KR100768021B1 - Cis-2,4,5-triaryl-imidazolines - Google Patents
Cis-2,4,5-triaryl-imidazolines Download PDFInfo
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- KR100768021B1 KR100768021B1 KR1020057024295A KR20057024295A KR100768021B1 KR 100768021 B1 KR100768021 B1 KR 100768021B1 KR 1020057024295 A KR1020057024295 A KR 1020057024295A KR 20057024295 A KR20057024295 A KR 20057024295A KR 100768021 B1 KR100768021 B1 KR 100768021B1
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Abstract
본 발명은 본원에 기재된 명칭부를 갖는 하기 화학식 I 에 따른 화합물, 및 이의 약학적으로 허용가능한 염 및 에스테르를 제공한다:The present invention provides a compound according to formula (I) having the names described herein, and pharmaceutically acceptable salts and esters thereof:
[화학식 I][Formula I]
상기 화합물은 MDM2 단백질과 p53유사 펩티드의 상호작용을 억제하고, 항증식 활성을 갖는다.The compound inhibits the interaction of p53-like peptide with MDM2 protein and has antiproliferative activity.
Description
본 발명은 하기 화학식 I 의 화합물에서 선택되는 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염에 관한 것이다:The present invention relates to one or more compounds selected from compounds of formula (I) or pharmaceutically acceptable salts thereof:
[식 중, X1, X2, X3, 및 R 은 본 출원에 기재되어 있음]. 상기 화합물은 MDM2 단백질과 p-53유사 펩티드의 상호작용을 억제한다고 여겨지며, 항증식(anti-proliferative) 활성을 갖는다.Wherein X 1 , X 2 , X 3 , and R are described in this application. The compound is believed to inhibit the interaction of MDM2 protein with a p-53 like peptide and has anti-proliferative activity.
p53 은 암 발생의 예방에 중심적인 역할을 하는 종양 억제 단백질이다. 이는 세포의 통합성을 호위하고, 성장 정지 또는 세포자멸사 (apoptosis)를 도입함으로써 세포들 중 영구 손상된 클론의 전파를 방지한다. 분자 수준에서, p53 은 세포 주기 및 세포자멸사의 조절에 관련되는 유전자 패널을 활성화할 수 있는 전사 인자이다. p53 은, 세포 수준에서 MDM2 에 의해 엄격히 조절되는 강력한 세포 주기 억제제이다. MDM2 및 p53 은 피드백 제어 루프를 형성한다. MDM2 는 p53 을 결합하고 p53 조절 유전자를 전사활성화하는(transactivating) 그의 능력을 억제할 수 있다. 또한, MDM2 는 p53 의 유비퀴틴 의존성 분해를 중재한다. p53 은 MDM2 유전자의 발현을 활성화할 수 있고, 따라서, MDM2 단백질의 세포 수준을 상승시킨다. 상기 피드백 제어 루프는, 정상적으로 증식하는 세포에서는 MDM2 및 p53 모두가 낮은 수준으로 유지되는 것을 보장한다. 또한, MDM2 는, 세포 주기 조절에서 중심적인 역할을 하는 E2F 에 대한 보조인자이다.p53 is a tumor suppressor protein that plays a central role in the prevention of cancer development. It escorts the integrity of the cells and prevents the propagation of permanently damaged clones among the cells by introducing growth arrest or apoptosis. At the molecular level, p53 is a transcription factor capable of activating a panel of genes involved in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor that is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can inhibit its ability to bind p53 and transactivate p53 regulatory genes. MDM2 also mediates the ubiquitin dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. The feedback control loop ensures that both MDM2 and p53 are kept at low levels in normally proliferating cells. MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation.
MDM2 대 p53 (E2F)의 비는 많은 암에서 조절곤란이다. 예를 들어, p16INK4/p19ARF 유전자 자리 (locus)에서 빈번히 발생하는 분자 결함은 MDM2 단백질 분해에 영향을 미치는 것으로 나타났다. 야생형 p53 을 갖는 종양 세포에서 MDM2-p53 상호작용의 억제는, p53 의 축적, 세포 주기 정지 및/또는 세포자멸사에 이르게 할 것이다. 따라서, MDM2 안타고니스트는 단일 작용제로서 또는 광범위한 다른 항종양 요법과 조합하여 암 요법에 대한 신규한 접근법을 제공할 수 있다. 상기 전략의 실행가능성은 MDM2-p53 상호작용의 억제를 위한 상이한 거대분자성 수단 (예를 들어, 항체, 안티센스 올리고뉴클레오티드, 펩티드)의 사용에 의해 나타났다. 또한, MDM2 는 p53 으로서의 보존성 결합 구역을 통해 E2F 와 결합하고, 사이클린 A 의 E2F 의존성 전사를 활성화하며, 이는 MDM2 안타고니스트가 p53 돌연변이 세포에서 효과를 가질 수 있다는 것을 시사한다.The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. For example, frequently occurring molecular defects in the p16INK4 / p19ARF locus have been shown to affect MDM2 proteolysis. Inhibition of MDM2-p53 interaction in tumor cells with wild type p53 will lead to accumulation of p53, cell cycle arrest and / or apoptosis. Thus, MDM2 antagonists may provide a novel approach to cancer therapy as a single agent or in combination with a wide variety of other antitumor therapies. The feasibility of this strategy has been demonstrated by the use of different macromolecular means (eg, antibodies, antisense oligonucleotides, peptides) for the inhibition of MDM2-p53 interactions. In addition, MDM2 binds to E2F via a conservative binding zone as p53 and activates E2F dependent transcription of cyclin A, suggesting that MDM2 antagonists may have effects in p53 mutant cells.
[Wells 등, J. Org. Chem., 1972, 37, 2158∼2161]은 이미다졸린의 합성을 보고한다. [Hunter 등, Can. J. Chem., 1972, Vol. 50, p.669∼77]은, 화학발광에 대해 이미 연구되어있는 (McCapra 등, Photochem. and Photobiol. 1965, 4, 1111∼1121) 아마린 및 이소아마린 화합물의 제조를 보고한다. [Zupanc 등, Bull. Soc. Chem. & Tech. (유고슬라비아) 1980∼81, 27/28, 71∼80]은 EDTA 유도체의 제조에 있어 출발 물질로서 트리아릴 이미다졸린의 사용을 보고한다. Matsumoto 에게 허여된 EP 363 061 은 면역조절제로서 유용한 이미다졸린 유도체를 보고한다. 상기 화합물은 독성이 낮은 것으로 나타났다. 류마티스 관절염, 다발성 경화증, 전신성 루푸스, 홍반, 및 류마티스 열의 치료 및/또는 예방이 관련되었다. WO 00/78725 (Choueiry 등)은, 치환된 아미딘 화합물의 제조 방법을 보고하며, 이미다졸린형 화합물이 당뇨병, 또는 손상된 글루코스 폐기를 수반하는 관련 질환의 치료에 유용할 수 있음을 나타낸다.Wells et al., J. Org. Chem., 1972, 37, 2158-2161, report the synthesis of imidazolines. Hunter et al., Can. J. Chem., 1972, Vol. 50, p. 669-77, report the preparation of amarine and isomarin compounds already studied for chemiluminescence (McCapra et al., Photochem. And Photobiol. 1965, 4, 1111-1121). Zupanc et al., Bull. Soc. Chem. & Tech. (Yugoslavia) 1980-81, 27/28, 71-80 report the use of triaryl imidazolines as starting materials in the preparation of EDTA derivatives. EP 363 061 to Matsumoto reports imidazoline derivatives useful as immunomodulators. The compound was shown to be low toxicity. Treatment and / or prevention of rheumatoid arthritis, multiple sclerosis, systemic lupus, erythema, and rheumatic fever were involved. WO 00/78725 (Choueiry et al.) Reports a method for preparing substituted amidine compounds and indicates that imidazoline-type compounds may be useful for the treatment of diabetes or related diseases involving impaired glucose discard.
본 발명은 하기 화학식 I 의 화합물에서 선택되는 하나 이상의 화합물, 또는 이의 약학적으로 허용가능한 염 또는 에스테르를 제공한다:The present invention provides one or more compounds selected from compounds of formula (I), or pharmaceutically acceptable salts or esters thereof:
[화학식 I][Formula I]
[식 중,[In the meal,
X1 및 X2 는 할로겐이고;X 1 and X 2 are halogen;
X3 는 저급 알콕시이고;X 3 is lower alkoxy;
R 은 하기로 이루어진 군에서 선택되며:R is selected from the group consisting of:
상기에서,In the above,
R1 은 하기로 이루어진 군에서 선택되고:R 1 is selected from the group consisting of:
N-저급 알킬,N-lower alkyl,
비치환 헤테로환, 및Unsubstituted heterocyclic ring, and
하기로 이루어진 군에서 선택되는 하나 이상의 치환체에 의해 치환된 헤테로환: Heterocycle substituted by one or more substituents selected from the group consisting of:
NH2, NH-C(O)-저급 알킬, C(O)-저급 알킬, C(O)-저급 알콕시, 옥소, 헤테로환, 및 히드록시에 의해 치환된 저급 알킬;Lower alkyl substituted by NH 2 , NH—C (O) -lower alkyl, C (O) -lower alkyl, C (O) -lower alkoxy, oxo, heterocycle, and hydroxy;
R2 는 수소, 메틸 및 저급 알콕시에서 선택되고;R 2 is selected from hydrogen, methyl and lower alkoxy;
R3 는 하기로 이루어진 군에서 선택되고:R 3 is selected from the group consisting of:
헤테로아릴, Heteroaryl,
헤테로환, Heterocycle,
R7 로 치환된 저급 알킬, Lower alkyl substituted with R 7 ,
아릴, Aryl,
저급 알콕시, 및 Lower alkoxy, and
저급 알킬;Lower alkyl;
R4 는 하기로 이루어진 군에서 선택되고:R 4 is selected from the group consisting of:
C(O)-저급 알콕시, C (O) -lower alkoxy,
저급 알콕시, Lower alkoxy,
CH2-N-저급 알킬, CH 2 -N-lower alkyl,
CH2-헤테로환, CH 2 -heterocycle,
옥소에 의해 치환된 CH2-헤테로환, CH 2 -heterocyclic substituted by oxo,
아릴, Aryl,
NH-C(S)-N-저급 알킬, NH-C (S) -N-lower alkyl,
NH-C(S)-N-아릴, NH-C (S) -N-aryl,
NH-C(O)-R8, NH-C (O) -R 8 ,
C(O)Rl6 에 의해 치환된 N-알킬, 및N-alkyl substituted by C (O) R l6 , and
트리플루오로메틸; Trifluoromethyl;
R5 는 하기로 이루어진 군에서 선택되고:R 5 is selected from the group consisting of:
옥소, Oxo,
헤테로아릴, Heteroaryl,
저급 알콕시 및 플루오로에서 선택되는 치환체에 의해 치환된 아릴, Aryl substituted by a substituent selected from lower alkoxy and fluoro,
C(S)-N-저급 알킬, C (S) -N-lower alkyl,
C(S)-N-아릴, C (S) -N-aryl,
C(O)-CH2-R12, C (O) -CH 2 -R 12 ,
C(O)-R13, C (O) -R 13 ,
SO2-Rl4 및 SO 2 -R l4 and
R15 및 C(O)-R16 에서 선택되는 치환체에 의해 치환된 저급 알킬; Lower alkyl substituted by a substituent selected from R 15 and C (O) —R 16 ;
R6 은 하기로 이루어진 군에서 선택되고:R 6 is selected from the group consisting of:
-N-저급 알킬에 의해 치환된 저급 알킬, Lower alkyl substituted by -N-lower alkyl,
헤테로환에 의해 치환된 저급 알킬, Lower alkyl substituted by heterocycle,
하기에서 선택되는 1 또는 2개 치환체에 의해 치환된 헤테로환에 의해 치환된 저급 알킬:Lower alkyl substituted by heterocycle substituted by one or two substituents selected from:
저급 알킬, 히드록실에 의해 치환된 저급 알킬, 저급 알콕시에 의해 치환된 저급 알킬, 및 옥소; Lower alkyl, lower alkyl substituted by hydroxyl, lower alkyl substituted by lower alkoxy, and oxo;
R7 은 하기로 이루어진 군에서 선택되고:R 7 is selected from the group consisting of:
시아노, Cyano,
히드록시, Hydroxy,
저급 알콕시, Lower alkoxy,
헤테로아릴, Heteroaryl,
헤테로환, Heterocycle,
옥소에 의해 치환된 헤테로환, Heterocycle substituted by oxo,
N-저급 알킬; 및 N-lower alkyl; And
SO2NH2, 저급 알콕시 및 히드록시로 이루어진 군에서 선택되는 치환체에 의해 치환된 아릴; Aryl substituted with a substituent selected from the group consisting of SO 2 NH 2 , lower alkoxy and hydroxy;
R8 은 하기로 이루어진 군에서 선택되고:R 8 is selected from the group consisting of:
N-저급 알킬, N-lower alkyl,
헤테로환, Heterocycle,
옥소, C(O)-NH2 및 C(O)-NH-저급 알킬로 이루어진 군에서 선택되는 치환체에 의해 치환된 헤테로환, Heterocycle substituted by a substituent selected from the group consisting of oxo, C (O) -NH 2 and C (O) -NH-lower alkyl,
CH2-R9, 및 CH 2 -R 9 , and
CH2-R10; CH 2 -R 10 ;
R9 은 하기로 이루어진 군에서 선택되고:R 9 is selected from the group consisting of:
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
히드록시 및 저급 알콕시에서 선택되는 치환체에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by substituents selected from hydroxy and lower alkoxy,
C(O)-NH-저급 알콕시, C (O) -NH-lower alkoxy,
C(O)-NH-벤질옥시, C (O) -NH-benzyloxy,
트리플루오로메틸 또는 히드록시에서 선택되는 치환체에 의해 치환된 C(O)-헤테로환, 및 C (O) -heterocycle substituted by a substituent selected from trifluoromethyl or hydroxy, and
C(O)-NH-R11; C (O) —NH—R 11 ;
R10 은 하기에서 선택되고: R 10 is selected from:
헤테로환, 및 Heterocycle, and
하기로 이루어진 군에서 선택되는 하나 이상의 기에 의해 치환된 헤테로환: Heterocycles substituted by one or more groups selected from the group consisting of:
C(O)-저급 알킬, C(O)-NH2, C(O)-N-저급 알킬, 히드록시에 의해 치환된 저급 알킬, 히드록시, 저급 알콕시 및 옥소; C (O) -lower alkyl, C (O) -NH 2 , C (O) -N-lower alkyl, lower alkyl substituted by hydroxy, hydroxy, lower alkoxy and oxo;
R11 은 하기에서 선택되고:R 11 is selected from:
저급 알킬, 및 Lower alkyl, and
하기로 이루어진 군에서 선택되는 치환체에 의해 치환된 저급 알킬:Lower alkyl substituted by a substituent selected from the group consisting of:
알콕시, 저급 알킬에 의해 치환된 헤테로아릴, 시아노, 및 트리플루오로메틸; Heteroaryl, cyano, and trifluoromethyl substituted by alkoxy, lower alkyl;
R12 은 하기로 이루어진 군에서 선택되고:R 12 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
히드록시 및 저급 알콕시에서 선택되는 치환체에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by substituents selected from hydroxy and lower alkoxy,
헤테로아릴, 및 Heteroaryl, and
R17 에 의해 치환된 헤테로환; Heterocycle substituted by R 17 ;
R13 은 하기로 이루어진 군에서 선택되고:R 13 is selected from the group consisting of:
헤테로아릴, Heteroaryl,
저급 알킬, 아릴 및 할로겐으로 이루어진 군에서 선택되는 1 또는 2개 치환체에 의해 치환된 헤테로아릴, Heteroaryl substituted by one or two substituents selected from the group consisting of lower alkyl, aryl and halogen,
헤테로환, Heterocycle,
저급 알킬, 아릴 및 할로겐으로 이루어진 군에서 선택되는 하나 이상의 치환체에 의해 치환된 헤테로환,Heterocycles substituted by one or more substituents selected from the group consisting of lower alkyl, aryl and halogen,
C(O)-저급 알킬, C (O) -lower alkyl,
C(O)-NH2, C (O) -NH 2 ,
C(O)-N-저급 알킬, C (O) -N-lower alkyl,
옥소, 및 Oxo, and
-OC(O)CH3 으로 치환된 저급 알킬;Lower alkyl substituted with -OC (O) CH 3 ;
R14 는 하기로 이루어진 군에서 선택되고:R 14 is selected from the group consisting of:
트리플루오로메틸, Trifluoromethyl,
저급 알킬, Lower alkyl,
저급 알킬에 의해 치환된 아릴,Aryl substituted by lower alkyl,
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
저급 알콕시, 시아노, 아미노 및 트리플루오로메틸에서 선택되는 치환체에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by substituents selected from lower alkoxy, cyano, amino and trifluoromethyl,
헤테로아릴, Heteroaryl,
하기로 이루어진 군에서 선택되는 치환체에 의해 치환된 헤테로아릴:Heteroaryl substituted by a substituent selected from the group consisting of:
아미노, 할로겐, 히드록시, 옥소, C(O)-저급 알콕시, 저급 알킬 및 히드록실에 의해 치환된 저급 알킬, Lower alkyl substituted by amino, halogen, hydroxy, oxo, C (O) -lower alkoxy, lower alkyl and hydroxyl,
헤테로환, 및 Heterocycle, and
하기로 이루어진 군에서 선택되는 치환체에 의해 치환된 헤테로환:Heterocycle substituted by a substituent selected from the group consisting of:
할로겐, 히드록시, 옥소, C(O)-저급 알콕시, 저급 알킬 및 히드록실에 의해 치환된 저급 알킬; Lower alkyl substituted by halogen, hydroxy, oxo, C (O) -lower alkoxy, lower alkyl and hydroxyl;
R15 는 하기로 이루어진 군에서 선택되고:R 15 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
시아노, Cyano,
트리플루오로메틸, Trifluoromethyl,
N-저급 알킬, N-lower alkyl,
SO2-저급 알킬, SO 2 -lower alkyl,
C(O)-저급 알킬,C (O) -lower alkyl,
SO2-NH2, SO 2 -NH 2 ,
SO2-N-저급 알킬, SO 2 -N-lower alkyl,
헤테로아릴, Heteroaryl,
헤테로환; Heterocycle;
R16 은 하기로 이루어진 군에서 선택되고:R 16 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
N-저급 알콕시, N-lower alkoxy,
N-저급 알케닐, N-lower alkenyl,
N-벤질옥시, N-benzyloxy,
R18 에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by R 18 ,
헤테로환, 및 Heterocycle, and
하기로 이루어진 군에서 선택되는 1 또는 2개 치환체에 의해 치환된 헤테로환:Heterocycle substituted by one or two substituents selected from the group consisting of:
히드록시, 알콕시, 트리플루오로메틸, C(O)-저급 알킬, C(O)- NH2, C(0)-N-저급 알킬, 히드록시에 의해 치환된 저급 알킬 및 옥소; Hydroxy, alkoxy, trifluoromethyl, C (O) -lower alkyl, C (O) -NH 2 , C (0) -N-lower alkyl, lower alkyl and oxo substituted by hydroxy;
R17 은 하기로 이루어진 군에서 선택되고:R 17 is selected from the group consisting of:
C(O)-저급 알킬, C (O) -lower alkyl,
C(O)-NH2, C (O) -NH 2 ,
C(O)-N-저급 알킬, C (O) -N-lower alkyl,
히드록시, Hydroxy,
옥소, 및 Oxo, and
히드록시에 의해 치환된 저급 알킬; 및 Lower alkyl substituted by hydroxy; And
R18 은 하기로 이루어진 군에서 선택됨:R 18 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
시아노, Cyano,
트리플루오로메틸, Trifluoromethyl,
헤테로환, 및 Heterocycle, and
히드록실].Hydroxyl].
하나의 구현예에 있어서, 본 발명은 하기 화학식 I 의 화합물에서 선택되는 하나 이상의 화합물, 또는 이의 약학적으로 허용가능한 염 또는 에스테르를 제공한다:In one embodiment, the present invention provides one or more compounds selected from compounds of formula I, or a pharmaceutically acceptable salt or ester thereof:
[화학식 I][Formula I]
[식 중,[In the meal,
X1 및 X2 는 할로겐이고; X 1 and X 2 are halogen;
X3 는 저급 알콕시이고; X 3 is lower alkoxy;
R 은 하기로 이루어진 군에서 선택되고:R is selected from the group consisting of:
상기에서,In the above,
R1 은 하기로 이루어진 군에서 선택되고:R 1 is selected from the group consisting of:
N-저급 알킬, N-lower alkyl,
비치환 헤테로환, 및 Unsubstituted heterocyclic ring, and
하기로 이루어진 군에서 선택되는 하나 이상의 치환체에 의해 치환된 헤테로환:Heterocycle substituted by one or more substituents selected from the group consisting of:
NH2, NH-C(0)-저급 알킬, C(O)-저급 알킬, C(O)-저급 알콕시, 옥소, 헤테로환, 및 히드록시에 의해 치환된 저급 알킬; Lower alkyl substituted by NH 2 , NH—C (0) -lower alkyl, C (O) -lower alkyl, C (O) -lower alkoxy, oxo, heterocycle, and hydroxy;
R2 는 수소 및 메틸에서 선택되고; R 2 is selected from hydrogen and methyl;
R3 는 하기로 이루어진 군에서 선택되고: R 3 is selected from the group consisting of:
헤테로아릴, Heteroaryl,
헤테로환, 및 Heterocycle, and
CH2-R7; CH 2 -R 7 ;
R4 는 하기로 이루어진 군에서 선택되고:R 4 is selected from the group consisting of:
C(O)-저급 알콕시, C (O) -lower alkoxy,
저급 알콕시, Lower alkoxy,
CH2-N-저급 알킬, CH 2 -N-lower alkyl,
CH2-헤테로환, CH 2 -heterocycle,
옥소에 의해 치환된 CH2-헤테로환, CH 2 -heterocyclic substituted by oxo,
아릴, Aryl,
NH-C(S)-N-저급 알킬, NH-C (S) -N-lower alkyl,
NH-C(S)-N-아릴 및 NH-C (S) -N-aryl and
NH-C(O)-R8; NH-C (O) -R 8 ;
R5 는 하기로 이루어진 군에서 선택되고:R 5 is selected from the group consisting of:
옥소, Oxo,
헤테로아릴, Heteroaryl,
저급 알콕시 및 플루오로에서 선택되는 치환체에 의해 치환된 아릴, Aryl substituted by a substituent selected from lower alkoxy and fluoro,
C(S)-N-저급 알킬, C (S) -N-lower alkyl,
C(S)-N-아릴, C (S) -N-aryl,
C(O)-CH2-Rl2, C (O) -CH 2 -R l2 ,
C(0)-R13, C (0) -R 13 ,
S02-R14, 및 S0 2 -R 14 , and
R15 및 C(0)-R16 에서 선택되는 치환체에 의해 치환된 저급 알킬; Lower alkyl substituted by a substituent selected from R 15 and C (0) -R 16 ;
R6 는 하기로 이루어진 군에서 선택되고:R 6 is selected from the group consisting of:
-N-저급 알킬에 의해 치환된 저급 알킬, Lower alkyl substituted by -N-lower alkyl,
헤테로환에 의해 치환된 저급 알킬, Lower alkyl substituted by heterocycle,
하기에서 선택되는 1 또는 2개 치환체에 의해 치환된 헤테로환에 의해 치환된 저급 알킬:Lower alkyl substituted by heterocycle substituted by one or two substituents selected from:
저급 알킬, 히드록실에 의해 치환된 저급 알킬, 저급 알콕시에 의해 치환된 저급 알킬, 및 옥소; Lower alkyl, lower alkyl substituted by hydroxyl, lower alkyl substituted by lower alkoxy, and oxo;
R7 는 하기로 이루어진 군에서 선택되고:R 7 is selected from the group consisting of:
시아노, Cyano,
히드록시, Hydroxy,
저급 알콕시, Lower alkoxy,
헤테로아릴, Heteroaryl,
헤테로환, Heterocycle,
옥소에 의해 치환된 헤테로환, Heterocycle substituted by oxo,
N-저급 알킬; 및 N-lower alkyl; And
SO2NH2, 저급 알콕시 및 히드록시로 이루어진 군에서 선택되는 치환체에 의해 치환된 아릴; Aryl substituted with a substituent selected from the group consisting of SO 2 NH 2 , lower alkoxy and hydroxy;
R8 는 하기로 이루어진 군에서 선택되고:R 8 is selected from the group consisting of:
N-저급 알킬, N-lower alkyl,
헤테로환, Heterocycle,
옥소, C(O)-NH2 및 C(O)-NH-저급 알킬로 이루어진 군에서 선택되는 치환체에 의해 치환된 헤테로환, Heterocycle substituted by a substituent selected from the group consisting of oxo, C (O) -NH 2 and C (O) -NH-lower alkyl,
CH2-R9, 및 CH 2 -R 9 , and
CH2-R10; CH 2 -R 10 ;
R9 는 하기로 이루어진 군에서 선택되고:R 9 is selected from the group consisting of:
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
히드록시 및 저급 알콕시에서 선택되는 치환체에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by substituents selected from hydroxy and lower alkoxy,
C(O)-NH-저급 알콕시, C (O) -NH-lower alkoxy,
C(O)-NH-벤질옥시, C (O) -NH-benzyloxy,
트리플루오로메틸 또는 히드록시에서 선택되는 치환체에 의해 치환된 C(O)-헤테로환, 및 C (O) -heterocycle substituted by a substituent selected from trifluoromethyl or hydroxy, and
C(O)-NH-R11; C (O) —NH—R 11 ;
R10 는 하기에서 선택되고:R 10 is selected from:
헤테로환, 및 Heterocycle, and
하기로 이루어진 군에서 선택되는 하나 이상의 기에 의해 치환된 헤테로환:Heterocycles substituted by one or more groups selected from the group consisting of:
C(O)-저급 알킬, C(O)-NH2, C(O)-N-저급 알킬, 히드록시에 의해 치환된 저급 알킬, 히드록시, 저급 알콕시 및 옥소; C (O) -lower alkyl, C (O) -NH 2 , C (O) -N-lower alkyl, lower alkyl substituted by hydroxy, hydroxy, lower alkoxy and oxo;
R11 는 하기에서 선택되고:R 11 is selected from:
저급 알킬, 및 Lower alkyl, and
하기로 이루어진 군에서 선택되는 치환체에 의해 치환된 저급 알킬:Lower alkyl substituted by a substituent selected from the group consisting of:
알콕시, 저급 알킬에 의해 치환된 헤테로아릴, 시아노, 및 트리플루오로메틸; Heteroaryl, cyano, and trifluoromethyl substituted by alkoxy, lower alkyl;
R12 는 하기로 이루어진 군에서 선택되고:R 12 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
히드록시 및 저급 알콕시에서 선택되는 치환체에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by substituents selected from hydroxy and lower alkoxy,
헤테로아릴, 및 Heteroaryl, and
R17 에 의해 치환된 헤테로환; Heterocycle substituted by R 17 ;
R13 는 하기로 이루어진 군에서 선택되고:R 13 is selected from the group consisting of:
헤테로아릴, Heteroaryl,
저급 알킬, 아릴 및 할로겐으로 이루어진 군에서 선택되는 1 또는 2개 치환체에 의해 치환된 헤테로아릴, Heteroaryl substituted by one or two substituents selected from the group consisting of lower alkyl, aryl and halogen,
헤테로환, Heterocycle,
저급 알킬, 아릴 및 할로겐으로 이루어진 군에서 선택되는 하나 이상의 치환체에 의해 치환된 헤테로환, Heterocycles substituted by one or more substituents selected from the group consisting of lower alkyl, aryl and halogen,
C(0)-저급 알킬, C (0) -lower alkyl,
C(O)-NH2, C (O) -NH 2 ,
C(O)-N-저급 알킬, 및 C (O) -N-lower alkyl, and
옥소; Oxo;
R14 는 하기로 이루어진 군에서 선택되고:R 14 is selected from the group consisting of:
트리플루오로메틸, Trifluoromethyl,
저급 알킬, Lower alkyl,
저급 알킬에 의해 치환된 아릴, Aryl substituted by lower alkyl,
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
저급 알콕시 및 시아노에서 선택되는 치환체에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by substituents selected from lower alkoxy and cyano,
헤테로아릴, Heteroaryl,
하기로 이루어진 군에서 선택되는 치환체에 의해 치환된 헤테로아릴:Heteroaryl substituted by a substituent selected from the group consisting of:
할로겐, 히드록시, 옥소, C(O)-저급 알콕시, 저급 알킬 및 히드록실에 의해 치환된 저급 알킬, Lower alkyl substituted by halogen, hydroxy, oxo, C (O) -lower alkoxy, lower alkyl and hydroxyl,
헤테로환, 및 Heterocycle, and
하기로 이루어진 군에서 선택되는 치환체에 의해 치환된 헤테로환:Heterocycle substituted by a substituent selected from the group consisting of:
할로겐, 히드록시, 옥소, C(O)-저급 알콕시, 저급 알킬 및 히드록실에 의해 치환된 저급 알킬; Lower alkyl substituted by halogen, hydroxy, oxo, C (O) -lower alkoxy, lower alkyl and hydroxyl;
R15 는 하기로 이루어진 군에서 선택되고:R 15 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
시아노, Cyano,
트리플루오로메틸, Trifluoromethyl,
N-저급 알킬, N-lower alkyl,
S02-저급 알킬, S0 2 -lower alkyl,
C(O)-저급 알킬, C (O) -lower alkyl,
SO2-NH2, SO 2 -NH 2 ,
S02-N-저급 알킬, S0 2 -N-lower alkyl,
헤테로아릴, 및 Heteroaryl, and
헤테로환; Heterocycle;
R16 는 하기로 이루어진 군에서 선택되고:R 16 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
N-저급 알콕시, N-lower alkoxy,
N-벤질옥시, N-benzyloxy,
R18 에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by R 18 ,
헤테로환, 및 Heterocycle, and
하기로 이루어진 군에서 선택되는 1 또는 2개 치환체에 의해 치환된 헤테로환:Heterocycle substituted by one or two substituents selected from the group consisting of:
히드록시, 알콕시, 트리플루오로메틸, C(O)-저급 알킬, C(O)-NH2, C(O)-N-저급 알킬, 히드록시에 의해 치환된 저급 알킬 및 옥소; Hydroxy, alkoxy, trifluoromethyl, C (O) -lower alkyl, C (O) -NH 2 , C (O) -N-lower alkyl, lower alkyl and oxo substituted by hydroxy;
R17 는 하기로 이루어진 군에서 선택되고:R 17 is selected from the group consisting of:
C(O)-저급 알킬, C (O) -lower alkyl,
C(O)-NH2, C (O) -NH 2 ,
C(O)-N-저급 알킬, C (O) -N-lower alkyl,
히드록시, Hydroxy,
옥소, 및 Oxo, and
히드록시에 의해 치환된 저급 알킬; 및 Lower alkyl substituted by hydroxy; And
R18 는 하기로 이루어진 군에서 선택됨:R 18 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
시아노, Cyano,
트리플루오로메틸, Trifluoromethyl,
헤테로환, 및 Heterocycle, and
히드록실].Hydroxyl].
바람직한 구현예에 있어서, 이미다졸린 고리의 두 수소는 서로 시스 공간배열에 있다. 상기 화합물은 라세미 형태일 수 있고, 광학 활성일 수 있다. 상기 화합물은 이성질체일 수 있다.In a preferred embodiment, the two hydrogens of the imidazoline ring are in cis space arrangement with each other. The compound may be in racemic form and may be optically active. The compound may be an isomer.
본 발명은 MDM2-p53 상호작용의 소분자 억제제인 시스-이미다졸린을 제공한 다. 무세포 및 세포기초 분석법에서, 본 발명의 화합물은 p53 유래 펩티드보다 대략 100배 더 큰 역가로 p53유사 펩티드와 MDM2 단백질의 상호작용을 억제하는 것으로 나타난다. 세포기초 분석법에서, 상기 화합물은 기계적 활성을 나타낸다. 야생형 p53 과의 암 세포 배양은, p53 단백질의 축적, p53 조절되는 p21 유전자의 유도, 및 G1 및 G2 기에서의 세포 주기 정지를 일으켜, 생체외 야생형 p53 세포에 대한 강력한 항증식 활성을 발생시킨다. 이와 대조적으로, 상기 활성은 대등하는 화합물 농도에서 돌연변이 p53 과의 암 세포에서는 관찰되지 않았다. 따라서, MDM2 안타고니스트의 활성이 그의 작용 메커니즘에 연관있는 듯하다. 이들 화합물은 강력하고 선택적인 항암제일 수 있다.The present invention provides cis-imidazoline, which is a small molecule inhibitor of the MDM2-p53 interaction. In cell-free and cell-based assays, the compounds of the invention appear to inhibit the interaction of the p53-like peptide with the MDM2 protein at approximately 100-fold greater titer than the p53-derived peptide. In cell based assays, the compound exhibits mechanical activity. Cancer cell culture with wild type p53 results in accumulation of p53 protein, induction of p53 regulated p21 gene, and cell cycle arrest in G1 and G2 phases, resulting in potent antiproliferative activity against wild type p53 cells in vitro. In contrast, this activity was not observed in cancer cells with mutant p53 at comparable compound concentrations. Thus, the activity of MDM2 antagonists seems to be related to its mechanism of action. These compounds may be potent and selective anticancer agents.
본 발명은 하기 화학식 I 의 화합물에서 선택되는 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염 또는 에스테르를 제공한다:The present invention provides one or more compounds or pharmaceutically acceptable salts or esters thereof selected from compounds of formula I:
[화학식 I][Formula I]
[식 중,[In the meal,
X1 및 X2 는 할로겐이고; X 1 and X 2 are halogen;
X3 는 저급 알콕시이고; X 3 is lower alkoxy;
R 는 하기로 이루어진 군에서 선택되고:R is selected from the group consisting of:
상기에서,In the above,
R1 은 하기로 이루어진 군에서 선택되고:R 1 is selected from the group consisting of:
N-저급 알킬, N-lower alkyl,
비치환 헤테로환, 및 Unsubstituted heterocyclic ring, and
하기로 이루어진 군에서 선택되는 하나 이상의 치환체에 의해 치환된 헤테로환:Heterocycle substituted by one or more substituents selected from the group consisting of:
NH2, NH-C(O)-저급 알킬, C(O)-저급 알킬, C(0)-저급 알콕시, 옥소, 헤테로환, 및 히드록시에 의해 치환된 저급 알킬; Lower alkyl substituted by NH 2 , NH—C (O) -lower alkyl, C (O) -lower alkyl, C (0) -lower alkoxy, oxo, heterocycle, and hydroxy;
R2 은 수소, 메틸 및 저급 알콕시에서 선택되고; R 2 is selected from hydrogen, methyl and lower alkoxy;
R3 은 하기로 이루어진 군에서 선택되고:R 3 is selected from the group consisting of:
헤테로아릴, Heteroaryl,
헤테로환, Heterocycle,
R7 로 치환된 저급 알킬, Lower alkyl substituted with R 7 ,
아릴, Aryl,
저급 알콕시, 및 Lower alkoxy, and
저급 알킬; Lower alkyl;
R4 는 하기로 이루어진 군에서 선택되고:R 4 is selected from the group consisting of:
C(O)-저급 알콕시, C (O) -lower alkoxy,
저급 알콕시, Lower alkoxy,
CH2-N-저급 알킬, CH 2 -N-lower alkyl,
CH2-헤테로환, CH 2 -heterocycle,
옥소에 의해 치환된 CH2-헤테로환, CH 2 -heterocyclic substituted by oxo,
아릴, Aryl,
NH-C(S)-N-저급 알킬, NH-C (S) -N-lower alkyl,
NH-C(S)-N-아릴, NH-C (S) -N-aryl,
NH-C(O)-R8, NH-C (O) -R 8 ,
C(O)R16 에 의해 치환된 N-알킬, 및 N-alkyl substituted by C (O) R 16 , and
트리플루오로메틸; Trifluoromethyl;
R5 는 하기로 이루어진 군에서 선택되고:R 5 is selected from the group consisting of:
옥소, Oxo,
헤테로아릴, Heteroaryl,
저급 알콕시 및 플루오로에서 선택되는 치환체에 의해 치환된 아릴, Aryl substituted by a substituent selected from lower alkoxy and fluoro,
C(S)-N-저급 알킬, C (S) -N-lower alkyl,
C(S)-N-아릴, C (S) -N-aryl,
C(O)-CH2-R12, C (O) -CH 2 -R 12 ,
C(O)-R13, C (O) -R 13 ,
SO2-R14, 및 SO 2 -R 14 , and
R15 및 C(O)-R16 에서 선택되는 치환체에 의해 치환된 저급 알킬; Lower alkyl substituted by a substituent selected from R 15 and C (O) —R 16 ;
R6 는 하기로 이루어진 군에서 선택되고:R 6 is selected from the group consisting of:
-N-저급 알킬에 의해 치환된 저급 알킬, Lower alkyl substituted by -N-lower alkyl,
헤테로환에 의해 치환된 저급 알킬, Lower alkyl substituted by heterocycle,
하기에서 선택되는 1 또는 2개 치환체에 의해 치환된 헤테로환에 의해 치환된 저급 알킬:Lower alkyl substituted by heterocycle substituted by one or two substituents selected from:
저급 알킬, 히드록실에 의해 치환된 저급 알킬, 저급 알콕시에 의해 치환된 저급 알킬, 및 옥소; Lower alkyl, lower alkyl substituted by hydroxyl, lower alkyl substituted by lower alkoxy, and oxo;
R7 는 하기로 이루어진 군에서 선택되고:R 7 is selected from the group consisting of:
시아노, Cyano,
히드록시, Hydroxy,
저급 알콕시, Lower alkoxy,
헤테로아릴, Heteroaryl,
헤테로환, Heterocycle,
옥소에 의해 치환된 헤테로환, Heterocycle substituted by oxo,
N-저급 알킬; 및 N-lower alkyl; And
SO2NH2, 저급 알콕시 및 히드록시로 이루어진 군에서 선택되는 치환체에 의해 치환된 아릴; Aryl substituted with a substituent selected from the group consisting of SO 2 NH 2 , lower alkoxy and hydroxy;
R8 는 하기로 이루어진 군에서 선택되고:R 8 is selected from the group consisting of:
N-저급 알킬, N-lower alkyl,
헤테로환, Heterocycle,
옥소, C(O)-NH2 및 C(O)-NH-저급 알킬로 이루어진 군에서 선택되는 치환체에 의해 치환된 헤테로환, Heterocycle substituted by a substituent selected from the group consisting of oxo, C (O) -NH 2 and C (O) -NH-lower alkyl,
CH2-R9, 및 CH 2 -R 9 , and
CH2-R10; CH 2 -R 10 ;
R9 는 하기로 이루어진 군에서 선택되고:R 9 is selected from the group consisting of:
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
히드록시 및 저급 알콕시에서 선택되는 치환체에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by substituents selected from hydroxy and lower alkoxy,
C(O)-NH-저급 알콕시, C (O) -NH-lower alkoxy,
C(O)-NH-벤질옥시, C (O) -NH-benzyloxy,
트리플루오로메틸 또는 히드록시에서 선택되는 치환체에 의해 치환된 C(O)-헤테로환, 및 C (O) -heterocycle substituted by a substituent selected from trifluoromethyl or hydroxy, and
C(O)-NH-R11; C (O) —NH—R 11 ;
R10 는 하기에서 선택되고:R 10 is selected from:
헤테로환, 및 Heterocycle, and
하기로 이루어진 군에서 선택되는 하나 이상의 기에 의해 치환된 헤테로환:Heterocycles substituted by one or more groups selected from the group consisting of:
C(O)-저급 알킬, C(O)-NH2, C(O)-N-저급 알킬, 히드록시에 의해 치환된 저급 알킬, 히드록시, 저급 알콕시 및 옥소; C (O) -lower alkyl, C (O) -NH 2 , C (O) -N-lower alkyl, lower alkyl substituted by hydroxy, hydroxy, lower alkoxy and oxo;
R11 는 하기에서 선택되고:R 11 is selected from:
저급 알킬, 및 Lower alkyl, and
하기로 이루어진 군에서 선택되는 치환체에 의해 치환된 저급 알킬:Lower alkyl substituted by a substituent selected from the group consisting of:
알콕시, 저급 알킬에 의해 치환된 헤테로아릴, 시아노, 및 트리플루오로메틸; Heteroaryl, cyano, and trifluoromethyl substituted by alkoxy, lower alkyl;
R12 는 하기로 이루어진 군에서 선택되고:R 12 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
히드록시 및 저급 알콕시에서 선택되는 치환체에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by substituents selected from hydroxy and lower alkoxy,
헤테로아릴, 및 Heteroaryl, and
R17 에 의해 치환된 헤테로환; Heterocycle substituted by R 17 ;
R13 는 하기로 이루어진 군에서 선택되고:R 13 is selected from the group consisting of:
헤테로아릴, Heteroaryl,
저급 알킬, 아릴 및 할로겐으로 이루어진 군에서 선택되는 1개 또는 2개 치환체에 의해 치환된 헤테로아릴, Heteroaryl substituted by one or two substituents selected from the group consisting of lower alkyl, aryl and halogen,
헤테로환, Heterocycle,
저급 알킬, 아릴 및 할로겐으로 이루어진 군에서 선택되는 하나 이상의 치환체에 의해 치환된 헤테로환,Heterocycles substituted by one or more substituents selected from the group consisting of lower alkyl, aryl and halogen,
C(O)-저급 알킬,C (O) -lower alkyl,
C(O)-NH2, C (O) -NH 2 ,
C(O)-N-저급 알킬, C (O) -N-lower alkyl,
옥소, 및 Oxo, and
-OC(O)CH3 로 치환된 저급 알킬; Lower alkyl substituted with -OC (O) CH 3 ;
R14 는 하기로 이루어진 군에서 선택되고:R 14 is selected from the group consisting of:
트리플루오로메틸, Trifluoromethyl,
저급 알킬, Lower alkyl,
저급 알킬에 의해 치환된 아릴, Aryl substituted by lower alkyl,
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
저급 알콕시, 시아노, 아미노 및 트리플루오로메틸에서 선택되는 치환체에 의해 치환된 N-저급 알킬,N-lower alkyl substituted by substituents selected from lower alkoxy, cyano, amino and trifluoromethyl,
헤테로아릴, Heteroaryl,
하기로 이루어진 군에서 선택되는 치환체에 의해 치환된 헤테로아릴:Heteroaryl substituted by a substituent selected from the group consisting of:
아미노, 할로겐, 히드록시, 옥소, C(O)-저급 알콕시, 저급 알킬 및 히드록실에 의해 치환된 저급 알킬, Lower alkyl substituted by amino, halogen, hydroxy, oxo, C (O) -lower alkoxy, lower alkyl and hydroxyl,
헤테로환, 및 Heterocycle, and
하기로 이루어진 군에서 선택되는 치환체에 의해 치환된 헤테로환:Heterocycle substituted by a substituent selected from the group consisting of:
할로겐, 히드록시, 옥소, C(O)-저급 알콕시, 저급 알킬 및 히드록실에 의해 치환된 저급 알킬; Lower alkyl substituted by halogen, hydroxy, oxo, C (O) -lower alkoxy, lower alkyl and hydroxyl;
R15 는 하기로 이루어진 군에서 선택되고:R 15 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
시아노, Cyano,
트리플루오로메틸, Trifluoromethyl,
N-저급 알킬, N-lower alkyl,
SO2-저급 알킬, SO 2 -lower alkyl,
C(O)-저급 알킬, C (O) -lower alkyl,
SO2-NH2, SO 2 -NH 2 ,
SO2-N-저급 알킬, SO 2 -N-lower alkyl,
헤테로아릴, Heteroaryl,
헤테로환; Heterocycle;
R16 는 하기로 이루어진 군에서 선택되고:R 16 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
N-저급 알콕시, N-lower alkoxy,
N-저급 알케닐, N-lower alkenyl,
N-벤질옥시, N-benzyloxy,
R18 에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by R 18 ,
헤테로환, 및 Heterocycle, and
하기로 이루어진 군에서 선택되는 1 또는 2개 치환체에 의해 치환된 헤테로환:Heterocycle substituted by one or two substituents selected from the group consisting of:
히드록시, 알콕시, 트리플루오로메틸, C(O)-저급 알킬, C(O)- NH2, C(O)-N-저급 알킬, 히드록시에 의해 치환된 저급 알킬 및 옥소; Hydroxy, alkoxy, trifluoromethyl, C (O) -lower alkyl, C (O) -NH 2 , C (O) -N-lower alkyl, lower alkyl and oxo substituted by hydroxy;
R17 는 하기로 이루어진 군에서 선택되고:R 17 is selected from the group consisting of:
C(O)-저급 알킬, C (O) -lower alkyl,
C(O)-NH2, C (O) -NH 2 ,
C(O)-N-저급 알킬, C (O) -N-lower alkyl,
히드록시, Hydroxy,
옥소, 및 Oxo, and
히드록시에 의해 치환된 저급 알킬; 및 Lower alkyl substituted by hydroxy; And
R18 는 하기로 이루어진 군에서 선택됨:R 18 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
시아노, Cyano,
트리플루오로메틸, Trifluoromethyl,
헤테로환, 및 Heterocycle, and
히드록실]. Hydroxyl].
하나의 구현예에 있어서, 본 발명은 하기 화학식 I 의 화합물에서 선택되는 하나 이상의 화합물, 또는 이의 약학적으로 허용가능한 염 또는 에스테르를 제공한다:In one embodiment, the present invention provides one or more compounds selected from compounds of formula I, or a pharmaceutically acceptable salt or ester thereof:
[화학식 I][Formula I]
[식 중,[In the meal,
X1 및 X2 는 할로겐이고; X 1 and X 2 are halogen;
X3 는 저급 알콕시이고; X 3 is lower alkoxy;
R 는 하기로 이루어진 군에서 선택되고:R is selected from the group consisting of:
상기에서From above
R1 는 하기로 이루어진 군에서 선택되고:R 1 is selected from the group consisting of:
N-저급 알킬, N-lower alkyl,
비치환 헤테로환, 및 Unsubstituted heterocyclic ring, and
하기로 이루어진 군에서 선택되는 하나 이상의 치환체에 의해 치환된 헤테로환:Heterocycle substituted by one or more substituents selected from the group consisting of:
NH2, NH-C(O)-저급 알킬, C(O)-저급 알킬, C(O)-저급 알콕시, 옥소, 헤테로환, 및 히드록시에 의해 치환된 저급 알킬; Lower alkyl substituted by NH 2 , NH—C (O) -lower alkyl, C (O) -lower alkyl, C (O) -lower alkoxy, oxo, heterocycle, and hydroxy;
R2 는 수소 및 메틸에서 선택되고; R 2 is selected from hydrogen and methyl;
R3 는 하기로 이루어진 군에서 선택되고:R 3 is selected from the group consisting of:
헤테로아릴, Heteroaryl,
헤테로환, 및 Heterocycle, and
CH2-R7; CH 2 -R 7 ;
R4 는 하기로 이루어진 군에서 선택되고:R 4 is selected from the group consisting of:
C(O)-저급 알콕시, C (O) -lower alkoxy,
저급 알콕시, Lower alkoxy,
CH2-N-저급 알킬, CH 2 -N-lower alkyl,
CH2-헤테로환, CH 2 -heterocycle,
옥소에 의해 치환된 CH2-헤테로환, CH 2 -heterocyclic substituted by oxo,
아릴, Aryl,
NH-C(S)-N-저급 알킬, NH-C (S) -N-lower alkyl,
NH-C(S)-N-아릴 및 NH-C (S) -N-aryl and
NH-C(O)-R8; NH-C (O) -R 8 ;
R5 는 하기로 이루어진 군에서 선택되고:R 5 is selected from the group consisting of:
옥소, Oxo,
헤테로아릴, Heteroaryl,
저급 알콕시 및 플루오로에서 선택되는 치환체에 의해 치환된 아릴, Aryl substituted by a substituent selected from lower alkoxy and fluoro,
C(S)-N-저급 알킬, C (S) -N-lower alkyl,
C(S)-N-아릴, C (S) -N-aryl,
C(O)-CH2-R12, C (O) -CH 2 -R 12 ,
C(O)-R13, C (O) -R 13 ,
SO2-R14, 및 SO 2 -R 14 , and
R15 및 C(O)-R16 에서 선택되는 치환체에 의해 치환된 저급 알킬; Lower alkyl substituted by a substituent selected from R 15 and C (O) —R 16 ;
R6 는 하기로 이루어진 군에서 선택되고:R 6 is selected from the group consisting of:
-N-저급 알킬에 의해 치환된 저급 알킬, Lower alkyl substituted by -N-lower alkyl,
헤테로환에 의해 치환된 저급 알킬, Lower alkyl substituted by heterocycle,
하기에서 선택되는 1 또는 2개 치환체에 의해 치환된 헤테로환에 의해 치환된 저급 알킬:Lower alkyl substituted by heterocycle substituted by one or two substituents selected from:
저급 알킬, 히드록실에 의해 치환된 저급 알킬, 저급 알콕시에 의해 치환된 저급 알킬, 및 옥소; Lower alkyl, lower alkyl substituted by hydroxyl, lower alkyl substituted by lower alkoxy, and oxo;
R7 는 하기로 이루어진 군에서 선택되고:R 7 is selected from the group consisting of:
시아노, Cyano,
히드록시, Hydroxy,
저급 알콕시, Lower alkoxy,
헤테로아릴, Heteroaryl,
헤테로환, Heterocycle,
옥소에 의해 치환된 헤테로환, Heterocycle substituted by oxo,
N-저급 알킬; 및 N-lower alkyl; And
S02NH2, 저급 알콕시 및 히드록시로 이루어진 군에서 선택되는 치환체에 의해 치환된 아릴; Aryl substituted by a substituent selected from the group consisting of SO 2 NH 2 , lower alkoxy and hydroxy;
R8 는 하기로 이루어진 군에서 선택되고:R 8 is selected from the group consisting of:
N-저급 알킬, N-lower alkyl,
헤테로환, Heterocycle,
옥소, C(O)-NH2 및 C(O)-NH-저급 알킬로 이루어진 군에서 선택되는 치환체에 의해 치환된 헤테로환, Heterocycle substituted by a substituent selected from the group consisting of oxo, C (O) -NH 2 and C (O) -NH-lower alkyl,
CH2-R9, 및 CH 2 -R 9 , and
CH2-R10; CH 2 -R 10 ;
R9 는 하기로 이루어진 군에서 선택되고:R 9 is selected from the group consisting of:
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
히드록시 및 저급 알콕시에서 선택되는 치환체에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by substituents selected from hydroxy and lower alkoxy,
C(O)-NH-저급 알콕시, C (O) -NH-lower alkoxy,
C(O)-NH-벤질옥시, C (O) -NH-benzyloxy,
트리플루오로메틸 또는 히드록시에서 선택되는 치환체에 의해 치환된 C(O)-헤테로환, 및 C (O) -heterocycle substituted by a substituent selected from trifluoromethyl or hydroxy, and
C(O)-NH-R11;C (O) —NH—R 11 ;
R10 는 하기에서 선택되고:R 10 is selected from:
헤테로환, 및 Heterocycle, and
하기로 이루어진 군에서 선택되는 하나 이상의 기에 의해 치환된 헤테로환:Heterocycles substituted by one or more groups selected from the group consisting of:
C(O)-저급 알킬, C(O)-NH2, C(O)-N-저급 알킬, 히드록시에 의해 치환된 저급 알킬, 히드록시, 저급 알콕시 및 옥소; C (O) -lower alkyl, C (O) -NH 2 , C (O) -N-lower alkyl, lower alkyl substituted by hydroxy, hydroxy, lower alkoxy and oxo;
R11 는 하기에서 선택되고:R 11 is selected from:
저급 알킬, 및 Lower alkyl, and
하기로 이루어진 군에서 선택되는 치환체에 의해 치환된 저급 알킬:Lower alkyl substituted by a substituent selected from the group consisting of:
알콕시, 저급 알킬에 의해 치환된 헤테로아릴, 시아노, 및 트리플루오로메틸; Heteroaryl, cyano, and trifluoromethyl substituted by alkoxy, lower alkyl;
R12 는 하기로 이루어진 군에서 선택되고:R 12 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
히드록시 및 저급 알콕시에서 선택되는 치환체에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by substituents selected from hydroxy and lower alkoxy,
헤테로아릴, 및 Heteroaryl, and
R17 에 의해 치환된 헤테로환; Heterocycle substituted by R 17 ;
R13 는 하기로 이루어진 군에서 선택되고:R 13 is selected from the group consisting of:
헤테로아릴, Heteroaryl,
저급 알킬, 아릴 및 할로겐으로 이루어진 군에서 선택되는 1 또는 2개 치환체에 의해 치환된 헤테로아릴, Heteroaryl substituted by one or two substituents selected from the group consisting of lower alkyl, aryl and halogen,
헤테로환, Heterocycle,
저급 알킬, 아릴 및 할로겐으로 이루어진 군에서 선택되는 하나 이상의 치환체에 의해 치환된 헤테로환, Heterocycles substituted by one or more substituents selected from the group consisting of lower alkyl, aryl and halogen,
C(O)-저급 알킬, C (O) -lower alkyl,
C(O)-NH2, C (O) -NH 2 ,
C(O)-N-저급 알킬, 및 C (O) -N-lower alkyl, and
옥소; Oxo;
R14 는 하기로 이루어진 군에서 선택되고:R 14 is selected from the group consisting of:
트리플루오로메틸, Trifluoromethyl,
저급 알킬, Lower alkyl,
저급 알킬에 의해 치환된 아릴, Aryl substituted by lower alkyl,
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
저급 알콕시 및 시아노에서 선택되는 치환체에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by substituents selected from lower alkoxy and cyano,
헤테로아릴, Heteroaryl,
하기로 이루어진 군에서 선택되는 치환체에 의해 치환된 헤테로아릴:Heteroaryl substituted by a substituent selected from the group consisting of:
할로겐, 히드록시, 옥소, C(O)-저급 알콕시, 저급 알킬 및 히드록실에 의해 치환된 저급 알킬, Lower alkyl substituted by halogen, hydroxy, oxo, C (O) -lower alkoxy, lower alkyl and hydroxyl,
헤테로환, 및 Heterocycle, and
하기로 이루어진 군에서 선택되는 치환체에 의해 치환된 헤테로환:Heterocycle substituted by a substituent selected from the group consisting of:
할로겐, 히드록시, 옥소, C(O)-저급 알콕시, 저급 알킬 및 히드록실에 의해 치환된 저급 알킬; Lower alkyl substituted by halogen, hydroxy, oxo, C (O) -lower alkoxy, lower alkyl and hydroxyl;
R15 는 하기로 이루어진 군에서 선택되고:R 15 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
시아노, Cyano,
트리플루오로메틸, Trifluoromethyl,
N-저급 알킬, N-lower alkyl,
SO2-저급 알킬, SO 2 -lower alkyl,
C(O)-저급 알킬, C (O) -lower alkyl,
S02-NH2, S0 2 -NH 2 ,
SO2-N-저급 알킬, SO 2 -N-lower alkyl,
헤테로아릴, 및 Heteroaryl, and
헤테로환; Heterocycle;
R16 는 하기로 이루어진 군에서 선택되고:R 16 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
NH2, NH 2 ,
N-저급 알킬, N-lower alkyl,
N-저급 알콕시, N-lower alkoxy,
N-벤질옥시, N-benzyloxy,
R18 에 의해 치환된 N-저급 알킬, N-lower alkyl substituted by R 18 ,
헤테로환, 및 Heterocycle, and
하기로 이루어진 군에서 선택되는 1 또는 2개 치환체에 의해 치환된 헤테로환:Heterocycle substituted by one or two substituents selected from the group consisting of:
히드록시, 알콕시, 트리플루오로메틸, C(O)-저급 알킬, C(O)-NH2, C(O)-N-저급 알킬, 히드록시에 의해 치환된 저급 알킬 및 옥소; Hydroxy, alkoxy, trifluoromethyl, C (O) -lower alkyl, C (O) -NH 2 , C (O) -N-lower alkyl, lower alkyl and oxo substituted by hydroxy;
R17 는 하기로 이루어진 군에서 선택되고:R 17 is selected from the group consisting of:
C(O)-저급 알킬, C (O) -lower alkyl,
C(O)-NH2, C (O) -NH 2 ,
C(O)-N-저급 알킬, C (O) -N-lower alkyl,
히드록시, Hydroxy,
옥소, 및 Oxo, and
히드록시에 의해 치환된 저급 알킬; 및 Lower alkyl substituted by hydroxy; And
R18 는 하기로 이루어진 군에서 선택됨:R 18 is selected from the group consisting of:
저급 알콕시, Lower alkoxy,
시아노, Cyano,
트리플루오로메틸, Trifluoromethyl,
헤테로환, 및 Heterocycle, and
히드록실].Hydroxyl].
바람직한 구현예에 있어서, 이미다졸린 고리의 두 수소는 서로 시스 공간배열에 있다. 상기 화합물은 라세미 형태일 수 있고, 광학 활성일 수 있다. 상기 화합물은 이성질체일 수 있다.In a preferred embodiment, the two hydrogens of the imidazoline ring are in cis space arrangement with each other. The compound may be in racemic form and may be optically active. The compound may be an isomer.
또다른 바람직한 구현예에 있어서, X1 및 X2 모두가 클로로이고; X3 는 에톡시 또는 이소프로폭시이다.In another preferred embodiment, both X 1 and X 2 are chloro; X 3 is ethoxy or isopropoxy.
또다른 바람직한 구현예에 있어서, 트리플루오로메틸 기는 이미다졸린 고리에 대해 파라이다. 트리플루오로메틸 기는 이미다졸린 고리에 대해 메타이다.In another preferred embodiment, the trifluoromethyl group is para to the imidazoline ring. Trifluoromethyl groups are meta to the imidazoline ring.
R 기는 C(O)-페닐-CH2-R1, C(O)-NR2R3, R4 에 의해 치환된 C(O)-피페리딘, R5 에 의해 치환된 C(O)-피페라진, 및 SO2-R6 인 것이 바람직하다.R group is C (O) -phenyl-CH 2 -R 1 , C (O) -NR 2 R 3 , C (O) -piperidine substituted by R 4 , C (O) substituted by R 5 -Piperazine, and SO 2 -R 6 .
다른 바람직한 구현예에 있어서, X1 및 X2 는 클로로이고, X3 는 에톡시 또는 이소프로폭시이고, 트리플루오로메틸 기는 이미다졸린 고리에 대해 파라이고, R 은 R4 에 의해 치환된 C(O)-피페리딘이다.In another preferred embodiment, X 1 and X 2 are chloro, X 3 is ethoxy or isopropoxy, the trifluoromethyl group is para to the imidazoline ring, and R is C substituted by R 4 (O) -piperidine.
다른 바람직한 구현예에 있어서, X1 및 X2 는 클로로이고, X3 는 에톡시 또는 이소프로폭시이고, 트리플루오로메틸 기는 이미다졸린 고리에 대해 파라이고, R 은 R5 에 의해 치환된 C(O)-피페라진이다.In another preferred embodiment, X 1 and X 2 are chloro, X 3 is ethoxy or isopropoxy, the trifluoromethyl group is para to the imidazoline ring, and R is C substituted by R 5 (O) -piperazine.
다른 바람직한 구현예에 있어서, X1 및 X2 는 클로로이고, X3 는 에톡시 또는 이소프로폭시이고, 트리플루오로메틸 기는 이미다졸린 고리에 대해 메타이고, R 은 R4 에 의해 치환된 C(O)-피페리딘이다.In another preferred embodiment, X 1 and X 2 are chloro, X 3 is ethoxy or isopropoxy, trifluoromethyl group is meta to the imidazoline ring and R is C substituted by R 4 (O) -piperidine.
다른 바람직한 구현예에 있어서, X1 및 X2 는 클로로이고, X3 는 에톡시 또는 이소프로폭시이고, 트리플루오로메틸 기는 이미다졸린 고리에 대해 메타이고, R 은 R5 에 의해 치환된 C(O)-피페라진이다.In another preferred embodiment, X 1 and X 2 are chloro, X 3 is ethoxy or isopropoxy, the trifluoromethyl group is meta to the imidazoline ring and R is C substituted by R 5 (O) -piperazine.
다른 바람직한 구현예에 있어서, R5 는 R15 에 의해 치환된 저급 알킬이다. In another preferred embodiment, R 5 is lower alkyl substituted by R 15 .
다른 바람직한 구현예에 있어서, 피페라진은 옥소, 및 R15 에 의해 치환된 저급 알킬에 의해 치환된다. In another preferred embodiment, the piperazine is substituted by oxo and lower alkyl substituted by R 15 .
다른 바람직한 구현예에 있어서, R15 는 -SO2-메틸, 히드록시 및 저급 알콕시로 이루어진 군에서 선택된다. In another preferred embodiment, R 15 is selected from the group consisting of —SO 2 -methyl, hydroxy and lower alkoxy.
"알콕시" 는 -0-알킬을 나타낸다. "Alkoxy" refers to -0-alkyl.
"알킬" 은 직쇄형 또는 분지형 포화 지방족 탄화수소를 나타낸다. "저급 알킬" 기는 C1-C6 알킬 기를 나타내고, 메틸, 에틸, 프로필, 이소프로필, 부틸, t-부틸, 2-부틸, 펜틸, 헥실 등이 포함된다. 통상적으로, 저급 알킬은 바람직하게는 C1-C4 알킬, 더욱 바람직하게는 C1-C3 알킬이다. "Alkyl" refers to a straight or branched saturated aliphatic hydrocarbon. "Lower alkyl" groups represent C1-C6 alkyl groups and include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl and the like. Typically, lower alkyl is preferably C1-C4 alkyl, more preferably C1-C3 alkyl.
"아릴" 은 1가, 1환 또는 2환식, 방향족 탄소환식 탄화수소 라디칼, 바람직하게는 6∼10원 방향족 고리계를 의미한다. 바람직한 아릴 기로는 페닐, 나프틸, 톨릴, 및 자일릴이 포함되나, 이에 제한되지 아니한다."Aryl" means a monovalent, monocyclic or bicyclic, aromatic carbocyclic hydrocarbon radical, preferably a 6-10 membered aromatic ring system. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
"시클로알킬" 은 원자수 3 내지 8개의, 비방향족, 부분 또는 완전 포화된 1가 환식 탄화수소 라디칼을 의미한다. 시클로알킬 기의 예로는 시클로프로필, 시클로부틸, 시클로펜틸 및 시클로헥실이 포함된다. "Cycloalkyl" means a monovalent, partially or fully saturated monovalent cyclic hydrocarbon radical having 3 to 8 atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
"유효량" 은 질환의 증상을 예방, 경감, 또는 개선하거나, 치료되는 대상체의 생존을 연장시키기에 유효한 양을 의미한다.An “effective amount” means an amount effective to prevent, alleviate, or ameliorate the symptoms of a disease, or to prolong the survival of a subject to be treated.
"할로겐" 은 불소, 염소, 브롬 또는 요오드, 바람직하게는 브롬 또는 염소를 의미한다."Halogen" means fluorine, chlorine, bromine or iodine, preferably bromine or chlorine.
"헤테로 원자" 는 N, O 및 S 에서 선택되는 원자를 의미한다. "Hetero atom" means an atom selected from N, O and S.
"헤테로아릴" 은 2개 이하의 고리를 포함하는 방향족 헤테로환식 고리계를 의미한다. 바람직한 헤테로아릴 기로는, 티에닐, 푸릴, 인돌릴, 피롤릴, 피리디닐, 피리딘, 피라지닐, 옥사졸릴, 티악솔릴, 퀴놀리닐, 피리미디닐, 이미다졸 및 테트라졸릴이 포함되나, 이에 제한되지 아니한다. "Heteroaryl" means an aromatic heterocyclic ring system containing up to two rings. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyridine, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole and tetrazolyl Not.
"헤테로환" 또는 "헤테로환식" 은 고리 원자수 3 내지 8개이고 그 중 1 내지 3개의 고리 원자가 질소, 산소, S(O)n (여기서, n 은 0 내지 2 의 정수임), 또는 이의 조합에서 선택되는 헤테로 원자이고, 나머지 고리 원자가 C 인, 포화 또는 부분 불포화, 비방향족 환식 라디칼을 의미한다. 바람직한 헤테로환의 예는 피페리딘, 피페라진, 피롤리딘, 모르폴린, 인돌린, 테트라히드로피라닐, 티오모르폴리노, 펜타메틸렌 술피드, 및 펜타메틸렌 술폰이다. "Heterocyclic" or "heterocyclic" means 3 to 8 ring atoms, of which 1 to 3 ring atoms are nitrogen, oxygen, S (O) n where n is an integer from 0 to 2, or a combination thereof Heteroatoms of choice, the remaining ring atoms being C, saturated or partially unsaturated, non-aromatic cyclic radicals. Examples of preferred heterocycles are piperidine, piperazine, pyrrolidine, morpholine, indolin, tetrahydropyranyl, thiomorpholino, pentamethylene sulfide, and pentamethylene sulfone.
"IC5O" 는 구체적인 측정 활성의 50% 를 억제하는데 요구되는 특정 화합물의 농도를 칭한다. IC50 은 특히, 하기 기재되는 바와 같이 측정될 수 있다."IC 50 " refers to the concentration of the specific compound required to inhibit 50% of the specific measured activity. IC 50 can in particular be measured as described below.
단독으로의 또는 다른 용어와 결합되어 있는(예를 들어, 저급 알킬-헤테로환) "저급 알킬" 은 탄소수 1 내지 6, 바람직하게는 1 내지 4 의, 직쇄형 또는 분지형 포화 지방족 탄화수소를 나타낸다. 전형적인 저급 알킬 기로는 메틸, 에틸, 프로필, 이소프로필, 부틸, t-부틸, 2-부틸, 펜틸, 헥실 등이 포함된다.“Lower alkyl”, alone or in combination with other terms (eg, lower alkyl-heterocycle), refers to a straight or branched saturated aliphatic hydrocarbon having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl and the like.
"저급 알콕시" 는 산소 원자에 부착되어 있는 임의의 상기 저급 알킬 기를 칭한다. 전형적인 저급 알콕시 기로는 메톡시, 에톡시, 프로필옥시 또는 프로폭시, 부틸옥시 등이 포함된다."Lower alkoxy" refers to any of the above lower alkyl groups attached to an oxygen atom. Typical lower alkoxy groups include methoxy, ethoxy, propyloxy or propoxy, butyloxy and the like.
"옥소"는 =O 을 의미한다. "Oxo" means = O.
"약학적으로 허용가능한 에스테르" 는 그 에스테르가 생물학적 효능 및 화학식 I 의 화합물의 성질을 보유하고 생체 내에서 (유기체 내에서) 대응하는 활성 카르복실산으로 절단되는, 카르복실기를 갖는 화학식 I 의 통상적으로 에스테르화된 화합물을 칭한다."Pharmaceutically acceptable ester" is a compound of formula (I) having a carboxyl group, wherein the ester retains biological efficacy and properties of the compound of formula (I) and is cleaved to the corresponding active carboxylic acid (in organic) in vivo. Referred to esterified compounds.
에스테르 및 약학적 화합물의 수송을 위한 에스테르의 용도에 관한 정보는 [Design of Prodrugs. Bundgaard H 편집. (Elsevier, 1985)]에서 입수가능하다. 또한, [H. Ansel 등, Pharmaceutical Dosage Forms and Drug Delivery Systems (제 6 판, 1995), pp. 108-109]; [Krogsgaard-Larsen 등, Textbook of Drug Design and Development (제 2 판, 1996), pp. 152-191] 을 참조하라.Information on the use of esters for the transport of esters and pharmaceutical compounds is given in Design of Prodrugs. Compiled Bundgaard H. (Elsevier, 1985). In addition, [H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th edition, 1995), pp. 108-109; Krogsgaard-Larsen et al., Textbook of Drug Design and Development (2nd edition, 1996), pp. 152-191.
"약학적으로 허용가능한 염" 은 생물학적 효능 및 본 발명의 화합물의 성질을 보유하고 적합한 무독성 유기 또는 무기 산 또는 유기 또는 무기 염기로부터 형성되는, 통상적인 산 부가 염 또는 염기 부가 염을 칭한다. 산 부가 염의 견본으로는 무기산, 예컨대 염산, 브롬화수소산, 요오드화수소산, 황산, 술팜산, 인산 및 질산에서 유래하는 것들, 및 유기 산, 예컨대 p-톨루엔술폰산, 살리실산, 메탄술폰산, 옥살산, 숙신산, 시트르산, 말산, 락트산, 푸마르산 등에서 유래하는 것들이 포함된다. 염기 부가 염의 견본으로는 암모늄, 칼륨, 나트륨 및 4급 수산화암모 늄, 예컨대 테트라메틸암모늄 수산화물에서 유래하는 것들이 포함된다. 염으로의 약학적 화합물 (즉, 약물)의 화학적 개질은 화합물의 개선된 물리적 및 화학적 안정성, 흡습성, 유동성 및 용해성을 얻기 위한 약학 화학자들에게 잘 공지된 기술이다. 예를 들어, [H. Ansel 등, Pharmaceutical Dosage Forms and Drug Delivery Systems (제 6 판, 1995), pp. 196 및 1456-1457] 을 참조하라. "Pharmaceutically acceptable salts" refer to conventional acid addition salts or base addition salts, which retain the biological efficacy and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid And those derived from malic acid, lactic acid, fumaric acid and the like. Samples of base addition salts include those derived from ammonium, potassium, sodium and quaternary ammonium hydroxides such as tetramethylammonium hydroxide. Chemical modification of pharmaceutical compounds (ie drugs) to salts is a technique well known to pharmacists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of the compounds. For example, [H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th edition, 1995), pp. 196 and 1456-1457.
약학적으로 허용가능한 담체, 부형제 등에서와 같은 "약학적으로 허용가능한" 은 약리학적으로 허용가능하고 특정 화합물이 투여되는 대상체에 대해 실질적으로 무독성이라는 것을 의미한다.“Pharmaceutically acceptable”, such as in pharmaceutically acceptable carriers, excipients, etc., means pharmacologically acceptable and substantially nontoxic to the subject to which the particular compound is administered.
치환된 알킬에서와 같은 "치환된" 은 치환이 하나 이상의 위치에서 일어날 수 있다는 것, 및 달리 나타내지 않는 한, 각 치환 자리에서의 치환체가 상술된 선택사항들에서 독립적으로 선택된다는 것을 의미한다."Substituted" as in substituted alkyl, means that the substitution can occur at one or more positions, and unless indicated otherwise, the substituents at each substitution site are independently selected from the options described above.
"치료적 유효량" 은 현저하게 증식을 억제하고/하거나 인간 종양 세포주를 포함하는 인간 종양 세포의 분화를 예방하는 하나 이상의 지정된 화합물의 양을 의미한다. A "therapeutically effective amount" means the amount of one or more designated compounds that significantly inhibit proliferation and / or prevent differentiation of human tumor cells, including human tumor cell lines.
예시된 바와 같은 본 발명의 화합물은, 유리하게는 약 70 ηM 내지 약 100 μM 의 IC50 을 나타낸다. Compounds of the invention as exemplified advantageously exhibit an IC 50 of about 70 ηΜ to about 100 μΜ.
본 발명의 화합물은 세포 증식 장애, 특히 종양학적 장애의 치료 또는 제어에 유용하다. 상기 화합물 및 상기 화합물을 함유하는 제형물은 고형 종양, 예를 들어 유방, 결장, 폐 및 전립선 종양의 치료 또는 제어에 유용할 수 있다.The compounds of the present invention are useful for the treatment or control of cell proliferative disorders, especially oncological disorders. The compound and formulations containing the compound may be useful for the treatment or control of solid tumors such as breast, colon, lung and prostate tumors.
본 발명에 따른 화합물의 치료적 유효량은 질환의 증상을 예방, 경감 또는 개선하거나 치료되는 대상체의 생존을 연장시키기에 유효한 화합물의 양을 의미한다. 치료적 유효량의 결정은 당업계의 기술범위내에 있다.A therapeutically effective amount of a compound according to the invention means an amount of the compound effective to prevent, alleviate or ameliorate the symptoms of the disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill of the art.
본 발명에 따른 화합물의 치료적 유효량 또는 투약량은, 광범한 제한범위 내에서 변화할 수 있고, 당업계에 공지된 방식으로 결정될 수 있다. 상기 투약량은 투여되는 구체적 화합물(들), 투여 경로, 치료되는 상태 뿐만 아니라 치료되는 환자를 포함하는 각각의 특정 경우에서의 개별적 요건에 따라 조정될 것이다. 통상적으로, 체중이 대략 70 kg 인 성인 인간에 대한 경구 또는 비경구 투여의 경우, 비록 그 상한치는 지시될 경우 초과할 수도 있지만, 약 10 mg 내지 약 10,000 mg, 바람직하게는 약 200 mg 내지 약 1,000 mg 의 1일 투약량이 적당할 것이다. 1일 투약량은 단일 투여량으로 또는 분할된 투여량으로 투여될 수 있거나, 또는 비경구 투여에 대하여는, 연속적 주입으로서 주어질 수 있다.A therapeutically effective amount or dosage of a compound according to the invention can vary within wide limits and can be determined in a manner known in the art. The dosage will be adjusted according to the individual requirements in each particular case, including the specific compound (s) being administered, the route of administration, the condition being treated as well as the patient being treated. Typically, for oral or parenteral administration to adult humans weighing approximately 70 kg, about 10 mg to about 10,000 mg, preferably about 200 mg to about 1,000, although the upper limit may be exceeded if indicated. Daily dosages of mg will be appropriate. The daily dose may be administered in a single dose or in divided doses, or for parenteral administration, may be given as a continuous infusion.
합성synthesis
화학식 I 의 화합물은 하기 반응식 I 에 따라서 제조될 수 있다:Compounds of formula (I) can be prepared according to the following scheme (I):
Harrison, C. R. 등의 WO 9203421 에 의해 제공된 절차에 따라서 제조된 벤조니트릴 1 을 에탄올 중에서 HCl 가스를 사용하여 에틸 벤즈이미데이트 2 로 전환한다. 이미데이트 2 와 1,2-디아민 3 의 축합을 트리에틸아민과 같은 염기의 존재 하에 40∼100℃ 에서 에탄올 중에 수행한다.Benzonitrile 1 prepared according to the procedure provided by WO 9203421 of Harrison, C. R. et al. Is converted to ethyl benzimidate 2 using HCl gas in ethanol. Condensation of imidate 2 and 1,2-diamine 3 is carried out in ethanol at 40-100 ° C. in the presence of a base such as triethylamine.
화학식 3 의 메소-1,2-디아민은 공지된 화합물이고, 문헌의 절차에 따라서 제조된다 (참조, Jennerwein, M. 등, Cancer Res. Clin. Oncol. 1988, 114, 347-58; Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40).Meso-1,2-diamine of formula (3) is a known compound and is prepared according to literature procedures (see Jennerwein, M. et al., Cancer Res. Clin. Oncol. 1988, 114, 347-58; Vogtle, F Goldschmitt, E. Chem. Ber. 1976, 109, 1-40).
반응식 I 에서 보는 바와 같이, 화학식 7 의 화합물은, 트리에틸아민과 같은 염기의 존재 하에 벤조일 클로라이드 5 와의 반응, 및 디메틸포름아미드와 같은 용 매 중 아민과의 반응에 의해, 화합물 4 로부터 제조될 수 있다.As shown in Scheme I, the compound of formula 7 can be prepared from compound 4 by reaction with benzoyl chloride 5 in the presence of a base such as triethylamine and with an amine in a solvent such as dimethylformamide. have.
반응식 I 에서 보는 바와 같이, 화학식 8 의 화합물은, 트리에틸아민과 같은 염기의 존재 하에 술포닐 클로라이드 6 과의 반응, 및 디메틸포름아미드와 같은 용매 중 아민과의 반응에 의해, 화합물 4 로부터 제조될 수 있다.As shown in Scheme I, the compound of formula 8 can be prepared from compound 4 by reaction with sulfonyl chloride 6 in the presence of a base such as triethylamine and with an amine in a solvent such as dimethylformamide. Can be.
화학식 4 의 화합물은 트리에틸아민과 같은 염기의 존재 하에 포스겐을 사용하여 화학식 9 의 화합물로 전환될 수 있다 (반응식 2). 그 후, 9 와 적합한 아민 기 (공지된 화합물 또는 공지된 방법에 의해 제조한 화합물)와의 반응에 의해, 화합물 10, 11, 또는 12 가 수득될 수 있다.The compound of formula 4 can be converted to the compound of formula 9 using phosgene in the presence of a base such as triethylamine (Scheme 2). Thereafter, compounds 10, 11, or 12 can be obtained by reaction of 9 with a suitable amine group (known compound or compound prepared by known methods).
원하는 경우, 화합물 11 및 12 에서 R4 및 R5 기는 반응식 3 에 묘사된 바와 같이 추가로 관능화될 수 있다.If desired, the R 4 and R 5 groups in compounds 11 and 12 can be further functionalized as depicted in Scheme 3.
반응식 III 에서 보는 바와 같이, 화학식 9 의 화합물을 적당히 보호된 피페라진과 반응시켜, 탈보호 이후에 화학식 13 의 화합물을 제공할 수 있다. 그 후, 13 의 화합물을 WX (예를 들어, X = 할로겐화물, Ms, Ts, 에폭시드, 알켄, 또는 아실 등)와 반응시켜, 화학식 14 의 화합물을 제공한다.As shown in Scheme III, the compound of formula 9 can be reacted with a suitably protected piperazine to provide a compound of formula 13 after deprotection. Thereafter, the compound of 13 is reacted with WX (eg, X = halide, Ms, Ts, epoxide, alkene, or acyl, etc.) to provide a compound of formula (14).
반응식 III 에서 보는 바와 같이, 화학식 9 의 화합물을 적당히 보호된 피페리딘과 반응시켜, 탈보호 이후에 화학식 15 의 화합물을 제공할 수 있다. 그 후, 15 의 화합물을 WX (예를 들어, X = 할로겐화물, 또는 아실 등)와 반응시켜, 화학식 16 의 화합물을 제공한다.As shown in Scheme III, the compound of formula 9 can be reacted with a suitably protected piperidine to provide a compound of formula 15 after deprotection. Thereafter, the compound of 15 is reacted with WX (eg, X = halide, acyl or the like) to provide a compound of formula 16.
반응식 III 에서 보는 바와 같이, 화학식 17 의 화합물은, 화합물 9 로부터, 4-히드록시에틸피페리딘 및 트리에틸아민과의 반응 후, 히드록실기를 톨루엔메틸술포네이트와 같은 적합한 이탈기 (LG)로 전환시킴으로써 제조될 수 있다. 화합물 18 은, 화합물 17 로부터, 상기 이탈기를 아민으로 대체시킴으로써 제조될 수 있다.As shown in Scheme III, the compound of formula 17 is a suitable leaving group (LG) such as toluenemethylsulfonate, after reaction of compound 9 with 4-hydroxyethylpiperidine and triethylamine. It can be prepared by the conversion. Compound 18 can be prepared from compound 17 by replacing the leaving group with an amine.
출발 물질이 시판되지 않는 화학식 11 또는 12 의 화합물을 제조하기 원하는 경우, 당업계에 공지된 많은 합성 방법이 이용될 수 있다. 피페라진-2-온의 합성을 위한 대표적인 방법을 실시예에서 제공한다. 다음의 반응식은 이들 방법 중의 일부를 묘사한다.If it is desired to prepare a compound of formula 11 or 12 where no starting material is commercially available, many synthetic methods known in the art can be used. Representative methods for the synthesis of piperazin-2-ones are provided in the Examples. The following scheme depicts some of these methods.
화학식 21 의 화합물 (W 가 R5 에서 정의된 바와 같은 임의의 적합한 기일 수 있음)은, 통상적인 방법을 사용하여 WX (X 는 Cl, Br, I 와 같은 임의의 적합한 이탈기일 수 있음)로 화학식 19 의 적당한 보호된 화합물을 알킬화함으로써 제조될 수 있다 (반응식 IV). 수소화나트륨과 같은 염기에 의해 아미드 음이온이 발생한다. 상기 반응은 통상적으로는 디메틸포름아미드 중에서 수행된다.Compounds of formula 21 (W may be any suitable group as defined in R5) may be formulated as WX (X may be any suitable leaving group such as Cl, Br, I) using conventional methods It can be prepared by alkylating a suitable protected compound of (Scheme IV). Amide anions are generated by bases such as sodium hydride. The reaction is usually carried out in dimethylformamide.
화학식 24 의 화합물 (W 가 R5 에서 정의된 바와 같은 임의의 적합한 기일 수 있음)은, 통상적인 방법을 사용하여 WX (X 는 Cl, Br, I 와 같은 임의의 적합한 이탈기일 수 있음), 에폭시드, 또는 알켄과 화학식 19 의 적당한 보호된 화합물을 반응시킴으로써 제조될 수 있다 (반응식 V).Compounds of formula 24, wherein W can be any suitable group as defined in R 5, can be formulated using conventional methods, WX (X can be any suitable leaving group such as Cl, Br, I), epoxide Or by reacting the alkene with a suitable protected compound of formula (19) (Scheme V).
하기의 실시예는 본 발명의 화합물을 합성하기 위한 바람직한 방법을 묘사한다. 구조식은 다음과 같다. 구조식과 관련하여, 화합물 명에서 나타나 있는 바와 같이, 이용성있는 전자가 있는 산소 및 질소 원자는 그에 수소가 결합되어 있음을 이해한다. 이들 실시예 및 제조예는 예시적인 것이며, 제한하고자 하는 것은 아니다. 본원에 첨부된 청구범위에 의해 정의되는 바와 같은 본 발명의 사상 및 범주 내에 들어가는 다른 구현예가 있을 수 있음을 이해하여야 한다.The following examples depict preferred methods for synthesizing the compounds of the present invention. The structural formula is as follows. Regarding the structural formula, as indicated in the compound name, oxygen and nitrogen atoms with available electrons are understood to have hydrogen bonded thereto. These examples and preparations are illustrative and not intended to be limiting. It should be understood that there may be other embodiments that fall within the spirit and scope of the invention as defined by the claims appended hereto.
본 실시예에서 합성되는 화합물은 라세미체이다. 흥미있는 화합물의 에난티오머는 키랄 칼럼 크로마토그래피 (예를 들어, ChiralPak
실시예Example 1 One
4,5-4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )-4,5-) -4,5- 디히드로Dehydro -1H-이미다졸-1H-imidazole
실온에서 무수 에탄올 (400 mL) 중 2-니트로-4-트리플루오로메틸-벤조니트릴 (71.7 g, 318.5 mmol)의 용액에 소듐 에톡시드 (238 mL, 637 mmol, 에탄올 중 21% 용액)를 30 분의 기간에 걸쳐 적가하였다. 반응 혼합물을 실온에서 1 시간 동안 교반하였다. 물 (1 L)을 첨가하고, 혼합물을 15 분 동안 교반하였다. 고체를 여과 제거하고, 물로 세척하고, 진공 오븐 (40℃)에서 하룻밤 건조하여 2-에톡시-4-트리플루오로메틸-벤조니트릴 (64 g, 93% 수율)을 얻었다.To a solution of 2-nitro-4-trifluoromethyl-benzonitrile (71.7 g, 318.5 mmol) in dry ethanol (400 mL) at room temperature was added sodium ethoxide (238 mL, 637 mmol, 21% solution in ethanol) 30 Dropping over a period of minutes. The reaction mixture was stirred at rt for 1 h. Water (1 L) was added and the mixture was stirred for 15 minutes. The solid was filtered off, washed with water and dried overnight in a vacuum oven (40 ° C.) to afford 2-ethoxy-4-trifluoromethyl-benzonitrile (64 g, 93% yield).
2-에톡시-4-트리플루오로메틸-벤조니트릴 (64 g)을 750 mL 의 무수 에탄올에 용해하였다. 상기 용액을 0℃로 냉각하고 염화수소 가스로 포화시켰다. 그 후, 반응 플라스크를 테플론(Teflon) 마개로 밀봉하고, 실온에서 11 일 동안 교반하였다. 반응의 경과를 매 수일마다 확인하고, 상기 용액을 다시 염화수소 가스로 포화시켰다. 질소 가스를 상기 용액을 통해 버블링하여, 과량의 염화수소 가스를 제거하였다. 용매를 제거하고, 잔류물을 디에틸 에테르 중에서 연화(triturating)하여, 에틸 2-에톡시-4-트리플루오로메틸-벤즈이미데이트 히드로클로라이드 (59.5 g, 67% 수율)를 백색 고체로서 얻었다.2-ethoxy-4-trifluoromethyl-benzonitrile (64 g) was dissolved in 750 mL of absolute ethanol. The solution was cooled to 0 ° C. and saturated with hydrogen chloride gas. The reaction flask was then sealed with Teflon stopper and stirred at room temperature for 11 days. The progress of the reaction was checked every few days and the solution was again saturated with hydrogen chloride gas. Nitrogen gas was bubbled through the solution to remove excess hydrogen chloride gas. The solvent was removed and the residue triturated in diethyl ether to give ethyl 2-ethoxy-4-trifluoromethyl-benzimidate hydrochloride (59.5 g, 67% yield) as a white solid.
메소-1,2-비스-(4-클로로-페닐)-에탄-1,2-디아민 (50.16 g, 178.4 mmol, [Jennerwein, M. 등, Cancer Res. Clin. Oncol. 1988, 114, 347-58; Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40]에 기재된 절차에 따라 제조됨), 에 틸 2-에톡시-4-트리플루오로메틸-벤즈이미데이트 히드로클로라이드 (59 g, 178.4 mmol), 및 트리에틸아민 (49.7 mL, 356.8 mmol)의 에탄올 (700 mL) 중 용액을 4 시간 동안 환류하며 가열하였다. 용매를 제거하고, 잔류물을 에틸 아세테이트 (800 mL) 및 탄산나트륨 포화 용액 (300 mL) 중에서 취하였다. 층이 분리되고, 생성물을 에틸 아세테이트로 추출하였다(1 × 200 mL). 유기 층을 염수 (1 × 100 mL)로 세척하고, 무수 황산마그네슘으로 건조하였다. 그 후, 고체를 여과 제거하고, 여과물을 진공 농축하였다. 헥산 중 50% 에틸 아세테이트로 용리하며 플래쉬 칼럼 크로마토그래피 (60Å 실리카 겔)에 의해 조(crude) 잔류물을 정제하여, 4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-1H-이미다졸 (64.47 g, 75% 수율)을 황색 고체로서 산출하였다.Meso-1,2-bis- (4-chloro-phenyl) -ethane-1,2-diamine (50.16 g, 178.4 mmol, Jennerwein, M. et al., Cancer Res. Clin. Oncol. 1988, 114, 347- 58; Vogtle, F .; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40), ethyl 2-ethoxy-4-trifluoromethyl-benzimidate hydro A solution in chloride (59 g, 178.4 mmol), and triethylamine (49.7 mL, 356.8 mmol) in ethanol (700 mL) was heated to reflux for 4 hours. Solvent was removed and the residue was taken up in ethyl acetate (800 mL) and saturated sodium carbonate solution (300 mL). The layers were separated and the product was extracted with ethyl acetate (1 × 200 mL). The organic layer was washed with brine (1 x 100 mL) and dried over anhydrous magnesium sulfate. The solid was then filtered off and the filtrate was concentrated in vacuo. Purify the crude residue by flash column chromatography (60Å silica gel) eluting with 50% ethyl acetate in hexanes to give 4,5-bis- (4-chloro-phenyl) -2- (2- Toxy-4-trifluoromethyl-phenyl) -4,5-dihydro-1H-imidazole (64.47 g, 75% yield) was calculated as a yellow solid.
실시예Example 2 2
실시예 1 에 기재된 바와 유사한 방식으로 하기를 수득하였다: In a manner similar to that described in Example 1, the following was obtained:
4,5-비스-(4-클로로-페닐)-2-(2-이소프로폭시-4-트리플루오로메틸-페닐)-4,5-디히드로-1H-이미다졸4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-1 H-imidazole
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-5-트리플루오로메틸-페닐)-4,5-디히드로-1H-이미다졸 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-trifluoromethyl-phenyl) -4,5-dihydro-1 H-imidazole
실시예Example 3 3
4,5-4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )-4,5-) -4,5- 디히Dihi 드로-이미다졸-1-카르보닐 클로라이드Dro-imidazole-1-carbonyl chloride
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-1H-이미다졸 (46 g, 95.97 mmol, 실시예 1) 및 트리에틸아민 (66.9 mL, 479.9 mmol)의 0℃ 로 냉각한 메틸렌 클로라이드 (2 L) 중 용액에 포스겐 (124.3 mL, 239.9 mmol, 톨루엔 중 ∼20% 용액)을 30 분의 기간에 걸쳐 적가하였다. 반응 혼합물을 실온에서 1 시간 동안 교반하였다. 질소 가스를 반응 혼합물을 통해 버블링하여, 과량의 포스겐을 제거하였다. 반응 혼합물을 농축 건조하고, 잔류물을 1 시간 동안 진공 건조하여, 4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐 클로라이드 (51 g, 98% 수율)를 미백색(off-white) 고체로서 얻었다. 생성물은 추가의 정제없이 사용되었다.4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-1 H-imidazole (46 g, 95.97 mmol, Example 1) and triethylamine (66.9 mL, 479.9 mmol) in a solution of methylene chloride (2 L) cooled to 0 ° C. with phosgene (124.3 mL, 239.9 mmol, ˜20% solution in toluene) for a period of 30 minutes Dropwise over. The reaction mixture was stirred at rt for 1 h. Nitrogen gas was bubbled through the reaction mixture to remove excess phosgene. The reaction mixture is concentrated to dryness and the residue is dried in vacuo for 1 hour to give 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4 , 5-dihydro-imidazole-1-carbonyl chloride (51 g, 98% yield) was obtained as an off-white solid. The product was used without further purification.
실시예Example 4 4
실시예 3 에 기재된 바와 유사한 방식으로, 하기를 수득하였다: In a similar manner as described in Example 3, the following was obtained:
4,5-비스-(4-클로로-페닐)-2-(2-이소프로폭시-4-트리플루오로메틸-페닐)- 4,5-디히드로-이미다졸-1-카르보닐 클로라이드 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl chloride
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-5-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐 클로라이드 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl chloride
실시예Example 5 5
1-카르보닐 클로라이드 9 (실시예 3 및 4)와 시판중인 아민의 반응을 위해 다음의 일반적 절차가 사용되었다.The following general procedure was used for the reaction of 1-carbonyl chloride 9 (Examples 3 and 4) with commercial amines.
1-카르보닐 클로라이드 9 (1 eq., 실시예 3 에 기재된 절차에 따라서 제조됨)의 메틸렌 클로라이드 중 용액을 아민(1∼2 eq.) 및 트리에틸아민의 메틸렌 클로라이드 중 용액에 첨가하였다. 반응 혼합물을 실온에서 1 시간 동안 교반하였다. 수성 중탄산나트륨으로 상기 반응을 워크업하고, 메틸렌 클로라이드로 추출하였다. 유기 추출물을 물 및 염수로 세척하고, 무수 황산나트륨으로 건조하였다. 고체를 여과 제거하고, 여과물을 진공 농축하였다. 플래쉬 칼럼 크로마토그래피에 의해 조 잔류물을 정제하여, 목적하는 우레아 생성물을 얻었다.A solution in methylene chloride of 1-carbonyl chloride 9 (1 eq., Prepared according to the procedure described in Example 3) was added to a solution in methylene chloride of amines (1-2 eq.) And triethylamine. The reaction mixture was stirred at rt for 1 h. The reaction was worked up with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extract was washed with water and brine and dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography to give the desired urea product.
실시예Example 6 6
[4,5-[4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )-4,5-) -4,5- 디히 드로Didro -이미다졸-1-일]-[4-(프로판-2-술포닐)-피페라진-1-일]-메타논-Imidazol-1-yl]-[4- (propane-2-sulfonyl) -piperazin-1-yl] -methanone
1-BOC-피페라진 (0.617 mmol) 및 디이소프로필에틸아민 (0.679 mmol)의 메틸렌 클로라이드 0.5 mL 중 용액을 4 mL 바이알에 첨가하였다. 프로판-2-술포닐 클로라이드 (0.679 mmol)를 상기 바이알에 첨가하고, 반응 혼합물을 실온에서 하룻밤 진탕하였다. 반응이 완료되었을 때, 그를 1.5 mL 의 메틸렌 클로라이드로 희석하고, 1 mL 의 1N 염화수소 용액으로 추출한 후, 1 mL 의 10% 탄산칼륨 용액으로 추출하였다. 유기 층을 진공 농축하였다. 잔류물을 0.5 mL 의 테트라히드로푸란 및 디옥산 중 염화수소의 4M 용액 (0.5 mL)에 용해하였다. 용액을 실온에서 하룻밤 진탕한 다음, 진공 농축하여, 1-(프로판-2-술포닐)-피페라진을 얻었다. A solution in 0.5 mL of methylene chloride of 1-BOC-piperazine (0.617 mmol) and diisopropylethylamine (0.679 mmol) was added to a 4 mL vial. Propane-2-sulfonyl chloride (0.679 mmol) was added to the vial and the reaction mixture was shaken at room temperature overnight. When the reaction was complete, it was diluted with 1.5 mL of methylene chloride and extracted with 1 mL of 1N hydrogen chloride solution, followed by 1 mL of 10% potassium carbonate solution. The organic layer was concentrated in vacuo. The residue was dissolved in 0.5 mL of tetrahydrofuran and 4M solution of hydrogen chloride in dioxane (0.5 mL). The solution was shaken overnight at room temperature and then concentrated in vacuo to give 1- (propane-2-sulfonyl) -piperazine.
1-(프로판-2-술포닐)-피페라진 (0.0286 mmol)을 0.25 mL 의 메틸렌 클로라이드에 용해하고, 4 mL 바이알에서 4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐 클로라이드 (0.024 mmol, 실시예 3) 및 디이소프로필에틸아민 (0.072 mmol)의 메틸렌 클로라이드 0.25 mL 중 용액에 첨가하였다. 바이알을 캡핑(capping)하고 실온에서 하룻밤 진탕하였다. 반응 혼합물을 1 mL 의 메틸렌 클로라이드 및 1 mL 의 물로 희석하였다. 상기 바이알을 흔들고(agitating), 원심분리하였다. 유기 층을 4 mL 바이알로 옮기고, 진공 농축하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐 )-4,5-디히드로-이미다졸-1-일]-[4-(프로판-2-술포닐)-피페라진-1-일]-메타논을 얻었다. LR-MS (M+H)+ = 697.4. 1- (Propan-2-sulfonyl) -piperazine (0.0286 mmol) is dissolved in 0.25 mL of methylene chloride and 4,5-bis- (4-chloro-phenyl) -2- (2- in 4 mL vials Methylene chloride of ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl chloride (0.024 mmol, Example 3) and diisopropylethylamine (0.072 mmol) 0.25 to the solution in mL. The vial was capped and shaken overnight at room temperature. The reaction mixture was diluted with 1 mL of methylene chloride and 1 mL of water. The vial was agitated and centrifuged. The organic layer was transferred to 4 mL vials and concentrated in vacuo to give [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5- Dihydro-imidazol-1-yl]-[4- (propane-2-sulfonyl) -piperazin-1-yl] -methanone was obtained. LR-MS (M + H) + = 697.4.
실시예Example 7A 7A
1-벤질-4-[4,5-1-benzyl-4- [4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-2-온 ) -4,5-dihydro-imidazol-1-carbonyl] -piperazin-2-one 히드로클로라이드Hydrochloride
수소화나트륨 (80 mg, 2.0 mmol, 광물유 중 60%)을 0℃ 에서 4-tert-부틸옥시카르보닐-피페라진-2-온 (200 mg, 1.0 mmol)의 디메틸포름아미드 (5.0 mL) 중 용액에 첨가하였다. 반응물을 0.5 시간 동안 0℃ 에서 교반하였다. 상기 혼합물에 벤질 브로마이드 (300 μL, 2.5 mmol)를 첨가하고 반응을 실온에서 2 시간 동안 교반하였다. 반응 혼합물을 중탄산나트륨의 희석 수용액으로 반응을 중단시키고, 메틸렌 클로라이드로 추출하였다. 유기 추출물을 염수로 세척하고, 무수 황산나트륨으로 건조하였다. 헥산 중 30% 에틸 아세테이트를 사용하여 실리카 겔 상의 크로마토그래피에 의해 조 잔류물을 정제하여, 4-tert-부틸옥시카르보닐-2-벤질-피페라진-2-온 (174 mg, 60 % 수율)을 얻었다. Sodium hydride (80 mg, 2.0 mmol, 60% in mineral oil) was dissolved in dimethylformamide (5.0 mL) of 4-tert-butyloxycarbonyl-piperazine-2-one (200 mg, 1.0 mmol) at 0 ° C. Was added. The reaction was stirred at 0 ° C. for 0.5 h. Benzyl bromide (300 μL, 2.5 mmol) was added to the mixture and the reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched with a dilute aqueous solution of sodium bicarbonate and extracted with methylene chloride. The organic extract was washed with brine and dried over anhydrous sodium sulfate. Purify the crude residue by chromatography on silica gel using 30% ethyl acetate in hexanes to afford 4-tert-butyloxycarbonyl-2-benzyl-piperazin-2-one (174 mg, 60% yield). Got.
염산 (0.25 mL, 1.00 mmol, 1,4-디옥산 중 4 M)을 4-tert-부틸옥시카르보닐-2-벤질-피페라진-2-온 (174 mg, 0.60 mmol)의 1,4-디옥산 (1.0 mL) 중 용액에 첨가 하였다. 혼합물을 하룻밤 교반하였다. 반응물을 농축하여, 2-벤질-피페라진-2-온 히드로클로라이드를 미백색 고체로서 얻었다 (130 mg, 97% 수율). Hydrochloric acid (0.25 mL, 1.00 mmol, 4 M in 1,4-dioxane) was added 1,4- of 4-tert-butyloxycarbonyl-2-benzyl-piperazin-2-one (174 mg, 0.60 mmol). To the solution in dioxane (1.0 mL) was added. The mixture was stirred overnight. The reaction was concentrated to give 2-benzyl-piperazin-2-one hydrochloride as an off-white solid (130 mg, 97% yield).
실시예 5 에 기재된 바와 같은 절차를 사용하여 4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐 클로라이드 (실시예 3)를 2-벤질-피페라진-2-온 히드로클로라이드와 반응시켜, 4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-카르보닐]-1-벤질-피페라진-2-온을 얻었다. 그 후, 이를 희석 염산 (0.5 N, 1 mL)에 용해시키고, 동결건조하여, 4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-카르보닐]-1-벤질-피페라진-2-온 히드로클로라이드를 미백색 분말로서 얻었다 (65 mg; 89% 수율). LR-MS (APCI): 695.6 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro- using the procedure as described in Example 5 Imidazole-1-carbonyl chloride (Example 3) was reacted with 2-benzyl-piperazin-2-one hydrochloride to give 4- [4,5-bis- (4-chloro-phenyl) -2- ( 2-Ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-carbonyl] -1-benzyl-piperazin-2-one was obtained. It was then dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to afford 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoro Romethyl-phenyl) -4,5-dihydro-imidazole-carbonyl] -1-benzyl-piperazin-2-one hydrochloride was obtained as an off-white powder (65 mg; 89% yield). LR-MS (APCI): 695.6 [(M + H) + ].
실시예Example 7B 7B
[4,5-[4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )-4,5-) -4,5- 디히드로Dehydro - - 이미다졸Imidazole -1-일]-[4-(모르폴린-4--1-yl]-[4- (morpholin-4- 술포닐Sulfonyl )-피페라진-1-일]-) -Piperazin-1-yl]- 메타논Metanon
메틸화된 술푸릴디이미다졸 (3.14 g, 8.04 mmol)의 트리플레이트 염을 아세토니트릴 중에 용해하였다. 1-Boc-피페라진 (1.0 g, 5.37 mmol) 및 디이소프로필 에틸아민 (1 eq.)을 동시에 첨가하였다. 반응 혼합물을 실온에서 하룻밤 교반하였다. 에틸 아세테이트로 희석하고, 물로 세척하였다. 유기 층을 건조, 여과, 및 진공 농축하여, 점성 오일을 얻었다 (2.6 g). 플래쉬 크로마토그래피에 의해 상기 오일을 정제하여, 4-(2-메틸-이미다졸-1-술포닐)-피페라진-1-카르복실산 tert-부틸 에스테르를 얻었다 (1.4 g, 79% 수율). LR-MS: 331 [(M+H)+]. Triflate salt of methylated sulfyldiimidazole (3.14 g, 8.04 mmol) was dissolved in acetonitrile. 1-Boc-piperazine (1.0 g, 5.37 mmol) and diisopropyl ethylamine (1 eq.) Were added simultaneously. The reaction mixture was stirred at rt overnight. Diluted with ethyl acetate and washed with water. The organic layer was dried, filtered and concentrated in vacuo to give a viscous oil (2.6 g). The oil was purified by flash chromatography to give 4- (2-methyl-imidazole-1-sulfonyl) -piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 79% yield). LR-MS: 331 [(M + H) + ].
4-(2-메틸-이미다졸-1-술포닐)-피페라진-1-카르복실산 tert-부틸 에스테르 (1.4 g, 4.24 mmol)의 메틸렌 클로라이드 중 용액을 얼음조에서 냉각하고, 트리플루오로메탄술폰산 메틸 에스테르 (0.56 mL, 4.9 mmol)를 피펫을 통해 첨가하였다. 3 시간 동안 빙온에서 교반한 후, 용매를 증발시켜, 4-(2-메틸-이미다졸-1-술포닐)-피페라진-1-카르복실산 tert-부틸 에스테르 트리플레이트 염을 황색 고체로서 얻었다. A solution of 4- (2-methyl-imidazole-1-sulfonyl) -piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 4.24 mmol) in methylene chloride was cooled in an ice bath and trifluoro Methanesulfonic acid methyl ester (0.56 mL, 4.9 mmol) was added via pipette. After stirring for 3 hours at ice temperature, the solvent was evaporated to give 4- (2-methyl-imidazole-1-sulfonyl) -piperazine-1-carboxylic acid tert-butyl ester triflate salt as a yellow solid. .
상기 트리플레이트 염 (60 mg, 0.12 mmol), 모르폴린 (31.7 mg, 0.36 mmol) 및 63 μL 의 디이소프로필에틸아민 (0.36 mmol)의 0.25 mL 아세토니트릴 중 용액을 주변 온도에서 하룻밤 교반하였다. 반응물을 1 mL 의 메틸렌 클로라이드 및 0.5 mL 의 1.0 M 염산으로 희석하였다. 유기 상을 소형 실리카 겔 패드를 통해 여과하고 용매를 증발시켜, 4-(모르폴린-4-술포닐)-피페라진-1-카르복실산 tert-부틸 에스테르 (39 mg, 95%)를 산출하였다. LR-MS: 336 [(M+H)+]. A solution in 0.25 mL acetonitrile of the triflate salt (60 mg, 0.12 mmol), morpholine (31.7 mg, 0.36 mmol) and 63 μL of diisopropylethylamine (0.36 mmol) was stirred overnight at ambient temperature. The reaction was diluted with 1 mL of methylene chloride and 0.5 mL of 1.0 M hydrochloric acid. The organic phase was filtered through a small pad of silica gel and the solvent was evaporated to yield 4- (morpholine-4-sulfonyl) -piperazine-1-carboxylic acid tert-butyl ester (39 mg, 95%). . LR-MS: 336 [(M + H) + ].
4-(모르폴린-4-술포닐)-피페라진-1-카르복실산 tert-부틸 에스테르 (39 mg)를 4 mL 의 디옥산 중에 용해하고, 디옥산 중 4.0 M 염산 4 mL 를 첨가하였다. 주변 온도에서 하룻밤 방치한 후, 용매를 제거하여 4-(피페라진-1-술포닐)-모르폴린 히드로클로라이드를 백색 고체로서 얻었다.4- (morpholine-4-sulfonyl) -piperazine-1-carboxylic acid tert-butyl ester (39 mg) was dissolved in 4 mL of dioxane and 4 mL of 4.0 M hydrochloric acid in dioxane was added. After standing overnight at ambient temperature, the solvent was removed to give 4- (piperazin-1-sulfonyl) -morpholine hydrochloride as a white solid.
4-(피페라진-1-술포닐)-모르폴린 히드로클로라이드 (0.042 mmol)를 메틸렌 클로라이드 중에 현탁시키고, 400 μL 의 디이소프로필에틸아민을 첨가하였다. 혼합물을 4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐 클로라이드 (10 mg, 0.019 mmol, 실시예 3)에 첨가하고, 반응 혼합물을 하룻밤 방치시켰다. 이를 메틸렌 클로라이드로 희석하고, 물로 세척하였다. 유기 층을 증발시키고, 에틸 아세테이트 및 헥산을 사용하여 플래쉬 크로마토그래피에 의해 잔류물을 정제하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(모르폴린-4-술포닐)-피페라진-1-일]-메타논 (9.0 mg)을 얻었다. LR-MS: 740.2 [(M+H)+]. 4- (piperazin-1-sulfonyl) -morpholine hydrochloride (0.042 mmol) was suspended in methylene chloride and 400 μL of diisopropylethylamine were added. The mixture was prepared with 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl chloride ( 10 mg, 0.019 mmol, Example 3), and the reaction mixture was left overnight. It was diluted with methylene chloride and washed with water. The organic layer was evaporated and the residue was purified by flash chromatography using ethyl acetate and hexanes to give [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-tri Fluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (morpholin-4-sulfonyl) -piperazin-1-yl] -methanone (9.0 mg) Got it. LR-MS: 740.2 [(M + H) + ].
실시예Example 8A 8A
3-{4-[4,5-3- {4- [4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-프로피오니트릴 히드로클로라) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -propionitrile hydrochlora 이드Id
포스겐 (3.8 mL, 7.22 mmol, 톨루엔 중 1.9 M)을 트리에틸아민 (1.3 mL, 9.62 mmol) 및 4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로-페닐)-4,5-디히드로-1H-이미다졸 (1.15 g, 2.41 mmol)의 메틸렌 클로라이드 (20 mL) 중 냉각(0℃) 혼합물에 적가하였다. 반응 혼합물을 0.5 시간 동안 0℃ 에서 교반하고, 용매를 증발시켰다. 잔류물을 30 분 동안 고진공 하에 유지시키고, 메틸렌 클로라이드 (20 mL)에 용해하였다. 상기 용액을 4-tert-부틸옥시카르보닐피페라진 (0.90 g, 4.81 mmol)의 메틸렌 클로라이드 (16 mL) 중 냉각(0℃) 용액에 적가하였다. 1 시간 후, 반응물을 중탄산나트륨 수용액으로 워크업하고, 메틸렌 클로라이드로 추출하였다. 유기 추출물을 물, 염수로 세척하고, 무수 황산나트륨으로 건조하였다. 용매를 증발시키고, 헥산 중 50% 에틸 아세테이트를 사용하여 실리카 겔 상에서 잔류물을 크로마토그래피하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-tert-부틸옥시카르보닐피페라진-1-일]-메타논을 황색 발포물로서 얻었다 (1.30 g, 78%). Phosgene (3.8 mL, 7.22 mmol, 1.9 M in toluene) was added to triethylamine (1.3 mL, 9.62 mmol) and 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-tri Fluoro-phenyl) -4,5-dihydro-1H-imidazole (1.15 g, 2.41 mmol) was added dropwise to a cooled (0 ° C.) mixture in methylene chloride (20 mL). The reaction mixture was stirred for 0.5 h at 0 ° C. and the solvent was evaporated. The residue was kept under high vacuum for 30 minutes and dissolved in methylene chloride (20 mL). The solution was added dropwise to a cooled (0 ° C.) solution of 4-tert-butyloxycarbonylpiperazine (0.90 g, 4.81 mmol) in methylene chloride (16 mL). After 1 hour, the reaction was worked up with aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic extract was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel using 50% ethyl acetate in hexanes to give [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-tri Fluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4-tert-butyloxycarbonylpiperazin-1-yl] -methanone was obtained as a yellow foam (1.30 g , 78%).
염산 (10 mL, 40 mmol, 1,4-디옥산 중 4 M)을 [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-tert-부틸옥시카르보닐피페라진-1-일]-메타논의 1,4-디옥산 (10 mL) 중 냉각 (0℃) 용액에 첨가하였다. 상기 혼합물을 실온에서 하룻밤 교반하였다. 용매를 증발시키고, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(피페라진-1-일)-메타논 히드로클로라이드를 미백색 고체로서 얻었다 (1.10 g, 98 % 수율). Hydrochloric acid (10 mL, 40 mmol, 4 M in 1,4-dioxane) was purified by [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl ) -4,5-dihydro-imidazol-1-yl]-[4-tert-butyloxycarbonylpiperazin-1-yl] -methanone cooled in 1,4-dioxane (10 mL) (0 C) was added to the solution. The mixture was stirred at rt overnight. The solvent was evaporated and [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Il]-(piperazin-1-yl) -methanone hydrochloride was obtained as an off-white solid (1.10 g, 98% yield).
2-브로모프로피오니트릴 (10 μL, 0.120 mmol)을 [4,5-비스-(4-클로로-페닐 )-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[피페라진-1-일]-메타논 히드로클로라이드 및 디이소프로필에틸아민 (42 μL, 0.240 mmol)의 디메틸포름아미드 (1.0 mL) 중 혼합물에 첨가하였다. 반응물을 실온에서 하룻밤 교반하였다. 용매를 증발시키고, 메틸렌 클로라이드 중 1∼2% 메탄올을 사용하여 실리카 겔 상에서 플래쉬 크로마토그래피에 의해 조 잔류물을 정제하여, 3-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-프로피오니트릴을 얻고, 이를 희석 염산 (0.5 N, 1 mL) 중에 용해하고 동결건조하여, 3-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-프로피오니트릴 히드로클로라이드를 미백색 분말로서 얻었다 (20 mg, 39% 수율). LR-MS (APCI): 644.4 [(M+H)+]. 2-bromopropionitrile (10 μL, 0.120 mmol) was dissolved in [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4, To a mixture of 5-dihydro-imidazol-1-yl]-[piperazin-1-yl] -methanone hydrochloride and diisopropylethylamine (42 μL, 0.240 mmol) in dimethylformamide (1.0 mL) Added. The reaction was stirred at rt overnight. The solvent was evaporated and the crude residue was purified by flash chromatography on silica gel using 1-2% methanol in methylene chloride to give 3- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-carbonyl] -piperazin-1-yl} -propionitrile Soluble in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to afford 3- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl -Phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -propionitrile hydrochloride was obtained as an off-white powder (20 mg, 39% yield). LR-MS (APCI): 644.4 [(M + H) + ].
실시예Example 8B 8B
2-{4-[4,5-2- {4- [4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )-4,5-) -4,5- 디히드로Dehydro -- 이미다졸Imidazole -1-카르보닐]-피페라진-1-일}-N--1-carbonyl] -piperazin-1-yl} -N- 메틸methyl -- 아세트아미드Acetamide
클로로아세틸클로라이드 (8.85 mmol)의 10 mL 메틸렌 클로라이드 중 용액을 밀봉된 40 mL 바이알에서 대략 -40℃ 로 냉각하였다. 관통가능한 고무마개 (septum)를 통해 시린지를 사용하여 메틸아민 (18.6 mmol, 9.3 mL, 테트라히드로푸란 중 2M)을 교반 중인 상기 용액에 일부씩 첨가하였다. 반응물을 감온에서 1 시간 동안 교반하였다. 그 후, 상기 용액을 1 N 염산을 사용해 산성으로 만든 다음, 10 mL 메틸렌 클로라이드로 희석하였다. 상기 바이알을 흔들고 원심분리하였다. 유기 층을 40 mL 바이알에 옮기고 진공 농축하여, 2-클로로-N,N-디메틸-아세트아미드를 얻었다. The solution in 10 mL methylene chloride of chloroacetylchloride (8.85 mmol) was cooled to approximately −40 ° C. in a sealed 40 mL vial. Methylamine (18.6 mmol, 9.3 mL, 2M in tetrahydrofuran) was added in portions to the stirring solution using a syringe through a permeable rubber stopper (septum). The reaction was stirred at rt for 1 h. The solution was then made acidic with 1 N hydrochloric acid and then diluted with 10 mL methylene chloride. The vial was shaken and centrifuged. The organic layer was transferred to 40 mL vials and concentrated in vacuo to afford 2-chloro-N, N-dimethyl-acetamide.
디메틸포름아미드 (0.25 mL) 중 2-클로로-N,N-디메틸-아세트아미드 (0.0194 mmol)를 4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-1H-이미다졸 (0.0169 mmol, 실시예 1) 및 디이소프로필에틸아민 (0.0194 mmol)의 0.25 mL 디메틸포름아미드 중 용액을 포함하는 4 mL 바이알에 피펫첨가하였다. 상기 바이알을 캡핑하고, 2 일 동안 65℃ 로 가열하였다. 반응물을 1.5 mL 메틸렌 클로라이드 및 0.5 mL 물로 희석하였다. 바이알을 흔들고 원심분리하였다. 유기 층을 4 mL 바이알에 옮기고, 진공 농축하여, 2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-메틸-아세트아미드를 얻었다. LR-MS: 663 [(M+H)+]. 2-chloro-N, N-dimethyl-acetamide (0.0194 mmol) in dimethylformamide (0.25 mL) was added to 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-tri 4 mL vials containing a solution in 0.25 mL dimethylformamide of fluoromethyl-phenyl) -4,5-dihydro-1H-imidazole (0.0169 mmol, Example 1) and diisopropylethylamine (0.0194 mmol) Pipette in. The vial was capped and heated to 65 ° C. for 2 days. The reaction was diluted with 1.5 mL methylene chloride and 0.5 mL water. The vial was shaken and centrifuged. The organic layer was transferred to a 4 mL vial and concentrated in vacuo to give 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-carbonyl] -piperazin-1-yl} -N-methyl-acetamide was obtained. LR-MS: 663 [(M + H) + ].
실시예Example 9 9
1-{4-[4,5-1- {4- [4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )-4,5-) -4,5- 디히드로Dehydro -- 이미다졸Imidazole -1-카르보닐]-피페라진-1-일}-2-디메틸아미노--1-carbonyl] -piperazin-1-yl} -2-dimethylamino- 에타논Ethanon
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-피페라진-1-일-메타논 (372 mg, 0.63 mmol, 실시예 8A) 및 디이소프로필에틸아민 (230 μL, 1.32 mmol)을 메틸렌 클로라이드 (4 mL) 중에 용해하고 빙온으로 냉각하였다. 메틸렌 클로라이드 (1 mL) 중 클로로아세틸 클로라이드 (100 μL, 1.26 mmol)를 적가하고, 상기 혼합물을 빙온에서 30 분 동안 교반하였다. 반응물을 메틸렌 클로라이드로 희석하고, 물로 세척하였다. 유기 층을 무수 황산마그네슘으로 건조하였다. 고체를 여과제거하고, 여과물을 농축하였다. 에틸 아세테이트 및 헥산을 사용하여 플래쉬 크로마토그래피에 의해 조 물질을 정제하여, 1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-클로로-에타논 (193 mg, 0.29 mmol)을 얻었다. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine -1-yl-methanone (372 mg, 0.63 mmol, Example 8A) and diisopropylethylamine (230 μL, 1.32 mmol) were dissolved in methylene chloride (4 mL) and cooled to ice temperature. Chloroacetyl chloride (100 μL, 1.26 mmol) in methylene chloride (1 mL) was added dropwise and the mixture was stirred at ice temperature for 30 minutes. The reaction was diluted with methylene chloride and washed with water. The organic layer was dried over anhydrous magnesium sulfate. The solid was filtered off and the filtrate was concentrated. Purification of the crude material by flash chromatography using ethyl acetate and hexanes gave 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoro Romethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -2-chloro-ethanone (193 mg, 0.29 mmol) was obtained.
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-클로로-에타논 (9.65 mg) 및 디이소프로필에틸아민 (5 μL)의 용액에 디메틸아민 (50 μL, 테트라히드로푸란 중 2.0 M 용액)을 첨가하였다. 반응 혼합물을 캡핑하고, 60℃ 에서 하룻밤 가열하였다. 상기를 메틸렌 클로라이드로 희석하고, 물로 세척하였다. 유기 층을 농축 건조하여, 1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-디메틸아미노-에타논을 얻었다 (9.17 mg, 92% 수율). LR-MS: 677.3 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- To a solution of carbonyl] -piperazin-1-yl} -2-chloro-ethanone (9.65 mg) and diisopropylethylamine (5 μL) add dimethylamine (50 μL, 2.0 M solution in tetrahydrofuran). Added. The reaction mixture was capped and heated at 60 ° C. overnight. It was diluted with methylene chloride and washed with water. The organic layer was concentrated to dryness and 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-di Hydro-imidazole-1-carbonyl] -piperazin-1-yl} -2-dimethylamino-ethanone was obtained (9.17 mg, 92% yield). LR-MS: 677.3 [(M + H) + ].
실시예Example 10 10
4-[4,5-4- [4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )-4,5-) -4,5- 디D 히드로-이미다졸-1-카르보닐]-피페라진-1-카르보티오산 Hydro-imidazole-1-carbonyl] -piperazine-1-carbothioic acid 메틸아미드Methylamide
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-피페라진-1-일-메타논 (279 mg, 0.47 mmol, 실시예 8A)을 메틸렌 클로라이드 (3 mL) 중에 용해하고 메틸이소티오시아네이트 (64 μL)를 첨가하였다. 3 시간 교반한 후, 반응 혼합물을 농축 건조하였다. 에틸 아세테이트 및 헥산으로 용리하며 플래쉬 크로마토그래피 (실리카 겔)에 의해 조 잔류물을 정제하여, 4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-카르보티오산 메틸아미드를 얻었다 (195 mg). LR-MS: 664.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine -1-yl-methanone (279 mg, 0.47 mmol, Example 8A) was dissolved in methylene chloride (3 mL) and methylisothiocyanate (64 μL) was added. After stirring for 3 hours, the reaction mixture was concentrated to dryness. Purification of the crude residue by flash chromatography (silica gel) eluting with ethyl acetate and hexanes gave 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4- Trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine-1-carbothioic acid methylamide was obtained (195 mg). LR-MS: 664.4 [(M + H) + ].
실시예Example 11 11
4-{4-[4,5-4- {4- [4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )- 4,5-) -4,5- 디히드로Dehydro -- 이미다졸Imidazole -1-카르보닐]-피페라진-1-카르보닐}-피페라진-2-온-1-carbonyl] -piperazin-1-carbonyl} -piperazin-2-one
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-피페라진-1-일-메타논 (50 mg, 0.085 mmol, 실시예 8A)을 메틸렌 클로라이드 (1 mL)중에 용해하고 얼음조에서 냉각하였다. 포스겐 (250 μL, 톨루엔 중 20% 용액)을 첨가하고, 상기 혼합물을 30 분 동안 교반하였다. 용매를 증발시키고, 잔류물을 메틸렌 클로라이드 중에서 취하였다. 1/3의 상기 용액 (0.028 mmol)을 2-피페라지논 (8.5 mg) 및 디이소프로필에틸아민 (15 μl)로 처리하였다. 아민의 용해를 보조하기 위하여 상기 혼합물을 초음파처리하고 주변 온도에서 하룻밤 방치하였다. 상기를 메틸렌 클로라이드로 희석하고, 물로 세척하였다. 유기 부분을 분리하고 증발시켜, 조 우레아를 얻었다. 에틸 아세테이트 및 헥산을 사용하여 플래쉬 크로마토그래피 (실리카 겔)에 의해 조 우레아를 정제하여, 4-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-카르보닐}-피페라진-2-온을 얻었다 (9.0 mg). LR-MS: 718.4 [(M+H)+].[4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine -1-yl-methanone (50 mg, 0.085 mmol, Example 8A) was dissolved in methylene chloride (1 mL) and cooled in an ice bath. Phosgene (250 μL, 20% solution in toluene) was added and the mixture was stirred for 30 minutes. Solvent was evaporated and the residue was taken up in methylene chloride. One third of the solution (0.028 mmol) was treated with 2-piperazinone (8.5 mg) and diisopropylethylamine (15 μl). The mixture was sonicated and left overnight at ambient temperature to aid in dissolution of the amine. It was diluted with methylene chloride and washed with water. The organic portion was separated and evaporated to give crude urea. The crude urea was purified by flash chromatography (silica gel) using ethyl acetate and hexanes to afford 4- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy- 4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-carbonyl} -piperazin-2-one was obtained (9.0 mg). LR-MS: 718.4 [(M + H) + ].
실시예Example 12 12
[4,5-[4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )-4,5-) -4,5- 디히Dihi 드로-이미다졸-1-일]-[4-(2-메탄술포닐-에틸)-피페라진-1-일]-메타논 Dro-imidazol-1-yl]-[4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone 히드로클로라이드Hydrochloride
메틸 비닐 술폰 (11 μL, 0.125 mmol)을 [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[피페라진-1-일]-메타논 (40 mg, 0.064 mmol, 실시예 8A), 및 디이소프로필에틸아민 (35 μL, 0.205 mmol)의 무수 디메틸포름아미드 (1.0 mL) 중 혼합물에 첨가하였다. 반응물을 하룻밤 교반하였다. 용매를 증발시키고 메틸렌 클로라이드 중 0 ∼ 5% 메탄올을 사용하여 잔류물을 실리카 겔 상에서 플래쉬 크로마토그래피하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-(메틸술폰)에틸)-피페라진-1-일]-메타논을 얻었고, 이를 희석 염산 (0.5 N, 1 mL) 중에 용해하고 동결건조하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-(메틸술폰)에틸)-피페라진-1-일]-메타논 히드로클로라이드를 미백색 분말로서 얻었다 (28 mg, 80%). LR-MS (APCI): 697.7 [(M+H)+]. Methyl vinyl sulfone (11 μL, 0.125 mmol) was dissolved in [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro. Anhydrous dimethylformamide of -imidazol-1-yl]-[piperazin-1-yl] -methanone (40 mg, 0.064 mmol, Example 8A), and diisopropylethylamine (35 μL, 0.205 mmol) (1.0 mL) to the mixture. The reaction was stirred overnight. The solvent was evaporated and the residue was flash chromatographed on silica gel using 0-5% methanol in methylene chloride to give [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4 -Trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2- (methylsulfon) ethyl) -piperazin-1-yl] -methanone was obtained, It was dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to afford [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl)- 4,5-Dihydro-imidazol-1-yl]-[4- (2- (methylsulfon) ethyl) -piperazin-1-yl] -methanone hydrochloride was obtained as an off-white powder (28 mg, 80 %). LR-MS (APCI): 697.7 [(M + H) + ].
실시예Example 13A 13A
4-{1-[4,5-4- {1- [4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )- 4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일메틸}-피페라진-2-온 히드로클로라이) -4,5-dihydro-imidazol-1-carbonyl] -piperidin-4-ylmethyl} -piperazin-2-one hydrochloric 드De
포스겐 (1.8 mL, 3.6 mmol, 톨루엔 중 1.9 M)을 트리에틸아민 (0.57 mL, 4.0 mmol) 및 4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로-페닐)-4,5-디히드로-1H-이미다졸 (550 mg, 1.2 mmol, 실시예 1)의 메틸렌 클로라이드 (5.0 mL) 중 냉각(0℃) 용액에 적가하였다. 반응 혼합물을 0℃ 에서 0.5 시간 동안 교반하였다. 용매를 감압 하에 제거하였다. 잔류물을 30 분 동안 고진공 하에 놓고, 메틸렌 클로라이드 (5.0 mL)에 용해하였다. 트리에틸아민 (0.170, 1.2 mmol) 및 4-(히드록시메틸)피페리딘 (0.50 g, 4.4 mmol)을 첨가하였다. 1 시간 후, 반응물을 수성 중탄산나트륨으로 워크업하고 메틸렌 클로라이드로 추출하였다. 유기 추출물을 염수로 세척하고, 무수 황산나트륨으로 건조하였다. 용매를 증발시키고 메틸렌 클로라이드 중 1∼4% 메탄올을 사용하여 실리카 겔 상에서 잔류물을 플래쉬 크로마토그래피하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-히드록시메틸-피페리딘-1-일]-메타논을 얻었다 (560 mg, 79%). Phosgene (1.8 mL, 3.6 mmol, 1.9 M in toluene) was added to triethylamine (0.57 mL, 4.0 mmol) and 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-tri Fluoro-phenyl) -4,5-dihydro-1H-imidazole (550 mg, 1.2 mmol, Example 1) was added dropwise to a cooled (0 ° C.) solution in methylene chloride (5.0 mL). The reaction mixture was stirred at 0 ° C for 0.5 h. The solvent was removed under reduced pressure. The residue was placed under high vacuum for 30 minutes and dissolved in methylene chloride (5.0 mL). Triethylamine (0.170, 1.2 mmol) and 4- (hydroxymethyl) piperidine (0.50 g, 4.4 mmol) were added. After 1 hour, the reaction was worked up with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was flash chromatographed on silica gel using 1-4% methanol in methylene chloride to give [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4 -Trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4-hydroxymethyl-piperidin-1-yl] -methanone was obtained (560 mg, 79% ).
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히 드로-이미다졸-1-일]-[4-히드록시메틸-피페리딘-1-일]-메타논 (60 mg, 0.096 mmol)의 메틸렌 클로라이드 (2 mL) 중 냉각(0℃) 용액에 카본 테트라브로마이드 (70 mg, 0.210 mmol), 이어서 트리페닐 포스핀 (55 mg, 0.21 mmol)을 첨가하였다. 반응 혼합물을 2.5 시간 동안 주변 온도에서 교반하였다. 반응물을 물로 희석하고, 메틸렌 클로라이드로 추출하였다. 유기 추출물을 물, 염수로 세척하고, 무수 황산나트륨으로 건조하였다. 용매를 증발시키고 메틸렌 클로라이드 중 1∼5% 메탄올을 사용하여 잔류물을 실리카 겔 상에서 크로마토그래피하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-브로모메틸-피페리딘-1-일]-메타논을 얻었다 (50 mg, 76%). [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 To a cooled (0 ° C.) solution of hydroxymethyl-piperidin-1-yl] -methanone (60 mg, 0.096 mmol) in methylene chloride (2 mL) followed by carbon tetrabromide (70 mg, 0.210 mmol) Triphenyl phosphine (55 mg, 0.21 mmol) was added. The reaction mixture was stirred for 2.5 hours at ambient temperature. The reaction was diluted with water and extracted with methylene chloride. The organic extract was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel using 1-5% methanol in methylene chloride to give [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4- Trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4-bromomethyl-piperidin-1-yl] -methanone was obtained (50 mg, 76%) .
피페라진-2-온 (21 mg, 0.21 mmol)을 [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-브로모메틸-피페리딘-1-일]-메타논 (48 mg, 0.07 mmol)의 무수 디메틸포름아미드 (2.0 mL) 중 용액에 첨가하였다. 혼합물을 70℃ 에서 하룻밤 교반하였다. 반응 혼합물을 주변 온도로 냉각하고, 메틸렌 클로라이드 및 염화암모늄 포화 수용액 사이를 분획시켰다. 수성 상을 메틸렌 클로라이드로 추출하고, 조합한 유기 추출물을 염수로 세척하고 무수 황산나트륨으로 건조하였다. 용매를 증발시키고 메틸렌 클로라이드 중 1∼5% 메탄올을 사용하여 잔류물을 실리카 겔 상에서 크로마토그래피하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(피페라진-2-온-4-일-메틸)-피페리딘-1-일]-메타논을 얻었고, 이를 희석 염산 (0.5 N, 1 mL) 중에 용해시키고 동결건조하여, [4,5-비스-(4-클로로-페닐)-2- (2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(피페라진-2-온-4-일-메틸)-피페리딘-1-일]-메타논 히드로클로라이드를 미백색 분말로서 얻었다 (23 mg, 45%). LR-MS (APCI): 702.4 [(M+H)+]. Piperazin-2-one (21 mg, 0.21 mmol) was purified by [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5 -Dihydro-imidazol-1-yl]-[4-bromomethyl-piperidin-1-yl] -methanone (48 mg, 0.07 mmol) was added to a solution in anhydrous dimethylformamide (2.0 mL) It was. The mixture was stirred at 70 ° C. overnight. The reaction mixture was cooled to ambient temperature and partitioned between methylene chloride and saturated aqueous ammonium chloride solution. The aqueous phase was extracted with methylene chloride and the combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel using 1-5% methanol in methylene chloride to give [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4- Trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (piperazin-2-one-4-yl-methyl) -piperidin-1-yl]- Methanone was obtained, which was dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to afford [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoro). Methyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (piperazin-2-one-4-yl-methyl) -piperidin-1-yl] -methanone hydro Chloride was obtained as an off-white powder (23 mg, 45%). LR-MS (APCI): 702.4 [(M + H) + ].
실시예Example 13B 13B
[4,5-[4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )-4,5-) -4,5- 디히드로Dehydro -- 이미다졸Imidazole -1-일]-[4-(3,3,3--1-yl]-[4- (3,3,3- 트리플루오로Trifluoro -2-히드록시-프로필)-피페라진-1-일]--2-hydroxy-propyl) -piperazin-1-yl]- 메타Meta 논 Paddy field 히드로클로라이드Hydrochloride
1,1,1-트리플루오로-2,3-에폭시프로판 (9 μL, 0.10 mmol)을 [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[피페라진-1-일]-메타논 (30 mg, 0.048 mmol) 및 트리에틸아민 (20 μL, 0.144 mmol)의 무수 메탄올 (1.0 mL) 중 혼합물에 첨가하였다. 반응물을 하룻밤 교반하였다. 용매를 증발시키고 메틸렌 클로라이드 중 0∼5% 메탄올을 사용하여 잔류물을 실리카 겔 상에서 크로마토그래피하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-히드록시-2-트리플루오로메틸에틸)-피페라진-1-일]-메타논을 얻었고, 이를 희석 염산 (0.5 N, 1 mL) 중에 용해하고 동결건조시켜, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리 플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-히드록시-2-트리플루오로메틸에틸)-피페라진-1-일]-메타논 히드로클로라이드를 미백색 분말로서 얻었다 (38 mg, 84%). LR-MS (APCI): 703.5 [(M+H)+]. 1,1,1-trifluoro-2,3-epoxypropane (9 μL, 0.10 mmol) was dissolved in [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-tri Fluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[piperazin-1-yl] -methanone (30 mg, 0.048 mmol) and triethylamine (20 μL, 0.144 mmol ) In anhydrous methanol (1.0 mL). The reaction was stirred overnight. The solvent was evaporated and the residue was chromatographed on silica gel using 0-5% methanol in methylene chloride to give [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4- Trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2-hydroxy-2-trifluoromethylethyl) -piperazin-1-yl] -meta Rice fields were obtained, which were dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl -Phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2-hydroxy-2-trifluoromethylethyl) -piperazin-1-yl] -methanone hydrochloride Obtained as an off white powder (38 mg, 84%). LR-MS (APCI): 703.5 [(M + H) + ].
실시예Example 14 14
[4,5-[4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -5--5- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )-4,5-) -4,5- 디히드로Dehydro -이미다졸-1-일]-{4-[4-(2-히드록시-에틸)-피페라진-1-일메틸]-페닐}-메타논 히-Imidazol-1-yl]-{4- [4- (2-hydroxy-ethyl) -piperazin-1-ylmethyl] -phenyl} -methanone hy 드로클로라이드Drochloride
4-클로로메틸벤조일 클로라이드 (140 mg, 0.74 mmol)를 트리에틸아민 (0.20 mL, 1.44 mmol) 및 4,5-비스-(4-클로로-페닐)-2-(2-에톡시-5-트리플루오로메틸-페닐)-4,5-디히드로-1H-이미다졸 (300 mg, 0.61 mmol)의 냉각 용액에 첨가하였다. 반응 혼합물을 2 시간 동안 실온에서 교반하였다. 반응물을 메틸렌 클로라이드로 희석하고, 물 및 염수로 세척하고, 무수 황산나트륨으로 건조하였다. 용매를 감압 하에 제거하고, 헥산 중 10∼25% 에틸 아세테이트를 사용하여 잔류물을 실리카 겔 상에서 플래쉬 크로마토그래피하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-5-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(4-클로로메틸-페닐)-메타논 을 얻었다 (330 mg, 84%). 4-chloromethylbenzoyl chloride (140 mg, 0.74 mmol) was added triethylamine (0.20 mL, 1.44 mmol) and 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-tri To a cold solution of fluoromethyl-phenyl) -4,5-dihydro-1H-imidazole (300 mg, 0.61 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature. The reaction was diluted with methylene chloride, washed with water and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was flash chromatographed on silica gel using 10-25% ethyl acetate in hexanes to afford [4,5-bis- (4-chloro-phenyl) -2- (2- Methoxy-5-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-chloromethyl-phenyl) -methanone was obtained (330 mg, 84%).
4-(2-히드록시에틸)-피페라진 (10 μL, 0.08 mmol)을 [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-5-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(4-클로로메틸-페닐)-메타논 (20 mg, 0.03 mmol) 및 디이소프로필에틸아민 (7 μL, 0.04 mmol)의 무수 디메틸포름아미드 (1.0 mL) 중 용액에 첨가하였다. 혼합물을 80℃ 에서 하룻밤 교반하였다. 용매를 증발시키고, 메틸렌 클로라이드 중 1∼5% 메탄올을 사용하여 잔류물을 실리카 겔 상에서 크로마토그래피하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-5-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-{(4-(2-히드록시에틸)피페라진-1-일)메틸}페닐]메타논을 얻고, 이를 희석 염산 (0.5 N, 1 mL)에 용해하고 동결건조하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-5-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-{(4-(2-히드록시에틸)피페라진-1-일)메틸}페닐]메타논 히드로클로라이드를 미백색 분말로서 얻었다 (21 mg, 98%). LR-MS (APCI): 726.1 [(M+H)+]. 4- (2-hydroxyethyl) -piperazine (10 μL, 0.08 mmol) was added [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-trifluoromethyl- Phenyl) -4,5-dihydro-imidazol-1-yl]-(4-chloromethyl-phenyl) -methanone (20 mg, 0.03 mmol) and diisopropylethylamine (7 μL, 0.04 mmol) To a solution in anhydrous dimethylformamide (1.0 mL). The mixture was stirred at 80 ° C. overnight. The solvent was evaporated and the residue was chromatographed on silica gel using 1-5% methanol in methylene chloride to give [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5 -Trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4-{(4- (2-hydroxyethyl) piperazin-1-yl) methyl} phenyl] meta Rice fields were obtained, dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to afford [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-trifluoromethyl -Phenyl) -4,5-dihydro-imidazol-1-yl]-[4-{(4- (2-hydroxyethyl) piperazin-1-yl) methyl} phenyl] methanone hydrochloride off white Obtained as a powder (21 mg, 98%). LR-MS (APCI): 726.1 [(M + H) + ].
실시예Example 15 15
4-{2-[4,5-4- {2- [4,5- 비스Vis -(4--(4- 클로로Chloro -- 페닐Phenyl )-2-(2-) -2- (2- 에톡시Ethoxy -4--4- 트리플루오로메틸Trifluoromethyl -- 페닐Phenyl )-4,5-디히드로-이미다졸-1-술포닐]-에틸}-모르폴린 ) -4,5-dihydro-imidazole-1-sulfonyl] -ethyl} -morpholine 히드로클로라이드Hydrochloride
2-클로로에틸술포닐 클로라이드 (0.26 mL, 2.5 mmol)를 트리에틸아민 (0.24 mL, 1.67 mmol) 및 4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-1H-이미다졸 (400 mg, 0.834 mmol, 실시예 1)의 메틸렌 클로라이드 (20 mL) 중 냉각(0℃) 용액에 첨가하였다. 반응 혼합물을 3 시간 동안 실온에서 교반하고, 포화 수성 염화암모늄으로 반응을 중단시켰다. 수성 상을 메틸렌 클로라이드로 추출하였다. 유기 추출물을 물, 염수로 세척하고, 무수 황산나트륨으로 건조하였다. 용매를 감압 하에 제거하고, 헥산 중 10∼50% 에틸 아세테이트를 사용하여 조 잔류물을 실리카 겔 상에서 플래쉬 크로마토그래피로 정제하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[비닐]술폰 (220 mg, 46%)을 얻었다.2-chloroethylsulfonyl chloride (0.26 mL, 2.5 mmol) was added triethylamine (0.24 mL, 1.67 mmol) and 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4- Trifluoromethyl-phenyl) -4,5-dihydro-1H-imidazole (400 mg, 0.834 mmol, Example 1) was added to a cooled (0 ° C.) solution in methylene chloride (20 mL). The reaction mixture was stirred for 3 hours at room temperature and the reaction was stopped with saturated aqueous ammonium chloride. The aqueous phase was extracted with methylene chloride. The organic extract was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography on silica gel using 10-50% ethyl acetate in hexanes to give [4,5-bis- (4-chloro-phenyl) -2- ( 2-Ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[vinyl] sulfone (220 mg, 46%) was obtained.
모르폴린 (19 μL, 0.22 mmol)을 [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[비닐]술폰 (40 mg, 0.07 mmol)의 벤젠 (2.0 mL) 중 용액에 첨가하였다. 혼합물을 50℃ 에서 하룻밤 교반하였다. 용매를 증발시키고, 헥산 중 50∼80% 에틸 아세테이트를 사용하여 잔류물을 실리카 겔 상에서 크로마토그래피하여, [4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[2-(모르폴린-1-일)에틸]술폰을 얻고, 이를 희석 염산 (0.5 N, 1 mL) 에 용해하고 동결건조하여, 4-{2-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-술포닐]-에틸}-모르폴린 히드로클로라이드를 미백색 분말로서 얻었다 (25 mg). LR-MS : 656.2 [(M+H)+]. Morpholine (19 μL, 0.22 mmol) was added [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro- Imidazol-1-yl]-[vinyl] sulfone (40 mg, 0.07 mmol) was added to the solution in benzene (2.0 mL). The mixture was stirred at 50 ° C. overnight. The solvent was evaporated and the residue was chromatographed on silica gel using 50-80% ethyl acetate in hexanes to give [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4 -Trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[2- (morpholin-1-yl) ethyl] sulfone, which is diluted with hydrochloric acid (0.5 N, 1 mL ) And freeze-dried to give 4- {2- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5- Dihydro-imidazole-1-sulfonyl] -ethyl} -morpholine hydrochloride was obtained as a white powder (25 mg). LR-MS: 656.2 [(M + H) + ].
실시예Example 16 16
1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-카르복실산 메틸 에스테르를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS : 648.3 [(M+H)+]. 1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperidine-4-carboxylic acid methyl ester was prepared in a similar manner as described in Example 5. LR-MS: 648.3 [(M + H) + ].
실시예Example 17 17
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 시아노메틸-메틸-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS : 575.2 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid cyanomethyl -Methyl-amide was prepared in a similar manner as described in Example 5. LR-MS: 575.2 [(M + H) + ].
실시예Example 18 18
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(1,4-디옥사-8-아자-스피로[4.5]데크-8-일)-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 648.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-(1 , 4-Dioxa-8-aza-spiro [4.5] dec-8-yl) -methanone was prepared in a similar manner as described in Example 5. LR-MS: 648.3 [(M + H) + ].
실시예Example 19 19
1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-3-카르복실산 에틸 에스테르를 실시예 5 에기재된 바와 유사한 방식으로 제조하였다. LR-MS: 662.3 [(M+H)+]. 1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -Piperidine-3-carboxylic acid ethyl ester was prepared in a similar manner as described in Example 5. LR-MS: 662.3 [(M + H) + ].
실시예Example 20 20
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 [1,3]디옥솔란-2-일메틸-메틸-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS : 622.2 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid [1, 3] dioxolan-2-ylmethyl-methyl-amide was prepared in a similar manner as described in Example 5. LR-MS: 622.2 [(M + H) + ].
실시예Example 21 21
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 (3-히드록시-프로필)-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 580.2 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid (3- Hydroxy-propyl) -amide was prepared in a similar manner as described in Example 5. LR-MS: 580.2 [(M + H) + ].
실시예Example 22 22
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 [2-(1-메틸-피롤리딘-2-일)-에틸]-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 633.3 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid [2- (1-Methyl-pyrrolidin-2-yl) -ethyl] -amide was prepared in a similar manner as described in Example 5. LR-MS: 633.3 [(M + H) + ].
실시예Example 23 23
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 (2-피리딘-2-일-에틸)-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 627.2 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid (2- Pyridin-2-yl-ethyl) -amide was prepared in a similar manner as described in Example 5. LR-MS: 627.2 [(M + H) + ].
실시예Example 24 24
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 (푸란-2-일메틸)-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 602.2 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid (furan- 2-ylmethyl) -amide was prepared in a similar manner as described in Example 5. LR-MS: 602.2 [(M + H) + ].
실시예Example 25 25
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 (피리딘-3-일메틸)-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 613.2 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid (pyridine- 3-ylmethyl) -amide was prepared in a similar manner as described in Example 5. LR-MS: 613.2 [(M + H) + ].
실시예Example 26 26
1-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-1,3-디히드로-벤조이미다졸-2-온을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 722.3 [(M+H)+]. 1- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-yl} -1,3-dihydro-benzoimidazol-2-one was prepared in a similar manner as described in Example 5. LR-MS: 722.3 [(M + H) + ].
실시예Example 27 27
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 메틸-(1-메틸-피롤리딘-3-일)-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 619.3 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid methyl- ( 1-Methyl-pyrrolidin-3-yl) -amide was prepared in a similar manner as described in Example 5. LR-MS: 619.3 [(M + H) + ].
실시예Example 28 28
1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-2-카르복실산 에틸 에스테르를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 662.3 [(M+H)+]. 1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperidine-2-carboxylic acid ethyl ester was prepared in a similar manner as described in Example 5. LR-MS: 662.3 [(M + H) + ].
실시예Example 29 29
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(4-피리미딘-2-일-피페라진-1-일)-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 669.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-(4 -Pyrimidin-2-yl-piperazin-1-yl) -methanone was prepared in a similar manner as described in Example 5. LR-MS: 669.3 [(M + H) + ].
실시예Example 30 30
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 3-메톡시-벤질아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 642.2 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid 3-meth Toxy-benzylamide was prepared in a similar manner as described in Example 5. LR-MS: 642.2 [(M + H) + ].
실시예Example 31 31
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 (2-히드록시-에틸)-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 566.2 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid (2- Hydroxy-ethyl) -amide was prepared in a similar manner as described in Example 5. LR-MS: 566.2 [(M + H) + ].
실시예Example 32 32
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 (2-히드록시-에틸)-메틸-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 580.2 [(M+H)+].4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid (2- Hydroxy-ethyl) -methyl-amide was prepared in a similar manner as described in Example 5. LR-MS: 580.2 [(M + H) + ].
실시예Example 33 33
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 (2-메톡시-1-메틸-에틸)-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 594.2 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid (2- Methoxy-1-methyl-ethyl) -amide was prepared in a similar manner as described in Example 5. LR-MS: 594.2 [(M + H) + ].
실시예Example 34 34
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 (1-에틸-피롤리딘-2-일메틸)-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 633.3 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid (1- Ethyl-pyrrolidin-2-ylmethyl) -amide was prepared in a similar manner as described in Example 5. LR-MS: 633.3 [(M + H) + ].
실시예Example 35 35
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 (2-시아노-에틸)-메틸-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 589.2 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid (2- Cyano-ethyl) -methyl-amide was prepared in a similar manner as described in Example 5. LR-MS: 589.2 [(M + H) + ].
실시예Example 36 36
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 메틸-피리딘-2-일-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 613.47 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid methyl-pyridine 2-yl-amide was prepared in a similar manner as described in Example 5. LR-MS: 613.47 [(M + H) + ].
실시예Example 37 37
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 메틸-(1-메틸-피페리딘-4-일)-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 633.3 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid methyl- ( 1-Methyl-piperidin-4-yl) -amide was prepared in a similar manner as described in Example 5. LR-MS: 633.3 [(M + H) + ].
실시예Example 38 38
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 푸란-2-일메틸-메틸-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 616.3 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid furan-2 -Ylmethyl-methyl-amide was prepared in a similar manner as described in Example 5. LR-MS: 616.3 [(M + H) + ].
실시예Example 39 39
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 (2-히드록시-벤질)-메틸-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 642.3 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid (2- Hydroxy-benzyl) -methyl-amide was prepared in a similar manner as described in Example 5. LR-MS: 642.3 [(M + H) + ].
실시예Example 40 40
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 4-술파모일-벤질아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 691.2 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid 4-sulfa Moyl-benzylamide was prepared in a similar manner as described in Example 5. LR-MS: 691.2 [(M + H) + ].
실시예Example 41 41
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 메톡시-메틸-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 566.2 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid methoxy- Methyl-amide was prepared in a similar manner as described in Example 5. LR-MS: 566.2 [(M + H) + ].
실시예Example 42 42
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 (3-이미다졸-1-일-프로필)-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 630.3 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid (3- Imidazol-1-yl-propyl) -amide was prepared in a similar manner as described in Example 5. LR-MS: 630.3 [(M + H) + ].
실시예Example 43 43
1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피롤리딘-2-카르복실산 메틸 에스테르를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 634.2 [(M+H)+]. 1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -Pyrrolidine-2-carboxylic acid methyl ester was prepared in a similar manner as described in Example 5. LR-MS: 634.2 [(M + H) + ].
실시예Example 44 44
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(3-피롤리딘-1-일-프로필)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 702.5 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(3-Pyrrolidin-1-yl-propyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 702.5 [(M + H) + ].
실시예Example 45 45
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(푸란-2-카르보닐)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 684.5 (M+). [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(Furan-2-carbonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 684.5 (M + ).
실시예Example 46 46
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(4-피리딘-4-일-피페라진-1-일)-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 667.8 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-(4 -Pyridin-4-yl-piperazin-1-yl) -methanone was prepared in a similar manner as described in Example 5. LR-MS: 667.8 [(M + H) + ].
실시예Example 47 47
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2,3-디히드로-벤조[1,4]디옥신-2-카르보닐)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 752.9 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2,3-Dihydro-benzo [1,4] dioxin-2-carbonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 752.9 [(M + H) + ].
실시예Example 48 48
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-1-피페리딘-1-일-에타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 715.9 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -1-piperidin-1-yl-ethanone was prepared in a similar manner as described in Example 5. LR-MS: 715.9 [(M + H) + ].
실시예Example 49 49
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-모르폴린-4-일-에틸)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 704 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2-Morpholin-4-yl-ethyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 704 [(M + H) + ].
실시예Example 50 50
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(3-피페리딘-1-일-프로필)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 716 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(3-piperidin-1-yl-propyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 716 [(M + H) + ].
실시예Example 51 51
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 [2-(2-옥소-이미다졸리딘-1-일)-에틸]-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 633.9 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid [2- (2-oxo-imidazolidin-1-yl) -ethyl] -amide was prepared in a similar manner as described in Example 5. LR-MS: 633.9 [(M + H) + ].
실시예Example 52 52
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(3-디프로필아미노-프로필)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 732 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(3-Dipropylamino-propyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 732 [(M + H) + ].
실시예Example 53 53
6-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-니코티노니트릴을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 692.9 [(M+H)+]. 6- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -nicotinonitrile was prepared in a similar manner as described in Example 5. LR-MS: 692.9 [(M + H) + ].
실시예Example 54 54
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(3-디메틸아미노-프로필)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 675.9 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(3-dimethylamino-propyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 675.9 [(M + H) + ].
실시예Example 55 55
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(4-피리딘-4-일메틸-피페라진-1-일)-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 682.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-(4 -Pyridin-4-ylmethyl-piperazin-1-yl) -methanone was prepared in a similar manner as described in Example 5. LR-MS: 682.4 [(M + H) + ].
실시예Example 56 56
{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-아세트산 에틸 에스테르를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 676.9 [(M+H)+]. {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl ] -Piperazin-1-yl} -acetic acid ethyl ester was prepared in a similar manner as described in Example 5. LR-MS: 676.9 [(M + H) + ].
실시예Example 57 57
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-에톡시-에틸)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 662.9 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2-Ethoxy-ethyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 662.9 [(M + H) + ].
실시예Example 58 58
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-디이소프로필아미노-에틸)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 718 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2-Diisopropylamino-ethyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 718 [(M + H) + ].
실시예Example 59 59
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-디메틸아미노-에틸)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 661.9 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2-Dimethylamino-ethyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 661.9 [(M + H) + ].
실시예Example 60 60
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(테트라히드로-푸란-2-카르보닐)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 688.9 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(Tetrahydro-furan-2-carbonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 688.9 [(M + H) + ].
실시예Example 61 61
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-디프로필아미노-에틸)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 718 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2-Dipropylamino-ethyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 718 [(M + H) + ].
실시예Example 62 62
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(3-디에틸아미노-프로필)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 704 [ (M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(3-Diethylamino-propyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 704 [(M + H) + ].
실시예Example 63 63
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-피롤리딘-1-일-에틸)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 688 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2-Pyrrolidin-1-yl-ethyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 688 [(M + H) + ].
실시예Example 64 64
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N,N-디메틸-아세트아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 676.3 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N, N-dimethyl-acetamide was prepared in a similar manner as described in Example 5. LR-MS: 676.3 [(M + H) + ].
실시예Example 65 65
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-메톡시-에틸)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS:648.9 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2-methoxy-ethyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 648.9 [(M + H) + ].
실시예Example 66 66
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-디에틸아미노-에틸)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 690 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2-Diethylamino-ethyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 690 [(M + H) + ].
실시예Example 67 67
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(5-트리플루오로메틸-피리딘-2-일)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 735.9 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(5-Trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 735.9 [(M + H) + ].
실시예Example 68 68
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(3-메톡시-프로필)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 662.9 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(3-methoxy-propyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 662.9 [(M + H) + ].
실시예Example 69 69
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-1-피롤리딘-1-일-에타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 701.9 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -1-pyrrolidin-1-yl-ethanone was prepared in a similar manner as described in Example 5. LR-MS: 701.9 [(M + H) + ].
실시예Example 70 70
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(1-메틸-피페리딘-3-일메틸)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 702 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(1-Methyl-piperidin-3-ylmethyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 702 [(M + H) + ].
실시예Example 71 71
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(테트라히드로-푸란-2-일메틸)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 675 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(Tetrahydro-furan-2-ylmethyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 675 [(M + H) + ].
실시예Example 72 72
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-니코티노니트릴을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 692.9 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -nicotinonitrile was prepared in a similar manner as described in Example 5. LR-MS: 692.9 [(M + H) + ].
실시예Example 73 73
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(4-페닐-피페리딘-1-일)-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 665.9 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-(4 -Phenyl-piperidin-1-yl) -methanone was prepared in a similar manner as described in Example 5. LR-MS: 665.9 [(M + H) + ].
실시예Example 74 74
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-피페리딘-1-일-에틸)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 702.5 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2-piperidin-1-yl-ethyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 702.5 [(M + H) + ].
실시예Example 75 75
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 메틸아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 535.8 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid methylamide Prepared in a similar manner as described in Example 5. LR-MS: 535.8 [(M + H) + ].
실시예Example 76 76
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 (2-메톡시-에틸)-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 579.9 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid (2- Methoxy-ethyl) -amide was prepared in a similar manner as described in Example 5. LR-MS: 579.9 [(M + H) + ].
실시예Example 77 77
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(2,3,5,6-테트라히드로-[1,2']비피라지닐-4-일)-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 669.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-(2 , 3,5,6-tetrahydro- [1,2 '] bipyrazinyl-4-yl) -methanone was prepared in a similar manner as described in Example 5. LR-MS: 669.4 [(M + H) + ].
실시예Example 78 78
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 메톡시-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 551.8 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid methoxy- Amides were prepared in a similar manner as described in Example 5. LR-MS: 551.8 [(M + H) + ].
실시예Example 79 79
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 에톡시-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 565.9 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid ethoxy- Amides were prepared in a similar manner as described in Example 5. LR-MS: 565.9 [(M + H) + ].
실시예Example 80 80
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 (2,5-디메톡시-페닐)-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 657.9 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid (2, 5-dimethoxy-phenyl) -amide was prepared in a similar manner as described in Example 5. LR-MS: 657.9 [(M + H) + ].
실시예Example 81 81
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-1-모르폴린-4-일-에타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 718.4 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -1-morpholin-4-yl-ethanone was prepared in a similar manner as described in Example 5. LR-MS: 718.4 [(M + H) + ].
실시예Example 82 82
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(3,5-디메톡시-페닐)-피페라진-1-일]-메타논을 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 727 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(3,5-Dimethoxy-phenyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 5. LR-MS: 727 [(M + H) + ].
실시예Example 83 83
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-메톡시-에타논 히드로클로라이드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 663.4 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2-methoxy-ethanone hydrochloride was prepared in a similar manner as described in Example 5. LR-MS: 663.4 [(M + H) + ].
실시예Example 84 84
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(4-플루오로-페닐)-피페라진-1-일]-메타논 히드로클로라이드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 685.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(4-Fluoro-phenyl) -piperazin-1-yl] -methanone hydrochloride was prepared in a similar manner as described in Example 5. LR-MS: 685.3 [(M + H) + ].
실시예Example 85 85
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르복실산 비스-(2-메톡시-에틸)-아미드를 실시예 5 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 638.3 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carboxylic acid bis- ( 2-methoxy-ethyl) -amide was prepared in a similar manner as described in Example 5. LR-MS: 638.3 [(M + H) + ].
실시예Example 86 86
4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(4-프로필-벤젠술포닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 773.5 [(M+H)+]. 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (4-propyl-benzenesulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 773.5 [(M + H) + ].
실시예Example 87 87
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(티오펜-2-카르보닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 701.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(Thiophene-2-carbonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 701.4 [(M + H) + ].
실시예Example 88 88
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(1,5-디메틸-1H-피라졸-3-카르보닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 713.4 [(M+H)+] [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(1,5-Dimethyl-1H-pyrazole-3-carbonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 713.4 [(M + H) + ]
실시예Example 89 89
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(5-클로로-1,3-디메틸-1H-피라졸-4-술포닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 783.50 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 783.50 [(M + H) + ].
실시예Example 90 90
아세트산 2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-1,1-디메틸-2-옥소-에틸 에스테르를 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 719.5 [(M+H)+]. Acetic acid 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -1,1-dimethyl-2-oxo-ethyl ester was prepared in a similar manner as described in Example 6. LR-MS: 719.5 [(M + H) + ].
실시예Example 91 91
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(푸란-3-카르보닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 685.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(Furan-3-carbonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 685.4 [(M + H) + ].
실시예Example 92 92
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(피리딘-4-카르보닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 696.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(Pyridine-4-carbonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 696.4 [(M + H) + ].
실시예Example 93 93
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(티오펜-3-카르보닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 701.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(Thiophene-3-carbonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 701.4 [(M + H) + ].
실시예Example 94 94
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(티오펜-2-술포닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 737.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(Thiophene-2-sulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 737.4 [(M + H) + ].
실시예Example 95 95
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(4-메틸-[1,2,3]티아디아졸-5-카르보닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 717.4 [(M+H)+] [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(4-Methyl- [1,2,3] thiadiazole-5-carbonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 717.4 [(M + H) + ]
실시예Example 96 96
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2,4-디메틸-티아졸-5-술포닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 766.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2,4-Dimethyl-thiazole-5-sulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 766.4 [(M + H) + ].
실시예Example 97 97
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(3,5-디메틸-이속사졸-4-카르보닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 714.5 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(3,5-Dimethyl-isoxazole-4-carbonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 714.5 [(M + H) + ].
실시예Example 98 98
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(티오펜-3-술포닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 737.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(Thiophen-3-sulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 737.3 [(M + H) + ].
실시예Example 99 99
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2,5-디클로로-티오펜-3-카르보닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 769.3 (M+). [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2,5-Dichloro-thiophene-3-carbonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 769.3 (M + ).
실시예Example 100 100
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2,5-디메틸-푸란-3-카르보닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 713.5 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2,5-Dimethyl-furan-3-carbonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 713.5 [(M + H) + ].
실시예Example 101 101
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(1,2-디메틸-1H-이미다졸-4-술포닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 749.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(1,2-Dimethyl-1H-imidazol-4-sulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 749.4 [(M + H) + ].
실시예Example 102 102
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-메톡시-에타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 663.4 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2-methoxy-ethanone was prepared in a similar manner as described in Example 6. LR-MS: 663.4 [(M + H) + ].
실시예Example 103 103
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2,5-디클로로-티오펜-3-술포닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 805.3 (M+). [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2,5-Dichloro-thiophen-3-sulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 805.3 (M + ).
실시예Example 104 104
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-티오펜-2-일-에타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 715.4 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2-thiophen-2-yl-ethanone was prepared in a similar manner as described in Example 6. LR-MS: 715.4 [(M + H) + ].
실시예Example 105 105
1-(4-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-카르보닐}-피페리딘-1-일)-에타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 744.5 [(M+H)+]. 1- (4- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole -1-carbonyl] -piperazin-1-carbonyl} -piperidin-1-yl) -ethanone was prepared in a similar manner as described in Example 6. LR-MS: 744.5 [(M + H) + ].
실시예Example 106 106
4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-술폰산 디메틸아미드를 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 698.4 [(M+H)+]. 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperazine-1-sulfonic acid dimethylamide was prepared in a similar manner as described in Example 6. LR-MS: 698.4 [(M + H) + ].
실시예Example 107 107
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(부탄-1-술포닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 711.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(Butane-1-sulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 711.4 [(M + H) + ].
실시예Example 108 108
3-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-술포닐}-티오펜-2-카르복실산 메틸 에스테르를 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 795.4 [(M+H)+]. 3- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-sulfonyl} -thiophene-2-carboxylic acid methyl ester was prepared in a similar manner as described in Example 6. LR-MS: 795.4 [(M + H) + ].
실시예Example 109 109
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(5-클로로-티오펜-2-술포닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 771.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(5-Chloro-thiophen-2-sulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 771.3 [(M + H) + ].
실시예Example 110 110
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(4-트리플루오로메탄술포닐-피페라진-1-일)-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 723.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-(4 -Trifluoromethanesulfonyl-piperazin-1-yl) -methanone was prepared in a similar manner as described in Example 6. LR-MS: 723.4 [(M + H) + ].
실시예Example 111 111
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(3,5-디메틸-이속사졸-4-술포닐)-피페라진-1-일]-메타논을 실시예 6 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 750.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(3,5-Dimethyl-isoxazole-4-sulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 6. LR-MS: 750.4 [(M + H) + ].
실시예Example 112 112
4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-1-(2-메톡시-에틸)-피페라진-2-온을 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 663.2 [(M+H)+]. 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -1- (2-methoxy-ethyl) -piperazin-2-one was prepared in a similar manner as described in Example 7. LR-MS: 663.2 [(M + H) + ].
실시예Example 113 113
4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-1-(2-모르폴린-4-일-에틸)-피페라진-2-온 히드로클로라이드를 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 718.4 [(M+H)+]. 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -1- (2-Morpholin-4-yl-ethyl) -piperazin-2-one hydrochloride was prepared in a similar manner as described in Example 7. LR-MS: 718.4 [(M + H) + ].
실시예Example 114 114
4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-술폰산 아미드를 실시예 7 에 기재된 바 와 유사한 방식으로 제조하였다. LR-MS: 670.3 [(M+H)+]. 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperazine-1-sulfonic acid amide was prepared in a similar manner as described in Example 7. LR-MS: 670.3 [(M + H) + ].
실시예Example 115 115
4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-술폰산 메틸아미드를 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 684.2 [(M+H)+]. 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperazine-1-sulfonic acid methylamide was prepared in a similar manner as described in Example 7. LR-MS: 684.2 [(M + H) + ].
실시예Example 116 116
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(피롤리딘-1-술포닐)-피페라진-1-일]-메타논을 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 724.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(Pyrrolidin-1-sulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 7. LR-MS: 724.3 [(M + H) + ].
실시예Example 117 117
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(피페리딘-1-술포닐)-피페라진-1-일]-메타논을 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 738.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(Piperidin-1-sulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 7. LR-MS: 738.3 [(M + H) + ].
실시예Example 118 118
4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-술폰산 이소부틸-아미드를 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 726.3 [(M+H)+]. 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperazine-1-sulfonic acid isobutyl-amide was prepared in a similar manner as described in Example 7. LR-MS: 726.3 [(M + H) + ].
실시예Example 119 119
4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-술폰산 (2-메톡시-에틸)-아미드를 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 728.2 [(M+H)+]. 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperazine-1-sulfonic acid (2-methoxy-ethyl) -amide was prepared in a similar manner as described in Example 7. LR-MS: 728.2 [(M + H) + ].
실시예Example 120 120
4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-술폰산 비스-(2-메톡시-에틸)-아미드를 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 786.3 [(M+H)+]. 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperazine-1-sulfonic acid bis- (2-methoxy-ethyl) -amide was prepared in a similar manner as described in Example 7. LR-MS: 786.3 [(M + H) + ].
실시예Example 121 121
4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-술폰산 (테트라히드로-푸란-2-일메틸)-아미드를 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 754.3 [(M+H)+]. 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperazine-1-sulfonic acid (tetrahydro-furan-2-ylmethyl) -amide was prepared in a similar manner as described in Example 7. LR-MS: 754.3 [(M + H) + ].
실시예Example 122 122
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(3-히드록시-피페리딘-1-술포닐)-피페라진-1-일]-메타논을 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 754.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(3-hydroxy-piperidin-1-sulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 7. LR-MS: 754.3 [(M + H) + ].
실시예Example 123 123
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-{4-[4-(2-히드록시-에틸)-피페라진-1-술포닐]-피페라진-1-일}-메타논을 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 783.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-{4 -[4- (2-hydroxy-ethyl) -piperazin-1-sulfonyl] -piperazin-1-yl} -methanone was prepared in a similar manner as described in Example 7. LR-MS: 783.3 [(M + H) + ].
실시예Example 124 124
1-(4-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-술포닐}-피페라진-1-일)-에타논을 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 781.3 [(M+H)+]. 1- (4- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole -1-carbonyl] -piperazin-1-sulfonyl} -piperazin-1-yl) -ethanone was prepared in a similar manner as described in Example 7. LR-MS: 781.3 [(M + H) + ].
실시예Example 125 125
4-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-술포닐}-피페라진-2-온을 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 753.2 [(M+H)+]. 4- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-sulfonyl} -piperazin-2-one was prepared in a similar manner as described in Example 7. LR-MS: 753.2 [(M + H) + ].
실시예Example 126 126
4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-술폰산 (2-디메틸아미노-에틸)-아미드를 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 741.2 [(M+H)+]. 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperazine-1-sulfonic acid (2-dimethylamino-ethyl) -amide was prepared in a similar manner as described in Example 7. LR-MS: 741.2 [(M + H) + ].
실시예Example 127 127
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(4-피롤리딘-1-일-피페리딘-1-술포닐)-피페라진-1-일]-메타논을 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 807.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(4-Pyrrolidin-1-yl-piperidine-1-sulfonyl) -piperazin-1-yl] -methanone was prepared in a similar manner as described in Example 7. LR-MS: 807.3 [(M + H) + ].
실시예Example 128 128
4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-술폰산 (2,2,2-트리플루오로-에틸)-아미드를 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 752.2 [(M+H)+]. 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperazine-1-sulfonic acid (2,2,2-trifluoro-ethyl) -amide was prepared in a similar manner as described in Example 7. LR-MS: 752.2 [(M + H) + ].
실시예Example 129 129
4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-술폰산 (2-시아노-에틸)-메틸-아미드를 실시예 7 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 737.3 [(M+H)+]. 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperazine-1-sulfonic acid (2-cyano-ethyl) -methyl-amide was prepared in a similar manner as described in Example 7. LR-MS: 737.3 [(M + H) + ].
실시예Example 130 130
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(3,3,3-트리플루오로-프로필)-피페라진-1-일]-메타논 히드로클로라이드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 687.5 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(3,3,3-trifluoro-propyl) -piperazin-1-yl] -methanone hydrochloride was prepared in a similar manner as described in Example 8. LR-MS: 687.5 [(M + H) + ].
실시예Example 131 131
{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-아세토니트릴 히드로클로라이드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 630.2 [(M+H)+]. {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl ] -Piperazin-1-yl} -acetonitrile hydrochloride was prepared in a similar manner as described in Example 8. LR-MS: 630.2 [(M + H) + ].
실시예Example 132 132
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-메톡시-에틸)-피페라진-1-일]-메타논 히드로클로라이드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 649.5 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2-methoxy-ethyl) -piperazin-1-yl] -methanone hydrochloride was prepared in a similar manner as described in Example 8. LR-MS: 649.5 [(M + H) + ].
실시예Example 133 133
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-(2-메톡시-1-메틸-에틸)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS : 720.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N- (2-methoxy-1-methyl-ethyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 720.5 [(M + H) + ].
실시예Example 134 134
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-(2-메톡시-에틸)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 706.4 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N- (2-methoxy-ethyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 706.4 [(M + H) + ].
실시예Example 135 135
N-벤질옥시-2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 754.5 [(M+H)+]. N-benzyloxy-2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro- Imidazole-1-carbonyl] -piperazin-1-yl} -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 754.5 [(M + H) + ].
실시예Example 136 136
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-메톡시-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 678.4 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N-methoxy-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 678.4 [(M + H) + ].
실시예Example 137 137
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-에톡시-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 692.4 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N-ethoxy-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 692.4 [(M + H) + ].
실시예Example 138 138
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-(5-메틸-푸란-2-일메틸)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 742.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N- (5-methyl-furan-2-ylmethyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 742.5 [(M + H) + ].
실시예Example 139 139
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-1-(4-트리플루오로메틸-피페리딘-1-일)-에타논을 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 784.5 [(M+H)+] 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -1- (4-trifluoromethyl-piperidin-1-yl) -ethanone was prepared in a similar manner as described in Example 8. LR-MS: 784.5 [(M + H) + ]
실시예Example 140 140
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-프로필-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 690.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N-propyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 690.5 [(M + H) + ].
실시예Example 141 141
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-이소프로필-N-메틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 704.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N-isopropyl-N-methyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 704.5 [(M + H) + ].
실시예Example 142 142
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-메톡시-N-메틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 692.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N-methoxy-N-methyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 692.5 [(M + H) + ].
실시예Example 143 143
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-(2-시아노-에틸)-N-메틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 715.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N- (2-cyano-ethyl) -N-methyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 715.5 [(M + H) + ].
실시예Example 144 144
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-시아노메틸-N-메틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 701.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N-cyanomethyl-N-methyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 701.5 [(M + H) + ].
실시예Example 145 145
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-1-(3-히드록시-피페리딘-1-일)-에타논을 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 732.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -1- (3-hydroxy-piperidin-1-yl) -ethanone was prepared in a similar manner as described in Example 8. LR-MS: 732.5 [(M + H) + ].
실시예Example 146 146
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-(2-히드록시-에틸)-N-메틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 706.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N- (2-hydroxy-ethyl) -N-methyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 706.5 [(M + H) + ].
실시예Example 147 147
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-이소부틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 704.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N-isobutyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 704.5 [(M + H) + ].
실시예Example 148 148
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N,N-비스-(2-메톡시-에틸)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 764.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N, N-bis- (2-methoxy-ethyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 764.5 [(M + H) + ].
실시예Example 149 149
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-1-티오모르폴린-4-일-에타논을 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 734.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -1-thiomorpholin-4-yl-ethanone was prepared in a similar manner as described in Example 8. LR-MS: 734.5 [(M + H) + ].
실시예Example 150 150
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-푸란-2-일메틸-N-메틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 742.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N-furan-2-ylmethyl-N-methyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 742.5 [(M + H) + ].
실시예Example 151 151
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-[1,3]디옥솔란-2-일메틸-N-메틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 748.4 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N- [1,3] dioxolan-2-ylmethyl-N-methyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 748.4 [(M + H) + ].
실시예Example 152 152
1-(4-아세틸-피페라진-1-일)-2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-에타논을 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 759.5 [(M+H)+]. 1- (4-acetyl-piperazin-1-yl) -2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl- Phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -ethanone was prepared in a similar manner as described in Example 8. LR-MS: 759.5 [(M + H) + ].
실시예Example 153 153
1-({4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-아세틸)-피페리딘-3-카르복실산 디에틸아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 815.6 [(M+H)+]. 1-({4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -acetyl) -piperidine-3-carboxylic acid diethylamide was prepared in a similar manner as described in Example 8. LR-MS: 815.6 [(M + H) + ].
실시예Example 154 154
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-시클로프로필-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 688.4 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N-cyclopropyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 688.4 [(M + H) + ].
실시예Example 155 155
4-({4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-아세틸)-피페라진-2-온을 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 731.5 [(M+H)+]. 4-({4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -acetyl) -piperazin-2-one was prepared in a similar manner as described in Example 8. LR-MS: 731.5 [(M + H) + ].
실시예Example 156 156
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-(2,2,2-트리플루오로-에틸)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 730.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N- (2,2,2-trifluoro-ethyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 730.5 [(M + H) + ].
실시예Example 157 157
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 648.4 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 648.4 [(M + H) + ].
실시예Example 158 158
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N,N-디에틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 704.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N, N-diethyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 704.5 [(M + H) + ].
실시예Example 159 159
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-(2-메틸-알릴)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 702.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N- (2-methyl-allyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 702.5 [(M + H) + ].
실시예Example 160 160
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-(1-히드록시메틸-3-메틸-부틸)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 748.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N- (1-hydroxymethyl-3-methyl-butyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 748.5 [(M + H) + ].
실시예Example 161 161
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-1-[4-(2-히드록시-에틸)-피페리딘-1-일]-에타논을 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 760.50 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -1- [4- (2-hydroxy-ethyl) -piperidin-1-yl] -ethanone was prepared in a similar manner as described in Example 8. LR-MS: 760.50 [(M + H) + ].
실시예Example 162 162
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-1-(4-히드록시메틸-피페리딘-1-일)-에타논을 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 746.50 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -1- (4-hydroxymethyl-piperidin-1-yl) -ethanone was prepared in a similar manner as described in Example 8. LR-MS: 746.50 [(M + H) + ].
실시예Example 163 163
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-1-(1,4-디옥사-8-아자-스피로 [4.5]데크-8-일)-에타논을 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 774.50 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -1- (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -ethanone is prepared in a similar manner as described in Example 8 It was. LR-MS: 774.50 [(M + H) + ].
실시예Example 164 164
1-({4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-아세틸)-피페리딘-3-카르복실산 아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 760 [(M+H)+]. 1-({4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -acetyl) -piperidine-3-carboxylic acid amide was prepared in a similar manner as described in Example 8. LR-MS: 760 [(M + H) + ].
실시예Example 165 165
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-(테트라히드로-푸란-2-일메틸)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 732.5 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N- (tetrahydro-furan-2-ylmethyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 732.5 [(M + H) + ].
실시예Example 166 166
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-N-(3-히드록시-프로필)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 706.30 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -N- (3-hydroxy-propyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 706.30 [(M + H) + ].
실시예Example 167 167
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-메틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 676.5 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N-methyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 676.5 [(M + H) + ].
실시예Example 168 168
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-(2-메톡시-1-메틸-에틸)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 734.5 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N- (2-methoxy-1-methyl-ethyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 734.5 [(M + H) + ].
실시예Example 169 169
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-(2-메톡시-에틸)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 720.5 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N- (2-methoxy-ethyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 720.5 [(M + H) + ].
실시예Example 170 170
N-벤질옥시-2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 768.5 [(M+H)+]. N-benzyloxy-2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro- Imidazole-1-carbonyl] -piperidin-4-ylamino} -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 768.5 [(M + H) + ].
실시예Example 171 171
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-메톡시-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 692.4 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N-methoxy-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 692.4 [(M + H) + ].
실시예Example 172 172
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-(5-메틸-푸란-2-일메틸)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 756.5 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N- (5-methyl-furan-2-ylmethyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 756.5 [(M + H) + ].
실시예Example 173 173
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-1-(4-트리플루오로메틸-피페리딘-1-일)-에타논을 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 798.5 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -1- (4-trifluoromethyl-piperidin-1-yl) -ethanone was prepared in a similar manner as described in Example 8. LR-MS: 798.5 [(M + H) + ].
실시예Example 174 174
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-프로필-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 704.5 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N-propyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 704.5 [(M + H) + ].
실시예Example 175 175
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-메톡시-N-메틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 706.4 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N-methoxy-N-methyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 706.4 [(M + H) + ].
실시예Example 176 176
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-(2-시아노-에틸)-N-메틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 729.5 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N- (2-cyano-ethyl) -N-methyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 729.5 [(M + H) + ].
실시예Example 177 177
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-시아노메틸-N-메틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 715.5 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N-cyanomethyl-N-methyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 715.5 [(M + H) + ].
실시예Example 178 178
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-1-(3-히드록시-피페리딘-1-일)-에타논을 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 746.5 [(M+H)+] 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -1- (3-hydroxy-piperidin-1-yl) -ethanone was prepared in a similar manner as described in Example 8. LR-MS: 746.5 [(M + H) + ]
실시예Example 179 179
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-(2-히드록시-에틸)-N-메틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 720.4 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N- (2-hydroxy-ethyl) -N-methyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 720.4 [(M + H) + ].
실시예Example 180 180
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-이소부틸-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 718.5 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N-isobutyl-acetamide was prepared in a similar manner as described in Example 8. LR-MS: 718.5 [(M + H) + ].
실시예Example 181 181
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 662.4 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 662.4 [(M + H) + ].
실시예Example 182 182
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-(2,2,2-트리플루오로-에틸)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 744.5 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N- (2,2,2-trifluoro-ethyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 744.5 [(M + H) + ].
실시예Example 183 183
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-(2-메틸-알릴)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 716.5 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N- (2-methyl-allyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 716.5 [(M + H) + ].
실시예Example 184 184
2-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일아미노}-N-(1-히드록시메틸-3-메틸-부틸)-아세트아미드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 762.6 [(M+H)+]. 2- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-ylamino} -N- (1-hydroxymethyl-3-methyl-butyl) -acetamide was prepared in a similar manner as described in Example 8. LR-MS: 762.6 [(M + H) + ].
실시예Example 185 185
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-에탄술폰산 디메틸아미드 히드로클로라이드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 726.2 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -ethanesulfonic acid dimethylamide hydrochloride was prepared in a similar manner as described in Example 8. LR-MS: 726.2 [(M + H) + ].
실시예Example 186 186
2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-에탄술폰산 아미드 히드로클로라이드를 실시예 8 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 698.1 [(M+H)+]. 2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -ethanesulfonic acid amide hydrochloride was prepared in a similar manner as described in Example 8. LR-MS: 698.1 [(M + H) + ].
실시예Example 187 187
2-(4-아세틸-피페라진-1-일)-N-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-아세트아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 773.4 [(M+H)+]. 2- (4-acetyl-piperazin-1-yl) -N- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl- Phenyl) -4,5-dihydro-imidazol-1-carbonyl] -piperidin-4-yl} -acetamide was prepared in a similar manner as described in Example 9. LR-MS: 773.4 [(M + H) + ].
실시예Example 188 188
N-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-2-(3-옥소-피페라진-1-일)-아세트아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 745.4 [(M+H)+]. N- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-yl} -2- (3-oxo-piperazin-1-yl) -acetamide was prepared in a similar manner as described in Example 9. LR-MS: 745.4 [(M + H) + ].
실시예Example 189 189
1-({1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일카르바모일}-메틸)-피페리딘-4-카르복실산 아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 773.4 [(M+H)+]. 1-({1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperidin-4-ylcarbamoyl} -methyl) -piperidine-4-carboxylic acid amide was prepared in a similar manner as described in Example 9. LR-MS: 773.4 [(M + H) + ].
실시예Example 190 190
1-({1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일카르바모일}-메틸)-피페리딘-3-카르복실산 아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 773.4 [(M+H)+]. 1-({1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperidin-4-ylcarbamoyl} -methyl) -piperidine-3-carboxylic acid amide was prepared in a similar manner as described in Example 9. LR-MS: 773.4 [(M + H) + ].
실시예Example 191 191
1-({1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일카르바모일}-메틸)-피페리딘-3-카르복실산 디에틸아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 829.5 [(M+H)+]. 1-({1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperidin-4-ylcarbamoyl} -methyl) -piperidine-3-carboxylic acid diethylamide was prepared in a similar manner as described in Example 9. LR-MS: 829.5 [(M + H) + ].
실시예Example 192 192
N-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-2-(3-히드록시-피페리딘-1-일)-아세트아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS : 746.4 [(M+H)+]. N- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-yl} -2- (3-hydroxy-piperidin-1-yl) -acetamide was prepared in a similar manner as described in Example 9. LR-MS: 746.4 [(M + H) + ].
실시예Example 193 193
N-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-2-(4-히드록시메틸-피페리딘-1-일)-아세트아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 760.7 [(M+H)+]. N- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-yl} -2- (4-hydroxymethyl-piperidin-1-yl) -acetamide was prepared in a similar manner as described in Example 9. LR-MS: 760.7 [(M + H) + ].
실시예Example 194 194
N-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-2-[비스-(2-히드록시-에틸)-아미노]-아세트아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 750.4 [(M+H)+]. N- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-yl} -2- [bis- (2-hydroxy-ethyl) -amino] -acetamide was prepared in a similar manner as described in Example 9. LR-MS: 750.4 [(M + H) + ].
실시예Example 195 195
N-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-2-(1,4-디옥사-8-아자-스피로 [4.5]데크-8-일)-아세트아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 788.4 [(M+H)+]. N- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-yl} -2- (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -acetamide in a similar manner as described in Example 9 Prepared. LR-MS: 788.4 [(M + H) + ].
실시예Example 196 196
N-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-2-[비스-(2-메톡시-에틸)-아미노]-아세트아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 778.4 [(M+H)+]. N- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-yl} -2- [bis- (2-methoxy-ethyl) -amino] -acetamide was prepared in a similar manner as described in Example 9. LR-MS: 778.4 [(M + H) + ].
실시예Example 197 197
N-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-2-([1,3]디옥솔란-2-일메틸-메틸-아미노)-아세트아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS : 762.4 [(M+H)+]. N- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-yl} -2-([1,3] dioxolan-2-ylmethyl-methyl-amino) -acetamide was prepared in a similar manner as described in Example 9. LR-MS: 762.4 [(M + H) + ].
실시예Example 198 198
N-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-2-메틸아미노-아세트아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 676.4 [(M+H)+]. N- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-yl} -2-methylamino-acetamide was prepared in a similar manner as described in Example 9. LR-MS: 676.4 [(M + H) + ].
실시예Example 199 199
N-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-2-디메틸아미노-아세트아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 690.4 [(M+H)+]. N- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-yl} -2-dimethylamino-acetamide was prepared in a similar manner as described in Example 9. LR-MS: 690.4 [(M + H) + ].
실시예Example 200 200
2-아미노-N-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-아세트아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 662 [(M+H)+]. 2-amino-N- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imi Dazole-1-carbonyl] -piperidin-4-yl} -acetamide was prepared in a similar manner as described in Example 9. LR-MS: 662 [(M + H) + ].
실시예Example 201 201
2-(4-아세틸-피페라진-1-일)-1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-에타논을 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 759.4 [(M+H)+]. 2- (4-acetyl-piperazin-1-yl) -1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl- Phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -ethanone was prepared in a similar manner as described in Example 9. LR-MS: 759.4 [(M + H) + ].
실시예Example 202 202
4-(2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-옥소-에틸)-피페라진-2-온을 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 732.2 [(M+H)+]. 4- (2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole -1-carbonyl] -piperazin-1-yl} -2-oxo-ethyl) -piperazin-2-one was prepared in a similar manner as described in Example 9. LR-MS: 732.2 [(M + H) + ].
실시예Example 203 203
1-(2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-옥소-에틸)-피페리딘-4-카르복실산 아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 759.4 [(M+H)+]. 1- (2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole -1-carbonyl] -piperazin-1-yl} -2-oxo-ethyl) -piperidine-4-carboxylic acid amide was prepared in a similar manner as described in Example 9. LR-MS: 759.4 [(M + H) + ].
실시예Example 204 204
1-(2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-옥소-에틸)-피페리딘-3-카르복실산 아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 759.4 [(M+H)+]. 1- (2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole -1-carbonyl] -piperazin-1-yl} -2-oxo-ethyl) -piperidine-3-carboxylic acid amide was prepared in a similar manner as described in Example 9. LR-MS: 759.4 [(M + H) + ].
실시예Example 205 205
1-(2-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-옥소-에틸)-피페리딘-3-카르복실산 디에틸아미드를 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 815.6 [(M+H)+]. 1- (2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole -1-carbonyl] -piperazin-1-yl} -2-oxo-ethyl) -piperidine-3-carboxylic acid diethylamide was prepared in a similar manner as described in Example 9. LR-MS: 815.6 [(M + H) + ].
실시예Example 206 206
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-(2-디메틸아미노-에틸아미노)-에타논을 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 719.7 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2- (2-dimethylamino-ethylamino) -ethanone was prepared in a similar manner as described in Example 9. LR-MS: 719.7 [(M + H) + ].
실시예Example 207 207
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-[메틸-(1-메틸-피롤리딘-3-일)-아미노]-에타논을 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 745.6 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2- [methyl- (1-methyl-pyrrolidin-3-yl) -amino] -ethanone was prepared in a similar manner as described in Example 9. LR-MS: 745.6 [(M + H) + ].
실시예Example 208 208
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-(3-히드록시-피페리딘-1-일)-에타논을 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 732.6 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2- (3-hydroxy-piperidin-1-yl) -ethanone was prepared in a similar manner as described in Example 9. LR-MS: 732.6 [(M + H) + ].
실시예Example 209 209
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-(2-히드록시-에틸아미노)-에타논을 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 692.3 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2- (2-hydroxy-ethylamino) -ethanone was prepared in a similar manner as described in Example 9. LR-MS: 692.3 [(M + H) + ].
실시예Example 210 210
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-(4-히드록시메틸-피페리딘-1-일)-에타논을 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 746.4 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2- (4-hydroxymethyl-piperidin-1-yl) -ethanone was prepared in a similar manner as described in Example 9. LR-MS: 746.4 [(M + H) + ].
실시예Example 211 211
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-[비스-(2-히드록시-에틸)-아미노]-에타논을 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 736.4 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2- [bis- (2-hydroxy-ethyl) -amino] -ethanone was prepared in a similar manner as described in Example 9. LR-MS: 736.4 [(M + H) + ].
실시예Example 212 212
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-(2-메톡시-에틸아미노)-에타논을 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 706.3 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2- (2-methoxy-ethylamino) -ethanone was prepared in a similar manner as described in Example 9. LR-MS: 706.3 [(M + H) + ].
실시예Example 213 213
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-[비스-(2-메톡시-에틸)-아미노]-에타논을 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 764.4 [(M+H)+] 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2- [bis- (2-methoxy-ethyl) -amino] -ethanone was prepared in a similar manner as described in Example 9. LR-MS: 764.4 [(M + H) + ]
실시예Example 214 214
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-([1,3]디옥솔란-2-일메틸-메틸-아미노)-에타논을 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 748.6 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2-([1,3] dioxolan-2-ylmethyl-methyl-amino) -ethanone was prepared in a similar manner as described in Example 9. LR-MS: 748.6 [(M + H) + ].
실시예Example 215 215
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-일}-2-메틸아미노-에타논을 실시예 9 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 662.1 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2-methylamino-ethanone was prepared in a similar manner as described in Example 9. LR-MS: 662.1 [(M + H) + ].
실시예Example 216 216
1-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-3-메틸-티오우레아를 실시예 10 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 678.3 [(M+H)+]. 1- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-yl} -3-methyl-thiourea was prepared in a similar manner as described in Example 10. LR-MS: 678.3 [(M + H) + ].
실시예Example 217 217
1-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-3-페닐-티오우레아를 실시예 10 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 740.3 [(M+H)+]. 1- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-yl} -3-phenyl-thiourea was prepared in a similar manner as described in Example 10. LR-MS: 740.3 [(M + H) + ].
실시예Example 218 218
4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-카르보티오산 페닐아미드를 실시예 10 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 726.3 [(M+H)+]. 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperazine-1-carbothioic acid phenylamide was prepared in a similar manner as described in Example 10. LR-MS: 726.3 [(M + H) + ].
실시예Example 219 219
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페라진-1-카르보닐}-피페리딘-4-카르복실산 아미드를 실시예 11 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 745.5 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-carbonyl} -piperidine-4-carboxylic acid amide was prepared in a similar manner as described in Example 11. LR-MS: 745.5 [(M + H) + ].
실시예Example 220 220
3-옥소-피페라진-1-카르복실산 {1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-아미드를 실시예 11 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 732.4 [(M+H)+]. 3-oxo-piperazin-1-carboxylic acid {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4, 5-dihydro-imidazole-1-carbonyl] -piperidin-4-yl} -amide was prepared in a similar manner as described in Example 11. LR-MS: 732.4 [(M + H) + ].
실시예Example 221 221
피페리딘-1,4-디카르복실산 4-아미드 1-({1-[4,5-비스-(4-클로로-페닐)-2-(2에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-아미드)를 실시예 11 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 759.5 [(M+H)+]. Piperidine-1,4-dicarboxylic acid 4-amide 1-({1- [4,5-bis- (4-chloro-phenyl) -2- (2ethoxy-4-trifluoromethyl- Phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperidin-4-yl} -amide) was prepared in a similar manner as described in Example 11. LR-MS: 759.5 [(M + H) + ].
실시예Example 222 222
3-{1-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-피페리딘-4-일}-1,1-디메틸-우레아를 실시예 11 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 676.4 [(M+H)+]. 3- {1- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperidin-4-yl} -1,1-dimethyl-urea was prepared in a similar manner as described in Example 11. LR-MS: 676.4 [(M + H) + ].
실시예Example 223 223
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(4-피페라진-1-일메틸-피페리딘-1-일)-메타논 히드로클로라이드를 실시예 13 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 688.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-(4 Piperazin-1-ylmethyl-piperidin-1-yl) -methanone hydrochloride was prepared in a similar manner as described in Example 13. LR-MS: 688.4 [(M + H) + ].
실시예Example 224 224
[4,5-비스-(4-클로로-페닐)-2-(2-이소프로폭시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-{4-[4-(2-히드록시-에틸)-피페라진-1-일메틸]-페닐}-메타논 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 741.6 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-{ 4- [4- (2-hydroxy-ethyl) -piperazin-1-ylmethyl] -phenyl} -methanone hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 741.6 [(M + H) + ].
실시예Example 225 225
[4,5-비스-(4-클로로-페닐)-2-(2-이소프로폭시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(4-피롤리딘-1-일-피페리딘-1-일메틸)-페닐]-메타논 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 763.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[ 4- (4-Pyrrolidin-1-yl-piperidin-1-ylmethyl) -phenyl] -methanone hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 763.3 [(M + H) + ].
실시예Example 226 226
[4,5-비스-(4-클로로-페닐)-2-(2-이소프로폭시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(4-디에틸아미노메틸-페닐)-메타논 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 682.3 [(M+H)+].[4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-( 4-diethylaminomethyl-phenyl) -methanone hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 682.3 [(M + H) + ].
실시예Example 227 227
[4,5-비스-(4-클로로-페닐)-2-(2-이소프로폭시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(4-피페라진-1-일메틸-페닐)-메타논 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 695.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-( 4-piperazin-1-ylmethyl-phenyl) -methanone hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 695.3 [(M + H) + ].
실시예Example 228 228
[4-(4-아미노-피페리딘-1-일메틸)-페닐]-[4,5-비스-(4-클로로-페닐)-2-(2-이소프로폭시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-메타논 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 709.3 [(M+H)+] . [4- (4-Amino-piperidin-1-ylmethyl) -phenyl]-[4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-trifluoro Methyl-phenyl) -4,5-dihydro-imidazol-1-yl] -methanone hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 709.3 [(M + H) + ].
실시예Example 229 229
1-(4-{4-[4,5-비스-(4-클로로-페닐)-2-(2-이소프로폭시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-벤질}-피페라진-1-일)-에타논 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 737.3 [(M+H)+]. 1- (4- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imi Dazole-1-carbonyl] -benzyl} -piperazin-1-yl) -ethanone hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 737.3 [(M + H) + ].
실시예Example 230 230
N-(1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-이소프로폭시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-벤질}-피페리딘-4-일)-아세트아미드 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 751.4 [(M+H)+]. N- (1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imi Dazole-1-carbonyl] -benzyl} -piperidin-4-yl) -acetamide hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 751.4 [(M + H) + ].
실시예Example 231 231
4-{4-[4,5-비스-(4-클로로-페닐)-2-(2-이소프로폭시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-벤질}-피페라진-2-온 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 709.3 [(M+H)+]. 4- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -benzyl} -piperazin-2-one hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 709.3 [(M + H) + ].
실시예Example 232 232
[4,5-비스-(4-클로로-페닐)-2-(2-이소프로폭시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(2-히드록시메틸-피페리딘-1-일메틸)-페닐]-메타논 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 724.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[ 4- (2-hydroxymethyl-piperidin-1-ylmethyl) -phenyl] -methanone hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 724.3 [(M + H) + ].
실시예Example 233 233
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-이소프로폭시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-벤질}-피롤리딘-2-카르복실산 메틸 에스테르 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 738.3 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -benzyl} -pyrrolidine-2-carboxylic acid methyl ester hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 738.3 [(M + H) + ].
실시예Example 234 234
[4,5-비스-(4-클로로-페닐)-2-(2-이소프로폭시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(4-모르폴린-4-일메틸-페닐)-메타논 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 696.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-( 4-Morpholin-4-ylmethyl-phenyl) -methanone hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 696.3 [(M + H) + ].
실시예Example 235 235
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-5-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-[4-(4-피롤리딘-1-일-피페리딘-1-일메틸)-페닐]-메타논 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 749.4 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(4-Pyrrolidin-1-yl-piperidin-1-ylmethyl) -phenyl] -methanone hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 749.4 [(M + H) + ].
실시예Example 236 236
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-5-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(4-디에틸아미노메틸-페닐)-메타논 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 668.1 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-(4 -Diethylaminomethyl-phenyl) -methanone hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 668.1 [(M + H) + ].
실시예Example 237 237
4-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-5-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-벤질}-피페라진-2-온 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 695.3 [(M+H)+]. 4- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -benzyl} -piperazin-2-one hydrochloride was prepared in a similar manner as described in Example 14. LR-MS: 695.3 [(M + H) + ].
실시예Example 238 238
[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-5-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-일]-(4-모르폴린-4-일메틸-페닐)-메타논을 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 682.3 [(M+H)+]. [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-trifluoromethyl-phenyl) -4,5-dihydro-imidazol-1-yl]-(4 -Morpholin-4-ylmethyl-phenyl) -methanone was prepared in a similar manner as described in Example 14. LR-MS: 682.3 [(M + H) + ].
실시예Example 239 239
1-{4-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-5-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-카르보닐]-벤질}-피롤리딘-2-카르복실산 메틸 에스테르 히드로클로라이드를 실시예 14 에 기재된 바와 유사한 방식으로 제조하였다. LR- MS: 724.3 [(M+H)+]. 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -benzyl} -pyrrolidine-2-carboxylic acid methyl ester hydrochloride was prepared in a similar manner as described in Example 14. LR- MS: 724.3 [(M + H) + ].
실시예Example 240 240
4-{2-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-술포닐]-에틸}-피페라진-2-온 히드로클로라이드를 실시예 15 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 669.2 [(M+H)+]. 4- {2- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1- Sulfonyl] -ethyl} -piperazin-2-one hydrochloride was prepared in a similar manner as described in Example 15. LR-MS: 669.2 [(M + H) + ].
실시예Example 241 241
{2-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-술포닐]-에틸}-디에틸-아민 히드로클로라이드를 실시예 15 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 642.2 [(M+H)+]. {2- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole-1-sulfonyl ] -Ethyl} -diethyl-amine hydrochloride was prepared in a similar manner as described in Example 15. LR-MS: 642.2 [(M + H) + ].
실시예Example 242 242
2-(4-{2-[4,5-비스-(4-클로로-페닐)-2-(2-에톡시-4-트리플루오로메틸-페닐)-4,5-디히드로-이미다졸-1-술포닐]-에틸}-피페라진-1-일)-에탄올 히드로클로라이드를 실시예 15 에 기재된 바와 유사한 방식으로 제조하였다. LR-MS: 699.3 [(M+H)+]. 2- (4- {2- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-trifluoromethyl-phenyl) -4,5-dihydro-imidazole -1-sulfonyl] -ethyl} -piperazin-1-yl) -ethanol hydrochloride was prepared in a similar manner as described in Example 15. LR-MS: 699.3 [(M + H) + ].
실시예Example 243 243
생체외In vitro 검정 black
p53 과 MDM2 단백질 사이의 상호작용을 억제하는 화합물의 능력은, 재조합 GST 표지화된 MDM2 가 p53 의 MDM2 상호작용 구역을 닮은 펩티드에 결합하는 HTRF (균질 시간 분해 형광) 검정법에 의해 측정하였다 (Lane 등). GST-MDM2 단백질과 p53-펩티드 (그의 N-종말 말단부 상에 비오틴화되어 있음)의 결합은, 유로퓸(Eu) 라벨링된 항GST 항체 및 스트렙트아비딘 콘쥬게이트화된 알로피코시아닌 (APC) 사이의 FRET (형광 공명 에너지 전이)에 의해 기록되었다. The ability of compounds to inhibit the interaction between p53 and MDM2 protein was determined by HTRF (homogeneous time resolved fluorescence) assay in which recombinant GST labeled MDM2 binds to a peptide resembling the MDM2 interaction region of p53 (Lane et al.) . The binding of the GST-MDM2 protein with the p53-peptide (which is biotinylated on its N-terminal terminus) between the europium (Eu) labeled anti-GST antibody and streptavidin conjugated allophycocyanin (APC) Was recorded by FRET (Fluorescence Resonance Energy Transfer).
시험은, 90 nM 비오틴화 펩티드, 160 ng/㎖ GST-MDM2, 20 nM 스트렙트아비딘 -APC (PerkinElmerWallac), 2 nM Eu 라벨링된 항GST 항체 (PerkinElmerWallac), 0.2% 소 혈청 알부민 (BSA), 1 mM 디티오트레이톨 (DTT) 및 20 mM 트리스-보레이트 식염수 (TBS) 완충제를 다음과 같이 포함하는 전체 부피 40 μL 로, 흑색 넓적바닥 384-웰 플레이트 (Costar)에서 실시하였다: 반응 완충제 중 10 μL 의 GST-MDM2 (640 ng/ml 작업 용액)를 각 웰에 첨가한다. 10 μL 희석 화합물 (반응 완충제 중 1:5 희석물)을 각 웰에 첨가하고, 진탕하여 혼합한다. 반응 완충제 중 20 μL 비오틴화 p53 펩티드 (180 nM 작업 용액)를 각 웰에 첨가하고, 진탕기에서 혼합한다. 1 시간 동안 37℃ 에서 배양한다. TBS 완충제 중 20 μL 스트렙트아비딘-APC 및 Eu-항GST 항체 혼합물 (6 nM Eu-항GST 및 60 nM 스트렙트아비딘-APC 작업 용액)을 0.2% BSA와 함께 첨가하고, 실온에서 30 분 동안 진탕하고, TRF가 가능한 플레이트 판독기 (Victor 5, Perkin ElmerWallac)을 사용하여 665 및 615 nm 에서 판독한다. 상술되어 있지 않을 경우, 반응물은 Sigma Chemical Co.에서 구입하였다.Tests were 90 nM biotinylated peptide, 160 ng / ml GST-MDM2, 20 nM streptavidin-APC (PerkinElmerWallac), 2 nM Eu labeled anti-GST antibody (PerkinElmerWallac), 0.2% bovine serum albumin (BSA), 1 40 μL total volume containing mM dithiothreitol (DTT) and 20 mM tris-borate saline (TBS) buffer was performed in black tread 384-well plates (Costar): 10 μL in reaction buffer GST-MDM2 (640 ng / ml working solution) is added to each well. 10 μL diluted compound (1: 5 dilution in reaction buffer) is added to each well, and shaken to mix. 20 μL biotinylated p53 peptide (180 nM working solution) in reaction buffer is added to each well and mixed in shaker. Incubate at 37 ° C. for 1 hour. 20 μL streptavidin-APC and Eu-antiGST antibody mixture (6 nM Eu-antiGST and 60 nM streptavidin-APC working solution) in TBS buffer is added with 0.2% BSA and shaken for 30 minutes at room temperature And read at 665 and 615 nm using a TRF capable plate reader (Victor 5, Perkin ElmerWallac). If not specified above, the reaction was purchased from Sigma Chemical Co.
본 발명의 주제인 화합물에 적용되는 생물학적 활성을 보여주는 IC50 는 약 0.020 μM 내지 약 5 μM 범위이다. 일부 실시예에 대한 구체적 데이터는 다음과 같다:IC 50 showing the biological activity applied to the compound of the present invention ranges from about 0.020 μM to about 5 μM. Specific data for some embodiments are as follows:
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| NZ568285A (en) * | 2005-12-01 | 2011-08-26 | Hoffmann La Roche | 2,4,5-triphenyl imidazoline derivatives as inhibitors of the interaction between P53 and MDM2 proteins for use as anticancer agents |
| US8114095B2 (en) * | 2006-11-10 | 2012-02-14 | Bausch & Lomb Incorporated | Intraocular lens injection apparatus and method |
| WO2008072655A1 (en) | 2006-12-14 | 2008-06-19 | Daiichi Sankyo Company, Limited | Imidazothiazole derivatives |
| US7625895B2 (en) * | 2007-04-12 | 2009-12-01 | Hoffmann-Le Roche Inc. | Diphenyl-dihydro-imidazopyridinones |
| JPWO2009151069A1 (en) | 2008-06-12 | 2011-11-17 | 第一三共株式会社 | Imidazothiazole derivatives having 4,7-diazaspiro [2.5] octane ring structure |
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| JP2019522633A (en) | 2016-05-20 | 2019-08-15 | ジェネンテック， インコーポレイテッド | PROTAC antibody conjugates and methods of use |
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| EP0433682A2 (en) * | 1989-11-22 | 1991-06-26 | Marion Merrell Dow Inc. | Use of 2,4,5-tri(4-methoxyphenyl)-4,5-dihydroimidazole for the treatment of cancer |
| WO2002020017A2 (en) * | 2000-09-04 | 2002-03-14 | Merck Patent Gmbh | Use of ectoin or ectoin derivatives for stabilizing p53 |
| WO2003051359A1 (en) * | 2001-12-18 | 2003-06-26 | F.Hoffmann-La Roche Ag | Cis-2,4,5- triphenyl-imidazolines and their use in the treatment of tumors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0433682A2 (en) * | 1989-11-22 | 1991-06-26 | Marion Merrell Dow Inc. | Use of 2,4,5-tri(4-methoxyphenyl)-4,5-dihydroimidazole for the treatment of cancer |
| WO2002020017A2 (en) * | 2000-09-04 | 2002-03-14 | Merck Patent Gmbh | Use of ectoin or ectoin derivatives for stabilizing p53 |
| WO2003051359A1 (en) * | 2001-12-18 | 2003-06-26 | F.Hoffmann-La Roche Ag | Cis-2,4,5- triphenyl-imidazolines and their use in the treatment of tumors |
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