TW201817714A - Compounds that inhibit 3C and 3CL proteases and methods of use thereof - Google Patents

Compounds that inhibit 3C and 3CL proteases and methods of use thereof Download PDF

Info

Publication number
TW201817714A
TW201817714A TW106129220A TW106129220A TW201817714A TW 201817714 A TW201817714 A TW 201817714A TW 106129220 A TW106129220 A TW 106129220A TW 106129220 A TW106129220 A TW 106129220A TW 201817714 A TW201817714 A TW 201817714A
Authority
TW
Taiwan
Prior art keywords
alkyl
cycloalkyl
heterocycloalkyl
substituted
halo
Prior art date
Application number
TW106129220A
Other languages
Chinese (zh)
Inventor
傑諾斯 柏彥斯基
約翰 G 凱特藍諾
碧玉 張
漢彌頓 D 狄克森
琦 金
安娜 李維斯
廖湘民
安卓 梅那
約翰 米勒
約翰 布萊德 夏威爾
永輝 戴
瑞瑪 塔理傑
Original Assignee
英商葛蘭素史密斯克藍智慧財產權有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 英商葛蘭素史密斯克藍智慧財產權有限公司 filed Critical 英商葛蘭素史密斯克藍智慧財產權有限公司
Publication of TW201817714A publication Critical patent/TW201817714A/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Compounds, specifically protease inhibitors, more specifically 3C and 3CL protease inhibitors, for the treatment of viral infections, and methods of preparing and using such compounds.

Description

抑制3C及3CL蛋白酶之化合物及其使用方法Compounds that inhibit 3C and 3CL proteases and methods of use

本發明係關於用於治療病毒感染之化合物、具體而言蛋白酶抑制劑，以及製備及使用此等化合物之方法。The present invention relates to compounds for treating viral infections, specifically protease inhibitors, and methods of making and using such compounds.

每年全世界數百萬人之死亡與病毒有關。(例如，參見Fact Sheets on HIV/AIDS, Hepatitis C Virus, and Influenza ，世界衛生組織(WORLD HEALTH ORGANIZATION))。由病毒感染所引起之疾病眾多且多樣，引起該等疾病之病毒的結構、大小、基因體及感染週期同樣如此，這些事實使得此領域中的研究工作趨於複雜及不完整。儘管存在這些困難，但研究者卻持續在病毒疾病之預防、控制及治療方面取得進展。通常，成功的研究工作專注於單一種或屬之病毒。 最成功的廣譜抗病毒藥劑中之一者係利巴韋林(ribavirin)。利巴韋林(1-B-D-呋喃核糖基-1-1,2,4-三唑-3-甲醯胺)係以商標名Virazole®出售之合成性、非干擾素誘導、廣譜抗病毒核苷類似物。(THE MERCK INDEX 1304 (Budavari, S.編輯，第11版，1989)。Witkowski之美國專利第3,798,209號及第RE 29,835號揭示及主張利巴韋林。利巴韋林在結構上類似於鳥苷，且具有抗若干DNA及RNA病毒(包括黃病毒科(Flaviviridae ))之活體外活性。(Gary L. Davis, 118 GASTROENTEROLOGY S104 (2000))。利巴韋林經表明係用於治療嚴重呼吸道融合病毒(RSV)感染、C型肝炎病毒(HCV)感染以及其他(包括拉沙熱(lassa fever)、漢他病毒(hantavirus)、流行性感冒及狂犬病)。然而利巴韋林之主要副作用(溶血性貧血)太過於嚴重，以致於其保留僅用於治療致死病毒。另外，利巴韋林係人類中之潛在畸胎原。因此，極需開發新穎治療性抗病毒藥劑，尤其廣譜抗病毒藥劑。 病毒可藉由評估若干特徵加以分類，包括病毒基因體之類型。病毒基因體可由DNA或RNA組成，可為雙鏈或單鏈(其可進一步為正義或負義)，且可因大小及基因體組織顯著變化。正義單鏈RNA病毒(「正鏈RNA病毒」)組成來自許多不同亞科之病毒之廣大超科。該等病毒跨越植物及動物界，引起輕微表型至嚴重虛弱性疾病範圍內之病理學。正鏈RNA病毒聚合酶超群之組成物包括至少以下各科：光亮噬菌體病毒(levivirus)、裸露核糖核酸病毒(narnavirus)、小核糖核酸病毒(picornavirus)、雙順反子病毒(dicistrovirus)、海洋核糖核酸病毒(marnavirus)、伴生病毒(sequivirus)、豇豆鑲嵌病毒(comovirus)、馬鈴薯Y病毒(potyvirus)、杯狀病毒(calicivirus)、星狀病毒(astrovirus)、野田病毒(nodavirus)、四病毒(tetravirus)、黃症病毒(luteovirus)、番茄叢矮病毒(tombusvirus)、冠狀病毒(coronavirus)、動脈炎病毒(arterivirus)、黃頭症病毒(ronivirus)、黃病毒(flavivirus)、披膜病毒(togavirus)、雀麥花葉病毒(bromovirus)、蕪菁變黃鑲嵌病毒(tymovirus)、修道院病毒(closterovirus)、彎曲病毒(flexivirus)、塞科病毒(secovirus)、桿菌狀核糖核酸病毒(barnavirus)、傳染性家蠶軟化症病毒(iflavirus)、溫州蜜柑矮縮病毒(sadwavirus)、櫻桃銼葉病毒(cheravirus)、肝炎病毒(hepevirus)、南方菜豆花葉病毒(sobemovirus)、幽影病毒(umbravirus)、菸草鑲嵌病毒(tobamovirus)、菸草脆裂病毒(tobravirus)、大麥病毒(hordeivirus)、真菌傳桿狀病毒(furovirus)、馬鈴薯病毒(pomovirus)、花生叢簇病毒(pecluvirus)、甜菜壞死黃脈病毒(benyvirus)、歐爾密病毒(ourmiavirus)及懸鈎子病毒(idaeovirus)。 人類鼻病毒(Human Rhinovirus，「HRV」)係小核糖核酸病毒科(Picornaviridae family)之腸病毒(Enterovirus)且具有單鏈正鏈RNA基因體。裸RNA基因體(約8 kb)由衣殼以二十面體構形包圍，該衣殼係由表示為VP1 - VP4之4種結構蛋白各自之60個拷貝構成。HRV藉由觸發受體介導之胞吞作用進入細胞，藉助胞內體發生脫殼。HRV複製需要病毒RNA-依賴性RNA聚合酶，以及多種病毒源及宿主細胞源輔助蛋白。HRV基因體經轉譯為單個多蛋白，其首先在藉由病毒編碼之蛋白酶轉譯為三種蛋白質後經裂解，該三種蛋白質自身經裂解以產生至少11種蛋白質。病毒基因體複製在感染後最短1小時內就可以開始，且在細胞進入後最短4小時內發生細胞死亡時釋放近一百萬完全組裝之病毒顆粒。 HRV感染係與以下各項之30%至50%相關之重要健康問題：所有上呼吸道感染(普通感冒)、患急性中耳炎及竇炎之傾向以及患有潛在呼吸障礙(例如，囊性纖維化)之個體、老人及免疫抑制者中下呼吸道症候群之發展。(Gern, 23 PEDIATR. INFECT. DIS. J. S78 (2004)；Anzueto等人，123 CHEST 1664 (2003)；Rotbart, 53 ANTIVIR. RES. 83 (2002))。另外，成人中HRV感染會促使約50%之氣喘惡化且會使嬰兒免疫系統引向哮喘表型之因素中之一者。(D. J. Jackson等人，178 AM. J. RESPIR. CRIT. CARE MED. 667 (2008))。HRV亦與慢性阻塞性肺病之惡化(COPD)相關聯。J-M Perotin等人，第85卷，J. MED. VIROL. 866 (2013)。 普通感冒係最常發生之人類疾病中之一者且會造成實質性地發病率。儘管HRV誘導之上呼吸道疾病通常輕微且無須醫療介入即可消除，但社會經濟影響巨大且治療常常不當使用包括抗生素。據估計在美國，每年普通感冒導致至少2500萬人工作缺勤，且學校缺勤幾乎同樣多。(Rotbart, 53 ANTIVIR. RES. 83 (2002))。估計在美國僅哮喘患者之普通感冒及相關併發症之直接及間接成本高達每年400億美元。(A. M. Fendrick等人，163 ARCH. INTERN. MED. 487 (2003)。 藉由特定抗血清已鑑別超過100種HRV之不同血清型，基於藉助其介導細胞進入之細胞受體可將其分為兩個大組。約90%之HRV血清型藉助人類細胞內黏著分子(ICAM-1)進入宿主細胞，而剩餘約10%利用低密度脂蛋白受體進行細胞進入。血清型之間之差異不僅防止身體發生交叉免疫，而且其顯著阻礙開發疫苗及其他預防及治療之病毒特異性方法。 普通感冒導致諸如以下之症狀：發熱、咳嗽及鼻塞。據信該等症狀係免疫系統之過度反應或非特異性反應之結果。用於HRV感染之主要療法目前包括用以下各項之組合治療：諸如阿斯匹林(aspirin)或乙醯胺酚(acetaminophen)之止痛藥(包括靶向喉之局部化形式)、鼻去充血劑、咳嗽抑制劑(鎮咳劑)及抗組織胺。然而，人們廣泛認識到該等「治療」僅改善感冒症狀；該等治療不會治癒潛在疾病。有一些有限證據證明，其他形式之治療具有縮短HRV感染之時間段的功效，包括投與鋅(由於金屬味不實用)、紫花馬蘭菊及維生素C (需要高劑量，不適用於兒童)。該等形式之治療非靶向感冒病毒本身，而是具有影響身體對HRV之一般免疫反應的功效。目前，尚無治癒潛在HRV感染之經批准用於人類之藥劑。 最近，少數直接攻擊HRV之嘗試已顯示出一定前景。原本稱為「吡羅達韋(pirodavir)」之化合物4-[2-[1-(6-甲基-3-嗒嗪基)-4-六氫吡啶基]-乙氧基]苯甲酸酯能夠起衣殼-結合抑制劑之作用並藉助人類中之臨床試驗進展，但溶解度、內源性裂解及成本之問題已破壞其抗HRV之效用。普來可那立(Pleconaril，PICOVIR®)顯示可有效抑制HRV複製，但目前由於重大安全性顧慮受到美國FDA拒絕。某些咪唑并吡嗪已表明為抗HRV及其他病毒之有效抗病毒藥劑。儘管不確定其作用模式，但據信並非係因其對週期蛋白依賴性激酶之效應。(Macleod等人，美國公開申請案第2011/0166147號)。鑒於上文，仍然需要抗HRV之新型治療劑並且特別需要開發廣譜抗病毒劑。 冠狀病毒係具有病毒套膜之單鏈正鏈RNA病毒科，歸類在網巢病毒目(Nidovirales order)內。冠狀病毒科包含許多動物物種之病原體，包括人類、馬、牛、豬、鳥、貓及猴，且已為人所知60年以上。舉例而言，在1949年報告原型鼠類冠狀病毒株JHM之分離。冠狀病毒係通常引起人類之輕微至中度上呼吸道疾病之常見病毒，且係以其套膜表面上之冠狀峰命名。存在四個主要亞組，稱為α、β、γ及δ冠狀病毒，其中在1960年代中期鑑別出第一種冠狀病毒。已知冠狀病毒感染人類，包括α冠狀病毒229E及NL63；及β冠狀病毒OC43、HKU1、SARS-CoV (引起嚴重急性呼吸症候群或SARS之冠狀病毒)及MERS-CoV (引起中東呼吸症候群或MERS之冠狀病毒)。人通常感染人類冠狀病毒229E、NL63、OC43及HKU1，且症狀通常包括具有短持續時間之輕微至中度上呼吸道疾病，例如流鼻涕、咳嗽、咽喉痛及發熱。人類冠狀病毒偶爾導致下呼吸道疾病，例如肺炎，但此在患有心肺疾病或受損免疫系統之人中或在老人中更常見。常見人類冠狀病毒之傳播並未完全瞭解。然而，可能人類冠狀病毒藉由咳嗽及噴嚏藉助空氣並藉助密切個別接觸(例如，觸摸或握手)自感染者傳播至他人。該等病毒亦可藉由觸摸污染物品或表面然後觸摸你的口、鼻或眼來傳播。 SARS-CoV係於2002年11月在中國首度被辨識，且其導致在2002年與2003年之間全世界爆發8,000例以上，包括774例死亡。自2004年以來，在世界各處未報告任何已知之SARS-CoV感染病例。 中東呼吸症候群(MERS)係由新穎冠狀病毒(MERS-CoV)所引起之病毒呼吸疾病，該病毒在2012年於沙烏地阿拉伯首次鑑別，但回溯分析確定已知之首例MERS係在2012年4月在約旦發生。截至2015年，病毒似乎主要在整個阿拉伯半島流傳，其中自2012年至2015年85%之病例係在沙烏地阿拉伯報告。2015年在大韓民國記錄了爆發且其與自阿拉伯半島返回之旅客有關。 MERS之大部分人類病例歸因於人類間傳染，但據信駱駝為MERS-CoV之主要儲存宿主及人類之MERS感染之動物源。自動物至人類之傳播途徑並未完全瞭解。因此，駱駝在病毒傳播中之確切作用及動物與人類或人類與人類之間之確切傳播途徑未知。然而，除非存在密切接觸，否則病毒似乎並不易於在人與人之間傳播，例如當向患者提供未加保護之照護時發生。而且儘管已在保健機構中報告許多病例，尤其在感染預防及控制實踐不足時，但至今未曾記錄持續的社區傳播。 典型MERS症狀包括發熱、咳嗽及呼吸短促。肺炎雖甚為常見，但並非始終存在。亦已報告胃腸症狀，包括腹瀉。MERS可感染任何人，在＜1歲至99歲年齡範圍內之患者中具有報告病例。CDC正在全球範圍內監測MERS，且認識到MERS-CoV具有在全球範圍內傳播並引起額外病例之潛力，包括美國及歐洲。迄今為止，約36%之經報告患有MERS之患者已死亡。因此，迫切需要開發抗MERS-CoV之治療劑。 脊髓灰質炎(「小兒麻痺症(polio)」)係由感染脊髓灰白質炎病毒(poliovirus，「PV」)而引起。PV係腸病毒屬之成員，其係小核糖核酸病毒科中之一個屬。PV基因體係單個約7.5 kb之正鏈RNA分子且由編碼具有約2500個胺基酸之多蛋白的單個大開放閱讀框及在5’端及3’端(5’-UTR及3’-UTR)之側接非轉譯區組成。單該個多蛋白係約11種病毒蛋白之前體，該等病毒蛋白對於複製及組裝後代病毒顆粒甚為關鍵。儘管PV感染最初在胃腸道中開始，但PV感染可擴散且在身體其他部位具有嚴重健康效應，包括末梢及中樞神經系統。 在1950年代之前，小兒麻痺症流行病使數以千計之兒童及成人癱瘓。儘管引入廣泛疫苗接種後，在世界各地已較大程度地控制住活脊髓灰白質炎病毒之本地傳播，但自仍未含有其之國家再引入脊髓灰白質炎病毒仍為嚴重健康顧慮。(Thompson等人，127 PUB.HEALTH REP.23 (2012))。小兒麻痺症之持續威脅之另一來源係疫苗源脊髓灰白質炎病毒之爆發，如最近2000年在多明尼加共和國及海地及2001年在菲律賓所發生。因此，需要新的抗PV之治療劑。 儘管存在其他差異，但若干科之正鏈RNA病毒，包括HRV及其他小核糖核酸病毒、人類冠狀病毒(例如，SARS-CoV及MERS-CoV)及諾羅病毒(noroviruses)需要將病毒RNA轉移為多蛋白，其必須經解離成個別酶用於接下來複製。多蛋白之成熟需要病毒編碼之酶來催化大部分裂解事件。此係藉由以下各項來實施：針對HRV及其他小核糖核酸病毒之稱為3C蛋白酶或小核糖核酸病毒內肽酶(picornain)之酶，以及針對冠狀病毒及諾羅病毒之或者稱為3CL (3C樣(3C-like))、M (主(main))蛋白酶或nsp5之類似酶。此步驟對病毒生命週期至關重要；在無其之情形下病毒將不能複製/存活。 小核糖核酸病毒之3C蛋白酶酵素係20 kD大小之半胱胺酸蛋白酶。其係以作為病毒多蛋白之一部分產生且會催化絕大多數裂解事件，其導致產生所有病毒編碼蛋白質之活性形式。該等蛋白質對病毒複製而言至關重要，使得病毒「生命週期」無法在沒有裂解情況下持續。亦已知一些病毒之3C酶會使宿主細胞中之調節蛋白裂解，可能能夠達成更高程度之病毒複製。舉例而言，經報導柯薩奇病毒(coxsackievirus)之3C蛋白使人類MAVS及TRIF蛋白質裂解，以降低細胞對病毒感染之反應(A Mukherjee等人，第7卷，PLOS Pathogens, 3 e1001311)。 冠狀病毒及諾羅病毒之3CL蛋白酶酵素係約50 kD大小之半胱胺酸蛋白酶。儘管其與小核糖核酸病毒之3C蛋白具有類似功能，但該蛋白含有容許產生催化活性所需同二聚體形式之額外結構域。3CL蛋白酶係經若干病毒多蛋白中之一者產生，且催化絕大多數來自多蛋白之裂解事件，此導致活性病毒編碼之酶的產生。該等蛋白質對病毒複製而言至關重要，使得病毒「生命週期」無法在沒有裂解情況下持續。亦已知一些病毒之3CL酶使宿主細胞中之調節蛋白裂解，可能能夠達成更高程度之病毒複製。舉例而言，經報導SARS冠狀病毒之3CL蛋白使人類STING蛋白裂解，以降低細胞對病毒感染之反應(L Sun等人，第7卷，PLOS One, 2 e30802)。Every year millions of deaths worldwide are related to viruses. (For example, see Fact Sheets on HIV / AIDS, Hepatitis C Virus, and Influenza , World Health Organization (WORLD HEALTH ORGANIZATION)). The diseases caused by viral infections are numerous and diverse, as are the structure, size, genome and infection cycle of the viruses that cause these diseases. These facts make the research work in this field more complicated and incomplete. Despite these difficulties, researchers continue to make progress in the prevention, control, and treatment of viral diseases. In general, successful research work focuses on a single virus or genus. One of the most successful broad-spectrum antiviral agents is ribavirin. Ribavirin (1-BD-ribofuranosyl-1-1,2,4-triazole-3-carboxamide) is a synthetic, non-interferon-induced, broad-spectrum antiviral sold under the brand name Virazole® Nucleoside analogues. (THE MERCK INDEX 1304 (Edited by Budavari, S., 11th edition, 1989). Witkowski, US Patent Nos. 3,798,209 and RE 29,835 disclose and claim ribavirin. Ribavirin is similar in structure to guanosine And has in vitro activity against several DNA and RNA viruses (including Flaviviridae ) (Gary L. Davis, 118 GASTROENTEROLOGY S104 (2000)). Ribavirin has been shown to be used to treat severe respiratory tract fusion Virus (RSV) infection, hepatitis C virus (HCV) infection and others (including lassa fever, hantavirus, influenza and rabies). However, the main side effects of ribavirin (hemolysis Sexual anemia) is so severe that it is reserved only for the treatment of lethal viruses. In addition, ribavirin is a potential teratogen in humans. Therefore, there is a great need to develop novel therapeutic antiviral agents, especially broad-spectrum antivirus Drugs. Viruses can be classified by evaluating several characteristics, including the type of viral genome. The viral genome can be composed of DNA or RNA, can be double-stranded or single-stranded (which can be further sense or negative), and can vary depending on size Kiji Significant changes in body organization. The single-stranded RNA virus ("positive-strand RNA virus") constitutes a vast superfamily of viruses from many different subfamilies. These viruses span the plant and animal kingdoms, causing mild phenotypes to severe debilitating diseases Pathology. The composition of the positive strand RNA virus polymerase supergroup includes at least the following families: bright bacteriophage virus (levivirus), naked ribonucleic acid virus (narnavirus), picornavirus (picornavirus), bicistronic virus ( dicistrovirus), marine ribonucleic acid virus (marnavirus), associated virus (sequivirus), cowpea mosaic virus (comovirus), potato Y virus (potyvirus), calicivirus (calicivirus), astrovirus (astrovirus), noda virus (nodavirus) , Tetravirus, luteovirus, tomato bushy dwarf virus (tombusvirus), coronavirus (coronavirus), arteritis virus (arterivirus), yellow head virus (ronivirus), flavivirus (flavivirus), Phi Togavirus, bromovirus, turnip yellowing virus (tymovirus), closterovirus, bend virus (fle) xivirus), secovirus, barnavirus, infectious silkworm softener virus (iflavirus), Wenzhou tangerine dwarf virus (sadwavirus), cherry file virus (cheravirus), hepatitis virus (hepevirus) ), Southern bean mosaic virus (sobemovirus), umbravirus (tombamovirus), tobacco mosaic virus (tobamovirus), tobacco brittle virus (tobravirus), barley virus (hordeivirus), fungal baculovirus (furovirus), potato virus (pomovirus), peanut cluster virus (pecluvirus), beet necrosis yellow vein virus (benyvirus), urmia virus (ourmiavirus) and rubus virus (idaeovirus). Human Rhinovirus ("HRV") is Enterovirus of the Picornaviridae family and has a single-stranded positive-strand RNA genome. The naked RNA gene body (approximately 8 kb) is surrounded by a capsid in an icosahedral configuration. The capsid is composed of 60 copies of each of the four structural proteins expressed as VP1-VP4. HRV enters the cell by triggering receptor-mediated endocytosis, and shelling occurs through the endosome. HRV replication requires viral RNA-dependent RNA polymerase, as well as a variety of viral and host cell-derived accessory proteins. The HRV gene body is translated into a single polyprotein, which is first cleaved after being translated into three proteins by a virus-encoded protease, and the three proteins themselves are cleaved to produce at least 11 proteins. Viral genome replication can begin within a minimum of 1 hour after infection and release nearly one million fully assembled viral particles when cell death occurs within a minimum of 4 hours after cell entry. HRV infection is an important health problem related to 30% to 50% of the following: all upper respiratory tract infections (common cold), the tendency to have acute otitis media and sinusitis, and potential respiratory disorders (eg, cystic fibrosis) The development of middle and lower respiratory syndrome in individuals, the elderly and immunosuppressed individuals. (Gern, 23 PEDIATR. INFECT. DIS. J. S78 (2004); Anzueto et al., 123 CHEST 1664 (2003); Rotbart, 53 ANTIVIR. RES. 83 (2002)). In addition, HRV infection in adults can cause approximately 50% of asthma to worsen and cause the infant's immune system to be one of the factors that contribute to the asthma phenotype. (DJ Jackson et al., 178 AM. J. RESPIR. CRIT. CARE MED. 667 (2008)). HRV is also associated with the exacerbation of chronic obstructive pulmonary disease (COPD). JM Perotin et al., Volume 85, J. MED. VIROL. 866 (2013). The common cold is one of the most common human diseases and can cause substantial morbidity. Although HRV-induced upper respiratory diseases are usually mild and can be eliminated without medical intervention, the socioeconomic impact is huge and treatment is often inappropriately used including antibiotics. It is estimated that in the United States, a common cold causes at least 25 million people to be absent from work each year, and school absences are almost the same. (Rotbart, 53 ANTIVIR. RES. 83 (2002)). It is estimated that the direct and indirect costs of the common cold and related complications of asthma patients in the United States are as high as $ 40 billion per year. (AM Fendrick et al., 163 ARCH. INTERN. MED. 487 (2003). With specific antisera, over 100 different serotypes of HRV have been identified, which can be classified based on cell receptors that mediate cell entry through them Two large groups. About 90% of the HRV serotypes enter the host cells with the help of human intracellular adhesion molecule (ICAM-1), while the remaining about 10% use low-density lipoprotein receptors for cell entry. Prevent cross-immunization of the body, and it significantly hinders the development of vaccines and other virus-specific methods of prevention and treatment. The common cold causes symptoms such as fever, cough, and nasal congestion. It is believed that these symptoms are an overreaction or non-reaction of the immune system The result of a specific response. The main therapies for HRV infections currently include treatment with a combination of: analgesics such as aspirin or acetaminophen (including localized forms targeted to the larynx), Nasal decongestants, cough suppressants (antitussives), and antihistamines. However, it is widely recognized that these "treatments" only improve cold symptoms; these treatments will not cure underlying diseases There is some limited evidence to prove that other forms of treatment have the effect of shortening the period of HRV infection, including the administration of zinc (due to the metallic taste is not practical), marguerite and vitamin C (requires high doses, not suitable for children). These forms of treatment are not targeted to the cold virus itself, but have the effect of affecting the body ’s general immune response to HRV. At present, there are no approved agents for humans that cure potential HRV infections. Recently, a few directly attacked HRV Attempts have shown certain prospects. The compound 4- [2- [1- (6-methyl-3-pyridazinyl) -4-hexahydropyridyl], originally called "pirodavir" Ethoxy] benzoate can act as a capsid-binding inhibitor and has progressed through clinical trials in humans, but issues of solubility, endogenous cleavage, and cost have destroyed its anti-HRV effectiveness. Pracona Pleconaril (PICOVIR®) has been shown to effectively inhibit HRV replication, but is currently being rejected by the US FDA due to major safety concerns. Some imidazopyrazines have been shown to be effective antiviral agents against HRV and other viruses. Mode of action, It is not believed to be due to its effect on cyclin-dependent kinases (Macleod et al., U.S. Published Application No. 2011/0166147). In view of the above, new therapeutic agents against HRV are still needed and development of broad-spectrum antibodies Viral agent. Coronavirus is a single-stranded positive-strand RNA virus family with a viral envelope and is classified in the order of Nidovirales. The coronavirus family contains pathogens of many animal species, including humans, horses, cattle, and pigs. , Birds, cats and monkeys, and has been known for more than 60 years. For example, in 1949 the isolation of the prototype murine coronavirus strain JHM was reported. Coronaviruses are common viruses that usually cause mild to moderate upper respiratory tract diseases in humans, and are named after the corona peaks on their mantle surface. There are four main subgroups called alpha, beta, gamma, and delta coronaviruses, of which the first coronavirus was identified in the mid-1960s. Coronaviruses are known to infect humans, including alpha-coronavirus 229E and NL63; and beta-coronaviruses OC43, HKU1, SARS-CoV (coronavirus that causes severe acute respiratory syndrome or SARS) and MERS-CoV (causes of the Middle East respiratory syndrome or MERS Coronavirus). Humans are usually infected with human coronaviruses 229E, NL63, OC43, and HKU1, and symptoms usually include mild to moderate upper respiratory tract diseases with a short duration, such as runny nose, cough, sore throat, and fever. Human coronavirus occasionally causes diseases of the lower respiratory tract, such as pneumonia, but this is more common in people with cardiopulmonary disease or damaged immune system or in the elderly. The spread of common human coronaviruses is not fully understood. However, it is possible that human coronavirus spreads from the infected person to others by coughing and sneezing through the air and through close individual contact (eg, touching or shaking hands). These viruses can also be spread by touching contaminated objects or surfaces and then touching your mouth, nose, or eyes. The SARS-CoV system was first identified in China in November 2002, and it led to an outbreak of more than 8,000 cases worldwide, including 774 deaths, between 2002 and 2003. Since 2004, no known cases of SARS-CoV infection have been reported anywhere in the world. The Middle East Respiratory Syndrome (MERS) is a viral respiratory disease caused by the novel coronavirus (MERS-CoV). The virus was first identified in Saudi Arabia in 2012, but a retrospective analysis determined that the first known MERS was in 2012 4 The month happened in Jordan. As of 2015, the virus appears to have spread mainly throughout the Arabian Peninsula, of which 85% of cases from 2012 to 2015 were reported in Saudi Arabia. The outbreak was recorded in the Republic of Korea in 2015 and it was related to travelers returning from the Arabian Peninsula. Most human cases of MERS are due to human-to-human infections, but it is believed that camels are the main reservoir of MERS-CoV and the animal source of MERS infection in humans. The transmission of animals to humans is not fully understood. Therefore, the exact role of camels in virus transmission and the exact route of transmission between animals and humans or between humans and humans are unknown. However, unless there is close contact, the virus does not seem to spread easily from person to person, such as when unprotected care is provided to patients. And although many cases have been reported in health care institutions, especially when the practice of infection prevention and control is inadequate, so far no continuous community transmission has been recorded. Typical MERS symptoms include fever, cough, and shortness of breath. Although pneumonia is very common, it is not always present. Gastrointestinal symptoms have also been reported, including diarrhea. MERS can infect anyone, and there are reported cases in patients within the age range of <1 year to 99 years. CDC is monitoring MERS worldwide and recognizes that MERS-CoV has the potential to spread globally and cause additional cases, including the United States and Europe. To date, approximately 36% of patients reported to have MERS have died. Therefore, there is an urgent need to develop anti-MERS-CoV therapeutic agents. Poliomyelitis ("polio") is caused by infection with poliovirus (poliovirus, "PV"). PV is a member of the Enterovirus genus, which is a genus in the picornaviridae family. The PV gene system is a single positive-strand RNA molecule of about 7.5 kb and consists of a single large open reading frame encoding a polyprotein with about 2500 amino acids and at the 5 'and 3' ends (5'-UTR and 3'-UTR ) Is composed of non-translation area. This polyprotein alone is the precursor of about 11 viral proteins, which are critical for the replication and assembly of progeny virus particles. Although PV infection initially begins in the gastrointestinal tract, PV infection can spread and have serious health effects in other parts of the body, including the peripheral and central nervous systems. Before the 1950s, the polio epidemic paralyzed thousands of children and adults. Although the introduction of extensive vaccination has largely controlled the local spread of live poliovirus around the world, it is still a serious health concern to introduce poliovirus from countries that do not yet contain it. (Thompson et al., 127 PUB. HEALTH REP. 23 (2012)). Another source of the continuing threat of polio is the outbreak of vaccine-derived poliovirus, which occurred recently in the Dominican Republic and Haiti in 2000 and in the Philippines in 2001. Therefore, new anti-PV therapeutic agents are needed. Despite other differences, positive RNA viruses of several families, including HRV and other picornaviruses, human coronaviruses (eg, SARS-CoV and MERS-CoV), and noroviruses need to transfer viral RNA into Polyproteins, which must be dissociated into individual enzymes for subsequent replication. The maturation of multiple proteins requires virally encoded enzymes to catalyze most cleavage events. This is implemented by the following: an enzyme called 3C protease or picornain against HRV and other picornaviruses, or 3CL against coronavirus and norovirus (3C-like), M (main) protease or similar enzymes of nsp5. This step is critical to the virus life cycle; the virus will not be able to replicate / survive without it. The 3C protease enzyme of picornavirus is a 20 kD cysteine protease. It is produced as part of a viral polyprotein and catalyzes most cleavage events, which results in the production of active forms of all virally encoded proteins. These proteins are essential for virus replication, making the virus'"lifecycle" unsustainable without cleavage. It is also known that the 3C enzymes of some viruses cleave the regulatory proteins in the host cell and may be able to achieve a higher degree of virus replication. For example, the 3C protein of coxsackievirus has been reported to cleave human MAVS and TRIF proteins to reduce the cellular response to viral infection (A Mukherjee et al., Volume 7, PLOS Pathogens, 3 e1001311). The 3CL protease enzymes of coronavirus and norovirus are approximately 50 kD cysteine proteases. Although it has a similar function to the 3C protein of picornavirus, the protein contains additional domains that allow the formation of the homodimeric form required for catalytic activity. The 3CL protease is produced by one of several viral polyproteins, and catalyzes most cleavage events from polyproteins, which results in the production of enzymes encoded by active viruses. These proteins are essential for virus replication, making the virus'"lifecycle" unsustainable without cleavage. It is also known that some viral 3CL enzymes cleave regulatory proteins in host cells and may be able to achieve a higher degree of viral replication. For example, the 3CL protein of SARS coronavirus has been reported to cleave the human STING protein to reduce the cellular response to viral infection (L Sun et al., Volume 7, PLOS One, 2 e30802).

本發明之實施例以下式I化合物為特徵：式I 其係3C及3CL蛋白酶抑制劑，且因此可用於治療人類鼻病毒(HRV)、人類冠狀病毒、小核糖核酸病毒及諾羅病毒感染，以及與此等病毒相關之疾病及症狀。 在本發明之某些實施例中，3C及3CL蛋白酶抑制劑係下式I化合物：其中A 係 芳基或雜芳基；R1 、 R′1 及 R′′1 獨立地選自H；C1-C6-烷基；鹵基；鹵代烷基；NR6 R7 ；OR8 ；SR9 ；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8環烷基或C3-C8雜環烷基；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、硫代烷基取代之C3-C8環烷基或C3-C8雜環烷基；或R2 係 C1-C6-烷基、經芳基、雜芳基、C1-C6-烷基、C3-C8-環烷基、C3-C8雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基、NR6 R7 取代之C1-C6-烷基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、鹵基取代烷氧基取代之C3-C8-環烷基，或該C3-C8環烷基與芳基稠合以形成二環或三環稠合環；C3-C8-雜環烷基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、鹵基取代烷氧基取代之C3-C8-環烷基或C3-C8-雜環烷基，或該C3-C8雜環烷基與芳基稠合以形成二環或三環稠合環；其中該芳基、雜芳基、C1-C6-烷基、C3-C8-環烷基、C3-C8雜環烷基或NR6 R7 進一步視情況經鹵基、烷氧基、鹵基取代烷氧基、NR6 R7 、OR8 、SR9 取代；R3 及 R4 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基；或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之5員至10員環結構；R5 係C1-C6烷基；經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、芳基、雜芳基取代之C1-C6烷基；或視情況經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8環烷基；R6 及 R7 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8-環烷基或C3-C8-雜環烷基；或R6 與R7 一起形成視情況經鹵基、鹵代烷基、胺基、NR6 R7 、OR8 、SR9 取代之3員至10員環烷基或雜環烷基環；芳基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之芳基；雜芳基；或經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之雜芳基；且R8 及 R9 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基， 或其鹽。 在本發明之某些實施例中，3C及3CL蛋白酶抑制劑係下式IA化合物：式IA 其中A 係 芳基或雜芳基；R1 、 R′1 及 R′′1 獨立地選自H；C1-C6-烷基；鹵基；鹵代烷基；NR6 R7 ；OR8 ；SR9 ；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8環烷基或C3-C8雜環烷基；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、硫代烷基取代之C3-C8環烷基或C3-C8雜環烷基；或R2 係 C1-C6-烷基；經芳基、雜芳基、C1-C6-烷基、C3-C8-環烷基、C3-C8雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基、NR6 R7 取代之C1-C6-烷基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、鹵基取代烷氧基取代之C3-C8-環烷基，或該C3-C8環烷基與芳基稠合以形成二環或三環稠合環；C3-C8-雜環烷基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、鹵基取代烷氧基取代之C3-C8-環烷基或C3-C8-雜環烷基，或該C3-C8雜環烷基與芳基稠合以形成二環或三環稠合環；其中該芳基、雜芳基、C1-C6-烷基、C3-C8-環烷基、C3-C8雜環烷基或NR6 R7 進一步視情況經鹵基、烷氧基、鹵基取代烷氧基、NR6 R7 、OR8 、SR9 取代；R3 及 R4 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基；或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之5員至10員環結構；R5 係C1-C6烷基；經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、芳基、雜芳基取代之C1-C6烷基；或視情況經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8環烷基；R6 及 R7 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8-環烷基或C3-C8-雜環烷基；或R6 與R7 一起形成視情況經鹵基、鹵代烷基、胺基、NR6 R7 、OR8 、SR9 取代之3員至10員環烷基或雜環烷基環；芳基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之芳基；雜芳基；或經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之雜芳基；且R8 及 R9 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基， 或其鹽。 在某些實施例中提供下式IA化合物，式IA 其中：A 係 苯基或噁唑基；R1 、 R′1 及 R′′1 獨立地選自H；C1-C6-烷基；鹵基；鹵代烷基；NR6 R7 ；OR8 ；SR9 ；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C1-C6烷基；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8環烷基或C3-C8雜環烷基；或R2 係 C1-C6-烷基、經芳基、雜芳基、C1-C6-烷基、C1-C6-環烷基、C3-C8雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6-烷基；NR6 R7 ；其中芳基、雜芳基、C1-C6-烷基、C3-C8-環烷基、C3-C8雜環烷基或NR6 R7 進一步視情況經鹵基、烷氧基、鹵基取代烷氧基、O、N、S、NR6 R7 、OR8 、SR9 取代；R3 及 R4 獨立地係 H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基；經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基；C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-雜環烷基；或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之5員至10員環結構；R5 係 C1-C6烷基；經C1-C6-烷基、C3-C8環烷基、C3-C8-雜環烷基、芳基、雜芳基取代之C1-C6烷基；或C3-C8環烷基；R6 及 R7 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8-環烷基或C3-C8-雜環烷基；或R6 與R7 一起形成視情況經鹵基、鹵代烷基、胺基、NR6 R7 、OR8 、SR9 取代之3員至10員環烷基或雜環烷基環；芳基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之芳基；雜芳基；或經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之雜芳基；且R8 及 R9 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基，或其鹽。 一個實施例提供下式IA化合物，式IA 其中：A 係 苯基；R1 、 R′1 及 R′′1 獨立地選自H；C1-C6-烷基；鹵基；鹵代烷基；NR6 R7 ；OR8 ；SR9 ；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C1-C6烷基；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8環烷基或C3-C8雜環烷基；或R2 係 C1-C6-烷基；經六氫吡啶基取代之C1-C6-烷基；嗎啉基；茚基；苯基；噻唑基；吡啶基；嘧啶基；喹啉基；萘基；C1-C6-烷基、烷氧基；鹵基取代烷氧基；NR6 R7 ；其中六氫吡啶基、嗎啉基、茚基、苯基、噻唑基、吡啶基、嘧啶基、喹啉基、萘基、NR6 R7 進一步視情況經鹵基、O、N、S、NR6 R7 、OR8 、SR9 取代；R3 及 R4 獨立地係 H、C1-C6-烷基；經C1-C6-烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之5員至10員環結構；R5 係 C1-C6烷基；經C1-C6-烷基、C3-C8環烷基或C3-C8雜環烷基、苯基取代之C1-C6烷基；或經C1-C6-烷基取代之C3-C8-環烷基或C3-C8-雜環烷基；R6 及 R7 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基取代之C1-C6烷基；或R6 與R7 一起形成視情況經鹵基、鹵代烷基取代之3員至10員環烷基或雜環烷基環；且R8 及 R9 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基，或其鹽。 一個具體實施例提供如所述之式I或式IA化合物或鹽，其中R3 係H，且R4 獨立地選自H、C1-C6-烷基及經C1-C6-烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之5員至10員環烷基或雜環烷基環結構。 另一具體實施例提供如所述之式I或式IA化合物或鹽，其中R5 選自基團C1-C6烷基；經C1-C6-烷基、苯基取代之C1-C6烷基；經C1-C6-烷基取代之C3-C8-環烷基或C3-C8-雜環烷基。 另一具體實施例提供如所述之式I或式IA化合物或鹽，其中A選自由以下組成之群：芳基及經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基或硫代烷基取代之芳基。 另一具體實施例提供如所述之式I或式IA化合物或鹽，其中A選自由以下組成之群：雜芳基及經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基或硫代烷基取代之雜芳基。 又一具體實施例提供如所述之式I或式IA化合物或鹽，其中A選自由以下組成之群：苯基及經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基或硫代烷基取代之苯基。 在另一具體實施例中提供如所述之式I或式IA化合物或鹽，其中A選自由以下組成之群：噁唑基及經取代之噁唑基。 在本發明之另一實施例中提供選自由以下各項組成之群之化合物： N-[(1S)-1-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(二甲基胺基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-(六氫吡啶-1-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-(嗎啉-4-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[4-(三氟甲基)六氫吡啶-1-基]乙基]胺基甲酸苄基酯； N-[(1S)-2-(4,4-二氟六氫吡啶-1-基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-2-(4-氟六氫吡啶-1-基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[4-(三氟甲基)六氫吡啶-1-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(4,4-二氟六氫吡啶-1-基)乙基]胺基甲酸苄基酯； N-[(1S)-2-[(環丙基甲基)(甲基)胺基]-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(環戊基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[4-(三氟甲基)六氫吡啶-1-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[甲基(2,2,2-三氟乙基)胺基]乙基]胺基甲酸苄基酯； N-[(2S)-1-[(2S)-4,4-二乙基-2-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}吡咯啶-1-基]-1-側氧基-3-[4-(三氟甲基)六氫吡啶-1-基]丙-2-基]胺基甲酸苄基酯； N-[(1S)-2-(4-氟苯基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-2-環戊基乙基]胺甲醯基}-2-(喹啉-5-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-{[(1S)-1-苯基乙基]胺甲醯基}丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-(吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-3-甲基-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}丁基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-3-苯丙基]胺基甲酸苄基酯； N-[2-(6-甲氧基吡啶-2-基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S,2S)-2-甲氧基-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}丙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[4-(三氟甲基)嘧啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-2-(5-氟吡啶-2-基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[6-(三氟甲基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[5-(三氟甲基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-{[(1S)-1-環己基乙基]胺甲醯基}-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-(3-甲基苯基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[4-(三氟甲基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(1,3-噻唑-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[4-(丙-2-基氧基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[6-(三氟甲基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(1,3-噻唑-4-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[6-(三氟甲氧基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[6-(三氟甲氧基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[5-(三氟甲基)嘧啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[4-(三氟甲基)-1,3-噻唑-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(5-甲基-1,3-噻唑-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(6-甲氧基吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(2-甲氧基-1,3-噻唑-4-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-{4H,5H,6H-環戊并[d][1,3]噻唑-2-基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(6-甲氧基-4-甲基吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(6-乙氧基吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-2-環己基乙基]胺甲醯基}-2-(萘-1-基)乙基]胺基甲酸{4-[3-(嗎啉-4-基)丙氧基]苯基}甲酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(萘-1-基)乙基]胺基甲酸{4-[2-(六氫吡啶-1-基)乙氧基]苯基}甲酯； N-[(1S)-2-(4-氟苯基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸(4-{[環丙基(甲基)胺基]甲基}苯基)甲酯； N-[(S)-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}(2,3-二氫-1H-茚-2-基)甲基]胺基甲酸(5-甲基-1,2-噁唑-3-基)甲基酯； N-[(2S)-1-[(1S,3aR,6aS)-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}-八氫環戊并[c]吡咯-2-基]-3-(4-氟苯基)-1-側氧基丙-2-基]胺基甲酸苄基酯； N-[(2S)-1-側氧基-1-[(3S)-3-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}-2-氮雜螺[4.4]壬-2-基]-3-(吡啶-2-基)丙-2-基]胺基甲酸苄基酯；及 N-[(2S)-1-[(2S)-4,4-二乙基-2-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}吡咯啶-1-基]-3-(4-氟苯基)-1-側氧基丙-2-基]胺基甲酸苄基酯或其鹽。 在一個實施例中提供治療或預防易患或患有病毒感染之個體中病毒感染之方法，其包含向個體投與3C蛋白酶之抑制劑，其中該抑制劑係如本文所述之式I或式IA化合物或其醫藥上可接受之鹽、溶劑合物或水合物。 一個具體實施例提供治療或預防易患或患有基於RNA之病毒感染之個體中來自基於RNA之病毒之病毒感染之方法，其包含向個體投與3C蛋白酶之抑制劑，其中該抑制劑係如本文所述之式I或式IA化合物、其醫藥上可接受之鹽、溶劑合物或水合物。 另一具體實施例提供治療或預防易患或患有鼻病毒感染之個體中冠狀病毒感染之方法，其包含向個體投與3C蛋白酶之抑制劑，其中該抑制劑係如本文所述之式I或式IA化合物或其醫藥上可接受之鹽、溶劑合物或水合物。 又一具體實施例提供治療或預防易患或患有病毒感染之個體中病毒感染之方法，其包含向個體投與3C蛋白酶之抑制劑，其中該抑制劑包含來自表2之化合物或其醫藥上可接受之鹽、溶劑合物或水合物。 另一具體實施例提供抑制哺乳動物中病毒3C蛋白酶或病毒3CL蛋白酶之方法，其包含向該哺乳動物投與治療有效量之如本文所述之式I或式IA化合物或其醫藥上可接受之鹽、溶劑合物或水合物。 在一個實施例中，哺乳動物係人類。 在另一具體實施例中，病毒係鼻病毒、冠狀病毒、小核糖核酸病毒或諾羅病毒。 在具體實施例中，冠狀病毒係229E、NL63、OC43、HKU1、SARS-CoV或MERS冠狀病毒。 在具體實施例中，小核糖核酸病毒係脊髓灰白質炎病毒、EV-68病毒、EV-71病毒、肝炎A病毒、腸病毒或柯薩奇病毒。表格簡單說明 本發明之實施例以為3C及3CL蛋白酶抑制劑之化合物為特徵且因此其可用於治療人類鼻病毒(HRV)、人類冠狀病毒、小核糖核酸病毒及諾羅病毒感染以及與此等病毒相關之疾病及症狀。藉由參照以下詳細說明並參照隨附表格，將更易於理解本發明之前述特徵，其中： 表1係正義單鏈RNA病毒、負義單鏈RNA病毒及雙鏈RNA病毒及DNA病毒之清單。 表2係本文所述化合物之清單。 表3係表2中化合物之生物分析數據之匯總。The embodiments of the present invention are characterized by the following compounds of formula I: Formula I It is a 3C and 3CL protease inhibitor, and therefore can be used to treat human rhinovirus (HRV), human coronavirus, picornavirus, and norovirus infections, as well as diseases and symptoms associated with these viruses. In certain embodiments of the invention, the 3C and 3CL protease inhibitors are compounds of formula I: Wherein A is aryl or heteroaryl; R 1 , R ′ 1 and R ′ 1 are independently selected from H; C1-C6-alkyl; halo; haloalkyl; NR 6 R 7 ; OR 8 ; SR 9 ; C1-C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl ; C3-C8 cycloalkyl or C3-C8 heterocycloalkyl; via C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, hydroxyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl substituted with alkoxy, thioalkyl; or R 2 is C1-C6-alkyl, aryl, heteroaryl, C1-C6-alkyl , C3-C8-cycloalkyl, C3-C8 heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl, NR 6 R 7 substituted C1- C6-alkyl; optionally via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, hydroxyl, alkoxy C3-C8-cycloalkyl substituted by alkoxy or halo substituted alkoxy, or the C3-C8 cycloalkyl is fused with an aryl group to form a bicyclic or tricyclic fused ring; C3-C8-heterocycloalkyl ;Subject to availability C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, amine alkyl, hydroxy, alkoxy, halo substituted alkoxy Substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, or the C3-C8 heterocycloalkyl is fused with an aryl group to form a bicyclic or tricyclic fused ring; wherein the aryl, heterocyclic Aryl, C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyl or NR 6 R 7 is further substituted with halo, alkoxy, halo for alkoxy, NR 6 R 7 , OR 8 , SR 9 substitution; R 3 and R 4 are independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkane C1-C6 alkyl group substituted by alkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl ; Via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl Substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R 3 and R 4 together form C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-hetero Cycloalkyl, halo, haloalkyl, NR 6 5-membered to 10-membered ring structure substituted with R 7 , OR 8 , and SR 9 ; R 5 is C1-C6 alkyl; C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocyclic C1-C6 alkyl substituted with alkyl, aryl, heteroaryl; or optionally C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl , NR 6 R 7 , OR 8 , SR 9 substituted C3-C8 cycloalkyl; R 6 and R 7 are independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-ring C1-C6 alkyl substituted with alkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkane Group; C3-C8-ring substituted with C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 Alkyl or C3-C8-heterocycloalkyl; or R 6 and R 7 together form a 3- to 10-membered ring optionally substituted by halo, haloalkyl, amine, NR 6 R 7 , OR 8 and SR 9 Alkyl or heterocycloalkyl ring; aryl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , Aryl substituted by SR 9 ; heteroaryl; or C1-C6-alkyl, C 3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 substituted heteroaryl; and R 8 and R 9 are independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, C1-C6 alkyl substituted by hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8 -C3-C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl, or Its salt. In certain embodiments of the invention, the 3C and 3CL protease inhibitors are compounds of formula IA: Formula IA wherein A is aryl or heteroaryl; R 1 , R ′ 1 and R ′ ′ 1 are independently selected from H; C1-C6-alkyl; halo; haloalkyl; NR 6 R 7 ; OR 8 ; SR 9 ; C1-C6 substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, amine alkyl, alkoxy, hydroxy, thioalkyl Alkyl; C3-C8 cycloalkyl or C3-C8 heterocycloalkyl; via C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl substituted with hydroxy, alkoxy, thioalkyl; or R 2 is C1-C6-alkyl; via aryl, heteroaryl, C1-C6- Alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl, NR 6 R 7 C1-C6-alkyl; optionally via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, hydroxy, C3-C8-cycloalkyl substituted by alkoxy or halogen substituted alkoxy, or the C3-C8 cycloalkyl is fused with aryl to form a bicyclic or tricyclic fused ring; C3-C8-heterocyclic Alkyl Substituted by C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, hydroxy, alkoxy, halo substituted alkyl Oxygen substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, or the C3-C8 heterocycloalkyl is fused with an aryl group to form a bicyclic or tricyclic fused ring; wherein the aryl group , Heteroaryl, C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyl, or NR 6 R 7 is further substituted with halo, alkoxy, halo for alkoxy, NR 6 R 7 , OR 8 , SR 9 substitution; R 3 and R 4 are independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-hetero C1-C6 alkyl substituted with cycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycle Alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thio Alkyl-substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R 3 and R 4 together form C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8 as appropriate -Heterocycloalkyl, halo, haloalkane , NR 6 R 7, OR 8 , SR 9 substituted of from 5 to 10 ring structure; R 5 lines C1-C6 alkyl; C1-C6- alkyl by, C3-C8- cycloalkyl, C3-C8- C1-C6 alkyl substituted with heterocycloalkyl, aryl, heteroaryl; or optionally C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, C3-C8 cycloalkyl substituted with haloalkyl, NR 6 R 7 , OR 8 , SR 9 ; R 6 and R 7 are independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8 -C1-C6 alkyl substituted with cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8- Cycloalkyl; C3-C8 substituted with C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 -Cycloalkyl or C3-C8-heterocycloalkyl; or R 6 and R 7 together form 3 to 10 members optionally substituted by halo, haloalkyl, amine, NR 6 R 7 , OR 8 , SR 9 Member cycloalkyl or heterocycloalkyl ring; aryl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , oR 8, SR 9 of substituted aryl; heteroaryl; or by C1-C6- alkoxy , C3-C8- cycloalkyl or C3-C8- heterocycloalkyl, halo, haloalkyl, NR 6 R 7, OR 8 , SR 9 of a substituted heteroaryl group; and R 8 and R 9 are independently H system , C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy , Hydroxy, thioalkyl substituted C1-C6 alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3- C8-heterocycloalkyl, halo, haloalkyl, amine, amine alkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, Or its salt. In certain embodiments, compounds of formula IA are provided, Formula IA where: A is phenyl or oxazolyl; R 1 , R ′ 1 and R ′ ′ 1 are independently selected from H; C1-C6-alkyl; halo; haloalkyl; NR 6 R 7 ; OR 8 ; SR 9 ; C1-C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 ; via C3-C8 -C3-C8 cycloalkyl or C3-C8 heterocycloalkyl substituted with cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 ; or R 2 Department C1-C6- alkyl, aryl, heteroaryl, C1-C6- alkyl, C1-C6- cycloalkyl, C3-C8 heterocycloalkyl, halo, haloalkyl, amino, amine C1-C6-alkyl substituted with alkyl, alkoxy, hydroxy, thioalkyl; NR 6 R 7 ; wherein aryl, heteroaryl, C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyl or NR 6 R 7 is further optionally substituted with halo, alkoxy, halo substituted alkoxy, O, N, S, NR 6 R 7 , OR 8 , SR 9 ; R 3 And R 4 is independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, amine Alkyl, alkoxy, hydroxy, thioalkyl Substituted C1-C6 alkyl; C3-C8-cycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, C3-C8-cycloalkyl substituted with aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-heterocycloalkyl; or R 3 and R 4 Together form 5 members to 1-6 optionally substituted with C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 10-membered ring structure; R 5 is C1-C6 alkyl; C1-C6 alkyl substituted with C1-C6-alkyl, C3-C8 cycloalkyl, C3-C8-heterocycloalkyl, aryl, heteroaryl Group; or C3-C8 cycloalkyl; R 6 and R 7 are independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkane C1-C6 alkyl group substituted by alkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkane , NR 6 R 7, OR 8 , SR 9 of substituted C3-C8- cycloalkyl or C3-C8- heterocycloalkyl; or R 6 and R 7 together form an optionally by halo, haloalkyl, amino, NR 6 R 7 , OR 8 , SR 9 substituted 3 to 10 member cycloalkyl or heterocycloalkyl ring; aryl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8- Heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 substituted aryl; heteroaryl; or C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8 -Heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 substituted heteroaryl; and R 8 and R 9 are independently H, C1-C6-alkyl; via C1-C6 -C1-C6 substituted with alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl Alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl , Amino, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, or salts thereof. An embodiment provides a compound of formula IA, Formula IA wherein: A is phenyl; R 1 , R ′ 1 and R ′ 1 are independently selected from H; C1-C6-alkyl; halo; haloalkyl; NR 6 R 7 ; OR 8 ; SR 9 ; C1-C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 ; via C3-C8-cycloalkyl , C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 substituted C3-C8 cycloalkyl or C3-C8 heterocycloalkyl; or R 2 is C1-C6 -Alkyl; C1-C6-alkyl substituted with hexahydropyridyl; morpholinyl; indenyl; phenyl; thiazolyl; pyridyl; pyrimidinyl; quinolinyl; naphthyl; C1-C6-alkyl , Alkoxy; halogen substituted alkoxy; NR 6 R 7 ; of which hexahydropyridyl, morpholinyl, indenyl, phenyl, thiazolyl, pyridyl, pyrimidinyl, quinolinyl, naphthyl, NR 6 R 7 is further substituted with halogen, O, N, S, NR 6 R 7 , OR 8 , SR 9 as appropriate; R 3 and R 4 are independently H, C1-C6-alkyl; via C1-C6- C1-C6 alkyl substituted with alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R 3 and R 4 together form C1-C6-alkyl, C3-C8-ring as appropriate Alkyl or C3-C8-hetero The substituted alkyl, halo, haloalkyl, amino, aminoalkyl, alkoxy, hydroxyl, thioalkyl 5-10 ring structure; R 5 lines C1-C6 alkyl; C1-C6 via -Alkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl, phenyl substituted C1-C6 alkyl; or C1-C6-alkyl substituted C3-C8-cycloalkyl or C3-C8 -Heterocyclic alkyl; R 6 and R 7 are independently H, C1-C6-alkyl; C1 substituted with C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl -C6 alkyl; or R 6 and R 7 together form a 3- to 10-membered cycloalkyl or heterocycloalkyl ring optionally substituted by halo or haloalkyl; and R 8 and R 9 are independently H and C1 -C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy , C1-C6 alkyl substituted by thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8- Heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, or salt. A specific embodiment provides a compound or salt of formula I or formula IA as described, wherein R 3 is H, and R 4 is independently selected from H, C1-C6-alkyl and C1-C6-alkyl substituted C1 -C6 alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R 3 and R 4 together form optionally C1-C6-alkyl, C3-C8-cycloalkyl or C3- C8-heterocycloalkyl, halo, haloalkyl, amine, amine alkyl, alkoxy, hydroxy, thioalkyl substituted 5- to 10-membered cycloalkyl or heterocycloalkyl ring structure. Another specific embodiment provides the compound or salt of formula I or formula IA as described, wherein R 5 is selected from the group C1-C6 alkyl; C1-C6 alkyl substituted with C1-C6-alkyl, phenyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with C1-C6-alkyl. Another specific embodiment provides a compound or salt of formula I or formula IA as described, wherein A is selected from the group consisting of: aryl and C1-C6-alkyl, C3-C8-cycloalkyl, or C3-C8 -Heterocyclic alkyl, halo, haloalkyl, amine, amine alkyl, alkoxy, hydroxy or thioalkyl substituted aryl. Another specific embodiment provides a compound or salt of formula I or formula IA as described, wherein A is selected from the group consisting of heteroaryl and C1-C6-alkyl, C3-C8-cycloalkyl or C3- C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy or thioalkyl substituted heteroaryl. Yet another embodiment provides a compound or salt of formula I or formula IA as described, wherein A is selected from the group consisting of phenyl and C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8 -Phenyl substituted with heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy or thioalkyl. In another specific embodiment, there is provided a compound or salt of formula I or formula IA as described, wherein A is selected from the group consisting of oxazolyl and substituted oxazolyl. In another embodiment of the present invention, a compound selected from the group consisting of N-[(1S) -1-{[(1S) -1-{[(2S) -1- (三 丁丁Amino carbamoyl) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl ] Aminomethanyl} -2- (dimethylamino) ethyl] benzyl carbamate; N-[(1S) -1-{[(1S) -3-methyl-1-{[ (2S) -1-Penoxy-3-[(3S) -2-Penoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminemethylamide] prop-2-yl ] Aminomethanyl} butyl] aminomethanyl} -2- (hexahydropyridin-1-yl) ethyl] benzyl carbamate; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) Aminoacetoyl] propan-2-yl] aminoformyl} butyl] aminoformyl} -2- (morpholin-4-yl) ethyl] carbamic acid benzyl ester; N-[(1S ) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1 -[(Prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} -2- [4- (trifluoromethyl) hexahydropyridine-1 -Yl] ethyl] carbamic acid benzyl ester; N-[(1S) -2- (4,4-difluorohexahydropyridin-1-yl) -1-{[(1S) -3-methyl -1-{[(2S) -1- Oxy-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminomethylamino] propan-2-yl] aminomethylamino} butan Group] Aminocarbamoyl} ethyl] carbamic acid benzyl ester; N-[(1S) -2- (4-fluorohexahydropyridin-1-yl) -1-{[(1S) -3-methyl Yl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamide ] Propan-2-yl] aminomethanyl} butyl] aminomethanyl} ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[( 2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminecarboxyl} -3-methylbutyl] aminecarboxamide} -2- [4- (trifluoromethyl) hexahydropyridin-1-yl] ethyl] benzyl carbamate; N-[(1S)- 1-{[(1S) -1-{[(2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidine-3- Yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (4,4-difluorohexahydropyridin-1-yl) ethyl] aminocarboxylic acid Benzyl ester; N-[(1S) -2-[(cyclopropylmethyl) (methyl) amino] -1-{[(1S) -3-methyl-1-{[(2S)- 1-Ptoxy-3-[(3S) -2-Ptoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamido] prop-2-yl] aminecarboxamide } Butyl] aminomethayl} ethyl] aminocarbamic acid Ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (cyclopentylaminecarboxamide) -1-pentoxy-3-[(3S -2-oxo-pyrrolidin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl] aminomethanyl} -2- [4- (trifluoromethyl) hexa Hydropyridin-1-yl] ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminemethylamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethayl} -3-methylbutyl] aminemethyl} -2- [methyl (2,2,2-trifluoroethyl) amino] ethyl] carbamic acid benzyl ester; N-[(2S) -1-[(2S) -4,4-di Ethyl-2-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamide Yl] propan-2-yl] aminecarboxamido} pyrrolidin-1-yl] -1-oxo-3- [4- (trifluoromethyl) hexahydropyridin-1-yl] propan-2- Benzyl ester of amino] carbamic acid; N-[(1S) -2- (4-fluorophenyl) -1-{[(1S) -3-methyl-1-{[(2S) -1-side Oxy-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminomethylamino] propan-2-yl] aminomethylamino} butan Group] Aminoformyl} ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (third butylaminoformamide Yl) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2- ] Aminoacetoyl} -2-cyclopentylethyl] aminoformamide} -2- (quinolin-5-yl) ethyl] benzyl carbamate; N-[(1S) -1- {[(1S) -1-{[(2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] Prop-2-yl] aminomethanyl} -3-methylbutyl] aminomethanyl} -2- (pyridin-2-yl) ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1- {[(1S) -1-Phenylethyl] aminecarboxamide} propan-2-yl] aminecarboxyl} butyl] aminecarboxyl} -2- (pyridin-2-yl) ethyl] Benzyl carbamate; N-[(1S) -3-methyl-1-{[(1S) -3-methyl-1-{[(2S) -1-pentoxy-3-[( 3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} Butyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-pentoxy-3-[(3S -2-oxo-pyrrolidin-3-yl] -1-[(prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} -3 -Phenylpropyl] carbamic acid benzyl ester; N- [2- (6-methoxypyridin-2-yl) -1-{[(1S) -3-methyl-1-{[(2S -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1- [ (Prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} ethyl] benzyl carbamate; N-[(1S, 2S)- 2-methoxy-1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidine-3- Yl] -1-[(prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} propyl] carbamic acid benzyl ester; N- [ (1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(Prop-2-yl) aminomethylamido] propan-2-yl] aminomethylamino} butyl] aminomethylamino-2--2-4- (trifluoromethyl) pyrimidine-2 -Yl] ethyl] carbamic acid benzyl ester; N-[(1S) -2- (5-fluoropyridin-2-yl) -1-{[(1S) -3-methyl-1-{[ (2S) -1-Penoxy-3-[(3S) -2-Penoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminemethylamide] prop-2-yl ] Aminomethanyl} butyl] aminomethanyl} ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S ) -1-Penoxy-3-[(3S) -2-Penoxypyrrolidin-3-yl] -1-[(Prop-2-yl) aminemethylacetoyl] propan-2-yl] amine Methyl} butyl] aminomethanyl} -2- [6- (trifluoromethyl) pyridin-2-yl] ethyl] benzyl aminocarbamate; N-[(1S) -1- { [(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2- Oxypyrrolidin-3-yl] -1-[(prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} -2- [5- (Trifluoromethyl) pyridin-2-yl] ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1-{[( 1S) -1-cyclohexylethyl] aminecarboxamide} -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminecarboxamide Yl} -3-methylbutyl] aminomethanyl} -2- (pyridin-2-yl) ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S)- 3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) amine Formyl] propan-2-yl] amine formyl} butyl] amine formyl} -2- (3-methylphenyl) ethyl] benzyl carbamate; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1- [(Prop-2-yl) aminecarboxamide] propan-2-yl] aminecarboxyl} butyl] aminecarboxyl} -2- [4- (trifluoromethyl) pyridin-2-yl] Ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-pentyloxy- 3-[(3S) -2-Penoxypyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (1,3 -Thiazol-2-yl) ethyl] benzyl carbamate; N- [(1S) -1-{[(1S) -1-{[(2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxo Pyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- [4- (prop-2-yloxy) pyridine-2- Group] ethyl] benzyl aminocarbamate; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-pentaoxy Yl-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethylamino} -3-methylbutyl] aminomethylamino} -2- [6 -(Trifluoromethyl) pyridin-2-yl] ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butyl Amino carbamoyl) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl ] Aminomethyl amide-2--2- (1,3-thiazol-4-yl) ethyl] benzyl carbamate; N-[(1S) -1-{[(1S) -1-{[( 2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminecarboxyl} -3-methylbutyl] aminecarboxamide} -2- [6- (trifluoromethoxy) pyridin-2-yl] ethyl] benzyl carbamate; N-[(1S) -1 -{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[( Propan-2-yl) aminomethyl] propan-2-yl] aminomethyl} butyl] aminomethylamino-2- [6- (trifluoromethoxy) pyridin-2-yl] ethyl] benzyl carbamate; N-[(1S) -1-{[(1S) -1-{[(2S) -1 -(Butylaminomethylacetoyl) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminemethyl} -3-methyl Benzylbutyl] aminecarboxamide} -2- [5- (trifluoromethyl) pyrimidin-2-yl] ethyl] benzyl carbamate; N-[(1S) -1-{[(1S ) -1-{[(2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2- ] Aminomethylamino} -3-methylbutyl] aminomethylamino} -2- [4- (trifluoromethyl) -1,3-thiazol-2-yl] ethyl] carbamic acid benzyl Base ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-pentoxy-3-[(3S)- 2-oxopyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (5-methyl-1,3-thiazole -2-yl) ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1 -Oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethylamino} -3-methylbutyl] aminomethylamino} -2 -(6-methoxypyridin-2-yl) ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butyl Aminoaminemethyl) -1-oxo-3-[(3S) -2-oxopyrrole Pyridin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl] aminomethanyl} -2- (2-methoxy-1,3-thiazol-4-yl) Ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-pentyloxy- 3-[(3S) -2-Penoxypyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- {4H, 5H , 6H-cyclopenta [d] [1,3] thiazol-2-yl} ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[( 2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminecarboxyl} -3-methylbutyl] aminecarboxamido} -2- (6-methoxy-4-methylpyridin-2-yl) ethyl] benzyl carbamate; N-[(1S)- 1-{[(1S) -1-{[(2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidine-3- Yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (6-ethoxypyridin-2-yl) ethyl] benzyl carbamate ; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (tert-butylaminecarboxamide) -1-pentoxy-3-[(3S)- 2-oxopyrrolidin-3-yl] propan-2-yl] aminecarboxamide} -2-cyclohexylethyl] aminecarboxamide} -2- (naphthalen-1-yl) ethyl] amine Carboxylic acid {4- [3- (morpholin-4-yl) propoxy] benzene } Methyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (tert-butylaminecarboxamide) -1-pentoxy-3-[( 3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl] aminomethanyl} -2- (naphthalen-1-yl) ethyl ] Aminocarboxylic acid {4- [2- (hexahydropyridin-1-yl) ethoxy] phenyl} methyl ester; N-[(1S) -2- (4-fluorophenyl) -1- { [(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop- 2-yl) aminomethylamino] propan-2-yl] aminomethylamino} butyl] aminomethylamino} ethyl] aminocarboxylic acid (4-{[cyclopropyl (methyl) amino] methyl Yl} phenyl) methyl ester; N-[(S)-{[(1S) -1-{[(2S) -1- (tert-butylaminecarboxamide) -1-pentoxy-3- [(3S) -2-Penoxypyrrolidin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl] aminomethanyl} (2,3-dihydro-1H -Inden-2-yl) methyl] aminocarboxylic acid (5-methyl-1,2-oxazol-3-yl) methyl ester; N-[(2S) -1-[(1S, 3aR, 6aS ) -1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamide ] Propan-2-yl] aminecarboxamide} -octahydrocyclopenta [c] pyrrol-2-yl] -3- (4-fluorophenyl) -1-oxopropan-2-yl] amine Benzyl carbamate; N-[(2S) -1-oxo-1-[(3S) -3-{[(2S) -1-oxo -3-[(3S) -2-Penoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} -2- Azaspiro [4.4] non-2-yl] -3- (pyridin-2-yl) prop-2-yl] carbamic acid benzyl ester; and N-[(2S) -1-[(2S)- 4,4-Diethyl-2-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2- Yl) aminomethanyl] propan-2-yl] aminomethanyl} pyrrolidin-1-yl] -3- (4-fluorophenyl) -1-oxopropan-2-yl] aminocarboxylic acid Benzyl ester or its salt. In one embodiment, there is provided a method of treating or preventing viral infection in an individual susceptible or suffering from a viral infection, which comprises administering an inhibitor of 3C protease to the individual, wherein the inhibitor is of Formula I or Formula as described herein IA compound or a pharmaceutically acceptable salt, solvate or hydrate thereof. A specific embodiment provides a method for treating or preventing viral infections from RNA-based viruses in individuals susceptible to or suffering from RNA-based virus infections, which comprises administering an inhibitor of 3C protease to the individual, wherein the inhibitor is such as The compounds of formula I or formula IA described herein, their pharmaceutically acceptable salts, solvates or hydrates. Another specific embodiment provides a method of treating or preventing coronavirus infection in an individual susceptible or suffering from rhinovirus infection, which comprises administering an inhibitor of 3C protease to the individual, wherein the inhibitor is of formula I as described herein Or a compound of formula IA or a pharmaceutically acceptable salt, solvate or hydrate thereof. Yet another embodiment provides a method of treating or preventing viral infection in an individual susceptible or suffering from a viral infection, which comprises administering an inhibitor of 3C protease to the individual, wherein the inhibitor comprises a compound from Table 2 or a pharmaceutical Acceptable salts, solvates or hydrates. Another specific embodiment provides a method of inhibiting viral 3C protease or viral 3CL protease in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I or formula IA as described herein or a pharmaceutically acceptable Salt, solvate or hydrate. In one embodiment, the mammal is a human. In another specific embodiment, the virus is rhinovirus, coronavirus, picornavirus or norovirus. In specific embodiments, the coronavirus line 229E, NL63, OC43, HKU1, SARS-CoV or MERS coronavirus. In a specific embodiment, the picornavirus is poliovirus, EV-68 virus, EV-71 virus, hepatitis A virus, enterovirus, or coxsackievirus. The table briefly illustrates that the embodiments of the present invention are characterized by compounds that are 3C and 3CL protease inhibitors and therefore they can be used to treat human rhinovirus (HRV), human coronavirus, picornavirus and norovirus infections and the like Related diseases and symptoms. By referring to the following detailed description and referring to the accompanying table, it will be easier to understand the aforementioned features of the present invention, where: Table 1 is a list of sense single-stranded RNA viruses, negative single-stranded RNA viruses, and double-stranded RNA viruses and DNA viruses. Table 2 is a list of compounds described herein. Table 3 is a summary of the bioanalysis data of the compounds in Table 2.

在本申請案通篇中，參考關於化合物、組合物及方法之各個實施例。所述之各個實施例意欲提供多個說明性實例且不應理解為替代種類之說明。而應注意，本文所提供之各個實施例之說明可具有重疊範圍。本文所論述之實施例僅具說明性且不意欲限制本發明之範圍。 應理解，本文所使用之術語僅係出於闡述具體實施例之目的且不意欲限制本發明之範圍。在本說明書及隨後申請專利範圍中，將參考多個應定義為具有以下含義之術語。 除非另外規定，否則如本文所用「烷基」係指具有1至14個碳原子且在一些實施例中具有1至6個碳原子之單價飽和脂肪族烴基。術語「烷基」包括(例如)直鏈及具支鏈烴基，例如甲基(CH3 -)、乙基(CH3 CH2 -)、正丙基(CH3 CH2 CH2 -)、異丙基((CH3 )2 CH-)、正丁基(CH3 CH2 CH2 CH2 -)、異丁基((CH3 )2 CHCH2 -)、第二丁基((CH3 )(CH3 CH2 )CH-)、第三丁基((CH3 )3 C-)、正戊基(CH3 CH2 CH2 CH2 CH2 -)及新戊基((CH3 )3 CCH2 -)。 「烷氧基」係指基團-O-烷基，其中烷基在本文中定義。烷氧基包括(例如)甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第三丁氧基、第二丁氧基、正戊氧基、嗎啉基丙氧基、六氫吡啶基乙氧基。 「胺基」係指基團-NR6 R7 ，其中R6 及R7 獨立地選自氫、烷基、烯基、芳基、環烷基、雜環烷基、雜芳基、雜環基，且其中R6 及R7 視情況與鍵結至其之氮連接在一起以形成雜環基。倘若R6 係氫且R7 係烷基，則胺基在本文中有時係指烷基胺基。倘若R6 及R7 係烷基，則胺基在本文中有時係指二烷基胺基。當提及單取代胺基時，其意指R6 或R7 係氫但並非皆係氫。當提及二取代胺基時，其意指R6 及R7 皆非氫。 「芳基」係指具有5至14個碳原子而無環雜原子且具有單環(例如，苯基)或多個縮合(稠合)環(例如，萘基或蒽基)之芳香族基團。對於包括稠合、橋接及螺環系統(其具有無環雜原子之芳香族環及非芳香族環)之多環系統而言，當附接點位於芳香族碳原子處時，術語「芳基」或「Ar」適用(例如，5,6,7,8四氫萘-2-基係芳基，此乃因其附接點係位於芳香族苯基環之2位處)。 「環烷基」係指具有3至14個碳原子而無環雜原子且具有包括稠合、橋接及螺環系統之單環或多環之飽和或部分飽和環狀基團。對於具有無環雜原子之芳香族環及非芳香族環之多環系統而言，當附接點位於非芳香族碳原子處時，術語「環烷基」適用(例如，5,6,7,8,-四氫萘-5-基)。術語「環烷基」包括環烯基，例如環己烯基。環烷基之實例包括(例如)金剛烷基、環丙基、環丁基、環己基、環戊基、環辛基、環戊烯基及環己烯基。包括多個二環烷基環系統之環烷基之實例係二環己基、二環戊基、二環辛基及諸如此類。 「鹵基」或「鹵素」係指氟、氯、溴及碘。 「鹵代烷基」係指烷基經1至9個鹵基(例如，當烷基具有3個碳原子時，例如經鹵素完全取代之第三丁基)或在一些實施例中經1至3個鹵基(例如，三氟甲基)取代。 「羥基(Hydroxy或hydroxyl)」係指基團-OH。 「雜芳基」係指具有1至14個碳原子及1至6個選自以下各項之雜原子之芳香族基團：氧、氮、硫、磷、矽及硼，且其包括單環(例如，咪唑基)及多環系統(例如，苯并咪唑-2-基及苯并咪唑-6-基)。對於包括稠合、橋接及螺環系統(其具有芳香族環及非芳香族環)之多環系統而言，若存在至少一個環雜原子且附接點在芳香族環之原子處，則術語「雜芳基」適用(例如，1,2,3,4-四氫喹啉-6-基及5,6,7,8-四氫喹啉-3-基)。在一些實施例中，雜芳基之氮及/或硫環原子視情況經氧化以提供N-氧化物(N→O)、亞磺醯基或磺醯基部分。更具體而言，術語雜芳基包括(但不限於)吡啶基、呋喃基、噻吩基、噻唑基、異噻唑基、三唑基、咪唑基、咪唑啉基、異噁唑基、吡咯基、吡唑基、嗒嗪基、嘧啶基、嘌呤基、酞嗪基、萘基、萘基吡啶基、噁唑基、喹啉基、苯并呋喃基、四氫苯并呋喃基、異苯并呋喃基、苯并噻唑基、苯并異噻唑基、苯并三唑基、吲哚基、異吲哚基、吲嗪基、二氫吲哚基、吲唑基、吲哚啉基、苯并噁唑基、喹啉基、異喹啉基、喹嗪基、喹唑啉基、喹喔啉基、四氫喹啉基、異喹啉基、喹唑啉酮基、苯并咪唑基、苯并異噁唑基、苯并噻吩基、苯并嗒嗪基、蝶啶基、咔唑基、哢啉基、啡啶基、吖啶基、啡啉基、吩嗪基、吩噁嗪基、吩噻嗪基及鄰苯二甲醯亞胺基。 「雜環狀」或「雜環」或「雜環烷基」或「雜環基」係指具有1至14個碳原子及1至6個選自氮、硫、磷或氧之雜原子之飽和或部分飽和環狀基團，且包括單環及包括稠合、橋接及螺環系統之單環及多環系統。對於具有芳香族及/或非芳香族環之多環系統而言，當存在至少一個環雜原子且附接點位於非芳香族環之原子處時，術語「雜環狀」、「雜環」、「雜環烷基」或「雜環基」適用(例如，1,2,3,4-四氫喹啉-3-基、5,6,7,8-四氫喹啉-6-基及十氫喹啉-6-基)。在一個實施例中，雜環基之氮、磷及/或硫原子視情況經氧化以提供N-氧化物、磷雜環己烷氧化物(phosphinane oxide)、亞磺醯基、磺醯基部分。更具體而言，雜環基包括(但不限於)四氫吡喃基、六氫吡啶基、六氫吡嗪基、3-吡咯啶基、2-吡咯啶酮-1-基、嗎啉基及吡咯啶基。指示碳原子數之前綴(例如，C3 -C10 )係指雜環基部分中除雜原子數之外之碳原子總數。 雜環及雜芳基之實例包括(但不限於)氮雜環丁烷、吡咯、咪唑、吡唑、吡啶、吡嗪、嘧啶、嗒嗪、吡啶酮、吲嗪、異吲哚、吲哚、二氫吲哚、吲唑、嘌呤、喹嗪、異喹啉、喹啉、酞嗪、萘基吡啶、喹喏啉、喹唑啉、㖕啉、喋啶、咔唑、哢啉、菲啶、吖啶、菲咯啉、異噻唑、吩嗪、異噁唑、吩噁嗪、吩噻嗪、咪唑啶、咪唑啉、萘、噁唑、側氧基吡咯啶、六氫吡啶、六氫吡嗪、吲哚啉、酞醯亞胺、喹啉、1,2,3,4-四氫異喹啉、4,5,6,7-四氫苯并[b]噻吩、噻唑、環戊并噻唑、噻唑啶、噻吩、苯并[b]噻吩、嗎啉、硫嗎啉(亦稱為硫代嗎啉)、六氫吡啶、吡咯啶及四氫呋喃基。 「稠合雜環狀」係指藉由替代環烷基環結構中不同碳原子上之兩個氫原子所形成之3員至10員環狀取代基，如藉由以下環戊并噻唑結構所例示：。 「稠合芳基及稠合雜芳基」係指在芳基結構或雜芳基結構中之不同碳原子上與5員至6員芳基、雜芳基或環烷基環稠合之5員至6員芳基結構或雜芳基結構，其可在稠合芳基或稠合雜芳基中碳之任一個上經取代並在碳中之另一個上與核心分子連接，如藉由以下環戊基噻唑、喹啉或萘結構所例示：、、。 如本文所用「化合物(Compound、compounds)」及「化學實體(chemical entity、chemical entities)」係指由本文所揭示之通式、彼等通式中之任一亞屬及任何形式之通式及子通式內之化合物所涵蓋之化合物，包括一或多種化合物之外消旋物、立體異構物及互變異構物。 術語「雜原子」意指氮、氧或硫，且包括氮之任一氧化形式(例如，N(O) {N+ —O− })及硫之任一氧化形式(例如，S(O)及S(O)2 )及任一鹼性氮之四級銨化形式。 「噁唑」及「噁唑基」係指含有一個氮及一個氧作為雜原子之5員雜環，並亦含有三個碳並可在三個碳中之一個上經取代且可在三個碳中之另一個上與另一分子連接，如藉由以下結構中之任一者所例示，其中在此所顯示之噁唑啶酮基團鍵結至母體分子，此係藉由結合至母體分子之鍵中之波形線指示：、。 「側氧基吡咯啶」及「側氧基吡咯啶基」係指含有氮及4個碳之5員雜環，其在雜環中碳之任一個上由羰基取代且可在雜環中之另一個碳上與另一取代基連接，如藉由以下結構所例示：。 「吡啶」及「吡啶基」係指含有1個氮及5個碳之6員雜芳基環，其亦可在雜芳基環中碳之一或多個上經取代且可在雜芳基環中之另一個碳上與另一取代基連接，如藉由以下結構所例示：、、、。 「噻唑」及「噻唑基」係指在雜芳基環中含有1個硫及1個氮及在雜芳基環中含有3個碳之5員雜芳基，其亦可在雜芳基環中碳之一或多個上經取代且可在雜芳基環中之另一個碳上與另一取代基連接，如藉由以下結構所例示：。 「嘧啶」及「嘧啶基」係指在雜芳基環中含有兩個氮且在雜芳基環中含有4個碳之6員雜芳基環，其可在雜芳基環中碳之一或多個上經取代且可在雜芳基環中之另一個碳上與另一取代基連接，如藉由以下結構所例示：。 「外消旋物」係指鏡像異構物之混合物。在本發明之實施例中，式I化合物或其醫藥上可接受之鹽鏡像異構富集一種鏡像異構物，其中所提及之所有手性碳係呈一種構形。一般而言，提及鏡像異構富集之化合物或鹽時，其意指指示指定鏡像異構物將包含化合物或鹽之所有鏡像異構物總重量之50重量%以上。 化合物之「溶劑合物(solvate或solvates)」係指如上文所定義之彼等化合物，其經結合至化學計量或非化學計量量之溶劑。化合物之溶劑合物包括所有形式之化合物之溶劑合物。在某些實施例中，溶劑具揮發性、無毒性及/或可接受以痕量投與人類。適宜溶劑合物包括水。 「立體異構物(stereoisomer或stereoisomers)」係指一或多個立體中心之手性不同之化合物。立體異構物包括鏡像異構物及非鏡像異構物。 「互變異構物」係指質子位置不同之化合物之替代形式，例如酮-烯醇及亞胺-烯胺互變異構物，或含有環原子(其經附接至環-NH-部分及環=N-部分二者)之雜芳基之互變異構形式，例如吡唑、咪唑、苯并咪唑、三唑及四唑。 「醫藥上可接受之鹽」係指源自業內熟知之各種有機及無機相對離子之醫藥上可接受之鹽，且包括(僅作為實例)鈉、鉀、鈣、鎂、銨及四烷基銨及當分子含有鹼性官能基時，有機或無機酸之鹽，例如鹽酸鹽、氫溴酸鹽、酒石酸鹽、甲磺酸鹽、乙酸鹽、馬來酸鹽及草酸鹽。適宜鹽包括闡述於P. Heinrich Stahl, Camille G. Wermuth (編輯), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002中之彼等。 「患者」或「個體」係指哺乳動物且包括人類及非人類哺乳動物。 「治療(treating或treatment)」患者之疾病係指1)預防易患或尚未顯示疾病症狀之患者中疾病之發生；2)抑制疾病或停止其發展；或3)改善或引起疾病之消退。 只要在毗鄰實線所表示之單鍵出現虛線，則該虛線代表該位置處之可選雙鍵。同樣，只要虛線圓出現於由實線或實線圓所表示之環結構內，則虛線圓代表一至三個根據其適當化合價配置之可選雙鍵，此慮及環是否在環周圍具有任何可選取代，如由熟習此項技術者所將瞭解。舉例而言，以下結構中之虛線可指示該位置之雙鍵或該位置之單鍵：。 類似地，下文之環A可係無任何雙鍵之環己基環，或其亦可係具有三個雙鍵之苯基環，該三個雙鍵配置於任一位置但仍繪示苯基環之適當化合價。同樣，在下文之環B中，X1 -X5 中之任一者皆可選自：C、CH或CH2 、N或NH，且虛線圓意指環B可係環己基或苯基環或無雙鍵之含N雜環或具有一至三個雙鍵之含N雜芳基環，該一至三個雙鍵配置于任一位置但仍繪示適當化合價：。 倘若特定化合物或通式經繪製具有芳香族環，例如芳基或雜芳基環，則熟習此項技術者將瞭解，任何雙鍵之特定芳香族定位係等效位置之組合，即使其在化合物之間或式之間經繪製於不同定位。舉例而言，在以下兩個吡啶環(A及B)中，雙鍵係以不同定位繪製，然而已知其係相同結構及化合物：。 除非另外指示，否則本文並未明確定義之取代基之命名法係藉由命名該官能基之末端部分及之後朝向附接點之毗鄰官能基來達成。舉例而言，取代基「芳基烷基氧基羰基」係指基團(芳基)-(烷基)-O-C(O)-。在諸如「-C(Rx )2 」之術語中，應理解若Rx 定義為具有一種以上可能屬性，則兩個Rx 基團可相同或其可不同。另外，某些取代基經繪製為-Rx Ry ，其中「-「指示毗鄰母體分子之鍵且Ry 為官能基之末端部分。類似地，應理解以上定義並不意欲包括不允許之取代模式(例如，甲基經5個氟基取代)。此等不允許之取代模式為熟習此項技術者所熟知。 根據本發明之一個實施例提供具有下式IA結構之化合物：式IAA 係 芳基或雜芳基；R1 、 R′1 及 R′′1 獨立地選自H；C1-C6-烷基；鹵基；鹵代烷基；NR6 R7 ；OR8 ；SR9 ；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8環烷基或C3-C8雜環烷基；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、硫代烷基取代之C3-C8環烷基或C3-C8雜環烷基；R2 係 C1-C6-烷基；經芳基、雜芳基、C1-C6-烷基、C3-C8-環烷基、C3-C8雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基、NR6 R7 取代之C1-C6-烷基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、鹵基取代烷氧基取代之C3-C8-環烷基，或該C3-C8環烷基與芳基稠合以形成二環或三環稠合環；C3-C8-雜環烷基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、鹵基取代烷氧基取代之C3-C8-環烷基或C3-C8-雜環烷基。或該C3-C8雜環烷基與芳基稠合以形成二環或三環稠合環；其中該芳基、雜芳基、C1-C6-烷基、C3-C8-環烷基、C3-C8雜環烷基或NR6 R7 進一步視情況經鹵基、烷氧基、鹵基取代烷氧基、NR6 R7 、OR8 、SR9 取代；R3 及 R4 獨立地係 H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基；或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之5員至10員環結構；R5 係C1-C6烷基；經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、芳基、雜芳基取代之C1-C6烷基；或視情況經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8環烷基；R6 及 R7 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8-環烷基或C3-C8-雜環烷基；或R6 與R7 一起形成視情況經鹵基、鹵代烷基、胺基、NR6 R7 、OR8 、SR9 取代之3員至10員環烷基或雜環烷基環；芳基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之芳基；雜芳基；或經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之雜芳基；且R8 及 R9 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基， 或其鹽。 在某些實施例中提供式IA化合物，式IA 其中：A 係 苯基或噁唑基；R1 、 R′1 及 R′′1 獨立地選自H；C1-C6-烷基；鹵基；鹵代烷基；NR6 R7 ；OR8 ；SR9 ；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C1-C6烷基；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8環烷基或C3-C8雜環烷基；R2 係 C1-C6-烷基、經芳基、雜芳基、C1-C6-烷基、C1-C6-環烷基、C3-C8雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6-烷基；NR6 R7 ；其中芳基、雜芳基、C1-C6-烷基、C3-C8-環烷基、C3-C8雜環烷基或NR6 R7 進一步視情況經鹵基、烷氧基、鹵基取代烷氧基、O、N、S、NR6 R7 、OR8 、SR9 取代；R3 及 R4 獨立地係 H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基；經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基；C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-雜環烷基；或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之5員至10員環結構；R5 係 C1-C6烷基；經C1-C6-烷基、C3-C8環烷基、C3-C8-雜環烷基、芳基、雜芳基取代之C1-C6烷基；或C3-C8環烷基；R6 及 R7 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8-環烷基或C3-C8-雜環烷基；或R6 與R7 一起形成視情況經鹵基、鹵代烷基、胺基、NR6 R7 、OR8 、SR9 取代之3員至10員環烷基或雜環烷基環；芳基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之芳基；雜芳基；或經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之雜芳基；且R8 及 R9 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基，或其鹽。 一個實施例提供式IA化合物，式IA 其中：A 係 苯基；R1 、 R′1 及 R′′1 獨立地選自H；C1-C6-烷基；鹵基；鹵代烷基；NR6 R7 ；OR8 ；SR9 ；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C1-C6烷基；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8環烷基或C3-C8雜環烷基；R2 係 C1-C6-烷基；經六氫吡啶基取代之C1-C6-烷基；嗎啉基；茚基；苯基；噻唑基；吡啶基；嘧啶基；喹啉基；萘基；C1-C6-烷基、烷氧基；鹵基取代烷氧基；NR6 R7 ；其中六氫吡啶基、嗎啉基、茚基、苯基、噻唑基、吡啶基、嘧啶基、喹啉基、萘基、NR6 R7 進一步視情況經鹵基、O、N、S、NR6 R7 、OR8 、SR9 取代；R3 及 R4 獨立地係 H、C1-C6-烷基；經C1-C6-烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之5員至10員環結構；R5 係 C1-C6烷基；經C1-C6-烷基、C3-C8環烷基或C3-C8雜環烷基、苯基取代之C1-C6烷基；或經C1-C6-烷基取代之C3-C8-環烷基或C3-C8-雜環烷基；R6 及 R7 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基取代之C1-C6烷基；或R6 與R7 一起形成視情況經鹵基、鹵代烷基取代之3員至10員環烷基或雜環烷基環；且R8 及 R9 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基，或其鹽。 在本發明之另一實施例中提供具有如所述之式I或式IA結構之化合物，其中R3 係H且R4 選自由C1-C6烷基及經取代之C1-C6烷基組成之群或R3 與R4 一起形成環結構。 在本發明之另一實施例中提供具有如所述之式I或式IA結構之化合物，其中R5 選自由以下各項組成之群：C1-C6-烷基；經C1-C6-烷基、苯基取代之C1-C6烷基；經C1-C6-烷基取代之C3-C8-環烷基或C3-C8-雜環烷基。 在本發明之另一實施例中提供具有式I或式IA結構之化合物，其中A選自由以下組成之群：芳基及經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基或硫代烷基取代之芳基。 在本發明之另一實施例中提供具有式I或式IA結構之化合物，其中A選自由以下組成之群：雜芳基及經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基或硫代烷基取代之雜芳基。 在本發明之另一實施例中提供具有式I或式IA結構之化合物，其中A選自由以下組成之群：苯基及經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基或硫代烷基取代之苯基。 在本發明之另一實施例中提供具有式I或式IA結構之化合物，其中A選自由以下組成之群：噁唑基及經取代之噁唑基。 在本發明之另一實施例中提供選自由以下各項組成之群之化合物： N-[(1S)-1-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(二甲基胺基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-(六氫吡啶-1-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-(嗎啉-4-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[4-(三氟甲基)六氫吡啶-1-基]乙基]胺基甲酸苄基酯； N-[(1S)-2-(4,4-二氟六氫吡啶-1-基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-2-(4-氟六氫吡啶-1-基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[4-(三氟甲基)六氫吡啶-1-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(4,4-二氟六氫吡啶-1-基)乙基]胺基甲酸苄基酯； N-[(1S)-2-[(環丙基甲基)(甲基)胺基]-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(環戊基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[4-(三氟甲基)六氫吡啶-1-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[甲基(2,2,2-三氟乙基)胺基]乙基]胺基甲酸苄基酯； N-[(2S)-1-[(2S)-4,4-二乙基-2-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}吡咯啶-1-基]-1-側氧基-3-[4-(三氟甲基)六氫吡啶-1-基]丙-2-基]胺基甲酸苄基酯； N-[(1S)-2-(4-氟苯基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-2-環戊基乙基]胺甲醯基}-2-(喹啉-5-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-{[(1S)-1-苯基乙基]胺甲醯基}丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-(吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-3-甲基-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}丁基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-3-苯丙基]胺基甲酸苄基酯； N-[2-(6-甲氧基吡啶-2-基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S,2S)-2-甲氧基-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}丙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[4-(三氟甲基)嘧啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-2-(5-氟吡啶-2-基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[6-(三氟甲基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[5-(三氟甲基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-{[(1S)-1-環己基乙基]胺甲醯基}-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-(3-甲基苯基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[4-(三氟甲基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(1,3-噻唑-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[4-(丙-2-基氧基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[6-(三氟甲基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(1,3-噻唑-4-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[6-(三氟甲氧基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[6-(三氟甲氧基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[5-(三氟甲基)嘧啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[4-(三氟甲基)-1,3-噻唑-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(5-甲基-1,3-噻唑-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(6-甲氧基吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(2-甲氧基-1,3-噻唑-4-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-{4H,5H,6H-環戊并[d][1,3]噻唑-2-基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(6-甲氧基-4-甲基吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(6-乙氧基吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-2-環己基乙基]胺甲醯基}-2-(萘-1-基)乙基]胺基甲酸{4-[3-(嗎啉-4-基)丙氧基]苯基}甲酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(萘-1-基)乙基]胺基甲酸{4-[2-(六氫吡啶-1-基)乙氧基]苯基}甲酯； N-[(1S)-2-(4-氟苯基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸(4-{[環丙基(甲基)胺基]甲基}苯基)甲酯； N-[(S)-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}(2,3-二氫-1H-茚-2-基)甲基]胺基甲酸(5-甲基-1,2-噁唑-3-基)甲基酯； N-[(2S)-1-[(1S,3aR,6aS)-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}-八氫環戊并[c]吡咯-2-基]-3-(4-氟苯基)-1-側氧基丙-2-基]胺基甲酸苄基酯； N-[(2S)-1-側氧基-1-[(3S)-3-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}-2-氮雜螺[4.4]壬-2-基]-3-(吡啶-2-基)丙-2-基]胺基甲酸苄基酯；及 N-[(2S)-1-[(2S)-4,4-二乙基-2-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}吡咯啶-1-基]-3-(4-氟苯基)-1-側氧基丙-2-基]胺基甲酸苄基酯或其鹽。 本文所闡述之化合物可以具體幾何異構或立體異構形式存在。本發明涵蓋所有此等化合物，包括順式-及反式-異構物、(-)-及(+)-鏡像異構物、(R)-及(S)-鏡像異構物、非鏡像異構物、(D)-異構物、(L)-異構物、其外消旋混合物、及其其他混合物(例如，鏡像異構或非鏡像異構富集之混合物)，其皆落在本發明之範圍內。在諸如烷基等取代基中可存在額外之不對稱碳原子。所有此等異構物以及其混合物皆意欲包括在本發明中。 光學活性(R)-及(S)-異構物以及d及l異構物可使用手性合成組元或手性試劑來製備或使用習用技術來進行拆分。舉例而言，若期望本發明化合物之特定鏡像異構物，則其可藉由不對稱合成或藉由利用手性輔助劑衍生來製備，其中分離出所得非鏡像異構混合物並解離輔助基團以提供純期望之鏡像異構物。或者，倘若分子含有鹼性官能基(例如，胺基)或酸性官能基(例如，羧基)，則非鏡像異構鹽可利用適當光學活性酸或鹼形成，隨後藉由業內已知之分段結晶或層析方式拆分由此形成之非鏡像異構物並隨後回收純鏡像異構物。另外，鏡像異構物及非鏡像異構物之分離通常係使用採用手性固定相之層析，視情況與化學衍生組合來實現(例如，自胺形成胺基甲酸酯)。 在本發明之另一實施例中提供式I或式IA化合物用於療法中。 在本發明之另一實施例中提供式I或式IA化合物用於治療病毒感染。 在本發明之另一實施例中提供式I或式IA化合物之用途，其用於製造供治療人類之病毒感染用之藥劑。 在本發明之另一實施例中提供醫藥組合物，其包含醫藥上可接受之稀釋劑及治療有效量之如式I或式IA中所定義之化合物。 在一個實施例中，含有式I或式IA化合物或其鹽之醫藥調配物係適用於非經腸投與之調配物。在另一實施例中，調配物係長效非經腸調配物。在另一實施例中，調配物係奈米顆粒調配物。 在一個實施例中，含有式I或式IA化合物或其鹽之醫藥調配物係適用於經口、直腸、局部或靜脈內投與之調配物，其中該醫藥調配物視情況包含醫藥上可接受之載劑、佐劑或媒劑中之任一或多者。 在一個實施例中，式I或式IA化合物經調配用於經口投與，且可以習用製劑之形式投與，例如以下列各項中之任一劑型投與：固體藥劑，例如錠劑、粉末、顆粒、膠囊及諸如此類；水性藥劑；油性懸浮液；或液體藥劑，例如糖漿及酏劑。在一個實施例中，式I或式IA化合物經調配用於非經腸投與，且可以水性或油性懸浮液可注射劑或滴鼻劑之形式投與。在利用式I或式IA化合物製備非經腸調配物時，可隨意使用習用賦形劑、黏合劑、潤滑劑、水性溶劑、油性溶劑、乳化劑、懸浮劑、防腐劑、穩定劑及諸如此類。作為抗病毒藥物，特定而言經口藥劑較佳。式I或式IA化合物之製劑可藉由將治療有效量之式I或式IA化合物與醫藥上可接受之載劑或稀釋劑組合(例如，混合)來製備。 適用於經口投與之醫藥調配物可以如下形式呈遞：離散單元，例如膠囊或錠劑；粉劑或顆粒；於水性或非水性液體中之溶液或懸浮液；可食用發泡體或發泡物質；或水包油型液體乳液或油包水型液體乳液。 舉例而言，對於以錠劑或膠囊形式經口投與而言，可將式I或式IA化合物與經口、無毒性醫藥上可接受之惰性載劑(例如，乙醇、甘油、水及諸如此類)組合。粉末係藉由將式I或式IA化合物粉碎成適宜細粒度並與以類似方式粉碎之醫藥載劑(例如，可食用碳水化合物，如例如澱粉或甘露醇)混合來製備。矯味劑、防腐劑、分散劑及著色劑亦可存在。 膠囊係藉由製備如上文所述之粉末混合物並填充成型明膠外殼來製得。可在填充操作之前向粉末混合物中添加助流劑及潤滑劑(例如，膠質二氧化矽、滑石粉、硬脂酸鎂、硬脂酸鈣或固體聚乙二醇)。亦可添加崩解劑或增溶劑(例如，瓊脂、碳酸鈣或碳酸鈉)以在攝入膠囊時改良藥劑之可用性。 此外，在期望或需要時，亦可將適宜黏合劑、潤滑劑、崩解劑及著色劑納入混合物中。適宜黏合劑包括澱粉、明膠、天然糖(例如，葡萄糖或β-乳糖)、玉米甜味劑、天然及合成膠(例如，阿拉伯膠、磺蓍膠或海藻酸鈉)、羧甲基纖維素、聚乙二醇、蠟及諸如此類。用於該等劑型中之潤滑劑包括油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉及諸如此類。崩解劑包括(但不限於)澱粉、甲基纖維素、瓊脂、膨潤土、黃原膠及諸如此類。錠劑係藉由(例如)製備粉末混合物、製粒或擊壓、添加潤滑劑及崩解劑並壓製成錠劑來調配。粉末混合物係藉由混合適宜粉碎之化合物與如上文所述之稀釋劑或鹼、及視情況黏合劑(例如，羧甲基纖維素、海藻酸鹽、明膠或聚乙烯吡咯啶酮)、溶液阻滯劑(例如，石蠟)、再吸收加速劑(例如，四級鹽)及/或吸收劑(例如，膨潤土、高嶺土或磷酸氫鈣)製備。粉末混合物可藉由用黏合劑(例如，糖漿、澱粉膏糊、阿卡迪亞(acadia)黏液或纖維素或聚合物材料之溶液)潤濕並加壓穿過網篩來製粒。作為製粒之替代方案，可使粉末混合物通過錠劑機且結果係使成形不佳之團塊破碎成顆粒。可藉助添加硬脂酸、硬脂酸鹽、滑石粉或礦物油對顆粒進行潤滑以防止黏至錠劑形成模具。然後將經潤滑混合物壓製成錠劑。亦可將本發明化合物與自由流動惰性載劑組合且不經歷製粒或擊壓步驟即直接壓製成錠劑。亦可提供由蟲膠之密封殼、糖或聚合物材料之塗層及蠟之拋光塗層組成之透明或不透明保護塗層。可向該等塗層中添加染料以區分不同單位劑量。 諸如溶液、糖漿及酏劑之口服液可製成劑量單位形式，以使給定量含有預定量之化合物。糖漿可藉由將化合物溶解於經適宜調味之水溶液中製備，而酏劑係透由使用無毒性的醇媒劑(alcoholic vehicle)加以製備。懸浮液可藉由將化合物分散於無毒性媒劑中加以調配。亦可添加增溶劑及乳化劑(例如，乙氧基化異硬脂基醇及聚氧化乙烯山梨醇醚)、防腐劑、矯味添加劑(例如，薄荷油或天然甜味劑或糖精或其他人造甜味劑及諸如此類)。 在適當情況下，用於經口投與之劑量單位調配物可經微囊化。式I或式IA化合物之調配物亦可經製備以延長或持續釋放化合物，例如藉由將顆粒材料塗佈或包埋於聚合物、蠟或諸如此類中。 式I或式IA化合物或其鹽、溶劑合物或水合物亦可以脂質體遞送系統之形式投與，例如小單層囊泡、大單層囊泡及多層囊泡。脂質體可自多種磷脂形成，例如膽固醇、硬脂胺或磷脂醯膽鹼。 式I或式IA化合物或其鹽、溶劑合物或水合物亦可藉由使用單株抗體作為與化合物分子偶合之個別載劑來遞送。亦可將化合物與作為可靶向藥物載劑之可溶性聚合物偶合。此等聚合物可包括聚乙烯基吡咯啶酮、吡喃共聚物、聚羥丙基甲基丙烯醯胺-酚、聚羥基乙基天冬醯胺-酚或經棕櫚醯基殘基取代之聚氧化乙烯聚離胺酸。此外，可將化合物與一類可用於達成控制釋放藥物之生物可降解聚合物偶合，例如聚乳酸、聚ε己內酯、聚羥基丁酸、聚原酸酯、聚縮醛、聚二氫吡喃、聚氰基丙烯酸酯及水凝膠之交聯或兩親性嵌段共聚物。 適用於經皮投與之醫藥調配物可以意欲保持與接受者表皮長期密切接觸之離散貼片形式呈遞。舉例而言，式I或式IA化合物可藉由離子電滲自貼片遞送，如Pharmaceutical Research, 3(6), 318 (1986)中所概述。 適用於局部投與之醫藥調配物可調配為軟膏、乳膏、懸浮液、乳液、粉末、溶液、糊劑、凝膠、噴霧、氣溶膠或油。當活性成分於軟膏中調配時，其可與石蠟或水混溶性軟膏基質一起使用。或者，活性成分可於乳膏中與水包油型乳膏基質或油包水型基質調配在一起。 適用於直腸投與之醫藥調配物可以栓劑或灌腸劑形式呈遞。 其中載劑係固體之適用於經鼻投與之醫藥調配物包括粒徑在(例如) 20微米至500微米範圍內之粗粉末，其係以吸取鼻煙之方式投與，即藉由自保持緊靠鼻子之粉末容器經由鼻道快速吸入。其中載劑係液體之適宜調配物係用於以鼻噴霧劑形式或以滴鼻劑形式投與，包括活性成分之水性或油溶液。 適用於藉由吸入投與之醫藥調配物包括細顆粒粉劑或霧劑，其可藉助多種類型之計量劑量加壓溶膠、霧化器或吹入器來生成。 適用於非經腸投與之醫藥調配物包括水性及非水性無菌注射溶液，其可含有抗氧化劑、緩衝劑、抑菌劑及可使調配物與預期受體之血液等滲之溶質；及水性及非水性無菌懸浮液，其可包括懸浮劑及增稠劑。該等調配物可以單位劑量或多劑量容器(例如，密封安瓿及小瓶)呈遞且可儲存於冷凍乾燥(凍乾)條件下，僅需在即將使用前添加無菌液體載劑(例如，注射用水)。臨時配製注射溶液及懸浮液可自無菌粉末、顆粒及錠劑製備。 應理解除上文所特別提及之成分外，本文所述調配物可包括關於所討論調配物類型之其他業內習用藥劑，舉例而言適於經口投與之彼等可包括矯味劑。 式I或式IA化合物之治療有效量將取決於多個因素，包括(例如)人類或其他動物之年齡及體重、需要治療之精確病況及其嚴重程度、調配物之性質及投與途徑，且最終將由會診醫師或獸醫斷定。其鹽或水合物之有效量可確定為式I或式IA化合物或其鹽、溶劑合物或水合物本身之有效量之比例。 本發明之實施例提供：以單一藥劑形式或與(a)有效治療或預防鼻病毒、冠狀病毒、小核糖核酸病毒及/或諾羅病毒感染之另一藥劑(b)改良免疫反應及穩健性之另一藥劑或(c)減少發炎及/或疼痛之另一藥劑之組合形式向健康或病毒感染患者投與式I或式IA化合物。 據信式I或式IA化合物或其鹽、溶劑合物或水合物具有藉由抑制病毒3C或3C蛋白酶，從而干擾或預防宿主細胞中經轉譯病毒基因體之多蛋白進展，使得病毒無法複製來預防、停止或減少鼻病毒、冠狀病毒、小核糖核酸病毒及/或諾羅病毒之效應之活性。 因此，提供治療哺乳動物之對3C或3CL蛋白酶抑制敏感之病毒之方法，其包括向該哺乳動物投與治療有效量之式I或式IA化合物或其醫藥上可接受之鹽、溶劑合物或水合物。在一個實施例中，病毒係鼻病毒。在一個實施例中，病毒係冠狀病毒。在一個實施例中，病毒係小核糖核酸病毒。在一個實施例中，病毒係諾羅病毒。 在另一實施例中，蛋白酶係3C蛋白酶。在另一實施例中，蛋白酶係3CL蛋白酶。在一個實施例中，哺乳動物係人類。 在本發明之另一態樣中提供抑制哺乳動物中病毒3C蛋白酶或病毒3CL蛋白酶之方法，其包括向該哺乳動物投與治療有效量之式I或式IA化合物或其醫藥上可接受之鹽、溶劑合物或水合物。在一個實施例中，哺乳動物係人類。 在另一態樣中，本發明提供治療呼吸障礙(包括COPD、氣喘、纖維化、慢性氣喘及急性氣喘、繼發於環境暴露之肺疾病、急性肺感染、慢性肺感染、α1抗胰蛋白酶疾病、囊性纖維化及自體免疫疾病)之方法，其包含向有需要之人類投與式I化合物或式IA化合物或其鹽、特別地其醫藥上可接受之鹽。 在一態樣中，本發明係關於治療COPD之方法，其包含向有需要之人類投與式I化合物或式IA化合物或其鹽、特別地其醫藥上可接受之鹽。 在又一態樣中，本發明提供式I化合物或式IA化合物或其鹽、特別地其醫藥上可接受之鹽之用途，其用於治療呼吸障礙，包括COPD、氣喘、纖維化、慢性氣喘及急性氣喘、繼發於環境暴露之肺疾病、急性肺感染、慢性肺感染、α1抗胰蛋白酶疾病、囊性纖維化及自體免疫疾病。 在一態樣中，本發明係關於式I化合物或式IA化合物或其鹽、特別地其醫藥上可接受之鹽之用途，其用於治療COPD。 在另一態樣中，本發明係關於式I化合物或式IA化合物或其鹽、特別地其醫藥上可接受之鹽之用途，其用於製造供治療呼吸障礙用之藥劑，該呼吸障礙包括COPD、氣喘、纖維化、慢性氣喘及急性氣喘、繼發於環境暴露之肺疾病、急性肺感染、慢性肺感染、α1抗胰蛋白酶疾病、囊性纖維化及自體免疫疾病。 在一態樣中，本發明係關於式I化合物或式IA化合物或其鹽、特別地醫藥上可接受之鹽之用途，其用於製造供治療COPD用之藥劑。 在另一態樣中，本發明係關於式I化合物或式IA化合物或其鹽、特別地其醫藥上可接受之鹽，其用於醫學療法中。本發明係關於式I化合物或式IA化合物或其鹽、特別地其醫藥上可接受之鹽，其用於療法中，特定地用於治療呼吸障礙，包括COPD、氣喘、纖維化、慢性氣喘及急性氣喘、繼發於環境暴露之肺疾病、急性肺感染、慢性肺感染、α1抗胰蛋白酶疾病、囊性纖維化及自體免疫疾病。 在一態樣中，本發明係關於式I化合物或式IA化合物或其鹽、特別地其醫藥上可接受之鹽，其用於治療COPD。 在其他實施例中，本發明化合物可與可用於預防或治療病毒疾病或相關病理生理學之一或多種抗病毒治療劑或消炎藥劑組合使用。因此，本發明化合物及其鹽、溶劑合物或其其他醫藥上可接受之衍生物可單獨或與其他抗病毒或消炎治療劑組合採用。式I或式IA化合物及其醫藥上可接受之鹽可與一或多種可用於預防或治療呼吸疾病、發炎性疾病、自體免疫疾病之其他藥劑組合使用，例如抗組織胺、皮質類固醇(例如，氟替卡松丙酸酯(fluticasone propionate)、氟替卡松呋喃甲酸酯(fluticasone furoate)、倍氯米松二丙酸酯(beclomethasone dipropionate)、布地奈德(budesonide)、環索奈德(ciclesonide)、莫米松呋喃甲酸酯(mometasone furoate)、曲安奈德(triamcinolone)、氟尼縮松(flunisolide))、NSAID、白三烯調節劑(例如，孟魯司特(montelukast)、紮魯司特(zafirlukast)、普侖司特(pranlukast))、類胰蛋白酶抑制劑、IKK2抑制劑、p38抑制劑、Syk抑制劑、蛋白酶抑制劑，例如彈性蛋白酶抑制劑、整聯蛋白拮抗劑(例如，β-2整聯蛋白拮抗劑)、腺苷A2a激動劑、介質釋放抑制劑，例如色甘酸鈉、5-脂肪加氧酶抑制劑(zyflo)、DP1拮抗劑、DP2拮抗劑、PI3K δ抑制劑、ITK抑制劑、LP (溶血磷脂)抑制劑或FLAP (5-脂肪加氧酶活化蛋白)抑制劑(例如，3-(3-(第三丁硫基)-1-(4-(6-乙氧基吡啶-3-基)苄基)-5-((5-乙基吡啶-2-基)甲氧基)-1H-吲哚-2-基)-2,2-二甲基丙酸鈉)、支氣管擴張劑(例如，毒蕈鹼拮抗劑、β-2激動劑)、胺甲喋呤(methotrexate)及類似藥劑；單株抗體療法，例如抗IgE、抗TNF、抗IL-5、抗IL-6、抗IL-12、抗IL-1及類似藥劑；細胞介素受體療法，例如依那西普(etanercept)及類似藥劑；抗原非特異性免疫療法(例如，干擾素或其他細胞介素/趨化介素、趨化介素受體調節劑，例如CCR3、CCR4或CXCR2拮抗劑、其他細胞介素/趨化介素激動劑或拮抗劑、TLR激動劑及類似藥劑)、適宜抗感染藥劑，包括抗生素藥劑、抗真菌劑藥劑、驅蟲藥劑、抗瘧疾藥劑、抗原生動物藥劑、抗結核症藥劑及抗病毒藥劑，包括在https://www.drugs.com/drug-class/anti-infectives.html所列之彼等。 適宜地，對於氣喘之治療，本發明之化合物或醫藥調配物可與消炎藥劑(例如，皮質類固醇或其醫藥調配物)一起投與。舉例而言，本發明化合物可與消炎藥劑(例如，皮質類固醇)一起調配於單一調配物中，例如吸入用乾粉調配物。或者，包含本發明化合物之醫藥調配物可結合包含消炎藥劑(例如，皮質類固醇)之醫藥調配物同時或依序投與。在一個實施例中，包含本發明化合物之醫藥調配物及包含消炎藥劑(例如，皮質類固醇)之醫藥調配物可各自保持在適於經由吸入同時投與兩種調配物之裝置中。 用於與本發明化合物一起投與之適宜皮質類固醇包括(但不限於)氟替卡松呋喃甲酸酯、氟替卡松丙酸酯、倍氯米松二丙酸酯、布地奈德、環索奈德、莫米松呋喃甲酸酯、曲安奈德、氟尼縮松及波尼松龍(prednisolone)。在本發明之一個實施例中，用於經由吸入與本發明化合物一起投與之皮質類固醇包括氟替卡松呋喃甲酸酯、氟替卡松丙酸酯、倍氯米松二丙酸酯、布地奈德、環索奈德、莫米松呋喃甲酸酯及氟尼縮松。 適宜地，對於COPD、COPD-支氣管擴張重疊症候群及支氣管擴張之治療，本發明之化合物或醫藥調配物可與一或多種支氣管擴張劑或其醫藥調配物一起投與。舉例而言，本發明化合物可與一或多種支氣管擴張劑一起調配於單一調配物中，例如吸入用乾粉調配物。或者，包含本發明化合物之醫藥調配物可結合包含一或多種支氣管擴張劑之醫藥調配物同時或依序投與。在另一替代選擇中，包含本發明化合物及支氣管擴張劑之調配物可結合包含另一支氣管擴張劑之醫藥調配物投與。在一個實施例中，包含本發明化合物之醫藥調配物及包含一或多種支氣管擴張劑之醫藥調配物可各自保持在適於經由吸入同時投與兩種調配物之裝置中。在另一實施例中，包含本發明化合物連同支氣管擴張劑之醫藥調配物及包含另一支氣管擴張劑之醫藥調配物可各自保持在適於經由吸入同時投與兩種調配物之一或多個裝置中。 用於與本發明化合物一起投與之適宜支氣管擴張劑包括(但不限於) β2-腎上腺素受體激動劑及抗副交感神經藥劑。β2-腎上腺素受體激動劑之實例包括(例如)維蘭特羅(vilanterol)、沙美特羅(salmeterol)、沙丁胺醇(salbutamol)、福莫特羅(formoterol)、沙甲胺醇(salmefamol)、非諾特羅(fenoterol)、卡莫特羅(carmoterol)、依坦特羅(etanterol)、那明特羅(naminterol)、克倫特羅(clenbuterol)、吡布特羅(pirbuterol)、氟丁特羅(flerbuterol)、瑞普特羅(reproterol)、班布特羅(bambuterol)、茚達特羅(indacaterol)、特布他林(terbutaline)及其鹽，例如沙美特羅之昔萘酸鹽(xinafoate，1-羥基-2-萘羧酸鹽)、沙丁胺醇之硫酸鹽或福莫特羅之富馬酸鹽。適宜抗副交感神經藥劑包括蕪地溴銨(umeclidinium，例如呈溴化物形式)、異丙托銨(ipratropium，例如呈溴化物形式)、氧托品(oxitropium，例如呈溴化物形式)及噻托溴銨(tiotropium，例如呈溴化物形式)。在本發明之一個實施例中，本發明化合物可與β2-腎上腺素受體激動劑(例如，維蘭特羅)及抗副交感神經藥劑(例如，蕪地溴銨)一起投與。 本發明化合物及任何其他醫藥上活性劑可一起或分開投與，且在分開投與時，投與可同時或以任一順序依序投與發生。將選擇本發明化合物及其他醫藥上活性劑之量以及投與之相對時機，以達成期望之組合治療效應。本發明化合物及其鹽、溶劑合物或其他醫藥上可接受之衍生物與其他治療劑之組合投與可藉由以以下形式同時投與來組合：(1)包括兩種化合物之整體醫藥組合物；或(2)各包括化合物中一者之單獨醫藥組合物。 或者，組合可以依序方式分開投與，其中首先投與一種治療劑且其次另一種或反之亦然。此依序投與可在時間上接近或遠離。將選擇式I或式IA化合物或其鹽及其他醫藥上活性劑之量及投與之相對時機，以達成期望之組合治療效應。 更具體而言，實施例提供如所述之方法，其包含投與選自以下各項之額外藥劑：抗病毒劑、抗生素、止痛劑、非類固醇消炎(NSAID)劑、抗真菌劑劑、抗寄生蟲劑、抗噁心劑、抗腹瀉劑或免疫抑制劑。在某些實施例中，抗病毒劑係抗肝炎A藥劑或抗反轉錄病毒劑。更具體而言，額外藥劑係以該醫藥調配物之部分單一劑型或以單獨劑型投與。 本發明係關於化合物、組合物及醫藥組合物，其具有作為針對病毒感染之新穎治療及/或預防性療法之效用。儘管不願受任一特定理論束縛，但認為本發明化合物能抑制鼻病毒及冠狀病毒自裂解酶(鼻病毒中之3C蛋白酶及冠狀病毒中之3CL (3C樣)蛋白酶)之活性，該等酶在將多蛋白前體蛋白質處理為功能性病毒蛋白及酶方面起重要作用。因此，預計3C及3CL蛋白酶之抑制降低鼻病毒及冠狀病毒在宿主細胞內複製之能力。藉由在病毒基因體於宿主細胞中經轉譯後破壞鼻病毒或冠狀病毒處理其多蛋白前體之能力，可治療及/或預防由鼻病毒及冠狀病毒感染所致之疾病及症狀。 因此，在本發明之另一實施例中提供治療或預防患有病毒感染之個體中病毒感染之方法，其包含向個體投與3C蛋白酶之抑制劑，其中該抑制劑係式I或式IA化合物。 在本發明之另一實施例中提供治療或預防患有病毒感染之個體中來自基於RNA之病毒之病毒感染之方法，其包含向個體投與3C蛋白酶之抑制劑，其中該抑制劑係式I或式IA化合物。 在本發明之另一實施例中提供治療患有鼻病毒感染之個體中冠狀病毒感染之方法，其包含向個體投與3C蛋白酶之抑制劑，其中該抑制劑係式I或式IA化合物。 在本發明之另一實施例中提供治療患有病毒感染之個體中病毒感染之方法，其包含向個體投與3C蛋白酶之選擇性化學抑制劑，其中該抑制劑包含來自表2之化合物。 在本發明之一個實施例中，本文所述之化合物可用於預防或治療由單鏈RNA病毒所引起之個體中之病毒感染。 RNA病毒係具有RNA (核糖核酸)作為其遺傳物質之病毒。此核酸通常係單鏈RNA (ssRNA)。RNA病毒可根據其RNA之義性或極性進一步歸類為負義及正義。正義病毒RNA與mRNA類似且由此可立即由宿主細胞轉譯。負義病毒RNA與mRNA互補，且由此必須在轉譯之前由RNA聚合酶轉化為正義RNA。因此，正義病毒之純化RNA可直接引起感染，但其可較整個病毒顆粒具較少感染性。負義病毒之純化RNA並非自身具感染性，此乃因其需要經轉移為正義RNA；每個病毒粒子可經轉移為若干正義RNA。 在本發明之一個實施例中，本文所述之化合物可用於預防或治療個體中由正義單鏈RNA病毒所引起之病毒感染。 在本發明之一個實施例中，本文所述之化合物可用於預防或治療個體中由負義單鏈RNA病毒所引起之病毒感染。 在一些實施例中提供治療個體中至少部分由小核糖核酸病毒科或冠狀病毒科病毒中之病毒所介導之病毒感染之方法，其包含向個體投與包含式I或式IA中任一者之化合物或其醫藥上可接受之鹽之組合物。 在又一態樣中，本發明之另一實施例提供抑制處於感染小核糖核酸病毒科或冠狀病毒科病毒中之病毒之風險下之個體中病毒感染進展之方法，其包含向個體投與治療有效量之式I或式IA化合物或其醫藥上可接受之鹽。 在又一態樣中，本發明之另一實施例提供預防處於感染小核糖核酸病毒科或冠狀病毒科病毒中之病毒之風險下之個體中病毒感染之方法，其包含向個體投與治療有效量之式I或式IA化合物或其醫藥上可接受之鹽。 在又一態樣中，本發明之另一實施例提供治療患有該病毒感染之個體中病毒感染之方法，其中病毒係為小核糖核酸病毒科或冠狀病毒科之病毒，其包含向個體投與治療有效量之式I或式IA化合物或其醫藥上可接受之鹽。 治療患有病毒感染之個體中病毒感染之方法，其包含向個體投與式I或式IA中任一者之化合物或其醫藥上可接受之鹽。 預防個體中病毒感染之方法包含向個體投與式I或式IA中任一者之化合物或其醫藥上可接受之鹽。 治療患有冠狀病毒感染之個體中冠狀病毒感染之方法包含向個體投與選自由以下各項組成之群之冠狀病毒3CL蛋白酶之化學抑制劑：229E 3CL蛋白酶、NL63 3CL蛋白酶、OC43 3CL蛋白酶、HKU1 3CL蛋白酶、SARS-CoV 3CL蛋白酶及MERS-CoV 3CL蛋白酶。 治療患有冠狀病毒感染之個體中冠狀病毒感染之方法包含向個體投與冠狀病毒229E 3CL蛋白酶之化學抑制劑。 治療患有冠狀病毒感染之個體中冠狀病毒感染之方法包含向個體投與冠狀病毒OC43 3CL蛋白酶之化學抑制劑。 治療患有冠狀病毒感染之個體中冠狀病毒感染之方法包含向個體投與冠狀病毒HKU1 3CL蛋白酶之化學抑制劑。 治療患有冠狀病毒感染之個體中冠狀病毒感染之方法包含向個體投與冠狀病毒SARS-CoV 3CL蛋白酶之化學抑制劑。 治療患有冠狀病毒感染之個體中冠狀病毒感染之方法包含向個體投與冠狀病毒MERS-CoV 3CL蛋白酶之化學抑制劑。 治療患有鼻病毒感染之個體中鼻病毒感染之方法包含向個體投與選自由HRV-15 3C蛋白酶及HRV-16 3C蛋白酶組成之群之鼻病毒3C蛋白酶之化學抑制劑。 治療患有鼻病毒感染之個體中鼻病毒感染之方法包含向個體投與鼻病毒HRV-15 3C之化學抑制劑。 治療患有鼻病毒感染之個體中鼻病毒感染之方法包含向個體投與鼻病毒HRV-16 3C之化學抑制劑。 在其他實施例中，本文所述之化合物可用於預防或治療個體中之病毒感染，其中該感染係由屬以下各科之病毒引起：光亮噬菌體病毒、裸露核糖核酸病毒、小核糖核酸病毒、雙順反子病毒、海洋核糖核酸病毒、伴生病毒、豇豆鑲嵌病毒、馬鈴薯Y病毒、杯狀病毒、星狀病毒、野田病毒、四病毒、黃症病毒、番茄叢矮病毒、冠狀病毒、動脈炎病毒、黃頭症病毒、黃病毒、披膜病毒、雀麥花葉病毒、蕪菁變黃鑲嵌病毒、修道院病毒、彎曲病毒、塞科病毒、桿菌狀核糖核酸病毒、傳染性家蠶軟化症病毒、溫州蜜柑矮縮病毒、櫻桃銼葉病毒、肝炎病毒、南方菜豆花葉病毒、幽影病毒、菸草鑲嵌病毒、菸草脆裂病毒、大麥病毒、真菌傳桿狀病毒、馬鈴薯病毒、花生叢簇病毒、甜菜壞死黃脈病毒、歐爾密病毒及懸鈎子病毒。 本發明揭示用於藉由以治療有效量投與式I或式IA化合物治療病毒感染之化合物、方法及醫藥組合物。亦揭示製備式I或式IA化合物之方法及使用其化合物及醫藥組合物之方法。具體而言，揭示病毒感染之治療及預防，該等病毒感染係(例如)由RNA或DNA病毒引起之彼等。 在其他實施例中，本文所述之化合物可用於預防或治療來自任一系譜目、屬、科或表1中所列示之特定種之病毒感染。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中感染係由屬小核糖核酸病毒科或冠狀病毒科之病毒引起。在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由屬小核糖核酸病毒科之病毒引起。在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由屬冠狀病毒科之病毒引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由屬小核糖核酸病毒科之病毒引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由任意一或多種選自由以下各項組成之群之病毒引起：鼻病毒、中東呼吸症候群冠狀病毒(MERS-CoV)、嚴重急性呼吸症候群冠狀病毒(SARS-CoV)、常見冠狀病毒科(包括(但不限於) OC43、HKU1、229e及NL63)、腸病毒、脊髓灰白質炎病毒、柯薩奇病毒、肝炎A病毒、口蹄疫疾病病毒(FMDV)及杯狀病毒(calicivirus)。 在其他實施例中，本文所述之化合物可用於治療個體中之感染，其中該感染係由人類冠狀病毒中之任一者引起。 在其他實施例中，本文所述之化合物可用於治療個體中之感染，其中該感染係由人類冠狀病毒229E、NL63、OC43、HKU1、SARS-CoV及MERS-CoV中之任一者引起。 在其他實施例中，本文所述之化合物可用於治療個體中之感染，其中該感染係由α人類冠狀病毒中之任一者引起。 在其他實施例中，本文所述之化合物可用於治療個體中之感染，其中該感染係由α人類冠狀病毒229E及NL63引起。 在其他實施例中，本文所述之化合物可用於治療個體中之感染，其中該感染係由β人類冠狀病毒中之任一者引起。 在其他實施例中，本文所述之化合物可用於治療個體中之感染，其中該感染係由β人類冠狀病毒OC43、HKU1、SARS-CoV及MERS-CoV引起。 在其他實施例中，本文所述之化合物可用於治療個體中之感染，其中該感染係由人類冠狀病毒MERS-CoV或SARS-CoV引起。 在其他實施例中，本文所述之化合物可用於治療個體中之感染，其中該感染係由人類冠狀病毒MERS-CoV引起。 在其他實施例中，本文所述之化合物可用於治療個體中之感染，其中該感染係由人類冠狀病毒SARS-CoV引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由人類腸病毒A-D中之任一者引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由腸病毒A71引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由腸病毒D68引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由人類鼻病毒A-C中之任一者引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由人類鼻病毒A引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由人類鼻病毒B引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由人類鼻病毒C引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由脊髓灰白質炎病毒引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由柯薩奇病毒引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由EV-68病毒或EV-71病毒引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由埃可病毒(echovirus)引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由肝炎A病毒引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由杯狀病毒中之任一者引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由諾羅病毒中之任一者引起。 在其他實施例中，本文所述之化合物可用於治療個體中之病毒感染，其中該感染係由諾沃克病毒(Norwalk virus)引起。在其他實施例中，本發明化合物或其醫藥上可接受之鹽係選自表2中所列之化合物。實例 合成方案 本發明之式(I)化合物，式(I) 或其相應醫藥上可接受之鹽係使用習用有機合成來製備，其中A 係 苯基或噁唑基；R1 、 R′1 及 R′′1 獨立地選自H；C1-C6-烷基；鹵基；鹵代烷基；NR6 R7 ；OR8 ；SR9 ；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C1-C6烷基；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8環烷基或C3-C8雜環烷基；R2 係 C1-C6-烷基、視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6-烷基；C3-C8-環烷基或C3-C8-雜環烷基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基取代之C3-C8-環烷基或C3-C8-雜環烷基；NR6 R7 ；視情況經以下基團取代之芳基 ：C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、鹵基取代烷氧基、羥基、硫代烷基；視情況經以下基團取代之雜芳基 ：C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、鹵基取代烷氧基；其中C1-C6-烷基或C1-C6-環烷基進一步視情況經鹵基、O、N、S、NR6 R7 、OR8 、SR9 取代；R3 及 R4 獨立地係 H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基；或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之5員至10員環結構；R5 係 C1-C6烷基；經C1-C6-烷基或芳基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；R6 及 R7 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8-環烷基或C3-C8-雜環烷基；或R6 與R7 一起形成視情況經鹵基、鹵代烷基、胺基、NR6 R7 、OR8 、SR9 取代之3員至10員環烷基或雜環烷基環；芳基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之芳基；雜芳基；或經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之雜芳基；且R8 及 R9 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基，或其鹽。 適宜合成途徑在下文中以下一般反應方案中繪示。熟習此項技術者將瞭解，若本文所述取代基與本文所述合成方法不相容，則該取代基可用對反應條件穩定之適宜保護基團來保護。保護基團可在反應序列中之適宜點去除，以提供期望之中間體或目標化合物。熟習此項技術者熟知使用適宜保護基團來保護及去保護不同取代基之此等適宜保護基團及方法；其實例可發現於T. Greene及P. Wuts，Protecting Groups in Chemical Synthesis (第3版), John Wiley & Sons, NY (1999)。在一些情況下，取代基可經特定選擇以在所選反應條件下具反應性。在該等環境下，反應條件將所選取代基轉化為另一取代基，其用作中間體化合物或係目標化合物中之期望取代基。方案 1 如方案1中所顯示，可根據文獻(Journal of Medicinal Chemistry 48(22), 6767-6771, 2005)製備內醯胺醇1 。藉由使1 與SO3 -吡啶複合物反應將其氧化以產生醛2 ，且隨後2 與異氰化物(例如，異氰異丙烷)在適當酸(例如，苯甲酸)存在下之反應產生酯3 。藉由在鹼性條件下去除3 之苯甲醯基，隨後使用適當酸(例如，HCl)在適宜溶劑(例如，1,4-二噁烷)中去保護4 之Boc基團可獲得胺基醇5 。可使用任何適宜醯胺形成條件來製備化合物6 。較佳地，在本發明中使用2,4,6-三丙基-1,3,5,2,4,6-三氧雜三磷雜環己烷-2,4,6-三氧化物。利用HCl去除化合物6 之Boc基團產生作為關鍵中間體之胺7 。 方案2如方案2中所顯示，藉由使用2,4,6-三丙基-1,3,5,2,4,6-三氧雜三磷雜環己烷-2,4,6-三氧化物作為較佳偶合劑，使胺7 (游離或其鹽)經受與適宜Cbz-胺基酸(例如，(S)-2-(((苄基氧基)羰基)胺基)-3-(4-(三氟甲基)六氫吡啶-1-基)丙酸(B4 -購得或如實例中所述製備))之醯胺形成反應，以得到醯胺8 。利用戴斯-馬丁(Dess-Martin)過碘烷完成隨後氧化，以產生最終產物。化合物實例 縮寫 在闡述實例時，化學元素係根據元素週期表來標識。本文所用之縮寫及符號符合熟習化學技術者對此等縮寫及符號之常見用法。本文使用以下縮寫： AcOH 乙酸 Ac2 O 乙酸酐 aq 水性 B4 (S)-2-(((苄基氧基)羰基)胺基)-3-(4-(三氟甲基)六氫吡啶-1-基)丙酸 BOC (Boc) N-第三丁氧基羰基或第三丁基氧基羰基 CBz 羧基苄基 CellTiter-Glo® 來自Promega之CellTiter-Glo®發光細胞活力分析 CHAPS 3-[(3-膽醯胺丙基)二甲基銨基]-1-丙磺酸鹽 Combiflash® 來自Teledyne Isco之自動化急速層析 CPE 細胞病變效應或致細胞病變效應 dba 二亞苄基丙酮或二亞苄丙酮 DCE 二氯乙烷 DCM 二氯甲烷 DCM/EA 二氯甲烷/乙醇 DIPEA (或DIEA) N,N-二異丙基乙胺或Hünig鹼 DME 二甲氧基乙烷 DMEM 杜爾貝寇改良之伊格爾培養基(Dulbecco’s Modified Eagle Medium) DMF 二甲基甲醯胺 DMP 戴斯-馬丁過碘烷 DMSO-d6 氘代二甲亞碸 DMSO 二甲亞碸 EC50 50%有效濃度 EDTA 乙二胺四乙酸 Envision 來自PerkinElmer之EnVision多標記讀取器 Et2 O 二乙醚 EtOH 乙醇 EtOAc、EA、AcOEt 乙酸乙酯 FBS 胎牛血清 FRET 螢光共振能量轉移(Förster Resonance Energy Transfer) GlutaMAX™ 來自Life Technologies之細胞培養補充劑 h 小時 HEPES 4-(2-羥乙基)-1-六氫吡嗪乙磺酸 HPLC 高效液相層析 IC50 50%抑制濃度 iPrOH 異丙醇(isopropyl alcohol或isopropanol) LCMS 液相層析質譜 MeOH 甲醇 NBS N-溴琥珀醯亞胺 NCS N-氯琥珀醯亞胺 NIS N-碘琥珀醯亞胺 NXS N-鹵基琥珀醯亞胺 NaBH(OAc)3 三乙醯氧基硼氫化鈉 NMR 質子核磁共振光譜 Pd2 (dba)3 參(二亞苄基丙酮)二鈀(0) PE 石油醚 PPh3 三苯基膦 RB 圓底 rt或r.t. 室溫 RT 保留時間 SFC 超臨界流體層析 SO3 pyr 三氧化硫吡啶複合物-式C5 H5 NSO3 SPhos 2-二環己基膦-2',6'-二甲氧基聯苯或二環己基(2',6'-二甲氧基-[1,1'-聯苯]-2-基) t-BuOMe 甲基第三丁基醚 T3P 1-丙烷膦酸酐溶液、2,4,6-三丙基-1,3,5,2,4,6-三氧雜三磷雜環己烷-2,4,6-三氧化物 TFA 三氟乙酸 Thermi Combi 來自Thermo Fisher Scientific之Multidrop™ Combi試劑分配器 THF 四氫呋喃 uv 紫外的 除非另外說明，否則所有起始材料皆係自供應商獲得且不經進一步純化即使用。除非另外指示，否則所有溫度皆以℃表述(攝氏度)表述。除非另外指示，否則所有反應皆在惰性氣氛下且在環境溫度下進行。 倘若需要，所有溫度皆以℃給出，所有溶劑具有最高可得純度且所有反應皆在無水條件下且在氬(Ar)或氮(N2 )氣氛中運行。 以下實例闡釋本發明。該等實例並不意欲限制本發明之範圍，而是向熟習此項技術者提供製備及使用本發明化合物、組合物及方法之指導。 儘管已闡述本發明之具體實施例，但熟習此項技術者應瞭解，在不偏離本發明之精神及範圍之情形下可作出多種變化及修改。 如本文所使用，該等製程、方案及實例中所用之符號及慣例與當代科學文獻(例如，Journal of the American Chemical Society 或Journal of Biological Chemistry )中所用之彼等一致。除非另外說明，否則所有起始材料皆係自供應商獲得且未經進一步純化即使用。 所有對醚之提及皆係指二乙醚；鹽水係指NaCl之飽和水溶液。除非另外指示，否則所有溫度皆係以℃(攝氏度)表述。除非另外說明，否則所有反應皆係在惰性氣氛下且在室溫下進行，且除非另外說明，否則所有溶劑皆具有最高可得純度。1 H NMR (下文中亦稱為「NMR」)光譜係在Varian VXR-300、Varian Unity-300、Varian Unity-400 instrument、Brucker AVANCE-400、General Electric QE-300或Bruker AM 400光譜儀上記錄。化學位移係以百萬分率(ppm, δ單位)表述。偶合常數係以赫茲(Hz)之單位給出。裂分圖案闡述表觀多重性且指定為s (單峰)、d (雙峰)、t (三重峰)、q (四重峰)、quint (五重峰)、m (多重峰)、br (寬峰)。 質譜係使用功能電噴霧離子化在開放式存取LC-MS系統上運行。LC條件：10%至80% CH3 CN (0.018% TFA)，3.0分鐘，其中保持1.25分鐘並再平衡0.5分鐘；藉由MS檢測，214 nm下之UV及光散射檢測器(ELS)。管柱：2.1 × 50 mm Zorbax SB-C8。 急速層析係在Merck矽膠60 (230 - 400目)上，或使用具有正相拋棄式Redi-Sep急速管柱之Teledyne Isco Combiflash Companion運行。中間體 實例 1 中間體 A 中間體A(3S)- 苯甲酸 3-(( 第三丁氧基羰基 ) 胺基 )-1-( 異丙基胺基 )-1- 側氧基 -4-((S)-2- 側氧基吡咯啶 -3- 基 ) 丁 -2- 基酯 3 將((S)-1-羥基-3-((S)-2-側氧基吡咯啶-3-基)丙-2-基)胺基甲酸第三丁基酯(1.0g, 3.87mmol)於DMSO (1.4mL, 19.35mmol)及DCM (10mL)之混合物中之溶液冷卻至-5℃，在攪拌的同時添加休尼格鹼(Hunig's base)(2.366 mL, 13.55 mmol)。在另一圓底燒瓶中，將三氧化硫吡啶複合物(1.232 g, 7.74 mmol)於吡啶(0.626 mL, 7.74 mmol)及DMSO (1.4mL, 19.35mmol)中之懸浮液在室溫下攪拌10分鐘。然後在-5℃下將此懸浮液添加至以上預形成之溶液。使用額外體積之DCM (6mL)來完成轉移。將所得混合物在-5℃下再攪拌2小時。然後將2-異氰基丙烷(0.438 mL, 4.65 mmol)添加至反應混合物中，隨後添加苯甲酸(3.07 g, 25.2 mmol)，並將反應混合物在rt下攪拌過夜(在添加後5分鐘移除乾冰浴)。用EtOAc稀釋反應混合物。分離出EtOAc層後，用飽和NaHCO3 水溶液、1M aq Na2 CO3 、鹽水洗滌有機相並經Na2 SO4 乾燥、過濾並濃縮。藉由矽膠上管柱層析進一步純化粗材料，利用0-100%於己烷中之EtOAc溶析(25分鐘)並然後用EtOAc:EtOH (50%)之3:1混合物替代EtOAc達10分鐘。收集期望之部分並濃縮以得到呈白色固體形式之(3S)-苯甲酸3-((第三丁氧基羰基)胺基)-1-(異丙基胺基)-1-側氧基-4-((S)-2-側氧基吡咯啶-3-基)丁-2-基酯(1.36 g, 79%產率)。LCMS: M+1 = 448.4。(兩種緊接溶析之非鏡像異構物之混合物)。((2S)-3- 羥基 -4-( 異丙基胺基 )-4- 側氧基 -1-((S)-2- 側氧基吡咯啶 -3- 基 ) 丁 -2- 基 ) 胺基甲酸第三丁基酯 將(3S)- 苯甲酸 3-(( 第三丁氧基羰基 ) 胺基 )-1-( 異丙基胺基 )-1- 側氧基 -4-((S)-2- 側氧基吡咯啶 -3- 基 ) 丁 -2- 基酯 (16.27 g, 36.4 mmol)溶解於四氫呋喃(THF) (30 mL)及水(30 mL)中。將氫氧化鋰(3.05 g, 127 mmol)添加至反應混合物。將反應混合物攪拌2小時並藉由LCMS監測確認完成。在減壓下蒸發THF並利用乙酸乙酯萃取水層，且用NaHCO3 溶液、鹽水洗滌萃取物，過濾，經硫酸鈉乾燥並在真空中濃縮。將粗材料與二乙醚一起研磨以產生呈白色固體形式之((2S)-3-羥基-4-(異丙基胺基)-4-側氧基-1-((S)-2-側氧基吡咯啶-3-基)丁-2-基)胺基甲酸第三丁基酯(10.61g, 85%)。LCMS: [M+1]=344.3，(兩個峰，每種醇非鏡像異構物一個)。(3S)-3- 胺基 -2- 羥基 -N- 異丙基 -4-((S)-2- 側氧基吡咯啶 -3- 基 ) 丁醯胺鹽酸鹽 在0℃下向((2S)-3-羥基-4-(異丙基胺基)-4-側氧基-1-((S)-2-側氧基吡咯啶-3-基)丁-2-基)胺基甲酸第三丁基酯(10 g, 29.1 mmol)於二氯甲烷(DCM) (15 mL)及乙酸乙酯(100 mL)中之攪拌混合物添加鹽酸(29.1 mL, 116 mmol)。添加後5分鐘，移除冰浴並將反應混合物在rt下攪拌過夜。LCMS指示反應完成。過濾並收集沈澱之固體以得到呈白色固體形式之(3S)-3-胺基-2-羥基-N-異丙基-4-((S)-2-側氧基吡咯啶-3-基)丁醯胺鹽酸鹽(8.0g, 28.6mmol, 98%產率)。鹽酸鹽不經任何進一步純化即用於下一步驟。LCMS: [M+1]=244.2, (兩個峰，每種醇非鏡像異構物一個)。((2S)-1-(((2S)-3- 羥基 -4-( 異丙基胺基 )-4- 側氧基 -1-((S)-2- 側氧基吡咯啶 -3- 基 ) 丁 -2- 基 ) 胺基 )-4- 甲基 -1- 側氧基戊 -2- 基 ) 胺基甲酸第三丁基酯 在RB燒瓶中添加於DCM (20 mL)中之(S)-2-((第三丁氧基羰基)胺基)-4-甲基戊酸(0.909 g, 3.93 mmol)、DIPEA (1.87 mL, 10.72 mmol)及(3S)-3-胺基-2-羥基-N-異丙基-4-((S)-2-側氧基吡咯啶-3-基)丁醯胺鹽酸鹽(1.00 g, 3.57 mmol)。在0℃下且在逐滴添加T3P (50 wt %於EtOAc中，2.34 mL, 3.93 mmol)時攪拌混合物。將混合物在冰浴中攪拌2小時。用EtOAc稀釋混合物，用1N HCl (aq)、NaHCO3 (aq)、鹽水洗滌並然後經Na2 SO4 乾燥、過濾並濃縮以得到((2S)-1-(((2S)-3-羥基-4-(異丙基胺基)-4-側氧基-1-((S)-2-側氧基吡咯啶-3-基)丁-2-基)胺基)-4-甲基-1-側氧基戊-2-基)胺基甲酸第三丁基酯(1.36 g, 83%粗產率)。此材料未經進一步純化即用於下一步驟中。LCMS: M+1 = 457.3。(非鏡像異構物之混合物之兩個峰)(2S)-2- 胺基 -N-((2S)-3- 羥基 -4-( 異丙基胺基 )-4- 側氧基 -1-((S)-2- 側氧基吡咯啶 -3- 基 ) 丁 -2- 基 )-4- 甲基戊醯胺鹽酸鹽 在0℃下向((2S)-1-(((2S)-3-羥基-4-(異丙基胺基)-4-側氧基-1-((S)-2-側氧基吡咯啶-3-基)丁-2-基)胺基)-4-甲基-1-側氧基戊-2-基)胺基甲酸第三丁基酯(7 g, 15.33 mmol)於二氯甲烷(DCM) (80 mL)中之經攪拌溶液添加鹽酸(15.33 mL, 61.3 mmol)。添加後5分鐘，移除冰浴並將反應混合物在rt下攪拌過夜。LCMS指示反應完成。過濾並收集沈澱之固體以產生呈白色固體形式之(2S)-2-胺基-N-((2S)-3-羥基-4-(異丙基胺基)-4-側氧基-1-((S)-2-側氧基吡咯啶-3-基)丁-2-基)-4-甲基戊醯胺鹽酸鹽(6 g, 15.27 mmol, 100 %產率)。LCMS: M+1 = 357.2。實例 2 (S)-2-((( 苄基氧基 ) 羰基 ) 胺基 )-3-(4-( 三氟甲基 ) 六氫吡啶 -1- 基 ) 丙酸 在N2 下，在RB燒瓶中添加於乙腈(80 mL)中之4-(三氟甲基)六氫吡啶(2.97 g, 19.39 mmol)及(Z)-N-(三甲基矽基)乙醯亞胺酸三甲基矽基酯(2.371 mL, 9.70 mmol)。將混合物在rt下攪拌5小時，隨後添加(S)-(2-側氧基氧雜環丁-3-基)胺基甲酸苄基酯(3.3 g, 14.92 mmol)並持續攪拌過夜。濃縮混合物並將殘餘物溶解於醚中，用1N HCl水溶液萃取。在冰浴中用6N NaOH將水層調節成pH為6.6並用EtOAc萃取。經Na2 SO4 乾燥有機層，濃縮以得到(S)-2-(((苄基氧基)羰基)胺基)-3-(4-(三氟甲基)六氫吡啶-1-基)丙酸(4.62 g, 12.34 mmol, 83%產率)。LCMS: M+1 = 375.2, 0.68分鐘。((2S)-1-(((2S)-1-(((2S)-3- 羥基 -4-( 異丙基胺基 )-4- 側氧基 -1-((S)-2- 側氧基吡咯啶 -3- 基 ) 丁 -2- 基 ) 胺基 )-4- 甲基 -1- 側氧基戊 -2- 基 ) 胺基 )-1- 側氧基 -3-(4-( 三氟甲基 ) 六氫吡啶 -1- 基 ) 丙 -2- 基 ) 胺基甲酸苄基酯 在RB燒瓶中添加於二氯甲烷(DCM) (30 mL)中之(2S)-2-胺基-N-((2S)-3-羥基-4-(異丙基胺基)-4-側氧基-1-((S)-2-側氧基吡咯啶-3-基)丁-2-基)-4-甲基戊醯胺鹽酸鹽(900 mg, 2.291 mmol)、(S)-2-(((苄基氧基)羰基)胺基)-3-(4-(三氟甲基)六氫吡啶-1-基)丙酸(917 mg, 2.451 mmol)。將混合物在-5℃下攪拌5分鐘，添加N-乙基-N-異丙基丙-2-胺(1.600 mL, 9.16 mmol)。將混合物在-5℃下攪拌15分鐘，並然後經由另一漏斗逐滴添加於10mL EtOAc中之2,4,6-三丙基-1,3,5,2,4,6-三氧雜三磷雜環己烷-2,4,6-三氧化物(1.501 mL, 2.52 mmol)並持續攪拌2小時。用EtOAc稀釋混合物，用NaHCO3 水溶液、鹽水洗滌，經Na2 SO4 乾燥，濃縮以得到粗產物，藉由正相層析將其進一步純化，用DCM及iPrOH溶析，其中iPrOH在30分鐘內高達50% (80 g管柱)，獲得呈白色固體形式之((2S)-1-(((2S)-1-(((2S)-3-羥基-4-(異丙基胺基)-4-側氧基-1-((S)-2-側氧基吡咯啶-3-基)丁-2-基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)-1-側氧基-3-(4-(三氟甲基)六氫吡啶-1-基)丙-2-基)胺基甲酸苄基酯(1.36 g, 1.908 mmol, 83%產率)。LCMS M+1 = 713.6((S)-1-(((S)-1-(((S)-4-( 異丙基胺基 )-3,4- 二側氧基 -1-((S)-2- 側氧基吡咯啶 -3- 基 ) 丁 -2- 基 ) 胺基 )-4- 甲基 -1- 側氧基戊 -2- 基 ) 胺基 )-1- 側氧基 -3-(4-( 三氟甲基 ) 六氫吡啶 -1- 基 ) 丙 -2- 基 ) 胺基甲酸苄基酯 在一次性添加戴斯-馬丁過碘烷(2.356 g, 5.56 mmol)時，在0℃下於RB燒瓶中攪拌((2S)-1-(((2S)-1-(((2S)-3-羥基-4-(異丙基胺基)-4-側氧基-1-((S)-2-側氧基吡咯啶-3-基)丁-2-基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)-1-側氧基-3-(4-(三氟甲基)六氫吡啶-1-基)丙-2-基)胺基甲酸酯(2.64g, 3.70 mmol)於二氯甲烷(DCM) (50 mL)中之溶液。5分鐘後移除冰浴，將混合物攪拌2小時。添加額外DMP (0.5g, 1.17mmol)並保持攪拌1小時。濃縮混合物並藉由自動化正相層析直接純化殘餘物，用DCM及丙酮溶析，其中在丙酮50分鐘內高達90% (240 g管柱)。將各部分靜置過夜並沈澱且過濾出DMP副產物。濃縮濾液，以得到呈白色固體形式之((S)-1-(((S)-1-(((S)-4-(異丙基胺基)-3,4-二側氧基-1-((S)-2-側氧基吡咯啶-3-基)丁-2-基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)-1-側氧基-3-(4-(三氟甲基)六氫吡啶-1-基)丙-2-基)胺基甲酸苄基酯(2.2 g, 3.10 mmol, 84 %產率)。藉由與EtOAc/醚一起研磨進一步純化材料並再一次進行正相管柱純化，以得到1.98 g材料(75%)。LCMS 711.51 H NMR (400 MHz, DMSO-d 6 ) d ppm 0.77 - 0.95 (m, 6 H) 1.09 (d,J =6.34 Hz, 6 H) 1.32 - 1.52 (m, 4 H) 1.54 - 1.80 (m, 5 H) 1.85 - 1.96 (m, 1 H) 1.96 - 2.08 (m, 2 H) 2.09 - 2.29 (m, 2 H) 2.30 - 2.39 (m, 1 H) 2.40 - 2.48 (m, 2 H) 2.96 (d,J =9.38 Hz, 2 H) 3.06 - 3.23 (m, 2 H) 3.90 (dd,J =14.70, 6.59 Hz, 1 H) 4.18 (q,J =7.44 Hz, 1 H) 4.29 - 4.43 (m, 1 H) 4.93 - 5.13 (m, 3 H) 7.24 - 7.42 (m, 6 H) 7.69 (s, 1 H) 8.24 (d,J =8.11 Hz, 1 H) 8.46 - 8.50 (m, 1 H) 8.50 - 8.63 (m, 2 H)實例 3 (S)-2-(( 第三丁氧基羰基 ) 胺基 )-3-(6-( 三氟甲基 ) 吡啶 -2- 基 ) 丙酸甲酯 在N2 下向50-mL燒瓶添加鋅(0.894 g, 13.67 mmol) (粉末)，隨後添加N,N-二甲基甲醯胺(DMF) (10 mL)及I2 (0.174 g)。放出一些熱量且混合物自深紅色變為無色懸浮液。10分鐘後添加(R)-2-((第三丁氧基羰基)胺基)-3-碘丙酸甲酯(1.5 g, 4.56 mmol)及I2 (0.174 g)，並將混合物在rt下攪拌90分鐘。添加2-溴-6-(三氟甲基)吡啶(1.339 g, 5.92 mmol)、Pd2 (dba)3 (0.104 g, 0.114 mmol)及二環己基(2',6'-二甲氧基-[1,1'-聯苯]-2-基)膦(或Sphos) (0.094 g, 0.228 mmol)並將混合物在50℃下攪拌過夜。用EtOAc (50 mL)稀釋反應物並過濾。用水(5 × 15 mL)洗滌有機溶液，乾燥(Na2 SO4 )，過濾並濃縮。藉由Combiflash自動化矽膠層析純化殘餘物，用[EtOAc/EtOH 76:24]/己烷5-40%溶析以提供呈淡綠色油狀物形式之(S)-2-((第三丁氧基羰基)胺基)-3-(6-(三氟甲基)吡啶-2-基)丙酸甲酯(0.783 g, 2.248 mmol, 49.3%產率)。LCMS: [M+Na]+: 371.2。(S)-2-((( 苄基氧基 ) 羰基 ) 胺基 )-3-(6-( 三氟甲基 ) 吡啶 -2- 基 ) 丙酸甲酯 在0℃下向100 mL RB燒瓶添加於DCM (15 mL)中之(S)-2-((第三丁氧基羰基)胺基)-3-(6-(三氟甲基)吡啶-2-基)丙酸甲酯(0.783 g, 2.248 mmol)，隨後添加HCl (11.24 mL, 45.0 mmol) (4 M於二噁烷中)。將混合物在rt下攪拌1小時。在真空下將有機溶液濃縮至乾燥。將殘餘物溶解於DCM (20 mL)中，並添加DIPEA (1.178 mL, 6.74 mmol)及Cbz-Cl (0.385 mL, 2.70 mmol)。將混合物在rt下攪拌1小時。將混合物在真空下濃縮至乾燥並藉由Combiflash自動化矽膠管柱層析(120 g Gold管柱，運行18分鐘)純化殘餘物，用[EtOAc/EtOH 76:24]/己烷0-30%溶析以提供呈澄清油狀物形式之(S)-2-(((苄基氧基)羰基)胺基)-3-(6-(三氟甲基)吡啶-2-基)丙酸甲酯(0.879 g, 2.138 mmol, 95%產率)。LCMS: [M+H]+: 383.2。(S)-2-((( 苄基氧基 ) 羰基 ) 胺基 )-3-(6-( 三氟甲基 ) 吡啶 -2- 基 ) 丙酸 在rt下在0℃下向50 mLRB燒瓶添加於四氫呋喃(THF) (10 mL)中之(S)-2-(((苄基氧基)羰基)胺基)-3-(6-(三氟甲基)吡啶-2-基)丙酸甲酯(0.879 g, 2.138 mmol)，隨後添加氫氧化鋰(3.21 mL, 3.21 mmol) (1 M於水中)。將混合物在rt下攪拌0.5小時。添加HCl (3.21 mL, 3.21 mmol) (1 M於水中)，並用水(10 mL)稀釋混合物且用EtOAc (2 × 20 mL)萃取。乾燥(Na2 SO4 )合併之有機溶液，過濾並濃縮以提供呈淡綠色固體形式之(S)-2-(((苄基氧基)羰基)胺基)-3-(6-(三氟甲基)吡啶-2-基)丙酸(0.891 g, 2.141mmol, 100%產率)。LCMS: [M+H]+: 369.1。((2S)-1-(((2S)-1-(((2S)-3- 羥基 -4-( 異丙基胺基 )-4- 側氧基 -1-((S)-2- 側氧基吡咯啶 -3- 基 ) 丁 -2- 基 ) 胺基 )-4- 甲基 -1- 側氧基戊 -2- 基 ) 胺基 )-1- 側氧基 -3-(6-( 三氟甲基 ) 吡啶 -2- 基 ) 丙 -2- 基 ) 胺基甲酸苄基酯 在N2 下向50 mL RB燒瓶添加於二氯甲烷(DCM) (10 mL)中之(2S)-2-胺基-N-((2S)-3-羥基-4-(異丙基胺基)-4-側氧基-1-((S)-2-側氧基吡咯啶-3-基)丁-2-基)-4-甲基戊醯胺鹽酸鹽(0.301 g, 0.767 mmol)及(S)-2-(((苄基氧基)羰基)胺基)-3-(6-(三氟甲基)吡啶-2-基)丙酸(0.319 g, 0.767 mmol)，隨後添加DIPEA (0.669 mL, 3.83 mmol)及2,4,6-三丙基-1,3,5,2,4,6-三氧雜三磷雜環己烷-2,4,6-三氧化物(0.671 mL, 1.150 mmol)。將混合物攪拌在rt下2小時。LCMS指示期望產物之形成。濃縮有機溶液並藉由Combiflash自動化矽膠管柱層析(40 g Gold管柱，運行25分鐘)純化殘餘物，用[EtOAc/EtOH 76:24]/己烷5-80%溶析，以提供呈白色固體形式之對應於2種非鏡像異構物(P1 105 mg且P2 205 mg)之兩部分。將兩部分合併作為A1，以產生呈白色固體形式之((2S)-1-(((2S)-1-(((2S)-3-羥基-4-(異丙基胺基)-4-側氧基-1-((S)-2-側氧基吡咯啶-3-基)丁-2-基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)-1-側氧基-3-(6-(三氟甲基)吡啶-2-基)丙-2-基)胺基甲酸苄基酯(0.31 g, 0.439 mmol, 57.2%產率)。LCMS: [M+H]+:707.4。((S)-1-(((S)-1-(((S)-4-( 異丙基胺基 )-3,4- 二側氧基 -1-((S)-2- 側氧基吡咯啶 -3- 基 ) 丁 -2- 基 ) 胺基 )-4- 甲基 -1- 側氧基戊 -2- 基 ) 胺基 )-1- 側氧基 -3-(6-( 三氟甲基 ) 吡啶 -2- 基 ) 丙 -2- 基 ) 胺基甲酸苄基酯 在N2 下向50-mL RB燒瓶添加於二氯甲烷(DCM) (15 mL)中之((2S)-1-(((2S)-1-(((2S)-3-羥基-4-(異丙基胺基)-4-側氧基-1-((S)-2-側氧基吡咯啶-3-基)丁-2-基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)-1-側氧基-3-(6-(三氟甲基)吡啶-2-基)丙-2-基)胺基甲酸苄基酯(0.31 g, 0.439 mmol)，隨後添加戴斯-馬丁過碘烷(0.205 g, 0.482 mmol)。將混合物在rt下攪拌2小時。LCMS指示反應之完成。添加飽和硫代硫酸鈉水溶液(3 mL)及飽和碳酸氫鈉水溶液(3 mL)，並將混合物再攪拌15分鐘。用水(20 mL)稀釋混合物並用DCM (2 × 30 mL)萃取。乾燥(Na2 SO4 )合併之有機溶液，過濾並濃縮。藉由Combiflash® 自動化矽膠管柱層析(24 g Gold管柱，運行20分鐘)純化殘餘物，用i-PrOH/DCM 0-40%溶析以提供呈白色固體形式之((S)-1-(((S)-1-(((S)-4-(異丙基胺基)-3,4-二側氧基-1-((S)-2-側氧基吡咯啶-3-基)丁-2-基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)-1-側氧基-3-(6-(三氟甲基)吡啶-2-基)丙-2-基)胺基甲酸苄基酯(0.228 g, 0.304 mmol, 69.3%產率)。LCMS: [M+H]+: 705.61 H NMR (400 MHz, DMSO-d 6) δ ppm 0.87 (dd,J =18.44, 6.57 Hz, 6 H) 1.09 (d,J =6.57 Hz, 6 H) 1.38 - 1.50 (m, 2 H) 1.52 - 1.74 (m, 3 H) 1.84 -1.98 (m, 1 H) 2.10 - 2.24 (m, 1 H) 2.30 - 2.43 (m, 1 H) 2.95 - 3.07 (m, 1 H) 3.09 - 3.28 (m, 3 H) 3.83 - 3.98 (m, 1 H) 4.27 - 4.40 (m, 1 H) 4.46 - 4.60 (m, 1 H) 4.94 (s, 2 H) 4.96 - 5.06 (m, 1 H) 7.23 (s, 2 H) 7.33 (s, 1 H) 7.61 (d,J =8.34 Hz, 2 H) 7.69 (s, 1 H) 7.71 - 7.79 (m, 1 H) 7.91 - 8.03 (m, 1 H) 8.09 - 8.16 (m, 1 H) 8.47 - 8.61 (m, 2 H)。生物實例 實例 4 HRV-16 3C 蛋白酶方案 自10 mM之高濃度開始，利用100% DMSO之溶劑將測試化合物以11點曲線連續稀釋3倍。將各稀釋液在100 nL體積下轉移至黑色384孔Greiner (784076)板中，從而在分析中產生10 μM之最高最終濃度。第18行(0%反應，100%抑制)中之低對照孔含有100 nL DMSO加緩衝液，不含酶。第6行(100%反應，0%抑制)中之高對照孔含有100 nL DMSO加緩衝液及酶。整個板之最大DMSO濃度係約1%。 分析緩衝液由25 mM Hepes (pH 7.5)、100 mM NaCl、1 mM CHAPS、1 mM EDTA及0.05%牛血清白蛋白組成。分析板製備包括在反應添加之前旋轉板，及僅將5 μL分析緩衝液(無酶)添加至第18行(低對照---代表100%抑制)並將5 μL於分析緩衝液中之10 nM酶(HRV-16 3C蛋白酶，5 nM最終濃度)添加至第1-17行及第19 -24行。 將FRET受質肽(FAM-GRAVFQGPVG-TAMRA)以4 μM濃度懸浮，並利用Thermo Combi液體處置器將5 μL添加至各反應孔使最終反應濃度為2 μM。將反應物在黑暗中且在室溫下培育60分鐘。在該時刻利用Envision或等效讀板儀量測FRET信號並使用其來量化表觀EC50 計算之分析終點。 分析來自每一板之數據並繪製為%抑制對化合物濃度。使用式100*(對照1-未知)/(對照1-對照2)將數據正規化，其中對照1係該板對應於0%抑制對照孔(DMSO，第6行)之值的平均數且對照2係對應於100%對照孔(第18行)之值的平均數。利用4參數曲線擬合方程y=A+((B-A)/(1+(10^ x/10^ C)^ D))實施曲線擬合，其中A係最小反應，B係最大反應，C係log(XC50 )且D係希爾斜率(Hill slope)。將各測試化合物之結果記錄為pIC50 值(上文方程中之-C)及給定濃度下之最大反應值。實例 5 HRV-15 3C 蛋白酶方案 自10 mM之高濃度開始，利用100% DMSO之溶劑將測試化合物以11點曲線連續稀釋3倍。將各稀釋液在100 nL體積下轉移至黑色384孔Greiner (784076)板中，從而在分析中產生10 μM最高最終濃度。第18行(0%反應，100%抑制)中之低對照孔含有100 nL DMSO加緩衝液，不含酶。第6行(100%反應，0%抑制)中之高對照孔含有100 nL DMSO加緩衝液及酶。整個板之最大DMSO濃度係約1%。 分析緩衝液由25 mM HEPES (pH 7.5)、100 mM NaCl、1 mM CHAPS、1 mM EDTA及0.05%牛血清白蛋白組成。分析板製備包括在反應添加之前旋轉板，及僅將5 μL分析緩衝液(無酶)添加至第18行(低對照---代表100%抑制)並將5 μL於分析緩衝液中之10 nM酶(HRV-15 3C蛋白酶，5 nM最終濃度)添加至第1 - 17行及第19 -24行。 將FRET受質肽(FAM-GRAVFQGPVG-TAMRA)以4 μM濃度懸浮並利用Thermo Combi液體處置器將5 μL添加至各反應孔使最終反應濃度為2 μM。將反應物在黑暗中且在室溫下培育60分鐘。在該時刻利用Envision或等效讀板儀量測FRET信號並使用其來量化表觀EC50 計算之分析終點。 分析來自每一板之數據並繪製為%抑制對化合物濃度。使用式100*(對照1-未知)/(對照1-對照2)將數據正規化，其中對照1係該板對應於0%抑制對照孔(DMSO，第6行)之值的平均數，且對照2係對應於100%對照孔(第18行)之值的平均數。利用4參數曲線擬合方程y=A+((B-A)/(1+(10^ x/10^ C)^ D))實施曲線擬合，其中A係最小反應，B係最大反應，C係log(XC50 )且D係希爾斜率。將各測試化合物之結果記錄為pIC50 值(上文方程中之-C)及給定濃度下之最大反應值。實例 6 冠狀病毒 OC43 3CL 蛋白酶方案 自10 mM之高濃度開始，利用100% DMSO之溶劑將測試化合物以11點曲線連續稀釋3倍。將各稀釋液在100 nL體積下轉移至黑色384孔Greiner (784076)板中，從而在分析中產生10 μM最高最終濃度。第18行(0%反應，100%抑制)中之低對照孔含有100 nL DMSO加緩衝液，不含酶。第6行(100%反應，0%抑制)中之高對照孔含有100 nL DMSO加緩衝液及酶。整個板之最大DMSO濃度係約1%。 分析緩衝液由25 mM HEPES (pH 7.5)、50 mM NaCl、1 mM CHAPS及1 mM EDTA組成。分析板製備包括在反應添加之前旋轉板，及僅將5 μL分析緩衝液(無酶)添加至第18行(低對照---代表100%抑制)並將5 μL於分析緩衝液中之2 nM酶(OC43 3CL蛋白酶，1 nM最終濃度)添加至第1-17行及第19-24行。 將FRET受質肽(FAM-VARLQSGFG-TAMRA)以4 μM濃度懸浮並利用Thermo Combi液體處置器將5 μL添加至各反應孔使最終反應濃度為2 μM。將反應物在黑暗中且在室溫下培育60分鐘。在該時刻利用Envision或等效讀板儀量測FRET信號並使用其來量化表觀EC50 計算之分析終點。 分析來自每一板之數據並繪製為%抑制對化合物濃度。使用式100*(對照1-未知)/(對照1-對照2)將數據正規化，其中對照1係該板對應於0%抑制對照孔(DMSO，第6行)之值的平均數且對照2係對應於100%對照孔(第18行)之值的平均數。利用4參數曲線擬合方程y=A+((B-A)/(1+(10^ x/10^ C)^ D))實施曲線擬合，其中A係最小反應，B係最大反應，C係log(XC50 )且D係希爾斜率。將各測試化合物之結果記錄為pIC50 值(上文方程中之-C)及給定濃度下之最大反應值。實例 7 冠狀病毒 229e 3CL 蛋白酶方案 自10 mM之高濃度開始，利用100% DMSO之溶劑將測試化合物以11點曲線連續稀釋3倍。將各稀釋液在100 nL體積下轉移至黑色384孔Greiner (784076)板中，從而在分析中產生10 μM最高最終濃度。第18行(0%反應，100%抑制)中之低對照孔含有100 nL DMSO加緩衝液，不含酶。第6行(100%反應，0%抑制)中之高對照孔含有100 nL DMSO加緩衝液及酶。整個板之最大DMSO濃度係約1%。 分析緩衝液由25 mM Hepes (pH 7.5)、50 mM NaCl、1 mM CHAPS及1 mM EDTA組成。分析板製備包括在反應添加之前旋轉板，及僅將5 μL分析緩衝液(無酶)添加至第18行(低對照---代表100%抑制)並將5 μL於分析緩衝液中之200 pM酶(229e 3CL蛋白酶，100 pM最終濃度)添加至第1-17行及第19-24行。 將FRET受質肽(FAM-VARLQSGFG-TAMRA)以4 μM濃度懸浮並利用Thermo Combi液體處置器將5 μL添加至各反應孔使最終反應濃度為2 μM。將反應物在黑暗中且在室溫下培育60分鐘。在該時刻利用Envision或等效讀板儀量測FRET信號並使用其來量化表觀EC50 計算之分析終點。 分析來自每一板之數據並繪製為%抑制對化合物濃度。使用式100*(對照1-未知)/(對照1-對照2)將數據正規化，其中對照1係該板對應於0%抑制對照孔(DMSO，第6行)之值的平均數且對照2係對應於100%對照孔(第18行)之值的平均數。利用4參數曲線擬合方程y=A+((B-A)/(1+(10^ x/10^ C)^ D))實施曲線擬合，其中A係最小反應，B係最大反應，C係log(XC50 )且D係希爾斜率。將各測試化合物之結果記錄為pIC50值(上文方程中之-C)及給定濃度下之最大反應值。實例 8 SARS 冠狀病毒 3CL 蛋白酶方案 自10 mM之高濃度開始，利用100% DMSO之溶劑將測試化合物以11點曲線連續稀釋3倍。將各稀釋液在100 nL體積下轉移至黑色384孔Greiner (784076)板中，從而在分析中產生10 μM最高最終濃度。第18行(0%反應，100%抑制)中之低對照孔含有100 nL DMSO加緩衝液，不含酶。第6行(100%反應，0%抑制)中之高對照孔含有100 nL DMSO加緩衝液及酶。整個板之最大DMSO濃度係約1%。 分析緩衝液由25 mM Hepes (pH 7.5)、50 mM NaCl、1 mM CHAPS及1 mM EDTA組成。分析板製備包括在反應添加之前旋轉板，及僅將5 μL分析緩衝液(無酶)添加至第18行(低對照---代表100%抑制)並將5 μL於分析緩衝液中之60 nM酶(SARS 3CL蛋白酶，30 nM 最終濃度)添加至第1-17行及第19-24行。 將FRET受質肽(FAM-KTSAVLQSGFRKME-TAMRA)以6 μM濃度懸浮並利用Thermo Combi液體處置器將5 μL添加至各反應孔使最終反應濃度為3 μM。將反應物在黑暗中且在室溫下培育60分鐘。在該時刻利用Envision或等效讀板儀量測FRET信號並使用其來量化表觀EC50 計算之分析終點。 分析來自每一板之數據並繪製為%抑制對化合物濃度。使用式100*(對照1-未知)/(對照1-對照2)將數據正規化，其中對照1係該板對應於0%抑制對照孔(DMSO，第6行)之值的平均數且對照2係對應於100%對照孔(第18行)之值的平均數。利用4參數曲線擬合方程y=A+((B-A)/(1+(10^ x/10^ C)^ D))實施曲線擬合，其中A係最小反應，B係最大反應，C係log(XC50 )且D係希爾斜率。將各測試化合物之結果記錄為pIC50值(上文方程中之-C)及給定濃度下之最大反應值。實例 9 人類鼻病毒 (HRV) 細胞病變效應分析之方案 經由利用細胞病變效應(CPE)及細胞毒性作為終點之高通量細胞分析測試本發明化合物。對於CPE分析，在生物安全性2級(BSL-2)環境中利用人類鼻病毒(HRV) B型株14 (ATCC VR-284號；美國模式培養物保藏所，Manassas, VA)或HRV A型株16 (ATCC VR-283號；美國模式培養物保藏所，Manassas, VA)感染人類上皮HeLa Ohio細胞(ECACC 84121901號；Sigma-Aldrich Corporation, St. Louis, MO)。具有抗病毒活性之化合物保護HeLa Ohio細胞免於由病毒感染所誘導之CPE，並使用CellTiter-Glo® 試劑(CTG) Promega Corporation, Madison, WI)量測細胞存活率，其係基於ATP (一種具代謝活性細胞之指示物)之發光檢測。使用具有未感染HeLa Ohio細胞之CTG分析平行量測由單獨化合物治療效應所致之細胞毒性。 為準備分析，將測試化合物在DMSO中自5 mM之典型最高濃度連續稀釋3倍並將其在0.25 µL下平鋪於具有蓋之384孔聚苯乙烯透明底組織培養物處理之板中(Corning Incorporated, Tewksbury, MA)，以生成11點劑量反應曲線。低對照孔(100% CPE或100%細胞毒性)在用於CPE分析之病毒感染細胞存在下含有0.25 µL DMSO或在用於細胞毒性分析之細胞不存在下0.25 µL DMSO，且高對照孔(0% CPE或0%細胞毒性)在用於CPE分析之病毒感染細胞存在下含有0.25 µL小分子對照測試化合物或在用於細胞毒性分析之未感染細胞存在下0.25 µL相同無毒小分子對照測試化合物。 在補充有以下各項之DMEM高葡萄糖培養基(Life Technologies Corporation, Grand Island, NY)中洗滌並回收HeLa Ohio細胞之冷凍原液：10% v/v合格熱不活化之胎牛血清(FBS) (Life Technologies Corporation, Grand Island, NY)、1X GlutaMAX™ (Life Technologies Corporation, Grand Island, NY)及1X青黴素-鏈黴素抗生素溶液(Life Technologies Corporation, Grand Island, NY)。將細胞在經補充DMEM培養基中稀釋至40,000細胞/mL，然後將該培養基之體積等分至兩個燒瓶中。在先前所製備384孔化合物板之一半上，將來自一個燒瓶之50 µL細胞懸浮液添加至所有孔，唯低對照孔除外，產生2,000個細胞/孔用於細胞毒性分析。在0.01之感染複數(MOI)下將HRV添加至細胞之第二燒瓶，並將50 µL同質性病毒及細胞混合物添加至剩餘384孔化合物板上之所有孔，產生2,000個細胞/孔用於CPE分析。然後將具有蓋之板置於33℃下5% CO2 加濕培育器中5天。 培育後，移除用於兩種分析之384孔板並將其置於生物安全櫃以平衡至室溫達30分鐘。根據製造商說明書製備CellTiter-Glo® 並將20 µL添加至每一板孔。在室溫下培育20分鐘後，在EnVision® 多標記讀取器(PerkinElmer Inc., Waltham, MA)上讀取發光。 使用式100*((U-C2)/(C1-C2))正規化後，將CPE分析中劑量反應之數據繪製為%存活率對化合物濃度，其中U係未知值，C1係高(0% CPE)對照孔之平均數且C2係低(100% CPE)對照孔之平均數。使用式100-(100*((U-C2)/(C1-C2)))正規化後，將細胞毒性分析中劑量反應之數據繪製為%細胞毒性對化合物濃度，其中U係未知值，C1係高(0%細胞毒性)對照孔之平均數且C2係低(100%細胞毒性)對照孔之平均數。 利用方程y=A+((B-A)/(1+(10x /10C )D ))實施曲線擬合，其中A係最小反應，B係最大反應，C係log(XC50 )且D係希爾斜率。將各測試化合物之結果記錄為CPE分析之pIC50值及細胞毒性分析pCC50值(上文方程中之‑C)。實例 10 MERS 冠狀病毒細胞分析之方案 經由利用冠狀病毒纖突蛋白之表現作為終點之細胞分析測試本發明化合物。利用MERS冠狀病毒(Jordan株)感染人類肺纖維母細胞MRC-5細胞。具有抗病毒活性之化合物減少纖突蛋白之表現，如以免疫方式所量測，並減少細胞存活率，如藉由核完整性所量測。 在分析準備中，將測試化合物在100% DMSO中以8點曲線連續稀釋3倍，用於50 uM之最高分析濃度。將DMSO在反應孔中正規化至1%之最終濃度。低對照孔(100% CPE或100%細胞毒性)在病毒感染細胞之存在下含有DMSO。 利用化合物將MRC-5細胞處理2小時，然後在1之MOI下利用MERS感染。使病毒複製48小時，此後利用福馬林(formalin)使病毒不活化。藉由用抗S蛋白抗體免疫染色來檢測感染細胞並藉由PE Opera共焦平臺量化。將S蛋白染色之信號轉化為%感染，並使用陽性及陰性對照計算%抑制。使用GeneData軟體以標準方程計算EC50。 本文所述本發明之實施例意欲僅具實例性；熟習此項技術者將瞭解眾多變化形式及修改形式。所有此等眾多變化形式及修改形式意欲在本發明之範圍內，如任何隨附申請專利範圍中所定義。 表1 表 2 表 3 生物分析數據 Throughout this application, reference is made to various examples of compounds, compositions, and methods. The various embodiments described are intended to provide multiple illustrative examples and should not be construed as an alternative kind of description. It should be noted that the description of the various embodiments provided herein may have overlapping ranges. The embodiments discussed herein are illustrative only and are not intended to limit the scope of the invention. It should be understood that the terminology used herein is for the purpose of illustrating specific embodiments only and is not intended to limit the scope of the present invention. In this specification and subsequent patent applications, reference will be made to a number of terms that should be defined as having the following meanings. Unless otherwise specified, "alkyl" as used herein refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 14 carbon atoms and in some embodiments having 1 to 6 carbon atoms. The term "alkyl" includes, for example, linear and branched hydrocarbon groups, such as methyl (CH3 -), Ethyl (CH3 CH2 -), N-propyl (CH3 CH2 CH2 -), Isopropyl ((CH3 )2 CH-), n-butyl (CH3 CH2 CH2 CH2 -), Isobutyl ((CH3 )2 CHCH2 -), Second butyl ((CH3 ) (CH3 CH2 ) CH-), tert-butyl ((CH3 )3 C-), n-pentyl (CH3 CH2 CH2 CH2 CH2 -) And neopentyl ((CH3 )3 CCH2 -). "Alkoxy" refers to the group -O-alkyl, where alkyl is defined herein. Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, third butoxy, second butoxy, n-pentyloxy, morpholinyl Propoxy, hexahydropyridyl ethoxy. "Amino" refers to the group -NR6 R7 , Where R6 And R7 Independently selected from hydrogen, alkyl, alkenyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocyclyl, and wherein R6 And R7 The nitrogen to which it is bonded is optionally joined together to form a heterocyclic group. If R6 Hydrogen and R7 In the case of an alkyl group, the amino group is sometimes referred to herein as an alkylamine group. If R6 And R7 In the case of an alkyl group, the amine group is sometimes referred to herein as a dialkylamine group. When referring to a mono-substituted amine group, it means R6 Or R7 It is hydrogen but not all hydrogen. When referring to a disubstituted amine group, it means R6 And R7 None are hydrogen. "Aryl" means an aromatic group having 5 to 14 carbon atoms without acyclic heteroatoms and having a single ring (eg, phenyl) or multiple condensed (fused) rings (eg, naphthyl or anthracenyl) group. For polycyclic systems including fused, bridged, and spiro ring systems (which have aromatic and non-aromatic rings with acyclic heteroatoms), when the attachment point is at an aromatic carbon atom, the term "aryl "Or" Ar "applies (for example, 5,6,7,8 tetrahydronaphthalen-2-yl aryl, because its attachment point is located at the 2 position of the aromatic phenyl ring). "Cycloalkyl" means a saturated or partially saturated cyclic group having 3 to 14 carbon atoms without a ring heteroatom and having a monocyclic or polycyclic ring including fused, bridged, and spiro ring systems. For polycyclic systems with aromatic rings and non-aromatic rings with acyclic heteroatoms, the term "cycloalkyl" applies when the attachment point is at a non-aromatic carbon atom (for example, 5, 6, 7 , 8, -tetrahydronaphthalene-5-yl). The term "cycloalkyl" includes cycloalkenyl, such as cyclohexenyl. Examples of cycloalkyl include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups that include multiple bicycloalkyl ring systems are dicyclohexyl, dicyclopentyl, bicyclooctyl, and the like. "Halo" or "halogen" means fluorine, chlorine, bromine and iodine. "Haloalkyl" refers to an alkyl group having 1 to 9 halo groups (for example, when the alkyl group has 3 carbon atoms, such as a third butyl group completely substituted with halogen) or in some embodiments, 1 to 3 halo groups. Halo (for example, trifluoromethyl) substitution. "Hydroxy (hydroxyl or hydroxyl)" refers to the group -OH. "Heteroaryl" means an aromatic group having 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, and boron, and it includes a single ring (Eg, imidazolyl) and polycyclic systems (eg, benzimidazol-2-yl and benzimidazol-6-yl). For polycyclic systems including fused, bridged and spiro ring systems (which have aromatic and non-aromatic rings), if there is at least one ring heteroatom and the point of attachment is at the atom of the aromatic ring, the term "Heteroaryl" applies (for example, 1,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl). In some embodiments, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N → O), sulfinyl, or sulfonyl moiety. More specifically, the term heteroaryl includes (but is not limited to) pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyl, pyrrolyl, Pyrazolyl, pyrazinyl, pyrimidinyl, purinyl, phthalazinyl, naphthyl, naphthylpyridyl, oxazolyl, quinolinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuran Group, benzothiazolyl, benzisothiazolyl, benzotriazolyl, indolyl, isoindolyl, indolizinyl, indoline, indazolyl, indolinyl, benzox Oxazolyl, quinolinyl, isoquinolinyl, quinazinyl, quinazolinyl, quinoxalinyl, tetrahydroquinolinyl, isoquinolinyl, quinazolinone, benzimidazolyl, benzo Isoxazolyl, benzothienyl, benzoxazinyl, pteridinyl, carbazolyl, oxolinyl, phenanthridinyl, acridinyl, morpholinyl, phenazinyl, phenoxazinyl, phen Thiazinyl and phthalimide. "Heterocyclic" or "heterocyclic" or "heterocyclic alkyl" or "heterocyclic group" means having 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, sulfur, phosphorus or oxygen Saturated or partially saturated cyclic groups, and includes monocyclic and monocyclic and polycyclic systems including fused, bridged and spiro ring systems. For polycyclic ring systems with aromatic and / or non-aromatic rings, when there is at least one ring heteroatom and the attachment point is located at the atom of the non-aromatic ring, the terms "heterocyclic", "heterocyclic" , "Heterocycloalkyl" or "heterocyclyl" apply (for example, 1,2,3,4-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-6-yl And decahydroquinolin-6-yl). In one embodiment, the nitrogen, phosphorus and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide N-oxides, phosphinane oxide, sulfinyl, sulfonyl moieties . More specifically, heterocyclic groups include, but are not limited to, tetrahydropyranyl, hexahydropyridyl, hexahydropyrazinyl, 3-pyrrolidinyl, 2-pyrrolidinone-1-yl, morpholinyl And pyrrolidinyl. A prefix indicating the number of carbon atoms (for example, C3 -C10 ) Refers to the total number of carbon atoms other than the number of heteroatoms in the heterocyclic moiety. Examples of heterocyclic and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyrazine, pyridone, indazine, isoindole, indole, Indoline, indazole, purine, quinazine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, oxoline, pyridine, carbazole, oxazoline, phenanthridine, Acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, naphthalene, oxazole, pendant pyrrolidine, hexahydropyridine, hexahydropyrazine , Indoline, phthalimide, quinoline, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo [b] thiophene, thiazole, cyclopentathiazole , Thiazolidine, thiophene, benzo [b] thiophene, morpholine, thiomorpholine (also known as thiomorpholine), hexahydropyridine, pyrrolidine and tetrahydrofuranyl. "Fused heterocyclic" refers to a 3- to 10-membered cyclic substituent formed by replacing two hydrogen atoms on different carbon atoms in a cycloalkyl ring structure, as shown by the following cyclopentathiazole structure Examples:. "Fused aryl and fused heteroaryl" means 5 fused to a 5- to 6-membered aryl, heteroaryl or cycloalkyl ring on different carbon atoms in the aryl structure or heteroaryl structure Member to 6 member aryl structure or heteroaryl structure, which may be substituted on any one of the carbons in the fused aryl or fused heteroaryl group and connected to the core molecule on the other of the carbons, such as by Illustrated by the following cyclopentylthiazole, quinoline or naphthalene structure:,,. As used herein, "compound (compound, compound)" and "chemical entity (chemical entity)" refer to the general formula, any subgenus and any form of the general formula and the general formula disclosed by this text and Compounds encompassed by compounds within the sub-formula include racemates, stereoisomers and tautomers of one or more compounds. The term "heteroatom" means nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen (eg, N (O) {N+ —O− }) And any oxidized form of sulfur (for example, S (O) and S (O)2 ) And any four-level ammonium form of basic nitrogen. "Oxazole" and "oxazolyl" means a 5-membered heterocyclic ring containing a nitrogen and an oxygen as a heteroatom, and also contains three carbons and may be substituted on one of the three carbons and may be on three The other of the carbons is connected to another molecule, as exemplified by any of the following structures, where the oxazolidinone group shown here is bonded to the parent molecule by binding to the parent The wavy line in the molecular bond indicates:,. "Penoxypyrrolidine" and "pendoxypyrrolidinyl" means a 5-membered heterocyclic ring containing nitrogen and 4 carbons, which is substituted by a carbonyl group on any of the carbons in the heterocyclic ring and may The other carbon is connected to another substituent, as exemplified by the following structure:. "Pyridine" and "pyridyl" refer to a 6-membered heteroaryl ring containing 1 nitrogen and 5 carbons, which may also be substituted on one or more of the carbons in the heteroaryl ring and may be substituted on the heteroaryl group The other carbon in the ring is connected to another substituent, as exemplified by the following structure:,,,. "Thiazole" and "thiazolyl" means a 5-membered heteroaryl group containing 1 sulfur and 1 nitrogen in the heteroaryl ring and 3 carbons in the heteroaryl ring, which may also be in the heteroaryl ring One or more of the middle carbons are substituted and can be attached to another substituent on another carbon in the heteroaryl ring, as exemplified by the following structure:. "Pyrimidine" and "pyrimidinyl" refer to a 6-membered heteroaryl ring containing two nitrogens in the heteroaryl ring and 4 carbons in the heteroaryl ring, which may be one of the carbons in the heteroaryl ring Or more than one of the above is substituted and may be connected to another substituent on another carbon in the heteroaryl ring, as exemplified by the following structure:. "Racemate" means a mixture of mirror isomers. In an embodiment of the present invention, the compound of formula I or a pharmaceutically acceptable salt thereof is enantiomerically enriched in an enantiomer, in which all the chiral carbons mentioned are in a configuration. Generally speaking, when referring to an enantiomerically enriched compound or salt, it is meant to indicate that the specified enantiomer will contain more than 50% by weight of the total weight of all enantiomers of the compound or salt. "Solvate (solvate or solvates)" of a compound refers to their compounds as defined above, which are bound to a stoichiometric or non-stoichiometric amount of solvent. Solvates of compounds include all forms of solvates of compounds. In certain embodiments, the solvent is volatile, non-toxic, and / or acceptable for administration to humans in trace amounts. Suitable solvates include water. "Stereoisomers (stereoisomers or stereoisomers)" refer to one or more stereogenic compounds with different chiral centers. Stereoisomers include mirror isomers and diastereomers. "Tautomers" refer to alternative forms of compounds with different proton positions, such as keto-enol and imine-enamine tautomers, or contain ring atoms (which are attached to the ring-NH- moiety and ring = N-both) tautomeric forms of heteroaryl groups, such as pyrazole, imidazole, benzimidazole, triazole and tetrazole. "Pharmaceutically acceptable salt" means a pharmaceutically acceptable salt derived from various organic and inorganic relative ions well known in the industry, and includes (by way of example only) sodium, potassium, calcium, magnesium, ammonium and tetraalkylammonium And when the molecule contains basic functional groups, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate and oxalate. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (editor), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002 and others. "Patient" or "individual" refers to mammals and includes human and non-human mammals. "Treatment (treatment)" of a patient's disease refers to 1) preventing the occurrence of the disease in patients who are susceptible or have not shown symptoms of the disease; 2) inhibiting the disease or stopping its development; or 3) improving or causing the regression of the disease. As long as the dashed line appears on the single bond adjacent to the solid line, the dashed line represents the optional double bond at that position. Similarly, as long as the dashed circle appears within the ring structure represented by the solid line or the solid circle, the dashed circle represents one to three optional double bonds configured according to their appropriate valence, considering whether the ring has any Alternatives, as will be understood by those skilled in the art. For example, the dotted line in the following structure can indicate the double bond at that position or the single bond at that position:. Similarly, ring A below may be a cyclohexyl ring without any double bonds, or it may also be a phenyl ring with three double bonds, the three double bonds being arranged at any position but still showing the phenyl ring Appropriate price. Similarly, in ring B below, X1 -X5 Any one of them can be selected from: C, CH or CH2 , N or NH, and the dotted circle means that ring B can be a cyclohexyl or phenyl ring or an N-containing heterocyclic ring without double bonds or an N-containing heteroaryl ring having one to three double bonds, the one to three double bonds being arranged at Any position but still showing the appropriate valence:. If a particular compound or general formula is drawn with an aromatic ring, such as an aryl or heteroaryl ring, those skilled in the art will understand that the specific aromatic positioning of any double bond is a combination of equivalent positions, even if it is in a compound Between or between formulas are drawn at different locations. For example, in the following two pyridine rings (A and B), the double bond system is drawn in different positions, but it is known that they are the same structure and compound:. Unless otherwise indicated, the nomenclature of substituents not explicitly defined herein is achieved by naming the terminal portion of the functional group and thereafter the adjacent functional group toward the attachment point. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl) -O-C (O)-. In such as "-C (Rx )2 ”In the term, it should be understood that if Rx Defined as having more than one possible attribute, then two Rx The groups may be the same or they may be different. In addition, some substituents are drawn as -Rx Ry , Where "-" indicates the bond adjacent to the parent molecule and Ry It is the terminal part of the functional group. Similarly, it should be understood that the above definition is not intended to include unacceptable substitution patterns (eg, methyl substituted with 5 fluoro groups). These disallowed substitution patterns are well known to those skilled in the art. According to an embodiment of the present invention, a compound having the structure of formula IA is provided:IAA system Aryl or heteroaryl;R 1 , R ′ 1 and R '' 1 Independently selected from H; C1-C6-alkyl; halo; haloalkyl; NR6 R7 ; OR8 ; SR9 ; C1-C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl ; C3-C8 cycloalkyl or C3-C8 heterocycloalkyl; via C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, hydroxyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl substituted with alkoxy or thioalkyl;R 2 system C1-C6-alkyl; via aryl, heteroaryl, C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyl, halo, haloalkyl, amine, amine alkyl Group, alkoxy, hydroxyl, thioalkyl,NR 6 R 7 Substituted C1-C6-alkyl; optionally via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, C3-C8-cycloalkyl substituted with hydroxy, alkoxy, or halogen substituted alkoxy, or the C3-C8 cycloalkyl is fused with an aryl group to form a bicyclic or tricyclic fused ring; C3-C8- Heterocycloalkyl; optionally via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, hydroxy, alkoxy Group, halogen-substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl substituted by alkoxy. Or the C3-C8 heterocycloalkyl is fused with an aryl group to form a bicyclic or tricyclic fused ring; wherein the aryl, heteroaryl, C1-C6-alkyl, C3-C8-cycloalkyl, C3 -C8 heterocycloalkyl orNR 6 R 7 Further substitution of alkoxy, NR by halogen, alkoxy, halogen6 R7 , OR8 , SR9 ReplaceR 3 and R 4 Independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy C1-C6 alkyl substituted with hydroxy, hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; -C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl ; Or R3 With R4 Together form C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Replace the ring structure of 5 to 10 members;R 5 C1-C6 alkyl; C1-C6 alkyl substituted with C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, aryl, heteroaryl; or as appropriate C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Substituted C3-C8 cycloalkyl;R 6 and R 7 Independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl , Alkoxy, hydroxy, thioalkyl substituted C1-C6 alkyl; C3-C8-cycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkane Group, halo, haloalkyl, NR6 R7 , OR8 , SR9 Substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R6 With R7 Together form halo, haloalkyl, amine, NR6 R7 , OR8 , SR9 Substituted 3- to 10-membered cycloalkyl or heterocycloalkyl ring; aryl; C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl , NR6 R7 , OR8 , SR9 Substituted aryl; heteroaryl; or C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Substituted heteroaryl; andR 8 and R 9 Independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl , Alkoxy, hydroxy, thioalkyl substituted C1-C6 alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkane Group or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-cycloalkyl or C3-C8-hetero Cycloalkyl, or its salt. In certain embodiments, compounds of formula IA are provided,Formula IA where:A system Phenyl or oxazolyl;R 1 , R ′ 1 and R '' 1 Independently selected from H; C1-C6-alkyl; halo; haloalkyl; NR6 R7 ; OR8 ; SR9 ; Via C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Substituted C1-C6 alkyl; via C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Substituted C3-C8 cycloalkyl or C3-C8 heterocycloalkyl;R 2 system C1-C6-alkyl, via aryl, heteroaryl, C1-C6-alkyl, C1-C6-cycloalkyl, C3-C8 heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl C1-C6-alkyl substituted with alkyl, alkoxy, hydroxy, thioalkyl; NR6 R7 ; Where aryl, heteroaryl, C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyl or NR6 R7 Further substitution of alkoxy, O, N, S, NR by halogen, alkoxy, halogen6 R7 , OR8 , SR9 ReplaceR 3 and R 4 Independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy C1-C6 alkyl substituted with hydroxy, hydroxy, thioalkyl; C3-C8-cycloalkyl; C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halogen C3-C8-cycloalkyl substituted with alkyl, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-heterocycloalkane Base; or R3 With R4 Together form C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Replace the ring structure of 5 to 10 members;R 5 system C1-C6 alkyl; C1-C6 alkyl substituted with C1-C6-alkyl, C3-C8 cycloalkyl, C3-C8-heterocycloalkyl, aryl, heteroaryl; or C3-C8 cycloalkyl base;R 6 and R 7 Independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl , Alkoxy, hydroxy, thioalkyl substituted C1-C6 alkyl; C3-C8-cycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkane Group, halo, haloalkyl, NR6 R7 , OR8 , SR9 Substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R6 With R7 Together form halo, haloalkyl, amine, NR6 R7 , OR8 , SR9 Substituted 3- to 10-membered cycloalkyl or heterocycloalkyl ring; aryl; C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl , NR6 R7 , OR8 , SR9 Substituted aryl; heteroaryl; or C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Substituted heteroaryl; andR 8 and R 9 Independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl , Alkoxy, hydroxy, thioalkyl substituted C1-C6 alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkane Group or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-cycloalkyl or C3-C8-hetero Cycloalkyl, or its salt. An embodiment provides a compound of formula IA,Formula IA where:A system PhenylR 1 , R ′ 1 and R '' 1 Independently selected from H; C1-C6-alkyl; halo; haloalkyl; NR6 R7 ; OR8 ; SR9 ; Via C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Substituted C1-C6 alkyl; via C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Substituted C3-C8 cycloalkyl or C3-C8 heterocycloalkyl;R 2 system C1-C6-alkyl; C1-C6-alkyl substituted with hexahydropyridyl; morpholinyl; indenyl; phenyl; thiazolyl; pyridyl; pyrimidinyl; quinolinyl; naphthyl; C1-C6 -Alkyl, alkoxy; halogen substituted alkoxy; NR6 R7 ; Among them hexahydropyridyl, morpholinyl, indenyl, phenyl, thiazolyl, pyridyl, pyrimidinyl, quinolinyl, naphthyl, NR6 R7 Further depending on the situation via halogen, O, N, S, NR6 R7 , OR8 , SR9 ReplaceR 3 and R 4 Independently H, C1-C6-alkyl; C1-C6-alkyl substituted with C1-C6-alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R3 With R4 Together form C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxyl, sulfur Alkyl substituted 5- to 10-membered ring structure;R 5 system C1-C6 alkyl; C1-C6 alkyl substituted with C1-C6-alkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl, phenyl; or C3 substituted with C1-C6-alkyl -C8-cycloalkyl or C3-C8-heterocycloalkyl;R 6 and R 7 Independently H, C1-C6-alkyl; C1-C6 alkyl substituted with C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R6 With R7 Together form a 3- to 10-membered cycloalkyl or heterocycloalkyl ring optionally substituted by halo or haloalkyl; andR 8 and R 9 Independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl , Alkoxy, hydroxy, thioalkyl substituted C1-C6 alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkane Group or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-cycloalkyl or C3-C8-hetero Cycloalkyl, or its salt. In another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula IA as described, wherein R3 Department H and R4 Selected from the group consisting of C1-C6 alkyl and substituted C1-C6 alkyl or R3 With R4 Together form a ring structure. In another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula IA as described, wherein R5 Selected from the group consisting of: C1-C6-alkyl; C1-C6 alkyl substituted with C1-C6-alkyl, phenyl; C3-C8-cycloalkyl substituted with C1-C6-alkyl Or C3-C8-heterocycloalkyl. In another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula IA, wherein A is selected from the group consisting of: aryl and C1-C6-alkyl, C3-C8-cycloalkyl or C3- C8-heterocycloalkyl, halo, haloalkyl, amine, amine alkyl, alkoxy, hydroxy or thioalkyl substituted aryl. In another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula IA, wherein A is selected from the group consisting of heteroaryl and C1-C6-alkyl, C3-C8-cycloalkyl or C3 -C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy or thioalkyl substituted heteroaryl. In another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula IA, wherein A is selected from the group consisting of: phenyl and C1-C6-alkyl, C3-C8-cycloalkyl or C3- C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy or thioalkyl substituted phenyl. In another embodiment of the present invention, there is provided a compound having the structure of Formula I or Formula IA, wherein A is selected from the group consisting of oxazolyl and substituted oxazolyl. In another embodiment of the present invention, a compound selected from the group consisting of N-[(1S) -1-{[(1S) -1-{[(2S) -1- (三 丁丁Amino carbamoyl) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl ] Aminomethanyl} -2- (dimethylamino) ethyl] benzyl carbamate; N-[(1S) -1-{[(1S) -3-methyl-1-{[ (2S) -1-Penoxy-3-[(3S) -2-Penoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminemethylamide] prop-2-yl ] Aminomethanyl} butyl] aminomethanyl} -2- (hexahydropyridin-1-yl) ethyl] benzyl carbamate; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) Aminoacetoyl] propan-2-yl] aminoformyl} butyl] aminoformyl} -2- (morpholin-4-yl) ethyl] carbamic acid benzyl ester; N-[(1S ) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1 -[(Prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} -2- [4- (trifluoromethyl) hexahydropyridine-1 -Yl] ethyl] carbamic acid benzyl ester; N-[(1S) -2- (4,4-difluorohexahydropyridin-1-yl) -1-{[(1S) -3-methyl -1-{[(2S) -1- Oxy-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminomethylamino] propan-2-yl] aminomethylamino} butan Group] Aminocarbamoyl} ethyl] carbamic acid benzyl ester; N-[(1S) -2- (4-fluorohexahydropyridin-1-yl) -1-{[(1S) -3-methyl Yl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamide ] Propan-2-yl] aminomethanyl} butyl] aminomethanyl} ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[( 2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminecarboxyl} -3-methylbutyl] aminecarboxamide} -2- [4- (trifluoromethyl) hexahydropyridin-1-yl] ethyl] benzyl carbamate; N-[(1S)- 1-{[(1S) -1-{[(2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidine-3- Yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (4,4-difluorohexahydropyridin-1-yl) ethyl] aminocarboxylic acid Benzyl ester; N-[(1S) -2-[(cyclopropylmethyl) (methyl) amino] -1-{[(1S) -3-methyl-1-{[(2S)- 1-Ptoxy-3-[(3S) -2-Ptoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamido] prop-2-yl] aminecarboxamide } Butyl] aminomethayl} ethyl] aminocarbamic acid Ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (cyclopentylaminecarboxamide) -1-pentoxy-3-[(3S -2-oxo-pyrrolidin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl] aminomethanyl} -2- [4- (trifluoromethyl) hexa Hydropyridin-1-yl] ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminemethylamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethayl} -3-methylbutyl] aminemethyl} -2- [methyl (2,2,2-trifluoroethyl) amino] ethyl] carbamic acid benzyl ester; N-[(2S) -1-[(2S) -4,4-di Ethyl-2-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamide Yl] propan-2-yl] aminecarboxamido} pyrrolidin-1-yl] -1-oxo-3- [4- (trifluoromethyl) hexahydropyridin-1-yl] propan-2- Benzyl ester of amino] carbamic acid; N-[(1S) -2- (4-fluorophenyl) -1-{[(1S) -3-methyl-1-{[(2S) -1-side Oxy-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminomethylamino] propan-2-yl] aminomethylamino} butan Group] Aminoformyl} ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (third butylaminoformamide Yl) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2- ] Aminoacetoyl} -2-cyclopentylethyl] aminoformamide} -2- (quinolin-5-yl) ethyl] benzyl carbamate; N-[(1S) -1- {[(1S) -1-{[(2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] Prop-2-yl] aminomethanyl} -3-methylbutyl] aminomethanyl} -2- (pyridin-2-yl) ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1- {[(1S) -1-Phenylethyl] aminecarboxamide} propan-2-yl] aminecarboxyl} butyl] aminecarboxyl} -2- (pyridin-2-yl) ethyl] Benzyl carbamate; N-[(1S) -3-methyl-1-{[(1S) -3-methyl-1-{[(2S) -1-pentoxy-3-[( 3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} Butyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-pentoxy-3-[(3S -2-oxo-pyrrolidin-3-yl] -1-[(prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} -3 -Phenylpropyl] carbamic acid benzyl ester; N- [2- (6-methoxypyridin-2-yl) -1-{[(1S) -3-methyl-1-{[(2S -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1- [ (Prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} ethyl] benzyl carbamate; N-[(1S, 2S)- 2-methoxy-1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidine-3- Yl] -1-[(prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} propyl] carbamic acid benzyl ester; N- [ (1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(Prop-2-yl) aminomethylamido] propan-2-yl] aminomethylamino} butyl] aminomethylamino-2--2-4- (trifluoromethyl) pyrimidine-2 -Yl] ethyl] carbamic acid benzyl ester; N-[(1S) -2- (5-fluoropyridin-2-yl) -1-{[(1S) -3-methyl-1-{[ (2S) -1-Penoxy-3-[(3S) -2-Penoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminemethylamide] prop-2-yl ] Aminomethanyl} butyl] aminomethanyl} ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S ) -1-Penoxy-3-[(3S) -2-Penoxypyrrolidin-3-yl] -1-[(Prop-2-yl) aminemethylacetoyl] propan-2-yl] amine Methyl} butyl] aminomethanyl} -2- [6- (trifluoromethyl) pyridin-2-yl] ethyl] benzyl aminocarbamate; N-[(1S) -1- { [(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2- Oxypyrrolidin-3-yl] -1-[(prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} -2- [5- (Trifluoromethyl) pyridin-2-yl] ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1-{[( 1S) -1-cyclohexylethyl] aminecarboxamide} -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminecarboxamide Yl} -3-methylbutyl] aminomethanyl} -2- (pyridin-2-yl) ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S)- 3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) amine Formyl] propan-2-yl] amine formyl} butyl] amine formyl} -2- (3-methylphenyl) ethyl] benzyl carbamate; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1- [(Prop-2-yl) aminecarboxamide] propan-2-yl] aminecarboxyl} butyl] aminecarboxyl} -2- [4- (trifluoromethyl) pyridin-2-yl] Ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-pentyloxy- 3-[(3S) -2-Penoxypyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (1,3 -Thiazol-2-yl) ethyl] benzyl carbamate; N- [(1S) -1-{[(1S) -1-{[(2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxo Pyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- [4- (prop-2-yloxy) pyridine-2- Group] ethyl] benzyl aminocarbamate; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-pentaoxy Yl-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethylamino} -3-methylbutyl] aminomethylamino} -2- [6 -(Trifluoromethyl) pyridin-2-yl] ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butyl Amino carbamoyl) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl ] Aminomethyl amide-2--2- (1,3-thiazol-4-yl) ethyl] benzyl carbamate; N-[(1S) -1-{[(1S) -1-{[( 2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminecarboxyl} -3-methylbutyl] aminecarboxamide} -2- [6- (trifluoromethoxy) pyridin-2-yl] ethyl] benzyl carbamate; N-[(1S) -1 -{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[( Propan-2-yl) aminomethyl] propan-2-yl] aminomethyl} butyl] aminomethylamino-2- [6- (trifluoromethoxy) pyridin-2-yl] ethyl] benzyl carbamate; N-[(1S) -1-{[(1S) -1-{[(2S) -1 -(Butylaminomethylacetoyl) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminemethyl} -3-methyl Benzylbutyl] aminecarboxamide} -2- [5- (trifluoromethyl) pyrimidin-2-yl] ethyl] benzyl carbamate; N-[(1S) -1-{[(1S ) -1-{[(2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2- ] Aminomethylamino} -3-methylbutyl] aminomethylamino} -2- [4- (trifluoromethyl) -1,3-thiazol-2-yl] ethyl] carbamic acid benzyl Base ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-pentoxy-3-[(3S)- 2-oxopyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (5-methyl-1,3-thiazole -2-yl) ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1 -Oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethylamino} -3-methylbutyl] aminomethylamino} -2 -(6-methoxypyridin-2-yl) ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butyl Aminoaminemethyl) -1-oxo-3-[(3S) -2-oxopyrrole Pyridin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl] aminomethanyl} -2- (2-methoxy-1,3-thiazol-4-yl) Ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-pentyloxy- 3-[(3S) -2-Penoxypyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- {4H, 5H , 6H-cyclopenta [d] [1,3] thiazol-2-yl} ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[( 2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminecarboxyl} -3-methylbutyl] aminecarboxamido} -2- (6-methoxy-4-methylpyridin-2-yl) ethyl] benzyl carbamate; N-[(1S)- 1-{[(1S) -1-{[(2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidine-3- Yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (6-ethoxypyridin-2-yl) ethyl] benzyl carbamate ; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (tert-butylaminecarboxamide) -1-pentoxy-3-[(3S)- 2-oxopyrrolidin-3-yl] propan-2-yl] aminecarboxamide} -2-cyclohexylethyl] aminecarboxamide} -2- (naphthalen-1-yl) ethyl] amine Carboxylic acid {4- [3- (morpholin-4-yl) propoxy] benzene } Methyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (tert-butylaminecarboxamide) -1-pentoxy-3-[( 3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl] aminomethanyl} -2- (naphthalen-1-yl) ethyl ] Aminocarboxylic acid {4- [2- (hexahydropyridin-1-yl) ethoxy] phenyl} methyl ester; N-[(1S) -2- (4-fluorophenyl) -1- { [(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop- 2-yl) aminomethylamino] propan-2-yl] aminomethylamino} butyl] aminomethylamino} ethyl] aminocarboxylic acid (4-{[cyclopropyl (methyl) amino] methyl Yl} phenyl) methyl ester; N-[(S)-{[(1S) -1-{[(2S) -1- (tert-butylaminecarboxamide) -1-pentoxy-3- [(3S) -2-Penoxypyrrolidin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl] aminomethanyl} (2,3-dihydro-1H -Inden-2-yl) methyl] aminocarboxylic acid (5-methyl-1,2-oxazol-3-yl) methyl ester; N-[(2S) -1-[(1S, 3aR, 6aS ) -1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamide ] Propan-2-yl] aminecarboxamide} -octahydrocyclopenta [c] pyrrol-2-yl] -3- (4-fluorophenyl) -1-oxopropan-2-yl] amine Benzyl carbamate; N-[(2S) -1-oxo-1-[(3S) -3-{[(2S) -1-oxo -3-[(3S) -2-Penoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} -2- Azalo [4. 4] non-2-yl] -3- (pyridin-2-yl) prop-2-yl] carbamic acid benzyl ester; and N-[(2S) -1-[(2S) -4,4- Diethyl-2-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) amine Acetyl] propan-2-yl] aminomethanyl} pyrrolidin-1-yl] -3- (4-fluorophenyl) -1-oxopropan-2-yl] carbamic acid benzyl ester or Its salt. The compounds described herein may exist in specific geometric or stereoisomeric forms. The present invention covers all such compounds, including cis- and trans-isomers, (-)-and (+)-mirrors, (R)-and (S) -mirrors, non-mirrors Isomers, (D) -isomers, (L) -isomers, their racemic mixtures, and other mixtures (eg, mirror-isomeric or non-mirror-enriched mixtures), all of which fall Within the scope of the present invention. There may be additional asymmetric carbon atoms in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention. Optically active (R)-and (S) -isomers and d and l isomers can be prepared using chiral synthetic components or chiral reagents or resolved using conventional techniques. For example, if a specific mirror image isomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting asymmetric mixture is separated and the auxiliary group is dissociated To provide the purely desired mirror image isomer. Alternatively, if the molecule contains basic functional groups (for example, amine groups) or acidic functional groups (for example, carboxyl groups), diastereomeric salts can be formed using appropriate optically active acids or bases, followed by staged crystallization known in the industry Or chromatographically resolve the diastereomers thus formed and then recover the pure mirror isomers. In addition, the separation of enantiomers and diastereomers is usually achieved by using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (for example, the formation of carbamates from amines). In another embodiment of the present invention, compounds of formula I or formula IA are provided for use in therapy. In another embodiment of the present invention, compounds of formula I or formula IA are provided for the treatment of viral infections. In another embodiment of the present invention there is provided the use of a compound of formula I or formula IA for the manufacture of a medicament for the treatment of viral infections in humans. In another embodiment of the present invention there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in formula I or formula IA. In one embodiment, a pharmaceutical formulation containing a compound of Formula I or Formula IA or a salt thereof is suitable for parenteral administration. In another embodiment, the formulation is a long-acting parenteral formulation. In another embodiment, the formulation is a nanoparticle formulation. In one embodiment, a pharmaceutical formulation containing a compound of formula I or formula IA or a salt thereof is suitable for oral, rectal, topical, or intravenous administration, wherein the pharmaceutical formulation optionally includes a pharmaceutically acceptable formulation Any one or more of the carrier, adjuvant or vehicle. In one embodiment, the compound of formula I or formula IA is formulated for oral administration and can be administered in the form of a conventional formulation, for example, in any of the following dosage forms: solid medicament, such as lozenges, Powders, granules, capsules and the like; aqueous agents; oily suspensions; or liquid agents such as syrups and elixirs. In one embodiment, the compound of formula I or formula IA is formulated for parenteral administration and can be administered in the form of an aqueous or oily suspension injectable or nasal drops. In preparing parenteral formulations using compounds of formula I or formula IA, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers, and the like can be used at will. As antiviral drugs, oral agents are particularly preferred. A formulation of a compound of formula I or formula IA can be prepared by combining (eg, mixing) a therapeutically effective amount of a compound of formula I or formula IA with a pharmaceutically acceptable carrier or diluent. Pharmaceutical formulations suitable for oral administration can be presented in the form of discrete units such as capsules or lozenges; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foaming substances ; Or oil-in-water liquid emulsion or water-in-oil liquid emulsion. For example, for oral administration in the form of tablets or capsules, the compound of Formula I or Formula IA can be administered orally with a non-toxic, pharmaceutically acceptable inert carrier (eg, ethanol, glycerin, water, and the like) )combination. The powder is prepared by pulverizing the compound of formula I or formula IA to a suitable fine particle size and mixing with a pharmaceutical carrier pulverized in a similar manner (for example, edible carbohydrates such as, for example, starch or mannitol). Flavoring agents, preservatives, dispersing agents and coloring agents may also be present. Capsules are made by preparing a powder mixture as described above and filling a molded gelatin shell. Glidants and lubricants (eg, colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol) can be added to the powder mixture before the filling operation. Disintegrants or solubilizers (eg, agar, calcium carbonate, or sodium carbonate) can also be added to improve the usability of the medicament when ingesting the capsule. In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (eg, glucose or β-lactose), corn sweeteners, natural and synthetic gums (eg, gum arabic, tragacanth, or sodium alginate), carboxymethyl cellulose, Polyethylene glycol, wax and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, but are not limited to starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. Lozenges are formulated by, for example, preparing powder mixtures, granulating or impacting, adding lubricants and disintegrating agents, and compressing into lozenges. The powder mixture is prepared by mixing a compound suitable for pulverization with a diluent or base as described above, and optionally a binder (for example, carboxymethyl cellulose, alginate, gelatin, or polyvinylpyrrolidone) A retarder (for example, paraffin), a resorption accelerator (for example, a quaternary salt), and / or an absorbent (for example, bentonite, kaolin, or calcium hydrogen phosphate) are prepared. The powder mixture can be granulated by wetting with a binder (for example, syrup, starch paste, acadia mucus, or a solution of cellulose or polymer material) and pressurizing through a mesh screen. As an alternative to granulation, the powder mixture can be passed through a tablet machine and the result is that the poorly formed agglomerates are broken into granules. The granules can be lubricated with the addition of stearic acid, stearate, talc or mineral oil to prevent sticking to the tablets to form a mold. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with free-flowing inert carriers and directly compressed into tablets without going through the granulation or compression steps. Transparent or opaque protective coatings consisting of shellac shells, sugar or polymer coatings and wax polishing coatings can also be provided. Dyestuffs can be added to these coatings to distinguish different unit doses. Oral solutions such as solutions, syrups and elixirs can be formulated in dosage unit form so that a given amount contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared by using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers (eg, ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavoring additives (eg, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners) can also be added Flavors and the like). Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation of the compound of formula I or formula IA can also be prepared to prolong or sustain the release of the compound, for example by coating or embedding particulate material in a polymer, wax or the like. The compounds of formula I or formula IA or salts, solvates or hydrates thereof can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phospholipid choline. Compounds of formula I or formula IA or salts, solvates or hydrates thereof can also be delivered by using monoclonal antibodies as individual carriers coupled to compound molecules. Compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polymers substituted with palmitoyl residues Ethylene oxide polyimide. In addition, the compound can be coupled with a class of biodegradable polymers that can be used to achieve controlled release of drugs, such as polylactic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyranes , Polycyanoacrylate and hydrogel cross-linked or amphiphilic block copolymer. Pharmaceutical formulations suitable for transdermal administration can be presented in discrete patches intended to maintain long-term close contact with the recipient's epidermis. For example, compounds of Formula I or Formula IA can be delivered from the patch by iontophoresis, as outlined in Pharmaceutical Research, 3 (6), 318 (1986). Pharmaceutical preparations suitable for local administration can be formulated as ointments, creams, suspensions, emulsions, powders, solutions, pastes, gels, sprays, aerosols or oils. When the active ingredient is formulated in an ointment, it can be used with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated with an oil-in-water cream base or a water-in-oil base in a cream. Pharmaceutical formulations suitable for rectal administration can be presented in the form of suppositories or enema. The carrier is a solid pharmaceutical formulation suitable for nasal administration, including a coarse powder with a particle size in the range of, for example, 20 microns to 500 microns, which is administered by snuff smoking, that is, by self-retention The powder container close to the nose is quickly inhaled through the nasal passages. A suitable formulation of the carrier liquid is for administration in the form of nasal spray or nasal drops, including aqueous or oil solutions of the active ingredient. Pharmaceutical formulations suitable for administration by inhalation include fine-grained powders or aerosols, which can be produced by means of various types of metered-dose pressurized sols, nebulizers or insufflators. Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous And non-aqueous sterile suspensions, which may include suspending agents and thickening agents. These formulations can be presented in unit-dose or multi-dose containers (for example, sealed ampoules and vials) and can be stored in freeze-dried (lyophilized) conditions, just adding a sterile liquid carrier (for example, water for injection) just before use . Temporary preparation of injection solutions and suspensions can be prepared from sterile powders, granules and lozenges. It should be understood that in addition to the ingredients specifically mentioned above, the formulations described herein may include other industry-used agents with regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents. The therapeutically effective amount of the compound of formula I or formula IA will depend on a number of factors, including (for example) the age and weight of the human or other animal, the precise condition requiring treatment and its severity, the nature of the formulation and the route of administration, and The final decision will be made by the consulting physician or veterinarian. The effective amount of its salt or hydrate can be determined as the ratio of the effective amount of the compound of Formula I or Formula IA or its salt, solvate or hydrate itself. Embodiments of the present invention provide: another agent effective to treat or prevent rhinovirus, coronavirus, picornavirus and / or norovirus infection in a single agent form or (a) to improve immune response and robustness The combination of another agent or (c) another agent that reduces inflammation and / or pain is administered to a healthy or virally infected patient with a compound of formula I or formula IA. It is believed that the compound of Formula I or Formula IA or its salt, solvate or hydrate has the ability to inhibit or prevent the multiprotein progression of the translated viral genome in the host cell by inhibiting the viral 3C or 3C protease, preventing the virus from replicating Prevent, stop or reduce the activity of rhinovirus, coronavirus, picornavirus and / or norovirus. Therefore, a method for treating a virus susceptible to 3C or 3CL protease inhibition in a mammal is provided, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I or formula IA or a pharmaceutically acceptable salt, solvate or Hydrate. In one embodiment, the virus is rhinovirus. In one embodiment, the virus is a coronavirus. In one embodiment, the virus is a picornavirus. In one embodiment, the virus is Norovirus. In another embodiment, the protease is a 3C protease. In another embodiment, the protease is a 3CL protease. In one embodiment, the mammal is a human. In another aspect of the present invention, there is provided a method for inhibiting viral 3C protease or viral 3CL protease in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I or formula IA or a pharmaceutically acceptable salt thereof , Solvate or hydrate. In one embodiment, the mammal is a human. In another aspect, the present invention provides treatment of respiratory disorders (including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposure, acute lung infection, chronic lung infection, α1 antitrypsin disease , Cystic fibrosis and autoimmune diseases), which comprises administering a compound of formula I or a compound of formula IA or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to a human in need. In one aspect, the invention relates to a method of treating COPD, which comprises administering a compound of formula I or a compound of formula IA or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to a human in need. In yet another aspect, the present invention provides the use of a compound of formula I or a compound of formula IA or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for the treatment of respiratory disorders including COPD, asthma, fibrosis, chronic asthma And acute asthma, lung disease secondary to environmental exposure, acute lung infection, chronic lung infection, α1 antitrypsin disease, cystic fibrosis and autoimmune disease. In one aspect, the invention relates to the use of a compound of formula I or a compound of formula IA or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for the treatment of COPD. In another aspect, the invention relates to the use of a compound of formula I or a compound of formula IA or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of respiratory disorders, the respiratory disorders including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposure, acute lung infection, chronic lung infection, α1 antitrypsin disease, cystic fibrosis and autoimmune disease. In one aspect, the invention relates to the use of a compound of formula I or a compound of formula IA or a salt thereof, particularly a pharmaceutically acceptable salt, for the manufacture of a medicament for the treatment of COPD. In another aspect, the invention relates to a compound of formula I or a compound of formula IA or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for use in medical therapy. The present invention relates to a compound of formula I or a compound of formula IA or a salt thereof, particularly a pharmaceutically acceptable salt thereof, which is used in therapy, specifically for the treatment of respiratory disorders, including COPD, asthma, fibrosis, chronic asthma and Acute asthma, lung disease secondary to environmental exposure, acute lung infection, chronic lung infection, α1 antitrypsin disease, cystic fibrosis and autoimmune disease. In one aspect, the invention relates to a compound of formula I or a compound of formula IA or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for use in the treatment of COPD. In other embodiments, the compounds of the present invention can be used in combination with one or more antiviral therapeutic agents or anti-inflammatory agents that can be used to prevent or treat viral diseases or related pathophysiology. Therefore, the compounds of the present invention and their salts, solvates or other pharmaceutically acceptable derivatives can be used alone or in combination with other antiviral or anti-inflammatory therapeutic agents. Compounds of formula I or formula IA and their pharmaceutically acceptable salts can be used in combination with one or more other agents that can be used to prevent or treat respiratory diseases, inflammatory diseases, autoimmune diseases, such as antihistamines, corticosteroids (e.g. , Fluticasone propionate (fluticasone propionate), fluticasone furanate (fluticasone furoate), beclomethasone dipropionate (beclomethasone dipropionate), budesonide (budesonide), ciclesonide (ciclesonide), mometasone furan Formate (mometasone furoate), triamcinolone (triamcinolone), flunisolide (flunisolide), NSAID, leukotriene modifier (e.g., montelukast (montelukast), zafirlukast), Pranlukast), tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors, such as elastase inhibitors, integrin antagonists (eg, β-2 integrin) Protein antagonists), adenosine A2a agonists, mediator release inhibitors such as cromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors Preparations, LP (lysophospholipid) inhibitors or FLAP (5-lipoxygenase activated protein) inhibitors (for example, 3- (3- (third butylthio) -1- (4- (6-ethoxy Pyridin-3-yl) benzyl) -5-((5-ethylpyridin-2-yl) methoxy) -1H-indol-2-yl) -2,2-dimethyl sodium propionate) , Bronchodilators (eg, muscarinic antagonists, β-2 agonists), methotrexate (methotrexate) and similar agents; monoclonal antibody therapy, such as anti-IgE, anti-TNF, anti-IL-5, anti-IL -6, anti-IL-12, anti-IL-1 and similar agents; cytokinin receptor therapy, such as etanercept and similar agents; antigen non-specific immunotherapy (for example, interferon or other cell-mediated Chemokine / chemokine, chemokine receptor modulators, such as CCR3, CCR4 or CXCR2 antagonists, other cytokines / chemokine agonists or antagonists, TLR agonists and similar agents), suitable Infectious agents, including antibiotic agents, antifungal agents, anthelmintic agents, antimalarial agents, antiprotozoal agents, antituberculosis agents, and antiviral agents, are included at https: // www. drugs. com / drug-class / anti-infectives. Those listed in html. Suitably, for the treatment of asthma, the compounds or pharmaceutical formulations of the present invention can be administered with anti-inflammatory agents (eg, corticosteroids or pharmaceutical formulations thereof). For example, the compounds of the present invention can be formulated in a single formulation with an anti-inflammatory agent (eg, corticosteroid), such as a dry powder formulation for inhalation. Alternatively, pharmaceutical formulations containing compounds of the present invention can be administered simultaneously or sequentially in combination with pharmaceutical formulations containing anti-inflammatory agents (eg, corticosteroids). In one embodiment, a pharmaceutical formulation containing a compound of the present invention and a pharmaceutical formulation containing an anti-inflammatory agent (eg, corticosteroid) can each be kept in a device suitable for simultaneous administration of both formulations via inhalation. Suitable corticosteroids for administration with the compounds of the invention include, but are not limited to, fluticasone furan formate, fluticasone propionate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furan Formate, triamcinolone acetonide, flunisolide and prednisolone. In one embodiment of the present invention, corticosteroids for administration with the compounds of the present invention via inhalation include fluticasone furan formate, fluticasone propionate, beclomethasone dipropionate, budesonide, ciclesonide German, mometasone furan formate and flunisolide. Suitably, for the treatment of COPD, COPD-bronchodilator overlap syndrome and bronchiectasis, the compound or pharmaceutical formulation of the present invention may be administered with one or more bronchodilators or pharmaceutical formulations thereof. For example, the compounds of the present invention can be formulated in a single formulation with one or more bronchodilators, such as a dry powder formulation for inhalation. Alternatively, the pharmaceutical formulation containing the compound of the present invention can be administered simultaneously or sequentially in combination with the pharmaceutical formulation containing one or more bronchodilators. In another alternative, the formulation comprising the compound of the invention and the bronchodilator can be administered in combination with a pharmaceutical formulation comprising another bronchodilator. In one embodiment, the pharmaceutical formulation comprising the compound of the invention and the pharmaceutical formulation comprising one or more bronchodilators can each be maintained in a device suitable for simultaneous administration of both formulations via inhalation. In another embodiment, the pharmaceutical formulation comprising the compound of the present invention together with a bronchodilator and the pharmaceutical formulation comprising another bronchodilator may each be maintained in a form suitable for simultaneous administration of one or more of the two formulations via inhalation In the device. Suitable bronchodilators for administration with the compounds of the present invention include, but are not limited to, β2-adrenoceptor agonists and anti-parasympathetic agents. Examples of β2-adrenoceptor agonists include, for example, vilanterol, salmeterol, salbutamol, formoterol, salmefamol, Fenoterol, carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, fluorobutanol Terro (flerbuterol), reproterol (reproterol), bambuterol (bambuterol), indacaterol (indacaterol), terbutaline (terbutaline) and its salts, such as salmeterol xinafoate (xinafoate, 1-hydroxy-2-naphthalene carboxylate), sulfate of salbutamol or fumarate of formoterol. Suitable anti-parasympathetic agents include umeclidinium (eg in the form of bromide), ipratropium (eg in the form of bromide), oxitropium (eg in the form of bromide) and tiotropium Ammonium (tiotropium, for example in the form of bromide). In one embodiment of the present invention, the compound of the present invention can be administered together with a β2-adrenergic receptor agonist (eg, vilanterol) and an anti-parasympathetic agent (eg, urdesium bromide). The compound of the present invention and any other pharmaceutically active agent may be administered together or separately, and when administered separately, administration may occur simultaneously or sequentially in any order. The amount of the compound of the present invention and other pharmaceutically active agents and the relative timing of administration will be selected to achieve the desired combined therapeutic effect. The combination of the compound of the present invention and its salt, solvate or other pharmaceutically acceptable derivative with other therapeutic agents can be combined by simultaneous administration in the following form: (1) an overall pharmaceutical combination including two compounds Or (2) a separate pharmaceutical composition each including one of the compounds. Alternatively, the combination can be administered separately in a sequential manner, where one therapeutic agent is administered first and the other or vice versa. This sequential administration can be close or far in time. The amount and relative timing of the compound of Formula I or Formula IA or its salt and other pharmaceutically active agents will be selected to achieve the desired combined therapeutic effect. More specifically, the embodiments provide the method as described, which includes administration of additional agents selected from the group consisting of antiviral agents, antibiotics, analgesics, nonsteroidal anti-inflammatory (NSAID) agents, antifungal agents, anti-fungal agents Parasitic agents, anti-nausea agents, anti-diarrhea agents or immunosuppressive agents. In certain embodiments, the antiviral agent is an anti-hepatitis A agent or an antiretroviral agent. More specifically, the additional agent is administered in part of a single dosage form of the pharmaceutical formulation or in a separate dosage form. The present invention relates to compounds, compositions and pharmaceutical compositions, which have utility as novel treatments and / or preventive therapies against viral infections. Although not wishing to be bound by any particular theory, it is believed that the compounds of the present invention can inhibit the activity of rhinovirus and coronavirus self-lyases (3C protease in rhinovirus and 3CL (3C-like) protease in coronavirus). It plays an important role in processing multi-protein precursor proteins into functional viral proteins and enzymes. Therefore, the inhibition of 3C and 3CL proteases is expected to reduce the ability of rhinovirus and coronavirus to replicate in host cells. Diseases and symptoms caused by rhinovirus and coronavirus infections can be treated and / or prevented by disrupting the ability of rhinoviruses or coronaviruses to process their polyprotein precursors after viral genomes are translated in host cells. Therefore, in another embodiment of the present invention, there is provided a method of treating or preventing a viral infection in an individual with a viral infection, which comprises administering an inhibitor of 3C protease to the individual, wherein the inhibitor is a compound of formula I or formula IA . In another embodiment of the present invention, there is provided a method of treating or preventing a viral infection from an RNA-based virus in an individual with a viral infection, which comprises administering an inhibitor of 3C protease to the individual, wherein the inhibitor is Formula I Or a compound of formula IA. In another embodiment of the present invention, there is provided a method for treating coronavirus infection in an individual suffering from rhinovirus infection, which comprises administering an inhibitor of 3C protease to the individual, wherein the inhibitor is a compound of formula I or formula IA. In another embodiment of the present invention, there is provided a method of treating a viral infection in an individual suffering from a viral infection, which comprises administering to the individual a selective chemical inhibitor of 3C protease, wherein the inhibitor comprises a compound from Table 2. In one embodiment of the invention, the compounds described herein can be used to prevent or treat viral infections in individuals caused by single-stranded RNA viruses. RNA viruses are viruses that have RNA (ribonucleic acid) as their genetic material. This nucleic acid is usually a single-stranded RNA (ssRNA). RNA viruses can be further classified as negative and positive according to the sense or polarity of their RNA. The sense virus RNA is similar to mRNA and can thus be immediately translated by the host cell. The negative-sense viral RNA is complementary to the mRNA, and thus must be converted to sense RNA by RNA polymerase before translation. Therefore, the purified RNA of the sense virus can directly cause infection, but it can be less infectious than the entire virus particle. The purified RNA of the negative-sense virus is not infectious by itself, because it needs to be transferred into sense RNA; each virus particle can be transferred into several sense RNA. In one embodiment of the invention, the compounds described herein can be used to prevent or treat viral infections caused by sense single-stranded RNA viruses in an individual. In one embodiment of the invention, the compounds described herein can be used to prevent or treat viral infections caused by negative-sense single-stranded RNA viruses in an individual. In some embodiments, there is provided a method of treating a viral infection mediated at least in part by a virus in the picornaviridae or coronaviridae viruses in an individual, which comprises administering to the individual comprising any of formula I or formula IA Of compounds or pharmaceutically acceptable salts thereof. In yet another aspect, another embodiment of the present invention provides a method of inhibiting the progress of viral infection in an individual at risk of infection with a virus in the picornaviridae or coronaviridae virus, which comprises administering treatment to the individual An effective amount of a compound of formula I or formula IA or a pharmaceutically acceptable salt thereof. In yet another aspect, another embodiment of the present invention provides a method of preventing viral infection in an individual at risk of infection with a virus in the picornaviridae or coronaviridae virus, which comprises administering effective treatment to the individual Amount of the compound of formula I or formula IA or a pharmaceutically acceptable salt thereof. In yet another aspect, another embodiment of the present invention provides a method of treating a viral infection in an individual suffering from the viral infection, wherein the virus is a virus of the picornaviridae or coronaviridae, which comprises administering to the individual With a therapeutically effective amount of a compound of formula I or formula IA or a pharmaceutically acceptable salt thereof. A method of treating a viral infection in an individual suffering from a viral infection, which comprises administering to the individual a compound of any one of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof. A method of preventing viral infection in an individual includes administering to the individual a compound of any one of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof. A method of treating a coronavirus infection in an individual suffering from a coronavirus infection includes administering to the individual a chemical inhibitor of a coronavirus 3CL protease selected from the group consisting of: 229E 3CL protease, NL63 3CL protease, OC43 3CL protease, HKU1 3CL protease, SARS-CoV 3CL protease and MERS-CoV 3CL protease. A method of treating a coronavirus infection in an individual suffering from a coronavirus infection involves administering to the individual a chemical inhibitor of coronavirus 229E 3CL protease. A method of treating coronavirus infection in an individual suffering from a coronavirus infection involves administering to the individual a chemical inhibitor of the coronavirus OC43 3CL protease. A method of treating a coronavirus infection in an individual with a coronavirus infection involves administering to the individual a chemical inhibitor of the coronavirus HKU1 3CL protease. A method of treating a coronavirus infection in an individual suffering from a coronavirus infection involves administering to the individual a chemical inhibitor of the coronavirus SARS-CoV 3CL protease. A method of treating a coronavirus infection in an individual with a coronavirus infection involves administering to the individual a chemical inhibitor of the coronavirus MERS-CoV 3CL protease. A method of treating rhinovirus infection in an individual suffering from rhinovirus infection comprises administering to the individual a chemical inhibitor of rhinovirus 3C protease selected from the group consisting of HRV-15 3C protease and HRV-16 3C protease. A method of treating rhinovirus infection in an individual suffering from rhinovirus infection involves administering to the individual a chemical inhibitor of rhinovirus HRV-15 3C. A method of treating rhinovirus infection in an individual suffering from rhinovirus infection involves administering to the individual a chemical inhibitor of rhinovirus HRV-16 3C. In other embodiments, the compounds described herein can be used to prevent or treat viral infections in an individual, where the infection is caused by a virus belonging to the following families: bright bacteriophage virus, naked ribonucleic acid virus, small ribonucleic acid virus, double Cistronic virus, marine ribonucleic acid virus, associated virus, cowpea mosaic virus, potato virus Y, calicivirus, astrovirus, noda virus, tetravirus, yellow virus, tomato bushy stunt virus, coronavirus, arteritis virus , Yellow head virus, flavivirus, togavirus, brome mosaic virus, turnip yellowing mosaic virus, monastery virus, Campylovirus, Secovirus, bacillus ribonucleic acid virus, infectious silkworm softener virus, Wenzhou mandarin orange Dwarf virus, cherry file virus, hepatitis virus, southern bean mosaic virus, phantom virus, tobacco mosaic virus, tobacco brittle virus, barley virus, fungal baculovirus, potato virus, peanut cluster virus, beet necrosis Yellow vein virus, ulmi virus and rubus virus. The present invention discloses compounds, methods and pharmaceutical compositions for treating viral infections by administering compounds of Formula I or Formula IA in therapeutically effective amounts. Also disclosed are methods of preparing compounds of Formula I or Formula IA and methods of using the compounds and pharmaceutical compositions thereof. Specifically, the treatment and prevention of viral infections, which are caused by RNA or DNA viruses, for example, are revealed. In other embodiments, the compounds described herein can be used to prevent or treat viral infections from any genealogy, genus, family, or specific species listed in Table 1. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by a virus belonging to the family Picornaviridae or Coronaviridae. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by a virus belonging to the family Picornaviridae. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by a virus belonging to the Coronaviridae family. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by a virus belonging to the family Picornaviridae. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, wherein the infection is caused by any one or more viruses selected from the group consisting of rhinovirus, Middle East respiratory syndrome coronavirus ( MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), common coronaviridae (including (but not limited to) OC43, HKU1, 229e, and NL63), enterovirus, poliovirus, coxsackievirus , Hepatitis A virus, foot-and-mouth disease virus (FMDV) and calicivirus. In other embodiments, the compounds described herein can be used to treat an infection in an individual, wherein the infection is caused by any of the human coronaviruses. In other embodiments, the compounds described herein can be used to treat an infection in an individual, wherein the infection is caused by any of human coronavirus 229E, NL63, OC43, HKU1, SARS-CoV, and MERS-CoV. In other embodiments, the compounds described herein can be used to treat an infection in an individual, wherein the infection is caused by any of the alpha human coronaviruses. In other embodiments, the compounds described herein can be used to treat infections in an individual, where the infection is caused by alpha human coronavirus 229E and NL63. In other embodiments, the compounds described herein can be used to treat an infection in an individual, wherein the infection is caused by any of the beta human coronaviruses. In other embodiments, the compounds described herein can be used to treat infections in an individual, where the infection is caused by beta human coronavirus OC43, HKU1, SARS-CoV, and MERS-CoV. In other embodiments, the compounds described herein can be used to treat infections in an individual, where the infection is caused by the human coronavirus MERS-CoV or SARS-CoV. In other embodiments, the compounds described herein can be used to treat infections in an individual, where the infection is caused by the human coronavirus MERS-CoV. In other embodiments, the compounds described herein can be used to treat infections in an individual, where the infection is caused by the human coronavirus SARS-CoV. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, wherein the infection is caused by any of human enteroviruses A-D. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by enterovirus A71. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by enterovirus D68. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, wherein the infection is caused by any of the human rhinoviruses A-C. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by human rhinovirus A. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by human rhinovirus B. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by human rhinovirus C. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by poliovirus. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by Coxsackie virus. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by EV-68 virus or EV-71 virus. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by echovirus. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by hepatitis A virus. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by any of the caliciviruses. In other embodiments, the compounds described herein can be used to treat a viral infection in an individual, wherein the infection is caused by any of the Noroviruses. In other embodiments, the compounds described herein can be used to treat viral infections in an individual, where the infection is caused by Norwalk virus. In other embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the compounds listed in Table 2.Examples Synthesis scheme The compound of formula (I) of the present invention,Formula (I) or its corresponding pharmaceutically acceptable salt is prepared using conventional organic synthesis, whereA system Phenyl or oxazolyl;R 1 , R ′ 1 and R '' 1 Independently selected from H; C1-C6-alkyl; halo; haloalkyl; NR6 R7 ; OR8 ; SR9 ; Via C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Substituted C1-C6 alkyl; via C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Substituted C3-C8 cycloalkyl or C3-C8 heterocycloalkyl;R 2 system C1-C6-alkyl, optionally C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy C1-C6-alkyl substituted with alkyl, hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; optionally via C1-C6-alkyl, C3-C8-cycloalkane C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; NR6 R7 ;Aryl substituted with the following groups as appropriate : C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, halo substituted alkoxy, hydroxy, thio alkyl;Heteroaryl substituted by the following groups as appropriate : C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, amine alkyl, alkoxy, halo substituted alkoxy; Wherein C1-C6-alkyl or C1-C6-cycloalkyl is further subject to halogen, O, N, S, NR6 R7 , OR8 , SR9 ReplaceR 3 and R 4 Independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy C1-C6 alkyl substituted with hydroxy, hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; -C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl ; Or R3 With R4 Together form C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Replace the ring structure of 5 to 10 members;R 5 system C1-C6 alkyl; C1-C6 alkyl substituted with C1-C6-alkyl or aryl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl;R 6 and R 7 Independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl , Alkoxy, hydroxy, thioalkyl substituted C1-C6 alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkane Group or C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R6 With R7 Together form halo, haloalkyl, amine, NR6 R7 , OR8 , SR9 Substituted 3- to 10-membered cycloalkyl or heterocycloalkyl ring; aryl; C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl , NR6 R7 , OR8 , SR9 Substituted aryl; heteroaryl; or C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR6 R7 , OR8 , SR9 Substituted heteroaryl; andR 8 and R 9 Independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl , Alkoxy, hydroxy, thioalkyl substituted C1-C6 alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkane Group or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-cycloalkyl or C3-C8-hetero Cycloalkyl, or its salt. Suitable synthetic routes are shown below in the general reaction scheme below. Those skilled in the art will understand that if the substituents described herein are incompatible with the synthesis methods described herein, the substituents can be protected with suitable protecting groups that are stable to the reaction conditions. The protecting group can be removed at a suitable point in the reaction sequence to provide the desired intermediate or target compound. Those skilled in the art are familiar with these suitable protecting groups and methods using suitable protecting groups to protect and deprotect different substituents; examples of these can be found in T. Greene and P. Wuts,Protecting Groups in Chemical Synthesis (3rd edition), John Wiley & Sons, NY (1999). In some cases, substituents may be specifically selected to be reactive under the selected reaction conditions. Under these circumstances, the reaction conditions convert the selected substituent into another substituent, which is used as the desired substituent in the intermediate compound or the target compound.Program 1 As shown in Scheme 1, lactam can be prepared according to the literature (Journal of Medicinal Chemistry 48 (22), 6767-6771, 2005)1 . By making1 With SO3 -Pyridine complex reacts to oxidize it to produce aldehyde2 And then2 Reaction with isocyanide (e.g. isocyanoisopropane) in the presence of a suitable acid (e.g. benzoic acid) produces an ester3 . By removing under alkaline conditions3 The benzoyl group is subsequently deprotected using a suitable acid (eg HCl) in a suitable solvent (eg 1,4-dioxane)4 Amino group alcohol5 . Compounds can be prepared using any suitable amide formation conditions6 . Preferably, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorane-2,4,6-trioxide is used in the present invention . Use HCl to remove compounds6 The Boc group produces an amine as a key intermediate7 . Scenario 2As shown in Scheme 2, by using 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorane-2,4,6-trioxide As a preferred coupling agent, the amine7 (Free or its salt) subjected to a suitable Cbz-amino acid (for example, (S) -2-(((benzyloxy) carbonyl) amino) -3- (4- (trifluoromethyl) hexahydro Pyridin-1-yl) propionic acid (B4 -Acetylamine formation reaction purchased or prepared as described in the examples)) to obtain amide8 . Subsequent oxidation is accomplished using Dess-Martin periodiodine to produce the final product.Compound examples abbreviation When explaining examples, chemical elements are identified according to the periodic table of elements. The abbreviations and symbols used in this article conform to the common usage of these abbreviations and symbols by those familiar with chemical technology. This article uses the following abbreviations: AcOH Acetic acid Ac2 O Acetic anhydride aq Aqueous B4 (S) -2-(((benzyloxy) carbonyl) amino) -3- (4- (trifluoromethyl) hexahydropyridin-1-yl) propionic acid BOC (Boc ) N-third butoxycarbonyl or third butyloxycarbonyl CBz carboxybenzyl CellTiter-Glo® CellTiter-Glo® luminescent cell viability analysis from Promega CHAPS 3-[(3-cholamidopropyl) di Methylammonium] -1-propanesulfonate Combiflash® automated rapid chromatography CPE cytopathic effect or cytopathic effect from Teledyne Isco dba dibenzylideneacetone or dibenzylideneacetone DCE dichloroethane DCM dichloro Methane DCM / EA Dichloromethane / ethanol DIPEA (or DIEA) N, N-diisopropylethylamine or Hünig base DME Dimethoxyethane DMEM Dulbeco's modified Eagle's medium (Dulbecc o ’s Modified Eagle Medium) DMF dimethylformamide DMP Dess-Martin periodiodine DMSO-d6 deuterated dimethyl sulfoxide DMSO dimethyl sulfoxide EC50 50% effective concentration EDTA EDTA Envision EnVision Multi-Mark Reader Et from PerkinElmer2 O Diethyl ether EtOH ethanol EtOAc, EA, AcOEt ethyl acetate FBS fetal bovine serum FRET fluorescence resonance energy transfer (Förster Resonance Energy Transfer) GlutaMAX ™ cell culture supplement from Life Technologies h hour HEPES 4- (2-hydroxyethyl ) -1-Hexahydropyrazineethanesulfonic Acid HPLC High Performance Liquid Chromatography IC50 50% inhibition concentration iPrOH isopropyl alcohol (isopropyl alcohol or isopropanol) LCMS liquid chromatography mass spectrometry MeOH methanol NBS N-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide NXS N-halogen Succinimide NaBH (OAc)3 Sodium triethoxyborohydride NMR proton nuclear magnetic resonance spectroscopy Pd2 (dba)3 Ginseng (dibenzylideneacetone) dipalladium (0) PE petroleum ether PPh3 Triphenylphosphine RB round bottom rt or r.t. room temperature RT retention time SFC supercritical fluid chromatography SO3 pyr Sulfur trioxide pyridine complex-formula C5 H5 NSO3 SPhos 2-dicyclohexylphosphine-2 ', 6'-dimethoxybiphenyl or dicyclohexyl (2', 6'-dimethoxy- [1,1'-biphenyl] -2-yl) t-BuOMe methyl tertiary butyl ether T3P 1-propanephosphonic anhydride solution, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorane- 2,4,6-Trioxide TFA Trifluoroacetic acid Thermi Combi Multidrop ™ Combi reagent dispenser from Thermo Fisher Scientific THF Tetrahydrofuran uv UV Unless otherwise stated, all starting materials are obtained from the supplier without further Use immediately after purification. Unless otherwise indicated, all temperatures are expressed in degrees Celsius (degrees Celsius). Unless otherwise indicated, all reactions are carried out under an inert atmosphere and at ambient temperature. If necessary, all temperatures are given in ° C, all solvents have the highest available purity and all reactions are under anhydrous conditions and under argon (Ar) or nitrogen (N2 ) Run in an atmosphere. The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but provide guidance to those skilled in the art for preparing and using the compounds, compositions, and methods of the present invention. Although specific embodiments of the present invention have been described, those skilled in the art should understand that various changes and modifications can be made without departing from the spirit and scope of the present invention. As used herein, the symbols and conventions used in these processes, schemes, and examples and contemporary scientific literature (eg,Journal of the American Chemical Society orJournal of Biological Chemistry ) Used in the same. Unless otherwise stated, all starting materials were obtained from suppliers and used without further purification. All references to ether refer to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in degrees Celsius (degrees Celsius). Unless otherwise stated, all reactions are carried out under an inert atmosphere and at room temperature, and unless otherwise stated, all solvents have the highest purity available.1 H NMR (hereinafter also referred to as "NMR") spectra were recorded on a Varian VXR-300, Varian Unity-300, Varian Unity-400 instrument, Brucker AVANCE-400, General Electric QE-300, or Bruker AM 400 spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). The coupling constant is given in units of hertz (Hz). The split pattern illustrates the apparent multiplicity and is designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (Broad peak). The mass spectrometry system uses functional electrospray ionization to run on an open access LC-MS system. LC conditions: 10% to 80% CH3 CN (0.018% TFA), 3.0 minutes, including 1.25 minutes and reequilibration for 0.5 minutes; detection by MS, UV and light scattering detector (ELS) at 214 nm. Column: 2.1 × 50 mm Zorbax SB-C8. The flash chromatography is run on Merck Silicone 60 (230-400 mesh), or using a Teledyne Isco Combiflash Companion with a normal phase disposable Redi-Sep rapid column.Intermediate Examples 1 Intermediate A Intermediate A(3S)- benzoic acid 3-((( Third butoxycarbonyl ) Amine )-1-( Isopropylamino )-1- Pendant -4-((S) -2- Pyridoxine -3- base ) Ding -2- Ester 3 ((S) -1-Hydroxy-3-((S) -2-oxopyrrolidin-3-yl) prop-2-yl) aminocarboxylic acid tert-butyl ester (1.0 g, 3.87 mmol) The solution in a mixture of DMSO (1.4 mL, 19.35 mmol) and DCM (10 mL) was cooled to -5 ° C, and Hunig's base (2.366 mL, 13.55 mmol) was added while stirring. In another round bottom flask, a suspension of sulfur trioxide pyridine complex (1.232 g, 7.74 mmol) in pyridine (0.626 mL, 7.74 mmol) and DMSO (1.4 mL, 19.35 mmol) was stirred at room temperature for 10 minutes . This suspension was then added to the above preformed solution at -5 ° C. An additional volume of DCM (6 mL) was used to complete the transfer. The resulting mixture was stirred at -5 ° C for another 2 hours. Then 2-isocyanopropane (0.438 mL, 4.65 mmol) was added to the reaction mixture, followed by benzoic acid (3.07 g, 25.2 mmol), and the reaction mixture was stirred at rt overnight (removed 5 minutes after addition) Dry ice bath). The reaction mixture was diluted with EtOAc. After separating the EtOAc layer, use saturated NaHCO3 Aqueous solution, 1M aq Na2 CO3 , The organic phase was washed with brine and washed with Na2 SO4 Dry, filter and concentrate. The crude material was further purified by column chromatography on silica gel, eluting with 0-100% EtOAc in hexane (25 minutes) and then replacing EtOAc with a 3: 1 mixture of EtOAc: EtOH (50%) for 10 minutes . Collect the desired fractions and concentrate to give (3S) -benzoic acid 3-((third butoxycarbonyl) amino) -1- (isopropylamino) -1-pentoxy as white solid 4-((S) -2-oxopyrrolidin-3-yl) but-2-yl ester (1.36 g, 79% yield). LCMS: M + 1 = 448.4. (A mixture of two diastereomers immediately following leaching).((2S) -3- Hydroxyl -4- ( Isopropylamino ) -4- Pendant -1-((S) -2- Pyridoxine -3- base ) Ding -2- base ) Tertiary butyl carbamate will(3S)- benzoic acid 3-((( Third butoxycarbonyl ) Amine )-1-( Isopropylamino )-1- Pendant -4-((S) -2- Pyridoxine -3- base ) Ding -2- Ester (16.27 g, 36.4 mmol) was dissolved in tetrahydrofuran (THF) (30 mL) and water (30 mL). Lithium hydroxide (3.05 g, 127 mmol) was added to the reaction mixture. The reaction mixture was stirred for 2 hours and confirmed to be complete by LCMS monitoring. THF was evaporated under reduced pressure and the aqueous layer was extracted with ethyl acetate, and NaHCO3 The extract was washed with solution, brine, filtered, dried over sodium sulfate and concentrated in vacuo. The crude material was triturated with diethyl ether to produce ((2S) -3-hydroxy-4- (isopropylamino) -4-oxo-1-((S) -2-side as a white solid Oxypyrrolidin-3-yl) but-2-yl) aminocarboxylic acid tert-butyl ester (10.61 g, 85%). LCMS: [M + 1] = 344.3, (two peaks, one for each alcohol diastereomer).(3S) -3- Amine -2- Hydroxyl -N- Isopropyl -4-((S) -2- Pyridoxine -3- base ) Butylamide hydrochloride To ((2S) -3-hydroxy-4- (isopropylamino) -4-oxo-1-((S) -2-oxopyrrolidin-3-yl) butane at 0 ° C A stirred mixture of 2-butyl) aminocarboxylic acid tert-butyl ester (10 g, 29.1 mmol) in dichloromethane (DCM) (15 mL) and ethyl acetate (100 mL) was added hydrochloric acid (29.1 mL, 116 mmol). 5 minutes after the addition, the ice bath was removed and the reaction mixture was stirred at rt overnight. LCMS indicated the reaction was complete. Filter and collect the precipitated solid to obtain (3S) -3-amino-2-hydroxy-N-isopropyl-4-((S) -2-oxopyrrolidin-3-yl) as a white solid ) Butylamide hydrochloride (8.0 g, 28.6 mmol, 98% yield). The hydrochloride salt was used in the next step without any further purification. LCMS: [M + 1] = 244.2, (two peaks, one for each alcohol diastereomer).((2S) -1-(((2S) -3- Hydroxyl -4- ( Isopropylamino ) -4- Pendant -1-((S) -2- Pyridoxine -3- base ) Ding -2- base ) Amine ) -4- methyl -1- Pendant -2- base ) Tertiary butyl carbamate In an RB flask, add (S) -2-((third butoxycarbonyl) amino) -4-methylpentanoic acid (0.909 g, 3.93 mmol), DIPEA (1.87 mL) in DCM (20 mL) , 10.72 mmol) and (3S) -3-amino-2-hydroxy-N-isopropyl-4-((S) -2-oxopyrrolidin-3-yl) butyramide hydrochloride ( 1.00 g, 3.57 mmol). The mixture was stirred at 0 ° C. and T3P (50 wt% in EtOAc, 2.34 mL, 3.93 mmol) was added dropwise. The mixture was stirred in an ice bath for 2 hours. Dilute the mixture with EtOAc, use 1N HCl (aq), NaHCO3 (aq), brine washing and then Na2 SO4 Dry, filter, and concentrate to give ((2S) -1-(((2S) -3-hydroxy-4- (isopropylamino) -4-oxo-1-((S) -2-side Oxypyrrolidin-3-yl) but-2-yl) amino) -4-methyl-1-pentoxypent-2-yl) aminocarboxylic acid tert-butyl ester (1.36 g, 83% crude Yield). This material was used in the next step without further purification. LCMS: M + 1 = 457.3. (Two peaks of a mixture of non-image isomers)(2S) -2- Amine -N-((2S) -3- Hydroxyl -4- ( Isopropylamino ) -4- Pendant -1-((S) -2- Pyridoxine -3- base ) Ding -2- base ) -4- Methylpentylamide hydrochloride To ((2S) -1-(((2S) -3-hydroxy-4- (isopropylamino) -4-oxo-1-((S) -2-oxo Pyrrolidin-3-yl) but-2-yl) amino) -4-methyl-1-pentoxypent-2-yl) aminocarboxylic acid tert-butyl ester (7 g, 15.33 mmol) in di Hydrochloric acid (15.33 mL, 61.3 mmol) was added to the stirred solution in methyl chloride (DCM) (80 mL). 5 minutes after the addition, the ice bath was removed and the reaction mixture was stirred at rt overnight. LCMS indicated the reaction was complete. Filter and collect the precipitated solid to produce (2S) -2-amino-N-((2S) -3-hydroxy-4- (isopropylamino) -4-oxo-1 as a white solid -((S) -2-oxopyrrolidin-3-yl) but-2-yl) -4-methylpentylamide hydrochloride (6 g, 15.27 mmol, 100% yield). LCMS: M + 1 = 357.2.Examples 2 (S) -2-(((( Benzyloxy ) Carbonyl ) Amine ) -3- (4- ( Trifluoromethyl ) Hexahydropyridine -1- base ) Propionic acid In N2 Next, add 4- (trifluoromethyl) hexahydropyridine (2.97 g, 19.39 mmol) and (Z) -N- (trimethylsilyl) acetonitrile in acetonitrile (80 mL) to the RB flask Trimethylsilyl amine (2.371 mL, 9.70 mmol). The mixture was stirred at rt for 5 hours, and then (S)-(2-oxooxetan-3-yl) carbamic acid benzyl ester (3.3 g, 14.92 mmol) was added and stirring was continued overnight. The mixture was concentrated and the residue was dissolved in ether and extracted with 1N aqueous HCl. The aqueous layer was adjusted to pH 6.6 with 6N NaOH in an ice bath and extracted with EtOAc. Via Na2 SO4 The organic layer was dried and concentrated to give (S) -2-(((benzyloxy) carbonyl) amino) -3- (4- (trifluoromethyl) hexahydropyridin-1-yl) propionic acid (4.62 g, 12.34 mmol, 83% yield). LCMS: M + 1 = 375.2, 0.68 minutes.((2S) -1-(((2S) -1-(((2S) -3- Hydroxyl -4- ( Isopropylamino ) -4- Pendant -1-((S) -2- Pyridoxine -3- base ) Ding -2- base ) Amine ) -4- methyl -1- Pendant -2- base ) Amine )-1- Pendant -3- (4- ( Trifluoromethyl ) Hexahydropyridine -1- base ) C -2- base ) Benzyl Carbamate Add (2S) -2-amino-N-((2S) -3-hydroxy-4- (isopropylamino) -4- in dichloromethane (DCM) (30 mL) to the RB flask Pendant-1-((S) -2-pentoxypyrrolidin-3-yl) but-2-yl) -4-methylpentylamide hydrochloride (900 mg, 2.291 mmol), (S ) -2-(((benzyloxy) carbonyl) amino) -3- (4- (trifluoromethyl) hexahydropyridin-1-yl) propanoic acid (917 mg, 2.451 mmol). The mixture was stirred at -5 ° C for 5 minutes, and N-ethyl-N-isopropylpropan-2-amine (1.600 mL, 9.16 mmol) was added. The mixture was stirred at -5 ° C for 15 minutes, and then 2,4,6-tripropyl-1,3,5,2,4,6-trioxa was added dropwise in 10 mL EtOAc via another funnel Triphosphorane-2,4,6-trioxide (1.501 mL, 2.52 mmol) and continued stirring for 2 hours. The mixture was diluted with EtOAc and NaHCO3 Aqueous solution, brine washing, after Na2 SO4 Dry and concentrate to obtain the crude product, which is further purified by normal phase chromatography, and eluted with DCM and iPrOH, where iPrOH is up to 50% (80 g column) in 30 minutes to obtain (( 2S) -1-(((2S) -1-(((2S) -3-hydroxy-4- (isopropylamino) -4-oxo-1-((S) -2-oxo Pyrrolidin-3-yl) but-2-yl) amino) -4-methyl-1-oxopent-2-yl) amino) -1-oxo-3- (4- ( Trifluoromethyl) hexahydropyridin-1-yl) prop-2-yl) carbamic acid benzyl ester (1.36 g, 1.908 mmol, 83% yield). LCMS M + 1 = 713.6((S) -1-(((S) -1-(((S) -4- ( Isopropylamino ) -3,4- Dioxo -1-((S) -2- Pyridoxine -3- base ) Ding -2- base ) Amine ) -4- methyl -1- Pendant -2- base ) Amine )-1- Pendant -3- (4- ( Trifluoromethyl ) Hexahydropyridine -1- base ) C -2- base ) Benzyl Carbamate When Dess-Martin periodiodine (2.356 g, 5.56 mmol) was added at one time, stir ((2S) -1-(((2S) -1-(((2S)- 3-hydroxy-4- (isopropylamino) -4-oxo-1-((S) -2-oxopyrrolidin-3-yl) but-2-yl) amino) -4 -Methyl-1-oxopent-2-yl) amino) -1-oxo-3- (4- (trifluoromethyl) hexahydropyridin-1-yl) propan-2-yl) A solution of carbamate (2.64 g, 3.70 mmol) in dichloromethane (DCM) (50 mL). After 5 minutes, the ice bath was removed and the mixture was stirred for 2 hours. Add additional DMP (0.5 g, 1.17 mmol) and keep stirring for 1 hour. The mixture was concentrated and the residue was directly purified by automated normal phase chromatography, eluting with DCM and acetone, which was as high as 90% (240 g column) in 50 minutes of acetone. The parts were left overnight and precipitated and the DMP by-product was filtered out. The filtrate was concentrated to give ((S) -1-(((S) -1-(((S) -4- (isopropylamino) -3,4-diisopropylamino) -3,4-bis- pendantoxy- 1-((S) -2-oxopyrrolidin-3-yl) but-2-yl) amino) -4-methyl-1-oxopent-2-yl) amino) -1 -Benzyl-3-oxo-3- (4- (trifluoromethyl) hexahydropyridin-1-yl) prop-2-yl) carbamate (2.2 g, 3.10 mmol, 84% yield). The material was further purified by triturating with EtOAc / ether and again subjected to normal phase column purification to obtain 1.98 g of material (75%). LCMS 711.51 H NMR (400 MHz, DMSO-d 6 ) d ppm 0.77-0.95 (m, 6 H) 1.09 (d,J = 6.34 Hz, 6 H) 1.32-1.52 (m, 4 H) 1.54-1.80 (m, 5 H) 1.85-1.96 (m, 1 H) 1.96-2.08 (m, 2 H) 2.09-2.29 (m, 2 H) 2.30-2.39 (m, 1 H) 2.40-2.48 (m, 2 H) 2.96 (d,J = 9.38 Hz, 2 H) 3.06-3.23 (m, 2 H) 3.90 (dd,J = 14.70, 6.59 Hz, 1 H) 4.18 (q,J = 7.44 Hz, 1 H) 4.29-4.43 (m, 1 H) 4.93-5.13 (m, 3 H) 7.24-7.42 (m, 6 H) 7.69 (s, 1 H) 8.24 (d,J = 8.11 Hz, 1 H) 8.46-8.50 (m, 1 H) 8.50-8.63 (m, 2 H)Examples 3 (S) -2-(( Third butoxycarbonyl ) Amine ) -3- (6- ( Trifluoromethyl ) Pyridine -2- base ) Methyl propionate In N2 Next, add zinc (0.894 g, 13.67 mmol) (powder) to the 50-mL flask, followed by N, N-dimethylformamide (DMF) (10 mL) and I2 (0.174 g). Some heat was released and the mixture changed from dark red to a colorless suspension. After 10 minutes, (R) -2-((third butoxycarbonyl) amino) -3-iodopropionic acid methyl ester (1.5 g, 4.56 mmol) and I2 (0.174 g) were added, and the mixture was at rt Stir for 90 minutes. Add 2-bromo-6- (trifluoromethyl) pyridine (1.339 g, 5.92 mmol), Pd2 (dba)3 (0.104 g, 0.114 mmol) and dicyclohexyl (2 ', 6'-dimethoxy- [1,1'-biphenyl] -2-yl) phosphine (or Sphos) (0.094 g, 0.228 mmol) and The mixture was stirred at 50 ° C overnight. The reaction was diluted with EtOAc (50 mL) and filtered. Wash the organic solution with water (5 × 15 mL) and dry (Na2 SO4 ), Filtered and concentrated. The residue was purified by Combiflash automated silica gel chromatography and eluted with [EtOAc / EtOH 76:24] / hexane 5-40% to provide (S) -2-((third butyl) as a light green oil Oxyoxycarbonyl) amino) -3- (6- (trifluoromethyl) pyridin-2-yl) propionic acid methyl ester (0.783 g, 2.248 mmol, 49.3% yield). LCMS: [M + Na] +: 371.2.(S) -2-(((( Benzyloxy ) Carbonyl ) Amine ) -3- (6- ( Trifluoromethyl ) Pyridine -2- base ) Methyl propionate To a 100 mL RB flask was added (S) -2-((third butoxycarbonyl) amino) -3- (6- (trifluoromethyl) pyridine- in DCM (15 mL) at 0 ° C 2-yl) methyl propionate (0.783 g, 2.248 mmol), followed by the addition of HCl (11.24 mL, 45.0 mmol) (4 M in dioxane). The mixture was stirred at rt for 1 hour. The organic solution was concentrated to dryness under vacuum. The residue was dissolved in DCM (20 mL), and DIPEA (1.178 mL, 6.74 mmol) and Cbz-Cl (0.385 mL, 2.70 mmol) were added. The mixture was stirred at rt for 1 hour. The mixture was concentrated to dryness under vacuum and the residue was purified by Combiflash automated silica gel column chromatography (120 g Gold column, run for 18 minutes), dissolved with [EtOAc / EtOH 76:24] / hexane 0-30% To provide (S) -2-((((benzyloxy) carbonyl) amino) amino) -3- (6- (trifluoromethyl) pyridin-2-yl) propanoate in the form of a clear oil Ester (0.879 g, 2.138 mmol, 95% yield). LCMS: [M + H] +: 383.2.(S) -2-(((( Benzyloxy ) Carbonyl ) Amine ) -3- (6- ( Trifluoromethyl ) Pyridine -2- base ) Propionic acid To a 50 mL RB flask was added (S) -2-((((benzyloxy) carbonyl) amino) amino) -3- (6- (tris) in tetrahydrofuran (THF) (10 mL) at 0 ° C at rt Fluoromethyl) pyridin-2-yl) propionic acid methyl ester (0.879 g, 2.138 mmol), followed by the addition of lithium hydroxide (3.21 mL, 3.21 mmol) (1 M in water). The mixture was stirred at rt for 0.5 hour. HCl (3.21 mL, 3.21 mmol) (1 M in water) was added, and the mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 20 mL). Dry (Na2 SO4 ) The combined organic solution, filtered and concentrated to provide (S) -2-((((benzyloxy) carbonyl) amino) -3- (6- (trifluoromethyl) pyridine- 2-yl) propionic acid (0.891 g, 2.141 mmol, 100% yield). LCMS: [M + H] +: 369.1.((2S) -1-(((2S) -1-(((2S) -3- Hydroxyl -4- ( Isopropylamino ) -4- Pendant -1-((S) -2- Pyridoxine -3- base ) Ding -2- base ) Amine ) -4- methyl -1- Pendant -2- base ) Amine )-1- Pendant -3- (6- ( Trifluoromethyl ) Pyridine -2- base ) C -2- base ) Benzyl Carbamate In N2 To a 50 mL RB flask, add (2S) -2-amino-N-((2S) -3-hydroxy-4- (isopropylamino)-in dichloromethane (DCM) (10 mL) 4-oxo-1-((S) -2-oxopyrrolidin-3-yl) but-2-yl) -4-methylpentylamide hydrochloride (0.301 g, 0.767 mmol) and (S) -2-(((benzyloxy) carbonyl) amino) -3- (6- (trifluoromethyl) pyridin-2-yl) propanoic acid (0.319 g, 0.767 mmol), followed by the addition of DIPEA (0.669 mL, 3.83 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxaphosphorane-2,4,6-trioxide ( 0.671 mL, 1.150 mmol). The mixture was stirred at rt for 2 hours. LCMS indicated the formation of the desired product. The organic solution was concentrated and the residue was purified by Combiflash automated silica gel column chromatography (40 g Gold column, run for 25 minutes) and eluted with [EtOAc / EtOH 76:24] / hexane 5-80% to provide The white solid form corresponds to two parts of two diastereomers (P1 105 mg and P2 205 mg). The two parts are combined as A1 to produce ((2S) -1-(((2S) -1-(((2S) -3-hydroxy-4- (isopropylamino) -4 -Penoxy-1-((S) -2-oxopyrrolidin-3-yl) but-2-yl) amino) -4-methyl-1-oxopent-2-yl) Amino) -1-oxo-3- (6- (trifluoromethyl) pyridin-2-yl) propan-2-yl) carbamic acid benzyl ester (0.31 g, 0.439 mmol, 57.2% yield ). LCMS: [M + H] +: 707.4.((S) -1-(((S) -1-(((S) -4- ( Isopropylamino ) -3,4- Dioxo -1-((S) -2- Pyridoxine -3- base ) Ding -2- base ) Amine ) -4- methyl -1- Pendant -2- base ) Amine )-1- Pendant -3- (6- ( Trifluoromethyl ) Pyridine -2- base ) C -2- base ) Benzyl Carbamate In N2 To a 50-mL RB flask, add ((2S) -1-(((2S) -1-(((2S) -3-hydroxy-4- (iso Propylamino) -4-oxo-1-((S) -2-oxopyrrolidin-3-yl) but-2-yl) amino) -4-methyl-1-oxo Pentyl-2-yl) amino) -1-oxo-3- (6- (trifluoromethyl) pyridin-2-yl) propan-2-yl) carbamic acid benzyl ester (0.31 g, 0.439 mmol), followed by Dess-Martin periodiodine (0.205 g, 0.482 mmol). The mixture was stirred at rt for 2 hours. LCMS indicated the completion of the reaction. Saturated aqueous sodium thiosulfate solution (3 mL) and saturated aqueous sodium bicarbonate solution (3 mL) were added, and the mixture was stirred for another 15 minutes. The mixture was diluted with water (20 mL) and extracted with DCM (2 × 30 mL). Dry (Na2 SO4 ) The combined organic solution is filtered and concentrated. With Combiflash® Automated silica gel column chromatography (24 g Gold column, run for 20 minutes) to purify the residue and elute with i-PrOH / DCM 0-40% to provide ((S) -1-((( S) -1-(((S) -4- (isopropylamino) -3,4-bi- pendant-1-((S) -2- pendylpyrrolidin-3-yl) butane -2-yl) amino) -4-methyl-1-oxopent-2-yl) amino) -1-oxo-3- (6- (trifluoromethyl) pyridine-2- Yl) propan-2-yl) carbamic acid benzyl ester (0.228 g, 0.304 mmol, 69.3% yield). LCMS: [M + H] +: 705.61 H NMR (400 MHz, DMSO-d 6) δ ppm 0.87 (dd,J = 18.44, 6.57 Hz, 6 H) 1.09 (d,J = 6.57 Hz, 6 H) 1.38-1.50 (m, 2 H) 1.52-1.74 (m, 3 H) 1.84 -1.98 (m, 1 H) 2.10-2.24 (m, 1 H) 2.30-2.43 (m, 1 H) 2.95-3.07 (m, 1 H) 3.09-3.28 (m, 3 H) 3.83-3.98 (m, 1 H) 4.27-4.40 (m, 1 H) 4.46-4.60 (m, 1 H) 4.94 (s , 2 H) 4.96-5.06 (m, 1 H) 7.23 (s, 2 H) 7.33 (s, 1 H) 7.61 (d,J = 8.34 Hz, 2 H) 7.69 (s, 1 H) 7.71-7.79 (m, 1 H) 7.91-8.03 (m, 1 H) 8.09-8.16 (m, 1 H) 8.47-8.61 (m, 2 H) .Biological example Examples 4 HRV-16 3C Protease protocol Starting from a high concentration of 10 mM, the test compound is serially diluted 3 times with an 11-point curve using 100% DMSO solvent. Each dilution was transferred to a black 384-well Greiner (784076) plate at a volume of 100 nL, resulting in the highest final concentration of 10 μM in the analysis. The low control well in row 18 (0% response, 100% inhibition) contains 100 nL DMSO plus buffer and no enzyme. The high control well in row 6 (100% response, 0% inhibition) contains 100 nL DMSO plus buffer and enzyme. The maximum DMSO concentration of the entire board is about 1%. The analysis buffer consisted of 25 mM Hepes (pH 7.5), 100 mM NaCl, 1 mM CHAPS, 1 mM EDTA, and 0.05% bovine serum albumin. The analysis plate preparation includes rotating the plate before the reaction is added, and adding only 5 μL of analysis buffer (no enzyme) to line 18 (low control—representing 100% inhibition) and 5 μL of 10 in analysis buffer nM enzyme (HRV-16 3C protease, 5 nM final concentration) was added to lines 1-17 and 19-24. The FRET substrate peptide (FAM-GRAVFQGPVG-TAMRA) was suspended at a concentration of 4 μM, and 5 μL was added to each reaction well using a Thermo Combi liquid handler to make the final reaction concentration 2 μM. The reaction was incubated in the dark at room temperature for 60 minutes. At this moment, use Envision or equivalent plate reader to measure the FRET signal and use it to quantify the apparent EC50 Calculated analysis endpoint. The data from each plate was analyzed and plotted as% inhibition on compound concentration. Normalize the data using the formula 100 * (Control 1-Unknown) / (Control 1-Control 2), where Control 1 is the average of the values of the plate corresponding to 0% inhibition control well (DMSO, line 6) 2 is the average of the values corresponding to 100% control wells (row 18). Use 4 parameter curve fitting equation y = A + ((B-A) / (1+ (10^ x / 10^ C)^ D)) Implement curve fitting, in which A is the minimum response, B is the maximum response, and C is log (XC50 ) And D is Hill slope. Record the results of each test compound as pIC50 Value (-C in the equation above) and the maximum response value at a given concentration.Examples 5 HRV-15 3C Protease protocol Starting from a high concentration of 10 mM, the test compound is serially diluted 3 times with an 11-point curve using 100% DMSO solvent. Each dilution was transferred to a black 384-well Greiner (784076) plate at a volume of 100 nL, resulting in the highest final concentration of 10 μM in the analysis. The low control well in row 18 (0% response, 100% inhibition) contains 100 nL DMSO plus buffer and no enzyme. The high control well in row 6 (100% response, 0% inhibition) contains 100 nL DMSO plus buffer and enzyme. The maximum DMSO concentration of the entire board is about 1%. The analysis buffer consists of 25 mM HEPES (pH 7.5), 100 mM NaCl, 1 mM CHAPS, 1 mM EDTA, and 0.05% bovine serum albumin. The analysis plate preparation includes rotating the plate before the reaction is added, and adding only 5 μL of analysis buffer (no enzyme) to line 18 (low control—representing 100% inhibition) and 5 μL of 10 in analysis buffer nM enzyme (HRV-15 3C protease, 5 nM final concentration) was added to lines 1-17 and lines 19-24. The FRET substrate peptide (FAM-GRAVFQGPVG-TAMRA) was suspended at a concentration of 4 μM and 5 μL was added to each reaction well using a Thermo Combi liquid handler to make the final reaction concentration 2 μM. The reaction was incubated in the dark at room temperature for 60 minutes. At this moment, use Envision or equivalent plate reader to measure the FRET signal and use it to quantify the apparent EC50 Calculated analysis endpoint. The data from each plate was analyzed and plotted as% inhibition on compound concentration. Normalize the data using formula 100 * (Control 1-Unknown) / (Control 1-Control 2), where Control 1 is the average of the values of the plate corresponding to the 0% inhibition control well (DMSO, line 6), and Control 2 is the average of the values corresponding to 100% control wells (row 18). Use 4 parameter curve fitting equation y = A + ((B-A) / (1+ (10^ x / 10^ C)^ D)) Implement curve fitting, in which A is the minimum response, B is the maximum response, and C is log (XC50 ) And D is the Hill slope. Record the results of each test compound as pIC50 Value (-C in the equation above) and the maximum response value at a given concentration.Examples 6 Coronavirus OC43 3CL Protease protocol Starting from a high concentration of 10 mM, the test compound is serially diluted 3 times with an 11-point curve using 100% DMSO solvent. Each dilution was transferred to a black 384-well Greiner (784076) plate at a volume of 100 nL, resulting in the highest final concentration of 10 μM in the analysis. The low control well in row 18 (0% response, 100% inhibition) contains 100 nL DMSO plus buffer and no enzyme. The high control well in row 6 (100% response, 0% inhibition) contains 100 nL DMSO plus buffer and enzyme. The maximum DMSO concentration of the entire board is about 1%. The analysis buffer consists of 25 mM HEPES (pH 7.5), 50 mM NaCl, 1 mM CHAPS and 1 mM EDTA. The analysis plate preparation includes rotating the plate before the reaction is added, and adding only 5 μL of analysis buffer (no enzyme) to line 18 (low control—representing 100% inhibition) and 5 μL of analysis buffer 2 nM enzyme (OC43 3CL protease, 1 nM final concentration) was added to lines 1-17 and 19-24. The FRET substrate peptide (FAM-VARLQSGFG-TAMRA) was suspended at a concentration of 4 μM and 5 μL was added to each reaction well using a Thermo Combi liquid handler to make the final reaction concentration 2 μM. The reaction was incubated in the dark at room temperature for 60 minutes. At this moment, use Envision or equivalent plate reader to measure the FRET signal and use it to quantify the apparent EC50 Calculated analysis endpoint. The data from each plate was analyzed and plotted as% inhibition on compound concentration. Normalize the data using the formula 100 * (Control 1-Unknown) / (Control 1-Control 2), where Control 1 is the average of the values of the plate corresponding to 0% inhibition control well (DMSO, line 6) 2 is the average of the values corresponding to 100% control wells (row 18). Use 4 parameter curve fitting equation y = A + ((B-A) / (1+ (10^ x / 10^ C)^ D)) Implement curve fitting, in which A is the minimum response, B is the maximum response, and C is log (XC50 ) And D is the Hill slope. Record the results of each test compound as pIC50 Value (-C in the equation above) and the maximum response value at a given concentration.Examples 7 Coronavirus 229e 3CL Protease protocol Starting from a high concentration of 10 mM, the test compound is serially diluted 3 times with an 11-point curve using 100% DMSO solvent. Each dilution was transferred to a black 384-well Greiner (784076) plate at a volume of 100 nL, resulting in the highest final concentration of 10 μM in the analysis. The low control well in row 18 (0% response, 100% inhibition) contains 100 nL DMSO plus buffer and no enzyme. The high control well in row 6 (100% response, 0% inhibition) contains 100 nL DMSO plus buffer and enzyme. The maximum DMSO concentration of the entire board is about 1%. The analysis buffer consists of 25 mM Hepes (pH 7.5), 50 mM NaCl, 1 mM CHAPS and 1 mM EDTA. The analysis plate preparation includes rotating the plate before the reaction is added, and adding only 5 μL of analysis buffer (no enzyme) to line 18 (low control—representing 100% inhibition) and adding 5 μL of 200 in analysis buffer The pM enzyme (229e 3CL protease, 100 pM final concentration) was added to lines 1-17 and 19-24. The FRET substrate peptide (FAM-VARLQSGFG-TAMRA) was suspended at a concentration of 4 μM and 5 μL was added to each reaction well using a Thermo Combi liquid handler to make the final reaction concentration 2 μM. The reaction was incubated in the dark at room temperature for 60 minutes. At this moment, use Envision or equivalent plate reader to measure the FRET signal and use it to quantify the apparent EC50 Calculated analysis endpoint. The data from each plate was analyzed and plotted as% inhibition on compound concentration. Normalize the data using the formula 100 * (Control 1-Unknown) / (Control 1-Control 2), where Control 1 is the average of the values of the plate corresponding to the 0% inhibition control well (DMSO, line 6) and the control 2 is the average of the values corresponding to 100% control wells (row 18). Use 4 parameter curve fitting equation y = A + ((B-A) / (1+ (10^ x / 10^ C)^ D)) Implement curve fitting, in which A is the minimum response, B is the maximum response, and C is log (XC50 ) And D is the Hill slope. Record the results of each test compound as the pIC50 value (-C in the equation above) and the maximum response value at the given concentration.Examples 8 SARS Coronavirus 3CL Protease protocol Starting from a high concentration of 10 mM, the test compound is serially diluted 3 times with an 11-point curve using 100% DMSO solvent. Each dilution was transferred to a black 384-well Greiner (784076) plate at a volume of 100 nL, resulting in the highest final concentration of 10 μM in the analysis. The low control well in row 18 (0% response, 100% inhibition) contains 100 nL DMSO plus buffer and no enzyme. The high control well in row 6 (100% response, 0% inhibition) contains 100 nL DMSO plus buffer and enzyme. The maximum DMSO concentration of the entire board is about 1%. The analysis buffer consists of 25 mM Hepes (pH 7.5), 50 mM NaCl, 1 mM CHAPS and 1 mM EDTA. The analysis plate preparation includes rotating the plate before the reaction is added, and adding only 5 μL of analysis buffer (no enzyme) to line 18 (low control—representing 100% inhibition) and 5 μL of 60 in analysis buffer nM enzyme (SARS 3CL protease, 30 nM final concentration) was added to lines 1-17 and 19-24. The FRET substrate peptide (FAM-KTSAVLQSGFRKME-TAMRA) was suspended at a concentration of 6 μM and 5 μL was added to each reaction well using a Thermo Combi liquid handler to make the final reaction concentration 3 μM. The reaction was incubated in the dark at room temperature for 60 minutes. At this moment, use Envision or equivalent plate reader to measure the FRET signal and use it to quantify the apparent EC50 Calculated analysis endpoint. The data from each plate was analyzed and plotted as% inhibition on compound concentration. Normalize the data using the formula 100 * (Control 1-Unknown) / (Control 1-Control 2), where Control 1 is the average of the values of the plate corresponding to 0% inhibition control well (DMSO, line 6) 2 is the average of the values corresponding to 100% control wells (row 18). Use 4 parameter curve fitting equation y = A + ((B-A) / (1+ (10^ x / 10^ C)^ D)) Implement curve fitting, in which A is the minimum response, B is the maximum response, and C is log (XC50 ) And D is the Hill slope. Record the results of each test compound as the pIC50 value (-C in the equation above) and the maximum response value at the given concentration.Examples 9 Human rhinovirus (HRV) Solutions for cytopathic effect analysis The compounds of the present invention were tested via high-throughput cell analysis using cytopathic effect (CPE) and cytotoxicity as endpoints. For CPE analysis, use human rhinovirus (HRV) type B strain 14 (ATCC VR-284; American Type Culture Collection, Manassas, VA) or HRV type A in a Biosafety Level 2 (BSL-2) environment Strain 16 (ATCC VR-283; American Type Culture Collection, Manassas, VA) infected human epithelial HeLa Ohio cells (ECACC 84121901; Sigma-Aldrich Corporation, St. Louis, MO). Compounds with antiviral activity protect HeLa Ohio cells from CPE induced by viral infection and use CellTiter-Glo® Reagent (CTG) Promega Corporation, Madison, WI) measures cell survival rate, which is based on luminescence detection of ATP (an indicator of metabolically active cells). The CTG analysis with uninfected HeLa Ohio cells was used in parallel to measure the cytotoxicity caused by the therapeutic effect of the compound alone. To prepare for analysis, the test compound was serially diluted 3 times in DMSO from a typical maximum concentration of 5 mM and plated at 0.25 µL in a 384-well polystyrene transparent bottom tissue culture treated plate with a lid (Corning Incorporated , Tewksbury, MA) to generate an 11-point dose response curve. Low control wells (100% CPE or 100% cytotoxicity) contain 0.25 µL DMSO in the presence of virus-infected cells used for CPE analysis or 0.25 µL DMSO in the absence of cells used for cytotoxicity analysis, and high control wells (0 % CPE or 0% cytotoxicity) contains 0.25 µL of small molecule control test compound in the presence of virus-infected cells used for CPE analysis or 0.25 µL of the same nontoxic small molecule control test compound in the presence of uninfected cells used for cytotoxicity analysis. Wash and recover the frozen stock solution of HeLa Ohio cells in DMEM high glucose medium (Life Technologies Corporation, Grand Island, NY) supplemented with the following: 10% v / v qualified heat-inactivated fetal bovine serum (FBS) (Life Technologies Corporation, Grand Island, NY), 1X GlutaMAX ™ (Life Technologies Corporation, Grand Island, NY) and 1X Penicillin-Streptomycin Antibiotic Solution (Life Technologies Corporation, Grand Island, NY). Dilute the cells to 40,000 cells / mL in supplemented DMEM medium, and then aliquot the volume of the medium into two flasks. On one and a half of the previously prepared 384-well compound plates, 50 µL of cell suspension from one flask was added to all wells except the low control well, which produced 2,000 cells / well for cytotoxicity analysis. Add HRV to the second flask of cells at a MOI of 0.01, and add 50 µL of the homogeneous virus and cell mixture to all wells of the remaining 384-well compound plate to produce 2,000 cells / well for CPE analysis. Then place the covered plate at 33 ° C with 5% CO2 Humidify the incubator for 5 days. After incubation, the 384-well plate used for both analyses was removed and placed in a biosafety cabinet to equilibrate to room temperature for 30 minutes. Prepare CellTiter-Glo according to manufacturer's instructions® Add 20 µL to each plate well. After incubation at room temperature for 20 minutes, in EnVision® Multi-tag reader (PerkinElmer Inc., Waltham, MA) reads luminescence. After normalization using the formula 100 * ((U-C2) / (C1-C2)), the data of dose response in CPE analysis is plotted as% survival rate versus compound concentration, where U is an unknown value and C1 is high (0% CPE) The average number of control wells and C2 is the average of low (100% CPE) control wells. After normalization using the formula 100- (100 * ((U-C2) / (C1-C2))), the data of dose response in cytotoxicity analysis is plotted as% cytotoxicity to compound concentration, where U is an unknown value, C1 It is the average of high (0% cytotoxicity) control wells and C2 is the average of low (100% cytotoxicity) control wells. Use the equation y = A + ((B-A) / (1+ (10x / 10C )D )) Implement curve fitting, in which A is the minimum response, B is the maximum response, and C is log (XC50 ) And D is the Hill slope. Record the results of each test compound as the pIC50 value of the CPE analysis and the pCC50 value of the cytotoxicity analysis (‑C in the equation above).Examples 10 MERS Coronavirus cell analysis protocol The compounds of the present invention were tested by cell analysis using the performance of coronavirus spike protein as an endpoint. Human lung fibroblast MRC-5 cells were infected with MERS coronavirus (Jordan strain). Compounds with antiviral activity reduce the performance of fibronectin, as measured by immunological methods, and reduce cell viability, as measured by nuclear integrity. In preparation for analysis, the test compound was serially diluted 3 times in an 8-point curve in 100% DMSO for the highest analytical concentration of 50 uM. Normalize DMSO to a final concentration of 1% in the reaction well. Low control wells (100% CPE or 100% cytotoxicity) contain DMSO in the presence of virus-infected cells. MRC-5 cells were treated with the compound for 2 hours, and then infected with MERS at a MOI of 1. The virus was allowed to replicate for 48 hours, after which formalin was used to inactivate the virus. Infected cells were detected by immunostaining with anti-S protein antibodies and quantified by the PE Opera confocal platform. The signal of S protein staining was converted to% infection, and positive and negative controls were used to calculate% inhibition. The EC50 was calculated with the standard equation using GeneData software. The embodiments of the invention described herein are intended to be exemplary only; those skilled in the art will understand many variations and modifications. All these numerous variations and modifications are intended to be within the scope of the invention, as defined in the scope of any accompanying patent applications. Table 1 table 2 table 3 Bioanalysis data

Claims (27)

一種式I化合物，其中A 係 芳基或雜芳基；R1 、 R′1 及 R′′1 獨立地選自H；C1-C6-烷基；鹵基；鹵代烷基；NR6 R7 ；OR8 ；SR9 ；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8環烷基或C3-C8雜環烷基；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、硫代烷基取代之C3-C8環烷基或C3-C8雜環烷基；或R2 係 C1-C6-烷基；經芳基、雜芳基、C1-C6-烷基、C3-C8-環烷基、C3-C8雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基、NR6 R7 取代之C1-C6-烷基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、鹵基取代烷氧基取代之C3-C8-環烷基，或該C3-C8環烷基與芳基稠合以形成二環或三環稠合環；C3-C8-雜環烷基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、鹵基取代烷氧基取代之C3-C8-環烷基或C3-C8-雜環烷基，或該C3-C8雜環烷基與芳基稠合以形成二環或三環稠合環；其中該芳基、雜芳基、C1-C6-烷基、C3-C8-環烷基、C3-C8雜環烷基或NR6 R7 進一步視情況經鹵基、烷氧基、鹵基取代烷氧基、NR6 R7 、OR8 、SR9 取代；R3 及 R4 獨立地係H、C1-C6-烷基、經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基；或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之5員至10員環結構；R5 係C1-C6烷基；經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、芳基、雜芳基取代之C1-C6烷基；或視情況經C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8環烷基；R6 及 R7 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8-環烷基或C3-C8-雜環烷基；或R6 與R7 一起形成視情況經鹵基、鹵代烷基、胺基、NR6 R7 、OR8 、SR9 取代之3員至10員環烷基或雜環烷基環；芳基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之芳基；雜芳基；或經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之雜芳基；且R8 及 R9 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基， 或其鹽。A compound of formula I, Wherein A is aryl or heteroaryl; R 1 , R ′ 1 and R ′ 1 are independently selected from H; C1-C6-alkyl; halo; haloalkyl; NR 6 R 7 ; OR 8 ; SR 9 ; C1-C6 alkyl substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl ; C3-C8 cycloalkyl or C3-C8 heterocycloalkyl; via C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, hydroxyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl substituted with alkoxy, thioalkyl; or R 2 is C1-C6-alkyl; via aryl, heteroaryl, C1-C6-alkyl , C3-C8-cycloalkyl, C3-C8 heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl, NR 6 R 7 substituted C1- C6-alkyl; optionally via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, hydroxyl, alkoxy C3-C8-cycloalkyl substituted by alkoxy or halo substituted alkoxy, or the C3-C8 cycloalkyl is fused with an aryl group to form a bicyclic or tricyclic fused ring; C3-C8-heterocycloalkyl ;Subject to availability C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, amine alkyl, hydroxy, alkoxy, halo substituted alkoxy Substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, or the C3-C8 heterocycloalkyl is fused with an aryl group to form a bicyclic or tricyclic fused ring; wherein the aryl, heterocyclic Aryl, C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyl or NR 6 R 7 is further substituted with halo, alkoxy, halo for alkoxy, NR 6 R 7 , OR 8 , SR 9 substitution; R 3 and R 4 are independently H, C1-C6-alkyl, C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkane C1-C6 alkyl group substituted by alkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl ; Via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl Substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R 3 and R 4 together form C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-hetero Cycloalkyl, halo, haloalkyl, NR 6 5-membered to 10-membered ring structure substituted with R 7 , OR 8 , and SR 9 ; R 5 is C1-C6 alkyl; C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocyclic C1-C6 alkyl substituted with alkyl, aryl, heteroaryl; or optionally C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl , NR 6 R 7 , OR 8 , SR 9 substituted C3-C8 cycloalkyl; R 6 and R 7 are independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-ring C1-C6 alkyl substituted with alkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkane Group; C3-C8-ring substituted with C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 Alkyl or C3-C8-heterocycloalkyl; or R 6 and R 7 together form a 3- to 10-membered ring optionally substituted by halo, haloalkyl, amine, NR 6 R 7 , OR 8 and SR 9 Alkyl or heterocycloalkyl ring; aryl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , Aryl substituted by SR 9 ; heteroaryl; or C1-C6-alkyl, C 3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 substituted heteroaryl; and R 8 and R 9 are independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, C1-C6 alkyl substituted by hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8 -C3-C8-cycloalkyl or C3-C8-heterocycloalkyl substituted with heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl, or Its salt. 一種式IA化合物，式IA 其中A 係 芳基或雜芳基；R1 、 R′1 及 R′′1 獨立地選自H；C1-C6-烷基；鹵基；鹵代烷基；NR6 R7 ；OR8 ；SR9 ；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8環烷基或C3-C8雜環烷基；經C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、硫代烷基取代之C3-C8環烷基或C3-C8雜環烷基；R2 係 C1-C6-烷基；經芳基、雜芳基、C1-C6-烷基、C3-C8-環烷基、C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、鹵基取代烷氧基、羥基、硫代烷基、NR6 R7 取代之C1-C6-烷基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、羥基、烷氧基、鹵基取代烷氧基取代之C3-C8-環烷基，或該環烷基與芳基稠合以形成二環或三環稠合環；C3-C8-雜環烷基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基或NR6 R7 取代之；其中該芳基、雜芳基、C1-C6-烷基、C3-C8-環烷基、C3-C8雜環烷基或NR6 R7 進一步視情況經鹵基、羥基、烷氧基、鹵基取代烷氧基、NR6 R7 、OR8 、SR9 取代；R3 及 R4 獨立地係 H、C1-C6-烷基、取代C1-C6烷基、C3-C8-環烷基、視情況經取代之C3-C8-環烷基或視情況經取代之C3-C8-雜環烷基，或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之5員至10員環結構；R5 係 C1-C6烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、芳基、雜芳基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8-環烷基；R6 及 R7 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C1-C6環烷基，或R6 與R7 一起形成視情況經鹵基、鹵代烷基取代之3員至10員環烷基或雜環烷基環；且R8 及 R9 獨立地係C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基， 或其鹽。A compound of formula IA, Formula IA wherein A is aryl or heteroaryl; R 1 , R ′ 1 and R ′ 1 are independently selected from H; C1-C6-alkyl; halo; haloalkyl; NR 6 R 7 ; OR 8 ; SR 9 ; C1-C6 substituted with C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxyl, thioalkyl Alkyl; C3-C8 cycloalkyl or C3-C8 heterocycloalkyl; via C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl substituted with hydroxy, alkoxy, thioalkyl; R 2 is C1-C6-alkyl; via aryl, heteroaryl, C1-C6-alkane Group, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, halo-substituted alkoxy, hydroxyl, thioalkyl , C1-C6-alkyl substituted with NR 6 R 7 ; optionally C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, Aminoalkyl, hydroxy, alkoxy, halo substituted alkoxy substituted C3-C8-cycloalkyl, or the cycloalkyl is fused with an aryl group to form a bicyclic or tricyclic fused ring; C3- C8- Cycloalkyl; optionally C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy , Thioalkyl or NR 6 R 7 ; wherein the aryl, heteroaryl, C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8 heterocycloalkyl or NR 6 R 7 further Optionally substituted by halo, hydroxy, alkoxy, halo substituted alkoxy, NR 6 R 7 , OR 8 , SR 9 ; R 3 and R 4 are independently H, C1-C6-alkyl, substituted C1 -C6 alkyl, C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkyl or optionally substituted C3-C8-heterocycloalkyl, or R 3 and R 4 together form optional Substituted by C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl Ring structure of 5 to 10 members; R 5 is C1-C6 alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl substituted by halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 ; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3 -C8-cycloalkyl or C3-C8-hetero C3-C8-cycloalkyl substituted with cycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 ; R 6 and R 7 are independently H, C1-C6-alkyl; via C1- C1-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C1- C6 alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkane Group, NR 6 R 7 , OR 8 , SR 9 substituted C1-C6 cycloalkyl, or R 6 and R 7 together form a 3- to 10-membered cycloalkyl or heterocyclic ring optionally substituted by halo, haloalkyl Alkyl ring; and R 8 and R 9 are independently C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl , C1-C6 alkyl substituted by amine, aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl Group, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-ring Alkyl or C3-C8-heterocycloalkyl, or . 如請求項1或2之化合物，其中：A 係 苯基或噁唑基；R1 係 H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8-環烷基或C3-C8-雜環烷基；R2 係 C1-C6-烷基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6-烷基；C3-C8-環烷基或C3-C8-雜環烷基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基取代之C3-C8-環烷基或C3-C8-雜環烷基；NR6 R7 ；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、鹵基取代烷氧基、羥基、硫代烷基取代之芳基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、鹵基取代烷氧基取代之雜芳基；其中C1-C6-烷基或C1-C6-環烷基進一步視情況經鹵基、O、N、S、NR6 R7 、OR8 、SR9 取代；R3 及 R4 獨立地係 H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基；或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之5員至10員環結構；R5 係 C1-C6烷基；經C1-C6-烷基、C3-C8環烷基、芳基、雜芳基、C3-C8環烷基、C3-C8雜環烷基取代之C1-C6烷基；或C3-C8-環烷基；視情況經取代之芳基；視情況經取代之雜芳基；R6 及 R7 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8-環烷基或C3-C8-雜環烷基；或R6 與R7 一起形成視情況經鹵基、鹵代烷基、胺基、NR6 R7 、OR8 、SR9 取代之3員至10員環烷基或雜環烷基環；芳基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之芳基；雜芳基；或經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之雜芳基；且R8 及 R9 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基， 或其鹽。 A compound as claimed in claim 1 or 2, wherein: A is phenyl or oxazolyl; R 1 is H, C1-C6-alkyl; C1-C6-alkyl, C3-C8-cycloalkyl or C3- C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 substituted C1-C6 alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1 -C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 substituted C3-C8-cycloalkyl or C3 -C8-heterocycloalkyl; R 2 is C1-C6-alkyl; optionally C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl , Amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C1-C6-alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; optionally via C1- C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy substituted C3-C8-cycloalkyl or C3 -C8-heterocycloalkyl; NR 6 R 7 ; optionally via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, amine Alkyl, halogen substituted alkoxy, hydroxyl, thioalkyl substituted aryl Group; optionally substituted by C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, halo Alkoxy-substituted heteroaryl; wherein C1-C6-alkyl or C1-C6-cycloalkyl is further substituted with halogen, O, N, S, NR 6 R 7 , OR 8 , SR 9 as appropriate; R 3 and R 4 are independently H, C1-C6-alkyl; C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, C1-C6 alkyl substituted with aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl, C3- C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-cycloalkyl or C3 -C8-heterocycloalkyl; or R 3 and R 4 together form C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 5-membered to 10-membered ring structure substituted with R 7 , OR 8 and SR 9 ; R 5 is C1-C6 alkyl; via C1-C6-alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl substitution C1-C6 alkyl; or C3-C8-cycloalkyl; optionally substituted aryl; optionally substituted heteroaryl; R 6 and R 7 are independently H, C1-C6-alkyl; Substituted by C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl C1-C6 alkyl; C3-C8-cycloalkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 substituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R 6 and R 7 together form halo, haloalkyl, amine, NR 6 R 7 , OR 8 and SR 9 substituted 3- to 10-membered cycloalkyl or heterocycloalkyl rings; aryl; C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, Halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 substituted aryl; heteroaryl; or C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl , Halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 substituted heteroaryl; and R 8 and R 9 are independently H, C1-C6-alkyl; via C1-C6-alkyl, C3 -C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, C1-C6 alkyl substituted by haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6 -C3-C8 substituted with alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl -Cycloalkyl or C3-C8-heterocycloalkyl, or a salt thereof. 如請求項1或2之化合物，其中：A 係 苯基；R1 係 H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、NR6 R7 、OR8 、SR9 取代之C3-C8-環烷基或C3-C8-雜環烷基；R2 係 視情況經C1-C6-烷基、烷氧基取代之C1-C6-烷基；NR6 R7 ；視情況經C1-C6-烷基、鹵代烷基取代之芳基；視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、鹵基取代烷氧基取代之雜芳基；其中C1-C6-烷基或C1-C6-環烷基進一步視情況經鹵基、O、N、S、NR6 R7 、OR8 、SR9 取代；R3 及 R4 獨立地係 H、C1-C6-烷基；經C1-C6-烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之5員至10員環結構；R5 係 C1-C6烷基；經C1-C6-烷基、C3-C8環烷基、苯基取代之C1-C6烷基；或經C1-C6-烷基取代之C3-C8-環烷基或C3-C8-雜環烷基；R6 及 R7 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基取代之C1-C6烷基；或R6 與R7 一起形成視情況經鹵基、鹵代烷基取代之3員至10員環烷基或雜環烷基環；且R8 及 R9 獨立地係H、C1-C6-烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之C3-C8-環烷基或C3-C8-雜環烷基， 或其鹽。 A compound as claimed in claim 1 or 2, wherein: A is phenyl; R 1 is H, C1-C6-alkyl; C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycle C1-C6 alkyl substituted with alkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkane Group; C3-C8-ring substituted with C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, NR 6 R 7 , OR 8 , SR 9 Alkyl or C3-C8-heterocycloalkyl; R 2 is C1-C6-alkyl substituted by C1-C6-alkyl, alkoxy as appropriate; NR 6 R 7 ; optionally C1-C6-alkyl Aryl group substituted by alkyl, haloalkyl; optionally substituted by C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, Alkoxy, halo substituted alkoxy substituted heteroaryl; where C1-C6-alkyl or C1-C6-cycloalkyl is further optionally halogenated, O, N, S, NR 6 R 7 , OR 8. SR 9 substitution; R 3 and R 4 are independently H, C1-C6-alkyl; C1-C6 alkyl substituted with C1-C6-alkyl; C3-C8-cycloalkyl or C3-C8- form as appropriate together with R 3 or R 4; heterocycloalkyl Substituted by C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxyl, thioalkyl Ring structure of 5 to 10 members; R 5 is C1-C6 alkyl; C1-C6 alkyl substituted with C1-C6-alkyl, C3-C8 cycloalkyl, phenyl; or C1-C6-alkyl C3-C8-cycloalkyl or C3-C8-heterocycloalkyl substituted by a group; R 6 and R 7 are independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-ring C1-C6 alkyl substituted with alkyl or C3-C8-heterocycloalkyl; or R 6 and R 7 together form a 3- to 10-membered cycloalkyl or heterocycloalkyl substituted with halo, haloalkyl as appropriate Ring; and R 8 and R 9 are independently H, C1-C6-alkyl; via C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl , C1-C6 alkyl substituted by amine, aminoalkyl, alkoxy, hydroxy, thioalkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; via C1-C6-alkyl Group, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, amine, aminoalkyl, alkoxy, hydroxy, thioalkyl substituted C3-C8-ring Alkyl or C3-C8-heterocycloalkyl, or a salt thereof. 如請求項1或請求項2之化合物，其中R3 獨立地選自H、C1-C6-烷基及經C1-C6-烷基取代之C1-C6烷基；C3-C8-環烷基或C3-C8-雜環烷基；或R3 與R4 一起形成視情況經C1-C6-烷基、C3-C8-環烷基或C3-C8-雜環烷基、鹵基、鹵代烷基、胺基、胺基烷基、烷氧基、羥基、硫代烷基取代之5員至10員環結構。A compound as claimed in claim 1 or claim 2, wherein R 3 is independently selected from H, C1-C6-alkyl and C1-C6-alkyl substituted with C1-C6-alkyl; C3-C8-cycloalkyl or C3-C8-heterocycloalkyl; or R 3 and R 4 together form C1-C6-alkyl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, halo, haloalkyl, 5-membered to 10-membered ring structure substituted by amine group, aminoalkyl group, alkoxy group, hydroxyl group, thioalkyl group. 如請求項1或請求項2之化合物，其中R5 選自基團C1-C6烷基；經C1-C6-烷基、苯基取代之C1-C6烷基；經C1-C6-烷基取代之C3-C8-環烷基或C3-C8-雜環烷基。A compound as claimed in claim 1 or claim 2, wherein R 5 is selected from the group C1-C6 alkyl; C1-C6-alkyl substituted with C1-C6-alkyl, phenyl; substituted with C1-C6-alkyl C3-C8-cycloalkyl or C3-C8-heterocycloalkyl. 如請求項1或請求項2之化合物，其中A選自由芳基及雜芳基組成之群。A compound as claimed in claim 1 or claim 2, wherein A is selected from the group consisting of aryl and heteroaryl. 如請求項1或請求項2之化合物，其中A係苯基或A係噁唑基。A compound as claimed in claim 1 or claim 2, wherein A is phenyl or A is oxazolyl. 如請求項1或請求項2之化合物，其選自由以下各項組成之群： N-[(1S)-1-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(二甲基胺基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-(六氫吡啶-1-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-(嗎啉-4-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[4-(三氟甲基)六氫吡啶-1-基]乙基]胺基甲酸苄基酯； N-[(1S)-2-(4,4-二氟六氫吡啶-1-基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-2-(4-氟六氫吡啶-1-基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[4-(三氟甲基)六氫吡啶-1-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(4,4-二氟六氫吡啶-1-基)乙基]胺基甲酸苄基酯； N-[(1S)-2-[(環丙基甲基)(甲基)胺基]-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(環戊基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[4-(三氟甲基)六氫吡啶-1-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[甲基(2,2,2-三氟乙基)胺基]乙基]胺基甲酸苄基酯； N-[(2S)-1-[(2S)-4,4-二乙基-2-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}吡咯啶-1-基]-1-側氧基-3-[4-(三氟甲基)六氫吡啶-1-基]丙-2-基]胺基甲酸苄基酯； N-[(1S)-2-(4-氟苯基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-2-環戊基乙基]胺甲醯基}-2-(喹啉-5-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-{[(1S)-1-苯基乙基]胺甲醯基}丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-(吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-3-甲基-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}丁基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-3-苯丙基]胺基甲酸苄基酯； N-[2-(6-甲氧基吡啶-2-基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S,2S)-2-甲氧基-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}丙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[4-(三氟甲基)嘧啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-2-(5-氟吡啶-2-基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[6-(三氟甲基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[5-(三氟甲基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-{[(1S)-1-環己基乙基]胺甲醯基}-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-(3-甲基苯基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[4-(三氟甲基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(1,3-噻唑-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[4-(丙-2-基氧基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[6-(三氟甲基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(1,3-噻唑-4-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[6-(三氟甲氧基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}-2-[6-(三氟甲氧基)吡啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[5-(三氟甲基)嘧啶-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-[4-(三氟甲基)-1,3-噻唑-2-基]乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(5-甲基-1,3-噻唑-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(6-甲氧基吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(2-甲氧基-1,3-噻唑-4-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-{4H,5H,6H-環戊并[d][1,3]噻唑-2-基}乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(6-甲氧基-4-甲基吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(6-乙氧基吡啶-2-基)乙基]胺基甲酸苄基酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-2-環己基乙基]胺甲醯基}-2-(萘-1-基)乙基]胺基甲酸{4-[3-(嗎啉-4-基)丙氧基]苯基}甲酯； N-[(1S)-1-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}-2-(萘-1-基)乙基]胺基甲酸{4-[2-(六氫吡啶-1-基)乙氧基]苯基}甲酯； N-[(1S)-2-(4-氟苯基)-1-{[(1S)-3-甲基-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}丁基]胺甲醯基}乙基]胺基甲酸(4-{[環丙基(甲基)胺基]甲基}苯基)甲酯； N-[(S)-{[(1S)-1-{[(2S)-1-(第三丁基胺甲醯基)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]丙-2-基]胺甲醯基}-3-甲基丁基]胺甲醯基}(2,3-二氫-1H-茚-2-基)甲基]胺基甲酸(5-甲基-1,2-噁唑-3-基)甲酯； N-[(2S)-1-[(1S,3aR,6aS)-1-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}-八氫環戊并[c]吡咯-2-基]-3-(4-氟苯基)-1-側氧基丙-2-基]胺基甲酸苄基酯； N-[(2S)-1-側氧基-1-[(3S)-3-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}-2-氮雜螺[4.4]壬-2-基]-3-(吡啶-2-基)丙-2-基]胺基甲酸苄基酯；及 N-[(2S)-1-[(2S)-4,4-二乙基-2-{[(2S)-1-側氧基-3-[(3S)-2-側氧基吡咯啶-3-基]-1-[(丙-2-基)胺甲醯基]丙-2-基]胺甲醯基}吡咯啶-1-基]-3-(4-氟苯基)-1-側氧基丙-2-基]胺基甲酸苄基酯， 或其鹽。If the compound of claim 1 or claim 2, it is selected from the group consisting of: N-[(1S) -1-{[(1S) -1-{[(2S) -1- (三 丁丁Amino carbamoyl) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl ] Aminomethanyl} -2- (dimethylamino) ethyl] benzyl carbamate; N-[(1S) -1-{[(1S) -3-methyl-1-{[ (2S) -1-Penoxy-3-[(3S) -2-Penoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminemethylamide] prop-2-yl ] Aminomethanyl} butyl] aminomethanyl} -2- (hexahydropyridin-1-yl) ethyl] benzyl carbamate; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) Aminoacetoyl] propan-2-yl] aminoformyl} butyl] aminoformyl} -2- (morpholin-4-yl) ethyl] carbamic acid benzyl ester; N-[(1S ) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1 -[(Prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} -2- [4- (trifluoromethyl) hexahydropyridine-1 -Yl] ethyl] carbamic acid benzyl ester; N-[(1S) -2- (4,4-difluorohexahydropyridin-1-yl) -1-{[(1S) -3-methyl -1-{[(2S) -1-Penoxy -3-[(3S) -2-Penoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] Aminomethyl} ethyl] benzyl aminocarbamate; N-[(1S) -2- (4-fluorohexahydropyridin-1-yl) -1-{[(1S) -3-methyl- 1-{[(2S) -1-Penoxy-3-[(3S) -2-Penoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamido] propane -2-yl] aminomethylamino} butyl] aminomethylamino} ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (Butylaminecarboxamide) -1-pentoxy-3-[(3S) -2-pendoxypyrrolidin-3-yl] propan-2-yl] aminecarboxyl} -3 -Methylbutyl] aminecarboxamide} -2- [4- (trifluoromethyl) hexahydropyridin-1-yl] ethyl] benzyl carbamate; N-[(1S) -1- {[(1S) -1-{[(2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] Propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (4,4-difluorohexahydropyridin-1-yl) ethyl] carbamic acid benzyl Ester; N-[(1S) -2-[(cyclopropylmethyl) (methyl) amino] -1-{[(1S) -3-methyl-1-{[(2S) -1- Pendant-3-[(3S) -2-Pentoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminomethayl] propan-2-yl] aminemethyl} Butyl] aminomethanyl} ethyl] carbamic acid benzyl ; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (cyclopentylaminecarboxamide) -1-pentoxy-3-[(3S) -2 -Penoxypyrrolidin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl] aminomethanyl} -2- [4- (trifluoromethyl) hexahydropyridine -1-yl] ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1 -Oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethylamino} -3-methylbutyl] aminomethylamino} -2 -[Methyl (2,2,2-trifluoroethyl) amino] ethyl] benzyl aminocarbamate; N-[(2S) -1-[(2S) -4,4-diethyl -2-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamide] Propan-2-yl] aminecarboxamido} pyrrolidin-1-yl] -1-pentoxy-3- [4- (trifluoromethyl) hexahydropyridin-1-yl] prop-2-yl] Benzyl carbamate; N-[(1S) -2- (4-fluorophenyl) -1-{[(1S) -3-methyl-1-{[(2S) -1-pentoxy -3-[(3S) -2-Penoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] Aminoformyl} ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (third butylaminomethylacetate) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] amine Acetyl} -2-cyclopentylethyl] aminemethylacetoyl} -2- (quinolin-5-yl) ethyl] benzyl carbamate; N-[(1S) -1-{[( 1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2 -Yl] aminomethylamino} -3-methylbutyl] aminomethylamino-2- (pyridin-2-yl) ethyl] benzyl aminocarbamate; N-[(1S) -1- {[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-{[( 1S) -1-phenylethyl] aminoformyl} propan-2-yl] aminoformyl} butyl] aminoformyl} -2- (pyridin-2-yl) ethyl] aminocarboxylic acid Benzyl ester; N-[(1S) -3-methyl-1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S)- 2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminomethanyl] prop-2-yl] aminomethanyl} butyl] aminomethanyl} butyl] Benzyl carbamate; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2- Pendant pyrrolidin-3-yl] -1-[(propan-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} -3-phenylpropyl Benzyl ester of amino] carbamic acid; N- [2- (6-methoxypyridin-2-yl) -1-{[(1S) -3-methyl-1-{[(2S) -1- Pendant-3-[(3S) -2-Pentoxypyrrolidin-3-yl] -1-[(prop-2- )) Aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} ethyl] benzyl aminocarbamate; N-[(1S, 2S) -2-methoxy -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1- [(Prop-2-yl) aminomethylamino] propan-2-yl] aminomethylamino} butyl] aminomethylpropyl} propyl] carbamic acid benzyl ester; N-[(1S) -1 -{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[( Propan-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} -2- [4- (trifluoromethyl) pyrimidin-2-yl] ethyl ] Benzyl carbamate; N-[(1S) -2- (5-fluoropyridin-2-yl) -1-{[(1S) -3-methyl-1-{[(2S) -1 -Oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamido] prop-2-yl] aminecarboxamido } Butyl] aminomethanyl} ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-side Oxy-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminomethylamino] propan-2-yl] aminomethylamino} butan Yl] aminecarboxamide} -2- [6- (trifluoromethyl) pyridin-2-yl] ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S)- 3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxo Pyrrolidin-3-yl] -1-[(prop-2-yl) aminomethanyl] prop-2-yl] aminomethanyl} butyl] aminomethanyl} -2- [5- (tri Fluoromethyl) pyridin-2-yl] ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1-{[(1S -1-cyclohexylethyl] aminecarboxamide} -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminecarboxyl} -3-methylbutyl] aminecarboxamide} -2- (pyridin-2-yl) ethyl] benzyl carbamate; N-[(1S) -1-{[(1S) -3- Methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamide Yl] propan-2-yl] aminoformyl} butyl] aminoformyl} -2- (3-methylphenyl) ethyl] benzyl aminocarbamate; N-[(1S) -1 -{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[( Propan-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} -2- [4- (trifluoromethyl) pyridin-2-yl] ethyl ] Benzyl aminocarbamate; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamido) -1-pentoxy-3- [(3S) -2-Penoxypyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (1,3-thiazole -2-yl) ethyl] benzyl carbamate; N-[(1S) -1 -{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-pentoxy-3-[(3S) -2-pentoxypyrrolidin-3-yl ] Propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- [4- (prop-2-yloxy) pyridin-2-yl] ethyl] amine Benzyl carbamate; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (Butylaminecarboxamide) -1-pentoxy-3-[( 3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- [6- (trifluoromethyl ) Pyridin-2-yl] ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethayl} -3-methylbutyl] aminemethyl} -2- (1,3-thiazol-4-yl) ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- ( Butylaminomethylacetoyl) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminemethyl} -3-methylbutyl Benzyl] aminecarboxamide} -2- [6- (trifluoromethoxy) pyridin-2-yl] ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) Aminomethyl] propan-2-yl] aminomethylamino} butyl] aminomethylamino-2--2- [6- (tri Fluoromethoxy) pyridin-2-yl] ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylamine Methyl) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] amine methymyl} -3-methylbutyl] amine Formamide} -2- [5- (trifluoromethyl) pyrimidin-2-yl] ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1- { [(2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] amine Yl} -3-methylbutyl] aminomethanyl} -2- [4- (trifluoromethyl) -1,3-thiazol-2-yl] ethyl] carbamic acid benzyl ester; N- [(1S) -1-{[(1S) -1-{[(2S) -1- (Butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxo Pyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (5-methyl-1,3-thiazol-2-yl) Ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-pentyloxy- 3-[(3S) -2-Penoxypyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (6-methyl Oxypyridin-2-yl) ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide ) -1-Penoxy-3-[(3S) -2-Penoxypyrrolidin-3- ] Propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (2-methoxy-1,3-thiazol-4-yl) ethyl] amino Benzyl formate; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-pentoxy-3-[(3S ) -2-oxopyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- {4H, 5H, 6H-cyclopentane [D] [1,3] thiazol-2-yl} ethyl] carbamic acid benzyl ester; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (Butylaminomethylacetoyl) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2-yl] aminemethyl} -3-methyl Butyl] aminecarboxamide} -2- (6-methoxy-4-methylpyridin-2-yl) ethyl] benzyl carbamate; N-[(1S) -1-{[( 1S) -1-{[(2S) -1- (butylaminecarboxamide) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] propan-2 -Yl] aminomethanyl} -3-methylbutyl] aminomethanyl} -2- (6-ethoxypyridin-2-yl) ethyl] benzyl carbamate; N-[( 1S) -1-{[(1S) -1-{[(2S) -1- (Third-butylaminecarboxamido) -1-oxo-3-[(3S) -2-oxo Pyrrolidin-3-yl] propan-2-yl] aminomethanyl} -2-cyclohexylethyl] aminomethanyl} -2- (naphthalen-1-yl) ethyl] aminocarboxylic acid {4- [3- (morpholin-4-yl) propoxy] phenyl} methyl ; N-[(1S) -1-{[(1S) -1-{[(2S) -1- (tert-butylaminecarboxamide) -1-pentoxy-3-[(3S)- 2-oxopyrrolidin-3-yl] propan-2-yl] aminoformyl} -3-methylbutyl] aminoformyl} -2- (naphthalen-1-yl) ethyl] amine Carboxylic acid {4- [2- (hexahydropyridin-1-yl) ethoxy] phenyl} methyl ester; N-[(1S) -2- (4-fluorophenyl) -1-{[(1S ) -3-methyl-1-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl ) Aminomethanyl] propan-2-yl] aminomethanyl} butyl] aminomethanyl} ethyl] aminocarboxylic acid (4-{[cyclopropyl (methyl) amino] methyl} benzene Methyl) methyl ester; N-[(S)-{[(1S) -1-{[(2S) -1- (tert-butylaminemethanyl) -1-pentoxy-3-[(3S ) -2-oxopyrrolidin-3-yl] propan-2-yl] aminomethanyl} -3-methylbutyl] aminomethanyl} (2,3-dihydro-1H-indene- 2-yl) methyl] aminocarboxylic acid (5-methyl-1,2-oxazol-3-yl) methyl ester; N-[(2S) -1-[(1S, 3aR, 6aS) -1- {[(2S) -1-Penoxy-3-[(3S) -2-Penoxypyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamide] propan-2 -Yl] aminecarboxamide} -octahydrocyclopenta [c] pyrrol-2-yl] -3- (4-fluorophenyl) -1-oxopropan-2-yl] carbamic acid benzyl Ester; N-[(2S) -1-oxo-1-[(3S) -3-{[(2S) -1-oxo-3-[(3S) -2-oxo-pyrrolidin-3-yl] -1-[(prop-2-yl) aminomethanyl] propan-2-yl] aminomethanyl} -2-azaspiro [4.4] non -2-yl] -3- (pyridin-2-yl) prop-2-yl] carbamic acid benzyl ester; and N-[(2S) -1-[(2S) -4,4-diethyl -2-{[(2S) -1-oxo-3-[(3S) -2-oxopyrrolidin-3-yl] -1-[(prop-2-yl) aminecarboxamide] Prop-2-yl] aminomethanyl} pyrrolidin-1-yl] -3- (4-fluorophenyl) -1-oxopropan-2-yl] aminocarboxylic acid benzyl ester, or a salt thereof . 如請求項1或請求項2之化合物，其用於療法中。The compound of claim 1 or claim 2 is used in therapy. 如請求項1或請求項2之化合物，其用於治療病毒感染。The compound of claim 1 or claim 2 is used for the treatment of viral infections. 如請求項1或請求項2之化合物，其用於治療呼吸障礙，包括COPD、氣喘、纖維化、慢性氣喘及急性氣喘、繼發於環境暴露之肺疾病、急性肺感染、慢性肺感染、α1抗胰蛋白酶疾病、囊性纖維化及自體免疫疾病。The compound as claimed in claim 1 or claim 2, which is used to treat respiratory disorders, including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposure, acute lung infection, chronic lung infection, α1 Anti-trypsin diseases, cystic fibrosis and autoimmune diseases. 一種醫藥組合物，其包含如請求項1至9中任一項之化合物及醫藥上可接受之載劑或賦形劑。A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier or excipient. 如請求項13之醫藥組合物，其用於療法中。The pharmaceutical composition according to claim 13, which is used in therapy. 如請求項13或14之醫藥組合物，其用於治療病毒感染。The pharmaceutical composition according to claim 13 or 14, which is used for the treatment of viral infections. 如請求項13或14之醫藥組合物，其用於治療呼吸障礙，包括COPD、氣喘、纖維化、慢性氣喘及急性氣喘、繼發於環境暴露之肺疾病、急性肺感染、慢性肺感染、α1抗胰蛋白酶疾病、囊性纖維化及自體免疫疾病。The pharmaceutical composition according to claim 13 or 14, which is used for the treatment of respiratory disorders, including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposure, acute lung infection, chronic lung infection, α1 Anti-trypsin diseases, cystic fibrosis and autoimmune diseases. 一種如請求項1至9中任一項之化合物或如請求項13之醫藥組合物之用途，其用於製造供治療或預防易患或患有病毒感染之個體之該病毒感染用之藥劑，該病毒感染包括來自基於RNA之病毒、冠狀病毒(coronavirus)、鼻病毒(rhinovirus)及諾羅病毒(norovirus)之病毒感染。A use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 13 for the manufacture of a medicament for the treatment or prevention of infection of the virus in an individual susceptible or suffering from a virus infection, The viral infections include viral infections from RNA-based viruses, coronaviruses, rhinoviruses and noroviruses. 一種3C蛋白酶酵素之抑制劑之用途，其用於製造供治療或預防易患或患有病毒感染之個體之該病毒感染用之藥劑，其中該抑制劑包含來自表2之化合物。Use of an inhibitor of 3C protease enzyme for the manufacture of a medicament for the treatment or prevention of infection of the virus in an individual susceptible or suffering from a viral infection, wherein the inhibitor contains compounds from Table 2. 一種如請求項1至9中任一項之化合物或其醫藥上可接受之鹽、溶劑合物或水合物之用途，其用於製造供抑制哺乳動物之病毒3C蛋白酶或病毒3CL蛋白酶用之藥劑。Use of a compound as claimed in any one of claims 1 to 9 or a pharmaceutically acceptable salt, solvate or hydrate thereof for the manufacture of a medicament for inhibiting viral 3C protease or viral 3CL protease in mammals . 如請求項19之用途，其中該哺乳動物係人類。The use according to claim 19, wherein the mammal is a human. 如請求項17之用途，其中該病毒係選自以下各項之冠狀病毒：229E、NL63、OC43、HKU1、SARS-CoV或MERS冠狀病毒。The use according to claim 17, wherein the virus is a coronavirus selected from 229E, NL63, OC43, HKU1, SARS-CoV or MERS coronavirus. 如請求項17之用途，其中該病毒係選自以下各項之小核糖核酸病毒(picornavirus)：脊髓灰白質炎病毒、EV-68病毒、EV-71病毒、肝炎A病毒、腸病毒(enterovirus)或柯薩奇病毒(coxsackievirus)。The use according to claim 17, wherein the virus is a picornavirus selected from the group consisting of poliovirus, EV-68 virus, EV-71 virus, hepatitis A virus, and enterovirus Or coxsackie virus (coxsackievirus). 一種如請求項1至9中任一項之化合物或如請求項13之醫藥組合物之用途，其用於製造供治療人類之呼吸障礙用之藥劑，該呼吸障礙包括COPD、氣喘、纖維化、慢性氣喘及急性氣喘、繼發於環境暴露之肺疾病、急性肺感染、慢性肺感染、α1抗胰蛋白酶疾病、囊性纖維化及自體免疫疾病。Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 13 for the manufacture of a medicament for the treatment of respiratory disorders in humans, the respiratory disorders including COPD, asthma, fibrosis, Chronic asthma and acute asthma, lung disease secondary to environmental exposure, acute lung infection, chronic lung infection, α1 antitrypsin disease, cystic fibrosis and autoimmune disease. 如請求項23之用途，其中該藥劑係經口、靜脈內或藉由吸入投與。The use according to claim 23, wherein the medicament is administered orally, intravenously or by inhalation. 如請求項24之用途，其中該藥劑係藉由吸入投與。The use according to claim 24, wherein the medicament is administered by inhalation. 如請求項23之用途，其中該疾病係COPD。For use according to claim 23, wherein the disease is COPD. 一種如請求項1至9中任一項之化合物或如請求項13之醫藥組合物連同諸如維蘭特羅(vilanterol)之β2-腎上腺素受體激動劑及諸如蕪地溴銨(umeclidinium)之抗副交感神經藥劑之用途。A compound as claimed in any one of claims 1 to 9 or a pharmaceutical composition as claimed in claim 13 together with a β2-adrenoceptor agonist such as vilanterol and such as umeclidinium Use of anti-parasympathetic agent.
TW106129220A 2016-08-30 2017-08-28 Compounds that inhibit 3C and 3CL proteases and methods of use thereof TW201817714A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201662381560P 2016-08-30 2016-08-30
US62/381,560 2016-08-30
US201662382410P 2016-09-01 2016-09-01
US62/382,410 2016-09-01

Publications (1)

Publication Number Publication Date
TW201817714A true TW201817714A (en) 2018-05-16

Family

ID=59966793

Family Applications (1)

Application Number Title Priority Date Filing Date
TW106129220A TW201817714A (en) 2016-08-30 2017-08-28 Compounds that inhibit 3C and 3CL proteases and methods of use thereof

Country Status (3)

Country Link
TW (1) TW201817714A (en)
UY (1) UY37381A (en)
WO (1) WO2018042343A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117209555A (en) * 2021-09-30 2023-12-12 中国科学院上海药物研究所 Cyano compound, preparation method and application thereof

Families Citing this family (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110818691A (en) * 2018-08-09 2020-02-21 中国科学院上海药物研究所 Ketoamide compound and preparation method, pharmaceutical composition and application thereof
KR20220134772A (en) * 2020-01-31 2022-10-05 상하이 인스티튜트 오브 마테리아 메디카 차이니즈 아카데미 오브 싸이언시즈 Drug use of ketoamide compounds
TW202202167A (en) 2020-03-26 2022-01-16 英商葛蘭素史密斯克藍智慧財產發展有限公司 Medical use
WO2021191875A1 (en) 2020-03-26 2021-09-30 Glaxosmithkline Intellectual Property Development Limited Cathepsin inhibitors for preventing or treating viral infections
WO2021206877A1 (en) * 2020-04-10 2021-10-14 Cocrystal Pharma, Inc. Inhibitors of norovirus and coronavirus replication
WO2021207729A1 (en) * 2020-04-10 2021-10-14 Mubarak Kamal Khan Compositions and methods for modulating ace2 receptor
US11124497B1 (en) 2020-04-17 2021-09-21 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
EP4146267A1 (en) * 2020-05-08 2023-03-15 The Board of Trustees of the Leland Stanford Junior University Protease inhibitors for treatment or prevention of coronavirus disease
US11174231B1 (en) 2020-06-09 2021-11-16 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
EP4178955A1 (en) 2020-07-11 2023-05-17 Pfizer Inc. Antiviral heteroaryl ketone derivatives
US20220033383A1 (en) 2020-07-20 2022-02-03 Enanta Pharmaceuticals, Inc. Functionalized peptides as antiviral agents
US11351149B2 (en) * 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
US11384090B2 (en) 2020-11-23 2022-07-12 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
MX2023005984A (en) 2020-11-23 2023-08-17 Enanta Pharm Inc Novel spiropyrrolidine derived antiviral agents.
US11352363B1 (en) 2020-11-23 2022-06-07 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
MX2023005983A (en) 2020-11-23 2023-08-15 Enanta Pharm Inc Novel spiropyrrolidine derived antiviral agents.
AU2021402179A1 (en) * 2020-12-18 2023-07-06 Nxera Pharma Uk Limited Sars-cov-2 mpro inhibitor compounds
WO2022208262A1 (en) * 2021-03-30 2022-10-06 Pfizer Inc. Ether-linked antiviral compounds
TW202304859A (en) * 2021-04-01 2023-02-01 美商普姆治療公司 Sars-3cl protease inhibitors
BR112023006761A2 (en) * 2021-04-16 2024-02-06 Fujian Akeylink Biotechnology Co Ltd SHORT RING MODIFIED PROLINE PEPTIDE COMPOUNDS, PHARMACEUTICAL COMPOSITION AND USE THEREOF
WO2022235605A1 (en) 2021-05-04 2022-11-10 Enanta Pharmaceuticals, Inc. Novel macrocyclic antiviral agents
US11319325B1 (en) 2021-05-11 2022-05-03 Enanta Pharmaceuticals, Inc. Macrocyclic spiropyrrolidine derived antiviral agents
WO2022265577A2 (en) * 2021-06-15 2022-12-22 Agency For Science, Technology And Research Coronavirus enzyme modulators, methods of synthesis and uses thereof
EP4366831A1 (en) 2021-07-09 2024-05-15 Aligos Therapeutics, Inc. Anti-viral compounds
CN113773259A (en) * 2021-07-14 2021-12-10 上海药明康德新药开发有限公司 Virus main protease inhibitor and preparation method and application thereof
WO2023003610A1 (en) * 2021-07-23 2023-01-26 Enanta Pharmaceuticals, Inc. Novel spiropyrrolidine derived antiviral agents
US11339170B1 (en) 2021-07-23 2022-05-24 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
CN114149415A (en) * 2021-07-26 2022-03-08 中国药科大学 Peptide-like compound and derivative, preparation method, pharmaceutical composition and application thereof
US11325916B1 (en) 2021-07-29 2022-05-10 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
WO2023009187A1 (en) * 2021-07-29 2023-02-02 Enanta Pharmaceuticals, Inc. Novel spiropyrrolidine derived antiviral agents
EP4368610A1 (en) * 2021-08-02 2024-05-15 The Global Health Drug Discovery Institute 3cl protease small-molecule inhibitor for treating or preventing coronavirus infection, and use thereof
WO2023036093A1 (en) * 2021-09-09 2023-03-16 广东众生睿创生物科技有限公司 Ketoamide derivative and application thereof
WO2023043816A1 (en) * 2021-09-17 2023-03-23 Aligos Therapeutics, Inc. Anti-viral compounds for treating coronavirus, picornavirus, and norovirus infections
WO2023044171A1 (en) * 2021-09-20 2023-03-23 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
US11858945B2 (en) 2021-11-12 2024-01-02 Enanta Pharmaceuticals, Inc. Alkyne-containing antiviral agents
US11919910B2 (en) 2021-11-12 2024-03-05 Enanta Pharmaceuticals, Inc. Spiropyrrolidine derived antiviral agents
WO2023086352A1 (en) * 2021-11-12 2023-05-19 Enanta Pharmaceuticals, Inc. Novel spiropyrrolidine derived antiviral agents
US20230174542A1 (en) * 2021-12-08 2023-06-08 Enanta Pharmaceuticals, Inc. Heterocyclic antiviral agents
US11993600B2 (en) 2021-12-08 2024-05-28 Enanta Pharmaceuticals, Inc. Saturated spirocyclics as antiviral agents
WO2023149982A1 (en) * 2022-02-07 2023-08-10 Purdue Research Foundation Compounds for the treatment of sars
CN114957383A (en) * 2022-04-01 2022-08-30 中国科学院上海药物研究所 Peptide-like compound, preparation method thereof, pharmaceutical composition and application
WO2024078294A1 (en) * 2022-10-13 2024-04-18 广东众生睿创生物科技有限公司 Amorphous form of ketoamide derivative, and preparation method therefor
WO2024078302A1 (en) * 2022-10-13 2024-04-18 广东众生睿创生物科技有限公司 Crystal form of ketoamide derivative and preparation method therefor

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3798209A (en) 1971-06-01 1974-03-19 Icn Pharmaceuticals 1,2,4-triazole nucleosides
USRE29835E (en) 1971-06-01 1978-11-14 Icn Pharmaceuticals 1,2,4-Triazole nucleosides
WO2006061714A2 (en) * 2004-12-09 2006-06-15 Pfizer Inc. Anticoronaviral compounds and compositions, their pharmaceutical uses and materials for their synthesis
GB0716292D0 (en) 2007-08-21 2007-09-26 Biofocus Dpi Ltd Imidazopyrazine compounds
US9474759B2 (en) * 2011-09-27 2016-10-25 Kansas State University Research Foundation Broad-spectrum antivirals against 3C or 3C-like proteases of picornavirus-like supercluster: picornaviruses, caliciviruses and coronaviruses

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117209555A (en) * 2021-09-30 2023-12-12 中国科学院上海药物研究所 Cyano compound, preparation method and application thereof

Also Published As

Publication number Publication date
WO2018042343A3 (en) 2018-04-19
WO2018042343A2 (en) 2018-03-08
UY37381A (en) 2018-03-23

Similar Documents

Publication Publication Date Title
TW201817714A (en) Compounds that inhibit 3C and 3CL proteases and methods of use thereof
TWI625330B (en) Substituted polycyclic pyridone derivatives and prodrug thereof
Pan et al. Development of benzimidazole derivatives to inhibit HIV-1 replication through protecting APOBEC3G protein
CN105722831B (en) Pyridazinone compound and application thereof
Chang et al. Design, synthesis, and antipicornavirus activity of 1-[5-(4-arylphenoxy) alkyl]-3-pyridin-4-ylimidazolidin-2-one derivatives
CN101087755A (en) Substituted aryl acylthioureas and related compounds, inhibitors of viral replication
KR20080019213A (en) Thiazole compounds and methods of use
ES2399101T3 (en) Thiazole derivatives and their use
CA2650323A1 (en) N-(2-thiazolyl)-amide derivatives as gsk-3 inhibitors
TW201930315A (en) Novel, highly active amino-thiazole substituted indole-2-carboxamides active against the hepatitis B virus (HBV)
TW200808763A (en) Novel compounds I
Tang et al. Identification of dibucaine derivatives as novel potent enterovirus 2C helicase inhibitors: in vitro, in vivo, and combination therapy study
JP2008517968A (en) 4-methoxymethyl-pyrrolidine-2-carboxylic acid compounds and derivatives thereof as hepatitis C virus inhibitors
Jia et al. Design, synthesis and evaluation of pyrazole derivatives as non-nucleoside hepatitis B virus inhibitors
JP2005511573A (en) 4- (5-membered) -heteroarylacylpyrrolidine derivatives as HCV inhibitors
JP2023537402A (en) Functionalized peptides as antiviral agents
BR112019013287A2 (en) pyrazolopyrimidine compounds and methods of use thereof
Kim et al. A novel series of highly potent small molecule inhibitors of rhinovirus replication
Obakachi et al. Design and synthesis of pyrazolone-based compounds as potent blockers of SARS-CoV-2 viral entry into the host cells
Wang et al. Discovery of (1 H-Pyrazolo [3, 4-c] pyridin-5-yl) sulfonamide analogues as hepatitis B virus capsid assembly modulators by conformation constraint
Jia et al. Design, diversity-oriented synthesis and biological evaluation of novel heterocycle derivatives as non-nucleoside HBV capsid protein inhibitors
Han et al. Identification and structure–activity relationships of diarylhydrazides as novel potent and selective human enterovirus inhibitors
WO2010073235A1 (en) Ppar agonist compositions and methods of use
JP2008546839A (en) Non-nucleoside reverse transcriptase inhibitors
Geng et al. A systematic survey of reversibly covalent dipeptidyl inhibitors of the SARS-CoV-2 main protease