KR20230051939A - 신규한 캡시드 조립 저해제 - Google Patents

신규한 캡시드 조립 저해제 Download PDF

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KR20230051939A
KR20230051939A KR1020210134939A KR20210134939A KR20230051939A KR 20230051939 A KR20230051939 A KR 20230051939A KR 1020210134939 A KR1020210134939 A KR 1020210134939A KR 20210134939 A KR20210134939 A KR 20210134939A KR 20230051939 A KR20230051939 A KR 20230051939A
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methyl
urea
pyrazol
fluorophenyl
chloro
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KR1020210134939A
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정낙철
이미선
심희우
김명진
김정희
한수봉
정영식
김혜진
윤창수
조희영
김미현
이주연
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(주)에이엠사이언스
한국화학연구원
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Priority to KR1020210134939A priority Critical patent/KR20230051939A/ko
Priority to PCT/KR2022/015333 priority patent/WO2023063697A1/en
Priority to AU2022366587A priority patent/AU2022366587A1/en
Priority to TW111138674A priority patent/TWI835344B/zh
Priority to CN202280069270.0A priority patent/CN118103363A/zh
Publication of KR20230051939A publication Critical patent/KR20230051939A/ko

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Abstract

본 발명은 일련의 신규한 피라졸릴메틸우레아 유도체에 관한 것으로, 이의 캡시드 조립 저해 및 이를 통한 바이러스 감염 질환의 예방 또는 치료 용도에 관한 것이다.

Description

신규한 캡시드 조립 저해제{Novel capsid assembly inhibitors}
본 발명은 일련의 신규한 피라졸릴메틸우레아 유도체에 관한 것으로, 이의 캡시드 조립 저해 및 이를 통한 바이러스 감염 질환의 예방 또는 치료 용도에 관한 것이다.
만성 B형 간염 바이러스(chronic hepatitis B virus; HBV) 감염은 전세계적인 주된 건강 문제이며, 간경변(cirrhosis) 또는 간암과 같은 심각한 건강 문제를 유발할 수 있다. 최근 WHO의 보고에 따르면, 2015년 당시 전세계적으로 257 백만명의 사람들이 만성 HBV 감염을 보유한 채로 살아가며 매년 1.34 백만명이 간염 관련 합병증으로 사망한 것으로 추산된다. 현재까지 HBV 치료를 위해 승인된 물질로는 인터페론(interferons; IFNs, 비-페길화된 또는 페길화된) 및 뉴클레오시(티)드 유사체(nucleos(t)ide analogues, 라미부딘(lamivudine), 아데포비르(adefovir), 엔테카비르(entecavir), 테노포비르(tenofovir) 등)가 있다. IFNs 치료법은 HBV 복제 억제 및 간 질환의 차도(remission)를 유도하며, 뉴클레오시(티)드 약물은 역전사효소(reverse transcriptase) 및 DNA 중합효소(polymerase) 활성을 억제한다. 뉴클레오시(티)드 유사체들은 바이러스 증식을 효과적으로 제어하나, HBV의 열쇠인 바이러스 유전자가 cccDNA 형태로 숙주의 미니-크로모솜(mini-chromosom)의 형태로 같이 잔류하게 되어 이의 완전한 제거(complete elimination)는 어렵다. 따라서, HBV 보균자들은 신규 바이러스 증식을 막기 위해 약물을 장기간 사용해야 하므로 약물 내성이 빈번하게 발생한다. 이러한 충족되지 않은 의학적 요구를 극복하기 위하여, 새로운 분자 표적을 갖는 효율적이며 안전한 항-HBV 약물의 발굴이 필요하다.
HBV 코어 단백질은 바이러스 생애 주기(life cycle)에서 중요한 역할을 담당한다. 코아 단백질의 집합에 의해 형성되는 HBV 캡시드는 pregenomicRNA(pgRNA)와 역전사효소(reverse transcriptase) 및 DNA 중합효소(polymerase)를 함께 캡슐화(encapsidation)하여 pgRNA의 역전사 및 뉴클레오캡시드(nucleocapsids)의 재활용(recycling)을 조절한다(modulate). 또한, 코어 단백질은 바이러스성 게놈의 수송(transport) 및 핵 방출(nuclear release)을 조절하고, cccDNA의 후성적 조절(epigenetic regulation)에 관여하여, 호스트 유전자 발현을 조절한다. 따라서, HBV 복제 주기(replication cycle)에 기초하여 코어 단백질의 작용 조절과 코어 단백질로 이루어진 캡시드 단백질 형성을 방해하는 표적 항-HBV 제제의 발굴이 광범위하게 연구되고 있다.
몇몇 연구단과 제약회사들이 캡시드 조립 조절제를 개발하고 있다. Bay-41-4109, 헤테로아릴디하이드로피리미딘(heteroaryldihydropyrimidine; HAP) 유사체는 임상 시험에 돌입한 최초의 캡시드 조립 저해제로서, 캡시드의 비정상적인 형성(aberrant formation) 및 캡시드 단백질 응집(aggregation)을 유도한다. 캡시드 단백질의 부정확한 조립(incorrect assembly)의 결과로서, HBV DNA 복제를 저해하여 이를 감소시키고, HBV 코어 단백질은 프로테아좀에 의해 분해(proteasome mediated degradation)되는 것이 HepG2.2.15 세포에서 관찰되었다. GLS-4는 BAY-41-4109와 동일한 작용 기전을 갖는 2세대 HAP 유사체이며, GLS-4에 의한 CYP 효소 유도를 방지하기 위해 리토나비르(ritonavir; RTV)와 함께 2상 임상시험(phase II clinical trials)이 진행 중이다. 또한, 동일한 연구진은 in vitro 효능(potency)을 일정 부분 희생하고 CYP 효소 유도가 감소되고, hERG K+ 채널의 억제도 낮추며, 경구 생체이용률(oral bioavailability)은 개선된, HEC72702를 보고하였다.
HAPs와는 상이한 작용 기전을 갖는, 다른 종류의 캡시드 조립 조절제, AT130, NVR 3-778 및 JNJ-632도 보고되었다. 예를 들어, NVR 3-778을 처리한 경우, 캡시드는 정상적으로 형성되나, 캡시드 내에 pregenomicRNA(pgRNA)와 역전사효소(reverse transcriptase) 및 DNA 중합효소(polymerase)가 들어있지 않은 빈 캡시드로 얻어진다. JNJ-632가 신규한 설파모일벤즈아미드(sulfamoylbenzamide) 캡시드 조립 조절제로 보고되었으며, 이의 최적화된 유사체 JNJ-6379가 현재 2상 임상시험 중에 있다. 최근, Kang, J. A. 외 GIST의 연구진은 FDA 승인된 항진균제(antifungal drug)인 시클로피록스(ciclopirox)을 약물 재배치 전략(drug repositioning strategy)을 통하여 경구로 이용 가능한 캡시드 조립 저해제로서 보고한 바 있다.
국제공개특허 WO 2017/210545; 미국공개특허 US 2017/0355708.
Kang, J. A. et al., Nat. Commun., 2019, 10(2184): 1-14.
본 발명자들은 캡시드 조립을 저해함으로써 바이러스 감염을 억제할 수 있는 신규한 소분자 화합물을 발굴하고자 예의 연구 노력한 결과, 일련의 피라졸릴메틸우레아 유도체들이 캡시드 조립을 잠재적으로 저해함으로써 바이러스 감염을 억제하는 활성을 갖는 것을 확인하고 본 발명을 완성하였다.
본 발명에서 개시되는 각각의 설명 및 실시 형태는 각각의 다른 설명 및 실시 형태에도 적용될 수 있다. 즉, 본 발명에서 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기 기술되는 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 할 수 없다.
또한, 당해 기술분야의 통상의 지식을 가진 자는 통상의 실험 만을 사용하여 본 발명에 기재된 본 발명의 특정 양태에 대한 다수의 등가물을 인지하거나 확인할 수 있다. 또한, 이러한 등가물은 본 발명에 포함되는 것으로 의도된다.
아울러, 본 발명의 명세서 전체에 있어서, 어떤 부분이 어떤 구성 요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.
이하, 본 발명을 보다 자세히 설명한다.
본 발명의 제1양태는 하기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용 가능한 염을 제공한다:
[화학식 1]
Figure pat00001
상기 화학식 1에서,
R1은 C6-10 아릴, C3-10 사이클로알킬, 5 내지 10원 헤테로아릴, 또는 3 내지 10원 헤테로사이클릴;
R2는 C6-10 아릴, C3-10 사이클로알킬, 5 내지 10원 헤테로아릴, 또는 3 내지 10원 헤테로사이클릴;
R3 내지 R6은 각각 독립적으로 결합, 수소, 시아노, 할로겐, C1-4 알킬, C1-4 알케닐, C1-4 할로알킬, C1-4 히드록시알킬, C1-4 알콕시, C1-3 아실, C1-4 알콕시-C1-4 알킬, C1-4 알콕시-C1-4 알케닐, 3 내지 10원 헤테로사이클릴옥시-C1-4 알킬, 또는 (4,4,5,5-테트라(C1-4 알킬)-1,3-디옥솔라닐)-C1-4 알킬이거나,
R3과 R4가 서로 연결되어 이들이 결합된 탄소를 포함하여 5원 내지 10원 고리구조를 형성,
R3 또는 R6 중 하나를 통해 우레아 골격에 연결되고;
이때, C6-10 아릴, C3-10 사이클로알킬, 5 내지 10원 헤테로아릴, 또는 3 내지 10원 헤테로사이클릴 및 R3과 R4가 서로 연결되어 형성된 고리구조는 비치환 또는 시아노, 히드록시, 카르복실, 옥소, 할로겐, C1-4 알킬, C1-4 알킬티오, C1-4 알콕시, C1-4 알콕시-C1-4 알킬, C1-4 알킬카보닐, C1-4 알콕시카보닐, C1-4 알킬아미노술포닐, C1-4 알킬술포닐아미노, C1-4 히드록시알킬, C1-4 할로알킬, C1-4 알킬아미노, 디(C1-4 알킬)아미노, 및 5원 내지 10원 헤테로아릴로 이루어진 군으로부터 선택되는 하나 이상으로 치환됨.
예컨대, 상기 화학식 1에서, R1은 페닐, 바이사이클로[1.1.1]펜틸, 디하이드로피리디닐, 이속사졸릴, 피라졸릴, 피리다지닐, 피리디닐, 피리미디닐, 또는 티아디아졸릴일 수 있으나, 이에 제한되지 않는다.
예컨대, 상기 화학식 1에서, R2는 페닐, 바이사이클로[1.1.1]펜틸, 이미다졸릴, 피리디닐, 또는 피리미디닐일 수 있으나, 이에 제한되지 않는다.
예컨대, 상기 화학식 1에서, R3은 수소, 브로모, 메틸, 프로페닐. 트리플루오로메틸, 히드록시메틸, 히드록시에틸, 히드록시이소프로필, 히드록시프로필, 히드록시이소부틸, 메톡시, 메톡시에틸, 메톡시메틸, 에톡시에틸, 에톡시에테닐, 또는 (4,4,5,5-테트라메틸-1,3-디옥솔라닐)메틸일 수 있으나, 이에 제한되지 않는다.
예컨대, 상기 화학식 1에서, R4는 결합, 수소, 시아노, 메틸, 에틸, 이소프로필, 디플루오로메틸, 트리플루오로메틸, 또는 메톡시일 수 있으나, 이에 제한되지 않는다.
예컨대, 상기 화학식 1에서, R3 및 R4는 서로 연결되어 이들이 결합된 탄소를 포함하여 테트라하이드로티오피라닐(tetrahydrothiopyranyl), 테트라하이드로피라닐(tetrahydropyranyl), 테트라하이드로퓨라닐(tetrahydrofuranyl), 피페리디닐(piperidinyl), 페닐(phenyl), 디옥사닐(dioxanyl), 사이클로펜틸(cyclopentyl), 사이클로헥실(cyclohexyl), 사이클로헵틸(cycloheptyl), 또는 바이사이클로[2.2.1]헵틸을 형성할 수 있으나, 이에 제한되지 않는다.
예컨대, 상기 화학식 1에서, R5는 수소, 메틸, 히드록시메틸, 히드록시에틸, 에틸카보닐, 또는 테트라하이드로피라닐옥시에틸일 수 있으나, 이에 제한되지 않는다.
예컨대, 상기 화학식 1에서, R6은 결합, 또는 메틸일 수 있으나, 이에 제한되지 않는다.
예컨대, 상기 화학식 1에서, C6-10 아릴, C3-10 사이클로알킬, 5 내지 10원 헤테로아릴, 또는 3 내지 10원 헤테로사이클릴 및 R3과 R4가 서로 연결되어 형성된 고리구조는 비치환 또는 시아노, 히드록시, 카르복실, 옥소, 브로모, 플루오로, 클로로, 메틸, 메틸티오, 메톡시, 메톡시메틸, 메틸카보닐, 메톡시카보닐, 메틸술포닐아미노, 메틸아미노술포닐, 히드록시메틸, 히드록시이소프로필, 디플루오로메틸, 트리플루오로메틸, 메틸아미노, 및 디메틸아미노로 이루어진 군으로부터 선택되는 하나 이상으로 치환될 수 있으나, 이에 제한되지 않는다.
구체적으로, 상기 화합물은
1. 3-(바이사이클로[1.1.1]펜탄-1-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(bicyclo[1.1.1]pentan-1-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
2. 1-(2-메톡시피리미딘-5-일)-3-(피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(1-(2-methoxypyrimidin-5-yl)-3-(pyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
3. 3-(3-플루오로-4-(1H-이미다졸-1-일)피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-fluoro-4-(1H-imidazol-1-yl)pyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
4. 3-(2-브로모-3-플루오로피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-bromo-3-fluoropyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
5. 3-(6-클로로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-chloropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
6. 3-(3-클로로바이사이클로[1.1.1]펜탄-1-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chlorobicyclo[1.1.1]pentan-1-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
7. 3-(3-클로로-4-시아노페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-cyanophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
8. 3-(5-클로로-6-시아노피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(5-chloro-6-cyanopyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
9. 3-(3-클로로-4-이소시아노페닐)-1-((5-시아노-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-isocyanophenyl)-1-((5-cyano-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
10. 3-(3-시아노-4,5-디플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-cyano-4,5-difluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
11. 3-(3-클로로-4,5-디플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4,5-difluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
12. 3-(3-클로로-4,5-디플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4,5-difluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
13. 3-(6-클로로-4,5-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-chloro-4,5-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
14. 3-(3-클로로-4-플루오로페닐)-1-(6-옥소-1,6-디하이드로피리딘-3-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-oxo-1,6-dihydropyridin-3-yl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
15. 3-(3-클로로-4-플루오로페닐)-1-(2-옥소-1,2-디하이드로피리딘-4-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-oxo-1,2-dihydropyridin-4-yl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
16. N-(4-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레이도)페닐)메탄술폰아미드(N-(4-(3-(3-chloro-4-fluorophenyl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)ureido)phenyl)methanesulfonamide),
17. N-(5-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레이도)피리딘-2-일)메탄술폰아미드(N-(5-(3-(3-chloro-4-fluorophenyl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)ureido)pyridin-2-yl)methanesulfonamide),
18. N-(5-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레이도)피리딘-2-일)메탄술폰아미드(N-(5-(3-(3-chloro-4-fluorophenyl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)ureido)pyridin-2-yl)methanesulfonamide),
19. N-(4-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레이도)페닐)메탄술폰아미드(N-(4-(3-(3-chloro-4-fluorophenyl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)ureido)phenyl)methanesulfonamide),
20. 1-(6-아세틸피리딘-3-일)-3-(3-클로로-4-플루오로페닐)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(1-(6-acetylpyridin-3-yl)-3-(3-chloro-4-fluorophenyl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
21. 1-(6-아세틸피리딘-3-일)-3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(1-(6-acetylpyridin-3-yl)-3-(3-chloro-4-fluorophenyl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
22. 1-(2-아세틸피리딘-4-일)-3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(1-(2-acetylpyridin-4-yl)-3-(3-chloro-4-fluorophenyl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
23. 4-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레이도)-N-메틸벤젠술폰아미드(4-(3-(3-chloro-4-fluorophenyl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)ureido)-N-methylbenzenesulfonamide),
24. 3-(3-클로로-4-플루오로페닐)-1-(1-메틸-1H-피라졸-4-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(1-methyl-1H-pyrazol-4-yl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
25. 3-(3-클로로-4-플루오로페닐)-1-(1-메틸-1H-피라졸-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(1-methyl-1H-pyrazol-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
26. 3-(3-클로로-4-플루오로페닐)-1-(5-메틸이속사졸-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(5-methylisoxazol-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
27. 3-(3-클로로-4-플루오로페닐)-1-(3-메틸바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(3-methylbicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
28. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시-4-메틸피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-methoxy-4-methylpyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
29. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시-2,6-디메틸페닐)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxy-2,6-dimethylphenyl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
30. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시-4,6-디메틸피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
31. 메틸 4-(3-(3-클로로-4-플루오로페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레이도)벤조에이트(methyl 4-(3-(3-chloro-4-fluorophenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)ureido)benzoate),
32. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
33. 1-((5-아세틸-4,5,6,7-테트라하이드로-1H-피라졸로[4,3-c]피리딘-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)우레아(1-((5-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)urea),
34. 1-((1H-피라졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)우레아(1-((1H-pyrazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)urea),
35. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1-메틸-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((1-methyl-1H-pyrazol-3-yl)methyl)urea),
36. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1-메틸-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((1-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
37. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((5-메틸-4,5,6,7-테트라하이드로-1H-피라졸로[4,3-c]피리딘-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((5-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methyl)urea),
38. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
39. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1-메틸-1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((1-methyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
40. 3-(3-클로로-4-플루오로페닐)-1-((5,5-디플루오로-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5,5-difluoro-4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
41. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
42. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
43. 1-((1H-인다졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레아(1-((1H-indazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)urea),
44. 3-(3-클로로-4-플루오로페닐)-1-((5-(히드록시메틸)-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
45. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1,4,6,7-테트라하이드로티오피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)methyl)urea),
46. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
47. 3-(3-클로로-4-플루오로페닐)-1-((5,5-디메틸-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
48. 3-(3-클로로-4-플루오로페닐)-1-((5-히드록시-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-hydroxy-4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
49. 3-(3-클로로-4-플루오로페닐)-1-((5,5-디옥시도-1,4,6,7-테트라하이드로티오피라노[4,3-c]피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5,5-dioxido-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
50. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((5-메틸-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((5-methyl-1H-pyrazol-3-yl)methyl)urea),
51. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4,5,6,7-테트라하이드로-1H-4,7-메타노인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)methyl)urea),
52. 3-((3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레이도)메틸)-4,5,6,7-테트라하이드로-1H-인다졸-5-카르복실산(3-((3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)ureido)methyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid),
53. 메틸 3-((3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레이도)메틸)-4,5,6,7-테트라하이드로-1H-인다졸-5-카복실레이트(methyl 3-((3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)ureido)methyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate),
54. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리딘-4-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyridin-4-yl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
55. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
56. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4-메틸-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((4-methyl-1H-pyrazol-3-yl)methyl)urea),
57. 3-(3-클로로-4-플루오로페닐)-1-((4,5-디메틸-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4,5-dimethyl-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
58. 3-(3-클로로-4-플루오로페닐)-1-((5-이소프로필-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-isopropyl-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
59. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((6-메틸-1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((6-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
60. 3-(3-클로로-4-플루오로페닐)-1-((5-에틸-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-ethyl-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
61. 1-((4-브로모-1H-피라졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)우레아(1-((4-bromo-1H-pyrazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)urea),
62. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
63. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
64. 3-(3-클로로-4-플루오로페닐)-1-((5-메톡시-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-methoxy-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
65. 3-(3-클로로-4-플루오로페닐)-1-(1-메틸-6-옥소-1,6-디하이드로피리딘-3-일)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
66. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1-(2-(테트라하이드로-2H-피란-2-일옥시)에틸)-1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
67. 3-(3-클로로-4-플루오로페닐)-1-((1-(2-히드록시에틸)-1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((1-(2-hydroxyethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
68. 3-(3-클로로-4-플루오로페닐)-1-((1,3a,4,5,6,7a-헥사하이드로피라노[2,3-c]피라졸-3-일)메틸)-1-(2-메톡시피리딘-4-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((1,3a,4,5,6,7a-hexahydropyrano[2,3-c]pyrazol-3-yl)methyl)-1-(2-methoxypyridin-4-yl)urea),
69. 3-(3-클로로-4-플루오로페닐)-1-((4,6-디하이드로-1H-퓨로[3,4-c]피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4,6-dihydro-1H-furo[3,4-c]pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
70. 3-(3-클로로-4-플루오로페닐)-1-((4,6-디하이드로-1H-퓨로[3,4-c]피라졸-3-일)메틸)-1-(2-메톡시피리딘-4-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4,6-dihydro-1H-furo[3,4-c]pyrazol-3-yl)methyl)-1-(2-methoxypyridin-4-yl)urea),
71. 3-(3-클로로-4-플루오로페닐)-1-((5,6-디하이드로-1H-[1,4]디옥시노[2,3-c]피라졸-3-일)메틸)-1-(2-메톡시피리딘-4-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5,6-dihydro-1H-[1,4]dioxino[2,3-c]pyrazol-3-yl)methyl)-1-(2-methoxypyridin-4-yl)urea),
72. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
73. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리딘-4-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyridin-4-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
74. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리딘-4-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyridin-4-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
75. 3-(3-클로로-4-플루오로페닐)-1-(5-메톡시피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(5-methoxypyridin-3-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
76. 3-(3-클로로-4-플루오로페닐)-1-(5-메톡시피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(5-methoxypyridin-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
77. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(5-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(5-methoxypyridin-3-yl)urea),
78. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4-메틸-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((4-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
79. 3-(3-클로로-4-플루오로페닐)-1-((1-(히드록시메틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((1-(hydroxymethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
80. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
81. 1-((4-브로모-5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((4-bromo-5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
82. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(메톡시메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-(methoxymethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
83. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-에톡시비닐)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-ethoxyvinyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
84. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
85. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-에톡시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-ethoxyethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
86. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
87. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4-((4,4,5,5-테트라메틸-1,3-디옥솔란-2-일)메틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((4-((4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
88. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(2-메톡시에틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-(2-methoxyethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
89. 3-(4-클로로-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-chloro-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
90. 3-(3-클로로-4-플루오로페닐)-1-((5-메톡시-4-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-methoxy-4-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
91. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
92. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(2-히드록시프로판-2-일)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-(2-hydroxypropan-2-yl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
93. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(프로프-1-엔-2-일)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-(prop-1-en-2-yl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
94. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리다진-4-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridazin-4-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
95. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시프로필)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
96. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리다진-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridazin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
97. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리다진-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridazin-3-yl)urea),
98. 1-((4-브로모-5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((4-bromo-5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
99. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리다진-4-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridazin-4-yl)urea),
100. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-메톡시-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-methoxy-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
101. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시-2-메틸프로필)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
102. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시프로판-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
103. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(2-히드록시-2-메틸프로필)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
104. 3-(3-클로로-4-플루오로페닐)-1-((5-시아노-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-cyano-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
105. 3-(3-클로로-4-플루오로페닐)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
106. 3-(6-클로로-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-chloro-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
107. 3-(5-클로로-6-플루오로피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(5-chloro-6-fluoropyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
108. 3-(3-클로로-4-플루오로페닐)-1-((1,3-디메틸-1H-피라졸-5-일)메틸)-1-(4-메톡시페닐)우레아(3-(3-chloro-4-fluorophenyl)-1-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)-1-(4-methoxyphenyl)urea),
109. 3-(3-클로로-4-플루오로페닐)-1-(3-(2-히드록시프로판-2-일)이속사졸-5-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(3-(2-hydroxypropan-2-yl)isoxazol-5-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
110. 3-(3-클로로-4-플루오로페닐)-1-(6-(2-히드록시프로판-2-일)피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
111. 3-(3-클로로-4-플루오로페닐)-1-(6-(2-히드록시프로판-2-일)피리딘-3-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
112. 3-(3-클로로-4-플루오로페닐)-1-(2-(2-히드록시프로판-2-일)피리딘-4-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-(2-hydroxypropan-2-yl)pyridin-4-yl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
113. 3-(3-클로로-4-플루오로페닐)-1-(2-(2-히드록시프로판-2-일)피리딘-4-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-(2-hydroxypropan-2-yl)pyridin-4-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
114. 3-(3-클로로-4-플루오로페닐)-1-(4-히드록시페닐)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-hydroxyphenyl)-1-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
115. 3-(3-클로로-4-플루오로페닐)-1-(3-(2-히드록시프로판-2-일)이속사졸-5-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(3-(2-hydroxypropan-2-yl)isoxazol-5-yl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
116. 3-(3-클로로-4-플루오로페닐)-1-(3,4-디메톡시페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(3,4-dimethoxyphenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
117. 3-(3-클로로-4-플루오로페닐)-1-(3,5-디메톡시페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(3,5-dimethoxyphenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
118. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노-5-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyano-5-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
119. 3-(3-클로로-4-플루오로페닐)-1-(5-시아노-6-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(5-cyano-6-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
120. 3-(3-클로로-4-플루오로페닐)-1-(5-시아노피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(5-cyanopyridin-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
121. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
122. 3-(3-클로로-4-플루오로페닐)-1-(2-시아노피리딘-4-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-cyanopyridin-4-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
123. 3-(3-클로로-4-플루오로페닐)-1-(2-시아노피리딘-4-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-cyanopyridin-4-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
124. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
125. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
126. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
127. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
128. 3-(3-클로로-4-플루오로페닐)-1-(2-시아노피리딘-4-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-cyanopyridin-4-yl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
129. 3-(3-클로로-4-플루오로페닐)-1-(5-시아노피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(5-cyanopyridin-3-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
130. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
131. 4-(3-(3-클로로-4-플루오로페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레이도)벤조산(4-(3-(3-chloro-4-fluorophenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)ureido)benzoic acid),
132. 3-(3-클로로-4-플루오로페닐)-1-(이속사졸-3-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(isoxazol-3-yl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
133. 3-(3-클로로-4-플루오로페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(1,3,4-티아디아졸-2-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)-1-(1,3,4-thiadiazol-2-yl)urea),
134. 3-(3-클로로-4-플루오로페닐)-1-(이속사졸-3-일)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(isoxazol-3-yl)-1-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
135. 3-(3-클로로-4-플루오로페닐)-1-(1H-피라졸-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(1H-pyrazol-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
136. 3-(3-클로로-4-플루오로페닐)-1-(이속사졸-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(isoxazol-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
137. 1-(바이사이클로[1.1.1]펜탄-1-일)-3-(3-클로로-4-플루오로페닐)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(1-(bicyclo[1.1.1]pentan-1-yl)-3-(3-chloro-4-fluorophenyl)-1-((5-((trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
138. 3-(6-클로로-4-(디메틸아미노)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-chloro-4-(dimethylamino)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
139. 3-(3-클로로-4-플루오로-5-메틸페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluoro-5-methylphenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
140. 3-(3-클로로-4-플루오로-5-메틸페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluoro-5-methylphenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
141. 3-(6-클로로-3-플루오로-4-메틸피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-chloro-3-fluoro-4-methylpyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
142. 3-(6-클로로-5-플루오로-4-메틸피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-chloro-5-fluoro-4-methylpyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
143. 3-(2-클로로피리미딘-5-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-chloropyrimidin-5-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
144. 3-(3-시아노페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-cyanophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
145. 3-(6-시아노피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-cyanopyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
146. 3-(2-시아노피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-cyanopyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
147. 3-(3-시아노페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-cyanophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
148. 3-(6-시아노피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-cyanopyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
149. 3-(3-시아노-4,5-디플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-cyano-4,5-difluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
150. 3-(3-시아노-4,5-디플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-cyano-4,5-difluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
151. 3-(6-시아노-4,5-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-cyano-4,5-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
152. 3-(4-시아노-3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-cyano-3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
153. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(4-시아노-3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(4-cyano-3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)urea),
154. 3-(3-시아노-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-cyano-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
155. 3-(3-시아노-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-cyano-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
156. 3-(4-시아노-3-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-cyano-3-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
157. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(3-시아노-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(3-cyano-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
158. 3-(2-시아노-3-플루오로피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-cyano-3-fluoropyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
159. 3-(3-클로로-4-플루오로페닐)-1-((1,3-디메틸-1H-피라졸-4-일)메틸)-1-(4-메톡시페닐)우레아(3-(3-chloro-4-fluorophenyl)-1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-1-(4-methoxyphenyl)urea),
160. 3-(6-시아노-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-cyano-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
161. 3-(4-시아노-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-cyano-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
162. 3-(3-시아노-4-플루오로페닐)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-cyano-4-fluorophenyl)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
163. 3-(3-시아노-4-플루오로페닐)-1-(6-메톡시피리다진-4-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-cyano-4-fluorophenyl)-1-(6-methoxypyridazin-4-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
164. 3-(6-시아노-4-(디메틸아미노)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-cyano-4-(dimethylamino)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
165. 3-(2,6-디클로로피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2,6-dichloropyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
166. 3-(2,6-디클로로피리딘-3-일)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(2,6-dichloropyridin-3-yl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
167. 3-(3,4-디시아노페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3,4-dicyanophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
168. 3-(3,4-디플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3,4-difluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
169. 3-(3,6-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3,6-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
170. 3-(5,6-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(5,6-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
171. 3-(5,6-디플루오로피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(5,6-difluoropyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
172. 3-(4,5-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4,5-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
173. 3-(3,4-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3,4-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
174. 3-(5-(디플루오로메틸)피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(5-(difluoromethyl)pyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
175. 3-(2-(디플루오로메틸)피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-(difluoromethyl)pyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
176. 3-(3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
177. 3-(6-(디플루오로메틸)피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-(difluoromethyl)pyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
178. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)urea),
179. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(6-(디플루오로메틸)피리딘-2-일)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(6-(difluoromethyl)pyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)urea),
180. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)urea),
181. 3-(3-(디플루오로메틸)페닐)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)phenyl)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
182. 1-((4-(2-에톡시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레아(1-((4-(2-ethoxyethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(4-fluorophenyl)-1-(6-methoxypyridin-3-yl)urea),
183. 3-(6-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
184. 3-(6-플루오로피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-fluoropyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
185. 3-(3-플루오로바이사이클로[1.1.1]펜탄-1-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
186. 3-(2-플루오로피리미딘-5-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-fluoropyrimidin-5-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
187. 3-(4-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
188. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
189. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
190. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
191. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)urea),
192. 3-(4-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
193. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-((4-(2-히드록시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-((4-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
194. 1-((4-브로모-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((4-bromo-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
195. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리다진-3-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridazin-3-yl)urea),
196. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)urea),
197. 1-((4-브로모-5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((4-bromo-5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
198. 1-((5-(디플루오로메틸)-4-(2-히드록시프로판-2-일)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-4-(2-hydroxypropan-2-yl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
199. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-((4-(2-히드록시프로필)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-((4-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
200. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리다진-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridazin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
201. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리다진-4-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridazin-4-yl)urea),
202. 3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
203. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리다진-4-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridazin-4-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
204. 3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
205. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-((4-(2-히드록시-2-메틸프로필)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-((4-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
206. 3-(4-(디플루오로메틸)-3-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-(difluoromethyl)-3-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
207. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-((4-(2-히드록시프로판-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-((4-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
208. 1-((5-(디플루오로메틸)-4-(2-히드록시-2-메틸프로필)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-4-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
209. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
210. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)urea),
211. 3-(2-(디플루오로메틸)-3-플루오로피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
212. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)urea),
213. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
214. 3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
215. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(4-플루오로-3-(트리플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)urea),
216. 1,3-비스(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(1,3-bis(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
217. 1-(2-메톡시피리미딘-5-일)-3-(3-메틸바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(1-(2-methoxypyrimidin-5-yl)-3-(3-methylbicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
218. 1-(2-메톡시피리미딘-5-일)-3-(2-(메틸티오)피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(1-(2-methoxypyrimidin-5-yl)-3-(2-(methylthio)pyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
219. 1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3,4,5-트리플루오로페닐)우레아(1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3,4,5-trifluorophenyl)urea),
220. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)-3-(3,4,5-트리플루오로페닐)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)-3-(3,4,5-trifluorophenyl)urea),
221. 1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3,5,6-트리플루오로피리딘-2-일)우레아(1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3,5,6-trifluoropyridin-2-yl)urea),
222. 1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3,4,5-트리플루오로페닐)우레아(1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3,4,5-trifluorophenyl)urea),
223. 1-((5-시아노-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)-3-(3,4,5-트리플루오로페닐)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)-3-(3,4,5-trifluorophenyl)urea),
224. 1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(4,5,6-트리플루오로피리딘-2-일)우레아(1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(4,5,6-trifluoropyridin-2-yl)urea),
225. 1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(6-(트리플루오로메틸)피리딘-2-일)우레아(1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea), 또는
226. 3-(3-시아노-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((1-프로피오닐-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-cyano-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((1-propionyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)일 수 있으나, 이에 제한되지 않는다.
본 발명의 화합물은 약학적으로 허용 가능한 염의 형태로 존재할 수 있다. 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산가염이 유용하다. 본 발명의 용어 "약학적으로 허용 가능한 염"이란 환자에게 유효작용을 갖는 농도에서 비교적 비독성이고 무해한 염의 형태를 의미하며, 이 염에 기인한 부작용이 화학식 1로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기 또는 무기 부가염을 의미한다.
산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올(예, 글리콜 모노메틸에테르)을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.
이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(ci트리c acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 요오드화수소산(hydroiodic acid) 등을 사용할 수 있으며, 이들에 제한되지 않는다.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.
본 발명의 화합물의 약학적으로 허용 가능한 염은, 달리 지시되지 않는 한, 상기 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용 가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용 가능한 염으로는 히드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄술포네이트(메실레이트) 및 p-톨루엔술포네이트(토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.
본 발명의 피라졸릴메틸우레아 유도체 화합물의 염으로는 약학적으로 허용 가능한 염으로서, 피라졸릴메틸우레아 유도체 화합물과 동등한 약리활성을 나타내는 피라졸릴메틸우레아 유도체 화합물의 염이면 제한없이 모두 사용 가능하다.
또한, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은, 이의 약학적으로 허용 가능한 염뿐만 아니라 이로부터 제조될 수 있는 가능한 수화물 등의 용매화물 및 가능한 모든 입체 이성질체를 제한없이 포함한다. 상기 화학식 1로 표시되는 화합물의 용매화물 및 입체이성질체는 당업계에 공지된 방법을 사용하여 화학식 1로 표시되는 화합물로부터 제조할 수 있다.
나아가, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 결정 형태 또는 비결정 형태로 제조될 수 있으며, 결정 형태로 제조될 경우 임의로 수화되거나 용매화될 수 있다. 본 발명에서는 상기 화학식 1로 표시되는 화합물의 화학양론적 수화물뿐만 아니라 다양한 양의 물을 함유하는 화합물이 포함될 수 있다. 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 용매화물은 화학양론적 용매화물 및 비화학양론적 용매화물 모두를 포함한다.
본 발명의 제2양태는 피라졸릴메틸 전구체와 R1 전구체를 반응시키는 제1단계; 및 이전 단계에서 수득한 화합물을 R2 전구체와 반응시키는 제2단계;를 포함하는 제1양태의 화합물, 또는 이의 약학적으로 허용 가능한 염의 제조방법을 제공한다.
예컨대, 상기 제1단계의 반응은 하기 반응식 1 내지 3 중 어느 하나의 방법으로 수행할 수 있으나, 이에 제한되지 않는다:
[반응식 1]
Figure pat00002
[반응식 2]
Figure pat00003
[반응식 3]
Figure pat00004
.
예컨대, 상기 제2단계의 반응은 하기 반응식 4 내지 7 중 어느 하나의 방법으로 수행할 수 있으나, 이에 제한되지 않는다:
[반응식 4]
Figure pat00005
[반응식 5]
Figure pat00006
[반응식 6]
Figure pat00007
[반응식 7]
Figure pat00008
.
상기 일련의 반응식에서, pyrazolyl은 비치환 또는 치환된 피라졸 고리로서 이에 포함된 질소 원자는 보호기를 포함할 수 있고, R1' 및 R2'은 각각 R1' 및 R2'과 동일하거나 이들의 전구체이며, X는 할로겐 또는 이외의 이탈기이다.
본 발명의 제3양태는 상기 제1양태의 화합물, 또는 이의 약학적으로 허용 가능한 염을 포함하는, 캡시드 조립(capsid assembly) 저해용 조성물을 제공한다.
본 발명의 용어, "제1양태의 화합물", 및 "약학적으로 허용 가능한 염"은 상기에서 설명한 바와 같다.
본 발명의 용어, "캡시드(capsid)"는 유전물질(genetic material)과 역전사에 필요한 효소 등을 둘러싸고 있는 바이러스의 단백질 구조체를 의미한다. 프로토머(protomer)라 불리는 단백질로 된 몇몇 올리고머(반복적인) 구조의 서브유닛으로 구성된다. 개별 단백질에 상응하거나, 또는 상응하지 않는, 관찰 가능한 3차원적 형태학적 서브유닛을 캡소미어(capsomere)라고 한다. 캡시드를 구성하는 단백질은 캡시드 단백질 또는 바이러스 코트 단백질(viral coat proteins; VCP)이라 한다. 캡시드와 이에 포함된 게놈은 뉴클레오캡시드(nucleocapsid)라고 한다. 상기 캡시드는 구조에 따라 광범위하게 분류되며, 대부분의 바이러스는 나선형(herical)또는 정이십면체(icosahedral) 구조의 캡시드를 갖는다. 박테리오파지(bacteriophages) 등의 몇몇 바이러스는 탄성(elasticity)과 정전기(electrostatics)의 제약으로 보다 복잡한 구조로 발전되었다. 캡시드면(capsid surface)은 하나 이상의 단백질로 구성될 수 있으며, 예컨대, 구제역(foot-and-mouth disease) 바이러스 캡시드는 3개 단백질 VP1-3로 구성된 면을 갖는다. 바이러스가 세포를 감염시키고 스스로 복제를 시작하면 세포의 단백질 생합성 메커니즘을 사용하여 새로운 캡시드 서브유닛이 합성된다. 캡시드에 의해 봉입되는 유전물질은 RNA 또는 DNA일 수 있으나, 이에 제한되지 않는다.
예컨대, 바이러스에 감염되면 숙주 세포는 원래 바이러스의 동일한 사본 수천 개를 신속하게 생성해야 한다. 감염된 세포 내부가 아니거나 세포를 감염시키는 과정 중에 있을 때, 바이러스는 (i) 유전 물질, 즉, 바이러스가 자신을 증식하는데 필요한 단백질을 암호화하는 DNA 또는 RNA의 긴 분자; (ii) 상기 유전 물질을 둘러싸고 보호하는 단백질 외투인 캡시드; 및 선택적으로 (iii) 지질 외피로 둘러쌓여 바이러스 정체성을 규정하는 독립적인 입자 또는 비리온(virions)의 형태로 존재한다.
본 발명의 제4양태는 상기 제1양태의 화합물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 항바이러스 조성물을 제공한다.
본 발명의 용어, "제1양태의 화합물", 및 "약학적으로 허용 가능한 염"은 상기에서 설명한 바와 같다.
본 발명의 제5양태는 상기 제1양태의 화합물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 바이러스 감염 질환의 예방 또는 치료용 약학적 조성물을 제공한다.
본 발명의 용어, "제1양태의 화합물", 및 "약학적으로 허용 가능한 염"은 상기에서 설명한 바와 같다.
본 발명의 용어, "예방"이란 본 발명의 조성물의 투여로 바이러스 감염 질환의 발생, 확산 및 재발을 억제시키거나 지연시키는 모든 행위를 의미하고, "치료"란 본 발명의 조성물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.
본 발명의 약학적 조성물은 유전물질과 그를 복제하는 요소들이 제거된 비정상 캡시드 형성을 촉진함으로써 바이러스 감염에 의해 유발되는 질환을 예방 또는 치료할 수 있다.
상기 바이러스 감염 질환은 B형 간염 바이러스(hepatitis B virus; HBV), C형 간염 바이러스(hepatitis C virus; HCV), 또는 인간 면역결핍 바이러스(human immunodeficiency virus; HIV)에 의한 감염 질환일 수 있으나, 이에 제한되지 않는다.
바람직하게, 본 발명에 따른 약학적 조성물은 유효성분으로서 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용 가능한 염을 조성물의 총중량을 기준으로 0.1 내지 75 중량%로, 보다 바람직하게는 1 내지 50 중량%로 함유할 수 있다.
본 발명의 조성물은 약학적으로 허용 가능한 담체, 희석제 또는 부형제를 추가로 포함할 수 있으며, 각각의 사용 목적에 맞게 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁제, 에멀젼, 시럽, 에어로졸 등의 경구 제형, 멸균 주사 용액의 주사제 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구 투여하거나 정맥내, 복강내, 피하, 직장, 국소 투여 등을 포함한 다양한 경로를 통해 투여될 수 있다. 이러한 조성물에 포함될 수 있는 적합한 담체, 부형제 또는 희석제의 예로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸셀룰로즈, 미정질셀룰로스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수 있다. 또한, 본 발명의 조성물은 충전제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.
경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로스, 락토즈, 젤라틴 등을 혼합하여 제형화한다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크와 같은 윤활제가 사용될 수 있다.
경구용 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 예시될 수 있으며, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.
비경구 투여를 위한 제제에는 멸균된 수용액제, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 한편, 주사제에는 용해제, 등장화제, 현탁화제, 유화제, 안정화제, 방부제 등과 같은 종래의 첨가제가 포함될 수 있다.
이때, 본 발명의 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명의 용어 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.
예컨대, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.
구체적으로, 본 발명의 조성물에서 화합물의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 kg 당 1 내지 100 mg, 바람직하게는 5 내지 60 mg을 매일 또는 격일 투여하거나 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.
본 발명의 제6양태는 상기 제5양태의 약학적 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 바이러스 감염 질환의 치료방법을 제공한다.
본 발명의 용어, "제5양태의 약학적 조성물" 및 "바이러스 감염 질환"은 상기에서 설명한 바와 같다.
본 발명의 용어 "개체"란, 상기 바이러스 감염 질환이 발명하였거나 발병할 수 있는 인간을 포함한 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함한 모든 동물을 의미하고, 본 발명의 약학적 조성물을 개체에게 투여함으로써 상기 질환을 효과적으로 예방 또는 치료할 수 있다. 본 발명의 약학적 조성물은 기존의 치료제와 병행하여 투여될 수 있다.
본 발명의 용어 "투여"란, 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내투여, 직장내 투여될 수 있으나, 이에 제한되지는 않는다. 또한, 본 발명의 약학적 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥 주사제, 피하 주사제, 피내 주사제, 근육 주사제, 점적 주사제 등이다. 주사제는 생리식염액, 링겔액 등의 수성 용제, 식물유, 고급 지방산 에스테르(예, 올레인산에칠 등), 알코올 류(예, 에탄올, 벤질알코올, 프로필렌글리콜, 글리세린 등) 등의 비수성 용제 등을 이용하여 제조할 수 있고, 변질 방지를 위한 안정화제(예, 아스코르빈산, 아황산수소나트륨, 피로아황산나트륨, BHA, 토코페롤, EDTA 등), 유화제, pH 조절을 위한 완충제, 미생물 발육을 저지하기 위한 보존제(예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레솔, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.
본 발명에서 유효성분과 결합하여 사용된 "치료학적으로 유효한 양"이란 용어는 대상 질환을 예방 또는 치료하는데 유효한 피라졸릴메틸우레아 유도체 화합물, 또는 이의 약학적으로 허용 가능한 염의 양을 의미한다.
본 발명의 약학적 조성물은 예방 또는 치료하고자 하는 질환의 종류에 따라, 유효성분으로서 피라졸릴메틸우레아 유도체 화합물, 또는 이의 약학적으로 허용 가능한 염 이외의 공지된 각 질환의 예방 또는 치료에 사용되는 공지의 약물을 추가로 포함할 수 있다. 예컨대, 바이러스 감염 질환의 예방 또는 치료에 사용되는 경우 유효성분으로서 피라졸릴메틸우레아 유도체 화합물, 또는 이의 약학적으로 허용 가능한 염 이외에 공지된 약물을 추가로 포함할 수 있고, 이들 질환의 치료를 위해 공지된 다른 치료와 병용될 수 있다.
본 발명에 따라 새롭게 합성된 분자 내에 피라졸릴메틸우레아 유도체는 낮은 세포독성을 나타내면서 캡시드 조립을 저해하는 효과를 나타내므로 이와 관련된 질환, 예컨대, HBV, HCV, HIV 등의 바이러스 감염 질환의 예방 또는 치료에 유용하게 사용될 수 있다.
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.
합성예
본 발명의 화합물은 하기 일련의 반응식 중에서 선택되는 2단계의 반응을 포함하는 공정을 통해 합성할 수 있다.
단계 1: 피라졸릴메틸 전구체 및 R 1 전구체의 반응
단계 1-1
Figure pat00009
단계 1-2
Figure pat00010
단계 1-3
Figure pat00011
단계 2: R 2 전구체와의 반응
단계 2-1
Figure pat00012
단계 2-2
Figure pat00013
단계 2-3
Figure pat00014
단계 2-4
Figure pat00015
상기 일련의 반응식에서, pyrazolyl은 비치환 또는 치환된 피라졸 고리로서 이에 포함된 질소 원자는 보호기를 포함할 수 있고, R1' 및 R2'은 각각 R1' 및 R2'과 동일하거나 이들의 전구체이며, X는 할로겐이다.
실시예 1. 3-(바이사이클로[1.1.1]펜탄-1-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 383.2,
1H NMR (400 MHz, CDCl3) δ 8.33 - 8.22 (m, 2H), 6.28 (s, 1H), 4.66 (s, 1H), 4.62 (s, 2H), 4.05 (s, 3H), 2.44 (s, 1H), 2.02 (s, 6H).
실시예 2. 1-(2-메톡시피리미딘-5-일)-3-(피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 395.2,
1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 2H), 8.80 (s, 1H), 8.58 (s, 2H), 6.65 (s, 1H), 4.92 (s, 2H), 3.95 (s, 3H).
실시예 3. 3-(3-플루오로-4-(1H-이미다졸-1-일)피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H]+ = 478.2,
1H NMR (400 MHz, DMSO-d6) δ 13.88 - 13.27 (m, 1H), 9.46 - 9.04 (m, 1H), 8.49 (s, 2H), 8.30 - 8.26 (m, 1H), 8.24 (s, 1H), 7.75 - 7.71 (m, 1H), 7.65 - 7.60 (m, 1H), 7.23 - 7.20 (m, 1H), 6.64 - 6.60 (m, 1H), 5.01 - 4.86 (m, 2H), 3.96 - 3.88 (m, 3H).
실시예 4. 3-(2-브로모-3-플루오로피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 492.15,
1H NMR (300 MHz, Chloroform-d) δ 11.26 (s, 1H), 8.43 (t, J = 1.6 Hz, 2H), 8.17 (tt, J = 9.5, 6.6 Hz, 2H), 6.58 (s, 1H), 6.41 (d, J = 2.2 Hz, 1H), 4.81 (d, J = 2.2 Hz, 2H), 4.13 (t, J = 1.6 Hz, 3H).
실시예 5. 3-(6-클로로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 428.1,
1H NMR (400 MHz, CDCl3) δ 11.19 (br s, 1H), 8.36 (s, 2H), 8.10 - 8.01 (m, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.79 (s, 1H), 6.35 (s, 1H), 4.75 (s, 2H), 4.11 (s, 3H).
실시예 6. 3-(3-클로로바이사이클로[1.1.1]펜탄-1-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 417.2,
1H NMR (400 MHz, CDCl3) δ 11.69 - 11.18 (m, 1H), 8.27 (s, 2H), 6.30 (s, 1H), 4.78 (s, 1H), 4.64 (s, 2H), 4.06 (s, 3H), 2.39 (s, 6H).
실시예 7. 3-(3-클로로-4-시아노페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 2H), 7.90 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.61 (dd, J = 8.7, 2.0 Hz, 1H), 6.65 (s, 1H), 4.92 (s, 2H), 3.95 (s, 3H).
실시예 8. 3-(5-클로로-6-시아노피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
1H NMR (300 MHz, Chloroform-d) δ 11.14 (s, 1H), 8.39 (d, J = 10.0 Hz, 3H), 7.87 (d, J = 9.2 Hz, 1H), 6.94 (s, 1H), 6.40 (s, 1H), 4.79 (s, 2H), 4.14 (s, 3H).
실시예 9. 3-(3-클로로-4-이소시아노페닐)-1-((5-시아노-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 409.4,
1H NMR (500 MHz, Methanol-d4) δ 8.45 (s, 2H), 7.90 (s, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 9.8 Hz, 1H), 6.78 (s, 1H), 4.98 (s, 2H), 4.07 (s, 3H).
실시예 10. 3-(3-시아노-4,5-디플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 436.1,
1H NMR (400MHz, CDCl3) δ = 8.42 (s, 2H), 7.84 (ddd, J = 1.9, 3.8, 9.3 Hz, 1H), 7.43 (q, J = 9.4 Hz, 1H), 6.87 - 6.55 (m, 2H), 6.36 (s, 1H), 4.78 (s, 2H), 4.08 (s, 3H).
실시예 11. 3-(3-클로로-4,5-디플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 463.1,
1H NMR (400 MHz, DMSO-d6) δ 13.57 (br s, 1H), 8.55 (s, 3H), 7.66 - 7.46 (m, 2H), 6.64 (s, 1H), 4.90 (s, 2H), 3.96 (s, 3H).
실시예 12. 3-(3-클로로-4,5-디플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 445.1,
1H NMR (400 MHz, CDCl3) δ 8.33 (s, 2H), 7.30 (ddd, J=2.7, 6.3, 11.5 Hz, 1H), 7.18 (dd, J=2.4, 5.2 Hz, 1H), 6.85 - 6.54 (m, 1H), 6.47 (br s, 1H), 6.31 (s, 1H), 4.73 (s, 2H), 4.05 (s, 3H).
실시예 13. 3-(6-클로로-4,5-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 463.9,
1H NMR (400 MHz, CDCl3) δ 11.76 - 10.67 (m, 1H), 8.30 - 8.26 (m, 2H), 7.96 (dd, J = 4.8, 10.9 Hz, 1H), 6.77 (s, 1H), 6.30 (s, 1H), 4.70 - 4.65 (m, 2H), 4.06 - 4.01 (m, 3H).
실시예 14. 3-(3-클로로-4-플루오로페닐)-1-(6-옥소-1,6-디하이드로피리딘-3-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아의 제조
1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.71(dd, J = 3.0 Hz, 1H) 7.44(m, 1H), 7.31 (s, 1H), 7.28 - 7.16 (m, 2H), 6.29 (d, J = 7.2 Hz, 1H), 4.46 (s, 2H), 2.28 (s, 2H), 1.65 - 1.64 (m, 4H).
실시예 15. 3-(3-클로로-4-플루오로페닐)-1-(2-옥소-1,2-디하이드로피리딘-4-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아의 제조
[M+H+] = 416.3
1H NMR (500 MHz, Methanol-d4) δ 7.66 (dd, J = 6.6, 2.6 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.16 (t, J = 9.0 Hz, 1H), 6.44 (d, J = 7.3 Hz, 1H), 6.32 (d, J = 2.2 Hz, 1H), 4.92 (s, 2H), 2.59 (t, J = 6.1 Hz, 2H), 2.45 (t, J = 6.0 Hz, 2H), 1.87 - 1.65 (m, 4H).
실시예 16. N-(4-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레이도)페닐)메탄술폰아미드의 제조
[M+H+] = 494.1,
1H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.13 (s, 1 H), 7.71 - 7.69 (dd, J = 2.4 Hz, 6.8 Hz, 1H), 7.40 - 7.37 (m, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.19 - 7.14 (m, 4H), 4.78 (s, 2H), 4.54 (s, 2H), 3.67 (t, J = 5.2 Hz, 2H), 3.00 (s, 3H), 2.32 - 2.31 (m, 2H).
실시예 17. N-(5-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레이도)피리딘-2-일)메탄술폰아미드의 제조
[M+H+] = 495.2,
1H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 8.04 (s, 1H), 7.71 - 7.69 (m, 1H), 7.53 - 7.52 (m, 1H), 7.41 - 7.40 (m, 1H), 7.40 - 7.26 (m, 1H), 6.92 - 6.90 (m, 1H), 4.79 (s, 2H), 4.57 (s, 2H), 3.72 - 3.70 (m, 2H), 3.48 - 3.24 (m, 3H), 2.45 - 2.34 (m, 2H).
실시예 18. N-(5-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레이도)피리딘-2-일)메탄술폰아미드의 제조
[M+H+] = 495.2,
1H NMR (400 MHz, CDCl3) δ = 8.18 (d, J = 1.9 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.44 (dd, J = 2.6, 6.5 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.17 - 7.12 (m, 1H), 7.06 - 6.99 (m, 1H), 6.41 (br s, 1H), 4.69 (s, 2H), 4.22 - 4.16 (m, 2H), 3.28 (s, 3H), 2.31 (br t, J = 6.2 Hz, 2H), 1.91 - 1.82 (m, 2H).
실시예 19. N-(4-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레이도)페닐)메탄술폰아미드A의 제조
[M+H+] = 494.2,
1H NMR (400 MHz, CDCl3) δ = 8.57 (d, J = 11.4 Hz, 1H), 8.36 (s, 1H), 7.74 (dd, J = 2.8, 6.5 Hz, 1H), 7.42 (dd, J = 2.6, 6.5 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.28 (s, 1H), 7.20 - 7.17 (m, 1H), 7.17 - 7.15 (m, 1H), 7.13 - 7.09 (m, 1H), 7.05 - 6.99 (m, 1H), 6.91 (t, J = 8.8 Hz, 1H), 6.69 (dd, J = 2.8, 6.1 Hz, 1H), 6.50 (td, J = 3.3, 8.8 Hz, 1H), 6.17 (s, 1H), 4.65 (s, 2H), 4.21 - 4.15 (m, 2H), 3.11 (s, 3H), 2.28 - 2.19 (m, 2H), 1.88 - 1.80 (m, 2H).
실시예 20. 1-(6-아세틸피리딘-3-일)-3-(3-클로로-4-플루오로페닐)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 444.2,
1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 2.5, 8.4 Hz, 1H), 7.46 (dd, J = 2.6, 6.5 Hz, 1H), 7.17 - 7.11 (m, 1H), 7.09 - 7.01 (m, 1H), 6.58 (br s, 1H), 4.73 (s, 2H), 4.23 - 4.14 (m, 2H), 2.73 (s, 3H), 2.16 (t, J = 6.3 Hz, 2H), 1.89 - 1.79 (m, 2H).
실시예 21. 1-(6-아세틸피리딘-3-일)-3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 444.3,
1H NMR (400 MHz, DMSO) δ 12.45 (s, 1H), 8.88 (s, 1H), 8.63 (s, 1H), 7.98 - 7.95 (m, 1H), 7.72 - 7.70 (m, 2H), 7.39 - 7.34 (m, 1H), 7.32 - 7.29 (m, 1H), 4.97 (s, 2H), 4.58 (s, 2H), 3.72 - 3.69 (m, 2H), 2.52 (m, 3H), 2.51 - 2.43 (m, 2H).
실시예 22. 1-(2-아세틸피리딘-4-일)-3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 444.5,
1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 5.4 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.80 (s, 1H), 7.53 (dd, J = 2.6, 6.4 Hz, 1H), 7.46 (dd, J = 2.3, 5.4 Hz, 1H), 7.22 (td, J = 3.4, 8.8 Hz, 1H), 7.12 - 7.05 (m, 1H), 4.90 (s, 2H), 4.71 (s, 2H), 3.83 (t, J = 5.5 Hz, 2H), 2.73 (s, 3H), 2.42 (t, J = 5.4 Hz, 2H).
실시예 23. 4-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레이도)-N-메틸벤젠술폰아미드의 제조
[M+H+] = 494.0,
1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.93 - 7.86 (m, 2H), 7.60 - 7.54 (m, 1H), 7.49 - 7.45 (m, 2H), 7.37 - 7.30 (m, 1H), 7.22 - 7.13 (m, 1H), 4.95 (s, 2H), 4.60 (m, 2H), 3.71 - 3.63 (m, 2H), 2.54 (s, 3H), 2.49 - 2.31 (m, 2H), 1.75 - 1.67 (m, 3H).
실시예 24. 3-(3-클로로-4-플루오로페닐)-1-(1-메틸-1H-피라졸-4-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아의 제조
[M+H+] = 405.1,
1H NMR (500 MHz, CDCl3) δ 7.48 (dd, J = 6.5, 2.6 Hz, 1H), 7.37 (s, 2H), 7.14 - 7.08 (m, 1H), 6.99 (t, J = 8.8 Hz, 2H), 4.69 (s, 2H), 3.86 (s, 3H), 2.60 (t, J = 6.1 Hz, 2H), 2.31 (t, J = 5.9 Hz, 2H), 1.76 (dd, J = 10.6, 4.7 Hz, 2H), 1.68 (dd, J = 10.4, 4.7 Hz, 2H).
실시예 25. 3-(3-클로로-4-플루오로페닐)-1-(1-메틸-1H-피라졸-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 405.0,
1H NMR (300 MHz, DMSO) δ 11.56 (s, 1H), 10.37 (s, 1H), 7.89 (dd, J = 6.8, 2.6 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.47 (ddd, J = 9.0, 4.3, 2.7 Hz, 1H), 7.36 (t, J = 9.1 Hz, 1H), 6.04 (d, J = 2.1 Hz, 1H), 4.87 (s, 2H), 4.03 (d, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.32 (t, J = 6.3 Hz, 2H), 1.79 - 1.67 (m, 2H).
실시예 26. 3-(3-클로로-4-플루오로페닐)-1-(5-메틸이속사졸-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 506,
1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 9.73 (s, 1H), 7.80 (dd, J = 6.8, 2.6 Hz, 1H), 7.45 (ddd, J = 9.1, 4.4, 2.6 Hz, 1H), 7.38 (t, J = 9.0 Hz, 1H), 6.43 (s, 1H), 4.94 (s, 2H), 4.15 - 3.96 (m, 2H), 2.39 (s, 3H), 1.82 - 1.71 (m, 2H).
실시예 27. 3-(3-클로로-4-플루오로페닐)-1-(3-메틸바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 416.9,
1H NMR (400 MHz, CDCl3) δ 11.61 - 10.85 (m, 1H), 7.53 (dd, J = 2.6, 6.4 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.13 - 7.07 (m, 1H), 6.75 (s, 1H), 6.40 (s, 1H), 4.45 (s, 2H), 2.09 (s, 6H), 1.32 (s, 3H).
실시예 28. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시-4-메틸피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 459.1,
1H NMR (400 MHz, DMSO-d6) δ 13.49 (s, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 7.71 (dd, J = 2.5, 6.9 Hz, 1H), 7.45 - 7.38 (m, 1H), 7.33 - 7.26 (m, 1H), 6.61 (s, 1H), 5.11 - 4.51 (m, 2H), 3.94 (s, 3H), 2.13 (s, 3H).
실시예 29. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시-2,6-디메틸페닐)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 471.1,
1H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 7.93 - 7.78 (m, 1H), 7.73 (dd, J = 2.6, 6.8 Hz, 1H), 7.44 (ddd, J = 2.8, 4.2, 9.1 Hz, 1H), 7.25 (t, J = 9.1 Hz, 1H), 6.74 (s, 2H), 6.49 (s, 1H), 4.66 (s, 2H), 3.34 (s, 2H), 1.92 (s, 6H).
실시예 30. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시-4,6-디메틸피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 473.1,
1H NMR (400 MHz, Chloroform-d) δ 11.59 (s, 1H), 7.50 (dd, J = 2.7, 6.4 Hz, 1H), 7.21 - 7.15 (m, 2H), 7.00 (t, J = 8.8 Hz, 1H), 6.68 (s, 1H), 6.25 (s, 1H), 4.55 (s, 2H), 3.91 (s, 3H), 2.09 (s, 6H).
실시예 31. 메틸 4-(3-(3-클로로-4-플루오로페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레이도)벤조에이트의 제조
[M+H+] = 457.3,
1H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.81 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.71 (dd, J = 6.8, 2.6 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.39 (ddd, J = 6.9, 4.3, 2.2 Hz, 1H), 7.31 (t, J = 9.1 Hz, 1H), 4.86 (s, 2H), 3.84 (s, 3H), 2.50 (d, J = 2.0 Hz, 2H), 2.29 (t, J = 6.0 Hz, 2H), 1.73 - 1.54 (m, 4H).
실시예 32. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아의 제조
[M+H+] = 431.05,
1H NMR (300 MHz, Chloroform-d) δ 7.44 (dd, J = 6.5, 2.6 Hz, 1H), 7.14 - 7.05 (m, 3H), 7.00 (t, J = 8.8 Hz, 1H), 6.96 - 6.90 (m, 2H), 6.27 (s, 1H), 4.70 (s, 2H), 3.84 (s, 3H), 2.64 (t, J = 6.2 Hz, 2H), 2.20 (t, J = 6.0 Hz, 2H), 1.77 (dt, J = 10.6, 5.9 Hz, 2H), 1.71 - 1.59 (m, 2H).
실시예 33. 1-((5-아세틸-4,5,6,7-테트라하이드로-1H-피라졸로[4,3-c]피리딘-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)우레아의 제조
[M+H+] = 472.2,
1H NMR (500 MHz, DMSO-d6) δ 12.37 - 12.29 (m, 1H), 8.06, 8.00 (s, 1 H), 7.73 - 7.71 (m, 1H), 7.44 - 7.40 (m, 1H), 7.28 - 7.24 (m, 1H), 7.17 - 7.13 (m, 2H), 6.94 (t, J = 11.1 Hz, 2H), 4.78, 4.74 (s, 2H), 4.38 (d, J = 8.40 Hz, 1H), 4.27, 4.23 (s, 1H), 3.77, 3.76 (s, 3H), 3.68 - 3.61 (m, 2H), 2.70 - 2.50 (m, 2H), 2.08 - 1.93 (m, 3H).
실시예 34. 1-((1H-피라졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)우레아의 제조
[M+H+] = 375,
1H NMR (300 MHz, Chloroform-d) δ 7.52 (d, J = 1.7 Hz, 1H), 7.47 (dd, J = 6.5, 2.6 Hz, 1H), 7.12 (dd, J = 9.3, 2.8 Hz, 3H), 7.03 (t, J = 8.7 Hz, 1H), 6.97 (d, J = 8.9 Hz, 2H), 6.20 (s, 1H), 6.18 (s, 1H), 4.81 (s, 2H), 3.87 (s, 3H).
실시예 35. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1-메틸-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 389,
1H NMR (300 MHz, Chloroform-d) δ 7.53 (dd, J = 6.5, 2.6 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.17 (d, J = 8.9 Hz, 2H), 7.13 (dt, J = 4.0, 2.3 Hz, 1H), 7.01 (t, J = 8.8 Hz, 1H), 6.94 (d, J = 8.9 Hz, 2H), 6.43 (s, 1H), 6.28 (d, J = 2.2 Hz, 1H), 4.86 (s, 2H), 3.85 (d, J = 1.6 Hz, 6H).
실시예 36. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1-메틸-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아의 제조
1H NMR (300 MHz, CDCl3) δ 7.43 (dd, J = 6.5, 2.6 Hz, 1H), 7.14 - 7.05 (m, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.97 - 6.87 (m, 4H), 6.06 (s, 1H), 4.86 (s, 2H), 3.84 (s, 3H), 3.72 (s, 3H), 2.57 (t, J = 6.4 Hz, 2H), 1.92 (t, J = 6.0 Hz, 2H), 1.72 - 1.60 (m, 2H), 1.54 - 1.47 (m, 2H).
실시예 37. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((5-메틸-4,5,6,7-테트라하이드로-1H-피라졸로[4,3-c]피리딘-3-일)메틸)우레아의 제조
[M+H+] = 444.6,
1H NMR (500 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.02 (s, 1H), 7.70 (dd, J = 7.2, 2.6 Hz, 1H), 7.41 (ddd, J = 9.1, 4.3, 2.6 Hz, 1H), 7.27 (t, J = 9.1 Hz, 1H), 7.11 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 4.71 (s, 2H), 3.76 (s, 3H), 3.26 (s, 2H), 2.63 (s, 4H), 2.34 (s, 3H).
실시예 38. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 431.1,
1H NMR (300 MHz, CDCl3) δ 7.43 (dd, J = 6.5, 2.5 Hz, 1H), 7.14 - 7.02 (m, 3H), 6.95 (dd, J = 19.6, 8.8 Hz, 3H), 6.29 (s, 1H), 4.70 (s, 2H), 4.38 (s, 2H), 3.86 (t, J = 5.6 Hz, 2H), 3.82 (s, 3H), 3.43 (s, 1H), 2.75 (t, J = 5.5 Hz, 2H).
실시예 39. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1-메틸-1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 445.3,
1H NMR (500 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.69 (dd, J = 6.9, 2.6 Hz, 1H), 7.46 - 7.34 (m, 1H), 7.26 (t, J = 9.1 Hz, 1H), 7.14 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 4.67 (s, 2H), 4.43 (s, 2H), 3.79 - 3.76 (m, 5H), 3.60 (s, 3H), 2.64 (t, J = 5.6 Hz, 2H).
실시예 40. 3-(3-클로로-4-플루오로페닐)-1-((5,5-디플루오로-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 466.2,
1H NMR (500 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.20 (s, 1H), 7.96 (d, J = 2.7 Hz, 1H), 7.69 (dd, J = 6.9, 2.6 Hz, 1H), 7.53 (dd, J = 8.8, 2.7 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.28 (t, J = 9.1 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 4.73 (s, 2H), 3.86 (s, 3H), 2.92 (t, J = 14.4 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H), 2.25 - 2.19 (dt, J = 13.9, 7.1 Hz, 2H).
실시예 41. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 418.2,
1H NMR (300 MHz, CDCl3) δ 8.02 (d, J = 2.6 Hz, 1H), 7.44 (dd, J = 6.5, 2.5 Hz, 1H), 7.34 (dd, J = 8.7, 2.6 Hz, 1H), 7.27 (s, 1H), 7.15 - 7.06 (m, 1H), 6.99 (t, J = 8.7 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.46 (s, 1H), 4.70 (s, 2H), 3.95 (s, 3H), 2.67 (t, J = 6.9 Hz, 2H), 2.51 - 2.27 (m, 4H), 2.16 (s, 1H).
실시예 42. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아의 제조
[M+H+] = 431.19,
1H NMR (500 MHz, MeOD) δ 7.83 (d, J = 2.6 Hz, 1H), 7.57 (dd, J = 6.7, 2.6 Hz, 1H), 7.43 (dd, J = 8.8, 2.7 Hz, 1H), 7.25 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 4.82 (s, 2H), 3.90 (s, 3H), 2.59 (t, J = 6.1 Hz, 2H), 2.33 (s, 2H), 1.81 - 1.74 (m, 2H), 1.70 (d, J = 5.5 Hz, 2H).
실시예 43. 1-((1H-인다졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 426.1,
1H NMR (500 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.25 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.51 - 7.40 (m, 3H), 7.35 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 8.7 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 5.19 (s, 2H), 3.82 (s, 3H).
실시예 44. 3-(3-클로로-4-플루오로페닐)-1-((5-(히드록시메틸)-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 460.2,
1H NMR (500 MHz, DMSO-d6) δ 12.08 (s, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.69 (d, J = 6.4 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.46 - 7.33 (m, 1H), 7.27 (t, J = 9.1 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 4.77 (d, J = 15.2 Hz, 1H), 4.68 (d, J = 15.2 Hz, 1H), 4.52 (t, J = 5.2 Hz, 1H), 3.85 (s, 3 H), 3.36 - 3.30 (m, 2H), 2.63 - 2.55 (m, 1H), 2.49 - 2.40 (m, 2H), 1.92 - 1.85 (m, 2H), 1.72 - 1.63 (m, 1H), 1.33 - 1.25 (m, 1H).
실시예 45. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1,4,6,7-테트라하이드로티오피라노[4,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 448.3,
1H NMR (500 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.19 (s, 1H), 7.97 (t, J = 2.1 Hz, 1H), 7.69 (d, J = 6.8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.48 - 7.36 (m, 1H), 7.27 (t, J = 9.1 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 4.75 (s, 2H), 3.86 (s, 3H), 3.51 (s, 2H), 2.97 J 2.61 (m, 4H).
실시예 46. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 417.2,
1H NMR (300 MHz, CDCl3) δ 7.44 (dd, J = 6.5, 2.6 Hz, 1H), 7.16 - 7.08 (m, 3H), 7.06 - 6.95 (m, 3H), 6.17 (s, 1H), 4.69 (s, 2H), 3.87 (s, 3H), 2.72 (t, J = 7.4 Hz, 2H), 2.39 (dd, J = 9.4, 4.0 Hz, 4H).
실시예 47. 3-(3-클로로-4-플루오로페닐)-1-((5,5-디메틸-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 458.19,
1H NMR (300 MHz, CDCl3) δ 8.01 (s, 1H), 7.53 - 7.46 (m, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.15 (s, 1H), 7.04 (t, J = 8.7 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 4.73 (d, J = 1.6 Hz, 2H), 3.98 (d, J = 2.1 Hz, 3H), 2.64 (s, 2H), 1.98 (s, 2H), 1.57 (d, J = 6.1 Hz, 2H), 0.92 (d, J = 1.8 Hz, 6H).
실시예 48. 3-(3-클로로-4-플루오로페닐)-1-((5-히드록시-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 446.24,
1H NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 7.46 (d, J = 6.4 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 7.01 (t, J = 8.5 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.40 (s, 1H), 4.75 - 4.67 (m, 2H), 4.10 (s, 1H), 3.96 (s, 3H), 2.82 (dd, J = 14.6, 8.3 Hz, 1H), 2.72 - 2.64 (m, 1H), 2.60 (dd, J = 15.5, 4.5 Hz, 1H), 2.26 (dd, J = 15.4, 6.8 Hz, 1H), 1.95 (s, 1H), 1.92 - 1.86 (m, 1H).
실시예 49. 3-(3-클로로-4-플루오로페닐)-1-((5,5-디옥시도-1,4,6,7-테트라하이드로티오피라노[4,3-c]피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 480.3,
1H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.19 (s, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.68 (d, J = 6.9 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.49 - 7.38 (m, 1H), 7.29 (t, J = 9.1 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 4.72 (s, 2H), 4.19 (s, 2H), 3.86 (s, 3H), 3.39 (t, J = 6.5 Hz, 2H), 3.10 (d, J = 6.6 Hz, 2H).
실시예 50. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((5-메틸-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 390.14,
1H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 2.6 Hz, 1H), 7.48 (dd, J = 6.5, 2.6 Hz, 1H), 7.41 (dd, J = 8.8, 2.7 Hz, 1H), 7.16 - 7.08 (m, 1H), 7.01 (t, J = 8.7 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.46 (s, 1H), 5.96 (s, 1H), 4.74 (s, 2H), 3.96 (s, 3H), 2.27 (s, 3H).
실시예 51. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4,5,6,7-테트라하이드로-1H-4,7-메타노인다졸-3-일)메틸)우레아의 제조
[M+H+] = 442.3,
1H NMR (500 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.28 (s, 1H), 7.94 (s, 1H), 7.72 (d, J = 6.8 Hz, 1H), 7.45 (t, J = 12.3 Hz, 2H), 7.29 (t, J = 9.1 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 4.90 - 4.64 (m, 2H), 3.86 (s, 3H), 3.18 (s, 1H), 3.05 (s, 1H), 1.91 - 1.63 (m, 3H), 1.54 (d, J = 8.5 Hz, 1H), 1.01 (s, 1H), 0.86 (t, J = 10.1 Hz, 1H).
실시예 52. 3-((3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레이도)메틸)-4,5,6,7-테트라하이드로-1H-인다졸-5-카르복실산의 제조
[M+H+] = 474.3.
실시예 53. 메틸 3-((3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레이도)메틸)-4,5,6,7-테트라하이드로-1H-인다졸-5-카복실레이트의 제조
[M+H+] = 488.2,
1H NMR (500 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 7.68 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.45 - 7.35 (m, 1H), 7.28 (t, J = 9.1 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 4.82 (d, J = 14.9 Hz, 1H), 4.64 (d, J = 15.3 Hz, 1H), 3.86 (s, 3H), 3.62 (s, 3H), 2.76 - 2.53 (m, 4H), 2.49 - 2.32 (m, 1H), 2.06 (d, J = 13.0 Hz, 1H), 1.74 (s, 1H).
실시예 54. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리딘-4-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아의 제조
[M+H+] = 432.0,
1H NMR (300 MHz, CDCl3) δ 8.11 (d, J = 5.6 Hz, 1H), 7.93 (s, 1H), 7.53 (dd, J = 6.5, 2.6 Hz, 1H), 7.25 - 7.17 (m, 1H), 7.02 (t, J = 8.8 Hz, 1H), 6.83 (dd, J = 5.6, 1.7 Hz, 1H), 6.65 (d, J = 1.6 Hz, 1H), 4.82 (s, 2H), 3.93 (s, 3H), 2.72 - 2.47 (m, 2H), 2.25 (t, J = 5.9 Hz, 2H), 1.72 (ddd, J = 15.5, 9.6, 3.6 Hz, 4H).
실시예 55. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 432.2,
1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 2.6 Hz, 1H), 7.45 (dd, J = 6.4, 2.7 Hz, 1H), 7.35 (dd, J = 8.7, 2.7 Hz, 1H), 7.15 - 7.09 (m, 1H), 7.02 (t, J = 8.7 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.17 (s, 1H), 4.68 (s, 2H), 4.47 (s, 2H), 3.97 (s, 3H), 3.90 (t, J = 5.6 Hz, 2H), 2.79 (t, J = 5.6 Hz, 2H).
실시예 56. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4-메틸-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 390.2,
1H NMR (500 MHz, DMSO) δ 8.20 (s, 1H), 7.93 - 7.87 (m, 1H), 7.70 (dd, J = 6.9, 2.6 Hz, 1H), 7.48 (dd, J = 8.7, 2.7 Hz, 1H), 7.42 (ddd, J = 9.1, 4.3, 2.7 Hz, 1H), 7.35 (s, 1H), 7.27 (t, J = 9.1 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 4.79 (s, 2H), 3.84 (s, 3H), 1.88 (s, 3H).
실시예 57. 3-(3-클로로-4-플루오로페닐)-1-((4,5-디메틸-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 406.3,
1H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 8.22 (s, 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.70 (dd, J = 6.8, 2.3 Hz, 1H), 7.49 (dd, J = 8.6, 2.3 Hz, 1H), 7.42 (ddd, J = 9.1, 4.3, 2.7 Hz, 1H), 7.27 (t, J = 9.1 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 4.74 (s, 2H), 3.84 (s, 3H), 2.06 (s, 3H), 1.80 (s, 3H).
실시예 58. 3-(3-클로로-4-플루오로페닐)-1-((5-이소프로필-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 420.3,
1H NMR (500 MHz, DMSO) δ 12.29 (s, 1H), 8.29 (s, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.72 (dd, J = 6.8, 2.5 Hz, 1H), 7.56 (dd, J = 8.7, 2.7 Hz, 1H), 7.43 (ddd, J = 9.1, 4.2, 2.7 Hz, 1H), 7.28 (t, J = 9.1 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.92 (s, 1H), 4.71 (s, 2H), 3.85 (s, 3H), 2.88 (s, 1H), 1.17 (d, J = 6.7 Hz, 6H).
실시예 59. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((6-메틸-1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 430.31,
1H NMR (500 MHz, CDCl3) δ 8.04 (dd, J = 2.7, 0.5 Hz, 1H), 7.45 (dd, J = 6.5, 2.7 Hz, 1H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 7.11 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 7.03 (dd, J = 14.9, 6.2 Hz, 1H), 6.82 (dd, J = 8.8, 0.6 Hz, 1H), 6.17 (s, 1H), 4.72 - 4.63 (m, 2H), 3.98 (s, 3H), 3.11 (dd, J = 14.4, 6.9 Hz, 1H), 2.63 ? 2.55 (m, 1H), 2.38 - 2.27 (m, 2H), 1.97 - 1.90 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H).
실시예 60. 3-(3-클로로-4-플루오로페닐)-1-((5-에틸-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 404.1,
1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 2.4 Hz, 1H), 7.50 (dd, J = 6.5, 2.6 Hz, 1H), 7.42 (dd, J = 8.8, 2.7 Hz, 1H), 7.18 - 7.10 (m, 1H), 7.02 (t, J = 8.8 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 6.41 (s, 1H), 6.01 (s, 1H), 4.76 (s, 2H), 3.97 (s, 3H), 2.66 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H).
실시예 61. 1-((4-브로모-1H-피라졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)우레아의 제조
[M+H+] = 456.23,
1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 2.5 Hz, 1H), 7.50 (s, 1H), 7.47 (dd, J = 6.4, 2.6 Hz, 1H), 7.37 (d, J = 11.4 Hz, 1H), 7.12 - 7.08 (m, 1H), 7.04 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 6.2 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.12 (s, 1H), 4.77 (s, 2H), 3.98 (s, 3H).
실시예 62. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아의 제조
[M+H+] = 498.36,
1H NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 7.45 (d, J = 2.5 Hz, 1H), 7.37 (dd, J = 5.8, 2.8 Hz, 1H), 7.11 (s, 1H), 7.03 (dd, J = 8.5, 3.2 Hz, 1H), 6.85 - 6.79 (m, 1H), 6.25 (s, 1H), 4.71 (s, 2H), 3.99 - 3.94 (m, 3H), 2.88 (d, J = 16.4 Hz, 1H), 2.66 (s, 1H), 2.50 (d, J = 14.7 Hz, 1H), 2.32 (s, 1H), 2.25 - 2.19 (m, 2H), 1.74 - 1.67 (m, 1H).
실시예 63. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 432.3,
1H NMR (300 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.19 (s, 1H), 7.96 (dd, J = 2.7, 0.7 Hz, 1H), 7.72 (dd, J = 6.9, 2.6 Hz, 1H), 7.50 (dd, J = 8.8, 2.7 Hz, 1H), 7.43 (ddd, J = 9.1, 4.4, 2.6 Hz, 1H), 7.28 (t, J = 9.1 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 4.71 (s, 2H), 4.14 - 3.98 (m, 2H), 3.87 (s, 3H), 2.27 (t, J = 6.3 Hz, 2H), 1.73 (t, J = 4.83 Hz, 2H).
실시예 64. 3-(3-클로로-4-플루오로페닐)-1-((5-메톡시-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 406.1,
1H NMR (300 MHz, MeOD) δ 7.98 (d, J = 2.6 Hz, 1H), 7.60 (dd, J = 6.7, 2.6 Hz, 1H), 7.50 (dd, J = 8.8, 2.7 Hz, 1H), 7.27 (ddd, J = 9.0, 4.2, 2.7 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.65 (s, 1H), 4.78 (s, 2H), 3.93 (s, 3H), 3.81 (s, 3H).
실시예 65. 3-(3-클로로-4-플루오로페닐)-1-(1-메틸-6-옥소-1,6-디하이드로피리딘-3-일)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 418.0,
1H NMR (300 MHz, MeOD) δ 7.62 (d, J = 2.8 Hz, 1H), 7.59 (dd, J = 6.7, 2.6 Hz, 1H), 7.29 (ddd, J = 9.0, 4.2, 2.7 Hz, 1H), 7.23 (dd, J = 9.5, 2.8 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 6.51 (d, J = 9.5 Hz, 1H), 4.74 (s, 2H), 3.52 (s, 3H), 2.66 (t, J = 6.9 Hz, 2H), 2.56 - 2.35 (m, 4H).
실시예 66. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1-(2-(테트라하이드로-2H-피란-2-일옥시)에틸)-1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 544.2,
1H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 6.5, 2.6 Hz, 1H), 7.45 (dd, J = 8.8, 2.7 Hz, 1H), 7.19 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 7.01 (t, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.72 (s, 2H), 4.51 (d, J = 3.7 Hz, 1H), 4.14 (dd, J = 7.7, 3.4 Hz, 2H), 4.04 - 3.96 (m, 1H), 3.94 (s, 3H), 3.66 (ddd, J = 11.4, 9.7, 4.6 Hz, 2H), 3.43 (dd, J = 10.4, 5.6 Hz, 1H), 2.73 (d, J = 4.9 Hz, 2H), 2.52 (d, J = 4.0 Hz, 4H), 1.70 (dd, J = 21.3, 10.6 Hz, 2H), 1.51 (dd, J = 9.2, 3.4 Hz, 4H).
실시예 67. 3-(3-클로로-4-플루오로페닐)-1-((1-(2-히드록시에틸)-1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 460.3,
1H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 2.5 Hz, 1H), 7.51 (ddd, J = 11.5, 7.6, 2.7 Hz, 2H), 7.17 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 7.03 (t, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.63 (s, 1H), 4.76 (s, 2H), 4.07 - 4.01 (m, 2H), 3.97 (s, 3H), 3.92 (d, J = 4.6 Hz, 2H), 2.70 (t, J = 6.6 Hz, 2H), 2.62 - 2.52 (m, 4H).
실시예 68. 3-(3-클로로-4-플루오로페닐)-1-((1,3a,4,5,6,7a-헥사하이드로피라노[2,3-c]피라졸-3-일)메틸)-1-(2-메톡시피리딘-4-일)우레아의 제조
상기 실시예 63과 유사한 방법으로 표제 화합물을 합성하였다.
실시예 69. 3-(3-클로로-4-플루오로페닐)-1-((4,6-디하이드로-1H-퓨로[3,4-c]피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 418.2,
1H NMR (400 MHz, Chloroform-d) δ 8.07 - 8.04 (m, 1H), 7.48 - 7.44 (m, 1H), 7.37 - 7.32 (m, 1H), 7.13 - 7.08 (m, 1H), 7.07 - 7.01 (m, 1H), 6.87 - 6.83 (m, 1H), 6.08 - 6.05 (m, 1H), 4.87 - 4.83 (m, 2H), 4.70 - 4.68 (m, 2H), 4.68 - 4.64 (m, 2H), 4.01 - 3.97 (m, 3H).
실시예 70. 3-(3-클로로-4-플루오로페닐)-1-((4,6-디하이드로-1H-퓨로[3,4-c]피라졸-3-일)메틸)-1-(2-메톡시피리딘-4-일)우레아의 제조
4-(디메틸아미노메틸렌)테트라하이드로퓨란-3-온의 제조
DMFDMA(40.36 g, 339 mmol, 45 mL, 1.94 eq)에 용해시킨 테트라하이드로퓨란-3-온(tetrahydrofuran-3-one, 15.0 g, 174 mmol, 1 eq) 용액을 110℃에서 2시간 동안 교반하였다. 상기 혼합물을 농축하여 빨간색 고체로서 표제 화합물(50 g, crude)을 수득하여 추가적인 정제 없이 다음 단계에 사용하였다.
4,6-디하이드로-1H-퓨로[3,4-c]피라졸의 제조
EtOH(150 mL)에 용해시킨 4-(디메틸아미노메틸렌)테트라하이드로퓨란-3-온(25 g, 177.09 mmol, 1 eq) 용액에 15℃에서 98% NH2NH2·H2O (9.05 g, 177 mmol, 8.78 mL, 1 eq)을 첨가하였다. 상기 용액을 N2 분위기 하에 80℃에서 20시간 동안 교반한 후 농축하였다. 상기 반응을 동일한 규모로 1회 반복하였다. 2개 배치의 잔여물을 합하고 실리카 젤 크로마토그래피(Petroleum ether/Ethyl acetate=1/1, 1/2)로 정제하여 노란색 고체로서 표제 화합물 4,6-디하이드로-1H-퓨로[3,4-c]피라졸(4,6-dihydro-1H-furo[3,4-c]pyrazole, 2.2 g for two batches, 5.6% yield)을 수득하였다.
1H NMR (400 MHz, CDCl3) δ7.19 (s, 1H), 4.85 (s, 2H), 4.82 (s, 2H).
1-(테트라하이드로-2H-피란-2-일)-4,6-디하이드로-1H-퓨로[3,4-c]피라졸의 제조
톨루엔(50 mL)에 용해시킨 4,6-디하이드로-1H-퓨로[3,4-c]피라졸(4.5 g, 40.9 mmol, 1 eq), DHP(4.47 g, 53.1 mmol, 4.86 mL, 1.3 eq) 및 TosOH(352 mg, 2.04 mmol, 0.05 eq) 용액을 N2 분위기 하에 100℃에서 16시간 동안 교반하였다. 상기 혼합물을 농축하고 잔여물을 실리카 젤 크로마토그래피(Petroleum ether/Ethyl acetate=3/1, 1/1)로 정제하여 무색의 오일로서 표제 화합물(3.8 g, 48% yield)을 수득하였다.
1H NMR (300 MHz, CDCl3) δ 7.31 (s, 1H), 5.39 - 5.28 (m, 1H), 4.89 (d, J = 0.9 Hz, 2H), 4.85 (d, J = 1.5 Hz, 2H), 4.13 - 4.03 (m, 1H), 3.77 - 3.64 (m, 1H), 2.28 - 2.07 (m, 2H), 1.71 - 1.62 (m, 4H).
1-(테트라하이드로-2H-피란-2-일)-4,6-디하이드로-1H-퓨로[3,4-c]피라졸-3-카브알데하이드의 제조
THF(3 mL)에 용해시킨 1-(테트라하이드로-2H-피란-2-일)-4,6-디하이드로-1H-퓨로[3,4-c]피라졸(250 mg, 1.29 mmol, 1 eq) 용액에 N2 분위기 하에 -70℃에서 n-BuLi(2.2 M in THF, 702 μL, 1.2 eq)을 첨가하여 노란색 현탁액을 형성하였다. 5분 후, THF( mL)에 용해시킨 DMF (188 mg, 2.57 mmol, 198 μL, 2 eq)를 첨가하였다. 상기 혼합물을 -70℃에서 10분 동안 교반한 후 물(20 mL)에 붓고 30분 동안 교반하였다. 상기 반응이 종결된 혼합물을 EtOAc(15 mL×2)로 추출하였다. 회수한 유기상을 합하여 염수(15 mL×2)로 세척하고, 무수 Na2SO4로 건조시켜 여과하였다. 상기 여과액을 진공 하에 농축하였다. 상기 잔여물을 Prep-TLC(Petroleum ether/Ethyl acetate=2/1)로 정제하여 흰색 고체로서 표제 화합물(90 mg, 31% yield)를 수득하였다.
1H NMR (400 MHz, CDCl3) δ9.97 (s, 1H), 5.98 (dd, J = 2.4, 9.6 Hz, 1H), 5.13 - 5.02 (m, 2H), 4.93 - 4.83 (m, 2H), 4.10 - 4.03 (m, 1H), 3.79 - 3.70 (m, 1H), 2.42 - 2.31 (m, 1H), 2.16 - 2.05 (m, 2H), 1.79 - 1.59 (m, 3H).
2-메톡시-N-((1-(테트라하이드로-2H-피란-2-일)-4,6-디하이드로-1H-퓨로[3,4-c]피라졸-3-일)메틸)피리딘-4-아민의 제조
톨루엔(10 mL)에 용해시킨 1-(테트라하이드로-2H-피란-2-일)-4,6-디하이드로-1H-퓨로[3,4-c]피라졸-3-카브알데하이드(90 mg, 405 μmol, 1 eq), 2-메톡시피리딘-4-아민(2-methoxypyridin-4-amine, 65 mg, 526 μmol, 1.3 eq) 및 TosOH(7 mg, 40 μmol, 0.1 eq) 용액을 100℃에서 4시간 동안 교반하였다. 상기 용액을 20℃까지 냉각시켰다. 상기 용액에 NaBH3CN(76 mg, 1.21 mmol, 3 eq)를 첨가하고 20℃에서 1시간 동안 교반하였다. 상기 혼합물을 농축하고 잔여물을 역상 HPLC(0.1% FA condition)로 정제한 후, 동결건조하여 무색의 수지로서 표제 화합물(60 mg, 39% yield, FA salt)을 수득하였다.
3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리딘-4-일)-1-((1-(테트라하이드로-2H-피란-2-일)-4,6-디하이드로-1H-퓨로[3,4-c]피라졸-3-일)메틸)우레아의 제조
DCM(3 mL)에 용해시킨 2-메톡시-N-((1-(테트라하이드로-2H-피란-2-일)-4,6-디하이드로-1H-퓨로[3,4-c]피라졸-3-일)메틸)피리딘-4-아민(60 mg, 159 μmol, 1 eq, FA salt) 및 DIPEA(62 mg, 478 μmol, 83 μL, 3 eq) 용액에 0℃에서 2-클로로-1-플루오로-4-이소시아나토벤젠(2-chloro-1-fluoro-4-isocyanatobenzene, 41 mg, 239 μmol, 1.5 eq)을 첨가하였다. 상기 용액을 N2 분위기 하에 0℃에서 1시간 동안 교반하였다. 상기 용액을 20℃에서 농축하였다. 조 생성물을 역상 HPLC(0.1% NH3·H2O)로 정제하고, 동결건조하여, 흰색 고체로서 표제 화합물(20 mg, 25% yield)을 수득하였다.
3-(3-클로로-4-플루오로페닐-1-((4,6-디하이드로-1H-퓨로[3,4-c]피라졸-3-일)메틸)-1-(2-메톡시피리딘-4-일)우레아의 제조
DCM(4 mL)에 용해시킨 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리딘-4-일)-1-((1-(테트라하이드로-2H-피란-2-일)-4,6-디하이드로-1H-퓨로[3,4-c]피라졸-3-일)메틸)우레아(20 mg, 40 μmol, 1 eq) 용액에 20℃에서 TFA(1 mL)를 첨가하고, 상기 용액을 20℃에서 1시간 동안 교반하였다. 상기 혼합물을 농축하고 잔사를 Prep-HPLC(column: Phenomenex Synergi C18 150×25×10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 27%-57%, 10min)로 정제하고, 동결건조하여, 흰색 고체로서 표제 화합물(3.3 mg, 18.6% yield, 94% purity)을 수득하였다.
[M+H+] = 418.0,
1H NMR (400 MHz, CD3OD) δ 8.10 (d, J = 5.6 Hz, 1H), 7.62 (dd, J = 2.6, 6.8 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.18 - 7.12 (m, 1H), 6.86 (dd, J = 1.6, 5.6 Hz, 1H), 6.68 (d, J = 1.2 Hz, 1H), 4.95 (s, 2H), 4.75 (s, 2H), 4.71 (s, 2H), 3.91 (s, 3H).
실시예 71. 3-(3-클로로-4-플루오로페닐)-1-((5,6-디하이드로-1H-[1,4]디옥시노[2,3-c]피라졸-3-일)메틸)-1-(2-메톡시피리딘-4-일)우레아의 제조
1H NMR (400 MHz, Acetone) δ 8.11 (d, J = 5.6 Hz, 1H), 7.83 (dd, J = 6.7, 2.5 Hz, 1H), 7.43 - 7.36 (m, 1H), 7.19 (t, J = 9.0 Hz, 1H), 6.96 (dd, J = 5.6, 1.8 Hz, 1H), 6.77 (d, J = 1.5 Hz, 1H), 4.87 (s, 2H), 4.26 - 4.20 (m, 2H), 4.14 - 4.07 (m, 2H), 3.88 (s, 3H).
실시예 72. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 426.1,
1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.28 (s, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.74 (dd, J = 6.9, 2.6 Hz, 1H), 7.59 (dd, J = 8.8, 2.7 Hz, 1H), 7.43 (ddd, J = 9.1, 4.3, 2.6 Hz, 1H), 7.28 (t, J = 9.1 Hz, 1H), 7.11 - 6.71 (m, 2H), 6.36 (s, 1H), 4.86 (s, 2H), 3.87 (s, 3H).
실시예 73. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리딘-4-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 432.1,
1H NMR (400 MHz, Methanol-d4) δ 8.08 (d, J = 5.7 Hz, 1H), 7.65 (dd, J = 6.7, 2.6 Hz, 1H), 7.33 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.16 (t, J = 9.0 Hz, 1H), 6.89 (dd, J = 5.7, 2.0 Hz, 1H), 6.71 (d, J = 1.9 Hz, 1H), 4.94 (s, 2H), 4.62 (s, 2H), 3.91 (s, 3H), 3.88 (t, J = 5.6 Hz, 2H), 2.73 (t, J = 5.6 Hz, 2H).
실시예 74. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리딘-4-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 445.3,
1H NMR (300 MHz, CDCl3) δ 8.27 (d, J = 5.5 Hz, 1H), 7.47 (dd, J = 6.4, 2.5 Hz, 1H), 7.10 (m, 2H), 6.73 (dd, J = 5.5, 1.7 Hz, 1H), 6.61 (d, J = 1.5 Hz, 1H), 6.43 (s, 1H), 6.37 (s, 1H), 4.81 (s, 2H), 3.99 (s, 3H).
실시예 75. 3-(3-클로로-4-플루오로페닐)-1-(5-메톡시피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 433.2,
1H NMR (300 MHz, CDCl3) δ 8.26 (d, J = 2.7 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.47 (dd, J = 6.5, 2.6 Hz, 1H), 7.14 - 7.08 (m, 1H), 7.06 - 6.96 (m, 2H), 6.75 (s, 1H), 4.75 (s, 2H), 4.43 (s, 2H), 3.87 (t, J = 5.6 Hz, 2H), 3.83 (s, 3H), 2.74 (t, J = 5.6 Hz, 2H).
실시예 76. 3-(3-클로로-4-플루오로페닐)-1-(5-메톡시피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아의 제조
1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.42 (s, 1H), 8.23 (d, J = 2.7 Hz, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.73 (dd, J = 6.9, 2.6 Hz, 1H), 7.43 - 7.39 (m, 1H), 7.31 - 7.27 (m, 2H), 4.70 (s, 2H), 4.05 - 4.02 (m, 2H), 3.81 (s, 3H), 2.28 (t, J = 6.3 Hz, 2H), 1.80 - 1.70 (m, 2H).
실시예 77. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(5-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 427.9,
1H NMR (400 MHz, CDCl3) δ 11.27 (s, 1H), 8.39 (d, J = 2.6 Hz, 1H), 8.15 (d, J = 1.9 Hz, 1H), 7.55 - 7.39 (m, 1H), 7.07 (dd, J = 8.9, 5.1 Hz, 2H), 6.93 (t, J = 2.3 Hz, 1H), 6.70 (t, J = 55.0 Hz, 1H), 6.31 (s, 1H), 6.18 (s, 1H), 4.78 (s, 2H), 3.86 (s, 3H).
실시예 78. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4-메틸-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 460.1,
1H NMR (500 MHz, CDCl3) δ 11.22 (s, 1H), 8.04 (d, J = 2.7 Hz, 1H), 7.42 (dd, J = 6.4, 2.6 Hz, 1H), 7.31 (dd, J = 8.8, 2.7 Hz, 1H), 7.12 - 7.07 (m, 1H), 7.04 (t, J = 8.7 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.05 (s, 1H), 4.68 (s, 2H), 3.99 (s, 3H), 1.85 (s, 3H).
실시예 79. 3-(3-클로로-4-플루오로페닐)-1-((1-(히드록시메틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 444.2,
*?*H1H NMR (400 MHz, MeOD) δ 7.99 - 7.95 (m, 1H), 7.62 - 7.57 (m, 1H), 7.52 - 7.45 (m, 1H), 7.30 - 7.23 (m, 1H), 7.14 - 7.06 (m, 1H), 6.89 - 6.83 (m, 1H), 6.52 - 6.48 (m, 1H), 4.94 - 4.91 (m, 2H), 4.62 - 4.58 (m, 1H), 3.93 (s, 3H).
실시예 80. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 445.03,
1H NMR (400 MHz, Chloroform-d) δ 11.56 (s, 1H), 8.35 (s, 2H), 7.52 (dd, J = 6.5, 2.7 Hz, 1H), 7.18 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 7.07 (t, J = 8.7 Hz, 1H), 6.60 (s, 1H), 6.35 (s, 1H), 4.76 (s, 2H), 4.06 (s, 3H).
실시예 81. 1-((4-브로모-5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 508.1,
1H NMR (300 MHz, CDCl3) δ 11.87 (s, 1H) 8.35 (s, 2H), 7.54 (dd, J = 6.5, 2.6 Hz, 1H), 7.18 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 7.04 (dd, J = 14.3, 5.5 Hz, 2H), 6.69 (t, J = 53.5 Hz, 1H), 4.76 (s, 2H), 4.03 (s, 3H).
실시예 82. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(메톡시메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 470.2,
1H NMR (400 MHz, DMSO-d6) δ 13.32 - 12.88 (m, 1H), 8.17 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 2.4, 6.9 Hz, 1H), 7.55 (dd, J = 2.8, 8.8 Hz, 1H), 7.43 (ddd, J = 2.8, 4.3, 9.1 Hz, 1H), 7.27 (t, J = 9.2 Hz, 1H), 7.12 - 6.74 (m, 2H), 4.90 (s, 2H), 4.24 (s, 2H), 3.85 (s, 3H), 3.09 (s, 3H).
실시예 83. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-에톡시비닐)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 514.2,
1H NMR (400 MHz, CDCl3) δ 11.15 (brs, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 4.0 Hz), 7.27 - 7.25 (m, 1H), 7.09 - 6.97 (m, 2H), 6.78 (d, J = 8.8 Hz, 1H), 6.06 - 5.99 (m, 2H), 5.23 (d, J = 12.8 Hz, 1H), 4.65 (s, 3H), 3.91 (s, 3H), 3,59 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H).
실시예 84. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 427.0,
1H NMR (300 MHz, CDCl3) δ 8.40 (s, 2H), 7.51 (dd, J = 6.5, 2.4 Hz, 1H), 7.16 - 7.03 (m, 2H), 6.72 (t, J = 54.9 Hz, 1H), 6.34 (s, 1H), 6.07 (s, 1H), 4.76 (s, 2H), 4.11 (s, 3H).
실시예 85. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-에톡시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 516.2,
1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 2.8 Hz, 1H), 7.43 (dd, J = 2.5, 6.4 Hz, 1H), 7.32 (dd, J = 2.8, 8.8 Hz, 1H), 7.14 - 7.08 (m, 1H), 7.07 - 7.02 (m, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.04 (s, 1H), 4.76 (s, 2H), 3.99 (s, 3H), 3.31 (q, J = 7.0 Hz, 2H), 3.26 (t, J = 6.6 Hz, 2H), 2.55 - 2.44 (m, 2H), 1.10 - 1.07 (m, 3H).
실시예 86. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 487.9,
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 2.6, 6.4 Hz, 1H), 7.38 (dd, J = 2.8, 8.8 Hz, 1H), 7.11 (dd, J = 2.7, 4.2 Hz, 1H), 7.09 - 7.03 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.09 (s, 1H), 4.81 (s, 2H), 4.00 (s, 3H), 3.61 (t, JJ= 6.2 Hz, 2H), 2.55 (t, J = 6.1 Hz, 2H).
실시예 87. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4-((4,4,5,5-테트라메틸-1,3-디옥솔란-2-일)메틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 2.6 Hz, 1H), 7.47 - 7.43 (m, 1H), 7.37 - 7.32 (m, 1H), 7.17 - 7.11 (m, 1H), 7.10 - 7.03 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.06 (s, 1H), 4.96 - 4.92 (m, 1H), 4.89 - 4.84 (m, 2H), 4.04 - 3.99 (m, 3H), 2.56 (d, J = 4.5 Hz, 2H), 1.12 (s, 6H), 1.03 - 0.99 (m, 6H).
실시예 88. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(2-메톡시에틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
1H NMR (400 MHz, CDCl3) δ 11.15 (s, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.44 (dd, J = 2.6, 6.4 Hz, 1H), 7.33 (dd, J = 2.8, 8.8 Hz, 1H), 7.17 - 7.08 (m, 1H), 7.08 - 7.00 (m, 1H), 6.85 (s, 1H), 6.84 - 6.57 (m, 1H), 6.04 (s, 1H), 4.73 (s, 2H), 3.98 (s, 3H), 3.26 (t, J = 6.6 Hz, 2H), 3.17 (s, 3H), 2.54 (t, J = 6.5 Hz, 2H).
실시예 89. 3-(4-클로로-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 446.1,
1H NMR (300 MHz, MeOD) δ 8.45 (s, 2H), 8.21 (d, J = 5.6 Hz, 1H), 8.19 (d, J = 1.0 Hz, 1H), 6.59 (s, 1H), 5.00 (s, 2H), 4.06 (s, 3H).
실시예 90. 3-(3-클로로-4-플루오로페닐)-1-((5-메톡시-4-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
2-벤질-5-(벤진옥시메틸)피라졸-3-올의 제조
메탄올(80 mL)에 용해시킨 에틸 4-(벤질옥시)-3-옥소부타노에이트(ethyl 4-benzyloxy-3-oxobutanoate, 10.0 g, 42.3 mmol, 1 eq) 용액에 TsOH(729 mg, 4.23 mmol, 0.1 eq) 및 벤질하이드라진 이염산염(benzylhydrazine dihydrochloride salt, 8.26 g, 42.3 mmol, 1 eq)을 첨가하고, 상기 혼합물을 80℃에서 16시간 동안 교반하였다. 상기 반응 혼합물을 상온으로 냉각시키고 감압 하에 농축시켜 건조하였다. 잔류물(residue)을 2 N NaOH(25 mL)에 용해시키고 상기 용액을 EtOAc(1×30 mL)로 추출하였다. pH 3에 이를 때까지 수상(aqueous phase)을 HCl로 산성화시키고, 여과하여 침전물을 회수하여, 노란색 고체로서 표제 화합물(3.98 g, 32%)을 수득하였다.
1-벤질-3-(벤질옥시메틸)-5-메톡시-1H-피라졸의 제조
DMF(10 mL)에 용해시킨 메틸 4-메틸벤젠설포네이트(methyl 4-methylbenzenesulfonate, 1.39 g, 7.47 mmol, 1.1 eq) 용액에 K2CO3(2.35 g, 17.0 mmol, 2.5 eq) 및 2-벤질-5-(벤질옥시메틸)피라졸-3-올(2.0 g, 6.79 mmol, 1 eq)을 첨가하였다. 상기 혼합물을 25℃에서 20시간 동안 교반하였다. 상기 반응 혼합물을 여과하고, 여과액(filtrate)을 감압 하에 농축시켰다. 조생성물(crude product)을 역상 컬럼 크로마토그래피(0.1% FA)로 정제하여 노란색 오일로서 표제 화합물(1.09 g, 52% yield)을 수득하였다.
1-벤질-3-(벤질옥시메틸)-4-아이오도-5-메톡시-1H-피라졸의 제조
H2O (5.5 mL)에 혼합한 1-벤질-3-(벤질옥시메틸)-5-메톡시-피라졸(1.0 g, 3.24 mmol, 1 eq)에 NaOAc(585 mg, 7.13 mmol, 2.20 eq)를 첨가하고, 수득한 혼합물을 100℃까지 가열한 후 I2(1.65 g, 6.48 mmol, 2 eq) 및 KI(3.23 g, 19.4 mmol, 6 eq)와 H2O(7 mL)로 구성된 용액을 첨가하였다. 상기 반응 혼합물을 100℃에서 10분 동안 교반한 후, 상온으로 냉각시키고, EtOAc (50 mL) 및 H2O(20 mL)로 분할하였다(partitioned). 유기상을 분리하여 염수(brine, 30 mL)로 세척하고, 무수 Na2SO4 상에서 건조시켜 여과하고 감압 하에 농축하였다. 잔류물을 컬럼 크로마토그래피(Petroleum ether/Ethyl acetate=100/1 to 10/1)로 정제하여 흰색 고체로서 표제 화합물(1.14 g, 81% yield)을 수득하였다.
1-벤질-3-(벤질옥시메틸)-5-메톡시-4-(트리플루오로메틸)-1H-피라졸의 제조
DMF(4 mL)에 용해시킨 1-벤질-3-(벤질옥시메틸)-4-아이오도-5-메톡시-피라졸(533 mg, 1.23 mmol, 1 eq)용액에 N2 분위기 하에 CuI(584 mg, 3.07 mmol, 2.5 eq), KF(143 mg, 2.45 mmol, 2 eq) 및 트리메틸(트리플루오로메틸)실란(trimethyl(trifluoromethyl)silane, 872.27 mg, 6.13 mmol, 5 eq)을 첨가하였다. 상기 혼합물을 100℃에서 22시간 동안 교반하고, 상온으로 냉각시킨 후, 여과하고 농축시켜 건조하였다. 조생성물을 역상 HPLC(0.1% FA condition)로 정제하여 흰색 고체로서 표제 화합물(180 mg, 39% yield)을 수득하였다.
(5-메톡시-4-(트리플루오로메틸)-1H-피라졸-3-일)메탄올의 제조
MeOH(10 mL)에 용해시킨 1-벤질-3-(벤직옥시메틸)-5-메톡시-4-(트리플루오로메틸)피라졸(100 mg, 266 μmol, 1 eq) 용액에 10% Pd/C(43 mg)를 첨가하고, 상기 혼합물을 H2(15 PSI) 하에 50℃에서 16시간 동안 교반하였다. 상기 혼합몰을 셀라이트 패드(pad of Celite)로 여과하고, 여과액을 감압 하에 농축시켜 건조하여 표제 화합물(67 mg, crude)을 수득하고, 이를 추가적인 정제 없이 다음 단계에 사용하였다.
3-(클로로메틸)-5-메톡시-4-(트리플루오로메틸)-1H-피라졸의 제조
SOCl2(2 mL)에 용해시킨 [5-메톡시-4-(트리플루오로메틸)-1H-피라졸-3-일] 메탄올(50 mg, 255 μmol, 1 eq) 용액을 80℃에서 2시간 동안 교반하였다. 상기 혼합물을 실온까지 냉각시키고 감압 하에 농축시켜 건조하여 노란색 오일로서 표제 화합물(54 mg, crude)을 수득하였다.
3-(클로로메틸)-5-메톡시-1-(테트라하이드로-2H-피란-2-일)-4-(트리플루오로메틸)-1H-피라졸의 제조
DCM(5 mL)에 용해시킨 To a solution of 3-(클로로메틸)-5-메톡시-4-(트리플루오로메틸)-1H-피라졸(54 mg, 252 μmol, 1 eq) 용액에 DHP(42 mg, 503 μmol, 46 uL, 2 eq)를 첨가하고, 상기 혼합물을 25℃에서 16시간 동안 교반하였다. 상기 반응 혼합물을 감압 하에 건조하여 농축시켜 노란색 오일로서 표제 화합물(70 mg, crude)을 수득하였다.
6-메톡시-N-((5-메톡시-1-(테트라하이드로-2H-피란-2-일)-4-(트리플루오로메틸)-1H-피라졸-3-일)메틸)피리딘-3-아민의 제조
CH3CN(0.5 mL)에 용해시킨 3-(클로로메틸)-5-메톡시-1 테트라하이드로피란-2-일-4-(트리플루오로메틸) 피라졸(20 mg, 67 μmol, 1 eq), 6-메톡시피리딘-3-아민(17 mg, 134 μmol, 2 eq) 및 K2CO3(28 mg, 201 μmol, 3 eq)의 혼합물을 70℃에서 1시간 동안 교반하였다. 상기 반응 혼합물을 실온까지 냉각시키고 농축하였다. 잔여물을 역상 컬럼 크로마토그래피(0.1% FA)에 적용하여 무색의 오일로서 표제 화합물(30 mg, crude)을 수득하였다.
3-(3-클로로-4-플루오로페닐)-1-((5-메톡시-1-(테트라하이드로-2H-피란-2-일)-4-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
CH3CN(2 mL)에 용해시킨 6-메톡시-N-((5-메톡시-1-(테트라하이드로-2H-피란-2-일)-4-(트리플루오로메틸)-1H-피라졸-3-일)메틸)피리딘-3-아민(30 mg, 78 μmol, 1 eq), 2-클로로-1-플루오로-4-이소시아나토-벤젠(2-chloro-1-fluoro-4-isocyanato-benzene, 40 mg, 233 μmol, 3 eq) 및 DMAP(19 mg, 155 μmol, 2 eq)의 혼합물을 60℃에서 30분 동안 교반하였다. 상기 반응 혼합물을 냉각시키고 농축하였다. 잔여물을 역상 컬럼 크로마토그래피(0.1% FA)에 적용하여 무색 오일로서 표제 화합물(20 mg, 46% yield)을 수득하였다.
3-(3-클로로-4-플루오로페닐)-1-((5-메톡시-4-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
TFA(1 mL)와 DCM(2 mL)에 용해시킨 3-(3-클로로-4-플루오로페닐)-1-((5-메톡시-1-(테트라하이드로-2H-피란-2-일)-4-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(20 mg, 36 μmol, 1 eq) 용액을 25℃에서 1시간 동안 교반한 후 진공 하에 농축시켜 건조하였다. 상기 잔여물을 Prep-HPLC(column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water (0.1%TFA)-ACN]; B%: 45%-75%, 7min)로 정제하고, 동결건조시켜 흰색 고체로서 표제 화합물(5.5 mg, 32% yield, 99% purity)을 수득하였다.
[M+H+] = 474.1,
1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 2.4 Hz, 1H), 7.46 (dd, J = 2.3, 6.4 Hz, 1H), 7.36 (dd, J = 2.6, 8.7 Hz, 1H), 7.12 - 7.02 (m, 2H), 6.85 (d, J = 8.7 Hz, 1H), 6.11 (s, 1H), 4.78 (s, 2H), 3.98 (d, J = 8.3 Hz, 6H).
실시예 91. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 489.1,
1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.46 (dd, J = 2.8 Hz, 6.4 Hz 1H), 7.04-7.13 (m, 2H), 6.30 (s, 1H), 4.82 (s, 2H), 4.07 (s, 3H), 3.63 (t, J = 6 Hz, 2H), 2.54 (t, J = 6 Hz, 2H).
실시예 92. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(2-히드록시프로판-2-일)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 485.1,
1H NMR (400 MHz, CDCl3) δ 8.48 - 8.40 (m, 2H), 7.54 - 7.49 (m, 1H), 7.18 - 7.13 (m, 1H), 7.11 - 7.03 (m, 1H), 6.99 - 6.68 (m, 1H), 6.37 - 6.25 (m, 1H), 5.24 - 5.09 (m, 2H), 3.99 (s, 3H), 1.52 (s, 6H).
실시예 93. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(프로프-1-엔-2-일)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 467.1,
1H NMR (400 MHz, CDCl3) δ 11.61 - 10.76 (m, 1H), 8.39 - 8.32 (m, 2H), 7.52 (s, 1H), 7.16 - 7.11 (m, 1H), 7.10 - 7.05 (m, 1H), 6.84 - 6.54 (m, 1H), 6.24 - 6.12 (m, 1H), 5.12 - 5.04 (m, 1H), 4.80 - 4.71 (m, 2H), 4.60 - 4.50 (m, 1H), 4.10 - 4.02 (m, 3H), 1.86 - 1.81 (m, 3H).
실시예 94. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리다진-4-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 445.4,
1H NMR (500 MHz, Methanol-d4) δ 8.03 (s, 1H), 7.71 (dd, J = 6.7, 2.7 Hz, 1H), 7.37 (ddd, J = 8.8, 4.2, 2.3 Hz, 1H), 7.21 (td, J = 9.0, 1.7 Hz, 1H), 6.76 (s, 1H), 6.62 (s, 1H), 5.10 (s, 2H), 3.75 (s, 3H).
실시예 95. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시프로필)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 503.1,
1H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.48 (s, 2H), 8.34 (s, 1H), 7.72 (dd, J = 6.8, 2.4 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.33 - 7.28 (m, 1H), 4.94 (s, 2H), 4.63 (s, 1H), 3.94 (s, 3H), 3.65 - 3.55 (m, 1H), 2.48 - 2.40 (m, 1H), 0.97 (d, J = 6.0 Hz, 3H).
실시예 96. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리다진-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 445.1,
1H NMR (400 MHz, DMSO-d6) δ 13.92 (s, 1H), 9.40 (s, 1H), 8.52 (d, J = 10.0 Hz, 1H), 7.98 (d, J = 5.0 Hz, 1H), 7.48 (d, J = 2.9 Hz, 1H), 7.31 (t, J = 9.0 Hz, 1H), 7.26 (d, J = 10.0 Hz, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 3.83 (s, 3H).
실시예 97. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리다진-3-일)우레아의 제조
[M+H+] = 427.1,
1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 3 H) 5.43 (s, 2 H) 6.61 (s, 1 H) 6.84 (s, 1 H) 6.98 (s, 1 H) 7.11 (s, 1 H) 7.21 - 7.35 (m, 2 H) 7.50 (br d, J = 7.95 Hz, 1 H) 7.98 (br d, J = 5.50 Hz, 1 H) 8.51 (s, 1 H) 8.54 (s, 1 H) 9.42 (br s, 1 H) 13.38 (s, 1 H).
실시예 98. 1-((4-브로모-5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 507.0,
1H NMR (400 MHz, DMSO-d6) δ 13.73 (br s, 1H), 8.51 - 8.47 (m, 2H), 8.40 (s, 1H), 7.71 (dd, J = 2.6, 6.8 Hz, 1H), 7.43 - 7.36 (m, 1H), 7.33 - 7.25 (m, 1H), 7.12 - 6.81 (m, 1H), 4.88 (s, 2H), 3.94 (s, 3H).
실시예 99. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리다진-4-일)우레아의 제조
[M+H+] = 427.3,
1H NMR (500 MHz,Methanol-d4) δ 8.05 (s, 1H), 7.71 (dd, J = 6.7, 2.4 Hz, 1H), 7.44 - 7.33 (m, 1H), 7.21 (t, J = 9.0 Hz, 1H), 6.94 - 6.63 (m, 2H), 6.53 (s, 1H), 5.08 (s, 2H), 3.74 (s, 3H).
실시예 100. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-메톡시-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아의 제조
1H NMR (400 MHz, CDCl3) δ 10.88 (s, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.44 (dd, J = 2.6, 6.5 Hz, 1H), 7.41 (dd, J = 2.8, 8.7 Hz, 1H), 7.13 - 7.07 (m, 1H), 7.06 - 7.00 (m, 1H), 6.89 - 6.84 (m, 1H), 6.84 - 6.55 (m, 1H), 6.09 (s, 1H), 4.67 (s, 2H), 3.98 (s, 3H), 3.64 (s, 3H).
실시예 101. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시-2-메틸프로필)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 517.0,
1H NMR (400 MHz, CDCl3) δ 8.39 - 8.33 (m, 2H), 7.51 - 7.47 (m, 1H), 7.18 - 7.12 (m, 1H), 7.11 - 7.06 (m, 1H), 6.26 - 6.17 (m, 1H), 4.94 (s, 2H), 4.09 (s, 3H), 2.52 - 2.46 (m, 2H), 1.16 (s, 6H).
실시예 102. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시프로판-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 503.2,
1H NMR (400 MHz, CDCl3) δ 8.37 (s, 2H), 7.47 (dd, J = 2.6, 6.4 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.09 - 6.98 (m, 1H), 6.27 (s, 1H), 5.19 (s, 2H), 4.19 - 3.95 (m, 3H), 1.49 (s, 1H), 1.47 (s, 6H).
실시예 103. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(2-히드록시-2-메틸프로필)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 499.0,
1H NMR (400 MHz, CDCl3) δ 8.37 (s, 2H), 7.52 - 7.48 (m, 1H), 7.18 - 7.12 (m, 1H), 7.11 - 7.05 (m, 1H), 6.92 - 6.63 (m, 1H), 6.21 (s, 1H), 4.96 - 4.90 (m, 2H), 4.11 - 4.04 (m, 3H), 2.56 - 2.50 (m, 2H), 1.31 - 1.26 (m, 1H), 1.17 (s, 6H).
실시예 104. 3-(3-클로로-4-플루오로페닐)-1-((5-시아노-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 402.2,
1H NMR (400 MHz, DMSO-d6) δ 13.9 (s, 1H), 8.55 (s, 2H), 8.44 (s, 1H), 7.82 - 7.62 (m, 1H), 7.49 - 7.35 (m, 1H), 7.30 (td, J = 9.1, 1.4 Hz, 1H), 6.90 (s, 1H), 4.90 (s, 2H), 3.96 (s, 3H).
실시예 105. 3-(3-클로로-4-플루오로페닐)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 432.9,
1H NMR (400 MHz, CDCl3) δ 11.43 - 10.70 (m, 1H), 7.45 (dd, J = 2.6, 6.4 Hz, 1H), 7.15 - 7.10 (m, 1H), 7.07 - 6.98 (m, 1H), 6.65 - 6.51 (m, 1H), 6.35 (s, 1H), 4.44 - 4.38 (m, 2H), 3.32 - 3.23 (m, 3H), 2.28 - 2.22 (m, 6H).
실시예 106. 3-(6-클로로-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 446.1,
1H NMR (400 MHz, DMSO-d6) δ 13.55 (br s, 1H), 9.52 (br s, 1H), 8.51 (s, 2H), 7.96 - 7.88 (m, 2H), 6.63 (s, 1H), 4.93 (s, 2H), 3.94 (s, 3H).
실시예 107. 3-(5-클로로-6-플루오로피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 446.1,
1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 2H), 8.25 (dd, J = 2.4, 8.4 Hz, 1H), 8.19 (t, J = 2.0 Hz, 1H), 6.65 (s, 1H), 4.91 (s, 2H), 3.96 (s, 3H).
실시예 108. 3-(3-클로로-4-플루오로페닐)-1-((1,3-디메틸-1H-피라졸-5-일)메틸)-1-(4-메톡시페닐)우레아의 제조
[M+H+] = 404.86,
1H NMR (300 MHz, CDCl3) δ 7.44 (dd, J = 6.5, 2.6 Hz, 1H), 7.09 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 7.07 - 6.86 (m, 5H), 6.09 (s, 1H), 5.79 (s, 1H), 4.86 (s, 2H), 3.85 (s, 3H), 3.69 (s, 3H), 2.18 (s, 3H).
실시예 109. 3-(3-클로로-4-플루오로페닐)-1-(3-(2-히드록시프로판-2-일)이속사졸-5-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 450.2,
1H NMR (300 MHz, MeOD) δ 7.65 (d, J = 7.1 Hz, 1H), 7.30 (s, 1H), 7.14 (t, J = 8.9 Hz, 1H), 5.11 (s, 2H), 4.74 (s, 1H), 3.91 (t, J = 5.6 Hz, 2H), 3.63 (s, 2H), 2.76 (d, J = 5.6 Hz, 2H), 1.29 (s, 6H).
실시예 110. 3-(3-클로로-4-플루오로페닐)-1-(6-(2-히드록시프로판-2-일)피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 460.2,
1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.56 - 7.48 (m, 2H), 7.44 (dd, J = 2.6, 6.4 Hz, 1H), 7.17 - 7.09 (m, 1H), 7.07 - 7.01 (m, 1H), 6.17 (s, 1H), 4.66 (s, 2H), 4.21 - 4.14 (m, 2H), 2.13 (t, J = 6.3 Hz, 2H), 1.87 - 1.77 (m, 2H), 1.59 (s, 6H).
실시예 111. 3-(3-클로로-4-플루오로페닐)-1-(6-(2-히드록시프로판-2-일)피리딘-3-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 460.3,
1H NMR (400 MHz, DMSO) δ 12.45 (s, 1H), 8.52 (s, 1H), 8.31 (s, 1H), 7.72 - 7.70 (m, 1H), 7.65 - 7.60 (m, 2H), 7.38 - 7.32 (m, 1H), 7.29 - 7.27 (m, 1H), 5.24 (s, 1H), 4.84 (s, 2H) 4.60 - 4.56 (m, 2H), 3.68 - 3.64 (m, 2H), 2.33 - 2.29 (m, 2H), 1.44 (s, 6H).
실시예 112. 3-(3-클로로-4-플루오로페닐)-1-(2-(2-히드록시프로판-2-일)피리딘-4-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 460.2,
1H NMR (400 MHz, CDCl3) δ 8.60 - 8.54 (m, 1H), 7.52 (dd, J = 2.6, 6.4 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.18 - 7.13 (m, 1H), 7.12 - 7.09 (m, 1H), 7.09 - 7.02 (m, 2H), 4.86 (s, 2H), 4.71 (s, 2H), 3.82 - 3.77 (m, 2H), 2.35 (t, J = 5.4 Hz, 2H), 1.55 (s, 6H).
실시예 113. 3-(3-클로로-4-플루오로페닐)-1-(2-(2-히드록시프로판-2-일)피리딘-4-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 460.3,
1H NMR (400 MHz, MeOD) δ 8.44 (d, J = 5.5 Hz, 1H), 7.64 (dd, J = 2.6, 6.6 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.31 (ddd, J = 2.6, 4.2, 9.0 Hz, 1H), 7.17 (t, J = 2.8 Hz, 1H), 7.16 - 7.11 (m, 1H), 4.94 (s, 2H), 4.16 - 4.08 (m, 2H), 2.39 (t, J = 6.3 Hz, 2H), 1.89 - 1.78 (m, 2H), 1.52 (s, 6H).
실시예 114. 3-(3-클로로-4-플루오로페닐)-1-(4-히드록시페닐)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 401.3,
1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.55 (s, 1H), 7.94 (s, 1H), 7.71 (dd, J = 6.9, 2.6 Hz, 1H), 7.41 (td, J = 4.5, 2.7 Hz, 1H), 7.24 (t, J = 9.1 Hz, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 4.67 (s, 2H), 2.51 (s, 2H), 2.33 (s, 4H).
실시예 115. 3-(3-클로로-4-플루오로페닐)-1-(3-(2-히드록시프로판-2-일)이속사졸-5-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 450.2,
1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 7.61 (dd, J = 2.7, 6.5 Hz, 1H), 7.35 - 7.28 (m, 1H), 7.09 (t, J = 8.7 Hz, 1H), 6.17 (s, 1H), 4.97 (s, 2H), 4.74 (s, 2H), 3.89 (t, J = 5.6 Hz, 2H), 2.73 (t, J = 5.5 Hz, 2H), 1.60 (s, 6H)
실시예 116. 3-(3-클로로-4-플루오로페닐)-1-(3,4-디메톡시페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아의 제조
[M+H+] = 460.1,
1H NMR (300 MHz, CDCl3) δ 7.46 (dd, J = 6.5, 2.6 Hz, 1H), 7.18 - 7.06 (m, 1H), 7.00 (t, J = 8.7 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.77 (dd, J = 8.4, 2.3 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 6.33 (s, 1H), 4.71 (s, 2H), 3.92 (s, 3H), 3.80 (s, 3H), 3.49 (s, 1H), 2.65 (t, J = 6.2 Hz, 2H), 2.22 (t, J = 6.0 Hz, 2H), 1.84 - 1.57 (m, 4H).
실시예 117. 3-(3-클로로-4-플루오로페닐)-1-(3,5-디메톡시페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아의 제조
[M+H+] = 459.14,
1H NMR (300 MHz, CDCl3) δ 7.47 (dd, J = 6.4, 2.6 Hz, 1H), 7.16 - 7.09 (m, 1H), 7.01 (t, J = 8.7 Hz, 1H), 6.48 (d, J = 8.0 Hz, 2H), 6.32 (d, J = 2.1 Hz, 2H), 4.72 (s, 2H), 3.76 (s, 6H), 2.64 (t, J = 6.1 Hz, 2H), 2.26 (t, J = 6.0 Hz, 2H), 1.73 (ddt, J = 15.7, 9.3, 4.8 Hz, 4H).
실시예 118. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노-5-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 467.24,
1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 8.84 (s, 1H), 8.31 (d, J = 1.9 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.75 (dd, J = 6.9, 2.4 Hz, 1H), 7.46 - 7.20 (m, 2H), 6.63 (s, 1H), 5.07 (s, 2H), 3.96 (s, 3H).
실시예 119. 3-(3-클로로-4-플루오로페닐)-1-(5-시아노-6-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 469.1,
1H NMR (500 MHz, Chloroform-d) δ 11.43 (s, 1H), 8.22 (s, 1H), 7.79 (s, 1H), 7.47 (d, J = 6.6 Hz, 1H), 7.19 - 7.05 (m, 2H), 6.37 (s, 1H), 6.06 (s, 1H), 4.76 (s, 2H), 4.15 (s, 3H).
실시예 120. 3-(3-클로로-4-플루오로페닐)-1-(5-시아노피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 427.0,
1H NMR (400 MHz, DMSO) δ 11.55 (s, 1H), 8.94 (s, 1H), 8.70 (s, 1H), 8.59 (s, 1H), 8.34 -.8.32 (m, 1H), 7.70 - 7.68 (m, 1H), 7.36 - 7.32 (m, 2H), 4.85 (s, 1H), 4.06 - 4.01 (m, 2H), 2.34 - 2.32 (m, 2H), 1.74 (s, 2H).
실시예 121. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 427.1,
1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.94 (d, J = 1.8 Hz, 1H), 8.70 (d, J = 2.5 Hz, 1H), 8.59 (s, 1H), 8.33 (t, J = 2.2 Hz, 1H), 7.69 (dd, J = 6.8, 2.3 Hz, 1H), 7.44 - 7.25 (m, 2H), 4.84 (s, 2H), 4.17 - 3.94 (m, 2H), 2.32 (t, J = 6.4 Hz, 2H), 1.87 - 1.66 (m, 2H).
실시예 122. 3-(3-클로로-4-플루오로페닐)-1-(2-시아노피리딘-4-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 427.2,
1H NMR (400 MHz, CDCl3) δ 8.69 (br s, 1H), 8.61 (d, J = 5.8 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.57 (dd, J = 2.8, 6.5 Hz, 1H), 7.52 - 7.45 (m, 1H), 7.34 - 7.27 (m, 1H), 7.09 (t, J = 8.8 Hz, 1H), 4.81 (s, 2H), 4.28 - 4.21 (m, 2H), 2.33 (t, J = 6.2 Hz, 2H), 1.94 (s, 2H).
실시예 123. 3-(3-클로로-4-플루오로페닐)-1-(2-시아노피리딘-4-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 427.3,
1H NMR (400 MHz, Methanol-d4) δ 8.54 (d, J = 5.7 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.66 (dd, J = 6.7, 2.7 Hz, 1H), 7.56 (dd, J = 5.8, 2.3 Hz, 1H), 7.33 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 7.17 (t, J = 8.9 Hz, 1H), 5.00 (s, 2H), 4.62 (s, 2H), 3.85 (t, J = 5.6 Hz, 2H), 2.71 (t, J = 5.6 Hz, 2H).
실시예 124. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 427.1,
1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.85 (s, 1H), 8.70 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.71 (dd, J = 2.4, 6.8 Hz, 1H), 7.40 - 7.30 (m, 2H), 4.91 (s, 2H), 4.03 (s, 2H), 2.34 - 2.30 (m, 2H), 1.74 (s, 2H).
실시예 125. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 427.2,
1H NMR (500 MHz, Methanol-d4) δ 8.63 (t, J = 1.7 Hz, 1H), 7.90 (s, 2H), 7.62 (dd, J = 6.7, 2.6 Hz, 1H), 7.30 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.17 (t, J = 9.0 Hz, 1H), 4.97 (s, 2H), 4.66 (s, 2H), 3.89 (t, J = 5.6 Hz, 2H), 2.74 (s, 2H).
실시예 126. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 421.2,
1H NMR (500 MHz, Methanol-d4) δ 8.68 (t, J = 1.7 Hz, 1H), 7.97 - 7.85 (m, 2H), 7.65 (dd, J = 6.7, 2.6 Hz, 1H), 7.31 (ddd, J = 9.0, 4.1, 2.6 Hz, 1H), 7.17 (t, J = 9.0 Hz, 1H), 6.71 (t, J = 55.2 Hz, 1H), 6.46 (s, 1H), 5.09 (s, 2H).
실시예 127. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 427.2,
1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.98 (s, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.12 - 8.01 (m, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.69 (dd, J = 2.4, 6.8 Hz, 1H), 7.41 - 7.35 (m, 1H), 7.35 - 7.29 (m, 1H), 4.97 (s, 2H), 4.56 (br s, 2H), 3.70 (t, J = 5.5 Hz, 2H), 2.43 (s, 2H).
실시예 128. 3-(3-클로로-4-플루오로페닐)-1-(2-시아노피리딘-4-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아의 제조
3-(아지도메틸)-1-(테트라하이드로-2H-피란-2-일)-1,4,5,7-테트라하이드로피라노[3,4-c]피라졸의 제조
THF(5 mL) 중의 (1-테트라하이드로피란-2-일-1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메탄올(300 mg, 1.26 mmol, 1 eq) 용액에 N2 분위기 하에 DPPA(520 mg, 1.89 mmol, 409 μL, 1.5 eq) 및 DBU(288 mg, 1.89 mmol, 285 μL, 1.5 eq)를 첨가하였다. 상기 반응 혼합물을 20℃에서 48시간 동안 교반한 후, H2O(20 mL)로 반응을 종결시켰다. 수득한 혼합물을 EtOAc로 추출하였다(10 mL×3). 유기층을 합하여 무수 Na2SO4 상에서 건조시키고 여과하여 감압 하에 농축하였다. 상기 잔여물을 플래시 실리카 젤 크로마토그래피(Petroleum ether/Ethyl acetate=100/1 to 1/1)로 정제하여, 흰색 오일로서 표제 화합물(200 mg, 56% yield, 93% purity)을 수득하였다.
(1-(테트라하이드로-2H-피란-2-일)-1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메탄아민 의 제조
THF(4 mL) 중의 3-(아지도메틸)-1-테트라하이드로피란-2-일-5,7-dihydro-4H-피라노[3,4-c]피라졸(200 mg, 760 μmol, 1 eq) 용액에 10% Pd/C(800 mg)를 첨가하였다. 상기 혼합물을 H2 분위기 하에(15 PSI) 20℃에서 1시간 동안 교반하였다. 상기 반응 혼합물을 셀라이트 패드로 여과하고 여과액을 농축하여, 무색의 오일로서 표제 화합물(200 mg, 80% yield, 72% purity)을 수득하였다.
4-((1-(테트라하이드로-2H-피란-2-일)-1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸아미노)피콜리노니트릴의 제조
DMF(4 mL) 중의 (1-(테트라하이드로-2H-피란-2-일)-1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메탄아민(195 mg, 822 μmol, 1 eq) 및 4-플루오로피리딘-2-카보니트릴(100 mg, 822 μmol, 1 eq) 용액에 K2CO3(341 mg, 2.47 mmol, 3 eq)을 첨가하였다. 상기 혼합물을 100℃에서 16시간 동안 교반하였다. 상기 혼합물을 포화 NH4Cl 용액(30 mL)에 붓고, 에틸 아세테이트로 추출하였다(30 mL×3). 유기층을 합하여 Na2SO4 상에서 건조시키고 여고하여 진공 하에 농축하였다. 상기 조 생성물을 역상 컬럼 크로마토그래피(0.1% FA)로 정제하여, 노란색 고체로서 표제 화합물(80 mg, 27% yield, 95% purity)을 수득하였다.
3-(3-클로로-4-플루오로페닐)-1-(2-시아노피리딘-4-일)-1-((1-(테트라하이드로-2H-피란-2-일)-1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아의 제조
CH3CN(1.5 mL) 중의 4-((1-(테트라하이드로-2H-피란-2-일)-1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸아미노)피콜리노니트릴 (60 mg, 177 μmol, 1 eq) 및 2-클로로-1-fluoro-4-isocyanato-benzene (91 mg, 530 μmol, 3 eq) 용액에 DMAP(65 mg, 530 μmol, 3 eq)를 첨가하였다. 상기 혼합물을 80℃에서 0.2시간 동안 교반하고 진공 하에 농축하여 건조시켰다. 상기 잔여물을 역상 크로마토그래피(0.1% FA)로 정제하여, 흰색 고체로서 표제 화합물(16 mg, 16% yield, 90% purity)을 수득하였다.
3-(3-클로로-4-플루오로페닐)-1-(2-시아노피리딘-4-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아의 제조
DCM(2 mL) 중의3-(3-클로로-4-플루오로페닐)-1-(2-시아노피리딘-4-일)-1-((1-(테트라하이드로-2H-피란-2-일)-1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(15 mg, 29 μmol, 1 eq) 용액에 TFA(1 mL)를 첨가하고, 상기 혼합물을 20℃에서 2시간 동안 교반하였다. 상기 혼합물을 농축시키고 잔여물을 prep-HPLC(column: Phenomenex Synergi C18 150 mm×25 mm×10 μm; mobile phase: [water (0.225% FA) - ACN]; 30%-60%, 10 min)로 정제하여, 흰색 고체로서 표제 화합물(10.8 mg, 85% yield, 99% purity)을 수득하였다.
[M+H+] = 427.2,
1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.50 (s, 1H), 8.59 (d, J = 5.6 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.75 (dd, J = 2.3, 6.8 Hz, 1H), 7.64 (d, J = 3.8 Hz, 1H), 7.42 - 7.40 (m, 2H), 5.03 (s, 2H), 4.58 (s, 2H), 3.72 (t, J = 5.6 Hz, 2H), 2.49 - 2.46 (m, 2H).
실시예 129. 3-(3-클로로-4-플루오로페닐)-1-(5-시아노피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 425.25,
1H NMR (400 MHz, Chloroform-d) δ 10.52 (s, 1H), 8.92 - 8.61 (m, 2H), 7.97 (t, J = 2.3 Hz, 1H), 7.84 (s, 1H), 7.50 (dd, J = 6.5, 2.7 Hz, 1H), 7.21 (dt, J = 8.9, 3.4 Hz, 1H), 7.07 (t, J = 8.7 Hz, 1H), 4.82 (s, 2H), 4.45 (s, 2H), 3.91 (t, J = 5.6 Hz, 2H), 2.77 (t, J = 5.6 Hz, 2H).
실시예 130. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 437.26,
1H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1H), 8.79 (d, J = 2.4 Hz, 2H), 8.10 (d, J = 8.4 Hz, 1H), 8.02 (dd, J = 8.4, 2.6 Hz, 1H), 7.72 (dd, J = 6.9, 2.4 Hz, 1H), 7.41 - 7.28 (m, 2H), 6.60 (s, 1H), 5.07 (s, 2H).
실시예 131. 4-(3-(3-클로로-4-플루오로페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레이도)벤조산의 제조
[M+H+] = 443.3,
1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.71 (dd, J = 6.8, 2.6 Hz, 1H), 7.47 - 7.37 (m, 3H), 7.30 (t, J = 9.1 Hz, 1H), 4.90 (s, 2H), 2.55 (t, J = 6.1 Hz, 2H), 2.29 (t, J = 6.1 Hz, 2H), 1.71 - 1.58 (m, 4H).
실시예 132. 3-(3-클로로-4-플루오로페닐)-1-(이속사졸-3-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아의 제조
[M+H+] = 392.2,
1H NMR (300 MHz, CDCl3) δ 10.27 (s, 1H), 8.27 (d, J = 1.7 Hz, 1H), 7.74 (dd, J = 6.5, 2.6 Hz, 1H), 7.49 - 7.34 (m, 1H), 7.11 (t, J = 8.8 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 5.09 (s, 2H), 2.62 (t, J = 5.6 Hz, 2H), 2.51 (t, J = 5.6 Hz, 2H), 1.86 - 1.64 (m, 4H).
실시예 133. 3-(3-클로로-4-플루오로페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(1,3,4-티아디아졸-2-일)우레아의 제조
[M+H+] = 409.05,
1H NMR (500 MHz, DMSO) δ 12.45 (s, 1H), 10.15 (s, 1H), 9.14 (s, 1H), 7.76 (d, J = 4.9 Hz, 1H), 7.44 (dd, J = 19.5, 10.5 Hz, 2H), 5.47 (s, 2H), 2.53 (s, 2H), 2.44 (s, 2H), 1.66 (d, J = 5.4 Hz, 4H).
실시예 134. 3-(3-클로로-4-플루오로페닐)-1-(이속사졸-3-일)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 376.17,
1H NMR (300 MHz, CDCl3) δ 10.20 (s, 1H), 8.30 (d, J = 1.8 Hz, 1H), 7.73 (dd, J = 6.5, 2.6 Hz, 1H), 7.37 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 7.10 (t, J = 8.8 Hz, 1H), 6.49 (d, J = 1.7 Hz, 1H), 4.97 (s, 2H), 2.74 - 2.67 (m, 2H), 2.63 - 2.56 (m, 2H), 2.53 - 2.43 (m, 2H).
실시예 135. 3-(3-클로로-4-플루오로페닐)-1-(1H-피라졸-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 391.2,
1H NMR (300 MHz, DMSO-d6) δ 12.76 (s, 1H), 11.57 (s, 1H), 10.55 (s, 1H), 7.86 (dd, J = 6.6, 2.5 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.44 - 7.31 (m, 2H), 6.10 (d, J = 2.4 Hz, 1H), 4.90 (s, 2H), 4.01 (t, J = 4.65 Hz, 2H), 2.32 (t, J = 6.4 Hz, 2H), 1.83 - 1.63 (m, 2H).
실시예 136. 3-(3-클로로-4-플루오로페닐)-1-(이속사졸-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아의 제조
[M+H+] = 392.3,
1H NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 8.32 (d, J = 1.6 Hz, 1H), 7.72 (dd, J = 2.6, 6.6 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.11 (t, J = 8.8 Hz, 1H), 6.44 (d, J = 1.5 Hz, 1H), 4.90 (s, 2H), 4.26 - 4.19 (m, 2H), 2.62 - 2.56 (m, 2H), 2.00 - 1.92 (m, 2H)
실시예 137. 1-(바이사이클로[1.1.1]펜탄-1-일)-3-(3-클로로-4-플루오로페닐)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 402.9,
1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 2.7, 6.4 Hz, 1H), 7.21 (ddd, J = 2.7, 4.0, 8.9 Hz, 1H), 7.14 - 7.07 (m, 1H), 6.75 (s, 1H), 6.42 (s, 1H), 4.47 (s, 2H), 2.64 (s, 1H), 2.23 (s, 6H).
실시예 138. 3-(6-클로로-4-(디메틸아미노)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 489.2,
1H NMR (400MHz, CDCl3) δ 11.69 - 10.42 (m, 1H), 8.33 (s, 2H), 7.41 (d, J = 6.1 Hz, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 4.72 (s, 2H), 4.09 (s, 3H), 3.14 (d, J = 2.1 Hz, 6H).
실시예 139. 3-(3-클로로-4-플루오로-5-메틸페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 441.1,
1H NMR (400 MHz, CDCl3) δ 8.37 (s, 2H), 7.32 - 7.27 (m, 1H), 7.01 - 6.96 (m, 1H), 6.87 - 6.51 (m, 1H), 6.31 (s, 1H), 5.96 (s, 1H), 4.73 (s, 2H), 4.08 (s, 3H), 2.27 (d, J=2.3 Hz, 3H).
실시예 140. 3-(3-클로로-4-플루오로-5-메틸페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 459.2,
1H NMR (400 MHz, CDCl3) δ 11.58 - 10.91 (m, 1H), 8.38 (s, 2H), 7.24 (d, J = 2.8 Hz, 1H), 6.98 (dd, J = 2.4, 5.8 Hz, 1H), 6.34 (s, 1H), 5.94 (s, 1H), 4.73 (s, 2H), 4.09 (s, 3H), 2.27 (d, J = 2.3 Hz, 3H).
실시예 141. 3-(6-클로로-3-플루오로-4-메틸피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 460.2,
1H NMR (400 MHz, CDCl3) δ 8.39 (s, 2H), 7.01 (d, J = 3.8 Hz, 1H), 6.55 (s, 1H), 6.35 (s, 1H), 4.78 (s, 2H), 4.05 (s, 3H), 2.32 (d, J = 1.3 Hz, 3H).
실시예 142. 3-(6-클로로-5-플루오로-4-메틸피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 460.1,
1H NMR (400 MHz, CDCl3) δ 11.78 - 10.53 (m, 1H), 8.40 - 8.28 (m, 2H), 7.91 (d, J = 4.5 Hz, 1H), 6.70 (s, 1H), 6.35 (s, 1H), 4.74 (s, 2H), 4.10 (s, 3H), 2.39 (d, J = 1.5 Hz, 3H).
실시예 143. 3-(2-클로로피리미딘-5-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 429.1,
1H NMR (400 MHz, CDCl3) δ 8.81 (s, 2H), 8.32 (s, 2H), 7.28 (br s, 1H), 6.36 (s, 1H), 4.75 (s, 2H), 4.00 (s, 3H), 2.01 (s, 1H).
실시예 144. 3-(3-시아노페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 418.2,
1H NMR (400 MHz, CDCl3) δ 11.51 (s, 1H), 8.35 (s, 2H), 7.75 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.41 - 7.37 (m, 2H), 6.73 (s, 1H), 6.36 (s, 1H), 4.77 (s, 2H), 4.05 (s, 3H).
실시예 145. 3-(6-시아노피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 419.1,
1H NMR (300 MHz, MeOD) δ 8.43 (s,2H), 8.27 (d, J = 8.6 Hz, 1H), 7.90 (dd, J = 8.6, 7.5 Hz, 1H), 7.56 - 7.40 (m, 1H), 6.58 (s, 1H), 4.98 (s, 2H), 4.04 (s, 3H).
실시예 146. 3-(2-시아노피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 419.6,
1H NMR (500 MHz, DMSO-d6) δ 13.56 (s, 1H), 9.01 (s, 1H), 8.58 (s, 2H), 8.50 (d, J = 5.7 Hz, 1H), 8.07 (s, 1H), 7.75 (d, J = 5.6 Hz, 1H), 6.67 (s, 1H), 4.93 (s, 2H), 3.96 (s, 3H).
실시예 147. 3-(3-시아노페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 400.1,
1H NMR (400 MHz, CDCl3) δ 11.77 - 10.63 (m, 1H), 8.36 (s, 2H), 7.77 (d, J = 1.5 Hz, 1H), 7.55 (td, J = 2.1, 7.5 Hz, 1H), 7.44 - 7.33 (m, 2H), 6.87 - 6.53 (m, 2H), 6.32 (s, 1H), 4.76 (s, 2H), 4.06 (s, 3H).
실시예 148. 3-(6-시아노피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 418.9,
1H NMR (400 MHz, CDCl3) δ 8.42 - 8.38 (m, 3H), 7.87 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.01 (s, 1H), 6.40 (s, 1H), 4.80 (s, 2H), 4.13 (s, 3H).
실시예 149. 3-(3-시아노-4,5-디플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 454.1,
1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 2H), 7.80 (q, J = 9.5 Hz, 1H), 7.26 (br dd, J = 2.8, 9.0 Hz, 1H), 6.69 (s, 1H), 4.91 (s, 2H), 3.95 (s, 3H).
실시예 150. 3-(3-시아노-4,5-디플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 436.1,
1H NMR (400 MHz, CDCl3) δ 8.42 (s, 2H), 7.84 (ddd, J = 1.9, 3.8, 9.3 Hz, 1H), 7.43 (q, J = 9.4 Hz, 1H), 6.87 - 6.55 (m, 2H), 6.36 (s, 1H), 4.78 (s, 2H), 4.08 (s, 3H).
실시예 151. 3-(6-시아노-4,5-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 455.1,
1H NMR (400 MHz, CDCl3) δ 11.33 - 10.86 (m, 1H), 8.41 - 8.36 (m, 3H), 7.01 - 6.93 (m, 1H), 6.43 - 6.37 (m, 1H), 4.78 (s, 2H), 4.13 (s, 3H).
실시예 152. 3-(4-시아노-3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 468.05,
1H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H) δ 8.87 (s, 1H), 8.58 (s, 2H), 7.94 (s, 1H), 7.87 (q, J = 8.7 Hz, 2H), 7.20 (t, J = 54.3 Hz, 1H), 6.64 (s, 1H), 4.93 (s, 2H), 3.95 (s, 3H).
실시예 153. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(4-시아노-3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 425.2,
1H NMR (500 MHz, DMSO-d6) δ 13.89 (s, 1H), 8.91 (s, 1H), 8.59 (s, 2H), 7.94 (s, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.21 (t, J = 54.4 Hz, 1H), 6.91 (s, 1H), 4.93 (s, 2H), 3.96 (s, 3H).
실시예 154. 3-(3-시아노-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 436.3,
1H NMR (500 MHz, Methanol-d4) δ 8.45 (s, 2H), 7.87 (dd, J = 6.0, 2.7 Hz, 1H), 7.69 (ddd, J = 9.0, 4.7, 2.6 Hz, 1H), 7.27 (t, J = 9.0 Hz, 1H), 6.58 (s, 1H), 4.98 (s, 2H), 4.07 (s, 3H).
실시예 155. 3-(3-시아노-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 418.1,
1H NMR (300 MHz, DMSO) δ 13.19 (s, 1H), 8.58 (s, 1H), 8.52 (s, 2H), 7.94 (dd, J = 5.8, 2.7 Hz, 1H), 7.77 (ddd, J = 9.2, 4.9, 2.8 Hz, 1H), 7.44 (t, J = 9.1 Hz, 1H), 6.93 (t, J = 54.5 Hz, 1H), 6.45 (s, 1H), 4.90 (s, 2H), 3.95 (s, 3H).
실시예 156. 3-(4-시아노-3-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 436.1,
1H NMR (400 MHz, DMSO) δ 8.56 (s, 1H), 7.81 - 7.66 (m, 1H), 7.41 (d, J = 9.3 Hz, 1H), 6.64 (s, 1H), 4.92 (s, 1H), 3.95 (s, 1H).
실시예 157. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(3-시아노-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 393.2,
1H NMR (500 MHz, DMSO-d6) δ 13.87 (s, 1H), 8.59 (s, 1H), 8.55 (s, 2H), 7.93 (dd, J = 6.2, 2.8 Hz, 1H), 7.75 (dt, J = 8.2, 3.5 Hz, 1H), 7.44 (t, J = 9.1 Hz, 1H), 6.91 (s, 1H), 4.90 (s, 2H), 3.96 (s, 3H).
실시예 158. 3-(2-시아노-3-플루오로피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 437.1,
1H NMR (500 MHz, DMSO-d6) δ 13.57 (s, 1H), 9.02 (s, 1H), 8.58 (s, 2H), 8.46 (d, J = 5.4 Hz, 1H), 8.05 (t, J = 5.9 Hz, 1H), 6.65 (s, 1H), 4.95 (s, 2H), 3.95 (s, 3H).
실시예 159. 3-(3-클로로-4-플루오로페닐)-1-((1,3-디메틸-1H-피라졸-4-일)메틸)-1-(4-메톡시페닐)우레아의 제조
1H NMR (300 MHz, DMSO) δ 7.90 (br, 1H), 7.73 (dd, J = 6.90 Hz, 2.61 Hz, 1H), 7.40 (m, 2H), 7.27 (t, J = 9.15 Hz, 1H), 7.07 (d, J = 8.91 Hz, 2H), 6.96 (d, J = 8.94 Hz, 2H), 4.56 (s, 2H), 3.76 (s, 3H), 3.66 (s, 3H), 1.80 (s, 3H).
실시예 160. 3-(6-시아노-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
1H NMR (300 MHz, DMSO-d6) δ 13.59 (s, 1H), 9.50 (s, 1H), 8.49 (s, 2H), 8.12 - 7.83 (m, 2H), 6.62 (s, 1H), 4.92 (s, 2H), 3.93 (s, 3H).
실시예 161. 3-(4-시아노-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 437.2,
1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 4.5 Hz, 1H), 8.41 - 8.35 (m, 2H), 8.22 (s, 1H), 6.94 (s, 1H), 6.38 (s, 1H), 4.78 (s, 2H), 4.14 - 4.06 (m, 3H).
실시예 162. 3-(3-시아노-4-플루오로페닐)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 424.2,
1H NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 2.8, 5.3 Hz, 1H), 7.61 (ddd, J = 2.8, 4.4, 9.0 Hz, 1H), 7.21 (t, J = 8.6 Hz, 1H), 6.81 (s, 1H), 6.45 (s, 1H), 4.52 (s, 2H), 3.37 (s, 3H), 2.36 (s, 6H)
실시예 163. 3-(3-시아노-4-플루오로페닐)-1-(6-메톡시피리다진-4-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
페닐 3-시아노-4-플루오로페닐카바메이트의 제조
DCM(20 mL) 중의 5-아미노-2-플루오로벤조니트릴(1 g, 7.35 mmol, 1 eq) 혼합물에 Py(697 mg, 8.82 mmol, 712 μL, 1.2 eq) 및 페닐 카르보노클로리데이트(phenyl carbonochloridate, 1.27 g, 8.08 mmol, 1.01 mL, 1.1 eq)을 첨가하였다. 상기 혼합물을 25℃에서 1시간 동안 교반하였다. 상기 혼합물을 구연산 수용액(5%, 20 mL)에 붓고, DCM으로 추출하였다(20 mL×3). 유기층을 합하여 Na2SO4 상에서 건조시켜 여과하여 진공 하에 농축시켜, 무색의 오일로서 표제 화합물(1.7 g, 6.63 mmol, 90.31% yield)을 수득하였다. 상기 잔여물은 추가적인 정제 없이 다음 단계에 사용하였다.
3-(3-시아노-4-플루오로-페닐)-1-(6-메톡시피리다진-4-일)-1-((1-테트라하이드로 -2H-피란 -2-일-5-(트리플루오로메틸 )-1H-피라졸 -3-일)메틸)우레아의 제조
DMF(1 mL) 중의 6-메톡시-N-((1-(테트라하이드로-2H-피란-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)피리다진-4-아민(25 mg, 70 μmol, 1 eq) 혼합물에 NaH(4 mg, 84 umol, 60% purity, 1.2 eq)를 첨가하고, 상기 혼합물을 30℃에서 30분 동안 교반하였다. 이후, 상기 혼합물에 페닐 N-(3-시아노-4-플루오로-페닐) 카바메이트(27 mg, 104.94 μmol, 1.5 eq)를 첨가하여 30℃에서 5분 동안 교반하였다. 상기 혼합물을 NH4Cl 포화 용액(10 mL)에 붓고, EtOAc로 추출하였다(10 mL×3). 유기층을 합하여 Na2SO4 상에서 건조시키고 여과하여 진공 하에 농축하였다. 상기 잔여물을 prep-TLC(Petroleum ether: Ethyl acetate= 1:1)로 정제하고 여과 및 농축하여, 노란색 오일로서 표제 화합물(15 mg, 29 μmol, 41.27% yield)을 수득하였다.
3-(3-시아노-4-플루오로-페닐)-1-(6-메톡시피리다진-4-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
DCM(3 mL) 중의 3-(3-시아노-4-플루오로-페닐)-1-(6-메톡시피리다진-4-일)-1-((1-테트라하이드로-2H-피란-2-일-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(15 mg, 29 umol, 1 eq) 혼합물에 TFA(1.54 g, 13.51 mmol, 1 mL, 467.72 eq)를 첨가하여 30℃에서 1시간 동안 교반하고 농축하였다. 상기 잔여물을 prep-HPLC(column: Unisil 3-100 C18 Ultra 150×50 mm×3 μm; mobile phase: [water (0.225%FA)-ACN]; B%: 35%-55%, 10min)로 정제하고 동결건조시켜, 미색(off-white) 고체로서 표제 화합물(6.3 mg, 14.33 μmol, 49.61% yield, 99% purity)을 수득하였다.
[M+H+] = 436.1,
1H NMR (400 MHz, CDCl3) δ 8.79 - 8.69 (m, 1H), 7.85 - 7.76 (m, 1H), 7.75 - 7.67 (m, 1H), 7.58 - 7.42 (m, 1H), 7.21 - 7.16 (m, 1H), 6.90 - 6.73 (m, 1H), 6.37 (s, 1H), 4.98 - 4.79 (m, 2H), 4.14 - 4.00 (m, 3H).
실시예 164. 3-(6-시아노-4-(디메틸아미노)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 480.2,
1H NMR (400 MHz, CDCl3) δ 11.69 - 10.79 (m, 1H), 8.36 (s, 2H), 7.64 (d, J = 7.0 Hz, 1H), 6.75 (s, 1H), 6.37 (s, 1H), 4.74 (s, 2H), 4.10 (s, 3H), 3.18 (d, J = 2.1 Hz, 6H).
실시예 165. 3-(2,6-디클로로피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 462.1,
1H NMR (400 MHz, CDCl3) δ 11.14 (br s, 1H), 8.54 (d, J=8.4 Hz, 1H), 8.44 (s, 2H), 7.31 (d, J=8.6 Hz, 1H), 6.62 (s, 1H), 6.39 (s, 1H), 4.77 (s, 2H), 4.11 (s, 3H).
실시예 166. 3-(2,6-디클로로피리딘-3-일)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 444.1,
1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=8.6 Hz, 1H), 8.44 (s, 2H), 7.31 (d, J=8.6 Hz, 1H), 6.86 - 6.54 (m, 2H), 6.36 (s, 1H), 4.77 (s, 2H), 4.10 (s, 3H).
실시예 167. 3-(3,4-디시아노페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 443.1,
1H NMR (500 MHz, Methanol-d4) δ 8.45 (s, 2H), 8.18 (d, J = 2.2 Hz, 1H), 7.88 (dd, J = 8.8, 2.2 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 6.60 (s, 1H), 5.00 (s, 2H), 4.07 (s, 3H).
실시예 168. 3-(3,4-디플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 428.2,
1H NMR (500 MHz, CDCl3) δ 11.40 (s, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.43 - 7.30 (m, 2H), 7.05 (dd, J = 18.6, 8.9 Hz, 1H), 6.92 - 6.78 (m, 2H), 6.33 (s, 1H), 6.09 (s, 1H), 4.74 (s, 2H), 4.00 (s, 3H).
실시예 169. 3-(3,6-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 430.2,
1H NMR (400 MHz, CDCl3) δ 11.47 - 10.54 (m, 1H), 8.41 (s, 2H), 7.67 - 7.47 (m, 1H), 6.80 - 6.71 (m, 1H), 6.36 (s, 1H), 6.32 (s, 1H), 4.78 (s, 2H), 4.07 (s, 3H).
실시예 170. 3-(5,6-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
3-(5,6-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((1-(테트라하이드로-2H-피란-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
DCM(2 mL) 중의 5,6-디플루오로피리딘-2-아민(55 mg, 423 μmol, 1 eq) 및 DIPEA(164 mg, 1.27 mmol, 221 μL, 3 eq) 혼합물에 CDI(89 mg, 550 μmol, 1.3 eq)를 첨가하고, 상기 용액을 30℃에서 16시간 동안 교반하였다. 이후, 2-메톡시-N-((1-(테트라하이드로-2H-피란-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)피리미딘-5-아민(100 mg, 280 μmol, 0.66 eq)을 첨가하여 30℃에서20시간 동안 교반하고 농축시켜, 회색 고체로서 표제 화합물(0.22 g, crude)을 수득하였다. 상기 수득한 조 생성물을 추가적인 정제 없이 이후 공정에 사용하였다.
3-(5,6-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
4 M HCl(1 mL) 및 CH3CN(1 mL)에 용해시킨 이전 단계로부터 수득한 3-(5,6-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((1-(테트라하이드로-2H-피란-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(0.22 g, 429 μmol, 1 eq) 용액을 30℃에서 2시간 동안, 그리고 40℃에서 1시간 동안 교반하였다. 상기 반응 혼합물을 포화 NaHCO3 수용액(30 mL)에 붓고, 에틸 아세테이트로 추출하였다(15 mL×3). 유기층을 합하여 염수(brine, 10 mL)로 세척하고, 무수 Na2SO4로 건조시켜 여과하였다. 상기 여과액을 진공 하에 농축하였다. 조 생성물을 Prep-HPLC(column: Shim-pack C18 150 mm×25 mm×10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 42%-62%, 10min)로 정제하고 동결건조시켜, 흰색 고체로서 표제 화합물(12.3 mg, 6.6% yield, 99% purity)을 수득하였다.
[M+H+] = 430.0,
1H NMR (400 MHz, CDCl3) δ 11.46 - 11.15 (m, 1H), 8.37 (s, 2H), 7.96 (dd, J = 2.6, 8.7 Hz, 1H), 7.61 (q, J = 8.7 Hz, 1H), 6.68 (s, 1H), 6.37 (s, 1H), 4.76 (s, 2H), 4.11 (s, 3H).
실시예 171. 3-(5,6-디플루오로피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 430.1,
1H NMR (400 MHz, CDCl3) δ 12.40 - 10.27 (m, 1H), 8.33 (s, 2H), 8.08 (ddd, J=2.3, 8.3, 10.6 Hz, 1H), 7.80 (br s, 1H), 6.92 (br s, 1H), 6.36 (s, 1H), 4.74 (s, 2H), 4.03 (s, 3H), 2.17 (s, 1H), 2.00 (s, 1H).
실시예 172. 3-(4,5-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 429.9,
1H NMR (400 MHz, CDCl3) δ 11.66 - 11.03 (m, 1H), 8.39 (s, 2H), 8.12 - 8.01 (m, 2H), 6.97 - 6.87 (m, 1H), 6.43 - 6.30 (m, 1H), 4.82 - 4.61 (m, 2H), 4.18 - 4.05 (m, 3H).
실시예 173. 3-(3,4-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H]+ = 429.9,
1H NMR (400 MHz, CDCl3) δ11.88 - 11.27 (m, 1H), 8.43 (s, 2H), 8.08 (t, J = 6.0 Hz, 1H), 7.07 - 7.02 (m, 1H), 6.84 - 6.77 (m, 1H), 6.40 - 6.35 (m, 1H), 4.85 - 4.74 (m, 2H), 4.10 - 4.01 (m, 3H).
실시예 174. 3-(5-(디플루오로메틸)피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 444.2,
1H NMR (500 MHz, DMSO-d6) δ 13.56 (s, 1H), 8.80 (s, 1H), 8.66 (s, 1H), 8.59 (s, 2H), 8.39 (s, 1H), 8.12 (s, 1H), 7.14 (t, J = 55.3 Hz, 1H), 6.65 (s, 1H), 4.93 (s, 2H), 3.96 (s, 3H).
실시예 175. 3-(2-(디플루오로메틸)피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 444.2,
1H NMR (500 MHz, DMSO-d6) δ 13.57 (s, 1H), 8.88 (s, 1H), 8.59 (s, 2H), 8.44 (d, J = 5.6 Hz, 1H), 7.84 (s, 1H), 7.69 (d, J = 5.6 Hz, 1H), 6.86 (t, J = 55.2 Hz, 1H), 6.65 (s, 1H), 4.94 (s, 2H), 3.96 (s, 3H).
실시예 176. 3-(3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 443,
1H NMR (400 MHz, Chloroform-d) δ 11.36 (s, 1H), 8.42 (s, 2H), 7.51 (s, 1H), 7.43 (d, J = 6.2 Hz, 2H), 6.64 (t, J = 56.4 Hz, 1H), 6.37 (s, 1H), 6.18 (s, 1H), 4.78 (s, 2H), 4.12 (s, 3H).
실시예 177. 3-(6-(디플루오로메틸)피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 444.2,
1H NMR (500 MHz, DMSO-d6) δ 13.56 (s, 1H), 9.41 (s, 1H), 8.53 (d, J = 1.4 Hz, 2H), 8.06 (d, J = 8.5 Hz, 1H), 7.93 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.4 Hz, 1H), 6.79 (t, J = 55.0 Hz, 1H), 6.65 (s, 1H), 4.95 (s, 2H), 3.94 (s, 3H).
실시예 178. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 425.2,
1H NMR (400 MHz, DMSO-d6) δ 13.25 (br s, 1H), 8.53 - 8.47 (m, 3H), 7.69 (s, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.20 - 6.75 (m, 3H), 6.43 (s, 1H), 4.91 (s, 2H), 3.95 (s, 3H).
실시예 179. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(6-(디플루오로메틸)피리딘-2-일)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 426.1,
1H NMR (400 MHz, CDCl3) δ 8.43 - 8.33 (m, 2H), 8.20 (d, J=7.9 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 6.88 - 6.55 (m, 2H), 6.53 - 6.23 (m, 2H), 4.77 (s, 2H), 4.10 (s, 3H).
실시예 180. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 400.0,
1H NMR (400 MHz, DMSO-d6) δ 13.86 (br s, 1H), 8.55 (s, 2H), 8.47 (s, 1H), 7.68 (s, 1H), 7.62 (br d, J = 8.2 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.12 - 6.81 (m, 2H), 4.91 (s, 2H), 3.96 (s, 3H).
실시예 181. 3-(3-(디플루오로메틸)페닐)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 431.2,
1H NMR (400 MHz, CDCl3) δ 11.65 - 10.87 (m, 1H), 7.54 (s, 1H), 7.51 - 7.47 (m, 1H), 7.45 - 7.39 (m, 1H), 7.24 (s, 1H), 6.80 (s, 1H), 6.78 - 6.49 (m, 1H), 6.42 (s, 1H), 4.49 (s, 2H), 3.41 - 3.31 (m, 3H), 2.34 (s, 6H).
실시예 182. 1-((4-(2-에톡시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 482.2,
1H NMR (400 MHz, CDCl3) δ 11.36 (s, 1H), 8.04 (d, J = 2.6 Hz, 1H), 7.33 (dd, J = 2.8, 8.8 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.02 - 6.95 (m, 2H), 6.84 (d, J = 8.8 Hz, 1H), 6.04 (s, 1H), 4.75 (s, 2H), 3.98 (s, 3H), 3.31 (q, J = 7.0 Hz, 2H), 3.25 (t, J = 6.6 Hz, 2H), 2.50 (t, J = 6.7 Hz, 2H), 1.09 (t, J = 7.0 Hz, 3H).
실시예 183. 3-(6-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 412.1,
1H NMR (400 MHz, CDCl3) δ 11.24 (br s, 1H), 8.72 (s, 1H), 8.36 (s, 2H), 7.97 (dd, J = 1.8, 8.1 Hz, 1H), 7.81 (q, J = 8.2 Hz, 1H), 6.68 (s, 1H), 6.63 (dd, J = 2.1, 7.9 Hz, 1H), 6.36 (s, 1H), 4.75 (s, 2H), 4.12 - 4.09 (m, 3H).
실시예 184. 3-(6-플루오로피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 446.1,
1H NMR (400 MHz, DMSO-d6) δ 8.64 - 8.46 (m, 3H), 8.25 - 8.20 (m, 1H), 8.00 (ddd, J = 2.8, 7.4, 8.9 Hz, 1H), 7.11 (dd, J = 3.2, 8.9 Hz, 1H), 6.64 (s, 1H), 4.91 (s, 2H), 3.95 (s, 3H).
실시예 185. 3-(3-플루오로바이사이클로[1.1.1]펜탄-1-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 401.1,
1H NMR (400 MHz, CDCl3) δ 11.36 (br s, 1H), 8.27 (s, 2H), 6.30 (s, 1H), 4.66 (s, 1H), 4.63 (s, 2H), 4.05 (s, 3H), 2.35 (d, J=2.0 Hz, 6H), 2.17 (s, 1H).
실시예 186. 3-(2-플루오로피리미딘-5-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 413.1,
1H NMR (400 MHz, CDCl3) δ 12.13 - 10.28 (m, 1H), 8.74 (s, 2H), 8.36 (s, 2H), 6.77 (br s, 1H), 6.37 (s, 1H), 4.76 (s, 2H), 4.05 (s, 3H).
실시예 187. 3-(4-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 412.0,
1H NMR (400 MHz, CDCl3) δ 11.66 - 11.15 (m, 1H), 8.43 - 8.33 (m, 2H), 8.17 - 8.09 (m, 1H), 7.97 - 7.85 (m, 1H), 7.18 - 6.96 (m, 1H), 6.84 - 6.74 (m, 1H), 6.38 (s, 1H), 4.82 - 4.74 (m, 2H), 4.14 - 4.08 (m, 3H).
실시예 188. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 461.3,
1H NMR (500 MHz, CDCl3) δ 11.56 (s, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.52 - 7.43 (m, 1H), 7.41 - 7.39 (m, 1H), 7.35 (dd, J = 8.8, 2.8 Hz, 1H), 7.06 (t, J = 9.2 Hz, 1H), 6.98 - 6.70 (m, 2H), 6.32 (s, 1H), 6.18 (s, 1H), 4.75 (s, 2H), 3.99 (s, 3H).
실시예 189. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 461.1,
1H NMR (300 MHz, CDCl3) δ 11.34 (s, 1H), 8.41 (s, 2H), 7.53 - 7.48 (m, 2H), 7.12 (t, J = 9.1 Hz, 1H), 6.88 (t, J = 54.9 Hz, 1H), 6.37 (s, 1H), 6.22 (s, 1H), 4.77 (s, 2H), 4.11 (s, 3H).
실시예 190. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 442.3,
1H NMR (300 MHz, CDCl3) δ 11.19 (s, 1H), 8.41 (s, 2H), 7.56 - 7.41 (m, 2H), 7.11 (t, J = 9.3 Hz, 1H), 6.80 (td, J = 54.9, 46.4 Hz, 2H), 6.34 (s, 1H), 6.21 (s, 1H), 4.77 (s, 2H), 4.11 (s, 3H).
실시예 191. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레아의 제조
[M+H+] = 443.2,
1H NMR (400 MHz, CDCl3) δ 11.18 (s, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.41 (d, J = 5.2 Hz, 1H), 7.35 (dd, J = 8.7, 2.4 Hz, 1H), 7.07 (t, J = 9.1 Hz, 1H), 6.97 - 6.55 (m, 3H), 6.29 (s, 1H), 6.14 (s, 1H), 4.73 (s, 2H), 4.00 (s, 2H).
실시예 192. 3-(4-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 463.3,
1H NMR (500 MHz, DMSO-d6) δ 13.56 (s, 1H), 9.51 (s, 1H), 8.54 (s, 2H), 8.41 (s, 1H), 8.17 (d, J = 5.1 Hz, 1H), 7.32 (t, J = 53.6 Hz, 1H), 6.65 (s, 1H), 4.95 (s, 2H), 3.96 (s, 3H).
실시예 193. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-((4-(2-히드록시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 505.2,
1H NMR (400 MHz, CDCl3) δ 11.42 - 11.22 (br, 1H), 8.38 (s, 2H), 7.59-7.44 (m, 2H), 7.08 (t, J = 6.8 Hz, 1H), 6.84 (t, J = 54.5 Hz, 1H), 6.25 (s, 1H), 4.81 (s, 2H), 4.07 (s, 3H), 3.62 (t, J = 8.0 Hz, 2H), 2.53 (t, J = 8.0 Hz, 2H).
실시예 194. 1-((4-브로모-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 539.1, 541.1,
1H NMR (400 MHz, CDCl3) δ = 11.57 (br s, 1H), 8.44 (s, 2H), 7.52 - 7.41 (m, 2H), 7.09 (t, J = 9.1 Hz, 1H), 6.99 - 6.70 (m, 1H), 6.18 (s, 1H), 4.77 (s, 2H), 4.10 (s, 3H)
실시예 195. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리다진-3-일)우레아의 제조
[M+H+] = 443.1,
1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 9.43 (s, 1H), 8.53 (d, J = 10.0 Hz, 1H), 7.99 (s, 1H), 7.74 (s, 1H), 7.32 - 6.82 (m, 4H), 6.61 (s, 1H), 5.42 (s, 2H), 3.83 (s, 3H).
실시예 196. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 444.1,
1H NMR (400 MHz, CDCl3) δ 11.66 - 10.69 (m, 1H), 8.41 - 8.36 (m, 2H), 8.31 - 8.24 (m, 1H), 7.57 (t, J = 8.9 Hz, 1H), 7.02 - 6.95 (m, 1H), 6.86 - 6.50 (m, 2H), 6.34 (s, 1H), 4.78 (s, 2H), 4.14 - 4.07 (m, 3H).
실시예 197. 1-((4-브로모-5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 521.0, 523.0,
1H NMR (400 MHz, DMSO-d6) δ 13.77 (s, 1H), 8.50 (s, 2H), 8.46 (s, 1H), 7.70 (d, J = 6.0 Hz, 1H), 7.67 - 7.59 (m, 1H), 7.35 - 6.78 (m, 3H), 4.89 (s, 2H), 3.98 - 3.88 (m, 3H).
실시예 198. 1-((5-(디플루오로메틸)-4-(2-히드록시프로판-2-일)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 501.2,
1H NMR (400 MHz, CDCl3) δ 11.47 - 10.67 (m, 1H), 8.34 (s, 2H), 7.49 - 7.37 (m, 2H), 7.01 (t, J = 9.2 Hz, 1H), 6.94 - 6.59 (m, 2H), 6.33 (s, 1H), 5.07 (s, 2H), 3.99 (s, 3H), 1.64 (s, 1H), 1.43 (s, 6H).
실시예 199. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-((4-(2-히드록시프로필)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 519.2,
1H NMR (400 MHz, CDCl3) δ 11.89 - 11.03 (m, 1H), 8.38 (s, 2H), 7.47 (s, 2H), 7.08 (s, 1H), 7.01 - 6.65 (m, 1H), 6.34 (s, 1H), 5.07 - 4.58 (m, 2H), 4.07 (s, 3H), 3.81 (s, 1H), 2.57 (d, J = 14.9 Hz, 1H), 2.24 (s, 1H), 1.14 (s, 3H).
실시예 200. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리다진-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 461.2,
1H NMR (400 MHz, DMSO-d6) δ 13.68 (s, 1H), 9.42 (s, 1H), 8.54 (d, J = 10.0 Hz, 1H), 7.99 (s, 1H), 7.74 (s, 1H), 7.35 - 7.17 (m, 3H), 6.83 (s, 1H), 5.45 (s, 2H), 3.84 (s, 3H).
실시예 201. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리다진-4-일)우레아의 제조
[M+H+] = 443.0,
1H NMR (400 MHz, DMSO-d6) δ 13.46 - 13.15 (m, 1H), 9.68 - 9.25 (m, 1H), 8.96 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 2.2, 6.4 Hz, 1H), 7.63 (dd, J = 3.7, 8.4 Hz, 1H), 7.33 (d, J = 9.2 Hz, 1H), 7.30 - 6.75 (m, 3H), 6.41 (s, 1H), 5.09 (s, 2H), 4.01 (s, 3H).
실시예 202. 3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 462.1,
1H NMR (400 MHz, CDCl3) δ 11.32 (s, 1H), 8.41 (s, 2H), 8.28 (dd, J = 9.2, 2.8 Hz, 1H), 7.60 (t, J = 8.9 Hz, 1H), 7.00 (s, 1H), 6.68 (t, J = 53.7 Hz, 1H), 6.39 (s, 1H), 4.79 (s, 2H), 4.13 (s, 3H).
실시예 203. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리다진-4-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 2.0 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.41 - 7.30 (m, 1H), 7.14 (t, J = 9.0 Hz, 1H), 7.03 - 6.75 (m, 2H), 6.44 (s, 1H), 4.91 (s, 2H), 4.13 (s, 3H).
실시예 204. 3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 462.0,
1H NMR (400 MHz, Acetonitrile-d3) δ 11.68 - 11.54 (m, 1H), 8.39 (s, 2H), 8.21 (dd, J = 3.4, 9.2 Hz, 1H), 7.67 (t, J = 9.2 Hz, 1H), 7.59 (s, 1H), 7.53 (s, 1H), 6.88 - 6.57 (m, 1H), 6.51 (s, 1H), 4.88 (s, 2H), 4.00 (s, 3H).
실시예 205. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-((4-(2-히드록시-2-메틸프로필)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 533.0,
1H NMR (400 MHz, CDCl3) δ 8.39 - 8.31 (m, 2H), 7.55 - 7.49 (m, 1H), 7.49 - 7.44 (m, 1H), 7.10 (t, J = 9.2 Hz, 1H), 7.01 - 6.71 (m, 1H), 6.35 - 6.27 (m, 1H), 4.96 - 4.91 (m, 2H), 4.08 (s, 3H), 2.50 - 2.46 (m, 2H), 1.16 - 1.12 (m, 6H).
실시예 206. 3-(4-(디플루오로메틸)-3-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 461.1,
1H NMR (400 MHz, Chloroform-d) δ 11.29 (s, 1H), 8.41 (s, 2H), 7.59 - 7.43 (m, 2H), 7.15 - 6.65 (m, 2H), 6.36 (d, J = 10.8 Hz, 2H), 4.78 (s, 2H), 4.11 (s, 3H).
실시예 207. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-((4-(2-히드록시프로판-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 519.2,
1H NMR (400 MHz, CDCl3) δ 11.37 (s, 1H), 8.38 (s, 2H), 7.55 - 7.49 (m, 1H), 7.46 (dd, J =2.6, 5.8 Hz, 1H), 7.08 (t, J = 9.1 Hz, 1H), 7.00 - 6.68 (m, 1H), 6.32 (s, 1H), 5.20 (s, 2H), 4.06 (s, 3H), 1.50 (s, 1H), 1.47 (s, 6H)
실시예 208. 1-((5-(디플루오로메틸)-4-(2-히드록시-2-메틸프로필)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 515.0,
1H NMR (400 MHz, CDCl3) δ 8.39 - 8.35 (m, 2H), 7.58 - 7.47 (m, 2H), 7.10 (t, J = 9.2 Hz, 1H), 7.03 - 6.63 (m, 2H), 6.48 - 6.38 (m, 1H), 4.96 - 4.91 (m, 2H), 4.10 - 4.07 (m, 3H), 2.56 - 2.51 (m, 2H), 1.21 - 1.13 (m, 6H).
실시예 209. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 418.2,
1H NMR (500 MHz, DMSO-d6) δ 13.87 (s, 1H), 8.57 (s, 2H), 8.48 (s, 1H), 7.78 - 7.69 (m, 1H), 7.65 (dd, J = 8.7, 4.1 Hz, 1H), 7.30 - 7.08 (m, 2H), 6.90 (s, 1H), 4.91 (s, 2H), 3.96 (s, 3H).
실시예 210. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 444.2,
1H NMR (500 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.46 (s, 1H), 8.49 (s, 2H), 8.10 (dd, J = 9.4, 3.1 Hz, 1H), 7.91 (t, J = 9.4 Hz, 1H), 6.96 (td, J = 54.8, 54.0, 45.8 Hz, 2H), 6.43 (s, 1H), 4.93 (s, 2H), 3.94 (s, 3H).
실시예 211. 3-(2-(디플루오로메틸)-3-플루오로피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 462.04,
1H NMR (500 MHz, Methanol-d4) δ 8.50 (s, 2H), 8.34 (d, J = 5.4 Hz, 1H), 8.14 (t, J = 5.7 Hz, 1H), 6.88 (t, J = 53.4 Hz, 1H), 5.02 (s, 2H), 4.07 (s, 3H).
실시예 212. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 418.9,
1H NMR (400 MHz, DMSO-d6) δ 13.81 (br s, 1H), 9.50 (br s, 1H), 8.52 (s, 2H), 8.08 (dd, J = 3.5, 9.2 Hz, 1H), 7.91 (t, J = 9.4 Hz, 1H), 7.00 (br t, J = 53.2 Hz, 1H), 6.89 (s, 1H), 4.93 (s, 2H), 3.94 (s, 3H).
실시예 213. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 449.2,
1H NMR (400 MHz, CDCl3) δ 11.31 (br s, 1H), 7.62 - 7.53 (m, 1H), 7.50 (dd, J = 2.6, 5.9 Hz, 1H), 7.12 (t, J = 9.1 Hz, 1H), 7.04 - 6.72 (m, 2H), 6.42 (s, 1H), 4.49 (s, 2H), 3.38 - 3.29 (m, 3H), 2.38 - 2.32 (m, 6H).
실시예 214. 3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 450.2,
1H NMR (400 MHz, CDCl3) δ 11.28 (s, 1H), 8.18 (dd, J = 3.4, 9.2 Hz, 1H), 7.62 - 7.49 (m, 2H), 6.87 - 6.52 (m, 1H), 6.44 (s, 1H), 4.51 (s, 2H), 3.35 (s, 3H), 2.38 (s, 6H).
실시예 215. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(4-플루오로-3-(트리플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)우레아의 제조
[M+H+] = 436.1,
1H NMR (400 MHz, CDCl3) δ 8.40 - 8.35 (m, 2H), 7.63 - 7.57 (m, 1H), 7.55 - 7.50 (m, 1H), 7.16 (t, J = 9.3 Hz, 1H), 6.52 - 6.47 (m, 1H), 6.42 - 6.38 (m, 1H), 4.77 - 4.72 (m, 2H), 4.11 - 4.06 (m, 3H).
실시예 216. 1,3-비스(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 425.2,
1H NMR (400 MHz, DMSO-d6) δ 13.61 (br s, 1H), 8.58 (d, J = 4.8 Hz, 4H), 6.63 (s, 1H), 4.92 (s, 2H), 3.95 (s, 3H), 3.87 (s, 3H).
실시예 217. 1-(2-메톡시피리미딘-5-일)-3-(3-메틸바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 397.2,
1H NMR (400 MHz, CDCl3) δ 11.91 - 10.92 (m, 1H), 8.27 (s, 2H), 6.28 (s, 1H), 4.61 (s, 2H), 4.58 (s, 1H), 4.06 (s, 3H), 2.17 (s, 1H), 1.87 (s, 6H), 1.22 (s, 3H).
실시예 218. 1-(2-메톡시피리미딘-5-일)-3-(2-(메틸티오)피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
[M+H+] = 441.1,
1H NMR (400 MHz, CDCl3) δ 8.56 (s, 2H), 8.26 (s, 2H), 7.19 (s, 1H), 6.90 (s, 1H), 6.27 (s, 1H), 4.68 (s, 2H), 3.93 (s, 3H), 2.48 (s, 3H).
실시예 219. 1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3,4,5-트리플루오로페닐)우레아의 제조
[M+H+] = 447.1,
1H NMR (400 MHz, CDCl3) δ 8.27 (s, 2H), 7.07 - 6.97 (m, 2H), 6.33 (s, 1H), 6.28 (s, 1H), 4.66 (s, 2H), 4.00 (s, 3H).
실시예 220. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)-3-(3,4,5-트리플루오로페닐)우레아의 제조
1,2,3-트리플루오로-5-이소시아나토벤젠의 제조
톨루엔(2 mL) 중의 비스(트리클로로메틸) 카보네이트(bis(trichloro메틸) carbonate, 81 mg, 272 μmol, 0.4 eq) 혼합물을 25℃에서 10분 동안 교반한 후, 톨루엔(1 mL)에 용해시킨 3,4,5-트리플루오로아닐린(3,4,5-trifluoroaniline, 100 mg, 680 μmol, 1 eq)을 첨가하여, 120℃에서 1시간 동안 교반하였다. 생성된 표제 화합물을 포함하는 톨루엔 용액을 별도의 정제 없이 다음 단계에 사용하였다.
1-((5-(디플루오로메틸)-1-(테트라하이드로-2H-피란-2-일)- 1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)-3-(3,4,5-트리플루오로페닐)우레아의 제조
ACN(5 mL) 중의 N-((5-(디플루오로메틸)-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸-3-일)메틸)-2-메톡시피리미딘-5-아민(100 mg, 295 μmol, 1 eq) 혼합물에 이전 단계로부터 수득한 톨루엔에 용해시킨 1,2,3-트리플루오로-5-이소시아나토벤젠 용액을 첨가하였다. 상기 혼합물에 DMAP(108 mg, 884 μmol, 3 eq)를 첨가하고, 25℃에서 16시간 동안 교반하였다. 상기 반응액을 농축시킨 후, 잔여물을 실리카 젤 크로마토그래피(Petroleum ether: Ethyl acetate = 10:1 to 1:1)로 정제하여, 노란색 오일로서 표제 화합물(91 mg, 60% yield)을 수득하였다.
1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)-3-(3,4,5-트리플루오로페닐)우레아의 제조
DCM (6 mL) 중의 1-((5-(디플루오로메틸)-1-(테트라하이드로-2H-피란-2-일)- 1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)-3-(3,4,5-트리플루오로페닐)우레아(91 mg, 178 μmol, 1 eq) 혼합물에 TFA(2 mL)를 첨가하고, 상기 혼합물을 25℃에서 1시간 동안 교반하였다. 상기 반응액을 농축시킨 후, 잔여물을 prep-HPLC(column: Unisil 3-100 C18 Ultra 150 mm×50 mm×3 μm; mobile phase: [water (0.225%FA)-ACN]; B%: 43%-63%, 10min)로 정제하고, 동결건조시켜 미색(off-white) 고체로서 표제 화합물(29.5 mg, 38.4% yield, 99% purity)을 수득하였다.
[M+H+] = 429.1,
1H NMR (400 MHz, CDCl3) δ 11.65 - 10.38 (m, 1H), 8.31 (s, 2H), 7.18 - 7.05 (m, 2H), 6.88 - 6.50 (m, 2H), 6.31 (s, 1H), 4.73 (s, 2H), 4.04 (s, 3H).
실시예 221. 1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3,5,6-트리플루오로피리딘-2-일)우레아의 제조
[M+H+] = 448.2,
1H NMR (400 MHz, DMSO-d6) δ 13.63 (s, 1H), 9.14 (s, 1H), 8.48 (s, 2H), 8.37 - 8.28 (m, 1H), 6.61 (s, 1H), 4.90 (s, 2H), 3.93 (s, 3H).
실시예 222. 1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3,4,5-트리플루오로페닐)우레아의 제조
[M+H+] = 435.2,
1H NMR (400 MHz, CDCl3) δ 11.70 - 10.70 (m, 1H), 7.14 - 7.05 (m, 2H), 6.71 (s, 1H), 6.42 (s, 1H), 4.48 (s, 2H), 3.34 (s, 3H), 2.37 - 2.28 (m, 6H).
실시예 223. 1-((5-시아노-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)-3-(3,4,5-트리플루오로페닐)우레아의 제조
[M+H+] = 404.0,
1H NMR (400 MHz, DMSO-d6) δ 13.84 (s, 1H), 8.54 (s, 3H), 7.45 - 7.37 (m, 2H), 6.89 (s, 1H), 4.89 (s, 2H), 3.96 (s, 3H).
실시예 224. 1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(4,5,6-트리플루오로피리딘-2-일)우레아의 제조
2-메톡시피리미딘-5-일((1-(테트하라이드로-2H-피란-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)카르바믹 클로라이드의 제조
DCM(10 mL) 중의 트리포스겐(triphosgene, 145 mg, 490 μmol, 0.35 eq) 용액에 0℃에서 2-메톡시-N-((1-(테트라하이드로-2H-피란-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)피리미딘-5-아민(0.5 g, 1.40 mmol, 1 eq)을 첨가하였다. 이후, DIPEA(543 mg, 4.20 mmol, 731 μL, 3 eq)를 적가하고, 상기 혼합물을 15℃에서 1시간 동안 교반하였다. 상기 혼합물을 HCl 수용액(0.5 M, 10 ml)에 붓고, DCM(30 mL×3)으로 추출하였다. 유기층을 합하여 NaHCO3 포화 용액(20 ml)으로 세척하고, Na2SO4 상에서 건조시켜 여과하였다. 상기 여과액을 진공 하에 농축하여, 노란색 수지(gum)로서 표제 화합물(0.62 g, crude)을 수득하였다.
1-(2-메톡시피리미딘-5-일)-1-((1-(테트라하이드로-2H-피란-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(4,5,6-트리플루오로피리딘-2-일)우레아의 제조
THF(2 mL) 중의 4,5,6-트리플루오로피리딘-2-아민(65 mg, 439 μmol, 1 eq) 용액에 0℃에서 배치처리방식으로(batch-wise) NaH(35 mg, 878 μmol, 60% in oil, 2 eq)를 첨가하였다. 상기 혼합물을 20℃에서 30분 동안 교반한 후, 이전 단계로부터 수득한 2-메톡시피리미딘-5-일((1-(테트라하이드로-2H-피란-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)카르바믹 클로라이드(129 mg, 307 μmol, 0.7 eq)를 첨가하였다. 상기 혼합물을 20℃에서 1시간 동안 교반한 후, NH4Cl 수용액(15 mL)에 붓고, 에틸 아세테이트로 추출하였다(15 mL×3). 유기층을 합하여 염수(brine, 10 mL)로 세척하고, 무수 Na2SO4로 건조시켜 여과하였다. 상기 여과액을 진공 하에 농축하였다. 조 생성물을 역상 MPLC(0.1% FA condition)로 정제하여, 노란색 고체로서 표제 화합물(90 mg, 39% yield)을 수득하였다.
1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(4,5,6-트리플루오로피리딘-2-일)우레아의 제조
TFA(0.5 mL) 및 DCM(2 mL) 중의 1-(2-메톡시피리미딘-5-일)-1-((1-(테트라하이드로-2H-피란-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(4,5,6-트리플루오로피리딘-2-일)우레아(90 mg, 169 μmol, 1 eq) 용액을 20℃에서 1시간 동안 교반하였다. 상기 용액을 농축하여 건조시켰다. 상기 조 생성물을 prep-HPLC(column: Shim-pack C18 150 mm×25 mm×10 μm; mobile phase: [water (0.225%FA)-ACN]; B%: 48%-68%, 10min)로 정제하고 동결건조시켜, 흰색 고체로서 표제 화합물(54.2 mg, 71% yield, 99% purity)을 수득하였다.
[M+H+] = 448.2,
1H NMR (400 MHz, CDCl3) δ 11.22 (s, 1H), 8.37 (s, 2H), 7.94 (dd, J = 4.2, 10.7 Hz, 1H), 6.69 (s, 1H), 6.38 (s, 1H), 4.76 (s, 2H), 4.11 (s, 3H).
실시예 225. 1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(6-(트리플루오로메틸)피리딘-2-일)우레아의 제조
[M+H+] = 462.1,
1H NMR (500 MHz, CDCl3) δ 11.32 (s, 1H), 8.39 (s, 2H), 8.30 (d, J = 8.5 Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 6.98 (s, 1H), 6.37 (s, 1H), 4.77 (s, 2H), 4.11 (s, 4H).
실시예 226. 3-(3-시아노-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((1-프로피오닐-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아의 제조
1H NMR (300 MHz, DMSO) δ 7.90 (br, 1H), 7.73 (dd, J = 6.90 Hz, 2.61 Hz, 1H), 7.40 (m, 2H), 7.27 (t, J = 9.15 Hz, 1H), 7.07 (d, J = 8.91 Hz, 2H), 6.96 (d, J = 8.94 Hz, 2H), 4.56 (s, 2H), 3.76 (s, 3H), 3.66 (s, 3H), 1.80 (s, 3H).
실험예 1: 세포 배양 및 화합물 처리
HepAD38 세포를 200 unit/mL 페니실린, 200 μg/mL 스트렙토마이신 및 10% FBS를 첨가한 DMEM 배지(Welgene)에 배양하였다. 유지(maintenance) 및 계대(passage) 동안, 상기 세포를 0.4 μg/mL의 테트라사이클린과 함께 배양하였다. HBV 복제 유도를 위한 화합물 처리를 시작하기 2일 전 테트라사이클린이 없는(tetracycline-free) 완전 성장 배지로 교환하였다. HepAD38 세포를 48-웰 배양 플레이트에 1×105 cells/well 밀도로 분주하고 DMSO(0.2%, 대조군) 또는 테스트 화합물(1.5 nM 내지 0.37 μM 범위의 최종 농도)로 처리하였다.
실험예 2: 세포 내 HBV DNA에 대한 실시간 PCR
65시간의 화합물 처리 후, HepAD38 세포를 회수하여 DNeasy Blood & Tissue Kit(Qiagen) 내의 프로토콜에 따라 세포 내 HBV DNA를 추출하였다. HBV DNA를 정량하기 위해 사용된 프라이머와 프로브는 5'-CTCGTGGTGGACTTCTCTC-3', 5'-CTGCAGGATGAAGAGGAA-3' 및 5'-/56-FAM/ TGT CCT GGT /ZEN/ TAT CGC TGG ATG TGT CT /3IABkFQ/-3'였다. LightCycler 480(Roche)을 이용한 실시간 PCR 어세이로 HBV DNA를 증폭시켰다(J. Virol., 2018, 92(16): e00339-18). 모든 과정은 중복하여 확인하였다.
실험예 3: 세포 생존율 어세이
HepAD38 세포를 테트라사이클린 없이 10% FBS를 첨가한 Dulbecco's Modified Eagle's medium(Welgene, LM001-05)에 2일 동안 배양하였다. 상기 세포를 48-웰 배양 플레이트에 분주하고(1×105 cells/well), 5개 농도(0 μM(0.8% DMSO as a control), 33 μM, 50 μM, 66 μM, 및 100 μM)의 각 화합물로 처리하였다. 65시간 처리 후 제조업자의 지시에 따라 EZ-Cytox cell viability assay kit(Daeil Lab Service)로 생존율을 측정하였다. 분광광도계(spectrophotometer, Spark, Tecan)로 450nm에서 흡광도를 측정하였다. 이들 화합물의 IC50, 단백질 저해율, 세포독성 및 CLogP 값을 하기 표 1에 나타내었다. 이때, 양성대조군으로는 NVR-3-778(NVR로 표기)을 사용하였다.
실시예 IC50 (μM)
(NVR: 0.34)		 Protein Cytotoxicity CLogP
% 저해율
(@30 μM)		 EC50 (μM)
(NVR: 3.6)		 % Livability
(@ 100 μM)		 CC50
(μM)
1 ＞1.1
2 ＞1.1
3 ＞1.1 74.2 ＞100
4 0.021
5 0.38
6 ＞1.1 100.5 ＞100
7 0.019 59.3 ＞100
8 ＞1.1
9 0.31 105.0 ＞100
10 ＞1.1
11 0.010
12 0.045
13 0.21 100.0 ＞100
14 0.11 14 7.3 95.4 ＞100
15 0.31 64.7 1.4 84.0 ＞100
16 ＞1.1 97.6 3.04
17 ＞1.1 ＞100 1.68
18 ＞1.1 ＞100 3.23
19 ＞1.1 ＞100 3.4
20 ＞1.1 ＞100 4.03
21 ＞1.1 ＞100 2.47
22 ＞1.1
23 ＞1.1 ＞100 1.93
24 0.16 53.4 ＞100
25 ＞1.1 100 ＞100 2.82
26 ＞1.1 93.0 ＞100 3.43
27 0.16
28 0.06 7.0 47.2
29 ＞1.1 6.9 12.2
30 ＞1.1 52.4 ＞100
31 0.41 90.4 3.3 91.2 ＞100
32 0.0099 5 9.4 4.1 81.4
33 ＞1.1 77.8 96.0
34 ＞1.1 55.2 92.9
35 ＞1.1 33.7 90.5
36 0.036 91.6 9.2 100.2 ＞100
37 ＞1.1 28.3 22.4
38 0.018 80 1.6 104.0 ＞100
39 0.33 96.0 ＞100
40 0.016 99.5 3.8 4.6 82.5
41 0.018 59* 2.6 97.8 ＞100
42 0.037 13* 4.3 99.5 ＞100
43 0.043 96.7 6.06 92.0 ＞100
44 ＞1.1 58 100.0 ＞100
45 0.012 95.6 3.3 3.3 ＞50
46 0.0094 92.8 4.3 100.1 ＞100
47 0.99 95.3 9.6 50.7 ＞100
48 1.1 90 6.4 ＞100 3.0
49 ＞1.1 72 ＞100 1.9
50 0.26 94.3 3.8 ＞100 4.1
51 0.035 87.1 3.4 36.7 ＞50
52 ＞1.1 4.0 100.0 ＞100
53 ＞1.1 20.1 58.9 ＞100
54 0.013 84.0 3.5 17.4 40.6
55 0.017 102.4 ＞100
56 0.40 86.4 6.6 98.2 ＞100
57 0.023 96.2 2.0 93.2 ＞100
58 0.16 93.1 5.0 92.7 ＞100
59 0.013 94.9 4.0 91.2 ＞100
60 0.11 94.7 3.0 76.0 ＞100
61 0.502 81.8 4.4 40.8 98.8
62 0.20 100.4 6.9 6.5 86.68
63 0.014 90.5 2.6 94.5 ＞100
64 0.18 91.1 5.8 100.0 ＞100
65 ＞1.1 53.5 ＞30 112.2 ＞100
66 ＞0.3 81.9 5.06
67 ＞0.3 ＞100 3.68
68 0.0093 48.9 98.6 4.46
69 0.021 94.5 ＞100 3.28
70 0.009 98.0 ＞100 3.28
71 0.076 ＞100 4.3
72 0.048 48.5 ＞66.6 3.99
73 0.019 96.6 ＞100 3.04
74 0.022 55.6 ＞100 5.07
75 0.036 92.1 ＞100 2.64
76 4.19
77 0.036 86.7 ＞100 3.59
78 0.0303 94.0 ＞100 5.29
79 0.019 18.5
80 0.019 21.4 88.4 4.51
81 0.0145 76.0 ＞100 4.52
82 ＞1.1 85.8 ＞100 3.69
83 ＞1.1 95.1 ＞100 5.59
84 0.017 3.43
85 0.23
86 0.016
87 0.034
88 ＞1.1 74.5 ＞100
89 0.05 96.0 ＞100
90
91
92 ＞1.1 ＞100
93 0.32 ＞100
94 0.26 4.8 64.4
95 0.83 29.9 62.2
96 ＞1.1 93.4 ＞100
97 ＞1.1 86.2 ＞100
98 0.018 30.1 ＞66
99 0.89 83.4 ＞100
100 0.036
101 ＞1.1
102 ＞1.1 3.8 ＞66
103 ＞1.1 ND ND
104 0.027
105 0.034 3.5 55.8
106 0.12
107 0.062
108 0.36 89.9 5.3
109 0.15 82.0 ＞100 2.83
110 ＞1.1 ＞100 3.47
111 ＞1.1 ＞100 1.92
112 ＞1.1 ＞66 1.92
113 ＞1.1 102.0 ＞100 3.47
114 0.014 74.6 1.6 7.9 54.5
115 ＞1.1 84.1 ＞100 1.28
116 ＞1.1 69.5 103.9 ＞100
117 ＞1.1 7 3.2 ＞33
118 ＞1.1 31.3 ＜50 4.50
119 0.32 18.8 ＜50 4.70
120 0.095 92.0 ＞100 3.45
121 0.013 92.8 ＞100 3.96
122 0.35 ＞100 3.64
123 0.249 2.09
124 0.047
125 0.23 109.0 ＞100 2.1
126 0.54 3.05
127 0.51 95.0 ＞100 2.09
128 0.34 65.9 ＞100 2.09
129 0.06 93.1 ＞100 1.89
130 0.065 68.0 ＞100 4.13
131 ＞1.1 94.7 3.8 100.3 ＞100
132 0.055 86.9 5.3 81.9 ＞100
133 0.11 5 NA 4.3 74.2 3.7
134 0.069 84.5 3.5 6.5 70.3 2.9
135 0.2 ＞100 3.34
136 0.048 7.3 64 3.16
137 0.37
138 ＞1.1 71.9 ＞100
139 0.04
140 0.037
141 0.42
142 0.1 21.0 46.9
143 ＞1.1
144 0.022 6.3 59.9
145 ＞1.1 99.4 ＞100
146 0.12 112.5 ＞100
147 0.08
148 ＞1.1
149 0.6
150 ＞1.1
151 ＞1.1 87.4 ＞100
152 0.026 82.7 ＞100
153 0.21 94.2 ＞100
154 0.013 73 ＞100
155 0.035 97.0 ＞100
156 0.083 106.9 ＞100
157 0.066
158 0.23
159 ＞3.3 4
160 0.43
161 0.074
162 0.035
163 0.007 99.0 ＞100
164 ＞1.1 100.0 ＞100
165 ＞1.1
166 ＞1.1
167 0.19 ND ND
168 0.073 59.8 ＞100 4.43
169 ＞1.1
170 0.3
171 0.28
172 0.24 ＞100 2.5
173 ＞1.1 ＞100 2.0
174 0.48 96.2 ＞100 2.42
175 0.041
176 0.036 53.5 ＞100
177 0.1
178 0.022 68.5 ＞100
179 0.7 79.3 ＞100
180 0.064 88.1 ＞100
181 0.13 64.9 ＞100
182 ＞1.1 103.9 ＞100
183 ＞1.1
184 0.25
185 ＞1.1
186 ＞1.1 86.4 ＞100
187 ＞1.1 ＞100 2.4
188 0.016 97.9 ＞100 4.53
189 0.0065 58.0 ＞100 3.98
190 0.02 2.90
191 0.024 3.45
192 0.059 104.0 ＞100
193 0.18 ＞100
194 0.021 ＞100
195 ＞1.1 100.5 ＞100
196 0.16 29.2 76.4
197 0.019 11.5 79.1
198 ＞1.1 102.2 ＞100
199 0.75 95.7 ＞100
200 ＞1.1
201 0.028 107.2 ＞100
202 0.046 82.3 ＞100
203 0.013
204 0.036
205 ＞1.1
206 0.18 89.6 ＞100
207 0.74 87.7 ＞100
208 ＞1.1 ND ND
209 0.016
210 0.13
211 0.031
212 0.21 99.4 ＞100
213 0.016 63.1 ＞100
214 0.22 76.8 ＞100
215 0.02 67.0 ＞100
216 ＞1.1
217 ＞1.1
218 ＞1.1
219 0.012 53.7 ＞100
220 0.048
221 ＞1.1
222 0.12 2.5 31.7
223 0.07 87.5 ＞100
224 0.21 100.0 ＞100
225 0.21 104.7 ＞100
226 ＞3.3 4
*: % 저해율(@3 μM)
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.

Claims (14)

  1. 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염:
    [화학식 1]
    Figure pat00016

    상기 화학식 1에서,
    R1은 C6-10 아릴, C3-10 사이클로알킬, 5 내지 10원 헤테로아릴, 또는 3 내지 10원 헤테로사이클릴;
    R2는 C6-10 아릴, C3-10 사이클로알킬, 5 내지 10원 헤테로아릴, 또는 3 내지 10원 헤테로사이클릴;
    R3 내지 R6은 각각 독립적으로 결합, 수소, 시아노, 할로겐, C1-4 알킬, C1-4 알케닐, C1-4 할로알킬, C1-4 히드록시알킬, C1-4 알콕시, C1-3 아실, C1-4 알콕시-C1-4 알킬, C1-4 알콕시-C1-4 알케닐, 3 내지 10원 헤테로사이클릴옥시-C1-4 알킬, 또는 (4,4,5,5-테트라(C1-4 알킬)-1,3-디옥솔라닐)-C1-4 알킬이거나,
    R3과 R4가 서로 연결되어 이들이 결합된 탄소를 포함하여 5원 내지 10원 고리구조를 형성,
    R3 또는 R6 중 하나를 통해 우레아 골격에 연결되고;
    이때, C6-10 아릴, C3-10 사이클로알킬, 5 내지 10원 헤테로아릴, 또는 3 내지 10원 헤테로사이클릴 및 R3과 R4가 서로 연결되어 형성된 고리구조는 비치환 또는 시아노, 히드록시, 카르복실, 옥소, 할로겐, C1-4 알킬, C1-4 알킬티오, C1-4 알콕시, C1-4 알콕시-C1-4 알킬, C1-4 알킬카보닐, C1-4 알콕시카보닐, C1-4 알킬아미노술포닐, C1-4 알킬술포닐아미노, C1-4 히드록시알킬, C1-4 할로알킬, C1-4 알킬아미노, 디(C1-4 알킬)아미노, 및 5원 내지 10원 헤테로아릴로 이루어진 군으로부터 선택되는 하나 이상으로 치환됨.
  2. 제1항에 있어서,
    R1은 페닐, 바이사이클로[1.1.1]펜틸, 디하이드로피리디닐, 이속사졸릴, 피라졸릴, 피리다지닐, 피리디닐, 피리미디닐, 또는 티아디아졸릴인 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
  3. 제1항에 있어서,
    R2는 페닐, 바이사이클로[1.1.1]펜틸, 이미다졸릴, 피리디닐, 또는 피리미디닐인 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
  4. 제1항에 있어서,
    R3은 수소, 브로모, 메틸, 프로페닐. 트리플루오로메틸, 히드록시메틸, 히드록시에틸, 히드록시이소프로필, 히드록시프로필, 히드록시이소부틸, 메톡시, 메톡시에틸, 메톡시메틸, 에톡시에틸, 에톡시에테닐, 또는 (4,4,5,5-테트라메틸-1,3-디옥솔라닐)메틸인 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
  5. 제1항에 있어서,
    R4는 결합, 수소, 시아노, 메틸, 에틸, 이소프로필, 디플루오로메틸, 트리플루오로메틸, 또는 메톡시인 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
  6. 제1항에 있어서,
    R3 및 R4는 서로 연결되어 이들이 결합된 탄소를 포함하여 테트라하이드로티오피라닐(tetrahydrothiopyranyl), 테트라하이드로피라닐(tetrahydropyranyl), 테트라하이드로퓨라닐(tetrahydrofuranyl), 피페리디닐(piperidinyl), 페닐(phenyl), 디옥사닐(dioxanyl), 사이클로펜틸(cyclopentyl), 사이클로헥실(cyclohexyl), 사이클로헵틸(cycloheptyl), 또는 바이사이클로[2.2.1]헵틸을 형성하는 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
  7. 제1항에 있어서,
    R5는 수소, 메틸, 히드록시메틸, 히드록시에틸, 에틸카보닐, 또는 테트라하이드로피라닐옥시에틸인 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
  8. 제1항에 있어서,
    R6은 결합, 또는 메틸인 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
  9. 제1항에 있어서,
    C6-10 아릴, C3-10 사이클로알킬, 5 내지 10원 헤테로아릴, 또는 3 내지 10원 헤테로사이클릴 및 R3과 R4가 서로 연결되어 형성된 고리구조는 비치환 또는 시아노, 히드록시, 카르복실, 옥소, 브로모, 플루오로, 클로로, 메틸, 메틸티오, 메톡시, 메톡시메틸, 메틸카보닐, 메톡시카보닐, 메틸술포닐아미노, 메틸아미노술포닐, 히드록시메틸, 히드록시이소프로필, 디플루오로메틸, 트리플루오로메틸, 메틸아미노, 및 디메틸아미노로 이루어진 군으로부터 선택되는 하나 이상으로 치환된 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
  10. 제1항에 있어서,
    상기 화합물은
    1. 3-(바이사이클로[1.1.1]펜탄-1-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(bicyclo[1.1.1]pentan-1-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    2. 1-(2-메톡시피리미딘-5-일)-3-(피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(1-(2-methoxypyrimidin-5-yl)-3-(pyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    3. 3-(3-플루오로-4-(1H-이미다졸-1-일)피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-fluoro-4-(1H-imidazol-1-yl)pyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    4. 3-(2-브로모-3-플루오로피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-bromo-3-fluoropyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    5. 3-(6-클로로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-chloropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    6. 3-(3-클로로바이사이클로[1.1.1]펜탄-1-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chlorobicyclo[1.1.1]pentan-1-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    7. 3-(3-클로로-4-시아노페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-cyanophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    8. 3-(5-클로로-6-시아노피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(5-chloro-6-cyanopyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    9. 3-(3-클로로-4-이소시아노페닐)-1-((5-시아노-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-isocyanophenyl)-1-((5-cyano-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    10. 3-(3-시아노-4,5-디플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-cyano-4,5-difluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    11. 3-(3-클로로-4,5-디플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4,5-difluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    12. 3-(3-클로로-4,5-디플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4,5-difluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    13. 3-(6-클로로-4,5-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-chloro-4,5-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    14. 3-(3-클로로-4-플루오로페닐)-1-(6-옥소-1,6-디하이드로피리딘-3-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-oxo-1,6-dihydropyridin-3-yl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
    15. 3-(3-클로로-4-플루오로페닐)-1-(2-옥소-1,2-디하이드로피리딘-4-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-oxo-1,2-dihydropyridin-4-yl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
    16. N-(4-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레이도)페닐)메탄술폰아미드(N-(4-(3-(3-chloro-4-fluorophenyl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)ureido)phenyl)methanesulfonamide),
    17. N-(5-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레이도)피리딘-2-일)메탄술폰아미드(N-(5-(3-(3-chloro-4-fluorophenyl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)ureido)pyridin-2-yl)methanesulfonamide),
    18. N-(5-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레이도)피리딘-2-일)메탄술폰아미드(N-(5-(3-(3-chloro-4-fluorophenyl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)ureido)pyridin-2-yl)methanesulfonamide),
    19. N-(4-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레이도)페닐)메탄술폰아미드(N-(4-(3-(3-chloro-4-fluorophenyl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)ureido)phenyl)methanesulfonamide),
    20. 1-(6-아세틸피리딘-3-일)-3-(3-클로로-4-플루오로페닐)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(1-(6-acetylpyridin-3-yl)-3-(3-chloro-4-fluorophenyl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
    21. 1-(6-아세틸피리딘-3-일)-3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(1-(6-acetylpyridin-3-yl)-3-(3-chloro-4-fluorophenyl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
    22. 1-(2-아세틸피리딘-4-일)-3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(1-(2-acetylpyridin-4-yl)-3-(3-chloro-4-fluorophenyl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
    23. 4-(3-(3-클로로-4-플루오로페닐)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레이도)-N-메틸벤젠술폰아미드(4-(3-(3-chloro-4-fluorophenyl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)ureido)-N-methylbenzenesulfonamide),
    24. 3-(3-클로로-4-플루오로페닐)-1-(1-메틸-1H-피라졸-4-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(1-methyl-1H-pyrazol-4-yl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
    25. 3-(3-클로로-4-플루오로페닐)-1-(1-메틸-1H-피라졸-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(1-methyl-1H-pyrazol-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
    26. 3-(3-클로로-4-플루오로페닐)-1-(5-메틸이속사졸-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(5-methylisoxazol-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
    27. 3-(3-클로로-4-플루오로페닐)-1-(3-메틸바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(3-methylbicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    28. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시-4-메틸피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-methoxy-4-methylpyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    29. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시-2,6-디메틸페닐)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxy-2,6-dimethylphenyl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    30. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시-4,6-디메틸피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    31. 메틸 4-(3-(3-클로로-4-플루오로페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레이도)벤조에이트(methyl 4-(3-(3-chloro-4-fluorophenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)ureido)benzoate),
    32. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
    33. 1-((5-아세틸-4,5,6,7-테트라하이드로-1H-피라졸로[4,3-c]피리딘-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)우레아(1-((5-acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)urea),
    34. 1-((1H-피라졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)우레아(1-((1H-pyrazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)urea),
    35. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1-메틸-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((1-methyl-1H-pyrazol-3-yl)methyl)urea),
    36. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1-메틸-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((1-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
    37. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((5-메틸-4,5,6,7-테트라하이드로-1H-피라졸로[4,3-c]피리딘-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((5-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methyl)urea),
    38. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
    39. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1-메틸-1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((1-methyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
    40. 3-(3-클로로-4-플루오로페닐)-1-((5,5-디플루오로-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5,5-difluoro-4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    41. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
    42. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
    43. 1-((1H-인다졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레아(1-((1H-indazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)urea),
    44. 3-(3-클로로-4-플루오로페닐)-1-((5-(히드록시메틸)-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    45. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1,4,6,7-테트라하이드로티오피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)methyl)urea),
    46. 3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
    47. 3-(3-클로로-4-플루오로페닐)-1-((5,5-디메틸-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    48. 3-(3-클로로-4-플루오로페닐)-1-((5-히드록시-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-hydroxy-4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    49. 3-(3-클로로-4-플루오로페닐)-1-((5,5-디옥시도-1,4,6,7-테트라하이드로티오피라노[4,3-c]피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5,5-dioxido-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    50. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((5-메틸-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((5-methyl-1H-pyrazol-3-yl)methyl)urea),
    51. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4,5,6,7-테트라하이드로-1H-4,7-메타노인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)methyl)urea),
    52. 3-((3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레이도)메틸)-4,5,6,7-테트라하이드로-1H-인다졸-5-카르복실산(3-((3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)ureido)methyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid),
    53. 메틸 3-((3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레이도)메틸)-4,5,6,7-테트라하이드로-1H-인다졸-5-카복실레이트(methyl 3-((3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)ureido)methyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate),
    54. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리딘-4-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyridin-4-yl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
    55. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
    56. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4-메틸-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((4-methyl-1H-pyrazol-3-yl)methyl)urea),
    57. 3-(3-클로로-4-플루오로페닐)-1-((4,5-디메틸-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4,5-dimethyl-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    58. 3-(3-클로로-4-플루오로페닐)-1-((5-이소프로필-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-isopropyl-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    59. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((6-메틸-1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((6-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
    60. 3-(3-클로로-4-플루오로페닐)-1-((5-에틸-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-ethyl-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    61. 1-((4-브로모-1H-피라졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(4-메톡시페닐)우레아(1-((4-bromo-1H-pyrazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)urea),
    62. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
    63. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
    64. 3-(3-클로로-4-플루오로페닐)-1-((5-메톡시-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-methoxy-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    65. 3-(3-클로로-4-플루오로페닐)-1-(1-메틸-6-옥소-1,6-디하이드로피리딘-3-일)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
    66. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((1-(2-(테트라하이드로-2H-피란-2-일옥시)에틸)-1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
    67. 3-(3-클로로-4-플루오로페닐)-1-((1-(2-히드록시에틸)-1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((1-(2-hydroxyethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    68. 3-(3-클로로-4-플루오로페닐)-1-((1,3a,4,5,6,7a-헥사하이드로피라노[2,3-c]피라졸-3-일)메틸)-1-(2-메톡시피리딘-4-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((1,3a,4,5,6,7a-hexahydropyrano[2,3-c]pyrazol-3-yl)methyl)-1-(2-methoxypyridin-4-yl)urea),
    69. 3-(3-클로로-4-플루오로페닐)-1-((4,6-디하이드로-1H-퓨로[3,4-c]피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4,6-dihydro-1H-furo[3,4-c]pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    70. 3-(3-클로로-4-플루오로페닐)-1-((4,6-디하이드로-1H-퓨로[3,4-c]피라졸-3-일)메틸)-1-(2-메톡시피리딘-4-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4,6-dihydro-1H-furo[3,4-c]pyrazol-3-yl)methyl)-1-(2-methoxypyridin-4-yl)urea),
    71. 3-(3-클로로-4-플루오로페닐)-1-((5,6-디하이드로-1H-[1,4]디옥시노[2,3-c]피라졸-3-일)메틸)-1-(2-메톡시피리딘-4-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5,6-dihydro-1H-[1,4]dioxino[2,3-c]pyrazol-3-yl)methyl)-1-(2-methoxypyridin-4-yl)urea),
    72. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    73. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리딘-4-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyridin-4-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
    74. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리딘-4-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyridin-4-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    75. 3-(3-클로로-4-플루오로페닐)-1-(5-메톡시피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(5-methoxypyridin-3-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
    76. 3-(3-클로로-4-플루오로페닐)-1-(5-메톡시피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(5-methoxypyridin-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
    77. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(5-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(5-methoxypyridin-3-yl)urea),
    78. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4-메틸-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((4-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    79. 3-(3-클로로-4-플루오로페닐)-1-((1-(히드록시메틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((1-(hydroxymethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    80. 3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    81. 1-((4-브로모-5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((4-bromo-5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
    82. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(메톡시메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-(methoxymethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    83. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-에톡시비닐)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-ethoxyvinyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    84. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    85. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-에톡시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-ethoxyethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    86. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    87. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((4-((4,4,5,5-테트라메틸-1,3-디옥솔란-2-일)메틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((4-((4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    88. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(2-메톡시에틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-(2-methoxyethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    89. 3-(4-클로로-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-chloro-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    90. 3-(3-클로로-4-플루오로페닐)-1-((5-메톡시-4-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-methoxy-4-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    91. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    92. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(2-히드록시프로판-2-일)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-(2-hydroxypropan-2-yl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    93. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(프로프-1-엔-2-일)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-(prop-1-en-2-yl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    94. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리다진-4-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridazin-4-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    95. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시프로필)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    96. 3-(3-클로로-4-플루오로페닐)-1-(6-메톡시피리다진-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridazin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    97. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리다진-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridazin-3-yl)urea),
    98. 1-((4-브로모-5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-클로로-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((4-bromo-5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
    99. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(6-메톡시피리다진-4-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridazin-4-yl)urea),
    100. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-메톡시-1H-피라졸-3-일)메틸)-1-(6-메톡시피리딘-3-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-methoxy-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea),
    101. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시-2-메틸프로필)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    102. 3-(3-클로로-4-플루오로페닐)-1-((4-(2-히드록시프로판-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    103. 3-(3-클로로-4-플루오로페닐)-1-((5-(디플루오로메틸)-4-(2-히드록시-2-메틸프로필)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    104. 3-(3-클로로-4-플루오로페닐)-1-((5-시아노-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((5-cyano-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    105. 3-(3-클로로-4-플루오로페닐)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    106. 3-(6-클로로-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-chloro-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    107. 3-(5-클로로-6-플루오로피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(5-chloro-6-fluoropyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    108. 3-(3-클로로-4-플루오로페닐)-1-((1,3-디메틸-1H-피라졸-5-일)메틸)-1-(4-메톡시페닐)우레아(3-(3-chloro-4-fluorophenyl)-1-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)-1-(4-methoxyphenyl)urea),
    109. 3-(3-클로로-4-플루오로페닐)-1-(3-(2-히드록시프로판-2-일)이속사졸-5-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(3-(2-hydroxypropan-2-yl)isoxazol-5-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
    110. 3-(3-클로로-4-플루오로페닐)-1-(6-(2-히드록시프로판-2-일)피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
    111. 3-(3-클로로-4-플루오로페닐)-1-(6-(2-히드록시프로판-2-일)피리딘-3-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
    112. 3-(3-클로로-4-플루오로페닐)-1-(2-(2-히드록시프로판-2-일)피리딘-4-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-(2-hydroxypropan-2-yl)pyridin-4-yl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
    113. 3-(3-클로로-4-플루오로페닐)-1-(2-(2-히드록시프로판-2-일)피리딘-4-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-(2-hydroxypropan-2-yl)pyridin-4-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
    114. 3-(3-클로로-4-플루오로페닐)-1-(4-히드록시페닐)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(4-hydroxyphenyl)-1-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
    115. 3-(3-클로로-4-플루오로페닐)-1-(3-(2-히드록시프로판-2-일)이속사졸-5-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(3-(2-hydroxypropan-2-yl)isoxazol-5-yl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
    116. 3-(3-클로로-4-플루오로페닐)-1-(3,4-디메톡시페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(3,4-dimethoxyphenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
    117. 3-(3-클로로-4-플루오로페닐)-1-(3,5-디메톡시페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(3,5-dimethoxyphenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
    118. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노-5-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyano-5-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    119. 3-(3-클로로-4-플루오로페닐)-1-(5-시아노-6-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(5-cyano-6-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    120. 3-(3-클로로-4-플루오로페닐)-1-(5-시아노피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(5-cyanopyridin-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
    121. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
    122. 3-(3-클로로-4-플루오로페닐)-1-(2-시아노피리딘-4-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-cyanopyridin-4-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
    123. 3-(3-클로로-4-플루오로페닐)-1-(2-시아노피리딘-4-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-cyanopyridin-4-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
    124. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
    125. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
    126. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    127. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
    128. 3-(3-클로로-4-플루오로페닐)-1-(2-시아노피리딘-4-일)-1-((1,4,5,7-테트라하이드로피라노[3,4-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(2-cyanopyridin-4-yl)-1-((1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)methyl)urea),
    129. 3-(3-클로로-4-플루오로페닐)-1-(5-시아노피리딘-3-일)-1-((1,4,6,7-테트라하이드로피라노[4,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(5-cyanopyridin-3-yl)-1-((1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)methyl)urea),
    130. 3-(3-클로로-4-플루오로페닐)-1-(6-시아노피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    131. 4-(3-(3-클로로-4-플루오로페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레이도)벤조산(4-(3-(3-chloro-4-fluorophenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)ureido)benzoic acid),
    132. 3-(3-클로로-4-플루오로페닐)-1-(이속사졸-3-일)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(isoxazol-3-yl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea),
    133. 3-(3-클로로-4-플루오로페닐)-1-((4,5,6,7-테트라하이드로-1H-인다졸-3-일)메틸)-1-(1,3,4-티아디아졸-2-일)우레아(3-(3-chloro-4-fluorophenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)-1-(1,3,4-thiadiazol-2-yl)urea),
    134. 3-(3-클로로-4-플루오로페닐)-1-(이속사졸-3-일)-1-((1,4,5,6-테트라하이드로사이클로펜타[c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(isoxazol-3-yl)-1-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea),
    135. 3-(3-클로로-4-플루오로페닐)-1-(1H-피라졸-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(1H-pyrazol-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
    136. 3-(3-클로로-4-플루오로페닐)-1-(이속사졸-3-일)-1-((1,4,5,6-테트라하이드로피라노[2,3-c]피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluorophenyl)-1-(isoxazol-3-yl)-1-((1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-3-yl)methyl)urea),
    137. 1-(바이사이클로[1.1.1]펜탄-1-일)-3-(3-클로로-4-플루오로페닐)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(1-(bicyclo[1.1.1]pentan-1-yl)-3-(3-chloro-4-fluorophenyl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    138. 3-(6-클로로-4-(디메틸아미노)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-chloro-4-(dimethylamino)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    139. 3-(3-클로로-4-플루오로-5-메틸페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-chloro-4-fluoro-5-methylphenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    140. 3-(3-클로로-4-플루오로-5-메틸페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-chloro-4-fluoro-5-methylphenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    141. 3-(6-클로로-3-플루오로-4-메틸피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-chloro-3-fluoro-4-methylpyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    142. 3-(6-클로로-5-플루오로-4-메틸피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-chloro-5-fluoro-4-methylpyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    143. 3-(2-클로로피리미딘-5-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-chloropyrimidin-5-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    144. 3-(3-시아노페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-cyanophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    145. 3-(6-시아노피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-cyanopyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    146. 3-(2-시아노피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-cyanopyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    147. 3-(3-시아노페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-cyanophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    148. 3-(6-시아노피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-cyanopyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    149. 3-(3-시아노-4,5-디플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-cyano-4,5-difluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    150. 3-(3-시아노-4,5-디플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-cyano-4,5-difluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    151. 3-(6-시아노-4,5-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-cyano-4,5-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    152. 3-(4-시아노-3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-cyano-3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    153. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(4-시아노-3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(4-cyano-3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)urea),
    154. 3-(3-시아노-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-cyano-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    155. 3-(3-시아노-4-플루오로페닐)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-cyano-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    156. 3-(4-시아노-3-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-cyano-3-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    157. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(3-시아노-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(3-cyano-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
    158. 3-(2-시아노-3-플루오로피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-cyano-3-fluoropyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    159. 3-(3-클로로-4-플루오로페닐)-1-((1,3-디메틸-1H-피라졸-4-일)메틸)-1-(4-메톡시페닐)우레아(3-(3-chloro-4-fluorophenyl)-1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-1-(4-methoxyphenyl)urea),
    160. 3-(6-시아노-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-cyano-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    161. 3-(4-시아노-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-cyano-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    162. 3-(3-시아노-4-플루오로페닐)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-cyano-4-fluorophenyl)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    163. 3-(3-시아노-4-플루오로페닐)-1-(6-메톡시피리다진-4-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-cyano-4-fluorophenyl)-1-(6-methoxypyridazin-4-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    164. 3-(6-시아노-4-(디메틸아미노)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-cyano-4-(dimethylamino)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    165. 3-(2,6-디클로로피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2,6-dichloropyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    166. 3-(2,6-디클로로피리딘-3-일)-1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(2,6-dichloropyridin-3-yl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    167. 3-(3,4-디시아노페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3,4-dicyanophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    168. 3-(3,4-디플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3,4-difluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    169. 3-(3,6-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3,6-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    170. 3-(5,6-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(5,6-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    171. 3-(5,6-디플루오로피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(5,6-difluoropyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    172. 3-(4,5-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4,5-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    173. 3-(3,4-디플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3,4-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    174. 3-(5-(디플루오로메틸)피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(5-(difluoromethyl)pyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    175. 3-(2-(디플루오로메틸)피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-(difluoromethyl)pyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    176. 3-(3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    177. 3-(6-(디플루오로메틸)피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-(difluoromethyl)pyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    178. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)urea),
    179. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(6-(디플루오로메틸)피리딘-2-일)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(6-(difluoromethyl)pyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)urea),
    180. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)urea),
    181. 3-(3-(디플루오로메틸)페닐)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)phenyl)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    182. 1-((4-(2-에톡시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레아(1-((4-(2-ethoxyethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(4-fluorophenyl)-1-(6-methoxypyridin-3-yl)urea),
    183. 3-(6-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    184. 3-(6-플루오로피리딘-3-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-fluoropyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    185. 3-(3-플루오로바이사이클로[1.1.1]펜탄-1-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    186. 3-(2-플루오로피리미딘-5-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-fluoropyrimidin-5-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    187. 3-(4-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    188. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    189. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    190. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
    191. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리딘-3-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)urea),
    192. 3-(4-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    193. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-((4-(2-히드록시에틸)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-((4-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    194. 1-((4-브로모-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((4-bromo-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
    195. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리다진-3-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridazin-3-yl)urea),
    196. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)urea),
    197. 1-((4-브로모-5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((4-bromo-5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
    198. 1-((5-(디플루오로메틸)-4-(2-히드록시프로판-2-일)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-4-(2-hydroxypropan-2-yl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
    199. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-((4-(2-히드록시프로필)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-((4-(2-hydroxypropyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    200. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리다진-3-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridazin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    201. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리다진-4-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridazin-4-yl)urea),
    202. 3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    203. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(6-메톡시피리다진-4-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridazin-4-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    204. 3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    205. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-((4-(2-히드록시-2-메틸프로필)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-((4-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    206. 3-(4-(디플루오로메틸)-3-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(4-(difluoromethyl)-3-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    207. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-((4-(2-히드록시프로판-2-일)-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-((4-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea),
    208. 1-((5-(디플루오로메틸)-4-(2-히드록시-2-메틸프로필)-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-4-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
    209. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea),
    210. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)urea),
    211. 3-(2-(디플루오로메틸)-3-플루오로피리딘-4-일)-1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    212. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)urea),
    213. 3-(3-(디플루오로메틸)-4-플루오로페닐)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    214. 3-(6-(디플루오로메틸)-5-플루오로피리딘-2-일)-1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    215. 1-((5-시아노-1H-피라졸-3-일)메틸)-3-(4-플루오로-3-(트리플루오로메틸)페닐)-1-(2-메톡시피리미딘-5-일)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)urea),
    216. 1,3-비스(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(1,3-bis(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    217. 1-(2-메톡시피리미딘-5-일)-3-(3-메틸바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(1-(2-methoxypyrimidin-5-yl)-3-(3-methylbicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    218. 1-(2-메톡시피리미딘-5-일)-3-(2-(메틸티오)피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(1-(2-methoxypyrimidin-5-yl)-3-(2-(methylthio)pyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),
    219. 1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3,4,5-트리플루오로페닐)우레아(1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3,4,5-trifluorophenyl)urea),
    220. 1-((5-(디플루오로메틸)-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)-3-(3,4,5-트리플루오로페닐)우레아(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)-3-(3,4,5-trifluorophenyl)urea),
    221. 1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3,5,6-트리플루오로피리딘-2-일)우레아(1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3,5,6-trifluoropyridin-2-yl)urea),
    222. 1-(3-메톡시바이사이클로[1.1.1]펜탄-1-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(3,4,5-트리플루오로페닐)우레아(1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3,4,5-trifluorophenyl)urea),
    223. 1-((5-시아노-1H-피라졸-3-일)메틸)-1-(2-메톡시피리미딘-5-일)-3-(3,4,5-트리플루오로페닐)우레아(1-((5-cyano-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)-3-(3,4,5-trifluorophenyl)urea),
    224. 1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(4,5,6-트리플루오로피리딘-2-일)우레아(1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(4,5,6-trifluoropyridin-2-yl)urea),
    225. 1-(2-메톡시피리미딘-5-일)-1-((5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)-3-(6-(트리플루오로메틸)피리딘-2-일)우레아(1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea), 또는
    226. 3-(3-시아노-4-플루오로페닐)-1-(2-메톡시피리미딘-5-일)-1-((1-프로피오닐-5-(트리플루오로메틸)-1H-피라졸-3-일)메틸)우레아(3-(3-cyano-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((1-propionyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)인 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
  11. 제1항 내지 제10항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 캡시드 조립(capsid assembly) 저해용 조성물.
  12. 제1항 내지 제10항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 항바이러스 조성물.
  13. 제1항 내지 제10항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 바이러스 감염 질환의 예방 또는 치료용 약학적 조성물.
  14. 제13항에 있어서,
    상기 바이러스 감염 질환은 B형 간염 바이러스(hepatitis B virus; HBV), C형 간염 바이러스(hepatitis C virus; HCV), 또는 인간 면역결핍 바이러스(human immunodeficiency virus; HIV)에 의한 감염 질환인 것인, 약학적 조성물.
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