KR20040028769A - Novel compounds and compositions as cathepsin inhibitors - Google Patents

Novel compounds and compositions as cathepsin inhibitors Download PDF

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KR20040028769A
KR20040028769A KR10-2003-7015837A KR20037015837A KR20040028769A KR 20040028769 A KR20040028769 A KR 20040028769A KR 20037015837 A KR20037015837 A KR 20037015837A KR 20040028769 A KR20040028769 A KR 20040028769A
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cyclohexylmethyl
phenylmethanesulfonylmethyl
alkyl
cyanomethyl
malonamide
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존 더블유. 패터슨
실러 집펠
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액시스 파마슈티컬스 인코포레이티드
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Abstract

본 발명은 선택적인 신규한 카텝신 S 억제제, 이의 약제학적으로 허용되는 염 및 N-산화물, 치료제로서의 이의 용도 및 이를 제조하는 방법에 관한 것이다.The present invention relates to selective novel cathepsin S inhibitors, pharmaceutically acceptable salts and N-oxides thereof, their use as therapeutics and methods of making the same.

Description

카텝신 억제제로서의 화합물 및 조성물 {NOVEL COMPOUNDS AND COMPOSITIONS AS CATHEPSIN INHIBITORS}NOVEL COMPOUNDS AND COMPOSITIONS AS CATHEPSIN INHIBITORS

시스테인은 효소의 촉매 부위에 시스테인 부분이 존재함을 특징으로 하는 펩티다아제의 부류를 나타낸다. 시스테인 프로테아제는 단백질의 정상적인 분해 및 프로세싱과 관련된다. 그러나, 예를 들어 발현 증가 또는 향상된 활성화의 결과로써의 시스테인 프로테아제의 비정상적 활성은 병리학적 결과를 나타낼 수 있다. 이와 관련하여, 특정 시스테인 프로테아제는 관절염, 근이영양증, 염증, 종양 침범, 사구체신염, 말라리아, 치주 질환, 이염성 백질 이영양증 등을 포함하는 다수의 질병 상태와 관련된다. 카텝신 S 활성의 증가는 수많은 질병의 병리학 및/또는 증상학에 기여한다. 따라서, 카텝신 S 프로테아제의 활성을 억제하는 분자는 이러한 질병의 치료에 있어서 치료제로서 유용하다.Cysteine refers to a class of peptidases characterized by the presence of cysteine moieties at the catalytic sites of the enzyme. Cysteine proteases are involved in normal degradation and processing of proteins. However, abnormal activity of cysteine proteases, for example as a result of increased expression or enhanced activation, may indicate pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, otitis white matter dystrophy and the like. Increasing cathepsin S activity contributes to the pathology and / or symptom of numerous diseases. Thus, molecules that inhibit the activity of cathepsin S protease are useful as therapeutic agents in the treatment of such diseases.

발명의 개요Summary of the Invention

본 발명은 하기 화학식(I)의 화합물; 및 이의 N-산화물 유도체, 전구약물 유도체, 보호된 유도체, 개개의 이성질체 및 이성질체들의 혼합물; 및 이러한 화합물및 이의 N-산화물 유도체, 전구약물 유도체, 보호된 유도체, 개개의 이성질체 및 이성질체들의 혼합물의 약제학적으로 허용되는 염 및 용매화물(예컨대, 수화물)에 관한 것이다:The present invention is a compound of formula (I); And 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 and their N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof:

상기 식에서,Where

X1은 -NHC(R1)(R2)X2또는 -NHX3이고,X 1 is —NHC (R 1 ) (R 2 ) X 2 or —NHX 3 ,

X2는 시아노, -C(R7)(R8)X3, -C(R7)(R8)CF3, -C(R7)(R8)CF2CF2R9, -CH=CHS(O)2R5, -C(O)CF2C(O)NR5R5, -C(O)C(O)NR5R6, -C(O)C(O)OR5, -C(O)CH20R5, -C(O)CH2N(R6)SO2R5또는 -C(O)C(O)R5이고, 여기에서, R5는 (C1-4)알킬, (C5-10)아릴(C0-6)알킬 또는 (C5-lO)헤테로아릴(CO-6)알킬이고; R6은 수소 또는 (C1-6)알킬이고; R7은 수소 또는 (C1-4)알킬이고, R8은 히드록시이거나, R7과 R8이 함께 옥소를 형성하고; R9는 수소, 할로, (C1-4)알킬, (C5-10)아릴(C0-6)알킬 또는 (C5-1O)헤테로아릴(C0-6)알킬이며,X 2 is cyano, -C (R 7 ) (R 8 ) X 3 , -C (R 7 ) (R 8 ) CF 3 , -C (R 7 ) (R 8 ) CF 2 CF 2 R 9 ,- CH = CHS (O) 2 R 5 , -C (O) CF 2 C (O) NR 5 R 5 , -C (O) C (O) NR 5 R 6 , -C (O) C (O) OR 5 , -C (O) CH 2 0R 5 , -C (O) CH 2 N (R 6 ) SO 2 R 5 or -C (O) C (O) R 5 , wherein R 5 is (C 1-4 ) alkyl, (C 5-10 ) aryl (C 0-6 ) alkyl or (C 5-lO ) heteroaryl (C O-6 ) alkyl; R 6 is hydrogen or (C 1-6 ) alkyl; R 7 is hydrogen or (C 1-4 ) alkyl and R 8 is hydroxy or R 7 and R 8 together form oxo; R 9 is hydrogen, halo, (C 1-4 ) alkyl, (C 5-10 ) aryl (C 0-6 ) alkyl or (C 5-1O ) heteroaryl (C 0-6 ) alkyl,

X3은 4 내지 6원 고리 원자를 함유하는 헤테로모노시클릭 고리 또는 8 내지 14원 고리 원자를 함유하는 접합된 헤테로비시클릭 고리 시스템 및 이의 임의의 카르보시클릭 케톤, 이미노케톤 또는 티오케톤 유도체를 포함하고,X 3 is a heteromonocyclic ring containing 4 to 6 membered ring atoms or a conjugated heterobicyclic ring system containing 8 to 14 membered ring atoms and any carbocyclic ketone, iminoketone or thioketone derivative thereof Including,

R5, X2또는 X3내에서 임의의 지환족 또는 방향족 고리 시스템이, (C1-6)알킬, (C1-6)알킬리덴, 시아노, 할로, 할로-치환된 (C1-4)알킬, 니트로, -X4NR12R12, -X4NR12C(O)R12, -X4NR12C(O)OR12, -X4NR12C(O)NR12R12, -X4NR12C(NR12)NR12R12, -X4OR12, -X4SR12, -X4C(O)OR12, -X4C(O)R12, -X4OC(O)R12, -X4C(O)NR12R12, -X4S(O)2NR12R12, -X4NR12S(O)2R12, -X4P(O)(OR12)OR12, -X4OP(O)(OR12)OR12, -X4NR12C(O)R13, -X4S(O)R13및 -X4S(O)2R13으로부터 독립적으로 선택된 1 내지 5개의 라디칼 및/또는 -R14, -X4OR14, -X4SR14, -X4S(O)R14, -X4S(O)2R14, -X4C(O)R14, -X4C(O)OR14, -X4OC(O)R14, -X4NR14R12, -X4NR12C(O)R14, -X4NR12C(O)OR14, -X4C(O)NR12R12, -X4S(O)2NR14R12, -X4NR12S(O)2R14, -X4NR12C(O)NR14R12및 -X4NR12C(NR12)NR14R12로부터 선택된 하나의 라디칼에 의해 추가로 치환될 수 있고, 여기에서, X4는 단일 결합 또는 (C1-6)알킬이고, R12는 각각의 경우, 독립적으로 수소, (C1-6)알킬 또는 할로-치환된 (C1-6)알킬이고, R13은 (C1-6)알킬 또는 할로-치환된 (C1-6)알킬이고, R14은 (C3-10)시클로알킬(C0-6)알킬, 헤테로(C3-10)시클로알킬(C0-3)알킬, (C6-10)아릴(C0-6)알킬, 헤테로(C5-10)아릴(C0-6)알킬, (C9-10)비시클로아릴(C0-6)알킬 또는 헤테로(C8-10)비시클로아릴(C0-6)알킬이고,Any cycloaliphatic or aromatic ring system in R 5 , X 2 or X 3 is a (C 1-6 ) alkyl, (C 1-6 ) alkylidene, cyano, halo, halo-substituted (C 1- 4 ) alkyl, nitro, -X 4 NR 12 R 12 , -X 4 NR 12 C (O) R 12 , -X 4 NR 12 C (O) OR 12 , -X 4 NR 12 C (O) NR 12 R 12 , -X 4 NR 12 C (NR 12 ) NR 12 R 12 , -X 4 OR 12 , -X 4 SR 12 , -X 4 C (O) OR 12 , -X 4 C (O) R 12 ,- X 4 OC (O) R 12 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 12 R 12 , -X 4 NR 12 S (O) 2 R 12 , -X 4 P (O) (OR 12 ) OR 12 , -X 4 OP (O) (OR 12 ) OR 12 , -X 4 NR 12 C (O) R 13 , -X 4 S (O) R 13 and -X 4 1 to 5 radicals independently selected from S (O) 2 R 13 and / or -R 14 , -X 4 OR 14 , -X 4 SR 14 , -X 4 S (O) R 14 , -X 4 S ( O) 2 R 14 , -X 4 C (O) R 14 , -X 4 C (O) OR 14 , -X 4 OC (O) R 14 , -X 4 NR 14 R 12 , -X 4 NR 12 C (O) R 14 , -X 4 NR 12 C (O) OR 14 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 14 R 12 , -X 4 NR 12 S ( O) 2 R 14, -X 4 NR 12 C (O) NR 14 R 12 and -X 4 NR 12 C (NR 12 ) NR 14 R 12, a radical selected from More may be substituted by 0, in which, X 4 is a single bond or (C 1-6) alkyl, R 12 is for each occurrence, independently hydrogen, (C 1-6) alkyl or halo-substituted (C 1-6 ) alkyl, R 13 is (C 1-6 ) alkyl or halo-substituted (C 1-6 ) alkyl, R 14 is (C 3-10 ) cycloalkyl (C 0-6 ) Alkyl, hetero (C 3-10 ) cycloalkyl (C 0-3 ) alkyl, (C 6-10 ) aryl (C 0-6 ) alkyl, hetero (C 5-10 ) aryl (C 0-6 ) alkyl, (C 9-10 ) bicycloaryl (C 0-6 ) alkyl or hetero (C 8-10 ) bicycloaryl (C 0-6 ) alkyl,

R1은 수소, 할로 또는 (C1-6)알킬이고, R2는 수소, 시아노, 할로, -X4NR12R12, -X4NR12C(O)R12, -X4NR12C(O)OR12, -X4NR12C(O)NR12R12, -X4NR12C(NR12)NR12R12, -X4OR12, -X4SR12, -X4C(O)OR12, -X4C(O)R12, -X4OC(O)R12, -X4C(O)NR12R12, -X4S(O)2NR12R12, -X4NR12S(O)2R12, -X4P(O)(OR12)OR12, -X4OP(O)(OR12)OR12, -X4NR12C(O)R13, -X4S(O)R13, -X4S(O)2R13, -R14, -X4OR14, -X4SR14, -X4S(O)R14, -X4S(O)2R14, -X4C(O)R14, -X4C(O)OR4, -X4OC(O)R14, -X4NR14R12, -X4NR12C(O)R14, -X4NR12C(O)OR14, -X4C(O)NR12R12, -X4S(O)2NR14R12, -X4NR12S(O)2R14, -X4NR12C(O)NR14R12및 -X4NR12C(NR12)NR14R12으로 구성된 군으로부터 선택되거나 (여기서, X4, R12, R13및 R14는 상기에서 정의된 바와 같음); R1과 R2는, R1과 R2둘 모두가 부착되어 있는 탄소 원자와 함께 (C3-8)시아노알킬렌 또는 (C3-8)헤테로시클로알킬렌을 형성하고, 여기에서, 상기 R2내의 임의의 헤테로아릴, 아릴, 시클로알킬, 헤테로시클로알킬, 시클로알킬렌 또는 헤테로시클로알킬렌은 (C1-6)알킬, (C1-6)알킬리덴, 시아노, 할로, 할로-치환된 (C1-4)알킬, 니트로, -X4NR12R12, -X4NR12C(O)R12, -X4NR12C(O)OR12, -X4NR12C(O)NR12R12, -X4NR12C(NR12)NR12R12, -X4OR12, -X4SR12, -X4C(O)OR12, -X4C(O)R12, -X4OC(O)R12, -X4C(O)NR12R12, -X4S(O)2NR12R12, -X4NR12S(O)2R12, -X4P(O)(OR12)OR12, -X4OP(O)(OR12)OR12, -X4NR12C(O)R13, -X4S(O)R13, -X4S(O)2R13및 -X4C(O)R13으로부터 독립적으로 선택된 1 내지 3개의 라디칼에 의해 치환되거나 비치환되며 (여기서 X4, R12및 R13은 상기에서 정의된 바와 같음),R 1 is hydrogen, halo or (C 1-6 ) alkyl, R 2 is hydrogen, cyano, halo, -X 4 NR 12 R 12 , -X 4 NR 12 C (O) R 12 , -X 4 NR 12 C (O) OR 12 , -X 4 NR 12 C (O) NR 12 R 12 , -X 4 NR 12 C (NR 12 ) NR 12 R 12 , -X 4 OR 12 , -X 4 SR 12 ,- X 4 C (O) OR 12 , -X 4 C (O) R 12 , -X 4 OC (O) R 12 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 12 R 12 , -X 4 NR 12 S (O) 2 R 12 , -X 4 P (O) (OR 12 ) OR 12 , -X 4 OP (O) (OR 12 ) OR 12 , -X 4 NR 12 C (O) R 13 , -X 4 S (O) R 13 , -X 4 S (O) 2 R 13 , -R 14 , -X 4 OR 14 , -X 4 SR 14 , -X 4 S (O ) R 14 , -X 4 S (O) 2 R 14 , -X 4 C (O) R 14 , -X 4 C (O) OR 4 , -X 4 OC (O) R 14 , -X 4 NR 14 R 12 , -X 4 NR 12 C (O) R 14 , -X 4 NR 12 C (O) OR 14 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 14 R 12 , -X 4 NR 12 S (O) 2 R 14 , -X 4 NR 12 C (O) NR 14 R 12 and -X 4 NR 12 C (NR 12 ) NR 14 R 12 ; Wherein X 4 , R 12 , R 13 and R 14 are as defined above); R 1 and R 2 together with the carbon atom to which both R 1 and R 2 are attached form (C 3-8 ) cyanoalkylene or (C 3-8 ) heterocycloalkylene, wherein any heteroaryl, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocyclic cycloalkylene in said R 2 is (C 1-6) alkyl, (C 1-6) alkylidene, cyano, halo, halo -Substituted (C 1-4 ) alkyl, nitro, -X 4 NR 12 R 12 , -X 4 NR 12 C (O) R 12 , -X 4 NR 12 C (O) OR 12 , -X 4 NR 12 C (O) NR 12 R 12 , -X 4 NR 12 C (NR 12 ) NR 12 R 12 , -X 4 OR 12 , -X 4 SR 12 , -X 4 C (O) OR 12 , -X 4 C (O) R 12 , -X 4 OC (O) R 12 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 12 R 12 , -X 4 NR 12 S (O) 2 R 12 , -X 4 P (O) (OR 12 ) OR 12 , -X 4 OP (O) (OR 12 ) OR 12 , -X 4 NR 12 C (O) R 13 , -X 4 S (O ) R 13 , -X 4 S (O) 2 R 13 and -X 4 C (O) R 13 is substituted or unsubstituted by 1 to 3 radicals independently selected from (where X 4 , R 12 and R 13 Is defined above As shown),

R3는 -C(R6)(R6)X5이고, 여기서 R6은 상기에서 정의된 바와 같고, X5는 -X4NR12R12, -X4NR12C(O)R12, -X4NR12C(O)OR12, -X4NR12C(O)NR12R12, -X4NR12C(NR12)NR12R12, -X4OR12, -X4SR12, -X4C(O)OR12, -X4C(O)R12, -X4OC(O)R12, -X4C(O)NR12R12, -X4S(O)2NR12R12, -X4NR12S(O)2R12, -X4P(O)(OR12)OR12, -X4R12, -X4OP(O)(OR12)OR12, -X4C(O)R13, -X4NR12C(O)R13, -X4S(O)R13및 -X4S(O)2R13, -R14, -X4OR14, -X4SR14, -X4S(O)R14, -X4S(O)2R14, -X4C(O)R14, -X4C(O)OR14, -X4OC(O)R14, -X4NR14R12, -X4NR12C(O)R14, -X4NR12C(O)OR14, -X4C(O)NR14R12, -X4S(O)2NR14R12, -X4NR12S(O)2R14, -X4NR12C(O)NR14R12및-X4NR12C(NR12)NR14R12로부터 선택되며 (여기서 X4, R12, R13및 R14는 상기에서 정의된 바와 같음),R 3 is —C (R 6 ) (R 6 ) X 5 , wherein R 6 is as defined above and X 5 is —X 4 NR 12 R 12 , -X 4 NR 12 C (O) R 12 , -X 4 NR 12 C (O) OR 12 , -X 4 NR 12 C (O) NR 12 R 12 , -X 4 NR 12 C (NR 12 ) NR 12 R 12 , -X 4 OR 12 , -X 4 SR 12 , -X 4 C (O) OR 12 , -X 4 C (O) R 12 , -X 4 OC (O) R 12 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 12 R 12 , -X 4 NR 12 S (O) 2 R 12 , -X 4 P (O) (OR 12 ) OR 12 , -X 4 R 12 , -X 4 OP (O) ( OR 12 ) OR 12 , -X 4 C (O) R 13 , -X 4 NR 12 C (O) R 13 , -X 4 S (O) R 13 and -X 4 S (O) 2 R 13 ,- R 14 , -X 4 OR 14 , -X 4 SR 14 , -X 4 S (O) R 14 , -X 4 S (O) 2 R 14 , -X 4 C (O) R 14 , -X 4 C (O) OR 14 , -X 4 OC (O) R 14 , -X 4 NR 14 R 12 , -X 4 NR 12 C (O) R 14 , -X 4 NR 12 C (O) OR 14 , -X 4 C (O) NR 14 R 12 , -X 4 S (O) 2 NR 14 R 12 , -X 4 NR 12 S (O) 2 R 14 , -X 4 NR 12 C (O) NR 14 R 12 and -X 4 NR 12 C (NR 12 ) NR 14 R 12 , wherein X 4 , R 12 , R 13 and R 14 are as defined above,

R4는 -NR6R6, -NR6R14, -NR6R15또는 -NR6X5C(O)R14이고 (여기서, R6, X5및 R14는 상기에서 기술한대로이고, R15는 수소, -(C1-6)알킬 또는 -X5OR6이거나 (여기서, X5는 상기에서 기술한대로임); R6및 R15는, R6및 R15둘 모두가 부착되어 있는 질소 원자와 함께 헤테로(C3-10)시클로알킬, 헤테로(C5-10)아릴 또는 헤테로(C8-10)비시클로아릴을 형성함),R 4 is —NR 6 R 6 , —NR 6 R 14 , —NR 6 R 15 or —NR 6 X 5 C (O) R 14 , wherein R 6 , X 5 and R 14 are as described above and R 15 is hydrogen, — (C 1-6 ) alkyl or —X 5 OR 6 (wherein X 5 is as described above); R 6 and R 15 are both attached to R 6 and R 15 Together with the nitrogen atom to form hetero (C 3-10 ) cycloalkyl, hetero (C 5-10 ) aryl or hetero (C 8-10 ) bicycloaryl),

R3및 R4내에서 임의의 지환족 또는 방향족 고리 시스템이, (C1-6)알킬, (C1-6)알킬리덴, 시아노, 할로, 할로-치환된 (C1-4)알킬, 니트로, -X4NR12R12, -X4NR12C(O)R12, -X4NR12C(O)OR12, -X4NR12C(O)NR12R12, -X4NR12C(NR12)NR12R12, -X4OR12, -X4SR12, -X4C(O)OR12, -X4C(O)R12, -X4OC(O)R12, -X4C(O)NR12R12, -X4S(O)2NR12R12, -X4NR12S(O)2R12, -X4P(O)(OR12)OR12, -X4OP(O)(OR12)OR12, -X4NR12C(O)R13, -X4S(O)R13, -X4C(O)R13및 -X4S(O)2R13으로부터 독립적으로 선택된 1 내지 5개의 라디칼 및/또는 -R14, -X4OR14, -X4SR14, -X4S(O)R14, -X4S(O)2R14, -X4C(O)R14, -X4C(O)OR14, -X4OC(O)R14, -X4NR14R12, -X4NR12C(O)R14, -X4NR12C(O)OR14, -X4C(O)NR14R12, -X4S(O)2NR14R12, -X4NR12S(O)2R14, -X4NR12C(O)NR14R12및 -X4NR12C(NR12)NR14R12으로부터 선택된 하나의 라디칼에 의해 추가로 치환될 수 있고, R3및 R4내에서 임의의 지방족 부분은 시아노, 할로, 니트로, -NR12R12, -NR12C(O)R12, -NR12C(O)OR12, -NR12C(O)NR12R12, -NR12C(NR12)NR12R12, -OR12, -SR12, -C(O)OR12, -C(O)R12, -OC(O)R12, -C(O)NR12R12, -S(O)2NR12R12, -NR12S(O)2R12, -P(O)(OR12)OR12, -OP(O)(OR12)OR12, -NR12C(O)R13, -S(O)R13및 -S(0)2R13으로부터 독립적으로 선택된 1 내지 5개의 라디칼에 의해 추가로 치환될 수 있고 (여기서, X4, R12, R13및 R14는 상기에서 기술한 바와 같음),Any of the alicyclic or aromatic ring system in R 3 and R 4 is (C 1-6 ) alkyl, (C 1-6 ) alkylidene, cyano, halo, halo-substituted (C 1-4 ) alkyl , Nitro, -X 4 NR 12 R 12 , -X 4 NR 12 C (O) R 12 , -X 4 NR 12 C (O) OR 12 , -X 4 NR 12 C (O) NR 12 R 12 ,- X 4 NR 12 C (NR 12 ) NR 12 R 12 , -X 4 OR 12 , -X 4 SR 12 , -X 4 C (O) OR 12 , -X 4 C (O) R 12 , -X 4 OC (O) R 12 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 12 R 12 , -X 4 NR 12 S (O) 2 R 12 , -X 4 P (O ) (OR 12 ) OR 12 , -X 4 OP (O) (OR 12 ) OR 12 , -X 4 NR 12 C (O) R 13 , -X 4 S (O) R 13 , -X 4 C (O 1-5 radicals and / or -R 14 , -X 4 OR 14 , -X 4 SR 14 , -X 4 S (O) R independently selected from R 13 and -X 4 S (O) 2 R 13 14 , -X 4 S (O) 2 R 14 , -X 4 C (O) R 14 , -X 4 C (O) OR 14 , -X 4 OC (O) R 14 , -X 4 NR 14 R 12 , -X 4 NR 12 C (O) R 14 , -X 4 NR 12 C (O) OR 14 , -X 4 C (O) NR 14 R 12 , -X 4 S (O) 2 NR 14 R 12 , -X 4 NR 12 S (O) 2 R 14, -X 4 NR 12 C (O) NR 14 R 12 and -X 4 NR 12 C (NR 12 ) NR 14 R 12 selected from May be further substituted by a radical, R 3 and R 4 optionally in the aliphatic moiety is a cyano, halo, nitro, -NR 12 R 12, -NR 12 C (O) R 12, -NR 12 C ( O) OR 12 , -NR 12 C (O) NR 12 R 12 , -NR 12 C (NR 12 ) NR 12 R 12 , -OR 12 , -SR 12 , -C (O) OR 12 , -C (O R 12 , -OC (O) R 12 , -C (O) NR 12 R 12 , -S (O) 2 NR 12 R 12 , -NR 12 S (O) 2 R 12 , -P (O) ( OR 12 ) 1 to independently selected from OR 12 , -OP (O) (OR 12 ) OR 12 , -NR 12 C (O) R 13 , -S (O) R 13, and -S (0) 2 R 13 May be further substituted by five radicals, wherein X 4 , R 12 , R 13 and R 14 are as described above;

단, 하나의 비시클릭 고리 구조만이 R3또는 R4내에 존재한다.Provided that only one bicyclic ring structure is present in R 3 or R 4 .

본 발명의 두번째 양태는 하나 이상의 적합한 부형제와 함께, 화학식(I)의 화합물 또는 이의 N-산화물 유도체, 개개의 이성질체 또는 이성질체들의 혼합물, 또는 이의 약제학적으로 허용되는 염을 함유하는 약제 조성물에 관한 것이다.A second aspect of the invention relates to a pharmaceutical composition containing a compound of formula (I) or an N-oxide derivative thereof, an individual isomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, together with one or more suitable excipients. .

본 발명의 세번째 양태는 동물에게 치료적 유효량의 화학식(I)의 화합물 또는 이의N-산화물 유도체, 개개의 이성질체 또는 이성질체들의 혼합물; 또는 약제학적으로 허용되는 염을 투여하는 것을 포함하여, 카텝신 S의 억제가 질병의 병리 및/또는 증상을 예방시키거나, 억제시키거나, 개선시켜주는 동물의 질병을 치료하는 방법에 관한 것이다.A third aspect of the invention provides a therapeutically effective amount of a compound of formula (I) or an N -oxide derivative, individual isomer or mixture of isomers in an animal; Or to a method of treating a disease in an animal wherein the inhibition of cathepsin S prevents, inhibits or ameliorates the pathology and / or symptoms of the disease, including administering a pharmaceutically acceptable salt.

본 발명의 네번째 양태는 화학식(I)의 화합물 및 이의N-산화물 유도체, 전구약물 유도체, 보호된 유도체, 개개의 이성질체 및 이성질체들의 혼합물, 및 약제학적으로 허용되는 염을 제조하기 위한 방법에 관한 것이다.A fourth aspect of the present invention relates to compounds of formula (I) and their N -oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers, and methods for preparing pharmaceutically acceptable salts. .

본 발명은 시스테인 프로테아제 활성과 관련된 질병, 특히 카텝신 S의 활성과 관련된 질병을 치료하기 위한 화합물 및 조성물에 관한 것이다.The present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity, in particular diseases associated with the activity of cathepsin S.

정의:Justice:

별도로 언급하지 않는 한 하기 용어들은 본 명세서 및 청구범위에서 본 장에서 정의된 의미를 갖는다:Unless stated otherwise, the following terms have the meanings defined in this chapter in this specification and in the claims:

"지환족"은 지방족물질의 특성과 유사한 닫힌 비-방향족 고리 구조 형태의 탄소원자의 배열을 특징으로 하는 부분을 의미하며, 포화되거나 두개 이상의 이중 또는 삼중결합에 의해 부분적으로 불포화될 수 있다."Alkali" means a moiety characterized by an arrangement of carbon atoms in the form of closed non-aromatic ring structures similar to those of aliphatic materials, which may be saturated or partially unsaturated by two or more double or triple bonds.

"지방족"은 구성 탄소 원자의 선형 또는 분지형 사슬 배열을 특징으로 하는 부분을 의미하며, 포화되거나 두개 이상의 이중 또는 삼중결합에 의해 부분적으로 불포화될 수 있다.By "aliphatic" is meant a moiety characterized by a linear or branched chain arrangement of constituent carbon atoms, which may be saturated or partially unsaturated by two or more double or triple bonds.

"알킬"은 단독으로 나타난 경우 표시된 수의 탄소원자를 갖는 선형이거나 분지형인 포화 또는 불포화 지방족 라디칼을 의미한다 (예를 들어, (C1-6)알킬로는 메틸, 에틸, 프로필, 이소프로필, 부틸, 2차부틸, 이소부틸, 3차부틸, 비닐, 알릴,1-프로페닐, 이소프로페닐, 1-부테닐, 2-부테닐, 3-부테닐, 2-메틸알릴, 에티닐, 1-프로피닐, 2-프로피닐 등이 있다). 또다른 라디칼과 함께 표시된 알킬(예를 들어, 아릴알킬에서와 같이)은, 표시된 원자수를 갖는 선형이거나 분지형인 포화 또는 불포화 지방족 2가 라디칼을 의미하거나, 원자수가 0으로 나타난 경우 단일 결합을 의미한다 (예를 들어, (C6-10)아릴(C0-3)알킬로는 페닐, 벤질, 페네틸, 1-페닐에틸, 3-페닐프로필 등이 있다)."Alkyl" when used alone means a linear or branched saturated or unsaturated aliphatic radical having the indicated number of carbon atoms (e.g., (C 1-6 ) alkyl includes methyl, ethyl, propyl, isopropyl, Butyl, secondary butyl, isobutyl, tertiary butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1 -Propynyl, 2-propynyl and the like). Alkyl (along with, for example, arylalkyl) denoted with another radical means a linear or branched saturated or unsaturated aliphatic divalent radical having the indicated number of atoms, or a single bond when the number of atoms appears to be zero. (For example, (C 6-10 ) aryl (C 0-3 ) alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, and the like).

"알킬렌"은 별도로 언급하지 않는 한, 표시된 수의 탄소원자를 갖는 선형이거나 분지형인 포화 또는 불포화 지방족, 2가 라디칼을 의미한다(예를 들어, (C1-6)알킬렌으로는 메틸렌(-CH2-), 에틸렌(-CH2CH2-), 트리메틸렌(-CH2CH2CH2-), 테트라메틸렌(-CH2CH2CH2CH2-), 2-부테닐렌(-CH2CH=CHCH2-), 2-메틸테트라메틸렌(-CH2CH(CH3)CH2CH2-), 펜타메틸렌(-CH2CH2CH2CH2CH2-) 등이 있다)."Alkylene" means a linear or branched saturated or unsaturated aliphatic, divalent radical having the indicated number of carbon atoms, unless otherwise indicated (for example, (C 1-6 ) alkylene is methylene ( -CH 2 -), ethylene (-CH 2 CH 2 -), trimethylene (-CH 2 CH 2 CH 2 - ), tetramethylene (-CH 2 CH 2 CH 2 CH 2 -), 2- butenylene (- and the like)) - CH 2 CH = CHCH 2 -), 2- methyl-tetramethylene (-CH 2 CH (CH 3) CH 2 CH 2 -), pentamethylene (-CH 2 CH 2 CH 2 CH 2 CH 2 .

"알킬리덴"은 표시된 수의 탄소원자를 갖는 선형이거나 분지형인 포화 또는 불포화 지방족 2가 라디칼을 의미한다 (예를 들어, (C1-6)알킬리덴으로는 메틸리덴(=CH2), 에틸리덴(=CHCH3), 이소프로필리덴(=C(CH3)2), 프로필리덴(=CHCH2CH3), 알릴리덴(=CHCH=CH2) 등이 있다)."Alkylidene" means a linear or branched saturated or unsaturated aliphatic divalent radical having the indicated number of carbon atoms (e.g., (C 1-6 ) alkylidene is methylidene (= CH 2 ), ethyl (I.e., lidene (= CHCH 3 ), isopropylidene (= C (CH 3 ) 2 ), propylidene (= CHCH 2 CH 3 ), allylidene (= CHCH = CH 2 )).

"아미노"는 -NH2라디칼을 의미한다. 별도로 언급하지 않는 한, 아미노 부분을 함유하는 본 발명의 화합물은 이의 보호된 유도체를 포함한다. 아미노 부분에 대한 적절한 보호기로는 아세틸, 3차-부톡시카르보닐, 벤질옥시카르보닐 등이 있다."Amino" means the -NH 2 radical. Unless stated otherwise, compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for the amino moiety include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.

"동물"은 인간, 인간을 제외한 포유동물(예를 들어, 개, 고양이, 토끼, 소, 말, 양, 염소, 돼지, 사슴 등) 및 비-포유동물(예를 들어, 새 등)을 포함한다."Animals" include humans, mammals other than humans (eg, dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, deer, etc.) and non-mammals (eg, birds, etc.) do.

"방향족"은 구성 원자가 불포화된 고리 시스템을 구성하는 부분을 의미하며, 고리 시스템내의 모든 원자는sp 2 혼성화되어 있고 pi 전자의 총수는 4n+2와 같다."Aromatic" refers to the portion of which a constituent atom constitutes an unsaturated ring system, in which all atoms in the ring system are sp 2 hybridized and the total number of pi electrons equals 4n + 2.

"아릴"은 표시된 총 수의 고리 탄소원자를 함유하는 모노시클릭 또는 접합된 비시클릭 고리 어셈블리를 의미하며, 여기서 각각의 고리는 6개의 고리 탄소원자로 구성되고 방향족이거나, 제 2의 고리와 접합되는 경우 방향족 고리 어셈블리를 형성한다. 예를 들어, 본원에서 사용된 치환되거나 비치환된 (C6-10)아릴로는, 이에 제한하는 것은 아니나, 비페닐-2-일, 2-브로모페닐, 2-브로모카르보닐페닐, 2-브로모-5-플루오로페닐, 4-tert-부틸페닐, 4-카르바모일페닐, 4-카르복시-2-니트로페닐, 2-클로로페닐, 4-클로로페닐, 3-클로로카르보닐페닐, 4-클로로카르보닐페닐, 2-클로로-4-플루오로페닐, 2-클로로-6-플루오로페닐, 4-클로로-2-니트로페닐, 6-클로로-2-니트로페닐, 2,6-디브로모페닐, 2,3-디클로로페닐, 2,5-디클로로페닐, 3,4-디클로로페닐, 2-디플루오로메톡시페닐, 3,5-디메틸페닐, 2-에톡시카르보닐페닐, 2-플루오로페닐, 2-요오드페닐, 4-이소프로필페닐, 2-메톡시페닐, 4-메톡시페닐, 2-메틸페닐, 3-메틸페닐, 4-메틸페닐, 5-메틸-2-니트로페닐, 4-메틸술포닐페닐, 나프트-2-일, 2-니트로페닐, 3-니트로페닐, 4-니트로페닐, 2,3,4,5,6-펜타플루오로페닐, 페닐, 2-트리플루오로메톡시페닐, 3-트리플루오로메톡시페닐, 4-트리플루오로메톡시페닐, 2-트리플루오로메틸페닐, 3-트리플루오로메틸페닐, 4-트리플루오로메틸페닐, 2-트리플루오로메틸술파닐페닐, 4-트리플루오로메틸술파닐페닐 등이 있다. 본원에서 사용된 치환되거나 비치환된 (C6-10)아릴로는 3-아세틸페닐, 3-tert-부톡시카르보닐아미노메틸페닐, 비페닐-4-일, 3-히드록시페닐, 4-히드록시페닐, 3-메톡시페닐, 나프트-2-일, 3-페녹시페닐, 페닐 등이 있다."Aryl" means a monocyclic or conjugated bicyclic ring assembly containing the indicated total number of ring carbon atoms, wherein each ring consists of six ring carbon atoms and is aromatic or conjugated with a second ring To form an aromatic ring assembly. For example, substituted or unsubstituted (C 6-10 ) aryl as used herein includes, but is not limited to, biphenyl-2-yl, 2-bromophenyl, 2-bromocarbonylphenyl, 2-bromo-5-fluorophenyl, 4- tert -butylphenyl, 4-carbamoylphenyl, 4-carboxy-2-nitrophenyl, 2-chlorophenyl, 4-chlorophenyl, 3-chlorocarbonylphenyl , 4-chlorocarbonylphenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 4-chloro-2-nitrophenyl, 6-chloro-2-nitrophenyl, 2,6- Dibromophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-difluoromethoxyphenyl, 3,5-dimethylphenyl, 2-ethoxycarbonylphenyl, 2 -Fluorophenyl, 2-iodinephenyl, 4-isopropylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 5-methyl-2-nitrophenyl, 4 -Methylsulfonylphenyl, naphth-2-yl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl , 2,3,4,5,6-pentafluorophenyl, phenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-trifluoromethylphenyl, 3 -Trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethylsulfanylphenyl, 4-trifluoromethylsulfanylphenyl, and the like. As used herein, substituted or unsubstituted (C 6-10 ) aryl includes 3-acetylphenyl, 3- tert -butoxycarbonylaminomethylphenyl, biphenyl-4-yl, 3-hydroxyphenyl, 4-hydrate Oxyphenyl, 3-methoxyphenyl, naphth-2-yl, 3-phenoxyphenyl, phenyl and the like.

"비시클로아릴"은 표시된 수의 고리 탄소원자를 함유하는 비시클릭 고리 어셈블리를 의미하며, 여기서 고리는 단일 결합에 의해 결합되거나 접합되며, 이 어셈블리를 포함하는 하나 이상의 고리는 방향족, 및 이의 임의의 카르보시클릭 케톤, 티오케톤 또는 이미노케논 유도체이다 (예를 들어, (예를 들어, (C9-10)비시클로아릴로는 시클로헥실페닐, 1,2-디히드로나프틸, 2,4-디옥소-1,2,3,4-테트라히드로나프틸, 인다닐, 인데닐, 1,2,3,4-테트라히드로나프틸 등이 있다)."Bicycloaryl" means a bicyclic ring assembly containing the indicated number of ring carbon atoms, wherein the rings are joined or bonded by a single bond, wherein at least one ring comprising the assembly is aromatic, and any carbo Bocyclic ketone, thioketone or iminokenone derivative (e.g., (e.g., (C 9-10 ) bicycloaryl is cyclohexylphenyl, 1,2-dihydronaphthyl, 2,4- Dioxo-1,2,3,4-tetrahydronaphthyl, indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl and the like).

"카르바모일"은 -C(O)NH2라디칼을 의미한다. 별도로 언급하지 않는 한, 카르바모일 부분을 함유하는 본 발명의 화합물은 이의 보호된 유도체를 포함한다. 카르바모일 부분에 대한 적절한 보호기로는 아세틸, 3차-부톡시카르보닐, 벤질옥시카르보닐 등이 있으며, 보호된 유도체 및 보호되지 않은 유도체 둘 모두는 본 발명의 범주에 포함된다."Carbamoyl" means the -C (O) NH 2 radical. Unless stated otherwise, compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for the carbamoyl moiety include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like, and both protected and unprotected derivatives are included within the scope of the present invention.

"카르보시클릭 케톤 유도체"는 -C(O)- 부분을 함유하는 유도체를 의미한다."Carbocyclic ketone derivative" means a derivative containing a -C (O)-moiety.

"카르복시"는 -C(O)OH 라디칼을 의미한다. 별도로 언급하지 않는 한, 카르복시 부분을 함유하는 본 발명의 화합물은 이의 보호된 유도체를 포함한다. 카르복시 부분에 대한 적절한 보호기로는 벤질, 3차부틸 등이 있다."Carboxy" means the -C (O) OH radical. Unless stated otherwise, compounds of the invention containing a carboxy moiety include protected derivatives thereof. Suitable protecting groups for the carboxy moiety include benzyl, tertiary butyl and the like.

"시클로알킬"은 표시된 수의 고리 탄소원자를 함유하는, 포화되거나 부분적으로 불포화된 모노시클릭 고리, 접합된 비시클릭 또는 가교된 폴리시클릭 고리 어셈블리, 및 이의 임의의 카르보시클릭 케톤, 티오케톤 또는 이미노케톤 유도체를 의미한다 (예를 들어, (C3-10)시클로알킬로는 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실, 시클로헥세닐, 2,5-시클로헥사디에닐, 비시클로[2.2.2]옥틸, 아다만탄-1-일, 데카히드로나프틸, 옥소시클로헥실, 디옥소시클로헥실, 티오시클로헥실, 2-옥소비시클로[2.2.1]헵트-1-일 등이 있다)."Cycloalkyl" means a saturated or partially unsaturated monocyclic ring, a conjugated bicyclic or crosslinked polycyclic ring assembly, containing any indicated number of ring carbon atoms, and any carbocyclic ketone, thioketone or imide thereof ( E.g. , (C 3-10 ) cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo [2.2 .2] octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo [2.2.1] hept-1-yl, etc.) .

"시클로알킬렌"은 표시된 수의 고리 탄소원자를 함유하는 포화되거나 부분적으로 불포화된 모노시클릭 고리 또는 가교된 폴리시클릭 고리 어셈블리, 및 이의 임의의 카르보시클릭 케톤, 티오케톤 또는 이미노케톤 유도체를 의미한다. 예를 들어, "R1및 R2가, R1및 R2둘 모두가 부착되어 있는 탄소원자와 함께 (C3-8)시클로알킬렌을 형성"하는 예로는 하기 화학식이 있지만, 이로 제한되는 것은 아니다:"Cycloalkylene" means a saturated or partially unsaturated monocyclic ring or crosslinked polycyclic ring assembly containing the indicated number of ring carbon atoms, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. do. For example, examples of “R 1 and R 2 together with the carbon atom to which both R 1 and R 2 are attached form (C 3-8 ) cycloalkylene” include, but are not limited to: It is not:

"질환"은 구체적으로는 동물 또는 이의 일부의 여하한 건강하지 못한 상태를 포함하고, 동물에 수행되는 의학적 또는 수의학적 요법에 의해 유발되거나 이에 부수될 수 있는 건강하지 못한 상태, 즉, "부작용"을 포함한다.A "disease" specifically includes any unhealthy condition of an animal or part thereof and is an unhealthy condition, ie, "side effect" that can be caused or accompanied by a medical or veterinary therapy performed on the animal. It includes.

"할로"는 플루오로, 클로로, 브로모 또는 요오도를 의미한다."Halo" means fluoro, chloro, bromo or iodo.

"할로-치환된 알킬"은, 하나의 분리된 기로서 또는 보다 큰 기의 일부로서, 하나 이상의 "할로" 원자에 의해 치환된 "알킬"을 의미하며, 이러한 용어들은 본원에 정의되어 있다. 할로-치환된 알킬로는 할로알킬, 디할로알킬, 트리할로알킬, 퍼할로알킬 등이 있다 (예를 들어, 할로-치환된 (C1-3)알킬로는 클로로메틸, 디클로로메틸, 디플루오로메틸, 트리플루오로메틸, 2,2,2-트리플루오로에틸, 퍼플루오로에틸, 2,2,2-트리플루오로-1,1-디클로로에틸 등이 있다)."Halo-substituted alkyl" means "alkyl" substituted by one or more "halo" atoms, either as a separate group or as part of a larger group, and these terms are defined herein. Halo-substituted alkyls include haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g., halo-substituted (C 1-3 ) alkyls include chloromethyl, dichloromethyl, di Fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like).

"헤테로원자 부분"으로는 -N=, -NR-, -O-, -S- 또는 -S(O)2(여기서, R은 수소, (C1-6)알킬 또는 보호기임)가 있다.A "heteroatom moiety" includes -N =, -NR-, -O-, -S- or -S (O) 2 , wherein R is hydrogen, (C 1-6 ) alkyl or a protecting group.

"헤테로시클로알킬렌"은 본원에 정의된 시클로알킬렌을 의미하며, 단, 표시된 하나 이상의 고리 탄소원자는 -N=, -NR-, -O-, -S- 또는 -S(O)2(여기서, R은 수소, (C1-6)알킬임)로부터 선택된 헤테로원자 부분에 의해 대체된다. 예를 들어, "R1및 R2가, R1및 R2둘 모두가 부착되어 있는 탄소원자와 함께 헤테로(C3-8)시클로알킬을 형성"하는 예로는 하기 화학식이 있지만, 이로 제한되는 것은 아니다:"Heterocycloalkylene" means a cycloalkylene as defined herein, provided that one or more of the ring carbon atoms indicated is -N =, -NR-, -O-, -S- or -S (O) 2 , wherein , R is replaced by a heteroatom moiety selected from hydrogen, (C 1-6 ) alkyl. For example, examples of “R 1 and R 2 together with the carbon atom to which both R 1 and R 2 are attached form hetero (C 3-8 ) cycloalkyl” include, but are not limited to: It is not:

상기 식에서, R은 수소, (C1-6)알킬 또는 보호기이다.Wherein R is hydrogen, (C 1-6 ) alkyl or a protecting group.

"헤테로아릴"은 본원에 정의된 아릴을 의미하며, 단, 표시된 하나 이상의 고리 탄소원자는 -N=, -NR-, -O- 또는 -S- (여기서, R은 수소, (C1-6)알킬 또는 보호기이거나, 고리 질소의 부착점으로서 소용되는 유리 원자가를 나타냄)로부터 선택된 헤테로원자 부분에 의해 대체되고, 각각의 고리는 5 내지 6개의 고리 원자로 이루어져 있다. 예를 들어, 본원에서 사용된 치환되거나 비치환된 헤테로(C5-10)아릴로는 4-아미노-2-히드록시피리미딘-5-일, 벤조티아졸-2-일, 1H-벤조이미다졸-2-일, 2-브로모피리드-5-일, 5-브로모피리드-2-일, 4-카르바모일티아졸-2-일, 3-카르복시피리드-4-일, 5-카르복시-2,6-디메틸피리드-3-일, 3,5-디메틸이속사졸-4-일, 5-에톡시-2,6-디메틸피리드-3-일, 5-플루오로-6-히드록시피리미딘-4-일, 푸르-2-일, 푸르-3-일, 5-히드록시-4,6-디메틸피리드-3-일, 8-히드록시-5,7-디메틸퀴놀린-2-일, 5-히드록시메틸이속사졸-3-일, 3-히드록시-6-메틸피리드-2-일, 3-히드록시피리드-2-일, lH-이미다졸-2-일, lH-이미다졸-4-일, lH-인돌-3-일, 이소티아졸-4-일, 이속사졸-4-일, 2-메틸푸르-3-일, 5-메틸푸르-2-일, 1-메틸-lH-이미다졸-2-일, 5-메틸-3H-이미다졸-4-일, 5-메틸이속사졸-3-일, 5-메틸-2H-피라졸-3-일, 3-메틸피리드-2-일, 4-메틸피리드-2-일, 5-메틸피리드-2-일, 6-메틸피리드-2-일, 2-메틸피리드-3-일, 2-메틸티아졸-4-일, 5-니트로피리드-2-일, 2H-피라졸-3-일, 3H-피라졸-4-일, 피리다진-3-일, 피리드-2-일, 피리드-3-일, 피리드-4-일, 5-피리드-3-일-2H-[1,2,4]트리아졸-3-일, 피리미딘-4-일, 피리미딘-5-일, lH-피롤-3-일, 퀴놀린-2-일, 1H-테트라졸-5-일, 티아졸-2-일, 티아졸-5-일, 티엔-2-일, 티엔-3-일, 2H-[1,2,4]트리아졸-3-일, 3H-[1,2,3]트리아졸-4-일, 5-트리플루오로메틸피리드-2-일 등이 있으나, 이로 제한되는 것은 아니다. 적절한 보호기로는 3차-부톡시카르보닐, 벤질옥시카르보닐, 벤질, 4-메톡시벤질, 2-니트로벤질 등이 있다. R4를 정의하기 위해 본원에서 사용된 치환되거나 비치환된 헤테로(C5-10)아릴로는 벤조푸르-2-일, 푸르-2-일, 푸르-3-일, 피리드-3-일, 피리드-4-일, 퀴놀-2-일, 퀴놀-3-일, 티엔-2-일, 티엔-3-일 등이 있다."Heteroaryl" means aryl as defined herein, provided that one or more of the ring carbon atoms indicated is -N =, -NR-, -O- or -S-, wherein R is hydrogen, (C 1-6 ) Or an alkyl or protecting group, or a heteroatom moiety selected from free valency serving as the point of attachment of ring nitrogen, each ring consisting of 5 to 6 ring atoms. For example, substituted or unsubstituted hetero (C 5-10 ) aryl as used herein includes 4-amino-2-hydroxypyrimidin-5-yl, benzothiazol-2-yl, 1 H -benzo Imidazol-2-yl, 2-bromopyrid-5-yl, 5-bromopyrid-2-yl, 4-carbamoylthiazol-2-yl, 3-carboxypyrid-4-yl, 5 -Carboxy-2,6-dimethylpyrid-3-yl, 3,5-dimethylisoxazol-4-yl, 5-ethoxy-2,6-dimethylpyrid-3-yl, 5-fluoro- 6-hydroxypyrimidin-4-yl, fur-2-yl, fur-3-yl, 5-hydroxy-4,6-dimethylpyrid-3-yl, 8-hydroxy-5,7-dimethyl Quinolin-2-yl, 5-hydroxymethylisoxazol-3-yl, 3-hydroxy-6-methylpyrid-2-yl, 3-hydroxypyrid-2-yl, l H -imidazole -2-yl, l H -imidazol-4-yl, l H -indol-3-yl, isothiazol-4-yl, isoxazol-4-yl, 2-methylfur-3-yl, 5- Methylfur-2-yl, 1-methyl-l H -imidazol-2-yl, 5-methyl-3 H -imidazol-4-yl, 5-methylisoxazol-3-yl, 5-methyl- 2 H -pyrazol-3-yl, 3-methylpyrid-2-yl, 4-methylpyrid-2-yl, 5-methylpyrid-2-yl, 6-methylpyrid-2-yl, 2-methylpyrid-3-yl, 2-Methylthiazol-4-yl, 5-nitropyrid-2-yl, 2 H -pyrazol-3-yl, 3 H -pyrazol-4-yl, pyridazin-3-yl, pyrided- 2-yl, pyrid-3-yl, pyrid-4-yl, 5-pyrid-3-yl-2 H- [1,2,4] triazol-3-yl, pyrimidin-4-yl , Pyrimidin-5-yl, l H -pyrrole-3-yl, quinolin-2-yl, 1 H -tetrazol-5-yl, thiazol-2-yl, thiazol-5-yl, thien-2 -yl, thien-3-yl, 2 H - [1,2,4] triazol-3-yl, 3 H - [1,2,3] triazol-4-yl, methyl-5-trifluoromethyl blood Lead-2-yl, etc., but is not limited thereto. Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl and the like. Substituted or unsubstituted hetero (C 5-10 ) aryl used herein to define R 4 include benzofur-2-yl, fur-2-yl, fur-3-yl, pyrid-3-yl , Pyrid-4-yl, quinol-2-yl, quinol-3-yl, thien-2-yl, thien-3-yl and the like.

"헤테로비시클로아릴"은 본원에 정의된 대로, 표시된 하나 이상의 고리 탄소원자가 -N=, -NR-, -O- 또는 -S- (여기서, R은 수소, (C1-6)알킬 또는 보호기이거나, 고리 질소의 부착점으로서 소용되는 유리 원자가를 나타냄)로부터 선택된 헤테로원자 부분에 의해 대체된 비시클로아릴 및 이의 임의의 카르보시클릭 케톤, 티오케톤 또는 이미노케톤 유도체를 의미한다. 예를 들어, 본원에서 사용된 치환되거나 비치환된 헤테로(C8-10)비시클로아릴로는 2-아미노-4-옥소-3,4-디히드로프테리딘-6-일 등이 있으나, 이로 제한되는 것은 아니다. 일반적으로, 본원에서 사용된 헤테로비시클로아릴이란 용어는, 예를 들어 벤조[1,3]-디옥솔-5-일, 3,4-디히드로-2H-[1,8]나프티리디닐, 3,4-디히드로-2H-퀴놀리닐, 2,4-디옥소-3,4-디히드로-2H-퀴나졸리닐, 1,2,3,4,5,6-헥사히드로[2.2']비피리디닐일, 3-옥소-2,3-디히드로벤조[1,4]옥사지닐, 5,6,7,8-테트라히드로퀴놀리닐 등을 포함한다.“Heterobicycloaryl” means one or more of the ring carbon atoms indicated is —N═, —NR—, —O— or —S—, where R is hydrogen, (C 1-6 ) alkyl or a protecting group Or bicycloaryl substituted by a heteroatom moiety selected from the group consisting of free valences serving as the point of attachment of ring nitrogen and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, substituted or unsubstituted hetero (C 8-10 ) bicycloaryl, as used herein, includes 2-amino-4-oxo-3,4-dihydrophthyridin-6-yl, and the like. It is not limited to this. In general, the term heterobicycloaryl as used herein refers to, for example, benzo [1,3] -dioxol-5-yl, 3,4-dihydro-2 H- [1,8] naphthyridinyl , 3,4-dihydro-2 H -quinolinyl, 2,4-dioxo-3,4-dihydro-2 H -quinazolinyl, 1,2,3,4,5,6-hexahydro [2.2 '] bipyridinylyl, 3-oxo-2,3-dihydrobenzo [1,4] oxazinyl, 5,6,7,8-tetrahydroquinolinyl and the like.

"헤테로시클로알킬"은 본원에 정의된 대로, 표시된 하나 이상의 고리 탄소원자가 -N=, -NR-, -O- 또는 -S- (여기서, R은 수소, (C1-6)알킬 또는 보호기이거나, 고리 질소의 부착점으로서 소용되는 유리 원자가를 나타냄)로부터 선택된 헤테로원자에 의해 대체된 시클로알킬 및 이의 임의의 카르보시클릭 케톤, 티오케톤 또는 이미노케톤 유도체를 의미한다 (예를 들어, 헤테로(C5-10)시클로알킬이란 용어는 이미다졸리디닐, 모르폴리닐, 피페라지닐, 피페리딜, 피롤리디닐, 피롤리닐, 퀴누클리디닐 등을 포함한다). 적절한 보호기로는 3차-부톡시카르보닐, 벤질옥시카르보닐, 벤질, 4-메톡시벤질, 2-니트로벤질 등이 있다. 보호된 유도체 및 보호되지 않은 유도체 둘 모두는 본 발명의 범주에 포함된다."Heterocycloalkyl" means one or more of the ring carbon atoms indicated is -N =, -NR-, -O- or -S-, wherein R is hydrogen, (C 1-6 ) alkyl or a protecting group By cycloalkyl substituted by a heteroatom selected from a free atom which serves as the point of attachment of the ring nitrogen, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., hetero ( C 5-10 ) cycloalkyl includes imidazolidinyl, morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl and the like). Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl and the like. Both protected and unprotected derivatives are included within the scope of the present invention.

"히드록시"는 -OH 라디칼을 의미한다. 별도로 언급하지 않는 한, 히드록시 라디칼을 함유하는 본 발명의 화합물은 이의 보호된 유도체를 포함한다. 히드록시 부분에 대한 적절한 보호기로는 벤질 등이 있다."Hydroxy" means an -OH radical. Unless stated otherwise, compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for the hydroxy moiety include benzyl and the like.

"이미노케톤 유도체"는 -C(NR)- 부분 (여기서, R은 수소 또는 (C1-6)알킬임)을 함유하는 유도체를 의미한다."Iminoketone derivative" means a derivative containing a -C (NR)-moiety, wherein R is hydrogen or (C 1-6 ) alkyl.

"이성질체"는 화학식(I)과 동일한 분자식을 가지나 특성 또는 이들의 원자의결합 순서 또는 이들의 원자의 공간 배열이 상이한 화학식(I)의 화합물을 의미한다. 이들 원자의 공간적 배열이 다른 이성질체는 "입체이성질체"로 언급된다. 상호간에 거울상이 아닌 입체이성질체는 "부분입체이성질체"로 언급되며, 비중복성 거울상인 입체이성질체는 "에난티오머" 또는 "광학 이성질체"로서 언급된다. 4개의 동일하지 않은 치환기에 결합된 탄소원자는 "키랄 중심"으로 언급된다. 하나의 키랄 중심을 지닌 화합물은 상반된 키랄성을 갖는 2개의 에난티오머 형태를 지니며, "라세미 혼합물"로 언급된다. 하나 보다 많은 키랄 중심을 갖는 화합물은 2 n -1(여기서, n은 키랄 중심의 갯수)개의 에난티오머 쌍을 갖는다. 하나 보다 많은 키랄 중심을 지닌 화합물이 개별적인 부분입체이성질체로서 또는 부분입체이성질체들의 혼합물("부분입체이성질체 혼합물"로서 언급됨)로서 존재할 수 있다. 하나의 키랄 중심이 존재하는 경우, 입체이성질체는 그 키랄 중심의 절대적 입체배치를 특징으로 한다. 절대적 입체배치는 키랄 중심에 부착된 치환기의 공간적 배열을 의미한다. 에난티오머는 이들의 키랄 중심의 절대적 입체배치를 특징으로 하며, 칸(Cahn), 잉골드(Ingold) 및 프리로그 (Prelog)의R- 및S-시퀀싱 규칙에 의해 기술된다. 입체화학적 명명법, 입체화학의 결정 방법, 및 입체 이성질체의 구분에 관한 약정은 당업계에 공지되어 있다(참조: "Advanced Organic Chemistry", 4rd edition, March, Jerry, John Wiley & Sons, New York, 1985). 화학식(I)의 화합물을 기술하기 위해 본원에서 사용한 명칭 및 예시는 모든 가능한 입체이성질체를 포함하고자 하는 것으로 이해된다. 따라서, 예를 들어, 명칭N-[1-(1-벤질카르바모일-메타노일)-프로필]-4-모르폴린-4-일-4-옥소-2-페닐메탄술포닐메틸-부티르아미드는N-[(S)-1-(1-벤질카르바모일-메타노일)-프로필]-4-모르폴린-4-일-4-옥소-2-페닐메탄술포닐메틸-부티르아미드 및N-[(R)-1-(1-벤질카르바모일-메타노일)-프로필]-4-모르폴린-4-일-4-옥소-2-페닐메탄술포닐메틸-부티르아미드 및 이의 임의의 혼합물, 라세미체 등을 포함하는 것으로 해석된다."Isomer" means a compound of formula (I) which has the same molecular formula as formula (I) but differs in the nature or order in which their atoms are bonded or in the arrangement of their atoms in space. Isomers that differ in the spatial arrangement of these atoms are referred to as "stereoisomers". Stereoisomers that are not mirror images of one another are referred to as "diastereomers", and stereoisomers that are nonredundant mirror images are referred to as "enantiomers" or "optical isomers". Carbon atoms bonded to four nonidentical substituents are referred to as "chiral centers". Compounds with one chiral center have two enantiomeric forms with opposite chirality and are referred to as "racemic mixtures". Compounds with more than one chiral center have 2 n -1 where n is the number of chiral centers. Compounds with more than one chiral center may exist as individual diastereomers or as a mixture of diastereomers (referred to as "diastereomeric mixtures"). If one chiral center is present, the stereoisomer is characterized by the absolute stereoconfiguration of that chiral center. Absolute stereoconfiguration refers to the spatial arrangement of substituents attached to the chiral center. Enantiomers are characterized by the absolute stereoconfiguration of their chiral centers and described by the R -and S -sequencing rules of Cahn, Ingold and Prelog. Arrangements for stereochemical nomenclature, methods for determining stereochemistry, and stereoisomers are known in the art ("Advanced Organic Chemistry", 4rd edition, March, Jerry, John Wiley & Sons, New York, 1985). ). It is understood that the names and examples used herein to describe the compounds of formula (I) are intended to include all possible stereoisomers. Thus, for example, the name N- [1- (1-benzylcarbamoyl-methanoyl) -propyl] -4-morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyr Amide is N -[(S) -1- (1-benzylcarbamoyl-methanoyl) -propyl] -4-morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamide And N -[(R) -1- (1-benzylcarbamoyl-methanoyl) -propyl] -4-morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamide and It is understood to include any mixtures thereof, racemates and the like.

"케톤 유도체"는 부분 -C(O)-를 함유하는 유도체를 의미한다. 예를 들어, 본원에서 X3는 2-아세톡시-아제티딘-3-일이 될 수 있다. 구체적으로 X3의 "카르보시클릭 케톤 유도체"는 2-아세톡시-4-옥소-아제티딘-3-일(표 3, C32 참조)이다."Ketone derivative" means a derivative containing the part -C (O)-. For example, X 3 here can be 2-acetoxy-azetidin-3-yl. Specifically the "carbocyclic ketone derivative" of X 3 is 2-acetoxy-4-oxo-azetidin-3-yl (see Table 3, C32).

"니트로"는 -NO2라디칼을 의미한다."Nitro" means a -NO 2 radical.

"임의적" 또는 "임의로"는 후속하여 기술되는 사건 또는 상황이 발생하거나 발생하지 않을 수 있으며, 이 표현이 사건 또는 상황이 일어나는 예 또는 일어나지 않는 예를 포함함을 의미한다. 예를 들어, "R3및 R4내에서 임의의 지환족 또는 방향족 고리 시스템은....1 내지 5개의 라디칼에 의해 추가로 치환될 수 있다"라는 표현은 R3및 R4가 본 발명의 범주에 포함되기 위해 치환되거나 치환되지 않을 수 있음을 의미한다.“Arbitrarily” or “optionally” means that an event or situation described later may or may not occur, and that expression includes an example where an event or situation occurs or an example that does not occur. For example, the phrase "R 3 and R 4 any alicyclic or aromatic ring system is within .... may be further substituted by 1-5 radicals of" the present invention is that R 3 and R 4 It means that it may be substituted or unsubstituted to be included in the category of.

"옥소알킬"은 상기에서 정의된 알킬을 의미하며, 표시된 수의 탄소 원자 중의 하나가 산소기(-O-)에 의해 대체되고, 예를 들어, 옥소(C2-6)알킬은 메톡시메틸등을 포함한다."Oxoalkyl" means alkyl as defined above, wherein one of the indicated number of carbon atoms is replaced by an oxygen group (-O-), for example, oxo (C 2-6 ) alkyl is methoxymethyl, etc. It includes.

"N-산화물 유도체"는 질소가 산화된 상태 (즉, O-N)로 존재하면서 원하는 약리 활성을 지니는 화학식(I)의 화합물의 유도체를 의미한다." N -oxide derivative" means a derivative of a compound of formula (I) which has the desired pharmacological activity while the nitrogen is present in the oxidized state (ie, ON).

질환의 "병리학"은 질환의 본질적인 특성, 원인, 및 전개 뿐만 아니라 질환의 진행에 따른 구조적 및 기능적 변화를 의미한다."Pathology" of a disease refers to structural and functional changes as the disease progresses, as well as the essential characteristics, causes, and development of the disease.

"약제학적으로 허용되는"이란 용어는 일반적으로 안전하고, 비독성이고 생물학적으로 또는 기타 측면에서 바람직한 약제학적 조성물의 제조에 유용한 것을 의미하며, 이는 수의학적 용도 뿐만 아니라 인간 약제 용도에도 적합한 것을 포함한다.The term "pharmaceutically acceptable" means generally useful for the preparation of pharmaceutical compositions that are safe, non-toxic and biologically or otherwise desirable, including those suitable for veterinary as well as human pharmaceutical use. .

"약제학적으로 허용되는 염"은 상기한 바와 같이 약제학적으로 허용되면서 원하는 약리 활성을 지닌 화학식(I)의 화합물을 의미한다. 이러한 염은 무기산, 예컨대, 염산, 브롬산, 황산, 질산, 인산 등에 의해 형성되거나; 유기산, 예컨대, 아세트산, 프로피온산, 헥산산, 헵탄산, 시클로펜탄프로피온산, 글리콜산, 피루브산, 락트산, 말론산, 숙신산, 말산, 말레산, 푸마르산, 타르타르산, 시트르산, 벤조산,o-(4-히드록시벤조일)벤조산, 신남산, 마델산, 메탄술폰산, 에탄술폰산, 1,2-에탄디술폰산, 2-히드록시에탄술폰산, 벤젠술폰산,p-클로로벤젠술폰산, 2-나프탈렌술폰산,p-톨루엔술폰산, 캄포르술폰산, 4-메틸비시클로[2.2.2]옥트-2-엔-1-카르복실산, 글루코헵톤산, 4,4'-메틸렌비스(3-히드록시-2-엔-1-카르복실산), 3-페닐프로피온산, 트리메틸아세트산, 3차 부틸아세트산, 라우릴 황산, 글루콘산, 글루탐산, 히드록시나프토산, 살리실산, 스테아르산, 무콘산 등에 의해 형성된 산 부가염을 포함한다."Pharmaceutically acceptable salt" means a compound of formula (I) that is pharmaceutically acceptable and has the desired pharmacological activity as described above. Such salts are formed with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; Organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (4-hydroxy Benzoyl) benzoic acid, cinnamic acid, madeelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p -chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p -toluenesulfonic acid, Camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis (3-hydroxy-2-ene-1-carbox Acids), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.

약제학적으로 허용되는 염은 또한 존재하는 산 양성자가 무기 또는 유기 염기와 반응할 수 있는 경우에 형성될 수 있는 염기 부가 염을 포함한다. 허용되는 무기 염기로는 수산화나트륨, 탄산나트륨, 수산화칼륨, 수산화알루미늄 및 수산화칼슘이 있다. 허용되는 유기 염기로는 에탄올아민, 디에탄올아민, 트리에탄올아민, 트로메타민,N-메틸글루카민 등이 있다.Pharmaceutically acceptable salts also include base addition salts which may be formed when the acid protons present can react with an inorganic or organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N -methylglucamine and the like.

"전구약물"은 대사 수단 (예를 들어, 가수분해)에 의해 화학식(I)의 화합물로 생체내에서 전환될 수 있는 화합물을 의미한다. 예를 들어, 히드록시기를 함유하는 화학식(I)의 화합물의 에스테르는 생체내에서의 가수분해에 의해 모(母)분자로 전환될 수 있다. 대안적으로, 카르복시기를 함유하는 화학식(I)의 화합물의 에스테르도 생체내에서의 가수분해에 의해 모분자로 전환될 수 있다. 히드록시기를 함유하는 화학식(I)의 화합물의 적합한 에스테르는, 예를 들어, 아세테이트, 시트레이트, 락테이트, 타르트레이트, 말로네이트, 옥살레이트, 살리실레이트, 프로피오네이트, 숙시네이트, 푸마레이트, 말레이트, 메틸렌-비스-b-히드록시나프토에이트, 젠티세이트, 이세티오네이트, 디-p-톨루오일타르트레이트, 메탄술포네이트, 에탄술포네이트, 벤젠술포네이트, p-톨루엔술포네이트, 시클로헥실술파메이트 및 퀴네이트이다. 카르복시기를 함유하는 화학식(I)의 화합물의 적합한 에스테르는, 예를 들어, 에프.제이.라인베버 (F.J.Leinweber)의 문헌[Drug Metab. Res., 1987, 18, page 379]에 기재된 것들이다. 히드록시기를 함유하는 화학식(I)의 화합물의 에스테르 중 특히 유용한 종류는 분드가드(Bundgaard) 등의 문헌[J. Med. Chem.,1989, 32, page 2503-2507]에 기재된 것들로부터 선택된 산 부분으로부터 형성될 수 있으며, 치환된 (아미노메틸)-벤조에이트, 예를 들어 두 개의 알킬기가 함께 결합되고/되거나 산소 원자 또는 임의로 치환된 질소 원자, 예를 들어 알킬화된 질소 원자에 의해 중단된 디알킬아미노-메틸벤조에이트, 더욱 상세하게는 (모르폴리노-메틸)벤조에이트, 예를 들어 3- 또는 4-(모르폴리노메틸)-벤조에이트, 및 (4-알킬피페라진-1-일)벤조에이트, 예를 들어 3- 또는 4-(4-알킬피페라진-1-일)벤조에이트를 포함한다."Prodrug" means a compound that can be converted in vivo to a compound of formula (I) by metabolic means (eg hydrolysis). For example, esters of compounds of formula (I) containing hydroxy groups can be converted to parent molecules by hydrolysis in vivo. Alternatively, esters of compounds of formula (I) containing carboxyl groups can also be converted to parent molecules by hydrolysis in vivo. Suitable esters of compounds of formula (I) containing hydroxy groups are, for example, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, Maleate, methylene-bis-b-hydroxynaphthoate, gentiate, isethionate, di- p -toluoyl tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclo Hexylsulfamate and quinate. Suitable esters of compounds of formula (I) containing carboxyl groups are described, for example, in FJ Leinweber of Drug Metab. Res., 1987, 18, page 379. Particularly useful types of esters of compounds of formula (I) containing hydroxy groups are Bungaard et al. Med. Chem., 1989, 32, page 2503-2507, which may be formed from an acid moiety selected from those described, and substituted (aminomethyl) -benzoates, for example two alkyl groups bound together and / or an oxygen atom or Dialkylamino-methylbenzoate interrupted by an optionally substituted nitrogen atom, for example an alkylated nitrogen atom, more particularly (morpholino-methyl) benzoate, for example 3- or 4- (morpholi Nomethyl) -benzoate, and (4-alkylpiperazin-1-yl) benzoate, for example 3- or 4- (4-alkylpiperazin-1-yl) benzoate.

"보호된 유도체"는 반응 부위 또는 부위들이 보호기에 의해 차단된 화학식(I)의 화합물의 유도체를 의미한다. 화학식(I)의 화합물의 보호된 유도체는 화학식(I)의 화합물의 제조에 유용하거나, 그들 자체가 활성 카텝신 S 억제제일 수 있다. 적절한 보호기의 포괄적인 목록은 문헌[T.W. Green,Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999]에서 발견될 수 있다."Protected derivative" means a derivative of a compound of formula (I) in which a reaction site or sites are blocked by a protecting group. Protected derivatives of compounds of formula (I) may be useful for the preparation of compounds of formula (I) or may themselves be active cathepsin S inhibitors. For a comprehensive list of suitable protectors, see TW Green, Protecting Groups in Organic Synthesis , 3rd edition, John Wiley & Sons, Inc. 1999].

"치료적 유효량"은 질환의 치료를 위해 동물에 투여되는 경우, 질환을 치료하기에 충분히 효과적인 양을 의미한다.By "therapeutically effective amount" is meant an amount effective enough to treat a disease when administered to an animal for the treatment of the disease.

"티오케톤 유도체"는 -C(S)- 부분을 함유하는 유도체를 의미한다."Tioketone derivative" means a derivative containing a -C (S)-moiety.

"치료" 또는 "치료하는"은 본 발명의 화합물의 임의 투여를 의미하며, 하기를 포함한다:"Treatment" or "treating" means any administration of a compound of the invention, including:

(1) 질병에 걸리기 쉬울 수 있지만, 질병의 병리학 또는 증상학을 아직 체험하지 않거나 나타내지 아니한 동물에게서 발병을 예방하거나,(1) prevent the onset in animals that may be susceptible to disease but have not yet experienced or exhibited the pathology or symptom of the disease,

(2) 질병의 병리학 또는 증상학을 체험하거나 나타내고 있는 동물에게서 질병을 억제하거나 (즉, 병리학 및/또는 증상학의 추가 진전을 억제시킴),(2) inhibit disease (ie, inhibit further development of pathology and / or symptom) in an animal experiencing or exhibiting the pathology or symptom of the disease,

(3) 질병의 병리학 또는 증상학을 체험하거나 나타내고 있는 동물에게서 질병을 개선시키는 것 (즉, 병리학 및/또는 증상학을 역전시킴).(3) improving disease (ie, reversing pathology and / or symptom) in an animal experiencing or exhibiting the pathology or symptom of the disease.

명명법:nomenclature:

화학식(I)의 화합물 및 이들의 제조에 사용되는 중간 물질 및 출발 물질은, 주요 기로서 인용함에 있어서 특징이 되는 기의 우선도가 산, 에스테르, 아미드 등의 순이 되는 IUPAC 명명법 규칙에 따라 명명된다. 대안적으로, 화합물은 AutoNom 4.0(Beilstein Information Systems, Inc.)에 의해 명명된다. 예를 들어, X1가 -NHC(R1)(R2)X2(여기서, R1과 R2는 각각 수소임)이고, X2가 시아노이고, R3가 시클로헥실메틸이고, R4가 페닐아미노인 화학식(I)의 화합물, 즉, 하기 구조식을 지닌 화합물은 N -시아노메틸-2-시클로헥실메틸- N '-페닐-말론아미드로 명명된다:The compounds of formula (I) and the intermediates and starting materials used in their preparation are named according to the IUPAC nomenclature rules in which the order of priority of the groups characterized by reference to the main groups is acid, ester, amide, etc. . Alternatively, the compound is named by AutoNom 4.0 (Beilstein Information Systems, Inc.). For example, X 1 is —NHC (R 1 ) (R 2 ) X 2 , wherein R 1 and R 2 are each hydrogen, X 2 is cyano, R 3 is cyclohexylmethyl, R Compounds of formula (I) in which tetravalent phenylamino, ie, compounds having the following structure, are designated N -cyanomethyl-2-cyclohexylmethyl- N' -phenyl-malonamide :

본 발명의 바람직한 양태:Preferred embodiments of the present invention:

본 발명의 최광의의 정의가 발명의 개요에 기재되어 있지만, 본 발명의 특정 양태들이 바람직하다. 예를 들어, X1은 -NHC(R1)(R2)X2또는 -NHX3이고, X2는 시아노, -C(O)X3, -C(O)CF3, -C(O)CF2CF2R9, -CH=CHS(0)2R5, -C(O)CF2C(O)NR5R5, -C(O)C(O)NR5R6, -C(O)C(O)OR5, -C(O)CH20R5, -C(O)CH2N(R6)SO2R5또는 -C(O)C(O)R5이고 (여기서, R5및 R6은 상기에서 기술한대로임), X3은 4 내지 6원 고리 원자를 함유하는 헤테로모노시클릭 고리 또는 8 내지 14원 고리 원자를 함유하는 접합된 헤테로비시클릭 고리 시스템 및 이의 임의의 카르보시클릭 케톤, 이미노케톤 또는 티오케톤 유도체를 포함하고, R5, X2또는 X3내에서 임의의 지환족 또는 방향족 고리 시스템이 (C1-6)알킬 및 -X4OC(O)R12로부터 독립적으로 선택된 1 내지 5개의 라디칼 및/또는 -R14, -X4C(O)R14및 -X4OC(O)R14로부터 선택된 하나의 라디칼에 의해 추가로 치환될 수 있고 (여기서, X4, R12및 R14는 상기에서 기술한대로임), R1은 수소 또는 (C1-6)알킬이고, R2는 수소, -X4OR12, (C5-10)헤테로아릴(C0-6)알킬, (C5-10)아릴(C0-6)알킬, (C5-10)시클로알킬(C0-6)알킬, (C5-10)헤테로시클로알킬(C0-6)알킬 또는 (C1-6)알킬이거나; R1과 R2는, R1과 R2둘 모두가 부착되어 있는 탄소 원자와 함께 (C3-8)시클로알킬렌 또는 (C3-8)헤테로시클로알킬렌을 형성하고, 여기에서, 상기 R2내의 임의의 헤테로아릴, 아릴, 시클로알킬, 헤테로시클로알킬, 시클로알킬렌 또는 헤테로시클로알킬렌은 (C1-6)알킬 및 히드록시로부터 독립적으로 선택된 1 내지 3개의 라디칼에 의해 치환되거나 비치환되며, R3는 -CH2X5이고, 여기서 X5는 각 경우에 -X4SR12, -X4C(O)NR12R12, -X4S(O)2R13, -X4C(O)R13, -X4SR14, -X4R12, -R14, -X4S(O)2R14, -X4C(O)R14, -X4C(O)NR14R12로부터 독립적으로 선택되며 (여기서 X4, R12, R13및 R14는 상기에서 정의된 바와 같음), R4는 -NR6R6, -NR6R14, -NR6R15또는 -NR6X5C(O)R14이고 (여기서, R6, X5및 R14는 상기에서 기술한대로이고, R15는 수소, -(C1-6)알킬 또는 -X5OR6이거나 (여기서, X5는 상기에서 기술한대로임); R6및 R15는, R6및 R15둘 모두가 부착되어 있는 질소 원자와 함께 헤테로(C3-10)시클로알킬, 헤테로(C5-10)아릴 또는 헤테로(C8-10)비시클로아릴을 형성함), R3및 R4내에서 임의의 지환족 또는 방향족 고리 시스템이, (C1-6)알킬, 시아노, 할로, 니트로, 할로-치환된 (C1-4)알킬, -X4OR12, -X4C(O)OR12, -X4C(O)R13, -X4C(O)NR12R12및 -X4NR12S(O)2R12으로부터 독립적으로 선택된 1 내지 5개의 라디칼 및/또는 -R14, -X4OR14, 및 -X4C(O)NR14R12로부터 선택된 하나의 라디칼에 의해 추가로 치환될 수 있고, R3및 R4내에서 임의의 지방족 부분은 시아노에서 독립적으로 선택된 1 내지 5개의 라디칼에 의해 추가로 치환될 수 있고 (여기서, X4, R12, R13및 R14는 상기에서 기술한대로임), 단, 하나의 비시클릭 고리 구조만이 R3또는 R4내에 존재한다.While the broadest definition of the invention is described in the Summary of the Invention, certain aspects of the invention are preferred. For example, X 1 is -NHC (R 1 ) (R 2 ) X 2 or -NHX 3 , X 2 is cyano, -C (O) X 3 , -C (O) CF 3 , -C ( O) CF 2 CF 2 R 9 , -CH = CHS (0) 2 R 5 , -C (O) CF 2 C (O) NR 5 R 5 , -C (O) C (O) NR 5 R 6 , -C (O) C (O) OR 5 , -C (O) CH 2 0R 5 , -C (O) CH 2 N (R 6 ) SO 2 R 5 or -C (O) C (O) R 5 Where R 5 and R 6 are as described above, X 3 is a heteromonocyclic ring containing 4 to 6 membered ring atoms or a conjugated heterobicyclic ring containing 8 to 14 membered ring atoms System and any carbocyclic ketone, iminoketone or thioketone derivative thereof, wherein any alicyclic or aromatic ring system in R 5 , X 2 or X 3 is a (C 1-6 ) alkyl and -X Addition by 1 to 5 radicals independently selected from 4 OC (O) R 12 and / or one radical selected from -R 14 , -X 4 C (O) R 14 and -X 4 OC (O) R 14 is the optionally substituted, and (wherein, X 4, R 12 and R 14 with As technology Im), R 1 is hydrogen or (C 1-6) alkyl, R 2 is hydrogen, -X 4 OR 12, (C 5-10) heteroaryl (C 0-6) alkyl, (C 5- 10 ) aryl (C 0-6 ) alkyl, (C 5-10 ) cycloalkyl (C 0-6 ) alkyl, (C 5-10 ) heterocycloalkyl (C 0-6 ) alkyl or (C 1-6 ) Alkyl; R 1 and R 2 together with the carbon atom to which both R 1 and R 2 are attached form (C 3-8 ) cycloalkylene or (C 3-8 ) heterocycloalkylene, wherein any heteroaryl group within R 2, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocycloalkyl alkylene (1-6 C) optionally substituted by 1 to 3 radicals independently selected from alkyl and hydroxy or unsubstituted R 3 is —CH 2 X 5 , wherein X 5 in each case is —X 4 SR 12 , —X 4 C (O) NR 12 R 12 , —X 4 S (O) 2 R 13 , — X 4 C (O) R 13 , -X 4 SR 14 , -X 4 R 12 , -R 14 , -X 4 S (O) 2 R 14 , -X 4 C (O) R 14 , -X 4 C (O) NR 14 R 12 is selected independently (wherein X 4 , R 12 , R 13 and R 14 are as defined above) and R 4 is —NR 6 R 6 , —NR 6 R 14 , — NR 6 R 15 or -NR 6 X 5 C (O) R 14 a (wherein, R 6, X 5 and R 14 is a technology As in the above, R 15 is hydrogen, - (C 1-6) alkyl in -X 5 OR 6, or (wherein, X 5 As is described in the Lim); R 6 and R 15 is hetero (C 3-10) cycloalkyl, with R 6 and R 15 both the nitrogen atom to which both are attached , Hetero (C 5-10 ) aryl or hetero (C 8-10 ) bicycloaryl), any alicyclic or aromatic ring system in R 3 and R 4 is a (C 1-6 ) alkyl, Cyano, halo, nitro, halo-substituted (C 1-4 ) alkyl, -X 4 OR 12 , -X 4 C (O) OR 12 , -X 4 C (O) R 13 , -X 4 C ( O) NR 12 R 12 and -X 4 1-5 radicals independently selected from NR 12 S (O) 2 R 12 and / or -R 14 , -X 4 OR 14 , and -X 4 C (O) NR 14 may be further substituted by one radical selected from R 12 , and any aliphatic moiety in R 3 and R 4 may be further substituted by 1 to 5 radicals independently selected from cyano (where , X 4 , R 12 , R 13 and R 14 are as described above), provided that one Only the click ring structure is present in R 3 or R 4 .

특히, X1은 -NHC(R1)(R2)X2또는 -NHX3이고, X2는 시아노, -C(0)X3, -CF3, -CF2CF3, (E)-2-벤젠술포닐-비닐, 2-디메틸카르바모일-2,2-디플루오로-아세틸, 1-벤질카르바모일-메타노일, 1-벤질옥시(옥살릴), 2-벤질옥시-아세틸, 2-벤젠술포닐아미노-에타노일 또는 2-옥소-2-페닐-에타노일이고, X3는 1H-벤조이미다졸-2-일, 피리미딘-2-일, 벤조옥사졸-2-일, 벤조티아졸-2-일, 피리다진-3-일, 3-페닐-[1,2,4]옥사디아졸-5-일, 3-에틸-[1,2,4]옥사디아졸-5-일, 2-메틸-4-옥소-테트라히드로-푸란-3-일, 2-에틸-4-옥소-테트라히드로-푸란-3-일, 4-옥소-1-(1-페닐-메타노일)-피롤리딘-3-일 또는 (S)-2-아세톡시-4-옥소-아제티딘-3-일이고, R1은 수소 또는 메틸이고, R2는 수소, 메톡시메틸, (C1-6)알킬, 페네틸, 티오펜-2-일 또는 5-메틸-푸란-2-일이거나; (ii) R1및 R2는, R1및 R2둘 모두가 부착되어 있는 탄소 원자와 함께 시클로프로필렌, 테트라히드로-피란-4-일렌 또는 메틸-피페리딘-4-일렌을 형성한다.In particular, X 1 is -NHC (R 1 ) (R 2 ) X 2 or -NHX 3 , X 2 is cyano, -C (0) X 3 , -CF 3 , -CF 2 CF 3 , (E) 2-benzenesulfonyl-vinyl, 2-dimethylcarbamoyl-2,2-difluoro-acetyl, 1-benzylcarbamoyl-methanoyl, 1-benzyloxy (oxalyl), 2-benzyloxy- Acetyl, 2-benzenesulfonylamino-ethanoyl or 2-oxo-2-phenyl-ethanoyl, X 3 is 1 H -benzoimidazol-2-yl, pyrimidin-2-yl, benzoxazole-2 -Yl, benzothiazol-2-yl, pyridazin-3-yl, 3-phenyl- [1,2,4] oxadiazol-5-yl, 3-ethyl- [1,2,4] oxadia Zol-5-yl, 2-methyl-4-oxo-tetrahydro-furan-3-yl, 2-ethyl-4-oxo-tetrahydro-furan-3-yl, 4-oxo-1- (1-phenyl -Methanoyl) -pyrrolidin-3-yl or (S) -2-acetoxy-4-oxo-azetidin-3-yl, R 1 is hydrogen or methyl, R 2 is hydrogen, methoxymethyl , (C 1-6 ) alkyl, phenethyl, thiophen-2-yl or 5-methyl-furan-2-yl; (ii) R 1 and R 2 together with the carbon atom to which both R 1 and R 2 are attached form cyclopropylene, tetrahydro-pyran-4-ylene or methyl-piperidin-4-ylene.

보다 바람직한 R3으로는 티오펜-2-술포닐메틸, 3-클로로-2-플루오로-페닐메탄술포닐메틸, 벤젠술포닐메틸, 페닐메탄술포닐메틸, 2-(1,1-디플루오로-메톡시)-페닐메탄술포닐메틸, 2-벤젠술포닐-에틸, 2-(피리딘-2-술포닐)-에틸, 2-(피리딘-4-술포닐)-에틸, 2-페닐메탄술포닐-에틸, 옥시-피리딘-2-일메탄술포닐메틸, 프로프-2-엔-1-술포닐메틸, 4-메톡시-페닐메탄술포닐메틸,p-톨릴메탄술포닐메틸, 4-클로로-페닐메탄술포닐메틸,o-톨릴메탄술포닐메틸, 3,5-디메틸-페닐메탄술포닐메틸, 4-트리플루오로메틸-페닐메탄술포닐메틸, 4-트리플루오로메톡시-페닐메탄술포닐메틸, 2-브로모-페닐메탄술포닐메틸, 피리딘-2-일메탄술포닐메틸, 피리딘-3-일메탄술포닐메틸, 피리딘-4-일메탄술포닐메틸, 나프탈렌-2-일메탄술포닐메틸, 3-메틸-페닐메탄술포닐메틸, 3-트리플루오로메틸-페닐메탄술포닐메틸, 3-트리플루오로메톡시-페닐메탄술포닐메틸, 4-플루오로-2-트리플루오로메톡시-페닐메탄술포닐메틸, 2-플루오로-6-트리플루오로메틸-페닐메탄술포닐메틸, 3-클로로-페닐메탄술포닐메틸, 2-플루오로-페닐메탄술포닐메틸, 2-트리플루오로-페닐메탄술포닐메틸, 2-시아노-페닐메탄술포닐메틸, 4-tert-부틸-페닐메탄술포닐메틸, 2-플루오로-3-메틸-페닐메탄술포닐메틸, 3-플루오로-페닐메탄술포닐메틸, 4-플루오로-페닐메탄술포닐메틸, 2-클로로-페닐메탄술포닐메틸, 2,5-디플루오로-페닐메탄술포닐메틸, 2,6-디플루오로-페닐메탄술포닐메틸, 2,5-디클로로-페닐메탄술포닐메틸, 3,4-디클로로-페닐메탄술포닐메틸, 2-(1,1-디플루오로-메톡시)-페닐메탄술포닐메틸, 2-시아노-페닐메탄술포닐메틸, 3-시아노-페닐메탄술포닐메틸, 2-트리플루오로메톡시-페닐메탄술포닐메틸, 2,3-디플루오로-페닐메탄술포닐메틸, 2,5-디플루오로-페닐메탄술포닐메틸, 비페닐-2-일메탄술포닐메틸, 시클로헥실메틸, 3-플루오로-페닐메탄술포닐메틸, 3,4-디플루오로-페닐메탄술포닐메틸, 2,4-디플루오로-페닐메탄술포닐메틸, 2,4,6-트리플루오로-페닐메탄술포닐메틸, 2,4,5-트리플루오로-페닐메탄술포닐메틸, 2,3,4-트리플루오로-페닐메탄술포닐메틸, 2,3,5-트리플루오로-페닐메탄술포닐메틸, 2,5,6-트리플루오로-페닐메탄술포닐메틸, 2-클로로-5-트리플루오로메틸페닐메탄술포닐메틸, 2-메틸-프로판-1-술포닐, 2-플루오로-3-트리플루오로메틸페닐메탄술포닐메틸, 2-플루오로-4-트리플루오로메틸페닐메탄술포닐메틸, 2-플루오로-5-트리플루오로메틸페닐메탄술포닐메틸, 4-플루오로-3-트리플루오로메틸페닐메탄술포닐메틸, 2-메톡시-페닐메탄술포닐메틸, 3,5-비스-트리플루오로메틸-페닐메탄술포닐메틸, 4-디플루오로메톡시-페닐메탄술포닐메틸, 2-디플루오로메톡시-페닐메탄술포닐메틸, 3-디플루오로메톡시-페닐메탄술포닐메틸, 2,6-디클로로-페닐메탄술포닐메틸, 비페닐-4-일메탄술포닐메틸, 3,5-디메틸-이속사졸-4-일메탄술포닐메틸, 5-클로로-티오펜-2-일메탄술포닐메틸, 2-[4-(1,1-디플루오로-메톡시)-벤젠술포닐]-에틸, 2-[2-(l,1-디플루오로-메톡시)-벤젠술포닐]-에틸, 2-[3-(1,1-디플루오로-메톡시)-벤젠술포닐]-에틸, 2-(4-트리플루오로메톡시-벤젠술포닐)-에틸, 2-(3-트리플루오로메톡시-벤젠술포닐)-에틸, 2-(2-트리플루오로메톡시-벤젠술포닐)-에틸, (시아노메틸-메틸-카르바모일)-메틸, 부틸, 비페닐-3-일메틸, 2-옥소-2-피롤리딘-1-일-에틸, 2-벤젠술포닐-에틸, 이소부틸술파닐메틸, 2-페닐술파닐-에틸, 시클로헥실메탄술포닐메틸, 2-시클로헥실-에탄술포닐, 벤질, 나프탈렌-2-일, 벤질술파닐메틸, 2-트리플루오로메틸-벤질술파닐메틸, 5-브로모-티오펜-2-일메틸, 페닐술파닐-에틸 및 시클로프로필메탄술포닐메틸이있다.More preferred R 3 is thiophene-2-sulfonylmethyl, 3-chloro-2-fluoro-phenylmethanesulfonylmethyl, benzenesulfonylmethyl, phenylmethanesulfonylmethyl, 2- (1,1-difluoro Rho-methoxy) -phenylmethanesulfonylmethyl, 2-benzenesulfonyl-ethyl, 2- (pyridine-2-sulfonyl) -ethyl, 2- (pyridine-4-sulfonyl) -ethyl, 2-phenylmethane Sulfonyl-ethyl, oxy-pyridin-2-ylmethanesulfonylmethyl, prop-2-ene-1-sulfonylmethyl, 4-methoxy-phenylmethanesulfonylmethyl, p -tolylmethanesulfonylmethyl, 4 -Chloro-phenylmethanesulfonylmethyl, o -tolylmethanesulfonylmethyl, 3,5-dimethyl-phenylmethanesulfonylmethyl, 4-trifluoromethyl-phenylmethanesulfonylmethyl, 4-trifluoromethoxy-phenyl Methanesulfonylmethyl, 2-bromo-phenylmethanesulfonylmethyl, pyridin-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-ylmethanesulfonylmethyl, naphthalene-2- Ylmethanesulfonylmethyl, 3-methyl-phenylmethanesulfonylmethyl, 3-trifluoro Tyl-phenylmethanesulfonylmethyl, 3-trifluoromethoxy-phenylmethanesulfonylmethyl, 4-fluoro-2-trifluoromethoxy-phenylmethanesulfonylmethyl, 2-fluoro-6-trifluoromethyl -Phenylmethanesulfonylmethyl, 3-chloro-phenylmethanesulfonylmethyl, 2-fluoro-phenylmethanesulfonylmethyl, 2-trifluoro-phenylmethanesulfonylmethyl, 2-cyano-phenylmethanesulfonylmethyl 4- tert -butyl-phenylmethanesulfonylmethyl, 2-fluoro-3-methyl-phenylmethanesulfonylmethyl, 3-fluoro-phenylmethanesulfonylmethyl, 4-fluoro-phenylmethanesulfonylmethyl, 2-chloro-phenylmethanesulfonylmethyl, 2,5-difluoro-phenylmethanesulfonylmethyl, 2,6-difluoro-phenylmethanesulfonylmethyl, 2,5-dichloro-phenylmethanesulfonylmethyl, 3,4-dichloro-phenylmethanesulfonylmethyl, 2- (1,1-difluoro-methoxy) -phenylmethanesulfonylmethyl, 2-cyano-phenylmethanesulfonylmethyl, 3-cyano-phenyl Methanesulfonylmethyl, 2-trifluorome C-phenylmethanesulfonylmethyl, 2,3-difluoro-phenylmethanesulfonylmethyl, 2,5-difluoro-phenylmethanesulfonylmethyl, biphenyl-2-ylmethanesulfonylmethyl, cyclohexylmethyl , 3-fluoro-phenylmethanesulfonylmethyl, 3,4-difluoro-phenylmethanesulfonylmethyl, 2,4-difluoro-phenylmethanesulfonylmethyl, 2,4,6-trifluoro- Phenylmethanesulfonylmethyl, 2,4,5-trifluoro-phenylmethanesulfonylmethyl, 2,3,4-trifluoro-phenylmethanesulfonylmethyl, 2,3,5-trifluoro-phenylmethane Sulfonylmethyl, 2,5,6-trifluoro-phenylmethanesulfonylmethyl, 2-chloro-5-trifluoromethylphenylmethanesulfonylmethyl, 2-methyl-propane-1-sulfonyl, 2-fluoro 3-trifluoromethylphenylmethanesulfonylmethyl, 2-fluoro-4-trifluoromethylphenylmethanesulfonylmethyl, 2-fluoro-5-trifluoromethylphenylmethanesulfonylmethyl, 4-fluoro-3 -Trifluoromethylphenylmethanesulfonylmethyl, 2-methoxy-phen Nylmethanesulfonylmethyl, 3,5-bis-trifluoromethyl-phenylmethanesulfonylmethyl, 4-difluoromethoxy-phenylmethanesulfonylmethyl, 2-difluoromethoxy-phenylmethanesulfonylmethyl, 3 -Difluoromethoxy-phenylmethanesulfonylmethyl, 2,6-dichloro-phenylmethanesulfonylmethyl, biphenyl-4-ylmethanesulfonylmethyl, 3,5-dimethyl-isoxazol-4-ylmethanesulfonyl Methyl, 5-chloro-thiophen-2-ylmethanesulfonylmethyl, 2- [4- (1,1-difluoro-methoxy) -benzenesulfonyl] -ethyl, 2- [2- (l, 1-difluoro-methoxy) -benzenesulfonyl] -ethyl, 2- [3- (1,1-difluoro-methoxy) -benzenesulfonyl] -ethyl, 2- (4-trifluorome Methoxy-benzenesulfonyl) -ethyl, 2- (3-trifluoromethoxy-benzenesulfonyl) -ethyl, 2- (2-trifluoromethoxy-benzenesulfonyl) -ethyl, (cyanomethyl-methyl- Carbamoyl) -methyl, butyl, biphenyl-3-ylmethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 2-benzenesulfonyl-ethyl, isobutylsulfanylmethyl, 2-phenyl Sulfanyl- Methyl, cyclohexyl methanesulfonylmethyl, 2-cyclohexyl-ethanesulfonyl, benzyl, naphthalen-2-yl, benzylsulfanylmethyl, 2-trifluoromethyl-benzylsulfanylmethyl, 5-bromo-thiophene 2-ylmethyl, phenylsulfanyl-ethyl and cyclopropylmethanesulfonylmethyl.

보다 바람직한 R4로는 페닐아미노, 벤질아미노, 4-페녹시-페닐아미노, 페네틸아미노, 3-페닐-프로필아미노, 모르폴린-4-일, 시클로헥실아미노, 나프탈렌-1- 일메틸-아미노, 피리딘-3-일아미노, 6-메톡시-피리딘-3-일아미노, 디이소부틸아미노, 4-니트로-벤질아미노, 2-티오펜-2-일-에틸아미노, 3-페녹시-페닐아미노, 시아노메틸-아미노, (피리딘-3-일메틸)-아미노, 5,6,7,8-테트라히드로-나프탈렌-1-일아미노, 2-피리딘-2-일-에틸아미노, 2,3-디히드로-인돌-1-일, 3,4-디히드로-lH-이소퀴놀린-2-일, 시클로헥실메틸-아미노, 2-메톡시-벤질아미노, l-페닐-에틸아미노, (피리딘-4-일메틸)-아미노, 벤질-메틸-아미노, 3-니트로-벤질아미노, 4-메톡시-페닐아미노, 3-카르바모일-페닐아미노, 4-카르바모일-페닐아미노, (테트라히드로-푸란-2-일메틸)-아미노, 3,4-디히드로-2H-퀴놀린-1-일, 디메틸아미노, 부틸메틸아미노, 디이소프로필아미노, 프로필메틸아미노, 1-(벤조옥사졸-2-카르보닐)-프로필아미노 및 이소부틸메틸아미노가 있다.More preferred R 4 includes phenylamino, benzylamino, 4-phenoxy-phenylamino, phenethylamino, 3-phenyl-propylamino, morpholin-4-yl, cyclohexylamino, naphthalen-1-ylmethyl-amino, Pyridin-3-ylamino, 6-methoxy-pyridin-3-ylamino, diisobutylamino, 4-nitro-benzylamino, 2-thiophen-2-yl-ethylamino, 3-phenoxy-phenylamino , Cyanomethyl-amino, (pyridin-3-ylmethyl) -amino, 5,6,7,8-tetrahydro-naphthalen-1-ylamino, 2-pyridin-2-yl-ethylamino, 2,3 -Dihydro-indol-1-yl, 3,4-dihydro-l H -isoquinolin-2-yl, cyclohexylmethyl-amino, 2-methoxy-benzylamino, l-phenyl-ethylamino, (pyridine 4-ylmethyl) -amino, benzyl-methyl-amino, 3-nitro-benzylamino, 4-methoxy-phenylamino, 3-carbamoyl-phenylamino, 4-carbamoyl-phenylamino, (tetra dihydro-furan-2-ylmethyl) -amino, 3,4-dihydro -2 H-quinoline-1 , Dimethylamino, butyl methylamino, di-isopropylamino, methyl-amino-1- (benzoxazole-2-carbonyl) has propylamino and methyl-isobutyl-amino.

상기 설명된 바람직한 양태를 참조로 특정한 기와 바람직한 기의 모든 조합을 포함시키고자 한다.It is intended to include all combinations of specific groups and preferred groups with reference to the preferred embodiments described above.

본 발명의 바람직한 화합물은 표 1에 도시된 하나의 단편(A1 내지 A37)의 아실 탄소 원자(C*)를 표 2에 도시된 하나의 단편(B1 내지 B88)의 메틴 탄소 원자(*CH*)에 결합시키고, 표 2에 도시된 하나의 단편(B1 내지 B88)의 메틴 탄소 원자(*CH*)를 표 3에 도시된 하나의 단편(C1 내지 C36)의 아실 탄소 원자(*C*)에결합시킴에 의해 형성된 화합물로부터 선택된다.Preferred compounds of the invention include acyl carbon atoms (C *) of one fragment (A1 to A37) shown in Table 1 and methine carbon atoms (* CH *) of one fragment (B1 to B88) shown in Table 2. Methine carbon atoms (* CH *) of one fragment (B1 to B88) shown in Table 2 to the acyl carbon atoms (* C *) of one fragment (C1 to C36) shown in Table 3 Selected from compounds formed by binding.

하기 표는 본 발명을 용이하게 수행하기 위한 지침을 제공하려는 것이다. 그러나, 이들이 본 발명의 범주를 제한하지는 않는다. 당업자라면 표 1에 도시된 하나의 단편을 표 2에 도시된 임의의 하나의 단편에 결합시키고, 이후 표 2에 도시된 단편을 도 3에 도시된 임의의 하나의 단편에 결합시킴에 의해 특정 화합물을 선택적으로 제조할 수 있다.The following table is intended to provide guidance to facilitate the invention. However, these do not limit the scope of the present invention. Those skilled in the art will recognize certain compounds by binding one fragment shown in Table 1 to any one fragment shown in Table 2, and then binding the fragment shown in Table 2 to any one fragment shown in FIG. Can be prepared selectively.

표 1Table 1

표 2TABLE 2

표 3TABLE 3

따라서, 예를 들어, 표 4에 A2-B45-C35로서 표시된 화합물은 표 1의 A2기와 표 2의 B45기 및 표 3의 C35기의 조합 생성물로서, 즉 N -[1-(벤조옥사졸-2-일-메타노일)-3-페닐-프로필]- N '-벤질-2-시클로헥실메틸-말론아미드이다:Thus, for example, the compound represented as A2-B45-C35 in Table 4 is a combination product of the A2 group in Table 1 and the B45 group in Table 2 and the C35 group in Table 3, ie N- [1- (benzooxazole- 2-1-meth alkanoyl) -3-phenyl-propyl] - N '- malonamide a-benzyl-2-cyclohexylmethyl-:

추가로 화학식(I)의 바람직한 화합물이 하기로 구성된 군으로부터 선택된다:Further preferred compounds of formula (I) are selected from the group consisting of:

2-부틸- N -시아노메틸- N' -페닐-말론아미드(화합물 1; Al-B88-C1으로서 표시됨); 2-butyl- N -cyanomethyl- N' -phenyl-malonamide (Compound 1; represented as Al-B88-C1);

N -시아노메틸-2-시클로헥실메틸- N' -페닐-말론아미드(화합물 2 ; Al-B45-Cl으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N' -phenyl-malonamide (Compound 2; represented as Al-B45-Cl);

N -시아노메틸-2-시클로헥실메틸- N' -페네틸-말론아미드(화합물 3; A4-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N' -phenethyl-malonamide (Compound 3; represented as A4-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -피리딘-4-일메틸-말론아미드(화합물 4; A24-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N' -pyridin-4-ylmethyl-malonamide (compound 4; represented as A24-B45-C1);

N -[1-(벤조옥사졸-2-카르보닐)-3-페닐-프로필]- N' -벤질-2-시클로헥실메틸-말론아미드(화합물 5; A2-B45-C35로서 표시됨); N - [1- (benzoxazole-2-carbonyl) -3-phenyl-propyl] - N '- malonamide-benzyl-2-cyclohexylmethyl (Compound 5; denoted as A2-B45-C35);

N -시아노메틸- N' -시클로헥실-2-시클로헥실메틸-말론아미드(화합물 6; A7-B45-C1으로서 표시됨); N -cyanomethyl- N' -cyclohexyl-2-cyclohexylmethyl-malonamide (Compound 6; represented as A7-B45-C1);

N -벤질- N' -시아노메틸-2-시클로헥실메틸-말론아미드(화합물 7; A2-B45-C1으로서 표시됨); N -benzyl- N' -cyanomethyl-2-cyclohexylmethyl-malonamide (compound 7; represented as A2-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -(4-페녹시-페닐)-말론아미드(화합물 8; A3-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N ' -(4-phenoxy-phenyl) -malonamide (Compound 8; represented as A3-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -(3-페닐-프로필)-말론아미드(화합물 9; A5-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N ' -(3-phenyl-propyl) -malonamide (Compound 9; represented as A5-B45-C1);

N -시아노메틸-2-시클로헥실메틸-3-모르폴린-4-일-3-옥소-프로피온아미드(화합물 10; A6-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl-3-morpholin-4-yl-3-oxo-propionamide (Compound 10; represented as A6-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -나프탈렌-1-일메틸-말론아미드(화합물 11; A8-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N' -naphthalen-1-ylmethyl-malonamide (Compound 11; represented as A8-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -피리딘-3-일-말론아미드(화합물 12; A9-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N' -pyridin-3-yl-malonamide (compound 12; represented as A9-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N',N' -디이소부틸-말론아미드(화합물 13; A11-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N ', N' -diisobutyl-malonamide (Compound 13; represented as A11-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N',N' -디이소프로필-말론아미드(화합물 14; A36-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N ', N' -diisopropyl-malonamide (Compound 14; represented as A36-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -(6-메톡시-피리딘-3-일)-말론아미드(화합물 15; A10-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N ' -(6-methoxy-pyridin-3-yl) -malonamide (compound 15; represented as A10-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -(2-티오펜-2-일-에틸)-말론아미드(화합물 16; A13-B45-C1으로서 표시됨) ; N -cyanomethyl-2-cyclohexylmethyl- N ' -(2-thiophen-2-yl-ethyl) -malonamide (Compound 16; represented as A13-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -(3-페녹시-페닐)-말론아미드(화합물 17; A14-B45-C1으로서 표시됨) ; N -cyanomethyl-2-cyclohexylmethyl- N ' -(3-phenoxy-phenyl) -malonamide (Compound 17; represented as A14-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -(4-니트로-벤질)-말론아미드(화합물 18; A12-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N ' -(4-nitro-benzyl) -malonamide (Compound 18; represented as A12-B45-C1);

N,N '-비스-시아노메틸-2-시클로헥실메틸-말론아미드(화합물 19; A15-B45-C1으로서 표시됨); N, N' -bis-cyanomethyl-2-cyclohexylmethyl-malonamide (Compound 19; represented as A15-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N '-(5,6,7,8-테트라히드로-나프탈렌-1-일)-말론아미드(화합물 20; A17-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N '-(5,6,7,8-tetrahydro-naphthalen-1-yl) -malonamide (Compound 20; represented as A17-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N '-(2-피리딘-2-일-에틸)-말론아미드(화합물 21; A18-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N '-(2-pyridin-2-yl-ethyl) -malonamide (Compound 21; represented as A18-B45-C1);

N -시아노메틸-2-시클로헥실메틸-3-(2,3-디히드로-인돌-1-일)-3-옥소-프로피온아미드(화합물 22; A19-B45-Cl으로서 표시됨) ; N -cyanomethyl-2-cyclohexylmethyl-3- (2,3-dihydro-indol-1-yl) -3-oxo-propionamide (Compound 22; represented as A19-B45-Cl);

N -시아노메틸-2-시클로헥실메틸-3-(3,4-디히드로-1H-이소퀴놀린-2-일)-3-옥소-프로피온아미드(화합물 23; A20-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl-3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxo-propionamide (Compound 23; represented as A20-B45-C1) ;

N -시아노메틸-2, N '-비스-시클로헥실메틸-말론아미드(화합물 24; A21-B45-C1으로서 표시됨); N -cyanomethyl-2, N' -bis-cyclohexylmethyl-malonamide (compound 24; represented as A21-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -(2-메톡시-벤질)-말론아미드(화합물 25; A22-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N ' -(2-methoxy-benzyl) -malonamide (Compound 25; represented as A22-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -(1-페닐-에틸)-말론아미드(화합물 26; A23-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N ' -(1-phenyl-ethyl) -malonamide (Compound 26; represented as A23-B45-C1);

N -벤질- N' -시아노메틸-2-시클로헥실메틸- N -메틸-말론아미드(화합물 27; A25-B45-C1으로서 표시됨); N -benzyl- N' -cyanomethyl-2-cyclohexylmethyl- N -methyl-malonamide (compound 27; represented as A25-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N '-(3-니트로-벤질)-말론아미드(화합물 28; A26-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N '-(3-nitro-benzyl) -malonamide (Compound 28; represented as A26-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N '-(4-메톡시-벤질)-말론아미드(화합물 29; A27-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N '-(4-methoxy-benzyl) -malonamide (Compound 29; represented as A27-B45-C1);

N -(3-카르바모일-페닐)- N' -시아노메틸-2-시클로헥실메틸-말론아미드(화합물 30; A28-B45-C1으로서 표시됨); N - (3- carbamoyl-phenyl) - N '- cyano-2-cyclohexylmethyl-malonamide (Compound 30; denoted as A28-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -피리딘-3-일메틸-말론아미드(화합물 31 ; A16-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N' -pyridin-3-ylmethyl-malonamide (Compound 31; represented as A16-B45-C1);

N -(4-카르바모일페닐)- N' -시아노메틸-2-시클로헥실메틸말론아미드(화합물 32; A29-B45-C1으로서 표시됨); N - (4- carbamoyl-phenyl) - N '- cyano-2-cyclohexylmethyl-malonamide (Compound 32; denoted as A29-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -테트라히드로푸르-2-일메틸말론아미드(화합물 33; A30-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N' -tetrahydrofur-2-ylmethylmalonamide (Compound 33; represented as A30-B45-C1);

N -시아노메틸-2-시클로헥실메틸-3-(3,4-디히드로-2 H -퀴놀린-1-일)-3-옥소프로피온아미드(화합물 34; A31-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl-3- (3,4-dihydro-2 H -quinolin-1-yl) -3-oxopropionamide (Compound 34; represented as A31-B45-C1);

N - tert -부틸- N' -시아노메틸-2-시클로헥실메틸- N -메틸말론아미드(화합물 35; A35-B45-C1으로서 표시됨); N - tert -butyl- N' -cyanomethyl-2-cyclohexylmethyl- N -methylmalonamide (Compound 35; represented as A35-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N' -메틸- N' -프로필말론아미드(화합물 36; A34-B45-C1으로서 표시됨); N - cyano-2-cyclohexyl-methyl - N '- methyl - N' - propyl malonamide (Compound 36; denoted as A34-B45-C1);

N -부틸- N' -시아노메틸-2-시클로헥실메틸- N -메틸말론아미드(화합물 37; A33-B45-C1으로서 표시됨); N -butyl- N' -cyanomethyl-2-cyclohexylmethyl- N -methylmalonamide (Compound 37; represented as A33-B45-C1);

N -시아노메틸-2-시클로헥실메틸- N',N' -디메틸말론아미드(화합물 38; A32-B45-C1으로서 표시됨); N -cyanomethyl-2-cyclohexylmethyl- N ', N' -dimethylmalonamide (Compound 38; represented as A32-B45-C1);

N -벤질- N' -시아노메틸-2-(2-페닐술파닐에틸)말론아미드(화합물 39 ; A2-B80-C1으로서 표시됨); N -benzyl- N' -cyanomethyl-2- (2-phenylsulfanylethyl) malonamide (Compound 39; represented as A2-B80-C1);

2-(2-페닐술포닐에틸)- N -벤질- N '-시아노메틸말론아미드(화합물 40; A2-B6-C1으로서 표시됨); 2- (2-phenylsulfonylethyl) -N -benzyl- N' -cyanomethylmalonamide (compound 40; represented as A2-B6-C1);

2-(2-벤젠술포닐-에틸)- N -[(S)-1-(1-벤조옥사졸-2-일-메타노일)-펜틸]- N '-벤질-말론아미드(화합물 41 ; A2-B6-C12으로서 표시됨); 2- (2-benzenesulfonyl-ethyl) - N - [(S) -1- (1- 2-yl-methanone alkanoyl) - pentyl] - N '- benzyl-malonamide (Compound 41; Represented as A2-B6-C12);

N,N '-비스-[(S)-1-(1-벤조옥사졸-2-일-메타노일)-프로필]-2-시클로헥실메틸-말론아미드(화합물 42; A37-B45-C13으로서 표시됨); 및 N, N' -bis-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propyl] -2-cyclohexylmethyl-malonamide (Compound 42; as A37-B45-C13 Displayed); And

이의 N-산화물 유도체, 전구약물 유도체, 보호된 유도체, 개개의 입체이성질체 및 이성질체들의 혼합물; 및 이러한 화합물 및 이의 N-산화물 유도체, 전구약물유도체, 보호된 유도체, 개개의 이성질체 및 이성질체들의 혼합물의 약제학적으로 허용되는 염 및 용매화물(예컨대, 수화물).N-oxide derivatives, prodrug derivatives, protected derivatives, individual stereoisomers and mixtures of isomers thereof; And pharmaceutically acceptable salts and solvates (eg hydrates) of such compounds and their N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.

약리학 및 유용성:Pharmacology and usability:

본 발명의 화합물은 카텝신 S의 선택적인 억제제이며, 예컨대 카텝신 S의 활성이 질병의 병리학 및/또는 증상학에 기여하는 질병을 치료하는 데에 유용하다. 예를 들어, 본 발명의 화합물은 유년발병형 당뇨병, 다발성 경화증, 심상성 천포창, 그레이브스병, 중증 근무력증, 전신성 홍반성 루푸스, 류마티스성 관절염, 하시모토 갑상선염을 포함하지만 이들에 제한되지 않는 자가면역 질환, 천식을 포함하지만 이에 제한되지 않는 알레르기성 질환, 및 장기 이식편 또는 조직 이식편 거부반응을 포함하지만 이들에 제한되지 않는 동종이형 면역 반응을 치료하는 데에 또한 유용하다.Compounds of the present invention are selective inhibitors of cathepsin S, for example useful for treating diseases in which the activity of cathepsin S contributes to the pathology and / or symptom of the disease. For example, compounds of the present invention include but are not limited to juvenile diabetes mellitus, multiple sclerosis, vulgaris ulcer, Graves' disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, Hashimoto's thyroiditis, It is also useful for treating allergic diseases, including but not limited to asthma, and allogeneic immune responses including but not limited to organ graft or tissue graft rejection.

카텝신 S는 또한 만성 폐쇄성 폐질환(예컨대, 기종), 세기관지염, 천식 및 기관지염에서 과도한 기도 엘라스틴 분해와 같은 과도한 엘라스틴 분해, 폐렴, 및 플라크 파열 및 죽종과 같은 심혈관 질환을 수반하는 질병과 관련된다. 카텝신 S는 원섬유의 형성과 관련이 있으므로, 카텝신 S 억제제는 전신성 아밀로이드증의 치료에 이용된다.Cathepsin S is also associated with diseases involving excessive elastin degradation, such as excessive airway elastin degradation, pneumonia, and cardiovascular diseases such as plaque rupture and atheromatosis in chronic obstructive pulmonary disease (eg, emphysema), bronchiolitis, asthma and bronchitis. Cathepsin S is involved in the formation of fibrils, so cathepsin S inhibitors are used to treat systemic amyloidosis.

본 발명의 화합물의 시스테인 프로테아제 억제 활성은 당업자에게 공지된 방법에 의해 결정될 수 있다. 프로테아제 활성 및 시험 화합물에 의한 이의 활성의 억제를 측정하기 위한 적합한 시험관내 검정은 공지되어 있다. 전형적으로는, 검정은 펩티드 기초 기질의 프로테아제 유도된 가수분해를 측정한다. 프로테아제 억제 활성을 측정하기 위한 검정의 상세한 내용은 하기 실시예 6 내지 9에 기재되어 있다.Cysteine protease inhibitory activity of the compounds of the present invention can be determined by methods known to those skilled in the art. Suitable in vitro assays for determining protease activity and inhibition of its activity by test compounds are known. Typically, the assay measures protease induced hydrolysis of peptide based substrates. Details of the assays for measuring protease inhibitory activity are described in Examples 6-9 below.

투여 및 약제학적 조성물:Administration and Pharmaceutical Compositions:

일반적으로, 화학식(I)의 화합물은 단독으로 또는 하나 이상의 치료제와 조합된 형태로 당 분야에 공지된 통상적이고 허용되는 방식 중의 어느 하나에 의해 치료적 유효량으로 투여될 것이다. 치료적 유효량은 질병의 중증도, 환자의 연령 및 상대적 건강 정도, 사용되는 화합물의 역가 및 그 밖의 인자에 따라 광범위하게 달라질 수 있다. 예를 들어, 화학식(I)의 화합물의 치료적 유효량은 1일 당 체중 1킬로그램 당 약 1 마이크로그램 (㎍/㎏) 내지 1일 당 체중 1킬로그램 당 약 1 밀리그램 (mg/㎏)일 것이고, 전형적으로는 약 10㎍/㎏/일 내지 약 0.1㎎/㎏/일의 범위일 수 있다. 따라서, 80㎏의 인간 환자에 대한 치료적 유효량은 약 100㎍/일 내지 약 100㎎/일, 전형적으로는 약 1㎍/일 내지 약 10㎎/일의 범위일 수 있다. 일반적으로, 개인적인 지식과 본원의 기재내용에 의존하여 실행하는 당업자는 주어진 질병을 치료하기 위한 화학식(I)의 화합물의 치료적 유효량을 확인할 수 있을 것이다.In general, the compounds of formula (I) will be administered in a therapeutically effective amount, either alone or in combination with one or more therapeutic agents, by any of the usual and acceptable modes known in the art. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the patient, the titer of the compound used and other factors. For example, a therapeutically effective amount of a compound of formula (I) will be about 1 microgram (μg / kg) per kilogram of body weight per day to about 1 milligram (mg / kg) per kilogram of body weight per day, Typically it may range from about 10 μg / kg / day to about 0.1 mg / kg / day. Thus, a therapeutically effective amount for an 80 kg human patient may range from about 100 μg / day to about 100 mg / day, typically from about 1 μg / day to about 10 mg / day. In general, one of ordinary skill in the art, depending on individual knowledge and the teachings herein, will be able to ascertain the therapeutically effective amount of a compound of formula (I) for treating a given disease.

화학식(I)의 화합물은 경구적 경로, 전신적 경로 (예를 들어, 경피적, 비내적 또는 좌약에 의해) 또는 비경구적 경로 (예를 들어, 근내, 정맥내 또는 피하) 중의 하나에 의해 약제학적 조성물로서 투여될 수 있다. 조성물은 정제, 알약, 캡슐, 반고체, 분말, 서방성 제형, 용액, 현탁액, 엘릭시르, 에어로졸 또는 임의의 다른 적합한 조성물의 형태를 취할 수 있고, 일반적으로, 화학식(I)의 화합물과 함께 하나 이상의 약제학적으로 허용되는 부형제로 이루어진다. 허용되는 부형제는 비독성이고, 투여를 보조하지만, 활성 성분의 치료적 이점에 불리한 영향을 미치지 않는다. 이러한 부형제는 임의의 고체, 액체, 반고체이거나, 에어로졸 조성물의 경우, 당업자가 일반적으로 이용할 수 있는 기체상 부형제일 수 있다.Compounds of formula (I) may be used in pharmaceutical compositions by either oral route, systemic route (eg, by transdermal, intranasal or suppository) or parenteral route (eg, intramuscular, intravenous or subcutaneous). It can be administered as. The composition may take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or any other suitable composition, generally in combination with one or more of the compounds of formula (I) Consist of excipients which are academically acceptable. Acceptable excipients are nontoxic and assist with administration but do not adversely affect the therapeutic benefit of the active ingredient. Such excipients may be any solid, liquid, semisolid, or, in the case of aerosol compositions, gaseous excipients generally available to those skilled in the art.

고체 약제학적 부형제로는 전분, 셀룰로스, 탤크, 글루코스, 락토오스, 수크로스, 젤라틴, 맥아, 쌀, 밀가루, 쵸크, 실리카겔, 마그네슘 스테아레이트, 나트륨 스테아레이트, 글리세롤 모노스테아레이트, 염화나트륨, 건조 탈지유 등이 있다. 액체 및 반고체 부형제는 물, 에탄올, 글리세롤, 프로필렌 글리콜, 및 석유, 동물, 식물 또는 합성 기원의 오일을 포함하는 다양한 오일 (예를 들어, 땅콩유, 대두유, 광유, 참기름 등)로부터 선택될 수 있다. 특히 주사 용액을 위한 바람직한 액체 담체로는 물, 식염수, 수성 덱스트로스 및 글리콜이 있다.Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride and dry skim milk. have. Liquid and semisolid excipients can be selected from a variety of oils (eg, peanut oil, soybean oil, mineral oil, sesame oil, etc.) including water, ethanol, glycerol, propylene glycol, and oils of petroleum, animal, vegetable or synthetic origin. . Particularly preferred liquid carriers for injection solutions are water, saline, aqueous dextrose and glycols.

조성물 중의 화학식(I)의 화합물의 양은 제형의 유형, 단위 용량의 크기, 부형제의 종류 및 약제학 분야의 당업자에게 알려진 그 밖의 인자에 따라 광범위하게 달라질 수 있다. 일반적으로, 주어진 질병을 치료하기 위한 화학식(I)의 화합물의 조성물 중 활성 성분은 0.01%w 내지 10%w, 바람직하게는 0.3%w 내지 1%w 이며, 나머지는 부형제 또는 부형제들로 이루어진다. 바람직하게는, 약제학적 조성물은 연속적인 치료를 위해 1회 단위 용량으로 투여되거나, 특히 증상을 완화시킬 필요가 있는 경우 임의로 1회 단위 용량으로 투여된다. 화학식(I)의 화합물을 함유하는 대표적인 약제학적 제형은 실시예 10에 기재되어 있다.The amount of the compound of formula (I) in the composition can vary widely depending on the type of formulation, the size of the unit dose, the type of excipient and other factors known to those skilled in the pharmaceutical art. Generally, the active ingredient in the composition of the compound of formula (I) for the treatment of a given disease is from 0.01% w to 10% w, preferably from 0.3% w to 1% w, with the remainder consisting of excipients or excipients. Preferably, the pharmaceutical composition is administered in a single unit dose for continuous treatment, or optionally in a single unit dose, especially when it is necessary to alleviate the symptoms. Representative pharmaceutical formulations containing a compound of formula (I) are described in Example 10.

화학:chemistry:

화학식(I)의 화합물을 제조하는 방법:Process for preparing compound of formula (I):

본 발명의 화합물은 공지된 방법의 응용 또는 적용에 의해 제조될 수 있고, 공지된 방법이란 앞서 이용된 방법 또는 알.씨.라록(R.C.Larock)에 의해 문헌[Comprehensive Organic Transformations, VCH publishers, 1989]에 기술된 것들과 같이, 문헌에 개시된 방법을 의미한다.The compounds of the present invention can be prepared by the application or application of known methods, and known methods include those used previously or by R. Lac., Comprehensive Organic Transformations, VCH publishers, 1989. As described in the following, it refers to the method disclosed in the literature.

이후 기술하는 반응에서, 최종 생성물에서 요망되는 히드록시, 아미노, 이미노, 티오 또는 카르복시기와 같은 반응성 작용기를 보호하여, 반응에서 이들의 불필요한 침전을 피하는 것이 반드시 필요할 수 있다. 통상의 보호기가 표준의 실시에 따라 이용될 수 있고, 예를 들어, 티.더블유.그린(T.W.Greene) 및 피.지.엠.우츠(P.G.C.Wuts)의 문헌["Protective Groups in Organic Chemistry" John Wiley and Sons, 1991]을 참조한다.In the reactions described below, it may be necessary to protect reactive functional groups such as hydroxy, amino, imino, thio or carboxyl groups desired in the final product, to avoid their unnecessary precipitation in the reaction. Conventional protecting groups can be used in accordance with the practice of the standard and are described, for example, in TWGreene and PGCWuts, "Protective Groups in Organic Chemistry" John. Wiley and Sons, 1991.

X1이 -NHC(R1)(R2)X2인 화학식(I)의 화합물은 하기 반응식 1에서와 같이 수행함으로써 제조될 수 있다:Compounds of formula (I) wherein X 1 is -NHC (R 1 ) (R 2 ) X 2 can be prepared by performing as in Scheme 1 below:

반응식 1Scheme 1

상기 식에서, X2, R1, R2, R3및 R4는 발명의 개요에서 정의된 바와 같다.Wherein X 2 , R 1 , R 2 , R 3 and R 4 are as defined in the Summary of the Invention.

화학식(I)의 화합물은, 화학식 2의 산을 화학식 NH2CR1R2X2의 화합물과 축합시킴에 의해 제조될 수 있다. 축합 반응은 적합한 용매 (N-메틸피롤리디논 등) 중의 적절한 커플링제 (예를 들어, 벤조트리아졸-1-일옥시트리스피롤리디노-포스포늄 헥사플루오로포스페이트 (PyBOP), 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 히드로클로라이드 (EDCI),O-벤조트리아졸-1-일-N,N,N',N'-테트라메틸우로늄 헥사플루오로포스페이트 (HBTU), 1,3-디시클로헥실-카르보디이미드 (DCC) 등) 및 임의의 적절한 촉매 (예를 들어, 1-히드록시벤조트리아졸 (HOBt), 1-히드록시-7-아자벤조트리아졸 (HOAt) 등) 및 비-친핵성 염기 (예를 들어,N-메틸모르폴린, 트리에틸아민 등이나, 이의 임의의 적절합 조합)에 의해 주위 온도에서 수행될 수 있으며, 완료되기까지 3 내지 10시간을 필요로 한다. 반응식 1에 따라 화학식(I)의 화합물을 합성하는 것에 관한 상세한 설명은 하기 실시예에 기재되어 있다.Compounds of formula (I) may be prepared by condensing an acid of formula (2) with a compound of formula NH 2 CR 1 R 2 X 2 . The condensation reaction can be carried out with a suitable coupling agent (eg benzotriazol-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP) in a suitable solvent ( N -methylpyrrolidinone, etc.). ), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), O -benzotriazol-1-yl- N, N, N ', N' -tetramethyluronium hexafluor Lophosphate (HBTU), 1,3-dicyclohexyl-carbodiimide (DCC) and the like and any suitable catalyst (eg, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7- Azabenzotriazole (HOAt, etc.) and non-nucleophilic bases (e.g., N -methylmorpholine, triethylamine, etc., or any suitable combination thereof) and are completed. It takes 3 to 10 hours to complete. Details regarding the synthesis of compounds of formula (I) according to Scheme 1 are set forth in the Examples below.

X1이 -NHX3인 화학식(I)의 화합물은 하기 반응식 2에서와 같이 수행함으로써 제조될 수 있다:Compounds of formula (I) wherein X 1 is -NHX 3 can be prepared by performing as in Scheme 2:

반응식 2Scheme 2

상기 식에서, X3, R3및 R4는 발명의 개요에서 정의된 바와 같다.Wherein X 3 , R 3 and R 4 are as defined in the Summary of the Invention.

화학식(I)의 화합물은, 화학식 2의 산을 화학식 NH2X3의 화합물과 축합시킴에 의해 제조될 수 있다. 축합 반응은 적합한 용매 (N-메틸피롤리디논 등) 중의 적절한 커플링제 (예를 들어, 벤조트리아졸-1-일옥시트리스피롤리디노-포스포늄 헥사플루오로포스페이트 (PyBOP), 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 히드로클로라이드 (EDCI),O-벤조트리아졸-1-일-N,N,N',N'-테트라메틸우로늄 헥사플루오로포스페이트 (HBTU), 1,3-디시클로헥실-카르보디이미드 (DCC) 등) 및 임의의 적절한 촉매 (예를 들어, 1-히드록시벤조트리아졸 (HOBt), 1-히드록시-7-아자벤조트리아졸 (HOAt) 등) 및 비-친핵성 염기 (예를 들어,N-메틸모르폴린, 트리에틸아민 등이나, 이의 임의의 적절합 조합)에 의해 주위 온도에서 수행될 수 있으며, 완료되기까지 3 내지 10시간을 필요로 한다. 반응식 2에 따라 화학식(I)의 화합물을 합성하는 것에 관한 상세한 설명은 하기 실시예에 기재되어 있다.Compounds of formula (I) may be prepared by condensing an acid of formula (2) with a compound of formula NH 2 X 3 . The condensation reaction can be carried out with a suitable coupling agent (eg benzotriazol-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP) in a suitable solvent ( N -methylpyrrolidinone, etc.). ), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), O -benzotriazol-1-yl- N, N, N ', N' -tetramethyluronium hexafluor Lophosphate (HBTU), 1,3-dicyclohexyl-carbodiimide (DCC) and the like and any suitable catalyst (eg, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7- Azabenzotriazole (HOAt, etc.) and non-nucleophilic bases (e.g., N -methylmorpholine, triethylamine, etc., or any suitable combination thereof) and are completed. It takes 3 to 10 hours to complete. Details regarding the synthesis of compounds of formula (I) according to Scheme 2 are set forth in the Examples below.

화학식(I)의 화합물을 제조하기 위한 추가의 방법들:Further methods for preparing compounds of formula (I):

화학식(I)의 화합물은 유리 염기 형태의 화합물을 약제학적으로 허용되는 무기 또는 유기산과 반응시킴으로써 약제학적으로 허용되는 산 부가염으로 제조될 수 있다. 대안적으로, 화학식(I)의 화합물의 약제학적으로 허용되는 염기 부가염은 유리 산 형태의 화합물을 약제학적으로 허용되는 무기 또는 유기 염기와 반응시킴으로써 제조될 수 있다. 화학식(I)의 화합물의 약제학적으로 허용되는 염을 제조하기에 적당한 무기 및 유기 산 및 염기는 본 출원의 정의 부분에 개시되어 있다. 대안적으로, 화학식(I)의 화합물의 염 형태는 출발 물질 또는 중간 물질의 염을 사용하여 제조될 수 있다.Compounds of formula (I) may be prepared as pharmaceutically acceptable acid addition salts by reacting a compound in free base form with a pharmaceutically acceptable inorganic or organic acid. Alternatively, pharmaceutically acceptable base addition salts of compounds of formula (I) may be prepared by reacting a compound in free acid form with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for preparing pharmaceutically acceptable salts of compounds of formula (I) are disclosed in the definition of this application. Alternatively, salt forms of the compounds of formula (I) may be prepared using salts of the starting material or intermediates.

유리 산 또는 유리 염기 형태의 화학식(I)의 화합물은 대응하는 염기 부가염 또는 산 부가염 형태로부터 제조될 수 있다. 예를 들어, 산 부가염 형태의 화학식(I)의 화합물은 적당한 염기(예를 들어, 수산화암모늄 용액, 수산화나트륨 등)로 처리함으로써 대응하는 유리 염기로 전환될 수 있다. 염기 부가염 형태의 화학식(I)의 화합물은 적당한 산(예를 들어, 염산 등)으로 처리함으로써 대응하는 유리 산으로 전환될 수 있다.Compounds of formula (I) in free acid or free base form may be prepared from the corresponding base addition salt or acid addition salt form. For example, the compound of formula (I) in acid addition salt form can be converted to the corresponding free base by treatment with a suitable base (eg, ammonium hydroxide solution, sodium hydroxide, etc.). Compounds of formula (I) in base addition salt form may be converted to the corresponding free acids by treatment with a suitable acid (eg hydrochloric acid, etc.).

화학식(I)의 화합물의N-산화물은 당업자에게 알려진 방법에 의해 제조될 수 있다. 예를 들어,N-산화물은 산화되지 않은 형태의 화학식(I)의 화합물을 적당한불활성 유기 용매(예를 들어, 디클로로메탄과 같은 할로겐화 탄화수소)내에서 산화제(예를 들어, 트리플루오로퍼아세트산, 퍼말레산, 퍼벤조산, 퍼아세트산, 메타-클로로퍼옥시벤조산 등)로 약 0℃에서 처리함으로써 제조될 수 있다. 대안적으로, 화학식(I)의 화합물의N-산화물은 적당한 출발 물질의N-산화물로부터 제조될 수 있다. N -oxides of compounds of formula (I) can be prepared by methods known to those skilled in the art. For example, N -oxides can be used to prepare compounds of formula (I) in their non-oxidized form in an inert organic solvent (e.g., halogenated hydrocarbons such as dichloromethane). Maleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, and the like). Alternatively, N of a compound of formula (I) - N oxide of an appropriate starting material can be prepared from an oxide.

산화되지 않은 형태의 화학식(I)의 화합물은 적당한 불활성 유기 용매(예를 들어, 아세토니트릴, 에탄올, 수성 디옥산 등)내에서 환원제(예를 들어, 황, 이산화황, 트리페닐 포스핀, 리튬 보로히드리드, 나트륨 보로히드리드, 삼염화인, 트리브로마이드 등)로 0 내지 80℃에서 처리함으로써 화학식(I)의 화합물의N-산화물로부터 제조될 수 있다.Compounds of formula (I) in their unoxidized form may be used as reducing agents (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium boro) in suitable inert organic solvents (e.g. Hydride, sodium borohydride, phosphorus trichloride, tribromide, and the like), can be prepared from the N -oxides of compounds of formula (I).

화학식(I)의 화합물의 전구약물 유도체는 당업자에게 공지된 방법[참고: 예를 들어, 보다 상세하게는 Saulnier et al. (1994),Bioorganic and Medicinal Chemistry Letters. Vol.4, p.1985]에 의해 제조될 수 있다. 예를 들어, 적당한 전구약물은 화학식(I)의 유도체화되지 않은 화합물을 적당한 카르바밀화제(예를 들어, 1,1-아실옥시알킬카르보노클로리데이트, 파라-니트로페닐 카르보네이트 등)와 반응시킴으로써 제조될 수 있다.Prodrug derivatives of the compounds of formula (I) may be prepared by methods known to those skilled in the art [see, for example, Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters . Vol. 4, p. 1985]. For example, suitable prodrugs may be selected from non-derivatized compounds of formula (I) with suitable carbamylating agents (eg, 1,1-acyloxyalkylcarbonochlorates, para-nitrophenyl carbonate, etc.). It can be prepared by reacting with.

화학식(I)의 화합물의 보호된 유도체는 당업자에게 공지된 수단으로 제조될 수 있다. 보호기의 생성 및 그 제거에 응용가능한 기술에 대한 보다 상세한 설명은 참고문헌[T.W. Greene,Protecting Group in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999]에서 찾을 수 있다. 본 발명의 화합물은 본 발명의공정 동안 용매화물(예컨대, 수화물)로서 편리하게 제조되거나 형성될 수 있다. 본 발명의 화합물의 수화물은 디옥신, 테트라히드로푸란 또는 메탄올과 같은 유기 용매를 이용하여, 수성/유기 용매 혼합물로부터의 재결정화에 의해 편리하게 제조될 수 있다. 화학식(I)의 화합물은 화합물의 라세미 혼합물을 광학적으로 활성인 분리제와 반응시킴으로써 한 쌍의 부분입체 이성질체 화합물을 형성하고, 부분입체 이성질체를 분리하고, 광학적으로 순수한 거울상 이성질체를 회수하여 개별적 입체 이성질체로 제조될 수 있다. 거울상 이성질체의 분리가 화학식(I)의 화합물의 공유결합 부분입체 이성질체 유도체를 사용하여 수행될 수 있는 경우에, 분리가능한 착물이 바람직하다(예를 들어, 결정성 부분입체 이성질체 염). 부분입체 이성질체는 독특한 물리적 성질(예를 들어, 녹는점, 끓는점, 용해도, 반응성 등)을 갖고, 이러한 차이점을 이용하여 즉시 분리될 수 있다. 부분입체 이성질체는 크로마토그래피 또는 바람직하게는 용해도 차이에 기초한 분별/분리 기술에 의해 분리될 수 있다. 그 후, 광학적으로 순수한 거울상 이성질체는 분리제와 함께 라세미화에 이르지 않는 실제적 수단으로 회수된다. 라세미 혼합물로부터 화합물의 입체 이성질체를 분리하는 데 응용가능한 기술에 대한 보다 상세한 설명은 참고문헌[Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolution, Honh Wiley & Sons, Inc. (1981)]에서 찾을 수 있다.Protected derivatives of compounds of formula (I) may be prepared by means known to those skilled in the art. For a more detailed description of techniques applicable to the creation and removal of protecting groups, see TW Greene, Protecting Group in Organic Synthesis , 3rd edition, John Wiley & Sons, Inc. 1999]. The compounds of the present invention may be conveniently prepared or formed as solvates (eg hydrates) during the process of the present invention. Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol. Compounds of formula (I) react with racemic mixtures of compounds with an optically active separation agent to form a pair of diastereomeric compounds, separate diastereomers, and recover optically pure enantiomers to separate stereo It can be prepared as isomers. If the separation of the enantiomers can be carried out using covalent diastereomeric derivatives of the compound of formula (I), separable complexes are preferred (eg crystalline diastereomeric salts). Diastereomers have unique physical properties (eg, melting point, boiling point, solubility, reactivity, etc.) and can be readily separated using these differences. Diastereomers can be separated by chromatography or preferably by fractionation / separation techniques based on solubility differences. The optically pure enantiomers are then recovered with the separating agent by practical means that do not lead to racemization. For a more detailed description of the techniques applicable to the separation of stereoisomers of compounds from racemic mixtures, see Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolution, Honh Wiley & Sons, Inc. (1981).

요약하면, 하기 단계를 포함하는 공정에 의해 화학식(I)의 화합물을 제조한다:In summary, compounds of formula (I) are prepared by processes comprising the following steps:

(A) 화학식 2의 화합물을 화학식 NH2CR1R2X2의 화합물과 반응시키는 단계 (여기에서, R1, R2, R3, R4및 X2은 발명의 개요에서 화학식(I)에 대하여 정의된 바와 같다):(A) reacting a compound of Formula 2 with a compound of Formula NH 2 CR 1 R 2 X 2 , wherein R 1 , R 2 , R 3 , R 4 and X 2 are represented by Formula (I) As defined for):

; 또는 ; or

(B) 화학식 2의 화합물을 화학식 NH2X3의 화합물과 반응시키는 단계 (여기에서, R3, R4및 X3은 발명의 개요에서 화학식(I)에 대하여 정의된 바와 같다);(B) reacting a compound of Formula 2 with a compound of Formula NH 2 X 3 , wherein R 3 , R 4 and X 3 are as defined for Formula (I) in the Summary of the Invention;

(C) 화학식(I)의 화합물을 약제학적으로 허용되는 염으로 선택적으로 전환시키는 단계;(C) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt;

(D) 염 형태의 화학식(I)의 화합물을 염 이외의 형태로 선택적으로 전환시키는 단계;(D) optionally converting the compound of formula (I) in salt form to a form other than salt;

(E) 산화되지 않은 형태의 화학식(I)의 화합물을 약제학적으로 허용되는N-산화물로 선택적으로 전환시키는 단계;(E) selectively converting a compound of formula (I) in unoxidized form into a pharmaceutically acceptable N -oxide;

(F)N-산화물 형태의 화학식(I)의 화합물을 이의 산화되지 않은 형태로 선택적으로 전환시키는 단계;(F) selectively converting the compound of formula (I) in N -oxide form into its non-oxidized form;

(G) 화학식(I)의 화합물의 개개의 이성질체를 이성질체들의 혼합물로부터 선택적으로 분리시키는 단계;(G) selectively separating the individual isomers of the compound of formula (I) from the mixture of isomers;

(H) 유도체화되지 않은 화학식(I)의 화합물을 약제학적으로 허용되는 전구약물 유도체로 선택적으로 전환시키는 단계; 및(H) optionally converting a non-derivatized compound of formula (I) into a pharmaceutically acceptable prodrug derivative; And

(I) 화학식(I)의 화합물의 전구약물 유도체를 이의 유도체화되지 않은 형태로 선택적으로 전환시키는 단계.(I) optionally converting a prodrug derivative of the compound of formula (I) to its underivatized form.

화학식(I)의 화합물(실시예) 및 본 발명에 따른 중간 물질(참조)의 제조를 예시하는 하기 실시예에 의해 본 발명을 추가로 구체화하나, 이로 제한하는 것은 아니다.The invention is further illustrated by, but not limited to, the following examples illustrating the preparation of compounds of formula (I) (examples) and intermediates according to the invention (reference).

참조 1Reference 1

2-페닐카르바모일-헥산산2-phenylcarbamoyl-hexanoic acid

염화메틸렌(150ml) 중의 아닐린(5.47ml, 60mmol)과 트리에틸아민(8.36ml, 60mmol)의 용액을 -20℃까지 냉각하고, 염화메틸렌(20ml) 중의 메틸말로닐클로라이드(8.36ml, 60mmol)로 처리하였다. 반응 혼합물을 3시간 동안 주위 온도까지 가온하고, 차가운 1N의 HCl에 부었다. 유기층을 분리하고, 수성 나트륨 비카르보네이트에 이어 염수로 세척하고, 마그네슘 술페이트하에 건조시키고, 증발시켜, 메틸 2-페닐카르바모일아세테이트를 수득하였다.A solution of aniline (5.47 ml, 60 mmol) and triethylamine (8.36 ml, 60 mmol) in methylene chloride (150 ml) was cooled to −20 ° C., and methylmalonyl chloride (8.36 ml, 60 mmol) in methylene chloride (20 ml) Treated. The reaction mixture was warmed to ambient temperature for 3 hours and poured into cold 1N HCl. The organic layer was separated, washed with aqueous sodium bicarbonate followed by brine, dried under magnesium sulphate and evaporated to afford methyl 2-phenylcarbamoylacetate.

N-메틸피롤리디논(10ml) 중의 메틸 2-페닐카르바모일아세테이트(1.159g, 6mmol), 수산화 리튬(0.43g, 18mmol) 및 1-요오드부탄(0.91ml, 8mmol)의 혼합물을 주위 온도에서 1.5시간 동안 교반하였다. 반응 혼합물을 얼음물에 붓고, 에틸아세테이트(2회, 각 50ml)로 추출하였다. 합친 추출물을 염수로 세척하고, 마그네슘술페이트하에 건조시키고, 증발시켰다. 20%의 에틸아세테이트/헥산으로 용리시키며 실리카겔상의 플래시 크로마토그래피에 의해 잔사를 정제시켜 메틸 2-페닐카르바모일헥사노에이트(0.715g, 48% 수율)를 수득하였다. A mixture of methyl 2-phenylcarbamoyl acetate (1.159 g, 6 mmol), lithium hydroxide (0.43 g, 18 mmol) and 1-iodine butane (0.91 ml, 8 mmol) in N -methylpyrrolidinone (10 ml) at ambient temperature Stir for 1.5 hours. The reaction mixture was poured into iced water and extracted with ethyl acetate (twice, 50 ml each). The combined extracts were washed with brine, dried under magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate / hexanes to afford methyl 2-phenylcarbamoylhexanoate (0.715 g, 48% yield).

메탄올(10ml) 중의 메틸 2-페닐카르바모일헥사노에이트(0.98g, 3.9mmol)의 용액을 주위 온도에서 17시간 동안 수산화 나트륨(4ml, 4mmol)으로 처리하였다. 감압하에 메탄올을 제거하고, 잔사를 1N의 HCl로 처리하고, 에틸아세테이트(2회, 각 50ml)로 추출하였다. 유기층을 염수로 세척하고, 마그네슘 술페이트하에 건조시키고, 증발시켜2-페닐카르바모일헥산산(0.68g, 2.9mmol, 74% 수율)을 수득하였다.A solution of methyl 2-phenylcarbamoylhexanoate (0.98 g, 3.9 mmol) in methanol (10 ml) was treated with sodium hydroxide (4 ml, 4 mmol) at ambient temperature for 17 hours. Methanol was removed under reduced pressure, and the residue was treated with 1N HCl, and extracted with ethyl acetate (2 times, 50 ml each). The organic layer was washed with brine, dried over magnesium sulfate and evaporated to afford 2-phenylcarbamoylhexanoic acid (0.68 g, 2.9 mmol, 74% yield).

참조 2Reference 2

2-시클로헥실메틸-2-cyclohexylmethyl- NN -페닐-말로나민산-Phenyl-malonamic acid

N-메틸피롤리디논(25ml) 중의 메틸 2-페닐카르바모일아세테이트(참조 실시예 1에서 제조됨)(4.39g, 22.7mmol), 수산화 리튬(1.08g, 45mmol) 및 브로모메틸시클로헥산(3.76ml, 27mmol)의 혼합물을 주위 온도에서 17시간 동안 교반하였다. 반응 혼합물을 얼음물에 붓고, 에테르(3회, 각 100ml)로 추출하였다. 추출물을 물과 염수로 세척하고, 마그네슘 술페이트하에 건조시키고, 증발시켰다. 10%의 에틸아세테이트(헥산)로 용리시키며 실리카겔 상에서 플래시 크로마토그래피에 의해 잔사를 정제시켜 메틸 2-시클로헥실메틸-N-페닐 말로나메이트(1.89g, 6.5mmol, 29% 수율)를 수득하였다. 상기 수성층을 얼음상에서 냉각하고, 1N의 HCl을 이용하여 pH 2까지 산화시켰다. 수성층을 에테르(3회, 각 100ml)로 추출하고, 추출물을 물과 염수로 세척하고, 마그네슘 술페이트하에 건조시키고, 증발시켜2-시클로헥실메틸-N-페닐 말로나민산(1.12g, 18% 수율)을 수득하였다.Methyl 2-phenylcarbamoyl acetate (prepared in Reference Example 1) (4.39 g, 22.7 mmol), lithium hydroxide (1.08 g, 45 mmol) and bromomethylcyclohexane in N -methylpyrrolidinone (25 ml) 3.76 ml, 27 mmol) was stirred at ambient temperature for 17 hours. The reaction mixture was poured into iced water and extracted with ether (3 times, 100 ml each). The extract was washed with water and brine, dried under magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate (hexane) to afford methyl 2-cyclohexylmethyl- N -phenyl malonamate (1.89 g, 6.5 mmol, 29% yield). The aqueous layer was cooled on ice and oxidized to pH 2 with 1N HCl. The aqueous layer is extracted with ether (3 times, 100 ml each), the extract is washed with water and brine, dried under magnesium sulfate and evaporated to 2-cyclohexylmethyl-N-phenyl malonamic acid (1.12 g , 18% Yield).

참조 3Reference 3

2-시클로헥실메틸-N-페네틸-말로나민산2-cyclohexylmethyl-N-phenethyl-malonamic acid

나트륨(6.9g, 0.3mol)을 에탄올(300ml)에 용해한 다음, 디에틸말로네이트(50.3ml, 0.3mol)를 첨가하였다. 브로모메틸시클로헥산(46ml, 0.33mol)을 첨가하고, 반응 혼합물을 70℃에서 14시간 동안 가열하였다. 반응 혼합물을 냉각하고, 증발에 의해 에탄올을 제거하였다. 생성된 매스를 얼음물에 용해하고, 에틸아세테이트로 추출하였다. 유기층을 물과 염수로 세척하고, 마그네슘 술페이트하에 건조시켰다. 감압하에 용매를 제거하여 디에틸시클로헥실 말로네이트를 수득하였다.Sodium (6.9 g, 0.3 mol) was dissolved in ethanol (300 ml) and then diethylmalonate (50.3 ml, 0.3 mol) was added. Bromomethylcyclohexane (46 ml, 0.33 mol) was added and the reaction mixture was heated at 70 ° C. for 14 hours. The reaction mixture was cooled down and the ethanol was removed by evaporation. The resulting mass was dissolved in ice water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried under magnesium sulfate. The solvent was removed under reduced pressure to give diethylcyclohexyl malonate.

에탄올(100ml) 중의 디에틸시클로헥실말로네이트(12.8g, 0.05mol)의 용액을 물(50ml) 중의 수산화 리튬(1.2g, 0.05mol)의 용액으로 처리하고, 주위 온도에서 15시간 동안 교반하였다. 감압하에 에탄올을 제거하고, 잔사에 물(50ml)을 첨가하였다. 반응 혼합물을 에테르로 추출하고, 얼음상에서 냉각하고, HCl을 이용하여 pH 1.5까지 산화시켰다. 수성상을 NaCl로 포화시키고, 에틸아세테이트(2회, 각 150ml)로 추출하였다. 마그네슘 술페이트하에 건조시키고, 용매를 증발시켜 에틸 2-시클로헥실말로네이트(8.52g, 37mmol, 74% 수율)를 수득하였다.A solution of diethylcyclohexylmalonate (12.8 g, 0.05 mol) in ethanol (100 ml) was treated with a solution of lithium hydroxide (1.2 g, 0.05 mol) in water (50 ml) and stirred at ambient temperature for 15 hours. Ethanol was removed under reduced pressure and water (50 ml) was added to the residue. The reaction mixture was extracted with ether, cooled on ice and oxidized to pH 1.5 with HCl. The aqueous phase was saturated with NaCl and extracted with ethyl acetate (twice, 150 ml each). Dry under magnesium sulfate and evaporate the solvent to afford ethyl 2-cyclohexylmalonate (8.52 g, 37 mmol, 74% yield).

에틸아세테이트(80ml) 중의 에틸 2-시클로헥실말로네이트(8.52g, 37mmol)를 0℃까지 냉각하고, 디메틸포르메이드(50㎕)에 이어 옥살릴클로라이드(3.93ml,45mmol)로 처리하였다. 반응 혼합물을 실온까지 상승시키고, 2시간 후 감압하에 용매를 제거하여, 에틸 2-시클로헥실말로닐 클로라이드를 수득하였다.Ethyl 2-cyclohexylmalonate (8.52 g, 37 mmol) in ethyl acetate (80 ml) was cooled to 0 ° C. and treated with dimethyl formade (50 μl) followed by oxalyl chloride (3.93 ml, 45 mmol). The reaction mixture was raised to room temperature and after 2 hours the solvent was removed under reduced pressure to afford ethyl 2-cyclohexylmalonyl chloride.

상기 말로닐클로라이드를 28ml 부피의 에틸아세테이트로 희석하고, 2ml의 이 용액을 에틸아세테이트(4ml) 중의 페네틸아민(0.376ml, 3mmol) 및N-메틸모르폴린(0.40g, 4mmol)의 용액으로 -20℃에서 첨가하였다. 15분 후, 반응 혼합물을 하룻밤동안 주위 온도까지 가온시켰다. 반응 혼합물을 에틸아세테이트(5ml) 및 얼음물(5ml)로 희석하였다. 유기층을 분리하고, 차가운 0.05N의 HCl에 이어 수성 NaHCO3에 이어 염수로 세척하고, 마그네슘 술페이트하에 건조시키고, 감압하에 증발시켰다. 잔사를 라디칼 크로마토그래피에 의해 정제시켜 에틸 2-시클로헥실메틸-N-페네틸 말로나메이트(0.366g, 1.10mmol, 42% 수율)를 수득하였다.The malonylchloride was diluted with 28 ml volume of ethyl acetate and 2 ml of this solution was diluted with a solution of phenethylamine (0.376 ml, 3 mmol) and N -methylmorpholine (0.40 g, 4 mmol) in ethyl acetate (4 ml). Add at 20 ° C. After 15 minutes, the reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (5 ml) and ice water (5 ml). The organic layer was separated and washed with cold 0.05N HCl followed by aqueous NaHCO 3 followed by brine, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by radical chromatography to give ethyl 2-cyclohexylmethyl-N-phenethyl malonamate (0.366 g, 1.10 mmol, 42% yield).

에탄올(10ml) 중의 상기 에스테르(0.366g, 1.10mmol)를 주위 온도에서 수성 수산화 나트륨(1N의 1.3ml)으로 2.5시간 동안 처리하였다. 반응 혼합물을 물(30ml)로 희석하고, 에테르(3회, 각 30ml)로 세척하였다. 수성층을 냉각하고, 1N의 HCl(2ml)로 산화시키고, 에틸아세테이트(3회, 각 30ml)로 추출하였다. 에틸아세테이트 추출물을 염수로 세척하고, 마그네슘 술페이트하에 건조시키고, 증발시켜2-시클로헥실메틸-N-페네틸 말로나민산(0.138g, 0.46mmol, 42% 수율)을 수득하였다.The ester (0.366 g, 1.10 mmol) in ethanol (10 ml) was treated with aqueous sodium hydroxide (1.3 ml of 1 N) for 2.5 h at ambient temperature. The reaction mixture was diluted with water (30 ml) and washed with ether (3 times, 30 ml each). The aqueous layer was cooled, oxidized with 1N HCl (2 ml) and extracted with ethyl acetate (3 times, 30 ml each). The ethyl acetate extract was washed with brine, dried under magnesium sulfate and evaporated to afford 2-cyclohexylmethyl-N-phenethyl malonamic acid (0.138 g, 0.46 mmol, 42% yield).

참조 4Reference 4

2-시클로헥실메틸-2-cyclohexylmethyl- NN -피리딘-4-일메틸-말로나민산-Pyridin-4-ylmethyl-malonamic acid

참조 3에서 제조된 에틸 2-시클로헥실메틸말로닐 클로라이드(0.307g, 1.25mmol)를 참조 3의 방법을 이용하여 4-아미노메틸 피리딘과 축합시켜 에틸 2-시클로헥실메틸-4-피린-4-일메틸말로나메이트(0.237g, 0.74mmol, 58% 수율)를 수득하였다.Ethyl 2-cyclohexylmethylmalonyl chloride (0.307 g, 1.25 mmol) prepared in Reference 3 was condensed with 4-aminomethyl pyridine using the method of Reference 3 to yield ethyl 2-cyclohexylmethyl-4-pyriline-4-. Ilmethylmalonamate (0.237 g, 0.74 mmol, 58% yield) was obtained.

이 에스테르를 참조 3의 방법을 이용하여 수산화 나트륨으로 가수분해하여2-시클로헥실메틸- N -피리딘-4-일메틸말로나민산(0.041g, 0.14mmol, 19% 수율)을 수득하였다.This ester was hydrolyzed with sodium hydroxide using the method of reference 3 to yield 2-cyclohexylmethyl- N -pyridin-4-ylmethylmalonamic acid (0.041 g, 0.14 mmol, 19% yield).

하기 화합물에 대하여 상기 참조 실시예와 같이 수행하였다:The following compounds were carried out as above Reference Examples:

N-벤질-2-시클로헥실메틸-말로나민산; N -benzyl-2-cyclohexylmethyl-malonamic acid;

2-시클로헥실메틸-N-(4-페녹시-페닐)-말로나민산;2-cyclohexylmethyl- N- (4-phenoxy-phenyl) -malonamic acid;

2-시클로헥실메틸-N-(3-페닐-프로필)-말로나민산;2-cyclohexylmethyl- N- (3-phenyl-propyl) -malonamic acid;

2-시클로헥실메틸-3-모르폴린-4-일-3-옥소-프로피온산;2-cyclohexylmethyl-3-morpholin-4-yl-3-oxo-propionic acid;

N-시클로헥실-2-시클로헥실메틸-말로나민산; N -cyclohexyl-2-cyclohexylmethyl-malonamic acid;

2-시클로헥실메틸-N-나프탈렌-1-일메틸-말로나민산;2-cyclohexylmethyl- N -naphthalen-1-ylmethyl-malonamic acid;

2-시클로헥실메틸-N-피리딘-3-일-말로나민산;2-cyclohexylmethyl- N -pyridin-3-yl-malonamic acid;

2-시클로헥실메틸-N,N-디이소부틸-말로나민산;2-cyclohexylmethyl- N, N -diisobutyl-malonamic acid;

2-시클로헥실메틸-N-(6-메톡시-피리딘-3-일)-말로나민산;2-cyclohexylmethyl- N- (6-methoxy-pyridin-3-yl) -malonamic acid;

2-시클로헥실메틸-N-(2-티오펜-2-일-에틸)-말로나민산;2-cyclohexylmethyl- N- (2-thiophen-2-yl-ethyl) -malonamic acid;

2-시클로헥실메틸-N-(3-페녹시-페닐)-말로나민산;2-cyclohexylmethyl- N- (3-phenoxy-phenyl) -malonamic acid;

2-시클로헥실메틸-N-(4-니트로-벤질)-말로나민산;2-cyclohexylmethyl- N- (4-nitro-benzyl) -malonamic acid;

N-시아노메틸-2-시클로헥실메틸-말로나민산; N -cyanomethyl-2-cyclohexylmethyl-malonamic acid;

2-시클로헥실메틸-N-(5,6,7,8-테트라히드로-나프탈렌-1-일)-말로나민산;2-cyclohexylmethyl- N- (5,6,7,8-tetrahydro-naphthalen-1-yl) -malonamic acid;

2-시클로헥실메틸-N-(2-피리딘-2-일-에틸)-말로나민산;2-cyclohexylmethyl- N- (2-pyridin-2-yl-ethyl) -malonamic acid;

2-시클로헥실메틸-3-(2,3-디히드로-인돌-1-일)-3-옥소-프로피온산;2-cyclohexylmethyl-3- (2,3-dihydro-indol-1-yl) -3-oxo-propionic acid;

2-시클로헥실메틸-3-(3,4-디히드로-lH-이소퀴놀린-2-일)-3-옥소-프로피온산;2-cyclohexylmethyl-3- (3,4-dihydro-1 H -isoquinolin-2-yl) -3-oxo-propionic acid;

2,N-비스-시클로헥실메틸-3-옥소-부티르아미드;2, N -bis-cyclohexylmethyl-3-oxo-butyrylamide;

2-시클로헥실메틸-N-(2-메톡시-벤질)-3-옥소-부티르아미드;2-cyclohexylmethyl- N- (2-methoxy-benzyl) -3-oxo-butyramide;

2-시클로헥실메틸-N-(l-페닐-에틸)-말로나민산;2-cyclohexylmethyl- N- (l-phenyl-ethyl) -malonamic acid;

N-벤질-2-시클로헥실메틸-N-메틸-말로나민산; N -benzyl-2-cyclohexylmethyl- N -methyl-malonamic acid;

2-시클로헥실메틸-N-(3-니트로-벤질)-3-옥소-부티르아미드;2-cyclohexylmethyl- N- (3-nitro-benzyl) -3-oxo-butyramide;

2-시클로헥실메틸-N-(4-메톡시-벤질)-말로나민산;2-cyclohexylmethyl- N- (4-methoxy-benzyl) -malonamic acid;

N-(3-카르바모일-페닐)-2-시클로헥실메틸-말로나민산; N- (3-carbamoyl-phenyl) -2-cyclohexylmethyl-malonamic acid;

2-시클로헥실메틸-N-피리딘-3-일메틸-말로나민산;2-cyclohexylmethyl- N -pyridin-3-ylmethyl-malonamic acid;

N-(4-카르바모일-페닐)-2-시클로헥실메틸-말로나민산; N- (4-carbamoyl-phenyl) -2-cyclohexylmethyl-malonamic acid;

2-시클로헥실메틸-N-(테트라히드로-푸란-2-일메틸)-말로나민산;2-cyclohexylmethyl- N- (tetrahydro-furan-2-ylmethyl) -malonamic acid;

2-시클로헥실메틸-3-(3,4-디히드로-2H-퀴놀린-1-일)-3-옥소-프로피온산;2-cyclohexylmethyl-3- (3,4-dihydro-2 H -quinolin-1-yl) -3-oxo-propionic acid;

N-tert-부틸-2-시클로헥실메틸-N-메틸-말로나민산; N - tert -butyl-2-cyclohexylmethyl- N -methyl-malonamic acid;

2-시클로헥실메틸-N-메틸-N-프로필-말로나민산;2-cyclohexylmethyl- N -methyl- N -propyl-malonamic acid;

N-부틸-2-시클로헥실메틸-N-메틸-말로나민산; N -butyl-2-cyclohexylmethyl- N -methyl-malonamic acid;

2-시클로헥실메틸-N,N-디메틸-말로나민산;2-cyclohexylmethyl- N, N -dimethyl-malonamic acid;

(R)-2-벤질카르바모일-4-페닐술파닐-부티르산; 및(R) -2-benzylcarbamoyl-4-phenylsulfanyl-butyric acid; And

4-벤젠술포닐-2-벤질카르바모일-부티르산.4-benzenesulfonyl-2-benzylcarbamoyl-butyric acid.

실시예 1Example 1

2-부틸-2-butyl- NN -시아노메틸--Cyanomethyl- N'N ' -페닐말론아미드-Phenylmalonamide

(화합물 1)(Compound 1)

DMF(5.0ml) 중의, 참조 1에서 제조된 2-페닐카르바모일-헥산산(188g, 0.8mmol)으로 구성된 용액을 PyBOP(425 0.8mmol), 아미노아세토니트릴 비술페이트(140mg, 0.9mmol) 및 트리에틸아민(600㎕, 4.3mmol)으로 처리하였다. 이 혼합물을 3시간 동안 교반하고, 물(20ml)과 에틸 아세테이트(50ml) 사이에서 분배시켰다. 유기층을 분리하고, 1M의 나트륨 비카르보네이트 포화 용액, 1M의 염산 용액 및 물로 세척하고, 건조(MgSO4)시키고, 농축시켰다. 잔사로부터, 헥산 중의 50%의 에틸 아세테이트를 이용하여 실리카겔(60°A)상에서 플래시 칼럼에 의해 생성물을 정제시켜2-부틸-N-시아노메틸-N'-페닐말론아미드(125mg, 57% 수율)를 수득하였다.1H NMR : (DMSO) 10.01 (s, 1H), 7.59 (d, J=8Hz, 2H), 7.31 (t, J=7Hz, 2H), 7.06 (t, J=7Hz, 1H), 4.13 (d, J=6Hz, 2H), 3.32 (t, J=8Hz, 1H), 1.80 (m, 2H), 1.25(m, 4H), 0.86 (t, J=7Hz, 3H). MS: m/e 273.9.PyBOP in DMF (5.0 ml) consisting of 2-phenylcarbamoyl-hexanoic acid (188 g, 0.8 mmol) prepared in Reference 1 (425 0.8 mmol), aminoacetonitrile bisulfate (140 mg, 0.9 mmol) and triethylamine (600 μL, 4.3 mmol). The mixture was stirred for 3 hours and partitioned between water (20 ml) and ethyl acetate (50 ml). The organic layer was separated and washed with 1M saturated sodium bicarbonate solution, 1M hydrochloric acid solution and water, dried (MgSO 4 ) and concentrated. From the residue, the product was purified by flash column on silica gel (60 ° A) using 50% ethyl acetate in hexane to give 2-butyl-N-cyanomethyl-N'-phenylmalonamide (125 mg, 57% yield). ) Was obtained. 1 H NMR: (DMSO) 10.01 (s, 1H), 7.59 (d, J = 8 Hz, 2H), 7.31 (t, J = 7 Hz, 2H), 7.06 (t, J = 7 Hz, 1H), 4.13 (d , J = 6 Hz, 2H), 3.32 (t, J = 8 Hz, 1H), 1.80 (m, 2H), 1.25 (m, 4H), 0.86 (t, J = 7 Hz, 3H). MS: m / e 273.9.

실시예 2Example 2

NN -시아노메틸-2-시클로헥실메틸--Cyanomethyl-2-cyclohexylmethyl- NN '-페닐-말론아미드'-Phenyl-malonamide

(화합물 2)(Compound 2)

N.N-디메틸피롤리디논(5ml) 중의, 참조 2에서 제조된 2-시클로헥실메틸-N-페닐-말로나민산(350mg, 1.2mmol), EDCI(250mg, 1.3mmol), HOBt 수화물(199mg, 1.3mmol), 아미노 아세토니트릴 비술페이트(200mg, 1.3mmol) 및 N-메틸모르폴린(0.30ml, 2.7mmol)으로 구성된 용액을 주위 온도에서 15시간 동안 교반하였다. 반응 혼합물을 차가운 1N의 HCl에 붓고, 에틸아세테이트로 추출하였다. 유기상을 수성의 포화된 나트륨 비카르보네이트에 이어 염수(각 50ml)로 세척하고, 마그네슘 술페이트하에 건조시키고, 증발시켰다. 50%의 에틸아세테이트/헥산을 용리액으로서 이용하여 라디칼 크로마토그래피에 의해 잔사를 정제시켜 N -시아노메틸-2-시클로헥실메틸- N '-페닐-말론아미드(179mg, 48% 수율)를 수득하였다.1H NMR: (DMSO) 10.01 (s, 1H), 8.47 (t, J=5Hz, 1H), 7.59 (d, J=7Hz, 2H), 7.31 (t, J=8Hz, 2H), 7.07 (t, J=7Hz, 1H), 4.13 (d, J=5Hz, 2H), 3.47 (t, J=7Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H). MS: m/e 313.2.2-cyclohexylmethyl- N -phenyl-malonamic acid (350 mg, 1.2 mmol), EDCI (250 mg, 1.3 mmol), HOBt hydrate (199 mg, 1.3) prepared in Reference 2 in NN -dimethylpyrrolidinone (5 ml). mmol), amino acetonitrile bisulfate (200 mg, 1.3 mmol) and N-methylmorpholine (0.30 ml, 2.7 mmol) were stirred at ambient temperature for 15 hours. The reaction mixture was poured into cold 1N HCl and extracted with ethyl acetate. The organic phase was washed with aqueous saturated sodium bicarbonate followed by brine (50 ml each), dried under magnesium sulphate and evaporated. Purify the residue by radical chromatography using 50% ethylacetate / hexane as eluent to afford N -cyanomethyl-2-cyclohexylmethyl- N' -phenyl-malonamide (179 mg, 48% yield). . 1 H NMR: (DMSO) 10.01 (s, 1H), 8.47 (t, J = 5 Hz, 1H), 7.59 (d, J = 7 Hz, 2H), 7.31 (t, J = 8 Hz, 2H), 7.07 (t , J = 7Hz, 1H), 4.13 (d, J = 5Hz, 2H), 3.47 (t, J = 7Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H) . MS: m / e 313.2.

실시예 3Example 3

NN -시아노메틸-2-시클로헥실메틸--Cyanomethyl-2-cyclohexylmethyl- NN '-페네틸말론아미드'-Phenethylmalonamide

(화합물 3)(Compound 3)

N.N-디메틸피롤리디논(4ml) 중의, 참조 3에서 제조된 2-시클로헥실메틸-N-페네틸-말론산(138mg, 0.46mmol), EDCI(115mg, 0.60mmol), HOBt 수화물(92mg, 0.60mmol) 및N-메틸모르폴린(0115ml, 1.38mmol)으로 구성된 용액을 주위 온도에서 10분간 교반하였다. 아미노아세토니트릴 비술페이트(106mg, 0.69mmol)를 첨가하였다. 반응 혼합물을 주위 온도에서 2시간 동안 교반하고, 차가운 1N의 HCl에 붓고, 에틸아세테이트로 2회 추출(각 50ml)하였다. 유기상을 수성의 나트륨 비카르보네이트에 이어 염수(각 50ml)로 세척하고, 마그네슘 술페이트하에 건조시키고, 증발시켰다. 50%의 에틸아세테이트/헥산을 용리액으로서 이용하여 라디칼 크로마토그래피에 의해 잔사를 정제시켜 N -시아노메틸-2-시클로헥실로메틸- N '-페네틸말론아미드(56mg, 36% 수율)를 수득하였다.1H NMR : (DMSO) 8.38 (t, J=5Hz, 1H), 7.98 (t, J=6Hz, 1H), 7.25 (m, 5H), 4.10 (d, J=6Hz, 2H), 3.2 (m, 3H), 2.71 (t, J=7Hz, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H). MS: m/e 342. 10.2-cyclohexylmethyl- N -phenethyl-malonic acid (138 mg, 0.46 mmol), EDCI (115 mg, 0.60 mmol), HOBt hydrate (92 mg, 0.60) prepared in Reference 3 in NN -dimethylpyrrolidinone (4 ml) mmol) and N -methylmorpholine (0115 ml, 1.38 mmol) were stirred at ambient temperature for 10 minutes. Aminoacetonitrile bisulfate (106 mg, 0.69 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours, poured into cold 1N HCl and extracted twice with ethyl acetate (50 ml each). The organic phase was washed with aqueous sodium bicarbonate followed by brine (50 ml each), dried under magnesium sulphate and evaporated. Purify the residue by radical chromatography using 50% ethylacetate / hexane as eluent to afford N -cyanomethyl-2-cyclohexylmethyl- N' -phenethylmalonamide (56 mg, 36% yield). It was. 1 H NMR: (DMSO) 8.38 (t, J = 5Hz, 1H), 7.98 (t, J = 6Hz, 1H), 7.25 (m, 5H), 4.10 (d, J = 6Hz, 2H), 3.2 (m , 3H), 2.71 (t, J = 7 Hz, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H). MS: m / e 342. 10.

실시예 4Example 4

NN -시아노메틸-2-시클로헥실메틸--Cyanomethyl-2-cyclohexylmethyl- N'N ' -피리드-4-일메틸말론아미드-Pyrid-4-ylmethylmalonamide

(화합물 4)(Compound 4)

참조 4에서 제조된 2-시클로헥실메틸-N-피리딘-4-일메틸-말론산(41mg, 0.14mmol)으로 구성된 용액을 실시예 3에 기술된 아미노아세토니트릴에 커플링시켜 N -시아노메틸-2-시클로헥실메틸- N '-피리드-4-일메틸말론아미드(13mg, 28% 수율)를 수득하였다.1H NMR: (DMSO) 8.5 (m, 4H), 7.20 (d, J=6Hz, 2H), 4.3 (m, 2H), 4.13 (d, J=5Hz, 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.83 (m, 2H). MS: m/e 329.08.A solution consisting of 2-cyclohexylmethyl- N -pyridin-4-ylmethyl-malonic acid (41 mg, 0.14 mmol) prepared in Reference 4 was coupled to the aminoacetonitrile described in Example 3 by N -cyanomethyl 2-cyclohexylmethyl- N' -pyrid-4-ylmethylmalonamide (13 mg, 28% yield) was obtained. 1 H NMR: (DMSO) 8.5 (m, 4H), 7.20 (d, J = 6 Hz, 2H), 4.3 (m, 2H), 4.13 (d, J = 5 Hz, 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.83 (m, 2H). MS: m / e 329.08.

실시예 5Example 5

NN -[1-(1-벤조옥사졸-2-일-메타노일)-3-페닐-프로필]--[1- (1-Benzooxazol-2-yl-methanoyl) -3-phenyl-propyl]- N'N ' -벤질-2-시클로헥실메틸-말론아미드-Benzyl-2-cyclohexylmethyl-malonamide

(화합물 5)(Compound 5)

N-벤질-2-시클로헥실메틸-말로나민산(200mg, 0.69mmol), HOBt(159mg, 1.04mmol), EDCI(146mg, 0.76mmol),2-아미노-1-벤조옥사졸-2-일-4-페닐-부탄-1-온(195mg, 0.69mmol), 디클로로메탄(3ml) 및 트리에틸아민(106㎕, 0.76mmol)을 2시간 동안 교반하였다. 생성물을 에틸 아세테이트(60ml)로 추출하고, 15ml의 두 부분의 1N HCl과, 15ml의 두 부분의 NaHSO3로 세척하고, MgSO4하에 건조하고, 농축하였다. 에틸 아세테이트(5ml)를 첨가하고, 형성된 백색 침전물을 수집하여,N-[1-(1-벤조옥사졸-2-일-1-히드록시-메틸)-3-페닐-프로필]-N'-벤질-2-시클로헥실메틸-말론아미드(81mg, 0.12mmol, 21% 수율)를 수득하였다. N -benzyl-2-cyclohexylmethyl-malonamic acid (200 mg, 0.69 mmol), HOBt (159 mg, 1.04 mmol), EDCI (146 mg, 0.76 mmol), 2-amino-1-benzooxazol-2-yl 4-phenyl-butan-1-one (195 mg, 0.69 mmol), dichloromethane (3 ml) and triethylamine (106 μl, 0.76 mmol) were stirred for 2 hours. The product was extracted with ethyl acetate (60 ml) and washed with 15 ml two portions of 1N HCl, 15 ml two portions of NaHSO 3 , dried over MgSO 4 and concentrated. By the addition of ethyl acetate (5ml), and the collected white precipitate was formed, N - [1- (1- 2-yl-1-hydroxy-methyl) -3-phenyl-propyl] - N '- Benzyl-2-cyclohexylmethyl-malonamide (81 mg, 0.12 mmol, 21% yield) was obtained.

N-[1-(1-벤조옥사졸-2-일-1-히드록시-메틸)-3-페닐-프로필]-N'-벤질-2-시클로헥실메틸-말론아미드(70mg, 0.126mmol)를 0.6ml의 디클로로메탄에 용해시키고, 데스 마틴 페리오디난(Dess Martin periodinane)(107mg, 0.253mmol)으로 처리하였다. 이 혼합물을 2시간 동안 교반하고, 포화 NaHSO3중의 8ml의 0.26M NaS2O3를 첨가하고, 이 혼합물을 15ml의 두 부분의 에틸아세테이트로 추출하고, 4ml의 두 부분의 포화 NaHSO3으로 세척하였다. 유기층을 MgSO4하에 건조하고, 농축시켰다. 에틸 아세테이트와 헥산으로부터 생성물을 재결정화하여 N -[1-(1-벤조옥사졸-2-일-메타노일)-3-페닐-프로필]- N' -벤질-2-시클로헥실메틸-말론아미드(40mg, 0.072mmol, 57% 수율)를 수득하였다.1H NMR: (DMSO) 7.88 (m, 1H), 7.68-7.40 (m, 3H), 7.35-7.10 (m, 10H)M, 6.90 (m, 1H), 5.65 (m, 1H), 4.43 (d, J=5.7Hz, 2H), 3.25 (m, 1H), 2.74 (t, J=8. 0Hz, 1H), 2.46 (m, 1H), 2.17 (m, 1H), 1.77 (t, J=7.4Hz, 1H), 1.64 (m, 7H), 1.22 (m, 4H), 0.87 (m, 2H); MS: (M++1) 552.8; 551.68. N - [1- (1- 2-yl-1-hydroxy-methyl) -3-phenyl-propyl] - N '- benzyl-2-cyclohexylmethyl-malonamide (70mg, 0.126mmol) Was dissolved in 0.6 ml of dichloromethane and treated with Dess Martin periodinane (107 mg, 0.253 mmol). The mixture was stirred for 2 hours, 8 ml of 0.26 M NaS 2 O 3 in saturated NaHSO 3 were added, the mixture was extracted with 15 ml of two portions of ethyl acetate and washed with 4 ml of two portions of saturated NaHSO 3 . . The organic layer was dried over MgSO 4 and concentrated. The product was recrystallized from ethyl acetate and hexane N - [1- (1- 2-yl-methanone alkanoyl) -3-phenyl-propyl] - N '- benzyl-2-cyclohexylmethyl-malonamide (40 mg, 0.072 mmol, 57% yield) was obtained. 1 H NMR: (DMSO) 7.88 (m, 1H), 7.68-7.40 (m, 3H), 7.35-7.10 (m, 10H) M, 6.90 (m, 1H), 5.65 (m, 1H), 4.43 (d , J = 5.7 Hz, 2H), 3.25 (m, 1H), 2.74 (t, J = 8.0 Hz, 1H), 2.46 (m, 1H), 2.17 (m, 1H), 1.77 (t, J = 7.4 Hz, 1H), 1.64 (m, 7H), 1.22 (m, 4H), 0.87 (m, 2H); MS: (M ++ l) 552.8; 551.68.

상기 실시예의 절차를 수행하여 하기 화학식(I)의 화합물을 수득하였다:The procedure of the above example was carried out to obtain a compound of formula (I):

N -시아노메틸- N' -시클로헥실-2-시클로헥실메틸말론아미드(화합물 6);1H NMR (DMSO): 8.31 (t, J=6Hz, 1H), 7.82 (d, J=8Hz, 1H), 4.10 (d, J=8Hz, 2H), 3.52 (m, 1H), 3.20 (t, J=7Hz, 1H), 1. 6 (m, 12H), 1. 1 (m, 9H), 0.83 (m, 2H); MS (m/e) =320.11; N -cyanomethyl- N' -cyclohexyl-2-cyclohexylmethylmalonamide (Compound 6); 1 H NMR (DMSO): 8.31 (t, J = 6Hz, 1H), 7.82 (d, J = 8Hz, 1H), 4.10 (d, J = 8Hz, 2H), 3.52 (m, 1H), 3.20 (t , J = 7 Hz, 1H), 1. 6 (m, 12H), 1.1 (m, 9H), 0.83 (m, 2H); MS (m / e) = 320.11;

N -벤질- N' -시아노메틸-2-시클로헥실메틸말론아미드(화합물 7);1H NMR (DMSO): 8.45 (m, 2H), 7.3 (m, 5H), 4.33 (dd, J=6,15Hz, 1H), 4.23 (dd, J=6,15Hz, 1H), 4.12 (d, 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H) ; MS (m/e) = 328.15, M. Wt. = 327.43; N -benzyl- N' -cyanomethyl-2-cyclohexylmethylmalonamide (Compound 7); 1 H NMR (DMSO): 8.45 (m, 2H), 7.3 (m, 5H), 4.33 (dd, J = 6,15 Hz, 1H), 4.23 (dd, J = 6,15 Hz, 1H), 4.12 (d , 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m / e) = 328.15, M. Wt. = 327.43;

N -시아노메틸-2-시클로헥실메틸- N '-(4-페녹시페닐)말론아미드(화합물 8);1H NMR (DMSO): 10.1 (s, 1H), 8.50 (t, J=5Hz, 1H), 7.61 (d, J=7Hz, 2H), 7.37 (t, J=7Hz, 2H), 7.11 (t, J=7Hz, 1H), 7.0 (m, 4H), 4.14 (d, J=5Hz, 2H), 3.47 (t, J=7Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.92 (m, 2H); MS (m/e) = 406.10, M. Wt. = 405.49; N -cyanomethyl-2-cyclohexylmethyl- N '-(4-phenoxyphenyl) malonamide (Compound 8); 1 H NMR (DMSO): 10.1 (s, 1H), 8.50 (t, J = 5 Hz, 1H), 7.61 (d, J = 7 Hz, 2H), 7.37 (t, J = 7 Hz, 2H), 7.11 (t , J = 7Hz, 1H), 7.0 (m, 4H), 4.14 (d, J = 5Hz, 2H), 3.47 (t, J = 7Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H) , 0.92 (m, 2 H); MS (m / e) = 406.10, M. Wt. = 405.49;

N -시아노메틸-2-시클로헥실메틸- N' -(3-페닐프로필)말론아미드(화합물 9);1H NMR (DMSO): 8.38 (t, J=6Hz, 1H), 8.00 (t, J=6Hz, 1H), 7.2 (m, 5H), 4.10 (d, J=5Hz, 2H), 3.23 (t, J=7Hz, 1H), 3.1 (m, 2H), 2.5 (m, 2H), 1.6 (m, 9H), 1. 1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 356.02; N -cyanomethyl-2-cyclohexylmethyl- N ' -(3-phenylpropyl) malonamide (Compound 9); 1 H NMR (DMSO): 8.38 (t, J = 6Hz, 1H), 8.00 (t, J = 6Hz, 1H), 7.2 (m, 5H), 4.10 (d, J = 5Hz, 2H), 3.23 (t , J = 7 Hz, 1H), 3.1 (m, 2H), 2.5 (m, 2H), 1.6 (m, 9H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m / e) = 356.02;

N -시아노메틸-2-시클로헥실메틸-3-모르폴린-4-일-3-옥소프로피온아미드(화합물 10);1H NMR (DMSO): 8. 54 (t, J=4Hz, 1H), 4.12 (d, J=5Hz, 2H), 3.5 (m, 8H), 1.65 (m, 8H), 1.15 (m, 4H), 0.85 (m, 2H); MS (m/e) = 308.05; N -cyanomethyl-2-cyclohexylmethyl-3-morpholin-4-yl-3-oxopropionamide (Compound 10); 1 H NMR (DMSO): 8. 54 (t, J = 4Hz, 1H), 4.12 (d, J = 5Hz, 2H), 3.5 (m, 8H), 1.65 (m, 8H), 1.15 (m, 4H ), 0.85 (m, 2 H); MS (m / e) = 308.05;

N -시아노메틸-2-시클로헥실메틸-N'-나프트-1-일메틸말론아미드(화합물 11);1H NMR (DMSO): 8.53 (t, J=5Hz, 1H), 8.43 (t, J=6Hz, 1H), 8. 04 (m, 1H), 7.94 (m, 1H), 7.86 (d, J=8Hz, 1H), 7.5 (m, 4H), 4.85 (dd, J=6,15Hz, 1H), 4.65 (dd, J=5, 15Hz, 1H), 4.12 (d, J=3Hz, 2H), 3.3 (m, 1H), 1.6 (m, 8H), 1.0 (m, 5H) ; MS (m/e) = 378.18, M. Wt.377.18; N -cyanomethyl-2-cyclohexylmethyl-N'-naphth-1-ylmethylmalonamide (Compound 11); 1 H NMR (DMSO): 8.53 (t, J = 5Hz, 1H), 8.43 (t, J = 6Hz, 1H), 8. 04 (m, 1H), 7.94 (m, 1H), 7.86 (d, J = 8Hz, 1H), 7.5 (m, 4H), 4.85 (dd, J = 6,15Hz, 1H), 4.65 (dd, J = 5, 15Hz, 1H), 4.12 (d, J = 3Hz, 2H), 3.3 (m, 1H), 1.6 (m, 8H), 1.0 (m, 5H); MS (m / e) = 378.18, M. Wt. 377.18;

N -시아노메틸-2-시클로헥실메틸- N '-피리드-3-일말론아미드(화합물 12);1H NMR (DMSO): 10.24 (s, 1H), 8. 75 (s, 1H), 8. 54 (t, J=5Hz, 1H), 8.29 (d, J=5Hz, 1H), 8.04 (d, J=7Hz, 1H), 7.36 (m, 1H), 4.13 (d, J=5Hz, 2H), 3.49 (t, J=7Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H); MS (m/e) = 314.91; N -cyanomethyl-2-cyclohexylmethyl- N' -pyrid-3-ylmalonamide (Compound 12); 1 H NMR (DMSO): 10.24 (s, 1H), 8. 75 (s, 1H), 8. 54 (t, J = 5 Hz, 1H), 8.29 (d, J = 5 Hz, 1H), 8.04 (d , J = 7Hz, 1H), 7.36 (m, 1H), 4.13 (d, J = 5Hz, 2H), 3.49 (t, J = 7Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H) , 0.9 (m, 2 H); MS (m / e) = 314.91;

N -시아노메틸-2-시클로헥실메틸- N',N' -디이소부틸말론아미드(화합물 13);1H NMR (DMSO): 8.50 (t, J=4Hz, 1H), 4.09 (m, 2H), 3.63 (t, J=7Hz, 1H), 3. 2 (m, 2H), 3.05 (m, 2H), 1.9 (m, 2H), 1. 6 (m, 7H), 1.1 (m, 4H), 0.8 (m, 14H); MS (m/e) = 350.08, M. Wt. 349.51; N -cyanomethyl-2-cyclohexylmethyl- N ', N' -diisobutylmalonamide (Compound 13); 1 H NMR (DMSO): 8.50 (t, J = 4Hz, 1H), 4.09 (m, 2H), 3.63 (t, J = 7Hz, 1H), 3. 2 (m, 2H), 3.05 (m, 2H ), 1.9 (m, 2H), 1. 6 (m, 7H), 1.1 (m, 4H), 0.8 (m, 14H); MS (m / e) = 350.08, M. Wt. 349.51;

N -시아노메틸-2-시클로헥실메틸- N',N' -디이소프로필말론아미드(화합물 14);1H NMR (DMSO): 8. 45 (t, J=5Hz, 1H), 4.1 (m, 3H), 3.55 (t, J=7Hz, 1H), 3.46(m, 1H), 1.6 (m, 7H), 1.27 (d, J=7Hz, 6H), 1.11 (m, 10H), 0.85 (m, 2H); MS (m/e) = 321.99, M. Wt. 321.24; N -cyanomethyl-2-cyclohexylmethyl- N ', N' -diisopropylmalonamide (Compound 14); 1 H NMR (DMSO): 8. 45 (t, J = 5 Hz, 1H), 4.1 (m, 3H), 3.55 (t, J = 7 Hz, 1H), 3.46 (m, 1H), 1.6 (m, 7H ), 1.27 (d, J = 7 Hz, 6H), 1.11 (m, 10H), 0.85 (m, 2H); MS (m / e) = 321.99, M. Wt. 321.24;

N -시아노메틸-2-시클로헥실메틸- N '-(6-메톡시피리드-3-일)말론아미드(화합물 15);1H NMR (DMSO): 10.04 (s, 1H), 8.50 (t, J=5Hz, 1H), 8. 35 (s, 1H), 7.88 (d, J=9Hz, 1H), 6.80 (d, J=9Hz, 1H), 4.13 (m, 2H), 3.81 (s, 3H), 3.44 (t, J=8Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.91 (m, 2H); MS (m/e) = 345.01, M. Wt. 344.18; N -cyanomethyl-2-cyclohexylmethyl- N '-(6-methoxypyrid-3-yl) malonamide (Compound 15); 1 H NMR (DMSO): 10.04 (s, 1H), 8.50 (t, J = 5 Hz, 1 H), 8. 35 (s, 1 H), 7.88 (d, J = 9 Hz, 1 H), 6.80 (d, J = 9 Hz, 1H), 4.13 (m, 2H), 3.81 (s, 3H), 3.44 (t, J = 8 Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.91 (m, 2H ); MS (m / e) = 345.01, M. Wt. 344.18;

N -시아노메틸-2-시클로헥실메틸- N '-(2-티엔-2-일에틸)말론아미드(화합물 16);1H NMR (DMSO): 8. 40 (t, J=5Hz, 1H), 8. 07 (t, J=5Hz, 1H), 7.33 (d, J=5Hz, 1H), 6.95 (m, 1H), 6. 87 (m, 1H), 4.10 (d, J=5Hz, 2H), 3.3 (m, 3H), 3.21 (t, J=7Hz, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 348.09, M. Wt. 347.48; N -cyanomethyl-2-cyclohexylmethyl- N '-(2-thien-2-ylethyl) malonamide (Compound 16); 1 H NMR (DMSO): 8. 40 (t, J = 5Hz, 1H), 8. 07 (t, J = 5Hz, 1H), 7.33 (d, J = 5Hz, 1H), 6.95 (m, 1H) , 6. 87 (m, 1H), 4.10 (d, J = 5 Hz, 2H), 3.3 (m, 3H), 3.21 (t, J = 7 Hz, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m / e) = 348.09, M. Wt. 347.48;

N -시아노메틸-2-시클로헥실메틸- N '-(3-페녹시페닐)말론아미드(화합물 17);1H NMR (DMSO): 10.1 (s, 1H), 8.45 (t, J=5Hz, 1H), 7.41 (t, J=8Hz, 2H), 7.33 (m, 3H), 7.16 (t, J=7Hz, 1H), 7.03 (d, J=8Hz, 2H), 6.73 (m, 1H), 4.1 (m, 2H), 3.42 (t, J=7Hz, 1H), 1.6 (m, 7H), 1. 1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 406.04, M. Wt. 405.49; N -cyanomethyl-2-cyclohexylmethyl- N '-(3-phenoxyphenyl) malonamide (Compound 17); 1 H NMR (DMSO): 10.1 (s, 1H), 8.45 (t, J = 5 Hz, 1H), 7.41 (t, J = 8 Hz, 2H), 7.33 (m, 3H), 7.16 (t, J = 7 Hz , 1H), 7.03 (d, J = 8Hz, 2H), 6.73 (m, 1H), 4.1 (m, 2H), 3.42 (t, J = 7Hz, 1H), 1.6 (m, 7H), 1. 1 (m, 4H), 0.85 (m, 2H); MS (m / e) = 406.04, M. Wt. 405.49;

N -시아노메틸-2-시클로헥실메틸- N '-(4-니트로벤질)말론아미드(화합물 18);1H NMR (DMSO): 8. 61 (t, J=6Hz, 1H), 8. 53 (t, J=6Hz, 1H), 8.17 (d, J=9Hz, 2H), 7.47 (d, J=9Hz, 2H), 4.41 (d, J=6Hz, 2H), 4.14 (d, J=6Hz, 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.87 (m, 2H); MS (m/e) = 373.02, M. Wt. 372.42; N -cyanomethyl-2-cyclohexylmethyl- N '-(4-nitrobenzyl) malonamide (Compound 18); 1 H NMR (DMSO): 8. 61 (t, J = 6 Hz, 1H), 8. 53 (t, J = 6 Hz, 1H), 8.17 (d, J = 9 Hz, 2H), 7.47 (d, J = 9Hz, 2H), 4.41 (d, J = 6Hz, 2H), 4.14 (d, J = 6Hz, 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.87 ( m, 2H); MS (m / e) = 373.02, M. Wt. 372.42;

N,N' -비스시아노메틸-2-시클로헥실메틸말론아미드(화합물 19);1H NMR (DMSO): 8.59 (t, J=5Hz, 2H), 4.14 (d, J=6Hz, 4H), 3.28 (t, J=8Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.86 (m, 2H); MS (m/e) = 276.99, M. Wt. 276.34; N, N' -biscyanomethyl-2-cyclohexylmethylmalonamide (Compound 19); 1 H NMR (DMSO): 8.59 (t, J = 5Hz, 2H), 4.14 (d, J = 6Hz, 4H), 3.28 (t, J = 8Hz, 1H), 1.6 (m, 7H), 1.1 (m , 4H), 0.86 (m, 2H); MS (m / e) = 276.99, M. Wt. 276.34;

N -시아노메틸-2-시클로헥실메틸- N '-(5,6,7,8-테트라히드로나프트-1-일)말론아미드(화합물 20);1H NMR (DMSO): 9.28 (s, 1H), 8.57 (t, J=6Hz, 1H), 7.21 (d, J=8Hz, 1H), 7.05 (t, J=8Hz, 1H), 6.90 (d, J=7Hz, 1H), 4.16 (d, J=6Hz, 2H), 3.49 (t, J=7Hz, 1H), 2.7 (m, 2H), 2.5 (m, 2H), 1.7 (m, 11H), 1.1 (m, 4H), 0.91 (m, 2H); MS (m/e) = 368. 04, M. Wt. 367.48; N -cyanomethyl-2-cyclohexylmethyl- N '-(5,6,7,8-tetrahydronaphth-1-yl) malonamide (Compound 20); 1 H NMR (DMSO): 9.28 (s, 1H), 8.57 (t, J = 6 Hz, 1H), 7.21 (d, J = 8 Hz, 1H), 7.05 (t, J = 8 Hz, 1H), 6.90 (d , J = 7Hz, 1H), 4.16 (d, J = 6Hz, 2H), 3.49 (t, J = 7Hz, 1H), 2.7 (m, 2H), 2.5 (m, 2H), 1.7 (m, 11H) , 1.1 (m, 4H), 0.91 (m, 2H); MS (m / e) = 368. 04, M. Wt. 367.48;

N -시아노메틸-2-시클로헥실메틸- N '-(2-피리드-2-일에틸)말론아미드(화합물 21);1H NMR (DMSO): 8.49 (m, 1H), 8.40 (t, J=6Hz, 1H), 8.00 (t, J=5Hz, 1H), 7.68 (dt, J=2,8Hz, 1H), 7.2 (m, 2H), 4.09 (d, J=6Hz, 2H), 3.42 (m, 2H), 3.17 (t, J=8Hz, 1H), 2.85 (t, J=7Hz, 2H), 1.6 (m, 7H), 1.07 (m, 4H), 0.83 (m, 2H); MS (m/e) = 343.04, M. Wt. 342.44; N -cyanomethyl-2-cyclohexylmethyl- N '-(2-pyrid-2-ylethyl) malonamide (Compound 21); 1 H NMR (DMSO): 8.49 (m, 1H), 8.40 (t, J = 6 Hz, 1H), 8.00 (t, J = 5 Hz, 1H), 7.68 (dt, J = 2,8 Hz, 1H), 7.2 (m, 2H), 4.09 (d, J = 6Hz, 2H), 3.42 (m, 2H), 3.17 (t, J = 8Hz, 1H), 2.85 (t, J = 7Hz, 2H), 1.6 (m, 7H), 1.07 (m, 4H), 0.83 (m, 2H); MS (m / e) = 343.04, M. Wt. 342.44;

N -시아노메틸-2-시클로헥실메틸-3-(2,3-디히드로인돌-1-일)-3-옥소프로피온아미드(화합물 22);1H NMR (DMSO): 8.73 (t, J=5Hz, 1H), 8.06 (d, J=8Hz, 1H), 7.24 (d, J=7Hz, 1H), 7.15 (t, J=7Hz, 1H), 7.00 (t, J=7Hz, 1H), 4.15 (d, J=5Hz, 2H), 4.1 (m, 2H), 3.66 (t, J=7Hz, 1H), 3.14 (m, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.91 (m, 2H); MS (m/e) = 340.07, M. Wt. 339.19; N -cyanomethyl-2-cyclohexylmethyl-3- (2,3-dihydroindol-1-yl) -3-oxopropionamide (Compound 22); 1 H NMR (DMSO): 8.73 (t, J = 5Hz, 1H), 8.06 (d, J = 8Hz, 1H), 7.24 (d, J = 7Hz, 1H), 7.15 (t, J = 7Hz, 1H) , 7.00 (t, J = 7Hz, 1H), 4.15 (d, J = 5Hz, 2H), 4.1 (m, 2H), 3.66 (t, J = 7Hz, 1H), 3.14 (m, 2H), 1.6 ( m, 7H), 1.1 (m, 4H), 0.91 (m, 2H); MS (m / e) = 340.07, M. Wt. 339.19;

N -시아노메틸-2-시클로헥실메틸-3-(3,4-디히드로-1 H -이소퀴놀린-2-일)-3-옥소프로피온아미드(화합물 23);1H NMR (DMSO): 8.64 (t, J=5Hz, 1H), 7.15 (s, 4H), 4.65 (m, 2H), 4.11 (t, J=6Hz, 2H), 3.77 (m, 2H), 2.8 (m, 2H), 1.7 (m, 7H), 1.1 (m, 4H), 0.89 (m, 2H), 3.54 (m, 1H); MS (m/e) = 354.05, M. Wt. 353.46; N -cyanomethyl-2-cyclohexylmethyl-3- (3,4-dihydro-1 H -isoquinolin-2-yl) -3-oxopropionamide (Compound 23); 1 H NMR (DMSO): 8.64 (t, J = 5Hz, 1H), 7.15 (s, 4H), 4.65 (m, 2H), 4.11 (t, J = 6Hz, 2H), 3.77 (m, 2H), 2.8 (m, 2H), 1.7 (m, 7H), 1.1 (m, 4H), 0.89 (m, 2H), 3.54 (m, 1H); MS (m / e) = 354.05, M. Wt. 353.46;

N -시아노메틸-2, N '-비스시클로헥실메틸말론아미드(화합물 24);1H NMR (DMSO): 8.34 (t, J=5Hz, 1H), 7.93 (t, J=5Hz, 1H), 4.09 (d, J=6Hz, 2H), 3.23 (dd, J=7,9Hz, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 1.6 (m, 12H), 1.4 (m, 1H), 1.1 (m, 7H), 0.86 (m, 4H); MS (m/e) = 334.00, M. Wt. 333.47; N -cyanomethyl-2, N' -biscyclohexylmethylmalonamide (Compound 24); 1 H NMR (DMSO): 8.34 (t, J = 5 Hz, 1H), 7.93 (t, J = 5 Hz, 1H), 4.09 (d, J = 6 Hz, 2H), 3.23 (dd, J = 7,9 Hz, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 1.6 (m, 12H), 1.4 (m, 1H), 1.1 (m, 7H), 0.86 (m, 4H); MS (m / e) = 334.00, M. Wt. 333.47;

N -시아노메틸-2-시클로헥실메틸- N' -(2-메톡시벤질)말론아미드(화합물 25);1H NMR (DMSO): 8. 44 (t, J=5Hz, 1H), 8.27 (t, J=6Hz, 1H), 7.24 (dt, J=2,7Hz, 1H), 7.10 (dd, J=2,7Hz, 1H), 6.96 (d, J=7Hz, 1H), 6.88 (dt, J=7, lHz, 1H), 4.30 (dd, J=6,16Hz, 1H), 4.20 (dd, J=5,16Hz, 1H), 4.12 (d, J=6Hz, 2H), 3.79 (s, 3H), 3.3 (m, 1H), 1.6 (m, 7H), 1. 1 (m, 4H), 0.85 (m, 2H); MS (m/e) =358.03, M. Wt. 357.45; N -cyanomethyl-2-cyclohexylmethyl- N ' -(2-methoxybenzyl) malonamide (Compound 25); 1 H NMR (DMSO): 8. 44 (t, J = 5 Hz, 1H), 8.27 (t, J = 6 Hz, 1H), 7.24 (dt, J = 2,7 Hz, 1H), 7.10 (dd, J = 2,7Hz, 1H), 6.96 (d, J = 7Hz, 1H), 6.88 (dt, J = 7, lHz, 1H), 4.30 (dd, J = 6,16Hz, 1H), 4.20 (dd, J = 5,16 Hz, 1H), 4.12 (d, J = 6 Hz, 2H), 3.79 (s, 3H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 ( m, 2H); MS (m / e) = 358.03, M. Wt. 357.45;

N -시아노메틸-2-시클로헥실메틸- N '-(1-페닐에틸)말론아미드(화합물 26);1H NMR (DMSO): 8.25 (m, 1H), 7.4 (m, 5H), 4.02 (m, 2H), 3.18 (s, 3H), 3.25 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.7 (m, 2H); MS (m/e) = 328. 08, M. Wt. 327.42; N -cyanomethyl-2-cyclohexylmethyl- N '-(1-phenylethyl) malonamide (Compound 26); 1 H NMR (DMSO): 8.25 (m, 1H), 7.4 (m, 5H), 4.02 (m, 2H), 3.18 (s, 3H), 3.25 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.7 (m, 2H); MS (m / e) = 328. 08, M. Wt. 327.42;

N -벤질- N' -시아노메틸-2-시클로헥실메틸- N -메틸말론아미드(화합물 27);1H NMR (DMSO): 8.62 (m, 1H), 7.3 (m, 5H), 4.5 (m, 2H), 4.13 (d, J=6Hz, 2H), 3.7 (m, 1H), 2.93 (s, 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.88 (m, 2H); MS (m/e) = 342.09, M. Wt. 341.45; N -benzyl- N' -cyanomethyl-2-cyclohexylmethyl- N -methylmalonamide (Compound 27); 1 H NMR (DMSO): 8.62 (m, 1H), 7.3 (m, 5H), 4.5 (m, 2H), 4.13 (d, J = 6 Hz, 2H), 3.7 (m, 1H), 2.93 (s, 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.88 (m, 2H); MS (m / e) = 342.09, M. Wt. 341.45;

N -시아노메틸-2-시클로헥실메틸- N '-(3-니트로벤질)말론아미드(화합물 28);1H NMR (DMSO): 8.6 (t, 1H), 8.5 (t, 1H), 8.1 (m, 2H), 7.6 (m, 2H), 4.1 (m, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.8 (m, 2H); MS (m/e) = 373.07, M. Wt. 372.42; N -cyanomethyl-2-cyclohexylmethyl- N '-(3-nitrobenzyl) malonamide (Compound 28); 1 H NMR (DMSO): 8.6 (t, 1H), 8.5 (t, 1H), 8.1 (m, 2H), 7.6 (m, 2H), 4.1 (m, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.8 (m, 2H); MS (m / e) = 373.07, M. Wt. 372.42;

N -시아노메틸-2-시클로헥실메틸- N '-(4-메톡시벤질)말론아미드(화합물 29);1H NMR (DMSO): 8.42 (t, J=5Hz, 1H), 8.38 (t, J=6Hz, 1H), 7.14 (d, J=9Hz, 2H), 6.86 (d, J=9Hz, 2H), 4.25 (dd, J=6, 15Hz, 1H), 4.15 (dd, J=7,16Hz, 1H), 3.71 (s, 3H), 3.27 (t, J=8Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.84 (m, 2H), 4.11 (d, J=6Hz, 2H); MS (m/e) = 356.97, M. Wt. 357.45; N -cyanomethyl-2-cyclohexylmethyl- N '-(4-methoxybenzyl) malonamide (Compound 29); 1 H NMR (DMSO): 8.42 (t, J = 5Hz, 1H), 8.38 (t, J = 6Hz, 1H), 7.14 (d, J = 9Hz, 2H), 6.86 (d, J = 9Hz, 2H) , 4.25 (dd, J = 6, 15Hz, 1H), 4.15 (dd, J = 7,16Hz, 1H), 3.71 (s, 3H), 3.27 (t, J = 8Hz, 1H), 1.6 (m, 7H ), 1.1 (m, 4H), 0.84 (m, 2H), 4.11 (d, J = 6 Hz, 2H); MS (m / e) = 356.97, M. Wt. 357.45;

N -(3-카르바모일페닐)- N '-시아노메틸-2-시클로헥실메틸말론아미드(화합물30);1H NMR (DMSO): 10.14 (s, 1H), 8.48 (t, 1H), 8.03 (s, 1H), 7.75 (d, 1H), 7.54 (d, 1H), 7.35 (m, 2H), 4.12 (d, 2H), 3.4 (t, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H), 3.29 (s, 3H); MS (m/e) = 357.11, M. Wt. 356.42; N - (3- carbamoyl-phenyl) - N '- cyano-2-cyclohexylmethyl-malonamide (Compound 30); 1 H NMR (DMSO): 10.14 (s, 1H), 8.48 (t, 1H), 8.03 (s, 1H), 7.75 (d, 1H), 7.54 (d, 1H), 7.35 (m, 2H), 4.12 (d, 2H), 3.4 (t, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H), 3.29 (s, 3H); MS (m / e) = 357.11, M. Wt. 356.42;

N -시아노메틸-2-시클로헥실메틸- N '-피리드-3-일메틸말론아미드(화합물 31);1H NMR (DMSO): 8.4 (m, 4H), 7.55 (d, 1H), 7.25 (dd, 1H), 4.28 (dd, 1H), 4.18 (dd, 1H), 4.05 (d, 2H), 3.2 (m, 1H), 1.6 (m, 7H), 1. 01 (m, 4H), 0.78 (m, 2H); MS (m/e) = 329.03, M. Wt. 328.41; N -cyanomethyl-2-cyclohexylmethyl- N' -pyrid-3-ylmethylmalonamide (Compound 31); 1 H NMR (DMSO): 8.4 (m, 4H), 7.55 (d, 1H), 7.25 (dd, 1H), 4.28 (dd, 1H), 4.18 (dd, 1H), 4.05 (d, 2H), 3.2 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.78 (m, 2H); MS (m / e) = 329.03, M. Wt. 328.41;

N -(4-카르바모일페닐)- N '-시아노메틸-2-시클로헥실메틸말론아미드(화합물 32);1H NMR (DMSO): 10.22 (s, 2H), 8. 50 (t, J=6Hz, 1H), 7.83 (d, J=9Hz 2H), 7.64 (d, J=9Hz, 2H), 7.52 (s, 1H), 4.13 (d, J=6Hz, 2H), 3.48 (t, J=7Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H); MS (m/e) = 357.04, M. Wt. 356.42; N - (4- carbamoyl-phenyl) - N '- cyano-2-cyclohexylmethyl-malonamide (Compound 32); 1 H NMR (DMSO): 10.22 (s, 2H), 8. 50 (t, J = 6 Hz, 1H), 7.83 (d, J = 9 Hz 2H), 7.64 (d, J = 9 Hz, 2H), 7.52 ( s, 1H), 4.13 (d, J = 6 Hz, 2H), 3.48 (t, J = 7 Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H); MS (m / e) = 357.04, M. Wt. 356.42;

N -시아노메틸-2-시클로헥실메틸- N '-테트라히드로푸르-2-일메틸말론아미드(화합물 33);1H NMR (DMSO): 8.38 (t, J=5Hz, 1H), 7.98 (t, J=4Hz, 1H), 4.10 (d, J=6Hz 2H), 3.8 (m, 2H), 3.6 (m, 1H), 3.2 (m, 4H), 1.8 (m, 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 322.02, M. Wt. 321.41; N -cyanomethyl-2-cyclohexylmethyl- N' -tetrahydrofur-2-ylmethylmalonamide (Compound 33); 1 H NMR (DMSO): 8.38 (t, J = 5Hz, 1H), 7.98 (t, J = 4Hz, 1H), 4.10 (d, J = 6Hz 2H), 3.8 (m, 2H), 3.6 (m, 1H), 3.2 (m, 4H), 1.8 (m, 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m / e) = 322.02, M. Wt. 321.41;

N -시아노메틸-2-시클로헥실메틸-3-(3,4-디히드로-2 H -퀴놀린-1-일)-3-옥소프로피온아미드(화합물 34);1H NMR (DMSO): 8.5 (m, 1H), 7.35 (m, 1H), 7.2 (m, 4H), 4.1 (m, 2H), 3.82 (dd, 1H), 2.78 (t, 1H), 2.72 (t, 1H), 2.59 (m, 1H),1.8 (m, 2H), 1.5 (m, 7H), 1.0 (m, 4H), 0.7 (m, 2H); MS (m/e) = 354.02, M. Wt. 353.46; N -cyanomethyl-2-cyclohexylmethyl-3- (3,4-dihydro-2 H -quinolin-1-yl) -3-oxopropionamide (Compound 34); 1 H NMR (DMSO): 8.5 (m, 1H), 7.35 (m, 1H), 7.2 (m, 4H), 4.1 (m, 2H), 3.82 (dd, 1H), 2.78 (t, 1H), 2.72 (t, 1H), 2.59 (m, 1H), 1.8 (m, 2H), 1.5 (m, 7H), 1.0 (m, 4H), 0.7 (m, 2H); MS (m / e) = 354.02, M. Wt. 353.46;

N - tert -부틸- N '-시아노메틸-2-시클로헥실메틸- N -메틸말론아미드(화합물 35);1H NMR (DMSO): 8. 41 (t, J=5Hz, 1H), 4.09 (d, J=5Hz, 1H), 3.56 (t, J=7Hz, 1H), 2.86 (s, 3H), 1.6 (m, 7H), 1.31 (s, 9H), 1.1 (m, 4H), 0.8 (m, 2H); MS (m/e) = 308. 04, M. Wt. 307.43; N - tert -butyl- N' -cyanomethyl-2-cyclohexylmethyl- N -methylmalonamide (Compound 35); 1 H NMR (DMSO): 8. 41 (t, J = 5Hz, 1H), 4.09 (d, J = 5Hz, 1H), 3.56 (t, J = 7Hz, 1H), 2.86 (s, 3H), 1.6 (m, 7H), 1.31 (s, 9H), 1.1 (m, 4H), 0.8 (m, 2H); MS (m / e) = 308. 04, M. Wt. 307.43;

N -시아노메틸-2-시클로헥실메틸- N '-메틸- N '-프로필말론아미드(화합물 36);1H NMR (DMSO): 8. 5 (m, 1H), 4.10 (m, 2H), 3.60 (t, J=7Hz, 1H), 3.2 (m, 2H), 2.96 (s, 3H), 1.65 (m, 7H), 1. 45 (m, 2H), 1. 1 (m, 4H), 0.8 (m, 5H) ; MS (m/e) = 294.02, M. Wt. 293.40; N -cyanomethyl-2-cyclohexylmethyl- N' -methyl- N' -propylmalonamide (Compound 36); 1 H NMR (DMSO): 8. 5 (m, 1H), 4.10 (m, 2H), 3.60 (t, J = 7 Hz, 1H), 3.2 (m, 2H), 2.96 (s, 3H), 1.65 ( m, 7H), 1. 45 (m, 2H), 1.1 (m, 4H), 0.8 (m, 5H); MS (m / e) = 294.02, M. Wt. 293.40;

N -부틸- N '-시아노메틸-2-시클로헥실메틸- N -메틸말론아미드(화합물 37);1H NMR (DMSO): 8.5 (m, 1H), 4.10 (d, J=5Hz, 2H), 3.60 (t, 1H), 3.3 (m, 2H), 2.95 (s, 3H), 1.6 (m, 7H), 1.4 (m, 2H), 1. 1 (m, 6H), 0.8 (m, 5H) ; MS (m/e) = 308.01, M. Wt. 307.43; N -butyl- N' -cyanomethyl-2-cyclohexylmethyl- N -methylmalonamide (Compound 37); 1 H NMR (DMSO): 8.5 (m, 1H), 4.10 (d, J = 5 Hz, 2H), 3.60 (t, 1H), 3.3 (m, 2H), 2.95 (s, 3H), 1.6 (m, 7H), 1.4 (m, 2H), 1.1 (m, 6H), 0.8 (m, 5H); MS (m / e) = 308.01, M. Wt. 307.43;

N -시아노메틸-2-시클로헥실메틸- N',N' -디메틸말론아미드(화합물 38);1H NMR (DMSO) : 8.55 (t, J=5Hz, 1H), 4.11 (d, J=7Hz, 2H), 3.62 (t, J=8Hz, 1H), 2.99 (s, 3H), 2.81 (s, 3H), 1.6 (m, 7H), 1. 1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 266.01, M. Wt. 265.18; N -cyanomethyl-2-cyclohexylmethyl- N ', N' -dimethylmalonamide (Compound 38); 1 H NMR (DMSO): 8.55 (t, J = 5Hz, 1H), 4.11 (d, J = 7Hz, 2H), 3.62 (t, J = 8Hz, 1H), 2.99 (s, 3H), 2.81 (s , 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m / e) = 266.01, M. Wt. 265.18;

N -벤질- N '-시아노메틸-2-(2-페닐술파닐에틸)말론아미드(화합물 39);1H NMR (DMSO): 8.56 (t, J=6Hz, 1H), 8.49 (t, J=6Hz, 1H), 7.3 (m, 10H), 4.29 (d, J=6Hz, 2H), 4.14 (d, J=6Hz, 2H), 3.40 (t, J=7Hz, 1H), 2.86 (t, J=8Hz, 2H), 2.05 (m, 2H); MS (m/e) = 368.02, M. Wt. 367.14; 및 N -benzyl- N' -cyanomethyl-2- (2-phenylsulfanylethyl) malonamide (Compound 39); 1 H NMR (DMSO): 8.56 (t, J = 6Hz, 1H), 8.49 (t, J = 6Hz, 1H), 7.3 (m, 10H), 4.29 (d, J = 6Hz, 2H), 4.14 (d , J = 6 Hz, 2H), 3.40 (t, J = 7 Hz, 1H), 2.86 (t, J = 8 Hz, 2H), 2.05 (m, 2H); MS (m / e) = 368.02, M. Wt. 367.14; And

2-(2-페닐술포닐에틸)- N -벤질- N '-시아노메틸말론아미드(화합물 40);1H NMR (DMSO): 8.56 (t, J=6Hz, 1H), 8.43 (t, J=6Hz, 1H), 7.86 (d, J=7Hz, 2H), 7.79 (t, J=5Hz, 1H), 7.68 (t, J=8Hz, 2H), 7.25 (m, 5H), 4.26 (d, J=6Hz, 2H), 4.13 (d, J=6Hz, 2H), 3.36 (m, 1H), 3.19 (m, 2H), 2.00 (m, 2H); MS (m/e) = 400.04, M. Wt. 399.47; 2- (2-phenylsulfonylethyl) -N -benzyl- N' -cyanomethylmalonamide (Compound 40); 1 H NMR (DMSO): 8.56 (t, J = 6Hz, 1H), 8.43 (t, J = 6Hz, 1H), 7.86 (d, J = 7Hz, 2H), 7.79 (t, J = 5Hz, 1H) , 7.68 (t, J = 8Hz, 2H), 7.25 (m, 5H), 4.26 (d, J = 6Hz, 2H), 4.13 (d, J = 6Hz, 2H), 3.36 (m, 1H), 3.19 ( m, 2H), 2.00 (m, 2H); MS (m / e) = 400.04, M. Wt. 399.47;

2-(2-벤젠술포닐-에틸)- N -[(S)-1-(1-벤조옥사졸-2-일-메타노일)-펜틸]- N '-벤질-말론아미드(화합물 41);1H NMR (DMSO) : 8.56 (d, J=6Hz, 1H), 8. 2 (m, 1H), 8.0-7.5 (m, 9H), 7.3-7.1 (m, 5H), 5.3 (m, 1H), 4.24 (t, J=6Hz, 2H), 3.41 (t, J=7Hz, 1H), 3.18 (m, 2H), 1.96 (m, 3H), 1.67 (m, 1H), 1.30 (m, 4H), 0.82 (m, 3H); MS (m/e) = 576.27, M. Wt. 575.21; 및 2- (2-benzenesulfonyl-ethyl) - N - [(S) -1- (1- 2-yl-methanone alkanoyl) - pentyl] - N '- benzyl-malonamide (Compound 41) ; 1 H NMR (DMSO): 8.56 (d, J = 6Hz, 1H), 8. 2 (m, 1H), 8.0-7.5 (m, 9H), 7.3-7.1 (m, 5H), 5.3 (m, 1H ), 4.24 (t, J = 6Hz, 2H), 3.41 (t, J = 7Hz, 1H), 3.18 (m, 2H), 1.96 (m, 3H), 1.67 (m, 1H), 1.30 (m, 4H ), 0.82 (m, 3 H); MS (m / e) = 576.27, M. Wt. 575.21; And

N,N '-비스-[(S)-1-(1-벤조옥사졸-2-일-메타노일)-프로필l-2-시클로헥실메틸- 말론아미드(화합물 42);1H NMR (DMSO): 8.41 (d, J=6Hz, 2H), 8.00 (d, J=8Hz, 2H), 7.89 (d, J=8Hz, 2H), 7.65 (t, J=7Hz, 2H), 7.53 (t, J=8Hz, 2H), 5.19 (m, 2H), 3.42 (t, J=8Hz, 1H), 1.98 (m, 2H), 1.74 (m, 2H), 1.52 (m, 7H), 0.94 (m,10H), 0.77 (m, 2H); MS (m/e) = 572.26, M. Wt. 573.4. N, N' -bis-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propyll-2-cyclohexylmethyl-malonamide (Compound 42); 1 H NMR (DMSO): 8.41 (d, J = 6Hz, 2H), 8.00 (d, J = 8Hz, 2H), 7.89 (d, J = 8Hz, 2H), 7.65 (t, J = 7Hz, 2H) , 7.53 (t, J = 8Hz, 2H), 5.19 (m, 2H), 3.42 (t, J = 8Hz, 1H), 1.98 (m, 2H), 1.74 (m, 2H), 1.52 (m, 7H) , 0.94 (m, 10 H), 0.77 (m, 2 H); MS (m / e) = 572.26, M. Wt. 573.4.

실시예 6Example 6

카텝신 S 검정Cathepsin S Black

디메틸 술폭시드(DMSO) 10㎕중에서 시험 화합물 용액을 여러 가지 농도로 제조한 다음, 검정용 완충액(40㎕, MES 50mM (pH 6); EDTA 2.5mM; 및 NaCl 100mM 함유)으로 희석시켰다. 인간 카텝신 S(검정용 완충액 25㎕ 중 0.158pMol)를 상기 희석액에 첨가하였다. 검정용 용액을 진탕기 플레이트상에서 5 내지 10초간 혼합시키고, 뚜껑을 덮어 주위 온도에서 30분간 인큐베이션시켰다. Z-Val-Val-Arg-AMC(검정용 완충액 25㎕ 중 9nMol)를 상기 검정용 용액에 첨가한 후, 5분간 (λ460nm)에서 분광광도법으로 가수분해시켰다. 표준 수학 모델을 사용하여 효소 진행 곡선(enzyme progress curve)으로부터 겉보기 억제 상수(Ki)를 계산하였다.Test compound solutions were prepared at various concentrations in 10 μl of dimethyl sulfoxide (DMSO) and then diluted with assay buffer (40 μl, MES 50 mM (pH 6); EDTA 2.5 mM; and 100 mM NaCl). Human cathepsin S (0.158 pMol in 25 μl of assay buffer) was added to the dilution. The assay solution was mixed for 5-10 seconds on a shaker plate and incubated for 30 minutes at ambient temperature with a lid. Z-Val-Val-Arg-AMC (9 nMol in 25 μl of assay buffer) was added to the assay solution and then hydrolyzed by spectrophotometry at 5 min (λ 460 nm). The apparent inhibition constant (K i ) was calculated from the enzyme progress curve using a standard mathematical model.

실시예 7Example 7

카텝신 B 검정Cathepsin B black

디메틸 술폭시드(DMSO) 10㎕중에서 시험 화합물 용액을 여러 가지 농도로 제조한 다음, 검정용 완충액(40㎕,N,N-비스(2-히드록시에틸)-2-아미노에탄술폰산 (BES) 50mM (pH 6); 폴리옥시에틸렌소르비탄 모노라우레이트 0.05%; 및 디티오트레이톨(DTT) 2.5mM 함유)으로 희석시켰다. 인간 카텝신 B(검정용 완충액 25㎕ 중 0.025pMol)를 상기 희석액에 첨가하였다. 검정용 용액을 진탕기 플레이트상에서 5 내지 10초간 혼합시키고, 뚜껑을 덮어 주위 온도에서 30분간 인큐베이션시켰다.Z-FR-AMC(검정용 완충액 25㎕ 중 20nMol)를 상기 검정용 용액에 첨가한 후, 5분간 (λ460nm)에서 분광광도법으로 가수분해시켰다. 표준 수학 모델을 사용하여 효소 진행 곡선으로부터 겉보기 억제 상수(Ki)를 계산하였다.Test compound solutions were prepared in various concentrations in 10 μl of dimethyl sulfoxide (DMSO), followed by 50 mM assay buffer (40 μl, N, N -bis (2-hydroxyethyl) -2-aminoethanesulfonic acid (BES) (pH 6); 0.05% polyoxyethylenesorbitan monolaurate; and 2.5 mM dithiothreitol (DTT)). Human cathepsin B (0.025 pMol in 25 μl of assay buffer) was added to the dilution. The assay solution was mixed for 5-10 seconds on a shaker plate and incubated for 30 minutes at ambient temperature with a lid. Z-FR-AMC (20 nMol in 25 μl of assay buffer) was added to the assay solution. Hydrolysis was carried out by spectrophotometry at (λ 460 nm) for 5 minutes. The apparent mathematical constant (K i ) was calculated from the enzyme progression curve using a standard mathematical model.

실시예 8Example 8

카텝신 K 검정Cathepsin K black

디메틸 술폭시드(DMSO) 10㎕중에서 시험 화합물 용액을 여러 가지 농도로 제조한 다음, 검정용 완충액(40㎕, MES 50mM (pH 5.5); EDTA 2.5mM; 및 DTT 2.5mM 함유)으로 희석시켰다. 인간 카텝신 K(검정용 완충액 25㎕ 중 0.0906pMol)를 상기 희석액에 첨가하였다. 검정용 용액을 진탕기 플레이트상에서 5 내지 10초간 혼합시키고, 뚜껑을 덮어 주위 온도에서 30분간 인큐베이션시켰다. Z-Phe-Arg-AMC(검정용 완충액 25㎕ 중 4nMol)를 상기 검정용 용액에 첨가한 후, 5분간 (λ460nm)에서 분광광도법으로 가수분해시켰다. 표준 수학 모델을 사용하여 효소 진행 곡선으로부터 겉보기 억제 상수(Ki)를 계산하였다.Test compound solutions were prepared at various concentrations in 10 μl of dimethyl sulfoxide (DMSO) and then diluted with assay buffer (40 μl, MES 50 mM (pH 5.5); EDTA 2.5 mM; and DTT 2.5 mM). Human cathepsin K (0.0906 pMol in 25 μl of assay buffer) was added to the dilution. The assay solution was mixed for 5-10 seconds on a shaker plate and incubated for 30 minutes at ambient temperature with a lid. Z-Phe-Arg-AMC (4 nMol in 25 μl of assay buffer) was added to the assay solution and then hydrolyzed spectrophotometrically at 5 min (λ 460 nm). The apparent mathematical constant (K i ) was calculated from the enzyme progression curve using a standard mathematical model.

실시예 9Example 9

카텝신 L 검정Cathepsin L black

디메틸 술폭시드(DMSO) 10㎕중에서 시험 화합물 용액을 여러 가지 농도로 제조한 다음, 검정용 완충액(40㎕, MES 50mM (pH 5.5); EDTA 2.5mM; 및 DTT 2.5mM 함유)으로 희석시켰다. 인간 카텝신 L(검정용 완충액 25㎕ 중 0.05pMol)를 상기 희석액에 첨가하였다. 검정용 용액을 진탕기 플레이트상에서 5 내지 10초간 혼합시키고, 뚜껑을 덮어 주위 온도에서 30분간 인큐베이션시켰다. Z-Phe-Arg-AMC(검정용 완충액 25㎕ 중 1nMol)를 상기 검정용 용액에 첨가한 후, 5분간 (λ460nm)에서 분광광도법으로 가수분해시켰다. 표준 수학 모델을 사용하여 효소 진행 곡선으로부터 겉보기 억제 상수(Ki)를 계산하였다.Test compound solutions were prepared at various concentrations in 10 μl of dimethyl sulfoxide (DMSO) and then diluted with assay buffer (40 μl, MES 50 mM (pH 5.5); EDTA 2.5 mM; and DTT 2.5 mM). Human cathepsin L (0.05 pMol in 25 μl of assay buffer) was added to the dilution. The assay solution was mixed for 5-10 seconds on a shaker plate and incubated for 30 minutes at ambient temperature with a lid. Z-Phe-Arg-AMC (1 nMol in 25 μl of assay buffer) was added to the assay solution and then hydrolyzed by spectrophotometry at 5 min (λ 460 nm). The apparent mathematical constant (K i ) was calculated from the enzyme progression curve using a standard mathematical model.

상기 기술한 검정에 따라 본 발명의 화합물의 프로테아제 억제능을 시험하고, 선택적인 카텝신 S 억제 활성을 나타냄을 확인하였다. 예를 들어, 본 발명의 화합물은 카텝신 K 프로테아제 활성의 상동활성 억제를 제공하는데 요구되는 농도보다 적어도 50배 적은 농도로 카텝신 S 프로테아제 활성을 억제하는 것으로 나타났다. 카텝신 S에 대한 본 발명의 화합물의 겉보기 억제 상수(Ki)는 약 10-10M 내지 약 10-7M의 범위였다.The protease inhibitory ability of the compounds of the present invention was tested according to the assay described above and found to exhibit selective cathepsin S inhibitory activity. For example, the compounds of the present invention have been shown to inhibit cathepsin S protease activity at a concentration at least 50 times less than the concentration required to provide homologous inhibition of cathepsin K protease activity. The apparent inhibition constant (K i ) of the compounds of the present invention for cathepsin S ranged from about 10 −10 M to about 10 −7 M.

실시예 10Example 10

화학식(I)의 화합물을 함유하는 대표적인 약제학적 제형Representative Pharmaceutical Formulations Containing Compound of Formula (I)

경구용 제형Oral Formulations

화학식(I)의 화합물 10 내지 100mg10 to 100 mg of compound of formula (I)

시트르산 일수화물 105mgCitric Acid Monohydrate 105mg

수산화 나트륨 18mgSodium hydroxide 18mg

향료Spices

물 100ml가 되도록 하는 양Volume to make 100ml of water

정맥주사용 제형Intravenous Formulation

화학식(I)의 화합물 0.1 내지 10mg0.1 to 10 mg of compound of formula (I)

덱스트로오스 일수화물 등장성이 되도록 하는 양Amount to make dextrose monohydrate isotonic

시트르산 일수화물 1.05mgCitric Acid Monohydrate 1.05mg

수산화 나트륨 0.18mgSodium Hydroxide 0.18mg

주사용수 1.0ml가 되도록 하는 양Amount to be 1.0 ml of water for injection

정제용 제형Tablet formulation

화학식(I)의 화합물 1%1% compound of formula (I)

미정질 셀룰로오스 73%Microcrystalline Cellulose 73%

스테아르산 25%25% stearic acid

콜로이드성 실리카 1%Colloidal Silica 1%

Claims (10)

하기 화학식(I)의 화합물; 또는 이의 N-산화물 유도체, 전구약물 유도체, 보호된 유도체, 개개의 이성질체 또는 이성질체들의 혼합물; 또는 상기 화합물 또는 이의 N-산화물 유도체, 전구약물 유도체, 보호된 유도체, 개개의 이성질체 또는 이성질체들의 혼합물의 약제학적으로 허용되는 염이나 용매화물:A compound of formula (I); Or N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers or mixtures of isomers thereof; Or a pharmaceutically acceptable salt or solvate of said compound or an N-oxide derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomers thereof: 상기 식에서,Where X1은 -NHC(R1)(R2)X2또는 -NHX3이고,X 1 is —NHC (R 1 ) (R 2 ) X 2 or —NHX 3 , X2는 시아노, -C(R7)(R8)X3, -C(R7)(R8)CF3, -C(R7)(R8)CF2CF2R9, -CH=CHS(O)2R5, -C(O)CF2C(O)NR5R5, -C(O)C(O)NR5R6, -C(O)C(O)OR5, -C(O)CH20R5, -C(O)CH2N(R6)SO2R5또는 -C(O)C(O)R5이고, 여기에서, R5는 (C1-4)알킬, (C5-10)아릴(C0-6)알킬 또는 (C5-lO)헤테로아릴(CO-6)알킬이고; R6은 수소 또는 (C1-6)알킬이고; R7은 수소 또는 (C1-4)알킬이고, R8은 히드록시이거나, R7과 R8이 함께 옥소를 형성하고; R9는 수소, 할로,(C1-4)알킬, (C5-10)아릴(C0-6)알킬 또는 (C5-1O)헤테로아릴(C0-6)알킬이며,X 2 is cyano, -C (R 7 ) (R 8 ) X 3 , -C (R 7 ) (R 8 ) CF 3 , -C (R 7 ) (R 8 ) CF 2 CF 2 R 9 ,- CH = CHS (O) 2 R 5 , -C (O) CF 2 C (O) NR 5 R 5 , -C (O) C (O) NR 5 R 6 , -C (O) C (O) OR 5 , -C (O) CH 2 0R 5 , -C (O) CH 2 N (R 6 ) SO 2 R 5 or -C (O) C (O) R 5 , wherein R 5 is (C 1-4 ) alkyl, (C 5-10 ) aryl (C 0-6 ) alkyl or (C 5-lO ) heteroaryl (C O-6 ) alkyl; R 6 is hydrogen or (C 1-6 ) alkyl; R 7 is hydrogen or (C 1-4 ) alkyl and R 8 is hydroxy or R 7 and R 8 together form oxo; R 9 is hydrogen, halo, (C 1-4 ) alkyl, (C 5-10 ) aryl (C 0-6 ) alkyl or (C 5-1O ) heteroaryl (C 0-6 ) alkyl, X3은 4 내지 6원 고리 원자를 함유하는 헤테로모노시클릭 고리 또는 8 내지 14원 고리 원자를 함유하는 접합된 헤테로비시클릭 고리 시스템 및 이의 임의의 카르보시클릭 케톤, 이미노케톤 또는 티오케톤 유도체를 포함하고,X 3 is a heteromonocyclic ring containing 4 to 6 membered ring atoms or a conjugated heterobicyclic ring system containing 8 to 14 membered ring atoms and any carbocyclic ketone, iminoketone or thioketone derivative thereof Including, R5, X2또는 X3내에서 임의의 지환족 또는 방향족 고리 시스템이, (C1-6)알킬, (C1-6)알킬리덴, 시아노, 할로, 할로-치환된 (C1-4)알킬, 니트로, -X4NR12R12, -X4NR12C(O)R12, -X4NR12C(O)OR12, -X4NR12C(O)NR12R12, -X4NR12C(NR12)NR12R12, -X4OR12, -X4SR12, -X4C(O)OR12, -X4C(O)R12, -X4OC(O)R12, -X4C(O)NR12R12, -X4S(O)2NR12R12, -X4NR12S(O)2R12, -X4P(O)(OR12)OR12, -X4OP(O)(OR12)OR12, -X4NR12C(O)R13, -X4S(O)R13및 -X4S(O)2R13으로부터 독립적으로 선택된 1 내지 5개의 라디칼 및/또는 -R14, -X4OR14, -X4SR14, -X4S(O)R14, -X4S(O)2R14, -X4C(O)R14, -X4C(O)OR14, -X4OC(O)R14, -X4NR14R12, -X4NR12C(O)R14, -X4NR12C(O)OR14, -X4C(O)NR12R12, -X4S(O)2NR14R12, -X4NR12S(O)2R14, -X4NR12C(O)NR14R12및 -X4NR12C(NR12)NR14R12로부터 선택된 하나의 라디칼에 의해 추가로치환될 수 있고, 여기에서, X4는 단일 결합 또는 (C1-6)알킬이고, R12는 각각의 경우, 독립적으로 수소, (C1-6)알킬 또는 할로-치환된 (C1-6)알킬이고, R13은 (C1-6)알킬 또는 할로-치환된 (C1-6)알킬이고, R14은 (C3-10)시클로알킬(C0-6)알킬, 헤테로(C3-10)시클로알킬(C0-3)알킬, (C6-10)아릴(C0-6)알킬, 헤테로(C5-10)아릴(C0-6)알킬, (C9-10)비시클로아릴(C0-6)알킬 또는 헤테로(C8-10)비시클로아릴(C0-6)알킬이고,Any cycloaliphatic or aromatic ring system in R 5 , X 2 or X 3 is a (C 1-6 ) alkyl, (C 1-6 ) alkylidene, cyano, halo, halo-substituted (C 1- 4 ) alkyl, nitro, -X 4 NR 12 R 12 , -X 4 NR 12 C (O) R 12 , -X 4 NR 12 C (O) OR 12 , -X 4 NR 12 C (O) NR 12 R 12 , -X 4 NR 12 C (NR 12 ) NR 12 R 12 , -X 4 OR 12 , -X 4 SR 12 , -X 4 C (O) OR 12 , -X 4 C (O) R 12 ,- X 4 OC (O) R 12 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 12 R 12 , -X 4 NR 12 S (O) 2 R 12 , -X 4 P (O) (OR 12 ) OR 12 , -X 4 OP (O) (OR 12 ) OR 12 , -X 4 NR 12 C (O) R 13 , -X 4 S (O) R 13 and -X 4 1 to 5 radicals independently selected from S (O) 2 R 13 and / or -R 14 , -X 4 OR 14 , -X 4 SR 14 , -X 4 S (O) R 14 , -X 4 S ( O) 2 R 14 , -X 4 C (O) R 14 , -X 4 C (O) OR 14 , -X 4 OC (O) R 14 , -X 4 NR 14 R 12 , -X 4 NR 12 C (O) R 14 , -X 4 NR 12 C (O) OR 14 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 14 R 12 , -X 4 NR 12 S ( O) 2 R 14, -X 4 NR 12 C (O) NR 14 R 12 and -X 4 NR 12 C (NR 12 ) NR 14 R 12, a radical selected from More may be substituted by 0, in which, X 4 is a single bond or (C 1-6) alkyl, R 12 is for each occurrence, independently hydrogen, (C 1-6) alkyl or halo-substituted (C 1-6 ) alkyl, R 13 is (C 1-6 ) alkyl or halo-substituted (C 1-6 ) alkyl, R 14 is (C 3-10 ) cycloalkyl (C 0-6 ) Alkyl, hetero (C 3-10 ) cycloalkyl (C 0-3 ) alkyl, (C 6-10 ) aryl (C 0-6 ) alkyl, hetero (C 5-10 ) aryl (C 0-6 ) alkyl, (C 9-10 ) bicycloaryl (C 0-6 ) alkyl or hetero (C 8-10 ) bicycloaryl (C 0-6 ) alkyl, R1은 수소, 할로 또는 (C1-6)알킬이고, R2는 수소, 시아노, 할로, -X4NR12R12, -X4NR12C(O)R12, -X4NR12C(O)OR12, -X4NR12C(O)NR12R12, -X4NR12C(NR12)NR12R12, -X4OR12, -X4SR12, -X4C(O)OR12, -X4C(O)R12, -X4OC(O)R12, -X4C(O)NR12R12, -X4S(O)2NR12R12, -X4NR12S(O)2R12, -X4P(O)(OR12)OR12, -X4OP(O)(OR12)OR12, -X4NR12C(O)R13, -X4S(O)R13, -X4S(O)2R13, -R14, -X4OR14, -X4SR14, -X4S(O)R14, -X4S(O)2R14, -X4C(O)R14, -X4C(O)OR4, -X4OC(O)R14, -X4NR14R12, -X4NR12C(O)R14, -X4NR12C(O)OR14, -X4C(O)NR12R12, -X4S(O)2NR14R12, -X4NR12S(O)2R14, -X4NR12C(O)NR14R12및 -X4NR12C(NR12)NR14R12으로 구성된 군으로부터 선택되거나 (여기서, X4, R12, R13및 R14는 상기에서 정의된 바와 같음);R1과 R2는, R1과 R2둘 모두가 부착되어 있는 탄소 원자와 함께 (C3-8)시아노알킬렌 또는 (C3-8)헤테로시클로알킬렌을 형성하고, 여기에서, 상기 R2내의 임의의 헤테로아릴, 아릴, 시클로알킬, 헤테로시클로알킬, 시클로알킬렌 또는 헤테로시클로알킬렌은 (C1-6)알킬, (C1-6)알킬리덴, 시아노, 할로, 할로-치환된 (C1-4)알킬, 니트로, -X4NR12R12, -X4NR12C(O)R12, -X4NR12C(O)OR12, -X4NR12C(O)NR12R12, -X4NR12C(NR12)NR12R12, -X4OR12, -X4SR12, -X4C(O)OR12, -X4C(O)R12, -X4OC(O)R12, -X4C(O)NR12R12, -X4S(O)2NR12R12, -X4NR12S(O)2R12, -X4P(O)(OR12)OR12, -X4OP(O)(OR12)OR12, -X4NR12C(O)R13, -X4S(O)R13, -X4S(O)2R13및 -X4C(O)R13으로부터 독립적으로 선택된 1 내지 3개의 라디칼에 의해 치환되거나 비치환되며 (여기서 X4, R12및 R13은 상기에서 정의된 바와 같음),R 1 is hydrogen, halo or (C 1-6 ) alkyl, R 2 is hydrogen, cyano, halo, -X 4 NR 12 R 12 , -X 4 NR 12 C (O) R 12 , -X 4 NR 12 C (O) OR 12 , -X 4 NR 12 C (O) NR 12 R 12 , -X 4 NR 12 C (NR 12 ) NR 12 R 12 , -X 4 OR 12 , -X 4 SR 12 ,- X 4 C (O) OR 12 , -X 4 C (O) R 12 , -X 4 OC (O) R 12 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 12 R 12 , -X 4 NR 12 S (O) 2 R 12 , -X 4 P (O) (OR 12 ) OR 12 , -X 4 OP (O) (OR 12 ) OR 12 , -X 4 NR 12 C (O) R 13 , -X 4 S (O) R 13 , -X 4 S (O) 2 R 13 , -R 14 , -X 4 OR 14 , -X 4 SR 14 , -X 4 S (O ) R 14 , -X 4 S (O) 2 R 14 , -X 4 C (O) R 14 , -X 4 C (O) OR 4 , -X 4 OC (O) R 14 , -X 4 NR 14 R 12 , -X 4 NR 12 C (O) R 14 , -X 4 NR 12 C (O) OR 14 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 14 R 12 , -X 4 NR 12 S (O) 2 R 14 , -X 4 NR 12 C (O) NR 14 R 12 and -X 4 NR 12 C (NR 12 ) NR 14 R 12 ; Wherein X 4 , R 12 , R 13 and R 14 are as defined above); R 1 and R 2 together with the carbon atom to which both R 1 and R 2 are attached (C 3-8 ) cyanoalkylene or (C 3-8 ) heterocycloalkylene, wherein any heteroaryl, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocyclo in said R 2 Alkylene is (C 1-6 ) alkyl, (C 1-6 ) alkylidene, cyano, halo, halo-substituted (C 1-4 ) alkyl, nitro, -X 4 NR 12 R 12 , -X 4 NR 12 C (O) R 12 , -X 4 NR 12 C (O) OR 12 , -X 4 NR 12 C (O) NR 12 R 12 , -X 4 NR 12 C (NR 12 ) NR 12 R 12 , -X 4 OR 12 , -X 4 SR 12 , -X 4 C (O) OR 12 , -X 4 C (O) R 12 , -X 4 OC (O) R 12 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 12 R 12 , -X 4 NR 12 S (O) 2 R 12 , -X 4 P (O) (OR 12 ) OR 12 , -X 4 OP (O ) (OR 12 ) OR 12 , -X 4 NR 12 C (O) R 13 , -X 4 S (O) R 13 , -X 4 S (O) 2 R 13 and -X 4 C (O) R 13 Unsubstituted or substituted by one to three radicals independently selected from (wherein X 4 , R 12 and R 13 are as defined above), R3는 -C(R6)(R6)X5이고, 여기서 R6은 상기에서 정의된 바와 같고, X5는 -X4NR12R12, -X4NR12C(O)R12, -X4NR12C(O)OR12, -X4NR12C(O)NR12R12, -X4NR12C(NR12)NR12R12, -X4OR12, -X4SR12, -X4C(O)OR12, -X4C(O)R12, -X4OC(O)R12, -X4R12, -X4C(O)NR12R12, -X4S(O)2NR12R12, -X4NR12S(O)2R12, -X4P(O)(OR12)OR12, -X4OP(O)(OR12)OR12, -X4C(O)R13, -X4NR12C(O)R13, -X4S(O)R13및 -X4S(O)2R13, -R14, -X4OR14, -X4SR14, -X4S(O)R14, -X4S(O)2R14, -X4C(O)R14, -X4C(O)OR14, -X4OC(O)R14, -X4NR14R12, -X4NR12C(O)R14, -X4NR12C(O)OR14, -X4C(O)NR14R12, -X4S(O)2NR14R12, -X4NR12S(O)2R14, -X4NR12C(O)NR14R12및 -X4NR12C(NR12)NR14R12로부터 선택되며 (여기서 X4, R12, R13및 R14는 상기에서 정의된 바와 같음),R 3 is —C (R 6 ) (R 6 ) X 5 , wherein R 6 is as defined above and X 5 is —X 4 NR 12 R 12 , -X 4 NR 12 C (O) R 12 , -X 4 NR 12 C (O) OR 12 , -X 4 NR 12 C (O) NR 12 R 12 , -X 4 NR 12 C (NR 12 ) NR 12 R 12 , -X 4 OR 12 , -X 4 SR 12 , -X 4 C (O) OR 12 , -X 4 C (O) R 12 , -X 4 OC (O) R 12 , -X 4 R 12 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 12 R 12 , -X 4 NR 12 S (O) 2 R 12 , -X 4 P (O) (OR 12 ) OR 12 , -X 4 OP (O) ( OR 12 ) OR 12 , -X 4 C (O) R 13 , -X 4 NR 12 C (O) R 13 , -X 4 S (O) R 13 and -X 4 S (O) 2 R 13 ,- R 14 , -X 4 OR 14 , -X 4 SR 14 , -X 4 S (O) R 14 , -X 4 S (O) 2 R 14 , -X 4 C (O) R 14 , -X 4 C (O) OR 14 , -X 4 OC (O) R 14 , -X 4 NR 14 R 12 , -X 4 NR 12 C (O) R 14 , -X 4 NR 12 C (O) OR 14 , -X 4 C (O) NR 14 R 12 , -X 4 S (O) 2 NR 14 R 12 , -X 4 NR 12 S (O) 2 R 14 , -X 4 NR 12 C (O) NR 14 R 12 and -X 4 NR 12 C (NR 12 ) NR 14 R 12 , wherein X 4 , R 12 , R 13 and R 14 are as defined above, R4는 -NR6R6, -NR6R14, -NR6R15또는 -NR6X5C(O)R14이고 (여기서, R6, X5및 R14는 상기에서 기술한대로이고, R15는 수소, -(C1-6)알킬 또는 -X5OR6이거나 (여기서, X5는 상기에서 기술한대로임); R6및 R15는, R6및 R15둘 모두가 부착되어 있는 질소 원자와 함께 헤테로(C3-10)시클로알킬, 헤테로(C5-10)아릴 또는 헤테로(C8-10)비시클로아릴을 형성함),R 4 is —NR 6 R 6 , —NR 6 R 14 , —NR 6 R 15 or —NR 6 X 5 C (O) R 14 , wherein R 6 , X 5 and R 14 are as described above and R 15 is hydrogen, — (C 1-6 ) alkyl or —X 5 OR 6 (wherein X 5 is as described above); R 6 and R 15 are both attached to R 6 and R 15 Together with the nitrogen atom to form hetero (C 3-10 ) cycloalkyl, hetero (C 5-10 ) aryl or hetero (C 8-10 ) bicycloaryl), R3및 R4내에서 임의의 지환족 또는 방향족 고리 시스템이, (C1-6)알킬, (C1-6)알킬리덴, 시아노, 할로, 할로-치환된 (C1-4)알킬, 니트로, -X4NR12R12, -X4NR12C(O)R12, -X4NR12C(O)OR12, -X4NR12C(O)NR12R12, -X4NR12C(NR12)NR12R12, -X4OR12, -X4SR12, -X4C(O)OR12, -X4C(O)R12, -X4OC(O)R12, -X4C(O)NR12R12, -X4S(O)2NR12R12, -X4NR12S(O)2R12, -X4P(O)(OR12)OR12, -X4OP(O)(OR12)OR12, -X4NR12C(O)R13, -X4S(O)R13, -X4C(O)R13및 -X4S(O)2R13으로부터 독립적으로 선택된 1 내지 5개의 라디칼 및/또는 -R14, -X4OR14, -X4SR14, -X4S(O)R14, -X4S(O)2R14, -X4C(O)R14, -X4C(O)OR14, -X4OC(O)R14, -X4NR14R12, -X4NR12C(O)R14, -X4NR12C(O)OR14, -X4C(O)NR14R12, -X4S(O)2NR14R12, -X4NR12S(O)2R14, -X4NR12C(O)NR14R12및 -X4NR12C(NR12)NR14R12으로부터 선택된 하나의 라디칼에 의해 추가로 치환될 수 있고, R3및 R4내에서 임의의 지방족 부분은 시아노, 할로, 니트로, -NR12R12, -NR12C(O)R12, -NR12C(O)OR12, -NR12C(O)NR12R12, -NR12C(NR12)NR12R12, -OR12, -SR12, -C(O)OR12, -C(O)R12, -OC(O)R12, -C(O)NR12R12, -S(O)2NR12R12, -NR12S(O)2R12, -P(O)(OR12)OR12, -OP(O)(OR12)OR12, -NR12C(O)R13, -S(O)R13및 -S(0)2R13으로부터 독립적으로 선택된 1 내지 5개의 라디칼에 의해 추가로 치환될 수 있고 (여기서, X4, R12, R13및 R14는 상기에서 기술한 바와 같음),Any of the alicyclic or aromatic ring system in R 3 and R 4 is (C 1-6 ) alkyl, (C 1-6 ) alkylidene, cyano, halo, halo-substituted (C 1-4 ) alkyl , Nitro, -X 4 NR 12 R 12 , -X 4 NR 12 C (O) R 12 , -X 4 NR 12 C (O) OR 12 , -X 4 NR 12 C (O) NR 12 R 12 ,- X 4 NR 12 C (NR 12 ) NR 12 R 12 , -X 4 OR 12 , -X 4 SR 12 , -X 4 C (O) OR 12 , -X 4 C (O) R 12 , -X 4 OC (O) R 12 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 NR 12 R 12 , -X 4 NR 12 S (O) 2 R 12 , -X 4 P (O ) (OR 12 ) OR 12 , -X 4 OP (O) (OR 12 ) OR 12 , -X 4 NR 12 C (O) R 13 , -X 4 S (O) R 13 , -X 4 C (O 1-5 radicals and / or -R 14 , -X 4 OR 14 , -X 4 SR 14 , -X 4 S (O) R independently selected from R 13 and -X 4 S (O) 2 R 13 14 , -X 4 S (O) 2 R 14 , -X 4 C (O) R 14 , -X 4 C (O) OR 14 , -X 4 OC (O) R 14 , -X 4 NR 14 R 12 , -X 4 NR 12 C (O) R 14 , -X 4 NR 12 C (O) OR 14 , -X 4 C (O) NR 14 R 12 , -X 4 S (O) 2 NR 14 R 12 , -X 4 NR 12 S (O) 2 R 14, -X 4 NR 12 C (O) NR 14 R 12 and -X 4 NR 12 C (NR 12 ) NR 14 R 12 selected from May be further substituted by a radical, R 3 and R 4 optionally in the aliphatic moiety is a cyano, halo, nitro, -NR 12 R 12, -NR 12 C (O) R 12, -NR 12 C ( O) OR 12 , -NR 12 C (O) NR 12 R 12 , -NR 12 C (NR 12 ) NR 12 R 12 , -OR 12 , -SR 12 , -C (O) OR 12 , -C (O R 12 , -OC (O) R 12 , -C (O) NR 12 R 12 , -S (O) 2 NR 12 R 12 , -NR 12 S (O) 2 R 12 , -P (O) ( OR 12 ) 1 to independently selected from OR 12 , -OP (O) (OR 12 ) OR 12 , -NR 12 C (O) R 13 , -S (O) R 13, and -S (0) 2 R 13 May be further substituted by five radicals, wherein X 4 , R 12 , R 13 and R 14 are as described above; 단, 하나의 비시클릭 고리 구조만이 R3또는 R4내에 존재한다.Provided that only one bicyclic ring structure is present in R 3 or R 4 . 제 1항에 있어서,The method of claim 1, X1은 -NHC(R1)(R2)X2또는 -NHX3이고,X 1 is —NHC (R 1 ) (R 2 ) X 2 or —NHX 3 , X2는 시아노, -C(O)X3, -C(O)CF3, -C(O)CF2CF2R9, -CH=CHS(0)2R5, -C(O)CF2C(O)NR5R5, -C(O)C(O)NR5R6, -C(O)C(O)OR5, -C(O)CH20R5, -C(O)CH2N(R6)SO2R5또는 -C(O)C(O)R5이고 (여기서, R5및 R6은 상기에서 기술한대로임),X 2 is cyano, -C (O) X 3 , -C (O) CF 3 , -C (O) CF 2 CF 2 R 9 , -CH = CHS (0) 2 R 5 , -C (O) CF 2 C (O) NR 5 R 5 , -C (O) C (O) NR 5 R 6 , -C (O) C (O) OR 5 , -C (O) CH 2 0R 5 , -C ( O) CH 2 N (R 6 ) SO 2 R 5 or —C (O) C (O) R 5 , wherein R 5 and R 6 are as described above, X3은 4 내지 6원 고리 원자를 함유하는 헤테로모노시클릭 고리 또는 8 내지 14원 고리 원자를 함유하는 접합된 헤테로비시클릭 고리 시스템 및 이의 임의의 카르보시클릭 케톤, 이미노케톤 또는 티오케톤 유도체를 포함하고,X 3 is a heteromonocyclic ring containing 4 to 6 membered ring atoms or a conjugated heterobicyclic ring system containing 8 to 14 membered ring atoms and any carbocyclic ketone, iminoketone or thioketone derivative thereof Including, R5, X2또는 X3내에서 임의의 지환족 또는 방향족 고리 시스템이 (C1-6)알킬 및 -X4OC(O)R12로부터 독립적으로 선택된 1 내지 5개의 라디칼 및/또는 -R14, -X4C(O)R14및 -X4OC(O)R14로부터 선택된 하나의 라디칼에 의해 추가로 치환될 수 있고 (여기서, X4, R12및 R14는 상기에서 기술한대로임),Wherein any alicyclic or aromatic ring system in R 5 , X 2 or X 3 is independently selected from (C 1-6 ) alkyl and —X 4 OC (O) R 12 and / or —R 14 , -X 4 C (O) R 14 and -X 4 OC (O) R 14 which may be further substituted by (wherein X 4 , R 12 and R 14 are as described above being), R1은 수소 또는 (C1-6)알킬이고, R2는 수소, -X4OR12, (C5-10)헤테로아릴(C0-6)알킬, (C5-10)아릴(C0-6)알킬, (C5-10)시클로알킬(C0-6)알킬, (C5-10)헤테로시클로알킬(C0-6)알킬 또는 (C1-6)알킬이거나; R1과 R2는, R1과 R2둘 모두가 부착되어 있는 탄소 원자와 함께 (C3-8)시클로알킬렌 또는 (C3-8)헤테로시클로알킬렌을 형성하고, 여기에서, 상기 R2내의 임의의 헤테로아릴, 아릴, 시클로알킬, 헤테로시클로알킬, 시클로알킬렌 또는 헤테로시클로알킬렌은 (C1-6)알킬 및 히드록시로부터 독립적으로 선택된 1 내지 3개의 라디칼에 의해 치환되거나 비치환되며,R 1 is hydrogen or (C 1-6 ) alkyl, R 2 is hydrogen, —X 4 OR 12 , (C 5-10 ) heteroaryl (C 0-6 ) alkyl, (C 5-10 ) aryl (C 0-6 ) alkyl, (C 5-10 ) cycloalkyl (C 0-6 ) alkyl, (C 5-10 ) heterocycloalkyl (C 0-6 ) alkyl or (C 1-6 ) alkyl; R 1 and R 2 together with the carbon atom to which both R 1 and R 2 are attached form (C 3-8 ) cycloalkylene or (C 3-8 ) heterocycloalkylene, wherein any heteroaryl group within R 2, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocycloalkyl alkylene (1-6 C) optionally substituted by 1 to 3 radicals independently selected from alkyl and hydroxy or unsubstituted Is R3는 -CH2X5이고, 여기서 X5는 각 경우에 -X4SR12, -X4C(O)NR12R12, -X4S(O)2R13, -X4C(O)R13, -X4SR14, -R14, -X4S(O)2R14, -X4R12, -X4C(O)R14및 -X4C(O)NR14R12로부터 독립적으로 선택되며 (여기서 X4, R12, R13및 R14는 상기에서 정의된 바와 같음),R 3 is -CH 2 X 5 , where X 5 in each case is -X 4 SR 12 , -X 4 C (O) NR 12 R 12 , -X 4 S (O) 2 R 13 , -X 4 C (O) R 13 , -X 4 SR 14 , -R 14 , -X 4 S (O) 2 R 14 , -X 4 R 12 , -X 4 C (O) R 14 and -X 4 C (O) Independently selected from NR 14 R 12 , wherein X 4 , R 12 , R 13 and R 14 are as defined above; R4는 -NR6R6, -NR6R14, -NR6R15또는 -NR6X5C(O)R14이고 (여기서, R6, X5및 R14는 상기에서 기술한대로이고, R15는 수소, -(C1-6)알킬 또는 -X5OR6이거나 (여기서, X5는 상기에서 기술한대로임); R6및 R15는, R6및 R15둘 모두가 부착되어 있는 질소 원자와 함께 헤테로(C3-10)시클로알킬, 헤테로(C5-10)아릴 또는 헤테로(C8-10)비시클로아릴을 형성함),R 4 is —NR 6 R 6 , —NR 6 R 14 , —NR 6 R 15 or —NR 6 X 5 C (O) R 14 , wherein R 6 , X 5 and R 14 are as described above and R 15 is hydrogen, — (C 1-6 ) alkyl or —X 5 OR 6 (wherein X 5 is as described above); R 6 and R 15 are both attached to R 6 and R 15 Together with the nitrogen atom to form hetero (C 3-10 ) cycloalkyl, hetero (C 5-10 ) aryl or hetero (C 8-10 ) bicycloaryl), R3및 R4내에서 임의의 지환족 또는 방향족 고리 시스템이, (C1-6)알킬, 시아노, 할로, 니트로, 할로-치환된 (C1-4)알킬, -X4OR12, -X4C(O)OR12, -X4C(O)R13, -X4C(O)NR12R12및 -X4NR12S(O)2R12으로부터 독립적으로 선택된 1 내지 5개의 라디칼 및/또는 -R14, -X4OR14및 -X4C(O)NR14R12로부터 선택된 하나의 라디칼에 의해 추가로 치환될 수 있고, R3및 R4내에서 임의의 지방족 부분은 시아노에서 독립적으로 선택된 1 내지 5개의 라디칼에 의해 추가로 치환될 수 있고 (여기서, X4, R12, R13및 R14는 상기에서 기술한대로임), 단, 하나의 비시클릭 고리 구조만이 R3또는 R4내에 존재하는 화합물; 또는 이의 N-산화물 유도체, 전구약물 유도체, 보호된 유도체, 개개의 이성질체 또는 이성질체들의 혼합물; 또는 상기 화합물 또는 이의 N-산화물 유도체, 전구약물 유도체, 보호된 유도체, 개개의 이성질체 또는 이성질체들의 혼합물의 약제학적으로 허용되는 염이나 용매화물.Any alicyclic or aromatic ring system in R 3 and R 4 may be selected from (C 1-6 ) alkyl, cyano, halo, nitro, halo-substituted (C 1-4 ) alkyl, —X 4 OR 12 , 1 to independently selected from -X 4 C (O) OR 12 , -X 4 C (O) R 13 , -X 4 C (O) NR 12 R 12 and -X 4 NR 12 S (O) 2 R 12 May be further substituted by five radicals and / or one radical selected from —R 14 , —X 4 OR 14 and —X 4 C (O) NR 14 R 12 , optionally substituted in R 3 and R 4 Aliphatic moieties may be further substituted by 1 to 5 radicals independently selected from cyano (wherein X 4 , R 12 , R 13 and R 14 are as described above), provided that one bicyclic Compounds in which only ring structures are present in R 3 or R 4 ; Or N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers or mixtures of isomers thereof; Or a pharmaceutically acceptable salt or solvate of said compound or an N-oxide derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomers thereof. 제 2항에 있어서,The method of claim 2, X1은 -NHC(R1)(R2)X2또는 -NHX3이고,X 1 is —NHC (R 1 ) (R 2 ) X 2 or —NHX 3 , X2는 시아노, -C(0)X3, -CF3, -CF2CF3, (E)-2-벤젠술포닐-비닐, 2-디메틸카르바모일-2,2-디플루오로-아세틸, 1-벤질카르바모일-메타노일, 1-벤질옥시(옥살릴), 2-벤질옥시-아세틸, 2-벤젠술포닐아미노-에타노일 또는 2-옥소-2-페닐-에타노일이고,X 2 is cyano, -C (0) X 3 , -CF 3 , -CF 2 CF 3 , (E) -2-benzenesulfonyl-vinyl, 2-dimethylcarbamoyl-2,2-difluoro -Acetyl, 1-benzylcarbamoyl-methanoyl, 1-benzyloxy (oxalyl), 2-benzyloxy-acetyl, 2-benzenesulfonylamino-ethanoyl or 2-oxo-2-phenyl-ethanoyl , X3는 1H-벤조이미다졸-2-일, 피리미딘-2-일, 벤조옥사졸-2-일, 벤조티아졸-2-일, 피리다진-3-일, 3-페닐-[1,2,4]옥사디아졸-5-일, 3-에틸-[1,2,4]옥사디아졸-5-일, 2-메틸-4-옥소-테트라히드로-푸란-3-일, 2-에틸-4-옥소-테트라히드로-푸란-3-일, 4-옥소-1-(1-페닐-메타노일)-피롤리딘-3-일 또는 (S)-2-아세톡시-4-옥소-아제티딘-3-일이고,X 3 is 1 H -benzoimidazol-2-yl, pyrimidin-2-yl, benzooxazol-2-yl, benzothiazol-2-yl, pyridazin-3-yl, 3-phenyl- [1 , 2,4] oxadiazol-5-yl, 3-ethyl- [1,2,4] oxadiazol-5-yl, 2-methyl-4-oxo-tetrahydro-furan-3-yl, 2 -Ethyl-4-oxo-tetrahydro-furan-3-yl, 4-oxo-1- (1-phenyl-methanoyl) -pyrrolidin-3-yl or (S) -2-acetoxy-4- Oxo-azetidin-3-yl, R1은 수소 또는 메틸이고, R2는 수소, 메톡시메틸, (C1-6)알킬, 페네틸, 티오펜-2-일 또는 5-메틸-푸란-2-일이거나; (ii) R1및 R2는, R1및 R2둘 모두가 부착되어 있는 탄소 원자와 함께 시클로프로필렌, 테트라히드로-피란-4-일렌 또는 메틸-피페리딘-4-일렌을 형성함을 특징으로 하는 화합물.R 1 is hydrogen or methyl and R 2 is hydrogen, methoxymethyl, (C 1-6 ) alkyl, phenethyl, thiophen-2-yl or 5-methyl-furan-2-yl; (ii) R 1 and R 2 together with the carbon atom to which both R 1 and R 2 are attached form cyclopropylene, tetrahydro-pyran-4-ylene or methyl-piperidin-4-ylene Characterized by a compound. 제 3항에 있어서, R3이 티오펜-2-술포닐메틸, 3-클로로-2-플루오로-페닐메탄술포닐메틸, 벤젠술포닐메틸, 페닐메탄술포닐메틸, 2-(1,1-디플루오로-메톡시)-페닐메탄술포닐메틸, 2-벤젠술포닐-에틸, 2-(피리딘-2-술포닐)-에틸, 2-(피리딘-4-술포닐)-에틸, 2-페닐메탄술포닐-에틸, 옥시-피리딘-2-일메탄술포닐메틸, 프로프-2-엔-1-술포닐메틸, 4-메톡시-페닐메탄술포닐메틸,p-톨릴메탄술포닐메틸, 4-클로로-페닐메탄술포닐메틸,o-톨릴메탄술포닐메틸, 3,5-디메틸-페닐메탄술포닐메틸, 4-트리플루오로메틸-페닐메탄술포닐메틸, 4-트리플루오로메톡시-페닐메탄술포닐메틸,2-브로모-페닐메탄술포닐메틸, 피리딘-2-일메탄술포닐메틸, 피리딘-3-일메탄술포닐메틸, 피리딘-4-일메탄술포닐메틸, 나프탈렌-2-일메탄술포닐메틸, 3-메틸-페닐메탄술포닐메틸, 3-트리플루오로메틸-페닐메탄술포닐메틸, 3-트리플루오로메톡시-페닐메탄술포닐메틸, 4-플루오로-2-트리플루오로메톡시-페닐메탄술포닐메틸, 2-플루오로-6-트리플루오로메틸-페닐메탄술포닐메틸, 3-클로로-페닐메탄술포닐메틸, 2-플루오로-페닐메탄술포닐메틸, 2-트리플루오로-페닐메탄술포닐메틸, 2-시아노-페닐메탄술포닐메틸, 4-tert-부틸-페닐메탄술포닐메틸, 2-플루오로-3-메틸-페닐메탄술포닐메틸, 3-플루오로-페닐메탄술포닐메틸, 4-플루오로-페닐메탄술포닐메틸, 2-클로로-페닐메탄술포닐메틸, 2,5-디플루오로-페닐메탄술포닐메틸, 2,6-디플루오로-페닐메탄술포닐메틸, 2,5-디클로로-페닐메탄술포닐메틸, 3,4-디클로로-페닐메탄술포닐메틸, 2-(1,1-디플루오로-메톡시)-페닐메탄술포닐메틸, 2-시아노-페닐메탄술포닐메틸, 3-시아노-페닐메탄술포닐메틸, 2-트리플루오로메톡시-페닐메탄술포닐메틸, 2,3-디플루오로-페닐메탄술포닐메틸, 2,5-디플루오로-페닐메탄술포닐메틸, 비페닐-2-일메탄술포닐메틸, 시클로헥실메틸, 3-플루오로-페닐메탄술포닐메틸, 3,4-디플루오로-페닐메탄술포닐메틸, 2,4-디플루오로-페닐메탄술포닐메틸, 2,4,6-트리플루오로-페닐메탄술포닐메틸, 2,4,5-트리플루오로-페닐메탄술포닐메틸, 2,3,4-트리플루오로-페닐메탄술포닐메틸, 2,3,5-트리플루오로-페닐메탄술포닐메틸, 2,5,6-트리플루오로-페닐메탄술포닐메틸, 2-클로로-5-트리플루오로메틸페닐메탄술포닐메틸, 2-메틸-프로판-1-술포닐, 2-플루오로-3-트리플루오로메틸페닐메탄술포닐메틸, 2-플루오로-4-트리플루오로메틸페닐메탄술포닐메틸, 2-플루오로-5-트리플루오로메틸페닐메탄술포닐메틸, 4-플루오로-3-트리플루오로메틸페닐메탄술포닐메틸, 2-메톡시-페닐메탄술포닐메틸, 비스-트리플루오로메틸-페닐메탄술포닐메틸, 4-디플루오로메톡시-페닐메탄술포닐메틸, 2-디플루오로메톡시-페닐메탄술포닐메틸, 3-디플루오로메톡시-페닐메탄술포닐메틸, 2,6-디클로로-페닐메탄술포닐메틸, 비페닐-4-일메탄술포닐메틸, 3,5-디메틸-이속사졸-4-일메탄술포닐메틸, 5-클로로-티오펜-2-일메탄술포닐메틸, 2-[4-(1,1-디플루오로-메톡시)-벤젠술포닐]-에틸, 2-[2-(l,1-디플루오로-메톡시)-벤젠술포닐]-에틸, 2-[3-(1,1-디플루오로-메톡시)-벤젠술포닐]-에틸, 2-(4-트리플루오로메톡시-벤젠술포닐)-에틸, 2-(3-트리플루오로메톡시-벤젠술포닐)-에틸, 2-(2-트리플루오로메톡시-벤젠술포닐)-에틸, (시아노메틸-메틸-카르바모일)-메틸, 부틸, 비페닐-3-일메틸, 2-옥소-2-피롤리딘-1-일-에틸, 2-벤젠술포닐-에틸, 이소부틸술파닐메틸, 2-페닐술파닐-에틸, 시클로헥실메탄술포닐메틸, 2-시클로헥실-에탄술포닐, 벤질, 나프탈렌-2-일, 벤질술파닐메틸, 2-트리플루오로메틸-벤질술파닐메틸, 5-브로모-티오펜-2-일메틸, 페닐술파닐-에틸 및 시클로프로필메탄술포닐메틸로부터 선택됨을 특징으로 하는 화합물.The compound of claim 3, wherein R 3 is thiophene-2-sulfonylmethyl, 3-chloro-2-fluoro-phenylmethanesulfonylmethyl, benzenesulfonylmethyl, phenylmethanesulfonylmethyl, 2- (1,1 -Difluoro-methoxy) -phenylmethanesulfonylmethyl, 2-benzenesulfonyl-ethyl, 2- (pyridine-2-sulfonyl) -ethyl, 2- (pyridine-4-sulfonyl) -ethyl, 2 -Phenylmethanesulfonyl-ethyl, oxy-pyridin-2-ylmethanesulfonylmethyl, prop-2-ene-1-sulfonylmethyl, 4-methoxy-phenylmethanesulfonylmethyl, p -tolylmethanesulfonyl Methyl, 4-chloro-phenylmethanesulfonylmethyl, o -tolylmethanesulfonylmethyl, 3,5-dimethyl-phenylmethanesulfonylmethyl, 4-trifluoromethyl-phenylmethanesulfonylmethyl, 4-trifluorome Methoxy-phenylmethanesulfonylmethyl, 2-bromo-phenylmethanesulfonylmethyl, pyridin-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-ylmethanesulfonylmethyl, naphthalene 2-ylmethanesulfonylmethyl, 3-methyl-phenylmethanesulfonylmethyl, 3-trifluoromethyl -Phenylmethanesulfonylmethyl, 3-trifluoromethoxy-phenylmethanesulfonylmethyl, 4-fluoro-2-trifluoromethoxy-phenylmethanesulfonylmethyl, 2-fluoro-6-trifluoromethyl- Phenylmethanesulfonylmethyl, 3-chloro-phenylmethanesulfonylmethyl, 2-fluoro-phenylmethanesulfonylmethyl, 2-trifluoro-phenylmethanesulfonylmethyl, 2-cyano-phenylmethanesulfonylmethyl, 4- tert -butyl-phenylmethanesulfonylmethyl, 2-fluoro-3-methyl-phenylmethanesulfonylmethyl, 3-fluoro-phenylmethanesulfonylmethyl, 4-fluoro-phenylmethanesulfonylmethyl, 2 -Chloro-phenylmethanesulfonylmethyl, 2,5-difluoro-phenylmethanesulfonylmethyl, 2,6-difluoro-phenylmethanesulfonylmethyl, 2,5-dichloro-phenylmethanesulfonylmethyl, 3 , 4-dichloro-phenylmethanesulfonylmethyl, 2- (1,1-difluoro-methoxy) -phenylmethanesulfonylmethyl, 2-cyano-phenylmethanesulfonylmethyl, 3-cyano-phenylmethane Sulfonylmethyl, 2-trifluoromethok -Phenylmethanesulfonylmethyl, 2,3-difluoro-phenylmethanesulfonylmethyl, 2,5-difluoro-phenylmethanesulfonylmethyl, biphenyl-2-ylmethanesulfonylmethyl, cyclohexylmethyl, 3-fluoro-phenylmethanesulfonylmethyl, 3,4-difluoro-phenylmethanesulfonylmethyl, 2,4-difluoro-phenylmethanesulfonylmethyl, 2,4,6-trifluoro-phenyl Methanesulfonylmethyl, 2,4,5-trifluoro-phenylmethanesulfonylmethyl, 2,3,4-trifluoro-phenylmethanesulfonylmethyl, 2,3,5-trifluoro-phenylmethanesulphate Ponylmethyl, 2,5,6-trifluoro-phenylmethanesulfonylmethyl, 2-chloro-5-trifluoromethylphenylmethanesulfonylmethyl, 2-methyl-propane-1-sulfonyl, 2-fluoro- 3-trifluoromethylphenylmethanesulfonylmethyl, 2-fluoro-4-trifluoromethylphenylmethanesulfonylmethyl, 2-fluoro-5-trifluoromethylphenylmethanesulfonylmethyl, 4-fluoro-3- Trifluoromethylphenylmethanesulfonylmethyl, 2-methoxy-phenyl Tansulfonylmethyl, bis-trifluoromethyl-phenylmethanesulfonylmethyl, 4-difluoromethoxy-phenylmethanesulfonylmethyl, 2-difluoromethoxy-phenylmethanesulfonylmethyl, 3-difluoromethoxy- Phenylmethanesulfonylmethyl, 2,6-dichloro-phenylmethanesulfonylmethyl, biphenyl-4-ylmethanesulfonylmethyl, 3,5-dimethyl-isoxazol-4-ylmethanesulfonylmethyl, 5-chloro- Thiophen-2-ylmethanesulfonylmethyl, 2- [4- (1,1-difluoro-methoxy) -benzenesulfonyl] -ethyl, 2- [2- (l, 1-difluoro- Methoxy) -benzenesulfonyl] -ethyl, 2- [3- (1,1-difluoro-methoxy) -benzenesulfonyl] -ethyl, 2- (4-trifluoromethoxy-benzenesulfonyl) -Ethyl, 2- (3-trifluoromethoxy-benzenesulfonyl) -ethyl, 2- (2-trifluoromethoxy-benzenesulfonyl) -ethyl, (cyanomethyl-methyl-carbamoyl) -methyl , Butyl, biphenyl-3-ylmethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 2-benzenesulfonyl-ethyl, isobutylsulfanylmethyl, 2-phenylsulfanyl-ethyl, Clohexylmethanesulfonylmethyl, 2-cyclohexyl-ethanesulfonyl, benzyl, naphthalen-2-yl, benzylsulfanylmethyl, 2-trifluoromethyl-benzylsulfanylmethyl, 5-bromo-thiophen-2 -Methyl, phenylsulfanyl-ethyl and cyclopropylmethanesulfonylmethyl. 제 4항에 있어서, R4가 페닐아미노, 벤질아미노, 4-페녹시-페닐아미노, 페네틸아미노, 3-페닐-프로필아미노, 모르폴린-4-일, 시클로헥실아미노, 나프탈렌-1- 일메틸-아미노, 피리딘-3-일아미노, 6-메톡시-피리딘-3-일아미노, 디이소부틸아미노, 4-니트로-벤질아미노, 2-티오펜-2-일-에틸아미노, 3-페녹시-페닐아미노, 시아노메틸-아미노, (피리딘-3-일메틸)-아미노, 5,6,7,8-테트라히드로-나프탈렌-1-일아미노, 2-피리딘-2-일-에틸아미노, 2,3-디히드로-인돌-1-일, 3,4-디히드로-lH-이소퀴놀린-2-일, 시클로헥실메틸-아미노, 2-메톡시-벤질아미노, l-페닐-에틸아미노, (피리딘-4-일메틸)-아미노, 벤질-메틸-아미노, 3-니트로-벤질아미노, 4-메톡시-페닐아미노, 3-카르바모일-페닐아미노, 4-카르바모일-페닐아미노, (테트라히드로-푸란-2-일메틸)-아미노, 3,4-디히드로-2H-퀴놀린-1-일, 디메틸아미노, 부틸메틸아미노, 디이소프로필아미노, 프로필메틸아미노, 1-(벤조옥사졸-2-카르보닐)-프로필아미노 및 이소부틸메틸아미노로부터 선택됨을 특징으로 하는 화합물.The compound of claim 4, wherein R 4 is phenylamino, benzylamino, 4-phenoxy-phenylamino, phenethylamino, 3-phenyl-propylamino, morpholin-4-yl, cyclohexylamino, naphthalen-1-yl Methyl-amino, pyridin-3-ylamino, 6-methoxy-pyridin-3-ylamino, diisobutylamino, 4-nitro-benzylamino, 2-thiophen-2-yl-ethylamino, 3-phenoxy Cy-phenylamino, cyanomethyl-amino, (pyridin-3-ylmethyl) -amino, 5,6,7,8-tetrahydro-naphthalen-1-ylamino, 2-pyridin-2-yl-ethylamino , 2,3-dihydro-indol-1-yl, 3,4-dihydro-l H -isoquinolin-2-yl, cyclohexylmethyl-amino, 2-methoxy-benzylamino, l-phenyl-ethyl Amino, (pyridin-4-ylmethyl) -amino, benzyl-methyl-amino, 3-nitro-benzylamino, 4-methoxy-phenylamino, 3-carbamoyl-phenylamino, 4-carbamoyl-phenyl amino, (tetrahydro-furan-2-ylmethyl) -amino, 3,4-dihydro -2 H-quinoline-1 , Dimethylamino, butyl methylamino, di-isopropylamino, methyl-amino-1- (benzoxazole-2-carbonyl) - propylamino and isobutyl compound as claimed selected from methylamino. 제 5항에 있어서, 2-부틸-N-시아노메틸-N'-페닐-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-페닐-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-페네틸-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-피리딘-4-일메틸-말론아미드,N-[1-(벤조옥사졸-2-카르보닐)-3-페닐-프로필]-N'-벤질-2-시클로헥실메틸-말론아미드,N-시아노메틸-N'-시클로헥실-2-시클로헥실메틸-말론아미드,N-벤질-N'-시아노메틸-2-시클로헥실메틸-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-(4-페녹시-페닐)-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-(3-페닐-프로필)-말론아미드,N-시아노메틸-2-시클로헥실메틸-3-모르폴린-4-일-3-옥소-프로피온아미드,N-시아노메틸-2-시클로헥실메틸-N'-나프탈렌-1-일메틸-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-피리딘-3-일-말론아미드,N-시아노메틸-2-시클로헥실메틸-N',N'-디이소부틸-말론아미드,N-시아노메틸-2-시클로헥실메틸-N',N'-디이소프로필-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-(6-메톡시-피리딘-3-일)-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-(2-티오펜-2-일-에틸)-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-(3-페녹시-페닐)-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-(4-니트로-벤질)-말론아미드,N,N'-비스-시아노메틸-2-시클로헥실메틸-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-(5,6,7,8-테트라히드로-나프탈렌-1-일)-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-(2-피리딘-2-일-에틸)-말론아미드,N-시아노메틸-2-시클로헥실메틸-3-(2,3-디히드로-인돌-1-일)-3-옥소-프로피온아미드,N-시아노메틸-2-시클로헥실메틸-3-(3,4-디히드로-1H-이소퀴놀린-2-일)-3-옥소-프로피온아미드,N-시아노메틸-2,N'-비스-시클로헥실메틸-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-(2-메톡시-벤질)-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-(1-페닐-에틸)-말론아미드,N-벤질-N'-시아노메틸-2-시클로헥실메틸-N-메틸-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-(3-니트로-벤질)-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-(4-메톡시-벤질)-말론아미드,N-(3-카르바모일-페닐)-N'-시아노메틸-2-시클로헥실메틸-말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-피리딘-3-일메틸-말론아미드,N-(4-카르바모일페닐)-N'-시아노메틸-2-시클로헥실메틸말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-테트라히드로푸르-2-일메틸말론아미드,N-시아노메틸-2-시클로헥실메틸-3-(3,4-디히드로-2H-퀴놀린-1-일)-3-옥소프로피온아미드,N-tert-부틸-N'-시아노메틸-2-시클로헥실메틸-N-메틸말론아미드,N-시아노메틸-2-시클로헥실메틸-N'-메틸-N'-프로필말론아미드,N-부틸-N'-시아노메틸-2-시클로헥실메틸-N-메틸말론아미드,N-시아노메틸-2-시클로헥실메틸-N',N'-디메틸말론아미드,N-벤질-N'-시아노메틸-2-(2-페닐술파닐에틸)말론아미드, 2-(2-페닐술포닐에틸)-N-벤질-N'-시아노메틸말론아미드, 2-(2-벤젠술포닐-에틸)-N-[(S)-1-(1-벤조옥사졸-2-일-메타노일)-펜틸]-N'-벤질-말론아미드 및N,N'-비스-[(S)-1-(1-벤조옥사졸-2-일-메타노일)-프로필]-2-시클로헥실메틸-말론아미드로 구성된 군으로부터 선택됨을 특징으로 하는 화합물; 또는 이의 N-산화물 유도체, 전구약물 유도체, 보호된 유도체, 개개의 이성질체 또는 이성질체들의 혼합물; 또는 상기 화합물 또는 이의 N-산화물 유도체, 전구약물 유도체, 보호된 유도체, 개개의 이성질체 또는 이성질체들의 혼합물의 약제학적으로 허용되는 염이나 용매화물.The compound of claim 5, wherein 2-butyl- N -cyanomethyl- N' -phenyl-malonamide, N -cyanomethyl-2-cyclohexylmethyl- N' -phenyl-malonamide, N -cyanomethyl- 2-cyclohexylmethyl- N' -phenethyl-malonamide, N -cyanomethyl-2-cyclohexylmethyl- N' -pyridin-4-ylmethyl-malonamide, N- [1- (benzooxazole- 2-carbonyl) -3-phenyl-propyl] - N '- benzyl-2-cyclohexylmethyl-malonamide, N - cyanomethyl - N' - cyclohexyl-2-cyclohexylmethyl-malonamide, N - Benzyl- N' -cyanomethyl-2-cyclohexylmethyl-malonamide, N -cyanomethyl-2-cyclohexylmethyl- N ' -(4-phenoxy-phenyl) -malonamide, N -cyanomethyl 2-cyclohexylmethyl- N ' -(3-phenyl-propyl) -malonamide, N -cyanomethyl-2-cyclohexylmethyl-3-morpholin-4-yl-3-oxo-propionamide, N -cyanomethyl-2-cyclohexylmethyl-N '- naphthalene-1-ylmethyl-malonamide, N-cyanomethyl-2-cyclohexylmethyl-N' - pyridin-3- - malonamide, N-cyanomethyl-2-cyclohexylmethyl-N ', N' - di-isobutyl-malonamide, N-cyanomethyl-2-cyclohexylmethyl-N ', N' - di-isopropyl Malonamide, N -cyanomethyl-2-cyclohexylmethyl- N ' -(6-methoxy-pyridin-3-yl) -malonamide, N -cyanomethyl-2-cyclohexylmethyl- N' (2-thiophen-2-yl-ethyl) -malonamide, N -cyanomethyl-2-cyclohexylmethyl- N ' -(3-phenoxy-phenyl) -malonamide, N -cyanomethyl-2 -Cyclohexylmethyl- N ' -(4-nitro-benzyl) -malonamide, N, N' -bis-cyanomethyl-2-cyclohexylmethyl-malonamide, N -cyanomethyl-2-cyclohexylmethyl N '-(5,6,7,8-tetrahydro-naphthalen-1-yl) -malonamide, N -cyanomethyl-2-cyclohexylmethyl- N '-(2-pyridin-2-yl- Ethyl) -malonamide, N -cyanomethyl-2-cyclohexylmethyl-3- (2,3-dihydro-indol-1-yl) -3-oxo-propionamide, N -cyanomethyl-2- Cyclohexylmethyl-3- (3,4-dihydro-1H- Small-2-yl) -3-oxo-propionamide, N-cyanomethyl--2, N '- bis-cyclohexylmethyl-malonamide, N-cyanomethyl-2-cyclohexylmethyl-N' - (2-methoxy-benzyl) -malonamide, N -cyanomethyl-2-cyclohexylmethyl- N ' -(1-phenyl-ethyl) -malonamide, N -benzyl- N' -cyanomethyl-2 -Cyclohexylmethyl- N -methyl-malonamide, N -cyanomethyl-2-cyclohexylmethyl- N '-(3-nitro-benzyl) -malonamide, N -cyanomethyl-2-cyclohexylmethyl- N '- (4- methoxy-benzyl) -malonamide, N - (3- carbamoyl-phenyl) - N' - cyano-2-cyclohexylmethyl-malonamide, N - cyano-methyl-2 -cyclohexyl-methyl-N '- pyridin-3-ylmethyl-malonamide, N - (4- carbamoyl-phenyl) - N' - cyano-2-cyclohexylmethyl-malonamide, N - cyanomethyl - 2-cyclohexylmethyl- N' -tetrahydrofur-2-ylmethylmalonamide, N -cyanomethyl-2-cyclohexylmethyl-3- (3,4-dihydro-2 H -quinoline-1- Yl) -3-oxopropionamide, N - tert -butyl- N' -cyanomethyl-2-cyclohexylmethyl- N -methylmalonamide, N -cyanomethyl-2-cyclohexylmethyl- N' -methyl - N '- propyl malonamide, N - butyl - N' - cyano-2-methyl-cyclohexyl - N - methyl-malonamide, N - cyano-2-cyclohexylmethyl - N ', N' - dimethyl Malonamide, N -benzyl- N' -cyanomethyl-2- (2-phenylsulfanylethyl) malonamide, 2- (2-phenylsulfonylethyl) -N -benzyl- N' -cyanomethylmalonamide , 2- (2-benzenesulfonyl-ethyl) - N - [(S) -1- (1- 2-yl-methanone alkanoyl) - pentyl] - N '- benzyl-malonamide and N, N' -bis-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propyl] -2-cyclohexylmethyl-malonamide; Or N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers or mixtures of isomers thereof; Or a pharmaceutically acceptable salt or solvate of said compound or an N-oxide derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomers thereof. 약제학적으로 허용되는 부형제와 함께, 치료적 유효량의 제 1항의 화합물을 포함하는 약제학적 조성물.A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 together with a pharmaceutically acceptable excipient. 치료적 유효량의 제 1항의 화합물 또는 이의 N-산화물 유도체, 개개의 이성질체 또는 이성질체들의 혼합물; 또는 상기 화합물 또는 이의 N-산화물 유도체, 전구약물 유도체, 보호된 유도체, 개개의 이성질체 또는 이성질체들의 혼합물의 약제학적으로 허용되는 염이나 용매화물을 동물에게 투여하는 것을 포함하여, 카텝신 S의 억제가 질병의 병리 및/또는 증상을 예방시키거나, 억제시키거나, 개선시켜주는 동물의 질병을 치료하는 방법.A therapeutically effective amount of a compound of claim 1 or an N-oxide derivative thereof, an individual isomer or a mixture of isomers; Or inhibiting cathepsin S, including administering to the animal a pharmaceutically acceptable salt or solvate of said compound or an N-oxide derivative, prodrug derivative, protected derivative, individual isomer or mixture of isomers thereof. A method of treating a disease in an animal that prevents, inhibits or ameliorates the pathology and / or symptoms of the disease. 카텝신 S의 활성이 질병의 병리학 및/또는 증상학에 기여하는 동물의 질병을 치료하기 위한 약제 제조에서 제 1항의 화합물의 용도.Use of the compound of claim 1 in the manufacture of a medicament for treating a disease in an animal in which the activity of cathepsin S contributes to the pathology and / or symptom of the disease. 하기 단계를 포함하여 화학식(I)의 화합물을 제조하는 방법:A process for preparing a compound of formula (I) comprising the following steps: (A) 화학식 2의 화합물을 화학식 NH2CR1R2X2의 화합물과 반응시키는 단계 (여기에서, R1, R2, R3, R4및 X2은 발명의 개요에서 화학식(I)에 대하여 정의된 바와 같다):(A) reacting a compound of Formula 2 with a compound of Formula NH 2 CR 1 R 2 X 2 , wherein R 1 , R 2 , R 3 , R 4 and X 2 are represented by Formula (I) As defined for): ; 또는 ; or (B) 화학식 2의 화합물을 화학식 NH2X3의 화합물과 반응시키는 단계 (여기에서, R3, R4및 X3은 발명의 개요에서 화학식(I)에 대하여 정의된 바와 같다);(B) reacting a compound of Formula 2 with a compound of Formula NH 2 X 3 , wherein R 3 , R 4 and X 3 are as defined for Formula (I) in the Summary of the Invention; (C) 화학식(I)의 화합물을 약제학적으로 허용되는 염으로 선택적으로 전환시키는 단계;(C) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt; (D) 염 형태의 화학식(I)의 화합물을 염 이외의 형태로 선택적으로 전환시키는 단계;(D) optionally converting the compound of formula (I) in salt form to a form other than salt; (E) 산화되지 않은 형태의 화학식(I)의 화합물을 약제학적으로 허용되는N-산화물로 선택적으로 전환시키는 단계;(E) selectively converting a compound of formula (I) in unoxidized form into a pharmaceutically acceptable N -oxide; (F)N-산화물 형태의 화학식(I)의 화합물을 이의 산화되지 않은 형태로 선택적으로 전환시키는 단계;(F) selectively converting the compound of formula (I) in N -oxide form into its non-oxidized form; (G) 화학식(I)의 화합물의 개개의 이성질체를 이성질체들의 혼합물로부터 선택적으로 분리시키는 단계;(G) selectively separating the individual isomers of the compound of formula (I) from the mixture of isomers; (H) 유도체화되지 않은 화학식(I)의 화합물을 약제학적으로 허용되는 전구약물 유도체로 선택적으로 전환시키는 단계; 및(H) optionally converting a non-derivatized compound of formula (I) into a pharmaceutically acceptable prodrug derivative; And (I) 화학식(I)의 화합물의 전구약물 유도체를 이의 유도체화되지 않은 형태로 선택적으로 전환시키는 단계.(I) optionally converting a prodrug derivative of the compound of formula (I) to its underivatized form.
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