KR101656382B1 - pyrimidine-2,4-diamine derivatives and pharmaceutical composition for anti cancer containing the same as an active ingredient - Google Patents

pyrimidine-2,4-diamine derivatives and pharmaceutical composition for anti cancer containing the same as an active ingredient Download PDF

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KR101656382B1
KR101656382B1 KR1020140023897A KR20140023897A KR101656382B1 KR 101656382 B1 KR101656382 B1 KR 101656382B1 KR 1020140023897 A KR1020140023897 A KR 1020140023897A KR 20140023897 A KR20140023897 A KR 20140023897A KR 101656382 B1 KR101656382 B1 KR 101656382B1
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phenyl
pyrimidine
diamine
isopropylsulfonyl
chloro
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KR1020140023897A
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KR20150102252A (en
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정희정
김형래
김필호
박지훈
안선주
윤창수
이광호
이정옥
조성윤
채종학
하재두
황종연
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한국화학연구원
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Priority to CN201580010933.1A priority patent/CN106029646B/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

본 발명은 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물에 관한 것으로, 본 발명에 의한 화합물은 역형성 림프종 키나아제(ALK) 활성을 억제하는 효과가 우수하므로 이에 따른 EML4-ALK, NPM-ALK 등의 역형성 림프종 키나아제(ALK) 융합 단백질을 가진 암세포에 대한 치료효과가 향상될 수 있으며, 암의 재발을 막는데 효과적일 것으로 예상되므로 암의 예방 또는 치료용 약학적 조성물로 유용하게 사용될 수 있다.The present invention relates to a pharmaceutical composition for the prevention or treatment of a pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof and a cancer containing the same as an active ingredient. The compound according to the present invention is used for the treatment of inverse lymphoma kinase (ALK) activity. Therefore, it is possible to improve the therapeutic effect on the cancer cells having the inverse-forming lymphoma kinase (ALK) fusion protein such as EML4-ALK and NPM-ALK and to prevent cancer recurrence And thus can be usefully used as a pharmaceutical composition for preventing or treating cancer.

Description

피리미딘-2,4-디아민 유도체 및 이를 유효성분으로 함유하는 항암용 약학적 조성물{pyrimidine-2,4-diamine derivatives and pharmaceutical composition for anti cancer containing the same as an active ingredient}Pyrimidine-2,4-diamine derivatives and pharmaceutical compositions containing the same as an active ingredient. The present invention also relates to pyrimidine-2,4-diamine derivatives and pharmaceutical compositions containing the same as an active ingredient.

본 발명은 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다.
The present invention relates to a pharmaceutical composition for preventing or treating a pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof and a cancer containing the same as an active ingredient.

암이란 개체의 필요에 따라 규칙적이고 절제 있는 증식과 억제를 할 수 있는 정상세포와 달리 조직 내에서 필요한 상태를 무시하고 무제한의 증식을 하는 미분화 세포로 구성된 세포덩어리로서 종양이라고도 한다. 이러한 무제한의 증식을 하는 암 세포는 주위의 조직으로 침투하고 더 심각한 경우는 신체의 다른 기관으로 전이가 되어 심각한 고통을 수반하고 결국 죽음을 초래하는 난치병이다.Cancer is a mass of cells composed of undifferentiated cells which, unlike normal cells, can regulate and inhibit proliferation and suppression according to the individual's needs, ignoring the necessary conditions in the tissues and is called a tumor. These unlimited, proliferating cancer cells penetrate into surrounding tissues and, in the worse case, become metastasized to other organs of the body, resulting in severe pain and ultimately death.

미국암협회(American Cancer Society) 자료에 따르면 2007년 한해 세계적으로 새로이 암 진단을 받은 환자는 1200만 명 이상이며 사망자는 760만 명으로 매일 약 2만 명씩 암으로 사망하는 것으로 보고되었다. 우리나라의 경우 2006년 통계청 보고에 따르면 암으로 인한 사망이 사망원인 1위를 차지하였다. 따라서, 암 발생 및 투병으로 인한 정신적, 육체적 고통의 감소와 삶의 질 향상을 위해 치료 효과가 우수한 종양 치료제의 개발이 절실히 요구된다.According to the American Cancer Society data, there are more than 12 million new cases of cancer diagnosed globally in 2007, with 7.6 million deaths and about 20,000 deaths every day. In Korea, according to 2006 National Statistical Office, death from cancer was the leading cause of death. Therefore, the development of a tumor treatment agent having excellent therapeutic effect for the reduction of mental and physical pain caused by cancer and bruising and improvement of the quality of life is urgently required.

그러나 많은 노력에도 아직까지 정상세포가 어떠한 기전을 거쳐 암 세포로 형질전환이 되는지에 대해서는 정확하게 규명되지는 않았으나, 환경요인, 화학물질, 방사선, 바이러스 등 외적 요인 및 유전 인자, 면역학적 요인 등의 내적 요인 등이 복잡하게 얽혀 결과적으로 암이 발생한다. 암의 발생에 관련되는 유전자에는 종양형성 유전자(oncogenes)와 종양억제 유전자(tumor suppressor genes)가 있는데, 이들 사이의 균형이 위에서 설명한 내적 혹은 외적 요인들에 의해 무너질 때 암이 발생하게 된다.
However, in many efforts, it has not yet been accurately determined how normal cells are transformed into cancer cells. However, the internal factors such as environmental factors, chemical substances, radiation, and viruses, and external factors such as genetic factors and immunological factors Factors are complexly entangled, resulting in cancer. The genes involved in the development of cancer include oncogenes and tumor suppressor genes. Cancer occurs when the balance between them is destroyed by the internal or external factors described above.

암은 혈액암과 고형암으로 크게 분류되며, 폐암, 위암, 유방암, 구강암, 간암, 자궁암, 식도암, 피부암 등 신체의 거의 모든 부위에서 발생하며, 이들의 치료방법으로 최근 글리벡 또는 허셉틴과 같은 소수의 표적치료제가 특정암의 치료에 이용되고 있으나 현재까지는 수술이나 방사선 요법 및 세포증식을 억제하는 화학요법제를 이용한 항암제 치료가 주된 방법이다. 그러나 표적치료제가 아니기 때문에 기존 화학요법제의 가장 큰 문제는 세포독성으로 인한 부작용과 약제 내성으로써, 항암제에 의한 초기의 성공적인 반응에도 불구하고 결국에는 치료가 실패하게 되는 주요 요인이다. 따라서, 이러한 화학요법제의 한계를 극복하기 위해서는 항암작용 기전이 명확한 표적 치료제 개발이 지속적으로 필요하다.
Cancer is largely classified into blood cancer and solid cancer and occurs in almost all parts of the body such as lung cancer, stomach cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer and skin cancer. Recently, a few targets such as Gleevec or Herceptin Therapeutics are currently being used to treat certain cancers, but until now, chemotherapy with chemotherapeutic agents that inhibit surgery, radiation therapy and cell proliferation is the main method. However, since it is not a target drug, the biggest problem of conventional chemotherapy is cytotoxic side effects and drug resistance, which are the main factors that eventually fail treatment despite successful initial response by anticancer drugs. Therefore, in order to overcome the limitations of these chemotherapeutic agents, it is necessary to develop a targeted therapeutic agent with clear mechanism of action.

이에, 표적 치료제를 개발하기 위한 종양 형성에 관여하는 특정 분자생물학적 인자들에 관한 많은 연구가 진행되고 있으며, 특히, 분자생물학적 인자들은 암의 예후예측이나 화학요법 및 방사선치료 여부를 결정하는데 다양하게 이용되고 있다.Therefore, many studies on specific molecular biologic factors involved in tumorigenesis for developing a target therapeutic agent are under way, and in particular, molecular biological factors are widely used to determine the prognosis of cancer, chemotherapy, and radiation therapy .

특정 분자생물학적 인자 중의 하나인 타이로신 키나아제 수용체를 저해하는 가장 대표적인 약물로는 글리벡을 들 수 있다. 상기 글리벡은 만성골수성백혈병에서 관찰되는 필라델피아 염색체에서 염색체 전좌에 의해 형성되는 Bcr-Abl 융합유전자의 작용을 억제하여 항암 작용을 하며, 타이로신 키나아제 저해제로써, 만성골수성백혈병 환자에 투여 시 만족할 만한 성과를 거두고 있다. 이 후, 타이로신 키나아제 저해제로 항암 효과를 나타내는 약물로는 비소세포성 폐암 치료제로 사용되는 EGFR(epidermal growth factor receptor) 타이로신 키나아제 억제제인 게피티닙(gefitinib)와 엘로티닙(erlotinib)가 있고, 신장 세포암종 치료제로 소라페닙(sorafenib)과 수니티닙(sunitinib)이 사용되고 있으나, 출혈, 심장마비, 심부전, 간부전 등의 부작용이 있는 것으로 알려진바 있다.
Gleevec is one of the most representative drugs that inhibit tyrosine kinase receptors, one of the specific molecular biological factors. The Gleevec inhibits the action of the Bcr-Abl fusion gene, which is formed by chromosomal translocation in the Philadelphia chromosome observed in chronic myelogenous leukemia, and thus acts as an anticancer agent. As a tyrosine kinase inhibitor, Gleevec exhibits satisfactory results when administered to patients suffering from chronic myelogenous leukemia have. Thereafter, the drugs that exhibit anticancer effects with tyrosine kinase inhibitors include gefitinib and erlotinib, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, which are used as therapeutic agents for non-small cell lung cancer, and kidney cells Sorafenib and sunitinib have been used to treat cancer, but they have been known to have side effects such as bleeding, heart attack, heart failure, and liver failure.

최근에는 역형성 림프종 키나아제(ALK, Anaplastic lymphoma kinase)가 인체 여러 종양에서 발견되어 표적치료의 목표물로 연구되고 있다. Recently, anaplastic lymphoma kinase (ALK) has been found in many human tumors and has been studied as a target of target treatment.

역형성 림프종 키나아제(ALK)의 발암과정은 주로 역형성 큰세포 림프종에서 관찰되는 ALK-NPM(Nucleophosmin, 뉴클레오포스민)의 융합유전자인 것으로 알려져 있다. 유전자 융합에 의해 역형성 림프종 키나아제(ALK)가 활성화되면 역형성 림프종 키나아제(ALK)가 갖고 있는 타이로신 키나아제는 비정상적으로 행동하여 암을 유발하게 된다. 즉, 비정상적으로 활성화된 역형성 림프종 키나아제(ALK)는 세포의 증식을 유도하고 아포프토시스를 방해해 세포가 사멸되지 않게 하며 세포뼈대를 재배열시키며 세포 형태를 변형시킨다. 역형성 림프종 키나아제(ALK)의 암 유전자화는 역형성 림프종 키나아제(ALK)의 표적 물질인 하위 분자(downstream molecule)와의 상호작용에 의해 이루어지는데, 하위 분자는 세포내 신호전달을 매개하는 물질이다. 역형성 림프종 키나아제(ALK)는 정상이거나 암 유전자화한 다른 타이로신 키나아제와 연결되어 상호작용을 하거나 여러 종류의 다른 경로들을 활성화시킨다.The carcinogenic process of inverse lymphoma kinase (ALK) is known to be a fusion gene of ALK-NPM (nucleophosmin, nucleophosphin), which is mainly observed in inverse large cell lymphoma. When the inverse lymphoma kinase (ALK) is activated by gene fusion, the tyrosine kinase of the inverse lymphoma kinase (ALK) acts abnormally and causes cancer. In other words, abnormally activated degenerative lymphoma kinase (ALK) induces cell proliferation, prevents apoptosis, prevents cell death, rearranges the cellular skeleton, and modifies cell morphology. Cancer geneation of inverted lymphoma kinase (ALK) is mediated by interaction with a downstream molecule, the target of reverse forming lymphoma kinase (ALK), which mediates intracellular signaling. Inverse lymphoma kinase (ALK) is linked to other tyrosine kinases that are normal or cancer-genetically modified to interact or activate a variety of other pathways.

특히, 폐암 세포의 내부에서 역형성 림프종 키나아제(ALK) 유전자는 EML4(Echinoderm Microtubule-Associated Protein-Like 4) 유전자와 융합하여 활성형 티로신 인산화 효소(tyrosine kinase)인 EML4-ALK를 생산하고, 이때, EML4-역형성 림프종 키나아제(ALK)의 암화 능력이 효소활성에 의존적이라는 것이 알려진 바 있고, 또한, Mosse 등은 491개의 신경모세포종 검체에서 약 26 %의 역형성 림프종 키나아제(ALK) 유전자 증폭에 대하여 보고한 바 있다. 뿐만 아니라, 역형성 림프종 키나아제(ALK) 유전자는 대형 B-세포 림프종, 전신성 조식구증, 염증성 근섬유아세포성 육종, 식도 편평 세포암, 비소세포폐암, 횡문근육종, 근섬유모세포종, 유방암 및 흑색종 세포주 등 수많은 비조혈세포 종양에서 발현되는 것으로 밝혀졌고, 염증성 골수섬유모세포종양이라는 희귀한 질환의 경우 여러 종류의 역형성 림프종 키나아제(ALK) 융합 단백질이 흔히 발견되어 이러한 융합 단백질들이 종양의 발생에 깊이 관련된 것으로 여겨지고 있다.
In particular, the inverse Lymphoma kinase (ALK) gene in lung cancer cells is fused with EML4 (Echinoderm Microtubule-Associated Protein-Like 4) gene to produce active tyrosine kinase, EML4-ALK, In addition, Mosse et al. Reported that 26% of the 491 neuroblastoma specimens were amplified with the reverse priming lymphoma kinase (ALK) gene amplification, and that EML4-reverse forming lymphoma kinase (ALK) There is one. In addition, the inverse lymphoma kinase (ALK) gene may be useful for the treatment of numerous B-cell lymphomas, systemic breakfast necrosis, inflammatory myoblastic fibrosarcoma, esophageal squamous cell carcinoma, non-small cell lung carcinoma, rhabdomyosarcoma, myoblastoma, melanoma and melanoma cell lines In the rare disease of inflammatory bone marrow fibroblastoma tumor, several types of reverse priming lymphoma kinase (ALK) fusion proteins have been found to be expressed in non-hematopoietic cell tumors, and these fusion proteins are thought to be deeply involved in tumor development have.

이에, 역형성 림프종 키나아제(ALK)의 활성화 경로를 차단함으로써, 암 치료를 목적으로 하는 ALK-NPM를 대상으로 한 치료제가 개발되고 있다. 최근 화이자(Pfizer)에서 종양원성 변이에 대한 선택적 억제제로 개발한 약물로 소분자 타이로신 인산화효소 억제제의 하나인 크리조티닙(PF-02341066)이 ATP 경쟁성 c-Met/HGFR와 역형성 림프종 키나아제(ALK) 저해제로써, 비소세포폐암의 치료에 효과가 있는 것으로 알려져 있으며, 2011년 FDA에서 신약으로 허가를 받았다.Thus, therapeutic agents targeting ALK-NPM for the treatment of cancer are being developed by blocking the activation pathway of inverse lymphoma kinase (ALK). Recently, Crytotinib (PF-02341066), a small molecule tyrosine phosphorylase inhibitor, has been developed as a selective inhibitor of tumorigenic mutation in Pfizer. It has been shown that ATP competitiveness c-Met / HGFR and inverse lymphoma kinase ) Inhibitor, which is known to be effective in the treatment of non-small cell lung cancer. In 2011, the FDA received a new drug approval.

또한, 노바티스(Novartis)사의 NVP-TAE684, LDK-378과 쥬가이(Chugai)사의 CH5424802도 역형성 큰세포 림프종 세포주 이외에 신경모세포종 세포주에서도 종양의 크기를 감소시키는 효과가 있는 것으로 알려져 있다.
In addition, NVP-TAE684 and LDK-378 from Novartis and CH5424802 from Chugai are known to have the effect of reducing the tumor size in neuroblastoma cell lines in addition to the reverse large-cell lymphoma cell line.

특허문헌 1 내지 3에서는, 종래 역형성 림프종 키나아제(ALK) 활성을 저해하기 위한 용도로 다양한 골격을 가진 치료후보 물질이 개발되고 있고, 피리미딘 유도체가 림프종 키나아제(ALK)를 선택적으로 저해하여 항암제로 개발될 수 있음을 개시하고 있다.
In Patent Documents 1 to 3, therapeutic candidates having various skeletons have been developed to inhibit the activity of conventional inverse lymphoma kinase (ALK), and pyrimidine derivatives selectively inhibit lymphoma kinase (ALK) Can be developed.

이에, 본 발명자들은 역형성 역형성 림프종 키나아제(ALK, Anaplastic lymphoma kinase) 활성억제 효과를 나타내는 화합물을 개발하기 위해 노력하던 중, 특정 구조의 피리미딘-2,4-디아민 유도체가 역형성 림프종 키나아제(ALK)의 활성억제 효과가 현저히 우수한 것을 알아내어, 암의 예방 또는 치료제로 유용할 수 있음을 밝히고 본 발명을 완성하였다.
Accordingly, the present inventors have made efforts to develop a compound having an inhibitory effect on ALK (Anaplastic lymphoma kinase) activity, and have found that a pyrimidine-2,4-diamine derivative of a specific structure can be used for the treatment of inverse lymphoma kinase ALK) is remarkably excellent, and thus it can be useful as a preventive or therapeutic agent for cancer, and the present invention has been completed.

WO 2009143389 A1WO 2009143389 A1 WO 2008051547 A1WO 2008051547 A1 WO 2004080980 A1WO 2004080980 A1

본 발명의 목적은 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.
It is an object of the present invention to provide a pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof.

본 발명의 다른 목적은 상기 피리미딘-2,4-디아민 유도체의 제조방법을 제공하는 것이다.
Another object of the present invention is to provide a process for preparing the pyrimidine-2,4-diamine derivative.

본 발명의 또 다른 목적은 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.
It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating cancer comprising as an active ingredient a pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof.

본 발명의 다른 목적은 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 역형성 림프종 키나아제(ALK, Anaplastic Lymphoma Kinase) 과활성으로 인하여 유발되는 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.
Another object of the present invention is to provide a method for preventing or preventing diseases caused by an activity of anaplastic lymphoma kinase (ALK) comprising an pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient, And to provide a therapeutic pharmaceutical composition.

본 발명의 또 다른 목적은 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 역형성 림프종 키나아제(ALK)의 저해제를 제공하는 것이다.
Another object of the present invention is to provide an inhibitor of reversed lymphoma kinase (ALK) comprising as an active ingredient a pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof.

상기 목적을 달성하기 위하여, In order to achieve the above object,

본 발명은 하기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a pyrimidine-2,4-diamine derivative represented by the following general formula (I): or a pharmaceutically acceptable salt thereof.

[화학식 1][Chemical Formula 1]

Figure 112014019931035-pat00001
Figure 112014019931035-pat00001

상기 화학식 1에서,In Formula 1,

Figure 112014019931035-pat00002
는 단일결합 또는 이중결합이고;
Figure 112014019931035-pat00002
Is a single bond or a double bond;

Figure 112014019931035-pat00003
이 단일결합인 경우,
Figure 112014019931035-pat00003
If this is a single bond,

R1, R2 및 R3는 독립적으로 -H, 할로겐, 또는 비치환 또는 하나 이상의 할로겐이 치환된 C1 -10 직쇄 알킬이고;R 1 , R 2, and R 3 are independently -H, halogen, or C 1 -10 straight chain alkyl unsubstituted or substituted with one or more halogens;

R4는 -H, 비치환 또는 하나 이상의 -OH기가 치환된 C1 -10 직쇄 또는 측쇄 알킬, 또는 -C(=O)R5이고, 여기서 R5는 -H, -OH, 또는 C1 -10 직쇄 또는 측쇄 알킬이고;
R 4 is -H, an unsubstituted or at least one -OH group is substituted C 1 -10 straight or branched chain alkyl, or -C (= O) R 5, wherein R 5 is -H, -OH, or C 1 - 10 linear or branched alkyl;

Figure 112014019931035-pat00004
이 이중결합인 경우,
Figure 112014019931035-pat00004
In the case of this double bond,

R1, R2 및 R3는 독립적으로 -H, 할로겐, 또는 비치환 또는 하나 이상의 할로겐이 치환된 C1 -10 직쇄 또는 측쇄 알킬이고;R 1 , R 2 and R 3 are independently -H, halogen, or C 1 -10 straight chain or branched alkyl substituted unsubstituted or substituted with at least one halogen;

R4는 -H, 비치환 또는 하나 이상의 -OH기가 치환된 C1 -10 직쇄 또는 측쇄 알킬, 또는 -C(=O)R5이고, 여기서 R5는 -H, -OH, 또는 C1 -10 직쇄 또는 측쇄 알킬이다.
R 4 is -H, an unsubstituted or at least one -OH group is substituted C 1 -10 straight or branched chain alkyl, or -C (= O) R 5, wherein R 5 is -H, -OH, or C 1 - 10 linear or branched alkyl.

또한, 본 발명은 하기 반응식 1에 나타낸 바와 같이,Also, as shown in the following Reaction Scheme 1,

화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계(단계 1); 및Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And

상기 단계 1에서 제조한 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계(단계 2);를 포함하는 상기 피리미딘-2,4-디아민 유도체의 제조방법을 제공한다.
Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (1) (step 2); and reacting the pyrimidine-2,4-diamine derivative Of the present invention.

[반응식 1][Reaction Scheme 1]

Figure 112014019931035-pat00005
Figure 112014019931035-pat00005

(상기 반응식 1에서,(In the above Reaction Scheme 1,

R1, R2, R3 및 R4는 상기 화학식 1에서 정의한 바와 같다).
R 1 , R 2 , R 3 And R < 4 > are the same as defined in Formula 1).

나아가, 본 발명은 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.
Further, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the pyrimidine-2,4-diamine derivative represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

또한, 본 발명은 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 역형성 림프종 키나아제(ALK, Anaplastic Lymphoma Kinase) 과활성으로 인하여 유발되는 질환의 예방 또는 치료용 약학적 조성물을 제공한다.
The present invention also relates to a pharmaceutical composition for inducing an activation of anaplastic lymphoma kinase (ALK) comprising the pyrimidine-2,4-diamine derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Or a pharmaceutically acceptable salt thereof.

나아가, 본 발명은 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 역형성 림프종 키나아제(ALK)의 저해제를 제공한다.
Further, the present invention provides an inhibitor of reversed-type lymphoma kinase (ALK) comprising the pyrimidine-2,4-diamine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명에 의한 화합물은 역형성 림프종 키나아제(ALK) 활성을 억제하는 효과가 현저히 우수하므로 이에 따른 EML4-ALK, NPM-ALK 등의 역형성 림프종 키나아제(ALK) 융합 단백질을 가진 암세포에 대한 치료효과가 향상될 수 있으며, 암의 재발을 막는데 효과적일 것으로 예상되므로 암의 예방 또는 치료용 약학적 조성물로 유용하게 사용될 수 있다.
The compounds according to the present invention are remarkably effective in inhibiting the activity of the anti-forming lymphoma kinase (ALK). Therefore, the therapeutic effect of the compounds according to the present invention on cancer cells having an inverse lymphoma kinase (ALK) fusion protein such as EML4-ALK and NPM- And can be effectively used as a pharmaceutical composition for prevention or treatment of cancer since it is expected to be effective in preventing recurrence of cancer.

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

본 발명은 하기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a pyrimidine-2,4-diamine derivative represented by the following general formula (I): or a pharmaceutically acceptable salt thereof.

[화학식 1][Chemical Formula 1]

Figure 112014019931035-pat00006
Figure 112014019931035-pat00006

상기 화학식 1에서,In Formula 1,

Figure 112014019931035-pat00007
는 단일결합 또는 이중결합이고;
Figure 112014019931035-pat00007
Is a single bond or a double bond;

Figure 112014019931035-pat00008
이 단일결합인 경우,
Figure 112014019931035-pat00008
If this is a single bond,

R1, R2 및 R3는 독립적으로 -H, 할로겐, 또는 비치환 또는 하나 이상의 할로겐이 치환된 C1 -10 직쇄 알킬이고;R 1 , R 2, and R 3 are independently -H, halogen, or C 1 -10 straight chain alkyl unsubstituted or substituted with one or more halogens;

R4는 -H, 비치환 또는 하나 이상의 -OH기가 치환된 C1 -10 직쇄 또는 측쇄 알킬, 또는 -C(=O)R5이고, 여기서 R5는 -H, -OH, 또는 C1 -10 직쇄 또는 측쇄 알킬이고;
R 4 is -H, an unsubstituted or at least one -OH group is substituted C 1 -10 straight or branched chain alkyl, or -C (= O) R 5, wherein R 5 is -H, -OH, or C 1 - 10 linear or branched alkyl;

Figure 112014019931035-pat00009
이 이중결합인 경우,
Figure 112014019931035-pat00009
In the case of this double bond,

R1, R2 및 R3는 독립적으로 -H, 할로겐, 또는 비치환 또는 하나 이상의 할로겐이 치환된 C1 -10 직쇄 또는 측쇄 알킬이고;R 1 , R 2 and R 3 are independently -H, halogen, or C 1 -10 straight chain or branched alkyl substituted unsubstituted or substituted with at least one halogen;

R4는 -H, 비치환 또는 하나 이상의 -OH기가 치환된 C1 -10 직쇄 또는 측쇄 알킬, 또는 -C(=O)R5이고, 여기서 R5는 -H, -OH, 또는 C1 -10 직쇄 또는 측쇄 알킬이다
R 4 is -H, an unsubstituted or at least one -OH group is substituted C 1 -10 straight or branched chain alkyl, or -C (= O) R 5, wherein R 5 is -H, -OH, or C 1 - 10 straight chain or branched chain alkyl

바람직하게는,Preferably,

Figure 112014019931035-pat00010
이 단일결합인 경우,
Figure 112014019931035-pat00010
If this is a single bond,

상기 R1, R2 및 R3는 독립적으로 -H, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 C1 -5 직쇄 알킬이고;Wherein R 1, R 2 and R 3 are independently -H, halogen, unsubstituted or at least one halogen-substituted straight-chain C 1 -5 alkyl;

R4는 -H, 비치환 또는 하나 이상의 -OH기가 치환된 C1 -5 직쇄 또는 측쇄 알킬, 또는 -C(=O)R5이고, 여기서 R5는 -OH, 또는 C1 -5 직쇄 또는 측쇄 알킬이고;
R 4 is -H, an unsubstituted or at least one -OH group is substituted C 1 -5 straight or branched chain alkyl, or -C (= O) R 5, wherein R 5 is -OH, or a C 1 -5 straight or Branched alkyl;

Figure 112014019931035-pat00011
이 이중결합인 경우,
Figure 112014019931035-pat00011
In the case of this double bond,

상기 R1, R2 및 R3는 독립적으로 -H, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 C1 -5 직쇄 또는 측쇄 알킬이고;R 1 , R 2 and R 3 are independently -H, halogen, C 1 -5 straight-chain or branched alkyl substituted with at least one halogen or unsubstituted halogen;

R4는 -H, 비치환 또는 하나 이상의 -OH기가 치환된 C1 -5 직쇄 또는 측쇄 알킬, 또는 -C(=O)R5이고, 여기서 R5는 -OH, 또는 C1 -5 직쇄 또는 측쇄 알킬이다.
R 4 is -H, an unsubstituted or at least one -OH group is substituted C 1 -5 straight or branched chain alkyl, or -C (= O) R 5, wherein R 5 is -OH, or a C 1 -5 straight or Lt; / RTI >

더욱 바람직하게는,More preferably,

Figure 112014019931035-pat00012
이 단일결합인 경우,
Figure 112014019931035-pat00012
If this is a single bond,

상기 R1은 -Cl, 또는 -CF3이고;Wherein R 1 is -Cl, or a -CF 3;

R2는 -H, -CH3, 또는 -F이고;R 2 is -H, -CH 3 , or -F;

R3는 -CH3, 또는 -CHF2이고;R 3 is -CH 3 , or -CHF 2 ;

R4는 -H, -CH3, -CH2CH3, -CH2CH2OH, -C(=O)CH3, 또는 -C(=O)OH이고;
R 4 is -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, -C (= O) CH 3 , or -C (= O) OH;

Figure 112014019931035-pat00013
이 이중결합인 경우,
Figure 112014019931035-pat00013
In the case of this double bond,

상기 R1은 -Cl, 또는 -CF3이고;Wherein R 1 is -Cl, or a -CF 3;

R2는 -H, -CH3, 또는 -F이고;R 2 is -H, -CH 3 , or -F;

R3는 -CH3, -CH(CH3)2, 또는 -CHF2이고;R 3 is -CH 3 , -CH (CH 3 ) 2 , or -CHF 2 ;

R4는 -H, -CH3, -CH2CH3, -CH2CH2OH, -C(=O)CH3, 또는 -C(=O)OH이다.
R 4 is -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, -C (= O) CH 3 , or -C (= O) OH.

상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체의 바람직한 예로는 하기의 화합물들을 들 수 있다.Preferred examples of the pyrimidine-2,4-diamine derivative represented by the above formula (1) include the following compounds.

(1) 5-클로로-N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)피리미딘-2,4-디아민;(1) Synthesis of 5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy- 4- (1,2,3,6-tetrahydropyridin- Pyrimidine-2,4-diamine;

(2) 5-클로로-N2-(2-이소프로폭시-5-메틸-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)-N4-(2-(이소프로필술포닐)페닐)피리미딘-2,4-디아민;(2) Synthesis of 5-chloro-N2- (2-isopropoxy-5-methyl-4- (1,2,3,6-tetrahydropyridin- Sulfonyl) phenyl) pyrimidine-2,4-diamine;

(3) 5-클로로-N2-(2-(디플루오로메톡시)-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)-N4-(2(이소프로필술포닐_페닐)피리미딘-2,4-디아민;(3) Synthesis of 5-chloro-N2- (2- (difluoromethoxy) -4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl) -N4- Phenyl) pyrimidine-2,4-diamine;

(4) 5-클로로-N2-(2-(디플루오로메톡시)-4-(피페리딘-4-일)페닐)-N4 (2(이소프로필술포닐)페닐)피리미딘-2,4-디아민;(4) Synthesis of 5-chloro-N2- (2- (difluoromethoxy) -4- (piperidin-4-yl) phenyl) -N4 (2- (isopropylsulfonyl) - diamines;

(5) 5-클로로-N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-4-(피페리딘-4-일)페닐)피리미딘-2,4-디아민;(5) Synthesis of 5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- methoxy- 4- (piperidin- 4- yl) phenyl) pyrimidine- ;

(6) N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)-5-(트리플루오로메틸)피리미딘-2,4-디아민;(6) Synthesis of N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy-4- (1,2,3,6-tetrahydropyridin- Trifluoromethyl) pyrimidine-2,4-diamine;

(7) N2-(2-이소프로폭시-5-메틸-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)-N4-(2(이소프로필술포닐)페닐)-5-(트리플루오로메틸)피리미딘-2,4-디아민;(7) Synthesis of N2- (2-isopropoxy-5-methyl-4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) -5- (trifluoromethyl) pyrimidine-2,4-diamine;

(8) N2-(2-(디플루오로메톡시)-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)-N4-(2-(이소프로필술포닐)페닐)-5-(트리플루오로메틸)피리미딘-2,4-디아민;(8) Synthesis of N2- (2- (difluoromethoxy) -4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) -5- (trifluoromethyl) pyrimidine-2,4-diamine;

(9) N2-(2-(디플루오로메톡시)-4-(피페리딘-4-일)페닐)-N4-(2-(이소프로필술포닐)페닐)-5-(트리플루오로메틸)피리미딘-2,4-디아민;(9) Synthesis of N2- (2- (difluoromethoxy) -4- (piperidin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl ) Pyrimidine-2,4-diamine;

(10) 5-클로로-N2-(5-플루오로-2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)-N4-(2-(이소프로필술포닐)페닐)피리미딘-2,4-디아민;(10) Synthesis of 5-chloro-N2- (5-fluoro-2-methoxy-4- (1,2,3,6-tetrahydropyridin- Sulfonyl) phenyl) pyrimidine-2,4-diamine;

(11) 5-클로로-N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-5-메틸-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)피리미딘-2,4-디아민;(11) Synthesis of 5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy- Yl) phenyl) pyrimidine-2,4-diamine;

(12) 5-클로로-N2-(5-플루오로-2-메톡시-4-(피페리딘-4-일)페닐)-N4-(2-(이소프로필술포닐)페닐)피리미딘-2,4-디아민;(12) 5-Chloro-N2- (5-fluoro-2-methoxy-4- (piperidin- 4- yl) phenyl) -N4- (2- (isopropylsulfonyl) 2,4-diamine;

(13) 5-클로로-N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-5-메틸-4-(피페리딘-4-일)페닐)피리미딘-2,4-디아민;(13) Synthesis of 5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy- , 4-diamine;

(14) 5-클로로-N2-(4-(1-에틸-1,2,3,6-테트라하이드로피리딘-4-일)-2-메톡시페닐)-N4-(2-(이소프로필술포닐)페닐)피리미딘-2,4-디아민;(14) Synthesis of 5-chloro-N2- (4- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -2- methoxyphenyl) -N4- (2- Phenyl) pyrimidine-2,4-diamine;

(15) 5-클로로-N2-(4-(1-에틸-1,2,3,6-테트라하이드로피리딘-4-일)-2-메톡시페닐)-N4-(2-(이소프로필술포닐)페닐)피리미딘-2,4-디아민;(15) Synthesis of 5-chloro-N2- (4- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -2- methoxyphenyl) -N4- (2- Phenyl) pyrimidine-2,4-diamine;

(16) 1-(4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-3-메톡시페닐)-5,6-디하이드로피리딘-1(2H)-일)에탄온;(16) Synthesis of 1- (4- (4 - ((5-chloro-4 - ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin- 5,6-dihydropyridin-1 (2H) -yl) ethanone;

(17) 4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-3-메톡시페닐)-5,6-디하이드로피리딘-1(2H)-카르복시산;(17) Synthesis of 4- (4 - ((5-chloro-4 - ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin- - dihydropyridin-1 (2H) -carboxylic acid;

(18) 4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-3-메톡시페닐)-5,6-디하이드로피리딘-1(2H)-메틸.
(18) 4- (4-chloro-4 - ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin- - dihydropyridin-1 (2H) -methyl.

본 발명의 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체는 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산, 아세트산, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산과 같은 유기산으로부터 얻었다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.The pyrimidine-2,4-diamine derivative represented by the above formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt. Examples of the salt include pharmaceutically acceptable acid addition salts formed by free acid Salts are useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, and the like. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

본 발명에 따른 산 부가염은 통상의 방법, 예를 들면 피리미딘-2,4-디아민 유도체를 유기용매, 예를 들면 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조하여 제조되거나, 용매와 과량의 산을 감압 증류한 후 건조하거나 유기용매 하에서 결정화시켜서 제조할 수 있다.
The acid addition salt according to the present invention may be prepared by dissolving the pyrimidine-2,4-diamine derivative in an organic solvent, for example, methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., Filtration and drying of the resulting precipitate, or by distillation of the solvent and excess acid under reduced pressure, followed by drying or crystallization in an organic solvent.

또한, 본 발명은 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체 및 이의 약학적으로 허용하는 염뿐만 아니라, 이로부터 제조될 수 있는 가능한 용매화물, 수화물, 이성질체 등을 모두 포함한다.
The present invention also encompasses pyrimidine-2,4-diamine derivatives represented by the above formula (1) and pharmaceutically acceptable salts thereof, as well as possible solvates, hydrates, and isomers thereof.

또한, 본 발명은 하기 반응식 1에 나타난 바와 같이,The present invention also relates to a process for producing a compound represented by the formula (1)

화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계(단계 1); 및Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And

상기 단계 1에서 제조한 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계(단계 2);를 포함하는 제1항의 피리미딘-2,4-디아민 유도체의 제조방법을 제공한다.(2) reacting a compound represented by the formula (4) and a compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (1) (step 2) And a method for producing a diamine derivative.

[반응식 1][Reaction Scheme 1]

Figure 112014019931035-pat00014
Figure 112014019931035-pat00014

상기 반응식 1에서, R1 내지 R4는 본 명세서에서 정의한 바와 같다.
In the above Reaction Scheme 1, R 1 to R 4 are as defined in the present specification.

이하, 본 발명에 따른 제조방법을 단계별로 상세히 설명한다.
Hereinafter, the manufacturing method according to the present invention will be described step by step.

본 발명에 따른 제조방법에 있어서, 상기 단계 1은 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계이다.In the preparation method according to the present invention, the step 1 is a step of reacting a compound represented by the formula (2) and a compound represented by the formula (3) to prepare a compound represented by the formula (4).

구체적으로, 상기 화학식 2로 표시되는 화합물을 유기용매 및 염기 하에서 화학식 3으로 표시되는 화합물과 알킬화 반응시켜 화학식 4로 표시되는 화합물을 얻을 수 있다.Specifically, the compound represented by the formula (2) may be alkylated with the compound represented by the formula (3) under an organic solvent and a base to obtain a compound represented by the formula (4).

이때, 사용가능한 용매는 테트라하이드로퓨란; 다이옥산; 에틸에테르, 1,2-다이메톡시에탄 등을 포함하는 에테르용매; 메탄올, 에탄올, 프로판올 및 부탄올을 포함하는 저급 알코올; 디메틸포름아미드(DMF), 디메틸설폭사이드(DMSO), 아세토나젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시크레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.At this time, usable solvents include tetrahydrofuran; Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; But are not limited to, dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonazenesulfonate, toluene sulfonate, chlorobenzene sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, -Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

또한, 상기 염기는 피리딘, 트리에틸아민, N,N-다이이소프로필에틸아민(DIPEA), 1,8-디아자비사이클로[5.4.0]-7-운테센(DBU) 등의 유기염기; 또는 소듐하이드록사이드, 소듐카보네이트, 포타슘카보네이트, 세슘카보네이트, 소듐하이드라이드 등의 무기염기를 당량 또는 과량으로 사용할 수 있으며, 반응온도는 50-200 ℃, 교반시간은 0.5-20 시간을 가진다.The base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA), or 1,8-diazabicyclo [5.4.0] -7-anthesene (DBU); Or inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride may be used in an equivalent amount or in an excess amount, and the reaction temperature is 50-200 ° C and the stirring time is 0.5-20 hours.

상기 반응을 수행한 후, 유기용매로 추출, 건조, 여과 및 감압 증류하는 과정을 수행하고 추가적으로 칼럼크로마토그래피를 수행하여 상기 화학식 4로 표시되는 화합물을 얻을 수 있다.
After carrying out the above reaction, extraction with an organic solvent, drying, filtration and distillation under reduced pressure are performed, and further column chromatography is carried out to obtain the compound represented by the formula (4).

본 발명에 따른 제조방법에 있어서, 상기 단계 2는 상기 단계 1에서 제조한 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계이다.In the preparation method according to the present invention, the step 2 is a step of reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (1).

구체적으로, 상기 화학식 4로 표시되는 화합물을 유기용매 및 염기 하에서 화학식 5로 표시되는 화합물과 알킬화 반응시켜 화학식 1로 표시되는 화합물을 얻을 수 있다.Specifically, the compound represented by the general formula (4) may be alkylated with the compound represented by the general formula (5) under an organic solvent and a base to obtain a compound represented by the general formula (1).

이때, 사용가능한 용매는 테트라하이드로퓨란; 다이옥산; 에틸에테르, 1,2-다이메톡시에탄 등을 포함하는 에테르용매; 메탄올, 에탄올, 프로판올 및 부탄올을 포함하는 저급 알코올; 디메틸포름아미드(DMF), 디메틸설폭사이드(DMSO); 아세토나젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시크레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.At this time, usable solvents include tetrahydrofuran; Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethylsulfoxide (DMSO); Butyrate, glycolate, maleate, tartrate, glutarate, glutarate, glutarate, glutarate, glutaraldehyde, glutaraldehyde, glutaraldehyde, glutaraldehyde, Methane sulfonate, propane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

또한, 상기 염기는 피리딘, 트리에틸아민, N,N-다이이소프로필에틸아민(DIPEA), 1,8-디아자비사이클로[5.4.0]-7-운테센(DBU) 등의 유기염기; 또는 소듐하이드록사이드, 소듐카보네이트, 포타슘카보네이트, 세슘카보네이트, 소듐하이드라이드 등의 무기염기를 당량 또는 과량으로 사용할 수 있으며, 반응온도는 50-200 ℃, 교반시간은 0.5-20 시간을 가진다.The base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA), or 1,8-diazabicyclo [5.4.0] -7-anthesene (DBU); Or inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride may be used in an equivalent amount or in an excess amount, and the reaction temperature is 50-200 ° C and the stirring time is 0.5-20 hours.

상기 반응을 수행한 후, 유기용매로 추출, 건조, 여과 및 감압 증류하는 과정을 수행하고 추가적으로 칼럼크로마토그래피를 수행하여 상기 화학식 1로 표시되는 화합물을 얻을 수 있다.
The reaction is carried out, followed by extraction with an organic solvent, drying, filtration and distillation under reduced pressure, and further performing column chromatography to obtain a compound represented by the formula (1).

나아가, 본 발명은 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.
Further, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the pyrimidine-2,4-diamine derivative represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

또한, 본 발명은 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 역형성 림프종 키나아제(ALK, Anaplastic Lymphoma Kinase) 과활성으로 인하여 유발되는 질환의 예방 또는 치료용 약학적 조성물을 제공한다.
The present invention also relates to a pharmaceutical composition for inducing an activation of anaplastic lymphoma kinase (ALK) comprising the pyrimidine-2,4-diamine derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Or a pharmaceutically acceptable salt thereof.

나아가, 본 발명은 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 역형성 림프종 키나아제(ALK, Anaplastic Lymphoma Kinase) 저해제를 제공한다.
Further, the present invention provides an inhibitor of Anaplastic Lymphoma Kinase (ALK) comprising the pyrimidine-2,4-diamine derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명에 따른 상기 약학적 조성물 및 저해제는 역형성 림프종 키나아제(ALK, Anaplastic Lymphoma Kinase)의 활성을 억제하여 암세포의 발현 및 성장을 억제하는 것을 특징으로 한다.
The pharmaceutical composition and the inhibitor according to the present invention are characterized by inhibiting the activity of anaplastic lymphoma kinase (ALK) and inhibiting the expression and growth of cancer cells.

역형성 림프종 키나아제(ALK)는 암세포에 존재하는 암의 세포증식을 유도하는 유전자로써, 유전자 융합 과정에 의해 역형성 림프종 키나아제(ALK)가 활성화되고, 이때, 역형성 림프종 키나아제(ALK)가 가지고 있는 타이로신 키나아제가 비정상적으로 행동하여 세포의 증식을 유도하고, 아포프토시스를 방해해 세포가 사멸되지 않게 하며 세포뼈대를 재배열시키며 세포 형태를 변형시킬 뿐만 아니라, 역형성 림프종 키나아제(ALK)는 정상이거나 암 유전자화한 다른 타이로신 키나아제와 연결되어 상호작용을 하거나 여러 종류의 다른 경로들을 활성화시킨다.
Reverse transforming lymphoma kinase (ALK) is a gene that induces cell proliferation of cancer cells in cancer cells. The gene fusion process activates reverse transforming lymphoma kinase (ALK), and in turn activates lymphocyte kinase (ALK) Tyrosine kinase acts abnormally to induce cell proliferation, prevents apoptosis, prevents cell death, rearranges cellular skeletons, and modifies cell morphology. In addition, reverse lymphoma kinase (ALK) It interacts with other tyrosine kinases that are differentiated and activates several different pathways.

이에, 본 발명에 따른 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체의 역형성 림프종 키나아제(ALK) 활성을 검증하기 위해, 본 발명에 따른 화합물들을 역형성 림프종 키나아제(ALK) 효소 및 여러 암세포에 처리한 후 IC50 및 GI50을 측정한 결과, 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체 중 대부분의 화합물들이 대조군(크리조티닙 및 LDK-378) 화합물에 비하여 활성이 우수한 것으로 나타났다(실험예 1-4 참조).
Thus, in order to verify the inverse lymphoma kinase (ALK) activity of the pyrimidine-2,4-diamine derivative represented by the formula 1 according to the present invention, the compounds according to the present invention can be used for the inverse lymphoma kinase (ALK) IC 50 and GI 50 were measured after treatment with various cancer cells. As a result, it was found that most of the pyrimidine-2,4-diamine derivatives represented by Chemical Formula 1 were more active than the control compounds (clitorotinib and LDK-378) (See Experimental Examples 1-4).

본 발명에 따른 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체들은 역형성 림프종 키나아제(ALK)의 활성을 억제하여 암을 예방 또는 치료하는데 사용될 수 있다. 예를 들어, 비소세포폐암, 신경모세포종, 염증성 골수섬유모세포종양, 종횡문근육종, 근섬유모세포종, 유방암, 위암, 폐암, 흑색종, 대형 B-세포 림프종, 전신성 조식구증, 염증성 근섬유아세포성 육종, 식도 편평 세포암, 자궁암, 전립선암 등에 유용할 수 있다.
The pyrimidine-2,4-diamine derivatives represented by the formula (1) according to the present invention can be used for preventing or treating cancer by inhibiting the activity of reversed lymphoma kinase (ALK). For example, there is provided a method of treating a disease selected from the group consisting of non-small cell lung cancer, neuroblastoma, inflammatory myelofibroblastoma, endometrioid sarcoma, myofiber neoplasia, breast cancer, gastric cancer, lung cancer, melanoma, large B-cell lymphoma, Squamous cell cancer, uterine cancer, prostate cancer, and the like.

본 발명의 조성물을 의약품으로 사용하는 경우, 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물은 임상투여 시에 다양한 하기의 경구 또는 비경구 투여 형태로 제제화되어 투여될 수 있으나, 이에 한정되는 것은 아니다.When the composition of the present invention is used as a medicament, the pharmaceutical composition containing the pyrimidine-2,4-diamine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient can be used in a variety of Orally, parenterally, or parenterally.

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

상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체를 유효성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다.The pharmaceutical composition comprising the pyrimidine-2,4-diamine derivative represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be carried out by subcutaneous injection, intravenous injection, intramuscular injection, And the like.

이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용되는 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.In this case, in order to formulate the formulation for parenteral administration, the pyrimidine-2,4-diamine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water or a stabilizer or a buffer to prepare a solution or suspension , Which can be prepared in an ampoule or vial unit dosage form. The composition may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wettable or emulsifying accelerators, salts for the control of osmotic pressure and / or buffers, and other therapeutically useful substances, Or a coating method.

상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체를 유효성분으로 함유하는 약학적 조성물의 인체에 대한 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달리질 수 있으며, 바람직하게는 0.01 내지 1000 mg/kg/일의 양으로 의사 또는 약사의 판단에 따라 일정 시간 간격을 1일 수회, 바람직하게는 1일 1회 내지 3회로 분할하여 경구 또는 비경구적 경로를 통해 투여할 수 있다.
The dosage of the pharmaceutical composition containing the pyrimidine-2,4-diamine derivative represented by the above formula (1) as an active ingredient in the human body depends on the age, body weight, sex, dosage form, Preferably at a dose of 0.01 to 1000 mg / kg / day, divided into several times a day, preferably once or three times a day, depending on the judgment of a physician or pharmacist, ≪ / RTI >

이하, 본 발명에 따른 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체의 제조방법을 제조예 또는 실시예를 통해 상세하게 설명한다. 하기 실시예는 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체를 제조하는 방법의 일례로서, 본 발명을 예시하는 것일 뿐, 이에 한정하지 않는다. 하기 실시예에 의해 설명되는 제조방법은 유기합성 분야에서 잘 알려진 합성조건, 적절한 시약 등을 사용하여 얻을 수 있다.
Hereinafter, the process for preparing the pyrimidine-2,4-diamine derivative represented by the formula (1) according to the present invention will be described in detail with reference to the following Production Examples or Examples. The following example is an example of a method for producing the pyrimidine-2,4-diamine derivative represented by the above formula (1), but the present invention is not limited thereto. The preparation methods described by the following examples can be obtained by using synthetic conditions well-known in the art of organic synthesis, suitable reagents and the like.

<< 실시예Example 1> 5- 1 > 5- 클로로Chloro -- N4N4 -(2-(이소프로필술포닐)페닐)-- (2- (isopropylsulfonyl) phenyl) - N2N2 -(2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)피리미딘-2,4-디아민의 제조- (2-methoxy-4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl) pyrimidine-2,4-diamine

단계 1 : Step 1: terttert -부틸 4-(4-((5--Butyl 4- (4 - ((5- 클로로Chloro -4-((2-(-4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )아미노)피리미딘-2-일)아미노)-3-) Amino) pyrimidin-2-yl) amino) -3- 메톡시페닐Methoxyphenyl )-5,6-) -5,6- 디하이드로피리딘Dihydropyridine -1(2H)-카복시레이트-1 (2H) -carboxylate 의of 제조 Produce

Figure 112014019931035-pat00015
Figure 112014019931035-pat00015

2,5-디클로로-N-(2-(이소프로필술포닐)페닐)피리미딘-4-아민 1.6g(4.6mmol)을 THF 25ml에 녹인 후 tert-부틸 4-(4-아미노-3-메톡시페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 1.4g(4.6mmol)을 첨가하고, 잔트포스 266mg (0.46mmol), Cs2CO3 4.5g(13.8mmol)을 순서대로 첨가한 후, 질소를 충전하여 탈 가스 하였다. Pd(OAc)2 (51.6mg, 0.23mmol)를 첨가하고, 질소 충전 후 130℃에서 18시간 교반하였다. 반응 종료 후, EA/H2O로 추출한 후 유기층은 MgSO4로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피(Hx:EA 4:1)를 이용하여 목적 화합물 330mg을 20%의 수율로 얻었다.1.6 g (4.6 mmol) of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine was dissolved in 25 ml of THF, methoxyphenyl) -5,6-dihydropyridin--1 (2H) - addition of a carboxy acrylate 1.4g (4.6mmol), and janteu force 266mg (0.46mmol), Cs 2 CO 3 (13.8 mmol) were added in this order, and then degassed by filling with nitrogen. Pd (OAc) 2 (51.6 mg, 0.23 mmol) was added, and after charging with nitrogen, the mixture was stirred at 130 캜 for 18 hours. After completion of the reaction, the reaction mixture was extracted with EA / H 2 O, and the organic layer was dried over MgSO 4 , filtered and concentrated. 330 mg of the title compound was obtained in a yield of 20% using column chromatography (Hx: EA 4: 1).

1H NMR (CDCl3, 300MHz) δ 9.55(s,1H),8.58(d,J=8.4Hz,1H), 8.24(d,J=8.7Hz,1H),8.16(s,1H), 7.94(d,J=8.1Hz,1H),7.68(t,J=7.8Hz,1H), 7.59(s,1H), 6.92(s,2H),6.0-5.98(m,1H), 4.09(s,2H), 3.92(s,3H),3,65-3.63(m,2H),3.29-3.19(m,1H),2.53(s,2H),1.66(s,3H),1.49(s,9H), 1.32(d,J=6.9Hz,6H).
 1 H NMR (CDCl 3, 300MHz ) δ 9.55 (s, 1H), 8.58 (d, J = 8.4Hz, 1H), 8.24 (d, J = 8.7Hz, 1H), 8.16 (s, 1H), 7.94 ( (d, J = 8.1 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.59 (s, 1H), 6.92 (s, 2H), 6.0-5.98 2H), 1.66 (s, 3H), 1.49 (s, 9H), 3.92 (s, 3H), 3,65-3.63 (m, 2H), 3.29-3.19 1.32 (d, J = 6.9 Hz, 6 H).

단계 2 : 5-Step 2: 5- 클로로Chloro -- N4N4 -(2-(이소프로필술포닐)페닐)-- (2- (isopropylsulfonyl) phenyl) - N2N2 -(2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)피리미딘-2,4-디아민의 제조- (2-methoxy-4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl) pyrimidine-2,4-diamine

Figure 112014019931035-pat00016
Figure 112014019931035-pat00016

상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-3-메톡시페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 화합물 1.13mg(1.84mmol)을 MeOH에 녹인 후, 4M HCl이 용해된 디옥산 6ml를 첨가한 후, 상온에서 0.5시간 교반하였다. 반응이 종료된 후, HCl을 제거하고 에테르로 디캔팅(decanting)하여 목적 화합물 300mg을 99%의 수율로 얻었다.Amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) -4- (4- (4- ) -5,6-dihydropyridin-1 (2H) -carboxylate compound (1.13 mg, 1.84 mmol) was dissolved in MeOH, 6 ml of 4M HCl-dissolved dioxane was added thereto, and the mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, HCl was removed and decanting with ether gave 300 mg of the target compound in a yield of 99%.

1H NMR (MeOH, 300MHz) δ 8.28(s,1H), 8.22-8.21(m,1H), 8.04(d,J=4.8Hz,1H), 7.75-7.56(m,1H),7.62-7.58(m,1H),7.51(d,J=5.1Hz,1H),7.20(s,1H),7.01-7.00(m,1H),6.24(s,1H),3.94(s,3H), 3.91(s,2H), 3.43-3.40(m,1H), 2.85(s,2H), 1.26(d,J=13.2,6Hz).
 1 H NMR (MeOH, 300MHz) δ 8.28 (s, 1H), 8.22-8.21 (m, 1H), 8.04 (d, J = 4.8Hz, 1H), 7.75-7.56 (m, 1H), 7.62-7.58 ( 1H), 7.51 (d, J = 5.1 Hz, 1H), 7.20 (s, 1H), 7.01-7.00 , 2H), 3.43-3.40 (m, 1H), 2.85 (s, 2H), 1.26 (d, J = 13.2,6Hz).

<< 실시예Example 2> 5- 2> 5- 클로로Chloro -- N2N2 -(2--(2- 이소프로폭시Isopropoxy -5--5- 메틸methyl -4-(1,2,3,6--4- (1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)Yl) 페닐Phenyl )-) - N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

단계 1 : Step 1: terttert -부틸 4-(4-((5--Butyl 4- (4 - ((5- 클로로Chloro -4-((2-(-4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )아미노)피리미딘-2-일)아미노)-5-) Amino) pyrimidin-2-yl) amino) -5- 이소프로폭시Isopropoxy -2--2- 메틸페닐Methylphenyl )-5,6-) -5,6- 디하이드로피리딘Dihydropyridine -1(2H)-카복시레이트의 제조-1 (2H) -carboxylate

Figure 112014019931035-pat00017
Figure 112014019931035-pat00017

2,5-디클로로-N-(2-(이소프로필술포닐)페닐)피리미딘-4-아민 1g(2.88 mmol)을 THF 20ml에 녹인 후 tert-부틸 4-(4-아미노-5-이소프로폭시-2-메틸페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 955mg(2.88 mmol)을 첨가하고, 잔트포스 167mg(0.288mmol) 및 Cs2CO3 2.8g(8.64mmol)을 순서대로 넣어 준 후 질소 충전시켜 준 후 탈 가스 하였다. Pd(OAc)2 (32mg,0.144mmol)를 첨가하고, 질소 충전 후 130℃에서 18시간 교반하였다. 반응 종료 후, EA/H2O로 추출한 후 유기층은 MgSO4로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피(Hx:EA 4:1)를 이용하여 목적 화합물 642 mg을 34%의 수율로 얻었다.1 g (2.88 mmol) of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine was dissolved in 20 ml of THF, (2.88 mmol) was added, and 167 mg (0.288 mmol) of Zafthos and 16 mg (0.288 mmol) of Cs 2 CO 3 2.8 g (8.64 mmol) were added in this order, and the mixture was degassed after being charged with nitrogen. Pd (OAc) 2 (32 mg, 0.144 mmol) was added, and after charging with nitrogen, the mixture was stirred at 130 캜 for 18 hours. After completion of the reaction, the reaction mixture was extracted with EA / H 2 O, and the organic layer was dried over MgSO 4 , filtered and concentrated. 642 mg of the title compound was obtained in a yield of 34% by column chromatography (Hx: EA 4: 1).

1H NMR (CDCl3, 300MHz) δ 9.49(s,1H), 8.57(d,J=8.4Hz,1H), 8.16(s,1H), 8.04(s,1H), 7.94(dd,J=0.9Hz, 1.2Hz,1H), 7.66-7.59(m,2H), 6.63(s,1H), 5.54(brs,1H), 4.58-4.54(m,1H), 4.04(s,2H), 3.63(t,J=5.4Hz,2H), 3.30-3.21(m,1H), 2.35-2.33(m,2H), 2.09(s,3H), 1.50(s,9H), 1.38(d,J=6.0Hz, 6H), 1.33(d,J=6.9Hz,6H).
 1 H NMR (CDCl 3 , 300 MHz)? 9.49 (s, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.16 2H), 3.63 (s, IH), 5.54 (brs, IH), 4.58-4.54 2H, J = 5.4 Hz, 2H), 3.30-3.21 (m, 1H), 2.35-2.33 (m, 2H), 2.09 (s, 6H), 1.33 (d, J = 6.9 Hz, 6H).

단계 2 : 5-Step 2: 5- 클로로Chloro -- N2N2 -(2--(2- 이소프로폭시Isopropoxy -5--5- 메틸methyl -4-(1,2,3,6--4- (1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)Yl) 페닐Phenyl )-) - N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00018
Figure 112014019931035-pat00018

상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 화합물 600mg(0.91mmol)을 MeOH에 녹인 후, 4M HCl이 용해된 디옥산 5ml를 첨가한 후, 상온에서 0.5시간 교반하였다. 반응이 종료된 후, HCl을 제거하고 에테르로 디캔팅(decanting)하여 목적 화합물 630 mg을 99%의 수율로 얻었다.To a solution of tert-butyl 4- (4 - ((5-chloro-4 - ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin- -5,6-dihydropyridin-1 (2H) -carboxylate (600 mg, 0.91 mmol) was dissolved in MeOH, and 5 ml of 4M HCl- Lt; / RTI &gt; After the reaction was completed, HCl was removed and decanting with ether gave 630 mg of the target compound in a yield of 99%.

1H NMR (CDCl3, 300MHz) δ 8.27(brs,2H), 8.04(d,J=7.5Hz,1H), 7.78-7.73(m,1H), 7.60-7.55(m,1H), 7.34(s,1H), 6.87(s,1H), 5.66(s,1H), 3.84(s,2H), 3.65(s,3H), 2.61(s,2H), 2.13(s,3H), 1.30(d,J=6Hz,6H), 1.26(d,J=6.9Hz,6H).
 1 H NMR (CDCl 3, 300MHz ) δ 8.27 (brs, 2H), 8.04 (d, J = 7.5Hz, 1H), 7.78-7.73 (m, 1H), 7.60-7.55 (m, 1H), 7.34 (s 3H), 2.61 (s, 2H), 2.13 (s, 3H), 1.30 (d, 2H) J = 6 Hz, 6H), 1.26 (d, J = 6.9 Hz, 6H).

<< 실시예Example 3> 5- 3> 5- 클로로Chloro -- N2N2 -(2-(-(2-( 디플루오로메톡시Difluoromethoxy )-4-(1,2,3,6-) -4- (1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)Yl) 페닐Phenyl )-) - N4N4 -(2-(-(2-( 이소프로필술포닐페닐Isopropylsulfonylphenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

단계 1 : Step 1: terttert -부틸 4-(4-((5--Butyl 4- (4 - ((5- 클로로Chloro -4-((2-(-4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )피리미딘-2-일)아미노)-3-() Pyrimidin-2-yl) amino) -3- ( 디플루오로메톡시Difluoromethoxy )) 페닐Phenyl )-5,6-) -5,6- 디하이드로피리딘Dihydropyridine -1(2H)--1 (2H) - 카복시레이Carboxy ray 트The 의of 제조 Produce

Figure 112014019931035-pat00019
Figure 112014019931035-pat00019

2,5-디클로로-N-(2-(이소프로필술포닐)페닐)피리미딘-4-아민 200 mg(0.58 mmol)을 THF 5 ml에 녹인 후 tert-부틸 4-(4-아미노-3-(디플루오로메톡시)페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 195 mg(0.58 mmol)을 첨가해주고 잔트포스 33 mg (0.058 mmol), Cs2CO3 550 mg(1.74 mmol)을 순서대로 넣어 준 후 질소 충전시켜 준 후에 탈 가스 하였다. Pd(OAc)2를 첨가하고, 질소 충전 후 130℃에서 18시간 교반하였다. EA/H2O로 추출한 후 유기층은 MgSO4로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피(Hx:EA 6:1)를 이용하여 목적 화합물 120 mg을 32%의 수율로 얻었다.After 200 mg (0.58 mmol) of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine was dissolved in 5 ml of THF, tert- butyl 4- (difluoromethoxy) phenyl) -5,6-dihydropyridine -1 (2H) - addition of a carboxy acrylate 195 mg (0.58 mmol) haejugo janteu phosphine 33 mg (0.058 mmol), Cs 2 CO 3 550 mg (1.74 mmol) were added in this order, and then degassed after being charged with nitrogen. Pd (OAc) 2 was added, and after charging with nitrogen, the mixture was stirred at 130 DEG C for 18 hours. After extraction with EA / H 2 O, the organic layer was dried over MgSO 4 , filtered and concentrated. 120 mg of the desired compound was obtained in a yield of 32% using column chromatography (Hx: EA 6: 1).

1H-NMR (300 MHz, CDCl3) δ 8.53(d, J=8.4Hz, 1H), 8.31(d, J=9.0Hz, 1H) , 8.18(s, 1H), 7.94(d, J=8.1Hz, 1H) 7.66(t, J=7.2, 1H) 7.33-7.29(m, 2H), 7.17(d, J=5.1Hz, 2H), 6.01(s, 1H), 4.08(s,2H) 3.66(t, J=5.4Hz, 2H), 3.26-3.21(m, 1H), 2.50(s, 2H), 1.49(s,9H), 1.33(d, J=6.6, 6H).
 1 H-NMR (300 MHz, CDCl 3) δ 8.53 (d, J = 8.4Hz, 1H), 8.31 (d, J = 9.0Hz, 1H), 8.18 (s, 1H), 7.94 (d, J = 8.1 1H), 7.66 (t, J = 7.2, 1H) 7.33-7.29 (m, 2H), 7.17 (d, J = 5.1 Hz, 2H) t, J = 5.4 Hz, 2H), 3.26-3.21 (m, IH), 2.50 (s, 2H), 1.49 (s, 9H), 1.33 (d, J = 6.6, 6H).

단계 2 : 5-Step 2: 5- 클로로Chloro -- N2N2 -(2-(-(2-( 디플루오로메톡시Difluoromethoxy )-4-(1,2,3,6-) -4- (1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)Yl) 페닐Phenyl )-) - N4N4 -(2-(-(2-( 이소프로필술포닐페닐Isopropylsulfonylphenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00020
Figure 112014019931035-pat00020

상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)피리미딘-2-일)아미노)-3-(디플루오로메톡시)페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 화합물 100 mg(0.154 mmol)을 MeOH에 녹인 후, 4M HCl이 용해된 디옥산 7 ml를 첨가한 후 , 상온에서 1시간 교반하였다. 반응이 종료된 후, HCl을 제거하고 에테르로 디캔팅(decanting)하여 목적 화합물(노란색 고체, 90mg)을 95%의 수율로 얻었다.Amino) -3- (difluoromethoxyphenyl) pyrimidin-2-yl) amino] -3- (4-fluoro- ) Phenyl) -5,6-dihydropyridin-1 (2H) -carboxylate A solution of 100 mg (0.154 mmol) of the compound in MeOH was added 7 ml of 4M HCl-dissolved dioxane, After completion of the reaction, HCl was removed and decanting with ether gave the target compound (yellow solid, 90 mg) in a yield of 95%.

1H-NMR (300 MHz, MeOD) δ 8.31(s, 1H), 8.11-8.00(m, 1H), 8.00(d, J=10.8Hz, 1H), 7.62-7.55(m, 4H), 7.38(s,1H), 6.24(d, J=0.9Hz, 1H) 3.9(s, 2H), 3.50(s,2H), 2.82(s, 2H), 1.23(d, J=4.2Hz, 6H).
 1 H-NMR (300 MHz, MeOD) δ 8.31 (s, 1H), 8.11-8.00 (m, 1H), 8.00 (d, J = 10.8Hz, 1H), 7.62-7.55 (m, 4H), 7.38 ( (s, 2H), 2.82 (s, 2H), 1.23 (d, J = 4.2 Hz, 6H).

<< 실시예Example 4> 5- 4> 5- 클로로Chloro -- N2N2 -(2-(-(2-( 디플루오로메톡시Difluoromethoxy )-4-(피페리딘-4-일)) -4- (piperidin-4-yl) 페닐Phenyl )-) - N4N4 -(2-(이- (2- ( 소프로필술Sopropyl alcohol 포닐)&Lt; / RTI & 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

단계 1 :Step 1: terttert -부틸 4-(4-((5--Butyl 4- (4 - ((5- 클로로Chloro -4-((2-(-4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )아미노)피리미딘-2-일)아미노)-3-() Amino) pyrimidin-2-yl) amino) -3- ( 디플루오로메톡시Difluoromethoxy )) 페닐Phenyl )피페리딘-1-) Piperidin-l- 카복시레이트의Carboxy 제조 Produce

Figure 112014019931035-pat00021
Figure 112014019931035-pat00021

2,5-디클로로-N-(2-(이소프로필술포닐)페닐)피리미딘-4-아민 87mg(0.25mmol)을 THF 3ml에 녹인 후 tert-부틸 4-(아미노-3-(디플루오로메톡시)페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 85mg(0.25mmol)을 첨가하고, 잔트포스 15mg(0.025mmol), Cs2CO3 244g(0.75mmol)을 순서대로 첨가한 후, 질소를 충전하여 탈 가스 하였다. Pd(OAc)2 (2.8mg,0.013mmol)를 첨가하고, 질소 충전 후 130℃에서 18시간 교반하였다. 반응 종료 후, EA/H2O로 추출한 후 유기층은 MgSO4로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피(Hx:EA 4:1)를 이용하여 목적 화합물 25mg을 18%의 수율로 얻었다.(0.25 mmol) of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine was dissolved in 3 ml of THF, (2H) -carboxylate (85 mg, 0.25 mmol) was added, and 15 mg (0.025 mmol) of Zafthos, Cs 2 CO 3 244g (0.75mmol) were added in this order, and then degassed by filling with nitrogen. Pd (OAc) 2 (2.8 mg, 0.013 mmol) was added, and after charging with nitrogen, the mixture was stirred at 130 캜 for 18 hours. After completion of the reaction, the reaction mixture was extracted with EA / H 2 O, and the organic layer was dried over MgSO 4 , filtered and concentrated. 25 mg of the title compound was obtained in a yield of 18% using column chromatography (Hx: EA 4: 1).

1H-NMR (300 MHz,CDCl3) δ 9.61(s, 1H), 8.53(d, J=8.4Hz, 1H), 8.22(t, J=8.1Hz, 2H), 7.93(d, J=7.8, 1H), 7.64(t, J=8.1, 1H), 7.28(d, J=7.5Hz, 2H), 7.01(d, J=8.7Hz, 2H), 4.28-4.24(m, 2H), 3.25-3.21(m, 1H), 2.84(t, J=12.9Hz, 2H) 2.67(t, J=12.3Hz, 1H), 2.17(s, 1H), 1.85(d, J=12.3Hz, 2H), 1.49(s,9H), 1.32(d, J=6.6Hz, 6H).
 1 H-NMR (300 MHz, CDCl3) δ 9.61 (s, 1H), 8.53 (d, J = 8.4Hz, 1H), 8.22 (t, J = 8.1Hz, 2H), 7.93 (d, J = 7.8, 2H), 7.28 (d, J = 7.5 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 4.28-4.24 (m, 2H), 3.25-3.21 (m, 1H), 2.84 (t, J = 12.9 Hz, 2H) 2.67 (t, J = 12.3 Hz, 1H) s, 9H), 1.32 (d, J = 6.6 Hz, 6H).

단계 2 : 5-Step 2: 5- 클로로Chloro -- N2N2 -(2-(-(2-( 디플루오로메톡시Difluoromethoxy )-4-(피페리딘-4-일)) -4- (piperidin-4-yl) 페닐Phenyl )-) - N4N4 -(2-(이- (2- ( 소프로필술Sopropyl alcohol 포닐)&Lt; / RTI & 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00022
Figure 112014019931035-pat00022

상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-3-(디플루오로메톡시)페닐)피페리딘-1-카복시레이트 화합물 23mg(0.042mmol)을 MeOH에 녹인 후, 4M HCl이 용해된 디옥산 3ml를 첨가한 후, 상온에서 1시간 교반하였다. 반응이 종료된 후, HCl을 제거하고 에테르로 디캔팅(decanting)하여 목적 화합물(노란색 고체, 21mg)을 93%의 수율로 얻었다.Amino) -3- (difluoro-phenyl) amino) pyrimidin-2-yl) amino) -3- (4- (0.042 mmol) of the compound was dissolved in MeOH, 3 ml of 4M HCl-dissolved dioxane was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the HCl was removed and decanting with ether gave the target compound (yellow solid, 21 mg) in a yield of 93%.

1H-NMR (300 MHz,MeOD) δ 8.26-8.25(m,1H), 8.16-8.14(m,1H) 7.95-7.94(m,1H) 7.68-7.48(m,2H), 7.24-7.07(m,1H), 3.64(s,1H), 3.57-3.51(m,1H), 1.28(d, J=19.8Hz, 6H).
 1 H-NMR (300 MHz, MeOD) δ 8.26-8.25 (m, 1H), 8.16-8.14 (m, 1H) 7.95-7.94 (m, 1H) 7.68-7.48 (m, 2H), 7.24-7.07 (m , 3.64 (s, 1H), 3.57-3.51 (m, 1H), 1.28 (d, J = 19.8 Hz, 6H).

<< 실시예Example 5> 5- 5> 5- 클로로Chloro -- N4N4 -(2-(이소프로필술포닐)페닐)-- (2- (isopropylsulfonyl) phenyl) - N2N2 -(2-메톡시-4-(피페리딘-4-yl)페닐)피리미딘-2,4-디아민의 제조- (2-methoxy-4- (piperidin-4-yl) phenyl) pyrimidine-2,4-diamine

단계 1 : Step 1: terttert -부틸 4-(4-((5--Butyl 4- (4 - ((5- 클로로Chloro -4-((2-(-4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )아미노)피리미딘-2-일)아미노)-3-) Amino) pyrimidin-2-yl) amino) -3- 메톡시페닐Methoxyphenyl )피페리딘-1-) Piperidin-l- 카복시레이트의Carboxy 제조 Produce

Figure 112014019931035-pat00023
Figure 112014019931035-pat00023

2,5-디클로로-N-(2-(이소프로필술포닐)페닐)피리미딘-4-아민 274g(0.79mmol)을 THF 20ml에 녹인 후 tert-부틸 4-(4-아미노-3-메톡시페닐)피페리딘-1-카복시레이트 243g(0.79mmol)을 첨가하고, 잔트포스 46mg (0.079mmol), Cs2CO3 772g(2.37mmol)을 순서대로 첨가한 후, 질소를 충전하여 탈 가스 하였다. Pd(OAc)2 (8.86mg,0.039mmol)를 첨가하고, 질소 충전 후 130℃에서 18시간 교반하였다. 반응 종료 후, EA/H2O로 추출한 후 유기층은 MgSO4로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피(Hx:EA 4:1)를 이용하여 목적 화합물 180mg을 37%의 수율로 얻었다.(0.79 mmol) of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine was dissolved in 20 ml of THF, Phenyl) piperidine-1-carboxylate were added, and 46 mg (0.079 mmol) of Zafthor, Cs 2 CO 3 (2.37 mmol) were sequentially added, and the mixture was degassed by filling with nitrogen. Pd (OAc) 2 (8.86 mg, 0.039 mmol) was added, and after charging with nitrogen, the mixture was stirred at 130 캜 for 18 hours. After completion of the reaction, the reaction mixture was extracted with EA / H 2 O, and the organic layer was dried over MgSO 4 , filtered and concentrated. 180 mg of the title compound was obtained in a yield of 37% using column chromatography (Hx: EA 4: 1).

1H-NMR (300 MHz, CDCl3) δ 9.54(s, 1H), 8.59(d, J=8.4Hz, 1H), 8.17(d, J=7.5Hz, 2H), 7.93-7.90(m,1H), 7.67-7.50(m,1H), 7.30(s,1H), 7.30-7.28(d, J=7.8Hz, 1H), 6.75-6.73(m,2H), 4.23(brs, 2H), 4.15-4.08(m, 1H), 3.8(s, 3H), 3.26-3.22(m,1H), 2.85-2.76(m,2H), 2.66-2.58(m,1H), 1.86-1.81(m,2H), 1.49(s, 9H), 1.32(d, J=6.6Hz, 6H).
 1 H-NMR (300 MHz, CDCl3) δ 9.54 (s, 1H), 8.59 (d, J = 8.4Hz, 1H), 8.17 (d, J = 7.5Hz, 2H), 7.93-7.90 (m, 1H) 2H), 4.23 (brs, 2H), 4.15-4.08 (m, IH), 7.30-7.28 (m, IH), 1.86-1.81 (m, 2H), 1.49 (m, IH) (s, 9H), 1.32 (d, J = 6.6 Hz, 6H).

단계 2 : 5-Step 2: 5- 클로로Chloro -- N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )-) - N2N2 -(2--(2- 메톡시Methoxy -4-(피페리딘-4--4- (piperidin-4- ylyl )) 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00024
Figure 112014019931035-pat00024

상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-3-메톡시페닐)피페리딘-1-카복시레이트 화합물 170mg(0.28mmol)을 MeOH에 녹인 후, 4M HCl이 용해된 디옥산 3ml를 첨가한 후, 상온에서 0.5시간 교반하였다. 반응이 종료된 후, HCl을 제거하고 에테르로 디캔팅(decanting)하여 목적 화합물 150 mg을 99%의 수율로 얻었다.Amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) -4- (4- (4- ) Piperidine-1-carboxylate compound (170 mg, 0.28 mmol) was dissolved in MeOH, 3 ml of 4M HCl-dissolved dioxane was added, and the mixture was stirred at room temperature for 0.5 hours. After completion of the reaction, HCl was removed and decanting with ether gave 150 mg of the target compound in a yield of 99%.

1H-NMR (300 MHz, MeOD) δ 8.22(brs,1H), 8.01(d, J=5.7Hz , 1H) 7.75-7.73(m,1H), 7.59-7.57(m,1H), 7.38-7.36(m, 1H), 7.05(s,1H), 6.86-6.83(m, 1H), 3.89(s, 3H), 3.55-3.49(m,2H) 3.20-3.16(m, 2H), 3.01-2.94(m,1H), 2.11-1.95(m, 4H), 1.25(d, J=5.4Hz, 6H).
 1 H-NMR (300 MHz, MeOD) δ 8.22 (brs, 1H), 8.01 (d, J = 5.7Hz, 1H) 7.75-7.73 (m, 1H), 7.59-7.57 (m, 1H), 7.38-7.36 (s, 3H), 3.55-3.49 (m, 2H), 3.20-3.16 (m, 2H), 3.01-2.94 (m, m, 1H), 2.11-1.95 (m, 4H), 1.25 (d, J = 5.4 Hz, 6H).

<< 실시예Example 6>  6> N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )-) - N2N2 -(2--(2- 메톡시Methoxy -4-(1,2,3,6--4- (1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)Yl) 페닐Phenyl )-5-() -5- ( 트리플루오로메틸Trifluoromethyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

단계 1 : Step 1: terttert -부틸 4-(4-((4-((2-(- butyl 4- (4 - ((4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )아미노)-5-() Amino) -5- ( 트리플루오로메틸Trifluoromethyl )피리미딘-2-일)아미노)-3-) Pyrimidin-2-yl) amino) -3- 메톡시페닐Methoxyphenyl )-5,6-) -5,6- 디하이드로피리딘Dihydropyridine -1(2H)-카복시레이트의 제조-1 (2H) -carboxylate

Figure 112014019931035-pat00025
Figure 112014019931035-pat00025

2-클로로-N-(2-(이소프로필술포닐)페닐)-5-(트리플루오로메틸)피리미딘-4-아민 100mg(0.26mmol)을 THF 2ml에 녹인 후 tert-부틸 4-(4-아미노-3-메톡시페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 160mg(0.53mmol)을 첨가하고, 잔트포스 15mg (0.026mmol), Cs2CO3 275g(0.79mmol)을 순서대로 첨가한 후, 질소를 충전하여 탈 가스 하였다. Pd(OAc)2 (3mg, 0.013mmol)를 첨가하고, 질소 충전 후 150℃에서 2시간 교반하였다. 반응 종료 후, EA/H2O로 추출한 후 유기층은 MgSO4로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피(Hx:EA 4:1)를 이용하여 목적 화합물 15mg을 8.4%의 수율로 얻었다.(0.26 mmol) of 2-chloro-N- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidin- (2H) -carboxylate (160 mg, 0.53 mmol) was added, and 15 mg (0.026 mmol) of Zafthos, Cs 2 CO 3 275g (0.79mmol) were added in this order, and then degassed by filling with nitrogen. Pd (OAc) 2 (3 mg, 0.013 mmol) was added, and after charging with nitrogen, the mixture was stirred at 150 ° C for 2 hours. After completion of the reaction, the reaction mixture was extracted with EA / H 2 O, and the organic layer was dried over MgSO 4 , filtered and concentrated. 15 mg of the title compound was obtained in a yield of 8.4% using column chromatography (Hx: EA 4: 1).

1H-NMR (300 MHz,CDCl3) δ 9.63(s,1H), 8.60(s,1H), 7.92(d,J=6Hz, 1H), 7.82(d,J=9Hz,1H), 7.14-7.06(m,3H), 6.98-6.88(m,1H), 6.19(s,1H),4.17(s,1H), 4.07(brs,1H), 3.90(s,1H), 3.73(s,1H), 3.64(s,3H), 3.17-3.13(m,1H). 2.62(s,1H), 2.51-2.49(m,1H), 2.2(s,1H), 1.49(s,9H), 1.27(d,J=5.7Hz,6H).
 1 H-NMR (300 MHz, CDCl3) δ 9.63 (s, 1H), 8.60 (s, 1H), 7.92 (d, J = 6Hz, 1H), 7.82 (d, J = 9Hz, 1H), 7.14-7.06 (m, 3H), 6.98-6.88 (m, IH), 6.19 (s, IH), 4.17 (s, IH), 4.07 (brs, 3.64 (s, 3 H), 3.17 - 3.13 (m, 1 H). 1H), 2.62 (s, 1H), 2.51-2.49 (m, 1H), 2.2 (s, 1H), 1.49 (s, 9H), 1.27 (d, J = 5.7 Hz, 6H).

단계 2 : Step 2: N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )-) - N2N2 -(2--(2- 메톡시Methoxy -4-(1,2,3,6--4- (1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)Yl) 페닐Phenyl )-5-() -5- ( 트리플루오로메틸Trifluoromethyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00026
Figure 112014019931035-pat00026

상기 단계 1에서 얻은 tert-부틸 4-(4-((4-((2-(이소프로필술포닐)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)-3-메톡시페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 14mg(0.021mmol)을 MeOH에 녹인 후, 4M HCl이 용해된 디옥산 2ml를 첨가한 후, 상온에서 0.5시간 교반하였다. 반응이 종료된 후, HCl을 제거하고 에테르로 디캔팅(decanting)하여 목적 화합물 14mg을 99%의 수율로 얻었다.Amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) - (4 - ((4 - ((2- (isopropylsulfonyl) phenyl) (0.021 mmol) of 4-methoxyphenyl) -5,6-dihydropyridin-1 (2H) -carboxylate was dissolved in MeOH, followed by the addition of 2 ml of 4M HCl- Lt; / RTI &gt; After the reaction was completed, HCl was removed and decanting with ether gave 14 mg of the target compound in 99% yield.

1H-NMR (300MHz,MeOD) δ 8.49-8.47?m,1H), 8.00(d,J=1.5Hz,2H), 7.77-7.76(m,1H),7.61-7.58(m,3H), 7.13-7.11(m,1H), 6.86-6.84(m,1H),6.18(s,1H), 3.9(s,3H), 3.88-3.86(m,2H), 3.50-3.47(m,2H), 2.82-2.79(m,2H), 1.22(d,J=3Hz, 6H).
 1 H-NMR (300MHz, MeOD ) δ 8.49-8.47? M, 1H), 8.00 (d, J = 1.5Hz, 2H), 7.77-7.76 (m, 1H), 7.61-7.58 (m, 3H), 7.13 2H), 3.50-3.47 (m, 2H), 2.82 (m, IH) -2.79 (m, 2H), 1.22 (d, J = 3 Hz, 6H).

<< 실시예Example 7>  7> N2N2 -(2--(2- 이소프로폭시Isopropoxy -5--5- 메틸methyl -4-(1,2,3,6--4- (1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)Yl) 페닐Phenyl )-) - N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )-5-() -5- ( 트리플루오로메틸Trifluoromethyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

단계 1 : Step 1: terttert -부틸 4-(5--Butyl 4- (5- 이소프로폭시Isopropoxy -4-((4-((2-(-4 - ((4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )아미노)-5-() Amino) -5- ( 트리플루오로메틸Trifluoromethyl )피리미딘-2-일)아미노)-2-) Pyrimidin-2-yl) amino) -2- 메틸페닐Methylphenyl )-5,6-) -5,6- 디하이드로피리딘Dihydropyridine -1(2H)-카복시레이트-1 (2H) -carboxylate 의of 제조 Produce

Figure 112014019931035-pat00027
Figure 112014019931035-pat00027

2-클로로-N-(2-(이소프로필술포닐)페닐)-5-(트리플루오로메틸)피리미딘-4-아민 5mg(0.58mmol)을 THF 2ml에 녹인 후 tert-부틸 4-(4-아미노-5-이소프로폭시-2-메틸페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 139mg(0.42mmol)을 첨가하고, 잔트포스 12mg (0.021mmol), Cs2CO3 205g(0.63mmol)을 순서대로 첨가한 후, 질소를 충전하여 탈 가스 하였다. Pd(OAc)2(3mg,0.0105mmol)를 첨가하고, 질소 충전 후 150℃에서 2시간 동안 가열하였다. 반응 종료 후, EA/H2O로 추출한 후 유기층은 MgSO4로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피(Hx:EA 4:1)를 이용하여 목적 화합물 26mg을 17%의 수율로 얻었다.(0.58 mmol) of 2-chloro-N- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidin- -amino-5-isopropoxy-2-methylphenyl) -5,6-dihydropyridin--1 (2H) - addition of a carboxy acrylate 139mg (0.42mmol), and the force janteu 12mg (0.021mmol), Cs 2 CO 3 (0.63 mmol) were sequentially added, and then degassed by filling with nitrogen. Pd (OAc) 2 (3 mg, 0.0105 mmol) was added and heated at 150 &lt; 0 &gt; C for 2 h after the addition of nitrogen. After completion of the reaction, the reaction mixture was extracted with EA / H 2 O, and the organic layer was dried over MgSO 4 , filtered and concentrated. 26 mg of the target compound was obtained in a yield of 17% using column chromatography (Hx: EA 4: 1).

1H-NMR (300 MHz,CDCl3) δ 9.12(s,1H), 8.41(s,1H), 8.31-8.28(m,1H), 7.97(d,J=7.8Hz,2H), 7.82(s,1H), 7.64-7.58(m,1H), 7.34-7.26(m,1H),6.63(s,1H), 5.54-5.53(m,1H), 4.59(t,J=6Hz,1H), 4.03(s,2H), 3.63-3.59(m,2H), 3.26-3.21(m,1H), 2.32(s,2H), 1.97(s,3H), 1.50(s,9H), 1.38(d,J=6.3Hz,6H), 1.31(d,J=6.9Hz,6H).
 1 H-NMR (300 MHz, CDCl3) δ 9.12 (s, 1H), 8.41 (s, 1H), 8.31-8.28 (m, 1H), 7.97 (d, J = 7.8Hz, 2H), 7.82 (s, 1H), 7.64-7.58 (m, IH), 7.34-7.26 (m, IH), 6.63 (s, IH), 5.54-5.53 (s, 2H), 3.63-3.59 (m, 2H), 3.26-3.21 (m, IH), 2.32 (s, 2H), 1.97 6.3 Hz, 6H), 1.31 (d, J = 6.9 Hz, 6H).

단계 2 : Step 2: N2N2 -(2--(2- 이소프로폭시Isopropoxy -5--5- 메틸methyl -4-(1,2,3,6--4- (1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)Yl) 페닐Phenyl )-) - N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )페닐)-5-() Phenyl) -5- ( 트리플루오로메틸Trifluoromethyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00028
Figure 112014019931035-pat00028

상기 단계 1에서 얻은 tert-부틸 4-(5-이소프로폭시-4-((4-((2-(이소프로필술포닐)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)-2-메틸페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 26mg(0.038mmol)을 MeOH에 녹인 후, 4M HCl이 용해된 디옥산 3ml를 첨가한 후, 상온에서 1시간 교반하였다. 반응이 종료된 후, HCl을 제거하고 에테르로 디캔팅(decanting)하여 목적 화합물 25mg을 99%의 수율로 얻었다.To a solution of tert-butyl 4- (5-isopropoxy-4 - ((4 - ((2- (isopropylsulfonyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin- (2H) -carboxylate was dissolved in MeOH, and 3 ml of 4M HCl-dissolved dioxane was added thereto. Then, And the mixture was stirred at room temperature for 1 hour. After the reaction was completed, HCl was removed and decanting with ether gave 25 mg of the title compound in 99% yield.

1H-NMR (300 MHz,MeOD) δ 8.54-8.50(m,1H), 8.05(d,J=9Hz,1H), 7.80-7.75(m,1H), 7.63-7.58(m,1H),7.35(s,1H), 6.82(s,1H), 5.63(d,J=1.2Hz,1H), 4.66-4.62(m,1H), 3.83(s,2H), 3.74-3.72(m,1H), 3.59-3.57(m,1H), 2.58(s,2H), 2.03-2.01(s,3H), 1.32(d,J=6Hz,6H), 1.24(d,J=6.9Hz, 6H).
 1 H-NMR (300 MHz, MeOD)? 8.54-8.50 (m, 1 H), 8.05 (d, J = 9 Hz, 1 H), 7.80-7.75 (s, 1H), 6.82 (s, 1H), 5.63 (d, J = 1.2 Hz, 1H), 4.66-4.62 2H), 2.03-2.01 (s, 3H), 1.32 (d, J = 6 Hz, 6H), 1.24 (d, J = 6.9 Hz, 6H).

<< 실시예Example 8>  8> N2N2 -(2-(-(2-( 디플루오로메톡시Difluoromethoxy )-4-(1,2,3,6-) -4- (1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)Yl) 페닐Phenyl )-) - N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )-5-() -5- ( 트리플루오로메틸Trifluoromethyl )피리미딘-2,4-) Pyrimidine-2,4- 디아Dia 민의 제조Manufacture of Min

단계 1 : Step 1: terttert -부틸 4-(3-(-Butyl 4- (3- ( 디플루오로메톡시Difluoromethoxy )-4-((4-((2-() -4 - ((4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )페닐)아미노)-5-() Phenyl) amino) -5- ( 트리플루오로메틸Trifluoromethyl )피리미딘-2-일)아미노)) Pyrimidin-2-yl) amino) 페닐Phenyl )-5,6-) -5,6- 디하이드로피리딘Dihydropyridine -1(2H)-카복시레이트-1 (2H) -carboxylate 의of 제조 Produce

Figure 112014019931035-pat00029
Figure 112014019931035-pat00029

2-클로로-N-(2-(이소프로필술포닐)페닐)-5-(트리플루오로메틸)피리미딘-4-아민 35mg(0.08mmol)을 THF 2ml에 녹인 후 tert-부틸 4-(4-아미노-3-(디플루오로메톡시)페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 54mg(0.16mmol)을 첨가하고, 잔트포스 5mg(0.008mmol), Cs2CO3 77mg(0.24mmol)을 순서대로 첨가한 후, 질소를 충전하여 탈 가스 하였다. Pd(OAc)2 (1mg, 0.004mmol)를 첨가하고, 질소 충전 후 150℃에서 1시간 교반하였다. 반응 종료 후, EA/H2O로 추출한 후 유기층은 MgSO4로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피(Hx:EA 4:1)를 이용하여 목적 화합물 3.5mg을 7%의 수율로 얻었다.35 mg (0.08 mmol) of 2-chloro-N- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidin-4-amine was dissolved in 2 ml of THF, -amino-3- (difluoromethoxy) phenyl) -5,6-dihydropyridine -1 (2H) - addition of a carboxy acrylate 54mg (0.16mmol), and the force janteu 5mg (0.008mmol), Cs 2 CO 3 77 mg (0.24 mmol) were added in this order, and the mixture was degassed by filling with nitrogen. Pd (OAc) 2 (1 mg, 0.004 mmol) was added, and after charging with nitrogen, the mixture was stirred at 150 ° C for 1 hour. After completion of the reaction, the reaction mixture was extracted with EA / H 2 O, and the organic layer was dried over MgSO 4 , filtered and concentrated. Column chromatography (Hx: EA 4: 1) afforded 3.5 mg of the title compound in 7% yield.

1H-NMR (300 MHz, CDCl3) δ 9.25(s,1H), 8.43(s,1H), 8.30-8.27(m,1H), 8.23-8.20(m,1H),7.97-7.94(m,1H),7.65-7.59(m,1H), 7.54(s,1H), 7.37-7.32(m,1H), 7.16(s,1H), 7.11-7.08(m,1H), 6.03-6.00(m,1H), 4.10(s,2H), 3.66-3.63(m,2H), 3.25-3.16(m,1H), 2.49-2.48(m,2H), 2.04(s,3H), 1.49(s,9H), 1.31(d,J=6,9Hz,6H).
 1 H-NMR (300 MHz, CDCl 3)? 9.25 (s, IH), 8.43 (s, IH), 8.30-8.27 ), 7.65-7.59 (m, IH), 7.54 (s, IH), 7.37-7.32 (m, IH), 7.16 2H), 2.04 (s, 3H), 1.49 (s, 9H) 1.31 (d, J = 6.9 Hz, 6H).

단계 2 : Step 2: N2N2 -(2-(-(2-( 디플루오로메톡시Difluoromethoxy )-4-(1,2,3,6-) -4- (1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)페닐)-Yl) phenyl) - N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )-5-() -5- ( 트리플루오로메틸Trifluoromethyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00030
Figure 112014019931035-pat00030

상기 단계 1에서 얻은 tert-부틸 4-(3-(디플루오로메톡시)-4-((4-((2-(이소프로필술포닐)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 3.5mg(3.53mmol)을 MeOH에 녹인 후, 4M HCl이 용해된 디옥산 1ml를 첨가한 후, 상온에서 0.5시간 교반하였다. 반응이 종료된 후, HCl을 제거하고 에테르로 디캔팅(decanting)하여 목적 화합물 7mg을 99%의 수율로 얻었다.To a solution of tert-butyl 4- (3- (difluoromethoxy) -4 - ((4 - ((2- (isopropylsulfonyl) phenyl) amino) -5- (trifluoromethyl) 3,5-dihydropyridin-1 (2H) -carboxylate (3.5 mg, 3.53 mmol) was dissolved in MeOH, and 1 ml of 4M HCl-dissolved dioxane was added , And the mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, HCl was removed and decanting with ether gave 7 mg of the target compound in a yield of 99%.

1H-NMR (300 MHz, MeOD) δ 8.51(s,1H), 7.99(d,J=4.5Hz,1H), 7.71(s,1H), 7.63(d,J=4.2Hz,1H), 7.58-7.55(m,1H), 7.33(s,1H), 7.20-7.18(m,1H), 6.21(s,1H), 3.90(s,2H), 3.51-3.50(m,3H), 2.81(s,2H), 1.22(d,J=3.9Hz,6H).
 1 H-NMR (300 MHz, MeOD) δ 8.51 (s, 1H), 7.99 (d, J = 4.5Hz, 1H), 7.71 (s, 1H), 7.63 (d, J = 4.2Hz, 1H), 7.58 (S, 2H), 3.51-3.50 (m, 3H), 2.81 (s, 2H) , 2H), 1.22 (d, J = 3.9 Hz, 6H).

<< 실시예Example 9>  9> N2N2 -(2-(-(2-( 디플루오로메톡시Difluoromethoxy )-4-(피페리딘-4-일)) -4- (piperidin-4-yl) 페닐Phenyl )-) - N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )-5-() -5- ( 트리플루오로메틸Trifluoromethyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

단계 1 : Step 1: terttert -부틸 4-(3-(-Butyl 4- (3- ( 디플루오로메톡시Difluoromethoxy )-4-((4-((2-() -4 - ((4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )아미노)-5-() Amino) -5- ( 트리플루오로메틸Trifluoromethyl )피리미딘-2-일)아미노)) Pyrimidin-2-yl) amino) 페닐Phenyl )피페리딘-1-카복시레이트) Piperidine-1-carboxylate 의of 제조 Produce

Figure 112014019931035-pat00031
Figure 112014019931035-pat00031

2-클로로-N-(2-(이소프로필술포닐)페닐)-5-(트리플루오로메틸)피리미딘-4-아민 60mg(0.16mmol)을 THF 3ml에 녹인 후 tert-부틸 4-(4-아미노-3-(디플루오로메톡시)페닐)피페리딘-1-카복시레이트 110mg(0.32mmol)을 첨가하고, 잔트포스 9mg (0.32mmol), Cs2CO3 156g(0.48mmol)을 순서대로 첨가한 후, 질소를 충전하여 탈 가스 하였다. Pd(OAc)2 (2mg, 0.008mmol)를 첨가하고, 질소 충전 후 130℃에서 18시간 교반하였다. 반응 종료 후, EA/H2O로 추출한 후 유기층은 MgSO4로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피(Hx:EA 4:1)를 이용하여 목적 화합물 35mg을 32%의 수율로 얻었다.60 mg (0.16 mmol) of 2-chloro-N- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidin- -amino-3- (difluoromethoxy) phenyl) piperidine-1-carboxylic rate was added to 110mg (0.32mmol), and the force janteu 9mg (0.32mmol), Cs 2 CO 3 156g (0.48mmol) were added in this order, and then degassed by filling with nitrogen. Pd (OAc) 2 (2 mg, 0.008 mmol) was added, and after charging with nitrogen, the mixture was stirred at 130 캜 for 18 hours. After completion of the reaction, the reaction mixture was extracted with EA / H 2 O, and the organic layer was dried over MgSO 4 , filtered and concentrated. Column chromatography (Hx: EA 4: 1) afforded 35 mg of the title compound in 32% yield.

1H-NMR (300 MHz,CDCl3), δ 9.43(s,1H), 8.38(s,1H), 8.19(d,J=8.4Hz,1H), 7.89(dd,J=7.8Hz,8.1Hz, 1H), 7.53-7.48(m,1H), 7.39(s,1H), 7.22(t,J=7.5Hz,1H), 7.11-7.08(m,1H), 7.04(s,1H), 4.29-4.23(m,2H), 3.29-3.20(m,1H), 2.86-2.77(m,1H), 2.72-2.63(m,1H), 2.17(s,1H), 2.04(s,1H), 1.87-1.83(m,4H),1.49(s,9H), 1.31(d,J=6.9Hz,6H).
 1 H-NMR (300 MHz, CDCl3), δ 9.43 (s, 1H), 8.38 (s, 1H), 8.19 (d, J = 8.4Hz, 1H), 7.89 (dd, J = 7.8Hz, 8.1Hz, 1H), 7.04 (s, 1H), 4.29-4.23 (m, 1H), 7.53-7.48 (m, 2H), 3.29-3.20 (m, IH), 2.86-2.77 (m, IH), 2.72-2.63 (m, 4H), 1.49 (s, 9H), 1.31 (d, J = 6.9 Hz, 6H).

단계 2 : Step 2: N2N2 -(2-(-(2-( 디플루오로메톡시Difluoromethoxy )-4-(피페리딘-4-일)) -4- (piperidin-4-yl) 페닐Phenyl )-) - N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )-5-() -5- ( 트리플루오로메틸Trifluoromethyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00032
Figure 112014019931035-pat00032

상기 단계 1에서 얻은 tert-부틸 4-(3-(디플루오로메톡시)-4-((4-((2-(이소프로필술포닐)페닐)아미노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-1-카복시레이트 35mg(0.051mmol)을 MeOH에 녹인 후, 4M HCl이 용해된 디옥산 3ml를 첨가한 후, 상온에서 0.5시간 교반하였다. 반응이 종료된 후, HCl을 제거하고 에테르로 디캔팅(decanting)하여 목적 화합물 29mg을 99%의 수율로 얻었다.To a solution of tert-butyl 4- (3- (difluoromethoxy) -4 - ((4 - ((2- (isopropylsulfonyl) phenyl) amino) -5- (trifluoromethyl) 2-yl) amino) phenyl) piperidine-1-carboxylate was dissolved in MeOH, 3 ml of 4M HCl-dissolved dioxane was added thereto, and the mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, HCl was removed and decanting with ether gave 29 mg of the target compound in a yield of 99%.

1H-NMR (300 MHz, MeOD), δ 8.50(s,1H), 7.90-7.78(m,2H), 7.48-4.45(m,3H), 7.23-7.19(m,2H), 3.75-3.72(m,1H), 3.59-3.53(m,2H), 2.14-1.88(m,5H), 1.19-1.15(m,6H).
 1 H-NMR (300 MHz, MeOD), δ 8.50 (s, 1H), 7.90-7.78 (m, 2H), 7.48-4.45 (m, 3H), 7.23-7.19 (m, 2H), 3.75-3.72 ( m, 1H), 3.59-3.53 (m, 2H), 2.14-1.88 (m, 5H), 1.19-1.15 (m, 6H).

<< 실시예Example 10> 5- 10> 5- 클로로Chloro -- N2N2 -(5-- (5- 플루오로Fluoro -2--2- 메톡시Methoxy -4-(1,2,3,6--4- (1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)Yl) 페닐Phenyl )-) - N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

단계 1 : Step 1: terttert -부틸 4-(4-((5--Butyl 4- (4 - ((5- 클로로Chloro -4-((2-(-4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )아미노)피리미딘-2-일)아미노)-2-) Amino) pyrimidin-2-yl) amino) -2- 플루오로Fluoro -5--5- 메톡시페닐Methoxyphenyl )-5,6-) -5,6- 디하이드로피리딘Dihydropyridine -1(2H)-카복시레이트-1 (2H) -carboxylate 의of 제조 Produce

Figure 112014019931035-pat00033
Figure 112014019931035-pat00033

2,5-디클로로-N-(2-(이소프로필술포닐)페닐)피리미딘-4-아민 123mg (0.35mmol)을 THF 4ml에 녹인 후 tert-부틸 4-(4-아미노-2-플루오로-5-메톡시페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 115mg(0.35mmol)을 첨가하고, 잔트포스 20mg (0.033mmol), Cs2CO3 322mg(1mmol)을 순서대로 첨가한 후, 질소를 충전하여 탈 가스 하였다. Pd(OAc)2 (4mg, 0.033mmol)를 첨가하고, 질소 충전 후 130℃에서 8시간 교반하였다. 반응 종료 후, EA/H2O로 추출한 후 유기층은 MgSO4로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피(Hx:EA 4:1)를 이용하여 목적 화합물 82mg을 37%의 수율로 얻었다.123 mg (0.35 mmol) of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine was dissolved in 4 ml of THF and tert- butyl 4- (0.035 mmol) of Cs 2 CO 3 (0.033 mmol) were added to a solution of the compound 322 mg (1 mmol) were added in this order, and the mixture was degassed by filling with nitrogen. Pd (OAc) 2 (4 mg, 0.033 mmol) was added, and after nitrogen charging, the mixture was stirred at 130 캜 for 8 hours. After completion of the reaction, the reaction mixture was extracted with EA / H 2 O, and the organic layer was dried over MgSO 4 , filtered and concentrated. Using column chromatography (Hx: EA 4: 1) 82 mg of the desired compound was obtained in a yield of 37%.

1H-NMR (300 MHz, CDCl3) δ 9.54(brs, 1H), 8.52-8.49(m, 1H), 8.19-8.12(m, 2H), 7.95-7,92(m,1H), 7.74-7.66(m,2H), 7.33-7.26(m, 2H), 6.72-6.69(m, 1H), 5.92-5.90(m, 1H) 4.08(s, 2H), 3.90(d, J=3.9Hz, 3H), 3.64-3.62(m, 2H), 3.24-3.22(m,1H), 2.52(brs,2H), 2.05(d, J=3.9Hz, 1H), 1.61(d, 4H), 1.51(d, J=3.9Hz, 9H) , 1.31-1.29(m, 6H).
 1 H-NMR (300 MHz, CDCl 3)? 9.54 (brs, IH), 8.52-8.49 (m, IH), 8.19-8.12 (m, 2H), 7.95-7.92 (m, 2H), 7.33-7.26 (m, 2H), 6.72-6.69 (m, IH), 5.92-5.90 (M, 2H), 3.64-3.62 (m, 2H), 3.24-3.22 (m, 1H), 2.52 (brs, 2H), 2.05 (d, J = 3.9 Hz, = 3.9 Hz, 9H), 1.31-1.29 (m, 6H).

단계 2 : 5-Step 2: 5- 클로로Chloro -- N2N2 -(5-플루오로-2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)-N4-(2-(이소프로필술포닐)페닐)피리미딘-2,4-디아민의 제조- (5-fluoro-2-methoxy-4- (1,2,3,6-tetrahydropyridin-4- yl) phenyl) -N4- (2- (isopropylsulfonyl) Preparation of 2,4-diamine

Figure 112014019931035-pat00034
Figure 112014019931035-pat00034

상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-2-플루오로-5-메톡시페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 70mg(0.11mmol)을 MeOH에 녹인 후, 4M HCl이 용해된 디옥산 3ml를 첨가한 후, 상온에서 0.5시간 교반하였다. 반응이 종료된 후, HCl을 제거하고 에테르로 디캔팅(decanting)하여 목적 화합물 77mg을 99%의 수율로 얻었다.Amino) pyrimidin-2-yl) amino) -2-fluoro-benzoic acid obtained in the above step 1 and 4- (4- (0.11 mmol) of 5-methoxyphenyl) -5,6-dihydropyridin-1 (2H) -carboxylate was dissolved in MeOH, and 3 ml of 4M HCl-dissolved dioxane was added thereto. Lt; / RTI &gt; After the reaction was completed, HCl was removed and decanting with ether gave 77 mg of the desired compound in a yield of 99%.

1H NMR (MeOD, 300MHz) δ 8.43(s, 1H), 8.17-8.11(m, 2H), 7.91-7.86(m,1H), 7.72-7.67(m,1H), 7.53(d, J=12.3Hz, 1H), 7.08(d, J=6.6Hz, 1H),6.12(s, 1H), 4.0(s, 3H), 3.81(d, J=5.1Hz, 1H), 3.67(d, J=3.4Hz, 1H), 3.53(m, 3H), 2.85(s, 2H), 1.32(d,J=6.6Hz, 6H).
 1 H NMR (MeOD, 300 MHz)? 8.43 (s, IH), 8.17-8.11 (m, 2H), 7.91-7.86 (m, IH), 7.72-7.67 (S, 3H), 3.81 (d, J = 5.1 Hz, 1H), 3.67 (d, J = Hz, 1 H), 3.53 (m, 3H), 2.85 (s, 2H), 1.32 (d, J = 6.6 Hz, 6H).

<< 실시예Example 11> 5- 11> 5- 클로로Chloro -- N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )-) - N2N2 -(2--(2- 메톡시Methoxy -5--5- 메틸methyl -4-(1,2,3,6-테-4- (1,2,3,6-te 트라하이Trahai 드로피리딘-4-일)Doropyridin-4-yl) 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

단계 1 : Step 1: terttert -부틸 4-(4-((5--Butyl 4- (4 - ((5- 클로로Chloro -4-((2-(-4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )아미노)피리미딘-2-일)아미노)-5-) Amino) pyrimidin-2-yl) amino) -5- 메톡시Methoxy -2--2- 메틸페닐Methylphenyl )-5,6-) -5,6- 디하이드로피리딘Dihydropyridine -1(2H)-카복시레이트-1 (2H) -carboxylate 의of 제조 Produce

Figure 112014019931035-pat00035
Figure 112014019931035-pat00035

2,5-디클로로-N-(2-(이소프로필술포닐)페닐)피리미딘-4-아민 107mg (0.31mmol)을 THF 4ml에 녹인 후 tert-부틸 4-(4-아미노-5-메톡시-2-메틸페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 100mg(0.31mmol)을 첨가하고, 잔트포스 18mg (0.31mmol), Cs2CO3 303mg(0.93mmol)을 순서대로 첨가한 후, 질소를 충전하여 탈 가스 하였다. Pd(OAc)2 (4mg, 0.015mmol)를 첨가하고, 질소 충전 후 130℃에서 18시간 교반하였다. 반응 종료 후, EA/H2O로 추출한 후 유기층은 MgSO4로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피(Hx:EA 4:1)를 이용하여 목적 화합물 32mg을 17%의 수율로 얻었다.After dissolving 107 mg (0.31 mmol) of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine in 4 ml of THF, tert- butyl 4- 2-methylphenyl) -5,6-dihydropyridin--1 (2H) - carboxy acrylate 100mg (0.31mmol) and a, janteu force 18mg (0.31mmol), Cs 2 CO 3 was added (0.93 mmol) were sequentially added, and then degassed by filling with nitrogen. Pd (OAc) 2 (4 mg, 0.015 mmol) was added, and after charging with nitrogen, the mixture was stirred at 130 캜 for 18 hours. After completion of the reaction, the reaction mixture was extracted with EA / H 2 O, and the organic layer was dried over MgSO 4 , filtered and concentrated. 32 mg of the desired compound was obtained in a yield of 17% using column chromatography (Hx: EA 4: 1).

1H NMR (CDCl3, 300MHz) δ 9.5(s,1H), 8.57(d, J=8.4Hz, 1H), 8.16(s,1H), 7.94(dd, J=7.8, 8.1Hz , 1H), 7.66-7.60(m, 1H), 7.51(s,1H), 6.61(s,1H), 5.55(s,1H), 4.04(d, 2.4Hz, 2H), 3.87(s,3H), 3.64(t,J=5.4Hz), 3.27-3.23(m,1H), 2.34(d,J=0.9Hz), 2.12(s,3H), 1.50(s,9H), 1.32(d,J=6.9Hz).
 1 H NMR (CDCl 3, 300MHz ) δ 9.5 (s, 1H), 8.57 (d, J = 8.4Hz, 1H), 8.16 (s, 1H), 7.94 (dd, J = 7.8, 8.1Hz, 1H), 7.66-7.60 (m, 1 H), 7.51 (s, 1 H), 7.51 2H), 3.87 (s, 3H), 3.64 (t, J = 5.4 Hz), 3.27-3.23 (m, 2.34 (d, J = 0.9 Hz), 2.12 (s, 3H), 1.50 (s, 9H), 1.32 (d, J = 6.9 Hz).

단계 2 :5-Step 2: 5- 클로로Chloro -- N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )-) - N2N2 -(2--(2- 메톡시Methoxy -5--5- 메틸methyl -4-(1,2,3,6-테-4- (1,2,3,6-te 트라하이드Tracheid 로피리딘-4-일)Yl pyridin-4-yl) 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00036
Figure 112014019931035-pat00036

상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-5-메톡시-2-메틸페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 27mg(0.04mmol)을 MeOH에 녹인 후, 4M HCl이 용해된 디옥산 3ml를 첨가한 후, 상온에서 1시간 교반하였다. 반응이 종료된 후, HCl을 제거하고 에테르로 디캔팅(decanting)하여 목적 화합물 30mg을 99%의 수율로 얻었다.Amino) pyrimidin-2-yl) amino) -5-methoxy-benzenesulfonamide obtained in the above Step 1 and 4- (4- (2-methylphenyl) -5,6-dihydropyridin-1 (2H) -carboxylate was dissolved in MeOH, 3 ml of 4M HCl-dissolved dioxane was added, and the mixture was stirred at room temperature for 1 hour . After the reaction was completed, HCl was removed and decanting with ether gave 30 mg of the target compound in a yield of 99%.

1H NMR (MeOD, 300MHz) δ 8.24(s,1H), 8.03(d,J=7.56Hz,1H), 6.52-6.46(m,1H), 6.34(t,J=7.5Hz, 1H), 7.31(s,1H), 6.88(s,1H), 5.67(s,1H), 3.85(s,3H), 3.75-3.71(m,1H), 3.59-3.57(m,1H), 2.62(s,2H), 2.14(s,3H), 1.26(d, J=6.3Hz, 6H).
 1 H NMR (MeOD, 300MHz) δ 8.24 (s, 1H), 8.03 (d, J = 7.56Hz, 1H), 6.52-6.46 (m, 1H), 6.34 (t, J = 7.5Hz, 1H), 7.31 (m, IH), 2.62 (s, IH), 6.68 (s, ), 2.14 (s, 3H), 1.26 (d, J = 6.3 Hz, 6H).

<< 실시예Example 12> 5- 12> 5- 클로로Chloro -- N2N2 -(5-- (5- 플루오로Fluoro -2--2- 메톡시Methoxy -4-(피페리딘-4-일)-4- (piperidin-4-yl) 페닐Phenyl )-) - N4N4 -(2-(이- (2- ( 소프로필술Sopropyl alcohol 포닐)&Lt; / RTI & 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

단계 1 : Step 1: terttert -부틸 4-(4-((5--Butyl 4- (4 - ((5- 클로로Chloro -4-((2-(-4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )아미노)피리미딘-2-일)아미노)-2-) Amino) pyrimidin-2-yl) amino) -2- 플루오로Fluoro -5--5- 메톡시페닐Methoxyphenyl )피페리딘-1-카복시레이트) Piperidine-1-carboxylate 의of 제조 Produce

Figure 112014019931035-pat00037
Figure 112014019931035-pat00037

2,5-디클로로-N-(2-(이소프로필술포닐)페닐)피리미딘-4-아민 97mg(0.28mmol)을 THF 5ml에 녹인 후 tert-부틸 4-(4-아미노-2-플루오로-5-메톡시페닐)-5,6-디하이드로피리딘-1(2H)-카복시레이트 90mg(0.28mmol)을 첨가하고, 잔트포스 17mg (0.03mmol), Cs2CO3 275mg(0.84mmol)을 순서대로 첨가한 후, 질소를 충전하여 탈 가스 하였다. Pd(OAc)2 (4mg, 0.05mmol)를 첨가하고, 질소 충전 후 120℃에서 18시간 교반하였다. 반응 종료 후, EA/H2O로 추출한 후 유기층은 MgSO4로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피(Hx:EA 4:1)를 이용하여 목적 화합물 75.5mg을 42%의 수율로 얻었다.97 mg (0.28 mmol) of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine was dissolved in 5 ml of THF, (2H) -carboxylate was added to the solution, and 17 mg (0.03 mmol) of AztForce, Cs 2 CO 3 275 mg (0.84 mmol) were added in this order, and the mixture was degassed by filling with nitrogen. Pd (OAc) 2 (4 mg, 0.05 mmol) was added, and after charging with nitrogen, the mixture was stirred at 120 캜 for 18 hours. After completion of the reaction, the reaction mixture was extracted with EA / H 2 O, and the organic layer was dried over MgSO 4 , filtered and concentrated. Column chromatography (Hx: EA 4: 1) afforded 75.5 mg of the title compound in 42% yield.

1H NMR (CDCl3, 300MHz) δ 9.5(s,1H), 8.51(d, J=8.4Hz,1H), 8.17(s,1H), 8.13(d, J=12.9Hz, 1H), 7.94(dd, J=8.1Hz,8.1Hz), 7.74-7.69(m, 1H), 7.60(s,1H),6.65(d, J=6.6Hz), 4.15-4.08(m,1H), 3.87(s,3H), 3.24-3.19(m,1H), 2.86(t,J=12.6Hz, 2H), 1.82(d,J=12.3Hz , 2H), 1.49(s,9H), 1.32(d,J=6.9Hz,1H).
 1 H NMR (CDCl 3, 300MHz ) δ 9.5 (s, 1H), 8.51 (d, J = 8.4Hz, 1H), 8.17 (s, 1H), 8.13 (d, J = 12.9Hz, 1H), 7.94 ( (d, J = 8.1 Hz, 8.1 Hz), 7.74-7.69 (m, IH), 7.60 (s, IH), 6.65 (d, J = 6.6Hz), 4.15-4.08 3H), 3.24-3.19 (m, 1H), 2.86 (t, J = 12.6 Hz, 2H), 1.82 (d, J = Hz, 1H).

단계 2 : 5-Step 2: 5- 클로로Chloro -- N2N2 -(5-- (5- 플루오로Fluoro -2--2- 메톡시Methoxy -4-(피페리딘-4-일)-4- (piperidin-4-yl) 페닐Phenyl )-) - N4N4 -(2-(이- (2- ( 소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00038
Figure 112014019931035-pat00038

상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-2-플루오로-5-메톡시페닐)피페리딘-1-카복시레이트 75mg(0.048mmol)을 MeOH에 녹인 후, 4M HCl이 용해된 디옥산 3ml를 첨가한 후, 상온에서 1시간 교반하였다. 반응이 종료된 후, HCl을 제거하고 에테르로 디캔팅(decanting)하여 목적 화합물 65mg을 99%의 수율로 얻었다.Amino) pyrimidin-2-yl) amino) -2-fluoro-benzoic acid obtained in the above step 1 and 4- (4- (0.048 mmol) of 5-methoxyphenyl) piperidine-1-carboxylate was dissolved in MeOH, 3 ml of 4M HCl-dissolved dioxane was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, HCl was removed and decanting with ether gave 65 mg of the desired compound in a yield of 99%.

1H NMR (MeOD, 300MHz) δ 8.34(s, 1H), 8.12-8.09(m,1H), 8.04-8.02(d,J=7.8Hz,1H), 7.82-7.77(m,1H), 7.63-7.58(m,1H), 7.40(d,J=11.7Hz,1H), 6.96(d,J = 6.6Hz,1H), 3.91(s,3H),3.73(d,J=5.1Hz,1H),3.59(d,J=4.5Hz,2H),3.40-3.36(m,1H), 3.18-3.16(m,3H),1.24(d,J=6.6Hz, 6H).
 1 H NMR (MeOD, 300MHz) δ 8.34 (s, 1H), 8.12-8.09 (m, 1H), 8.04-8.02 (d, J = 7.8Hz, 1H), 7.82-7.77 (m, 1H), 7.63- J = 6.7 Hz, 1H), 7.58 (m, 1H), 7.40 (d, J = 11.7 Hz, 1H), 6.96 3.59 (d, J = 4.5 Hz, 2H), 3.40-3.36 (m, 1H), 3.18-3.16 (m, 3H), 1.24 (d, J = 6.6Hz, 6H).

<< 실시예Example 13> 5- 13> 5- 클로로Chloro -- N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )-) - N2N2 -(2--(2- 메톡시Methoxy -5--5- 메틸methyl -4-(피페리딘-4-일)-4- (piperidin-4-yl) 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

단계 1 : Step 1: terttert -부틸 4-(4-((5--Butyl 4- (4 - ((5- 클로로Chloro -4-((2-(-4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )아미노)피리미딘-2-일)아미노)-5-) Amino) pyrimidin-2-yl) amino) -5- 메톡시Methoxy -2--2- 메틸페닐Methylphenyl )피페리딘-1-카복시레이트) Piperidine-1-carboxylate 의of 제조 Produce

Figure 112014019931035-pat00039
Figure 112014019931035-pat00039

2,5-디클로로-N-(2-(이소프로필술포닐)페닐)피리미딘-4-아민 86mg(0.25mmol)을 THF 3ml에 녹인 후 tert-부틸 4-(4-아미노-5-메톡시-2-메틸페닐)피페리딘-1-카복시레이트 80mg(0.25mmol)을 첨가하고, 잔트포스 15mg (0.025mmol), Cs2CO3 244mg(0.75mmol)을 순서대로 첨가한 후, 질소를 충전하여 탈 가스 하였다. Pd(OAc)2 (3mg, 0.012mmol)를 첨가하고, 질소 충전 후 130℃에서 18시간 교반하였다. 반응 종료 후, EA/H2O로 추출한 후 유기층은 MgSO4로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피(Hx:EA = 4:1)를 이용하여 목적 화합물 30mg을 20%의 수율로 얻었다.86 mg (0.25 mmol) of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine was dissolved in 3 ml of THF and tert- butyl 4- 2-methylphenyl) piperidin-1-carboxy-rate addition of 80mg (0.25mmol), and the force janteu 15mg (0.025mmol), Cs 2 CO 3 (0.75 mmol) were sequentially added, and then degassed by filling with nitrogen. Pd (OAc) 2 (3 mg, 0.012 mmol) was added, and after charging with nitrogen, the mixture was stirred at 130 캜 for 18 hours. After completion of the reaction, the reaction mixture was extracted with EA / H 2 O, and the organic layer was dried over MgSO 4 , filtered and concentrated. 30 mg of the title compound was obtained in a yield of 20% using column chromatography (Hx: EA = 4: 1).

1H NMR (CDCl3, 300MHz) δ 9.51(s,1H), 8.59(d,J=8.4Hz,1H), 8.15(s,1H), 8.00(s,1H), 7.94(dd, J=12,8.1Hz, 1H), 7.65-7.59(m,1H), 7.47((s,1H), 6.69(s,1H), 4.29(d,J=20.1Hz,2H), 3.86(s,3H), 3.28-3.23(m,1H), 2.86-2.78(m,3H), 2.19(s,3H), 1.77-1.73(d, J=12.6Hz, 2H), 1.49(s,9H), 1.32(d,J=6.9Hz,6H).
 1 H NMR (CDCl 3, 300MHz ) δ 9.51 (s, 1H), 8.59 (d, J = 8.4Hz, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.94 (dd, J = 12 2H), 3.86 (s, 3H), 6.99 (s, 1H), 8.19 (s, 1H), 7.65-7.59 (M, 3H), 2.19 (s, 3H), 1.77-1.73 (d, J = 12.6 Hz, 2H), 1.49 (s, 9H), 1.32 J = 6.9 Hz, 6H).

단계 2 : 5-Step 2: 5- 클로로Chloro -- N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )-) - N2N2 -(2--(2- 메톡시Methoxy -5--5- 메틸methyl -4-(피페리딘-4-일)-4- (piperidin-4-yl) 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00040
Figure 112014019931035-pat00040

상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-5-메톡시-2-메틸페닐)피페리딘-1-카복시레이트 17mg(0.026mmol)을 MeOH에 녹인 후, 4M HCl이 용해된 디옥산 3ml를 첨가한 후, 상온에서 0.5시간 교반하였다. 반응이 종료된 후, HCl을 제거하고 에테르로 디캔팅(decanting)하여 목적 화합물 15mg을 99%의 수율로 얻었다.Amino) pyrimidin-2-yl) amino) -5-methoxy-benzenesulfonamide obtained in the above Step 1 and 4- (4- (0.026 mmol) of 2-methylphenyl) piperidine-1-carboxylate was dissolved in MeOH, 3 ml of 4M HCl-dissolved dioxane was added, and the mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, HCl was removed and decanting with ether gave 15 mg of the desired compound in 99% yield.

1H NMR (MeOD, 300MHz) δ 8.27-8.23(m,1H), 8.01(d,J=7.5Hz,1H), 7.75-7.71(m,1H), 7.57-7.52(m,1H), 7.31(s,1H), 6.9(s,1H), 3.88(s,3H),3.73(d,J=5.1Hz,1H), 3.65(s,2H), 3.57-3.47(m,3H), 3.21-3.18(m,2H), 2.22(s,3H), 1.25(d,J=5.4Hz,6H).
 1 H NMR (MeOD, 300 MHz)? 8.27-8.23 (m, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.75-7.71 (m, 1H), 7.57-7.52 (m, 3H), 3.21-3.18 (m, 3H), 3.85 (s, 3H) (m, 2H), 2.22 (s, 3H), 1.25 (d, J = 5.4 Hz, 6H).

<< 실시예Example 14> 5- 14> 5- 클로로Chloro -- N2N2 -(4-(1-에틸-1,2,3,6-- (4- (1-ethyl-1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)-2-메Yl) -2- 톡시페Toxifee 닐)-Nyl) - N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00041
Figure 112014019931035-pat00041

상기 실시예 1에서 얻은 5-클로로-N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)피리미딘-2,4-디아민 50mg(0.097 mmol)을 EtOH 1ml에 넣어준 후 교반하면서 DIPEA(0.06ml,0.375mmol)을 첨가하였다. 아이오도에텐(0.016ml,0.15mmol)를 첨가하여주고 상온에서 18시간 동안 교반하였다. 반응 종료 후, MC/H2O로 추출 후 유기층은 MgSO4로 건조한 뒤에 농축하여 칼럼 크로마토그래피를 사용하여 목적 화합물 19.3mg을 얻었다.-N- (2-methoxy-4- (1, 2, 3, 6-tetrahydropyridin-4-yl) ) Phenyl) pyrimidine-2,4-diamine (50 mg, 0.097 mmol) was dissolved in EtOH (1 ml) and DIPEA (0.06 ml, 0.375 mmol) was added with stirring. Iodoethane (0.016 ml, 0.15 mmol) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, extraction with MC / H 2 O, the organic layer was dried over MgSO 4 , concentrated, and purified by column chromatography to obtain the desired compound (19.3 mg).

1H-NMR (300MHz,CDCl3), δ 9.55(s,1H), 8.56(d,J=8.4Hz,1H), 8.25(d,J=9Hz,1H),8.16(s,1H), 7.94(dd,J=1.5,1.5Hz ,1H), 7.68-7.63(m,1H), 7.59(s,1H), 7.31-7.28(m,1H), 6.91-6.88(m,2H), 5.98(s,1H), 5.29(s,1H), 3.92(s,3H), 3.56(s,2H), 3.26-3.21(m,1H), 3.15-3.11(m,2H),2.99-2.92(m,2H), 2.83(s,2H), 1.42(t,J=7.2Hz,3H), 1.32(d,J=6.6Hz,6H).
 1 H-NMR (300MHz, CDCl 3), δ 9.55 (s, 1H), 8.56 (d, J = 8.4Hz, 1H), 8.25 (d, J = 9Hz, 1H), 8.16 (s, 1H), 7.94 (d, J = 1.5, 1.5 Hz, 1H), 7.68-7.63 (m, 1H), 7.59 (s, 1H), 7.31-7.28 (M, 2H), 2.99-2.92 (m, 2H), 3.26-3.21 (m, ), 2.83 (s, 2H), 1.42 (t, J = 7.2 Hz, 3H), 1.32 (d, J = 6.6 Hz, 6H).

<< 실시예Example 15> 5- 15> 5- 클로로Chloro -- N2N2 -(4-(1-에틸-1,2,3,6-- (4- (1-ethyl-1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)-2-메Yl) -2- 톡시페Toxifee 닐)-Nyl) - N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00042
Figure 112014019931035-pat00042

상기 실시예 1에서 얻은 5-클로로-N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)피리미딘-2,4-디아민 40mg을 DMF 1mL에 녹여준 후 교반 하면서 CS2CO3(65mg,0.2mmol)을 첨가하였다. 브로모에탄올(0.01ml,0.12mmol)을 첨가하여주고 상온에서 18시간 동안 교반하였다. 반응 종료 후, MC/H2O로 추출 후 유기층은 MgSO4로 건조한 뒤 농축하여 칼럼 크로마토그래피를 사용하여 목적 화합물 12mg을 얻었다.-N- (2-methoxy-4- (1, 2, 3, 6-tetrahydropyridin-4-yl) ) Phenyl) pyrimidine-2,4-diamine (40 mg) was dissolved in DMF (1 mL) and CS 2 CO 3 (65 mg, 0.2 mmol) was added with stirring. Bromoethanol (0.01 ml, 0.12 mmol) was added and stirred at ambient temperature for 18 hours. After completion of the reaction, the reaction mixture was extracted with MC / H 2 O, and the organic layer was dried over MgSO 4 , concentrated and purified by column chromatography to obtain the desired compound (12 mg).

1H-NMR (300MHz,CDCl3), δ 9.55(s,1H),8.58(d,J=7.8Hz,1H), 8.25(d,J=9Hz,1H), 8.17(s,1H), 7.94-7.91(m,1H), 7.68-7.63(m,1H), 7.60(s,1H), 6.93(s,2H), 6.01(s,1H), 3.92(s,3H), 3.83-3.80(m,2H), 3.64(s,1H), 3.45(s,2H), 3.28-3.19(m,1H), 3.02-2.99(m,2H), 2.88-2.85(m,2H),2.71-2.70(m,2H),1.32(d,J=6.9Hz,6H).
 1 H-NMR (300MHz, CDCl 3), δ 9.55 (s, 1H), 8.58 (d, J = 7.8Hz, 1H), 8.25 (d, J = 9Hz, 1H), 8.17 (s, 1H), 7.94 (S, 3H), 3.83-3.80 (m, 1H), 7.92-7.91 (m, 2H), 3.64 (s, 1H), 3.45 (s, 2H), 3.28-3.19 (m, 1H), 3.02-2.99 (m, 2H), 2.88-2.85 , 2H), 1.32 (d, J = 6.9 Hz, 6H).

<< 실시예Example 16> 1-(4-(4-((5- 16> 1- (4- (4 - ((5- 클로로Chloro -4-((2-(-4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )아미노)피리미딘-2-일)아미노)-3-) Amino) pyrimidin-2-yl) amino) -3- 메톡시페닐Methoxyphenyl )-5,6-) -5,6- 디하이드로피리딘Dihydropyridine -1(2H)-일)-1 (2H) -yl) 에탄온의Ethane 제조 Produce

Figure 112014019931035-pat00043
Figure 112014019931035-pat00043

상기 실시예 1에서 얻은 5-클로로-N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)피리미딘-2,4-디아민 50mg(0.097 mmol)을 CH2Cl2 1ml에 넣어준 후 교반하며 Et3N(0.03ml,0.23mmol)을 첨가하였다. 아세트산무수물 (0.02ml,0.15mmol)을 첨가하여주고 상온에서 18시간 동안 교반하였다. 반응 종료 후, MC/H2O로 추출 후 유기층은 MgSO4로 건조한 뒤 농축하여 칼럼 크로마토그래피를 사용하여 목적 화합물 40mg을 얻었다.-N- (2-methoxy-4- (1, 2, 3, 6-tetrahydropyridin-4-yl) ) Phenyl) pyrimidine-2,4-diamine (50 mg, 0.097 mmol) was added to 1 ml of CH 2 Cl 2 , and Et 3 N (0.03 ml, 0.23 mmol) was added with stirring. Acetic anhydride (0.02 ml, 0.15 mmol) was added and stirred at ambient temperature for 18 hours. After completion of the reaction, extraction with MC / H 2 O, the organic layer was dried over MgSO 4 , concentrated, and purified by column chromatography to obtain the desired compound (40 mg).

1H-NMR (300MHz,CDCl3), δ 9.57(s,1H), 8.58(d,J=8.1Hz,1H), 8.23(dd,J=2.4,0.9Hz,1H),8.16(s,1H), 7.94(dd,J=1.5,1.5Hz,1H),7.67-7.62(m,2H),6.92-6.87(m,2H),6.03(d,16.5Hz,1H), 4.26(d,J=2.7Hz,1H),4.15(d,J=2.7Hz,1H),3.93(s,3H), 3.85(t,J=5.7Hz,1H), 3.70-3.66(m,1H), 3.28-3.19(m,1H), 2.60-2.55(m,2H), 2.18(d,J=8.7Hz,3H),1.32(d,J=6.9Hz,6H).
 1 H-NMR (300MHz, CDCl 3), δ 9.57 (s, 1H), 8.58 (d, J = 8.1Hz, 1H), 8.23 (dd, J = 2.4,0.9Hz, 1H), 8.16 (s, 1H J = 1.5, 1.5 Hz, 1H), 7.67-7.62 (m, 2H), 6.92-6.87 (m, 2H), 6.03 (d, 16.5 Hz, (M, 1H), 3.28-3.19 (m, 3H), 3.85 (d, J = m, 1H), 2.60-2.55 (m, 2H), 2.18 (d, J = 8.7 Hz, 3H), 1.32 (d, J = 6.9 Hz, 6H).

<< 실시예Example 17> 4-(4-((5- 17> 4- (4 - ((5- 클로로Chloro -4-((2-(-4 - ((2- ( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )아미노)피리미딘-2-일)아미노)-3-) Amino) pyrimidin-2-yl) amino) -3- 메톡시페닐Methoxyphenyl )-5,6-) -5,6- 디하이드로피리딘Dihydropyridine -1(2H)-카르복시산의 제조-1 (2H) -carboxylic acid &lt; / RTI &gt;

Figure 112014019931035-pat00044
Figure 112014019931035-pat00044

상기 실시예 1에서 얻은 5-클로로-N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)피리미딘-2,4-디아민 50mg(0.097 mmol)을 CH2Cl2 1ml에 녹여준 후 교반하며 Et3N 0.2ml를 첨가하였다. 글리콜산(0.01ml,0.15mmol), EDCI(24mg,0.15mmol), DMAP(20mg,0.15mmol)을 순서대로 첨가하여주고 상온에서 18시간 동안 교반하였다. 반응 종료 후, MC/H2O로 추출한 후 유기층은 MgSO4로 건조한 뒤 농축하여 칼럼 크로마토그래피를 사용하여 목적 화합물 28.4mg을 얻었다.-N- (2-methoxy-4- (1, 2, 3, 6-tetrahydropyridin-4-yl) ) Phenyl) pyrimidine-2,4-diamine (50 mg, 0.097 mmol) was dissolved in CH 2 Cl 2 And then 0.2 ml of Et 3 N was added with stirring. Glycolic acid (0.01 ml, 0.15 mmol), EDCI (24 mg, 0.15 mmol) and DMAP (20 mg, 0.15 mmol) were added in this order and stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was extracted with MC / H 2 O, and the organic layer was dried over MgSO 4 , concentrated, and subjected to column chromatography to obtain the desired compound (28.4 mg).

1H-NMR (300 MHz, CDCl3), δ 9.57(s,1H), 8.58(d,J=8.7Hz,1H), 8.27(d,J=8.1Hz,1H),8.17(s,1H), 7.94(d,J=7.2Hz,1H), 7.68-7.60(m,1H), 7.31(d,J=8.1Hz,1H), 6.92-6.87(m,2H), 4.31-4.20(m,3H),3.96(s,3H), 3.68(s,1H), 3.52-3.49(m,1H), 3.26-3.19(m,1H), 2.60(s,2H), 1.32(d,J=6.9Hz,6H).
 1 H-NMR (300 MHz, CDCl 3), δ 9.57 (s, 1H), 8.58 (d, J = 8.7Hz, 1H), 8.27 (d, J = 8.1Hz, 1H), 8.17 (s, 1H) , 7.94 (d, J = 7.2 Hz, 1H), 7.68-7.60 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.92-6.87 ), 3.96 (s, 3H), 3.68 (s, IH), 3.52-3.49 (m, IH), 3.26-3.19 6H).

<< 실시예Example 18> 5- 18 > 5- 클로로Chloro -- N2N2 -(4-(1-- (4- (1- 메틸methyl -1,2,3,6--1,2,3,6- 테트라하이드로피리딘Tetrahydropyridine -4-일)-2-메Yl) -2- 톡시페Toxifee 닐)-Nyl) - N4N4 -(2-(-(2-( 이소프로필술포닐Isopropylsulfonyl )) 페닐Phenyl )피리미딘-2,4-) Pyrimidine-2,4- 디아민의Diamine 제조 Produce

Figure 112014019931035-pat00045
Figure 112014019931035-pat00045

상기 실시예 1에서 얻은 5-클로로-N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)피리미딘-2,4-디아민 50mg(0.097 mmol)을 EtOH 1ml에 녹여준 후 교반하면서 DIPEA(0.08ml,0.45mmol)을 첨가하여준다. 메틸아이오다이드(0.01ml,0.15mmol) 첨가하여주고 상온에서 18시간 동안 교반하였다. 반응 종료 후, MC/H2O로 추출한 후 유기층은 MgSO4로 건조한 뒤에 농축하여 칼럼 크로마토그래피를 사용하여 목적 화합물 6.1mg을 얻었다.-N- (2-methoxy-4- (1, 2, 3, 6-tetrahydropyridin-4-yl) ) Phenyl) pyrimidine-2,4-diamine (50 mg, 0.097 mmol) was dissolved in 1 ml of EtOH and DIPEA (0.08 ml, 0.45 mmol) was added with stirring. Methyl iodide (0.01 ml, 0.15 mmol) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was extracted with MC / H 2 O, and the organic layer was dried over MgSO 4 , concentrated and purified by column chromatography to obtain 6.1 mg of the title compound.

1H-NMR (300 MHz, CDCl3), δ 9.56(s,1H), 8.55-8.53(m,1H), 8.29-8.26(m,1H),8.17(s,1H), 7.94(d,J=8.1Hz,1H),7.70-7.63(m,2H), 6.90(s,2H), 5.97(s,1H), 3.93(s,3H), 3.74(s,2H), 3.64(s,1H), 3.24-3.21(m,1H), 2.97-2.94(m,2H), 2.85(s,3H), 1.32(d,J=6.9Hz,6H).
 1 H-NMR (300 MHz, CDCl 3),? 9.56 (s, IH), 8.55-8.53 (m, IH), 8.29-8.26 2H), 3.64 (s, 1H), 3.74 (s, 3H), 3.74 (s, 3.24-3.21 (m, 1H), 2.97-2.94 (m, 2H), 2.85 (s, 3H), 1.32 (d, J = 6.9Hz, 6H).

하기 표 1에 실시예 1-18에서 제조한 화합물의 화학구조식을 정리하여 나타내었다.
Table 1 summarizes the chemical structures of the compounds prepared in Examples 1-18.

실시예Example 화학구조식Chemical structural formula 1One

Figure 112014019931035-pat00046
Figure 112014019931035-pat00046
22
Figure 112014019931035-pat00047
Figure 112014019931035-pat00047
 33
Figure 112014019931035-pat00048
Figure 112014019931035-pat00048
 44
Figure 112014019931035-pat00049
Figure 112014019931035-pat00049
 55
Figure 112014019931035-pat00050
Figure 112014019931035-pat00050
 66
Figure 112014019931035-pat00051
Figure 112014019931035-pat00051
 77
Figure 112014019931035-pat00052
Figure 112014019931035-pat00052
 88
Figure 112014019931035-pat00053
Figure 112014019931035-pat00053
 99
Figure 112014019931035-pat00054
Figure 112014019931035-pat00054
 1010
Figure 112014019931035-pat00055
Figure 112014019931035-pat00055
 1111
Figure 112014019931035-pat00056
Figure 112014019931035-pat00056
 1212
Figure 112014019931035-pat00057
Figure 112014019931035-pat00057
 1313
Figure 112014019931035-pat00058
Figure 112014019931035-pat00058
 1414
Figure 112014019931035-pat00059
Figure 112014019931035-pat00059
 1515
Figure 112014019931035-pat00060
Figure 112014019931035-pat00060
 1616
Figure 112014019931035-pat00061
Figure 112014019931035-pat00061
 1717
Figure 112014019931035-pat00062
Figure 112014019931035-pat00062
 1818
Figure 112014019931035-pat00063
Figure 112014019931035-pat00063

<< 실험예Experimental Example 1>  1> 역형성Inverse formation 림프종  Lymphoma 키나아제Kinase (( ALKALK ) 억제활성 실험) Inhibitory activity experiment

본 발명에 따른 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체의 림프종 키나아제(ALK)의 증식 억제 활성을 효소단계에서 측정하기 위하여 하기와 같은 실험을 수행하였다.
In order to measure the inhibitory activity of the pyrimidine-2,4-diamine derivative represented by the formula (1) according to the present invention on lymphoma kinase (ALK) proliferation, the following experiment was carried out.

역형성 림프종 키나아제(ALK)에 대한 저해활성을 측정하기 위하여 그레이너 96 웰 라운드 형 바닥 플레이트에 실시예 1 내지 18에서 제조된 화합물(2 ㎕)을 가하고, 역형성 림프종 키나아제(ALK) 효소(1 ㎕)와 바이오틴이 붙은 펩타이드 기질(2 ㎕)을 15분 동안 혼합하여 배양하였다. 여기에 ATP 용액(5 ㎕)을 가하여 상온에서 30분 동안 키나아제 반응을 수행하였다. 에틸렌다이아민테트라아세트산 용액에 녹은 스트렙트아비딘이 붙은 엑스엘(XL 665)(5 ㎕)와 유로피움(Eu3+)이 붙은 항-포스포타이로신 항체(5 ㎕)를 반응액에 첨가하여 반응을 중지시키고 1시간 동안 배양한 후, 시간분해형광도(Homogeneous Time-resolved fluorescence, HTRF, Cisbio)를 이용하여 분석하였다. 왈락 인비전 2103(Wallac Envision 2103) 기기로 615/665 nm의 파장 범위에서 판독하였다. 상기 실험을 수행한 시험화합물의 IC50은 프리즘(버전 5.01, 그래프패드) 소프트웨어를 이용하여 구현하였다.In order to measure the inhibitory activity against inverse lymphoma kinase (ALK), the compound (2 쨉 l) prepared in Examples 1 to 18 was added to a Grayer 96 well round bottom plate, and the reverse forming lymphoma kinase (ALK) enzyme Mu] l) and biotin-adhered peptide substrate (2 [mu] l) were mixed for 15 minutes and cultured. ATP solution (5 ㎕) was added thereto and the kinase reaction was carried out at room temperature for 30 minutes. Phosphotyrosine antibody (5 μl) with streptavidin dissolved in ethylenediaminetetraacetic acid solution (5 μl) and Eu-phosphotyrosine antibody (5 μl) with europium (Eu 3+ ) After incubation for 1 hour, the cells were analyzed using homogeneous time-resolved fluorescence (HTRF, Cisbio). And read in a wavelength range of 615/665 nm with a Wallac Envision 2103 instrument. The IC 50 of the test compound subjected to the above experiments was implemented using prism (version 5.01, GraphPad) software.

역형성 림프종 키나아제(ALK) 효소활성 및 역형성 림프종 키나아제(ALK) 효소를 포함하고 있는 비소세포폐암세포인 L1196M의 세포활성을 50%로 감소시키는 상기 화합물의 IC50을 하기 표 2에 나타내었다.
The IC 50 of the compound, which reduces the cellular activity of L1196M, a non-small cell lung cancer cell containing inverse lymphoma kinase (ALK) enzyme activity and reverse forming lymphoma kinase (ALK) enzyme, to 50% is shown in Table 2 below.

실시예Example ALK wt.
IC50 (uM)ALK wt.
IC50 (uM) ALK L1196M
IC50 (uM)ALK L1196M
IC50 (uM) 대조군 1
(crizotinib)Control 1
(crizotinib) 0.010.01 0.220.22 대조군 2
(LDK-378)_기준Control group 2
(LDK-378) _ standard 0.0010.001 0.0090.009 1One <0.001<0.001 <0.001<0.001 22 <0.001<0.001 <0.001<0.001 33 <0.001<0.001 <0.001<0.001 44 <0.001<0.001 <0.001<0.001 55 <0.001<0.001 <0.001<0.001 66 <0.001<0.001 <0.001<0.001 77 >0.001> 0.001 >0.001> 0.001 88 <0.001<0.001 <0.001<0.001 99 >0.001> 0.001 >0.001> 0.001 1010 <0.001<0.001 <0.001<0.001 1111 <0.001<0.001 <0.001<0.001 1212 <0.001<0.001 <0.001<0.001 1313 <0.001<0.001 <0.001<0.001 1414 <0.001<0.001 <0.001<0.001 1515 <0.001<0.001 <0.001<0.001 1616 <0.001<0.001 <0.001<0.001 1717 <0.001<0.001 <0.001<0.001 1818 <0.001<0.001 <0.001<0.001

상기 표 2에 나타낸 바와 같이, 본 발명에 따른 실시예의 화합물들은 대부분이 대조군 1 및 2의 화합물에 비하여 활성이 우수한 것으로 나타났다.As shown in Table 2, most of the compounds of Examples according to the present invention were found to be more active than the compounds of Controls 1 and 2.

구체적으로, 상기 실시예 1-18의 화합물은 모두 대조군 1인 크리조티닙(crizotinib)보다 활성이 우수한 것으로 나타났으며, 또한 상기 실시예 1-18중, 실시예 7 및 9를 제외한 나머지 화합물들은 대조군 2인 LDK-378보다 활성이 우수한 것으로 나타났다.
Specifically, all of the compounds of Examples 1-18 were found to be more active than the control 1, crizotinib. Of the compounds of Examples 1-18, except for Examples 7 and 9, the compounds Was more active than control group 2 LDK-378.

본 실험결과로부터 본 발명에 따른 피리미딘-2,4-디아민 유도체들이 낮은 농도에서도 효소단계에서의 역형성 림프종 키나아제(ALK)의 활성 억제 효과가 있으며, 특히 종래 역형성 림프종 키나아제(ALK) 활성을 억제함으로써, 비소세포폐암의 치료제로 이용되고 있는 크리조티닙(양성대조군)보다 우수한 저해 활성을 가진다는 것을 알 수 있다.
These results suggest that the pyrimidine-2,4-diamine derivatives according to the present invention have the effect of inhibiting the activity of the inverse lymphoma kinase (ALK) at the enzyme level even at a low concentration. In particular, the activity of the conventional inverse lymphoma kinase (ALK) (Positive control), which is used as a therapeutic agent for non-small cell lung cancer.

따라서, 본 발명에 따른 피리미딘-2,4-디아민 유도체는 역형성 림프종 키나아제(ALK)활성을 억제하는 효과가 우수하므로 비소세포폐암, 신경모세포종, 염증성 골수섬유모세포종양, 종횡문근육종, 근섬유모세포종, 유방암, 위암, 폐암, 흑색종 등의 암의 예방 또는 치료용 조성물뿐만 아니라, 역형성 림프종 키나아제(ALK) 활성 억제제로 유용하게 사용될 수 있다.
Accordingly, the pyrimidine-2,4-diamine derivative according to the present invention is excellent in inhibiting the activity of inverse lymphoma kinase (ALK), and thus can be used for the treatment of non-small cell lung cancer, neuroblastoma, inflammatory myeloblastic fibroblastoma, rhabdomyosarcoma sarcoma, , Breast cancer, stomach cancer, lung cancer, melanoma and the like, as well as compositions for preventing or treating cancer, as well as inhibitors of reversed-type lymphoma kinase (ALK) activity.

<< 실험예Experimental Example 2> 암세포 증식억제 실험 2> Cancer cell proliferation inhibition experiment

본 발명에 따른 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체의 암세포 증식 억제능을 알아보기 위해 하기와 같은 실험을 수행하였다.
In order to examine the inhibitory effect of the pyrimidine-2,4-diamine derivative represented by the formula (1) according to the present invention on cancer cell proliferation, the following experiment was conducted.

<2-1> 실험 재료&Lt; 2-1 >

시약reagent

세포배양액인 RPMI 1640 배지, FBS(fetal bovine serum) 및 크립신은 Gibco사(Grand Island, NY)로부터 구입하였으며, 탄산수소나트륨, 암포테리신 B 및 겐타마이신은 시그마케미컬 제품을 사용하였다.Cell culture medium, RPMI 1640 medium, fetal bovine serum (FBS) and creosin were purchased from Gibco (Grand Island, NY). Sodium bicarbonate, amphotericin B and gentamycin were purchased from Sigma Chemical.

또한, 세포독성 측정 실험에 사용한 시약인 SRB(sulforhod아민) B, 트리스마 염기(trisma base), 트리클로로아세트산(TCA) 등의 시약은 시그마케미컬사로부터 구입하였다. MTS assay를 위해서는 CellTiter 96R Aqueous Non-Radioactive Cell Proliferation Assay 제품을 프로메가(Promega)사로부터 구입하였다.Reagents such as SRB (sulforhodamine) B, trisma base, and trichloroacetic acid (TCA), reagents used in the cytotoxicity measurement experiment, were purchased from Sigma Chemical Company. For the MTS assay, the CellTiter 96 R Aqueous Non-Radioactive Cell Proliferation Assay product was purchased from Promega.

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

사용기기Used equipment

세포독성 측정을 위한 엘라이자 리더기(microplate reader)는 Molecular Devices사(Sunnyvale, CA)의 E-max나 SpectraMax250 기종을 사용하였다.
An E-max or SpectraMax 250 instrument from Molecular Devices (Sunnyvale, Calif.) Was used as a microplate reader for cytotoxicity measurements.

<2-2> 실험방법<2-2> Experimental method

단계 1 : 세포 배양Step 1: Cell culture

최종 디메틸설폭사이드 농도는 0.5% 이하가 되도록 하였다.The final dimethyl sulfoxide concentration was adjusted to be 0.5% or less.

실험에 사용한 암세포주는 모두 인체기원 암세포주들로서, 구체적으로는 비소세포폐암 세포주인 H2228, H3122를 사용하였다.The cancer cell lines used in the experiment were all human cancer cell lines, specifically H2228 and H3122, which are non - small cell lung cancer cell lines.

배양액으로는 10% FBS(fetal bovine serum)가 첨가된 RPMI 1640 배지를 사용하여 37℃ 및 5% 이산화탄소 인큐베이터에서 배양하였고, 3 내지 4일에 한 번씩 계대 유지하였다.
As the culture medium, the cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) at 37 ° C and 5% carbon dioxide incubator, and kept in the passage every 3 to 4 days.

단계 2 : 화합물 처리에 따른 증식억제 활성 평가Step 2: Evaluation of proliferation inhibitory activity by compound treatment

96 웰(well) 평평한 바닥 마이크로플레이트(flat-bottom microplate)의 각 웰(well)에 1 ×104 cells를 분주하고, 세포가 바닥면에 부착하도록 24시간 동안 배양한 후, 배양액을 제거하였다. 여기에 실시예 1 내지 18의 화합물이 각각 희석된 배양액을 가하고 72시간 동안 배양하였다. 상기 화합물과의 배양이 종료된 후, 세포독성의 측정은 단백질 염색 시약인 SRB를 이용하여 측정하거나 MTS assay법을 이용하여 측정하였다. 실시예 1 내지 18의 화합물과의 배양이 종료된 후, 배양액을 제거하고 각 웰(well)에 차가운 TCA 용액을 처리하고 4℃에서 1시간 동안 방치하여 세포들을 고정시켰다. 상기 TCA 용액을 제거하고 실온에서 건조시킨 후, 1% 아세트산 용액에 0.4% SRB를 녹인 염색용액을 가하여 실온에서 30분 동안 방치하여 세포를 염색하였다. 세포와 결합하지 않은 여분의 SRB를 1% 아세트산 용액으로 세척하여 제거하고, 염색된 세포들에 pH 10.3 내지 10.5의 10mM 트리스 완충용액(Trisma base; unbuffered)을 가하여 SRB를 용출시켰다. 각 웰(well)의 흡광도는 엘라이자 리더기(microplate reader)를 이용하여 520 mM의 파장 범위에서 측정하였다.1 × 10 4 cells were dispensed into each well of a 96-well flat-bottom microplate and cultured for 24 hours to allow the cells to adhere to the bottom surface, and then the culture medium was removed. The culture medium in which each of the compounds of Examples 1 to 18 was diluted was added thereto and cultured for 72 hours. After completion of the culture with the compound, cytotoxicity was measured using SRB, a protein staining reagent, or MTS assay. After completion of the cultivation with the compounds of Examples 1 to 18, the culture medium was removed, cold TCA solution was treated in each well, and the cells were allowed to stand at 4 DEG C for 1 hour. After removing the TCA solution and drying at room temperature, a staining solution in which 0.4% SRB was dissolved in 1% acetic acid solution was added and left at room temperature for 30 minutes to stain the cells. Extra SRB not bound to the cells was washed away with 1% acetic acid solution and SRB was eluted by adding 10 mM Tris buffer (Trisma base; unbuffered) of pH 10.3 to 10.5 to the stained cells. The absorbance of each well was measured in a wavelength range of 520 mM using a microplate reader.

약물을 가하지 않은 웰(well)(C)과 약물을 가한 각 웰(well)(T) 및 약물을 처음 가할 때의 웰(well)(Tz)의 OD값으로부터,From the OD value of the well (C) in which the drug is not added, the well (T) in which the drug is added, and the well (Tz)

Tz=T인 경우에는 [(T-Tz)/(C-Tz)]100의 수식에 의해; 또는(T-Tz) / (C-Tz) 100 when Tz = T; or

Tz＞T인 경우에는 [(T-Tz)/(Tz)]100 의 수식에 의해 약물의 세포독성을 계산하였다. When Tz> T, the cytotoxicity of the drug was calculated by the formula [(T-Tz) / (Tz)] 100.

MTS assay 법을 이용한 암세포 증식억제 측정은 다음과 같이 실험하였다. 구체적으로, 실시예 1 내지 실시예 18에서 제조된 화합물과의 배양이 종료된 후, Promega사의 CellTiter 96R AQueous Non-Radioactive Cell Proliferation Assay 제품을 구성하고 있는 PMS 용액과 MTS 용액을 섞은 후 well당 20 L를 넣어주었다. 4시간 동안 배양기에 놓아둔 후 꺼내어 상온에서 10분간 방치하였다. Molecular Device사의 SpectraMax250 기종을 이용하여 490 nM에서의 흡광도를 측정한 후 증식억제 효과인 GI50(Growth Inhibition 50%)값을 계산하였고, 그 결과를 하기 표 3에 나타내었다.
The inhibition of cancer cell proliferation using the MTS assay was tested as follows. Specifically, after completion of the culture with the compounds prepared in Examples 1 to 18, the PMS solution constituting the product of Promega's CellTiter 96 R AQueous Non-Radioactive Cell Proliferation Assay was mixed with the MTS solution, and 20 L. Placed in an incubator for 4 hours, removed, and left at room temperature for 10 minutes. The absorbance at 490 nM was measured using SpectraMax250 from Molecular Device, and the value of GI 50 (Growth Inhibition 50%), which is a proliferation inhibitory effect, was calculated. The results are shown in Table 3 below.

실시예Example H2228
GI50 (uM)H2228
GI 50 (uM) H3122
GI50 (uM)H3122
GI 50 (uM) 대조군 1
(crizotinib)Control 1
(crizotinib) 0.8510.851 0.2770.277 대조군 2
(LDK-378)_기준Control group 2
(LDK-378) _ standard 0.0250.025 0.0230.023 1One <0.01<0.01 <0.01<0.01 22 <0.01<0.01 <0.01<0.01 33 <0.01<0.01 <0.01<0.01 44 <0.01<0.01 >0.01> 0.01 55 <0.01<0.01 <0.01<0.01 66 <0.01<0.01 <0.01<0.01 77 >0.01> 0.01 >0.01> 0.01 88 <0.01<0.01 >0.01> 0.01 99 >0.01> 0.01 >0.01> 0.01 1010 <0.01<0.01 <0.01<0.01 1111 >0.01> 0.01 <0.01<0.01 1212 >0.01> 0.01 <0.01<0.01 1313 <0.01<0.01 <0.01<0.01 1414 >0.01> 0.01 <0.01<0.01 1515 >0.01> 0.01 <0.01<0.01 1616 <0.01<0.01 <0.01<0.01 1717 <0.01<0.01 <0.01<0.01 1818 <0.01<0.01 <0.01<0.01

상기 표 3에 나타난 바와 같이, 본 발명에 따른 실시예 화합물들은 비소세포폐암 세포주인 H2228 및 H3122의 역형성 림프종 키나아제(ALK)를 억제함으로써 그 증식활성을 감소시키는 것으로 나타났다. 본 실험결과로부터 본 발명의 실시예 화합물들 대부분은 현재 비소세포폐암 치료제로 사용되고 있는 대조군 1 및 2의 화합물보다 우수한 증식억제효과가 있음을 알 수 있었다.
As shown in Table 3, the compounds according to the present invention were found to reduce their proliferative activity by inhibiting the inverse lymphoma kinase (ALK) of H2228 and H3122, non-small cell lung cancer cell lines. From the results of this experiment, it was found that most of the compounds of the examples of the present invention had better proliferation inhibitory effect than the compounds of the control groups 1 and 2 currently used as therapeutic agents for non-small cell lung cancer.

따라서, 본 발명에 따른 피리미딘-2,4-디아민 유도체는 역형성 림프종 키나아제(ALK)활성을 억제하는 효과가 우수하므로 비소세포폐암, 신경모세포종, 염증성 골수섬유모세포종양, 종횡문근육종, 근섬유모세포종, 유방암, 위암, 폐암, 흑색종 등의 암의 예방 또는 치료용 조성물뿐만 아니라, 역형성 림프종 키나아제(ALK) 활성 억제제로 유용하게 사용될 수 있다.
Accordingly, the pyrimidine-2,4-diamine derivative according to the present invention is excellent in inhibiting the activity of inverse lymphoma kinase (ALK), and thus can be used for the treatment of non-small cell lung cancer, neuroblastoma, inflammatory myeloblastic fibroblastoma, rhabdomyosarcoma sarcoma, , Breast cancer, stomach cancer, lung cancer, melanoma and the like, as well as compositions for preventing or treating cancer, as well as inhibitors of reversed-type lymphoma kinase (ALK) activity.

<< 실험예Experimental Example 3>  3> EML4EML4 -- ALKALK 로 형질 감염된 Transfected with BaF3BaF3 세포의 세포독성 평가 Cell cytotoxicity assessment

본 발명에 따른 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체의 BaF3 EML4-ALK L1196M 및 BaF3 EML4-ALK WT 세포에 대한 세포독성을 측정하기 위하여 하기와 같은 실험을 수행하였다.
In order to measure the cytotoxicity of the pyrimidine-2,4-diamine derivative represented by Formula 1 according to the present invention on BaF3 EML4-ALK L1196M and BaF3 EML4-ALK WT cells, the following experiment was conducted.

구체적으로, BaF3세포에 EML4-ALK wt(wild-type) 유전자를 렌티바이러스(lentivirus)로 감염시켜 EML4-ALK wt가 안정적으로 발현하는 BaF3 EML4-ALK wt 세포주를 준비하였다. 또한, BaF3세포에 EML4-ALK L1196M 유전자를 렌티바이러스(lentivirus)로 감염시켜 EML4-ALK L1196M이 안정적으로 발현하는 BaF3 EML4-ALK L1196M 세포주를 준비하였다. 상기 두 개의 세포주의 세포 개수를 잘 측정한 다음 96 웰 플레이트(well plate)의 각 웰(well)에 4,000개씩 90㎕의 부피로 넣은 후, 상기 실시예에서 제조한 화합물의 농도를 10uM, 2uM, 0.4uM, 0.08uM, 0.016uM, 0.0032uM, 0.00064uM 및 0uM로 각 웰(well)에 첨가하고, 3일 동안 37℃의 세포배양기 안에 넣었다. 3일 후, 각 웰(well)에 WST-1 용액을 10㎕씩 첨가하고, 각 웰(well)의 용액의 색깔이 변하면 ELISA(제조사 : Molecular Devices, 모델명 : EMax Endpoint ELISA Microplate reader)를 이용하여 450nm에서 측정하였다. 측정된 값을 이용해서 세포의 양을 계산함으로써 각 화합물의 세포독성에서의 IC50를 계산하였고, 그 결과를 하기 표 4에 나타내었다.
Specifically, a BaF3 EML4-ALK wt cell line stably expressing EML4-ALK wt was prepared by infecting BaF3 cells with EML4-ALK wt (wild-type) gene as a lentivirus. In addition, a BaF3 EML4-ALK L1196M cell line stably expressing EML4-ALK L1196M was prepared by infecting BaF3 cells with EML4-ALK L1196M gene as a lentivirus. The cell counts of the two cell lines were measured and then placed in a volume of 90 μl in 4,000 wells of a 96-well plate. The concentrations of the compounds prepared in the above examples were adjusted to 10 uM, 2 uM, Was added to each well at 0.4 uM, 0.08 uM, 0.016 uM, 0.0032 uM, 0.00064 uM and 0 uM and placed in a 37 [deg.] C cell incubator for 3 days. After 3 days, 10 占 퐇 of WST-1 solution was added to each well. When the color of the solution in each well changed, an ELISA (manufacturer: Molecular Devices, Model: EMax Endpoint ELISA Microplate reader) Lt; / RTI &gt; IC 50 on cytotoxicity of each compound was calculated by calculating the amount of cells using the measured values, and the results are shown in Table 4 below.

실시예Example BaF3
EML4-ALK
L1196M (uM)BaF3
EML4-ALK
L1196M (uM) BaF3
EML4-ALK
WT (uM)BaF3
EML4-ALK
WT (uM) 대조군 1
(crizotinib)Control 1
(crizotinib) 1.11.1 0.060.06 대조군 2
(LDK-378)_기준Control group 2
(LDK-378) _ standard 0.0410.041 0.0190.019 1One <0.01<0.01 <0.01<0.01 22 >0.01> 0.01 <0.01<0.01 33 >0.01> 0.01 <0.01<0.01 44 <0.01<0.01 <0.01<0.01 55 <0.01<0.01 <0.01<0.01 66 >0.01> 0.01 <0.01<0.01 77 >0.01> 0.01 >0.01> 0.01 88 <0.01<0.01 <0.01<0.01 99 >0.01> 0.01 >0.01> 0.01 1010 <0.01<0.01 <0.01<0.01 1111 <0.01<0.01 <0.01<0.01 1212 <0.01<0.01 <0.01<0.01 1313 <0.01<0.01 <0.01<0.01 1414 <0.01<0.01 <0.01<0.01 1515 <0.01<0.01 <0.01<0.01 1616 <0.01<0.01 <0.01<0.01 1717 <0.01<0.01 <0.01<0.01 1818 <0.01<0.01 <0.01<0.01

상기 표 4에 나타난 바와 같이, 본 발명에 따른 실시예 화합물들은 대부분이 BaF3 EML4-ALK WT(wild-type) 세포 및 크리조티닙(crizotinib)에 내성을 갖는 BaF3 EML4-ALK L1196M 세포에서 세포독성 IC50값이 대조군 1 및 2에 비하여 낮은 것으로 나타났다. 본 실험결과로부터 본 발명의 실시예 화합물들 대부분은 현재 비소세포폐암 치료제로 사용되고 있는 대조군 1 및 2의 화합물보다 우수한 ALK 억제활성이 있음을 알 수 있었다.
As shown in Table 4, the compounds according to the present invention are most effective against BaF3 EML4-ALK WT (wild-type) cells and BaF3 EML4-ALK L1196M cells resistant to crizotinib, 50 values were lower than those of control 1 and 2. From the results of this experiment, it can be seen that most of the compounds of the present invention have better ALK inhibitory activity than the compounds of the control groups 1 and 2 currently used for the treatment of non-small cell lung cancer.

따라서, 본 발명에 따른 피리미딘-2,4-디아민 유도체는 역형성 림프종 키나아제(ALK) 활성을 억제하는 효과가 뛰어나므로, 비소세포폐암, 신경모세포종, 염증성 골수섬유모세포종양, 종횡문근육종, 근섬유모세포종, 유방암, 위암, 폐암, 흑색종 등의 암의 예방 또는 치료용 조성물뿐만 아니라, 역형성 림프종 키나아제(ALK)의 저해제로 유용하게 사용될 수 있다.
Therefore, the pyrimidine-2,4-diamine derivative according to the present invention is excellent in inhibiting the activity of inverse lymphoma kinase (ALK), and thus can be used for the treatment of non-small cell lung cancer, neuroblastoma, inflammatory myelofibroblastoma, (ALK) as well as a composition for the prevention or treatment of cancer such as breast cancer, breast cancer, stomach cancer, lung cancer, melanoma and the like.

참조로 하기 표 5에, 실험예 1-3(표 2-4)에서 얻은 실험결과를 종합하여 나타내었다.
The experimental results obtained in Experimental Example 1-3 (Table 2-4) are summarized in Table 5 below.

실시예Example 실험예 1Experimental Example 1 실험예 2Experimental Example 2 실험예 3Experimental Example 3 ALK wt.
IC50 (uM)ALK wt.
IC 50 (uM) ALK L1196M
IC50 (uM)ALK L1196M
IC 50 (uM) H2228
GI50 (uM)H2228
GI 50 (uM) H3122CP
GI50 (uM)H3122CP
GI 50 (uM) BaF3
EML4-ALK
L1196M (uM)BaF3
EML4-ALK
L1196M (uM) BaF3
EML4-ALK
WT (uM)BaF3
EML4-ALK
WT (uM) 대조군 1
(crizotinib)Control 1
(crizotinib) 0.010.01 0.220.22 0.8510.851 0.2770.277 1.11.1 0.060.06 대조군 2
(LDK-378)_기준Control group 2
(LDK-378) _ standard 0.0010.001 0.0090.009 0.0250.025 0.0230.023 0.0410.041 0.0190.019 1One <0.001<0.001 <0.001<0.001 <0.01<0.01 <0.01<0.01 <0.01<0.01 <0.01<0.01 22 <0.001<0.001 <0.001<0.001 <0.01<0.01 <0.01<0.01 >0.01> 0.01 <0.01<0.01 33 <0.001<0.001 <0.001<0.001 <0.01<0.01 <0.01<0.01 >0.01> 0.01 <0.01<0.01 44 <0.001<0.001 <0.001<0.001 <0.01<0.01 >0.01> 0.01 <0.01<0.01 <0.01<0.01 55 <0.001<0.001 <0.001<0.001 <0.01<0.01 <0.01<0.01 <0.01<0.01 <0.01<0.01 66 <0.001<0.001 <0.001<0.001 <0.01<0.01 <0.01<0.01 >0.01> 0.01 <0.01<0.01 77 >0.001> 0.001 >0.001> 0.001 >0.01> 0.01 >0.01> 0.01 >0.01> 0.01 >0.01> 0.01 88 <0.001<0.001 <0.001<0.001 <0.01<0.01 >0.01> 0.01 <0.01<0.01 <0.01<0.01 99 >0.001> 0.001 >0.001> 0.001 >0.01> 0.01 >0.01> 0.01 >0.01> 0.01 >0.01> 0.01 1010 <0.001<0.001 <0.001<0.001 <0.01<0.01 <0.01<0.01 <0.01<0.01 <0.01<0.01 1111 <0.001<0.001 <0.001<0.001 >0.01> 0.01 <0.01<0.01 <0.01<0.01 <0.01<0.01 1212 <0.001<0.001 <0.001<0.001 >0.01> 0.01 <0.01<0.01 <0.01<0.01 <0.01<0.01 1313 <0.001<0.001 <0.001<0.001 <0.01<0.01 <0.01<0.01 <0.01<0.01 <0.01<0.01 1414 <0.001<0.001 <0.001<0.001 >0.01> 0.01 <0.01<0.01 <0.01<0.01 <0.01<0.01 1515 <0.001<0.001 <0.001<0.001 >0.01> 0.01 <0.01<0.01 <0.01<0.01 <0.01<0.01 1616 <0.001<0.001 <0.001<0.001 <0.01<0.01 <0.01<0.01 <0.01<0.01 <0.01<0.01 1717 <0.001<0.001 <0.001<0.001 <0.01<0.01 <0.01<0.01 <0.01<0.01 <0.01<0.01 1818 <0.001<0.001 <0.001<0.001 <0.01<0.01 <0.01<0.01 <0.01<0.01 <0.01<0.01

한편, 본 발명에 따른 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체는 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화학식 1로 표시되는 피리미딘-2,4-디아민 유도체를 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.
Meanwhile, the pyrimidine-2,4-diamine derivative represented by Formula 1 according to the present invention can be formulated into various forms according to the purpose. Hereinafter, some formulation methods of containing the pyrimidine-2,4-diamine derivative represented by the formula 1 according to the present invention as an active ingredient are illustrated, but the present invention is not limited thereto.

<< 제제예Formulation example 1> 약학적 제제의 제조 1> Preparation of pharmaceutical preparations

1-1. 1-1. 산제의Sanje 제조 Produce

화학식 1의 유도체 500 ㎎500 mg of the derivative of formula (1)

유당 100 ㎎Lactose 100 mg

탈크 10 ㎎
10 mg of talc

상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.
The above components are mixed and filled in airtight bags to prepare powders.

1-2. 정제의 제조1-2. Manufacture of tablets

화학식 1의 유도체 500 ㎎500 mg of the derivative of formula (1)

옥수수전분 100 ㎎Corn starch 100 mg

유당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎
2 mg of magnesium stearate

상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.
After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.

1-3. 캅셀제의 제조1-3. Manufacture of capsules

화학식 1의 유도체 500 ㎎500 mg of the derivative of formula (1)

옥수수전분 100 ㎎Corn starch 100 mg

유당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎
2 mg of magnesium stearate

통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.
The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.

1-4. 주사제의 제조1-4. Injection preparation

화학식 1의 유도체 500 ㎎500 mg of the derivative of formula (1)

주사용 멸균 증류수 적량Sterile sterilized water for injection

pH 조절제 적량
pH adjuster

통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조한다.
(2 ml) per ampoule in accordance with the usual injection method.

1-5. 1-5. 액제의Liquid 제조 Produce

화학식 1의 유도체 100 ㎎100 mg of the derivative of formula (1)

이성화당 10 g10 g per isomer

만니톨 5 g5 g mannitol

정제수 적량
Purified water quantity

통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬 향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색 병에 충진하여 멸균시켜 액체를 제조한다.Each component was added to purified water in accordance with the usual liquid preparation method and dissolved, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was adjusted to 100 ml with purified water, The liquid is prepared by sterilization.

Claims (10)

하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용 가능한 염:
(1) 5-클로로-N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)피리미딘-2,4-디아민;
(2) 5-클로로-N2-(2-이소프로폭시-5-메틸-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)-N4-(2-(이소프로필술포닐)페닐)피리미딘-2,4-디아민;
(3) 5-클로로-N2-(2-(디플루오로메톡시)-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)-N4-(2(이소프로필술포닐_페닐)피리미딘-2,4-디아민;
(4) 5-클로로-N2-(2-(디플루오로메톡시)-4-(피페리딘-4-일)페닐)-N4 (2(이소프로필술포닐)페닐)피리미딘-2,4-디아민;
(5) 5-클로로-N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-4-(피페리딘-4yl)페닐)피리미딘-2,4-디아민;
(6) N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)-5-(트리플루오로메틸)피리미딘-2,4-디아민;
(10) 5-클로로-N2-(5-플루오로-2-메톡시-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)-N4-(2-(이소프로필술포닐)페닐)피리미딘-2,4-디아민;
(11) 5-클로로-N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-5-메틸-4-(1,2,3,6-테트라하이드로피리딘-4-일)페닐)피리미딘-2,4-디아민;
(12) 5-클로로-N2-(5-플루오로-2-메톡시-4-(피페리딘-4-일)페닐)-N4-(2-(이소프로필술포닐)페닐)피리미딘-2,4-디아민;
(13) 5-클로로-N4-(2-(이소프로필술포닐)페닐)-N2-(2-메톡시-5-메틸-4-(피페리딘-4-일)페닐)피리미딘-2,4-디아민;
(14) 5-클로로-N2-(4-(1-에틸-1,2,3,6-테트라하이드로피리딘-4-일)-2-메톡시페닐)-N4-(2-(이소프로필술포닐)페닐)피리미딘-2,4-디아민;
(15) 5-클로로-N2-(4-(1-에틸-1,2,3,6-테트라하이드로피리딘-4-일)-2-메톡시페닐)-N4-(2-(이소프로필술포닐)페닐)피리미딘-2,4-디아민;
(16) 1-(4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-3-메톡시페닐)-5,6-디하이드로피리딘-1(2H)-일)에탄온;
(17) 4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-3-메톡시페닐)-5,6-디하이드로피리딘-1(2H)-카르복시산; 및
(18) 4-(4-((5-클로로-4-((2-(이소프로필술포닐)페닐)아미노)피리미딘-2-일)아미노)-3-메톡시페닐)-5,6-디하이드로피리딘-1(2H)-메틸.
Or a pharmaceutically acceptable salt thereof, wherein the compound is any one selected from the group consisting of the following compounds:
(1) Synthesis of 5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy- 4- (1,2,3,6-tetrahydropyridin- Pyrimidine-2,4-diamine;
(2) Synthesis of 5-chloro-N2- (2-isopropoxy-5-methyl-4- (1,2,3,6-tetrahydropyridin- Sulfonyl) phenyl) pyrimidine-2,4-diamine;
(3) Synthesis of 5-chloro-N2- (2- (difluoromethoxy) -4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl) -N4- Phenyl) pyrimidine-2,4-diamine;
(4) Synthesis of 5-chloro-N2- (2- (difluoromethoxy) -4- (piperidin-4-yl) phenyl) -N4 (2- (isopropylsulfonyl) - diamines;
(5) 5-Chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy-4- (piperidin-4yl) phenyl) pyrimidine-2,4-diamine;
(6) Synthesis of N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy-4- (1,2,3,6-tetrahydropyridin- Trifluoromethyl) pyrimidine-2,4-diamine;
(10) Synthesis of 5-chloro-N2- (5-fluoro-2-methoxy-4- (1,2,3,6-tetrahydropyridin- Sulfonyl) phenyl) pyrimidine-2,4-diamine;
(11) Synthesis of 5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy- Yl) phenyl) pyrimidine-2,4-diamine;
(12) 5-Chloro-N2- (5-fluoro-2-methoxy-4- (piperidin- 4- yl) phenyl) -N4- (2- (isopropylsulfonyl) 2,4-diamine;
(13) Synthesis of 5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy- , 4-diamine;
(14) Synthesis of 5-chloro-N2- (4- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -2- methoxyphenyl) -N4- (2- Phenyl) pyrimidine-2,4-diamine;
(15) Synthesis of 5-chloro-N2- (4- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -2- methoxyphenyl) -N4- (2- Phenyl) pyrimidine-2,4-diamine;
(16) Synthesis of 1- (4- (4 - ((5-chloro-4 - ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin- 5,6-dihydropyridin-1 (2H) -yl) ethanone;
(17) Synthesis of 4- (4 - ((5-chloro-4 - ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin- - dihydropyridin-1 (2H) -carboxylic acid; And
(18) 4- (4-chloro-4 - ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin- - dihydropyridin-1 (2H) -methyl.
삭제delete 삭제delete 삭제delete 하기 반응식 1에 나타낸 바와 같이,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계(단계 1); 및
상기 단계 1에서 제조한 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계(단계 2);를 포함하는 제1항의 화합물 군으로부터 선택되는 어느 하나인 화합물의 제조방법:

[반응식 1]
Figure 112016045339038-pat00072

(상기 반응식 1에서,
R1, R2, R3 및 R4는 제1항에 기재된 화합물들의 치환기 범위와 동일하다).As shown in Scheme 1 below,
Reacting a compound represented by formula (2) with a compound represented by formula (3) to prepare a compound represented by formula (4) (step 1); And
A step of reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (1) (step 2) Preparation of phosphorus compounds:

[Reaction Scheme 1]
Figure 112016045339038-pat00072

(In the above Reaction Scheme 1,
R 1 , R 2 , R 3 And R &lt; 4 &gt; are the same as the substituent range of the compounds described in claim 1). 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete
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