TWI810547B - Pd-l1拮抗劑化合物 - Google Patents
Pd-l1拮抗劑化合物 Download PDFInfo
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- TWI810547B TWI810547B TW110113480A TW110113480A TWI810547B TW I810547 B TWI810547 B TW I810547B TW 110113480 A TW110113480 A TW 110113480A TW 110113480 A TW110113480 A TW 110113480A TW I810547 B TWI810547 B TW I810547B
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Abstract
本發明提供了一種式(I)化合物及其藥物組合物,以及使用式(I)化合物預防和/或治療免疫相關病症的方法。
Description
本發明涉及一種PD-L1拮抗劑化合物,以及使用其治療/預防免疫相關病症的方法。
腫瘤免疫治療由於其卓越的療效和創新性,在2013年被《科學》雜誌評為年度最重要的科學突破。腫瘤免疫治療有望成為繼手術、化療、放療、靶向治療後腫瘤治療領域的一場革新。腫瘤免疫治療是應用免疫學原理和方法,提高腫瘤細胞的免疫原性和對效應細胞殺傷的敏感性,激發和增強機體抗腫瘤免疫應答,並應用免疫細胞和效應分子輸注宿主體內,協同機體免疫系統殺傷腫瘤、抑制腫瘤生長。腫瘤免疫治療近來備受關注,是腫瘤治療領域的焦點。近幾年,腫瘤免疫治療的好消息不斷,目前已在一些腫瘤類型如黑色素瘤,非小細胞肺癌等的治療中展示出了強大的抗腫瘤活性,並已有腫瘤免疫治療藥物獲得美國食品藥物管理局(Food and Drug Administration,FDA)批准臨床應用。
程式性死亡受體1(programmed death 1,PD-1)為CD28超家族成員。以PD-1為靶點的免疫調節在抗腫瘤、抗感染、抗自身免疫性疾病及器官移植存活等方面均有重要的意義。其配體PD-L1也可作為靶點,相應的抗體也可以起到相同的作用。程式性死亡受體-配體1(programmed cell death-Ligand 1,PD-L1)是大小為40kDa的第一型跨膜蛋白。正常情形下免疫系統會對聚集在淋巴結或脾臟的外來抗原產生反應,促進具有抗原特異性的T細胞增殖。而PD-1與PD-
L1結合,可以傳導抑制性的信號,減低T細胞的增殖。
腫瘤細胞逃避T細胞摧毀的一種途徑是通過在它表面產生PD-L1。當免疫細胞T細胞表面的PD-1識別PD-L1後,可以傳導抑制性信號,T細胞就不能發現腫瘤細胞和向腫瘤細胞發出攻擊信號。PD-1是通過解除腫瘤細胞逃避免疫系統的新型免疫療法。PD-1免疫療法的作用機制是針對PD-1或PD-L1設計特定的蛋白質抗體,阻止PD-1和PD-L1的識別過程,部分恢復T細胞功能,從而使T細胞可以殺死腫瘤細胞。
PD-1表達於活化的T細胞,B細胞及髓系細胞,其有兩個配體,即PD-L1和PD-L2。PD-L1/L2在抗原遞呈細胞都表達,PD-L1在多種組織也有表達。PD-1與PD-L1的結合介導T細胞活化的共抑制信號,調節T細胞活化和增殖,起到類似於CTLA-4的負調節作用。華裔科學家陳列平實驗室首先發現PD-L1在腫瘤組織高表達,而且調節腫瘤浸潤CD8 T細胞的功能。因此,以PD-1/PD-L1為靶點的免疫調節對抗腫瘤有重要的意義。
多個靶向PD-1/PD-L1相互作用的治療性單克隆抗體(mAbs)已被美國FDA批准上市。除了開發相關單克隆抗體之外,尋找方便癌症患者的口服小分子化合物用來靶向抑制免疫檢查點也是腫瘤免疫療法的前沿領域。小分子化合物能夠穿過細胞膜作用於細胞內靶點,所以應用範圍廣泛。其次,小分子經化學修飾後往往具有良好的生物利用度和依從性,有效避免消化腸道中酶類的分解失活。最後,在生產工藝、劑型設計和給藥方式等多種層面,小分子的研究也頗為成熟。
大多數單克隆抗體(monoclonal antibody,mAbs)的使用途徑是高劑量的靜脈注射。小分子藥物,其更適合口服給藥,可以減少嚴重的免疫相關不良事件。與單克隆抗體相比,小分子藥物抑制劑有很多其他好處,例如,製造成本更經濟、穩定,且器官和腫瘤的滲
透性更好。考慮到小分子藥物動力學性質的眾多優點,它將會在單一療法或其它組合方案裡體現出劑量上的靈活性。本發明的小分子化合物的可為患者和醫生提供一個引人注目的治療選擇。
本發明提供了一種式(I)化合物或其藥學上可接受的鹽、前藥、同位素衍生物、水合物、異構體、溶劑化物、或其代謝產物:
其中,RL表示:氫、C1-C6烷基、-O(C1-C6烷基)、-O(C3-C6環烷基)、
鹵素、硝基、氰基、-NRaRb、鹵代(C1-C6烷基)或C3-C6環烷基;T、A各自獨立地表示:被0、1、2或3個取代基所取代的-(C1-C6烷基)、-(C0-C6亞烷基)-(C3-C12環烷基)、-(C0-C6亞烷基)-(3-12元雜環)、-(C0-C6亞烷基)-(C6-C10芳基)或-(C0-C6亞烷基)-(5-10元雜芳基),其中所述取代基選自:氰基、氧代、鹵素、C1-C6烷基、-(C0-C6亞烷基)ORa、氰基C1-C6烷基、鹵代(C1-C6烷基)、C3-C8環烷基、-(C0-C6亞烷基)C(O)Ra、-(C0-C6亞烷基)C(O)ORa、-(C0-C6亞烯基)C(O)ORa、-(C0-C6亞烷基)NRaRb、-C(O)NRaRb、-NRaSO2Rb、-C(O)NRaSO2Rb和-NRaC(O)Rb;
其中,RA、RB各自獨立地表示:氫、C1-C6烷基、-(C0-C3亞烷基)(C3-C12環烷基)、-(C0-C3亞烷基)(3-12元雜環)、鹵代(C1-C6烷基)或鹵素,或者RA與RB連同其共同相連的碳原子一起形成3-6元環;RC、RD各自獨立地表示:氫、C1-C6烷基、-(C0-C3亞烷基)(C3-C12環烷基)、-(C0-C3亞烷基)(3-12元雜環)、鹵代(C1-C6烷基)或鹵素,或者RC與RD連同其共同相連的碳原子一起形成3-6元環;Ra、Rb各自獨立地表示:氫、C1-C6烷基、鹵代(C1-C6烷基)、-(C0-C6
亞烷基)OH、-(C0-C3亞烷基)(C3-C12環烷基)、-(C0-C3亞烷基)(3-12元雜環)、-(C0-C3亞烷基)(C6-C10元芳環)、-(C0-C3亞烷基)(5-10元雜芳環)或鹵代(C1-C6烷基),或者Ra與Rb連同其共同相連的原子一起形成3-6元環;其中,m、o均各自獨立地表示0、1或2;其中,p、q均各自獨立地表示0、1、2或3。
優選地,所述式(I)化合物具有以下式(II)結構:
優選地,所述式(I)化合物具有以下式(III)結構:
優選地,所述式(I)化合物具有以下式(IV)結構:
在本發明的化合物中,L1優選地選自-CRARB-,其中RA、RB各自獨立地選自氫、鹵素、C1-C6烷基和鹵代(C1-C6烷基),優選為氫。
在本發明的化合物中,L2和L3各自優選地獨立地選自-CRCRD-和-CRCRD-NRa-(CRCRD)q-,其中,q選自0、1或2,其中RC、RD各自獨立地選自氫、鹵素、C1-C6烷基和鹵代(C1-C6烷基),優選為氫;Ra各自獨立地選自氫、C1-C6烷基、鹵代(C1-C6烷基)和-(C0-C3亞烷基)C3-C12環烷基。
在本發明的化合物中,W1、W2各自優選地獨立地表示CH或者N。
在本發明的化合物中,W3優選地表示CH或者N。
在本發明的化合物中,W4優選地表示CH或者N。
在本發明的化合物中,T、A各自優選地獨立地表示被0、1、2或3個取代基所取代的:-(C1-C6烷基)、-(C0-C6亞烷基)-(C3-C12環烷基)
或-(C0-C6亞烷基)-(3-12元雜環),其中所述取代基選自:氰基、氧代、鹵素、C1-C6烷基、-(C0-C6亞烷基)ORa、C1-C6氰基烷基、鹵代(C1-C6烷基)、C3-C8環烷基、-(C0-C6亞烷基)C(O)Ra、-(C0-C6亞烷基)C(O)ORa、-(C0-C6亞烯基)C(O)ORa、-(C0-C6亞烷基)NRaRb、-C(O)NRaRb、-NRaSO2Rb、-C(O)NRaSO2Rb和-NRaC(O)Rb,其中,Ra和Rb各自獨立地表示氫、C1-C6烷基或者鹵代(C1-C6烷基)。
在本發明的化合物中,T、A各自優選地獨立地表示被0、1或2個取代基所取代的C1-C6烷基、C3-C12環烷基或3-12元雜環,其中所述取代基選自:氰基、氧代、-ORa、-(C0-C6亞烷基)C(O)ORa、-(C0-C6亞烯基)C(O)ORa、-NRaC(O)Rb、-NRaSO2Rb和-C(O)NRaSO2Rb,其中,Ra和Rb各自獨立地表示氫、C1-C6烷基或者鹵代(C1-C6烷基)。
在本發明的化合物中,T、A各自優選地獨立地表示任選地被選自0、1或2個取代基所取代的以下基團:、,其中所述取代基選自:C1-C6烷基、-ORa、-(C0-C6亞烷基)C(O)ORa和-(C0-C6亞烯基)C(O)ORa,其中,Ra表示氫或者C1-C6烷基,優選為氫,其中,α表示1、2或3。
在本發明的化合物中,T、A各自優選地獨立地表示以下基團:
在本發明的化合物中,T、A各自優選地獨立地表示任選地被選自0、1或2個取代基所取代的以下基團:,其中,所述取代基選自:C1-C6烷基、-ORa和鹵素,其中,Re、Ra各自獨立地表示氫或者C1-C6烷基;其中α表示1、2、3或4。
在本發明的化合物中,T、A各自優選地獨立地表示:
在本發明的化合物中,R1優選地表示被0、1、2或3個取代基所取代的-O(C1-C6烷基)、-O(C0-C6亞烷基)(C5-C10芳基)、-O(C0-C6亞烷基)(5-10元雜芳基)、-O(C0-C6亞烷基)(C3-C6環烷基)或-O(C0-C6亞烷基)(3-6元雜環烷基);其中所述取代基選自:氰基、氧代、鹵素、氰基C1-C6烷基和C1-C6鹵代烷基。
在本發明的化合物中,R2優選地表示氫、鹵素、硝基、氰基、-SO2Ra、C1-C6烷基、鹵代(C1-C6烷基)或者C3-C6環烷基;其中,Ra表示氫、C1-C6烷基或者鹵代(C1-C6烷基)。
在本發明的化合物中,R3、R4各自優選地獨立地表示氫、鹵素、硝基或氰基。
在本發明的化合物中,R5優選地表示氫、鹵素、硝基、氰基、C1-C6烷基、鹵代(C1-C6烷基)或者C3-C6環烷基。
在本發明的化合物中,R6優選地表示氫、鹵素、硝基、氰基、-SO2Ra、C1-C6烷基、鹵代(C1-C6烷基)或C3-C6環烷基或者被0、1、2或3個取代基所取代的-O(C1-C6烷基)、-O(C0-C6亞烷基)(C5-C10芳基)、-O(C0-C6亞烷基)(5-10元雜芳基)、-O(C0-C6亞烷基)(C3-C6環烷基)或-O(C0-C6亞烷基)(3-6元雜環烷基);其中所述取代基選自:氰基、氧代、鹵素、氰基C1-C6烷基和C1-C6鹵代烷基。
在本發明的化合物中,RL優選地表示氫或者鹵素。
在本發明的化合物中,RM、RN各自優選地獨立地表示氫。
具體地,本發明提供了具有如下結構的化合物:
除此之外,本發明還提供了一種藥物組合物,其包含本發明所述的化合物,並且任選地進一步包含另外的治療劑和/或免疫檢查點抑制劑。本發明的藥物組合物可以包含可藥用載體。
除此之外,本發明還提供了本發明的化合物或者含有本發明化合物的藥物組合物在製備用於預防或治療可通過抑制PD-L1與PD-1結合來治療的疾病或病症的藥物中的應用。優選地,所述疾病選自腫瘤、
癌症、病毒感染、炎症相關疾病和自身免疫性疾病。
本發明還提供了本發明化合物或者含有本發明化合物的藥物組合物在製備用於預防或治療對抑制PD-L1與PD-1之結合有回應的疾病或病症的藥物中的應用。優選地,所述疾病或病症選自腫瘤、癌症、病毒感染、炎症相關疾病和自身免疫性疾病。
除此之外,本發明還提供了一種預防或治療可通過抑制PD-L1與PD-1結合來治療的疾病或病症(優選腫瘤、癌症、病毒感染、炎症相關疾病和自身免疫性疾病)的方法,其包括向有此需要的哺乳動物施用本發明的化合物或者本發明的藥物組合物。
本發明還提供了一種預防或治療對抑制PD-L1與PD-1之結合有回應的疾病或病症的方法,其包括向有此需要的哺乳動物施用本發明的化合物或者本發明的藥物組合物。術語“對抑制PD-L1與PD-1之結合有回應的疾病或病症”意指這樣的任何疾病或病症:通過抑制PD-L1與PD-1之結合可改變疾病進程,或可導致疾病、病症、障礙等的緩和、抑制、消除和改善效果或者可預防這樣的疾病或病症。優選地,所述對抑制PD-L1與PD-1之結合有回應的疾病或病症選自腫瘤、癌症、病毒感染、炎症相關疾病和自身免疫性疾病。
本發明還提供了一種抑制PD-L1和PD-1結合的方法,其包括使本發明化合物或者本發明的藥物組合物暴露於所述的PD-L1和/或PD-1。
在上述涉及本發明的化合物、藥物組合物以及利用本發明化合物或藥物組合物的用途和方法的實施方案中,所述的本發明化合物尤其包括其藥學上可接受的鹽的形式。
炎症性疾病、自身免疫性疾病和免疫介導性疾病的代表性實例可包括但不限於,關節炎、類風濕性關節炎、脊柱關節炎、痛風性關節炎、骨關節炎、幼年型關節炎、其他關節炎性病症、狼瘡、系統性紅斑狼瘡(Systemic lupus erythematosus,SLE)、皮膚相關疾病、
銀屑病、濕疹、皮炎、過敏性皮膚炎、疼痛、肺病、肺部炎症、成人呼吸窘迫綜合征(Acute respiratory distress syndrome,ARDS)、肺結節病、慢性肺部炎症性疾病、慢性阻塞性肺病(Chronic obstructive pulmonary disease,COPD)、心血管疾病、動脈粥樣硬化、心肌梗塞、充血性心力衰竭、心肌缺血再灌注損傷、炎性腸病、克羅恩病、潰瘍性結腸炎、腸易激綜合征、哮喘、乾燥綜合征、自身免疫甲狀腺疾病、蕁麻疹(風疹)、多發性硬化、硬皮症、器官移植排斥、異種移植、特發性血小板減少性紫癜(Idiopathic thrombocytopenic purpura,ITP)、帕金森病、阿爾茲海默病、糖尿病相關疾病、炎症、盆腔炎性疾病、過敏性鼻炎、過敏性支氣管炎、過敏性鼻竇炎、白血病、淋巴瘤、B細胞淋巴瘤、T細胞淋巴瘤、骨髓瘤、急性淋巴性白血病(Acute Lymphoblastic Leukemia,ALL)、慢性淋巴性白血病(Chronic lymphocytic leukemia,CLL)、急性髓性白血病(Acute myeloid leukemia,AML)、慢性髓性白血病(Chronic myloid leukemia,CML)、毛細胞白血病、何傑金氏病、非何傑金淋巴瘤、多發性骨髓瘤、骨髓增生異常綜合征(Myelodysplastic syndromes,MDS)、骨髓增生性腫瘤(Myeloproliferative neoplasm,MPN)、彌漫性大B細胞淋巴瘤和濾泡性淋巴瘤。
癌症或腫瘤的代表性實例可包括但不限於,皮膚癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、結腸癌、肺癌、骨癌、腦癌、神經細胞瘤、直腸癌、結腸癌、家族性腺瘤性息肉性癌、遺傳性非息肉性結直腸癌、食管癌、唇癌、喉癌、下嚥癌、舌癌、唾液腺癌、胃癌、腺癌、甲狀腺髓樣癌、乳頭狀甲狀腺癌、腎癌、腎實質癌、卵巢癌、宮頸癌、子宮體癌、子宮內膜癌、絨毛膜癌、胰腺癌、前列腺癌、睾丸癌、泌尿癌、黑素瘤、腦腫瘤諸如成膠質細胞瘤、星形細胞瘤、腦膜瘤、成神經管細胞瘤和外周神經外胚層腫瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴
性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒細胞白血病(CML)、成人T細胞白血病淋巴瘤、彌漫性大B細胞淋巴瘤(Diffuse large B cell lymphomas,DLBCL)、肝細胞癌、膽囊癌、支氣管癌、小細胞肺癌、非小細胞肺癌、多發性骨髓瘤、基底細胞瘤、畸胎瘤、成視網膜細胞瘤、脈絡膜黑素瘤、精原細胞瘤、橫紋肌肉瘤、顱咽管瘤、骨肉瘤、軟骨肉瘤、肌肉瘤、脂肪肉瘤、纖維肉瘤、尤因肉瘤或漿細胞瘤。
當將本發明化合物或其可藥用鹽與另外的用於治療癌症或腫瘤的治療劑或免疫檢查點抑制劑組合施用時,本發明化合物或其可藥用鹽可提供增強的抗癌作用。
用於治療癌症或腫瘤的治療劑的代表性實例可包括但不限於細胞信號轉導抑制劑、苯丁酸氮芥、美法侖、環磷醯胺、異環磷醯胺、白消安、卡莫司汀、洛莫司汀、鏈脲佐菌素、順鉑、卡鉑、奧沙利鉑、達卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他濱、巰基嘌呤、氟達拉濱、長春堿、長春新堿、長春瑞濱、紫杉醇、多西紫杉醇、拓撲替康、伊立替康、依託泊苷、曲貝替定、更生黴素、多柔比星、表柔比星、道諾黴素、米托蒽醌、博來黴素、絲裂黴素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林類似物、甲地孕酮、強的松、地塞米松、甲潑尼龍、沙利度胺、干擾素α、亞葉酸鈣、西羅莫司、西羅莫司脂化物、依維莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、達拉菲尼、達可替尼、達努塞替、達沙替尼、多維替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依魯替尼、埃克替尼、伊馬替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、馬賽替尼、momelotinib、莫替沙尼、來那替尼、尼祿替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普納替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、盧梭利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、
tivantinib、替沃紮尼、托法替尼、曲美替尼、凡德他尼、維利帕尼、威羅菲尼、維莫德吉、volasertib、阿侖單抗、貝伐單抗、貝倫妥單抗維多汀、卡妥索單抗、西妥昔單抗、地諾單抗、吉妥珠單抗、伊匹單抗、尼妥珠單抗、奧法木單抗、帕尼單抗、利妥昔單抗、托西莫單抗、曲妥珠單抗、PI3K抑制劑、CSF1R抑制劑、A2A和/或A2B受體拮抗劑、IDO抑制劑、抗PD-1抗體、LAG3抗體、TIM-3抗體及抗CTLA-4抗體或其任意組合。
當將本發明化合物或其可藥用鹽與另外的用於治療炎症性疾病、自身免疫性疾病和免疫介導性疾病的治療劑組合施用時,本發明化合物或其可藥用鹽可提供增強的治療作用。
用於治療炎症性疾病、自身免疫性疾病和免疫介導性疾病的治療劑的代表性實例可包括但不限於,甾體藥物(例如,強的松、氫化潑尼松、甲基氫化潑尼松、可的松、羥基可的松、倍他米松、地塞米松等)、甲氨蝶呤、來氟米特、抗TNFα劑(例如,依那西普、英夫利昔單抗、阿達利單抗等)、鈣調神經磷酸酶抑制劑(例如,他克莫司、吡美莫司等)和抗組胺藥(例如,苯海拉明、羥嗪、氯雷他定、依巴斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等),並且選自其中的至少一種治療劑可包含于本發明藥物組合物中。
本發明的化合物或其可藥用鹽可作為活性成分通過口服或腸胃外施用,其有效量的範圍為在哺乳動物包括人(體重約70kg)的情況下0.1至2,000mg/kg體重/天、優選1至1,000mg/kg體重/天,並且每天以單次或4次分次劑量,或者遵循/不遵循預定時間施用。活性成分的劑量可根據多個相關因素(例如待治療物件的情況、疾病類型和嚴重性、施用頻率和醫生意見)進行調整。在某些情況下,小於以上劑量的量可能是合適的。如果不引起有害的副作用則可使用大於以上劑量的量並且該量可以每天以分次劑量施用。
除此之外,本發明還提供了一種抑制PD-L1的方法,其包含使本發明的所述的化合物、其藥學上可接受的鹽或者本發明所述的藥物組合暴露於所述的PD-L1。
術語定義
特別注意的是,在本文中,當提及具有特定結構式的“化合物”時,一般地還涵蓋其立體異構體、非對映異構體、對映異構體、外消旋混合物和同位素衍生物,以及作為其替代性存在形式的可藥用鹽、溶劑合物、水合物等形式。本領域技術人員公知,一種化合物的鹽、溶劑合物、水合物是化合物的替代性存在形式,它們都可以在一定條件下轉化為所述化合物,因此,特別注意的是在本文中當提到一種化合物時,一般地還包括它的可藥用鹽,進而還包括其溶劑合物和水合物。
相似地,在本文中當提到一種化合物時,一般地還包括其前藥、代謝產物和氮氧化物。
本發明所述的可藥用鹽或藥學上可接受的鹽可使用無機酸或有機酸而形成,所述的“可藥用鹽”或“藥學上可接受的鹽”是指這樣的鹽:在合理的醫學判斷範圍內,其適用於接觸人和較低等動物的組織,而沒有不適當的毒性、刺激性、過敏反應等,稱得上合理的受益/風險比。可以在本發明化合物的最終分離和純化期間原位製備所述鹽,或單獨通過將游離堿或游離酸與合適的試劑反應製備所述鹽,如下概述。例如,游離堿可以與合適的酸反應。此外,當本發明的化合物帶有酸性部分時,其合適的可藥用鹽可包括金屬鹽,例如鹼金屬鹽(如鈉鹽或鉀鹽)和鹼土金屬鹽(如鈣鹽或鎂鹽)。可藥用的無毒酸加成鹽的示例是氨基與無機酸(例如,鹽酸、氫溴酸、磷酸、硫酸和高氯酸)或有機酸(例如,醋酸、草酸、馬來酸、酒石酸、檸檬酸、琥珀酸或丙二酸)形成的鹽,或通過使用現有技術中的其他方法如離子交換形成
的鹽。其他可藥用鹽包括己二酸鹽、海藻酸鈉、抗壞血酸鹽、天門冬氨酸鹽、苯磺酸鹽、苯甲酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、檸檬酸鹽、環戊烷丙酸鹽、二葡糖酸鹽、十二烷基硫酸鹽、乙磺酸鹽、甲酸鹽、富馬酸鹽、葡庚糖酸鹽、甘油磷酸鹽、葡萄糖酸鹽、庚酸鹽、己酸鹽、氫碘酸鹽、2-羥基-乙磺酸鹽、乳糖酸鹽、乳酸鹽、月桂酸鹽、月桂基硫酸鹽、蘋果酸鹽、馬來酸鹽、丙二酸鹽、甲磺酸鹽、2-萘磺酸鹽、煙酸鹽、硝酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、撲酸鹽、果膠酸鹽、過硫酸鹽、3-苯丙酸鹽、磷酸鹽、苦味鹽、新戊酸鹽、丙酸鹽、硬脂酸鹽、琥珀酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、對甲苯磺酸鹽、十一酸鹽、戊酸鹽等。代表性鹼金屬或鹼土金屬鹽包括鈉鹽、鋰鹽、鉀鹽、鈣鹽、鎂鹽等。其他可藥用鹽包括(適當時)無毒銨鹽、季銨鹽和用反離子形成的銨陽離子,例如,鹵化物、氫氧化物、羧酸鹽、硫酸鹽、磷酸鹽、硝酸鹽、低級烷基磺酸鹽和芳基磺酸鹽。
本發明的可藥用鹽可通過常規方法製備,例如通過將本發明的化合物溶解于與水可混溶的有機溶劑(例如丙酮、甲醇、乙醇和乙腈)中,向其中添加過量的有機酸或無機酸水溶液,以使得鹽從所得混合物中沉澱,從中除去溶劑和剩餘的游離酸,然後分離所沉澱的鹽。
本發明所述的前體或代謝物可以為本領域公知的前體或代謝物,只要所述的前體或代謝物通過體內代謝轉化形成化合物即可。例如“前藥”是指本發明化合物的那些前藥,在合理的醫學判斷範圍內,其適用於接觸人和更低等動物的組織,而沒有不適當的毒性、刺激性、過敏反應等,稱得上合理的受益/風險比並且對其預期用途有效。術語“前藥”是指在體內迅速經轉化產生上述式的母體化合物的化合物,例如通過在體內代謝,或本發明化合物的N-去甲基化。
本發明所述的“溶劑合物”意指本發明化合物與一個或更多個溶
劑分子(無論有機的還是無機的)的物理締合。該物理締合包括氫鍵。在某些情形中,例如當一個或更多個溶劑分子納入結晶固體的晶格中時,溶劑合物將能夠被分離。溶劑合物中的溶劑分子可按規則排列和/或無序排列存在。溶劑合物可包含化學計量或非化學計量的溶劑分子。“溶劑合物”涵蓋溶液相和可分離的溶劑合物。示例性溶劑合物包括但不限於水合物、乙醇合物、甲醇合物和異丙醇合物。溶劑化方法是本領域公知的。
本發明所述的“立體異構”分為構象異構和構型異構,構型異構還可分為順反異構和旋光異構(即光學異構)。構象異構是指具有一定構型的有機物分子由於碳、碳單鍵的旋轉或扭曲而使得分子各原子或原子團在空間產生不同的排列方式的一種立體異構現象,常見的有烷烴和環烷烴類化合物的結構,如環己烷結構中出現的椅式構象和船式構象。“立體異構體”是指當本發明化合物含有一個或更多個不對稱中心,因而可作為外消旋體和外消旋混合物、單一對映異構體、非對映異構體混合物和單一非對映異構體。本發明化合物可以有不對稱中心,每個不對稱中心會產生兩個光學異構體,本發明的範圍包括所有可能的光學異構體和非對映異構體混合物和純的或部分純的化合物。本發明所述的化合物可以以互變異構體形式存在,其通過一個或更多個雙鍵位移而具有不同的氫的連接點。例如,酮和它的烯醇形式是酮-烯醇互變異構體。各互變異構體及其混合物都包括在本發明的化合物中。所有式(I)化合物的對映異構體、非對映異構體、外消旋體、內消旋體、順反異構體、互變異構體、幾何異構體、差向異構體及其混合物等,均包括在本發明範圍中。
本發明的“同位素衍生物”是指在本專利中化合物被同位素標記的分子。通常用作同位素標記的同位素是:氫同位素:2H和3H;碳同位素:11C,13C和14C;氯同位素:35Cl和37Cl;氟同位素:18F;碘同位素:123I和125I;氮同位素:13N和15N;氧同位素:15O,17O和18O
和硫同位素35S。這些同位素標記化合物可以用來研究藥用分子在組織中的分佈情況。尤其是氘2H和碳13C,由於它們容易標記且方便檢測,運用更為廣泛。某些重同位素,比如重氫(2H),的取代能增強代謝的穩定性,延長半衰期從而達到減少劑量的目而提供療效優勢的。同位素標記的化合物一般從已被標記的起始物開始,用已知的合成技術象合成非同位素標記的化合物一樣來完成其合成。
可根據常規方法中的任何一種將本發明化合物或藥物組合物配製成用於口服施用或腸胃外施用(包括肌內、靜脈內和皮下途徑、瘤內注射)的劑型,例如片劑、顆粒、粉末、膠囊、糖漿、乳劑、微乳劑、溶液或混懸液。
用於口服施用的本發明藥物組合物可通過將活性成分與例如以下的載體混合來製備:纖維素、矽酸鈣、玉米澱粉、乳糖、蔗糖、右旋糖、磷酸鈣、硬脂酸、硬脂酸鎂、硬脂酸鈣、明膠、滑石、表面活性劑、助懸劑、乳化劑和稀釋劑。在本發明的注射組合物中採用的載體的實例是水、鹽溶液、葡萄糖溶液、葡萄糖樣溶液(glucose-like solution)、醇、二醇、醚(例如,聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性劑、助懸劑和乳化劑。
本發明描述示例性實施方案的過程中,本發明的其它特徵將變得顯而易見,給出所述實施方案用於說明本發明而不意欲成為其限制,以下實施例使用本發明所公開的方法製備、分離和表徵。
如果無另外說明,用於本發明申請(包括說明書和申請專利範圍)中的術語定義如下。必須注意,在說明書和所附的申請專利範圍中,如果文中無另外清楚指示,單數形式“一個”包括複數意義。如果無另外說明,使用質譜、核磁、HPLC、蛋白化學、生物化學、重組DNA技術和藥理的常規方法。在本申請中,如果無另外說明,使用“或”或“和”指“和/或”。
在說明書和申請專利範圍中,給定化學式或名稱應涵蓋所有立體和光學異構體及其中存在上述異構體的外消旋物。除非另外指明,否則所有手性(對映異構體和非對映異構體)和外消旋形式均在本發明範圍內。所述化合物中還可存在C=C雙鍵、C=N雙鍵、環系統等的許多幾何異構體,且所有上述穩定異構體均涵蓋于本發明內。本發明描述了本發明化合物的順式-和反式-(或E-和Z-)幾何異構體,且其可分離成異構體的混合物或分開的異構體形式。本發明化合物可以光學活性或外消旋形式加以分離。用於製備本發明化合物和其中製備的中間體的所有方法均視為本發明的部分。在製備對映異構體或非對映異構體產物時,其可通過常規方法(例如通過色譜或分段結晶)進行分離。取決於方法條件,以游離(中性)或鹽形式獲得本發明的終產物。這些終產物的游離形式和鹽均在本發明的範圍內。如果需要的話,則可將化合物的一種形式轉化成另一種形式。可將游離堿或酸轉化成鹽;可將鹽轉化成游離化合物或另一種鹽;可將本發明異構體化合物的混合物分離成單獨的異構體。本發明化合物、其游離形式和鹽可以多種互變異構體形式存在,其中氫原子轉置到分子的其它部分上且由此分子的原子之間的化學鍵發生重排。應當理解的是,可存在的所有互變異構體形式均包括在本發明內。
除非另有定義,本發明的取代基的定義是各自獨立而非互相關聯的,例如對於取代基中Ra(或者Rb)而言,其在不同的取代基的定義中是各自獨立的。具體而言,對於Ra(或者Rb)在一種取代基中選擇一種定義時,並不意味著該Ra(或者Rb)在其他取代基中都具有該相同的定義。更具體而言,例如(僅列舉非窮舉)對於NRaRb中,當Ra(或者Rb)的定義選自氫時,其並不意味著在-C(O)-NRaRb中,Ra(或者Rb)必然為氫。
除非另有定義,否則當取代基被標注為“任選取代的”時,所述取代基選自例如以下取代基,諸如烷基、環烷基、芳基、雜環基、鹵素、
羥基、烷氧基、氧代、烷醯基、芳基氧基、烷醯基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺基團(其中兩個氨基取代基選自烷基、芳基或芳基烷基)、烷醯基氨基、芳醯基氨基、芳烷醯基氨基、取代的烷醯基氨基、取代的芳基氨基、取代的芳烷醯基氨基、硫基、烷基硫基、芳基硫基、芳基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺醯基、芳基磺醯基、芳基烷基磺醯基、磺醯氨基例如-SO2NH2、取代的磺醯氨基、硝基、氰基、羧基、氨基甲醯基例如-CONH2、取代的氨基甲醯基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有兩個選自烷基、芳基或芳基烷基的取代基的情況、烷氧基羰基、芳基、取代的芳基、胍基、雜環基,例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、呱啶基、嗎啉基、呱嗪基、高呱嗪基等和取代的雜環基。
本文使用的術語“烷基”或“亞烷基”意欲包括具有指定碳原子數的支鏈和直鏈飽和脂族烴基團。例如,“C1-C6烷基”表示具有1個至6個碳原子的烷基。烷基的實例包括但不限於甲基(Me)、乙基(Et)、正丙基、異丙基、正丁基、異丁基、叔丁基、正戊基、異戊基、新戊基。
術語“烯基”表示含一個或更多個雙鍵且通常長度為2至20個碳原子的直鏈或支鏈的烴基。例如,“C2-C6烯基”含有兩個至六個碳原子。烯基包括但不限於例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。
術語“炔基”表示含一個或更多個三鍵且通常長度為2至20個碳原子的直鏈或支鏈的烴基。例如,“C2-C6炔基”含有兩個至六個碳原子。代表性炔基包括但不限於例如乙炔基、1-丙炔基、1-丁炔基等。
術語“烷氧基”或“烷基氧基”是指-O-烷基。“C1-C6烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5、C6烷氧基。烷氧基的實例包括但不限於甲氧基、乙氧基、丙氧基(例如正丙氧基和異丙氧基)和叔丁氧基。類似地,“烷基硫基”或“硫代烷氧基”表示具有指定數量
碳原子的經硫橋連接的如上文所定義的烷基;例如甲基-S-和乙基-S-。
術語“羰基”是指由碳和氧兩種原子通過雙鍵連接而成的有機官能團(C=O)。
術語“芳基”,單獨或作為較大部分諸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分,是指具有總計5至12個環成員的單環、二環或三環的環系統,其中所述系統中的至少一個環為芳族的且其中所述系統中的每個環含有3至7個環成員。在本發明的某些實施方案中,“芳基”是指芳族環系統,其包括但不限於苯基、聯苯基、茚滿基、1-萘基、2-萘基和四氫萘基。術語“芳烷基”或“芳基烷基”是指連接至芳基環的烷基殘基。非限制性實例包括苄基、苯乙基等。稠合的芳基可在環烷基環或芳族環的合適位置上連接至另一基團。例從環系統中畫出的虛線表明鍵可連接至任意合適的環原子。
術語“環烷基”是指單環或二環的環狀烷基。單環的環狀烷基指非支化或者支化的的環狀烷基,包括但不限於環丙基、環丁基、環戊基、環己基、降莰烷基、1-甲基環丙基和2-甲基環丙基。二環的環狀烷基包括橋環、螺環或融合環的環烷基。
術語“環烯基”是指單環或二環的環狀烯基。單環的環狀烯基指非支化或者支化的環狀烯基,包括但不限於環丙烯基、環丁烯基、環戊烯基、環己烯基和降莰烯基、1-甲基環丙烯基和2-甲基環丙烯基。二環的環狀烯基包括橋環、螺環或稠合環的環狀烯基。
“鹵代”或“鹵素”包括氟、氯、溴和碘。“鹵代烷基”意欲包括具有指定碳原子數且取代有1個或多個鹵素的支鏈和直鏈飽和脂族烴基團。鹵代烷基的實例包括但不限於氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。鹵代烷基的實例還包括意欲包括具有指定碳原子數且取代有1個或多個氟原子的支鏈和直鏈飽和脂族烴基團的“氟烷基”。
“鹵代烷氧基”或“鹵代烷基氧基”表示具有指定數量碳原子的經
氧橋連接的如上文所定義的鹵代烷基。例如,“C1-C6鹵代烷氧基”意欲包括C1、C2、C3、C4、C5、C6鹵代烷氧基。鹵代烷氧基的實例包括但不限於三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。類似地,“鹵代烷基硫基”或“硫代鹵代烷氧基”表示具有指定數量碳原子的經硫橋連接的如上文所定義的鹵代烷基;例如三氟甲基-S-和五氟乙基-S-。
本公開內容中,當提到一些取代基團時使用Cx1-Cx2的表述,這表示所述取代基團中的碳原子數可以是x1至x2個。例如,C0-C8表示所述基團含有0、1、2、3、4、5、6、7或8個碳原子,C1-C8表示所述基團含有1、2、3、4、5、6、7或8個碳原子,C2-C8表示所述基團含有2、3、4、5、6、7或8個碳原子,C3-C8表示所述基團含有3、4、5、6、7或8個碳原子,C4-C8表示所述基團含有4、5、6、7或8個碳原子,C0-C6表示所述基團含有0、1、2、3、4、5或6個碳原子,C1-C6表示所述基團含有1、2、3、4、5或6個碳原子,C2-C6表示所述基團含有2、3、4、5或6個碳原子,C3-C6表示所述基團含有3、4、5或6個碳原子。
本公開內容中,當提到環狀基團(例如芳基、雜芳基、環烷基和雜環烷基)時使用“x1-x2元環”的表述,這表示該基團的環原子數可以是x1至x2個。例如,所述3-12元環狀基團可以是3、4、5、6、7、8、9、10、11或12元環,其環原子數可以是3、4、5、6、7、8、9、10、11或12個;3-6元環表示該環狀基團可以是3、4、5或6元環,其環原子數可以是3、4、5或6個;3-8元環表示該環狀基團可以是3、4、5、6、7或8元環,其環原子數可以是3、4、5、6、7或8個;3-9元環表示該環狀基團可以是3、4、5、6、7、8或9元環,其環原子數可以是3、4、5、6、7、8或9個;4-7元環表示該環狀基團可以是4、5、6或7元環,其環原子數可以是4、5、6或7個;5-8元環表示該環狀基團可以是5、6、7或8元環,其環原子數可以是
5、6、7或8個;5-12元環表示該環狀基團可以是5、6、7、8、9、10、11或12元環,其環原子數可以是5、6、7、8、9、10、11或12個;6-12元環表示該環狀基團可以是6、7、8、9、10、11或12元環,其環原子數可以是6、7、8、9、10、11或12個。所述環原子可以是碳原子或雜原子,例如選自N、O和S的雜原子。當所述環是雜環時,所述雜環可以含有1、2、3、4、5、6、7、8、9、10或更多個環雜原子,例如選自N、O和S的雜原子。
本發明內容中,一個或更多個鹵素可以各自獨立地選自氟、氯、溴和碘。
術語“雜芳基”意指穩定的3元、4元、5元、6元、或7元芳香單環或芳香二環或7元、8元、9元、10元、11元、12元芳香多環雜環,其為完全不飽和的、部分不飽和的,且其含有碳原子和1個、2個、3個或4個獨立地選自N、O和S的雜原子;且包括任何以下多環基團,其中上文所定義的任意雜環與苯環稠合。氮和硫雜原子可任選地被氧化。氮原子為取代的或未取代的(即N或NR,其中R為H或如果被定義,則為另一取代基)。雜環可在得到穩定結構的任何雜原子或碳原子處連接至其側基。如果所得化合物是穩定的,則本文所述的雜環基可在碳或氮原子上被取代。雜環中的氮可任選地被季銨化。優選地,當雜環中S和O原子的總數超過1時,則這些雜原子彼此不相鄰。優選地,雜環中S和O原子的總數不大於1。當使用術語“雜環”時,其意欲包括雜芳基。芳雜基的實施例包括但不限於吖啶基、氮雜環丁基、吖辛因基、苯並咪唑基、苯並呋喃基、苯並硫代呋喃基、苯並噻吩基、苯並噁唑基、苯並噁唑啉基、苯並噻唑基、苯並三唑基、苯並四唑基、苯並異噁唑基、苯並異噻唑基、苯並咪唑啉基、哢唑基、4aH-哢唑基、哢啉基、色滿基、色烯基、噌啉基、十氫喹啉基、2H,6H-1,5,2-二噻嗪基、二氫呋喃並[2,3-b]四氫呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑並吡啶基、假吲哚基
(indolenyl)、二氫吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛紅醯基(isatinoyl)、異苯並呋喃基、異色滿基、異吲唑基、異二氫吲哚基、異吲哚基、異喹啉基、異噻唑基、異噻唑並吡啶基、異噁唑基、異噁唑並吡啶基、亞甲基二氧基苯基、嗎啉基、二氮雜萘基、八氫異喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑並吡啶基、噁唑烷基、萘嵌間二氮雜苯基、羥吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、呱嗪基、呱啶基、呱啶酮基、4-呱啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑並吡啶基、吡唑基、噠嗪基、吡啶並噁唑基、吡啶並咪唑基、吡啶並噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎寧環基、四唑基、四氫呋喃基、四氫異喹啉基、四氫喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑並吡啶基、噻吩並噻唑基、噻吩並噁唑基、噻吩並咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫噸基、喹啉基、異喹啉基、酞嗪基、喹唑啉基、吲哚基、異吲哚基、二氫吲哚基、1H-吲唑基、苯並咪唑基、1,2,3,4-四氫喹啉基、1,2,3,4-四氫異喹啉基、5,6,7,8-四氫-喹啉基、2,3-二氫-苯並呋喃基、色滿基、1,2,3,4-四氫-喹喔啉基和1,2,3,4-四氫-喹唑啉基。術語“雜芳基”還可以包括由上述所定義的“芳基”與單環“雜芳基”所形成的聯芳基結構,例如但不限於“-苯基聯吡啶基-”、“-苯基聯嘧啶基”、“-吡啶基聯苯基”、“-吡啶基聯嘧啶基-”、“-嘧啶基聯苯基-”;其中本發明還包括含有例如上述雜環的稠環和螺環化合物。
本文使用的術語“雜環烷基”或“雜環”指的是一個單環雜環烷基體系,或為一個二環雜環烷基體系,同時還包括螺雜環或橋雜環烷
基。單環的雜環烷基指的是至少含一個選自O、N、S、P的雜原子的飽和或不飽和但不為芳香性的環狀烷基體系。二環雜環烷基體系指的是一個雜環烷基與一個苯基、或一個環烷基、或一個環烯基、或一個雜環烷基、或一個雜芳基稠合。優選地,所述“雜環烷基”或“雜環”中包含至少一個或兩個選自O、N、S的雜原子。
本文使用的術語“橋環烷基”指的是共用兩個或兩個以上碳原子的多環化合物。可分為二環橋環烴及多環橋環烴。前者由兩個脂環共用兩個以上碳原子所構成;後者是由三個以上的環組成的橋環烴。
本文使用的術語“螺環烷基”指的是單環之間共用一個碳原子(稱螺原子)的多環烴。
本文使用的術語“橋環雜基”指的是共用兩個或兩個以上碳原子的多環化合物,該環中至少含一個選自O、N、S原子。可分為二環橋環雜環及多環橋雜環。
本文使用的術語“雜螺環基”指的是單環之間共用一個碳原子(稱螺原子)的多環烴,該環中至少含一個選自O、N、S的雜原子。
本文中所用的術語“取代”意指至少一個氫原子被非氫基團替代,條件是維持正常化合價且所述取代得到穩定的化合物。本文所用的環雙鍵為在兩個相鄰環原子之間形成的雙鍵(例如C=C、C=N或N=N)。
在本發明化合物上存在氮原子(例如胺)的情形下,可通過使用氧化劑(例如mCPBA和/或過氧化氫)進行處理來將這些氮原子轉化成N-氧化物以獲得本發明的其它化合物。因此,所顯示和要求保護的氮原子視為均涵蓋所顯示氮及其N-氧化物以獲得本發明衍生物。
當任何變數在化合物的任何組成或式中出現一次以上時,其每次出現時的定義均獨立於其在其它每種情況下出現時的定義。因此,例如如果顯示基團取代有0-3個R,則所述基團可任選地取代有至多三個R基團,且在每次出現時R獨立地選自R的定義。此外,取代基
和/或變數的組合僅在上述組合可產生穩定的化合物時才容許存在。
本文使用的術語“患者”是指通過本發明的方法進行治療的有機體。這類有機體優選包括但不限於哺乳動物(例如鼠類、猿/猴、馬、牛、豬、犬、貓等)且最優選是指人類。
本文使用的術語“有效量”意指將會引起例如研究人員或臨床醫師所尋求的組織、系統、動物或人的生物學或醫學回應的藥物或藥劑(即本發明化合物)的量。此外,術語“治療有效量”意指這樣的量:與未接受上述量的相應受試者相比,所述量導致改善的治療、治癒、預防或減輕疾病、病症或副作用,或降低在疾病或病症的進展速度。有效量可以一個或更多個給藥、施用或劑量給予且不意欲被特定的製劑或給藥途徑限制。該術語還包括在其範圍內的增強正常生理機能的有效量。
本文使用的術語“治療”包括其廣義上的含義,涵蓋對物件的治療性處理和/或預防性處理。具體而言,所述“治療”包括導致病症、疾病、障礙等的緩和、抑制、消除和改善和/或預防的任何處理,例如減輕、減少、調節、改善、消除、預防、防止或改善其症狀。所述治療性處理包括緩和、抑制或改善疾病的症狀或狀況;抑制併發症的產生;改善潛在代謝綜合征;抑制疾病或症狀的產生,如控制疾病或情況的發展;減輕疾病或症狀;使疾病或症狀減退;減輕由疾病或症狀引起的併發症,或治療由疾病或症狀引起的徵兆。所述預防性處理包括事先處理以防止、阻斷或延遲、減緩疾病或病症的發生或發展或者減弱疾病或病症的嚴重程度。
同樣,“治療劑”也包括對物件具有治療性處理和/或預防性處理的藥劑或試劑。
術語“藥用”或“藥學上可接受的”在本文中用於指如下那些化合物、物質、組合物和/或劑型:在合理醫學判斷的範圍內,其適於與人類和動物的組織接觸使用而無過高毒性、刺激性、過敏反應和/或其它
問題或併發症,並與合理的益處/風險比相稱。
特定藥學及醫學術語
術語“癌症”,如本文所用,指一種不能控制的細胞的異常生長,並且在某種條件下能夠轉移(傳播)。這種類型的癌症包括但不限於,實體腫瘤(如膀胱、腸、腦、胸、子宮、心臟、腎、肺、淋巴組織(淋巴瘤)、卵巢、胰腺或其它內分泌器官(如甲狀腺)、前列腺、皮膚(黑色素瘤)或血液瘤(如非白血性白血病)。
術語“聯合給藥”或其類似術語,如本文所用,指將幾種所選的治療藥物給一個病人用藥,以相同或不同的給藥方式在相同或不同的時間給藥。
術語“增強”或“能增強”,如本文所用,指預期的結果能夠在效價或是持續時間方面都有增加或延長。因此,在增強藥物的治療效果方面,術語“能增強”指藥物在系統中有提高或延長效價或持續時間的能力。本文所用的“增效值”,指在理想的系統中,能夠最大限度地的增強另外一個治療藥物的能力。
術語“免疫性疾病”指對內源性或外源性抗原產生的不良或有害反應的疾病或症狀。結果通常會造成細胞的功能障礙、或因此而破壞並造成機能障礙、或破壞可能產生免疫症狀的器官或組織。
術語“試劑盒”與“產品包裝”是同義詞。
術語“對象”、“受試者”或“病人”包括哺乳動物和非哺乳動物。哺乳動物包括但不限於,哺乳類:人、非人靈長類如猩猩、猿及猴類;農業動物如牛、馬、山羊、綿羊、豬;家畜如兔、狗;實驗動物包括齧齒類,如大鼠、小鼠及豚鼠等。非哺乳類動物包括但不限於,鳥、魚等。在一優選例中,所選哺乳動物是人。
如本文所用,某一化合物或藥物組合物,給藥後,可以使某一疾病、症狀或情況得到改善,尤指其嚴重度得到改善,延遲發病,減緩
病情進展,或減少病情持續時間。無論固定給藥或臨時給藥、持續給藥或斷續給藥,可以歸因於或與給藥有關的情況。
給藥途徑
適合的給藥途徑包括但不限於,口服、靜脈注射、直腸、氣霧劑、非腸道給藥、眼部給藥、肺部給藥、經皮給藥、陰道給藥、耳道給藥、鼻腔給藥及局部給藥。此外,僅作舉例說明,腸道外給藥,包括肌肉注射、皮下注射、靜脈注射、髓內注射、心室注射、腹膜內注射、淋巴管內注射、及鼻內注射。
本發明化合物給藥方式可以是局部的給藥方式。在特定的具體實施例中,長效製劑通過植入給藥(例如皮下或肌肉)或通過肌肉注射。此外,在另一具體化實施例中,藥物通過靶向藥物給藥系統來給藥。例如,由器官特異性抗體包裹的脂質體。在這種具體實施例中,所述脂質體被選擇性的導向特定器官並吸收。
藥物組合物和劑量
本文使用的短語“可藥用載體”意指藥用物質、組合物或媒介物,諸如液體或固體填充劑、稀釋劑、賦形劑、製造助劑(例如潤滑劑、滑石、硬脂酸鎂、硬脂酸鈣或硬脂酸鋅或硬脂酸)或溶劑包囊物質,其涉及將主題化合物從一個器官或身體的部分攜帶或運送至另一個器官或身體的部分。每種載體在與製劑的其它成分相容和對患者無害的意義上必須是“可接受的”。
術語“藥物組合物”意指包含本發明化合物與任選的其它可藥用載體的組合物。“可藥用載體”是指本領域中通常接受用於將生物活性劑遞送至動物(具體為哺乳動物)的介質,包括(即)佐劑、賦形劑或媒介物,諸如稀釋劑、防腐劑、填充劑、流動調控劑、崩解劑、潤濕劑、乳化劑、懸浮劑、增甜劑、矯味劑、芳香劑、抗細菌劑、抗真菌劑、
潤滑劑和分散劑,這取決於給藥模式和劑型的性質。
本發明的藥用組合物可包含治療有效量的與任選的一種或多種可藥用載體(添加劑)和/或稀釋劑一起配製的一種或多種本發明的化合物,以及任選的一種或多種其它治療劑。可通過任意合適方式給予本發明化合物以用於任意上述用途,例如口服,諸如片劑、丸劑、粉劑、顆粒劑、酏劑、酊劑、懸浮液(包括納米懸浮液、微懸浮液、噴霧乾燥的分散液)、糖漿和乳液;經舌下;含服;經腸胃外,諸如通過皮下、靜脈內、肌內或胸骨內注射或輸注技術(例如以無菌可注射水性或非水性溶液或懸浮液形式);經鼻,包括向鼻膜給藥,諸如通過吸入噴霧;局部,諸如以乳膏劑或軟膏劑形式;或經直腸,諸如以栓劑形式;或經瘤內注射。它們可單獨給藥,但通常使用基於所選給藥途徑和標準藥學實踐選擇的藥物載體給藥。
根據本領域技術人員認識範圍內的諸多因素來調配可藥用載體。這些因素包括,但不限於:所調配活性劑的類型和性質;含有活性劑的組合物所要給藥的受試者;組合物的預期給藥途徑;及所靶向的治療適應症。藥用載體包括水性和非水性液體介質及各種固體和半固體劑型。
上述載體可包括除活性劑外的諸多不同成分和添加劑,上述其它成分出於本領域技術人員公知的各種原因包括於製劑中,例如穩定活性劑、粘合劑等。關於合適的藥用載體和載體選擇中所涉及的因素的描述可參見多個容易獲得的來源,例如Allen L.V.Jr.et al.Remington:The Science and Practice of Pharmacy(2 Volumes),22nd Edition(2012),Pharmaceutical Press。
當然,本發明化合物的劑量方案取決於已知因素而有所變化,諸如具體藥劑的藥效學特性及其給藥模式和途徑;接受者的物種、年齡、性別、健康狀況、醫學病狀和重量;症狀的性質和程度;同時治療的種類;治療頻率;給藥途徑、患者的腎和肝功能及期望效應。根據一
般指導,當用於指定效應時,各活性成分的日口服劑量應為約0.001mg/天至約10-5000mg/天,優選地為約0.01mg/天至約1000mg/天,且最優選地為約0.1mg/天至約250mg/天。在恒速輸注期間,靜脈內最優選劑量應為約0.01mg/kg/分鐘至約10mg/kg/分鐘。本發明化合物可以單一日劑量給藥,或可以每日兩次、三次或四次的分開劑量給藥總日劑量。
所述化合物通常以與根據預期給藥形式(例如口服片劑、膠囊劑、酏劑和糖漿劑)適當地選擇且與常規藥學實踐相符合的合適藥物稀釋劑、賦形劑或載體(在本文中統稱為藥物載體)的混合物形式進行給藥。
適於給藥的劑型(藥物組合物)可含有約1毫克至約2000毫克活性成分/劑量單位。在這些醫藥組合物中,以組合物的總重量計,活性成分通常將以約0.1-95重量%的量存在。
用於口服給藥的典型膠囊劑含有至少一種本發明化合物(250mg)、乳糖(75mg)和硬脂酸鎂(15mg)。使該混合物穿過60目網篩,並包裝成1號明膠膠囊。
典型的可注射製劑可如下製備:以無菌方式將至少一種本發明化合物(250mg)置於瓶中、以無菌方式凍幹並密封。為進行使用,將瓶內容物與2mL生理鹽水混合,以產生可注射製劑。
本發明範圍包括(單獨或與可藥物載體組合)包含治療有效量的至少一種本發明化合物作為活性成分的藥物組合物。任選地,本發明化合物可單獨使用、與本發明其它化合物組合使用或與一種或多種其它治療劑(例如抗癌劑或其它藥學活性物質)組合使用。
不考慮所選擇的給藥路徑,通過本領域技術人員已知的常規方法來將本發的化合物(其可以合適的水合形式使用)和/或本發明的藥物組合物配製成藥用劑量形式。
可改變活性成分在本發明的藥物組合物中的實際劑量水準,從而獲得對於實現特定患者的期望的治療回應、組成和給藥模式有效的而
對患者無毒的活性成分量。
選定的劑量水準會取決於多種因素,包括所用的本發明的特定化合物或其酯、鹽或醯胺的活性;給藥路徑;給藥時間;所用的特定化合物的排泄速率;吸收速率和程度;治療的持續時間;與所用的特定化合物組合使用的其它藥物、化合物和/或物質;所治療的患者的年齡、性別、重量、狀況、一般健康和先前的醫學史等醫學領域公知的因素。
具有本領域普通技術的醫生或獸醫可容易地確定並開出有效量的所需藥物組合物。例如,為了達到所期望的治療效果,醫師或獸醫可在低於所需的水準開始藥物組合物中所用的本發明化合物的較量,並逐步增加劑量直至實現所期望的效果。通常,合適日劑量的本發明化合物將是有效產生治療效果的最低劑量的化合物的量。此種有效劑量通常取決於上述因素。通常,口服、靜脈內、腦室內和皮下劑量的用於患者的本發明化合物的範圍為約0.01至約50mg/kg體重/天。如果需要的話,有效日劑量的活性化合物可以兩個、三個、四個、五個、六個或更多個亞劑量在一天當中的適當的間隔分別給藥,任選地呈單位劑型形式。在本發明的某些方面中,服藥為每天一次給藥。
雖然本發明化合物可單獨給藥,但優選以藥物製劑(組合物)形式給予化合物。
試劑盒/產品包裝
為了用於上述適應症的治療,試劑盒/產品包裝也在此進行描述。這些試劑盒可以由輸送器、藥包或容器盒組成,容器盒可被劃分成多格,以容納一種或多種容器,如管形瓶、試管及類似物等,每個容器中包含所述方法中的單獨一種成分。合適的容器包括瓶子,管形瓶,注射器和試管等。容器由可接受的玻璃或塑膠等材料製作而成。
舉例來講,容器可裝有一種或多種在此所述的化合物,化合物可能以藥物組分形式存在,也可能與在本文中所述的其它成分組成混合
物體存在。容器可有一個無菌輸出口(例如容器可為靜脈輸液包或瓶,瓶塞可被皮下注射器針頭刺破)。這樣的試劑盒可帶有一種化合物,及本文中所述的使用方法的說明、標籤或操作說明。
一個典型的試劑盒可包括一種或多種容器,為適應商業推廣和使用者對化合物使用的需求,每個容器裝有一種或多種材料(如試劑,也可以是濃縮的母液,和/或器械)。這些材料包括但不局限於緩衝液,稀釋液,濾器,針頭,注射器,輸送器,包,容器,瓶和/或試管,附有內容清單和/或使用說明書,內置包裝也附有說明書。整套的說明都要包括在內。
標籤可顯示在容器上或與容器緊密相關。標籤出現在容器上即指標籤字母、數位或其它特徵被粘貼、鑄模、刻在容器上;標籤也可出現在裝有多種容器的容器盒或運輸盒內,如在產品插頁中。一個標籤可用來提示內容物的某種特定治療用途。標籤也可標示內容物使用說明,諸如在上述方法中描述的。
在本說明書中被描述的所有特徵(包括任何所述的請求項、摘要),和/或任何方法或過程中涉及的所有步驟,均有可能以任意一種組合存在,除非某些特徵或步驟在同一組合中是相互排斥的。
本發明提到的上述特徵,或實施例提到的特徵可以任意組合。本案說明書所揭示的所有特徵可與任何組合物形式並用,說明書中所揭示的各個特徵,可以任何可提供相同、均等或相似目的的替代性特徵取代。因此除有特別說明,所揭示的特徵僅為均等或相似特徵的一般性例子。
下面結合具體實施例,進一步闡述本發明。應理解,這些實施例僅用於說明本發明而不用於限制本發明的範圍。下列實施例中未注明具體條件的實驗方法,通常按照常規條件或按照製造廠商所建議的條件。除非另外說明,否則所有的百分數、比率、比例、或份數按重量計。
本發明中的重量體積百分比中的單位是本領域技術人員所熟知的,例如是指在100毫升的溶液中溶質的重量。除非另行定義,文中所使用的所有專業與科學用語與本領域熟練人員所熟悉的意義相同。此外,任何與所記載內容相似或均等的方法及材料皆可應用于本發明方法中。文中所述的較佳實施方法與材料僅作示範之用。
具體實施例
當未提及製備途徑時,相關中間體是市售的(例如來自Sigma Aldrich,Alfa)。
通用過程
使用市售試劑而不需進一步純化。1H-NMR譜在Bruker儀器上於500MHz記錄。化學位移值以百萬分率表示,即δ值。以下簡寫用於NMR信號的多重性:s=單峰,brs=寬峰,d=二重峰,t=三重峰,m=多重峰。耦合常數以J值列出,以Hz測量。NMR和質譜結果根據背景峰校正。色譜是指使用100篩目矽膠進行並在氮氣壓力(快速色譜)條件下完成的柱色譜。用於監測反應的TLC指使用特定流動相和來自Merck的矽膠F254作為固定相進行的TLC。
LC-MS實驗在以下條件下測量:
儀器:Thermo U3000,ALLtech ELSD,MSQ,UV檢測器結合ELSD和MSD(流出比為4:1)。柱:Waters X-Bridge C-18,3.5μm,4.6x50mm;柱溫:30℃。梯度【時間(min)/溶劑B在A中(%)】:0.00/5.0,0.70/95,1.40/95,1.41/5,1.50/5。(溶劑A=0.01%三氟乙酸在水中;溶劑B=0.01%三氟乙酸在乙腈中)。UV檢測:214/254/280/300nm;DAD檢測:200-400nm;流速:4mL/min;MS:ESI,100-1500 m/z
製備型HPLC通常使用鹼性方法(乙腈和水的梯度,水中含有10
mM碳酸氫銨);用Thermo U3000 AFC-3000;柱:Globalsil C-18 12nm,250 x 20mm,10μm,或相當;流速:20mL/min,進行分離。
中間體的合成
化合物INT-1的製備:
將2-氯-5-羥基苯甲酸(29.0g,168mmol)溶於四氫呋喃(100mL)中,在氮氣氛圍和冰浴下滴加硼烷(1.0M的四氫呋喃溶液,336mL)。滴加完畢,反應液升至室溫攪拌16小時。TLC檢測原料消耗完全,冰浴下向反應液中滴加甲醇淬滅反應,直至不再有氣泡冒出。濃縮溶劑得到淡黃色固體INT-1a(26.6g,收率:99.8%)。
將化合物INT-1a(26.6g,168mmol)和咪唑(11.5g,169mmol)
溶於二氯甲烷(300mL)中,在0℃條件下分批加入預先溶於二氯甲烷(100mL)溶液中的叔丁基二甲基氯矽烷(25.5g,169mmol)。混合物升溫至30℃攪拌16小時,用水(100mL)淬滅反應,水相用二氯甲烷萃取(100mL x 2)。合併有機相用飽和食鹽水(500mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離得到淡黃色液體INT-1b(33.4g,收率:73%)。
將化合物INT-1b(8.0g,29.3mmol)溶於乙腈(100mL),相繼加入三乙胺(14.8g,147mmol),氯化鎂(5.58g,58.6mmol)和多聚甲醛(8.80g,293mmol)。混合物在氮氣氛圍下加熱至90℃,劇烈攪拌20小時。向反應液中加入水(100mL)稀釋,用飽和檸檬酸水溶液調節pH=3-4,然後用乙酸乙酯萃取(200mL x 2)。合併有機相用飽和食鹽水(300mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離得到白色固體INT-1c(5.0g,收率:56.7%)。1H NMR(500MHz,DMSO-d6)δ 10.97(s,1H),10.23(s,1H),7.58(s,1H),7.25(s,1H),4.72(s,2H),0.96(s,9H),0.14(s,6H).
將5-氯甲基-3-氰基吡啶鹽酸鹽(3.20g,17.0mmol)溶於N,N-二甲基甲醯胺(20mL)中,在冰浴下加入N,N-二異丙基乙胺(5.48g,42.4mmol)和碳酸鉀(5.86g,42.4mmol)。攪拌10分鐘後,在上述反應液中加入INT-1c(4.25g,14.1mmol)和碘化鉀(234mg,1.41mmol)。反應液在冰浴下攪拌30分鐘,然後升至50℃攪拌16小時。將反應液在冰浴下冷卻,加入100mL水後有固體析出,過濾固體,用水洗滌,乾燥,然後固體粗品用矽膠柱層析分離得到白色固體INT-1d(5.00g,收率:84.9%)。MS(ESI):m/z 417.2(M+H)+.
將化合物INT-1d(5.0g,12.0mmol)溶於甲苯(10mL)中,加入乙二醇(14.9g,240mmol)和對甲苯磺酸(228mg,1.20mmol),然後滴加原甲酸三甲酯(2.55g,24.0mmol)。混合物在氮氣氛圍下加熱至80℃攪拌16小時。反應液在冰浴下冷卻,用飽和碳酸氫鈉水溶液(50
mL)淬滅,水相用乙酸乙酯萃取(100mL x 2)。合併有機相用飽和食鹽水(200mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離得到白色固體INT-1e(5.50g,收率:99.5%)。MS(ESI):m/z 461.2(M+H)+.
將化合物INT-1e(2.20g,4.77mmol)溶於四氫呋喃(10mL)中,加入四丁基氟化銨的四氫呋喃溶液(1M,7.16mL),反應液在30℃條件下攪拌半小時。用水(30mL)稀釋,水相用乙酸乙酯萃取(50mL x 2)。合併有機相用飽和食鹽水(50mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用乙酸乙酯和石油醚混合液(v/v=3/100,20mL)打漿,過濾得到淡黃色固體INT-1f(1.58g,收率:95.5%)。MS(ESI):m/z 347.2(M+H)+.
將化合物INT-1f(1.50g,4.33mmol)溶於二氯甲烷(30mL)中,加入N,N-二異丙基乙胺(1.68g,13.0mmol),在0℃和氮氣氛圍下加入甲磺酸酐(1.51g,8.65mmol)。然後加入N,N-二異丙基乙胺(1.68g,13.0mmol)和鹽酸二氧六環(4M,1.62mL)的二氯甲烷(10mL)混合液。反應液在25℃條件下攪拌16小時。用水(30mL)淬滅反應,水相用二氯甲烷萃取(50mL x 2)。合併有機相用飽和食鹽水(50mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離得到淡黃色固體INT-1g(1.40g,收率:88.6%)。MS(ESI):m/z 365.2(M+H)+.
將化合物INT-1g(1.36g,3.72mmol),4-溴-1H-吲唑(734mg,3.72mmol)和碳酸鉀(1.03g,7.45mmol)溶於N,N-二甲基甲醯胺(10mL)中。混合物在50℃下攪拌16小時。反應液在冰浴下冷卻,加入100mL水有固體析出,過濾,用水洗滌,乾燥;所得固體粗品再用矽膠柱層析分離得到淡黃色固體INT-1h(1.08g,收率:55.2%)。1H NMR(500MHz,DMSO-d6)δ 8.96(d,J=2.0Hz,1H),8.82(s,1H),8.27(s,1H),8.05(s,1H),7.70(d,J=8.5Hz,1H),7.45(s,1H),7.40(d,J=7.5
Hz,1H),7.32(t,J=7.5Hz,1H),6.91(s,1H),6.04(s,1H),5.71(s,2H),5.16(s,2H),4.04-4.01(m,2H),3.97-3.89(m,2H);MS(ESI):m/z 525.0(M+H)+.
將化合物INT-1h(1.00g,1.90mmol)溶於四氫呋喃(20mL)中,加入鹽酸(4.0M的水溶液,5.0mL)。反應液在30℃條件下攪拌1小時。然後用飽和碳酸氫鈉水溶液中和,水相用乙酸乙酯萃取(50mL x 2)。合併有機相,用飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮得到淡黃色固體INT-1i(900mg,收率:98.2%)。MS(ESI):m/z 481.0(M+H)+.
將化合物INT-1i(840mg,1.74mmol)溶於N,N-二甲基甲醯胺(5mL)中,加入O-叔丁基-L-絲氨酸叔丁酯(418mg,1.92mmol)和乙酸(209mg,3.48mmol),反應液在30℃下攪拌1小時。然後向反應液中加入三乙醯氧基硼氫化鈉(1.48g,6.96mmol),反應在30℃下攪拌1小時。然後加入水(50mL)淬滅,水相用乙酸乙酯萃取(50mL x 2)。合併有機相用飽和食鹽水(50mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離得到淡黃色固體INT-1j(720mg,收率:60.5%)。MS(ESI):m/z 682.1(M+H)+.
將中間體INT-1j(1.00g,1.46mmol),聯硼酸頻哪醇酯(558mg,2.20mmol),醋酸鉀(431mg,4.39mmol)和Pd(dppf)Cl2(107mg,0.15mmol)混合於二氧六環(15mL)中。反應液在氮氣氛圍下加熱至90℃攪拌過夜。待反應液冷卻至室溫,用乙酸乙酯(100mL)稀釋,矽藻土過濾,再用100mL乙酸乙酯洗滌,所得濾液濃縮。殘留物用矽膠柱層析分離(二氯甲烷/甲醇,v/v=20/1)得到淡黃色固體INT-1(600mg,收率:56.1%)。MS(ESI):m/z 730.7(M+H)+.
化合物INT-2的製備:
將(S)-5-羥甲基-2-吡咯烷酮(10.0g,86.9mmol)溶于無水四氫呋喃(200mL)中,加入鄰苯二甲醯亞胺(12.8g,86.9mmol)和三苯基膦(34.2g,130mmol)。在冰浴條件和氮氣氛圍下向反應液中緩慢滴加偶氮二甲酸二異丙酯(26.4g,130mmol)。反應液升至室溫攪拌過夜,過濾所產生的沉澱,乾燥得到白色固體INT-2a(11.4g,收率:53.7%)。MS(ESI):m/z 245.1(M+H)+.
將化合物INT-2a(1.0g,4.09mmol)溶於乙醇(20mL)中,加入80%水合肼(512mg,8.19mmol)。反應液加熱至85℃攪拌2小時,待反應冷卻至室溫,過濾除去所產生的沉澱。濾液濃縮後加入二氯甲烷(50mL),過濾所得濾液進一步真空濃縮後得到黃色油狀液體INT-2(430mg,收率:92.0%)。1H NMR(500MHz,DMSO-d 6)δ 7.65(s,1H),3.43-3.37(m,1H),2.47-2.42(m,2H),2.12-2.04(m,2H),2.03-1.96(m,1H),1.66-1.60(m,1H),1.58(s,2H).
化合物INT-3的製備:
將4-甲醯基苯硼酸頻哪醇酯(4.50g,19.4mmol)和1,3-二溴-2-氯苯(10.5g,38.8mmol)溶於二氧六環和水(60mL,v/v=5/1)的混合溶劑中,加入碳酸鉀(8.04g,58.2mmol)和Pd(dppf)Cl2(1.42g,1.94
mmol)。反應液在氮氣氛圍下加熱至80℃攪拌3小時。用水(100mL)淬滅反應,水相用乙酸乙酯萃取(200mL x 2)。合併有機相,用飽和食鹽水(200mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離(石油醚/乙酸乙酯,v/v=4/1)得到白色固體INT-3a(3.7g,收率:64.6%)。
將化合物INT-3a(1.00g,3.38mmol)溶於N,N-二甲基甲醯胺(10mL)中,依次加入化合物INT-2(541mg,4.74mmol)和醋酸(203mg,3.38mmol)。所得反應液在室溫下攪拌1小時,然後加入三乙醯氧基硼氫化鈉(2.87g,13.5mmol)。所得反應液進一步在室溫下攪拌過夜,用飽和碳酸氫鈉水溶液(50mL)淬滅反應,水相用乙酸乙酯萃取(50mL x 3)。合併有機相,依次用水(100mL)和飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮得到黃色固體INT-3b(1.41g,收率:99.5%)。MS(ESI):m/z 393.3(M+H)+.
將化合物INT-3b(1.41g,3.58mmol)溶於二氯甲烷(15mL)中,依次加入三乙胺(725mg,7.16mmol)和二碳酸二叔丁酯(860mg,3.94mmol)。反應液在室溫下攪拌2小時,接著用200mL二氯甲烷稀釋;所得有機相依次用水(100mL)和飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離(二氯甲烷/甲醇,v/v=20/1)得到白色固體INT-3(1.55g,收率:87.6%)。1H NMR(500MHz,DMSO-d 6)δ 7.78(dd,J=7.8Hz,1H),7.69(s,1H),7.44-7.25(m,6H),4.53-4.39(m,2H),3.80-3.70(m,1H),3.26-3.10(m,2H),2.17-1.99(m,3H),1.76-1.66(m,1H),1.38(s,9H);MS(ESI):m/z 493.3(M+H)+.
化合物INT-4的製備:
從1,3-二溴-2-甲苯起,參照化合物INT-3的合成方法,可以得到白色固體INT-4。1H NMR(500MHz,Chloroform-d)δ 7.76(d,J=7.2Hz,1H),7.28-7.22(m,7H),4.53(s,2H),4.05-3.67(m,1H),3.42-3.20(m,2H),2.40(s,3H),2.01-1.90(m,3H),1.82-1.71(m,1H),1.36(s,9H);MS(ESI):m/z 473.4(M+H)+.
化合物INT-5的製備:
將化合物INT-3a(1.50g,5.08mmol)溶於N,N-二甲基甲醯胺(20mL)中,依次加入(R)-3-羥基吡咯烷鹽酸鹽(1.88g,15.2mmol)和無水醋酸鈉(1.25g,15.2mmol)。反應液在室溫下攪拌過夜。然後加入三乙醯氧基硼氫化鈉(4.31g,20.3mmol),反應液在室溫下進一步繼續攪拌2小時;用飽和碳酸氫鈉水溶液(100mL)淬滅反應,水相用乙酸乙酯萃取(100mL x 2)。合併有機相,用飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離(二氯甲烷/甲醇,v/v=20/1)得到淡黃色固體INT-5(1.60g,收率:80.6%)。1H NMR(500MHz,Methanol-d 4)δ 7.71-7.67(m,1H),7.46-7.41(m,2H),7.38-7.33(m,2H),7.32(d,J=7.8Hz,1H),7.25(t,J=7.8Hz,1H),4.41-4.31(m,1H),3.81-3.66(m,2H),2.88-2.83(m,1H),2.83-2.76(m,1H),2.64-2.58(m,1H),2.56-2.51(m,1H),2.22-2.12(m,1H),1.79-1.70(m,1H);MS(ESI):m/z 366.1(M+H)+.
化合物INT-6的製備:
從4-溴-2-甲氧基苯甲醛起,參照化合物INT-1的最後一步Suzuki硼酯化反應得到化合物INT-6a。
從化合物INT-6a起,參照化合物INT-3的合成方法,可以得到化合物INT-6。1H NMR(500MHz,DMSO-d 6)δ 7.78(d,J=8.0Hz,1H),7.70(s,1H),7.42-7.38(m,1H),7.33(t,J=7.5Hz,1H),7.11-7.03(m,1H),7.02-7.00(m,1H),6.98-6.93(m,1H),4.47-4.34(m,2H),3.81(s,3H),3.77-3.71(m,1H),3.26-3.17(m,2H),2.18-2.10(m,1H),2.09-2.00(m,2H),1.74-1.64(m,1H),1.47-1.26(m,9H).MS(ESI):m/z 523.2(M+H)+.
化合物INT-7的製備:
將中間體INT-1i(1.00g,2.08mmol),聯硼酸頻那醇酯(635mg,2.50mmol),醋酸鉀(612mg,6.24mmol)和Pd(dppf)Cl2(152mg,0.21mmol)混合於二氧六環(20mL)溶液中,反應液在氮氣氛圍下加熱至90℃攪拌過夜。待反應液冷卻至室溫,用乙酸乙酯(100mL)稀釋,矽藻土過濾,濾餅再用乙酸乙酯(100mL)進一步洗滌;所得濾液減壓濃縮。殘留物用矽膠柱層析分離(石油醚/乙酸乙酯,v/v=1/1)得到淡黃色固體INT-7a(940mg,收率:85.5%)。MS(ESI):m/z 529.2(M+H)+.
將化合物INT-7a(96.4mg,0.18mmol)和化合物INT-3(75.0mg,0.15mmol)溶於二氧六環和水(11mL,v/v=10/1)的混合溶劑中,加入
碳酸鉀(63.0mg,0.46mmol)和Pd(dppf)Cl2(11.1mg,0.015mmol),混合物在氮氣氛圍下加熱至80℃攪拌3小時。然後用水(50mL)淬滅反應,水相用乙酸乙酯萃取(50mL x 2)。合併有機相,用飽和食鹽水(50mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用製備薄層層析分離(二氯甲烷/甲醇,v/v=95/5)得到淡黃色固體INT-7(120mg,收率:96.9%)。MS(ESI):m/z 815.2(M+H)+.
化合物INT-8的製備:
從化合物INT-1c和碘甲烷起,參照INT-1i的合成得到化合物INT-8b。MS(ESI):m/z 379.1(M+H)+.
從化合物INT-8b起,參照化合物INT-7的合成得到化合物INT-8c和化合物INT-8。它們的譜圖資訊如下:
INT-8c:1H NMR(500MHz,Chloroform-d)δ 10.31(s,1H),8.50(s,1H),7.83(s,1H),7.69(d,J=7.0Hz,1H),7.47(d,J=8.5Hz,1H),7.44-7.37(m,1H),6.42(s,1H),5.73(s,2H),3.60(s,3H),1.42(s,12H);MS(ESI):m/z 427.3(M+H)+.
INT-8:MS(ESI):m/z 713.5(M+H)+.
化合物INT-9的製備:
從化合物INT-8c和化合物INT-6起,參照化合物INT-8的合成得到化合物INT-9。MS(ESI):m/z 743.6(M+H)+.
化合物INT-10的製備:
從3-溴-2-氯苯酚起,參照化合物INT-7a的合成方法得到化合物INT-10a。MS(ESI):m/z 253.3(M-H)-.
從化合物INT-10a和6-氯-2-甲氧基-3-吡啶甲醛起,參照化合物INT-3a的合成方法得到化合物INT-10b。MS(ESI):m/z 262.0(M-H)-.
將化合物INT-10b(500mg,1.90mmol)溶于無水二氯甲烷(10mL)中,加入N,N-二異丙基乙胺(490mg,3.80mmol),冰浴冷卻至0℃,隨後慢慢滴加三氟甲磺酸酐(804mg,2.85mmol)。反應液逐漸升至室溫,繼續攪拌2小時。用50mL飽和氯化銨水溶液淬滅反應,水相用乙酸乙酯萃取(30mL x 2)。合併有機相,用50mL飽和食鹽水洗,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離得到桔黃色油狀物INT-10(482mg,收率:64.2%)。MS(ESI):m/z 396.2(M+H)+.
化合物INT-11的製備:
在25℃條件下,將溶有(R)-1-Boc-3-羧基吡咯烷(1.00g,4.65mmol),碘甲烷(1.00g,7.05mmol)和碳酸鉀(2.00g,14.5mmol)的N’N-二甲基甲醯胺(3mL)反應液攪拌3小時。隨後加入水(50mL)稀釋,並用乙酸乙酯萃取(50mL x 2);合併有機相,用50mL飽和
食鹽水洗,無水硫酸鈉乾燥,過濾,濃縮得到黃色油狀物INT-11a(1.00g,收率:93.9%)。
在溶有化合物INT-11a(1.00g,4.36mmol)的二氯甲烷(2mL)溶液中加入鹽酸(4M的1,4-二氧六環溶液,5mL);反應液在25℃條件下攪拌3小時。所得反應液濃縮後得到黃色固體INT-11(700mg,收率:96.9%)。1H NMR(500MHz,DMSO-d6)δ 9.70(brs,2H),3.66(s,3H),3.42-3.35(m,1H),3.30-3.22(m,2H),3.19-3.13(m,2H),2.22-2.14(m,1H),2.06-1.99(m,1H).
化合物INT-12的製備:
從化合物INT-8c和化合物INT-5起,參照化合物INT-8的合成得到化合物INT-12。MS(ESI):m/z 586.4(M+H)+.
化合物INT-13的製備:
在冰浴條件下,將二氯亞碸(11.7g,98.6mmol)加到溶有2-羥基-4-甲基苯甲酸(5.0g,32.9mmol)的甲醇(20mL)溶液;反應液在65℃條件下攪拌16小時。反應液濃縮,殘餘物中加入乙酸乙酯(100mL)和水(100mL);有機相用飽和碳酸氫鈉溶液(100mL),飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮得到黃色油狀物INT-13a(5.25g,收率:96.1%)。
在溶有化合物INT-13a(5.25g,31.6mmol)的N,N-二甲基甲醯胺(30mL)中加入碘甲烷(5.83g,41.1mmol)和碳酸鉀(8.73g,63.2
mmol);反應液在25℃條件下攪拌6小時。反應液濃縮,殘餘物中加入乙酸乙酯(100mL)和水(100mL);有機相用飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮得到黃色油狀物INT-13b(5.6g,收率:98.4%)。
在溶有化合物INT-13b(1.0g,5.55mmol)的甲醇(15mL)溶液中加入三氟甲磺酸銀(1.57g,6.10mmol)和碘(1.55g,6.10mmol);反應液在25℃條件下攪拌2小時。隨後過濾,濾液用乙酸乙酯(50mL)稀釋,並用亞硫酸鈉水溶液(5% w/w,50mL)和飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮得到橘色固體INT-13(1.6g,收率:94.2%)。1H NMR(500MHz,Chloroform-d)δ 8.20(s,1H),6.86(s,1H),3.88(s,3H),3.87(s,3H),2.45(s,3H);MS(ESI):m/z 306.9(M+H)+.
化合物INT-14的製備:
將二氯亞碸(185mg,1.55mol)加入至溶有反式-(N-Boc-4-氨基環己基)乙酸(100mg,0.39mmol)的甲醇(3mL)溶液;反應液在70℃條件下攪拌3小時。反應液濃縮後得到白色固體INT-14(70mg,收率:86.7%)。1H NMR(500MHz,DMSO-d6)δ 8.15-7.92(m,3H),3.56(s,3H),2.87(s,1H),2.21-2.15(m,2H),1.95-1.87(m,2H),1.74-1.66(m,2H),1.63-1.53(m,1H),1.35-1.25(m,2H),1.06-0.95(m,2H).
化合物INT-15的製備:
在冰浴條件下,在溶有4-溴-2,6-二氟苯甲醛(1.10g,4.98mmol)的甲醇(10mL)溶液中逐滴加入甲醇鈉(5.4M的甲醇溶液,1.11mL);
反應液在相同條件下攪拌3小時。反應液用鹽酸(1M的水溶液,12mL)淬滅並攪拌10分鐘;所得溶液進一步用水(100mL)稀釋,並用乙酸乙酯(100mL x 2)萃取。合併有機相用飽和食鹽水(150mL)洗滌,無水硫酸鈉乾燥,濃縮。殘餘物用矽膠柱層析(石油醚/乙酸乙酯,v/v=10/1)純化得到白色固體INT-15a(660mg,收率:56.9%)和白色固體INT-15b(204mg,收率:16.7%)。
化合物INT-15a:1H NMR(500MHz,Chloroform-d)δ 10.36(s,1H),6.97-6.93(m,2H),3.94(s,3H).
化合物INT-15b:1H NMR(500MHz,Chloroform-d)δ 10.42(s,1H),6.76(s,2H),3.90(s,6H).
從化合物INT-15a起,參照化合物INT-6的合成方法,可以得到化合物INT-15。1H NMR(500MHz,DMSO-d6)δ 7.83(d,J=8.0Hz,1H),7.71(s,1H),7.45(d,J=7.8Hz,1H),7.37(t,J=7.8Hz,1H),6.90-6.86(m,2H),4.54-4.50(m,2H),3.84(s,3H),3.77-3.73(m,1H),3.17(d,J=5.3Hz,2H),2.12-2.02(m,3H),1.71-1.65(m,1H),1.40-1.32(m,9H);MS(ESI):m/z 541.5(M+H)+.
化合物INT-16的製備:
從化合物INT-8c和化合物INT-15起,參照化合物INT-8的合成得到化合物INT-16。MS(ESI):m/z 761.7(M+H)+.
化合物INT-17的製備:
在110℃條件下,將溶有S-2-氨基己二酸(5g,31mmol)的醋酸和水(25mL,v/v=1/4)的溶液攪拌16小時。反應液濃縮後所得殘餘物用乙醇溶解;其中沒有反應完的起始原料不會被乙醇所溶解。乙醇濾液濃縮後得到白色固體INT-17a(3g,收率:67.6%)。MS(ESI):m/z 142.1(M-H)-
從化合物INT-17a起,參照化合物INT-13a的合成方法,可以得到無色油狀物INT-17b。
在0℃條件下,將硼氫化鈉(433mg,11.5mmol)加入溶有化合物INT-17b(450mg,2.9mmol)的乙醇(10mL)溶液中;所得混合液在室溫下攪拌16小時。少量醋酸加入去淬滅反應,所得反應液濃縮後所得殘餘物用二氯甲烷溶解。有機相用少量飽和食鹽水洗滌,無水硫酸鈉乾燥,濃縮後得到無色油狀物INT-17c(369mg,收率:99.8%)。MS(ESI):m/z 130.2(M+H)+.
從化合物INT-17c起,參考化合物INT-2的合成方法,可以得到淡黃色油狀物INT-17。1H NMR(500MHz,DMSO-d6)δ 7.34(s,1H),3.22-3.06(m,1H),2.59-2.42(m,2H),2.18-1.98(m,2H),1.75(brs,2H),1.64-1.50(m,2H),1.37-1.18(m,2H)。
化合物INT-18的製備:
從化合物INT-15a起,參照化合物INT-1的最後一步Suzuki硼酯化反應和化合物INT-3a的合成方法,可以得到化合物INT-18a。1H NMR(500MHz,DMSO-d6)δ 10.34(s,1H),7.91-7.87(m,1H),7.52-7.48(m,1H),7.44-7.38(m,1H),7.13-7.10(m,1H),7.04-7.00(m,1H),3.96(s,3H).
從化合物INT-18a起,參照化合物INT-1的最後一步Suzuki硼酯化反應得到化合物INT-18。1H NMR(500MHz,DMSO-d6)δ 10.31(s,1H),7.68-7.64(m,1H),7.55-7.51(m,1H),7.44(t,J=7.5Hz,1H),7.05(s,1H),6.97-6.89(m,1H),3.93(s,3H),1.31(s,12H);MS(ESI):m/z 391.7(M+H)+.
實施例化合物的合成
實施例1:
從化合物INT-1和化合物INT-5起,參照化合物INT-7的合成,得到化合物1a。MS(ESI):m/z 889.9(M+H)+.
將化合物1a(20mg,0.022mmol)溶於二氯甲烷(2mL)中,並加入三氟乙酸(2mL),反應液在25℃條件下攪拌6小時。反應液濃縮後,殘餘物用經製備高效液相色譜柱層析純化得到白色固體1(6.5mg,
收率:37.4%)。1H NMR(500MHz,DMSO-d6)δ 8.95(s,1H),8.84(s,1H),8.33(s,1H),7.87(s,1H),7.72-7.67(m,1H),7.55-7.45(m,7H),7.40(d,J=8.0Hz,2H),7.18-7.15(m,1H),6.83(s,1H),5.74-5.69(m,2H),5.11-5.05(m,2H),4.24-4.18(m,1H),3.93(d,J=14.5Hz,1H),3.85(d,J=14.5Hz,1H),3.65(d,J=13.0Hz,1H),3.61-3.55(m,2H),3.12-3.07(m,1H),2.72-2.68(m,1H),2.65-2.58(m,2H),2.38-2.32(m,2H),2.05-1.97(m,1H),1.59-1.52(m,1H);MS(ESI):m/z 777.8(M+H)+.
實施例2:
從化合物INT-1和化合物INT-4起,參照化合物1的合成,得到化合物2。1H NMR(500MHz,DMSO-d6)δ 8.95(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),8.34(t,J=2.0Hz,1H),7.84(s,1H),7.71-7.64(m,2H),7.55(s,1H),7.46-7.37(m,6H),7.34-7.31(m,1H),7.28(d,J=7.5,1H),7.09(d,J=7.0Hz,1H),6.86(s,1H),5.71(s,2H),5.14-5.08(m,2H),3.96-3.84(m,2H),3.79-3.74(m,2H),3.64-3.57(m,3H),3.13-3.09(m,1H),2.55(d,J=6.0Hz,2H),2.15-2.05(m,3H),1.99(s,3H),1.73-1.67(m,1H);MS(ESI):m/z 784.3(M+H)+.
實施例3:
從化合物INT-1和化合物INT-3a起,參照化合物INT-7的合成,得到化合物3a。MS(ESI):m/z 818.4(M+H)+.
從化合物3a和嗎啡啉起,參照化合物INT-3b合成過程中的還原胺化步驟,得到化合物3b。MS(ESI):m/z 889.9(M+H)+.
從化合物3b起,參照化合物1合成中的最後一步脫Boc保護步驟,得到化合物3。1H NMR(500MHz,DMSO-d6)δ 8.95(s,1H),8.84(s,1H),8.33(s,1H),7.86(s,1H),7.72-7.67(m,1H),7.56-7.45(m,7H),7.41(d,J=7.5Hz,2H),7.17(d,J=7.0Hz,1H),6.83(s,1H),5.72(s,2H),5.13-5.05(m,2H),3.92(d,J=14.0Hz,1H),3.85(d,J=14.0Hz,1H),3.63-3.56(m,6H),3.52(s,2H),3.13-3.06(m,1H),2.40(s,4H);MS(ESI):m/z 777.6(M+H)+.
實施例4:
從化合物3a和N-甲基乙醇胺起,參照化合物3的合成,得到化合物4。1H NMR(500MHz,DMSO-d6)δ 8.95(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),8.33(d,J=2.5Hz,1H),7.87(s,1H),7.71(d,J=8.5Hz,1H),7.56(s,1H),7.55-7.46(m,6H),7.41(d,J=8.0Hz,2H),7.17(d,J=7.0Hz,1H),6.84(s,1H),5.72(s,2H),5.14-5.06(m,2H),3.96(d,J=14.0Hz,1H),3.88(d,J=14.0Hz,1H),3.69-3.63(m,1H),3.61-3.58(m,1H),3.57(s,2H),3.54(t,J=6.5Hz,2H),3.18-3.14(m,1H),2.55-2.53(m,2H),2.20(s,3H);MS(ESI):m/z 765.7(M+H)+.
實施例5:
從化合物3a和乙醇胺起,參照化合物3的合成,得到化合物5。1H NMR(500MHz,DMSO-d6)δ 8.94(s,1H),8.83(s,1H),8.32(s,1H),7.86(s,1H),7.70(d,J=8.5Hz,1H),7.56-7.50(m,3H),7.49-7.43(m,6H),7.17(d,J=7.0Hz,1H),6.83(s,1H),5.72(s,2H),5.13-5.05(m,2H),3.90(d,J=14.0Hz,1H),3.86-3.80(m,3H),3.60-3.54(m,2H),3.51(t,J=6.0Hz,2H),3.10-3.05(m,1H),2.65(t,J=6.0Hz,2H);MS(ESI):m/z 751.4(M+H)+.
實施例6:
從化合物INT-3a和N-甲基乙醇胺起,參照化合物INT-3b合成中的還原胺化步驟,得到化合物6a。MS(ESI):m/z 354.2(M+H)+.
在冰浴條件下,在溶有化合物6a(207mg,0.58mmol)的四氫呋喃(5mL)溶液中依次加入N,N-二異丙基乙胺(226mg,1.75mmol)和甲基磺酸酐(203mg,1.17mmol)。反應液在冰浴條件下攪拌半小時後升溫至25℃,並在相同溫度下繼續攪拌2小時。反應液中加入水(20mL)稀釋,水相用二氯甲烷(20mL x 2)萃取,合併有機相用無水硫酸鈉乾燥,過濾,濃縮得到化合物6b。在冰浴條件和氮氣氛圍下,在溶有(R)-(-)-3-羥基四氫呋喃(103mg,1.17mmol)的四氫呋喃(5mL)中加入鈉氫(60% w/w在煤油中,46.8mg);反應液在冰浴條件下攪拌半小時,然後加入上述得到的化合物6b。所得反應液升溫至50℃攪拌過夜;冷卻至室溫後,反應液用水(20mL)淬滅,水相用乙酸乙酯(20mL x 2)萃取;合併有機相用飽和食鹽水(30mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用製備薄層層析分離(二氯甲烷/甲醇,v/v=15/1)得到黃色油狀物6c(110mg,收率:44.4%)。MS(ESI):m/z 424.3(M+H)+.
從化合物INT-1和化合物6c起,參照化合物1的合成,得到化合物6。1H NMR(500MHz,DMSO-d6)δ 8.94(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),8.34-8.32(m,1H),7.86(s,1H),7.70(d,J=8.5Hz,1H),7.55-7.45(m,7H),7.40(d,J=8.0Hz,2H),7.20-7.15(m,1H),
6.81(s,1H),5.72(s,2H),5.12-5.05(m,2H),4.12-4.08(m,1H),3.89-3.77(m,2H),3.73-3.68(m,1H),3.67-3.62(m,3H),3.57(s,2H),3.55-3.48(m,4H),3.02-2.94(m,1H),2.55(t,J=6.0Hz,2H),2.20(s,3H),1.94-1.83(m,2H);MS(ESI):m/z 835.7(M+H)+.
實施例7:
在冰浴條件下,在溶有化合物INT-3(200mg,0.40mmol)的四氫呋喃(2mL)中加入鈉氫(60% w/w在煤油中,32.4mg),反應液在冰浴條件下繼續攪拌半小時。隨後在室溫條件下,將反應液中加入碘甲烷(86mg,0.61mmol);所得反應液在室溫條件下攪拌過夜。反應液用水(20mL)淬滅,水相用乙酸乙酯(20mL x 2)萃取;合併有機相用飽和食鹽水(30mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物矽膠柱層析分離(二氯甲烷/甲醇,v/v=10/1)得到黃色油狀物7a(200mg,收率:97%)。MS(ESI):m/z 507.4(M+H)+.
從化合物INT-1和化合物7a起,參照化合物1的合成,得到化合物7。1H NMR(500MHz,DMSO-d6)δ 8.99-8.90(m,1H),8.90-8.79(m,1H),8.32(s,1H),7.86(s,1H),7.70(d,J=8.5Hz,1H),7.57-7.43(m,9H),7.17(d,J=7.0Hz,1H),6.83(s,1H),5.72(s,2H),5.15-5.05(m,2H),3.97-3.91(m,1H),3.89-3.83(m,1H),3.78(s,2H),3.68-3.52(m,3H),3.18-3.10(m,1H),2.73-2.63(m,5H),2.33-2.22(m,1H),
2.18-2.08(m,1H),2.06-1.98(m,1H),1.87-1.77(m,1H);MS(ESI):m/z 818.6(M+H)+.
實施例8:
從化合物INT-1和化合物INT-6起,參照化合物1的合成,得到化合物8。1H NMR(500MHz,DMSO-d6)δ 8.95(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),8.34(d,J=2.0Hz,1H),7.88(s,1H),7.74-7.68(m,2H),7.57-7.49(m,4H),7.48-7.45(m,1H),7.42(d,J=8.0Hz,1H),7.19-7.15(m,1H),7.11-7.04(m,2H),6.85(s,1H),5.72(s,2H),5.15-5.06(m,2H),3.95(d,J=14.5Hz,1H),3.87(d,J=14.5Hz,1H),3.83(s,3H),3.76-3.73(m,2H),3.66-3.62(m,2H),3.61-3.55(m,1H),3.15-3.11(m,1H),2.58-2.54(m,2H),2.14-2.06(m,3H),1.74-1.66(m,1H);MS(ESI):m/z 834.7(M+H)+.
實施例9:
從化合物INT-1和1,3-二溴-2-氯苯起,參照化合物INT-7合成中的最後一步Suzuki反應,得到化合物9a。MS(ESI):m/z 792.6(M+H)+.
從化合物9a起,參照化合物INT-7a的合成,得到化合物9b。MS(ESI):m/z 840.6(M+H)+.
從化合物9b和2-溴-5-醛基吡啶起,參照化合物INT-7合成中的最後一步Suzuki反應,得到化合物9c。MS(ESI):m/z 819.4(M+H)+.
從化合物9c和化合物INT-2起,參照化合物INT-3b合成中的還原胺化步驟,得到化合物9d。MS(ESI):m/z 917.8(M+H)+.
從化合物9d起,參照化合物1合成中的最後一步脫Boc步驟,得到化合物9。1H NMR(500MHz,DMSO-d6)δ 8.96(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),8.65(d,J=2.0Hz,1H),8.33(s,1H),7.92-7.83(m,2H),7.75-7.66(m,3H),7.65-7.55(m,3H),7.52-7.44(m,1H),7.21-7.14(m,1H),6.86(s,1H),5.73(s,2H),5.15-5.05(m,2H),3.99-3.73(m,4H),3.69-3.55(m,3H),3.21-3.15(m,1H),2.58-2.52(m,
2H),2.18-2.03(m,3H),1.75-1.64(m,1H);MS(ESI):m/z 805.8(M+H)+.
實施例10:
從化合物9b和5-溴-2-吡啶甲醛起,參照化合物9的合成,得到化合物10。1H NMR(500MHz,DMSO-d6)δ 8.95(s,1H),8.84(s,1H),8.64(s,1H),8.33(s,1H),7.96(d,J=8.0Hz,1H),7.90(s,1H),7.74-7.69(m,2H),7.62-7.44(m,6H),7.18(d,J=7.0Hz,1H),6.83(s,1H),5.72(s,2H),5.14-5.05(m,2H),3.93-3.73(m,4H),3.68-3.50(m,3H),3.03-2.94(m,1H),2.58(d,J=6.2Hz,2H),2.16-2.05(m,3H),1.75-1.66(m,1H);MS(ESI):m/z 805.3(M+H)+.
實施例11:
從化合物9b和4-溴-3-甲氧基苯甲醛起,參照化合物9的合成,得到化合物11。1H NMR(500MHz,DMSO-d6)δ 8.88(d,J=2.0Hz,1H),8.77(d,J=2.0Hz,1H),8.27-8.25(m,1H),7.73(s,1H),7.66-7.59(m,2H),7.47(s,1H),7.45-7.37(m,3H),7.32-7.28(m,1H),7.15-7.08
(m,2H),7.05(s,1H),6.93(d,J=7.7Hz,1H),6.78(s,1H),5.64(s,2H),5.06-5.00(m,2H),3.87-3.82(m,1H),3.80-3.75(m,1H),3.74-3.67(m,6H),3.58-3.56(m,1H),3.51-3.50(m,1H),3.04-2.99(m,1H),2.51-2.47(m,2H),2.08-1.99(m,3H),1.68-1.59(m,1H);MS(ESI):m/z 834.7(M+H)+.
實施例12:
從4-甲醯基苯硼酸頻哪醇酯和1,3-二溴-2-氟苯起,參照化合物INT-3a的合成,得到化合物12a。1H NMR(500MHz,Chloroform-d)δ 10.08(s,1H),7.97(d,J=8.0Hz,2H),7.70(d,J=8.0Hz,2H),7.61(t,J=7.0Hz,1H),7.40(t,J=7.0Hz,1H),7.14(t,J=7.5Hz,1H).
從化合物12a,化合物INT-2和化合物INT-1起,參照化合物INT-3和化合物1的合成得到化合物12。1H NMR(500MHz,DMSO-d6)δ 8.93(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),8.34-8.32(m,1H),8.02(d,J=2.5Hz,1H),7.72(d,J=8.5Hz,1H),7.68(s,1H),7.64-7.57(m,4H),7.53(s,1H),7.51-7.42(m,4H),7.30-7.26(m,1H),6.85(s,1H),5.72(s,2H),5.15-5.07(m,2H),3.90(d,J=14.5Hz,1H),3.85-3.72(m,3H),3.65-3.60(m,1H),3.56(d,J=5.5Hz,2H),3.07-2.99(m,1H),2.54-2.52(m,2H),2.14-2.05(m,3H),1.73-1.64(m,1H);MS(ESI):m/z 788.3(M+H)+.
實施例13:
從4-甲醯基苯硼酸頻哪醇酯和2,6-二溴-苯腈起,參照化合物INT-3a的合成,得到化合物13a。1H NMR(500MHz,Chloroform-d)δ 10.11(s,1H),8.02(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,2H),7.54(t,J=8.0Hz,1H),7.47(d,J=8.0Hz,1H).
從化合物13a,化合物INT-2和化合物INT-1起,參照化合物INT-3和化合物1的合成得到化合物13。1H NMR(500MHz,DMSO-d6)δ 8.94(d,J=2.0Hz,1H),8.81(d,J=2.0Hz,1H),8.31-8.29(m,1H),8.07(d,J=2.5Hz,1H),7.93-7.87(m,1H),7.80-7.72(m,2H),7.70-7.63(m,4H),7.56-7.45(m,4H),7.37-7.33(m,1H),6.70(s,1H),5.78-5.73(m,2H),5.06-4.99(m,2H),3.90(d,J=15.0Hz,1H),3.84-3.75(m,3H),3.71(d,J=15.0Hz,1H),3.66-3.61(m,1H),3.58-3.54(m,1H),3.09-3.02(m,1H),2.56-2.53(m,2H),2.14-2.05(m,3H),1.73-1.65(m,1H);MS(ESI):m/z 795.7(M+H)+.
實施例14:
從4-甲醯基苯硼酸頻哪醇酯和1-溴-3-碘苯起,參照化合物INT-3a的合成,得到化合物14a。
從化合物14a,化合物INT-2和化合物INT-1起,參照化合物INT-3和化合物1的合成得到化合物14。1H NMR(500MHz,DMSO-d6)δ
8.91(d,J=2.0Hz,1H),8.83(d,J=2.0Hz,1H),8.32-8.30(m,1H),8.21-8.18(m,1H),7.96-7.94(m,1H),7.76-7.71(m,4H),7.69-7.62(m,3H),7.55(s,1H),7.51-7.44(m,3H),7.38(d,J=7.0Hz,1H),6.83(s,1H),5.76-5.70(m,2H),5.16-5.08(m,2H),3.94(d,J=14.0Hz,1H),3.87(d,J=14.0Hz,1H),3.79(d,J=14.0Hz,1H),3.75(d,J=14.0Hz,1H),3.66-3.61(m,2H),3.61-3.55(m,1H),3.15-3.12(m,1H),2.54-2.52(m,2H),2.13-2.04(m,3H),1.72-1.64(m,1H);MS(ESI):m/z 770.7(M+H)+.
實施例15:
在室溫條件下,將3-溴-4-氯苯胺(2.06g,9.98mmol)溶於硫酸(25% w/w的水溶液,40mL),並且攪拌半小時;隨後將反應液冷卻至-5℃,將預先溶有亞硝酸鈉(826mg,12.0mmol)的水(10mL)溶液慢慢滴入。滴加完成後,反應液在-5℃的條件下進一步攪拌一小時;隨後將預先溶有碘化鉀(3.31g,20.0mmol)的乙酸乙酯和水的混合溶液(50mL,v/v=3/2),在滴加過程中保證反應內溫在-5℃以下。水相進一步用乙酸乙酯(50mL x 2)萃取,合併有機相依次用飽和硫代硫酸鈉溶液(100mL x 2)和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物矽膠柱層析分離得到淡黃色固體15a(2.05g,收率:64.7%)。1H NMR(500MHz,CDCl3)δ 7.95(d,J=2.0Hz,1H),
7.57-7.53(m,1H),7.17(d,J=8.5Hz,1H).
將4-甲醯基苯硼酸頻哪醇酯(439mg,1.89mmol)和化合物15a(500mg,1.58mmol)溶於二氧六環和水(10mL,v/v=4/1)的混合溶劑中,加入碳酸氫鈉(397mg,4.73mmol)和Pd(dppf)Cl2(58mg,0.079mmol)。反應液在氮氣氛圍下加熱至80℃攪拌3小時。用水(50mL)淬滅反應,水相用乙酸乙酯萃取(50mL x 2)。合併有機相,用飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離(石油醚/乙酸乙酯,v/v=10/1)得到黃色油狀物15b(271mg,收率:58.2%)。
從化合物15b,化合物INT-2和化合物INT-1起,參照化合物INT-3和化合物1的合成得到化合物15。1H NMR(500MHz,DMSO-d6)δ 8.93(s,1H),8.84(s,1H),8.34(s,1H),7.85(s,1H),7.81-7.76(m,2H),7.74-7.65(m,5H),7.55-7.40(m,4H),7.25-7.19(m,1H),6.81(s,1H),5.72(s,2H),5.13-5.04(m,2H),3.90-3.83(m,1H),3.78-3.69(m,3H),3.63-3.53(m,3H),3.06-2.97(m,1H),2.57-2.55(m,2H),2.13-2.03(m,3H),1.70-1.63(m,1H);MS(ESI):m/z 804.7(M+H)+.
實施例16:
在室溫條件下,在溶有3-溴-4-甲基苯胺(584mg,3.14mmol)的N,N-二甲基甲醯胺(3mL)溶液中加入N-氯代丁二醯亞胺(419mg,
3.14mmol);反應液升溫至80℃,並且在該溫度下攪拌1小時。用水(50mL)淬滅反應,水相用乙酸乙酯萃取(50mL x 2)。合併有機相,用飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離(石油醚/乙酸乙酯,v/v=10/1)得到白色固體16a(292mg,收率:42.2%)。1H NMR(500MHz,DMSO-d 6)δ 6.97(d,J=8.2Hz,1H),6.70(d,J=8.2Hz,1H),5.41(s,2H),2.22(s,3H).從4-甲醯基苯硼酸頻哪醇酯和化合物16a起,參照化合物INT-3a的合成,得到化合物16b。
在室溫條件下,在溶有化合物16b(100mg,0.41mmol)的乙腈(1mL)溶液中加入亞硝酸叔丁酯(50mg,0.49mmol)和溴化亞銅(91mg,0.63mmol);反應液升溫至60℃,並且在該溫度下攪拌一小時。用水(20mL)淬滅反應,水相用乙酸乙酯萃取(20mL x 2)。合併有機相,用飽和食鹽水(50mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離(石油醚/乙酸乙酯,v/v=10/1)得到白色固體16c(28mg,收率:22.2%)。1H NMR(500MHz,Chloroform-d)δ 10.09(s,1H),8.02-7.95(m,2H),7.56(d,J=8.2Hz,1H),7.35(d,J=8.0Hz,2H),7.08(d,J=8.2Hz,1H),2.01(s,3H).
從化合物16c,化合物INT-2和化合物INT-1起,參照化合物INT-3和化合物1的合成得到化合物16。1H NMR(500MHz,DMSO-d6)δ 8.98-8.88(m,1H),8.85-8.77(m,1H),8.32-8.23(m,1H),7.81(s,1H),7.67-7.63(m,2H),7.53(s,1H),7.47-7.42(m,3H),7.42-7.39(m,2H),7.27-7.21(m,2H),7.14-7.09(m,1H),6.82(s,1H),5.69(s,2H),5.11-5.04(m,2H),3.95-3.82(m,2H),3.82-3.75(m,2H),3.66-3.61(m,2H),3.59-3.55(m,1H),3.17-3.13(m,1H),2.62-2.56(m,2H),2.14-2.10(m,1H),2.08(s,3H),2.08-2.04(m,1H),2.02-1.92(m,1H),1.74-1.64(m,1H);MS(ESI):m/z 818.5(M+H)+.
實施例17:
從3-溴-4-氯苯胺起,參照化合物16的合成,得到化合物17。1H NMR(500MHz,DMSO-d6)δ 8.95-8.88(m,1H),8.85-8.76(m,1H),8.34-8.27(m,1H),7.90-7.84(m,1H),7.72-7.64(m,3H),7.54(d,J=8.3Hz,1H),7.49-7.40(m,4H),7.29(d,J=7.7Hz,2H),7.14(d,J=7.0Hz,1H),6.73(s,1H),5.68(s,2H),5.09-4.99(m,2H),3.80-3.71(m,2H),3.66(s,2H),3.63-3.57(m,1H),3.42-3.34(m,2H),3.21-3.16(m,1H),2.56-2.52(m,2H),2.13-2.04(m,3H),1.70-1.64(m,1H);MS(ESI):m/z 838.2(M+H)+.
實施例18:
從4-溴苯乙醇起,參照化合物INT-7a的合成得到化合物18a。MS(ESI):m/z 249.1(M+H)+.
從化合物18a和1,3-二溴-2-甲苯起,參照化合物INT-3a的合成,得到化合物18b。MS(ESI):m/z 311.0(M+H)+.
從化合物18b起,參照化合物6b的合成得到化合物18c。MS(ESI):m/z 389.0(M+H)+.
在50℃條件下,將混有化合物18c(290mg,0.74mmol),(R)-3-羥基吡咯烷鹽酸鹽(138mg,1.12mmol)和碳酸銫(727mg,2.23mmol)的乙腈(10mL)溶液攪拌16小時。用水(30mL)淬滅反應,水相用乙酸乙酯萃取(30mL x 2)。合併有機相,用飽和食鹽水(50mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離(二氯甲烷/甲醇,v/v=10/1)得到黃色油狀物18d(140mg,收率:49.0%)。MS(ESI):m/z 380.2(M+H)+.
從化合物18d和化合物INT-1起,參照化合物1的合成得到化合物18。1H NMR(500MHz,DMSO-d6)δ 8.93(d,J=2.0Hz,1H),8.83(d,J=2.0Hz,1H),8.33-8.31(m,1H),7.86(s,1H),7.69(d,J=8.5Hz,1H),7.53-7.51(m,2H),7.48-7.45(m,2H),7.44-7.41(m,2H),7.34-7.32(m,3H),7.16(d,J=7.0Hz,1H),6.79(s,1H),5.71(s,2H),5.08(d,J=3.0Hz,2H),4.20-4.18(m,1H),3.86-3.81(m,2H),3.53-3.51(m,2H),2.97(t,J=6.0Hz,1H),2.80-2.76(m,4H),2.68-2.63(m,4H),2.00-1.96(m,1H),1.57-1.53(m,1H);MS(ESI):m/z 791.5(M+H)+.
實施例19:
從4-溴苯丙醇起,參照化合物18的合成,得到化合物19。1H NMR(500MHz,DMSO-d6)δ 8.94(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),8.54(s,1H),8.35-8.33(m,1H),7.86(s,1H),7.69(d,J=8.5Hz,1H),7.55-7.51(m,2H),7.49-7.42(m,5H),7.30(d,J=8.0Hz,2H),7.16(d,J=7.0Hz,1H),6.75(s,1H),5.70(s,2H),5.13-4.98(m,2H),4.22-4.15(m,2H),3.71-3.64(m,2H),3.24-3.17(m,3H),2.71-2.63(m,3H),
2.56-2.53(m,1H),2.42-2.38(m,3H),2.30-2.27(m,1H),2.01-1.93(m,1H),1.79-1.73(m,2H),1.56-1.50(m,1H);MS(ESI):m/z 805.7(M+H)+.
實施例20:
在25℃條件下,將N-氯代丁二醯亞胺(639mg,4.78mmol)分批加入至溶有2,6-二溴苯胺(1.00g,3.99mmol)的乙腈(20mL)溶液中;所得反應液在相同溫度下攪拌16小時。反應液中加水,有固體析出;所得到的固體進一步用水洗滌,乾燥後得到白色固體20a(1.10g,收率:96.7%)。1H NMR(500MHz,DMSO-d6)δ 7.53(s,2H),5.48(s,2H).
從化合物20a起,參照化合物16c的合成,其中將溴化亞銅換成氯化亞銅,得到化合物20b。1H NMR(500MHz,DMSO-d6)δ 8.00(s,2H).
從化合物20b起,參照化合物12的合成,得到化合物20。1H NMR(500MHz,DMSO-d6)δ 8.95-8.88(m,1H),8.83-8.76(m,1H),8.32-8.23(m,1H),7.90(s,1H),7.70(d,J=8.5Hz,1H),7.68-7.64(m,1H),7.61-7.58(m,1H),7.56-7.41(m,7H),7.21-7.14(m,1H),6.79-6.66(m,1H),5.70(s,2H),5.13-5.01(m,2H),3.83-3.70(m,4H),3.61(t,J=6.5Hz,1H),3.51-3.47(m,1H),3.44-3.41(m,1H),2.86(s,1H),2.53-2.52(m,2H),2.16-2.00(m,3H),1.73-1.63(m,1H);MS(ESI):m/z 838.3(M+H)+.
實施例21:
在25℃條件下,將N-溴代丁二醯亞胺(6.28g,35.3mmol)分批加入至溶有5-氯-2-甲基苯胺(2.00g,14.1mmol)的乙腈(30mL)溶液中;所得反應液在相同溫度下攪拌16小時。用水(100mL)淬滅反應,水相用乙酸乙酯萃取(100mL x 3)。合併有機相,用飽和食鹽水(200mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離得到深紅色固體21a(4.00g,收率:94.6%)。1H NMR(500MHz,Chloroform-d)δ 7.27(s,1H),4.25(s,2H),2.18(s,3H).
在25℃條件和氮氣氛圍下,將亞硝酸叔丁酯(3.91g,33.4mmol)緩慢滴加至溶有化合物21a(4.00g,13.4mmol)的乙醇(30mL)溶液;反應液在50度條件下攪拌2小時。反應液冷卻後濃縮,所得殘餘物用矽膠柱層析分離得到白色固體21b(2.1g,收率:55.3%)。1H NMR(500MHz,Chloroform-d)δ 7.41(s,2H),2.29(s,3H).
從化合物21b起,參照化合物12的合成,得到化合物21。1H NMR(500MHz,DMSO-d6)δ 8.93(d,J=2.0Hz,1H),8.82(d,J=2.0Hz,1H),8.31-8.29(m,1H),7.84(s,1H),7.72-7.63(m,2H),7.53(s,1H),7.48-7.39(m,5H),7.33-7.25(m,2H),7.13(d,J=7.0Hz,1H),6.82(s,1H),5.70(s,2H),5.14-5.04(m,2H),3.93(d,J=14.5Hz,1H),3.85(d,J=14.5Hz,1H),3.80-3.73(m,2H),3.67-3.54(m,3H),3.14(t,J=5.5Hz,
1H),2.54-2.53(m,2H),2.38(s,3H),2.12-2.04(m,3H),1.72-1.64(m,1H);MS(ESI):m/z 818.8(M+H)+.
實施例22:
從化合物INT-7和甘氨酸叔丁酯起,參照化合物INT-1j合成中的還原胺化以及化合物1合成中的脫Boc保護基步驟得到化合物22。1H NMR(500MHz,DMSO-d6)δ 8.95(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),8.34-8.32(m,1H),7.87(s,1H),7.71(d,J=8.5Hz,1H),7.67(s,1H),7.56-7.46(m,9H),7.17(d,J=7.0Hz,1H),6.86(s,1H),5.73(s,2H),5.11(s,2H),3.93(s,2H),3.90-3.82(m,2H),3.71-3.67(m,1H),3.18(s,2H),2.73-2.61(m,2H),2.17-2.09(m,3H),1.75-1.69(m,1H);MS(ESI):m/z 774.7(M+H)+.
實施例23:
從化合物INT-7和絲氨酸異丙酯起,參照化合物22的合成得到化合物23。1H NMR(500MHz,DMSO-d6)δ 8.97(d,J=1.9Hz,1H),8.83
(d,J=1.9Hz,1H),8.30(d,J=1.9Hz,1H),7.87(s,1H),7.74-7.68(m,2H),7.55-7.43(m,9H),7.17(d,J=7.0Hz,1H),6.85(s,1H),5.71(s,2H),5.09(s,2H),4.86-4.80(m,1H),3.81-3.72(m,3H),3.66-3.60(m,2H),3.54(d,J=5.0Hz,2H),3.19(t,J=5.0Hz,1H),2.56-2.54(m,2H),2.14-2.07(m,3H),1.74-1.65(m,1H),1.11(d,J=6.0Hz,3H),1.08(d,J=6.5Hz,3H);MS(ESI):m/z 846.7(M+H)+.
實施例24:
從化合物INT-7和乙醇胺起,參照化合物22的合成得到化合物24。1H NMR(500MHz,DMSO-d6)δ 8.96(d,J=2.0Hz,1H),8.83(d,J=2.0Hz,1H),8.29(s,1H),7.87(s,1H),7.71(d,J=9.5Hz,2H),7.54(t,J=7.5Hz,1H),7.52-7.43(m,8H),7.17(d,J=7.0Hz,1H),6.84(s,1H),5.72(s,2H),5.09(s,2H),3.79(d,J=13.5Hz,1H),3.77-3.73(m,3H),3.66-3.61(m,1H),3.47(t,J=5.5Hz,2H),2.59(t,J=5.5Hz,2H),2.57-2.54(m,2H),2.15-2.06(m,3H),1.72-1.66(m,1H);MS(ESI):m/z 760.6(M+H)+.
實施例25:
從化合物INT-7和脯氨酸叔丁酯起,參照化合物22的合成得到化合物25。1H NMR(500MHz,DMSO-d6)δ 8.95(d,J=2.0Hz,1H),8.82
(d,J=2.0Hz,1H),8.35-8.33(m,1H),7.88(s,1H),7.72-7.68(m,2H),7.55-7.44(m,9H),7.17(d,J=7.0Hz,1H),6.82(s,1H),5.72(s,2H),5.14-5.06(m,2H),3.98(d,J=14.0Hz,1H),3.82(d,J=14.0Hz,1H),3.77(d,J=7.5Hz,2H),3.65-3.62(m,1H),3.05-3.02(m,1H),2.56-2.54(m,2H),2.15-2.03(m,5H),1.90-1.84(m,1H),1.81-1.65(m,4H);MS(ESI):m/z 814.8(M+H)+.
實施例26:
從化合物INT-1j起,參照化合物INT-1j合成中的還原胺化以及化合物INT-1合成中硼酯化步驟得到化合物26b。MS(ESI):m/z 744.6(M+H)+.
從化合物26b和化合物INT-3起,參照化合物1的合成得到化合物26。1H NMR(500MHz,DMSO-d6)δ 8.94(d,J=2.0Hz,1H),8.80(d,J=2.0Hz,1H),8.27(s,1H),7.87(s,1H),7.72-7.68(m,2H),7.57-7.43(m,9H),7.17(d,J=7.0Hz,1H),6.80(s,1H),5.71(s,2H),5.09(s,2H),3.82-3.69(m,6H),3.66-3.58(m,2H),2.55(d,J=6.0Hz,2H),2.28(s,3H),2.14-2.07(m,3H),1.74-1.66(m,1H);MS(ESI):m/z 818.8(M+H)+.
實施例27:
從化合物INT-7起,參照化合物1合成過程中的脫Boc保護基步驟得到化合物27a。MS(ESI):m/z 715.5(M+H)+.
在25℃條件下,在溶有化合物27a(45mg,0.054mmol)的N’N-二甲基甲醯胺(2mL)中加入(R)-3-羥基吡咯烷鹽酸鹽(21mg,0.14mmol)和N,N-二異丙基乙胺(70mg,0.54mmol);所得反應液在相同溫度下攪拌一小時。隨後加入三醋酸硼氫化鈉(58mg,0.27mmol),反應液進一步在25℃條件下攪拌16小時。反應液中加入水(20mL);並用乙酸乙酯(15mL x 2)萃取。有機相濃縮,殘餘物用經製備高效液相色譜柱層析純化得到白色固體27(10mg,收率:22.6%)。1H NMR(500MHz,DMSO-d6)δ 8.93(d,J=2.0Hz,1H),8.79(d,J=2.0Hz,1H),8.26-8.24(m,1H),7.85(s,1H),7.71-7.65(m,2H),7.52-7.40(m,9H),7.15(d,J=6.9Hz,1H),6.80(s,1H),5.69(s,2H),5.07(s,2H),3.77(d,J=12.5Hz,1H),3.74(d,J=12.5Hz,1H),3.62-3.56(m,3H),2.92-2.86(m,1H),2.69-2.61(m,2H),2.54-2.52(m,4H),2.11-2.05(m,3H),1.95-1.90(m,2H),1.70-1.64(m,1H);MS(ESI):m/z 814.8(M+H)+.
實施例28:
從化合物INT-7a,化合物INT-6和絲氨酸異丙酯起,參照化合物INT-7和化合物23的合成得到化合物28。1H NMR(500MHz,DMSO-d6)δ 8.96(d,J=2.0Hz,1H),8.82(d,J=2.0Hz,1H),8.30-8.28(m,1H),7.88(s,1H),7.71(d,J=8.6Hz,1H),7.68(s,1H),7.56-7.47(m,4H),7.46(s,1H),7.42(d,J=7.7Hz,1H),7.17(d,J=7.1Hz,1H),7.09(d,J=1.6Hz,1H),7.08-7.04(m,1H),6.84(s,1H),5.71(s,2H),5.09(s,2H),4.87-4.81(m,1H),4.78(t,J=5.8Hz,1H),3.83(s,3H),3.77(d,J=14.7Hz,1H),3.75-3.73(m,1H),3.66-3.60(m,2H),3.54(t,J=5.6Hz,2H),3.30-3.28(m,1H),3.19(t,J=5.3Hz,1H),2.56(d,J=6.0Hz,2H),2.16-2.05(m,3H),1.75-1.64(m,1H),1.11(d,J=6.2Hz,3H),1.09(d,J=6.2Hz,3H);MS(ESI):m/z 876.2(M+H)+.
實施例29:
從化合物INT-10,化合物INT-2,化合物INT-7a和乙醇胺起,參照化合物INT-3,化合物INT-7和化合物23的合成得到化合物29。1H NMR(500MHz,DMSO-d6)δ 8.97(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),8.33-8.31(m,1H),7.85(s,1H),7.83(d,J=7.5Hz,1H),7.73(d,J=9.0Hz,1H),7.72(s,1H),7.69-7.65(m,1H),7.60-7.54(m,2H),7.52-7.47(m,2H),7.32(d,J=7.5Hz,1H),7.18(d,J=7.0Hz,1H),6.87(s,1H),5.72(s,2H),5.11(s,2H),3.92(s,3H),3.80(s,2H),3.72(d,J=4.0Hz,2H),3.66-3.62(m,1H),3.48(t,J=5.5Hz,2H),2.64(t,J=5.5Hz,2H),2.56(d,J=6.0Hz,2H),2.14-2.07(m,3H),1.74-1.66(m,1H);MS(ESI):m/z 791.6(M+H)+.
實施例30:
從化合物INT-8和O-叔丁基-L-絲氨酸叔丁酯起,參照化合物22的合成得到化合物30。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.78(d,J=8.5Hz,1H),7.69(s,1H),7.56-7.44(m,9H),7.17(d,J=7.0Hz,1H),6.72(s,1H),5.75(s,2H),3.89(d,J=14.5Hz,1H),3.83-3.75(m,3H),3.68-3.63(m,2H),3.61(s,3H),3.60-3.57(m,1H),3.14(t,J=5.5Hz,1H),2.57(d,J=6.5Hz,2H),2.16-2.07(m,3H),1.74-1.67(m,1H);MS(ESI):m/z 702.5(M+H)+.
實施例31:
從化合物INT-8和(R)-(-)-4-氨基-3-羥基丁酸起,參照化合物27的合成得到化合物31。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.77(d,J=8.5Hz,1H),7.67(s,1H),7.55-7.50(m,2H),7.49-7.43(m,7H),7.17(d,J=7.0Hz,1H),6.69(s,1H),5.74(s,2H),3.94-3.90(m,1H),3.80-3.77(m,2H),3.69-3.68(m,2H),3.65-3.63(m,1H),3.60(s,3H),2.57-2.53(m,4H),2.45-2.39(m,1H),2.28-2.22(m,1H),2.13-2.05(m,3H),1.75-1.65(m,1H);MS(ESI):m/z 716.7(M+H)+.
實施例32:
從化合物INT-8和甘氨酸叔丁酯起,參照化合物22的合成得到化合物32。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.77(d,J=9.0Hz,1H),7.67(s,1H),7.55-7.50(m,2H),7.49-7.42(m,7H),7.17(d,J=7.0Hz,1H),6.70(s,1H),5.74(s,2H),3.80-3.72(m,4H),3.65-3.62(m,1H),3.60(s,3H),3.07(s,2H),2.55-2.53(m,2H),2.14-2.07(m,3H),1.72-1.66(m,1H);MS(ESI):m/z 672.6(M+H)+.
實施例33:
從化合物INT-8和化合物INT-11起,參照化合物INT-5的合成得到化合物33a。MS(ESI):m/z 826.7(M+H)+.
在25℃條件下,在溶有化合物33a(90mg,0.11mmol)的甲醇和水(9mL,v/v=8/1)的混合溶液中加入氫氧化鋰(10mg,0.42mmol);反應液在相同溫度下攪拌一小時。反應液濃縮後加飽和氯化銨稀釋,水相用乙酸乙酯(10mL x 2)萃取;合併有機相濃縮。殘餘物溶於二氯甲烷和三氟乙酸的混合溶液(4mL,v/v=3/1),在25℃條件下進一步反應2小時。反應液濃縮後,殘餘物用經製備高效液相色譜柱層析
純化得到白色固體33(10.3mg,收率:23.5%)。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.77(d,J=8.5Hz,1H),7.69(s,1H),7.55-7.50(m,2H),7.49-7.43(m,6H),7.37(s,1H),7.17(d,J=7.0Hz,1H),6.68(s,1H),5.73(s,2H),3.83-3.74(m,2H),3.67-3.62(m,1H),3.58(s,3H),3.56-3.48(m,2H),2.95-2.88(m,1H),2.68-2.64(m,2H),2.59-2.54(m,2H),2.54-2.51(m,1H),2.15-2.06(m,3H),1.98-1.90(m,2H),1.74-1.66(m,1H);MS(ESI):m/z 712.7(M+H)+.
實施例34:
從(R)-1-Boc-3-羧基吡咯烷起,參照化合物INT-11的合成得到化合物34a。
從化合物34a和化合物INT-8起,參照化合物33的合成得到化合物34。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.77(d,J=8.5Hz,1H),7.68(s,1H),7.55-7.43(m,8H),7.37(s,1H),7.17(d,J=7.0Hz,1H),6.67(s,1H),5.73(s,2H),3.81-3.73(m,2H),3.66-3.61(m,1H),3.58(s,3H),3.56-3.47(m,2H),2.92-2.86(m,1H),2.69-2.62(m,2H),2.56-2.53(m,2H),2.49-2.46(m,1H),2.14-2.07(m,3H),1.96-1.90(m,2H),1.74-1.66(m,1H);MS(ESI):m/z 712.7(M+H)+.
實施例35:
從N-Boc-(R)-3-甲酸呱啶,參照化合物INT-11的合成得到化合物35a。
從化合物35a和化合物INT-8起,參照化合物33的合成得到化合物35。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.77(d,J=8.5Hz,1H),7.68(s,1H),7.55-7.42(m,8H),7.39(s,1H),7.17(d,J=7.0Hz,1H),6.68(s,1H),5.73(s,2H),3.80-3.73(m,2H),3.65-3.61(m,1H),3.58(s,3H),3.41(s,2H),2.78-2.72(m,1H),2.59-2.53(m,3H),2.44-2.40(m,1H),2.24-2.18(m,1H),2.13-2.04(m,4H),1.79-1.73(m,1H),1.72-1.67(m,1H),1.64-1.59(m,1H),1.50-1.42(m,1H),1.40-1.33(m,1H);MS(ESI):m/z 726.7(M+H)+.
實施例36:
從N-Boc-(S)-3-甲酸呱啶,參照化合物INT-11的合成得到化合物36a。
從化合物36a和化合物INT-8起,參照化合物33的合成得到化合物36。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.77(d,J=8.5Hz,1H),7.68(s,1H),7.55-7.50(m,2H),7.49-7.43(m,6H),7.39(s,1H),7.17(d,J=7.0Hz,1H),6.68(s,1H),5.73(s,2H),3.83-3.74(m,2H),3.66-3.63(m,1H),3.58(s,3H),3.42(s,2H),2.77-2.73(m,1H),2.56
(m,3H),2.45-2.39(m,1H),2.23-2.16(m,1H),2.15-2.04(m,4H),1.79-1.73(m,1H),1.72-1.66(m,1H),1.64-1.59(m,1H),1.50-1.42(m,1H),1.41-1.33(m,1H);MS(ESI):m/z 726.7(M+H)+.
實施例37:
從4-呱啶甲酸甲酯和化合物INT-8起,參照化合物33的合成得到化合物37。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.78-7.76(m,1H),7.67(s,1H),7.53-7.46(m,7H),7.35(s,1H),7.32(s,1H),7.17(d,J=7.0Hz,1H),6.69(s,1H),5.73(s,2H),3.81-3.73(m,2H),3.65-3.62(m,1H),3.58(s,3H),3.52-3.50(m,2H),2.80-2.77(m,1H),2.74-2.70(m,1H),2.20-2.15(m,1H),2.13-2.08(m,3H),2.02-1.98(m,4H),1.78-1.74(m,2H),1.72-1.67(m,1H),1.56-1.52(m,2H);MS(ESI):m/z 726.7(M+H)+.
實施例38:
從3-甲酸甲酯氮雜環丁烷鹽酸鹽和化合物INT-8起,參照化合物33的合成得到化合物38。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.77(d,J=8.5Hz,1H),7.68(s,1H),7.55-7.44(m,8H),7.27(s,1H),7.17(d,J=7.0Hz,1H),6.67(s,1H),5.72(s,2H),3.84-3.77(m,2H),
3.68-3.63(m,1H),3.58(s,3H),3.47(s,2H),3.42-3.38(m,2H),3.23-3.17(m,3H),2.58(d,J=6.0Hz,2H),2.16-2.06(m,3H),1.74-1.66(m,1H);MS(ESI):m/z 698.7(M+H)+.
實施例39:
從止血環酸甲酯鹽酸鹽和化合物INT-8起,參照化合物33的合成得到化合物39。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.77(d,J=8.5Hz,1H),7.69(s,1H),7.55-7.50(m,2H),7.48-7.41(m,7H),7.17(d,J=7.0Hz,1H),6.70(s,1H),5.74(s,2H),3.83-3.75(m,2H),3.68(s,2H),3.67-3.62(m,1H),3.60(s,3H),2.57(d,J=6.0Hz,2H),2.40(d,J=6.5Hz,2H),2.15-2.06(m,4H),1.88(d,J=11.0Hz,2H),1.80(d,J=11.0Hz,2H),1.74-1.67(m,1H),1.43-1.37(m,1H),1.32-1.22(m,2H),0.94-0.84(m,2H);MS(ESI):m/z 754.8(M+H)+.
實施例40:
從反式-4-氨基環己甲酸甲酯鹽酸鹽和化合物INT-8起,參照化合物33的合成得到化合物40。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.79(d,J=8.5Hz,1H),7.67(s,1H),7.56-7.51(m,3H),7.50-7.45(m,6H),7.18(d,J=7.0Hz,1H),6.78(s,1H),5.76(s,2H),3.95(s,2H),3.88-3.80(m,2H),3.69-3.65(m,1H),3.64(s,3H),2.81(s,1H),2.62
(d,J=6.5Hz,2H),2.18-2.09(m,4H),2.04(d,J=11.0Hz,2H),1.94(d,J=11.0Hz,2H),1.75-1.67(m,1H),1.37-1.22(m,4H);MS(ESI):m/z 740.7(M+H)+.
實施例41:
從順式-4-氨基環己甲酸甲酯鹽酸鹽和化合物INT-8起,參照化合物33的合成得到化合物41。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.78(d,J=8.5Hz,1H),7.67(s,1H),7.56-7.51(m,3H),7.50-7.45(m,6H),7.18(d,J=7.0Hz,1H),6.76(s,1H),5.76(s,2H),3.92-3.78(m,4H),3.69-3.66(m,1H),3.63(s,3H),2.87-2.83(m,1H),2.61(d,J=6.0Hz,2H),2.46-2.44(m,1H),2.15-2.07(m,3H),2.00-1.92(m,2H),1.81-1.67(m,3H),1.53-1.44(m,4H);MS(ESI):m/z 740.7(M+H)+.
實施例42:
從反式-4-羥基-L-脯氨酸甲酯鹽酸鹽和化合物INT-8起,參照化合物33的合成得到化合物42。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.77(d,J=8.5Hz,1H),7.67(s,1H),7.55-7.50(m,2H),7.49-7.43(m,7H),7.17(d,J=7.0Hz,1H),6.69(d,J=7.0Hz,1H),5.74(s,2H),
4.21-4.15(m,1H),3.87-3.82(m,1H),3.80-3.76(m,2H),3.67-3.62(m,2H),3.61-3.57(m,3H),3.50-3.45(m,1H),3.21-3.19(m,1H),2.58-2.53(m,3H),2.13-2.07(m,3H),2.02-1.90(m,1H),1.81-1.75(m,1H),1.73-1.67(m,1H);MS(ESI):m/z 728.7(M+H)+.
實施例43:
從L-脯氨酸甲酯鹽酸鹽和化合物INT-8起,參照化合物33的合成得到化合物43。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.78(d,J=8.5Hz,1H),7.69(s,1H),7.55-7.43(m,10H),7.17(d,J=7.0Hz,1H),6.70(s,1H),5.75(s,2H),3.93(d,J=14.0Hz,1H),3.84-3.77(m,3H),3.67-3.62(m,1H),3.60(s,3H),3.37-3.33(m,1H),3.10-3.04(m,1H),2.59-2.52(m,3H),2.14-2.05(m,4H),1.90-1.83(m,1H),1.80-1.74(m,1H),1.73-1.66(m,2H);MS(ESI):m/z 712.7(M+H)+.
實施例44:
從化合物INT-8和4-氨甲基苯甲酸甲酯鹽酸鹽起,參照化合物INT-5的合成得到化合物44a。MS(ESI):m/z 862.7(M+H)+.
從化合物44a起,參照化合物INT-1j合成中的還原胺化步驟得到化合物44b。MS(ESI):m/z 876.8(M+H)+.
從化合物44b起,參照化合物33合成中的最後兩步得到化合物44。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.88(d,J=8.0Hz,2H),7.77(d,J=8.5Hz,1H),7.68(s,1H),7.54-7.50(m,2H),7.49-7.44(m,7H),7.40(d,J=7.5Hz,2H),7.17(d,J=7.0Hz,1H),6.68(s,1H),5.74(s,2H),3.81-3.73(m,2H),3.66-3.62(m,1H),3.59-3.53(m,2H),3.57(s,3H),3.45(s,2H),2.56-2.53(m,2H),2.14-2.07(m,6H),1.72-1.66(m,1H);MS(ESI):m/z 762.7(M+H)+.
實施例45:
從化合物INT-8和對氨基苯乙酸甲酯起,參照化合物44的合成得到化合物45。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.77(d,J=8.5Hz,1H),7.68(s,1H),7.54-7.50(m,2H),7.49-7.43(m,6H),7.17(d,J=7.0Hz,1H),7.02(d,J=8.0Hz,2H),6.92(s,1H),6.75(s,1H),6.55(d,J=8.0Hz,2H),5.72(s,2H),4.41(s,2H),3.81-3.73(m,2H),3.66-3.61(m,4H),3.35(s,2H),2.98(s,3H),2.58-2.53(m,2H),2.14-2.06(m,3H),1.74-1.66(m,1H);MS(ESI):m/z 762.7(M+H)+.
實施例46:
從化合物INT-8和對氨基苯甲酸甲酯起,參照化合物44的合成得到化合物46。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.79(d,J=8.6Hz,1H),7.74-7.70(m,2H),7.64-7.60(m,5H),7.59-7.50(m,3H),7.50-7.46(m,1H),7.17(d,J=7.1Hz,1H),6.87(s,1H),6.85-6.81(m,1H),6.68-6.63(m,2H),5.72(s,2H),4.53(s,2H),4.25(s,2H),3.91-3.85(m,1H),3.68(s,3H),3.09(s,3H),2.57-2.53(m,2H),2.23-2.14(m,3H),1.83-1.77(m,1H);MS(ESI):m/z 748.7(M+H)+.
實施例47:
從化合物INT-8和止血環酸甲酯鹽酸鹽起,參照化合物44的合成得到化合物47。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.75(d,J=8.5Hz,1H),7.67(s,1H),7.53-7.40(m,8H),7.36(s,1H),7.15(d,J=7.0Hz,1H),6.65(s,1H),5.71(s,2H),3.78-3.71(m,2H),3.64-3.60(m,1H),3.55(s,3H),3.35-3.31(m,2H),2.53-2.51(m,2H),2.13-2.07(m,4H),2.07(s,3H),2.01-1.96(m,1H),1.85-1.76(m,4H),1.71-1.65(m,1H),1.46-1.39(m,1H),1.28-1.17(m,3H),0.82-0.73(m,2H);MS(ESI):m/z 768.4(M+H)+.
實施例48:
從4-溴-2-甲基苯甲醛起,參照化合物INT-7a的硼酯化合成步驟得到化合物48a。1H NMR(500MHz,DMSO-d6)δ 10.26(s,1H),7.79(d,J=7.5Hz,1H),7.66(d,J=7.5Hz,1H),7.60(s,1H),2.61(s,3H),1.29(s,12H).
從化合物48a和1,3-二溴-2-氯苯起,參照化合物INT-3a的合成得到化合物48b。1H NMR(500MHz,DMSO-d6)δ 10.27(s,1H),7.89(d,J=7.9Hz,1H),7.85-7.81(m,1H),7.48-7.34(m,4H),2.66(s,3H).
從化合物48b,化合物INT-2,化合物INT-8c和化合物INT-11起,參照化合物INT-3,化合物INT-8和化合物33的合成得到化合物48。1H NMR(500MHz,DMSO-d6)δ 7.88(s,1H),7.75(d,J=8.6Hz,1H),7.67(s,1H),7.53-7.38(m,5H),7.35(s,1H),7.30-7.23(m,2H),7.14(d,J=7.0Hz,1H),6.66(s,1H),5.71(s,2H),3.74-3.67(m,2H),3.65-3.61(m,1H),3.56(s,3H),3.52-3.48(m,2H),2.92-2.85(m,1H),2.64-2.61(m,2H),2.59-2.56(m,2H),2.34(s,3H),2.11-2.05(m,3H),1.94-1.89(m,2H),1.71-1.66(m,1H);MS(ESI):m/z 726.2(M+H)+.
實施例49:
從4-溴-2-氯苯甲醛起,參照化合物48的合成得到化合物49。1H NMR(500MHz,DMSO-d6)δ 7.94(s,1H),7.77(d,J=8.5Hz,1H),7.69(s,1H),7.65(d,J=7.9Hz,1H),7.59(d,J=1.8Hz,1H),7.57-7.45(m,5H),7.37(s,1H),7.17(d,J=7.0Hz,1H),6.68(s,1H),5.73(s,2H),3.90-3.80(m,2H),3.70-3.61(m,1H),3.58(s,3H),3.56-3.49(m,2H),2.96-2.86(m,1H),2.69-2.63(m,2H),2.61-2.56(m,2H),2.53-2.50(m,2H),2.17-2.06(m,3H),1.97-1.90(m,2H),1.75-1.66(m,1H);MS(ESI):m/z 746.6(M+H)+.
實施例50:
從4-溴-3-氯苯甲醛起,參照化合物48的合成得到化合物50。1H NMR(500MHz,DMSO-d6)δ 7.80(s,1H),7.76(d,J=8.5Hz,1H),7.66(s,1H),7.57-7.47(m,4H),7.39-7.38(m,3H),7.34(s,1H),7.16(d,J=7.0Hz,1H),6.66(s,1H),5.71(s,2H),3.80-3.72(m,2H),3.63-3.60(m,1H),3.56(s,3H),3.53-3.47(m,2H),2.90-2.83(m,1H),2.65-2.59(m,2H),2.55-2.51(m,2H),2.47-2.45(m,2H),2.14-2.03(m,3H),1.95-1.87(m,2H),1.72-1.63(m,1H);MS(ESI):m/z 746.5(M+H)+.
實施例51:
從4-溴-2-(三氟甲氧基)苯甲醛起,參照化合物48的合成得到化合物51。1H NMR(500MHz,DMSO-d6)δ 7.96(s,1H),7.82-7.73(m,2H),7.69(s,1H),7.61-7.50(m,5H),7.51-7.48(m,1H),7.38(s,1H),7.19(d,J=7.0Hz,1H),6.69(s,1H),5.75(s,2H),3.88-3.80(m,2H),3.65(t,J=6.5Hz,1H),3.59(s,3H),3.57-3.49(m,2H),2.85-2.75(m,1H),2.70-2.60(m,2H),2.60-2.55(m,2H),2.56-2.53(m,1H),2.50-2.43(m,1H),2.18-2.08(m,3H),1.98-1.85(m,2H),1.77-1.67(m,1H);MS(ESI):m/z 796.7(M+H)+.
實施例52:
從化合物INT-9和化合物INT-11起,參照化合物33的合成得到化合物52。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.77(d,J=8.6Hz,1H),7.68(s,1H),7.57-7.47(m,4H),7.42(d,J=7.7Hz,1H),7.37(s,1H),7.17(d,J=7.0Hz,1H),7.09(d,J=1.7Hz,1H),7.08-7.04(m,1H),6.69(s,1H),5.73(s,2H),3.83(s,3H),3.75-3.72(m,2H),3.66-3.62(m,1H),3.59(s,3H),3.55-3.50(m,2H),2.95-2.87(m,1H),2.70-2.62(m,2H),2.60-2.54(m,2H),2.53-2.51(m,2H),2.17-2.04(m,
3H),1.97-1.90(m,2H),1.75-1.65(m,1H);MS(ESI):m/z 742.2(M+H)+.
實施例53:
從化合物INT-9和O-叔丁基-L-絲氨酸叔丁酯起,參照化合物22的合成得到化合物53。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.78(d,J=8.4Hz,1H),7.67(s,1H),7.55-7.48(m,5H),7.42(d,J=7.7Hz,1H),7.17(d,J=7.0Hz,1H),7.10(s,1H),7.07(d,J=8.1Hz,1H),6.73(s,1H),5.74(s,2H),3.88(d,J=14.6Hz,1H),3.84(s,3H),3.81-3.74(m,3H),3.68-3.63(m,2H),3.61(s,3H),3.60-3.57(m,1H),3.14(t,J=5.4Hz,1H),2.62-2.57(m,2H),2.18-2.04(m,3H),1.76-1.66(m,1H);MS(ESI):m/z 732.6(M+H)+.
實施例54:
從化合物INT-9和止血環酸甲酯鹽酸鹽起,參照化合物33的合成得到化合物54。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.77(d,J=8.6Hz,1H),7.67(s,1H),7.57-7.45(m,5H),7.45-7.39(m,2H),7.17(d,J=7.0Hz,1H),7.09(d,J=1.6Hz,1H),7.06(d,J=7.2Hz,1H),6.70(s,1H),5.73(s,2H),3.83(s,3H),3.75-3.73(m,2H),3.66-3.62
(m,3H),3.60(s,3H),2.59-2.54(m,2H),2.37-2.33(m,2H),2.18-2.05(m,4H),1.90-1.84(m,2H),1.82-1.76(m,2H),1.72-1.68(m,1H),1.42-1.32(m,1H),1.32-1.20(m,3H),0.95-0.82(m,2H);MS(ESI):m/z 784.7(M+H)+.
實施例55:
從化合物INT-9和止血環酸甲酯鹽酸鹽起,參照化合物44的合成得到化合物55。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.77(d,J=8.6Hz,1H),7.67(s,1H),7.56-7.46(m,4H),7.42(d,J=7.7Hz,1H),7.38(s,1H),7.17(d,J=7.0Hz,1H),7.09(d,J=1.6Hz,1H),7.08-7.04(m,1H),6.69(s,1H),5.73(s,2H),3.83(s,3H),3.79-3.71(m,2H),3.66-3.62(m,1H),3.58(s,3H),3.36(s,2H),2.58-2.56(m,2H),2.15-2.06(m,9H),1.89-1.80(m,4H),1.74-1.66(m,1H),1.51-1.42(m,1H),1.33-1.23(m,2H),0.88-0.76(m,2H);MS(ESI):m/z 798.7(M+H)+.
實施例56:
從反式-4-氨基環己甲酸甲酯鹽酸鹽和化合物INT-9起,參照化合物33的合成得到化合物56。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.74(d,J=8.5Hz,1H),7.66(s,1H),7.54-7.43(m,4H),7.42(s,
1H),7.40(d,J=8.0Hz,1H),7.15(d,J=7.0Hz,1H),7.07(d,J=1.5Hz,1H),7.05-7.01(m,1H),6.67(s,1H),5.71(s,2H),3.81(s,3H),3.75-3.68(m,2H),3.65-3.59(m,3H),3.58(s,3H),2.56-2.52(m,2H),2.32-2.24(m,1H),2.14-2.03(m,4H),1.92-1.80(m,4H),1.72-1.63(m,1H),130-1.18(m,2H),1.05-0.95(m,2H);MS(ESI):m/z 770.7(M+H)+.
實施例57:
從反式-4-氨基環己甲酸甲酯鹽酸鹽和化合物INT-9起,參照化合物44的合成得到化合物57。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.75(d,J=8.5Hz,1H),7.66(s,1H),7.55-7.43(m,4H),7.39(d,J=8.0Hz,1H),7.36(s,1H),7.15(d,J=7.0Hz,1H),7.07(d,J=1.5Hz,1H),7.07-7.01(m,1H),6.67(s,1H),5.71(s,2H),3.81(s,3H),3.75-3.67(m,2H),3.64-3.59(m,1H),3.57(s,3H),3.44(s,2H),2.56-2.52(m,2H),2.39-2.31(m,1H),2.14-2.10(m,7H),1.95-1.86(m,2H),1.81-1.74(m,2H),1.71-1.65(m,1H),1.31-1.23(m,4H);MS(ESI):m/z 784.8(M+H)+.
實施例58:
從化合物INT-9和化合物INT-2起,參照化合物22的合成得到化合物58。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.75(d,J=8.5Hz,1H),7.66(s,1H),7.63(s,1H),7.53-7.44(m,4H),7.41(s,1H),7.40(d,J=8.0Hz,1H),7.15(d,J=7.0Hz,1H),7.06(s,1H),7.04(d,J=8.0Hz,1H),6.68(s,1H),5.71(s,2H),3.81(s,3H),3.76-3.68(m,2H),3.66-3.59(m,4H),3.58(s,3H),2.56-2.52(m,2H),2.47-2.42(m,2H),2.14-2.03(m,6H),1.70-1.60(m,2H);MS(ESI):m/z 741.8(M+H)+.
實施例59:
從順式-4-氨基環己甲酸甲酯鹽酸鹽和化合物INT-9起,參照化合物33的合成得到化合物59。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.74(d,J=8.5Hz,1H),7.67(s,1H),7.53-7.45(m,4H),7.43(s,1H),7.39(d,J=7.5Hz,1H),7.15(d,J=7.0Hz,1H),7.08-7.06(m,1H),7.05-7.02(m,1H),6.67(s,1H),5.70(s,2H),3.81(s,3H),3.75-3.67(m,2H),3.62-3.60(m,3H),3.58(s,3H),2.55-2.52(m,3H),2.31-2.25(m,1H),2.13-2.04(m,3H),1.87-1.79(m,2H),1.72-1.63(m,1H),1.57-1.48(m,2H),1.46-1.37(m,4H);MS(ESI):m/z 770.7(M+H)+.
實施例60:
從順式-4-氨基環己甲酸甲酯鹽酸鹽和化合物INT-9起,參照化合物44的合成得到化合物60。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.75(d,J=8.5Hz,1H),7.66(s,1H),7.53-7.44(m,4H),7.40(d,J=7.5Hz,1H),7.35(s,1H),7.15(d,J=7.0Hz,1H),7.09-7.06(m,1H),7.05-7.01(m,1H),6.67(s,1H),5.71(s,2H),3.81(s,3H),3.75-3.67(m,2H),3.64-3.60(m,1H),3.56(s,2H),3.42-3.35(m,3H),2.57-2.52(m,2H),2.45-2.40(m,1H),2.38-2.31(m,1H),2.14-2.07(m,3H),2.06(s,3H),2.01-1.93(m,2H),1.72-1.63(m,1H),1.60-1.52(m,2H),1.50-1.37(m,4H);MS(ESI):m/z 784.7(M+H)+.
實施例61:
從化合物INT-11和化合物INT-12起,參照化合物33的合成得到化合物61。1H NMR(500MHz,DMSO-d6)δ 7.88(s,1H),7.75(d,J=8.5Hz,1H),7.53-7.48(m,2H),7.48-7.43(m,4H),7.41-7.36(m,2H),7.35(s,1H),7.15(d,J=7.0Hz,1H),6.65(s,1H),5.71(s,2H),4.21-4.16(m,1H),3.70-3.45(m,4H),3.56(s,3H),2.92-2.85(m,1H),2.72-2.66(m,1H),2.64-2.57(m,3H),2.45-2.40(m,3H),2.36-2.32(m,1H),2.02-1.96(m,1H),1.95-1.88(m,2H),1.58-1.52(m,1H);MS(ESI):m/z 685.8(M+H)+.
實施例62:
從化合物INT-12和化合物35a起,參照化合物33的合成得到化合物62。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.77(d,J=8.5Hz,1H),7.55-7.50(m,2H),7.49-7.45(m,4H),7.42-7.37(m,3H),7.17(d,J=7.0Hz,1H),6.67(s,1H),5.73(s,2H),4.24-4.19(m,1H),3.66-3.58(m,2H),3.57(s,3H),3.41(s,2H),2.80-2.72(m,1H),2.73-2.67(m,1H),2.64-2.55(m,2H),2.46-2.43(m,1H),2.42-2.38(m,1H),2.37-2.34(m,1H),2.22-2.12(m,1H),2.08-1.98(m,2H),1.80-1.71(m,1H),1.65-1.53(m,2H),1.50-1.42(m,1H),1.40-1.31(m,1H);MS(ESI):m/z 699.7(M+H)+.
實施例63:
從化合物INT-12和止血環酸甲酯鹽酸鹽起,參照化合物33的合成得到化合物63。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.76(d,J=8.5Hz,1H),7.55-7.50(m,2H),7.49-7.45(m,4H),7.42-7.38(m,3H),7.17(d,J=7.0Hz,1H),6.67(s,1H),5.73(s,2H),4.24-4.18(m,1H),3.64(d,J=13.0Hz,1H),3.60-3.56(m,6H),2.73-2.67(m,1H),2.64-2.60(m,1H),2.46-2.42(m,1H),2.37-2.34(m,1H),2.31(d,J=6.5Hz,2H),2.12-2.06(m,1H),2.04-1.98(m,1H),1.89-1.84
(m,2H),1.82-1.77(m,2H),1.59-1.52(m,1H),1.39-1.32(m,1H),1.31-1.21(m,2H),0.93-0.83(m,2H);MS(ESI):m/z 727.5(M+H)+.
實施例64:
從(S)-3-羥基吡咯烷鹽酸鹽和化合物INT-3a起,參照化合物INT-5和化合物INT-8的合成得到化合物64a。MS(ESI):m/z 586.4(M+H)+.
從化合物64a和化合物INT-11起,參照化合物33的合成得到化合物64。1H NMR(500MHz,DMSO-d6)δ 7.88(s,1H),7.75(d,J=8.5Hz,1H),7.52-7.47(m,2H),7.47-7.42(m,4H),7.39(s,1H),7.37(d,J=8.0Hz,1H),7.35(s,1H),7.15(d,J=7.0Hz,1H),6.65(s,1H),5.71(s,2H),4.22-4.15(m,1H),3.64-3.57(m,2H),3.56(s,3H),3.52-3.45(m,2H),2.90-2.82(m,1H),2.70-2.56(m,4H),2.45-2.38(m,3H),2.35-2.30(m,1H),2.02-1.95(m,1H),1.94-1.86(m,2H),1.62-1.50(m,1H);MS(ESI):m/z 685.5(M+H)+.
實施例65:
從3-羥基氮雜環丁烷鹽酸鹽起,參照化合物64的合成得到化合物65。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.76(d,J=8.6Hz,1H),7.54-7.50(m,2H),7.49-7.44(m,4H),7.38-7.33(m,3H),7.17(d,J=7.0Hz,1H),6.67(s,1H),5.73(s,2H),5.34-5.26(m,1H),4.23-4.19(m,1H),3.61(s,2H),3.58(s,3H),3.56-3.46(m,6H),2.94-2.88(m,1H),2.82-2.78(m,2H),2.67-2.64(m,2H),1.97-1.91(m,2H);MS(ESI):m/z 671.6(M+H)+.
實施例66:
從N-乙醯基乙二胺和化合物INT-3a起,參照化合物INT-3的合成得到化合物66a。MS(ESI):m/z 481.2(M+H)+.
從化合物66a,化合物INT-8c和化合物INT-11起,參照化合物INT-8和化合物33的合成得到化合物66。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.82-7.77(m,1H),7.75(d,J=8.5Hz,1H),7.53-7.48(m,2H),7.47-7.40(m,6H),7.35(s,1H),7.15(d,J=7.0Hz,1H),6.65(s,1H),5.71(s,2H),3.73(s,2H),3.56(s,3H),3.52-3.47(m,2H),3.16-3.12(m,2H),2.93-2.84(m,1H),2.67-2.61(m,2H),2.57(t,J=6.5Hz,2H),2.45-2.42(m,2H),1.96-1.87(m,2H),1.77(s,3H);MS(ESI):m/z 700.2(M+H)+.
實施例67:
從(R)-5-羥甲基-2-吡咯烷酮和化合物INT-3a起,參照化合物INT-2和化合物INT-3的合成得到化合物67a。MS(ESI):m/z 493.2(M+H)+.
從化合物67a,化合物INT-8c和化合物INT-11起,參照化合物INT-8和化合物33的合成得到化合物67。1H NMR(500MHz,DMSO-d6)δ 7.88(s,1H),7.74(d,J=8.5Hz,1H),7.65(s,1H),7.53-7.48(m,2H),7.47-7.39(m,6H),7.35(s,1H),7.15(d,J=7.0Hz,1H),6.65(s,1H),5.71(s,2H),3.77-3.71(m,2H),3.64-3.59(m,1H),3.56(s,3H),3.52-3.48(m,2H),2.91-2.83(m,1H),2.66-2.60(m,2H),2.55-2.51(m,2H),2.47-2.45(m,2H),2.15-2.04(m,3H),1.95-1.88(m,2H),1.72-1.64(m,1H);MS(ESI):m/z 712.6(M+H)+.
實施例68:
在冰浴條件下,在溶有N-叔丁氧羰基-1,2-乙二胺(99mg,0.62mmol)的二氯甲烷(3mL)中依次加入甲磺酸酐(135mg,0.77mmol)和三乙胺(102mg,1.01mmol);反應液在相同條件下攪拌一小時。反應液中加入飽和碳酸氫鈉溶液(20mL),並用乙酸乙酯(20mL x 2)
萃取。合併有機相用飽和食鹽水(30mL)洗滌,無水硫酸鈉乾燥;濾液濃縮後得到白色固體68a(160mg,收率:86.6%)。
在溶有化合物68a(160mg,0.67mmol)的二氯甲烷(2mL)溶液中加入鹽酸(4M的1,4-二氧六環溶液,1.7mL);反應液在20℃條件下攪拌16小時。反應液濃縮得到黃色油狀物68b(90mg,收率:76.8%)。1H NMR(500MHz,DMSO-d6)δ 8.14(s,3H),7.36(t,J=6.0Hz,1H),3.27-3.16(m,2H),2.94(s,3H),2.92-2.84(m,2H).
從化合物68b起,參照化合物64的合成得到化合物68。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.75(d,J=8.5Hz,1H),7.53-7.48(m,2H),7.47-7.43(m,4H),7.43-7.40(m,2H),7.35(s,1H),7.15(d,J=7.0Hz,1H),6.94(s,1H),6.65(s,1H),5.71(s,2H),3.74(s,2H),3.56(s,3H),3.54-3.52(m,2H),3.05(t,J=6.5Hz,2H),2.92-2.89(m,1H),2.88(s,3H),2.67-2.60(m,4H),2.47-2.45(m,2H),1.95-1.87(m,2H);MS(ESI):m/z 736.9(M+H)+.
實施例69:
從化合物INT-11,化合物INT-3a和化合物INT-8c起,參照化合物INT-5和化合物INT-8的合成得到化合物69a。MS(ESI):m/z 628.5(M+H)+.
從化合物69a和(R)-3-羥基吡咯烷鹽酸鹽起,參照化合物33的合
成得到化合物69。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.76(d,J=8.5Hz,1H),7.55-7.50(m,2H),7.50-7.45(m,4H),7.40(d,J=8.0Hz,2H),7.37(s,1H),7.17(d,J=7.0Hz,1H),6.67(s,1H),5.73(s,2H),4.20-4.15(m,1H),3.66-3.59(m,2H),3.58(s,3H),3.53(d,J=14.5Hz,1H),3.48(d,J=14.5Hz,1H),2.96-2.91(m,1H),2.74(t,J=8.5Hz,1H),2.66-2.62(m,2H),2.61-2.58(m,1H),2.42-2.32(m,4H),2.01-1.94(m,3H),1.56-1.49(m,1H);MS(ESI):m/z 685.3(M+H)+.
實施例70:
從化合物INT-11,4-溴-2-甲氧基苯甲醛和化合物INT-8c起,參照化合物INT-5和化合物INT-8的合成得到化合物70a。MS(ESI):m/z 658.4(M+H)+.
從化合物70a和化合物INT-2起,參照化合物33的合成得到化合物70。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.75(d,J=8.5Hz,1H),7.63(s,1H),7.53-7.44(m,4H),7.41(s,1H),7.37(d,J=8.0Hz,1H),7.15(d,J=7.0Hz,1H),7.09-7.07(m,1H),7.06-7.02(m,1H),6.67(s,1H),5.71(s,2H),3.80(s,3H),3.62-3.59(m,4H),3.58-3.56(m,4H),2.95-2.89(m,1H),2.77-2.71(m,1H),2.70-2.65(m,1H),2.58-2.52(m,2H),2.47-2.43(m,2H),2.11-2.02(m,3H),1.98-1.92(m,2H),1.67-1.60(m,1H);MS(ESI):m/z 742.7(M+H)+.
實施例71:
從化合物70a和(R)-3-羥基吡咯烷鹽酸鹽起,參照化合物33的合成得到化合物71。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.75(d,J=8.5Hz,1H),7.52-7.44(m,4H),7.36(d,J=7.5Hz,1H),7.35(s,1H),7.15(d,J=7.0Hz,1H),7.09-7.07(m,1H),7.06-7.02(m,1H),6.66(s,1H),5.71(s,2H),4.18-4.11(m,1H),3.80(s,3H),3.61-3.59(m,2H),3.56(s,3H),3.53-3.46(m,2H),2.95-2.87(m,1H),2.78-2.71(m,1H),2.69-2.64(m,1H),2.64-2.53(m,4H),2.41-2.35(m,1H),2.34-2.29(m,1H),1.99-1.92(m,3H),1.55-1.48(m,1H);MS(ESI):m/z 715.8(M+H)+.
實施例72:
在溶有4-(溴甲基)-3-氯苯甲酸甲酯(200mg,0.76mmol)和4-溴吲唑(150mg,0.76mmol)的乙腈(6mL)溶液中加入碳酸鉀(231mg,1.67mmol);反應液在65℃條件下攪拌10小時。反應液冷卻至室溫後,濾液濃縮後所得殘餘物用矽膠柱層析(石油醚/乙酸乙酯,v/v
=100/0-100/30)得到白色固體72a(150mg,收率:52.1%)。MS(ESI):m/z 379.2(M+H)+.
在-65℃條件下,在溶有化合物72a(150mg,0.40mmol)的二氯甲烷(10mL)溶液中緩慢滴加二異丁基氫化鋁(1.5M的甲苯溶液,0.79mL);所得反應液在相同溫度下攪拌半小時。反應液隨後用甲醇(2mL)淬滅,並升至室溫;加入酒石酸鉀鈉(10% w/w水溶液,10mL)後劇烈攪拌2小時。所得混合液中再加入二氯甲烷(20mL);有機相進一步用飽和食鹽水(30mL)洗滌,無水硫酸鈉乾燥。濾液濃縮後得到無色油狀物72b(130mg,收率:93.6%)。MS(ESI):m/z 351.1(M+H)+.
在溶有化合物72b(130mg,0.37mmol)的二氯甲烷(6mL)溶液中加入戴斯-馬丁氧化劑(157mg,0.37mmol);反應液在25℃條件下攪拌一小時。反應液中加入飽和碳酸氫鈉溶液(20mL)和二氯甲烷(20mL),所得有機相進一步用飽和食鹽水(30mL)洗滌,無水硫酸鈉乾燥。濾液濃縮,殘餘物用矽膠柱層析(石油醚/乙酸乙酯,v/v=100/0-100/30)得到無色油狀物72c(120mg,收率:92.8%)。MS(ESI):m/z 349.1(M+H)+.
從化合物72c,O-叔丁基-L-絲氨酸叔丁酯和化合物INT-3起,參照化合物INT-1和化合物1的合成得到化合物72。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.75(d,J=8.5Hz,1H),7.69(s,1H),7.56(d,J=1.5Hz,1H),7.52-7.44(m,8H),7.29-7.25(m,1H),7.18(d,J=7.0Hz,1H),6.92(d,J=8.0Hz,1H),5.77(s,2H),3.90(d,J=14.0Hz,1H),3.81-3.76(m,3H),3.65-3.63(m,1H),3.62-3.56(m,2H),3.09(t,J=5.5Hz,1H),2.57-2.54(m,2H),2.13-2.07(m,3H),1.74-1.67(m,1H);MS(ESI):m/z 672.5(M+H)+.
實施例73:
在溶有2-甲氧基-4-甲基苯甲酸甲酯(250mg,1.39mmol)和N-溴代丁二醯亞胺(296mg,1.66mmol)的四氯化碳(8mL)溶液中加入偶氮二異丁腈(9.4mg,0.17mmol);反應液在80℃條件下攪拌16小時。反應液濃縮,殘餘物用矽膠柱層析(石油醚/乙酸乙酯,v/v=100/0-100/25)得到白色固體73a(204mg,收率:34.0%)。
從化合物73a,4-溴吲唑,O-叔丁基-L-絲氨酸叔丁酯和化合物INT-3起,參照化合物INT-1和化合物1的合成得到化合物73。1H NMR(500MHz,DMSO-d6)δ 8.18-8.16(m,2H),7.87(s,1H),7.77(d,J=8.6Hz,1H),7.66(s,1H),7.52-7.49(m,1H),7.48-7.25(m,5H),7.13(d,J=7.0Hz,1H),7.04(s,1H),6.77(d,J=7.6Hz,1H),5.68(s,2H),3.96-3.92(m,1H),3.78(d,J=7.1Hz,2H),3.75(s,3H),3.69-3.61(m,2H),3.60-3.51(m,2H),3.14-3.08(m,1H),2.56(d,J=6.4Hz,2H),2.12-2.06(m,3H),1.73-1.65(m,1H);MS(ESI):m/z 668.7(M+H)+.
實施例74:
在溶有6-羥甲基煙酸甲酯(470mg,2.81mmol)的二氯甲烷(10mL)溶液中加入二氯亞碸(1.67g,14.1mmol);反應液在25℃條件下攪拌3小時。反應液濃縮,殘餘物用矽膠柱層析(乙酸乙酯/石油醚
=0/100-40/100)得到白色固體74a(420mg,收率:80.5%)。MS(ESI):m/z 186.0(M+H)+.
從化合物74a起,參照化合物73的合成得到化合物74。1H NMR(500MHz,DMSO-d6)δ 8.49(d,J=2.0Hz,1H),8.18(s,1H),7.87(s,1H),7.77-7.69(m,2H),7.67(s,1H),7.51(d,J=7.5Hz,1H),7.48-7.44(m,6H),7.15(d,J=7.0Hz,1H),7.05(d,J=8.0Hz,1H),5.77(s,2H),3.91(d,J=13.5Hz,1H),3.82-3.73(m,3H),3.66-3.60(m,1H),3.60-3.53(m,2H),3.09(t,J=5.5Hz,1H),2.55(d,J=6.0Hz,2H),2.16-2.03(m,3H),1.78-1.61(m,1H);MS(ESI):m/z 639.5(M+H)+.
實施例75:
在溶有化合物INT-13(550mg,1.80mmol)的N,N-二甲基甲醯胺(5mL)溶液中加入氰化亞銅(322mg,3.59mmol);反應液在120℃和氮氣氛圍下攪拌16小時。反應液過濾,濾液濃縮,殘餘物用矽膠柱層析(石油醚/乙酸乙酯,v/v=100/0-100/30)得到白色固體75a(210mg,收率:57.0%)。
從化合物75a起,參照化合物73的合成得到化合物75。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.84-7.82(m,2H),7.67(s,1H),7.54-7.50(m,2H),7.50-7.42(m,6H),7.18(d,J=6.9Hz,1H),6.92(s,1H),5.82(s,2H),3.85(d,J=14.9Hz,1H),3.80-3.73(m,3H),3.71(s,3H),3.64-3.60(m,2H),3.60-3.54(m,1H),3.15-3.11(m,1H),2.55-2.54(m,2H),2.13-2.06(m,3H),1.71-1.67(m,1H);MS(ESI):m/z 693.2(M+H)+.
實施例76:
在冰浴條件下,在溶有化合物INT-13b(100mg,0.55mmol)的濃硫酸(2mL)中滴加預先溶有硝酸鉀(56.1mg,0.55mmol)的濃硫酸(0.5mL)溶液;反應液在相同條件下繼續攪拌半小時。反應液中加入大量冰水,析出固體經用冰水洗後,乾燥得到白色固體76a(115mg,收率:92.0%)。1H NMR(500MHz,DMSO-d6)δ 8.39(s,1H),7.29(s,1H),3.95(s,3H),3.82(s,3H),2.64(s,3H).
從化合物76a起,參照化合物73的合成得到化合物76。1H NMR(500MHz,DMSO-d6)δ 8.29(s,1H),7.96(s,1H),7.79(d,J=8.5Hz,1H),7.67(s,1H),7.53(d,J=7.5Hz,1H),7.51-7.49(m,3H),7.47-7.43(m,4H),7.19(d,J=7.0Hz,1H),6.13(s,1H),6.11(s,1H),3.87(d,J=15.4Hz,1H),3.81-3.72(m,3H),3.67-3.57(m,3H),3.51(s,3H),3.15-3.12(m,1H),2.56-2.52(m,2H),2.14-2.08(m,3H),1.72-1.66(m,1H);MS(ESI):m/z 713.8(M+H)+.
實施例77:
在溶有化合物INT-13b(300mg,1.66mmol)的濃硫酸(3mL)中加入N-氯代丁二醯亞胺(467mg,3.50mmol);反應液在25℃條件下攪拌2小時。反應液中加入冰水(25mL)和乙酸乙酯(25mL);有機
相進一步用飽和碳酸氫鈉溶液(30mL)和飽和食鹽水(30mL)洗滌,無水硫酸鈉乾燥。濾液濃縮得到黃色固體77a(360mg,收率:86.8%)。1H NMR(500MHz,DMSO-d6)δ 7.74(s,1H),3.84(s,3H),3.80(s,3H),2.45(s,3H);MS(ESI):m/z 249.7(M+H)+.
從化合物77a起,參照化合物73的合成得到化合物77。1H NMR(500MHz,DMSO-d6)δ 7.86(d,J=8.5Hz,1H),7.80(s,1H),7.67(s,1H),7.65(s,1H),7.56-7.50(m,2H),7.48-7.43(m,6H),7.17(d,J=7.0Hz,1H),5.81(s,2H),3.95(d,J=14.5Hz,1H),3.82-3.79(m,3H),3.77(s,3H),3.66-3.59(m,3H),3.20(t,J=5.1Hz,1H),2.57-2.58(m,2H),2.13-2.07(m,3H),1.74-1.66(m,1H);MS(ESI):m/z 736.7(M+H)+.
實施例78:
在冰浴條件下,在溶有3-氯-4-甲基苯甲酸甲酯(500mg,2.71mmol)的濃硫酸(2mL)中加入N-碘代丁二醯亞胺(731mg,3.25mmol);反應液在25℃條件下攪拌2小時。反應液中加入冰水(50mL)和乙酸乙酯(50mL);有機相進一步用飽和碳酸氫鈉溶液(50mL)和飽和食鹽水(50mL)洗滌,無水硫酸鈉乾燥。濾液濃縮,殘餘物用矽膠柱層析(石油醚/乙酸乙酯=100/0-100/15)分離得到白色固體78a(820mg,收率:97.5%)。
在氮氣氛圍和100℃條件下,將混有化合物78a(1.00g,3.22mmol),碘化亞銅(61.3mg,0.32mmol),1,10-菲羅啉(116mg,0.64mmol)和碳酸銫(2.10g,6.44mmol)的甲醇(5mL)溶液攪拌24小時。反應
液過濾後,濾液濃縮;殘餘物用甲醇(5mL)溶解,然後加入二氯亞碸(1.4mL);所得到反應液在60℃條件下攪拌2小時。反應液中加入乙酸乙酯(50mL)和水(50mL);有機相進一步用飽和碳酸氫鈉溶液(50mL)和飽和食鹽水(50mL)洗滌,無水硫酸鈉乾燥。殘餘物用矽膠柱層析(石油醚/乙酸乙酯,v/v=100/0-100/5)分離得到白色固體78b(480mg,收率:69.4%)。1H NMR(500MHz,Chloroform-d)δ 7.67(d,J=1.6Hz,1H),7.39(d,J=1.6Hz,1H),3.91(s,3H),3.88(s,3H),2.31(s,3H).
從化合物78b起,參照化合物73的合成得到化合物78。1H NMR(500MHz,DMSO-d6)δ 8.22(s,1H),7.77(d,J=8.5Hz,1H),7.74(s,1H),7.66(s,1H),7.52-7.48(m,2H),7.46-7.43(m,5H),7.14-7.11(m,3H),5.67(s,2H),3.94(d,J=14.2Hz,1H),3.81-3.78(m,2H),3.77(s,3H),3.65-3.61(m,4H),3.15-3.09(m,1H),2.57-2.55(d,J=6.0Hz,2H),2.13-2.07(m,3H),1.73-1.66(m,1H);MS(ESI):m/z 702.7(M+H)+.
實施例79:
從化合物78a起,參照化合物75a的合成方法得到化合物79a。
從化合物79a起,參照化合物73的合成得到化合物79。1H NMR(500MHz,DMSO-d6)δ 8.20(s,1H),7.93(d,J=1.6Hz,1H),7.90-7.85(m,2H),7.83(s,1H),7.67(s,1H),7.58-7.54(m,1H),7.51(d,J=7.4Hz,1H),7.48-7.42(m,5H),7.18(d,J=7.1Hz,1H),5.82(s,2H),3.95(d,J=14.8Hz,1H),3.81-3.74(m,3H),3.65-3.62(m,1H),3.61-3.56(m,2H),3.12(t,J=5.3Hz,1H),2.56(d,J=6.1Hz,2H),2.13-2.07(m,
3H),1.72-1.66(m,1H);MS(ESI):m/z 697.5(M+H)+.
實施例80:
在溶有2-羥基-6-甲基煙酸(1.00g,6.53mmol)的氯仿(35mL)溶液中加入碘甲烷(3.24g,22.9mmol)和碳酸銀(1.81g,6.55mmol);反應液在65℃條件下攪拌16小時。反應液過濾,濾液濃縮得到無色油狀物80a(390mg,收率:33.0%)。1H NMR(500MHz,Chloroform-d)δ 8.06(d,J=7.7Hz,1H),6.77(d,J=7.7Hz,1H),4.03(s,3H),3.87(s,3H),2.48(s,3H);MS(ESI):m/z 182.0(M+H)+.
在溶有化合物80a(363mg,2.00mmol)的乙腈(10mL)溶液中加入N-氯代丁二醯亞胺(321mg,2.40mmol);反應液在70℃條件下攪拌10小時。反應液濃縮,殘餘物用矽膠柱層析(石油醚/乙酸乙酯,v/v=100/0-100/20)分離得到無色油狀物80b(420mg,收率:97.2%)。1H NMR(500MHz,DMSO-d6)δ 8.09(s,1H),3.91(s,3H),3.80(s,3H),2.51(s,3H).
從化合物80b起,參照化合物73的合成得到化合物80。1H NMR(500MHz,DMSO-d6)δ 7.86(s,1H),7.84(s,1H),7.79(d,J=8.4Hz,1H),7.67(s,1H),7.53-7.51(m,1H),7.48-7.44(m,7H),7.14(d,J=7.0Hz,1H),5.82(s,2H),3.79-3.76(m,2H),3.66-3.55(m,5H),3.38(s,3H),3.13-3.08(m,1H),2.58-2.54(m,2H),2.13-2.08(m,3H),1.73-1.67(m,1H);MS(ESI):m/z 703.2(M+H)+.
實施例81:
從3-甲氧基-4-甲基苯甲酸起,參照化合物80b的合成得到化合物81a。1H NMR(500MHz,DMSO-d6)δ 13.25(s,1H),7.32(s,1H),7.30(s,1H),3.82(s,3H),2.17(s,3H).
在溶有化合物81a(300mg,1.50mmol)的二氯甲烷(8mL)溶液中加入草醯氯(345mg,2.72mmol)和1滴N,N-二甲基甲醯胺;反應液在25℃條件下攪拌3小時,隨後反應液濃縮。所得殘餘物用二氯甲烷(3mL)再次溶解後加入到溶有4-溴吲唑(265mg,1.35mmol),4-二甲氨基吡啶(18.3mg,0.15mmol)和三乙胺(302mg,2.99mmol)的二氯甲烷(8mL)溶液;反應液在25℃條件下攪拌16小時。反應液濃縮,殘餘物用矽膠柱層析(石油醚/乙酸乙酯,v/v=100/0-100/20)分離得到白色固體81b(410mg,收率:72.2%)。
從化合物81b起,參照化合物73a的合成得到化合物81c。
在溶有化合物81c(120mg,0.26mmol)和O-叔丁基-L-絲氨酸叔丁酯(171mg,0.78mmol)的N’N-二甲基甲醯胺(2mL)中加入碳酸鉀(72mg,0.52mmol);反應液在25℃條件下攪拌一小時。反應液中加入乙酸乙酯(20mL)和水(20mL);有機相進一步用飽和食鹽水
(20mL)洗滌,無水硫酸鈉乾燥。殘餘物用矽膠薄層層析板(石油醚/乙酸乙酯,v/v=4/1)分離得到白色固體81d(70mg,收率:45.0%)。MS(ESI):m/z 594.4(M+H)+.
從化合物81d起,參照INT-1合成過程中的硼酯化步驟得到化合物81e。MS(ESI):m/z 642.8(M+H)+.
在90℃條件和氮氣氛圍下,將混有化合物81e(35mg,0.038mmol),化合物INT-3(18.9mg,0.038mmol),Pd(dppf)Cl2(2.8mg,0.0038mmol)和氟化鉀(6.7mg,0.11mmol)的1.4-二氧六環(4mL)溶液攪拌16小時。反應液濃縮,殘餘物用矽膠薄層層析板(二氯甲烷/甲醇,v/v=20/1)分離得到無色油狀物81f(20mg,收率:36.7%)。MS(ESI):m/z 928.2(M+H)+.
從化合物81f起,參照化合物1合成的最後一步脫Boc保護基步驟得到化合物81。1H NMR(500MHz,DMSO-d6)δ 8.49(d,J=8.0Hz,1H),8.27(s,1H),7.82(t,J=8.0Hz,1H),7.65(s,1H),7.57(s,1H),7.55-7.53(m,1H),7.52-7.49(m,3H),7.47-7.40(m,5H),3.79(s,3H),3.76-3.74(m,2H),3.62-3.59(m,3H),3.50-3.48(m,2H),3.12-3.11(m,1H),2.53-2.52(m,2H),2.10-2.06(m,3H),1.69-1.65(m,1H);MS(ESI):m/z 716.0(M+H)+.
實施例82:
從化合物80b起,依次參照化合物73a的溴代步驟,化合物72a的取代步驟和化合物INT-11d合成過程中的酯水解和酸胺縮合步驟得到化合物82a。MS(ESI):m/z 595.4(M+H)+.
從化合物82a和化合物INT-3起,參照化合物81合成過程中的最後兩步得到化合物82。1H NMR(500MHz,DMSO-d6)δ 8.51(d,J=7.0Hz,1H),8.23(s,1H),7.88(s,1H),7.76(d,J=8.5Hz,1H),7.68(s,1H),7.55-7.45(m,7H),7.15(d,J=7.0Hz,1H),5.93(s,2H),4.28-4.26(m,1H),3.85-3.75(m,3H),3.67-3.60(m,2H),3.39(s,3H),2.59(d,J=6.2Hz,2H),2.14-2.07(m,3H),1.72-1.69(m,1H);MS(ESI):m/z 717.2(M+H)+.
實施例83:
在80℃條件下,溶有4-溴吲唑(500mg,2.54mmol)和1-氟-4-甲基-1,4-二氮雜雙環[2.2.2]辛烷四氟硼酸鹽(4.49g,12.7mmol)的乙腈(20mL)溶液攪拌15小時。反應液加入乙酸乙酯(100mL),隨後用水(100mL)和飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥。殘餘物用矽膠柱層析分離得到白色固體83a(231mg,收率:42.3%)。MS(ESI):m/z 215.1(M+H)+.
從化合物83a,O-叔丁基-L-絲氨酸叔丁酯和化合物INT-3起,參照化合物INT-8和化合物1的合成得到化合物83。1H NMR(500MHz,DMSO-d6)δ 7.84-7.79(m,1H),7.66(s,1H),7.62-7.58(m,1H),7.52-7.43(m,8H),7.17(d,J=7.0Hz,1H),6.84(s,1H),5.62(s,2H),3.91-3.79(m,4H),3.67(s,3H),3.65-3.56(m,3H),3.17-3.15(m,1H),2.60-2.55(m,2H),2.14-2.09(m,3H),1.73-1.67(m,1H);MS(ESI):m/z
720.6(M+H)+.
實施例84:
在25℃條件下,溶有4-溴吲唑(200mg,1.02mmol),N-氯代丁二醯亞胺(149mg,1.12mmol)的N’N-二甲基甲醯胺(3mL)的溶液攪拌15小時。反應液加入乙酸乙酯(50mL),隨後用水(50mL)和飽和食鹽水(50mL)洗滌,無水硫酸鈉乾燥。殘餘物用矽膠柱層析分離得到白色固體84a(122mg,收率:51.9%)。MS(ESI):m/z 231.3(M+H)+.
從化合物84a起,參照化合物83的合成得到化合物84。1H NMR(500MHz,DMSO-d6)δ 7.85(d,J=8.5Hz,1H),7.65(s,1H),7.59-7.55(m,1H),7.50-7.47(m,2H),7.45-7.39(m,6H),7.11(d,J=7.0Hz,1H),6.84(d,J=1.5Hz,1H),5.75-5.68(m,1H),5.70(s,1H),3.89-3.86(m,1H),3.79-3.75(m,3H),3.65(s,3H),3.62-3.59(m,3H),3.14-3.12(m,1H),2.54(d,J=6.0Hz,2H),2.11-2.06(m,3H),1.70-1.65(m,1H);MS(ESI):m/z 736.5(M+H)+.
實施例85:
從化合物INT-8和5-氨乙基四氮唑起,參照化合物22的合成得到化合物85。1H NMR(500MHz,DMSO-d6)δ 7.86(s,1H),7.74(d,J=8.5Hz,1H),7.55-7.38(m,9H),7.14(d,J=7.0Hz,1H),6.71(s,1H),
5.72(s,2H),3.95-3.91(m,2H),3.79-3.71(m,4H),3.65-3.62(m,1H),3.57(s,3H),2.55(d,J=6.0Hz,2H),2.15-2.04(m,3H),1.72-1.61(m,1H);MS(ESI):m/z 696.1(M+H)+.
實施例86:
從化合物INT-1c,溴乙酸叔丁酯,4-溴吲唑起,參照化合物INT-1i的合成得到化合物86a。MS(ESI):m/z 479.4(M+H)+.
從化合物86a,化合物INT-3和乙醇胺起,參照化合物INT-7和化合物22的合成得到化合物86。1H NMR(500MHz,DMSO-d6)δ 7.88(s,1H),7.77(d,J=8.5Hz,1H),7.67(s,1H),7.53-7.41(m,9H),7.15(d,J=6.9Hz,1H),6.94(s,1H),5.70(s,2H),4.26(s,2H),4.01(s,2H),3.81-3.72(m,2H),3.67-3.58(m,3H),2.86(t,J=5.4Hz,2H),2.57-2.50(m,2H),2.13-2.04(m,3H),1.72-1.64(m,1H);MS(ESI):m/z 702.4(M+H)+.
實施例87:
從(R)-3-羥基吡咯烷鹽酸鹽,4-溴-2-甲氧基苯甲醛和化合物INT-8c起,參照化合物INT-5和化合物INT-8的合成得到化合物87a。MS(ESI):m/z 616.4(M+H)+.
從化合物87a和化合物INT-11起,參照化合物33的合成得到化合物87。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.77(d,J=8.5Hz,1H),7.55-7.47(m,4H),7.39(d,J=7.5Hz,1H),7.36(s,1H),7.17(d,J=7.0Hz,1H),7.08(s,1H),7.06(d,J=7.5Hz,1H),6.68(s,1H),5.73(s,2H),4.23-4.17(m,1H),3.82(s,3H),3.64-3.56(m,5H),3.55-3.47(m,2H),2.88-2.82(m,1H),2.75-2.69(m,1H),2.67-2.61(m,3H),2.47-2.43(m,2H),2.41-2.36(m,2H),2.05-1.97(m,1H),1.95-1.89(m,2H),1.58-1.52(m,1H);MS(ESI):m/z 715.7(M+H)+.
實施例88:
從乙醇胺,4-溴-2-甲氧基苯甲醛和化合物INT-8c起,參照化合物INT-3和化合物INT-8的合成得到化合物88a。MS(ESI):m/z 690.4(M+H)+.
從化合物88a和化合物INT-11起,參照化合物33的合成得到化合物88。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.77(d,J=8.5Hz,1H),7.55-7.47(m,4H),7.41(d,J=7.5Hz,1H),7.37(s,1H),7.17(d,J=7.0Hz,1H),7.11(s,1H),7.09-7.04(m,1H),6.69(s,1H),5.73(s,2H),3.84(s,3H),3.79(d,J=3.5Hz,2H),3.58(s,3H),3.56-3.47(m,4H),2.94-2.85(m,1H),2.70-2.62(m,4H),2.50-2.48(m,2H),1.96-1.90(m,2H);MS(ESI):m/z 689.6(M+H)+.
實施例89:
從化合物76a起,參照化合物73的合成得到化合物89a。MS(ESI):m/z 925.5(M+H)+.
在溶有化合物89a(150mg,0.16mmol)的醋酸(3mL)溶液加入鋅粉(32mg,0.49mmol);反應液在70℃條件下攪拌半小時。反應液濃縮,殘餘物用製備薄層層析(二氯甲烷/甲醇,v/v=20/1)得到黃色油狀物89b(30mg,收率:20.7%)。MS(ESI):m/z 895.9(M+H)+.
從化合物89b起,參照化合物1合成過程中最後一步脫Boc保護基步驟得到化合物89。1H NMR(500MHz,DMSO-d6)δ 7.88(s,1H),7.84(d,J=8.6Hz,1H),7.67(s,1H),7.54-7.42(m,8H),7.14(d,J=6.9Hz,1H),6.80(s,1H),6.68(s,1H),5.55(s,2H),5.00-4.95(m,1H),3.84-3.73(m,4H),3.63(s,3H),3.60-3.51(m,3H),3.04-3.02(m,1H),2.56-2.52(m,2H),2.13-2.06(m,3H),1.73-1.66(m,1H);MS(ESI):m/z 683.1(M+H)+.
實施例90:
從1,3-二溴-2-甲苯,4-溴-2-甲氧基苯甲醛,化合物INT-2和化合物INT-8c起,參照化合物INT-3和化合物INT-8的合成得到化合物90a。MS(ESI):m/z 723.5(M+H)+.
從化合物90a和化合物INT-11起,參照化合物33的合成得到化合物90。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.73(d,J=8.5Hz,1H),7.66(s,1H),7.49(t,J=8.5Hz,1H),7.43-7.36(m,3H),7.34-7.30(m,2H),7.10(d,J=7.0Hz,1H),7.03(s,1H),7.00(d,J=7.0Hz,1H),6.67(s,1H),5.73(s,2H),3.84(s,3H),3.82-3.77(m,2H),3.70-3.65(m,1H),3.58(s,3H),3.53(d,J=9.0Hz,2H),2.95-2.88(m,1H),2.68-2.62(m,4H),2.53-2.52(m,2H),2.16-2.08(m,3H),2.00(s,3H),1.97-1.91(m,2H),1.75-1.68(m,1H);MS(ESI):m/z 722.3(M+H)+.
實施例91:
從化合物INT-10,化合物INT-2,化合物INT-8c和止血環酸甲酯鹽酸鹽起,參照化合物INT-3,化合物INT-8和化合物44的合成得到化合物91。1H NMR(500MHz,DMSO-d6)δ 7.88(s,1H),7.86(d,J
=7.4Hz,1H),7.79(d,J=8.5Hz,1H),7.68-7.64(m,2H),7.59-7.49(m,3H),7.43-7.32(m,2H),7.18(d,J=7.0Hz,1H),6.71(s,1H),5.74(s,2H),3.94(s,3H),3.91-3.77(m,2H),3.73-3.67(m,1H),3.59(s,3H),3.41-3.35(m,2H),2.72-2.65(m,1H),2.53-2.52(m,1H),2.19-2.01(m,9H),1.91-1.79(m,4H),1.77-1.68(m,1H),1.53-1.40(m,1H),1.34-1.21(m,2H),0.88-0.78(m,2H);MS(ESI):m/z 799.7(M+H)+.
實施例92:
從化合物76a,4-溴吲唑,化合物INT-6起,參照化合物73a,化合物82a和化合物INT-8的合成得到化合物92a。MS(ESI):m/z 754.5(M+H)+.
從化合物92a和反式-4-氨基環己甲酸甲酯鹽酸鹽起,參照化合物44的合成得到化合物92。1H NMR(500MHz,DMSO-d6)δ 8.18(s,1H),7.96(s,1H),7.78(d,J=8.5Hz,1H),7.65(s,1H),7.54-7.48(m,4H),7.41(d,J=7.5Hz,1H),7.17(d,J=7.0Hz,1H),7.09(d,J=1.5Hz,1H),7.08-7.04(m,1H),6.11-6.08(m,3H),3.82(s,3H),3.78-3.72(m,2H),3.66-3.62(m,1H),3.51-3.49(m,2H),3.48(s,3H),2.57(d,J=6.0Hz,2H),2.46-2.36(m,2H),2.13(s,3H),2.11-2.07(m,3H),1.94-1.89(m,2H),1.82-1.77(m,2H),1.72-1.65(m,1H),1.32-1.26(m,4H);MS(ESI):m/z 795.7(M+H)+.
實施例93:
從反式-4-氨基環丁甲酸甲酯鹽酸鹽和化合物INT-9起,參照化合物44的合成得到化合物93。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.75(d,J=8.5Hz,1H),7.66(s,1H),7.54-7.44(m,4H),7.40(d,J=7.5Hz,1H),7.33(s,1H),7.15(d,J=7.5Hz,1H),7.08-7.06(m,1H),7.05-7.01(m,1H),6.68(s,1H),5.71(s,2H),3.81(s,3H),3.75-3.67(m,2H),3.64-3.60(m,1H),3.57(s,3H),3.30-3.24(m,2H),3.04-2.98(m,1H),2.84-2.79(m,1H),2.55-2.50(m,2H),2.20-2.12(m,2H),2.12-2.03(m,5H),1.91(s,3H),1.70-1.64(m,1H);MS(ESI):m/z 756.6(M+H)+.
實施例94:
從(4-呱啶)乙酸甲酯和化合物INT-9起,參照化合物44的合成得到化合物94。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.75(d,J=8.5Hz,1H),7.66(s,1H),7.54-7.44(m,4H),7.40(d,J=7.5Hz,1H),7.33(s,1H),7.15(d,J=7.0Hz,1H),7.09-7.06(m,1H),7.05-7.01(m,1H),6.68(s,1H),5.71(s,2H),3.81(s,3H),3.74-3.68(m,2H),3.64-3.59(m,1H),3.56(s,3H),2.76-2.69(m,2H),2.56-2.51(m,2H),2.14-2.03(m,5H),1.96-1.87(m,2H),1.77-1.64(m,2H),1.63-1.54(m,
2H),1.22-1.14(m,2H);MS(ESI):m/z 770.6(M+H)+.
實施例95:
從化合物INT-9和化合物INT-14起,參照化合物44的合成得到化合物95。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.75(d,J=8.5Hz,1H),7.66(s,1H),7.53-7.44(m,4H),7.39(d,J=7.5Hz,1H),7.36(s,1H),7.15(d,J=7.0Hz,1H),7.08-7.05(m,1H),7.05-7.01(m,1H),6.67(s,1H),5.70(s,2H),3.81(s,3H),3.72-3.69(m,2H),3.64-3.58(m,1H),3.56(s,3H),3.44-3.35(m,2H),2.54-2.51(m,2H),2.35-2.29(m,1H),2.12-2.10(m,1H),2.09(s,3H),2.07-2.05(m,1H),2.04(d,J=7.0Hz,2H),1.76-1.71(m,4H),1.69-1.63(m,1H),1.59-1.51(m,1H),1.29-1.20(m,2H),0.99-0.86(m,2H);MS(ESI):m/z 798.7(M+H)+.
實施例96:
參照化合物92的合成,將反式-4-氨基環己甲酸甲酯鹽酸鹽替換成止血環酸甲酯鹽酸鹽得到化合物96。1H NMR(500MHz,DMSO-d6)δ 8.21(s,1H),7.98(s,1H),7.80(d,J=8.5Hz,1H),7.66(s,1H),7.56-7.48(m,4H),7.44-7.43(m,1H),7.19(d,J=6.9Hz,1H),7.13-7.11(m,
1H),7.09-7.07(m,1H),6.13-6.11(m,3H),3.85(s,3H),3.80-3.79(m,2H),3.71-3.64(m,1H),3.49(s,3H),3.41(s,2H),2.64-2.62(m,2H),2.59-2.51(m,2H),2.14(s,3H),2.13-2.07(m,4H),1.89-1.81(m,4H),1.73-1.68(m,1H),1.50-1.45(m,1H),1.33-1.24(m,2H),0.88-0.80(m,2H);MS(ESI):m/z 809.8(M+H).
實施例97:
從化合物4-溴-2-羥基苯甲醛起,參照化合物INT-7a的硼酯化和化合物INT-3a的合成得到化合物97a。
從化合物97a起,參照化合物INT-8a的烷基化反應步驟得到化合物97b。1H NMR(500MHz,DMSO-d6)δ 10.40(s,1H),7.86-7.82(m,1H),7.74(d,J=8.0Hz,1H),7.47-7.43(m,1H),7.37(t,J=8.0Hz,1H),7.24(d,J=1.4Hz,1H),7.10-7.06(m,1H),4.23(q,J=7.0Hz,2H),1.38(t,J=7.0Hz,3H).
從化合物97b,化合物INT-2,化合物INT-8c和止血環酸甲酯鹽酸鹽起,參照化合物48的合成得到化合物97。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.75(d,J=8.5Hz,1H),7.65(s,1H),7.55-7.44(m,4H),7.39(d,J=7.7Hz,1H),7.36(s,1H),7.15(d,J=7.0Hz,1H),7.05(d,J=1.7Hz,1H),7.04-7.00(m,1H),6.67(s,1H),5.71(s,2H),4.08(q,J=6.9Hz,2H),3.74-3.68(m,2H),3.64-3.59(m,1H),3.56(s,3H),3.34(s,2H),2.55-2.53(m,2H),2.13-2.03(m,9H),1.86-
1.75(m,4H),1.72-1.66(m,1H),1.46-1.40(m,1H),1.33(t,J=6.9Hz,3H),1.27-1.21(m,2H),0.84-0.75(m,2H);MS(ESI):m/z 812.8(M+H).
實施例98:
參照化合物97的合成,將碘乙烷替換成2-碘代丙烷,得到化合物98。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.76(d,J=8.5Hz,1H),7.64(s,1H),7.55-7.43(m,4H),7.39(d,J=7.7Hz,1H),7.36(s,1H),7.15(d,J=7.0Hz,1H),7.07(d,J=1.6Hz,1H),7.01-6.97(m,1H),6.67(s,1H),5.71(s,2H),4.70-4.62(m,1H),3.74-3.66(m,2H),3.64-3.60(m,1H),3.56(s,3H),3.34(s,2H),2.54-2.52(m,2H),2.13-2.03(m,9H),1.89-1.78(m,4H),1.71-1.65(m,1H),1.48-1.39(m,1H),1.29-1.26(m,6H),1.26-1.20(m,2H),0.86-0.74(m,2H);MS(ESI):m/z 826.7(M+H).
實施例99:
從(R)-N-Boc-3-四氫吡咯乙酸起,參照化合物INT-14的合成得到化合物99a。1H NMR(500MHz,DMSO-d6)δ 9.27-8.91(m,2H),3.59(s,3H),3.32-3.26(m,1H),3.23-3.15(m,1H),3.13-3.02(m,1H),2.80-2.71(m,1H),2.55-2.49(m,3H),2.10-2.02(m,1H),1.55-1.48(m,
1H).
從化合物99a和化合物INT-9起,參照化合物44的合成得到化合物99。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.75(d,J=8.5Hz,1H),7.66(s,1H),7.54-7.45(m,4H),7.40(d,J=7.5Hz,1H),7.33(s,1H),7.15(d,J=7.0Hz,1H),7.08-7.06(m,1H),7.05-7.02(m,1H),6.67(s,1H),5.71(s,2H),3.81(s,3H),3.75-3.68(m,2H),3.64-3.60(m,1H),3.56(s,3H),3.48(s,2H),2.68-2.62(m,1H),2.55-2.51(m,2H),2.47-2.42(m,2H),2.40-2.34(m,1H),2.28-2.23(m,2H),2.15-2.05(m,4H),1.97-1.89(m,1H),1.72-1.64(m,1H),1.37-1.29(m,1H);MS(ESI):m/z 756.7(M+H).
實施例100:
從化合物INT-9和止血環酸甲酯鹽酸鹽起,參照化合物INT-5的合成以及化合物1的合成中最後一步脫Boc保護基的步驟得到化合物100a。MS(ESI):m/z 798.7(M+H).
在溶有化合物100a(40mg,0.050mmol)的N,N-二甲基甲醯胺(2mL)中加入甲醛(34%水溶液,0.10mL),醋酸(6.0mg,0.10mmol)和三醋酸硼氫化鈉(42mg,0.20mmol);反應液在25℃條件下攪拌2小時。反應液中加入飽和碳酸氫鈉溶液(20mL),並用乙酸乙酯萃取(20mL x 2)。合併有機相用飽和食鹽水(30mL)洗滌,無水硫酸鈉乾燥,濃縮得到棕色油狀物100b(35mg,收率:84.5%)。MS(ESI):m/z
826.7(M+H).
從化合物100b起,參照化合物33合成過程中的酯水解步驟得到化合物100。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.75(d,J=8.5Hz,1H),7.55-7.45(m,5H),7.44(d,J=7.5Hz,1H),7.36(s,1H),7.15(d,J=7.0Hz,1H),7.09-7.07(m,1H),7.06-7.03(m,1H),6.67(s,1H),5.71(s,2H),3.80(s,3H),3.74-3.68(m,1H),3.56(s,3H),3.53-3.49(m,2H),3.36(s,2H),2.44-2.39(m,1H),2.36-2.30(m,1H),2.17(s,3H),2.11-2.05(m,9H),1.87-1.78(m,4H),1.70-1.64(m,1H),1.48-1.40(m,1H),1.32-1.21(m,2H),0.86-0.76(m,2H);MS(ESI):m/z 812.7(M+H).
實施例101:
從化合物INT-16和止血環酸甲酯鹽酸鹽起,參照化合物44的合成得到化合物101。1H NMR(500MHz,DMSO-d6)δ 7.95(s,1H),7.78(d,J=8.5Hz,1H),7.65(s,1H),7.57-7.49(m,4H),7.38(s,1H),7.17(d,J=7.0Hz,1H),7.00-6.96(m,2H),6.69(s,1H),5.73(s,2H),3.87(s,3H),3.79-3.71(m,2H),3.61-3.59(m,1H),3.58(s,3H),3.36(s,2H),2.53-2.51(m,2H),2.13-2.03(m,6H),2.09(s,3H),1.88-1.78(m,4H),1.70-1.62(m,1H),1.49-1.41(m,1H),1.32-1.22(m,2H),0.87-0.76(m,2H);MS(ESI):m/z 816.3(M+H).
實施例102:
從化合物INT-15b起,參照化合物INT-3的合成得到化合物102a。MS(ESI):m/z 553.6(M+H).
從化合物102a,化合物INT-8c和止血環酸甲酯鹽酸鹽起,參照化合物INT-8和化合物44的合成得到化合物102。1H NMR(500MHz,DMSO-d6)δ 7.93(s,1H),7.78(d,J=8.5Hz,1H),7.63(s,1H),7.56-7.48(m,4H),7.38(s,1H),7.17(d,J=7.0Hz,1H),6.77(s,2H),6.70(s,1H),5.73(s,2H),3.82(s,6H),3.76-3.70(m,2H),3.60-3.56(m,4H),3.36(s,2H),2.53-2.52(m,2H),2.13-2.04(m,9H),1.89-1.79(m,4H),1.70-1.61(m,1H),1.50-1.42(m,1H),1.32-1.23(m,2H),0.87-0.77(m,2H);MS(ESI):m/z 828.5(M+H).
實施例103:
在25℃條件下,將溶有L-脯氨酸(132mg,1.14mmol),氫氧化鈉(46mg,1.14mmol)的二甲亞碸(5mL)溶液攪拌1小時:隨後加入化合物INT-13(350mg,1.14mmol),甲烷亞磺酸鈉(1.17g,11.4mmol)和碘化亞銅(218mg,1.14mmol);所得反應液用氮氣置換3次,並在氮氣氛圍和120℃條件下攪拌2小時。反應液用水(50mL)稀釋,並用乙酸乙酯萃取(50mL x 2);合併有機相用飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,濃縮。殘餘物用矽膠柱層析(石油醚/乙
酸乙酯,v/v=1/1)分離得到白色固體103a(232mg,收率:94.5%)。1H NMR(500MHz,Chloroform-d)δ 8.48(s,1H),6.89(s,1H),3.98(s,3H),3.89(s,3H),3.07(s,3H),2.74(s,3H);MS(ESI):m/z 259.1(M+H).
從化合物103a起,參照化合物92的合成得到化合物103。1H NMR(500MHz,DMSO-d6)δ 7.98(s,1H),7.96(s,1H),7.78(d,J=8.5Hz,1H),7.66(s,1H),7.56-7.47(m,4H),7.40(d,J=7.6Hz,1H),7.18(d,J=7.0Hz,1H),7.07(d,J=1.6Hz,1H),7.06-7.02(m,1H),6.31(s,1H),6.14(s,2H),3.82(s,3H),3.76-3.67(m,2H),3.64-3.59(m,1H),3.48(s,2H),3.47(s,3H),3.21(s,3H),2.56-2.52(m,2H),2.39-2.33(m,1H),2.11(s,3H),2.11-2.07(m,3H),2.07-2.04(m,1H),1.94-1.87(m,2H),1.82-1.76(m,2H),1.71-1.64(m,1H),1.32-1.23(m,4H);MS(ESI):m/z 828.2(M+H).
實施例104:
從化合物INT-9和順式-3-氨基環丁烷羧酸甲酯鹽酸鹽起,參照化合物44的合成得到化合物104。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.75(d,J=8.0Hz,1H),7.66(s,1H),7.52-7.47(m,4H),7.40(d,J=7.5Hz,1H),7.32(s,1H),7.15(d,J=7.0Hz,1H),7.07(s,1H),7.04(d,J=7.5Hz,1H),6.68(s,1H),5.72(s,2H),3.81(s,3H),3.75-3.68(m,2H),3.64-3.60(m,1H),3.57(s,3H),3.26(s,2H),2.82-2.75(m,1H),2.67-2.60(m,1H),2.57-2.52(m,2H),2.23-2.17(m,2H),2.14-2.04(m,3H),1.94-1.87(m,2H),1.92(s,3H),1.71-1.64(m,1H);MS(ESI):m/z 755.9(M+H).
實施例105:
從化合物INT-9和4-氨基雙環[2.2.2]辛烷-1-羧酸甲酯鹽酸鹽起,參照化合物44的合成得到化合物105。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.75(d,J=8.5Hz,1H),7.66(s,1H),7.54-7.43(m,4H),7.40(d,J=7.5Hz,1H),7.38(s,1H),7.15(d,J=7.0Hz,1H),7.07(d,J=1.5Hz,1H),7.05-7.02(m,1H),6.66(s,1H),5.70(s,2H),3.81(s,3H),3.74-3.68(m,2H),3.64-3.59(m,1H),3.57(s,3H),3.41(s,2H),2.56-2.52(m,2H),2.14-2.04(m,3H),1.99(s,3H),1.75-1.66(m,7H),1.60-1.49(m,6H);MS(ESI):m/z 810.2(M+H).
實施例106:
從化合物INT-9和6-氨基螺[3.3]庚烷-2-羧酸甲酯鹽酸鹽起,參照化合物44的合成得到化合物106。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.75(d,J=8.5Hz,1H),7.66(s,1H),7.54-7.44(m,4H),7.40(d,J=7.5Hz,1H),7.30(s,1H),7.15(d,J=7.0Hz,1H),7.08-7.06(m,1H),7.05-7.02(m,1H),6.67(s,1H),5.71(s,2H),3.81(s,3H),3.75-3.67(m,2H),3.64-3.59(m,1H),3.56(s,3H),3.21(s,2H),2.93-2.86(m,1H),2.74-2.68(m,1H),2.55-2.52(m,2H),2.20-1.98(m,9H),1.88(s,3H),1.80-1.74(m,1H),1.72-1.65(m,2H);MS(ESI):m/z 796.2
(M+H).
實施例107:
從化合物75a起,參照化合物92的合成得到化合物107。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.82(d,J=8.5Hz,1H),7.70(s,1H),7.65(s,1H),7.53-7.46(m,4H),7.40(d,J=7.5Hz,1H),7.17(d,J=7.0Hz,1H),7.07(d,J=1.5Hz,1H),7.06-7.02(m,1H),6.90(s,1H),5.80(s,2H),3.81(s,3H),3.71(d,J=3.0Hz,2H),3.69(s,3H),3.63-3.60(m,1H),3.47(s,2H),2.54-2.52(m,2H),2.39-2.36(m,1H),2.12-2.06(m,4H),2.10(s,3H),1.93-1.88(m,2H),1.81-1.76(m,2H),1.70-1.66(m,1H),1.30-1.25(m,4H);MS(ESI):m/z 775.3(M+H).
實施例108:
參照化合物107的合成,將反式-4-氨基環己甲酸甲酯鹽酸鹽替換成化合物INT-14,得到化合物108。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.83(d,J=8.5Hz,1H),7.71(s,1H),7.63(s,1H),7.54-7.46(m,4H),7.42(d,J=7.5Hz,1H),7.17(d,J=7.0Hz,1H),7.11(s,1H),7.07(d,J=7.5Hz,1H),6.92(s,1H),5.80(s,2H),3.87-3.78(m,
2H),3.83(s,3H),3.71-3.66(m,1H),3.70(s,3H),3.51-3.45(m,2H),2.54-2.52(m,2H),2.14-2.04(m,8H),1.78-1.68(m,5H),1.59-1.53(m,1H),1.31-1.21(m,2H),0.98-0.90(m,2H);MS(ESI):m/z 789.1(M+H).
實施例109:
從順式-(N-BOC-4-氨基環己基)乙酸起,參照化合物INT-14的合成得到化合物109a。1H NMR(500MHz,DMSO-d6)δ 7.95(brs,3H),3.57(s,3H),3.18-3.08(m,1H),2.27(d,J=7.5Hz,2H),1.95-1.86(m,1H),1.69-1.56(m,4H),1.54-1.38(m,4H).
從化合物109a和化合物INT-9起,參照化合物44的合成得到化合物109。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.76(d,J=8.5Hz,1H),7.65(s,1H),7.54-7.46(m,4H),7.40(d,J=7.5Hz,1H),7.37(s,1H),7.15(d,J=7.0Hz,1H),7.08-7.06(m,1H),7.05-7.02(m,1H),6.67(s,1H),5.71(s,2H),3.81(s,3H),3.71(d,J=3.0Hz,2H),3.64-3.59(m,1H),3.57(s,3H),3.43(s,2H),2.56-2.52(m,2H),2.36-2.31(m,1H),2.21-2.16(m,2H),2.13-2.04(m,3H),2.07(s,3H),1.98-1.91(m,1H),1.72-1.66(m,1H),1.61-1.53(m,2H),1.51-1.39(m,6H);MS(ESI):m/z 798.3(M+H).
實施例110:
在冰浴條件下,在溶有化合物INT-8b(500mg,1.32mmol)的二氯甲烷(10mL)溶液中滴加三溴化硼(1M的二氯甲烷溶液,3.95mL);反應液在相同條件下攪拌1小時。反應液中加入冰水(30mL)淬滅,所得混合液進一步攪拌半小時;水相後二氯甲烷萃取(50mL x 2)。合併有機相用飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,濃縮。殘餘物用矽膠柱層析得到白色固體110a(370mg,收率:76.8%)。MS(ESI):m/z 365.2(M+H).
從化合物110a起,參照化合物INT-8a的烷基化反應步驟得到化合物110b。1H NMR(500MHz,DMSO-d6)δ 10.21(s,1H),8.13(s,1H),7.79(d,J=8.3Hz,1H),7.48-7.24(m,2H),6.80(s,1H),5.78(s,2H),4.55-4.32(m,1H),1.19(d,J=6.0Hz,6H).
從化合物110b,化合物INT-6和止血環酸甲酯鹽酸鹽起,參照化合物INT-8和化合物44的合成得到化合物110。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.74(d,J=8.5Hz,1H),7.64(s,1H),7.54-7.45(m,4H),7.43(d,J=8.0Hz,1H),7.35(s,1H),7.15(d,J=7.0Hz,1H),7.12(s,1H),7.08(d,J=7.5Hz,1H),6.41(s,1H),5.72(s,2H),4.20-4.12(m,1H),3.86-3.82(m,2H),3.84(s,3H),3.71-3.66(m,1H),3.33(s,2H),2.73-2.63(m,2H),2.14-2.06(m,9H),1.87-1.77(m,4H),1.72-1.68(m,1H),1.48-1.39(m,1H),1.30-1.22(m,2H),1.05(d,J=6.0
Hz,6H),0.86-0.76(m,2H);MS(ESI):m/z 826.3(M+H).
實施例111:
從2-氟-5-羥基苯甲酸起,參照化合物INT-1c和化合物INT-8b的合成得到化合物111a。MS(ESI):m/z 363.1(M+H).
從化合物111a,化合物INT-2和止血環酸甲酯鹽酸鹽起,參照化合物INT-8和化合物44的合成得到化合物111。1H NMR(500MHz,DMSO-d6)δ 7.86(s,1H),7.79(d,J=8.5Hz,1H),7.67(s,1H),7.53-7.49(m,2H),7.48-7.42(m,6H),7.18-7.12(m,2H),6.88(d,J=6.0Hz,1H),5.69(s,2H),3.80-3.72(m,2H),3.66-3.60(m,1H),3.65(s,3H),3.36(s,2H),2.56-2.53(m,2H),2.14-2.07(m,6H),2.09(s,3H),1.89-1.78(m,4H),1.73-1.66(m,1H),1.50-1.40(m,1H),1.31-1.22(m,2H),0.85-0.76(m,2H);MS(ESI):m/z 752.3(M+H).
實施例112:
從5-羥基-2-甲基苯甲酸起,參照化合物INT-1c和化合物INT-8b的合成得到化合物112a。MS(ESI):m/z 359.2(M+H).
從化合物112a,化合物INT-6和止血環酸甲酯鹽酸鹽起,參照化合物INT-8和化合物44的合成得到化合物112。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.75(d,J=8.5Hz,1H),7.66(s,1H),7.55-7.46(m,4H),7.44(d,J=7.5Hz,1H),7.15(d,J=7.0Hz,1H),7.12(s,
2H),7.09(d,J=7.5Hz,1H),6.60(s,1H),5.66(s,2H),3.88-3.82(m,2H),3.85(s,3H),3.72-3.67(m,1H),3.57(s,3H),3.43-3.40(m,2H),2.67(d,J=6.0Hz,2H),2.25(s,3H),2.18-2.04(m,9H),1.89-1.80(m,4H),1.76-1.68(m,1H),1.55-1.45(m,1H),1.32-1.23(m,2H),0.86-0.75(m,2H);MS(ESI):m/z 778.4(M+H).
實施例113:
從化合物INT-16和反式-4-氨基環丁甲酸甲酯鹽酸鹽起,參照化合物101的合成得到化合物113。1H NMR(500MHz,DMSO-d6)δ 7.93(s,1H),7.76(d,J=8.5Hz,1H),7.62(s,1H),7.56-7.45(m,4H),7.34(s,1H),7.15(d,J=7.0Hz,1H),7.02-6.93(m,2H),6.68(s,1H),5.72(s,2H),3.86(s,3H),3.83-3.72(m,2H),3.62-3.58(m.1H),3.57(s,3H),3.27-3.25(m,2H),3.06-2.97(m,1H),2.87-2.78(m,1H),2.56-2.52(m,2H),2.22-2.15(m,2H),2.14-1.99(m,5H),1.92(s,3H),1.69-1.60(m,1H);MS(ESI):m/z 774.2(M+H).
實施例114:
從化合物INT-16和反式-4-氨基環己甲酸甲酯鹽酸鹽起,參照化合物101的合成得到化合物114。1H NMR(500MHz,DMSO-d6)δ
7.92(s,1H),7.76(d,J=8.5Hz,1H),7.63(s,1H),7.55-7.47(m,4H),7.36(s,1H),7.15(d,J=7.0Hz,1H),6.98-6.93(m,2H),6.67(s,1H),5.71(s,2H),3.86(s,3H),3.77-3.70(m,2H),3.60-3.56(m,1H),3.57(s,3H),3.45(brs,2H),2.52-2.50(m,2H),2.40-2.35(m,1H),2.12-2.03(m,7H),1.94-1.87(m,2H),1.81-1.75(m,2H),1.69-1.60(m,1H),1.32-1.23(m,4H);MS(ESI):m/z 802.2(M+H).
實施例115:
從化合物INT-16和化合物109a起,參照化合物101的合成得到化合物115。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.76(d,J=8.5Hz,1H),7.63(s,1H),7.55-7.45(m,4H),7.36(s,1H),7.15(d,J=7.0Hz,1H),6.99-6.93(m,2H),6.67(s,1H),5.71(s,2H),3.86(s,3H),3.78-3.69(m,2H),3.60-3.58(m,1H),3.57(s,3H),3.45(s,2H),2.53-2.50(m,2H),2.36-2.31(m,1H),2.09(s,3H),2.07-2.02(m,5H),1.78-1.70(m,4H),1.68-1.60(m,1H),1.59-1.50(m,1H),1.31-1.18(m,2H),0.98-0.86(m,2H);MS(ESI):m/z 816.2(M+H).
實施例116:
從化合物INT-16和4-氨基雙環[2.2.2]辛烷-1-羧酸甲酯鹽酸鹽起,
參照化合物101的合成得到化合物116。1H NMR(500MHz,DMSO-d6)δ 7.97-7.88(m,1H),7.76(d,J=8.5Hz,1H),7.63(s,1H),7.55-7.47(m,4H),7.38(s,1H),7.15(d,J=7.0Hz,1H),6.98-6.94(m,2H),6.66(s,1H),5.70(s,2H),3.85(s,3H),3.77-3.69(m,2H),3.65-3.59(m,1H),3.57(s,3H),3.41(s,2H),2.60-2.54(m,2H),2.14-2.03(m,3H),1.99(s,3H),1.76-1.69(m,6H),1.67-1.61(m,1H),1.58-1.52(m,6H);MS(ESI):m/z 828.1(M+H).
實施例117:
從4-溴-6-氯吲唑起,參照化合物INT-8和化合物30的合成得到化合物117。1H NMR(500MHz,DMSO-d6)δ 8.03(s,1H),7.93(s,1H),7.66(s,1H),7.55-7.44(m,8H),7.24(s,1H),6.78(s,1H),5.74(brs,2H),3.91-3.85(m,1H),3.79-3.76(m,2H),3.69-3.57(m,7H),3.15-3.08(m,1H),2.57-2.55(m,2H),2.15-2.07(m,3H),1.74-1.66(m,1H);MS(ESI):m/z 736.0(M+H).
實施例118:
從化合物118a起,參照化合物INT-14的合成得到化合物118b。
從化合物118b和化合物INT-9起,參照化合物44的合成得到化合物118。1H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.75(d,J=8.5
Hz,1H),7.65(s,1H),7.53-7.45(m,4H),7.40(d,J=7.5Hz,1H),7.36(s,1H),7.15(d,J=7.5Hz,1H),7.08-7.06(m,1H),7.04(d,J=8.5Hz,1H),6.67(s,1H),5.71(s,2H),3.81(s,3H),3.75-3.67(m,2H),3.65-3.59(m,1H),3.56(s,3H),3.34(s,2H),2.56-2.52(m,2H),2.14-2.03(m,10H),1.80-1.73(m,2H),1.72-1.65(m,3H),1.58-1.53(m,1H),1.44-1.36(m,1H),0.97-0.86(m,2H),0.83-0.75(m,2H);MS(ESI):m/z 812.2(M+H).
實施例119:
在氮氣氣氛下,將溶有3-氧代環丁基氨基甲酸叔丁酯(1.0g,5.4mmol)和乙氧甲醯基亞甲基三苯基膦(2.1g,5.9mmol)的甲苯(15mL)溶液在110℃條件下攪拌6小時。反應液中加入水(100mL)和乙酸乙酯(100mL);水相進一步用乙酸乙酯萃取(100mL x 2)。合併有機相用飽和食鹽水(200mL)洗滌,無水硫酸鈉乾燥,濃縮。殘餘物用矽膠柱層析得到白色固體119a(1.1g,收率:79.8%)。MS(ESI):m/z 256.3(M+H)。
在氫氣氣氛下,將混有化合物119a(1.1g,4.3mmol),鈀(10% w/w吸附在活性炭,150mg)的甲醇(15mL)溶液在25℃條件下攪拌過夜。反應液過濾,濾液濃縮得到白色固體119b(1.1g,收率:99.8%)。MS(ESI):m/z 258.3(M+H)。
在溶有化合物119b(1.1g,4.3mmol)的二氯甲烷(15mL)溶液中加入鹽酸(4M在1,4-二氧六環中,5.4mL);所得反應液在室溫條
件下攪拌2小時。反應液濃縮後得到無色油狀物119c(0.83g,收率:99.5%)。
從化合物119c和化合物INT-9起,參照化合物44的合成得到化合物119(從核磁判斷,該化合物應該為順反異構體的混合物,比例為6:4)。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.77(d,J=8.5Hz,1H),7.68(s,1H),7.55-7.47(m,4H),7.42(d,J=7.0Hz,1H),7.34(d,J=8.5Hz,1H),7.17(d,J=7.0Hz,1H),7.09(d,J=1.5Hz,1H),7.06(dd,J=7.5,1.5Hz,1H),6.69(s,1H),5.73(s,2H),3.83(s,3H),3.77-3.69(m,2H),3.66-3.61(m,1H),3.58(s,3H),3.25(s,2H),3.03-2.95(m,0.4H),2.74-2.69(m,0.6H),2.58-2.54(m,2H),2.43-2.35(m,1H),2.31-2.27(m,1.2H),2.23-2.06(m,5H),2.04-1.97(m,0.8H),1.91(s,3H),1.80-1.73(m,0.8H),1.72-1.64(m,1H),1.51-1.41(m,1.2H);MS(ESI):m/z 770.0(M+H)。
實施例120:
從反式-4-(Boc-氨基)環己基甲醛起,參照化合物119a和化合物119c的合成得到化合物120b。MS(ESI):m/z 198.6(M+H)。
從化合物120b和化合物INT-9起,參照化合物44的合成得到化合物120。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.78(d,J=8.5Hz,1H),7.66(s,1H),7.56-7.47(m,4H),7.42(d,J=7.7Hz,1H),7.39(s,1H),7.17(d,J=7.0Hz,1H),7.10(s,1H),7.09-7.05(m,1H),6.77-
6.71(m,1H),6.69(s,1H),5.73(s,2H),5.72-5.66(m,1H),3.84(s,3H),3.82-3.73(m,2H),3.68-3.63(m,1H),3.59(s,3H),3.53-3.42(m,2H),2.61-2.56(m,2H),2.44-2.36(m,1H),2.17-2.06(m,7H),1.86-1.75(m,4H),1.75-1.66(m,1H),1.40-1.27(m,2H),1.18-1.08(m,2H);MS(ESI):m/z 810.2(M+H)。
實施例121:
從化合物120a起,參照化合物119的合成得到化合物121。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.77(d,J=8.5Hz,1H),7.67(s,1H),7.56-7.46(m,4H),7.41(d,J=7.7Hz,1H),7.38(s,1H),7.17(d,J=7.0Hz,1H),7.08(d,J=1.7Hz,1H),7.08-7.04(m,1H),6.68(s,1H),5.72(s,2H),3.83(s,3H),3.77-3.69(m,2H),3.66-3.61(m,1H),3.58(s,3H),3.46(brs,2H),2.57-2.54(m,2H),2.38-2.30(m,1H),2.18(t,J=7.5Hz,2H),2.15-2.05(m,6H),1.81-1.65(m,5H),1.38(t,J=7.5Hz,2H),1.29-1.17(m,2H),1.17-1.08(m,1H),0.92-0.82(m,2H);MS(ESI):m/z 812.2(M+H)。
實施例122和123:
從化合物INT-9,環丙胺和4-氧代環己甲酸甲酯起,參照化合物44的合成得到化合物122和化合物123。
化合物122:1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.76(d,J=8.5Hz,1H),7.67(s,1H),7.55-7.45(m,4H),7.41(d,J=7.5Hz,1H),7.31(s,1H),7.17(d,J=7.0Hz,1H),7.09-7.07(m,1H),7.07-7.03(m,1H),6.66(s,1H),5.71(s,2H),3.83(s,3H),3.73-3.72(m,2H),3.68(s,2H),3.65-3.60(m,1H),3.59(s,3H),2.56-2.53(m,2H),2.46-2.42(m,1H),2.14-2.03(m,5H),1.93-1.87(m,2H),1.83-1.78(m,2H),1.72-1.67(m,1H),1.38-1.30(m,2H),1.26-1.20(m,2H),0.40-0.35(m,2H),0.26-0.17(m,2H);MS(ESI):m/z 810.2(M+H)。
化合物123:1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.74(d,J=8.5Hz,1H),7.65(s,1H),7.52-7.45(m,4H),7.40(d,J=7.5Hz,1H),7.29(s,1H),7.15(d,J=7.0Hz,1H),7.07-7.06(m,1H),7.05-7.02(m,1H),6.63(s,1H),5.70(s,2H),3.81(s,3H),3.72-3.70(m,2H),3.68-3.66(m,1H),3.64(s,2H),3.57(s,3H),2.55-2.52(m,2H),2.45-2.42(m,1H),2.13-2.03(m,5H),1.70-1.65(m,1H),1.60-1.55(m,2H),1.47-1.40(m,2H),1.31-1.25(m,4H),0.37-0.32(m,2H),0.22-0.17(m,2H);MS(ESI):m/z 810.2(M+H)。
實施例124:
參照化合物110的合成,將異丙基碘換成碘乙烷,得到化合物124。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.76(d,J=8.5Hz,1H),7.68(s,1H),7.55-7.47(m,4H),7.42(d,J=7.7Hz,1H),7.37(s,1H),7.17(d,J=7.0Hz,1H),7.09(d,J=1.6Hz,1H),7.08-7.05(m,1H),6.59(s,1H),5.73(s,2H),3.83(s,3H),3.78(q,J=7.0Hz,2H),3.75-3.71(m,2H),3.65-3.61(m,1H),3.36(brs,2H),2.56-2.53(m,2H),2.14-2.03(m,6H),2.08(s,3H),1.89-1.80(m,4H),1.72-1.66(m,1H),1.50-1.42(m,1H),1.29-1.24(m,2H),1.18(t,J=7.0Hz,3H),0.85-0.79(m,2H);MS(ESI):m/z 812.2(M+H)。
實施例125:
從化合物INT-9,反式-4-氨基環己甲酸甲酯鹽酸鹽和苯甲醛起,參照化合物44的合成得到化合物125。1H NMR(500MHz,DMSO-d6)δ 7.88(s,1H),7.74(d,J=8.5Hz,1H),7.65(s,1H),7.53-7.43(m,4H),7.44(s,1H),7.40(d,J=7.5Hz,1H),7.30-7.23(m,4H),7.22-7.13(m,2H),7.08-7.06(m,1H),7.05-7.02(m,1H),6.62(s,1H),5.68(s,2H),3.81(s,3H),3.77-3.70(m,2H),3.66-3.61(m,1H),3.57(s,2H),3.54(s,3H),3.51(s,2H),2.59-2.54(m,2H),2.41-2.36(m,1H),2.14-2.04(m,4H),1.94-1.87(m,2H),1.84-1.79(m,2H),1.71-1.65(m,1H),
1.41-1.32(m,2H),1.20-1.11(m,2H);MS(ESI):m/z 860.1(M+H)。
實施例126:
從化合物INT-9,反式-4-氨基環己甲酸甲酯鹽酸鹽和環丙甲醛起,參照化合物44的合成得到化合物126。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.77(d,J=8.5Hz,1H),7.67(s,1H),7.56(s,1H),7.55-7.46(m,4H),7.41(d,J=7.5Hz,1H),7.17(d,J=7.0Hz,1H),7.10-7.08(m,1H),7.08-7.03(m,1H),6.67(s,1H),5.72(s,3H),3.83(s,3H),3.76-7.68(m,2H),3.66-3.62(m,1H),3.59(s,3H),3.55(s,2H),2.56-2.53(m,2H),2.32(d,J=6.0Hz,2H),2.15-2.05(m,4H),1.93-1.88(m,2H),1.80-1.73(m,2H),1.72-1.66(m,1H),1.30-1.21(m,5H),0.75-0.69(m,1H),0.37-0.31(m,2H),0.03-0.00(m,2H);MS(ESI):m/z 824.1(M+H)。
實施例127:
參照化合物110的合成,將異丙基碘換成2-溴乙醯胺,得到化合物127。1H NMR(500MHz,DMSO-d6)δ 7.87(d,J=1.0Hz,1H),7.73(d,J=8.5Hz,1H),7.65(s,1H),7.54(s,1H),7.51-7.47(m,4H),7.40(d,J=7.5Hz,1H),7.37(s,1H),7.34(s,1H),7.15(d,J=7.0Hz,1H),7.07(d,J=1.5Hz,1H),7.06-7.02(m,1H),6.79(s,1H),5.68(s,2H),4.28(s,
2H),3.81(s,3H),3.72(d,J=3.0Hz,2H),3.64-3.61(m,1H),3.43(s,2H),2.58-2.55(m,2H),2.15-2.09(m,6H),2.08(s,3H),1.83-1.76(m,4H),1.69-1.66(m,1H),1.46-1.43(m,1H),1.26-1.22(m,2H),0.83-0.78(m,2H);MS(ESI):m/z 841.2(M+H)。
實施例128:
參照化合物110的合成,將異丙基碘換成2-溴乙酸叔丁酯,得到化合物128。1H NMR(500MHz,DMSO-d6)δ 7.87(s,1H),7.73(d,J=8.5Hz,1H),7.67(s,1H),7.51-7.46(m,4H),7.42-7.37(m,2H),7.14(d,J=7.0Hz,1H),7.07(d,J=1.5Hz,1H),7.06-7.01(m,1H),6.79(s,1H),5.65(s,2H),4.09(brs,2H),3.81(s,3H),3.73-3.69(m,2H),3.63-3.60(m,1H),3.41(s,2H),2.54-2.52(m,2H),2.33-2.28(m,1H),2.20(s,3H),2.12-2.05(m,5H),1.86-1.80(m,4H),1.71-1.66(m,1H),1.59-1.50(m,1H),1.29-1.23(m,2H),0.87-0.80(m,2H);MS(ESI):m/z 843.2(M+H)。
實施例129:
從化合物INT-9和反式-4-氨基環己甲酸甲酯鹽酸鹽起,參照化合物44的合成(不包括最後一步脫Boc)得到化合物129a。MS(ESI):m/z 883.6(M+H)。
從化合物129a和甲磺醯胺起,參照化合物82a合成中酸胺縮合條件和化合物1的最後一步脫Boc條件得到化合物129。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.78(d,J=8.5Hz,1H),7.67(s,1H),7.56-7.47(m,4H),7.44(d,J=7.5Hz,1H),7.41(s,1H),7.17(d,J=7.0Hz,1H),7.12(s,1H),7.08(d,J=7.5Hz,1H),6.70(s,1H),5.73(s,2H),3.85(s,3H),3.84-3.79(m,2H),3.71-3.65(m,1H),3.59(s,3H),3.53(s,2H),3.05(s,3H),2.65(d,J=6.0Hz,2H),2.46-2.40(m,1H),2.15(s,3H),2.14-2.05(m,4H),1.88-1.78(m,4H),1.75-1.68(m,1H),1.35-1.22(m,4H);MS(ESI):m/z 861.3(M+H)。
實施例130:
從化合物INT-16和化合物118b起,參照化合物101的合成得到化合物130。1H NMR(500MHz,DMSO-d6)δ 7.93(s,1H),7.75(d,J=8.5Hz,2H),7.63(s,1H),7.54-7.48(m,4H),7.36(s,1H),7.15(d,J=7.0Hz,1H),6.99-6.93(m,2H),6.67(s,1H),5.71(s,2H),3.85(s,3H),3.76-3.70(m,2H),3.60-3.57(m,1H),3.56(s,3H),3.34(s,2H),2.53-2.50(m,2H),2.11-2.02(m,10H),1.79-1.74(m,2H),1.71-1.66(m,2H),1.65-1.60(m,1H),1.58-1.51(m,1H),1.44-1.36(m,1H),0.95-0.87(m,2H),0.83-0.74(m,2H);MS(ESI):m/z 830.1(M+H)。
實施例131:
從化合物INT-16和化合物121a起,參照化合物101的合成得到化合物131。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.76(d,J=8.5Hz,1H),7.63(s,1H),7.55-7.47(m,4H),7.36(s,1H),7.15(d,J=7.0Hz,1H),6.98-6.92(m,2H),6.66(s,1H),5.71(s,2H),3.85(s,3H),3.77-3.69(m,2H),3.62-3.59(m,1H),3.56(s,3H),3.44(s,2H),2.55-2.52(m,2H),2.36-2.31(m,1H),2.19-2.14(m,2H),2.09(s,3H),2.07-2.02(m,3H),1.77-1.69(m,4H),1.66-1.60(m,1H),1.39-1.33(m,2H),1.24-1.17(m,2H),1.13-1.08(m,1H),0.89-0.82(m,2H);MS(ESI):m/z 830.1(M+H)。
實施例132:
從化合物INT-16和化合物120b起,參照化合物101的合成得到化合物132。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.76(d,J=8.5Hz,1H),7.63(s,1H),7.54-7.47(m,4H),7.37(s,1H),7.15(d,J=7.0Hz,1H),6.99-6.94(m,2H),6.76-6.69(m,1H),6.67(s,1H),5.71(s,2H),5.69-5.64(m,1H),3.86(s,3H),3.77-3.71(m,2H),3.61-3.58(m,1H),3.57(s,3H),3.46(s,2H),2.52-2.50(m,2H),2.14-2.02(m,8H),1.84-1.74(m,4H),1.69-1.60(m,1H),1.34-1.24(m,2H),1.16-1.07(m,2H);MS(ESI):m/z 828.1(M+H)。
實施例133:
參考化合物91的合成,將止血環酸甲酯鹽酸鹽換成4-氨基雙環[2.2.2]辛烷-1-羧酸甲酯鹽酸鹽,得到化合物133。1H NMR(500MHz,DMSO-d6)δ 7.87(s,1H),7.82(d,J=7.5Hz,1H),7.78(d,J=8.6Hz,1H),7.68-7.64(m,2H),7.58-7.49(m,3H),7.40(s,1H),7.32(d,J=7.5Hz,1H),7.17(d,J=7.0Hz,1H),6.69(s,1H),5.72(s,2H),3.92(s,3H),3.76-3.68(m,2H),3.66-3.62(m,1H),3.59(s,3H),3.43(s,2H),2.60-2.54(m,2H),2.16-2.07(m,3H),2.01(s,3H),1.77-1.65(m,7H),1.61-1.54(m,6H);MS(ESI):m/z 811.1(M+H)。
實施例134:
參照化合物110的合成,將異丙基碘換成(S)-5-溴甲基-2-吡咯烷酮,得到化合物134。1H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.78-7.73(m,2H),7.66(s,1H),7.52-7.46(m,4H),7.40(d,J=7.5Hz,1H),7.37(s,1H),7.15(d,J=7.0Hz,1H),7.07(s,1H),7.04(d,J=7.5Hz,1H),6.72(s,1H),5.70(s,2H),3.81(s,3H),3.80-3.76(m,1H),3.75-3.72(m,1H),3.72-3.70(m,2H),3.66-3.60(m,2H),3.40-3.35(m,2H),2.57-2.52(m,2H),2.17(d,J=11.0Hz,1H),2.12-2.08(m,6H),2.08(s,3H),2.06-2.04(m,1H),1.87-1.75(m,5H),1.70-1.64(m,1H),1.47-1.40(m,1H),1.30-1.20(m,3H),0.85-0.77(m,2H);MS(ESI):m/z 881.2(M+H)。
實施例135:
從化合物80b,4-溴吲唑和化合物INT-15起,參照化合物73a和化合物INT-16的合成得到化合物135a。MS(ESI):m/z 661.4(M+H)。
從化合物135a和4-氨基雙環[2.2.2]辛烷-1-羧酸甲酯鹽酸鹽起,參
照化合物101的合成得到化合物135。1H NMR(500MHz,DMSO-d6)δ 7.85(s,1H),7.79(d,J=8.5Hz,1H),7.69(s,1H),7.63(s,1H),7.57-7.43(m,4H),7.12(d,J=7.0Hz,1H),6.96(s,1H),6.94(d,J=8.5Hz,1H),5.78(s,2H),3.85(s,3H),3.74-3.73(m,2H),3.58-3.56(m,3H),3.37(s,3H),2.51-2.50(m,2H),2.10-2.03(m,3H),1.99(s,3H),1.70-1.67(m,6H),1.64-1.62(m,1H),1.54-1.51(m,6H);MS(ESI):m/z 829.2(M+H)。
實施例136:
從化合物INT-16和3-氨基雙環[1.1.1]戊烷-1-羧酸甲酯鹽酸鹽起,參照化合物101的合成得到化合物136。1H NMR(500MHz,DMSO-d6)δ 7.93(s,1H),7.75(d,J=8.5Hz,1H),7.63(s,1H),7.56-7.46(m,4H),7.33(s,1H),7.15(d,J=7.0Hz,1H),7.00-6.94(m,2H),6.67(s,1H),5.72(s,2H),3.86(s,3H),3.78-3.70(m,2H),3.57(s,3H),3.56-3.52(m,1H),3.40(s,2H),2.55-2.52(m,2H),2.10-2.03(m,6H),1.89(s,6H),1.68-1.60(m,1H);MS(ESI):m/z 786.0(M+H)。
實施例137:
從化合物INT-10,化合物INT-2,化合物80b和4-溴吲唑起,參照化合物INT-3,化合物73a和化合物16的合成得到化合物137a。MS(ESI):m/z 644.3(M+H)。
從化合物137a和4-氨基雙環[2.2.2]辛烷-1-羧酸甲酯鹽酸鹽起,參照化合物101的合成得到化合物137。1H NMR(500MHz,DMSO-d6)δ 7.83-7.80(m,3H),7.70-7.65(m,3H),7.55(t,J=7.5Hz,1H),7.50-7.47(m,2H),7.31(d,J=7.4Hz,1H),7.14(d,J=7.0Hz,1H),5.80(s,2H),3.92(s,3H),3.73-3.71(m,2H),3.65-3.63(m,1H),3.39(s,3H),3.36(brs,2H),2.56(d,J=6.0Hz,2H),2.14-2.07(m,3H),2.00(s,3H),1.72-1.68(m,7H),1.56-1.52(m,6H);MS(ESI):m/z 812.1(M+H)。
實施例138:
參照化合物107的合成,將化合物INT-6換成化合物INT-15,得到化合物138。1H NMR(500MHz,DMSO-d6)δ 7.96(s,1H),7.84(d,J=8.6Hz,1H),7.71(s,1H),7.65(s,1H),7.56-7.50(m,4H),7.18(d,J=
7.0Hz,1H),6.99-6.97(m,2H),6.92(s,1H),5.82(s,2H),3.87(s,3H),3.76-3.73(m,2H),3.71(s,3H),3.62-3.58(m,1H),3.49(s,2H),2.60-2.55(m,2H),2.45-2.35(m,1H),2.12(s,3H),2.10-2.04(m,3H),1.94-1.92(m,2H),1.81-1.79(m,2H),1.69-1.62(m,1H),1.34-1.23(m,5H);MS(ESI):m/z 793.0(M+H)。
實施例139:
參照化合物138的合成,將反式-4-氨基環己甲酸甲酯鹽酸鹽換成反式-4-氨基環丁甲酸甲酯鹽酸鹽,得到化合物139。1H NMR(500MHz,DMSO-d6)δ 7.94(s,1H),7.82(d,J=8.5Hz,1H),7.69(s,1H),7.63(s,1H),7.55-7.48(m,4H),7.17(d,J=7.1Hz,1H),6.99-6.95(m,2H),6.91(s,1H),5.80(s,2H),3.85(s,3H),3.73(d,J=4.2Hz,2H),3.69(s,3H),3.58-3.56(m,1H),3.26(brs,2H),3.03-3.01(m,1H),2.80-2.76(m,1H),2.51-2.48(m,2H),2.20-2.15(m,2H),2.09-2.02(m,5H),1.92(s,3H),1.66-1.62(m,1H);MS(ESI):m/z 765.1(M+H)。
實施例140:
參照化合物138的合成,將反式-4-氨基環己甲酸甲酯鹽酸鹽換成4-氨基雙環[2.2.2]辛烷-1-羧酸甲酯鹽酸鹽,得到化合物140。1H
NMR(500MHz,DMSO-d6)δ 7.95(s,1H),7.84(d,J=8.5Hz,1H),7.73(s,1H),7.65(s,1H),7.56-7.49(m,4H),7.18(d,J=7.0Hz,1H),7.00-6.97(m,2H),6.91(s,1H),5.81(s,2H),3.87(s,3H),3.75(d,J=4.5Hz,2H),3.70(s,3H),3.62-3.56(m,1H),3.45(s,2H),2.54-2.52(m,2H),2.09-2.05(m,3H),2.02(s,3H),1.75-1.72(m,6H),1.68-1.63(m,1H),1.59-1.56(m,6H);MS(ESI):m/z 819.0(M+H)。
實施例141:
參照化合物138的合成,將反式-4-氨基環己甲酸甲酯鹽酸鹽換成化合物INT-14,得到化合物141。1H NMR(500MHz,DMSO-d6)δ 7.94(s,1H),7.82(d,J=8.5Hz,1H),7.69(s,1H),7.63(s,1H),7.56-7.48(m,4H),7.17(d,J=7.0Hz,1H),6.97-6.95(m,2H),6.90(s,1H),5.80(s,2H),3.85(s,3H),3.73(d,J=4.1Hz,2H),3.69(s,3H),3.58-3.55(m,1H),3.46(s,2H),2.52-2.49(m,2H),2.36-2.33(m,1H),2.10(s,3H),2.08-2.01(m,5H),1.77-1.70(m,4H),1.66-1.61(m,1H),1.58-1.52(m,1H),1.29-1.22(m,2H),0.96-0.89(m,2H);MS(ESI):m/z 807.1(M+H)。
實施例142:
參照化合物92的合成,將化合物INT-6換成化合物INT-15,得到化合物142。1H NMR(500MHz,DMSO-d6)δ 8.17(s,1H),7.99(s,1H),7.78(d,J=8.5Hz,1H),7.64(s,1H),7.57-7.46(m,4H),7.17(d,J=7.0Hz,1H),7.00-6.95(m,2H),6.10(s,1H),6.09(s,2H),3.86(s,3H),3.73(d,J=4.5Hz,2H),3.59-3.55(m,1H),3.49(s,2H),3.48(s,3H),2.53-2.51(m,2H),2.43-2.37(m,1H),2.13(s,3H),2.11-2.01(m,4H),1.95-1.86(m,2H),1.84-1.75(m,2H),1.68-1.59(m,1H),1.33-1.23(m,4H);MS(ESI):m/z 813.3(M+H)。
實施例143:
參照化合物142的合成,將反式-4-氨基環己甲酸甲酯鹽酸鹽換成反式-4-氨基環丁甲酸甲酯鹽酸鹽,得到化合物143。1H NMR(500MHz,DMSO-d6)δ 8.13(s,1H),7.99(s,1H),7.79(d,J=8.5Hz,1H),7.63(s,1H),7.55-7.48(m,4H),7.17(d,J=6.5Hz,1H),7.00-6.96(m,2H),6,12(s,1H),6.09(s,2H),3.86(s,3H),3.77-3.70(m,2H),3.59-3.55(m,1H),3.48(s,3H),3.32-3.30(m,2H),3.09-3.02(m,1H),2.87-2.78(m,1H),2.52-2.48(m,2H),2.21-2.16(m,2H),2.12-2.02(m,5H),1.95(s,3H),1.67-1.60(m,1H);MS(ESI):m/z 785.3(M+H)。
實施例144:
參照化合物142的合成,將反式-4-氨基環己甲酸甲酯鹽酸鹽換成化合物INT-14,得到化合物144。1H NMR(500MHz,DMSO-d6)δ 8.17(s,1H),7.98(s,1H),7.78(d,J=8.5Hz,1H),7.63(s,1H),7.57-7.47(m,4H),7.17(d,J=6.5Hz,1H),7.00-6.95(m,2H),6.09(s,1H),6.09(s,2H),3.86(s,3H),3.77-3.70(m,2H),3.59-3.55(m,1H),3.49(s,2H),3.48(s,3H),2.54-2.50(m,2H),2.36-2.33(m,1H),2.13(s,3H),2.10-2.02(m,5H),1.78-1.70(m,4H),1.67-1.64(m,1H),1.57-1.52(m,1H),1.32-1.21(m,2H),0.98-0.88(m,2H);MS(ESI):m/z 827.1(M+H)。
實施例145:
參照化合物142的合成,將反式-4-氨基環己甲酸甲酯鹽酸鹽換成4-氨基雙環[2.2.2]辛烷-1-羧酸甲酯鹽酸鹽,得到化合物145。1H NMR(500MHz,DMSO-d6)δ 8.18(s,1H),7.98(s,1H),7.78(d,J=8.5Hz,1H),7.63(s,1H),7.56-7.47(m,4H),7.17(d,J=7.0Hz,1H),7.00-6.95(m,2H),6.09(s,1H),6.08(s,2H),3.86(s,3H),3.77-3.70(m,2H),3.59-3.55(m,1H),3.48(s,3H),3.45(s,2H),2.54-2.50(m,2H),2.10-2.04(m,3H),2.03(s,3H),1.74-1.69(m,6H),1.68-1.62(m,1H),1.60-1.55(s,6H);MS(ESI):m/z 839.1(M+H)。
實施例146:
在混有化合物INT-13(50mg,0.16mmol)和氟磺醯基二氟乙酸甲酯(314mg,1.6mmol)的N,N-二甲基甲醯胺(2mL)溶液中加入碘化亞銅(156mg,0.82mmol);所得混合液在150度條件下攪拌4小時。反應液過濾後,濾液中加入乙酸乙酯和水的混合液(100mL,v/v=1/1)。所得有機相用飽和食鹽水(50mL)洗滌,無水硫酸鈉乾燥,濃縮。殘餘物用矽膠柱層析得到白色固體146a(40mg,收率:98.7%)。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.27(s,1H),3.90(s,3H),3.80(s,3H);MS(ESI):m/z 249.0(M+H)。
從化合物146a起,參照化合物92的合成,其中將反式-4-氨基環己甲酸甲酯鹽酸鹽換成化合物INT-14,得到化合物146。1H NMR(500MHz,DMSO-d6)δ 7.95(s,1H),7.70(s,1H),7.67-7.62(m,2H),7.54-7.46(m,4H),7.40(d,J=7.7Hz,1H),7.17(d,J=7.0Hz,1H),7.07(d,J=1.6Hz,1H),7.04(dd,J=7.5,1.6Hz,1H),6.32(s,1H),5.82(s,2H),3.82(s,3H),3.71(d,J=3.0Hz,2H),3.65-3.59(m,1H),3.48(s,2H),3.46(s,3H),2.55-2.53(m,2H),2.37-2.33(m,1H),2.12-2.06(m,6H),2.02(d,J=7.1Hz,2H),1.76-1.67(m,5H),1.58-1.51(m,1H),1.29-1.21(m,2H),0.97-0.87(m,2H);MS(ESI):m/z 832.2(M+H)。
實施例147:
參照化合物146的合成,將化合物INT-6換成化合物INT-15,得到化合物147。1H NMR(500MHz,DMSO-d6)δ 7.98(s,1H),7.70(s,1H),7.68-7.61(m,2H),7.57-7.47(m,4H),7.17(d,J=7.0Hz,1H),7.01-6.94(m,2H),6.33(s,1H),5.82(s,2H),3.86(s,3H),3.78-3.70(m,2H),3.62-3.54(m,1H),3.48(s,2H),3.46(s,3H),2.55-2.50(m,2H),2.36-2.31(m,1H),2.10(s,3H),2.09-2.01(m,5H),1.77-1.69(m,4H),1.67-1.61(m,1H),1.59-1.52(m,1H),1.31-1.24(m,2H),0.97-0.88(m,2H);MS(ESI):m/z 850.1(M+H)。
實施例148:
參照化合物147的合成,將化合物INT-14換成反式-4-氨基環己甲酸甲酯鹽酸鹽,得到化合物148。1H NMR(500MHz,DMSO-d6)δ 7.98(s,1H),7.70(s,1H),7.69-7.61(m,2H),7.57-7.46(m,4H),7.17(d,J=7.0Hz,1H),7.00-6.95(m,2H),6.33(s,1H),5.82(s,2H),3.86(s,3H),3.78-3.68(m,2H),3.61-3.55(m,1H),3.48(s,2H),3.46(s,3H),2.56-2.50(m,2H),2.39-2.33(m,1H),2.10(s,3H),2.09-2.02(m,4H),1.94-1.87(m,2H),1.82-1.74(m,2H),1.68-1.60(m,1H),1.34-1.24(m,4H);MS(ESI):m/z 836.1(M+H)。
實施例149:
參照化合物147的合成,將化合物INT-14換成反式-4-氨基環己甲酸甲酯鹽酸鹽,得到化合物149。1H NMR(500MHz,DMSO-d6)δ 7.99(s,1H),7.69-7.62(m,3H),7.57-7.47(m,4H),7.17(d,J=6.9Hz,1H),7.04-6.92(m,2H),6.34(s,1H),5.83(s,2H),3.86(s,3H),3.79-3.70(m,2H),3.61-3.54(m,1H),3.46(s,3H),3.29(s,2H),3.06-2.97(m,1H),2.83-2.75(m,1H),2.56-2.52(m,2H),2.19-2.14(m,2H),2.11-2.01(m,5H),1.91(s,3H),1.68-1.61(m,1H);MS(ESI):m/z 808.1(M+H)。
實施例150:
參照化合物147的合成,將化合物INT-14換成4-氨基雙環[2.2.2]辛烷-1-羧酸甲酯鹽酸鹽,得到化合物150。1H NMR(500MHz,DMSO-d6)δ 7.98(s,1H),7.72(s,1H),7.67-7.61(m,2H),7.58-7.47(m,4H),7.17(d,J=7.0Hz,1H),7.05-6.94(m,2H),6.32(s,1H),5.82(s,2H),3.86(s,3H),3.78-3.70(m,2H),3.61-3.55(m,1H),3.46(s,3H),3.44(s,2H),2.60-2.54(m,2H),2.10-2.02(m,3H),1.99(s,3H),1.74-1.68(m,6H),1.66-1.62(m,1H),1.59-1.53(m,6H);MS(ESI):m/z 862.1(M+H)。
實施例151:
參照化合物137的合成,將4-氨基雙環[2.2.2]辛烷-1-羧酸甲酯鹽酸鹽換成反式-4-氨基環己甲酸甲酯鹽酸鹽,得到化合物151。1H NMR(500MHz,DMSO-d6)δ 7.83-7.78(m,3H),7.72-7.63(m,3H),7.54(t,J=7.5Hz,1H),7.50-7.45(m,2H),7.30(d,J=7.5Hz,1H),7.13(d,J=7.0Hz,1H),5.80(s,2H),3.90(s,3H),3.70(d,J=3.5Hz,2H),3.65-3.60(m,1H),3.39(s,2H),3.37(s,3H),2.55-2.53(m,2H),2.37-2.33(m,1H),2.12-2.05(m,4H),2.08(s,3H),1.93-1.87(m,2H),1.78-1.73(m,2H),1.71-1.66(m,1H),1.29-1.23(m,4H);MS(ESI):m/z 786.0(M+H)。
實施例152:
參考化合物91的合成,將止血環酸甲酯鹽酸鹽換成反式-4-氨基環己甲酸甲酯鹽酸鹽,得到化合物152。1H NMR(500MHz,DMSO-d6)δ 7.88(s,1H),7.83(d,J=7.5Hz,1H),7.78(d,J=8.5Hz,1H),7.70-7.65(m,2H),7.59-7.49(m,3H),7.38(s,1H),7.32(d,J=7.4Hz,1H),7.18(d,J=7.0Hz,1H),6.69(s,1H),5.73(s,2H),3.92(s,3H),3.76-3.70(m,2H),3.66-3.61(m,1H),3.59(s,3H),3.46(s,2H),2.56-2.55(m,2H),2.42-2.35(m,1H),2.16-2.06(m,4H),2.12(s,3H),1.96-1.88(m,2H),1.83-1.76(m,2H),1.74-1.66(m,1H),1.34-1.23(m,4H);
MS(ESI):m/z 784.8(M+H)。
實施例153:
參考化合物57的合成,將化合物INT-2換成化合物INT-17,得到化合物153。1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.77(d,J=8.5Hz,1H),7.54-7.48(m,4H),7.41(d,J=8.0Hz,1H),7.38(s,1H),7.19-7.14(m,2H),7.10(brs,1H),7.07-7.03(m,1H),6.68(s,1H),5.73(s,2H),3.83(s,3H),3.76-3.66(m,2H),3.58(s,3H),3.46(s,2H),3.41-3.36(m,1H),2.61-2.58(m,2H),2.16-2.05(m,3H),2.13(s,3H),1.95-1.89(m,2H),1.83-1.74(m,4H),1.63-1.54(m,1H),1.36-1.23(m,6H);MS(ESI):m/z 799.1(M+H)。
實施例154:
在-78℃條件下,將二異丙基氨基鋰(2.0M的四氫呋喃溶液,2.6mL)加入至溶有1-氯-2-溴-4-氟苯(1.0g,4.8mmol)的四氫呋喃(6mL)溶液中;所得反應液在相同溫度下攪拌1小時。隨後N,N-二甲基甲醯胺(1.7g,24mmol)加入至反應液中,所得混合液進一步在-78℃條件下攪拌1小時。反應液用氯化銨水溶液(40mL,5% w/w)淬滅,水相用乙酸乙酯萃取(30mL x 3)。合併有機相,用飽和食鹽水
(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析(乙酸乙酯/石油醚=10/1)分離得到白色固體154a(830mg,收率:73.2%)。MS(ESI):m/z 237.1(M+H)。
在90℃條件下,將混有化合物154a(830mg,3.5mmol),水合肼(2.0mL,85%分析純度)的乙二醇二甲醚(5mL)攪拌3小時。待反應冷卻後,乙酸乙酯(50mL)和水(50mL)加入至反應液;有機相用飽和食鹽水(50mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析(乙酸乙酯/石油醚=10/1)分離得到淡黃色固體154b(725mg,收率:89.6%)。MS(ESI):m/z 231.0(M+H)。
從化合物154b起,參照化合物INT-9和化合物30的合成得到化合物154。1H NMR(500MHz,DMSO-d6)δ 7.83(d,J=9.0Hz,1H),7.71(s,1H),7.65(s,1H),7.57(d,J=9.0Hz,1H),7.55-7.53(m,2H),7.48(s,1H),7.43-7.39(m,2H),7.07-7.02(m,2H),6.75(s,1H),5.73(s,2H),3.88-3.84(m,1H),3.82(s,3H),3.79-3.73(m,3H),3.65-3.64(m,1H),3.62(s,3H),3.60-3.55(m,2H),3.13-3.11(m,1H),2.59-2.54(m,2H),2.11-2.06(m,3H),1.71-1.65(m,1H);MS(ESI):m/z 765.9(M+H)。
實施例155:
在溶有4-溴-2-氟苯胺(1.0g,5.3mmol)的乙腈(10mL)溶液中分批加入N-氯代丁二醯亞胺(843mg,6.3mmol);反應液在回流條件下攪拌2小時。待反應液冷卻後加入5%碳酸鉀水溶液(50mL);所得水相用
二氯甲烷萃取(50mL x 2)。合併有機相用飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析(石油醚作為洗脫劑)分離得到白色固體155a(1.0g,收率:84.6%)。1H NMR(500MHz,Chloroform-d)δ 7.21(t,J=2.0Hz,1H),7.09(dd,J=10.0,2.0Hz,1H),4.04(brs,2H)。
在室溫條件下,將溶有化合物155a(1.0g,4.5mmol)的硫酸水溶液(25% w/w)攪拌半小時;隨後冷卻至-5℃後緩慢滴加溶有亞硝酸鈉(369mg,5.4mmol)的水(5mL)溶液。反應液在-5℃條件下進一步攪拌1小時;並在相同溫度下緩慢滴加溶有碘化鉀(1.5g,8.9mmol)的乙酸乙酯和水的混合溶液(50mL,v/v=3/2)。所得反應液在室溫條件下反應1小時。反應液經分層後,水相進一步用乙酸乙酯萃取(30mL x 2);合併有機相用飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析(石油醚作為洗脫劑)分離得到無色油狀物155b(800mg,收率:53.6%)。1H NMR(500MHz,Chloroform-d)δ 7.45(t,J=2.0Hz,1H),7.13(dd,J=7.0,2.0Hz,1H)。
在氮氣氛圍和80℃條件下,將混有化合物155b(1.0g,3.0mmol),乙烯基硼酸頻哪醇酯(1.4g,9.0mmol),Pd(dppf)Cl2(109mg,0.15mmol)和碳酸氫鈉(504mg,6.0mmol)的1,4-二氧六環和水的混合溶液(11mL,v/v=10/1)攪拌16小時。反應液用矽藻土過濾,濾液濃縮,殘留物用矽膠柱層析(石油醚作為洗脫劑)分離得到無色油狀物155c(550mg,收率:58.7%)。
在室溫條件下,將混有化合物155c(520mg,2.2mmol)的1,4-二氧六環和水的混合溶液(6mL,v/v=1/1)中加入二水合鋨酸鉀(8.1mg,0.02mmol)和高碘酸鈉(1.4g,6.6mmol);反應液在相同溫度下攪拌2小時。反應液中加入水(30mL),並用乙酸乙酯萃取(30mL x 2)。合併有機相用飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析(石油醚/乙酸乙酯,v/v=10/1)分離
得到無色油狀物155d(400mg,收率:76.3%)。1H NMR(500MHz,Chloroform-d)δ 10.40(brs,1H),7.48(d,J=1.5Hz,1H),7.33-7.29(m,1H)。
從化合物155d起,參照化合物INT-16和化合物101的合成得到化合物155。1H NMR(500MHz,DMSO-d6)δ 7.93(s,1H),7.76(d,J=8.5Hz,1H),7.63(s,1H),7.55-7.48(m,4H),7.36(s,1H),7.19-7.17(m,1H),7.15(d,J=7.0Hz,1H),7.11-7.09(m,1H),6.67(s,1H),5.71(s,2H),3.85(s,3H),3.85-3.83(m,2H),3.62-3.57(m,1H),3.56(s,3H),3.34(s,2H),2.54-2.51(m,2H),2.11-2.04(m,8H),1.86-1.77(m,4H),1.67-1.61(m,1H),1.48-1.39(m,1H),1.27-1.19(m,3H),0.85-0.75(m,2H);MS(ESI):m/z 832.2(M+H)。
實施例156:
將甲醇鈉(1.8g,33.5mmol)加入至溶有4,6-二氯煙酸甲酯(4.6g,22.3mmol)的四氫呋喃(40mL)溶液;所得反應液在50℃條件下攪拌16小時。反應液中加入水(100mL);並用乙酸乙酯萃取(100mL x 2)。合併有機相用飽和食鹽水(150mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離得到白色固體156a(2.8g,收率:62.2%)。MS(ESI):m/z 202.1(M+H)。
從化合物156a起,參照化合物72c的合成得到化合物156b。MS(ESI):m/z 172.1(M+H)。
從化合物156b起,參照化合物INT-10和化合物133的合成得到化合物156。1H NMR(500MHz,DMSO-d6)δ 8.24(d,J=1.7Hz,1H),
7.94(s,1H),7.78(d,J=8.5Hz,1H),7.68(s,1H),7.61-7.48(m,5H),7.40(s,1H),7.18(d,J=7.0Hz,1H),6.68(s,1H),5.72(s,2H),3.88(s,3H),3.86(s,2H),3.65-3.60(m,1H),3.58(s,3H),3.43(s,2H),2.66-2.56(m,2H),2.15-2.05(m,3H),2.00(s,3H),1.77-1.67(m,7H),1.61-1.52(m,6H);MS(ESI):m/z 811.1(M+H)。
實施例157:
從化合物INT-15a起,參照化合物INT-1c的合成得到化合物157a。MS(ESI):m/z 276.8(M+H)。
從化合物157a起,參照155c的合成得到化合物157c。1H NMR(500MHz,DMSO-d6)δ 10.27(s,1H),7.31(d,J=1.5Hz,1H),6.19(d,J=1.5Hz,1H),4.11-4.07(m,2H),3.96-3.92(m,2H),3.90(s,3H)。
在0℃條件下,將硼氫化鈉(29mg,0.77mmol)加入至溶有化合物157c(400mg,1.53mmol)的四氫呋喃(20mL)溶液;反應液隨後在室溫條件下攪拌半小時。反應液中加入飽和碳酸氫鈉(20mL)溶液,並用乙酸乙酯萃取(20mL x 2)。合併有機相用飽和食鹽水(50mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮得到黃色固體157d(400mg,收率:99.2%)。MS(ESI):m/z 263.3(M+H)。
從化合物157d起,參照化合物INT-8c和化合物INT-1i的合成得到化合物157e。MS(ESI):m/z 445.5(M+H)。
從化合物157e起,參照化合物133的合成得到化合物157。1H
NMR(500MHz,DMSO-d6)δ 7.87(s,1H),7.81(d,J=7.5Hz,1H),7.78(d,J=8.5Hz,1H),7.68-7.63(m,2H),7.56-7.49(m,3H),7.30(d,J=7.5Hz,1H),7.17(d,J=7.0Hz,1H),6.58(s,1H),5.76(s,2H),3.90(s,3H),3.70(d,J=3.5Hz,2H),3.64-3.61(m,1H),3.60(s,3H),3.45(s,2H),2.54(d,J=6.0Hz,2H),2.14-2.05(m,3H),1.89(s,3H),1.74-1.69(m,6H),1.69-1.64(m,1H),1.62-1.57(m,6H);MS(ESI):m/z 829.3(M+H)。
實施例158:
從1-氯-2-氟-4-溴苯起,參照化合物154的合成得到化合物158。
1H NMR(500MHz,DMSO-d6)δ 8.05(s,1H),7.66(s,1H),7.56-7.49(m,4H),7.45-7.39(m,2H),7.16(d,J=7.6Hz,1H),7.08(d,J=1.6Hz,1H),7.05(dd,J=7.6,1.6Hz,1H),6.04-6.00(m,3H),3.81(s,3H),3.73-3.69(m,2H),3.66-3.56(m,3H),3.45-3.41(m,2H),3.38(s,3H),3.25-3.22(m,1H),2.55-2.50(m,2H),2.11-2.05(m,3H),1.71-1.65(m,1H);MS(ESI):m/z 766.0(M+H)。
實施例159:
參照化合物116的合成,將還原胺化步驟中用的甲醛換成乙醛得
到化合物159。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.76(d,J=8.5Hz,1H),7.63(s,1H),7.55(s,1H),7.54-7.47(m,4H),7.15(d,J=7.0Hz,1H),7.00-6.95(m,2H),6.64(s,1H),5.70(s,2H),3.86(s,3H),3.77-3.71(m,2H),3.62-3.57(m,1H),3.60(s,3H),3.56(s,2H),2.57-2.50(m,4H),2.10-2.03(m,3H),1.72-1.66(m,6H),1.65-1.61(m,1H),1.56-1.51(m,6H),0.78(t,J=7.0Hz,3H);MS(ESI):m/z 842.1(M+H)。
實施例160:
在60℃條件下,將溶有4-(((苄氧基)羰基)氨基)雙環[2.2.2]辛烷-1-羧酸(150mg,0.49mmol)的二氯亞碸(2mL)溶液攪拌2小時。反應液濃縮後,殘餘物用乙腈(3mL)溶解,並加入三甲基矽烷化重氮甲烷(2M在正己烷中,0.24mL);所得反應液在室溫條件下攪拌2小時。隨後在0℃條件下,在上述溶液中加入三乙胺(0.13mL),三氟乙酸銀(154mg,0.70mmol)和甲醇(1mL);所得反應液在室溫條件下攪拌16小時。反應液過濾,濾液濃縮;殘留物用矽膠柱層析分離得到白色固體160a(50mg,收率:32.4%)。1H NMR(500MHz,DMSO-d6)δ 7.37-7.26(m,5H),6.87(s,1H),4.92(s,2H),3.53(s,3H),2.05(s,2H),1.75-1.66(m,6H),1.55-1.42(m,6H);MS(ESI):m/z 332.4(M+H)。
在室溫條件和氫氣氛圍下,將溶有化合物160a(100mg,0.30mmol)
和氫氧化鈀(10% w/w在活性炭,20mg)的甲醇(3mL)溶液攪拌1小時。反應液用矽藻土過濾,濾液濃縮後殘餘物用二氯甲烷(2mL)溶解,並且滴加鹽酸(4M在乙酸乙酯,0.15mL);所得反應液在室溫攪拌半小時。反應液濃縮後得到固體殘餘物,用乙酸乙酯洗滌得到白色固體160b(60mg,收率:85.1%)。MS(ESI):m/z 198.5(M+H)。
從化合物INT-16和化合物160b起,參照化合物101的合成得到化合物160。1H NMR(500MHz,DMSO-d6)δ 7.93(s,1H),7.76(d,J=8.5Hz,1H),7.63(s,1H),7.55-7.47(m,4H),7.40(s,1H),7.16(d,J=7.0Hz,1H),6.98-6.95(m,2H),6.67(s,1H),5.72(s,2H),3.87(s,3H),3.79-3.71(m,2H),3.65-3.59(m,1H),3.58(s,3H),3.41(s,2H),2.60-2.54(m,2H),2.14-2.03(m,3H),1.99(s,3H),1.96(s,2H),1.76-1.69(m,1H),1.60-1.46(m,12H);MS(ESI):m/z 842.3(M+H)。
實施例161:
參照化合物116的合成,將2-氯-1,3-二溴苯換成2-甲基-1,3-二溴苯,得到化合物161。1H NMR(500MHz,DMSO-d6)δ 7.92(d,J=1.5Hz,1H),7.73(d,J=8.5Hz,1H),7.65(s,1H),7.52-7.47(m,1H),7.40-7.36(m,2H),7.35-7.31(m,2H),7.09(d,J=7.0Hz,1H),6.93-6.88(m,2H),6.65(s,1H),5.72(s,2H),3.87(s,3H),3.78-3.71(m,2H),3.64-3.60(m,1H),3.57(s,3H),3.42(s,2H),2.56-2.53(m,2H),2.13-2.06(m,3H),2.03(s,3H),2.00(s,3H),1.76-1.68(m,6H),1.69-1.63(m,1H),1.60-1.53(m,6H);MS(ESI):m/z 808.1(M+H)。
實施例162:
從化合物INT-16和反式-4-氨基環己醇起,參照化合物101的合成得到化合物162。1H NMR(500MHz,DMSO-d6)δ 7.93(d,J=1.0Hz,1H),7.76(d,J=8.5Hz,1H),7.64(s,1H),7.54-7.48(m,4H),7.35(s,1H),7.15(d,J=7.0Hz,1H),6.98-6.94(m,2H),6.67(s,1H),5.71(s,2H),4.43(d,J=4.5Hz,1H),3.85(s,3H),3.77-3.70(m,2H),3.62-3.60(m,1H),3.56(s,3H),3.42(s,2H),3.35-3.32(m,1H),2.55-2.52(m,1H),2.36-2.33(m,1H),2.10-2.04(m,6H),1.84-1.78(m,2H),1.72-1.67(m,2H),1.65-1.59(m,1H),1.31-1.20(m,2H),1.14-1.06(m,2H);MS(ESI):m/z 774.1(M+H)。
實施例163:
參照化合物135的合成,將4-氨基雙環[2.2.2]辛烷-1-羧酸甲酯鹽酸鹽換成反式-4-氨基環己甲酸甲酯鹽酸鹽,得到化合物163。1H NMR(500MHz,DMSO-d6)δ 7.88-7.83(m,1H),7.81-7.75(m,1H),7.71-7.61(m,2H),7.55-7.44(m,4H),7.15-7.09(m,1H),6.99-6.92(m,2H),5.83-5.76(m,2H),3.88-3.83(m,3H),3.76-3.70(m,2H),3.59-3.54(m,1H),3.40-3.38(m,2H),3.37-3.36(m,3H),2.51-2.50(m,2H),2.35-2.30(m,1H),2.10-2.03(m,6H),1.90-1.81(m,3H),1.76-
1.69(m,2H),1.68-1.61(m,1H),1.24-1.16(m,4H);MS(ESI):m/z 803.1(M+H)。
實施例164:
參照化合物133的合成,將2-氯-1,3-二溴苯換成2-甲基-1,3-二溴苯,得到化合物164。1H NMR(500MHz,DMSO-d6)δ 7.81-7.77(m,2H),7.72(d,J=8.5Hz,1H),7.67(s,1H),7.50-7.44(m,2H),7.40-7.35(m,2H),7.34-7.30(m,1H),7.18(d,J=7.4Hz,1H),7.08(d,J=7.0Hz,1H),6.65(s,1H),5.70(s,2H),3.88(s,3H),3.75-3.68(m,2H),3.66-3.59(m,1H),3.57(s,3H),3.41(s,2H),2.54(d,J=6.0Hz,2H),2.15-2.05(m,3H),2.09(s,3H),1.99(s,3H),1.75-1.69(m,6H),1.69-1.65(m,1H),1.59-1.52(m,6H);MS(ESI):m/z 791.0(M+H)。
實施例165:
在-78℃條件和氮氣氛圍下,將二異丁基氫化鋁(1M在甲苯中,30.6mL)緩慢滴加至溶有5-溴-3-氟-2-吡啶甲腈(4.1g,20.4mmol)的四氫呋喃(40mL)溶液中;反應液隨後在相同溫度下攪拌2小時。隨後反應液中加入水(50mL),並用矽藻土過濾;所得濾液用乙酸乙酯萃取(50mL x 2)。合併有機相用飽和食鹽水(100mL)洗滌,無水
硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離得到白色固體165a(2.7g,收率:64.9%)。MS(ESI):m/z 204.0(M+H)。
從化合物165a起,參照化合物156a的合成得到化合物165b。MS(ESI):m/z 216.3(M+H)。
從化合物165b和3-溴-2-甲基苯酚起,參照化合物INT-10和化合物133的合成得到化合物165。1H NMR(500MHz,DMSO-d6)δ 8.44(s,1H),7.83(s,1H),7.74(d,J=8.5Hz,1H),7.68(s,1H),7.52-7.48(m,1H),7.46-7.43(m,1H),7.42-7.38(m,2H),7.37-7.33(m,1H),7.19(s,1H),7.09(d,J=6.9Hz,1H),6.66(s,1H),5.72(s,2H),3.92(s,3H),3.78-3.69(m,2H),3.67-3.60(m,1H),3.58(s,3H),3.43-3.38(m,2H),2.55(d,J=6.0Hz,2H),2.15-2.06(m,3H),2.05(s,3H),2.01(s,3H),1.77-1.71(m,6H),1.71-1.65(m,1H),1.61-1.54(m,6H);MS(ESI):m/z 791.0(M+H)。
實施例166:
參照化合物135的合成,將2-氯-1,3-二溴苯換成2-甲基-1,3-二溴苯,得到化合物166。1H NMR(500MHz,DMSO-d6)δ 7.87(d,J=1.0Hz,1H),7.79-7.75(m,1H),7.72(s,1H),7.67(s,1H),7.50-7.46(m,1H),7.41-7.37(m,1H),7.36-7.29(m,2H),7.09-7.05(m,1H),6.95-6.89(m,2H),5.82(s,2H),3.88(s,3H),3.80-3.72(m,2H),3.65-3.55(m,1H),3.38(s,3H),3.35-3.30(m,2H),2.54-2.50(m,2H),2.13-2.05(m,3H),2.02(s,6H),1.76-1.70(m,6H),1.69-1.64(m,1H),1.60-1.53(m,6H);MS(ESI):m/z 809.1(M+H)。
實施例167:
參照化合物133的合成,將化合物INT-2換成化合物67a,得到化合物167。1H NMR(500MHz,DMSO-d6)δ 7.94(s,1H),7.78(d,J=8.5Hz,1H),7.69(s,1H),7.57-7.49(m,4H),7.39(s,1H),7.16(d,J=7.0Hz,1H),7.05-6.97(m,2H),6.69(s,1H),5.72(s,2H),3.87(s,3H),3.78-3.71(m,2H),3.59-3.53(m,1H),3.58(s,3H),3.42(s,2H),2.54-2.53(m,2H),2.11-2.04(m,3H),2.00(s,3H),1.75-1.70(m,6H),1.67-1.63(m,1H),1.60-1.54(m,6H);MS(ESI):m/z 828.1(M+H)。
實施例168:
參照化合物133的合成,將化合物INT-2換成化合物INT-18,得到化合物168。1H NMR(500MHz,DMSO-d6)δ 7.94(s,1H),7.78(d,J=8.7Hz,1H),7.55-7.50(m,4H),7.39(s,1H),7.19-7.11(m,2H),7.01-6.97(m,2H),6.69(s,1H),5.72(s,2H),3.87(s,3H),3.75-3.70(m,2H),3.58(s,3H),3.42(s,2H),3.36-3.35(m,1H),2.53-2.52(m,2H),2.12-2.07(m,2H),2.00(s,3H),1.76-1.70(m,8H),1.58-1.54(m,7H),1.34-1.27(m,1H);MS(ESI):m/z 842.1(M+H)。
實施例169:
參照化合物137的合成,將2-氯-1,3-二溴苯換成2-甲基-1,3-二溴苯,得到化合物169。1H NMR(500MHz,DMSO-d6)δ 7.81(d,J=7.5Hz,1H),7.79-7.74(m,2H),7.73-7.69(m,2H),7.51-7.44(m,2H),7.42-7.37(m,1H),7.35-7.29(m,1H),7.20(d,J=7.5Hz,1H),7.07(d,J=7.5Hz,1H),5.81(s,2H),3.90(s,3H),3.75-3.67(m,2H),3.66-3.59(m,1H),3.37(s,3H),3.35(s,2H),2.58-2.54(m,2H),2.14-2.06(m,3H),2.10(s,3H),2.00(s,3H),1.75-1.66(m,7H),1.61-1.44(m,6H);MS(ESI):m/z 792.2(M+H)。
實施例170:
在0℃條件下,將溶有亞硝酸鈉(10g,147mmol)的水(50mL)溶液緩慢滴入預先溶有2-氨基-5-溴-3-甲氧基吡嗪(2g,9.8mmol)和氫碘酸(57% w/w,50mL)的乙腈和水的混合溶液(250mL,v/v=3/2)。反應液在攪拌條件下升至50℃,並且在該條件下反應16小時。反應液用20%氫氧化鈉水溶液中和,並用乙酸乙酯萃取(100mL x 2)。合併有機相用飽和硫代硫酸鈉溶液和飽和食鹽水(各150mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離得到棕色固體170a(1.55g,收率:50.2%)。
在氮氣氛圍和-40℃條件下,將異丙基氯化鎂-氯化鋰(1.3M的四氫呋喃溶液,1.83mL)緩慢滴至預先溶有化合物170a(500mg,1.6mmol)的四氫呋喃(10mL)溶液中。反應液在相同條件下進一步攪拌半小時,隨後升至15℃後緩慢加入N,N-二甲基甲醯胺(1.2mL);所得反應液在15℃條件下進一步攪拌2小時。反應液用檸檬酸中和,並用乙酸乙酯萃取(50mL x 2)。合併有機相用飽和食鹽水(100mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析分離得到淡黃色固體170b(300mg,收率:87.1%)。MS(ESI):m/z 217.0(M+H)。
從化合物165b和3-溴-2-甲基苯酚起,參照化合物INT-10和化合物133的合成得到化合物170。1H NMR(500MHz,DMSO-d6)δ 8.38(s,1H),7.81(s,1H),7.74(d,J=8.4Hz,1H),7.67(s,1H),7.53(d,J=7.4Hz,1H),7.51-7.46(m,1H),7.44-7.37(m,3H),7.09(d,J=7.0Hz,1H),6.66(s,1H),5.70(s,2H),3.95(s,3H),3.87(s,2H),3.63-3.60(m,1H),3.57(s,3H),3.41(s,2H),2.60-2.57(m,2H),2.11(s,3H),2.10-2.02(m,3H),1.99(s,3H),1.73-1.67(m,7H),1.58-1.53(m,6H);MS(ESI):m/z 792.1(M+H)。
實施例171:
從化合物INT-16,反式-4-氨基環己甲酸甲酯鹽酸鹽和叔丁基二甲基矽氧烷基乙醛起,參照化合物125的合成得到化合物171。1H NMR(500MHz,DMSO-d6)δ 7.96(s,1H),7.80(d,J=8.5Hz,1H),7.69(s,1H),7.60-7.50(m,5H),7.17(d,J=7.1Hz,1H),7.09-6.99(m,2H),6.69(s,1H),5.73(s,2H),3.89(s,3H),3.85-3.80(m,2H),3.78-3.47
(m,5H),3.60(s,3H),2.56-2.53(m,2H),2.16-2.04(m,5H),1.94-1.87(m,2H),1.81-1.65(m,4H),1.63-1.53(m,1H),1.31-1.20(m,4H);MS(ESI):m/z 832.0(M+H)。
實施例172:
參照化合物135的合成,將化合物INT-2換成化合物INT-18,得到化合物172。1H NMR(500MHz,DMSO-d6)δ 7.88(s,1H),7.81(d,J=8.5Hz,1H),7.71(s,1H),7.57-7.47(m,4H),7.17-7.12(m,2H),7.01-6.96(m,2H),5.81(s,2H),3.88(s,3H),3.76-3.69(m,2H),3.38(s,3H),3.36-3.29(m,3H),2.57-2.53(m,2H),2.15-2.05(m,2H),2.00(s,3H),1.79-1.68(m,8H),1.60-1.52(m,7H),1.35-1.28(m,1H);MS(ESI):m/z 843.1(M+H)。
實施例173:
在0℃條件下,將溶有硝酸鉀(55mg,0.54mmol)的濃硫酸(1mL)滴加至預先溶有3-氯-4-甲基苯甲酸甲酯(100mg,0.54mmol)的濃硫酸(2mL)。反應液在相同條件下攪拌半小時;隨後將反應液倒至冰水中,並用乙酸乙酯萃取(15mL x 2)。合併有機相用飽和食鹽水(30mL)洗滌,無水硫酸鈉乾燥,過濾,濃縮。殘留物用矽膠柱層析(石油醚/乙酸乙酯=10/1,v/v)分離得到無色油狀物173a(100mg,收率:80.4%)。1H NMR(500MHz,DMSO-d6)δ 8.13(s,1H),7.93(s,1H),3.83(s,3H),2.44(s,3H).
從化合物173a和反式-4-氨基環己甲酸甲酯鹽酸鹽起,參照化合物72c的合成和化合物44的還原胺化得到化合物173c。MS(ESI):m/z 549.0(M+H)。
將鋅粉(44mg,0.67mmol)加至溶有化合物173c(74mg,0.13mmol)的醋酸(4mL)溶液;所得反應液在60℃條件下加熱攪拌2小時。反應液濃縮後加入乙酸乙酯(20mL)和飽和碳酸氫鈉溶液(20mL);有機相用無水硫酸鈉乾燥,濃縮後得到化合物173d。MS(ESI):m/z 519.0(M+H)。
從化合物173d,化合物INT-18和化合物INT-2起,依次參照化合物INT-7的Suzuki反應,化合物INT-3b的還原胺化反應以及化合物33的酯水解反應得到化合物173。1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.69(d,J=8.6Hz,1H),7.64(s,1H),7.55-7.46(m,4H),7.15(d,J=7.0Hz,1H),7.04(s,1H),6.98-6.96(m,2H),6.23(s,1H),5.60(s,2H),5.38(s,2H),3.86(s,3H),3.73(d,J=4.3Hz,2H),3.58-3.56(m,1H),3.42(s,2H),2.53-2.50(m,2H),2.34-2.30(m,1H),2.23(brs,1H),2.10-1.95(m,3H),2.03(s,3H),1.92-1.86(m,2H),1.77-1.71(m,2H),1.66-1.61(m,1H),1.32-1.18(m,4H);MS(ESI):m/z 787.8(M+H)。
測試實施例
細胞水準PD-1/PD-L1信號抑制的生物活性檢測
本檢測方法用於本發明所述化合物的細胞水準生物學活性評價。實驗原理
本檢測方法採用螢光素酶報告基因法檢測化合物對細胞水準PD-1/PD-L1信號抑制的生物活性。PD-1/NFAT-Reporter-Jurkat細胞穩定表達人PD-1,且表達由NFAT元件調控的螢光素酶報告基因;TCR activator/PD-L1-CHO細胞穩定表達人PD-L1和TCR啟動元件。當兩株細胞共培養時,PD-1/PD-L1的結合會抑制TCR信號通路,從而抑制下游NFAT控制的螢光素酶報告基因表達。當加入PD-1/PD-L1抗體或者抑制劑,這種抑制作用被反轉,螢光素酶表達,從而可以檢測PD-1/PD-L1抑制劑對螢光素酶活性影響。
實驗材料與設備
PD-1/NFAT-Reporter-Jurkat細胞(貨號60535)以及TCR
activator/PD-L1-CHO細胞(貨號60536)購自BPS Bioscience公司;PD-L1抗體(Atezolizumab,貨號A2004)購自Selleck公司;螢光素酶檢測試劑(ONE-GloTM Luciferase Assay System,貨號E6120)購自Promega公司;多功能微孔板檢測儀(型號SpectraMax i3x)購自Molecular Devices公司。
實驗主要過程
按常規細胞培養實驗操作流程培養PD-1/NFAT-Reporter-Jurkat細胞和TCR activator/PD-L1-CHO細胞。
收集TCR activator/PD-L1-CHO細胞並按照35000個/每孔,接種到96孔培養板中,培養基體積為100微升,37℃孵育過夜。第二天,棄去培養基,加入化合物孵育30分鐘,同時設置溶劑對照(二甲基亞碸,DMSO,終濃度0.1%)和PD-L1抗體(Atezolizumab,終濃度約10nM)陽性對照。再加入PD-1/NFAT-reporter-Jurkat細胞。繼續培養6小時後,按螢光素酶檢測試劑說明書檢測螢光素酶活性。
以PD-L1抗體作為陽性對照,計算測試化合物的PD-1/PD-L1結合抑制率(%)=(化合物處理孔化學發光值/溶劑對照孔化學發光值平均值-1)/(PD-L1抗體孔化學發光值平均值/溶劑對照孔化學發光值平均值-1)×100%。
根據上述檢測方法,對本發明所述化合物進行細胞水準生物學活性評價,活性結果見下表。
由上述結果可見,本發明的化合物可有效抑制PD-1/PD-L1,具有良好的PD-1/PD-L1抑制活性。
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