KR100848205B1 - New substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory activity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and pharmaceutical composition comprising the same - Google Patents

New substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory activity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and pharmaceutical composition comprising the same Download PDF

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KR100848205B1
KR100848205B1 KR1020060054351A KR20060054351A KR100848205B1 KR 100848205 B1 KR100848205 B1 KR 100848205B1 KR 1020060054351 A KR1020060054351 A KR 1020060054351A KR 20060054351 A KR20060054351 A KR 20060054351A KR 100848205 B1 KR100848205 B1 KR 100848205B1
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thiazol
pyrimidin
fluorophenyl
amine
piperidin
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KR20060133464A (en
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최인영
이광준
이경재
채명윤
김호순
김환묵
박성규
이기호
한상배
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주식회사 동부하이텍
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Abstract

본 발명은 면역 억제 및 염증 억제 활성을 갖는 신규한 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염, 중간체 화합물 또는 이의 약학적으로 허용가능한 염, 이의 제조방법, 및 이를 포함하는 약학적 조성물에 관한 것이다.The present invention provides novel substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof, intermediate compounds or pharmaceutically acceptable salts thereof, methods for preparing the same, and immunosuppressive and inflammatory inhibitory activities It relates to a pharmaceutical composition.

본 발명의 화합물은 TNF-α 억제 활성 및 염증 억제 활성이 우수함으로, TNF-α 관련 질환의 예방 및 치료에 유용하게 사용할 수 있다.Since the compound of the present invention has excellent TNF-α inhibitory activity and inflammatory inhibitory activity, it can be usefully used for the prevention and treatment of TNF-α related diseases.

1,3-티아졸 유도체, TNF-α 억제 활성, 염증 억제 활성 1,3-thiazole derivatives, TNF-α inhibitory activity, inflammation inhibitory activity

Description

면역 억제 및 염증 억제 활성을 갖는 신규한 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염, 중간체 화합물 또는 이의 약학적으로 허용가능한 염, 이의 제조방법, 및 이를 포함하는 약학적 조성물{New substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory activity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and pharmaceutical composition comprising the same}Novel substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts, intermediate compounds or pharmaceutically acceptable salts thereof, preparations thereof, and pharmaceutical compositions comprising the same, having immunosuppressive and inflammatory inhibitory activity {New substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts according to immuno having suppression and inflammation inhibitory activity, intermediate compounds or pharmaceutically acceptable salts, etc.

도 1a는 염증성 장질환 유발물질인 TNBS(2,4,6-trinitrobenzenesulfonic acid solution)에 의해 궤양이 유발된 랫트를 희생시켜 절취한 비히클(vehicle) 처리군의 콜론 사진이고,1A is a colon photograph of a vehicle treated group cut at the expense of rats induced by ulcers by TNBS (2,4,6-trinitrobenzenesulfonic acid solution) which is an inflammatory bowel disease-causing agent,

도 1b는 염증성 장질환 유발물질인 TNBS에 의해 궤양이 유발된 후, 프레드니솔론(Prednisolone)으로 처리한 랫트를 희생시켜 절취한 처리군의 콜론 사진이고,Figure 1b is a colon picture of the treated group taken at the expense of rats treated with prednisolone after ulceration was induced by TNBS, an inflammatory bowel disease-causing agent,

도 1c는 염증성 장질환 유발물질인 TNBS에 의해 궤양이 유발된 후, 본 발명에 따른 실시예 334의 화합물로 처리한 랫트를 희생시켜 절취한 콜론 사진이다.Figure 1c is a colon photograph taken at the expense of rats treated with the compound of Example 334 according to the invention after the ulcer is induced by TNBS, an inflammatory bowel disease-causing agent.

본 발명은 면역 억제 및 염증 억제 활성을 갖는 신규한 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염, 중간체 화합물 또는 이의 약학적으로 허용가능한 염, 이의 제조방법, 및 이를 포함하는 약학적 조성물에 관한 것이다.The present invention provides novel substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof, intermediate compounds or pharmaceutically acceptable salts thereof, methods for preparing the same, and immunosuppressive and inflammatory inhibitory activities It relates to a pharmaceutical composition.

면역 반응과 염증 반응에 중요한 역할을 하는 생물학적 물질로 TNF-α(종양 괴사 인자-α), IL-1(인터루킨-1) 등과 같은 전염증성 사이토카인류(proinflammatory cytokines)가 알려져 있다. 이들은 감염 및 기타 세포성 스트레스에 대한 반응으로 단핵구 또는 대식구와 같은 각종 세포에 의하여 생성된다. 이들 사이토카인류는 적정량 존재하는 경우에는 면역반응 또는 염증 반응에 중요한 역할을 하는 반면, 이들이 과잉생성되는 경우에는 각종 염증성 질환과 관련되어 있는 것으로 알려져 있다. Proinflammatory cytokines such as TNF-α (tumor necrosis factor-α) and IL-1 (interleukin-1) are known as biological substances that play an important role in immune and inflammatory responses. They are produced by various cells, such as monocytes or macrophages, in response to infection and other cellular stresses. These cytokines are known to play an important role in immune or inflammatory responses when present in the right amounts, while they are associated with various inflammatory diseases when they are overproduced.

상기 TNF-α, IL-1 등과 같은 전염증성 사이토카인류는 미토겐에 의해 활성화되는 단백질 키나아제(mitogen-activated protein kinases, MAPK)의 일종인 p38에 의해 조절된다(Seiji Miwatashi et al., J. Med. Chem. 48, 5966-5979, 2005). 알려진 바에 의하면, 단백질 키나아제(PK)로는 세포 외 시그널(signal)에 대한 다양한 세포의 반응에 관여하는 효소로서 인산화에 의해 그들의 기질의 활성화에 관여하는 Ser/Thr 키나아제 등이 있다(B. Stein et al., Ann. Rep. Med. Chem., 31, 289-298, 1996). 이러한 PK들 중 MAPK는 일반적으로 성장인자, 사이토카인, UV 조사 및 스트레스 유도제를 포함하는 다양한 시그널에 의해 자체 활성화가 이루어진 다. The proinflammatory cytokines such as TNF-α and IL-1 are regulated by p38, a type of mitogen-activated protein kinases (MAPK) that is activated by mitogen (Seiji Miwatashi et al., J. Med. Chem. 48, 5966-5979, 2005 ). As is known, protein kinases (PKs) are enzymes involved in the response of various cells to extracellular signals, such as Ser / Thr kinases, which are involved in the activation of their substrates by phosphorylation (B. Stein et al. , Ann.Rep. Med. Chem., 31, 289-298, 1996 ). Among these PKs, MAPKs are generally self-activated by various signals including growth factors, cytokines, UV radiation, and stress inducing agents.

특히 흥미로운 MAPK로 상기 p38이다. 상술한 바와 같이, 사이토카인 억제성 항염증성 약물 결합 단백질(cycling sequence binding protein, CSBP) 및 RK(reactivating kinases)로도 알려진 p38은 지다당류(lipopolysaccharides, LPS) 수용체 CD14를 형질감염시킨 쥐과의 B세포 전구체(pre-B cell)를 LPS로 유도시킨 후 분리하여 서열화되었고, 사람 및 마우스의 p38을 암호화하는 cDNA도 분리 및 서열화되었다. 상기 p38은 백혈구 축적, 대식세포/단핵세포 활성화, 조직 재흡수, 발열, 급성 상 반응 및 호중구증가증과 같은 염증성 자극에 대한 세포의 반응을 매개하는 역할을 하는 것으로 여겨진다. p38이 관여하는 질환으로는 암, 트롬빈에 의해 유도된 혈소판 응집, 면역 결핍 질환, 자가면역 질환, 세포 괴사, 알러지, 골다공증 및 신경 퇴행성 질병 등이 있다. Of particular interest is MAPK p38 above. As described above, p38, also known as cytokine inhibitory anti-inflammatory drug binding protein (CSBP) and reactivating kinases (RK), is a murine B-cell precursor transfected with lipopolysaccharides (LPS) receptor CD14. (pre-B cells) were isolated and sequenced after induction with LPS, and cDNA encoding p38 of human and mouse was also isolated and sequenced. The p38 is believed to play a role in mediating the cellular response to inflammatory stimuli such as leukocyte accumulation, macrophage / monocyte activation, tissue resorption, fever, acute phase reactions and neutropenia. Diseases involving p38 include cancer, thrombin-induced platelet aggregation, immunodeficiency diseases, autoimmune diseases, cell necrosis, allergies, osteoporosis and neurodegenerative diseases.

또한, 상기 p38은 스트레스(예를 들면, LPS 처리, UV, 아니소마이신 또는 삼투성 쇼크) 및 상술한 TNF-α, IL-1과 같은 사이토카인류에 의해 자극받은 세포에서 활성화되는 것이 관찰되었다. 따라서, IL-1, TNF-α 등의 사이토카인류의 생성을 차단하면 p38의 활성화를 저해할 수 있게 된다. 따라서, IL-1, TNF-α에 의해 자극을 받아 생성되는 다른 친염증성 사이토카인류, 예를 들면, IL-6 또는 IL-8의 생성도 차단함으로써, 상기 사이토카인류가 매개하는 질환 또는 상술한 p38이 관여하는 질환들을 치료할 수 있게 된다. 이하, 상기 TNF-α, IL-1, IL-6 및 IL-8의 과잉생성과 관련된 질환들을 보다 구체적으로 살펴본다.In addition, the p38 was observed to be activated in cells stimulated by stress (eg, LPS treatment, UV, anisomycin or osmotic shock) and cytokines such as TNF-α and IL-1 described above. . Therefore, blocking the generation of cytokines such as IL-1 and TNF-α can inhibit the activation of p38. Thus, by blocking the production of other pro-inflammatory cytokines, such as IL-6 or IL-8, which are produced by stimulation by IL-1, TNF-α, the cytokine-mediated diseases or One p38 is able to treat the diseases involved. Hereinafter, the diseases related to overproduction of TNF-α, IL-1, IL-6, and IL-8 will be described in more detail.

1. TNF-α1.TNF-α

TNF-α는 활성화 단핵구 및 대식세포에 의하여 주로 생성되는 사이토카인으로서 강력한 전염증성 매개체이다. 과다 또는 비조절된 TNF-α의 생성은 류마티스성 관절염, 류마티스성 척추염, 골관절염 및 기타 관절염 질환; 패혈증, 패혈성 쇼크, 내독소 쇼크, 그램 음성 패혈증, 독성 쇼크 증후군, 성인 호흡 곤란 증후군, 뇌성 말라리아, 만성 폐 염증성 질환, 규폐증, 폐 췌육증, 골 재흡수 질환, 재관류 손상, 이식편 대 숙주반응, 동종이식거부, 감염으로 인한 근육통 및 발열, 예를 들면 인플루엔자 감염으로 인한 2차 악액질, 후천성 면역 결핍증(AIDS)에 대한 2차 악액질, AIDS, AIDS 관련 합병증, 켈로이드 형성, 상처 조직 형성, 크론병, 궤양성 대장염, 마비, 비-인슐린 의존성 당뇨병, 다발성 경화증, 및 염증성 장질환과 관련되며, 바이러스 감염증, 예컨대 HIV, 인플루엔자 바이러스, 및 단순 헤르페스 바이러스 1형(HSV-1), 단순 헤르페스 바이러스 2형(HSV-2), 거대세포바이러스(CMV), 수두(varicella-zoster) 바이러스(VZV), 엡스테인-바 바이러스, 인간 헤르페스바이러스-6(HHV-6), 인간 헤르페스바이러스-7(HHV-7), 인간 헤르페스바이러스-8(HHV-8), 가성 광견병 및 비기관지염을 포함하는 헤르페스 바이러스와도 관련된다. TNF-α is a cytokine produced primarily by activated monocytes and macrophages and is a potent proinflammatory mediator. The production of excessive or unregulated TNF-α can be attributed to rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritis diseases; Sepsis, septic shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary pancreatitis, bone resorption disease, reperfusion injury, graft versus host reaction, Allograft rejection, myalgia and fever resulting from infection, eg secondary cachexia due to influenza infection, secondary cachexia for AIDS, AIDS, AIDS-related complications, keloid formation, wound tissue formation, Crohn's disease, Associated with ulcerative colitis, paralysis, non-insulin dependent diabetes mellitus, multiple sclerosis, and inflammatory bowel disease, viral infections such as HIV, influenza virus, and herpes simplex virus type 1 (HSV-1), simple herpes virus type 2 ( HSV-2), cytomegalovirus (CMV), varicella (zoster) virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpes Virus -7 (HHV-7), may also be referred to as the human herpesvirus -8 (HHV-8), herpes viruses, including rabies caustic and non bronchitis.

2. IL-12. IL-1

IL-1은 상기 TNF-α와 마찬가지로 활성화 단핵구 및 대식세포에 의하여 주로 생성되는 사이토카인으로서 강력한 전염증성 매개체이다. 또한, 이러한 IL-1의 수치는 TNF-α의 과다 또는 비조절 생성에 의해서도 증가되는 것으로 밝혀졌다. 따라 서, TNF-α의 억제제는 IL-1의 수치를 감소시키며[European Cytokine Netw 6, 225, 1995], 비조절된 IL-1 합성에 의한 질환 상태를 개선시킨다. IL-1, like TNF-α, is a potent proinflammatory mediator that is primarily a cytokine produced by activated monocytes and macrophages. In addition, this level of IL-1 was found to be increased by excessive or unregulated production of TNF-α. Thus, inhibitors of TNF-α decrease the levels of IL-1 (European Cytokine Netw 6, 225, 1995) and improve disease states by unregulated IL-1 synthesis.

과다 또는 비조절된 IL-1의 생성에 의해 악화 및/또는 유발되는 다수의 질환 상태에는 류마티스 관절염, 류마티스 척추염, 골관절염, 통풍, 외상성 관절염, 풍진성 관절염, 급성 활막염, 패혈증, 패혈 쇼크, 내독소 쇼크, 그람 음성 패혈증, 독소 쇼크 증후군, 성인 호흡 곤란 증후군, 뇌말라리아, 만성 폐 염증 질환, 규폐증, 폐 사르코이드증, 골 흡수 질환, 허혈성 재관류 손상, 동맥경화증, 뇌 외상, 다발성 경화증, 이식편 대 숙주 반응, 동종이식편 거부, 감염으로 인한 열 및 근육통, 감염 또는 악성종양에 대한 이차 악액질, 후천성 면역 결핍증(AIDS)에 대한 이차 악액질, AIDS 관련 합병증(ARC), 켈로이드 형성, 흉터 조직 형성, 건선, 크론병, 궤양 결장염, 과민증, 근육 변성, 로이터 증후군, 제1형 및 제2형 당뇨, 마비 등을 포함한다.Many disease states exacerbated and / or caused by the production of excessive or unregulated IL-1 include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout, traumatic arthritis, rubella arthritis, acute synovitis, sepsis, septic shock, endotoxin Shock, gram negative sepsis, toxin shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, ischemic reperfusion injury, arteriosclerosis, brain trauma, multiple sclerosis, graft-versus-host Reaction, allograft rejection, fever and myalgia from infection, secondary cachexia to infection or malignancy, secondary cachexia to AIDS, AIDS related complications (ARC), keloid formation, scar tissue formation, psoriasis, crohn Diseases, ulcerative colitis, hypersensitivity, muscle degeneration, Reuters syndrome, type 1 and type 2 diabetes, paralysis, and the like.

IL-1은 또한 T-헬퍼 세포의 활성화, 열 유도, 프로스타글란딘 또는 콜라게나제 생성의 자극, 호중구 화학주성, 및 혈장 내 철 농도의 억제와 같은 다양한 생물학적 활성을 조절하는 것으로 보고되었다(Rev. Infect. Disease, 6, 51(1984)). 나아가, TNF 억제에 민감한 바이러스, 예컨대 HIV-1, HIV-2, HIV-3가 또한 IL-1 생성에 의해 영향을 받는다. 류마티스 관절염에서, IL-1과 TNF 모두가 콜라게나제 합성을 유도하여, 결국엔 관절내에 조직 파괴를 일으킨다(Lymphokine Cytokine Res.(11): 253-256, (1992) 및 Clin. Exp. Immunol. 989: 244-250, 1992).IL-1 has also been reported to modulate various biological activities such as activation of T-helper cells, heat induction, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, and inhibition of iron concentrations in plasma (Rev. Infect Disease, 6, 51 (1984)). Furthermore, viruses sensitive to TNF inhibition, such as HIV-1, HIV-2, HIV-3, are also affected by IL-1 production. In rheumatoid arthritis, both IL-1 and TNF induce collagenase synthesis, eventually leading to tissue destruction in the joints (Lymphokine Cytokine Res. (11): 253-256, (1992) and Clin.Exp. Immunol. 989: 244-250, 1992).

3. IL-63. IL-6

IL-6은 또다른 염증성 사이토카인으로서, 염증을 포함한 수많은 증상과 관련된다. IL-6은 다발성 골수종 및 관련 혈장 세포 이혼화증을 포함하는 다수의 종양학적 질환에서의 성장 인자이다.IL-6 is another inflammatory cytokine associated with numerous symptoms, including inflammation. IL-6 is a growth factor in many oncological diseases, including multiple myeloma and related plasma cell dysplasia.

과다 또는 비조절된 IL-6와 관련된 질환은 에이즈성 복합 치매, 알츠하이머병, 다발성 경화증, 전신성 홍반성 루프스, CNS 외상 및 바이러스 및 세균성 수막염을 포함하는 신경학적 장애(Gruol, et al., 1997, Molecular Neurobiology 15:307), 다발성 골수종, 류마티스 관절염, 건선 및 폐경 후 골다공증 등과 같은 수많은 질환을 포함한다(Simpson, et al., Protein Sci. 6, 929, 1997).Diseases associated with excessive or unregulated IL-6 include neurological disorders including AIDS complex dementia, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma and viral and bacterial meningitis (Gruol, et al., 1997, Molecular Neurobiology 15: 307), multiple myeloma, rheumatoid arthritis, psoriasis and postmenopausal osteoporosis and many other diseases (Simpson, et al., Protein Sci. 6, 929, 1997).

4. IL-84. IL-8

IL-8은 단핵세포, 섬유아세포, 내피세포 및 각질 형성 세포를 비롯한 몇 가지 세포에서 생성되는 특성화된 화학 주성 인자이다. IL-8의 생성은 내피 세포에서 IL-1, TNF-α 또는 지질다당류(LPS)에 의하여 유도되는데, 이는 정상 및 아토피성 개체의 호염구로부터 히스타민을 방출시킬 뿐만 아니라 호중구로부터 리소좀 효소의 방출 유도 및 호중구의 혈관 내피세포 유착 증가에도 기여할 수 있다. IL-8 is a characterized chemotactic factor produced in several cells, including monocytes, fibroblasts, endothelial cells and keratinocytes. The production of IL-8 is induced by IL-1, TNF-α or lipopolysaccharide (LPS) in endothelial cells, which not only release histamine from basophils of normal and atopic individuals but also induce release of lysosomal enzymes from neutrophils and It may also contribute to increased vascular endothelial adhesions of neutrophils.

과다 또는 비조절된 IL-8과 관련된 질환 상태는 뇌졸중 및 심근 경색과 같이 호중구에 의해 주로 매개되는 질환, 열손상, 성인 호흡 곤란 증후군(ARDS), 외상에 부수적인 다발성 기관 손상, 급성 사구체 신염, 급성 염증성 성분을 수반한 피부병, 급성 화농성 수막염 또는 다른 중추 신경계 장애, 혈액 투석, 류코페리시스, 과립구 수혈과 관련된 증상, 괴사성 소결장염 등을 포함한다.Disease conditions associated with excessive or unregulated IL-8 include diseases primarily mediated by neutrophils, such as stroke and myocardial infarction, heat damage, adult respiratory distress syndrome (ARDS), multiple organ damage concomitant to trauma, acute glomerulonephritis, Skin diseases with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leucoperisis, symptoms associated with granulocyte transfusion, necrotic sinteritis, and the like.

5. 기타5. Other

상기한 사이토카인류 이외에도 GM-CSF, IFN-γ 등이 면역 및 염증 반응과 관련되어 있는데, GM-CSF는 간세포의 증식 및 분화에 영향을 나타낼 뿐만 아니라 급성 및 만성 염증과 관련이 있는 수 개의 다른 세포를 조절하고, IFN-γ는 이식편 대 숙주 질환의 주요 조직병리학적 특징인 콜라겐 침착과 관련이 있으며, 다발성 경화증 및 AIDS 복합 치매와 같은 질환에서 중추 신경계의 기능장애가 진행하기 전에 대부분의 말초 T-세포의 활성화를 유도한다[Martino et al., 1998, Ann Neurol. 43, 430].In addition to the cytokines described above, GM-CSF, IFN-γ, etc., are involved in immune and inflammatory responses. GM-CSF not only affects the proliferation and differentiation of hepatocytes, but also several other factors associated with acute and chronic inflammation. Regulates cells, IFN- [gamma] is associated with collagen deposition, a major histopathological feature of graft-versus-host disease, and in most diseases such as multiple sclerosis and AIDS complex dementia, most peripheral T- Induces activation of cells [Martino et al., 1998, Ann Neurol. 43, 430].

또한, 염증에 관여하는 생체 내 물질로 사이클로옥시케나제(COX)와 같은 단백질이 존재하는데, 이는 발현 조절 방식에 따라 항시발현 사이클로옥시게나제(COX-1)와 유도성 사이클로옥시게나제(COX-2)로 구분된다. COX-2의 발현은 사이토카인류에 의해 증가되는 것으로 이미 밝혀졌으며, 따라서 상기와 같은 사이토카인류의 억제제는 COX-2의 발현을 차단할 것으로 예상된다(M. K. O'Banion et al., Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 4888). 따라서, IL-1 등의 사이토카인류를 억제하는 것으로 잘 알려져 있는 NSAID처럼 COX 억제제로서 현재 치료되고 있는 질환에 대해 효능을 나타낼 것으로 기대된다.In addition, there are proteins such as cyclooxykenase (COX) that are involved in inflammation in vivo, which expresses the expression of cyclooxygenase (COX-1) and inducible cyclooxygenase (COX-1) depending on the expression regulation. -2). The expression of COX-2 has already been found to be increased by cytokines, so inhibitors of such cytokines are expected to block the expression of COX-2 (MK O'Banion et al., Proc. Natl Acad.Sci. USA, 1992, 89, 4888). Thus, it is expected to be effective against diseases currently being treated as COX inhibitors, such as NSAIDs, which are well known to inhibit cytokines such as IL-1.

종래, 상기 사이토카인류를 억제하여 다양한 면역 및 염증 질환을 치료하기 위해 p38 저해제를 개발하고자 하는 연구가 수행되어 오고 있다. 이를 구체적으로 살펴본다. In the past, research has been conducted to develop p38 inhibitors to inhibit the cytokines and treat various immune and inflammatory diseases. Let's look at this in detail.

염증성 질환에 대해 p38 MAPK의 역할을 조명한 초기의 항염증성 약물은 피리디닐 이미다졸계열이었다. 이들 중 최초로 개발된 것은 Lee, J. C. 그룹에 의해 보고된 두 고리 피리디닐 이미다졸 SKF-86002이다[Lee, J. C. et. al., Int. J. Immunopharmacol. 10, 835-843, 1992]. 이후, 두 고리 이미다졸계열의 화합물의 사이토카인 합성 저해 효과에 대한 구조-활성 관계(SAR)가 보고되면서 이미다졸계열의 화합물에 대한 연구 결과가 보고되기 시작하였다. 예를 들면, 글락소스미스클라인(GlaxoSmithKline)사의 SB-203580[Badger, A. M. et. al., J. Pharmacol. Exp. Therap. 279, 1453-1461, 1996]와 그 외, 2,4,5-트리아릴이미다졸 유도체[Gallagher, T. F. et. al., Bioorg. Med. Chem. Lett. 5, 1171-1176, 1995] 등이 있다.The earliest anti-inflammatory drugs illuminating the role of p38 MAPK on inflammatory diseases were pyridinyl imidazoles. The first of these was the bicyclic pyridinyl imidazole SKF-86002 reported by Lee, J. C. Group [Lee, J. C. et. al., Int. J. Immunopharmacol. 10, 835-843, 1992]. Subsequently, as a structure-activity relationship (SAR) was reported on the cytokine synthesis inhibitory effect of two cyclic imidazole compounds, the results of studies on imidazole compounds were reported. For example, SB-203580 by GlaxoSmithKline (Badger, A. M. et. al., J. Pharmacol. Exp. Therap. 279, 1453-1461, 1996 and others, 2,4,5-triarylimidazole derivatives [Gallagher, T. F. et. al., Bioorg. Med. Chem. Lett. 5, 1171-1176, 1995].

이후, 상기 이미다졸 약물작용 발생단(pharmacophore)을 다른 헤테로아릴 약물작용 발생단으로 대체하여 합성된 새로운 아릴-피리디닐-헤테로고리계 화합물에 대하여 보고되었으며, 상기 아릴-피디디닐-헤테로고리계 화합물로는, 예를 들면, 글락소스미스클라인사의 SB-242235, RW 존슨사의 RWJ-67657 등이 보고된 바 있다[Badger, A. M. et. al., Arthritis Rheum. 43. 175-183, 2000; Wadsworth, S. A. et. al., J. Pharmacol. Exp. Ther. 291, 680-687, 1999].Subsequently, a new aryl-pyridinyl-heterocyclic compound synthesized by replacing the imidazole pharmacophore with another heteroaryl pharmacophore has been reported, and the aryl-pyridinyl-heterocyclic compound For example, SB-242235 from GlaxoSmithKline, RWJ-67657 from RW Johnson, etc. have been reported [Badger, AM et. al., Arthritis Rheum. 43. 175-183, 2000; Wadsworth, S. A. et. al., J. Pharmacol. Exp. Ther. 291, 680-687, 1999].

또한, 구조적으로 다양화된 새로운 p38 MAPK 저해제들로서는 Cirillo 그룹이 개발한 트리아자나프탈레논류, N,N'-디아릴우레아류, N,N-디아릴우레아류, 벤조페 논류, 피라졸케톤류, 인돌 아마이드류, 디아마이드류, 퀴나졸리논류, 피리미도[4,5-d]피리미디논류, 피리딜-아미노-퀴나졸린류 등을 포함하는 비-아릴-피리디닐 화합물도 보고되었다[Cirillo, P. F. et. al., Curr. Top. Med. Chem. 2, 1021-1035, 2002]. 상기 비-아릴-피디디닐-헤테로고리계 화합물로는, 예를 들면, Vertex사의 트리아자나프탈레논류로 분류되는 VX-745, Boehringer Ingelheim사의 N,N'-디아릴우레아류로 분류되는 BIRB-796[Regan, J. et. al., J. Med. Chem. 45, 2994-3008, 2002] 등이 있다. In addition, structurally diversified new p38 MAPK inhibitors include triazanaphthalenones, N, N'-diarylureas, N, N-diarylureas, benzophenones, and pyrazoles developed by Cirillo Group. Non-aryl-pyridinyl compounds have also been reported, including ketones, indole amides, diamides, quinazolinones, pyrimido [4,5-d] pyrimidinones, pyridyl-amino-quinazolins, and the like. Cirillo, PF et. al., Curr. Top. Med. Chem. 2, 1021-1035, 2002]. Examples of the non-aryl-pidininyl-heterocyclic compounds include, for example, VX-745 classified as a triazanaphthalenone from Vertex, and BIRB classified as N, N'-diarylureas from Boehringer Ingelheim. -796 [Regan, J. et. al., J. Med. Chem. 45, 2994-3008, 2002.

최근에는 헤테로아릴이 융합된 피리디논 구조와 매우 밀접하게 관련된 화합물에 대하여 글락소스미스클라인사(WO02/059083) 및 머크사(WO02/058695)에 의해 공지된 바도 있다. Recently, a compound known to be very closely related to a pyridinone structure in which heteroaryl is fused has been known by GlaxoSmithKline (WO02 / 059083) and Merck (WO02 / 058695).

상술한 p38 MAPK 저해제들을 포함하여 그 외에도 여러 가지 구조들을 약물작용 발생단으로 하여 합성이 보고된 예들로는 이미다졸, 옥사졸 또는 피라졸 유도체(WO 93/14081, WO 93/14082, WO 95/02591, WO 95/13067, WO 95/31451, WO 99/58523, WO 98/56377, WO 97/16442, WO 99/57101, WO 00/39116 및 WO 00/31063), 시클로알케닐, 피리미딘, 피라진 및 트리아졸 화합물들(WO 00/25791, WO 98/24782, WO 99/17776, WO 00/10563, WO 00/25791, 및 WO 00/35911) 및 다중 고리계 화합물들(WO 99/64400, WO 98/22457, WO 00/20402, WO 00/12497, WO 99/61426 및 WO 99/58502) 등이 있다.Examples of synthesis reported using the above-described p38 MAPK inhibitors and other structures as drug-generating groups include imidazole, oxazole or pyrazole derivatives (WO 93/14081, WO 93/14082, WO 95/02591). , WO 95/13067, WO 95/31451, WO 99/58523, WO 98/56377, WO 97/16442, WO 99/57101, WO 00/39116 and WO 00/31063), cycloalkenyl, pyrimidine, pyrazine And triazole compounds (WO 00/25791, WO 98/24782, WO 99/17776, WO 00/10563, WO 00/25791, and WO 00/35911) and multi-ring compounds (WO 99/64400, WO 98/22457, WO 00/20402, WO 00/12497, WO 99/61426 and WO 99/58502).

상술한 바와 같이, 염증 억제 또는 면역 억제 활성을 갖는 다양한 약물작용 발생단 화합물을 기본으로 하여 염증성 질환 또는 면역성 질환의 예방 및 치료에 유용한 유효 성분 화합물의 개발에 대한 연구 결과가 보고되어 왔으나, 상술한 다양한 화합물 중에 현재까지 티아졸을 약물작용 발생단 화합물로 선택하여 수행한 연구는 거의 없는 것으로 판단된다. As described above, studies on the development of active ingredient compounds useful for the prevention and treatment of inflammatory diseases or immune diseases have been reported based on various drug action generating compound having inflammatory or immunosuppressive activity. Among the various compounds, few studies have been conducted to select thiazole as a drug-acting compound.

이에, 본 발명자들은 TNF-α 및 IL-1과 같은 전염증성 사이토카인의 억제 활성이 우수하여 이들에 의해 매개되는 질병 치료에 유용한 화합물의 약물작용 발생단으로서 티아졸 화합물을 선택하여 연구를 수행하던 중, 치환된 1,3-티아졸 유도체에서 면역 억제 또는 염증 억제 효과가 우수함을 확인하고 본 발명을 완성하였다.Accordingly, the inventors of the present invention have been conducted to select a thiazole compound as a drug-acting occurrence group of compounds that are excellent in inhibiting activities of proinflammatory cytokines such as TNF-α and IL-1 and are useful for treating diseases mediated by them. Among them, the substituted 1,3-thiazole derivatives were confirmed to have excellent immunosuppressive or inflammatory inhibitory effects and completed the present invention.

본 발명은 면역 억제 및 염증 억제 활성을 갖는 신규한 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염을 제공하고자 한다.The present invention seeks to provide novel substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppressive and inflammatory inhibitory activity.

또한, 본 발명은 중간체 화합물 또는 이의 약학적으로 허용가능한 염을 제공하고자 한다.It is also an object of the present invention to provide an intermediate compound or a pharmaceutically acceptable salt thereof.

또한, 본 발명은 상기 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염, 및 중간체 화합물 또는 이의 약학적으로 허용가능한 염의 제조방법을 제공하고자 한다.It is also an object of the present invention to provide a method for preparing the substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof, and intermediate compounds or pharmaceutically acceptable salts thereof.

또한, 본 발명은 상기 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용 가능한 염을 포함하는 약학적 조성물을 제공하고자 한다.The present invention also provides a pharmaceutical composition comprising the substituted 1,3-thiazole derivative or a pharmaceutically acceptable salt thereof.

본 발명은 하기 화학식 1로 표시되는 면역 억제 및 염증 억제 활성을 갖는 신규한 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides novel substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppressive and inflammatory inhibitory activities represented by the following formula (1).

Figure 112006042290445-pat00001
Figure 112006042290445-pat00001

(상기 화학식 1에서,(In Formula 1,

Z는 CH 또는 N이고,Z is CH or N,

R1은 할로겐 원자, C1~C4의 할로알킬, C1~C4의 알킬 또는 C1~C4의 알콕시이고,R1 is a halo of a halogen atom, C 1 ~ C 4 alkyl, C 1 ~ C 4 Of alkyl or C 1 to C 4 Alkoxy,

R2는 H, 할로겐 원자, C1~C4의 알킬, -NH-R4, C1~C4의 알킬-S(O)n-페닐,

Figure 112006042290445-pat00002
,
Figure 112006042290445-pat00003
,
Figure 112006042290445-pat00004
,
Figure 112006042290445-pat00005
,
Figure 112006042290445-pat00006
,
Figure 112006042290445-pat00007
이며, 여기서 X는 CH, C-OH, 또는 N이고, Y는 CH2, CH-C1~C4의 알킬, NH, N-C1~C4의 알 킬, N-C1~C4의 아미노-C1~C4의 알킬, N-CO-C1~C4의 알킬, N-CO-C3~C8의 시클로알킬, N-CO-C5~C8의 아릴, N-CO-C1~C4의 아미노-C1~C4의 알킬 또는 N-CO-C1~C4의 알콕시이며,R2 is H, a halogen atom, C 1 ~ C 4 Of alkyl, -NH-R4, C 1 -C 4 Alkyl-S (O) n -phenyl,
Figure 112006042290445-pat00002
,
Figure 112006042290445-pat00003
,
Figure 112006042290445-pat00004
,
Figure 112006042290445-pat00005
,
Figure 112006042290445-pat00006
,
Figure 112006042290445-pat00007
Wherein X is CH, C-OH, or N, and Y is CH 2 , CH-C 1 to C 4 Of alkyl, NH, NC 1 -C 4 Al Kiel, NC 1 ~ C 4 of the amino -C 1 ~ C 4 alkyl, N-CO-C 1 ~ C 4 alkyl, N-CO-C 3 ~ C 8 cycloalkyl, N-CO-C 5 Aryl of ~ C 8 , N-CO-C 1 ~ C 4 of amino-C 1 ~ C 4 alkyl or N-CO-C 1 ~ C 4 of Alkoxy,

R3는 할로겐 원자, -NH-R4, -NH-CO-R5, -N-(CO-R5)2, -S(O)n-C1~C4의 알킬이며,R 3 represents a halogen atom, -NH-R 4, -NH-CO-R 5, -N- (CO-R 5) 2 , -S (O) n -C 1 -C 4 Alkyl,

R4는 H, C1~C4의 알킬, C3~C8의 시클로알킬, C3~C8의 시클로알킬알킬, C5~C8의 아릴, CH(C1~C4의 알킬)-페닐 또는 아민이고,R4 is H, COne~ C4of Alkyl, C3~ C8of Cycloalkyl, C3~ C8of Cycloalkylalkyl, C5~ C8Aryl, CH (COne~ C4of Alkyl) -phenyl or amine,

R5는 C1~C4의 알킬, C3~C8의 시클로알킬 , C5~C8의 아릴 또는 C1~C4의 알콕시이고,R5 is C 1 ~ C 4 Alkyl, C 3 -C 8 Cycloalkyl, C 5 -C 8 aryl or C 1 -C 4 Alkoxy,

m은 1 또는 2이며,m is 1 or 2,

n은 0, 1 또는 2이다.)n is 0, 1 or 2.)

바람직하게는 상기 화학식 1에서,Preferably in Formula 1,

Z는 CH 또는 N 이고,Z is CH or N,

R1은 2-F, 3-F, 4-F, 3-Cl, 3-CF3, 3-CH3 또는 4-OCH3 이며,R 1 is 2-F, 3-F, 4-F, 3-Cl, 3-CF 3 , 3-CH 3 or 4-OCH 3 ,

R2는 H, Cl, 에틸, 아미노, NHNH2, 메틸아미노, 6,N-디메틸니코티닐아미노, 4-메틸설파닐페닐, 4-메탄설피닐페닐, 4-메탄설포닐페닐, 피페리딘-1-일, 4-메틸-피페리딘-1-일, 피페리딘-4-일, N-메틸-피페리딘-4-일, N-에틸-피페리딘-4일, N-이 소프로필-피페리딘-4일, N-시클로프로필메틸-피페리딘-4일, N-디메틸아미노에틸-피페리딘-4-일, N-메틸카보닐-피페리딘-4-일, N-시클로프로필카보닐-피페리딘-4-일, N-디메틸아미노메틸카보닐-피페리딘-4-일, N-페닐카보닐-피페리딘-4-일, 에톡시카보닐-피페리딘-4-일, N-부톡시카보닐-피페리딘-4-일, 피페라진-1-일, N-메틸-피페라진-1-일, N-부톡시카보닐-피페라진-1-일, 4-메틸-4-옥시피페라진-1-일, 4-히드록시-피페리딘-4-일, N-메틸-4-히드록시-피페리딘-4-일, N-부톡시카보닐-4-히드록시-피페리딘-4-일, 2,5-디아자비시클로[2.2.1]-헵트-2-일, N-t-부톡시카보닐-2,5-디아자비시클로[2.2.1]-헵트-2-일, 피페리딘-4-일아미노, N-t-부톡시카보닐-피페리딘-4-일아미노, 피페리딘-4-일옥시 또는 N-t-부톡시카보닐-피페리딘-4-일옥시이고,R2 is H, Cl, ethyl, amino, NHNH 2 , methylamino, 6, N-dimethylnicotinylamino, 4-methylsulfanylphenyl, 4-methanesulfinylphenyl, 4-methanesulfonylphenyl, piperidine- 1-yl, 4-methyl-piperidin-1-yl, piperidin-4-yl, N-methyl-piperidin-4-yl, N-ethyl-piperidin-4yl, N- Sopropyl-piperidin-4yl, N-cyclopropylmethyl-piperidin-4yl, N-dimethylaminoethyl-piperidin-4-yl, N-methylcarbonyl-piperidin-4-yl , N-cyclopropylcarbonyl-piperidin-4-yl, N-dimethylaminomethylcarbonyl-piperidin-4-yl, N-phenylcarbonyl-piperidin-4-yl, ethoxycarbonyl -Piperidin-4-yl, N-butoxycarbonyl-piperidin-4-yl, piperazin-1-yl, N-methyl-piperazin-1-yl, N-butoxycarbonyl-pipe Razin-1-yl, 4-methyl-4-oxypiperazin-1-yl, 4-hydroxy-piperidin-4-yl, N-methyl-4-hydroxy-piperidin-4-yl, N-butoxycarbonyl-4-hydroxy-piperidin-4-yl, 2,5-diazabicyclo [2.2.1] -hept-2-yl, Nt- Butoxycarbonyl-2,5-diazabicyclo [2.2.1] -hept-2-yl, piperidin-4-ylamino, Nt-butoxycarbonyl-piperidin-4-ylamino, pipe Ferridin-4-yloxy or Nt-butoxycarbonyl-piperidin-4-yloxy,

R3는 F, 아미노, 시클로프로필아미노, 시클로프로필메틸아미노, 시클로부틸아미노, 시클로펜틸아미노, 시클로헥실아미노, 시클로헵틸아미노, 페닐아미노, 벤질아미노, (S)-1-페닐에틸아미노, (R)-1-페닐에틸아미노, 에틸카보닐아미노, N,N-디에틸카보닐아미노, 시클로헥실카보닐아미노, N,N-디시클로헥실카보닐아미노, 페닐카보닐아미노, t-부톡시카보닐아미노, 메틸설파닐, 메탄설피닐 또는 메탄설포닐이다.R3 is F, amino, cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, phenylamino, benzylamino, (S) -1-phenylethylamino, (R) -1-phenylethylamino, ethylcarbonylamino, N, N-diethylcarbonylamino, cyclohexylcarbonylamino, N, N-dicyclohexylcarbonylamino, phenylcarbonylamino, t-butoxycarbonyl Amino, methylsulfanyl, methanesulfinyl or methanesulfonyl.

상기 화학식 1의 화합물들 중 특히 바람직한 화합물은 구체적으로 하기와 같다.Particularly preferred compounds among the compounds of Formula 1 are as follows.

1. [4-(3-클로로페닐)-5-(2-플루오로피리딘-4-일)티아졸-2-일]메틸아민, 1. [4- (3-chlorophenyl) -5- (2-fluoropyridin-4-yl) thiazol-2-yl] methylamine,

2. [4-(3-클로로페닐)-5-(2-플루오로피리딘-4-일)티아졸-2-일]히드라진,2. [4- (3-chlorophenyl) -5- (2-fluoropyridin-4-yl) thiazol-2-yl] hydrazine,

3. 4-[2-에틸-4-(4-플루오로페닐)티아졸-5-일]-2-플루오로피리딘,3. 4- [2-ethyl-4- (4-fluorophenyl) thiazol-5-yl] -2-fluoropyridine,

4. {4-[4-(4-플루오로페닐)-2-(4-메틸설파닐페닐)티아졸-5-일]피리딘-2-일}카바민산 tert-부틸 에스터,4. {4- [4- (4-fluorophenyl) -2- (4-methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl} carbamic acid tert -butyl ester,

5. 4-[4-(4-플루오로페닐)-2-(4-메틸설파닐페닐)티아졸-5-일]피리딘-2-일아민,5. 4- [4- (4-fluorophenyl) -2- (4-methylsulfanylphenyl) thiazol-5-yl] pyridin-2-ylamine,

6. 4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민,6. 4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine,

7. [4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]메틸아민,7. [4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] methylamine,

8. 4-[4-(3-클로로페닐)-2-에틸티아졸-5-일]-2-메틸설파닐피리미딘,8. 4- [4- (3-chlorophenyl) -2-ethylthiazol-5-yl] -2-methylsulfanylpyrimidine,

9. 4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민,9. 4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine,

10. 4-(3-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민,10. 4- (3-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine,

11. 4-(2-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민,11. 4- (2-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine,

12. 4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민,12. 4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine,

13. 5-(2-메틸설파닐피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일아민,13. 5- (2-methylsulfanylpyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-ylamine,

14. 5-(2-메틸설파닐피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일아민,14. 5- (2-methylsulfanylpyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-ylamine,

15. 4-(4-메톡시페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민,15. 4- (4-methoxyphenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine,

16. [4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]메틸아민,16. [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] methylamine,

17. 4-[4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카복실산 tert-부틸 에스터,17. 4- [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester,

18. 4-[5-(2-아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,18. 4- [5- (2-aminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

19. 4-[4-(3-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,19. 4- [4- (3-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

20. 4-[4-(2-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,20. 4- [4- (2-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

21. 4-[4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,21. 4- [4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

22. 4-[5-(2-메틸설파닐피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,22. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

23. 4-[5-(2-메틸설파닐피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,23. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

24. 4-[4-(4-메톡시페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,24. 4- [4- (4-methoxyphenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

25. 4-[4-(4-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘,25. 4- [4- (4-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

26. 4-[4-(3-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘,26. 4- [4- (3-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

27. 4-[4-(2-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘,27. 4- [4- (2-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

28. 4-[4-(3-클로로페닐)티아졸-5-일]-2-메틸설파닐피리미딘,28. 4- [4- (3-chlorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

29. 2-메틸설파닐-4-[4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘,29. 2-methylsulfanyl-4- [4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine,

30. 2-메틸설파닐-4-[4-(3-메틸페닐)티아졸-5-일]피리미딘,30. 2-methylsulfanyl-4- [4- (3-methylphenyl) thiazol-5-yl] pyrimidine,

31. 4-[4-(4-메톡시페닐)티아졸-5-일]-2-메틸설파닐피리미딘,31. 4- [4- (4-methoxyphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

32. 4-[2-클로로-4-(4-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘,32. 4- [2-chloro-4- (4-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

33. 4-[2-클로로-4-(3-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘,33. 4- [2-chloro-4- (3-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

34. 4-[2-클로로-4-(2-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘,34. 4- [2-chloro-4- (2-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

35. 4-[2-클로로-4-(3-클로로페닐)티아졸-5-일]-2-메틸설파닐피리미딘,35. 4- [2-chloro-4- (3-chlorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

36. 4-[2-클로로-4-(3-트리플르오로메틸페닐)티아졸-5-일]-2-메틸설파닐피리미딘,36. 4- [2-chloro-4- (3-trifluoromethylphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

37. 4-[2-클로로-4-(3-메틸페닐)티아졸-5-일]-2-메틸설파닐피리미딘,37. 4- [2-chloro-4- (3-methylphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

38. 4-[2-클로로-4-(4-메톡시페닐)티아졸-5-일]-2-메틸설파닐피리미딘,38. 4- [2-chloro-4- (4-methoxyphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

39. 4-[4-(4-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메틸설파닐피리미딘,39. 4- [4- (4-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine,

40. 4-[4-(3-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메틸설파닐피리미딘,40. 4- [4- (3-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine,

41. 4-[4-(2-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메틸설파닐피리미딘,41. 4- [4- (2-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine,

42. 4-[4-(3-클로로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메틸설파닐피리미딘,42. 4- [4- (3-chlorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine,

43. 2-메틸설파닐-4-[2-피페리딘-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘,43. 2-methylsulfanyl-4- [2-piperidin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine,

44. 2-메틸설파닐-4-[2-피페리딘-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘,44. 2-methylsulfanyl-4- [2-piperidin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidine,

45. 4-[4-(4-메톡시페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메틸설파닐피리미딘,45. 4- [4- (4-methoxyphenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine,

46. 4-[4-(4-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메틸설파닐피리미딘,46. 4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

47. 4-[4-(3-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메틸설파닐피리미딘,47. 4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

48. 4-[4-(2-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메틸설파닐피리미딘,48. 4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

49. 4-[4-(3-클로로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메틸설파닐피리미딘,49. 4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

50. 4-[2-(4-메틸피페리딘-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]-2-메틸설파닐피리미딘,50. 4- [2- (4-methylpiperidin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

51. 4-[2-(4-메틸피페리딘-1-일)-4-(3-메틸페닐)티아졸-5-일]-2-메틸설파닐피리미딘,51. 4- [2- (4-methylpiperidin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

52. 4-[4-(4-메톡시페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메틸설파닐피리미딘,52. 4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

53. 4-[4-(4-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]-2-메틸설파닐피리미딘,53. 4- [4- (4-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine,

54. 4-[4-(3-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]-2-메틸설파닐피리미딘,54. 4- [4- (3-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine,

55. 4-[4-(2-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]-2-메틸설파닐피리미딘,55. 4- [4- (2-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine,

56. 4-[4-(3-클로로페닐)-2-피페라진-1-일-티아졸-5-일]-2-메틸설파닐피리미딘,56. 4- [4- (3-chlorophenyl) -2-piperazin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine,

57. 2-메틸설파닐-4-[2-피페라진-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘,57. 2-methylsulfanyl-4- [2-piperazin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine,

58. 2-메틸설파닐-4-[2-피페라진-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘,58. 2-methylsulfanyl-4- [2-piperazin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidine,

59. 4-[4-(4-메톡시페닐)-2-피페라진-1-일-티아졸-5-일]-2-메틸설파닐피리미딘,59. 4- [4- (4-methoxyphenyl) -2-piperazin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine,

60. 2-[4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]-2,5-디아자비시클로[2.2.1]헵탄,60. 2- [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -2,5-diazabicyclo [2.2.1] Heptane,

61. 4-[4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일옥시]피페리딘-1-카르복실산 tert-부틸 에스터,61. 4- [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yloxy] piperidine-1-carboxylic acid tert-butyl Ester,

62. 4-[4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아미노]피페리딘-1-카르복실산 tert-부틸 에스터,62. 4- [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamino] piperidine-1-carboxylic acid tert-butyl Ester,

63. 4-[4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페라진-1-카복실산 tert-부틸 에스터, 63. 4- [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

64. 4-[4-(3-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,64. 4- [4- (3-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

65. 4-[4-(2-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페 라진-1-카르복실산 tert-부틸 에스터,65. 4- [4- (2-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

66. 4-[4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,66. 4- [4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

67. 4-[5-(2-메틸설파닐피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸 -2-일]피페라진-1-카르복실산 tert-부틸 에스터,67. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester ,

68. 4-[5-(2-메틸설파닐피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,68. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

69. 4-[4-(4-메톡시페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,69. 4- [4- (4-methoxyphenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

70. 5-[4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]-2,5-디아자비시클로[2.2.1]헵탄-2-카르복실산 tert-부틸 에스터,70. 5- [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -2,5-diazabicyclo [2.2.1] Heptane-2-carboxylic acid tert-butyl ester,

71. 4-(3-클로로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일아민, 71. 4- (3-chlorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-ylamine,

72. 4-[4-(3-클로로페닐)-2-에틸티아졸-5-일]-2-메탄설피닐피리미딘, 72. 4- [4- (3-chlorophenyl) -2-ethylthiazol-5-yl] -2-methanesulfinylpyrimidine,

73. 4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일아민,73. 4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-ylamine,

74. [4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]메틸아민,74. [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] methylamine,

75. 4-[4-(4-플루오로페닐)-5-(2-메탄설포닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카복실산 에틸 에스터, 75. 4- [4- (4-fluorophenyl) -5- (2-methanesulfonylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

76. 4-[4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카복실산 tert-부틸 에스터,76. 4- [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester,

77. 4-[4-(3-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,77. 4- [4- (3-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

78. 4-[4-(2-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,78. 4- [4- (2-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

79. 4-[4-(3-클로로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,79. 4- [4- (3-chlorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

80. 4-[5-(2-메탄설피닐피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,80. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

81. 4-[5-(2-메탄설피닐피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,81. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

82. 4-[5-(2-메탄설피닐피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,82. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

83. 4-[4-(4-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메탄설피닐피리미딘,83. 4- [4- (4-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methanesulfinylpyrimidine,

84. 4-[4-(3-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메탄설피닐피리미딘, 84. 4- [4- (3-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methanesulfinylpyrimidine,

85. 4-[4-(2-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메탄설피닐피리미딘,85. 4- [4- (2-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methanesulfinylpyrimidine,

86. 4-[4-(3-클로로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메탄설피닐피리미딘,86. 4- [4- (3-chlorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methanesulfinylpyrimidine,

87. 2-메탄설피닐-4-[2-피페리딘-1-일-4-(3-트리플르오로메틸페닐)티아졸 -5-일]피리미딘,87. 2-methanesulfinyl-4- [2-piperidin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine,

88. 2-메탄설피닐-4-[2-피페리딘-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘,88. 2-methanesulfinyl-4- [2-piperidin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidine,

89. 2-메탄설피닐-4-[4-(4-메톡시페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘,89. 2-methanesulfinyl-4- [4- (4-methoxyphenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidine,

90. 4-[4-(4-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메탄설피닐피리미딘,90. 4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methanesulfinylpyrimidine,

91. 4-[4-(3-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메탄설피닐피리미딘,91. 4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methanesulfinylpyrimidine,

92. 4-[4-(2-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메탄설피닐피리미딘,92. 4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methanesulfinylpyrimidine,

93. 4-[4-(3-클로로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메탄설피닐피리미딘,93. 4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methanesulfinylpyrimidine,

94. 2-메탄설피닐-4-[2-(4-메틸피페리딘-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘,94. 2-methanesulfinyl-4- [2- (4-methylpiperidin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine,

95. 2-메탄설피닐-4-[2-(4-메틸피페리딘-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘,95. 2-methanesulfinyl-4- [2- (4-methylpiperidin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidine,

96. 2-메탄설피닐-4-[4-(4-메톡시페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘,96. 2-methanesulfinyl-4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidine,

97. 4-[4-(4-플루오로페닐)-2-(4-메틸-4-옥시피페라진-1-일)티아졸-5-일]-2- 메틸설파닐피리미딘, 97. 4- [4- (4-fluorophenyl) -2- (4-methyl-4-oxypiperazin-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

98. 4-[4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페라진-1-카복실산 tert-부틸 에스터, 98. 4- [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

99. 4-[4-(3-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,99. 4- [4- (3-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

100. 4-[4-(2-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,100. 4- [4- (2-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

101. 4-[4-(3-클로로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,101. 4- [4- (3-chlorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

102. 4-[5-(2-메탄설피닐피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,102. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester ,

103. 4-[5-(2-메탄설피닐피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,103. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

104. 4-[5-(2-메탄설피닐피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,104. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

105. 4-[4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일옥시]피페리딘-1-카르복실산 tert-부틸 에스터,105. 4- [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yloxy] piperidine-1-carboxylic acid tert-butyl Ester,

106. 4-[4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일아미노]피페리딘-1-카르복실산 tert-부틸 에스터,106. 4- [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-ylamino] piperidine-1-carboxylic acid tert-butyl Ester,

107. 5-[4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]- 2,5-디아자비시클로[2.2.1]헵탄-2-카르복실산 tert-부틸 에스터,107. 5- [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] -2,5-diazabicyclo [2.2.1] Heptane-2-carboxylic acid tert-butyl ester,

108. 4-[4-(4-플루오로페닐)티아졸-5-일]-2-메탄설피닐피리미딘,108. 4- [4- (4-fluorophenyl) thiazol-5-yl] -2-methanesulfinylpyrimidine,

109. 4-[4-(3-플루오로페닐)티아졸-5-일]-2-메탄설피닐피리미딘,109. 4- [4- (3-fluorophenyl) thiazol-5-yl] -2-methanesulfinylpyrimidine,

110. 4-[4-(2-플루오로페닐)티아졸-5-일]-2-메탄설피닐피리미딘,110. 4- [4- (2-fluorophenyl) thiazol-5-yl] -2-methanesulfinylpyrimidine,

111. 4-[4-(3-클로로페닐)티아졸-5-일]-2-메탄설피닐피리미딘,111. 4- [4- (3-chlorophenyl) thiazol-5-yl] -2-methanesulfinylpyrimidine,

112. 2-메탄설피닐-4-[4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘,112. 2-methanesulfinyl-4- [4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine,

113. 2-메탄설피닐-4-[4-(3-메틸페닐)티아졸-5-일]피리미딘,113. 2-methanesulfinyl-4- [4- (3-methylphenyl) thiazol-5-yl] pyrimidine,

114. 2-메탄설피닐-4-[4-(4-메톡시페닐)티아졸-5-일]피리미딘,114. 2-methanesulfinyl-4- [4- (4-methoxyphenyl) thiazol-5-yl] pyrimidine,

115. {4-[2-아미노-4-(3-클로로페닐)티아졸-5-일]피리딘-2-일}시클로헥실아민,115. {4- [2-amino-4- (3-chlorophenyl) thiazol-5-yl] pyridin-2-yl} cyclohexylamine,

116. {4-[4-(3-클로로페닐)-2-메틸아미노티아졸-5-일]피리딘-2-일}시클로헥실아민,116. {4- [4- (3-chlorophenyl) -2-methylaminothiazol-5-yl] pyridin-2-yl} cyclohexylamine,

117. {4-[4-(3-클로로페닐)-2-히드라지노티아졸-5-일]피리딘-2-일}시클로헥실아민,117. {4- [4- (3-chlorophenyl) -2-hydrazinothiazol-5-yl] pyridin-2-yl} cyclohexylamine,

118. {4-[4-(3-클로로페닐)-2-에틸티아졸-5-일]피리딘-2-일}-(1-(S)-페닐에틸)아민,118. {4- [4- (3-chlorophenyl) -2-ethylthiazol-5-yl] pyridin-2-yl}-(1- (S) -phenylethyl) amine,

119. 시클로헥실-{4-[4-(4-플루오로페닐)티아졸-5-일]피리딘-2-일}아민,119. cyclohexyl- {4- [4- (4-fluorophenyl) thiazol-5-yl] pyridin-2-yl} amine,

120. {4-[4-(4-플루오로페닐)티아졸-5-일]피리딘-2-일}-(1-(S)-페닐에틸)아민,120. {4- [4- (4-fluorophenyl) thiazol-5-yl] pyridin-2-yl}-(1- (S) -phenylethyl) amine,

121. 시클로헥실-{4-[2-에틸-4-(4-플루오로페닐)티아졸-5-일]피리딘-2-일}아 민,121. Cyclohexyl- {4- [2-ethyl-4- (4-fluorophenyl) thiazol-5-yl] pyridin-2-yl} amine,

122. {4-[2-아미노-4-(3-클로로페닐)티아졸-5-일]피리미딘-2-일}시클로헥실아민,122. {4- [2-amino-4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine,

123. {4-[4-(3-클로로페닐)-2-메틸아미노티아졸-5-일]피리미딘-2-일}시클로펜틸아민,123. {4- [4- (3-chlorophenyl) -2-methylaminothiazol-5-yl] pyrimidin-2-yl} cyclopentylamine,

124. {4-[4-(3-클로로페닐)-2-에틸티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,124. {4- [4- (3-chlorophenyl) -2-ethylthiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine,

125. {4-[4-(3-클로로페닐)-2-메틸아미노티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,125. {4- [4- (3-chlorophenyl) -2-methylaminothiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine,

126. {4-[2-아미노-4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,126. {4- [2-amino-4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine,

127. {4-[4-(4-플루오로페닐)-2-메틸아미노티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,127. {4- [4- (4-fluorophenyl) -2-methylaminothiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine,

128. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카복실산 에틸 에스터,128. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

129. 4-[5-(2-시클로부틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,129. 4- [5- (2-cyclobutylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

130. 4-[5-(2-시클로헵틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,130. 4- [5- (2-cycloheptylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

131. 4-[5-[2-(시클로프로필메틸아미노)피리미딘-4-일]-4-(4-플루오로페닐) 티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,131. 4- [5- [2- (cyclopropylmethylamino) pyrimidin-4-yl] -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl Ester,

132. 4-[5-(2-벤질아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,132. 4- [5- (2-benzylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

133. 4-[4-(4-플루오로페닐)-5-(2-페닐아미노피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,133. 4- [4- (4-fluorophenyl) -5- (2-phenylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

134. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,134. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

135. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,135. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

136. 4-[4-(3-클로로페닐)-5-(2-시클로프로필아미노피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,136. 4- [4- (3-chlorophenyl) -5- (2-cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

137. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,137. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

138. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,138. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

139. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,139. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

140. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카복실산 tert-부틸 에스터,140. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester,

141. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2- 일]피페리딘-1-카복실산 tert-부틸 에스터,141. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester,

142. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터, 142. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

143. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,143. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

144. 4-[4-(3-클로로페닐)-5-(2-시클로펜틸아미노피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,144. 4- [4- (3-chlorophenyl) -5- (2-cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

145. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,145. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

146. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,146. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

147. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,147. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

148. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카복실산 tert-부틸 에스터,148. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester,

149. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,149. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

150. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,150. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

151. 4-[4-(3-클로로페닐)-5-(2-시클로헥실아미노피리미딘-4-일)티아졸-151. 4- [4- (3-chlorophenyl) -5- (2-cyclohexylaminopyrimidin-4-yl) thiazole-

2-일]피페리딘-1-카르복실산 에틸 에스터2-yl] piperidine-1-carboxylic acid ethyl ester

152. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-트리플르오로메틸152. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-trifluoromethyl

페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터 Phenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester

153. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,153. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

154. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,154. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

155. 4-{4-(4-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카복실산 tert-부틸 에스터,155. 4- {4- (4-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-1 Carboxylic acid tert-butyl ester,

156. 4-{4-(4-플루오로페닐)-5-[2-(1-(R)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카르복실산 에틸 에스터,156. 4- {4- (4-fluorophenyl) -5- [2- (1- (R) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-1 Carboxylic acid ethyl ester,

157. 4-{4-(3-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카르복실산 에틸 에스터,157. 4- {4- (3-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-1 Carboxylic acid ethyl ester,

158. 4-{4-(2-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카르복실산 에틸 에스터,158. 4- {4- (2-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-1 Carboxylic acid ethyl ester,

159. 4-{4-(3-클로로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카르복실산 에틸 에스터,159. 4- {4- (3-chlorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-1- Carboxylic acid ethyl ester,

160. 4-[5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,160. 4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine- 1-carboxylic acid ethyl ester,

161. 4-{5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-메틸페닐)티아졸-2-일}피페리딘-1-카르복실산 에틸 에스터,161. 4- {5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-methylphenyl) thiazol-2-yl} piperidine-1-car Ethyl acid ester,

162. 4-{4-(4-메톡시페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카르복실산 에틸 에스터,162. 4- {4- (4-methoxyphenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-1 Carboxylic acid ethyl ester,

163. 시클로프로필-{4-[4-(4-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민,163. cyclopropyl- {4- [4- (4-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

164. 시클로프로필-{4-[4-(3-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민,164. cyclopropyl- {4- [4- (3-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

165. 시클로프로필-{4-[4-(2-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민,165. cyclopropyl- {4- [4- (2-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

166. {4-[4-(3-클로로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}시클로프로필아민,166. {4- [4- (3-chlorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine,

167. 시클로프로필-{4-[2-피페리딘-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,167. cyclopropyl- {4- [2-piperidin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

168. 시클로프로필-{4-[2-피페리딘-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,168. cyclopropyl- {4- [2-piperidin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

169. 시클로프로필-{4-[4-(4-메톡시페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민,169. cyclopropyl- {4- [4- (4-methoxyphenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

170. 시클로펜틸-{4-[4-(4-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민,170. cyclopentyl- {4- [4- (4-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

171. 시클로펜틸-{4-[4-(3-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민,171. cyclopentyl- {4- [4- (3-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

172. 시클로펜틸-{4-[4-(2-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민,172. cyclopentyl- {4- [4- (2-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

173. {4-[4-(3-클로로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}시클로펜틸아민,173. {4- [4- (3-chlorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine,

174. 시클로펜틸-{4-[2-피페리딘-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,174. cyclopentyl- {4- [2-piperidin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

175. 시클로펜틸-{4-[2-피페리딘-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,175. cyclopentyl- {4- [2-piperidin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

176. 시클로펜틸-{4-[4-(4-메톡시페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민,176. cyclopentyl- {4- [4- (4-methoxyphenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

177. 시클로헥실-{4-[4-(4-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민,177. cyclohexyl- {4- [4- (4-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

178. 시클로헥실-{4-[4-(3-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민,178. cyclohexyl- {4- [4- (3-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

179. 시클로헥실-{4-[4-(2-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민,179. cyclohexyl- {4- [4- (2-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

180. {4-[4-(3-클로로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}시클로헥실아민,180. {4- [4- (3-chlorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine,

181. 시클로헥실-{4-[2-피페리딘-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,181. cyclohexyl- {4- [2-piperidin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

182. 시클로헥실-{4-[2-피페리딘-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,182. cyclohexyl- {4- [2-piperidin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

183. 시클로헥실-{4-[4-(4-메톡시페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민,183. cyclohexyl- {4- [4- (4-methoxyphenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

184. {4-[4-(4-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,184. {4- [4- (4-Fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl Amines,

185. {4-[4-(3-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,185. {4- [4- (3-Fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl Amines,

186. {4-[4-(2-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,186. {4- [4- (2-Fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl Amines,

187. {4-[4-(3-클로로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,187. {4- [4- (3-Chlorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) Amine,

188. (1-(S)-페닐에틸)-{4-[2-피페리딘-1-일-4-(3-트리플르오로메틸페닐) 티아졸-5-일]피리미딘-2-일}아민,188. (1- (S) -phenylethyl)-{4- [2-piperidin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl } Amine,

189. (1-(S)-페닐에틸)-{4-[2-피페리딘-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,189. (1- (S) -phenylethyl)-{4- [2-piperidin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

190. {4-[4-(4-메톡시페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,190. {4- [4- (4-methoxyphenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl Amines,

191. 시클로프로필-{4-[4-(4-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민,191. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

192. 시클로프로필-{4-[4-(3-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민,192. cyclopropyl- {4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

193. 시클로프로필-{4-[4-(2-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민,193. cyclopropyl- {4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

194. {4-[4-(3-클로로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}시클로프로필아민,194. {4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine,

195. 시클로프로필-{4-[2-(4-메틸피페리딘-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,195. cyclopropyl- {4- [2- (4-methylpiperidin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

196. 시클로프로필-{4-[2-(4-메틸피페리딘-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,196. Cyclopropyl- {4- [2- (4-methylpiperidin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

197. 시클로프로필-{4-[4-(4-메톡시페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민,197. cyclopropyl- {4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

198. 시클로펜틸-{4-[4-(4-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민,198. cyclopentyl- {4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

199. 시클로펜틸-{4-[4-(3-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민,199. cyclopentyl- {4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

200. 시클로펜틸-{4-[4-(2-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민,200. cyclopentyl- {4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

201. {4-[4-(3-클로로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}시클로펜틸아민,201. {4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine,

202. 시클로펜틸-{4-[2-(4-메틸피페리딘-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,202. cyclopentyl- {4- [2- (4-methylpiperidin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

203. 시클로펜틸-{4-[2-(4-메틸피페리딘-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,203. cyclopentyl- {4- [2- (4-methylpiperidin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

204. 시클로펜틸-{4-[4-(4-메톡시페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민,204. cyclopentyl- {4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

205. 시클로헥실-{4-[4-(4-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민,205. cyclohexyl- {4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

206. 시클로헥실-{4-[4-(3-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민,206. cyclohexyl- {4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

207. 시클로헥실-{4-[4-(2-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민,207. cyclohexyl- {4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

208. {4-[4-(3-클로로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}시클로헥실아민,208. {4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine,

209. 시클로헥실-{4-[2-(4-메틸피페리딘-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,209. cyclohexyl- {4- [2- (4-methylpiperidin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

210. 시클로헥실-{4-[2-(4-메틸피페리딘-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,210. cyclohexyl- {4- [2- (4-methylpiperidin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

211. 시클로헥실-{4-[4-(4-메톡시페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민,211. cyclohexyl- {4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

212. {4-[4-(4-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,212. {4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine,

213. {4-[4-(3-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,213. {4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine,

214. {4-[4-(2-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,214. {4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine,

215. {4-[4-(3-클로로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,215. {4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -Phenylethyl) amine,

216. {4-[2-(4-메틸피페리딘-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,216. {4- [2- (4-Methylpiperidin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- ( S) -phenylethyl) amine,

217. {4-[2-(4-메틸피페리딘-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,217. {4- [2- (4-Methylpiperidin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S)- Phenylethyl) amine,

218. {4-[4-(4-메톡시페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,218. {4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine,

219. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페라진-1-카복실산 tert-부틸 에스터,219. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

220. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,220. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

221. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,221. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

222. 4-[4-(3-클로로페닐)-5-(2-시클로프로필아미노피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,222. 4- [4- (3-chlorophenyl) -5- (2-cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

223. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,223. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester ,

224. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,224. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

225. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,225. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

226. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페라진-1-카복실산 tert-부틸 에스터,226. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

227. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터, 227. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

228. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,228. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

229. 4-[4-(3-클로로페닐)-5-(2-시클로펜틸아미노피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,229. 4- [4- (3-chlorophenyl) -5- (2-cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

230. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,230. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester ,

231. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,231. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

232. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,232. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

233. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페라진-1-카복실산 tert-부틸 에스터,233. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

234. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,234. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

235. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,235. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

236. 4-[4-(3-클로로페닐)-5-(2-시클로헥실아미노피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,236. 4- [4- (3-chlorophenyl) -5- (2-cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

237. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,237. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester ,

238. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,238. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

239. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,239. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester,

240. 4-{4-(4-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일]피페라진-1-카복실산 tert-부틸 에스터,240. 4- {4- (4-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl] piperazin-1- Carboxylic acid tert-butyl ester,

241. 4-{4-(3-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페라진-1-카르복실산 tert-부틸 에스터,241. 4- {4- (3-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperazin-1- Carboxylic acid tert-butyl ester,

242. 4-{4-(2-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페라진-1-카르복실산 tert-부틸 에스터,242. 4- {4- (2-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperazin-1- Carboxylic acid tert-butyl ester,

243. 4-{4-(3-클로로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-피페라진-1-카르복실산 tert-부틸 에스터,243. 4- {4- (3-Chlorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -piperazin-1- Carboxylic acid tert-butyl ester,

244. 4-[5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터,244. 4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazin-1 Carboxylic acid tert-butyl ester,

245. 4-{5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-메틸페닐)티아졸-2-일}-피페라진-1-카르복실산 tert-부틸 에스터,245. 4- {5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-methylphenyl) thiazol-2-yl} -piperazin-1-car Acid tert-butyl ester,

246. 4-{4-(4-메톡시페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-피페라진-1-카르복실산 tert-부틸 에스터,246. 4- {4- (4-methoxyphenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -piperazin-1 Carboxylic acid tert-butyl ester,

247. 5-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-2,5-디아자비시클로[2.2.1]헵탄-2-카르복실산 tert-부틸 에스터,247. 5- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -2,5-diazabicyclo [2.2.1] Heptane-2-carboxylic acid tert-butyl ester,

248. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐) 티아졸-2-일옥시]피페리딘-1-카르복실산 tert-부틸 에스터,248. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yloxy] piperidine-1-carboxylic acid tert-butyl Ester,

249. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일아미노]피페리딘-1-카르복실산 tert-부틸 에스터,249. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-ylamino] piperidine-1-carboxylic acid tert-butyl Ester,

250. 시클로프로필-{4-[4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민,250. cyclopropyl- {4- [4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

251. 시클로프로필-{4-[4-(3-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민,251. cyclopropyl- {4- [4- (3-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

252. 시클로프로필-{4-[4-(2-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민,252. cyclopropyl- {4- [4- (2-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

253. {4-[4-(3-클로로페닐)티아졸-5-일]피리미딘-2-일}시클로프로필아민,253. {4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine,

254. 시클로프로필-{4-[4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,254. cyclopropyl- {4- [4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

255. 시클로프로필-{4-[4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,255. cyclopropyl- {4- [4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

256. 시클로프로필-{4-[4-(4-메톡시페닐)티아졸-5-일]피리미딘-2-일}아민,256. cyclopropyl- {4- [4- (4-methoxyphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

257. 시클로펜틸-{4-[4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민,257. cyclopentyl- {4- [4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

258. 시클로펜틸-{4-[4-(3-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민,258. cyclopentyl- {4- [4- (3-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

259. 시클로펜틸-{4-[4-(2-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민,259. cyclopentyl- {4- [4- (2-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

260. {4-[4-(3-클로로페닐)티아졸-5-일]피리미딘-2-일}시클로펜틸아민,260. {4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine,

261. 시클로펜틸-{4-[4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,261. cyclopentyl- {4- [4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

262. 시클로펜틸-{4-[4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,262. cyclopentyl- {4- [4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

263. 시클로펜틸-{4-[4-(4-메톡시페닐)티아졸-5-일]피리미딘-2-일}아민,263. cyclopentyl- {4- [4- (4-methoxyphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

264. 시클로헥실-{4-[4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민,264. cyclohexyl- {4- [4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

265. 시클로헥실-{4-[4-(3-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민,265. cyclohexyl- {4- [4- (3-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

266. 시클로헥실-{4-[4-(2-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민,266. cyclohexyl- {4- [4- (2-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

267. {4-[4-(3-클로로페닐)티아졸-5-일]피리미딘-2-일}시클로헥실아민,267. {4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine,

268. 시클로헥실-{4-[4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,268. cyclohexyl- {4- [4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

269. 시클로헥실-{4-[4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,269. cyclohexyl- {4- [4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

270. 시클로헥실-{4-[4-(4-메톡시페닐)티아졸-5-일]피리미딘-2-일}아민,270. cyclohexyl- {4- [4- (4-methoxyphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

271. {4-[4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,271. {4- [4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine,

272. {4-[4-(3-플루오로페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,272. {4- [4- (3-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine,

273. {4-[4-(2-플루오로페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,273. {4- [4- (2-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine,

274. {4-[4-(3-클로로페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,274. {4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine,

275. (1-(S)-페닐에틸)-{4-[4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,275. (1- (S) -phenylethyl)-{4- [4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

276. (1-(S)-페닐에틸)-{4-[4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,276. (1- (S) -phenylethyl)-{4- [4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

277. {4-[4-(4-메톡시페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,277. {4- [4- (4-methoxyphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine,

278. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올,278. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

279. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸- 2-일]-1-메틸피페리딘-4-올,279. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

280. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올,280. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

281. 4-[4-(3-클로로페닐)-5-(2-시클로프로필아미노피리미딘-4-일)티아졸-2-일]-1-메틸피페리딘-4-올,281. 4- [4- (3-chlorophenyl) -5- (2-cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] -1-methylpiperidin-4-ol,

282. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]-1-메틸피페리딘-4-올,282. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

283. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]-1-메틸피페리딘-4-올,283. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

284. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]-1-메틸피페리딘-4-올,284. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

285. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올,285. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

286. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올,286. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

287. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올,287. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

288. 4-[4-(3-클로로페닐)-5-(2-시클로펜틸아미노피리미딘-4-일)티아졸-2-일]-1-메틸피페리딘-4-올,288. 4- [4- (3-chlorophenyl) -5- (2-cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] -1-methylpiperidin-4-ol,

289. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐) 티아졸-2-일]-1-메틸피페리딘-4-올,289. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

290. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]-1-메틸피페리딘-4-올,290. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

291. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]-1-메틸피페리딘-4-올,291. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

292. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올,292. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

293. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올,293. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

294. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올,294. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

295. 4-[4-(3-클로로페닐)-5-(2-시클로헥실아미노피리미딘-4-일)티아졸-2-일]-1-메틸피페리딘-4-올,295. 4- [4- (3-chlorophenyl) -5- (2-cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] -1-methylpiperidin-4-ol,

296. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]-1-메틸피페리딘-4-올,296. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

297. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]-1-메틸피페리딘-4-올,297. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

298. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]-1-메틸피페리딘-4-올,298. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol,

299. 4-{4-(4-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티 아졸-2-일}-1-메틸피페리딘-4-올,299. 4- {4- (4-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -1-methylpy Ferridin-4-ol,

300. 4-{4-(3-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-1-메틸피페리딘-4-올,300. 4- {4- (3-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -1-methylpy Ferridin-4-ol,

301. 4-{4-(2-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-1-메틸피페리딘-4-올,301. 4- {4- (2-Fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -1-methylpy Ferridin-4-ol,

302. 4-{4-(3-클로로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-1-메틸피페리딘-4-올,302. 4- {4- (3-chlorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -1-methylpiperi Din-4-ol,

303. 1-메틸-4-[5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-4-올,303. 1-Methyl-4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-trifluoromethylphenyl) thiazol-2-yl] Piperidine-4-ol,

304. 1-메틸-4-{5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-메틸페닐)티아졸-2-일}-피페리딘-4-올,304. 1-Methyl-4- {5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-methylphenyl) thiazol-2-yl} -piperi Din-4-ol,

305. 4-{4-(4-메톡시페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-1-메틸피페리딘-4-올,305. 4- {4- (4-methoxyphenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -1-methylpy Ferridin-4-ol,

306. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카복실산 tert-부틸 에스터,306. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert Butyl ester,

307. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,307. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester,

308. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,308. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester,

309. 4-[4-(3-클로로페닐)-5-(2-시클로프로필아미노피리미딘-4-일)티아졸-2- 일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,309. 4- [4- (3-chlorophenyl) -5- (2-cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert-butyl ester,

310. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,310. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-car Acid tert-butyl ester,

311. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,311. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert Butyl ester,

312. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,312. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester,

313. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카복실산 tert-부틸 에스터,313. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert Butyl ester,

314. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,314. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester,

315. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,315. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester,

316. 4-[4-(3-클로로페닐)-5-(2-시클로펜틸아미노피리미딘-4-일)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,316. 4- [4- (3-chlorophenyl) -5- (2-cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert-butyl ester,

317. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,317. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-car Acid tert-butyl ester,

318. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,318. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert Butyl ester,

319. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2- 일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,319. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester,

320. 4-[5-(시클로헥실아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카복실산 tert-부틸 에스터,320. 4- [5- (cyclohexylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert-butyl Ester,

321. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,321. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester,

322. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,322. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester,

323. 4-[4-(3-클로로페닐)-5-(2-시클로헥실아미노피리미딘-4-일)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,323. 4- [4- (3-chlorophenyl) -5- (2-cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert-butyl ester,

324. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,324. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-car Acid tert-butyl ester,

325. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,325. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert Butyl ester,

326. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,326. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester,

327. 4-{4-(4-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-4-히드록시피페리딘-1-카복실산 tert-부틸 에스터,327. 4- {4- (4-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -4-hydroxy Cipiperidine-1-carboxylic acid tert-butyl ester,

328. 4-{4-(3-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,328. 4- {4- (3-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -4-hydroxy Cipiperidine-1-carboxylic acid tert-butyl ester,

329. 4-{4-(2-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티 아졸-2-일}-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,329. 4- {4- (2-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -4-hydroxy Cipiperidine-1-carboxylic acid tert-butyl ester,

330. 4-{4-(3-클로로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터,330. 4- {4- (3-Chlorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -4-hydroxypy Ferridine-1-carboxylic acid tert-butyl ester,

331. 4-히드록시-4-[5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 tert-부틸 에스터,331. 4-hydroxy-4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-trifluoromethylphenyl) thiazol-2-yl ] Piperidine-1-carboxylic acid tert-butyl ester,

332. 4-히드록시-4-{5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-메틸페닐)티아졸-2-일}피페리딘-1-카르복실산 tert-부틸 에스터,332. 4-hydroxy-4- {5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-methylphenyl) thiazol-2-yl} piperi Dine-1-carboxylic acid tert-butyl ester,

333. 4-히드록시-4-{4-(4-메톡시페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카르복실산 tert-부틸 에스터,333. 4-hydroxy-4- {4- (4-methoxyphenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} Piperidine-1-carboxylic acid tert-butyl ester,

334. 시클로프로필-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,334. cyclopropyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

335. 시클로부틸-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,335. cyclobutyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

336. 시클로헵틸-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,336. cycloheptyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

337. 시클로프로필메틸-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,337. cyclopropylmethyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

338. 벤질-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,338. benzyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

339. {4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일} 페닐아민,339. {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} phenylamine,

340. 시클로프로필-{4-[4-(3-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,340. cyclopropyl- {4- [4- (3-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

341. 시클로프로필-{4-[4-(2-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,341. cyclopropyl- {4- [4- (2-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

342. {4-[4-(3-클로로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}시클로프로필아민,342. {4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine,

343. 시클로프로필-{4-[2-피페리딘-4-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,343. cyclopropyl- {4- [2-piperidin-4-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

344. 시클로프로필-{4-[2-피페리딘-4-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,344. cyclopropyl- {4- [2-piperidin-4-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

345. 시클로프로필-{4-[4-(4-메톡시페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,345. cyclopropyl- {4- [4- (4-methoxyphenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

346. 4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]-2-메틸설파닐피리미딘,346. 4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine,

347. 4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]-2-메탄설피닐피리미딘,347. 4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] -2-methanesulfinylpyrimidine,

348. 시클로펜틸-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,348. cyclopentyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

349. 시클로펜틸-{4-[4-(3-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리 미딘-2-일}아민,349. cyclopentyl- {4- [4- (3-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

350. 시클로펜틸-{4-[4-(2-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,350. cyclopentyl- {4- [4- (2-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

351. {4-[4-(3-클로로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}시클로펜틸아민,351. {4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine,

352. 시클로펜틸-{4-[2-피페리딘-4-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,352. cyclopentyl- {4- [2-piperidin-4-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

353. 시클로펜틸-{4-[2-피페리딘-4-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,353. cyclopentyl- {4- [2-piperidin-4-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

354. 시클로펜틸-{4-[4-(4-메톡시페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,354. cyclopentyl- {4- [4- (4-methoxyphenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

355. 시클로헥실-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,355. cyclohexyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

356. 시클로헥실-{4-[4-(3-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,356. cyclohexyl- {4- [4- (3-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

357. 시클로헥실-{4-[4-(2-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,357. cyclohexyl- {4- [4- (2-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

358. {4-[4-(3-클로로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}시클로헥실아민,358. {4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine,

359. 시클로헥실-{4-[2-피페리딘-4-일-4-(3-트리플르오로메틸페닐)티아졸-5- 일]피리미딘-2-일}아민,359. cyclohexyl- {4- [2-piperidin-4-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

360. 시클로헥실-{4-[2-피페리딘-4-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,360. cyclohexyl- {4- [2-piperidin-4-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

361. 시클로헥실-{4-[4-(4-메톡시페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민,361. cyclohexyl- {4- [4- (4-methoxyphenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

362. {4-[4-(3-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,362. {4- [4- (3-Fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl Amines,

363. {4-[4-(2-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,363. {4- [4- (2-Fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl Amines,

364. {4-[4-(3-클로로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,364. {4- [4- (3-Chlorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) Amine,

365. (1-(S)-페닐에틸)-{4-[2-피페리딘-4-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,365. (1- (S) -phenylethyl)-{4- [2-piperidin-4-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl } Amine,

366. (1-(S)-페닐에틸)-{4-[2-피페리딘-4-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,366. (1- (S) -phenylethyl)-{4- [2-piperidin-4-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

367. {4-[4-(4-메톡시페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,367. {4- [4- (4-methoxyphenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl Amines,

368. {4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}-(1-(R)-페닐에틸)아민,368. {4- [4- (4-Fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (R) -phenylethyl Amines,

369. 시클로프로필-{4-[4-(4-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피 리미딘-2-일}아민,369. cyclopropyl- {4- [4- (4-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

370. 시클로프로필-{4-[4-(3-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민,370. cyclopropyl- {4- [4- (3-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

371. 시클로프로필-{4-[4-(2-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민,371. cyclopropyl- {4- [4- (2-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

372. {4-[4-(3-클로로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}시클로프로필아민,372. {4- [4- (3-Chlorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine,

373. 시클로프로필-{4-[2-피페라진-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,373. cyclopropyl- {4- [2-piperazin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

374. 시클로프로필-{4-[2-피페라진-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,374. cyclopropyl- {4- [2-piperazin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

375. 시클로프로필-{4-[4-(4-메톡시페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민,375. cyclopropyl- {4- [4- (4-methoxyphenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

376. 시클로펜틸-{4-[4-(4-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민,376. cyclopentyl- {4- [4- (4-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

377. 시클로펜틸-{4-[4-(3-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민,377. cyclopentyl- {4- [4- (3-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

378. 시클로펜틸-{4-[4-(2-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민,378. cyclopentyl- {4- [4- (2-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

379. {4-[4-(3-클로로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}시 클로펜틸아민,379. {4- [4- (3-chlorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine,

380. 시클로펜틸-{4-[2-피페라진-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,380. cyclopentyl- {4- [2-piperazin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

381. 시클로펜틸-{4-[2-피페라진-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,381. cyclopentyl- {4- [2-piperazin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

382. 시클로펜틸-{4-[4-(4-메톡시페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민,382. cyclopentyl- {4- [4- (4-methoxyphenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

383. 시클로헥실-{4-[4-(4-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민,383. cyclohexyl- {4- [4- (4-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

384. 시클로헥실-{4-[4-(3-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민,384. cyclohexyl- {4- [4- (3-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

385. 시클로헥실-{4-[4-(2-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민,385. cyclohexyl- {4- [4- (2-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

386. {4-[4-(3-클로로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}시클로헥실아민,386. {4- [4- (3-chlorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine,

387. 시클로헥실-{4-[2-피페라진-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,387. cyclohexyl- {4- [2-piperazin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

388. 시클로헥실-{4-[2-피페라진-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,388. cyclohexyl- {4- [2-piperazin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

389. 시클로헥실-{4-[4-(4-메톡시페닐)-2-피페라진-1-일-티아졸-5-일]피리미 딘-2-일}아민,389. cyclohexyl- {4- [4- (4-methoxyphenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine,

390. {4-[4-(4-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,390. {4- [4- (4-Fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) Amine,

391. {4-[4-(3-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,391. {4- [4- (3-Fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) Amine,

392. {4-[4-(2-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,392. {4- [4- (2-Fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) Amine,

393. {4-[4-(3-클로로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,393. {4- [4- (3-Chlorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine ,

394. (1-(S)-페닐에틸)-{4-[2-피페라진-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,394. (1- (S) -phenylethyl)-{4- [2-piperazin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} Amine,

395. (1-(S)-페닐에틸)-{4-[2-피페라진-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,395. (1- (S) -phenylethyl)-{4- [2-piperazin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

396. {4-[4-(4-메톡시페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,396. {4- [4- (4-methoxyphenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) Amine,

397. 시클로프로필-{4-[2-(2,5-디아자비시클로[2.2.1]헵트-2-일)-4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민,397. Cyclopropyl- {4- [2- (2,5-diazabicyclo [2.2.1] hept-2-yl) -4- (4-fluorophenyl) thiazol-5-yl] pyrimidine- 2-yl} amine,

398. 시클로프로필-{4-[4-(4-플루오로페닐)-2-(피페리딘-4-일옥시)티아졸-5-일]피리미딘-2-일}아민,398. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (piperidin-4-yloxy) thiazol-5-yl] pyrimidin-2-yl} amine,

399. 시클로프로필-{4-[4-(4-플루오로페닐)-2-(피페리딘-4-일아미노)티아졸- 5-일]피리미딘-2-일}아민,399. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (piperidin-4-ylamino) thiazol-5-yl] pyrimidin-2-yl} amine,

400. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-4-올,400. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-4-ol,

401. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페리딘-4-올,401. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperidin-4-ol,

402. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페리딘-4-올,402. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperidin-4-ol,

403. 4-[4-(3-클로로페닐)-5-(2-시클로프로필아미노피리미딘-4-일)티아졸-2-일]피페리딘-4-올,403. 4- [4- (3-chlorophenyl) -5- (2-cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] piperidin-4-ol,

404. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-4-올,404. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol,

405. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-4-올,405. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidin-4-ol,

406. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-4-올,406. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidin-4-ol,

407. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-4-올,407. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-4-ol,

408. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페리딘-4-올,408. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperidin-4-ol,

409. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2- 일]피페리딘-4-올,409. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperidin-4-ol,

410. 4-[4-(3-클로로페닐)-5-(2-시클로펜틸아미노피리미딘-4-일)티아졸-2-일]피페리딘-4-올,410. 4- [4- (3-chlorophenyl) -5- (2-cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] piperidin-4-ol,

411. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-4-올,411. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol,

412. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-4-올,412. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidin-4-ol,

413. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-4-올,413. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidin-4-ol,

414. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-4-올,414. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-4-ol,

415. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페리딘-4-올,415. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperidin-4-ol,

416. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페리딘-4-올,416. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperidin-4-ol,

417. 4-[4-(3-클로로페닐)-5-(2-시클로헥실아미노피리미딘-4-일)티아졸-2-일]피페리딘-4-올,417. 4- [4- (3-chlorophenyl) -5- (2-cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] piperidin-4-ol,

418. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-4-올,418. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol,

419. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일] 피페리딘-4-올,419. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidin-4-ol,

420. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-4-올,420. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidin-4-ol,

421. 4-{4-(4-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-4-올,421. 4- {4- (4-Fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-4 -All,

422. 4-{4-(3-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-4-올,422. 4- {4- (3-Fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-4 -All,

423. 4-{4-(2-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-4-올,423. 4- {4- (2-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-4 -All,

424. 4-{4-(3-클로로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-피페리딘-4-올,424. 4- {4- (3-Chlorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -piperidine-4 -All,

425. 4-[5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-4-올,425. 4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine- 4-ol,

426. 4-{5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-메틸페닐)티아졸-2-일}-피페리딘-4-올,426. 4- {5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-methylphenyl) thiazol-2-yl} -piperidine-4- All,

427. 4-{4-(4-메톡시페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-피페리딘-4-올,427. 4- {4- (4-methoxyphenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -piperidine- 4-ol,

428. 4-[4-(4-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]-2-메틸설파닐피리미딘,428. 4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

429. 시클로프로필-{4-[4-(4-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸- 5-일]피리미딘-2-일}아민,429. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

430. 시클로프로필-{4-[4-(3-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민,430. cyclopropyl- {4- [4- (3-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

431. 시클로프로필-{4-[4-(2-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민,431. cyclopropyl- {4- [4- (2-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

432. {4-[4-(3-클로로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}시클로프로필아민,432. {4- [4- (3-chlorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine,

433. 시클로프로필-{4-[2-(1-메틸피페리딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,433. cyclopropyl- {4- [2- (1-methylpiperidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

434. 시클로프로필-{4-[2-(1-메틸피페리딘-4-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,434. cyclopropyl- {4- [2- (1-methylpiperidin-4-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

435. 시클로프로필-{4-[4-(4-메톡시페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민,435. Cyclopropyl- {4- [4- (4-methoxyphenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

436. 4-[4-(4-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]-2-메틸설파닐피리미딘,436. 4- [4- (4-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine,

437. 시클로펜틸-{4-[4-(4-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민,437. cyclopentyl- {4- [4- (4-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

438. 시클로펜틸-{4-[4-(3-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민,438. cyclopentyl- {4- [4- (3-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

439. 시클로펜틸-{4-[4-(2-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5- 일]피리미딘-2-일}아민,439. cyclopentyl- {4- [4- (2-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

440. {4-[4-(3-클로로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}시클로펜틸아민,440. {4- [4- (3-chlorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine,

441. 시클로펜틸-{4-[2-(1-메틸피페리딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,441. cyclopentyl- {4- [2- (1-methylpiperidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

442. 시클로펜틸-{4-[2-(1-메틸피페리딘-4-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,442. cyclopentyl- {4- [2- (1-methylpiperidin-4-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

443. 시클로펜틸-{4-[4-(4-메톡시페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민,443. cyclopentyl- {4- [4- (4-methoxyphenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

444. 시클로헥실-{4-[4-(4-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민,444. cyclohexyl- {4- [4- (4-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

445. 시클로헥실-{4-[4-(3-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민,445. cyclohexyl- {4- [4- (3-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

446. 시클로헥실-{4-[4-(2-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민,446. cyclohexyl- {4- [4- (2-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

447. {4-[4-(3-클로로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}시클로헥실아민,447. {4- [4- (3-chlorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine,

448. 시클로헥실-{4-[2-(1-메틸피페리딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,448. cyclohexyl- {4- [2- (1-methylpiperidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

449. 시클로헥실-{4-[2-(1-메틸피페리딘-4-일)-4-(3-메틸페닐)티아졸-5-일] 피리미딘-2-일}아민,449. cyclohexyl- {4- [2- (1-methylpiperidin-4-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

450. 시클로헥실-{4-[4-(4-메톡시페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민,450. cyclohexyl- {4- [4- (4-methoxyphenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

451. {4-[4-(3-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,451. {4- [4- (3-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine,

452. {4-[4-(2-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,452. {4- [4- (2-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine,

453. {4-[4-(3-클로로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,453. {4- [4- (3-chlorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -Phenylethyl) amine,

454. {4-[2-(1-메틸피페리딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,454. {4- [2- (1-methylpiperidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- ( S) -phenylethyl) amine,

455. {4-[2-(1-메틸피페리딘-4-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,455. {4- [2- (1-methylpiperidin-4-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S)- Phenylethyl) amine,

456. {4-[4-(4-메톡시페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,456. {4- [4- (4-methoxyphenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine,

457. 시클로프로필-{4-[4-(4-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민,457. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

458. 시클로프로필-{4-[4-(3-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민,458. cyclopropyl- {4- [4- (3-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

459. 시클로프로필-{4-[4-(2-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸- 5-일]피리미딘-2-일}아민,459. cyclopropyl- {4- [4- (2-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5 yl] pyrimidin-2-yl} amine,

460. {4-[4-(3-클로로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}시클로프로필아민,460. {4- [4- (3-chlorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine,

461. 시클로프로필-{4-[2-(4-메틸피페라진-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,461. cyclopropyl- {4- [2- (4-methylpiperazin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

462. 시클로프로필-{4-[2-(4-메틸피페라진-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,462. cyclopropyl- {4- [2- (4-methylpiperazin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

463. 시클로프로필-{4-[4-(4-메톡시페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민,463. cyclopropyl- {4- [4- (4-methoxyphenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

464. 시클로펜틸-{4-[4-(4-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민,464. cyclopentyl- {4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

465. 시클로펜틸-{4-[4-(3-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민,465. cyclopentyl- {4- [4- (3-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

466. 시클로펜틸-{4-[4-(2-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민,466. cyclopentyl- {4- [4- (2-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

467. {4-[4-(3-클로로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}시클로펜틸아민,467. {4- [4- (3-chlorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine,

468. 시클로펜틸-{4-[2-(4-메틸피페라진-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,468. cyclopentyl- {4- [2- (4-methylpiperazin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

469. 시클로펜틸-{4-[2-(4-메틸피페라진-1-일)-4-(3-메틸페닐)티아졸-5-일] 피리미딘-2-일}아민,469. cyclopentyl- {4- [2- (4-methylpiperazin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

470. 시클로펜틸-{4-[4-(4-메톡시페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민,470. cyclopentyl- {4- [4- (4-methoxyphenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

471. 시클로헥실-{4-[4-(4-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민,471. cyclohexyl- {4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

472. 시클로헥실-{4-[4-(3-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민,472. cyclohexyl- {4- [4- (3-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

473. 시클로헥실-{4-[4-(2-플루오로페닐)-2-(4-메틸피페라진-1-,일)티아졸-5-일]피리미딘-2-일}아민,473. cyclohexyl- {4- [4- (2-fluorophenyl) -2- (4-methylpiperazin-1-, yl) thiazol-5-yl] pyrimidin-2-yl} amine,

474. {4-[4-(3-클로로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}시클로헥실아민,474. {4- [4- (3-chlorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine,

475. 시클로헥실-{4-[2-(4-메틸피페라진-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민,475. cyclohexyl- {4- [2- (4-methylpiperazin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

476. 시클로헥실-{4-[2-(4-메틸피페라진-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민,476. cyclohexyl- {4- [2- (4-methylpiperazin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

477. 시클로헥실-{4-[4-(4-메톡시페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민,477. cyclohexyl- {4- [4- (4-methoxyphenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

478. {4-[4-(4-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,478. {4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -Phenylethyl) amine,

479. {4-[4-(3-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘 -2-일}-(1-(S)-페닐에틸)아민,479. {4- [4- (3-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -Phenylethyl) amine,

480. {4-[4-(2-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,480. {4- [4- (2-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -Phenylethyl) amine,

481. {4-[4-(3-클로로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,481. {4- [4- (3-Chlorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S)- Phenylethyl) amine,

482. {4-[2-(4-메틸피페라진-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,482. {4- [2- (4-methylpiperazin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine,

483. {4-[2-(4-메틸피페라진-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,483. {4- [2- (4-Methylpiperazin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenyl Ethyl) amine,

484. {4-[4-(4-메톡시페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민,484. {4- [4- (4-methoxyphenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -Phenylethyl) amine,

485. 시클로프로필-{4-[2-(1-에틸피페리딘-4-일)-4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민,485. cyclopropyl- {4- [2- (1-ethylpiperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine,

486. 시클로프로필-{4-[4-(4-플루오로페닐)-2-(1-이소프로필피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민,486. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (1-isopropylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine,

487. 1-{4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-일}에탄온,487. 1- {4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-1-yl} ethanone ,

488. 1-{4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-일}-2-디메틸아미노에탄온,488. 1- {4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-1-yl} -2 Dimethylaminoethanone,

489. 시클로프로필-{4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오 로페닐)티아졸-2-일]피페리딘-1-일}메탄온,489. Cyclopropyl- {4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-1-yl} methane On,

490. {4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-일}페닐메탄온,490. {4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-1-yl} phenylmethanone,

491. 시클로프로필-{4-[2-(1-시클로프로필메틸피페리딘-4-일)-4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민,491. Cyclopropyl- {4- [2- (1-cyclopropylmethylpiperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine ,

492. 시클로프로필-{4-[2-[1-(2-디메틸아미노에틸)피페리딘-4-일]-4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민,492. Cyclopropyl- {4- [2- [1- (2-dimethylaminoethyl) piperidin-4-yl] -4- (4-fluorophenyl) thiazol-5-yl] pyrimidine-2 -Yl} amine,

493. N-{4-[4-(4-플루오로페닐)-2-(4-메틸설파닐페닐)티아졸-5-일]피리딘-2-일}프로피온아미드,493. N- {4- [4- (4-fluorophenyl) -2- (4-methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl} propionamide,

494. 4-[4-(4-플루오로페닐)-5-(2-프로피오닐아미노피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,494. 4- [4- (4-fluorophenyl) -5- (2-propionylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

495. 4-[5-(2-디프로피오닐아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,495. 4- [5- (2-dipropionylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

496. 4-[5-[2-(시클로헥산카르보닐아미노)피리미딘-4-일]-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,496. 4- [5- [2- (cyclohexanecarbonylamino) pyrimidin-4-yl] -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid Ethyl ester,

497. 4-[5-[2-(비스시클로헥산카르보닐아미노)피리미딘-4-일]-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,497. 4- [5- [2- (biscyclohexanecarbonylamino) pyrimidin-4-yl] -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxyl Acid ethyl ester,

498. 4-[5-(2-벤조일아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터,498. 4- [5- (2-benzoylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester,

499. N-{4-[4-(4-플루오로페닐)-2-(4-메탄설피닐페닐)티아졸-5-일]피리딘-2- 일}프로피온아미드,499. N- {4- [4- (4-fluorophenyl) -2- (4-methanesulfinylphenyl) thiazol-5-yl] pyridin-2-yl} propionamide,

500. N-{4-[4-(4-플루오로페닐)-2-(4-메탄설포닐페닐)티아졸-5-일]피리딘-2-일}프로피온아미드,500. N- {4- [4- (4-fluorophenyl) -2- (4-methanesulfonylphenyl) thiazol-5-yl] pyridin-2-yl} propionamide,

501. N-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}프로피온아미드,501. N- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} propionamide,

502. N-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}벤즈아미드,502. N- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} benzamide,

503. 시클로헥산카르복실산 {4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아미드,503. Cyclohexanecarboxylic acid {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amide,

504. N-[4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]-6,N-디메틸니코틴아미드,504. N- [4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -6, N-dimethylnicotinamide,

505. N-[4-(3-클로로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]-6,N-디메틸니코틴아미드,505. N- [4- (3-chlorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] -6, N-dimethylnicotinamide,

506. N-{4-(3-클로로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-6,N-디메틸니코틴아미드.506.N- {4- (3-chlorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -6, N-dimethyl Nicotinamide.

또한, 본 발명은 하기 화학식 2로 표시되는 중간체 화합물 및 이의 약학적으로 허용가능한 염을 제공한다.The present invention also provides an intermediate compound represented by the following formula (2) and a pharmaceutically acceptable salt thereof.

Figure 112006042290445-pat00008
Figure 112006042290445-pat00008

상기 화학식 2에서, In Chemical Formula 2,

R1은 할로겐 원자, C1~C4의 할로알킬, C1~C4의 알킬 또는 C1~C4의 알콕시이며, Hal은 F, Cl, 또는 I이다.R1 is a halo of a halogen atom, C 1 ~ C 4 alkyl, C 1 ~ C 4 Of alkyl or C 1 to C 4 Alkoxy and Hal is F, Cl, or I.

바람직하게는 상기 화학식 2에서,Preferably in Formula 2,

R1은 2-F, 3-F, 4-F, 3-Cl, 3-CF3, 3-CH3 또는 4-OCH3이며, Hal은 Cl이다.R 1 is 2-F, 3-F, 4-F, 3-Cl, 3-CF 3 , 3-CH 3 or 4-OCH 3 , and Hal is Cl.

상기 화학식 1로 표시되는 본 발명의 치환된 1,3-티아졸 유도체 및 화학식 2로 표시되는 중간체 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며, 예를 들어, 금속염, 유기 염기와의 염, 무기산과의 염, 유기산과의 염, 염기성 또는 산성 아미노산과의 염 등이 있다. 적합한 금속염으로서, 나트륨염, 칼륨염 등과 같은 알칼리 금속염; 칼슘염, 마그네슘염, 바륨염 등과 같은 알칼리 토금속염; 알루미늄염 등이 있다. 유기 염기와의 염의 적합한 예로서, 예를 들어, 트리메틸아민, 트리에틸아민, 피리딘, 피콜린, 2,6-루티딘, 에탄올아민, 디에탄올아민, 트리에탄올아민, 시클로헥실아민, 디시클로헥실아민, N,N-디벤질에틸렌디아민 등과의 염이 있다. 무기산과의 염의 적합한 예로서, 예를 들어, 염산, 브롬화수소산, 질산, 황산, 인산 등과의 염이 있다. 유기산과의 염의 적합한 예로서, 예를 들어, 포름산, 아세트산, 트리플루오로아세트산, 프탈산, 푸마르산, 옥살산, 타르타르산, 말레인산, 시트르산, 숙신산, 메탄술폰산, 벤젠술폰산, p-톨루엔술폰산 등과의 염이 있다. 염기성 아미노산과의 염의 적합한 예로서, 예를 들어, 알기닌, 라이신, 오르니틴 등과의 염이 있다. 산성 아미노산과의 염의 적합한 예로서, 예를 들어, 아스파르트산, 글루탐산 등과의 염이 있다. 특히 바람직한 염으로는, 화합물이 그 내에 산성 관능기를 가지는 경우, 알칼리 금속염 (예컨대, 나트륨염, 칼륨염 등), 알칼리 토금속염 (예컨대, 칼슘염, 마그네슘염, 바륨염 등) 등과 같은 무기염, 및 암모늄염과 같은 유기 염이 있으며, 화합물이 그 내에 염기성 관능기를 가지는 경우, 염산, 브롬화수소산, 질산, 황산, 인산 등과 같은 무기산과의 염, 아세트산, 프탈산, 푸마르산, 옥살산, 타르타르산, 말레인산, 시트르산, 숙신산, 메탄술폰산, p-톨루엔술폰산 등과 같은 유기산과의 염이 있다.Substituted 1,3-thiazole derivatives of the present invention represented by the formula (1) and the intermediate compound represented by the formula (2) can be used in the form of a pharmaceutically acceptable salt, for example, salts with metal salts, organic bases , Salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Suitable metal salts include alkali metal salts such as sodium salts, potassium salts and the like; Alkaline earth metal salts such as calcium salts, magnesium salts, barium salts, and the like; Aluminum salts; Suitable examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-rutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine , Salts with N, N-dibenzylethylenediamine and the like. Suitable examples of salts with inorganic acids are, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. . Suitable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine and the like. Suitable examples of salts with acidic amino acids are, for example, salts with aspartic acid, glutamic acid and the like. Particularly preferred salts include inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.) when the compound has an acidic functional group therein, And organic salts such as ammonium salts and when the compound has a basic functional group therein, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, Salts with organic acids such as succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

또한, 본 발명은 하기 반응식 1 내지 6으로 표시되는 화학식 1의 치환된 1,3-티아졸 유도체의 제조방법을 제공한다.The present invention also provides a method for preparing a substituted 1,3-thiazole derivative represented by the following formulas (1) to (6).

하기 반응식 1로 표시되는 치환된 1,3-티아졸 유도체의 제조방법은,Method for producing a substituted 1,3-thiazole derivative represented by the following Scheme 1,

1) 화합물 (Ⅱ)를 염기로 처리하고, 화합물 (Ⅲ)과 반응시켜 화합물 (Ⅳ)를 얻는 단계;1) treating compound (II) with a base and reacting with compound (III) to obtain compound (IV);

2) 상기 1)단계에서 제조된 화합물 (Ⅳ)를 할로겐화시켜 화합물 (Ⅴ)를 얻는 단계;2) halogenating compound (IV) prepared in step 1) to obtain compound (V);

3) 상기 2)단계에서 제조된 화합물 (Ⅴ)와 티오아미드 화합물 (Ⅵ)을 반응시켜 화합물 (Ⅶ)을 얻는 단계; 및3) obtaining compound (VII) by reacting compound (V) prepared in step 2) with thioamide compound (VI); And

4) 상기 3)단계에서 제조된 화합물 (Ⅶ)과 아민 화합물 (Ⅷ)을 반응시켜 치환된 1,3-티아졸 화합물 (I-a)를 얻는 단계를 포함한다.4) reacting the compound (iii) prepared in step 3) with the amine compound (iii) to obtain a substituted 1,3-thiazole compound (I-a).

Figure 112006042290445-pat00009
Figure 112006042290445-pat00009

(상기 반응식 1에서, R1, R2, R4는 화학식 1에서 정의한 바와 같고, Hal, Hal'는 할로겐 원자이며, L은 이탈기이다.)(In Reaction Scheme 1, R1, R2, and R4 are as defined in Formula 1, Hal, Hal 'is a halogen atom, and L is a leaving group.)

화합물 (Ⅱ), (Ⅲ), (Ⅵ), 및 (Ⅷ)은 시판되는 것인 경우 그대로 사용될 수 있으며, 또는 공지된 그 자체의 방법으로나 이와 유사한 방법에 따라 제조될 수 있다.Compounds (II), (III), (VI), and (iii) can be used as they are commercially available, or can be prepared by known methods or by analogous methods.

화합물 (Ⅳ)는 화합물 (Ⅱ)를 염기로 처리하고, 화합물 (Ⅲ)과 반응시킴으로써 제조된다. Compound (IV) is prepared by treating compound (II) with a base and reacting with compound (III).

화합물 (Ⅱ)에서, Hal'은 불소, 염소, 브롬 및 요오드와 같은 할로겐 원자를 나타낸다.In compound (II), Hal 'represents a halogen atom such as fluorine, chlorine, bromine and iodine.

사용되는 염기의 양은 화합물 (Ⅱ) 1 몰에 대해 약 0.8 내지 약 5 몰, 바람직하게는 약 1 내지 약 1.2 몰이다.The amount of base used is about 0.8 to about 5 moles, preferably about 1 to about 1.2 moles, per 1 mole of compound (II).

"염기"는, 예를 들어 n-부틸리튬 등과 같은 알킬리튬, 나트륨 아미드, 리튬 디이소프로필아미드, 리튬 헥사메틸디실라이드 등과 같은 금속 아미드가 사용된다."Base" includes, for example, metal amides such as alkyllithium, such as n-butyllithium, sodium amide, lithium diisopropylamide, lithium hexamethyldisilide and the like.

이 반응은 용매 없이, 또는 반응용 불활성 용매의 존재 하에서 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 지방족 탄화수소, 방향족 탄화 수소, 에테르 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 -78 내지 약 60℃, 바람직하게는 약 -78℃ 내지 상온이다. 반응 시간은 일반적으로 약 5분 내지 약 24시간, 바람직하게는 약 0.5 내지 약 3 시간이다.The reaction temperature is generally about -78 to about 60 ℃, preferably about -78 ℃ to room temperature. The reaction time is generally about 5 minutes to about 24 hours, preferably about 0.5 to about 3 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있 지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like. .

화합물 (V)는 화합물 (Ⅳ)를 할로겐 또는 금속 할라이드로 처리함으로써 제조된다. 이 반응은 필요한 경우 염기 또는 염기성 염의 존재 하에 수행된다. Compound (V) is prepared by treating compound (IV) with a halogen or metal halide. This reaction is carried out in the presence of a base or basic salt, if necessary.

화합물 (V)에서, Hal 또는 Hal'은 불소, 염소, 브롬 및 요오드와 같은 할로겐 원자를 나타낸다.In compound (V), Hal or Hal 'represents halogen atoms such as fluorine, chlorine, bromine and iodine.

사용되는 할로겐 또는 금속 할라이드의 양은 화합물 (Ⅳ) 1 몰에 대해 약 1 내지 약 8 몰, 바람직하게는 약 1 내지 약 2 몰이다.The amount of halogen or metal halide used is about 1 to about 8 moles, preferably about 1 to about 2 moles, per 1 mole of compound (IV).

"할로겐"으로는, 브롬, 염소, 요오드 등이 있다."Halogen" includes bromine, chlorine, iodine and the like.

"금속 할라이드"로는 구리(Ⅱ) 브로마이드, 구리(Ⅱ) 클로라이드 등과 같은 구리 할라이드가 있다."Metal halides" include copper halides such as copper (II) bromide, copper (II) chloride and the like.

사용되는 염기의 양은 화합물 (Ⅳ) 1 몰에 대해 약 1 내지 약 10 몰, 바람직하게는 약 1 내지 약 3 몰이다.The amount of base used is about 1 to about 10 moles, preferably about 1 to about 3 moles per 1 mole of compound (IV).

"염기"로는, 예를 들어, 수산화나트륨, 수산화칼륨, 수산화리튬 등과 같은 금속 수산화물, 탄산나트륨, 탄산칼륨, 탄산세슘, 탄산수소나트륨, 아세트산나트륨 등과 같은 염기성 염, 피리딘, 루티딘 등과 같은 방향족 아민, 트리에틸아민, 트리프로필아민, 트리부틸아민, 시클로헥실디메틸아민, 4-디메틸아민노피리딘, N,N-디메틸아닐린, N-메틸피페리딘, N-메틸피롤리딘, N-메틸모르폴린 등과 같은 3차 아민이 있다.“Bases” include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine, and the like, Triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminenopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine Tertiary amines, and the like.

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 에테르, 에스테르, 방향족 탄화수소, 지방족 탄화수소, 아미드, 할로겐화 탄화수소, 니트릴, 술폭시드, 유기산, 방향족 아민 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but, for example, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromatic amines or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 -20 내지 약 150℃, 바람직하게는 약 0 내지 약 100℃ 이다. 반응 시간은 일반적으로 약 5분 내지 약 24시간, 바람직하게는 약 10 분 내지 약 5시간이다.The reaction temperature is generally about -20 to about 150 ° C, preferably about 0 to about 100 ° C. The reaction time is generally about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

화합물 (Ⅶ)은 화합물 (V) 및 티오아미드 화합물 (Ⅵ)을 반응시킴으로써 제조된다. 이 반응은, 필요한 경우, 염기의 존재 하에 수행된다. Compound (VIII) is prepared by reacting compound (V) and thioamide compound (VI). This reaction is carried out in the presence of a base, if necessary.

화합물 (Ⅶ)에서 Hal'은 불소, 염소, 브롬 및 요오드와 같은 할로겐 원자를 나타낸다.Hal 'in compound (iii) represents a halogen atom such as fluorine, chlorine, bromine and iodine.

사용되는 티오아미드 화합물 (Ⅵ)의 양은 화합물 (V) 1 몰에 대해 약 0.5 내지 약 6 몰, 바람직하게는 약 0.8 내지 약 3 몰이다.The amount of thioamide compound (VI) used is about 0.5 to about 6 moles, preferably about 0.8 to about 3 moles, per 1 mole of compound (V).

사용되는 염기의 양은 화합물 (V) 1 몰에 대해 약 1 내지 약 30 몰, 바람직하게는 약 1 내지 약 10 몰이다.The amount of base used is about 1 to about 30 moles, preferably about 1 to about 10 moles, per 1 mole of compound (V).

"염기"로는, 예를 들어, 탄산나트륨, 탄산칼륨, 탄산세슘, 탄산수소나트륨, 아세트산나트륨 등과 같은 염기성 염, 피리딘, 루티딘 등과 같은 방향족 아민, 트리에틸아민, 트리프로필아민, 트리부틸아민, 시클로헥실디메틸아민, 4-디메틸아민노피리딘, N,N-디메틸아닐린, N-메틸피페리딘, N-메틸피롤리딘, N-메틸모르폴린 등과 같은 3차 아민이 있다."Base" includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, aromatic amines such as pyridine, lutidine, etc., triethylamine, tripropylamine, tributylamine, cyclo Tertiary amines such as hexyldimethylamine, 4-dimethylaminenopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like.

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 할로겐화 탄화수소, 지방족 탄화수소, 방향족 탄화수소, 에테르, 아미드, 알콜, 니트릴 또는 이들 둘 이상의 혼합물 등이 사용된다This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, nitriles or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 -5 내지 약 200℃, 바람직하게는 약 5 내지 약 150℃ 이다. 반응 시간은 일반적으로 약 5 분 내지 약 72 시간, 바람직하게는 약 0.5 내지 약 30 시간이다.The reaction temperature is generally about -5 to about 200 ° C, preferably about 5 to about 150 ° C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 30 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

화합물 (I-a)는 화합물 (Ⅶ) 및 아민 화합물 (Ⅷ)을 반응시킴으로써 제조된다. 이 반응은, 필요한 경우, 염기의 존재 하에 수행된다. Compound (Ia) is produced by reacting compound (VII) and amine compound (VII). This reaction is carried out in the presence of a base, if necessary.

사용되는 아민 화합물 (Ⅷ)의 양은 화합물 (Ⅶ) 1 몰에 대해 약 0.8 내지 약 30 몰, 바람직하게는 약 1 내지 약 10 몰이다.The amount of the amine compound (VIII) to be used is about 0.8 to about 30 moles, preferably about 1 to about 10 moles, per 1 mole of the compound (VIII).

사용되는 염기의 양은 화합물 (Ⅶ) 1 몰에 대해 약 0.8 내지 약 30 몰, 바람 직하게는 약 1 내지 약 10 몰이다.The amount of base used is about 0.8 to about 30 moles, preferably about 1 to about 10 moles per one mole of compound (iii).

"염기"로는, 예를 들어, 탄산나트륨, 탄산칼륨, 탄산세슘 등과 같은 염기성 염, 수산화나트륨, 수산화칼륨 등과 같은 금속 수산화물, 피리딘, 루티딘 등과 같은 방향족 아민, 트리에틸아민, 트리프로필아민, 트리부틸아민, 시클로헥실디메틸아민, 4-디메틸아미노피리딘, N,N-디메틸아닐린, N-메틸피페리딘, N-메틸피롤리딘, N-메틸모르폴린 등과 같은 3차 아민, 나트륨 히드리드, 칼륨 히드리드 등과 같은 알칼리 금속 히드리드, 나트륨 아미드, 리튬 디이소프로필아미드, 리륨 헥사메틸디실라지드 등과 같은 금속 아미드, 나트륨 메톡시드, 나트륨 에톡시드, 칼륨 tert-부톡시드 등과 같은 금속 알콕시드가 있다.“Bases” include, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and the like, metal hydroxides such as sodium hydroxide, potassium hydroxide and the like, aromatic amines such as pyridine, lutidine, and the like, triethylamine, tripropylamine, tributyl Tertiary amines such as amines, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, sodium hydride, potassium Alkali metal hydrides such as hydrides, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 지방족 탄화수소, 방향족 탄화수소, 에테르 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but for example, aliphatic hydrocarbons, aromatic hydrocarbons, mixtures of two or more thereof, and the like are used.

반응 온도는 일반적으로 약 -78 내지 약 200℃, 바람직하게는 약 실온 내지 약 170℃ 이다. 반응 시간은 일반적으로 약 5 분 내지 약 72 시간, 바람직하게는 약 0.5 내지 약 24 시간이다.The reaction temperature is generally about -78 to about 200 ° C, preferably about room temperature to about 170 ° C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 24 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

만일, 화합물 (I-a)에서 R2 가

Figure 112006042290445-pat00010
이며, 이때 X는 CH, C-OH, 또는 N이고, Y는 N-CO- C 1 ~ C 4 의 알콕시인 경우, If, the R2 in the compound (Ia)
Figure 112006042290445-pat00010
And, where X is a CH, C-OH, or N, Y is N-CO- C 1 ~ C 4 For alkoxy ,

화합물 (I-a)를 산 또는 염기를 사용하여 탈보호화한다.Compound (I-a) is deprotected with acid or base.

이때 사용되는 산 또는 염기의 양은 화합물 (I-a) 1 몰에 대해 약 0.1 내지 약 50 몰, 바람직하게는 약 1 내지 약 20 몰이다.The amount of acid or base used at this time is about 0.1 to about 50 moles, preferably about 1 to about 20 moles, per 1 mole of compound (I-a).

"산"으로는, 예를 들어 염산, 브롬화 수소산, 황산 등과 같은 무기산, 삼염화붕소, 삼브롬화붕소, 트리메틸실릴 할라이드 등과 같은 루이스산, 루이스산과 더불어 티올 또는 술파이드의 사용, 트리플루오로아세트산, p-톨루엔술폰산 등과 같은 유기산이 사용된다."Acids" include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and the like, Lewis acids such as boron trichloride, boron tribromide, trimethylsilyl halide and the like, the use of thiols or sulfides with Lewis acids, trifluoroacetic acid, p Organic acids such as toluenesulfonic acid and the like are used.

"염기"로는, 예를 들어 수산화나트륨, 수산화칼륨, 수산화바륨 등과 같은 금속 수산화물, 탄산나트륨, 탄산칼륨 등과 같은 염기성 염, 나트륨 메톡시드, 나트륨 에톡시드, 칼륨 tert-부톡시드 등과 같은 금속 알콕시드, 트리에틸아민, 이미다졸, 포름아미딘 등과 같은 유기 염기가 사용된다.“Bases” include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, basic salts such as sodium carbonate, potassium carbonate, etc., metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, tri Organic bases such as ethylamine, imidazole, formamidine and the like are used.

이 반응은 용매 없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 알콜, 에테르, 방향족 탄화수소, 할로겐화 탄화수소, 지방족 탄화수소, 술폭시드, 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but, for example, alcohols, ethers, aromatic hydrocarbons, halogenated hydrocarbons, aliphatic hydrocarbons, sulfoxides, or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 0 내지 약 200℃, 바람직하게는 약 20 내지 약 120℃ 이다. 반응 시간은 일반적으로 약 10 분 내지 약 50 시간, 바람직하게는 약 0.5 내지 약 12 시간이다.The reaction temperature is generally about 0 to about 200 ° C, preferably about 20 to about 120 ° C. The reaction time is generally about 10 minutes to about 50 hours, preferably about 0.5 to about 12 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

또한, 탈보호화된 화합물 (I-a)를 메틸화할 수 있다. 이 반응은, 필요한 경우, 염기의 존재 하에 수행된다.It is also possible to methylate deprotected compounds (I-a). This reaction is carried out in the presence of a base, if necessary.

이때 사용되는 메틸화제의 양은 탈보호화된 화합물 (I-a) 1 몰에 대해 약 1 내지 약 30 몰, 바람직하게는 약 1 내지 약 5 몰이다.The amount of methylating agent used at this time is about 1 to about 30 moles, preferably about 1 to about 5 moles, per 1 mole of deprotected compound (I-a).

"메틸화제"로는, 예를 들어 메틸 할라이드 또는 디메틸설페이트 등이 있고, 포름아미드를 이용한 환원성 아미노화 (reductive amination) 등이 있다.Examples of the "methylating agent" include methyl halide, dimethyl sulfate, and the like, and reductive amination using formamide.

사용되는 염기 양은 상응하는 탈보호화된 화합물 (I-a) 1 몰에 대해 약 1 내지 약 5 몰, 바람직하게는 약 1 내지 약 2 몰이다.The amount of base used is about 1 to about 5 moles, preferably about 1 to about 2 moles per 1 mole of the corresponding deprotected compound (I-a).

"염기"로는, 예를 들어 수산화나트륨, 수산화칼륨, 수산화바륨 등과 같은 금속 수산화물, 탄산나트륨, 탄산칼륨 등과 같은 염기성 염, 나트륨 메톡시드, 나트륨 에톡시드, 칼륨 tert-부톡시드 등과 같은 금속 알콕시드, 트리에틸아민, 이미다졸, 포름아미딘 등과 같은 유기 염기가 사용된다.“Bases” include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, basic salts such as sodium carbonate, potassium carbonate, etc., metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, tri Organic bases such as ethylamine, imidazole, formamidine and the like are used.

환원성 아미노화는 탈보호화된 화합물 (I-a)를 알콜 용매 존재 하에 환원제를 사용하여 포름알데하이드와 반응시킴으로써 메틸화된 화합물(I-a)를 제조한다.Reductive amination produces methylated compound (I-a) by reacting deprotected compound (I-a) with formaldehyde using a reducing agent in the presence of an alcohol solvent.

이때 사용되는 포름알데하이드의 양은 탈보호화된 화합물 (I-a) 1 몰에 대해 약 1 내지 약 10 몰, 바람직하게는 약 1 내지 약 3 몰이다.The amount of formaldehyde used at this time is about 1 to about 10 moles, preferably about 1 to about 3 moles, per 1 mole of deprotected compound (I-a).

환원제로는 소듐보로하이드라이드(NaBH4), 소듐시아노보로하이드라이드(NaBH3CN), 소듐트리아세톡시보로하이드라이드(NaB(OAc)3H) 등을 사용하며, 환원제의 양은 탈보호화된 화합물 (I-a) 1 몰에 대해 약 1 내지 약 10 몰, 바람직하게는 약 1 내지 약 3 몰이다.Reducing agents include sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaBH 3 CN), sodium triacetoxyborohydride (NaB (OAc) 3 H), and the amount of reducing agent is deprotected. From about 1 to about 10 moles, preferably from about 1 to about 3 moles, per 1 mole of the compound (Ia).

용매로는 특별한 제한은 없지만, 예를 들어 알콜, 에테르, 방향족 탄화수소, 할로겐화 탄화수소, 지방족 탄화수소, 술폭시드, 또는 이들 둘 이상의 혼합물 등이 사용된다.The solvent is not particularly limited, but alcohol, ether, aromatic hydrocarbon, halogenated hydrocarbon, aliphatic hydrocarbon, sulfoxide, or a mixture of two or more thereof is used, for example.

반응 온도는 약 -20 내지 약 100℃ 이며, 바람직하게는 약 0℃ 내지 상온이다. 반응 시간은 일반적으로 약 10 분 내지 약 50 시간, 바람직하게는 약 0.5 내지 약 12 시간이다.The reaction temperature is about -20 to about 100 ° C, preferably about 0 ° C to room temperature. The reaction time is generally about 10 minutes to about 50 hours, preferably about 0.5 to about 12 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

하기 반응식 2로 표시되는 치환된 1,3-티아졸 유도체의 제조방법은,Method for producing a substituted 1,3-thiazole derivative represented by the following scheme 2,

1) 화합물 (IX)의 아민기를 보호화하여 얻어진 화합물 (X)을 염기로 처리하고, 화합물 (Ⅲ)과 반응시켜 화합물 (XI)을 얻는 단계;1) treating compound (X) obtained by protecting an amine group of compound (IX) with a base, and reacting with compound (III) to obtain compound (XI);

2) 상기 1)단계에서 제조된 화합물 (XI)을 할로겐화시켜 화합물 (XII)를 얻는 단계;2) halogenating compound (XI) prepared in step 1) to obtain compound (XII);

3) 상기 2)단계에서 제조된 화합물 (XII)와 티오아미드 화합물 (Ⅵ)을 반응시켜 화합물 (XIII)를 얻는 단계;3) reacting compound (XII) prepared in step 2) with thioamide compound (VI) to obtain compound (XIII);

4) 상기 3)단계에서 제조된 화합물 (XIII)을 탈보호화시키고, 아실화제 (XV)를 반응시켜 치환된 1,3-티아졸 화합물 (I-b)를 얻는 단계를 포함한다.4) deprotecting the compound (XIII) prepared in step 3) and reacting the acylating agent (XV) to obtain a substituted 1,3-thiazole compound (I-b).

Figure 112006042290445-pat00011
Figure 112006042290445-pat00011

(상기 반응식 2에서, R1, R2, R5는 화학식 1에서 정의한 바와 같으며, Hal은 할로겐 원자이며, L은 이탈기이다.)(In Scheme 2, R1, R2, R5 are as defined in formula (1), Hal is a halogen atom, L is a leaving group.)

화합물 (X)은, 문헌 [Synthesis, 877~822 쪽, 1996] 또는 [Journal of Organic Chemistry, 61권, 4810~4811 쪽, 1996]에 기술된 방법에 의해 화합물 (IX)로부터 제조된다. Compound (X) is prepared from Compound (IX) by the method described in Synthesis, pp. 877-822, 1996 or Journal of Organic Chemistry, Vol. 61, 4810-4811, 1996.

화합물 (XI)은, 화합물 (X)와 화합물 (Ⅲ)을 상기 반응식 1의 1)단계와 동일한 방법으로 반응시킴으로써 제조된다. Compound (XI) is prepared by reacting compound (X) and compound (III) in the same manner as in step 1) of Scheme 1 above.

사용되는 염기의 양은 화합물 (X) 1 몰에 대해 약 0.8 내지 약 5 몰, 바람직하게는 약 2 내지 약 2.5 몰이다.The amount of base used is about 0.8 to about 5 moles, preferably about 2 to about 2.5 moles per 1 mole of compound (X).

화합물 (XII)는, 상기에서 얻은 화합물 (XI)을 상기 반응식 1의 2)단계와 동일한 방법으로 할로겐화시킴으로써 제조된다. Compound (XII) is prepared by halogenating Compound (XI) obtained above in the same manner as in step 2) of Scheme 1.

화합물 (XIII)은, 상기에서 얻은 화합물 (XII)를 티오아미드 화합물 (VI)과 상기 반응식 1의 3)단계와 동일한 방법으로 반응시킴으로써 제조된다. Compound (XIII) is prepared by reacting compound (XII) obtained above with thioamide compound (VI) in the same manner as in step 3) of Scheme 1 above.

화합물 (XII)에서 Hal은 염소, 브롬 및 요오드와 같은 할로겐 원자를 나타낸다.Hal in compound (XII) represents a halogen atom such as chlorine, bromine and iodine.

티오아미드 화합물 (VI)이 시판되는 경우에는, 이를 구입한 그대로 사용할 수 있으며, 또는 공지된 그 자체의 방법이나 공지 방법에 따른 방법에 의해, 또는 나아가 반응식 7에 나타난 방법에 의해 제조될 수 있다.If a thioamide compound (VI) is commercially available, it can be used as it is purchased, or it can be manufactured by the method according to a well-known per se method or a well-known method, or further by the method shown by Reaction Formula 7.

화합물(XIV)는, 산 또는 염기를 사용하여 화합물(XIII)을 탈보호함으로써 제조된다. Compound (XIV) is prepared by deprotecting compound (XIII) with an acid or a base.

화합물 (I-b)는 화합물 (XIV)를 아실화제 (XV)와 임의로 염기의 존재 하에 반응시킴으로써 제조된다. Compound (Ib) is prepared by reacting compound (XIV) with an acylating agent (XV), optionally in the presence of a base.

사용되는 아실화제 (XV)의 양은 화합물 (XIV) 1 몰에 대해 약 0.8 내지 약 5 몰, 바람직하게는 약 1 내지 약 3 몰이다.The amount of acylating agent (XV) used is about 0.8 to about 5 moles, preferably about 1 to about 3 moles, per 1 mole of compound (XIV).

사용되는 염기의 양은 화합물 (XIV) 1 몰에 대해 약 0.1 내지 약 3 몰, 바람직하게는 약 0.3 내지 약 1.2 몰이다.The amount of base used is about 0.1 to about 3 moles, preferably about 0.3 to about 1.2 moles per one mole of compound (XIV).

"염기"로는, 예를 들어, 탄산나트륨, 탄산칼륨, 탄산세슘 등과 같은 염기성 염, 수산화나트륨, 수산화칼륨 등과 같은 금속 수산화물, 피리딘, 루티딘 등과 같은 방향족 아민, 트리에틸아민, 트리프로필아민, 트리부틸아민, 시클로헥실디메틸아민, 4-디메틸아미노피리딘, N,N-디메틸아닐린, N-메틸피페리딘, N-메틸피롤리딘, N-메틸모르폴린 등과 같은 3차 아민, 나트륨 히드리드, 칼륨 히드리드 등과 같은 알칼리 금속 히드리드, 나트륨 아미드, 리튬 디이소프로필아미드, 리륨 헥사메틸디실라지드 등과 같은 금속 아미드, 나트륨 메톡시드, 나트륨 에톡시드, 칼륨 tert-부톡시드 등과 같은 금속 알콕시드가 있다.“Bases” include, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and the like, metal hydroxides such as sodium hydroxide, potassium hydroxide and the like, aromatic amines such as pyridine, lutidine, and the like, triethylamine, tripropylamine, tributyl Tertiary amines such as amines, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, sodium hydride, potassium Alkali metal hydrides such as hydrides, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 지방족 탄화수소, 방향족 탄화수소, 에테르 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but for example, aliphatic hydrocarbons, aromatic hydrocarbons, mixtures of two or more thereof, and the like are used.

반응 온도는 일반적으로 약 -78 내지 약 100℃, 바람직하게는 약 -78 내지 약 70℃ 이다. 반응 시간은 일반적으로 약 5 분 내지 약 24 시간, 바람직하게는 약 0.5 내지 약 20 시간이다.The reaction temperature is generally about -78 to about 100 ° C, preferably about -78 to about 70 ° C. The reaction time is generally about 5 minutes to about 24 hours, preferably about 0.5 to about 20 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

하기 반응식 3으로 표시되는 치환된 1,3-티아졸 유도체의 제조방법은,Method for producing a substituted 1,3-thiazole derivative represented by the following Scheme 3,

1) 화합물 (XVI)을 염기로 처리하고, 화합물 (Ⅲ)과 반응시켜 화합물 (XVII)을 얻는 단계;1) treating compound (XVI) with a base and reacting with compound (III) to give compound (XVII);

2) 상기 1)단계에서 제조된 화합물 (XVII)을 할로겐화시켜 화합물 (XVIII)을 얻는 단계;2) halogenating the compound (XVII) prepared in step 1) to obtain a compound (XVIII);

3) 상기 2)단계에서 제조된 화합물 (XVIII)와 티오아미드 화합물 (Ⅵ)을 반응시켜 화합물 (XIX)를 얻는 단계;3) reacting compound (XVIII) prepared in step 2) with thioamide compound (VI) to obtain compound (XIX);

4) 상기 3)단계에서 제조된 화합물 (XIX)를 유기 과산화산으로 처리하여 화합물 (XX)을 얻는 단계; 및4) treating compound (XIX) prepared in step 3) with organic peroxide to obtain compound (XX); And

5) 상기 4)단계에서 제조된 화합물 (XX)을 아민 화합물 (VIII)과 반응시켜 치환된 1,3-티아졸 화합물 (I-c)를 얻는 단계를 포함한다.5) reacting compound (XX) prepared in step 4) with an amine compound (VIII) to obtain a substituted 1,3-thiazole compound (I-c).

Figure 112006042290445-pat00012
Figure 112006042290445-pat00012

(상기 반응식 3에서, R1, R2, R4는 화학식 1에서 정의한 바와 같고, Hal은 할로겐 원자이며, L은 이탈기이다.)(In Reaction Scheme 3, R1, R2, and R4 are as defined in Formula 1, Hal is a halogen atom, and L is a leaving group.)

화합물 ( XVI )은, 문헌 [Bioorganic & Medicinal Chemistry Letters, 13(3), 347~350 쪽, 2003], [Organic Letters, 4(6), 979~981 쪽, 2002] 또는 [Zhurnal Organicheskoi Khimii, 12(10), 2063~6 쪽, 1976] 에 기술된 방법에 의해 제조할 수 있다. Compounds ( XVI ) are described in Bioorganic & Medicinal Chemistry Letters, 13 (3), pp. 347-350, 2003, Organic Letters, 4 (6), pp. 979-981, 2002 or Zhurnal Organicheskoi Khimii, 12 (10), pp. 2063-6, 1976].

화합물 ( XVII )은, 화합물 (XVI)과 화합물 (III)을 상기 반응식 1의 1)단계와 동일한 방법으로 반응시킴으로써 제조된다. Compound ( XVII ) is prepared by reacting compound (XVI) and compound (III) in the same manner as in step 1) of Scheme 1 above.

화합물 ( XVIII )은, 상기에서 얻은 화합물 (XVII)을 상기 반응식 1의 2)단계와 동일한 방법으로 할로겐화시킴으로써 제조될 수 있다. Compound ( XVIII ) can be prepared by halogenating Compound (XVII) obtained above in the same manner as in step 2) of Scheme 1 above.

특히, 모노클로라이드 화합물(XVIII)을 얻기 위하여, 화합물 (XVII)을 ① LDA, CF3SO2Cl 또는 ② TBAB, TMSCl, DMSO로 처리하면, 목적하는 모노클로라이드 화합물(XVIII)을 높은 수율(80% 이상)로 얻을 수 있으며, 하기 반응식 3a로 표시된다.In particular, in order to obtain a monochloride compound (XVIII), when compound (XVII) is treated with ① LDA, CF 3 SO 2 Cl or ② TBAB, TMSCl, DMSO, the desired monochloride compound (XVIII) is obtained in high yield (80%). Or above), and is represented by the following Scheme 3a.

Figure 112006042290445-pat00013
Figure 112006042290445-pat00013

(상기 반응식 3a에서, R1은 상기 화학식 2에서 정의한 바와 같고, R2는 상기 화학식 1에서 정의한 바와 같으며, Hal은 Cl이다.)(In Scheme 3a, R1 is as defined in Formula 2, R2 is as defined in Formula 1, and Hal is Cl.)

상기 ① 염소화에서 사용되는 염기로는 LDA 외에, n-부틸리튬 등과 같은 알 킬리튬, 나트륨 아미드, 리튬 헥사메틸디실라이드 등과 같은 금속 아미드를 사용할 수 있다.In addition to LDA, as the base used in the chlorination, metal amides such as alkyllithium such as n-butyllithium, sodium amide, and lithium hexamethyldisilide may be used.

또한, 염소화 시약으로는 트리플루오로메탄설포닐 클로라이드 외에, 메탄설포닐 클로라이드, 벤젠설포닐 클로라이드, p-톨루엔설포닐 클로라이드, 4-(트리플루오로메틸)벤젠설포닐 클로라이드, 설퓨릴 클로라이드 등을 사용할 수 있다.In addition to trifluoromethanesulfonyl chloride, chlorination reagents include methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 4- (trifluoromethyl) benzenesulfonyl chloride, sulfuryl chloride, and the like. Can be used.

사용되는 염소화 시약의 양은 화합물 (XVII) 1 몰에 대해 약 1 내지 약 8 몰, 바람직하게는 약 1 내지 약 2 몰이다.The amount of chlorination reagent used is about 1 to about 8 moles, preferably about 1 to about 2 moles per 1 mole of compound (XVII).

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 에테르, 에스테르, 방향족 탄화수소, 지방족 탄화수소, 아미드, 할로겐화 탄화수소, 니트릴, 술폭시드, 유기산, 방향족 아민 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but, for example, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromatic amines or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 -78 내지 약 150℃, 바람직하게는 약 -78 내지 약 상온이다. 반응 시간은 일반적으로 약 5분 내지 약 24시간, 바람직하게는 약 10 분 내지 약 5시간이다.The reaction temperature is generally about -78 to about 150 ° C, preferably about -78 to about room temperature. The reaction time is generally about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

상기 ② 염소화의 경우, 사용되는 TBAB의 양은 화합물 (XVII) 1 몰에 대해 약 0.01 내지 약 5 몰, 바람직하게는 약 0.05 내지 약 0.5 몰이다.In the case of ② chlorination, the amount of TBAB used is about 0.01 to about 5 moles, preferably about 0.05 to about 0.5 moles, per 1 mole of compound (XVII).

사용되는 TMSCl의 양은 화합물 (XVII) 1 몰에 대해 약 0.1 내지 약 8 몰, 바람직하게는 약 1 내지 약 5 몰이다.The amount of TMSCl used is about 0.1 to about 8 moles, preferably about 1 to about 5 moles, per 1 mole of compound (XVII).

사용되는 DMSO의 양은 화합물 (XVII) 1 몰에 대해 약 0.1 내지 약 8 몰, 바람직하게는 약 1 내지 약 5 몰이다.The amount of DMSO used is about 0.1 to about 8 moles, preferably about 1 to about 5 moles, per 1 mole of compound (XVII).

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 에테르, 에스테르, 방향족 탄화수소, 지방족 탄화수소, 아미드, 할로겐화 탄화수소, 니트릴, 술폭시드, 유기산, 방향족 아민 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but, for example, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromatic amines or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 -20 내지 약 150℃, 바람직하게는 약 0 내지 약 50℃ 이다. 반응 시간은 일반적으로 약 5분 내지 약 24시간, 바람직하게는 약 10 분 내지 약 5시간이다.The reaction temperature is generally about -20 to about 150 ° C, preferably about 0 to about 50 ° C. The reaction time is generally about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

화합물 ( XIX )는, 상기에서 얻은 화합물 (XVIII)을 티오아미드 화합물 (VI)과 상기 반응식 1의 3)단계와 동일한 방법으로 반응시킴으로써 제조된다. Compound ( XIX ) is prepared by reacting compound (XVIII) obtained above with thioamide compound (VI) in the same manner as in step 3) of Scheme 1 above.

국제 특허공개 WO 01/30778에 의하면, R1이 4-F이고, Hal이 브롬인 화합물 (XVIII)의 경우, R2가 N-에톡시카보닐-피페리딘-4-일인 티오아미드 화합물 (VI)과 반응하여 화합물 (XIX)를 제조할 시 수율이 24%로 기재되어 있다. 그러나, 본 발명 자들이 상기 특허에 기재되어 있는 방법과 같은 조건으로 반응시킨 결과 화합물 (XIX)의 수율은 7%로 정도로 매우 낮게 나왔다.According to International Patent Publication WO 01/30778, for compounds (XVIII) in which R 1 is 4-F and Hal is bromine, thioamide compounds (VI) wherein R 2 is N-ethoxycarbonyl-piperidin-4-yl The yield is described as 24% when preparing compound (XIX) in reaction with. However, when the present inventors reacted under the same conditions as described in the above patent, the yield of compound (XIX) was very low as low as 7%.

그러나, 본 발명의 상기 반응식 3a에 의한, R1이 4-F이고, Hal이 Cl인 화합물 (XVIII)을 티오아미드 화합물 (VI)과 반응시켜 화합물 (XIX)를 제조할 시 수율이 60~70%로 매우 높게 나왔다.However, according to the above Scheme 3a of the present invention, when the compound (XVIII) wherein R1 is 4-F and Hal is Cl is reacted with the thioamide compound (VI), the yield is 60-70%. Came out very high.

화합물 ( XX )은, 화합물 (XIX)를 유기 과산화산으로 처리함으로써 제조된다. Compound ( XX ) is produced by treating compound (XIX) with organic peroxide acid.

사용되는 유기 과산화산의 양은 화합물 (XIX) 1 몰에 대해 약 0.8 내지 약 10 몰, 바람직하게는 약 1 내지 약 3 몰이다.The amount of organic peroxide used is from about 0.8 to about 10 moles, preferably from about 1 to about 3 moles, per 1 mole of compound (XIX).

"유기 과산화산"으로는, 예를 들어 퍼아세트산, 트리플루오로퍼아세트산, m-클로로퍼벤조산 등이 있다.Examples of the "organic peroxide acid" include peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid and the like.

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 할로겐화 탄화수소, 지방족 탄화수소, 방향족 탄화수소, 유기산, 에테르, 아미드, 술폭시드, 알콜, 니트릴, 케톤 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, there are no particular restrictions on the solvent, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketones or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 -20 내지 약 130℃, 바람직하게는 약 0 내지 약 100℃ 이다. 반응 시간은 일반적으로 약 5 분 내지 약 72 시간, 바람직하게는 약 0.5 내지 약 12 시간이다.The reaction temperature is generally about -20 to about 130 ° C, preferably about 0 to about 100 ° C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 12 hours.

대안적으로는, 화합물 (XX)은, 또한 화합물 (XIX)를 임의로 염기, 산 또는 산화금속의 존재하에 과산화수소 또는 알킬 히드로페록시드로 처리함으로써 제조된 다.Alternatively, compound (XX) is also prepared by treating compound (XIX) with hydrogen peroxide or alkyl hydroperoxide, optionally in the presence of a base, acid or metal oxide.

사용되는 과산화수소 또는 알킬 히드로페록시드로의 양은 화합물 (XIX) 1 몰에 대해 약 0.8 내지 약 10 몰, 바람직하게는 약 1 내지 약 3 몰이다.The amount of hydrogen peroxide or alkyl hydroperoxide used is from about 0.8 to about 10 moles, preferably from about 1 to about 3 moles, per 1 mole of compound (XIX).

"알킬 히드로페록시드"로는, 예를 들어 tert-부틸 히드로페록시드, 쿠멘 히드로페록시드 등이 있다."Alkyl hydroperoxide" includes, for example, tert-butyl hydroperoxide, cumene hydroperoxide and the like.

사용되는 염기, 산 또는 산화금속의 양은 화합물 (XIX) 1 몰에 대해 약 0.1 내지 약 30 몰, 바람직하게는 약 0.8 내지 약 5 몰이다.The amount of base, acid or metal oxide used is about 0.1 to about 30 moles, preferably about 0.8 to about 5 moles, per 1 mole of compound (XIX).

"염기"로는, 예를 들어 수산화나트륨, 수산화칼륨 등과 같은 금속 수산화물, 탄산나트륨, 탄산칼륨, 아세트산나트륨 등과 같은 염기성 염이 있다."Bases" include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and the like.

"산"으로는, 예를 들면 염산, 황산, 과염소산 등과 같은 무기산, 붕소 트리플루오라이드, 알루미늄 클로라이드, 티탄 테트라클로라이드 등과 같은 루이스 산, 포름산, 아세트산 등과 같은 유기산이 있다."Acids" include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid and the like, Lewis acids such as boron trifluoride, aluminum chloride, titanium tetrachloride and the like, organic acids such as formic acid, acetic acid and the like.

"산화금속"으로는, 예를 들어 산화 바나듐(V2O5), 사산화오스뮴(OsO4), 산화텅스텐(WO3), 이산화셀레늄(SeO2), 산화크롬(CrO3) 등이 있다.Examples of the "metal oxide" include vanadium oxide (V 2 O 5 ), osmium tetraoxide (OsO 4 ), tungsten oxide (WO 3 ), selenium dioxide (SeO 2 ), and chromium oxide (CrO 3 ). .

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 할로겐화 탄화수소, 지방족 탄화수소, 방향족 탄화수소, 유기산, 에테르, 아미드, 술폭시드, 알콜, 니트릴, 케톤 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, there are no particular restrictions on the solvent, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketones or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 -20 내지 약 130℃, 바람직하게는 약 0 내지 약 100℃ 이다. 반응 시간은 일반적으로 약 5 분 내지 약 72 시간, 바람직하게는 약 0.5 내지 약 12 시간이다.The reaction temperature is generally about -20 to about 130 ° C, preferably about 0 to about 100 ° C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 12 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

화합물 (I-c)는 상기에서 얻은 화합물 (XX)을 화합물 (VIII)과 상기 반응식 1의 4)단계와 동일한 방법으로 반응시킴으로써 제조된다. Compound (Ic) is prepared by reacting compound (XX) obtained above with compound (VIII) in the same manner as in step 4) of Scheme 1 above.

만일, 화합물 (I-c)에서 R2 가

Figure 112006042290445-pat00014
이며, 이때 X는 CH, C-OH, 또는 N이고, Y는 N-CO- C 1 ~ C 4 의 알콕시인 경우, If, the R2 in the compound (Ic)
Figure 112006042290445-pat00014
And, where X is a CH, C-OH, or N, Y is N-CO- C 1 ~ C 4 For alkoxy ,

화합물 (I-c)를 산 또는 염기를 사용하여 상기 반응식 1에서의 탈보호화 방법과 동일하게 하여 탈보호화 한다.Compound (I-c) is deprotected using an acid or base in the same manner as the deprotection method in Scheme 1 above.

또한, 탈보호화된 화합물 (I-c)를 상기 반응식 1에서의 메틸화 반응과 동일하게 하여 메틸화할 수 있다.In addition, the deprotected compound (I-c) can be methylated in the same manner as in the methylation reaction in Scheme 1 above.

하기 반응식 4로 표시되는 치환된 1,3-티아졸 유도체의 제조방법은,Method for producing a substituted 1,3-thiazole derivative represented by Scheme 4,

1) 화합물 (XVIII)을 티오우레아 화합물 (XXI)과 반응시켜 화합물 (XXII)를 얻는 단계;1) reacting compound (XVIII) with thiourea compound (XXI) to give compound (XXII);

2) 상기 1)단계에서 제조된 화합물 (XXII)를 할로겐화시켜 화합물 (XXIII)을 얻는 단계;2) halogenating compound (XXII) prepared in step 1) to obtain compound (XXIII);

3) 상기 2)단계에서 제조된 화합물 (XXIII)과 화합물 (XXIV)를 반응시켜 화합물 (XXV)를 얻는 단계;3) reacting compound (XXIII) prepared in step 2) with compound (XXIV) to obtain compound (XXV);

4) 상기 3)단계에서 제조된 화합물 (XXV)를 유기 과산화산으로 처리하여 화합물 (XXVI)을 얻는 단계; 및4) treating compound (XXV) prepared in step 3) with organic peroxide to obtain compound (XXVI); And

5) 상기 4)단계에서 제조된 화합물 (XXVI)을 아민 화합물 (VIII)과 반응시켜 치환된 1,3-티아졸 화합물 (XXVII)을 얻는 단계를 포함한다.5) reacting the compound (XXVI) prepared in step 4) with an amine compound (VIII) to obtain a substituted 1,3-thiazole compound (XXVII).

또는, 상기 4)단계에서 화합물 (XXV)를 산화반응시키기 전에 질소를 보호화한 다음, 산화반응을 진행시킬 수 있다.Alternatively, nitrogen may be protected before oxidation of the compound (XXV) in step 4), followed by oxidation.

Figure 112006042290445-pat00015
Figure 112006042290445-pat00015

(상기 반응식 4에서, R1, R4, 및 Y는 화학식 1에서 정의한 바와 같고, Hal는 할로겐 원자이며, PG는 보호기이다.)(In Reaction Scheme 4, R1, R4, and Y are as defined in Formula 1, Hal is a halogen atom, PG is a protecting group.)

화합물 ( XXII )는 상기 반응식 3의 3)단계와 동일한 방법으로 제조될 수 있다. Compound ( XXII ) may be prepared by the same method as 3) of Scheme 3 above.

화합물 ( XXIII )은 화합물 (XXII)를 tert-부틸나이트라이트와 금속 할라이드로 할로겐화함으로써 제조된다(샌드마이어 반응). 상기 할로겐화 반응은 일반적인 할로겐화 반응으로도 할로겐화 할 수 있다. Compound ( XXIII ) is prepared by halogenating compound (XXII) with tert-butylnitrite and a metal halide (Sandmeyer reaction). The halogenation reaction can also be halogenated by a general halogenation reaction.

화합물 (XXIII)에서, Hal은 불소, 염소, 브롬 및 요오드와 같은 할로겐 원자를 나타낸다.In compound (XXIII), Hal represents halogen atoms such as fluorine, chlorine, bromine and iodine.

사용되는 tert-부틸나이트라이트의 양은 화합물 (XXII) 1 몰에 대해 약 1 내지 약 8 몰, 바람직하게는 약 1 내지 약 2 몰이다.The amount of tert-butylnitrite used is about 1 to about 8 moles, preferably about 1 to about 2 moles, per 1 mole of compound (XXII).

사용되는 금속 할라이드의 양은 화합물 (XXII) 1 몰에 대해 약 1 내지 약 8 몰, 바람직하게는 약 1 내지 약 2 몰이다.The amount of metal halide used is about 1 to about 8 moles, preferably about 1 to about 2 moles, per 1 mole of compound (XXII).

"금속 할라이드"로는, 구리(II) 브로마이드, 구리(II) 클로라이드 등과 같은 구리 할라이드가 있다."Metal halides" include copper halides such as copper (II) bromide, copper (II) chloride and the like.

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 에테르, 에스테르, 방향족 탄화수소, 지방족 탄화수소, 아미드, 할로겐화 탄화수소, 니트릴, 술폭시드, 유기산, 방향족 아민 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but, for example, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromatic amines or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 -20 내지 약 150℃, 바람직하게는 약 0 내지 약 100℃ 이다. 반응 시간은 일반적으로 약 5분 내지 약 24시간, 바람직하게는 약 10 분 내지 약 5 시간이다.The reaction temperature is generally about -20 to about 150 ° C, preferably about 0 to about 100 ° C. The reaction time is generally about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

화합물 ( XXV )는 화합물 (XXIII) 및 화합물 (XXIV)을 반응시킴으로써 제조된다. 이 반응은, 필요한 경우, 염기의 존재 하에 수행된다. Compound ( XXV ) is prepared by reacting compound (XXIII) and compound (XXIV). This reaction is carried out in the presence of a base, if necessary.

화합물 (XXIV)는 시판되는 것인 경우 그대로 사용될 수 있으며, 또는 공지된 그 자체의 방법으로나 이와 유사한 방법에 따라 제조될 수 있다.Compound (XXIV) can be used as is, if it is commercially available, or can be prepared by known methods or by analogous methods.

사용되는 화합물 (XXIV)의 양은 화합물 (XXIII) 1 몰에 대해 약 0.8 내지 약 30 몰, 바람직하게는 약 1 내지 약 10 몰이다.The amount of compound (XXIV) used is about 0.8 to about 30 moles, preferably about 1 to about 10 moles, per 1 mole of compound (XXIII).

사용되는 염기의 양은 화합물 (XXIII) 1 몰에 대해 약 0.8 내지 약 30 몰, 바람직하게는 약 1 내지 약 10 몰이다.The amount of base used is about 0.8 to about 30 moles, preferably about 1 to about 10 moles, per 1 mole of compound (XXIII).

"염기"로는, 예를 들어, 탄산나트륨, 탄산칼륨, 탄산세슘 등과 같은 염기성 염, 수산화나트륨, 수산화칼륨 등과 같은 금속 수산화물, 피리딘, 루티딘 등과 같은 방향족 아민, 트리에틸아민, 트리프로필아민, 트리부틸아민, 시클로헥실디메틸아민, 4-디메틸아미노피리딘, N,N-디메틸아닐린, N-메틸피페리딘, N-메틸피롤리딘, N-메틸모르폴린 등과 같은 3차 아민, 나트륨 히드리드, 칼륨 히드리드 등과 같은 알칼리 금속 히드리드, 나트륨 아미드, 리튬 디이소프로필아미드, 리륨 헥사메틸디 실라지드 등과 같은 금속 아미드, 나트륨 메톡시드, 나트륨 에톡시드, 칼륨 tert-부톡시드 등과 같은 금속 알콕시드가 있다.“Bases” include, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and the like, metal hydroxides such as sodium hydroxide, potassium hydroxide and the like, aromatic amines such as pyridine, lutidine, and the like, triethylamine, tripropylamine, tributyl Tertiary amines such as amines, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, sodium hydride, potassium Alkali metal hydrides such as hydrides, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldi silazide and the like, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 지방족 탄화수소, 방향족 탄화수소, 에테르 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but for example, aliphatic hydrocarbons, aromatic hydrocarbons, mixtures of two or more thereof, and the like are used.

반응 온도는 일반적으로 약 -78 내지 약 200℃, 바람직하게는 약 실온 내지 약 170℃ 이다. 반응 시간은 일반적으로 약 5 분 내지 약 72 시간, 바람직하게는 약 0.5 내지 약 24 시간이다.The reaction temperature is generally about -78 to about 200 ° C, preferably about room temperature to about 170 ° C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 24 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

화합물 (Compound ( XXVXXV )에서)in

- 만일 Y가 -If Y CHCH 22 또는  or CHCHCHCH 33 인 경우, If is

화합물 (XXVI) 및 화합물 (XXVII)은, 각각 반응식 3의 4)단계 및 5)단계에 의하여 제조될 수 있다.Compound (XXVI) and compound (XXVII) can be prepared by the steps 4) and 5) of Scheme 3 , respectively.

- 만일 Y가 NH 인 경우,If Y is NH,

화합물 (XXV)의 NH를 보호화하여 화합물 (XXVIII)을 제조하고, 화합물 (XXIX), 화합물 (XXX)은 각각 반응식 3의 4)단계 및 5)단계에 의하여 제조될 수 있다.Compound (XXVIII) is prepared by protecting the NH of compound (XXV), and compound (XXIX) and compound (XXX) can be prepared by steps 4) and 5) of Scheme 3, respectively.

상기 화합물 (XXX)에서 보호기(PG)는 상기 반응식 1에서의 탈보호화 방법과 동일하게 하여 탈보호화 한다.In the compound (XXX), the protecting group (PG) is deprotected in the same manner as the deprotection method in Scheme 1 above.

또한, 탈보호화된 화합물을 상기 반응식 1에서의 메틸화 반응과 동일하게 하여 메틸화할 수 있다.In addition, the deprotected compound can be methylated in the same manner as in the methylation reaction in Scheme 1 above.

하기 반응식 5로 표시되는 치환된 1,3-티아졸 유도체의 제조방법은,Method for producing a substituted 1,3-thiazole derivative represented by Scheme 5,

1) 화합물 (XVIII)을 티오포름아미드 화합물 (XXXI)과 반응시켜 화합물 (XXXII)를 얻는 단계;1) reacting compound (XVIII) with a thioformamide compound (XXXI) to give compound (XXXII);

2) 상기 1)단계에서 제조된 화합물 (XXXII)를 유기 과산화산으로 처리하여 화합물 (XXXIII)을 얻는 단계;2) treating compound (XXXII) prepared in step 1) with organic peroxide to obtain compound (XXXIII);

3) 상기 2)단계에서 제조된 화합물 (XXXIII)과 아민 화합물 (VIII)을 반응시켜 화합물 (XXXIV)를 얻는 단계;3) reacting compound (XXXIII) prepared in step 2) with amine compound (VIII) to obtain compound (XXXIV);

4) 상기 3)단계에서 제조된 화합물 (XXXIV)를 염기로 처리하고, 화합물 (XXXV)와 반응시켜 화합물 (XXXVI)을 얻는 단계 ; 및4) treating compound (XXXIV) prepared in step 3) with a base and reacting with compound (XXXV) to obtain compound (XXXVI); And

5) 상기 4)단계에서 제조된 화합물 (XXXVI)을 탈보호화하여, 치환된 1,3-티아졸 화합물 (XXXVII)을 얻는 단계를 포함한다.5) deprotecting the compound (XXXVI) prepared in step 4) to obtain a substituted 1,3-thiazole compound (XXXVII).

Figure 112006042290445-pat00016
Figure 112006042290445-pat00016

(상기 반응식 5에서, R1, R4, 및 Y는 화학식 1에서 정의한 바와 같고, Hal는 할로겐 원자이다.)(In Scheme 5, R1, R4, and Y are as defined in Formula 1, and Hal is a halogen atom.)

화합물 ( XXXII ), 화합물 ( XXXIII ), 화합물 ( XXXIV )는 각각 반응식 3의 3), 4), 5)에 의하여 제조될 수 있다. Compound ( XXXII ), compound ( XXXIII ) and compound ( XXXIV ) can be prepared by 3), 4) and 5) of Scheme 3, respectively.

화합물 ( XXXVI )은, 화합물 (XXXV)에서 Y가 N-C1~C4 알킬인 경우, 화합물 (XXXIV)를 염기로 처리하고, 화합물 (XXXV)와 반응시킴으로써 제조된다. Compound ( XXXVI ) is prepared by treating compound (XXXIV) with a base and reacting with compound (XXXV) when Y in the compound (XXXV) is NC 1 -C 4 alkyl.

만일 화합물 (XXXV)에서 Y가 N-CO2t-Bu 인 경우, 상기 4)단계에 의해 제조된 화합물 (XXXVI)을 상기 반응식 1에서의 탈보호화 방법과 동일하게 탈보호화하여 화합물 (XXXVII)을 제조한다.If Y in compound (XXXV) is N-CO 2 t-Bu, compound (XXXVI) prepared by step 4) was deprotected in the same manner as in the deprotection method in Scheme 1 to obtain compound (XXXVII). Manufacture.

사용되는 염기의 양은 화합물 (XXXIV) 1 몰에 대해 약 0.8 내지 약 5 몰, 바람직하게는 약 1 내지 약 1.2 몰이다.The amount of base used is about 0.8 to about 5 moles, preferably about 1 to about 1.2 moles, per 1 mole of compound (XXXIV).

"염기"는, 예를 들어 n-부틸리튬 등과 같은 알킬리튬, 나트륨 아미드, 리튬 디이소프로필아미드, 리튬 헥사메틸디실라이드 등과 같은 금속 아미드가 사용된다."Base" includes, for example, metal amides such as alkyllithium, such as n-butyllithium, sodium amide, lithium diisopropylamide, lithium hexamethyldisilide and the like.

이 반응은 용매 없이, 또는 반응용 불활성 용매의 존재 하에서 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 지방족 탄화수소, 방향족 탄화 수소, 에테르 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 -78 내지 약 60℃, 바람직하게는 약 -78℃ 내지 약 상온이다. 반응 시간은 일반적으로 약 5분 내지 약 24시간, 바람직하게는 약 0.5 내지 약 3 시간이다.The reaction temperature is generally about -78 to about 60 ℃, preferably about -78 ℃ to about room temperature. The reaction time is generally about 5 minutes to about 24 hours, preferably about 0.5 to about 3 hours.

대안적으로, 반응식 3의 화합물 (XIX)의 다른 제조방법은 하기 반응식 6으로 표시되며,Alternatively, another method for preparing compound (XIX) of Scheme 3 is represented by Scheme 6 below.

1) 화합물 (XXXVIII)을 할로겐화시켜 화합물 (XXXIX)를 제조하는 단계,1) halogenating compound (XXXVIII) to produce compound (XXXIX),

2) 상기 1)단계에서 제조된 화합물 (XXXIX)를 티오아미드 화합물(VI)과 반응 시켜 화합물 (XXXX)을 제조하는 단계, 및2) preparing a compound (XXXX) by reacting the compound (XXXIX) prepared in step 1) with a thioamide compound (VI), and

3) 상기 2)단계에서 제조된 화합물 (XXXX)을 염기, ZnCl2로 처리하고, Pd(PPh3)4과 화합물 (XXXXI)로 반응시키는 단계를 포함한다.3) treating the compound (XXXX) prepared in step 2) with a base, ZnCl 2 , and reacting Pd (PPh 3 ) 4 with the compound (XXXXI).

화학식 1의 기본 골격은 네기쉬 타입 커플링 반응(Negishi type coupling reaction)으로 제조할 수 있다.The basic skeleton of Formula 1 may be prepared by a Negishi type coupling reaction.

Figure 112006042290445-pat00017
Figure 112006042290445-pat00017

(상기 반응식 6에서, R1, R2는 화학식 1에서 정의한 바와 같으며, Hal 및 Hal'는 할로겐 원자이다.)(In Scheme 6, R1, R2 are as defined in Formula 1, Hal and Hal 'is a halogen atom.)

화합물 ( XXXX )은 반응식 3의 2), 3)단계에 의하여 제조될 수 있다. Compound ( XXXX ) may be prepared by Steps 2) and 3 ) of Scheme 3.

화합물 ( XXXXI )은 문헌 [Tetrahedron, 45(3), 993, 1989]에 기술된 방법에 의해 제조할 수 있다. Compound ( XXXXI ) can be prepared by the method described in Tetrahedron, 45 (3), 993, 1989.

화합물 ( XIX )는 화합물 (XXXX)를 염기, ZnCl2를 처리하고, Pd(PPh3)4과 화합물 (XXXXI)으로 반응시킴으로써 제조된다. Compound ( XIX ) is prepared by treating compound (XXXX) with a base, ZnCl 2 , and reacting with Pd (PPh 3 ) 4 with compound (XXXXI).

사용되는 염기의 양은 화합물 (XXXX) 1 몰에 대해 약 0.8 내지 약 5 몰, 바람직하게는 약 1 내지 약 1.5 몰이다.The amount of base used is about 0.8 to about 5 moles, preferably about 1 to about 1.5 moles, per 1 mole of compound (XXXX).

사용되는 ZnCl2의 양은 화합물 (XXXX) 1 몰에 대해 약 0.8 내지 약 5 몰, 바람직하게는 약 1 내지 약 1.5 몰이다.The amount of ZnCl 2 used is about 0.8 to about 5 moles, preferably about 1 to about 1.5 moles, per 1 mole of compound (XXXX).

사용되는 Pd(PPh3)4의 양은 화합물 (XXXX) 1 몰에 대해 약 0.01 내지 약 1 몰, 바람직하게는 약 0.01 내지 약 0.1 몰이다.The amount of Pd (PPh 3 ) 4 used is about 0.01 to about 1 mole, preferably about 0.01 to about 0.1 mole per 1 mole of compound (XXXX).

사용되는 (XXXXI)의 양은 화합물 (XXXX) 1 몰에 대해 약 0.8 내지 약 5 몰, 바람직하게는 약 1 내지 약 1.5 몰이다.The amount of (XXXXI) used is about 0.8 to about 5 moles, preferably about 1 to about 1.5 moles, per 1 mole of compound (XXXX).

"염기"로는, 예를 들어 n-부틸리튬 등과 같은 알킬리튬, 나트륨 아미드, 리튬 디이소프로필아미드, 리튬 헥사메틸디실라이드 등과 같은 금속 아미드가 사용된다.As the "base", for example, metallithium amides such as alkyllithium such as n-butyllithium, sodium amide, lithium diisopropylamide, lithium hexamethyldisilide and the like are used.

이 반응은 용매 없이, 또는 반응용 불활성 용매의 존재 하에서 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 지방족 탄화수소, 방향족 탄화 수소, 에테르 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 -78 내지 약 200℃, 바람직하게는 약 -78 내지 약 100℃ 이다. 반응 시간은 일반적으로 약 5분 내지 약 24시간, 바람직하게는 약 0.5 내지 약 12 시간이다.The reaction temperature is generally about -78 to about 200 ° C, preferably about -78 to about 100 ° C. The reaction time is generally about 5 minutes to about 24 hours, preferably about 0.5 to about 12 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

티오아미드 화합물(Ⅵ)은 하기 반응식 7에 의해 제조된다.Thioamide compound (VI) is prepared by following Scheme 7.

Figure 112006042290445-pat00018
Figure 112006042290445-pat00018

(상기 반응식 7에서, R2는 화학식 1에서 정의한 바와 같다.)(In Scheme 7, R2 is as defined in Formula 1.)

티오아미드 화합물 (VI)은, 염기의 존재 하에 화합물 (XXXXII)를 황화수소 처리함으로써 제조될 수 있다. Thioamide compound (VI) can be prepared by hydrogen sulfide treatment of compound (XXXXII) in the presence of a base.

황화수소의 양은 화합물 (XXXXII) 1 몰에 대해 약 1 내지 약 30 몰이다.The amount of hydrogen sulfide is about 1 to about 30 moles per 1 mole of the compound (XXXXII).

사용되는 염기의 양은 화합물 (XXXXII) 1 몰에 대해 약 1 내지 약 30 몰, 바람직하게는 약 1 내지 약 10 몰이다.The amount of base used is about 1 to about 30 moles, preferably about 1 to about 10 moles, per 1 mole of compound (XXXXII).

"염기"로는, 예를 들어, 피리딘, 루티딘 등과 같은 방향족 아민, 트리에틸아민, 트리프로필아민, 트리부틸아민, 시클로헥실디메틸아민, 4-디메틸아미노피리딘, N,N-디메틸아닐린, N-메틸피페리딘, N-메틸피롤리딘, N-메틸모르폴린 등과 같은 3차 아민, 암모니아 등이 있다."Base" includes, for example, aromatic amines such as pyridine, lutidine, and the like, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N- Tertiary amines such as methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, ammonia and the like.

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 할로겐화 탄화수소, 지방족 탄화수소, 방향족 탄화수소, 에테르, 방향족 아민 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, aromatic amines or mixtures of two or more thereof are used.

이 반응은 대기압 또는 가압 조건에서 수행된다. 반응 온도는 일반적으로 약 -20 내지 약 80℃, 바람직하게는 약 -10 내지 약 30℃ 이다. 반응 시간은 일반적으로 약 5 분 내지 약 72 시간, 바람직하게는 약 0.5 내지 약 30 시간이다.This reaction is carried out at atmospheric or pressurized conditions. The reaction temperature is generally about -20 to about 80 ° C, preferably about -10 to about 30 ° C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 30 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

대안적으로, 화합물 (VI)은 산 존재 하에 화합물 (XXXXII)를 디에틸 디티오포스페이트를 처리함으로써 제조될 수 있다.Alternatively, compound (VI) can be prepared by treating compound (XXXXII) with diethyl dithiophosphate in the presence of an acid.

디에틸 디티오포스페이트의 양은 화합물 (XXXXII) 1 몰에 대해 약 1 내지 약 10 몰, 바람직하게는 약 1 내지 약 3 몰이다.The amount of diethyl dithiophosphate is about 1 to about 10 moles, preferably about 1 to about 3 moles, per 1 mole of compound (XXXXII).

사용되는 산의 양은 화합물 (XXXXII) 1 몰에 대해 약 1 내지 약 30 몰, 바 람직하게는 약 1 내지 약 8 몰이다.The amount of acid used is about 1 to about 30 moles, preferably about 1 to about 8 moles, per 1 mole of compound (XXXXII).

"산"으로는, 예를 들면 염산, 황산, 과염소산 등과 같은 무기산, 붕소 트리플루오라이드, 알루미늄 클로라이드, 티탄 테트라클로라이드 등과 같은 루이스 산, 포름산, 아세트산 등과 같은 유기산이 있다."Acids" include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid and the like, Lewis acids such as boron trifluoride, aluminum chloride, titanium tetrachloride and the like, organic acids such as formic acid, acetic acid and the like.

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 할로겐화 탄화수소, 지방족 탄화수소, 방향족 탄화수소, 유기산, 에테르, 알콜, 에스테르 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, alcohols, esters or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 -20 내지 약 100℃, 바람직하게는 약 0 내지 약 50℃ 이다. 반응 시간은 일반적으로 약 5 분 내지 약 72 시간, 바람직하게는 약 0.5 내지 약 24 시간이다.The reaction temperature is generally about -20 to about 100 ° C, preferably about 0 to about 50 ° C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 24 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

또한, 화합물 (VI)은, 염기의 존재 하에 화합물 (XXXXIII)을 오황화인 또는 라베쏜(Lawesson) 시약으로 처리함으로써 제조될 수 있다.In addition, compound (VI) can be prepared by treating compound (XXXXIII) with phosphorus pentasulfide or Lawesson reagent in the presence of a base.

사용되는 오황화인 또는 라베쏜 시약의 양은 화합물 (XXXXIII) 1 몰에 대해 약 1 내지 약 10 몰, 바람직하게는 약 0.5 내지 약 3 몰이다.The amount of phosphorus pentasulfide or lavethone reagent used is about 1 to about 10 moles, preferably about 0.5 to about 3 moles, per 1 mole of compound (XXXXIII).

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 할로겐화 탄화수소, 지방족 탄화수소, 방향족 탄화수소, 에테르 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, there are no particular restrictions on the solvent, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers or mixtures of two or more thereof are used.

반응 시간은 일반적으로 약 10 분 내지 약 50 시간, 바람직하게는 약 0.5 내지 약 12 시간이다. 반응 온도는 일반적으로 약 0 내지 약 150℃, 바람직하게는 약 상온 내지 약 120℃ 이다.The reaction time is generally about 10 minutes to about 50 hours, preferably about 0.5 to about 12 hours. The reaction temperature is generally about 0 to about 150 ° C, preferably about room temperature to about 120 ° C.

생성물 (VI)은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product (VI) can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography, and the like. Can be.

또한, 화합물 (I) (화합물 (1-a), (1-b) 및 (1-c) 포함)이 아실 아미노 화합물인 경우, 상응하는 아민 화합물을 공지된 그 자체의 아실화 반응에 적용시킴으로써 제조된다.Furthermore, when compound (I) (including compounds (1-a), (1-b) and (1-c)) is an acyl amino compound, by applying the corresponding amine compound to its own known acylation reaction Are manufactured.

예를 들어, 화합물 (I) 중에서 R2가 치환기를 임의로 갖는 아실아미노인 화합물은 상응하는 2-티아졸아민 화합물 및 아실화제를 임의의 염기 또는 산 존재 하에서 반응시킴으로써 제조된다.For example, in compound (I), a compound wherein R 2 is acylamino optionally having a substituent is prepared by reacting the corresponding 2-thiazoleamine compound and acylating agent in the presence of any base or acid.

사용되는 아실화제의 양은 상응하는 2-티아졸아민 1몰에 대해 약 1 내지 약 5 몰, 바람직하게는 약 1 내지 약 2 몰이다.The amount of acylating agent used is about 1 to about 5 moles, preferably about 1 to about 2 moles, relative to 1 mole of the corresponding 2-thiazolamine.

"아실화제"로는, 예를들어 목적 아실기에 상응하는 카복실산 또는 그의 반응성 유도체 (예컨대, 산 할라이드, 산 무수물, 에스테르 등) 등이 있다."Acylating agents" include, for example, carboxylic acids or reactive derivatives thereof (eg, acid halides, acid anhydrides, esters, etc.) corresponding to the desired acyl groups.

사용되는 염기 또는 산의 양은 상응하는 2-티아졸아민 1몰에 대해 약 0.8 내지 약 5 몰, 바람직하게는 약 1 내지 약 2 몰이다.The amount of base or acid used is about 0.8 to about 5 moles, preferably about 1 to about 2 moles, relative to 1 mole of the corresponding 2-thiazolamine.

"염기"로는, 예를 들어 트리에틸아민, 피리딘, 4-디메틸아미노피리딘 등이 있다."Base" includes, for example, triethylamine, pyridine, 4-dimethylaminopyridine and the like.

"산"으로는, 예를 들어 메탄술폰산, p-톨루엔술폰산, 캄포르술폰산 등이 있다.Examples of the "acid" include methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like.

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 할로겐화 탄화수소, 지방족 탄화수소, 방향족 탄화수소, 에테르, 아미드, 니트릴, 술폭시드, 방향족 아민 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, the solvent is not particularly limited, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, nitriles, sulfoxides, aromatic amines or mixtures of two or more thereof are used.

반응 온도는 약 -20 내지 약 150℃, 바람직하게는 약 0 내지 약 100℃ 이다. 반응 시간은 일반적으로 약 5 분 내지 약 24 시간, 바람직하게는 약 10분 내지 약 5 시간이다.The reaction temperature is about -20 to about 150 ° C, preferably about 0 to about 100 ° C. The reaction time is generally about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

또한, 화합물 (I) (화합물 (1-a), (1-b) 및 (1-c) 포함)이 설포닐 또는 설피닐 화합물인 경우, 상응하는 설파이드 화합물을 공지된 산화 반응에 적용시킴으로써 제조된다.In addition, when compound (I) (including compounds (1-a), (1-b) and (1-c)) is a sulfonyl or sulfinyl compound, it is prepared by applying the corresponding sulfide compound to a known oxidation reaction. do.

예를 들어, 화합물 (I) 중에서 R2가 치환기를 임의로 갖는 메탄설포닐페닐, 메탄설피닐페닐인 화합물은 상응하는 2-메틸설파닐페닐 티아졸 화합물을 유기 과산화산으로 처리함으로써 제조된다.For example, compounds in which R2 in the compound (I) is methanesulfonylphenyl, methanesulfinylphenyl optionally having substituents are prepared by treating the corresponding 2-methylsulfanylphenyl thiazole compound with organic peroxide acid.

사용될 유기 과산화산의 양은 2-메틸설파닐페닐 티아졸 화합물 1 몰에 대해 약 0.8 내지 약 10 몰, 바람직하게는 약 1 내지 약 3 몰이다.The amount of organic peroxide to be used is about 0.8 to about 10 moles, preferably about 1 to about 3 moles, per 1 mole of 2-methylsulfanylphenyl thiazole compound.

"유기 과산화산"으로는, 예를 들어 퍼아세트산, 트리플루오로퍼아세트산, m-클로로퍼벤조산 등이 있다.Examples of the "organic peroxide acid" include peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid and the like.

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 할로겐화 탄화수소, 지방족 탄화수소, 방향족 탄화수소, 유기산, 에테르, 아미드, 술폭시드, 알콜, 니트릴, 케톤 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, there are no particular restrictions on the solvent, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketones or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 -20 내지 약 130℃, 바람직하게는 약 0 내지 약 100℃ 이다. 반응 시간은 일반적으로 약 5 분 내지 약 72 시간, 바람직하게는 약 0.5 내지 약 12 시간이다.The reaction temperature is generally about -20 to about 130 ° C, preferably about 0 to about 100 ° C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 12 hours.

대안적으로는, 2-메틸설파닐페닐 티아졸 화합물을 임의로 염기, 산 또는 산화금속의 존재 하에 과산화수소 또는 알킬 히드로페록시드로 처리함으로써 제조된다.Alternatively, the 2-methylsulfanylphenyl thiazole compound is prepared by treating with hydrogen peroxide or alkyl hydroperoxide, optionally in the presence of a base, acid or metal oxide.

사용되는 과산화수소 또는 알킬 히드로페록시드로의 양은 2-메틸설파닐페닐 티아졸 화합물 1 몰에 대해 약 0.8 내지 약 10 몰, 바람직하게는 약 1 내지 약 3 몰이다.The amount of hydrogen peroxide or alkyl hydroperoxide used is from about 0.8 to about 10 moles, preferably from about 1 to about 3 moles, per 1 mole of 2-methylsulfanylphenyl thiazole compound.

"알킬 히드로페록시드"로는, 예를 들어 tert-부틸 히드로페록시드, 쿠멘 히드로페록시드 등이 있다."Alkyl hydroperoxide" includes, for example, tert-butyl hydroperoxide, cumene hydroperoxide and the like.

사용되는 염기, 산 또는 산화금속의 양은 2-메틸설파닐페닐 티아졸 화합물 1 몰에 대해 약 0.1 내지 약 30 몰, 바람직하게는 약 0.8 내지 약 5 몰이다.The amount of base, acid or metal oxide used is about 0.1 to about 30 moles, preferably about 0.8 to about 5 moles, per 1 mole of 2-methylsulfanylphenyl thiazole compound.

"염기"로는, 예를 들어 수산화나트륨, 수산화칼륨 등과 같은 금속 수산화물, 탄산나트륨, 탄산칼륨, 아세트산나트륨 등과 같은 염기성 염이 있다."Bases" include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and the like.

"산"으로는, 예를 들면 염산, 황산, 과염소산 등과 같은 무기산, 붕소 트리플루오라이드, 알루미늄 클로라이드, 티탄 테트라클로라이드 등과 같은 루이스 산, 포름산, 아세트산 등과 같은 유기산이 있다."Acids" include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid and the like, Lewis acids such as boron trifluoride, aluminum chloride, titanium tetrachloride and the like, organic acids such as formic acid, acetic acid and the like.

"산화금속"으로는, 예를 들어 산화 바나듐(V2O5), 사산화오스뮴(OsO4), 산화텅스텐(WO3), 이산화셀레늄(SeO2), 산화크롬(CrO3) 등이 있다.Examples of the "metal oxide" include vanadium oxide (V 2 O 5 ), osmium tetraoxide (OsO 4 ), tungsten oxide (WO 3 ), selenium dioxide (SeO 2 ), and chromium oxide (CrO 3 ). .

이 반응은 용매없이, 또는 반응용 불활성 용매의 존재 하에 수행되는 것이 유익하다. 반응이 진행되는 한, 용매에 특별한 제한은 없지만, 예를 들어 할로겐화 탄화수소, 지방족 탄화수소, 방향족 탄화수소, 유기산, 에테르, 아미드, 술폭시드, 알콜, 니트릴, 케톤 또는 이들 둘 이상의 혼합물 등이 사용된다.This reaction is advantageously carried out without solvent or in the presence of an inert solvent for the reaction. As long as the reaction proceeds, there are no particular restrictions on the solvent, but, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketones or mixtures of two or more thereof are used.

반응 온도는 일반적으로 약 -20 내지 약 130℃, 바람직하게는 약 0 내지 약 100℃ 이다. 반응 시간은 일반적으로 약 5 분 내지 약 72 시간, 바람직하게는 약 0.5 내지 약 12 시간이다.The reaction temperature is generally about -20 to about 130 ° C, preferably about 0 to about 100 ° C. The reaction time is generally about 5 minutes to about 72 hours, preferably about 0.5 to about 12 hours.

생성물은 반응 용액 그 자체로 또는 조 생성물로 다음 반응에 사용될 수 있지만, 통상적인 방법에 따라 반응 혼합물에서 단리할 수 있으며, 재결정, 증류, 크로마토그래피 등과 같은 분리 수단에 의해 용이하게 정제될 수 있다.The product can be used for the next reaction either by itself or as a crude product, but can be isolated from the reaction mixture according to conventional methods and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

상기 각각의 반응에서, 출발 물질이 치환기로서 아미노, 카복시, 히드록시를 갖는 경우, 펩티드 화학 등에서 통상 사용되는 보호기를 이들 기에 도입할 수 있으며, 반응 후, 필요한 경우 보호기를 제거함으로써 목적 화합물을 제조할 수 있다.In each of the above reactions, when the starting material has amino, carboxy, hydroxy as substituents, protecting groups commonly used in peptide chemistry and the like can be introduced into these groups, and after the reaction, the protecting compound can be prepared if necessary to remove the protecting compound Can be.

아미노에 대한 보호기로서, 예를 들어 포르밀, 또는 각각 치환기를 가질 수 있는 C1 ∼6 알킬-카보닐(예컨대, 아세틸, 프로피오닐 등), 페닐카보닐, C1 ∼6 알콕시-카보닐(예컨대, 메톡시카보닐, 에톡시카보닐 등), 페닐옥시카보닐, C7 ∼10 아르알킬옥시-카보닐(예컨대, 벤질옥시카보닐 등), 트리틸, 프탈로일 등이 사용된다. 이들 치환기로서, 할로겐 원자(예컨대, 불소, 염소, 브롬, 요오드 등), C1 ∼6 알킬-카보닐(예컨대, 아세틸, 프로피오닐, 발레릴 등), 니트로 등이 사용되며, 치환기의 수는 1 내지 3 이다.As a protecting group for amino, for example, formyl, or C 1 to 6 optionally having a substituent alkyl-carbonyl (e.g., acetyl, propionyl etc.), phenylcarbonyl, C 1 to 6 alkoxy-carbonyl ( for example, methoxycarbonyl, ethoxycarbonyl, etc.), phenyl-oxy-carbonyl, C 7 ~10 aralkyloxy-carbonyl, etc. (e.g., benzyloxycarbonyl etc.), trityl, phthaloyl, is used. As these substituents, halogen atoms (e.g., fluorine, chlorine, bromine and iodine), C 1 ~6 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl etc.), nitro, etc. are used, the number of substituents 1 to 3.

카복시에 대한 보호기로서, 예를 들어 각각 치환기를 가질 수 있는 C1 ∼6 알킬(예컨대, 메틸, 에틸, 프로필, 이소프로필, 부틸, tert-부틸 등), 페닐, 트리틸, 실릴 등이 사용된다. 이들 치환기로서, 할로겐 원자(예컨대, 불소, 염소, 브롬, 요오드 등), 포르밀, C1 ∼6 알킬-카보닐(예컨대, 아세틸, 프로피오닐, 부틸카보닐 등), 니트로 C1 ∼6 알킬(예컨대, 메틸, 에틸, tert-부틸 등), C6 ∼10 아릴(예컨대, 페닐, 나프틸 등) 등이 사용되며, 치환기의 수는 1 내지 3 이다.Is a protecting group, for example C 1 ~6 alkyl or the like (for example, methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, etc.), phenyl, trityl, silyl each of which may have a substituent is used for the carboxymethylcellulose . As these substituents, halogen atoms (e.g., fluorine, chlorine, bromine and iodine), formyl, C 1 ~6 alkyl-carbonyl (e.g., acetyl, propionyl, butyl carbonyl, etc.), nitro, C 1 alkyl ~6 (e. g., methyl, ethyl, tert- butyl), C 6 ~10 aryl (e.g., phenyl, naphthyl) and the like are used, the number of the substituent is 1 to 3.

히드록시에 대한 보호기로서, 예를 들어 각각 치환기를 가질 수 있는 C1 ∼6 알킬(예컨대, 메틸, 에틸, 프로필, 이소프로필, 부틸, tert-부틸 등), 페닐, C7 ∼11 아르알킬(예컨대, 벤질 등), 포르밀, C1 ∼6 알킬 - 카보닐(예컨대, 아세틸, 프로피오닐 등), 페닐옥시카보닐, C7 ∼11 아르알킬(예컨대, 벤질 등), C7 ∼11 아르알킬옥시-카보닐(예컨대, 벤질옥시카보닐 등), 테트라히드로피라닐, 테트라히드로푸라닐, 실릴 등이 사용된다. 이들 치환기로서 할로겐 원자(예컨대, 불소, 염소, 브롬, 요오드 등), C1 ∼6 알킬(예컨대, 메틸, 에틸, tert-부틸 등), C7 ∼11 아르알킬(예컨대, 벤질 등), C6 ∼10 아릴(예컨대, 페닐, 나프틸 등), 니트로 등이 사용되며, 치환기의 수는 1 내지 4이다.As a protecting group for hydroxy, for example C 1 ~6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, etc.), phenyl, C 7 ~11 aralkyl each of which may have a substituent ( e.g., benzyl etc.), formyl, C 1 ~6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), phenyl-oxy-carbonyl, C 7 ~11 aralkyl (e.g., benzyl etc.), C 7 ~11 ahreu Alkyloxy-carbonyl (eg benzyloxycarbonyl and the like), tetrahydropyranyl, tetrahydrofuranyl, silyl and the like are used. A halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.) as the substituents, C 1 ~6 alkyl (e.g., methyl, ethyl, tert- butyl), (such as for example, benzyl), C 7 ~11 aralkyl, C 6-10 aryl (e.g., phenyl, naphthyl), a nitro is used, the number of the substituents is 1 to 4.

또한, 보호기 제거 방법으로서, 공지된 그 자체의 방법 또는 이 방법에 따른 방법이 사용되며, 예를 들어 산, 염기, 자외선, 히드라진, 페닐히드라진, 나트륨 N-메틸디티오카바메이트, 테트라부틸암모늄 플루오라이드, 팔라듐 아세테이트 등으로 처리하는 방법 또는 환원하는 방법이 사용된다.In addition, as the protecting group removal method, a known method or a method according to this method is used, for example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoro Processes or methods of reduction with ride, palladium acetate and the like are used.

어떤 경우에서든, 화합물 (I)은 추가로, 임의로는, 공지된 탈보호, 아실화, 알킬화, 수소화, 산화, 환원, 탄소 사슬 확장 및 치환기 교환 반응을 단독으로 또 는 이들 둘 이상의 조합으로 수행함으로써 합성될 수 있다. 이들 반응으로서, 문헌[Shinjikkenkagakukoza 14, 15권, 1997 (Maruzen Press)]에 기술된 반응이 사용된다.In any case, compound (I) is further optionally optionally by carrying out known deprotection, acylation, alkylation, hydrogenation, oxidation, reduction, carbon chain expansion and substituent exchange reactions alone or in combination of two or more thereof. Can be synthesized. As these reactions, the reaction described in Shinjikkenkagakukoza 14, 15, 1997 (Maruzen Press) is used.

상기 반응에 의해 목적 생성물이 유리 형태로 제조되는 경우, 통상적인 방법에 따라 염으로 전환시킬 수 있으며, 또는 목적 생성물이 염으로 제조되는 경우, 통상적인 방법에 따라 유리 형태 또는 다른 염으로 전환시킬 수 있다. 그렇게 제조된 화합물 (I)은 공지된 수단, 예컨대 농축, 용매 추출, 분별 증류, 결정화, 재결정, 크로마토그래피 등에 의해 반응 용액으로부터 단리 및 정제될 수 있다.When the desired product is prepared in free form by the above reaction, it can be converted into a salt according to a conventional method, or when the desired product is prepared into a salt, it can be converted into a free form or another salt according to a conventional method. have. Compound (I) so prepared can be isolated and purified from the reaction solution by known means such as concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography and the like.

화합물 (I)이 배위 이성질체, 부분입체이성질체, 이형태체 등으로 존재하는 경우, 각각은 상기 분리 및 정제 수단에 의해 선택적으로 단리될 수 있다. 또한, 화합물 (I)이 그의 라세미체의 형태인 경우, 이들은 임의의 통상적인 광학 분할에 의해 S- 또는 R- 형태로 분리될 수 있다.When compound (I) is present in coordination isomers, diastereomers, isoforms and the like, each may be selectively isolated by the above separation and purification means. In addition, when compound (I) is in the form of its racemates, they may be separated into S- or R- form by any conventional optical cleavage.

화합물 (I)이 입체이성질체로 존재하는 경우, 두 이성질체 단독 및 각 이성질체의 혼합물이 본 발명의 범주에 포함된다.When compound (I) is present as stereoisomer, both isomers alone and mixtures of each isomer are included within the scope of the present invention.

또한, 화합물 (I)은 수화 또는 무수화될 수 있다.In addition, compound (I) may be hydrated or anhydrous.

화합물 (I)은 동위원소(예컨대, 3H, 14C, 35S) 등으로 표지될 수 있다.Compound (I) may be labeled with isotopes (eg, 3 H, 14 C, 35 S) and the like.

화합물 (I)의 프로드럭은 생리조건 하에서 효소, 위산 등에 의해 화합물 (I)로 전환되는 화합물, 즉, 효소적 산화, 환원, 가수분해 등으로 화합물 (I)로 전환되는 화합물, 및 위산 등에 의한 가수분해 등으로 화합물 (I)로 전환되는 화합물을 칭한다. 화합물 (I)의 프로드럭으로서, 화합물 (I)의 아미노기를 아실화, 알킬화 또는 인산화한 화합물 (예컨대, 화합물 (I)의 아미노기를 에이코사노일화, 알라닐화, 펜틸아미노카보닐화, (5-메틸-2-옥소-1,3-디옥솔렌-4-일)메톡시카보닐화, 테트라히드로퓨라닐화, 피롤리디닐메틸화, 피발로일옥시메틸화, tert-부틸화한 화합물); 화합물 (I)의 히드록시기를 아실화, 알킬화, 인산화 또는 붕산화한 화합물(예컨대, 화합물 (I)의 하드록시기를 아세틸화, 팔미토일화, 프로파노일화, 피발로일화, 숙시닐화, 푸마릴화, 알라닐화, 디메틸아미노메틸카보닐화한 화합물); 화합물 (I)의 카복시기를 에스테르화 또는 아미드화한 화합물(예컨대, 화합물 (I)의 카복시기를 에틸에스테르화, 페닐에스테르화, 카르복시메틸에스트로화, 디메틸아미노메틸에스테르화, 피발로일옥시메틸에스테르화, 에톡시카보닐옥시에틸에스테르화, 프탈리딜에스테르화, (5-메틸-2-옥소-1,3-디옥솔-4-일)메틸에스테르화, 시클로헥실옥시카보닐에틸에스테르화, 메틸아미드화한 화합물); 등이 있다. 이들 화합물은 공지된 그 자체의 방법에 의해 화합물 (I)로부터 제조될 수 있다.The prodrug of compound (I) is a compound which is converted to compound (I) by enzymes, gastric acid, etc. under physiological conditions, that is, a compound which is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, etc., and gastric acid. The compound converted into compound (I) by hydrolysis etc. is called. As a prodrug of compound (I), a compound in which the amino group of compound (I) is acylated, alkylated or phosphorylated (e.g., the amino group of compound (I) is eicosanylated, alanylated, pentylaminocarbonylated, (5-methyl -2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidinylmethylated, pivaloyloxymethylated, tert-butylated compounds); Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or borated (e.g., the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, Alanylated, dimethylaminomethylcarbonylated compounds); A compound in which the carboxy group of compound (I) is esterified or amidated (e.g., the carboxy group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl estradiol, dimethylaminomethyl esterified, pivaloyloxymethyl ester Ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, Methylated compounds); Etc. These compounds can be prepared from compound (I) by known methods of their own.

대안적으로, 화합물 (I)의 프로드럭은 문헌 [Iyakuhin no kaihatsu, Hirokawashoten 출판, 1990, 7권, Melecular Design, 163∼198 쪽]에 기술되어 있는 생리조건 하에서 화합물 (I)로 변화하는 화합물일 수 있다.Alternatively, the prodrug of compound (I) may be a compound that changes to compound (I) under physiological conditions as described in Iyakuhin no kaihatsu, published by Hirokawashoten, 1990, Vol. 7, Melecular Design, pp. 163-198. Can be.

또한, 본 발명은 상기 화학식 1의 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 TNF-α 관련 질환의 예방 및 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing and treating TNF-α-related diseases, including the substituted 1,3-thiazole derivative of Formula 1 or a pharmaceutically acceptable salt thereof.

본 발명의 화합물은 인체 유방암 세포주인 MDA-MB-231, 인체 폐암 세포주인 A549, 인체 신장암 세포주인 ACHN, 인체 위장암 세포주인 SUN216, 및 인체 간암 세포주인 SUN709에서, 3 μM의 농도에서는 매우 약한 독성을, 10 μM의 농도에서는 독성을 나타내며, 마우스 대식세포 유래 암세포주인 RAW264.7 세포에 대해서는 거의 세포독성을 나타내지 않는다.The compound of the present invention is very weak at a concentration of 3 μM in human breast cancer cell line MDA-MB-231, human lung cancer cell line A549, human kidney cancer cell line ACHN, human gastric cancer cell line SUN216, and human liver cancer cell line SUN709. Toxicity is toxic at a concentration of 10 μM and little cytotoxicity to RAW264.7 cells, a mouse macrophage-derived cancer cell line.

또한, 본 발명의 화합물은 인체 대식세포 유래 암세포주인 THP-1 세포, 마우스 대식세포 유래 암세포주인 RAW264.7, 마우스 골수세포 유래 대식세포, 및 생체 내에서 대식세포의 TNF-α 생성을 강력히 억제한다.In addition, the compounds of the present invention strongly inhibit TNF-α production of human macrophage-derived cancer cell line THP-1 cells, mouse macrophage-derived cancer cell line RAW264.7, mouse myeloid cell-derived macrophages, and macrophages in vivo .

또한, 본 발명의 화합물은 생체내 염증반응을 억제한다.In addition, the compounds of the present invention inhibit inflammatory responses in vivo.

따라서, 본 발명의 화합물은 TNF-α 억제 활성 및 염증 억제 활성이 우수함으로, 이들 활성을 기초로 한 안전한 약물로서 유용하게 사용할 수 있다.Therefore, the compound of the present invention is excellent in TNF-α inhibitory activity and inflammatory inhibitory activity, and thus can be usefully used as a safe drug based on these activities.

예를 들어, 화합물 (I)을 함유한 본 발명의 약학적 조성물은 TNF-α 관련 질환, 예를 들어 관절염(예컨대, 류마티스 관절염, 골관절염, 류마티스 척추염, 통풍 성 관절염, 활막염), 독혈증(예컨대, 패혈증, 패혈성 쇼크, 내독소 쇼크, 그람 음성 패혈증, 독소 쇼크 증후군), 염증성 장 질환(예컨대, 크론씨병, 궤양성 대장염), 염증성 폐 질환(예컨대, 만성 폐렴, 규폐증, 폐형 사르코이드증, 폐결핵), 또는 악액질(예컨대, 감염으로 인한 악액질, 암성 악액질, 후천성면역결핍증(AIDS)으로 인한 악액질), 암(혈액암, 유방암, 폐암, 신장암, 위장암, 간암), 다발성 골수종, 심혈관계 질환(동맥경화증, 고지혈증, 고혈압), 관상동맥 심장병(협심증, 심근경색), 만성폐색성 폐질환(성인 호흡 곤란 증후군(ARDS)), 크로이츠펠트 - 야콥 병, 바이러스 감염(예컨대, 시토메칼로 바이러스, 인플루엔자 바이러스, 헤르페스 바이러스 등과 같은 바이러스 감염), 자가면역질환(베체트병, 전신성 홍반성 루푸스, 류마티스 관절염), 아토피 피부염, 건선, 중풍, 치매, 뇌졸중, AIDS 뇌병증, 수막염, 울혈성 심부전, 간염, 이식, 투석 저혈압, 파종성 혈관내응고 등의 예방제 또는 치료제로서 포유동물(예컨대, 마우스, 래트, 햄스터, 토끼, 고양이, 개, 소, 양, 원숭이, 인간 등)에게 사용될 수 있다.For example, a pharmaceutical composition of the present invention containing Compound (I) may be used for TNF-α related diseases such as arthritis (eg, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, synovitis), toxins (eg, Sepsis, septic shock, endotoxin shock, gram negative sepsis, toxin shock syndrome), inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis), inflammatory lung disease (e.g. chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis) , Or cachexia (e.g. cachexia due to infection, cancer cachexia, cachexia due to AIDS), cancer (blood cancer, breast cancer, lung cancer, kidney cancer, gastrointestinal cancer, liver cancer), multiple myeloma, cardiovascular disease ( Arteriosclerosis, hyperlipidemia, hypertension), coronary heart disease (angina, myocardial infarction), chronic obstructive pulmonary disease (adult respiratory distress syndrome (ARDS)), Creutzfeldt-Jakob disease, viral infections (e.g., cytomegalovirus) Viral infections such as murine, influenza virus, and herpes virus), autoimmune diseases (Behcet's disease, systemic lupus erythematosus, rheumatoid arthritis), atopic dermatitis, psoriasis, stroke, dementia, stroke, AIDS encephalopathy, meningitis, congestive heart failure, hepatitis It can be used in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans, etc.) as a prophylactic or therapeutic agent, such as transplantation, dialysis hypotension, disseminated vascular coagulation.

화합물 (I)을 함유한 본 발명의 제제는 독성이 낮고, 약학적 제제의 제조에 통상 사용되는 공지된 그 자체의 방법에 따라, 그대로 또는 제약학적으로 허용가능한 담체와 화합물 (I)을 혼합하여, 예를 들어 제약학적 제제, 예컨대 정제(당의정, 필름 코팅정 등 포함), 산제, 과립제, 캡슐제(소프트 (soft) 캡슐제 포함), 용액제, 주사제, 좌제, 서방제 등으로 경구 또는 비경구적으로(예컨대, 국소, 직장 또는 정맥내적으로 등) 안전하게 투여될 수 있다. 본 발명의 제제 중에서 화합물 (I)의 함량은 전체 제제에 대해 약 0.01 내지 100 중량% 이다.Formulations of the present invention containing compound (I) are of low toxicity and can be mixed as is or with a pharmaceutically acceptable carrier and compound (I) according to known per se methods commonly used in the preparation of pharmaceutical preparations. Oral or parenteral, for example, in pharmaceutical preparations such as tablets (including dragees, film coated tablets, etc.), powders, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained releases, and the like. It can be safely administered in a globular manner (eg, topically, rectally or intravenously, etc.). The content of compound (I) in the formulations of the present invention is about 0.01 to 100% by weight relative to the total formulation.

본 발명의 제제를 제조하는데 사용될 수 있는 약학적으로 허용가능한 담체로서, 약학적 물질로 통상적인 각종 유기 또는 무체 담체, 예를 들어, 고형제제에서는 부형제, 윤활제, 결합제 및 붕해제, 액체제제에서는 용매, 가용화제, 현탁화제, 등장화제, 완충제 및 무통화제(soothing agent)가 있다. 또한, 필요한 경우, 통상적인 보존제, 산화방지제, 착색제, 감미제, 흡착제, 습윤제 등과 같은 첨가제가 적절량으로 적절하게 사용될 수 있다.Pharmaceutically acceptable carriers which may be used in the preparation of the preparations of the invention, various organic or intangible carriers customary as pharmaceutical substances, for example excipients, lubricants, binders and disintegrants in solid formulations, solvents in liquid formulations Solubilizers, suspending agents, isotonic agents, buffers and soothing agents. In addition, if necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like may be appropriately used in appropriate amounts.

부형제로는, 예를 들어 락토오스, 수크로오스, D-만니톨, 전분, 옥수수 전분, 결정성 셀롤로스, 경질 규산 무수물 등이 있다.Excipients include, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, hard silicic anhydride and the like.

윤활제로는, 예를 들어 스테아르산마그네슘, 스테아르산칼슘, 탈크, 콜로이성 실리카 등이 있다.Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.

결합제로는, 예를 들어 결정성 셀롤로스, 수크로오스, D-만니톨, 덱스트린, 히드록시프로필 셀룰로스, 히드록시프로필메틸 셀룰로스, 폴리비닐피롤리돈, 전분, 수크로오스, 젤라틴, 메틸 셀룰로스, 나트륨 카르복시메틸 전분, L-히드록시프로필 셀룰로스 등이 있다.As the binder, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl starch , L-hydroxypropyl cellulose and the like.

용매로는, 예를 들어 주사용 물, 알콜, 프로필렌 글리콜, 마크로골, 참깨유, 옥수수유, 올리브유 등이 있다.Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.

가용화제로는, 예를 들어 폴리에틸렌 글리콜, 프로필렌 글리콜, D-만니톨, 벤질 벤조에이트, 에톤올, 트리스아미노메탄, 콜레스테롤, 트리에탄올아민, 탄산나트륨, 시트르산나트륨 등이 있다.Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like.

현탁화제로는, 예를 들어 스테아릴 트리에탄올아민, 나트륨 라우릴 술페이트, 라우릴 아미노프로피오네이트, 레시틴, 벤즈알코늄 클로라이드, 벤즈에토늄 클로라이드, 글리세릴 모노스테아레이트 등과 같은 계면 활성제; 폴리비닐 알콜, 폴리비닐피롤리돈, 나트륨 카르복시메틸 셀룰로스, 메틸 셀룰로스, 히드록시메틸 셀룰로스, 히드록시에틸 셀룰로스, 히드록시프로필 셀룰로스 등과 같은 친수성 고분자가 있다.Suspending agents include, for example, surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate and the like; Hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like.

등장화제로는, 예를 들어 글루코스, D-소르비톨, 염화나트륨, 글리세린, D-만니톨 등이 있다.Isotonic agents include, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.

완충제로는, 예를 들어 포스페이트, 아세테이트, 카보네이트, 시트레이트 등과 같은 완충액이 있다.Buffers include, for example, buffers such as phosphate, acetate, carbonate, citrate and the like.

무통화제로는, 예를 들어 벤질 알콜 등이 있다.Examples of non-solvent agents include benzyl alcohol and the like.

보존제로는, 예를 들어 p-히드록시벤조에이트, 클로로부탄올, 벤질 알콜, 페네틸 알콜, 데히드로아세트산, 소르브산 등이 있다.Preservatives include, for example, p-hydroxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

산화방지제로는, 예를 들어 술파이트, 아스코르브산, α-토코페롤 등이 있다.Examples of the antioxidant include sulfite, ascorbic acid and α-tocopherol.

이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예 및 실험예를 제시하였다. 그러나 하기의 실시예 및 실험예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 이에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples and experimental examples are presented to help understand the present invention. However, the following Examples and Experimental Examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited thereto.

하기 제조예 및 실시예에서의 "실온"은 통상 약 10 내지 약 35℃를 가리킨 다. "%"는 지적이 없으면 중량%를 가리키는 것이며, 단 수율은 몰/몰%를 나타낸다."Room temperature" in the following Preparation Examples and Examples generally refers to about 10 to about 35 ° C. "%" Refers to weight percent unless otherwise indicated, with the yield indicating mole / mol%.

그밖에 사용된 약칭은 하기의 의미를 가리킨다:Other abbreviations used have the following meanings:

s : 단일선(singlet),s: singlet,

d : 이중선(doublet),d: doublet,

t : 삼중선(triplet),t: triplet,

q : 사중선(quartet),q: quartet,

dd : 이중 이중선(double doublet),dd: double doublet,

ddd : 이중 이중 이중선(double double doublet),ddd: double double doublet,

dt : 이중 삼중선(double triplet),dt: double triplet,

br : 광범위(broad),br: broad,

J : 커플링 상수,J: coupling constant,

Hz : 헤르쯔(Hertz),Hz: Hertz,

CDCl3 : 중수소화 클로로포름,CDCl 3 : Deuterated chloroform,

DMSO-d6 : 중수소화 메틸설폭사이드,DMSO-d 6 Deuterated methyl sulfoxide,

1H-NMR : 양성자 핵자기공명 스펙트럼, 1 H-NMR: proton nuclear magnetic resonance spectrum,

Me : 메틸,Me is methyl,

Et : 에틸,Et: ethyl,

t-Bu : t-부틸.t-Bu: t-butyl.

제조예Production Example 1 One : N- N- 에톡시카보닐피페리딘Ethoxycarbonylpiperidine -4--4- 티오아미드의Thioamide 제조 Produce

Figure 112006042290445-pat00019
Figure 112006042290445-pat00019

톨루엔(600 ㎖) 내 N-에톡시카보닐피페리딘-4-카복시아미드(12.5 g, 62.5 mmol)의 용액에 라베쏜 시약(Lawesson's reagent; 12.6g, 31.2 mmol)을 첨가하고, 혼합물을 실온에서 18시간 동안 교반하였다. 반응 혼합물을 농축하고, 잔류물을 실리카겔 컬럼 크로마토그래피(아세톤:시클로헥산 = 1:4)로 정제하여 표제 화합물(12.1 g, 55.9 mmol, 수율 89%)을 얻었다.To a solution of N-ethoxycarbonylpiperidine-4-carboxyamide (12.5 g, 62.5 mmol) in toluene (600 mL) was added Lawesson's reagent (12.6 g, 31.2 mmol) and the mixture was allowed to come to room temperature. Stir for 18 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (acetone: cyclohexane = 1: 4) to give the title compound (12.1 g, 55.9 mmol, 89% yield).

1H-NMR (CDCl3) δ : 1.27 (t, 3H), 1.72-1.83 (dq, 2H), 1.93 (d, 2H), 2.68-2.88 (m, 3H), 4.14 (q, 2H), 4.28 (br s, 2H), 6.97 (br s, 1H), 7.56 (br s, 1H) 1 H-NMR (CDCl 3 ) δ: 1.27 (t, 3H), 1.72-1.83 (dq, 2H), 1.93 (d, 2H), 2.68-2.88 (m, 3H), 4.14 (q, 2H), 4.28 (br s, 2H), 6.97 (br s, 1H), 7.56 (br s, 1H)

제조예Production Example 2 2 : N- N- terttert -- 부톡시카보닐피페리딘Butoxycarbonylpiperidine -4--4- 티오아미드Thioamide

Figure 112006042290445-pat00020
Figure 112006042290445-pat00020

제조예 1과 같은 방법으로, N-에톡시카보닐피페리딘-4-카복시아미드 대신에 N-tert-부톡시카보닐피페리딘-4-카복시아미드를 사용하여 제조예 화합물 2를 얻었다.In the same manner as in Production Example 1, Production Example Compound 2 was obtained using N-tert-butoxycarbonylpiperidine-4-carboxyamide instead of N-ethoxycarbonylpiperidine-4-carboxyamide.

1H-NMR (CDCl3) δ : 1.47 (s, 9H), 1.66-1.80 (m, 2H), 1.91 (br d, 2H), 2.66-2.80 (m, 3H), 4.23 (br d, 2H), 6.98 (br s, 1H), 7.55 (br s, 1H) 1 H-NMR (CDCl 3 ) δ: 1.47 (s, 9H), 1.66-1.80 (m, 2H), 1.91 (br d, 2H), 2.66-2.80 (m, 3H), 4.23 (br d, 2H) , 6.98 (br s, 1H), 7.55 (br s, 1H)

제조예Production Example 3 3 : 4-( : 4-( 메틸티오Methylthio )) 티오벤즈아미드Thiobenzamide

Figure 112006042290445-pat00021
Figure 112006042290445-pat00021

4-(메틸티오)벤조니트릴(12 g, 80.0 mmol)을 에틸 아세테이트 내 염화수소의 4 N 용액(130 ㎖)에 용해시켰다. 상기 용액에 O,O-디에틸 디티오포스페이트(18.2 g, 88.0 mmol)를 첨가하고, 혼합물을 실온에서 22시간 동안 교반하였다. 물(100 ㎖)을 반응 혼합물에 첨가하고, 에틸 아세테이트로 추출하였다. 불용성 물질을 여과제거한 후, 여과물을 염화나트륨의 포화 수용액으로 세척하고 건조한 다음 용매를 증류하였다. 잔류물을 에틸 아세테이트로부터 재결정시켜 표제 화합물(10 g, 54.5 mmol, 수율 68%)을 얻었다.4- (methylthio) benzonitrile (12 g, 80.0 mmol) was dissolved in a 4 N solution (130 mL) of hydrogen chloride in ethyl acetate. To the solution was added O, O-diethyl dithiophosphate (18.2 g, 88.0 mmol) and the mixture was stirred at rt for 22 h. Water (100 mL) was added to the reaction mixture and extracted with ethyl acetate. After the insoluble matter was filtered off, the filtrate was washed with a saturated aqueous solution of sodium chloride, dried and the solvent was distilled off. The residue was recrystallized from ethyl acetate to give the title compound (10 g, 54.5 mmol, 68% yield).

1H-NMR (DMSO-d3) δ : 2.43 (s, 3H), 7.13 (s, 2H), 7.81 (m, 2H), 8.32 (br s, 2H) 1 H-NMR (DMSO-d 3 ) δ: 2.43 (s, 3H), 7.13 (s, 2H), 7.81 (m, 2H), 8.32 (br s, 2H)

제조예Production Example 4 4 :  : 티오프로피오아미드의Of thiopropioamide 제조 Produce

Figure 112006042290445-pat00022
Figure 112006042290445-pat00022

제조예 3과 같은 방법으로, 4-(메틸티오)벤조니트릴 대신에 프로피오니트릴을 사용하여 제조예 화합물 4를 합성하였다.In the same manner as in Preparation Example 3, Preparation Compound 4 was synthesized using propionitrile instead of 4- (methylthio) benzonitrile.

1H-NMR (CDCl3) δ : 1.31 (t, 3H), 2.70 (q, 2H), 7.00 (br s, 1H), 7.85 (br s, 1H) 1 H-NMR (CDCl 3 ) δ: 1.31 (t, 3H), 2.70 (q, 2H), 7.00 (br s, 1H), 7.85 (br s, 1H)

제조예Production Example 5 5 : 4- : 4- 아이오도Iodo -2--2- 메틸티오피리미딘의Methylthiopyrimidine 제조 Produce

Figure 112006042290445-pat00023
Figure 112006042290445-pat00023

4-클로로-2-메틸티오피리미딘(9 g, 56.0 mmol)을 47% HI (55 ㎖) 용액에 가하고 상온에서 48시간 동안 교반하였다. 생성된 고체를 여과한 다음 물(100 ㎖)에 녹이고 20% 수산화나트륨 용액을 첨가하여 pH를 8로 맞추었다. 혼합물을 클로로포름으로 추출하고, 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하여 용매를 증류제거시켰다. 잔류물을 석유에테르로부터 재결정하여 표제 화합물(9.5 g, 36.7 mmol, 수율 67%)을 얻었다.4-Chloro-2-methylthiopyrimidine (9 g, 56.0 mmol) was added to a 47% HI (55 mL) solution and stirred at room temperature for 48 hours. The resulting solid was filtered and then dissolved in water (100 mL) and pH was adjusted to 8 by addition of 20% sodium hydroxide solution. The mixture was extracted with chloroform, the extract was washed with water, dried over magnesium sulfate and filtered to distill off the solvent. The residue was recrystallized from petroleum ether to give the title compound (9.5 g, 36.7 mmol, yield 67%).

1H-NMR (CDCl3) δ : 2.54 (s, 3H), 7.41 (d, 1H), 8.01 (d, 1H) 1 H-NMR (CDCl 3 ) δ: 2.54 (s, 3H), 7.41 (d, 1H), 8.01 (d, 1H)

제조예Production Example 6 6 : 1-(3- : 1- (3- 클로로페닐Chlorophenyl )-2-(2-) -2- (2- 플루오로Fluoro -4--4- 피리딜Pyridyl )) 에타논의Ethanon 제조 Produce

Figure 112006042290445-pat00024
Figure 112006042290445-pat00024

무수 테트라하이드로퓨란(14 ㎖) 내 2-플루오로-4-메틸피리딘(3.0 g, 27.0 mmol)의 용액을 -78 ℃ 로 냉각시키고, 헥산 내 1.8 M 리튬 디이소프로필아미드의 용액(17 ㎖, 34 mmol)을 교반하면서 적가하였다. 첨가 완료 후, 혼합물을 30분 동안 교반시켰다. 그 다음 무수 테트라하이드로퓨란 내 3-클로로-N-메톡시-N-메틸벤즈아미드(5.4 g, 27.3 mmol)의 용액(3 ㎖)을 적가하였다. 첨가 완료 후, 혼합물을 실온으로 가온시키고, 물(50 ㎖)을 혼합물에 첨가하고, 에틸 아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하여 용매를 증류제거하였다. 잔류물을 tert-부틸 메틸 케톤/헥산으로부터 재결정하여 표제 화합물(5.2 g, 20.8 mmol, 수율 77%)을 얻었다.A solution of 2-fluoro-4-methylpyridine (3.0 g, 27.0 mmol) in anhydrous tetrahydrofuran (14 mL) was cooled to -78 ° C and a solution of 1.8 M lithium diisopropylamide in hexane (17 mL, 34 mmol) was added dropwise with stirring. After the addition was completed, the mixture was stirred for 30 minutes. Then a solution (3 ml) of 3-chloro-N-methoxy-N-methylbenzamide (5.4 g, 27.3 mmol) in anhydrous tetrahydrofuran was added dropwise. After the addition was completed, the mixture was allowed to warm to room temperature, water (50 mL) was added to the mixture and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was recrystallized from tert-butyl methyl ketone / hexane to give the title compound (5.2 g, 20.8 mmol, yield 77%).

1H-NMR (CDCl3) δ : 4.32 (s, 2H), 6.86 (s, 1H), 7.09 (d, 1H), 7.47 (t, 1H), 7.60 (m, 1H), 7.88 (m, 1H), 7.98 (t, 1H), 8.21 (d, 1H) 1 H-NMR (CDCl 3 ) δ: 4.32 (s, 2H), 6.86 (s, 1H), 7.09 (d, 1H), 7.47 (t, 1H), 7.60 (m, 1H), 7.88 (m, 1H ), 7.98 (t, 1 H), 8.21 (d, 1 H)

제조예Production Example 7 7 : 1-(4- : 1- (4- 플루오로페닐Fluorophenyl )-2-(2-) -2- (2- 플루오로Fluoro -4--4- 피리딜Pyridyl )) 에타논Ethanon

Figure 112006042290445-pat00025
Figure 112006042290445-pat00025

제조예 6과 같은 방법으로, 3-클로로-N-메톡시-N-메틸벤즈아미드 대신에 4-플루오로-N-메톡시-N-메틸벤즈아미드를 사용하여 제조예 화합물 7을 합성하였다.In the same manner as in Preparation Example 6, Preparation Compound 7 was synthesized using 4-fluoro-N-methoxy-N-methylbenzamide instead of 3-chloro-N-methoxy-N-methylbenzamide.

1H-NMR (CDCl3) δ : 4.33 (s, 2H), 6.87 (s, 1H), 7.10 (d, 1H), 7.19 (t, 3H), 8.04 (m, 1H), 8.20 (d, 1H) 1 H-NMR (CDCl 3 ) δ: 4.33 (s, 2H), 6.87 (s, 1H), 7.10 (d, 1H), 7.19 (t, 3H), 8.04 (m, 1H), 8.20 (d, 1H )

제조예Production Example 8 8 : 2-(2- 2- (2- terttert -- 부톡시카보닐아미노Butoxycarbonylamino -4--4- 피리딜Pyridyl )-1-(4-) -1- (4- 플루오로페닐Fluorophenyl )) 에on 타논의 제조Manufacture of tannon

Figure 112006042290445-pat00026
Figure 112006042290445-pat00026

무수 테트라하이드로퓨란(15 ㎖) 내 2-tert-부톡시카보닐아미노-4-메틸피리딘(1.0 g, 4.8 mmol)의 용액을 -78 ℃ 로 냉각시키고, 핵산 내 1.6 M n-부틸리튬의 용액(7.1 ㎖, 11.3 mmol)을 교반하면서 적가하였다. 첨가 완료 후, 혼합물을 0 ℃ 에서 30분 동안 교반하였다. 그 다음, 혼합물을 -78 ℃ 로 냉각시켰다. 무수 테트라하이드로퓨란 내 4-플루오로-N-메톡시-N-메틸벤즈아미드(1.2 g, 6.4 mmol)의 용액(3 ㎖)을 적가하였다. 첨가 완료 후, 혼합물을 실온에서 2시간 동안 교반하였다. 물(50 ㎖)을 혼합물에 첨가하고, 에틸 아세테이트로 추출시켰다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하여 용매를 증류제거하였다. 잔류물을 에틸 아세테이트/헥산으로부터 재결정하여 표제 화합물(1.1 g, 3.3 mmol, 수율 70%)을 얻었다.A solution of 2-tert-butoxycarbonylamino-4-methylpyridine (1.0 g, 4.8 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to -78 ° C and a solution of 1.6 M n-butyllithium in nucleic acid (7.1 mL, 11.3 mmol) was added dropwise with stirring. After the addition was completed, the mixture was stirred at 0 ° C for 30 minutes. The mixture was then cooled to -78 ° C. A solution (4-ml) of 4-fluoro-N-methoxy-N-methylbenzamide (1.2 g, 6.4 mmol) in anhydrous tetrahydrofuran was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added to the mixture and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was recrystallized from ethyl acetate / hexanes to give the title compound (1.1 g, 3.3 mmol, yield 70%).

1H-NMR (CDCl3) δ : 1.54 (s, 9H), 4.27 (s, 2H), 6.88 (d, 1H), 7.17 (t, 2H), 7.80 (s, 1H), 7.94 (s, 1H), 8.01-8.06 (m, 2H), 8.20 (d, 1H) 1 H-NMR (CDCl 3 ) δ: 1.54 (s, 9H), 4.27 (s, 2H), 6.88 (d, 1H), 7.17 (t, 2H), 7.80 (s, 1H), 7.94 (s, 1H ), 8.01-8.06 (m, 2H), 8.20 (d, 1H)

제조예Production Example 9 9 : 1-(3- : 1- (3- 클로로페닐Chlorophenyl )-2-(2-) -2- (2- 메틸티오Methylthio -4--4- 피리미딜Pyrimidyl )) 에타논의Ethanon 제조 Produce

Figure 112006042290445-pat00027
Figure 112006042290445-pat00027

무수 테트라하이드로퓨란(40 ㎖) 내 2-메틸티오-4-메틸피리미딘(5.6 g, 40.0 mmol)의 용액을 -78 ℃ 로 냉각시키고, 핵산 내 1.8 M 리튬 디이소프로필아미드의 용액(25 ㎖, 45.1 mmol)을 교반하면서 적가하였다. 첨가 완료 후, 혼합물을 30분 동안 교반하였다. 그 다음 무수 테트라하이드로퓨란내 3-클로로-N-메톡시-N-메틸벤 즈아미드 (8.0g, 40.0mmol)의 용액(8 ㎖)을 적가하였다. 첨가 완료 후, 혼합물을 실온으로 가온시키고, 물(50 ㎖)을 혼합물에 첨가하고, 에틸 아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조하고, 여과하여 용매를 증류제거하였다. 잔류물을 tert-부틸 메틸 케톤/헥산으로부터 재결정하여, 9.2 g(33 mmol, 수율 83%)의 표제 화합물을 얻었다.A solution of 2-methylthio-4-methylpyrimidine (5.6 g, 40.0 mmol) in anhydrous tetrahydrofuran (40 mL) was cooled to -78 ° C and a solution of 1.8 M lithium diisopropylamide in nucleic acid (25 mL) , 45.1 mmol) was added dropwise with stirring. After the addition was completed, the mixture was stirred for 30 minutes. Then a solution (8 ml) of 3-chloro-N-methoxy-N-methylbenzamide (8.0 g, 40.0 mmol) in anhydrous tetrahydrofuran was added dropwise. After the addition was completed, the mixture was allowed to warm to room temperature, water (50 mL) was added to the mixture and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was recrystallized from tert-butyl methyl ketone / hexane to give 9.2 g (33 mmol, 83% yield) of the title compound.

1H-NMR (CDCl3) δ : 2.63 (s, 3H), 5.98 (s, 1H), 6.68 (d, 1H), 7.40 (m, 2H), 7.71 (m, 1H), 7.83 (m, 1H), 8.35 (d, 1H). pH에 따라 케토-엔올 호변이성체로 존재하므로 신호가 두 개씩 존재함. 1 H-NMR (CDCl 3 ) δ: 2.63 (s, 3H), 5.98 (s, 1H), 6.68 (d, 1H), 7.40 (m, 2H), 7.71 (m, 1H), 7.83 (m, 1H ), 8.35 (d, 1 H). It exists as a keto-enol tautomer depending on pH, so there are two signals.

제조예Production Example 10 10 : 1-(4- : 1- (4- 플루오로페닐Fluorophenyl )-2-(2-) -2- (2- 메틸티오Methylthio -4--4- 피리미딜Pyrimidyl )) 에타논의Ethanon 제조 Produce

Figure 112006042290445-pat00028
Figure 112006042290445-pat00028

제조예 9와 같은 방법으로, 3-클로로-N-메톡시-N-메틸벤즈아미드 대신에 4-플루오로-N-메톡시-N-메틸벤즈아미드를 사용하여 제조예 화합물 10을 합성하였다.In the same manner as in Preparation Example 9, Preparation Compound 10 was synthesized using 4-fluoro-N-methoxy-N-methylbenzamide instead of 3-chloro-N-methoxy-N-methylbenzamide.

1H-NMR (CDCl3) δ : 2.63 (s, 3H), 5.94 (s, 1H), 6.66 (d, 1H), 7.13 (t, 2H), 7.84 (dd, 2H), 8.29 (d, 1H). pH에 따라 케토-엔올 호변이성체로 존재하므로 신호가 두개씩 존재함. 1 H-NMR (CDCl 3 ) δ: 2.63 (s, 3H), 5.94 (s, 1H), 6.66 (d, 1H), 7.13 (t, 2H), 7.84 (dd, 2H), 8.29 (d, 1H ). It exists as a keto-enol tautomer depending on pH, so there are two signals.

제조예Production Example 11 11 : 2- : 2- 브로모Bromo -1-(3--1- (3- 클로로페닐Chlorophenyl )-2-(2-) -2- (2- 플루오로Fluoro -4--4- 피리딜Pyridyl )) 에타논의Ethanon 제조 Produce

Figure 112006042290445-pat00029
Figure 112006042290445-pat00029

브롬(3.3 g, 20.8 mmol)을 아세트산(50 ㎖) 내 1-(3-클로로페닐)-2-(2-플루오로-4-피리딜)에타논(5.2 g, 20.8 mmol)의 용액에 첨가하고, 상온에서 1시간 동안 교반하였다. 반응 혼합물을 농축하고, 에틸 아세테이트로 추출한 후, 탄산수소나트륨의 포화 수용액으로 세척하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하여 표제 화합물(6.8 g, 20.8 mmol, 수율 100%)을 수득하고 정제 없이 그 다음 반응에 사용하였다.Bromine (3.3 g, 20.8 mmol) is added to a solution of 1- (3-chlorophenyl) -2- (2-fluoro-4-pyridyl) ethanone (5.2 g, 20.8 mmol) in acetic acid (50 mL). And stirred at room temperature for 1 hour. The reaction mixture was concentrated, extracted with ethyl acetate and washed with a saturated aqueous solution of sodium hydrogen carbonate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off to give the title compound (6.8 g, 20.8 mmol, 100% yield) which was used for the next reaction without purification.

1H-NMR (CDCl3) δ : 6.14 (s, 1H), 7.14 (t, 1H), 7.34 (d, 1H), 7.48 (t, 1H), 7.63 (m, 1H), 7.90 (dd, 1H), 8.01 (t, 1H), 8.28 (d, 1H) 1 H-NMR (CDCl 3 ) δ: 6.14 (s, 1H), 7.14 (t, 1H), 7.34 (d, 1H), 7.48 (t, 1H), 7.63 (m, 1H), 7.90 (dd, 1H ), 8.01 (t, 1H), 8.28 (d, 1H)

제조예Production Example 12 12 : 2- : 2- 브로모Bromo -1-(4--1- (4- 플루오로페닐Fluorophenyl )-2-(2-) -2- (2- 플루오로Fluoro -4--4- 피리딜Pyridyl )) 에타논의Ethanon 제조 Produce

Figure 112006042290445-pat00030
Figure 112006042290445-pat00030

제조예 11과 같은 방법으로, 1-(3-클로로페닐)-2-(2-플루오로-4-피리딜)에타논 대신에 1-(4-플루오로페닐)-2-(2-플루오로-4-피리딜)에타논을 사용하여 제조예 화합물 12를 합성하였다.In the same manner as in Production Example 11, 1- (4-fluorophenyl) -2- (2-fluoro instead of 1- (3-chlorophenyl) -2- (2-fluoro-4-pyridyl) ethanone Preparation Compound 12 was synthesized using ro-4-pyridyl) ethanone.

1H-NMR (CDCl3) δ : 6.17 (s, 1H), 7.10-7.23 (m, 1H), 7.34 (d, 1H), 8.07 (m, 2H), 8.26 (d, 1H) 1 H-NMR (CDCl 3 ) δ: 6.17 (s, 1H), 7.10-7.23 (m, 1H), 7.34 (d, 1H), 8.07 (m, 2H), 8.26 (d, 1H)

제조예Production Example 13 13 : 2- : 2- 브로모Bromo -2-(2--2- (2- terttert -- 부톡시카보닐아미노Butoxycarbonylamino -4--4- 피리딜Pyridyl )-1-(4-) -1- (4- 플루오로페닐Fluorophenyl )에타논의 제조Production of ethanone

Figure 112006042290445-pat00031
Figure 112006042290445-pat00031

제조예 11과 같은 방법으로, 1-(3-클로로페닐)-2-(2-플루오로-4-피리딜)에타논 대신에 2-(2-tert-부톡시카보닐아미노-4-피리딜)-1-(4-플루오로페닐)에타논을 사용하여 제조예 화합물 13을 합성하였다.In the same manner as in Production Example 11, 2- (2-tert-butoxycarbonylamino-4-pyriin instead of 1- (3-chlorophenyl) -2- (2-fluoro-4-pyridyl) ethanone Preparative Compound 13 was synthesized using dill) -1- (4-fluorophenyl) ethanone.

1H-NMR (CDCl3) δ : 1.56 (s, 9H), 6.18 (s, 2H), 7.16-7.23 (m, 3H), 8.04-8.08 (m, 2H), 8.15 (s, 1H), 8.30 (d, 2H), 8.35 (s, 1H) 1 H-NMR (CDCl 3 ) δ: 1.56 (s, 9H), 6.18 (s, 2H), 7.16-7.23 (m, 3H), 8.04-8.08 (m, 2H), 8.15 (s, 1H), 8.30 (d, 2H), 8.35 (s, 1H)

제조예Production Example 14 14 : 2- : 2- 브로모Bromo -1-(3--1- (3- 클로로페닐Chlorophenyl )-2-(2-) -2- (2- 메틸티오Methylthio -4--4- 피리미딜Pyrimidyl )) 에타논의Ethanon 제조 Produce

Figure 112006042290445-pat00032
Figure 112006042290445-pat00032

제조예 11과 같은 방법으로, 1-(3-클로로페닐)-2-(2-플루오로-4-피리딜)에타논 대신에 1-(3-클로로페닐)-2-(2-메틸티오-4-피리미딜)에타논을 사용하여 제조예 화합물 14를 합성하였다.In the same manner as in Production Example 11, 1- (3-chlorophenyl) -2- (2-methylthio instead of 1- (3-chlorophenyl) -2- (2-fluoro-4-pyridyl) ethanone Preparation Compound 14 was synthesized using -4-pyrimidyl) ethanone.

1H-NMR (CDCl3) δ : 2.54 (s, 1H), 6.17 (s, 1H), 7.42 (t, 1H), 7.47 (d, 1H), 7.61 (m, 1H), 7.92 (d, 1H), 8.05 (m, 1H), 8.61 (d, 1H) 1 H-NMR (CDCl 3 ) δ: 2.54 (s, 1H), 6.17 (s, 1H), 7.42 (t, 1H), 7.47 (d, 1H), 7.61 (m, 1H), 7.92 (d, 1H ), 8.05 (m, 1H), 8.61 (d, 1H)

제조예Production Example 15 15 : 2- : 2- 브로모Bromo -1-(4--1- (4- 플루오로페닐Fluorophenyl )-2-(2-) -2- (2- 메틸티오Methylthio -4--4- 피리미딜Pyrimidyl )) 에타논Ethanon 의 제조Manufacture

Figure 112006042290445-pat00033
Figure 112006042290445-pat00033

제조예 11과 같은 방법으로, 1-(3-클로로페닐)-2-(2-플루오로-4-피리딜)에타논 대신에 1-(4-플루오로페닐)-2-(2-메틸티오-4-피리미딜)에타논을 사용하여 제조예 화합물 15를 합성하였다.In the same manner as in Production Example 11, 1- (4-fluorophenyl) -2- (2-methyl instead of 1- (3-chlorophenyl) -2- (2-fluoro-4-pyridyl) ethanone Preparation Compound 15 was synthesized using thio-4-pyrimidyl) ethanone.

1H-NMR (CDCl3) δ : 2.53 (s, 3H), 6.18 (s, 1H), 7.18 (t, 2H), 7.41 (d, 1H), 8.10 (dd, 2H), 8.61 (d, 1H) 1 H-NMR (CDCl 3 ) δ: 2.53 (s, 3H), 6.18 (s, 1H), 7.18 (t, 2H), 7.41 (d, 1H), 8.10 (dd, 2H), 8.61 (d, 1H )

제조예Production Example 16 16 : 4-[4-(4- : 4- [4- (4- 플루오로페닐Fluorophenyl )티아졸-5-일]-2-) Thiazol-5-yl] -2- 플루오로피리딘의Of fluoropyridine 제조 Produce

Figure 112006042290445-pat00034
Figure 112006042290445-pat00034

2-브로모-1-(4-플루오로페닐)-2-(2-플루오로-4-피리딜)에타논 (112 mg, 3.59 mmol)을 N,N-디메틸포름아미드(5 ㎖)에 용해시키고, 용액에 티오벤즈아미드(439 mg, 7.17 mmol)를 첨가하고, 혼합물을 80℃에서 4시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시키고, 탄산수소나트륨의 포화 수용액 (50 ㎖)을 첨가하고, 혼 합물을 에틸 아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(에틸 아세테이트:n-헥산 = 1:4)로 정제하여 표제 화합물(480 mg, 1.74 mmol, 수율 49%)을 얻었다.2-bromo-1- (4-fluorophenyl) -2- (2-fluoro-4-pyridyl) ethanone (112 mg, 3.59 mmol) was added to N, N-dimethylformamide (5 mL). Dissolved, thiobenzamide (439 mg, 7.17 mmol) was added to the solution, and the mixture was stirred at 80 ° C. for 4 hours. The reaction mixture was cooled to room temperature, saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to give the title compound (480 mg, 1.74 mmol, 49% yield).

1H-NMR (CDCl3) δ : 6.92 (d, 1H), 7.12 (m, 3H), 7.51 (m, 2H), 8.20 (d, 1H), 8.94 (s, 1H) 1 H-NMR (CDCl 3 ) δ: 6.92 (d, 1H), 7.12 (m, 3H), 7.51 (m, 2H), 8.20 (d, 1H), 8.94 (s, 1H)

제조예Production Example 17 17 : [4-(3- : [4- (3- 클로로페닐Chlorophenyl )-5-(2-) -5- (2- 플루오로피리딘Fluoropyridine -4-일)티아졸-2-일]-4-yl) thiazol-2-yl] 아민의Amine 제조 Produce

Figure 112006042290445-pat00035
Figure 112006042290445-pat00035

2-브로모-1-(3-클로로페닐)-2-(2-플루오로-4-피리딜)에타논(1.0 g, 3.04 mmol)을 에탄올(30 ㎖)에 용해시키고, 용액에 티오우레아(231 mg, 3.04 mmol)를 첨가하고, 혼합물을 1시간 동안 가열환류하였다. 반응 혼합물을 실온으로 냉각시킨 후, 농축하였다. 탄산수소나트륨의 포화 수용액(50 ㎖)을 잔류물에 첨가하고, 혼합물을 에틸 아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 메틸렌클로라이드/n-헥산으로부터 재결정하여 표제 화합물(820 mg, 2.68 mmol, 수율 88%)을 얻었다.2-bromo-1- (3-chlorophenyl) -2- (2-fluoro-4-pyridyl) ethanone (1.0 g, 3.04 mmol) was dissolved in ethanol (30 mL) and thiourea in solution (231 mg, 3.04 mmol) was added and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and then concentrated. A saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was recrystallized from methylene chloride / n-hexane to give the title compound (820 mg, 2.68 mmol, yield 88%).

1H-NMR (CDCl3) δ : 5.25 (br s, 2H), 6.75 (s, 1H), 6.98 (d, 1H), 7.27-7.37 (m 3H), 7.53 (s, 1H), 8.07 (d, 1H) 1 H-NMR (CDCl 3 ) δ: 5.25 (br s, 2H), 6.75 (s, 1H), 6.98 (d, 1H), 7.27-7.37 (m 3H), 7.53 (s, 1H), 8.07 (d , 1H)

제조예Production Example 18 18 : 4-[2-에틸-4-(3- : 4- [2-ethyl-4- (3- 클로로페닐Chlorophenyl )티아졸-5-일]-2-) Thiazol-5-yl] -2- 플루오로피리딘의Of fluoropyridine 제조 Produce

Figure 112006042290445-pat00036
Figure 112006042290445-pat00036

제조예 17과 같은 방법으로, 티오우레아 대신에 티오프로피오아미드를 사용하여 제조예 화합물 18을 합성하였다In the same manner as in Preparation Example 17, Preparation Example 18 was synthesized using thiopropioamide instead of thiourea.

1H-NMR (CDCl3) δ : 1.48 (t, 3H), 3.11 (q, 2H), 6.87 (s, 1H), 7.08 (m, 1H), 7.27-7.38 (m, 3H), 7.58 (s, 1H), 8.16 (d, 1H) 1 H-NMR (CDCl 3 ) δ: 1.48 (t, 3H), 3.11 (q, 2H), 6.87 (s, 1H), 7.08 (m, 1H), 7.27-7.38 (m, 3H), 7.58 (s , 1H), 8.16 (d, 1H)

제조예Production Example 19 19 : 4-[4-(4- : 4- [4- (4- 플루오로페닐Fluorophenyl )티아졸-2-일]피페리딘-1-) Thiazol-2-yl] piperidin-1- 카복실산Carboxylic acid terttert - 부틸 에스터의 제조Preparation of Butyl Ester

Figure 112006042290445-pat00037
Figure 112006042290445-pat00037

α-브로모-4-플루오로아세토페논(2.0 g, 9.0 mmol)을 에탄올(20 ㎖)에 용해시키고, 용액에 N-tert-부톡시카보닐피페리딘-4-티오아미드(2.0 g, 8.2 mmol)를 첨가하고, 혼합물을 1시간 동안 가열환류하였다. 반응 혼합물을 실온으로 냉각시킨 후, 농축하였다. 탄산수소나트륨의 포화 수용액(50 ㎖)을 잔류물에 첨가하고, 혼합물을 에틸 아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류 제거하였다. 잔류물을 N,N-디메틸포름아미드(15 ㎖)에 녹이고 디-tert-부틸디카보네이트(1.4 g, 6.1 mmol)와 트리에틸아민(0.7 g, 6.1 mmol)을 가하고 50 ℃에서 2시간 교반하였다. 반응 혼합물을 실온으로 냉각시킨 후, 물(150㎖)을 첨가하고, 혼합물을 에틸 아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(에틸 아세테이트:n-헥산 = 1:3)로 정제하여 표제 화합물(1.7 g, 4.7 mmol, 수율 53%)을 얻었다.α-bromo-4-fluoroacetophenone (2.0 g, 9.0 mmol) is dissolved in ethanol (20 mL) and in solution N-tert-butoxycarbonylpiperidine-4-thioamide (2.0 g, 8.2 mmol) was added and the mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temperature and then concentrated. A saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was taken up in N, N-dimethylformamide (15 mL), di-tert-butyldicarbonate (1.4 g, 6.1 mmol) and triethylamine (0.7 g, 6.1 mmol) were added and stirred at 50 ° C. for 2 hours. . After the reaction mixture was cooled to room temperature, water (150 mL) was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to give the title compound (1.7 g, 4.7 mmol, 53% yield).

1H-NMR (CDCl3) δ : 1.49 (s, 9H), 1.80 (d q, 2H), 2.17 (d, 2H), 2.94(t, 2H), 3.21(m, 1H), 4.24(m, 2H), 7.12 (t, 2H), 7.32(s, 1H), 7.87 (m, 2H) 1 H-NMR (CDCl 3 ) δ: 1.49 (s, 9H), 1.80 (dq, 2H), 2.17 (d, 2H), 2.94 (t, 2H), 3.21 (m, 1H), 4.24 (m, 2H ), 7.12 (t, 2H), 7.32 (s, 1H), 7.87 (m, 2H)

제조예Production Example 20 20 : 4-[4-(4- : 4- [4- (4- 플루오로페닐Fluorophenyl )-5-(2-) -5- (2- 메틸설파닐피리미딘Methylsulfanylpyrimidine -4-일)티아졸-2-일]피페리딘-1-카복실산 에틸 에스터의 제조Preparation of -4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester

Figure 112006042290445-pat00038
Figure 112006042290445-pat00038

황산나트륨(2.2 g, 15.4 mmol)을 N,N-디메틸포름아미드(30 ㎖)에 첨가하고 120 ℃에서 10분 동안 교반한 후, N-에톡시카보닐피페리딘-4-티오아미드(3.3 g, 15.5 mmol)를 고체로 첨가하고, 혼합물을 5분 동안 교반하였다. N,N-디메틸포름아미드(8 ㎖) 내 2-브로모-1-(4-플루오로페닐)-2-(2-메틸티오-4-피리미딜)에타논(2.6g, 7.7mmol) 용액을 3초 내에 첨가하고 5분 동안 교반하였다. 반응 혼합물을 실온으로 냉각시키고, 탄산수소나트륨의 포화 수용액 (200 ㎖)을 첨가한 후, 에틸 아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(에틸 아세테이트:n-헥산 = 1:4)로 정제하여 표제 화합물(260 mg, 0.57 mmol, 수율 7%)을 얻었다.Sodium sulfate (2.2 g, 15.4 mmol) was added to N, N-dimethylformamide (30 mL) and stirred at 120 ° C. for 10 minutes, followed by N-ethoxycarbonylpiperidine-4-thioamide (3.3 g, 15.5 mmol) was added as a solid and the mixture was stirred for 5 minutes. A solution of 2-bromo-1- (4-fluorophenyl) -2- (2-methylthio-4-pyrimidyl) ethanone (2.6 g, 7.7 mmol) in N, N-dimethylformamide (8 mL) Was added within 3 seconds and stirred for 5 minutes. The reaction mixture was cooled to room temperature, saturated aqueous solution of sodium hydrogen carbonate (200 mL) was added, and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to give the title compound (260 mg, 0.57 mmol, 7% yield).

제조예Production Example 21 21 : 4-[4-(4- : 4- [4- (4- 플루오로페닐Fluorophenyl )-5-(2-) -5- (2- 메탄설피닐피리미딘Methanesulfinylpyrimidine -4-일)티아졸-2-일]피페리딘-1-카복실산 에틸 에스터의 제조Preparation of -4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester

Figure 112006042290445-pat00039
Figure 112006042290445-pat00039

메틸렌클로라이드(3 ㎖) 내 4-[4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카복실산 에틸 에스터(360 mg, 0.78 mmol)의 용액을 0 ℃ 로 냉각시키고, 65% 메타-클로로퍼벤조산(250 mg, 0.94 mmol)을 교반하면서 첨가하였다. 첨가 완료 후, 혼합물을 30분 동안 교반하였다. 그 다음 반응 혼합물을 2 N 탄산나트륨 용액(30 ㎖)에 가하고, 혼합물을 메틸렌클로라이드로 추출시켰다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세톤 : n-헥산, 5:8)로 정제시켜, 250 mg의 표제 화합물(0.52 mmol, 수율 67%)을 얻었다.4- [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl in methylene chloride (3 mL) A solution of ester (360 mg, 0.78 mmol) was cooled to 0 ° C. and 65% meta-chloroperbenzoic acid (250 mg, 0.94 mmol) was added with stirring. After the addition was completed, the mixture was stirred for 30 minutes. The reaction mixture was then added to 2 N sodium carbonate solution (30 mL) and the mixture was extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (acetone: n-hexane, 5: 8) to give 250 mg of the title compound (0.52 mmol, 67% yield).

1H-NMR (CDCl3) δ : 1.29 (t, 3H), 1.83 (m, 2H), 2.18 (m, 2H), 2.96 (m, 5H), 3.21 (m, 1H), 4.17 (q, J=7.1, 2H), 4.30 (br, 2H), 7.16 (m, 3H), 7.55 (m, 2H), 8.73 (d, 1H) 1 H-NMR (CDCl 3 ) δ: 1.29 (t, 3H), 1.83 (m, 2H), 2.18 (m, 2H), 2.96 (m, 5H), 3.21 (m, 1H), 4.17 (q, J = 7.1, 2H), 4.30 (br, 2H), 7.16 (m, 3H), 7.55 (m, 2H), 8.73 (d, 1H)

실시예Example 1 One : [4-(3- : [4- (3- 클로로페닐Chlorophenyl )-5-(2-) -5- (2- 플루오로피리딘Fluoropyridine -4-일)티아졸-2-일]메틸아민(1)의 제조Preparation of -4-yl) thiazol-2-yl] methylamine (1)

2-브로모-1-(3-클로로페닐)-2-(2-플루오로-4-피리딜)에타논(1.0 g, 3.04 mmol)을 에탄올(30 mL)에 용해시키고, 용액에 N-메틸티오우레아(274 mg, 3.04 mmol)를 첨가한 후, 혼합물을 2시간 동안 가열 환류하였다. 반응 혼합물을 실온으로 냉각한 후, 농축하였다. 탄산수소나트륨의 포화 수용액 (50 mL)을 잔류물에 첨가하고, 혼합물을 에틸 아세테이트로 추출하였다. 추출물을 물로 세척하고, 황산마그네슘으로 건조한 후, 여과하여 용매를 증류제거하였다. 잔류물을 메틸렌클로라이드/n-헥산으로 재결정하여 표제 화합물(770 mg, 2.41 mmol, 수율 79%)을 얻었다. 화합물(5)의 구조 및 1H-NMR 데이타를 하기 표 1a에 나타내었다.2-bromo-1- (3-chlorophenyl) -2- (2-fluoro-4-pyridyl) ethanone (1.0 g, 3.04 mmol) was dissolved in ethanol (30 mL) and the solution After addition of methylthiourea (274 mg, 3.04 mmol), the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and then concentrated. A saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and filtered to distill off the solvent. The residue was recrystallized from methylene chloride / n-hexane to give the title compound (770 mg, 2.41 mmol, 79% yield). The structure of the compound (5) and the 1 H-NMR data are shown in Table 1A below.

실시예Example 2~4 2 ~ 4 : :

실시예 1과 같은 방법으로, 화합물 2~4를 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1a에 나타내었다.In the same manner as in Example 1, Compounds 2 to 4 were synthesized, and their structures and 1 H-NMR data are shown in Table 1A.

Figure 112006042290445-pat00040
Figure 112006042290445-pat00040

실시예Example 5 5 : 4-[4-(4- : 4- [4- (4- 플루오로페닐Fluorophenyl )-2-(4-) -2- (4- 메틸설파닐페닐Methylsulfanylphenyl )티아졸-5-일]피리딘-2-일아민(5)의 제조) Tazol-5-yl] pyridin-2-ylamine (5)

트리플루오로아세트산 (20 mL)을 {4-[4-(4-플루오로페닐)-2-(4-메틸설파닐페닐)티아졸-5-일]피리딘-2-일}카바민산 tert-부틸 에스터(1.12 g, 2.23 mmol)에 첨가하고, 혼합물을 상온에서 1시간 동안 교반하였다. 반응 혼합물을 농축하고, 탄산수소나트륨의 포화 수용액(50 mL)을 첨가한 후, 혼합물을 에틸 아세테이트로 추출하였다. 추출물을 물로 세척하고, 황산마그네슘으로 건조한 후, 여과하여 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(에틸 아세테이트:n-헥산 = 1:1)로 정제하여 표제 화합물(0.74 g, 1.88 mmol, 수율 83%)을 얻었다. 화합물(5)의 구조 및 1H-NMR 데이타를 하기 표 1b에 나타내었다.Acetic acid (20 mL) in trifluoroacetic {4- [4- (4-fluorophenyl) -2- (4-methylsulfanyl-phenyl) -thiazol-5-yl] pyridin-2-yl} cava acid tert - To butyl ester (1.12 g, 2.23 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added, and then the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and filtered to distill off the solvent. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to give the title compound (0.74 g, 1.88 mmol, 83% yield). The structure and 1 H-NMR data of compound (5) are shown in Table 1b below.

실시예Example 6 6 : 4-(3- 4- (3- 클로로페닐Chlorophenyl )-5-(2-) -5- (2- 메틸설파닐피리미딘Methylsulfanylpyrimidine -4-일)티아졸-2--4-yl) thiazole-2- 일아민(6)의Of monoamines (6) 제조 Produce

2-브로모-1-(3-클로로페닐)-2-(2-메틸티오-4-피리미딜)에타논(2.36 g, 6.60 mmol)을 에탄올(60 mL)에 용해시키고, 용액에 티오우레아(0.50 g, 6.60 mmol)를 첨가한 후, 혼합물을 1시간 동안 가열 환류시켰다. 반응 혼합물을 실온으로 냉각한 후 농축시켰다. 잔류물을 탄산수소나트륨의 포화 수용액 (50 mL)으로 교반하고, 여과하여 수집한 후, 아세톤(20 mL)으로 세척하여 표제 화합물(1.66 g, 4.96 mmol, 수율 75%)을 얻었다. 화합물(6)의 구조 및 1H-NMR 데이타를 하기 표 1b에 나타내었다.2-bromo-1- (3-chlorophenyl) -2- (2-methylthio-4-pyrimidyl) ethanone (2.36 g, 6.60 mmol) is dissolved in ethanol (60 mL) and thiourea in solution After addition of (0.50 g, 6.60 mmol), the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to rt and then concentrated. The residue was stirred with a saturated aqueous solution of sodium hydrogen carbonate (50 mL), collected by filtration and washed with acetone (20 mL) to give the title compound (1.66 g, 4.96 mmol, 75% yield). The structure of the compound (6) and the 1 H-NMR data are shown in Table 1b below.

실시예Example 7~31 7-31 : :

실시예 6과 같은 방법으로 화합물 7~31을 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1b에 나타내었다.Compounds 7-31 were synthesized in the same manner as in Example 6, and their structures and 1 H-NMR data are shown in Table 1b.

Figure 112006042290445-pat00041
Figure 112006042290445-pat00041

Figure 112006042290445-pat00042
Figure 112006042290445-pat00042

Figure 112006042290445-pat00043
Figure 112006042290445-pat00043

Figure 112006042290445-pat00044
Figure 112006042290445-pat00044

실시예Example 32 32 : 4-[2- : 4- [2- 클로로Chloro -4-(4--4- (4- 플루오로페닐Fluorophenyl )티아졸-5-일]-2-) Thiazol-5-yl] -2- 메틸설파닐피리미딘(32)의Of methylsulfanylpyrimidine (32) 제조 Produce

CuCl2(632 mg, 4.70 mmol)와 tert-부틸나이트라이트(567 mg, 5.50 mmol)를 아세토니트릴(60 mL)에 가하고, 4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민(1.25 g, 3.92 mmol)을 조금씩 용액에 첨가한 후, 상온에서 3시간 동안 교반시켰다. 반응 혼합물을 에틸 아세테이트로 희석하고, 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하여 용매를 증류제거시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피(에틸 아세테이트:n-헥산 = 1:4)로 정제하여 표제 화합물(540 mg, 1.60 mmol, 수율 41%)을 얻었다. 화합물(32)의 구조 및 1H-NMR 데이타를 하기 표 1c에 나타내었다.CuCl 2 (632 mg, 4.70 mmol) and tert-butylnitrite (567 mg, 5.50 mmol) were added to acetonitrile (60 mL) and 4- (4-fluorophenyl) -5- (2-methylsulfanyl Pyrimidin-4-yl) thiazol-2-ylamine (1.25 g, 3.92 mmol) was added portionwise to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and filtered to distill off the solvent. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to give the title compound (540 mg, 1.60 mmol, 41% yield). The structure and 1 H-NMR data of compound (32) are shown in Table 1c below.

실시예Example 33~38 33-38 : :

실시예 32와 같은 방법으로 화합물 33~38을 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1c에 나타내었다.Compounds 33 to 38 were synthesized in the same manner as in Example 32, and their structures and 1 H-NMR data are shown in Table 1c below.

Figure 112006042290445-pat00045
Figure 112006042290445-pat00045

실시예Example 39 39 : 4-[4-(4- : 4- [4- (4- 플루오로페닐Fluorophenyl )-2-피페리딘-1-일-티아졸-5-일]-2-) -2-piperidin-1-yl-thiazol-5-yl] -2- 메틸설파닐피리미딘(39)의Of methylsulfanylpyrimidine (39) 제조 Produce

4-[2-클로로-4-(4-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘(150 mg, 0.44 mmol)을 테트라하이드로퓨란(3 mL)에 용해시키고, 용액에 테트라하이드로퓨란(1 mL)내 피페리딘(76 mg, 0.89 mmol)을 0 ℃에서 적가한 후 상온에서 1일 동안 교반하였다. 반응 혼합물을 포화 탄산수소나트륨 수용액에 가하고, 에틸 아세테이트로 추출한 다음 황산마그네슘으로 건조한 후, 여과하여 용매를 증류제거하여 표제 화합물(163 mg, 0.42 mmol, 수율 95%)을 수득하여 정제 없이 그 다음 반응에 사용하였다. 화합물(39)의 구조 및 1H-NMR 데이타를 하기 표 1d에 나타내었다.4- [2-chloro-4- (4-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine (150 mg, 0.44 mmol) is dissolved in tetrahydrofuran (3 mL), Piperidine (76 mg, 0.89 mmol) in tetrahydrofuran (1 mL) was added dropwise at 0 ° C., followed by stirring at room temperature for 1 day. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvent was distilled off to yield the title compound (163 mg, 0.42 mmol, yield 95%) to give the next reaction without purification. Used for. The structure and 1 H-NMR data of compound (39) are shown in Table 1d below.

실시예Example 40~62 40-62 : :

실시예 39와 같은 방법으로 화합물 40~62를 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1d에 나타내었다.Compounds 40-62 were synthesized in the same manner as in Example 39, and their structures and 1 H-NMR data are shown in Table 1D.

Figure 112006042290445-pat00046
Figure 112006042290445-pat00046

Figure 112006042290445-pat00047
Figure 112006042290445-pat00047

Figure 112006042290445-pat00048
Figure 112006042290445-pat00048

실시예Example 63 63 : 4-[4-(4- : 4- [4- (4- 플루오로페닐Fluorophenyl )-5-(2-) -5- (2- 메틸설파닐피리미딘Methylsulfanylpyrimidine -4-일)티아졸-2-일]피페라진-1-카복실산 -4-yl) thiazol-2-yl] piperazin-1-carboxylic acid terttert -부틸 에스터(63)의 제조Preparation of -Butyl Ester 63

4-[4-(4-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]-2-메틸설파닐피리미딘(1.95 g, 5.03 mmol), 디-tert-부틸 디카보네이트(1.1 g, 5.03 mmol)와 트리에틸아민(0.51 g, 5.03 mmol)을 테트라하이드로퓨란(70 mL)에 용해시키고, 실온에서 1시간 교반하였다. 반응 혼합물을 물(150 mL)에 가하고, 혼합물을 에틸 아세테이트로 추출하였다. 추출물을 물로 세척하고, 황산마그네슘으로 건조한 후, 여과하여 용매를 증류제거하였다. 잔류물을 에틸 아세테이트/n-헥산으로　 재결정하여 표제 화합물(2.04 g, 4.18 mmol, 수율 83%)을 얻었다. 화합물(63)의 구조 및 1H-NMR 데이타를 하기 표 1e에 나타내었다.4- [4- (4-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine (1.95 g, 5.03 mmol), di-tert-butyl Dicarbonate (1.1 g, 5.03 mmol) and triethylamine (0.51 g, 5.03 mmol) were dissolved in tetrahydrofuran (70 mL) and stirred at room temperature for 1 hour. The reaction mixture was added to water (150 mL) and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and filtered to distill off the solvent. The residue was recrystallized from ethyl acetate / n-hexane to give the title compound (2.04 g, 4.18 mmol, 83% yield). The structure and 1 H-NMR data of compound (63) are shown in Table 1E below.

실시예 64~70 : Examples 64-70 :

실시예 63과 같은 방법으로 화합물 64~70을 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1e에 나타내었다.Compounds 64 to 70 were synthesized in the same manner as in Example 63, and their structures and 1 H-NMR data are shown in Table 1E below.

Figure 112006042290445-pat00049
Figure 112006042290445-pat00049

실시예Example 71 71 : 4-(3- 4- (3- 클로로페닐Chlorophenyl )-5-(2-) -5- (2- 메탄설피닐피리미딘Methanesulfinylpyrimidine -4-일)티아졸-2--4-yl) thiazole-2- 일아민(71)의Of monoamines (71) 제조 Produce

메틸렌클로라이드(200 mL)내 4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민(1.0g, 2.99 mmol) 용액을 0 ℃로 냉각하고, 교반하면서 65% 메타-클로로퍼벤조산(950 mg, 3.58 mmol)을 첨가하였다. 첨가 완료 후, 혼합물을 30분 동안 더 교반하였다. 그 다음 반응 혼합물을 2 N 탄산나트륨 용액(30 mL)에 가하고, 혼합물을 메틸렌클로라이드로 추출하였다. 추출물을 물로 세척하고, 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세톤:n-헥산 = 5:8)로 정제하여 표제 화합물(550 mg, 1.58 mmol, 수율 53%)을 얻었다. 화합물(71)의 구조 및 1H-NMR 데이타를 하기 표 1f에 나타내었다.Solution of 4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine (1.0 g, 2.99 mmol) in methylene chloride (200 mL) Cool and add 65% meta-chloroperbenzoic acid (950 mg, 3.58 mmol) with stirring. After the addition was completed, the mixture was further stirred for 30 minutes. The reaction mixture was then added to 2 N sodium carbonate solution (30 mL) and the mixture was extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (acetone: n-hexane = 5: 8) to give the title compound (550 mg, 1.58 mmol, 53% yield). The structure and 1 H-NMR data of compound (71) are shown in Table 1f below.

실시예Example 72~114 72-114 : :

실시예 71과 같은 방법으로 화합물 72~114를 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1f에 나타내었다.Compounds 72 to 114 were synthesized in the same manner as in Example 71, and their structures and 1 H-NMR data are shown in Table 1f.

Figure 112006042290445-pat00050
Figure 112006042290445-pat00050

Figure 112006042290445-pat00051
Figure 112006042290445-pat00051

Figure 112006042290445-pat00052
Figure 112006042290445-pat00052

Figure 112006042290445-pat00053
Figure 112006042290445-pat00053

Figure 112006042290445-pat00054
Figure 112006042290445-pat00054

실시예Example 115 115 : {4-[2-아미노-4-(3- : {4- [2-amino-4- (3- 클로로페닐Chlorophenyl )티아졸-5-일]피리딘-2-일}) Thiazol-5-yl] pyridin-2-yl} 시클로헥실아민Cyclohexylamine (115)의 제조Manufacture of 115

[4-(3-클로로페닐)-5-(2-플루오로피리딘-4-일)티아졸-2-일]아민(768 mg, 2.51 mmol)과 시클로헥실아민(1.99 g, 20.08 mmol)의 반응 혼합물을 150 ℃에서 4시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고, 생성된 결정을 여과한 후, 에틸 아세테이트(5 mL)로 세척하여 370 mg(0.96 mmol, 수율 38%)의 표제 화합물을 얻었다. 화합물(115)의 구조 및 1H-NMR 데이타를 하기 표 1g에 나타내었다.Of [4- (3-chlorophenyl) -5- (2-fluoropyridin-4-yl) thiazol-2-yl] amine (768 mg, 2.51 mmol) and cyclohexylamine (1.99 g, 20.08 mmol) The reaction mixture was stirred at 150 ° C for 4 h. The reaction mixture was cooled to room temperature and the resulting crystals were filtered and washed with ethyl acetate (5 mL) to give 370 mg (0.96 mmol, 38% yield) of the title compound. The structure and 1 H-NMR data of compound 115 are shown in Table 1g below.

실시예Example 116~121 116-121 : :

실시예 115와 같은 방법으로 화합물 116~121을 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1g에 나타내었다.Compounds 116-121 were synthesized in the same manner as in Example 115, and their structures and 1 H-NMR data are shown in Table 1g below.

Figure 112006042290445-pat00055
Figure 112006042290445-pat00055

실시예Example 122 122 : {4-[2-아미노-4-(3- : {4- [2-amino-4- (3- 클로로페닐Chlorophenyl )티아졸-5-일]피리미딘-2-일}) Thiazol-5-yl] pyrimidin-2-yl} 시클로헥실아민Cyclohexylamine (122)의 제조Manufacture of 122

4-(3-클로로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일아민(90 mg, 0.257 mmol)과 시클로헥실아민(216 mg, 2.18 mmol)의 반응 혼합물을 100 ℃에서 1시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시키고, 생성된 결정을 여과한 후, 에틸 아세테이트(5 mL)로 세척하여 표제 화합물(31 mg, 0.08 mmol, 수율 31%)을 얻었다. 화합물(122)의 구조 및 1H-NMR 데이타를 하기 표 1h에 나타내었다.4- (3-chlorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-ylamine (90 mg, 0.257 mmol) and cyclohexylamine (216 mg, 2.18 mmol) The reaction mixture was stirred at 100 ° C for 1 h. The reaction mixture was cooled to room temperature and the resulting crystals were filtered and washed with ethyl acetate (5 mL) to afford the title compound (31 mg, 0.08 mmol, 31% yield). The structure and 1 H-NMR data of compound (122) are shown in Table 1h below.

실시예Example 123~277 123-277 : :

실시예 122와 같은 방법으로 화합물 123~277을 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1h에 나타내었다.Compounds 123-277 were synthesized in the same manner as in Example 122, and their structures and 1 H-NMR data are shown in Table 1h below.

Figure 112006042290445-pat00056
Figure 112006042290445-pat00056

Figure 112006042290445-pat00057
Figure 112006042290445-pat00057

Figure 112006042290445-pat00058
Figure 112006042290445-pat00058

Figure 112006042290445-pat00059
Figure 112006042290445-pat00059

Figure 112006042290445-pat00060
Figure 112006042290445-pat00060

Figure 112006042290445-pat00061
Figure 112006042290445-pat00061

Figure 112006042290445-pat00062
Figure 112006042290445-pat00062

Figure 112006042290445-pat00063
Figure 112006042290445-pat00063

Figure 112006042290445-pat00064
Figure 112006042290445-pat00064

Figure 112006042290445-pat00065
Figure 112006042290445-pat00065

Figure 112006042290445-pat00066
Figure 112006042290445-pat00066

Figure 112006042290445-pat00067
Figure 112006042290445-pat00067

Figure 112006042290445-pat00068
Figure 112006042290445-pat00068

Figure 112006042290445-pat00069
Figure 112006042290445-pat00069

Figure 112006042290445-pat00070
Figure 112006042290445-pat00070

Figure 112006042290445-pat00071
Figure 112006042290445-pat00071

Figure 112006042290445-pat00072
Figure 112006042290445-pat00072

Figure 112006042290445-pat00073
Figure 112006042290445-pat00073

Figure 112006042290445-pat00074
Figure 112006042290445-pat00074

실시예Example 278 278 : 4-[5-(2- : 4- [5- (2- 시클로프로필아미노피리미딘Cyclopropylaminopyrimidine -4-일)-4-(4--4-yl) -4- (4- 플루오로페닐Fluorophenyl )티아졸-2-일]-1-메틸피페리딘-4-올(278)의 제조) Thiazol-2-yl] -1-methylpiperidin-4-ol (278)

무수 테트라하이드로퓨란(2 mL)내 시클로프로필-{4-[4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민(60 mg, 0.19 mmol) 용액을 -40 ℃로 냉각한 후, 교반하면서 헥산 내 1.6 M n-부틸리튬 용액(0.25 mL, 0.40 mmol)을 적가하였다. 첨가 완료 후, 혼합물을 30분 동안 더 교반하였다. 그 다음 무수 테트라하이드로퓨란(1 mL)에 N-메틸-4-피페리돈(57 mg, 0.51 mmol)을 적가하였다. 첨가 완료 후, 30분 동안 교반하고 반응 혼합물을 포화 소금물에 가하고 에틸 아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올:메틸렌클로라아드 = 1:1)로 정제하여 표제 화합물(48 mg, 0.11 mmol, 수율 59%)을 얻었다. 화합물(278)의 구조 및 1H-NMR 데이타를 하기 표 1i에 나타내었다.A solution of cyclopropyl- {4- [4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine (60 mg, 0.19 mmol) in anhydrous tetrahydrofuran (2 mL) After cooling to 40 ° C., 1.6 M n-butyllithium solution (0.25 mL, 0.40 mmol) in hexane was added dropwise with stirring. After the addition was completed, the mixture was further stirred for 30 minutes. N-methyl-4-piperidone (57 mg, 0.51 mmol) was then added dropwise to anhydrous tetrahydrofuran (1 mL). After the addition was completed, it was stirred for 30 minutes and the reaction mixture was added to saturated brine and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (methanol: methylenechlorad = 1: 1) to give the title compound (48 mg, 0.11 mmol, 59% yield). The structure of the compound 278 and the 1 H-NMR data are shown in Table 1i below.

실시예Example 279~305 279-305 : :

실시예 278과 같은 방법으로 화합물 279~305를 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1i에 나타내었다.Compounds 279 to 305 were synthesized in the same manner as in Example 278, and their structures and 1 H-NMR data are shown in Table 1i below.

Figure 112006042290445-pat00075
Figure 112006042290445-pat00075

Figure 112006042290445-pat00076
Figure 112006042290445-pat00076

Figure 112006042290445-pat00077
Figure 112006042290445-pat00077

Figure 112006042290445-pat00078
Figure 112006042290445-pat00078

실시예Example 306 306 : 4-[5-(2- : 4- [5- (2- 시클로프로필아미노피리미딘Cyclopropylaminopyrimidine -4-일)-4-(4--4-yl) -4- (4- 플루오로페닐Fluorophenyl )티아졸-2-일]-4-히드록시피페리딘-1-카복실산 ) Thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid terttert -부틸 에스터(305)의 제조Preparation of Butyl Ester 305

무수 테트라하이드로퓨란(4 mL)내 시클로프로필-{4-[4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민(150 mg, 0.48 mmol) 용액을 -40 ℃로 냉각한 후, 교반하면서 핵산 내 1.6 M n-부틸리튬 용액(0.6 mL, 0.96 mmol)을 적가하였다. 첨가 완료 후, 혼합물을 30분 동안 교반하였다. 다음으로 무수 테트라하이드로퓨란(1 mL)내 4-옥소피페리딘-1-카복실산 tert-부틸 에스터(258 mg, 1.23 mmol)을 적가하였다. 첨가 완료 후, 30분 동안 교반하고, 반응 혼합물을 포화 소금물에 가한 후, 에틸 아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조하 후, 여과하고 용매를 증류제거시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피 (에틸 아세테이트:n-헥산 = 1:2)로 정제하여 표제 화합물(106 mg, 0.21 mmol, 수율 43%)을 얻었다. 화합물(306)의 구조 및 1H-NMR 데이타를 하기 표 1j에 나타내었다.A solution of cyclopropyl- {4- [4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine (150 mg, 0.48 mmol) in anhydrous tetrahydrofuran (4 mL)- After cooling to 40 ° C., 1.6 M n-butyllithium solution (0.6 mL, 0.96 mmol) in nucleic acid was added dropwise with stirring. After the addition was completed, the mixture was stirred for 30 minutes. Then 4-oxopiperidine-1-carboxylic acid tert-butyl ester (258 mg, 1.23 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise. After the addition was completed, the mixture was stirred for 30 minutes, the reaction mixture was added to saturated brine, and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to give the title compound (106 mg, 0.21 mmol, 43% yield). The structure and 1 H-NMR data of compound 306 are shown in Table 1j below.

실시예Example 307~333  307-333 ::

실시예 306과 같은 방법으로 화합물 307~333을 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1j에 나타내었다.Compounds 307 to 333 were synthesized in the same manner as in Example 306, and their structures and 1 H-NMR data are shown in Table 1j below.

Figure 112006042290445-pat00079
Figure 112006042290445-pat00079

Figure 112006042290445-pat00080
Figure 112006042290445-pat00080

Figure 112006042290445-pat00081
Figure 112006042290445-pat00081

Figure 112006042290445-pat00082
Figure 112006042290445-pat00082

실시예Example 334 334 :  : 시클로프로필Cyclopropyl -{4-[4-(4--{4- [4- (4- 플루오로페닐Fluorophenyl )-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민(334)의 제조) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine (334)

클로로포름(5 mL) 내 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카복실산 에틸 에스터(180 mg, 0.38 mmol)의 용액에 아이오도트리메틸실란(230 mg, 1.16 mmol)을 가한 후 60 ℃에서 5시간 동안 반응시켰다. 반응 혼합물을 0 ℃로 냉각시키고, 프로판올 내 6 N 염화수소 용액(1.6 mL)을 혼합물에 가하고, 세게 교반하면서 균질화시켰다. 그 다음 반응 혼합물에 2 N 수산화나트륨 용액을 가하고, 혼합물을 메틸렌클로라이드로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카 겔 칼럼 크로마토그래피(메탄올:메틸렌클로라이드 = 1:1)로 정제하여 표제 화합물(100 mg, 0.25 mmol, 수율 66%)을 얻었다. 화합물(334)의 구조 및 1H-NMR 데이타를 하기 표 1k에 나타내었다.4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester in chloroform (5 mL) Iodotrimethylsilane (230 mg, 1.16 mmol) was added to a solution of (180 mg, 0.38 mmol), followed by reaction at 60 ° C. for 5 hours. The reaction mixture was cooled to 0 ° C. and 6N hydrogen chloride solution (1.6 mL) in propanol was added to the mixture and homogenized with vigorous stirring. Then 2N sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (methanol: methylenechloride = 1: 1) to give the title compound (100 mg, 0.25 mmol, 66% yield). The structure of the compound 334 and the 1 H-NMR data are shown in Table 1k below.

실시예Example 335~368 335-368 : :

실시예 334와 같은 방법으로 화합물 335~368을 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1k에 나타내었다.Compounds 335 to 368 were synthesized in the same manner as in Example 334, and their structures and 1 H-NMR data are shown in Table 1k below.

Figure 112006042290445-pat00083
Figure 112006042290445-pat00083

Figure 112006042290445-pat00084
Figure 112006042290445-pat00084

Figure 112006042290445-pat00085
Figure 112006042290445-pat00085

Figure 112006042290445-pat00086
Figure 112006042290445-pat00086

Figure 112006042290445-pat00087
Figure 112006042290445-pat00087

실시예Example 369 369 :  : 시클로프로필Cyclopropyl -{4-[4-(4--{4- [4- (4- 플루오로페닐Fluorophenyl )-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민(369)의 제조) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine (369)

메틸렌클로라이드(5 mL) 내 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페라진-1-카복실산 tert-부틸 에스터(352 mg, 0.67 mmol)의 용액에 트리플루오로아세트산(5 mL)을 가하고 혼합물을 1시간 상온에서 교반하였다. 반응 혼합물을 농축시키고 잔사에 메틸렌클로라이드를 가한 다음 포화 탄산수소나트륨 수용액과 물로 세척하고, 황산마그네슘으로 건조한 후 여과하고 용매를 증류제거하여 표제 화합물(254 mg, 0.60 mmol, 수율 89%)을 얻었다. 화합물(369)의 구조 및 1H-NMR 데이타를 하기 표 1l에 나타내었다.4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert- in methylene chloride (5 mL) Trifluoroacetic acid (5 mL) was added to a solution of butyl ester (352 mg, 0.67 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, methylene chloride was added to the residue, washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over magnesium sulfate, filtered, and the solvent was distilled off to obtain the title compound (254 mg, 0.60 mmol, 89% yield). The structure and 1 H-NMR data of compound (369) are shown in Table 1L below.

실시예Example 370~427 370-427 : :

실시예 369와 같은 방법으로 화합물 370~427을 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1l에 나타내었다.Compounds 370 to 427 were synthesized in the same manner as in Example 369, and their structures and 1 H-NMR data are shown in Table 1L below.

Figure 112006042290445-pat00088
Figure 112006042290445-pat00088

Figure 112006042290445-pat00089
Figure 112006042290445-pat00089

Figure 112006042290445-pat00090
Figure 112006042290445-pat00090

Figure 112006042290445-pat00091
Figure 112006042290445-pat00091

Figure 112006042290445-pat00092
Figure 112006042290445-pat00092

Figure 112006042290445-pat00093
Figure 112006042290445-pat00093

Figure 112006042290445-pat00094
Figure 112006042290445-pat00094

실시예Example 428 428 : 4-[4-(4- : 4- [4- (4- 플루오로페닐Fluorophenyl )-2-(4-) -2- (4- 메틸피페라진Methylpiperazine -1-일)티아졸-5-일]-2-메틸설파닐피리미딘(428)의 제조-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine (428)

4-[2-클로로-4-(4-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘(430 mg, 1.27 mmol)을 테트라하이드로퓨란(9 mL)에 용해시키고, 용액에 테트라하이드로퓨란(3 mL)내 4-메틸피페라진(255 mg, 2.55 mmol)을 0 ℃에서 적가한 후 상온에서 1일 교반하였다. 반응 혼합물을 포화 탄산수소나트륨 수용액에 가하고, 에틸 아세테이트로 추출한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하여 표제 화합물(473 mg, 1.18 mmol, 수율 93%)을 얻었다. 화합물(428)의 구조 및 1H-NMR 데이타를 하기 표 1m에 나타내었다.4- [2-chloro-4- (4-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine (430 mg, 1.27 mmol) is dissolved in tetrahydrofuran (9 mL), 4-methylpiperazine (255 mg, 2.55 mmol) in tetrahydrofuran (3 mL) was added dropwise at 0 ° C., followed by stirring at room temperature for 1 day. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvent was distilled off to give the title compound (473 mg, 1.18 mmol, 93% yield). The structure of the compound 428 and the 1 H-NMR data are shown in Table 1m below.

실시예Example 429 429 :  : 시클로프로필Cyclopropyl -{4-[4-(4--{4- [4- (4- 플루오로페닐Fluorophenyl )-2-(1-) -2- (1- 메틸피페리딘Methylpiperidine -4-일)티아졸-5-일]피리미딘-2-일}아민(429)의 제조Preparation of -4-yl) thiazol-5-yl] pyrimidin-2-yl} amine (429)

메탄올(1.5 mL) 내 시클로프로필-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민(50 mg, 0.13 mmol) 용액에 37% 포름알데히드(20 mg, 0.26 mmol)와 소듐보로하이드라이드(10 mg, 0.26 mmol)를 교반하면서 첨가하였다. 첨가 완료 후, 혼합물을 상온에서 30분 동안 교반한 후, 반응 혼합물을 물(15 mL)에 붓고, 혼합물을 에틸아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올:메틸렌클로라이드 = 1:1)로 정제하여 표제 화합물(33 mg, 0.08 mmol, 수율 31%)을 얻었다. 화합물(429)의 구조 및 1H-NMR 데이타를 하기 표 1m에 나타내었다.Cyclopropyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine in methanol (1.5 mL) (50 mg, 0.13 mmol) was added with stirring 37% formaldehyde (20 mg, 0.26 mmol) and sodium borohydride (10 mg, 0.26 mmol). After the addition was completed, the mixture was stirred at room temperature for 30 minutes, then the reaction mixture was poured into water (15 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 1) to give the title compound (33 mg, 0.08 mmol, 31% yield). The structure and 1 H-NMR data of compound (429) are shown in Table 1m below.

실시예Example 430~484 430-484 : :

실시예 429와 같은 방법으로 화합물 430~484를 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1m에 나타내었다.Compounds 430-484 were synthesized in the same manner as in Example 429, and their structures and 1 H-NMR data are shown in Table 1m below.

Figure 112006042290445-pat00095
Figure 112006042290445-pat00095

Figure 112006042290445-pat00096
Figure 112006042290445-pat00096

Figure 112006042290445-pat00097
Figure 112006042290445-pat00097

Figure 112006042290445-pat00098
Figure 112006042290445-pat00098

Figure 112006042290445-pat00099
Figure 112006042290445-pat00099

Figure 112006042290445-pat00100
Figure 112006042290445-pat00100

Figure 112006042290445-pat00101
Figure 112006042290445-pat00101

실시예Example 485 485 :  : 시클로프로필Cyclopropyl -{4-[2-(1--{4- [2- (1- 에틸피페리딘Ethyl piperidine -4-일)-4-(4--4-yl) -4- (4- 플루오로페닐Fluorophenyl )티아졸-5-일]피리미딘-2-일}아민(485)의 제조 ) Thiazol-5-yl] pyrimidin-2-yl} amine (485)

에탄올(8 mL) 내 시클로프로필-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민(100 mg, 0.25 mmol) 용액에 아이오도에탄(241 mg, 1.54 mmol)와 탄산칼륨(253 mg, 1.83 mmol)를 가하고 상온에서 1일 동안 교반하였다. 반응 혼합물에 물(50 mL) 첨가하고 에틸아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올:메틸렌클로라이드 = 1:1)로 정제하여 표제 화합물(65 mg, 0.15 mmol, 수율 61%)을 얻었다. 화합물(485)의 구조 및 1H-NMR 데이타를 하기 표 1n에 나타내었다.Cyclopropyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine in ethanol (8 mL) (100 mg, 0.25 mmol) was added to iodoethane (241 mg, 1.54 mmol) and potassium carbonate (253 mg, 1.83 mmol) and stirred at room temperature for 1 day. Water (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 1) to give the title compound (65 mg, 0.15 mmol, 61% yield). The structure and 1 H-NMR data of compound (485) are shown in Table 1n below.

실시예Example 486 486 :  : 시클로프로필Cyclopropyl -{4-[4-(4--{4- [4- (4- 플루오로페닐Fluorophenyl )-2-(1-) -2- (1- 이소프로필피페리딘Isopropylpiperidine -4-일)티아졸-5-일]피리미딘-2-일}아민(486)의 제조Preparation of -4-yl) thiazol-5-yl] pyrimidin-2-yl} amine (486)

실시예 485와 같은 방법으로 아이오도에탄 대신에 2-아이오도프로판을 사용하여 실시예 화합물 486을 합성하였다. 화합물(486)의 구조 및 1H-NMR 데이타를 하기 표 1n에 나타내었다.Example compound 486 was synthesized in the same manner as in Example 485, using 2-iodopropane instead of iodoethane. The structure and 1 H-NMR data of compound (486) are shown in Table 1n below.

실시예Example 487 487 : 1-{4-[5-(2- : 1- {4- [5- (2- 시클로프로필아미노피리미딘Cyclopropylaminopyrimidine -4-일)-4-(4--4-yl) -4- (4- 플루오로페닐Fluorophenyl )티아졸-2-일]피페리딘-1-일}에탄온(487)의 제조) Thiazol-2-yl] piperidin-1-yl} ethanone (487)

테트라하이드로퓨란(6 mL) 내 4-[4-(4-플루오로페닐)-2-(4-메틸설파닐페닐)티아졸-5-일]피리딘-2-일아민(238 mg, 0.60 mmol)과 트리에틸아민(61 mg, 0.60 mmol) 용액에 아세틸 클로라이드(47 mg, 0.60 mmol)을 교반하면서 첨가하였다. 첨가 완료 후, 혼합물을 상온에서 1시간 동안 더 교반하고, 반응 혼합물을 물(50 mL)에 붓고 에틸아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(에틸아세테이트)로 정제하여 표제 화합물(140 mg, 0.32 mmol, 수율 53%)을 얻었다. 화합물(487)의 구조 및 1H-NMR 데이타를 하기 표 1n에 나타내었다.4- [4- (4-fluorophenyl) -2- (4-methylsulfanylphenyl) thiazol-5-yl] pyridin-2-ylamine (238 mg, 0.60 mmol in tetrahydrofuran (6 mL) ) And triethylamine (61 mg, 0.60 mmol) were added with stirring of acetyl chloride (47 mg, 0.60 mmol). After the addition was completed, the mixture was further stirred at room temperature for 1 hour, and the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (140 mg, 0.32 mmol, 53% yield). The structure and 1 H-NMR data of compound (487) are shown in Table 1n below.

실시예Example 488~490 488-490 : :

실시예 487과 같은 방법으로 화합물 488~490을 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1n에 나타내었다.Compounds 488 to 490 were synthesized in the same manner as in Example 487, and their structures and 1 H-NMR data are shown in Table 1n.

Figure 112006042290445-pat00102
Figure 112006042290445-pat00102

실시예Example 491 491 :  : 시클로프로필Cyclopropyl -{4-[2-(1--{4- [2- (1- 시클로프로필메틸피페리딘Cyclopropylmethylpiperidine -4-일)-4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민(491)의 제조Preparation of -4-yl) -4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine (491)

테트라하이드로퓨란(8 mL) 내 시클로프로필-{4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-일}메탄온(200 mg, 0.43 mmol)과 리튬알루미늄 하이드라이드(32 mg, 0.84 mmol) 용액을 상온에서 1시간 동안 교반하였다. 반응 혼합물을 물(50 mL)에 붓고, 에틸아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올:메틸렌클로라이드 = 1:20)로 정제하여 표제 화합물(74 mg, 0.16 mmol, 수율 38%)을 얻었다. 화합물(491)의 구조 및 1H-NMR 데이타를 하기 표 1o에 나타내었다.Cyclopropyl- {4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine in tetrahydrofuran (8 mL) The solution of -1-yl} methanone (200 mg, 0.43 mmol) and lithium aluminum hydride (32 mg, 0.84 mmol) was stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1:20) to give the title compound (74 mg, 0.16 mmol, 38% yield). The structure and 1 H-NMR data of compound (491) are shown in Table 1o below.

실시예Example 492 492 :  : 시클로프로필Cyclopropyl -{4-[2-[1-(2--{4- [2- [1- (2- 디메틸아미노에틸Dimethylaminoethyl )피페리딘-4-일]-4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민(492)의 제조) Piperidin-4-yl] -4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine (492)

실시예 491과 동일한 방법으로, 시클로프로필-{4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일] 피페리딘-1-일}메탄온 대신에 1-{4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐) 티아졸-2-일]피페리딘-1-일}-2-디메틸아미노 에탄온을 사용하여 실시예 화합물 492를 합성하였다. 화합물(492)의 구조 및 1H-NMR 데이타를 하기 표 1o에 나타내었다.In the same manner as in Example 491, cyclopropyl- {4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine 1- {4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine instead of -1-yl} methanone Example Compound 492 was synthesized using -1-yl} -2-dimethylamino ethanone. The structure and 1 H-NMR data of compound (492) are shown in Table 1o below.

실시예Example 493 493 : N-{4-[4-(4- : N- {4- [4- (4- 플루오로페닐Fluorophenyl )-2-(4-) -2- (4- 메틸설파닐페닐Methylsulfanylphenyl )티아졸-5-일]피리딘-2-일}프로피온아미드(493)의 제조) Thiazol-5-yl] pyridin-2-yl} propionamide (493)

테트라하이드로퓨란(10 mL) 내 4-[4-(4-플루오로페닐)-2-(4-메틸설파닐페닐)티아졸-5-일]피리딘-2-일아민(710 mg, 1.80 mmol)의 용액을 0 ℃로 냉각시키고, 프로피오닐 클로라이드(190 mg, 2.00 mmol)와 트리에틸아민(190 mg, 1.87 mmol)을 교반하면서 첨가하였다. 첨가 완료 후, 혼합물을 상온에서 1시간 동안 교반한 다음 반응 혼합물을 탄산수소나트륨의 포화 수용액(50 mL)에 첨가하였다. 생성된 결정을 여과하고, 물로 세척하였다. 에틸 아세테이트(10 mL) 내에 결정을 첨가시키고, 1 시간 동안 교반하고, 여과하여 표제 화합물(660 mg, 1.46 mmol, 수율 81%)을 얻었다. 화합물(493)의 구조 및 1H-NMR 데이타를 하기 표 1o에 나타내었다.4- [4- (4-fluorophenyl) -2- (4-methylsulfanylphenyl) thiazol-5-yl] pyridin-2-ylamine (710 mg, 1.80 mmol) in tetrahydrofuran (10 mL) ) Solution was cooled to 0 ° C. and propionyl chloride (190 mg, 2.00 mmol) and triethylamine (190 mg, 1.87 mmol) were added with stirring. After the addition was completed, the mixture was stirred at room temperature for 1 hour and then the reaction mixture was added to a saturated aqueous solution of sodium hydrogen carbonate (50 mL). The resulting crystals were filtered off and washed with water. Crystals were added in ethyl acetate (10 mL), stirred for 1 hour, and filtered to afford the title compound (660 mg, 1.46 mmol, yield 81%). The structure and 1 H-NMR data of compound (493) are shown in Table 1o below.

실시예Example 494~498 494-498 :  :

실시예 493과 같은 방법으로 화합물 494~498을 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1o에 나타내었다.Compounds 494-498 were synthesized in the same manner as in Example 493, and their structures and 1 H-NMR data are shown in Table 1o below.

Figure 112006042290445-pat00103
Figure 112006042290445-pat00103

실시예Example 499 499 : N-{4-[4-(4- : N- {4- [4- (4- 플루오로페닐Fluorophenyl )-2-(4-) -2- (4- 메탄설피닐페닐Methanesulfinylphenyl )티아졸-5-일]피리딘-2-일}프로피온아미드(499)의 제조) Thiazol-5-yl] pyridin-2-yl} propionamide (499)

메틸렌클로라이드(100 mL) 내 N-{4-[4-(4-플루오로페닐)-2-(4-메틸설파닐페닐)티아졸-5-일]피리딘-2-일}프로피온아미드(300 mg, 0.66 mmol)의 용액을 0 ℃로 냉각시키고, 65% 메타-클로로퍼벤조산(212 mg, 0.80 mmol)을 교반하면서 첨가하였다. 첨가 완료 후, 혼합물을 30분 동안 더 교반한 다음 반응 혼합물에 2 N 탄산나트륨 용액(100 mL)을 가하고, 메틸렌클로라이드 층을 분리하였다. 유기층을 물로 세척한 다음 황산마그네슘으로 건조시킨 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올:메틸렌클로라이드 = 1:1)로 정제하여 표제 화합물(139 mg, 0.300 mmol, 수율 45%)을 얻었다. 화합물(499)의 구조 및 1H-NMR 데이타를 하기 표 1p에 나타내었다.N- {4- [4- (4-fluorophenyl) -2- (4-methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl} propionamide (300 mL) in methylene chloride (100 mL) mg, 0.66 mmol) was cooled to 0 ° C. and 65% meta-chloroperbenzoic acid (212 mg, 0.80 mmol) was added with stirring. After the addition was completed, the mixture was further stirred for 30 minutes, then 2N sodium carbonate solution (100 mL) was added to the reaction mixture, and the methylene chloride layer was separated. The organic layer was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 1) to give the title compound (139 mg, 0.300 mmol, 45% yield). The structure and 1 H-NMR data of compound (499) are shown in Table 1p below.

실시예Example 500 500 : N-{4-[4-(4- : N- {4- [4- (4- 플루오로페닐Fluorophenyl )-2-(4-) -2- (4- 메탄설포닐페닐Methanesulfonylphenyl )티아졸-5-일]피리딘-2-일}프로피온아미드(500)의 제조) Thiazol-5-yl] pyridin-2-yl} propionamide (500)

메틸렌클로라이드(100 mL) 내 N-{4-[4-(4-플루오로페닐)-2-(4-메틸설파닐페닐)티아졸-5-일]피리딘-2-일}프로피온아미드(300 mg, 0.66 mmol)의 용액에 65% 메타-클로로퍼벤조산(400 mg, 1.50 mmol)을 교반하면서 첨가하였다. 첨가 완료 후, 혼합물을 1시간 동안 더 교반한 다음 반응 혼합물에 2 N 탄산나트륨 용액(100 mL)을 가하고, 메틸렌클로라이드 층을 분리하였다. 유기층을 물로 세척한 다음, 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올:메틸렌클로라이드 = 1:1)로 정제하여 표제 화합물(70 mg, 0.14 mmol, 수율 22%)을 얻었다. 화합물(500)의 구조 및 1H-NMR 데이타를 하기 표 1p에 함께 나타내었다.N- {4- [4- (4-fluorophenyl) -2- (4-methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl} propionamide (300 mL) in methylene chloride (100 mL) mg, 0.66 mmol) was added with stirring 65% meta-chloroperbenzoic acid (400 mg, 1.50 mmol). After the addition was completed, the mixture was further stirred for 1 hour, then 2N sodium carbonate solution (100 mL) was added to the reaction mixture, and the methylene chloride layer was separated. The organic layer was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 1) to give the title compound (70 mg, 0.14 mmol, yield 22%). The structure of the compound 500 and the 1 H-NMR data are shown together in Table 1p.

실시예Example 501 501 : N-{4-[4-(4- : N- {4- [4- (4- 플루오로페닐Fluorophenyl )-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}프로피온아미드(501)의 제조) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} propionamide (501)

클로로포름(3 mL) 내 4-[4-(4-플루오로페닐)-5-(2-프로피오닐아미노피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터(56 mg, 0.12 mmol)의 용액에 아이오도트리메틸실란(140 mg, 0.52 mmol)을 가한 후, 60 ℃에서 5시간 동안 반응시켰다. 반응 혼합물을 0 ℃로 냉각한 후, 프로판올 내 염화수소의 6 N 용액(1 mL)을 혼합물에 가하고, 세게 교반하면서 균질화시켰다. 그 다음 반응 혼합물에 2 N 수산화나트륨 용액을 가하고, 혼합물을 메틸렌클로라이드로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카 겔 칼럼 크로마토그래피(메탄올:메틸렌클로라이드 = 1:1)로 정제하여 표제 화합물(8 mg, 0.02 mmol, 수율 17%)을 얻었다. 화합물(501)의 구조 및 1H-NMR 데이타를 하기 표 1p에 함께 나타내었다.4- [4- (4-fluorophenyl) -5- (2-propionylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid in chloroform (3 mL) Iodotrimethylsilane (140 mg, 0.52 mmol) was added to a solution of ethyl ester (56 mg, 0.12 mmol) and reacted at 60 ° C. for 5 hours. After the reaction mixture was cooled to 0 ° C., a 6 N solution of hydrogen chloride in propanol (1 mL) was added to the mixture and homogenized with vigorous stirring. Then 2N sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 1) to give the title compound (8 mg, 0.02 mmol, yield 17%). The structure of the compound 501 and the 1 H-NMR data are shown together in Table 1p.

실시예Example 502~503 502-503 : :

실시예 501과 같은 방법으로 화합물 502~503를 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1p에 함께 나타내었다.Compounds 502 to 503 were synthesized in the same manner as in Example 501, and their structures and 1 H-NMR data are shown together in Table 1p.

실시예Example 504 504 : N-[4-(3- : N- [4- (3- 클로로페닐Chlorophenyl )-5-(2-) -5- (2- 메틸설파닐피리미딘Methylsulfanylpyrimidine -4-일)티아졸-2-일]-6,N-디메틸니코틴아미드(504)의 제조Preparation of -4-yl) thiazol-2-yl] -6, N-dimethylnicotinamide 504

벤젠(5 mL) 내 6-메틸니코틴산 310 mg, 4.44 mmol) 용액을 0 ℃로 냉각시키고, 벤젠(2 mL) 내 옥사릴클로라이드 (378 mL, 4.44 mmol) 용액을 교반하면서 적가하였다. 첨가 완료 후, N,N-디메틸포름아미드(25 mL)를 첨가하였다. 반응 혼합물에 4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민(1.03 g, 3.07 mmol)과 4-(디메틸아미노)피리딘(126 mg, 1.03 mmol)을 첨가하고, 80 ℃에서 철야 교반하였다. 반응 혼합물을 실온으로 냉각시킨 후 반응 혼합물에 탄산수소나트륨의 포화 수용액(200 mL)을 첨가하고, 혼합물을 에틸 아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(에틸 아세테이트:n-헥산 = 1:2)로 정제하여, 표제 화합물(570 mg,1.22 mmol, 수율 41%)을 얻었다. 화합물(504)의 구조 및 1H-NMR 데이타를 하기 표 1p에 함께 나타내었다.A solution of 310 mg, 4.44 mmol) of 6-methylnicotinic acid in benzene (5 mL) was cooled to 0 ° C. and a solution of oxarylyl chloride (378 mL, 4.44 mmol) in benzene (2 mL) was added dropwise with stirring. After the addition was completed, N, N-dimethylformamide (25 mL) was added. To the reaction mixture, 4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine (1.03 g, 3.07 mmol) and 4- (dimethylamino) pyridine ( 126 mg, 1.03 mmol) was added and stirred overnight at 80 ° C. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to give the title compound (570 mg, 1.22 mmol, yield 41%). The structure of the compound 504 and the 1 H-NMR data are shown together in Table 1p.

실시예Example 505 505 : N-[4-(3- : N- [4- (3- 클로로페닐Chlorophenyl )-5-(2-) -5- (2- 메탄설피닐피리미딘Methanesulfinylpyrimidine -4-일)티아졸-2-일]-6,N-디메틸니코틴아미드(505)의 제조Preparation of -4-yl) thiazol-2-yl] -6, N-dimethylnicotinamide 505

메틸렌클로라이드(20 mL) 내 N-[4-(3-클로로페닐)-5-(2-메틸설파닐 피리미딘-4-일)티아졸-2-일]-6,N-디메틸니코틴아미드(531 mg, 1.13 mmol)의 용액을 0 ℃ 로 냉각시키고, 65% 메타-클로로퍼벤조산(279 mg, 1.13 mmol)을 교반하면서 첨가하였다. 첨가 완료 후, 혼합물을 10분 동안 더 교반한 다음 반응 혼합물을 2 N 탄산나트륨 용액(30 mL)에 첨가하고, 혼합물을 메틸렌클로라이드로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(에틸아세테이트:메탄올 = 30:1)로 정제하여 표제 화합물(457 mg, 0.94 mmol, 수율 84%)을 얻었다. 화합물(505)의 구조 및 1H-NMR 데이타를 하기 표 1p에 함께 나타내었다.N- [4- (3-chlorophenyl) -5- (2-methylsulfanyl pyrimidin-4-yl) thiazol-2-yl] -6, N-dimethylnicotinamide in methylene chloride (20 mL) ( 531 mg, 1.13 mmol) was cooled to 0 ° C. and 65% meta-chloroperbenzoic acid (279 mg, 1.13 mmol) was added with stirring. After the addition was completed, the mixture was further stirred for 10 minutes and then the reaction mixture was added to 2 N sodium carbonate solution (30 mL) and the mixture was extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 30: 1) to obtain the title compound (457 mg, 0.94 mmol, 84% yield). The structure of the compound 505 and the 1 H-NMR data are shown together in Table 1p.

실시예Example 506 506 : N-{4-(3- : N- {4- (3- 클로로페닐Chlorophenyl )-5-[2-(1-(S)-) -5- [2- (1- (S)- 페닐에틸아미노Phenylethylamino )피리미딘-4-일]티아졸-2-일}-6,N-디메틸니코틴아미드(506)의 제조) Pyrimidin-4-yl] thiazol-2-yl} -6, N-dimethylnicotinamide (506)

벤젠(2 mL) 내 6-메틸니코티틴산(146 mg, 1.06 mmol) 용액을 0 ℃로 냉각시키고, 벤젠(1 mL) 내 옥사릴클로라이드(90 mL, 1.06 mmol) 용액을 교반하면서 적가하였다. 첨가 완료 후, N,N-디메틸포름아미드(10 mL)를 첨가하였다. 반응 혼합물에 {4-[4-(3-클로로페닐)-2-메틸아미노티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민(300 mg, 0.71 mmol)과 4-(디메틸아미노)피리딘(28 mg, 0.23 mmol)을 첨가한 후, 80 ℃에서 철야 교반하였다. 반응 혼합물을 실온으로 냉각시키고, 반응 혼합물에 탄산수소나트륨의 포화 수용액(100 mL)을 첨가한 후, 혼합물을 에틸 아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(에틸 아세테이트:n-헥산 = 1:2)로 정제하여 표제 화합물(142 mg, 0.26 mmol, 수율 37%)을 얻었다. 화합물(506)의 구조 및 1H-NMR 데이타를 하기 표 1p에 함께 나타내었다.A solution of 6-methylnicotinic acid (146 mg, 1.06 mmol) in benzene (2 mL) was cooled to 0 ° C and a solution of oxarylyl chloride (90 mL, 1.06 mmol) in benzene (1 mL) was added dropwise with stirring. After the addition was completed, N, N-dimethylformamide (10 mL) was added. To the reaction mixture {4- [4- (3-chlorophenyl) -2-methylaminothiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine (300 mg, 0.71 mmol) and 4- (dimethylamino) pyridine (28 mg, 0.23 mmol) were added, followed by stirring overnight at 80 ° C. The reaction mixture was cooled to room temperature and a saturated aqueous solution of sodium hydrogen carbonate (100 mL) was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to give the title compound (142 mg, 0.26 mmol, yield 37%). The structure of the compound 506 and the 1 H-NMR data are shown together in Table 1p.

Figure 112006042290445-pat00104
Figure 112006042290445-pat00104

실시예Example 507 507 : 2- : 2- 클로로Chloro -1-(4--1- (4- 플루오로페닐Fluorophenyl )-2-(2-) -2- (2- 메틸티오Methylthio -4--4- 피리미딜Pyrimidyl )) 에타Eta 논(507)의 제조(화학식 2의 화합물)Preparation of the paddy 507 (compound of formula 2)

무수 테트라하이드로퓨란(3 mL)내 1-(4-플루오로페닐)-2-(2-메틸티오-4-피리미딜)에타논(131 mg, 0.5 mmol)의 용액을 -78 ℃로 냉각시키고, 핵산내 1.8 M 리튬 디이소프로필아미드의 용액 (306 mL, 0.55 mmol)을 교반하면서 적가하였다. 첨가 완료 후, 혼합물을 20분 동안 교반하였다. 그 다음 무수 트리플루오로메틸설포닐 클로라이드(53 mL, 0.50 mmol)를 적가하였다. 첨가 완료 후, 혼합물을 실온으로 가온시키고, 물(20 mL)을 혼합물에 첨가하고, 에틸 아세테이트로 추출하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조시킨 후, 여과하고 용매를 증류제거하여 표제 화합물(130 mg, 0.44 mmol, 수율 88%)을 수득하여 정제 없이 그 다음 반응에 사용하였다. 화합물(507)의 구조 및 1H-NMR 데이타를 하기 표 1q에 함께 나타내었다.A solution of 1- (4-fluorophenyl) -2- (2-methylthio-4-pyrimidyl) ethanone (131 mg, 0.5 mmol) in anhydrous tetrahydrofuran (3 mL) was cooled to -78 ° C and , A solution of 1.8 M lithium diisopropylamide in nucleic acid (306 mL, 0.55 mmol) was added dropwise with stirring. After the addition was completed, the mixture was stirred for 20 minutes. Anhydrous trifluoromethylsulfonyl chloride (53 mL, 0.50 mmol) was then added dropwise. After the addition was completed, the mixture was allowed to warm to room temperature, water (20 mL) was added to the mixture and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off to give the title compound (130 mg, 0.44 mmol, yield 88%) which was used in the next reaction without purification. The structure of the compound (507) and the 1 H-NMR data are shown together in Table 1q.

실시예Example 507-1 507-1 : 2-클로로-1-(4-플루오로페닐)-2-(2-메틸티오-4-피리미딜)에 : 2-chloro-1- (4-fluorophenyl) -2- (2-methylthio-4-pyrimidyl) 타논Thanon (507)의 또 다른 제조법Another recipe of 507

트리메틸클로로실란(11.7 g, 107.5 mmol)을 테트라하이드로퓨란(650 mL)내 테트라부틸암모늄브로마이드(2 g, 10.7 mmol)의 용액에 첨가하고, 상온에서 30분 동안 교반하였다. 반응 혼합물을 0 ℃로 냉각시키고, 1-(4-플루오로페닐)-2-(2-메틸티오-4-피리미딜)에타논 (9.4 g, 35.8 mmol)과 디메틸설폭사이드(2.9 g, 37.6 mmol)을 가한 후 상온으로 올리고 2시간 동안 교반하였다. 반응 혼합물을 농축시키고, 에틸 아세테이트로 추출하고, 탄산수소나트륨의 포화 수용액으로 세척하였다. 추출물을 물로 세척한 다음 황산마그네슘으로 건조한 후, 여과하고 용매를 증류제거하여 표제화합물(10.3 g, 34.7 mmol, 수율 97%)을 수득하여 정제 없이 그 다음 반응에 사용하였다.Trimethylchlorosilane (11.7 g, 107.5 mmol) was added to a solution of tetrabutylammonium bromide (2 g, 10.7 mmol) in tetrahydrofuran (650 mL) and stirred at room temperature for 30 minutes. The reaction mixture is cooled to 0 ° C. and 1- (4-fluorophenyl) -2- (2-methylthio-4-pyrimidyl) ethanone (9.4 g, 35.8 mmol) and dimethyl sulfoxide (2.9 g, 37.6 mmol) were added thereto, followed by raising to room temperature and stirring for 2 hours. The reaction mixture was concentrated, extracted with ethyl acetate and washed with a saturated aqueous solution of sodium hydrogen carbonate. The extract was washed with water, dried over magnesium sulfate, filtered and the solvent was distilled off to obtain the title compound (10.3 g, 34.7 mmol, yield 97%) which was used in the next reaction without purification.

실시예Example 508~513 508-513 :  :

실시예 507 또는 실시예 507-1과 같은 방법으로 화합물 508~513을 합성하고 이들의 구조 및 1H-NMR 데이타를 하기 표 1q에 함께 나타내었다.Compounds 508-513 were synthesized in the same manner as in Example 507 or 507-1, and their structures and 1 H-NMR data are shown together in Table 1q.

Figure 112006042290445-pat00105
Figure 112006042290445-pat00105

하기 표 1r에는 본 발명에 따른 상기 실시예 1~506의 화합물 내의 R1, R2, R3 및 Z에 대하여 이의 구별이 용이하도록 정리하여 나타내었다. Table 1r is summarized to facilitate the differentiation of R1, R2, R3 and Z in the compounds of Examples 1 to 506 according to the present invention.

Figure 112006042290445-pat00106
Figure 112006042290445-pat00106

Figure 112006042290445-pat00107
Figure 112006042290445-pat00107

Figure 112006042290445-pat00108
Figure 112006042290445-pat00108

Figure 112006042290445-pat00109
Figure 112006042290445-pat00109

Figure 112006042290445-pat00110
Figure 112006042290445-pat00110

Figure 112006042290445-pat00111
Figure 112006042290445-pat00111

Figure 112006042290445-pat00112
Figure 112006042290445-pat00112

Figure 112006042290445-pat00113
Figure 112006042290445-pat00113

Figure 112006042290445-pat00114
Figure 112006042290445-pat00114

Figure 112006042290445-pat00115
Figure 112006042290445-pat00115

Figure 112006042290445-pat00116
Figure 112006042290445-pat00116

Figure 112006042290445-pat00117
Figure 112006042290445-pat00117

Figure 112006042290445-pat00118
Figure 112006042290445-pat00118

Figure 112006042290445-pat00119
Figure 112006042290445-pat00119

Figure 112006042290445-pat00120
Figure 112006042290445-pat00120

Figure 112006042290445-pat00121
Figure 112006042290445-pat00121

Figure 112006042290445-pat00122
Figure 112006042290445-pat00122

Figure 112006042290445-pat00123
Figure 112006042290445-pat00123

Figure 112006042290445-pat00124
Figure 112006042290445-pat00124

Figure 112006042290445-pat00125
Figure 112006042290445-pat00125

Figure 112006042290445-pat00126
Figure 112006042290445-pat00126

Figure 112006042290445-pat00127
Figure 112006042290445-pat00127

Figure 112006042290445-pat00128
Figure 112006042290445-pat00128

Figure 112006042290445-pat00129
Figure 112006042290445-pat00129

Figure 112006042290445-pat00130
Figure 112006042290445-pat00130

Figure 112006042290445-pat00131
Figure 112006042290445-pat00131

Figure 112006042290445-pat00132
Figure 112006042290445-pat00132

실험예Experimental Example 1 One : 본 발명에 따른 화합물들의  Of the compounds according to the invention. 비면역세포들에On non-immune cells 대한 독성 실험 Toxicity test

본 발명에 따른 화합물들의 비면역세포들에 대한 독성을 알아보기 위하여, SRB (Sulforhodamine B)법을 이용하여 하기와 같은 실험을 수행하였다.In order to determine the toxicity of non-immune cells of the compounds according to the present invention, the following experiment was performed using SRB (Sulforhodamine B) method.

실험에 사용한 세포주로는 인체 유방암 세포주인 MDA-MB-231, 인체 폐암 세포주인 A549, 인체 신장암 세포주인 ACHN, 인체 위장암 세포주인 SUN216, 인체 간암 세포주인 SUN709 이며, 미국의 세포주 은행(American Type Culture Collection)으로부터 구입하여 사용하였다.Cell lines used in the experiments were human breast cancer cell line MDA-MB-231, human lung cancer cell line A549, human kidney cancer cell line ACHN, human gastric cancer cell line SUN216, human liver cancer cell line SUN709, and American cell line bank (American Type) Culture Collection) was used.

세포는 10% 소 태아 혈청(fetal bovine serum: FBS)을 포함하는 RPMI 배지에서 배양하였다. 세포들을 96 웰 플레이트에 적절한 농도(1 x 106 cells/ml)로 가한 후, 5% CO2, 37℃의 배양 조건 하에서 배양하였다. 24시간 후에 상기 실시예 115, 126, 334, 429에서 제조한 화합물을 1-10 μM 의 농도로 첨가하였다. 시료 첨가 후 48시간 동안 더 배양하였으며, 5% 트리클로로아세트산 (Trichloroacetic acid)을 첨가하여 세포를 배양용기의 바닥에 고정하였다. 고정된 세포들의 단백질을 SRB(sulforhodamine B) 용액으로 염색한 후 595㎚에서 흡광도를 측정하였다. 살아있는 세포가 많을수록 흡광도는 증가하게 되며, 결과는 대조군(100%)에 대한 비율로 표시하였다. 결과는 표 2 내지 표 6에 나타내었다.Cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS). Cells were added to 96 well plates at appropriate concentrations (1 × 10 6 cells / ml) and then incubated under culture conditions of 5% CO 2 , 37 ° C. After 24 hours the compounds prepared in Examples 115, 126, 334, 429 were added at a concentration of 1-10 μM. After 48 hours, the cells were further incubated, and 5% trichloroacetic acid was added to fix the cells to the bottom of the culture vessel. Proteins of fixed cells were stained with sulforhodamine B (SRB) solution and absorbance was measured at 595 nm. As the number of living cells increases, the absorbance increases, and the results are expressed as a ratio with respect to the control group (100%). The results are shown in Tables 2-6.

본 발명에 따른 화합물의 인체 유방암 세포주인 MDA-MB-231에 대한 독성Toxicity of the Compound of the Invention to MDA-MB-231, a Human Breast Cancer Cell Line 살아있는 세포수(%)Number of living cells (%) 실시예 115Example 115 실시예 126Example 126 실시예 334Example 334 실시예 429Example 429 대조군Control 100100 100100 100100 100100 1μM1 μM 97±397 ± 3 90±790 ± 7 97±297 ± 2 99±699 ± 6 3μM3 μM 95±195 ± 1 87±1087 ± 10 76±476 ± 4 91±891 ± 8 10μM10 μM 77±377 ± 3 53±853 ± 8 52±252 ± 2 61±661 ± 6

본 발명에 따른 화합물의 인체 폐암 세포주인 A549에 대한 독성Toxicity of the Compound of the Invention to A549, a Human Lung Cancer Cell Line 살아있는 세포수(%)Number of living cells (%) 실시예 115Example 115 실시예 126Example 126 실시예 334Example 334 실시예 429Example 429 대조군Control 100100 100100 100100 100100 1μM1 μM 89±289 ± 2 89±389 ± 3 87±287 ± 2 91±591 ± 5 3μM3 μM 79±779 ± 7 76±176 ± 1 62±162 ± 1 73±273 ± 2 10μM10 μM 53±453 ± 4 45±145 ± 1 40±140 ± 1 44±144 ± 1

본 발명에 따른 화합물의 인체 신장암 세포주인 ACHN에 대한 독성Toxicity of the Compound of the Invention to ACHN, a Human Kidney Cancer Cell Line 살아있는 세포수(%)Number of living cells (%) 실시예 115Example 115 실시예 126Example 126 실시예 334Example 334 실시예 429Example 429 대조군Control 100100 100100 100100 100100 1μM1 μM 96±496 ± 4 99±299 ± 2 99±599 ± 5 99±599 ± 5 3μM3 μM 99±299 ± 2 99±299 ± 2 86±386 ± 3 99±599 ± 5 10μM10 μM 79±979 ± 9 63±163 ± 1 55±255 ± 2 55±355 ± 3

본 발명에 따른 화합물의 인체 위장암 세포주인 SUN216에 대한 독성Toxicity of the compound according to the invention to SUN216, a human gastrointestinal cancer cell line 살아있는 세포수(%)Number of living cells (%) 실시예 115Example 115 실시예 126Example 126 실시예 334Example 334 실시예 429Example 429 대조군Control 100100 100100 100100 100100 1μM1 μM 80±280 ± 2 89±289 ± 2 93±393 ± 3 98±298 ± 2 3μM3 μM 78±178 ± 1 86±286 ± 2 73±373 ± 3 85±385 ± 3 10μM10 μM 54±454 ± 4 45±245 ± 2 35±135 ± 1 49±349 ± 3

본 발명에 따른 화합물의 인체 간암 세포주인 SUN709에 대한 독성Toxicity of SUN709, a Human Liver Cancer Cell Line, of the Compounds According to the Present Invention 살아있는 세포수(%)Number of living cells (%) 실시예 115Example 115 실시예 126Example 126 실시예 334Example 334 실시예 429Example 429 대조군Control 100100 100100 100100 100100 1μM1 μM 88±188 ± 1 88±288 ± 2 90±490 ± 4 86±286 ± 2 3μM3 μM 78±178 ± 1 75±175 ± 1 78±278 ± 2 79±479 ± 4 10μM10 μM 44±244 ± 2 27±327 ± 3 49±149 ± 1 48±648 ± 6

표 2 내지 표 6에 나타난 바와 같이, 본 발명에 따른 화합물(실시예 115, 126, 334, 429)은 3 μM의 농도에서 매우 약한 독성을, 10 μM의 농도에서는 독성을 나타내었다.As shown in Tables 2-6, the compounds according to the invention (Examples 115, 126, 334, 429) showed very weak toxicity at concentrations of 3 μM and toxicity at concentrations of 10 μM.

실험예Experimental Example 2 2 : 본 발명에 따른 화합물들의  Of the compounds according to the invention. 대식세포주에In macrophage lines 대한 독성 실험 Toxicity test

본 발명에 따른 화합물들의 대식세포주에 대한 독성을 알아보기 위하여, MTT법을 이용하여 하기와 같은 실험을 수행하였다.In order to determine the toxicity of macrophages of the compounds according to the present invention, the following experiment was performed using the MTT method.

MTT는 무색의 시약이지만, 살아있는 세포에 의해 분해되면 색깔을 나타내는 포마잔(formazam)으로 변하게 되는 시약으로 살아있는 세포의 양을 측정할 수 있어서 널리 사용되고 있다.MTT is a colorless reagent, but it is widely used because it can measure the amount of living cells as a reagent that turns into colored forazam when degraded by living cells.

실험에 사용한 세포주로는 마우스 대식세포 유래 암세포주인 RAW264.7 세포이며, 미국의 세포주 은행(American Type Culture Collection)으로부터 구입하여 사용하였다.The cell lines used in the experiment were RAW264.7 cells, which are mouse macrophage-derived cancer cell lines, which were purchased from the American Cell Line Bank (American Type Culture Collection).

세포는 10% 소 태아 혈청(fetal bovine serum: FBS)을 포함하는 RPMI 배지에서 배양하였다. RAW264.7 세포를 96 웰 플레이트에 적절한 농도(1 x 106 cells/ml)로 가한 후, 5% CO2, 37℃의 배양 조건 하에서 배양하였다. 24시간 후에 상기 실시예 115, 126, 334, 429에서 제조한 화합물을 0.1-10 μM 의 농도로 첨가하였다. 24시간 동안 배양한 후에 MTT 시약을 첨가 하였으며, 4시간 후에 살아있는 세포에 의해 생성된 포마잔의 양을 595 ㎚에서 측정한 후, 결과는 대조군(100%)에 대한 비율로 표시하였다. 결과는 표 7에 나타내었다.Cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS). RAW264.7 cells were added to an appropriate concentration (1 × 10 6 cells / ml) in a 96 well plate and then incubated under culture conditions of 5% CO 2 , 37 ° C. After 24 hours the compounds prepared in Examples 115, 126, 334, 429 were added at a concentration of 0.1-10 μM. After incubation for 24 hours, MTT reagent was added, and after 4 hours, the amount of formazan produced by living cells was measured at 595 nm, and the results were expressed as a ratio with respect to the control group (100%). The results are shown in Table 7.

본 발명에 따른 화합물의 마우스 대식세포 유래 암세포주인 RAW264.7 세포에 대한 독성Toxicity of RAW264.7 Cells, a Mouse Macrophage-Derived Cancer Cell Line, of the Compounds According to the Present Invention 살아있는 세포수(%)Number of living cells (%) 실시예 115Example 115 실시예 126Example 126 실시예 334Example 334 실시예 429Example 429 대조군Control 100100 100100 100100 100100 0.1μM0.1 μM 96±796 ± 7 93±293 ± 2 91±791 ± 7 96±296 ± 2 0.3μM0.3 μM 98±498 ± 4 102±4102 ± 4 95±695 ± 6 93±293 ± 2 1μM1 μM 100±4100 ± 4 100±4100 ± 4 89±689 ± 6 89±289 ± 2 3μM3 μM 98±498 ± 4 96±496 ± 4 88±488 ± 4 91±391 ± 3 10μM10 μM 98±698 ± 6 98±498 ± 4 74±674 ± 6 78±278 ± 2

표 7에 나타난 바와 같이, 실시예 115 및 126의 화합물은 10 μM의 농도까지 세포독성을 보이지 않았다. 그러나 실시예 334 및 429의 화합물은 10 μM의 농도에서 약한 세포독성을 나타내었다.As shown in Table 7, the compounds of Examples 115 and 126 showed no cytotoxicity up to a concentration of 10 μΜ. However, the compounds of Examples 334 and 429 showed weak cytotoxicity at a concentration of 10 μM.

이하의 실험예에서는 세포독성이 없는 농도에서의 화합물들의 면역억제효과를 측정하기 위하여 1 μM 이하의 농도를 사용하였다.In the following experimental examples, a concentration of 1 μM or less was used to measure the immunosuppressive effects of the compounds at the concentration without cytotoxicity.

실험예Experimental Example 3 3 : 본 발명에 따른 화합물들의 인체 대식세포 유래 암세포주인  : Human macrophage-derived cancer cell line of the compounds according to the invention THPTHP -1 세포의 -1 cell TNFTNF -α 생성억제 효과-α production inhibitory effect

본 발명에 따른 화합물들의 인체 대식세포 유래 암세포주인 THP-1 세포의 TNF-α 생성억제 효과를 알아보기 위하여, 하기와 같은 실험을 수행하였다.In order to investigate the effects of the TNF-α production of the compounds according to the present invention, THP-1 cells, a human macrophage-derived cancer cell line, the following experiment was performed.

실험에 사용한 세포주로는 인체 단핵구 세포주인 THP-1 세포이며, 미국의 세포주 은행(American Type Culture Collection)에서 구입하여 사용하였다.The cell lines used in the experiment were THP-1 cells, which are human monocyte cell lines, and were purchased from the American Cell Line Bank (American Type Culture Collection).

세포는 10% 소 태아 혈청(fetal bovine serum: FBS)을 포함하는 RPMI 배지에서 배양하였다. THP-1 세포를 96 웰 플레이트에 적절한 농도(1 x 106 cells/ml)로 가한 후, 5% CO2, 37 ℃의 배양 조건 하에서 배양하였다. TNF-α의 생성은 리포폴리사카라이드(최종 농도 1 mg/ml) (시그마, 미국)를 이용하여 유도하였으며, 상기 실시예 115, 126, 334, 429에서 제조한 화합물을 0.0003 ~ 1 μM 농도로 첨가하였다. 24시간 후에 배양액을 수거하여 세포배양액 내에 존재하는 TNF-α의 양을 ELISA 키트(Quantikine colorimetric sandwich ELISA assay kit, R&D systems사, USA)를 사용하여 정량하고 그 결과를 하기 표 8a에 나타내었다.Cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS). THP-1 cells were added to an appropriate concentration (1 × 10 6 cells / ml) in a 96 well plate and then cultured under 5% CO 2 , 37 ° C. culture conditions. Production of TNF-α was induced using lipopolysaccharide (final concentration 1 mg / ml) (Sigma, USA), and the compounds prepared in Examples 115, 126, 334, and 429 at 0.0003-1 μM concentrations. Added. After 24 hours, the culture was collected and the amount of TNF-α present in the cell culture was quantified using an ELISA kit (Quantikine colorimetric sandwich ELISA assay kit, R & D systems, USA) and the results are shown in Table 8A.

본 발명에 따른 화합물들의 인체 대식세포 유래 암세포주인 THP-1 세포의 TNF-α 생성억제 효과TNF-α Production Inhibitory Effects of THP-1 Cells, a Human Macrophage-Derived Cancer Cell Line, of the Compounds According to the Present Invention TNF-α(pg/㎖)TNF-α (pg / ml) 실시예 33Example 33 실시예 44Example 44 실시예 75Example 75 실시예 88Example 88 대조군Control 221±12221 ± 12 206±15206 ± 15 180±6180 ± 6 181±10181 ± 10 0.0003μM0.0003 μM 167±12167 ± 12 163±8163 ± 8 127±7127 ± 7 90±590 ± 5 0.001μM0.001 μM 116±5116 ± 5 110±10110 ± 10 85±785 ± 7 67±267 ± 2 0.003μM0.003 μM 116±15116 ± 15 65±465 ± 4 63±363 ± 3 43±143 ± 1 0.01μM0.01 μM 107±10107 ± 10 53±653 ± 6 31±331 ± 3 24±224 ± 2 0.03μM0.03 μM 86±386 ± 3 46±546 ± 5 24±124 ± 1 18±218 ± 2 0.1μM0.1 μM 58±458 ± 4 40±240 ± 2 17±217 ± 2 12±212 ± 2 0.3μM0.3 μM 37±237 ± 2 27±527 ± 5 9±39 ± 3 5±35 ± 3 1μM1 μM 30±130 ± 1 40±440 ± 4 11±111 ± 1 7±27 ± 2

표 8a에 나타난 바와 같이, 본 발명에 따른 실시예 115, 126, 334 및 429의 화합물은 THP-1 세포의 TNF-α의 생성을 농도의존적으로 억제하는 것으로 나타났다. 특히, 실시예 429의 화합물은 0.28 nM의 50% 억제농도(IC50)를 보여 가장 우수한 억제 효과를 나타내었으며, 실시예 334의 화합물은 1 nM, 실시예 126의 화합물은 1.4 nM, 실시예 115의 화합물은 0.48 nM의 IC50를 나타내었다.As shown in Table 8a, the compounds of Examples 115, 126, 334 and 429 according to the present invention were found to inhibit concentration of TNF-α production in THP-1 cells. In particular, the compound of Example 429 showed a 50% inhibitory concentration (IC 50 ) of 0.28 nM showed the best inhibitory effect, the compound of Example 334 is 1 nM, the compound of Example 126 is 1.4 nM, Example 115 The compound of showed an IC 50 of 0.48 nM.

상기 실시예 115, 126, 334 및 429에서와 동일한 조건에서 실시예 1~506에서 제조한 화합물 가운데 일부의 화합물을 선택하여 1 μM의 농도로 첨가하였다. 24시간 후에 배양액을 수거하여 세포배양액 내에 존재하는 LPS만을 처리하여 유도된 군의 TNF-α의 양을 100%로 하고, 본 발명에 따른 화합물 가운데 일부를 선택하여 투여한 실험군에서의 LPS에 의해 유도된 TNF-α의 양을 ELISA 키트(Quantikine colorimetric sandwich ELISA assay kit, R&D systems사, USA)를 사용하여 정량하고 그 결과를 하기 표 8b ~ 표 8f에 나타내었다. Some of the compounds prepared in Examples 1-506 were selected and added at a concentration of 1 μM under the same conditions as in Examples 115, 126, 334 and 429. After 24 hours, the culture was collected and treated with only LPS present in the cell culture to make the amount of TNF-α in the group induced by 100%, and induced by LPS in the experimental group in which some of the compounds according to the present invention were selected and administered. The amount of TNF-α was quantified using an ELISA kit (Quantikine colorimetric sandwich ELISA assay kit, R & D systems, USA) and the results are shown in Tables 8b to 8f.

하기의 각각의 표는 본 발명의 화합물들을 한 세트로 하여 상술한 조건하에서 배양된 하나의 배지에서 실험을 수행한 것을 의미한다.Each table below means that the experiment was carried out in one medium incubated under the conditions described above with a set of compounds of the present invention.

Figure 112006042290445-pat00133
Figure 112006042290445-pat00133

상기 표 8b의 결과로부터, 1 μM 농도로 배지에 투여된 대부분의 화합물들이 우수한 TNF-α 억제 효과를 나타냄을 알 수 있다. 이들 중에서 특히, 실시예 116, 117, 121, 127 등의 화합물이 우수함을 알 수 있다.From the results of Table 8b, it can be seen that most of the compounds administered in the medium at a concentration of 1 μM showed excellent TNF-α inhibitory effect. Among these, it can be seen that the compounds of Examples 116, 117, 121, and 127 are excellent.

Figure 112006042290445-pat00134
Figure 112006042290445-pat00134

상기 표 8c의 결과로부터, 몇몇 실시예 화합물 이외에는 1 μM 농도로 배지에 투여된 나머지 실시예 화합물 대부분이 우수한 TNF-α 억제 효과를 나타냄을 알 수 있다. 특히, 실시예 123, 124 등의 화합물이 우수한 TNF-α 억제 효과를 나타내었다.From the results of Table 8c, it can be seen that most of the remaining example compounds administered in the medium at a concentration of 1 μM except for some example compounds showed excellent TNF-α inhibitory effect. In particular, compounds such as Examples 123 and 124 showed excellent TNF-α inhibitory effect.

Figure 112006042290445-pat00135
Figure 112006042290445-pat00135

상기 표 8d의 결과로부터, 몇몇 실시예 화합물 이외에는 1 μM 농도로 배지에 투여된 대부분의 실시예 화합물들이 우수한 TNF-α 억제 효과를 나타냄을 알 수 있다. 이들 중에서 특히, 실시예 177, 184 등의 화합물이 우수한 TNF-α 억제 효과를 나타내었다.From the results of Table 8d, it can be seen that most of the example compounds administered in the medium at a concentration of 1 μM except for some example compounds showed excellent TNF-α inhibitory effect. Among these, especially compounds of Examples 177, 184 and the like showed excellent TNF-α inhibitory effect.

Figure 112006042290445-pat00136
Figure 112006042290445-pat00136

상기 표 8e의 결과로부터, 몇몇 실시예 화합물 이외에는 1 μM 농도로 배지에 투여된 대부분의 실시예 화합물들이 우수한 TNF-α 억제 효과를 나타냄을 알 수 있다. 이들 중에서 특히, 실시예 369, 376, 464 등의 화합물이 우수한 TNF-α 억제 효과를 나타내었다.From the results of Table 8e, it can be seen that most of the example compounds administered to the medium at a concentration of 1 μM except for some example compounds showed excellent TNF-α inhibitory effect. Among these, especially compounds of Examples 369, 376, 464 and the like showed excellent TNF-α inhibitory effect.

Figure 112006042290445-pat00137
Figure 112006042290445-pat00137

상기 표 8f의 결과로부터, 1 μM 농도로 배지에 투여된 실시예 화합물 대부분이 TNF-α의 생성량을 60% 이하로 억제함으로써, 매우 우수한 TNF-α 억제 효과를 나타냄을 알 수 있다.From the results of Table 8f, it can be seen that most of the example compounds administered to the medium at a concentration of 1 μM exhibited a very good TNF-α inhibitory effect by inhibiting the amount of TNF-α production to 60% or less.

상기 표 8b ~ 표 8f의 결과로부터, 우수한 TNF-α 억제 효과를 나타낸 화합물 334를 선택하여, 1 μM 투여 실험에서 배제된 나머지 화합물에 대하여 이번에는 투여량을 1/1000(1 nM)로 줄여서 TNF-α 억제 효과를 측정하는 실험을 수행하고 그 결과를 ELISA 키트(Quantikine colorimetric sandwich ELISA assay kit, R&D systems사, USA)를 사용하여 정량하여 하기 표 8g ~ 표 8w에 나타내었다.From the results of Table 8b to Table 8f, Compound 334, which exhibited an excellent TNF-α inhibitory effect, was selected, and this time the dose was reduced to 1/1000 (1 nM) for the remaining compounds excluded from the 1 μM administration experiment. Experiments to measure the -α inhibitory effect was performed and the results are quantified using an ELISA kit (Quantikine colorimetric sandwich ELISA assay kit, R & D systems, USA) and are shown in Table 8g to Table 8w.

Figure 112006042290445-pat00138
Figure 112006042290445-pat00138

표 8g의 결과로부터, 실시예 100 및 221 화합물이 우수한 TNF-α 억제 효과를 나타내었으며, 나머지 실시예 화합물들 중 화합물 334 또는 LPS 처리군보다 TNF-α 억제 효과가 낮은 것으로 나타난 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 우수한 TNF-α 억제 효과가 있음을 알 수 있다. From the results of Table 8g, the Examples 100 and 221 compounds showed excellent TNF-α inhibitory effect, even in the case of the compound of the other Example compounds showed lower TNF-α inhibitory effect than Compound 334 or LPS treatment group Considering that the amount is 1 nM concentration reduced to 1/1000, it can be seen that there is still a good TNF-α inhibitory effect.

Figure 112006042290445-pat00139
Figure 112006042290445-pat00139

표 8h의 결과로부터, 실시예 349, 356, 362, 378, 385, 392, 430, 438, 445 및 451의 화합물이 우수한 TNF-α 억제 효과를 나타내었으며, 특히 화합물 349 및 451의 경우에는 화합물 334의 2배 정도의 우수한 억제 효과를 나타내는 것으로 확인되었다. 한편, 나머지 실시예 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 우수한 TNF-α 억제 효과가 있음을 알 수 있다. From the results in Table 8h, the compounds of Examples 349, 356, 362, 378, 385, 392, 430, 438, 445 and 451 showed good TNF-α inhibitory effects, especially for the compounds 349 and 451 It was confirmed that it showed an excellent inhibitory effect of about 2 times. On the other hand, even in the case of the remaining Example compounds, considering that the dose is reduced to 1 / 1M concentration of 1/1000, it can be seen that there is still an excellent TNF-α inhibitory effect.

Figure 112006042290445-pat00140
Figure 112006042290445-pat00140

표 8i의 결과로부터, 실시예 266, 273, 289, 301, 423, 466, 473 등이 우수한 TNF-α 억제 효과를 나타내었으며, 특히 실시예 294, 409 및 416의 경우에는 화합물 334의 약 3배 정도의 매우 우수한 TNF-α 억제 효과를 나타내는 것으로 확인되었다. From the results in Table 8i, Examples 266, 273, 289, 301, 423, 466, 473 and the like showed excellent TNF-α inhibitory effects, particularly about 3 times Compound 334 for Examples 294, 409 and 416 It was confirmed to show a very good TNF-α inhibitory effect.

Figure 112006042290445-pat00141
Figure 112006042290445-pat00141

표 8j의 결과로부터, 화합물 84, 164 및 431의 경우에는 화합물 334에 비해 약 4배가 넘는 매우 우수한 TNF-α 억제 효과를 나타내는 것으로 확인되었다. 한편, 나머지 실시예 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 우수한 TNF-α 억제 효과가 있음을 알 수 있다.From the results in Table 8j, it was confirmed that Compounds 84, 164, and 431 exhibited a very good TNF-α inhibitory effect of about four times that of Compound 334. On the other hand, even in the case of the remaining Example compounds, considering that the dose is reduced to 1 / 1M concentration of 1/1000, it can be seen that there is still an excellent TNF-α inhibitory effect.

Figure 112006042290445-pat00142
Figure 112006042290445-pat00142

표 8k의 결과로부터, 화합물 377, 384, 391, 458, 465 및 472의 경우에는 화합물 334와 동등하거나 우수한 TNF-α 억제 효과를 나타내는 것으로 확인되었다. 한편, 나머지 실시예 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 우수한 TNF-α 억제 효과가 있음을 알 수 있다.From the results in Table 8k, it was confirmed that the compounds 377, 384, 391, 458, 465, and 472 exhibited a TNF-α inhibitory effect equivalent to or better than that of the compound 334. On the other hand, even in the case of the remaining Example compounds, considering that the dose is reduced to 1 / 1M concentration of 1/1000, it can be seen that there is still an excellent TNF-α inhibitory effect.

Figure 112006042290445-pat00143
Figure 112006042290445-pat00143

표 8l의 결과로부터, 화합물 286 및 401이 화합물 334에 비해 약 2~3배 정도의 우수한 TNF-α 억제 효과를 나타내는 것으로 확인되었으며, 나머지 화합물들 중 화합물 334보다 TNF-α 억제 효과가 낮은 것으로 나타난 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 유의성있는 결과를 나타냄을 알 수 있다.From the results in Table 8l, it was confirmed that Compounds 286 and 401 exhibited about 2 to 3 times better TNF-α inhibitory effect than Compound 334, showing that TNF-α inhibitory effect was lower than Compound 334 among the other compounds. Even in the case of compounds, considering the 1 nM concentration reduced to 1/1000, it can be seen that still shows significant results.

Figure 112006042290445-pat00144
Figure 112006042290445-pat00144

표 8m의 결과로부터, 실시예 335, 336의 화합물이 화합물 334에 비해 동등하거나 또는 우수한 TNF-α 억제 효과를 나타내는 것으로 확인되었다. 나머지 화합물들 중 화합물 334보다 TNF-α 억제 효과가 낮은 것으로 나타난 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 유의성있는 결과를 나타냄을 알 수 있다.From the results of Table 8m, it was confirmed that the compounds of Examples 335 and 336 showed the same or superior TNF-α inhibitory effect as compared to the compound 334. It can be seen that even in the case of a compound having a lower TNF-α inhibitory effect than the compound 334 among the remaining compounds, considering that the dose was reduced to 1/1000, the concentration was 1 nM, the results were still significant.

Figure 112006042290445-pat00145
Figure 112006042290445-pat00145

표 8n의 결과로부터, 실시예 352, 441, 448, 454 등의 화합물이 화합물 334에 비해 동등하거나 또는 우수한 TNF-α 억제 효과를 나타내는 것으로 확인되었다. 나머지 화합물들 중 화합물 334보다 TNF-α 억제 효과가 낮은 것으로 나타난 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 유의성있는 결과를 나타냄을 알 수 있다.From the results in Table 8n, it was confirmed that the compounds of Examples 352, 441, 448, 454 and the like exhibited the same or superior TNF-α inhibitory effect as compared to the compound 334. It can be seen that even in the case of a compound having a lower TNF-α inhibitory effect than the compound 334 among the remaining compounds, considering that the dose was reduced to 1/1000, the concentration was 1 nM, the results were still significant.

Figure 112006042290445-pat00146
Figure 112006042290445-pat00146

표 8o의 결과로부터, 실시예 387, 461 등의 화합물이 화합물 334에 비해 동등하거나 또는 우수한 TNF-α 억제 효과를 나타내는 것으로 확인되었다. 나머지 화합물들 중 화합물 334보다 TNF-α 억제 효과가 낮은 것으로 나타난 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 유의성있는 결과를 나타냄을 알 수 있다.From the results in Table 8o, it was confirmed that the compounds such as Examples 387 and 461 exhibited the same or superior TNF-α inhibitory effect as compared to the compound 334. It can be seen that even in the case of a compound having a lower TNF-α inhibitory effect than the compound 334 among the remaining compounds, considering that the dose was reduced to 1/1000, the concentration was 1 nM, the results were still significant.

Figure 112006042290445-pat00147
Figure 112006042290445-pat00147

표 8p의 결과로부터, 실시예 289, 296, 411 등의 화합물이 화합물 334에 비해 동등하거나 또는 우수한 TNF-α 억제 효과를 나타내는 것으로 확인되었다. 나머지 화합물들 중 화합물 334보다 TNF-α 억제 효과가 낮은 것으로 나타난 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 유의성있는 결과를 나타냄을 알 수 있다.From the results in Table 8p, it was confirmed that the compounds such as Examples 289, 296, and 411 exhibited the same or superior TNF-α inhibitory effect as compared to the compound 334. It can be seen that even in the case of a compound having a lower TNF-α inhibitory effect than the compound 334 among the remaining compounds, considering that the dose was reduced to 1/1000, the concentration was 1 nM, the results were still significant.

Figure 112006042290445-pat00148
Figure 112006042290445-pat00148

표 8q의 결과로부터, 실시예 382, 389, 396, 477, 484 등의 화합물이 화합물 334에 비해 동등하거나 또는 우수한 TNF-α 억제 효과를 나타내는 것으로 확인되었다. 나머지 화합물들 중 화합물 334보다 TNF-α 억제 효과가 낮은 것으로 나타난 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 유의성있는 결과를 나타냄을 알 수 있다.From the results in Table 8q, it was confirmed that the compounds of Examples 382, 389, 396, 477, 484 and the like exhibited the same or superior TNF-α inhibitory effect as compared to the compound 334. It can be seen that even in the case of a compound having a lower TNF-α inhibitory effect than the compound 334 among the remaining compounds, considering that the dose was reduced to 1/1000, the concentration was 1 nM, the results were still significant.

Figure 112006042290445-pat00149
Figure 112006042290445-pat00149

표 8r의 결과로부터, 실시예 284, 291, 298, 413, 435 등의 화합물이 화합물 334에 비해 동등하거나 또는 우수한 TNF-α 억제 효과를 나타내는 것으로 확인되었다. 나머지 화합물들 중 화합물 334보다 TNF-α 억제 효과가 낮은 것으로 나타난 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 유의성있는 결과를 나타냄을 알 수 있다.From the results in Table 8r, it was confirmed that the compounds such as Examples 284, 291, 298, 413, and 435 exhibited the same or superior TNF-α inhibitory effect as compared to the compound 334. It can be seen that even in the case of a compound having a lower TNF-α inhibitory effect than the compound 334 among the remaining compounds, considering that the dose was reduced to 1/1000, the concentration was 1 nM, the results were still significant.

Figure 112006042290445-pat00150
Figure 112006042290445-pat00150

표 8s의 결과로부터, 실시예 351, 364, 440, 447, 453 등의 화합물이 화합물 334에 비해 1.5배 내지 2배 정도의 TNF-α 억제 효과를 나타내었다. 나머지 화합물들 중 화합물 334보다 TNF-α 억제 효과가 낮은 것으로 나타난 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 유의성있는 결과를 나타냄을 알 수 있다.From the results in Table 8s, the compounds of Examples 351, 364, 440, 447, 453 and the like showed a TNF-α inhibitory effect of about 1.5 to 2 times that of Compound 334. It can be seen that even in the case of a compound having a lower TNF-α inhibitory effect than the compound 334 among the remaining compounds, considering that the dose was reduced to 1/1000, the concentration was 1 nM, the results were still significant.

Figure 112006042290445-pat00151
Figure 112006042290445-pat00151

표 8t의 결과로부터, 실시예 288, 295, 302 등의 화합물이 화합물 334에 비해 약 4.5배 내지 9배 정도의 TNF-α 억제 효과를 나타내었다. 나머지 화합물들 중 화합물 334보다 TNF-α 억제 효과가 낮은 것으로 나타난 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 유의성있는 결과를 나타냄을 알 수 있다.From the results in Table 8t, the compounds of Examples 288, 295, 302 and the like showed a TNF-α inhibitory effect of about 4.5 to 9 times that of Compound 334. It can be seen that even in the case of a compound having a lower TNF-α inhibitory effect than the compound 334 among the remaining compounds, considering that the dose was reduced to 1/1000, the concentration was 1 nM, the results were still significant.

Figure 112006042290445-pat00152
Figure 112006042290445-pat00152

표 8u의 결과로부터, 실시예 344, 353, 360, 366, 442 등의 화합물이 화합물 334에 비해 약 2배 정도의 TNF-α 억제 효과를 나타내었으며, 실시예 410, 417, 434, 499 등의 화합물들은 화합물 334에 비해 동등하거나 또는 우수한 TNF-α 억제 효과를 나타내는 것으로 확인되었다. 나머지 화합물들 중 화합물 334보다 TNF-α 억제 효과가 낮은 것으로 나타난 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 유의성있는 결과를 나타냄을 알 수 있다.From the results of Table 8u, the compounds of Examples 344, 353, 360, 366, 442 and the like showed about 2 times the TNF-α inhibitory effect compared to the compound 334, Examples 410, 417, 434, 499, etc. The compounds were found to show equivalent or superior TNF-α inhibitory effect compared to compound 334. It can be seen that even in the case of a compound having a lower TNF-α inhibitory effect than the compound 334 among the remaining compounds, considering that the dose was reduced to 1/1000, the concentration was 1 nM, the results were still significant.

Figure 112006042290445-pat00153
Figure 112006042290445-pat00153

표 8v의 결과로부터, 실시예 283, 290, 381, 388, 395, 469, 476 등의 화합물이 화합물 334에 비해 약 1.5배 내지 2배 정도의 TNF-α 억제 효과를 나타내었으며, 나머지 화합물들 중 대부분은 화합물 334에 비해 동등하거나 또는 우수한 TNF-α 억제 효과를 나타내는 것으로 확인되었다. 그 외, 화합물 334보다 TNF-α 억제 효과가 낮은 것으로 나타난 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 유의성있는 결과를 나타냄을 알 수 있다.From the results of Table 8v, the compounds of Examples 283, 290, 381, 388, 395, 469, 476 and the like showed about 1.5 to 2 times the TNF-α inhibitory effect compared to the compound 334, among the remaining compounds Most were found to exhibit equivalent or superior TNF-α inhibitory effects compared to compound 334. In addition, even in the case of a compound that is shown to have a lower TNF-α inhibitory effect than compound 334, considering that the dose is reduced to 1/1000, it can be seen that still significant results.

Figure 112006042290445-pat00154
Figure 112006042290445-pat00154

표 8w의 결과로부터, 실시예 412, 419, 297 등의 화합물이 화합물 334에 비해 약 1.5배 내지 2배 정도의 TNF-α 억제 효과를 나타내었다. 실시예 304, 318, 405, 426 등의 화합물들은 화합물 334에 비해 동등하거나 또는 우수한 TNF-α 억제 효과를 나타내는 것으로 확인되었다. 나머지 화합물들 중 화합물 334보다 TNF-α 억제 효과가 낮은 것으로 나타난 화합물의 경우에도 투여량이 1/1000로 줄어든 1 nM 농도임을 고려한다면, 여전히 유의성있는 결과를 나타냄을 알 수 있다.From the results of Table 8w, the compounds of Examples 412, 419, 297 and the like showed a TNF-α inhibitory effect of about 1.5 to 2 times that of Compound 334. Compounds such as Examples 304, 318, 405, 426, etc., were found to show equivalent or superior TNF-α inhibitory effect compared to Compound 334. It can be seen that even in the case of a compound having a lower TNF-α inhibitory effect than the compound 334 among the remaining compounds, considering that the dose was reduced to 1/1000, the concentration was 1 nM, the results were still significant.

결론적으로, 본 발명의 화합물은 상기 표 8a 내지 표 8w에 나타난 바와 같이 마이크로 농도 수준에서뿐만 아니라 나노 농도 수준에서도 THP-1 세포 내에서 LPS에 의해 유발되는 TNF-α의 생성을 억제하는 것을 알 수 있다. In conclusion, it can be seen that the compounds of the present invention inhibit the production of TNF-α induced by LPS in THP-1 cells not only at the micro concentration level but also at the nano concentration level, as shown in Tables 8A to 8W. .

실험예Experimental Example 4 4 : 본 발명에 따른 화합물들의 마우스 대식세포 유래 암세포주인 RAW264.7 세포의  : Expression of RAW264.7 Cells, a Mouse Macrophage-Derived Cancer Cell Line of the Compounds According to the Present Invention TNFTNF -α 생성억제 효과-α production inhibitory effect

본 발명에 따른 화합물들의 마우스 대식세포 유래 암세포주인 RAW264.7 세포의 TNF-α 생성억제 효과를 알아보기 위하여, 하기와 같은 실험을 수행하였다.In order to determine the effect of the TNF-α production inhibition of RAW264.7 cells, a mouse macrophage-derived cancer cell line of the compounds according to the present invention, the following experiment was performed.

실험에 사용한 세포주로는 마우스 대식세포 유래 암세포주인 RAW264.7 세포이며, 미국의 세포주 은행(American Type Culture Collection)에서 구입하여 사용하였다.The cell lines used in the experiment were RAW264.7 cells, which are mouse macrophage-derived cancer cell lines, which were purchased from the American Cell Line Bank (American Type Culture Collection).

세포는 10% 소 태아 혈청(fetal bovine serum: FBS)을 포함하는 RPMI 배지에서 배양하였다. RAW264.7 세포를 96 웰 플레이트에 적절한 농도(1 x 106 cells/ml)로 가한 후, 5% CO2, 37℃의 배양 조건 하에서 배양하였다. TNF-α의 생성은 리포폴리사카라이드(최종 농도 1 mg/ml) (시그마, 미국)를 이용하여 유도하였으며, 상기 실시예 334, 429에서 제조한 화합물을 0.01-1 μM 의 농도로 첨가하였다. 24시간 후에 배양액을 수거하여 세포배양액 내에 존재하는 TNF-α의 양을 ELISA 키트(Quantikine colorimetric sandwich ELISA assay kit, R&D systems사, USA)를 사용하여 정량하였다. 결과는 표 9에 나타내었다.Cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS). RAW264.7 cells were added to an appropriate concentration (1 × 10 6 cells / ml) in a 96 well plate and then incubated under culture conditions of 5% CO 2 , 37 ° C. The production of TNF-α was induced using lipopolysaccharide (final concentration 1 mg / ml) (Sigma, USA), and the compounds prepared in Examples 334 and 429 were added at a concentration of 0.01-1 μM. After 24 hours, the culture was collected and the amount of TNF-α present in the cell culture was quantified using an ELISA kit (Quantikine colorimetric sandwich ELISA assay kit, R & D systems, USA). The results are shown in Table 9.

본 발명에 따른 화합물들의 마우스 대식세포 유래 암세포주인 RAW264.7 세포의 TNF-α 생성억제 효과Inhibitory Effects of the Compounds of the Present Invention on TNF-α Production of RAW264.7 Cells TNF-α(ng/㎖)TNF-α (ng / ml) 실시예 334Example 334 실시예 429Example 429 대조군Control 39±339 ± 3 44±144 ± 1 0.01μM0.01 μM 32±332 ± 3 23±123 ± 1 0.03μM0.03 μM 22±122 ± 1 20±220 ± 2 0.1μM0.1 μM 17±217 ± 2 16±116 ± 1 0.3μM0.3 μM 8±18 ± 1 17±217 ± 2 1μM1 μM 3±23 ± 2 5±15 ± 1

표 9에 나타난 바와 같이, 실시예 334 및 429의 화합물은 RAW264.7 세포의 TNF-α의 생성을 농도의존적으로 억제하였다. 특히, 인체 대식세포 유래 암세포주인 THP-1세포에서 강력한 TNF-α 생성 억제효과를 보인 실시예 334 및 429의 화합물은 마우스 대식세포 유래 암세포주인 RAW264.7 세포에도 강력한 억제효과를 나타내었다.As shown in Table 9, the compounds of Examples 334 and 429 concentration-dependently inhibited the production of TNF-α in RAW264.7 cells. In particular, the compounds of Examples 334 and 429, which showed potent inhibitory effects on TNF-α production in THP-1 cells, which are human macrophage-derived cancer cell lines, also showed potent inhibitory effects on RAW264.7 cells, which are mouse macrophage-derived cancer cell lines.

실험예Experimental Example 5 5 : 본 발명에 따른 화합물들의 마우스 골수세포 유래 대식세포의 TNF-α 생성억제 효과 : Effects of Inhibiting TNF-α Production on Mouse Bone Marrow Cell-Derived Macrophages of the Present Invention

본 발명에 따른 화합물들의 마우스 골수세포 유래 대식세포의 TNF-α 생성억제 효과를 알아보기 위하여, 하기와 같은 실험을 수행하였다.In order to investigate the effects of the compounds inhibiting the TNF-α production of mouse myeloid cells-derived macrophages, the following experiment was performed.

정상 마우스의 골수세포를 분리한 후, 세포는 10% 소 태아 혈청(fetal bovine serum: FBS)을 포함하는 RPMI 배지에서 배양하였다. 10 ng/ml의 M-CSF를 첨가한 후 10일동안 배양하여 정상 대식세포를 만들었으며, TNF-α의 생성은 리포폴리사카라이드(최종 농도 1 mg/ml) (시그마, 미국)를 이용하여 유도하였다. 상기 실시예 334에서 제조한 화합물을 0.01-1 μM의 농도로 첨가하였으며, 24시간 후에 배양액을 수거하여 세포배양액 내에 존재하는 TNF-α의 양을 ELISA 키트(Quantikine colorimetric sandwich ELISA assay kit, R&D systems사, USA)를 사용하여 정량하였다. 결과는 표 10에 나타내었다.After the bone marrow cells of normal mice were isolated, the cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS). After adding 10 ng / ml of M-CSF, the cells were cultured for 10 days to produce normal macrophages. The production of TNF-α was performed using lipopolysaccharide (final concentration 1 mg / ml) (Sigma, USA). Induced. The compound prepared in Example 334 was added at a concentration of 0.01-1 μM, and after 24 hours, the culture solution was collected, and the amount of TNF-α present in the cell culture solution was determined using an ELISA kit (Quantikine colorimetric sandwich ELISA assay kit, R & D systems). , USA). The results are shown in Table 10.

본 발명에 따른 화합물의 마우스 골수세포 유래 대식세포의 TNF-α 생성억제 효과Inhibitory Effects of the Compounds of the Present Invention on TNF-α Production in Mouse Bone Marrow Cell-Derived Macrophages TNF-α(ng/㎖)TNF-α (ng / ml) 실시예 334Example 334 대조군Control 12±312 ± 3 0.01μM0.01 μM 4±34 ± 3 0.1μM0.1 μM 0.8±10.8 ± 1 1μM1 μM 0±20 ± 2

표 10에 나타난 바와 같이, 실시예 334의 화합물은 마우스 골수세포 유래 대식세포의 TNF-α의 생성을 농도의존적으로 억제하였다.As shown in Table 10, the compound of Example 334 concentration-dependently inhibited the production of TNF-α in mouse myeloid cell-derived macrophages.

실험예Experimental Example 6 6 : 본 발명에 따른 화합물의 T 세포 및 B 세포 증식에 미치는 영향 : Effect on T Cell and B Cell Proliferation of Compounds According to the Present Invention

본 발명에 따른 화합물들의 T 세포 및 B 세포 증식에 미치는 영향을 알아보기 위하여, 하기와 같은 실험을 수행하였다.In order to determine the effect of the compounds according to the invention on T cell and B cell proliferation, the following experiment was performed.

염증질환은 주로 대식세포에 의해서 유발되지만, T 세포도 관절염 등의 염증질환의 발병에 관여하고 있다고 알려져 있다. 마우스의 비장에서 면역세포를 분리한 후 10% 소 태아 혈청(fetal bovine serum: FBS)을 포함하는 RPMI 배지에서 배양하였다. 면역세포를 96 웰 플레이트에 적절한 농도(1 x 106 cells/ml)로 가한 후, 5% CO2, 37℃의 배양 조건 하에서 배양하였다. 콘카나발린 에이 (concanavalin A)를 1 ㎍/㎖의 농도로 첨가하여 T 세포의 증식을 유도하였으며, B 세포의 증식을 유도하기 위해서는 리포폴리사카라이드를 1 ㎍/㎖의 농도로 첨가하였으며, 상기 실시예 334, 429에서 제조한 화합물을 0.1~1 μM의 농도로 첨가하였다. 56시간 동안 배양한 후 [3H]-티미딘을 1 μCi/웰 의 농도로 첨가한 후 16시간을 더 배양하였다. 면역세포가 증식하는 동안 DNA내로 유입된 방사선의 양을 베타 카운터로 측정하였다.Inflammatory diseases are mainly caused by macrophages, but T cells are also known to be involved in the development of inflammatory diseases such as arthritis. Immune cells were isolated from the spleen of mice and cultured in RPMI medium containing 10% fetal bovine serum (FBS). Immune cells were added to appropriate concentrations (1 × 10 6 cells / ml) in 96 well plates, and then cultured under 5% CO 2 , 37 ° C. culture conditions. Concanavalin A was added at a concentration of 1 μg / ml to induce proliferation of T cells, and lipopolysaccharide was added at a concentration of 1 μg / ml to induce proliferation of B cells. The compounds prepared in Examples 334 and 429 were added at a concentration of 0.1-1 μM. After incubation for 56 hours, [3H] -thymidine was added at a concentration of 1 μCi / well, followed by further culture for 16 hours. The amount of radiation introduced into the DNA during immune cell proliferation was measured with a beta counter.

본 발명에 따른 화합물의 T 세포 증식에 미치는 영향은 표 11에 나타내었으며, B 세포 증식에 미치는 영향은 표 12에 나타내었다.The effect on the T cell proliferation of the compound according to the invention is shown in Table 11, the effect on the B cell proliferation is shown in Table 12.

본 발명에 따른 화합물의 T 세포 증식에 미치는 영향Effect of the compounds according to the invention on T cell proliferation 증식 (CPM)Proliferation (CPM) 증식 (CPM)Proliferation (CPM) 비처리군Untreated group 2,331±6002,331 ± 600 비처리군Untreated group 3,746±1093,746 ± 109 콘카나발린 에이Koncanavalin A 93,233±5,16293,233 ± 5,162 콘카나발린 에이Koncanavalin A 75,541±3,98275,541 ± 3,982 콘카나발린 에이 + 실시예 334의 화합물 0.01μMConcanavalin A + Compound 0.01μM of Example 334 106,916±5,001106,916 ± 5,001 콘카나발린 에이 + 실시예 429의 화합물 0.01μMConcanavalin A + Compound 0.01 μM of Example 429 62,246±1,62462,246 ± 1,624 콘카나발린 에이 + 실시예 334의 화합물 0.3μMConcanavalin A + Compound 0.3μM of Example 334 95,748±3,24895,748 ± 3,248 콘카나발린 에이 + 실시예 429의 화합물 0.3μM Concanavalin A + 0.3 μM compound of Example 429 62,920±2,94362,920 ± 2,943 콘카나발린 에이 + 실시예 334의 화합물 1μMConcanavalin A + Compound 1μM of Example 334 99,755±7,61499,755 ± 7,614 콘카나발린 에이 + 실시예 429의 화합물 1μMConcanavalin A + Compound 1 μM of Example 429 48,296±1,97448,296 ± 1,974

본 발명에 따른 화합물의 B 세포 증식에 미치는 영향Effect of the compound according to the invention on B cell proliferation 증식 (CPM)Proliferation (CPM) 비처리군Untreated group 2,331±6002,331 ± 600 리포폴리사카라이드Lipopolysaccharide 73,813±3,57173,813 ± 3,571 리포폴리사카라이드 + 실시예 334의 화합물 0.01μMLipopolysaccharide + 0.01 μM compound of Example 334 70,352±5,40470,352 ± 5,404 리포폴리사카라이드 + 실시예 334의 화합물 0.3μMLipopolysaccharide + 0.3 μM compound of Example 334 74,235±3,36374,235 ± 3,363 리포폴리사카라이드 + 실시예 334의 화합물 1μMLipopolysaccharide + 1 μM compound of Example 334 77,681±3,49677,681 ± 3,496

표 11 및 표 12에 나타난 바와 같이, 실시예 429의 화합물은 최고 농도인 0.1~1 μM에서 T 세포의 증식을 억제하였다. 그러나 상기의 실험예 3~5와 비교하여 볼 때 그 억제정도가 약함을 알 수 있다. 실시예 334의 화합물은 T 세포와 B 세포의 증식에 전혀 영향을 주지 못하였다. 따라서, 본 발명의 조성물은 주로 대식세포의 TNF-α 생성억제에서 유래함을 알 수 있다.As shown in Table 11 and Table 12, the compound of Example 429 inhibited the proliferation of T cells at the highest concentration of 0.1 ~ 1 μM. However, when compared with the above Experimental Examples 3 to 5 it can be seen that the degree of inhibition is weak. The compound of Example 334 had no effect on the proliferation of T cells and B cells. Therefore, it can be seen that the composition of the present invention is mainly derived from the inhibition of TNF-α production of macrophages.

실험예Experimental Example 7 7 : 본 발명에 따른 화합물의 마우스에 대한  : For the mouse of the compound according to the invention 급성독성Acute Toxicity 실험 Experiment

본 발명에 따른 화합물들의 마우스에 대한 급성독성을 알아보기 위하여, 하기와 같은 실험을 수행하였다.In order to determine the acute toxicity of mice according to the present invention, the following experiment was performed.

각 시험군당 10수의 마우스에 상기 실시예 334에서 제조한 화합물을 0.3~100 ㎎/㎏의 농도로 경구투여한 후 14일 동안 생존동물 수를 측정하였다. 결과는 표 13에 나타내었다.The number of surviving animals was measured for 14 days after orally administering the compound prepared in Example 334 to the concentration of 0.3 ~ 100 mg / kg to 10 mice in each test group. The results are shown in Table 13.

생존 동물수Survival Animals 마우스 몸무게 (g)Mouse weight (g) 대조군Control 1010 37.0±2.0137.0 ± 2.01 실시예 334Example 334 0.3 ㎎/㎏0.3 mg / kg 1010 38.1±1.7238.1 ± 1.72 1 ㎎/㎏1 mg / kg 1010 38.3±2.2638.3 ± 2.26 3 ㎎/㎏3 mg / kg 1010 38.6±2.2838.6 ± 2.28 10 ㎎/㎏10 mg / kg 1010 37.8±2.4737.8 ± 2.47 30 ㎎/㎏30 mg / kg 1010 37.3±1.4337.3 ± 1.43 100 ㎎/㎏100 mg / kg 1010 37.8±2.6737.8 ± 2.67

표 13에 나타난 바와 같이, 실시예 334의 화합물을 투여한 모든 동물은 14일 동안 생존하였으며 정상적인 체중증가를 보였다.As shown in Table 13, all animals administered the compound of Example 334 survived for 14 days and showed normal weight gain.

이하의 동물실험에서는 10 ㎎/㎏ 이하의 농도를 사용하였다.In the following animal experiment, a concentration of 10 mg / kg or less was used.

실험예Experimental Example 8 8 : 본 발명에 따른 화합물의 생체 내에서  : In vivo of the compound according to the invention TNFTNF -α 생성억제 효과-α production inhibitory effect

본 발명에 따른 화합물의 생체 내에서 TNF-α 생성억제 효과를 알아보기 위하여, 하기와 같은 실험을 수행하였다.In order to determine the TNF-α production inhibitory effect in vivo of the compound according to the present invention, the following experiment was performed.

마우스에 리포폴리사카라이드를 2 ㎎/㎏의 농도로 복강 주사하여 TNF-α 생성을 유도하였으며, 상기 실시예 334에서 제조한 화합물을 0.1~10 ㎎/㎏의 농도로 경구투여 하였다. 리포폴리사카라이드를 투여한 후 90분 후에 혈청을 분리하였으며, 혈청내 TNF-α의 양은 ELISA 키트(Quantikine colorimetric sandwich ELISA assay kit, R&D systems사, USA)를 사용하여 정량하였다. 결과는 표 14에 나타내었다.TNF-α production was induced by intraperitoneal injection of lipopolysaccharide at a concentration of 2 mg / kg, and the compound prepared in Example 334 was orally administered at a concentration of 0.1-10 mg / kg. Serum was separated 90 minutes after lipopolysaccharide was administered, and the amount of TNF-α in serum was quantified using an ELISA kit (Quantikine colorimetric sandwich ELISA assay kit, R & D systems, USA). The results are shown in Table 14.

TNF-α(ng/㎖)TNF-α (ng / ml) 대조군Control 2,071±5612,071 ± 561 실시예 334Example 334 0.1 ㎎/㎏0.1 mg / kg 1,167±1251,167 ± 125 0.3 ㎎/㎏0.3 mg / kg 1,088±581,088 ± 58 1 ㎎/㎏1 mg / kg 569±11569 ± 11 3 ㎎/㎏3 mg / kg 398±83398 ± 83 10 ㎎/㎏10 mg / kg 172±14172 ± 14

표 14에 나타난 바와 같이, 실시예 334의 화합물은 생체 내에서 대식세포의 TNF-α의 생성을 농도의존적으로 억제하였다. 따라서, 본 발명의 화합물이 생체 내에서 약리활성을 나타냄을 알 수 있다.As shown in Table 14, the compound of Example 334 concentration-dependently inhibited TNF-α production of macrophages in vivo. Therefore, it can be seen that the compound of the present invention exhibits pharmacological activity in vivo.

실험예Experimental Example 9 9 : 본 발명에 따른 화합물의  Of the compounds according to the invention 자이모산Zymosan (( zymosanzymosan ) 유도 염증에 대한 영향) Effects on induced inflammation

본 발명에 따른 화합물의 염증질환에 대한 치료효과를 알아보기 위하여, 하기와 같은 실험을 수행하였다.In order to determine the therapeutic effect of the compound according to the invention for the inflammatory disease, the following experiment was performed.

자이모산 등의 염증유발물질을 마우스의 뒷다리에 피하주사할 경우 관절에 염증질환이 유발되며, 주사부위에서 제일 가까운 림프절에 염증세포가 과도하게 침윤하는 림프절 비대증이 특징적으로 나타난다. 마우스 뒷다리의 피하조직에 자이모산을 150 ㎍씩 주사하여 염증을 유발하였으며, 1주일 후 오금 림프절(popliteal lymph node)을 분리하여 무게를 측정하였다. 상기 실시예 334에서 제조한 화합물을 0.1, 1, 10 ㎎/㎏의 농도로 매일 경구투여 하였다.Subcutaneous injection of inflammation-inducing substances such as Zymosan into the hind legs of mice causes inflammatory diseases in the joints, and lymph node hyperplasia with excessive infiltration of inflammatory cells in the lymph nodes closest to the injection site is characteristic. Inflammation was induced by injecting 150 μg of Zymosan into the subcutaneous tissue of the mouse hind limb. One week later, the popliteal lymph node was isolated and weighed. The compound prepared in Example 334 was orally administered daily at a concentration of 0.1, 1, 10 mg / kg.

또한, 상기 실험기간 동안 마우스의 무게를 기록하여 시료의 독성을 측정하였다. 결과는 표 15에 나타내었다.In addition, the toxicity of the sample was measured by recording the weight of the mouse during the experiment. The results are shown in Table 15.

림프절 무게 (㎎)Lymph node weight (mg) 시험 최종일 마우스 몸무게(g)Mouse weight (g) on test last day 정상 마우스Normal mouse 0.7±0.080.7 ± 0.08 22.7±1.4822.7 ± 1.48 자이모산 투여군Zymosan-administered group 6.9±0.586.9 ± 0.58 23.1±0.8423.1 ± 0.84 자이모산 + 실시예 334의 화합물 0.1㎎/㎏Zymoic Acid + 0.1 mg / kg Compound of Example 334 5.8±0.225.8 ± 0.22 22.4±1.1222.4 ± 1.12 자이모산 + 실시예 334의 화합물 1㎎/㎏Zymoic Acid + Compound 1mg / kg of Example 334 4.1±0.94.1 ± 0.9 21.7±0.9121.7 ± 0.91 자이모산 + 실시예 334의 화합물 10㎎/㎏Zymoic Acid + Compound 10mg / kg of Example 334 2.7±0.262.7 ± 0.26 22.1±1.0622.1 ± 1.06

표 15에 나타난 바와 같이, 실시예 334의 화합물은 생체 내 염증반응을 농도의존적으로 억제하였다. 또한, 투여기간동안 마우스의 체중이 변하지 않았으며, 육안적으로 관찰 시 유의한 독성증상이 관찰되지 않았다.As shown in Table 15, the compound of Example 334 concentration-dependently inhibited the inflammatory response in vivo. In addition, the body weight of the mice did not change during the administration period, and no significant toxic symptoms were observed upon visual observation.

따라서, 본 발명의 화합물은 생체 내 염증에 대한 치료효과가 있음을 알 수 있다.Therefore, it can be seen that the compound of the present invention has a therapeutic effect on inflammation in vivo.

실험예Experimental Example 10 10 : : 염증성 장질환(Inflammatory bowel disease ( InflamamtoryInflamamtory Bowel Disease :  Bowel Disease: IBDIBD )에 대한 약효 측정Efficacy measurement for

TNBS(2,4,6-trinitrobenzensulfonic acid solution, Fluka)에 의해 유발되는 IBD에 대하여 본 발명의 화합물의 염증성 장질환에 대한 효능을 알아보기 위해 하기의 동물 실험을 수행하였다. The following animal experiments were performed to determine the efficacy of the compounds of the present invention on inflammatory bowel disease with respect to IBD caused by TNBS (2,4,6-trinitrobenzensulfonic acid solution, Fluka).

시험 대상 동물은 체중 200~300 g 정도의 7주령 비병원성 수컷 SD 랫트(공급원: (주)오리엔트)를 그룹당 10마리를 이틀에 걸쳐 5마리씩 나누어 총 30마리에 대해 실험하였다. 실험 24시간 전부터 실험 동물들을 절식시킨 후, TNBS 투여 30분 전에 케타민과 세다젝트를 4:1로 혼합하여 0.74 ml씩 랫트의 뒷다리 근육에 주사하여 마취시켰다. 마취를 확인한 후, TNBS를 랫트 1마리당 50 mg/0.25 ml의 농도로 PE 튜브(8 cm)가 니들에 끼워진 시린지를 이용하여 상기 튜브가 직장을 통해 대장까지 완전히 삽입되었을 때 TNBS를 1차 주입하였다. 주입 후, 상기 튜브를 천천히 빼내고 변과 함께 TNBS가 소실되는 것을 막기 위해 50 ml 코니컬(conical) 튜브 위에 둔부 쪽을 올려주면서 항문을 손으로 3분 동안 봉하였다. 상기 1차 TNBS 주입이 종료 2시간 후에 1차 주입과 동일한 방법으로 랫트 1마리당 20 mg/0.14 ml의 농도로 TNBS를 2차 주입하였다. 단, 봉합시간은 5분으로 하였다. 약물투여는 본 발명에 따른 실시예 334의 화합물을 사용하였으며, 투여빈도는 IBD 유발 3시간 전에 1회, IBD 유발 후 6일간 1일 1회 투여함으로써 총 7일 동안 7회 투여하였다.The test subjects were tested on a total of 30 rats, each of which was divided into 10 dogs per group and 5 dogs for 7 days old non-pathogenic male SD rats (source: Orient Co., Ltd.) weighing about 200 to 300 g. The animals were fasted 24 hours before the experiment, and anesthetized by injection of 0.74 ml of ketamine and cedazect into the rat's hind limb muscle 30 minutes before TNBS administration. After confirming anesthesia, TNBS was first injected with a syringe with a PE tube (8 cm) inserted into the needle at a concentration of 50 mg / 0.25 ml per rat, when the tube was fully inserted through the rectum to the large intestine. . After injection, the tube was slowly pulled out and the anus was sealed for 3 minutes by hand while raising the buttock side over a 50 ml conical tube to prevent loss of TNBS with the stools. Two hours after the end of the first TNBS injection, TNBS was injected at a concentration of 20 mg / 0.14 ml per rat in the same manner as the first injection. However, the suture time was 5 minutes. Drug administration was performed using the compound of Example 334 according to the present invention, and the frequency of administration was administered 7 times for a total of 7 days by administering once before 3 hours of IBD induction and once a day for 6 days after IBD induction.

약효 평가는 1) IBD가 유발된 랫트를 희생시킨 후 콜론의 10 cm를 절취 후 무게를 측정하거나, 2) 콜론 절취 후, 손상이 발견되지 않으면 0, 출혈이 있으면 1, 장벽이 두꺼워지면서 출혈이 있으면 2, 출혈 또는 장벽이 두꺼워 지는 것 없이 선상 궤양 형성(linear ulceration)하면 3, 2 이상의 궤양 및/또는 염증 부위가 발생하면 4, 콜론의 길이방향으로 상기 2 이상의 궤양 및 염증 부위가 1 cm 이상으로 확장되면 5, 궤양의 크기가 2 cm 이상이면 6으로 평가하고, 1 cm가 증가할 때마다 +1을 하여 평가하였다(즉 3 cm 이면 7로 평가). 또한, 랫트를 희생시켜 콜론의 협착(colone adhesion) 정도를 정상이면 0, 손으로 분리가능하면 1, 가위로 분리가능하면 2, 가위로 분리시 천공이 발생하면 3으로 평가하였다. 나아가, IBD 유발 다음날부터 설사/혈변을 검사하여 정상이면 0, 설사가 관찰되면 1, 설사와 혈변이 모두 관찰되면 2로 평가하였으며, 7일 동안 체중을 측정하고 증감을 계산하는 방식의 평가를 함께 수행하였다. 모든 데이타는 평균치±표준오차로 표시하였으며, 모든 군은 대조군인 프레드니솔론(Prednisolone, PD) 및 비히클(vehicle)과 대비하여 t-시험으로 검정하였다. 평가 결과를 하기 표 16에 나타내었다.Efficacy evaluation was performed by 1) sacrificing IBD-induced rats, cutting 10 cm of colon and weighing them; or 2) after cutting colon, 0 if no damage was found, 1 if bleeding, 1, thickening of the barrier, bleeding 2, if linear ulceration occurs without bleeding or thickening of the barrier, 3, 2 or more ulcers and / or areas of inflammation occur; 4, 2 or more ulcers and areas of inflammation in the longitudinal direction of the colon. When it is expanded to 5, the size of the ulcer is 2 cm or more was evaluated as 6, and every 1 cm increase was evaluated by +1 (that is, to evaluate to 7 if 3 cm). In addition, the degree of colon adhesion (colon adhesion) of the rat at the expense of the rat was evaluated as 0, 1 by hand, 2 by scissors, and 3 by scissors. Furthermore, from the day after the induction of IBD, diarrhea / blood stool was examined and evaluated as 0 if normal, 1 when diarrhea was observed, and 2 when both diarrhea and blood stool were observed. Was performed. All data were expressed as mean ± standard error, and all groups were tested by t-test compared to the control groups Prednisolone (PD) and vehicle. The evaluation results are shown in Table 16 below.

군group 측정회수(N)Number of measurements (N) 콜론 무게Colon weight 육안검사Visual inspection 협착정도Stenosis 설사/혈변Diarrhea / blood stool 체중증감(g)Weight loss (g) 비히클Vehicle 88 4.20±0.794.20 ± 0.79 7.0±0.967.0 ± 0.96 2.5±0.272.5 ± 0.27 1±0.191 ± 0.19 -6.7±2.21-6.7 ± 2.21 프레드니솔론Prednisolone 1010 2.91±0.352.91 ± 0.35 5.7±0.525.7 ± 0.52 1.6±0.27**1.6 ± 0.27 ** 0.8±0.130.8 ± 0.13 -7.5±6.59-7.5 ± 6.59 실시예 334Example 334 1010 3.20±0.403.20 ± 0.40 5.7±0.825.7 ± 0.82 1.4±0.27**1.4 ± 0.27 ** 0.6±0.220.6 ± 0.22 17.9±7.16***17.9 ± 7.16 *** 1. 모든 측정값은 평균±표준평균오차로 측정. 2. *, ** 및 ***은 비히클군과 비교한 경우, 각각, p<0.1, p<0.01 및 p<0.001 레벨에서 중대한 차이를 지시한다.1. All measurements are taken as mean ± standard mean error. 2. *, ** and *** indicate significant differences at p <0.1, p <0.01 and p <0.001 levels, respectively, when compared to vehicle group.

표 16에 나타난 바와 같이, 콜론 무게에 있어서는 비히클군에 비하여 실시예 334의 화합물, PD군의 순서로 감소하였으나, 유의성 있는 차이를 나타내지는 않았다. 육안검사에서는 비히클군에 비하여 PD, 실시예 334 화합물의 두 군이 비슷한 값으로 감소하였으나 마찬가지로 유의성 있는 차이를 나타내지 않았다. 협착에서는 PD군, 실시예 334 화합물의 두 군 모두 유의성 있는 차이를 나타냈고, 설사/혈변 항목에서는 비히클군에 비해 PD, 실싱예 334의 화합물 모두 감소하였으나 마찬가지로 유의성 있는 차이를 나타내지는 않았다. 체중 증감의 항목에서는 비히클군, PD군 모두 감소하였으나, 실시예 334 화합물군은 체중 증가를 보였고 유의성 있는 차이를 나타내었다. As shown in Table 16, the colon weight was decreased in the order of the compound of Example 334 and the PD group in comparison with the vehicle group, but there was no significant difference. In the visual inspection, the two groups, PD and Example 334 compounds, were reduced to similar values as compared to the vehicle group, but did not show a significant difference. In stenosis, both groups of the PD and Example 334 compounds showed significant differences, and in the diarrhea / blood lesions, both the compounds of PD and Silencing Example 334 were reduced compared to the vehicle group, but did not show any significant differences. In the item of weight increase and decrease, both vehicle group and PD group decreased, but Example 334 compound group showed weight gain and showed a significant difference.

도 1에는 본 실험예에 사용된 콜론의 사진을 나타내고 있다. 비히클군의 콜론은 협착 정도, 궤양 발생 등이 육안으로 관찰한 경우에도 PD군 또는 실시예 334 화합물군에 비해 질환의 정도가 심한 것을 확연히 알 수 있다. PD군과 실시예 334의 화합물군에서도 PD군의 협착정도가 더 심한 것을 알 수 있다. 따라서, 본 발명의 화합물 가운데 하나인 실시예 334의 화합물은 염증성 장질환의 치료에 유용하게 사용될 수 있음을 알 수 있다.1 shows a photograph of the colon used in the present experimental example. The colon of the vehicle group can be clearly seen that the degree of disease is severe compared to the PD group or the Example 334 compound group even when the degree of narrowing, ulceration and the like are observed visually. In the PD group and the compound group of Example 334, it can be seen that the degree of narrowing of the PD group is more severe. Accordingly, it can be seen that the compound of Example 334, which is one of the compounds of the present invention, may be usefully used for the treatment of inflammatory bowel disease.

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

제제예Formulation example : 약학적 제제의 제조 : Preparation of Pharmaceutical Formulations

1. 산제의 제조1. Preparation of powder

화학식 1의 치환된 1,3-티아졸 유도체 2 g2 g of substituted 1,3-thiazole derivative of Formula 1

유당 1 g1 g lactose

상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.The above ingredients were mixed and filled in airtight cloth to prepare a powder.

2. 정제의 제조2. Preparation of Tablets

화학식 1의 치환된 1,3-티아졸 유도체 500 ㎎500 mg of substituted 1,3-thiazole derivative of Formula 1

옥수수전분 100 ㎎Corn starch 100 mg

유 당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎2 mg magnesium stearate

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

3. 캡슐제의 제조3. Preparation of Capsule

화학식 1의 치환된 1,3-티아졸 유도체 500 ㎎500 mg of substituted 1,3-thiazole derivative of Formula 1

옥수수전분 100 ㎎Corn starch 100 mg

유 당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎2 mg magnesium stearate

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

4. 주사액제의 제조4. Preparation of Injection Solution

화학식 1의 치환된 1,3-티아졸 유도체 500 ㎎500 mg of substituted 1,3-thiazole derivative of Formula 1

시트레이트 완충액 pH 3.5로 유지Maintain citrate buffer pH 3.5

덱스트로스 등장Dextrose appearance

멸균처리된 20 ㎖ 주사용 바이알에 화학식 1의 치환된 1,3-티아졸 유도체와 시트레이트 나트륨염, 시트릭산과 덱스트로스를 충진한 후 알미늄캡을 사용하여 밀봉하였다. 사용시 주사용 증류수를 이용하여 위의 혼합물을 용해시킨 후 적당한 부피의 주사용 증류수액에 희석하여 제조하였다.A sterile 20 ml injection vial was filled with the substituted 1,3-thiazole derivative of Formula 1, citrate sodium salt, citric acid and dextrose and sealed with an aluminum cap. It was prepared by dissolving the above mixture using distilled water for injection and then diluting with an appropriate volume of distilled water for injection.

본 발명의 치환된 1,3-티아졸 유도체는 TNF-α 억제 활성 및 염증 억제 활성이 우수함으로, TNF-α 관련 질환의 예방 및 치료에 유용하게 사용할 수 있다.Since the substituted 1,3-thiazole derivatives of the present invention have excellent TNF-α inhibitory activity and inflammatory inhibitory activity, they can be usefully used for the prevention and treatment of TNF-α related diseases.

Claims (17)

하기 화학식 1로 표시되는 면역 억제 및 염증 억제 활성을 갖는 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염.Substituted 1,3-thiazole derivative having a immunosuppressive and inflammatory inhibitory activity represented by the formula (1) or a pharmaceutically acceptable salt thereof. <화학식 1><Formula 1>
Figure 112006042290445-pat00155
Figure 112006042290445-pat00155
 (상기 화학식 1에서,(In Formula 1, Z는 CH 또는 N이고,Z is CH or N, R1은 할로겐 원자, C1~C4의 할로알킬, C1~C4의 알킬 또는 C1~C4의 알콕시이고,R1 is a halo of a halogen atom, C 1 ~ C 4 alkyl, C 1 ~ C 4 Of alkyl or C 1 to C 4 Alkoxy, R2는 H, 할로겐 원자, C1~C4의 알킬, -NH-R4, C1~C4의 알킬-S(O)n-페닐,
Figure 112006042290445-pat00156
,
Figure 112006042290445-pat00157
,
Figure 112006042290445-pat00158
,
Figure 112006042290445-pat00159
,
Figure 112006042290445-pat00160
또는
Figure 112006042290445-pat00161
이며, 여기서 X는 CH, C-OH, 또는 N이고, Y는 CH2, CH-C1~C4의 알킬, NH, N-C1~C4의 알킬, N-C1~C4의 아미노-C1~C4의 알킬, N-CO-C1~C4의 알킬, N-CO-C3~C8의 시 클로알킬, N-CO-C5~C8의 아릴, N-CO-C1~C4의 아미노-C1~C4의 알킬 또는 N-CO-C1~C4의 알콕시이며,R2 is H, a halogen atom, C 1 ~ C 4 Of alkyl, -NH-R4, C 1 -C 4 Alkyl-S (O) n -phenyl,
Figure 112006042290445-pat00156
,
Figure 112006042290445-pat00157
,
Figure 112006042290445-pat00158
,
Figure 112006042290445-pat00159
,
Figure 112006042290445-pat00160
or
Figure 112006042290445-pat00161
Wherein X is CH, C-OH, or N, and Y is CH 2 , CH-C 1 to C 4 Of alkyl, NH, NC 1 -C 4 Alkyl, NC 1 ~ C 4 of the amino -C 1 ~ C 4 alkyl, N-CO-C 1 ~ C 4 alkyl, N-CO-C 3 ~ C 8 when the claw-alkyl, N-CO-C 5 Aryl of ~ C 8 , N-CO-C 1 ~ C 4 of amino-C 1 ~ C 4 alkyl or N-CO-C 1 ~ C 4 of Alkoxy, R3는 할로겐 원자, -NH-R4, -NH-CO-R5, -N-(CO-R5)2, -S(O)n-C1~C4의 알킬이며,R 3 represents a halogen atom, -NH-R 4, -NH-CO-R 5, -N- (CO-R 5) 2 , -S (O) n -C 1 -C 4 Alkyl, R4는 H, C1~C4의 알킬, C3~C8의 시클로알킬, C3~C8의 시클로알킬알킬, C5~C8의 아릴, CH(C1~C4의 알킬)-페닐, 또는 아민이고,R4 is H, C 1 ~ C 4 Alkyl, C 3 -C 8 Cycloalkyl, C 3 to C 8 Cycloalkylalkyl, C 5 -C 8 aryl, CH (C 1 -C 4 of Alkyl) -phenyl, or amine, R5는 C1~C4의 알킬, C3~C8의 시클로알킬 , C5~C8의 아릴 또는 C1~C4의 알콕시이고,R5 is C 1 ~ C 4 Alkyl, C 3 -C 8 Cycloalkyl, C 5 -C 8 aryl or C 1 -C 4 Alkoxy, m은 1 또는 2이며,m is 1 or 2, n은 0, 1 또는 2이다)n is 0, 1 or 2) 제 1항에 있어서, 상기 화학식 1에서According to claim 1, in the formula 1 Z는 CH 또는 N 이고,Z is CH or N, R1은 2-F, 3-F, 4-F, 3-Cl, 3-CF3, 3-CH3 또는 4-OCH3 이며,R 1 is 2-F, 3-F, 4-F, 3-Cl, 3-CF 3 , 3-CH 3 or 4-OCH 3 , R2는 H, Cl, 에틸, 아미노, NHNH2, 메틸아미노, 6,N-디메틸니코티닐아미노, 4-메틸설파닐페닐, 4-메탄설피닐페닐, 4-메탄설포닐페닐, 피페리딘-1-일, 4-메틸-피페리딘-1-일, 피페리딘-4-일, N-메틸-피페리딘-4-일, N-에틸-피페리딘-4일, N-이 소프로필-피페리딘-4일, N-시클로프로필메틸-피페리딘-4일, N-디메틸아미노에틸-피페리딘-4-일, N-메틸카보닐-피페리딘-4-일, N-시클로프로필카보닐-피페리딘-4-일, N-디메틸아미노메틸카보닐-피페리딘-4-일, N-페닐카보닐-피페리딘-4-일, 에톡시카보닐-피페리딘-4-일, N-부톡시카보닐-피페리딘-4-일, 피페라진-1-일, N-메틸-피페라진-1-일, N-부톡시카보닐-피페라진-1-일, 4-메틸-4-옥시피페라진-1-일, 4-히드록시-피페리딘-4-일, N-메틸-4-히드록시-피페리딘-4-일, N-부톡시카보닐-4-히드록시-피페리딘-4-일, 2,5-디아자비시클로[2.2.1]-헵트-2-일, N-t-부톡시카보닐-2,5-디아자비시클로[2.2.1]-헵트-2-일, 피페리딘-4-일아미노, N-t-부톡시카보닐-피페리딘-4-일아미노, 피페리딘-4-일옥시 또는 N-t-부톡시카보닐-피페리딘-4-일옥시이고,R2 is H, Cl, ethyl, amino, NHNH 2 , methylamino, 6, N-dimethylnicotinylamino, 4-methylsulfanylphenyl, 4-methanesulfinylphenyl, 4-methanesulfonylphenyl, piperidine- 1-yl, 4-methyl-piperidin-1-yl, piperidin-4-yl, N-methyl-piperidin-4-yl, N-ethyl-piperidin-4yl, N- Sopropyl-piperidin-4yl, N-cyclopropylmethyl-piperidin-4yl, N-dimethylaminoethyl-piperidin-4-yl, N-methylcarbonyl-piperidin-4-yl , N-cyclopropylcarbonyl-piperidin-4-yl, N-dimethylaminomethylcarbonyl-piperidin-4-yl, N-phenylcarbonyl-piperidin-4-yl, ethoxycarbonyl -Piperidin-4-yl, N-butoxycarbonyl-piperidin-4-yl, piperazin-1-yl, N-methyl-piperazin-1-yl, N-butoxycarbonyl-pipe Razin-1-yl, 4-methyl-4-oxypiperazin-1-yl, 4-hydroxy-piperidin-4-yl, N-methyl-4-hydroxy-piperidin-4-yl, N-butoxycarbonyl-4-hydroxy-piperidin-4-yl, 2,5-diazabicyclo [2.2.1] -hept-2-yl, Nt- Butoxycarbonyl-2,5-diazabicyclo [2.2.1] -hept-2-yl, piperidin-4-ylamino, Nt-butoxycarbonyl-piperidin-4-ylamino, pipe Ferridin-4-yloxy or Nt-butoxycarbonyl-piperidin-4-yloxy, R3는 F, 아미노, 시클로프로필아미노, 시클로프로필메틸아미노, 시클로부틸아미노, 시클로펜틸아미노, 시클로헥실아미노, 시클로헵틸아미노, 페닐아미노, 벤질아미노, (S)-1-페닐에틸아미노, (R)-1-페닐에틸아미노, 에틸카보닐아미노, N,N-디에틸카보닐아미노, 시클로헥실카보닐아미노, N,N-디시클로헥실카보닐아미노, 페닐카보닐아미노, t-부톡시카보닐아미노, 메틸설파닐, 메탄설피닐 또는 메탄설포닐인 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염.R3 is F, amino, cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, phenylamino, benzylamino, (S) -1-phenylethylamino, (R) -1-phenylethylamino, ethylcarbonylamino, N, N-diethylcarbonylamino, cyclohexylcarbonylamino, N, N-dicyclohexylcarbonylamino, phenylcarbonylamino, t-butoxycarbonyl Substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof that are amino, methylsulfanyl, methanesulfinyl or methanesulfonyl. 제 1항에 있어서, 상기 화학식 1의 화합물은,According to claim 1, wherein the compound of Formula 1, 1. [4-(3-클로로페닐)-5-(2-플루오로피리딘-4-일)티아졸-2-일]메틸아민; 1. [4- (3-chlorophenyl) -5- (2-fluoropyridin-4-yl) thiazol-2-yl] methylamine; 2. [4-(3-클로로페닐)-5-(2-플루오로피리딘-4-일)티아졸-2-일]히드라진;2. [4- (3-chlorophenyl) -5- (2-fluoropyridin-4-yl) thiazol-2-yl] hydrazine; 3. 4-[2-에틸-4-(4-플루오로페닐)티아졸-5-일]-2-플루오로피리딘;3. 4- [2-ethyl-4- (4-fluorophenyl) thiazol-5-yl] -2-fluoropyridine; 4. {4-[4-(4-플루오로페닐)-2-(4-메틸설파닐페닐)티아졸-5-일]피리딘-2-일}카바민산 tert-부틸 에스터;4. {4- [4- (4-fluorophenyl) -2- (4-methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl} carbamic acid tert -butyl ester; 5. 4-[4-(4-플루오로페닐)-2-(4-메틸설파닐페닐)티아졸-5-일]피리딘-2-일아민;5. 4- [4- (4-fluorophenyl) -2- (4-methylsulfanylphenyl) thiazol-5-yl] pyridin-2-ylamine; 6. 4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민;6. 4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine; 7. [4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]메틸아민;7. [4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] methylamine; 8. 4-[4-(3-클로로페닐)-2-에틸티아졸-5-일]-2-메틸설파닐피리미딘;8. 4- [4- (3-chlorophenyl) -2-ethylthiazol-5-yl] -2-methylsulfanylpyrimidine; 9. 4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민;9. 4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine; 10. 4-(3-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민;10. 4- (3-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine; 11. 4-(2-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민;11. 4- (2-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine; 12. 4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민;12. 4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine; 13. 5-(2-메틸설파닐피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일아민;13. 5- (2-methylsulfanylpyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-ylamine; 14. 5-(2-메틸설파닐피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일아민;14. 5- (2-methylsulfanylpyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-ylamine; 15. 4-(4-메톡시페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아민;15. 4- (4-methoxyphenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine; 16. [4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]메틸아민;16. [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] methylamine; 17. 4-[4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카복실산 tert-부틸 에스터;17. 4- [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester; 18. 4-[5-(2-아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;18. 4- [5- (2-aminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 19. 4-[4-(3-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;19. 4- [4- (3-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 20. 4-[4-(2-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;20. 4- [4- (2-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 21. 4-[4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;21. 4- [4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 22. 4-[5-(2-메틸설파닐피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;22. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 23. 4-[5-(2-메틸설파닐피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;23. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 24. 4-[4-(4-메톡시페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;24. 4- [4- (4-methoxyphenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 25. 4-[4-(4-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘;25. 4- [4- (4-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 26. 4-[4-(3-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘;26. 4- [4- (3-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 27. 4-[4-(2-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘;27. 4- [4- (2-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 28. 4-[4-(3-클로로페닐)티아졸-5-일]-2-메틸설파닐피리미딘;28. 4- [4- (3-chlorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 29. 2-메틸설파닐-4-[4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘;29. 2-methylsulfanyl-4- [4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine; 30. 2-메틸설파닐-4-[4-(3-메틸페닐)티아졸-5-일]피리미딘;30. 2-methylsulfanyl-4- [4- (3-methylphenyl) thiazol-5-yl] pyrimidine; 31. 4-[4-(4-메톡시페닐)티아졸-5-일]-2-메틸설파닐피리미딘;31. 4- [4- (4-methoxyphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 32. 4-[2-클로로-4-(4-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘;32. 4- [2-chloro-4- (4-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 33. 4-[2-클로로-4-(3-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘;33. 4- [2-chloro-4- (3-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 34. 4-[2-클로로-4-(2-플루오로페닐)티아졸-5-일]-2-메틸설파닐피리미딘;34. 4- [2-chloro-4- (2-fluorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 35. 4-[2-클로로-4-(3-클로로페닐)티아졸-5-일]-2-메틸설파닐피리미딘;35. 4- [2-chloro-4- (3-chlorophenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 36. 4-[2-클로로-4-(3-트리플르오로메틸페닐)티아졸-5-일]-2-메틸설파닐피리미딘;36. 4- [2-chloro-4- (3-trifluoromethylphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 37. 4-[2-클로로-4-(3-메틸페닐)티아졸-5-일]-2-메틸설파닐피리미딘;37. 4- [2-chloro-4- (3-methylphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 38. 4-[2-클로로-4-(4-메톡시페닐)티아졸-5-일]-2-메틸설파닐피리미딘;38. 4- [2-chloro-4- (4-methoxyphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 39. 4-[4-(4-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메틸설파닐피리미딘;39. 4- [4- (4-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine; 40. 4-[4-(3-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메틸설파닐피리미딘;40. 4- [4- (3-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine; 41. 4-[4-(2-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메틸설파닐피리미딘;41. 4- [4- (2-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine; 42. 4-[4-(3-클로로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메틸설파닐피리미딘;42. 4- [4- (3-chlorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine; 43. 2-메틸설파닐-4-[2-피페리딘-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘;43. 2-methylsulfanyl-4- [2-piperidin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine; 44. 2-메틸설파닐-4-[2-피페리딘-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘;44. 2-methylsulfanyl-4- [2-piperidin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidine; 45. 4-[4-(4-메톡시페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메틸설파닐피리미딘;45. 4- [4- (4-methoxyphenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine; 46. 4-[4-(4-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메틸설파닐피리미딘;46. 4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 47. 4-[4-(3-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메틸설파닐피리미딘;47. 4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 48. 4-[4-(2-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메틸설파닐피리미딘;48. 4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 49. 4-[4-(3-클로로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메틸설파닐피리미딘;49. 4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 50. 4-[2-(4-메틸피페리딘-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]-2-메틸설파닐피리미딘;50. 4- [2- (4-methylpiperidin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 51. 4-[2-(4-메틸피페리딘-1-일)-4-(3-메틸페닐)티아졸-5-일]-2-메틸설파닐피리미딘;51. 4- [2- (4-methylpiperidin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 52. 4-[4-(4-메톡시페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메틸설파닐피리미딘;52. 4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 53. 4-[4-(4-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]-2-메틸설파닐피리미딘;53. 4- [4- (4-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine; 54. 4-[4-(3-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]-2-메틸설파닐피리미딘;54. 4- [4- (3-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine; 55. 4-[4-(2-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]-2-메틸설파닐피리미딘;55. 4- [4- (2-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine; 56. 4-[4-(3-클로로페닐)-2-피페라진-1-일-티아졸-5-일]-2-메틸설파닐피리미딘;56. 4- [4- (3-chlorophenyl) -2-piperazin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine; 57. 2-메틸설파닐-4-[2-피페라진-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘;57. 2-methylsulfanyl-4- [2-piperazin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine; 58. 2-메틸설파닐-4-[2-피페라진-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘;58. 2-methylsulfanyl-4- [2-piperazin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidine; 59. 4-[4-(4-메톡시페닐)-2-피페라진-1-일-티아졸-5-일]-2-메틸설파닐피리미딘;59. 4- [4- (4-methoxyphenyl) -2-piperazin-1-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine; 60. 2-[4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]-2,5-디아자비시클로[2.2.1]헵탄;60. 2- [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -2,5-diazabicyclo [2.2.1] Heptane; 61. 4-[4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일옥시]피페리딘-1-카르복실산 tert-부틸 에스터;61. 4- [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yloxy] piperidine-1-carboxylic acid tert-butyl Ester; 62. 4-[4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일아미노]피페리딘-1-카르복실산 tert-부틸 에스터;62. 4- [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-ylamino] piperidine-1-carboxylic acid tert-butyl Ester; 63. 4-[4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페라진-1-카복실산 tert-부틸 에스터; 63. 4- [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 64. 4-[4-(3-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;64. 4- [4- (3-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 65. 4-[4-(2-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페 라진-1-카르복실산 tert-부틸 에스터;65. 4- [4- (2-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 66. 4-[4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;66. 4- [4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 67. 4-[5-(2-메틸설파닐피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸 -2-일]피페라진-1-카르복실산 tert-부틸 에스터;67. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester ; 68. 4-[5-(2-메틸설파닐피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;68. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 69. 4-[4-(4-메톡시페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;69. 4- [4- (4-methoxyphenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 70. 5-[4-(4-플루오로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]-2,5-디아자비시클로[2.2.1]헵탄-2-카르복실산 tert-부틸 에스터;70. 5- [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -2,5-diazabicyclo [2.2.1] Heptane-2-carboxylic acid tert-butyl ester; 71. 4-(3-클로로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일아민; 71. 4- (3-chlorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-ylamine; 72. 4-[4-(3-클로로페닐)-2-에틸티아졸-5-일]-2-메탄설피닐피리미딘; 72. 4- [4- (3-chlorophenyl) -2-ethylthiazol-5-yl] -2-methanesulfinylpyrimidine; 73. 4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일아민;73. 4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-ylamine; 74. [4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]메틸아민;74. [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] methylamine; 75. 4-[4-(4-플루오로페닐)-5-(2-메탄설포닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카복실산 에틸 에스터; 75. 4- [4- (4-fluorophenyl) -5- (2-methanesulfonylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 76. 4-[4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카복실산 tert-부틸 에스터;76. 4- [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester; 77. 4-[4-(3-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;77. 4- [4- (3-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 78. 4-[4-(2-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;78. 4- [4- (2-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 79. 4-[4-(3-클로로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;79. 4- [4- (3-chlorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 80. 4-[5-(2-메탄설피닐피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;80. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 81. 4-[5-(2-메탄설피닐피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;81. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 82. 4-[5-(2-메탄설피닐피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;82. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 83. 4-[4-(4-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메탄설피닐피리미딘;83. 4- [4- (4-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methanesulfinylpyrimidine; 84. 4-[4-(3-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메탄설피닐피리미딘; 84. 4- [4- (3-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methanesulfinylpyrimidine; 85. 4-[4-(2-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메탄설피닐피리미딘;85. 4- [4- (2-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methanesulfinylpyrimidine; 86. 4-[4-(3-클로로페닐)-2-피페리딘-1-일-티아졸-5-일]-2-메탄설피닐피리미딘;86. 4- [4- (3-chlorophenyl) -2-piperidin-1-yl-thiazol-5-yl] -2-methanesulfinylpyrimidine; 87. 2-메탄설피닐-4-[2-피페리딘-1-일-4-(3-트리플르오로메틸페닐)티아졸 -5-일]피리미딘;87. 2-methanesulfinyl-4- [2-piperidin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine; 88. 2-메탄설피닐-4-[2-피페리딘-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘;88. 2-methanesulfinyl-4- [2-piperidin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidine; 89. 2-메탄설피닐-4-[4-(4-메톡시페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘;89. 2-methanesulfinyl-4- [4- (4-methoxyphenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidine; 90. 4-[4-(4-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메탄설피닐피리미딘;90. 4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methanesulfinylpyrimidine; 91. 4-[4-(3-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메탄설피닐피리미딘;91. 4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methanesulfinylpyrimidine; 92. 4-[4-(2-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메탄설피닐피리미딘;92. 4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methanesulfinylpyrimidine; 93. 4-[4-(3-클로로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]-2-메탄설피닐피리미딘;93. 4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] -2-methanesulfinylpyrimidine; 94. 2-메탄설피닐-4-[2-(4-메틸피페리딘-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘;94. 2-methanesulfinyl-4- [2- (4-methylpiperidin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine; 95. 2-메탄설피닐-4-[2-(4-메틸피페리딘-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘;95. 2-methanesulfinyl-4- [2- (4-methylpiperidin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidine; 96. 2-메탄설피닐-4-[4-(4-메톡시페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘;96. 2-methanesulfinyl-4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidine; 97. 4-[4-(4-플루오로페닐)-2-(4-메틸-4-옥시피페라진-1-일)티아졸-5-일]-2- 메틸설파닐피리미딘; 97. 4- [4- (4-fluorophenyl) -2- (4-methyl-4-oxypiperazin-1-yl) thiazol-5-yl] -2- methylsulfanylpyrimidine; 98. 4-[4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페라진-1-카복실산 tert-부틸 에스터; 98. 4- [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 99. 4-[4-(3-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;99. 4- [4- (3-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 100. 4-[4-(2-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;100. 4- [4- (2-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 101. 4-[4-(3-클로로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;101. 4- [4- (3-chlorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 102. 4-[5-(2-메탄설피닐피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;102. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester ; 103. 4-[5-(2-메탄설피닐피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;103. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 104. 4-[5-(2-메탄설피닐피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;104. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 105. 4-[4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일옥시]피페리딘-1-카르복실산 tert-부틸 에스터;105. 4- [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yloxy] piperidine-1-carboxylic acid tert-butyl Ester; 106. 4-[4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일아미노]피페리딘-1-카르복실산 tert-부틸 에스터;106. 4- [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-ylamino] piperidine-1-carboxylic acid tert-butyl Ester; 107. 5-[4-(4-플루오로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]- 2,5-디아자비시클로[2.2.1]헵탄-2-카르복실산 tert-부틸 에스터;107. 5- [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] -2,5-diazabicyclo [2.2.1] Heptane-2-carboxylic acid tert-butyl ester; 108. 4-[4-(4-플루오로페닐)티아졸-5-일]-2-메탄설피닐피리미딘;108. 4- [4- (4-fluorophenyl) thiazol-5-yl] -2-methanesulfinylpyrimidine; 109. 4-[4-(3-플루오로페닐)티아졸-5-일]-2-메탄설피닐피리미딘;109. 4- [4- (3-fluorophenyl) thiazol-5-yl] -2-methanesulfinylpyrimidine; 110. 4-[4-(2-플루오로페닐)티아졸-5-일]-2-메탄설피닐피리미딘;110. 4- [4- (2-fluorophenyl) thiazol-5-yl] -2-methanesulfinylpyrimidine; 111. 4-[4-(3-클로로페닐)티아졸-5-일]-2-메탄설피닐피리미딘;111. 4- [4- (3-chlorophenyl) thiazol-5-yl] -2-methanesulfinylpyrimidine; 112. 2-메탄설피닐-4-[4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘;112. 2-methanesulfinyl-4- [4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine; 113. 2-메탄설피닐-4-[4-(3-메틸페닐)티아졸-5-일]피리미딘;113. 2-methanesulfinyl-4- [4- (3-methylphenyl) thiazol-5-yl] pyrimidine; 114. 2-메탄설피닐-4-[4-(4-메톡시페닐)티아졸-5-일]피리미딘;114. 2-methanesulfinyl-4- [4- (4-methoxyphenyl) thiazol-5-yl] pyrimidine; 115. {4-[2-아미노-4-(3-클로로페닐)티아졸-5-일]피리딘-2-일}시클로헥실아민;115. {4- [2-amino-4- (3-chlorophenyl) thiazol-5-yl] pyridin-2-yl} cyclohexylamine; 116. {4-[4-(3-클로로페닐)-2-메틸아미노티아졸-5-일]피리딘-2-일}시클로헥실아민;116. {4- [4- (3-chlorophenyl) -2-methylaminothiazol-5-yl] pyridin-2-yl} cyclohexylamine; 117. {4-[4-(3-클로로페닐)-2-히드라지노티아졸-5-일]피리딘-2-일}시클로헥실아민;117. {4- [4- (3-Chlorophenyl) -2-hydrazinothiazol-5-yl] pyridin-2-yl} cyclohexylamine; 118. {4-[4-(3-클로로페닐)-2-에틸티아졸-5-일]피리딘-2-일}-(1-(S)-페닐에틸)아민;118. {4- [4- (3-chlorophenyl) -2-ethylthiazol-5-yl] pyridin-2-yl}-(1- (S) -phenylethyl) amine; 119. 시클로헥실-{4-[4-(4-플루오로페닐)티아졸-5-일]피리딘-2-일}아민;119. cyclohexyl- {4- [4- (4-fluorophenyl) thiazol-5-yl] pyridin-2-yl} amine; 120. {4-[4-(4-플루오로페닐)티아졸-5-일]피리딘-2-일}-(1-(S)-페닐에틸)아민;120. {4- [4- (4-fluorophenyl) thiazol-5-yl] pyridin-2-yl}-(1- (S) -phenylethyl) amine; 121. 시클로헥실-{4-[2-에틸-4-(4-플루오로페닐)티아졸-5-일]피리딘-2-일}아 민;121. Cyclohexyl- {4- [2-ethyl-4- (4-fluorophenyl) thiazol-5-yl] pyridin-2-yl} amine; 122. {4-[2-아미노-4-(3-클로로페닐)티아졸-5-일]피리미딘-2-일}시클로헥실아민;122. {4- [2-amino-4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine; 123. {4-[4-(3-클로로페닐)-2-메틸아미노티아졸-5-일]피리미딘-2-일}시클로펜틸아민;123. {4- [4- (3-chlorophenyl) -2-methylaminothiazol-5-yl] pyrimidin-2-yl} cyclopentylamine; 124. {4-[4-(3-클로로페닐)-2-에틸티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;124. {4- [4- (3-chlorophenyl) -2-ethylthiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine; 125. {4-[4-(3-클로로페닐)-2-메틸아미노티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;125. {4- [4- (3-chlorophenyl) -2-methylaminothiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine; 126. {4-[2-아미노-4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;126. {4- [2-amino-4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine; 127. {4-[4-(4-플루오로페닐)-2-메틸아미노티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;127. {4- [4- (4-fluorophenyl) -2-methylaminothiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine; 128. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카복실산 에틸 에스터;128. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 129. 4-[5-(2-시클로부틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;129. 4- [5- (2-cyclobutylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 130. 4-[5-(2-시클로헵틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;130. 4- [5- (2-cycloheptylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 131. 4-[5-[2-(시클로프로필메틸아미노)피리미딘-4-일]-4-(4-플루오로페닐) 티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;131. 4- [5- [2- (cyclopropylmethylamino) pyrimidin-4-yl] -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl Ester; 132. 4-[5-(2-벤질아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;132. 4- [5- (2-benzylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 133. 4-[4-(4-플루오로페닐)-5-(2-페닐아미노피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;133. 4- [4- (4-fluorophenyl) -5- (2-phenylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 134. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;134. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 135. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;135. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 136. 4-[4-(3-클로로페닐)-5-(2-시클로프로필아미노피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;136. 4- [4- (3-chlorophenyl) -5- (2-cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 137. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;137. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 138. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;138. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 139. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;139. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 140. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카복실산 tert-부틸 에스터;140. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester; 141. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2- 일]피페리딘-1-카복실산 tert-부틸 에스터;141. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester; 142. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터; 142. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 143. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;143. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 144. 4-[4-(3-클로로페닐)-5-(2-시클로펜틸아미노피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;144. 4- [4- (3-chlorophenyl) -5- (2-cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 145. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;145. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 146. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;146. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 147. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;147. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 148. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카복실산 tert-부틸 에스터;148. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester; 149. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;149. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 150. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;150. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 151. 4-[4-(3-클로로페닐)-5-(2-시클로헥실아미노피리미딘-4-일)티아졸-151. 4- [4- (3-chlorophenyl) -5- (2-cyclohexylaminopyrimidin-4-yl) thiazole- 2-일]피페리딘-1-카르복실산 에틸 에스터2-yl] piperidine-1-carboxylic acid ethyl ester 152. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-트리플르오로메틸152. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-trifluoromethyl 페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터 Phenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester 153. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;153. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 154. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;154. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 155. 4-{4-(4-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카복실산 tert-부틸 에스터;155. 4- {4- (4-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-1 Carboxylic acid tert-butyl esters; 156. 4-{4-(4-플루오로페닐)-5-[2-(1-(R)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카르복실산 에틸 에스터;156. 4- {4- (4-fluorophenyl) -5- [2- (1- (R) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-1 -Carboxylic acid ethyl ester; 157. 4-{4-(3-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카르복실산 에틸 에스터;157. 4- {4- (3-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-1 -Carboxylic acid ethyl ester; 158. 4-{4-(2-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카르복실산 에틸 에스터;158. 4- {4- (2-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-1 -Carboxylic acid ethyl ester; 159. 4-{4-(3-클로로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카르복실산 에틸 에스터;159. 4- {4- (3-chlorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-1- Carboxylic acid ethyl ester; 160. 4-[5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;160. 4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine- 1-carboxylic acid ethyl ester; 161. 4-{5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-메틸페닐)티아졸-2-일}피페리딘-1-카르복실산 에틸 에스터;161. 4- {5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-methylphenyl) thiazol-2-yl} piperidine-1-car Acid ethyl ester; 162. 4-{4-(4-메톡시페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카르복실산 에틸 에스터;162. 4- {4- (4-methoxyphenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-1 -Carboxylic acid ethyl ester; 163. 시클로프로필-{4-[4-(4-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민;163. cyclopropyl- {4- [4- (4-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 164. 시클로프로필-{4-[4-(3-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민;164. cyclopropyl- {4- [4- (3-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 165. 시클로프로필-{4-[4-(2-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민;165. cyclopropyl- {4- [4- (2-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 166. {4-[4-(3-클로로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}시클로프로필아민;166. {4- [4- (3-chlorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine; 167. 시클로프로필-{4-[2-피페리딘-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;167. cyclopropyl- {4- [2-piperidin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 168. 시클로프로필-{4-[2-피페리딘-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;168. cyclopropyl- {4- [2-piperidin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 169. 시클로프로필-{4-[4-(4-메톡시페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민;169. cyclopropyl- {4- [4- (4-methoxyphenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 170. 시클로펜틸-{4-[4-(4-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민;170. cyclopentyl- {4- [4- (4-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 171. 시클로펜틸-{4-[4-(3-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민;171. cyclopentyl- {4- [4- (3-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 172. 시클로펜틸-{4-[4-(2-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민;172. cyclopentyl- {4- [4- (2-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 173. {4-[4-(3-클로로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}시클로펜틸아민;173. {4- [4- (3-chlorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine; 174. 시클로펜틸-{4-[2-피페리딘-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;174. cyclopentyl- {4- [2-piperidin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 175. 시클로펜틸-{4-[2-피페리딘-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;175. cyclopentyl- {4- [2-piperidin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 176. 시클로펜틸-{4-[4-(4-메톡시페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민;176. cyclopentyl- {4- [4- (4-methoxyphenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 177. 시클로헥실-{4-[4-(4-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민;177. cyclohexyl- {4- [4- (4-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 178. 시클로헥실-{4-[4-(3-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민;178. cyclohexyl- {4- [4- (3-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 179. 시클로헥실-{4-[4-(2-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민;179. cyclohexyl- {4- [4- (2-fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 180. {4-[4-(3-클로로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}시클로헥실아민;180. {4- [4- (3-chlorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine; 181. 시클로헥실-{4-[2-피페리딘-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;181. cyclohexyl- {4- [2-piperidin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 182. 시클로헥실-{4-[2-피페리딘-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;182. cyclohexyl- {4- [2-piperidin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 183. 시클로헥실-{4-[4-(4-메톡시페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}아민;183. cyclohexyl- {4- [4- (4-methoxyphenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 184. {4-[4-(4-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;184. {4- [4- (4-Fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl ) Amine; 185. {4-[4-(3-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;185. {4- [4- (3-Fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl ) Amine; 186. {4-[4-(2-플루오로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;186. {4- [4- (2-Fluorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl ) Amine; 187. {4-[4-(3-클로로페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;187. {4- [4- (3-Chlorophenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) Amines; 188. (1-(S)-페닐에틸)-{4-[2-피페리딘-1-일-4-(3-트리플르오로메틸페닐) 티아졸-5-일]피리미딘-2-일}아민;188. (1- (S) -phenylethyl)-{4- [2-piperidin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl } Amine; 189. (1-(S)-페닐에틸)-{4-[2-피페리딘-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;189. (1- (S) -phenylethyl)-{4- [2-piperidin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 190. {4-[4-(4-메톡시페닐)-2-피페리딘-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;190. {4- [4- (4-methoxyphenyl) -2-piperidin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl ) Amine; 191. 시클로프로필-{4-[4-(4-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민;191. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 192. 시클로프로필-{4-[4-(3-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민;192. cyclopropyl- {4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 193. 시클로프로필-{4-[4-(2-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민;193. cyclopropyl- {4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 194. {4-[4-(3-클로로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}시클로프로필아민;194. {4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine; 195. 시클로프로필-{4-[2-(4-메틸피페리딘-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;195. cyclopropyl- {4- [2- (4-methylpiperidin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 196. 시클로프로필-{4-[2-(4-메틸피페리딘-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;196. Cyclopropyl- {4- [2- (4-methylpiperidin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 197. 시클로프로필-{4-[4-(4-메톡시페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민;197. cyclopropyl- {4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 198. 시클로펜틸-{4-[4-(4-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민;198. cyclopentyl- {4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 199. 시클로펜틸-{4-[4-(3-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민;199. cyclopentyl- {4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 200. 시클로펜틸-{4-[4-(2-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민;200. cyclopentyl- {4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 201. {4-[4-(3-클로로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}시클로펜틸아민;201. {4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine; 202. 시클로펜틸-{4-[2-(4-메틸피페리딘-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;202. cyclopentyl- {4- [2- (4-methylpiperidin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 203. 시클로펜틸-{4-[2-(4-메틸피페리딘-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;203. cyclopentyl- {4- [2- (4-methylpiperidin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 204. 시클로펜틸-{4-[4-(4-메톡시페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민;204. cyclopentyl- {4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 205. 시클로헥실-{4-[4-(4-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민;205. Cyclohexyl- {4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 206. 시클로헥실-{4-[4-(3-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민;206. cyclohexyl- {4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 207. 시클로헥실-{4-[4-(2-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민;207. cyclohexyl- {4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 208. {4-[4-(3-클로로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}시클로헥실아민;208. {4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine; 209. 시클로헥실-{4-[2-(4-메틸피페리딘-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;209. cyclohexyl- {4- [2- (4-methylpiperidin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 210. 시클로헥실-{4-[2-(4-메틸피페리딘-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;210. cyclohexyl- {4- [2- (4-methylpiperidin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 211. 시클로헥실-{4-[4-(4-메톡시페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}아민;211. cyclohexyl- {4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 212. {4-[4-(4-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;212. {4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine; 213. {4-[4-(3-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;213. {4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine; 214. {4-[4-(2-플루오로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;214. {4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine; 215. {4-[4-(3-클로로페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;215. {4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -Phenylethyl) amine; 216. {4-[2-(4-메틸피페리딘-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;216. {4- [2- (4-Methylpiperidin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- ( S) -phenylethyl) amine; 217. {4-[2-(4-메틸피페리딘-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;217. {4- [2- (4-Methylpiperidin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S)- Phenylethyl) amine; 218. {4-[4-(4-메톡시페닐)-2-(4-메틸피페리딘-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;218. {4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine; 219. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페라진-1-카복실산 tert-부틸 에스터;219. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 220. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;220. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 221. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;221. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 222. 4-[4-(3-클로로페닐)-5-(2-시클로프로필아미노피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;222. 4- [4- (3-chlorophenyl) -5- (2-cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 223. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;223. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester ; 224. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;224. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 225. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;225. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 226. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페라진-1-카복실산 tert-부틸 에스터;226. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 227. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터; 227. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 228. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;228. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 229. 4-[4-(3-클로로페닐)-5-(2-시클로펜틸아미노피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;229. 4- [4- (3-chlorophenyl) -5- (2-cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 230. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;230. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester ; 231. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;231. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 232. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;232. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 233. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페라진-1-카복실산 tert-부틸 에스터;233. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 234. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;234. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 235. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;235. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 236. 4-[4-(3-클로로페닐)-5-(2-시클로헥실아미노피리미딘-4-일)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;236. 4- [4- (3-chlorophenyl) -5- (2-cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 237. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;237. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester ; 238. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;238. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 239. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;239. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperazin-1-carboxylic acid tert-butyl ester; 240. 4-{4-(4-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일]피페라진-1-카복실산 tert-부틸 에스터;240. 4- {4- (4-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl] piperazin-1- Carboxylic acid tert-butyl ester; 241. 4-{4-(3-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페라진-1-카르복실산 tert-부틸 에스터;241. 4- {4- (3-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperazin-1- Carboxylic acid tert-butyl ester; 242. 4-{4-(2-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페라진-1-카르복실산 tert-부틸 에스터;242. 4- {4- (2-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperazin-1- Carboxylic acid tert-butyl ester; 243. 4-{4-(3-클로로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-피페라진-1-카르복실산 tert-부틸 에스터;243. 4- {4- (3-Chlorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -piperazin-1- Carboxylic acid tert-butyl ester; 244. 4-[5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페라진-1-카르복실산 tert-부틸 에스터;244. 4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazin-1 Carboxylic acid tert-butyl ester; 245. 4-{5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-메틸페닐)티아졸-2-일}-피페라진-1-카르복실산 tert-부틸 에스터;245. 4- {5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-methylphenyl) thiazol-2-yl} -piperazin-1-car Acid tert-butyl esters; 246. 4-{4-(4-메톡시페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-피페라진-1-카르복실산 tert-부틸 에스터;246. 4- {4- (4-methoxyphenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -piperazin-1 Carboxylic acid tert-butyl ester; 247. 5-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-2,5-디아자비시클로[2.2.1]헵탄-2-카르복실산 tert-부틸 에스터;247. 5- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -2,5-diazabicyclo [2.2.1] Heptane-2-carboxylic acid tert-butyl ester; 248. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐) 티아졸-2-일옥시]피페리딘-1-카르복실산 tert-부틸 에스터;248. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yloxy] piperidine-1-carboxylic acid tert-butyl Ester; 249. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일아미노]피페리딘-1-카르복실산 tert-부틸 에스터;249. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-ylamino] piperidine-1-carboxylic acid tert-butyl Ester; 250. 시클로프로필-{4-[4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민;250. cyclopropyl- {4- [4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 251. 시클로프로필-{4-[4-(3-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민;251. cyclopropyl- {4- [4- (3-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 252. 시클로프로필-{4-[4-(2-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민;252. cyclopropyl- {4- [4- (2-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 253. {4-[4-(3-클로로페닐)티아졸-5-일]피리미딘-2-일}시클로프로필아민;253. {4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine; 254. 시클로프로필-{4-[4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;254. cyclopropyl- {4- [4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 255. 시클로프로필-{4-[4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;255. cyclopropyl- {4- [4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 256. 시클로프로필-{4-[4-(4-메톡시페닐)티아졸-5-일]피리미딘-2-일}아민;256. cyclopropyl- {4- [4- (4-methoxyphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 257. 시클로펜틸-{4-[4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민;257. cyclopentyl- {4- [4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 258. 시클로펜틸-{4-[4-(3-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민;258. cyclopentyl- {4- [4- (3-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 259. 시클로펜틸-{4-[4-(2-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민;259. cyclopentyl- {4- [4- (2-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 260. {4-[4-(3-클로로페닐)티아졸-5-일]피리미딘-2-일}시클로펜틸아민;260. {4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine; 261. 시클로펜틸-{4-[4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;261. cyclopentyl- {4- [4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 262. 시클로펜틸-{4-[4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;262. cyclopentyl- {4- [4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 263. 시클로펜틸-{4-[4-(4-메톡시페닐)티아졸-5-일]피리미딘-2-일}아민;263. cyclopentyl- {4- [4- (4-methoxyphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 264. 시클로헥실-{4-[4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민;264. cyclohexyl- {4- [4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 265. 시클로헥실-{4-[4-(3-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민;265. cyclohexyl- {4- [4- (3-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 266. 시클로헥실-{4-[4-(2-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민;266. cyclohexyl- {4- [4- (2-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 267. {4-[4-(3-클로로페닐)티아졸-5-일]피리미딘-2-일}시클로헥실아민;267. {4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine; 268. 시클로헥실-{4-[4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;268. cyclohexyl- {4- [4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 269. 시클로헥실-{4-[4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;269. cyclohexyl- {4- [4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 270. 시클로헥실-{4-[4-(4-메톡시페닐)티아졸-5-일]피리미딘-2-일}아민;270. cyclohexyl- {4- [4- (4-methoxyphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 271. {4-[4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;271. {4- [4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine; 272. {4-[4-(3-플루오로페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;272. {4- [4- (3-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine; 273. {4-[4-(2-플루오로페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;273. {4- [4- (2-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine; 274. {4-[4-(3-클로로페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;274. {4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine; 275. (1-(S)-페닐에틸)-{4-[4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;275. (1- (S) -phenylethyl)-{4- [4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 276. (1-(S)-페닐에틸)-{4-[4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;276. (1- (S) -phenylethyl)-{4- [4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 277. {4-[4-(4-메톡시페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;277. {4- [4- (4-methoxyphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine; 278. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올;278. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 279. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸- 2-일]-1-메틸피페리딘-4-올;279. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 280. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올;280. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 281. 4-[4-(3-클로로페닐)-5-(2-시클로프로필아미노피리미딘-4-일)티아졸-2-일]-1-메틸피페리딘-4-올;281. 4- [4- (3-chlorophenyl) -5- (2-cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] -1-methylpiperidin-4-ol; 282. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]-1-메틸피페리딘-4-올;282. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 283. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]-1-메틸피페리딘-4-올;283. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 284. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]-1-메틸피페리딘-4-올;284. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 285. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올;285. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 286. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올;286. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 287. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올;287. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 288. 4-[4-(3-클로로페닐)-5-(2-시클로펜틸아미노피리미딘-4-일)티아졸-2-일]-1-메틸피페리딘-4-올;288. 4- [4- (3-chlorophenyl) -5- (2-cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] -1-methylpiperidin-4-ol; 289. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐) 티아졸-2-일]-1-메틸피페리딘-4-올;289. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 290. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]-1-메틸피페리딘-4-올;290. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 291. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]-1-메틸피페리딘-4-올;291. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 292. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올;292. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 293. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올;293. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 294. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]-1-메틸피페리딘-4-올;294. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 295. 4-[4-(3-클로로페닐)-5-(2-시클로헥실아미노피리미딘-4-일)티아졸-2-일]-1-메틸피페리딘-4-올;295. 4- [4- (3-chlorophenyl) -5- (2-cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] -1-methylpiperidin-4-ol; 296. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]-1-메틸피페리딘-4-올;296. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 297. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]-1-메틸피페리딘-4-올;297. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 298. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]-1-메틸피페리딘-4-올;298. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] -1-methylpiperidin-4-ol; 299. 4-{4-(4-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티 아졸-2-일}-1-메틸피페리딘-4-올;299. 4- {4- (4-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -1-methylpy Ferridin-4-ol; 300. 4-{4-(3-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-1-메틸피페리딘-4-올;300. 4- {4- (3-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -1-methylpy Ferridin-4-ol; 301. 4-{4-(2-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-1-메틸피페리딘-4-올;301. 4- {4- (2-Fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -1-methylpy Ferridin-4-ol; 302. 4-{4-(3-클로로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-1-메틸피페리딘-4-올;302. 4- {4- (3-chlorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -1-methylpiperi Din-4-ol; 303. 1-메틸-4-[5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-4-올;303. 1-Methyl-4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-trifluoromethylphenyl) thiazol-2-yl] Piperidin-4-ol; 304. 1-메틸-4-{5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-메틸페닐)티아졸-2-일}-피페리딘-4-올;304. 1-Methyl-4- {5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-methylphenyl) thiazol-2-yl} -piperi Din-4-ol; 305. 4-{4-(4-메톡시페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-1-메틸피페리딘-4-올;305. 4- {4- (4-methoxyphenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -1-methylpy Ferridin-4-ol; 306. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카복실산 tert-부틸 에스터;306. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert Butyl ester; 307. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;307. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester; 308. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;308. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester; 309. 4-[4-(3-클로로페닐)-5-(2-시클로프로필아미노피리미딘-4-일)티아졸-2- 일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;309. 4- [4- (3-chlorophenyl) -5- (2-cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert-butyl ester; 310. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;310. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-car Acid tert-butyl esters; 311. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;311. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert Butyl ester; 312. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;312. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester; 313. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카복실산 tert-부틸 에스터;313. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert Butyl ester; 314. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;314. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester; 315. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;315. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester; 316. 4-[4-(3-클로로페닐)-5-(2-시클로펜틸아미노피리미딘-4-일)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;316. 4- [4- (3-chlorophenyl) -5- (2-cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert-butyl ester; 317. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;317. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-car Acid tert-butyl esters; 318. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;318. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert Butyl ester; 319. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2- 일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;319. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester; 320. 4-[5-(시클로헥실아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카복실산 tert-부틸 에스터;320. 4- [5- (cyclohexylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert-butyl Ester; 321. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;321. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester; 322. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;322. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester; 323. 4-[4-(3-클로로페닐)-5-(2-시클로헥실아미노피리미딘-4-일)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;323. 4- [4- (3-chlorophenyl) -5- (2-cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert-butyl ester; 324. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;324. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-car Acid tert-butyl esters; 325. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;325. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxylic acid tert Butyl ester; 326. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;326. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] -4-hydroxypiperidine-1-carboxyl Acid tert-butyl ester; 327. 4-{4-(4-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-4-히드록시피페리딘-1-카복실산 tert-부틸 에스터;327. 4- {4- (4-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -4-hydroxy Cipiperidine-1-carboxylic acid tert-butyl ester; 328. 4-{4-(3-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;328. 4- {4- (3-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -4-hydroxy Cipiperidine-1-carboxylic acid tert-butyl ester; 329. 4-{4-(2-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티 아졸-2-일}-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;329. 4- {4- (2-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -4-hydroxy Cipiperidine-1-carboxylic acid tert-butyl ester; 330. 4-{4-(3-클로로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-4-히드록시피페리딘-1-카르복실산 tert-부틸 에스터;330. 4- {4- (3-Chlorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -4-hydroxypy Ferridine-1-carboxylic acid tert-butyl ester; 331. 4-히드록시-4-[5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-1-카르복실산 tert-부틸 에스터;331. 4-hydroxy-4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-trifluoromethylphenyl) thiazol-2-yl ] Piperidine-1-carboxylic acid tert-butyl ester; 332. 4-히드록시-4-{5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-메틸페닐)티아졸-2-일}피페리딘-1-카르복실산 tert-부틸 에스터;332. 4-hydroxy-4- {5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-methylphenyl) thiazol-2-yl} piperi Dine-1-carboxylic acid tert-butyl ester; 333. 4-히드록시-4-{4-(4-메톡시페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-1-카르복실산 tert-부틸 에스터;333. 4-hydroxy-4- {4- (4-methoxyphenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} Piperidine-1-carboxylic acid tert-butyl ester; 334. 시클로프로필-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;334. cyclopropyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 335. 시클로부틸-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;335. cyclobutyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 336. 시클로헵틸-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;336. cycloheptyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 337. 시클로프로필메틸-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;337. cyclopropylmethyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 338. 벤질-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;338. benzyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 339. {4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일} 페닐아민;339. {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} phenylamine; 340. 시클로프로필-{4-[4-(3-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;340. cyclopropyl- {4- [4- (3-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 341. 시클로프로필-{4-[4-(2-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;341. cyclopropyl- {4- [4- (2-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 342. {4-[4-(3-클로로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}시클로프로필아민;342. {4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine; 343. 시클로프로필-{4-[2-피페리딘-4-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;343. cyclopropyl- {4- [2-piperidin-4-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 344. 시클로프로필-{4-[2-피페리딘-4-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;344. cyclopropyl- {4- [2-piperidin-4-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 345. 시클로프로필-{4-[4-(4-메톡시페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;345. cyclopropyl- {4- [4- (4-methoxyphenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 346. 4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]-2-메틸설파닐피리미딘;346. 4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] -2-methylsulfanylpyrimidine; 347. 4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]-2-메탄설피닐피리미딘;347. 4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] -2-methanesulfinylpyrimidine; 348. 시클로펜틸-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;348. cyclopentyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 349. 시클로펜틸-{4-[4-(3-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리 미딘-2-일}아민;349. cyclopentyl- {4- [4- (3-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 350. 시클로펜틸-{4-[4-(2-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;350. cyclopentyl- {4- [4- (2-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 351. {4-[4-(3-클로로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}시클로펜틸아민;351. {4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine; 352. 시클로펜틸-{4-[2-피페리딘-4-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;352. cyclopentyl- {4- [2-piperidin-4-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 353. 시클로펜틸-{4-[2-피페리딘-4-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;353. cyclopentyl- {4- [2-piperidin-4-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 354. 시클로펜틸-{4-[4-(4-메톡시페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;354. cyclopentyl- {4- [4- (4-methoxyphenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 355. 시클로헥실-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;355. cyclohexyl- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 356. 시클로헥실-{4-[4-(3-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;356. cyclohexyl- {4- [4- (3-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 357. 시클로헥실-{4-[4-(2-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;357. cyclohexyl- {4- [4- (2-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 358. {4-[4-(3-클로로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}시클로헥실아민;358. {4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine; 359. 시클로헥실-{4-[2-피페리딘-4-일-4-(3-트리플르오로메틸페닐)티아졸-5- 일]피리미딘-2-일}아민;359. cyclohexyl- {4- [2-piperidin-4-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 360. 시클로헥실-{4-[2-피페리딘-4-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;360. cyclohexyl- {4- [2-piperidin-4-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 361. 시클로헥실-{4-[4-(4-메톡시페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아민;361. cyclohexyl- {4- [4- (4-methoxyphenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 362. {4-[4-(3-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;362. {4- [4- (3-Fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl ) Amine; 363. {4-[4-(2-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;363. {4- [4- (2-Fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl ) Amine; 364. {4-[4-(3-클로로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;364. {4- [4- (3-Chlorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) Amines; 365. (1-(S)-페닐에틸)-{4-[2-피페리딘-4-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;365. (1- (S) -phenylethyl)-{4- [2-piperidin-4-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl } Amine; 366. (1-(S)-페닐에틸)-{4-[2-피페리딘-4-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;366. (1- (S) -phenylethyl)-{4- [2-piperidin-4-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 367. {4-[4-(4-메톡시페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;367. {4- [4- (4-methoxyphenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl ) Amine; 368. {4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}-(1-(R)-페닐에틸)아민;368. {4- [4- (4-Fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (R) -phenylethyl ) Amine; 369. 시클로프로필-{4-[4-(4-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피 리미딘-2-일}아민;369. cyclopropyl- {4- [4- (4-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 370. 시클로프로필-{4-[4-(3-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민;370. cyclopropyl- {4- [4- (3-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 371. 시클로프로필-{4-[4-(2-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민;371. cyclopropyl- {4- [4- (2-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 372. {4-[4-(3-클로로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}시클로프로필아민;372. {4- [4- (3-chlorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine; 373. 시클로프로필-{4-[2-피페라진-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;373. cyclopropyl- {4- [2-piperazin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 374. 시클로프로필-{4-[2-피페라진-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;374. cyclopropyl- {4- [2-piperazin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 375. 시클로프로필-{4-[4-(4-메톡시페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민;375. cyclopropyl- {4- [4- (4-methoxyphenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 376. 시클로펜틸-{4-[4-(4-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민;376. cyclopentyl- {4- [4- (4-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 377. 시클로펜틸-{4-[4-(3-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민;377. cyclopentyl- {4- [4- (3-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 378. 시클로펜틸-{4-[4-(2-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민;378. cyclopentyl- {4- [4- (2-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 379. {4-[4-(3-클로로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}시 클로펜틸아민;379. {4- [4- (3-chlorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine; 380. 시클로펜틸-{4-[2-피페라진-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;380. cyclopentyl- {4- [2-piperazin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 381. 시클로펜틸-{4-[2-피페라진-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;381. cyclopentyl- {4- [2-piperazin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 382. 시클로펜틸-{4-[4-(4-메톡시페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민;382. cyclopentyl- {4- [4- (4-methoxyphenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 383. 시클로헥실-{4-[4-(4-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민;383. cyclohexyl- {4- [4- (4-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 384. 시클로헥실-{4-[4-(3-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민;384. cyclohexyl- {4- [4- (3-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 385. 시클로헥실-{4-[4-(2-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}아민;385. cyclohexyl- {4- [4- (2-fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 386. {4-[4-(3-클로로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}시클로헥실아민;386. {4- [4- (3-Chlorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine; 387. 시클로헥실-{4-[2-피페라진-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;387. cyclohexyl- {4- [2-piperazin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 388. 시클로헥실-{4-[2-피페라진-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;388. cyclohexyl- {4- [2-piperazin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 389. 시클로헥실-{4-[4-(4-메톡시페닐)-2-피페라진-1-일-티아졸-5-일]피리미 딘-2-일}아민;389. cyclohexyl- {4- [4- (4-methoxyphenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl} amine; 390. {4-[4-(4-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;390. {4- [4- (4-Fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) Amines; 391. {4-[4-(3-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;391. {4- [4- (3-Fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) Amines; 392. {4-[4-(2-플루오로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;392. {4- [4- (2-Fluorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) Amines; 393. {4-[4-(3-클로로페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;393. {4- [4- (3-Chlorophenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) amine ; 394. (1-(S)-페닐에틸)-{4-[2-피페라진-1-일-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;394. (1- (S) -phenylethyl)-{4- [2-piperazin-1-yl-4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} Amines; 395. (1-(S)-페닐에틸)-{4-[2-피페라진-1-일-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;395. (1- (S) -phenylethyl)-{4- [2-piperazin-1-yl-4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 396. {4-[4-(4-메톡시페닐)-2-피페라진-1-일-티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;396. {4- [4- (4-methoxyphenyl) -2-piperazin-1-yl-thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenylethyl) Amines; 397. 시클로프로필-{4-[2-(2,5-디아자비시클로[2.2.1]헵트-2-일)-4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민;397. Cyclopropyl- {4- [2- (2,5-diazabicyclo [2.2.1] hept-2-yl) -4- (4-fluorophenyl) thiazol-5-yl] pyrimidine- 2-yl} amine; 398. 시클로프로필-{4-[4-(4-플루오로페닐)-2-(피페리딘-4-일옥시)티아졸-5-일]피리미딘-2-일}아민;398. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (piperidin-4-yloxy) thiazol-5-yl] pyrimidin-2-yl} amine; 399. 시클로프로필-{4-[4-(4-플루오로페닐)-2-(피페리딘-4-일아미노)티아졸- 5-일]피리미딘-2-일}아민;399. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (piperidin-4-ylamino) thiazol-5-yl] pyrimidin-2-yl} amine; 400. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-4-올;400. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-4-ol; 401. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페리딘-4-올;401. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperidin-4-ol; 402. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페리딘-4-올;402. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperidin-4-ol; 403. 4-[4-(3-클로로페닐)-5-(2-시클로프로필아미노피리미딘-4-일)티아졸-2-일]피페리딘-4-올;403. 4- [4- (3-chlorophenyl) -5- (2-cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] piperidin-4-ol; 404. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-4-올;404. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol; 405. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-4-올;405. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidin-4-ol; 406. 4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-4-올;406. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidin-4-ol; 407. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-4-올;407. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-4-ol; 408. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페리딘-4-올;408. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperidin-4-ol; 409. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2- 일]피페리딘-4-올;409. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperidin-4-ol; 410. 4-[4-(3-클로로페닐)-5-(2-시클로펜틸아미노피리미딘-4-일)티아졸-2-일]피페리딘-4-올;410. 4- [4- (3-chlorophenyl) -5- (2-cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] piperidin-4-ol; 411. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-4-올;411. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol; 412. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일]피페리딘-4-올;412. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidin-4-ol; 413. 4-[5-(2-시클로펜틸아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-4-올;413. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidin-4-ol; 414. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-4-올;414. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-4-ol; 415. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-플루오로페닐)티아졸-2-일]피페리딘-4-올;415. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-fluorophenyl) thiazol-2-yl] piperidin-4-ol; 416. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(2-플루오로페닐)티아졸-2-일]피페리딘-4-올;416. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2-fluorophenyl) thiazol-2-yl] piperidin-4-ol; 417. 4-[4-(3-클로로페닐)-5-(2-시클로헥실아미노피리미딘-4-일)티아졸-2-일]피페리딘-4-올;417. 4- [4- (3-chlorophenyl) -5- (2-cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] piperidin-4-ol; 418. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-4-올;418. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol; 419. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(3-메틸페닐)티아졸-2-일] 피페리딘-4-올;419. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3-methylphenyl) thiazol-2-yl] piperidin-4-ol; 420. 4-[5-(2-시클로헥실아미노피리미딘-4-일)-4-(4-메톡시페닐)티아졸-2-일]피페리딘-4-올;420. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4-methoxyphenyl) thiazol-2-yl] piperidin-4-ol; 421. 4-{4-(4-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-4-올;421. 4- {4- (4-Fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-4 -Ol; 422. 4-{4-(3-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-4-올;422. 4- {4- (3-Fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-4 -Ol; 423. 4-{4-(2-플루오로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}피페리딘-4-올;423. 4- {4- (2-fluorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} piperidine-4 -Ol; 424. 4-{4-(3-클로로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-피페리딘-4-올;424. 4- {4- (3-Chlorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -piperidine-4 -Ol; 425. 4-[5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-트리플르오로메틸페닐)티아졸-2-일]피페리딘-4-올;425. 4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine- 4-ol; 426. 4-{5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]-4-(3-메틸페닐)티아졸-2-일}-피페리딘-4-올;426. 4- {5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] -4- (3-methylphenyl) thiazol-2-yl} -piperidine-4- Come; 427. 4-{4-(4-메톡시페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-피페리딘-4-올;427. 4- {4- (4-methoxyphenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -piperidine- 4-ol; 428. 4-[4-(4-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]-2-메틸설파닐피리미딘;428. 4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 429. 시클로프로필-{4-[4-(4-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸- 5-일]피리미딘-2-일}아민;429. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 430. 시클로프로필-{4-[4-(3-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민;430. cyclopropyl- {4- [4- (3-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 431. 시클로프로필-{4-[4-(2-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민;431. Cyclopropyl- {4- [4- (2-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 432. {4-[4-(3-클로로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}시클로프로필아민;432. {4- [4- (3-chlorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine; 433. 시클로프로필-{4-[2-(1-메틸피페리딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;433. cyclopropyl- {4- [2- (1-methylpiperidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 434. 시클로프로필-{4-[2-(1-메틸피페리딘-4-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;434. cyclopropyl- {4- [2- (1-methylpiperidin-4-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 435. 시클로프로필-{4-[4-(4-메톡시페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민;435. Cyclopropyl- {4- [4- (4-methoxyphenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 436. 4-[4-(4-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]-2-메틸설파닐피리미딘;436. 4- [4- (4-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine; 437. 시클로펜틸-{4-[4-(4-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민;437. cyclopentyl- {4- [4- (4-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 438. 시클로펜틸-{4-[4-(3-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민;438. cyclopentyl- {4- [4- (3-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 439. 시클로펜틸-{4-[4-(2-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5- 일]피리미딘-2-일}아민;439. cyclopentyl- {4- [4- (2-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 440. {4-[4-(3-클로로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}시클로펜틸아민;440. {4- [4- (3-chlorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine; 441. 시클로펜틸-{4-[2-(1-메틸피페리딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;441. cyclopentyl- {4- [2- (1-methylpiperidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 442. 시클로펜틸-{4-[2-(1-메틸피페리딘-4-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;442. cyclopentyl- {4- [2- (1-methylpiperidin-4-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 443. 시클로펜틸-{4-[4-(4-메톡시페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민;443. cyclopentyl- {4- [4- (4-methoxyphenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 444. 시클로헥실-{4-[4-(4-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민;444. cyclohexyl- {4- [4- (4-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 445. 시클로헥실-{4-[4-(3-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민;445. cyclohexyl- {4- [4- (3-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 446. 시클로헥실-{4-[4-(2-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민;446. cyclohexyl- {4- [4- (2-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 447. {4-[4-(3-클로로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}시클로헥실아민;447. {4- [4- (3-chlorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine; 448. 시클로헥실-{4-[2-(1-메틸피페리딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;448. cyclohexyl- {4- [2- (1-methylpiperidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 449. 시클로헥실-{4-[2-(1-메틸피페리딘-4-일)-4-(3-메틸페닐)티아졸-5-일] 피리미딘-2-일}아민;449. cyclohexyl- {4- [2- (1-methylpiperidin-4-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 450. 시클로헥실-{4-[4-(4-메톡시페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민;450. cyclohexyl- {4- [4- (4-methoxyphenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 451. {4-[4-(3-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;451. {4- [4- (3-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine; 452. {4-[4-(2-플루오로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;452. {4- [4- (2-fluorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine; 453. {4-[4-(3-클로로페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;453. {4- [4- (3-chlorophenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -Phenylethyl) amine; 454. {4-[2-(1-메틸피페리딘-4-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;454. {4- [2- (1-methylpiperidin-4-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- ( S) -phenylethyl) amine; 455. {4-[2-(1-메틸피페리딘-4-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;455. {4- [2- (1-methylpiperidin-4-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S)- Phenylethyl) amine; 456. {4-[4-(4-메톡시페닐)-2-(1-메틸피페리딘-4-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;456. {4- [4- (4-methoxyphenyl) -2- (1-methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine; 457. 시클로프로필-{4-[4-(4-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민;457. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 458. 시클로프로필-{4-[4-(3-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민;458. cyclopropyl- {4- [4- (3-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 459. 시클로프로필-{4-[4-(2-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸- 5-일]피리미딘-2-일}아민;459. cyclopropyl- {4- [4- (2-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 460. {4-[4-(3-클로로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}시클로프로필아민;460. {4- [4- (3-chlorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} cyclopropylamine; 461. 시클로프로필-{4-[2-(4-메틸피페라진-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;461. cyclopropyl- {4- [2- (4-methylpiperazin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 462. 시클로프로필-{4-[2-(4-메틸피페라진-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;462. cyclopropyl- {4- [2- (4-methylpiperazin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 463. 시클로프로필-{4-[4-(4-메톡시페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민;463. cyclopropyl- {4- [4- (4-methoxyphenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 464. 시클로펜틸-{4-[4-(4-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민;464. cyclopentyl- {4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 465. 시클로펜틸-{4-[4-(3-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민;465. cyclopentyl- {4- [4- (3-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 466. 시클로펜틸-{4-[4-(2-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민;466. cyclopentyl- {4- [4- (2-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 467. {4-[4-(3-클로로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}시클로펜틸아민;467. {4- [4- (3-chlorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} cyclopentylamine; 468. 시클로펜틸-{4-[2-(4-메틸피페라진-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;468. cyclopentyl- {4- [2- (4-methylpiperazin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 469. 시클로펜틸-{4-[2-(4-메틸피페라진-1-일)-4-(3-메틸페닐)티아졸-5-일] 피리미딘-2-일}아민;469. cyclopentyl- {4- [2- (4-methylpiperazin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 470. 시클로펜틸-{4-[4-(4-메톡시페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민;470. cyclopentyl- {4- [4- (4-methoxyphenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 471. 시클로헥실-{4-[4-(4-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민;471. cyclohexyl- {4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 472. 시클로헥실-{4-[4-(3-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민;472. cyclohexyl- {4- [4- (3-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 473. 시클로헥실-{4-[4-(2-플루오로페닐)-2-(4-메틸피페라진-1-;일)티아졸-5-일]피리미딘-2-일}아민;473. cyclohexyl- {4- [4- (2-fluorophenyl) -2- (4-methylpiperazin-1-; yl) thiazol-5-yl] pyrimidin-2-yl} amine; 474. {4-[4-(3-클로로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}시클로헥실아민;474. {4- [4- (3-chlorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} cyclohexylamine; 475. 시클로헥실-{4-[2-(4-메틸피페라진-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}아민;475. cyclohexyl- {4- [2- (4-methylpiperazin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 476. 시클로헥실-{4-[2-(4-메틸피페라진-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}아민;476. cyclohexyl- {4- [2- (4-methylpiperazin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 477. 시클로헥실-{4-[4-(4-메톡시페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}아민;477. cyclohexyl- {4- [4- (4-methoxyphenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 478. {4-[4-(4-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;478. {4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -Phenylethyl) amine; 479. {4-[4-(3-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘 -2-일}-(1-(S)-페닐에틸)아민;479. {4- [4- (3-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -Phenylethyl) amine; 480. {4-[4-(2-플루오로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;480. {4- [4- (2-fluorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -Phenylethyl) amine; 481. {4-[4-(3-클로로페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;481. {4- [4- (3-Chlorophenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S)- Phenylethyl) amine; 482. {4-[2-(4-메틸피페라진-1-일)-4-(3-트리플르오로메틸페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;482. {4- [2- (4-methylpiperazin-1-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S ) -Phenylethyl) amine; 483. {4-[2-(4-메틸피페라진-1-일)-4-(3-메틸페닐)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;483. {4- [2- (4-Methylpiperazin-1-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -phenyl Ethyl) amine; 484. {4-[4-(4-메톡시페닐)-2-(4-메틸피페라진-1-일)티아졸-5-일]피리미딘-2-일}-(1-(S)-페닐에틸)아민;484. {4- [4- (4-methoxyphenyl) -2- (4-methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl}-(1- (S) -Phenylethyl) amine; 485. 시클로프로필-{4-[2-(1-에틸피페리딘-4-일)-4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민;485. cyclopropyl- {4- [2- (1-ethylpiperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine; 486. 시클로프로필-{4-[4-(4-플루오로페닐)-2-(1-이소프로필피페리딘-4-일)티아졸-5-일]피리미딘-2-일}아민;486. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (1-isopropylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine; 487. 1-{4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-일}에탄온;487. 1- {4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-1-yl} ethanone ; 488. 1-{4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-일}-2-디메틸아미노에탄온;488. 1- {4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-1-yl} -2 Dimethylaminoethanone; 489. 시클로프로필-{4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오 로페닐)티아졸-2-일]피페리딘-1-일}메탄온;489. Cyclopropyl- {4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-1-yl} methane On; 490. {4-[5-(2-시클로프로필아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-일}페닐메탄온;490. {4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-1-yl} phenylmethanone; 491. 시클로프로필-{4-[2-(1-시클로프로필메틸피페리딘-4-일)-4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민;491. Cyclopropyl- {4- [2- (1-cyclopropylmethylpiperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine ; 492. 시클로프로필-{4-[2-[1-(2-디메틸아미노에틸)피페리딘-4-일]-4-(4-플루오로페닐)티아졸-5-일]피리미딘-2-일}아민;492. Cyclopropyl- {4- [2- [1- (2-dimethylaminoethyl) piperidin-4-yl] -4- (4-fluorophenyl) thiazol-5-yl] pyrimidine-2 -Yl} amine; 493. N-{4-[4-(4-플루오로페닐)-2-(4-메틸설파닐페닐)티아졸-5-일]피리딘-2-일}프로피온아미드;493. N- {4- [4- (4-fluorophenyl) -2- (4-methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl} propionamide; 494. 4-[4-(4-플루오로페닐)-5-(2-프로피오닐아미노피리미딘-4-일)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;494. 4- [4- (4-fluorophenyl) -5- (2-propionylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 495. 4-[5-(2-디프로피오닐아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;495. 4- [5- (2-dipropionylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 496. 4-[5-[2-(시클로헥산카르보닐아미노)피리미딘-4-일]-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;496. 4- [5- [2- (cyclohexanecarbonylamino) pyrimidin-4-yl] -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid Ethyl ester; 497. 4-[5-[2-(비스시클로헥산카르보닐아미노)피리미딘-4-일]-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;497. 4- [5- [2- (biscyclohexanecarbonylamino) pyrimidin-4-yl] -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxyl Acid ethyl ester; 498. 4-[5-(2-벤조일아미노피리미딘-4-일)-4-(4-플루오로페닐)티아졸-2-일]피페리딘-1-카르복실산 에틸 에스터;498. 4- [5- (2-benzoylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester; 499. N-{4-[4-(4-플루오로페닐)-2-(4-메탄설피닐페닐)티아졸-5-일]피리딘-2- 일}프로피온아미드;499. N- {4- [4- (4-fluorophenyl) -2- (4-methanesulfinylphenyl) thiazol-5-yl] pyridin-2-yl} propionamide; 500. N-{4-[4-(4-플루오로페닐)-2-(4-메탄설포닐페닐)티아졸-5-일]피리딘-2-일}프로피온아미드;500. N- {4- [4- (4-fluorophenyl) -2- (4-methanesulfonylphenyl) thiazol-5-yl] pyridin-2-yl} propionamide; 501. N-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}프로피온아미드;501. N- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} propionamide; 502. N-{4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}벤즈아미드;502. N- {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} benzamide; 503. 시클로헥산카르복실산 {4-[4-(4-플루오로페닐)-2-피페리딘-4-일-티아졸-5-일]피리미딘-2-일}아미드;503. cyclohexanecarboxylic acid {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amide; 504. N-[4-(3-클로로페닐)-5-(2-메틸설파닐피리미딘-4-일)티아졸-2-일]-6,N-디메틸니코틴아미드;504. N- [4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -6, N-dimethylnicotinamide; 505. N-[4-(3-클로로페닐)-5-(2-메탄설피닐피리미딘-4-일)티아졸-2-일]-6,N-디메틸니코틴아미드; 및505. N- [4- (3-chlorophenyl) -5- (2-methanesulfinylpyrimidin-4-yl) thiazol-2-yl] -6, N-dimethylnicotinamide; And 506. N-{4-(3-클로로페닐)-5-[2-(1-(S)-페닐에틸아미노)피리미딘-4-일]티아졸-2-일}-6,N-디메틸니코틴아미드인 치환된 1,3-티아졸 화합물 또는 이의 약학적으로 허용가능한 염.506.N- {4- (3-chlorophenyl) -5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -6, N-dimethyl A substituted 1,3-thiazole compound that is nicotinamide or a pharmaceutically acceptable salt thereof. 하기 화학식 2로 표시되는 중간체 화합물 또는 이의 약학적으로 허용가능한 염.Intermediate compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof. <화학식 2><Formula 2>
Figure 112006042290445-pat00162
Figure 112006042290445-pat00162
 (상기 화학식 2에서, (In Formula 2, R1은 할로겐 원자, C1~C4의 할로알킬, C1~C4의 알킬 또는 C1~C4의 알콕시이며,R1 is a halo of a halogen atom, C 1 ~ C 4 alkyl, C 1 ~ C 4 Of alkyl or C 1 to C 4 Alkoxy, Hal은 F, Cl, 또는 I이다.)Hal is F, Cl, or I.) 제 4항에 있어서, 상기 화학식 2에서 R1은 2-F, 3-F, 4-F, 3-Cl, 3-CF3, 3-CH3 또는 4-OCH3이며, Hal은 Cl인 중간체 화합물 또는 이의 약학적으로 허용가능한 염.The intermediate compound of claim 4, wherein R 1 in Formula 2 is 2-F, 3-F, 4-F, 3-Cl, 3-CF 3 , 3-CH 3 or 4-OCH 3 , and Hal is Cl. Or a pharmaceutically acceptable salt thereof. 1) 화합물 (Ⅱ)를 염기로 처리하고, 화합물 (Ⅲ)과 반응시켜 화합물 (Ⅳ)를 얻는 단계;1) treating compound (II) with a base and reacting with compound (III) to obtain compound (IV); 2) 상기 1)단계에서 제조된 화합물 (Ⅳ)를 할로겐화시켜 화합물 (Ⅴ)를 얻는 단계;2) halogenating compound (IV) prepared in step 1) to obtain compound (V); 3) 상기 2)단계에서 제조된 화합물 (Ⅴ)와 티오아미드 화합물 (Ⅵ)을 반응시 켜 화합물 (Ⅶ)을 얻는 단계; 및3) reacting compound (V) prepared in step 2) with thioamide compound (VI) to obtain compound (VII); And 4) 상기 3)단계에서 제조된 화합물 (Ⅶ)과 아민 화합물 (Ⅷ)을 반응시켜 치환된 1,3-티아졸 화합물 (I-a)를 얻는 단계를 포함하는 하기 반응식 1로 표시되는 제 1항의 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.4) Substitution of claim 1 represented by the following Reaction Scheme 1 comprising the step of reacting the compound (iii) prepared in step 3) with the amine compound (iii) to obtain a substituted 1,3-thiazole compound (Ia) To prepare 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof. <반응식 1><Scheme 1>
Figure 112006042290445-pat00163
Figure 112006042290445-pat00163
 (상기 반응식 1에서, R1, R2, R4는 화학식 1에서 정의한 바와 같고, Hal, Hal'는 할로겐 원자이며, L은 이탈기이다.)(In Reaction Scheme 1, R1, R2, and R4 are as defined in Formula 1, Hal, Hal 'is a halogen atom, and L is a leaving group.) 1) 화합물 (IX)의 아민기를 보호화하여 얻어진 화합물 (X)을 염기로 처리하고, 화합물 (Ⅲ)과 반응시켜 화합물(XI)을 얻는 단계;1) treating compound (X) obtained by protecting the amine group of compound (IX) with a base, and reacting with compound (III) to obtain compound (XI); 2) 상기 1)단계에서 제조된 화합물 (XI)을 할로겐화시켜 화합물 (XII)를 얻는 단계;2) halogenating compound (XI) prepared in step 1) to obtain compound (XII); 3) 상기 2)단계에서 제조된 화합물 (XII)와 티오아미드 화합물 (Ⅵ)을 반응시켜 화합물 (XIII)를 얻는 단계; 및3) reacting compound (XII) prepared in step 2) with thioamide compound (VI) to obtain compound (XIII); And 4) 상기 3)단계에서 제조된 화합물 (XIII)을 탈보호화시키고, 아실화제 (XV)를 반응시켜 치환된 1,3-티아졸 화합물 (I-b)를 얻는 단계를 포함하는 하기 반응식 2로 표시되는 제 1항의 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.4) Deprotecting the compound (XIII) prepared in step 3) and reacting the acylating agent (XV) to obtain a substituted 1,3-thiazole compound (Ib) represented by Scheme 2 below A process for preparing the substituted 1,3-thiazole derivatives of claim 1 or pharmaceutically acceptable salts thereof. <반응식 2><Scheme 2>
Figure 112006042290445-pat00164
Figure 112006042290445-pat00164
 (상기 반응식 2에서, R1, R2, R5는 화학식 1에서 정의한 바와 같으며, L은 이탈기이다.)(In Scheme 2, R1, R2, R5 are as defined in formula 1, L is a leaving group.) 1) 화합물 (XVI)을 염기로 처리하고, 화합물 (Ⅲ)과 반응시켜 화합물 (XVII)을 얻는 단계;1) treating compound (XVI) with a base and reacting with compound (III) to give compound (XVII); 2) 상기 1)단계에서 제조된 화합물 (XVII)을 할로겐화시켜 화합물 (XVIII)을 얻는 단계;2) halogenating the compound (XVII) prepared in step 1) to obtain a compound (XVIII); 3) 상기 2)단계에서 제조된 화합물 (XVIII)와 티오아미드 화합물 (Ⅵ)을 반응시켜 화합물 (XIX)를 얻는 단계;3) reacting compound (XVIII) prepared in step 2) with thioamide compound (VI) to obtain compound (XIX); 4) 상기 3)단계에서 제조된 화합물 (XIX)를 유기 과산화산으로 처리하여 화합물(XX)을 얻는 단계; 및4) treating compound (XIX) prepared in step 3) with organic peroxide to obtain compound (XX); And 5) 상기 4)단계에서 제조된 화합물 (XX)을 아민 화합물 (VIII)과 반응시켜 치환된 1,3-티아졸 화합물 (I-c)를 얻는 단계를 포함하는 하기 반응식 3으로 표시되는 제 1항의 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.5) Substitution of Claim 1 represented by the following Scheme 3, comprising the step of reacting compound (XX) prepared in step 4) with an amine compound (VIII) to obtain a substituted 1,3-thiazole compound (Ic). To prepare 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof. <반응식 3><Scheme 3>
Figure 112006042290445-pat00165
Figure 112006042290445-pat00165
 (상기 반응식 3에서, R1, R2, R4는 화학식 1에서 정의한 바와 같고, L은 이탈기이다.)(In Scheme 3, R1, R2, R4 are as defined in formula 1, L is a leaving group.) 제 8항에 있어서, 상기 2)단계에서 화합물 (XVII)을 리튬 디이소프로필 아마이드(LDA; Lithium diisopropylamide), CF3SO2Cl 또는 테트라부틸 암모니움 브로마이드(TBAB; Tetrabutyl Ammonium Bromide), 트리메틸실릴 클로라이드(TMSCl; Trimethylsilyl chloride), 디메틸설폭사이드(DMSO; Dimethyl sulfoxide)로 처리하여 염소화함으로써 화합물 (XVIII)을 제조하고, 화합물 (XVIII)를 티오아미드 화합물 (Ⅵ)과 반응시켜 화합물 (XIX)를 제조하는 것을 특징으로 하는, 하기 반응식 3a로 표시되는 제 1항의 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.The method of claim 8, wherein the compound (XVII) in step 2) is lithium diisopropylamide (LDA; Lithium diisopropylamide), CF 3 SO 2 Cl or tetrabutyl ammonium bromide (TBAB; Tetrabutyl Ammonium Bromide), trimethylsilyl chloride Compound (XVIII) was prepared by chlorination with (TMSCl; Trimethylsilyl chloride) and dimethyl sulfoxide (DMSO; Dimethyl sulfoxide) to react compound (XVIII) with thioamide compound (VI) to prepare compound (XIX). Characterized in that the substituted 1,3-thiazole derivatives of claim 1 represented by Scheme 3a or a pharmaceutically acceptable salt thereof. <반응식 3a><Scheme 3a>
Figure 112008003622487-pat00166
Figure 112008003622487-pat00166
 (상기 반응식 3a에서, R1은 상기 화학식 2에서 정의한 바와 같고, R2는 상기 화학식 1에서 정의한 바와 같으며, Hal은 Cl이다.)(In Scheme 3a, R1 is as defined in Formula 2, R2 is as defined in Formula 1, and Hal is Cl.) 1) 화합물 (XVIII)을 티오우레아 화합물 (XXI)과 반응시켜 화합물 (XXII)를 얻는 단계;1) reacting compound (XVIII) with thiourea compound (XXI) to give compound (XXII); 2) 상기 1)단계에서 제조된 화합물 (XXII)를 할로겐화시켜 화합물 (XXIII)을 얻는 단계;2) halogenating compound (XXII) prepared in step 1) to obtain compound (XXIII); 3) 상기 2)단계에서 제조된 화합물 (XXIII)과 화합물 (XXIV)를 반응시켜 화합물 (XXV)를 얻는 단계;3) reacting compound (XXIII) prepared in step 2) with compound (XXIV) to obtain compound (XXV); 4) 상기 3)단계에서 제조된 화합물 (XXV)를 유기 과산화산으로 처리하여 화합물 (XXVI)을 얻는 단계; 및4) treating compound (XXV) prepared in step 3) with organic peroxide to obtain compound (XXVI); And 5) 상기 4)단계에서 제조된 화합물 (XXVI)을 아민 화합물 (VIII)과 반응시켜 치환된 1,3-티아졸 화합물 (XXVII)을 얻는 단계를 포함하는 하기 반응식 4로 표시되는 제 1항의 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.5) Substitution of claim 1 represented by the following Scheme 4, comprising the step of reacting the compound (XXVI) prepared in step 4) with an amine compound (VIII) to obtain a substituted 1,3-thiazole compound (XXVII). To prepare 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof. <반응식 4><Scheme 4>
Figure 112006042290445-pat00167
Figure 112006042290445-pat00167
 (상기 반응식 4에서, R1, R4, 및 Y는 화학식 1에서 정의한 바와 같고, Hal는 할로겐 원자이며, PG는 보호기이다.)(In Reaction Scheme 4, R1, R4, and Y are as defined in Formula 1, Hal is a halogen atom, PG is a protecting group.) 제 10항에 있어서, 상기 4)단계에서 화합물(XXⅤ)에서 Y가 NH일 때, 화합물(XXV)을 산화반응시키기 전에 질소를 보호화한 다음, 산화반응시켜 화합물(XXIX)를 제조하고, 화합물(XXIX)를 아민 화합물(VIII)과 반응시켜 화합물(XXX)을 제조하는 것을 특징으로 하는 제 1항의 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.The compound (XXIX) according to claim 10, wherein when Y is NH in compound (XXV) in step 4), nitrogen is protected before oxidation of compound (XXV), followed by oxidation to prepare compound (XXIX). A process for preparing the substituted 1,3-thiazole derivatives according to claim 1 or a pharmaceutically acceptable salt thereof, wherein (XXIX) is reacted with an amine compound (VIII) to produce compound (XXX). 제 11항에 있어서, 상기 화합물(XXX)을 탈보호화하고, 탈보호화된 화합물을 메틸화하는 것을 특징으로 하는 제 1항의 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.12. The process for preparing the substituted 1,3-thiazole derivative of claim 1 or a pharmaceutically acceptable salt thereof according to claim 11, wherein the compound (XXX) is deprotected and the deprotected compound is methylated. 1) 화합물 (XVIII)을 티오포름아미드 화합물 (XXXI)과 반응시켜 화합물 (XXXII)를 얻는 단계;1) reacting compound (XVIII) with a thioformamide compound (XXXI) to give compound (XXXII); 2) 상기 1)단계에서 제조된 화합물 (XXXII)를 유기 과산화산으로 처리하여 화합물 (XXXIII)을 얻는 단계;2) treating compound (XXXII) prepared in step 1) with organic peroxide to obtain compound (XXXIII); 3) 상기 2)단계에서 제조된 화합물 (XXXIII)과 아민 화합물 (VIII)을 반응시켜 화합물 (XXXIV)를 얻는 단계;3) reacting compound (XXXIII) prepared in step 2) with amine compound (VIII) to obtain compound (XXXIV); 4) 상기 3)단계에서 제조된 화합물 (XXXIV)를 염기로 처리하고, 화합물 (XXXV)와 반응시켜 화합물 (XXXVI)을 얻는 단계; 및4) treating compound (XXXIV) prepared in step 3) with a base and reacting with compound (XXXV) to obtain compound (XXXVI); And 5) 상기 4)단계에서 제조된 화합물 (XXXVI)을 탈보호화하여, 치환된 1,3-티아졸 화합물 (XXXVII)을 얻는 단계를 포함하는 하기 반응식 5로 표시되는 제 1항의 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.5) The substituted 1,3 of claim 1 represented by the following Scheme 5, comprising the step of deprotecting the compound (XXXVI) prepared in step 4) to obtain a substituted 1,3-thiazole compound (XXXVII). A process for preparing a thiazole derivative or a pharmaceutically acceptable salt thereof. <반응식 5>Scheme 5
Figure 112006042290445-pat00168
Figure 112006042290445-pat00168
 (상기 반응식 5에서, R1, R4, 및 Y는 화학식 1에서 정의한 바와 같고, Hal는 할로겐 원자이다.)(In Scheme 5, R1, R4, and Y are as defined in Formula 1, and Hal is a halogen atom.) 제 8항에 있어서, 상기 3)단계의 화합물 (XIX)는 The compound of claim 8, wherein the compound of step 3) (XIX) 1) 화합물 (XXXVIII)을 할로겐화시켜 화합물 (XXXIX)를 제조하는 단계;1) halogenating compound (XXXVIII) to produce compound (XXXIX); 2) 상기 1)단계에서 제조된 화합물 (XXXIX)를 티오아미드 화합물(VI)과 반응시켜 화합물 (XXXX)을 제조하는 단계; 및2) preparing a compound (XXXX) by reacting the compound (XXXIX) prepared in step 1) with a thioamide compound (VI); And 3) 상기 2)단계에서 제조된 화합물 (XXXX)을 염기, ZnCl2로 처리하고, Pd(PPh3)4과 화합물 (XXXXI)로 반응시키는 단계를 포함하는 하기 반응식 6으로 표시되는 방법으로 제조되는 것을 특징으로 하는 제 1항의 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.3) The compound (XXXX) prepared in step 2) is treated with a base, ZnCl 2 , and prepared by the method represented by the following Scheme 6 including reacting Pd (PPh 3 ) 4 with a compound (XXXXI). A method for preparing the substituted 1,3-thiazole derivatives according to claim 1 or a pharmaceutically acceptable salt thereof. <반응식 6><Scheme 6>
Figure 112006042290445-pat00169
Figure 112006042290445-pat00169
 (상기 반응식 6에서, R1, R2는 화학식 1에서 정의한 바와 같으며, Hal 및 Hal'는 할로겐 원자이다.)(In Scheme 6, R1, R2 are as defined in Formula 1, Hal and Hal 'is a halogen atom.) 제 6항 또는 제 8항에서, 화합물(I-a) 또는 화합물(I-c)에서 R2가
Figure 112006042290445-pat00170
이며, 이때 X는 CH, C-OH, 또는 N이고, Y는 N-CO-C1~C4의 알콕시인 경우, 화합물(I-a) 또는 화합물(I-c)을 탈보호화하고, 탈보호화된 화합물(I-a) 또는 화합물(I-c)을 메틸화하는 것을 특징으로 하는 제 1항의 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법.The compound of claim 6 or 8, wherein R 2 in compound (Ia) or compound (Ic) is
Figure 112006042290445-pat00170
Wherein X is CH, C-OH, or N, and Y is N-CO-C 1 -C 4 In the case of alkoxy, the substituted 1,3-thiazole derivatives of claim 1 characterized by deprotecting compound (Ia) or compound (Ic) and methylating deprotected compound (Ia) or compound (Ic). Method for preparing a pharmaceutically acceptable salt thereof. 제 1항의 치환된 1,3-티아졸 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 하는 TNF-α 관련 질환인 관절염, 독혈증, 염증성 장 질환, 염증성 폐 질환, 악액질, 암, 다발성 골수종, 심혈관계 질환, 관상동맥 심장병, 만성폐색성 폐질환, 크로이츠펠트 - 야콥 병, 바이러스 감염, 자가면역질환, 아토피 피부염, 건선, 중풍, 치매, 뇌졸중, AIDS 뇌병증, 수막염, 울혈성 심부전, 간염, 이식, 투석 저혈압, 또는 파종성 혈관내응고의 예방 및 치료용 약학적 조성물.TNF-α-related diseases comprising the substituted 1,3-thiazole derivative of claim 1 or a pharmaceutically acceptable salt thereof as arthritis, toxemia, inflammatory bowel disease, inflammatory lung disease, cachexia, cancer, multiple myeloma, Cardiovascular disease, coronary heart disease, chronic obstructive pulmonary disease, Creutzfeldt-Jakob disease, viral infections, autoimmune diseases, atopic dermatitis, psoriasis, stroke, dementia, stroke, AIDS encephalopathy, meningitis, congestive heart failure, hepatitis, transplantation Pharmaceutical composition for the prevention and treatment of dialysis, hypotension, or disseminated intravascular coagulation. 삭제delete
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