TW202322803A - 新穎蛋白殼組裝抑制劑 - Google Patents
新穎蛋白殼組裝抑制劑 Download PDFInfo
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- TW202322803A TW202322803A TW111138676A TW111138676A TW202322803A TW 202322803 A TW202322803 A TW 202322803A TW 111138676 A TW111138676 A TW 111138676A TW 111138676 A TW111138676 A TW 111138676A TW 202322803 A TW202322803 A TW 202322803A
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- Prior art keywords
- methyl
- urea
- chloro
- fluorophenyl
- triazolo
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- 210000000234 capsid Anatomy 0.000 title abstract 2
- 239000003112 inhibitor Substances 0.000 title description 3
- 201000010099 disease Diseases 0.000 claims abstract description 23
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
Abstract
本發明涉及一系列新穎的三唑並甲基脲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。
Description
本發明涉及一系列新穎的三唑並甲基脲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，且可造成如肝硬化或肝癌的嚴重健康問題。根據WHO近期報告，預估全球有2.57億人患有慢性HBV感染，且預估每年有134萬人死於肝炎相關併發症。直至今日，核可治療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)及其他。IFN治療誘導HBV複製的抑制及肝病的緩解，而核(苷)酸藥物抑制反轉錄酶及DNA聚合酶活性。核酸結構類似物有效地控制病毒增殖，但作為HBV關鍵之病毒基因，以cccDNA的形式保持在一起，如同宿主的迷你染色體的形式一樣，因此難以完全消除。因此，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的針對新穎分子標的之抗HBV藥物。
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蛋白殼將前基因體RNA(pgRNA)、反轉錄酶及DNA聚合酶
包封在一起，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，已經廣泛研究了核心蛋白作用之調節及靶向抗HBV劑之發現，其預防由核心蛋白組成之蛋白殼之形成。
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)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複製來使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類似物，且正與利托那維爾(ritonavir，RTV)同時進行第二期臨床試驗中，以預防藉由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，但具有降低的CYP酶的誘發，降低hERG K+通道之抑制及改良的口服生體可用率。
有不同於HAP的作用機制之AT130、NVR 3-778及JNJ-632的其他類型的蛋白殼組裝調節劑亦已被報告。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，且其經優化之類似物JNJ-6379目前處於第二期臨床試驗。近期，GIST研究者Kang,J.A.等人報告將環吡酮(ciclopirox)，一種經FDA核可之抗黴菌藥物，舊藥新用為口服可用的蛋白殼組裝抑制劑。
[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
作為深入研究致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藉由潛在抑制蛋白殼組裝以抑制病毒感染之活性的三唑並甲基脲衍生物，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，在整個說明書中，當一部分被稱為「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，除非有特別描述相反內容。
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係C6-10芳基、C3-10環烷基、5-至10-員雜芳基(5- to 10-membered heteroaryl)或3-至10-員雜環基(3- to 10-membered heterocyclyl)；
R2係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各自獨立地為氫、氰基、鹵基、C1-4烷基(C1-4 alkyl)、C6-10芳基、C3-10環烷基、C1-4烷氧羰基-C1-4烷基(C1-4 alkoxycarbonyl-C1-4 alkyl)、C1-4烯基、C1-4鹵烷基、C1-4羥烷基、C1-4烷氧基、C1-4烷氧基-C1-4烷基(C1-4 alkoxy-C1-4 alkyl)、C1-4烷氧基-C1-4烯基、3-至10-員雜環氧基-C1-4烷基(3- to 10-membered heterocyclyloxy-C1-4 alkyl)或(4,4,5,5-四(C1-4烷基)-1,3-二氧雜環戊烷基)-C1-4烷基((4,4,5,5-tetra(C1-4 alkyl)-1,3-dioxolanyl)-C1-4 alkyl)，或
R3及R4彼此連接形成包含鍵結R3及R4的氮及碳的5-至10-員環狀結構；
R5及R6各自獨立地為氫或C1-4烷基；及
其中，由C6-10芳基、C3-10環烷基、5-至10-員雜芳基或3-至10-員雜環基與R3及R4彼此連接所形成的環狀結構係未經取代或經選自由氰基、羥基、羧基、氧基、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 alkoxy-C1-4 alkyl)、C1-4烷基羰基、C1-4烷氧羰基、C1-4烷氧羰基C1-4烷基(C1- 4 alkoxycarbonyl-C1-4 alkyl)、C1-4烷基胺基磺醯基(C1-4 alkylaminosulfonyl)、C1-4烷基磺醯基胺基(C1-4 alkylsulfonylamino)、C1-4羥烷基、C1-4鹵烷基、C1-4烷胺基、二(C1-4烷基)胺基(di(C1-4 alkyl)amino)、C6-10芳基、C3-10環烷基、C6-10芳基-C1-4烷氧羰基及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、苯並二噁茂基(benzodioxolyl)、二氫吡啶基(dihydropyridinyl)、環戊基(cyclopentyl)、吲哚基(indolyl)、苯並噻唑基(benzothiazolyl)、吡唑基(pyrazolyl)、異噁唑基(isoxazolyl)、噁唑基(oxazolyl)或吡啶基(pyridinyl)，但不限於此。
例如，於化學式1中，R2可為苯基、環戊基或吡啶基，但不限於此。
例如，於化學式1中，R3可為氫、甲基、苯基、異丙基、環丙基、環戊基、羥乙基或甲氧基乙基(methoxyethyl)，但不限於此。
例如，於化學式1中，R4可為甲基、異丙基、苯基、環戊基、甲氧羰基甲基(methoxycarbonylmethyl)、二氟甲基(difluoromethyl)或三氟甲基(trifluoromethyl)，但不限於此。
例如，於化學式1中，R3及R4可彼此連接形成氮雜環庚基(azepanyl)、嗎啉基(morpholinyl)、氧雜氮雜環庚基(oxazepanyl)、二氮雜環庚基(diazepanyl)或哌啶基(piperidinyl)，其包含鍵結R3及R4的碳與氮，但不限於此。
例如，於化學式1中，R5可為氫或甲基，但不限於此。
例如，於化學式1中，R6可為氫或甲基，但不限於此。
例如，於化學式1中，由C6-10芳基、C3-10環烷基、5-至10-員雜芳基或3-至10-員雜環基與R3及R4彼此連接所形成的環狀結構可為未經取代或經選自由氰基、羥基、氟基、氯基、甲基、異丙基、甲氧基、異丙氧基、甲氧基乙基、三級丁氧羰基(tert-butoxycarbonyl)、甲氧羰基甲基、羥乙基、二氟甲基、三氟甲基、甲胺基(methylamino)、二甲胺基(dimethylamino)、環丙基、環戊基、芐氧羰基(benzyloxycarbonyl)及苯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. 1-(苯並[d][1,3]二噁茂-5-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-3-間甲苯脲(1-(benzo[d][1,3]dioxol-5-yl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)-3-m-tolylurea)、
2. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(1-(benzo[d][1,3]dioxol-5-yl)-3-(3-chloro-4-fluorophenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
3. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
4. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((6,8-二氫-5H-[1,2,4]三唑並[3,4-c][1,4]噁嗪-3-基)甲基)脲(1-(benzo[d][1,3]dioxol-5-yl)-3-(3-chloro-4-fluorophenyl)-1-((6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)methyl)urea)、
5. 1-(苯並[d][1,3]二噁茂-5-基)-3-(2-氯苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(1-(benzo[d][1,3]dioxol-5-yl)-3-(2-chlorophenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
6. 3-(3-氯基-4-氟苯基)-1-環戊基-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-cyclopentyl-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
7. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲(1-(benzo[d][1,3]dioxol-5-yl)-3-(3-chloro-4-fluorophenyl)-1-((5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)methyl)urea)、
8. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氰基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(1-(benzo[d][1,3]dioxol-5-yl)-3-(3-cyanophenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
9. 1-(3-氯基-4-氟苯基)-3-(4-甲氧苯基)-1-甲基-3-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(1-(3-chloro-4-fluorophenyl)-3-(4-methoxyphenyl)-1-methyl-3-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
10. 3-(3-氯基-4-氟苯基)-1-(1H-吲哚-6-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(1H-indol-6-yl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
11. 1-(苯並[d][1,3]二噁茂-5-基)-3-環戊基-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(1-(benzo[d][1,3]dioxol-5-yl)-3-cyclopentyl-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
12. 3-(3-氯基-4-氟苯基)-1-(4-異丙氧基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-isopropoxyphenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
13. 3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-1-(4-(三氟甲基)苯基)脲(3-(3-chloro-4-fluorophenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)-1-(4-(trifluoromethyl)phenyl)urea)、
14. 3-(3-氯基-4-氟苯基)-1-(4-(甲胺基)苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-(methylamino)phenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
15. 3-(3-氯基-4-氟苯基)-1-((4,5-二甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲(3-(3-chloro-4-fluorophenyl)-1-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methyl)-1-(4-methoxyphenyl)urea)、
16. 1-(苯並[d]噻唑-6-基)-3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(1-(benzo[d]thiazol-6-yl)-3-(3-chloro-4-fluorophenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
17. 5-(3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲基)-1H-吲哚-1-羧酸三級丁基酯(tert-butyl 5-(3-(3-chloro-4-fluorophenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)ureido)-1H-indole-1-carboxylate)、
18. 3-(3-氯基-4-氟苯基)-1-(1H-吲哚-5-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(1H-indol-5-yl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
19. 3-(3-氯基-4-氟苯基)-1-(3-氰基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(3-cyanophenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
20. 1-(苯並[d][1,3]二噁茂-5-基)-3-(6-甲基吡啶-2-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(1-(benzo[d][1,3]dioxol-5-yl)-3-(6-methylpyridin-2-yl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
21. 3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-1-(3-(三氟甲基)苯基)脲(3-(3-chloro-4-fluorophenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)-1-(3-(trifluoromethyl)phenyl)urea)、
22. 3-(3-氯基-4-氟苯基)-1-(3,4-二氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(3,4-difluorophenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
23. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-(1-(6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)乙基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-(1-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)ethyl)urea)、
24. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)urea)、
25. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5-甲基-4-苯基-4H-1,2,4-三唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)methyl)urea)、
26. 3-(3-氯基-4-氟苯基)-1-((4-異丙基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲(3-(3-chloro-4-fluorophenyl)-1-((4-isopropyl-5-methyl-4H-1,2,4-triazol-3-yl)methyl)-1-(4-methoxyphenyl)urea)、
27. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)methyl)urea)、
28. 3-(3-氯基-4-氟苯基)-1-(4-氰基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-cyanophenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
29. 3-(3-氯基-4-氟苯基)-1-((5-異丙基-4-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-isopropyl-4-methyl-4H-1,2,4-triazol-3-yl)methyl)-1-(4-methoxyphenyl)urea)、
30. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((5,6,7,8,9,10-六氫-[1,2,4]三唑並[4,3-a]氮雜辛環-3-基)甲基)脲(1-(benzo[d][1,3]dioxol-5-yl)-3-(3-chloro-4-fluorophenyl)-1-((5,6,7,8,9,10-hexahydro-[1,2,4]triazolo[4,3-a]azocin-3-yl)methyl)urea)、
31. 3-(3-氯基-4-氟苯基)-1-((5-環戊基-4-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-cyclopentyl-4-methyl-4H-1,2,4-triazol-3-yl)methyl)-1-(4-methoxyphenyl)urea)、
32. 3-(3-氯基-4-氟苯基)-1-((4-環戊基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲(3-(3-chloro-4-fluorophenyl)-1-((4-cyclopentyl-5-methyl-4H-1,2,4-triazol-3-yl)methyl)-1-(4-methoxyphenyl)urea)、
33. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-(1-(5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)乙基)脲(1-(benzo[d][1,3]dioxol-5-yl)-3-(3-chloro-4-fluorophenyl)-1-(1-(5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)ethyl)urea)、
34. 3-(3-氯基-4-氟苯基)-1-(4-(二甲胺基)苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-(dimethylamino)phenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
35. 3-(3-氯基-4-氟苯基)-1-(1-甲基-1H-吡唑-3-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(1-methyl-1H-pyrazol-3-yl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
36. 3-(3-氯基-4-氟苯基)-1-(異噁唑-3-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(isoxazol-3-yl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
37. 3-(3-氯基-4-氟苯基)-1-((4-環丙基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲(3-(3-chloro-4-fluorophenyl)-1-((4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)methyl)-1-(4-methoxyphenyl)urea)、
38. 3-((3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)脲基)甲基)-8,9-二氫-5H-[1,2,4]三唑並[4,3-d][1,4]二氮呯-7(6H)-羧酸苄酯(benzyl 3-((3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)ureido)methyl)-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine-7(6H)-carboxylate)、
39. 3-(3-氯基-4-氟苯基)-1-(噁唑-2-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(oxazol-2-yl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
40. 3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)methyl)urea)、
41. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯苯基)-1-((5,6,7,8-四氫-[1,2,4]三唑並[4,3-a]吡啶-3-基)甲基)脲(1-(benzo[d][1,3]dioxol-5-yl)-3-(3-chlorophenyl)-1-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)urea)、
42. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((6,8-二氫-5H-[1,2,4]三唑並[3,4-c][1,4]噁嗪-3-基)甲基)脲(1-(Benzo[d][1,3]dioxol-5-yl)-3-(3-chloro-4-fluorophenyl)-1-((6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)methyl)urea)、
43. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5,6,7,8-四氫-[1,2,4]三唑並[4,3-a]吡啶-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(4-methoxyphenyl)-1-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)urea)、
44. 3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲(3-(3-Chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)urea)、
45. 2-(5-((1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)脲基)甲基)-4H-1,2,4-三唑-3-基)乙酸甲酯(methyl 2-(5-((1-(benzo[d][1,3]dioxol-5-yl)-3-(3-chloro-4-fluorophenyl)ureido)methyl)-4H-1,2,4-triazol-3-yl)acetate)、
46. 3-(3-氯基-4-氟苯基)-1-(2-羥基吡啶-4-基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(2-hydroxypyridin-4-yl)-1-((5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)methyl)urea)、
47. 3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(2-methoxypyridin-4-yl)-1-((5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)methyl)urea)、
48. 3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-methyl-4H-1,2,4-triazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea)、
49. 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)-4H-1,2,4-三唑-3-基)甲基)脲(3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)-1-((4-methyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)methyl)urea)、
50. 3-(3-氯基-4-氟苯基)-1-((4-(2-羥乙基)-5-(三氟甲基)-4H-1,2,4-三唑-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)-4H-1,2,4-triazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea)、
51. 3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-甲氧基乙基)-4H-1,2,4-三唑-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)-4H-1,2,4-triazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea)、
52. 3-(3-氯基-4-氟苯基)-1-((4-(2-甲氧基乙基)-5-(三氟甲基)-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((4-(2-methoxyethyl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)urea)、或
53. 3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-羥乙基)-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲(3-(3-chloro-4-fluorophenyl)-1-((5-(difluoromethyl)-4-(2-hydroxyethyl)-4H-1,2,4-triazol-3-yl)methyl)-1-(6-methoxypyridin-3-yl)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」是指該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，且其引發的副作用不至於減少由化學式1所表示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液如甲醇、乙醇、丙酮或乙腈沉澱此鹽。可加熱化
合物及水中等莫耳量之酸或醇(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)、苯甲酸(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。
可使用鹼製備該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鹽或鹼性鹽，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、鈣鹽及鉀鹽及其他。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(甲磺酸鹽)及對甲苯磺酸鹽(toluenesulfonate/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的鹽以及展現均等於該三唑並甲基脲衍生化合物之藥學活性的三唑並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。
根據本發明由化學式1所表示的化合物，不但包含其藥學上可接受的鹽，亦包含溶劑化物，諸溶劑化物如不限於可由鹽類及全部可能的立體異構物所製備之水合物。由化學式1所表示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所表示的化合物製備。
再者，根據本發明化學式1所表示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視需要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所表示的化合物的化學計量水合物之化合物。根據本發明化學式1所表示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，其中包括將由以下化學式2所表示之化合物與由以下化學式3所表示之化合物進行反應：
[化學式3]R2-N=C=O
在化學式2及化學式3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各自獨立地為氫、氰基、鹵基、C1-4烷基(C1-4 alkyl)、C6-10芳基、C3-10環烷基、C1-4烷氧羰基-C1-4烷基(C1-4alkoxycarbonyl-C1-4 alkyl)、C1-4烯基、C1-4鹵烷基、C1-4羥烷基,C1-4烷氧基、C1-4烷氧基-C1-4烷基(C1-4 alkoxy-C1-4 alkyl)、C1-4烷氧基-C1-4烯基、3-至10-員雜環氧基-C1-4烷基(3- to 10-membered heterocyclyloxy-C1-4 alkyl)或(4,4,5,5-四(C1-4烷基)-1,3-二氧雜環戊烷基)-C1-4烷基((4,4,5,5-tetra(C1-4 alkyl)-1,3-dioxolanyl)-C1-4 alkyl)，或
R3及R4連接彼此以形成5-至10-員環狀結構包含鍵結R3及R4的氮及碳；
R6為氫或C1-4烷基；及
其中，連接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彼此以形成環狀結構，其結構係未取代或以選自由氰基、羥基、羧基、氧基、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 alkoxy-C1-4 alkyl)、C1-4烷基羰基、C1-4烷氧羰基、C1-4烷氧羰基C1-4烷基(C1-4 alkoxycarbonyl-C1-4 alkyl)、C1-4烷基胺基磺醯基、C1-4烷基磺醯基胺基、C1-4羥烷基、C1-4鹵烷基、C1-4烷胺基、二(C1-4烷基)胺基(di(C1-4 alkyl)amino)、C6-10芳基、C3-10環烷基、C6-10芳基-C1-4烷氧羰基及5-至10-員雜芳基所組成之群組的一者或更多者取代。
例如，本發明的製備方法可在4-二甲胺基吡啶(4-dimethylaminopyridine(DMAP))存在下於有機溶劑中執行，但不限於此。
例如，該由化學式2所表示之化合物可藉由將i)由以下化學式4所表示之化合物與由以下化學式5所表示之化合物或ii)由以下化學式6所表示之化合物與由以下化學式7所表示之化合物進行反應來製備，但不限於此：
[化學式6]R1-NH2
在化學式5中，
R7為C1-4烷基。
例如，在本發明的製備方法中，可在將由化學式2所表示之化合物與由化學式3所表示之化合物進行反應後，執行與R5-X(R5為氫或C1-4烷基且X為鹵基)進行反應的步驟，以導入一個取代基。
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，含有該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」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，其環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)。該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。該蛋白殼依靠其構造大致分類，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成千個相同於原始病毒的複製。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)；以及視需要地以(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用於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用來抑制或延遲病毒性疾病發生、散播及再發的行動，且術語「治療」意指任何以施予本發明的組成改善或有利地改變疾病症狀的行動。
本發明的醫藥組成物可藉由促使異常蛋白殼形成，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由化學式1所表示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、局部及其他等各種途徑施予。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、纖維素、甲基纖維素、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、防腐劑及其他等。
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及其他等，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)、甘油明膠及其他等，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，本發明的組成物是以在藥學上有效的量施予。如本文中使用，術語「藥學上有效的量」是指一種以合理受益/風險比(benefit/risk ratio)進行藥物治療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，且可以單次或多次方式施予。在考慮上述所有因素後，重要的是以一定量施予組成物，從而以最小量獲得最大效果而沒有副作用，且本技術領域中具有通常知識者可容易地確定該量。
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、年齡及其他等而增減，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，且化合物一般可以每公斤體重1mg至100mg、較佳為每公斤體重5mg至60mg施予，每天或每隔一天1到3次而分次施予。惟，有效量可依施予的途徑、疾病的嚴重度、性別、體重、年齡及其他等而增減，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預定的物質給病患，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)及其他等來製備。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，是指三唑並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三唑並甲基脲衍生物化合物或其藥學上可接受的鹽作為活性成分以外的已知藥物作為活性成分，且可與其他已知的治療方法組合使用，以用於治療這些疾病。
依據本發明新合成分子中的三唑並甲基脲衍生物，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等所造成的病毒性疾病。
以下，透過例示性實施例對本發明的結構及效果進行更為詳細的描述。惟，這些例示性實施例僅供說明目的，這些例示性實施例非意欲以任何方式限制本發明的範疇。
實施例1：1-(苯並[d][1,3]二噁茂-5-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-3-間甲苯脲
步驟1-1：2-(苯並[d][1,3]二噁茂-5-胺基)乙酸甲酯(Methyl 2-(benzo[d][1,3]dioxol-5-ylamino)acetate)
苯並[d][1,3]二噁茂-5-胺(3.0mL，30.0mmol)及K2CO3(8.3g，60.0mmol)溶於150mL MeCN。該燒瓶於冰上降溫10分鐘且該溶液於N2大氣下攪拌。氯乙醯氯(Chloroacetyl chloride)(3.0mL，36.0mmol)於N2大氣下滴加至其溶液並攪拌混合物過夜。該反應以加水至混合物中止，且該反應混合物再攪拌5分鐘。分離該有機層，且以乙酸乙酯(ethyl acetate，EA)萃取該水層。收集該有機層，以鹽水洗滌，透過無水Na2SO4乾燥，並於真空濃縮。利用矽膠層析法(5% MeOH於DCM中)執行純化以取得本標題化合物。
步驟1-2：2-(苯並[d][1,3]二噁茂-5-胺基)乙醯肼(2-(Benzo[d][1,3]dioxol-5-ylamino)acetohydrazide)
水合肼(hydrazine hydrate)(1.2mL，38.2mmol)加至由上述步驟1-1取得之2-(苯並[d][1,3]二噁茂-5-胺基)乙酸甲酯(800mg，38.2mmol)乙醇(38mL，0.1M)溶液中，且該混合物於80℃攪拌過夜。過濾該反應混合物以取得本標題化合物。
步驟1-3：(E)-7-甲氧基-3,4,5,6-四氫-2H-氮呯((E)-7-Methoxy-3,4,5,6-tetrahydro-2H-azepine)
氮雜烷-2-酮(Azepan-2-one)(3.00g，26.5mmol)溶於DCM(133mL，0.2M)。三甲基側氧四氟硼酸(Trimethyloxonium tetrafluoroborate)(5.9g，39.7mmol)加至該反應混合物。該混合物於室溫(30℃)攪拌24小時。之後，降溫該混合物至0℃，並逐漸加入飽和NaHCO3水溶液至其中以調整該溶液之pH值至8.0。之後，於室溫攪拌該反應混合物30分鐘並以DNM萃取。該有機層以鹽水洗滌，透過無水Na2SO4乾燥，並於真空濃縮，以取得本標題化合物。
步驟1-4：N-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)苯並[d][1,3]二噁茂-5-胺(N-((6,7,8,9-Tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)benzo[d][1,3]dioxol-5-amine)
對由上述步驟1-2取得的2-(苯並[d][1,3]二噁茂-5-胺基)乙醯肼(1.00g，6.0mmol)於120mL 2-丙醇中之溶液，加入由上述步驟1-3取得的7-甲氧基-3,4,5,6-四氫-2H-氮呯(1.14g，9.0mmol)，並回流該混合物(80℃)。反應完成後，冷卻該混合物，過濾沉澱物並純化該濾液以取得本標題化合物。
步驟1-5：1-(苯並[d][1,3]二噁茂-5-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-3-間甲苯脲
上述步驟1-4取得的N-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)苯並[d][1,3]二噁茂-5-胺(100mg，0.35mmol)、1-異氰酸基-3-甲苯(0.11mL，0.88mmol)及DMAP(128mg，1.05mmol)於MeCN(1.2mL，0.3M)中於90℃攪拌過夜。該反應以EA/水終止並於真空蒸發。之後，利用矽膠層析法(MeOH於DCM系統中)純化該反應混合物，以EA洗滌並過濾以取得本標題化合物。
LC/MS[M+H]+：421.33
1H NMR(300MHz,CDCl3)δ 7.17(t,J=7.7Hz,1H),7.11(s,2H),6.84(d,J=8.1Hz,2H),6.70-6.63(m,2H),6.05(s,2H),5.08(s,2H),4.29-4.22(m,2H),3.05-2.98(m,2H),2.32(s,3H),1.91(d,J=4.7Hz,2H),1.86-1.72(m,4H)。
下列實施例2至47化合物之合成以類似實施例1的方式進行反應，利用考慮到該標題化合物之結構的反應物。在這些實施例中，保護及去保護官能基及/或導入額外取代基的反應係根據是否包含反應性取代基來額外進行。以下，實施例2至47的化合物、其中間體及用於鑑定這些化合物的數據依序揭露。
實施例2：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：460.28
1H NMR(300MHz,CDCl3)δ 7.47(dd,J=6.5Hz,2.6Hz,1H),7.09(dd,J=4.2Hz,2.6Hz,1H),7.03(t,J=8.7Hz,1H),6.84(d,J=8.1Hz,1H),6.73-6.64(m,
2H),6.38(s,1H),6.06(s,2H),5.04(s,2H),4.26-4.18(m,2H),3.05-2.97(m,2H),1.91(d,J=4.8Hz,2H),1.78(dd,J=11.6Hz,6.1Hz,4H)。
實施例3：3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟3-1：2-(4-甲氧基苯基胺)乙酸甲酯(Methyl 2-(4-methoxyphenylamino)acetate)
LC/MS[M+H]+：197
1H NMR(500MHz,DMSO-d6)δ 6.80-6.66(m,2H),6.56-6.45(m,2H),5.58(t,J=6.6Hz,1H),3.84(d,J=6.5Hz,2H),3.63(s,6H)。
步驟3-2：2-(4-甲氧基苯基胺)乙醯肼(2-(4-Methoxyphenylamino)acetohydrazide)
LC/MS[M+H]+：197
1H NMR(300MHz,DMSO-d6)δ 9.02(s,1H),6.77-6.66(m,2H),6.57-6.46(m,2H),5.44(t,J=6.2Hz,1H),4.22(s,2H),3.63(s,3H),3.55(d,J=6.2Hz,2H)。
步驟3-3：4-甲氧基-N-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)苯胺(4-Methoxy-N-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)aniline)
LC/MS[M+H]+：274
1H NMR(300MHz,DMSO-d6)δ 6.80-6.61(m,4H),5.72(t,J=5.7Hz,1H),4.28(d,J=5.7Hz,2H),4.09-3.94(m,2H),3.63(s,3H),2.94-2.77(m,2H),1.87-1.44(m,6H)。
步驟3-4：3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：446.24
1H NMR(300MHz,DMSO)δ 8.01(s,1H),7.68(d,J=6.8Hz,1H),7.47-7.35(m,1H),7.26(t,J=9.1Hz,1H),7.16(d,J=8.6Hz,1H),6.96(d,J=8.6Hz,1H),4.93(s,1H),4.06(d,J=4.3Hz,1H),3.78(s,2H),2.83(d,J=5.1Hz,1H),1.79(s,1H),1.71-1.47(m,2H)。
實施例4：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((6,8-二氫-5H-[1,2,4]三唑並[3,4-c][1,4]噁嗪-3-基)甲基)脲
步驟4-1：5-甲氧基-3,6-二氫-2H-1,4-噁嗪(5-Methoxy-3,6-dihydro-2H-1,4-oxazine)
1H NMR(300MHz,CDCl3)δ 4.05(s,2H),3.74-3.61(m,5H),3.54(t,J=4.6Hz,2H)。
步驟4-2：N-((6,8-二氫-5H-[1,2,4]三唑並[3,4-c][1,4]噁嗪-3-基)甲基)苯並[d][1,3]二噁茂-5-胺(N-((6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)methyl)benzo[d][1,3]dioxol-5-amine)
LC/MS[M+H]+：276.1
1H NMR(300MHz,CDCl3)δ 6.68(d,J=8.3Hz,1H),6.35(d,J=2.3Hz,1H),6.18(dd,J=8.3Hz,2.4Hz,1H),5.88(s,2H),4.96(s,2H),4.44(s,2H),4.32-3.81(m,4H)。
步驟4-3：2-氯基-1-氟基-4-異氰酸苯(2-Chloro-1-fluoro-4-isocyanotobenzene)
1H NMR(300MHz,CDCl3)δ 7.18-7.11(m,1H),7.07(d,J=8.6Hz,1H),6.99-6.93(m,1H)。
步驟4-4：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((6,8-二氫-5H-[1,2,4]三唑並[3,4-c][1,4]噁嗪-3-基)甲基)脲
LC/MS[M+H]+：448.1
1H NMR(300MHz,CDCl3)δ 7.44(dd,J=6.5Hz,2.4Hz,1H),7.20-6.95(m,2H),6.87-6.76(m,3H),6.29(s,1H),6.06(s,2H),4.98(s,4H),4.38-4.21(m,2H),4.19-3.98(m,2H)。
實施例5：1-(苯並[d][1,3]二噁茂-5-基)-3-(2-氯苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：442.2
1H NMR(300MHz,CDCl3)δ 8.17(d,J=8.3Hz,1H),7.24-7.20(m,1H),6.98-6.90(m,1H),6.82(d,J=8.0Hz,1H),6.69-6.64(m,1H),6.01(s,2H),5.06(s,2H),4.38-3.98(m,2H),3.24-2.87(m,2H),1.94-1.84(m,2H),1.84-1.67(m,4H)。
實施例6：3-(3-氯基-4-氟苯基)-1-環戊基-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟6-1：2-(環戊基胺基)乙酸甲酯(Methyl 2-(cyclopentylamino)acetate)
1H NMR(300MHz,CDCl3)δ 3.71(s,3H),3.40(s,2H),3.05(p,J=6.4Hz,1H),2.23(d,J=11.8Hz,1H),1.82-1.74(m,2H),1.71-1.62(m,2H),1.57-1.47(m,2H),1.39-1.28(m,2H)。
步驟6-2：2-(環戊基胺基)乙醯肼(2-(Cyclopentylamino)acetohydrazide)
1H NMR(300MHz,CDCl3)δ 8.23(s,1H),4.00-3.69(m,1H),3.33(d,J=12.4Hz,2H),3.13-3.02(m,1H),1.87-1.75(m,2H),1.68(dt,J=11.2Hz,5.8Hz,2H),1.56(ddt,J=7.5Hz,5.0Hz,2.9Hz,2H),1.37-1.27(m,2H)。
步驟6-3：N-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)環戊胺(N-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)cyclopentanamine)
1H NMR(300MHz,CDCl3)δ 4.06-3.99(m,2H),3.86(s,2H),3.42-3.34(m,2H),3.13-3.03(m,1H),2.94(dd,J=7.1Hz,4.1Hz,2H),2.40-2.30(m,2H),1.87-1.82(m,2H),1.76-1.71(m,4H),1.63(dd,J=4.8Hz,2.3Hz,2H),1.53-1.51(m,2H)。
步驟6-4：3-(3-氯基-4-氟苯基)-1-環戊基-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：408.24
1H NMR(300MHz,CDCl3)δ 8.38(s,1H),7.59(dd,J=6.6Hz,2.6Hz,1H),7.26-7.19(m,1H),7.03(t,J=8.8Hz,1H),4.56(s,2H),4.34(t,J=8.3Hz,1H),4.11-4.03(m,2H),3.05-2.97(m,2H),1.91(d,J=3.7Hz,4H),1.76(dd,J=11.1Hz,6.6Hz,6H),1.67-1.56(m,4H)。
實施例7：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲
步驟7-1：(E)-5-甲氧基-2,3,6,7-四氫-1,4-氧雜氮呯((E)-5-Methoxy-2,3,6,7-tetrahydro-1,4-oxazepine)
1H NMR(500MHz,CDCl3)δ 3.70-3.67(m,2H),3.65-3.62(m,2H),3.59(s,3H),3.56-3.52(m,2H),2.67-2.62(m,2H)。
步驟7-2：N-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)苯並[d][1,3]二噁茂-5-胺(N-((5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)methyl)benzo[d][1,3]dioxol-5-amine)
1H NMR(500MHz,CDCl3)δ 6.70(d,J=8.3Hz,2H),6.37(d,J=2.3Hz,2H),6.20(dd,J=8.3Hz,2.4Hz,2H),5.90(s,4H),4.39(d,J=5.6Hz,4H),4.22-4.17(m,4H),4.18-4.09(m,3H),3.92-3.85(m,8H),3.26(dd,J=5.7Hz,4.2Hz,4H)。
步驟7-3：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((8,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲
LC/MS[M+H]+：462.17
1H NMR(300MHz,DMSO)δ 8.04(s,1H),7.68(dd,J=6.9Hz,2.5Hz,1H),7.46-7.38(m,1H),7.26(t,J=9.1Hz,1H),6.93(dd,J=8.8Hz,5.1Hz,2H),6.74(dd,J=8.2Hz,2.0Hz,1H),6.07(s,2H),4.92(s,2H),4.22-4.16(m,2H),3.79-3.74(m,2H),3.74-3.67(m,2H),3.09-3.02(m,2H)。
實施例8：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氰基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：432.2
1H NMR(300MHz,CDCl3)δ 7.77(s,1H),7.42(dt,J=7.6Hz,2.1Hz,1H),7.37-7.27(m,2H),6.83(d,J=8.1Hz,1H),6.72(d,J=2.0Hz,1H),6.68(dd,J=8.1Hz,2.1Hz,1H),6.56(s,1H),6.04(s,2H),5.02(s,2H),4.38-4.08(m,2H),3.01-2.97(m,2H),1.99-1.86(m,2H),1.85-1.71(m,4H)。
實施例9：1-(3-氯基-4-氟苯基)-3-(4-甲氧苯基)-1-甲基-3-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：460.08
1H NMR(300MHz,CDCl3)δ 6.86(t,J=8.6Hz,1H),6.76-6.73(m,1H),6.72(s,1H),6.70-6.63(m,2H),6.58(d,J=9.0Hz,2H),4.91(s,2H),4.22-4.07(m,2H),3.72(s,3H),3.12(s,3H),3.03-2.93(m,2H),1.90(d,J=4.7Hz,2H),1.83-1.63(m,6H)。
實施例10：3-(3-氯基-4-氟苯基)-1-(1H-吲哚-6-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟10-1：2-(1H-吲哚-6-基胺基)乙酸甲酯(Methyl 2-(1H-indol-6-ylamino)acetate)
LC/MS[M+H]+：206
1H NMR(300MHz,DMSO)δ 10.55(s,1H),7.24(d,J=8.4Hz,1H),7.00(dd,J=3.0Hz,2.4Hz,1H),6.45(dd,J=8.4Hz,2.1Hz,1H),6.40(d,J=1.9Hz,1H),6.21(ddd,J=2.9Hz,1.9Hz,0.7Hz,1H),5.71(t,J=6.5Hz,1H),3.90(d,J=6.5Hz,2H),3.65(s,3H)。
步驟10-2：2-(1H-吲哚-6-基胺基)乙醯肼(2-(1H-indol-6-ylamino)acetohydrazide)
粗產物
步驟10-3：N-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-1H-吲哚-6-胺(N-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)-1H-indol-6-amine)
粗產物
步驟10-4：3-(3-氯基-4-氟苯基)-1-(1H-吲哚-6-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：455.22
1H NMR(300MHz,DMSO)δ 11.35-11.09(s,1H),7.99(s,1H),7.68(dd,J=6.9Hz,2.5Hz,1H),7.55(d,J=8.3Hz,1H),7.24(d,J=2.7Hz,1H),7.40-7.36(m,J=4.2,2.8Hz,1H),7.29(s,1H),7.24(dd,J=9.1Hz,1H),6.86(dd,J=8.3Hz,1.7Hz,1H),6.47(s,1H),5.00(s,2H),4.14-4.02(m,2H),2.93-2.74(m,2H),1.97-1.73(m,J=3.9Hz,2H),1.67-1.59(m,2H),1.59-1.50(m,2H)。
實施例11：1-(苯並[d][1,3]二噁茂-5-基)-3-環戊基-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]398
1H NMR(300MHz,Methanol-d4)δ 6.82(d,J=8.2Hz,1H),6.65(d,J=2.1Hz,1H),6.57(dd,J=8.2Hz,2.2Hz,1H),6.01(s,2H),5.00(s,2H),4.31-4.16(m,2H),4.09-3.94(m,1H),3.04-2.90(m,2H),1.99-1.85(m,4H),1.79-1.71(m,4H),1.64-1.54(m,4H),1.41-1.29(m,2H).。
實施例12：3-(3-氯基-4-氟苯基)-1-(4-異丙氧基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟12-1：1-異丙氧基-4-硝基苯(1-Isopropoxy-4-nitrobenzene)
1H NMR(300MHz,CDCl3)δ 8.23-8.15(m,2H),6.95-6.88(m,2H),4.73-4.60(m,1H),1.39(d,J=6.1Hz,6H)。
步驟12-2：4-異丙氧基苯胺(4-Isopropoxyaniline)
LC/MS[M+H]+：152.99
1H NMR(300MHz,CDCl3)δ 6.80-6.69(m,2H),6.68-6.58(m,2H),4.44-4.29(m,1H),3.40(s,2H),1.27(t,J=5.6Hz,6H)。
步驟12-3：2-(4-異丙氧基苯基胺)乙酸甲酯(Methyl 2-(4-isopropoxyphenylamino)acetate)
LC/MS[M+H]+：223.81
1H NMR(300MHz,CDCl3)δ 6.83-6.74(m,2H),6.60-6.52(m,2H),4.37(hept,J=6.1Hz,1H),4.02(s,1H),3.88(s,2H),3.77(s,3H),1.28(d,J=6.1Hz,6H)。
步驟12-4：2-(4-異丙氧基苯基胺)乙醯肼(2-(4-Isopropoxyphenylamino)acetohydrazide)
LC/MS[M+H]+：225.09
1H NMR(300MHz,DMSO)δ 9.02(s,1H),6.73-6.65(m,2H),6.51-6.44(m,2H),5.45(t,J=6.1Hz,1H),4.34(dt,J=12.1Hz,6.0Hz,1H),4.22(s,2H),3.55(d,J=6.2Hz,2H),1.18(d,J=6.0Hz,6H)。
步驟12-5：4-異丙氧基-N-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)苯胺(4-Isopropoxy-N-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)aniline)
LC/MS[M+H]+：302.32
1H NMR(300MHz,MeOD)δ 6.70(dd,J=20.8Hz,8.9Hz,4H),4.45-4.31(m,3H),4.20-4.12(m,2H),2.99-2.91(m,2H),1.88(d,J=5.1Hz,2H),1.77-1.63(m,4H),1.23(d,J=6.0Hz,6H)。
步驟12-6：3-(3-氯基-4-氟苯基)-1-(4-異丙氧基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：472.16
1H NMR(300MHz,DMSO)δ 8.01(s,1H),7.67(d,J=5.6Hz,1H),7.39(s,1H),7.26(t,J=8.9Hz,1H),7.12(d,J=8.1Hz,2H),6.91(d,J=8.2Hz,2H),4.92(s,2H),4.60(dt,J=11.2Hz,5.5Hz,1H),4.04(s,2H),2.84(s,2H),1.77(s,2H),1.58(s,4H),1.27(d,J=5.8Hz,6H)。
實施例13：3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-1-(4-(三氟甲基)苯基)脲
步驟13-1：2-(4-(三氟甲基)苯胺基)乙酸甲酯(Methyl 2-(4-(trifluoromethyl)phenylamino)acetate)
LC/MS[M+H]+：234.07
1H NMR(300MHz,CDCl3)δ 7.43(d,J=8.5Hz,2H),6.61(d,J=8.5Hz,2H),4.61(s,1H),3.95(d,J=5.1Hz,2H),3.81(s,3H)。
步驟13-2：2-(4-(三氟甲基)苯胺基)乙醯肼(2-(4-(Trifluoromethyl)phenylamino)acetohydrazide)
LC/MS[M+H]+：233.80
1H NMR(300MHz,DMSO)δ 9.17(s,1H),7.38(d,J=8.6Hz,2H),6.64(t,J=6.8Hz,2H),4.25(s,2H),3.69(d,J=6.1Hz,2H)。
步驟13-3：N-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-4-(三氟甲基)苯胺(N-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)-4-(trifluoromethyl)aniline)
粗產物
步驟13-4：3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-1-(4-(三氟甲基)苯基)脲
LC/MS[M+H]+：482.02
1H NMR(300MHz,CDCl3)δ 7.72(d,J=8.3Hz,2H),7.49(dd,J=8.1Hz,5.1Hz,3H),7.11(dd,J=8.2Hz,3.4Hz,1H),7.02(t,J=8.7Hz,1H),6.66(s,1H),5.05(s,2H),4.17-4.09(m,2H),3.04-2.94(m,2H),1.89(d,J=4.6Hz,2H),1.81-1.68(m,4H)。
實施例14：3-(3-氯基-4-氟苯基)-1-(4-(甲胺基)苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟14-1：2-(4-(三級丁氧羰基(甲基)胺)苯胺基)乙酸甲酯(Methyl 2-(4-(tert-butoxycarbonyl(methyl)amino)phenylamino)acetate)
粗產物
步驟14-2：4-(2-肼基-2-氧代乙胺基)苯基(甲基)胺甲酸三級丁基脂(tert-Butyl 4-(2-hydrazinyl-2-oxoethylamino)phenyl(methyl)carbamate)
粗產物
步驟14-3：甲基(4-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲胺基)苯基)胺甲酸三級丁基脂(tert-Butyl methyl(4-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methylamino)phenyl)carbamate)
粗產物
步驟14-4：4-(3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲基)苯基(甲基)胺甲酸三級丁基脂(tert-Butyl 4-(3-(3-chloro-4-fluorophenyl)-1-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)ureido)phenyl(methyl)carbamate)
LC/MS[M+H]+：545.27
步驟14-5：3-(3-氯基-4-氟苯基)-1-(4-(甲胺基)苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：445.16
1H NMR(300MHz,DMSO)δ 8.32(s,1H),7.70(m,1H),7.40(n,1H),7.28(m,3H),7.01(m,2H),5.14(s,2H),4.29(m,2H),3.70(m,1H),3.50-3.44(m,1H),2.78(s,3H),1.74(m,6H)。
實施例15：3-(3-氯基-4-氟苯基)-1-((4,5-二甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲
步驟15-1：N-((4,5-二甲基-4H-1,2,4-三唑-3-基)甲基)苯並[d][1,3]二噁茂-5-胺(N-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methyl)benzo[d][1,3]dioxol-5-amine)
粗產物
步驟15-2：3-(3-氯基-4-氟苯基)-1-((4,5-二甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲
LC/MS[M+H]+：406.12
1H NMR(300MHz,DMSO)δ 8.02(s,1H),7.70(dd,J=6.9Hz,2.5Hz,1H),7.47-7.37(m,1H),7.27(t,J=9.1Hz,1H),7.24-7.18(d,2H),6.96(d,J=8.8Hz,2H),4.92(s,2H),3.78(s,3H),3.51(s,3H),2.29(s,3H)。
實施例16：1-(苯並[d]噻唑-6-基)-3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟16-1：2-(苯並[d]噻唑-6-胺基)乙酸乙酯(Ethyl 2-(benzo[d]thiazol-6-ylamino)acetate)
1H NMR(300MHz,Chloroform-d)δ 8.69(s,1H),7.91(d,J=8.8Hz,1H),7.01(d,J=2.4Hz,1H),6.86(dd,J=8.9Hz,2.4Hz,1H),4.53(s,1H),4.27(q,J=7.2Hz,2H),3.96(d,J=4.6Hz,2H),1.31(t,J=7.1Hz,3H)。
步驟16-2：2-(苯並[d]噻唑-6-胺基)乙醯肼(2-(Benzo[d]thiazol-6-ylamino)acetohydrazide)
1H NMR(300MHz,DMSO-d6)δ 9.16(s,1H),7.77(d,J=8.8Hz,1H),7.05(d,J=2.3Hz,1H),6.89(dd,J=8.9Hz,2.3Hz,1H),6.28(t,J=6.1Hz,1H)。
步驟16-3：N-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)苯並[d]噻唑-6-胺(N-((6,7,8,9-tetrahydro-5H-
[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)benzo[d]thiazol-6-amine)
1H NMR(300MHz,DMSO)δ 8.94(s,1H),7.77(d,J=8.8Hz,1H),7.31(d,J=1.8Hz,1H),6.95(dd,J=8.8Hz,2.1Hz,1H),6.54(t,J=5.3Hz,1H),4.42(d,J=5.4Hz,2H),4.12-3.98(m,2H),2.96-2.80(m,2H),1.78(m,J=4.3Hz,2H),1.65(m,2H),1.57(m,J=5.0Hz,2H).。
步驟16-4：1-(苯並[d]噻唑-6-基)-3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
1H NMR(300MHz,DMSO)δ 9.44(s,1H),8.27(s,1H),8.17(d,J=1.8Hz,1H),8.10(d,J=8.6Hz,1H),7.66(dd,J=6.9Hz,2.5Hz,1H),7.44(dd,J=8.7Hz,1.9Hz,1H),7.38(dd,J=4.2Hz,2.7Hz,1H),7.27(t,J=9.1Hz,1H),5.06(s,2H),4.21-4.01(m,2H),2.94-2.77(m,2H),1.79(s,2H),1.63(s,2H),1.57(m,J=10.5Hz,2H)。
實施例17：5-(3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲基)-1H-吲哚-1-羧酸三級丁基酯
步驟17-1：5-硝基-1H-吲哚-1-羧酸三級丁基酯(tert-Butyl 5-nitro-1H-indol-1-carboxylate)
LC/MS[M+H]+：161.16
1H NMR(300MHz,CDCl3)δ 8.49(d,J=2.2Hz,1H),8.30-8.18(m,2H),7.74(d,J=3.7Hz,1H),6.72(d,J=3.7Hz,1H),1.70(s,9H)。
步驟17-2：5-胺基吲哚啉-1-羧酸三級丁基酯(tert-Butyl 5-aminoindolin-1-carboxylate)
LC/MS[M+H]+：232.85
1H NMR(300MHz,CDCl3)δ 7.91(s,1H),7.51(s,1H),6.84(d,J=2.2Hz,1H),6.71(dd,J=8.7Hz,2.3Hz,1H),6.40(d,J=3.6Hz,1H),3.60(s,2H),1.65(s,9H)。
步驟17-3：5-(2-甲氧基-2-氧代乙胺基)-1H-吲哚-1-羧酸三級丁基酯(tert-Butyl 5-(2-methoxy-2-oxoethylamino)-1H-indol-1-carboxylate)
LC/MS[M+H]+：305.02
1H NMR(300MHz,MeOD)δ 7.86(d,J=9.4Hz,1H),7.48(d,J=3.7Hz,1H),6.70(dd,J=7.9Hz,2.1Hz,2H),6.43(d,J=3.6Hz,1H),3.95(s,2H),3.73(s,3H),1.65(s,9H)。
步驟17-4：5-(2-肼基-2-氧代乙胺基)-1H-吲哚-1-羧酸三級丁基酯(tert-Butyl 5-(2-hydrazinyl-2-oxoethylamino)-1H-indol-1-carboxylate)
粗產物
步驟17-5：5-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲胺基)-1H-吲哚-1-羧酸三級丁基酯(tert-Butyl 5-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methylamino)-1H-indol-1-carboxylate)
1H NMR(300MHz,Chloroform-d)δ 7.94(d,J=7.8Hz,1H),7.52(d,J=3.1Hz,1H),6.90(s,1H),6.75(d,J=8.8Hz,1H),6.45(d,J=3.6Hz,1H),4.07-3.97(m,2H),3.04-2.95(m,2H),1.93-1.84(m,2H),1.74(s,5H),1.65(s,9H)。
步驟17-6：5-(3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲基)-1H-吲哚-1-羧酸三級丁基酯
LC/MS[M-H]-：551.28
1H NMR(300MHz,CDCl3)δ 8.20(d,J=9.0Hz,1H),7.67(d,J=3.6Hz,1H),7.47(d,J=1.8Hz,1H),7.42(dd,J=6.5Hz,2.4Hz,1H),7.12-7.06(m,1H),7.01(dt,J=17.3Hz,6.7Hz,2H),6.57(d,J=3.7Hz,1H),6.30(s,1H),5.12(s,2H),4.23(d,J=4.8Hz,2H),3.03-2.94(m,2H),1.89(s,2H),1.77(d,J=22.9Hz,4H),1.68(s,9H)。
實施例18：3-(3-氯基-4-氟苯基)-1-(1H-吲哚-5-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟18-1：5-硝基-1H-吲哚-1-羧酸三級丁基酯(tert-Butyl 5-nitro-1H-indol-1-carboxylate)
1H NMR(300MHz,CDCl3)δ 8.49(d,J=2.2Hz,1H),8.30-8.18(m,2H),7.74(d,J=3.7Hz,1H),6.72(d,J=3.7Hz,1H),1.70(s,9H)。
步驟18-2：5-胺基吲哚啉-1-羧酸三級丁基酯(tert-Butyl 5-aminoindolin-1-carboxylate)
LC/MS[M+H]+：234.81
1H NMR(300MHz,DMSO)δ 7.17(d,J=88.3Hz,1H),6.38(s,1H),6.28(dd,J=8.5Hz,2.2Hz,1H),4.66(s,2H),3.74(t,J=8.6Hz,2H),2.85(t,J=8.5Hz,2H),1.41(s,9H)。
步驟18-3：5-(2-甲氧基-2-氧代乙胺基)-1H-吲哚-1-羧酸三級丁基酯(tert-Butyl 5-(2-methoxy-2-oxoethylamino)-1H-indol-1-carboxylate)
LC/MS[M+H]+：305.02
1H NMR(300MHz,MeOD)δ 7.86(d,J=9.4Hz,1H),7.48(d,J=3.7Hz,1H),6.70(dd,J=7.9Hz,2.1Hz,2H),6.43(d,J=3.6Hz,1H),3.95(s,2H),3.73(s,3H),1.65(s,9H)。
步驟18-4：5-(2-肼基-2-氧代乙胺基)-1H-吲哚-1-羧酸三級丁基酯(tert-Butyl 5-(2-hydrazinyl-2-oxoethylamino)-1H-indol-1-carboxylate)
粗產物
步驟18-5：5-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲胺基)-1H-吲哚-1-羧酸三級丁基酯(tert-Butyl 5-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methylamino)-1H-indol-1-carboxylate)
1H NMR(300MHz,Chloroform-d)δ 7.94(d,J=7.8Hz,1H),7.52(d,J=3.1Hz,1H),6.90(s,1H),6.75(d,J=8.8Hz,1H),6.45(d,J=3.6Hz,1H),4.07-3.97(m,2H),3.04-2.95(m,2H),1.93-1.84(m,2H),1.74(s,5H),1.65(s,9H)。
步驟18-6：5-(3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲基)-1H-吲哚-1-羧酸三級丁基酯(tert-Butyl 5-(3-(3-chloro-4-fluorophenyl)-1-((6,7,8,9-
tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)ureido)-1H-indol-1-carboxylate)
LC/MS[M-H]-：551.28
1H NMR(300MHz,CDCl3)δ 8.20(d,J=9.0Hz,1H),7.67(d,J=3.6Hz,1H),7.47(d,J=1.8Hz,1H),7.42(dd,J=6.5Hz,2.4Hz,1H),7.12-7.06(m,1H),7.01(dt,J=17.3Hz,6.7Hz,2H),6.57(d,J=3.7Hz,1H),6.30(s,1H),5.12(s,2H),4.23(d,J=4.8Hz,2H),3.03-2.94(m,2H),1.89(s,2H),1.77(d,J=22.9Hz,4H),1.68(s,9H)。
步驟18-7：3-(3-氯基-4-氟苯基)-1-(1H-吲哚-5-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：453.06
1H NMR(300MHz,DMSO)δ 11.24(s,1H),7.86(s,1H),7.69-7.63(m,1H),7.39(d,J=10.3Hz,4H),7.22(t,J=9.1Hz,1H),6.89(d,J=8.4Hz,1H),6.44(s,1H),4.98(s,2H),4.06(s,2H),2.81(s,2H),1.77(s,2H),1.58(s,4H)。
實施例19：3-(3-氯基-4-氟苯基)-1-(3-氰基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟19-1：2-(3-氰基苯基胺)乙酸乙酯(Ethyl 2-(3-cyanophenylamino)acetate)
1H NMR(300MHz,CDCl3)δ 7.25(s,1H),7.04(d,J=7.6Hz,1H),6.86-6.79(m,2H),4.56(s,1H),4.29(q,J=7.1Hz,2H),3.92(d,J=5.3Hz,2H),1.34(t,J=7.1Hz,3H)。
步驟19-2：2-(3-氰基苯基胺)乙醯肼(2-(3-Cyanophenylamino)acetohydrazide)
1H NMR(300MHz,DMSO)δ 9.17(s,2H),7.26(t,J=7.8Hz,2H),6.91(dd,J=23.0Hz,8.5Hz,4H),6.45(t,J=6.1Hz,2H),4.26(s,3H),3.67(d,J=6.2Hz,4H)。
步驟19-3：3-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲胺基)苄腈(3-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methylamino)benzonitrile)
1H NMR(300MHz,DMSO)δ 7.27(t,J=7.8Hz,1H),7.08-6.95(m,3H),6.71(s,1H),4.40(d,J=5.5Hz,2H),4.03-3.98(m,2H),2.90-2.82(m,2H),1.79(d,J=4.6Hz,2H),1.60(dd,J=14.4Hz,8.3Hz,4H)。
步驟19-4：3-(3-氯基-4-氟苯基)-1-(3-氰基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：441.11
1H NMR(300MHz,CDCl3)δ 7.70(d,J=6.9Hz,3H),7.64(d,J=6.5Hz,1H),7.50(dd,J=6.4Hz,2.5Hz,1H),7.16-7.02(m,2H),6.72(s,1H),5.04(s,2H),4.16-4.06(m,2H),3.06-2.99(m,2H),1.92(s,2H),1.77(d,J=5.1Hz,4H)。
實施例20：1-(苯並[d][1,3]二噁茂-5-基)-3-(6-甲基吡啶-2-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟20-1：N-(6-甲基吡啶-2-基)-1H-咪唑並-1-羧醯胺(N-(6-methylpyridin-2-yl)-1H-imidazol-1-carboxamide)
粗產物
步驟20-2：1-(苯並[d][1,3]二噁茂-5-基)-3-(6-甲基吡啶-2-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：422.3
1H NMR(300MHz,CDCl3)δ 7.86(d,J=8.3Hz,1H),7.54(t,J=7.9Hz,1H),6.95(s,1H),6.80(dd,J=7.7Hz,4.4Hz,1H),6.63(dt,J=8.0Hz,2.0Hz,1H),6.03(s,1H),5.06(s,1H),4.32-4.13(m,1H),3.08-2.92(m,1H),2.35(s,2H),1.88-1.87(m,2H),1.83-1.69(m,3H)。
實施例21：3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-1-(3-(三氟甲基)苯基)脲
步驟21-1：2-(3-(三氟甲基)苯胺基)乙酸乙酯(Ethyl 2-(3-(trifluoromethyl)phenylamino)acetate)
LC/MS[M+H]+：248.99
1H NMR(500MHz,CDCl3)δ 7.29(d,J=7.9Hz,1H),6.99(d,J=7.7Hz,1H),6.79(s,1H),6.76(d,J=8.2Hz,1H),4.50(s,1H),4.27(q,J=7.1Hz,2H),3.92(d,J=5.3Hz,2H),1.31(t,J=7.1Hz,3H)。
步驟21-2：2-(3-(三氟甲基)苯胺基)乙醯肼(2-(3-(Trifluoromethyl)phenylamino)acetohydrazide)
LC/MS[M+H]+：234.95
1H NMR(300MHz,CDCl3)δ 7.67(s,1H),7.31(t,J=7.9Hz,1H),7.05(d,J=7.7Hz,1H),6.81(s,1H),6.79-6.71(m,1H),4.46(s,1H),3.89(d,J=4.7Hz,2H),3.84-3.30(m,2H)。
步驟21-3：N-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-3-(三氟甲基)苯胺(N-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)-3-(trifluoromethyl)aniline)
LC/MS[M+H]+：312.11
1H NMR(300MHz,MeOD)δ 7.27(t,J=7.7Hz,1H),6.98-6.87(m,3H),4.51(s,2H),4.20-4.11(m,2H),3.01-2.91(m,2H),1.89(d,J=4.9Hz,2H),1.81-1.63(m,4H)。
步驟21-4：3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-1-(3-(三氟甲基)苯基)脲
LC/MS[M+H]+：483.98
1H NMR(300MHz,CDCl3)δ 7.68-7.56(m,4H),7.48(dd,J=6.4Hz,2.4Hz,1H),7.06(ddd,J=22.2Hz,13.1Hz,6.4Hz,2H),6.72(s,1H),5.04(s,2H),4.15-4.05(m,2H),3.04-2.93(m,2H),1.88(d,J=4.4Hz,2H),1.74(d,J=5.0Hz,5H)。
實施例22：3-(3-氯基-4-氟苯基)-1-(3,4-二氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟22-1：2-(3,4-二氟苯基胺)乙酸甲酯(Methyl 2-(3,4-difluorophenylamino)acetate)
LC/MS[M+H]+：203
1H NMR(300MHz,Chloroform-d)δ 7.00(q,J=9Hz,1H),6.51-6.38(m,1H),6.35-6.24(m,1H),4.27(s,1H),3.88(s,2H),3.82(s,3H)。
步驟22-2：2-(3,4-二氟苯基胺)乙醯肼(2-(3,4-Difluorophenylamino)acetohydrazide)
LC/MS[M+H]202
1H NMR(300MHz,Chloroform-d)δ 7.60(s,1H),7.03(q,J=8.9Hz,1H),6.46-6.39(m,1H),6.36-6.24(m,1H),4.20(s,1H),3.91(s,2H),3.84(d,J=5.5Hz,2H)。
步驟22-3：3,4-二氟-N-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)苯胺(3,4-Difluoro-N-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)aniline)
LC/MS[M+H]279
1H NMR(300MHz,Chloroform-d)δ 7.02(q,J=9.0Hz,1H),6.55(ddd,J=12.3Hz,6.5Hz,2.8Hz,1H),6.49-6.35(m,1H),4.36(d,J=4.6Hz,2H),4.32(s,1H),4.06-3.93(m,2H),3.10-2.96(m,2H),1.92(d,J=4.4Hz,2H),1.87-1.67(m,4H)。
步驟22-4：3-(3-氯基-4-氟苯基)-1-(3,4-二氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]450
1H NMR(300MHz,Methanol-d4)δ 7.60(dd,J=6.7Hz,2.6Hz,1H),7.43-7.32(m,2H),7.31-7.23(m,1H),7.13(t,J=9.0Hz,2H),5.09(s,2H),4.33-4.18(m,2H),3.04-2.91(m,2H),2.00-1.89(m,2H),1.88-1.64(m,4H)。
實施例23：3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-(1-(6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)乙基)脲
步驟23-1：2-(4-甲氧基苯基胺)丙酸甲酯(Methyl 2-(4-methoxyphenylamino)propanoate)
1H NMR(300MHz,CDCl3)δ 6.79(d,J=8.91Hz,2H),6.61(d,J=8.91Hz,2H),4.12(q,J=6.996Hz,1H),3.75(s,3H),3.72(s,3H),1.47(d,J=6.93Hz,3H)。
步驟23-2：2-(4-甲氧基苯基胺)丙醯肼(2-(4-methoxyphenylamino)propanhydrazide)
1H NMR(300MHz,CDCl3)δ 6.79(d,J=8.91Hz,2H),6.61(d,J=8.91Hz,2H),4.12(q,J=6.996Hz,1H),3.75(s,3H),3.72(s,3H),1.47(d,J=6.93Hz,3H)。
步驟23-3：4-甲氧基-N-(1-(6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)乙基)苯胺(4-Methoxy-N-(1-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)ethyl)aniline)
1H NMR(300MHz,CDCl3)δ 6.70(d,J=8.97Hz,2H),6.61(d,J=9.00Hz,2H),5.58(d,J=7.95Hz,1H),4.75(m,1H),4.06(m,2H),3.62(s,3H),2.85(m,2H),1.75(m,2H),1.55(m,4H),1.49(d,J=6.69Hz,3H)。
步驟23-4：3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-(1-(6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)乙基)脲
1H NMR(300MHz,DMSO)δ 7.67(m,2H),7.42(m,1H),7.28(t,J=9.12Hz,1H),6.91(m,2H),6.74(m,1H),6.04(q,J=6.99Hz,1H),4.15(m,2H),3.77(s,3H),2.91(m,2H),2.09(s,3H),1.82(m,6H),1.40(d,J=6.87Hz,3H)。
實施例24：3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)甲基)脲
步驟24-1：(Z)-N-甲基苄亞胺酸甲酯((Z)-methyl N-methylbenzimidate)
1H NMR(300MHz,CDCl3)δ 7.54-7.27(m,5H),3.81(s,3H),3.10(s,3H)。
步驟24-2：4-甲氧基-N-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)甲基)苯胺(4-Methoxy-N-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)aniline)
LC/MS[M+H]+：296.2
1H NMR(300MHz,CDCl3)δ 7.77-7.58(m,2H),7.57-7.47(m,3H),6.80(td,J=9.1Hz,2.3Hz,4H),4.50(d,J=5.7Hz,2H),4.17-3.90(m,1H),3.76(s,3H),3.71(s,3H)。
步驟24-3：3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)甲基)脲
LC/MS[M+H]+：468.2
1H NMR(300MHz,CDCl3)δ 7.66-7.63(m,2H),7.56-7.48(m,3H),7.46(dd,J=6.5Hz,2.5Hz,1H),7.30-7.27(m,2H),7.14-6.90(m,4H),6.30(s,1H),5.12(s,2H),3.84(s,3H)3.82(s,3H)。
實施例25：3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5-甲基-4-苯基-4H-1,2,4-三唑-3-基)甲基)脲
步驟25-1：(Z)-N-苯基乙亞胺酸甲酯((Z)-methyl N-phenylacetimidate)
1H NMR(300MHz,CDCl3)δ 7.28(dd,J=10.7Hz,4.9Hz,2H),7.03(t,J=7.4Hz,1H),6.85-6.64(m,2H),3.79(s,3H),1.82(s,3H)。
步驟25-2：4-甲氧基-N-((5-甲基-4-苯基-4H-1,2,4-三唑-3-基)甲基)苯胺(4-Methoxy-N-((5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)methyl)aniline)
1H NMR(300MHz,CDCl3)δ 7.65-7.48(m,3H),7.26-7.21(m,2H),6.73(d,J=8.9Hz,2H),6.52(d,J=8.9Hz,2H),4.24(d,J=5.6Hz,2H),3.72(s,3H),2.27(s,3H)。
步驟25-3：3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5-甲基-4-苯基-4H-1,2,4-三唑-3-基)甲基)脲
LC/MS[M+H]+：468.2
1H NMR(300MHz,CDCl3)δ 7.57-7.46(m,3H),7.37-7.33(m,3H),7.23-7.20(m,2H),6.99(m,4H),6.31(s,1H),4.81(s,2H),3.84(s,3H),2.27(s,3H)。
實施例26：3-(3-氯基-4-氟苯基)-1-((4-異丙基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲
步驟26-1：N-異丙基乙醯胺(N-isopropylacetamide)
1H NMR(300MHz,Methanol-d4)δ 3.93(hept,J=6.5Hz,1H),1.89(s,3H),1.12(d,J=6.6Hz,6H)。
步驟26-2：(E)-N-異丙基乙亞胺酸甲酯((E)-methyl N-isopropylacetimidate)
1H NMR(500MHz,Chloroform-d)δ 3.59(s,3H),3.48(p,J=6.3Hz,1H),1.86(s,3H),1.09(d,J=6.3Hz,6H)。
步驟26-3：N-((4-異丙基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-4-甲氧基苯胺(N-((4-isopropyl-5-methyl-4H-1,2,4-triazol-3-yl)methyl)-4-methoxyaniline)
LC/MS[M+H]+：261.95
1H NMR(300MHz,Chloroform-d)δ 6.81(d,J=8.8Hz,2H),6.71(d,J=8.9Hz,2H),4.55(hept,J=6.9Hz,1H),4.39(s,2H),3.76(s,3H),2.53(s,3H),1.51(d,J=7.0Hz,6H)。
步驟26-4：3-(3-氯基-4-氟苯基)-1-((4-異丙基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲
LC/MS[M+H]+：433.96
1H NMR(300MHz,Chloroform-d)δ 7.45(dd,J=6.5Hz,2.5Hz,1H),7.18-7.11(m,2H),7.07(ddd,J=8.9Hz,4.2Hz,2.7Hz,1H),7.00(t,J=8.7Hz,1H),6.96-6.90(m,2H),6.34(s,1H),5.08(s,2H),4.87(hept,J=7.1Hz,1H),3.82(s,3H),2.55(s,3H),1.52(d,J=7.0Hz,6H).。
實施例27：3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲
步驟27-1：(E)-5-甲氧基-2,3,6,7-四氫-1,4-氧雜氮呯((E)-5-Methoxy-2,3,6,7-tetrahydro-1,4-oxazepine)
1H NMR(500MHz,CDCl3)δ 3.70-3.67(m,2H),3.65-3.62(m,2H),3.59(s,3H),3.56-3.52(m,2H),2.67-2.62(m,2H)。
步驟27-2：4-甲氧基-N-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)苯胺(4-Methoxy-N-((5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)methyl)aniline)
LC/MS[M+H]+：276.13
1H NMR(300MHz,Methanol-d4)δ 6.77-6.71(m,2H),6.68(d,J=9.1Hz,2H),4.41(s,2H),4.34-4.24(m,2H),3.86-3.76(m,4H),3.68(s,3H),3.19-3.11(m,2H)。
步驟27-3：3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲
LC/MS[M+H]+：448.13
1H NMR(300MHz,Chloroform-d)δ 7.41(dd,J=6.4Hz,2.2Hz,1H),7.17(d,J=8.8Hz,2H),7.09-6.99(m,2H),6.96(d,J=8.8Hz,2H),6.24(s,1H),5.00(s,2H),4.47-4.36(m,2H),3.95-3.85(m,4H),3.83(s,3H),3.30-3.18(m,2H)。
實施例28：3-(3-氯基-4-氟苯基)-1-(4-氰基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟28-1：2-(4-氰基苯基胺)乙酸甲酯(Methyl 2-(4-cyanophenylamino)acetate)
1H NMR(300MHz,CDCl3)δ 7.52-7.40(d,2H),6.62-6.51(d,2H),4.82(s,1H),4.28(q,J=7.1Hz,2H),3.92(d,J=5.1Hz,2H),1.31(t,J=7.1Hz,3H)。
步驟28-2：2-(4-氰基苯基胺)乙醯肼(2-(4-Cyanophenylamino)acetohydrazide)
1H NMR(300MHz,DMSO)δ 9.19(s,1H),7.47(d,J=8.7Hz,2H),6.93(t,J=6.0Hz,1H),6.64(d,J=7.4Hz,2H),4.26(s,2H),3.71(d,J=6.1Hz,2H)。
步驟28-3：4-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲胺基)苄腈(4-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methylamino)benzonitrile)
1H NMR(300MHz,DMSO-d6)δ 7.56-7.42(m,2H),7.19(t,J=5.5Hz,2H),6.85-6.74(m,2H),4.44(d,J=5.5Hz,2H),4.06-3.93(m,2H),2.95-2.77(m,2H),1.58(dtd,J=25.1Hz,13.2Hz,11.3Hz,6.9Hz,6H)。
步驟28-4：3-(3-氯基-4-氟苯基)-1-(4-氰基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
1H NMR(300MHz,DMSO)δ 8.75(s,1H),7.88(d,J=7.5Hz,2H),7.67(d,J=4.5Hz,1H),7.58(d,J=7.6Hz,2H),7.46-7.21(m,2H),5.07(s,2H),4.07(s,2H),2.84(s,2H),1.78(s,2H),1.60(m,J=25.2Hz,4H)。
實施例29：3-(3-氯基-4-氟苯基)-1-((5-異丙基-4-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲
步驟29-1：N-甲基異丁醯胺(N-methylisobutyramide)
1H NMR(500MHz,Chloroform-d)δ 5.87(s,1H),2.80(d,J=4.8Hz,3H),2.38(hept,J=6.9Hz,1H),1.15(d,J=6.9Hz,6H)。
步驟29-2：(E)-N-甲基異丁亞胺酸甲酯((E)-methyl N-methylisobutyrimidate)
1H NMR(300MHz,Chloroform-d)δ 3.58(s,3H),3.03(s,3H),2.93(p,J=6.9Hz,1H),1.09(d,J=6.9Hz,6H).。
步驟29-3：N-((5-異丙基-4-甲基-4H-1,2,4-三唑-3-基)甲基)-4-甲氧基苯胺(N-((5-isopropyl-4-methyl-4H-1,2,4-triazol-3-yl)methyl)-4-methoxyaniline)
LC/MS[M+H]+：262.08
1H NMR(300MHz,Methanol-d4)δ 6.74(d,J=9.2Hz,2H),6.69(d,J=9.2Hz,2H),4.41(s,2H),3.69(s,3H),3.66(s,3H),3.13(dq,J=13.8Hz,6.8Hz,1H),1.33(d,J=6.9Hz,6H)。
步驟29-4：3-(3-氯基-4-氟苯基)-1-((5-異丙基-4-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲
LC/MS[M+H]+：434.16
1H NMR(300MHz,Chloroform-d)δ 7.45(dd,J=6.5Hz,2.5Hz,1H),7.23-7.16(m,2H),7.09-7.03(m,1H),7.00(t,J=8.7Hz,1H),6.93(d,J=8.9Hz,2H),6.31(s,1H),5.03(s,2H),3.83(s,3H),3.70(s,3H),3.00(hept,J=6.7Hz,1H),1.39(d,J=6.9Hz,6H)。
實施例30：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((5,6,7,8,9,10-六氫-[1,2,4]三唑並[4,3-a]氮雜辛環-3-基)甲基)脲
步驟30-1：(E)-8-甲氧基-2,3,4,5,6,7-六氫氮雜辛環((E)-8-Methoxy-2,3,4,5,6,7-hexahydroazocine)
1H NMR(300MHz,CDCl3)δ 3.63(s,3H),3.56-3.33(m,2H),2.44-2.19(m,2H),1.77-1.54(m,4H),1.57-1.28(m,4H)。
步驟30-2：N-((5,6,7,8,9,10-六氫-[1,2,4]三唑並[4,3-a]氮雜辛環-3-基)甲基)苯並[d][1,3]二噁茂-5-胺(N-((5,6,7,8,9,10-hexahydro-[1,2,4]triazolo[4,3-a]azocin-3-yl)methyl)benzo[d][1,3]dioxol-5-amine)
粗產物
步驟30-3：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((5,6,7,8,9,10-六氫-[1,2,4]三唑並[4,3-a]氮雜辛環-3-基)甲基)脲
LC/MS[M+H]+：262.08
1H NMR(300MHz,Methanol-d4)δ 6.74(d,J=9.2Hz,2H),6.69(d,J=9.2Hz,2H),4.41(s,2H),3.69(s,3H),3.66(s,3H),3.13(dq,J=13.8Hz,6.8Hz,1H),1.33(d,J=6.9Hz,6H)。
實施例31：3-(3-氯基-4-氟苯基)-1-((5-環戊基-4-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲
步驟31-1：N-甲基環戊烷羧醯胺(N-methylcyclopentancarboxamide)
1H NMR(300MHz,CDCl3)δ 5.47(s,1H),2.83(d,J=4.8Hz,3H),2.50(dd,J=16.0Hz,7.9Hz,1H),1.91-1.73(m,6H),1.59(d,J=2.7Hz,2H)。
步驟31-2：(Z)-N-甲基環戊烷甲亞胺酸甲酯((Z)-methyl N-methylcyclopentancarbimidate)
1H NMR(300MHz,CDCl3)δ 3.58(s,12H),3.03(s,13H),2.98(dd,J=10.0Hz,5.9Hz,4H),1.81-1.71(m,24H),1.56(dd,J=6.0Hz,2.9Hz,10H)。
步驟31-3：N-((5-環戊基-4-甲基-4H-1,2,4-三唑-3-基)甲基)-4-甲氧基苯胺(N-((5-cyclopentyl-4-methyl-4H-1,2,4-triazol-3-yl)methyl)-4-methoxyaniline)
1H NMR(300MHz,DMSO)δ 6.76-6.64(m,7H),4.29(d,J=5.6Hz,3H),3.63(s,6H),3.56(d,J=7.6Hz,5H),3.22-3.06(m,2H),2.04-1.92(m,4H),1.92-1.91(m,1H),1.84-1.62(m,11H)。
步驟31-4：3-(3-氯基-4-氟苯基)-1-((5-環戊基-4-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲
LC/MS[M+H]+：460.08
1H NMR(300MHz,CDCl3)δ 7.46(dd,J=6.5Hz,2.5Hz,1H),7.25-7.19(m,2H),7.11-6.99(m,2H),6.95(d,J=8.9Hz,2H),6.31(s,1H),5.04(s,2H),3.84(s,
3H),3.70(s,3H),3.06(d,J=8.4Hz,1H),2.05(dd,J=12.8Hz,6.3Hz,4H),1.90-1.84(m,2H),1.70(dd,J=7.1Hz,4.5Hz,2H)。
實施例32：3-(3-氯基-4-氟苯基)-1-((4-環戊基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲
步驟32-1：N-環戊基乙醯胺(N-cyclopentylacetamide)
1H NMR(300MHz,CDCl3)δ 5.83(s,1H),4.17(dd,J=14.1Hz,7.0Hz,1H),1.94(s,3H),1.73-1.52(m,4H),1.43-1.29(m,2H)。
步驟32-2：(E)-N-環戊基乙亞胺酸甲酯((E)-methyl N-cyclopentylacetimidate)
1H NMR(300MHz,CDCl3)δ 4.31-4.19(m,6H),4.19(dd,J=14.1Hz,7.0Hz,4H),1.96(s,12H),1.62(tdd,J=8.5Hz,6.9Hz,2.1Hz,17H),1.42-1.25(m,8H)。
步驟32-3：N-((4-環戊基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-4-甲氧基苯胺(N-((4-cyclopentyl-5-methyl-4H-1,2,4-triazol-3-yl)methyl)-4-methoxyaniline)
1H NMR(300MHz,CDCl3)δ 6.88-6.81(m,2H),6.77-6.66(m,2H),4.72-4.53(m,1H),4.40(s,2H),3.78(d,J=2.1Hz,3H),2.54(s,2H),1.99-1.65(m,7H)。
步驟32-4：3-(3-氯基-4-氟苯基)-1-((4-環戊基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲
LC/MS[M+H]+：460.15
1H NMR(300MHz,CDCl3)δ 7.41(dd,J=6.5Hz,2.5Hz,1H),7.16(d,J=8.9Hz,2H),7.09-6.98(m,2H),6.93(d,J=8.9Hz,2H),6.29(s,1H),5.06(s,2H),5.01-
4.92(m,1H),3.82(s,3H),2.59(s,3H),2.16(s,2H),1.92(d,J=3.5Hz,4H),1.76(d,J=3.0Hz,2H)。
實施例33：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-(1-(5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)乙基)脲
步驟33-1：1,4-氧氮雜環庚烷-5-酮(1,4-Oxazepan-5-one)
1H NMR(300MHz,CDCl3)δ 6.73(s,1H),3.94-3.69(m,4H),3.35(dd,J=8.3Hz,5.4Hz,2H),2.80-2.59(m,2H)。
步驟33-2：(E)-5-甲氧基-2,3,6,7-四氫-1,4-氧雜氮呯((E)-5-Methoxy-2,3,6,7-tetrahydro-1,4-oxazepine)
粗產物
步驟33-3：N-(1-(5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)乙基)苯並[d][1,3]二噁茂-5-胺(N-(1-(5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)ethyl)benzo[d][1,3]dioxol-5-amine)
1H NMR(300MHz,CDCl3)δ 6.65(d,J=8.3Hz,1H),6.31(d,J=2.3Hz,1H),6.12(dd,J=8.3Hz,2.3Hz,1H),5.87(s,2H),4.71(q,J=6.6Hz,1H),4.34-4.19(m,2H),3.92-3.83(m,2H),3.87-3.77(m,2H),3.36-3.21(m,2H),1.68(d,J=6.7Hz,3H)。
步驟33-4：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-(1-(5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)乙基)脲
LC/MS[M+H]+：476.1
1H NMR(300MHz,DMSO)δ 7.73(s,1H),7.68(dd,J=6.9Hz,2.4Hz,1H),7.42-7.38(m,1H),7.26(t,J=9.1Hz,1H),6.87(d,J=8.2Hz,1H),6.53(s,1H),6.40(s,1H),6.07(s,2H),6.05-5.93(m,1H),4.31-4.20(m,2H),4.00-3.52(m,4H),3.16-3.09(m,2H),1.41(d,J=6.9Hz,3H)。
實施例34：3-(3-氯基-4-氟苯基)-1-(4-(二甲胺基)苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：457.9
1H NMR(300MHz,CDCl3)δ 7.44(dd,J=6.5Hz,2.5Hz,1H),7.16-7.04(m,1H),6.98(dd,J=16.1Hz,8.7Hz,3H),6.67(d,J=8.9Hz,2H),6.35(s,1H),5.05(s,2H),4.23(d,J=4.5Hz,2H),3.00(d,J=12.1Hz,8H),2.00-1.84(m,2H),1.83-1.59(m,4H)。
實施例35：3-(3-氯基-4-氟苯基)-1-(1-甲基-1H-吡唑-3-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟35-1：2-(1-甲基-1H-吡唑-3-胺基)乙酸甲酯(Methyl 2-(1-methyl-1H-pyrazol-3-ylamino)acetate)
LC/MS[M+H]+：171
1H NMR(300MHz,Chloroform-d)δ 7.10(d,J=2.2Hz,1H),5.54(d,J=2.3Hz,1H),4.18(d,J=15.0Hz,1H),3.98(s,2H),3.76(s,3H),3.71(s,3H)。
步驟35-2：2-(1-甲基-1H-吡唑-3-胺基)乙醯肼(2-(1-Methyl-1H-pyrazol-3-ylamino)acetohydrazide)
1H NMR(300MHz,Chloroform-d)δ 8.01(s,1H),7.13(d,J=2.2Hz,1H),5.53(d,J=2.3Hz,1H),3.89(s,2H),3.73(s,3H)。
步驟35-3：1-甲基-N-((6,7,8,9四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-1H-吡唑-3-胺(1-Methyl-N-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)-1H-pyrazol-3-amine)
1H NMR(300MHz,Chloroform-d)δ 7.13(d,J=2.2Hz,1H),5.59(s,1H),4.50(s,2H),4.15-3.99(m,2H),3.97-3.83(m,2H),3.75(s,3H),3.06-2.91(m,4H),1.99-1.84(m,2H)。
步驟35-4：3-(3-氯基-4-氟苯基)-1-(1-甲基-1H-吡唑-3-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：418
1H NMR(300MHz,Chloroform-d)δ 10.80(s,1H),7.68(dd,J=6.5Hz,2.6Hz,1H),7.44-7.30(m,2H),7.10(t,J=8.8Hz,1H),6.58(d,J=2.4Hz,1H),5.29(s,2H),4.19(m,2H),3.86(s,3H),2.97(m,2H),1.84(m,2H),1.68(m,4H)。
實施例36：3-(3-氯基-4-氟苯基)-1-(異噁唑-3-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟36-1：2-(異噁唑-3-胺基)乙酸甲酯(Methyl 2-(isoxazol-3-ylamino)acetate)
1H NMR(300MHz,Chloroform-d)δ 8.09(d,J=1.7Hz,1H),5.92(d,J=1.8Hz,1H),4.51(s,1H),4.07(d,J=5.6Hz,2H),3.82(s,3H)。
步驟36-2：2-(異噁唑-3-胺基)乙醯肼(2-(Isoxazol-3-ylamino)acetohydrazide)
1H NMR(300MHz,Methanol-d4)δ 8.23(d,J=1.8Hz,1H),6.02(d,J=1.8Hz,1H),3.85(s,2H)。
步驟36-3：N-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)異噁唑-3-胺(N-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)isoxazol-3-amine)
LC/MS[M+H]234
1H NMR(300MHz,Methanol-d4)δ 8.24(d,J=1.7Hz,1H),6.00(d,J=1.8Hz,1H),4.52(s,2H),4.15(d,J=9.7Hz,3H),2.99(d,J=11.1Hz,3H),1.94(s,2H),1.73(s,5H)。
步驟36-4：3-(3-氯基-4-氟苯基)-1-(異噁唑-3-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：405
1H NMR(300MHz,Chloroform-d)δ 10.58(s,1H),8.30(d,J=1.8Hz,1H),7.75(dd,J=6.5Hz,2.6Hz,1H),7.47-7.33(m,1H),7.21-7.03(m,2H),5.28(s,2H),4.37-4.22(m,2H),3.09-2.94(m,2H),1.95-1.85(m,2H),1.84-1.65(m,4H)。
實施例37：3-(3-氯基-4-氟苯基)-1-((4-環丙基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲
步驟37-1：N-((4-環丙基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-4-甲氧基苯胺(N-((4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)methyl)-4-methoxyaniline)
1H NMR(300MHz,CDCl3)δ 7.50-7.43(m,3H),7.07(s,1H),7.00(dd,J=15.0Hz,8.7Hz,3H),6.40(s,1H),5.08(s,2H),3.86(s,3H),3.12(dd,J=7.1Hz,3.3Hz,1H),2.50(s,3H),1.23(d,J=6.5Hz,2H),1.00(s,2H)。
步驟37-2：3-(3-氯基-4-氟苯基)-1-((4-環丙基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲
LC/MS[M+H]+：432.07
1H NMR(500MHz,CDCl3)δ 7.50-7.43(m,3H),7.07(s,1H),7.00(dd,J=15.0Hz,8.7Hz,3H),6.40(s,1H),5.08(s,2H),3.86(s,3H),3.12(dd,J=7.1Hz,3.3Hz,1H),2.50(s,3H),1.23(d,J=6.5Hz,2H),1.00(s,2H)。
實施例38：3-((3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)脲基)甲基)-8,9-二氫-5H-[1,2,4]三唑並[4,3-d][1,4]二氮呯-7(6H)-羧酸苄酯
步驟38-1：3-((4-甲氧基苯基胺)甲基)-8,9-二氫-5H-[1,2,4]三唑並[4,3-d][1,4]二氮呯-7(6H)-羧酸苄酯(Benzyl 3-((4-methoxyphenylamino)methyl)-8,9-dihydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7(6H)-carboxylate)
粗產物
步驟38-2：3-((3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)脲基)甲基)-8,9-二氫-5H-[1,2,4]三唑並[4,3-d][1,4]二氮呯-7(6H)-羧酸苄酯
1H NMR(500MHz,CDCl3)δ 7.40(m,6H),7.21(d,J=8.7Hz,2H),7.05(h,2H),6.98(d,J=8.8Hz,2H),6.23(br,1H),5.22(s,2H),5.01(m,2H),4.37(m,2H),3.85(m,5H),3.74(m,2H),3.19(m,2H)。
實施例39：3-(3-氯基-4-氟苯基)-1-(噁唑-2-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟39-1：噁唑-2-基胺甲酸三級丁基酯(tert-Butyl oxazol-2-ylcarbamate)
LC/MS[M+H]257
1H NMR(300MHz,Chloroform-d)δ 7.48(s,1H),7.00(s,1H),4.56(s,2H),3.80(s,3H),1.54(s,9H)。
步驟39-2：2-(三級丁氧羰基(噁唑-2-基)胺)乙酸甲酯(Methyl 2-(tert-butoxycarbonyl(oxazol-2-yl)amino)acetate)
LC/MS[M+H]257
1H NMR(300MHz,Chloroform-d)δ 7.48(s,1H),7.00(s,1H),4.56(s,2H),3.80(s,3H),1.54(s,9H)。
步驟39-3：2-(噁唑-2-胺基)乙酸甲酯(Methyl 2-(oxazol-2-ylamino)acetate)
LC/MS[M+H]157
1H NMR(300MHz,Chloroform-d)δ 7.20(s,1H),6.80(s,1H),5.21(s,1H),4.15(d,J=2.8Hz,2H),3.81(s,3H)。
步驟39-4：2-(噁唑-2-胺基)乙醯肼(2-(oxazol-2-ylamino)acetohydrazide)
粗產物
步驟39-5：N-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)噁唑-2-胺(N-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)oxazol-2-amine)
LC/MS[M+H]157
1H NMR(300MHz,Chloroform-d)δ 7.17(s,1H),6.77(s,1H),4.85(s,2H),2.24(d,J=29.1Hz,1H)。
步驟39-6：3-(3-氯基-4-氟苯基)-1-(噁唑-2-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]405
1H NMR(500MHz,Chloroform-d)δ 11.77(s,1H),7.73(dd,J=6.4Hz,2.4Hz,1H),7.54(s,1H),7.41-7.32(m,1H),7.12(t,J=8.8Hz,1H),7.02(s,1H),5.36(s,2H),4.28-4.10(m,2H),3.08-2.88(m,2H),1.95-1.70(m,6H)。
實施例40：3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲
步驟40-1：2-(6-甲氧基吡啶-3-胺基)乙酸甲酯(Methyl 2-(6-methoxypyridin-3-ylamino)acetate)
粗產物
步驟40-2：2-(6-甲氧基吡啶-3-胺基)乙醯肼(2-(6-Methoxypyridin-3-ylamino)acetohydrazide)
1H NMR(300MHz,CDCl3)δ 7.54(d,J=2.9Hz,1H),6.96(dd,J=8.8Hz,3.0Hz,1H),6.62(d,J=8.8Hz,1H),3.83(s,3H),3.78(d,J=5.3Hz,2H)。
步驟40-3：6-甲氧基-N-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)吡啶-3-胺(6-Methoxy-N-((5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)methyl)pyridin-3-amine)
粗產物
步驟40-4：3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲
LC/MS[M+H]+：449.14
1H NMR(300MHz,CDCl3)δ 8.05(d,J=2.6Hz,1H),7.59(dd,J=8.8Hz,2.8Hz,1H),7.46-7.41(m,1H),7.04(dd,J=7.3Hz,4.1Hz,2H),6.86(d,J=8.8Hz,1H),4.97(s,2H),4.45-4.37(m,2H),3.97(s,3H),3.95-3.85(m,4H),3.28-3.22(m,2H)。
實施例41：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯苯基)-1-((5,6,7,8-四氫-[1,2,4]三唑並[4,3-a]吡啶-3-基)甲基)脲
步驟41-1：6-甲氧基-2,3,4,5-四氫吡啶(6-Methoxy-2,3,4,5-tetrahydropyridine)
1H NMR(300MHz,CDCl3)δ 3.59(s,3H),3.50-3.42(m,2H),2.21-2.06(m,2H),1.70(dd,J=7.7Hz,4.4Hz,2H),1.59-1.49(m,2H)。
步驟41-2：N-((5,6,7,8-四氫-[1,2,4]三唑並[4,3-a]吡啶-3-基)甲基)苯並[d][1,3]二噁茂-5-胺(N-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)benzo[d][1,3]dioxol-5-amine)
1H NMR(300MHz,CDCl3)δ 6.70(d,J=8.3Hz,1H),6.38(d,J=2.3Hz,1H),6.24-6.17(m,1H),5.89(s,2H),4.38(s,2H),3.98(t,J=5.9Hz,2H),3.00(t,J=6.3Hz,2H),2.08-1.89(m,4H)。
步驟41-3：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯苯基)-1-((5,6,7,8-四氫-[1,2,4]三唑並[4,3-a]吡啶-3-基)甲基)脲
LC/MS[M+H]+：428.15
1H NMR(300MHz,CDCl3)δ 7.42(t,J=1.9Hz,1H),7.21-7.15(m,1H),7.12(dt,J=8.2Hz,1.5Hz,1H),7.03-6.98(m,1H),6.85(d,J=8.1Hz,1H),6.82-6.73(m,2H),6.42(s,1H),6.06(s,2H),5.01(s,2H),4.13(t,J=6.0Hz,2H),2.99(t,J=6.4Hz,2H),2.10-1.99(m,2H),1.99-1.87(m,2H)。
實施例42：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((6,8-二氫-5H-[1,2,4]三唑並[3,4-c][1,4]噁嗪-3-基)甲基)脲
步驟42-1：5-甲氧基-3,6-二氫-2H-1,4-噁嗪(5-Methoxy-3,6-dihydro-2H-1,4-oxazine)
1H NMR(300MHz,CDCl3)δ 4.05(s,2H),3.74-3.61(m,5H),3.54(t,J=4.6Hz,2H)。
步驟42-2：N-((6,8-二氫-5H-[1,2,4]三唑並[3,4-c][1,4]噁嗪-3-基)甲基)苯並[d][1,3]二噁茂-5-胺(N-((6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)methyl)benzo[d][1,3]dioxol-5-amine)
LC/MS[M+H]+：276.1
1H NMR(300MHz,CDCl3)δ 6.68(d,J=8.3Hz,1H),6.35(d,J=2.3Hz,1H),6.18(dd,J=8.3Hz,2.4Hz,1H),5.88(s,2H),4.96(s,2H),4.44(s,2H),4.32-3.81(m,4H)。
步驟42-3：1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((6,8-二氫-5H-[1,2,4]三唑並[3,4-c][1,4]噁嗪-3-基)甲基)脲
LC/MS[M+H]+：448.1
1H NMR(300MHz,CDCl3)δ 7.44(dd,J=6.5Hz,2.4Hz,1H),7.20-6.95(m,2H),6.87-6.76(m,3H),6.29(s,1H),6.06(s,2H),4.98(s,4H),4.38-4.21(m,2H),4.19-3.98(m,2H)。
實施例43：3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5,6,7,8-四氫-[1,2,4]三唑並[4,3-a]吡啶-3-基)甲基)脲
步驟43-1：4-甲氧基-N-((5,6,7,8-四氫-[1,2,4]三唑並[4,3-a]吡啶-3-基)甲基)苯胺(4-Methoxy-N-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)aniline)
粗產物
步驟43-2：3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5,6,7,8-四氫-[1,2,4]三唑並[4,3-a]吡啶-3-基)甲基)脲
LC/MS[M+H]+：432.1
1H NMR(300MHz,CDCl3)δ 7.46(dd,J=6.5Hz,2.4Hz,1H),7.24(d,J=8.8Hz,2H),7.12-6.90(m,4H),6.30(s,1H),5.02(s,2H),4.12(t,J=5.9Hz,2H),3.85(s,3H),2.99(t,J=6.3Hz,2H),2.13-1.87(m,4H)。
實施例44：3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
步驟44-1：6-甲氧基-N-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)吡啶-3-胺(6-Methoxy-N-((6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)methyl)pyridin-3-amine)
LC/MS[M+H]+：275.11
步驟44-2：3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲
LC/MS[M+H]+：445.09
1H NMR(300MHz,Chloroform-d)δ 7.98(m,1H),7.54-7.42(m,2H),7.08(m,1H),7.01(m,1H),6.80(m,1H),6.45(s,1H),5.00(s,2H),4.26-4.08(m,2H),3.94(s,2H),3.06-2.91(m,2H),1.89(m,2H),1.83-1.66(m,4H)。
實施例45：2-(5-((1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)脲基)甲基)-4H-1,2,4-三唑-3-基)乙酸甲酯
步驟45-1：(E)-3-胺基-3-乙氧基丙烯酸乙酯((E)-ethyl 3-amino-3-ethoxyacrylate)
粗產物
步驟45-2：3-(2-(2-(苯並[d][1,3]二噁茂-5-胺基)乙醯基)肼基)-3-亞胺基丙酸乙酯(Ethyl 3-(2-(2-(benzo[d][1,3]dioxol-5-ylamino)acetyl)hydrazinyl)-3-iminopropanoate)
LC/MS[M+H]+：324.3
步驟45-3：2-(5-((苯並[d][1,3]二噁茂-5-胺基)甲基)-4H-1,2,4-三唑-3-基)乙酸乙酯(Ethyl 2-(5-((benzo[d][1,3]dioxol-5-ylamino)methyl)-4H-1,2,4-triazol-3-yl)acetate)
LC/MS[M+H]+：463.2
1H NMR(300MHz,CDCl3)δ 7.47(dd,J=6.4Hz,2.6Hz,1H),7.18-7.08(m,1H),7.02(t,J=8.7Hz,1H),6.85(d,J=7.9Hz,1H),6.75(m,2H),6.37(s,1H),6.05(s,2H),4.86(s,2H),3.86(s,2H),3.76(s,3H)。
步驟45-4：2-(5-((苯並[d][1,3]二噁茂-5-胺基)甲基)-4H-1,2,4-三唑-3-基)乙酸(2-(5-((Benzo[d][1,3]dioxol-5-ylamino)methyl)-4H-1,2,4-triazol-3-yl)acetic acid)
粗產物
步驟45-5：2-(5-((苯並[d][1,3]二噁茂-5-胺基)甲基)-4H-1,2,4-三唑-3-基)乙酸甲酯(Methyl 2-(5-((benzo[d][1,3]dioxol-5-ylamino)methyl)-4H-1,2,4-triazol-3-yl)acetate)
粗產物
步驟45-6：2-(5-((1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)脲基)甲基)-4H-1,2,4-三唑-3-基)乙酸甲酯
LC/MS[M+H]+：463.2
1H NMR(300MHz,CDCl3)δ 7.47(dd,J=6.4Hz,2.6Hz,1H),7.18-7.08(m,1H),7.02(t,J=8.7Hz,1H),6.85(d,J=7.9Hz,1H),6.75(m,2H),6.37(s,1H),6.05(s,2H),4.86(s,2H),3.86(s,2H),3.76(s,3H)。
實施例46：3-(3-氯基-4-氟苯基)-1-(2-羥基吡啶-4-基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲
步驟46-1：2-(2-甲氧基吡啶-4-胺基)乙酸甲酯(Methyl 2-(2-methoxypyridin-4-ylamino)acetate)
粗產物
步驟46-2：2-(2-甲氧基吡啶-4-胺基)乙醯肼(2-(2-Methoxypyridin-4-ylamino)acetohydrazide)
粗產物
步驟46-3：2-甲氧基-N-((5,6,8,9-tetrahydro-[1,2,4]四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)吡啶-4-胺(2-Methoxy-N-((5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)methyl)pyridin-4-amine)
粗產物
步驟46-4：3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲(3-(3-Chloro-4-fluorophenyl)-1-(2-methoxypyridin-4-yl)-1-
((5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)methyl)urea
粗產物
步驟46-5：3-(3-氯基-4-氟苯基)-1-(2-羥基吡啶-4-基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲
LC/MS[M+H]+：433.4
1H NMR(300MHz,DMSO-d6)δ 9.09(s,1H),9.06(s,1H),7.82-7.70(m,1H),7.60(d,J=7.5Hz,1H),7.41-7.26(m,2H),6.56(d,J=2.3Hz,1H),6.36(dd,J=7.5Hz,2.4Hz,1H),5.13(s,2H),4.34-4.20(m,2H),3.87-3.66(m,4H),3.14-3.02(m,2H)。
實施例47：3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲
步驟47-1：2-(三級丁氧基羰基胺基)乙酸乙酯(Ethyl 2-(tert-butoxycarbonylamino)acetate)
1H NMR(400MHz,DMSO-d6)δ 7.18(t,J=6.2Hz,1H),4.09(q,J=7.2Hz,2H),3.65(d,J=6.2Hz,2H),1.39(s,9H),1.19(t,J=7.1Hz,3H)。
步驟47-2：2-肼基-2-氧代乙基胺甲酸三級丁基酯(tert-Butyl 2-hydrazinyl-2-oxoethylcarbamate)
1H NMR(400MHz,DMSO-d6)δ 8.93(s,1H),6.90(t,J=6.2Hz,1H),4.18(s,2H),3.48(d,J=6.1Hz,2H),1.38(s,9H)。
步驟47-3：(5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基胺甲酸三級丁基酯(tert-Bntyl(5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)methylcarbamate)
1H NMR(400MHz,DMSO-d6)δ 7.42(s,1H),4.25(d,J=5.9Hz,2H),4.21-4.07(m,2H),3.84-3.68(m,4H),3.15-2.97(m,2H),1.38(s,9H)。
步驟47-4：4-氯基-2-甲氧基吡啶(4-Chloro-2-methoxypyridine)
1H NMR(400MHz,DMSO-d6)δ 8.21(d,J=5.8Hz,1H),7.10(d,J=2.3Hz,1H),7.00(dd,J=5.8Hz,2.3Hz,1H),3.86(s,3H)。
步驟47-5：(5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲胺鹽酸鹽(5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)methanamine hydrochloride)
粗產物
步驟47-6：2-甲氧基-N-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)吡啶-4-胺(2-Methoxy-N-((5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxazepin-3-yl)methyl)pyridin-4-amine)
1H NMR(400MHz,Methanol-d6)δ 7.82(d,J=5.6Hz,1H),7.25(s,1H),6.30(dd,J=6.1Hz,1.8Hz,1H),6.16(d,J=1.8Hz,1H),4.67(d,J=1.8Hz,2H),4.32(dt,J=6.0Hz,1.9Hz,2H),3.88(dd,J=4.1Hz,1.9Hz,4H),3.81(s,3H),3.25-3.14(m,2H)。
步驟47-7：3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲
LC/MS[M+H]+：447.1
1H NMR(400MHz,DMSO-d6)δ 12.24(s,1H),8.31(d,J=5.9Hz,1H),7.87(dd,J=6.8Hz,2.7Hz,1H),7.51(ddd,J=9.0Hz,4.3Hz,2.7Hz,1H),7.37(t,J=9.1Hz,1H),7.12(d,J=2.2Hz,1H),6.85(dd,J=5.9Hz,2.1Hz,1H),5.26(s,2H),4.38-4.17(m,2H),3.86(s,3H),3.85-3.78(m,2H),3.79-3.66(m,2H),3.17-3.01(m,2H)。
實施例48：3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
步驟48-1：2,2-二氟乙醯肼(2,2-Difluoroacetohydrazide)
對98% NH2NH2．H2O(16.5g，323mmol，16mL，1.08eq)之MeOH(200mL)溶液，於0℃下滴加溶於MeOH(100mL)之2,2-二氟乙酸甲酯(methyl 2,2-difluoroacetate)超過一小時。該混合物於15℃攪拌1小時再於70℃攪拌1小時。濃縮該混合物以取得呈無色油之本標題化合物(35g粗產物)。
步驟48-2：2-(芐氧基)-N-甲基乙醯胺(2-(Benzyloxy)-N-methylacetamide)
DIPEA(7.00g，54.2mmol，9.43mL，2.5eq)加至甲胺鹽酸鹽(2.93g，43.3mmol，2eq)及DCM(30mL)混合物中。該混合物於15℃攪拌10分鐘。接著，於DCM中(20mL)之2-芐氧基乙醯氯(2-benzyloxyacetyl chloride)於0℃滴加至其中。該混合物於15℃攪拌1小時後，水(40mL)倒入其中以終止反應，並執行以DCM(40mL×3)萃取。收集該有機萃取物，透過Na2SO4乾燥，過濾並於真空濃縮。該殘留物利用矽膠層析法(石油醚：乙酸乙酯=5：1至1：1)純化以取得呈無色油之本標題化合物(2.54g，60.18%產率，92%純度)。
步驟48-3：3-(芐氧基甲基)-5-(二氟甲基)-4-甲基-4H-1,2,4-三唑(3-(Benzyloxymethyl)-5-(difluoromethyl)-4-methyl-4H-1,2,4-triazole)
於0℃將草醯氯(Oxalyl dichloride)(1.82g，14.3mmol，1.26mL，1.1eq)滴加至由上述步驟48-2取得的2-(芐氧基)-N-甲基乙醯胺(2.54g，13.0mmol，1eq)及溶於DCM(100mL)之2,6-二甲基吡啶(2,6-dimethylpyridine)(2.79g，26.1mmol，3.04mL，2eq)的混合物中。該混合物於15℃攪拌1小時。之後，由上述步驟48-1取得的2,2-二氟乙醯肼(1.87g，16.9mmol，1.3eq)加入其中，並於15℃攪拌該混合物36小時。在該混合物於真空濃縮乾燥後，將飽和NaHCO3水溶液(50mL)加入其中，且於100℃攪拌該混合物3小時。降溫該混合物至室溫並以EA(60mL×3)萃取。收集該有機層，透過Na2SO4乾燥，過濾並於真空濃縮。該殘留物利用矽膠層析法(石油醚：乙酸乙酯=5：1至1：1)及逆相層MPLC(0.1% FA狀況)純化以取得呈黃色油之本標題化合物(151mg，15.6%產率)。
步驟48-4：(5-(二氟甲基)-4-甲基-4H-1,2,4-三唑-3-基)甲醇((5-(Difluoromethyl)-4-methyl-4H-1,2,4-triazol-3-yl)methanol)
將Pd/C(0.05g，10%純度)加至由上述步驟48-3取得的3-(芐氧基甲基)-5-(二氟甲基)-4-甲基-4H-1,2,4-三唑(500mg，1.97mmol，1eq)之EtOH(20mL)溶液中。該混合物於H2(15psi)50℃攪拌16小時。過濾並濃縮該反應混合物以取得呈黑色油之本標題化合物(330mg粗產物)。
步驟48-5：5-(二氟甲基)-4-甲基-4H-1,2,4-三唑-3-甲醛(5-(Difluoromethyl)-4-methyl-4H-1,2,4-triazole-3-carbaldehyde)
於40℃攪拌由上述步驟48-4取得的5-(二氟甲基)-4-甲基-4H-1,2,4-三唑-3-基)甲醇(240mg，1.47mmol，1eq)及MnO2(1.28g，14.7mmol，10eq)混合之DCM(30mL)溶液4小時。過濾該反應混合物，並濃縮濾液以取得呈白色固體之本標題化合物(205mg粗產物)。
步驟48-6：N-((5-(二氟甲基)-4-甲基-4H-1,2,4-三唑-3-基)甲基)-6-甲氧基吡啶-3-胺(N-((5-(Difluoromethyl)-4-methyl-4H-1,2,4-triazol-3-yl)methyl)-6-methoxypyridin-3-amine)
於80℃攪拌6-甲氧基吡啶-3-胺(6-methoxypyridin-3-amine)(85mg，683μmol，1.1eq)及由上述步驟48-5取得的5-(二氟甲基)-4-甲基-4H-1,2,4-三唑-3-甲醛(100mg，621μmmol，1eq)之EtOH(1mL)溶液16小時。接著，將NaBH3CN(78mg，1.24mmol，2eq)加入其中，並於0℃攪拌該混合物0.5小時。該反應以水(20mL)終止，並以EA(15mL×3)執行萃取。收集該有機層，以鹽水(15mL)洗滌，透過無水Na2SO4乾燥，並過濾，且濾液於真空濃縮。該殘留物以Prep-TLC(石油醚：乙酸乙酯=1：1)純化以取得呈黃色膠之本標題化合物(40mg，24%產率)。
步驟48-7：3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
在由上述步驟48-6取得的N-((5-(二氟甲基)-4-甲基-4H-1,2,4-三唑-3-基)甲基)-6-甲氧基吡啶-3-胺(40mg，149μmol，1eq)及DMAP(18mg，149μmol，1eq)之CH3CN(3mL)溶液中，於15℃加入2-氯基-1-氟基-4-異氰酸基苯(2-chloro-1-fluoro-4-isocyanatobenzene)(51mg，297μmol，2eq)。該反應混合物於60℃攪拌0.5小時並濃縮。該殘留物以Prep-HPLC(管柱：Shim-pack C18 150mm×25mm×10μm；移動相：〔水(0.225%FA)-ACN〕；B%：33%至63%，10min)純化並冷凍乾燥以取得呈黃色固體之本標題化合物(19.8mg，29%產率，95.1%純度)。
LC/MS[M+H]+：441.1
1H NMR(400MHz,CDCl3)δ 8.14(d,J=2.5Hz,1H),7.66(dd,J=2.7Hz,8.8Hz,1H),7.48-7.42(m,1H),7.11-7.02(m,2H),6.94-6.76(m,2H),6.17(s,1H),5.09-4.98(m,2H),4.05-3.92(m,6H)。
下列實施例49至53化合物之合成以類似實施例48的方式進行反應，利用考慮到該標題化合物之結構的反應物。在這些實施例中，保護及去保護官能基及/或導入額外取代基的反應係根據是否包含反應性取代基額外進行。以下，實施例49至53的化合物、其中間體及用於鑑定這些化合物的數據依序揭露。
實施例49：3-(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)-4H-1,2,4-三唑-3-基)甲基)脲
步驟49-1：2-(芐氧基)-N-甲基乙醯胺(2-(Benzyloxy)-N-methylacetamide)
粗產物
步驟49-2：3-(芐氧基甲基)-4-甲基-5-(三氟甲基)-4H-1,2,4-三唑(3-(Benzyloxymethyl)-4-methyl-5-(trifluoromethyl)-4H-1,2,4-triazole)
粗產物
步驟49-3：(4-甲基-5-(三氟甲基)-4H-1,2,4-三唑-3-基)甲醇((4-Methyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)methanol)
粗產物
步驟49-4：4-甲基-5-(三氟甲基)-4H-1,2,4-三唑-3-甲醛(4-Methyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3-carbaldehyde)
粗產物
步驟49-5：6-甲氧基-N-((4-甲基-5-(三氟甲基)-4H-1,2,4-三唑-3-基)甲基)吡啶-3-胺(6-Methoxy-N-((4-methyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)methyl)pyridin-3-amine)
粗產物
步驟49-6：3-(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)-4H-1,2,4-三唑-3-基)甲基)脲
LC/MS[M+H]+：459.2
1H NMR(400MHz,DMSO-d6)δ 8.30(s,1H),8.17(d,J=2.6Hz,1H),7.75(dd,J=2.7Hz,8.8Hz,1H),7.68(dd,J=2.5Hz,6.9Hz,1H),7.42(ddd,J=2.8Hz,4.3Hz,9.1Hz,1H),7.32-7.25(m,1H),6.90(d,J=8.9Hz,1H),5.08(s,2H),3.88(s,3H),3.81(s,3H)。
實施例50：3-(3-氯基-4-氟苯基)-1-((4-(2-羥乙基)-5-(三氟甲基)-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
步驟50-1：2-(芐氧基)-N-(2-(三級丁基二甲基矽氧烷)乙基)乙醯胺(2-(Benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)acetamide)
粗產物
步驟50-2：3-(芐氧基甲基)-4-(2-(三級丁基二甲基矽氧烷)乙基)-5-(三氟甲基)-4H-1,2,4-三唑(3-(Benzyloxymethyl)-4-(2-(tert-butyldimethylsilyloxy)ethyl)-5-(trifluoromethyl)-4H-1,2,4-triazole)
粗產物
步驟50-3：(4-(2-(三級丁基二甲基矽氧烷)乙基)-5-(三氟甲基)-4H-1,2,4-三唑-3-基)甲醇((4-(2-(tert-Butyldimethylsilyloxy)ethyl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)methanol)
粗產物
步驟50-4：4-(2-(三級丁基二甲基矽氧烷)乙基)-5-(三氟甲基)-4H-1,2,4-三唑-3-甲醛(4-(2-(tert-Butyldimethylsilyloxy)ethyl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-carbaldehyde)
粗產物
步驟50-5：N-((4-(2-(三級丁基二甲基矽氧烷)乙基)-5-(三氟甲基)-4H-1,2,4-三唑-3-基)甲基)-6-甲氧基吡啶-3-胺(N-((4-(2-(tert-butyldimethylsilyloxy)ethyl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)methyl)-6-methoxypyridin-3-amine)
粗產物
步驟50-6：1-((4-(2-(三級丁基二甲基矽氧烷)乙基)-5-(三氟甲基)-4H-1,2,4-三唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲(1-((4-(2-(tert-Butyldimethylsilyloxy)ethyl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)urea)
粗產物
步驟50-7：3-(3-氯基-4-氟苯基)-1-((4-(2-羥乙基)-5-(三氟甲基)-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
LC/MS[M+H]+：489.2
1H NMR(400MHz,CDCl3-d)δ 8.24(d,J=2.8Hz,1H),7.80(dd,J=2.8Hz,8.8Hz,1H),7.40(dd,J=2.4Hz,6.4Hz,1H),7.08-7.02(m,1H),7.02-6.96(m,1H),6.86
(d,J=8.8Hz,1H),6.23(s,1H),5.08(s,2H),4.45(t,J=4.7Hz,2H),3.97(s,3H),3.97-3.94(m,2H)。
實施例51：3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-甲氧基乙基)-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
步驟51-1：2-(芐氧基)-N-(2-甲氧基乙基)乙醯胺(2-(Benzyloxy)-N-(2-methoxyethyl)acetamide)
1H NMR(400MHz,CDCl3)δ 7.42-7.30(m,5H),7.02-6.89(m,1H),4.60-4.54(m,2H),4.02-3.98(m,2H),3.53-3.43(m,4H),3.40-3.33(m,3H)。
步驟51-2：3-(芐氧基甲基)-5-(二氟甲基)-4-(2-甲氧基乙基)-4H-1,2,4-三唑(3-(Benzyloxymethyl)-5-(difluoromethyl)-4-(2-methoxyethyl)-4H-1,2,4-triazole)
1H NMR(400MHz,CDCl3)δ 7.28(s,5H),7.13-6.80(m,1H),4.93-4.82(m,2H),4.64-4.52(m,2H),4.45-4.36(m,2H),3.69-3.62(m,2H),3.30-3.24(m,3H)。
步驟51-3：(5-(二氟甲基)-4-(2-甲氧基乙基)-4H-1,2,4-三唑-3-基)甲醇((5-(Difluoromethyl)-4-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)methanol)
1H NMR(400MHz,CDCl3)δ 7.05-6.70(m,1H),4.86-4.76(m,2H),4.42-4.32(m,2H),4.22-4.08(m,1H),3.69-3.62(m,2H),3.31-3.24(m,3H)。
步驟51-4：5-(二氟甲基)-4-(2-甲氧基乙基)-4H-1,2,4-三唑-3-甲醛(5-(Difluoromethyl)-4-(2-methoxyethyl)-4H-1,2,4-triazol-3-carbaldehyde)
粗產物
步驟51-5：N-((5-(二氟甲基)-4-(2-甲氧基乙基)-4H-1,2,4-三唑-3-基)甲基)-6-甲氧基吡啶-3-胺(N-((5-(difluoromethyl)-4-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)methyl)-6-methoxypyridin-3-amine)
粗產物
步驟51-6：3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-甲氧基乙基)-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
LC/MS[M+H]+：485.2
1H NMR(400MHz,Chloroform-d)δ 8.26-8.21(m,1H),7.82-7.75(m,1H),7.50-7.44(m,1H),7.12-6.96(m,3H),6.91-6.84(m,1H),6.26-6.18(m,1H),5.09-5.04(m,2H),4.64-4.58(m,2H),4.03-3.96(m,3H),3.70-3.65(m,2H),3.31-3.27(m,3H)。
實施例52：3-(3-氯基-4-氟苯基)-1-((4-(2-甲氧基乙基)-5-(三氟甲基)-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
LC/MS[M+H]+：503.2
1H NMR(400MHz,DMSO-d6)δ 8.33-8.30(m,1H),8.19-8.15(m,1H),7.78-7.72(m,1H),7.70-7.65(m,1H),7.44-7.38(m,1H),7.31-7.23(m,1H),6.94-6.87(m,1H),5.11-5.05(m,2H),4.48-4.40(m,2H),3.92-3.86(m,3H),3.63-3.56(m,2H),3.23-3.17(m,3H)。
實施例53：3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-羥乙基)-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
步驟53-1：2-(芐氧基)-N-(2-(三級丁基二甲基矽氧烷)乙基)乙醯胺(2-(Benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)acetamide)
粗產物
步驟53-2：3-(芐氧基甲基2-(三級丁基二甲基矽氧烷)乙基)-5-(二氟甲基)-4H-1,2,4-三唑(3-(Benzyloxymethyl2-(tert-butyldimethylsilyloxy)ethyl)-5-(difluoromethyl)-4H-1,2,4-triazole)
粗產物
步驟53-3：(4-(2-(三級丁基二甲基矽氧烷)乙基)-5-(二氟甲基)-4H-1,2,4-三唑-3-基)甲醇((4-(2-(tert-Butyldimethylsilyloxy)ethyl)-5-(difluoromethyl)-4H-1,2,4-triazol-3-yl)methanol)
粗產物
步驟53-4：4-(2-(三級丁基二甲基矽氧烷)乙基)-5-(二氟甲基)-4H-1,2,4-三唑-3-甲醛(4-(2-(tert-Butyldimethylsilyloxy)ethyl)-5-(difluoromethyl)-4H-1,2,4-triazol-3-carbaldehyde)
粗產物
步驟53-5：N-((4-(2-(三級丁基二甲基矽氧烷)乙基)-5-(二氟甲基)-4H-1,2,4-三唑-3-基)甲基)-6-甲氧基吡啶-3-胺(N-((4-(2-(tert-butyldimethylsilyloxy)ethyl)-5-(difluoromethyl)-4H-1,2,4-triazol-3-yl)methyl)-6-methoxypyridin-3-amine)
粗產物
步驟53-6：1-((4-(2-(三級丁基二甲基矽氧烷)乙基)-5-((二氟甲基)-4H-1,2,4-三唑-3-基)甲基)-3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)脲(1-((4-(2-(tert-Butyldimethylsilyloxy)ethyl)-5-(difluoromethyl)-4H-1,2,4-triazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(6-methoxypyridin-3-yl)urea)
粗產物
步驟53-7：3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-羥乙基)-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲
LC/MS[M+H]+：471.1
1H NMR(400MHz,CDCl3)δ 8.23(d,J=2.4Hz,1H),7.80(dd,J=2.8Hz,8.8Hz,1H),7.41(dd,J=2.4Hz,6.4Hz,1H),7.08-7.03(m,1H),7.02-6.78(m,3H),6.24(s,1H),5.09(s,2H),4.53-4.41(m,2H),4.03-3.98(m,2H),3.97(s,3H)。
實驗例1：培養細胞及以化合物處理
HepAD38細胞在補充有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，該細胞與0.4μg/mL四環素一起培養。在誘發HBV複製化合物處理兩天前，置換培養基為無四環素完整培養基。該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
HepAD38細胞在以一化合物處理65小時後回收，並依照DNeasy Blood & Tissue Kit(Qiagen)操作手冊萃取其細胞內HBV DNA。該用於定量HBV DNA之引子及探針為5’-CTCGTGGTGGACTTCTCTC-3’(SEQ.ID NO：#1)、5’-CTGCAGGATGAAGAGGAA-3’(SEQ.ID NO：#2)及5’-/56-FAM/TGT CCT GGT/ZEN/TAT CGC TGG ATG TGT CT/3IABkFQ/-3’(SEQ.ID NO：#3)。用LightCycler 480(Roche)(J.Virol.,2018,92(16)：e00339-18)以即時PCR測定來放大該HBV DNA。重複所有程序以確認之。
實驗例3：細胞存活率測定
HepAD38細胞在補充有10% FBS且無四環素之Dulbecco’s Modified Eagle’s培養基(Welgene,LM001-05)中培養兩天。該細胞接種於48孔培養盤中(1×105細胞/孔)並以各化合物在五種濃度下處理(0μM(0.8% DMSO作為對照組)33μM、50μM、66μM及100μM)。在處理65小時後，存活率利用EZ-Cytox cell viability assay kit(Daeil Lab Service)依照生產商指示測量。吸收率利用分光光度計(Spark,Tecan)於450nm測量。這些化合物的IC50、蛋白抑制率、細胞毒性及CLogP標註於下表1。NVR-3-778(以NVR表示)於其中作為陽性對照組。
表1
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接包含於本專利範圍內。
111138676-A0202-15-0001.xml
Claims (18)
- 一種由以下化學式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係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係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各自獨立地為氫、氰基、鹵基、C1-4烷基、C6-10芳基、C3-10環烷基、C1-4烷氧羰基-C1-4烷基、C1-4烯基、C1-4鹵烷基、C1-4羥烷基、C1-4烷氧基、C1-4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)-1,3-二氧雜環戊烷基)-C1-4烷基，或R3及R4彼此連接以形成包含鍵結R3及R4的氮及碳的5-至10-員環狀結構；R5及R6各自獨立地為氫或C1-4烷基；以及其中，由C6-10芳基、C3-10環烷基、5-至10-員雜芳基或3-至10-員雜環基與R3及R4彼此連接所形成的環狀結構係未經取代或經選自由氰基、羥基、羧基、氧基、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、C1-4烷氧羰基C1-4烷基、C1-4烷基胺基磺醯基、C1-4烷基磺醯基胺基、C1-4羥烷基、C1-4鹵烷基、C1-4烷胺基、二(C1-4烷基)胺基、 C6-10芳基、C3-10環烷基、C6-10芳基-C1-4烷氧羰基及5-至10-員雜芳基所組成之群組的一者或更多者所取代。 - 如請求項1所述之化合物或該化合物藥學上可接受的鹽，其中，R1為苯基、苯並二噁茂基、二氫吡啶基、環戊基、吲哚基、苯並噻唑基、吡唑基、異噁唑基、噁唑基或吡啶基。
- 如請求項1所述之化合物或該化合物藥學上可接受的鹽，其中，R2為苯基、環戊基或吡啶基。
- 如請求項1所述之化合物或該化合物藥學上可接受的鹽，其中，R3為氫、甲基、苯基、異丙基、環丙基、環戊基、羥乙基或甲氧基乙基。
- 如請求項1所述之化合物或該化合物藥學上可接受的鹽，其中，R4為甲基、異丙基、苯基、環戊基、甲氧羰基甲基、二氟甲基或三氟甲基。
- 如請求項1所述之化合物或該化合物藥學上可接受的鹽，其中，R3及R4彼此連接以形成氮雜環庚基、嗎啉基、氧雜氮雜環庚基、二氮雜環庚基或哌啶基，其包含鍵結R3及R4的碳與氮。
- 如請求項1所述之化合物或該化合物藥學上可接受的鹽，其中，R5為氫或甲基。
- 如請求項1所述之化合物或該化合物藥學上可接受的鹽，其中，R6為氫或甲基。
- 如請求項1所述之化合物或該化合物藥學上可接受的鹽，其中，由C6-10芳基、C3-10環烷基、5-至10-員雜芳基或3-至10-員雜環基與R3及R4彼此連接所形成的環狀結構為未經取代或經選自由氰基、羥基、氟基、氯基、甲基、異丙基、甲氧基、異丙氧基、甲氧基乙基、三級丁氧羰基、甲氧羰基甲基、羥乙 基、二氟甲基、三氟甲基、甲胺基、二甲胺基、環丙基、環戊基、芐氧羰基及苯基所組成之群組的一者或更多者所取代。
- 如請求項1所述之化合物或該化合物藥學上可接受的鹽，其中，該化合物為：1. 1-(苯並[d][1,3]二噁茂-5-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-3-間甲苯脲、2. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、3. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、4. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((6,8-二氫-5H-[1,2,4]三唑並[3,4-c][1,4]噁嗪-3-基)甲基)脲、5. 1-(苯並[d][1,3]二噁茂-5-基)-3-(2-氯苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、6. 3-(3-氯基-4-氟苯基)-1-環戊基-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、7. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲、8. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氰基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、9. 1-(3-氯基-4-氟苯基)-3-(4-甲氧苯基)-1-甲基-3-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、10. 3-(3-氯基-4-氟苯基)-1-(1H-吲哚-6-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、11. 1-(苯並[d][1,3]二噁茂-5-基)-3-環戊基-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、12. 3-(3-氯基-4-氟苯基)-1-(4-異丙氧基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、13. 3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-1-(4-(三氟甲基)苯基)脲、14. 3-(3-氯基-4-氟苯基)-1-(4-(甲胺基)苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、15. 3-(3-氯基-4-氟苯基)-1-((4,5-二甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲、16. 1-(苯並[d]噻唑-6-基)-3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、17. 5-(3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲基)-1H-吲哚-1-羧酸三級丁基酯、18. 3-(3-氯基-4-氟苯基)-1-(1H-吲哚-5-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、19. 3-(3-氯基-4-氟苯基)-1-(3-氰基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、20. 1-(苯並[d][1,3]二噁茂-5-基)-3-(6-甲基吡啶-2-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、21. 3-(3-氯基-4-氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)-1-(3-(三氟甲基)苯基)脲、22. 3-(3-氯基-4-氟苯基)-1-(3,4-二氟苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、23. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-(1-(6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)乙基)脲、24. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)甲基)脲、25. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5-甲基-4-苯基-4H-1,2,4-三唑-3-基)甲基)脲、26. 3-(3-氯基-4-氟苯基)-1-((4-異丙基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲、27. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲、28. 3-(3-氯基-4-氟苯基)-1-(4-氰基苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、29. 3-(3-氯基-4-氟苯基)-1-((5-異丙基-4-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲、30. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((5,6,7,8,9,10-六氫-[1,2,4]三唑並[4,3-a]氮雜辛環-3-基)甲基)脲、31. 3-(3-氯基-4-氟苯基)-1-((5-環戊基-4-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲、32. 3-(3-氯基-4-氟苯基)-1-((4-環戊基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲、33. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-(1-(5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)乙基)脲、34. 3-(3-氯基-4-氟苯基)-1-(4-(二甲胺基)苯基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、35. 3-(3-氯基-4-氟苯基)-1-(1-甲基-1H-吡唑-3-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、36. 3-(3-氯基-4-氟苯基)-1-(異噁唑-3-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、37. 3-(3-氯基-4-氟苯基)-1-((4-環丙基-5-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(4-甲氧苯基)脲、38. 3-((3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)脲基)甲基)-8,9-二氫-5H-[1,2,4]三唑並[4,3-d][1,4]二氮呯-7(6H)-羧酸苄酯、39. 3-(3-氯基-4-氟苯基)-1-(噁唑-2-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、40. 3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲、41. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯苯基)-1-((5,6,7,8-四氫-[1,2,4]三唑並[4,3-a]吡啶-3-基)甲基)脲、42. 1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)-1-((6,8-二氫-5H-[1,2,4]三唑並[3,4-c][1,4]噁嗪-3-基)甲基)脲、43. 3-(3-氯基-4-氟苯基)-1-(4-甲氧苯基)-1-((5,6,7,8-四氫-[1,2,4]三唑並[4,3-a]吡啶-3-基)甲基)脲、44. 3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((6,7,8,9-四氫-5H-[1,2,4]三唑並[4,3-a]氮呯-3-基)甲基)脲、45. 2-(5-((1-(苯並[d][1,3]二噁茂-5-基)-3-(3-氯基-4-氟苯基)脲基)甲基)-4H-1,2,4-三唑-3-基)乙酸甲酯、46. 3-(3-氯基-4-氟苯基)-1-(2-羥基吡啶-4-基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲、47. 3-(3-氯基-4-氟苯基)-1-(2-甲氧基吡啶-4-基)-1-((5,6,8,9-四氫-[1,2,4]三唑並[4,3-d][1,4]氧雜氮呯-3-基)甲基)脲、48. 3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-甲基-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、49. 3-(3-氯基-4-氟苯基)-1-(6-甲氧基吡啶-3-基)-1-((4-甲基-5-(三氟甲基)-4H-1,2,4-三唑-3-基)甲基)脲、50. 3-(3-氯基-4-氟苯基)-1-((4-(2-羥乙基)-5-(三氟甲基)-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、51. 3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-甲氧基乙基)-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、52. 3-(3-氯基-4-氟苯基)-1-((4-(2-甲氧基乙基)-5-(三氟甲基)-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲、或53. 3-(3-氯基-4-氟苯基)-1-((5-(二氟甲基)-4-(2-羥乙基)-4H-1,2,4-三唑-3-基)甲基)-1-(6-甲氧基吡啶-3-基)脲。
- 一種如請求項1至10中任一項所述之化合物或該化合物藥學上可接受的鹽之製備方法，該方法包括將由以下化學式2所表示之化合物與由以下化學式3所表示之化合物進行反應：
[化學式3]R2-N=C=O在化學式2及化學式3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各自獨立地為氫、氰基、鹵基、C1-4烷基、C6-10芳基、C3-10環烷基、C1-4烷氧羰基-C1-4烷基、C1-4烯基、C1-4鹵烷基、C1-4羥烷基、C1-4烷氧基、C1-4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)-1,3-二氧雜環戊烷基)-C1-4烷基，或R3及R4彼此連接以形成包含鍵結R3及R4的氮及碳的5-至10-員環狀結構；R6為氫或C1-4烷基；以及其中，由C6-10芳基、C3-10環烷基、5-至10-員雜芳基或3-至10-員雜環基與R3及R4彼此連接所形成的環狀結構係未經取代或經選自由氰基、羥基、羧基、氧基、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、C1-4烷氧羰基C1-4烷基、C1-4烷基胺基磺醯基、C1- 4烷基磺醯基胺基、C1-4羥烷基、C1-4鹵烷基、C1-4烷胺基、二(C1-4烷基)胺基、C6-10芳基、C3-10環烷基、C6-10芳基-C1-4烷氧羰基及5-至10-員雜芳基所組成之群組的一者或更多者所取代。 - 如請求項11所述之製備方法，其在4-二甲胺基吡啶(DMAP)存在下於有機溶劑中執行。
- 如請求項11所述之製備方法，其中，該由化學式2所表示之化合物可藉由將i)由以下化學式4所表示之化合物與由以下化學式5所表示之化合物，或ii)由以下化學式6所表示之化合物與由以下化學式7所表示之化合物進行反應來製備：
[化學式6]R1-NH2
在化學式5中，R7為C1-4烷基。 - 如請求項11所述之製備方法，其復包括與R5-X(R5為氫或C1-4烷基且X為鹵基)進行反應。
- 一種用於蛋白殼組裝抑制的組成物，包括如請求項1至10中任一項所述之化合物或該化合物藥學上可接受的鹽。
- 一種抗病毒組成物，包括如請求項1至10中任一項所述之化合物或該化合物藥學上可接受的鹽作為活性成分。
- 一種用於預防或治療病毒性疾病的醫藥組成物，包括如請求項1至10中任一項所述之化合物或該化合物藥學上可接受的鹽作為活性成分。
- 如請求項17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)造成的傳染性疾病。
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