TWI734715B - 趨化因子受體調節劑 - Google Patents
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- TWI734715B TWI734715B TW105137000A TW105137000A TWI734715B TW I734715 B TWI734715 B TW I734715B TW 105137000 A TW105137000 A TW 105137000A TW 105137000 A TW105137000 A TW 105137000A TW I734715 B TWI734715 B TW I734715B
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- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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Abstract
本發明提供作為趨化因子抑制劑之化合物,其具有以下結構:
Description
趨化因子係由眾多種細胞釋放以將巨噬細胞、淋巴球、嗜酸性球、嗜鹼性球及嗜中性球吸引至發炎位點之趨化性細胞介素(綜述於Schall,Cytokine
,3
:165-183 (1991);Schall等人,Curr Opin. Immunol
.6
:865-873 (1994);及Murphy,Rev. Immun
.,12
:593-633 (1994)中)。除刺激趨化作用外,趨化因子因應細胞可選擇性誘導其他變化,包括細胞形狀改變、細胞內游離鈣離子([Ca2+
])濃度瞬時升高、顆粒胞吐作用、整聯蛋白上調、形成生物活性脂質(例如,白三烯)及呼吸爆發,其與白血球活化相關。因此,趨化因子係發炎反應之早期觸發,引起發炎調介劑釋放、趨化作用及外滲至感染或發炎位點。 存在兩大類趨化因子CXC (α)及CC (β),此端視前兩個半胱胺酸係經單一胺基酸分開(C-X-C)抑或毗鄰(C-C)。α-趨化因子(例如CXCL1 (GROα)及CXCL8 (介白素-8、IL-8))主要對嗜中性球具有趨化性,而β-趨化因子(例如CCL5 (RANTES)及CCL20 (LARC、MIP-3α))對T細胞、B細胞、巨噬細胞、嗜酸性球及嗜鹼性球具有趨化性(Deng等人,Nature
,381
:661-666 (1996))。趨化因子結合屬G-蛋白偶聯之七次跨膜結構域蛋白家族之特異性細胞表面受體(綜述於Horuk,Trends Pharm. Sci
.,15
:159-165 (1994)中),其稱為「趨化因子受體」。 在結合其同源配體時,趨化因子受體經由所締合之三聚體G蛋白轉導細胞內信號,從而使細胞內鈣濃度快速增加。存在至少11種結合或因應β-趨化因子之人類趨化因子受體及至少7種結合至α趨化因子之人類趨化因子受體。另外,CX3CR1 (fractalkine受體)可結合至fractalkine趨化因子,其係由前兩個半胱胺酸之間之一系列三胺基酸來辨別。已暗示趨化因子受體係發炎及免疫調控病症及疾病之重要調介劑,該等病症及疾病包括氣喘及過敏性疾病以及自體免疫病狀,例如類風濕性關節炎及動脈粥樣硬化。 已知趨化因子受體CCR6係由記憶(而非原初) CD4 T細胞、IL17分泌性αβ T細胞、IL17分泌性γδ T細胞、調控T細胞、B細胞及樹突細胞來表現。其唯一已知之配體係CCL20 (MIP-3α、LARC),其顯示對該配體之強結合。其在約30%-60%之成人末梢血效應/記憶CD4+ T細胞上表現。CCR6參與白血球至發炎組織、具體而言皮膚、肺及腸之歸巢;且在具有皮膚歸巢表型之T細胞子集(即,表現皮膚淋巴球抗原(CLA)及CCR4之T細胞)上共表現。因此,CCR6可為白血球所參與之皮膚病狀中之重要作用者。 CCR6表現與牛皮癬相關。在人類中,末梢血中之絕大多數表現IL17之皮膚歸巢CD4 T細胞表現CCR6 (Homey等人,JI
, 2000)。IL17分泌性細胞係若干發炎性疾病之關鍵動因。T細胞(例如γδ T細胞及TH17 T細胞)在活化後產生IL17。IL17之致病效應與諸如以下等人類疾病相關:類風濕性關節炎(Patel DD等人,Ann Rheum Dis
2013)、多發性硬化(Zepp J、Wu L及X LiTrends Immunol
2011)及牛皮癬(Martin DA等人,J Invest Dermatol
2012))。IL17與牛皮癬強烈相關之證據包括基因組相關性研究,其顯示牛皮癬與IL17信號傳導路徑上游之基因(IL-23)或下游之基因(NFκb)之間的強相關以及在臨床環境中靶向IL17之效能(Martin DA等人,J. Invest Dermat.
2012;Papp等人,NEJM
, 2012;Papp等人,NEJM
, 2012)。除增強的CCL20介導之趨化作用外,當與健康對照相比時,自牛皮癬患者分離之CCR6+ T細胞優先分泌IL-17A、IL22及TNFα (Kagami等人,J. Invest. Dermatol
., 2010)。最後,ccl20 mRNA在病灶性牛皮癬皮膚樣品中上調(Homey等人,JI
, 2000;Dieu-Nosjean等人,JEM
, 2000)。在小鼠中,CCR6剔除小鼠受保護免於IL-23驅動之牛皮癬(Hedrick M.N.等人,JCI, 2009)
。因此,小鼠及人類二者中之多個證據表明在牛皮癬及牛皮癬樣模型中CCR6阻斷之保護作用。 CCR6亦係由在發育期間關鍵階段之樹突細胞表現,且對其遷移通過組織至關重要(Sozzani等人,J Leuk Biol
, 66:1, 1999)。樹突細胞負責將抗原呈遞至淋巴結內之T細胞,且因此抑制樹突細胞輸送可對T細胞介導之發炎反應具有阻尼效應(Banchereau及Steinman,Nature
, 392:245, 1998)。 CCR6係由B細胞表現,且最近已證明CCR6介導之B細胞遷移是B細胞為從事針對可溶性抗原做出記憶反應所必須的(Elgueta等人,J Immunol
, 194:505, 2015)。因此,經由CCR6阻斷抑制該B細胞遷移可潛在地阻止諸如狼瘡、類風濕性關節炎及天皰瘡等病症中B細胞介導(及因此抗體介導)之發炎反應。 CCR6常係由結腸直腸癌(CRC)細胞表現。此受體之高表現與CRC患者之較差結果相關,且已提出CCR6自身有助於CRC細胞遷移,從而引起轉移(Liu J.等人,PLOSone
20149 (6):
e101137)。 結合至單獨受體CXCR2之趨化因子會促進嗜中性球累積及活化。該等趨化因子參與眾多種急性及慢性發炎性病症,例如牛皮癬、類風濕性關節炎、輻射誘發之纖維變性肺病、自體免疫大皰性皮膚病(AIBD)、慢性阻塞性肺病(COPD)及臭氧誘發之氣道發炎(參見Baggiolini等人,FEBS Lett
.307
:97 (1992);Miller等人,Crit. Rev. Immunol. 12
:17 (1992);Oppenheim等人,Annu. Rev. Immunol. 9
: 617 (1991);Seitz等人,J. Clin. Invest. 87:
463 (1991);Miller等人,Ann. Rev. Respir. Dis
.146
:427 (1992);及Donnely等人,Lancet 341
: 643 (1993);Fox及Haston,Radiation Oncology
,85
:215 (2013);Hirose等人,J. Genet. Syndr. Genet. Ther. S3
:005 (2013);Miller等人,Eur. J. Drug Metab. Pharmacokinet. 39
:173 (2014);Lazaar等人,Br. J. Clin. Pharmacol
.,72
:282 (2011))。 除發炎性病症外,一些CXCR2配體趨化因子(包括CXCL1、CXCL2、CXCL3及CXCL5)參與誘導腫瘤血管生成(Strieter等人,JBC 270
: 27348-27357 (1995))。在缺血性中風期間,一些CXCR2配體趨化因子係惡化劑(Connell等人,Neurosci. Lett., 15:30111 (2015)。其血管生成活性可能歸因於趨化因子對周圍血管中之血管內皮細胞(EC)表面上CXCR2表現之活化。 已知許多類型之腫瘤產生CXCR2配體趨化因子。該等趨化因子之產生與更具侵襲性之表型(Inoue等人,Clin Cancer Res 6
:2104-2119 (2000))及較差預後(Yoneda等人,J Nat Cancer Inst 90
:447-454 (1998))相關聯。由於趨化因子係EC趨化作用之強效趨化性因子,故其可誘導內皮細胞朝向其在腫瘤中之產生位點之趨化作用。此可為誘導腫瘤血管生成之關鍵步驟。CXCR2抑制劑將抑制ELR-CXC趨化因子之血管生成活性,且因此阻斷腫瘤生長。已展示此抗腫瘤活性用於針對CXCL8之抗體(Arenberg等人,J Clin Invest 97:
2792-2802 (1996))、針對ENA-78之抗體(Arenberg等人,J Clin Invest 102
:465-72 (1998))及針對CXCL1之抗體(Haghnegahdar等人,J. Leukoc Biology 67
:53-62 (2000))。 許多腫瘤細胞表現CXCR2且腫瘤細胞可藉由分泌ELR-CXC趨化因子來刺激其自身生長。因此,除減少腫瘤內之血管生成外,CXCR2抑制劑可直接抑制腫瘤細胞生長。 CXCR2通常係由腫瘤微環境內之髓源阻抑細胞(MDSC)表現。MDSC參與阻抑腫瘤免疫反應,且MDSC因應CXCR2配體趨化因子之遷移最可能負責將該等細胞吸引至腫瘤中(Marvel及Gabrilovich,J. Clin. Invest.
13:1 (2015)及Mackall等人,Sci. Trans. Med
.6
:237 (2014))。因此,CXCR2抑制劑可逆轉阻抑過程且由此允許免疫細胞可更有效地排斥腫瘤。事實上,阻斷CXC-趨化因子受體之活化已證實可作為與檢查點抑制劑之組合療法用於阻抑腫瘤生長,此表明CXCR2阻斷亦可與其他抗腫瘤療法組合來增強腫瘤排斥,該等其他抗腫瘤療法包括(但不限於)疫苗或傳統細胞毒性化學療法(參見Highfill等人,Science Translational Medicine
,6
:237 (2014))。 CCR6及CXCR2之活性各自與某些癌症類型(包括CRC)中之較差結果相關,但其各自可能經由不同的潛在互補機制起作用(Nandi等人,PLoS One
, 9:e97566, 2014;Liu等人,PLoS One
, 9:e101137, 2014;Cheluvappa,Int J Colorectal Dis
, 29:1181, 2014;Zhang,Biomed Pharmacother
. 69:242, 2014;Lee等人,Int J Cancer
, 135:232, 2014;Wang及DuBois,Oncoimmunology
, 29:e28581, 2014;Wu等人,Int J Clin Exp Med, 8:5883, 2015)。 鑒於CCR6及CXCR2之臨床重要性,調節該兩種受體中一者或兩者之功能之化合物的鑑別代表吸引至新治療劑研發中之途徑。本文提供關於其應用之該等化合物及方法。
相關申請案之交叉參考
本申請案係根據35 U.S.C. § 119(e)主張於2015年11月19日提出申請之美國臨時申請案第62/257,389號及於2016年1月12日提出申請之美國臨時申請案第62/277,711號之權益的申請案,該等申請案中之每一者之全文以引用方式併入本文中。關於在聯邦政府發起之研究及研發下作出之發明權利之聲明
不適用對光碟上提交之 「 序列表 」 、表或電腦程式列表附錄之參考
不適用 在進一步闡述本發明之前應理解,本發明並不限於本文所述之具體實施例,且亦應理解本文所用之術語僅出於闡述具體實施例之目的,且不欲具有限制性。 倘若提供值之範圍,則應理解本發明涵蓋該範圍之上限與下限之間之每一中間值及該所述範圍內之任何其他所述值或中間值,除非上下文另外明確指明,否則精確至下限單位之十分之一。該等較小範圍之上限及下限可獨立地包括於該等較小範圍內,且亦涵蓋於本發明內,任何在所述範圍中明確排除之限值仍被排除。倘若所述範圍包括限值中之一者或兩者,則本發明中亦包括排除彼等所包括限值中之任一者或兩者的範圍。除非另外定義,否則本文所用之所有技術及科學術語皆具有與熟習本發明所屬技術者通常所理解之含義相同的含義。 必須注意,除非上下文另外明確指明,否則如本文及隨附申請專利範圍中所用之單數形式「一(a、an)」及「該」包括複數個指示物應進一步注意,申請專利範圍可設計為不包括任何可選要素。因此,此陳述結合列舉申請專利範圍要素意欲充當使用該排他性術語(例如「獨自地」、「僅有地」及諸如此類)或使用「消極」限制的先行基礎。 本文所論述之公開案僅因為其揭示內容先於本發明的申請日期而提供。此外,所提供之公開日期可能與實際公開日期不同,實際公開日期可能需要單獨確認。概述
本發明源自以下發現:式(A)、(A1)、(A2)、(I)及(Ia1)化合物用作CCR6受體及/或CXCR2受體之強效拮抗劑。該等化合物具有活體內抗發炎活性且具有優異的藥物動力學性質。因此,本文所提供之化合物可用於醫藥組合物中,用於治療CCR6介導之疾病及/或CXCR2介導之疾病之方法中,及作為對照用於鑑別CCR6及/或CXCR2拮抗劑之分析中。縮寫及定義
除非另外指示,否則以下術語意欲具有下文所述之含義。其他術語定義於本說明書通篇之別處。 除非另有說明,否則術語「烷基」自身或作為另一取代基之一部分意指具有指定碳原子數之直鏈或具支鏈烴基(即C1-8
意指1至8個碳)。烷基之實例包括甲基、乙基、正丙基、異丙基、正丁基、第三丁基、異丁基、第二丁基、正戊基、正己基、正庚基、正辛基及諸如此類。 術語「環烷基」係指具有所指示環原子數(例如,C3-6
環烷基)且完全飽和或在環頂點之間具有不超過一個雙鍵之烴環。「環烷基」亦欲指二環及多環烴環,例如二環[2.2.1]庚烷、二環[2.2.2]辛烷等。 術語「環雜烷基」係指具有所指示環頂點(或成員)數且具有1至5個選自N、O及S之雜原子替代1至5個碳頂點之環烷基環,且其中氮及硫原子視情況經氧化,且氮原子視情況經四級銨化。環雜烷基可為單環、二環或多環系統。環雜烷基之非限制性實例包括吡咯啶、咪唑啶、吡唑啶、丁內醯胺、戊內醯胺、咪唑啶酮、乙內醯脲、二氧戊環、酞醯亞胺、六氫吡啶、1,4-二噁烷、嗎啉、硫嗎啉、硫嗎啉-S-氧化物、硫嗎啉-S,S-氧化物、六氫吡嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氫呋喃、四氫噻吩、喹核鹼及諸如此類。環雜烷基可經由環碳或雜原子附接至分子之其餘部分。 如本文所用使本文所繪示任一化學結構中之單鍵、雙鍵或三鍵相交之波形線「」表示單鍵、雙鍵或三鍵與分子其餘部分之附接點。另外,延伸至環(例如,苯基環)中心之鍵意欲指示在任一可用環頂點附接。熟習此項技術者應理解,顯示為附接至環之多個取代基將佔據提供穩定化合物且以其他方式在空間上相容之環頂點。對於二價組份,表示意欲包括任一取向(正向或反向)。舉例而言,基團「-C(O)NH-」意欲包括呈任一取向之連接:-C(O)NH-或-NHC(O)-,且類似地,「-O-CH2
CH2
-」意欲包括-O-CH2
CH2
-及-CH2
CH2
-O-二者。 術語「烷氧基」、「烷基胺基」及「烷基硫基」 (或硫烷氧基)係以其習用意義使用,且係指分別經由氧原子、胺基或硫原子附接至分子之其餘部分之彼等烷基。另外,對於二烷基胺基,烷基部分可相同或不同且亦可組合形成3-7員環,且每一烷基部分附接至氮原子。因此,表示為二烷基胺基或-NRa
Rb
之基團意欲包括六氫吡啶基、吡咯啶基、嗎啉基、氮雜環丁基及諸如此類。 除非另有說明,否則術語「鹵基」或「鹵素」自身或作為另一取代基之一部分意指氟、氯、溴或碘原子。另外,諸如「鹵烷基」等術語意欲包括單鹵烷基及多鹵烷基。舉例而言,術語「C1-4
鹵烷基」意欲包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基及諸如此類。 除非另有說明,否則術語「芳基」意指多不飽和、通常芳香族烴基,其可為單環或稠合在一起或共價連接之多環(至多3個環)。芳基之非限制性實例包括苯基、萘基及聯苯。 術語「雜芳基」係指含有1至5個選自N、O及S之雜原子之芳基(或環),其中氮及硫原子視情況經氧化,且氮原子視情況經四級銨化。雜芳基可經由雜原子附接至分子之其餘部分。雜芳基之非限制性實例包括吡啶基、嗒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、喹唑啉基、啉基、呔嗪基、苯并三嗪基、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并異噁唑基、異苯并呋喃基、異吲哚基、吲嗪基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、異喹啉基、異噻唑基、吡唑基、吲唑基、喋啶基、咪唑基、三唑基、四唑基、噁唑基、異噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基及諸如此類。雜芳基環之取代基可選自下文所述可接受之取代基之群。 在一些實施例中,以上術語(例如,「烷基」、「芳基」及「雜芳基」)將視情況經取代。下文提供每一類型基團之所選取代基。 烷基(包括通常稱為伸烷基、烯基、炔基及環烷基之彼等基團)之可選取代基可為多個選自以下之基團:鹵素、-OR’、-NR’R’’、-SR’、-SiR’R’’R’’’、-OC(O)R’、-C(O)R’、-CO2
R’、-CONR’R’’、-OC(O)NR’R’’、-NR’’C(O)R’、-NR’-C(O)NR’’R’’’、-NR’’C(O)2
R’、-NH-C(NH2
)=NH、-NR’C(NH2
)=NH、-NH-C(NH2
)=NR’、-S(O)R’、-S(O)2
R’、-S(O)2
NR’R’’、-NR’S(O)2
R’’、-CN及-NO2
,其數量介於0至(2m’+1)範圍內,其中m’係該基團中碳原子之總數。R’、R’’及R’’’各自獨立地指氫、未經取代之C1-8
烷基、未經取代之芳基、經1-3個鹵素取代之芳基、未經取代之C1-8
烷基、C1-8
烷氧基或C1-8
硫烷氧基或未經取代之芳基-C1-4
烷基。當R’及R’’附接至同一氮原子時,其可與氮原子組合形成3員、4員、5員、6員或7員環。舉例而言,-NR’R’’意欲包括1-吡咯啶基及4-嗎啉基。 類似地,芳基及雜芳基之可選取代基有所變化且通常選自:-鹵素、-OR’、-OC(O)R’、-NR’R’’、-SR’、-R’、-CN、-NO2
、-CO2
R’、-CONR’R’’、-C(O)R’、-OC(O)NR’R’’、-NR’’C(O)R’、-NR’’C(O)2
R’、-NR’-C(O)NR’’R’’’、-NH-C(NH2
)=NH、-NR’C(NH2
)=NH、-NH-C(NH2
)=NR’、-S(O)R’、-S(O)2
R’、-S(O)2
NR’R’’、-NR’S(O)2
R’’、-N3
、全氟(C1
-C4
)烷氧基及全氟(C1
-C4
)烷基,其數量介於0至芳香族環系統上之開放化合價之總數範圍內;且其中R’、R’’及R’’’獨立地選自氫、C1-8
烷基、C1-8
鹵烷基、C3-6
環烷基、C2-8
烯基及C2-8
炔基。其他適宜取代基包括藉由1-4個碳原子之伸烷基系鏈附接至環原子之上述芳基取代基中之每一者。 芳基或雜芳基環之毗鄰原子上之兩個取代基可視情況經式-T-C(O)-(CH2
)q
-U-取代基替代,其中T及U獨立地係-NH-、-O-、-CH2
-或單鍵,且q為0至2之整數。或者,芳基或雜芳基環之毗鄰原子上之兩個取代基可視情況經式-A-(CH2
)r
-B-取代基替代,其中A及B獨立地係-CH2
-、-O-、-NH-、-S-、-S(O)-、-S(O)2
-、-S(O)2
NR’-或單鍵,且r為1至3之整數。如此形成之新環之一個單鍵可視情況經雙鍵替代。或者,芳基或雜芳基環之毗鄰原子上之兩個取代基可視情況經式-(CH2
)s
-X-(CH2
)t
-取代基替代,其中s及t獨立地係0至3之整數,且X係-O-、-NR’-、-S-、-S(O)-、-S(O)2
-或-S(O)2
NR’-。-NR’-及-S(O)2
NR’-中之取代基R’選自氫或未經取代之C1-6
烷基。 如本文所用術語「雜原子」意欲包括氧(O)、氮(N)、硫(S)及矽(Si)。 當變量(例如R1
或Ra
)在任一化合物或取代基中出現一次以上時,其在每次出現時之定義獨立於其在其他每種情況下出現時之定義。另外,取代基及/或變量之組合僅在該等組合產生穩定化合物時容許存在。 術語「醫藥上可接受之鹽」意欲包括使用相對無毒之酸或鹼製備之活性化合物之鹽,此端視在本文所述化合物上發現之具體取代基而定。當本發明化合物含有相對酸性官能基時,可藉由使該等化合物之中性形式與足量的純淨或於適宜惰性溶劑中之期望鹼接觸來獲得鹼加成鹽。衍生自醫藥上可接受之無機鹼之鹽之實例包括鋁鹽、銨鹽、鈣鹽、銅鹽、鐵鹽、亞鐵鹽、鋰鹽、鎂鹽、錳鹽、亞錳鹽、鉀鹽、鈉鹽、鋅鹽及諸如此類。衍生自醫藥上可接受之有機鹼之鹽包括以下鹼之鹽:一級、二級及三級胺,包括經取代胺、環胺、天然胺及諸如此類,例如精胺酸、甜菜鹼、咖啡因(caffeine)、膽鹼、N,N’-二苄基乙二胺、二乙胺、2-二乙基胺基乙醇、2-二甲基胺基乙醇、乙醇胺、乙二胺、N-乙基-嗎啉、N-乙基六氫吡啶、還原葡糖胺、葡萄糖胺、組胺酸、哈胺(hydrabamine)、異丙胺、離胺酸、甲基還原葡糖胺、嗎啉、六氫吡嗪、六氫吡啶、聚胺樹脂、普魯卡因(procaine)、嘌呤、可可鹼(theobromine)、三乙胺、三甲胺、三丙胺、胺丁三醇及諸如此類。當本發明化合物含有相對鹼性官能基時,可藉由使該等化合物之中性形式與足量的純淨或於適宜惰性溶劑中之期望酸接觸來獲得酸加成鹽。醫藥上可接受之酸加成鹽之實例包括衍生自以下無機酸之彼等:如鹽酸、氫溴酸、硝酸、碳酸、一氫碳酸、磷酸、一氫磷酸、二氫磷酸、硫酸、一氫硫酸、氫碘酸或亞磷酸及諸如此類;以及衍生自以下相對無毒之有機酸之鹽:如乙酸、丙酸、異丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富馬酸、苦杏仁酸、鄰苯二甲酸、苯磺酸、對甲苯磺酸、檸檬酸、酒石酸、甲烷磺酸及諸如此類。亦包括胺基酸之鹽,例如精胺酸鹽及諸如此類,及如葡糖醛酸或半乳糖醛酸及諸如此類等有機酸的鹽(例如,參見Berge, S.M.等人,「Pharmaceutical Salts」,Journal of Pharmaceutical Science
,1977
,66
, 1-19)。本發明之某些特定化合物含有允許將化合物轉化成鹼或酸加成鹽之鹼性及酸性官能基二者。 該等化合物之中性形式可藉由使鹽與鹼或酸接觸並以習用方式分離出母體化合物來重新產生。化合物之母體形式在某些物理性質(例如在極性溶劑中之溶解度)方面不同於各種鹽形式,然而出於本發明之目的,該等鹽在其他方面與化合物之母體形式等效。 除鹽形式以外,本發明提供呈前藥形式之化合物。本文所述化合物之前藥係在生理條件下易於經歷化學變化以提供本發明化合物之彼等化合物。此外,前藥可藉由化學或生物化學方法在離體環境中轉化成本發明化合物。舉例而言,當將前藥與適宜酶或化學試劑一起放置於經皮貼片儲存器中時,前藥可緩慢轉化成本發明化合物。 本發明之某些化合物可以非溶劑合形式以及溶劑合形式(包括水合形式)存在。一般而言,溶劑合形式與非溶劑合形式等效且意欲涵蓋於本發明之範疇內。本發明之某些化合物可以多種結晶或非晶形形式存在。一般而言,所有物理形式對於本發明所涵蓋之用途而言係等效的且意欲在本發明之範疇內。 本發明之某些化合物具有不對稱碳原子(光學中心)或雙鍵;外消旋物、非鏡像異構物、幾何異構物、區域異構物及個別異構物(例如,單獨鏡像異構物)皆意欲涵蓋於本發明之範疇內。當顯示立體化學繪示時,欲指存在一種異構物且實質上不含另一異構物之化合物。「實質上不含」另一異構物指示至少80/20比率之兩種異構物,更佳90/10或95/5或更大。在一些實施例中,一種異構物將以至少99%之量存在。 本發明化合物亦可在構成該等化合物之原子中之一或多者處含有非天然比例之原子同位素。同位素之非天然比例可定義為介於自然界中所發現之量至由100%所討論原子組成之量之範圍內。舉例而言,化合物可納入放射性同位素(例如氚(3
H)、碘-125 (125
I)或碳-14 (14
C))或非放射性同位素(例如氘(2
H)或碳-13 (13
C))。該等同位素變化形式可向本申請案內別處所述之彼等提供額外用途。舉例而言,本發明化合物之同位素變體可發現額外用途,包括(但不限於)作為診斷及/或成像試劑或作為細胞毒性/放射性毒性治療劑。另外,本發明化合物之同位素變體可具有改變的藥物動力學及藥效學特徵,其可有助於增強治療期間之安全性、耐受性或效能。本發明化合物之所有同位素變化形式,無論是否為放射性,皆意欲涵蓋於本發明之範疇內。 術語「患者」或「個體」可互換使用且係指人類或非人類動物(例如,哺乳動物)。 術語「投與(administration、administer)」及諸如此類在其應用於例如個體、細胞、組織、器官或生物流體時係指使例如CCR6及/或CXCR2之拮抗劑、包含該拮抗劑之醫藥組合物或診斷劑與個體、細胞、組織、器官或生物流體接觸。在細胞背景下,投與包括使試劑與細胞接觸(例如,活體外或離體)以及使試劑與流體接觸,其中流體與細胞接觸。 術語「治療(treat、treating、treatment)」及諸如此類係指在疾病、病症或病況或其症狀已經診斷、觀察及諸如此類後起始,以暫時或永久地消除、減輕、阻抑、緩和或改善個體所患疾病、病症或病況之至少一個根本病因或與個體所患疾病、病症、病況相關之至少一種症狀的作用進程(例如投與CCR6及/或CXCR2之拮抗劑或包含該拮抗劑之醫藥組合物)。因此,治療包括抑制(例如,阻止疾病、病症或病況或與其相關之臨床症狀之發展或進一步發展)活動性疾病。 如本文所用術語「需要治療」係指由醫師或其他照護者所作出之個體需要或將受益於治療之判斷。此判斷係基於在醫師或照護者經驗之範圍內之多個要素來作出。 術語「預防(prevent、preventing、prevention)」及諸如此類係指通常在易患具體疾病、病症或病況之個體背景下,以一定方式(例如,在疾病、病症、病況或其症狀發作之前)起始以暫時或永久地預防、阻抑、抑制或減輕個體罹患疾病、病症、病況或諸如此類(如藉由例如臨床症狀之存在所確定)或延遲其發作之風險的作用進程(例如投與CCR6及/或CXCR2之拮抗劑或包含該拮抗劑之醫藥組合物)。在某些情況下,該等術語亦指減緩疾病、病症或病況之進展或抑制其進展至有害或原本不期望之狀態。 如本文所用術語「需要預防」係指由醫師或其他照護者所作出之個體需要或將受益於預防性護理之判斷。此判斷係基於根據醫師或照護者經驗之多個要素來作出。 片語「治療有效量」係指將藥劑單獨或作為醫藥組合物之一部分且以單一劑量或作為一系列劑量之一部分、以能夠在投與個體時對疾病、病症或病況之任一症狀、態樣或特徵具有任何可檢測到之正面效應的量投與個體。治療有效量可藉由量測相關生理效應來確定,且其可結合投藥方案及個體病況之診斷分析及諸如此類來調整。舉例而言,CCR6及/或CXCR2之拮抗劑(或例如其代謝物)在投與後具體時間之血清含量之量測可指示是否已使用治療有效量。 片語「足以實現變化之量」意指在投與具體療法之前(例如,基線含量)與之後量測之指示劑含量之間存在可檢測到之差異。指示劑包括任何客觀參數(例如,血清濃度)或主觀參數(例如,個體之幸福感)。 術語「小分子」係指具有小於約10 kDa、小於約2 kDa或小於約1 kDa之分子量之化學化合物。小分子包括(但不限於)無機分子、有機分子、含有無機組份之有機分子、包含放射性原子之分子及合成分子。在治療上,與大分子相比,小分子可對細胞更具滲透性、不易降解且不太可能引發免疫反應。 術語「抑制劑」及「拮抗劑」或「活化劑」及「激動劑」分別係指抑制分子或活化分子,例如用於活化例如配體、受體、輔因子、基因、細胞、組織或器官。抑制劑係減少、阻斷、阻止、延遲例如基因、蛋白質、配體、受體或細胞之活化、使其不活化、不敏感或下調之分子。活化劑係增加、活化、促進、增強例如基因、蛋白質、配體、受體或細胞之活化、使其敏感或上調之分子。抑制劑亦可定義為使組成性活性降低、阻斷或不活化之分子。「激動劑」係與靶標相互作用以引起或促進靶標活化增加之分子。「拮抗劑」係與激動劑之作用相反之分子。拮抗劑阻止、降低、抑制或中和激動劑之活性,且甚至在無經鑑別激動劑時拮抗劑亦可阻止、抑制或降低靶標(例如靶受體)之組成性活性。 術語「調節(modulate、modulation)」及諸如此類係指分子(例如,活化劑或抑制劑)直接或間接增加或降低CCR6及/或CXCR2之功能或活性之能力。調節劑可單獨起作用,或其可使用輔因子,例如蛋白質、金屬離子或小分子。 分子之「活性」可闡述或係指分子與受體之結合;催化活性;刺激基因表現或細胞信號傳導、分化或成熟之能力;抗原活性;調節其他分子之活性;及諸如此類。 如本文所用之「相當」、「相當活性」、「與……相當之活性」、「相當效應」、「與……相當之效應」及諸如此類係可定量及/或定性地觀察之相對術語。該等術語之含義通常端視其所用背景而定。舉例而言,自定性之角度來看,兩種皆活化受體之藥劑可視為具有相當效應,但自定量之角度來看,如在業內公認分析(例如,劑量-反應分析)中或在業內公認動物模型中所測定,若一種藥劑僅能夠達成另一藥劑活性之20%,則該兩種藥劑可視為缺少相當效應。當比較一個結果與另一結果(例如,一個結果與參考標準)時,「相當」通常(但並不始終)意指一個結果偏離參考標準不到35%、不到30%、不到25%、不到20%、不到15%、不到10%、不到7%、不到5%、不到4%、不到3%、不到2%或不到1%。在具體實施例中,若一個結果偏離參考標準不到15%、不到10%或不到5%,則該結果與參考標準相當。舉例而言但不加以限制,活性或效應可指效能、穩定性、溶解度或免疫原性。 「實質上純」指示組份佔組合物總含量之約50%以上,且通常佔組合物總含量之約60%以上。更通常而言,「實質上純」係指其中總組合物之至少75%、至少85%、至少90%或以上為所關注組份之組合物。在一些情形下,所關注組份將佔組合物總含量之約90%以上或約95%以上。化合物
本文提供具有式(I)之化合物:或其任何鹽、溶劑合物、水合物、N-氧化物、互變異構物或旋轉異構物,其中 B選自由呋喃基、噁唑基、苯基、吡啶基、嘧啶基及吡嗪基組成之群,其各自視情況經獨立地選自由鹵素、CN、C1-4
烷基、C1-4
烷氧基及C1-4
鹵烷基組成之群之R1a
、R1b
及R2
取代; R3
係選自H及D之成員; R4
係選自H、C1-8
烷基及Y之成員;其中C1-8
烷基視情況經以下基團取代:鹵素、-CN、-CO2
Ra
、-CONRa
Rb
、-C(O)Ra
、OC(O)NRa
Rb
、-NRa
C(O)Rb
、-NRa
C(O)2
Rc
、-NRa
C(O)NRa
Rb
、-NRa
Rb
、-ORa
、-S(O)2
NRa
Rb
、-NRa
S(O)2
Rb
及Y,其中每一Ra
及Rb
獨立地選自氫、C1-4
烷基、C1-4
羥基烷基及C1-4
鹵烷基,Rc
選自C1-4
烷基、C1-4
羥基烷基及C1-4
鹵烷基,且Y係視情況經1至4個選自以下之取代基取代之5或6員芳基或雜芳基:鹵素、-CN、-C1-4
烷基、-C1-4
烷氧基、-C1-4
羥基烷基、-C1-4
鹵烷基、OCF3
、-CO2
Ra
、-CONRa
Rb
、-C(O)Ra
、-OC(O)NRa
Rb
、-NRa
C(O)Rb
、-CH2
CO2
Ra
; R5a
及R5b
各自係獨立地選自以下之成員:H、鹵素、C1-4
烷基、C1-4
烷氧基、CO2
H及CN; R6a
及R6b
各自係獨立地選自以下之成員:H、C1-4
烷基、C1-4
羥基烷基及C1-4
鹵烷基;或視情況R6a
及R6b
一起形成側氧基(=O);且 下標n係1或2。 在一些實施例中,式I化合物係以下化合物:其中B係呋喃基或噁唑基,其視情況經獨立地選自由鹵素、CN、C1-4
烷基、C1-4
烷氧基及C1-4
鹵烷基組成之群之R1a
及R1b
取代。在此組實施例內,某些所選實施例係其中R1a
為CH3
之彼等。在其他所選實施例中,R3
係H。在其他所選實施例中,R5a
及R5b
中之每一者獨立地選自H、Cl及F。在其他所選實施例中,R6a
及R6b
中之每一者獨立地選自H及C1-4
烷基。在其他所選實施例中,R4
係Y。在其他所選實施例中,R4
選自H及視情況經取代之芳基或雜芳基。在具體實施例中,R1a
選自CH3
及Cl;且R1b
係不存在或係CH3
。 在一組所選實施例中,提供具有式(Ia1)之化合物:或其醫藥上可接受之鹽、溶劑合物或水合物,其中R1a
選自CH3
及Cl;R1b
係不存在(經H替代)或係CH3
;R3
係H或D;R4
係H或視情況經取代之芳基或雜芳基;R5a
及R5b
各自獨立地選自H、F、Cl、Br及CH3
;且R6a
及R6b
各自獨立地選自H及CH3
。 在某些實施例中,提供式(Ia1)化合物,其中R1a
係CH3
;R1b
係不存在(經H替代)或係CH3
;R3
係H或D;R4
係H或視情況經取代之芳基或雜芳基;R5a
係H或Cl或Br;R5b
係H或F;且R6a
及R6b
各自係H;或其醫藥上可接受之鹽、溶劑合物或水合物。 在一些所選實施例中,提供選自圖1中之彼等化合物之式(I)化合物。 本文亦提供具有式(A)之化合物:其中 B選自由呋喃基、噻吩基、噁唑基、苯基、吡啶基、嘧啶基及吡嗪基組成之群,其各自視情況經獨立地選自由鹵素、CN、C1-4
烷基、C1-4
烷氧基及C1-4
鹵烷基組成之群之R1a
、R1b
及R2
取代; R3
係選自由H及D組成之群之成員; R4
係選自由H、C1-8
烷基、OH、-NRa
Rb
、-C1-4
烷氧基及Y組成之群之成員;其中C1-8
烷基視情況經以下基團取代:鹵素、-CN、-CO2
Ra
、-CONRa
Rb
、-C(O)Ra
、OC(O)NRa
Rb
、-NRa
C(O)Rb
、-NRa
C(O)2
Rc
、-NRa
C(O)NRa
Rb
、-NRa
Rb
、-ORa
、-S(O)2
NRa
Rb
、-NRa
S(O)2
Rb
及Y,其中Y係4至8員環雜烷基或3至8員環烷基或5或6員芳基或雜芳基,其中之任一者視情況經1至4個選自以下之取代基取代:鹵素、側氧基、-CN、-C1-6
烷基、-C1-6
烷氧基、-C1-6
羥基烷基、-C1-6
鹵烷基、O-C1-6
鹵烷基、-C1-4
烷基-O-C1-4
烷基、-C1-6
烷基-NRa
Rb
、-C1-6
烷基-CO2
H、-C1-6
烷基-CO2
Ra
、-C1-6
烷基-CONRa
Rb
、-C1-6
烷基-C(O)Ra
、-C1-6
烷基-OC(O)NRa
Rb
、-C1-6
烷基-NRa
C(O)Rb
、-C1-6
烷基-NRa
C(O)2
Rc
、-C1-6
烷基-NRa
C(O)NRa
Rb
、-C1-6
烷基-ORa
、-C1-6
烷基-S(O)2
NRa
Rb
、-C1-6
烷基-NRa
S(O)2
Rb
、-CO2
Ra
、-CONRa
Rb
、-C(O)Ra
、-OC(O)NRa
Rb
、-NRa
C(O)Rb
、-NRa
C(O)2
Rc
、-NRa
C(O)NRa
Rb
、-NRa
Rb
、-ORa
、-S(O)2
NRa
Rb
、-NRa
S(O)2
Rb
、-CH2
CO2
Ra
;每一Ra
及Rb
獨立地選自氫、C1-4
烷基、C1-4
羥基烷基及C1-4
鹵烷基,且Rc
選自C1-4
烷基、C1-4
羥基烷基及C1-4
鹵烷基;且其中4至8員環雜烷基及3至8員環烷基可另外視情況經側氧基取代; R5a
及R5b
各自係獨立地選自由H、鹵素、C1-4
烷基、-C1-4
鹵烷基、O-C1-4
鹵烷基、C1-4
烷氧基、CO2
H及CN組成之群之成員; R6a
及R6b
各自係獨立地選自由H、C1-4
烷基、C1-4
羥基烷基及C1-4
鹵烷基組成之群之成員;或視情況R6a
及R6b
一起形成側氧基(=O)或4至6員環雜烷基或3至6員環烷基; R7
係選自由甲基、乙基及C1-2
鹵烷基組成之群之成員;且 下標n係1或2; 或其任何醫藥上可接受之鹽、溶劑合物、水合物、N-氧化物、互變異構物或旋轉異構物。 在一些實施例中,B選自由以下組成之群:在一些實施例中,B選自由以下組成之群:在一些實施例中,B係呋喃基或噁唑基,其各自視情況經獨立地選自由鹵素、CN、C1-4
烷基、C1-4
烷氧基及C1-4
鹵烷基組成之群之R1a
及R1b
取代。 在一些實施例中,B係經R1a
(其係CH3
或Cl)取代且視情況經R1b
(其係CH3
)取代之呋喃基。 在一些實施例中,R3
係H。 在一些實施例中,R5a
及R5b
中之每一者獨立地選自由H、CH3
、Cl及F組成之群。 在一些實施例中,選自由以下組成之群:在一些實施例中,選自由以下組成之群:在一些實施例中,R6a
及R6b
中之每一者獨立地選自由H及C1-2
烷基組成之群。 在一些實施例中,獨立地選自由以下組成之群在一些實施例中,獨立地選自由以下組成之群在一些實施例中,R4
係H、C1-3
烷基或Y,其中C1-3
烷基經四唑基或四唑酮基取代,其中四唑基或四唑酮基視情況經以下基團取代:C1-6
烷基、C1-6
羥基烷基或C1-4
烷基-O-C1-4
烷基,其中Y選自由吡啶基、吡唑基及苯基組成之群,其中吡啶基、吡唑基及苯基具有1至3個各自獨立地選自-C1-4
烷基、-C1-4
烷氧基及-CO2
H之取代基。 在一些實施例中,R4
係H。 在一些實施例中,R4
係C1-6
烷基,其中C1-6
烷基經四唑基或四唑酮基取代,其中四唑基或四唑酮基視情況經以下基團取代:-C1-6
烷基、-C1-6
烷氧基、-C1-6
羥基烷基、-C1-6
鹵烷基、O-C1-6
鹵烷基、-C1-4
烷基-O-C1-4
烷基、-C1-6
烷基-NRa
Rb
、-C1-6
烷基-CO2
H、-C1-6
烷基-CO2
Ra
、-C1-6
烷基-CONRa
Rb
、-C1-6
烷基-C(O)Ra
、-C1-6
烷基-OC(O)NRa
Rb
、-C1-6
烷基-NRa
C(O)Rb
、-C1-6
烷基-NRa
C(O)2
Rc
、-C1-6
烷基-NRa
C(O)NRa
Rb
、-C1-6
烷基-ORa
、-C1-6
烷基-S(O)2
NRa
Rb
或-C1-6
烷基-NRa
S(O)2
Rb
。 在一些實施例中,R4
係C1-3
烷基,其中C1-3
烷基經四唑基或四唑酮基取代,其中四唑基或四唑酮基視情況經以下基團取代:-C1-6
烷基、-C1-6
烷氧基、-C1-6
羥基烷基、-C1-6
鹵烷基、-C1-4
烷基-O-C1-4
烷基、-C1-6
烷基-NRa
Rb
或-C1-6
烷基-CO2
H。 在一些實施例中,R4
係C1-3
烷基,其中C1-3
烷基經四唑基或四唑酮基取代,其中四唑基或四唑酮基視情況經以下基團取代:C1-3
烷基、C1-3
羥基烷基或C1-3
烷基-O-C1-3
烷基。 在一些實施例中,R4
選自由吡啶基、吡唑基及苯基組成之群,其中吡啶基、吡唑基及苯基具有1至3個各自獨立地選自-C1-4
烷基、-C1-4
烷氧基及-CO2
H之取代基。 在一些實施例中,R4
係經四唑基或四唑酮基取代之C1-3
烷基,其中四唑基或四唑酮基視情況經C1-3
烷基取代。 在一些實施例中,R4
選自由以下組成之群:在一些實施例中,R7
選自由甲基、乙基及CF3
組成之群。在一些實施例中,R7
係甲基。 在一些實施例中,提供式(A1)化合物:其中R1a
選自CH3
及Cl;R1b
係不存在或係CH3
;R3
係H或D;R4
係H或Y;R5a
及R5b
各自獨立地選自H、F、Cl、Br及CH3
;R6a
及R6b
各自獨立地選自H及CH3
;且R7
係甲基或乙基;或其醫藥上可接受之鹽、溶劑合物或水合物。 在一些實施例中,R1a
係CH3
;R1b
係不存在或係CH3
;R3
係H或D;R4
係H;R5a
係H、F、Me或Cl或Br;R5b
係H或F;R6a
及R6b
各自係H;且R7
係甲基或乙基;或其醫藥上可接受之鹽、溶劑合物或水合物。 在一些實施例中,化合物在帶有R3
之碳原子處實質上不含其他異構物。 在一些實施例中,R4
係Y。 在一些實施例中,式(A2)化合物提供:其中R1a
選自CH3
及Cl;R1b
係H或CH3
;R3
係H或D;R4a
及R4b
獨立地選自鹵素、-CN、-C1-4
烷基、-C1-4
烷氧基、-C1-4
羥基烷基、-C1-4
鹵烷基、OCF3
、-CO2
Ra
、-CONRa
Rb
、-C(O)Ra
、-OC(O)NRa
Rb
、-NRa
C(O)Rb
、-CH2
CO2
Ra
,且Ra
及Rb
獨立地選自氫、C1-4
烷基、C1-4
羥基烷基及C1-4
鹵烷基;R5a
及R5b
各自獨立地選自H、F、Cl、Br及CH3
;R6a
及R6b
各自獨立地選自H及CH3
;且R7
選自由甲基、乙基及C1-2
鹵烷基組成之群;或其醫藥上可接受之鹽、溶劑合物或水合物。 在一些實施例中,提供化合物或其醫藥上可接受之鹽,其選自由以下組成之群:在一些實施例中,提供化合物或其醫藥上可接受之鹽,其選自由以下組成之群: 在一些實施例中,提供化合物或其醫藥上可接受之鹽,其選自由以下組成之群: 化合物之製備
下文實例中之方案提供某些可遵循以獲得某些本發明化合物之合成途徑。將其他途徑或下文所呈現途徑之修改將為熟習此項技術者顯而易見且在本發明之範疇內。醫藥組合物
除上文所提供之化合物外,用於調節人類及動物中之CCR6及/或CXCR2活性之組合物通常含有醫藥載劑或稀釋劑。 如本文所用術語「組合物」意欲涵蓋包含指定量之指定成分的產品以及直接或間接地自指定量之指定成分組合而成的任一產品。「醫藥上可接受」意指載劑、稀釋劑或賦形劑必須與調配物之其他成分相容且對其接受者無害。 用於投與本發明化合物之醫藥組合物可便捷地以單位劑型呈現且可藉由藥學及藥物遞送業內所熟知之任一方法來製備。所有方法包括使活性成分與構成一或多種輔助成分之載劑混合之步驟。一般而言,醫藥組合物係藉由以下方式來製備:使活性成分與液體載劑或精細固體載劑或二者均一且均勻地混合,且隨後(若需要)使產物成型。在醫藥組合物中,納入一定量之活性目標化合物以足以對疾病之過程或病況產生期望效應。 含有活性成分之醫藥組合物可呈適於經口使用之形式,例如呈錠劑、糖錠劑、菱形錠劑、水性或油性懸浮液、可分散粉末或顆粒、乳液及自乳化液(如美國專利第6,451,339號中所述)、硬質或軟質膠囊、糖漿、酏劑、溶液、經頰貼片、經口凝膠、口香糖、可咀嚼錠劑、起泡粉及起泡錠形式。意欲經口使用之組合物可根據業內已知用於製造醫藥組合物之任一方法來製備,且該等組合物可含有一或多種選自由甜味劑、矯味劑、著色劑、抗氧化劑及防腐劑組成之群之試劑以提供醫藥上美觀且可口之製劑。錠劑含有活性成分與適於製造錠劑之醫藥上可接受之無毒賦形劑的混合物。舉例而言,該等賦形劑可為:惰性稀釋劑,例如纖維素、二氧化矽、氧化鋁、碳酸鈣、碳酸鈉、葡萄糖、甘露醇、山梨醇、乳糖、磷酸鈣或磷酸鈉;造粒劑及崩解劑,例如玉米澱粉或海藻酸;黏合劑,例如PVP、纖維素、PEG、澱粉、明膠或阿拉伯樹膠(acacia);及潤滑劑,例如硬脂酸鎂、硬脂酸或滑石。錠劑可無包衣或其可藉由已知技術經腸溶或以其他方式包衣以延遲在胃腸道中之崩解及吸收並由此提供較長時間之持續作用。舉例而言,可採用諸如甘油單硬脂酸酯或甘油二硬脂酸酯等延時材料。其亦可藉由美國專利第4,256,108號、第4,166,452號及第4,265,874號中所述之技術來包衣以形成滲透性治療錠劑用於控制釋放。 用於經口使用之組合物亦可呈現為硬質明膠膠囊形式,其中活性成分與惰性固體稀釋劑(例如碳酸鈣、磷酸鈣或高嶺土)混合;或其可呈現為軟質明膠膠囊形式,其中活性成分與水或油介質(例如花生油、液體石蠟或橄欖油)混合。另外,乳液可使用非水可混溶成分(例如油)來製備且使用表面活性劑(例如單-二酸甘油酯、PEG酯及諸如此類)來穩定。 水性懸浮液含有活性材料與適於製造水性懸浮液之賦形劑之混合物。該等賦形劑係懸浮劑,例如羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、海藻酸鈉、聚乙烯基吡咯啶酮、黃蓍膠及阿拉伯樹膠;分散劑或潤濕劑可為天然磷脂(例如卵磷脂)、或環氧烷與脂肪酸之縮合產物(例如聚氧乙烯硬脂酸酯)、或環氧乙烷與長鏈脂肪族醇之縮合產物(例如十七伸乙氧基鯨蠟醇)、或環氧乙烷與衍生自脂肪酸及己醣醇之偏酯之縮合產物(例如聚氧乙烯山梨醇單油酸酯)、或環氧乙烷與衍生自脂肪酸及己醣醇酸酐之偏酯之縮合產物(例如聚乙烯山梨醇酐單油酸酯)。水性懸浮液亦可含有一或多種防腐劑,例如對羥基苯甲酸乙酯或對羥基苯甲酸正丙酯;一或多種著色劑;一或多種矯味劑;及一或多種甜味劑,例如蔗糖或糖精。 可藉由將活性成分懸浮於植物油(例如花生油、橄欖油、芝麻油或椰子油)中或懸浮於諸如液體石蠟等礦物油中來調配油性懸浮液。油性懸浮液可含有增稠劑,例如蜂蠟、硬石蠟或鯨蠟醇。可添加甜味劑(例如上文所述之彼等)及矯味劑以提供適口之口服製劑。該等組合物可藉由添加抗氧化劑(例如抗壞血酸)來保存。 適於藉由添加水來製備水性懸浮液之可分散粉末及顆粒提供活性成分與分散劑或潤濕劑、懸浮劑及一或多種防腐劑之混合物。適宜分散劑或潤濕劑及懸浮劑例示為上文已提及之彼等。亦可存在其他賦形劑,例如甜味劑、矯味劑及著色劑。 本發明之醫藥組合物亦可呈水包油乳液形式。油相可為植物油(例如橄欖油或花生油)或礦物油(例如液體石蠟)或該等物質之混合物。適宜乳化劑可為天然膠(例如阿拉伯樹膠或黃蓍膠)、天然磷脂(例如大豆、卵磷脂)及衍生自脂肪酸與己糖醇酐之酯或偏酯(例如山梨醇酐單油酸酯)及該等偏酯與環氧乙烷之縮合產物(例如聚氧乙烯山梨醇酐單油酸酯)。乳液亦可含有甜味劑及矯味劑。 糖漿及酏劑可使用甜味劑(例如甘油、丙二醇、山梨醇或蔗糖)加以調配。該等調配物亦可含有緩和劑、防腐劑及矯味劑及/或著色劑。經口溶液可與例如環糊精、PEG及表面活性劑組合製備。 醫藥組合物可呈無菌可注射水性或油性懸浮液形式。此懸浮液可根據已知技術使用上文所提及之彼等適宜分散劑或潤濕劑及懸浮劑來調配。無菌可注射製劑亦可為於無毒非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液,例如呈於1,3-丁二醇中之溶液形式。可用之可接受媒劑及溶劑尤其係水、林格氏溶液(Ringer's solution)及等滲氯化鈉溶液。另外,通常採用無菌不揮發性油作為溶劑或懸浮介質。出於此目的,可採用任何溫和不揮發性油,包括合成單酸甘油酯或二酸甘油酯。此外,在可注射製劑中可使用諸如油酸等脂肪酸。 本發明化合物亦可以栓劑形式投與以經直腸投與藥物。可藉由將藥物與適宜非刺激賦形劑混合來製備該等組合物,該賦形劑在常溫下為固體但在直腸溫度下為液體且由此在直腸中將熔化而釋放藥物。該等材料包括可可脂及聚乙二醇。另外,化合物可藉助溶液或軟膏劑經由眼部遞送來投與。另外,標題化合物之經皮遞送可藉助離子導入貼片及諸如此類來實現。對於局部應用而言,採用含有本發明化合物之乳霜、軟膏劑、凝膠劑、溶液或懸浮液等。如本文所用之局部應用亦欲包括使用漱口劑及漱口水。 本發明化合物可經調配以沈積至醫學裝置中,該醫學裝置可包括可佈置或永久地植入體腔內之多種習用移植物、支架(包括支架移植物)、導管、氣球、籠或其他裝置中之任一者。作為具體實例,業內期望具有可將本發明化合物遞送至已經介入技術治療之身體區域之裝置及方法。 在實例性實施例中,本發明抑制劑可沈積在諸如支架等醫學裝置內,且遞送至治療位點來治療身體之部分。 業內已使用支架作為治療劑(即,藥物)之遞送媒劑。血管內支架通常永久地植入冠狀或末梢血管中。支架設計包括美國專利第4,733,655號(Palmaz)、第4,800,882號(Gianturco)或第4,886,062號(Wiktor)之彼等。該等設計包括金屬及聚合支架以及自動擴張式及氣球擴張式支架二者。支架亦可用於將藥物遞送在與血管系統接觸之位點,如例如以下專利中所揭示:美國專利第5,102,417號(Palmaz)及國際專利申請案第WO 91/12779號(Medtronic, Inc.)及WO 90/13332 (Cedars-Sanai Medical Center)、美國專利第5,419,760號(Narciso, Jr.)及美國專利第5,429,634號(Narciso, Jr.)。支架亦已用於將病毒遞送至腔壁用於基因遞送,如美國專利第5,833,651號(Donovan等人)中所揭示。 在一個實施例中,抑制劑可在形成用於醫學裝置(例如支架)之生物相容性包衣期間與聚合物組合物一起納入。自該等組份產生之包衣通常為均質的且可用於包覆經設計用於植入之多種裝置。 端視期望釋放速率或期望聚合物穩定性程度,聚合物可為生物穩定性或生物吸收性聚合物,但生物吸收性聚合物對於此實施例而言較佳,此乃因與生物穩定性聚合物不同,其在植入後不會長期存在,故不會引起任何不利慢性局部反應。可使用之生物吸收性聚合物包括(但不限於)聚(L-乳酸)、聚己內酯、聚乙交酯(PGA)、聚(乳酸交酯-共-乙交酯) (PLLA/PGA)、聚(羥基丁酸酯)、聚(羥基丁酸酯-共-戊酸酯)、聚二噁烷酮、聚原酸酯、聚酸酐、聚(乙醇酸)、聚(D-乳酸)、聚(L-乳酸)、聚(D,L-乳酸)、聚(D,L-乳酸交酯) (PLA)、聚(L-乳酸交酯) (PLLA)、聚(乙醇酸-共-三亞甲基碳酸酯) (PGA/PTMC)、聚環氧乙烷(PEO)、聚二噁烷酮(PDS)、聚磷酸酯、聚磷酸酯胺基甲酸酯、聚(胺基酸)、氰基丙烯酸酯、聚(三亞甲基碳酸酯)、聚(亞胺基碳酸酯)、共聚(醚-酯) (例如,PEO/PLA)、聚草酸伸烷基酯、聚磷氮烯及生物分子(例如纖維蛋白、纖維蛋白原、纖維素、澱粉、膠原及玻尿酸)、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、水凝膠之交聯或兩親性嵌段共聚物及業內已知之其他適宜生物吸收性聚合物。而且,亦可使用具有相對較低之慢性組織反應之生物穩定性聚合物,例如聚胺基甲酸酯、聚矽氧及聚酯及可在醫學裝置上溶解並固化或聚合之其他聚合物,例如聚烯烴、聚異丁烯及乙烯-α烯烴共聚物;丙烯酸聚合物及共聚物、鹵乙烯聚合物及共聚物(例如聚氯乙烯);聚乙烯基吡咯啶酮;聚乙烯基醚,例如聚乙烯基甲醚;聚偏鹵乙烯,例如聚二氟亞乙烯及聚二氯亞乙烯;聚丙烯腈、聚乙烯基酮;聚乙烯基芳香族,例如聚苯乙烯、聚乙烯基酯(例如聚乙酸乙烯酯);乙烯基單體與彼此及烯烴之共聚物,例如乙烯-甲基丙烯酸甲酯共聚物、丙烯腈-苯乙烯共聚物、ABS樹脂及乙烯-乙酸乙烯酯共聚物;吡喃共聚物;聚羥基-丙基-甲基丙烯醯胺-酚;聚羥基乙基-天門冬醯胺-酚;聚環氧乙烷-經棕櫚醯基殘基取代之聚離胺酸;聚醯胺,例如耐綸66及聚己內醯胺;醇酸樹脂、聚碳酸酯;聚甲醛;聚醯亞胺;聚醚;環氧樹脂、聚胺基甲酸酯;人造絲;人造絲-三乙酸酯;纖維素、乙酸纖維素、丁酸纖維素;乙酸丁酸纖維素;賽璐玢(cellophane);硝酸纖維素;丙酸纖維素;纖維素醚;及羧甲基纖維素。 聚合物及半透性聚合物基質可形成成形物件,例如瓣膜、支架、管、假體及諸如此類。 在本發明之一個實施例中,使本發明之抑制劑偶合至形成為支架或支架移植物裝置之聚合物或半透性聚合物基質。 通常,藉由旋塗、浸漬或噴霧將聚合物施加至可植入裝置之表面。亦可將業內已知之其他方法用於此目的。噴霧之方法包括傳統方法以及使用噴墨型分配器之微沈積技術。另外,可使用光圖案化將聚合物沈積在可植入裝置上以使聚合物僅置於裝置之特定部分上。該裝置之此包衣在裝置周圍提供均勻層,此允許改良各種分析物擴散通過裝置包衣。 在本發明之較佳實施例中,抑制劑經調配以自聚合物包衣釋放至放置有醫學裝置之環境中。較佳地,抑制劑係使用涉及聚合物載劑或層之若干熟知技術中之至少一者以受控方式經延長的時段(例如,數月)釋放以控制溶析。該等技術中之一些先前闡述於美國專利申請案20040243225A1中。 此外,如例如美國專利第6,770,729號中所述,聚合物組合物之試劑及反應條件可經操縱以使得可控制抑制劑自聚合物包衣之釋放。舉例而言,可調節一或多個聚合物包衣之擴散係數以控制抑制劑自聚合物包衣之釋放。在此論題之變化形式中,可控制一或多個聚合物包衣之擴散係數以調節存在於放置有醫學裝置之環境中之分析物(例如促進聚合物之一些部分分解或水解之分析物)接近聚合物組合物內之一或多種組份(及例如由此調節抑制劑自聚合物包衣之釋放)的能力。本發明之另一實施例包括具有複數個聚合物包衣之裝置,每一包衣具有複數個擴散係數。在本發明之該等實施例中,抑制劑自聚合物包衣之釋放可藉由複數個聚合物包衣來調節。 在本發明之另一實施例中,抑制劑自聚合物包衣之釋放係藉由調節聚合物組合物之一或多種性質(例如一或多種內源或外源化合物之存在或者聚合物組合物之pH)來控制。舉例而言,某些聚合物組合物可經設計以因應聚合物組合物pH之減小來釋放抑制劑。或者,某些聚合物組合物可經設計以因應過氧化氫之存在來釋放抑制劑。 在一些實施例中,提供醫藥組合物,其包含本發明化合物。在一些實施例中,醫藥組合物進一步包含一或多種其他治療劑。在一些實施例中,一或多種其他治療劑選自由以下組成之群:細胞毒性化學療法、抗癌或抗腫瘤疫苗、抗免疫細胞介素療法、免疫細胞介素療法、嵌合抗原受體(CAR) T細胞受體、基因轉移療法、檢查點抑制劑、皮質類固醇、類視色素樣藥劑、抗瘤藥及干擾素類似物。在一些實施例中,一或多種其他治療劑選自由以下組成之群:TNF α配體抑制劑、TNF結合劑、IL-1配體抑制劑;IL-6配體抑制劑、IL-8配體抑制劑;IL-17拮抗劑、鈣調神經磷酸酶抑制劑、TNF拮抗劑、視黃酸受體γ拮抗劑、IL-17A配體抑制劑;IL-17F配體抑制劑、RIP-1激酶抑制劑、神經鞘胺醇-1-磷酸受體-1拮抗劑、神經鞘胺醇-1-磷酸受體-1調節劑、Rho相關蛋白激酶2抑制劑、IL-12拮抗劑;IL-23拮抗劑、II型TNF受體調節劑、IL-23A抑制劑、PDE 4抑制劑、JAK酪胺酸激酶抑制劑、Jak1酪胺酸激酶抑制劑;Jak3酪胺酸激酶抑制劑、組織胺H1受體拮抗劑、視黃酸受體激動劑、膜銅胺氧化酶抑制劑、PI3K調節劑、磷酸肌醇-3激酶δ抑制劑、粒腺體10kDa熱休克蛋白刺激物、腺苷A3受體激動劑、半乳糖凝集素-3抑制劑、F1F0 ATP合酶調節劑、GM-CSF配體抑制劑、維生素D3受體激動劑、糖皮質激素激動劑、組織胺H4受體拮抗劑、CCR3趨化因子拮抗劑、伊紅趨素配體抑制劑、神經鞘胺醇-1-磷酸受體-1調節劑、磷脂酶A2抑制劑、PDE 4抑制劑、白蛋白調節劑、TLR-7拮抗劑、TLR-8拮抗劑、TLR-9拮抗劑、CD40配體受體拮抗劑、Src酪胺酸激酶抑制劑、微管蛋白結合劑、介白素-1α配體抑制劑、組織蛋白去乙醯酶-1抑制劑、組織蛋白去乙醯酶-2抑制劑、組織蛋白去乙醯酶-3抑制劑、組織蛋白去乙醯酶-6抑制劑、核苷反轉錄酶抑制劑、核因子κ B抑制劑、STAT-3抑制劑、副甲狀腺激素配體抑制劑;維生素D3受體激動劑、T細胞表面醣蛋白CD28刺激物、組織胺H4受體拮抗劑、TGF β激動劑、P-選滯蛋白醣蛋白配體-1刺激物、DHFR抑制劑、視黃酸受體γ調節劑、胞質磷脂酶A2抑制劑、類視色素X受體調節劑、β-連環蛋白抑制劑、CREB結合蛋白抑制劑、TrkA受體拮抗劑、T-細胞分化抗原CD6抑制劑、ADP核糖基環化酶-1抑制劑、介白素-1β配體調節劑;胰島素受體受質-1抑制劑、DHFR抑制劑、IL-8拮抗劑、阻斷CTLA-4 (CD152)、PD-1 (CD279)、PDL-1 (CD274)、TIM-3、LAG-3 (CD223)、VISTA、KIR、NKG2A、BTLA、PD-1H、TIGIT、CD96、4-1BB (CD137)、4-1BBL (CD137L)、GARP、CSF-1R、A2AR、CD73、CD47、色胺酸2,3-二氧酶(TDO)或吲哚胺2,3二氧酶(IDO)之活性之藥物,及OX40、GITR、4-1BB、ICOS、STING或CD40之激動劑。治療由 CCR6 及 / 或 CXCR2 調節之疾病之方法
在一態樣中,本發明提供治療或預防CCR6介導之病況或疾病及/或CXCR2介導之病況或疾病之方法,其係藉由向患有該病況或疾病之個體投與治療有效量之任一本發明化合物來實施。用於本發明方法中之較佳化合物係上文作為較佳實施例提供之彼等化合物以及在下文實例中明確例示且在本文中提供特定結構之化合物。「個體」在本文中定義為包括動物,例如哺乳動物,包括(但不限於)靈長類動物(例如人類)、牛、綿羊、山羊、馬、狗、貓、兔、大鼠、小鼠及諸如此類。在較佳實施例中,個體係人類。 如本文所用片語「CCR6介導之病況或疾病」及相關片語及術語係指特徵在於不適當、例如小於或大於正常CCR6功能活性之病況或疾病。不適當CCR6功能活性可因CCR6在通常不表現CCR6細胞中表現、增加的CCR6表現(引起例如發炎及免疫調控病症及疾病)或減少的CCR6表現而出現。不適當CCR6功能活性亦可因通常不分泌CCL20之細胞分泌CCL20、增加的CCL20表現(引起例如發炎及免疫調控病症及疾病)或減少的CCL20表現而出現。CCR6介導之病況或疾病可完全或部分地由不適當CCR6功能活性來調介。然而,CCR6介導之病況或疾病係調節CCR6引起針對潛在病況或疾病之一定效應者(例如,CCR6拮抗劑引起至少一些患者之患者幸福感之一定改良)。 類似地,片語「CXCR2介導之病況或疾病」及相關片語及術語係指特徵在於不適當、例如小於或大於正常CXCR2功能活性之病況或疾病。不適當CXCR2功能活性可因CXCR2在通常不表現CXCR2之細胞中表現、增加的CXCR2表現(引起例如發炎及免疫調控病症及疾病)或減少的CXCR2表現而出現。CXCR2介導之病況或疾病可完全或部分地由不適當CXCR2功能活性來調介。然而,CXCR2介導之病況或疾病係調節CXCR2引起針對潛在病況或疾病之一定效應者(例如,CXCR2拮抗劑引起至少一些患者之患者幸福感之一定改良)。 術語「治療有效量」意指將使組織、系統、動物或人類產生研究者、獸醫、醫師或其他臨床醫師正尋求之生物或醫學反應之標題化合物的量。 可使用本發明化合物及組合物來治療或預防與發炎、感染及癌症相關之疾病及病況。在一組實施例中,可使用CCR6功能之抑制劑來治療人類或其他物種之疾病或病況,包括慢性疾病。該等疾病或病況包括:(1) 過敏性疾病,例如全身性過敏反應或過敏性反應、藥物過敏、昆蟲刺傷過敏及食物過敏,(2) 發炎性腸病,例如克隆氏病(Crohn's disease)、潰瘍性結腸炎、迴腸炎及腸炎,(3) 陰道炎,(4) 牛皮癬及發炎性皮膚病,例如皮膚炎、濕疹、異位性皮膚炎、過敏性接觸性皮膚炎、蕁麻疹及搔癢症、白斑病,(5) 血管炎,(6) 脊椎關節病,(7) 硬皮症,(8) 氣喘及呼吸過敏性疾病,例如過敏性氣喘、過敏性鼻炎、過敏性肺病及諸如此類,(9) 自體免疫疾病,例如關節炎(包括類風濕性關節炎及牛皮癬關節炎)以及例如橋本氏甲狀腺炎(Hashimoto’s thyroiditis)及格雷氏病(Grave’s disease)、多發性硬化、全身性紅斑狼瘡、I型糖尿病、腎小球性腎炎及諸如此類,(10) 移植物排斥(包括同種異體移植物排斥及移植物抗宿主病),及(11) 欲抑制不期望發炎反應之其他疾病,例如動脈粥樣硬化、肌炎、神經退化疾病(例如,阿茲海默氏病(Alzheimer's disease))、腦炎、腦膜炎、肝炎、腎炎、敗血症、類肉瘤病、過敏性結膜炎、耳炎、慢性阻塞性肺病、竇炎、貝塞特氏症候群(Behcet's syndrome)及痛風。 較佳地,本發明方法係關於治療選自以下之疾病或病況:過敏性疾病、牛皮癬、皮膚病況(例如異位性皮膚炎)及氣喘及硬皮症。 在另一組實施例中,可調節CCR6依賴性調控T細胞輸送之調節來治療疾病或病況,包括癌症、傳染病(病毒感染,例如HIV感染,及細菌感染)及免疫阻抑性疾病(例如器官移植病況及皮膚移植病況)。術語「器官移植病況」意欲包括骨髓移植病況及實體器官(例如,腎、肝、肺、心臟、胰臟或其組合)移植病況。 關於本發明化合物對CXCR2結合之抑制,本發明化合物可用於治療由CXCR2調介之病況或疾病,例如發炎性或過敏性病況或疾病,具體而言慢性阻塞性肺氣道疾病或肺病(COPD、COAD或COLD),包括慢性支氣管炎或與其相關之呼吸困難、肺氣腫、閉塞性細支氣管炎症候群及重度氣喘。 本發明化合物可進一步用於治療多種疾病,例如癌症,例如結腸直腸癌、卵巢癌、前列腺癌、黑色素瘤(包括轉移黑色素瘤)、肺癌(例如非小細胞肺癌)、腎細胞癌;腫瘤血管生成、缺血/再灌注損傷、移植物功能延遲、骨關節炎、伴有骨髓纖維化之骨髓樣化生、子宮肌腺症、接觸性過敏症(皮膚),及用於傷口癒合中。本發明之治療可具有症狀性或預防性。 治療慢性支氣管炎或COPD中之預防性效能將由降低的頻率或嚴重程度來證實,將提供症狀性緩解且減輕疾病進展,改良肺功能。其可進一步藉由減少的對其他症狀性療法(即,用於或欲限制或終止出現的症狀性發作之療法,例如抗發炎藥(如皮質類固醇)或支氣管擴張劑)之需求來證實。 本發明可適用之其他發炎性或阻塞性氣道疾病及病況包括急性肺損傷(ALI)、急性/成人呼吸窘迫症候群(ARDS)、特發性肺纖維化、類纖維瘤肺、氣道高反應性(hyperresponsiveness)、呼吸困難、肺纖維化、過敏性氣道發炎、小氣道疾病、肺癌、患有鐮狀細胞疾病及肺高血壓之患者之急性胸腔症候群以及其他藥物療法(具體而言其他吸入性藥物療法)之後續氣道高反應性(hyperreactivity)惡化。本發明亦可適用於治療任一類型或成因之支氣管炎,包括例如急性、花生仁吸入性、卡他性(catarrhal)、格魯布性(croupus)、慢性或結核性支氣管炎。本發明可適用之其他發炎性或阻塞性氣道疾病包括任一類型或成因之塵肺症(發炎性、通常為職業性肺病,無論慢性或急性皆常伴有氣道阻塞且由於反覆吸入粉塵而引起),包括例如礬土肺、煤肺、石棉肺、石末塵肺、毛髮塵肺、鐵塵肺、矽肺、煙草塵肺及棉塵肺。 本發明化合物亦可用於治療呼吸性病毒感染,其使潛在慢性病況(例如氣喘、慢性支氣管炎、COPD、中耳炎及竇炎)惡化。所治療之呼吸性病毒感染可與繼發性細菌感染(例如中耳炎、竇炎或肺炎)相關。 本發明化合物亦可用於治療皮膚發炎性病況,例如牛皮癬、異位性皮膚炎、紅斑狼瘡及其他皮膚發炎性或過敏性病況。 本發明化合物亦可用於治療其他疾病或病況,具體而言具有發炎組份之疾病或病況,例如侵襲鼻之疾病(包括過敏性鼻炎,例如萎縮性、慢性或季節性鼻炎)、胃腸道發炎性病況(例如發炎性腸病,例如潰瘍性結腸炎及克隆氏病)、骨及關節疾病(包括類風濕性關節炎、牛皮癬關節炎)及其他疾病,例如動脈粥樣硬化、多發性硬化及例如心臟、腎、肝、肺或骨髓移植後之急性及慢性同種異體移植物排斥。 本發明化合物亦可用於治療內毒素性休克、腎小球性腎炎、大腦及心臟缺血、阿茲海默氏病、囊性纖維化、病毒感染及與其相關之惡化、獲得性免疫缺失症候群(AIDS)、多發性硬化(MS)、幽門螺旋桿菌相關之胃炎及癌症(具體而言卵巢癌之生長)。 本發明化合物亦可用於治療人類之由病毒感染引起之症狀,該病毒感染係由人類鼻病毒、其他腸病毒、冠狀病毒、皰疹病毒、流行性感冒病毒、副流行性感冒病毒、呼吸道融合病毒或腺病毒引起。本發明化合物亦可用於治療胰臟炎。 本發明化合物在抑制發炎性病況(例如發炎氣道疾病)中之有效性可於氣道發炎或其他發炎性病況之動物模型(例如小鼠、大鼠或兔模型)中予以展示,例如如以下文獻中所述:Wada等人,J. Exp. Med 180
:1135-40 (1994);Sekido等人,Nature 365
:654-57 (1993);Modelska等人,Am. J. Respir. Crit. Care. Med 160
:1450-56 (1999);及Laffon等人,Am. J. Respir. Crit. Care Med. 160
:1443-49 (1999)。 在一些實施例中,本文提供用於治療由CXCR2調介之病況或疾病(例如發炎性或過敏性病況,具體而言發炎性或阻塞性氣道疾病)之方法,其包含向有需要之個體、具體而言人類個體投與有效量之如上文所述呈游離或醫藥上可接受之鹽形式之式(A)、(A1)、(A2)、(I)或(Ia1)化合物。在另一態樣中,本發明提供如上文所述呈游離或醫藥上可接受之鹽形式之式(A)、(A1)、(A2)、(I)或(Ia1)化合物之用途,其用於製造用來治療由CXCR2調介之病況或疾病(例如發炎性或過敏性病況或疾病,具體而言發炎性或阻塞性氣道疾病)之藥劑。 本文所述之式(A)、(A1)、(A2)、(I)及(Ia1)化合物亦可用作共治療化合物與其他原料藥(例如,抗發炎原料藥、支氣管擴張原料藥、抗組胺原料藥或止咳原料藥)組合使用,具體而言在治療阻塞性或發炎性氣道疾病(例如,上文所提及之彼等)中作為例如該等藥物之治療活性增效劑或作為降低該等藥物之所需劑量或潛在副作用之方式。本發明化合物可與另一原料藥混合於固定醫藥組合物中或其可在另一原料藥之前、同時或之後單獨投與。 端視欲治療之疾病及個體之病況,本發明化合物可藉由以下方式來投與:經口、非經腸(例如,肌內、腹膜內、靜脈內、ICV、腦池內注射或輸注、皮下注射或植入)、吸入、鼻、陰道、直腸、舌下或局部投與途徑,且可單獨或一起調配於含有適於每一投與途徑之習用無毒醫藥上可接受之載劑、佐劑及媒劑之適宜劑量單位調配物中。本發明亦涵蓋投與於儲積調配物中之本發明化合物。 熟習此項技術者應理解,調節CCR6活性之藥劑可與其他治療劑及/或與化學治療劑或輻射組合於治療方案中。在一些情形下,若化學治療劑或輻射並非與本發明組合物組合提供,則其量係將為亞治療量。熟習此項技術者應瞭解,「組合」可涉及治療之組合(即,兩種或更多種藥物可以混合物形式投與或至少同時或至少在不同時間引入個體中但使得二者同時處於個體之血流中)。另外,本發明組合物可在第二治療方案之前或之後投與,例如在一定劑量之化學療法或輻照之前或之後投與。 因此,本發明化合物可用於預防及治療眾多種發炎及免疫調控病症及疾病。 在需要趨化因子受體調節之病況的治療或預防中,適當劑量值通常將為約0.001 mg/kg至100 mg/kg患者體重/天,其可以單一劑量或多個劑量來投與。較佳地,劑量值將為約0.01 mg/kg/天至約25 mg/kg/天;更佳地為約0.05 mg/kg/天至約10 mg/kg/天。適宜劑量值可為約0.01 mg/kg/天至25 mg/kg/天、約0.05 mg/kg/天至10 mg/kg/天或約0.1 mg/kg/天至5 mg/kg/天。在此範圍內,劑量可為0.005 mg/kg/天至0.05 mg/kg/天、0.05 mg/kg/天至0.5 mg/kg/天或0.5 mg/kg/天至5.0 mg/kg/天。對於經口投與,組合物較佳係以含有1.0至1000毫克活性成分、具體而言1.0毫克、5.0毫克、10.0毫克、15.0毫克、20.0毫克、25.0毫克、50.0毫克、75.0毫克、100.0毫克、150.0毫克、200.0毫克、250.0毫克、300.0毫克、400.0毫克、500.0毫克、600.0毫克、750.0毫克、800.0毫克、900.0毫克及1000.0毫克活性成分之錠劑形式提供(根據欲治療患者之症狀調節劑量)。化合物可根據1至4次/天、較佳每天一次或兩次之方案來投與。 然而,應瞭解,對於任一具體患者,特定劑量值及投藥頻率可有所變化且將端視多種因素而定,包括所用特定化合物之活性、該化合物之代謝穩定性及作用時間長度、個體之年齡、體重、遺傳特徵、一般健康狀況、性別及飲食以及投與模式及時間、排泄速率、藥物組合及經歷療法之個體之具體病況之嚴重程度。 與發炎、免疫病症、感染及癌症相關之疾病及病況可使用本發明化合物、組合物及方法來治療或預防。 本發明之化合物及組合物可與具有相關效用之其他化合物及組合物組合來預防及治療所關注之病況或疾病,例如發炎或自體免疫病症、病況及疾病,包括發炎性腸病、類風濕性關節炎、骨關節炎、牛皮癬關節炎、多發性關節炎、多發性硬化、過敏性疾病、牛皮癬、異位性皮膚炎及氣喘及上文所述之彼等病狀。 舉例而言,在發炎或自體免疫性或例如關節炎相關之骨損失之治療或預防中,本發明化合物及組合物可與諸如以下等抗發炎或止痛劑結合使用:阿片激動劑(opiate agonist)、脂肪加氧酶抑制劑(例如5-脂肪加氧酶抑制劑)、環加氧酶抑制劑(例如環加氧酶-2抑制劑)、介白素抑制劑(例如介白素-1抑制劑)、NMDA拮抗劑、一氧化氮抑制劑或一氧化氮合成抑制劑、非類固醇抗發炎劑或細胞介素阻抑抗發炎劑,例如與諸如以下等化合物結合使用:乙醯胺酚(acetaminophen)、阿斯匹林(aspirin)、可待因(codeine)、芬太尼(fentanyl)、布洛芬(ibuprofen)、吲哚美辛(indomethacin)、酮咯酸(ketorolac)、嗎啡(morphine)、萘普生(naproxen)、非那西汀(phenacetin)、吡羅昔康(piroxicam)、類固醇止痛藥、舒芬太尼(sufentanyl)、蘇林酸(sunlindac)、替尼達普(tenidap)及諸如此類。類似地,本發明化合物及組合物可與以下各項一起投與:上文所列示之止痛藥;增強劑(例如咖啡因)、H2拮抗劑(例如,雷尼替丁(ranitidine))、聚二甲基矽氧烷、氫氧化鋁或氫氧化鎂;去充血劑,例如苯福林(phenylephrine)、苯基丙醇胺、偽麻黃鹼(pseudoephedrine)、羥甲唑啉(oxymetazoline)、腎上腺素、萘唑啉(naphazoline)、塞洛唑啉(xylometazoline)、丙己君(propylhexedrine)或左旋去氧麻黃鹼合劑(levo desoxy ephedrine);鎮咳劑,例如可待因、氫可酮(hydrocodone)、卡臘米芬(caramiphen)、咳必清(carbetapentane)或右旋美沙芬(dextromethorphan);利尿劑;及鎮靜型或非鎮靜型抗組織胺。 同樣,本發明之化合物及組合物可與用於治療、預防、阻抑或改善本發明化合物及組合物有用之疾病或病況之其他藥物組合使用。該等其他藥物可藉由其常用途徑及用量與本發明之化合物或組合物同時或依序投與。當本發明之化合物或組合物與一或多種其他藥物同時使用時,除本發明化合物或組合物外含有該等其他藥物之醫藥組合物較佳。因此,本發明之醫藥組合物包括除本發明化合物或組合物外亦含有一或多種其他活性成分或治療劑之彼等。可與本發明化合物或組合物組合、單獨或於相同醫藥組合物中投與之其他治療劑之實例包括(但不限於):(a) VLA-4拮抗劑,(b) 皮質類固醇,例如倍氯米松(beclomethasone)、甲基普賴蘇濃(methylprednisolone)、倍他米松(betamethasone)、普賴松(prednisone)、潑尼松龍(prenisolone)、地塞米松(dexamethasone)、氟替卡松(fluticasone)、氫化可體松(hydrocortisone)、布地奈德(budesonide)、曲安奈德(triamcinolone)、沙美特羅(salmeterol)、沙丁胺醇(salbutamol)、福莫特諾(formeterol);(c) 免疫阻抑劑,例如環孢素(環孢素A、Sandimmune®、Neoral®)、他克莫司(tacrolimus) (FK-506、Prograf®)、雷帕黴素(rapamycin) (西羅莫司(sirolimus)、Rapamune®)、托法替尼(Tofacitinib) (Xeljanz®)及其他FK-506型免疫阻抑劑以及麥考酚酯,例如嗎替麥考酚酯(CellCept®);(d) 抗組織胺(H1-組織胺拮抗劑),例如溴苯那敏(bromopheniramine)、氯苯那敏、右氯苯那敏(dexchloipheniramine)、曲普利啶(triprolidine)、克雷滿汀(clemastine)、苯海拉明(diphenhydramine)、二苯拉林(diphenylpyraline)、曲吡那敏(tripelennamine)、羥嗪(hydroxyzine)、甲地拉嗪(methdilazine)、異丙嗪(promethazine)、異丁嗪(trimeprazine)、阿紮他啶(azatadine)、賽庚啶(cyproheptadine)、安他唑啉(antazoline)、非尼拉敏(pheniramine)、吡拉明(pyrilamine)、阿司咪唑(astemizole)、特非那定(terfenadine)、氯雷他定(loratadine)、西替利嗪(cetirizine)、非索非那定(fexofenadine)、脫碳乙氧基氯雷他定(descarboethoxyloratadine)及諸如此類;(e) 非類固醇平喘藥(例如,特布他林(terbutaline)、異丙喘寧(metaproterenol)、非諾特羅(fenoterol)、異他林(isoetharine)、沙丁胺醇(albuterol)、比托特羅(bitolterol)及吡布特羅(pirbuterol))、茶鹼(theophylline)、色甘酸鈉、阿托品(atropine)、異丙托溴銨(ipratropium bromide)、白三烯(leukotriene)拮抗劑(例如,紮魯司特(zafmlukast)、孟魯司特(montelukast)、普侖司特(pranlukast)、伊拉司特(iralukast)、泊比司特(pobilukast)及SKB-106、203)、白三烯生物合成抑制劑(齊留通(zileuton)、BAY-1005);(f) 非類固醇抗發炎劑(NSAID),例如丙酸衍生物(例如,阿明洛芬(alminoprofen)、苯惡洛芬(benoxaprofen)、布氯酸、卡洛芬(carprofen)、芬布芬(fenbufen)、非諾洛芬(fenoprofen)、氟洛芬(fluprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、吲哚洛芬(indoprofen)、酮洛芬(ketoprofen)、米洛芬(miroprofen)、萘普生、奧沙普秦(oxaprozin)、吡洛芬(pirprofen)、普拉洛芬(pranoprofen)、舒洛芬(suprofen)、噻洛芬酸(tiaprofenic acid)及硫惡洛芬(tioxaprofen))、乙酸衍生物(例如吲哚美辛(indomethacin)、阿西美辛(acemetacin)、阿氯芬酸(alclofenac)、環氯茚酸(clidanac)、雙氯芬酸(diclofenac)、芬氯酸(fenclofenac)、芬克洛酸(fenclozic acid)、芬替酸(fentiazac)、呋羅芬酸(furofenac)、異丁芬酸(ibufenac)、伊索克酸(isoxepac)、奧匹酸(oxpinac)、舒林酸(sulindac)、硫平酸(tiopinac)、妥美汀(tolmetin)、齊多美辛(zidometacin)及左美酸(zomepirac))、芬那酸(fenamic acid)衍生物(例如,氟芬那酸、甲氯芬那酸、甲芬那酸、尼氟滅酸(niflumic acid)及托芬那酸(tolfenamic acid))、聯苯羧酸衍生物(例如,二氟尼柳(diflunisal)及氟苯沙酸(flufenisal))、氧昔康(oxicams) (例如,依索昔康(isoxicam)、吡羅昔康(piroxicam)、舒多昔康(sudoxicam)及替諾昔康(tenoxican))、柳酸鹽(例如,乙醯基柳酸及磺胺塞拉金(sulfasalazine))及吡唑啉酮(例如,阿紮丙宗(apazone)、貝哌洛隆(bezpiperylon)、非普拉宗(feprazone)、莫非布宗(mofebutazone)、羥保泰松(oxyphenbutazone)及苯基丁氮酮);(g) 環加氧酶-2 (COX-2)抑制劑,例如塞來昔布(celecoxib) (Celebrex®)及羅非昔布(rofecoxib) (Vioxx®);(h) 磷酸二酯酶IV型(PDE IV)抑制劑;(i) 金化合物,例如金諾芬(auranofin)及金硫代葡萄糖,(j) 依那西普(etanercept) (Enbrel®),(k) 抗體療法,例如奧素健體(orthoclone) (OKT3)、達克珠單抗(daclizumab) (Zenapax®)、巴利昔單抗(basiliximab) (Simulect®)及英利昔單抗(infliximab) (Remicade®)、阿達木單抗(adalimumab) (Humira®)、戈利木單抗(golimumab) (Simponi®)、利妥昔單抗(rituximab) (Rituxan®)、托珠單抗(tocilizumab) (Actemra®),(l) 趨化因子受體、尤其CCR5、CXCR2、CXCR3、CCR2、CCR3、CCR4、CCR7、CX3
CR1及CXCR6之其他拮抗劑;(m) 潤滑劑或軟化劑,例如石蠟脂及羊毛脂,(n) 角質層分離劑(例如,他紮羅汀(tazarotene)),(o) 維生素D3
衍生物,例如卡泊三烯(calcipotriene)或卡泊三醇(calcipotriol) (Dovonex®),(p) PUVA,(q) 蒽酚(Drithrocreme®),(r) 依曲替酯(etretinate) (Tegison®)及異維甲酸(isotretinoin),及(s) 多發性硬化治療劑,例如干擾素β-1β (Betaseron®)、干擾素β-1α (Avonex®)、硫唑嘌呤(Imurek®、Imuran®)、乙酸格拉替雷(glatiramer acetate) (Capoxone®)、糖皮質激素(例如,普賴蘇濃)及環磷醯胺,(t) DMARDS,例如胺甲喋呤(methotrexate)及來氟米特(leflunomide),(u) 其他化合物,例如5-胺基柳酸及其前藥;羥基氯喹(hydroxychloroquine);D-青黴胺(penicillamine);抗代謝物,例如硫唑嘌呤、6-巰嘌呤及胺甲喋呤;DNA合成抑制劑,例如羥基脲及微管干擾劑(例如秋水仙鹼(colchicine))及蛋白酶體抑制劑(例如硼替佐米(bortezomib) (Velcade®)),(v) 針對CTLA-4、PD1或PD-L1之抗體。本發明化合物對第二活性成分之重量比可有所變化且將端視每一成分之有效劑量而定。通常,將使用每一成分之有效劑量。因此,舉例而言,在本發明化合物與NSAID組合時,本發明化合物對NSAID之重量比通常將介於約1000:1至約1:1000、較佳約200:1至約1:200範圍內。本發明化合物與其他活性成分之組合通常亦將在上文所提及範圍內,但在每一情形下,應使用每一活性成分之有效劑量。 在一些實施例中,提供治療有需要之個體之CXCR2-及/或CCR6介導之疾病或病況之方法,該方法包含向該個體投與有效量之本發明化合物或其醫藥上可接受之鹽或包含本發明化合物之醫藥組合物。在一些實施例中,疾病或病況係急性或慢性發炎性病症。在一些實施例中,急性或慢性發炎性病症係牛皮癬、乾眼病、動脈粥樣硬化、盤狀紅斑狼瘡、類風濕性關節炎、狼瘡、輻射誘發之纖維變性肺病、自體免疫大皰性皮膚病(AIBD)、慢性阻塞性肺病或臭氧誘發之氣道發炎。在一些實施例中,急性或慢性發炎性病症係牛皮癬。 在一些實施例中,疾病係癌症。在一些實施例中,癌症選自由以下組成之群:皮膚T細胞淋巴瘤、非霍奇金氏淋巴瘤(non-Hodgkin lymphoma)、蕈狀肉芽腫、變形性骨炎網狀細胞增多症、西澤裡症候群(Sézary syndrome)、肉芽腫性鬆弛狀皮膚、淋巴瘤樣丘疹病、慢性苔癬樣糠疹、急性痘瘡樣苔癬樣糠疹、CD30+皮膚T細胞淋巴瘤、繼發性皮膚CD30+大細胞淋巴瘤、非蕈狀肉芽腫CD30皮膚大T細胞淋巴瘤、多形性T細胞淋巴瘤、倫納特淋巴瘤(Lennert lymphoma)、皮下T細胞淋巴瘤、血管中心性淋巴瘤、母細胞性NK細胞淋巴瘤、B細胞淋巴瘤、霍奇金氏淋巴瘤(HL)、頭頸腫瘤;鱗狀細胞癌、橫紋肌癌、路易士肺癌(Lewis lung carcinoma) (LLC)、非小細胞肺癌、食管鱗狀細胞癌、食管腺癌、腎細胞癌(RCC)、結腸直腸癌(CRC)、急性類骨髓性白血病(AML)、乳癌、胃癌、前列腺小細胞神經內分泌癌(SCNC)、肝癌、神經膠母細胞瘤、口鱗狀細胞癌、胰臟癌、甲狀腺乳頭狀癌、肝內膽管細胞癌、肝細胞癌、骨癌、轉移及鼻咽癌。在一些實施例中,疾病係結腸直腸癌。在一些實施例中,疾病係皮膚T細胞淋巴瘤。 在一些實施例中,化合物係單獨使用或與一或多種其他抗癌療法組合使用。在一些實施例中,化合物係與以下各項中之一或多者組合使用:細胞毒性化學療法、抗癌疫苗、抗腫瘤疫苗、抗免疫細胞介素療法、免疫細胞介素療法、檢查點抑制劑及嵌合抗原受體(CAR) T細胞受體、基因轉移療法。在一些實施例中,化合物係與至少檢查點抑制劑組合使用。在一些實施例中,化合物係與阻斷以下各項之活性之化合物中的一或多者組合使用:CTLA-4 (CD152)、PD-1 (CD279)、PDL-1 (CD274)、TIM-3、LAG-3 (CD223)、VISTA、KIR、NKG2A、BTLA、PD-1H、TIGIT、CD96、4-1BB (CD137)、4-1BBL (CD137L)、GARP、CSF-1R、A2AR、CD73、CD47、色胺酸2,3-二氧酶(TDO)或吲哚胺2,3二氧酶(IDO)。在一些實施例中,化合物係與OX40、GITR、4-1BB、ICOS、STING或CD40之激動劑中之一或多者組合使用。 在一些實施例中,本發明化合物或其醫藥上可接受之鹽及/或前藥或本發明組合物經投與以治療結腸直腸癌、轉移、晚期皮膚T細胞淋巴瘤、胰臟癌、非霍奇金氏淋巴瘤、蕈狀肉芽腫、變形性骨炎網狀細胞增多症、西澤裡症候群、肉芽腫性鬆弛狀皮膚、淋巴瘤樣丘疹病、慢性苔癬樣糠疹、急性痘瘡樣苔癬樣糠疹、CD30+皮膚T細胞淋巴瘤、繼發性皮膚CD30+大細胞淋巴瘤、非蕈狀肉芽腫CD30-皮膚大T細胞淋巴瘤、多形性T細胞淋巴瘤、倫納特淋巴瘤、皮下T細胞淋巴瘤、血管中心性淋巴瘤、母細胞性NK細胞淋巴瘤、B細胞淋巴瘤、霍奇金氏淋巴瘤(HL)、乾眼病、動脈粥樣硬化或盤狀紅斑狼瘡。 在一些實施例中,本發明化合物或其醫藥上可接受之鹽及/或前藥或本發明組合物係經投與以治療胰島素依賴性糖尿病、膀胱炎、胰島細胞移植排斥;腎移植排斥;肝移植排斥;肺移植排斥、COPD或流行性感冒。 在一些實施例中,本發明化合物或其醫藥上可接受之鹽及/或前藥或本發明組合物係經投與以治療黑色素瘤、神經膠母細胞瘤、食管腫瘤、鼻咽癌、葡萄膜黑色素瘤、淋巴瘤、淋巴球性淋巴瘤、原發性CNS淋巴瘤、T細胞淋巴瘤、瀰漫性大B細胞淋巴瘤、原發性縱膈大B細胞淋巴瘤、前列腺癌、閹割抗性前列腺癌、慢性骨髓細胞性白血病、卡波西氏肉瘤(Kaposi's sarcoma)、纖維肉瘤、脂肪肉瘤、軟骨肉瘤、骨原性肉瘤、血管肉瘤、淋巴管肉瘤、滑膜瘤、腦脊髓膜瘤、平滑肌肉瘤、橫紋肌肉瘤、軟組織肉瘤、肉瘤、敗血症、膽道腫瘤、基底細胞癌、胸腺腫瘤、甲狀腺癌、副甲狀腺癌、子宮癌、腎上腺癌、肝感染、默克細胞癌(Merkel cell carcinoma)、神經腫瘤、濾泡中心淋巴瘤、結腸癌、霍奇金氏病、非霍奇金氏淋巴瘤、白血病、慢性或急性白血病(包括急性類骨髓性白血病、慢性類骨髓性白血病、急性淋巴母細胞性白血病、慢性淋巴球性白血病)、多發性骨髓瘤、卵巢腫瘤、骨髓發育不良症候群、皮膚或眼內惡性黑色素瘤、腎細胞癌、小細胞肺癌、肺癌、間皮瘤、乳癌、鱗狀非小細胞肺癌(SCLC)、非鱗狀NSCLC、結腸直腸癌、卵巢癌、胃癌、肝細胞癌、胰臟癌、胰臟癌、胰臟導管腺癌、頭頸鱗狀細胞癌、頭頸癌、胃腸道、胃癌、骨癌、皮膚癌、直腸癌、肛區癌、睪丸癌、輸卵管癌、子宮內膜癌、子宮頸癌、陰道癌、陰門癌、食管癌、小腸癌、內分泌系統癌、尿道癌、陰莖癌、膀胱癌、腎癌、輸尿管癌、腎盂癌、中樞神經系統(CNS)腫瘤、腫瘤血管生成、脊軸腫瘤、腦幹膠質瘤、垂體腺瘤、表皮樣癌、石棉肺、癌瘤、腺癌、乳頭狀癌、囊腺癌、支氣管癌、腎細胞癌、移行細胞癌、絨毛膜癌、精原細胞瘤、胚胎性癌、威爾姆氏腫瘤(wilm's tumor)、多形性腺瘤、肝細胞乳頭狀瘤、腎小管腺瘤、囊腺瘤、乳頭狀瘤、腺瘤、平滑肌瘤、橫紋肌瘤、血管瘤、淋巴管瘤、骨瘤、軟骨瘤、脂瘤及/或纖維瘤。組合療法
本發明化合物可單獨或結合一或多種其他藥物來供應。可能的組合伴侶可包括其他抗血管生成因子及/或化學治療劑(例如,細胞毒性劑)或輻射、癌症疫苗、免疫調節劑、檢查點抑制劑、抗血管劑、信號轉導抑制劑、抗增生劑、細胞凋亡誘導物、烷基化劑、亞硝基脲劑、抗代謝物、抗癌抗生素、植物源生物鹼、拓撲異構酶抑制劑、激素藥物、激素拮抗劑、芳香酶抑制劑、P-醣蛋白抑制劑、鉑錯合物衍生物、抗纖維變性劑、放射性療法、放射性治療劑及基因表現調節劑。 可與本發明化合物或組合物組合、單獨或於相同醫藥組合物中投與之其他治療劑之實例包括(但不限於):CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCR11、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、CXCR6、CXCR7、CX3CR1、ChemR23、C5aR、C5a及C5之調節劑、或其任一組合。在一些實施例中,調節劑係拮抗劑。 可與本發明化合物或組合物組合、單獨或於相同醫藥組合物中投與之其他治療劑之實例包括(但不限於):治療性抗體、雙特異性抗體及「抗體樣」治療性蛋白質(例如DARTs®、Duobodies®、Bites®、XmAbs®、TandAbs®、Fab衍生物)、抗體-藥物偶聯物(ADC)、病毒、溶瘤病毒、基因修飾劑或編輯劑(例如CRISPR (包括CRISPR Cas9)、鋅指核酸酶或合成核酸酶(TALEN)、CAR (嵌合抗原受體) T細胞免疫治療劑、細胞介素、疫苗、疫苗佐劑、GM-CSF、M-CSF、G-CSF、干擾素-a、β或γ、IL-1、IL-2、IL-3、IL-12、聚(I:C)、CPG、環磷醯胺、環磷醯胺類似物、抗TGF及伊馬替尼(imatinib) (Gleevac))、有絲分裂抑制劑、激酶抑制劑、太平洋紫杉醇(paclitaxel)、舒尼替尼(Sunitinib) (舒癌特(Sutent))、抗血管生成劑、芳香酶抑制劑、來曲唑(letrozole)、A2a腺苷受體(A2AR)拮抗劑、腺苷受體調節劑、A3腺苷受體調節劑、血管生成抑制劑、蒽環、奧沙利鉑(oxaliplatin)、多柔比星(doxorubicin)、TLR4拮抗劑、IL-18拮抗劑、Btk酪胺酸激酶抑制劑、Erbb2酪胺酸激酶受體抑制劑;Erbb4酪胺酸激酶受體抑制劑、mTOR抑制劑、胸腺嘧啶核苷酸合酶抑制劑、EGFR酪胺酸激酶受體抑制劑、表皮生長因子拮抗劑、Fyn酪胺酸激酶抑制劑、Kit酪胺酸激酶抑制劑、Lyn酪胺酸激酶抑制劑、NK細胞受體調節劑、PDGF受體拮抗劑、PARP抑制劑、聚ADP核糖聚合酶抑制劑、聚ADP核糖聚合酶1抑制劑、聚ADP核糖聚合酶2抑制劑、聚ADP核糖聚合酶3抑制劑、半乳糖基轉移酶調節劑、二氫嘧啶去氫酶抑制劑、乳清酸磷酸核糖基轉移酶抑制劑、端粒酶調節劑、黏蛋白1抑制劑、黏蛋白抑制劑、胰泌素激動劑、誘導TNF相關之細胞凋亡之配體調節劑、IL17基因刺激物、介白素17E配體、神經激肽受體激動劑、週期蛋白G1抑制劑、檢查點抑制劑、PD-1抑制劑、PD-L1抑制劑、CTLA4抑制劑、拓撲異構酶I抑制劑、Alk-5蛋白激酶抑制劑、結締組織生長因子配體抑制劑、Notch-2受體拮抗劑、Notch-3受體拮抗劑、玻尿酸酶刺激物、MEK-1蛋白激酶抑制劑、磷酸肌醇-3激酶抑制劑、MEK-2蛋白激酶抑制劑、GM-CSF受體調節劑;TNF α配體調節劑、間皮素調節劑、天冬醯胺酶刺激物、CSF2基因刺激物、半胱天冬酶-3刺激物;半胱天冬酶-9刺激物、PKN3基因抑制劑、Hedgehog蛋白抑制劑;平滑受體拮抗劑、AKT1基因抑制劑、DHFR抑制劑、胸苷激酶刺激物、CD29調節劑、纖連蛋白調節劑、介白素-2配體、絲胺酸蛋白酶抑制劑、D40LG基因刺激物;TNFSF9基因刺激物、2戊二酸去氫酶抑制劑、II型TGF-β受體拮抗劑、Erbb3酪胺酸激酶受體抑制劑、膽囊收縮素CCK2受體拮抗劑、威爾姆氏腫瘤蛋白調節劑、Ras GTPase調節劑、組織蛋白去乙醯酶抑制劑、Raf B蛋白激酶抑制劑、週期蛋白依賴性激酶4抑制劑A調節劑、雌激素受體β調節劑、4-1BB抑制劑、4-1BBL抑制劑、PD-L2抑制劑、B7-H3抑制劑、B7-H4抑制劑、BTLA抑制劑、HVEM抑制劑、TIM3抑制劑、TIGIT抑制劑、NKG2A抑制劑、GAL9抑制劑、LAG3抑制劑、PD-1H抑制劑、PD96抑制劑、VISTA抑制劑、KIR抑制劑、2B4抑制劑、CD160抑制劑、CD66e調節劑、II型血管收縮肽受體拮抗劑、結締組織生長因子配體抑制劑、Jak1酪胺酸激酶抑制劑、Jak2酪胺酸激酶抑制劑、雙重Jak1/Jak2酪胺酸激酶抑制劑、血管收縮肽轉化酶2刺激物、生長激素受體拮抗劑、半乳糖凝集素-3抑制劑、檢查點激酶2調節劑、鈉葡萄糖運輸蛋白-2抑制劑、內皮素ET-A拮抗劑、鹽皮質激素受體拮抗劑、內皮素ET-B拮抗劑、晚期醣基化產物受體拮抗劑、促腎上腺皮質激素配體、法尼醇(Farnesoid) X受體激動劑、G-蛋白偶聯之膽汁酸受體1激動劑、醛醣還原酶抑制劑、黃嘌呤氧化酶抑制劑、PPAR γ激動劑、類前列腺素受體拮抗劑、FGF受體拮抗劑、PDGF受體拮抗劑、TGF β拮抗劑、P3蛋白調節劑、p38 MAP激酶抑制劑、VEGF-1受體拮抗劑、蛋白酪胺酸磷酸酶β抑制劑、Tek酪胺酸激酶受體刺激物、PDE 5抑制劑、鹽皮質激素受體拮抗劑、ACE抑制劑、I-κ B激酶抑制劑、NFE2L2基因刺激物、核因子κ B抑制劑、STAT3基因抑制劑、NADPH氧化酶1抑制劑、NADPH氧化酶4抑制劑、PDE 4抑制劑、腎素抑制劑、FURIN基因抑制劑、MEKK-5蛋白激酶抑制劑、膜銅胺氧化酶抑制劑、整聯蛋白α-V/β-3拮抗劑、胰島素敏化劑、激肽釋放酶1調節劑、環加氧酶抑制劑、補體C3調節劑、微管蛋白結合劑、巨噬細胞甘露糖受體1調節劑、苯丙胺酸羥酶刺激物、地尼白介素2、貝沙羅汀(Bexarotene)、伏立諾他(Vorinostat)、羅米地辛(Romidepsin)、普拉曲沙(Pralatrexate)、普賴松、普賴蘇濃、CCX354、CCX9588、CCX140、CCX872、CCX598、CCX6239、CCX9664、CCX2553、CCX 2991、CCX282、CCX025、CCX507、CCX430、CCX765、CCX224、CCX662、CCX650、CCX832、CCX168、CCX168-M1、巴維昔單抗(bavituximab)、IMM-101、CAP1-6D、雷克辛(Rexin)-G、金雀異黃酮、CVac、MM-D37K、PCI-27483、TG-01、莫賽替諾司他(mocetinostat)、LOAd-703、CPI-613、阿莫司他(upamostat)、CRS-207、NovaCap、曲美替尼(trametinib)、Atu-027、索尼得吉(sonidegib)、GRASPA、曲貝德森(trabedersen)、那妥派得(nastorazepide)、Vaccell、奧戈伏單抗(oregovomab)、依替珠單抗(istiratumab)、瑞法替尼(refametinib)、瑞格菲尼(regorafenib)、拉帕替尼(lapatinib)、司美替尼(selumetinib)、瑞卡帕尼(rucaparib)、派拉瑞普(pelareorep)、他瑞妥單抗(tarextumab)、聚乙二醇化玻尿酸酶、瓦尼替尼(varlitinib)、阿格百克(aglatimagene besadenovec)、GBS-01、GI-4000、WF-10、蓋尼塞替(galunisertib)、阿法替尼(afatinib)、RX-0201、FG-3019、帕妥珠單抗(pertuzumab)、DCVax-Direct、塞林可(selinexor)、葡磷醯胺、維如利金(virulizin)、泰坦克立瓦妥珠單抗(clivatuzumab tetraxetan)釔(90Y)、溴夫定(brivudine)、尼妥珠單抗(nimotuzumab)、阿根盤塞(algenpantucel)-L、替加氟(tegafur) + 吉莫斯特(gimeracil) + 氧嗪酸鉀(oteracil potassium) + 甲醯四氫葉酸鈣、奧拉帕尼(olaparib)、依魯替尼(ibrutinib)、吡柔比星(pirarubicin)、Rh-Apo2L、特脫莫泰(tertomotide)、替加氟 + 吉莫斯特 + 氧嗪酸鉀、替加氟 + 吉莫斯特 + 氧嗪酸鉀、馬賽替尼(masitinib)、雷克辛(Rexin)-G、絲裂黴素(mitomycin)、厄洛替尼(erlotinib)、阿德力黴素(adriamycin)、地塞米松(dexamethasone)、長春新鹼(vincristine)、環磷醯胺、氟尿嘧啶、托泊替康(topotecan)、紫杉醇(taxol)、干擾素、鉑衍生物、紫杉烷(taxane)、太平洋紫杉醇、長春花生物鹼(vinca alkaloid)、長春鹼(vinblastine)、蒽環、多柔比星(doxorubicin)、表鬼臼毒素(epipodophyllotoxin)、依託泊苷(etoposide)、順鉑、雷帕黴素(rapamycin)、胺甲喋呤(methotrexate)、放線菌素(actinomycin) D、多拉斯他汀(dolastatin) 10、秋水仙鹼、吐根素(emetine)、三甲曲沙(trimetrexate)、氯苯胺啶(metoprine)、環孢素(cyclosporine)、道諾黴素(daunorubicin)、替尼泊苷(teniposide)、雙性殺黴素(amphotericin)、烷基化劑、氮芥苯丁酸、5-氟尿嘧啶、喜樹鹼(campthothecin)、順鉑、甲硝唑(metronidazole)、基利克(Gleevec)、癌思停(Avastin)、維必施(Vectibix)、阿巴瑞克(abarelix)、阿地介白素(aldesleukin)、阿倫單抗(alemtuzumab)、阿曲諾英(alitretinoin)、別嘌呤醇(allopurinol)、六甲蜜胺(altretamine)、阿米福汀(amifostine)、阿那曲唑(anastrozole)、三氧化砷、天冬醯胺酶、阿紮胞苷(azacitidine)、AZD9291、BCG Live、貝伐珠單抗(bevacuzimab)、氟尿嘧啶、貝沙羅汀、博來黴素(bleomycin)、硼替佐米、白消安(busulfan)、卡普睪酮(calusterone)、卡培他濱(capecitabine)、喜樹鹼、卡鉑、卡莫司汀(carmustine)、塞來昔布、西妥昔單抗(cetuximab)、氮芥苯丁酸、克拉屈濱(cladribine)、氯法拉濱(clofarabine)、環磷醯胺、阿糖胞苷、放線菌素、阿法達貝伯汀(darbepoetin alfa)、道諾黴素、地尼白介素、右雷佐生(dexrazoxane)、多西他賽(docetaxel)、多柔比星(中性)、鹽酸多柔比星、丙酸屈他雄酮(dromostanolone propionate)、泛艾黴素(epirubicin)、阿法依伯汀(epoetin alfa)、雌氮芥(estramustine)、磷酸依託泊苷、依託泊苷、依西美坦(exemestane)、非格司亭(filgrastim)、氟尿苷、氟達拉濱(fludarabine)、氟維司群(fulvestrant)、吉非替尼(gefitinib)、吉西他濱(gemcitabine)、吉妥珠單抗(gemtuzumab)、乙酸戈舍瑞林(goserelin acetate)、乙酸組胺瑞林(histrelin acetate)、羥基脲、替伊莫單抗(ibritumomab)、伊達比星(idarubicin)、異環磷醯胺、甲磺酸伊馬替尼、干擾素α-2a、干擾素α-2b、伊立替康(irinotecan)、雷利竇邁(lenalidomide)、來曲唑、甲醯四氫葉酸、乙酸柳培林(leuprolide acetate)、左旋咪唑(levamisole)、洛莫司汀(lomustine)、乙酸甲地孕酮(megestrol acetate)、美法侖(melphalan)、巰嘌呤、6-MP、美司鈉(mesna)、胺甲喋呤、甲氧沙林(methoxsalen)、絲裂黴素C、米托坦(mitotane)、米托蒽醌(mitoxantrone)、諾龍(nandrolone)、奈拉濱(nelarabine)、諾非單抗(nofetumomab)、奧普瑞白介素(oprelvekin)、奧沙利鉑、白蛋白結合型紫杉醇(nab-paclitaxel)、帕立非明(palifermin)、帕米膦酸(pamidronate)、培加酶(pegademase)、培門冬酶、聚乙二醇非格司亭、培美曲塞二鈉(pemetrexed disodium)、噴司他汀(pentostatin)、哌泊溴烷(pipobroman)、普卡黴素(plicamycin)、卟吩姆鈉(porfimer sodium)、丙卡巴肼(procarbazine)、奎那克林(quinacrine)、拉布立酶(rasburicase)、利妥昔單抗、盧瑟替尼(rociletinib)、沙格司亭(sargramostim)、索拉菲尼(sorafenib)、鏈脲黴素(streptozocin)、馬來酸舒尼替尼、滑石、他莫昔芬(tamoxifen)、替莫唑胺(temozolomide)、替尼泊苷、VM-26、睪內酯(testolactone)、硫鳥嘌呤、6-TG、噻替派(thiotepa)、托泊替康、托瑞米芬(toremifene)、托西莫單抗(tositumomab)、曲妥珠單抗(trastuzumab)、維甲酸、ATRA、尿嘧啶氮芥、戊柔比星(valrubicin)、長春鹼、長春新鹼、長春瑞濱(vinorelbine)、唑來膦酸鹽(zoledronate)、唑來膦酸、派姆單抗(pembrolizumab)、尼沃魯單抗(nivolumab)、IBI-308、mDX-400、BGB-108、MEDI-0680、SHR-1210、PF-06801591、PDR-001、GB-226、STI-1110、德瓦魯單抗(durvalumab)、阿替珠單抗(atezolizumab)、阿維魯單抗(avelumab)、BMS-936559、ALN-PDL、TSR-042、KD-033、CA-170、STI-1014、FOLFIRINOX、KY-1003、奧美沙坦酯(olmesartan medoxomil)、坎地沙坦(candesartan)、PBI-4050、巴瑞替尼(baricitinib)、GSK-2586881、氯沙坦(losartan)、達格列淨丙二醇(dapagliflozin propanediol)、培維索孟(pegvisomant)、GR-MD-02、卡格列淨(canagliflozin)、厄貝沙坦(irbesartan)、FG-3019、阿曲生坦(atrasentan)、非任酮(finerenone)、斯帕森坦(sparsentan)、波生坦(bosentan)、去纖苷(defibrotide)、非馬沙坦(fimasartan)、阿齊瑞格(azeliragon)、吡哆胺(pyridoxamine)、促皮質素(corticotropin)、INT-767、依帕司他(epalrestat)、托匹司他(topiroxostat)、SER-150-DN、吡非尼酮(pirfenidone)、VEGFR-1 mAb、AKB-9778、PF-489791、SHP-627、CS-3150、咪唑普利(imidapril)、培哚普利(perindopril)、卡托普利(captopril)、依那普利(enalapril)、賴諾普利(lisinopril)、佐芬普利(Zofenopril)、賴諾普利(Lisinopril)、喹那普利(Quinapril)、貝那普利(Benazepril)、群多普利(Trandolapril)、西拉普利(Cilazapril)、福辛普利(Fosinopril)、雷米普利(Ramipril)、齊墩果酸(bardoxolone methyl)、厄貝沙坦(irbesartan) + 丙帕鍺(propagermanium)、GKT-831、MT-3995、TAK-648、TAK-272、GS-4997、DW-1029M、ASP-8232、VPI-2690B、DM-199、大黃酸(rhein)、PHN-033、GLY-230及沙丙喋呤(sapropterin)、舒洛地特(sulodexide)、利利單抗(lirilumab)、IPH-4102、IPH-2101、IMP-321、BMS-986016、MGD-013、LAG-525、德瓦魯單抗、莫奈株單抗(monalizumab)、MCLA-134、MBG-453、CA-170、AUPM-170、AUPM-327、瑞米司他(resminostat)、伊匹單抗(ipilimumab)、BGB-A317、曲美目單抗(tremelimumab)、REGN-2810、AZD-5069、馬賽替尼(masitinib)、比尼替尼(binimetinib)、曲美替尼、魯索替尼(ruxolitinib)、達拉菲尼(dabrafenib)、利那洛肽(linaclotide)、伊匹單抗、阿帕替尼(apatinib)、尼達尼布(nintedanib)、卡博替尼(cabozantinib)、帕唑帕尼(pazopanib)、貝林司他(belinostat)、帕尼單抗(panitumumab)、瓜地西他濱(guadecitabine)、維莫德吉(vismodegib)、威羅菲尼(vemurafenib)、達沙替尼(dasatinib)、曲美目單抗、貝伐珠單抗(bevacizumab)、奧沙利鉑、阿柏西普(aflibercept)、凡德他尼(vandetanib)、依維莫司(everolimus)、沙利竇邁(thalidomide)、維利帕尼(veliparib)、恩科菲尼(encorafenib)、奈布森(napabucasin)、奧派利斯(alpelisib)、阿西替尼(axitinib)、西地尼布(cediranib)、奈昔木單抗(necitumumab)、雷莫蘆單抗(ramucirumab)、依洛福芬(irofulven)、曲氟尿苷(trifluridine) + 地匹福林(tipiracil)、道那菲尼(donafenib)、帕克替尼(pacritinib)、派克斯-威克(pexastimogene devacirepvec)、提瓦替尼(tivantinib)、GNR-011、他拉泊芬(talaporfin)、皮裡諾森(piclidenoson)、地西他濱(decitabine)、蓋尼塔單抗(ganitumab)、帕比司他(panobinostat)、雷他莫德(rintatolimod)、泊馬昔布(polmacoxib)、左亞葉酸(levofolinate)、法米替尼(famitinib)、沃圖莫單抗(votumumab)、替肟紮尼(tivozanib)、恩替諾特(entinostat)、普利肽新(plitidepsin)、來非莫德(lefitolimod)、OSE-2101、維特斯朋(vitespen)、TroVax、溴隱亭(bromocriptine)、米哚妥林(midostaurin)、福他布林(fosbretabulin)、呋喹替尼(fruquintinib)、蓋那特匹(ganetespib)、布立尼布(brivanib)、安羅替尼(anlotinib)、L19-TNF-α、拉妥木單抗(racotumomab)、樂複能(Novaferon)、雷替曲塞(raltitrexed)、恩紮妥林(enzastaurin)、GM-CT-01、阿西莫單抗(arcitumomab)、地尼白介素2、貝沙羅汀、伏立諾他(vorinostat)、羅米地辛(romidepsin)、普拉曲沙(pralatrexate)、普賴松、普賴蘇濃或其任一組合。 可與本發明化合物或組合物組合、單獨或於相同醫藥組合物中投與之其他治療劑之實例包括(但不限於):MP-1032、蘇金單抗(secukinumab)、倍他米松、環孢素、賽妥珠單抗(certolizumab)、聚乙二醇化賽妥珠單抗、VTP-43742、比麥珠單抗(bimekizumab)、GSK-2982772、阿米莫德(amiselimod)、KD-025、優特克單抗(ustekinumab)、依那西普、庫賽珠單抗(guselkumab)、阿普斯特(apremilast)、富馬酸二甲酯 + 富馬酸單乙基酯鈣鹽 + 富馬酸單乙基酯鎂鹽 + 富馬酸單乙基酯鋅鹽、英利昔單抗、瑞薩珠單抗(risankizumab)、一刻珠單抗(ixekizumab)、莫米松(mometasone)、布羅達單抗(brodalumab)、阿達木單抗、托法替尼、奧洛他定(olopatadine)、他紮羅汀、富馬酸二甲酯、豬鞭蟲卵子(Trichuris suis ova)、BTT-1023、沃克普林(voclosporin)、塞萊斯布(seletalisib)、INV-103、皮裡諾森(piclidenoson)、GR-MD-02、PRX-167700、LYC-30937 EC、那米魯單抗(namilumab)、LY-3074828、LEO-32731、阿維A (acitretin)、卡泊三醇、WBI-1001、丙酸氯倍他索(clobetasol propionate)、倍他米松、ZPL-389、柏替木單抗(bertilimumab)、AKP-11、ZPL-521、克立薩硼(crisaborole)、CLS-008、IMO-8400、博萊魯單抗(bleselumab)、卡泊三醇、替可珠單抗(tildrakizumab)、KX-01、18C3、DSXS-1411、DLX-105、瑞孟斯他(remetinostat)、普如索爾(Prurisol)、S-414114、GLG-801、伊奈骨化醇(inecalcitol)、馬沙骨化醇(maxacalcitol) + 倍他米松、TAB-08、阿法西普(alefacept)、烏倍他索(ulobetasol)、托瑞福特(toreforant)、卡泊三醇、二丙酸倍他米松、曲加珠單抗(tregalizumab)、CJM-112、內湖珠單抗(neihulizumab)、戊酸倍他米松、P-3072、P-3073、胺甲喋呤、GSK2981278A、卡泊三醇 + 二丙酸倍他米松、LEO-124249、AVX-001、卡泊三醇 + 二丙酸倍他米松、富馬酸二甲酯、丙酸鹵倍他索(halobetasol propionate) + 他紮羅汀、卡泊三醇、卡泊三醇 + 倍他米松、阿曲諾英、DFD-06、孟加拉玫瑰紅鈉(rose bengal sodium)、C-82、TU-2100、CT-327、帕立骨化醇(pefcalcitol)、醋酸氟輕鬆(fluocinonide)、丙酸氯倍他索 + 維甲酸、GK-664-S、他紮羅汀 + 倍他米松、伊立珠單抗(itolizumab)、戊酸倍他米松、IMO-3100、PUR-0110、LEO-29102、奧瑞莫德(orilotimod)、馬沙骨化醇、IR-502、菸酸肉豆蔻基酯、阿加尼生(aganirsen)、胺甲喋呤、糠酸莫米松、BCG多醣 + 核酸注射液、琥珀酸鋰、奧瑞莫德、LAS-41004、骨化三醇(calcitriol)、GMDP、糠酸莫米松、MOL-4249、胺喋呤(aminopterin)、他卡西醇(tacalcitol)、蒽三酚(dithranol)、鹵米松(halometasone)、安波(anapsos)、塔格瑞斯(osimertinib)及AGEN-1884。套組及包裝
術語「套組」及「醫藥套組」係指在一或多個適宜容器中包含一或多種醫藥組合物及其使用說明書之商業套組或包裝。在一個實施例中,提供套組,其包含式(A)、(A1)、(A2)、(I)或(Ia1)化合物或其醫藥上可接受之鹽及其投與說明書。在一個實施例中,提供套組,其包含式(A)、(A1)、(A2)、(I)及(Ia1)化合物或其醫藥上可接受之鹽與一或多種(例如,一種、兩種、三種、一或兩種或一至三種)其他治療劑之組合及其投與說明書。 在一個實施例中,本發明化合物調配成包裝於單一包裝中之投與單元。單一包裝涵蓋(但不限於)瓶、兒童防護瓶、安瓿及管。在一個實施例中,本發明化合物及視情況其他治療劑調配成投與單元且每個單一投與單元個別地包裝於單一包裝中。該等經個別包裝之單元可含有呈任一形式之醫藥組合物,該形式包括(但不限於)液體形式、固體形式、粉末形式、顆粒形式、起泡粉或錠劑、硬質或軟質膠囊、乳液、懸浮液、糖漿、栓劑、錠劑、糖錠劑、菱形錠劑、溶液、經頰貼片、薄膜、經口凝膠、可咀嚼錠劑、口香糖及一次性注射器。該等經個別包裝之單元可組合於由紙、卡紙板、紙板、金屬箔及塑膠箔中之一或多者製得之包裝中,例如泡罩包。可每天一次或若干次投與一或多個投與單元。可每天三次投與一或多個投與單元。可每天兩次投與一或多個投與單元。可在第一天投與一或多個投與單元,且可在第二天投與一或多個投與單元。一般合成程序
實施例亦係關於可用於製備個別化合物或其醫藥上可接受之鹽之製程及中間體。 現將參考本文關於其一般製備之說明性合成方案及下文特定實例來闡述可用於實施例方法中之實例性化學實體。熟習此項技術者將意識到,為獲得本文之眾多種化合物,可適宜地選擇起始材料,以使得最終期望取代基係經由在適宜時具或不具保護之反應方案攜載以產生期望產物。或者,可能需要或期望採用可經由反應方案攜載且在適宜時經期望取代基替代之適宜基團來替代最終期望取代基。此外,熟習此項技術者將意識到,下文方案中所顯示之轉變可以與具體側基之官能基相容之任一順序來實施。 本發明化合物之代表性合成闡述於下文方案及下文具體實例中。方案1及2提供為本發明之其他實施例且圖解說明用於製備本發明化合物(包括式(A)、(A1)、(A2)、(I)及(Ia1)化合物)且可用於製備具有式(A)、(A1)、(A2)、(I)及(Ia1)之其他化合物的一般方法。該方法與眾多個官能基相容。方案 1 可使B1之胺基與3,4-二甲氧基環丁-3-烯-1,2-二酮反應以提供B2。然後可使B2與B3之胺基反應以提供B4。方案 2 B7可藉由例如氫化還原B6中之氰基、然後環化來獲得。或者,可使B5 (其中X代表諸如鹵素或甲苯磺酸根等脫離基且其中R係烷基)與NH3
反應以形成環化產物B7。可在酸(例如硫酸)存在下使B7與HNO3
反應以引入硝基來獲得B8。隨後藉由例如氫化還原B8中之硝基可提供B9。實例
提供以下實例進行說明,而非限制所主張之本發明。 下文所用之試劑及溶劑可自諸如Aldrich Chemical Co. (Milwaukee, Wisconsin, USA)等商業來源獲得。在Varian Mercury 400 MHz NMR光譜儀上記錄1
H-NMR。有效峰值係相對於TMS提供且按以下順序列成表格:多樣性(s,單峰;d,雙峰;t,三重峰;q,四重峰;m,多重峰)及質子數。將質譜結果報告為質荷比,後面跟有每一離子之相對豐度(於括弧內)。在表中,單一m/e值係針對含有最常見原子同位素之M+H (或如所註明M-H)離子來報告。在所有情形下,同位素模式對應於預期式。電噴霧離子化(ESI)質譜分析係在Hewlett-Packard MSD電噴霧質譜儀上使用配備有Agilent Zorbax SB-C18, 2.1×50 mm, 5 μ管柱用於樣品遞送之HP1100 HPLC來實施。通常,將分析物以0.1 mg/mL溶解於甲醇中且利用遞送溶劑將1毫升輸注至掃描100至1500道爾頓之質譜儀中。所有化合物可以陽性ESI模式、使用乙腈/含有1%甲酸之水作為遞送溶劑來分析。下文所提供之化合物亦可以陰性ESI模式、使用乙腈中之2 mM NH4
OAc/水作為遞送系統來分析。 在實例及本發明說明書通篇中使用以下縮寫: HPLC,高壓液相層析;DMF,二甲基甲醯胺;TFA,三氟乙酸;THF,四氫呋喃;EtOAc,乙酸乙酯;BOC2
O,二碳酸二-第三丁基酯或BOC酸酐;HPLC,高壓液相層析;DIPEA,二異丙基乙胺;HBTU,O
-(苯并三唑-1-基)-N
,N
,N’
,N’
-四甲基脲鎓六氟磷酸鹽;dppf,1,1'-雙(二苯基膦基)二茂鐵;Pd2
(dba)3
,參(二亞苄基丙酮)二鈀(0);DIPEA,二異丙基乙胺;DMP,鄰苯二甲酸二甲酯;Me,甲基;Et,乙基;DCM,二氯甲烷。 在本發明範疇內之化合物可如下文所述使用熟習此項技術者已知之多個反應來合成。熟習此項技術者亦將意識到,可採用替代方法來合成本發明之目標化合物,且本文件主體內所述之方法並不詳盡,但確實提供對於所關注化合物廣泛適用之實踐途徑。 此專利中所主張之某些分子可以不同鏡像異構及非鏡像異構形式存在且主張該等化合物之所有該等變體。 本文中用於合成關鍵化合物之實驗程序之詳細描述產生由鑑別其之物理數據以及與其相關之結構繪示闡述之分子。 熟習此項技術者亦將意識到,在有機化學中之標準處理程序期間,通常使用酸及鹼。有時在此專利內所述之實驗程序期間,若母化合物具有所需固有酸度或鹼度,則產生母化合物之鹽。實例 1 : 3-[[(1R
)-2,2- 二甲基 -1-(5- 甲基 -2- 呋喃基 ) 丙基 ] 胺基 ]-4- 乙氧基 - 環丁 -3- 烯 -1,2- 二酮之合成 步驟 a :
向配備有機械攪拌器之3頸5 L圓底燒瓶中添加二氯甲烷(1.5 L)中之(R
)-2-甲基丙烷-2-亞磺醯胺(100 g, 0.825 mol)、2,2-二甲基丙醛(78.2 g, 0.907 mol)及四乙醇鈦(414.1 g, 1.815 mol)。在室溫下將反應混合物攪拌12小時,然後添加硫酸鈉十水合物(260 g),隨後添加矽藻土(500 g)。在室溫下將混合物攪拌5小時,經由矽藻土過濾且用二氯甲烷(1 L)沖洗。在真空中濃縮濾液且在真空下乾燥過夜,以獲得棕色油狀[N
(E
),S
(R
)] -N-(
2,2-二甲基亞丙基)-2-甲基-丙烷-2-亞磺醯胺(150 g, 96%),其不經進一步純化即用於下一步驟中。1
H NMR (400 MHz, CD3
OD) δ 7.80 (s, 1 H), 1.10 (s, 9H), 1.08 (s, 9 H); MS: C19
H19
NOS [M + H]+
之(ES)m/z
計算值190.1,實驗值190.1。步驟 b :
向配備有加料漏斗之1 L 3頸燒瓶中裝填2-甲基呋喃(31.1 mL, 345.1 mmol, 1.5當量)及無水Et2
O (300 mL),且然後在冰浴中冷卻。經約35分鐘逐滴添加己烷中之n
-BuLi (2.5 M, 120 mL, 299 mmol, 1.3當量)。在0℃下將混合物攪拌30分鐘,然後在室溫下攪拌40分鐘,然後將其再冷卻至0℃。添加固體MgBr2
× Et2
O (77.2 g, 299.1 mmol, 1.3當量)且在0℃下將混合物攪拌30分鐘,然後在室溫下攪拌20分鐘。 在配備有磁力攪拌及內部溫度計之5 L 3頸燒瓶中,將步驟a之亞胺(43.5 g, 230.1 mmol)溶解於無水甲苯(1.2 L)中且將此冷卻至-70℃之內部溫度。經56分鐘添加來自上述段落之鋰鹽溶液,使內部溫度保持在-70℃至-67.8℃之間。添加後,在-70℃下將反應混合物攪拌1小時,然後在室溫下過夜。用飽和NH4
Cl水溶液(400 mL)及水(400 mL)緩慢驟冷反應混合物,然後在室溫下攪拌15分鐘。分離有機層且用鹽水(200 mL)洗滌。用乙酸乙酯(300 mL)萃取合併之水層。經MgSO4
乾燥有機物,過濾且蒸發,以獲得橙色油狀物。將粗產物溶解於己烷(500 mL)中且允許在-20℃下結晶過夜,以獲得黃色固體。過濾固體且將母液蒸發並自己烷(50 mL)再結晶,以獲得呈純非鏡像異構物形式之產物(51.9 g, 83%)。MS: C14
H26
NO2
S [M + H]+
之(ES) m/z計算值272.2,實驗值272.2。步驟 c :
將來自先前步驟之N
-[(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]-2-甲基-丙烷-2-亞磺醯胺(51.9 g, 191.5 mmol)溶解於甲醇(100 mL)中且在冰浴中冷卻,然後添加醚中之2M HCl (191.5 mL, 383.0 mmol, 2當量)。移除冷卻浴且在室溫下將反應混合物攪拌2小時。在真空中移除溶劑,且將無水醚(300 mL)添加至殘餘物中。過濾所得混合物。向固體中添加水(100 mL)及1M NaOH水溶液(200 mL)。用二氯甲烷(3 × 100 mL)萃取產物且經MgSO4
乾燥合併之有機層,過濾並蒸發,以獲得黃色油狀物(27.2 g, 85%)。MS: C10
H15
O [(M - NH3
) + H]+
之(ES)m/z
計算值151.1,實驗值151.1。步驟 d :
將3,4-二乙氧基環丁-3-烯-1,2-二酮(15.9 g, 93.5 mmol, 1.05當量)溶解於無水乙醇(150 mL)中且在冰浴中冷卻。然後,逐滴添加(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙-1-胺(14.9 g, 89.0 mmol)於無水乙醇(50 mL)中之溶液,且在室溫下將反應混合物攪拌過夜。蒸發過量溶劑且將殘餘物與己烷(500 mL)一起攪拌直至固體發生沈澱。過濾固體,用己烷(100 mL)洗滌且在高真空下乾燥,以提供標題化合物(24.4 g, 94%)。MS: C16
H22
NO4
[M + H]+
之(ES)m/z
計算值292.1,實驗值292.1。實例 2 :之合 成 2-[4- 氯 -7-[[2-[[(1R
)-2,2- 二甲基 -1-(5- 甲基 -2- 呋喃基 ) 丙基 ] 胺基 ]-3,4- 二側氧基 - 環丁 -1- 基 ] 胺基 ]-1- 側氧基 - 異吲哚啉 -2- 基 ] 苯甲酸 步驟 a :
在冰浴中冷卻含有濃H2
SO4
(500 mL)中之3-氯-2-甲基-苯甲酸(100.0 g, 0.586莫耳)之4 L錐形燒瓶。逐滴添加70% HNO3
(45.2 mL, 0.703莫耳,1.2當量)且在0℃下將反應混合物攪拌2小時,然後用冰小心地驟冷並用冷水稀釋至4 L。過濾白色固體,用水洗滌且在高真空下乾燥(127 g,定量),以提供3:1比率之3-氯-2-甲基-6-硝基-苯甲酸及3-氯-2-甲基-5-硝基-苯甲酸之混合物。MS: C8
H5
ClNO4
[M-H]-
之(ES)m/z
計算值214.0,實驗值214.0。步驟 b :
將來自先前步驟之異構酸混合物(50 g, 232.0 mmol)溶解於無水DMF (200 mL)中,添加無水Na2
CO3
(27.0 g, 255.2 mmol, 1.1當量),且在室溫下將反應物攪拌30分鐘。添加碘甲烷(15.9 mL, 255.2 mmol, 1.1當量)且在室溫下持續攪拌3小時。用水(1.2 L)稀釋反應混合物並使用Et2
O (3 × 250 mL)萃取產物。用鹽水(4 × 100 mL)洗滌合併之有機層,經MgSO4
乾燥,過濾且蒸發,以獲得黃色油狀物(49.7 g, 93%)。步驟 c :
將來自先前步驟之異構酯混合物(49.7 g, 216.5 mmol)溶解於CCl4
(400 mL)中,且添加N-溴琥珀醯亞胺(57.8 g, 324.7 mmol, 1.5當量),然後添加過氧化苯甲醯(10.4 g, 43.2 mmol, 0.20當量)。在回流下將反應混合物攪拌過夜,然後冷卻至室溫且過濾。蒸發濾液且藉由矽膠層析(100:0至9:1己烷:EtOAc)純化殘餘物,以獲得呈單一異構物形式之黃色固體(44.1 g, 66%)。1
H NMR (400 MHz, CDCl3
) δ 8.07 (d,J
= 9.2 Hz, 1H), 7.65 (d,J
= 9.2 Hz, 1H), 4.63 (s, 2H), 4.01 (s, 3H)。步驟 d :
在密封的40 mL反應瓶中,將來自先前步驟之產物(616 mg, 2 mmol)、胺基苯甲酸甲酯(302 mg, 2 mmol)及K2
CO3
(553 mg, 4 mmol)於無水乙腈中之懸浮液加熱至85℃過夜。然後將反應物冷卻至室溫,用乙酸乙酯稀釋且過濾。濃縮濾液,以提供非環化粗產物(800 mg)。將此粗產物溶解於乙酸(5 mL)中且加熱至120℃過夜,以提供環化產物。將其用乙酸乙酯稀釋,用水及飽和NaHCO3
水溶液洗滌,然後乾燥(Na2
SO4
),過濾,並濃縮。使殘餘物吸附於二氧化矽上且藉由矽膠層析(己烷中之0-50%乙酸乙酯)純化,以提供期望產物(350 mg, 50%)。MS: C16
H11
ClN2
O5
[M+H]+
之(ES)m/z
計算值347.0,實驗值347.0。步驟 e :
在室溫下,向2-(4-氯-7-硝基-1-側氧基-異吲哚啉-2-基)苯甲酸甲酯(347 mg, 1 mmol)於乙醇中之攪拌混合物中添加鐵粉(224 mg, 4 mmol),然後添加二噁烷中之4 M HCl (2 mL, 8 mmol)。在室溫下將反應混合物攪拌1小時,然後在真空中濃縮。用乙酸乙酯稀釋殘餘物且用飽和碳酸氫鈉溶液中和並用乙酸乙酯(2 × 5 mL)萃取。乾燥(Na2
SO4
)合併之有機層,過濾,並在真空中濃縮。藉由矽膠層析(己烷中之0-100%乙酸乙酯)純化粗產物,以提供黃色粉末狀2-(7-胺基-4-氯-1-側氧基-異吲哚啉-2-基)苯甲酸甲酯(200 mg, 0.63 mmol, 63%)。MS: C16
H13
ClN2
O3
[M+H]+
之(ES)m/z
計算值317.0,實驗值317.0。步驟 f :
在0℃下攪拌2-(7-胺基-4-氯-1-側氧基-異吲哚啉-2-基)苯甲酸甲酯(109 mg, 0.34 mmol)及3-[[(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]胺基]-4-乙氧基-環丁-3-烯-1,2-二酮(100 mg, 0.34 mmol)於二氯甲烷中之溶液,且添加三甲基鋁於甲苯中之2M溶液(0.68 mL, 1.36 mmol)。在0℃下將溶液攪拌1小時,然後升溫至室溫且再攪拌一小時。將反應混合物冷卻至0℃且用5%鹽酸溶液驟冷並用水稀釋,然後用乙酸乙酯(2 × 5 mL)萃取。乾燥(Na2
SO4
)有機層,過濾,並在真空中濃縮。藉由HPLC純化粗產物,以提供黃色固體狀2-[4-氯-7-[[2-[[(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]胺基]-3,4-二側氧基-環丁-1-基]胺基]-1-側氧基-異吲哚啉-2-基]苯甲酸甲酯(65 mg, 0.12 mmol, 34%)。MS: C30
H28
ClN3
O6
[M-H]+
之(ES)m/z
計算值560.0,實驗值560.0。步驟 g :
向2-[4-氯-7-[[2-[[(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]胺基]-3,4-二側氧基-環丁-1-基]胺基]-1-側氧基-異吲哚啉-2-基]苯甲酸甲酯(56 mg, 0.1 mmol)於四氫呋喃(1 mL)及甲醇(0.1 mL)及水(0.1 mL)中之溶液中添加過量氫氧化鋰。在室溫下將所得混合物攪拌1小時。用5%鹽酸溶液酸化反應物並用乙酸乙酯萃取。乾燥(Na2
SO4
)有機層,過濾,並在真空中濃縮。藉由HPLC純化粗產物,以提供黃色固體狀2-[4-氯-7-[[2-[[(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]胺基]-3,4-二側氧基-環丁-1-基]胺基]-1-側氧基-異吲哚啉-2-基]苯甲酸(30 mg, 0.05 mmol, 50%)。1
H NMR (400 MHz, DMSO-d 6
) δ 9.89 (s, 1 H), 9.06 (d,J
= 10 Hz, 1 H), 7.85 (dd,J
= 7.6, 1.6 Hz, 1 H), 7.65-7.41 (m, 5 H), 6.10 (d,J
= 2.6 Hz, 1 H), 5.95 (d,J
= 2.6 Hz, 1 H), 5.03 (d,J
= 10.4 Hz, 1 H), 4.80 (dd,J
= 20, 10 Hz, 2 H), 2.20 (s, 3 H), 0.87 (s, 9 H)。MS: C29
H26
ClN3
O6
[M-H]-
之(ES)m/z
計算值546.0,實驗值546.0。實例 3 : 3-[[(1R
)-2,2- 二甲基 -1-(5- 甲基 -2- 呋喃基 ) 丙基 ] 胺基 ]-4-[(5- 氟 -3- 側氧基 - 異吲哚啉 -4- 基 ) 胺基 ] 環丁 -3- 烯 -1,2- 二酮 步驟 a :
向500 mL圓底燒瓶中裝填2-溴-5-氟苯甲酸甲酯(48 g, 206 mmol)、氰化銅(37 g, 412 mmmol)及DMF (200 mL)。在110℃下將混合物加熱過夜,且然後冷卻至室溫。添加醚(1.5 L)及矽藻土(100 g)且在室溫下將混合物攪拌30分鐘。過濾固體並用鹽水(3 × 200 mL)洗滌濾液,且然後經MgSO4
乾燥。在減壓下蒸發溶劑以獲得無色固體狀期望產物(31 g, 84%)。MS: C9
H7
FNO2
[M+H]+
之(ES)m/z
計算值180.1,實驗值180.1。步驟 b :
在室溫下,向2-氰基-5-氟苯甲酸甲酯(10 g, 56 mmol)於甲醇(200 mL)中之溶液中添加10% Pd-C (1.0 g)。在氫(50 psi)氣氛下將所得混合物攪拌過夜。經由矽藻土過濾反應混合物且在減壓下濃縮濾液,以獲得無色固體狀期望產物(8.0 g, 90%)。MS: C8
H7
FNO[M+H]+
之(ES)m/z
計算值152,實驗值152。步驟 c :
向6-氟異吲哚啉-1-酮(8.0 g, 5.3 mmol)於濃H2
SO4
中之0℃懸浮液中逐滴添加濃H2
SO4
(26 mL)及硝酸(6 mL)之預冷卻混合物,同時將反應混合物保持在5℃以下。添加後,將反應混合物緩慢升溫至室溫過夜。將冰(50 g)添加至混合物中且收集固體並乾燥,然後用MTBE (50 mL)及乙酸乙酯(50 mL)洗滌,以獲得淺黃色固體狀期望產物(5.1 g, 50%)。MS: C8
H6
FN2
O3
[M+H]+
之(ES)m/z
計算值197.2,實驗值197.2。步驟 d :
在氫氣氛(氣球)下,將6-氟-7-硝基異吲哚啉-1-酮(11.3 g, 57 mmol)及10% Pd/C (50%潤濕,6.2 g, 2.9 mmol, 0.05當量)於THF (300 mL)中之溶液攪拌過夜。經由矽藻土過濾固體且在減壓下濃縮濾液,以獲得無色固體,藉由矽膠層析(100%乙酸乙酯)純化該固體,以獲得白色固體狀期望產物(6.4 g, 67%)。MS: C8
H9
FN2
O[M+H]+
之(ES)m/z
計算值168.1,實驗值168.1。步驟 e :
在60℃下,將7-胺基-6-二氟-異吲哚啉-1-酮(4.4 g, 26 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(7.4 g, 52 mmol)於無水甲醇(30 mL)中之混合物攪拌過夜,且然後在80℃下攪拌5小時。蒸發反應混合物且在50℃下將殘餘物於乙酸乙酯(200 mL)中攪拌30分鐘,然後冷卻至室溫。過濾混合物並乾燥,以獲得淺黃色固體(5.0 g, 70%)。MS: C13
H10
FN2
O4
[M+H]+
之(ES) m/z計算值277.2,實驗值277.2。步驟 f :
將無水乙醇(10 mL)添加至3-[(7-氟-3-側氧基-異吲哚啉-4-基)胺基]-4-甲氧基-環丁-3-烯-1,2-二酮(1.5 g, 5.4 mmol)及(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙-1-胺(1.1 g, 6.5 mmol)之混合物中,且在60℃下將此混合物攪拌過夜。將反應物冷卻至室溫,使其溶解於少量二氯甲烷中,且吸附至矽膠上。藉由矽膠層析(二氯甲烷中之40%乙酸乙酯)純化產物,以獲得白色固體(800 mg, 45%)。1
H NMR (400 MHz, DMSO-d 6
) δ 9.59 (s, 1 H), 8.65 (s, 1 H), 8.35 (d,J
= 10.4 Hz, 1 H), 7.41 (dd,J
= 11.6, 8.4 Hz, 1 H), 6.18 (dd,J
= 4.0, 8.4 Hz, 1 H), 6.12 (d,J
= 3.2 Hz, 1 H), 5.98 (d,J
= 2.0 Hz, 1 H), 4.97(d,J
= 4.10 Hz, 1 H), 4.26 (s, 2 H), 2.22 (s, 3 H), 0.90 (s, 9 H)。MS: C22
H22
FN3
O4
[M-H]-
之(ES) m/z計算值410.0,實驗值410.0。實例 4 : 3-[(5,7- 二氟 -3- 側氧基 - 異吲哚啉 -4- 基 ) 胺基 ]-4-[[(1R
)-2,2- 二甲基 -1-(5- 甲基 -2- 呋喃基 ) 丙基 ] 胺基 ] 環丁 -3- 烯 -1,2- 二酮 之合 成 步驟 a :
將3,5-二氟-2-甲基-苯甲酸(5.2 g, 30.2 mmol)溶解於無水DMF (30 mL)中。添加無水Na2
CO3
(3.5 g, 33.2 mmol, 1.1當量)且在室溫下將反應物攪拌30分鐘。添加碘甲烷(2.1 mL, 33.2 mmol, 1.1當量)且在室溫下將混合物攪拌4小時,然後用水(200 mL)稀釋反應物並使用Et2
O (3 × 50 mL)萃取產物。用鹽水(4 × 30 mL)洗滌合併之有機層,經MgSO4
乾燥,過濾且蒸發,以獲得黃色油狀物(5.4 g, 96%)。步驟 b :
將步驟a之產物(5.4 g, 29.0 mmol)溶解於四氯化碳(60 mL)中,且添加N-溴琥珀醯亞胺(7.7 g, 43.5 mmol, 1.5當量),然後添加過氧化苯甲醯(1.4 g, 5.8 mmol, 0.20當量)。在回流下將反應混合物攪拌過夜,然後冷卻至室溫且過濾。蒸發濾液且藉由管柱層析(矽膠,100%己烷至9:1己烷:乙酸乙酯)純化殘餘物,以獲得黃色油狀產物(7.4 g, 96%)。步驟 c :
將甲醇中之NH3
(7 M, 45 mL, 6.4 mmol)冷卻至0℃,且添加步驟b之產物(6 g, 22.6 mmol)。在0℃下將反應混合物攪拌10分鐘,且然後在室溫下過夜。蒸發過量溶劑且用水(50 mL)稀釋殘餘物。過濾所得固體且用水(2 × 20 mL)、然後用己烷(20 mL)洗滌,以獲得產物(3.4 g, 89%)。MS: C8
H6
F2
NO [M+H]+
之(ES)m/z
計算值170.0,實驗值170.3。步驟 d :
將步驟c之4,6-二氟異吲哚啉-1-酮(3.4 g, 20.1 mmol)溶解於濃H2
SO4
(40 mL)中且冷卻至0℃。逐滴添加70% HNO3
(1.5 mL, 24.1 mmol, 1.2當量)並在0℃下將反應混合物攪拌10分鐘,然後經1小時之時段升溫至室溫且攪拌過夜。添加冰且然後用冷水(100 mL)稀釋混合物。過濾所得黃色固體,用水(2 × 50 mL)、然後用己烷(50 mL)洗滌且在真空下乾燥(3.4 g, 79%)。MS: C8
H5
F2
N2
O3
[M+H]+
之(ES)m/z
計算值215.0,實驗值215.2。步驟 e :
用THF (50 mL)稀釋步驟d之4,6-二氟-7-硝基-異吲哚啉-1-酮(3.4 g, 15.9 mmol),且在氮氣氛下添加10% Pd/C (50%潤濕,1.7 g, 0.8 mmol, 0.05當量)。在室溫下在H2
(氣球)下將反應混合物劇烈攪拌1天,然後經由矽藻土過濾且蒸發,以獲得固體產物(2.7 g, 92%)。MS: C8
H7
F2
N2
O [M+H]+
之(ES)m/z
計算值185.1,實驗值185.3。步驟 f :
在60℃下,將步驟e之7-胺基-4,6-二氟-異吲哚啉-1-酮(2.3 g, 12.5 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(3.5 g, 25.0 mmol, 2.0當量)於無水MeOH (15 mL)中之混合物攪拌過夜。蒸發反應混合物且用MTBE:EtOAc (1:1, 200 mL)稀釋殘餘物,並在50℃下攪拌30分鐘,然後冷卻至室溫。過濾固體產物,用MTBE洗滌,然後溶解於MeOH:DCM (1:1, 200 mL)中並經由矽藻土過濾。蒸發濾液以獲得灰色固體(2.0 g, 54%)。MS: C13
H9
F2
N2
O4
[M+H]+
之(ES) m/z計算值295.1,實驗值295.2。步驟 g :
將無水甲醇(30 mL)添加至步驟f之3-[(5,7-二氟-3-側氧基-異吲哚啉-4-基)胺基]-4-甲氧基-環丁-3-烯-1,2-二酮(1.5 g, 5.1 mmol)及(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙-1-胺(852 mg, 5.1 mmol)之混合物中,且在60℃下將此混合物攪拌1天。將反應物冷卻至室溫,溶解於少量二氯甲烷中,且吸附於矽膠上。藉由矽膠層析(100:0至50:50二氯甲烷:乙酸乙酯)純化產物,以獲得棕色固體(1.4 g, 64%)。1
H NMR (400 MHz, DMSO-d 6
) δ 9.59 (s, 1 H), 8.92 (s, 1 H), 8.37 (d,J
= 10.2 Hz, 1 H), 7.62 (dd,J
= 10.9, 8.6 Hz, 1 H), 6.18 (d,J
= 3.1 Hz, 1 H), 6.04 (d,J
= 3.1 Hz, 1 H), 5.01 (d,J
= 10.2 Hz, 1H), 4.41 (s, 2 H), 2.27 (s, 3 H), 0.96 (s, 9 H)。MS: C22
H21
F2
N3
O4
[M-H]-
之(ES) m/z計算值428.1,實驗值428.1。實例 5 : 2-[4- 氯 -7-[[2-[[(1R
)-2,2- 二甲基 -1-(5- 甲基 -2- 呋喃基 ) 丙基 ] 胺基 ]-3,4- 二側氧基 - 環丁 -1- 基 ] 胺基 ]-1- 側氧基 - 異吲哚啉 -2- 基 ]-4- 甲氧基 - 苯甲酸 步驟 a :
在冰浴中冷卻含有濃H2
SO4
(50 mL)中之4-氯異吲哚啉-1-酮(25.0 g, 0.149莫耳)之1 L圓底燒瓶。逐滴添加濃H2
SO4
(50 mL)與70% HNO3
(10 mL, 0.16莫耳,1.05當量)之混合物,且在0℃下將反應混合物攪拌2小時,然後用冰小心地驟冷並用冷水稀釋至1 L。過濾固體,用水洗滌且在高真空下乾燥,以提供4-氯-7-硝基-異吲哚啉-1-酮(23 g, 73%)。MS: C8
H5
ClN2
O3
[M-H]-
之(ES)m/z
計算值212.0,實驗值212.0。步驟 b :
在室溫下,向4-氯-7-硝基-異吲哚啉-1-酮(23 g, 108 mmol)於乙醇中之攪拌混合物中添加鐵粉(18.2 g, 324 mmol),然後添加二噁烷中之4 M HCl (162 mL, 648 mmol)。在室溫下將反應混合物攪拌1小時,然後在真空中濃縮。用乙酸乙酯稀釋殘餘物且用飽和碳酸氫鈉溶液中和並用乙酸乙酯(2 × 500 mL)萃取。乾燥(Na2
SO4
)合併之有機層,過濾,且在真空中濃縮,以提供7-胺基-4-氯-異吲哚啉-1-酮(16.5 g, 72%)。MS: C8
H7
ClN2
O [M+H]+
之(ES)m/z
計算值183.2,實驗值183.2。步驟 c :
向含有二噁烷(10 mL)中之7-胺基-4-氯-異吲哚啉-1-酮(250 mg, 1.37 mmol)之反應瓶中添加2-溴-5-甲氧基-苯甲酸甲酯(502 mg, 2.05 mmol)、碳酸銫(893 mg, 2.74 mmol)、碘化銅(104 mg, 0.55 mmol)及(1S,2S)-N1,N2-二甲基環己烷-1,2-二胺(156 mg, 1.1 mmol)。用氮吹掃混合物,然後升溫至110℃。在110℃下將反應物攪拌1小時且藉由LC-MS來監測反應。完成後,將反應物冷卻,且然後經由矽藻土過濾並用乙酸乙酯沖洗。藉由矽膠層析(0-50%乙酸乙酯/己烷)純化粗製物,以獲得白色固體狀2-(7-胺基-4-氯-1-側氧基-異吲哚啉-2-基)-5-甲氧基-苯甲酸甲酯(284 mg, 60%)。MS: C17
H15
ClN2
O4
[M+H]+
之(ES)m/z
計算值347.1,實驗值347.1。步驟 d :
在60℃下,將2-(7-胺基-4-氯-1-側氧基-異吲哚啉-2-基)-5-甲氧基-苯甲酸甲酯(160 mg, 0.46 mmol)及3,4-二甲氧基環丁烷-1,2-二酮(131 mg, 0.92 mmol)於無水甲醇(5 mL)中之混合物攪拌過夜。蒸發反應混合物且在50℃下將殘餘物於乙酸乙酯(5 mL)中攪拌30分鐘,然後冷卻至室溫。過濾混合物並乾燥,以獲得淺黃色固體狀產物2-[4-氯-7-[(2-甲氧基-3,4-二側氧基-環丁基)胺基]-1-側氧基-異吲哚啉-2-基]-5-甲氧基-苯甲酸甲酯(170 mg, 81%)。MS: C22
H17
ClN2
O7
[M+H]+
之(ES) m/z計算值457.1,實驗值457.1。步驟 e :
將無水甲醇(10 mL)添加至2-[4-氯-7-[(2-甲氧基-3,4-二側氧基-環丁基)胺基]-1-側氧基-異吲哚啉-2-基]-5-甲氧基-苯甲酸甲酯(170 mg, 0.37 mmol)及(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙-1-胺(62 mg, 0.37 mmol)之混合物中,且在60℃下將此混合物攪拌過夜。然後濃縮反應物,且粗2-[4-氯-7-[[2-[[(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]胺基]-3,4-二側氧基-環丁-1-基]胺基]-1-側氧基-異吲哚啉-2-基]-4-甲氧基-苯甲酸甲酯(218 mg, 0.37 mmol)不經進一步純化即用於下一步驟中。步驟 f :
向2-[4-氯-7-[[2-[[(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]胺基]-3,4-二側氧基-環丁-1-基]胺基]-1-側氧基-異吲哚啉-2-基]-4-甲氧基-苯甲酸甲酯(218 mg, 0.37 mmol)於四氫呋喃(4.0 mL)、甲醇(0.5 mL)及水(0.5 mL)中之溶液中添加氫氧化鋰(78 mg, 1.85 mmol)。在60℃下將所得混合物攪拌6小時。用5%鹽酸溶液酸化反應物並用乙酸乙酯萃取。乾燥(Na2
SO4
)有機層,過濾,並在真空中濃縮。藉由反相層析純化粗產物,以提供黃色固體狀2-[4-氯-7-[[2-[[(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙基]胺基]-3,4-二側氧基-環丁-1-基]胺基]-1-側氧基-異吲哚啉-2-基]-4-甲氧基-苯甲酸(37 mg, 17%)。1
H NMR (400 MHz, DMSO-d 6
) δ 9.94 (s, 1 H), 9.12 (d,J
= 10 Hz, 1 H), 7.90 (d,J
= 9.2, 1 H), 7.66 (d,J
= 8.8, 1 H), 7.49 (d,J
= 9.2, 1 H), 7.19 (d,J
= 2.4, 1 H), 7.04 (dd,J
= 8.8, 2.4, 1 H), 6.16 (d,J
= 3.2 Hz, 1 H), 6.02 (d,J
= 1.6 Hz, 1 H), 5.09 (d,J
= 10 Hz, 1 H), 4.78 (dd,J
= 23, 5.6 Hz, 2 H), 3.83 (s, 3 H), 2.24 (s, 3 H), 0.87 (s, 9 H)。MS: C30
H28
ClN3
O7
[M-H]-
之(ES)m/z
計算值576.0,實驗值576.0。實例 6 : 2-[4- 氯 -7-[[2-[[(1R
)-1-(4,5- 二甲基 -2- 呋喃基 )-2,2- 二甲基 - 丙基 ] 胺基 ]-3,4- 二側氧基 - 環丁 -1- 基 ] 胺基 ]-1- 側氧基 - 異吲哚啉 -2- 基 ]-4- 甲氧基 - 苯甲酸 步驟 a :
向配備有加料漏斗之1 L 3頸燒瓶中裝填2,3-二甲基呋喃(30.0 g, 312.5 mmol, 1.3當量)及無水Et2
O (300 mL),然後在冰浴中冷卻。經約35分鐘逐滴添加己烷中之n
-BuLi (2.5 M, 125 mL, 312.5 mmol, 1.3當量)。在0℃下將混合物攪拌30分鐘,然後在室溫下攪拌40分鐘,然後將其再冷卻至0℃。添加固體MgBr2
× Et2
O (80.6 g, 312.5 mmol, 1.3當量)且在0℃下將混合物攪拌30分鐘,然後在室溫攪拌20分鐘。 在配備有磁力攪拌及內部溫度計之5 L 3頸燒瓶中,將亞胺(45.4 g, 240.4 mmol)溶解於無水甲苯(1.2 L)中且將此冷卻至-70℃之內部溫度。經56分鐘添加來自上述段落之鋰鹽溶液,使內部溫度保持在-70℃至-67.8℃之間。添加後,在-70℃下將反應混合物攪拌1小時,然後在室溫下過夜。用飽和NH4
Cl水溶液(400 mL)及水(400 mL)緩慢驟冷反應混合物,然後在室溫下攪拌15分鐘。然後分離有機層且用鹽水(200 mL)洗滌。用乙酸乙酯(300 mL)萃取合併之水層。經MgSO4
乾燥有機物,過濾並濃縮,以獲得黃色油狀物。藉由矽膠層析(0-10% MTBE/DCM)純化粗產物,以獲得呈單一非鏡像異構物形式之產物(18.0 g, 26%)。MS: C15
H28
NO2
S [M+H]+
之(ES) m/z計算值286.1,實驗值286.1。步驟 b :
將來自先前步驟之N
-[(1R
)-2,2-二甲基-1-(4,5-二甲基-2-呋喃基)丙基]-2-甲基-丙烷-2-亞磺醯胺(18 g, 63.1 mmol)溶解於甲醇(200 mL)中且在冰浴中冷卻,然後添加醚中之2M HCl (31.5 mL, 126.2 mmol, 2當量)。移除冷卻浴且在室溫下將反應混合物攪拌2小時。在真空中移除溶劑,且將無水醚(100 mL)添加至殘餘物中。過濾所得混合物。向固體中添加水(100 mL)及1M NaOH水溶液(100 mL)。用二氯甲烷(3 × 100 mL)萃取產物且經MgSO4
乾燥合併之有機層,過濾並蒸發,以獲得黃色油狀(1R
)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙-1-胺(9.7 g, 85%)。MS: C11
H17
O [(M-NH3
)+H]+
之(ES)m/z
計算值165.1,實驗值165.1。步驟 c :
將無水甲醇(1 mL)添加至2-[4-氯-7-[(2-甲氧基-3,4-二側氧基-環丁基)胺基]-1-側氧基-異吲哚啉-2-基]-5-甲氧基-苯甲酸甲酯(60 mg, 0.13 mmol)及(1R
)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙-1-胺(24 mg, 0.13 mmol)之混合物中。在60℃下將此混合物攪拌3小時。將反應物濃縮至乾燥,且粗2-[4-氯-7-[[2-[[(1R
)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]胺基]-3,4-二側氧基-環丁-1-基]胺基]-1-側氧基-異吲哚啉-2-基]-4-甲氧基-苯甲酸甲酯(78 mg, 0.13 mmol)不經進一步純化即用於下一步驟中。步驟 d :
向2-[4-氯-7-[[2-[[(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]胺基]-3,4-二側氧基-環丁-1-基]胺基]-1-側氧基-異吲哚啉-2-基]-4-甲氧基-苯甲酸甲酯(78 mg, 0.13 mmol)於四氫呋喃(1.0 mL)、甲醇(0.1 mL)及水(0.1 mL)中之溶液中添加氫氧化鋰(27 mg, 0.65 mmol)。在室溫下將所得混合物攪拌過夜。用5%鹽酸溶液酸化反應物並用乙酸乙酯萃取。乾燥(Na2
SO4
)有機層,過濾,並在真空中濃縮。藉由反相層析純化粗產物,以提供黃色固體狀2-[4-氯-7-[[2-[[(1R)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]胺基]-3,4-二側氧基-環丁-1-基]胺基]-1-側氧基-異吲哚啉-2-基]-4-甲氧基-苯甲酸(12 mg, 15%)。1
H NMR (400 MHz, DMSO-d 6
) δ 9.93 (s, 1 H), 9.09 (d,J
= 10 Hz, 1 H), 7.90 (d,J
= 9.2, 1 H), 7.66 (d,J
= 8.8, 1 H), 7.49 (d,J
= 9.2, 1 H), 7.19 (d,J
= 2.4, 1 H), 7.04 (dd,J
= 8.8, 2.4, 1 H), 6.06 (d,J
= 3.2 Hz, 1 H), 5.04 (d,J
= 10 Hz, 1 H), 4.83 (dd,J
= 23, 5.6 Hz, 2 H), 3.83 (s, 3 H), 2.15 (s, 3 H), 1.85 (s, 3 H), 0.87 (s, 9 H)。MS: C31
H30
ClN3
O7
[M-H]-
之(ES)m/z
計算值590.2,實驗值590.2。實例 7 : 2-[4- 氯 -7-[[2-[[(1R
)-1-(4,5- 二甲基 -2- 呋喃基 )-2,2- 二甲基 - 丙基 ] 胺基 ]-3,4- 二側氧基 - 環丁 -1- 基 ] 胺基 ]-1- 側氧基 - 異吲哚啉 -2- 基 ]-4- 甲基 - 苯甲酸 步驟 a :
向含有二噁烷(10 mL)中之7-胺基-4-氯-異吲哚啉-1-酮(305 mg, 1.67 mmol)之反應瓶中添加2-溴-5-甲基-苯甲酸甲酯(575 mg, 2.51 mmol)、碳酸銫(1.63 g, 5 mmol)、碘化銅(190 mg, 1.0 mmol)及(1S,2S)-N1,N2-二甲基環己烷-1,2-二胺(285 mg, 2.0 mmol)。用氮吹掃混合物,且然後升溫至110℃。在110℃下將反應物攪拌1小時且藉由LC-MS來監測。完成後,將反應物冷卻,且然後經由矽藻土過濾且用EtOAc沖洗。藉由矽膠層析(0-50%乙酸乙酯/己烷)純化粗製物,以獲得白色固體狀2-(7-胺基-4-氯-1-側氧基-異吲哚啉-2-基)-5-甲基-苯甲酸甲酯(345 mg, 62%)。MS: C17
H15
ClN2
O3
[M+H]+
之(ES)m/z
計算值331.1,實驗值331.1。步驟 b :
向2-(7-胺基-4-氯-1-側氧基-異吲哚啉-2-基)-5-甲基-苯甲酸甲酯(689 mg, 2.08 mmol)於四氫呋喃(10 mL)、甲醇(1 mL)及水(1 mL)中之溶液中添加氫氧化鋰(874 mg, 20.83 mmol)。在60℃下將所得混合物攪拌過夜。然後冷卻反應物,然後用1N鹽酸溶液酸化至pH = 5並用乙酸乙酯/MeOH (10:1)萃取。乾燥(Na2
SO4
)有機層,過濾,並在真空中濃縮。將己烷添加至粗產物中且過濾所得固體並用己烷沖洗,以提供黃色固體狀2-(7-胺基-4-氯-1-側氧基-異吲哚啉-2-基)-4-甲基-苯甲酸(572 mg, 87%)。步驟 c :
在60℃下,將2-(7-胺基-4-氯-1-側氧基-異吲哚啉-2-基)-4-甲基-苯甲酸(570 mg, 1.80 mmol)及3,4-二甲氧基環丁烷-1,2-二酮(307 mg, 2.16 mmol)於無水甲醇(5 mL)中之溶液攪拌過夜。然後將反應混合物冷卻至室溫且過濾。然後用EtOAc洗滌固體並乾燥,以獲得黃色固體狀2-[4-氯-7-[(2-甲氧基-3,4-二側氧基-環丁-1-基)胺基]-1-側氧基-異吲哚啉-2-基]-4-甲基-苯甲酸(565 mg, 71%)。MS: C21
H15
ClN2
O6 [M+H]+
之(ES) m/z計算值427.1,實驗值427.1。步驟 d :
將無水甲醇(2 mL)添加至2-[4-氯-7-[(2-甲氧基-3,4-二側氧基-環丁-1-基)胺基]-1-側氧基-異吲哚啉-2-基]-4-甲基-苯甲酸(60 mg, 0.14 mmol)及(1R
)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙-1-胺(27 mg, 0.15 mmol)之混合物中,且在60℃下將此混合物攪拌過夜。然後濃縮反應物且藉由反相層析純化粗製物,以提供2-[4-氯-7-[[2-[[(1R
)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙基]胺基]-3,4-二側氧基-環丁-1-基]胺基]-1-側氧基-異吲哚啉-2-基]-4-甲基-苯甲酸(30 mg, 37%)。1
H NMR (400 MHz, DMSO-d 6
) δ 9.94 (s, 1 H), 9.09 (d,J
= 10 Hz, 1 H), 7.81 (d,J
= 9.2, 1 H), 7.66 (d,J
= 8.8, 1 H), 7.49 (d,J
= 9.2, 1 H), 7.42 (d,J
= 2.4, 1 H), 7.30 (dd,J
= 8.8, 2.4, 1 H), 6.07 (d,J
= 3.2 Hz, 1 H), 5.04 (d,J
= 10 Hz, 1 H), 4.83 (dd,J
= 23, 5.6 Hz, 2 H), 2.38 (s, 3 H), 2.15 (s, 3 H), 1.85 (s, 3 H), 0.87 (s, 9 H)。MS: C31
H30
ClN3
O6
[M-H]-
之(ES)m/z
計算值574.0,實驗值574.0。實例 8 : 3-[[(1R
)-2,2- 二甲基 -1-(5- 甲基 -2- 呋喃基 ) 丁基 ] 胺基 ]-4-[(5- 氟 -3- 側氧基 - 異吲哚啉 -4- 基 ) 胺基 ] 環丁 -3- 烯 -1,2- 二酮之合成 步驟 a :
將2,2-二甲基丁醛(5.0 g, 50 mmol)及(R
)-第三-丁烷亞磺醯胺(6.36 g, 52.5 mmol)溶解於CH2
Cl2
(100 mL)中,且添加Ti(OEt)4
(85%-95%, 22.81 g,約90 mmol)。在室溫下將反應物攪拌過夜。然後用CH2
Cl2
(200 mL)稀釋反應物,然後添加矽藻土及H2
O (90 mL),同時劇烈攪拌。將混合物攪拌5小時,然後經由矽藻土過濾,用CH2
Cl2
沖洗濾餅。濃縮濾液且在二氧化矽(己烷中之1%至30% EtOAc)上純化,以獲得產物。步驟 b :
在冰上冷卻Et2
O (52 mL)中之2-甲基呋喃(5.06 mL, 56.2 mmol)。逐滴添加N
-BuLi (2.5 M, 22.5 mL, 56.3 mmol)且在冰上將反應物攪拌15分鐘,然後移除該浴並在室溫下繼續攪拌1小時。然後將反應物於冰上再冷卻,且一次性添加MgBr2
(14.5 g, 56.2 mmol)。在冰上將反應物攪拌20分鐘,然後移除該浴並在室溫下繼續攪拌50分鐘。然後於-78℃浴中冷卻反應物,並逐滴添加Et2
O (52 mL)中之(R,E
)-N-(2,2-二甲基亞丁基)-2-甲基-丙烷-2-亞磺醯胺(7.6 g, 37.4 mmol)。將反應物升溫至室溫過夜。添加飽和NH4
Cl水溶液以驟冷,且劇烈攪拌混合物,然後用H2
O稀釋並用EtOAc (3 × 150 mL)萃取。經MgSO4
乾燥合併之有機層,過濾並濃縮以獲得粗製物。然後在二氧化矽(己烷中之5%至40% EtOAc)上純化此粗製物,以獲得異構純產物。步驟 c :
向N
-[(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丁基]-2-甲基-丙烷-2-亞磺醯胺(6.0 g, 21 mmol)中添加MeOH (60 mL)及二噁烷中之HCl (4M, 21 mL, 84 mmol)。在室溫下將此混合物攪拌45分鐘。然後濃縮反應物且在真空下乾燥,以獲得產物。步驟 d :
將Et3
N (0.072 mL, 0.52 mmol)添加至方酸酯(72 mg, 0.26 mmol)及(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丁-1-胺鹽酸鹽(57 mg, 0.26 mmol)於MeOH (1.3 mL)之混合物中。在60℃下將反應物攪拌4小時,然後在室溫下過夜。將矽膠添加至反應物中,濃縮混合物,且藉由矽膠層析(CH2
Cl2
中之1%至10% MeOH)純化此混合物,以獲得產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.65 (s, 1H), 8.71 (s, 1H), 8.39 (d,J
= 10.2 Hz, 1H), 7.47 (dd,J
= 11.2, 8.2 Hz, 1H), 7.33 (dd,J
= 8.3, 3.8 Hz, 1H), 6.17 (d,J
= 3.1 Hz, 1H), 6.06 - 6.02 (m, 1H), 5.11 (d,J
= 10.2 Hz, 1H), 4.32 (s, 2H), 2.27 (s, 3H), 1.36-1.21(m, 2H), 0.94 (s, 3H), 0.88 (s, 3H), 0.83 (t,J
= 7.5 Hz, 3H)。MS: C23
H25
FN3
O4
[M+H]+
之(ES)m/z
計算值426.2,實驗值426.0。實例 9 : 3-[[(1R
)-1-(5- 氯 -2- 呋喃基 )-2,2- 二甲基 - 丙基 ] 胺基 ]-4-[(7- 氯 -3- 側氧基 - 異吲哚啉 -4- 基 ) 胺基 ] 環丁 -3- 烯 -1,2- 二酮之合成 步驟 a :
將5-氯呋喃-2-甲醛(5.0 g, 38 mmol)及(R
)-第三-丁烷亞磺醯胺(4.2 g, 35 mmol)溶解於CH2
Cl2
(75 mL)中,且添加Ti(OEt)4
(85%-95%, 17.6 g, 77 mmol)。在室溫下將反應物攪拌過夜。然後用CH2
Cl2
(150 mL)稀釋反應物,添加Na2
SO4
•10H2
O (100 g),且將混合物攪拌90分鐘。然後經由矽藻土過濾此混合物,用CH2
Cl2
(200 mL)沖洗濾餅。濃縮濾液以獲得產物。步驟 b :
將(R,E
)-N
-[(5-氯-2-呋喃基)亞甲基]-2-甲基-丙烷-2-亞磺醯胺(7.65 g, 32.7 mmol)溶解於CH2
Cl2
(131 mL)中,且在-78℃浴中同時在氮氣氛下冷卻。經由加料漏斗經30分鐘添加t
-BuMgCl (2M於Et2
O中,33 mL, 66 mmol),且然後將反應物攪拌4小時。添加飽和NH4
Cl水溶液,並將混合物升溫至室溫。然後添加H2
O (50 mL)且用CH2
Cl2
(2×)萃取混合物,經Na2
SO4
乾燥,過濾,並濃縮,以獲得非鏡像異構物之混合物。將粗製物吸附至二氧化矽上且藉由管柱層析(CH2
Cl2
中之10%甲基第三丁基醚)純化。收集早期溶析之非鏡像異構物且濃縮,以獲得產物。步驟 c :
將N
-[(1R
)-1-(5-氯-2-呋喃基)-2,2-二甲基-丙基]-2-甲基-丙烷-2-亞磺醯胺(0.98 g, 3.4 mmol)溶解於MeOH (3.4 mL)中,且添加HCl (2M於Et2
O中,3.4 mL, 6.8 mmol)。將反應物攪拌過夜,且然後濃縮。添加Et2
O (25 mL)且將混合物攪拌30分鐘,且然後過濾。用Et2
O (2×)洗滌固體,然後添加KOH水溶液(3M, 5 mL)且用CH2
Cl2
(3×)萃取產物。用KOH水溶液將合併之有機層洗滌兩次(1.5 M),經Na2
SO4
乾燥,過濾,並濃縮,以獲得產物。步驟 d :
將3-[(7-氯-3-側氧基-異吲哚啉-4-基)胺基]-4-甲氧基-環丁-3-烯-1,2-二酮(59 mg, 0.2 mmol)及(1R
)-1-(5-氯-2-呋喃基)-2,2-二甲基-丙-1-胺(38 mg, 0.2 mmol)合併於MeOH (0.2 mL)中,且在室溫下將混合物攪拌過夜。濃縮反應物,然後藉由反相層析(MeCN:含有0.1% TFA之H2
O作為溶析液)純化,以獲得產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.96 (s, 1H), 9.17 (d,J
= 10.0 Hz, 1H), 8.95 (s, 1H), 7.61 (d,J
= 8.7 Hz, 1H), 7.45 (d,J
= 8.7 Hz, 1H), 6.53 - 6.43 (m, 2H), 5.17 (d,J
= 9.9 Hz, 1H), 4.38 (s, 2H), 3.17 (s, 1H), 0.99 (s, 9H)。MS: C21
H20
Cl2
N3
O4
[M + H]+
之(ES)m/z
計算值448.1,實驗值448.1。實例 10 : (R
)-3-((2,2- 二甲基 -1-(5- 甲基呋喃 -2- 基 ) 丙基 ) 胺基 )-4-((5- 氟 -7- 甲基 -3- 側氧基異吲哚啉 -4- 基 ) 胺基 ) 環丁 -3- 烯 -1,2- 二酮 步驟 a :
在室溫下在水浴中,向7-胺基-6-氟異吲哚啉-1-酮(2.4 g, 14.4 mmol)於AcOH (30 mL)中之溶液中逐份添加N
-碘琥珀醯亞胺(4.55 g, 20.2 mmol)。在水浴中將所得混合物攪拌30分鐘,用水(20 mL)驟冷,並用乙酸乙酯(100 mL)萃取。用鹽水(100 mL)洗滌有機層,且然後經MgSO4
乾燥。在減壓下蒸發溶劑,以獲得棕色固體,藉由矽膠層析(己烷中之0-60%乙酸乙酯)純化該固體,以獲得產物。MS: C8
H6
FIN2
O[M+H]+
之(ES)m/z
計算值293.0,實驗值293.0。步驟 b :
向7-胺基-6-氟-4-碘異吲哚啉-1-酮(2.2 g, 7.53 mmol)於二噁烷(44 mL)中之溶液中添加CsF (4.57 g, 30.1 mmol)、2,4,6-三甲基-1,3,5,2,4,6-三氧雜三硼雜環己烷(1.35 g, 22.6 mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II) (551 mg, 0.753 mmol)。在80℃下將所得混合物攪拌過夜。然後將反應物分配於水(100 mL)與乙酸乙酯(100 mL)之間,且用鹽水(80 mL)洗滌有機層,且然後經MgSO4
乾燥。在減壓下蒸發溶劑,以獲得棕色固體,藉由矽膠層析(己烷中之0-80%乙酸乙酯)純化該固體,以獲得產物。MS: C9
H9
FN2
O[M+H]+
之(ES)m/z
計算值181.1,實驗值181.1步驟 c :
在60℃下,將7-胺基-6-氟-4-甲基異吲哚啉-1-酮(200 mg, 1.11 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(189.3 mg, 1.33 mmol)於無水甲醇(3 mL)中之混合物攪拌過夜,且然後在80℃下攪拌5小時。蒸發反應混合物且藉由矽膠層析(己烷中之0-100%乙酸乙酯)純化,以獲得產物。MS: C14
H11
FN2
O4
[M+H]+
之(ES) m/z計算值291.1,實驗值291.1步驟 d :
將無水甲醇(2 mL)添加至3-((5-氟-7-甲基-3-側氧基異吲哚啉-4-基)胺基)-4-甲氧基環丁-3-烯-1,2-二酮(95 mg, 0.327 mmol)及(R
)-2,2-二甲基-1-(5-甲基呋喃-2-基)丙-1-胺(55 mg, 0.329 mmol)之混合物中,且在60℃下將此混合物攪拌過夜。將反應物冷卻至室溫,使其溶解於少量二氯甲烷中,且吸附至矽膠上。藉由矽膠層析(二氯甲烷中之40%乙酸乙酯)純化產物,以獲得產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.46 (s, 1 H), 8.61 (s, 1 H), 8.24 (d,J
= 10.4 Hz, 1 H), 7.21 (d,J
= 11.6 Hz, 1 H), 6.07 (d,J
= 2.4 Hz, 1 H), 5.94 (d,J
= 2.4 Hz, 1 H), 4.90 (s, 2 H), 2.16 (s, 3 H), 2.15 (s, 3 H), 0.90 (s, 9 H)。MS: C23
H24
FN3
O4
[M-H]-
之(ES) m/z計算值426.2,實驗值426.2。實例 11 : (R
)-3-((1-(4,5- 二甲基呋喃 -2- 基 -2,2- 二甲基 丁基 ) 胺基 )-4-((5- 氟 -1,1,7- 三甲基 -3- 側氧基 異吲哚啉 -4- 基 ) 胺基 ) 環丁 -3- 烯 -1,2- 二酮 步驟 a :
在0℃下,向裝填有2-(溴甲基)-5-氟苯甲酸甲酯(25 g, 101 mmol)及THF (300 mL)之500 mL圓底燒瓶中緩慢添加4-甲氧基苄基胺(34.7 g, 253 mmol)。將混合物升溫至室溫過夜。將反應物與乙酸乙酯(300 mL)及HCl (1 N水溶液,200 mL)一起傾倒至2L分液漏斗中。用鹽水(2 × 200 mL)洗滌有機層,且然後經MgSO4
乾燥,過濾,濃縮,且藉由矽膠層析(己烷中之0-30%乙酸乙酯)純化,以獲得6-氟-2-(4-甲氧基苄基)異吲哚啉-1-酮。MS: C16
H14
FNO2
[M+H]+
之(ES)m/z
計算值272.1,實驗值272.1。步驟 b :
在0℃下,向6-氟-2-(4-甲氧基苄基)異吲哚啉-1-酮(10 g, 36.9 mmol)於THF (50 mL)中之溶液中添加NaH (7.4 g, 184.5 mmol)。在氮下將所得混合物攪拌30分鐘。在0℃下向反應混合物中添加碘甲烷(31.4 g, 221.2 mmol),然後在70℃下將此混合物加熱過夜,冷卻至室溫,用水(40 mL)驟冷,並用乙酸乙酯(100 mL)萃取。用鹽水(100 mL)洗滌有機層並經MgSO4
乾燥。濃縮溶劑,以獲得粗製物,藉由矽膠層析(己烷中之0-80%乙酸乙酯)純化該粗製物,以獲得6-氟-2-(4-甲氧基苄基)-3,3-二甲基異吲哚啉-1-酮。MS: C18
H18
FNO2
[M+H]+
之(ES)m/z
計算值300.1,實驗值300.1。步驟 c :
在100℃下,將6-氟-2-(4-甲氧基苄基)-3,3-二甲基異吲哚啉-1-酮(5 g, 16.7 mmol)於TFA (25 mL)及茴香醚(5 mL)中之溶液加熱過夜。將反應混合物傾倒至冰(20 g)上,用飽和NaHCO3
水溶液(50 mL)中和並用乙酸乙酯(100 mL)萃取。用鹽水(100 mL)洗滌有機層,且然後經MgSO4
乾燥。在減壓下蒸發溶劑,以獲得粗製物,藉由矽膠層析(己烷中之0-100%乙酸乙酯)純化該粗製物,以獲得6-氟-3,3-二甲基異吲哚啉-1-酮。MS: C10
H10
FNO [M+H]+
之(ES)m/z
計算值180.1,實驗值180.1。步驟 d :
向6-氟-3,3-二甲基異吲哚啉-1-酮(3.1 g, 17.3 mmol)於濃H2
SO4
(12 mL)中之0℃懸浮液中逐滴添加硝酸(1.34 mL),同時將反應混合物保持在5℃以下。添加後,將反應混合物緩慢升溫至室溫過夜。將冰(20 g)添加至混合物中且過濾固體,然後用MTBE (50 mL)及乙酸乙酯(50 mL)洗滌,以獲得6-氟-3,3-二甲基-7-硝基異吲哚啉-1-酮。MS: C10
H9
FN2
O3
[M+H]+
之(ES)m/z
計算值225.1,實驗值225.1。步驟 e :
在氫氣氛(35 psi)下,將6-氟-3,3-二甲基-7-硝基異吲哚啉-1-酮(2.0 g, 8.93 mmol)及10% Pd/C (50%潤濕,0.89 g, 0.45 mmol, 0.05當量)於MeOH (50 mL)中之溶液振盪2小時。經由矽藻土過濾固體且在減壓下濃縮濾液,以獲得粗製物,藉由矽膠層析(100%乙酸乙酯)純化該粗製物,以獲得7-胺基-6-氟-3,3-二甲基異吲哚啉-1-酮。MS: C10
H11
FN2
O [M+H]+
之(ES)m/z
計算值195.1,實驗值195.1。步驟 f :
在室溫下在室溫水浴中,向7-胺基-6-氟-3,3-二甲基異吲哚啉-1-酮(150 mg, 0.77 mmol)於AcOH (2 mL)中之溶液中逐份添加N-碘琥珀醯亞胺(244 mg, 1.08 mmol)。在水浴中將所得混合物攪拌30分鐘,用水(1 mL)驟冷並用乙酸乙酯(10 mL)萃取。用鹽水(10 mL)洗滌有機層,且然後經MgSO4
乾燥。在減壓下蒸發溶劑,以獲得粗製物,藉由矽膠層析(己烷中之0-60%乙酸乙酯)純化該粗製物,以獲得7-胺基-6-氟-4-碘-3,3-二甲基異吲哚啉-1-酮。MS: C10
H10
FIN2
O [M+H]+
之(ES)m/z
計算值321.0,實驗值321.0。步驟 g :
向7-胺基-6-氟-4-碘-3,3-二甲基異吲哚啉-1-酮(370 mg, 1.16 mmol)於二噁烷(12 mL)中之溶液中添加CsF (705 mg, 4.64 mmol)、2,4,6-三甲基-1,3,5,2,4,6-三氧雜三硼雜環己烷(435 mg, 3.47 mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II) (95 mg, 0.116 mmol)。在80℃下將所得混合物攪拌過夜,然後冷卻至室溫。將反應物分配於水(20 mL)與乙酸乙酯(30 mL)之間。用鹽水(20 mL)洗滌有機層,且然後經MgSO4
乾燥,過濾,並濃縮,以獲得粗製物,藉由矽膠層析(己烷中之0-80%乙酸乙酯)純化該粗製物,以獲得7-胺基-6-氟-3,3,4-三甲基異吲哚啉-1-酮。MS: C11
H13
FN2
O [M+H]+
之(ES)m/z
計算值209.1,實驗值209.1。步驟 h :
在60℃下,將7-胺基-6-氟-3,3,4-三甲基異吲哚啉-1-酮(129 mg, 0.62 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(176.3 mg, 1.24 mmol)於無水甲醇(2.5 mL)中之混合物攪拌過夜,且然後在80℃下攪拌5小時。濃縮反應混合物,且藉由矽膠層析(己烷中之0-100%乙酸乙酯)純化粗製物,以獲得3-((5-氟-1,1,7-三甲基-3-側氧基異吲哚啉-4-基)胺基)-4-甲氧基環丁-3-烯-1,2-二酮。MS: C16
H15
FN2
O4
[M+H]+
之(ES) m/z計算值319.1,實驗值319.1。步驟 i :
將無水甲醇(2 mL)添加至3-((5-氟-1,1,7-三甲基-3-側氧基異吲哚啉-4-基)胺基)-4-甲氧基環丁-3-烯-1,2-二酮(22 mg, 0.07 mmol)及(R)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丁-1-胺(15 mg, 0.077 mmol)之混合物中,且在60℃下將此混合物攪拌過夜。將反應物冷卻至室溫,溶解於少量二氯甲烷中,且吸附至矽膠上。藉由矽膠層析(二氯甲烷中之40%乙酸乙酯)純化此混合物,以獲得標題化合物。1
H NMR (400 MHz, Cd3
OD) δ 7.21 (d,J
= 12 Hz, 1 H), 6.04 (s, 1 H), 5.16 (d,J
= 4.10 Hz, 1 H), 2.47 (s, 3 H), 2.19 (s, 3 H), 1.92 (s, 3 H), 1.60 (s, 6 H), 1.40 (q,J
= 7.6 Hz, 2 H), 1.03 (s, 3 H), 0.97 (s, 3 H), 0.91 (t,J
= 7.6 Hz, 3 H)。MS: C27
H32
FN3
O4
[M-H]-
之(ES) m/z計算值482.2,實驗值482.2。實例 12 : (R
)-3-((7- 氯 -2-(3- 甲基 -1H- 吡唑 -5- 基 )-3- 側氧基 異吲哚啉 -4- 基 ) 胺基 )-4-((2,2- 二甲基 -1-(5- 甲基呋喃 -2- 基 ) 丙基 ) 胺基 ) 環丁 -3- 烯 -1,2- 二酮 之合 成 步驟 a :
向2-(溴甲基)-3-氯-6-硝基苯甲酸甲酯(500 mg, 1.62 mmol)及3-甲基-1H-吡唑-5-胺(158 mg, 1.62 mmol)於無水四氫呋喃(3 ml)中之溶液中添加三乙胺(0.5 ml, 3.56 mmol)。在密封的40 mL反應瓶中將所得反應溶液加熱至60℃並保持1小時。在反應期間固體發生沈澱。然後將反應物冷卻至室溫,並過濾。用二氯甲烷沖洗固體,以提供產物。MS: C12
H9
ClN4
O3
[M+H]+
之(ES)m/z
計算值293.0,實驗值293.0。步驟 b :
在室溫下,向4-氯-2-(3-甲基-1H-吡唑-5-基)-7-硝基異吲哚啉-1-酮(266 mg, 0.91 mmol)於乙醇中之攪拌混合物中添加鐵粉(203 mg, 3.60 mmol),然後添加二噁烷中之4 M HCl (0.91 ml, 3.64 mmol)。在室溫下將反應混合物攪拌1小時,然後濃縮至乾燥。用乙酸乙酯稀釋殘餘物且用飽和碳酸氫鈉溶液中和並用乙酸乙酯(2 × 5 ml)萃取。乾燥(Na2
SO4
)合併之有機層,過濾,並在真空中濃縮。藉由矽膠層析(己烷中之0-100%乙酸乙酯)純化粗製物,以提供產物。MS: C12
H11
ClN4
O [M+H]+
之(ES)m/z
計算值263.0,實驗值263.0。步驟 c :
向7-胺基-4-氯-2-(3-甲基-1H-吡唑-5-基)異吲哚啉-1-酮(200 mg, 0.76 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(130 mg, 0.91 mmol)於甲醇(1 ml)中之漿液中添加二噁烷中之4 M HCl (0.19 ml, 0.76 mmol)。將反應混合物升溫至60℃且攪拌1小時。然後將其冷卻至室溫,過濾且用甲醇沖洗,以獲得產物。MS: C17
H13
ClN4
O4
[M+H]+
之(ES)m/z
計算值373.0,實驗值373.0。步驟 d :
向3-((7-氯-2-(3-甲基-1H-吡唑-5-基)-3-側氧基異吲哚啉-4-基)胺基)-4-甲氧基環丁-3-烯-1,2-二酮(100 mg, 0.27 mmol)於甲醇(1 ml)中之漿液中添加(R
)-2,2-二甲基-1-(5-甲基呋喃-2-基)丙-1-胺(45 mg, 0.27 mmol)及三乙胺(0.04 ml, 0.27 mmol)。在室溫下將所得混合物攪拌過夜,且然後用二氯甲烷稀釋。藉由過濾移除固體且將濾液濃縮至乾燥。藉由反相層析純化此濾液,以提供產物。1
H NMR (400 MHz, DMSO-d 6
) δ 12.33 (s, 1H), 10.00 (s, 1 H), 9.13 (d,J
= 10 Hz, 1 H), 7.63 (d,J
= 10 Hz, 1 H), 7.46 (d,J
= 10 Hz, 1 H), 6.56 (s, 1 H), 6.20 (d,J
= 3.2 Hz, 1 H), 6.04 (d,J
= 3.2 Hz, 1 H), 5.12 (d,J
= 10 Hz, 1 H), 4.85 (s, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 0.97 (s, 9 H)。MS: C26
H26
ClN5
O4
[M-H]-
之(ES)m/z
計算值506.1,實驗值506.1。實例 13 : (R
)-3-((7- 氯 -5- 氟 -1,1- 二甲基 -3- 側氧基 異吲哚啉 -4- 基 ) 胺基 )-4-((2,2- 二甲基 -1-(5- 甲基呋喃 -2- 基 ) 丙基 ) 胺基 ) 環丁 -3- 烯 -1,2- 二酮 之合 成 步驟 a :
在90℃下,將2-溴-5-氟苯甲酸甲酯(5.00 g, 21.5 mmol)及氰化銅(2.12 g, 23.6 mmol)於DMF中之混合物加熱1天,然後冷卻至室溫,用乙酸乙酯(300 mL)稀釋,且過濾。用鹽水(5×50 mL)洗滌濾液,且然後用飽和NaHCO3
水溶液(50 mL)洗滌。經MgSO4
乾燥有機層,過濾,並在真空中濃縮。此產物不經進一步純化即用於下一步驟中。MS: C9
H6
FNO2
[M+H]+
之(ES)m/z
計算值180.0,實驗值180.0。步驟 b :
在0℃下,向2-氰基-5-氟苯甲酸甲酯(3.85 g, 21.5 mmol)於四氫呋喃(30 mL)及水(3 mL)中之攪拌溶液中添加氫氧化鋰一水合物(1.11 g, 26.5 mmol)。將反應物升溫至室溫且攪拌1小時。然後蒸發溶劑且用水(100 mL)及2 M HCl水溶液(20 mL)稀釋殘餘物。藉由過濾收集固體且在真空下乾燥,以獲得期望產物。MS: C8
H4
FNO2
[M+H]+
之(ES)m/z
計算值166.0,實驗值166.0。步驟 c :
在-78℃下,向2-氰基-5-氟苯甲酸(1.70 g, 10.3 mmol)於無水四氫呋喃(105 mL)中之攪拌溶液中逐滴添加甲基鋰於醚中之1.6 M溶液(25.74 mL, 41.2 mmol)。在-78℃下將混合物攪拌1小時,且然後緩慢升溫至室溫,用飽和氯化銨水溶液驟冷,並用乙酸乙酯萃取。藉由矽膠層析(己烷中之0-100%乙酸乙酯)純化有機層,以獲得6-氟-3,3-二甲基異吲哚啉-1-酮。MS: C10
H10
FNO [M+H]+
之(ES)m/z
計算值180.0,實驗值180.0。步驟 d :
在冰浴中冷卻含有濃H2
SO4
(1 mL)中之6-氟-3,3-二甲基異吲哚啉-1-酮(620 mg, 3.46 mmol)之反應瓶。逐滴添加濃H2
SO4
(1 mL)與70% HNO3
(0.25 mL, 3.8 mmol)之混合物且在0℃下將反應混合物攪拌2小時,然後用冰小心地驟冷並用冷水稀釋至10 mL。過濾固體,用水洗滌且在真空下乾燥,以獲得6-氟-3,3-二甲基-7-硝基異吲哚啉-1-酮。MS: C10
H9
FN2
O3
[M+H]+
之(ES)m/z
計算值225.0,實驗值225.0。步驟 e :
在室溫下,向6-氟-3,3-二甲基-7-硝基異吲哚啉-1-酮(0.56 g, 2.50 mmol)於乙醇(10 mL)及水(1 mL)中之溶液中添加鐵粉(0.58 g, 10.38 mmol)及氯化銨(1.90 g, 34.6 mmol)。將反應混合物升溫至90℃且攪拌1小時。然後將反應物冷卻至室溫,經由矽藻土過濾且用甲醇(20 ml)沖洗。將濾液濃縮至乾燥且用乙酸乙酯稀釋殘餘物,然後用水及鹽水洗滌。乾燥(Na2
SO4
)合併之有機層,過濾,在真空中濃縮,且藉由矽膠層析(己烷中之0-100%乙酸乙酯)純化,以提供7-胺基-6-氟-3,3-二甲基異吲哚啉-1-酮。MS: C10
H11
FN2
O [M+H]+
之(ES)m/z
計算值195.0,實驗值195.0。步驟 f :
在室溫下,向7-胺基-6-氟-3,3-二甲基異吲哚啉-1-酮(116 mg, 0.59 mmol)於乙酸(1 mL)中之溶液中添加N-氯琥珀醯亞胺(80 mg, 0.59 mmol)。將反應混合物升溫至45℃且攪拌過夜。然後將其冷卻至室溫,用乙酸乙酯稀釋,並用水及鹽水洗滌。乾燥(Na2
SO4
)合併之有機層,過濾,並在真空中濃縮。藉由矽膠層析(己烷中之0-30%乙酸乙酯)純化粗製物,以提供7-胺基-4-氯-6-氟-3,3-二甲基異吲哚啉-1-酮。MS: C10
H10
ClFN2
O [M+H]+
之(ES)m/z
計算值229.0,實驗值229.0。步驟 g :
向7-胺基-4-氯-6-氟-3,3-二甲基異吲哚啉-1-酮(73 mg, 0.32 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(54 mg, 0.38 mmol)於甲醇(3 mL)中之漿液中添加二噁烷中之4 M HCl (0.08 mL, 0.32 mmol)。將反應混合物升溫至60℃且攪拌1小時。然後將其冷卻至室溫並用二氯甲烷(2 ml)稀釋以產生澄清溶液。在真空中濃縮此溶液。藉由矽膠層析(二氯甲烷中之0-10%甲醇)純化粗製物,以提供期望產物。MS: C15
H12
ClFN2
O4
[M+H]+
之(ES)m/z
計算值338.0,實驗值338.0。步驟 h :
向3-((7-氯-5-氟-1,1-二甲基-3-側氧基異吲哚啉-4-基)胺基)-4-甲氧基環丁-3-烯-1,2-二酮(71 mg, 0.21 mmol)於甲醇(2 mL)中之漿液中添加(R
)-2,2-二甲基-1-(5-甲基呋喃-2-基)丙-1-胺(35 mg, 0.21 mmol)及三乙胺(0.03 mL, 0.21 mmol)。在室溫下將所得混合物攪拌過夜,且然後用二氯甲烷稀釋。然後藉由矽膠層析(二氯甲烷中之0-10%甲醇)純化此混合物,以提供標題化合物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.61 (s, 1 H), 8.97 (s, 1 H), 8.40 (d,J
= 10 Hz, 1 H), 7.62 (d,J
= 10 Hz, 1 H), 6.10 (d,J
= 2.6 Hz, 1 H), 5.95 (d,J
= 2.6 Hz, 1 H), 4.92 (d,J
= 10 Hz, 1 H), 2.19 (s, 3 H), 1.46 (s, 6 H), 0.87 (s, 9 H)。MS: C24
H25
ClFN3
O4
[M-H]-
之(ES)m/z
計算值472.0,實驗值472.0。實例 14 : 3-[(7- 氯 -5- 氟 -1,1- 二甲基 -3- 側氧基 - 異吲哚啉 -4- 基 ) 胺基 ]-4-[[(1R
)-1-(4,5- 二甲基 -2- 呋喃基 )-2,2- 二甲基 - 丙基 ] 胺基 ] 環丁 -3- 烯 -1,2- 二酮 之合 成 向3-((7-氯-5-氟-1,1-二甲基-3-側氧基異吲哚啉-4-基)胺基)-4-甲氧基環丁-3-烯-1,2-二酮(15 mg, 0.04 mmol)於甲醇(2 ml)中之漿液中添加(R
)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丙-1-胺(11 mg, 0.05 mmol)及三乙胺(0.01 ml, 0.05 mmol)。在室溫下將所得混合物攪拌過夜且濃縮至乾燥。藉由反相層析純化粗製物,以提供產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.68 (s, 1 H), 9.06 (s, 1 H), 8.44 (d,J
= 10 Hz, 1 H), 7.70 (d,J
= 10 Hz, 1 H), 6.08 (s, 1 H), 4.94 (d,J
= 10 Hz, 1 H), 2.17 (s, 3 H), 1.87 (s, 3 H), 1.54 (s, 6 H), 0.94 (s, 9 H)。MS: C25
H27
ClFN3
O4
[M-H]-
之(ES)m/z
計算值486.0,實驗值486.0。實例 15 : 3-[[7- 氯 -3- 側氧基 -2-[2-(5- 側氧基 -1H- 四唑 -4- 基 ) 乙基 ] 異吲哚啉 -4- 基 ] 胺基 ]-4-[[(1R
)-2,2- 二甲基 -1-(5- 甲基 -2- 呋喃基 ) 丙基 ] 胺基 ] 環丁 -3- 烯 -1,2- 二酮 之合 成 步驟 a :
向2-(溴甲基)-3-氯-6-硝基苯甲酸甲酯(10.0 g, 32.4 mmol)及3-胺基丙酸乙酯鹽酸鹽(5.5 g, 35.6 mmol)於四氫呋喃(120 ml)中之混合物添加三乙胺(10 ml, 71.3 mmol)。在室溫下將反應混合物攪拌過夜。然後用乙酸乙酯稀釋反應物,並用水及鹽水洗滌。乾燥(Na2
SO4
)合併之有機層,過濾,且在真空中濃縮,以獲得產物,其不經進一步純化即使用。MS: C13
H13
ClN2
O5
[M+H]+
之(ES)m/z
計算值313.0,實驗值313.0。步驟 b :
在室溫下,向3-(4-氯-7-硝基-1-側氧基異吲哚啉-2-基)丙酸乙酯(10.1 g, 32.4 mmol)於乙醇(90 ml)及水(10 ml)中之溶液添加鐵粉(6.0 g, 97.2 mmol)及氯化銨(9.0 g, 162 mmol)。將反應混合物升溫至90℃且攪拌1小時。然後將其冷卻至室溫,經由矽藻土過濾且用甲醇(120 ml)沖洗。將濾液濃縮至乾燥且用乙酸乙酯稀釋殘餘物,用水洗滌,且然後用鹽水洗滌。乾燥(Na2
SO4
)合併之有機層,過濾,且在真空中濃縮,
以獲得產物,其不經進一步純化即使用。MS: C13
H15
ClN2
O3
[M+H]+
之(ES)m/z
計算值283.0,實驗值283.0。步驟 c :
在室溫下,向3-(7-胺基-4-氯-1-側氧基異吲哚啉-2-基)丙酸乙酯(6.60 g, 23.2 mmol)於四氫呋喃(40 ml)中之溶液添加二碳酸二第三丁基酯(12.67 g, 58.0 mmol)及4-二(甲基胺基)吡啶(142 mg, 1.16 mmol)。將反應混合物升溫至100℃且攪拌過夜。然後將其冷卻至室溫,用飽和NaHCO3
水溶液(100 ml)稀釋且攪拌20分鐘。然後用乙酸乙酯稀釋反應混合物,且用水洗滌,然後用鹽水洗滌。乾燥(Na2
SO4
)合併之有機層,過濾,並在真空中濃縮。藉由矽膠層析(己烷中之0-40%乙酸乙酯)純化粗產物,以提供產物。MS: C23
H31
ClN2
O7
[M+Na]+
之(ES)m/z
計算值505.0,實驗值505.0。步驟 d :
在室溫下,向3-[7-[雙(第三丁氧基羰基)胺基]-4-氯-1-側氧基-異吲哚啉-2-基]丙酸乙酯(7.43 g, 15.4 mmol)於四氫呋喃(40 ml)、甲醇(4 ml)及水(4 ml)中之溶液中添加氫氧化鋰一水合物(1.9 g, 46.2 mmol)。將反應混合物攪拌過夜,然後濃縮至乾燥,且用1 M HCl將殘餘物酸化至pH = 4。然後用乙酸乙酯萃取混合物,且用水及鹽水洗滌。乾燥(Na2
SO4
)合併之有機層,過濾,且在真空中濃縮,
以獲得產物,其不經進一步純化即使用。MS: C21
H27
ClN2
O7
[M+H]+
之(ES)m/z
計算值455.0,實驗值455.0。步驟 e :
在0℃下,向3-[7-[雙(第三丁氧基羰基)胺基]-4-氯-1-側氧基-異吲哚啉-2-基]丙酸(4.66g, 10.2 mmol)於二氯甲烷(40 ml)中之漿液中逐滴添加草醯氯(1.3 ml, 15.4 mmol)。添加後,添加兩滴DMF。在0℃下將反應混合物攪拌10分鐘,然後升溫至室溫並保持3小時。將所得溶液濃縮至乾燥。將殘餘物溶解於二氯甲烷(40 ml)中且再濃縮至乾燥以移除過量草醯氯。粗製物不經進一步純化即用於下一步驟中。步驟 f :
在室溫下同時在氮氣氛下,將疊氮基三甲基矽烷一次性添加至上述醯氯中。將混合物加熱至100℃並保持2小時,且然後冷卻至室溫。然後將混合物濃縮至乾燥以移除過量疊氮基三甲基矽烷。用乙酸乙酯稀釋粗製物且用1 M HCl水溶液酸化至pH = 3。用水洗滌有機層,然後用鹽水洗滌。乾燥(Na2
SO4
)合併之有機層,過濾,並在真空中濃縮。藉由矽膠層析(己烷中之0-100%乙酸乙酯)純化粗產物,以提供產物。MS: C21
H27
ClN6
O6
[M+Na]+
之(ES)m/z
計算值517.0,實驗值517.0。步驟 g :
在室溫下,向N
-第三丁氧基羰基-N
-[7-氯-3-側氧基-2-[2-(5-側氧基-1H-四唑-4-基)乙基]異吲哚啉-4-基]胺基甲酸第三丁基酯(135 mg, 0.27 mmol)於二氯甲烷(1 ml)中之溶液中添加三氟乙酸(0.25 ml)。在室溫下將反應混合物攪拌1小時,且然後用飽和NaHCO3
水溶液中和。用二氯甲烷萃取混合物,然後用水及鹽水洗滌有機層。乾燥(Na2
SO4
)合併之有機層,過濾,並在真空中濃縮。藉由矽膠層析(己烷中之0-100%乙酸乙酯)純化粗產物,以提供產物。MS: C11
H11
ClN6
O2
[M+H]+
之(ES)m/z
計算值295.0,實驗值295.0。步驟 h :
向7-胺基-4-氯-2-(2-(5-側氧基-4,5-二氫-1H-四唑-1-基)乙基)異吲哚啉-1-酮(60 mg, 0.21 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(44 mg, 0.31 mmol)於甲醇(1 ml)中之漿液中添加二噁烷中之4 M HCl (0.05 ml, 0.21 mmol)。將所得澄清溶液升溫至60℃且攪拌1小時,且在此時間期間固體發生沈澱。將反應混合物冷卻至室溫,且過濾固體並用乙酸乙酯(2 ml)沖洗,以提供產物。MS: C16
H13
ClN6
O5
[M-H]-
之(ES)m/z
計算值403.0,實驗值403.0。步驟 i :
向3-((7-氯-3-側氧基-2-(2-(5-側氧基-4,5-二氫-1H-四唑-1-基)乙基)異吲哚啉-4-基)胺基)-4-甲氧基環丁-3-烯-1,2-二酮(40 mg, 0.10 mmol)於甲醇(2 ml)中之漿液中添加(R)-2,2-二甲基-1-(5-甲基呋喃-2-基)丙-1-胺(20 mg, 0.12 mmol)及一滴三乙胺。在室溫下將所得混合物攪拌過夜,且然後濃縮至乾燥。藉由矽膠層析(己烷中之0-100%乙酸乙酯)純化粗製物,以提供產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.84 (s, 1 H), 9.11 (d,J
= 10 Hz, 1 H), 7.58 (d,J
= 8 Hz, 1 H), 7.42 (d,J
= 8 Hz, 1 H), 6.18 (d,J
= 2.6 Hz, 1 H), 6.03 (d,J
= 2.6 Hz, 1 H), 5.10 (d,J
= 10.4 Hz, 1 H), 4.54 (s, 2 H), 4.22 (t,J
= 5.6, 5.6 Hz, 2 H), 3.85 (t,J
= 5.6, 5.6 Hz, 2 H), 2.27 (s, 3 H), 0.95 (s, 9 H)。MS: C25
H26
ClN7
O5
[M-H]-
之(ES)m/z
計算值538.0,實驗值538.0。實例 16 : (R
)-3-((7- 氯 -2-(2-(4- 甲基 -5- 側氧基 -4,5- 二氫 -1H- 四唑 -1- 基 ) 乙基 )-3- 側氧基 異吲哚啉 -4- 基 ) 胺基 )-4-((2,2- 二甲基 -1-(5- 甲基呋喃 -2- 基 ) 丙基 ) 胺基 ) 環丁 -3- 烯 -1,2- 二酮 之合 成 步驟 a :
在室溫下,向第三丁基N
-第三丁氧基羰基-N
-[7-氯-3-側氧基-2-[2-(5-側氧基-1H-四唑-4-基)乙基]異吲哚啉-4-基]胺基甲酸酯(100 mg, 0.20 mmol)於DMF (1 ml)中之溶液中添加碳酸鉀(70 mg, 0.51 mmol)及碘甲烷。在室溫下將反應混合物攪拌2小時,且然後用水驟冷。固體發生沈澱並過濾,且然後用水及己烷沖洗。在真空下乾燥所收集之固體以提供產物。MS: C22
H29
ClN6
O6
[M+H]+
之(ES)m/z
計算值509.0,實驗值509.0。步驟 b :
在室溫下,向N
-第三丁氧基羰基-N-[7-氯-2-[2-(4-甲基-5-側氧基-四唑-1-基)乙基]-3-側氧基-異吲哚啉-4-基]胺基甲酸第三丁基酯(80 mg, 0.16 mmol)於二氯甲烷(1 ml)中之溶液中添加三氟乙酸(0.25 mL)。在室溫下將反應混合物攪拌1小時,且然後用飽和NaHCO3
水溶液中和。用二氯甲烷萃取混合物,並用水洗滌有機層,且然後用鹽水洗滌。乾燥(Na2
SO4
)合併之有機層,過濾,並在真空中濃縮。藉由矽膠層析(己烷中之0-100%乙酸乙酯)純化粗製物,以提供產物。MS: C12
H13
ClN6
O2
[M+H]+
之(ES)m/z
計算值309.0,實驗值309.0。步驟 c :
向7-胺基-4-氯-2-(2-(4-甲基-5-側氧基-4,5-二氫-1H-四唑-1-基)乙基)異吲哚啉-1-酮(31 mg, 0.10 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(21 mg, 0.15 mmol)於甲醇(1 ml)中之漿液中添加二噁烷中之4 M HCl (0.025 ml, 0.10 mmol)。將所得澄清溶液升溫至60℃且攪拌1小時。將反應混合物冷卻至室溫且過濾固體沈澱,且然後用乙酸乙酯(2 ml)沖洗,以提供產物。MS: C17
H15
ClN6
O5
[M-H]-
之(ES)m/z
計算值417.0,實驗值417.0。步驟 d :
向3-((7-氯-2-(2-(4-甲基-5-側氧基-4,5-二氫-1H-四唑-1-基)乙基)-3-側氧基異吲哚啉-4-基)胺基)-4-甲氧基環丁-3-烯-1,2-二酮(32 mg, 0.076 mmol)於甲醇(2 ml)中之漿液中添加(R
)-2,2-二甲基-1-(5-甲基呋喃-2-基)丙-1-胺(15 mg, 0.09 mmol)及一滴三乙胺。在室溫下將所得混合物攪拌過夜且濃縮至乾燥。藉由矽膠層析(己烷中之0-100%乙酸乙酯)純化粗製物,以提供產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.85 (s, 1 H), 9.10 (d,J
= 10 Hz, 1 H), 7.59 (d,J
= 8.8 Hz, 1 H), 7.44 (d,J
= 8.8 Hz, 1 H), 6.18 (d,J
= 2.8 Hz, 1 H), 6.03 (d,J
= 2.8 Hz, 1 H), 5.10 (d,J
= 10.4 Hz, 1 H), 4.54 (s, 2 H), 4.22 (t,J
= 5.6, 5.6 Hz, 2 H), 3.86 (t,J
= 5.6, 5.6 Hz, 2 H), 2.27 (s, 3 H), 0.95 (s, 9 H)。MS: C26
H28
ClN7
O5
[M-H]-
之(ES)m/z
計算值552.0,實驗值552.0。實例 17 : 2-[4- 氯 -7-[[2-[[(1R
)-1-(5- 氯 -2- 呋喃基 )-2,2- 二甲基 - 丙基 ] 胺基 ]-3,4- 二側氧基 - 環丁 -1- 基 ] 胺基 ]-1- 側氧基 - 異吲哚啉 -2- 基 ]-6- 甲氧基 - 吡啶 -3- 甲酸 之合 成 步驟 a :
向含有二噁烷(2.0 mL)中之7-胺基-4-氯-異吲哚啉-1-酮(365 mg, 2.0 mmol)之反應瓶中添加2-氯-6-甲氧基菸酸甲酯(603 mg, 3.0 mmol)、碳酸銫(1.3 g, 4.0 mmol)、碘化銅(152 mg, 80 mmol)及(1S
,2S
)-N
1,N
2-二甲基環己烷-1,2-二胺(227 mg, 1.6 mmol)。用氮吹掃混合物,然後升溫至110℃。在110℃下攪拌反應物且藉由LC-MS來監測。完成後,將反應物冷卻,且然後經由矽藻土過濾並用乙酸乙酯沖洗。藉由矽膠層析(0-50%乙酸乙酯/己烷)純化粗製物,以獲得產物。步驟 b :
向2-(7-胺基-4-氯-1-側氧基-異吲哚啉-2-基)-6-甲氧基-吡啶-3-甲酸甲酯(440 mg, 1.27 mmol)於四氫呋喃(5.0 mL)、甲醇(0.5 mL)及水(0.5 mL)中之溶液中添加氫氧化鋰(533 mg, 12.7 mmol)。在室溫下攪拌所得混合物。完成後,使用1N HCl水溶液將反應物酸化至pH 5-7並用乙酸乙酯萃取。用鹽水洗滌有機層,乾燥(Na2
SO4
),過濾,並在真空中濃縮以獲得產物。步驟 c :
在60℃下,將2-(7-胺基-4-氯-1-側氧基-異吲哚啉-2-基)-6-甲氧基-吡啶-3-甲酸(334 mg, 1.00 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(156 mg, 1.10 mmol)於無水甲醇(5 mL)中之混合物攪拌3小時。然後過濾反應混合物,且用乙酸乙酯洗滌固體,然後乾燥,以獲得產物。步驟 d :
將Et3
N (0.08 mL, 0.6 mmol)添加至2-[4-氯-7-[(2-甲氧基-3,4-二側氧基-環丁-1-基)胺基]-1-側氧基-異吲哚啉-2-基]-6-甲氧基-吡啶-3-甲酸(97 mg, 0.22 mmol)及(1R
)-1-(5-氯-2-呋喃基)-2,2-二甲基-丙-1-胺(45 mg, 0.24 mmol)於MeOH (3.0 mL)中之混合物中。在60℃下將反應物攪拌4小時,且然後濃縮。藉由反相層析(MeCN:含有0.1% TFA之H2
O作為溶析液)純化所得粗製物,以獲得產物。1
H NMR (400 MHz,甲醇-d 4
) δ 8.20 (d,J
= 8.5 Hz, 1H), 7.94 (d,J
= 8.9 Hz, 1H), 7.62 (d,J
= 8.8, 1H), 6.81 (d,J
= 8.6 Hz, 1H), 6.39 (s, 1H), 6.25 (d,J
= 3.5 Hz, 1H), 5.28 (s, 1H), 5.17 (s, 2H), 4.02 (s, 3H), 1.06 (s, 9H)。MS: C28
H23
Cl2
N4
O7
[M-H]-
之(ES)m/z
計算值597.1,實驗值597.1。實例 18 : 2-[4- 氯 -7-[[2-[[(1R
)-1-(4,5- 二甲基 -2- 呋喃基 )-2,2- 二甲基 - 丙基 ] 胺基 ]-3,4- 二側氧基 - 環丁 -1- 基 ] 胺基 ]-1- 側氧基 - 異吲哚啉 -2- 基 ]-6- 甲氧基 - 吡啶 -3- 甲酸之合成 將Et3
N (0.08 mL, 0.6 mmol)添加至2-[4-氯-7-[(2-甲氧基-3,4-二側氧基-環丁-1-基)胺基]-1-側氧基-異吲哚啉-2-基]-6-甲氧基-吡啶-3-甲酸(90 mg, 0.15 mmol)及(1R
)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙-1-胺鹽酸鹽(45 mg, 0.23 mmol)於MeOH (3.0 mL)中之混合物中。在60℃下將反應物攪拌4小時,然後濃縮。藉由反相層析(MeCN:含有0.1% TFA之H2
O作為溶析液)純化所得粗製物,以獲得產物。1
H NMR (400 MHz,甲醇-d 4
) δ 8.19 (d,J
= 8.5 Hz, 1H), 7.92 (d,J
= 9.1 Hz, 1H), 7.61 (d,J
= 8.8 Hz, 1H), 6.80 (d,J
= 8.6 Hz, 1H), 6.06 (s, 1H), 5.24 - 5.09 (m, 3H), 4.02 (s, 3H), 2.18 (s, 3H), 1.91 (s, 3H), 1.04 (s, 9H)。MS: C30
H28
ClN4
O7
[M-H]-
之(ES)m/z
計算值591.2,實驗值591.1。實例 19 : 3-[[(1R
)-1-(4,5- 二甲基 -2- 呋喃基 )-2,2- 二甲基 - 丙基 ] 胺基 ]-4-[(5- 氟 -3- 側氧基 - 異吲哚啉 -4- 基 ) 胺基 ] 環丁 -3- 烯 -1,2- 二酮之合成
將Et3
N (0.08 mL, 0.6 mmol)添加至3-[(5-氟-3-側氧基-異吲哚啉-4-基)胺基]-4-甲氧基-環丁-3-烯-1,2-二酮(81 mg, 0.30 mmol)及(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丁-1-胺鹽酸鹽(72 mg, 0.33 mmol)於MeOH (3.0 mL)中之混合物中。在60℃下將反應物攪拌4小時。濃縮反應物,且然後藉由反相層析(MeCN:含有0.1% TFA之H2
O作為溶析液)純化,以獲得產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.64 (s, 1H), 8.72 (s, 1H), 8.39 (d,J
= 10.2 Hz, 1H), 7.47 (dd,J
= 11.2, 8.2 Hz, 1H), 7.33 (dd,J
= 8.3, 3.8 Hz, 1H), 6.07 (s, 1H), 4.97 (d,J
= 10.2 Hz, 1H), 4.32 (s, 2H), 2.18 (s, 3H), 1.87 (s, 3H), 0.95 (s, 9H)。實例 20 : 3-[(7'- 氯 -5'- 氟 -3'- 側氧基 - 螺 [ 環戊烷 -1,1'- 異吲哚啉 ]-4'- 基 ) 胺基 ]-4-[[(1R
)-2,2- 二甲基 -1-(5- 甲基 -2- 呋喃基 ) 丙基 ] 胺基 ] 環丁 -3- 烯 -1,2- 二酮之合成 步驟 a :
用N2
將2-溴-5-氟苯甲酸甲酯(2.5 g, 10.8 mmol)、2-環戊烯基-4,4,5,5-四甲基-1,3,2-二氧雜硼戊環(2.3 g, 11.9 mmol)及K2
CO3
(3.7 g, 27.0 mmol)於1,2-二甲氧基乙烷(27 mL)及H2
O (3.0 mL)中之混合物吹掃2分鐘。然後在室溫下添加Pd(PPh3
)4
(0.62 g, 0.54 mmol)。將所得混合物加熱至95℃並保持14小時,且完成反應後,將混合物冷卻至室溫。用EtOAc (100 mL)稀釋反應混合物,且用H2
O、然後用鹽水洗滌有機層,然後經Na2
SO4
乾燥,過濾並濃縮。藉由矽膠層析(己烷中之0-20%乙酸乙酯)純化粗化合物,以獲得2-環戊烯基-5-氟苯甲酸甲酯。步驟 b :
向2-環戊烯基-5-氟苯甲酸甲酯(2.2 g, 10.0 mmol)於MeOH (25 mL)中之溶液中添加PtO2
(448 mg, 2.0 mmol)。在H2
(40 psi)下將此混合物振盪3小時。經由矽藻土過濾混合物且用MeOH (40 mL)洗滌,並在減壓下濃縮濾液。粗產物不經進一步純化即直接用於下一步驟中。步驟 c :
在室溫下,向2-環戊基-5-氟苯甲酸甲酯(2.0 g, 14.9 mmol)於THF/H2
O (20:6 mL)中之攪拌溶液中添加LiOH•2H2
O (1.89 g, 61.0 mmol)。將反應混合物攪拌16小時。完成後,用2N HCl水溶液(4 mL)驟冷反應物以調節至pH= 7。用乙酸乙酯(2 × 75 mL)萃取水溶液且用鹽水洗滌合併之有機層,經Na2
SO4
乾燥,過濾並濃縮。粗產物不經進一步純化即直接用於下一步驟中。MS: C12
H13
FO2
[M+H]+
之(ES)m/z
計算值209.1,實驗值209.1。步驟 d :
在0℃下,向2-環戊基-5-氟苯甲酸(3.0 g, 14.4 mmol)於二氯甲烷(30 mL)中之攪拌溶液中添加DMF (2滴)。然後經5分鐘逐滴添加草醯氯(2.27 g, 18.0 mmol),且在室溫下將反應混合物攪拌16小時。完成反應後,在減壓下移除溶劑且在真空下將殘餘物乾燥2小時,以獲得2-環戊基-5-氟苯甲醯氯。 在0℃下,將上述獲得之於5 ml EtOAc中之2-環戊基-5-氟苯甲醯氯(3.0 g, 13.2 mmol)添加至O-甲基羥胺鹽酸鹽(1.32 g, 15.8 mmol)及K2
CO3
(3.6 g, 26.4 mmol)於EtOAc及H2
O (32:10 mL)中之冷溶液中。然後在室溫下將反應混合物攪拌14小時。完成反應後,用乙酸乙酯(2×50 mL)萃取混合物,且用鹽水溶液洗滌合併之有機層,經Na2
SO4
乾燥,過濾,並在真空中濃縮。藉由矽膠層析(己烷中之10%-40%乙酸乙酯)純化粗化合物,以獲得2-環戊基-5-氟-N
-甲氧基苯甲醯胺。MS: C13
H16
FNO2
[M + H]+
之(ES)m/z
計算值238.2,實驗值238.1。步驟 e :
在室溫下,向2-環戊基-5-氟-N-甲氧基苯甲醯胺(2.0 g, 8.4 mmol)及m
CPBA (2.16 g, 12.6 mmol)於六氟丙醇(3.5 mL)中之混合物中添加2-碘聯苯(468 mg, 1.68 mmol)。在室溫下將反應混合物攪拌1小時。完成後,用飽和NaHCO3
水溶液驟冷反應混合物,且用乙酸乙酯(100 mL)稀釋。用H2
O、然後用鹽水溶液洗滌有機層,經Na2
SO4
乾燥,過濾,並濃縮。藉由矽膠層析(己烷中之10%-60%乙酸乙酯)純化粗化合物,以獲得5'-氟-2'-甲氧基螺[環戊烷-1,1'-異吲哚啉]-3'-酮。MS: C13
H14
FNO2
[M + H]+
之(ES)m/z
計算值236.1,實驗值236.0。步驟 f :
在室溫下,向5'-氟-2'-甲氧基螺-[環戊烷-1,1'-異吲哚啉]-3'-酮(0.95 g, 4.04 mmol)於DMF (3.5 mL)中之攪拌溶液中添加60% NaH (185 mg, 8.08 mmol)。將所得混合物加熱至95℃並保持3小時,且然後將混合物冷卻至室溫。用乙酸乙酯(75 mL)稀釋反應混合物,且用H2
O、然後用鹽水洗滌有機層,經Na2
SO4
乾燥,過濾,並濃縮。粗產物不經進一步純化即直接用於下一步驟中。步驟 g :
將步驟 f
之5'-氟螺[環戊烷-1,1'-異吲哚啉]-3'-酮(0.75 g, 3.65 mmol)溶解於濃H2
SO4
(5 mL)中且冷卻至0℃。逐滴添加70% HNO3
(0.46 g, 7.31 mmol, 2.0當量)且在0℃下將反應混合物攪拌10分鐘,然後升溫至室溫並攪拌過夜。添加冰且然後用冷水(10 mL)稀釋混合物。用EtOAc (2 × 25 mL)萃取反應混合物,用H2
O洗滌,且然後用鹽水溶液洗滌,經Na2
SO4
乾燥,過濾,並濃縮。粗製物不經進一步純化即直接用於下一步驟中(0.55 g)。MS: C12
H11
FN2
O3
[M+H]+
之(ES)m/z
計算值251.1,實驗值251.0。步驟 h :
在氫氣氛(40 psi)下,將5'-氟-4'-硝基螺[環戊烷-1,1'-異吲哚啉]-3'-酮(0.55 g, 1.32 mmol)及10% Pd/C (50%潤濕,200 mg)於MeOH (20 mL)攪拌1小時。經由矽藻土過濾混合物且用MeOH (40 mL)洗滌,並在減壓下濃縮濾液,以獲得粗製物,藉由矽膠層析(己烷中之20%-100%乙酸乙酯)純化該粗製物,以獲得4'-胺基-5'-氟螺[環戊烷-1,1'-異吲哚啉]-3'-酮(0.45g, 56%)。MS: C12
H13
FN2
O[M+H]+
之(ES)m/z
計算值221.1,實驗值221.0。步驟 i :
在室溫下,向7'-胺基-6'-氟-螺[環戊烷-1,3'-異吲哚啉]-1'-酮(135 mg, 0.61 mmol)於AcOH (1.5 mL)中之攪拌溶液中添加N-氯琥珀醯亞胺(89 mg, 0.67 mmol)。將所得混合物加熱至45℃並保持16小時,且然後冷卻至室溫。用EtOAc (50 mL)稀釋反應混合物。用H2
O、且然後用鹽水溶液洗滌有機層,經Na2
SO4
乾燥,過濾,並濃縮。粗產物不經進一步純化即直接用於下一步驟中。步驟 j :
在室溫下,向4'-胺基-7'-氯-5'-氟螺[環戊烷-1,1'-異吲哚啉]-3'-酮(125 mg, 0.490 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(104 mg, 0.735 mmol)於無水甲醇(2 mL)中之混合物中添加二噁烷中之4N HCl (0.122 µl, 0.490 mmol)。在60℃下將反應混合物攪拌3小時,然後濃縮。將乙酸乙酯(5 mL)添加至殘餘物中且在50℃下將此混合物攪拌10分鐘,然後冷卻至室溫。過濾混合物並乾燥,以獲得3-((7'-氯-5'-氟-3'-側氧基螺-[環戊烷-1,1'-異吲哚啉]-4'-基)胺基)-4-甲氧基環丁-3-烯-1,2-二酮。MS: C17
H14
ClFN2
O4
[M+H]+
之(ES)m/z
計算值365.1,實驗值365.0。步驟 k :
在室溫下,向步驟 i
之3-((7'-氯-5'-氟-3'-側氧基螺[環戊烷-1,1'-異吲哚啉]-4'-基)胺基)-4-甲氧基環丁-3-烯-1,2-二酮(70 mg, 0.205 mmol)及(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙-1-胺(32 mg, 0.205 mmol)於甲醇(2.0 mL)中之混合物中添加三乙胺(114 mg, 0.41 mmol, 2.0當量)。在60℃下將混合物攪拌3小時,且然後冷卻至室溫。在減壓下移除溶劑,且藉由矽膠層析(己烷中之20%-100%乙酸乙酯)純化粗化合物,以獲得(R)
-3-((7'-氯-5'-氟-3'-側氧基螺[環戊烷-1,1'-異吲哚啉]-4'-基)胺基)-4-((2,2-二甲基-1-(5-甲基呋喃-2-基)丙基)胺基)環丁-3-烯-1,2-二酮。1
H NMR (400 MHz, DMSO-d 6
) δ 9.71 (s, 1 H), 9.42 (s, 1 H), 8.50 (d,J
= 10.2 Hz, 1 H), 7.70 (d,J
= 8.6 Hz, 1 H), 6.19 (d,J
= 4.2 Hz, 1 H), 6.03 - 6.01 (m, 1 H), 5.02 (d,J
= 10.2 Hz, 1 H), 2.27 (s, 3 H), 1.95 - 1.80 (m, 6 H), 1.70 - 1.80 (m, 2 H), 0.95 (s, 9 H)。MS: C26
H27
ClFN3
O4
[M+H]+
之(ES)m/z
計算值500.2,實驗值500.2。實例 21 : 3-[(7- 氯 -2- 羥基 -3- 側氧基 - 異吲哚啉 -4- 基 ) 胺基 ]-4-[[(1R
)-2,2- 二甲基 -1-(5- 甲基 -2- 呋喃基 ) 丙基 ] 胺基 ] 環丁 -3- 烯 -1,2- 二酮之合成 步驟 a :
將三乙胺(983 mg, 9.71 mmol)添加至2-(溴甲基)-3-氯-6-硝基-苯甲酸甲酯(1.5 g, 4.87 mmol)及N
-羥基胺基甲酸第三丁基酯(710 mg, 5.35 mmol)於THF (10 mL)中之混合物中,且將此混合物加熱至65℃並保持16小時。在完成後,用EtOAc稀釋反應物並用H2
O (3×)洗滌。用Na2
SO4
乾燥有機層,過濾,並濃縮,以獲得產物,其立即用於下一步驟中。步驟 b :
將8:2 EtOH:H2
O之混合物(24 mL)添加至來自先前步驟之粗4-氯-2-羥基-7-硝基-異吲哚啉-1-酮中。向此溶液中添加NH4
Cl (2.67 g, 49.9 mmol)及鐵粉(800 mg, 14.3 mmol)。將反應物加熱至85℃。完成後,立即濃縮反應物以移除EtOH,且添加EtOAc及H2
O。過濾混合物以移除鐵,然後用H2
O洗滌,經Na2
SO4
乾燥,過濾,並濃縮。將MeOH中之HCl (4M, 2.0 mL)添加至粗製物中,且藉由過濾收集固體,以獲得產物。步驟 c :
在60℃下,將(75 mg, 0.38 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(80 mg, 0.56 mmol)於無水甲醇(2.5 mL)中之混合物攪拌過夜。過濾反應混合物且用MeOH沖洗固體,然後在真空下乾燥,以獲得粗製物。步驟 d :
將來自先前步驟之粗3-[(7-氯-2-羥基-3-側氧基-異吲哚啉-4-基)胺基]-4-甲氧基-環丁-3-烯-1,2-二酮及(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙-1-胺鹽酸鹽(66 mg, 0.40 mmol)合併於MeOH (2.0 mL)中,且添加三乙胺(76 mg, 0.76 mmol)。在室溫下將混合物攪拌過夜。濃縮反應物且藉由矽膠層析、然後藉由反相層析(MeCN:含有0.1% TFA之H2
O作為溶析液)純化,以獲得產物。1
H NMR (400 MHz, DMSO-d 6
) δ 11.76 (s, 1 H), 10.42 (s, 1 H), 9.19 (d,J
= 9.7 Hz, 1 H), 7.65 (d,J
= 9.0 Hz, 1 H), 7.39 (d,J
= 9.0 Hz, 1 H), 6.22 - 6.18 (m, 1 H), 6.05 - 6.03 (m, 1 H), 5.09-5.15 (m, 3 H), 2.26 (s, 3 H), 0.95 (s, 9 H)。MS: C22
H22
ClN3
O5
[M + Na]+
之(ES)m/z
計算值464.1,實驗值464.0。實例 22 : 3-[(2- 胺基 -7- 氯 -3- 側氧基 - 異吲哚啉 -4- 基 ) 胺基 ]-4-[[(1R
)-1-(4,5- 二甲基 -2- 呋喃基 )-2,2- 二甲基 - 丙基 ] 胺基 ] 環丁 -3- 烯 -1,2- 二酮之合成 步驟 a :
將2-(溴甲基)-3-氯-6-硝基-苯甲酸甲酯(1.5 g, 4.87 mmol)及N-胺基胺基甲酸第三丁基酯(670 mg, 5.11 mmol)於THF (10 mL)中之混合物加熱至65℃並保持3小時。在完成後,用EtOAc稀釋反應物並用H2
O (3×)洗滌。用Na2
SO4
乾燥有機層,過濾,並濃縮,以獲得粗製物,藉由矽膠層析純化該粗製物,以獲得產物。步驟 b :
將MeOH (15 mL)添加至來自先前步驟之N-(4-氯-7-硝基-1-側氧基-異吲哚啉-2-基)胺基甲酸第三丁基酯(1.6 g, 4.9 mmol)中。向此溶液中添加PtO2
(221 mg, 0.97 mmol),且在氫化裝置中在H2
(30 psi)下振盪此混合物。完成反應後,過濾混合物且在真空下乾燥,以獲得產物。步驟 c :
在60℃下,將N
-(7-胺基-4-氯-1-側氧基-異吲哚啉-2-基)胺基甲酸第三丁基酯(420 mg, 1.84 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(392 mg, 2.7 mmol)於無水甲醇(5.0 mL)中之混合物攪拌12小時。過濾反應混合物且藉由矽膠層析純化固體,以獲得產物。步驟 d :
將N-[4-氯-7-[(2-甲氧基-3,4-二側氧基-環丁-1-基)胺基]-1-側氧基-異吲哚啉-2-基]胺基甲酸第三丁基酯(50 mg, 0.12 mmol)及(1R
)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙-1-胺鹽酸鹽(27 mg, 0.13 mmol)合併於MeOH (4.0 mL)中,且添加三乙胺(24 mg, 0.244 mmol)。在65℃下將混合物攪拌過夜。然後濃縮反應物,以獲得粗製物,其不經進一步純化即用於下一步驟中。步驟 e :
將來自先前步驟之粗製物溶解於MeOH (2.0 mL)中,且添加二噁烷中之HCl (4M,10滴)並在室溫下攪拌反應物。完成後,濃縮反應物且藉由反相層析(MeCN:含有0.1% TFA之H2
O作為溶析液)純化,以獲得產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.87 (s, 1 H), 9.01 (d,J
= 10.2 Hz, 1 H), 8.05 (d,J
= 6.0 Hz, 2 H), 7.43 (d,J
= 9.0 Hz, 1 H), 7.23 (d,J
= 9.0 Hz, 1 H), 6.1 (d,J
= 3.2 Hz, 1 H), 5.04 (d,J
= 4.2 Hz, 1 H), 4.40 (d,J
= 11.2 Hz, 2 H), 2.09 (s, 3 H), 1.79 (s, 3 H), 0.86 (s, 9 H)。MS: C23
H25
ClN4
O4
[M + H]+
之(ES)m/z
計算值457.2,實驗值457.0,實例 23 : 3-[(7- 氯 -2- 甲氧基 -3- 側氧基 - 異吲哚啉 -4- 基 ) 胺基 ]-4-[[(1R
)-1-(4,5- 二甲基 -2- 呋喃基 )-2,2- 二甲基 - 丙基 ] 胺基 ] 環丁 -3- 烯 -1,2- 二酮 之合 成 步驟 a :
將2-(溴甲基)-3-氯-6-硝基-苯甲酸甲酯(5.0 g, 16.2 mmol)及O-甲基羥胺鹽酸鹽(2.12 g, 17.9 mmol)於THF (30 mL)中之混合物加熱至65℃並保持2小時。在完成後,用EtOAc稀釋反應物並用H2
O (3×)洗滌。用Na2
SO4
乾燥有機層,過濾並濃縮以獲得產物,其不經進一步純化即用於下一步驟中。步驟 b :
將8:2 EtOH:H2
O之混合物(26 mL)添加至來自先前步驟之產物中。向此溶液中添加NH4
Cl (9.0 g, 170 mmol)及鐵粉(2.27 g, 40.6 mmol),且將混合物加熱至85℃。完成後,立即濃縮反應物以移除EtOH,且然後添加EtOAc及H2
O。過濾混合物以移除鐵,然後用H2
O洗滌,經Na2
SO4
乾燥,過濾,並濃縮。藉由矽膠層析(己烷中之10%至80% EtOAc)純化粗製物,以獲得產物。步驟 c :
在60℃下,將7-胺基-4-氯-2-甲氧基-異吲哚啉-1-酮(1.0 g, 4.1 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(0.88 g, 6.2 mmol)於無水甲醇(10 mL)中之混合物攪拌過夜。然後過濾此混合物且用MeOH沖洗固體並在真空下乾燥,以獲得產物。步驟 d :
將3-[(7-氯-2-甲氧基-3-側氧基-異吲哚啉-4-基)胺基]-4-甲氧基-環丁-3-烯-1,2-二酮(125 mg, 0.39 mmol)及(1R
)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙-1-胺鹽酸鹽(87 mg, 0.41 mmol)合併於MeOH (4.0 mL)中,且添加三乙胺(117 mg, 1.15 mmol)。在60℃下將混合物攪拌過夜。然後濃縮反應物,以獲得粗製物,藉由矽膠層析(CH2
Cl2
:MeOH)純化該粗製物,以獲得產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.87 (s, 1 H), 9.01 (d,J
= 10.2 Hz, 1 H), 7.63 (d,J
= 9.0 Hz, 1 H), 7.42 (d,J
= 9.0 Hz, 1 H), 6.09 (s, 1 H), 5.04 (d,J
= 10.1 Hz, 1 H), 4.73 (s, 2 H), 3.86 (s, 3 H), 2.18 (s, 3 H), 1.87 (s, 3 H), 0.95 (s, 9 H)。MS: C24
H26
ClN3
O5
[M - H]-
之(ES)m/z
計算值470.2,實驗值470.1。實例 24 : 3-(((R
)-1-(4,5- 二甲基呋喃 -2- 基 )-2,2- 二甲基丙基 ) 胺基 )-4-(((S
)-5- 氟 -1- 甲基 -3- 側氧基異吲哚啉 -4- 基 ) 胺基 ) 環丁 -3- 烯 -1,2- 二酮及 3-(((R
)-1-(4,5- 二甲基呋喃 -2- 基 )-2,2- 二甲基丙基 ) 胺基 )-4-(((R
)-5- 氟 -1- 甲基 -3- 側氧基異吲哚啉 -4- 基 ) 胺基 ) 環丁 -3- 烯 -1,2- 二酮之合成 步驟 a :
在室溫下,向6-氟異吲哚啉-1-酮(10 g, 66.2 mmol)於無水二氯甲烷(100 mL)中之攪拌溶液中添加三乙胺(16.72, 165.5 mmol, 21.8 mL)、二碳酸二第三丁基酯(17.3 g, 79.4 mmol)及催化DMAP (100 mg)。在室溫下將反應混合物攪拌16小時。完成後,用CH2
Cl2
稀釋此混合物,用H2
O洗滌,且然後用飽和NaHCO3
水溶液洗滌。經Na2
SO4
乾燥有機層,過濾並在真空中濃縮。藉由矽膠層析(己烷中之0-30%乙酸乙酯)純化粗化合物,以獲得產物。MS: C13
H14
FNO3
[M + H]+
之(ES)m/z
計算值252.3,實驗值252.3。步驟 b : 1)
在-78℃下在N2
氣氛下,向6-氟-1-側氧基異吲哚啉-2-甲酸第三丁基酯(5.0 g, 19.9 mmol)於無水THF (40 mL)中之攪拌溶液中逐滴添加LiHMDS (21.89 mL, 21.89 mmol)。攪拌30分鐘後,將碘甲烷(2.82 g, 19.92 mmol)於THF (5 mL)中之溶液添加至混合物中。在-78℃下將反應混合物攪拌1小時,且然後升溫至室溫並攪拌2小時。完成後,用飽和NH4
Cl水溶液驟冷反應混合物,用EtOAc (100 mL)稀釋,且用H2
O洗滌有機層,且然後用鹽水溶液洗滌。然後經Na2
SO4
乾燥有機層,過濾並在真空中濃縮。粗製物不經任何進一步純化即直接用於下一步驟中。2)
向5-氟-1-甲基-3-側氧基異吲哚啉-2-甲酸第三丁基酯(6.2 g, 66.2 mmol)於MeOH (60 mL)中之攪拌溶液中添加二噁烷中之4N HCl (79.6 mmol, 20 mL)。在室溫下將此混合物攪拌3小時。完成反應後,移除溶劑且用EtOAc (3 × 50 mL)稀釋反應混合物。用H2
O洗滌此混合物,且然後用飽和NaHCO3
水溶液洗滌。然後經Na2
SO4
乾燥有機層,過濾,並濃縮。藉由矽膠層析(己烷中之10%-80%乙酸乙酯)純化粗化合物,以獲得產物。MS: C9
H8
FNO[M + H]+
之(ES)m/z
計算值166.2,實驗值166.2。步驟 c : 1)
在-78℃下在N2
氣氛下,向6-氟-3-甲基異吲哚啉-1-酮(2.5 g, 15.1 mmol)於無水THF (25 mL)中之攪拌溶液中逐滴添加n
-BuLi (6.64 mL, 16.61 mmol, 2.5 M於己烷中),且在-78℃下將反應混合物攪拌30分鐘。然後將氯甲酸(1R
,2S
,5R
)-2-異丙基-5-甲基環己基酯(3.96 g, 18.18 mmol)於THF (5 mL)中之溶液添加至混合物中,並在-78℃下將此混合物攪拌30分鐘。然後將反應混合物升溫至室溫且攪拌3小時。完成反應後,用飽和NH4
Cl水溶液驟冷反應混合物,用EtOAc (2 × 75 mL)萃取,且然後用H2
O洗滌合併之有機層,然後用鹽水溶液洗滌,經Na2
SO4
乾燥,過濾,並在真空中濃縮。藉由矽膠層析純化粗化合物,以單獨獲得(1S
)-5-氟-1-甲基-3-側氧基異吲哚啉-2-甲酸(1R
,2S
,5R
)-2-異丙基-5-甲基環己基酯及(1R
)-5-氟-1-甲基-3-側氧基異吲哚啉-2-甲酸(1R
,2S
,5R
)-2-異丙基-5-甲基環己基酯。2)
在室溫下,向上述獲得之一種非鏡像異構物(1.2 g, 3.45 mmol)於MeOH (10 mL)中之攪拌溶液中添加MeOH (17.2 mmol, 10 mL)中之Mg(OMe)2
(10-12% wt)。在室溫下將反應混合物攪拌2小時。完成反應後,移除溶劑且用飽和NH4
Cl水溶液驟冷反應混合物,並用EtOAc (2 × 75 mL)萃取。用H2
O、然後用鹽水溶液洗滌合併之有機層,經Na2
SO4
乾燥,過濾,並在真空中濃縮。藉由矽膠層析(己烷中之20%-60%乙酸乙酯)純化粗化合物,以獲得期望產物。MS: C9
H8
FNO [M + H]+
之(ES)m/z
計算值166.2,實驗值166.2。以類似方式處理另一非鏡像異構物,以獲得另一期望產物。步驟 d : 1)
將自步驟c獲得之一種化合物(0.45 g, 2.72 mmol)溶解於濃H2
SO4
(5 mL)中且冷卻至0℃。逐滴添加70% HNO3
(0.34 g, 24.1 mmol, 2.0當量)且在0℃下將反應混合物攪拌10分鐘,然後升溫至室溫並攪拌過夜。添加冰,且然後用冷水(10 mL)稀釋混合物並用EtOAc (2 × 25 mL)萃取。用H2
O洗滌合併之有機層,然後用鹽水溶液洗滌,且然後經Na2
SO4
乾燥,過濾並濃縮。粗製物不經任何進一步純化即直接用於下一步驟中。MS: C9
H7
F2
N2
O3
[M+H]+
之(ES)m/z
計算值211.0,實驗值211.2。以類似方式處理另一鏡像異構物,以獲得另一期望產物。2)
在氫氣氛(40 psi)下,將上述獲得之一種化合物(0.35 g, 1.32 mmol)及10% Pd/C (50%潤濕,100 mg)於MeOH (25 mL)中攪拌1小時。經由矽藻土過濾混合物且用MeOH (40 mL)洗滌。在減壓下濃縮濾液,以獲得粗製物,藉由矽膠層析(20%-100%乙酸乙酯/己烷)純化該粗製物,以獲得期望產物。MS: C9
H9
FN2
O[M+H]+
之(ES)m/z
計算值181.1,實驗值181.2。以類似方式處理另一鏡像異構物,以獲得另一期望產物。步驟 e :
在60℃下,將在步驟d中獲得之一種化合物(170 mg, 0.939 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(200 mg, 1.40 mmol)於無水甲醇(4 mL)中之混合物攪拌3小時。蒸發反應混合物且在50℃下將殘餘物於乙酸乙酯(10 mL)中攪拌30分鐘,然後冷卻至室溫。過濾混合物並乾燥,以獲得期望產物。MS: C14
H11
FN2
O4
[M+H]+
之(ES) m/z計算值291.1,實驗值291.2。以類似方式處理另一鏡像異構物,以獲得另一期望產物。步驟 f :
向(1R
)-1-(4,5-二甲基-2-呋喃基)-2,2-二甲基-丙-1-胺鹽酸鹽(62 mg, 0.288 mmol, 1.05當量)於甲醇(2.5 mL)中之溶液中添加三乙胺(75 mg, 0.687 mmol, 2.5當量)。在室溫下將混合物攪拌10分鐘以變成澄清溶液,且然後在室溫下添加上述獲得之一種化合物。在60℃下將所得溶液攪拌3小時。完成後,將反應物冷卻至室溫。在減壓下移除溶劑且藉由製備型HPLC (乙腈-含有0.1% TFA之水)純化粗產物,以獲得期望產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.64 (s, 1 H), 8.79 (s, 1 H), 8.38 (d,J
= 10.2Hz, 1 H), 7.46 (dd,J
= 11.4, 8.2 Hz, 1 H), 7.34 (dd,J
= 3.9, 8.2 Hz, 1 H), 6.07 (s, 1 H), 4.95 (d,J
= 10.1 Hz, 1 H), 4.58 (q,J
= 6.6 Hz, 1 H), 2.18 (s, 3 H), 1.87 (s, 3 H), 1.33 (d,J
= 6.6 Hz, 3 H), 0.95 (s, 9 H)。MS: C24
H26
FN3
O4
[M - H]-
之(ES)m/z
計算值438.2,實驗值438.0。以類似方式獲得另一非鏡像異構物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.64 (s, 1 H), 8.79 (s, 1 H), 8.37 (d,J
= 10.2 Hz, 1 H), 7.44 (dd,J
= 11.0, 8.2 Hz, 1 H), 7.33 (dd,J
= 3.9, 8.8 Hz, 1 H), 6.07 (s, 1 H), 4.95 (d,J
= 10.1 Hz, 1 H), 4.56 (q,J
= 6.3 Hz, 1 H), 2.18 (s, 3 H), 1.87 (s, 3 H), 1.33 (d,J
= 6.6 Hz, 3 H), 0.95 (s, 9 H)。MS: C24
H26
FN3
O4
[M - H]之(ES)m/z
計算值438.2,實驗值438.0。實例 25 : 3-(((R
)-1-(4,5- 二甲基呋喃 -2- 基 )-2,2- 二甲基丁基 ) 胺基 )-4-(((S
)-5- 氟 -1,7- 二甲基 -3- 側氧基異吲哚啉 -4- 基 ) 胺基 ) 環丁 -3- 烯 -1,2- 二酮及 3-(((R
)-1-(4,5- 二甲基呋喃 -2- 基 )-2,2- 二甲基丁基 ) 胺基 )-4-(((R
)-5- 氟 -1,7- 二甲基 -3- 側氧基異吲哚啉 -4- 基 ) 胺基 ) 環丁 -3- 烯 -1,2- 二酮 步驟 a :
在室溫下在室溫水浴中,向7-胺基-6-氟-3-甲基異吲哚啉-1-酮之一種鏡像異構物(200 mg, 1.11 mmol)於AcOH (2.2 mL)中之溶液中逐份添加N-碘琥珀醯亞胺(350 mg, 1.56 mmol)。在水浴中將所得混合物攪拌30分鐘,用水(1 mL)驟冷,且然後用乙酸乙酯(10 mL)萃取。用鹽水(10 mL)洗滌有機層,且然後經MgSO4
乾燥,過濾並濃縮。藉由矽膠層析(己烷中之0-60%乙酸乙酯)純化粗製物,以獲得期望產物。MS: C9
H8
FIN2
O [M+H]+
之(ES)m/z
計算值307.0,實驗值307.0。以類似方式處理另一鏡像異構物,以獲得另一期望產物。步驟 b :
向步驟a中獲得之一種化合物(248 mg, 0.81 mmol)於二噁烷(8.1 mL)中之溶液中添加CsF (493 mg, 3.24 mmol)、2,4,6-三甲基-1,3,5,2,4,6-三氧雜三硼雜環己烷(305 mg, 2.43 mmol)及[1,1'-雙(二苯基膦基)二茂鐵]-二氯鈀(II) (66 mg, 0.08 mmol)。在80℃下將所得混合物攪拌過夜。將反應物分配於水(20 mL)與乙酸乙酯(30 mL)之間。用鹽水(20 mL)洗滌有機層,且然後經MgSO4
乾燥,過濾並濃縮。藉由矽膠層析(己烷中之0-80%乙酸乙酯)純化粗製物,以獲得期望產物。MS: C10
H11
FN2
O [M+H]+
之(ES)m/z
計算值195.1,實驗值195.1。以類似方式處理另一鏡像異構物,以獲得另一期望產物。步驟 c :
在60℃下,將步驟b中獲得之一種化合物(127 mg, 0.65 mmol)及3,4-二甲氧基環丁-3-烯-1,2-二酮(186 mg, 1.3 mmol)於無水甲醇(3 mL)中之混合物攪拌過夜,且然後在80℃下攪拌5小時。濃縮反應混合物且藉由矽膠層析(己烷中之0-100%乙酸乙酯)純化,以獲得期望產物。MS: C15
H13
FN2
O4
[M+H]+
之(ES) m/z計算值305.1,實驗值305.1。以類似方式處理另一鏡像異構物,以獲得另一期望產物。步驟 d :
將無水甲醇(2 mL)添加至步驟c中獲得之一種化合物(40 mg, 0.13 mmol)及(R
)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丁-1-胺(33.6 mg, 0.145 mmol)之混合物中,且在60℃下將此混合物攪拌過夜。將反應物冷卻至室溫,使其溶解於少量二氯甲烷中,且吸附至矽膠上。藉由矽膠層析(二氯甲烷中之40%乙酸乙酯)純化此混合物,以獲得期望產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.55 (s, 1 H), 8.78 (s, 1 H), 8.32 (d,J
= 10.0 Hz, 1 H), 7.29 (d,J
= 11.6 Hz, 1 H), 6.06 (s, 1 H), 5.05(d,J
= 10.4 Hz, 1 H), 4.63 (q,J
= 6.8 Hz, 1 H), 2.31 (s, 3 H), 2.18 (s, 3 H), 1.87 (s, 3 H), 1.34 (d,J
= 6.8 Hz, 3 H), 1.26 (q,J
= 7.2 Hz, 2 H), 0.93 (s, 3 H), 0.88 (s, 3 H), 0.82 (t,J
= 7.2 Hz, 3 H)。MS: C26
H30
FN3
O4
[M-H]-
之(ES) m/z計算值468.2,實驗值468.2。以類似方式獲得另一非鏡像異構物。實例 26 : 3-(((R
)-1-(4,5- 二甲基呋喃 -2- 基 )-2,2- 二甲基丙基 ) 胺基 )-4-(((S
)-5- 氟 -1,7- 二甲基 -3- 側氧基異吲哚啉 -4- 基 ) 胺基 ) 環丁 -3- 烯 -1,2- 二酮及 3-(((R
)-1-(4,5- 二甲基呋喃 -2- 基 )-2,2- 二甲基丙基 ) 胺基 )-4-(((R
)-5- 氟 -1,7- 二甲基 -3- 側氧基異吲哚啉 -4- 基 ) 胺基 ) 環丁 -3- 烯 -1,2- 二酮 將無水甲醇(2 mL)添加至3-((5-氟-1,7-二甲基-3-側氧基異吲哚啉-4-基)胺基)-4-甲氧基環丁-3-烯-1,2-二酮之一種鏡像異構物(40 mg, 0.13 mmol)及(R
)-1-(4,5-二甲基呋喃-2-基)-2,2-二甲基丁-1-胺(31.6 mg, 0.145 mmol)之混合物中,且在60℃下將此混合物攪拌過夜。將反應物冷卻至室溫,使其溶解於少量二氯甲烷中,且吸附至矽膠上。藉由矽膠層析(二氯甲烷中之40%乙酸乙酯)純化此混合物,以獲得期望產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.55 (s, 1 H), 8.74 (s, 1 H), 8.34 (d,J
= 10.4 Hz, 1 H), 7.28 (d,J
= 11.6 Hz, 1 H), 6.06 (s, 1 H), 4.95(d,J
= 10.0 Hz, 1 H), 4.61 (q,J
= 6.8 Hz, 1 H), 2.31 (s, 3 H), 2.16 (s, 3 H), 1.86 (s, 3 H), 1.33 (d,J
= 6.8 Hz, 3 H), 0.94 (s, 9 H)。MS: C25
H28
FN3
O4
[M-H]-
之(ES) m/z計算值454.2,實驗值454.2。以類似方式獲得另一非鏡像異構物。實例 27 : 3-(((R
)-2,2- 二甲基 -1-(5- 甲基呋喃 -2- 基 ) 丙基 ) 胺基 )-4-(((S
)-5- 氟 -1- 甲基 -3- 側氧基 異吲哚啉 -4- 基 ) 胺基 ) 環丁 -3- 烯 -1,2- 二酮 及 3-(((R
)-2,2- 二甲基 -1-(5- 甲基呋喃 -2- 基 ) 丙基 ) 胺基 )-4-(((R
)-5- 氟 -1- 甲基 -3- 側氧基 異吲哚啉 -4- 基 ) 胺基 ) 環丁 -3- 烯 -1,2- 二酮 之合 成 在室溫下,向3-((5-氟-1-甲基-3-側氧基異吲哚啉-4-基)胺基)-4-甲氧基環丁-3-烯-1,2-二酮之一種鏡像異構物(50 mg, 0.171 mmol)及(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丙-1-胺(30 mg, 0.180 mmol)於甲醇(3.0 mL)中之混合物中添加三乙胺(43 mg, 0.42 mmol, 2.5當量)。在60℃下將混合物攪拌3小時,且然後冷卻至室溫。在減壓下移除溶劑且藉由製備型HPLC (乙腈-含有0.1% TFA之水)純化粗產物,以獲得期望產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.65 (s, 1 H), 8.80 (s, 1 H), 8.42 (d,J
= 10.1Hz, 1 H), 7.46 (dd,J
= 3.1, 8.4 Hz, 1 H), 7.36 (dd,J
= 3.9, 8.2 Hz, 1 H), 6.18 (d,J
= 3.2, Hz, 1 H), 6.03 (d,J
= 2.4 Hz, 1 H), 5.00 (d,J
= 10.5 Hz, 1 H), 4.56 (q,J
= 7.1 Hz, 1 H), 2.27 (s, 3 H), 1.33 (d,J
= 6.6 Hz, 3 H), 0.95 (s, 9 H)。MS: C23
H24
FN3
O4
[M - H]-
之(ES) m/z計算值424.2,實驗值424.0。以類似方式獲得另一非鏡像異構物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.64 (s, 1 H), 8.79 (s, 1 H), 8.40 (d,J
= 10.5 Hz, 1 H), 7.46 (dd,J
= 11.3, 8.6 Hz, 1 H), 7.34 (dd,J
= 3.9, 8.2 Hz, 1 H), 6.17 (d,J
= 3.2, Hz, 1 H), 6.04 - 6.03 (m, 1 H), 5.00 (d,J
= 10.1 Hz, 1 H), 4.56 (q,J
= 6.6 Hz, 1 H), 2.27 (s, 3 H), 1.33 (d,J
= 6.6 Hz, 3 H), 0.95 (s, 9 H)。MS: C23
H24
FN3
O4
[M + H]+
之(ES)m/z
計算值426.2,實驗值426.0。實例 28 : 3-[[(1R
)-2,2- 二甲基 -1-(5- 甲基 -2- 呋喃基 ) 丁基 ] 胺基 ]-4-[[(1S
)-5- 氟 -1- 甲基 -3- 側氧基 - 異吲哚啉 -4- 基 ] 胺基 ] 環丁 -3- 烯 -1,2- 二酮及 3-[[(1R
)-2,2- 二甲基 -1-(5- 甲基 -2- 呋喃基 ) 丁基 ] 胺基 ]-4-[[(1R
)-5- 氟 -1- 甲基 -3- 側氧基 - 異吲哚啉 -4- 基 ] 胺基 ] 環丁 -3- 烯 -1,2- 二酮之合成 將三乙胺(0.025 mL, 0.18 mmol)添加至3-((5-氟-1-甲基-3-側氧基異吲哚啉-4-基)胺基)-4-甲氧基環丁-3-烯-1,2-二酮之一種鏡像異構物(26 mg, 0.09 mmol)及(1R
)-2,2-二甲基-1-(5-甲基-2-呋喃基)丁-1-胺鹽酸鹽(20 mg, 0.09 mmol)於MeOH (1.0 mL)中之混合物中。在室溫下將反應物攪拌18小時。然後將矽膠添加至反應物中,濃縮混合物,且藉由矽膠層析(CH2
Cl2
中之1%至10% MeOH)純化此混合物。然後藉由反相層析(MeCN:含有0.1% TFA之H2
O作為溶析液)純化產物,以獲得最終產物。1
H NMR (400 MHz, DMSO-d 6
) δ 9.65 (s, 1H), 8.79 (s, 1H), 8.40 (d,J
= 10.2 Hz, 1H), 7.47 (dd,J
= 11.1, 8.2 Hz, 1H), 7.35 (dd,J
= 8.3, 3.8 Hz, 1H), 6.17 (d,J
= 3.1 Hz, 1H), 6.06 - 6.01 (m, 1H), 5.10 (d,J
= 10.2 Hz, 1H), 4.58 (q,J
= 6.6 Hz, 1H), 2.27 (s, 3H), 1.34 (d,J
= 6.7 Hz, 3H), 1.32 - 1.24 (m, 2H), 0.94 (s, 3H), 0.88 (s, 3H), 0.83 (t,J
= 7.4 Hz, 3H)。MS: C24
H27
FN3
O4
[M+H]+
之(ES)m/z
計算值440.2,實驗值440.4。以類似方式獲得另一非鏡像異構物。 以下化合物係使用與本文所述類似之合成方法使用適宜試劑製得且由MS (質譜)及/或NMR來表徵,如表1中所圖解說明。表 1. 化合物之表徵 生物活性 生物實例 1 : CXCR2 活性之 配體結合 分析
使用配體結合分析來測定潛在CXCR2拮抗劑阻斷CXCR2與其任一配體之間之相互作用的能力。將穩定表現CXCR2之HEK-293細胞或表現CXCR2之人類嗜中性球離心且於分析緩衝液(20 mM HEPES pH 7.1、140 mM NaCl、1 mM CaCl2
、5 mM MgCl2
、0.1%疊氮化鈉且含有0.1%牛血清白蛋白)中重懸浮至5 × 105
個細胞/mL之濃度。結合分析設定如下:將用於篩選之化合物自最大20 μM連續稀釋,且將含有5 × 104
個細胞(對於HEK-293細胞)或3 × 104
個細胞(對於人類嗜中性球)之0.1 mL細胞添加至含有化合物之每一孔中。然後添加0.1 mL經125
I標記之CXCL8 (自PerkinElmer; Waltham, MA獲得),其於分析緩衝液中稀釋至約50 pM之最終濃度,從而產生約1 μCi/孔,且將板密封並在25℃下在振盪平臺上培育約3小時。將反應物抽吸至在真空細胞收穫機(Packard Instruments; Meriden, CT)上預浸於0.3%聚乙亞胺(PEI)溶液中之GF/B玻璃濾器上。將閃爍液(50 μL; Microscint 20, Packard Instruments)添加至每一孔中,將板密封且在Top Count閃爍計數器(Packard Instruments)上量測放射性。使用僅含有稀釋劑(對於總計數)或20 μM化合物之對照孔來計算化合物之總抑制%。使用來自GraphPad, Inc. (San Diego, Ca)之電腦程式Prism來計算IC50
值。IC50
值係使經標記CXCR8與受體之結合減少50%之彼等濃度。在圖1中在結合分析中具有小於100 nM之IC50
值之化合物標記為(+++);具有100-1000 nM之IC50
值之化合物標記為(++);且具有小於或等於20 µM但大於1000 nM之IC50
值之化合物標記為(+)。生物實例 2 : CXCR2 活性之遷移 / 趨化作用分析
可使用血清趨化作用分析來測定潛在受體拮抗劑在阻斷經由趨化因子受體(例如CXCR2)介導之遷移方面的效能。此分析通常係使用具有5 µm孔徑聚碳酸酯膜之ChemoTX®微室系統來實施。為起始該分析,藉由在室溫下在400 × g下離心來收集表現趨化因子受體之細胞(在此情形下嗜中性球係自人類全血分離),然後以400萬個/ml懸浮於人類血清中。將所測試化合物自10 μM之最大最終濃度(或等效體積之其溶劑(DMSO))連續稀釋,且然後添加至細胞/血清混合物中。單獨地,將重組人類CXCL5 (ENA-78)以其EC50
濃度(10 nM)置於ChemoTX®板之下排孔中。將5 µm (孔徑)聚碳酸酯膜置於板上,且將20 µL細胞/化合物混合物轉移至膜之每一孔上。在37℃下將板培育45分鐘,此後移除聚碳酸酯膜且將5 µl DNA嵌入劑CyQUANT (Invitrogen, Carlsbad, CA)添加至下排孔中。使用Spectrafluor Plus讀板儀(TECAN, San Jose, CA)來量測螢光量,其對應於遷移細胞數。生物實例 3 : CCR6 活性之遷移 / 趨化作用分析
可使用血清趨化作用分析來測定潛在受體拮抗劑在阻斷經由趨化因子受體(例如CCR6)介導之遷移方面的效能。此分析通常係使用具有5 µm孔徑聚碳酸酯膜之ChemoTX®微室系統來實施。為起始該分析,藉由在室溫下在400 × g下離心來收集表現趨化因子受體之細胞(在此情形下為KHYG-1細胞,Yagita等人,Leukemia
, 14:922, 2000),然後以400萬個/ml懸浮於人類血清中。將所測試化合物自10 μM之最大最終濃度(或等效體積之其溶劑(DMSO))連續稀釋,且然後添加至細胞/血清混合物中。單獨地,將重組人類CCL20 (MIP-3α/LARC)以其EC50
濃度(10 nM)置於ChemoTX®板之下排孔中。將5 µm (孔徑)聚碳酸酯膜置於板上,且將20 µL細胞/化合物混合物轉移至膜之每一孔上。在37℃下將板培育45分鐘,此後移除聚碳酸酯膜且將5 µl DNA嵌入劑CyQUANT (Invitrogen, Carlsbad, CA)添加至下排孔中。使用Spectrafluor Plus讀板儀(TECAN, San Jose, CA)來量測螢光量,其對應於遷移細胞數。在圖1中在趨化作用分析中具有小於100 nM之IC50
值之化合物標記為(+++);具有100-1000 nM之IC50
值之化合物標記為(++);且具有小於或等於20 µM但大於1000 nM之IC50
值之化合物標記為(+)。生物實例 4 :在用於牛皮癬之 IL-23 誘發之耳腫脹模型中之活體內效能
將IL-23真皮內注射至小鼠耳中可引起耳腫脹,其係CCR6依賴性的(Hedrick M.N等人,J. Clinical Investigation. 2009. 119:2317-2329)。給予C57Bl/6小鼠之右耳IL-23之真皮內注射。藉由真皮內注射至左耳中給予PBS作為對照。藉由皮下途徑投用化合物1.023(在實例6中合成)。該化合物係在3次IL-23真皮內注射後及中度耳腫脹開始時以治療方式投用。使用測徑器來量測腫脹程度。化合物1.023能夠完全抑制IL-23誘發之耳腫脹且能夠使腫脹減輕迴至基線值(圖2)。生物實例 5 :在咪喹莫特誘發之牛皮癬樣模型中之活體內效能
將咪喹莫特乳霜局部施用至小鼠之脫毛背會形成牛皮癬樣病灶,其特徵類似於人類牛皮癬,即皮膚紅斑、皮膚厚度及脫皮。(Van Der Fits L.等人,2009. J Immunology182:
5836-5845)。用局部施用至脫毛背皮膚之咪喹莫特乳霜來處理Balb/c小鼠。以預防性方式藉由經口途徑投用化合物1.129以在整個研究中達成適宜血漿濃度。以盲化方式藉由量測3個皮膚病態樣(即紅斑度、受脫皮影響之皮膚百分比及如藉由測徑器所量測之皮膚厚度)來測定牛皮癬樣病灶之形成。對每一量測分配介於0 (無疾病)與4 (最嚴重疾病)之間之疾病評分,使得計算累積PASI (牛皮癬活性嚴重程度指數)評分,最大值為12分。化合物1.129能夠藉由抑制紅斑、脫皮及皮膚厚度來減輕累積PASI評分之嚴重程度。與經媒劑處理之小鼠(圖3)相比,在投用化合物1.129之組中展現嚴重症狀(對於每一讀出評分≥3)之小鼠之百分比減小。 本文中闡述本發明之具體實施例,包括發明者已知用於實施本發明之最佳模式。在閱讀前述描述後,所揭示實施例之變化形式可對熟習此項技術者顯而易見,且預期彼等熟習此項技術者可在適宜時採用該等變化形式。因此,意欲以不同於本文所明確闡述之方式實踐本發明,且本發明意欲包括如適用法律所容許隨附申請專利範圍中所列舉標的物之所有修改及等效內容。此外,除非本文中另有指示或上下文另外明顯矛盾,否則本發明涵蓋上述要素在其所有可能的變化形式中之任何組合。 本說明書中所引用之所有公開案、專利申請案、登錄號及其他參考文獻均以引用方式併入本文中,如同將每一個別公開案或專利申請案特定且個別地指示以引用方式併入一般。
圖 1A-1AB
提供本文所述化合物之結構及生物活性。圖 2
提供IL-23誘發之耳腫脹模型中之化合物1.023。圖 3
提供在咪喹莫特(imiquimod)誘發之牛皮癬模型中經化合物1.129處理之小鼠之PASI評分。圖 4
提供在咪喹莫特誘發之牛皮癬模型中與經媒劑處理之小鼠相比在經化合物1.129處理之小鼠中之厚度、紅斑及脫皮評分≥3。
Claims (37)
- 一種具有式(A)之化合物或其醫藥上可接受之鹽:
- 如請求項1之化合物或其醫藥上可接受之鹽,其中該化合物具有式(I):
- 如請求項4之化合物或其醫藥上可接受之鹽,其中B係經為CH3或Cl之R1a取代及視情況經為CH3之R1b取代之呋喃基。
- 如請求項1至3中任一項之化合物或其醫藥上可接受之鹽,其中R3係H。
- 如請求項1至3中任一項之化合物或其醫藥上可接受之鹽,其中R5a及R5b中之每一者獨立地選自由H、CH3、Cl及F組成之群。
- 如請求項1至3中任一項之化合物或其醫藥上可接受之鹽,其中R6a及R6b中之每一者獨立地選自由H及C1-2烷基組成之群。
- 如請求項1或3之化合物或其醫藥上可接受之鹽,其中R4係H、C1-3烷基或Y,其中該C1-3烷基經四唑基或四唑酮基取代,其中該四唑基或四唑酮基視情況經C1-6烷基、C1-6羥基烷基或C1-4烷基-O-C1-4烷基取代,其中Y選自由吡啶基、吡唑基及苯基組成之群,其中該吡啶基、該吡唑基及該苯基具有1至3個各自獨立地選自-C1-4烷基、-C1-4烷氧基及-CO2H之取代基。
- 如請求項1或3之化合物或其醫藥上可接受之鹽,其中R7選自由甲基、乙基及CF3組成之群。
- 如請求項15之化合物或其醫藥上可接受之鹽,其中R1a係CH3;R1b係不存在或係CH3;R3係H或D;R4係H;R5a係H、F、Me或Cl或Br;R5b係H或F;R6a及R6b各自係H;且R7係甲基或乙基。
- 如請求項15之化合物或其醫藥上可接受之鹽,該化合物在帶有R3之碳原子處實質上沒有其他異構物。
- 如請求項15之化合物或其醫藥上可接受之鹽,其中R4係Y。
- 一種醫藥組合物,其包含如請求項1至24中任一項之化合物或其醫藥上可接受之鹽。
- 如請求項25之醫藥組合物,其進一步包含一或多種其他治療劑。
- 如請求項26之醫藥組合物,其中該一或多種其他治療劑選自由以下組成之群:細胞毒性化學療法、抗癌或抗腫瘤疫苗、抗免疫細胞介素療法、免疫細胞介素療法、嵌合抗原受體(chimeric antigen receptor;CAR)T細胞受體、基因轉移療法、檢查點抑制劑、皮質類固醇、類視色素樣藥劑、抗瘤藥及干擾素類似物。
- 如請求項26之醫藥組合物,其中該一或多種其他治療劑選自由以下組成之群:TNF α配體抑制劑、TNF結合劑、IL-1配體抑制劑;IL-6配體抑制劑、IL-8配體抑制劑;IL-17拮抗劑、TNF拮抗劑、視黃酸受體γ拮抗劑、IL-17A配體抑制劑;IL-17F配體抑制劑、神經鞘胺醇-1-磷酸受體-1拮抗劑、神經鞘胺醇-1-磷酸受體-1調節劑、IL-12拮抗劑;IL-23拮抗劑、II型TNF受體調節劑、IL-23A抑制劑、PDE 4抑制劑、JAK酪胺酸激酶抑 制劑、Jak1酪胺酸激酶抑制劑;Jak3酪胺酸激酶抑制劑、視黃酸受體激動劑、神經鞘胺醇-1-磷酸受體-1調節劑或TLR-7拮抗劑、TLR-8拮抗劑、TLR-9拮抗劑、IL-8拮抗劑、阻斷CTLA-4(CD152)、PD-1(CD279)、PDL-1(CD274)、TIM-3、LAG-3(CD223)、VISTA、KIR、NKG2A、BTLA、PD-1H、TIGIT、CD96、4-1BB(CD137)、4-1BBL(CD137L)、GARP、CSF-1R、A2AR、CD73、CD47、色胺酸2,3-二氧酶(TDO)或吲哚胺2,3二氧酶(IDO)之活性之藥物,及OX40、GITR、4-1BB、ICOS、STING或CD40之激動劑。
- 一種如請求項1至24中任一項之化合物或其醫藥上可接受之鹽或如請求項25至28中任一項之醫藥組合物的用途,其用於製造用來治療CXCR2及/或CCR6介導之疾病或病況之藥劑。
- 如請求項29之用途,其中該疾病或病況係急性或慢性發炎性病症。
- 如請求項30之用途,其中該急性或慢性發炎性病症係牛皮癬、乾眼病、動脈粥樣硬化、盤狀紅斑狼瘡、類風濕性關節炎、狼瘡、輻射誘發之纖維變性肺病、自體免疫大皰性皮膚病(autoimmune bullous dermatosis;AIBD)、慢性阻塞性肺病或臭氧誘發之氣道發炎。
- 如請求項29之用途,其中該疾病係選自由以下組成之群之癌症:皮膚T細胞淋巴瘤、非霍奇金氏淋巴瘤(non-Hodgkin lymphoma)、蕈狀肉芽腫、變形性骨炎網狀細胞增多症、西澤裡症候群(Sézary syndrome)、肉 芽腫性鬆弛狀皮膚、淋巴瘤樣丘疹病、慢性苔癬樣糠疹、急性痘瘡樣苔癬樣糠疹、CD30+皮膚T細胞淋巴瘤、繼發性皮膚CD30+大細胞淋巴瘤、非蕈狀肉芽腫CD30皮膚大T細胞淋巴瘤、多形性T細胞淋巴瘤、倫納特淋巴瘤(Lennert lymphoma)、皮下T細胞淋巴瘤、血管中心性淋巴瘤、母細胞性NK細胞淋巴瘤、B細胞淋巴瘤、霍奇金氏淋巴瘤(HL)、頭頸腫瘤;鱗狀細胞癌、橫紋肌癌、路易士肺癌(Lewis lung carcinoma;LLC)、非小細胞肺癌、食管鱗狀細胞癌、食管腺癌、腎細胞癌(renal cell carcinoma;RCC)、結腸直腸癌(colorectal cancer;CRC)、急性類骨髓性白血病(acute myeloid leukemia;AML)、乳癌、胃癌、前列腺小細胞神經內分泌癌(prostatic small cell neuroendocrine carcinoma;SCNC)、肝癌、神經膠母細胞瘤、口鱗狀細胞癌、胰臟癌、甲狀腺乳頭狀癌、肝內膽管細胞癌、骨癌、轉移及鼻咽癌。
- 如請求項32之用途,其中該藥劑係單獨或與一或多種其他抗癌療法組合使用。
- 如請求項33之用途,其中該藥劑係與以下各項中之一或多者組合使用:細胞毒性化學療法、抗癌疫苗、抗腫瘤疫苗、抗免疫細胞介素療法、免疫細胞介素療法、檢查點抑制劑及嵌合抗原受體(CAR)T細胞受體、基因轉移療法。
- 如請求項33之用途,其中該一或多種其他抗癌療法選自由以下組成之群:阻斷CTLA-4(CD152)、PD-1(CD279)、PDL-1(CD274)、TIM- 3、LAG-3(CD223)、VISTA、KIR、NKG2A、BTLA、PD-1H、TIGIT、CD96、4-1BB(CD137)、4-1BBL(CD137L)、GARP、CSF-1R、A2AR、CD73、CD47、色胺酸2,3-二氧酶(TDO)或吲哚胺2,3二氧酶(IDO)之活性之藥物,及OX40、GITR、4-1BB、ICOS、STING或CD40之激動劑。
- 如請求項31之用途,其中該藥劑係單獨或與一或多種其他治療劑組合使用。
- 如請求項36之用途,其中該藥劑係與以下各項中之一或多者組合使用:皮質類固醇、類視色素樣藥劑、抗瘤藥及干擾素類似物、TNF α配體抑制劑、TNF結合劑、IL-1配體抑制劑;IL-6配體抑制劑、IL-8配體抑制劑;IL-17拮抗劑、TNF拮抗劑、視黃酸受體γ拮抗劑、IL-17A配體抑制劑;IL-17F配體抑制劑、神經鞘胺醇-1-磷酸受體-1拮抗劑、神經鞘胺醇-1-磷酸受體-1調節劑、IL-12拮抗劑;IL-23拮抗劑、II型TNF受體調節劑、IL-23A抑制劑、PDE 4抑制劑、JAK酪胺酸激酶抑制劑、Jak1酪胺酸激酶抑制劑;Jak3酪胺酸激酶抑制劑、視黃酸受體激動劑、神經鞘胺醇-1-磷酸受體-1調節劑、TLR-7拮抗劑、TLR-8拮抗劑、TLR-9拮抗劑或IL-8拮抗劑。
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- 2016-11-17 CN CN201680068079.9A patent/CN108697684A/zh active Pending
- 2016-11-17 KR KR1020187017287A patent/KR20180100116A/ko not_active Application Discontinuation
- 2016-11-17 US US15/353,889 patent/US9834545B2/en active Active
- 2016-11-17 EP EP16867098.2A patent/EP3383386B8/en active Active
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AU2016357413B2 (en) | 2021-03-04 |
MX2018006150A (es) | 2019-05-27 |
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US9834545B2 (en) | 2017-12-05 |
IL259342A (en) | 2018-07-31 |
CA3005656A1 (en) | 2017-05-26 |
JP6923522B2 (ja) | 2021-08-18 |
CN108697684A (zh) | 2018-10-23 |
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EP3383386B8 (en) | 2024-03-20 |
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NZ742809A (en) | 2022-09-30 |
EP3383386A1 (en) | 2018-10-10 |
SG11201804133PA (en) | 2018-06-28 |
WO2017087607A1 (en) | 2017-05-26 |
EP3383386A4 (en) | 2019-07-03 |
US20180141934A1 (en) | 2018-05-24 |
KR20180100116A (ko) | 2018-09-07 |
AU2016357413A1 (en) | 2018-06-14 |
TW201720817A (zh) | 2017-06-16 |
IL259342B (en) | 2021-09-30 |
MA43382A (fr) | 2018-10-10 |
EA201891209A1 (ru) | 2018-12-28 |
US20170144997A1 (en) | 2017-05-25 |
US10988464B2 (en) | 2021-04-27 |
EA035666B1 (ru) | 2020-07-23 |
US11820759B2 (en) | 2023-11-21 |
BR112018009880A2 (pt) | 2018-11-13 |
PH12018501096A1 (en) | 2018-12-17 |
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