KR100935273B1 - Compounds and compositions as protein kinase inhibitors - Google Patents

Compounds and compositions as protein kinase inhibitors Download PDF

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KR100935273B1
KR100935273B1 KR1020067025907A KR20067025907A KR100935273B1 KR 100935273 B1 KR100935273 B1 KR 100935273B1 KR 1020067025907 A KR1020067025907 A KR 1020067025907A KR 20067025907 A KR20067025907 A KR 20067025907A KR 100935273 B1 KR100935273 B1 KR 100935273B1
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methyl
ylamino
phenyl
imidazol
pyrimidin
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핑다 렌
시아 왕
궈바오 장
뀌앙 딩
슐리 유우
뀌옹 장
그렉 쇼퓨크
파멜라 에이. 알바
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네이서넬 쉬안더 그레이
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아이알엠 엘엘씨
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

본 발명은 신규한 부류의 화합물, 상기 화합물을 포함하는 제약 조성물, 및 상기 화합물을 사용하여 비정상 또는 조절되지 않는 키나제 활성과 연관된 질환 또는 장애, 특히 Abl, BCR-Abl, PDGF-R, trkB, c-SRC, BMX, FGFR3, b-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c-RAF, MKK6, SAPK2α 및 SAPK2β 키나제의 비정상적 활성화와 관련된 질환 또는 장애를 치료 또는 예방하는 방법을 제공한다.The present invention provides a novel class of compounds, pharmaceutical compositions comprising the compounds, and diseases or disorders associated with abnormal or unregulated kinase activity using the compounds, in particular Abl, BCR-Abl, PDGF-R, trkB, c -Provides methods for treating or preventing diseases or disorders associated with abnormal activation of SRC, BMX, FGFR3, b-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c-RAF, MKK6, SAPK2α and SAPK2β kinase.

Abl, BCR-Abl, FGFR3, b-RAF, 키나제 활성화, 아벨슨 티로신 키나제, 골수성 백혈병Abl, BCR-Abl, FGFR3, b-RAF, kinase activation, Abelson tyrosine kinase, myeloid leukemia

Description

단백질 키나제 억제제 화합물 및 조성물 {COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS}Protein kinase inhibitor compounds and compositions {COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS}

관련 출원과의 상호 참조Cross Reference with Related Application

본 출원은 2004년 6월 10일 출원된 미국 가특허출원 제60/578,491호에 대하여 우선권의 이익을 주장한다. 상기 출원의 모든 개시사항은 그 전문이 모든 목적으로서 본 명세서에 포함된다.This application claims the benefit of priority to US Provisional Patent Application No. 60 / 578,491, filed June 10, 2004. All disclosures of this application are incorporated herein in their entirety for all purposes.

본 발명은 신규한 부류의 화합물, 상기 화합물을 포함하는 제약 조성물, 및 상기 화합물을 사용하여 비정상 또는 조절되지 않는 키나제 활성과 연관된 질환 또는 장애, 특히 Abl, BCR-Abl, PDGF-R, trkB, c-SRC, BMX, FGFR3, b-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c-RAF, MKK6, SAPK2α 및 SAPK2β 키나제의 비정상적 활성화와 관련된 질환 또는 장애를 치료 또는 예방하는 방법을 제공한다.The present invention provides a novel class of compounds, pharmaceutical compositions comprising the compounds, and diseases or disorders associated with abnormal or unregulated kinase activity using the compounds, in particular Abl, BCR-Abl, PDGF-R, trkB, c -Provides methods for treating or preventing diseases or disorders associated with abnormal activation of SRC, BMX, FGFR3, b-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c-RAF, MKK6, SAPK2α and SAPK2β kinase.

단백질 키나제는 다양한 세포 작용의 조절 및 세포 기능에 대해 조절을 유지하는데 중요한 역할을 하는 큰 단백질 부류를 나타낸다. 이러한 키나제들의 부분적이고 비제한적인 예로서 수용체 티로신 키나제, 예컨대 혈소판-연관 성장인자 수용체 키나제 (PDGF-R), 신경 성장인자 수용체, trkB, 섬유모세포 성장인자 수용체, FGFR3, B-RAF; 비-수용체 티로신 키나제, 예컨대 Abl 및 융합 키나제인 BCR-Abl, Lck, Bmx 및 c-src; 세린/트레오닌 키나제, 예컨대 c-RAF, sgk, MAP 키나제 (예를 들어, MKK4, MKK6 등) 및 SAPK2α와 SAPK2β가 있다. 양성 및 악성 증식성 장애 및 면역 및 신경계의 부적절한 활성화에 기인하는 질환을 포함하는 많은 질환의 증상에서 비정상적인 키나제 활성이 관찰된다.Protein kinases represent a large class of proteins that play an important role in regulating the regulation of various cellular functions and the regulation of cellular function. Partial and non-limiting examples of such kinases are receptor tyrosine kinases such as platelet-associated growth factor receptor kinase (PDGF-R), nerve growth factor receptor, trkB, fibroblast growth factor receptor, FGFR3, B-RAF; Non-receptor tyrosine kinases such as Abl and fusion kinases BCR-Abl, Lck, Bmx and c-src; Serine / threonine kinases such as c-RAF, sgk, MAP kinases (eg, MKK4, MKK6, etc.) and SAPK2α and SAPK2β. Abnormal kinase activity is observed in the symptoms of many diseases including benign and malignant proliferative disorders and diseases due to inappropriate activation of the immune and nervous systems.

본 발명의 신규한 화합물은 1종 이상의 단백질 키나제의 활성을 억제하므로, 키나제-연관 질환의 치료에 유용할 것으로 예상된다.The novel compounds of the invention inhibit the activity of one or more protein kinases and are therefore expected to be useful in the treatment of kinase-associated diseases.

<발명의 요약>Summary of the Invention

제1 국면에서, 본 발명은 하기 화학식 I의 화합물, 그의 N-옥시드 유도체, 전구약물 유도체, 보호된 유도체, 개별적인 이성질체 및 이성질체의 혼합물; 및 이러한 화합물의 제약적으로 허용가능한 염 및 용매화물 (예를 들어 수화물)을 제공한다.In a first aspect, the present invention provides a compound of formula I, N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; And pharmaceutically acceptable salts and solvates (eg hydrates) of such compounds.

Figure 112006091059442-pct00001
Figure 112006091059442-pct00001

상기 식에서, m 및 n은 독립적으로 0, 1 및 2로부터 선택되며;Wherein m and n are independently selected from 0, 1 and 2;

R1은 -XNR5R6, -XOR5, -XC(O)R5, -XR5 및 -XS(O)0-2R5로부터 선택되고; 여기서 X는 결합이거나, 1 내지 2개의 C1 - 6알킬 라디칼로 임의로 치환되는 C1 - 4알킬렌이며; R5는 수소, C1 - 6알킬, C6 - 10아릴-C0 - 4알킬, C5 - 10헤테로아릴-C0 - 4알킬, C3-10시클로알킬-C0-4알킬 및 C3-10헤테로시클로알킬-C0-4알킬로부터 선택되고; R6는 수소 및 C1-6알킬로부터 선택되거나; 또는 R5 및 R6는 이들이 결합되어 있는 질소 원자와 함께 헤테로아릴 또는 헤테로시클로알킬을 형성하고; R5 또는 R5 및 R6의 조합 내의 임의의 아릴, 헤테로아릴, 시클로알킬 및 헤테로시클로알킬은 임의로는 할로, 니트로, 시아노, 히드록시, C1-6알킬, C1-6알콕시, 할로-치환된-알킬, 할로-치환된-알콕시, -XNR7R8, -XOR7, -XNR7S(O)2R8, -XNR7S(O)R8, -XNR7SR8, -XC(O)NR7R8, -XC(O)NR7XNR7R8, -XNR7C(O)NR7R8, -XNR7XNR7R8, -XNR7XOR7, -XNR7C(=NR7)NR7R8, -XS(0)2R9, -XNR7C(O)R8, -XNR7C(O)R9, -XR9, -XC(O)OR8,- XS(0)2NR7R8, -XS(O)NR7R8 및 -XSNR7R8로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 치환될 수 있고; 여기서, X는 결합 또는 C1-4알킬렌이고; R7 및 R8은 독립적으로 수소 및 C1-4알킬로 이루어진 군으로부터 선택되며; R9은 C3-10헤테로시클로알킬 및 C5-10헤테로아릴로부터 선택되며; 상기 R9의 헤테로시클로알킬 또는 헤테로아릴은 임의로는 C1-4알킬, -XNR7XNR7R7, XNR7XOR7 및 -XOR7로 이루어진 군으로부터 선택되는 라디칼로 치환되고; R 1 is selected from —XNR 5 R 6 , —XOR 5 , —XC (O) R 5 , —XR 5 and —XS (O) 0-2 R 5 ; Wherein X is a bond or, 1 to 2 C 1 - C 6 alkyl radical optionally substituted with 1 to be - 4 alkylene, and; R 5 is hydrogen, C 1 - 6 alkyl, C 6 - 10 aryl -C 0 - 4 alkyl, C 5 - 10 heteroaryl, -C 0 - 4 alkyl, C 3-10 cycloalkyl, -C 0-4 alkyl, and C 3-10 heterocycloalkyl-C 0-4 alkyl; R 6 is selected from hydrogen and C 1-6 alkyl; Or R 5 and R 6 together with the nitrogen atom to which they are attached form heteroaryl or heterocycloalkyl; Any aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R 5 or a combination of R 5 and R 6 is optionally halo, nitro, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo -Substituted-alkyl, halo-substituted-alkoxy, -XNR 7 R 8 , -XOR 7 , -XNR 7 S (O) 2 R 8 , -XNR 7 S (O) R 8 , -XNR 7 SR 8 , -XC (O) NR 7 R 8 , -XC (O) NR 7 XNR 7 R 8 , -XNR 7 C (O) NR 7 R 8 , -XNR 7 XNR 7 R 8 , -XNR 7 XOR 7 , -XNR 7 C (= NR 7) NR 7 R 8, -XS (0) 2 R 9, -XNR 7 C (O) R 8, -XNR 7 C (O) R 9, -XR 9, -XC (O) OR 8 ,-XS (0) 2 NR 7 R 8 , -XS (O) NR 7 R 8 and -XSNR 7 R 8 may be substituted with 1 to 3 radicals independently selected from; Wherein X is a bond or C 1-4 alkylene; R 7 and R 8 are independently selected from the group consisting of hydrogen and C 1-4 alkyl; R 9 is selected from C 3-10 heterocycloalkyl and C 5-10 heteroaryl; The heterocycloalkyl or heteroaryl of R 9 is optionally substituted with a radical selected from the group consisting of C 1-4 alkyl, —XNR 7 XNR 7 R 7 , XNR 7 XOR 7 and —XOR 7 ;

R2 및 R4는 독립적으로 할로, 히드록시, C1-4알킬, C1-4알콕시, 할로-치환된-C1-4알킬 및 할로-치환된-C1-4알콕시로부터 선택되고; R 2 and R 4 are independently selected from halo, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl and halo-substituted-C 1-4 alkoxy;

R3는 -NR10R11, -NR10C(O)R11, -NR10S(O)0-2R11 및 -NR10C(O)NR10R11로부터 선택되고; 여기서, R10은 수소 및 C1-6알킬로부터 선택되고; R11은 C6-10아릴, C5-10헤테로아릴, C3-10시클로알킬 및 C3-10헤테로시클로알킬로부터 선택되며; R11의 임의의 아릴, 헤테로아릴, 시클로알킬 또는 헤테로시클로알킬은 임의로는 할로, 니트로, 시아노, 히드록시, C1-6알킬, C1-6알콕시, 할로-치환된-알킬, 할로-치환된-알콕시, -NR12C(O)R13, -NR12C(O)NR12R13, -C(O)NR12R13, -NR12S(O)0-2R13 및 -S(O)0-2NR12R13로부터 선택되는 1 내지 3개의 라디칼로 치환되고; R12는 수소 및 C1-6알킬로부터 선택되고; R13은 C6-10아릴, C5-10헤테로아릴, C3-10시클로알킬 및 C3-10헤테로시클로알킬로부터 선택되며; R13의 임의의 아릴, 헤테로아릴, 시클로알킬 또는 헤테로시클로알킬은 임의로는 할로, C1-6알킬, 할로-치환된-C1-6알킬, C1-6알콕시, 할로-치환된-C1-6알콕시, -XNR7R8, C6-10아릴-C0-4알킬, C5-10헤테로아릴-C0-4알킬, C3-10시클로알킬-C0-4알킬, C3-10헤테로시클로알킬-C0-4알콕시 및 C3-10헤테로시클로알킬-C0-4알킬로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 치환되고; 여기서, X, R7 및 R8은 상기 정의한 바와 같고, R13의 임의의 아릴, 헤테로아릴, 시클로알킬 또는 헤테로시클로알킬 치환체는 임의로는 할로, C1-6알킬, 할로-치환된-C1-6알킬, 히드록시-치환된-C1-6알킬, C1-6알콕시, C3-10헤테로시클로알킬 및 할로-치환된-C1-6알콕시로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 추가로 치환된다.R 3 is selected from —NR 10 R 11 , —NR 10 C (O) R 11 , —NR 10 S (O) 0-2 R 11 and —NR 10 C (O) NR 10 R 11 ; Wherein R 10 is selected from hydrogen and C 1-6 alkyl; R 11 is selected from C 6-10 aryl, C 5-10 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl; Any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 11 is optionally halo, nitro, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-alkyl, halo- Substituted-alkoxy, -NR 12 C (O) R 13 , -NR 12 C (O) NR 12 R 13 , -C (O) NR 12 R 13 , -NR 12 S (O) 0-2 R 13 and -S (O) 0-2 NR 12 R 13 is substituted with 1 to 3 radicals selected from; R 12 is selected from hydrogen and C 1-6 alkyl; R 13 is selected from C 6-10 aryl, C 5-10 heteroaryl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl; Any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 13 is optionally halo, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkoxy, -XNR 7 R 8 , C 6-10 aryl-C 0-4 alkyl, C 5-10 heteroaryl-C 0-4 alkyl, C 3-10 cycloalkyl-C 0-4 alkyl, C 3-10 heterocycloalkyl -C 0-4 alkoxy and C 3-10 heterocycloalkyl -C it is substituted with 1 to 3 alkyl radicals from 0-4 independently selected; Wherein X, R 7 and R 8 are as defined above and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent of R 13 is optionally halo, C 1-6 alkyl, halo-substituted-C 1 1-3 radicals independently selected from -6 alkyl, hydroxy-substituted-C 1-6 alkyl, C 1-6 alkoxy, C 3-10 heterocycloalkyl and halo-substituted-C 1-6 alkoxy Is further substituted.

제2 국면에서, 본 발명은 화학식 I의 화합물, 그의 N-옥시드 유도체, 개별적인 이성질체, 이성질체의 혼합물, 또는 제약적으로 허용가능한 염을 1종 이상의 적절한 부형제와 함께 함유하는 제약 조성물을 제공한다.In a second aspect, the present invention provides a pharmaceutical composition containing a compound of formula (I), an N-oxide derivative thereof, an individual isomer, a mixture of isomers, or a pharmaceutically acceptable salt together with one or more suitable excipients.

제3 국면에서, 본 발명은 화학식 I의 화합물, 그의 N-옥시드 유도체, 개별적인 이성질체, 이성질체의 혼합물, 또는 제약적으로 허용가능한 염의 치료적 유효량을 동물에게 투여하는 것을 포함하는, 키나제 활성, 특히 Abl, BCR-Abl, PDGF-R, trkB, c-SRC, BMX, FGFR3, B-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c-RAF, MKK6, SAPK2α 및(또는) SAPK2β 활성의 억제에 의해 질환의 병증 및(또는) 증상을 예방, 억제 또는 개선할 수 있는, 동물에서의 질환 치료 방법을 제공한다.In a third aspect, the present invention provides a kinase activity, in particular Abl, comprising administering to the animal a therapeutically effective amount of a compound of formula I, an N-oxide derivative thereof, an individual isomer, a mixture of isomers, or a pharmaceutically acceptable salt. , Inhibition of BCR-Abl, PDGF-R, trkB, c-SRC, BMX, FGFR3, B-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c-RAF, MKK6, SAPK2α and / or SAPK2β activity Provided are methods of treating a disease in an animal that can prevent, inhibit or ameliorate the symptoms and / or symptoms of the disease.

제4 국면에서, 본 발명은 동물에서 Abl, BCR-Abl, PDGF-R, trkB, c-SRC, BMX, FGFR3, b-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c-RAF, MKK6, SAPK2α 및(또는) SAPK2β 키나제 활성이 질환의 병증 및(또는) 증상에 기여하는 질환의 치료용 의약을 제조하기 위한 화학식 I의 화합물의 용도를 제공한다.In a fourth aspect, the invention provides Abl, BCR-Abl, PDGF-R, trkB, c-SRC, BMX, FGFR3, b-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c-RAF, MKK6, Provided is the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a disease in which SAPK2α and / or SAPK2β kinase activity contributes to the symptoms and / or symptoms of the disease.

제5 국면에서, 본 발명은 화학식 I의 화합물, 그의 N-옥시드 유도체, 전구약물 유도체, 보호된 유도체, 개별적인 이성질체, 이성질체의 혼합물 및 제약적으로 허용가능한 염의 제조 방법을 제공한다.In a fifth aspect, the present invention provides a method of preparing a compound of formula (I), an N-oxide derivative, a prodrug derivative, a protected derivative, an individual isomer, a mixture of isomers and a pharmaceutically acceptable salt thereof.

정의Justice

단일기, 및 다른 기, 예를 들어 할로-치환된-알킬 및 알콕시기의 구조적 요소로서의 "알킬"은 직쇄 또는 분지쇄일 수 있다. C1 -4-알콕시로는 메톡시, 에톡시 등을 포함한다. 할로-치환된 알킬로는 트리플루오로메틸, 펜타플루오로에틸 등을 포함한다."Alkyl" as a structural element of a single group and other groups, such as halo-substituted-alkyl and alkoxy groups, may be straight or branched chain. C 1 -4 - alkoxy include methoxy, ethoxy. Halo-substituted alkyls include trifluoromethyl, pentafluoroethyl, and the like.

"아릴"은 6 내지 10개의 고리 탄소 원자를 함유하는 모노시클릭 또는 융합된 바이시클릭 방향족 고리단을 의미한다. 예를 들어, 아릴은 페닐 또는 나프틸, 바람직하게는 페닐일 수 있다. "아릴렌"은 아릴기로부터 유도된 이가 라디칼을 의미한다."Aryl" means a monocyclic or fused bicyclic aromatic ring group containing 6 to 10 ring carbon atoms. For example, aryl can be phenyl or naphthyl, preferably phenyl. "Arylene" means a divalent radical derived from an aryl group.

"헤테로아릴"은 고리 구성원 중 1개 이상이 헤테로원자인 상기와 같은 아릴로 정의된다. 예를 들어, 헤테로아릴은 피리딜, 인돌릴, 인다졸릴, 퀴녹살리닐, 퀴놀리닐, 벤조푸라닐, 벤조피라닐, 벤조티아피라닐, 벤조[1,3]디옥솔, 이미다졸릴, 벤조이미다졸릴, 피리미디닐, 푸라닐, 옥사졸릴, 이속사졸릴, 트리아졸릴, 테트라졸릴, 피라졸릴, 티에닐 등을 포함한다."Heteroaryl" is defined as such aryl, wherein at least one of the ring members is a heteroatom. For example, heteroaryl may be pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiapyranyl, benzo [1,3] dioxol, imidazolyl, Benzoimidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl and the like.

"시클로알킬"은 명시된 고리 원자수를 함유하는 포화되거나 부분 불포화된 모노시클릭, 융합된 바이시클릭 또는 가교된 폴리시클릭 고리단을 의미한다. 예를 들어, C3 - 10시클로알킬은 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실 등을 포함한다. "Cycloalkyl" means a saturated or partially unsaturated monocyclic, fused bicyclic or crosslinked polycyclic ring group containing the specified number of ring atoms. For example, C 3 - 10 cycloalkyl, and includes such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

"헤테로시클로알킬"은 본 명세서에서 정의된 시클로알킬에서, 명시된 고리 탄소 중 1개 이상이 -0-, -N-, -NR- (여기서, R은 수소, C1 - 4알킬 또는 질소 보호기임), -C (O)-, -S-, -S(O)- 또는 -S(O)2-로부터 선택되는 잔기로 대체된 것을 의미한다. 예를 들어, 본 명세서에서 본 발명의 화합물을 설명하기 위해 사용되는 C3 - 8헤테로시클로알킬은 모르폴리노, 피롤리디닐, 피롤리디닐-2-온, 피페라지닐, 피페리디닐, 피페리디닐온, 1,4-디옥사-8-아자-스피로[4.5]데스-8-일 등을 포함한다."Heterocycloalkyl" is in the cycloalkyl as defined herein, at least one of the specified ring carbon -0-, -N-, -NR- (wherein, R is hydrogen, C 1 - 4 alkyl or a nitrogen protecting group ), -C (O)-, -S-, -S (O)-or -S (O) 2- . For example, C 3 is used to describe the compounds of the invention herein - 8 heterocycloalkyl is morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperazinyl Ridinylone, 1,4-dioxa-8-aza-spiro [4.5] dec-8-yl and the like.

"할로겐" (또는 할로)은 바람직하게는 클로로 또는 플루오로를 나타내나, 브로모 또는 요오도일 수도 있다."Halogen" (or halo) preferably denotes chloro or fluoro, but may also be bromo or iodo.

"BCR-Abl의 돌연변이형"은 야생형 서열에서 단일 또는 다수개의 아미노산 변이가 발생한 것을 의미한다. 현재까지 22종이 넘는 돌연변이형이 보고되었고, G250E, E255V,T315I, F317L 및 M351T이 가장 흔한 것으로 알려졌다."Mutant form of BCR-Abl" means that a single or multiple amino acid mutation has occurred in a wild-type sequence. To date, over 22 mutants have been reported, with G250E, E255V, T315I, F317L and M351T being the most common.

"치료"란 질환 및(또는) 그에 수반하는 증상을 경감시키거나 완화시키는 것을 말한다."Treatment" refers to alleviating or alleviating a disease and / or symptoms thereof.

바람직한 실시태양의 기술Description of the Preferred Embodiments

융합 단백질 BCR-Abl은 Abl 원-발암유전자를 Bcr 유전자와 융합시키는 상호전위의 결과이다. 그 결과 BCR-Abl은 유사분열 활성을 증가시켜 B-세포를 전환시킬 수 있게 된다. 이러한 활성 증가는 아폽토시스에 대한 민감성의 감소를 유발하고, CML 전구세포의 부착 및 안착을 변화시킨다. 본 발명은 키나제, 특히 Abl, BCR-Abl, PDGF-R, trkB, c-SRC, BMX, FGFR3, B-RAF, b-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c-RAF, MKK6, SAPK2α 및 SAPK2β 관련 질환을 치료하기 위한 화합물, 조성물 및 방법을 제공하며, 키나제 관련 질환. 예를 들어, 백혈병 및 다른 BCR-Abl 관련 증식성 장애는 BCR-Abl의 야생형 및 돌연변이형의 억제를 통해 치료될 수 있다. The fusion protein BCR-Abl is the result of the interpotential fusion of the Abl one-oncogene with the Bcr gene. As a result, BCR-Abl can increase mitotic activity and convert B-cells. This increase in activity leads to a decrease in sensitivity to apoptosis and alters the adhesion and settlement of CML progenitor cells. The present invention relates to kinases, in particular Abl, BCR-Abl, PDGF-R, trkB, c-SRC, BMX, FGFR3, B-RAF, b-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c-RAF, MKK6, Provided are compounds, compositions, and methods for treating SAPK2α and SAPK2β related diseases, and kinase related diseases. For example, leukemia and other BCR-Abl related proliferative disorders can be treated through inhibition of wild and mutant types of BCR-Abl.

화학식 I의 화합물에 관한 한 실시태양에서, 화학식 Ia의 화합물을 제공한다.In one embodiment, with respect to compounds of formula (I), compounds of formula (Ia) are provided.

Figure 112006091059442-pct00002
Figure 112006091059442-pct00002

상기 식에서, p는 0 및 1로부터 선택되며; In which p is selected from 0 and 1;

n은 0, 1, 2 및 3으로부터 선택되며; n is selected from 0, 1, 2 and 3;

q는 0 및 1로부터 선택되며; q is selected from 0 and 1;

R5는 수소, C1-6알킬, C6-10아릴-C0-4알킬, C5-10헤테로아릴-C0-4알킬, C3-10시클로알킬-C0-4알킬 및 C3-10헤테로시클로알킬-C0-4알킬로부터 선택되고; R6는 수소 및 C1-6알킬로부터 선택되거나; 또는 R5 및 R6는 이들이 결합되어 있는 질소 원자와 함께 헤테로아릴 또는 헤테로시클로알킬을 형성하고; R5 또는 R5 및 R6의 조합 내의 임의의 아릴, 헤테로아릴, 시클로알킬 및 헤테로시클로알킬은 임의로는 할로, 니트로, 시아노, 히드록시, C1-6알킬, C1-6알콕시, 할로-치환된-알킬, 할로-치환된-알콕시, -XNR7R8, -XOR7, -XNR7S(O)2R8, -XNR7S(O)R8, -XNR7SR8, -XC(O)NR7R8, -XC(O)NR7XNR7R8, -XNR7C(O)NR7R8, -XNR7XNR7R8, -XNR7XOR7, -XNR7C(=NR7)NR7R8, -XS(0)2R9, -XNR7C(O)R8, -XNR7C(O)R9, -XR9, -XC(O)OR8, -XS(0)2NR7R8, -XS(O)NR7R8 및 -XSNR7R8로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 치환될 수 있고; 여기서, X는 결합 또는 C1-4알킬렌이고; R7 및 R8은 독립적으로 수소 및 C1-4알킬로 이루어진 군으로부터 선택되며; R9은 C3-10헤테로시클로알킬 및 C5-10헤테로아릴로부터 선택되며; 상기 R9의 헤테로시클로알킬 또는 헤테로아릴은 임의로는 C1-4알킬, -XNR7XNR7R7, XNR7XOR7 및 -XOR7로 이루어진 군으로부터 선택되는 라디칼로 치환되고; 여기서, X 및 R7은 상기 정의한 바와 같고;R 5 is hydrogen, C 1-6 alkyl, C 6-10 aryl-C 0-4 alkyl, C 5-10 heteroaryl-C 0-4 alkyl, C 3-10 cycloalkyl-C 0-4 alkyl and C 3-10 heterocycloalkyl-C 0-4 alkyl; R 6 is selected from hydrogen and C 1-6 alkyl; Or R 5 and R 6 together with the nitrogen atom to which they are attached form heteroaryl or heterocycloalkyl; Any aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R 5 or a combination of R 5 and R 6 is optionally halo, nitro, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo -Substituted-alkyl, halo-substituted-alkoxy, -XNR 7 R 8 , -XOR 7 , -XNR 7 S (O) 2 R 8 , -XNR 7 S (O) R 8 , -XNR 7 SR 8 , -XC (O) NR 7 R 8 , -XC (O) NR 7 XNR 7 R 8 , -XNR 7 C (O) NR 7 R 8 , -XNR 7 XNR 7 R 8 , -XNR 7 XOR 7 , -XNR 7 C (= NR 7) NR 7 R 8, -XS (0) 2 R 9, -XNR 7 C (O) R 8, -XNR 7 C (O) R 9, -XR 9, -XC (O) Or may be substituted with 1 to 3 radicals independently selected from OR 8 , -XS (0) 2 NR 7 R 8 , -XS (O) NR 7 R 8 and -XSNR 7 R 8 ; Wherein X is a bond or C 1-4 alkylene; R 7 and R 8 are independently selected from the group consisting of hydrogen and C 1-4 alkyl; R 9 is selected from C 3-10 heterocycloalkyl and C 5-10 heteroaryl; The heterocycloalkyl or heteroaryl of R 9 is optionally substituted with a radical selected from the group consisting of C 1-4 alkyl, —XNR 7 XNR 7 R 7 , XNR 7 XOR 7 and —XOR 7 ; Wherein X and R 7 are as defined above;

R10은 수소 및 C1-6알킬로부터 선택되고; R 10 is selected from hydrogen and C 1-6 alkyl;

R15는 할로, 니트로, 시아노, 히드록시, C1-6알킬, C1-6알콕시, 할로-치환된-알킬 및 할로-치환된-알콕시로부터 선택되고; R 15 is selected from halo, nitro, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-alkyl and halo-substituted-alkoxy;

R16은 -NR12C(O)R13, -NR12C(O)NR12R13, -C(O)NR12R13, -NR12S(O)0-2R13 및 -S(O)0-2NR12R13로부터 선택되고; 여기서, R12는 수소 및 C1 - 6알킬로부터 선택되고; R13은 C6 - 10아릴, C5 - 10헤테로아릴, C3 - 10시클로알킬 및 C3 - 10헤테로시클로알킬로부터 선택되고; R13의 임의의 아릴, 헤테로아릴, 시클로알킬 또는 헤테로시클로알킬은 임의로는 할로, C1-6알킬, 할로-치환된-C1 - 6알킬, C1 - 6알콕시, 할로-치환된-C1 - 6알콕시, -XNR7R8, C6 - 10아 릴-C0-4알킬, C5 - 10헤테로아릴-C0 - 4알킬, C3 - 10시클로알킬-C0 - 4알킬, C3 - 10헤테로시클로알킬-C0-4알콕시 및 C3 - 10헤테로시클로알킬-C0 - 4알킬로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 치환되며; 여기서, X, R7 및 R8은 상기 정의된 바와 같고, R13의 임의의 아릴, 헤테로아릴, 시클로알킬 또는 헤테로시클로알킬은 임의로는 할로, C1 - 6알킬, 할로-치환된-C1 - 6알킬, 히드록시-치환된-C1 - 6알킬, C1 - 6알콕시, C3 - 10헤테로시클로알킬 및 할로-치환된-C1 - 6알콕시로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 추가로 치환된다.R 16 is -NR 12 C (O) R 13 , -NR 12 C (O) NR 12 R 13 , -C (O) NR 12 R 13 , -NR 12 S (O) 0-2 R 13 and -S (O) 0-2 NR 12 R 13 ; Wherein, R 12 is hydrogen and C 1 - 6 is selected from alkyl; R 13 is C 6 - 10 aryl, C 5 - 10 heteroaryl, C 3 - is selected from heterocycloalkyl 10 - 10 cycloalkyl and C 3; Any aryl of R 13, heteroaryl, cycloalkyl or heterocycloalkyl are optionally halo, C 1-6 alkyl, halo-substituted -C 1 - 6 alkyl, C 1 - 6 alkoxy, halo-substituted -C 1 - 6 alkoxy, -XNR 7 R 8, C 6 - 10 Ah reel -C 0-4 alkyl, C 5 - 10 heteroaryl, -C 0 - 4 alkyl, C 3 - 10 cycloalkyl, -C 0 - 4 alkyl, C 3 - 10 heterocycloalkyl -C 0-4 alkoxy and C 3 - 10 heterocycloalkyl -C 0 - 4 and substituted with 1 to 3 radicals independently selected from alkyl; Wherein, X, R 7 and R 8 are as defined above, any aryl of R 13, heteroaryl, cycloalkyl or heterocycloalkyl are optionally halo, C 1 - 6 alkyl, halo-substituted -C 1 - 6 alkyl, hydroxy-substituted -C 1 - 6 alkyl, C 1 - 6 alkoxy, C 3 - 10 heterocycloalkyl and halo-1 to 3 radicals independently selected from a 6-alkoxy-substituted -C 1 Is further substituted.

다른 실시태양에서, R5는 수소, 모르폴리노-에틸, 시클로프로필, 메틸, 3-(2-옥소-피롤리딘-1-일)-프로필, 벤조[1,3]디옥솔-5-일, 3-(4-메틸-피페라진-1-일)-프로필, 히드록시메틸-페닐, (1-히드록시에틸)-페닐, 모르폴리노, 피리디닐, 메틸-카르보닐, 메틸-술포닐, 메틸-피리디닐, 아미노-시클로헥실, 피페리디닐, 메틸-피페라지닐-에틸, 디메틸-피라졸릴, 메틸-피라졸릴, 디메틸-피리디닐, 메틸-피리디닐, 에틸-피페라지닐-피리디닐, 아미노-카르보닐-피리디닐, 시아노-피리디닐, 디메틸-아미노-에틸, 메톡시-에틸, 메틸-피롤리디닐-에틸, 에틸-피라졸릴, 디메틸-아미노-프로필, 이소프로필, 푸라닐-메틸, 메틸-피페라지닐-프로필, 벤조[1,3]디옥솔-5-일메틸, 2-메틸-6-모르폴린-4-일-피리딘-3-일, 메틸-피리미디닐, 메톡시-피리디닐, 플루오로-페닐, 디메틸-아미노-에틸-아미노카르보닐, 피리디닐-메틸, 티아졸릴-메틸, 메틸-피라지닐-메틸, 이미다졸릴-프로필, 아미노-카르보닐-페닐로부터 선택 되거나; 또는 R5 및 R6은 이들이 결합되어 있는 질소 원자와 함께 에틸, 피리디닐 및 모르폴리노로부터 선택되는 기로 임의로 치환되는 모르폴리노, 피페리디닐 및 피페라지닐로부터 선택되는 기를 형성한다.In another embodiment, R 5 is hydrogen, morpholino-ethyl, cyclopropyl, methyl, 3- (2-oxo-pyrrolidin-1-yl) -propyl, benzo [1,3] dioxol-5- 1, 3- (4-Methyl-piperazin-1-yl) -propyl, hydroxymethyl-phenyl, (1-hydroxyethyl) -phenyl, morpholino, pyridinyl, methyl-carbonyl, methyl-sul Ponyl, methyl-pyridinyl, amino-cyclohexyl, piperidinyl, methyl-piperazinyl-ethyl, dimethyl-pyrazolyl, methyl-pyrazolyl, dimethyl-pyridinyl, methyl-pyridinyl, ethyl-piperazinyl- Pyridinyl, amino-carbonyl-pyridinyl, cyano-pyridinyl, dimethyl-amino-ethyl, methoxy-ethyl, methyl-pyrrolidinyl-ethyl, ethyl-pyrazolyl, dimethyl-amino-propyl, isopropyl, Furanyl-methyl, methyl-piperazinyl-propyl, benzo [1,3] dioxol-5-ylmethyl, 2-methyl-6-morpholin-4-yl-pyridin-3-yl, methyl-pyrimidy Neyl, methoxy-pyridinyl, fluoro-phenyl, dimethyl-amino-ethyl-a Noka Viterbo carbonyl, pyridinyl-methyl, thiazolyl-methyl, methyl-pyrazinyl-methyl, imidazolyl-propyl, amino-carbonyl-or selected from phenyl; Or R 5 and R 6 together with the nitrogen atom to which they are attached form a group selected from morpholino, piperidinyl and piperazinyl optionally substituted with a group selected from ethyl, pyridinyl and morpholino.

추가의 실시태양에서, R16은 -NHC(O)R13, -NHC(O)NHR13, -C(O)NHR13, -NHS(O)0-2R13 및 -S(O)0-2NHR13로부터 선택되고; 여기서, R13은 페닐, 피리다지닐, 피리디닐, 푸라닐, 피롤릴, 이미다졸릴, 피라졸릴, 퀴녹살리닐, 티에닐 및 티아졸릴로부터 선택되고; R13은 임의로는 메틸, t-부틸, 할로, 트리플루오로메틸, 디에틸-아미노, 디메틸-아미노, 벤질, 피페리디닐-아미노, 피롤리디닐-메톡시, 에틸-피페라지닐-메틸, 모르폴리노, 메틸-피페라지닐, 메틸-피페라지닐-메틸, 에틸-피페라지닐, 메틸-이미다졸릴, 모르폴리노-메틸, 피롤리디닐-피페리디닐, 피페라지닐-메틸, 히드록시-피페리디닐, 1-메틸-피페리딘-4-일옥시, 피페리디닐-옥시, 메틸-피라지닐, 피라지닐 및 히드록시에틸-피페라지닐로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 치환된다.In further embodiments, R 16 is -NHC (O) R 13 , -NHC (O) NHR 13 , -C (O) NHR 13 , -NHS (O) 0-2 R 13 and -S (O) 0 -2NHR 13 ; Wherein R 13 is selected from phenyl, pyridazinyl, pyridinyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, quinoxalinyl, thienyl and thiazolyl; R 13 is optionally methyl, t-butyl, halo, trifluoromethyl, diethyl-amino, dimethyl-amino, benzyl, piperidinyl-amino, pyrrolidinyl-methoxy, ethyl-piperazinyl-methyl, Morpholino, methyl-piperazinyl, methyl-piperazinyl-methyl, ethyl-piperazinyl, methyl-imidazolyl, morpholino-methyl, pyrrolidinyl-piperidinyl, piperazinyl-methyl, 1 to 3 independently selected from hydroxy-piperidinyl, 1-methyl-piperidin-4-yloxy, piperidinyl-oxy, methyl-pyrazinyl, pyrazinyl and hydroxyethyl-piperazinyl Substituted with radicals.

본 발명의 바람직한 화합물은 하기 화합물들로부터 선택된다.Preferred compounds of the present invention are selected from the following compounds.

N-[4-메틸-3-(1-{6-[4-(2-모르폴린-4-일-에틸)-페닐아미노]-피리미딘-4-일)-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6- [4- (2-morpholin-4-yl-ethyl) -phenylamino] -pyrimidin-4-yl) -1H-imidazole-2- Monoamino) -phenyl] -3-trifluoromethyl-benzamide,

N-(3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(4-에틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- (3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (4-ethyl-piperazine -1-yl) -5-trifluoromethyl-benzamide,

N-(4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다 졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl ) -3-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benzamide ,

N-(4-메틸-3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-3-트리플루오로메틸-벤즈아미드, N- (4-methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -3-trifluoromethyl-benzamide,

N-[4-메틸-3-(1-{6-[3-(2-옥소-피롤리딘-1-일)-프로필아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6- [3- (2-oxo-pyrrolidin-1-yl) -propylamino] -pyrimidin-4-yl} -1 H-imidazole-2 -Ylamino) -phenyl] -3-trifluoromethyl-benzamide,

N-(3-{1-[6-(벤조[1,3]디옥솔-5-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (benzo [1,3] dioxol-5-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl- Phenyl) -3-trifluoromethyl-benzamide,

N-[4-메틸-3-(1-{6-[3-(4-메틸-피페라진-1-일)-프로필아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6- [3- (4-methyl-piperazin-1-yl) -propylamino] -pyrimidin-4-yl} -1 H-imidazole-2- Monoamino) -phenyl] -3-trifluoromethyl-benzamide,

{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일}-시클로프로필-아민, {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-yl} -cyclopropyl-amine,

(3-{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일아미노}-페닐)-메탄올, (3- {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-ylamino} -phenyl) -methanol,

1-(3-{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일아미노}-페닐)-에탄올, 1- (3- {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-ylamino} -phenyl) -ethanol,

{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일}-[4-(2-모르폴린-4-일-에틸)-페닐]-아민, {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-yl}-[4- (2-morpholin-4-yl-ethyl) -phenyl]- Amine,

{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일}-(4-모르폴린- 4-일-페닐)-아민,{6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-yl}-(4-morpholin-4-yl-phenyl) -amine,

N-(3-{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일아미노}-페닐)-아세트아미드, N- (3- {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-ylamino} -phenyl) -acetamide,

1-(3-{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일아미노}-프로필)-피롤리딘-2-온, 1- (3- {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-ylamino} -propyl) -pyrrolidin-2-one,

벤조[1,3]디옥솔-5-일-{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일}-아민, Benzo [1,3] dioxol-5-yl- {6- [2- (2-chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-yl} -amine,

{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일}-피리딘-3-일-아민, {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-yl} -pyridin-3-yl-amine,

N-(4-메틸-3-{1-[6-(피리딘-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-methyl-3- {1- [6- (pyridin-3-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -phenyl) -3-trifluoro Chloromethyl-benzamide,

{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일}-(6-메틸-피리딘-3-일)-아민, {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-yl}-(6-methyl-pyridin-3-yl) -amine,

N-(4-메틸-3-{1-[6-(6-메틸-피리딘-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (6-methyl-pyridin-3-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl)- 3-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-모르폴린-4-일-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-morpholin-4-yl- 5-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(4-메틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (4-methyl-piperazine -1-yl) -5-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4- 메틸-페닐}-3-(4-에틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4- methyl-phenyl} -3- (4-ethyl-piperazine -1-yl) -5-trifluoromethyl-benzamide,

N-(3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-모르폴린-4-일-3-트리플루오로메틸-벤즈아미드, N- (3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4-morpholin-4-yl- 3-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-(4-에틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4- (4-ethyl-piperazine -1-ylmethyl) -3-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-(4-메틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4- (4-methyl-piperazine -1-ylmethyl) -3-trifluoromethyl-benzamide,

N-(3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐)-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- (3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl) -3- (4-methyl-imidazole -1-yl) -5-trifluoromethyl-benzamide,

3-(4-메틸-이미다졸-1-일)-N-{4-메틸-3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-5-트리플루오로메틸-벤즈아미드, 3- (4-methyl-imidazol-1-yl) -N- {4-methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino ] -Phenyl} -5-trifluoromethyl-benzamide,

N-{4-메틸-3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-4-모르폴린-4-일-3-트리플루오로메틸-벤즈아미드, N- {4-methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -4-morpholin-4-yl-3 -Trifluoromethyl-benzamide,

3-(4-에틸-피페라진-1-일)-N-{4-메틸-3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-5-트리플루오로메틸-벤즈아미드, 3- (4-ethyl-piperazin-1-yl) -N- {4-methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino ] -Phenyl} -5-trifluoromethyl-benzamide,

N-{4-메틸-3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-3-(4-메틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- {4-Methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -3- (4-methyl-piperazine- 1-yl) -5-trifluoromethyl-benzamide,

N-(3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐)-4-(4-메틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드, N- (3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl) -4- (4-methyl-piperazin-1-ylmethyl ) -3-trifluoromethyl-benzamide,

3-(4-에틸-피페라진-1-일메틸)-N-{4-메틸-3-[1-(6-메틸아미노-피리미딘-4- 일)-1H-이미다졸-2-일아미노]-페닐}-5-트리플루오로메틸-벤즈아미드, 3- (4-ethyl-piperazin-1-ylmethyl) -N- {4-methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-yl Amino] -phenyl} -5-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-모르폴린-4-일메틸-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4-morpholin-4-ylmethyl 3-trifluoromethyl-benzamide,

N-{4-메틸-3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-4-모르폴린-4-일메틸-3-트리플루오로메틸-벤즈아미드, N- {4-Methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -4-morpholin-4-ylmethyl- 3-trifluoromethyl-benzamide,

N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐)-4-(4-에틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-Amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl) -4- (4-ethyl-piperazine-1 -Ylmethyl) -3-trifluoromethyl-benzamide,

N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-(4-메틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-Amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4- (4-methyl-piperazine-1 -Ylmethyl) -3-trifluoromethyl-benzamide,

N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐)-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-Amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl) -3- (4-methyl-imidazol-1-yl)- 5-trifluoromethyl-benzamide,

N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-모르폴린-4-일-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4-morpholin-4-yl-3- Trifluoromethyl-benzamide,

N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐-3-(4-에틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl-3- (4-ethyl-piperazine-1- Yl) -5-trifluoromethyl-benzamide,

N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(4-메틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-Amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (4-methyl-piperazine-1 -Yl) -5-trifluoromethyl-benzamide,

N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-모르폴린-4-일메틸-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-morpholin-4-ylmethyl-5 -Trifluoromethyl-benzamide,

3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-5-메 톡시-N-[4-(2-메틸-이미다졸-1-일)-3-트리플루오로메틸-페닐]-벤즈아미드, 3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -5-methoxy-N- [4- (2-methyl-imidazole-1 -Yl) -3-trifluoromethyl-phenyl] -benzamide,

N-{3-[1-(6-아세틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-acetylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benzamide,

N-{3-[1-(6-메탄술포닐아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-Methanesulfonylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benz amides,

N-{3-[1-(2-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (2-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benzamide ,

3-[1-(2-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-N-[4-(2-메틸-이미다졸-1-일)-3-트리플루오로메틸-페닐]-벤즈아미드, 3- [1- (2-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-N- [4- (2-methyl-imidazole-1- Yl) -3-trifluoromethyl-phenyl] -benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-피페라진-1-일메틸-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-piperazin-1-ylmethyl -5-trifluoromethyl-benzamide,

N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-피페라진-1-일메틸-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-piperazin-1-ylmethyl-5 -Trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-5-메톡시-페닐}-4-(4-메틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -5-methoxy-phenyl} -4- (4-methyl-pipe Razin-1-ylmethyl) -3-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-5-메톡시-페닐}-3-(4-에틸-피페라진-1-일메틸)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -5-methoxy-phenyl} -3- (4-ethyl-pipe Razin-1-ylmethyl) -5-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(피페리딘-4-일옥시)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (piperidin-4- Yloxy) -5-trifluoromethyl-benzamide,

N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}- 3-(피페리딘-4-일옥시)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3 (piperidin-4-yloxy ) -5-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-5-메톡시-페닐}-3-(4-피롤리딘-1-일-피페리딘-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -5-methoxy-phenyl} -3- (4-pyrrolidine -1-yl-piperidin-1-yl) -5-trifluoromethyl-benzamide,

1-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-[4-(2-메틸-이미다졸-1-일)-3-트리플루오로메틸-페닐]-우레아, 1- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- [4- (2-methyl -Imidazol-1-yl) -3-trifluoromethyl-phenyl] -urea,

1-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-[4-(4-에틸-피페라진-1-일메틸)-3-트리플루오로메틸-페닐]-우레아, 1- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- [4- (4-ethyl -Piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -urea,

피리다진-4-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, Pyridazine-4-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide,

2-클로로-N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-이소니코틴아미드, 2-chloro-N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -isonicotinamide,

푸란-2-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, Furan-2-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide,

1-메틸-1H-피롤-2-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 1-Methyl-1H-pyrrole-2-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl }-amides,

1H-이미다졸-2-카르복실산 (3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 1H-imidazole-2-carboxylic acid (3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide ,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4-trifluoromethyl-benzamide ,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4- 메틸-페닐}-6-메틸-니코틴아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4- methyl-phenyl} -6-methyl-nicotinamide,

1-tert-부틸-5-메틸-1H-피라졸-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 1-tert-butyl-5-methyl-1H-pyrazole-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino ] -4-methyl-phenyl} -amide,

N-[4-(4-에틸-피페라진-1-일메틸)-3-트리플루오로메틸-페닐]-4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- [4- (4-ethyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -4-methyl-3- {1- [6- (2-morpholin-4-yl -Ethylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -benzamide,

3-(4-메틸-이미다졸-1-일)-N-(4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-5-트리플루오로메틸-벤즈아미드, 3- (4-Methyl-imidazol-1-yl) -N- (4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl ] -1H-imidazol-2-ylamino} -phenyl) -5-trifluoromethyl-benzamide,

4-메틸-N-[4-(2-메틸-이미다졸-1-일)-3-트리플루오로메틸-페닐]-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, 4-Methyl-N- [4- (2-methyl-imidazol-1-yl) -3-trifluoromethyl-phenyl] -3- {1- [6- (2-morpholin-4-yl- Ethylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -benzamide,

N-(4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-(1-메틸-피페리딘-4-일옥시)-5-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl) -3- (1-methyl-piperidin-4-yloxy) -5-trifluoromethyl-benzamide,

피라진-2-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, Pyrazine-2-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide,

5-메틸-피라진-2-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 5-Methyl-pyrazine-2-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1 H-imidazol-2-ylamino] -4-methyl-phenyl}- amides,

퀴녹살린-6-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, Quinoxaline-6-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide,

5-tert-부틸-2-메틸-4-모르폴린-4-일메틸-푸란-3-카르복실산 {3-[1-(6-시클 로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 5-tert-butyl-2-methyl-4-morpholin-4-ylmethyl-furan-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H Imidazol-2-ylamino] -4-methyl-phenyl} -amide,

5-tert-부틸-2-메틸-2H-피라졸-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐)-아미드, 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino ] -4-methyl-phenyl) -amide,

2-벤질-5-tert-부틸-2H-피라졸-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 2-benzyl-5-tert-butyl-2H-pyrazole-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino ] -4-methyl-phenyl} -amide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(피페리딘-4-일아미노)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (piperidin-4- Monoamino) -5-trifluoromethyl-benzamide,

N-(3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(피롤리딘-2-일메톡시)-5-트리플루오로메틸-벤즈아미드, N- (3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (pyrrolidine-2- Monomethoxy) -5-trifluoromethyl-benzamide,

5-tert-부틸-2-메틸-푸란-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드,5-tert-butyl-2-methyl-furan-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4 -Methyl-phenyl} -amide,

5-tert-부틸-3-메틸-푸란-2-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 5-tert-Butyl-3-methyl-furan-2-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4 -Methyl-phenyl} -amide,

5-tert-부틸-2-디에틸아미노-푸란-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 5-tert-butyl-2-diethylamino-furan-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide,

5-tert-부틸-4-디에틸아미노-2-메틸-푸란-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 5-tert-butyl-4-diethylamino-2-methyl-furan-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazole-2 -Ylamino] -4-methyl-phenyl} -amide,

5-tert-부틸-티오펜-2-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 5-tert-Butyl-thiophene-2-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl- Phenyl} -amide,

5-tert-부틸-3-메틸-푸란-2-카르복실산 (4-메틸-3-{1-[6-(2-모르폴린-4-일- 에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-아미드, 5-tert-Butyl-3-methyl-furan-2-carboxylic acid (4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl ] -1H-imidazol-2-ylamino} -phenyl) -amide,

5-tert-부틸-티오펜-2-카르복실산 (4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-아미드,5-tert-Butyl-thiophene-2-carboxylic acid (4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1 H -Imidazol-2-ylamino} -phenyl) -amide,

5-tert-부틸-2-메틸-푸란-3-카르복실산 (4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-아미드, 5-tert-butyl-2-methyl-furan-3-carboxylic acid (4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl ] -1H-imidazol-2-ylamino} -phenyl) -amide,

N-(3-{1-[6-(4-아미노-시클로헥실아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (4-Amino-cyclohexylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -4-methyl-phenyl) -3-tri Fluoromethyl-benzamide,

N-(4-메틸-3-{1-[6-(피페리딘-4-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (piperidin-4-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl) -3- Trifluoromethyl-benzamide,

N-[4-메틸-3-(1-{6-[2-(4-메틸-피페라진-1-일)-에틸아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6- [2- (4-methyl-piperazin-1-yl) -ethylamino] -pyrimidin-4-yl} -1 H-imidazole-2- Monoamino) -phenyl] -3-trifluoromethyl-benzamide,

N-(3-{1-[6-(2,5-디메틸-2H-피라졸-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (2,5-dimethyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4- Methyl-phenyl) -3-trifluoromethyl-benzamide,

N-(4-메틸-3-{1-[6-(4-메틸-피페라진-1-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-methyl-3- {1- [6- (4-methyl-piperazin-1-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -phenyl) 3-trifluoromethyl-benzamide,

N-(4-메틸-3-{1-[6-(2-메틸-2H-피라졸-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-methyl-3- {1- [6- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino}- Phenyl) -3-trifluoromethyl-benzamide,

N-(3-{1-[6-(2,6-디메틸-피리딘-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (2,6-dimethyl-pyridin-3-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl ) -3-trifluoromethyl-benzamide,

N-(4-메틸-3-{1-[6-(2-메틸-피리딘-3-일아미노)-피리미딘-4-일]-1H-이미다졸 -2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (2-methyl-pyridin-3-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl)- 3-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(4-메틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (4-methyl-piperazine -1-yl) -5-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-[4-(2-히드록시-에틸)-피페라진-1-일]-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- [4- (2-hydrate Oxy-ethyl) -piperazin-1-yl] -5-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-피페라진-1-일-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-piperazin-1-yl- 5-trifluoromethyl-benzamide,

N-{4-클로로-3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-벤즈아미드, N- {4-Chloro-3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -benzamide,

N-(3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-플루오로-페닐}-벤즈아미드, N- (3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-fluoro-phenyl} -benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-메틸-페닐}-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-methyl-phenyl} -benzamide,

N-(5-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-플루오로-페닐}-벤즈아미드, N- (5- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-fluoro-phenyl} -benzamide,

N-{5-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-메틸-페닐}-벤즈아미드, N- {5- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-methyl-phenyl} -benzamide,

N-(4-클로로-3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-4-모르폴린-4-일메틸-3-트리플루오로메틸-벤즈아미드, N- (4-Chloro-3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -4-morpholin-4-ylmethyl 3-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-플루오로-페닐}-4-모르폴린-4-일메틸-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-fluoro-phenyl} -4-morpholin-4-yl Methyl-3-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-메틸-페닐}-4-모르폴린-4-일메틸-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-methyl-phenyl} -4-morpholin-4-ylmethyl 3-trifluoromethyl-benzamide,

N-{4-클로로-3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- {4-Chloro-3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl-3- (4-methyl-imidazole- 1-yl) -5-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-플루오로-페닐}-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-fluoro-phenyl} -3- (4-methyl-imi Dazol-1-yl) -5-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-메틸-페닐)-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-methyl-phenyl) -3- (4-methyl-imidazole -1-yl) -5-trifluoromethyl-benzamide,

N-{5-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-플루오로-페닐}-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- {5- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-fluoro-phenyl} -3- (4-methyl-imi Dazol-1-yl) -5-trifluoromethyl-benzamide,

N-{5-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-메틸-페닐}-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- {5- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-methyl-phenyl} -3- (4-methyl-imidazole -1-yl) -5-trifluoromethyl-benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메톡시-페닐}-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methoxy-phenyl} -benzamide,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤젠술폰아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benzenesulphone amides,

3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-N-(3-트리플루오로메틸-페닐)-벤젠술폰아미드, 3- [1- (6-Cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-N- (3-trifluoromethyl-phenyl) -benzenesulphone amides,

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-플루오로-페닐}-3-디메틸아미노-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-fluoro-phenyl} -3-dimethylamino-5-tri Fluoromethyl-benzamide,

N-{5-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-메틸-페닐}-3-디메틸아미노-5-트리플루오로메틸-벤즈아미드, N- {5- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-methyl-phenyl} -3-dimethylamino-5-trifluoro Chloromethyl-benzamide,

N-{4-클로로-3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-3-디메틸아미노-5-트리플루오로메틸-벤즈아미드, N- {4-Chloro-3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -3-dimethylamino-5-trifluoro Chloromethyl-benzamide,

3-(4-메틸-이미다졸-1-일)-N-(4-메틸-3-{1-[6-(피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-5-트리플루오로메틸-벤즈아미드, 3- (4-methyl-imidazol-1-yl) -N- (4-methyl-3- {1- [6- (pyridin-2-ylamino) -pyrimidin-4-yl] -1H-im Dazol-2-ylamino} -phenyl) -5-trifluoromethyl-benzamide,

4-(4-에틸-피페라진-1-일메틸)-N-(4-메틸-3-{1-[6-(피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, 4- (4-ethyl-piperazin-1-ylmethyl) -N- (4-methyl-3- {1- [6- (pyridin-2-ylamino) -pyrimidin-4-yl] -1H- Imidazol-2-ylamino} -phenyl) -3-trifluoromethyl-benzamide,

3-(4-에틸-피페라진-1-일)-N-(4-메틸-3-{1-[6-(피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-5-트리플루오로메틸-벤즈아미드, 3- (4-ethyl-piperazin-1-yl) -N- (4-methyl-3- {1- [6- (pyridin-2-ylamino) -pyrimidin-4-yl] -1H-im Dazol-2-ylamino} -phenyl) -5-trifluoromethyl-benzamide,

4-클로로-N-(4-메틸-3-{1-[6-(피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, 4-Chloro-N- (4-methyl-3- {1- [6- (pyridin-2-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl)- 3-trifluoromethyl-benzamide,

N-[3-(1-{6-[5-(4-에틸-피페라진-1-일)-피리딘-2-일아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-4-메틸-페닐]-3-트리플루오로메틸-벤즈아미드, N- [3- (1- {6- [5- (4-ethyl-piperazin-1-yl) -pyridin-2-ylamino] -pyrimidin-4-yl} -1H-imidazole-2- Monoamino) -4-methyl-phenyl] -3-trifluoromethyl-benzamide,

N-(4-메틸-3-{1-[6-(4-메틸-피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl)- 3-trifluoromethyl-benzamide,

N-(3-{1-[6-(4,6-디메틸-피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (4,6-dimethyl-pyridin-2-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl ) -3-trifluoromethyl-benzamide,

6-(6-{2-[2-메틸-5-(3-트리플루오로메틸-벤조일아미노)-페닐아미노]-이미다졸-1-일}-피리미딘-4-일아미노)-니코틴아미드, 6- (6- {2- [2-Methyl-5- (3-trifluoromethyl-benzoylamino) -phenylamino] -imidazol-1-yl} -pyrimidin-4-ylamino) -nicotinamide ,

N-(4-메틸-3-{1-[6-(5-메틸-피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (5-methyl-pyridin-2-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl)- 3-trifluoromethyl-benzamide,

N-(3-{1-[6-(5-시아노-피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (5-Cyano-pyridin-2-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) 3-trifluoromethyl-benzamide,

4-클로로-N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, 4-Chloro-N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoro Methyl-benzamide,

4-클로로-N-(4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, 4-Chloro-N- (4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino } -Phenyl) -3-trifluoromethyl-benzamide,

5-tert-부틸-2-메틸-2H-피라졸-3-카르복실산 (4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-아미드, 5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid (4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidine- 4-yl] -1H-imidazol-2-ylamino} -phenyl) -amide,

N-(3-{1-[6-(2-디메틸아미노-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (2-dimethylamino-ethylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) -3-tri Fluoromethyl-benzamide,

N-(4-메틸-3-{1-[6-(3-모르폴린-4-일-프로필아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (3-morpholin-4-yl-propylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl) 3-trifluoromethyl-benzamide,

N-(3-(1-[6-(2-메톡시-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- (1- [6- (2-methoxy-ethylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) -3-tri Fluoromethyl-benzamide,

N-[4-메틸-3-(1-{6-[2-(1-메틸-피롤리딘-2-일)-에틸아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6- [2- (1-methyl-pyrrolidin-2-yl) -ethylamino] -pyrimidin-4-yl} -1 H-imidazole-2 -Ylamino) -phenyl] -3-trifluoromethyl-benzamide,

N-(4-메틸-3-{1-[6-(피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (pyridin-2-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl) -3-trifluoro Chloromethyl-benzamide,

N-[4-메틸-3-(1-피리미딘-4-일-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-methyl-3- (1-pyrimidin-4-yl-1H-imidazol-2-ylamino) -phenyl] -3-trifluoromethyl-benzamide,

N-[4-메틸-3-(1-피리미딘-2-일-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-methyl-3- (1-pyrimidin-2-yl-1H-imidazol-2-ylamino) -phenyl] -3-trifluoromethyl-benzamide,

N-{4-메틸-3-[1-(4-메틸아미노-피리미딘-2-일)-1H-이미다졸-2-일아미노]-페닐}-3-트리플루오로메틸-벤즈아미드, N- {4-methyl-3- [1- (4-methylamino-pyrimidin-2-yl) -1H-imidazol-2-ylamino] -phenyl} -3-trifluoromethyl-benzamide,

N-{4-메틸-3-[1-(2-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-3-트리플루오로메틸-벤즈아미드, N- {4-methyl-3- [1- (2-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -3-trifluoromethyl-benzamide,

N-(4-메틸-3-{1-[4-(2-모르폴린-4-일-에틸아미노)-피리미딘-2-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [4- (2-morpholin-4-yl-ethylamino) -pyrimidin-2-yl] -1 H-imidazol-2-ylamino} -phenyl) 3-trifluoromethyl-benzamide,

N-(4-메틸-3-{1-[2-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [2- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl) 3-trifluoromethyl-benzamide,

N-(3-{1-[6-(2-에틸-2H-피라졸-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (2-ethyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl- Phenyl) -3-trifluoromethyl-benzamide,

N-(3-{1-[6-(3-디메틸아미노-프로필아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (3-dimethylamino-propylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) -3-tri Fluoromethyl-benzamide,

N-(3-[1-(6-이소프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, N- (3- [1- (6-isopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benzamide ,

N-[3-(1-(6-[(푸란-3-일메틸)-아미노]-피리미딘-4-일)-1H-이미다졸-2-일아미노)-4-메틸-페닐]-3-트리플루오로메틸-벤즈아미드, N- [3- (1- (6-[(furan-3-ylmethyl) -amino] -pyrimidin-4-yl) -1H-imidazol-2-ylamino) -4-methyl-phenyl]- 3-trifluoromethyl-benzamide,

N-[4-메틸-3-(1-(6-[3-(4-메틸-피페라진-1-일)-프로필아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- (6- [3- (4-methyl-piperazin-1-yl) -propylamino] -pyrimidin-4-yl} -1 H-imidazole-2- Monoamino) -phenyl] -3-trifluoromethyl-benzamide,

N-[3-(1-{6-[(벤조[1,3]디옥솔-5-일메틸)-아미노]피리미딘-4-일)-1H-이미다졸-2-일아미노)-4-메틸-페닐]-3-트리플루오로메틸-벤즈아미드, N- [3- (1- {6-[(benzo [1,3] dioxol-5-ylmethyl) -amino] pyrimidin-4-yl) -1H-imidazol-2-ylamino) -4 -Methyl-phenyl] -3-trifluoromethyl-benzamide,

N-(4-메틸-3-(1-[6-(2-메틸-6-모르폴린-4-일-피리딘-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- (1- [6- (2-methyl-6-morpholin-4-yl-pyridin-3-ylamino) -pyrimidin-4-yl] -1 H-imidazole- 2-ylamino} -phenyl) -3-trifluoromethyl-benzamide,

N-(4-메틸-3-{1-[6-(4-메틸-피리미딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-methyl-3- {1- [6- (4-methyl-pyrimidin-2-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -phenyl) 3-trifluoromethyl-benzamide,

N-(3-(1-[6-(6-메톡시-피리딘-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- (1- [6- (6-methoxy-pyridin-3-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) 3-trifluoromethyl-benzamide,

N-{4-메틸-3-[1-(6-모르폴린-4-일-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-3-트리플루오로메틸-벤즈아미드, N- {4-methyl-3- [1- (6-morpholin-4-yl-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -3-trifluoromethyl Benzamide,

N-(3-(1-[6-(4-에틸-피페라진-1-일)-피리미딘-4-일]-1H-이미다졸-2-일아미노)-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드,N- (3- (1- [6- (4-ethyl-piperazin-1-yl) -pyrimidin-4-yl] -1H-imidazol-2-ylamino) -4-methyl-phenyl)- 3-trifluoromethyl-benzamide,

N-(3-{1-[6-(3-플루오로-페닐아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (3-Fluoro-phenylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) -3-tri Fluoromethyl-benzamide,

N-(3-{1-[6-(3-디메틸아미노-에틸-포름아미드-페닐아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (3-Dimethylamino-ethyl-formamide-phenylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -4-methyl-phenyl ) -3-trifluoromethyl-benzamide,

N-[4-메틸-3-(1-{6-[(피리딘-3-일메틸)-아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6-[(pyridin-3-ylmethyl) -amino] -pyrimidin-4-yl} -1 H-imidazol-2-ylamino) -phenyl]- 3-trifluoromethyl-benzamide,

N-[4-메틸-3-(1-{6-[(피리딘-4-일메틸)-아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6-[(pyridin-4-ylmethyl) -amino] -pyrimidin-4-yl} -1 H-imidazol-2-ylamino) -phenyl]- 3-trifluoromethyl-benzamide,

N-(4-메틸-3-{1-[6-(4-모르폴린-4-일-피페리딘-1-일)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (4-morpholin-4-yl-piperidin-1-yl) -pyrimidin-4-yl] -1 H-imidazol-2-yl Amino} -phenyl) -3-trifluoromethyl-benzamide,

N-[4-메틸-3-(1-(6-[(티아졸-2-일메틸)-아미노]-피리미딘-4-일)-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- (6-[(thiazol-2-ylmethyl) -amino] -pyrimidin-4-yl) -1 H-imidazol-2-ylamino) -phenyl] 3-trifluoromethyl-benzamide,

N-[4-메틸-3-(1-{6-[(피리딘-2-일메틸)-아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6-[(pyridin-2-ylmethyl) -amino] -pyrimidin-4-yl} -1 H-imidazol-2-ylamino) -phenyl]- 3-trifluoromethyl-benzamide,

N-[4-메틸-3-(1-{6-[(6-메틸-피라진-2-일메틸)-아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-methyl-3- (1- {6-[(6-methyl-pyrazin-2-ylmethyl) -amino] -pyrimidin-4-yl} -1H-imidazol-2-ylamino) -Phenyl] -3-trifluoromethyl-benzamide,

N-(4-메틸-3-{1-[6-(4-피리딘-2-일-피페라진-1-일)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-methyl-3- {1- [6- (4-pyridin-2-yl-piperazin-1-yl) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -Phenyl) -3-trifluoromethyl-benzamide,

N-(3-{1-[6-(3-이미다졸-1-일-프로필아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (3-imidazol-1-yl-propylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) 3-trifluoromethyl-benzamide,

N-(4-메틸-3-{1-[6-(피라진-2-일)아미노-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-methyl-3- {1- [6- (pyrazin-2-yl) amino-pyrimidin-4-yl] -1H-imidazol-2-ylamino} -phenyl) -3-trifluoro Chloromethyl-benzamide,

N-(3-{1-[6-(3-포름아미드-페닐아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (3-formamide-phenylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) -3-tri Fluoromethyl-benzamide,

4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-N-(3-트리플루오로메틸-페닐)-벤즈아미드, 4-Methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -N- (3- Trifluoromethyl-phenyl) -benzamide,

4-메틸-3-{1-[6-(4-메틸-피페라진-1-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-N-(3-트리플루오로메틸-페닐)-벤즈아미드, 4-Methyl-3- {1- [6- (4-methyl-piperazin-1-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -N- (3- Trifluoromethyl-phenyl) -benzamide,

N-(4-클로로-3-트리플루오로메틸-페닐)-4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- (4-Chloro-3-trifluoromethyl-phenyl) -4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -benzamide,

N-(4-클로로-3-트리플루오로메틸-페닐)-4-메틸-3-{1-[6-(4-메틸-피페라진-1-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- (4-Chloro-3-trifluoromethyl-phenyl) -4-methyl-3- {1- [6- (4-methyl-piperazin-1-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -benzamide,

1-tert-부틸-5-(4-메틸-피페라진-1-일메틸)-1H-피라졸-3-카르복실산{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 1-tert-butyl-5- (4-methyl-piperazin-1-ylmethyl) -1H-pyrazole-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidine-4- Yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide,

1-tert-부틸-5-모르폴린-4-일메틸-1H-피라졸-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 1-tert-butyl-5-morpholin-4-ylmethyl-1H-pyrazole-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-already Dazol-2-ylamino] -4-methyl-phenyl} -amide,

N-(4-tert-부틸-티아졸-2-일)-4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- (4-tert-butyl-thiazol-2-yl) -4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -benzamide,

N-(4-tert-부틸-티아졸-2-일)-4-메틸-3-{1-[6-(4-메틸-피페라진-1-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- (4-tert-butyl-thiazol-2-yl) -4-methyl-3- {1- [6- (4-methyl-piperazin-1-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -benzamide,

N-(5-tert-부틸-2-메틸-2H-피라졸-3-일)-4-메틸-3-{1-[6-(4-메틸-피페라진-1-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -4-methyl-3- {1- [6- (4-methyl-piperazin-1-ylamino) -pyri Midin-4-yl] -1 H-imidazol-2-ylamino} -benzamide,

N-(4-메틸-3-{1-[6-(4-메틸-피페라진-1-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-벤즈아미드, N- (4-methyl-3- {1- [6- (4-methyl-piperazin-1-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -phenyl) Benzamide,

N-(5-tert-부틸-2-메틸-2H-피라졸-3-일)-4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyri Midin-4-yl] -1 H-imidazol-2-ylamino} -benzamide,

N-(4-메틸-3-{1-[2-(2-모르폴린-4-일-에틸아미노)-피리딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [2- (2-morpholin-4-yl-ethylamino) -pyridin-4-yl] -1 H-imidazol-2-ylamino} -phenyl)- 3-trifluoromethyl-benzamide,

N-{3-[1-(4-아세틸아미노-피리딘-2-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, 및N- {3- [1- (4-acetylamino-pyridin-2-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benzamide, and

2-{2-[2-메틸-5-(3-트리플루오로메틸-벤조일아미노)-페닐아미노]-이미다졸-1-일}-이소니코틴아미드.2- {2- [2-Methyl-5- (3-trifluoromethyl-benzoylamino) -phenylamino] -imidazol-1-yl} -isonicotinamide.

추가적인 본 발명의 바람직한 화합물은 하기 실시예 및 표 1에 상술한다.Further preferred compounds of the invention are detailed in the Examples and Table 1 below.

약리활성 및 용도Pharmacological activity and uses

본 발명의 화합물은 키나제의 활성을 조절하며, 그러므로 키나제가 질환의 병증 및(또는) 증상에 기여하는 질환 또는 장애를 치료하는데 유용하다. 본 명세서에 기재된 화합물 및 조성물로 억제되고, 본 명세서에 기재된 방법이 유용하게 작용하는 키나제의 예로는 Abl, BCR-Abl (야생형 및 돌연변이형), PDGF-R, trkB, c-SRC, BMX, FGFR3, b-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c- RAF, MKK6, SAPK2α 및 SAPK2β를 포함하나 이에 한정되지 않는다.The compounds of the present invention modulate the activity of kinases and are therefore useful for treating diseases or disorders in which kinases contribute to the symptoms and / or symptoms of the disease. Examples of kinases that are inhibited by the compounds and compositions described herein and in which the methods described herein work usefully include Abl, BCR-Abl (wild and mutant), PDGF-R, trkB, c-SRC, BMX, FGFR3 , b-RAF, SGK, Tie2, Lck, JNK2α2, MKK4, c-RAF, MKK6, SAPK2α and SAPK2β.

아벨슨 티로신 키나제 (즉, Abl, c-Abl)는 세포 주기 조절, 유전자 독성 스트레스에 대한 세포 반응, 및 내부 신호 전달을 통한 세포 내 환경에 대한 정보 전달에 관여한다. 전체적으로, Abl 단백질은 다양한 세포 내/외부 출처로부터의 신 호를 통합하고, 세포 주기 및 아폽토시스에 관한 결정에 영향을 미치는 세포 조절자로서의 복잡한 역할을 수행하는 것으로 보인다. 아벨슨 티로신 키나제는 아형 유도체, 예컨대 조절되지 않는 티로신 키나제 활성을 가지는 키메라 융합체 (발암단백질) BCR-Abl, 또는 v-Abl을 포함한다. BCR-Abl은 만성 골수성 백혈병 (CML)의 95% 및 급성 림프성 백혈병의 10%의 발병기작에 중요하다. STI-571 (글리벡)은 발암성 BCR-Abl 티로신 키나제의 억제제이고, 만성 골수성 백혈병 (CML)의 치료에 사용된다. 그러나, CML의 모구성 발증 단계에 있는 일부 환자는 BCR-Abl 키나제에 돌연변이가 생성되어 STI-571에 내성을 가진다. 현재까지 22종이 넘는 돌연변이체가 보고되었으며, 그 중 250E, E255V, T315I, F317L 및 M351T가 가장 흔하다. Abelson tyrosine kinases (ie, Abl, c-Abl) are involved in cell cycle regulation, cellular responses to genotoxic stress, and the transfer of information about the intracellular environment through internal signal transduction. Overall, the Abl protein appears to play a complex role as a cell regulator, integrating signals from various intracellular / external sources and influencing decisions regarding cell cycle and apoptosis. Abelson tyrosine kinases include subtype derivatives such as chimeric fusions (carcinogenic proteins) BCR-Abl, or v-Abl with unregulated tyrosine kinase activity. BCR-Abl is important for the pathogenesis of 95% of chronic myeloid leukemia (CML) and 10% of acute lymphocytic leukemia. STI-571 (Gleevec) is an inhibitor of oncogenic BCR-Abl tyrosine kinase and is used for the treatment of chronic myeloid leukemia (CML). However, some patients in the parental development phase of CML are mutated to BCR-Abl kinase and are resistant to STI-571. To date, more than 22 mutants have been reported, of which 250E, E255V, T315I, F317L and M351T are the most common.

본 발명의 화합물은 abl 키나제, 특히 v-abl 키나제를 억제한다. 본 발명의 화합물은 또한 야생형 BCR-Abl 키나제 및 BCR-Abl 키나제의 돌연변이체도 억제하며, 따라서 BCR-Abl-양성 암 또는 종양성 질환, 예컨대 백혈병 (특히 아폽토시스 기작이 작용하는 것으로 알려진 만성 골수성 백혈병 및 급성 림프성 백혈병)의 치료에 적합하며, 백혈병 줄기 세포의 하위군에 대해 효과가 있을 뿐만 아니라, 상기 세포를 제거하여 (예를 들어, 골수 제거) 시험관 내에서 이들 세포를 정제하고, 이들 세포로부터 암세포를 제거한 뒤 재이식하는 것에 대한 잠재성을 보여준다 (예를 들어, 정제된 골수 세포의 재이식).The compounds of the present invention inhibit abl kinases, in particular v-abl kinases. The compounds of the invention also inhibit mutants of wild-type BCR-Abl kinase and BCR-Abl kinase and are thus a BCR-Abl-positive cancer or neoplastic disease, such as leukemia (especially chronic myeloid leukemia and acute known to act on apoptosis mechanisms). Suitable for the treatment of lymphoid leukemia) and are effective against a subgroup of leukemia stem cells, as well as removing these cells (eg, removing bone marrow) to purify these cells in vitro, and from these cells to cancer cells. Shows potential for replanting after removal (eg, replanting of purified bone marrow cells).

Ras-Raf-MEK-ERK 신호전달 경로는 성장 신호에 대한 세포 반응을 매개한다. Ras는 인간 암의 약 15%에서 발암성 형태로 돌연변이된다. Raf 일족은 세린/트레오닌 단백질 키나제에 속하며, A-Raf, B-Raf 및 c-Raf (또는 Raf-1)의 3종의 구성 원을 포함한다. 약물 표적으로서 Raf는 Ras의 하류 이펙터로서의 관계에 대하여 관심이 집중되고 있다. 그러나, 최근의 데이터에서는, 활성화된 Ras 대립유전자를 필요로 하지 않는 특정 암의 형성에 B-Raf가 중요한 역할을 할지도 모른다는 것을 암시한다 (Nature 417,949 - 954(01 Jul 2002)). 특히, B-Raf 돌연변이는 대부분의 악성 흑색종에서 탐지된다.Ras-Raf-MEK-ERK signaling pathway mediates cellular response to growth signals. Ras is mutated to a carcinogenic form in about 15% of human cancers. The Raf family belongs to serine / threonine protein kinases and includes three members of A-Raf, B-Raf and c-Raf (or Raf-1). Raf as a drug target is of interest for its relationship as a downstream effector of Ras. However, recent data suggest that B-Raf may play an important role in the formation of certain cancers that do not require an activated Ras allele (Nature 417, 949-954 (01 Jul 2002)). In particular, B-Raf mutations are detected in most malignant melanoma.

현존하는 흑색종에 대한 치료법은 특히 말기 흑색종에 대한 효율에 국한되어 있다. 본 발명의 화합물은 또한 B-Raf 키나제가 관여하는 세포 기작도 억제하여, 인간 암, 특히 흑색종에 대한 새로운 치료 방법을 제공한다.Existing therapies for melanoma are limited to efficiency, especially for late melanoma. The compounds of the invention also inhibit the cellular mechanisms involved in B-Raf kinase, providing new methods of treatment for human cancers, especially melanoma.

본 발명의 화합물은 또한 c-Raf 키나제가 관여하는 세포 기작도 억제한다. c-Raf는 다수의 인간 암에서 돌연변이 되는 Ras 발암유전자에 의해 활성화된다. 따라서, c-Raf의 키나제 활성의 억제는 Ras 매개 종양 성장을 방지하는 방법을 제공할 수 있다 (Campbell, S. L., Oncogene, 17,1395(1998)). The compounds of the invention also inhibit the cellular mechanisms involved in c-Raf kinase. c-Raf is activated by the Ras oncogene, which is mutated in many human cancers. Thus, inhibition of kinase activity of c-Raf may provide a method for preventing Ras mediated tumor growth (Campbell, S. L., Oncogene, 17, 1395 (1998)).

PDGF (혈소판-연관 성장인자)는 정상적인 성장과 병리학적 세포 증식 양자 모두에 중요한 역할을 하는 흔히 분비되는 성장인자로서, 예컨대 발암현상 및 혈관의 평활근 세포의 질환, 예를 들어 죽상동맥경화증 및 혈전증에서 나타난다. 본 발명의 화합물은 PDGF 수용체 (PDGFR) 활성을 억제할 수 있고, 따라서 종양 질환, 예컨대 신경아교종, 육종, 전립선 종양, 및 결장, 유방 및 난소 종양의 치료에 적합하다.PDGF (platelet-associated growth factor) is a commonly secreted growth factor that plays an important role in both normal growth and pathological cell proliferation, such as in carcinogenesis and disease of vascular smooth muscle cells, such as atherosclerosis and thrombosis. appear. The compounds of the present invention can inhibit PDGF receptor (PDGFR) activity and are therefore suitable for the treatment of tumor diseases such as glioma, sarcoma, prostate tumors, and colon, breast and ovarian tumors.

본 발명의 화합물은 예를 들어 소세포 폐암에서 종양 억제제로 사용될 뿐만 아니라, 비-악성 증식성 장애, 예컨대 죽상동맥경화증, 혈전증, 건선, 공피증 및 섬유증, 및 화학요법제, 예컨대 5-플루오로우라실의 혈액독성 효과에 대항하는 줄기 세포의 보호, 및 천식에 사용될 수 있다. 본 발명의 화합물은 특히 PDGF 수용체 키나제의 억제에 반응하는 질환의 치료에 사용할 수 있다.The compounds of the invention are not only used as tumor suppressors, for example in small cell lung cancer, but also non-malignant proliferative disorders such as atherosclerosis, thrombosis, psoriasis, scleroderma and fibrosis, and chemotherapeutic agents such as 5-fluorouracil Can be used for the protection of stem cells against the hematotoxic effects of, and asthma. The compounds of the present invention can be used in particular for the treatment of diseases which respond to the inhibition of PDGF receptor kinases.

본 발명의 화합물은 이식의 결과로 발생하는 장애, 예를 들어, 동종 이식, 특히 조직 거부 반응, 예컨대, 동종 폐 이식체의 만성 거부반응인 폐색 세기관지염 (OB)의 치료에 유효한 효과를 나타낸다. OB를 나타내지 않는 환자와 달리, OB를 가진 환자들은 종종 기관지 폐포액에 상승된 PDGF 농도를 나타낸다. The compounds of the present invention show an effective effect in the treatment of disorders resulting from transplantation, for example, allograft, particularly tissue rejection, such as obstructive bronchiolitis (OB), which is a chronic rejection of allograft lung transplants. Unlike patients who do not exhibit OB, patients with OB often exhibit elevated PDGF concentrations in bronchoalveolar fluid.

본 발명의 화합물은 또한 혈관 평활근 세포 이동 및 증식 (PDGF 및 PDGF-R도 종종 중요한 역할을 수행함)과 연관된 질환, 예컨대 재협착 및 죽상동맥경화증에도 효과적이다. 본 발명의 화합물을 투여하고, 생체내의 기계적 손상에 따르는 혈관 내막의 비후에 대한 그 효과를 조사함으로써, 혈관 평활근 세포의 증식 또는 이동에 대한 이러한 효과 및 그 시험관내 및 생체내 결과가 예증될 수 있다.The compounds of the present invention are also effective in diseases associated with vascular smooth muscle cell migration and proliferation (PDGF and PDGF-R often play an important role), such as restenosis and atherosclerosis. By administering a compound of the present invention and investigating its effect on thickening of vascular endothelium following mechanical damage in vivo, such effects on the proliferation or migration of vascular smooth muscle cells and their in vitro and in vivo results can be illustrated. .

뉴로트로핀 수용체 (trkA, trkB, trkC)의 trk 일족은 신경 및 비-신경 조직의 생존, 성장 및 분화를 촉진한다. TrkB 단백질은 소장 및 결장, 이자의 알파 세포, 림프절 및 비장의 단핵구 및 대식세포, 및 표피의 과립층의 신경내분비형 세포에서 발현된다 (Shibayama and Koizumi, 1996). TrkB 단백질의 발현은 윌름즈 종양 및 신경모세포종의 부정적인 진행과 연관되어 있다. 또한, TkrB는 정상 세포가 아니라 암성 전립선 세포에서 발현된다. trk 수용체의 신호 전달 경로는 Shc, 활성화된 Ras, ERK-1 및 ERK-2 유전자, PLC-감마 전달 경로를 통한 MAPK 활성화 캐스캐이드를 포함한다 (Sugimoto et al., 2001).The trk family of neurotropin receptors (trkA, trkB, trkC) promotes survival, growth and differentiation of neuronal and non-neuronal tissues. TrkB protein is expressed in the small intestine and colon, alpha cells of interest, monocytes and macrophages of lymph nodes and spleen, and neuroendocrine cells of the granular layer of the epidermis (Shibayama and Koizumi, 1996). Expression of the TrkB protein is associated with negative progression of Wilms' tumors and neuroblastomas. In addition, TkrB is expressed in cancerous prostate cells, not normal cells. Signal transduction pathways for trk receptors include the Shc, activated Ras, ERK-1 and ERK-2 genes, MAPK activation cascade via PLC-gamma transduction pathways (Sugimoto et al., 2001).

키나제인 c-Src는 많은 수용체의 발암성 신호를 전달한다. 예를 들어, 종양에서 EGFR 또는 HER2/neu의 과발현은 정상 세포에서는 나타나지 않는 악성 세포의 특징인 c-src의 활성화 유지로 이어진다. 반면, c-src가 발현되지 않는 마우스는 골화 표현형을 나타내고, 이는 c-src가 파골세포 기능에 중요한 역할을 하며, 관련 장애에도 관여할 수 있음을 나타낸다.The kinase c-Src carries carcinogenic signals of many receptors. For example, overexpression of EGFR or HER2 / neu in tumors leads to the maintenance of activation of c-src, which is characteristic of malignant cells that do not appear in normal cells. On the other hand, mice without c-src expression exhibit an osteogenic phenotype, indicating that c-src plays an important role in osteoclast function and may be involved in related disorders.

Tec 일족 키나제, Bmx, 비-수용체 단백질-티로신 키나제는 유선 상피 암 세포의 증식을 조절한다. Tec family kinase, Bmx, non-receptor protein-tyrosine kinase regulates proliferation of mammary epithelial cancer cells.

섬유모세포 성장인자 수용체 3은 골 성장 및 연골세포 증식의 억제에 음성 조절 효과를 발휘하는 것으로 나타났다. 치사성 형성이상은 섬유모세포 성장인자 수용체 3에 발생하는 상이한 돌연변이에 의하여 발생하며, 그 중 TDII FGFR3은 전사 인자 Stat1을 활성화하여 세포-주기 억제제의 발현, 성장 멈춤 및 비정상적인 골 형성을 야기하는, 계속적인 티로신 키나제 활성을 가진다 (Su et al. , Nature, 1997,386, 288-292). FGFR3는 또한 종종 다발성 골수종-형 암에서도 발현된다. FGFR3 활성의 억제제는 류마티스 관절염 (RA), 콜라겐 II 관절염, 다발성 경화증 (MS), 전신성 홍반 루푸스 (SLE), 건선, 소아 발병 당뇨병, 쇼그렌(Sjogren) 병, 갑상선 질환, 사코이드증, 자가면역성 포도막염, 염증성 장 질환 (크론(Crohn)병 및 궤양대장염), 만성소화장애증 및 중증근육무력증을 포함하나, 이에 한정되지 않는 T-세포 매개 염증성 또는 자가면역성 질환의 치료에 유용하다.Fibroblast growth factor receptor 3 has been shown to exert a negative regulatory effect on the inhibition of bone growth and chondrocyte proliferation. Lethal dysplasia is caused by different mutations occurring in fibroblast growth factor receptor 3, of which TDII FGFR3 activates the transcription factor Stat1, which leads to expression of cell-cycle inhibitors, growth arrest and abnormal bone formation. Have tyrosine kinase activity (Su et al., Nature, 1997,386, 288-292). FGFR3 is also often expressed in multiple myeloma-type cancers. Inhibitors of FGFR3 activity include rheumatoid arthritis (RA), collagen II arthritis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), psoriasis, childhood onset diabetes, Sjogren's disease, thyroid disease, sarcoidosis, autoimmune uveitis Useful for the treatment of T-cell mediated inflammatory or autoimmune diseases including, but not limited to, inflammatory bowel disease (Crohn's disease and ulcerative colitis), chronic digestive disorders and myasthenia gravis.

혈청 및 글루코코르티코이드-조절 키나제 (SGK)의 활성은 변동적인 이온 채널, 특히 나트륨 및(또는) 칼륨 채널 활동과 연관이 있으며, 본 발명의 화합물은 고혈압을 치료하는데 유용할 수 있다.The activity of serum and glucocorticoid-regulated kinase (SGK) is associated with variable ion channel, especially sodium and / or potassium channel activity, and the compounds of the present invention may be useful for treating hypertension.

문헌[Lin et al(1997) J. Clin. Invest. 100,8: 2072-2078 and P. Lin (1998) PNAS 95, 8829-8834]은 유방 종양 및 흑색종 이종이식 모델에 Tie-2 (Tek) 세포외부 도메인을 주사하거나, 아데노 바이러스를 감염시킬 때, 종양 성장 및 혈관화의 억제 및 폐 전이의 감소를 보인 바 있다. Tie2 억제제는 부적절한 혈관신생증식 일어나는 상황 (즉, 당뇨성 망막병증, 만성 염증, 건선, 카포시 육종, 및 류마티스 관절염, 유아 혈관종 및 암으로 인해 만성 혈관신생증식이 일어나는 경우)에 사용될 수 있다.Lin et al (1997) J. Clin. Invest. 100,8: 2072-2078 and P. Lin (1998) PNAS 95, 8829-8834, when injected with Tie-2 (Tek) extracellular domains or infecting adenoviruses in breast tumor and melanoma xenograft models , Inhibition of tumor growth and vascularization, and reduction of lung metastasis. Tie2 inhibitors can be used in situations where inappropriate angiogenesis occurs (ie, diabetic retinopathy, chronic inflammation, psoriasis, Kaposi's sarcoma, and chronic angiogenesis due to rheumatoid arthritis, infantile hemangioma and cancer).

Lck는 T-세포 신호 전달에 참여한다. Lck 유전자가 없는 마우스에서는 흉선세포가 제대로 발달되지 않았다. T-세포 신호 전달의 양성 활성화제로서의 Lck의 기능은 Lck 억제제가 자가면역성 질환, 예컨대 류마티스 관절염을 치료하는데 유용할 수 있다는 것을 암시한다.Lck participates in T-cell signaling. Thymic cells did not develop properly in mice without the Lck gene. The function of Lck as a positive activator of T-cell signalling suggests that Lck inhibitors may be useful for treating autoimmune diseases such as rheumatoid arthritis.

JNK 및 기타 MAPK는 암, 트롬빈-유도 혈소판 응집, 면역결핍성 장애, 자가면역성 질환, 세포 사멸, 알레르기, 골다공증 및 심장 질환으로의 세포 반응을 매개하는데 관여하는 것으로 알려졌다. JNK 경로의 활성화와 관련된 치료적 표적은 만성 골수성 백혈병 (CML), 류마티스 관절염, 천식, 골관절염, 허혈, 암 및 신경퇴행성 질환을 포함한다. 간 질환 또는 간 허혈과 연관된 JNK 활성화의 중요성의 결과로서, 본 발명의 화합물은 다양한 간 장애를 치료하는데도 유용할 수 있다. 심혈관 질환, 예컨대 심근경색증 또는 울혈성 심부전증에서, JNK의 역할은 다양한 형태의 심장 스트레스로의 비대 반응을 매개하는 것임이 보고되었다. JNK 캐스캐이드 는 또한 IL-2 프로모터 불활성화를 포함하는 T-세포 활성화에도 관여하는 것이 예증되었다. 따라서, JNK 억제제는 병리학적 면역 반응을 개선하는 치료적 가치를 가질 수 있다. 다양한 암에서 JNK 활성화의 역할 또한 확립되었는데, 암에서 JNK 억제제가 사용될 수 있음을 암시한다. 예를 들어서, 항상 활성화되는 JNK는 HTLV-1 매개 종양발생과 연관되어 있다 (Oncogene 13:135-42 (1996)). JNK는 카포시 육종 (KS)에 관여할 수 있다. KS 증식에 관여하는 다른 시토킨, 예컨대 혈관 상피 성장인자 (VEGF), IL-6 및 TNFα의 기타 증식 효과도 JNK에 의하여 매개되는 것일 수도 있다.JNK and other MAPKs are known to be involved in mediating cellular responses to cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and heart disease. Therapeutic targets associated with activation of the JNK pathway include chronic myeloid leukemia (CML), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer and neurodegenerative diseases. As a result of the importance of JNK activation associated with liver disease or liver ischemia, the compounds of the present invention may also be useful for treating various liver disorders. In cardiovascular diseases such as myocardial infarction or congestive heart failure, the role of JNK has been reported to mediate hypertrophy response to various forms of cardiac stress. JNK cascade has also been demonstrated to be involved in T-cell activation, including IL-2 promoter inactivation. Thus, JNK inhibitors may have therapeutic value to improve pathological immune responses. The role of JNK activation in various cancers has also been established, suggesting that JNK inhibitors can be used in cancer. For example, always activated JNK is associated with HTLV-1 mediated oncogenesis (Oncogene 13: 135-42 (1996)). JNK may be involved in Kaposi's sarcoma (KS). Other proliferative effects of other cytokines involved in KS proliferation such as vascular epithelial growth factor (VEGF), IL-6 and TNFα may also be mediated by JNK.

또한, p210 BCR-ABL 변형된 세포에서 c-jun 유전자의 조절은 JNK 활성에 상응하며, 이는 만성 골수성 백혈병 (CML)의 치료에서 JNK 억제제의 역할을 암시하는 것이다 (Blood 92: 2450-60 (1998)).In addition, the regulation of the c-jun gene in p210 BCR-ABL modified cells corresponds to JNK activity, suggesting the role of JNK inhibitors in the treatment of chronic myeloid leukemia (CML) (Blood 92: 2450-60 (1998). )).

특정 비정상적인 증식 증상은 raf 발현과 연관되어 있다고 보이며, 따라서 raf 발현 억제에 반응할 것으로 여겨진다. 비정상적으로 높은 수준의 raf 단백질 발현 또한 변형 및 비정상적인 세포 증식과 연관되어 있다. 이러한 비정상적인 증식 증상은 또한 raf 발현 억제에 반응할 것으로 여겨진다. 예를 들어, c-raf 단백질의 발현은 모든 폐 암종 세포주의 60%가 비정상적으로 높은 수준의 c-raf mRNA 및 단백질을 발현한다고 보고 되었기 때문에, 비정상적 세포 증식에 관여할 것으로 여겨진다. 비정상적 증식 증상의 다른 예로는, 과증식성 장애, 예컨대 암, 종양, 과다형성, 폐 섬유증, 혈관신생, 죽상동맥경화증 및 혈관벽에서의 평활근 세포 증식, 예컨대 혈관성형술 후의 협착증 또는 재협착이다. raf가 관여하는 세포적 신 호 전달 경로는 또한 T-세포 증식 (T-세포 활성화 및 성장)으로 특징지워지는 염증성 장애, 예컨대 조직 이식편 거부 반응, 내독소 쇼크 및 사구체 신염과도 연관된다.Certain abnormal proliferative symptoms appear to be associated with raf expression and are therefore expected to respond to raf expression inhibition. Abnormally high levels of raf protein expression are also associated with alterations and abnormal cell proliferation. These abnormal proliferative symptoms are also believed to respond to inhibition of raf expression. For example, the expression of c-raf protein is believed to be involved in abnormal cell proliferation since 60% of all lung carcinoma cell lines have been reported to express abnormally high levels of c-raf mRNA and protein. Other examples of abnormal proliferative symptoms are hyperproliferative disorders such as cancer, tumors, hyperplasia, pulmonary fibrosis, angiogenesis, atherosclerosis and smooth muscle cell proliferation in the vessel wall, such as stenosis or restenosis after angioplasty. The cellular signal transduction pathway in which raf is involved is also associated with inflammatory disorders characterized by T-cell proliferation (T-cell activation and growth), such as tissue graft rejection, endotoxin shock and glomerulonephritis.

스트레스-활성화 단백질 키나제 (SAPK)는 c-jun 전사 인자의 활성화 및 c-jun에 의해 조절되는 유전자 발현을 야기하는 신호 전달 경로에서 마지막에서 두번째 단계인 단백질 키나제의 일족이다. 특히, c-jun은 유전자 독성에 의하여 손상되는 DNA의 복구에 관여하는 단백질을 코딩하는 유전자의 전사에 관여한다. 따라서, 세포에서 SAPK 활성을 억제하는 약물은 DNA 복구를 막고, DNA 손상을 유도하거나 DNA 합성을 막고 세포의 아폽토시스를 유도하는 약물 또는 세포 증식을 억제하는 약물에 세포가 감작되도록 한다.Stress-activated protein kinases (SAPKs) are a family of protein kinases that are the last to second step in the signal transduction pathway leading to the activation of c-jun transcription factors and gene expression regulated by c-jun. In particular, c-jun is involved in the transcription of genes encoding proteins involved in the repair of DNA damaged by genotoxicity. Thus, a drug that inhibits SAPK activity in a cell prevents DNA repair, and causes the cell to be sensitized to a drug that inhibits DNA repair, prevents DNA synthesis or inhibits cell proliferation, or a drug that inhibits cell apoptosis.

미토겐-활성화 단백질 키나제 (MAPK)는 다양한 세포외부 신호에 대응하여 전사 인자, 번역 인자 및 다른 표적 분자를 활성화하는 보존적인 신호 전달 경로의 구성원이다. MAPK는 미토겐-활성화 단백질 키나제 키나제 (MKK)에 의하여, Thr-X-Tyr의 서열을 가지는 2개의 인산화 모티프에 인산화됨으로서 활성화된다. 고등 진핵생물에서, MAPK 신호 전달의 생리학적 역할은 세포성 사건, 예컨대 증식, 발암, 발생 및 분화와 연관되어 있다. 따라서, 이들 경로 (특히, MKK4 및 MKK6)를 통한 신호 전달을 조절하는 능력은 MAPK 신호 전달과 연관된 인간 질환, 예컨대 염증성 질환, 자가면역성 질환 및 암의 치료 및 예방 방법을 제공할 수 있다.Mitogen-activated protein kinases (MAPKs) are members of conservative signal transduction pathways that activate transcription factors, translation factors, and other target molecules in response to various extracellular signals. MAPK is activated by phosphorylation by mitogen-activated protein kinase kinase (MKK) to two phosphorylation motifs having the sequence of Thr-X-Tyr. In higher eukaryotes, the physiological role of MAPK signaling is associated with cellular events such as proliferation, carcinogenesis, development and differentiation. Thus, the ability to modulate signal transduction through these pathways (particularly MKK4 and MKK6) may provide a method for the treatment and prevention of human diseases associated with MAPK signal transduction, such as inflammatory diseases, autoimmune diseases and cancer.

인간 리보솜 S6 단백질 키나제 일족은 8개 이상의 구성원 (RSK1, RSK2, RSK3, RSK4, MSKI, MSK2, p70S6K 및 p70S6 Kb)으로 이루어진다. 리보솜 S6 단백질 키나제는 중요한 다면성발현 작용을 하며, 특히 단백질 생합성 중 mRNA 번역의 조절에 중요한 역할을 한다 (Eur. J. Biochem 2000 November; 267(21): 6321-30, Exp Cell Res. Nov. 25,1999; 253 (1) :100-9, Mol Cell Endocrinol. May 25,1999;151(1-2):65-77). p70S6에 의한 리보솜 S6 단백질의 인산화는 세포 사멸 (Immunol. Cell Biol. 2000 August;78(4):447-51) 및 세포 성장 (Prog. Nucleic Acid Res. Mol. Biol., 2000;65:101-27) 조절에도 연관되므로, 종양 전이, 면역 반응 및 조직 회복과 기타 질환 증상에 중요할 수 있다.The human ribosomal S6 protein kinase family consists of at least eight members (RSK1, RSK2, RSK3, RSK4, MSKI, MSK2, p70S6K and p70S6 Kb). Ribosome S6 protein kinases play an important polyhedral expression, especially in the regulation of mRNA translation during protein biosynthesis (Eur. J. Biochem 2000 November; 267 (21): 6321-30, Exp Cell Res. Nov. 25 , 1999; 253 (1): 100-9, Mol Cell Endocrinol.May 25,1999; 151 (1-2): 65-77). Phosphorylation of ribosomal S6 protein by p70S6 resulted in cell death (Immunol. Cell Biol. 2000 August; 78 (4): 447-51) and cell growth (Prog. Nucleic Acid Res. Mol. Biol., 2000; 65: 101- 27) It is also involved in regulation and may be important for tumor metastasis, immune response and tissue recovery and other disease symptoms.

SAPK ("jun N-말단 키나제" 또는 "JNK"로도 불리움)은 c-jun 전사 인자의 활성화와 c-jun에 의해 조절되는 유전자 발현을 일으키는 신호 전달 경로의 끝에서 두번째 단계에 해당하는 단백질 키나제 일족이다. 특히, c-jun은 유전자 독성에 의하여 손상되는 DNA의 복구에 관여하는 단백질을 코딩하는 유전자의 전사에 관여한다. 세포에서 SAPK 활성을 억제하는 약물은 DNA 복구를 막고, DNA 손상을 유도하거나 DNA 합성을 막고 세포의 아폽토시스를 유도하는 약물 또는 세포 증식을 억제하는 약물에 세포가 감작되도록 한다.SAPK (also called "jun N-terminal kinase" or "JNK") is a protein kinase family that corresponds to the second stage at the end of the signaling pathway that leads to the activation of c-jun transcription factors and gene expression regulated by c-jun. to be. In particular, c-jun is involved in the transcription of genes encoding proteins involved in the repair of DNA damaged by genotoxicity. Drugs that inhibit SAPK activity in the cell prevent DNA repair, induce cell sensitization to drugs that inhibit DNA proliferation or prevent DNA synthesis and induce cell apoptosis or drugs that inhibit cell proliferation.

BTK는 자가면역성 및(또는) 염증성 질환, 예컨대 전신성 홍반 루푸스 (SLE), 류마티스 관절염, 다발성 맥관염, 특발성 혈소판 감소성 자반병 (ITP), 중증근육무력증 및 천식에 관여한다. BTK의 B-세포 활성화에의 역할 때문에, BTK의 억제는 B-세포 매개 병리 활성, 예컨대 자가항체 생산에 대한 억제제로 유용하고, B-세포 림프종 및 백혈병의 치료에 유용하다.BTK is involved in autoimmune and / or inflammatory diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis and asthma. Because of its role in B-cell activation, the inhibition of BTK is useful as an inhibitor for B-cell mediated pathological activity such as autoantibody production and for the treatment of B-cell lymphoma and leukemia.

CHK2는 세린/트레오닌 단백질 키나제의 체크포인트 키나제 일족의 구성원이 며, DNA 손상, 예컨대 외래 돌연변이 유도물질 및 내생 반응성 산소종에 의한 손상의 감시에 이용되는 기작에 관여한다. 결과적으로, CHK2는 종양 억제자 및 암 치료의 표적일 것이다.CHK2 is a member of the checkpoint kinase family of serine / threonine protein kinases and is involved in the mechanisms used to monitor DNA damage, such as damage by foreign mutant inducers and endogenous reactive oxygen species. As a result, CHK2 will be a target of tumor suppressor and cancer treatment.

CSK는 암 세포, 특히 결장암의 전이 잠재성에 영향을 미친다.CSK affects the metastatic potential of cancer cells, especially colon cancer.

Fes는 다양한 시토킨 신호 전달 경로와 골수 세포의 분화에 관여하는 비-수용체 단백질 티로신 키나제이다. Fes는 또한 과립구 분화 기작의 주요한 요소이기도 하다.Fes is a non-receptor protein tyrosine kinase involved in various cytokine signal transduction pathways and differentiation of bone marrow cells. Fes is also a major component of granulocyte differentiation mechanism.

Flt3 수용체 티로신 키나제 활성은 백혈병 및 골수형성이상증후군에 관여한다. 약 25%의 AML에서, 백혈병 세포는 세포 표면에 자가-인산화된 (p) FLT3 티로신 키나제를 활성이 유지되는 형태로 발현한다. p-FLT3의 활성은 백혈병 세포에 성장 및 생존이라는 장점을 부여한다. 백혈병 세포에서 p-FLT3 키나제 활성이 발현되는 급성 백혈병에 걸린 환자들은 전체적으로 좋지 않은 임상적 결과를 나타낸다. p-FLT3 키나제 활성의 억제는 백혈병 세포의 아폽토시스 (프로그램된 세포 사멸)를 유도한다.Flt3 receptor tyrosine kinase activity is involved in leukemia and myelodysplastic syndrome. At about 25% AML, leukemia cells express self-phosphorylated (p) FLT3 tyrosine kinase in a form that maintains activity on the cell surface. The activity of p-FLT3 confers advantages of growth and survival to leukemia cells. Patients with acute leukemia, whose p-FLT3 kinase activity is expressed in leukemia cells, have poor overall clinical results. Inhibition of p-FLT3 kinase activity leads to apoptosis (programmed cell death) of leukemia cells.

IKKα 및 IKKβ (1 및 2)의 억제제는 류마티스 관절염, 이식 거부 반응, 염증성 장 질환, 골관절염, 천식, 만성 폐쇄 폐 질환, 죽상동맥경화증, 건선, 다발성 경화증, 뇌졸중, 전신성 홍반 루푸스, 알츠하이머병, 뇌 허혈, 외상성 뇌 손상, 파킨슨병, 근위축성 측삭 경화증, 지주막하 출혈을 포함하는 질환, 또는 뇌 및 중추 신경계에 염증성 매개체가 과도하게 생산되는 것과 연관있는 기타 질환 또는 장애의 치료제이다.Inhibitors of IKKα and IKKβ (1 and 2) are rheumatoid arthritis, transplant rejection, inflammatory bowel disease, osteoarthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, psoriasis, multiple sclerosis, stroke, systemic lupus erythematosus, Alzheimer's disease, brain Therapeutic agents for ischemia, traumatic brain injury, Parkinson's disease, amyotrophic lateral sclerosis, subarachnoid hemorrhage, or other diseases or disorders associated with excessive production of inflammatory mediators in the brain and central nervous system.

Met는 주요 인간 암의 대부분의 유형과 연관되어 있으며, 그 발현은 종종 불량한 예후 및 전이와 연관된다. Met의 억제제는 암, 예컨대 폐암, NSCLC (비-소세포 폐암), 골암, 이자암, 피부암, 두부 및 경부의 암, 피부 또는 안구 흑색종, 자궁암, 난소암, 직장암, 항문 부위의 암, 위암, 결장암, 유방암, 부인과 종양 (예를 들어, 자궁 육종, 난관 암종, 자궁내막 암종, 자궁경부 암종, 질 암종 또는 음문 암종), 호지킨병, 식도암, 소장암, 내분비계 암 (예를 들어, 갑상선암, 부갑상선암 또는 부신암), 연조직 육종, 요도암, 음경암, 전립선 암, 만성 또는 급성 백혈병, 아동기의 고체 종양, 림프성 림프종, 방광암, 신장 또는 요관암 (예를 들어, 신세포 암종, 신우 암종), 소아과암, 중추 신경계의 종양 (예를 들어, 원발성 CNS 림프종, 척추 축 종양, 뇌간 신경아교종 또는 뇌하수체선종), 혈액암, 예컨대 급성 골수성 백혈병, 만성 골수성 백혈병 등; 바레트 식도 (전-악성 증후군); 종양성 피부병; 건선; 균상식육종 및 양성 전립선 비대증; 당뇨관련질환, 예컨대 당뇨성 망막병증, 신허혈 및 신장혈관신생증식; 간경화증; 심혈관 질환, 예컨대 죽상동맥경화증; 면역성 질환, 예컨대 자가면역성 질환 및 신장 질환을 포함하는 질환의 치료제이다. 바람직하게는, 상기 질환은 암, 예컨대 급성 골수성 백혈병 및 직장결장암이다. Met is associated with most types of major human cancers, and its expression is often associated with poor prognosis and metastasis. Inhibitors of Met include cancers such as lung cancer, NSCLC (non-small cell lung cancer), bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or ocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, Colon cancer, breast cancer, gynecological tumors (e.g., uterine sarcoma, tubal carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma or vulvar carcinoma), Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer (e.g. thyroid cancer) , Parathyroid cancer or adrenal cancer), soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, solid tumors in childhood, lymphoid lymphoma, bladder cancer, kidney or ureter cancers (eg renal cell carcinoma, pyelonephritis) Carcinoma), pediatric cancer, tumors of the central nervous system (eg primary CNS lymphoma, spinal axis tumor, brain stem glioma or pituitary adenoma), hematological cancers such as acute myeloid leukemia, chronic myeloid leukemia and the like; Barrett's esophagus (pre-malignant syndrome); Neoplastic skin disease; psoriasis; Atherosclerosis and benign prostatic hyperplasia; Diabetes related diseases such as diabetic retinopathy, renal ischemia and renal angiogenesis; Cirrhosis of the liver; Cardiovascular diseases such as atherosclerosis; Therapeutic agents for diseases including immune diseases such as autoimmune diseases and kidney diseases. Preferably, the disease is cancer such as acute myeloid leukemia and colorectal cancer.

Nima-관련 키나제 2 (Nek2)는 유사분열 개시시에 최대 활성을 보이는, 중심체에 편재하는 세포 주기-조절 단백질 키나제이다. 기능 연구에 의하여, Nek2가 중심체 분리 및 방추사 생성의 조절에 관여한다는 것이 알려졌다. Nek2 단백질은 경부, 난소, 전립선 및 특히 유방암을 포함하는 다양한 범위의 인간 종양으로부터 유래한 세포주에서 2 내지 5배 상승한다.Nima-associated kinase 2 (Nek2) is a cell cycle-regulating protein kinase ubiquitous in the centrosome that exhibits maximal activity at the onset of mitosis. Functional studies have shown that Nek2 is involved in the regulation of centrosome separation and spindle production. Nek2 protein is elevated two to five times in cell lines derived from a wide range of human tumors, including the cervical, ovarian, prostate and particularly breast cancers.

p70S6K-매개 질환 또는 증상으로는 증식성 장애, 예컨대 암 및 결절성 경화증을 포함하나 이에 한정되지 않는다.p70S6K-mediated diseases or symptoms include, but are not limited to, proliferative disorders such as cancer and nodular sclerosis.

전술한 바에 따라, 본 발명은 화학식 I의 화합물 또는 그의 제약적으로 허용가능한 염의 치료적 유효량 (하기 "투여 및 제약 조성물"을 참조)을 상기 기재한 질환 또는 장애의 치료를 필요로 하는 대상에게 투여하는 것을 포함하는, 상기 대상에서 상기 질환 또는 장애를 예방 또는 치료하는 방법을 추가로 제공한다. 상기 기재한 것 중 임의의 용도를 위하여, 필요한 투여량은 투여 방식, 치료할 특정 증상 및 원하는 효과에 따라 달라질 것이다.As described above, the present invention provides a method of administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (see "Administration and Pharmaceutical Composition" below) to a subject in need thereof. Further comprising a method of preventing or treating said disease or disorder in said subject. For any of the above-described uses, the dosage required will depend upon the mode of administration, the particular condition to be treated and the effect desired.

투여 및 제약 조성물 Dosing and Pharmaceutical Compositions

일반적으로, 본 발명의 화합물은 당업계에 알려진 통상의 허용가능한 임의의 방식으로 단독으로 또는 1종 이상의 치료제와 함께 투여될 것이다. 치료적 유효량은 질환의 중함, 대상의 연령 및 상대적인 건강상태, 사용할 화합물의 효능 및 기타 요소들에 따라 크게 달라질 것이다. 일반적으로, 체중 kg 당 약 0.03 내지 2.5 mg의 일일 투여량에서 전신적으로 만족할만한 결과가 나타난다. 대형 포유동물, 예를 들어 인간에서, 일일 투여량은 편리하게는 하루에 4회까지 분할하거나 서방형으로서 약 0.5 mg 내지 약 100 mg의 범위로 투여될 수 있다. 경구 투여에 적합한 단위투여형은 약 1 내지 50 mg의 활성 성분을 포함한다.In general, the compounds of the present invention will be administered alone or in combination with one or more therapeutic agents in any conventionally acceptable manner known in the art. The therapeutically effective amount will vary greatly depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compound to be used and other factors. In general, systemically satisfactory results are obtained at a daily dosage of about 0.03 to 2.5 mg per kg body weight. In large mammals, such as humans, the daily dose may conveniently be divided up to four times a day or as a sustained release in the range of about 0.5 mg to about 100 mg. Suitable unit dosage forms for oral administration comprise from about 1 to 50 mg of active ingredient.

본 발명의 화합물은 임의의 통상적인 경로로, 특히 장관적으로, 예를 들어 정제 또는 캡슐의 형태로 경구적으로; 또는 예를 들어 주사가능한 용액 또는 현탁 액으로 비경구적으로; 예를 들어 로션, 젤, 연고 또는 크림의 형태로 국소적으로; 또는 비내 또는 좌약 형태로 제약 조성물로서 투여될 수 있다. 본 발명의 화합물의 유리형 또는 제약적으로 허용가능한 염 형태를 1종 이상의 제약적으로 허용가능한 담체 또는 희석제와 함께 포함하는 제약 조성물은 혼합, 과립화 또는 코팅법에 의하여 통상의 방법으로 제조될 수 있다. 예를 들어, 경구용 조성물은The compounds of the present invention may be administered by any conventional route, in particular orally, for example orally in the form of tablets or capsules; Or parenterally, for example, as an injectable solution or suspension; Topically in the form of a lotion, gel, ointment or cream, for example; Or as a pharmaceutical composition in the form of a nasal or suppository. Pharmaceutical compositions comprising free or pharmaceutically acceptable salt forms of the compounds of the present invention with one or more pharmaceutically acceptable carriers or diluents may be prepared by conventional methods by mixing, granulating or coating methods. For example, oral compositions

a) 희석제, 예를 들어, 락토스, 덱스트로스, 수크로스, 만니톨, 소르비톨, 셀룰로스 및(또는) 글리신;a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

b) 윤활제, 예를 들어, 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘 염 및(또는) 폴리에틸렌글리콜;b) lubricants, for example silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols;

정제를 위해서는 c) 결합제, 예를 들어, 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸트, 메틸셀룰로스, 소듐 카르복시메틸셀룰로스 및(또는) 폴리비닐피롤리돈;For purification, c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone;

필요한 경우 d) 붕해제, 예를 들어, 전분, 아가, 알긴산 또는 그의 나트륨 염, 또는 발포 혼합물; 및(또는)If necessary d) disintegrants, for example starch, agar, alginic acid or its sodium salt, or effervescent mixtures; And / or

e) 흡수제, 착색제, 향료 및 감미료e) absorbents, colorants, fragrances and sweeteners

를 활성 성분과 함께 포함하는 정제 또는 젤라틴 캡슐일 수 있다.It may be a tablet or gelatin capsule containing together with the active ingredient.

주사가능한 조성물은 등이온성 수용액 또는 수현탁액일 수 있고, 좌약은 지방 유액 또는 현탁액으로부터 제조할 수 있다. 조성물은 멸균되고(되거나) 보조제, 예컨대 보존제, 안정화제, 습윤화제 또는 유화제, 용액화 촉진제, 삼투압 조절을 위한 염 또는 완충액을 포함할 수 있다. 또한, 조성물은 다른 치료적 활성 물 질을 포함할 수도 있다. 경피적 적용을 위한 적합한 제제는 본 발명의 화합물의 유효량과 담체를 포함한다. 담체는 숙주 피부를 통한 침투를 돕는 약리학적으로 허용가능한 흡수성 용매를 포함할 수 있다. 예를 들어, 경피적 장치는 지지재, 화합물 및 임의로는 담체를 함유하는 저장고, 임의로는 상기 화합물을 숙주 피부에 조절되는 소정의 속도로 연장된 기간에 걸쳐 전달하는 속도 조절 배리어, 및 피부에 장치를 고정하는 수단을 포함하는 붕대 형태이다. 매트릭스 경피 제제 또한 사용될 수 있다. 국소, 예를 들어 피부 및 안구 적용에 적합한 제제는 바람직하게는 당업계에 널리 공지된 수용액, 연고, 크림 또는 겔이다. 이러한 것들은 가용화제, 안정화제, 긴장성 강화제, 완충액 및 방부제를 함유할 수 있다.Injectable compositions can be isoionic aqueous solutions or water suspensions, and suppositories can be prepared from fatty emulsions or suspensions. The composition may be sterile and / or include adjuvants such as preservatives, stabilizers, wetting or emulsifiers, solution accelerators, salts or buffers for controlling osmotic pressure. The composition may also comprise other therapeutically active substances. Suitable formulations for transdermal application include an effective amount of a compound of the invention and a carrier. The carrier may comprise a pharmacologically acceptable absorbent solvent that aids penetration through the host skin. For example, a transdermal device may be a reservoir containing a support material, a compound, and optionally a carrier, a rate controlling barrier that optionally delivers the compound over a prolonged period of time at a controlled rate to the host skin, and the device to the skin. In the form of a bandage comprising means for fixing. Matrix transdermal formulations may also be used. Formulations suitable for topical, eg skin and ocular applications are preferably aqueous solutions, ointments, creams or gels well known in the art. These may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

본 발명의 화합물은 그 치료적 유효량이 1종 이상의 치료제와 함께 투여될 수 있다 (제약 조합물). 예를 들어, 다른 면역 조절성 또는 항-염증성 물질과의 사이에서, 예를 들어 시클로스포린, 라파마이신 또는 아스코마이신, 또는 그의 면역억제적 유사체, 예를 들어, 시클로스포린 A (CsA), 시클로스포린 G, FK-506, 라파마이신 또는 그에 상응하는 화합물, 코르티코스테로이드, 시클로포스파미드, 아자티오프린, 메토트렉세이트, 브레퀴나르, 레플루노미드, 미조리빈, 마이코페놀산, 마이코페놀레이트 모페틸, 15-데옥시스페르쿠알린, 면역억제성 항체, 특히 백혈구 수용체, 예를 들어, MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 또는 이들의 리간드에 대한 모노클로날 항체, 또는 예컨대 CTLA41g와 같은 다른 면역조절성 화합물과 함께 사용할 때 상승 효과가 발생할 수 있다. 본 발명의 화합물이 다른 치료제와 함께 투여되는 경우, 화합물의 투여량은 사용되는 병용 치료제의 종 류, 사용되는 특정 약물, 치료할 증상 등에 따라 달라질 것이다.Compounds of the invention may be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). For example, among other immunomodulatory or anti-inflammatory substances, for example cyclosporin, rapamycin or ascomycin, or immunosuppressive analogues thereof such as cyclosporin A (CsA), cyclosporin G, FK-506, rapamycin or a corresponding compound, corticosteroid, cyclophosphamide, azathioprine, methotrexate, brequinar, leflunomide, mizoribin, mycophenolic acid, mycophenolate mofetil, Monoclonal against 15-deoxysperqualin, immunosuppressive antibodies, in particular leukocyte receptors such as MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands Synergistic effects may occur when used with antibodies, or other immunomodulatory compounds such as CTLA41g. When a compound of the present invention is administered in combination with other therapeutic agents, the dosage of the compound will vary depending on the type of combination therapeutic used, the particular drug used, the condition to be treated, and the like.

본 발명은 또한 예를 들어, 본 명세서에 개시한 바와 같은 본 발명의 화합물의 유리형 또는 제약적으로 허용가능한 염 형태인 제1 제제; 및 b) 1종 이상의 병용 투여제를 포함하는 키트와 같은 제약 조합물을 제공한다. 상기 키트는 투여를 위한 지시사항을 포함할 수 있다.The present invention also provides a formulation comprising a first agent, for example in the form of a free or pharmaceutically acceptable salt of a compound of the invention as disclosed herein; And b) at least one combination dosage form. The kit may comprise instructions for administration.

본 명세서에서 "병용 투여" 또는 "조합 투여" 등의 용어는 1명의 환자에게 선택한 치료제를 투여하는 것을 포괄하며, 약제들이 반드시 동일한 투여 경로로, 또는 동시에 투여되는 치료 방법을 포함하려는 의도는 아니다.The term "concomitant administration" or "combined administration" as used herein encompasses administering a selected therapeutic agent to one patient, and is not intended to include therapeutic methods in which the agents are administered by the same route of administration or simultaneously.

본 명세서에서 "제약 조합물"은 1종 이상의 활성 성분을 혼합 또는 조합하여 생성된 결과물을 의미하며, 활성 성분들의 고정적 및 비고정적 조합 양자 모두를 포함한다. "고정적 조합물"은 활성 성분, 예를 들어 화학식 I의 화합물과 병용 투여제가 단일체 또는 투여형으로서 환자에게 동시에 투여되는 것이다. "비고정적 조합물"은 활성 성분, 예를 들어 화학식 I의 화합물과 병용 투여제가 별도의 개체로서, 동시에 또는 특정한 시간 제한 없이 순차적으로 환자에게 투여되는 것이며, 이러한 투여는 환자의 체내에 2종의 화합물의 치료적 유효 수준을 제공한다. 후자는 또한 칵테일 치료법, 예를 들어 3종 이상의 활성 성분의 투여에도 적용할 수 있다."Pharmaceutical combination" as used herein means the result produced by mixing or combining one or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. "Fixed combination" is the simultaneous administration of the active ingredient, eg, a compound of formula (I), in combination with a single agent or dosage form to a patient simultaneously. A "non-combination combination" is one in which the active ingredient, eg, a compound of formula (I), in combination with a dosage form is administered to a patient as a separate individual, either simultaneously or sequentially without specific time limit, such administration being carried out by To provide a therapeutically effective level of the compound. The latter is also applicable to cocktail therapy, eg the administration of three or more active ingredients.

본 발명의 화합물의 제조 방법Process for the preparation of the compound of the present invention

본 발명은 또한 본 발명의 화합물의 제조 방법을 포함한다. 상술한 반응에서는, 최종 생성물에서 원하지 않는 반응에의 참여를 피하는 것이 바람직한 경우, 예를 들어 히드록시, 아미노, 이미노, 티오 또는 카르복시기와 같은 반응성 관능기를 보호하는 것이 필수적일 수 있다. 통상의 보호기는 표준 방법, 예를 들어 문헌[T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991]에 기재된 바에 따라 사용될 수 있다.The invention also includes a process for the preparation of the compounds of the invention. In the reactions described above, where it is desirable to avoid participation in unwanted reactions in the final product, it may be necessary to protect reactive functional groups such as, for example, hydroxy, amino, imino, thio or carboxyl groups. Conventional protecting groups are standard methods, for example, T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.

화학식 I의 화합물은 하기 반응식 I에 따라 제조될 수 있다.Compounds of formula (I) can be prepared according to the following scheme (I).

Figure 112006091059442-pct00003
Figure 112006091059442-pct00003

상기 식에서, R1, R2, R3, R4, n 및 m은 본 발명의 요약에서 화학식 I에 대하여 정의된 바와 같다. 화학식 I의 화합물은 화학식 2의 화합물을 화학식 3의 화합물과, 적합한 염기 (예를 들어, DIPEA 등) 및 적합한 용매 (예를 들어, 부탄올, THF, DMF 등)의 존재하에서 반응시켜 제조할 수 있다. 반응은 약 80 내지 약 120 ℃의 온도 범위에서 진행되고, 완료되는데 약 20 시간 정도 걸릴 수 있다.Wherein R 1 , R 2 , R 3 , R 4 , n and m are as defined for Formula I in the Summary of the Invention. Compounds of formula (I) may be prepared by reacting a compound of formula (2) with a compound of formula (3) in the presence of a suitable base (eg, DIPEA, etc.) and a suitable solvent (eg, butanol, THF, DMF, etc.). . The reaction proceeds in a temperature range of about 80 to about 120 ° C. and may take about 20 hours to complete.

화학식 I의 화합물의 합성의 자세한 예는 하기 실시예에 기재하였다.Detailed examples of the synthesis of compounds of formula (I) are described in the Examples below.

본 발명의 화합물의 다른 제조 방법Other Processes for Making Compounds of the Invention

본 발명의 화합물은 상기 화합물의 유리 염기형을 제약적으로 허용가능한 무기 또는 유기 산과 반응시켜, 제약적으로 허용가능한 산 부가염으로서 제조할 수 있다. 별법으로, 본 발명의 화합물의 제약적으로 허용가능한 염기 부가염은 상기 화합물의 유리 산 형태를 제약적으로 허용가능한 무기 또는 유기 염기와 반응시켜 제조할 수 있다. 별법으로, 본 발명의 화합물의 염 형태는 출발 물질 또는 중간체의 염을 사용하여 제조할 수 있다.The compounds of the present invention can be prepared as pharmaceutically acceptable acid addition salts by reacting the free base forms of the compounds with pharmaceutically acceptable inorganic or organic acids. Alternatively, pharmaceutically acceptable base addition salts of the compounds of the present invention may be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Alternatively, salt forms of the compounds of the present invention may be prepared using salts of the starting materials or intermediates.

본 발명의 화합물의 유리 산 또는 유리 염기 형태는 상응하는 염기 부가염 또는 산 부가염으로부터 각각 제조할 수 있다. 예를 들어, 본 발명의 화합물의 산 부가염 형태는 적합한 염기 (예를 들어, 수산화암모늄 용액, 수산화나트륨 등)으로 처리하여 상응하는 유리 염기로 전환될 수 있다. 본 발명의 화합물의 염기 부가염 형태는 적합한 산 (예를 들어, 염산 등)으로 처리하여 상응하는 유리 산으로 전환될 수 있다.The free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salts or acid addition salts, respectively. For example, acid addition salt forms of the compounds of the invention can be converted to the corresponding free base by treatment with a suitable base (eg, ammonium hydroxide solution, sodium hydroxide, etc.). Base addition salt forms of the compounds of the invention can be converted to the corresponding free acids by treatment with a suitable acid (eg hydrochloric acid, etc.).

본 발명의 화합물의 비-산화된 형태는 본 발명의 화합물의 N-옥시드를 환원제 (예를 들어, 황, 이산화황, 트리페닐 포스핀, 리튬 보로히드리드, 소듐 보로히드리드, 삼염화인, 삼브롬화인 등)로 적합한 비활성 유기 용매 (예를 들어, 아세토니트릴, 에탄올, 디옥산 수용액 등) 중에서 0 내지 80 ℃에서 처리하여 제조될 수 있다.Non-oxidized forms of the compounds of the invention may be prepared by reducing the N-oxides of the compounds of the invention with reducing agents (eg, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, Phosphorus bromide) and the like, and can be prepared by treating in a suitable inert organic solvent (for example, acetonitrile, ethanol, aqueous dioxane solution, etc.) at 0 to 80 ° C.

본 발명의 화합물의 전구약물 유도체는 당업자에게 공지된 방법 (예를 들어, 상세한 사항은 문헌[Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985]를 참조)으로 제조할 수 있다. 예를 들어, 적절한 전구약물은 본 발명의 화합물의 비-유도체를 적합한 카르바밀화제 (예를 들어, 1,1-아실옥시알킬카르바노클로리데이트, para-니트로페닐 카르보네이트 등)와 반응시켜 제조할 수 있다.Prodrug derivatives of the compounds of the invention may be prepared by methods known to those skilled in the art (for example, see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). It can be prepared by. For example, suitable prodrugs react the non-derivatives of the compounds of the invention with suitable carbamylating agents (eg, 1,1-acyloxyalkylcarbanochlorates, para-nitrophenyl carbonate, etc.) Can be prepared.

본 발명의 화합물의 보호된 유도체는 당업자에게 공지된 방법으로 제조할 수 있다. 보호기의 생성 및 제거에 적용가능한 기법에 대한 상세한 설명은 문헌[T. W. Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999]에 기재되어 있다.Protected derivatives of the compounds of the invention can be prepared by methods known to those skilled in the art. A detailed description of the techniques applicable to the generation and removal of protecting groups is given in T. W. Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999.

본 발명의 화합물은 편리하게는 본 발명의 방법 중 용매화물 (예를 들어, 수화물)로서 제조되거나 형성될 수 있다. 본 발명의 화합물의 수화물은 편리하게는 수성, 또는 디옥신, 테트라히드로푸란 또는 메탄올과 같은 유기 용매를 사용한 유기 용매 혼합물로부터의 재결정화에 의하여 제조할 수 있다.The compounds of the present invention may conveniently be prepared or formed as solvates (eg hydrates) in the process of the present invention. Hydrates of the compounds of the present invention may conveniently be prepared by aqueous or recrystallization from an organic solvent mixture using an organic solvent such as dioxin, tetrahydrofuran or methanol.

본 발명의 화합물은 상기 화합물의 라세미 혼합물을 광학적 활성있는 분할제와 반응시켜 부분입체이성질체 화합물 쌍을 형성하고, 부분입체이성질체들을 분리하고, 광학적으로 순수한 거울상이성질체를 회수하여, 그들의 개별적인 입체이성질체로서 제조할 수 있다. 거울상이성질체의 분할이 본 발명의 화합물의 공유적 부분입체이성질체 유도체를 사용하여 실시될 수 있는 경우, 분리될 수 있는 복합체가 바람직하다 (예를 들어, 결정성 부분입체이성질체 염). 부분입체이성질체는 구별되는 물성을 가지며 (예를 들어, 융점, 비점, 용해도, 반응성 등), 이러한 차이점을 이용하여 쉽게 분리할 수 있다. 부분입체이성질체는 크로마토그래피에 의하여, 또는 바람직하게는 용해도 차이에 기초하는 분리/분할법에 의하여 분리될 수 있다. 그후 라세미화를 일으키지 않는 임의의 실험 방법으로서 광학적으로 순수한 거울상이성질체를 분할제와 함께 회수할 수 있다. 화합물의 라세미 혼합물로부터의 입체 이성질체의 분할에 적용가능한 기법에 대한 더욱 상세한 설명은 문헌[Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981]에 기재되어 있다.The compounds of the present invention react racemic mixtures of the compounds with an optically active splitting agent to form diastereomeric compound pairs, separate diastereomers, and recover optically pure enantiomers, as their individual stereoisomers. It can manufacture. Where the cleavage of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, separable complexes are preferred (eg crystalline diastereomeric salts). Diastereomers have distinct physical properties (eg, melting point, boiling point, solubility, reactivity, etc.) and can be easily separated using these differences. Diastereomers may be separated by chromatography, or preferably by separation / fractionation based on solubility differences. The optically pure enantiomer can then be recovered with the splitting agent as any experimental method that does not cause racemization. A more detailed description of the techniques applicable to the cleavage of stereoisomers from racemic mixtures of compounds is given by Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.

요약하면, 화학식 I의 화합물은,In summary, the compound of formula (I) is

(a) 반응식 I 및 II의 단계, 예를 들어 화학식 8의 화합물을 R6YOH와 반응식 I에 따라 커플링하는 단계;(a) steps of Schemes I and II, eg, coupling a compound of Formula 8 with R 6 YOH according to Scheme I;

(b) 임의로는 본 발명의 화합물을 제약적으로 허용가능한 염으로 전환하는 단계;(b) optionally converting a compound of the invention into a pharmaceutically acceptable salt;

(c) 임의로는 본 발명의 화합물의 염 형태를 염이 아닌 형태로 전환하는 단계;(c) optionally converting a salt form of a compound of the invention to a non-salt form;

(d) 임의로는 본 발명의 화합물의 비-산화된 형태를 제약적으로 허용가능한 N-옥시드로 전환하는 단계;(d) optionally converting a non-oxidized form of a compound of the invention into a pharmaceutically acceptable N-oxide;

(e) 임의로는 본 발명의 화합물의 N-옥시드 형태를 그의 비-산화된 형태로 전환하는 단계;(e) optionally converting the N-oxide form of the compound of the invention to its non-oxidized form;

(f) 임의로는 본 발명의 화합물의 이성질체의 혼합물로부터 개별적인 이성질체를 분할하는 단계;(f) optionally dividing the individual isomers from the mixture of isomers of the compounds of the present invention;

(g) 임의로는 본 발명의 화합물의 비-유도된 형태를 제약적으로 허용가능한 전구약물 유도체로 전환하는 단계; 및(g) optionally converting a non-derived form of a compound of the invention into a pharmaceutically acceptable prodrug derivative; And

(h) 임의로는 본 발명의 화합물의 전구약물 유도체를 그의 비-유도된 형태로 전환하는 단계(h) optionally converting a prodrug derivative of a compound of the invention to its non-derived form

를 포함하는 방법에 의하여 제조할 수 있다.It can manufacture by the method containing.

출발 물질의 제조에 관하여는 특별히 기재하지 않았고, 상기 화합물은 공지되어 있거나, 당업계에 공지된 방법에 따라, 또는 하기 실시예에 개시된 바에 따라 제조할 수 있다.The preparation of starting materials is not specifically described and the compounds can be prepared by known methods or according to methods known in the art or as disclosed in the examples below.

당업자는 상기 변형이 본 발명의 화합물의 제조 방법에 대한 대표예이고, 다른 널리 공지된 방법도 유사하게 사용될 수 있음을 인식할 것이다.Those skilled in the art will recognize that such modifications are representative of the methods for the preparation of the compounds of the present invention, and other well known methods may similarly be used.

이하, 본 발명에 따른 화학식 I의 화합물의 제조를 예시하는 하기 실시예에 의하여 본 발명을 추가로 예시하나, 이에 한정하지는 않는다.Hereinafter, the present invention is further illustrated by the following examples which illustrate the preparation of compounds of formula (I) according to the invention, but is not limited thereto.

실시예Example 1 One

N-[4-N- [4- 메틸methyl -3-(1-{6-[4-(2-모르폴린-4-일-에틸)--3- (1- {6- [4- (2-Morpholin-4-yl-ethyl)- 페닐아미노피리미딘Phenylaminopyrimidine -4-일}-1H--4-yl} -1H- 이미다졸Imidazole -2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드 -2-ylamino) -phenyl] -3-trifluoromethyl-benzamide

Figure 112006091059442-pct00004
Figure 112006091059442-pct00004

N-(2,2-N- (2,2- 디에톡시에틸Diethoxyethyl )카르보디이미드 Carbodiimide

Figure 112006091059442-pct00005
Figure 112006091059442-pct00005

에테르 (35 mL) 중 아미노아세트알데히드 디에틸 아세탈 (13.16 g, 99 mmol) 의 용액을 헥산 (35 mL) 중 CNBr (10.47 g, 99 mmol)의 현탁액에 실온에서 가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 고체를 여과로 제거하고, 에테르로 세척하였다. 합한 여액을 농축하였다. 컬럼 크로마토그래피 (실리카 겔, 디클로로메탄 내지 디클로로메탄 중 4% 메탄올 구배로 용리)로 정제하여 표제 화합물 (7.0 g, 44.7%, 출발 아민의 절반이 반응 중에서 희생적 염기로 작용하였다)을 수득하였다 (Rf; 2.70, 디클로로메탄 중 4% 메탄올, 10% 에탄올 몰립다토인산으로 염색).A solution of aminoacetaldehyde diethyl acetal (13.16 g, 99 mmol) in ether (35 mL) was added to a suspension of CNBr (10.47 g, 99 mmol) in hexane (35 mL) at room temperature. The reaction mixture was stirred at rt overnight. The solid was removed by filtration and washed with ether. The combined filtrates were concentrated. Purification by column chromatography (silica gel, eluting with a 4% methanol gradient in dichloromethane to dichloromethane) gave the title compound (7.0 g, 44.7%, half of the starting amine served as a sacrificial base in the reaction) (R f ; 2.70, stained with 4% methanol in dichloromethane, 10% ethanol molybdate phosphoric acid).

Figure 112006091059442-pct00006
Figure 112006091059442-pct00006

N-[3-(1H-N- [3- (1H- 이미다졸Imidazole -2--2- 일아미노Monoamino )-4-)-4- 메틸methyl -페닐]-3--Phenyl] -3- 트리플루오로메틸Trifluoromethyl -- 벤즈아미드Benzamide

Figure 112006091059442-pct00007
Figure 112006091059442-pct00007

에탄올 (25 mL) 중 N-(2,2-디에톡시에틸)카르보디이미드 (398 mg, 2.51 mmol), 3-아미노-4-메틸-페닐]-3-트리플루오로메틸-벤즈아미드 (649 mg, 2.20 mmol), 메탄술폰산 (143 ㎕, 2.20 mmol)의 혼합물을 16시간 동안 가열환류하였다. N-(2,2-디에톡시에틸)카르보디이미드 (525 mg, 3.32 mmol) 및 메탄술폰산 (143 ㎕, 2.20 mmol)의 추가분을 가하였다. 추가로 3시간 더 환류한 뒤, 반응 혼합물을 농축하였다. 잔류물을 HCl (6N, 5 mL) 및 에탄올 (5 mL)에 용해시켰다. 밤새 교반한 뒤, 반응 혼합물을 농축하고, 25% NaOH 용액로 pH 14까지 염기화하였다. 혼합 물을 30분간 교반한 뒤, CH2Cl2로 추출하고, 건조하고, 농축한 뒤 컬럼 크로마토그래피 (실리카 겔, 메탄올 중 7N NH3: 2% 내지 4% 디클로로메탄으로 용리)하여 표제 화합물을 수득하였다.N- (2,2-diethoxyethyl) carbodiimide (398 mg, 2.51 mmol) in 3-ethanol (25 mL), 3-amino-4-methyl-phenyl] -3-trifluoromethyl-benzamide (649 mg, 2.20 mmol) and methanesulfonic acid (143 μL, 2.20 mmol) were heated to reflux for 16 h. An additional portion of N- (2,2-diethoxyethyl) carbodiimide (525 mg, 3.32 mmol) and methanesulfonic acid (143 μl, 2.20 mmol) was added. After refluxing for another 3 hours, the reaction mixture was concentrated. The residue was dissolved in HCl (6N, 5 mL) and ethanol (5 mL). After stirring overnight, the reaction mixture was concentrated and basified to pH 14 with 25% NaOH solution. The mixture was stirred for 30 min, extracted with CH 2 Cl 2 , dried, concentrated and column chromatography (silica gel, 7N NH 3 in methanol: eluting with 2% to 4% dichloromethane) to afford the title compound. Obtained.

N-{3-[1-(6-N- {3- [1- (6- 클로로Chloro -피리미딘-4-일}-1H--Pyrimidin-4-yl} -1H- 이미다졸Imidazole -2--2- 일아미노Monoamino ]-4-]-4- 메틸methyl -- 페닐Phenyl }-3-} -3- 트리플루오로메틸Trifluoromethyl -벤즈아미드-Benzamide

Figure 112006091059442-pct00008
Figure 112006091059442-pct00008

2-부탄올 (20 mL) 중 N-[3-(1H-이미다졸-2-일아미노)-4-메틸-페닐]-3-트리플루오로메틸-벤즈아미드 (330 mg, 0.92 mmol), 4,6-디클로로피리미딘 (409 mg, 2.75 mmol), N,N-디이소프로필에틸 아민 (500 ㎕, 2.87 mmol)의 혼합물을 110 ℃에서 가열하였다. 16시간 후, 반응 혼합물을 농축하였다. 고체를 포화 탄산 나트륨 수용액, 물, 에틸 아세테이트로 세척한 뒤, 건조하여 표제 화합물을 수득하였다. N- [3- (1H-imidazol-2-ylamino) -4-methyl-phenyl] -3-trifluoromethyl-benzamide (330 mg, 0.92 mmol) in 2-butanol (20 mL), 4 A mixture of, 6-dichloropyrimidine (409 mg, 2.75 mmol), N, N-diisopropylethyl amine (500 μl, 2.87 mmol) was heated at 110 ° C. After 16 hours, the reaction mixture was concentrated. The solid was washed with saturated aqueous sodium carbonate solution, water, ethyl acetate and then dried to afford the title compound.

Figure 112006091059442-pct00009
Figure 112006091059442-pct00009

N-[4-N- [4- 메틸methyl -3-(1-{6-[4-(2-모르폴린-4-일-에틸)--3- (1- {6- [4- (2-Morpholin-4-yl-ethyl)- 페닐아미노Phenylamino ]-피리미딘-4-일}-1H-] -Pyrimidin-4-yl} -1H- 이미다졸Imidazole -2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드 -2-ylamino) -phenyl] -3-trifluoromethyl-benzamide

Figure 112006091059442-pct00010
Figure 112006091059442-pct00010

스미스 바이알 (2 내지 5 mL)에 N-{3-[1-(6-클로로-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드 (16.8 mg, 0.035 mmol), 4-(2-모르폴린-4-일-에틸)-페닐아민 mg, 0.11 mmol), p-톨루엔술폰산 일수화물 (4.4 mg, 0.023 mmol) 및 DMSO (0.5 mL)를 충전하였다. 아르곤으로 퍼징한 뒤, 바이알을 밀봉하고, 100 ℃에서 5시간 동안 스미스 신세사이저(Smith Synthesizer)에서 조사하였다. 생성된 용액을 역상 LC-MS로 정제하여 표제 화합물을 수득하였다.In a Smith vial (2-5 mL) N- {3- [1- (6-chloro-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- Trifluoromethyl-benzamide (16.8 mg, 0.035 mmol), 4- (2-morpholin-4-yl-ethyl) -phenylamine mg, 0.11 mmol), p-toluenesulfonic acid monohydrate (4.4 mg, 0.023 mmol ) And DMSO (0.5 mL). After purging with argon, the vial was sealed and irradiated in a Smith Synthesizer at 100 ° C. for 5 hours. The resulting solution was purified by reverse phase LC-MS to give the title compound.

Figure 112006091059442-pct00011
Figure 112006091059442-pct00011

실시예Example 2 2

N-{3-[1-(6-N- {3- [1- (6- 시클로프로필아미노Cyclopropylamino -피리미딘-4-일)-1H--Pyrimidin-4-yl) -1H- 이미다졸Imidazole -2--2- 일아미노Monoamino ]-4-]-4- 메틸methyl -페닐}-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드 -Phenyl} -3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-benzamide

Figure 112006091059442-pct00012
Figure 112006091059442-pct00012

N-(3-아미노-4-N- (3-amino-4- 메틸methyl -- 페닐Phenyl )-)- 벤즈아미드Benzamide

Figure 112006091059442-pct00013
Figure 112006091059442-pct00013

CH2Cl2 (150 mL) 중 4-메틸-3-니트로-아닐린 (15.86 g, 104 mmol), 피리딘 (17.0 mL, 208 mmol)의 용액에 벤조일 클로라이드 (13.30 mL, 114 mmol)를 0 ℃에서 적가하였다. 2시간 동안 실온에서 교반한 뒤, 반응 혼합물을 농축하였다. 잔류물을 포화 탄산 나트륨 수용액, 물, 그후 에틸 에테르로 세척하여, 원하는 니트로 화합물을 수득하였으며, 이를 다음 단계에서 추가의 정제 없이 사용하였다.To a solution of 4-methyl-3-nitro-aniline (15.86 g, 104 mmol), pyridine (17.0 mL, 208 mmol) in CH 2 Cl 2 (150 mL) was added benzoyl chloride (13.30 mL, 114 mmol) at 0 ° C. Added dropwise. After stirring for 2 hours at room temperature, the reaction mixture was concentrated. The residue was washed with saturated aqueous sodium carbonate solution, water and then ethyl ether to afford the desired nitro compound which was used in the next step without further purification.

Figure 112006091059442-pct00014
Figure 112006091059442-pct00014

상기 니트로 화합물을 에탄올 (250 mL)에 용해시켰다. 파르 진탕기를 사용하여, 20-30 psi H2하에서 16 시간 동안 팔라듐 (활성탄 상 10 중량%, 습식, 데구사 타입, 5 g) 상 수소화 후, 반응 혼합물을 셀라이트 패트를 통해 여과하고, 에탄올로 세척하였다. 합한 여액 및 세척액을 농축하여 표제 화합물 N-(3-아미노-4-메틸-페닐)-벤즈아미드 (22.43 g, 2단계에 걸쳐 95 %)를 수득하였으며, 이를 다음 반응에 추가의 정제 없이 사용하였다.The nitro compound was dissolved in ethanol (250 mL). After hydrogenation over palladium (10 wt.% On activated carbon, wet, degussa type, 5 g) over 20-30 psi H 2 using a Parr shaker, the reaction mixture was filtered through celite pad and ethanol Washed. The combined filtrates and washes were concentrated to give the title compound N- (3-amino-4-methyl-phenyl) -benzamide (22.43 g, 95% over two steps), which was used in the next reaction without further purification. .

Figure 112006091059442-pct00015
Figure 112006091059442-pct00015

N-[3-(1H-N- [3- (1H- 이미다졸Imidazole -2--2- 일아미노Monoamino )-4-)-4- 메틸methyl -- 페닐Phenyl ]-]- 벤즈아미드Benzamide

Figure 112006091059442-pct00016
Figure 112006091059442-pct00016

에탄올 (200 mL) 중 N-(2,2-디에톡시에틸)카르보디이미드 (10.38 g, 65.6 mmol), 3-아미노-4-메틸-페닐]-벤즈아미드 (7.42 g, 32.8 mmol), 메탄술폰산 (3.20 mL, 49.3 mmol)의 혼합물을 19시간 동안 가열환류하였다. 반응 혼합물을 농축하였다 (이 단계에서 정제하지 않았다). 잔류물을 HCl 용액 (6N, 30 mL)에 용해시켰다. 밤새 교반한 뒤, 반응 혼합물을 0℃에서 25% NaOH 용액으로 pH 6으로 중화시킨 뒤, 포화 탄산 나트륨 용액으로 pH 11로 염기화하였다. 혼합물을 30분간 교반 한 뒤, CH2C12 중 에탄올 (100 mL), 그후 CH2C12 중 10% 에탄올 (2 x 100 mL)로 추출하였다. 합한 유기층을 Na2S04로 건조하고, 여과하고, 농축한 뒤 진공하에서 건조하였다. 잔류물을 CH2Cl2 (50 mL) 중에서 분쇄하였다. 고체를 여과로 수집하고, CH2Cl2로 세척한 뒤, 건조하여 표제 화합물 N-[3-(1H 이미다졸-2-일아미노)-4-메틸-페닐]-벤즈아미드를 백색 고체로서 수득하였다 (4.80 g, 50%).N- (2,2-diethoxyethyl) carbodiimide (10.38 g, 65.6 mmol) in ethanol (200 mL), 3-amino-4-methyl-phenyl] -benzamide (7.42 g, 32.8 mmol), methane A mixture of sulfonic acid (3.20 mL, 49.3 mmol) was heated to reflux for 19 h. The reaction mixture was concentrated (not purified at this stage). The residue was dissolved in HCl solution (6N, 30 mL). After stirring overnight, the reaction mixture was neutralized to pH 6 with 25% NaOH solution at 0 ° C. and then basified to pH 11 with saturated sodium carbonate solution. The mixture was extracted with of after stirring for 30 minutes, CH 2 C1 2 in ethanol (100 mL), then 10% ethanol (2 x 100 mL) of CH 2 C1 2. The combined organic layers were dried over Na 2 SO 4 , filtered, concentrated and dried under vacuum. The residue was triturated in CH 2 Cl 2 (50 mL). The solid was collected by filtration, washed with CH 2 Cl 2 and dried to afford the title compound N- [3- (1H imidazol-2-ylamino) -4-methyl-phenyl] -benzamide as a white solid. (4.80 g, 50%).

Figure 112006091059442-pct00017
Figure 112006091059442-pct00017

N-{3-[1-(6-N- {3- [1- (6- 클로로Chloro -피리미딘-4-일)-1H--Pyrimidin-4-yl) -1H- 이미다졸Imidazole -2--2- 일아미노Monoamino ]-4-]-4- 메틸methyl -- 페닐Phenyl }-}- 벤즈아 미드Benzamide

Figure 112006091059442-pct00018
Figure 112006091059442-pct00018

2-부탄올 (150 mL) 중 N-[3-(1H-이미다졸-2-일아미노)-4-메틸-페닐]-3-벤즈아미드(3.41 g, 11.7 mmol), 4, 6-디클로로피리미딘 (5.20 g, 34.9 mmol), N,N-디이소프로필에틸 아민 (6.10 mL, 35.0 mmol)의 혼합물을 100 ℃에서 가열하였다. 16시간 뒤, 반응 혼합물을 농축하였다. 잔류물을 포화 탄산 나트륨 수용액, 물, 에틸 아세테이트로 세척하고 건조하여 표제 화합물을 수득하였으며 (2.65 g, 56%), 에틸 아세테이트 여액을 농축하고, 이를 플래쉬 크로마토그래피 (실리카 겔, 디클로로메탄 중 1% 내지 5% 메탄올 구배로 용리)로 정제하여, 표제 화합물의 추가분을 수득하였다 (500 mg, 10%). N- [3- (1H-imidazol-2-ylamino) -4-methyl-phenyl] -3-benzamide (3.41 g, 11.7 mmol) in 2-butanol (150 mL), 4, 6-dichloropyri A mixture of midine (5.20 g, 34.9 mmol), N, N-diisopropylethyl amine (6.10 mL, 35.0 mmol) was heated at 100 ° C. After 16 hours, the reaction mixture was concentrated. The residue was washed with saturated aqueous sodium carbonate solution, water, ethyl acetate and dried to afford the title compound (2.65 g, 56%), and the ethyl acetate filtrate was concentrated and flash chromatography (silica gel, 1% in dichloromethane). Purification with a gradient of 5% methanol) afforded an additional portion of the title compound (500 mg, 10%).

Figure 112006091059442-pct00019
Figure 112006091059442-pct00019

N-{3-[1-(6-N- {3- [1- (6- 시클로프로필아미노Cyclopropylamino -피리미딘-4-일)-1H--Pyrimidin-4-yl) -1H- 이미다졸Imidazole -2--2- 일아미노Monoamino ]-4-]-4- 메틸methyl -- 페닐Phenyl }-}- 벤즈아미드Benzamide

Figure 112006091059442-pct00020
Figure 112006091059442-pct00020

2-프로판올 (30 mL) 중 N-{3-[1-(6-클로로-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-벤즈아미드 (2.65 g, 6.55 mmol), 시클로프로필아민 (8.8 mL, 124.43 mmol)의 혼합물을 16시간 동안 65 ℃에서 가열하였다. 그런 다음 반응 혼합물을 실온으로 냉각시키고 농축하였다. 노란색 잔류 고체를 물로 세척하고, 진공하에서 건조하여 표제 화합물을 수득하였다. 수득한 조 표제 화합물을 다음 단계 반응에서 추가의 정제 없이 바로 사용하였다.N- {3- [1- (6-chloro-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -benzamide in 2-propanol (30 mL) ( 2.65 g, 6.55 mmol), cyclopropylamine (8.8 mL, 124.43 mmol) were heated at 65 ° C. for 16 h. The reaction mixture was then cooled to room temperature and concentrated. The yellow residual solid was washed with water and dried in vacuo to afford the title compound. The crude title compound obtained was used directly in the next reaction without further purification.

Figure 112006091059442-pct00021
Figure 112006091059442-pct00021

N-3-[1-(6-N-3- [1- (6- 시클로프로필아미노Cyclopropylamino -피리미딘-4-일)-1H--Pyrimidin-4-yl) -1H- 이미다졸Imidazole -2-일]-4--2-yl] -4- 메틸methyl -벤젠-1,3--Benzene-1,3- 디아민Diamine

Figure 112006091059442-pct00022
Figure 112006091059442-pct00022

N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-벤즈아미드의 조 생성물을 HCl 수용액 (6 N, 50 mL)에 용해시키고, 105 ℃에서 6시간 가열하였다. 그런 다음 반응 혼합물을 실온으로 냉각하였다. 백색 침전물을 여과로 분리하여, 물로 세척하였다. 합한 여액을 농축하여 점성 있는 오일을 수득하였다. 포화 탄산 나트륨 수용액을 오일에 가하여 분쇄하여 표제 화합물을 황색 고체로 수득하였으며, 이를 여과로 수집하고, 물로 세척한 뒤 공기 건조 하였다 (1.6 g, 2단계에 걸쳐 74%).The crude product of N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -benzamide was dissolved in an aqueous HCl solution ( 6 N, 50 mL) and heated at 105 ° C for 6 h. The reaction mixture was then cooled to room temperature. The white precipitate was separated by filtration and washed with water. The combined filtrates were concentrated to give a viscous oil. Saturated aqueous sodium carbonate solution was added to the oil and triturated to afford the title compound as a yellow solid which was collected by filtration, washed with water and air dried (1.6 g, 74% over two steps).

Figure 112006091059442-pct00023
Figure 112006091059442-pct00023

N-{3-[1-(6-N- {3- [1- (6- 시클로프로필아미노Cyclopropylamino -피리미딘-4-일)-1H--Pyrimidin-4-yl) -1H- 이미다졸Imidazole -2--2- 일아미노Monoamino ]-4-]-4- 메틸methyl -- 페닐}Phenyl} -3-(4--3- (4- 메틸methyl -- 이미다졸Imidazole -1-일)-5--1-yl) -5- 트리플루오로메틸Trifluoromethyl -- 벤즈아미드Benzamide

Figure 112006091059442-pct00024
Figure 112006091059442-pct00024

DMF (20 mL) 중 N-3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일]-4-메틸-벤젠-1,3-디아민 (1.38 g, 4.28 mmol), 3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤조산 (1.18 g, 4.37 mmol) 및 DIPEA (3 mL, 17.2 mmol)의 용액에 HATU (1.68 g, 4.42 mmol)를 고체로서 가하였다. 반응 혼합물을 실온에서 1시간 교반하였다. 용매를 증발시키고, 잔류 오일을 포화 중탄산 나트륨 수용액으로 처리하였다. 침전된 회백색 고체를 여과로 수집하고, 물로 세척하였다. 그런 다음 고체를 메탄올 중, 50 ℃에서 30분간 슬러리화 하였다. 고체를 여과로 수집하고, MeOH로 세척한 뒤 진공에서 건조하여 표제 화합물을 수득하였다 (2.14 g, 87%). N-3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-yl] -4-methyl-benzene-1,3-diamine in DMF (20 mL) ( 1.38 g, 4.28 mmol), HATU in a solution of 3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-benzoic acid (1.18 g, 4.37 mmol) and DIPEA (3 mL, 17.2 mmol) (1.68 g, 4.42 mmol) was added as a solid. The reaction mixture was stirred at rt for 1 h. The solvent was evaporated and the residual oil was treated with saturated aqueous sodium bicarbonate solution. The precipitated off-white solid was collected by filtration and washed with water. The solid was then slurried for 30 minutes at 50 ° C. in methanol. The solid was collected by filtration, washed with MeOH and dried in vacuo to afford the title compound (2.14 g, 87%).

Figure 112006091059442-pct00025
Figure 112006091059442-pct00025

실시예Example 3  3

3-[1-(6-3- [1- (6- 시클로프로필아미노Cyclopropylamino -피리미딘-4-일)-1H--Pyrimidin-4-yl) -1H- 이미다졸Imidazole -2--2- 일아미노Monoamino ]-N-[4-(4-에틸-피페라진-1-일메틸)-3-트리플루오로메틸-페닐]-4-메틸-벤즈아미드의 합성Synthesis of] -N- [4- (4-ethyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -4-methyl-benzamide

Figure 112006091059442-pct00026
Figure 112006091059442-pct00026

4-4- 클로로Chloro -6-(2--6- (2- 클로로Chloro -- 이미다졸Imidazole -1-일)-피리미딘 -1-yl) -pyrimidine

Figure 112006091059442-pct00027
Figure 112006091059442-pct00027

40 mL 부탄올 중 2-클로로-1H-이미다졸 (2.0 g, 20 mmol), 4,6-디클로로피리미딘 (6 g, 40 mmol) 및 DIEA (10.4 ml, 60 mmol)를 혼합하고, 120 ℃에서 24시간 동안 환류하였다. 용매를 회전 증류로 제거하였다. 조 생성물을 실리카 겔 상의 크로마토그래피 (0% EtOAc/헥산 내지 20% EtOAc/헥산 구배)로 정제하여, 표제 화합물 (2.6 g, 62% 수율)을 노란색 고체로 수득하였다. Rf= 0.25 (20% EtOAc/헥산).2-chloro-1H-imidazole (2.0 g, 20 mmol), 4,6-dichloropyrimidine (6 g, 40 mmol) and DIEA (10.4 ml, 60 mmol) in 40 mL butanol were mixed and at 120 ° C. Reflux for 24 hours. The solvent was removed by rotary distillation. The crude product was purified by chromatography on silica gel (0% EtOAc / hexanes to 20% EtOAc / hexanes gradient) to afford the title compound (2.6 g, 62% yield) as a yellow solid. R f = 0.25 (20% EtOAc / hexanes).

Figure 112006091059442-pct00028
Figure 112006091059442-pct00028

[6-(2-[6- (2- 클로로Chloro -- 이미다졸Imidazole -1-일)-피리미딘-4-일]--1-yl) -pyrimidin-4-yl]- 시클로프로필Cyclopropyl -아민-Amine

Figure 112006091059442-pct00029
Figure 112006091059442-pct00029

4-클로로-6-(2-클로로-이미다졸-1-일)-피리미딘 (0.85 g, 4 mmol) 및 시클로프로필아민 (1.4 mL, 20 mmol)을 10 mL 메탄올에 혼합하고, 50 ℃에서 12시간 동안 교반하였다. 반응이 완료된 뒤, 용매를 회전 증류로 제거하였다. 조 생성물을 물로 세척한 뒤, 건조 상태로 만들어 표제 화합물 (0.84 g, 90%)을 수득하였다.4-Chloro-6- (2-chloro-imidazol-1-yl) -pyrimidine (0.85 g, 4 mmol) and cyclopropylamine (1.4 mL, 20 mmol) were mixed in 10 mL methanol and at 50 ° C. Stir for 12 hours. After the reaction was completed, the solvent was removed by rotary distillation. The crude product was washed with water and then dried to give the title compound (0.84 g, 90%).

Figure 112006091059442-pct00030
Figure 112006091059442-pct00030

Figure 112006091059442-pct00031
Figure 112006091059442-pct00031

디클로로메탄 (5.2 ml) 중 4-(4-에틸-피페라진-1-일메틸)-3-트리플루오로메틸-페닐아민 (3.0 g, 1.04 mmol, 1.0 당량)의 용액에 디이소프로필에틸 아민 (2.00 ml, 1.14 mmol, 1.1 당량)을 가하였다. 용액을 0 ℃로 냉각시킨 뒤, 4-메틸-3-니트로벤조일클로라이드 (2.13 g, 1.07 mmol, 1.03 당량)를 수회에 나누어 반응 혼합물에 가하고, 30분간 추가로 평형을 유지하였다. 그런 다음 반응 혼합물을 디클로 로메탄 및 포화 탄산 나트륨 용액으로 분리하였다. 유기층을 분리한 뒤, 수층을 디클로로메탄으로 추출하였다. 합한 유기 추출물을 물 및 염수로 세척한 뒤, Na2S04로 건조하고, 여과하고, 농축하여 원하는 생성물을 수득하였다 (4.58 g, 98%). 원하는 화합물을 다음 단계에서 추가의 정제 없이 사용하였다.Diisopropylethyl amine in a solution of 4- (4-ethyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenylamine (3.0 g, 1.04 mmol, 1.0 equiv) in dichloromethane (5.2 ml) (2.00 ml, 1.14 mmol, 1.1 equiv) was added. After the solution was cooled to 0 ° C., 4-methyl-3-nitrobenzoylchloride (2.13 g, 1.07 mmol, 1.03 equiv) was added to the reaction mixture in several portions and the mixture was held for another 30 minutes. The reaction mixture was then separated into dichloromethane and saturated sodium carbonate solution. After separating the organic layer, the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with water and brine, then dried over Na 2 SO 4 , filtered and concentrated to give the desired product (4.58 g, 98%). The desired compound was used without further purification in the next step.

Figure 112006091059442-pct00032
Figure 112006091059442-pct00032

MeOH (50 ml) 중 N-[4-(4-에틸-피페라진-1-일메틸)-3-트리플루오로메틸-페닐]-4-메틸-3-니트로-벤즈아미드 (4.5 g, 1.00 mmol, 1.0 당량)의 용액에 레이니(Raney) 니켈 (0.45 g, 10 중량%)을 가하였다. 현탁액을 수소 대기 (1 기압) 하에서 24시간 동안 교반하였다. HPLC에 의하여 나타난 반응 말기에, 반응체를 셀라이트를 통하여 여과하고, 여액을 감압하에서 농축하여 원하는 생성물을 수득하였다 (4.1 g, 97%).N- [4- (4-ethyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -4-methyl-3-nitro-benzamide (4.5 g, 1.00 in MeOH (50 ml)) To a solution of mmol, 1.0 equiv), Raney nickel (0.45 g, 10 wt%) was added. The suspension was stirred for 24 h under hydrogen atmosphere (1 atm). At the end of the reaction indicated by HPLC, the reaction was filtered through celite and the filtrate was concentrated under reduced pressure to give the desired product (4.1 g, 97%).

Figure 112006091059442-pct00033
Figure 112006091059442-pct00033

3-[1-(6-3- [1- (6- 시클로프로필아미노Cyclopropylamino -피리미딘-4-일)-1H--Pyrimidin-4-yl) -1H- 이미다졸Imidazole -2--2- 일아미노Monoamino ]-N-[4-(4-에틸-피페라진-1-일메틸)-3-트리플루오로메틸-페닐]-4-메틸-벤즈아미드 ] -N- [4- (4-ethyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -4-methyl-benzamide

Figure 112006091059442-pct00034
Figure 112006091059442-pct00034

1,3-디메틸-이미다졸리딘-2-온 (4 mL) 중 [6-(2-클로로-이미다졸-1-일)-피리미딘-4-일]-시클로프로필-아민 (2.24 g, 9.53 mmol), xxxx (2.00 g, 4.76 mmol) 및 MeS03H (930 ㎕, 14.3 mol)의 혼합물을 밀봉된 튜브 안에서 90 ℃에서 가열하였다. 반응 혼합물을 실온으로 냉각시키고, CHCl3로 희석한 뒤, 포화 NaHC03 수용액으로 세척하였다. 유기층을 Na2S04로 건조하고 농축하였다. 잔류물을 CHCl3에 용해시키고, 컬럼 크로마토그래피(EtOAc/Hex/MeOH = 9/3/1)로 정제하여, 생성물을 백색 고체로 수득하였으며, 이를 CHCl3/MeOH로부터 재결정화하여 표제 화합물을 수득하였다 (1.15 g, 39 % 수율).[6- (2-Chloro-imidazol-1-yl) -pyrimidin-4-yl] -cyclopropyl-amine (2.24 g in 1,3-dimethyl-imidazolidin-2-one (4 mL) , 9.53 mmol), xxxx (2.00 g, 4.76 mmol) and MeSO 3 H (930 μl, 14.3 mol) were heated at 90 ° C. in a sealed tube. The reaction mixture was cooled to room temperature, diluted with CHCl 3 and washed with saturated aqueous NaHC0 3 solution. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was dissolved in CHCl 3 and purified by column chromatography (EtOAc / Hex / MeOH = 9/3/1) to give the product as a white solid, which was recrystallized from CHCl 3 / MeOH to give the title compound. (1.15 g, 39% yield).

Figure 112006091059442-pct00035
Figure 112006091059442-pct00035

적절한 출발 물질을 사용하여 상기 실시예에 기재된 과정을 반복하여, 하기 표 1에 제시한 바와 같은 하기 화학식 I의 화합물을 수득하였다.The procedure described in the examples above was repeated using the appropriate starting material to afford the compound of formula (I) as shown in Table 1 below.

Figure 112006091059442-pct00036
Figure 112006091059442-pct00036

Figure 112006091059442-pct00037
Figure 112006091059442-pct00037

Figure 112006091059442-pct00038
Figure 112006091059442-pct00038

Figure 112006091059442-pct00039
Figure 112006091059442-pct00039

Figure 112006091059442-pct00040
Figure 112006091059442-pct00040

Figure 112006091059442-pct00041
Figure 112006091059442-pct00041

Figure 112006091059442-pct00042
Figure 112006091059442-pct00042

Figure 112006091059442-pct00043
Figure 112006091059442-pct00043

Figure 112006091059442-pct00044
Figure 112006091059442-pct00044

Figure 112006091059442-pct00045
Figure 112006091059442-pct00045

Figure 112006091059442-pct00046
Figure 112006091059442-pct00046

Figure 112006091059442-pct00047
Figure 112006091059442-pct00047

Figure 112006091059442-pct00048
Figure 112006091059442-pct00048

Figure 112006091059442-pct00049
Figure 112006091059442-pct00049

Figure 112006091059442-pct00050
Figure 112006091059442-pct00050

Figure 112006091059442-pct00051
Figure 112006091059442-pct00051

Figure 112006091059442-pct00052
Figure 112006091059442-pct00052

Figure 112006091059442-pct00053
Figure 112006091059442-pct00053

Figure 112006091059442-pct00054
Figure 112006091059442-pct00054

Figure 112006091059442-pct00055
Figure 112006091059442-pct00055

Figure 112006091059442-pct00056
Figure 112006091059442-pct00056

Figure 112006091059442-pct00057
Figure 112006091059442-pct00057

Figure 112006091059442-pct00058
Figure 112006091059442-pct00058

Figure 112006091059442-pct00059
Figure 112006091059442-pct00059

Figure 112006091059442-pct00060
Figure 112006091059442-pct00060

Figure 112006091059442-pct00061
Figure 112006091059442-pct00061

Figure 112006091059442-pct00062
Figure 112006091059442-pct00062

Figure 112006091059442-pct00063
Figure 112006091059442-pct00063

Figure 112006091059442-pct00064
Figure 112006091059442-pct00064

Figure 112006091059442-pct00065
Figure 112006091059442-pct00065

Figure 112006091059442-pct00066
Figure 112006091059442-pct00066

Figure 112006091059442-pct00067
Figure 112006091059442-pct00067

Figure 112006091059442-pct00068
Figure 112006091059442-pct00068

Figure 112006091059442-pct00069
Figure 112006091059442-pct00069

Figure 112006091059442-pct00070
Figure 112006091059442-pct00070

Figure 112006091059442-pct00071
Figure 112006091059442-pct00071

Figure 112006091059442-pct00072
Figure 112006091059442-pct00072

Figure 112006091059442-pct00073
Figure 112006091059442-pct00073

Figure 112006091059442-pct00074
Figure 112006091059442-pct00074

Figure 112006091059442-pct00075
Figure 112006091059442-pct00075

검정black

본 발명의 화합물이 모(母) 32D 세포에 비하여 BCR-Abl (32D-p210)을 발현하는 32D 세포의 증식을 선택적으로 억제하는 능력을 측정하기 위하여 본 발명의 화합물을 검정하였다. 이러한 BCR-Abl로 형질전환된 세포의 증식을 선택적으로 억제하는 화합물을 야생형 또는 돌연변이형 BCR-Abl을 발현하는 Ba/F3 세포 상에서의 항-증식성 활성에 대하여 시험하였다. 또한, 화합물이 FGFR3, b-RAF, Abl, BMX, BTK, CHK2, c- RAF, CSK, c-SRC, Fes, Flt3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MST2, NEK2, p70S6K, PDGFRa, PKA,PKBa, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 및 TrkB 키나제를 억제하는 능력을 측정하기 위하여 화합물을 검정하였다.Compounds of the invention were assayed to determine their ability to selectively inhibit proliferation of 32D cells expressing BCR-Abl (32D-p210) as compared to parent 32D cells. Compounds that selectively inhibit the proliferation of these BCR-Abl transformed cells were tested for anti-proliferative activity on Ba / F3 cells expressing wild-type or mutant BCR-Abl. The compounds also contain FGFR3, b-RAF, Abl, BMX, BTK, CHK2, c-RAF, CSK, c-SRC, Fes, Flt3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MST2, NEK2, Compounds were assayed to determine their ability to inhibit p70S6K, PDGFRa, PKA, PKBa, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and TrkB kinase.

BCRBCR -- AblAbl 의존적 세포 증식의 억제 (대량 검정법) Inhibition of dependent cell proliferation (mass assay)

사용된 쥐 세포주는 BCR-Abl cDNA(32D-p210)로 형질전환된 32D 조혈 전구세포주이다. 이 세포를 페니실린 50 g/mL, 스트렙토마이신 50 g/mL 및 L-글루타민 200 mM로 보충한 RPMI/10% 소 태아 혈청 (RPMI/FCS)에서 배양하였다. 형질전환되지 않은 32D 세포를 유사하게, IL3 공급원으로서 WEHI 조절된 배지 15%를 첨가하여 배양하였다.The mouse cell line used is a 32D hematopoietic progenitor cell line transformed with BCR-Abl cDNA (32D-p210). The cells were cultured in RPMI / 10% fetal bovine serum (RPMI / FCS) supplemented with 50 g / mL penicillin, 50 g / mL streptomycin and 200 mM L-glutamine. Untransformed 32D cells were similarly cultured with the addition of 15% WEHI regulated medium as an IL3 source.

32D 또는 32D-p210 세포 현탁액 50 ㎕을 그레이너(Greiner) 384 웰 마이크로플레이트 (검정색)에 웰 당 세포 5000개의 밀도로 플레이팅하였다. 시험 화합물 (DMSO 스톡 용액 중 1 mM) 50 nl을 각 웰에 가하였다 (STI571은 양성 대조군으로서 포함시켰다). 세포를 37 ℃, 5% CO2 하에서 72시간 동안 배양하였다. 60% 알라마르 블루 용액 (Alamar Blue; Tek diagnostics) 10 ㎕을 각 웰에 가한 뒤, 세포를 추가로 24시간 인큐베이션하였다. 아퀘스트(Acquest)TM 시스템 (Molecular Devices)을 사용하여 형광 강도 (530 nm에서 여기, 580 nm에서 방출)를 측정하였다.50 μl of a 32D or 32D-p210 cell suspension was plated at a density of 5000 cells per well in a Greiner 384 well microplate (black). 50 nl of test compound (1 mM in DMSO stock solution) was added to each well (STI571 was included as a positive control). Cells were incubated for 72 hours at 37 ° C., 5% CO 2 . 10 μl of 60% Alamar Blue (Tek diagnostics) was added to each well and the cells were further incubated for 24 hours. Fluorescence intensity (excitation at 530 nm, emission at 580 nm) was measured using an Acquest ™ system (Molecular Devices).

BCRBCR -- AblAbl 의존적 세포 증식의 억제 Inhibition of dependent cell proliferation

32D-p210 세포를 웰 당 세포 15000개의 밀도로 96 웰 TC 플레이트에 플레이팅하였다. 시험 화합물의 2배 순차 희석액 50 ㎕ (Cmax는 40 μM)을 각 웰에 가하였다 (STI571은 양성 대조군으로서 포함시켰다). 세포를 37 ℃, 5% CO2 하에서 48시간 동안 배양한 뒤, MTT (Promega) 15 ㎕을 각 웰에 가하고, 세포를 추가로 5시간 인큐베이션하였다. 570 nm에서의 광학 밀도를 분광 측정기로 측정하고, 사용량-반응성 곡선으로부터 IC50 값, 즉 50% 억제를 위해 필요한 화합물의 농도를 측정하였다.32D-p210 cells were plated in 96 well TC plates at a density of 15000 cells per well. 50 μl of 2-fold serial dilutions of the test compound (C max is 40 μM) were added to each well (STI571 was included as a positive control). Cells were incubated for 48 hours at 37 ° C., 5% CO 2 , then 15 μl of MTT (Promega) was added to each well and the cells were incubated for an additional 5 hours. The optical density at 570 nm was measured with a spectrometer and the IC 50 value, ie the concentration of compound required for 50% inhibition, was determined from the usage-reactivity curve.

세포 주기 분배에 대한 효과Effect on Cell Cycle Distribution

32D 및 32D-p210 세포를 6웰 TC 플레이트에, 웰 당 배지 5 ml 중 2.5 x 106 세포의 밀도로 플레이팅하고, 1 또는 10 μM의 시험 화합물을 가하였다 (STI571은 대조군으로서 포함시켰다). 그런 다음 세포를 37 ℃, 5% CO2 하에서 24 내지 48시간 동안 인큐베이션 하였다. 세포 현탁액 2 ml을 PBS로 세척하고, 70% EtOH로 1시간 동안 고정시키고, PBS/EDTA/RNA 분해효소 A로 30분간 처리하였다. 프로피듐 요오드 (Cf = 10 ㎍/ml)를 가한 뒤, 형광 강도를 팩스칼리버(FACScalibur)TM 시스템 (BD Biosciences)에서 유세포 분석법으로 측정하였다. 본 발명의 시험 화합물은 32D-p210 세포에 대하여 아폽토시스 효과를 나타냈으나, 32D 모 세포에서는 아폽토시스를 유도하지 않았다.32D and 32D-p210 cells were plated in 6-well TC plates at a density of 2.5 × 10 6 cells in 5 ml of medium per well and 1 or 10 μM of test compound was added (STI571 was included as a control). Cells were then incubated for 24 to 48 hours at 37 ° C., 5% CO 2 . 2 ml of cell suspension were washed with PBS, fixed with 70% EtOH for 1 hour and treated with PBS / EDTA / RNA Degradase A for 30 minutes. After adding propidium iodine (Cf = 10 μg / ml), the fluorescence intensity was measured by flow cytometry on a FACScalibur ™ system (BD Biosciences). The test compounds of the present invention showed an apoptosis effect on 32D-p210 cells but did not induce apoptosis in 32D parent cells.

세포적Cellular BCRBCR -- AblAbl 자가인산화에Autophosphorylation 대한 효과 For effect

BCR-Abl 자가인산화를 c-abl 특이적 포획(capture) 항체 및 항-포스포티로신 항체를 사용하여, 포획 엘라이자(ELISA)로 측정하였다. 32D-p210 세포를 96 웰 TC 플레이트 상에, 웰 당 배지 50 ㎕ 중 2 x 105로 플레이팅하였다. 시험 화합물 (Cmax는 10 μM)의 2배 순차 희석액을 각 웰에 가하였다 (STI571은 양성 대조군으로 포함시켰다). 세포를 37 ℃, 5% CO2 하에서 90시간 동안 인큐베이션 하였다. 그런 다음, 세포를 얼음 상에서 프로테아제 및 포스파타아제 억제제를 함유하는 용해 완충액 (50 mM 트리스-HCl, pH 7.4, 150 mM NaCl, 5 mM EDTA, 1 mM EGTA 및 1% NP-40) 150 ㎕로 처리하였다. 세포 용해물 50 ㎕를 항-abl 특이적 항체로 미리 코팅시키고, 블록킹 해 둔 96 웰 광학플레이트에 가하였다. 플레이트를 4℃에서 4시간 인큐베이션하였다. TBS-트윈 20 완충액으로 세척한 뒤, 알칼리-포스파타제-접합된 항-포스포티로신 항체를 가하고, 플레이트는 밤새 4℃에서 인큐베이션하였다. TBS-트윈 20 완충액으로 세척한 뒤, 발광성 기질 90 ㎕을 가한 뒤, 발광을 아퀘스트TM 시스템 (Molecular Devices)으로 정량화하였다. BCR-Abl 발현 세포의 증식을 억제하는 본 발명의 시험 화합물은 세포적 BCR-Abl 자가인산화를 사용량 의존적인 방식으로 억제하였다.BCR-Abl autophosphorylation was measured by capture ELISA (ELISA) using c-abl specific capture antibodies and anti-phosphotyrosine antibodies. 32D-p210 cells were plated on 96 well TC plates at 2 × 10 5 in 50 μl of medium per well. Two-fold serial dilutions of test compound (C max is 10 μM) were added to each well (STI571 was included as a positive control). Cells were incubated for 90 hours at 37 ° C., 5% CO 2 . Cells are then treated with 150 μl of lysis buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 5 mM EDTA, 1 mM EGTA, and 1% NP-40) containing protease and phosphatase inhibitors on ice. It was. 50 μl of cell lysate was previously coated with anti-abl specific antibody and added to a blocked 96 well optical plate. Plates were incubated at 4 ° C. for 4 hours. After washing with TBS-Tween 20 buffer, alkali-phosphatase-conjugated anti-phosphotyrosine antibody was added and plates were incubated overnight at 4 ° C. After washing with TBS-Tween 20 buffer, 90 [mu] l of luminescent substrate was added and luminescence was quantified by the Arquest ™ system (Molecular Devices). Test compounds of the invention that inhibit the proliferation of BCR-Abl expressing cells inhibited cellular BCR-Abl autophosphorylation in a dose dependent manner.

돌연변이형Mutant BcrBcr -- ablabl 을 발현하는 세포의 증식에 대한 효과On the proliferation of cells expressing

본 발명의 화합물을 야생형 또는 STI571에 대하여 내성 또는 감소된 민감성을 지니는 돌연변이형 BCR-Abl (G250E, E255V, T315I, F317L, M351T)을 발현하는 Ba/F3 세포에서 그들의 항증식성 효과에 대하여 시험하였다. 돌연변이형 BCR-Abl-발현 세포 및 비-형질전환된 세포에 대한 이들 화합물의 항증식성 효과를 상기 기재한 바와 같이 10, 3.3, 1.1 및 0.37 μM에서 시험하였다 (IL3를 포함하지 않는 배지 중에서). 비-형질전환된 세포에 대하여 독성을 가지지 않는 상기 화합물의 IC50 값을 상기 기재한 바와 같이 수득한 사용량-반응성 곡선으로부터 결정하였다.Compounds of the invention were tested for their antiproliferative effects in Ba / F3 cells expressing mutant BCR-Abl (G250E, E255V, T315I, F317L, M351T) with resistance or reduced sensitivity to wild type or STI571. . The antiproliferative effects of these compounds on mutant BCR-Abl-expressing cells and non-transformed cells were tested at 10, 3.3, 1.1 and 0.37 μM as described above (in medium without IL3). . IC 50 values of the compounds that are not toxic to non-transformed cells were determined from the dosing-reactivity curves obtained as described above.

FGFR3FGFR3 (효소 검정)  (Enzyme assay)

정제된 FGFR3 (Upstate)를 이용한 키나제 활성 검정을 키나제 완충액 (30 mM 트리스-HCl pH 7.5, 15 mM MgCl2, 4.5 mM MnCl2, 15 M Na3V04 및 50 g/mL BSA) 및 기질 (5 g/mL 바이오틴-폴리-EY(Glu, Tyr) (CIS-US, Inc.) 및 3 M ATP) 중에 효소 0.25 ㎍/mL을 포함하는 최종 부피 10 ㎕로 실시하였다. 2종의 용액을 제조하였는데, 키나제 완충액 중 FGFR3 효소를 함유하는 제1 용액 5 ㎕을 먼저 384 포맷 프록시플레이트(ProxiPlate)® (퍼킨-엘머)에 분산시킨 뒤, DMSO에 용해된 화합물 50 nL을 가하고, 그후 키나제 완충액 중 기질 (폴리-EY) 및 ATP를 함유하는 제2 용액 5 ㎕을 각 웰에 가하였다. 반응물을 실온에서 1시간 동안 인큐베이션 하고, 30 mM 트리스-HCl pH7.5, 0.5 M KF, 50 mM ETDA, 0.2 mg/mL BSA, 15 g/mL 스트렙타비딘-XL665 (CIS-US, Inc.) 및 150 ng/mL 크립테이트 접합된 항-포스포티로신 항체 (CIS-US, Inc.)를 함유하는 HTRF 탐지 혼합물 10 ㎕을 가하여 중지하였다. 1시간 동안 실온에서 인큐베이션하여 스트렙타비딘-바이오틴이 상호작용하도록 한 뒤, 아날리스트(Analyst) GT (Molecular Devices Corp.)로 시간에 따른 발광 신호를 읽었다. 12개의 농도 (50 μM 내지 0.28 nM의 1:3 희석)에서의 각 화합물의 억제 백분율에 대한 직선 회귀 분석에 의하여 IC50 값을 계산하였다. 이 검정에서, 본 발명의 화합물은 10 nM 내지 2 μM 범위의 IC50 값을 나타냈다.Kinase activity assays using purified FGFR3 (Upstate) were performed using kinase buffer (30 mM Tris-HCl pH 7.5, 15 mM MgCl 2 , 4.5 mM MnCl 2 , 15 M Na 3 V0 4 and 50 g / mL BSA) and substrate (5). A final volume of 10 μl containing 0.25 μg / mL of enzyme in g / mL Biotin-Poly-EY (Glu, Tyr) (CIS-US, Inc.) and 3 M ATP). Was prepared a solution of the two kinds kinase claim 384 format proxy plate for 5 ㎕ 1 solution first (ProxiPlate) containing the FGFR3 enzyme in buffer ® (Perkin-Elmer) after dispersed in, was added to the compound 50 nL dissolved in DMSO Then, 5 μl of a second solution containing substrate (poly-EY) and ATP in kinase buffer was added to each well. The reaction was incubated for 1 hour at room temperature, 30 mM Tris-HCl pH7.5, 0.5 M KF, 50 mM ETDA, 0.2 mg / mL BSA, 15 g / mL streptavidin-XL665 (CIS-US, Inc.) And 10 μl of HTRF detection mixture containing 150 ng / mL cryptate conjugated anti-phosphotyrosine antibody (CIS-US, Inc.). After incubation at room temperature for 1 hour to allow streptavidin-biotin to interact, the luminescent signal over time was read with Analyst GT (Molecular Devices Corp.). IC 50 values were calculated by linear regression analysis of percent inhibition of each compound at 12 concentrations (1: 3 dilution of 50 μM to 0.28 nM). In this assay, the compounds of the present invention exhibited IC 50 values ranging from 10 nM to 2 μM.

FGFR3FGFR3 (세포 검정)  (Cell assay)

본 발명의 화합물을 FGFR3 세포적 키나제 활성에 의존적인, 형질전환된 Ba/F3-TEL-FGFR3 세포의 증식을 억제하는 그들의 능력에 대하여 시험하였다. Ba/F3-TEL-FGFR3을 배양 배지로서 10% 소 태아 혈청을 보충한 RPMI 1640을 사용하여 현탁액 중에서 800,000 세포/mL까지 배양하였다. 세포를 384-웰 포맷 플레이트에 50 ㎕ 배양 배지 중 5000 세포/웰로 분산시켰다. 본 발명의 화합물을 디메틸술폭시드 (DMSO) 중에 용해하고 희석하였다. 12 지점의 1:3 순차 희석액을 DMSO로 제조하여 전형적으로 10 mM 내지 0.05 μM 범위의 농도 구배를 형성하였다. 세포에 희석한 화합물 50 ㎕를 가한 뒤, 세포 배양 인큐베이터에서 48시간 인큐베이션하였다. 증식하는 세포에 의해 형성되는 환경 감소를 모니터하는데 사용될 수 있는 알라마르 블루 (TREK Diagnostic Systems)를 세포에 최종 농도 10%로 가하였다. 37 ℃ 세포 배양 인큐베이터에서 추가로 4시간 더 인큐베이션 한 뒤, 감소된 알라마르 블루 (530 nm에서 여기, 580 nm에서 방출)로부터의 형광 신호를 아날리스트 GT (Molecular Devices Corp.)로 정량화하였다. 12 농도점에서의 각 화합물의 억제 백분율에 대한 직선 회귀 분석에 의하여 IC50 값을 계산하였다. Compounds of the invention were tested for their ability to inhibit proliferation of transformed Ba / F3-TEL-FGFR3 cells, which depend on FGFR3 cellular kinase activity. Ba / F3-TEL-FGFR3 was cultured up to 800,000 cells / mL in suspension using RPMI 1640 supplemented with 10% fetal bovine serum as the culture medium. Cells were dispersed at 5000 cells / well in 50 μl culture medium in 384-well format plates. Compounds of the invention were dissolved and diluted in dimethylsulfoxide (DMSO). Twelve spot 1: 3 serial dilutions were prepared in DMSO to form concentration gradients typically ranging from 10 mM to 0.05 μM. 50 μl of the diluted compound was added to the cells, and then incubated for 48 hours in a cell culture incubator. Alamar Blue (TREK Diagnostic Systems) was added to the cells at a final concentration of 10%, which could be used to monitor the environmental degradation formed by the proliferating cells. After an additional 4 hours of incubation in a 37 ° C. cell culture incubator, fluorescence signals from reduced Alamar blue (excitation at 530 nm, emission at 580 nm) were quantified with Analog GT (Molecular Devices Corp.). IC 50 values were calculated by linear regression analysis of percent inhibition of each compound at 12 concentration points.

FLT3FLT3 및  And PDGFRPDGFR β (세포 검정) β (cell assay)

본 발명의 화합물의 FLT3 및 PDGFR의 세포적 활성에 대한 효과에 대한 검정을, Ba/F3-TEL-FGFR3 대신 Ba/F3-FLT3-ITD 및 Ba/F3-Tel-PDGFRβ를 각각 사용한 것을 제외하고는 상기 FGFR3 세포적 활성에 대하여 기술한 바와 동일한 방법으로 실시하였다.Assays for the effect of the compounds of the invention on the cellular activities of FLT3 and PDGFR were used except Ba / F3-FLT3-ITD and Ba / F3-Tel-PDGFRβ, respectively, instead of Ba / F3-TEL-FGFR3. The same method as described for the FGFR3 cellular activity was carried out.

b-b- RafRaf - 효소 검정 -Enzyme assay

본 발명의 화합물을 b-Raf의 활성을 억제하는 그들의 능력에 대하여 시험하였다. 검정색 벽과 투명한 바닥을 가진 384 웰 맥시소르프(MaxiSorp) 플레이트 (NUNC)에서 검정을 실시하였다. 기질인 IκBα를 DPBS 중에 희석하고 (1:750), 15 ㎕를 각 웰에 가하였다. 플레이트를 밤새 4 ℃에서 인큐베이션 하고, EMBLA 플레이트 세척기를 사용하여 TBST (25 mM 트리스, pH 8.0, 150 mM NaCl 및 0.05% 트윈-20)로 3회 세척하였다.Compounds of the invention were tested for their ability to inhibit the activity of b-Raf. The assay was performed on 384 well MaxiSorp plates (NUNC) with black walls and clear bottoms. Substrate IκBα was diluted in DPBS (1: 750) and 15 μl was added to each well. Plates were incubated overnight at 4 ° C. and washed three times with TBST (25 mM Tris, pH 8.0, 150 mM NaCl and 0.05% Tween-20) using an EMBLA plate washer.

플레이트를 실온에서 3시간 동안 수퍼블록(Superblock)으로 블로킹하고 (15 ㎕/웰), TBST로 3회 세척한 뒤 톡톡 두들겨 건조시켰다. 20 μM ATP 을 함유하는 검정 완충액 (10 ㎕)을 각 웰에 가한 뒤, 화합물 100 nl 또는 500 nl을 가하였다. B-Raf를 검정 완충액으로 희석하고 (1 ㎕를 25 ㎕로), 희석된 b-Raf 10 ㎕을 각 웰에 가하였다 (0.4 ㎍/웰). 플레이트를 실온에서 2.5 시간 인큐베이션하였다. 플레이트를 TBST로 6회 세척하여 키나제 반응을 중지시켰다. 포스포-IκBα (Ser32/36) 항체를 수퍼블록으로 희석하고 (1:10,000), 15 ㎕을 각 웰에 가하였다. 플레이트를 4 ℃에서 밤새 인큐베이션 하고, TBST로 6회 세척하였다. AP-접합된 염소-항-마우스 IgG를 수퍼블록에 희석하고 (1:1,500), 15 ㎕을 각 웰에 가하였다. 플레이트를 실온에서 1시간 인큐베이션 하고, TBST로 6회 세척하였다. 형광 아토포스(Attophos) AP 기질 (Promega) 15 ㎕을 각 웰에 가하고, 플레이트를 실온에서 15분간 인큐베이션하였다. 아퀘스트 또는 아날리스트 GT 상에서 형광 강도 프로그램(Fluorescence Intensity Program)을 이용하여 플레이트를 읽었다 (455 nm에서 여기, 580 nm에서 방출).Plates were blocked with Superblock for 3 hours at room temperature (15 μl / well), washed three times with TBST and patted dry. Assay buffer (10 μl) containing 20 μM ATP was added to each well, followed by 100 nl or 500 nl of compound. B-Raf was diluted with assay buffer (1 μl to 25 μl) and 10 μl of diluted b-Raf was added to each well (0.4 μg / well). Plates were incubated for 2.5 hours at room temperature. The plate was washed six times with TBST to stop the kinase reaction. Phospho-IκBα (Ser32 / 36) antibody was diluted with superblock (1: 10,000) and 15 μl was added to each well. Plates were incubated overnight at 4 ° C. and washed six times with TBST. AP-conjugated goat-anti-mouse IgG was diluted in superblock (1: 1,500) and 15 μl was added to each well. Plates were incubated for 1 hour at room temperature and washed six times with TBST. 15 μl of fluorescent Attophos AP substrate (Promega) was added to each well and the plate was incubated for 15 minutes at room temperature. Plates were read using Fluorescence Intensity Program on Arquest or Analyst GT (excitation at 455 nm, emission at 580 nm).

b-b- RafRaf - 세포 검정 -Cell assay

본 발명의 화합물을 MEK 인산화 억제능에 대하여 A375 세포에서 시험하였다. A375 세포주 (ATCC)는 인간 흑색종 환자로부터 유래되었고, B-Raf 유전자 상에 V599E 돌연변이를 가지고 있다. B-Raf의 돌연변이로 인하여 인산화된 MEK의 수준이 상승한다. 반-융합성 내지 융합성 A375 세포를 화합물과 함께 혈청 불포함 배지, 37℃에서 2시간 인큐베이션하였다. 그후 세포를 냉각된 PBS로 1회 세척하고, 1% 트리톤 X100을 함유하는 용해 완충액으로 용해시켰다. 원심분리 후, 상등액에 대하여 SDS-PAGE한 뒤, 니트로셀룰로스 막으로 옮겼다. 그런 다음, 막에서 항-포스포-MEK 항체 (ser217/221) (Cell Signaling)를 이용하여 웨스턴 블롯팅하였다. 인산화된 MEK의 양을 니트로셀룰로스 막 상의 포스포-MEK 밴드의 밀도로 모니터하였다.Compounds of the invention were tested in A375 cells for their ability to inhibit MEK phosphorylation. A375 cell line (ATCC) was derived from human melanoma patients and has a V599E mutation on the B-Raf gene. Mutations in B-Raf cause elevated levels of phosphorylated MEK. Semi-fusion to confluent A375 cells were incubated with compound for 2 hours at 37 ° C. in serum free medium. Cells were then washed once with cold PBS and lysed with lysis buffer containing 1% Triton X100. After centrifugation, SDS-PAGE was performed on the supernatant and then transferred to nitrocellulose membrane. Then, the membranes were Western blotting using anti-phospho-MEK antibody (ser217 / 221) (Cell Signaling). The amount of phosphorylated MEK was monitored by the density of phospho-MEK bands on the nitrocellulose membrane.

업스테이트 Upstate 키나제프로파일러Kinase Profiler (( UpstateUpstate KinaseProfilerKinaseProfiler )) TMTM - 방사능- - radiation- 효소적Enzymatic 필터 결합 검정 Filter coupling test

본 발명의 화합물에 대하여 키나제 패널의 개별적인 구성원을 억제하는 능력을 평가하였다. 다음의 포괄적인 방법에 따라, 최종 농도 10 μM에서 화합물을 두 세트로 시험하였다. 키나제 완충액 조성물 및 기질은 "업스테이트 키나제프로파일러TM" 패널에 포함된 상이한 키나제에 따라 다르다는 것을 주지해야 한다. 키나제 완충액 (2,5 ㎕, 1Ox - 필요한 경우 MnCl2 함유), 활성 키나제 (0.001-0.01 유닛; 2.5 ㎕), 키나제 완충액 중 특이적 또는 폴리(Glu4-Tyr) 펩티드 (5 내지 500 μM 또는 0.01 mg/ml) 및 키나제 완충액 (50 μM; 5 ㎕)을 얼음 상에서 에펜도르프 튜브에 혼합하였다. Mg/ATP 믹스 (10 ㎕; 67.5 (또는 33.75) mM MgCl2, 450 (또는 225) μM ATP 및 1 μCi/㎕[γ-32P]-ATP (3000 Ci/mmol))을 가하고, 반응물을 약 30 ℃에서 약 10분간 인큐베이션하였다. 2 cm x 2 cm P81 (양성 전하를 띠는 펩티드 기질을 위한 포스포셀룰로스) 또는 왓맨(Whatman) 1번 (폴리 (Glu4-Tyr) 펩티드 기질을 위함) 페이퍼 상에 반응 혼합물을 스포팅 (20 ㎕)하였다. 검정용 페이퍼를 0.75% 인산으로 4회 각 5분씩 세척한 뒤, 아세톤으로 5분간 1회 세척하였다. 검정용 페이퍼를 섬광 바이알로 옮기고, 섬광 혼합물 5 ml을 가한 뒤, 펩티드 기질에 대한 P 혼입 (cpm)을 벡맨(Beckman) 섬광 계수계로 정량화하였다. 억제 백분율을 각 반응에 대하여 계산하였다.Compounds of the invention were evaluated for their ability to inhibit individual members of the kinase panel. According to the following comprehensive method, two sets of compounds were tested at a final concentration of 10 μM. It should be noted that the kinase buffer compositions and substrates depend on the different kinases included in the "Upstate Kinase Profiler ™ " panel. Kinase buffer (2,5 μl, 10 × -containing MnCl 2 if necessary), active kinase (0.001-0.01 units; 2.5 μl), specific or poly (Glu4-Tyr) peptides (5-500 μM or 0.01 mg in kinase buffer) / ml) and kinase buffer (50 μM; 5 μl) were mixed in eppendorf tubes on ice. Mg / ATP mix (10 μl; 67.5 (or 33.75) mM MgCl 2 , 450 (or 225) μM ATP and 1 μCi / μl [γ- 32 P] -ATP (3000 Ci / mmol)) were added and the reaction was quenched. Incubate at 30 ° C. for about 10 minutes. Spotting the reaction mixture on a 2 cm x 2 cm P81 (phosphocellulose for positively charged peptide substrate) or Whatman 1 (for poly (Glu4-Tyr) peptide substrate) paper (20 μl) It was. The assay paper was washed four times with 0.75% phosphoric acid each for 5 minutes and then once with acetone for 5 minutes. Assay paper was transferred to scintillation vials, 5 ml of scintillation mixture was added, and P incorporation (cpm) for peptide substrates was quantified with a Beckman scintillation counter. Percent inhibition was calculated for each response.

화학식 I의 화합물의 유리형 또는 제약적으로 허용가능한 염 형태는 본 명세서에 기재한 시험관내 시험에 의해 나타낸 바와 같은 가치있는 약리학적 특성을 나타낸다. 예를 들어, 바람직하게는 화학식 I의 화합물은 야생형 BCR-Abl 및 G250E, E255V, T315I, F317L 및 M351T BCR-Abl 돌연변이체에 대하여 1 x 10-10 내지 1 x 10-5 M 범위, 바람직하게는 50 nM 미만의 IC50을 나타낸다. 화학식 I의 화합물은 바람직하게는, Abl, Bcr-abl, c-RAF, c-SRC, JNK2α2, lck, MKK6, PDGFRa, SAPK2α, SAPK2β, Tie2 및 TrkB 키나제에 대하여 10 mM의 농도에서 50%를 넘는, 바람직하게는 약 70%를 넘는 억제 백분율을 나타낸다. 예를 들어: The free or pharmaceutically acceptable salt form of the compound of formula (I) exhibits valuable pharmacological properties as indicated by the in vitro tests described herein. For example, preferably the compound of formula I ranges from 1 × 10 −10 to 1 × 10 −5 M, preferably for wild type BCR-Abl and G250E, E255V, T315I, F317L and M351T BCR-Abl mutants An IC 50 of less than 50 nM is shown. Compounds of formula (I) are preferably greater than 50% at concentrations of 10 mM for Abl, Bcr-abl, c-RAF, c-SRC, JNK2α2, lck, MKK6, PDGFRa, SAPK2α, SAPK2β, Tie2 and TrkB kinase Preferably, a percentage of inhibition above about 70%. E.g:

a) N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드 (화합물 27)은 야생형, G250E, E255V, T315I, F317L 및 M351T Bcr-abl에 대하여 각각 0.5 nM 미만, 20 nM, 36 nM, 59 nM, 0.5 nM 미만 및 0.5 nM 미만의 IC50을 나타낸다.a) N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (4-methyl- Imidazol-1-yl) -5-trifluoromethyl-benzamide (Compound 27) was less than 0.5 nM, 20 nM, 36 nM, 59 for wild type, G250E, E255V, T315I, F317L and M351T Bcr-abl, respectively IC 50 of nM, less than 0.5 nM and less than 0.5 nM.

b) N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노] -4-메틸-페닐}-4-(4-에틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드 (화합물 25)는 FGFR3 효소 및 세포 검정에 대하여 각각 130 nM 및 34 nM, FLT3 및 PDGFRβ에 대하여 각각 149 nM 및 2 nM의 IC50을 나타낸다.b) N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4- (4-ethyl- Piperazin-1-ylmethyl) -3-trifluoromethyl-benzamide (Compound 25) has an IC of 130 nM and 34 nM for FGFR3 enzyme and cell assay, and 149 nM and 2 nM for FLT3 and PDGFRβ, respectively. 50 is represented.

c) N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-(4-메틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드 (화합물 26)는 FGFR3 효소 및 세포 검정에 대하여 각각 65 nM 및 37 nM, FLT3 및 PDGFRβ에 대하여 각각 89 nM 및 2 nM의 IC50을 나타낸다.c) N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4- (4-methyl- Piperazin-1-ylmethyl) -3-trifluoromethyl-benzamide (Compound 26) had an IC of 65 nM and 37 nM for FGFR3 enzyme and cell assay, 89 nM and 2 nM for FLT3 and PDGFRβ, respectively 50 is represented.

d) N-(4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드 (화합물 3)은 10 μM의 농도에서, 야생형 Abl (97%), c-RAF (100%), c-SRC (99%), JNK2α2 (97%), lck(100%), MKK6 (100%), PDGFRα (97%), SAPK2α(100%), SAPK2β (100%), Tie2 (99%) 및 TrkB (97%)의 억제를 나타낸다 (예를 들어, 100%는 완전한 억제를 의미하고, 0%는 전혀 억제하지 못하는 것을 의미한다).d) N- (4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino}- Phenyl) -3-trifluoromethyl-benzamide (Compound 3), at a concentration of 10 μM, wild-type Abl (97%), c-RAF (100%), c-SRC (99%), JNK2α2 (97% ), lck (100%), MKK6 (100%), PDGFRα (97%), SAPK2α (100%), SAPK2β (100%), Tie2 (99%) and TrkB (97%). 100% means complete inhibition, 0% means no inhibition at all).

본 명세서에 기재된 실시예 및 실시태양은 예시적인 목적일 뿐이며, 본 발명의 본지에 따른 다양한 변형 또는 변경이 당업자에게 암시되어 있고, 본 명세서 및 첨부된 청구항의 보호 범위의 본지 및 영역 내에 포함될 것이다. 본 명세서에 인용된 모든 간행물, 특허 및 특허 출원은 모든 목적으로 본 명세서에 포함된다.The examples and embodiments described herein are for illustrative purposes only and various modifications or changes in accordance with the subject matter of this invention are implied to those skilled in the art and will be included within the spirit and scope of the protection scope of this specification and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims (9)

하기 화학식 I의 화합물, 그의 제약적으로 허용가능한 염 또는 수화물.A compound of formula (I), a pharmaceutically acceptable salt or hydrate thereof. <화학식 I><Formula I>
Figure 112009001421078-pct00076
Figure 112009001421078-pct00076
 상기 식에서, m은 0이며;Wherein m is 0; n은 0 및 1로부터 선택되며;n is selected from 0 and 1; R1은 -XNR5R6, 및 -XS(O)0-2R5로부터 선택되고; 여기서 X는 결합이거나, C1-4알킬렌이며; R5는 수소, C1-6알킬, C6-10아릴-C0-4알킬, N, O 및 S로부터 선택된 1 이상의 원자를 함유하는 C5-10헤테로아릴-C0-4알킬, C3-10시클로알킬-C0-4알킬, 및 1 이상의 N 원자를 함유하는 C3-10헤테로시클로알킬-C0-4알킬로부터 선택되고; R6는 수소 및 C1-6알킬로부터 선택되거나; 또는 R5 및 R6는 이들이 결합되어 있는 질소 원자와 함께 헤테로시클로알킬을 형성하고; R5 또는 R5 및 R6의 조합 내의 아릴, 헤테로아릴, 시클로알킬 및 헤테로시클로알킬은 할로, 시아노, C1-6알킬, C1-6알콕시, -XNR7R8, -XOR7, -XC(O)NR7R8, -XC(O)NR7XNR7R8, -XNR7XOR7, -XNR7C(O)R8, 및 -XR9로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 치환 또는 비치환될 수 있고; 여기서, X는 결합 또는 C1-4알킬렌이고; R7 및 R8은 독립적으로 수소 및 C1-4알킬로 이루어진 군으로부터 선택되며; R9은 N 및 O로부터 선택된 1 이상의 원자를 함유하는 C3-10헤테로시클로알킬, 및 1 이상의 N 원자를 함유하는 C5-10헤테로아릴로부터 선택되며; 상기 R9의 헤테로시클로알킬 또는 헤테로아릴은 C1-4알킬로 치환 또는 비치환되고; R 1 is selected from —XNR 5 R 6 , and —XS (O) 0-2 R 5 ; Wherein X is a bond or C 1-4 alkylene; R 5 is C 5-10 heteroaryl-C 0-4 alkyl, C containing one or more atoms selected from hydrogen, C 1-6 alkyl, C 6-10 aryl-C 0-4 alkyl, N, O and S 3-10 cycloalkyl-C 0-4 alkyl and C 3-10 heterocycloalkyl-C 0-4 alkyl containing at least one N atom; R 6 is selected from hydrogen and C 1-6 alkyl; Or R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocycloalkyl; Aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R 5 or a combination of R 5 and R 6 are halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —XNR 7 R 8 , —XOR 7 , 1 to 3 independently selected from -XC (O) NR 7 R 8 , -XC (O) NR 7 XNR 7 R 8 , -XNR 7 XOR 7 , -XNR 7 C (O) R 8 , and -XR 9 Substituted or unsubstituted with 2 radicals; Wherein X is a bond or C 1-4 alkylene; R 7 and R 8 are independently selected from the group consisting of hydrogen and C 1-4 alkyl; R 9 is selected from C 3-10 heterocycloalkyl containing at least one atom selected from N and O, and C 5-10 heteroaryl containing at least one N atom; The heterocycloalkyl or heteroaryl of R 9 is unsubstituted or substituted with C 1-4 alkyl; R2 및 R4는 독립적으로 C1-4알킬로부터 선택되고; R 2 and R 4 are independently selected from C 1-4 alkyl; R3는 -NR10R11, 및 -NR10C(O)R11로부터 선택되고; 여기서, R10은 수소이고; R11은 C6-10아릴이며; R11의 아릴은 할로, C1-6알킬, C1-6알콕시, -NR12C(O)R13, -NR12C(O)NR12R13, -C(O)NR12R13, -NR12S(O)0-2R13 및 -S(O)0-2NR12R13로부터 선택되는 1 내지 3개의 라디칼로 치환 또는 비치환되고; R12는 수소이고; R13은 C6-10아릴, 및 N, O 및 S로부터 선택된 1 이상의 원자를 함유하는 C5-10헤테로아릴로부터 선택되며; R13의 아릴 또는 헤테로아릴은 할로, C1-6알킬, 할로-치환된-C1-6알킬, -XNR7R8, C6-10아릴-C0-4알킬, 1 이상의 N 원자를 함유하는 C5-10헤테로아릴-C0-4알킬, N 및 O로부터 선택된 1 이상의 원자를 함유하는 C3-10헤테로시클로알킬-C0-4알콕시 및 C3-10헤테로시클로알킬-C0-4알킬로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 치환 또는 비치환되고; 여기서, X, R7 및 R8은 상기 정의한 바와 같고, R13의 아릴 또는 헤테로아릴 치환체는 C1-6알킬, 히드록시-치환된-C1-6알킬, 및 1 이상의 N 원자를 함유하는 C3-10헤테로시클로알킬로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 추가로 치환 또는 비치환된다.R 3 is selected from —NR 10 R 11 , and —NR 10 C (O) R 11 ; Wherein R 10 is hydrogen; R 11 is C 6-10 aryl; The aryl of R 11 is halo, C 1-6 alkyl, C 1-6 alkoxy, -NR 12 C (O) R 13 , -NR 12 C (O) NR 12 R 13 , -C (O) NR 12 R 13 , Substituted or unsubstituted with 1 to 3 radicals selected from -NR 12 S (O) 0-2 R 13 and -S (O) 0-2 NR 12 R 13 ; R 12 is hydrogen; R 13 is selected from C 6-10 aryl and C 5-10 heteroaryl containing one or more atoms selected from N, O and S; The aryl or heteroaryl of R 13 is halo, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, -XNR 7 R 8 , C 6-10 aryl-C 0-4 alkyl, one or more N atoms C 3-10 heterocycloalkyl-C 0-4 alkoxy and C 3-10 heterocycloalkyl-C 0 containing one or more atoms selected from containing C 5-10 heteroaryl-C 0-4 alkyl, N and O -Substituted or unsubstituted with 1 to 3 radicals independently selected from -4 alkyl; Wherein X, R 7 and R 8 are as defined above and the aryl or heteroaryl substituent of R 13 contains C 1-6 alkyl, hydroxy-substituted-C 1-6 alkyl, and at least one N atom Further substituted or unsubstituted with 1 to 3 radicals independently selected from C 3-10 heterocycloalkyl. 제1항에 있어서, 하기 화학식 Ia의 화합물, 그의 제약적으로 허용가능한 염, 또는 수화물.The compound of formula Ia, a pharmaceutically acceptable salt thereof, or a hydrate of claim 1, wherein: <화학식 Ia><Formula Ia>
Figure 112009001421078-pct00077
Figure 112009001421078-pct00077
 상기 식에서, p는 1이며; Wherein p is 1; n은 0, 1, 및 2로부터 선택되며; n is selected from 0, 1, and 2; q는 0 및 1로부터 선택되며; q is selected from 0 and 1; R5는 수소, C1-6알킬, C6-10아릴-C0-4알킬, C5-10헤테로아릴-C0-4알킬, C3-10시클로알킬-C0-4알킬 및 C3-10헤테로시클로알킬-C0-4알킬로부터 선택되고; R6는 수소 및 C1-6알킬로부터 선택되거나; 또는 R5 및 R6는 이들이 결합되어 있는 질소 원자와 함께 헤테로시클로알킬을 형성하고; R5 또는 R5 및 R6의 조합 내의 아릴, 헤테로아릴, 시클로알킬 및 헤테로시클로알킬은 할로, 시아노, C1-6알킬, C1-6알콕시, -XNR7R8, -XOR7, -XC(O)NR7R8, -XC(O)NR7XNR7R8, -XNR7XOR7, -XNR7C(O)R8, 및 -XR9로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 치환 또는 비치환될 수 있고; 여기서, X는 결합 또는 C1-4알킬렌이고; R7 및 R8은 독립적으로 수소 및 C1-4알킬로 이루어진 군으로부터 선택되며; R9은 C3-10헤테로시클로알킬 및 C5-10헤테로아릴로부터 선택되며; 상기 R9의 헤테로시클로알킬 또는 헤테로아릴은 C1-4알킬로 치환 또는 비치환되고; 여기서, X 및 R7은 상기 정의한 바와 같고;R 5 is hydrogen, C 1-6 alkyl, C 6-10 aryl-C 0-4 alkyl, C 5-10 heteroaryl-C 0-4 alkyl, C 3-10 cycloalkyl-C 0-4 alkyl and C 3-10 heterocycloalkyl-C 0-4 alkyl; R 6 is selected from hydrogen and C 1-6 alkyl; Or R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocycloalkyl; Aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R 5 or a combination of R 5 and R 6 are halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —XNR 7 R 8 , —XOR 7 , 1 to 3 independently selected from -XC (O) NR 7 R 8 , -XC (O) NR 7 XNR 7 R 8 , -XNR 7 XOR 7 , -XNR 7 C (O) R 8 , and -XR 9 May be substituted or unsubstituted with 3 radicals; Wherein X is a bond or C 1-4 alkylene; R 7 and R 8 are independently selected from the group consisting of hydrogen and C 1-4 alkyl; R 9 is selected from C 3-10 heterocycloalkyl and C 5-10 heteroaryl; The heterocycloalkyl or heteroaryl of R 9 is unsubstituted or substituted with C 1-4 alkyl; Wherein X and R 7 are as defined above; R10은 수소이고; R 10 is hydrogen; R15는 할로, C1-6알킬, 및 C1-6알콕시로부터 선택되고; R 15 is selected from halo, C 1-6 alkyl, and C 1-6 alkoxy; R16은 -NR12C(O)R13, -NR12C(O)NR12R13, -C(O)NR12R13, -NR12S(O)0-2R13 및 -S(O)0-2NR12R13로부터 선택되고; 여기서, R12는 수소이고; R13은 C6-10아릴, 및 C5-10헤테로아릴로부터 선택되고; R13의 아릴, 헤테로아릴, 시클로알킬 또는 헤테로시클로알킬은 할로, C1-6알킬, 할로-치환된-C1-6알킬, -XNR7R8, C6-10아릴-C0-4알킬, C5-10헤테로아릴-C0-4알킬, C3-10시클로알킬-C0-4알킬, 및 C3-10헤테로시클로알킬-C0-4알콕시로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 치환 또는 비치환되며; 여기서, X, R7 및 R8은 상기 정의된 바와 같고, R13의 아릴, 헤테로아릴, 시클로알킬 또는 헤테로시클로알킬 치환체는 C1-6알킬, 히드록시-치환된-C1-6알킬, 및 C3-10헤테로시클로알킬로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 추가로 치환 또는 비치환된다.R 16 is -NR 12 C (O) R 13 , -NR 12 C (O) NR 12 R 13 , -C (O) NR 12 R 13 , -NR 12 S (O) 0-2 R 13 and -S (O) 0-2 NR 12 R 13 ; Wherein R 12 is hydrogen; R 13 is selected from C 6-10 aryl, and C 5-10 heteroaryl; Aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 13 is halo, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, -XNR 7 R 8 , C 6-10 aryl-C 0-4 1-3 independently selected from alkyl, C 5-10 heteroaryl-C 0-4 alkyl, C 3-10 cycloalkyl-C 0-4 alkyl, and C 3-10 heterocycloalkyl-C 0-4 alkoxy Substituted or unsubstituted with 3 radicals; Wherein X, R 7 and R 8 are as defined above and the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent of R 13 is C 1-6 alkyl, hydroxy-substituted-C 1-6 alkyl, And 1 to 3 radicals independently selected from C 3-10 heterocycloalkyl. 제2항에 있어서, R5가 수소, 모르폴리노에틸, 시클로프로필, 메틸, 3-(2-옥소-피롤리딘-1-일)-프로필, 벤조[1,3]디옥솔-5-일, 3-(4-메틸-피페라진-1-일)-프로필, 히드록시메틸-페닐, (1-히드록시에틸)-페닐, 모르폴리노, 피리디닐, 메틸-카르보닐, 메틸-술포닐, 메틸-피리디닐, 아미노시클로헥실, 피페리디닐, 메틸-피페라지닐-에틸, 디메틸-피라졸릴, 메틸-피라졸릴, 디메틸-피리디닐, 메틸-피리디닐, 에틸-피페라지닐-피리디닐, 아미노-카르보닐-피리디닐, 시아노-피리디닐, 디메틸-아미노-에틸, 메톡시-에틸, 메틸-피롤리디닐-에틸, 에틸-피라졸릴, 디메틸-아미노-프로필, 이소프로필, 푸라닐-메틸, 메틸-피페라지닐-프로필, 벤조[1,3]디옥솔-5-일메틸, 2-메틸-6-모르폴린-4-일-피리딘-3-일, 메틸-피리미디닐, 메톡시-피리디닐, 플루오로-페닐, 디메틸-아미노-에틸-아미노카르보닐, 피리디닐-메틸, 티아졸릴-메틸, 메틸-피라지닐-메틸, 이미다졸릴-프로필 및 아미노-카르보닐-페닐로부터 선택되거나; 또는 R5 및 R6이 이들이 결합되어 있는 질소 원자와 함께 에틸, 피리디닐 및 모르폴리노로부터 선택되는 기로 치환 또는 비치환되는 모르폴리노, 피페리디닐 및 피페라지닐로부터 선택되는 기를 형성하는 것인 화합물.The compound of claim 2, wherein R 5 is hydrogen, morpholinoethyl, cyclopropyl, methyl, 3- (2-oxo-pyrrolidin-1-yl) -propyl, benzo [1,3] dioxol-5- 1, 3- (4-Methyl-piperazin-1-yl) -propyl, hydroxymethyl-phenyl, (1-hydroxyethyl) -phenyl, morpholino, pyridinyl, methyl-carbonyl, methyl-sul Ponyl, methyl-pyridinyl, aminocyclohexyl, piperidinyl, methyl-piperazinyl-ethyl, dimethyl-pyrazolyl, methyl-pyrazolyl, dimethyl-pyridinyl, methyl-pyridinyl, ethyl-piperazinyl-pyri Diyl, amino-carbonyl-pyridinyl, cyano-pyridinyl, dimethyl-amino-ethyl, methoxy-ethyl, methyl-pyrrolidinyl-ethyl, ethyl-pyrazolyl, dimethyl-amino-propyl, isopropyl, fura Neyl-methyl, methyl-piperazinyl-propyl, benzo [1,3] dioxol-5-ylmethyl, 2-methyl-6-morpholin-4-yl-pyridin-3-yl, methyl-pyrimidinyl , Methoxy-pyridinyl, fluoro-phenyl, dimethyl-amino-ethyl-amino Viterbo carbonyl, pyridinyl-methyl, thiazolyl-methyl, methyl-pyrazinyl-methyl, imidazolyl-propyl and amino-carbonyl-or selected from phenyl; Or R 5 and R 6 together with the nitrogen atom to which they are attached form a group selected from morpholino, piperidinyl and piperazinyl, which is unsubstituted or substituted with a group selected from ethyl, pyridinyl and morpholino Phosphorus compounds. 제3항에 있어서, R16이 -NHC(O)R13, -NHC(O)NHR13, -C(O)NHR13, -NHS(O)2R13 및 -S(O)2NHR13으로부터 선택되고; 여기서, R13은 페닐, 피리다지닐, 피리디닐, 푸라닐, 피롤릴, 이미다졸릴, 피라졸릴, 퀴녹살리닐, 티에닐 및 티아졸릴로부터 선택되고; R13은 메틸, t-부틸, 할로, 트리플루오로메틸, 디에틸-아미노, 디메틸-아미노, 벤질, 피페리디닐-아미노, 피롤리디닐-메톡시, 에틸-피페라지닐-메틸, 모르폴리노, 메틸-피페라지닐, 메틸-피페라지닐-메틸, 에틸-피페라지닐, 메틸-이미다졸릴, 모르폴리노-메틸, 피롤리디닐-피페리디닐, 피페라지닐-메틸, 히드록시-피페리디닐, 1-메틸피페리딘-4-일옥시, 피페리디닐-옥시, 메틸-피라지닐, 피라지닐 및 히드록시에틸피페라지닐로부터 독립적으로 선택되는 1 내지 3개의 라디칼로 치환 또는 비치환되는 것인 화합물.4. The compound of claim 3, wherein R 16 is —NHC (O) R 13 , —NHC (O) NHR 13 , —C (O) NHR 13 , —NHS (O) 2 R 13 and —S (O) 2 NHR 13 Is selected from; Wherein R 13 is selected from phenyl, pyridazinyl, pyridinyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, quinoxalinyl, thienyl and thiazolyl; R 13 is methyl, t-butyl, halo, trifluoromethyl, diethyl-amino, dimethyl-amino, benzyl, piperidinyl-amino, pyrrolidinyl-methoxy, ethyl-piperazinyl-methyl, morpholi Furnace, methyl-piperazinyl, methyl-piperazinyl-methyl, ethyl-piperazinyl, methyl-imidazolyl, morpholino-methyl, pyrrolidinyl-piperidinyl, piperazinyl-methyl, hydroxy Substituted with 1 to 3 radicals independently selected from piperidinyl, 1-methylpiperidin-4-yloxy, piperidinyl-oxy, methyl-pyrazinyl, pyrazinyl and hydroxyethylpiperazinyl Unsubstituted compound. 제1항에 있어서,The method of claim 1, N-[4-메틸-3-(1-{6-[4-(2-모르폴린-4-일-에틸)-페닐아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6- [4- (2-morpholin-4-yl-ethyl) -phenylamino] -pyrimidin-4-yl} -1 H-imidazole-2- Monoamino) -phenyl] -3-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(4-에틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (4-ethyl-piperazine -1-yl) -5-trifluoromethyl-benzamide, N-(4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl) 3-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benzamide , N-{4-메틸-3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-3-트리플루오로메틸-벤즈아미드, N- {4-methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -3-trifluoromethyl-benzamide, N-[4-메틸-3-(1-{6-[3-(2-옥소-피롤리딘-1-일)-프로필아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6- [3- (2-oxo-pyrrolidin-1-yl) -propylamino] -pyrimidin-4-yl} -1 H-imidazole-2 -Ylamino) -phenyl] -3-trifluoromethyl-benzamide, N-(3-{1-[6-(벤조[1,3]디옥솔-5-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (benzo [1,3] dioxol-5-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl- Phenyl) -3-trifluoromethyl-benzamide, N-[4-메틸-3-(1-{6-[3-(4-메틸-피페라진-1-일)-프로필아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6- [3- (4-methyl-piperazin-1-yl) -propylamino] -pyrimidin-4-yl} -1 H-imidazole-2- Monoamino) -phenyl] -3-trifluoromethyl-benzamide, {6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일}-시클로프로필-아민, {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-yl} -cyclopropyl-amine, (3-{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일아미노}-페닐)-메탄올, (3- {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-ylamino} -phenyl) -methanol, 1-(3-{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일아미노}-페닐)-에탄올, 1- (3- {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-ylamino} -phenyl) -ethanol, {6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일}-[4-(2-모르폴린-4-일-에틸)-페닐]-아민, {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-yl}-[4- (2-morpholin-4-yl-ethyl) -phenyl]- Amine, {6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일}-(4-모르폴린-4-일-페닐)-아민,{6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-yl}-(4-morpholin-4-yl-phenyl) -amine, N-(3-{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일아미노}-페닐)-아세트아미드, N- (3- {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-ylamino} -phenyl) -acetamide, 1-(3-{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일아미노}-프로필)-피롤리딘-2-온, 1- (3- {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-ylamino} -propyl) -pyrrolidin-2-one, 벤조[1,3]디옥솔-5-일-{6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일}-아민, Benzo [1,3] dioxol-5-yl- {6- [2- (2-chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-yl} -amine, {6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일}-피리딘-3-일-아민, {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-yl} -pyridin-3-yl-amine, N-(4-메틸-3-{1-[6-(피리딘-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-methyl-3- {1- [6- (pyridin-3-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -phenyl) -3-trifluoro Chloromethyl-benzamide, {6-[2-(2-클로로-페닐아미노)-이미다졸-1-일]-피리미딘-4-일}-(6-메틸-피리딘-3-일)-아민, {6- [2- (2-Chloro-phenylamino) -imidazol-1-yl] -pyrimidin-4-yl}-(6-methyl-pyridin-3-yl) -amine, N-(4-메틸-3-{1-[6-(6-메틸-피리딘-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (6-methyl-pyridin-3-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl)- 3-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-모르폴린-4-일-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-morpholin-4-yl- 5-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(4-메틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (4-methyl-piperazine -1-yl) -5-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(4-에틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (4-ethyl-piperazine -1-yl) -5-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-모르폴린-4-일-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4-morpholin-4-yl- 3-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-(4-에틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4- (4-ethyl-piperazine -1-ylmethyl) -3-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-(4-메틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4- (4-methyl-piperazine -1-ylmethyl) -3-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (4-methyl-imidazole -1-yl) -5-trifluoromethyl-benzamide, 3-(4-메틸-이미다졸-1-일)-N-{4-메틸-3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-5-트리플루오로메틸-벤즈아미드, 3- (4-methyl-imidazol-1-yl) -N- {4-methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino ] -Phenyl} -5-trifluoromethyl-benzamide, N-{4-메틸-3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-4-모르폴린-4-일-3-트리플루오로메틸-벤즈아미드, N- {4-methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -4-morpholin-4-yl-3 -Trifluoromethyl-benzamide, 3-(4-에틸-피페라진-1-일)-N-{4-메틸-3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-5-트리플루오로메틸-벤즈아미드, 3- (4-ethyl-piperazin-1-yl) -N- {4-methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino ] -Phenyl} -5-trifluoromethyl-benzamide, N-{4-메틸-3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-3-(4-메틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- {4-Methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -3- (4-methyl-piperazine- 1-yl) -5-trifluoromethyl-benzamide, N-{3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-4-(4-메틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -4- (4-methyl-piperazin-1-ylmethyl ) -3-trifluoromethyl-benzamide, 3-(4-에틸-피페라진-1-일메틸)-N-{4-메틸-3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-5-트리플루오로메틸-벤즈아미드, 3- (4-ethyl-piperazin-1-ylmethyl) -N- {4-methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-yl Amino] -phenyl} -5-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-모르폴린-4-일메틸-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4-morpholin-4-ylmethyl 3-trifluoromethyl-benzamide, N-{4-메틸-3-[1-(6-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-4-모르폴린-4-일메틸-3-트리플루오로메틸-벤즈아미드, N- {4-Methyl-3- [1- (6-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -4-morpholin-4-ylmethyl- 3-trifluoromethyl-benzamide, N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-(4-에틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4- (4-ethyl-piperazine-1 -Ylmethyl) -3-trifluoromethyl-benzamide, N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-(4-메틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-Amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4- (4-methyl-piperazine-1 -Ylmethyl) -3-trifluoromethyl-benzamide, N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-Amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -3- (4-methyl-imidazol-1-yl)- 5-trifluoromethyl-benzamide, N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-모르폴린-4-일-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4-morpholin-4-yl-3- Trifluoromethyl-benzamide, N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(4-에틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-Amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (4-ethyl-piperazine-1 -Yl) -5-trifluoromethyl-benzamide, N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(4-메틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-Amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (4-methyl-piperazine-1 -Yl) -5-trifluoromethyl-benzamide, N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-모르폴린-4-일메틸-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-morpholin-4-ylmethyl-5 -Trifluoromethyl-benzamide, 3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-5-메톡시-N-[4-(2-메틸-이미다졸-1-일)-3-트리플루오로메틸-페닐]-벤즈아미드, 3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -5-methoxy-N- [4- (2-methyl-imidazole-1 -Yl) -3-trifluoromethyl-phenyl] -benzamide, N-{3-[1-(6-아세틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-acetylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benzamide, N-{3-[1-(6-메탄술포닐아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-Methanesulfonylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benz amides, N-{3-[1-(2-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (2-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benzamide , 3-[1-(2-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-N-[4-(2-메틸-이미다졸-1-일)-3-트리플루오로메틸-페닐]-벤즈아미드, 3- [1- (2-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-N- [4- (2-methyl-imidazole-1- Yl) -3-trifluoromethyl-phenyl] -benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-피페라진-1-일메틸-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-piperazin-1-ylmethyl -5-trifluoromethyl-benzamide, N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-피페라진-1-일메틸-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-piperazin-1-ylmethyl-5 -Trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-5-메톡시-페닐}-4-(4-메틸-피페라진-1-일메틸)-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -5-methoxy-phenyl} -4- (4-methyl-pipe Razin-1-ylmethyl) -3-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-5-메톡시-페닐}-3-(4-에틸-피페라진-1-일메틸)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -5-methoxy-phenyl} -3- (4-ethyl-pipe Razin-1-ylmethyl) -5-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(피페리딘-4-일옥시)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (piperidin-4- Yloxy) -5-trifluoromethyl-benzamide, N-{3-[1-(6-아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(피페리딘-4-일옥시)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-amino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (piperidin-4-yloxy ) -5-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-5-메톡시-페닐}-3-(4-피롤리딘-1-일-피페리딘-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -5-methoxy-phenyl} -3- (4-pyrrolidine -1-yl-piperidin-1-yl) -5-trifluoromethyl-benzamide, 1-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-[4-(2-메틸-이미다졸-1-일)-3-트리플루오로메틸-페닐]-우레아, 1- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- [4- (2-methyl -Imidazol-1-yl) -3-trifluoromethyl-phenyl] -urea, 1-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-[4-(4-에틸-피페라진-1-일메틸)-3-트리플루오로메틸-페닐]-우레아, 1- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- [4- (4-ethyl -Piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -urea, 피리다진-4-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, Pyridazine-4-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide, 2-클로로-N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-이소니코틴아미드, 2-chloro-N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -isonicotinamide, 푸란-2-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, Furan-2-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide, 1-메틸-1H-피롤-2-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 1-Methyl-1H-pyrrole-2-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl }-amides, 1H-이미다졸-2-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 1H-imidazole-2-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide , N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-4-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -4-trifluoromethyl-benzamide , N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-6-메틸-니코틴아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -6-methyl-nicotinamide, 1-tert-부틸-5-메틸-1H-피라졸-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 1-tert-butyl-5-methyl-1H-pyrazole-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino ] -4-methyl-phenyl} -amide, N-[4-(4-에틸-피페라진-1-일메틸)-3-트리플루오로메틸-페닐]-4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- [4- (4-ethyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -4-methyl-3- {1- [6- (2-morpholin-4-yl -Ethylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -benzamide, 3-(4-메틸-이미다졸-1-일)-N-(4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-5-트리플루오로메틸-벤즈아미드, 3- (4-Methyl-imidazol-1-yl) -N- (4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl ] -1H-imidazol-2-ylamino} -phenyl) -5-trifluoromethyl-benzamide, 4-메틸-N-[4-(2-메틸-이미다졸-1-일)-3-트리플루오로메틸-페닐]-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, 4-Methyl-N- [4- (2-methyl-imidazol-1-yl) -3-trifluoromethyl-phenyl] -3- {1- [6- (2-morpholin-4-yl- Ethylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -benzamide, N-(4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-(1-메틸-피페리딘-4-일옥시)-5-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl) -3- (1-methyl-piperidin-4-yloxy) -5-trifluoromethyl-benzamide, 피라진-2-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, Pyrazine-2-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide, 5-메틸-피라진-2-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 5-Methyl-pyrazine-2-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1 H-imidazol-2-ylamino] -4-methyl-phenyl}- amides, 퀴녹살린-6-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, Quinoxaline-6-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide, 5-tert-부틸-2-메틸-4-모르폴린-4-일메틸-푸란-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 5-tert-butyl-2-methyl-4-morpholin-4-ylmethyl-furan-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H- Imidazol-2-ylamino] -4-methyl-phenyl} -amide, 5-tert-부틸-2-메틸-2H-피라졸-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐)-아미드, 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino ] -4-methyl-phenyl) -amide, 2-벤질-5-tert-부틸-2H-피라졸-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 2-benzyl-5-tert-butyl-2H-pyrazole-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino ] -4-methyl-phenyl} -amide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(피페리딘-4-일아미노)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (piperidin-4- Monoamino) -5-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(피롤리딘-2-일메톡시)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (pyrrolidine-2- Monomethoxy) -5-trifluoromethyl-benzamide, 5-tert-부틸-2-메틸-푸란-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드,5-tert-butyl-2-methyl-furan-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4 -Methyl-phenyl} -amide, 5-tert-부틸-3-메틸-푸란-2-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 5-tert-Butyl-3-methyl-furan-2-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4 -Methyl-phenyl} -amide, 5-tert-부틸-2-디에틸아미노-푸란-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 5-tert-butyl-2-diethylamino-furan-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide, 5-tert-부틸-4-디에틸아미노-2-메틸-푸란-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 5-tert-butyl-4-diethylamino-2-methyl-furan-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazole-2 -Ylamino] -4-methyl-phenyl} -amide, 5-tert-부틸-티오펜-2-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 5-tert-Butyl-thiophene-2-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl- Phenyl} -amide, 5-tert-부틸-3-메틸-푸란-2-카르복실산 (4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-아미드, 5-tert-Butyl-3-methyl-furan-2-carboxylic acid (4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl ] -1H-imidazol-2-ylamino} -phenyl) -amide, 5-tert-부틸-티오펜-2-카르복실산 (4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-아미드,5-tert-Butyl-thiophene-2-carboxylic acid (4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1 H -Imidazol-2-ylamino} -phenyl) -amide, 5-tert-부틸-2-메틸-푸란-3-카르복실산 (4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-아미드, 5-tert-butyl-2-methyl-furan-3-carboxylic acid (4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl ] -1H-imidazol-2-ylamino} -phenyl) -amide, N-(3-{1-[6-(4-아미노-시클로헥실아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (4-Amino-cyclohexylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -4-methyl-phenyl) -3-tri Fluoromethyl-benzamide, N-(4-메틸-3-{1-[6-(피페리딘-4-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (piperidin-4-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl) -3- Trifluoromethyl-benzamide, N-[4-메틸-3-(1-{6-[2-(4-메틸-피페라진-1-일)-에틸아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6- [2- (4-methyl-piperazin-1-yl) -ethylamino] -pyrimidin-4-yl} -1 H-imidazole-2- Monoamino) -phenyl] -3-trifluoromethyl-benzamide, N-(3-{1-[6-(2,5-디메틸-2H-피라졸-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (2,5-dimethyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4- Methyl-phenyl) -3-trifluoromethyl-benzamide, N-(4-메틸-3-{1-[6-(4-메틸-피페라진-1-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-methyl-3- {1- [6- (4-methyl-piperazin-1-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -phenyl) 3-trifluoromethyl-benzamide, N-(4-메틸-3-{1-[6-(2-메틸-2H-피라졸-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-methyl-3- {1- [6- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino}- Phenyl) -3-trifluoromethyl-benzamide, N-(3-{1-[6-(2,6-디메틸-피리딘-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (2,6-dimethyl-pyridin-3-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl ) -3-trifluoromethyl-benzamide, N-(4-메틸-3-{1-[6-(2-메틸-피리딘-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (2-methyl-pyridin-3-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl)- 3-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-(4-메틸-피페라진-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- (4-methyl-piperazine -1-yl) -5-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-[4-(2-히드록시-에틸)-피페라진-1-일]-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3- [4- (2-hydrate Oxy-ethyl) -piperazin-1-yl] -5-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-피페라진-1-일-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-piperazin-1-yl- 5-trifluoromethyl-benzamide, N-{4-클로로-3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-벤즈아미드, N- {4-Chloro-3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-플루오로-페닐}-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-fluoro-phenyl} -benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-메틸-페닐}-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-methyl-phenyl} -benzamide, N-(5-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-플루오로-페닐}-벤즈아미드, N- (5- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-fluoro-phenyl} -benzamide, N-{5-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-메틸-페닐}-벤즈아미드, N- {5- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-methyl-phenyl} -benzamide, N-(4-클로로-3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-4-모르폴린-4-일메틸-3-트리플루오로메틸-벤즈아미드, N- (4-Chloro-3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -4-morpholin-4-ylmethyl 3-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-플루오로-페닐}-4-모르폴린-4-일메틸-3-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-fluoro-phenyl} -4-morpholin-4-yl Methyl-3-trifluoromethyl-benzamide, N-(3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-메틸-페닐}-4-모르폴린-4-일메틸-3-트리플루오로메틸-벤즈아미드, N- (3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-methyl-phenyl} -4-morpholin-4-ylmethyl 3-trifluoromethyl-benzamide, N-(4-클로로-3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- (4-Chloro-3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -3- (4-methyl-imidazole -1-yl) -5-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-플루오로-페닐}-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-fluoro-phenyl} -3- (4-methyl-imi Dazol-1-yl) -5-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-메틸-페닐)-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-methyl-phenyl) -3- (4-methyl-imidazole -1-yl) -5-trifluoromethyl-benzamide, N-{5-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-플루오로-페닐}-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- {5- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-fluoro-phenyl} -3- (4-methyl-imi Dazol-1-yl) -5-trifluoromethyl-benzamide, N-{5-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-메틸-페닐}-3-(4-메틸-이미다졸-1-일)-5-트리플루오로메틸-벤즈아미드, N- {5- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-methyl-phenyl} -3- (4-methyl-imidazole -1-yl) -5-trifluoromethyl-benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메톡시-페닐}-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methoxy-phenyl} -benzamide, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤젠술폰아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benzenesulphone amides, 3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-N-(3-트리플루오로메틸-페닐)-벤젠술폰아미드, 3- [1- (6-Cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-N- (3-trifluoromethyl-phenyl) -benzenesulphone amides, N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-플루오로-페닐}-3-디메틸아미노-5-트리플루오로메틸-벤즈아미드, N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-fluoro-phenyl} -3-dimethylamino-5-tri Fluoromethyl-benzamide, N-{5-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-2-메틸-페닐}-3-디메틸아미노-5-트리플루오로메틸-벤즈아미드, N- {5- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -2-methyl-phenyl} -3-dimethylamino-5-trifluoro Chloromethyl-benzamide, N-{4-클로로-3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-3-디메틸아미노-5-트리플루오로메틸-벤즈아미드, N- {4-Chloro-3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -3-dimethylamino-5-trifluoro Chloromethyl-benzamide, 3-(4-메틸-이미다졸-1-일)-N-(4-메틸-3-{1-[6-(피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-5-트리플루오로메틸-벤즈아미드, 3- (4-methyl-imidazol-1-yl) -N- (4-methyl-3- {1- [6- (pyridin-2-ylamino) -pyrimidin-4-yl] -1H-im Dazol-2-ylamino} -phenyl) -5-trifluoromethyl-benzamide, 4-(4-에틸-피페라진-1-일메틸)-N-(4-메틸-3-{1-[6-(피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, 4- (4-ethyl-piperazin-1-ylmethyl) -N- (4-methyl-3- {1- [6- (pyridin-2-ylamino) -pyrimidin-4-yl] -1H- Imidazol-2-ylamino} -phenyl) -3-trifluoromethyl-benzamide, 3-(4-에틸-피페라진-1-일)-N-(4-메틸-3-{1-[6-(피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-5-트리플루오로메틸-벤즈아미드, 3- (4-ethyl-piperazin-1-yl) -N- (4-methyl-3- {1- [6- (pyridin-2-ylamino) -pyrimidin-4-yl] -1H-im Dazol-2-ylamino} -phenyl) -5-trifluoromethyl-benzamide, 4-클로로-N-(4-메틸-3-{1-[6-(피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, 4-Chloro-N- (4-methyl-3- {1- [6- (pyridin-2-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl)- 3-trifluoromethyl-benzamide, N-[3-(1-{6-[5-(4-에틸-피페라진-1-일)-피리딘-2-일아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-4-메틸-페닐]-3-트리플루오로메틸-벤즈아미드, N- [3- (1- {6- [5- (4-ethyl-piperazin-1-yl) -pyridin-2-ylamino] -pyrimidin-4-yl} -1H-imidazole-2- Monoamino) -4-methyl-phenyl] -3-trifluoromethyl-benzamide, N-(4-메틸-3-{1-[6-(4-메틸-피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl)- 3-trifluoromethyl-benzamide, N-(3-{1-[6-(4,6-디메틸-피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (4,6-dimethyl-pyridin-2-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl ) -3-trifluoromethyl-benzamide, 6-(6-{2-[2-메틸-5-(3-트리플루오로메틸-벤조일아미노)-페닐아미노]-이미다졸-1-일}-피리미딘-4-일아미노)-니코틴아미드, 6- (6- {2- [2-Methyl-5- (3-trifluoromethyl-benzoylamino) -phenylamino] -imidazol-1-yl} -pyrimidin-4-ylamino) -nicotinamide , N-(4-메틸-3-{1-[6-(5-메틸-피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (5-methyl-pyridin-2-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl)- 3-trifluoromethyl-benzamide, N-(3-{1-[6-(5-시아노-피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (5-Cyano-pyridin-2-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) 3-trifluoromethyl-benzamide, 4-클로로-N-{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, 4-Chloro-N- {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoro Methyl-benzamide, 4-클로로-N-(4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, 4-Chloro-N- (4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino } -Phenyl) -3-trifluoromethyl-benzamide, 5-tert-부틸-2-메틸-2H-피라졸-3-카르복실산 (4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-아미드, 5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid (4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidine- 4-yl] -1H-imidazol-2-ylamino} -phenyl) -amide, N-(3-{1-[6-(2-디메틸아미노-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (2-dimethylamino-ethylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) -3-tri Fluoromethyl-benzamide, N-(4-메틸-3-{1-[6-(3-모르폴린-4-일-프로필아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (3-morpholin-4-yl-propylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl) 3-trifluoromethyl-benzamide, N-(3-{1-[6-(2-메톡시-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (2-methoxy-ethylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) -3-tri Fluoromethyl-benzamide, N-[4-메틸-3-(1-{6-[2-(1-메틸-피롤리딘-2-일)-에틸아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6- [2- (1-methyl-pyrrolidin-2-yl) -ethylamino] -pyrimidin-4-yl} -1 H-imidazole-2 -Ylamino) -phenyl] -3-trifluoromethyl-benzamide, N-(4-메틸-3-{1-[6-(피리딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (pyridin-2-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl) -3-trifluoro Chloromethyl-benzamide, N-[4-메틸-3-(1-피리미딘-4-일-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-methyl-3- (1-pyrimidin-4-yl-1H-imidazol-2-ylamino) -phenyl] -3-trifluoromethyl-benzamide, N-[4-메틸-3-(1-피리미딘-2-일-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-methyl-3- (1-pyrimidin-2-yl-1H-imidazol-2-ylamino) -phenyl] -3-trifluoromethyl-benzamide, N-{4-메틸-3-[1-(4-메틸아미노-피리미딘-2-일)-1H-이미다졸-2-일아미노]-페닐}-3-트리플루오로메틸-벤즈아미드, N- {4-methyl-3- [1- (4-methylamino-pyrimidin-2-yl) -1H-imidazol-2-ylamino] -phenyl} -3-trifluoromethyl-benzamide, N-{4-메틸-3-[1-(2-메틸아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-3-트리플루오로메틸-벤즈아미드, N- {4-methyl-3- [1- (2-methylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -3-trifluoromethyl-benzamide, N-(4-메틸-3-{1-[4-(2-모르폴린-4-일-에틸아미노)-피리미딘-2-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [4- (2-morpholin-4-yl-ethylamino) -pyrimidin-2-yl] -1 H-imidazol-2-ylamino} -phenyl) 3-trifluoromethyl-benzamide, N-(4-메틸-3-{1-[2-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [2- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -phenyl) 3-trifluoromethyl-benzamide, N-(3-{1-[6-(2-에틸-2H-피라졸-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (2-ethyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl- Phenyl) -3-trifluoromethyl-benzamide, N-(3-{1-[6-(3-디메틸아미노-프로필아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (3-dimethylamino-propylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) -3-tri Fluoromethyl-benzamide, N-(3-[1-(6-이소프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, N- (3- [1- (6-isopropylamino-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benzamide , N-[3-(1-{6-[(푸란-3-일메틸)-아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-4-메틸-페닐]-3-트리플루오로메틸-벤즈아미드, N- [3- (1- {6-[(furan-3-ylmethyl) -amino] -pyrimidin-4-yl} -1 H-imidazol-2-ylamino) -4-methyl-phenyl]- 3-trifluoromethyl-benzamide, N-[4-메틸-3-(1-{6-[3-(4-메틸-피페라진-1-일)-프로필아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6- [3- (4-methyl-piperazin-1-yl) -propylamino] -pyrimidin-4-yl} -1 H-imidazole-2- Monoamino) -phenyl] -3-trifluoromethyl-benzamide, N-[3-(1-{6-[(벤조[1,3]디옥솔-5-일메틸)-아미노]피리미딘-4-일}-1H-이미다졸-2-일아미노)-4-메틸-페닐]-3-트리플루오로메틸-벤즈아미드, N- [3- (1- {6-[(benzo [1,3] dioxol-5-ylmethyl) -amino] pyrimidin-4-yl} -1H-imidazol-2-ylamino) -4 -Methyl-phenyl] -3-trifluoromethyl-benzamide, N-(4-메틸-3-{1-[6-(2-메틸-6-모르폴린-4-일-피리딘-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (2-methyl-6-morpholin-4-yl-pyridin-3-ylamino) -pyrimidin-4-yl] -1 H-imidazole- 2-ylamino} -phenyl) -3-trifluoromethyl-benzamide, N-(4-메틸-3-{1-[6-(4-메틸-피리미딘-2-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-methyl-3- {1- [6- (4-methyl-pyrimidin-2-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -phenyl) 3-trifluoromethyl-benzamide, N-(3-{1-[6-(6-메톡시-피리딘-3-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (6-methoxy-pyridin-3-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) 3-trifluoromethyl-benzamide, N-{4-메틸-3-[1-(6-모르폴린-4-일-피리미딘-4-일)-1H-이미다졸-2-일아미노]-페닐}-3-트리플루오로메틸-벤즈아미드, N- {4-methyl-3- [1- (6-morpholin-4-yl-pyrimidin-4-yl) -1H-imidazol-2-ylamino] -phenyl} -3-trifluoromethyl Benzamide, N-(3-{1-[6-(4-에틸-피페라진-1-일)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드,N- (3- {1- [6- (4-ethyl-piperazin-1-yl) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl)- 3-trifluoromethyl-benzamide, N-(3-{1-[6-(3-플루오로-페닐아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (3-Fluoro-phenylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) -3-tri Fluoromethyl-benzamide, N-(3-{1-[6-(3-디메틸아미노-에틸-포름아미드-페닐아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (3-Dimethylamino-ethyl-formamide-phenylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -4-methyl-phenyl ) -3-trifluoromethyl-benzamide, N-[4-메틸-3-(1-{6-[(피리딘-3-일메틸)-아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6-[(pyridin-3-ylmethyl) -amino] -pyrimidin-4-yl} -1 H-imidazol-2-ylamino) -phenyl]- 3-trifluoromethyl-benzamide, N-[4-메틸-3-(1-{6-[(피리딘-4-일메틸)-아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6-[(pyridin-4-ylmethyl) -amino] -pyrimidin-4-yl} -1 H-imidazol-2-ylamino) -phenyl]- 3-trifluoromethyl-benzamide, N-(4-메틸-3-{1-[6-(4-모르폴린-4-일-피페리딘-1-일)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [6- (4-morpholin-4-yl-piperidin-1-yl) -pyrimidin-4-yl] -1 H-imidazol-2-yl Amino} -phenyl) -3-trifluoromethyl-benzamide, N-[4-메틸-3-(1-{6-[(티아졸-2-일메틸)-아미노]-피리미딘-4-일)-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6-[(thiazol-2-ylmethyl) -amino] -pyrimidin-4-yl) -1 H-imidazol-2-ylamino) -phenyl] 3-trifluoromethyl-benzamide, N-[4-메틸-3-(1-{6-[(피리딘-2-일메틸)-아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-Methyl-3- (1- {6-[(pyridin-2-ylmethyl) -amino] -pyrimidin-4-yl} -1 H-imidazol-2-ylamino) -phenyl]- 3-trifluoromethyl-benzamide, N-[4-메틸-3-(1-{6-[(6-메틸-피라진-2-일메틸)-아미노]-피리미딘-4-일}-1H-이미다졸-2-일아미노)-페닐]-3-트리플루오로메틸-벤즈아미드, N- [4-methyl-3- (1- {6-[(6-methyl-pyrazin-2-ylmethyl) -amino] -pyrimidin-4-yl} -1H-imidazol-2-ylamino) -Phenyl] -3-trifluoromethyl-benzamide, N-(4-메틸-3-{1-[6-(4-피리딘-2-일-피페라진-1-일)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-methyl-3- {1- [6- (4-pyridin-2-yl-piperazin-1-yl) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -Phenyl) -3-trifluoromethyl-benzamide, N-(3-{1-[6-(3-이미다졸-1-일-프로필아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (3-imidazol-1-yl-propylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) 3-trifluoromethyl-benzamide, N-(4-메틸-3-{1-[6-(피라진-2-일)아미노-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-methyl-3- {1- [6- (pyrazin-2-yl) amino-pyrimidin-4-yl] -1H-imidazol-2-ylamino} -phenyl) -3-trifluoro Chloromethyl-benzamide, N-(3-{1-[6-(3-포름아미드-페닐아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-4-메틸-페닐)-3-트리플루오로메틸-벤즈아미드, N- (3- {1- [6- (3-formamide-phenylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -4-methyl-phenyl) -3-tri Fluoromethyl-benzamide, 4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-N-(3-트리플루오로메틸-페닐)-벤즈아미드, 4-Methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -N- (3- Trifluoromethyl-phenyl) -benzamide, 4-메틸-3-{1-[6-(4-메틸-피페라진-1-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-N-(3-트리플루오로메틸-페닐)-벤즈아미드, 4-Methyl-3- {1- [6- (4-methyl-piperazin-1-ylamino) -pyrimidin-4-yl] -1 H-imidazol-2-ylamino} -N- (3- Trifluoromethyl-phenyl) -benzamide, N-(4-클로로-3-트리플루오로메틸-페닐)-4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- (4-Chloro-3-trifluoromethyl-phenyl) -4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -benzamide, N-(4-클로로-3-트리플루오로메틸-페닐)-4-메틸-3-{1-[6-(4-메틸-피페라진-1-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- (4-Chloro-3-trifluoromethyl-phenyl) -4-methyl-3- {1- [6- (4-methyl-piperazin-1-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -benzamide, 1-tert-부틸-5-(4-메틸-피페라진-1-일메틸)-1H-피라졸-3-카르복실산{3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 1-tert-butyl-5- (4-methyl-piperazin-1-ylmethyl) -1H-pyrazole-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidine-4- Yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -amide, 1-tert-부틸-5-모르폴린-4-일메틸-1H-피라졸-3-카르복실산 {3-[1-(6-시클로프로필아미노-피리미딘-4-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-아미드, 1-tert-butyl-5-morpholin-4-ylmethyl-1H-pyrazole-3-carboxylic acid {3- [1- (6-cyclopropylamino-pyrimidin-4-yl) -1H-already Dazol-2-ylamino] -4-methyl-phenyl} -amide, N-(4-tert-부틸-티아졸-2-일)-4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- (4-tert-butyl-thiazol-2-yl) -4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -benzamide, N-(4-tert-부틸-티아졸-2-일)-4-메틸-3-{1-[6-(4-메틸-피페라진-1-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- (4-tert-butyl-thiazol-2-yl) -4-methyl-3- {1- [6- (4-methyl-piperazin-1-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -benzamide, N-(5-tert-부틸-2-메틸-2H-피라졸-3-일)-4-메틸-3-{1-[6-(4-메틸-피페라진-1-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -4-methyl-3- {1- [6- (4-methyl-piperazin-1-ylamino) -pyri Midin-4-yl] -1 H-imidazol-2-ylamino} -benzamide, N-(4-메틸-3-{1-[6-(4-메틸-피페라진-1-일아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-벤즈아미드, N- (4-methyl-3- {1- [6- (4-methyl-piperazin-1-ylamino) -pyrimidin-4-yl] -1H-imidazol-2-ylamino} -phenyl) Benzamide, N-(5-tert-부틸-2-메틸-2H-피라졸-3-일)-4-메틸-3-{1-[6-(2-모르폴린-4-일-에틸아미노)-피리미딘-4-일]-1H-이미다졸-2-일아미노}-벤즈아미드, N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -4-methyl-3- {1- [6- (2-morpholin-4-yl-ethylamino) -pyri Midin-4-yl] -1 H-imidazol-2-ylamino} -benzamide, N-(4-메틸-3-{1-[2-(2-모르폴린-4-일-에틸아미노)-피리딘-4-일]-1H-이미다졸-2-일아미노}-페닐)-3-트리플루오로메틸-벤즈아미드, N- (4-Methyl-3- {1- [2- (2-morpholin-4-yl-ethylamino) -pyridin-4-yl] -1 H-imidazol-2-ylamino} -phenyl)- 3-trifluoromethyl-benzamide, N-{3-[1-(4-아세틸아미노-피리딘-2-일)-1H-이미다졸-2-일아미노]-4-메틸-페닐}-3-트리플루오로메틸-벤즈아미드, 및N- {3- [1- (4-acetylamino-pyridin-2-yl) -1H-imidazol-2-ylamino] -4-methyl-phenyl} -3-trifluoromethyl-benzamide, and 2-{2-[2-메틸-5-(3-트리플루오로메틸-벤조일아미노)-페닐아미노]-이미다졸-1-일}-이소니코틴아미드2- {2- [2-Methyl-5- (3-trifluoromethyl-benzoylamino) -phenylamino] -imidazol-1-yl} -isonicotinamide 로부터 선택되는 화합물.Compound selected from. 삭제delete 삭제delete 삭제delete 삭제delete
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US6747031B2 (en) * 1997-02-19 2004-06-08 Berlex Laboratories, Inc. N-heterocyclic derivatives as NOS inhibitors

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