2 Preparation of tritrifluoroacetic acid salt of -ylmethyl) benz [d] oxazol-7-amine

Figure 112012052254195-pat00022
Figure 112012052254195-pat00022

2,4-다이메톡시아민 대신 싸이오펜-2-일메탄아민을 사용한 것을 제외하고는 실시예 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-4-일)-N-(싸이오펜-2-일메틸)벤즈[d]옥사졸-7-아민의 삼트리플루오로아세트산염)을 얻었다(27 mg, 65%).Except for using thiophen-2-ylmethanamine instead of 2,4-dimethoxyamine, the same procedure as in Example 2 was carried out to give the target compound as a solid (2- (2-amino-5- (1- ( Tritrifluoro of piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-4-yl) -N- (thiophen-2-ylmethyl) benz [d] oxazol-7-amine Roacetate) (27 mg, 65%).

1H NMR (300 MHz, CD3OD) δ 8.47 (d, J = 2.3 Hz, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 7.81 (s, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.24- 7.31 (m, 2H), 6.20 (t, J = 4.2, 2.1 Hz, 1H), 5.4 (s, 2H), 4.45-4.48 (m, 1H), 3.44-3.47 (m, 2H), 3.20-3.43 (m, 3H), 2.21-2.28 (m, 3H); GC-MS (EI) m/z calcd for C25H25N7OS (M+) 471.5, found 471.5.
 1 H NMR (300 MHz, CD 3 OD) δ 8.47 (d, J = 2.3 Hz, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 7.81 (s, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.24- 7.31 (m, 2H), 6.20 (t, J = 4.2, 2.1 Hz, 1H), 5.4 (s, 2H), 4.45-4.48 (m, 1H), 3.44-3.47 ( m, 2H), 3.20-3.43 (m, 3H), 2.21-2.28 (m, 3H); GC-MS (EI) m / z calcd for C 25 H 25 N 7 OS (M + ) 471.5, found 471.5.

< 실시예 6> 3-(7-(4- 메틸피페라진 -1-일) 벤즈 [d] 옥사졸 -2일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 사트리플루오로아세트산염의 제조 <Example 6> 3- (7- (4-methylpiperazin-1-yl) benz [d] oxazol -2-yl) -5- (1- (piperidin-4-yl) -1H- pyrazol Preparation of Satrifluoroacetic Acid of Zol-4-yl) pyridin-2-amine

Figure 112012052254195-pat00023
Figure 112012052254195-pat00023

2,4-다이메톡시아민 대신 1-메틸피페라진을 사용한 것을 제외하고는 실시예 2와 동일한 방법으로 수행하여 고체의 목적화합물(3-(7-(4-메틸피페라진-1-일)벤즈[d]옥사졸-2일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 사트리플루오로아세트산염)을 얻었다(13 mg, 58%).Except for using 1-methylpiperazine in place of 2,4-dimethoxyamine was carried out in the same manner as in Example 2 to give a solid target compound (3- (7- (4-methylpiperazin-1-yl) Benz [d] oxazol-2yl) -5- (satrifluoroacetic acid salt of 1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine) was obtained. (13 mg, 58%).

1H NMR (300 MHz, DMSO-d6) δ 8.96 (d, J = 2.2 Hz, 1H), 8.84 (s, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 8.48 (d, J = 1.2 Hz, 1H), 8.43 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 5.76-5.77 (m, 1H), 4.71-4.75 (m, 2H), 4.5 (s, 3H), 4.36-4.39 (m, 2H), 3.48-3.57 (m, 6H), 3.30-3.35 (m, 6H); GC-MS (EI) m/z calcd for C25H30N8O (M+) 458.5, found 458.2.
 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.96 (d, J = 2.2 Hz, 1H), 8.84 (s, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 8.48 (d, J = 1.2 Hz, 1H), 8.43 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 5.76-5.77 (m, 1H), 4.71-4.75 (m, 2H), 4.5 (s, 3H ), 4.36-4.39 (m, 2H), 3.48-3.57 (m, 6H), 3.30-3.35 (m, 6H); GC-MS (EI) m / z calcd for C 25 H 30 N 8 O (M + ) 458.5, found 458.2.

< 실시예 7> 3-(7- 모폴리노벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H- 피라졸-4-일)피리딘-2-아민의 삼트리플루오로아세트산염의 제조 <Example 7> 3- (7-morpholino benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- blood rajol 4-yl) pyridine Preparation of Tritrifluoroacetic Acid Salt of 2-amine

Figure 112012052254195-pat00024
Figure 112012052254195-pat00024

2,4-다이메톡시아민 대신 모폴린을 사용한 것을 제외하고는 실시예 2와 동일한 방법으로 수행하여 고체의 목적화합물(3-(7-모폴리노벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 삼트리플루오로아세트산염)을 얻었다(8 mg, 57%).Except for using morpholine instead of 2,4-dimethoxyamine, it was carried out in the same manner as in Example 2 to obtain the target compound as a solid (3- (7-morpholinobenz [d] oxazol-2-yl) -5- (3-trifluoroacetic acid salt of 1-(piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine) was obtained (8 mg, 57%).

1H NMR (300 MHz, CD3OD) δ 9.46 (s, 1H), 9.10 (s, 1H), 8.95 (d, J = 2.1 Hz, 1H), 8.86 (dd, J = 3.2, 1.2 Hz, 1H), 8.83 (d, J = 1.1 Hz, 1H), 8.71 (s, 1H), 8.48 (dd, J = 6.8, 1.2 Hz, 1H), 5.76-5.77 (m, 1H), 4.71-4.76 (m, 4H), 4.33-4.39 (m, 2H), 3.47-3.59 (m, 6H), 3.30-3.35 (m, 4H); GC-MS (EI) m/z calcd for C24H27N7O2 (M+) 445.5, found 445.2.
 1 H NMR (300 MHz, CD 3 OD) δ 9.46 (s, 1H), 9.10 (s, 1H), 8.95 (d, J = 2.1 Hz, 1H), 8.86 (dd, J = 3.2, 1.2 Hz, 1H ), 8.83 (d, J = 1.1 Hz, 1H), 8.71 (s, 1H), 8.48 (dd, J = 6.8, 1.2 Hz, 1H), 5.76-5.77 (m, 1H), 4.71-4.76 (m, 4H), 4.33-4.39 (m, 2H), 3.47-3.59 (m, 6H), 3.30-3.35 (m, 4H); GC-MS (EI) m / z calcd for C 24 H 27 N 7 O 2 (M + ) 445.5, found 445.2.

< 실시예 8> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)-N-(피페리딘-4-일메틸)벤즈[d]옥사졸-7-아민의 사트리플루오로아세트산염의 제조 <Example 8> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) -N- (piperidin- Preparation of Satrifluoroacetate of 4-ylmethyl) benz [d] oxazol-7-amine

Figure 112012052254195-pat00025
Figure 112012052254195-pat00025

2,4-다이메톡시아민 대신 피페리딘-4-일 메탄아민을 사용한 것을 제외하고는 실시예 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(피페리딘-4-일메틸)벤즈[d]옥사졸-7-아민의 사트리플루오로아세트산염)을 얻었다(23 mg, 76%).A solid target compound (2- (2-amino-5- (1- (Piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N- (piperidin-4-ylmethyl) benz [d] oxazol-7-amine Trifluoroacetic acid salt) was obtained (23 mg, 76%).

1H NMR (300 MHz, CD3OD) δ 8.25 (s, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.74 (s, 1H), 7.58 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 2.7 Hz, 1H), 4.56 (s, 2H), 3.99-4.03 (m, 6H), 3.00-3.05 (m, 4H), 2.88-2.91 (m, 2H), 2.39-2.50 (m, 2H), 1.58-1.75 (m, 4H); GC-MS (EI) m/z calcd for C26H32N8O (M+) 472.5, found 472.2.
 1 H NMR (300 MHz, CD 3 OD) δ 8.25 (s, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.74 (s, 1H), 7.58 (s, 1H), 7.52 (d , J = 8.1 Hz, 1H), 7.41 (d, J = 2.7 Hz, 1H), 4.56 (s, 2H), 3.99-4.03 (m, 6H), 3.00-3.05 (m, 4H), 2.88-2.91 ( m, 2H), 2.39-2.50 (m, 2H), 1.58-1.75 (m, 4H); GC-MS (EI) m / z calcd for C 26 H 32 N 8 O (M + ) 472.5, found 472.2.

< 실시예 9> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)-N-(3-(벤질옥시)페닐)벤즈[d]옥사졸-7-아민의 삼트리플루오로아세트산염의 제조 <Example 9> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) -N- (3- (benzyl Preparation of Trifluorofluoroacetic Acid of Oxy) phenyl) benz [d] oxazol-7-amine

Figure 112012052254195-pat00026
Figure 112012052254195-pat00026

2,4-다이메톡시아민 대신 3-(벤질옥시)벤젠아민을 사용한 것을 제외하고는 실시예 2와 동일한 방법으로 수행하여 고체의 목적화합물(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-(3-(벤질옥시)페닐)벤즈[d]옥사졸-7-아민의 삼트리플루오로아세트산염)을 얻었다(32 mg, 96%).Except for using 2- (benzyloxy) benzeneamine in place of 2,4-dimethoxyamine was carried out in the same manner as in Example 2 to obtain a solid target compound (2- (2-amino-5- (1- ( Tritrifluoro of piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N- (3- (benzyloxy) phenyl) benz [d] oxazol-7-amine Roacetate) (32 mg, 96%).

1H NMR (300 MHz, CD3OD) δ 8.46 (d, J = 2.2 Hz, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 7.82 (s, 2H), 7.79 (d, J = 10.4 Hz, 2H), 7.59 (d, J = 1.9 Hz, 2H), 7.44-7.48 (m, 3H), 7.31-7.33 (m, 2H), 6.21 (t, J = 4.2, 2.0 Hz, 2H), 4.80 (s, 2H), 4.43-4.48 (m, 1H), 3.22-3.51 (m, 2H), 3.19-3.22 (m, 2H), 2.11-2.26 (m, 4H); GC-MS (EI) m/z calcd for C33H31N7O2 (M+) 557.6, found 557.6.
 1 H NMR (300 MHz, CD 3 OD) δ 8.46 (d, J = 2.2 Hz, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 7.82 (s, 2H), 7.79 (d, J = 10.4 Hz, 2H), 7.59 (d, J = 1.9 Hz, 2H), 7.44-7.48 (m, 3H), 7.31-7.33 (m, 2H), 6.21 (t, J = 4.2, 2.0 Hz, 2H) , 4.80 (s, 2H), 4.43-4.48 (m, 1H), 3.22-3.51 (m, 2H), 3.19-3.22 (m, 2H), 2.11-2.26 (m, 4H); GC-MS (EI) m / z calcd for C 33 H 31 N 7 O 2 (M + ) 557.6, found 557.6.

< 실시예 10> N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)벤즈[d]옥사졸-4-일)메탄설폰아마이드의 이트리플루오로아세트산염의 제조 <Example 10> N- (2- (2- amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole Preparation of Itrifluoroacetic Acid of Zol-4-yl) methanesulfonamide

Figure 112012052254195-pat00027
Figure 112012052254195-pat00027

t-부틸-4-(3-(5-(6-아미노벤즈[d]옥사졸-2-일)-6-(t-부틸아미노)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(20 mg, 0.04 mmol)를 다이클로로메탄(1 mL)에 녹이고, 피리딘(3.5 μL, 0.044 mmol)과 메탄설포닐클로라이드 클로라이드(9 mg, 0.044 mmol)를 가한 뒤 실온에서 교반시켰다. 반응이 종결되면 물을 가하고 추출한 뒤 MgSO4로 건조하고 에테르로 세척하여 엷은 노란색 고체의 t-부틸-4-(3-(6-(t-부틸아미노)-5-(6-(4-메탄설폰아미도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(20 mg, 71 %)를 얻었다.t-butyl-4- (3- (5- (6-aminobenz [d] oxazol-2-yl) -6- (t-butylamino) pyridin-3-yl) -1H-pyrazole-1- (1) Piperidine-1-carboxylate (20 mg, 0.04 mmol) is dissolved in dichloromethane (1 mL), pyridine (3.5 μL, 0.044 mmol) and methanesulfonylchloride chloride (9 mg, 0.044 mmol) Was added and stirred at room temperature. At the end of the reaction, water was added, extracted, dried over MgSO 4 and washed with ether to give pale yellow solid t-butyl-4- (3- (6- (t-butylamino) -5- (6- (4-methane). Sulfonamido) benz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (20 mg, 71%) was obtained.

다음으로, 실시예 2에서의 방법과 동일한 방법으로 수행하여 고체의 목적화합물(N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-4-일)메탄설폰아마이드의 이트리플루오로아세트산 염)을 얻었다(14 mg, 96%).Next, the same procedure as in Example 2 was carried out to obtain the target compound of solid (N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazole-). 4-tri) pyridin-3-yl) benz [d] oxazol-4-yl) methanesulfonamide) was obtained (14 mg, 96%).

1H NMR (300 MHz, CD3OD) δ 7.94 (s, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.25 (t, J = 15.2, 7.4 Hz, 1H), 7.11 (d, J = 7.3 Hz, 1H), 6.18 (t, J = 4.2, 2.1 Hz, 1H), 4.73 (s, 1H), 4.23-4.29 (m, 2H), 4.07-4.15 (m, 2H), 3.20 (s, 3H), 1.78-1.82 (m, 4H); GC-MS (EI) m/z calcd for C21H23N7O3S (M+) 453.5, found 453.2.
 1 H NMR (300 MHz, CD 3 OD) δ 7.94 (s, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.25 (t, J = 15.2, 7.4 Hz, 1H), 7.11 (d, J = 7.3 Hz, 1H), 6.18 (t, J = 4.2, 2.1 Hz, 1H), 4.73 (s, 1H ), 4.23-4.29 (m, 2H), 4.07-4.15 (m, 2H), 3.20 (s, 3H), 1.78-1.82 (m, 4H); GC-MS (EI) m / z calcd for C 21 H 23 N 7 O 3 S (M + ) 453.5, found 453.2.

< 실시예 11> 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)벤즈[d]옥사졸-4-일)-3-(4-메톡시페닐)우레아의 이트리플루오로아세트산염의 제조 <Example 11> 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole Preparation of ditrifluoroacetic acid salt of zol-4-yl) -3- (4-methoxyphenyl) urea

Figure 112012052254195-pat00028
Figure 112012052254195-pat00028

t-부틸-4-(4-(6-(t-부틸아미노)-5-(4-아미노벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(25 mg, 0.05 mmol)를 테트라히드로퓨란(1 mL)에 녹이고, 0 ℃에서 4-플루오로페닐 이소시아네이트(6 μL, 0.056 mmol)을 적가한 뒤, 실온에서 교반시켰다. 반응이 종결되면 휘발성 물질을 제거한 뒤 컬럼 크로마토그래피로 정제하여 엷은 노란색 고체의 t-부틸-4-(4-(6-(t-부틸아미노)-5-(4-(3-(4-메톡시오르벤질)유레이도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(22 mg, 66%)를 얻었다. t-butyl-4- (4- (6- (t-butylamino) -5- (4-aminobenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1- (I) piperidine-1-carboxylate (25 mg, 0.05 mmol) is dissolved in tetrahydrofuran (1 mL), 4-fluorophenyl isocyanate (6 μL, 0.056 mmol) is added dropwise at 0 ° C., Stir at room temperature. At the end of the reaction, volatiles were removed and purified by column chromatography to give pale yellow solid t-butyl-4- (4- (6- (t-butylamino) -5- (4- (3- (4-meth). Oxyorbenzyl) ureido) benz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (22 mg, 66%) Got.

다음으로 실시예 2의 방법대로 수행하여 목적화합물(1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-4-일)-3-(4-메톡시페닐)우레아의 이트리플루오로아세트산 염)을 얻었다(17 mg, 34%).Next, it was carried out according to the method of Example 2 to obtain the target compound (1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine-3 -Trifluoroacetic acid salt of -yl) benz [d] oxazol-4-yl) -3- (4-methoxyphenyl) urea) (17 mg, 34%).

1H NMR (300 MHz, CD3OD) δ 8.06 (s, 1H), 7.88 (s, 2H), 7.71 (s, 1H), 7.57 (dd, J = 3.2, 1.3 Hz, 3H), 7.38 (dd, J = 7.4, 1.7 Hz, 2H), 7.23 (d, J = 4.3 Hz, 1H), 7.19 (t, J = 2.4, 1.2 Hz, 1H), 4.54-4.61 (m, 1H), 3.57-3.62 (m, 2H), 3.56 (s, 3H) 3.19-3.28 (m, 2H), 2.28-2.38 (m, 4H); GC-MS (EI) m/z calcd for C28H28N8O3 (M+) 524.5, found 524.2.
 1 H NMR (300 MHz, CD 3 OD) δ 8.06 (s, 1H), 7.88 (s, 2H), 7.71 (s, 1H), 7.57 (dd, J = 3.2, 1.3 Hz, 3H), 7.38 (dd , J = 7.4, 1.7 Hz, 2H), 7.23 (d, J = 4.3 Hz, 1H), 7.19 (t, J = 2.4, 1.2 Hz, 1H), 4.54-4.61 (m, 1H), 3.57-3.62 ( m, 2H), 3.56 (s, 3H) 3.19-3.28 (m, 2H), 2.28-2.38 (m, 4H); GC-MS (EI) m / z calcd for C 28 H 28 N 8 O 3 (M + ) 524.5, found 524.2.

< 실시예 12> 3-(6-(4- 메톡시페닐 ) 벤즈 [d] 옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 <Example 12> 3- (6- (4-methoxyphenyl) benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- pyrazol -4 Preparation of Ditrifluoroacetic Acid of -yl) pyridin-2-amine

단계 1: t-부틸-4-(4-(6-(t- 부틸아미노 )-5-(6-(4- 메톡시페닐 ) 벤즈 [d] 옥사졸 - 2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t-butyl-4- (4- (6- (t- butylamino ) -5- (6- (4 -methoxyphenyl ) benz [d] oxazol - 2 -yl ) pyridin-3-yl Preparation of) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00029
Figure 112012052254195-pat00029

압력반응기에 t-부틸-4-(3-(6-(t-부틸아미노)-5-(6-클로로벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(50 mg, 0.09 mmol)을 1.4-다이옥산(1 mL)에 녹이고, Pd(pph3)2Cl2(10 mg, 0.005 mmol), 4-메톡시페닐보론산(21 mg, 0.14 mmol)을 가하고, 실온에서 30분간 교반시킨 후, 1M Na2CO3(38 mg, 0.36 mmol)를 가하고, 110 ℃에서 1시간 동안 교반시켰다. 반응이 종결되면, 상온으로 냉각한 후 감압농축하고, 여기에 에틸아세테이트와 물을 가하여, 생성물을 유기층으로 추출한 다음, Na2SO4를 이용하여 건조하고, 컬럼 크로마토그래피로 정제하여 t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-(4-메톡시페닐)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(10 mg, 18%)를 얻었다.T-butyl-4- (3- (6- (t-butylamino) -5- (6-chlorobenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazole in a pressure reactor -1-yl) piperidine-1-carboxylate (50 mg, 0.09 mmol) is dissolved in 1.4-dioxane (1 mL), Pd (pph 3 ) 2 Cl 2 (10 mg, 0.005 mmol), 4- Methoxyphenylboronic acid (21 mg, 0.14 mmol) was added and stirred at room temperature for 30 minutes, then 1M Na 2 CO 3 (38 mg, 0.36 mmol) was added and stirred at 110 ° C. for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, ethyl acetate and water were added thereto, the product was extracted with an organic layer, dried over Na 2 SO 4 , purified by column chromatography, and purified by t-butyl-. 4- (4- (6- (t-butylamino) -5- (6- (4-methoxyphenyl) benz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazole- 1-yl) piperidine-1-carboxylate (10 mg, 18%) was obtained.

1H NMR (MeOH-d4, 300 MHz) δ 8.74 (s, 1H), 8.44 (d, J = 2.5 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H), 7.79-7.72 (m, 3H), 7.66 (s, 1H), 7.6-7.56 (m, 3H), 7.02 (d, J = 8.8 Hz, 1H) 4.36-4.28 (m, 3H), 3.87 (s, 3H), 2.92-2.88 (m, 2H), 2.22-2.17 (m, 2H), 2.03-1.95 (m, 2H), 1.63 (s, 9H), 1.49 (s, 9H).
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.74 (s, 1H), 8.44 (d, J = 2.5 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H), 7.79-7.72 (m, 3H), 7.66 (s, 1H), 7.6-7.56 (m, 3H), 7.02 (d, J = 8.8 Hz, 1H) 4.36-4.28 (m, 3H), 3.87 (s, 3H), 2.92-2.88 ( m, 2H), 2.22-2.17 (m, 2H), 2.03-1.95 (m, 2H), 1.63 (s, 9H), 1.49 (s, 9H).

단계 2: 3-(6-(4- 메톡시페닐 ) 벤즈 [d] 옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H- 피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 Step 2: 3- (6- (4 -methoxyphenyl ) benz [d] oxazol- 2 -yl ) -5- (1- (piperidin-4-yl) -1H- pyrazol -4 -yl Preparation of Itrifluoroacetic Acid Salt of Pyridin-2-amine

Figure 112012052254195-pat00030
Figure 112012052254195-pat00030

압력반응기에 상기 단계 1에서 제조된 t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-(4-메톡시페닐)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(54 mg, 0.089 mmol)를 넣고 트리플루오로아세트산(3 mL)을 가한 다음, 60 ℃에서 13시간 동안 교반시켰다. 반응이 종결되면 상온으로 냉각시키고 감압농축하였다. 여기에 에테르를 가하여 생성된 고체를 여과하여 3-(6-(4-메톡시페닐)벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산염(20 mg, 32 %)을 얻었다.T-butyl-4- (4- (6- (t-butylamino) -5- (6- (4-methoxyphenyl) benz [d] oxazol-2-yl prepared in Step 1 above in a pressure reactor ) Pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (54 mg, 0.089 mmol) was added and trifluoroacetic acid (3 mL) was added. Stir for 13 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ether was added thereto, and the resulting solid was filtered to afford 3- (6- (4-methoxyphenyl) benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl)- Ditrifluoroacetic acid salt of 1H-pyrazol-4-yl) pyridin-2-amine (20 mg, 32%) was obtained.

1H NMR (MeOH-d4, 300 MHz) δ 8.88 (d, J = 2.2 Hz, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.27 (s, 1H), 8.04 (s, 1H), 7.94 (d, J = 1.3 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.75-7.66 (m, 3H), 7.08 (d, J = 8.8 Hz, 1H), 4.65-4.62 (m, 1H), 3.64-3.55 (m, 2H), 3.3-3.2 (m, 2H), 2.39-2.3 (m, 4H); LC-MS m/z calcd for C27H26N6O2 (MH+) 465.7, found 466.98.
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.88 (d, J = 2.2 Hz, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.27 (s, 1H), 8.04 (s, 1H) , 7.94 (d, J = 1.3 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.75-7.66 (m, 3H), 7.08 (d, J = 8.8 Hz, 1H), 4.65-4.62 ( m, 1H), 3.64-3.55 (m, 2H), 3.3-3.2 (m, 2H), 2.39-2.3 (m, 4H); LC-MS mlz calcd for C 27 H 26 N 6 O 2 (MH + ) 465.7, found 466.98.

< 실시예 13> 3-(6- 페닐벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H- 피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 <Example 13> 3- (6-phenyl-benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-2 Preparation of Ditrifluoroacetic Acid of Amine

단계 1: t-부틸-4-(4-(6-(t- 부틸아미노 )-5-(6- 페닐벤즈[d]옥사졸 -2-일)피리 딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t-butyl-4- (4- (6- (t- butylamino ) -5- (6- phenylbenz [d] oxazol- 2 -yl) pyridin-3-yl) -1H-pyra Preparation of zol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00031
Figure 112012052254195-pat00031

4-메톡시페닐보론산 대신 페닐보론산을 사용한 것을 제외하고는 실시예 12의 단계 1과 동일한 방법으로 수행하여 노란색 고체의 목적화합물 t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-페닐벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 얻었다(38 mg, 71%). The target compound as a yellow solid, t-butyl-4- (4- (6- (t-butyl) Amino) -5- (6-phenylbenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (38 mg) , 71%).

1H NMR (MeOH-d4, 300 MHz) δ 8.80 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 7.8-7.77(m, 3H), 7.69-7.6 (m, 4H), 7.53-7.43 (m, 2H), 7.43-7.28 (m, 1H), 4.35-4.29 (m, 3H), 2.94 (m, 2H), 2.3-2.19 (m, 2H), 2.10-1.90 (m, 2H), 1.51 (s, 9H).
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.80 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 7.8-7.77 (m, 3H), 7.69-7.6 (m, 4H), 7.53-7.43 (m, 2H), 7.43-7.28 (m, 1H), 4.35-4.29 (m, 3H), 2.94 (m, 2H), 2.3-2.19 ( m, 2H), 2.10-1.90 (m, 2H), 1.51 (s, 9H).

단계 2: 3-(6- 페닐벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H- 피라졸 -4- 일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 Step 2: 3- (6- phenylbenz [d] oxazol- 2 -yl ) -5- (1- (piperidin-4-yl) -1H- pyrazol -4 - yl) pyridin-2-amine Of ditrifluoroacetic acid salts

Figure 112012052254195-pat00032
Figure 112012052254195-pat00032

상기 t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-페닐벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 출발물질로 사용하여, 실시예 12의 단계 2와 동일하게 수행하여 목적화합물 3-(6-페닐벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산염을 얻었다(35 mg, 85 %).T-butyl-4- (4- (6- (t-butylamino) -5- (6-phenylbenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazole-1 -Il) Piperidine-1-carboxylate was carried out in the same manner as Step 2 of Example 12, using the target compound 3- (6-phenylbenz [d] oxazol-2-yl)- Ditrifluoroacetic acid salt of 5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine was obtained (35 mg, 85%).

1H NMR (MeOH-d4, 300 MHz) δ 8.86 (d, J = 2.2 Hz, 1H), 8.42 (d, J = 2.3 Hz, 1H), 8.25 (s, 1H), 8.03-7.99 (m, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.78-7.72 (m, 2H), 7.6-7.42 (m, 4H), 4.67-4.61 (m, 1H), 3.64-.47 (m, 2H), 3.26-3.23 (m, 2H), 2.39-2.32 (m, 4H); LC/MS m/z calcd for C26H24N6O (MH+) 436.2, found 437.02.
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.86 (d, J = 2.2 Hz, 1H), 8.42 (d, J = 2.3 Hz, 1H), 8.25 (s, 1H), 8.03-7.99 (m, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.78-7.72 (m, 2H), 7.6-7.42 (m, 4H), 4.67-4.61 (m, 1H), 3.64-.47 (m, 2H ), 3.26-3.23 (m, 2H), 2.39-2.32 (m, 4H); LC / MS mlz calcd for C 26 H 24 N 6 O (MH + ) 436.2, found 437.02.

< 실시예 14> 5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)-3-(6-(피리딘-3-일) 벤즈[d]옥사졸-2-일)피리딘-2-아민의 삼트리플루오로아세트산염의 제조 <Example 14> 5- (l- (piperidin-4-yl) -1H- pyrazol-4-yl) -3- (6- (pyridin-3-yl) Ben's [d] oxazole- Preparation of tritrifluoroacetic acid salt of 2-yl) pyridin-2-amine

단계 1: 4-(4-(6-(t- 부틸아미노 )-5-(6-(피리딘-3-일) 벤즈 [d] 옥사졸 -2-일)피 리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: 4- (4- (6- (t- butylamino ) -5- (6- (pyridin-3-yl) benz [d] oxazol- 2 -yl ) pyridin -3-yl) -1H Preparation of -pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00033
Figure 112012052254195-pat00033

4-메톡시페닐보론산 대신 3-피리딜보론산을 사용한 것을 제외하고는 실시예 12의 단계 1과 동일한 방법으로 수행하여 노란색 고체의 목적화합물 4-(4-(6-(t-부틸아미노)-5-(6-(피리딘-3-일)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 얻었다(5 mg, 9 %). Except for using 3-pyridylboronic acid instead of 4-methoxyphenylboronic acid was carried out in the same manner as in Step 1 of Example 12 to give the target compound of the yellow solid 4- (4- (6- ) -5- (6- (pyridin-3-yl) benz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate Was obtained (5 mg, 9%).

1H NMR (CDCl3, 300 MHz) δ 8.92 (s, 1H), 8.72 (s, 1H), 8.64 (d, J = 4.2 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 7.83-7.39 (m, 1H), 7.60 (s, 1H), 7.58 (dd, J = 8.2, 1.4 Hz, 1H), 7.57-7.39 (m, 1H), 4.36-4.27 (m, 3H), 2.96-2.88 (m, 2H), 2.21-2.04 (m, 2H), 1.93 (m, 2H), 1.63 (s, 9H), 1.49 (s, 9H).
1 H NMR (CDCl 3 , 300 MHz) δ 8.92 (s, 1H), 8.72 (s, 1H), 8.64 (d, J = 4.2 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 7.83 -7.39 (m, 1H), 7.60 (s, 1H), 7.58 (dd, J = 8.2, 1.4 Hz, 1H), 7.57-7.39 (m, 1H), 4.36-4.27 (m, 3H), 2.96-2.88 (m, 2H), 2.21-2.04 (m, 2H), 1.93 (m, 2H), 1.63 (s, 9H), 1.49 (s, 9H).

단계 2: 5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)-3-(6-(피리딘 -3-일) 벤즈 [d] 옥사졸-2-일)피리딘-2-아민의 삼트리플루오로아세트산염의 제조 Step 2: 5- (1- (piperidin-4-yl) -1H- pyrazol -4 -yl) -3- (6- (pyridin-3-yl) benz [d] oxazol-2-yl Preparation of tritrifluoroacetic acid salt of pyridin-2-amine

Figure 112012052254195-pat00034
Figure 112012052254195-pat00034

상기 4-(4-(6-(t-부틸아미노)-5-(6-(피리딘-3-일)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 출발물질로 사용하여 실시예 12의 단계 2와 동일하게 수행하여 목적화합물 5-(1-(피페리딘-4-일)-1H-피라졸-4-일)-3-(6-(피리딘-3-일)벤즈[d]옥사졸-2-일)피리딘-2-아민의 삼트리플루오로아세트산염을 얻었다(4 mg, 61 %).4- (4- (6- (t-butylamino) -5- (6- (pyridin-3-yl) benz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazole -1-yl) Piperidine-1-carboxylate was carried out in the same manner as in Step 2 of Example 12, using the target compound 5- (1- (piperidin-4-yl) -1H- Tritrifluoroacetic acid salt of pyrazol-4-yl) -3- (6- (pyridin-3-yl) benz [d] oxazol-2-yl) pyridin-2-amine was obtained (4 mg, 61 %).

1H NMR (MeOH-d4, 300 MHz) δ 9.06 (s, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.75-8.7 (m, 1H), 8.5-8.45 (m, 2H), 8.21 (s, 1H), 8.13 (s, 1H), 8.00-7.98 (m, 2H), 7.86-7.83 (m, 3H), 4.65-4.61 (m, 1H), 3.6-3.54 (m, 2H), 3.26-3.22 (m, 2H), 2.4-2.37 (m, 4H); LC/MS m/z calcd for C25H23N7O (MH+) 436.2, found 437.9.
 1 H NMR (MeOH-d 4 , 300 MHz) δ 9.06 (s, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.75-8.7 (m, 1H), 8.5-8.45 (m, 2H), 8.21 (s, 1H), 8.13 (s, 1H), 8.00-7.98 (m, 2H), 7.86-7.83 (m, 3H), 4.65-4.61 (m, 1H), 3.6-3.54 (m, 2H), 3.26-3.22 (m, 2 H), 2.4-2.37 (m, 4H); LC / MS mlz calcd for C 25 H 23 N 7 O (MH + ) 436.2, found 437.9.

< 실시예 15> 3-(6-(1H- 피라졸 -5-일) 벤즈 [d] 옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 <Example 15> 3- (6- (1H- pyrazol-5-yl) benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- pyrazol Preparation of ditrifluoroacetic acid salt of zol-4-yl) pyridin-2-amine

Figure 112012052254195-pat00035
Figure 112012052254195-pat00035

실시예 12의 방법대로 목적화합물 3-(6-(1H-피라졸-5-일)벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민이트리플루오로아세트산염을 얻었다(40 mg, 75 %).Target compound 3- (6- (1H-pyrazol-5-yl) benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl)-as described in Example 12 1H-pyrazol-4-yl) pyridin-2-aminedifluorotriacetic acid salt (40 mg, 75%).

1H NMR (300MHz, CD3OD) δ 8.88 (d, J = 1.8 Hz, 1H), 8.39 (d, J = 1.8 Hz, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.93-7.84 (m, 2H), 7.74 (d, J = 1.5 Hz, 1H), 4.65-4.59 (m, 1H), 3.62-3.58 (m, 2H), 3.26-3.20 (m, 2H), 2.41-2.30 (m, 4H); LC/MS m/z calcd for C23H22N8O (MH+) 451.3, found 452.2.
 1 H NMR (300MHz, CD 3 OD) δ 8.88 (d, J = 1.8 Hz, 1H), 8.39 (d, J = 1.8 Hz, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.93-7.84 (m, 2H), 7.74 (d, J = 1.5 Hz, 1H), 4.65-4.59 (m, 1H), 3.62-3.58 (m, 2H), 3.26-3.20 (m , 2H), 2.41-2.30 (m, 4H); LC / MS mlz calcd for C 23 H 22 N 8 O (MH + ) 451.3, found 452.2.

< 실시예 16> 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-3-(4-플루오로페닐)우레아의 이트리플루오로아세트산염의 제조 <Example 16> 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole Preparation of Ditrifluoroacetic Acid of Zol-6-yl) -3- (4-fluorophenyl) urea

단계 1: t-부틸-4-(4-(6-(t- 부틸아미노 )-5-(6-(3-(4- 플루오로벤질 ) 우레이 도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t-butyl-4- (4- (6- (t- butylamino ) -5- (6- (3- (4 -fluorobenzyl ) ureido ) benz [d] oxazol-2-yl Preparation of Pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00036
Figure 112012052254195-pat00036

t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-아미노벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(25 mg, 0.05 mmol)를 테트라히드로퓨란(1 mL)에 녹이고, 0 ℃에서 4-플루오로페닐 이소시아네이트(6 ㎕, 0.056 mmol)를 적가한 뒤, 실온에서 교반시켰다. 반응이 종결되면 휘발성 물질을 제거한 뒤 컬럼 크로마토그래피로 정제하여 t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-(3-(4-플루오로벤질)우레이도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(22 mg, 연한 노란색 고체, 66%)를 얻었다.t-butyl-4- (4- (6- (t-butylamino) -5- (6-aminobenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1- (1) Piperidine-1-carboxylate (25 mg, 0.05 mmol) is dissolved in tetrahydrofuran (1 mL), 4-fluorophenyl isocyanate (6 μl, 0.056 mmol) is added dropwise at 0 ° C., Stir at room temperature. At the end of the reaction, the volatiles were removed and purified by column chromatography to give t-butyl-4- (4- (6- (t-butylamino) -5- (6- (3- (4-fluorobenzyl) urei) Benz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (22 mg, light yellow solid, 66%) Got it.

1H NMR (MeOH-d4, 300 MHz) δ 8.64 (s, 1H), 8.43 (d, J = 2.4 Hz, H), 8.3 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.77 (s, 1H), 7.65-7.6 (m, 2H), 7.39-7.32 (m, 2H), 7.13-6.91 (m, 3H), 6.90 (s, 1H), 6.52 (s, 1H), 6.38 (s, 1H), 4.31-4.13 (m, 3H), 2.97-2.89 (m, 2H), 2.21-2.17 (m, 2H), 2.07-1.95 (m, 2H), 1.61 (s, 9H), 1.49 (s, 9H); LC/MS m/z calcd for C36H41FN8O4 (MH+) 667.76, found 668.76.
1 H NMR (MeOH-d 4 , 300 MHz) δ 8.64 (s, 1H), 8.43 (d, J = 2.4 Hz, H), 8.3 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.77 (s, 1H), 7.65-7.6 (m, 2H), 7.39-7.32 (m, 2H), 7.13-6.91 (m, 3H), 6.90 (s, 1H), 6.52 (s , 1H), 6.38 (s, 1H), 4.31-4.13 (m, 3H), 2.97-2.89 (m, 2H), 2.21-2.17 (m, 2H), 2.07-1.95 (m, 2H), 1.61 (s , 9H), 1.49 (s, 9H); LC / MS mlz calcd for C 36 H 41 FN 8 O 4 (MH + ) 667.76, found 668.76.

단계 2: 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일) 벤즈[d]옥사졸-6-일)-3-(4-플루오로페닐)우레아의 이트리플루오로아세트산염의 제조 Step 2: 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -4 -yl) pyridin-3-yl) benz [d] oxazole- Preparation of ditrifluoroacetic acid salt of 6-yl) -3- (4-fluorophenyl) urea

Figure 112012052254195-pat00037
Figure 112012052254195-pat00037

상기 단계 1에서 제조된 t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-(3-(4-플루오로벤질)우레이도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(22 mg, 0.033 mmol)를 출발물질로 사용하여 실시예 12의 단계 2와 동일하게 수행하여 목적화합물 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-3-(4-플루오로페닐)우레아의 이트리플루오로아세트산염을 얻었다(22 mg, 90%).T-butyl-4- (4- (6- (t-butylamino) -5- (6- (3- (4-fluorobenzyl) ureido) benz [d] oxazole-prepared in step 1 2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (22 mg, 0.033 mmol) was used as starting material in Example 12 To the desired compound 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxa Obtained tritriacetic acid salt of zol-6-yl) -3- (4-fluorophenyl) urea (22 mg, 90%).

1H NMR (MeOH-d4, 300 MHz) δ 8.82 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.26 (s, 2H), 8.02 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.48-7.44 (m, 2H), 7.22 (dd, J = 8.7, 2.1 Hz, 1H), 7.09-7.03 (m, 2H), 4.83-4.82 (m, 1H), 3.62-3.57 (m, 2H), 3.29-3.37 (m, 2H), 2.37-2.33 (m, 4H); LC/MS m/z calcd for C27H25FN8O2 (MH+) 512.05, found 513.05.
1 H NMR (MeOH-d 4 , 300 MHz) δ 8.82 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.26 (s, 2H), 8.02 (s, 1H) , 7.73 (d, J = 8.4 Hz, 1H), 7.48-7.44 (m, 2H), 7.22 (dd, J = 8.7, 2.1 Hz, 1H), 7.09-7.03 (m, 2H), 4.83-4.82 (m , 1H), 3.62-3.57 (m, 2H), 3.29-3.37 (m, 2H), 2.37-2.33 (m, 4H); LC / MS mlz calcd for C 27 H 25 FN 8 O 2 (MH + ) 512.05, found 513.05.

< 실시예 17> 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘 -3-일)벤즈[d]옥사졸-6-일)-3-(2,4-다이클로로페닐)우레아의 이트리플루오로아세트산염의 제조 <Example 17> 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole Preparation of ditrifluoroacetic acid salt of zol-6-yl) -3- (2,4-dichlorophenyl) urea

단계 1: t- 부틸아미노 -4-(4-(6-(t- 부틸아미노 )-5-(6-(3-(2,4- 다이클로로페 닐)우레이도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t- butylamino- 4- (4- (6- (t- butylamino ) -5- (6- (3- (2,4 -dichlorophenyl ) ureido) benz [d] oxazole Preparation of 2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00038
Figure 112012052254195-pat00038

t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-아미노벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(25 mg, 0.05 mmol)를 이용하여 실시예 16의 단계 1의 방법과 동일하게 수행하여 목적화합물 t-부틸아미노-(4-(6-(t-부틸아미노)-5-(6-(3-(2,4-다이클로로페닐)우레이도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 얻었다(27 mg, 75%).t-butyl-4- (4- (6- (t-butylamino) -5- (6-aminobenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1- (I) Using the piperidine-1-carboxylate (25 mg, 0.05 mmol) in the same manner as in the step 1 of Example 16 to the target compound t-butylamino- (4- (6- (t- Butylamino) -5- (6- (3- (2,4-dichlorophenyl) ureido) benz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl ) Piperidine-1-carboxylate was obtained (27 mg, 75%).

1H NMR (CDCl3, 300 MHz) δ 8.67 (brs, 1H), 8.44 (d, J = 2.5 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 7.85 (s, 1H), 7.77 (s, 1H), 7.7-7.65 (m, 2H), 7.37 (d, J = 2.3 Hz, 1H), 7.3-7.2 (m, 1H), 7.06 (brs, 1H), 6.7 (brs, 1H), 4.35-4.23 (m, 3H), 2.96-2.89 (m, 2H), 2.20-2.17 (m, 2H), 2.05-1.92 (m, 2H), 1.61 (s, 9H), 1.49 (s, 9H).
 1 H NMR (CDCl 3 , 300 MHz) δ 8.67 (brs, 1H), 8.44 (d, J = 2.5 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 9.0 Hz , 1H), 7.85 (s, 1H), 7.77 (s, 1H), 7.7-7.65 (m, 2H), 7.37 (d, J = 2.3 Hz, 1H), 7.3-7.2 (m, 1H), 7.06 ( brs, 1H), 6.7 (brs, 1H), 4.35-4.23 (m, 3H), 2.96-2.89 (m, 2H), 2.20-2.17 (m, 2H), 2.05-1.92 (m, 2H), 1.61 ( s, 9H), 1.49 (s, 9H).

단계 2: 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일) 벤즈[d]옥사졸-6-일)-3-(2,4-다이클로로페닐)우레아의 이트리플루오로아세트산염의 제조 Step 2: 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -4 -yl) pyridin-3-yl) benz [d] oxazole- Preparation of ditrifluoroacetic acid salt of 6-yl) -3- (2,4-dichlorophenyl) urea

Figure 112012052254195-pat00039
Figure 112012052254195-pat00039

상기 단계 1에서 제조된 t-부틸아미노-(4-(6-(t-부틸아미노)-5-(6-(3-(2,4- 다이클로로페닐)우레이도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(27 mg, 0.038 mmol)를 출발물질로 사용하여 실시예 16의 단계 2와 동일하게 수행하여 목적화합물 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-3-(2,4-다이클로로페닐)우레아의 이트리플루오로아세트산염을 얻었다(3 mg, 10 %).T-butylamino- (4- (6- (t-butylamino) -5- (6- (3- (2,4-dichlorophenyl) ureido) benz [d] oxazole prepared in step 1 2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (27 mg, 0.038 mmol) as a starting material In the same manner, the target compound 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] The ditrifluoroacetic acid salt of oxazol-6-yl) -3- (2,4-dichlorophenyl) urea was obtained (3 mg, 10%).

1H NMR (MeOH-d4, 300 MHz) δ 8.69 (d, J = 2.1 Hz, 1H), 8.32 (d, J = 2.25 Hz, 1H), 8.24 (d, J = 1.89 Hz, 1H), 8.17-8.14 (m, 2H), 7.95 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 2.46 Hz, 1 H), 7.28 (dd, J = 8.9, 2.3 Hz, 1H), 7.17 (dd, J = 8.6, 1.9 Hz, 1H), 4.58-4.55 (m, 1H), 3.58-3.49 (m, 2H), 3.2-3.0 (m, 2H), 2.33-2.25 (m, 4H); LC/MS m/z calcd for C27H24Cl2N8O2 (MH+) 562.04, found 563.05.
1 H NMR (MeOH-d 4 , 300 MHz) δ 8.69 (d, J = 2.1 Hz, 1H), 8.32 (d, J = 2.25 Hz, 1H), 8.24 (d, J = 1.89 Hz, 1H), 8.17 -8.14 (m, 2H), 7.95 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 2.46 Hz, 1H), 7.28 (dd, J = 8.9, 2.3 Hz , 1H), 7.17 (dd, J = 8.6, 1.9 Hz, 1H), 4.58-4.55 (m, 1H), 3.58-3.49 (m, 2H), 3.2-3.0 (m, 2H), 2.33-2.25 (m , 4H); LC / MS mlz calcd for C 27 H 24 Cl 2 N 8 O 2 (MH + ) 562.04, found 563.05.

< 실시예 18> 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -3-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-3-페닐우레아의 이트리플루오로아세트산의 제조 <Example 18> 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-3-yl) pyridin-3-yl) benz [d] oxazole Preparation of Itrifluoroacetic Acid of Zol-6-yl) -3-phenylurea

단계 1 : t-부틸-4-(3-(6-(t- 부틸아미노 )-5-(6-(3- 페닐우레이도 ) 벤즈 [d] 옥사 졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t-butyl-4- (3- (6- (t- butylamino ) -5- (6- (3 -phenylureido ) benz [d] oxazol- 2 - yl) pyridin-3-yl Preparation of) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00040

Figure 112012052254195-pat00040

*t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-아미노벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(25 mg, 0.05 mmol)를 이용하여 실시예 16의 단계 1의 방법과 동일하게 수행하여 목적화합물(t-부틸-4-(3-(6-(t-부틸 아미노)-5-(6-(3-페닐우레이도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트)를 얻었다(23 mg, 71%).* t-butyl-4- (4- (6- (t-butylamino) -5- (6-aminobenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazole-1 -Yl) piperidine-1-carboxylate (25 mg, 0.05 mmol) was carried out in the same manner as in the step 1 of Example 16, and the target compound (t-butyl-4- (3- (6- (t-butyl amino) -5- (6- (3-phenylureido) benz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine- 1-carboxylate) (23 mg, 71%).

1H NMR (CDCl3, 300 MHz) δ 8.64 (s, 1H), 8.43 (d, J = 2.46 Hz, 1H), 8.3 (d, J = 2.46 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.77 (s, 1H), 7.63 (dd, J = 11.6, 3.0 Hz, 3H), 7.4-7.38 (m, 3H), 7.19-7.09 (m, 1H), 6.91 (s, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 4.31-4.13 (m, 3H), 2.97-2.17 (m, 2H), 2.07-1.95 (m, 2H), 1.61 (s, 9H), 1.49 (s, 9H); LC/MS m/z calcd for C36H42N8O4 (MH+) 650.15, found 651.15.
 1 H NMR (CDCl 3 , 300 MHz) δ 8.64 (s, 1H), 8.43 (d, J = 2.46 Hz, 1H), 8.3 (d, J = 2.46 Hz, 1H), 7.94 (d, J = 2.1 Hz , 1H), 7.77 (s, 1H), 7.63 (dd, J = 11.6, 3.0 Hz, 3H), 7.4-7.38 (m, 3H), 7.19-7.09 (m, 1H), 6.91 (s, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 4.31-4.13 (m, 3H), 2.97-2.17 (m, 2H), 2.07-1.95 (m, 2H), 1.61 (s, 9H), 1.49 ( s, 9H); LC / MS mlz calcd for C 36 H 42 N 8 O 4 (MH + ) 650.15, found 651.15.

단계 2 : 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -3-일)피리딘-3- 일)벤즈[d]옥사졸-6-일)-3-페닐우레아의 이트리플루오로아세트산의 제조 Step 2: 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -3-yl) pyridin-3-yl ) benz [d] oxazole- Preparation of 6-yl) -3-phenylurea ditrifluoroacetic acid

Figure 112012052254195-pat00041
Figure 112012052254195-pat00041

상기 단계 1에서 제조된 t-부틸-4-(3-(6-(t-부틸아미노)-5-(6-(3-페닐우레이도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(23 mg, 0.04 mmol)를 사용하여 실시예 16의 단계 2의 방법과 동일하게 반응하여 목적화합물(1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-3-페닐우레아의 이트리플루오로아세트산)을 얻었다(21 mg, 83%).T-butyl-4- (3- (6- (t-butylamino) -5- (6- (3-phenylureido) benz [d] oxazol-2-yl) pyridine-prepared in step 1 Using the 3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (23 mg, 0.04 mmol) in the same manner as in Step 2 of Example 16, the target compound (1 -(2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-3-yl) benz [d] oxazol-6-yl) Ditrifluoroacetic acid of -3-phenylurea) was obtained (21 mg, 83%).

1H NMR (MeOH-d4, 300 MHz) δ 8.87 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.25 (s, 2H), 8.03 (s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 7.5 Hz, 2H), 7.37-7.29 (m, 2H), 7.22 (dd, J = 8.7, 2.1 Hz, 1H), 7.07-7.05 (m, 1H), 4.67-4.6 (m, 1H), 3.62-3.53 (m, 2H), 3.24-3.2 (m, 2H), 2.36-2.29 (m, 4H).
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.87 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.25 (s, 2H), 8.03 (s, 1H) , 7.73 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 7.5 Hz, 2H), 7.37-7.29 (m, 2H), 7.22 (dd, J = 8.7, 2.1 Hz, 1H), 7.07- 7.05 (m, 1H), 4.67-4.6 (m, 1H), 3.62-3.53 (m, 2H), 3.24-3.2 (m, 2H), 2.36-2.29 (m, 4H).

< 실시예 19> N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -3-일)피리딘-3-일)벤즈[d]옥사졸-6-일카바모일-4-메틸벤젠설폰아마이드의 이트리플루오로아세트산의 제조 <Example 19> N- (2- (2- amino-5- (1- (piperidin-4-yl) -1H- pyrazol-3-yl) pyridin-3-yl) benz [d] oxazole Preparation of Itrifluoroacetic Acid of Sol-6-ylcarbamoyl-4-methylbenzenesulfonamide

단계 1: t-부틸-4-(3-(6-(t- 부틸아미노 )-5-(6-(3- 토실우레이드 ) 벤즈 [d] 옥사 졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t-butyl-4- (3- (6- (t- butylamino ) -5- (6- (3- tosylurade ) benz [d] oxazol- 2 - yl) pyridin-3-yl Preparation of) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00042
Figure 112012052254195-pat00042

t-부틸-4-(3-(5-(6-아미노벤즈[d]옥사졸-2-일)-6-(t-부틸아미노)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(20 mg, 0.04 mmol)를 THF(1 mL)에 녹이고 0 ℃에서 4-메틸벤젠설포닐 이소시아네이트(12 μL, 0.08 mmol)를 적가한 뒤 실온으로 올려 교반시켰다. 반응이 종결되면 휘발성 물질을 제거한 뒤 컬럼 크로마토그래피로 정제하여 t-부틸-4-(3-(6-(t-부틸아미노)-5-(6-(3-토실우레이도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(37 mg)를 얻었다.
t-butyl-4- (3- (5- (6-aminobenz [d] oxazol-2-yl) -6- (t-butylamino) pyridin-3-yl) -1H-pyrazole-1- I) Dissolve piperidine-1-carboxylate (20 mg, 0.04 mmol) in THF (1 mL), add 4-methylbenzenesulfonyl isocyanate (12 μL, 0.08 mmol) dropwise at 0 ° C. and raise to room temperature. Stirred. At the end of the reaction, the volatiles were removed and purified by column chromatography to obtain t-butyl-4- (3- (6- (t-butylamino) -5- (6- (3-tosylureido) benz [d] Oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (37 mg) was obtained.

단계 2: N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -3-일)피리딘-3-일) 벤즈[d]옥사졸-6-일카바모일)-4-메틸벤젠설폰아마이드의 이트리플루오로아세트산의 제조 Step 2: N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -3-yl) pyridin-3-yl) benz [d] oxazole- Preparation of ditrifluoroacetic acid of 6-ylcarbamoyl) -4-methylbenzenesulfonamide

Figure 112012052254195-pat00043
Figure 112012052254195-pat00043

상기 단계 1에서 제조된 t-부틸-4-(3-(6-(t-부틸아미노)-5-(6-(3-토실우레이도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(37 mg, 0.051 mmol)를 출발물질로 사용하여 실시예 16의 단계 2의 방법과 동일하게 수행하여 N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-3-일)벤즈[d]옥사졸-6-일카바모일)-4-메틸벤젠설폰아마이드의 이트리플루오로아세트산염을 목적화합물로 얻었다(25 mg, 61 %).T-butyl-4- (3- (6- (t-butylamino) -5- (6- (3-tosylureido) benz [d] oxazol-2-yl) pyridine-prepared in step 1 above- 3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (37 mg, 0.051 mmol) was used as the starting material in the same manner as in Step 2 of Example 16, where N was used. -(2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-3-yl) benz [d] oxazol-6-ylcarba Moyl) -4-methylbenzenesulfonamide was obtained as the target compound (25 mg, 61%).

1H NMR (MeOH-d4, 300 MHz) δ 8.8 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.83-7.78 (m, 2H), 7.62 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 1.8 Hz, 1H), 6.96 (dd, J = 8.5, 2.0 Hz, 1H), 4.66-4.6(m, 1H), 3.64-3.55 (m, 2H), 3.27-3.09 (m, 2H), 2.45-2.31 (m, 7H).
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.8 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 8.27 (s, 1H), 8.03 (s, 1H) , 7.83-7.78 (m, 2H), 7.62 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 1.8 Hz, 1H), 6.96 (dd, J = 8.5, 2.0 Hz, 1H), 4.66-4.6 (m, 1H), 3.64-3.55 (m, 2H), 3.27-3.09 (m, 2H), 2.45-2.31 (m, 7H).

< 실시예 20> N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -3-일)피리딘-3-일)벤즈[d]옥사졸-6-일)메탄설폰아마이드의 이트리플루오로아세트산염의 제조 <Example 20> N- (2- (2- amino-5- (1- (piperidin-4-yl) -1H- pyrazol-3-yl) pyridin-3-yl) benz [d] oxazole Preparation of Ditrifluoroacetic Acid of Zol-6-yl) methanesulfonamide

단계 1: t-부틸-4-(3-(6-(t- 부틸아미노 )-5-(6-( 메틸설폰아미도 ) 벤즈 [d] 옥사 졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t-butyl-4- (3- (6- (t- butylamino ) -5- (6- ( methylsulfonamido ) benz [d] oxazol- 2 - yl) pyridin-3-yl) Preparation of -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00044
Figure 112012052254195-pat00044

t-부틸-4-(3-(5-(6-아미노벤즈[d]옥사졸-2-일)-6-(t-부틸아미노)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(20 mg, 0.04 mmol)를 메틸렌클로라이드 1 mL에 녹이고 피리딘(3.5 μL, 0.044 mmol)과 메탄설포닐클로라이드(4 μL, 0.044 mmol)을 가한뒤 실온하에서 교반시켰다. 반응이 종결되면 물을 넣고 2~3회 추출한 뒤 MgSO4로 건조하고 에테르로 씻어주어 t-부틸-4-(3-(6-(t-부틸아미노)-5-(6-(메틸설폰아미도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(20 mg, 82 %)를 얻었다.t-butyl-4- (3- (5- (6-aminobenz [d] oxazol-2-yl) -6- (t-butylamino) pyridin-3-yl) -1H-pyrazole-1- (1) Piperidine-1-carboxylate (20 mg, 0.04 mmol) is dissolved in 1 mL of methylene chloride, pyridine (3.5 μL, 0.044 mmol) and methanesulfonyl chloride (4 μL, 0.044 mmol) are added, and then at room temperature. Stirred. When the reaction is completed, add water and extract 2-3 times, dry with MgSO 4 and wash with ether to give t-butyl-4- (3- (6- (t-butylamino) -5- (6- (methylsulfonami) Benz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (20 mg, 82%) was obtained.

1H NMR (CDCl3, 300MHz) δ 8.6 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.3 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.69-7.61 (m, 3H), 7.14 (dd, J = 8.4, 2.1 Hz, 1H), 4.33-4.27 (m, 3H), 3.04 (s, 3H), 2.93-2.88 (m, 2H), 2.21-2.17 (m, 2H), 1.99-1.95 (m, 2H), 1.61 (s, 9H), 1.49 (s, 9H).
 1 H NMR (CDCl 3 , 300 MHz) δ 8.6 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.3 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.69- 7.61 (m, 3H), 7.14 (dd, J = 8.4, 2.1 Hz, 1H), 4.33-4.27 (m, 3H), 3.04 (s, 3H), 2.93-2.88 (m, 2H), 2.21-2.17 ( m, 2H), 1.99-1.95 (m, 2H), 1.61 (s, 9H), 1.49 (s, 9H).

단계 2 : N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -3-일)피리딘-3- 일)벤즈[d]옥사졸-6-일)메탄설폰아마이드의 이트리플루오로아세트산염의 제조 Step 2: N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -3-yl) pyridin-3-yl ) benz [d] oxazole- Preparation of 6-yl) methanesulfonamide ditrifluoroacetate

Figure 112012052254195-pat00045
Figure 112012052254195-pat00045

상기 단계 1에서 제조도니 t-부틸-4-(3-(6-(t-부틸아미노)-5-(6-(메틸설폰아미도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(20 mg, 0.04 mmol)를 출발물질로 사용하여 실시예 16의 단계 2의 방법과 동일하게 수행하여 N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-3-일)벤즈[d]옥사졸-6-일)메탄설폰아마이드의 이트리플루오로아세트산염을 목적화합물로 얻었다(11.4 mg, 51 %).T-butyl-4- (3- (6- (t-butylamino) -5- (6- (methylsulfonamido) benz [d] oxazol-2-yl) pyridine-3 -Yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (20 mg, 0.04 mmol) was carried out in the same manner as in Step 2 of Example 16, using N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-3-yl) benz [d] oxazol-6-yl) methane Ditrifluoroacetic acid salt of sulfonamide was obtained as the target compound (11.4 mg, 51%).

1H NMR (MeOH-d4, 300MHz) δ 8.77 (d, J = 2.2 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.23 (s, 1H), 8.01 (s, 1H), 7.81-7.75 (m, 2H), 7.29 (dd, J = 8.6, 2.0 Hz, 1H), 4.67-4.61 (m, 1H), 3.59-3.54 (m, 2H), 3.34-3.22 (m, 2H), 3.03 (s, 3H), 2.44-2 (m, 4H); LC/MS m/z calcd for C21H23N7O3S (MH+) 452.52, found 453.9.
1 H NMR (MeOH-d 4 , 300 MHz) δ 8.77 (d, J = 2.2 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.23 (s, 1H), 8.01 (s, 1H), 7.81-7.75 (m, 2H), 7.29 (dd, J = 8.6, 2.0 Hz, 1H), 4.67-4.61 (m, 1H), 3.59-3.54 (m, 2H), 3.34-3.22 (m, 2H), 3.03 (s, 3 H), 2.44-2 (m, 4 H); LC / MS mlz calcd for C 21 H 23 N 7 O 3 S (MH + ) 452.52, found 453.9.

< 실시예 21> N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -3-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-4-메톡시벤젠설폰아마이드의 이트리플루오로아세트산염의 제조 <Example 21> N- (2- (2- amino-5- (1- (piperidin-4-yl) -1H- pyrazol-3-yl) pyridin-3-yl) benz [d] oxazole Preparation of ditrifluoroacetic acid salt of zol-6-yl) -4-methoxybenzenesulfonamide

단계 1: t-부틸-4-(3-(6-(t- 부틸아미노 -5-(6-(4- 메톡시페닐설폰아미도 ) 벤 즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t- butyl -4- (3- (6- (t- butylamino-5- (6- (4-methoxy-phenyl sulfonamido) Ben's [d] oxazol-2-yl) pyridin- Preparation of 3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00046
Figure 112012052254195-pat00046

t-부틸-4-(3-(5-(6-아미노벤즈[d]옥사졸-2-일)-6-(t-부틸아미노)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(20 mg, 0.04 mmol)를 다이클로로메탄 (1 mL)에 녹이고, 피리딘(3.5 μL, 0.044 mmol)과 4-메톡시벤젠-1-설포닐 클로라이드(9 mg, 0.044 mmol)를 가한 뒤 실온에서 교반시켰다. 반응이 종결되면 물을 가하고 추출한 뒤 MgSO4로 건조하고 에테르로 씻어주어 t-부틸-4-(3-(6-(t-부틸아미노)-5-(6-(4-메톡시페닐설폰아미도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(20 mg, 엷은 노란색 고체, 71 %)를 얻었다.t-butyl-4- (3- (5- (6-aminobenz [d] oxazol-2-yl) -6- (t-butylamino) pyridin-3-yl) -1H-pyrazole-1- 1) Piperidine-1-carboxylate (20 mg, 0.04 mmol) is dissolved in dichloromethane (1 mL), pyridine (3.5 μL, 0.044 mmol) and 4-methoxybenzene-1-sulfonyl chloride ( 9 mg, 0.044 mmol) was added and stirred at room temperature. When the reaction is complete, water is added, extracted, dried over MgSO 4 and washed with ether to give t-butyl-4- (3- (6- (t-butylamino) -5- (6- (4-methoxyphenylsulfonami) Benz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (20 mg, pale yellow solid, 71%) Got it.

1H NMR (CDCl3, 300 MHz) δ 8.59 (s, 1H), 8.43 (d, J = 2.49 Hz, 1H), 8.28 (d, J = 2.49 Hz, 1H), 7.77 (s, 1H), 7.69-7.65 (m, 3H), 7.54 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 1.95 Hz, 1H), 6.95 (dd, J = 8.5, 2.0 Hz, 1H) 6.89-6.85(m, 2H), 6.78 (s, 1H), 4.36-4.27 (m, 3H), 3.80 (s, 3H), 2.97-2.88 (m, 2H), 2.21-2.17 (m, 2H), 2.04-1.92 (m, 2H), 1.59 (s, 9H), 1.49 (s, 9H).
 1 H NMR (CDCl 3 , 300 MHz) δ 8.59 (s, 1H), 8.43 (d, J = 2.49 Hz, 1H), 8.28 (d, J = 2.49 Hz, 1H), 7.77 (s, 1H), 7.69 -7.65 (m, 3H), 7.54 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 1.95 Hz, 1H), 6.95 (dd, J = 8.5, 2.0 Hz, 1H) 6.89-6.85 (m , 2H), 6.78 (s, 1H), 4.36-4.27 (m, 3H), 3.80 (s, 3H), 2.97-2.88 (m, 2H), 2.21-2.17 (m, 2H), 2.04-1.92 (m , 2H), 1.59 (s, 9H), 1.49 (s, 9H).

단계 2 : N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -3-일)피리딘-3- 일)벤즈[d]옥사졸-6-일)-4-메톡시벤젠설폰아마이드의 이트리플루오로아세트산염의 제조 Step 2: N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -3-yl) pyridin-3-yl ) benz [d] oxazole- Preparation of 6-yl) -4-methoxybenzenesulfonamide ditrifluoroacetate

Figure 112012052254195-pat00047
Figure 112012052254195-pat00047

상기 단계 1에서 제조된 t-부틸-4-(3-(6-(t-부틸아미노)-5-(6-(4- 메톡시페닐설폰아미도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(20 mg, 0.028 mmol)를 출발물질로 사용하여 실시예 16의 단계 2의 방법과 동일하게 수행하여 N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-4-메톡시벤젠설폰아마이드의 이트리플루오로아세트산염을 목적화합물로 얻었다(18 mg, 84 %).T-butyl-4- (3- (6- (t-butylamino) -5- (6- (4-methoxyphenylsulfonamido) benz [d] oxazol-2-yl prepared in Step 1 above. ) Pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (20 mg, 0.028 mmol) was used as a starting material in the same manner as in Step 2 of Example 16. N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-3-yl) benz [d] oxazole-6 -Tri) -4-methoxybenzenesulfonamide was obtained as the target compound (18 mg, 84%).

1H NMR (MeOH-d4, 300 MHz) δ 8.78 (d, J = 2.1 Hz, 1H), 8.4 (d, J = 2.1 Hz, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.76-7.62 (m, 4H), 7.06 (dd, J = 8.6, 2.0 Hz, 1H), 7(d, J = 9.0 Hz, 1H), 4.67-3.54 (m, 1H), 3.83 (s, 3H), 3.64-3.56 (m, 2H), 3.26-3.23 (m, 2H), 2.39-2.31 (m, 4H); LC/MS m/z calcd for C27H27N7O4S (MH+) 544.82, found 545.93.
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.78 (d, J = 2.1 Hz, 1H), 8.4 (d, J = 2.1 Hz, 1H), 8.25 (s, 1H), 8.02 (s, 1H) , 7.76-7.62 (m, 4H), 7.06 (dd, J = 8.6, 2.0 Hz, 1H), 7 (d, J = 9.0 Hz, 1H), 4.67-3.54 (m, 1H), 3.83 (s, 3H ), 3.64-3.56 (m, 2H), 3.26-3.23 (m, 2H), 2.39-2.31 (m, 4H); LC / MS mlz calcd for C 27 H 27 N 7 O 4 S (MH + ) 544.82, found 545.93.

< 실시예 22> N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-4-플루오로벤젠설폰아마이드의 이트리플루오로아세트산의 제조 <Example 22> N- (2- (2- amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole Preparation of Itrifluoroacetic Acid of Zol-6-yl) -4-fluorobenzenesulfonamide

단계 1: t-부틸-4-(3-(6-(t- 부틸아미노 )-5-(6-(4- 플루오로페닐설폰아미도 ) 벤 즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t- butyl -4- (3- (6- (t- butylamino) -5- (6- (4-fluoro-phenyl sulfonamido) Ben's [d] oxazol-2-yl) pyridine Preparation of -3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00048
Figure 112012052254195-pat00048

4-메톡시벤젠-1-설포닐 클로라이드 대신 4-플루오로벤젠-1-설포닐 클로라이드(8.6 mg, 0.04 mmol)를 사용하는 것을 제외하고 실시예 21의 단계 1의 방법과 동일하게 수행하여 t-부틸-4-(3-(6-(t-부틸아미노)-5-(6-(4-플루오로페닐설폰아미도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 목적화합물로 얻었다(20 mg, 72%).Performing the same method as in Step 1 of Example 21, except using 4-fluorobenzene-1-sulfonyl chloride (8.6 mg, 0.04 mmol) instead of 4-methoxybenzene-1-sulfonyl chloride t -Butyl-4- (3- (6- (t-butylamino) -5- (6- (4-fluorophenylsulfonamido) benz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate was obtained as the target compound (20 mg, 72%).

1H NMR (CDCl3, 300 MHz) δ 8.59 (s, 1H), 8.44 (d, J = 2.49Hz, 1H), 8.28 (d, J = 2.49 Hz, 1H), 7.77-7.73 (m, 3H), 7.65 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 1.95 Hz, 1H), 7.13-7.07 (m, 2H), 6.95 (dd, J = 8.5, 2.0 Hz, 1H), 6.79 (s, 1H), 4.37-4.27 (m, 3H), 2.97-2.89 (m, 2H), 2.21-2.17 (m, 2H), 2.0-1.94 (m, 2H), 1.61 (s, 9H), 1.49 (s, 9H).
 1 H NMR (CDCl 3 , 300 MHz) δ 8.59 (s, 1H), 8.44 (d, J = 2.49 Hz, 1H), 8.28 (d, J = 2.49 Hz, 1H), 7.77-7.73 (m, 3H) , 7.65 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 1.95 Hz, 1H), 7.13-7.07 (m, 2H), 6.95 (dd, J = 8.5, 2.0 Hz, 1H), 6.79 (s, 1H), 4.37-4.27 (m, 3H), 2.97-2.89 (m, 2H), 2.21-2.17 (m, 2H), 2.0-1.94 (m, 2H), 1.61 ( s, 9H), 1.49 (s, 9H).

단계 2 : N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3- 일)벤즈[d]옥사졸-6-일)-4-플루오로벤젠설폰아마이드의 이트리플루오로아세트산염의 제조 Step 2: N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -4 -yl) pyridin-3-yl ) benz [d] oxazole- Preparation of 6-yl) -4-fluorobenzenesulfonamide ditrifluoroacetate

Figure 112012052254195-pat00049
Figure 112012052254195-pat00049

상기 단계 1에서 제조된 t-부틸-4-(3-(6-(t-부틸아미노)-5-(6-(4-플루오로페닐설폰아미도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(20 mg, 0.103 mmol)을 출발물질로 사용하여 실시예 21의 단계 2의 방법과 동일하게 수행하여 N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-4-플루오로벤젠설폰아마이드의 이트리플루오로아세트산염을 목적화합물로 얻었다(6 mg, 8 %).T-butyl-4- (3- (6- (t-butylamino) -5- (6- (4-fluorophenylsulfonamido) benz [d] oxazol-2-yl prepared in Step 1 above. ) Pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (20 mg, 0.103 mmol) was used as a starting material in the same manner as in Step 2 of Example 21. N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-6 -Tri) -4-fluorobenzenesulfonamide ditrifluoroacetic acid salt was obtained as the target compound (6 mg, 8%).

1H NMR (MeOH-d4, 300 MHz) δ 8.76 (d, J = 2.3 Hz, 1H), 8.4 (d, J = 2.3 Hz, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.88-7.83 (m, 2H), 7.69-7.63 (m, 2H), 7.27- 7.21 (m, 2H), 7.1 (dd, J=8.6, 2.0 Hz, 1H), 4.63-4.6 (m, 1H), 3.64-3.52 (m, 2H), 3.26-3.23 (m, 2H), 2.42-2.31 (m, 4H); LC/MS m/z calcd for C26H24FN7O3S (MH+) 532.82, found 533.9.
1 H NMR (MeOH-d 4 , 300 MHz) δ 8.76 (d, J = 2.3 Hz, 1H), 8.4 (d, J = 2.3 Hz, 1H), 8.23 (s, 1H), 8.02 (s, 1H) , 7.88-7.83 (m, 2H), 7.69-7.63 (m, 2H), 7.27-7.21 (m, 2H), 7.1 (dd, J = 8.6, 2.0 Hz, 1H), 4.63-4.6 (m, 1H) , 3.64-3.52 (m, 2H), 3.26-3.23 (m, 2H), 2.42-2.31 (m, 4H); LC / MS mlz calcd for C 26 H 24 FN 7 O 3 S (MH + ) 532.82, found 533.9.

< 실시예 23> N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -3-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-2,5-다이클로로벤젠설폰아마이드의 이트리플루오로아세트산염의 제조 <Example 23> N- (2- (2- amino-5- (1- (piperidin-4-yl) -1H- pyrazol-3-yl) pyridin-3-yl) benz [d] oxazole Preparation of ditrifluoroacetic acid salt of zol-6-yl) -2,5-dichlorobenzenesulfonamide

단계 1: t-부틸-4-(3-(6-(t- 부틸아미노 )-5-(6-(2,5- 다이클로로페닐설폰아미 도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t-butyl-4- (3- (6- (t- butylamino ) -5- (6- (2,5 -dichlorophenylsulfonamido ) benz [d] oxazol-2-yl) Preparation of Pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00050
Figure 112012052254195-pat00050

4-메톡시벤젠-1-설포닐 클로라이드 대신 2,5-다이클로로벤젠-1-설포닐 클로라이드(11 mg, 0.04 mmol)를 가하는 것을 제외하고는 실시예 21의 단계 1의 방법과 동일하게 수행하여 t-부틸-4-(3-(6-(t-부틸아미노)-5-(6-(2,5-다이클로로페닐설폰아미도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 목적화합물로 얻었다(5 mg, 17%).Perform the same procedure as in step 1 of Example 21, except adding 2,5-dichlorobenzene-1-sulfonyl chloride (11 mg, 0.04 mmol) instead of 4-methoxybenzene-1-sulfonyl chloride T-butyl-4- (3- (6- (t-butylamino) -5- (6- (2,5-dichlorophenylsulfonamido) benz [d] oxazol-2-yl) pyridine- 3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate was obtained as the target compound (5 mg, 17%).

1H NMR (CDCl3, 300 MHz) δ 8.58 (s, 1H), 8.46 (d, J = 3.9 Hz, 1H), 8.3 (d, J = 3.6 Hz, 1H), 7.97 (d, J = 3.0 Hz, 1H), 7.8 (s, 1H), 7.78 (s, 1H), 7.66-7.45 (m, 4H), 7.18 (s, 1H), 7.1-7.05 (m, 1H), 4.34-4.28 (m, 3H), 2.94-2.89 (m, 2H), 2.23-2.19 (m, 2H), 2.06-1.94 (m, 2H), 1.59 (s, 9H), 1.49 (s, 9H).
 1 H NMR (CDCl 3 , 300 MHz) δ 8.58 (s, 1H), 8.46 (d, J = 3.9 Hz, 1H), 8.3 (d, J = 3.6 Hz, 1H), 7.97 (d, J = 3.0 Hz , 1H), 7.8 (s, 1H), 7.78 (s, 1H), 7.66-7.45 (m, 4H), 7.18 (s, 1H), 7.1-7.05 (m, 1H), 4.34-4.28 (m, 3H ), 2.94-2.89 (m, 2H), 2.23-2.19 (m, 2H), 2.06-1.94 (m, 2H), 1.59 (s, 9H), 1.49 (s, 9H).

단계 2 : N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -3-일)피리딘-3- 일)벤즈옥사졸-6-일)-2,5-다이클로로벤젠설폰아마이드의 이트리플루오로아세트산염의 제조 Step 2: N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -3-yl) pyridin-3-yl ) benzoxazol-6-yl Preparation of Ditrifluoroacetic Acid of 2,5-Dichlorobenzenesulfonamide

Figure 112012052254195-pat00051
Figure 112012052254195-pat00051

상기 단계 1에서 제조된 t-부틸-4-(3-(6-(t-부틸아미노)-5-(6-(2,5-다이클로로페닐설폰아미도)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(5 mg, 0.02 mmol)를 출발물질로 사용하여 실시예 21의 단계 2의 방법과 동일하게 수행하여 N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-2,5-다이클로로벤젠설폰아마이드의 이트리플루오로아세트산염을 목적화합물로 얻었다(1 mg, 6%).T-butyl-4- (3- (6- (t-butylamino) -5- (6- (2,5-dichlorophenylsulfonamido) benz [d] oxazole-2 prepared in step 1 above. -Yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (5 mg, 0.02 mmol) as a starting material and the method of step 2 of Example 21 In the same manner, N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-3-yl) benz [d] oxazole Ditrifluoroacetic acid salt of -6-yl) -2,5-dichlorobenzenesulfonamide was obtained as a target compound (1 mg, 6%).

LC/MS m/z calcd for C26H23Cl2N7O3S (MH+) 584.48, found 586.97.
LC / MS mlz calcd for C 26 H 23 Cl 2 N 7 O 3 S (MH + ) 584.48, found 586.97.

< 실시예 24> 5-(1-(피페리딘-4-일)-1H- 피라졸 -3-일)-3-(4,5,7- 트리클로로벤즈[d]옥사졸-2-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 <Example 24> 5- (l- (piperidin-4-yl) -1H- pyrazol-3-yl) -3- (4,5,7- trichloro Robben's [d] oxazol-2- Production of Itrifluoroacetic Acid Salt of Pyridin-2-amine

Figure 112012052254195-pat00052
Figure 112012052254195-pat00052

2-아미노-3-니트로페놀 대신 2,3,6-트리클로로페놀을 사용하는 것을 제외하고는 실시예 1과 동일한 방법으로 수행하여 5-(1-(피페리딘-4-일)-1H-피라졸-3-일)-3-(4,5,7-트리클로로벤즈[d]옥사졸-2-일)피리딘-2-아민의 이트리플루오로아세트산염(19 mg, 41 %)을 목적화합물로 얻었다.5- (1- (piperidin-4-yl) -1H was carried out in the same manner as in Example 1 except for using 2,3,6-trichlorophenol instead of 2-amino-3-nitrophenol. Ditrifluoroacetic acid salt of pyrazol-3-yl) -3- (4,5,7-trichlorobenz [d] oxazol-2-yl) pyridin-2-amine (19 mg, 41%) Was obtained as the target compound.

1H NMR (MeOH-d4, 300 MHz) δ 8.57(s, 1H), 8.49(s, 1H), 8.18(s, 1H), 8.06(s, 1H), 7.73 (s, 1H), 4.62-4.6(m, 1H), 3.64-3.55(m, 2H), 3.27-3.08(m, 2H), 2.39-2.31(m, 4H): LC-MS m/z calcd for C20H17Cl3N6O (MH+) 463.75 found 464.86.
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.57 (s, 1H), 8.49 (s, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 7.73 (s, 1H), 4.62- 4.6 (m, 1H), 3.64-3.55 (m, 2H), 3.27-3.08 (m, 2H), 2.39-2.31 (m, 4H): LC-MS m / z calcd for C 20 H 17 Cl 3 N 6 O (MH + ) 463.75 found 464.86.

< 실시예 25> 3-(5,7- 다이클로로벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 <Example 25> 3- (5,7-dichloro-benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) - 1H- pyrazol-3-yl) Preparation of Itrifluoroacetic Acid Salts of Pyridin-2-amine

Figure 112012052254195-pat00053
Figure 112012052254195-pat00053

2-아미노-3-니트로페놀 대신 2,6-다이클로로페놀을 사용하는 것을 제외하고는 실시예 1과 동일한 방법으로 수행하여 3-(5,7-다이클로로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-2-아민의 이트리플루오로아세트산염(3 mg, 30 %)을 목적화합물로 얻었다.3- (5,7-dichlorobenz [d] oxazole-2-in the same manner as in Example 1, except that 2,6-dichlorophenol was used instead of 2-amino-3-nitrophenol. Il) -5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-2-amine as a trifluoroacetic acid salt (3 mg, 30%) as a target compound Got it.

1H NMR (MeOH-d4, 300 MHz) δ 8.52 (d, J = 2.3 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.08 (s, 1H), 7.87 (s, 1H), 7.71 (d, J = 1.83 Hz, 1H), 7.46 (d, J = 1.86 Hz, 1H), 4.53-4.48 (m, 1H), 3.52-3.4 (m, 2H), 3.2-3.1 (m, 2H), 2.28-2.19 (m, 4H): LC-MS m/z calcd for C20H18Cl2N6O (MH+) 428.09 found 428.92.
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.52 (d, J = 2.3 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.08 (s, 1H), 7.87 (s, 1H) , 7.71 (d, J = 1.83 Hz, 1H), 7.46 (d, J = 1.86 Hz, 1H), 4.53-4.48 (m, 1H), 3.52-3.4 (m, 2H), 3.2-3.1 (m, 2H ), 2.28-2.19 (m, 4H): LC-MS m / z calcd for C 20 H 18 Cl 2 N 6 O (MH + ) 428.09 found 428.92.

< 실시예 26> 3-(7- 클로로 -5- 플루오로벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 <Example 26> 3- (7-chloro-5-fluoro-benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- pyrazol-3- Production of Itrifluoroacetic Acid Salt of Pyridin-2-amine

단계 1: t-부틸-4-(3-(6-(t- 부틸아미노 )-5-(7- 클로로 -5- 플루오로벤즈[d]옥사 졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t-butyl-4- (3- (6- (t- butylamino ) -5- (7 -chloro- 5- fluorobenz [d] oxazol- 2 - yl) pyridin-3-yl) Preparation of -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00054
Figure 112012052254195-pat00054

5-브로모-N-t-부틸-3-(4-니트로벤즈[d]옥사졸-2-일)피리딘-2-아민 대신 5-브로모-N-t-부틸-3-(7-클로로-5-플루오로벤즈[d]옥사졸-2-일)피리딘-2-아민(190 mg, 0.48 mmol)을 사용하는 것을 제외하고 실시예 1의 단계 6의 방법과 동일하게 수행하여 t-부틸-4-(3-(6-(t-부틸아미노)-5-(7-클로로-5-플루오로벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 목적화합물로 얻었다(64 mg, 23 %).5-Bromo-Nt-butyl-3- (7-chloro-5- instead of 5-bromo-Nt-butyl-3- (4-nitrobenz [d] oxazol-2-yl) pyridin-2-amine T-butyl-4- was carried out in the same manner as in Step 6 of Example 1, except using fluorobenz [d] oxazol-2-yl) pyridin-2-amine (190 mg, 0.48 mmol). (3- (6- (t-butylamino) -5- (7-chloro-5-fluorobenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl ) Piperidine-1-carboxylate was obtained as the target compound (64 mg, 23%).

1H NMR (CDCl3, 300 MHz) δ 8.52 (s, 1H), 8.47 (d, J = 2.5 Hz, 1H), 8.33 (d, J = 2.5 Hz, 1H), 7.77 (s, 1H), 7.6 (s, 1H), 7.33 (dd, J = 8.0, 2.4 Hz, 1H), 7.13 (dd, J = 9.2, 2.3 Hz, 1H), 4.36-4.31(m, 3H), 2.96-2.87 (m, 2H), 2.21-2.17 (m, 2H), 2.04-1.95 (m, 2H), 1.6 (s, 9H), 1.49 (s, 9H).
 1 H NMR (CDCl 3 , 300 MHz) δ 8.52 (s, 1H), 8.47 (d, J = 2.5 Hz, 1H), 8.33 (d, J = 2.5 Hz, 1H), 7.77 (s, 1H), 7.6 (s, 1H), 7.33 (dd, J = 8.0, 2.4 Hz, 1H), 7.13 (dd, J = 9.2, 2.3 Hz, 1H), 4.36-4.31 (m, 3H), 2.96-2.87 (m, 2H ), 2.21-2.17 (m, 2H), 2.04-1.95 (m, 2H), 1.6 (s, 9H), 1.49 (s, 9H).

단계 2 : 3-(7- 클로로 -5- 플루오로벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4- 일)-1H-피라졸-3-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 Step 2: 3- (7 -Chloro- 5- fluorobenz [d] oxazol- 2 -yl ) -5- (1- (piperidin-4-yl ) -1 H-pyrazol-3-yl) Preparation of Itrifluoroacetic Acid Salts of Pyridin-2-amine

Figure 112012052254195-pat00055
Figure 112012052254195-pat00055

상기 단계 1의 t-부틸-4-(3-(6-(t-부틸아미노)-5-(7-클로로-5-플루오로벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 출발물질로 사용하여 실시예 1의 단계 7의 방법과 동일하게 수행하여 3-(7-클로로-5-플루오로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-2-아민의 이트리플루오로아세트산을 목적화합물로 얻었다(15 mg, 노란색 고체, 90 %).T-butyl-4- (3- (6- (t-butylamino) -5- (7-chloro-5-fluorobenz [d] oxazol-2-yl) pyridin-3-yl of step 1 above 3- (7-chloro-5-fluoro) in the same manner as in step 7 of Example 1, using the 1-1H-pyrazol-1-yl) piperidine-1-carboxylate as starting material. Target compound of ditrifluoroacetic acid of benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-2-amine Obtained (15 mg, yellow solid, 90%).

1H NMR (MeOH-d4, 300 MHz) δ 8.57 (s, 1H), 8.46 (s, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.54 (d, J = 6.8 Hz, 1H), 7.37 (dd, J = 9.4, 2.4 Hz, 1H), 4.65-4.58 (m, 1H), 3.63-3.5 (m, 2H), 3.26-3.22 (m, 2H), 2.42-2.3 (m, 4H): LC-MS m/z calcd for C20H18ClFN6O (MH+) 412.12 found 412.94.
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.57 (s, 1H), 8.46 (s, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.54 (d, J = 6.8 Hz, 1H), 7.37 (dd, J = 9.4, 2.4 Hz, 1H), 4.65-4.58 (m, 1H), 3.63-3.5 (m, 2H), 3.26-3.22 (m, 2H), 2.42-2.3 (m, 4H): LC-MS mlz calcd for C 20 H 18 ClFN 6 O (MH + ) 412.12 found 412.94.

< 실시예 27> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -3-일)피리딘-3-일)-5-플루오로벤즈[d]옥사졸-7-올의 이트리플루오로아세트산염의 제조 <Example 27> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-3-yl) pyridin-3-yl) -5-fluoro-benz [d ] Preparation of Ditrifluoroacetic Acid of Oxazole-7-ol

단계 1: t-부틸-4-(3-(6-(t- 부틸아미노 )-5-(5- 플루오로 -7- 히드록시벤즈[d]옥 사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t-butyl-4- (3- (6- (t- butylamino ) -5- (5- fluoro- 7 -hydroxybenz [d] oxazol -2-yl) pyridin-3-yl Preparation of) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00056
Figure 112012052254195-pat00056

t-부틸-4-(3-(6-(t-부틸아미노)-5-(7-클로로-5-플루오로벤즈[d]옥사졸-2-일)-피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(39 mg, 0.068 mmol)를 압력반응기에 가하고 수산화칼륨(12 mg, 0.2 mmol), t-butyl X-phos(4.6 mg, 0.01 mmol), Pd2(dba)3(2.5 mg, 0.003 mmol) 및 1,4-다이옥산:물(1:1, 2 mL)을 가하고, 100 ℃에서 13시간 동안 교반시켰다. 반응이 종결되면 냉각하고, 휘발성 물질을 제거한 다음, pH = 7로 중화시킨 뒤 MgSO4로 건조하고 컬럼 크로마토그래피로 정제하여 t-부틸-4-(3-(6-(t-부틸아미노)-5-(5-플루오로-7-히드록시벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(12 mg, 32%)를 얻었다.t-butyl-4- (3- (6- (t-butylamino) -5- (7-chloro-5-fluorobenz [d] oxazol-2-yl) -pyridin-3-yl) -1H Pyrazol-1-yl) piperidine-1-carboxylate (39 mg, 0.068 mmol) was added to the pressure reactor and potassium hydroxide (12 mg, 0.2 mmol), t-butyl X-phos (4.6 mg, 0.01 mmol), Pd 2 (dba) 3 (2.5 mg, 0.003 mmol) and 1,4-dioxane: water (1: 1, 2 mL) were added and stirred at 100 ° C. for 13 h. When the reaction is complete, it is cooled, the volatiles are removed, neutralized to pH = 7, dried over MgSO 4 and purified by column chromatography to give t-butyl-4- (3- (6- (t-butylamino)- 5- (5-fluoro-7-hydroxybenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (12 mg, 32%).

LC-MS m/z calcd for C29H35FN6O4 (MH+) 550.27 found 551.1.
LC-MS mlz calcd for C 29 H 35 FN 6 O 4 (MH + ) 550.27 found 551.1.

단계 2: 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -3-일)피리딘-3-일)-5- 플루오로벤즈[d]옥사졸-7-올의 이트리플루오로아세트산염의 제조 Step 2: 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -3-yl) pyridin-3-yl) -5- fluorobenz [d] oxa Preparation of Ditrifluoroacetic Acid of Sol-7-ol

Figure 112012052254195-pat00057
Figure 112012052254195-pat00057

상기 단계 1에서 제조된 t-부틸-4-(3-(6-(t-부틸아미노)-5-(5-플루오로-7-히드록시벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 출발물질로 사용하여 실시예 1의 단계 7의 방법과 동일한 방법으로 수행하여 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-3-일)-5-플루오로벤즈[d]옥사졸-7-올의 이트리플루오로아세트산염을 목적화합물로 얻었다(1.5 mg, 베이지색 고체, 64%).T-butyl-4- (3- (6- (t-butylamino) -5- (5-fluoro-7-hydroxybenz [d] oxazol-2-yl) pyridine-prepared in step 1 3- (yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate was carried out in the same manner as in step 7 of Example 1, using 2- (2-amino- Itrifluoro of 5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-3-yl) -5-fluorobenz [d] oxazol-7-ol Acetate was obtained as the target compound (1.5 mg, beige solid, 64%).

1H NMR (MeOH-d4, 300 MHz) δ 9.07 (d, J = 2.2 Hz, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.37 (s, 1H), 8.07 (s, 1H), 7.1 (dd, J = 8.2, 2.3 Hz, 1H), 6.76 (dd, J=8.2, 2.3 Hz, 1H), 4.7-4.63 (m, 1H), 3.64-3.54 (m, 2H), 3.4-3.2 (m, 2H), 2.4-2.33 (m, 4H).
 1 H NMR (MeOH-d 4 , 300 MHz) δ 9.07 (d, J = 2.2 Hz, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.37 (s, 1H), 8.07 (s, 1H) , 7.1 (dd, J = 8.2, 2.3 Hz, 1H), 6.76 (dd, J = 8.2, 2.3 Hz, 1H), 4.7-4.63 (m, 1H), 3.64-3.54 (m, 2H), 3.4-3.2 (m, 2H), 2.4-2.33 (m, 4H).

< 실시예 28> 3-(5- 클로로 -7- 플루오로벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 <Example 28> 3- (5-chloro-7-fluoro-benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- pyrazol-3- Production of Itrifluoroacetic Acid Salt of Pyridin-2-amine

Figure 112012052254195-pat00058
Figure 112012052254195-pat00058

t-부틸-4-(3-(6-(t-부틸아미노)-5-(5-클로로-7-플루오로벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(2.7 mg, 0.005 mmol)를 사용하는 것을 제외하고는 실시예 1의 단계 7의 방법과 동일하게 수행하여 3-(5-클로로-7-플루오로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-2-아민의 이트리플루오로아세트산염을 목적화합물로 얻었다(3 mg, 94%).t-butyl-4- (3- (6- (t-butylamino) -5- (5-chloro-7-fluorobenz [d] oxazol-2-yl) pyridin-3-yl) -1H- Except for using pyrazol-1-yl) piperidine-1-carboxylate (2.7 mg, 0.005 mmol) in the same manner as in Step 7 of Example 1 Itrifluoro of 7-fluorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-2-amine Acetate was obtained as the target compound (3 mg, 94%).

1H NMR (MeOH-d4, 300 MHz) δ 8.57 (d, J = 2.1 Hz, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.37 (dd, J = 9.2, 2.3 Hz, 1H), 4.7-4.62 (m, 1H), 3.65-3.52 (m, 2H), 3.3-3.2 (m, 2H), 2.38-2.3 (m, 4H): LC-MS m/z calcd for C20H18ClFN6O (MH+) 412.12 found 412.93.
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.57 (d, J = 2.1 Hz, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.17 (s, 1H), 7.97 (s, 1H) , 7.55 (d, J = 7.9 Hz, 1H), 7.37 (dd, J = 9.2, 2.3 Hz, 1H), 4.7-4.62 (m, 1H), 3.65-3.52 (m, 2H), 3.3-3.2 (m , 2H), 2.38-2.3 (m, 4H): LC-MS m / z calcd for C 20 H 18 ClFN 6 O (MH + ) 412.12 found 412.93.

< 실시예 29> 3-(5- 클로로 -6- 플루오로벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 <Example 29> 3- (5-chloro-6-fluoro-benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- pyrazol-3- Production of Itrifluoroacetic Acid Salt of Pyridin-2-amine

Figure 112012052254195-pat00059
Figure 112012052254195-pat00059

t-부틸-4-(3-(6-(t-부틸아미노)-5-(5-클로로-6-플루오로벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(27 mg, 0.047 mmol)를 사용하는 것을 제외하고는 실시예 1의 단계 7의 방법과 동일하게 수행하여 3-(5-클로로-6-플루오로벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-2-아민의 이트리플루오로아세트산염을 목적화합물로 얻었다(21 mg, 70 %).t-butyl-4- (3- (6- (t-butylamino) -5- (5-chloro-6-fluorobenz [d] oxazol-2-yl) pyridin-3-yl) -1H- Except for using pyrazol-1-yl) piperidine-1-carboxylate (27 mg, 0.047 mmol) in the same manner as in Step 7 of Example 1, the process was repeated with 3- (5-chloro- Itrifluoro of 6-fluorobenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-2-amine Acetate was obtained as the target compound (21 mg, 70%).

1H NMR (MeOH-d4, 300 MHz) δ 8.72 (d, J = 2.3 Hz, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.21 (s, 1H), 8.0-7.98 (m, 2H), 7.75 (d, J = 8.3 Hz, 1H), 4.79-4.76 (m, 1H), 3.64-3.52 (m, 2H), 3.27-3.22 (m, 2H), 2.39-2.31 (m, 4H): LC-MS m/z calcd for C20H18ClFN6O (MH+) 412.12 found 412.85.
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.72 (d, J = 2.3 Hz, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.21 (s, 1H), 8.0-7.98 (m, 2H), 7.75 (d, J = 8.3 Hz, 1H), 4.79-4.76 (m, 1H), 3.64-3.52 (m, 2H), 3.27-3.22 (m, 2H), 2.39-2.31 (m, 4H) : LC-MS m / z calcd for C 20 H 18 ClFN 6 O (MH + ) 412.12 found 412.85.

< 실시예 30> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일) 피리딘-3-일)-6-클로로-N-이소프로필벤즈[d]옥사졸-5-카르복스아마이드의 이트리플루오로아세트산염의 제조 <Example 30> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) -N- isopropyl-6-chloro Preparation of Ditrifluoroacetic Acid of Propyl Benz [d] oxazole-5-carboxamide

단계 1 : 2-Step 1: 2- 클로로Chloro -4-히드록시-N-4-hydroxy-N- 이소프로필벤즈아마이드의Of isopropylbenzamide 제조 Produce

Figure 112012052254195-pat00060
Figure 112012052254195-pat00060

2-클로로-4-히드록시벤조산(2.8 g, 0.011 mol)을 티오닐클로라이드(10 mL)에 녹이고, 13시간 동안 환류시켰다. 반응이 종결되면, 반응물을 감압증류하여 농축하고 여기에 이소프로필아민(1.8 mL)와 트리에틸아민(3.0 mL)을 0 ℃에서 가하고, 2시간 동안 상온에서 교반하였다. 반응이 종결되면 감압농축하고, 물과 에틸아세테이트를 가하여 생성물을 유기층으로 추출하였다. 무수망초로 건조, 여과한 후, 감압농축하여 얻은 생성물을 컬럼 크로마토그래피로 정제하여 목적화합물(2-클로로-4-히드록시-N-이소프로필벤즈아마이드)을 얻었다(2.5 g, 48 %).2-Chloro-4-hydroxybenzoic acid (2.8 g, 0.011 mol) was dissolved in thionylchloride (10 mL) and refluxed for 13 h. After the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and isopropylamine (1.8 mL) and triethylamine (3.0 mL) were added thereto at 0 ° C., and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, water and ethyl acetate were added, and the product was extracted into the organic layer. After drying over anhydrous and filtered, the product obtained by concentration under reduced pressure was purified by column chromatography to obtain the target compound (2-chloro-4-hydroxy-N-isopropylbenzamide) (2.5 g, 48%).

1H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 8.5 Hz, 1H), 6.85 (s, 1H), 6.75 (d, J = 8.5 Hz, 1H), 4.21 (m, 1H), 1.27 (d, J = 6.4 Hz, 1H)
 1 H NMR (300 MHz, CDCl 3 ) δ 7.64 (d, J = 8.5 Hz, 1H), 6.85 (s, 1H), 6.75 (d, J = 8.5 Hz, 1H), 4.21 (m, 1H), 1.27 (d, J = 6.4 Hz, 1H)

단계 2 : 2-Step 2: 2- 클로로Chloro -4-히드록시-N-이소프로필-5-4-hydroxy-N-isopropyl-5- 니트로벤즈아마이드의Of nitrobenzamide 제조 Produce

Figure 112012052254195-pat00061
Figure 112012052254195-pat00061

2-클로로-4-히드록시-N-이소프로필벤즈아마이드(560 mg, 2.62 mmol)를 초산 (10 mL)에 녹이고 여기에 질산(1 mL)을 가하였다. 상온에서 2시간 동안 교반시키고, 감압 농축하였다. 여기에 에틸아세테이트와 헥산을 이용하여 고체를 석출시키고, 여과하여 2-클로로-4-히드록시-N-이소프로필-5-니트로벤즈아마이드를 목적화합물로 얻었다(413 mg, 61 %)2-Chloro-4-hydroxy-N-isopropylbenzamide (560 mg, 2.62 mmol) was dissolved in acetic acid (10 mL) and nitric acid (1 mL) was added thereto. Stirred at room temperature for 2 hours, and concentrated under reduced pressure. The solid was precipitated using ethyl acetate and hexane, and filtered to obtain 2-chloro-4-hydroxy-N-isopropyl-5-nitrobenzamide as the target compound (413 mg, 61%).

1H NMR(300 MHz, CDCl3) δ 10.65 (s, 1H), 8.49 (d, J = 1.5 Hz, 1H), 7.23 (d, J = 1.5hz, 1H), 4.34-4.23 (m, 1H), 1.29 (s, 1H), 1.27 (s, 1H)
 1 H NMR (300 MHz, CDCl 3 ) δ 10.65 (s, 1H), 8.49 (d, J = 1.5 Hz, 1H), 7.23 (d, J = 1.5hz, 1H), 4.34-4.23 (m, 1H) , 1.29 (s, 1H), 1.27 (s, 1H)

단계 3: 5-아미노-2-Step 3: 5-amino-2- 클로로Chloro -4-히드록시-N-4-hydroxy-N- 이소프로필벤즈아마이드의Of isopropylbenzamide 제조 Produce

Figure 112012052254195-pat00062
Figure 112012052254195-pat00062

2-클로로-4-히드록시-N-이소프로필-5-니트로벤즈아마이드(200 mg, 0.78 mmol)를 에탄올(10 mL)에 녹이고, 여기에 이염화주석(444 mg, 2.3 mmol)을 가하였다. 반응혼합물을 5시간 동안 가열 환류한 후, 반응물을 농축시키고, 중탄산나트륨 용액으로 중화시켰다. 에틸아세테이트를 가하여, 생성물을 유기층으로 추출하고, 무수망초로 건조, 감압농축하여 얻은 생성물을 컬럼 크로마토그래피로 정제하여 5-아미노-2-클로로-4-히드록시-N-이소프로필 벤즈아마이드를 목적화합물로 얻었다(180 mg, 41 %). 2-Chloro-4-hydroxy-N-isopropyl-5-nitrobenzamide (200 mg, 0.78 mmol) was dissolved in ethanol (10 mL), and tin dichloride (444 mg, 2.3 mmol) was added thereto. . After the reaction mixture was heated to reflux for 5 hours, the reaction was concentrated and neutralized with sodium bicarbonate solution. Ethyl acetate was added, the product was extracted with an organic layer, dried over anhydrous manganese, concentrated under reduced pressure, and the product obtained by column chromatography was purified to give 5-amino-2-chloro-4-hydroxy-N-isopropyl benzamide. Obtained as a compound (180 mg, 41%).

1H NMR(MeOH-d4, 300 MHz) δ 6.76 (s, 1H), 6.68 (s, 1H), 4.15 ~ 4.08 (m, 1H), 1.22 (s, 3H), 1.21 (s, 3H)
 1 H NMR (MeOH-d 4 , 300 MHz) δ 6.76 (s, 1H), 6.68 (s, 1H), 4.15 to 4.08 (m, 1H), 1.22 (s, 3H), 1.21 (s, 3H)

단계 4: N-(5-( 이소프로필카바모일 )-4- 클로로 -2- 히드록시페닐 )-5- 브로모 -2- 클로로피리딘-3-카르복스아마이드의 제조 Step 4: Preparation of N- (5- ( isopropylcarbamoyl ) -4 -chloro -2 -hydroxyphenyl ) -5- bromo- 2 -chloropyridine-3-carboxamide

Figure 112012052254195-pat00063
Figure 112012052254195-pat00063

2-아미노-3-니트로페놀 대신 5-아미노-2-클로로-4-히드록시-N-이소프로필벤즈아마이드(180 mg, 0.79 mmol)를 사용한 것을 제외하고는 실시예 1의 단계 3의 방법과 동일하게 수행하여 N-(5-(이소프로필카바모일)-4-클로로-2-히드록시페닐)-5-브로모-2-클로로피리딘-3-카르복스아마이드를 목적화합물로 얻었다(77 mg, 21 %).Example 3 step 3 except that 5-amino-2-chloro-4-hydroxy-N-isopropylbenzamide (180 mg, 0.79 mmol) was used instead of 2-amino-3-nitrophenol. In the same manner, N- (5- (isopropylcarbamoyl) -4-chloro-2-hydroxyphenyl) -5-bromo-2-chloropyridine-3-carboxamide was obtained as a target compound (77 mg , 21%).

1H NMR(MeOH-d4, 300 MHz) δ 8.60 (d, J = 2.4 hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 6.94 (s, 1H), 4.16 ~ 4.12 (m, 1H), 1.25 (s, 3H), 1.23 (s, 3H)
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.60 (d, J = 2.4 hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 6.94 (s, 1H) , 4.16 to 4.12 (m, 1H), 1.25 (s, 3H), 1.23 (s, 3H)

단계 5: 2-(5- 브로모 -2- 클로로피리딘 -3-일)-6- 클로로 -N-이소프로필 벤즈[d] 옥사졸-5-카르복스아마이드의 제조 Step 5: Preparation of 2- (5- bromo- 2 -chloropyridin- 3 - yl) -6- chloro- N-isopropyl benz [d] oxazole-5-carboxamide

Figure 112012052254195-pat00064
Figure 112012052254195-pat00064

N-(5-(이소프로필카바모일)-4-클로로-2-히드록시페닐)-5-브로모-2-클로로피리딘-3-카르복스아마이드(77 mg, 0.16 mmol)를 사용하는 것을 제외하고는 실시예 1의 단계 4와 동일하게 수행하여 2-(5-브로모-2-클로로피리딘-3-일)-6-클로로-N-이소프로필벤즈[d]옥사졸-5-카르복스아마이드를 목적화합물로 얻었다(67 mg, 87 %).Except for using N- (5- (isopropylcarbamoyl) -4-chloro-2-hydroxyphenyl) -5-bromo-2-chloropyridine-3-carboxamide (77 mg, 0.16 mmol) And 2- (5-bromo-2-chloropyridin-3-yl) -6-chloro-N-isopropylbenz [d] oxazole-5-carbox in the same manner as in Step 4 of Example 1 Amide was obtained as the target compound (67 mg, 87%).

1H NMR (MeOH-d4, 300 MHz) δ 8.67 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 4.11 (m, 1H), 1.25 (d, J = 6.4 Hz, 3H).
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.67 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 1H) , 4.11 (m, 1 H), 1.25 (d, J = 6.4 Hz, 3H).

단계 6: 2-(2-(t- 부틸아미노 )-5- 브로모피리딘 -3-일)-6- 클로로 -N- 이소프로필 벤즈[d]옥사졸-5-카르복스아마이드의 제조 Step 6: Preparation of 2- (2- (t- butylamino ) -5- bromopyridin- 3 - yl) -6- chloro- N -isopropyl benz [d] oxazole-5-carboxamide

Figure 112012052254195-pat00065
Figure 112012052254195-pat00065

2-(5-브로모-2-클로로피리딘-3-일)-6-클로로-N-이소프로필벤즈[d]옥사졸-5-카르복스아마이드(67 mg, 0.021 mmol)를 사용하는 것을 제외하고는 실시예 1의 단계 5와 동일하게 수행하여 2-(2-(t-부틸아미노)-5-브로모피리딘-3-일)-6-클로로-N-이소프로필벤즈[d]옥사졸-5-카르복스아마이드를 목적화합물로 얻었다(27 mg, 41 %).Except for using 2- (5-bromo-2-chloropyridin-3-yl) -6-chloro-N-isopropylbenz [d] oxazole-5-carboxamide (67 mg, 0.021 mmol) And 2- (2- (t-butylamino) -5-bromopyridin-3-yl) -6-chloro-N-isopropylbenz [d] oxazole in the same manner as in Step 5 of Example 1 -5-Carboxamide was obtained as the target compound (27 mg, 41%).

1H NMR (MeOH-d4, 300 MHz) δ 8.23 (s, 2H), 7.71 (s, 1H), 7.25 (s, 1H), 4.11 (m, 1H), 1.30 (d, J = 6.4 Hz, 3H).
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.23 (s, 2H), 7.71 (s, 1H), 7.25 (s, 1H), 4.11 (m, 1H), 1.30 (d, J = 6.4 Hz, 3H).

단계 7: t-부틸-4-(4-(5-(5-( 이소프로필카바모일 )-6- 클로로벤즈[d]옥사졸 -2- 일)-6-(t-부틸아미노)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트 Step 7: t-butyl-4- (4- (5- (5- ( isopropylcarbamoyl ) -6- chlorobenz [d] oxazol- 2 -yl ) -6- (t-butylamino) pyridine- 3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00066
Figure 112012052254195-pat00066

2-(2-(t-부틸아미노)-5-브로모피리딘-3-일)-6-클로로-N-이소프로필벤즈[d]옥사졸-5-카르복스아마이드(27 mg, 0.058 mmol)를 사용하는 것을 제외하고는 실시예 1의 단계 6의 방법과 동일하게 수행하여 t-부틸-4-(4-(5-(5-(이소프로필 카바모일)-6-클로로벤즈[d]옥사졸-2-일)-6-(t-부틸아미노)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 목적화합물로 얻었다(34 mg, 92 %).2- (2- (t-butylamino) -5-bromopyridin-3-yl) -6-chloro-N-isopropylbenz [d] oxazole-5-carboxamide (27 mg, 0.058 mmol) T-butyl-4- (4- (5- (5- (5- (isopropyl carbamoyl) -6-chlorobenz [d] oxa) in the same manner as in Example 6 except that Zol-2-yl) -6- (t-butylamino) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate was obtained as the target compound (34 mg, 92 %).

1H NMR (MeOH-d4, 300 MHz) δ 8.58 (s, 1H), 8.46 (d, J = 2.5 Hz, 1H), 8.28 (d, J = 2.5 Hz, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 4.15 (m, 4H), 2.95 (m. 2H), 2.20 (m, 2H), 2.20 (m, 2H), 1.90 (m, 2H), 1.30 (d, J = 6.4 Hz, 3H).
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.58 (s, 1H), 8.46 (d, J = 2.5 Hz, 1H), 8.28 (d, J = 2.5 Hz, 1H), 7.94 (s, 1H) , 7.76 (s, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 4.15 (m, 4H), 2.95 (m. 2H), 2.20 (m, 2H), 2.20 (m, 2H), 1.90 (m, 2H), 1.30 (d, J = 6.4 Hz, 3H).

단계 8: 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)-6- 클로로-N-이소프로필벤즈[d]옥사졸-5-카르복스아마이드의 이트리플루오로아세트산염의 제조 Step 8: 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -4 -yl) pyridin-3-yl) -6- chloro-N-isopropylbenz [d] Preparation of ditrifluoroacetic acid salt of oxazole-5-carboxamide

Figure 112012052254195-pat00067
Figure 112012052254195-pat00067

출발물질로 4-(4-(5-(5-(이소프로필카바모일)-6-클로로벤즈[d]옥사졸-2-일)-6-(t-부틸아미노)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(5 mg, 7.8 μmol)를 사용하는 것을 제외하고는 실시예 16의 단계 2의 방법과 동일하게 수행하여 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-6-클로로-N-이소프로필벤즈[d]옥사졸-5-카르복스아마이드의 이트리플루오로아세트산염을 목적화합물로 얻었다(5 mg, 81 %).4- (4- (5- (5- (5- (isopropylcarbamoyl) -6-chlorobenz [d] oxazol-2-yl) -6- (t-butylamino) pyridin-3-yl) as starting material 2- (2) was carried out in the same manner as in Step 2 of Example 16, except that -1H-pyrazol-1-yl) piperidine-1-carboxylate (5 mg, 7.8 μmol) was used. -Amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -6-chloro-N-isopropylbenz [d] oxazole-5 -Trifluoroacetic acid salt of carboxamide was obtained as the target compound (5 mg, 81%).

1H NMR (acetone-d6, 300 MHz ) δ 8.97 (s, 1H), 8.75 (s, 1H), 8.62 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 4.86 (s, 1H), 4.44-4.27 (m, 1H), 3.07-3.01 (m, 2H), 2.71-2.66 (m, 2H), 1.89 (m, 4H), 1.35 (d, J = 6.5 Hz, 6H): LC-MS m/z calcd for C24H27N7O2Cl (MH+) 463.22 found 464.12.
 1 H NMR (acetone-d 6 , 300 MHz) δ 8.97 (s, 1H), 8.75 (s, 1H), 8.62 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 8.08 ( s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 4.86 (s, 1H), 4.44-4.27 (m, 1H), 3.07-3.01 (m, 2H), 2.71-2.66 (m, 2H) , 1.89 (m, 4H), 1.35 (d, J = 6.5 Hz, 6H): LC-MS m / z calcd for C 24 H 27 N 7 O 2 Cl (MH + ) 463.22 found 464.12.

< 실시예 31> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일) 피리딘-3-일)-6-히드록시-N-이소프로필벤즈[d]옥사졸-5-카르복스아마이드의 이트리플루오로아세트산염의 제조 <Example 31> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) -6-hydroxy -N- Preparation of ditrifluoroacetic acid salt of isopropylbenz [d] oxazole-5-carboxamide

단계 1: 4-(4-(5-(5-( 이소프로필카바모일 )-6- 히드록시벤즈[d]옥사졸 -2-일)- 6-(t-부틸아미노)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: 4- (4- (5- (5- ( isopropylcarbamoyl ) -6 -hydroxybenz [d] oxazol- 2 -yl ) -6- (t-butylamino) pyridin-3-yl Preparation of) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00068
Figure 112012052254195-pat00068

압력반응기에 t-부틸-4-(4-(5-(5-(이소프로필카바모일)-6-클로로벤즈[d]옥사졸-2-일)-6-(t-부틸아미노)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(26 mg, 0.041 mmol), 2-디-t-부틸포스피노-2,4,5,-트리이소프로필바이페닐(2.7 mg, 6.5 μmol), Pd2dba3(1.47 mg, 1.6 umol), KOH(6.9 mg, 0.12 mmol)을 1,4-다이옥산(1 mL)와 물(1 mL)에 녹이고 100 ℃에서 13 시간 반응시켰다. 반응이 종결되면, 에틸아세테이트로 희석하고 셀라이트를 통과시켰다. 에틸아세테이트와 물을 가하여 생성물을 유기층으로 추출하고, 무수망초로 건조, 여과한 뒤, 감압농축하여 얻은 생성물을 관트로마토 그래피로 정제하여 t-부틸-4-(4-(5-(5-(이소프로필카바모일)-6-히드록시벤즈[d]옥사졸-2-yl)-6-(t-부틸아미노)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 목적화합물로 얻었다(12 mg, 46 %).T-butyl-4- (4- (5- (5- (isopropylcarbamoyl) -6-chlorobenz [d] oxazol-2-yl) -6- (t-butylamino) pyridine- 3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (26 mg, 0.041 mmol), 2-di-t-butylphosphino-2,4,5, -triiso Dissolve propylbiphenyl (2.7 mg, 6.5 μmol), Pd 2 dba 3 (1.47 mg, 1.6 umol), KOH (6.9 mg, 0.12 mmol) in 1,4-dioxane (1 mL) and water (1 mL) It was made to react at 13 degreeC. At the end of the reaction, the mixture was diluted with ethyl acetate and passed through celite. Ethyl acetate and water were added, the product was extracted with an organic layer, dried over anhydrous forget-me-not, filtered, and the product obtained by concentration under reduced pressure was purified by tube chromatography to obtain t-butyl-4- (4- (5- (5- (Isopropylcarbamoyl) -6-hydroxybenz [d] oxazol-2-yl) -6- (t-butylamino) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine -1-carboxylate was obtained as the target compound (12 mg, 46%).

1H NMR (acetone-d6, 300 MHz) δ 12.8 (s, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 0.6 Hz, 1H), 7.69 (s, 1H), 7.65 (s, 1H), 7.13 (s, 1H), 4.86 (s, 1H), 4.44-4.27 (m, 3H), 3.07-3.01 (m, 2H), 2.71-2.66 (m, 2H), 2.20 (m, 2H), 1.95 (m, 2H), 1.61 (s, 9H), 1.49 (s, 9H), 1.34 (d, J = 6.6 Hz, 6H).
 1 H NMR (acetone-d 6 , 300 MHz) δ 12.8 (s, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 0.6 Hz, 1H), 7.69 (s, 1H), 7.65 (s, 1H), 7.13 (s, 1H), 4.86 (s, 1H), 4.44-4.27 (m, 3H), 3.07-3.01 (m, 2H ), 2.71-2.66 (m, 2H), 2.20 (m, 2H), 1.95 (m, 2H), 1.61 (s, 9H), 1.49 (s, 9H), 1.34 (d, J = 6.6 Hz, 6H) .

단계 2: 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)-6- 히드록시-N-이소프로필벤즈[d]옥사졸-5-카르복스아마이드의 이트리플루오로아세트산염의 제조 Step 2: 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -4 -yl) pyridin-3-yl) -6 -hydroxy-N-isopropyl Preparation of ditrifluoroacetic acid salt of benz [d] oxazole-5-carboxamide

Figure 112012052254195-pat00069
Figure 112012052254195-pat00069

출발물질로서 4-(4-(5-(5-(이소프로필카바모일)-6-히드록시벤즈[d]옥사졸-2-일)-6-(t-부틸아미노)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(12 mg, 19 μmol)를 사용한 것을 제외하고는 실시예 16의 단계 2의 방법과 동일하게 수행하여 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-6-히드록시-N-이소프로필벤즈[d]옥사졸-5-카르복스아마이드의 이트리플루오로아세트산염을 얻었다(9 mg, 68 %).4- (4- (5- (5- (isopropylcarbamoyl) -6-hydroxybenz [d] oxazol-2-yl) -6- (t-butylamino) pyridin-3-yl as starting material 2- (2) was carried out in the same manner as in Step 2 of Example 16, except that 1-1H-pyrazol-1-yl) piperidine-1-carboxylate (12 mg, 19 μmol) was used. -Amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -6-hydroxy-N-isopropylbenz [d] oxazole- Ditrifluoroacetic acid salt of 5-carboxamide was obtained (9 mg, 68%).

1H-NMR (MeOH-d4, 300 MHz) δ 8.75 (s, 1H), 8.41 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.15 (s, 1H), 7.13 (s, 1H), 4.62 (m, 2H), 4.27 (m, 2H), 3.65 (m, 3H), 2.35 (m, 4H), 1.37 (d, J = 6.5 Hz, 6H); LC/MS m/z calcd for C24H27N7O3 (MH+) 461.52, found 462.24.
 1 H-NMR (MeOH-d 4 , 300 MHz) δ 8.75 (s, 1H), 8.41 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.15 (s, 1H), 7.13 (s, 1H), 4.62 (m, 2H), 4.27 (m, 2H), 3.65 (m, 3H), 2.35 (m, 4H), 1.37 (d, J = 6.5 Hz, 6H); LC / MS mlz calcd for C 24 H 27 N 7 O 3 (MH + ) 461.52, found 462.24.

< 실시예 32> 3-(5-히드록시-6- 메틸벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이염산염의 제조 <Example 32> 3- (5-hydroxy-6-methyl-benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- pyrazol-4 (1) Preparation of Dihydrochloride of Pyridin-2-amine

단계 1: 5- 브로모 -2- 클로로 -N-(5- 클로로 -2-히드록시-4- 메틸 페닐 ) 니코틴아마 이드의 제조 Step 1: 5- Bromo- 2- chloro- N- (5 -chloro -2-hydroxy-4- methyl Phenyl ) Nicotinamide

Figure 112012052254195-pat00070
Figure 112012052254195-pat00070

문헌(R. G. Clewley, G. G. Cross et. al. Tetrahedron. 1989, 45, 1299-1310)에 개시된 방법대로 4-클로로-3-메틸페놀로부터 4-클로로-3-메틸-2-니트로페놀을 얻었다. 4-Chloro-3-methyl-2-nitrophenol was obtained from 4-chloro-3-methylphenol according to the method disclosed in R. G. Clewley, G. G. Cross et. Al. Tetrahedron. 1989, 45, 1299-1310.

상기 4-클로로-3-메틸-2-니트로페놀(8.5 g, 45 mmol)을 에탄올(90 mL)에 녹이고 라니-니켈(0.5 mL)을 넣어 주었다. 반응혼합물을 교반하면서 하이드라진(19.7 mL)를 0 ℃에서 천천히 넣었다. 반응물을 질소 대기하에 70 ℃에서 2시간 동안 교반한 후 식혀주었다. 반응물을 셀라이트로 여과하고 여액을 감압 농축하였다. 농축물을 에틸아세테이트에 녹이고 물로 씻어주고, 유층을 황산마그네슘으로 건조하고 감압농축하였다. 농축물에 이염화탄소를 넣고 30분간 교반한 후 여과하여 고체의 목적화합물 2-아미노-4-클로로-3-메틸페놀(4.2 g, 59%)을 얻었다.The 4-chloro-3-methyl-2-nitrophenol (8.5 g, 45 mmol) was dissolved in ethanol (90 mL) and Raney-nickel (0.5 mL) was added thereto. Hydrazine (19.7 mL) was added slowly at 0 ° C. while stirring the reaction mixture. The reaction was stirred at 70 ° C. for 2 hours under a nitrogen atmosphere and then cooled. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and washed with water, and the oil layer was dried over magnesium sulfate and concentrated under reduced pressure. Carbon dichloride was added to the concentrate, followed by stirring for 30 minutes, followed by filtration to obtain the title compound 2-amino-4-chloro-3-methylphenol (4.2 g, 59%) as a solid.

1H NMR (300 MHz, CD3OD) 6.65 (s, 1H), 6.61 (s, 1H), 2.15 (s, 3H). 1 H NMR (300 MHz, CD 3 OD) 6.65 (s, 1 H), 6.61 (s, 1 H), 2.15 (s, 3H).

5-브로모-2-클로로니코티노일 클로라이드(8.5 g, 33.3 mmol)가 녹아있는 디메틸포름아마이드(34 mL) 용액에 2-아미노-4-클로로-3-메틸페놀(4.9 g)과 트리에틸아민(4.3 mL)을 얼음중탕을 이용하여 0 ℃에서 천천히 넣었다. 반응물의 온도를 실온으로 높이고 질소분위기 하에서 16시간 동안 교반하였다. 반응물을 물에 넣고 생성된 침전물을 여과하여 목적화합물 5-브로모-2-클로로-N-(5-클로로-2-히드록시-4-메틸페닐)니코틴아마이드를 얻었다. 상기 화합물을 더 이상의 정제 없이 다음 반응에 사용하였다.
2-amino-4-chloro-3-methylphenol (4.9 g) and triethyl in dimethylformamide (34 mL) solution of 5-bromo-2-chloronicotinoyl chloride (8.5 g, 33.3 mmol) Amine (4.3 mL) was added slowly at 0 ° C. using an ice bath. The temperature of the reaction was raised to room temperature and stirred for 16 hours under nitrogen atmosphere. The reaction product was poured into water, and the produced precipitate was filtered to obtain target compound 5-bromo-2-chloro-N- (5-chloro-2-hydroxy-4-methylphenyl) nicotinamide. The compound was used for the next reaction without further purification.

단계 2: 2-(5- 브로모 -2- 클로로피리딘 -3-일)-5- 클로로 -4- 메틸벤즈[d]옥사졸의 제조 Step 2: of 2- (5- bromo- 2 -chloropyridin- 3 - yl) -5 -chloro- 4- methylbenz [d] oxazole Produce

Figure 112012052254195-pat00071
Figure 112012052254195-pat00071

반응용기에 위의 정제되지 않은 5-브로모-2-클로로-N-(5-클로로-2-히드록시-4-메틸페닐)니코틴아마이드, 파라톨루엔설폰산 피리딘염(2 g) 및 크실렌(xylene, 300 mL)을 넣고, 150~170 ℃에서 36시간 동안 교반하였다. 반응물의 온도를 약 100 ℃ 로 낮추고 반응 중 생성된 타르가 흘러나오지 않게 반응물을 여과하고, 뜨거운 톨루엔으로 생성된 타르를 여러 번 씻고 여과하였다. 여액을 감압농축하고, 에틸아세테이트에 농축물을 넣고 30분 동안 교반하였다. 에틸에테르에 용해되지 않은 고체를 여과하여 연두색 고체의 목적화합물(2-(5-브로모-2-클로로피리딘-3-일)-5-클로로-4-메틸벤즈[d]옥사졸)을 얻었다(2.2 g, 18%).The crude 5-bromo-2-chloro-N- (5-chloro-2-hydroxy-4-methylphenyl) nicotinamide, paratoluenesulfonic acid pyridine salt (2 g) and xylene on the reaction vessel , 300 mL) was added and stirred at 150-170 ° C for 36 hours. 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 produced with hot toluene was washed several times and filtered. The filtrate was concentrated under reduced pressure, the concentrate was added to ethyl acetate and stirred for 30 minutes. The solid which was not dissolved in ethyl ether was filtered to obtain the title compound (2- (5-bromo-2-chloropyridin-3-yl) -5-chloro-4-methylbenz [d] oxazole) as a light green solid. (2.2 g, 18%).

1H NMR (300 MHz, CDCl3) 8.63 (d, J = 2.4 Hz, 1H), 8.60 (d, J = 2.5 Hz, 1H), 7.85 (s, 1H), 7.53 (s, 1H), 2.54 (s, 3H).
 1 H NMR (300 MHz, CDCl 3 ) 8.63 (d, J = 2.4 Hz, 1H), 8.60 (d, J = 2.5 Hz, 1H), 7.85 (s, 1H), 7.53 (s, 1H), 2.54 ( s, 3H).

단계 3: 5- 브로모 -N-t-부틸-3-(5- 클로로 -4- 메틸벤즈[d]옥사졸 -2-일)피리딘- 2-아민의 제조 Step 3: Preparation of 5 - Bromo- Nt-butyl-3- (5 -chloro- 4- methylbenz [d] oxazol - 2 -yl) pyridin- 2-amine

Figure 112012052254195-pat00072
Figure 112012052254195-pat00072

고압반응용기(sealed tube)에 2-(5-브로모-2-클로로피리딘-3-일)-5-클로로 벤즈[d]옥사졸(2.2 g), t-부틸아민(20 mL) 및 디메틸포름아마이드(20 mL)를 넣고 마개를 막아 밀봉하였다. 반응물을 50-70 ℃에서 84시간 동안 교반한 후 반응혼합물양이 5-7 mL 되도록 감압농축하였다. 농축물을 여과하고 걸러진 고체를 차가운 에틸아세테이트로 씻어주어 등황색 고체의 목적화합물(5-브로모-N-t-부틸-3-(5-클로로-4-메틸벤즈[d]옥사졸-2-일)피리딘-2-아민)을 얻었다. 여액을 농축하고, 농축물을 에틸아세테이트로 재결정하여 5-브로모-N-t-부틸-3-(5-클로로-4-메틸벤즈[d]옥사졸-2-일)피리딘-2-아민)을 더 얻었다 (1.9 g, 79%).2- (5-bromo-2-chloropyridin-3-yl) -5-chloro benz [d] oxazole (2.2 g), t-butylamine (20 mL) and dimethyl in a sealed tube Formamide (20 mL) was added and the stopper was sealed by sealing. The reaction was stirred at 50-70 ° C. for 84 hours and then concentrated under reduced pressure to give 5-7 mL of reaction mixture. The concentrate was filtered and the filtered solid was washed with cold ethyl acetate to give the title compound (5-bromo-Nt-butyl-3- (5-chloro-4-methylbenz [d] oxazol-2-yl) as an orange solid. Pyridin-2-amine). The filtrate was concentrated and the concentrate was recrystallized from ethyl acetate to give 5-bromo-Nt-butyl-3- (5-chloro-4-methylbenz [d] oxazol-2-yl) pyridin-2-amine). More (1.9 g, 79%).

1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.30 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 7.72 (s, 1H), 7.41 (s, 1H), 2.51 (s, 3H), 1.56 (s, 9H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.64 (s, 1H), 8.30 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 7.72 (s, 1H), 7.41 (s, 1 H), 2.51 (s, 3 H), 1.56 (s, 9 H).

단계 4: t-부틸-4-(4-(6-(t- 부틸아미노 )-5-(5- 클로로 -4- 메틸 벤즈[d]옥사졸 - 2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트의 제조 Step 4: t-butyl-4- (4- (6- (t- butylamino ) -5- (5 -chloro- 4- methyl Preparation of benz [d] oxazol - 2 -yl ) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00073
Figure 112012052254195-pat00073

반응용기에 5-브로모-N-t-부틸-3-(5-클로로-4-메틸벤즈[d]옥사졸-2-일)피리딘-2-아민(1.9 g, 4.8 mmol), t-부틸-4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-피라졸-1-일)-피페리딘-1-카복실레이트(1.3 g), Pd(Ph3P)2Cl2(169 mg) 및 1,4-다이옥산(16 mL)을 넣고 질소분위기 및 실온에서 30분 동안 교반하였다. 반응물에 1 M 탄산나트륨 수용액(14.4 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(t-부틸-4-(4-(6-(t-부틸아미노)-5-(5-클로로벤즈-4-메틸[d]옥사졸-2-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트)을 얻었다(1.6 g, 60%). 5-bromo-Nt-butyl-3- (5-chloro-4-methylbenz [d] oxazol-2-yl) pyridin-2-amine (1.9 g, 4.8 mmol), t-butyl- in the reaction vessel. 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) -piperidine-1-carboxyl Rate (1.3 g), Pd (Ph 3 P) 2 Cl 2 (169 mg), and 1,4-dioxane (16 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 (14.4 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 (t-butyl-4- (4- (6- (t-butylamino) -5- (5-chlorobenz-4-methyl). [d] oxazol-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate) was obtained (1.6 g, 60%).

1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 8.44 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 2.1 Hz, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 4.40-4.20 (m, 3H), 3.00-2.90 (m, 2H), 2.52 (s, 3H), 2.21-2.17 (m, 2H), 2.05-1.94 (m, 2H), 1.60 (s, 9H), 1.49 (s, 9H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.63 (s, 1H), 8.44 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 2.1 Hz, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 4.40-4.20 (m, 3H), 3.00-2.90 (m, 2H), 2.52 (s, 3H), 2.21-2.17 (m , 2H), 2.05-1.94 (m, 2H), 1.60 (s, 9H), 1.49 (s, 9H).

단계 5: t-부틸-4-(4-(6-(t- 부틸아미노 )-5-(5-히드록시-6- 메틸벤즈[d]옥사졸 -2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트의 제조 Step 5: t-butyl-4- (4- (6- (t- butylamino ) -5- (5-hydroxy-6- methylbenz [d] oxazol- 2 -yl ) pyridin-3-yl) Preparation of -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00074
Figure 112012052254195-pat00074

고압반응용기에 t-부틸-4-(4-(6-(t-부틸아미노)-5-(5-클로로-6- 메틸벤즈[d]옥사졸-2-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트(1.47 g, 2.59 mmol), 수산화칼륨(436 mg), 트리스(디벤질리딘아세톤)디팔라듐(95 mg), 2-다이-t-부틸포스피노-2',4,'6'-트리이소프로필바이페닐(176 mg) 및 증류수/1,4-다이옥산(1/1, 8.6 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 컬럼 크로마토그래피로 정제하여 연두색 고체의 목적화합물(t-부틸-4-(4-(6-(t-부틸아미노)-5-(5-히드록시-6-메틸벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트)을 얻었다(960 mg, 68%).T-butyl-4- (4- (6- (t-butylamino) -5- (5-chloro-6-methylbenz [d] oxazol-2-yl) -1H-pyrazole- in a high pressure reaction vessel. 1-yl) piperidine-1-carboxylate (1.47 g, 2.59 mmol), potassium hydroxide (436 mg), tris (dibenzylideneacetone) dipalladium (95 mg), 2-di-t-butylphosphino -2 ', 4,' 6'-triisopropylbiphenyl (176 mg) and distilled water / 1,4-dioxane (1/1, 8.6 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 (t-butyl-4- (4- (6- (t-butylamino) -5- (5-hydroxy-6-methylbenz [d] oxazol-2-yl) pyridin-3-yl)- 1H-pyrazol-1-yl) piperidine-1-carboxylate) was obtained (960 mg, 68%).

1H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.32 (s, 1H), 7.11 (s, 1H), 4.33-4.27 (m, 3H), 2.92 (t, J = 12.8 Hz, 2H), 2.39 (s, 3H), 2.25-2.15 (m, 2H), 2.10-1.85 (m, 2H), 1.60 (s, 9H), 1.49 (s, 9H).
 1 H NMR (300 MHz, CDCl 3 ) δ 8.67 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.32 (s, 1H), 7.11 (s, 1H), 4.33-4.27 (m, 3H), 2.92 (t, J = 12.8 Hz, 2H), 2.39 (s, 3H), 2.25- 2.15 (m, 2H), 2.10-1.85 (m, 2H), 1.60 (s, 9H), 1.49 (s, 9H).

단계 6: 3-(5-히드록시-6- 메틸벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)- 1H-피라졸-4-일)피리딘-2-아민의 이염산염의 제조 Step 6: 3- (5-hydroxy-6- methylbenz [d] oxazol- 2 -yl ) -5- (1- (piperidin-4-yl) -1H-pyrazol -4 -yl) Preparation of Dihydrochloride of Pyridin-2-amine

Figure 112012052254195-pat00075
Figure 112012052254195-pat00075

반응용기에 t-부틸-4-(4-(6-(t-부틸아미노)-5-(5-히드록시-6-메틸벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트(960 mg, 1.76 mmol) 및 트리플루오로아세트산(6 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-히드록시-6-메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산염)을 얻었다.T-butyl-4- (4- (6- (t-butylamino) -5- (5-hydroxy-6-methylbenz [d] oxazol-2-yl) pyridin-3-yl) in the reaction vessel -1H-pyrazol-1-yl) piperidine-1-carboxylate (960 mg, 1.76 mmol) and trifluoroacetic acid (6 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 obtain the target compound as a light green solid (3- (5-hydroxy-6-methylbenz [d] oxazol-2-yl) -5- (1- ( Ditrifluoroacetic acid of piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine).

상기 3-(5-히드록시-6-메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산염을 메탄올에 녹이고 4N-HCl 다이옥산 용액을 넣어주고 5분간 교반한 후 농축하였다. 농축물을 다시 메탄올에 녹이고 4N-HCl 다이옥산 용액을 넣어주고 5분간 교반한 후 농축하였다. 농축물에 에테르를 넣고 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 이염산염)을 얻었다(596 mg, 75%).3- (5-hydroxy-6-methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1 H-pyrazol-4-yl) pyridine- Ditrifluoroacetic acid salt of 2-amine was dissolved in methanol, 4N-HCl dioxane solution was added thereto, stirred for 5 minutes, and concentrated. The concentrate was dissolved in methanol again, 4N-HCl dioxane solution was added thereto, stirred for 5 minutes, and concentrated. Ether was added to the concentrate, followed by stirring, followed by filtration to give the title compound as a light green solid (3- (5-ethoxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) Dihydrochloride of -1H-pyrazol-4-yl) pyridin-2-amine) (596 mg, 75%).

1H NMR (300 MHz, CD3OD) δ 9.01 (d, J = 2.2 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.37 (s, 1H), 8.07 (s, 1H), 7.51 (s, 1H), 7.19 (s, 1H), 3.68-3.59 (m, 3H), 3.40-3.24 (m, 2H), 2.42-2.35 (m, 7H); LC-MS (CI) m/z calcd for C21H23N6O2(MH+) 391.2, found 391.2.
 1 H NMR (300 MHz, CD 3 OD) δ 9.01 (d, J = 2.2 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.37 (s, 1H), 8.07 (s, 1H), 7.51 (s, 1H), 7.19 (s, 1H), 3.68-3.59 (m, 3H), 3.40-3.24 (m, 2H), 2.42-2.35 (m, 7H); LC-MS (CI) m / z calcd for C 21 H 23 N 6 O 2 (MH + ) 391.2, found 391.2.

< 실시예 33> 3-(6-히드록시-5- 메틸벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이염산염의 제조 <Example 33> 3- (6-hydroxy-5-methyl-benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- pyrazol-4 (1) Preparation of Dihydrochloride of Pyridin-2-amine

Figure 112012052254195-pat00076
Figure 112012052254195-pat00076

4-클로로-3-메틸페놀 대신 3-클로로-4-메틸페놀을 사용한 것을 제외하고는 실시예 32의 단계 1 내지 단계 6과 동일한 방법으로 수행하여 연두색 고체의 목적화합물(3-(6-히드록시-5-메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이염산염)을 얻었다.Except for using 3-chloro-4-methylphenol instead of 4-chloro-3-methylphenol, was carried out in the same manner as in Step 1 to Step 6 of Example 32 to obtain the target compound (3- (6-hydride) Dioxy-5-methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine dihydrochloride) Got.

1H NMR (300 MHz, CD3OD) δ 8.95 (d, J = 2.1 Hz, 1H), 8.36 (s, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.19 (s, 1H), 7.54 (s, 1H), 7.10 (s, 1H), 3.68-3.59 (m, 3H), 3.40-3.24 (m, 2H), 2.42-2.35 (m, 7H); GC-MS (EI) m/z calcd for C21H22N6O2(M+) 390.2, found 390.1.
 1 H NMR (300 MHz, CD 3 OD) δ 8.95 (d, J = 2.1 Hz, 1H), 8.36 (s, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.19 (s, 1H), 7.54 (s, 1 H), 7.10 (s, 1 H), 3.68-3.59 (m, 3H), 3.40-3.24 (m, 2H), 2.42-2.35 (m, 7H); GC-MS (EI) m / z calcd for C 21 H 22 N 6 O 2 (M + ) 390.2, found 390.1.

< 실시예 34> 3-(5-히드록시-6- 에틸벤즈[d]옥사졸 -2-일)-5-(1-( 피페리 -4-일)-1H-피라졸-4-일)피리딘-2-아민의 이염산염의 제조 <Example 34> 3- (5-hydroxy-6-ethyl-benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) - 1H- pyrazol-4-yl Preparation of Dihydrochloride of Pyridin-2-amine

Figure 112012052254195-pat00077
Figure 112012052254195-pat00077

4-클로로-3-메틸페놀 대신 4-클로로-3-에틸페놀을 사용한 것을 제외하고는 실시예 32의 단계 1 내지 단계 6와 동일한 방법으로 수행하여 연두색 고체의 목적화합물(3-(5-히드록시-6-에틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이염산염)을 얻었다. Except for using 4-chloro-3-ethylphenol instead of 4-chloro-3-methylphenol, the procedure was carried out in the same manner as in Step 1 to Step 6 of Example 32 to obtain the target compound as a pale green solid (3- (5-hydrate). Dioxychloride of oxy-6-ethylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine) Got.

1H NMR (300 MHz, CD3OD) δ 9.00 (d, J = 2.1 Hz, 1H), 8.38 (s, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.05 (s, 1H), 7.49 (s, 1H), 7.17 (s, 1H), 4.68-4.60 (m, 1H), 3.74-3.55 (m, 2H), 3.40-3.20 (m, 2H), 2.78 (q, J = 7.4 Hz, 2H), 2.40-2.32 (m, 4H), 1.27 (t, J= 7.5 Hz, 3H).
 1 H NMR (300 MHz, CD 3 OD) δ 9.00 (d, J = 2.1 Hz, 1H), 8.38 (s, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.05 (s, 1H), 7.49 (s, 1H), 7.17 (s, 1H), 4.68-4.60 (m, 1H), 3.74-3.55 (m, 2H), 3.40-3.20 (m, 2H), 2.78 (q, J = 7.4 Hz, 2H), 2.40-2.32 (m, 4H), 1.27 (t, J = 7.5 Hz, 3H).

< 실시예 35> 3-(3,5-디메틸-6- 히드록시벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이염산염의 제조 <Example 35> 3- (3, 5-dimethyl-6-hydroxy-benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- pyrazol- Preparation of 4-yl) pyridin-2-amine dihydrochloride

Figure 112012052254195-pat00078
Figure 112012052254195-pat00078

4-클로로-3-메틸페놀 대신 4-클로로-3,5-디메틸페놀을 사용한 것을 제외하고는 실시예 32의 단계 1 내지 단계 6과 동일한 방법으로 수행하여 연두색 고체의 목적화합물(3-(3,6-디메틸-5-히드록시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이염산염)을 얻었다.Except for using 4-chloro-3,5-dimethylphenol instead of 4-chloro-3-methylphenol, was carried out in the same manner as in Step 1 to Step 6 of Example 32 to obtain the target compound as a light green solid , 6-dimethyl-5-hydroxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine Dihydrochloride) was obtained.

1H NMR (300 MHz, D2O) δ 8.06 (d, J = 2.1 Hz, 1H), 7.98 (s, 1H), 7.82 (d, J = 2.1Hz, 1H), 7.69 (s, 1H), 6.99 (s, 1H), 4.65-4.45 (m, 1H), 3.58 (d, J= 13.1 Hz, 2H), 3.24-3.15 (m, 2H), 2.45-2.10 (m, 4H), 2.08 (s, 3H).
 1 H NMR (300 MHz, D 2 O) δ 8.06 (d, J = 2.1 Hz, 1H), 7.98 (s, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.69 (s, 1H), 6.99 (s, 1H), 4.65-4.45 (m, 1H), 3.58 (d, J = 13.1 Hz, 2H), 3.24-3.15 (m, 2H), 2.45-2.10 (m, 4H), 2.08 (s, 3H).

< 실시예 36> 3-(6-히드록시-7- 메틸벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이염산염의 제조 <Example 36> 3- (6-hydroxy-7-methyl-benz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H- pyrazol-4 (1) Preparation of Dihydrochloride of Pyridin-2-amine

단계 1: 3-(Step 1: 3- ( 벤질옥시Benzyloxy )-2-)-2- 메틸methyl -6-니트로페놀의 제조Preparation of -6-nitrophenol

Figure 112012052254195-pat00079
Figure 112012052254195-pat00079

질산(0.6 mL, 60% 수용액)과 아세틱앤하이드리드(1.0 mL) 혼합물에 2-메틸레조시놀(1.0 g, 8.1 mmol)을 0 ℃에서 강하게 교반하면서 천천히 넣었다. 0 ℃에서 1시간 동안 교반하였다. 반응물을 물에 쏟아 붇고 이염화탄소로 여러 번 추출하였다. 유층을 모아 무수 황산마그네슘으로 건조하고 농축하였다. 농축물은 컬럼 크로마토그래피로 정제하여 고체인 목적화합물(2-메틸-4-니트로벤젠-1,3-디올)(500 mg, 37%)을 얻었다.To a mixture of nitric acid (0.6 mL, 60% aqueous solution) and acetic & hydride (1.0 mL) was slowly added 2-methylresorcinol (1.0 g, 8.1 mmol) with vigorous stirring at 0 ° C. Stir at 0 ° C. for 1 h. The reaction was poured into water and extracted several times with carbon dichloride. The oil layers were combined, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by column chromatography to give the title compound (2-methyl-4-nitrobenzene-1,3-diol) (500 mg, 37%) as a solid.

1H NMR (300 MHz, CDCl3) δ 11.14 (s, 1H), 7.99 (d, J = 9.3 Hz, 1H), 7.43-7.35 (m, 5H), 6.58 (d, J = 9.6 Hz, 1H), 5.20 (s, 2H), 2.22 (s, 3H); GC-MS (EI) m/z calcd for C14H13NO4(M+) 259.1, found 259.1.
1 H NMR (300 MHz, CDCl 3 ) δ 11.14 (s, 1H), 7.99 (d, J = 9.3 Hz, 1H), 7.43-7.35 (m, 5H), 6.58 (d, J = 9.6 Hz, 1H) , 5.20 (s, 2 H), 2.22 (s, 3 H); GC-MS (EI) m / z calcd for C 14 H 13 NO 4 (M + ) 259.1, found 259.1.

2-메틸-4-니트로벤젠-1,3-디올(3.7 g, 21.9 mmol)을 아세톤(50 mL)에 녹이고 벤질브로마이드(2.6 mL)와 탄산칼륨(1.5 g)을 넣었다. 반응혼합물을 48시간 동안 끓인 후 식히고 감압 농축하였다. 농축물에 물을 넣고 이염화탄소로 여러번 추출하였다. 유층을 황산마그네슘으로 건조하고 감압농축하였다. 농축물에 에테르를 넣고 1시간 동안 교반한 후 여과하여 고체의 목적화합물(3-(벤질옥시)-2-메틸-6- 니트로페놀)(3.4 g, 60%)을 얻었다.2-Methyl-4-nitrobenzene-1,3-diol (3.7 g, 21.9 mmol) was dissolved in acetone (50 mL), and benzyl bromide (2.6 mL) and potassium carbonate (1.5 g) were added thereto. The reaction mixture was boiled for 48 hours, cooled, and concentrated under reduced pressure. Water was added to the concentrate and extracted several times with carbon dichloride. The oil layer was dried over magnesium sulfate and concentrated under reduced pressure. Ether was added to the concentrate, followed by stirring for 1 hour, followed by filtration to obtain a solid target compound (3- (benzyloxy) -2-methyl-6-nitrophenol) (3.4 g, 60%).

1H NMR (300 MHz, CDCl3) δ 7.45-7.30 (m, 5H), 6.68 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.01 (s, 2H), 2.05 (s, 3H).
 1 H NMR (300 MHz, CDCl 3 ) δ 7.45-7.30 (m, 5H), 6.68 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.01 (s, 2H) , 2.05 (s, 3 H).

단계 2: t-부틸-4-(4-(6-(t- 부틸아미노 )-5-(6- 벤질옥시 -7- 메틸벤즈[d]옥사졸 -2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트의 제조 Step 2: t-butyl-4- (4- (6- (t- butylamino ) -5- (6- benzyloxy- 7 - methylbenz [d] oxazol- 2 -yl ) pyridin-3-yl) Preparation of -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00080
Figure 112012052254195-pat00080

실시예 32의 단계 3에서 사용한 4-클로로-3-메틸-2-니트로페놀 대신 3-(벤질옥시)-2-메틸-6-니트로페놀을 사용한 것을 제외하고는 실시예 32의 단계 1 내지 단계 4과 동일한 방법으로 수행하여 연두색 고체의 목적화합물(t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-벤질옥시-7-메틸벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트)을 50% 순도로 얻었으며 더 이상의 정제 없이 다음 반응에 사용하였다.
Example 1-Step 1 of Example 32, except that 3- (benzyloxy) -2-methyl-6-nitrophenol was used instead of 4-chloro-3-methyl-2-nitrophenol used in Step 3 of Example 32. The target compound as a light green solid (t-butyl-4- (4- (6- (t-butylamino) -5- (6-benzyloxy-7-methylbenz [d] oxazole-) 2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate) was obtained in 50% purity and used in the next reaction without further purification.

단계 3: t-부틸-4-(4-(6-(t- 부틸아미노 )-5-(6-히드록시-7- 메틸벤즈[d]옥사졸 -2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트의 제조 Step 3: t-butyl-4- (4- (6- (t- butylamino ) -5- (6-hydroxy-7- methylbenz [d] oxazol- 2 -yl ) pyridin-3-yl) Preparation of -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00081
Figure 112012052254195-pat00081

t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-벤질옥시-7-메틸벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트(150 mg)를 테트라하이드로퓨란과 메탄올 혼합용액(2.0 mL, 2/1)에 녹이고 Pd/C(52 mg)을 넣었다. 반응혼합물을 수소대기하에서 24시간 동안 교반한 후 셀라이트로 여과하였다. 여액을 농축하고, 농축물에 메탄올을 넣고 30분간 교반한 후 여과하여 80% 순도의 연두색 고체의 목적화합물(t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-벤질옥시-7-메틸벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트)(30 mg)을 얻었다. 더 이상의 정제 없이 다음 반응에 사용하였다.
t-butyl-4- (4- (6- (t-butylamino) -5- (6-benzyloxy-7-methylbenz [d] oxazol-2-yl) pyridin-3-yl) -1H- Pyrazol-1-yl) piperidine-1-carboxylate (150 mg) was dissolved in a mixture of tetrahydrofuran and methanol (2.0 mL, 2/1) and Pd / C (52 mg) was added thereto. The reaction mixture was stirred under hydrogen atmosphere for 24 hours and then filtered through celite. The filtrate was concentrated, methanol was added to the concentrate, the mixture was stirred for 30 minutes, and then filtered to give the target compound as a pale green solid of 80% purity (t-butyl-4- (4- (6- (t-butylamino) -5- ( 6-benzyloxy-7-methylbenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate) (30 mg) was obtained. . Used for the next reaction without further purification.

단계 4: 3-(6-히드록시-7- 메틸벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)- 1H-피라졸-4-일)피리딘-2-아민의 이염산염의 제조 Step 4: 3- (6-hydroxy-7- methylbenz [d] oxazol- 2 -yl ) -5- (1- (piperidin-4-yl) -1H-pyrazol -4 -yl) Preparation of Dihydrochloride of Pyridin-2-amine

Figure 112012052254195-pat00082
Figure 112012052254195-pat00082

t-부틸-4-(4-(6-(t-부틸아미노)-5-(5-히드록시-6-메틸벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트 대신 t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-벤질옥시-7-메틸벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카복실레이트를 사용하는 것을 제외하고는 실시예 32의 단계 6과 동일한 방법으로 수행하여 연두색 고체의 목적화합물(3-(6-히드록시-7-메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이염산염)을 얻었다.t-butyl-4- (4- (6- (t-butylamino) -5- (5-hydroxy-6-methylbenz [d] oxazol-2-yl) pyridin-3-yl) -1H- T-butyl-4- (4- (6- (t-butylamino) -5- (6-benzyloxy-7-methylbenz [d] instead of pyrazol-1-yl) piperidine-1-carboxylate Except that oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate was used in the same manner as in step 6 of Example 32, Target compound of light green solid (3- (6-hydroxy-7-methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazole-4 -Yl) dihydrochloride of pyridin-2-amine).

1H NMR (300 MHz, D2O) δ 7.97 (d, J = 1.9 Hz, 1H), 7.86 (s, 1H), 7.64 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 4.60-4.40 (m, 1H), 3.57 (d, J = 13.5 Hz, 2H), 3.30-3.10 (m, 2H), 2.45-2.10 (m, 4H), 1.91 (s, 3H); LC-MS (CI) m/z calcd for C21H23N6O2 (MH+) 391.2, found 391.1.
 1 H NMR (300 MHz, D 2 O) δ 7.97 (d, J = 1.9 Hz, 1H), 7.86 (s, 1H), 7.64 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 4.60-4.40 (m, 1H), 3.57 (d, J = 13.5 Hz, 2H), 3.30-3.10 (m , 2H), 2.45-2.10 (m, 4H), 1.91 (s, 3H); LC-MS (CI) m / z calcd for C 21 H 23 N 6 O 2 (MH + ) 391.2, found 391.1.

< 실시예 37> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)-7-(1H-인돌-6-일)벤즈[d]옥사졸-6-올의 이트리플루오로아세트산염의 제조 <Example 37> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) -7- (1H- indol- Preparation of 6-yl) benz [d] oxazol-6-ol ditrifluoroacetate

단계 1: t-부틸-4-(4-(6-(t- 부틸아미노 )-5-(7-(1-( 테트라히드로 -2H-피란-2- 일)-1H-인돌-6-일)-6-히드록시벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t-butyl-4- (4- (6- (t- butylamino ) -5- (7- (1- ( tetrahydro- 2H-pyran-2- yl) -1H-indol-6-yl ) -6-hydroxybenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00083
Figure 112012052254195-pat00083

반응물로서 6-브로모(테트라히드로-2H-피란-2-일)-1H-인돌을 사용하는 것을 제외하고는 실시예 36의 단계 2와 동일한 방법으로 수행하여 목적화합물을 제조하였다(11 mg, 39 %).A target compound was prepared in the same manner as Step 2 of Example 36, except that 6-bromo (tetrahydro-2H-pyran-2-yl) -1H-indole was used as a reactant (11 mg, 39%).

1H NMR (MeOH-d4, 300 MHz) δ 8.65 (br s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 8.3, 0.6 Hz, 1H),7.91 (m, 1H), 7.64 (d, J = 0.6 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.53 (s, 1H), 7.44 (dd, J = 8.3, 1.3 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 5.35 (m, 1H), 4.28 (m, 3H), 3.97 (m, 1H), 3.69 (m, 1H), 2.92 (m, 2H), 2.58 (m, 1H), 2.19 (m, 2H), 1.98 (m, 2H), 1.60 (s, 9H), 1.48 (s, 9H).
1 H NMR (MeOH-d 4 , 300 MHz) δ 8.65 (br s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 8.07 (d, J = 2.4 Hz, 1H ), 7.95 (dd, J = 8.3, 0.6 Hz, 1H), 7.71 (m, 1H), 7.64 (d, J = 0.6 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.53 (s , 1H), 7.44 (dd, J = 8.3, 1.3 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 5.35 (m, 1H), 4.28 (m, 3H), 3.97 (m, 1H) , 3.69 (m, 1H), 2.92 (m, 2H), 2.58 (m, 1H), 2.19 (m, 2H), 1.98 (m, 2H), 1.60 (s, 9H), 1.48 (s, 9H).

단계 2: 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)-7- (1H-인돌-6-일)벤즈[d]옥사졸-6-올의 이트리플루오로아세트산염의 제조 Step 2: 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -4 -yl) pyridin-3-yl) -7- (1H-indole-6- I) Preparation of ditrifluoroacetic acid salt of benz [d] oxazol-6-ol

Figure 112012052254195-pat00084
Figure 112012052254195-pat00084

반응물로서 t-부틸-4-(4-(6-(t-부틸아미노)-5-(7-(1-(테트라히드로-2H-피란-2-일)-1H-인돌-6-일)-6-히드록시벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 사용하는 것을 제외하고는 실시예 36의 단계 3과 동일한 방법으로 수행하여 목적화합물을 얻었다(8 mg, 28 %).T-butyl-4- (4- (6- (t-butylamino) -5- (7- (1- (tetrahydro-2H-pyran-2-yl) -1H-indol-6-yl) as reactant Example except that 6-hydroxybenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate is used The target compound was obtained by the same method as the step 3 of 36 (8 mg, 28%).

1H-NMR (MeOH-d4, 300 MHz) δ 8.55 (d, J = 2.2 Hz,1H), 8.30 (d, J = 2.2 Hz, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.92 (dd, J = 8.5, 0.7 Hz, 1H), 7.87 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.57 (dd, J = 8.5, 1.3 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 4.63 (m, 1H), 3.53 (m, 2H), 3.29 (m, 2H), 2.39 (m, 4H): LC-MS calcd for C32H25F6N7O4 (MH+) 492.2 found 493.34.
 1 H-NMR (MeOH-d 4 , 300 MHz) δ 8.55 (d, J = 2.2 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.13 (s, 1H), 8.06 (s, 1H ), 7.96 (s, 1H), 7.92 (dd, J = 8.5, 0.7 Hz, 1H), 7.87 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.57 (dd, J = 8.5, 1.3 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 4.63 (m, 1H), 3.53 (m, 2H), 3.29 (m, 2H), 2.39 (m, 4H): LC-MS calcd for C 32 H 25 F 6 N 7 O 4 (MH + ) 492.2 found 493.34.

< 실시예 38> 3-(7-(1H-인돌-6-일)-6- 메톡시벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 <Example 38> 3- (7- (1H- indol-6-yl) -6-methoxy-benz [d] oxazol-2-yl) -5- (l- (l naphthyridin-4-yl) - Preparation of ditrifluoroacetic acid salt of 1H-pyrazol-4-yl) pyridin-2-amine

단계 1: t-부틸-4-(4-(6-(t- 부틸아미노 )-5-(7-(1-( 테트라히드로 -2H-피란-2- 일)-1H-인돌-6-일)-6-메톡시벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t-butyl-4- (4- (6- (t- butylamino ) -5- (7- (1- ( tetrahydro- 2H-pyran-2- yl) -1H-indol-6-yl ) -6-methoxybenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00085
Figure 112012052254195-pat00085

t-부틸-4-(4-(6-(t-부틸아미노)-5-(7-(1-(테트라히드로-2H-피란-2-일)-1H-인돌-6-일)-6-메톡시벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(10 mg, 13 μM), 요오드화메탄(4 g , 26 μmol) 및 탄산칼륨(9 mg, 52 μmol)을 N,N-디메틸포름아마이드(0.5 mL)에 가하고, 13시간 상온에서 교반하였다. 반응이 종결되면, 실시예 27의 단계 1의 방법과 동일하게 수행하여 목적화합물을 얻었다(8 mg, 80 %).t-butyl-4- (4- (6- (t-butylamino) -5- (7- (1- (tetrahydro-2H-pyran-2-yl) -1H-indol-6-yl) -6 -Methoxybenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (10 mg, 13 μM), methane iodide ( 4 g, 26 μmol) and potassium carbonate (9 mg, 52 μmol) were added to N, N-dimethylformamide (0.5 mL) and stirred at room temperature for 13 hours. When the reaction was terminated, it was carried out in the same manner as in the step 1 of Example 27 to obtain the target compound (8 mg, 80%).

1H NMR (MeOH-d4, 300 MHz) δ 8.65 (br s, 1H), 8.39 (d, J = 2.5 Hz, 1H), 8.13 (d, J = 2.5 Hz,1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.83 (dd, J = 8.4, 0.7 Hz, 1H), 7.69 (m, 2H), 7.52 (m, 2H), 7.01 (d, J = 8.8 Hz, 1H), 5.72 (dd, J = 9.3, 2.5 Hz, 1H), 5.61 (m, 1H), 4.37-4.15 (m, 3H), 3.97-3.84 (m, 3H), 3.97-3.84 (m, 1H), 3.61 (m, 1H), 2.89 (m, 2H), 2.55 (m, 1H), 2.21 (m, 2H), 1.98 (m, 2H), 1.60 (s, 9H), 1.50 (s, 9H).
 1 H NMR (MeOH-d 4 , 300 MHz) δ 8.65 (br s, 1H), 8.39 (d, J = 2.5 Hz, 1H), 8.13 (d, J = 2.5 Hz, 1H), 8.08 (s, 1H ), 7.98 (s, 1H), 7.83 (dd, J = 8.4, 0.7 Hz, 1H), 7.69 (m, 2H), 7.52 (m, 2H), 7.01 (d, J = 8.8 Hz, 1H), 5.72 (dd, J = 9.3, 2.5 Hz, 1H), 5.61 (m, 1H), 4.37-4.15 (m, 3H), 3.97-3.84 (m, 3H), 3.97-3.84 (m, 1H), 3.61 (m , 1H), 2.89 (m, 2H), 2.55 (m, 1H), 2.21 (m, 2H), 1.98 (m, 2H), 1.60 (s, 9H), 1.50 (s, 9H).

단계 2: 3-(7-(1H-인돌-6-일)-6- 메톡시벤즈[d]옥사졸 -2-일)-5-(1-(피페리딘- 4-일)-1H-피라졸-4-일)피리딘-2-아민의 이트리플루오로아세트산염의 제조 Step 2: 3- (7- (1H-indol-6-yl) -6 -methoxybenz [d] oxazol- 2 -yl ) -5- (1- (piperidin- 4-yl) -1H Preparation of Ditrifluoroacetic Acid of -pyrazol-4-yl) pyridin-2-amine

Figure 112012052254195-pat00086
Figure 112012052254195-pat00086

반응물로서 t-부틸-4-(4-(6-(t-부틸아미노)-5-(7-(1-(테트라히드로-2H-피란-2-일)-1H-인돌-6-일)-6-메톡시벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 사용하는 것을 제외하고는 실시예 36의 단계 3과 동일한 방법으로 수행하여 목적화합물을 얻었다(5 mg, 65 %).T-butyl-4- (4- (6- (t-butylamino) -5- (7- (1- (tetrahydro-2H-pyran-2-yl) -1H-indol-6-yl) as reactant Example except that 6-methoxybenz [d] oxazol-2-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate is used The target compound was obtained by the same method as Step 3 of 36 (5 mg, 65%).

1H-NMR (MeOH-d4, 300 MHz) δ 8.65 (br s, 1H), 8.39 (d, J = 2.5 Hz, 1H), 8.13 (d, J = 2.5 Hz, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.83 (dd, J = 8.4, 0.7 Hz, 1H), 7.69 (m, 2H), 7.52 (m, 2H), 7.01 (d, J = 8.8 Hz, 1H), 5.72 (dd, J = 9.3, 2.5 Hz, 1H), 5.61 (m, 1H), 4.37-4.15 (m, 3H), 3.97-3.84 (m, 3H), 3.97-3.84 (m, 1H), 3.61 (m, 1H), 2.89 (m, 2H), 2.55 (m, 1H), 2.21 (m, 2H), 1.98 (m, 2H), 1.60 (s, 9H), 1.50 (s, 9H).
 1 H-NMR (MeOH-d 4 , 300 MHz) δ 8.65 (br s, 1H), 8.39 (d, J = 2.5 Hz, 1H), 8.13 (d, J = 2.5 Hz, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.83 (dd, J = 8.4, 0.7 Hz, 1H), 7.69 (m, 2H), 7.52 (m, 2H), 7.01 (d, J = 8.8 Hz, 1H), 5.72 (dd, J = 9.3, 2.5 Hz, 1H), 5.61 (m, 1H), 4.37-4.15 (m, 3H), 3.97-3.84 (m, 3H), 3.97-3.84 (m, 1H), 3.61 ( m, 1H), 2.89 (m, 2H), 2.55 (m, 1H), 2.21 (m, 2H), 1.98 (m, 2H), 1.60 (s, 9H), 1.50 (s, 9H).

< 실시예 39> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)-7-페닐벤즈[d]옥사졸-6-올의 이트리플루오로아세트산염의 제조 <Example 39> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) -7-phenyl-benz [d] Preparation of Ditrifluoroacetic Acid of Oxazole-6-ol

단계 1: t-부틸-4-(4-(6-(t- 부틸아미노 )-5-(6-히드록시-7- 페닐벤즈[d]옥사졸 -2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t-butyl-4- (4- (6- (t- butylamino ) -5- (6-hydroxy-7- phenylbenz [d] oxazol- 2 -yl ) pyridin-3-yl) Preparation of -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00087
Figure 112012052254195-pat00087

반응물로서 브로모벤젠을 사용하는 것을 제외하고는 실시예 36의 단계 2와 동일한 방법으로 수행하여 목적화합물을 제조하였다(13 mg, 15 %).A target compound was prepared in the same manner as Step 2 of Example 36, except that bromobenzene was used as a reactant (13 mg, 15%).

1H-NMR(300 MHz, CDCl3) δ 8.65 (br s, 1H), 8.09 (s, 1H), 7.71-7.48 (m, 6H), 7.15 (d, J = 8.8 Hz, 1H), 5.42 (s, 1H), 4.42-4.25 (m, 3H), 2.96 (m, 1H), 2.18 (m, 2H), 1.95 (m, 2H), 1.60 (s, 9H), 1.50 (s, 9H).
 1 H-NMR (300 MHz, CDCl 3 ) δ 8.65 (br s, 1H), 8.09 (s, 1H), 7.71-7.48 (m, 6H), 7.15 (d, J = 8.8 Hz, 1H), 5.42 ( s, 1H), 4.42-4.25 (m, 3H), 2.96 (m, 1H), 2.18 (m, 2H), 1.95 (m, 2H), 1.60 (s, 9H), 1.50 (s, 9H).

단계 2: 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)-7- 페닐벤즈[d]옥사졸-6-올의 이트리플루오로아세트산염의 제조 Step 2: 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -4 -yl) pyridin-3-yl) -7- phenylbenz [d] oxazole Preparation of 2-triol ditrifluoroacetate

Figure 112012052254195-pat00088
Figure 112012052254195-pat00088

반응물로서 t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-히드록시-7-페닐벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 사용하는 것을 제외하고는 실시예 36의 단계 3과 동일한 방법으로 수행하여 목적화합물을 얻었다(4 mg, 26 %).T-butyl-4- (4- (6- (t-butylamino) -5- (6-hydroxy-7-phenylbenz [d] oxazol-2-yl) pyridin-3-yl)-as reactant Except for using 1H-pyrazol-1-yl) piperidine-1-carboxylate in the same manner as in Step 3 of Example 36 to obtain the target compound (4 mg, 26%).

1H-NMR (MeOH-d4, 300 MHz) δ 8.48 (d, J = 2.2 Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 0.9 Hz, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.77 (dd, J = 8.5, 1.4Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.60 (m, 2H), 7.05 (d, J = 8.6 Hz, 1H), 4.67-4.51 (m, 3H), 3.65-3.54 (m, 2H), 3.31-3.21 (m, 2H), 2.44-2.25 (m, 4H): LC-MS calcd for C26H24N6O2 (MH+) 452.51 found 453.18.
 1 H-NMR (MeOH-d 4 , 300 MHz) δ 8.48 (d, J = 2.2 Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 0.9 Hz, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.77 (dd, J = 8.5, 1.4 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.60 (m, 2H), 7.05 (d, J = 8.6 Hz, 1H), 4.67-4.51 (m, 3H), 3.65-3.54 (m, 2H), 3.31-3.21 (m, 2H), 2.44-2.25 (m, 4H): LC-MS calcd for C 26 H 24 N 6 O 2 (MH + ) 452.51 found 453.18.

< 실시예 40> 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)-7-(4-메톡시페닐)벤즈[d]옥사졸-6-올의 이트리플루오로아세트산염의 제조 <Example 40> 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol-4-yl) pyridin-3-yl) -7- (4-methoxy Preparation of Ditrifluoroacetic Acid of Phenyl) benz [d] oxazol-6-ol

단계 1: t-부틸-4-(4-(6-(t- 부틸아미노 )-5-(6-히드록시-7-(4- 메톡시페닐 ) 벤 즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조 Step 1: t- butyl -4- (4- (6- (t- butyl) -5- (6-hydroxy-7 (4-methoxyphenyl) Ben's [d] oxazol-2-yl Preparation of Pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate

Figure 112012052254195-pat00089
Figure 112012052254195-pat00089

실시예 37의 단계 1과 동일한 방법으로 수행하여 목적화합물을 얻었다(7 mg, 7 %).The target compound was obtained by the same method as Step 1 of Example 37 (7 mg, 7%).

1H-NMR(300 MHz, CDCl3) δ 8.76 (br s, 1H), 8.48 (s, 1H), 7.63 (s, 1H), 7.61-7.50 (m, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 4.36-4.17 (m, 3H), 3.92 (s, 3H), 2.91 (m, 2H), 2.80 (m, 2H), 1.99 (m, 2H), 1.60 (s, 9H), 1.52 (s, 9H).
 1 H-NMR (300 MHz, CDCl 3 ) δ 8.76 (br s, 1H), 8.48 (s, 1H), 7.63 (s, 1H), 7.61-7.50 (m, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 4.36-4.17 (m, 3H), 3.92 (s, 3H), 2.91 (m, 2H), 2.80 (m, 2H), 1.99 (m , 2H), 1.60 (s, 9H), 1.52 (s, 9H).

단계 2: 2-(2-아미노-5-(1-(피페리딘-4-일)-1H- 피라졸 -4-일)피리딘-3-일)-7- (4-메톡시페닐)벤즈[d]옥사졸-6-올의 제조 Step 2: 2- (2-amino-5- (1- (piperidin-4-yl) -1H- pyrazol -4 -yl) pyridin-3-yl) -7- (4-methoxyphenyl) Preparation of benz [d] oxazole-6-ol

Figure 112012052254195-pat00090
Figure 112012052254195-pat00090

반응물로서 t-부틸-4-(4-(6-(t-부틸아미노)-5-(6-히드록시-7-(4-메톡시페닐)벤즈[d]옥사졸-2-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트를 사용하는 것을 제외하고는 실시예 37의 단계 2과 동일한 방법으로 수행하여 목적화합물을 얻었다(8 mg, 80 %)T-butyl-4- (4- (6- (t-butylamino) -5- (6-hydroxy-7- (4-methoxyphenyl) benz [d] oxazol-2-yl) pyridine as reactant Except for using -3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate, it was carried out in the same manner as Step 2 of Example 37 to obtain the target compound (8 mg , 80%)

1H-NMR (MeOH-d4, 300 MHz) δ 8.48 (br s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.09 (s, 1H), 7.89 (s, 1H), 7.72 (d, J = 6.9 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 6.8 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 4.59-4.38 (m, 2H), 3.75 (s, 3H), 3.59-3.48 (m, 2H), 3.29-3.21 (m, 2H), 2.39-2.32 (m, 4H): LC-MS calcd for C31H26F6N6O5 (MH+) 482.2 found 483.18
 1 H-NMR (MeOH-d 4 , 300 MHz) δ 8.48 (br s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.09 (s, 1H), 7.89 (s, 1H), 7.72 ( d, J = 6.9 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 6.8 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 4.59-4.38 ( m, 2H), 3.75 (s, 3H), 3.59-3.48 (m, 2H), 3.29-3.21 (m, 2H), 2.39-2.32 (m, 4H): LC-MS calcd for C 31 H 26 F 6 N 6 O 5 (MH + ) 482.2 found 483.18

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

본 발명에 따른 다중치환 벤즈옥사졸로 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 pyridine derivative substituted with multi-substituted benzoxazole or a pharmaceutically acceptable salt thereof according to the present invention, the following experiment was 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 시험화합물(10 μL)을 가하고 c-Met 효소를 섞은 타이로신 키나아제 버퍼(20 μL)를 가한 후, 상기 효소 및 화합물의 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.Test compound (10 μL) was added to a Greyner 96-well V-type bottom plate, and tyrosine kinase buffer (20 μL) mixed with c-Met enzyme was added. The mixture of the enzyme and the compound was incubated for 15 minutes. 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 μL씩 가하고 진탕하에 배양하고 1시간 후, PBS-T 완충액(PBS 0.05% 트윈20)으로 5회 세척하였다.Anti-phosphotyrosine antibody with europium was diluted 1: 2,500, added to 100 μL per well, incubated under shaking, and washed 1 time with PBS-T buffer (PBS 0.05% Tween20).

개선제(enhancement solution, 100 μL)를 가하고 5분 동안 진탕배양한 후, 왈락 인비전 2103(Wallac Envision 2103) 기기로 615/665 nm의 파장 범위에서 판독하였다.Enhancement solution (100 μL) 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 화합물의 IC50는 2개씩의 데이터 세트로 결정하였고 프리즘(버전 5.01, 그래프패드) 소프트웨어를 이용하여 구하였다. The IC 50 of the compound on which the experiment was performed was determined in two data sets and was obtained using Prism (version 5.01, GraphPad) software.

c-Met 키나아제 효소활성을 50%로 감소시키는 상기 화합물의 IC50는 하기 표 1에 나타내었다.The IC 50 of this compound which reduces c-Met kinase enzyme activity by 50% is shown in Table 1 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 <10<10 1515 0.2180.218 2929 0.1860.186 22 <10<10 1616 0.0090.009 3030 <10<10 33 <10<10 1717 0.00190.0019 3131 <10<10 44 0.1350.135 1818 0.1380.138 3232 0.0270.027 55 <10<10 1919 0.0460.046 3333 0.180.18 66 <5<5 2020 0.0880.088 3434 0.0890.089 77 <5<5 2121 0.0360.036 3535 0.0290.029 88 <5<5 2222 0.0670.067 3636 0.00020.0002 99 <5<5 2323 0.3750.375 3737 0.00120.0012 1010 <10<10 2424 0.1260.126 3838 0.0420.042 1111 <10<10 2525 0.140.14 3939 0.0480.048 1212 6.76.7 2626 0.0570.057 4040 0.01770.0177 1313 0.00670.0067 2727 0.1960.196
1414 0.0620.062 2828 0.0420.042

표 1에 나타낸 바와 같이, 본 발명에 따른 화합물의 IC50가 10 μM 이하로 측정되었으며, 특히, 실시예 13, 14, 17, 26, 32, 36, 37 및 40의 화합물의 IC50가 0.1 μM 이하로 측정되었다. 이로부터 본 발명에 따른 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염은 c-Met 키나아제에 대한 우수한 억제효과가 있음을 알 수 있다.
As shown in Table 1, were the IC 50 of the compounds according to the invention measure less than 10 μM, in particular, the embodiments 13, 14, 17, 26, 32, 36, 37 and 40 The compounds of the IC 50 of 0.1 μM It measured as follows. From this it can be seen that the pyridine derivative or pharmaceutically acceptable salt thereof substituted with the multisubstituted benzoxazole according to the present invention has an excellent inhibitory effect on c-Met kinase.

<< 실험예Experimental Example 2>  2> 키나아제Kinase 억제활성 실험 Inhibitory activity test

Millipore(Upstate)의 키나아제 프로파일링 서비스(IC50 profiler express)를 이용하여 실시예 37에서 제조된 화합물의 다양한 키나아제의 저해 활성을 측정하였으며, 그 결과를 하기 표 2에 나타내었다.Inhibition activity of various kinases of the compound prepared in Example 37 was measured using Millipore (Upstate) kinase profiling service (IC 50 profiler express), and the results are shown in Table 2 below.

키나아제Kinase 저해활성(IC50, nM)Inhibitory activity (IC 50 , nM) Flt3Flt3 0.50.5 RonRon 1414 Aurora-AAurora-A 1818 KDRKDR 3030

표 2에 나타낸 바와 같이, 본 발명에 따른 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염은 Flt3, Ron, Aurora-A, KDR에 대한 우수한 억제효과가 있음을 알 수 있다.
As shown in Table 2, it can be seen that the pyridine derivative substituted with polysubstituted benzoxazole or a pharmaceutically acceptable salt thereof according to the present invention has an excellent inhibitory effect on Flt3, Ron, Aurora-A, KDR.

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> <1-1> 산제의Sanje 제조 Produce

화학식 1의 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 2 g2 g of pyridine derivative substituted with polysubstituted benzoxazole 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 tablets

화학식 1의 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 100 ㎎100 mg of pyridine derivative substituted with polysubstituted benzoxazole 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&Lt; 1-3 > Preparation of capsules

화학식 1의 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 100 ㎎100 mg of pyridine derivative substituted with polysubstituted benzoxazole 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 capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

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

화학식 1의 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 10 ㎍/㎖10 μg / ml pyridine derivative substituted with polysubstituted benzoxazole of formula (1)

묽은 염산 BP pH 3.5로 될 때까지Until dilute hydrochloric acid BP 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 다중치환 벤즈옥사졸로 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.Pyridine derivatives substituted with polysubstituted benzoxazoles according to the present invention are dissolved in an appropriate volume of sodium chloride BP for injection, the pH of the resulting solution is adjusted to pH 3.5 with dilute hydrochloric acid BP, and with sodium chloride BP for injection. The volume was adjusted 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.

Claims (10)

다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염에 있어서, 상기 다중치환 벤즈옥사졸로 치환된 피리딘 유도체는
13) 3-(6-페닐벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;
16) 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-3-(4-플루오로페닐)우레아;
17) 1-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-3-(2,4-다이클로로페닐)우레아;
21) N-(2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-3-일)피리딘-3-일)벤즈[d]옥사졸-6-일)-4-메톡시벤젠설폰아마이드;
32) 3-(5-히드록시-6-메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;
35) 3-(3,5-디메틸-6-히드록시벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;
36) 3-(6-히드록시-7-메틸벤즈[d]옥사졸-2-일)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-2-아민;
37) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-7-(1H-인돌-6-일)벤즈[d]옥사졸-6-올 및
40) 2-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-7-(4-메톡시페닐)벤즈[d]옥사졸-6-올로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염.
In a pyridine derivative substituted with polysubstituted benzoxazole or a pharmaceutically acceptable salt thereof, the pyridine derivative substituted with polysubstituted benzoxazole
13) 3- (6-phenylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine;
16) 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-6 -Yl) -3- (4-fluorophenyl) urea;
17) 1- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) benz [d] oxazole-6 -Yl) -3- (2,4-dichlorophenyl) urea;
21) N- (2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-3-yl) pyridin-3-yl) benz [d] oxazole-6 -Yl) -4-methoxybenzenesulfonamide;
32) 3- (5-hydroxy-6-methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine 2-amine;
35) 3- (3,5-dimethyl-6-hydroxybenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl ) Pyridin-2-amine;
36) 3- (6-hydroxy-7-methylbenz [d] oxazol-2-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridine 2-amine;
37) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -7- (1H-indol-6-yl ) Benz [d] oxazole-6-ol and
40) 2- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -7- (4-methoxyphenyl) benz [d] Pyridine derivative substituted with polysubstituted benzoxazole, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of oxazole-6-ol.
삭제delete 하기 반응식 1로 표시되는 바와 같이,
출발물질인 화학식 2의 화합물을 치환반응시켜 화학식 4의 화합물을 제조하는 단계(단계 1);
상기 단계 1에서 제조된 화학식 4의 화합물을 고리화반응시켜 화학식 5의 화합물을 제조하는 단계(단계 2);
상기 단계 2에서 제조된 화학식 5의 화합물과 아민화합물을 치환반응시켜 화학식 6의 화합물을 제조하는 단계(단계 3);
상기 단계 3에서 제조된 화학식 6의 화합물과 화학식 7의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 8의 화합물을 제조하는 단계(단계 4);
상기 단계 4에서 제조된 화학식 8의 화합물을 수소화반응시켜 화학식 9의 화합물을 제조하는 단계(단계 5);
상기 단계 5에서 제조된 화학식 9의 화합물을 화학식 10의 화합물과 부가반응시켜 화학식 11의 화합물을 제조하는 단계(단계 6); 및
상기 단계 6에서 제조된 화학식 11의 화합물을 탈보호반응시켜 화학식 1a의 화합물을 제조하는 단계(단계 7)를 포함하는 제1항의 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법:
[반응식 1]
Figure 112012085219978-pat00092

(상기 반응식 1에서, 화학식 1a는 제1항의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, n은 1~3의 정수이며, Ar은 4-플루오로페닐 또는 2,4-다이클로로페닐이고, Et3N는 트리에틸아민, PPTS는 파라톨루엔 피리디늄염, Pd(dppf)Cl2는 1,1`-비스(디페닐포스피노)페로센다이클로로 팔라듐, Pd(Ph3P)2Cl2는 비스트리페닐포스핀다이클로로팔라듐, NCO는 이소시아네이트, TFA는 트리플루오로아세트산, Boc는 t-부톡시카보닐이다).
As represented by Scheme 1 below,
Preparing a compound of Chemical Formula 4 by substituting a compound of Chemical Formula 2 as a starting material (Step 1);
Preparing a compound of formula 5 by cyclization of the compound of formula 4 prepared in step 1 (step 2);
Preparing a compound of Chemical Formula 6 by performing a substitution reaction between the compound of Chemical Formula 5 and an amine compound prepared in Step 2 (Step 3);
Preparing a compound of Chemical Formula 8 by performing a Suzuki coupling reaction between the compound of Chemical Formula 6 and the compound of Chemical Formula 7 prepared in Step 3 (Step 4);
Preparing a compound of formula 9 by hydrogenating the compound of formula 8 prepared in step 4 (step 5);
Preparing a compound of formula 11 by adding a compound of formula 9 prepared in step 5 with a compound of formula 10 (step 6); And
Depyrolyzing the compound of formula 11 prepared in step 6 to prepare a compound of formula 1a (step 7) of the pyridine derivative or pharmaceutically acceptable salt thereof substituted with the polysubstituted benzoxazole of claim 1 Manufacturing Method:
[Reaction Scheme 1]
Figure 112012085219978-pat00092

(In Scheme 1, Formula 1a is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, n is an integer of 1 to 3, Ar is 4-fluorophenyl or 2,4-dichlorophenyl Et 3 N is triethylamine, PPTS is paratoluene pyridinium salt, Pd (dppf) Cl 2 is 1,1′-bis (diphenylphosphino) ferrocenedichloro palladium, Pd (Ph 3 P) 2 Cl 2 is bistriphenylphosphinedichloropalladium, NCO isocyanate, TFA is trifluoroacetic acid, and Boc is t-butoxycarbonyl).
하기 반응식 3으로 표시되는 바와 같이,
화학식 9의 화합물을 화학식 15로 표시되는 아릴설포닐클로라이드 혹은 알킬설포닐 클로라이드와 부가반응시켜 화학식 16의 화합물을 제조하는 단계(단계 1);
상기 단계 1에서 제조된 화학식 16의 화합물을 탈보호반응시켜 화학식 1d의 화합물을 제조하는 단계(단계 2)를 포함하는 제1항의 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법:
[반응식 3]
Figure 112012085219978-pat00093

(상기 반응식 3에서, 화학식 1d는 제1항의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, n은 1~3의 정수이며, Ar(또는 R)은 4-메톡시페닐이고, ArSO2Cl는 아릴설포닐클로라이드이다).
As represented by Scheme 3 below,
Reacting the compound of Formula 9 with arylsulfonyl chloride or alkylsulfonyl chloride represented by Formula 15 to prepare a compound of Formula 16 (step 1);
Deprotection of the compound of Formula 16 prepared in Step 1 to prepare a compound of Formula 1d (Step 2) of the pyridine derivative substituted with a polysubstituted benzoxazole of claim 1 or a pharmaceutically acceptable salt thereof Manufacturing Method:
[Reaction Scheme 3]
Figure 112012085219978-pat00093

(In Scheme 3, Formula 1d is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, n is an integer of 1 to 3, Ar (or R) is 4-methoxyphenyl, ArSO 2 Cl is arylsulfonylchloride).
하기 반응식 4로 표시되는 바와 같이,
화학식 2의 화합물을 화학식 17의 화합물과 반응시켜 화학식 18의 화합물을 제조하는 단계(단계 1);
상기 단계 1에서 제조된 화학식 18의 화합물을 고리화반응시켜 화학식 19의 화합물을 제조하는 단계(단계 2);
상기 단계 2에서 제조된 화학식 19의 화합물과 아민화합물을 치환반응시켜 화학식 20의 화합물을 제조하는 단계(단계 3);
상기 단계 3에서 제조된 화학식 20의 화합물과 화학식 6의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 21의 화합물을 제조하는 단계(단계 4);
상기 단계 4에서 제조된 화학식 21의 화합물을 수산화칼륨과 스즈키 커플링 (Suzuki coupling reaction)을 수행하여 화학식 22의 화합물을 제조하는 단계(단계 5);
상기 단계 5에서 제조된 화학식 22의 화합물을 탈보호반응시켜 화학식 1e의 화합물을 제조하는 단계(단계 6)를 포함하는 제1항의 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법:
[반응식 4]
Figure 112012085219978-pat00094

(상기 반응식 4에서, 화학식 1e는 제1항의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, n은 1~3의 정수이며, R1은 메틸, 4-메톡시페닐 또는 1H-인돌-6-일이다).
As represented by Scheme 4 below,
Reacting a compound of Formula 2 with a compound of Formula 17 to prepare a compound of Formula 18 (step 1);
Preparing a compound of formula 19 by cyclization of the compound of formula 18 prepared in step 1 (step 2);
Preparing a compound of Chemical Formula 20 by performing a substitution reaction between the compound of Chemical Formula 19 and an amine compound prepared in Step 2 (Step 3);
Preparing a compound of Chemical Formula 21 by performing a Suzuki coupling reaction between the compound of Chemical Formula 20 and the compound of Chemical Formula 6 prepared in Step 3 (Step 4);
Preparing a compound of Chemical Formula 22 by performing a Suzuki coupling reaction with potassium hydroxide on the compound of Chemical Formula 21 prepared in Step 4 (Step 5);
Deprotecting the compound of Chemical Formula 22 prepared in Step 5 to prepare a compound of Chemical Formula 1e (Step 6), wherein the pyridine derivative substituted with polysubstituted benzoxazole of claim 1 or a pharmaceutically acceptable salt thereof Manufacturing Method:
[Reaction Scheme 4]
Figure 112012085219978-pat00094

(In Scheme 4, Formula 1e is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, n is an integer of 1 to 3, R 1 is methyl, 4-methoxyphenyl or 1H-indole- 6-days).
하기 반응식 7로 표시되는 바와 같이,
화학식 21의 화합물을 아릴보론산과 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 27의 화합물을 제조하는 단계(단계 1);
단계 1에서 제조된 화학식 27의 화합물을 탈보호반응시켜 화학식 1i의 화합물을 제조하는 단계(단계 2)를 포함하는 제1항의 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법:
[반응식 7]
Figure 112012085219978-pat00095

(상기 반응식 7에서, 화학식 1i는 제1항의 화합물 또는 이의 약학적으로 허용가능한 염이고, n은 1~3의 정수이며, Ar은 페닐이다).
As represented by Scheme 7,
Preparing a compound of Formula 27 by performing a Suzuki coupling reaction with an arylboronic acid with a compound of Formula 21 (step 1);
Preparation of a pyridine derivative substituted with the polysubstituted benzoxazole of claim 1 or a pharmaceutically acceptable salt thereof, comprising the step of deprotecting the compound of formula 27 prepared in step 1 to prepare a compound of formula 1i (step 2). Way:
[Reaction Scheme 7]
Figure 112012085219978-pat00095

(In Scheme 7, Formula 1i is the compound of claim 1 or a pharmaceutically acceptable salt thereof, n is an integer from 1 to 3, Ar is phenyl).
제1항의 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 및 치료용 약학적 조성물.
A pharmaceutical composition for preventing and treating cancer, comprising a pyridine derivative substituted with the multisubstituted benzoxazole of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
제1항의 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 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 질환의 예방 및 치료용 약학적 조성물.
Lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer containing a pyridine derivative substituted with the multisubstituted benzoxazole of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. , Perianal cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system 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 carcinoma, renal cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma and A pharmaceutical composition for the prevention and treatment of diseases selected from the group consisting of pituitary adenoma.
제1항의 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 건선, 양성 전립선 비대 또는 망막증의 예방 및 치료용 약학적 조성물.
A pharmaceutical composition for the prevention and treatment of psoriasis, benign prostatic hyperplasia or retinopathy, comprising a pyridine derivative substituted with the multisubstituted benzoxazole of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
제1항의 다중치환 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 섬유선종, 경화성 선질환 또는 유두종의 예방 및 치료용 약학적 조성물.A pharmaceutical composition for preventing and treating fibroadenoma, curable gland disease, or papilloma, comprising a pyridine derivative substituted with a multisubstituted benzoxazole of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
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