TW202227419A - 橋雜環基取代的嘧啶類化合物及其製備方法和醫藥用途 - Google Patents
橋雜環基取代的嘧啶類化合物及其製備方法和醫藥用途 Download PDFInfo
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Abstract
本發明關於橋雜環基取代的嘧啶類化合物及其製備方法和醫藥用途。本發明化合物或包含其的醫藥組成物可以作為JAK1和TYK2激酶抑制劑，用於治療與JAK1和TYK2激酶活性相關的疾病，例如炎症、自體免疫性病症、癌症等。
Description
本發明屬醫藥技術領域，具體關於一種橋雜環基取代的嘧啶類化合物、其製備方法及含有其的醫藥組成物，以及其用於調節Janus激酶1(JAK1)和酪胺酸蛋白質激酶2(TYK2)活性並且用於治療和/或預防與JAK1和TYK2活性相關的疾病的用途。
胞內信號傳遞過程是細胞對外界刺激產生反應，並最終引發特異性生物學效應的有效方式。細胞因子能夠藉由多種信號轉導通路進行胞內信號傳遞，從而參與調控造血功能和免疫相關的許多重要的生物學功能。蛋白酪胺酸激酶中的Janus激酶(JAK)家族和轉錄激活子(STAT)在細胞因子信號轉導過程中扮演重要角色(J.Immunol.2015,194,21)。
Janus激酶(JAK)家族在關於免疫應答的細胞增殖和功能的細胞因子依賴性調解中起著一定的作用。目前，有四種已知的哺乳動物JAK家族成員：JAK1(亦稱Janus激酶-1)、JAK2(亦稱Janus激酶-2)、JAK3(亦稱Janus激酶，白細胞，JAKL1，L-JAK和Janus激酶-3)、Tyk2(亦稱蛋白質-酪胺酸激
酶2)。JAK1、JAK2和Tyk2廣泛存在於各種組織和細胞中，而JAk3僅存在於骨髓和淋巴系統中(J.Med.Chem.2014,57,5023)。
Tyk2是第一個被發現的JAK激酶，在調控IL-12和細菌脂多糖(LPS)的生物學應答反應中起著重要作用，也參與IL-6、IL-10和IL-12介導的信號轉導通路。靶向Tyk2可成為治療IL-12、IL-23、或I型IFN介導的疾病的新策略，所述疾病包括但不限於類風濕性關節炎、多發性硬化症、狼瘡、銀屑病、銀屑病性關節炎、炎症性腸炎、葡萄膜炎、結節病、紅斑狼瘡和癌症。
JAK1在調控多種細胞因子受體家族的生物學應答功能中起著重要的作用。JAK1基因剔除小鼠具有早期的出生後致死因子顯型，神經系統也受到損害，導致幼鼠出現先天缺陷。研究表明JAK1基因剔除小鼠會出現胸腺細胞和B細胞的分泌缺陷，JAK1基因剔除的組織對LIF、IL-6、IL-10的反應明顯減弱。臨床試驗表明JAK1抑制劑在治療類風濕性關節炎、潰瘍性結腸炎、克羅恩病、紅斑狼瘡、斑禿、特應性皮炎等多種炎症和自體免疫性疾病方面都表現出很好的療效。
細胞因子與受體結合後，受體形成二聚體，與受體偶聯的JAK相互靠近並進行酪胺酸殘基磷酸化而活化。進而催化受體本身的酪胺酸殘基磷酸化，形成“停泊位點”。信號轉導和轉錄激活子(Signal Transducer and Activator of Transcription,STAT)是一組能與靶基因調控與DNA結合的胞質蛋白。STAT家族包括STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b和StAT6。STAT藉由SH2結構域識別“停泊位點”並被JAK激酶對其C端酪胺酸殘基進行磷酸化從而被激活。激活的STAT因子轉入細胞核內，在調節先天性和獲得性宿主免疫反應中起著重要的作用。
JAK/STAT信號轉導通路的激活促進各種疾病的發生，包括但不限於，許多異常免疫應答，如過敏、哮喘、類風濕性關節炎、肌萎縮性脊髓側索硬化症和多發性硬化症等。其還與癌症，例如白血病(急性髓性白血病和急性淋巴細胞白血病)、實體瘤(子宮平滑肌肉瘤、前列腺癌)等相關(Curr.Opin.Rheumatol.2014,26,237)。
鑒於JAK1和TYK2在炎症信號通路中扮演的重要角色，能同時抑制這兩種激酶的藥物有進一步提升藥效的潛力，給患者帶來更大的獲益。
本發明人經過潛心研究，設計合成了一系列橋雜環基取代的嘧啶類化合物，並對其進行了JAK1和TYK2活性的篩選，研究結果顯示該類化合物具有突出的JAK1和TYK2抑制活性，並且可以被開發為治療與JAK1和TYK2活性相關的疾病的藥物。
本發明的目的為提供選自以下的化合物或其可藥用鹽：
本發明進一步提供一種下式化合物1或其可藥用鹽的製備方法，其包括以下步驟：
將化合物1i的鹽酸鹽與化合物1j在鹼性條件和催化劑存在下反應得到化合物1；提供鹼性條件的試劑較佳為DIEA，催化劑較佳為HATU。
本發明還提供一種下式化合物2或其可藥用鹽的製備方法，其包括以下步驟：
將化合物1i的化合物與化合物2在鹼性條件和催化劑存在下反應得到化合物2；提供鹼性條件的試劑較佳為DIEA，催化劑較佳為HATU。
本發明還提供一種下式化合物1-a和/或1-b或其可藥用鹽的製備方法，其包括以下步驟：
將化合物1藉由超臨界流體色譜法分離得到化合物1-a和/或化合物1-b；其中，保留時間較短的為化合物1-a，保留時間較長的為化合物1-b。
本發明另外提供一種下式化合物2-a和/或2-b或其可藥用鹽的製備方法，其包括以下步驟：
將化合物2藉由超臨界流體色譜法分離得到化合物2-a和/或化合物2-b；其中，保留時間較短的為化合物2-a，保留時間較長的為化合物2-b。
本發明所述的超臨界流體色譜法是以超臨界流體作為流動相的一種色譜方法，所謂超臨界流體，是指既不是氣體也不是液體的一些物質，它們的物理性質介於氣體和液體之間。
本發明所述的超臨界流體色譜法較佳使用甲醇和二氧化碳作為流動相，更佳以含有氨水的甲醇與二氧化碳作為流動相，特別地使用MeOH(0.2% NH3．H2O)/CO2作為流動相，更特別地使用體積比為40：60的MeOH(0.2% NH3．H2O)/CO2作為流動相。
本發明另外提供一種醫藥組成物，其含有根據本發明所述的化合物以及藥學上可接受的載體。
本發明進一步關於根據本發明所述的化合物或者含有其的醫藥組成物在製備JAK1和TYK2抑制劑中的用途。
本發明進一步關於根據本發明所述的化合物或其可藥用鹽或者含有其的醫藥組成物在製備預防和/或治療與JAK1和TYK2活性相關的疾病的藥物中的用途，其中該疾病選自炎症、自體免疫性疾病和癌症，該炎症較佳選自類風濕性關節炎、銀屑病性關節炎、炎症性腸炎、葡萄膜炎、銀屑病和特應性皮炎，該自體免疫性疾病較佳選自多發性硬化症和狼瘡；該癌症較佳選自乳腺癌、
宮頸癌、結腸癌、肺癌、胃癌、直腸癌、胰腺癌、腦癌、皮膚癌、口腔癌、前列腺癌、骨癌、腎癌、卵巢癌、膀胱癌、肝癌、輸卵管腫瘤、卵巢瘤、腹膜腫瘤、黑色素瘤、實體瘤、神經膠質瘤、神經膠母細胞瘤、肝細胞癌、乳突腎性瘤、頭頸部腫瘤、白血病、淋巴瘤、骨髓瘤和非小細胞肺癌。
本發明進一步關於根據本發明所述的化合物或其可藥用鹽或者含有其的醫藥組成物，其用作藥物。
本發明進一步關於根據本發明所述的化合物或其可藥用鹽或者含有其的醫藥組成物，其用作JAK1和TYK2抑制劑。
本發明進一步關於根據本發明所述化合物或其可藥用鹽或者含有其的醫藥組成物，其用於預防和/或治療與JAK1和TYK2活性相關的疾病，其中該疾病選自炎症、自體免疫性疾病和癌症，該炎症較佳選自類風濕性關節炎、銀屑病性關節炎、炎症性腸炎、葡萄膜炎、銀屑病和特應性皮炎，該自體免疫性疾病較佳選自多發性硬化症和狼瘡；該癌症較佳選自乳腺癌、宮頸癌、結腸癌、肺癌、胃癌、直腸癌、胰腺癌、腦癌、皮膚癌、口腔癌、前列腺癌、骨癌、腎癌、卵巢癌、膀胱癌、肝癌、輸卵管腫瘤、卵巢瘤、腹膜腫瘤、黑色素瘤、實體瘤、神經膠質瘤、神經膠母細胞瘤、肝細胞癌、乳突腎性瘤、頭頸部腫瘤、白血病、淋巴瘤、骨髓瘤和非小細胞肺癌。
本發明進一步關於一種抑制JAK1和TYK2的方法，其包括將根據本發明所述的化合物或其可藥用鹽或者含有其的醫藥組成物與JAK1和TYK2接觸。
本發明進一步關於一種預防和/或治療與JAK1和TYK2活性相關的疾病的方法，其包括向需要其的受試者施用治療有效量的本發明所述的化合
物或其可藥用鹽或者含有其的醫藥組成物，其中該疾病選自炎症、自體免疫性疾病和癌症，該炎症較佳選自類風濕性關節炎、銀屑病性關節炎、炎症性腸炎、葡萄膜炎、銀屑病和特應性皮炎，該自體免疫性疾病較佳選自多發性硬化症和狼瘡；該癌症較佳選自乳腺癌、宮頸癌、結腸癌、肺癌、胃癌、直腸癌、胰腺癌、腦癌、皮膚癌、口腔癌、前列腺癌、骨癌、腎癌、卵巢癌、膀胱癌、肝癌、輸卵管腫瘤、卵巢瘤、腹膜腫瘤、黑色素瘤、實體瘤、神經膠質瘤、神經膠母細胞瘤、肝細胞癌、乳突腎性瘤、頭頸部腫瘤、白血病、淋巴瘤、骨髓瘤和非小細胞肺癌。
按照本發明所屬領域的常規方法，本發明化合物可以與酸生成藥學上可接受的酸式加成鹽。該酸包括無機酸和有機酸，特別較佳鹽酸、氫溴酸、硫酸、磷酸、甲磺酸、乙磺酸、對甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、馬來酸、檸檬酸、富馬酸、草酸、酒石酸、苯甲酸等。
按照本發明所屬領域的常規方法，本發明化合物可以與鹼生成藥學上可接受的鹼式加成鹽。該鹼包括無機鹼和有機鹼，可接受的有機鹼包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、胺丁三醇等，可接受的無機鹼包括氫氧化鋁、氫氧化鈣、氫氧化鉀、碳酸鈉和氫氧化鈉等。
含活性成分的醫藥組成物可以是適用於口服的形式，例如片劑、糖錠劑、錠劑、水或油混懸液、可分散粉末或顆粒、乳液、硬或軟膠囊，或糖漿劑或酏劑。可按照本領域任何已知製備醫藥組成物的方法製備口服組成物，此類組成物可含有一種或多種選自以下的成分：甜味劑、矯味劑、著色劑和防腐劑，以提供悅目和可口的藥用製劑。片劑含有活性成分和用於混合的適宜製備片劑的無毒的可藥用的賦形劑。這些賦形劑可以是惰性賦形劑，如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉；造粒劑和崩解劑，例如微晶纖維素、交聯羧甲基纖維素
鈉、玉米澱粉或藻酸；黏合劑，例如澱粉、明膠、聚乙烯吡咯烷酮或阿拉伯膠；和潤滑劑，例如硬脂酸鎂、硬脂酸或滑石粉。這些片劑可以不包衣或可藉由掩蓋藥物的味道或在胃腸道中延遲崩解和吸收，因而在較長時間內提供緩釋作用的已知技術將其包衣。例如，可使用水溶性味道掩蔽物質，例如羥丙基甲基纖維素或羥丙基纖維素，或延長時間物質例如乙基纖維素、醋酸丁酸纖維素。
也可用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的硬明膠膠囊，或其中活性成分與水溶性載體例如聚乙二醇或油溶媒例如花生油、液體石蠟或橄欖油混合的軟明膠膠囊提供口服製劑。
水混懸液含有活性物質和用於混合的適宜製備水混懸液的賦形劑。此類賦形劑是懸浮劑，例如羧基甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、藻酸鈉、聚乙烯吡咯烷酮和阿拉伯膠；分散劑或濕潤劑，可以是天然產生的磷脂例如卵磷脂，或烯化氧化物與脂肪酸的縮合產物，例如聚氧乙烯硬脂酸酯，或環氧乙烷與長鏈脂肪醇的縮合產物，例如十七碳亞乙基氧基鯨蠟醇(heptadecaethyleneoxy cetanol)，或環氧乙烷與由脂肪酸和己糖醇衍生的部分酯的縮合產物，例如聚環氧乙烷山梨醇單油酸酯，或環氧乙烷與由脂肪酸和己糖醇酐衍生的偏酯的縮合產物，例如聚環氧乙烷脫水山梨醇單油酸酯。水混懸液也可以含有一種或多種防腐劑例如尼泊金乙酯或尼泊金正丙酯、一種或多種著色劑、一種或多種矯味劑和一種或多種甜味劑，例如蔗糖、糖精或阿司帕坦。
油混懸液可藉由使活性成分懸浮於植物油如花生油、橄欖油、芝麻油或椰子油，或礦物油例如液體石蠟中配製而成。油混懸液可含有增稠劑，例如蜂蠟、硬石蠟或鯨蠟醇。可加入上述的甜味劑和矯味劑，以提供可口的製劑。可藉由加入抗氧化劑例如丁羥茴醚或α-生育酚保存這些組成物。
藉由加入水和用於混合的分散劑或濕潤劑、懸浮劑或一種或多種防腐劑，適用於製備水混懸液的可分散粉末和顆粒可以提供活性成分。適宜的分散劑或濕潤劑和懸浮劑如上所述。也可加入其他賦形劑例如甜味劑、矯味劑和著色劑。藉由加入抗氧化劑例如抗壞血酸保存這些組成物。
本發明的醫藥組成物也可以是水包油乳劑的形式。油相可以是植物油例如橄欖油或花生油，或礦物油例如液體石蠟或其混合物。適宜的乳化劑可以是天然產生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦單油酸酯，和該偏酯和環氧乙烷的縮合產物，例如聚環氧乙烷山梨醇單油酸酯。乳劑也可以含有甜味劑、矯味劑、防腐劑和抗氧劑。可用甜味劑例如甘油、丙二醇、山梨醇或蔗糖配製的糖漿和酏劑。此類製劑也可含有緩和劑、防腐劑、著色劑和抗氧劑。
本發明的醫藥組成物可以是無菌注射水溶液形式。可以使用的可接受的溶媒和溶劑有水、林格氏液和等滲氯化鈉溶液。無菌注射製劑可以是其中活性成分溶於油相的無菌注射水包油微乳。例如將活性成分溶於大豆油和卵磷脂的混合物中。然後將油溶液加入水和甘油的混合物中處理形成微乳。可藉由局部大量注射，將注射液或微乳注入患者的血流中。或者，最好按可保持本發明化合物恆定循環濃度的方式給予溶液和微乳。為保持這種恆定濃度，可使用連續靜脈內遞藥裝置。
本發明的醫藥組成物可以是用於肌內和皮下給藥的無菌注射水或油混懸液的形式。可按已知技術，用上述那些適宜的分散劑或濕潤劑和懸浮劑配製該混懸液。無菌注射製劑也可以是在無毒腸胃外可接受的稀釋劑或溶劑中製備的無菌注射溶液或混懸液，例如在1,3-丁二醇中製備的溶液。此外，可方便
地用無菌固定油作為溶劑或懸浮介質。為此目的，可使用包括合成甘油單或二酯在內的任何調和固定油。此外，脂肪酸例如油酸也可以製備注射劑。
可按用於直腸給藥的栓劑形式給予本發明化合物。可藉由將藥物與在普通溫度下為固體但在直腸中為液體，因而在直腸中會溶化而釋放藥物的適宜的無刺激性賦形劑混合來製備這些醫藥組成物。此類物質包括可可脂、甘油明膠、氫化植物油、各種分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。
所屬技術領域具有通常知識者熟知，藥物的給藥劑量依賴於多種因素，包括但並非限定於以下因素：所用特定化合物的活性、病人的年齡、病人的體重、病人的健康狀況、病人的行被、病人的飲食、給藥時間、給藥方式、排泄的速率、藥物的組合等。另外，最佳的治療方式如治療的模式、化合物的日用量或可藥用的鹽的種類可以根據傳統的治療方案來驗證。
本發明可以含有化合物，及其可藥用鹽、水合物或溶劑化物作為活性成分，與藥學上可接受的載體或賦型劑混合製備成組成物，並製備成臨床上可接受的劑型。
本發明的衍生物可以與其他活性成分組合使用，只要它們不產生其他不利的作用，例如過敏反應等。本發明化合物可作為唯一的活性成分，也可以與其它治療與JAK1和TYK2活性相關的疾病的藥物聯合使用。聯合治療藉由將各個治療組分同時、分開或相繼給藥來實現。
在本文中，“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上/可藥用的鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學/可藥用的載體和賦形劑。醫藥組成物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。
在本文中，“可藥用鹽”是指本發明化合物的鹽，這類鹽用於哺乳動物體內時具有安全性和有效性，且具有應有的生物活性。
圖1為本發明化合物的大鼠AIA藥效學評分結果圖。
以下結合實施例進一步描述本發明，但這些實施例並非限制著本發明的範圍。
化合物的結構是藉由核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移以10-6(ppm)的單位給出。NMR的測定是用Brukerdps300型核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d 6 )、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，內標為四甲基矽烷(TMS)。
MS的測定用1100 Series LC/MSD Trap(ESI)質譜儀(生產商：Agilent)。
實施例中無特殊說明，製備液相使用lc3000高效液相色譜儀以及lc6000高效液相色譜儀(生產商：創新通恆)。色譜管柱為DaisogelC18 10μm 60A(20mm×250mm)。流動相：乙腈，水(0.05甲酸%)。
高效液相色譜法(HPLC)使用島津LC-20AD高壓液相色譜儀(Agilent TC-C18 250×4.6mm 5μm色譜管柱)和島津LC-2010AHT高壓液相色譜儀(Phenomenex C18 250×4.6mm5μm色譜管柱)。
薄層層析矽膠板使用青島海洋化工GF254矽膠板，薄層色譜法(TLC)使用的矽膠板採用的規格是0.15mm~0.2mm，薄層層析分離純化產品採用的規格是0.4mm~0.5mm。
管柱層析一般使用青島海洋矽膠100~200目、200~300目矽膠為載體。
本發明的已知的起始原料可以採用或按照本領域已知的方法來合成，或可購買自網化商城、北京耦合、Sigma、百靈威、易世明、上海書亞、伊諾凱、南京藥石、安耐吉化學等公司。
實施例中無特殊說明，反應能夠均在氬氣氛或氮氣氛下進行。
氬氣氛或氮氣氛是指反應瓶連接一個約1L容積的氬氣或氮氣氣球。
微波反應使用CEM Discover SP型微波反應器。
實施例中無特殊說明，溶液是指水溶液。
實施例中無特殊說明，反應的溫度為室溫，為20℃~30℃。
實施例中的反應進程的監測採用薄層色譜法(TLC)，反應所使用的展開劑的體系有：A：二氯甲烷和甲醇體系，B：正己烷和乙酸乙酯體系，C：石油醚和乙酸乙酯體系，D：丙酮，溶劑的體積比根據化合物的極性不同而進行調節。
純化化合物採用的管柱層析的沖提劑的體系和薄層色譜法的展開劑體系包括：A：二氯甲烷和甲醇體系，B：石油醚、乙酸乙酯和二氯甲烷體系，C：石油醚和乙酸乙酯體系，溶劑的體積比根據化合物的極性不同而進行調節，也可以加入少量的三乙胺和醋酸等鹼性或酸性試劑進行調節。
[實施例]
實施例1：((1S,2R)-2-氟環丙基)(3-(2-((1-甲基-1H-吡唑-4-基)胺基)嘧啶-4-基)-8-氮雜雙環[3.2.1]辛-2-烯-8-基)甲酮(1)的製備
步驟1：3-(((三氟甲基)磺醯基)氧基)-8-氮雜雙環[3.2.1]辛-2-烯-8-羧酸第三丁酯(1b)的合成
於-78℃，氮氣氛下，將六甲基二矽基胺基鉀(KHMDS)(10.7mL，10.7mmol)加入3-側氧-8-氮雜雙環[3.2.1]辛烷-8-羧酸第三丁酯(2.00g，8.88mmol)的無水四氫呋喃(30mL)混合液中，-78℃攪拌0.5小時。滴加N-苯基雙(三氟甲烷磺醯)亞胺(3.82g，10.7mmol)的無水四氫呋喃溶液(20mL)中，
滴加完畢後於-78℃攪拌2小時。加入飽和氯化銨水溶液(20mL)淬滅，用乙酸乙酯(30mL×3)萃取，有機相用氫氧化鉀溶液(1mol/L)和飽和鹽水洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮，殘留液經快速(flash)管柱色譜法(流動相：石油醚/乙酸乙酯，10/1至2/1)純化，得到3.10g淡黃色油狀液體標題化合物。收率：97.8%。
步驟2：3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-8-氮雜雙環[3.2.1]辛-2-烯-8-甲酸第三丁酯(1d)的合成
於室溫，氮氣氛下，將Pd(dppf)Cl2二氯甲烷絡合物(423mg，0.518mmol)加入化合物1b(3.70g，10.4mmol)、醋酸鉀(3.05g，31.1mmol)和聯硼酸頻那醇酯(1c)(2.90g，11.4mmol)的二噁烷(50mL)溶液中，於80℃攪拌過夜。旋乾溶劑，加入水(40mL)中，用乙酸乙酯(50mL×3)萃取，有機相用飽和鹽水洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮，殘留液經快速管柱色譜法(流動相：石油醚/乙酸乙酯=10/1至2/1)純化，得到1.20g黃色油狀液體標題化合物。收率：34.6%。
步驟3：3-(2-氯嘧啶-4-基)-8-氮雜雙環[3.2.1]辛-2-烯-8-羧酸第三丁酯(1f)的合成
於室溫，氮氣氛下，將Pd(dppf)Cl2(262mg，0.358mmol)加入化合物1d(1.20g，3.58mmol)、碳酸鉀(1.24g，8.95mmol)和2,4-二氯嘧啶(1e)(534mg，3.58mmol)的二噁烷(40mL)和水(10mL)的混合溶液中，於80℃攪拌過夜。旋乾溶劑，加入水(40mL)中，用乙酸乙酯(50mL×3)萃取，有機相用飽和鹽水洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮，殘留液經快速
管柱色譜法(流動相：石油醚/乙酸乙酯=10/1至1/1)純化，得到830mg黃色油狀液體標題化合物。收率：72.1%。
步驟4：3-(2-((1-甲基-1H-吡唑-4-基)胺基)嘧啶-4-基)-8-氮雜雙環[3.2.1]辛-2-烯-8-羧酸第三丁酯(1h)的合成
於室溫，將對甲苯磺酸(TsOH)(37.3mg，0.217mmol)加入化合物1f(700mg，2.17mmol)和1-甲基-1H-吡唑-4-胺(1g)(211mg，2.17mmol)的二噁烷(10mL)溶液中，於90℃攪拌過夜。旋乾溶劑，加入水(40mL)中，用乙酸乙酯(50mL×3)萃取，有機相用飽和鹽水洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮，殘留液經快速管柱色譜法(流動相：石油醚/乙酸乙酯=10/1至1/1)得到600mg棕色油狀液體標題化合物。收率：72.4%。
步驟5：4-(8-氮雜雙環[3.2.1]辛-2-烯-3-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺鹽酸鹽(1i)的合成
於室溫，將HCl/1,4-二噁烷(6mL，4M)加入化合物1h(200mg，0.524mmol)的二氯甲烷(6mL)溶液中，攪拌30分鐘，低溫濃縮，得到157mg白色固體粗品標題化合物。
步驟6：((1S,2R)-2-氟環丙基)(3-(2-((1-甲基-1H-吡唑-4-基)胺基)嘧啶-4-基)-8-氮雜雙環[3.2.1]辛-2-烯-8-基)甲酮(1)的合成
於室溫，將2-(7-氧化苯并三唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(HATU)(224mg，0.590mmol)加入(1S,2R)-2-氟環丙烷-1-羧酸(1j)(51mg,0.492mmol)的N,N-二甲基甲醯胺(10mL)溶液中，於室溫攪拌30分鐘。加入化合物1i(132mg,0.414mmol)和N,N-二異丙基乙胺(DIEA)(190mg，1.48mmol)，於室溫攪拌過夜。加入水(50mL)中，用乙酸乙酯(30mL×3)萃取，
有機相用飽和鹽水洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮，殘留物經製備液相色譜法(管柱：30mm×250mm；填料：C18，10μm；方法：2-22min，乙腈10-40%；波長：254nm；流速：45mL/min；流動相：乙腈，水)純化，得95.0mg黃色固體標題化合物，收率：59.4%。
LC-MS：m/z 369[M+H]+；
1H NMR(300MHz,DMSO-d 6 )：δ ppm 9.34(s,1H),8.34-8.32(m,1H),7.81(s,1H),7.49(s,1H),7.28-7.11(m,1H),6.84-6.78(m,1H),5.94-4.61(m,3H),3.45(s,3H),2.92-2.83(m,1H),2.63-2.49(m,2H),2.39-2.25(m,1H),2.18-2.04(m,1H),2.01-1.83(m,1H),1.75-1.63(m,1H),1.37-1.19(m,1H),1.11-1.07(m,1H)。
實施例1-a和1-b：((1S,2R)-2-氟環丙基)((1S,5R)-3-(2-((1-甲基-1H-吡唑-4-基)胺基)嘧啶-4-基)-8-氮雜雙環[3.2.1]辛-2-烯-8-基)甲酮和((1S,2R)-2-氟環丙基)((1R,5S)-3-(2-((1-甲基-1H-吡唑-4-基)胺基)嘧啶-4-基)-8-氮雜雙環[3.2.1]辛-2-烯-8-基)甲酮的製備
化合物1-a和1-b由化合物1藉由超臨界流體色譜法(SFC)分離得到。
SFC分離條件：色譜管柱型號：AD-H 4.6mm x 250mm，5μm，流動相：MeOH(0.2% NH3．H2O)/CO2=40：60，流速：40g/min，管柱溫：40℃。
化合物1-a：
保留時間：14.97min。
LC-MS：m/z 369[M+H]+。
1H NMR(300MHz,DMSO-d 6)：9.32(s,1H),8.31(d,J=5.20,1H),7.79(d,J=5.60,1H),7.47(s,1H),7.17-7.14(m,1H),6.80-6.77(m,1H),5.00-4.61(m,3H),3.77(s,3H),2.90-2.80(m,1H),2.62-2.47(m,2H),2.36-2.30(m,1H),2.22-2.05(m,1H),2.00-1.86(m,1H),1.76-1.62(m,1H),1.35-1.17(m,1H),1.07-1.04(m,1H)。
化合物1-b：
保留時間：17.98min。
LC-MS：m/z 369[M+H]+。
1H NMR(300MHz,DMSO-d 6)：9.36(s,1H),8.35-8.33(m,1H),7.82(s,1H),7.51(s,1H),7.30-7.05(m,1H),6.85-6.81(m,1H),4.90-4.63(m,3H),3.09(s,3H),2.95-2.85(m,1H),2.65-2.58(m,2H),2.40-2.20(m,1H),2.10-2.00(m,1H),2.00-1.86(m,1H),1.76-1.62(m,1H),1.42-1.33(m,1H),1.19-1.07(m,1H)。
實施例2：((1R,2S)-2-氟環丙基)(3-(2-((1-甲基-1H-吡唑-4-基)胺基)嘧啶-4-基)-8-氮雜雙環[3.2.1]辛-2-烯-8-基)甲酮(2)的製備
與實施例1的製備方法相同，除了用(1R,2S)-2-氟環丙烷-1-羧酸(2a)替代(1S,2R)-2-氟環丙烷-1-羧酸(1j)，製得標題化合物2。
製備液相色譜純化方法：管柱：30mm×250mm；填料：C18，10μm；方法：2-22min，乙腈10-50%；波長：254nm；流速：45mL/min；流動相：乙腈，水。
LC-MS：m/z 365[M+H]+。
1H NMR(300MHz,DMSO-d 6)：δ ppm 9.34(s,1H),8.34-8.30(m,1H),7.83(s,1H),7.51(s,1H),7.18-7.12(m,1H),6.84-6.80(m,1H),4.98-4.64(m,3H),3.80(s,3H),2.93-2.87(m,1H),2.68-2.50(m,2H),2.35-2.24(m,1H),2.08-2.05(m,1H),1.92-1.84(m,1H),1.80-1.61(m,1H),1.41-1.34(m,1H),1.18-1.05(m,1H)。
實施例2-a和2-b：((1R,2S)-2-氟環丙基)((1S,5R)-3-(2-((1-甲基-1H-吡唑-4-基)胺基)嘧啶-4-基)-8-氮雜雙環[3.2.1]辛-2-烯-8-基)甲酮和((1R,2S)-2-氟環丙基)((1R,5S)-3-(2-((1-甲基-1H-吡唑-4-基)胺基)嘧啶-4-基)-8-氮雜雙環[3.2.1]辛-2-烯-8-基)甲酮的製備
化合物2-a和2-b由化合物2藉由超臨界流體色譜法(SFC)分離得到。
SFC分離條件：色譜管柱型號：AD-H 4.6mm x 250mm，5μm，流動相：MeOH(0.2% NH3．H2O)/CO2=40：60，流速：40g/min，管柱溫：40℃。
化合物2-a：
保留時間：12.53min。
LC-MS：m/z 369[M+H]+。
1H NMR(400MHz,DMSO)：δ9.35(s,1H),8.35-8.32(m,1H),7.82(s,1H),7.50(s,1H),7.19-7.15(m,1H),6.85-6.81(m,1H),4.90-4.63(m,3H),3.81(s,3H),2.91-2.89(m,1H),2.67-2.51(m,2H),2.47-2.29(m,1H),2.09-2.04(m,1H),1.91-1.81(m,1H),1.74-1.58(m,1H),1.45-1.31(m,1H),1.14-1.08(m,1H)。
化合物2-b：
保留時間：15.46min。
LC-MS：m/z 369[M+H]+。
1H NMR(400MHz,DMSO)：δ 9.35(s,1H),8.35-8.33(m,1H),7.82(s,1H),7.50(s,1H),7.19-7.15(m,1H),6.83-6.81(m,1H),5.03-4.65(m,3H),3.80(s,3H),2.91-2.89(m,1H),2.67-2.51(m,2H),2.48-2.28(m,1H),2.10-2.01(m,1H),1.98-1.86(m,1H),1.84-1.65(m,1H),1.38-1.33(m,1H),1.20-1.06(m,1H)。
生物學評價
試驗例1：本發明化合物體外JAK1激酶抑制活性的測定
實驗材料：JAK1激酶(Invitrogen，PV4744)、ATP(Promega，V915B)、ADP-Glo Kinase Assay(Promega，V9101)、IRS1(Signalchem，I40-58-1000)。
樣品配製：將本發明化合物和對照品分別溶於DMSO溶劑中，配成10mM母液。最終化合物反應最高濃度為10μM，3倍稀釋，10個濃度梯度，每個濃度梯度設2個複孔。
實驗方法：Echo轉移0.1μL的待測化合物到384孔反應板中(PE，6007290)，1000rpm/min，離心1min。轉移5μL的JAK1激酶(終濃度4nM)到384孔反應板中，1000rpm/min，離心1min，25℃孵育15min。轉移5μL受質混合物(1mM ATP，IRS1 0.05mg/ml，激酶緩衝溶液)到384孔反應板中，1000rpm/min，離心1min，25℃孵育60min。轉移10μL ADP-Glo到384孔反應板中1000rpm/min，離心1min，25℃孵育40min。轉移20μL檢測溶液到384孔反應板中1000rpm/min，離心1min，25℃孵育40min。使用Envision多功能讀板機讀取相對發光單元(RLU，Relative luminescence unit)信號。信號強度用於表徵激酶的活性程度。
利用以下非線性擬合公式得到化合物的IC50(半數抑制濃度)：
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))；
X：化合物濃度Log值；
Y：發射率(Emission Ratio)；
Bottom：最低值，Top：最高值，HillSlope：斜率；
本發明化合物對JAK1激酶的抑制活性見下表1。IC50值在0-100nM標記為A，100-300nM標記為B，300-1000nM標記為C，大於1000nM標記為D，NT代表未測試。
表1：本發明化合物對JAK1激酶的抑制活性
從上述試驗結果可以清楚地看出，本發明化合物具有良好的體外抗JAK1激酶活性。
試驗例2：本發明化合物對於人全血STAT3信號通路的抑制
實驗材料：CD3(BD，555335)，pSTAT3抗體(BD，612569)，IFN-2α(Biolegend，592702)。
樣品製備：將本發明化合物和對照品分別溶於DMSO溶劑中，配成10mM母液。最終化合物反應最高濃度為10μM，3倍稀釋，10個濃度梯度，每個濃度梯度設2個複孔。
實驗方法：向含有180μL經肝素鈉抗凝的流式細胞管(BD，352052)，加入20μL本發明化合物後，對照加20μL PBS，37℃孵育30min；加
入刺激因子2μL，37℃孵育20min；加入1mL紅細胞裂解液，迅速反復顛倒5-10次或者渦旋樣品，37℃孵育10min；600g離心6-8min，棄上清，渦旋至懸起沉澱；加入3mL PBS洗滌細胞；600g離心6-8min，棄上清；渦旋，懸起沉澱；加入1mL破膜液，輕輕混勻，冰上孵育30min；600g離心6-8min，棄上清；渦旋，懸起沉澱；洗滌細胞，加入3mL PBS，600g離心6-8min，棄上清；渦旋，懸起沉澱；重複2次，每個染色管加入100μL PBS，加入IFN-2α刺激，並加入CD3和pSTAT3抗體(20μL)，混勻，避光；室溫孵育60min。洗滌細胞，加入3mL PBS，600g離心6-8min，棄上清；渦旋，懸起沉澱。沉澱懸在150μL，避光，準備流式細胞儀分析。利用以下非線性擬合公式得到化合物的IC50(半數抑制濃度)：
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))；
X：化合物濃度Log值；
Y：發射率(Emission Ratio)；
Bottom：最低值，Top：最高值，HillSlope：斜率
本發明化合物對於IFN-2α刺激的TYK2/JAK1介導通路的抑制情況見下表2。IC50值在0-100nM標記為A，100-300nM標記為B，300-1000nM標記為C，大於1000nM標記為D，NT代表未測試。
表2：本發明化合物對於人全血STAT3信號通路的抑制情況
由表2可以看出，本發明化合物對於人全血TYK2/JAK1介導的信號通路具有很好的抑制作用。
試驗例3：大鼠體內藥物代謝動力學研究
樣品製備：實施例1-a和1-b化合物用20%環糊精配製成0.2mg/mL和0.5mg/mL溶液。
實驗方法：選用雄性SD大鼠(北京市維通利華實驗技術有限公司)，靜脈給藥劑量為1mg/kg(靜脈注射，i.v)，在給藥前及給藥後0、5分鐘、15分鐘、30分鐘、1小時、2小時、4小時、6小時及8小時從眼眥靜脈叢進行採血。口服給藥劑量為5mg/kg(口服，p.o)，在給藥前及給藥後15分鐘、30分鐘、1小時、2小時、4小時、6小時及8小時從眼眥靜脈叢進行採血。血液經肝素鈉抗凝，於4℃，3500rpm離心10分鐘，獲取血漿在-20℃保存直至測試。
精密量取於室溫下融化的血漿樣品50μL，置於1.5mL EP管中，向其中加入400μL維拉帕米內標工作液(中國藥品檢定研究院)，渦旋劇烈震盪1分鐘，16000rpm離心10分鐘。取上清液，用0.22μm有機膜(AS081320-T，Agela Technologies)過濾，加入進樣小瓶中，經LC/MS(Waters UPLC I Class/TQ-S micro)分析得出血藥濃度，並經過DAS3.3.0軟體分析得到化合物1-a和1-b在大鼠體內主要藥物代謝動力學參數，見下表3。
表化合物1-a和1-b的大鼠藥物代謝動力學參數，其中，AUC在<500μg/L*h標記為C，500-1000μg/L*h標記為B，>1000μg/L*h標記為A；Cmax在<300μg/L標記為C，300-500μg/L標記為B，>500μg/L標記為A；T1/2在<1h標記為B，>1h標記為A；F在<30%標記為C，30-50% h標記為B，>50%標記為A。
表3：本發明化合物1-a和1-b的大鼠藥物代謝動力學參數
由表3可以看出，本發明化合物1-a和1-b具有良好的藥物代謝動力學性質，適合用於口服給藥。
試驗例4：本發明化合物的大鼠AIA藥效學研究
實驗材料：完全弗氏佐劑(Chondrex，7027)；陽性對照化合物PF-06700841，其結構為
，根據J Med Chem,2018,61 8597-8612製備。
實驗方法：考察本發明化合物體內藥效，選8週雌性Lewis大鼠(維通利華實驗動物技術有限公司)，尾根部皮下單點注射完全弗氏佐劑0.1mL，造模13天後分組，實驗分為8組，分別是正常組、模型組、PF-06700841低劑量組、PF-06700841高劑量組、化合物1-a低劑量組、化合物1-a高劑量組、化合物1-b低劑量組和化合物1-b高劑量組(將待測化合物用20%環糊精溶液分別配製成0.1mg/mL和0.3mg/mL濃度的溶液)。模型組給予20%環糊精，低劑量組給予1mg/kg受試物，高劑量組給予3mg/kg受試物，給藥後每2天評1次分值。評分標準將按照如下所示：0分：無紅腫；1分：輕度的、踝關節、腕關節發紅、
腫脹；2分：踝關節、腕關節中度的發紅、腫脹；3分：爪子嚴重發紅、腫脹包括指端；4分：四肢最大程度發炎，包括多關節。評分結果由Graph prism9.0軟體進行統計。
圖1為本發明化合物的大鼠AIA藥效學評分結果圖。由AIA模型體內藥效實驗結果可以看出，在低劑量組和高劑量組，本發明化合物1-a和1-b的藥效均顯著優於對照品PF-06700841。同時，異構體1-a的藥效顯著優於異構體1-b。
Claims (9)
- 一種選自以下的化合物或其可藥用鹽，
- 一種下式化合物1或其可藥用鹽的製備方法，其包括以下步驟：
將化合物1i的鹽酸鹽與化合物1j在鹼性條件和催化劑存在下反應得到化合物1；提供鹼性條件的試劑較佳為DIEA，催化劑較佳為HATU。 - 一種下式化合物2或其可藥用鹽的製備方法，其包括以下步驟：
將化合物1i的鹽酸鹽與化合物2在鹼性條件和催化劑存在下反應得到化合物2；提供鹼性條件的試劑較佳為DIEA，催化劑較佳為HATU。 - 一種下式化合物1-a和/或1-b或其可藥用鹽的製備方法，其包括以下步驟：
將化合物1藉由超臨界流體色譜法分離得到化合物1-a和/或化合物1-b；其中，保留時間較短的為化合物1-a，保留時間較長的為化合物1-b。 - 一種下式化合物2-a和/或2-b或其可藥用鹽的製備方法，其包括以下步驟：
將化合物2藉由超臨界流體色譜法分離得到化合物2-a和/或化合物2-b；其中，保留時間較短的為化合物2-a，保留時間較長的為化合物2-b。 - 如請求項4或5所述的製備方法，其中超臨界流體色譜法中的流動相為甲醇和二氧化碳，較佳以含有氨水的甲醇與二氧化碳作為流動相。
- 一種醫藥組成物，其含有如請求項1所述的化合物或其可藥用鹽，以及藥學上可接受的載體。
- 一種如請求項1所述的化合物或其可藥用鹽或如請求項7所述的醫藥組成物在製備預防和/或治療與JAK1和TYK2活性相關的疾病的藥物中的用途。
- 一種如請求項8所述的用途，其中該疾病選自炎症、自體免疫性疾病和癌症，該炎症較佳選自類風濕性關節炎、銀屑病性關節炎、炎症性腸炎、葡萄膜炎、銀屑病和特應性皮炎，該自體免疫性疾病較佳選自多發性硬化症和狼瘡，該癌症較佳選自乳腺癌、宮頸癌、結腸癌、肺癌、胃癌、直腸癌、胰腺癌、腦癌、皮膚癌、口腔癌、前列腺癌、骨癌、腎癌、卵巢癌、膀胱癌、肝癌、輸卵管腫瘤、卵巢瘤、腹膜腫瘤、黑色素瘤、實體瘤、神經膠質瘤、神經膠母細胞瘤、肝細胞癌、乳突腎性瘤、頭頸部腫瘤、白血病、淋巴瘤、骨髓瘤和非小細胞肺癌。
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