TWI835344B - 新穎蛋白殼組裝抑制劑 - Google Patents
新穎蛋白殼組裝抑制劑 Download PDFInfo
- Publication number
- TWI835344B TWI835344B TW111138674A TW111138674A TWI835344B TW I835344 B TWI835344 B TW I835344B TW 111138674 A TW111138674 A TW 111138674A TW 111138674 A TW111138674 A TW 111138674A TW I835344 B TWI835344 B TW I835344B
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- Taiwan
- Prior art keywords
- methyl
- urea
- pyrazol
- fluorophenyl
- chloro
- Prior art date
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- 210000000234 capsid Anatomy 0.000 title abstract 2
- 239000003112 inhibitor Substances 0.000 title description 3
- -1 pyrazolylmethylurea derivatives Chemical class 0.000 claims abstract description 530
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- 230000003612 virological effect Effects 0.000 claims abstract description 15
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 550
- 239000004202 carbamide Substances 0.000 claims description 346
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 147
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims description 84
- 108090000623 proteins and genes Proteins 0.000 claims description 51
- 102000004169 proteins and genes Human genes 0.000 claims description 50
- 150000001875 compounds Chemical class 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 37
- 241000700721 Hepatitis B virus Species 0.000 claims description 20
- PYXNITNKYBLBMW-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrazole Chemical compound FC(F)(F)C1=CC=NN1 PYXNITNKYBLBMW-UHFFFAOYSA-N 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 12
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 10
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 8
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
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- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 claims 1
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 128
- 239000000203 mixture Substances 0.000 description 68
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- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 5
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- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 5
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Abstract
本發明涉及一系列新穎的吡唑基甲基脲衍生物及其用於抑制蛋白殼組裝及透過該抑制來預防或治療病毒性疾病的用途。
Description
本發明涉及一系列新穎的吡唑基甲基脲(pyrazolylmethylurea)衍生物及其抑制蛋白殼組裝及透過該抑制預防或治療病毒性疾病的用途。
慢性B型肝炎病毒(HBV)感染係一種全球重大健康問題,且可造成嚴重健康問題如肝硬化或肝癌。根據近期WHO報告,預估全球有2.57億人患有慢性HBV感染,且每年有134萬人因肝炎相關併發症死亡。迄今為止,經核可用於治療HBV的物質包含干擾素(IFN,非聚乙二醇化或聚乙二醇化)及核(苷)酸結構類似物,蘭弗定(lamivudine)、阿德福韋(adefovir)、恩替卡韋(entecavir)、泰諾福韋(tenofovir)等等。IFN治療誘導HBV複製的抑制及肝病緩解,而核(苷)酸藥物抑制反轉錄酶及DNA聚合酶活性。核(苷)酸結構類似物有效地控制病毒增殖,但對HBV而言為關鍵因素之病毒基因,以如同宿主迷你染色體形式之cccDNA的形式一同存在,因此難以將其完全排除。所以,HBV帶原者常因須長期使用藥物來預防新病毒的成長而發生抗藥性。為克服此未經滿足之醫療需求,需要發現有效且安全針對新穎分子標的之抗HBV藥物。
該HBV核心蛋白於病毒生命週期中扮演重要的角色。由核心蛋白組裝形成的HBV蛋白殼,將病毒前基因體RNA(pgRNA)、反轉錄酶及DNA聚合酶封裝在一起,以調節pgRNA之反轉錄及核酸蛋白殼之回收。核心蛋白調節病毒基因體的運輸及細胞核釋出,參與在cccDNA表觀遺傳性調節中,以調節宿主基因表現。因此,依據HBV複製循環,核心蛋白作用的調節以及預防由核心蛋白組成之蛋白殼形成之靶向抗HBV藥劑之發現,已被廣泛研究。
數個研究中心及製藥公司已開發出蛋白殼組裝調節劑。一種雜芳基二氫嘧啶(HAP)結構類似物Bay-41-4109係第一個進入臨床試驗的蛋白殼組裝抑制劑,且誘發異常蛋白殼形成及蛋白殼蛋白聚集。由於蛋白殼蛋白組裝不正確,在HepG2.2.15細胞中觀察到HBV核心蛋白被蛋白酶體降解(蛋白酶體介導的降解),同時以抑制HBV DNA複製使HBV DNA減量。GLS-4是一種具有同Bay-41-4109同樣作用機制的第二代HAP結構類似物,且與利托那維爾(ritonavir,RTV)一起處於第二期臨床試驗,以預防GLS-4誘發之CYP酶。據同一批研究者所報告,雖然HEC72702犧牲一些體外效力,但具有減少之CYP酶誘發、較低之hERG K+通道抑制及改良的口服生體可用率。
有不同於HAP的作用機制之其他類型的蛋白殼組裝調節劑AT130、NVR 3-778及JNJ-632亦已被報告。例如,當蛋白殼以NVR 3-778處理,蛋白殼正常形成,但取得的是不包含前基因體RNA(pgRNA)、反轉錄酶及DNA聚合酶的空蛋白殼。JNJ-632已被報告為新穎胺磺醯基苯甲醯胺(sulfamoylbenzamide)蛋白殼組裝調節劑,且其經優化的類似物JNJ-6379目前處於第二期臨床試驗。近期,GIST研究者Kang,J.A.等人報告一種將經FDA核可的抗黴菌藥物ciclopirox舊藥新用為口服可用蛋白殼組裝抑制劑。
[引用文獻]
[專利文件]
WO 2017/210545;以及
US 2017/0355708
[非專利文件]
Kang, J. A.等人,Nat. Commun., 2019, 10(2184): 1-14
作為深入研究努力發現可抑制蛋白殼組裝以抑制病毒感染的新穎小分子化合物之結果,本發明人已確認一系列具有可抑制蛋白殼組裝以抑制病毒感染之活性的吡唑基甲基脲衍生物,從而完成本發明。
揭示於本揭露內容中的各說明內容及實施態樣亦可被應用於其他說明內容及實施態樣。即,本揭露內容中所揭示的各種要素的所有組合皆落於本發明的範圍內。另外,本發明的範圍並不受限於以下具體說明。
此外,所屬技術領域中具有通常知識者將能夠在使用不超過常規實驗的情形下理解或是能夠確認許多均等於本文所述之本發明的特定實施態樣之內容。再者,這些均等內容應被詮釋為落於本發明的範圍中。
另外,當此說明書各處的段落指出「包含」一要素時,其應被理解為可進一步包含其他要素,而非排除其他要素,除非另有具體描述相反內容。
下文將詳細描述本發明。
本發明的第一方面提供一種化學式1由以下化學式1所表示之化合物或該化合物藥學上可接受的鹽:
在化學式1中,
R1為C6-10芳基、C3-10環烷基、5-至10-員雜芳基或3-至10-員雜環基;
R2為C6-10芳基、C3-10環烷基、5-至10-員雜芳基或3-至10-員雜環基;
R3及R4各自獨立地為鍵、氫、氰基、鹵基、C1-4烷基、C1-4烯基、C1-4鹵烷基、C1-4羥烷基、C1-4烷氧基、C1-3醯基、C1-4烷氧基-C1-4烷基、C1-4烷氧基-C1-4烯基、3-至10-員雜環氧基-C1-4烷基或(4,4,5,5-四(C1-4烷基)-1,3-二氧戊環基)-C1-4烷基,或
R3及R4彼此連接以形成5-至10-員環狀結構,其包含鍵結R3及R4的碳;
化學式1透過R3或R6任一者連接至脲主鏈;及
此處,C6-10芳基、C3-10環烷基、5-至10-員雜芳基或3-至10-員雜環基及R3及R4彼此連接以形成環狀結構,該環狀結構為未經取代或經選自由氰基、羥基、羧基、側氧基(oxo)、鹵基、C1-4烷基、C1-4烷硫基、C1-4烷氧基、C1-4烷氧基-C1-4烷基、C1-4烷基羰基、C1-4烷氧羰基(alkoxycarbonyl)、C1-4烷基胺基磺醯基(alkylaminosulfonyl)、C1-4烷基磺醯基胺基(alkylsulfonylamino)、C1-4羥烷基、C1-4鹵烷基、C1-4烷胺基、二(C1-4烷基)胺基及5-至10-員雜芳基所組成之群組的一者或更多者所取代。
例如,於化學式1中,R1可為苯基、雙環[1.1.1]戊基(bicyclo[1.1.1]pentyl)、二氫吡啶基(dihydropyridinyl)、異噁唑基(isoxazolyl)、吡唑基(pyrazolyl)、嗒嗪基(pyridazinyl)、吡啶基(pyridinyl)、嘧啶基(pyrimidinyl)或噻二唑基(thiadiazolyl),但不限於此。
例如,於化學式1中,R2可為苯基、雙環[1.1.1]戊基、咪唑基(imidazolyl)、吡啶基或嘧啶基,但不限於此。
例如,於化學式1中,R3可為氫、溴基、甲基、丙烯基、三氟甲基、羥甲基、羥乙基、羥異丙基、羥丙基、羥異丁基、甲氧基、甲氧基乙基、甲氧基甲基、乙氧乙基、乙氧乙烯基或(4,4,5,5-四甲基-1,3-二氧環戊基)甲基((4,4,5,5-tetramethyl-1,3-dioxolanyl)methyl),但不限於此。
例如,於化學式1中,R4可為鍵、氫、氰基、甲基、乙基、異丙基、二氟甲基、三氟甲基或甲氧基,但不限於此。
例如,於化學式1中,R3及R4可彼此連接以形成四氫噻喃基(tetrahydrothiopyranyl)、四氫哌喃基(tetrahydropyranyl)、四氫呋喃基(tetrahydrofuranyl)、哌啶基(piperidinyl)、苯基、二噁烷基(dioxanyl)、環戊基、環己基、環庚基或雙環[2.2.1]庚基,其包含鍵結R3及R4的碳,但不限於此。
例如,於化學式1中,R5可為氫、甲基、羥甲基、羥乙基、乙基羰基、四氫哌喃基氧乙基(tetrahydropyranyloxyethyl)或嘧啶基,但不限於此。
例如,於化學式1中,R6可為鍵或甲基,但不限於此。
例如,於化學式1中,C6-10芳基、C3-10環烷基、5-至10-員雜芳基或3-至10-員雜環基及R3及R4彼此連接以形成環狀結構,該環狀結構可為未經
取代或經選自由氰基、羥基、羧基、側氧基、溴基、氟基、氯基、甲基、甲硫基、甲氧基、甲氧基甲基、甲基羰基、甲氧基羰基、甲基磺醯基胺基(methylsulfonylamino)、甲基胺基磺醯基(methylaminosulfonyl)、羥基甲基、羥異丙基、二氟甲基、三氟甲基、甲胺基及二甲胺基所組成之群組的一者或更多者所取代,但不限於此。
具體而言,該化合物可為
1. 3-(雙環[1.1.1]戊-1-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-甲氧基嘧啶-5-基)-3-(嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(1-(2-methoxypyrimidin-5-yl)-3-(pyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
3. 3-(3-氟基-4-(1H-咪唑-1-基)吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-溴基-3-氟吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(2-bromo-3-fluoropyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
5. 3-(6-氯吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(6-chloropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
6. 3-(3-氯基雙環[1.1.1]戊-1-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-氯基-4-氰基苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-cyanophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
8. 3-(5-氯基-6-氰基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(5-chloro-6-cyanopyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
9. 3-(3-氯基-4-異氰苯基)-1-((5-氰基-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(3-(3-chloro-4-isocyanophenyl)-1-((5-cyano-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea)、
10. 3-(3-氰基-4,5-二氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(3-(3-cyano-4,5-difluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea)、
11. 3-(3-氯基-4,5-二氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4,5-difluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
12. 3-(3-氯基-4,5-二氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(3-(3-chloro-4,5-difluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea)、
13. 3-(6-氯基-4,5-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-側氧基-1,6-二氫吡啶-3-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(2-側氧基-1,2-二氫吡啶-4-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲基)苯基)甲烷磺胺(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-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲基)吡啶-2-基)甲烷磺胺(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-氯基-4-氟苯基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲基)吡啶-2-基)甲烷磺胺(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-氯基-4-氟苯基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲基)苯基)甲烷磺胺(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-乙醯基吡啶-3-基)-3-(3-氯基-4-氟苯基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲(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-乙醯基吡啶-3-基)-3-(3-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲(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-乙醯基吡啶-4-基)-3-(3-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲基)-N-甲基苯磺醯胺(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-氯基-4-氟苯基)-1-(1-甲基-1H-吡唑-4-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(1-甲基-1H-吡唑-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(5-甲基異噁唑-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(3-甲基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(2-甲氧基-4-甲基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(2-methoxy-4-methylpyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
29. 3-(3-氯基-4-氟苯基)-1-(4-甲氧基-2,6-二甲苯基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-methoxy-2,6-dimethylphenyl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
30. 3-(3-氯基-4-氟苯基)-1-(2-甲氧基-4,6-二甲嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
31. 4-(3-(3-氯基-4-氟苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲基)苄酸甲酯(methyl 4-(3-(3-chloro-4-fluorophenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)ureido)benzoate)、
32. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((4,5,6,7-tetrah舛ro-1H-indazol-3-yl)methyl)urea)、
33. 1-((5-乙醯基-4,5,6,7-四氫-1H-吡唑並[4,3-c]吡啶-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)脲(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-吡唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)脲(1-((1H-pyrazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)urea)、
35. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1-甲基-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((1-methyl-1H-pyrazol-3-yl)methyl)urea)、
36. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1-甲基-4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5-甲基-4,5,6,7-四氫-1H-吡唑並[4,3-c]吡啶-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1-甲基-1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-((5,5-二氟-4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(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-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲(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-吲唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲(1-((1H-indazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)urea)、
44. 3-(3-氯基-4-氟苯基)-1-((5-(羥甲基)-4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(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-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1,4,6,7-四氫噻喃[4,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea)、
47. 3-(3-氯基-4-氟苯基)-1-((5,5-二甲基-4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(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-氯基-4-氟苯基)-1-((5-羥基-4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(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-氯基-4-氟苯基)-1-((5,5-二氧基-1,4,6,7-四氫噻喃[4,3-c]吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(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-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5-甲基-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((5-methyl-1H-pyrazol-3-yl)methyl)urea)、
51. 3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4,5,6,7-四氫-1H-4,7-甲橋吲唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲基)甲基)-4,5,6,7-四氫-1H-吲唑-5-羧酸(3-((3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)ureido)methyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid)、
53. 3-((3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲基)甲基)-4,5,6,7-四氫-1H-吲唑-5-羧酸甲酯(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-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4-甲基-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((4-methyl-1H-pyrazol-3-yl)methyl)urea)、
57. 3-(3-氯基-4-氟苯基)-1-((4,5-二甲基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((4,5-dimethyl-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea)、
58. 3-(3-氯基-4-氟苯基)-1-((5-異丙基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-isopropyl-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea)、
59. 3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((6-甲基-1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-((5-乙基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-ethyl-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea)、
61. 1-((4-溴基-1H-吡唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)脲(1-((4-bromo-1H-pyrazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)urea)、
62. 3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-((5-甲氧基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-methoxy-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea)、
65. 3-(3-氯基-4-氟苯基)-1-(1-甲基-6-側氧基-1,6-二氫吡啶-3-基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1-(2-(四氫-2H-哌喃-2-基氧基)乙基)-1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-((1-(2-羥乙基)-1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(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-氯基-4-氟苯基)-1-((1,3a,4,5,6,7a-六氫哌喃並[2,3-c]吡唑-3-基)甲基)-1-(2-甲氧基吡啶-4-基)脲(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-氯基-4-氟苯基)-1-((4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(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-氯基-4-氟苯基)-1-((4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)-1-(2-甲氧基吡啶-4-基)脲(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-氯基-4-氟苯基)-1-((5,6-二氫-1H-[1,4]二咢辛[2,3-c]吡唑-3-基)甲基)-1-(2-甲氧基吡啶-4-基)脲(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-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea)、
73. 3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyridin-4-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
75. 3-(3-氯基-4-氟苯基)-1-(5-甲氧基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(5-甲氧基吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(5-甲氧基吡啶-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(5-methoxypyridin-3-yl)urea)、
78. 3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4-甲基-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((4-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
79. 3-(3-氯基-4-氟苯基)-1-((1-(羥甲基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((1-(hydroxymethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea)、
80. 3-(3-氯基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
81. 1-((4-溴基-5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲(1-((4-bromo-5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea)、
82. 3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(甲氧基甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-(methoxymethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea)、
83. 3-(3-氯基-4-氟苯基)-1-((4-(2-乙氧乙烯基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(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-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea)、
85. 3-(3-氯基-4-氟苯基)-1-((4-(2-乙氧乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(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-氯基-4-氟苯基)-1-((4-(2-羥乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(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-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4-((4,4,5,5-四甲基-1,3-二氧環戊-2-基)甲基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-甲氧基乙基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(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-氯基-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(4-chloro-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
90. 3-(3-氯基-4-氟苯基)-1-((5-甲氧基-4-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-methoxy-4-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea)、
91. 3-(3-氯基-4-氟苯基)-1-((4-(2-羥乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(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-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-羥基丙-2-基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(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-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(丙-1-烯-2-基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(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-氯基-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridazin-4-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
95. 3-(3-氯基-4-氟苯基)-1-((4-(2-羥丙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(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-氯基-4-氟苯基)-1-(6-甲氧嗒嗪-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridazin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
97. 3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧嗒嗪-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridazin-3-yl)urea)、
98. 1-((4-溴基-5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲(1-((4-bromo-5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea)、
99. 3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧嗒嗪-4-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridazin-4-yl)urea)、
100. 3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-甲氧基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-methoxy-1H-pyrazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea)、
101. 3-(3-氯基-4-氟苯基)-1-((4-(2-羥基-2-甲基丙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(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-氯基-4-氟苯基)-1-((4-(2-羥基丙-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(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-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-羥基-2-甲基丙基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(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-氯基-4-氟苯基)-1-((5-氰基-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-cyano-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea)、
105. 3-(3-氯基-4-氟苯基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-氯基-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(6-chloro-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
107. 3-(5-氯基-6-氟吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(5-chloro-6-fluoropyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
108. 3-(3-氯基-4-氟苯基)-1-((1,3-二甲基-1H-吡唑-5-基)甲基)-1-(4-甲氧苯基)脲(3-(3-chloro-4-fluorophenyl)-1-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)-1-(4-methoxyphenyl)urea)、
109. 3-(3-氯基-4-氟苯基)-1-(3-(2-羥基丙-2-基)異噁唑-5-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-(2-羥基丙-2-基)吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-(2-羥基丙-2-基)吡啶-3-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(2-(2-羥基丙-2-基)吡啶-4-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(2-(2-羥基丙-2-基)吡啶-4-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(4-羥基苯基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-hydroxyphenyl)-1-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea)、
115. 3-(3-氯基-4-氟苯基)-1-(3-(2-羥基丙-2-基)異噁唑-5-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(3,4-二甲氧苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(3,4-dimethoxyphenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea)、
117. 3-(3-氯基-4-氟苯基)-1-(3,5-二甲氧苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(3,5-dimethoxyphenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea)、
118. 3-(3-氯基-4-氟苯基)-1-(6-氰基-5-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(6-cyano-5-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
119. 3-(3-氯基-4-氟苯基)-1-(5-氰基-6-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(5-cyano-6-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
120. 3-(3-氯基-4-氟苯基)-1-(5-氰基吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
127. 3-(3-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(5-氰基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(6-cyanopyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
131. 4-(3-(3-氯基-4-氟苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲基)苄酸(4-(3-(3-chloro-4-fluorophenyl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)ureido)benzoic acid)、
132. 3-(3-氯基-4-氟苯基)-1-(異噁唑-3-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(isoxazol-3-yl)-1-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)urea)、
133. 3-(3-氯基-4-氟苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(1,3,4-噻二唑-2-基)脲(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-氯基-4-氟苯基)-1-(異噁唑-3-基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(isoxazol-3-yl)-1-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)urea)、
135. 3-(3-氯基-4-氟苯基)-1-(1H-吡唑-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲(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-氯基-4-氟苯基)-1-(異噁唑-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲(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-(雙環[1.1.1]戊-1-基)-3-(3-氯基-4-氟苯基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-氯基-4-(二甲胺基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-氯基-4-氟基-5-甲基苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(3-(3-chloro-4-fluoro-5-methylphenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea)、
140. 3-(3-氯基-4-氟基-5-甲基苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-chloro-4-fluoro-5-methylphenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
141. 3-(6-氯基-3-氟基-4-甲基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-氯基-5-氟基-4-甲基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-氯基嘧啶-5-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(2-chloropyrimidin-5-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
144. 3-(3-氰基苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-cyanophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
145. 3-(6-氰基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(6-cyanopyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
146. 3-(2-氰基吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(2-cyanopyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
147. 3-(3-氰基苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(3-(3-cyanophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea)、
148. 3-(6-氰基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(6-cyanopyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
149. 3-(3-氰基-4,5-二氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-cyano-4,5-difluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
150. 3-(3-氰基-4,5-二氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(3-(3-cyano-4,5-difluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea)、
151. 3-(6-氰基-4,5-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-氰基-3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(4-cyano-3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
153. 1-((5-氰基-1H-吡唑-3-基)甲基)-3-(4-氰基-3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)脲(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(4-cyano-3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)urea)、
154. 3-(3-氰基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-cyano-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
155. 3-(3-氰基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(3-(3-cyano-4-fluorophenyl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea)、
156. 3-(4-氰基-3-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(4-cyano-3-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
157. 1-((5-氰基-1H-吡唑-3-基)甲基)-3-(3-氰基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(3-cyano-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea)、
158. 3-(2-氰基-3-氟吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(2-cyano-3-fluoropyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
159. 3-(3-氯基-4-氟苯基)-1-((1,3-二甲基-1H-吡唑-4-基)甲基)-1-(4-甲氧苯基)脲(3-(3-chloro-4-fluorophenyl)-1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-1-(4-methoxyphenyl)urea)、
160. 3-(6-氰基-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(6-cyano-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
161. 3-(4-氰基-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(4-cyano-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
162. 3-(3-氰基-4-氟苯基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-氰基-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-cyano-4-fluorophenyl)-1-(6-methoxypyridazin-4-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
164. 3-(6-氰基-4-(二甲胺基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-(2,6-二氯吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(2,6-dichloropyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
166. 3-(2,6-二氯吡啶-3-基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(3-(2,6-dichloropyridin-3-yl)-1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)urea)、
167. 3-(3,4-二氰苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3,4-dicyanophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
168. 3-(3,4-二氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3,4-difluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
169. 3-(3,6-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3,6-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
170. 3-(5,6-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(5,6-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
171. 3-(5,6-二氟吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(5,6-difluoropyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
172. 3-(4,5-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(4,5-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
173. 3-(3,4-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3,4-difluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
174. 3-(5-(二氟甲基)吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(5-(difluoromethyl)pyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
175. 3-(2-(二氟甲基)吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(2-(difluoromethyl)pyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
176. 3-(3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
177. 3-(6-(二氟甲基)吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(6-(difluoromethyl)pyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
178. 1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)脲(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)urea)、
179. 1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(6-(二氟甲基)吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)脲(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(6-(difluoromethyl)pyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)urea)、
180. 1-((5-氰基-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)脲(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)urea)、
181. 3-(3-(二氟甲基)苯基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-乙氧乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲(1-((4-(2-ethoxyethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(4-fluorophenyl)-1-(6-methoxypyridin-3-yl)urea)、
183. 3-(6-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(6-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
184. 3-(6-氟吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(6-fluoropyridin-3-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
185. 3-(3-氟雙環[1.1.1]戊-1-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-氟嘧啶-5-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(2-fluoropyrimidin-5-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
187. 3-(4-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(4-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
188. 3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
189. 3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
190. 1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea)、
191. 1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)urea)、
192. 3-(4-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(4-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
193. 3-(3-(二氟甲基)-4-氟苯基)-1-((4-(2-羥乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(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-溴基-5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲(1-((4-bromo-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea)、
195. 1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧嗒嗪-3-基)脲(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridazin-3-yl)urea)、
196. 1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)脲(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)urea)、
197. 1-((4-溴基-5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲(1-((4-bromo-5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea)、
198. 1-((5-(二氟甲基)-4-(2-羥基丙-2-基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲(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-(二氟甲基)-4-氟苯基)-1-((4-(2-羥丙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(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-(二氟甲基)-4-氟苯基)-1-(6-甲氧嗒嗪-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridazin-3-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
201. 1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)脲(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridazin-4-yl)urea)、
202. 3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
203. 3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-(difluoromethyl)-4-fluorophenyl)-1-(6-methoxypyridazin-4-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
204. 3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
205. 3-(3-(二氟甲基)-4-氟苯基)-1-((4-(2-羥基-2-甲基丙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(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-(二氟甲基)-3-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(4-(difluoromethyl)-3-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
207. 3-(3-(二氟甲基)-4-氟苯基)-1-((4-(2-羥基丙-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲(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-(二氟甲基)-4-(2-羥基-2-甲基丙基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲(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-氰基-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)urea)、
210. 1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)脲(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidiu-5-yl)urea)、
211. 3-(2-(二氟甲基)-3-氟吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(2-(difluoromethyl)-3-fluoropyridin-4-yl)-1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
212. 1-((5-氰基-1H-吡唑-3-基)甲基)-3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)脲(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-(2-methoxypyrimidin-5-yl)urea)、
213. 3-(3-(二氟甲基)-4-氟苯基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-(二氟甲基)-5-氟吡啶-2-基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(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-氰基-1H-吡唑-3-基)甲基)-3-(4-氟基-3-(三氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)脲(1-((5-cyano-1H-pyrazol-3-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-methoxypyrimidin-5-yl)urea)、
216. 1,3-雙(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(1,3-bis(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
217. 1-(2-甲氧基嘧啶-5-基)-3-(3-甲基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(1-(2-methoxypyrimidin-5-yl)-3-(3-甲基雙環[1.1.1]戊-1-基)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
218. 1-(2-甲氧基嘧啶-5-基)-3-(2-(甲硫基)嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(1-(2-methoxypyrimidin-5-yl)-3-(2-(methylthio)pyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea)、
219. 1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(3,4,5-三氟苯基)脲(1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3,4,5-trifluorophenyl)urea)、
220. 1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)-3-(3,4,5-三氟苯基)脲(1-((5-(difluoromethyl)-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)-3-(3,4,5-trifluorophenyl)urea)、
221. 1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(3,5,6-三氟吡啶-2-基)脲(1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(3,5,6-trifluoropyridin-2-yl)urea)、
222. 1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(3,4,5-三氟苯基)脲(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-氰基-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)-3-(3,4,5-三氟苯基)脲(1-((5-cyano-1H-pyrazol-3-yl)methyl)-1-(2-methoxypyrimidin-5-yl)-3-(3,4,5-trifluorophenyl)urea)、
224. 1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(4,5,6-三氟吡啶-2-基)脲(1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(4,5,6-trifluoropyridin-2-yl)urea)、
225. 1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(6-(三氟甲基)吡啶-2-基)脲(1-(2-methoxypyrimidin-5-yl)-1-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea)、或
226. 3-(3-氰基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((1-丙醯基-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(3-(3-cyano-4-fluorophenyl)-1-(2-methoxypyrimidin-5-yl)-1-((1-propionyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)urea),但不限於此。
本發明的化合物可以藥學上可接受的鹽的形式存在。作為鹽,以藥學上可接受的游離酸形成之酸加成鹽是有用的。如本文中使用,術語「藥學上可接受的鹽」是指化合物的所有有機或無機加成鹽,其具有對病患相對無毒且無害卻展現有效作用的濃度,且其引發的副作用並不減少由化學式1所代表的化合物之有益功效。
經由常規方法製備酸加成鹽,例如,將化合物溶於過量的水性酸溶液中,並利用水混溶有機溶劑如甲醇、乙醇、丙酮或乙腈沉澱此鹽。可加熱水中等莫耳量之化合物及酸或醇(例如,乙二醇單甲醚(glycol monomethyl ether)),接著該混合物可經蒸發至乾燥,或可抽氣過濾該經沉澱的鹽。
此處,有機酸及無機酸可作為游離酸使用。鹽酸、磷酸、硫酸、硝酸及酒石酸等,可作為無機酸使用。甲磺酸(methanesulfonic acid)、對甲苯磺酸(p-toluenesulfonic acid)、乙酸、三氟乙酸(trifluoroacetic acid)、順丁烯二酸(maleic acid)、丁二酸(succinic acid)、草酸(oxalic acid)、苄酸(benzoic acid)、酒石酸(tartaric acid)、反丁烯二酸(fumaric acid)、苦杏仁酸(mandelic acid)、丙酸(propionic acid)、檸檬酸、乳酸、乙醇酸(glycolic acid)、葡萄糖酸(gluconic acid)、半乳醣醛酸(galacturonic acid)、麩胺酸(glutamic acid)、戊二酸(glutaric acid)、葡萄糖醛酸(glucuronic acid)、天冬胺酸(aspartic acid)、抗壞血酸(ascorbic acid)、碳酸(carbonic acid)、香草酸(vanillic acid)、氫碘酸(hydroiodic acid)等,可作為有機酸使用。游離酸不限於此。
可使用鹼製備藥學上可接受的金屬鹽。鹼金屬鹽或鹼土金屬鹽係藉由,例如,將化合物溶解於過量的鹼金屬氫氧化物或鹼土金屬氫氧化物溶液中,將不溶解的化合物鹽進行過濾,接著將濾液蒸發及乾燥所取得的。於此,鈉鹽、鉀鹽或鈣鹽為藥學上合適的金屬鹽,但金屬鹽不限於此。相應的銀鹽可由鹼金屬或鹼土金屬鹽與合適的銀鹽(例如,硝酸銀)反應所取得。
本發明的化合物之藥學上可接受的鹽包含酸性或鹼性基團的鹽,除非另有說明,否則這些鹽可存在於由化學式1所代表的化合物中。例如,該藥學上可接受的鹽可包含羥基之鈉鹽、鈣鹽及鉀鹽等。其他藥學上可接受的胺基鹽可包含氫溴酸鹽(hydrobromide)、硫酸鹽、硫酸氫鹽、磷酸鹽、磷酸氫鹽、磷酸二氫鹽、乙酸鹽、丁二酸鹽(succinate)、檸檬酸鹽、酒石酸鹽(tartrate)、乳酸鹽、杏仁酸鹽(mandelate)、甲烷磺酸鹽(methanesulfonate or mesylate)及
對甲苯磺酸鹽(p-toluenesulfonate or tosylate),且這些鹽可藉由本領域習知的鹽類製備方法來製備。
吡唑基甲基脲衍生化合物的藥學上可接受之鹽以及展現均等於該吡唑基甲基脲衍生化合物之藥學活性的吡唑基甲基脲衍生化合物的所有鹽類,皆可作為本發明的吡唑基甲基脲衍生化合物的鹽類,而不受限制地使用。
該根據本發明化學式1代表的化合物,不但包含其藥學上可接受的鹽,亦包含溶劑化物,諸如不限於由鹽類及全部可能的立體異構物所製備之水合物。該由化學式1代表的化合物之溶劑化物及立體異構物,可由本領域習知的方法由化學式1代表的化合物所製備。
再者,該根據本發明化學式1代表的化合物可製備為結晶型式或非晶型式,且當以結晶型式製備時可任選的為水合的或溶劑化的。在本發明中,可包含含有各種量的水以及由化學式1代表的化合物的化學計量水合物之化合物。該根據本發明化學式1代表的化合物之溶劑化物包含化學計量溶劑化物及非化學計量溶劑化物兩者。
本發明的第二方面提供一種製備該第一方面化合物或其藥學上可接受的鹽的方法,其包含將吡唑基甲基前驅物與R1前驅物反應之第一步驟;以及將前述步驟取得的化合物與R2前驅物反應之第二步驟。
例如,該第一步驟的反應可藉由下列反應方案1至3任何一者進行,但不限於此:
例如,該第二步驟的反應可藉由下列反應方案4至7任何一者進行,但不限於此:
在一系列反應方案中,吡唑基為未經取代或經取代之吡唑環,其
氮原子可包含保護基,R1’及R2’分別與R1’及R2’或其前驅物相同,且X為鹵素或另一種脫離基。
本發明的第三方面提供一種用於蛋白殼組裝抑制的組成物,含有第一方面的化合物或其藥學上可接受的鹽。
如本文中使用,術語「第一方面的化合物」及「藥學上可接受的鹽」係如上文所述。
如本文中使用,術語「蛋白殼」是指一種病毒的蛋白質建構體,其圍繞反轉錄所需的基因物質及酵素,且由稱為單元體(protomer)之多個寡聚(重複)蛋白質結構次單元所組成。可觀察到其三度空間型態可對應或不可對應至單獨蛋白質之次單位,稱為殼粒(capsomere)。構成蛋白殼的蛋白質稱為蛋白殼蛋白或病毒外殼蛋白(VCP)。該蛋白殼及其基因體稱為核酸蛋白殼。該蛋白殼依其構造大致分類,且大部分病毒具有螺旋或二十面體構造之蛋白殼。一些病毒,如噬菌體,因為彈性及靜電的限制發展出更複雜的結構。蛋白殼的表面可由一種或更多種蛋白質所組成;例如,口蹄疫病毒蛋白殼具有由VP1-3之3種蛋白質所組成的表面。當病毒感染細胞並開始自體複製,利用該細胞的蛋白質生物合成機制,合成新蛋白殼次單元。由蛋白殼封裝的基因物質可為RNA或DNA,但不限於此。
例如,當感染病毒時,宿主細胞必須快速產生上千個相同於原始病毒的拷貝。當病毒不在被感染的細胞內或正在感染細胞的過程中時,該病毒以(i)基因物質(即,編碼病毒自身增殖所需的蛋白質之DNA或RNA長分子);(ii)蛋白殼(其係包圍且保護基因物質之蛋白外殼);及可選地(iii)獨立顆粒或病毒粒子(由脂質外膜包圍並界定病毒身分)之形式存在。
本發明的第四方面提供一種抗病毒組成物,含有該第一方面的化合物或其藥學上可接受的鹽作為活性成分。
如本文中使用,術語「第一方面的化合物」及「藥學上可接受的鹽」如上文所述。
本發明的第五方面提供一種預防或治療病毒性疾病的醫藥組成物,含有該第一方面的化合物或其藥學上可接受的鹽作為活性成分。
如本文中使用,術語「第一方面的化合物」及「藥學上可接受的鹽」如上文所述。
如本文中使用,術語「預防」意指任何以施予本發明的組成物來抑制或延遲病毒性疾病發生、散播及再發的行為,且術語「治療」意指任何以施予本發明的組成物改善或有利地改變疾病症狀的行為。
本發明的醫藥組成物可藉由促使異常蛋白殼形成,其移除異常蛋白殼中之基因物質及複製基因物質的元件,以預防或治療由病毒感染造成的疾病。
該病毒性疾病可為一種由B型肝炎病毒(HBV)、C型肝炎病毒(HCV)或人類免疫缺陷病毒(HIV)造成的傳染性疾病,但不限於此。
根據本發明的醫藥組成物可含有化學式1代表的化合物或其藥學上可接受的鹽作為活性成分,基於組成物的總重,較佳為0.1重量%至75重量%,更佳為1重量%至50重量%。
本發明的組成物可復含有一種藥學上可接受的載體、稀釋液或賦形劑,可藉由常規方法,依各使用目的,以多種形式配成及使用,如口服劑型如粉劑、粒劑、錠劑、膠囊、懸浮液、乳劑、糖漿劑和氣霧劑及無菌注射液之注射
劑,且可經口或經包括靜脈內、腹膜內、皮下、直腸、局部等的各種途徑施予。在該組成物中可含有之合適的載體、稀釋液或賦形劑的實例包含乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藻糖醇、麥芽糖醇、澱粉、阿拉伯膠、褐藻膠、明膠、磷酸鈣、矽酸鈣、織維素、甲基織維素、微晶纖維素(microcrystalline cellulose)、聚乙烯吡咯烷酮(polyvinylpyrrolidone)、水、羥苯甲酸甲酯(methyl hydroxybenzoate)、羥苯甲酸丙酯(propyl hydroxybenzoate)、滑石、硬脂酸鎂(magnesium stearate)及礦物油。本發明的組成物可復包含填充劑、抗凝劑、潤滑劑、潤濕劑、香料、乳化劑、防腐劑等。
口服施予之固體製劑,包含錠劑、丸劑、粉劑、粒劑、膠囊等,且該等固體製劑係藉由將至少一種或更多種賦形劑如澱粉、碳酸鈣、蔗糖、乳糖或明膠與該組成物混合所配成。在簡單賦形劑之外,可使用如硬脂酸鎂及滑石的潤滑劑。
口服施予之液體製劑,包含懸浮液、內溶液(internal solution)、乳劑及糖漿劑,且除通常應用的簡單稀釋劑之水及液態石臘外,可含有各種賦形劑如潤濕劑、增甜劑、芳香劑與防腐劑。
非口服施予之製劑,包含無菌水性溶液、非水性溶液、懸浮液、乳劑、凍乾製劑與栓劑。可使用丙二醇、聚乙二醇、植物油如橄欖油、可注射酯類如油酸乙酯等,作為非水性溶劑及懸浮劑。可使用巫策首(Witepsol)、馬克夠(Macrogol)、妥文61(Tween 61)、可可油、月桂脂(laurin)、甘油明膠等,作為栓劑的基料。同時,該注射劑可含有常規添加劑,如助溶劑、等滲劑、懸浮劑、乳化劑、穩定劑及防腐劑。
此處,本發明的組成物以藥學有效量施予。如本文中使用,術語
「藥學上有效的量」是指一種足以合理受益/風險比(benefit/risk ratio)進行藥物治療的且不造成副作用下治療疾病的量。該有效劑量水平可取決於包含病患健康狀況、疾病種類和嚴重度、藥物活性、藥物敏感度、施予方法、施予時間、施予途徑和排出速率、治療長度、混合或相伴藥物及本醫學領域習知的其他因素的因素來決定。本發明的組成物可作為單獨治療劑施予或與其他治療劑組合施予,可與常規治療劑依序施予或同時施予,且可以單獨或多重方式施予。在考慮上述所有因素後,重要的是,以一定量施予組成物,用最小量獲得最大效力而沒有副作用,且本領域中具有通常知識者可輕易決定該量。
例如,該藥學上有效的量可依施予的途徑、疾病的嚴重度、性別、體重、年齡等而增減,因此該劑量非意欲以任何方式限制本發明的範疇。
具體而言,本發明的組成物中,化合物的有效量可依病患的年齡、性別及體重而有所不同,且該化合物一般可以每公斤體重1mg至100mg、較佳為5mg至60mg施予,可每天或每隔一天或以分開的方式每天1到3次施予。惟,有效量可依施予的途徑、疾病的嚴重度、性別、體重、年齡等而增減,因此該劑量非意欲以任何方式限制本發明的範疇。
本發明的第六方面提供一種治療病毒性疾病的方法,其包含施予該第五方面的醫藥組成物至需要其的個體。
如本文中使用,術語「第五方面的醫藥組成物」及「病毒性疾病」如同上文所述。
如本文中使用,術語「個體」是指患有或可能發展病毒性疾病的所有動物包含猴、牛、馬、羊、豬、雞、火雞、鵪鶉、貓、狗、小鼠、大鼠、兔、或豚鼠、及人類。藉由將本發明的醫藥組成物施予至一個體,可有效地預防或治
療該疾病。本發明的醫藥組成物可與常規的治療劑組合施予。
如本文中使用,術語「施予」意指藉由任意合適的方法,提供一預定的物質給一病患,且本發明的組成物可透過任何一般途徑施予,只要其能到達目標組織。該施予可為腹膜內施予、靜脈內施予、肌內施予、皮下施予、皮內施予、口服施予、局部施予、鼻內施予、肺內施予或直腸施予,但不限於此。本發明的醫藥組成物可利用有能力運送一活性物質至目標細胞之任意設備施予。較佳的施予模式及製劑係靜脈內注射、皮下注射、皮內注射、肌內注射、點滴注射等。注射劑可利用水性溶劑如生理食鹽水溶液及林格氏液(Ringer’s solution)、非水性溶劑如植物油、高級脂肪酸酯類(例如,油酸乙酯)、醇類(例如,乙醇、苯甲醇、丙二醇及甘油)等來製備。注射劑可含有醫藥載體如預防劣化的穩定劑(例如,抗壞血酸、亞硫酸氫鈉、焦亞硫酸鈉、BHA、生育酚及EDTA)、乳化劑、調整pH之緩衝溶液及抑制微生物的生長之防腐劑(例如,硝酸苯汞(phenylmercuric nitrate)、硫柳汞、氯化苄烷銨(benzalkonium chloride)、苯酚、甲酚及苯甲醇)。
如本文中使用,術語「治療有效量」與活性成分組合,是指吡唑基甲基脲衍生物化合物或其藥學上可接受的鹽對預防或治療目標疾病有效的量。
本發明的醫藥組成物,除了含有吡唑基甲基脲衍生物化合物或其藥學上可接受的鹽之外,可復含有用於預防或治療各已知疾病的已知藥物作為活性成分,該活性成分取決於所欲預防或治療之疾病種類。例如,當使用於預防或治療病毒性疾病時,本發明的醫藥組成物可復含有除吡唑基甲基脲衍生物化合物或其藥學上可接受的鹽以外的已知藥物作為活性成分,且可與其他已知的
治療組合使用,以用於治療這些疾病。
依據本發明新合成的分子中吡唑基甲基脲衍生物,展現低細胞毒性及抑制蛋白殼組裝的效用,因此可有用地用於預防或治療關於蛋白殼組裝的疾病,例如,由HBV、HCV、HIV等等所造成的病毒性疾病。
下文透過例示性實施態樣對本發明的結構及效果進行更為詳細的描述。惟,該等例示性實施態樣僅供說明目的,該等例示性實施例非意欲以任何方式限制本發明的範疇。
合成實例
本發明的化合物可透過包含選自由以下一系列反應方案之二步驟反應的製程合成。
步驟1:吡唑基甲基前驅物與R1前驅物反應
步驟1-1
步驟1-2
步驟1-3
步驟2:與R2前驅物反應
步驟2-1
步驟2-2
步驟2-3
步驟2-4
在這一系列反應方案中,吡唑基為未經取代或經取代之吡唑環,其氮原子可包含保護基。R1’及R2’分別與R1’及R2’或其前驅物相同,且X為鹵素。
實施例1:製備3-(雙環[1.1.1]戊-1-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=383.2,
1H NMR(400MHz,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).
實施例2:製備1-(2-甲氧基嘧啶-5-基)-3-(嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=395.2,
1H NMR(400MHz,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).
實施例3:製備3-(3-氟基-4-(1H-咪唑-1-基)吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H]+=478.2,
1H NMR(400MHz,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).
實施例4:製備3-(2-溴基-3-氟吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=492.15,
1H NMR(300MHz,Chloroform-d)δ 11.26(s,1H),8.43(t,J=1.6Hz,2H),8.17(tt,J=9.5Hz,6.6Hz,2H),6.58(s,1H),6.41(d,J=2.2Hz,1H),4.81(d,J=2.2Hz,2H),4.13(t,J=1.6Hz,3H).
實施例5:製備3-(6-氯吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=428.1,
1H NMR(400MHz,CDCl3)δ 11.19(br s,1H),8.36(s,2H),8.10-8.01(m,1H),7.68(t,J=8.0Hz,1H),7.04(d,J=7.6Hz,1H),6.79(s,1H),6.35(s,1H),4.75(s,2H),4.11(s,3H).
實施例6:製備3-(3-氯基雙環[1.1.1]戊-1-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=417.2,
1H NMR(400MHz,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).
實施例7:製備3-(3-氯基-4-氰基苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
1H NMR(400MHz,DMSO-d6)δ 8.57(s,2H),7.90(d,J=2.0Hz,1H),7.82(d,J=8.7Hz,1H),7.61(dd,J=8.7Hz,2.0Hz,1H),6.65(s,1H),4.92(s,2H),3.95(s,3H).
實施例8:製備3-(5-氯基-6-氰基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
1H NMR(300MHz,Chloroform-d)δ 11.14(s,1H),8.39(d,J=10.0Hz,3H),7.87(d,J=9.2Hz,1H),6.94(s,1H),6.40(s,1H),4.79(s,2H),4.14(s,3H).
實施例9:製備3-(3-氯基-4-異氰苯基)-1-((5-氰基-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=409.4,
1H NMR(500MHz,Methanol-d4)δ 8.45(s,2H),7.90(s,1H),7.66(d,J=8.7Hz,1H),7.54(d,J=9.8Hz,1H),6.78(s,1H),4.98(s,2H),4.07(s,3H)
實施例10:製備3-(3-氰基-4,5-二氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=436.1,
1H NMR(400MHz,CDCl3)δ=8.42(s,2H),7.84(ddd,J=1.9,3.8,9.3Hz,1H),7.43(q,J=9.4Hz,1H),6.87-6.55(m,2H),6.36(s,1H),4.78(s,2H),4.08(s,3H).
實施例11:製備3-(3-氯基-4,5-二氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=463.1,
1H NMR(400MHz,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).
實施例12:製備3-(3-氯基-4,5-二氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=445.1,
1H NMR(400MHz,CDCl3)δ 8.33(s,2H),7.30(ddd,J=2.7Hz,6.3Hz,11.5Hz,1H),7.18(dd,J=2.4Hz,5.2Hz,1H),6.85-6.54(m,1H),6.47(br s,1H),6.31(s,1H),4.73(s,2H),4.05(s,3H).
實施例13:製備3-(6-氯基-4,5-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=463.9,
1H NMR(400MHz,CDCl3)δ 11.76-10.67(m,1H),8.30-8.26(m,2H),7.96(dd,J=4.8Hz,10.9Hz,1H),6.77(s,1H),6.30(s,1H),4.70-4.65(m,2H),4.06-4.01(m,3H).
實施例14:製備3-(3-氯基-4-氟苯基)-1-(6-側氧基-1,6-二氫吡啶-3-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲
1H NMR(300MHz,DMSO-d6)δ 8.24(s,1H),7.71(dd,J=3.0Hz,1H)7.44(m,1H),7.31(s,1H),7.28-7.16(m,2H),6.29(d,J=7.2Hz,1H),4.46(s,2H),2.28(s,2H),1.65-1.64(m,4H).
實施例15:製備3-(3-氯基-4-氟苯基)-1-(2-側氧基-1,2-二氫吡啶-4-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲
[M+H+]=416.3
1H NMR(500MHz,Methanol-d4)δ 7.66(dd,J=6.6Hz,2.6Hz,1H),7.40-7.31(m,2H),7.16(t,J=9.0Hz,1H),6.44(d,J=7.3Hz,1H),6.32(d,J=2.2Hz,1H),4.92(s,2H),2.59(t,J=6.1Hz,2H),2.45(t,J=6.0Hz,2H),1.87-1.65(m,4H).
實施例16:製備N-(4-(3-(3-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲基)苯基)甲烷磺胺
[M+H+]=494.1,
1H NMR(400MHz,DMSO-d6)δ 9.81(s,1H),8.13(s,1 H),7.71-7.69(dd,J=2.4Hz,6.8Hz,1H),7.40-7.37(m,1H),7.25(t,J=9.2Hz,1H),7.19-7.14(m,4H),4.78(s,2H),4.54(s,2H),3.67(t,J=5.2Hz,2H),3.00(s,3H),2.32-2.31(m,2H).
實施例17:製備N-(5-(3-(3-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲基)吡啶-2-基)甲烷磺胺
[M+H+]=495.2,
1H NMR(400MHz,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).
實施例18:製備N-(5-(3-(3-氯基-4-氟苯基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲基)吡啶-2-基)甲烷磺胺
[M+H+]=495.2,
1H NMR(400MHz,CDCl3)δ 8.18(d,J=1.9Hz,1H),7.53-7.48(m,1H),7.44(dd,J=2.6Hz,6.5Hz,1H),7.20(d,J=8.6Hz,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=6.2Hz,2H),1.91-1.82(m,2H).
實施例19:製備N-(4-(3-(3-氯基-4-氟苯基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲基)苯基)甲烷磺胺
[M+H+]=494.2,
1H NMR(400MHz,CDCl3)δ 8.57(d,J=11.4Hz,1H),8.36(s,1H),7.74(dd,J=2.8Hz,6.5Hz,1H),7.42(dd,J=2.6Hz,6.5Hz,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=8.8Hz,1H),6.69(dd,J=2.8Hz,6.1Hz,1H),6.50(td,J=3.3Hz,8.8Hz,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).
實施例20:製備1-(6-乙醯基吡啶-3-基)-3-(3-氯基-4-氟苯基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲
[M+H+]=444.2,
1H NMR(400MHz,CDCl3)δ 8.58(d,J=2.4Hz,1H),8.11(d,J=8.4Hz,1H),7.69(dd,J=2.5Hz,8.4Hz,1H),7.46(dd,J=2.6Hz,6.5Hz,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=6.3Hz,2H),1.89-1.79(m,2H).
實施例21:製備1-(6-乙醯基吡啶-3-基)-3-(3-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲
[M+H+]=444.3,
1H NMR(400MHz,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).
實施例22:製備1-(2-乙醯基吡啶-4-基)-3-(3-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲
[M+H+]=444.5,
1H NMR(400MHz,CDCl3)δ 8.65(d,J=5.4Hz,1H),7.94(d,J=2.1Hz,1H),7.80(s,1H),7.53(dd,J=2.6Hz,6.4Hz,1H),7.46(dd,J=2.3Hz,5.4Hz,1H),7.22(td,J=3.4Hz,8.8Hz,1H),7.12-7.05(m,1H),4.90(s,2H),4.71(s,2H),3.83(t,J=5.5Hz,2H),2.73(s,3H),2.42(t,J=5.4Hz,2H).
實施例23:製備4-(3-(3-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲基)-N-甲基苯磺醯胺
[M+H+]=494.0,
1H NMR(400MHz,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).
實施例24:製備3-(3-氯基-4-氟苯基)-1-(1-甲基-1H-吡唑-4-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲
[M+H+]=405.1,
1H NMR(500MHz,CDCl3)δ 7.48(dd,J=6.5Hz,2.6Hz,1H),7.37(s,2H),7.14-7.08(m,1H),6.99(t,J=8.8Hz,2H),4.69(s,2H),3.86(s,3H),2.60(t,J=6.1Hz,2H),2.31(t,J=5.9Hz,2H),1.76(dd,J=10.6Hz,4.7Hz,2H),1.68(dd,J=10.4Hz,4.7Hz,2H).
實施例25:製備3-(3-氯基-4-氟苯基)-1-(1-甲基-1H-吡唑-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲
[M+H+]=405.0,
1H NMR(300MHz,DMSO)δ 11.56(s,1H),10.37(s,1H),7.89(dd,J=6.8Hz,2.6Hz,1H),7.71(d,J=1.9Hz,1H),7.47(ddd,J=9.0Hz,4.3Hz,2.7Hz,1H),7.36(t,J=9.1Hz,1H),6.04(d,J=2.1Hz,1H),4.87(s,2H),4.03(d,J=7.1Hz,2H),3.85(s,3H),2.32(t,J=6.3Hz,2H),1.79-1.67(m,2H).
實施例26:製備3-(3-氯基-4-氟苯基)-1-(5-甲基異噁唑-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲
[M+H+]=506,
1H NMR(400MHz,DMSO-d6)δ 11.72(s,1H),9.73(s,1H),7.80(dd,J=6.8Hz,2.6Hz,1H),7.45(ddd,J=9.1Hz,4.4Hz,2.6Hz,1H),7.38(t,J=9.0Hz,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).
實施例27:製備3-(3-氯基-4-氟苯基)-1-(3-甲基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=416.9,
1H NMR(400MHz,CDCl3)δ 11.61-10.85(m,1H),7.53(dd,J=2.6Hz,6.4Hz,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).
實施例28:製備3-(3-氯基-4-氟苯基)-1-(2-甲氧基-4-甲基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=459.1,
1H NMR(400MHz,DMSO-d6)δ 13.49(s,1H),8.31(s,1H),8.26(s,1H),7.71(dd,J=2.5Hz,6.9Hz,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).
實施例29:製備3-(3-氯基-4-氟苯基)-1-(4-甲氧基-2,6-二甲苯基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=471.1,
1H NMR(400MHz,DMSO-d6)δ 13.41(s,1H),7.93-7.78(m,1H),7.73(dd,J=2.6Hz,6.8Hz,1H),7.44(ddd,J=2.8Hz,4.2Hz,9.1Hz,1H),7.25(t,J=9.1Hz,1H),6.74(s,2H),6.49(s,1H),4.66(s,2H),3.34(s,2H),1.92(s,6H).
實施例30:製備3-(3-氯基-4-氟苯基)-1-(2-甲氧基-4,6-二甲嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=473.1,
1H NMR(400MHz,Chloroform-d)δ 11.59(s,1H),7.50(dd,J=2.7Hz,6.4Hz,1H),7.21-7.15(m,2H),7.00(t,J=8.8Hz,1H),6.68(s,1H),6.25(s,1H),4.55(s,2H),3.91(s,3H),2.09(s,6H).
實施例31:製備4-(3-(3-氯基-4-氟苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲基)苄酸甲酯
[M+H+]=457.3,
1H NMR(500MHz,DMSO-d6)δ 12.19(s,1H),8.81(s,1H),7.92(d,J=8.6Hz,2H),7.71(dd,J=6.8Hz,2.6Hz,1H),7.43(d,J=8.7Hz,2H),7.39(ddd,J=6.9Hz,
4.3hz,2.2Hz,1H),7.31(t,J=9.1Hz,1H),4.86(s,2H),3.84(s,3H),2.50(d,J=2.0Hz,2H),2.29(t,J=6.0Hz,2H),1.73-1.54(m,4H).
實施例32:製備3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲
[M+H+]=431.05,
1H NMR(300MHz,Chloroform-d)δ 7.44(dd,J=6.5Hz,2.6Hz,1H),7.14-7.05(m,3H),7.00(t,J=8.8Hz,1H),6.96-6.90(m,2H),6.27(s,1H),4.70(s,2H),3.84(s,3H),2.64(t,J=6.2Hz,2H),2.20(t,J=6.0Hz,2H),1.77(dt,J=10.6Hz,5.9Hz,2H),1.71-1.59(m,2H).
實施例33:製備1-((5-乙醯基-4,5,6,7-四氫-1H-吡唑並[4,3-c]吡啶-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)脲
[M+H+]=472.2,
1H NMR(500MHz,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=11.1Hz,2H),4.78,4.74(s,2H),4.38(d,J=8.40Hz,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).
實施例34:製備1-((1H-吡唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)脲
[M+H+]=375,
1H NMR(300MHz,Chloroform-d)δ 7.52(d,J=1.7Hz,1H),7.47(dd,J=6.5Hz,2.6Hz,1H),7.12(dd,J=9.3Hz,2.8Hz,3H),7.03(t,J=8.7Hz,1H),6.97(d,J=8.9Hz,2H),6.20(s,1H),6.18(s,1H),4.81(s,2H),3.87(s,3H).
實施例35:製備3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1-甲基-1H-吡唑-3-基)甲基)脲
[M+H+]=389,
1H NMR(300MHz,Chloroform-d)δ 7.53(dd,J=6.5Hz,2.6Hz,1H),7.30(d,J=2.2Hz,1H),7.17(d,J=8.9Hz,2H),7.13(dt,J=4.0Hz,2.3Hz,1H),7.01(t,J=8.8Hz,1H),6.94(d,J=8.9Hz,2H),6.43(s,1H),6.28(d,J=2.2Hz,1H),4.86(s,2H),3.85(d,J=1.6Hz,6H).
實施例36:製備3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1-甲基-4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲
1H NMR(300MHz,CDCl3)δ 7.43(dd,J=6.5Hz,2.6Hz,1H),7.14-7.05(m,1H),7.01(d,J=8.6Hz,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=6.4Hz,2H),1.92(t,J=6.0Hz,2H),1.72-1.60(m,2H),1.54-1.47(m,2H).
實施例37:製備3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5-甲基-4,5,6,7-四氫-1H-吡唑並[4,3-c]吡啶-3-基)甲基)脲
[M+H+]=444.6,
1H NMR(500MHz,DMSO-d6)δ 12.20(s,1H),8.02(s,1H),7.70(dd,J=7.2Hz,2.6Hz,1H),7.41(ddd,J=9.1Hz,4.3Hz,2.6Hz,1H),7.27(t,J=9.1Hz,1H),7.11(d,J=8.9Hz,2H),6.94(d,J=8.7Hz,2H),4.71(s,2H),3.76(s,3H),3.26(s,2H),2.63(s,4H),2.34(s,3H).
實施例38:製備3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲
[M+H+]=431.1,
1H NMR(300MHz,CDCl3)δ 7.43(dd,J=6.5Hz,2.5Hz,1H),7.14-7.02(m,3H),6.95(dd,J=19.6Hz,8.8Hz,3H),6.29(s,1H),4.70(s,2H),4.38(s,2H),3.86(t,J=5.6Hz,2H),3.82(s,3H),3.43(s,1H),2.75(t,J=5.5Hz,2H).
實施例39:製備3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1-甲基-1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲
[M+H+]=445.3,
1H NMR(500MHz,DMSO-d6)δ 8.01(s,1H),7.69(dd,J=6.9Hz,2.6Hz,1H),7.46-7.34(m,1H),7.26(t,J=9.1Hz,1H),7.14(d,J=8.9Hz,2H),6.95(d,J=8.9Hz,2H),4.67(s,2H),4.43(s,2H),3.79-3.76(m,5H),3.60(s,3H),2.64(t,J=5.6Hz,2H).
實施例40:製備3-(3-氯基-4-氟苯基)-1-((5,5-二氟-4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=466.2,
1H NMR(500MHz,DMSO-d6)δ 12.35(s,1H),8.20(s,1H),7.96(d,J=2.7Hz,1H),7.69(dd,J=6.9Hz,2.6Hz,1H),7.53(dd,J=8.8Hz,2.7Hz,1H),7.45-7.41(m,1H),7.28(t,J=9.1Hz,1H),6.84(d,J=8.7Hz,1H),4.73(s,2H),3.86(s,3H),2.92(t,J=14.4Hz,2H),2.74(t,J=6.8Hz,2H),2.25-2.19(dt,J=13.9Hz,7.1Hz,2H).
實施例41:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲
[M+H+]=418.2,
1H NMR(300MHz,CDCl3)δ 8.02(d,J=2.6Hz,1H),7.44(dd,J=6.5Hz,2.5Hz,1H),7.34(dd,J=8.7Hz,2.6Hz,1H),7.27(s,1H),7.15-7.06(m,1H),6.99(t,J
=8.7Hz,1H),6.78(d,J=8.8Hz,1H),6.46(s,1H),4.70(s,2H),3.95(s,3H),2.67(t,J=6.9Hz,2H),2.51-2.27(m,4H),2.16(s,1H).
實施例42:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲
[M+H+]=431.19,
1H NMR(500MHz,MeOD)δ 7.83(d,J=2.6Hz,1H),7.57(dd,J=6.7Hz,2.6Hz,1H),7.43(dd,J=8.8Hz,2.7Hz,1H),7.25(ddd,J=9.0Hz,4.1Hz,2.7Hz,1H),7.10(t,J=9.0Hz,1H),6.80(d,J=8.9Hz,1H),4.82(s,2H),3.90(s,3H),2.59(t,J=6.1Hz,2H),2.33(s,2H),1.81-1.74(m,2H),1.70(d,J=5.5Hz,2H).
實施例43:製備1-((1H-吲唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=426.1,
1H NMR(500MHz,DMSO-d6)δ 12.82(s,1H),8.25(s,1H),7.85(s,1H),7.80(s,1H),7.73(d,J=6.8Hz,1H),7.51-7.40(m,3H),7.35(t,J=7.6Hz,1H),7.29(t,J=8.7Hz,1H),7.12(t,J=7.5Hz,1H),6.79(d,J=8.7Hz,1H),5.19(s,2H),3.82(s,3H).
實施例44:製備3-(3-氯基-4-氟苯基)-1-((5-(羥甲基)-4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=460.2,
1H NMR(500MHz,DMSO-d6)δ 12.08(s,1H),8.22(s,1H),7.92(s,1H),7.69(d,J=6.4Hz,1H),7.50(d,J=8.5Hz,1H),7.46-7.33(m,1H),7.27(t,J=9.1Hz,1H),6.82(d,J=8.6Hz,1H),4.77(d,J=15.2Hz,1H),4.68(d,J=15.2Hz,1H),4.52
(t,J=5.2Hz,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).
實施例45:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1,4,6,7-四氫噻喃[4,3-c]吡唑-3-基)甲基)脲
[M+H+]=448.3,
1H NMR(500MHz,DMSO-d6)δ 12.29(s,1H),8.19(s,1H),7.97(t,J=2.1Hz,1H),7.69(d,J=6.8Hz,1H),7.55(d,J=8.8Hz,1H),7.48-7.36(m,1H),7.27(t,J=9.1Hz,1H),6.83(d,J=8.7Hz,1H),4.75(s,2H),3.86(s,3H),3.51(s,2H),2.97 J 2.61(m,4H).
實施例46:製備3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲
[M+H+]=417.2,
1H NMR(300MHz,CDCl3)δ 7.44(dd,J=6.5Hz,2.6Hz,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=7.4Hz,2H),2.39(dd,J=9.4Hz,4.0Hz,4H).
實施例47:製備3-(3-氯基-4-氟苯基)-1-((5,5-二甲基-4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=458.19,
1H NMR(300MHz,CDCl3)δ 8.01(s,1H),7.53-7.46(m,1H),7.35(d,J=8.7Hz,1H),7.15(s,1H),7.04(t,J=8.7Hz,1H),6.80(d,J=8.8Hz,1H),6.55(s,1H),4.73(d,J=1.6Hz,2H),3.98(d,J=2.1Hz,3H),2.64(s,2H),1.98(s,2H),1.57(d,J=6.1Hz,2H),0.92(d,J=1.8Hz,6H).
實施例48:製備3-(3-氯基-4-氟苯基)-1-((5-羥基-4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=446.24,
1H NMR(500MHz,CDCl3)δ 8.00(s,1H),7.46(d,J=6.4Hz,1H),7.38(d,J=8.6Hz,1H),7.12(d,J=9.0Hz,1H),7.01(t,J=8.5Hz,1H),6.80(d,J=8.6Hz,1H),6.40(s,1H),4.75-4.67(m,2H),4.10(s,1H),3.96(s,3H),2.82(dd,J=14.6Hz,8.3Hz,1H),2.72-2.64(m,1H),2.60(dd,J=15.5Hz,4.5Hz,1H),2.26(dd,J=15.4Hz,6.8Hz,1H),1.95(s,1H),1.92-1.86(m,1H).
實施例49:製備3-(3-氯基-4-氟苯基)-1-((5,5-二氧基-1,4,6,7-四氫噻喃[4,3-c]吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=480.3,
1H NMR(500MHz,DMSO-d6)δ 12.65(s,1H),8.19(s,1H),8.01(d,J=2.7Hz,1H),7.68(d,J=6.9Hz,1H),7.58(d,J=8.7Hz,1H),7.49-7.38(m,1H),7.29(t,J=9.1Hz,1H),6.85(d,J=8.7Hz,1H),4.72(s,2H),4.19(s,2H),3.86(s,3H),3.39(t,J=6.5Hz,2H),3.10(d,J=6.6Hz,2H).
實施例50:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5-甲基-1H-吡唑-3-基)甲基)脲
[M+H+]=390.14,
1H NMR(300MHz,CDCl3)δ 8.04(d,J=2.6Hz,1H),7.48(dd,J=6.5Hz,2.6Hz,1H),7.41(dd,J=8.8Hz,2.7Hz,1H),7.16-7.08(m,1H),7.01(t,J=8.7Hz,1H),6.79(d,J=8.8Hz,1H),6.46(s,1H),5.96(s,1H),4.74(s,2H),3.96(s,3H),2.27(s,3H).
實施例51:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4,5,6,7-四氫-1H-4,7-甲橋吲唑-3-基)甲基)脲
[M+H+]=442.3,
1H NMR(500MHz,DMSO-d6)δ 11.61(s,1H),8.28(s,1H),7.94(s,1H),7.72(d,J=6.8Hz,1H),7.45(t,J=12.3Hz,2H),7.29(t,J=9.1Hz,1H),6.85(d,J=8.7Hz,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=8.5Hz,1H),1.01(s,1H),0.86(t,J=10.1Hz,1H).
實施例52:製備3-((3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲基)甲基)-4,5,6,7-四氫-1H-吲唑-5-羧酸
[M+H+]=474.3
實施例53:製備3-((3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲基)甲基)-4,5,6,7-四氫-1H-吲唑-5-羧酸甲酯
[M+H+]=488.2,
1H NMR(500MHz,DMSO-d6)δ 12.15(s,1H),8.21(s,1H),7.93(s,1H),7.68(s,1H),7.51(d,J=8.5Hz,1H),7.45-7.35(m,1H),7.28(t,J=9.1Hz,1H),6.82(d,J=8.7Hz,1H),4.82(d,J=14.9Hz,1H),4.64(d,J=15.3Hz,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=13.0Hz,1H),1.74(s,1H).
實施例54:製備3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲
[M+H+]=432.0,
1H NMR(300MHz,CDCl3)δ 8.11(d,J=5.6Hz,1H),7.93(s,1H),7.53(dd,J=6.5Hz,2.6Hz,1H),7.25-7.17(m,1H),7.02(t,J=8.8Hz,1H),6.83(dd,J=5.6
Hz,1.7Hz,1H),6.65(d,J=1.6Hz,1H),4.82(s,2H),3.93(s,3H),2.72-2.47(m,2H),2.25(t,J=5.9Hz,2H),1.72(ddd,J=15.5Hz,9.6Hz,3.6Hz,4H).
實施例55:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲
[M+H+]=432.2,
1H NMR(500MHz,CDCl3)δ 8.02(d,J=2.6Hz,1H),7.45(dd,J=6.4Hz,2.7Hz,1H),7.35(dd,J=8.7Hz,2.7Hz,1H),7.15-7.09(m,1H),7.02(t,J=8.7Hz,1H),6.82(d,J=8.8Hz,1H),6.17(s,1H),4.68(s,2H),4.47(s,2H),3.97(s,3H),3.90(t,J=5.6Hz,2H),2.79(t,J=5.6Hz,2H).
實施例56:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4-甲基-1H-吡唑-3-基)甲基)脲
[M+H+]=390.2,
1H NMR(500MHz,DMSO)δ 8.20(s,1H),7.93-7.87(m,1H),7.70(dd,J=6.9Hz,2.6Hz,1H),7.48(dd,J=8.7Hz,2.7Hz,1H),7.42(ddd,J=9.1Hz,4.3Hz,2.7Hz,1H),7.35(s,1H),7.27(t,J=9.1Hz,1H),6.81(d,J=8.8Hz,1H),4.79(s,2H),3.84(s,3H),1.88(s,3H).
實施例57:製備3-(3-氯基-4-氟苯基)-1-((4,5-二甲基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=406.3,
1H NMR(500MHz,DMSO)δ 12.09(s,1H),8.22(s,1H),7.91(d,J=2.6Hz,1H),7.70(dd,J=6.8Hz,2.3Hz,1H),7.49(dd,J=8.6Hz,2.3Hz,1H),7.42(ddd,J=9.1Hz,4.3Hz,2.7Hz,1H),7.27(t,J=9.1Hz,1H),6.81(d,J=8.8Hz,1H),4.74(s,2H),3.84(s,3H),2.06(s,3H),1.80(s,3H).
實施例58:製備3-(3-氯基-4-氟苯基)-1-((5-異丙基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=420.3,
1H NMR(500MHz,DMSO)δ 12.29(s,1H),8.29(s,1H),8.00(d,J=2.5Hz,1H),7.72(dd,J=6.8Hz,2.5Hz,1H),7.56(dd,J=8.7Hz,2.7Hz,1H),7.43(ddd,J=9.1Hz,4.2Hz,2.7Hz,1H),7.28(t,J=9.1Hz,1H),6.83(d,J=8.8Hz,1H),5.92(s,1H),4.71(s,2H),3.85(s,3H),2.88(s,1H),1.17(d,J=6.7Hz,6H).
實施例59:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((6-甲基-1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲
[M+H+]=430.31,
1H NMR(500MHz,CDCl3)δ 8.04(dd,J=2.7Hz,0.5Hz,1H),7.45(dd,J=6.5Hz,2.7Hz,1H),7.34(dd,J=8.8Hz,2.7Hz,1H),7.11(ddd,J=8.9Hz,4.0Hz,2.7Hz,1H),7.03(dd,J=14.9Hz,6.2Hz,1H),6.82(dd,J=8.8Hz,0.6Hz,1H),6.17(s,1H),4.72-4.63(m,2H),3.98(s,3H),3.11(dd,J=14.4Hz,6.9Hz,1H),2.63-2.55(m,1H),2.38-2.27(m,2H),1.97-1.90(m,1H),1.27(d,J=6.9Hz,3H).
實施例60:製備3-(3-氯基-4-氟苯基)-1-((5-乙基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=404.1,
1H NMR(400MHz,CDCl3)δ 8.05(d,J=2.4Hz,1H),7.50(dd,J=6.5Hz,2.6Hz,1H),7.42(dd,J=8.8Hz,2.7Hz,1H),7.18-7.10(m,1H),7.02(t,J=8.8Hz,1H),6.81(d,J=8.7Hz,1H),6.41(s,1H),6.01(s,1H),4.76(s,2H),3.97(s,3H),2.66(q,J=7.6Hz,2H),1.26(t,J=7.6Hz,3H).
實施例61:製備1-((4-溴基-1H-吡唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)脲
[M+H+]=456.23,
1H NMR(400MHz,CDCl3)δ 8.07(d,J=2.5Hz,1H),7.50(s,1H),7.47(dd,J=6.4Hz,2.6Hz,1H),7.37(d,J=11.4Hz,1H),7.12-7.08(m,1H),7.04(d,J=8.5Hz,1H),7.00(d,J=6.2Hz,1H),6.83(d,J=8.8Hz,1H),6.12(s,1H),4.77(s,2H),3.98(s,3H).
實施例62:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲
[M+H+]=498.36,
1H NMR(500MHz,CDCl3)δ 8.00(s,1H),7.45(d,J=2.5Hz,1H),7.37(dd,J=5.8Hz,2.8Hz,1H),7.11(s,1H),7.03(dd,J=8.5Hz,3.2Hz,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=16.4Hz,1H),2.66(s,1H),2.50(d,J=14.7Hz,1H),2.32(s,1H),2.25-2.19(m,2H),1.74-1.67(m,1H).
實施例63:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲
[M+H+]=432.3,
1H NMR(300MHz,DMSO-d6)δ 11.52(s,1H),8.19(s,1H),7.96(dd,J=2.7Hz,0.7Hz,1H),7.72(dd,J=6.9Hz,2.6Hz,1H),7.50(dd,J=8.8Hz,2.7Hz,1H),7.43(ddd,J=9.1Hz,4.4Hz,2.6Hz,1H),7.28(t,J=9.1Hz,1H),6.85(d,J=8.7Hz,1H),4.71(s,2H),4.14-3.98(m,2H),3.87(s,3H),2.27(t,J=6.3Hz,2H),1.73(t,J=4.83Hz,2H).
實施例64:製備3-(3-氯基-4-氟苯基)-1-((5-甲氧基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=406.1,
1H NMR(300MHz,MeOD)δ 7.98(d,J=2.6Hz,1H),7.60(dd,J=6.7Hz,2.6Hz,1H),7.50(dd,J=8.8Hz,2.7Hz,1H),7.27(ddd,J=9.0Hz,4.2Hz,2.7Hz,1H),7.11(t,J=9.0Hz,1H),6.85(d,J=8.8Hz,1H),5.65(s,1H),4.78(s,2H),3.93(s,3H),3.81(s,3H).
實施例65:製備3-(3-氯基-4-氟苯基)-1-(1-甲基-6-側氧基-1,6-二氫吡啶-3-基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲
[M+H+]=418.0,
1H NMR(300MHz,MeOD)δ 7.62(d,J=2.8Hz,1H),7.59(dd,J=6.7Hz,2.6Hz,1H),7.29(ddd,J=9.0Hz,4.2Hz,2.7Hz,1H),7.23(dd,J=9.5Hz,2.8Hz,1H),7.11(t,J=9.0Hz,1H),6.51(d,J=9.5Hz,1H),4.74(s,2H),3.52(s,3H),2.66(t,J=6.9Hz,2H),2.56-2.35(m,4H).
實施例66:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1-(2-(四氫-2H-哌喃-2-基氧基)乙基)-1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲
[M+H+]=544.2,
1H NMR(300MHz,CDCl3)δ 8.01(d,J=2.4Hz,1H),7.55(dd,J=6.5Hz,2.6Hz,1H),7.45(dd,J=8.8Hz,2.7Hz,1H),7.19(ddd,J=8.9Hz,4.1Hz,2.7Hz,1H),7.01(t,J=8.8Hz,1H),6.77(d,J=8.8Hz,1H),4.72(s,2H),4.51(d,J=3.7Hz,1H),4.14(dd,J=7.7Hz,3.4Hz,2H),4.04-3.96(m,1H),3.94(s,3H),3.66(ddd,J=11.4Hz,9.7Hz,4.6Hz,2H),3.43(dd,J=10.4Hz,5.6Hz,1H),2.73(d,J=4.9Hz,2H),
2.52(d,J=4.0Hz,4H),1.70(dd,J=21.3Hz,10.6Hz,2H),1.51(dd,J=9.2Hz,3.4Hz,4H).
實施例67:製備3-(3-氯基-4-氟苯基)-1-((1-(2-羥乙基)-1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=460.3,
1H NMR(300MHz,CDCl3)δ 7.98(d,J=2.5Hz,1H),7.51(ddd,J=11.5Hz,7.6Hz,2.7Hz,2H),7.17(ddd,J=8.9Hz,4.0Hz,2.7Hz,1H),7.03(t,J=8.8Hz,1H),6.82(d,J=8.8Hz,1H),6.63(s,1H),4.76(s,2H),4.07-4.01(m,2H),3.97(s,3H),3.92(d,J=4.6Hz,2H),2.70(t,J=6.6Hz,2H),2.62-2.52(m,4H).
實施例68:製備3-(3-氯基-4-氟苯基)-1-((1,3a,4,5,6,7a-六氫哌喃並[2,3-c]吡唑-3-基)甲基)-1-(2-甲氧基吡啶-4-基)脲
本標題化合物以相似於上述實施例63的方法合成。
實施例69:製備3-(3-氯基-4-氟苯基)-1-((4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=418.2,
1H NMR(400MHz,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).
實施例70:製備3-(3-氯基-4-氟苯基)-1-((4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)-1-(2-甲氧基吡啶-4-基)脲
製備4-(二甲胺基亞甲基)四氫呋喃-3-酮
將四氫呋喃-3-酮(15.0g,174mmol,1eq)在DMFDMA(40.36g,339mmol,45mL,1.94eq)中的溶液於110℃攪拌2小時。濃縮該混合物,以提供呈紅色固體的4-(二甲胺基亞甲基)四氫呋喃-3-酮(50g,粗產物),其不經進一步純化而用於下一步驟。
製備4,6-二氫-1H-呋喃[3,4-c]吡唑
向4-(二甲胺基亞甲基)四氫呋喃-3-酮(25g,177.09mmol,1eq)在EtOH(150mL)中的溶液於15℃加入98% NH2NH2.H2O(9.05g,177mmol,8.78mL,1eq)。於80℃在N2氣氛下攪拌該溶液20小時,接著濃縮。以相同規格重複一次該反應。合併2批次的殘留物,並利用矽膠層析法(石油醚:乙酸乙酯=1:1,1:2)純化,以提供呈黃色固體的4,6-二氫-1H-呋喃[3,4-c]吡唑(2批次2.2g,5.6%產率)。
1H NMR(400MHz,CDCl3)δ 7.19(s,1H),4.85(s,2H),4.82(s,2H).
製備1-(四氫-2H-哌喃-2-基)-4,6-二氫-1H-呋喃[3,4-c]吡唑(1-(tetrahydro-2H-pyran-2-yl)-4,6-dihydro-1H-furo[3,4-c]pyrazole)
將4,6-二氫-1H-呋喃[3,4-c]吡唑(4.5g,40.9mmol,1eq)、DHP(4.47g,53.1mmol,4.86mL,1.3eq)及TosOH(352mg,2.04mmol,0.05eq)在甲苯(50mL)中的溶液於100℃在N2氣氛下攪拌16小時。濃縮混合物,並利用矽膠層析法(石油醚:乙酸乙酯=3:1,1:1)純化殘留物,以提供呈無色油的1-(四氫-2H-哌喃-2-基)-4,6-二氫-1H-呋喃[3,4-c]吡唑(3.8g,48%產率)。
1H NMR(300MHz,CDCl3)δ 7.31(s,1H),5.39-5.28(m,1H),4.89(d,J=0.9Hz,2H),4.85(d,J=1.5Hz,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).
製備1-(四氫-2H-哌喃-2-基)-4,6-二氫-1H-呋喃[3,4-c]吡唑-3-甲醛
向1-(四氫-2H-哌喃-2-基)-4,6-二氫-1H-呋喃[3,4-c]吡唑(250mg,1.29mmol,1eq)在THF(3mL)中的溶液於-70℃ N2氣氛下加入n-BuLi(THF中2.2M,702μL,1.2eq)。形成黃色懸浮液。在5分鐘後,加入於THF(1mL)中的DMF(188mg,2.57mmol,198μL,2eq)。該混合物於-70℃攪拌10分鐘後倒入水中(20mL)攪拌30分鐘。該淬滅混合物以乙酸乙酯(15mL×2)萃取。用滷水(15mL×2)洗滌合併的有機相,透過無水Na2SO4乾燥並過濾。真空濃縮濾液。以Prep-TLC(石油醚:乙酸乙酯=2:1)純化殘留物,以提供呈白色固體的1-(四氫-2H-哌喃-2-基)-4,6-二氫-1H-呋喃[3,4-c]吡唑-3-甲醛(90mg,31%產率)。
1H NMR(400MHz,CDCl3)δ 9.97(s,1H),5.98(dd,J=2.4Hz,9.6Hz,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).
製備2-甲氧基-N-((1-(四氫-2H-哌喃-2-基)-4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)吡啶-4-胺
將1-(四氫-2H-哌喃-2-基)-4,6-二氫-1H-呋喃[3,4-c]吡唑-3-甲醛(90mg,405μmol,1eq)、2-甲氧基吡啶-4-胺(2-methoxypyridin-4-amine)(65mg,526μmol,1.3eq)及TosOH(7mg,40μmol,0.1eq)在甲苯(10mL)中的溶液於100℃攪拌4小時。將該溶液冷卻至20℃。將NaBH3CN(76mg,1.21mmol,3eq)加至該溶液中,並將所產生的混合物於20℃攪拌1小時。濃縮該混合物並以逆相HPLC(0.1% FA條件)純化殘留物,接著冷凍乾燥以提供呈無色膠的2-甲氧基-N-((1-(四氫-2H-哌喃-2-基)-4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)吡啶-4-胺(60mg,39%產率,FA鹽)。
製備3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((1-(四氫-2H-哌喃-2-基)-4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)脲
對2-甲氧基-N-((1-(四氫-2H-哌喃-2-yl)-4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)吡啶-4-胺(60mg,159μmol,1eq,FA鹽)及DIPEA(62mg,478μmol,83μL,3eq在DCM(3mL)中的溶液於0℃下加入2-氯基-1-氟基-4-異氰酸基苯(41mg,239μmol,1.5eq)。將溶液於0℃在N2氣氛下攪拌1小時。於20℃濃縮該溶液。以逆相HPLC(0.1% NH3.H2O)純化粗產物,接著冷凍乾燥以提供呈白色固體的3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((1-(四氫-2H-哌喃-2-基)-4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)脲(20mg,25%產率)。
製備3-(3-氯基-4-氟苯基)-1-(4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)-1-(2-甲氧基吡啶-4-基))脲
向3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((1-(四氫-2H-哌喃-2-基)-4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)脲(20mg,40μmol,1eq)在DCM(4mL)中的溶液於20℃加入TFA(1mL)。將溶液於20℃攪拌1小時。濃縮該混合物,並以製備級液相層析(Prep-HPLC)(管柱:Phenomenex Synergi C18 150mm×25mm×10μm;移動相:[水(0.225% FA)-ACN];B%:27%-57%,10分鐘)純化殘留物,接著冷凍乾燥,以提供呈白色固體的3-(3-氯基-4-氟苯基)-1-(4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)-1-(2-甲氧基吡啶-4-基))脲(3.3mg,18.6%產率,94%純度)。
[M+H+]=418.0,
1H NMR(400MHz,CD3OD)δ 8.10(d,J=5.6Hz,1H),7.62(dd,J=2.6Hz,6.8Hz,1H),7.33-7.28(m,1H),7.18-7.12(m,1H),6.86(dd,J=1.6Hz,5.6Hz,1H),6.68(d,J=1.2Hz,1H),4.95(s,2H),4.75(s,2H),4.71(s,2H),3.91(s,3H).
實施例71:製備3-(3-氯基-4-氟苯基)-1-((5,6-二氫-1H-[1,4]二咢辛[2,3-c]吡唑-3-基)甲基)-1-(2-甲氧基吡啶-4-基)脲
1H NMR(400MHz,Acetone)δ 8.11(d,J=5.6Hz,1H),7.83(dd,J=6.7Hz,2.5Hz,1H),7.43-7.36(m,1H),7.19(t,J=9.0Hz,1H),6.96(dd,J=5.6Hz,1.8Hz,1H),6.77(d,J=1.5Hz,1H),4.87(s,2H),4.26-4.20(m,2H),4.14-4.07(m,2H),3.88(s,3H).
實施例72:製備3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=426.1,
1H NMR(400MHz,DMSO-d6)δ 13.14(s,1H),8.28(s,1H),8.06(d,J=2.7Hz,1H),7.74(dd,J=6.9Hz,2.6Hz,1H),7.59(dd,J=8.8Hz,2.7Hz,1H),7.43(ddd,J=9.1Hz,4.3Hz,2.6Hz,1H),7.28(t,J=9.1Hz,1H),7.11-6.71(m,2H),6.36(s,1H),4.86(s,2H),3.87(s,3H).
實施例73:製備3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲
[M+H+]=432.1,
1H NMR(400MHz,Methanol-d4)δ 8.08(d,J=5.7Hz,1H),7.65(dd,J=6.7Hz,2.6Hz,1H),7.33(ddd,J=9.0Hz,4.2Hz,2.6Hz,1H),7.16(t,J=9.0Hz,1H),6.89(dd,J=5.7Hz,2.0Hz,1H),6.71(d,J=1.9Hz,1H),4.94(s,2H),4.62(s,2H),3.91(s,3H),3.88(t,J=5.6Hz,2H),2.73(t,J=5.6Hz,2H).
實施例74:製備3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=445.3,
1H NMR(300MHz,CDCl3)δ 8.27(d,J=5.5Hz,1H),7.47(dd,J=6.4Hz,2.5Hz,1H),7.10(m,2H),6.73(dd,J=5.5Hz,1.7Hz,1H),6.61(d,J=1.5Hz,1H),6.43(s,1H),6.37(s,1H),4.81(s,2H),3.99(s,3H).
實施例75:製備3-(3-氯基-4-氟苯基)-1-(5-甲氧基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲
[M+H+]=433.2,
1H NMR(300MHz,CDCl3)δ 8.26(d,J=2.7Hz,1H),8.08(d,J=2.0Hz,1H),7.47(dd,J=6.5Hz,2.6Hz,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=5.6Hz,2H),3.83(s,3H),2.74(t,J=5.6Hz,2H).
實施例76:製備3-(3-氯基-4-氟苯基)-1-(5-甲氧基吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲
1H NMR(400MHz,DMSO-d6)δ 11.56(s,1H),8.42(s,1H),8.23(d,J=2.7Hz,1H),8.02(d,J=1.9Hz,1H),7.73(dd,J=6.9Hz,2.6Hz,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=6.3Hz,2H),1.80-1.70(m,2H).
實施例77:製備3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(5-甲氧基吡啶-3-基)脲
[M+H+]=427.9,
1H NMR(400MHz,CDCl3)δ 11.27(s,1H),8.39(d,J=2.6Hz,1H),8.15(d,J=1.9Hz,1H),7.55-7.39(m,1H),7.07(dd,J=8.9Hz,5.1Hz,2H),6.93(t,J=2.3Hz,1H),6.70(t,J=55.0Hz,1H),6.31(s,1H),6.18(s,1H),4.78(s,2H),3.86(s,3H).
實施例78:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4-甲基-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=460.1,
1H NMR(500MHz,CDCl3)δ 11.22(s,1H),8.04(d,J=2.7Hz,1H),7.42(dd,J=6.4Hz,2.6Hz,1H),7.31(dd,J=8.8Hz,2.7Hz,1H),7.12-7.07(m,1H),7.04(t,J=8.7Hz,1H),6.85(d,J=8.8Hz,1H),6.05(s,1H),4.68(s,2H),3.99(s,3H),1.85(s,3H).
實施例79:製備3-(3-氯基-4-氟苯基)-1-((1-(羥甲基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=444.2,
1H NMR(400MHz,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).
實施例80:製備3-(3-氯基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=445.03,
1H NMR(400MHz,Chloroform-d)δ 11.56(s,1H),8.35(s,2H),7.52(dd,J=6.5Hz,2.7Hz,1H),7.18(ddd,J=8.9Hz,4.0Hz,2.7Hz,1H),7.07(t,J=8.7Hz,1H),6.60(s,1H),6.35(s,1H),4.76(s,2H),4.06(s,3H).
實施例81:製備1-((4-溴基-5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=508.1,
1H NMR(300MHz,CDCl3)δ 11.87(s,1H)8.35(s,2H),7.54(dd,J=6.5Hz,2.6Hz,1H),7.18(ddd,J=8.9Hz,4.1Hz,2.7Hz,1H),7.04(dd,J=14.3Hz,5.5Hz,2H),6.69(t,J=53.5Hz,1H),4.76(s,2H),4.03(s,3H).
實施例82:製備3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(甲氧基甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=470.2,
1H NMR(400MHz,DMSO-d6)δ 13.32-12.88(m,1H),8.17(s,1H),8.01(d,J=2.6Hz,1H),7.73(dd,J=2.4Hz,6.9Hz,1H),7.55(dd,J=2.8 H,8.8Hz,1H),7.43(ddd,J=2.8Hz,4.3Hz,9.1Hz,1H),7.27(t,J=9.2Hz,1H),7.12-6.74(m,2H),4.90(s,2H),4.24(s,2H),3.85(s,3H),3.09(s,3H).
實施例83:製備3-(3-氯基-4-氟苯基)-1-((4-(2-乙氧乙烯基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=514.2,
1H NMR(400MHz,CDCl3)δ 11.15(br s,1H),7.98(d,J=2.4Hz,1H),7.36(d,J=4.0Hz),7.27-7.25(m,1H),7.09-6.97(m,2H),6.78(d,J=8.8Hz,1H),6.06-5.99(m,2H),5.23(d,J=12.8Hz,1H),4.65(s,3H),3.91(s,3H),3,59(q,J=7.2Hz,2H),1.15(t,J=7.2Hz,3H).
實施例84:製備3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=427.0,
1H NMR(300MHz,CDCl3)δ 8.40(s,2H),7.51(dd,J=6.5Hz,2.4Hz,1H),7.16-7.03(m,2H),6.72(t,J=54.9Hz,1H),6.34(s,1H),6.07(s,1H),4.76(s,2H),4.11(s,3H).
實施例85:製備3-(3-氯基-4-氟苯基)-1-((4-(2-乙氧乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=516.2,
1H NMR(400MHz,CDCl3)δ 8.03(d,J=2.8Hz,1H),7.43(dd,J=2.5Hz,6.4Hz,1H),7.32(dd,J=2.8Hz,8.8Hz,1H),7.14-7.08(m,1H),7.07-7.02(m,1H),6.84(d,J=8.8Hz,1H),6.04(s,1H),4.76(s,2H),3.99(s,3H),3.31(q,J=7.0Hz,2H),3.26(t,J=6.6Hz,2H),2.55-2.44(m,2H),1.10-1.07(m,3H).
實施例86:製備3-(3-氯基-4-氟苯基)-1-((4-(2-羥乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=487.9,
1H NMR(400MHz,CDCl3)δ 8.06(d,J=2.3Hz,1H),7.42(dd,J=2.6Hz,6.4Hz,1H),7.38(dd,J=2.8Hz,8.8Hz,1H),7.11(dd,J=2.7Hz,4.2Hz,1H),7.09-7.03(m,1H),6.87(d,J=8.8Hz,1H),6.09(s,1H),4.81(s,2H),4.00(s,3H),3.61(t,J=6.2Hz,2H),2.55(t,J=6.1Hz,2H).
實施例87:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4-((4,4,5,5-四甲基-1,3-二氧環戊-2-基)甲基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
1H NMR(400MHz,CDCl3)δ 8.08(d,J=2.6Hz,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=8.8Hz,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=4.5Hz,2H),1.12(s,6H),1.03-0.99(m,6H).
實施例88:製備3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-甲氧基乙基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
1H NMR(400MHz,CDCl3)δ 11.15(s,1H),8.02(d,J=2.6Hz,1H),7.44(dd,J=2.6Hz,6.4Hz,1H),7.33(dd,J=2.8Hz,8.8Hz,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=6.6Hz,2H),3.17(s,3H),2.54(t,J=6.5Hz,2H).
實施例89:製備3-(4-氯基-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=446.1,
1H NMR(300MHz,MeOD)δ 8.45(s,2H),8.21(d,J=5.6Hz,1H),8.19(d,J=1.0Hz,1H),6.59(s,1H),5.00(s,2H),4.06(s,3H).
實施例90:製備3-(3-氯基-4-氟苯基)-1-((5-甲氧基-4-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
製備2-苄基-5-(芐氧基甲基)吡唑-3-醇
向4-芐氧基-3-氧丁酸乙酯(10.0g,42.3mmol,1eq)在MeOH(80mL)中的溶液加入TsOH(729mg,4.23mmol,0.1eq)及二(氫氯酸)苄肼鹽(benzylhydrazine dihydrochloride salt)(8.26g,42.3mmol,1eq),並於80℃攪拌所產生的混合物16小時。將反應混合物冷卻至室溫,並於減壓下濃縮乾燥。將殘留物溶於2N NaOH(25mL)中,並以EtOAc(1×30mL)萃取該溶液。將水相以HCl酸化至pH 3,並以過濾收集沉澱物,以提供呈黃色固體的2-苄基-5-(芐氧基甲基)吡唑-3-醇(3.98g,32%)。
製備1-苄基-3-(芐氧基甲基)-5-甲氧基-1H-吡唑
向甲基4-甲基苯磺酸甲酯(1.39g,7.47mmol,1.1eq)在DMF(10mL)中的溶液加入K2CO3(2.35g,17.0mmol,2.5eq)及2-苄基-5-(芐氧基甲基)吡唑-3-醇(2.0g,6.79mmol,1eq)。於25℃攪拌該混合物20小時。過濾該反應混合物,並於減壓下濃縮濾液。以逆相管柱層析法(0.1% FA)純化粗產物,以提供呈黃色油的1-苄基-3-(芐氧基甲基)-5-甲氧基-1H-吡唑(1.09g,52%產率)。
製備1-苄基-3-(芐氧基甲基)-4-碘基-5-甲氧基-1H-吡唑
向1-苄基-3-(芐氧基甲基)-5-甲氧基-吡唑(1.0g,3.24mmol,1eq)在H2O(5.5mL)中的混合物加入NaOAc(585mg,7.13mmol,2.20eq),並將所產生的混合物加熱至100℃,再添加I2(1.65g,6.48mmol,2eq)及由KI(3.23g,19.4mmol,6eq)和H2O(7mL)所組成的溶液。將該反應混合物於100℃攪拌10分鐘後,冷卻至常溫並分配於EtOAc(50mL)及H2O(20mL)之間。分離有機相,以滷水(30mL)洗滌,用無水Na2SO4乾燥、過濾並於減壓下濃縮。以管柱層析法(石油醚:乙酸乙酯=100:1至10:1)萃取殘留物,以提供呈白色固體的1-苄基-3-(芐氧基甲基)-4-碘基-5-甲氧基-1H-吡唑(1.14g,81%產率)。
製備1-苄基-3-(芐氧基甲基)-5-甲氧基-4-(三氟甲基)-1H-吡唑
向1-苄基-3-(芐氧基甲基)-4-碘基-5-甲氧基-吡唑(533mg,1.23mmol,1eq)在DMF(4mL)中的溶液於N2氣氛下加入CuI(584mg,3.07mmol,2.5eq)、KF(143mg,2.45mmol,2eq)及三甲基(三氟甲基)矽烷(872.27mg,6.13mmol,5eq)。於100℃攪拌所產生的混合物22小時後冷卻至常溫,過濾並濃縮至乾燥。以逆相HPLC(0.1% FA條件)純化粗產物,以提供呈白色固體的1-苄基-3-(芐氧基甲基)-5-甲氧基-4-(三氟甲基)-1H-吡唑(180mg,39%產率)。
製備(5-甲氧基-4-(三氟甲基)-1H-吡唑-3-基)甲醇
向1-苄基-3-(芐氧基甲基)-5-甲氧基-4-(三氟甲基)吡唑(100mg,266μmol,1eq)在MeOH(10mL)中的溶液加入10% Pd/C(43mg),並於50℃在H2(15psi)下攪拌產生的混合物16小時。該混合物透過矽藻土墊過濾,且於減壓下濃縮該濾液至乾燥,以提供(5-甲氧基-4-(三氟甲基)-1H-吡唑-3-基)甲醇(67mg,粗產物),其不經進一步純化而用於下一步驟。
製備3-(氯基甲基)-5-甲氧基-4-(三氟甲基)-1H-吡唑
於80℃攪拌(5-甲氧基-4-(三氟甲基)-1H-吡唑-3-基)甲醇(50mg,255μmol,1eq)溶於SOCl2(2mL)的溶液2小時。將該混合物冷卻至室溫,並在減壓下濃縮至乾燥,以提供呈黃色油的3-(氯基甲基)-5-甲氧基-4-(三氟甲基)-1H-吡唑(54mg,粗產物)。
製備3-(氯基甲基)-5-甲氧基-1-(四氫-2H-哌喃-2-基)-4-(三氟甲基)-1H-吡唑
向3-(氯基甲基)-5-甲氧基-4-(三氟甲基)-1H-吡唑(54mg,252μmol,1eq)在DCM(5mL)中的溶液加入DHP(42mg,503μmol,46μL,2eq),且於25℃攪拌所產生的混合物16小時。將該反應混合物於減壓下濃縮至乾燥,以提供呈黃色油的3-(氯基甲基)-5-甲氧基-1-(四氫-2H-哌喃-2-基)-4-(三氟甲基)-1H-吡唑(70mg,粗產物)。
製備6-甲氧基-N-((5-甲氧基-1-(四氫-2H-哌喃-2-基)-4-(三氟甲基)-1H-吡唑-3-基)甲基)吡啶-3-胺
將3-(氯基甲基)-5-甲氧基-1-四氫哌喃-2-基-4-(三氟甲基)吡唑(20mg,67μmol,1eq)、6-甲氧基吡啶-3-胺(17mg,134μmol,2eq)及K2CO3(28mg,201μmol,
3eq)在CH3CN(0.5mL)中的混合物於70℃攪拌1小時。將該反應混合物冷卻至室溫並濃縮。將殘留物進行逆相管柱層析法(0.1% FA),以提供呈無色油的6-甲氧基-N-((5-甲氧基-1-(四氫-2H-哌喃-2-基)-4-(三氟甲基)-1H-吡唑-3-基)甲基)吡啶-3-胺(30mg,粗產物)。
製備3-(3-氯基-4-氟苯基)-1-((5-甲氧基-1-(四氫-2H-哌喃-2-基)-4-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
將6-甲氧基-N-((5-甲氧基-1-(四氫-2H-哌喃-2-基)-4-(三氟甲基)-1H-吡唑-3-基)甲基)吡啶-3-胺(30mg,78μmol,1eq)、2-氯基-1-氟基-4-異氰酸基苯(40mg,233μmol,3eq)及DMAP(19mg,155μmol,2eq)在CH3CN(2mL)中的混合物於60℃攪拌30分鐘。降溫並濃縮該反應混合物。將殘留物進行逆相管柱層析法(0.1% FA),以提供呈無色油的3-(3-氯基-4-氟苯基)-1-((5-甲氧基-1-(四氫-2H-哌喃-2-基)-4-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(20mg,46%產率)。
製備3-(3-氯基-4-氟苯基)-1-((5-甲氧基-4-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
將3-(3-氯基-4-氟苯基)-1-((5-甲氧基-1-(四氫-2H-哌喃-2-基)-4-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(20mg,36μmol,1eq)在TFA(1mL)及DCM(2mL)中的溶液於25℃攪拌1小時後,於真空濃縮乾燥。以製備級液相層析Prep-HPLC(管柱:Phenomenex Gemini-NX C18 75mm×30mm×3μm;移動相:〔水(0.1%TFA)-ACN〕;B%:45%-75%,7分鐘)純化殘留物,接著冷凍乾燥,以取得呈白色固體的3-(3-氯基-4-氟苯基)-1-((5-甲氧基-4-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(5.5mg,32%產率,99%純度)。
[M+H+]=474.1,
1H NMR(400MHz,CDCl3)δ 8.05(d,J=2.4Hz,1H),7.46(dd,J=2.3Hz,6.4Hz,1H),7.36(dd,J=2.6Hz,8.7Hz,1H),7.12-7.02(m,2H),6.85(d,J=8.7Hz,1H),6.11(s,1H),4.78(s,2H),3.98(d,J=8.3Hz,6H).
實施例91:製備3-(3-氯基-4-氟苯基)-1-((4-(2-羥乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=489.1,
1H NMR(400MHz,CDCl3)δ 8.37(s,1H),7.46(dd,J=2.8Hz,6.4Hz 1H),7.04-7.13(m,2H),6.30(s,1H),4.82(s,2H),4.07(s,3H),3.63(t,J=6Hz,2H),2.54(t,J=6Hz,2H).
實施例92:製備3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-羥基丙-2-基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=485.1,
1H NMR(400MHz,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).
實施例93:製備of3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(丙-1-烯-2-基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=467.1,
1H NMR(400MHz,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).
實施例94:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=445.4,
1H NMR(500MHz,Methanol-d4)δ 8.03(s,1H),7.71(dd,J=6.7Hz,2.7Hz,1H),7.37(ddd,J=8.8Hz,4.2Hz,2.3Hz,1H),7.21(td,J=9.0Hz,1.7Hz,1H),6.76(s,1H),6.62(s,1H),5.10(s,2H),3.75(s,3H).
實施例95:製備3-(3-氯基-4-氟苯基)-1-((4-(2-羥丙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=503.1,
1H NMR(400MHz,DMSO-d6)δ 13.29(s,1H),8.48(s,2H),8.34(s,1H),7.72(dd,J=6.8Hz,2.4Hz,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=6.0Hz,3H).
實施例96:製備3-(3-氯基-4-氟苯基)-1-(6-甲氧嗒嗪-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=445.1,
1H NMR(400MHz,DMSO-d6)δ 13.92(s,1H),9.40(s,1H),8.52(d,J=10.0Hz,1H),7.98(d,J=5.0Hz,1H),7.48(d,J=2.9Hz,1H),7.31(t,J=9.0Hz,1H),7.26(d,J=10.0Hz,1H),6.81(s,1H),5.45(s,2H),3.83(s,3H).
實施例97:製備3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧嗒嗪-3-基)脲
[M+H+]=427.1,
1H NMR(400MHz,DMSO-d6)δ 3.83(s,3H),5.43(s,2H),6.61(s,1H),6.84(s,1H),6.98(s,1H),7.11(s,1H),7.21-7.35(m,2H),7.50(br d,J=7.95Hz,1H),7.98(br d,J=5.50Hz,1H),8.51(s,1H),8.54(s,1H),9.42(br s,1H),13.38(s,1 H).
實施例98:製備1-((4-溴基-5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=507.0,
1H NMR(400MHz,DMSO-d6)δ 13.73(br s,1H),8.51-8.47(m,2H),8.40(s,1H),7.71(dd,J=2.6Hz,6.8Hz,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).
實施例99:製備3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧嗒嗪-4-基)脲
[M+H+]=427.3,
1H NMR(500MHz,Methanol-d4)δ 8.05(s,1H),7.71(dd,J=6.7Hz,2.4Hz,1H),7.44-7.33(m,1H),7.21(t,J=9.0Hz,1H),6.94-6.63(m,2H),6.53(s,1H),5.08(s,2H),3.74(s,3H).
實施例100:製備3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-甲氧基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
1H NMR(400MHz,CDCl3)δ 10.88(s,1H),8.09(d,J=2.2Hz,1H),7.44(dd,J=2.6Hz,6.5Hz,1H),7.41(dd,J=2.8Hz,8.7Hz,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).
實施例101:製備3-(3-氯基-4-氟苯基)-1-((4-(2-羥基-2-甲基丙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=517.0,
1H NMR(400MHz,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).
實施例102:製備3-(3-氯基-4-氟苯基)-1-((4-(2-羥基丙-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=503.2,
1H NMR(400MHz,CDCl3)δ 8.37(s,2H),7.47(dd,J=2.6Hz,6.4Hz,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).
實施例103:製備3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-羥基-2-甲基丙基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=499.0,
1H NMR(400MHz,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).
實施例104:製備3-(3-氯基-4-氟苯基)-1-((5-氰基-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=402.2,
1H NMR(400MHz,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=9.1Hz,1.4Hz,1H),6.90(s,1H),4.90(s,2H),3.96(s,3H).
實施例105:製備3-(3-氯基-4-氟苯基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=432.9,
1H NMR(400MHz,CDCl3)δ 11.43-10.70(m,1H),7.45(dd,J=2.6Hz,6.4Hz,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).
實施例106:製備3-(6-氯基-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=446.1,
1H NMR(400MHz,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).
實施例107:製備3-(5-氯基-6-氟吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=446.1,
1H NMR(400MHz,DMSO-d6)δ 8.57(s,2H),8.25(dd,J=2.4Hz,8.4Hz,1H),8.19(t,J=2.0Hz,1H),6.65(s,1H),4.91(s,2H),3.96(s,3H).
實施例108:製備3-(3-氯基-4-氟苯基)-1-((1,3-二甲基-1H-吡唑-5-基)甲基)-1-(4-甲氧苯基)脲
[M+H+]=404.86,
1H NMR(300MHz,CDCl3)δ 7.44(dd,J=6.5Hz,2.6Hz,1H),7.09(ddd,J=8.9Hz,4.1Hz,2.7Hz,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).
實施例109:製備3-(3-氯基-4-氟苯基)-1-(3-(2-羥基丙-2-基)異噁唑-5-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲
[M+H+]=450.2,
1H NMR(300MHz,MeOD)δ 7.65(d,J=7.1Hz,1H),7.30(s,1H),7.14(t,J=8.9Hz,1H),5.11(s,2H),4.74(s,1H),3.91(t,J=5.6Hz,2H),3.63(s,2H),2.76(d,J=5.6Hz,2H),1.29(s,6H).
實施例110:製備3-(3-氯基-4-氟苯基)-1-(6-(2-羥基丙-2-基)吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲
[M+H+]=460.2,
1H NMR(400MHz,CDCl3)δ 8.43(s,1H),7.56-7.48(m,2H),7.44(dd,J=2.6Hz,6.4Hz,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=6.3Hz,2H),1.87-1.77(m,2H),1.59(s,6H).
實施例111:製備3-(3-氯基-4-氟苯基)-1-(6-(2-羥基丙-2-基)吡啶-3-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲
[M+H+]=460.3,
1H NMR(400MHz,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).
實施例112:製備3-(3-氯基-4-氟苯基)-1-(2-(2-羥基丙-2-基)吡啶-4-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲
[M+H+]=460.2,
1H NMR(400MHz,CDCl3)δ 8.60-8.54(m,1H),7.52(dd,J=2.6Hz,6.4Hz,1H),7.34(d,J=1.8Hz,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=5.4Hz,2H),1.55(s,6H).
實施例113:製備3-(3-氯基-4-氟苯基)-1-(2-(2-羥基丙-2-基)吡啶-4-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲
[M+H+]=460.3,
1H NMR(400MHz,MeOD)δ 8.44(d,J=5.5Hz,1H),7.64(dd,J=2.6Hz,6.6Hz,1H),7.57(d,J=1.8Hz,1H),7.31(ddd,J=2.6Hz,4.2Hz,9.0Hz,1H),7.17(t,J=2.8Hz,1H),7.16-7.11(m,1H),4.94(s,2H),4.16-4.08(m,2H),2.39(t,J=6.3Hz,2H),1.89-1.78(m,2H),1.52(s,6H).
實施例114:製備3-(3-氯基-4-氟苯基)-1-(4-羥基苯基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲
[M+H+]=401.3,
1H NMR(400MHz,DMSO-d6)δ 11.92(s,1H),9.55(s,1H),7.94(s,1H),7.71(dd,J=6.9Hz,2.6Hz,1H),7.41(td,J=4.5Hz,2.7Hz,1H),7.24(t,J=9.1Hz,1H),6.97(d,J=8.7Hz,2H),6.74(d,J=8.7Hz,2H),4.67(s,2H),2.51(s,2H),2.33(s,4H).
實施例115:製備3-(3-氯基-4-氟苯基)-1-(3-(2-羥基丙-2-基)異噁唑-5-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲
[M+H+]=450.2,
1H NMR(400MHz,CDCl3)δ 9.00(s,1H),7.61(dd,J=2.7Hz,6.5Hz,1H),7.35-7.28(m,1H),7.09(t,J=8.7Hz,1H),6.17(s,1H),4.97(s,2H),4.74(s,2H),3.89(t,J=5.6Hz,2H),2.73(t,J=5.5Hz,2H),1.60(s,6H).
實施例116:製備3-(3-氯基-4-氟苯基)-1-(3,4-二甲氧苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲
[M+H+]=460.1,
1H NMR(300MHz,CDCl3)δ 7.46(dd,J=6.5Hz,2.6Hz,1H),7.18-7.06(m,1H),7.00(t,J=8.7Hz,1H),6.89(d,J=8.5Hz,1H),6.77(dd,J=8.4Hz,2.3Hz,1H),6.60(d,J=2.3Hz,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=6.2Hz,2H),2.22(t,J=6.0Hz,2H),1.84-1.57(m,4H).
實施例117:製備3-(3-氯基-4-氟苯基)-1-(3,5-二甲氧苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲
[M+H+]=459.14,
1H NMR(300MHz,CDCl3)δ 7.47(dd,J=6.4Hz,2.6Hz,1H),7.16-7.09(m,1H),7.01(t,J=8.7Hz,1H),6.48(d,J=8.0Hz,2H),6.32(d,J=2.1Hz,2H),4.72(s,2H),3.76(s,6H),2.64(t,J=6.1Hz,2H),2.26(t,J=6.0Hz,2H),1.73(ddt,J=15.7Hz,9.3Hz,4.8Hz,4H).
實施例118:製備3-(3-氯基-4-氟苯基)-1-(6-氰基-5-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=467.24,
1H NMR(400MHz,DMSO-d6)δ 13.54(s,1H),8.84(s,1H),8.31(d,J=1.9Hz,1H),7.89(d,J=1.9Hz,1H),7.75(dd,J=6.9Hz,2.4Hz,1H),7.46-7.20(m,2H),6.63(s,1H),5.07(s,2H),3.96(s,3H).
實施例119:製備3-(3-氯基-4-氟苯基)-1-(5-氰基-6-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=469.1,
1H NMR(500MHz,Chloroform-d)δ 11.43(s,1H),8.22(s,1H),7.79(s,1H),7.47(d,J=6.6Hz,1H),7.19-7.05(m,2H),6.37(s,1H),6.06(s,1H),4.76(s,2H),4.15(s,3H).
實施例120:製備3-(3-氯基-4-氟苯基)-1-(5-氰基吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲
[M+H+]=427.0,
1H NMR(400MHz,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).
實施例121:製備3-(3-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲
[M+H+]=427.1,
1H NMR(400MHz,DMSO-d6)δ 11.55(s,1H),8.94(d,J=1.8Hz,1H),8.70(d,J=2.5Hz,1H),8.59(s,1H),8.33(t,J=2.2Hz,1H),7.69(dd,J=6.8Hz,2.3Hz,1H),7.44-7.25(m,2H),4.84(s,2H),4.17-3.94(m,2H),2.32(t,J=6.4Hz,2H),1.87-1.66(m,2H).
實施例122:製備3-(3-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲
[M+H+]=427.2,
1H NMR(400MHz,CDCl3)δ 8.69(br s,1H),8.61(d,J=5.8Hz,1H),7.69(d,J=2.1Hz,1H),7.57(dd,J=2.8Hz,6.5Hz,1H),7.52-7.45(m,1H),7.34-7.27(m,1H),7.09(t,J=8.8Hz,1H),4.81(s,2H),4.28-4.21(m,2H),2.33(t,J=6.2Hz,2H),1.94(s,2H).
實施例123:製備3-(3-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲
[M+H+]=427.3,
1H NMR(400MHz,Methanol-d4)δ 8.54(d,J=5.7Hz,1H),7.88(d,J=2.3Hz,1H),7.66(dd,J=6.7Hz,2.7Hz,1H),7.56(dd,J=5.8Hz,2.3Hz,1H),7.33(ddd,J=9.0Hz,4.1Hz,2.7Hz,1H),7.17(t,J=8.9Hz,1H),5.00(s,2H),4.62(s,2H),3.85(t,J=5.6Hz,2H),2.71(t,J=5.6Hz,2H).
實施例124:製備3-(3-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲
[M+H+]=427.1,
1H NMR(400MHz,DMSO-d6)δ 11.59(s,1H),8.85(s,1H),8.70(s,1H),8.08(d,J=8.2Hz,1H),7.93(d,J=8.6Hz,1H),7.71(dd,J=2.4Hz,6.8Hz,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).
實施例125:製備3-(3-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲
[M+H+]=427.2,
1H NMR(500MHz,Methanol-d4)δ 8.63(t,J=1.7Hz,1H),7.90(s,2H),7.62(dd,J=6.7Hz,2.6Hz,1H),7.30(ddd,J=9.0Hz,4.2Hz,2.6Hz,1H),7.17(t,J=9.0Hz,1H),4.97(s,2H),4.66(s,2H),3.89(t,J=5.6Hz,2H),2.74(s,2H).
實施例126:製備3-(3-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=421.2,
1H NMR(500MHz,Methanol-d4)δ 8.68(t,J=1.7Hz,1H),7.97-7.85(m,2H),7.65(dd,J=6.7Hz,2.6Hz,1H),7.31(ddd,J=9.0Hz,4.1Hz,2.6Hz,1H),7.17(t,J=9.0Hz,1H),6.71(t,J=55.2Hz,1H),6.46(s,1H),5.09(s,2H).
實施例127:製備3-(3-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲
[M+H+]=427.2,
1H NMR(400MHz,DMSO-d6)δ 12.36(s,1H),8.98(s,1H),8.71(d,J=2.0Hz,1H),8.12-8.01(m,1H),7.96(d,J=8.1Hz,1H),7.69(dd,J=2.4Hz,6.8Hz,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=5.5Hz,2H),2.43(s,2H).
實施例128:製備3-(3-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲
製備3-(疊氮基甲基)-1-(四氫-2H-哌喃-2-基)-1,4,5,7-四氫哌喃並[3,4-c]吡唑
向(1-四氫哌喃-2-基-1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲醇(300mg,1.26mmol,1eq)在THF(5mL)中的溶液於N2氣氛下加入DPPA(520mg,1.89mmol,409μL,1.5eq)及DBU(288mg,1.89mmol,285μL,1.5eq)。於20℃攪拌該反應混合物48小時後,以H2O(20mL)淬滅。所產生的混合物以EtOAc(10mL×3)萃取。將合併的有機層透過無水Na2SO4乾燥、過濾並於減壓下濃縮。利用快速矽膠層析法(flash silica gel chromatography)(石油醚:乙酸乙酯=100:1至1:1)純化殘留物,以提供呈白色油的3-(疊氮基甲基)-1-(四氫-2H-哌喃-2-基)-1,4,5,7-四氫哌喃並[3,4-c]吡唑(200mg,56%產率,93%純度)。
製備(1-(四氫-2H-哌喃-2-基)-1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲胺
向3-(疊氮基甲基)-1-四氫哌喃-2-基-5,7-二氫-4H-哌喃並[3,4-c]吡唑(200mg,760μmol,1eq)在THF(4mL)中的溶液加入10% Pd/C(800mg)。於20℃ H2(15psi)氣氛下攪拌所產生的混合物1小時。反應混合物透過矽藻土墊過濾,並濃縮濾液,以提供呈無色油的(1-(四氫-2H-哌喃-2-基)-1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲胺(200mg,80%產率,72%純度)。
製備4-((1-(四氫-2H-哌喃-2-基)-1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲胺基)氰吡啶
向(1-(四氫-2H-哌喃-2-基)-1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲胺(195mg,822μmol,1eq)及4-氟吡啶-2-腈(100mg,822μmol,1eq)在DMF(4mL)中的溶液加入K2CO3(341mg,2.47mmol,3eq)。於100℃攪拌所產生的混合物16小時。將該混合物倒入飽和NH4Cl溶液(30mL)中,接著以乙酸乙酯(30mL×3)萃取。將合併的有機層透過無水Na2SO4乾燥,過濾並真空濃縮。以逆相管柱層析法(0.1% FA)純化粗產物,以提供呈黃色固體的4-((1-(四氫-2H-哌喃-2-基)-1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲胺基)氰吡啶(80mg,27%產率,95%純度)。
製備3-(3-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1-(四氫-2H-哌喃-2-基)-1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲
向4-((1-(四氫-2H-哌喃-2-基)-1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲胺基)氰吡啶(60mg,177μmol,1eq)及2-氯基-1-氟基-4-異氰酸基苯(91mg,530μmol,3eq)在CH3CN(1.5mL)中的溶液加入DMAP(65mg,530μmol,3eq)。於80℃攪拌混合物0.2小時候,於真空乾燥濃縮。以逆相層析法(0.1% FA)純化殘留物,以
提供呈白色固體的3-(3-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1-(四氫-2H-哌喃-2-基)-1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲(16mg,16%產率,90%純度)。
製備3-(3-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲
向3-(3-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1-(四氫-2H-哌喃-2-基)-1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲(15mg,29μmol,1eq)在DCM(2mL)中的溶液加入TFA(1mL),並於20℃攪拌所產生的混合物2小時。濃縮該混合物,以製備級液相層析(管柱:Phenomenex Synergi C18 150mm×25mm×10μm;移動相:[水(0.225% FA)-ACN];30%-60%,10分鐘)純化殘留物,以提供呈白色固體的3-(3-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲(10.8mg,85%產率,99%純度)。
[M+H+]=427.2,
1H NMR(400MHz,DMSO-d6)δ 12.40(s,1H),9.50(s,1H),8.59(d,J=5.6Hz,1H),8.09(d,J=2.1Hz,1H),7.75(dd,J=2.3Hz,6.8Hz,1H),7.64(d,J=3.8Hz,1H),7.42-7.40(m,2H),5.03(s,2H),4.58(s,2H),3.72(t,J=5.6Hz,2H),2.49-2.46(m,2H).
實施例129:製備3-(3-氯基-4-氟苯基)-1-(5-氰基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲
[M+H+]=425.25,
1H NMR(400MHz,Chloroform-d)δ 10.52(s,1H),8.92-8.61(m,2H),7.97(t,J=2.3Hz,1H),7.84(s,1H),7.50(dd,J=6.5Hz,2.7Hz,1H),7.21(dt,J=8.9Hz,3.4Hz,1H),7.07(t,J=8.7Hz,1H),4.82(s,2H),4.45(s,2H),3.91(t,J=5.6Hz,2H),2.77(t,J=5.6Hz,2H).
實施例130:製備3-(3-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=437.26,
1H NMR(400MHz,DMSO-d6)δ 13.59(s,1H),8.79(d,J=2.4Hz,2H),8.10(d,J=8.4Hz,1H),8.02(dd,J=8.4Hz,2.6Hz,1H),7.72(dd,J=6.9Hz,2.4Hz,1H),7.41-7.28(m,2H),6.60(s,1H),5.07(s,2H).
實施例131:製備4-(3-(3-氯基-4-氟苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲基)苄酸
[M+H+]=443.3,
1H NMR(500MHz,DMSO-d6)δ 8.73(s,1H),7.92(d,J=8.6Hz,2H),7.71(dd,J=6.8Hz,2.6Hz,1H),7.47-7.37(m,3H),7.30(t,J=9.1Hz,1H),4.90(s,2H),2.55(t,J=6.1Hz,2H),2.29(t,J=6.1Hz,2H),1.71-1.58(m,4H).
實施例132:製備3-(3-氯基-4-氟苯基)-1-(異噁唑-3-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲
[M+H+]=392.2,
1H NMR(300MHz,CDCl3)δ 10.27(s,1H),8.27(d,J=1.7Hz,1H),7.74(dd,J=6.5Hz,2.6Hz,1H),7.49-7.34(m,1H),7.11(t,J=8.8Hz,1H),6.71(d,J=1.6Hz,1H),5.09(s,2H),2.62(t,J=5.6Hz,2H),2.51(t,J=5.6Hz,2H),1.86-1.64(m,4H).
實施例133:製備3-(3-氯基-4-氟苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(1,3,4-噻二唑-2-基)脲
[M+H+]=409.05,
1H NMR(500MHz,DMSO)δ 12.45(s,1H),10.15(s,1H),9.14(s,1H),7.76(d,J=4.9Hz,1H),7.44(dd,J=19.5Hz,10.5Hz,2H),5.47(s,2H),2.53(s,2H),2.44(s,2H),1.66(d,J=5.4Hz,4H).
實施例134:製備3-(3-氯基-4-氟苯基)-1-(異噁唑-3-基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲
[M+H+]=376.17,
1H NMR(300MHz,CDCl3)δ 10.20(s,1H),8.30(d,J=1.8Hz,1H),7.73(dd,J=6.5Hz,2.6Hz,1H),7.37(ddd,J=8.9Hz,4.1Hz,2.7Hz,1H),7.10(t,J=8.8Hz,1H),6.49(d,J=1.7Hz,1H),4.97(s,2H),2.74-2.67(m,2H),2.63-2.56(m,2H),2.53-2.43(m,2H).
實施例135:製備3-(3-氯基-4-氟苯基)-1-(1H-吡唑-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲
[M+H+]=391.2,
1H NMR(300MHz,DMSO-d6)δ 12.76(s,1H),11.57(s,1H),10.55(s,1H),7.86(dd,J=6.6Hz,2.5Hz,1H),7.78(d,J=2.5Hz,1H),7.44-7.31(m,2H),6.10(d,J=2.4Hz,1H),4.90(s,2H),4.01(t,J=4.65Hz,2H),2.32(t,J=6.4Hz,2H),1.83-1.63(m,2H).
實施例136:製備3-(3-氯基-4-氟苯基)-1-(異噁唑-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲
[M+H+]=392.3,
1H NMR(400MHz,CDCl3)δ 10.18(s,1H),8.32(d,J=1.6Hz,1H),7.72(dd,J=2.6Hz,6.6Hz,1H),7.40-7.34(m,1H),7.11(t,J=8.8Hz,1H),6.44(d,J=1.5Hz,1H),4.90(s,2H),4.26-4.19(m,2H),2.62-2.56(m,2H),2.00-1.92(m,2H).
實施例137:製備1-(雙環[1.1.1]戊-1-基)-3-(3-氯基-4-氟苯基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=402.9,
1H NMR(400MHz,CDCl3)δ 7.53(dd,J=2.7Hz,6.4Hz,1H),7.21(ddd,J=2.7Hz,4.0Hz,8.9Hz,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).
實施例138:製備3-(6-氯基-4-(二甲胺基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=489.2,
1H NMR(400MHz,CDCl3)δ 11.69-10.42(m,1H),8.33(s,2H),7.41(d,J=6.1Hz,1H),6.57(s,1H),6.34(s,1H),4.72(s,2H),4.09(s,3H),3.14(d,J=2.1Hz,6H).
實施例139:製備3-(3-氯基-4-氟基-5-甲基苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=441.1,
1H NMR(400MHz,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=2.3Hz,3H).
實施例140:製備3-(3-氯基-4-氟基-5-甲基苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=459.2,
1H NMR(400MHz,CDCl3)δ 11.58-10.91(m,1H),8.38(s,2H),7.24(d,J=2.8Hz,1H),6.98(dd,J=2.4Hz,5.8Hz,1H),6.34(s,1H),5.94(s,1H),4.73(s,2H),4.09(s,3H),2.27(d,J=2.3Hz,3H).
實施例141:製備3-(6-氯基-3-氟基-4-甲基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=460.2,
1H NMR(400MHz,CDCl3)δ 8.39(s,2H),7.01(d,J=3.8Hz,1H),6.55(s,1H),6.35(s,1H),4.78(s,2H),4.05(s,3H),2.32(d,J=1.3Hz,3H).
實施例142:製備3-(6-氯基-5-氟基-4-甲基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=460.1,
1H NMR(400MHz,CDCl3)δ 11.78-10.53(m,1H),8.40-8.28(m,2H),7.91(d,J=4.5Hz,1H),6.70(s,1H),6.35(s,1H),4.74(s,2H),4.10(s,3H),2.39(d,J=1.5Hz,3H).
實施例143:製備3-(2-氯基嘧啶-5-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=429.1,
1H NMR(400MHz,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).
實施例144:製備3-(3-氰基苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=418.2,
1H NMR(400MHz,CDCl3)δ 11.51(s,1H),8.35(s,2H),7.75(s,1H),7.60(d,J=7.6Hz,1H),7.41-7.37(m,2H),6.73(s,1H),6.36(s,1H),4.77(s,2H),4.05(s,3H).
實施例145:製備3-(6-氰基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=419.1,
1H NMR(300MHz,MeOD)δ 8.43(s,2H),8.27(d,J=8.6Hz,1H),7.90(dd,J=8.6Hz,7.5Hz,1H),7.56-7.40(m,1H),6.58(s,1H),4.98(s,2H),4.04(s,3H).
實施例146:製備3-(2-氰基吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=419.6,
1H NMR(500MHz,DMSO-d6)δ 13.56(s,1H),9.01(s,1H),8.58(s,2H),8.50(d,J=5.7Hz,1H),8.07(s,1H),7.75(d,J=5.6Hz,1H),6.67(s,1H),4.93(s,2H),3.96(s,3H).
實施例147:製備3-(3-氰基苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=400.1,
1H NMR(400MHz,CDCl3)δ 11.77-10.63(m,1H),8.36(s,2H),7.77(d,J=1.5Hz,1H),7.55(td,J=2.1Hz,7.5Hz,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).
實施例148:製備3-(6-氰基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=418.9,
1H NMR(400MHz,CDCl3)δ 8.42-8.38(m,3H),7.87(t,J=7.9Hz,1H),7.43(d,J=7.6Hz,1H),7.01(s,1H),6.40(s,1H),4.80(s,2H),4.13(s,3H).
實施例149:製備3-(3-氰基-4,5-二氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=454.1,
1H NMR(400MHz,DMSO-d6)δ 8.52(s,2H),7.80(q,J=9.5Hz,1H),7.26(br dd,J=2.8Hz,9.0Hz,1H),6.69(s,1H),4.91(s,2H),3.95(s,3H).
實施例150:製備3-(3-氰基-4,5-二氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=436.1,
1H NMR(400MHz,CDCl3)δ 8.42(s,2H),7.84(ddd,J=1.9Hz,3.8Hz,9.3Hz,1H),7.43(q,J=9.4Hz,1H),6.87-6.55(m,2H),6.36(s,1H),4.78(s,2H),4.08(s,3H).
實施例151:製備3-(6-氰基-4,5-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=455.1,
1H NMR(400MHz,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).
實施例152:製備3-(4-氰基-3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=468.05,
1H NMR(400MHz,DMSO-d6)δ 13.57(s,1H)δ 8.87(s,1H),8.58(s,2H),7.94(s,1H),7.87(q,J=8.7Hz,2H),7.20(t,J=54.3Hz,1H),6.64(s,1H),4.93(s,2H),3.95(s,3H).
實施例153:製備1-((5-氰基-1H-吡唑-3-基)甲基)-3-(4-氰基-3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=425.2,
1H NMR(500MHz,DMSO-d6)δ 13.89(s,1H),8.91(s,1H),8.59(s,2H),7.94(s,1H),7.90(d,J=8.6Hz,1H),7.84(d,J=8.7Hz,1H),7.21(t,J=54.4Hz,1H),6.91(s,1H),4.93(s,2H),3.96(s,3H).
實施例154:製備3-(3-氰基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=436.3,
1H NMR(500MHz,Methanol-d4)δ 8.45(s,2H),7.87(dd,J=6.0Hz,2.7Hz,1H),7.69(ddd,J=9.0Hz,4.7Hz,2.6Hz,1H),7.27(t,J=9.0Hz,1H),6.58(s,1H),4.98(s,2H),4.07(s,3H).
實施例155:製備3-(3-氰基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=418.1,
1H NMR(300MHz,DMSO)δ 13.19(s,1H),8.58(s,1H),8.52(s,2H),7.94(dd,J=5.8Hz,2.7Hz,1H),7.77(ddd,J=9.2,4.9Hz,2.8Hz,1H),7.44(t,J=9.1Hz,1H),6.93(t,J=54.5Hz,1H),6.45(s,1H),4.90(s,2H),3.95(s,3H).
實施例156:製備3-(4-氰基-3-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=436.1,
1H NMR(400MHz,DMSO)δ 8.56(s,1H),7.81-7.66(m,1H),7.41(d,J=9.3Hz,1H),6.64(s,1H),4.92(s,1H),3.95(s,1H).
實施例157:製備1-((5-氰基-1H-吡唑-3-基)甲基)-3-(3-氰基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=393.2,
1H NMR(500MHz,DMSO-d6)δ 13.87(s,1H),8.59(s,1H),8.55(s,2H),7.93(dd,J=6.2Hz,2.8Hz,1H),7.75(dt,J=8.2Hz,3.5Hz,1H),7.44(t,J=9.1Hz,1H),6.91(s,1H),4.90(s,2H),3.96(s,3H).
實施例158:製備3-(2-氰基-3-氟吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=437.1,
1H NMR(500MHz,DMSO-d6)δ 13.57(s,1H),9.02(s,1H),8.58(s,2H),8.46(d,J=5.4Hz,1H),8.05(t,J=5.9Hz,1H),6.65(s,1H),4.95(s,2H),3.95(s,3H).
實施例159:製備3-(3-氯基-4-氟苯基)-1-((1,3-二甲基-1H-吡唑-4-基)甲基)-1-(4-甲氧苯基)脲
1H NMR(300MHz,DMSO)δ 7.90(br,1H),7.73(dd,J=6.90Hz,2.61Hz,1H),7.40(m,2H),7.27(t,J=9.15Hz,1H),7.07(d,J=8.91Hz,2H),6.96(d,J=8.94Hz,2H),4.56(s,2H),3.76(s,3H),3.66(s,3H),1.80(s,3H).
實施例160:製備3-(6-氰基-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
1H NMR(300MHz,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).
實施例161:製備3-(4-氰基-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=437.2,
1H NMR(400MHz,CDCl3)δ 8.44(d,J=4.5Hz,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).
實施例162:製備3-(3-氰基-4-氟苯基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=424.2,
1H NMR(400MHz,CDCl3)δ 7.74(dd,J=2.8Hz,5.3Hz,1H),7.61(ddd,J=2.8Hz,4.4Hz,9.0Hz,1H),7.21(t,J=8.6Hz,1H),6.81(s,1H),6.45(s,1H),4.52(s,2H),3.37(s,3H),2.36(s,6H).
實施例163:製備3-(3-氰基-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
製備3-氰基-4-氟苯基胺甲酸苯基酯
向5-胺-2-氟苄腈(1g,7.35mmol,1eq)在DCM(20mL)中的混合物加入Py(697mg,8.82mmol,712μL,1.2eq)及氯甲酸苯基酯(phenyl carbonochloridate)(1.27g,8.08mmol,1.01mL,1.1eq)。於25℃攪拌該混合物1小時。將該混合物倒入檸檬酸溶液(5%,20mL)中,並以DCM(20mL×3)萃取所產生的混合物。將合併的有機層透過Na2SO4乾燥,過濾並真空濃縮,以提供呈無色油的3-氰基-4-氟苯基胺甲酸苯基酯(1.7g,6.63mmol,90.31%產率)。殘留物不經進一步純化而用於下一步驟。
製備3-(3-氰基-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((1-四氫-2H-哌喃-2-基-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
向6-甲氧基-N-((1-四氫-2H-哌喃-2-基-5-(三氟甲基)-1H-吡唑-3-基)甲基)嗒嗪-4-胺(25mg,70μmol,1eq)在DMF(1mL)中的混合物加入NaH(4mg,84μmol,60%純度,1.2eq)。於30℃攪拌該混合物30分鐘。接著加入N-(3-氰基-4-氟苯基)胺甲酸苯基酯(27mg,104.94μmol,1.5eq)至該混合物,該產生的混合物於30℃
攪拌5分鐘。將該混合物倒入飽和NH4Cl溶液(10mL),並以EtOAc(10mL×3)萃取所產生的混合物。將合併的有機層透過Na2SO4乾燥,過濾並真空濃縮。以prep-TLC(石油醚:乙酸乙酯=1:1)純化殘留物,接著過濾及濃縮,以提供呈黃色油的3-(3-氰基-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((1-四氫-2H-哌喃-2-基-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(15mg,29μmol,41.27%產率)。
製備3-(3-氰基-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
向3-(3-氰基-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((1-四氫-2H-哌喃-2-基-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(15mg,29μmol,1eq)在DCM(3mL)中的混合物加入TFA(1.54g,13.51mmol,1mL,467.72eq)。於30℃攪拌該混合物1小時並濃縮。以製備級液相層析(管柱:Unisil 3-100 C18 Ultra 150mm×50mm×3μm;移動相:[水(0.225%FA)-ACN];B%:35%-55%,10分鐘)純化殘留物,接著冷凍乾燥,以提供呈灰白色(off-white)固體的3-(3-氰基-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(6.3mg,14.33μmol,49.61%產率,99%純度)。
[M+H+]=436.1,
1H NMR(400MHz,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).
實施例164:製備3-(6-氰基-4-(二甲胺基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=480.2,
1H NMR(400MHz,CDCl3)δ 11.69-10.79(m,1H),8.36(s,2H),7.64(d,J=7.0Hz,1H),6.75(s,1H),6.37(s,1H),4.74(s,2H),4.10(s,3H),3.18(d,J=2.1Hz,6H).
實施例165:製備3-(2,6-二氯吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=462.1,
1H NMR(400MHz,CDCl3)δ 11.14(br s,1H),8.54(d,J=8.4Hz,1H),8.44(s,2H),7.31(d,J=8.6Hz,1H),6.62(s,1H),6.39(s,1H),4.77(s,2H),4.11(s,3H).
實施例166:製備3-(2,6-二氯吡啶-3-基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=444.1,
1H NMR(400MHz,CDCl3)δ 8.56(d,J=8.6Hz,1H),8.44(s,2H),7.31(d,J=8.6Hz,1H),6.86-6.54(m,2H),6.36(s,1H),4.77(s,2H),4.10(s,3H).
實施例167:製備3-(3,4-二氰苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=443.1,
1H NMR(500MHz,Methamol-d4)δ 8.45(s,2H),8.18(d,J=2.2Hz,1H),7.88(dd,J=8.8Hz,2.2Hz,1H),7.82(d,J=8.7Hz,1H),6.60(s,1H),5.00(s,2H),4.07(s,3H).
實施例168:製備3-(3,4-二氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=428.2,
1H NMR(500MHz,CDCl3)δ 11.40(s,1H),8.06(d,J=2.7Hz,1H),7.43-7.30(m,2H),7.05(dd,J=18.6Hz,8.9Hz,1H),6.92-6.78(m,2H),6.33(s,1H),6.09(s,1H),4.74(s,2H),4.00(s,3H).
實施例169:製備3-(3,6-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=430.2,
1H NMR(400MHz,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).
實施例170:製備3-(5,6-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
製備3-(5,6-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((1-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
向5,6-二氟吡啶-2-胺(55mg,423μmol,1eq)及DIPEA(164mg,1.27mmol,221μL,3eq)在DCM(2mL)中的混合物加入CDI(89mg,550μmol,1.3eq),並於30℃攪拌所產生的溶液16小時。接著加入2-甲氧基-N-((1-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)嘧啶-5-胺(100mg,280μmol,0.66eq),並於30℃攪拌該溶液20小時後濃縮,以提供呈灰色固體的3-(5,6-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((1-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(0.22g,粗產物)。該粗產物不經進一步而純化用於下一步驟。
製備3-(5,6-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
將由上一步驟所取得之3-(5,6-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((1-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(0.22g,429μmol,1eq)在4M HCl(1mL)及CH3CN(1mL)中的溶液於30℃攪拌2小時及40℃攪拌1小時。將反應混合物倒入飽和NaHCO3水溶液(30mL)中,並以乙酸乙酯(15mL×3)萃取所產生的混合物。將合併的有機層用滷水(10mL)洗滌,透過無水Na2SO4乾燥並過濾。真空濃縮濾液。以製備級液相層析(管柱:Shim-pack C18 150mm×25mm×10μm;移動相:[水(0.225% FA)-ACN];B%:42%-62%,10分鐘)純化粗產物,接著冷凍乾燥,以提供呈白色固體的3-(5,6-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲(12.3mg,6.6%產率,99%純度)。
[M+H+]=430.0,
1H NMR(400MHz,CDCl3)δ 11.46-11.15(m,1H),8.37(s,2H),7.96(dd,J=2.6Hz,8.7Hz,1H),7.61(q,J=8.7Hz,1H),6.68(s,1H),6.37(s,1H),4.76(s,2H),4.11(s,3H).
實施例171:製備3-(5,6-二氟吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=430.1,
1H NMR(400MHz,CDCl3)δ 12.40-10.27(m,1H),8.33(s,2H),8.08(ddd,J=2.3Hz,8.3Hz,10.6Hz,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).
實施例172:製備3-(4,5-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=429.9,
1H NMR(400MHz,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).
實施例173:製備3-(3,4-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H]+=429.9,
1H NMR(400MHz,CDCl3)δ11.88-11.27(m,1H),8.43(s,2H),8.08(t,J=6.0Hz,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).
實施例174:製備3-(5-(二氟甲基)吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=444.2,
1H NMR(500MHz,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=55.3Hz,1H),6.65(s,1H),4.93(s,2H),3.96(s,3H).
實施例175:製備3-(2-(二氟甲基)吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=444.2,
1H NMR(500MHz,DMSO-d6)δ 13.57(s,1H),8.88(s,1H),8.59(s,2H),8.44(d,J=5.6Hz,1H),7.84(s,1H),7.69(d,J=5.6Hz,1H),6.86(t,J=55.2Hz,1H),6.65(s,1H),4.94(s,2H),3.96(s,3H).
實施例176:製備3-(3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=443,
1H NMR(400MHz,Ch1oroform-d)δ 11.36(s,1H),8.42(s,2H),7.51(s,1H),7.43(d,J=6.2Hz,2H),6.64(t,J=56.4Hz,1H),6.37(s,1H),6.18(s,1H),4.78(s,2H),4.12(s,3H).
實施例177:製備3-(6-(二氟甲基)吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=444.2,
1H NMR(500MHz,DMSO-d6)δ 13.56(s,1H),9.41(s,1H),8.53(d,J=1.4Hz,2H),8.06(d,J=8.5Hz,1H),7.93(t,J=8.0Hz,1H),7.31(d,J=7.4Hz,1H),6.79(t,J=55.0Hz,1H),6.65(s,1H),4.95(s,2H),3.94(s,3H).
實施例178:製備1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=425.2,
1H NMR(400MHz,DMSO-d6)δ 13.25(br s,1H),8.53-8.47(m,3H),7.69(s,1H),7.63(d,J=8.6Hz,1H),7.38(t,J=7.9Hz,1H),7.20-6.75(m,3H),6.43(s,1H),4.91(s,2H),3.95(s,3H).
實施例179:製備1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(6-(二氟甲基)吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=426.1,
1H NMR(400MHz,CDCl3)δ 8.43-8.33(m,2H),8.20(d,J=7.9Hz,1H),7.85(t,J=8.0Hz,1H),7.31(d,J=7.5Hz,1H),6.88-6.55(m,2H),6.53-6.23(m,2H),4.77(s,2H),4.10(s,3H).
實施例180:製備1-((5-氰基-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=400.0,
1H NMR(400MHz,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=8.2Hz,1H),7.38(t,J=7.9Hz,1H),7.17(d,J=7.6Hz,1H),7.12-6.81(m,2H),4.91(s,2H),3.96(s,3H).
實施例181:製備3-(3-(二氟甲基)苯基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=431.2,
1H NMR(400MHz,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).
實施例182:製備1-((4-(2-乙氧乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=482.2,
1H NMR(400MHz,CDCl3)δ 11.36(s,1H),8.04(d,J=2.6Hz,1H),7.33(dd,J=2.8Hz,8.8Hz,1H),7.24-7.18(m,2H),7.02-6.95(m,2H),6.84(d,J=8.8Hz,1H),6.04(s,1H),4.75(s,2H),3.98(s,3H),3.31(q,J=7.0Hz,2H),3.25(t,J=6.6Hz,2H),2.50(t,J=6.7Hz,2H),1.09(t,J=7.0Hz,3H).
實施例183:製備3-(6-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=412.1,
1H NMR(400MHz,CDCl3)δ 11.24(br s,1H),8.72(s,1H),8.36(s,2H),7.97(dd,J=1.8Hz,8.1Hz,1H),7.81(q,J=8.2Hz,1H),6.68(s,1H),6.63(dd,J=2.1Hz,7.9Hz,1H),6.36(s,1H),4.75(s,2H),4.12-4.09(m,3H).
實施例184:製備3-(6-氟吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=446.1,
1H NMR(400MHz,DMSO-d6)δ 8.64-8.46(m,3H),8.25-8.20(m,1H),8.00(ddd,J=2.8Hz,7.4Hz,8.9Hz,1H),7.11(dd,J=3.2Hz,8.9Hz,1H),6.64(s,1H),4.91(s,2H),3.95(s,3H).
實施例185:製備3-(3-氟雙環[1.1.1]戊-1-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=401.1,
1H NMR(400MHz,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=2.0Hz,6H),2.17(s,1H).
實施例186:製備3-(2-氟嘧啶-5-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=413.1,
1H NMR(400MHz,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).
實施例187:製備3-(4-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=412.0,
1H NMR(400MHz,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).
實施例188:製備3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=461.3,
1H NMR(500MHz,CDCl3)δ 11.56(s,1H),8.06(d,J=2.7Hz,1H),7.52-7.43(m,1H),7.41-7.39(m,1H),7.35(dd,J=8.8Hz,2.8Hz,1H),7.06(t,J=9.2Hz,1H),6.98-6.70(m,2H),6.32(s,1H),6.18(s,1H),4.75(s,2H),3.99(s,3H).
實施例189:製備3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=461.1,
1H NMR(300MHz,CDCl3)δ 11.34(s,1H),8.41(s,2H),7.53-7.48(m,2H),7.12(t,J=9.1Hz,1H),6.88(t,J=54.9Hz,1H),6.37(s,1H),6.22(s,1H),4.77(s,2H),4.11(s,3H).
實施例190:製備1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=442.3,
1H NMR(300MHz,CDCl3)δ 11.19(s,1H),8.41(s,2H),7.56-7.41(m,2H),7.11(t,J=9.3Hz,1H),6.80(td,J=54.9Hz,46.4Hz,2H),6.34(s,1H),6.21(s,1H),4.77(s,2H),4.11(s,3H).
實施例191:製備1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲
[M+H+]=443.2,
1H NMR(400MHz,CDCl3)δ 11.18(s,1H),8.06(d,J=2.1Hz,1H),7.54-7.45(m,1H),7.41(d,J=5.2Hz,1H),7.35(dd,J=8.7Hz,2.4Hz,1H),7.07(t,J=9.1Hz,1H),6.97-6.55(m,3H),6.29(s,1H),6.14(s,1H),4.73(s,2H),4.00(s,2H).
實施例192:製備3-(4-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=463.3,
1H NMR(500MHz,DMSO-d6)δ 13.56(s,1H),9.51(s,1H),8.54(s,2H),8.41(s,1H),8.17(d,J=5.1Hz,1H),7.32(t,J=53.6Hz,1H),6.65(s,1H),4.95(s,2H),3.96(s,3H).
實施例193:製備3-(3-(二氟甲基)-4-氟苯基)-1-((4-(2-羥乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=505.2,
1H NMR(400MHz,CDCl3)δ 11.42-11.22(br,1H),8.38(s,2H),7.59-7.44(m,2H),7.08(t,J=6.8Hz,1H),6.84(t,J=54.5Hz,1H),6.25(s,1H),4.81(s,2H),4.07(s,3H),3.62(t,J=8.0Hz,2H),2.53(t,J=8.0Hz,2H).
實施例194:製備1-((4-溴基-5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=539.1,541.1,
1H NMR(400MHz,CDCl3)δ 11.57(br s,1H),8.44(s,2H),7.52-7.41(m,2H),7.09(t,J=9.1Hz,1H),6.99-6.70(m,1H),6.18(s,1H),4.77(s,2H),4.10(s,3H).
實施例195:製備1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧嗒嗪-3-基)脲
[M+H+]=443.1,
1H NMR(400MHz,DMSO-d6)δ 13.34(s,1H),9.43(s,1H),8.53(d,J=10.0Hz,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).
實施例196:製備1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=444.1,
1H NMR(400MHz,CDCl3)δ 11.66-10.69(m,1H),8.41-8.36(m,2H),8.31-8.24(m,1H),7.57(t,J=8.9Hz,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).
實施例197:製備1-((4-溴基-5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=521.0,523.0,
1H NMR(400MHz,DMSO-d6)δ 13.77(s,1H),8.50(s,2H),8.46(s,1H),7.70(d,J=6.0Hz,1H),7.67-7.59(m,1H),7.35-6.78(m,3H),4.89(s,2H),3.98-3.88(m,3H).
實施例198:製備1-((5-(二氟甲基)-4-(2-羥基丙-2-基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=501.2,
1H NMR(400MHz,CDCl3)δ 11.47-10.67(m,1H),8.34(s,2H),7.49-7.37(m,2H),7.01(t,J=9.2Hz,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).
實施例199:製備3-(3-(二氟甲基)-4-氟苯基)-1-((4-(2-羥丙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=519.2,
1H NMR(400MHz,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=14.9Hz,1H),2.24(s,1H),1.14(s,3H).
實施例200:製備3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧嗒嗪-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=461.2,
1H NMR(400MHz,DMSO-d6)δ 13.68(s,1H),9.42(s,1H),8.54(d,J=10.0Hz,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).
實施例201:製備1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)脲
[M+H+]=443.0,
1H NMR(400MHz,DMSO-d6)δ 13.46-13.15(m,1H),9.68-9.25(m,1H),8.96(d,J=2.3Hz,1H),7.77(dd,J=2.2Hz,6.4Hz,1H),7.63(dd,J=3.7Hz,8.4Hz,1H),7.33(d,J=9.2Hz,1H),7.30-6.75(m,3H),6.41(s,1H),5.09(s,2H),4.01(s,3H).
實施例202:製備3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=462.1,
1H NMR(400MHz,CDCl3)δ 11.32(s,1H),8.41(s,2H),8.28(dd,J=9.2Hz,2.8Hz,1H),7.60(t,J=8.9Hz,1H),7.00(s,1H),6.68(t,J=53.7Hz,1H),6.39(s,1H),4.79(s,2H),4.13(s,3H).
實施例203:製備3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
1H NMR(400MHz,CDCl3)δ 8.76(d,J=2.0Hz,1H),7.66-7.59(m,2H),7.41-7.30(m,1H),7.14(t,J=9.0Hz,1H),7.03-6.75(m,2H),6.44(s,1H),4.91(s,2H),4.13(s,3H).
實施例204:製備3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=462.0,
1H NMR(400MHz,Acetonitrile-d3)δ 11.68-11.54(m,1H),8.39(s,2H),8.21(dd,J=3.4Hz,9.2Hz,1H),7.67(t,J=9.2Hz,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).
實施例205:製備3-(3-(二氟甲基)-4-氟苯基)-1-((4-(2-羥基-2-甲基丙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=533.0,
1H NMR(400MHz,CDCl3)δ 8.39-8.31(m,2H),7.55-7.49(m,1H),7.49-7.44(m,1H),7.10(t,J=9.2Hz,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).
實施例206:製備3-(4-(二氟甲基)-3-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=461.1,
1H NMR(400MHz,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=10.8Hz,2H),4.78(s,2H),4.11(s,3H).
實施例207:製備3-(3-(二氟甲基)-4-氟苯基)-1-((4-(2-羥基丙-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=519.2,
1H NMR(400MHz,CDCl3)δ 11.37(s,1H),8.38(s,2H),7.55-7.49(m,1H),7.46(dd,J=2.6Hz,5.8Hz,1H),7.08(t,J=9.1Hz,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).
實施例208:製備1-((5-(二氟甲基)-4-(2-羥基-2-甲基丙基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=515.0,
1H NMR(400MHz,CDCl3)δ 8.39-8.35(m,2H),7.58-7.47(m,2H),7.10(t,J=9.2Hz,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).
實施例209:製備1-((5-氰基-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=418.2,
1H NMR(500MHz,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=8.7Hz,4.1Hz,1H),7.30-7.08(m,2H),6.90(s,1H),4.91(s,2H),3.96(s,3H).
實施例210:製備1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=444.2,
1H NMR(500MHz,DMSO-d6)δ 13.18(s,1H),9.46(s,1H),8.49(s,2H),8.10(dd,J=9.4Hz,3.1Hz,1H),7.91(t,J=9.4Hz,1H),6.96(td,J=54.8Hz,54.0Hz,45.8Hz,2H),6.43(s,1H),4.93(s,2H),3.94(s,3H).
實施例211:製備3-(2-(二氟甲基)-3-氟吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=462.04,
1H NMR(500MHz,Methanol-d4)δ 8.50(s,2H),8.34(d,J=5.4Hz,1H),8.14(t,J=5.7Hz,1H),6.88(t,J=53.4Hz,1H),5.02(s,2H),4.07(s,3H).
實施例212:製備1-((5-氰基-1H-吡唑-3-基)甲基)-3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=418.9,
1H NMR(400MHz,DMSO-d6)δ 13.81(br s,1H),9.50(br s,1H),8.52(s,2H),8.08(dd,J=3.5Hz,9.2Hz,1H),7.91(t,J=9.4Hz,1H),7.00(br t,J=53.2Hz,1H),6.89(s,1H),4.93(s,2H),3.94(s,3H).
實施例213:製備3-(3-(二氟甲基)-4-氟苯基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=449.2,
1H NMR(400MHz,CDCl3)δ 11.31(br s,1H),7.62-7.53(m,1H),7.50(dd,J=2.6Hz,5.9Hz,1H),7.12(t,J=9.1Hz,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).
實施例214:製備3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=450.2,
1H NMR(400MHz,CDCl3)δ 11.28(s,1H),8.18(dd,J=3.4Hz,9.2Hz,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).
實施例215:製備1-((5-氰基-1H-吡唑-3-基)甲基)-3-(4-氟基-3-(三氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)脲
[M+H+]=436.1,
1H NMR(400MHz,CDCl3)δ 8.40-8.35(m,2H),7.63-7.57(m,1H),7.55-7.50(m,1H),7.16(t,J=9.3Hz,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).
實施例216:製備1,3-雙(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=425.2,
1H NMR(400MHz,DMSO-d6)δ 13.61(br s,1H),8.58(d,J=4.8Hz,4H),6.63(s,1H),4.92(s,2H),3.95(s,3H),3.87(s,3H).
實施例217:製備1-(2-甲氧基嘧啶-5-基)-3-(3-甲基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=397.2,
1H NMR(400MHz,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).
實施例218:製備1-(2-甲氧基嘧啶-5-基)-3-(2-(甲硫基)嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
[M+H+]=441.1,
1H NMR(400MHz,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).
實施例219:製備1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(3,4,5-三氟苯基)脲
[M+H+]=447.1,
1H NMR(400MHz,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).
實施例220:製備1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)-3-(3,4,5-三氟苯基)脲
製備1,2,3-三氟-5-異氰酸基苯
將雙(三氯甲基)碳酸酯(81mg,272μmol,0.4eq)溶於甲苯(2mL)的混合物於25℃攪拌10分鐘,接著加入3,4,5-三氟苯胺(100mg,680μmol,1eq)在甲苯(1mL)中的混合物,且所產生的混合物於120℃攪拌1小時,以提供1,2,3-三氟-5-異氰酸基苯在甲苯(3mL)中的溶液,其不經進一步純化而用於下一步驟。
製備1-((5-(二氟甲基)-1-(四氫-2H-哌喃-2-基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)-3-(3,4,5-三氟苯基)脲
向N-((5-(二氟甲基)-1-(四氫-2H-哌喃-2-基)-1H-吡唑-3-基)甲基)-2-甲氧基嘧啶-5-胺(100mg,295μmol,1eq)在ACN(5mL)中的混合物加入上一步驟所取得之1,2,3-三氟-5-異氰酸基苯在甲苯中的溶液。將DMAP(108mg,884μmol,3eq)加至該混合物,並於25℃攪拌所產生的混合物16小時。濃縮反應混合物後,利用矽膠層析法(石油醚:乙酸乙酯=10:1至1:1)純化殘留物,以提供呈黃色油的
1-((5-(二氟甲基)-1-(四氫-2H-哌喃-2-基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)-3-(3,4,5-三氟苯基)脲(91mg,60%產率)。
製備1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)-3-(3,4,5-三氟苯基)脲
向1-((5-(二氟甲基)-1-(四氫-2H-哌喃-2-基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)-3-(3,4,5-三氟苯基)脲(91mg,178μmol,1eq)在DCM(6mL)中的混合物加入TFA(2mL),且於25℃攪拌該混合物1小時。濃縮反應混合物後,以製備級液相層析(管柱:Unisil 3-100 C18 Ultra 150mm×50mm×3μm;移動相:[水(0.225%FA)-ACN];B%:43%-63%,10分鐘)純化殘留物,接著冷凍乾燥,以提供呈灰白色(off-white)固體的1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)-3-(3,4,5-三氟苯基)脲(29.5mg,38.4%產率,99%純度)。
[M+H+]=429.1,
1H NMR(400MHz,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).
實施例221:製備1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(3,5,6-三氟吡啶-2-基)脲
[M+H+]=448.2,
1H NMR(400MHz,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).
實施例222:製備1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(3,4,5-三氟苯基)脲
[M+H+]=435.2,
1H NMR(400MHz,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).
實施例223:製備1-((5-氰基-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)-3-(3,4,5-三氟苯基)脲
[M+H+]=404.0,
1H NMR(400MHz,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).
實施例224:製備1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(4,5,6-三氟吡啶-2-基)脲
製備2-甲氧基嘧啶-5-基((1-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)氯化胺甲醯
向三光氣(145mg,490μmol,0.35eq)在DCM(10mL)中的溶液於0℃分次加入2-甲氧基-N-((1-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)嘧啶-5-胺(0.5g,1.40mmol,1eq)。接著滴入DIPEA(543mg,4.20mmol,731μL,3eq)並於15℃攪拌所產生的混合物1小時。將該混合物倒入至HCl(0.5M,10mL)水溶液,接著以DCM(30mL×3)萃取。將合併的有機層用飽和NaHCO3溶液(20mL)洗滌,透過Na2SO4乾燥並過濾。真空濃縮濾液,以提供呈黃色膠的2-甲氧基嘧啶-5-基((1-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)氯化胺甲醯(0.62g,粗產物)。
製備1-(2-甲氧基嘧啶-5-基)-1-((1-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(4,5,6-三氟吡啶-2-基)脲
向4,5,6-三氟吡啶-2-胺(65mg,439μmol,1eq)在THF(2mL)中的溶液於0℃分批加入NaH(35mg,878μmol,油中60%,2eq)。於20℃攪拌所產生的混合物30分鐘後,加入上一步驟所取得之2-甲氧基嘧啶-5-基((1-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)氯化胺甲醯(129mg,307μmol,0.7eq)。於20℃攪拌該混合物1小時後倒入NH4Cl水溶液(15mL)中,接著以乙酸乙酯(15mL×3)萃取。將合併的有機層用滷水(10mL)洗滌,透過無水Na2SO4乾燥並過濾。真空濃縮濾液。以逆相MPLC(0.1% FA狀況)純化粗產物,以提供呈黃色固體的1-(2-甲氧基嘧啶-5-基)-1-((1-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(4,5,6-三氟吡啶-2-基)脲(90mg,39%產率)。
製備1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(4,5,6-三氟吡啶-2-基)脲
將1-(2-甲氧基嘧啶-5-基)-1-((1-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(4,5,6-三氟吡啶-2-基)脲(90mg,169μmol,1eq)在TFA(0.5mL)及DCM(2mL)中的溶液於20℃攪拌1小時。將該溶液濃縮至乾燥。以製備級液相層析(管柱:Shim-pack C18 150×25×10μm;移動相:[水(0.225%FA)-ACN];B%:48%-68%,10分鐘)純化粗產物,接著冷凍乾燥,以提供呈白色固體的1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(4,5,6-三氟吡啶-2-基)脲(54.2mg,71%產率,99%純度)。
[M+H+]=448.2,
1H NMR(400MHz,CDCl3)δ 11.22(s,1H),8.37(s,2H),7.94(dd,J=4.2Hz,10.7Hz,1H),6.69(s,1H),6.38(s,1H),4.76(s,2H),4.11(s,3H).
實施例225:製備1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(6-(三氟甲基)吡啶-2-基)脲
[M+H+]=462.1,
1H NMR(500MHz,CDCl3)δ 11.32(s,1H),8.39(s,2H),8.30(d,J=8.5Hz,1H),7.89(t,J=8.0Hz,1H),7.39(d,J=7.5Hz,1H),6.98(s,1H),6.37(s,1H),4.77(s,2H),4.11(s,4H).
實施例226:製備3-(3-氰基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((1-丙醯基-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲
1H NMR(300MHz,DMSO)δ 7.90(br,1H),7.73(dd,J=6.90Hz,2.61Hz,1H),7.40(m,2H),7.27(t,J=9.15Hz,1H),7.07(d,J=8.91Hz,2H),6.96(d,J=8.94Hz,2H),4.56(s,2H),3.76(s,3H),3.66(s,3H),1.80(s,3H).
實驗例1:培養細胞及以化合物處理
HepAD38細胞在補充200unit/mL青黴素、200μg/mL鏈黴素及10% FBS之DMEM培養基(Welgene)中培養。在維持和繼代時,將該細胞與0.4μg/mL四環素一起培養。在用誘發HBV複製化合物處理的兩天前,置換培養基為無四環素完整生長培養基。將HepAD38細胞接種於48孔培養盤中,密度為1×105細胞/孔,並以DMSO(0.2%,對照組)或測試化合物(最終濃度範圍自1.5nM至0.37μM)處理。
實驗例2:對細胞內HBV DNA行即時PCR
用化合物處理HepAD38細胞65小時後回收,並依照DNeasy Blood & Tissue Kit(Qiagen)中的操作手冊萃取其細胞內HBV DNA。用於定量HBV DNA之引子及探針為5’-CTCGTGGTGGACTTCTCTC-3’(SEQ.ID # 1)、5’-
CTGCAGGATGAAGAGGAA-3’(SEQ.ID # 2)及5’-/56-FAM/TGT CCT GGT/ZEN/TAT CGC TGG ATG TGT CT/3IABkFQ/-3’(SEQ.ID # 3)。用LightCycler 480(Roche)(J.Virol.,2018,92(16):e00339-18)以即時PCR測定擴增HBV DNA。重複所有程序以確認之。
實驗例3:細胞存活測定
HepAD38細胞在補充10% FBS且無四環素之Dulbecco’s Modified Eagle’s培養基(Welgene,LM001-05)中培養兩天。將該細胞接種於48孔培養盤中(1×105細胞/孔),並以五種濃度(0μM(0.8% DMSO作為對照組)33μM、50μM、66μM及100μM)處理各化合物。在處理65小時後,利用EZ-Cytox cell viability assay kit(Daeil Lab Service)依照生產商指示測量存活率。利用分光光度計(Spark,Tecan)於450nm測量吸收率。這些化合物的IC50、蛋白抑制率、細胞毒性及CLogP值標註於下表1。NVR-3-778(以NVR表示)於此處作為陽性對照組。
根據上述說明,所屬技術領域中具有通常知識者將理解,本揭露可在不改變其技術精神或實質特徵的情況下以不同的具體形式實現。因此,應當理解,上述實施態樣於所有方面均為說明性,並非限定性。本揭露內容的範疇係由本發明所附之申請專利範圍所定義,而非
由其前述說明所定義,因此,落於本專利範圍之邊界和界限內或其均等物之邊界和界限內所有的改變及修飾皆包含於本專利範圍內。
TW202328108A_111138674_SEQL.xml
Claims (3)
- 一種用於蛋白殼組裝抑制的醫藥組成物,包括化合物或該化合物藥學上可接受的鹽,其中,該化合物為:1.3-(雙環[1.1.1]戊-1-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、2.1-(2-甲氧基嘧啶-5-基)-3-(嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、3.3-(3-氟基-4-(1H-咪唑-1-基)吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、4.3-(2-溴基-3-氟吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、5.3-(6-氯吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、6.3-(3-氯基雙環[1.1.1]戊-1-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、7.3-(3-氯基-4-氰基苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、8.3-(5-氯基-6-氰基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、9.3-(3-氯基-4-異氰苯基)-1-((5-氰基-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、 10.3-(3-氰基-4,5-二氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、11.3-(3-氯基-4,5-二氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、12.3-(3-氯基-4,5-二氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、13.3-(6-氯基-4,5-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、14.3-(3-氯基-4-氟苯基)-1-(6-側氧基-1,6-二氫吡啶-3-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲、15.3-(3-氯基-4-氟苯基)-1-(2-側氧基-1,2-二氫吡啶-4-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲、16.N-(4-(3-(3-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲基)苯基)甲烷磺胺、17.N-(5-(3-(3-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲基)吡啶-2-基)甲烷磺胺、18.N-(5-(3-(3-氯基-4-氟苯基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲基)吡啶-2-基)甲烷磺胺、19.N-(4-(3-(3-氯基-4-氟苯基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲基)苯基)甲烷磺胺、20.1-(6-乙醯基吡啶-3-基)-3-(3-氯基-4-氟苯基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲、 21.1-(6-乙醯基吡啶-3-基)-3-(3-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲、22.1-(2-乙醯基吡啶-4-基)-3-(3-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲、23.4-(3-(3-氯基-4-氟苯基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲基)-N-甲基苯磺醯胺、24.3-(3-氯基-4-氟苯基)-1-(1-甲基-1H-吡唑-4-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲、25.3-(3-氯基-4-氟苯基)-1-(1-甲基-1H-吡唑-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲、26.3-(3-氯基-4-氟苯基)-1-(5-甲基異噁唑-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲、27.3-(3-氯基-4-氟苯基)-1-(3-甲基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、28.3-(3-氯基-4-氟苯基)-1-(2-甲氧基-4-甲基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、29.3-(3-氯基-4-氟苯基)-1-(4-甲氧基-2,6-二甲苯基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、30.3-(3-氯基-4-氟苯基)-1-(2-甲氧基-4,6-二甲嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、31.4-(3-(3-氯基-4-氟苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲基)苄酸甲酯、 32.3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲、33.1-((5-乙醯基-4,5,6,7-四氫-1H-吡唑並[4,3-c]吡啶-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)脲、34.1-((1H-吡唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)脲、35.3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1-甲基-1H-吡唑-3-基)甲基)脲、36.3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1-甲基-4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲、37.3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5-甲基-4,5,6,7-四氫-1H-吡唑並[4,3-c]吡啶-3-基)甲基)脲、38.3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲、39.3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1-甲基-1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲、40.3-(3-氯基-4-氟苯基)-1-((5,5-二氟-4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、41.3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲、42.3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲、43.1-((1H-吲唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲、 44.3-(3-氯基-4-氟苯基)-1-((5-(羥甲基)-4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、45.3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1,4,6,7-四氫噻喃[4,3-c]吡唑-3-基)甲基)脲、46.3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲、47.3-(3-氯基-4-氟苯基)-1-((5,5-二甲基-4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、48.3-(3-氯基-4-氟苯基)-1-((5-羥基-4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、49.3-(3-氯基-4-氟苯基)-1-((5,5-二氧基-1,4,6,7-四氫噻喃[4,3-c]吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、50.3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5-甲基-1H-吡唑-3-基)甲基)脲、51.3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4,5,6,7-四氫-1H-4,7-甲橋吲唑-3-基)甲基)脲、52.3-((3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲基)甲基)-4,5,6,7-四氫-1H-吲唑-5-羧酸、53.3-((3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲基)甲基)-4,5,6,7-四氫-1H-吲唑-5-羧酸甲酯、54.3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲、 55.3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲、56.3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4-甲基-1H-吡唑-3-基)甲基)脲、57.3-(3-氯基-4-氟苯基)-1-((4,5-二甲基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、58.3-(3-氯基-4-氟苯基)-1-((5-異丙基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、59.3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((6-甲基-1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲、60.3-(3-氯基-4-氟苯基)-1-((5-乙基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、61.1-((4-溴基-1H-吡唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)脲、62.3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲、63.3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲、64.3-(3-氯基-4-氟苯基)-1-((5-甲氧基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、65.3-(3-氯基-4-氟苯基)-1-(1-甲基-6-側氧基-1,6-二氫吡啶-3-基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲、 66.3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((1-(2-(四氫-2H-哌喃-2-基氧基)乙基)-1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲、67.3-(3-氯基-4-氟苯基)-1-((1-(2-羥乙基)-1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、68.3-(3-氯基-4-氟苯基)-1-((1,3a,4,5,6,7a-六氫哌喃並[2,3-c]吡唑-3-基)甲基)-1-(2-甲氧基吡啶-4-基)脲、69.3-(3-氯基-4-氟苯基)-1-((4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、70.3-(3-氯基-4-氟苯基)-1-((4,6-二氫-1H-呋喃[3,4-c]吡唑-3-基)甲基)-1-(2-甲氧基吡啶-4-基)脲、71.3-(3-氯基-4-氟苯基)-1-((5,6-二氫-1H-[1,4]二咢辛[2,3-c]吡唑-3-基)甲基)-1-(2-甲氧基吡啶-4-基)脲、72.3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、73.3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲、74.3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、75.3-(3-氯基-4-氟苯基)-1-(5-甲氧基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲、76.3-(3-氯基-4-氟苯基)-1-(5-甲氧基吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲、 77.3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(5-甲氧基吡啶-3-基)脲、78.3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4-甲基-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、79.3-(3-氯基-4-氟苯基)-1-((1-(羥甲基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、80.3-(3-氯基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、81.1-((4-溴基-5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲、82.3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(甲氧基甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、83.3-(3-氯基-4-氟苯基)-1-((4-(2-乙氧乙烯基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、84.3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、85.3-(3-氯基-4-氟苯基)-1-((4-(2-乙氧乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、86.3-(3-氯基-4-氟苯基)-1-((4-(2-羥乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、87.3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4-((4,4,5,5-四甲基-1,3-二氧環戊-2-基)甲基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、 88.3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-甲氧基乙基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、89.3-(4-氯基-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、90.3-(3-氯基-4-氟苯基)-1-((5-甲氧基-4-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、91.3-(3-氯基-4-氟苯基)-1-((4-(2-羥乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、92.3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-羥基丙-2-基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、93.3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(丙-1-烯-2-基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、94.3-(3-氯基-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、95.3-(3-氯基-4-氟苯基)-1-((4-(2-羥丙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、96.3-(3-氯基-4-氟苯基)-1-(6-甲氧嗒嗪-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、97.3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧嗒嗪-3-基)脲、98.1-((4-溴基-5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲、 99.3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(6-甲氧嗒嗪-4-基)脲、100.3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-甲氧基-1H-吡唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、101.3-(3-氯基-4-氟苯基)-1-((4-(2-羥基-2-甲基丙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、102.3-(3-氯基-4-氟苯基)-1-((4-(2-羥基丙-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、103.3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-羥基-2-甲基丙基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、104.3-(3-氯基-4-氟苯基)-1-((5-氰基-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、105.3-(3-氯基-4-氟苯基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、106.3-(6-氯基-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、107.3-(5-氯基-6-氟吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、108.3-(3-氯基-4-氟苯基)-1-((1,3-二甲基-1H-吡唑-5-基)甲基)-1-(4-甲氧苯基)脲、109.3-(3-氯基-4-氟苯基)-1-(3-(2-羥基丙-2-基)異噁唑-5-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲、 110.3-(3-氯基-4-氟苯基)-1-(6-(2-羥基丙-2-基)吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲、111.3-(3-氯基-4-氟苯基)-1-(6-(2-羥基丙-2-基)吡啶-3-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲、112.3-(3-氯基-4-氟苯基)-1-(2-(2-羥基丙-2-基)吡啶-4-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲、113.3-(3-氯基-4-氟苯基)-1-(2-(2-羥基丙-2-基)吡啶-4-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲、114.3-(3-氯基-4-氟苯基)-1-(4-羥基苯基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲、115.3-(3-氯基-4-氟苯基)-1-(3-(2-羥基丙-2-基)異噁唑-5-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲、116.3-(3-氯基-4-氟苯基)-1-(3,4-二甲氧苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲、117.3-(3-氯基-4-氟苯基)-1-(3,5-二甲氧苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲、118.3-(3-氯基-4-氟苯基)-1-(6-氰基-5-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、119.3-(3-氯基-4-氟苯基)-1-(5-氰基-6-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、120.3-(3-氯基-4-氟苯基)-1-(5-氰基吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲、 121.3-(3-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲、122.3-(3-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲、123.3-(3-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲、124.3-(3-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲、125.3-(3-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲、126.3-(3-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)脲、127.3-(3-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲、128.3-(3-氯基-4-氟苯基)-1-(2-氰基吡啶-4-基)-1-((1,4,5,7-四氫哌喃並[3,4-c]吡唑-3-基)甲基)脲、129.3-(3-氯基-4-氟苯基)-1-(5-氰基吡啶-3-基)-1-((1,4,6,7-四氫哌喃並[4,3-c]吡唑-3-基)甲基)脲、130.3-(3-氯基-4-氟苯基)-1-(6-氰基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、131.4-(3-(3-氯基-4-氟苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲基)苄酸、 132.3-(3-氯基-4-氟苯基)-1-(異噁唑-3-基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)脲、133.3-(3-氯基-4-氟苯基)-1-((4,5,6,7-四氫-1H-吲唑-3-基)甲基)-1-(1,3,4-噻二唑-2-基)脲、134.3-(3-氯基-4-氟苯基)-1-(異噁唑-3-基)-1-((1,4,5,6-四氫環戊[c]吡唑-3-基)甲基)脲、135.3-(3-氯基-4-氟苯基)-1-(1H-吡唑-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲、136.3-(3-氯基-4-氟苯基)-1-(異噁唑-3-基)-1-((1,4,5,6-四氫哌喃並[2,3-c]吡唑-3-基)甲基)脲、137.1-(雙環[1.1.1]戊-1-基)-3-(3-氯基-4-氟苯基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、138.3-(6-氯基-4-(二甲胺基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、139.3-(3-氯基-4-氟基-5-甲基苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、140.3-(3-氯基-4-氟基-5-甲基苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、141.3-(6-氯基-3-氟基-4-甲基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、142.3-(6-氯基-5-氟基-4-甲基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、 143.3-(2-氯基嘧啶-5-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、144.3-(3-氰基苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、145.3-(6-氰基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、146.3-(2-氰基吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、147.3-(3-氰基苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、148.3-(6-氰基吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、149.3-(3-氰基-4,5-二氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、150.3-(3-氰基-4,5-二氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、151.3-(6-氰基-4,5-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、152.3-(4-氰基-3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、153.1-((5-氰基-1H-吡唑-3-基)甲基)-3-(4-氰基-3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)脲、 154.3-(3-氰基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、155.3-(3-氰基-4-氟苯基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、156.3-(4-氰基-3-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、157.1-((5-氰基-1H-吡唑-3-基)甲基)-3-(3-氰基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲、158.3-(2-氰基-3-氟吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、159.3-(3-氯基-4-氟苯基)-1-((1,3-二甲基-1H-吡唑-4-基)甲基)-1-(4-甲氧苯基)脲、160.3-(6-氰基-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、161.3-(4-氰基-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、162.3-(3-氰基-4-氟苯基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、163.3-(3-氰基-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、164.3-(6-氰基-4-(二甲胺基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、 165.3-(2,6-二氯吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、166.3-(2,6-二氯吡啶-3-基)-1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、167.3-(3,4-二氰苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、168.3-(3,4-二氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、169.3-(3,6-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、170.3-(5,6-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、171.3-(5,6-二氟吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、172.3-(4,5-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、173.3-(3,4-二氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、174.3-(5-(二氟甲基)吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、175.3-(2-(二氟甲基)吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、 176.3-(3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、177.3-(6-(二氟甲基)吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、178.1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)脲、179.1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(6-(二氟甲基)吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)脲、180.1-((5-氰基-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)脲、181.3-(3-(二氟甲基)苯基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、182.1-((4-(2-乙氧乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲、183.3-(6-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、184.3-(6-氟吡啶-3-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、185.3-(3-氟雙環[1.1.1]戊-1-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、186.3-(2-氟嘧啶-5-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、 187.3-(4-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、188.3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、189.3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、190.1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲、191.1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲、192.3-(4-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、193.3-(3-(二氟甲基)-4-氟苯基)-1-((4-(2-羥乙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、194.1-((4-溴基-5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲、195.1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧嗒嗪-3-基)脲、196.1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)脲、197.1-((4-溴基-5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲、 198.1-((5-(二氟甲基)-4-(2-羥基丙-2-基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲、199.3-(3-(二氟甲基)-4-氟苯基)-1-((4-(2-羥丙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、200.3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧嗒嗪-3-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、201.1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)脲、202.3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、203.3-(3-(二氟甲基)-4-氟苯基)-1-(6-甲氧嗒嗪-4-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、204.3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、205.3-(3-(二氟甲基)-4-氟苯基)-1-((4-(2-羥基-2-甲基丙基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、206.3-(4-(二氟甲基)-3-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、207.3-(3-(二氟甲基)-4-氟苯基)-1-((4-(2-羥基丙-2-基)-5-(三氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)脲、208.1-((5-(二氟甲基)-4-(2-羥基-2-甲基丙基)-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲、 209.1-((5-氰基-1H-吡唑-3-基)甲基)-3-(3-(二氟甲基)-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)脲、210.1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)脲、211.3-(2-(二氟甲基)-3-氟吡啶-4-基)-1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、212.1-((5-氰基-1H-吡唑-3-基)甲基)-3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(2-甲氧基嘧啶-5-基)脲、213.3-(3-(二氟甲基)-4-氟苯基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、214.3-(6-(二氟甲基)-5-氟吡啶-2-基)-1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、215.1-((5-氰基-1H-吡唑-3-基)甲基)-3-(4-氟基-3-(三氟甲基)苯基)-1-(2-甲氧基嘧啶-5-基)脲、216.1,3-雙(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、217.1-(2-甲氧基嘧啶-5-基)-3-(3-甲基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、218.1-(2-甲氧基嘧啶-5-基)-3-(2-(甲硫基)嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)脲、219.1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(3,4,5-三氟苯基)脲、 220.1-((5-(二氟甲基)-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)-3-(3,4,5-三氟苯基)脲、221.1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(3,5,6-三氟吡啶-2-基)脲、222.1-(3-甲氧基雙環[1.1.1]戊-1-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(3,4,5-三氟苯基)脲、223.1-((5-氰基-1H-吡唑-3-基)甲基)-1-(2-甲氧基嘧啶-5-基)-3-(3,4,5-三氟苯基)脲、224.1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(4,5,6-三氟吡啶-2-基)脲、225.1-(2-甲氧基嘧啶-5-基)-1-((5-(三氟甲基)-1H-吡唑-3-基)甲基)-3-(6-(三氟甲基)吡啶-2-基)脲或226.3-(3-氰基-4-氟苯基)-1-(2-甲氧基嘧啶-5-基)-1-((1-丙醯基-5-(三氟甲基)-1H-吡唑-3-基)甲基)脲。
- 如請求項1所述之醫藥組成物,其中,該醫藥組成物藉由蛋白殼組裝抑制以預防或治療病毒性疾病。
- 如請求項2所述之醫藥組成物,其中,該病毒性疾病為由B型肝炎病毒(HBV)、C型肝炎病毒(HCV)或人類免疫缺陷病毒(HIV)所造成的傳染性疾病。
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