CN104341434A - Substituted rapamycin triazole derivative and application - Google Patents

Substituted rapamycin triazole derivative and application Download PDF

Info

Publication number
CN104341434A
CN104341434A CN 201410547357 CN201410547357A CN104341434A CN 104341434 A CN104341434 A CN 104341434A CN 201410547357 CN201410547357 CN 201410547357 CN 201410547357 A CN201410547357 A CN 201410547357A CN 104341434 A CN104341434 A CN 104341434A
Authority
CN
Grant status
Application
Patent type
Prior art keywords
1h
rapamycin
yl
triazole
3h
Prior art date
Application number
CN 201410547357
Other languages
Chinese (zh)
Other versions
CN104341434B (en )
Inventor
黄捷
谢立君
程元荣
李邦良
潘福生
李夸良
余辉
应加银
杨国新
金东伟
郑从燊
吕裕斌
Original Assignee
福建省微生物研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18Bridged systems

Abstract

The invention relates to a substituted rapamycin triazole derivative and application, and specifically relates to a compound of the formula I as shown in the specification, or pharmaceutically acceptable salts, solvates, isomers, esters and prodrugs of the compound, wherein in the formula I, the substituent groups X, R, R1 and n are all defined in the specification. The invention further relates to application of the compound of the formula I in preparing a medicine for treating and/or preventing cancer. The compound provided by the invention is excellent in biological activity.

Description

取代的雷帕霉素三氮唑衍生物和用途 Rapamycin substituted triazole derivatives and uses

技术领域 FIELD

[0001] 本发明属于医药技术领域,涉及新的雷帕霉素类衍生物、其光学活性体及其药学可接受的盐,特别是涉及一类取代的雷帕霉素三氮唑衍生物。 [0001] The present invention belongs to the field of medical technology, relates to novel rapamycin derivatives, an optically active substance and pharmaceutically acceptable salts thereof, in particular relates to a class of substituted triazole derivatives of rapamycin. 本发明还涉及它们的制备方法以及含有所述化合物的药物组合物。 The present invention further relates to a process for their preparation and pharmaceutical compositions containing said compounds. 本发明还涉及该衍生物用于制备治疗和/或预防癌症的药物中的用途。 The present invention further relates to the derivatives for the preparation of a medicament for the treatment and / or prevention of cancer. 技术背景 technical background

[0002] 癌症/恶性肿瘤严重危害人类健康,已成为一个全球性的健康问题,严重威胁人类的生命。 [0002] Cancer / malignancy serious harm to human health, has become a global health problem, a serious threat to human life. 2009年,WHO明确指出,癌症正成为人类最致命的"杀手",90%以上的恶性肿瘤尚无令人满意的治疗药物和措施。 In 2009, WHO made it clear that cancer is becoming mankind's most deadly "killer", more than 90% of cancer drugs and there is no satisfactory treatment measures. 目前每年全世界癌症病人约1000万,有760万人死亡; 我国癌症发病人数约200万,150万人死亡,已成为我国第二大致死疾病。 Currently cancer patients worldwide each year about 10 million, there are 7.6 million deaths; the number of cancer incidence of about 200 million and 150 million deaths, has become China's second largest killer diseases. 世界卫生组织预测,到2020年癌症将成为全球最大的公共卫生问题。 World Health Organization predicts that by 2020 cancer will become the world's largest public health problem. 抗肿瘤用药已成为全球第二大用药领域,2009年抗肿瘤用药市场达523. 72亿美元,仅次于心血管疾病的用药。 Anti-tumor drugs has become the world's second largest field of medicine, anti-tumor drug market in 2009 reached US $ 52.372 billion, second only to cardiovascular disease medication. 目前临床应用的传统抗癌药物主要有植物碱类、烷化剂类、抗生素类和激素类,绝大部分是细胞毒药物,选择性低、毒副作用很大,且易产生耐药性,疗效受到明显影响。 Traditional anti-cancer drugs currently in clinical use are mainly plant alkaloids, alkylating agents, antibiotics and hormones, the vast majority of cytotoxic agents, low selectivity, great side effects, and easy to produce drug resistance, efficacy significantly affected. 因此开发新的高效低毒的抗癌靶向药物已成为抗肿瘤药物研发的趋势。 Therefore, the development of new low toxicity anti-cancer targeted drugs has become a trend in the development of anticancer drugs. 近年来,分子靶向药物因具有针对性强、切实有效且毒副反应低等优点,已成为国内外肿瘤治疗领域研发的热点。 In recent years, due to molecular targeted drugs have targeted, and effective and low toxicity, has become a hot field of cancer treatment research and development at home and abroad. 其中哺乳动物雷帕霉素革巴位(mammaliantargetofrapamycin,mTOR)为最新发现的癌症治疗革巴位。 Wherein the mammalian rapamycin Gerba bit (mammaliantargetofrapamycin, mTOR) is a newly discovered cancer treatment Gerba bit.

[0003] 雷帕霉素(Rapamycin,RPM),又称为西罗莫司(Sirolimus),其化学结构式如下: [0003] Rapamycin (Rapamycin, RPM), also known as sirolimus (Sirolimus), whose chemical structure is as follows:

[0004] [0004]

Figure CN104341434AD00071

[0005] 如以上结构所示,本领域一般地对雷帕霉素进行母核结构进行标示,其中1-位为双键,28-位、43-位为羟基,本发明得到的新化合物是在43-羟基上取代的产物;另外,在某些文献中亦有将上述结构43-位标示为40-位的,本质上讲二者是相同的,只是标示方式的不同。 [0005] As shown in the above configuration, generally to the field of the present rapamycin core structure for labeling, wherein the 1-position is a double bond, 28-bit, 43-bit is hydroxy, novel compounds of the present invention is obtained on the 43 hydroxy-substituted product; Further, some documents in the above-described configuration also marked as 40-bit 43-bit, the two are essentially the same, but different ways of marking.

[0006] 替西罗莫司(Temsirolimus)是一种已在临床上使用的雷帕霉素类似物,替西罗莫司的化学结构式如下: [0006] temsirolimus (Temsirolimus) has been used in a clinical rapamycin analogue, for the chemical structural formula of sirolimus is as follows:

[0007] [0007]

Figure CN104341434AD00081

[0008] 已知雷帕霉素CAS登记号53123-88-9,分子式C51H79N013,分子量914. 17,从乙醚中得到的是无色结晶性固体,mp183-185°,[a]D25-58.2° (甲醇),溶于乙醚、氯仿、丙酮、甲醇和DMF,微溶于己烷和石油醚,不溶于水,小鼠LD50 (mg/kg)》600 (ip),>2, 500 ( 口服)(V6zina)。 [0008] Known rapamycin CAS Reg. No. 53123-88-9, molecular formula C51H79N013, molecular weight 914.17, is obtained from ether as a colorless crystalline solid, mp183-185 °, [a] D25-58.2 ° (methanol), dissolved in ether, chloroform, acetone, of DMF and methanol, slightly soluble in hexane and petroleum ether, water-insoluble, mouse LD50 (mg / kg) "600 (ip),> 2, 500 (oral) (V6zina).

[0009]Vezina等1975年报道从吸水链霉菌发酵液获得低毒性抗真菌抗生素雷帕霉素, 后经20余年的努力,成功地开发为新型强效免疫抑制剂。 [0009] Vezina et 1975 report to obtain low toxicity antifungal antibiotic rapamycin from the fermentation broth Streptomyces hygroscopicus, after 20 years of efforts, successfully developed for the new potent immunosuppressant. 雷帕霉素的免疫抑制活性比环孢素强数十倍,毒副作用比环孢素和FK506小。 Rapamycin immunosuppressive activity ten times stronger than the number of cyclosporine, FK506 side effects and less than cyclosporine. 它不仅用于器官移植的急性排斥反应,而且还能逆转正在进行的移植排斥反应;可以治疗各种自身免疫性疾病。 It is not only for acute rejection in organ transplants, but also to reverse the ongoing transplant rejection; can treat a variety of autoimmune diseases.

[0010] 雷帕霉素是由吸水链霉菌制得的大环三烯抗生素,它被发现在活体内和活体外均具有抗真菌活性,尤其是抗白色念珠菌[C.Vein等人J.Antibiot. 28,721 (1975); SNSega等人J.Antibiot. 28, 727 (1975) ;HABaker等人J.Antibiot. 31,539 (1978); 美国专利3, 929, 992 ;和美国专利3, 993, 749]。 [0010] Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus prepared, it is found in vivo and in vitro have antifungal activity, particularly against Candida albicans [C.Vein J. et al. . Antibiot 28,721 (1975); SNSega et al J.Antibiot 28, 727 (1975);. HABaker et al J.Antibiot 31,539 (1978);. U.S. Patent No. 3, 929, 992; and U.S. Patent No. 3, 993, 749]. 另外,雷帕霉素单独(美国专利4, 885, 171) 或与沙培林组合使用(美国专利4, 401,653)已表明具有抗肿瘤活性。 Additionally, rapamycin alone (U.S. Patent No. 4, 885, 171), or in combination with Sapylin (U.S. Patent No. 4, 401,653) have been shown to have antitumor activity.

[0011] 雷帕霉素的免疫抑制作用已被发现,环孢霉素A和FK-506(其他种大环分子)也表现出了作为免疫抑制剂的有效性,因此能用于防止移植排斥[RYCalne等人,Lancet1183(1978);和美国专利5, 100,899]。 [0011] The immunosuppressive effects of rapamycin have been found, cyclosporin A and FK-506 (other types of macrocyclic molecules) also showed effectiveness as an immunosuppressant, and thus can be used to prevent graft rejection [RYCalne et al., Lancet1183 (1978); and U.S. Patent No. 5, 100,899]. R.Martel等人[0&11,了.? R.Martel et al [0 & 11, a.? 1^8101· Pharmacol. 55,48(1977)]发现了雷帕霉素在实验性过敏性脑脊髓炎模型、多发性硬化模型、辅助关节炎模型、类风湿性关节炎模型中都有效;并且有效抑制类IgE抗体的形成。 . 1 ^ 8101 · Pharmacol 55,48 (1977)] found that rapamycin is effective in the experimental allergic encephalomyelitis model, model of multiple sclerosis, secondary arthritis model, rheumatoid arthritis model; and effectively inhibit the formation of IgE class antibodies.

[0012] 雷帕霉素也可以用来预防或治疗全身性红斑狼疮[美国专利5, 078, 999]、肺炎[美国专利5, 080, 899]、胰岛素依赖性糖尿病[美国专利5, 321,009]、皮肤病比如牛皮癣[美国专利5, 286, 730]、肠病[美国专利5, 286, 731]、平滑肌细胞增生和血管损伤后的内膜增厚[美国专利5, 288, 711和5, 516, 781]、成人T-细胞性白血病/淋巴瘤[欧洲专利申请525, 960A1]、眼炎症[美国专利5, 387, 589]、恶性癌病[美国专利5, 206, 018]、心炎症性疾病[美国专利5, 496, 832]、和贫血[美国专利5, 561,138]。 [0012] Rapamycin may be for preventing or treating systemic lupus erythematosus [U.S. Patent No. 5, 078, 999], pneumonia [U.S. Patent No. 5, 080, 899], insulin dependent diabetes mellitus [U.S. Patent No. 5, 321, 009], skin disorders such as psoriasis [U.S. Patent No. 5, 286, 730], bowel disorders [U.S. Patent No. 5, 286, 731], the intimal smooth muscle cell proliferation after vascular injury and thickening [U.S. Patent No. 5, 288, 711, and 5, 516, 781], T- cell adult leukemia / lymphoma [European Patent application No. 525, 960A1], ocular inflammation [U.S. Patent No. 5, 387, 589], malignant cancer [U.S. Patent No. 5, 206, 018], cardiac inflammatory disease [U.S. Patent No. 5, 496, 832], and anemia [U.S. Patent No. 5, 561,138].

[0013] 近年来,随着对雷帕霉素衍生物研究的不断深入,发现雷帕霉素及其衍生物具有抑制多种肿瘤生长的作用,对其作用机制研究表明,雷帕霉素及其衍生物都是通过与FKBP212蛋白生成复合物,此复合物与mTOR的FRB区域结合,抑制mTOR的功能,从而抑制下游相关因子的表达,促使细胞凋亡,发挥其独特的靶向抗肿瘤活性。 [0013] In recent years, along with the deepening of research of rapamycin derivatives, found that rapamycin and its derivatives can inhibit the growth of a variety of tumors, their mechanism of action studies showed that rapamycin and derivatives thereof are generated by FKBP212 protein complex, this complex binds to the FRB region of mTOR inhibition of mTOR function, thereby inhibiting expression of the downstream-related factors, induce apoptosis, to play its unique targeting antitumor activity .

[0014] 近年,已先后有多个雷帕霉素的化学半合成衍生物现已由FDA批准应用于癌症的治疗或用于临床试验,诺华公司(Novartis)研发的依维莫司于2009年被FDA批准用于晚期肾癌治疗。 [0014] In recent years, there have been multiple chemical semisynthetic derivatives of rapamycin has been approved by the FDA used in the treatment of cancer or clinical trials, Novartis (Novartis) developed everolimus in 2009 FDA-approved for the treatment of advanced kidney cancer. 惠氏制药(Wyeth)开发的替西罗莫司(CCI-779),已被FDA批准治疗晚期肾癌;Deferolimus为Ariad公司研发,无免疫抑制活性,现正处于临床试验。 Wyeth (Wyeth) developed temsirolimus (CCI-779), it has been approved by the FDA in patients with advanced kidney cancer; Deferolimus to Ariad research and development, non-immunosuppressive activity, is now in clinical trials.

[0015]mTOR是细胞内复杂的信号传导途径的中心,在细胞生长、增殖、细胞代谢、吞噬及血管形成中起关键作用。 [0015] mTOR complex intracellular signaling pathway centers, cell growth, proliferation, cell metabolism, plays a key role in phagocytosis and angiogenesis. mTOR抑制剂与FKBP12蛋白结合形成复合物抑制mTOR过度活化, 遏制核糖体的生物合成和蛋白质翻译,从而起到治疗肿瘤的作用。 mTOR inhibitor proteins binding to FKBP12 complex inhibits mTOR action form excessive activation, protein biosynthesis and contain ribosomes in translation, which play the treatment of tumors. mTOR抑制剂已作为重要的高效非细胞毒类靶向癌症治疗药物,目前作为mTOR抑制剂进行抗癌研究的有西罗莫司及其三个衍生物:替西罗莫司(temsirolimus,CCI-779)、依维莫司(everolimus,RAD001) 和AP23573(ridaforolimus)。 mTOR inhibitors have been targeted cancer therapy is an important and efficient non-cytotoxic, anti-cancer research mTOR inhibitors are currently used as sirolimus and its three derivatives: temsirolimus (temsirolimus, CCI- 779), everolimus (everolimus, RAD001) and AP23573 (ridaforolimus). 其中替西罗莫司是第一个被美国FDA批准上市的抗肿瘤的mTOR抑制剂,用于晚期肾细胞癌的治疗的孤儿药。 Wherein Temsirolimus was the first FDA approved for marketing in the U.S. antitumor mTOR inhibitor, an orphan drug for the treatment of advanced renal cell carcinoma.

[0016] 尽管人们在雷帕霉素及其衍生物的研究和临床应用方面已取得巨大成就,然而本领域技术人员仍然期待有更具临床应用价值的产品以为临床提供一种更理想的选择。 [0016] Although people have made great achievements in research and clinical application of rapamycin and its derivatives, however skilled in the art still expect more clinical value of clinical products that provide a more ideal choice.

发明内容 SUMMARY

[0017] 本发明的目的在于为临床提供一种更具应用价值的药物特别是雷帕霉素衍生物。 [0017] The object of the present invention is to provide a more clinical application of the drugs, particularly rapamycin derivative. 本发明人发现一系列的取代的雷帕霉素三氮唑衍生物,显示出对多种肿瘤细胞株具有强大的抗肿瘤活性和/或其它出人意料的优点。 The present inventors found that a series of substituted triazole derivatives of rapamycin, exhibit strong anti-tumor activity and / or other advantages of having a variety of tumor cell lines surprising. 本发明基于此发现而得以完成。 The present invention has been accomplished based on this finding.

[0018] 为此,本发明第一方面提供了以下式I化合物: [0018] To this end, a first aspect of the present invention provides a compound of the following formula I:

[0019] [0019]

Figure CN104341434AD00091

> 丄 > Shang

[0020] 或其药学可接受的盐、溶剂合物、异构体、酯、前药,其中, [0020] or a pharmaceutically acceptable salt, solvate, isomers, esters, prodrugs thereof, wherein

[0021] η为1、2或3; [0021] η is 1, 2 or 3;

[0022] 父为_|-或"一"; [0022] Father _ | - or "a";

[0023]R为氢、甲基、或(C「C4)烷基; [0023] R is hydrogen, methyl, or (C "C4) alkyl;

[0024]R1为(C1-C4)烷基氨基甲基_、苯胺基甲基_、或苯基_,其中苯基或者苯胺基甲基-上的苯环任选被1-4个相同或不同的R2基团取代; [0024] R1 is (C1-C4) alkyl aminomethyl _, _ methyl anilino, _ or phenyl, where the phenyl or anilino methyl - on the phenyl ring is optionally substituted with 1-4 same or different R2 groups;

[0025] 馬选自:氢、羟基、卤素、三氟甲基、三氟甲氧基、氨基、羧基、氰基、(C「C4)烷基、 (C1-C6)烧基、(C1-C4)烧氧基、(C1-C4)烯基、(C1-C4)炔基、N-(C1-C4)烧基氨基、N,N-二(C1-C4)烷基氨基、(C1-C4)烷基硫基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷氧基乙基、(C1-C4)烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、 N,N-二(C1-C4)烷基氨基甲酰基、(C1-C3)亚烷基二氧基。 [0025] Ma is selected from: hydrogen, hydroxy, halo, trifluoromethyl, trifluoromethoxy, amino, carboxy, cyano, (C "C4) alkyl, (C1-C6) group burning, (C1 C4) alkoxy burning, (C1-C4) alkenyl, (C1-C4) alkynyl, N- (C1-C4) burning group, N, N- two (C1-C4) alkylamino, (C1- C4) alkylthio, (C1-C4) alkylsulfinyl, (C1-C4) alkylsulfonyl, (C1-C4) alkoxymethyl, (C1-C4) alkoxy group, (C1-C4) alkyl group, carbamoyl, N- (C1-C4) alkylcarbamoyl, N, N- two (C1-C4) alkylcarbamoyl, (C1-C3) alkylene dioxy.

[0026] 根据本发明第一方面任一实施方案的化合物,其中所述(C1-C4)烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基。 [0026] The compounds of the first aspect of the present invention according to any one of the embodiments, wherein the (C1-C4) alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t butyl.

[0027] 根据本发明第一方面任一实施方案的化合物,其中所述卤素选自氟、氯、溴、碘。 [0027] The compounds of the first aspect of the present invention according to any one of the embodiments, wherein the halogen is selected from fluoro, chloro, bromo, iodo.

[0028] 根据本发明第一方面任一实施方案的化合物,其中所述包括(C1-C4)烷基部分的基团(例如(C1-C4)烷氧基中的(C1-C4)烷基、N-(C1-C4)烷基氨基中的(C1-C4)烷基等)中的(CfC4)烧基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基。 [0028] The compounds of the first aspect of the present invention according to any one of the embodiments, including wherein said (C1-C4) alkyl moiety (e.g., (C1-C4 (C1-C4) alkoxy) alkyl , N- (C1-C4) alkylamino (C1-C4) alkyl group (CfC4) selected from methyl burning) of ethyl, propyl, isopropyl, n-butyl, isobutyl, , t-butyl.

[0029] 根据本发明第一方面任一实施方案的化合物,其中R为氢、或甲基。 [0029] The compounds of the first aspect of the present invention to any one embodiment, wherein R is hydrogen or methyl.

[0030] 根据本发明第一方面任一实施方案的化合物,其中X为_|_5η为1。 [0030] The compounds of the first aspect of the present invention according to any one of the embodiments, wherein X is _ | _5η 1.

[0031] 根据本发明第一方面任一实施方案的化合物,其中X为"单键"(即X为"一"),η 为2或3 ; [0031] The compounds of the first aspect of the present invention according to any one of the embodiments, wherein X is a "bond" (i.e., X is "a"), [eta] is 2 or 3;

[0032] 根据本发明第一方面任一实施方案的化合物,其为选自下列的化合物或其药学可接受的盐、溶剂合物、异构体、酯、前药: [0032] The compounds of the first aspect of the present invention according to any one of the embodiments, which is selected from the group consisting of a compound or a pharmaceutically acceptable salt, solvate, isomers, esters, prodrugs:

[0033] 43-0- (2- (4- (4-氟苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素 [0033] 43-0- (2- (4- (4-fluorophenyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin

[0034] 43-0- (2- (4- (4-氯苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素 [0034] 43-0- (2- (4- (4-chlorophenyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin

[0035] 43-0- (2- (4- (4-甲基苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素 [0035] 43-0- (2- (4- (4-methylphenyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin

[0036] 43-0- (2- (4-(苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素 [0036] 43-0- (2- (4- (phenyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin

[0037] 43-0- (2- (4- (4-戊基苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素 [0037] 43-0- (2- (4- (4-pentylphenyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin

[0038] 43-0- (2- (4- (3-甲基苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素 [0038] 43-0- (2- (4- (3-methylphenyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin

[0039] 43-0- (2- (4- (2-氯苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素 [0039] 43-0- (2- (4- (2-chlorophenyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin

[0040] 43-0- (2- (4- (4-溴苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素 [0040] 43-0- (2- (4- (4-bromophenyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin

[0041] 43-0-(2-(4-(4-甲氧基苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素 [0041] 43-0- (2- (4- (4-methoxyphenyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin

[0042] 43-0-(2-(4-((2, 5二氯苯基)氨基甲基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素 [0042] 43-0- ((42--- ((2, 5-dichlorophenyl) aminomethyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin ADM

[0043] 43-0-(2-(4-((2, 4二氯苯基)氨基甲基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素 [0043] 43-0- (2- (4 - ((2, 4-dichlorophenyl) aminomethyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin ADM

[0044] 43-0-(2-(4-((2, 6二氟苯基)氨基甲基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素 [0044] 43-0- (2- (4 - ((2, 6-difluorophenyl) aminomethyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin ADM

[0045] 43-0-(2-(4-((2-氟苯基)氨基甲基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素 [0045] 43-0- ((42--- ((2-fluorophenyl) aminomethyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin

[0046] 43-0- (3- (4- (4-氟苯基)-1Η-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素 [0046] 43-0- (3- (4- (4-fluorophenyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0047] 43-0- (3- (4- (4-氯苯基)-1Η-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素 [0047] 43-0- (3- (4- (4-chlorophenyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0048] 43-0- (3- (4- (4-甲基苯基)-1Η-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素 [0048] 43-0- (3- (4- (4-methylphenyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0049] 43-0- (3- (4-苯基-1H-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素 [0049] 43-0- (3- (4-phenyl -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0050] 43-0- (3- (4- (3-甲基苯基)-1H-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素 [0050] 43-0- (3- (4- (3-methylphenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0051] 43-0- (3- (4- (2-氯苯基)-1H-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素 [0051] 43-0- (3- (4- (2-chlorophenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0052] 43-0- (3- (4- (4-溴苯基)-1H-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素 [0052] 43-0- (3- (4- (4-bromophenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0053] 43-0- (3- (4- (4-甲氧基苯基)-1H-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素 [0053] 43-0- (3- (4- (4-methoxyphenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0054] 43-0-(3-(4-((2, 5二氯苯基)氨基甲基)-1Η-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素 [0054] 43-0- ((43--- ((2, 5-dichlorophenyl) aminomethyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy Ray rapamycin

[0055] 43-0-(3-(4-((2, 4二氯苯基)氨基甲基)-1Η-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素 [0055] 43-0- (3- (4 - ((2, 4-dichlorophenyl) aminomethyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy Ray rapamycin

[0056] 43-0-(3-(4-((2, 6二氟苯基)氨基甲基)-1Η-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素 [0056] 43-0- (3- (4 - ((2, 6-difluorophenyl) aminomethyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy Ray rapamycin

[0057] 43-0-(3-(4-((2-氟苯基)氨基甲基)_1!1-1,2,3-三氮唑-1-基)正丙基)氧雷帕霉素 [0057] 43-0- (3- (4 -! ((2-fluorophenyl) aminomethyl) _1 1-1,2,3- triazole-1-yl) propyl) oxy-rapamycin ADM

[0058] 43-0- (2- (4- (4-氟苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素 [0058] 43-0- (2- (4- (4-fluorophenyl) -1H-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin

[0059] 43-0- (2- (4- (4-氯苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素 [0059] 43-0- (2- (4- (4-chlorophenyl) -1H-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin

[0060] 43-0-(2-(4-(4-甲基苯基)-1Η-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素 [0060] 43-0- (2- (4- (4-methylphenyl) -1Η-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin

[0061] 43-0-(2-(4-(苯基)-1Η-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素 [0061] 43-0- (2- (4- (phenyl) -1Η-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin

[0062] 43-0- (2- (4- (4-戊基苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素 [0062] 43-0- (2- (4- (4-pentylphenyl) -1H-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin

[0063] 43-0-(2-(4-(3-甲基苯基)-1Η-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素 [0063] 43-0- (2- (4- (3-methylphenyl) -1Η-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin

[0064] 43-0- (2- (4- (2-氯苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素 [0064] 43-0- (2- (4- (2-chlorophenyl) -1H-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin

[0065] 43-0- (2- (4- (4-溴苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素 [0065] 43-0- (2- (4- (4-bromophenyl) -1H-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin

[0066] 43-0-(2-(4-(4-甲氧基苯基)-1Η-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素 [0066] 43-0- (2- (4- (4-methoxyphenyl) -1Η-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin

[0067] 43-0-(2-(4-((2, 5二氯苯基)氨基甲基)-1Η-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素 [0067] 43-0- ((42--- ((2, 5-dichlorophenyl) aminomethyl) -1Η-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin ADM

[0068] 43-0-(2-(4-((2-氟苯基)氨基甲基)-1!1-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素 [0068] 43-0- (2- (4 -! ((2-fluorophenyl) methyl) -1 1-1,2,3- triazole-1-yl) acetyl) oxy rapamycin ADM

[0069] 43-0-(2-(4-(吡咯烷基-1-亚甲基)-1Η-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素 [0069] 43-0- (2- (4- (l-methyl-pyrrolidinyl) -1Η-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin

[0070] 43-0-(2-(4-(二乙氨基甲基2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素 [0070] 43-0- (2- (4- (2-diethylamino-methyl, 3-triazole-1-yl) acetyl) oxy rapamycin

[0071] 43-0-(2-(4-(4-氟苯基)-1Η-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素 [0071] 43-0- (2- (4- (4-fluorophenyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0072] 43-0- (2- (4- (4-氯苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素 [0072] 43-0- (2- (4- (4-chlorophenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0073] 43-0-(2-(4-(4-甲基苯基)-1Η-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素 [0073] 43-0- (2- (4- (4-methylphenyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0074] 43-0-(2-(4-(苯基)-1Η-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素 [0074] 43-0- (2- (4- (phenyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0075] 43-0- (2- (4- (4-戊基苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素 [0075] 43-0- (2- (4- (4-pentylphenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0076] 43-0-(2-(4-(3-甲基苯基)-1Η-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素 [0076] 43-0- (2- (4- (3-methylphenyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0077] 43-0- (2- (4- (2-氯苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素 [0077] 43-0- (2- (4- (2-chlorophenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0078] 43-0- (2- (4- (4-溴苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素 [0078] 43-0- (2- (4- (4-bromophenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0079] 43-0-(2-(4-(4-甲氧基苯基)-1Η-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素 [0079] 43-0- (2- (4- (4-methoxyphenyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin

[0080] 43-0-(2-(4-((2, 5二氯苯基)氨基甲基)-1Η-1,2, 3-三氮唑-1-基)异丙酰基) 氧雷帕霉素 [0080] 43-0- ((42--- ((2, 5-dichlorophenyl) aminomethyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy-Ray rapamycin

[0081] 43-0-(2-(4-((2, 4二氯苯基)氨基甲基)-1Η-1,2, 3-三氮唑-1-基)异丙酰基) 氧雷帕霉素 [0081] 43-0- (2- (4 - ((2, 4-dichlorophenyl) aminomethyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy-Ray rapamycin

[0082] 43-0-(2-(4-((2-氟苯基)氨基甲基)-1Η-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素 [0082] 43-0- ((42--- ((2-fluorophenyl) aminomethyl) -1Η-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin vegetarian

[0083] 本发明化合物本质上是雷帕霉素的43-羟基取代的衍生物,因此其名称可以仍然以雷帕霉素母核为准,以43-羟基上的取代基表述,S卩如上文所述的43-0-氧代的雷帕霉素。 [0083] The essence of the invention is a compound of rapamycin 43-hydroxy-substituted derivatives thereof, and therefore the name may still be subject to the rapamycin nucleus, to replace hydroxyl groups on the expression 43, S as Jie hereinabove rapamycin 43-0- oxo.

[0084] 根据本发明第一方面任一实施方案的化合物,其为下式所示化合物或其药学可接受的盐、溶剂合物、异构体、酯、前药: [0084] The compounds of the first aspect of the present invention according to any one of the embodiments, the compound is a pharmaceutically formula or a pharmaceutically acceptable salt, solvate, isomers, esters, prodrugs:

[0085] [0085]

Figure CN104341434AD00121

[0086] 并且该化合物是选自下表编号1-50的化合物,其中各化合物的X、R、札、η分别如下表所示: [0086] and the compound is selected from the compounds numbered 1 to 50 in the following table, wherein each compound X, R, Sapporo, [eta] are shown in the following table:

[0087] [0087]

Figure CN104341434AD00122

[0088] [0088]

Figure CN104341434AD00131

[0089] [0089]

Figure CN104341434AD00141

[0090] [0090]

Figure CN104341434AD00151

[0091] 进一步地,本发明第二方面提供了一种药物组合物,其中包括本发明第一方面任一实施方案所述化合物,以及任选的药学可接受的载体或辅料。 [0091] Further, a second aspect of the present invention, there is provided a pharmaceutical composition which comprises a first aspect of the present invention to any one embodiment of the compound, and optionally a pharmaceutically acceptable carrier or excipient. 根据此方面,本发明还涉及所述药物组合物作为用于预防或治疗肿瘤和/或癌症等疾病的药物中的应用。 According to this aspect, the present invention further relates to a pharmaceutical composition for use as a medicament for the prevention or treatment of tumor diseases and / or cancer.

[0092]进一步地,本发明第三方面提供了本发明第一方面任一实施方案所述化合物在制备用于预防或治疗肿瘤和/或癌症的药物中的用途。 [0092] Further, a third aspect of the present invention provides any of the first aspect of the present invention, an embodiment of the use of the compounds in tumor and / or cancer in the manufacture of a medicament for the prevention or treatment. 根据本发明的用途,其中所述肿瘤和/或癌症选自:肺癌、胰腺癌、食道癌、胃癌、宫颈癌、前列腺癌、白血病、肾癌。 The use according to the present invention, wherein the tumor and / or cancer selected from: lung cancer, pancreatic cancer, esophageal cancer, stomach cancer, cervical cancer, prostate cancer, leukemia, kidney cancer.

[0093]进一步地,本发明第四方面提供了预防和/或治疗肿瘤和/或癌症的方法,该方法包括向有此需要的受试者给予预防和/或治疗有效量的本发明第一方面的式I化合物。 [0093] Further, a fourth aspect of the present invention provides a method for the prevention and or tumor and / treating / or cancer, which method comprises administering to a subject in need of preventing the first and / or therapeutically effective amount of the present invention a compound of formula I aspects. [0094]进一步地,本发明第五方面提供了制备本发明第一方面任一实施方案所述化合物的方法,其包括以下步骤: [0094] Further, a fifth aspect of the present invention provides a process for preparing a first aspect of the present invention, any of the embodiments of the compound, which comprises the steps of:

[0095] 从以下化合物AI [0095] AI from the following compounds

Figure CN104341434AD00161

制备得到以下式A-2化合物: Preparation of Compound A-2 to give the following formula:

Figure CN104341434AD00162

[0096] 接着使A-2化合物与Rl芳基(例如苯基)取代的炔类化合物经五水硫酸酮和抗坏血酸钠反应得到式I化合物: [0096] compound A-2 then causes Rl and aryl (e.g. phenyl) substituted alkynyl compounds via one sulfate pentahydrate and sodium ascorbate to obtain a compound of formula I:

[0097] [0097]

Figure CN104341434AD00163

[0098] 任选地使式I化合物形成其药学可接受的盐、溶剂合物、异构体、酯、前药。 [0098] Optionally, the compound of formula I form pharmaceutically acceptable salts, solvates, isomers, esters, prodrugs. 其中各取代基如本发明第一方面任一实施方案所述。 Wherein the substituents are as in the first aspect of the present invention, any one of the embodiments.

[0099] 根据本发明第五方面的方法,其中,当X为"一",R为氢时,A-2化合物的制备方法为: [0099] According to the fifth aspect of the present invention, wherein, when X is "a", R is hydrogen, prepared as the compound A-2:

[0100] 以AI化合物为原料,与BI所示三氟甲磺酸酯化合物侧链反应得到B-2化合物: [0100] In the compound as a raw material AI, BI and triflate compound B-2 side chain obtained by reacting a compound represented by:

[0101] [0101]

Figure CN104341434AD00171

[0102] 接着使B-2化合物与叠氮化钠反应得到A-2化合物。 [0102] Next make B-2 compound with sodium azide to give compound A-2.

[0103] 根据本发明第五方面的方法,其中,当X为_|_时,A-2化合物的制备方法为: [0103] According to the fifth aspect of the present invention, wherein, when X is _ | _ when the preparation method of the compound A-2:

[0104] 以AI化合物为原料与三甲基氯硅烷反应,得到以下式CI化合物: [0104] In AI compound as raw materials and trimethylsilyl chloride, to give a compound of the following formula CI:

Figure CN104341434AD00172

[0105] 接着使CI化合物与式彳I的C-2化合物酯化,得到以下式C-3化合物: L· [0105] compound and then allowed CI esterifying a compound of formula C-2 I, left foot, to give a compound of the following formula C-3: L ·

Figure CN104341434AD00173

[0106] 接着使C-3化合物与叠氮化钠反应得到C-4化合物 [0106] Next make C-3 compound and sodium azide to give compound C-4

Figure CN104341434AD00181

[0107] 最后使C-4化合物脱保护得到A-2化合物。 [0107] and finally the C-4 compound deprotected to give compound A-2.

[0108] 本发明任一方面或该任一方面的任一项所具有的特征同样适用于其它任一方面或该其它任一方面的任一项,只要它们不会相互矛盾,当然在相互之间适用时,必要的话可对相应特征作适当修饰。 [0108] In one aspect of the present invention or any one of any one of any one of the possessed equally applicable to other features of any one or any of the other aspect of any one, so long as they do not contradict each other, in the course of each when inter applicable, if necessary, may be suitably modified for corresponding features. 在本发明中,例如,提及"本发明第一方面任一项"时,该"任一项" 是指本发明第一方面的任一子方面;在其它方面以类似方式提及时,亦具有相同含义。 In the present invention, for example, reference to "a first aspect of the present invention, any one of" the "any one" refers to any sub-aspect of the first aspect of the present invention; referred to hereafter in a similar manner in other respects, also It has the same meaning.

[0109] 下面对本发明的各个方面和特点作进一步的描述。 [0109] Various aspects and features of the present invention will be further described.

[0110] 本发明所引述的所有文献,它们的全部内容通过引用并入本文,并且如果这些文献所表达的含义与本发明不一致时,以本发明的表述为准。 Cited [0110] All documents of the present invention, the entire contents of which are incorporated herein by reference, and if the meaning expressed in these documents are inconsistent with the present invention, the present invention is subject to expression. 此外,本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。 In addition, various terms and phrases used in the present invention have the general meaning in the art known to the art, even so, still want the present invention herein in more detailed description and explanation of these terms and phrases, terms and phrases as mentioned there are inconsistent with the known meanings, subject to the meaning of the present invention is expressed.

[0111] 在本发明中,当X为"一"时,是指此处不存在基团,即表示X为化学键。 [0111] In the present invention, when X is "one", refers to the group does not exist here, it means that X is a bond.

[0112] 在本发明中,基团"(^-(;烷基"、"Ci_4烷基"、"(C「C4)烷基"等,它们具有相同含义, 均表示具有1-4个碳原子的直链或支链烷基。其它情况亦可作类似理解。 [0112] In the present invention, the group "(^ - (; alkyl", "Ci_4 alkyl", "(C" C4) alkyl "and the like, they have the same meaning and each is having 1-4 carbon a straight-chain or branched-chain alkyl group of atoms. other cases can be similarly understood.

[0113] 在本发明中,基团"Q_4烷基",包括其单独表述的、以及与其它基团组合存在的,例如可以选自Cp3烧基、Cp2烧基。 [0113] In the present invention, the group "Q_4 alkyl", including its individual expression, and the presence in combination with other groups, for example groups selected Cp3 burn, burn Cp2 is based. 同样地,Cp4烧氧基例如可以选自Cp3烧氧基、Cp2烧氧基。 Likewise, Cp4 burn burn Cp3 group may be selected from, for example, alkoxy, Cp2 burn group.

[0114] 在本发明合成式I化合物的方法中,反应所用的各种原材料是本领域技术人员根据已有知识可以制备得到的,或者是可以通过文献公知的方法制得的,或者是可以通过商业购得的。 [0114] In the method of synthesizing a compound of formula I of the present invention, various raw materials used in the reaction are skilled in the art can be prepared according to the prior knowledge, or may be prepared by literature known methods, or by commercially available. 以上反应方案中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术人员已有知识可以作适当改变的。 Used in the above reaction scheme intermediates, raw materials, reagents, reaction conditions, etc. may be suitably changed according to the prior art knowledge in the art can be made. 或者,本领域技术人员也可以根据本发明第五方面方法合成本发明未具体列举的其它式I化合物。 Alternatively, one skilled in the art can also be synthesized according to a fifth aspect of the present invention, the method of the present invention are not specifically exemplified other compound of Formula I.

[0115] 根据本发明,式I化合物的药用盐可以是酸加成盐或与碱形成的盐。 [0115] According to the present invention, pharmaceutically acceptable salts of compounds of formula I may be acid addition salts or salts with bases. 酸加成盐举例讲可以是无机酸盐例如但不限于盐酸盐、硫酸盐、磷酸盐、氢溴酸盐;或有机酸盐例如但不限于乙酸盐、草酸盐、柠檬盐、葡萄糖酸盐、琥珀酸盐、酒石酸盐、对甲苯磺酸盐、甲磺酸盐、苯甲酸盐、乳酸盐和马来酸盐;式I化合物与碱形成盐举例讲可以是碱金属盐例如但不限于锂、钠和钾盐;碱土金属盐例如但不限于钙和镁盐;有机碱盐例如但不限于二乙醇胺盐和胆碱盐等;或手性碱盐例如但不限于烷基苯基胺盐。 For example acid addition salts may be speaking, but not limited to, inorganic acid salts such as hydrochloride, sulfate, phosphate, hydrobromide; or organic acids such as, but not limited to, acetate, oxalate, citric salts, glucose , succinate, tartrate, p-toluenesulfonate, methanesulfonate, benzoate, lactate and maleate; compounds of formula I form salts with bases for example alkali metal salts such stresses may be but are not limited to, lithium, sodium and potassium; alkaline earth metal salts such as but not limited to calcium and magnesium; salts with organic bases such as but not limited to, diethanolamine and choline salts; salts or chiral bases such as but not limited to, alkyl amine salts.

[0116] 本发明的化合物的溶剂化物可以是水合物或包含其它的结晶溶剂如醇类例如乙醇。 Solvates invention [0116] The present compounds may be hydrates or comprising other solvents of crystallization such as alcohols such as ethanol.

[0117] 根据本发明,式I化合物可以存在顺/反异构体,本发明涉及顺式形式和反式形式以及这些形式的混合物。 [0117] According to the present invention, compounds of formula I can be present cis / trans isomers, the present invention relates to mixtures of these forms as well as the cis form and the trans form. 如果需要,单一立体异构体的制备可根据常规方法拆分混合物,或通过例如立体选择合成制备。 If desired, the preparation of a single stereoisomer mixture can be resolved according to conventional methods, for example, by stereoselective synthesis or preparation. 如果存在机动的氢原子,本发明也涉及式I化合物的互变异构形式。 If the motor is a hydrogen atom is present, the present invention also relates to tautomeric forms of the compounds of formula I.

[0118] 本发明因此还涉及含有作为活性成份的有效剂量的至少一种式I化合物,或其药用盐和/或其立体异构体以及常规药物赋形剂或辅剂的药物组合物。 [0118] The present invention therefore also relates to at least one compound of Formula I, or a pharmaceutically acceptable salt thereof and / or a stereoisomer thereof, and a pharmaceutical composition conventional pharmaceutical excipients or adjuvants comprising as an active ingredient an effective dose of. 通常本发明药物组合物含有〇. 1-90重量%的式I化合物和/或其生理上可接受的盐。 The present invention generally contain a pharmaceutical composition billion. 1-90% by weight of a compound of formula I or a pharmaceutically and / or physiologically salts. 药物组合物可根据本领域已知的方法制备。 The pharmaceutical composition can be prepared according to methods known in the art. 用于此目的时,如果需要,可将式I化合物和/或立体异构体与一种或多种固体或液体药物赋形剂和/或辅剂结合,制成可作为人用的适当的施用形式或剂量形式。 When used for this purpose, if desired, compounds of formula I and / or stereoisomer thereof with one or more solid or liquid pharmaceutical excipients and / or adjuvants in combination, can be made suitable for human use as administration form or dosage form.

[0119] 本发明的式I化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、肌肉、皮下、瘤内、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。 [0119] or a compound containing it may be administered in pharmaceutical compositions in unit dosage form, administration route may be intestinal or parenteral, such as oral, intramuscular, subcutaneous, intratumoral, intranasal, oral mucosa according to the present invention of formula I, skin, peritoneum or rectum. 给药剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、 口含片、栓剂、冻干粉针剂、注射剂等。 Administration forms such as tablets, capsules, dropping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agent, buccal tablets, suppositories, freeze-dried powder and injections. 可以是普通制剂、缓释制剂、控释制剂及各种微粒给药系统。 It may be an ordinary formulations, sustained release formulations, controlled release formulations and various particulate delivery systems. 为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载体。 To unit tableted dosage form, it may be widely known in the art using various carriers. 关于载体的例子是,例如稀释剂与吸收剂,如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等;湿润剂与粘合剂,如水、甘油、聚乙二醇、 乙醇、丙醇、淀粉楽、糊精、糖楽、蜂蜜、葡萄糖溶液、阿拉伯胶楽、明胶楽、羧甲基纤维素钠、 紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、海藻酸盐、琼脂粉、 褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂,例如季铵盐、十二烷基硫酸钠等;润滑剂,例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。 Examples of carriers are, for example, diluents and absorbents, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid aluminum and the like; wetting agent with a binder, such as water, glycerin, polyethylene glycol, ethanol, propanol, yue starch, dextrin, yue sugar, honey, glucose solution, acacia yue, yue gelatin, carboxymethyl cellulose sodium, shellac, methylcellulose, potassium phosphate, polyvinyl pyrrolidone and the like; disintegrants such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfonate, methyl cellulose, ethyl cellulose and the like; disintegration inhibitors such as sucrose, tristearin, cacao butter, hydrogenated oil; absorption enhancer agents such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants such as talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol and the like. 还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。 The tablets can be further coated tablets prepared, for example, sugar-coated tablets, film-coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets. 为了将给药单元制成丸剂,可以广泛使用本领域公知的各种载体。 For administration unit into pills, widely known in the art using various carriers. 关于载体的例子是,例如稀释剂与吸收剂,如葡萄糖、乳糖、淀粉、可可脂、 氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等;粘合剂如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。 Examples of carriers are, for example, diluents and absorbents, such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin , ethanol, honey, liquid sugar, rice paste or batter and the like; disintegrants such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose and the like. 为了将给药单元制成栓剂,可以广泛使用本领域公知的各种载体。 For administration unit into suppositories, widely known in the art using various carriers. 关于载体的例子是,例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶、半合成甘油酯等。 Examples of carriers are, for example polyethylene glycol, lecithin, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semisynthetic glycerides and the like. 为了将给药单元制成胶囊,将有效成分式I化合物或其立体异构体与上述的各种载体混合,并将由此得到的混合物置于硬的明明胶囊或软胶囊中。 For administration unit into capsules, the active ingredient is a compound of formula I or a stereoisomer mixed with the above various carriers, and the mixture thus obtained is obviously placed in a hard capsule or soft capsules. 也可将有效成分式I化合物或其立体异构体制成微囊剂,混悬于水性介质中形成混悬剂,亦可装入硬胶囊中或制成注射剂应用。 The active ingredient may also be a compound of formula I or isomers made into microcapsules, suspended to form a suspension in an aqueous medium, can be made into hard gelatin capsules or injections application perspective. 为了将给药单元制成注射用制剂,如溶液剂、乳剂、冻干粉针剂和混悬剂,可以使用本领域常用的所有稀释剂,例如,水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。 For administration unit into injection preparations, such as solutions, emulsions, suspensions and lyophilized powder can be used all diluents commonly used in the art, e.g., water, ethanol, polyethylene glycol, 1,3 - propylene glycol, ethoxylated isostearyl alcohols, oxidized isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like. 另外,为了制备等渗注射液, 可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还可以添加常规的助溶剂、 缓冲剂、PH调节剂等。 Further, to prepare isotonic injection, a suitable amount of sodium chloride can be added, glucose or glycerin in the injection preparation, in addition, may be added conventional solubilizers, buffers, PH adjusting agent.

[0120] 此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。 [0120] In addition, if desired, coloring agents may be added to the pharmaceutical formulation, preservatives, perfumes, flavors, sweeteners or other materials.

[0121] 本发明式I化合物,或其异构体的给药剂量取决于许多因素,例如所要预防或治疗疾病的性质和严重程度,患者或动物的性别、年龄、体重及个体反应,所用的具体化合物, 给药途径及给药次数等。 [0121] The present compounds of formula I, or an isomer dosage depends on many factors such as the desired prophylactic or therapeutic nature and severity of the patient or animal sex, age, weight, and response of the individual illness, used the particular compound, the route of administration and frequency of administration and the like. 上述剂量可以单一剂量形式或分成几个,例如二、三或四个剂量形式给药。 The above dosage may be a single dose or divided into several, for example, administration two, three or four dosage forms.

[0122] 本文所用的术语"组合物"意指包括包含指定量的各指定成分的产品,以及直接或间接从指定量的各指定成分的组合产生的任何产品。 [0122] As used herein, the term "composition" is intended to include each of the specified ingredients in the specified amounts comprising the product, and any product resulting directly or indirectly from combinations of the specified ingredients in the specified amounts.

[0123] 可改变本发明药物组合物中各活性成分的实际剂量水平,以便所得的活性化合物量能有效针对具体患者、组合物和给药方式得到所需的治疗反应。 [0123] Actual dosage levels may be varied each active ingredient in the pharmaceutical compositions of the present invention, the amount of active compound so obtained is effective for a particular patient, compositions and mode of administration to obtain the desired therapeutic response. 剂量水平须根据具体化合物的活性、给药途径、所治疗病况的严重程度以及待治疗患者的病况和既往病史来选定。 The dose level to be active, the route of administration of the particular compound, the severity of the condition being treated and the condition to be treated and prior medical history of the patient to select. 但是,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。 However, the present art is that practice, doses of the compound to a level below the requirements to obtain the desired therapeutic effect begins gradually increase the dosage until the desired effect is achieved.

[0124] 本发明的化合物可用于制备抗肿瘤药物。 Compound [0124] of the present invention may be used for preparing anti-tumor drugs. 所述肿瘤包括但不限定于黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔表皮癌、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌、膀胱癌、头颈部肿瘤、鼻咽癌、皮肤癌等恶性肿瘤和白血病。 The tumors include, but are not limited to melanoma, stomach cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral squamous carcinoma, cervical, ovarian, pancreatic, prostate, colon, bladder, head and neck cancer, nasopharyngeal cancer, skin cancer and leukemia and other malignant tumors. 所述的胃癌包括胃腺癌;所述的肺癌包括肺腺癌;所述的结肠癌包括结肠腺癌;所述的卵巢癌包括卵巢腺癌;所述的肾癌包括肾透明细胞腺癌;白血病包括急性淋巴细胞白血病、慢性白血病、特殊类型白血病。 The gastric cancer comprises gastric adenocarcinoma; the lung, including lung adenocarcinoma; colon adenocarcinoma of the colon comprising; the ovarian cancers include ovarian adenocarcinoma; the kidney, including renal clear cell adenocarcinoma; leukemia including acute lymphoblastic leukemia, chronic leukemia, particular types of leukemia.

[0125] 当用于上述治疗和/或预防或其他治疗和/或预防时,治疗和/或预防有效量的一种本发明化合物可以以纯形式应用,或者以药学可接受的酯或前药形式(在存在这些形式的情况下)应用。 [0125] When used in the above treatment and / or prophylaxis, or other therapeutic and / or prevention, treatment and / or prophylactically effective amount of a compound of the present invention, one may be applied in pure form, or a pharmaceutically acceptable ester or prodrug form (in the case where such forms exist) is applied. 或者,所述化合物可以以含有该目的化合物与一种或多种药物可接受赋形剂的药物组合物给药。 Alternatively, the compounds may be administered in a pharmaceutical composition of the object compound with one or more pharmaceutically acceptable excipients to contain. 词语"预防和/或治疗有效量"的本发明化合物指以适用于任何医学预防和/或治疗的合理效果/风险比治疗障碍的足够量的化合物。 The term "prevention and / or therapeutically effective amount" refers to a compound of the present invention is applicable to any reasonable effect of the treatment a sufficient amount of a compound of preventive medicine and / or / risk ratio treat the disorder. 但应认识到,本发明化合物和组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。 It will be appreciated that the total daily usage of the compounds and compositions of the present invention the attending physician to decide within the scope of sound medical judgment by him. 对于任何具体的患者,具体的治疗有效剂量水平须根据多种因素而定,所述因素包括所治疗的障碍和该障碍的严重程度;所采用的具体化合物的活性;所采用的具体组合物;患者的年龄、 体重、一般健康状况、性别和饮食;所采用的具体化合物的给药时间、给药途径和排泄率; 治疗持续时间;与所采用的具体化合物组合使用或同时使用的药物;及医疗领域公知的类似因素。 For any particular patient, specific therapeutically effective dose level shall depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet; time of administration of the particular compound employed, the route of administration, and rate of excretion; duration of the treatment; drugs used in combination with the particular compound employed or simultaneously; and medical like factors known in the art. 例如,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。 For example, the practice of the present art is, doses of the compound to a level below the requirements to obtain the desired therapeutic effect begins gradually increase the dosage until the desired effect is achieved. 一般说来,本发明式I化合物用于哺乳动物特别是人的剂量可以介于〇. 001〜l〇〇〇mg/kg体重/天,例如介于0. 01〜100mg/kg体重/天, 例如介于〇· 01〜l〇mg/kg体重/天。 In general, the present compounds of formula I to a mammal particularly a human dose may be between square. 001~l〇〇〇mg / kg body weight / day, for example between 0. 01~100mg / kg body weight / day, such as between square-01~l〇mg / kg body weight / day.

[0126] 除非另外指出,本发明所用的术语"烷基"以及包含碳原子数修饰的"烷基"以及包括这些"烷基"的基团组合中的"烷基"是指直链或支链的烷基,例如(C1-C4)烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基等;"亚烧基"是指直链或支链的亚烧基; "环烷基"是指取代或未取代的环烷基。 [0126] Unless otherwise indicated, as used herein, the term "alkyl" and "alkyl" include the carbon number of modifications and combinations of these groups comprising "alkyl" in the "alkyl" refers to straight or branched alkyl chains, for example (C1-C4) alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl and the like; "burning alkylene group" means a straight-chain or branched alkylene group burning; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl.

[0127] 本发明包括药物组合物,该组合物含有通式I的雷帕霉素类化合物、其旋光异构体、及其药学可接受的盐作为活性成分,以及药学可接受的赋型剂。 [0127] The present invention includes a pharmaceutical composition, the composition comprising a rapamycin compound of formula I, their optical isomers, and pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient . 所述药学可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。 The pharmaceutically acceptable excipient refers to any diluent can be used in the pharmaceutical art, adjuvants and / or carriers. 本发明的衍生物可以与其他活性成分组合使用,只要它们不产生其他不利的作用,例如过敏反应。 Derivatives of the invention may be used in combination with other active ingredients, provided they do not produce other adverse effects, such as allergic reactions.

[0128] 本发明的药物组合物可配制成若干种剂型,其中含有药学领域中常用的一些赋形齐U;例如,口服制剂(如片剂,胶囊剂,溶液或混悬液);可注射的制剂(如可注射的溶液或混悬液,或者是可注射的干燥粉末,在注射前加入注射用水可立即使用);局部制剂(例如软膏或溶液)。 [0128] The pharmaceutical compositions of the invention may be formulated into several dosage forms containing some common pharmaceutical field shaping homogeneous U; e.g., oral preparations (e.g., tablets, capsules, solutions or suspensions); Injectable formulation (e.g., injectable solution or suspension, or injectable dry powder, water for injection immediately prior to injection may be used); topical preparations (e.g. ointments or solutions).

[0129] 用于本发明药物组合物的载体是药学领域中可得到的常见类型,包括:口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂等;可注射制剂用的防腐剂、加溶剂、稳定剂等;局部制剂用的基质、稀释剂、润滑剂、防腐剂等。 [0129] carriers for the pharmaceutical compositions of the present invention are common types available in the pharmaceutical field, comprising: an oral formulation with binders, lubricants, disintegrants, co-solvents, diluents, stabilizers, suspending agents , no coloring, flavoring and the like; injectable formulation with preservatives, solubilizers, stabilizers and the like; topical formulation with a substrate, diluents, lubricants, preservatives and the like. 药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可将其配制成肠衣片剂。 The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenous, subcutaneous, intraperitoneal or topical) administration, if certain drugs are unstable under the conditions of the stomach, which may be formulated as enteric coated tablets.

[0130] 根据本发明的衍生物可作为活性成分用于制备治疗和/或预防各种癌症,本发明也提供治疗或预防上述疾病的方法,包括给予患有或易患有此病的病人治疗有效量的根据本发明的衍生物。 [0130] A method for treating and / or preventing a variety of cancers, the present invention also provides methods of treating or preventing the above diseases can be used as an active ingredient a derivative according to the present invention, comprises administering to a patient suffering from or susceptible treating disease an effective amount of a derivative according to the invention. 通式I的雷帕霉素类化合物用于患者的临床剂量必需依赖被治疗的主体、给药的具体途径、被治疗疾病的严重性而变化,而最佳剂量由治疗具体患者的医生确定。 Rapamycin compound of formula I for a patient required clinical dose dependent subject being treated, the particular route of administration, severity of the disease being treated varies, the optimal dose is determined by the physician treating a particular patient.

[0131] 本发明活性化合物可作为唯一的抗癌药物使用,或者可以与一种或多种其它抗肿瘤药物联合使用。 [0131] The active compounds of the present invention may be used as the sole anti-cancer drugs, or may be used in combination with one or more other anti-tumor drugs. 联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。 Combination therapy simultaneously, sequentially, or separated administration is achieved by the individual components of the treatment.

[0132] 本发明衍生物可以以立体异构体形式存在,这些立体异构形式可以是对映体或非对映体。 [0132] derivatives of the invention may exist in stereoisomeric forms, stereoisomeric forms which may be enantiomers or diastereomers. 本发明既涉及对映体或非对映体,也涉及它们各自的混合物,象非对映体一样,可按照自身已知的方法将外消旋形式分离成为立体异构的单一组分。 The present invention relates both to the enantiomers or diastereomers, and also to their respective mixtures, as diastereomers, as racemates may be separated stereoisomeric forms become a single component in accordance with a method known per se.

[0133] 此外,本发明还包括本发明衍生物的前药。 [0133] Further, the present invention also encompasses prodrugs of derivatives of the present invention. 依据本发明,前药是通式I的衍生物, 它们自身可能具有较弱的活性或甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。 According to the present invention, prodrugs are derivatives of the general formula I, which itself may have weaker activity or even no activity, but after administration, under physiological conditions (e.g., by metabolic, solvolysis or otherwise) is converted to the corresponding biologically active form.

[0134] 我们已发现本发明化合物体外具有抑制肿瘤细胞生长活性,因此,它可以用作制备治疗和/或预防癌症的药物。 [0134] We have found that the compounds of the present invention have in vitro tumor cell growth inhibiting activity, so that it can be used as a preparation for the treatment and / or prophylaxis of cancer. 尤其治疗乳腺、肺、结肠、直肠、胃、前列腺、膀胱、胰腺和卵巢的癌。 In particular, the treatment of breast, lung, colon, rectum, stomach, prostate, bladder, pancreas and ovarian cancer. 本发明化合物也被期望可以用于治疗其他细胞增生疾病如牛皮癣、良性前列腺肥大、动脉粥样硬化和再狭窄。 The compounds of this invention are also expected to be useful in the treatment of other cell proliferative disorders such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis. 另外预期本发明的雷帕霉素类化合物将具有抗白血病、恶性淋巴瘤和固体肿瘤如在组织如肝、肾、前列腺和胰腺中的癌和肉瘤范围的活性。 Also contemplated rapamycin compounds of the present invention will have anti-leukemia, malignant lymphoma, and solid tumors such as activity in liver tissue, kidney, prostate and pancreas carcinomas and sarcomas in the range.

[0135] 本发明活性化合物可作为唯一的抗癌药物使用,或者可以与一种或多种其它抗肿瘤药物联合使用。 [0135] The active compounds of the present invention may be used as the sole anti-cancer drugs, or may be used in combination with one or more other anti-tumor drugs. 联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。 Combination therapy simultaneously, sequentially, or separated administration is achieved by the individual components of the treatment.

[0136] 下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。 [0136] Examples are provided below further illustrate and Preparation Examples illustrate the compounds of this invention and their preparation. 应当理解,下述实施例和制备例的范围并不以任何方式限制本发明的范围。 It should be understood that the scope of the Examples and Preparation Examples below do not limit the scope of the present invention in any way.

[0137] 下面的合成路线描述了本发明的通式I化合物的一般性制备方法,所有的原料都是通过这些示意图中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。 [0137] The following general synthetic routes described in the preparation of compounds of the invention of general formula I, all raw materials by the methods described in these diagrams, prepared by methods well known to those of ordinary skill in organic chemistry or can be commercially purchase. 本发明的全部最终化合物都是通过这些示意图中描述的方法或通过与其类似的方法制备的,这些方法是有机化学领域普通技术人员熟知的。 All final compounds prepared by the process of the present invention are described by these diagrams or by methods analogous thereto, which are methods of organic chemistry well known to those of ordinary skill in the art. 这些示意图中应用的全部可变因数如下文的定义或如权利要求中的定义。 Defined herein or as defined in the claims all of these diagrams applied in variable factors are as follows.

[0138] 本发明化合物具有优异的生物学活性和药学性质。 Compound [0138] The present invention has an excellent biological activity and pharmaceutical properties. 例如采用自动吸附分析仪DVS-I仪器,测定本发明各实施例制备的水合物的吸湿性,并以雷帕霉素和替西罗莫司作对照。 E.g. automatic Sorption Analyzer DVS-I instrument measured hygroscopic hydrate prepared according to various embodiments of the present invention, and rapamycin and temsirolimus as control. 测定方法为:将约25mg的测试物料精确称重并置于样品盘中,将其暴露于相对湿度0〜 90%的湿度环境中;在0〜15%RH范围内采用1%RH梯度进行详细分析、在15〜90%RH 范围内采用15%RH梯度进行详细分析;分析温度为30°C,氮气流速为200立方厘米/min; 得到各化合物的吸湿等温线。 Detail using 1% RH gradient in the range of 0~15% RH; Approximately 25mg of test material was accurately weighed and placed in a sample pan, which was exposed to a relative humidity of 0~ 90% humidity: Determination of analysis, using in the range of 15~90% RH 15% RH gradient analyzed; analysis temperature was 30 ° C, nitrogen flow rate 200 cm3 / min; to give the respective compound hygroscopic isotherm. 结果显示,本发明全部化合物在0% -90%RH的范围内只吸收了低于0.3% (w/w)的水,而雷帕霉素和替西罗莫司吸水均大于0.8%,表明本发明化合物是不吸湿的,这是一种优良的原料药性质。 The results showed that all of the compounds of the present invention absorbs only water is less than 0.3% (w / w) in the range of 0% -90% RH, sirolimus rapamycin and 0.8% greater than for water absorption, showed compounds of the present invention is non-hygroscopic, which is an excellent drug properties.

[0139] 按照本发明的通式I衍生物,在路线A中,R、R,、X和η如发明内容所定义。 [0139] in accordance with the derivative of formula I of the present invention, in the route A, R, R ,, X The content and η defined herein.

Figure CN104341434AD00221

[0141] 将化合物AI经2-4步反应,生成叠氮化合物Α-2。 [0141] Step 2-4 Compound AI via reaction to produce azide Α-2. 将化合物Α-2与芳基炔类化合物经五水硫酸酮和抗坏血酸钠反应得到通式为I所示的衍生物。 Compound Α-2 acetylenic compound with an aryl derivative via one sulfate pentahydrate and sodium ascorbate reaction shown in formula I.

[0142] 其中,当X为"一",R为氢时,A-2根据路线B描述的方法制备:以AI为原料,与BI三氟甲磺酸酯侧链反应得到B-2,然后经与叠氮化钠反应得A-2。 [0142] wherein, when X is "a", where R is hydrogen, A-2 was prepared according to the method described in Scheme B: AI as a raw material in, the BI triflate reaction with side chains B-2, and then A-2 was reacted with sodium azide.

[01431 [01431

Figure CN104341434AD00222

[0144] 当X为_|__时,A-2根据路线C描述的方法制备:以AI为原料,经硅醚保护、酯化、叠氮化和脱保护得到A-2。 [0144] When X is _ | when __, A-2 was prepared according to the method described in Scheme C: The AI ​​as raw material, silyl ether protecting, esterification, and deprotection to give azide A-2.

[0145] [0145]

Figure CN104341434AD00231

[0146] 本发明制备方法简单,制备的化合物均具有显著的抗肿瘤活性。 [0146] The present production method is simple, the compounds prepared have significant anti-tumor activity.

[0147] 上述路线中,原料A-1,B-1,B-2,CI和C-2所示化合物可以通过有机化学领域普通技术人员熟知的方法制备或者可商购。 [0147] In the above scheme, starting material A-1, B-1, B-2, CI and C-2 shown in FIG compound may be prepared by the methods or commercially available to those of ordinary skill in organic chemistry art. 本发明制备方法简单,制备的化合物具有较好的抗肿瘤活性。 The preparation method is simple, the preparation of compounds having good antitumor activity.

具体实施方式 detailed description

[0148] 下面的具体实施例旨在阐述而不是限制本发明的范围。 [0148] The following specific examples are intended to illustrate and not limit the scope of the present invention.

[0149] 本发明中所制备化合物的核磁共振氢谱用Bruker ARX-300测定,质谱用Agilent 1100LC/MSD测定;所用试剂均为分析纯或化学纯。 [0149] The present invention is proton nuclear magnetic resonance spectrum of the compound prepared was measured by Bruker ARX-300, mass spectrometry using Agilent 1100LC / MSD; the reagents were of analytical grade or chemically pure.

[0150] 实施例I:43-0-(2-(4-(4-氟苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素(X-18) [0150] Example I: 43-0- (2- (4- (4- fluorophenyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy rapamycin ( X-18)

[0151] 步骤A:43-0-(2-溴乙基)_氧雷帕霉素的制备 Preparation of 43-0- (2-bromoethyl) rapamycin oxygen _: [0151] Step A

[0152] 将雷帕霉素(lOg, 10. 9mmol)、二异丙基乙胺(55mmol)加入到300mL的甲苯溶液中,加入2-溴乙基磺酸酯侧链(25g,98mmol),加毕,升温至6(TC反应3h。反应完毕后,将反应液冷却至室温,分别经稀盐酸、饱和碳酸氢钠和饱和食盐水中,有机层经无水硫酸钠干燥,蒸干得淡黄色固体,最后经柱层析分离得5. 2g白色固体,收率:46. 7%,1042. 5 (M+Na)+。 [0152] Rapamycin (lOg, 10. 9mmol), diisopropylethylamine (55mmol) was added to 300mL toluene solution was added 2-bromoethyl sulfonate ester side chain (25g, 98mmol), after addition, the temperature was raised to 6 (TC reaction 3h. after completion of the reaction, the reaction solution was cooled to room temperature, were treated with dilute hydrochloric acid, saturated sodium bicarbonate and saturated saline, the organic layer was dried over anhydrous sodium sulfate, and evaporated to dryness to give a pale yellow The solid was isolated by column chromatography and finally 5. 2g as a white solid, yield:.. 46 7%, 1042 5 (M + Na) +.

[0153] 步骤B:43-0-(2-叠氮乙基)-氧雷帕霉素的制备 [0153] Step B: 43-0- (2- azido-ethyl) - rapamycin production of oxygen

[0154] 分别将43-0-(2-溴乙基)_氧雷帕霉素(5. 2g, 5.Immol)和叠氮化钠(0.97g,15mmol)加入到(30mL)DMF溶液中,加入催化剂KI(0.lg),加料完毕后升温到50°C,反应完全后,将反应液倾入90mL水中,乙酸乙酯提取2次,合并提取液,水洗,无水硫酸钠干燥。 [0154] respectively, 43-0- (2-bromoethyl) _ oxygen rapamycin (5. 2g, 5.Immol) and sodium azide (0.97g, 15mmol) was added to (30mL) DMF solution , the catalyst was added KI (0.lg), after completion of the addition was warmed to 50 ° C, after completion of the reaction, the reaction solution was poured into 90mL water and extracted twice with ethyl acetate, the combined extracts washed with water, dried over anhydrous sodium sulfate. 蒸干得油状物,经柱层析分离分别得到2.lg,收率为41. 8%。 Evaporated to dryness to give an oil which was purified by column chromatography respectively 2.lg, yield 41.8%. MS(ESI)m/z:1005. 5(M+Na)+。 MS (ESI) m / z:. 1005 5 (M + Na) +.

[0155] 步骤C:43-0-(2-(4-(4-氟苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素的制备(X-18) [0155] Step C: (, 2- (4- (4- fluorophenyl) -1Η-1,2 3- triazole-1-yl) ethyl) Preparation of oxygen of rapamycin 43-0- (X-18)

[0156] 将43-0- (2-叠氮乙基)-氧雷帕霉素(0· 3mmoL, 0· 3g)和4-氟苯乙炔(0·Ig) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.05g)和五水硫酸铜(0.08g), 室温搅拌2h,反应完毕后,将反应倒加入40mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 15g,收率:45. 3%。 [0156] The 43-0- (2-azido-ethyl) - rapamycin oxygen (0 · 3mmoL, 0 · 3g) and 4-fluorophenyl acetylene (0 · Ig) was added to a DMF (IOmL) solution of , was added sodium ascorbate (0.05 g of) and copper sulfate pentahydrate (0.08 g of) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 40mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid by silica gel column chromatography and C18 preparative chromatography to give 0. 15g, yield pure product: 453%. MS(ESI)m/z: 1125. 7(M+Na)+〇1HNMR(500MHz,DMS0)δ8. 53 (s, 1H), 7. 87 (dd,J= 8. 7, 5. 5Hz, 2Η), 7. 28 (t,J= 8. 9Hz, 2Η), 6. 45 (s, 1Η), 6. 43-6. 32 (m, 1Η), 6. 26-6. 17 (m, 1 Η), 6. 16-6. 06 (m, 2Η), 5. 45 (dd,J= 14. 8, 9. 7Hz, 1Η), 5. 26 (d,J= 4. 5Hz, 1Η), 5. 09 (d,J =10. 2Hz, 1Η), 4. 99-4. 95 (m, 1Η), 4. 94-4. 89 (m, 1Η), 4. 53 (m, 1Η), 4. 06-3. 87 (m, 4Η), 3. 62 (m, 1Η), 3. 47-3. 38 (m, 1Η), 3. 29-3. 23 (m, 1Η), 3. 21 (s, 3Η), 3. 14 (s, 3Η), 3. 05 (s, 3Η),3· 02-2. 93 (m, 2Η),2· 83-2. 75 (m, 1Η),2· 75-2. 68 (m, 1Η),2· 43-2. 33 (m, 2Η),2· 25-2 • 15 (m,1Η),2· 10 (m,1Η),2· 06-1. 95 (m,1Η),1· 93-1. 77 (m,2Η),1· 73 (s,3Η),1· 62 (s,3 H),1.55(d,J= 39. 0Hz, 3Η),I. 45-1. 00(m, 9Η), 0. 98(d,J= 6. 5Ηζ, 3Η), 0. 87 (d,J= 6.5Hz,3H),0.81(d,J= 6.4Hz,3H),0.76(d,J= 6.7Hz,3H),0.72(d,J= 6·5Ηζ,3Η)。 MS (ESI) m / z:. 1125. 7 (M + Na) + 〇1HNMR (500MHz, DMS0) δ8 53 (s, 1H), 7. 87 (dd, J = 8. 7, 5. 5Hz, 2Η ), 7. 28 (t, J = 8. 9Hz, 2Η), 6. 45 (s, 1Η), 6. 43-6. 32 (m, 1Η), 6. 26-6. 17 (m, 1 Η), 6. 16-6. 06 (m, 2Η), 5. 45 (dd, J = 14. 8, 9. 7Hz, 1Η), 5. 26 (d, J = 4. 5Hz, 1Η), 5. 09 (d, J = 10. 2Hz, 1Η), 4. 99-4. 95 (m, 1Η), 4. 94-4. 89 (m, 1Η), 4. 53 (m, 1Η), 4. 06-3. 87 (m, 4Η), 3. 62 (m, 1Η), 3. 47-3. 38 (m, 1Η), 3. 29-3. 23 (m, 1Η), 3. 21 (s, 3Η), 3. 14 (s, 3Η), 3. 05 (s, 3Η), 3 · 02-2. 93 (m, 2Η), 2 · 83-2. 75 (m, 1Η) , 2 · 75-2. 68 (m, 1Η), 2 · 43-2. ​​33 (m, 2Η), 2 · 25-2 • 15 (m, 1Η), 2 · 10 (m, 1Η), 2 · 06-1. 95 (m, 1Η), 1 · 93-1. 77 (m, 2Η), 1 · 73 (s, 3Η), 1 · 62 (s, 3 H), 1.55 (d, J = 39. 0Hz, 3Η), I. 45-1. 00 (m, 9Η), 0. 98 (d, J = 6. 5Ηζ, 3Η), 0. 87 (d, J = 6.5Hz, 3H), 0.81 (d, J = 6.4Hz, 3H), 0.76 (d, J = 6.7Hz, 3H), 0.72 (d, J = 6 · 5Ηζ, 3Η). 13CNMR(126MHz,DMS0)δ210. 46, 207. 50, 198. 90, 169. 19, 166. 97, 145. 21, 139. 28, 137. 83,I 37. 13, 132. 32, 130. 42, 127. 48, 127. 03, 126. 97, 124. 89, 121. 61, 115. 87, 115. 70, 99. 00, 85 .51, 82. 38, 82. 23, 82. 15, 75. 73, 73. 60, 67. 64, 66. 18, 56. 91, 56. 64, 55. 45, 50. 73, 50. 22, 4 5. 18, 43. 47, 38. 16, 35. 62, 35. 16, 34. 79, 33. 33, 32. 13, 30. 79, 29. 62, 29. 47, 26. 41, 26. 21, 24. 44, 21. 63, 20. 35, 15. 55, 15. 52, 14. 66, 13. 41, 13. 35, 10. 44〇 13CNMR (126MHz, DMS0) δ210. 46, 207. 50, 198. 90, 169. 19, 166. 97, 145. 21, 139. 28, 137. 83, I 37. 13, 132. 32, 130. 42 , 127.48, 127.03, 126.97, 124.89, 121.61, 115.87, 115.70, 99.00, 85.51, 82.38, 82.23, 82.15, 75 73, 73.60, 67.64, 66.18, 56.91, 56.64, 55.45, 50.73, 50.22, 4 5.18, 43.47, 38.16, 35. 62, 35.16, 34.79, 33.33, 32.13, 30.79, 29.62, 29.47, 26.41, 26.21, 24.44, 21.63, 20.35, 15.55, 15.52, 14.66, 13.41, 13.35, 10. 44〇

[0157] 实施例2 :43-0-(2-(4-(4-氯苯基2, 3-三氮唑-1-基)乙基)氧雷帕霉素(Χ-48) [0157] Example 2: 43-0- (2- (4- (4-chlorophenyl 2, 3-triazole-1-yl) ethyl) oxy rapamycin (Χ-48)

[0158] 将43-0-(2-叠氮乙基)-氧雷帕霉素(0. 3mmoL, 0. 3g)和4-氯苯乙炔(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入40mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 17g,收率:50. 7%。 [0158] The 43-0- (2-azido-ethyl) - rapamycin oxygen (0. 3mmoL, 0. 3g) and 4-chlorophenyl acetylene (0.Ig) was added to a DMF (IOmL) solution of , was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 40mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 17g, yield: 507%. MS(ESI)m/ z:1141.6(M+Na)+。 MS (ESI) m / z: 1141.6 (M + Na) +. 1HNMR(500MHz,DMS0)S8.59(s,lH),7.85(d,J= 8.6Hz,2H),7.51(d,J =8. 6Hz, 2H), 6. 45 (s, 1H), 6. 43-6. 33 (m, 1H), 6. 24-6. 17 (m, 1H), 6. 15-6. 07 (m, 2H), 5. 45 ( dd,J= 14. 8, 9. 7Hz, 1H), 5. 26 (s, 1H), 5. 09 (d,J= 10. 2Hz, 1H), 4. 99-4. 95 (m, 1H), 4. 95- 4. 90 (m, 1H), 4. 56-4. 51 (m, 2H), 4. 03-3. 88 (m, 5H), 3. 63-3. 59 (m, 1H), 3. 46-3. 40 (m, 1H), 3 .29-3. 22 (m, 1H), 3. 20 (s, 3H), 3. 14 (s, 3H), 3. 05 (s, 3H), 3. 01-2. 90 (m, 2H), 2. 86-2. 68 (m, 2H),2. 44-2. 34 (m, 2H),2. 25-2. 16 (m, 1H),2. 13-2. 05 (m, 1H),2. 05-1. 95 (m, 2H),I. 94-1. 7 7 (m, 3H),I. 73 (s, 3H),I. 62 (s, 3H),I. 59-1. 00 (m, 10H), 0. 98 (d,J= 6. 5Hz, 3H), 0. 87 (d,J =6. 5Hz, 3H), 0. 81 (d,J= 6. 4Hz, 3H), 0. 76 (d,J= 6. 7Hz, 3H), 0. 72 (d,J= 6. 6Hz, 3H).13C NMR(126MHz,DMSO)δ210. 46, 207. 50, 198. 90, 169. 18, 166. 97, 144. 99, 139. 28, 137. 83, 137 .13, 132. 32, 132. 12, 130. 42, 129. 81, 128. 93, 126. 98, 126. 70, 124. 90, 122. 05, 99. 00, 85. 5 I, 82. 37, 82. 23, 82. 15, 75. 73, 73. 60, 1HNMR (500MHz, DMS0) S8.59 (s, lH), 7.85 (d, J = 8.6Hz, 2H), 7.51 (d, J = 8. 6Hz, 2H), 6. 45 (s, 1H), 6 . 43-6. 33 (m, 1H), 6. 24-6. 17 (m, 1H), 6. 15-6. 07 (m, 2H), 5. 45 (dd, J = 14. 8, 9. 7Hz, 1H), 5. 26 (s, 1H), 5. 09 (d, J = 10. 2Hz, 1H), 4. 99-4. 95 (m, 1H), 4. 95- 4. 90 (m, 1H), 4. 56-4. 51 (m, 2H), 4. 03-3. 88 (m, 5H), 3. 63-3. 59 (m, 1H), 3. 46- 3. 40 (m, 1H), 3 .29-3. 22 (m, 1H), 3. 20 (s, 3H), 3. 14 (s, 3H), 3. 05 (s, 3H), 3 . 01-2. 90 (m, 2H), 2. 86-2. 68 (m, 2H), 2. 44-2. 34 (m, 2H), 2. 25-2. 16 (m, 1H) , 2. 13-2. 05 (m, 1H), 2. 05-1. 95 (m, 2H), I. 94-1. 7 7 (m, 3H), I. 73 (s, 3H), I. 62 (s, 3H), I. 59-1. 00 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 5Hz, 3H ), 0. 81 (d, J = 6. 4Hz, 3H), 0. 76 (d, J = 6. 7Hz, 3H), 0. 72 (d, J = 6. 6Hz, 3H) .13C NMR ( 126MHz, DMSO) δ210. 46, 207. 50, 198. 90, 169. 18, 166. 97, 144. 99, 139. 28, 137. 83, 137 .13, 132. 32, 132. 12, 130. 42, 129. 81, 128. 93, 126. 98, 126. 70, 124. 90, 122. 05, 99. 00, 85. 5 I, 82. 37, 82. 23, 82. 15, 75. 73 , 73.60, 67. 61, 66. 18, 56. 91, 56. 63, 55. 45, 50. 72, 50. 26, 45. 18, 43. 48, 38. 15, 35. 61,35. 16, 34. 79, 33. 33, 32. 12, 30. 79, 29. 62, 29. 48, 26. 40, 26. 21,24•44, 21. 63, 20. 36, 15. 55, 15. 52, 14. 66, 13. 40, 13. 35, 10. 44。 67.61, 66.18, 56.91, 56.63, 55.45, 50.72, 50.26, 45.18, 43.48, 38.15, 35. 61,35. 16, 34. 79, 33. 33, 32. 12, 30. 79, 29. 62, 29. 48, 26. 40, 26. 21,24 • 44, 21. 63, 20. 36, 15. 55, 15. 52, 14.66, 13.40, 13.35, 10.44.

[0159] 实施例3 :43-0-(2-(4-(4-甲基苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素(X-15) [0159] Example 3: 43-0- (2- (4- (4-methylphenyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin (X-15)

[0160]将43-0-(2-叠氮乙基)-氧雷帕霉素(0. 3mmoL, 0. 3g)和4-甲基苯乙炔(0. Ig) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0. Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入40mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 13g,收率:39. 4%。 [0160] The 43-0- (2-azido-ethyl) - rapamycin oxygen (0. 3mmoL, 0. 3g) and 4-phenylacetylene (0. Ig) was added to a DMF (IOmL) was was added to the reaction mixture of sodium ascorbate (0. Ig) and copper sulfate pentahydrate (0.08 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 40mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 13g, yield: 394%. MS(ESI)m/ z:1121.8(M+Na)+。 MS (ESI) m / z: 1121.8 (M + Na) +. 1H NMR(500MHz,DMS0) S8.48(s,lH),7.71(d,J = 8.0Hz,2H),7.25(d,J =7. 9Hz,2H),6. 45 (s,1H),6. 38 (m,1H),6. 27-6. 16 (m,1H),6. 17-6. 06 (m,2H),5. 45 (dd, J = 13. 8, 10. 8Hz, 1H),5. 26 (s, 1H),5. 09 (d, J = 10. 4Hz, 1H),4. 97 (m, 1H),4. 93 (m, 1H) ,4. 59-4. 46 (m, 2H),4. 05-3. 86 (m, 4H),3. 62 (m, 1H),3. 50-3. 39 (m, 1H),3. 29-3. 23 (m,IH),3. 21 (s, 3H),3. 14 (s, 3H),3. 05 (s, 1H),2. 85-2. 75 (m, 1H),2. 76-2. 68 (m, 1H),2. 43-2. 34 (m, 2H),2. 33 (s, 3H),2. 28-2. 15 (m, 1H),2. 10 (m, 2H),2. 06-1. 95 (m, 1H),I. 96-1. 78(m ,2H),I. 73 (s, 3H),I. 62 (s, 3H),I. 61-1. 01 (m, 9H),0. 98 (d,J= 6. 5Hz, 3H),0. 87 (d,J= 6. 4Hz, 3H), 0· 81 (d,J= 6. 3Hz, 3H), 0· 76 (d,J= 6. 6Hz, 3H), 0· 73 (d,J= 6. 5Hz, 3H)。 1H NMR (500MHz, DMS0) S8.48 (s, lH), 7.71 (d, J = 8.0Hz, 2H), 7.25 (d, J = 7. 9Hz, 2H), 6. 45 (s, 1H), 6. 38 (m, 1H), 6. 27-6. 16 (m, 1H), 6. 17-6. 06 (m, 2H), 5. 45 (dd, J = 13. 8, 10. 8Hz , 1H), 5. 26 (s, 1H), 5. 09 (d, J = 10. 4Hz, 1H), 4. 97 (m, 1H), 4. 93 (m, 1H), 4. 59- 4. 46 (m, 2H), 4. 05-3. 86 (m, 4H), 3. 62 (m, 1H), 3. 50-3. 39 (m, 1H), 3. 29-3. 23 (m, IH), 3. 21 (s, 3H), 3. 14 (s, 3H), 3. 05 (s, 1H), 2. 85-2. 75 (m, 1H), 2. 76 -2. 68 (m, 1H), 2. 43-2. ​​34 (m, 2H), 2. 33 (s, 3H), 2. 28-2. 15 (m, 1H), 2. 10 (m , 2H), 2. 06-1. 95 (m, 1H), I. 96-1. 78 (m, 2H), I. 73 (s, 3H), I. 62 (s, 3H), I. 61-1. 01 (m, 9H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0 · 81 (d, J = 6 . 3Hz, 3H), 0 · 76 (d, J = 6. 6Hz, 3H), 0 · 73 (d, J = 6. 5Hz, 3H). 13C NMR(126MHz,DMSO)δ210. 46, 207. 51, 198. 90, 169. 18, 166. 97, 146. 13, 139. 28, 137. 83, 137 .13, 136. 96, 132. 32, 130. 42, 129. 40, 128. 15, 127. 00, 124. 95, 121. 26, 99. 00, 85. 51, 82. 36 ,82. 24, 82. 12, 75. 72, 73. 61, 67. 63, 66. 19, 56. 91, 56. 64, 55. 45, 50. 73, 50. 13, 45. 19, 43. 4 8, 38. 15, 35. 61, 35. 16, 34. 79, 33. 34, 32. 13, 30. 81, 29. 57, 29. 46, 26. 41, 26. 22, 24. 44, 21. 64, 20. 79, 20. 36, 15. 56, 15. 52, 14. 66, 13. 40, 13. 36, 10. 45〇 13C NMR (126MHz, DMSO) δ210. 46, 207. 51, 198. 90, 169. 18, 166. 97, 146. 13, 139. 28, 137. 83, 137 .13, 136. 96, 132. 32 , 130.42, 129.40, 128.15, 127.00, 124.95, 121.26, 99.00, 85.51, 82.36, 82.24, 82.12, 75.72, 73 61, 67.63, 66.19, 56.91, 56.64, 55.45, 50.73, 50.13, 45.19, 43.4 8 38.15, 35.61, 35. 16, 34.79, 33.34, 32.13, 30.81, 29.57, 29.46, 26.41, 26.22, 24.44, 21.64, 20.79, 20.36, 15.56, 15.52, 14.66, 13.40, 13.36, 10. 45〇

[0161] 实施例4 :43-0-(2-(4-(苯基2, 3-三氮唑-I-基)乙基)氧雷帕霉素(X-16) [0161] Example 4: 43-0- (2- (4- (2-phenyl, 3-triazole -I--yl) ethyl) oxy rapamycin (X-16)

[0162] 将43-0- (2-叠氮乙基)-氧雷帕霉素(0. 3mmoL, 0. 3g)和苯乙炔(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入40mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 23g,收率:70. 7%。 [0162] The 43-0- (2-azido-ethyl) - rapamycin oxygen (0. 3mmoL, 0. 3g) and phenylacetylene (0.Ig) was added to a DMF (IOmL) solution to the reaction was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 40mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 23g, yield: 707%. MS(ESI)m/ z: 1107. 3 (M+Na)+。 MS (ESI) m / z: 1107. 3 (M + Na) +. 1HNMR(500MHz,DMS0)δ8. 54 (s,1H),7. 83 (d,J= 7. 3Hz,2H),7. 44 (t,J =7. 7Hz,2H),7. 32 (m,1H),6. 45 (s,1H),6. 43-6. 33 (m,1H),6. 22 (m,1H),6. 16-6. 06 (m,2H), 5. 50-5. 42 (m, 1H),5. 25 (s, 1H),5. 09 (d,J= 9. 9Hz, 1H),4. 97 (m, 1H),4. 93 (m, 1H),4. 59-4. 47 (m, 2H),4. 06-3. 87 (m, 4H),3. 62 (m, 1H),3. 43 (m, 3. 6Hz, 1H),3. 30-3. 23 (m, 1H),3. 21 (s, 3 H),3. 14 (s, 3H),3. 05 (s, 3H),3. 02-2. 93 (m, 2H), 2. 84-2. 76 (m, 1H),2. 72 (m, 1H),2. 44-2. 31 (m, 2H),2. 22 (m, 1H),2. 15-2. 06 (m, 1H),2. 05-1. 96 (m, 1H),I. 94-1. 77 (m, 2H),I. 73 (s, 3H), I. 62 (s, 3H),I. 60-1. 00 (m, 10H),0. 98 (d,J= 6. 5Hz, 3H),0. 87 (d,J= 6. 4Hz, 3H),0. 81 (d,J=6. 3Hz, 2H),0· 76 (d,J= 6. 7Hz, 2H),0· 73 (d,J= 6. 5Hz, 3H)。 1HNMR (500MHz, DMS0) δ8. 54 (s, 1H), 7. 83 (d, J = 7. 3Hz, 2H), 7. 44 (t, J = 7. 7Hz, 2H), 7. 32 (m , 1H), 6. 45 (s, 1H), 6. 43-6. 33 (m, 1H), 6. 22 (m, 1H), 6. 16-6. 06 (m, 2H), 5. 50-5. 42 (m, 1H), 5. 25 (s, 1H), 5. 09 (d, J = 9. 9Hz, 1H), 4. 97 (m, 1H), 4. 93 (m, 1H), 4. 59-4. 47 (m, 2H), 4. 06-3. 87 (m, 4H), 3. 62 (m, 1H), 3. 43 (m, 3. 6Hz, 1H) , 3. 30-3. 23 (m, 1H), 3. 21 (s, 3 H), 3. 14 (s, 3H), 3. 05 (s, 3H), 3. 02-2. 93 ( m, 2H), 2. 84-2. 76 (m, 1H), 2. 72 (m, 1H), 2. 44-2. 31 (m, 2H), 2. 22 (m, 1H), 2 . 15-2. 06 (m, 1H), 2. 05-1. 96 (m, 1H), I. 94-1. 77 (m, 2H), I. 73 (s, 3H), I. 62 (s, 3H), I. 60-1. 00 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0 . 81 (d, J = 6. 3Hz, 2H), 0 · 76 (d, J = 6. 7Hz, 2H), 0 · 73 (d, J = 6. 5Hz, 3H). 13CNMR(126MHz,DMSO)δ2 10. 46, 207. 50, 198. 90, 169. 19, 166. 97, 146. 07, 139. 29, 137. 83, 137. 13, 132. 32, 130. 91,I 30. 42, 128. 86, 127. 70, 126. 98, 125. 01, 121. 68, 99. 00, 85. 51, 82. 37, 82. 23, 82. 13, 75. 72, 73. 61, 67. 63, 66. 18, 56. 91, 56. 64, 55. 45, 50. 73, 50. 18, 45. 19, 43. 48, 38. 15, 35. 61, 35. 16,34. 79, 33. 34, 32. 13, 30. 81, 29. 62, 29. 46, 26. 41, 26. 21, 24. 44, 21. 63, 20. 36, 15. 56, 15. 5 2, 14. 66, 13. 40, 13. 36, 10. 45〇 13CNMR (126MHz, DMSO) δ2 10. 46, 207. 50, 198. 90, 169. 19, 166. 97, 146. 07, 139. 29, 137. 83, 137. 13, 132. 32, 130. 91 , I 30. 42, 128. 86, 127. 70, 126. 98, 125. 01, 121. 68, 99. 00, 85. 51, 82. 37, 82. 23, 82. 13, 75. 72, 73.61, 67.63, 66.18, 56.91, 56.64, 55.45, 50.73, 50.18, 45.19, 43.48, 38.15, 35.61, 35. 16,34. 79, 33.34, 32.13, 30.81, 29.62, 29.46, 26.41, 26.21, 24.44, 21.63, 20.36, 15.56, 15.5 2 14.66, 13.40, 13.36, 10. 45〇

[0163] 实施例5 :43-0-(2-(4-(4-戊基苯基2, 3-三氮唑-1-基)乙基)氧雷帕霉素(X-17) [0163] Example 5: 43-0- (2- (4- (4-phenyl-2-pentyl, 3-triazole-1-yl) ethyl) oxy rapamycin (X-17)

[0164]将43-0-(2_叠氮乙基)-氧雷帕霉素(0.31111]1〇1^0.38)和4-正戊基苯乙炔(0.]^) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0. Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入40mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 09g,收率:27. 4%。 [0164] The 43-0- (2_ azidoethyl) - rapamycin oxygen (0.31111] 1〇1 ^ 0.38) and 4-n-pentyl phenyl acetylene (. 0] ^) was added to a DMF (IOmL ) was added sodium ascorbate (0. Ig) and copper sulfate pentahydrate (0.08 g of) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 40mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 09g, yield: 274%. MS(ESI)m/ z:1177.8(M+Na)+。 MS (ESI) m / z: 1177.8 (M + Na) +. 1H NMR (500MHz,DMS0)δ8.48(s,1H),7. 72(d,J=7. 7Hz,2H),7. 25(d,J =7. 6Hz,2H),6. 45(s,1H),6. 43-6. 34(m,1H),6. 25-6. 17(m,1H),6. 16-6. 07(m,2H),5. 45(dd, J = 14. 8, 9. 7Hz, 1H),5. 26 (d, J = 4. 3Hz, 1H),5. 09 (m, 1H),5. 00-4. 95 (m, 1H),4. 93m, 1H) ,4. 56-4. 48 (m, 2H),4. 04-3. 90 (m, 4H),3. 62 (m, 1H),3. 47-3. 40 (m, 1H),3. 21 (s, 3H),3. 14(s,3H),3. 05 (s, 3H),3. 02-2. 92 (m, 2H),2. 83-2. 77 (m, 1H),2. 75-2. 68 (m, 1H),2. 59 (m, 2H),2. 43-2. 33 (m, 2H),2. 26-2. 17 (m, 1H),2. 10 (m, 1H),2. 05-1. 96 (m, 1H),I. 94-1. 77 (m, 3H),I. 73 (s, 3H),I. 62 (s, 3H),I. 59-1. 00 (m, 15H),0. 97 (d,J= 6. 3Hz, 3H),0. 87 (s, 6H),0. 81 (d,J= 5. 9Hz, 4H),0· 76 (d,J= 6. 5Hz, 3H),0· 73 (d,J= 6. 3Hz, 3H)。 1H NMR (500MHz, DMS0) δ8.48 (s, 1H), 7. 72 (d, J = 7. 7Hz, 2H), 7. 25 (d, J = 7. 6Hz, 2H), 6. 45 ( s, 1H), 6. 43-6. 34 (m, 1H), 6. 25-6. 17 (m, 1H), 6. 16-6. 07 (m, 2H), 5. 45 (dd, J = 14. 8, 9. 7Hz, 1H), 5. 26 (d, J = 4. 3Hz, 1H), 5. 09 (m, 1H), 5. 00-4. 95 (m, 1H), 4. 93m, 1H), 4. 56-4. 48 (m, 2H), 4. 04-3. 90 (m, 4H), 3. 62 (m, 1H), 3. 47-3. 40 ( m, 1H), 3. 21 (s, 3H), 3. 14 (s, 3H), 3. 05 (s, 3H), 3. 02-2. 92 (m, 2H), 2. 83-2 . 77 (m, 1H), 2. 75-2. 68 (m, 1H), 2. 59 (m, 2H), 2. 43-2. ​​33 (m, 2H), 2. 26-2. 17 (m, 1H), 2. 10 (m, 1H), 2. 05-1. 96 (m, 1H), I. 94-1. 77 (m, 3H), I. 73 (s, 3H), I. 62 (s, 3H), I. 59-1. 00 (m, 15H), 0. 97 (d, J = 6. 3Hz, 3H), 0. 87 (s, 6H), 0. 81 ( d, J = 5. 9Hz, 4H), 0 · 76 (d, J = 6. 5Hz, 3H), 0 · 73 (d, J = 6. 3Hz, 3H). 13CNMR(126MHz,DMSO)δ210 .44, 207. 49, 198. 89, 169. 17, 166. 96, 146. 15, 141. 91, 139. 27, 137. 82, 137. 12, 132. 31, 130 .41, 128. 72, 128. 37, 126. 97, 124. 97, 121. 27, 98. 99, 85. 50, 82. 36, 82. 23, 82. 12, 75. 71, 73 .60, 67. 64, 66. 18, 56. 89, 56. 63, 55. 43, 50. 71, 50. 13, 45. 18, 43. 46, 38. 15, 35. 60, 35. 15, 3 4. 81, 33. 33, 32. 12, 30. 83, 30. 49, 29. 61, 29. 55, 29. 45, 26. 39, 26. 20, 24. 44, 21. 91, 21. 62, 20. 35, 15. 54, 15. 50, 14. 65, 13. 87, 13. 38, 13. 35, 10. 44〇 13CNMR (126MHz, DMSO) δ210 .44, 207. 49, 198. 89, 169. 17, 166. 96, 146. 15, 141. 91, 139. 27, 137. 82, 137. 12, 132. 31, 130.41, 128.72, 128.37, 126.97, 124.97, 121.27, 98.99, 85.50, 82.36, 82.23, 82.12, 75.71, 73. 60, 67.64, 66.18, 56.89, 56.63, 55.43, 50.71, 50.13, 45.18, 43.46, 38.15, 35.60, 35.15, 3 4.81, 33.33, 32.12, 30.83, 30.49, 29.61, 29.55, 29.45, 26.39, 26.20, 24.44, 21.91, 21 62, 20.35, 15.54, 15.50, 14.65, 13.87, 13.38, 13.35, 10. 44〇

[0165] 实施例6 :43-0-(2-(4-(3-甲基苯基2, 3-三氮唑-I-基)乙基)氧雷帕霉素(X-47) [0165] Example 6: 43-0- (2- (4- (3-phenyl-2, 3-triazole -I--yl) ethyl) oxy rapamycin (X-47)

[0166] 将43-0-(2-叠氮乙基)_氧雷帕霉素(0. 3mmoL, 0. 3g)和3-甲基苯乙炔(0.Ig) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g), 室温搅拌2h,反应完毕后,将反应倒加入40mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 13g,收率:39. 2%。 [0166] The 43-0- (2-azido-ethyl) _ oxygen rapamycin (0. 3mmoL, 0. 3g) and 3-methyl phenylacetylene (0.Ig) was added to a DMF (IOmL) was , the sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of) was added to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 40mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to give 0. 13g, yield pure product: 392%. MS(ESI) 7. 7Hz, 1H),7. 32 (t,J= 7. 6Hz, 1H),7. 14 (d,J= 7. 6Hz, 1H),6. 45 (s, 1H),6. 43-6. 33 (m,IH ),6. 25-6. 17 (m, 1H),6. 16-6. 07 (m, 2H),5. 45 (dd,J= 14. 9, 9. 6Hz, 1H),5. 26 (s, 1H),5. 09 ( d,J= 10. 2Hz, 1H),5. 01-4. 95 (m, 1H),4. 93 (t,J= 5. 9Hz, 1H),4. 56-4. 48 (m, 2H),4. 03-3. 89 (m, 5H),3. 66-3. 58 (m, 1H),3. 47-3. 39 (m, 1H),3. 28-3. 24 (m, 1H),3. 22 (s, 3H),3. 14 (s, 3 H),3. 05 (s, 3H),3. 02-2. 94 (m, 2H),2. 84-2. 68 (m, 2H),2. 44-2. 37 (m, 2H),2. 35 (s, 3H),2. 2 4-2. 20 (m, 1H),2. 13-2. 04 (m, 1H),2. 04-1. 95 (m, 2H),I. 94-1. 77 (m, 3H),I. 73 (s, 3H),I. 62 (s, 3H),I. 59-1. 01 (m, 10H),0. 97 (d,J= 6. 5Hz, 3H),0. 87 (d,J= 6. 5Hz, 3H),0. 81 (d,J= 6.4Hz,3H),0.76(d,J= 6.7Hz,3H),0.73(d,J= 6.6Hz,3H)Q13CNMR(126MHz,DMS0)S210. 46, 207. 50, 198. 90, 197. 22, 169. 18, 166. 97, 146. 16, 139. 28, 137. 96, 137. 82, 137. 13, 132. 32, 130. 83, 130. 42, 128. 75, 128. 34, 126. 99, 125. 56, 124. 91, 122. 19, 121. 60, 99. 00, 85. 52 ,82. 35, 82. 24, 82. 12, 75. 72, 73. 61, 67. MS (ESI) 7. 7Hz, 1H), 7. 32 (t, J = 7. 6Hz, 1H), 7. 14 (d, J = 7. 6Hz, 1H), 6. 45 (s, 1H), 6. 43-6. 33 (m, IH), 6. 25-6. 17 (m, 1H), 6. 16-6. 07 (m, 2H), 5. 45 (dd, J = 14. 9 , 9. 6Hz, 1H), 5. 26 (s, 1H), 5. 09 (d, J = 10. 2Hz, 1H), 5. 01-4. 95 (m, 1H), 4. 93 (t , J = 5. 9Hz, 1H), 4. 56-4. 48 (m, 2H), 4. 03-3. 89 (m, 5H), 3. 66-3. 58 (m, 1H), 3 . 47-3. 39 (m, 1H), 3. 28-3. 24 (m, 1H), 3. 22 (s, 3H), 3. 14 (s, 3 H), 3. 05 (s, 3H), 3. 02-2. 94 (m, 2H), 2. 84-2. 68 (m, 2H), 2. 44-2. 37 (m, 2H), 2. 35 (s, 3H) , 2. 2 4-2. 20 (m, 1H), 2. 13-2. 04 (m, 1H), 2. 04-1. 95 (m, 2H), I. 94-1. 77 (m , 3H), I. 73 (s, 3H), I. 62 (s, 3H), I. 59-1. 01 (m, 10H), 0. 97 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 5Hz, 3H), 0. 81 (d, J = 6.4Hz, 3H), 0.76 (d, J = 6.7Hz, 3H), 0.73 (d, J = 6.6Hz, 3H) Q13CNMR (126MHz, DMS0) S210. 46, 207. 50, 198. 90, 197. 22, 169. 18, 166. 97, 146. 16, 139. 28, 137. 96, 137. 82, 137. 13, 132.32, 130.83, 130.42, 128.75, 128.34, 126.99, 125.56, 124.91, 122.19, 121.60, 99.00, 85.52, 82.35, 82.24, 82.12, 75.72, 73.61, 67. 60, 66. 19, 56. 91, 56. 63, 55. 45, 50. 72, 50. 15, 45.I 9, 43. 48, 38. 16, 35. 60, 35. 16, 34. 79, 33. 34, 32. 30, 32. 13, 30. 81, 29. 62, 29. 57, 29. 45, 26. 40, 26. 21,24. 44, 21. 63, 21. 03, 20. 36, 15. 55, 15. 52, 14. 66, 13. 39, 13. 37, 10. 45。 60, 66. 19, 56. 91, 56. 63, 55. 45, 50. 72, 50. 15, 45.I 9, 43. 48, 38. 16, 35. 60, 35. 16, 34. 79 , 33.34, 32.30, 32.13, 30.81, 29.62, 29.57, 29.45, 26.40, 26. 21, 24. 44, 21.63, 21.03, 20 36, 15.55, 15.52, 14.66, 13.39, 13.37, 10.45.

[0167] 实施例7 :43-0-(2-(4-(2-氯苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素(X-49) [0167] Example 7: 43-0- (2- (4- (2-chlorophenyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy rapamycin ( X-49)

[0168] 将43-0-(2-叠氮乙基)-氧雷帕霉素(0.3臟〇1^0.38)和2-氯苯乙炔(0.18)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0. Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入40mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. llg,收率:33. 3%。 [0168] The 43-0- (2-azido-ethyl) - rapamycin oxygen (dirty 〇1 0.3 ^ 0.38) and 2-chlorophenyl acetylene (0.18) was added to a DMF (IOmL) solution to the reaction was added sodium ascorbate (0. Ig) and copper sulfate pentahydrate (0.08 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 40mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. llg, yield: 333%. MS(ESI)m/ z: 1141. 8 (M+Na)+。 MS (ESI) m / z: 1141. 8 (M + Na) +. 1H NMR (500MHz,DMS0) δ 8. 62 (s,1H),8. 06 (d,J = 7. 8Hz,1H),7. 56 (d,J =8. 0Hz, 1H),7. 48-7. 43 (m, 1H),7. 42-7. 36 (m, 1H),6. 45 (s, 1H),6. 43-6. 33 (m, 1H),6. 25-6. 17 (m, 1H),6. 16-6. 04 (m, 2H),5. 45 (dd, J = 14. 8, 9. 7Hz, 2H),5. 26 (s, 1H),5. 08 ( d, J = 10. 2Hz, 1H),4. 99-4. 95 (m, 1H),4. 95-4. 91 (m, 1H),4. 62-4. 56 (m, 2H),4. 03-3. 9 0 (m,5H),3. 65-3. 58 (m,1H),3. 47-3. 40 (m,1H),3. 29-3. 23 (m,1H),3. 20 (s,3H),3. 14(s ,3H),3. 05 (s,3H),2. 99-2. 92 (m,2H),2. 83-2. 69 (m,2H),2. 43-2. 33 (m,2H),2. 26-2. 15 (m, 1H),2. 13-2. 06 (m, 1H),2. 05-1. 95 (m, 2H),I. 94-1. 78 (m, 3H),I. 73 (s, 3H),I. 62 (s, 3H),I. 59-1. 00(m, 10H), 0. 97(d,J= 6. 5Hz, 3H),0. 87 (d,J= 6. 5Hz, 3H),0. 81 (d,J= 6. 4Hz, 3H),0· 76 (d,J= 6. 7Hz, 3H),0· 72 (d,J= 6. 7Hz, 3H)。 1H NMR (500MHz, DMS0) δ 8. 62 (s, 1H), 8. 06 (d, J = 7. 8Hz, 1H), 7. 56 (d, J = 8. 0Hz, 1H), 7. 48 -7. 43 (m, 1H), 7. 42-7. 36 (m, 1H), 6. 45 (s, 1H), 6. 43-6. 33 (m, 1H), 6. 25-6 . 17 (m, 1H), 6. 16-6. 04 (m, 2H), 5. 45 (dd, J = 14. 8, 9. 7Hz, 2H), 5. 26 (s, 1H), 5 . 08 (d, J = 10. 2Hz, 1H), 4. 99-4. 95 (m, 1H), 4. 95-4. 91 (m, 1H), 4. 62-4. 56 (m, 2H), 4. 03-3. 9 0 (m, 5H), 3. 65-3. 58 (m, 1H), 3. 47-3. 40 (m, 1H), 3. 29-3. 23 (m, 1H), 3. 20 (s, 3H), 3. 14 (s, 3H), 3. 05 (s, 3H), 2. 99-2. 92 (m, 2H), 2. 83- 2. 69 (m, 2H), 2. 43-2. ​​33 (m, 2H), 2. 26-2. 15 (m, 1H), 2. 13-2. 06 (m, 1H), 2. 05-1. 95 (m, 2H), I. 94-1. 78 (m, 3H), I. 73 (s, 3H), I. 62 (s, 3H), I. 59-1. 00 ( m, 10H), 0. 97 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 5Hz, 3H), 0. 81 (d, J = 6. 4Hz, 3H), 0 · 76 (d, J = 6. 7Hz, 3H), 0 · 72 (d, J = 6. 7Hz, 3H). 13CNMR(126MHz,DMSO)δ210 .51,207. 49, 198. 93, 169. 17, 166. 97, 142. 38, 139. 29, 137. 82, 137. 15, 132. 31,130. 41,130 .20, 129. 45, 129. 34, 129. 31, 127. 50, 126. 98, 124. 98, 124. 62,HO. 94, 99. 00, 85. 54, 82. 45 ,82. 25, 82. 13, 75. 70, 73. 61, 67. 72, 66. 19, 56. 93, 56. 65, 55. 45, 50. 69, 50. 22, 45. 18, 43. 4 6, 38. 14, 35. 59, 35. 17, 34. 79, 33. 35, 32. 12, 30. 82, 29. 57, 29. 52, 26. 41, 26. 21, 24. 44, 21. 64, 20. 35, 15. 55, 15. 51, 14. 65, 13. 41, 13. 34, 10. 45〇 13CNMR (126MHz, DMSO) δ210 .51,207. 49, 198. 93, 169. 17, 166. 97, 142. 38, 139. 29, 137. 82, 137. 15, 132. 31,130. 41, 130 .20, 129. 45, 129. 34, 129. 31, 127. 50, 126. 98, 124. 98, 124. 62, HO. 94, 99. 00, 85. 54, 82. 45, 82. 25, 82.13, 75.70, 73.61, 67.72, 66.19, 56.93, 56.65, 55.45, 50.69, 50.22, 45.18, 43.4. 6 , 38.14, 35.59, 35.17, 34.79, 33.35, 32.12, 30.82, 29.57, 29.52, 26.41, 26.21, 24.44, 21 64, 20.35, 15.55, 15.51, 14.65, 13.41, 13.34, 10. 45〇

[0169] 实施例8 :43-0-(2-(4-(4-溴苯基2, 3-三氮唑-I-基)乙基)氧雷帕霉素(X-50) [0169] Example 8: 43-0- (2- (4- (4-bromophenyl 2,3-triazole -I--yl) ethyl) oxy rapamycin (X-50)

[0170] 将43-0-(2-叠氮乙基)-氧雷帕霉素(0· 3mmoL, 0· 3g)和4-溴苯乙炔(0·Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入40mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 12g,收率:34. 4%。 [0170] The 43-0- (2-azido-ethyl) - rapamycin oxygen (0 · 3mmoL, 0 · 3g) and 4-bromophenyl acetylene (0 · Ig) was added to a DMF (IOmL) solution of , was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 40mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 12g, yield: 344%. MS(ESI)m/ z: 1186. 3 (M+Na)+。 MS (ESI) m / z: 1186. 3 (M + Na) +. 1HNMR(500MHz,DMS0)δ8. 60 (s,1H),7. 79 (d,J= 8. 5Hz,2H),7. 64 (d,J =8. 5Hz,2H),6. 45 (s,1H),6. 43-6. 34 (m,1H),6. 25-6. 18 (m,1H),6. 15-6. 07 (m,2H),5. 45 ( dd,J= 14. 7, 9. 7Hz, 1H),5. 26 (s, 1H),5. 08 (d,J= 10. 2Hz, 1H),4. 99-4. 95 (m, 1H),4. 95- 4. 90 (m, 1H),4. 57-4. 50 (m, 2H),4. 05-3. 89 (m, 5H),3. 64-3. 59 (m, 1H),3. 46-3. 40 (m, 1H),3 .29-3. 23 (m, 1H),3. 20 (s, 3H),3. 14 (s, 3H),3. 05 (s, 3H),3. 01-2. 90 (m, 2H),2. 83-2. 68 (m, 2H),2. 45-2. 33 (m, 2H),2. 25-2. 16 (m, 1H),2. 13-2. 07 (m, 1H),2. 06-1. 94 (m, 2H),I. 94-1. 7 7 (m, 3H),I. 73 (s, 3H),I. 62 (s, 3H),I. 58-1. 01 (m, 10H),0. 98 (d,J= 6. 5Hz, 3H),0. 87 (d,J =6. 5Hz, 3H),0. 81 (d,J= 6. 4Hz, 3H),0. 76 (d,J= 6. 7Hz, 3H),0. 72 (d,J= 6. 6Hz, 3H).13C NMR(126MHz,DMSO)δ210. 46, 207. 50, 198. 90, 188. 64, 169. 18, 166. 97, 145. 02, 139. 28, 137 .83, 137. 13, 132. 32, 131. 84, 130. 42, 130. 16, 126. 99, 124. 89, 122. 07, 120. 64, 99. 00, 85. 5 0, 82. 37, 82. 23, 82. 14, 75. 72, 73. 60, 6 1HNMR (500MHz, DMS0) δ8. 60 (s, 1H), 7. 79 (d, J = 8. 5Hz, 2H), 7. 64 (d, J = 8. 5Hz, 2H), 6. 45 (s , 1H), 6. 43-6. 34 (m, 1H), 6. 25-6. 18 (m, 1H), 6. 15-6. 07 (m, 2H), 5. 45 (dd, J = 14. 7, 9. 7Hz, 1H), 5. 26 (s, 1H), 5. 08 (d, J = 10. 2Hz, 1H), 4. 99-4. 95 (m, 1H), 4 . 95- 4. 90 (m, 1H), 4. 57-4. 50 (m, 2H), 4. 05-3. 89 (m, 5H), 3. 64-3. 59 (m, 1H) , 3. 46-3. 40 (m, 1H), 3 .29-3. 23 (m, 1H), 3. 20 (s, 3H), 3. 14 (s, 3H), 3. 05 (s , 3H), 3. 01-2. 90 (m, 2H), 2. 83-2. 68 (m, 2H), 2. 45-2. 33 (m, 2H), 2. 25-2. 16 (m, 1H), 2. 13-2. 07 (m, 1H), 2. 06-1. 94 (m, 2H), I. 94-1. 7 7 (m, 3H), I. 73 ( s, 3H), I. 62 (s, 3H), I. 58-1. 01 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 5Hz, 3H), 0. 81 (d, J = 6. 4Hz, 3H), 0. 76 (d, J = 6. 7Hz, 3H), 0. 72 (d, J = 6. 6Hz, 3H ) .13C NMR (126MHz, DMSO) δ210. 46, 207. 50, 198. 90, 188. 64, 169. 18, 166. 97, 145. 02, 139. 28, 137 .83, 137. 13, 132 32, 131.84, 130.42, 130.16, 126.99, 124.89, 122.07, 120.64, 99.00, 85.5 0 82.37, 82.23, 82. 14, 75.72, 73.60, 6 7. 60, 66. 18, 56. 91, 56. 63, 55. 45, 50. 73, 50. 27, 45. 19, 43. 47, 38. 15, 35. 61, 35. 16, 34. 79, 33. 33, 32. 12, 30. 79, 29. 57, 29. 47, 26. 40, 26. 21, 24 • 44, 21. 64, 20. 36, 15. 56, 15. 52, 14. 66, 13. 40, 13. 36, 10. 45。 7.60, 66.18, 56.91, 56.63, 55.45, 50.73, 50.27, 45.19, 43.47, 38.15, 35.61, 35.16, 34. 79, 33. 33, 32. 12, 30. 79, 29. 57, 29. 47, 26. 40, 26. 21, 24 • 44, 21. 64, 20. 36, 15. 56, 15. 52, 14.66, 13.40, 13.36, 10.45.

[0171] 实施例9 :43-0-(2-(4-(4-甲氧基苯基)-1Η-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素(X-67) [0171] Example 9: 43-0- (2- (4- (4-methoxyphenyl) -1Η-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin Su (X-67)

[0172] 将43-0-(2-叠氮乙基)_氧雷帕霉素(0. 3mmoL,0. 3g)和4-甲氧基苯乙炔(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0. 08g),室温搅拌2h,反应完毕后,将反应倒加入40mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 10g,收率: 30.3 %。 [0172] The 43-0- (2-azido-ethyl) _ oxygen rapamycin (0. 3mmoL, 0. 3g) and 4-methoxyphenylacetylene (0.Ig) was added to a DMF (IOmL) was added to the reaction mixture of sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0. 08g), room temperature and stirred for 2h, after completion of the reaction, the reaction was poured 40mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to give 0. 10g, yield of the pure product: 30.3%. MS(ESI)m/z:1137.5(M+Na)+。 MS (ESI) m / z: 1137.5 (M + Na) +. 1HNMR(500MHz,DMS0)S8.43(s,lH),7.75(d,J= 8. 6Hz,2H),7· 01 (d,J= 8. 6Hz,2H),6· 45 (s,1H),6· 43-6. 32 (m,1H),6· 25-6. 18 (m,2H),6 .16-6. 07 (m, 2H), 5. 46 (dd,J= 14. 7, 9. 6Hz, 1H), 5. 27 (s, 1H), 5. 12-5. 06 (m, 1H), 5. 01-4 .94 (m, 1H), 4. 95-4. 90 (m, 1H), 4. 56-4. 47 (m, 2H), 4. 04-3. 88 (m, 4H), 3. 79 (s, 3H), 3. 65-3 .58 (m, 1H), 3. 47-3. 40 (m, 1H), 3. 40-3. 29 (m, 2H), 3. 22 (s, 3H), 3. 14 (s, 3H), 3. 05 (s, 3H), 2. 83-2. 76 (m, 1H),2. 74-2. 71 (m, 1H),2. 43-2. 33 (m, 2H),2. 25-2. 17 (m, 1H),2. 14-2. 05(m ,1H),2. 05-1. 96 (m,2H),I. 94-1. 77 (m,3H),I. 73 (s,3H),I. 62 (s,3H),I. 56-1. 00 (m,10H) ,0. 98 (d,J= 6. 4Hz, 3H), 0. 87 (d,J= 6. 4Hz, 3H), 0. 82 (d,J= 6. 3Hz, 3H), 0. 76 (d,J= 6. 6Hz, 3H), 0· 73(d,J= 6. 5Hz, 3H)。 1HNMR (500MHz, DMS0) S8.43 (s, lH), 7.75 (d, J = 8. 6Hz, 2H), 7 · 01 (d, J = 8. 6Hz, 2H), 6 · 45 (s, 1H ), 6 · 43-6. 32 (m, 1H), 6 · 25-6. 18 (m, 2H), 6 .16-6. 07 (m, 2H), 5. 46 (dd, J = 14 . 7, 9. 6Hz, 1H), 5. 27 (s, 1H), 5. 12-5. 06 (m, 1H), 5. 01-4 .94 (m, 1H), 4. 95-4 . 90 (m, 1H), 4. 56-4. 47 (m, 2H), 4. 04-3. 88 (m, 4H), 3. 79 (s, 3H), 3. 65-3 .58 (m, 1H), 3. 47-3. 40 (m, 1H), 3. 40-3. 29 (m, 2H), 3. 22 (s, 3H), 3. 14 (s, 3H), 3. 05 (s, 3H), 2. 83-2. 76 (m, 1H), 2. 74-2. 71 (m, 1H), 2. 43-2. ​​33 (m, 2H), 2. 25-2. 17 (m, 1H), 2. 14-2. 05 (m, 1H), 2. 05-1. 96 (m, 2H), I. 94-1. 77 (m, 3H), I. 73 (s, 3H), I. 62 (s, 3H), I. 56-1. 00 (m, 10H), 0. 98 (d, J = 6. 4Hz, 3H), 0. 87 ( d, J = 6. 4Hz, 3H), 0. 82 (d, J = 6. 3Hz, 3H), 0. 76 (d, J = 6. 6Hz, 3H), 0 · 73 (d, J = 6 . 5Hz, 3H). 13CNMR(126MHz,DMSO)δ210. 46, 207. 50, 198. 90, 169 .19, 166. 97, 158. 88, 146. 01,139. 29, 137. 83, 137. 13, 132. 32, 130. 42, 126. 98, 126. 35, 124 .90, 123. 52, 120. 73, 114. 27, 99. 00, 85. 50, 82. 37, 82. 24, 82. 13, 75. 72, 73. 61, 67. 66, 66.I 9, 56. 91, 56. 66, 55. 45, 55. 10, 50. 73, 50. 11, 45. 19, 43. 48, 38. 17, 35. 62, 35. 16, 34. 79, 33. 34, 32. 14, 30. 81, 29. 56, 26. 40, 26. 21, 24. 45, 21. 63, 20. 36, 15. 56, 15. 52, 14. 66, 13. 40, 13 • 36,10. 45〇 13CNMR (126MHz, DMSO) δ210. 46, 207. 50, 198. 90, 169 .19, 166. 97, 158. 88, 146. 01,139. ​​29, 137. 83, 137. 13, 132. 32, 130.42, 126.98, 126.35, 124.90, 123.52, 120.73, 114.27, 99.00, 85.50, 82.37, 82.24, 82.13, 75. 72, 73. 61, 67. 66, 66.I 9, 56. 91, 56. 66, 55. 45, 55. 10, 50. 73, 50. 11, 45. 19, 43. 48, 38. 17 , 35.62, 35.16, 34.79, 33.34, 32.14, 30.81, 29.56, 26.40, 26.21, 24.45, 21.63, 20.36, 15 . 56, 15. 52, 14. 66, 13. 40, 13 • 36,10. 45〇

[0173] 实施例10 :43-0-(2-(4-((2, 5二氯苯基)氨基甲基2, 3-三氮唑-I-基) 乙基)氧雷帕霉素(X-14) [0173] Example 10: 43-0- (2- (4 - ((2, 5-dichlorophenyl) aminomethyl 2, 3-triazole -I--yl) ethyl) oxy-rapamycin (X-14)

[0174] 将43-0- (2-置氣乙基)-氧雷帕霉素(0· 3mmoL, 0· 3g)和N-(丙块基)-2, 5- _. 氯苯胺(〇.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0. 08g),室温搅拌2h,反应完毕后,将反应倒加入40mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0.llg,收率: 31.1 %。 [0174] The 43-0- (2-ethyl opposing gas) - rapamycin oxygen (0 · 3mmoL, 0 · 3g) and N- (prop-block-yl) -2, 5-chloro-aniline _ (square. .ig) was added to a DMF (IOmL) was added sodium ascorbate (0.Ig) to the reaction solution and copper sulfate pentahydrate (0. 08g), room temperature and stirred for 2h, after completion of the reaction, the reaction was poured added 40mL of water, precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0.llg, yield: 31.1%. MS(ESI)m/z:1205.6(M+Na)+。 MS (ESI) m / z: 1205.6 (M + Na) +. 1HNMR(500MHz,DMS0)S7.91(s,lH),7.24(d,J= 8. 3Hz, 1H),6. 78 (s, 1H),6. 58 (d,J= 8. 3Hz, 1H),6. 45 (s, 1H),6. 44-6. 35 (m, 1H),6. 26-6.I 8 (m, 2H),6. 17-6. 08 (m, 2H),5. 46 (dd,J= 14. 7, 9. 4Hz, 1H),5. 25 (s, 1H),5. 12-5. 06 (m, 1H) ,5. 00-4. 96 (m, 1H), 4. 96-4. 91 (m, 1H), 4. 49-4. 38 (m, 4H), 4. 04-3. 97 (m, 2H), 3. 95-3. 92 (m, 1H), 3. 88-3. 84 (m, 2H), 3. 65-3. 59 (m, 1H), 3. 48-3. 39 (m, 1H), 3. 15 (s, 3H), 3. 13 (s, 3H), 3. 0 5 (s, 3H), 2. 89-2. 82 (m, 1H), 2. 75-2. 69 (m, 1H), 2. 44-2. 34 (m, 2H), 2. 27-2. 16 (m, 1H), 2. 13- 2. 05 (m, 2H),2. 06-1. 94 (m, 1H),I. 92-1. 79 (m, 3H),I. 74 (s, 3H),I. 63 (s, 3H),I. 61-1. 03 (m, 9H), 0. 98 (d,J= 6. 3Hz, 3H), 0. 87 (d,J= 6. 4Hz, 3H), 0. 83 (d,J= 6. 2Hz, 3H), 0. 77 (d,J= 6. 6Hz, 3H), 0· 73(d,J= 6. 5Hz, 3H)。 1HNMR (500MHz, DMS0) S7.91 (s, lH), 7.24 (d, J = 8. 3Hz, 1H), 6. 78 (s, 1H), 6. 58 (d, J = 8. 3Hz, 1H ), 6. 45 (s, 1H), 6. 44-6. 35 (m, 1H), 6. 26-6.I 8 (m, 2H), 6. 17-6. 08 (m, 2H) , 5. 46 (dd, J = 14. 7, 9. 4Hz, 1H), 5. 25 (s, 1H), 5. 12-5. 06 (m, 1H), 5. 00-4. 96 ( m, 1H), 4. 96-4. 91 (m, 1H), 4. 49-4. 38 (m, 4H), 4. 04-3. 97 (m, 2H), 3. 95-3. 92 (m, 1H), 3. 88-3. 84 (m, 2H), 3. 65-3. 59 (m, 1H), 3. 48-3. 39 (m, 1H), 3. 15 ( s, 3H), 3. 13 (s, 3H), 3. 0 5 (s, 3H), 2. 89-2. 82 (m, 1H), 2. 75-2. 69 (m, 1H), 2. 44-2. 34 (m, 2H), 2. 27-2. 16 (m, 1H), 2. 13- 2. 05 (m, 2H), 2. 06-1. 94 (m, 1H ), I. 92-1. 79 (m, 3H), I. 74 (s, 3H), I. 63 (s, 3H), I. 61-1. 03 (m, 9H), 0. 98 ( d, J = 6. 3Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0. 83 (d, J = 6. 2Hz, 3H), 0. 77 (d, J = 6 . 6Hz, 3H), 0 · 73 (d, J = 6. 5Hz, 3H). 13CNMR(126MHz,DMSO)δ210. 49, 207. 49, 198. 90, 169 .19, 166. 97, 144. 81, 144. 66, 139. 31, 137. 84, 137. 13, 132. 48, 132. 33, 130. 42, 129. 99, 126 .99, 124. 91, 123. 12, 116. 46, 115. 93, HO. 84, 99. 00, 85. 52, 82. 43, 82. 24, 81. 92, 75. 74, 73 .62, 67. 65, 66. 19, 56. 93, 56. 57, 55. 45, 50. 74, 49. 97, 45. 20, 43. 48, 38. 09, 35. 58, 35. 17, 3 4. 79, 33. 38, 32. 14, 30. 82, 29. 63, 29. 38, 26. 42, 26. 23, 24. 45, 21. 64, 20. 36, 15. 57, 15. 53, 14. 70, 13. 40, 10. 46。 13CNMR (126MHz, DMSO) δ210. 49, 207. 49, 198. 90, 169 .19, 166. 97, 144. 81, 144. 66, 139. 31, 137. 84, 137. 13, 132. 48, 132. 33, 130. 42, 129. 99, 126 .99, 124. 91, 123. 12, 116. 46, 115. 93, HO. 84, 99. 00, 85. 52, 82. 43, 82. 24, 81.92, 75.74, 73.62, 67.65, 66.19, 56.93, 56.57, 55.45, 50.74, 49.97, 45.20, 43.48, 38.09, 35.58, 35.17, 3 4.79, 33.38, 32.14, 30.82, 29.63, 29.38, 26.42, 26.23, 24.45, 21 64, 20.36, 15.57, 15.53, 14.70, 13.40, 10.46.

[0175] 实施例11 :43-0-(2-(4-((2, 4二氯苯基)氨基甲基)-1Η-1,2, 3-三氮唑-1-基) 乙基)氧雷帕霉素(X-13) [0175] Example 11: 43-0- (2- (4 - ((2, 4-dichlorophenyl) aminomethyl) -1Η-1,2, 3- triazole-1-yl) ethyl ) oxygen rapamycin (X-13)

[0176]将43-0- (2-置氣乙基)-氧雷帕霉素(0·3mmoL,0·3g)和N-(丙块基)-2, 4-_. 氯苯胺(〇. Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0. Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入40mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0.09g,收率:25.5%。 [0176] The 43-0- (2-ethyl opposing gas) - rapamycin oxygen (0 · 3mmoL, 0 · 3g) and N- (prop-block-yl) -2, 4- chloroaniline _ (square . Ig) was added to a DMF (IOmL) was added sodium ascorbate (0. Ig) to the reaction solution and copper sulfate pentahydrate (0.08 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 40mL of water was added to precipitate light yellow solid, filtered off with suction, washed with water, and dried to give a pale yellow solid, was isolated by silica gel column chromatography and C18 preparative chromatography to yield pure product 0.09g, yield: 25.5%. MS (ESI) m/z : 1205.4(M+Na)+。 MS (ESI) m / z: 1205.4 (M + Na) +. 1H (500MHz,DMS0)δ7. 88 (s,1H),7. 32 (s,1H),7. 12(d,J =8. 8Hz, 1H),6. 75 (d, J = 8. 9Hz, 1H),6. 44 (s, 1H),6. 43-6. 34 (m, 1H),6. 25-6. 17 (m, 1H) ,6. 16-6. 05 (m, 2H),5. 46 (dd,J= 14. 8, 9. 7Hz, 1H),5. 25 (s, 1H),5. 12-5. 06 (m, 1H),5. 00 -4. 95 (m, 1H),4. 95-4. 90 (m, 1H),4. 46-4. 38 (m, 4H),4. 05-3. 97 (m, 2H),3. 95-3. 90 (m, 1H) ,3. 87-3. 79 (m, 2H), 3. 65-3. 59 (m, 1H), 3. 47-3. 39 (m, 1H), 3. 15 (s, 3H), 3. 13 (s, 3H), 3. 05 (s,3H),3. 02-2. 95 (m,2H),2. 89-2. 78 (m,1H),2. 75-2. 68 (m,2H),2. 44-2. 34 (m,1H),2. 28 -2. 17 (m,1H),2. 13-2. 06 (m,2H),2. 06-1. 96 (m,2H),I. 91-1. 79 (m,2H),I. 73 (s,3H),I. 63 (s, 3H),I. 61-1. 00 (m, 9H), 0. 98 (d,J= 6. 5Hz, 3H), 0. 87 (d,J= 6. 4Hz, 3H), 0. 83 (d,J= 6.3Hz,3H),0.77(d,J= 6.5Hz,3H),0.73(d,J= 6.6Hz,3H)Q13CNMR(126MHz,DMS0)S210. 99, 207. 99, 199. 39, 169. 69, 167. 48, 145. 35, 143. 29, 139. 82, 138. 36, 137. 63, 132. 85, 130. 94, 128. 61, 128. 14, 125. 46, 123. 59, 119. 1H (500MHz, DMS0) δ7. 88 (s, 1H), 7. 32 (s, 1H), 7. 12 (d, J = 8. 8Hz, 1H), 6. 75 (d, J = 8. 9Hz , 1H), 6. 44 (s, 1H), 6. 43-6. 34 (m, 1H), 6. 25-6. 17 (m, 1H), 6. 16-6. 05 (m, 2H ), 5. 46 (dd, J = 14. 8, 9. 7Hz, 1H), 5. 25 (s, 1H), 5. 12-5. 06 (m, 1H), 5. 00 -4. 95 (m, 1H), 4. 95-4. 90 (m, 1H), 4. 46-4. 38 (m, 4H), 4. 05-3. 97 (m, 2H), 3. 95-3 . 90 (m, 1H), 3. 87-3. 79 (m, 2H), 3. 65-3. 59 (m, 1H), 3. 47-3. 39 (m, 1H), 3. 15 (s, 3H), 3. 13 (s, 3H), 3. 05 (s, 3H), 3. 02-2. 95 (m, 2H), 2. 89-2. 78 (m, 1H), 2. 75-2. 68 (m, 2H), 2. 44-2. 34 (m, 1H), 2. 28 -2. 17 (m, 1H), 2. 13-2. 06 (m, 2H ), 2. 06-1. 96 (m, 2H), I. 91-1. 79 (m, 2H), I. 73 (s, 3H), I. 63 (s, 3H), I. 61- 1. 00 (m, 9H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0. 83 (d, J = 6.3Hz, 3H), 0.77 (d, J = 6.5Hz, 3H), 0.73 (d, J = 6.6Hz, 3H) Q13CNMR (126MHz, DMS0) S210. 99, 207. 99, 199. 39, 169. 69, 167. 48, 145.35, 143.29, 139.82, 138.36, 137.63, 132.85, 130.94, 128.61, 128.14, 125.46, 123.59, 119. 67, 118. 87, 113. 02, 100. 00, 99. 51, 86. 06, 82. 94, 82. 77, 82. 46, 76. 26, 74. 16, 68. 18, 66. 72, 57. 46, 57. 09, 55. 97, 51. 27, 50. 48, 45. 71, 43. 98 ,38. 81, 36. 12, 35. 67, 35. 30, 33. 91, 32. 71, 31. 33, 30. 15, 29. 90, 28. 28, 26. 94, 26. 74, 24. 9 7, 22. 15, 20. 88, 16. 07, 16. 06, 15. 24, 13. 93, 13. 90, 10. 99〇 67, 118.87, 113.02, 100.00, 99.51, 86.06, 82.94, 82.77, 82.46, 76.26, 74.16, 68.18, 66.72, 57.46, 57.09, 55.97, 51.27, 50.48, 45.71, 43.98, 38.81, 36.12, 35.67, 35.30, 33.91, 32. 71, 31.33, 30.15, 29.90, 28.28, 26.94, 26.74, 24.9 7 22.15, 20.88, 16.07, 16.06, 15.24 , 13.93, 13.90, 10. 99〇

[0177] 实施例12 :43-0-(2-(4-((2, 6二氟苯基)氨基甲基2, 3-三氮唑-I-基) 乙基)氧雷帕霉素(X-12) [0177] Example 12: 43-0- (2- (4 - ((2, 6-difluorophenyl) aminomethyl-2, 3-triazole -I--yl) ethyl) oxy-rapamycin (X-12)

[0178] 将43-0- (2-置氣乙基)-氧雷帕霉素(0. 3mmoL, 0. 3g)和N-(丙块基)-2, 6- _. 氟苯胺(〇.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0. 08g),室温搅拌2h,反应完毕后,将反应倒加入40mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 10g,收率:29. 0 %。 [0178] The 43-0- (2-ethyl opposing gas) - Oxygen rapamycin (0. 3mmoL, 0. 3g) and N- (prop-block-yl) -2, 6-fluoroaniline _ (square .ig) was added to a DMF (IOmL) was added sodium ascorbate (0.Ig) to the reaction solution and copper sulfate pentahydrate (0. 08g), room temperature and stirred for 2h, after completion of the reaction, the reaction was poured added 40mL of water, precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 10g, yield: 290%. MS(ESI)m/z:1172.7(M+Na)+。 MS (ESI) m / z: 1172.7 (M + Na) +. 1HNMR(500MHz,DMS0)S7.82(s,lH),6.89(t,J= 9·1Ηζ,2Η ),6· 67-6. 60 (m,1Η),6· 46 (s,1Η),6· 43-6. 32 (m,1Η),6· 28-6. 18 (m,1Η),6· 17-6. 03 (m,2Η) ,5. 59-5. 51(m,1Η), 5. 46 (dd,J= 14. 9, 9. 6Hz, 1Η), 5. 27 (s, 1Η), 5. 13-5. 06(m,1Η), 5. 02-4. 96(m,1Η), 4. 96-4. 90(m,1Η), 4. 47-4. 38(m,4Η), 4. 05-3. 97(m,2Η), 3. 97-3. 92(m,1Η), 3 .89-3. 79(m,2Η), 3. 65-3. 59(m,1Η), 3. 47-3. 40(m,1Η), 3. 32 (s, 3Η), 3. 16 (s, 3Η), 3. 05 (s, 3Η), 2. 91-2. 83(m,2Η), 2. 77-2. 69(m,1Η), 2. 44-2. 35(m,2Η), 2. 28-2. 18(m,1Η), 2. 15-2. 0 6(m,2Η), 2. 05-1. 98(m,2Η), 1. 92-1. 79(m,3Η), 1. 74 (s, 3Η),L63 (s, 3Η), 1. 58-1. 01(m,10 Η), 0. 98 (d,J= 6. 5Hz, 3Η), 0. 87 (d,J= 6. 5Hz, 3Η), 0. 83 (d,J= 6. 3Hz, 4Η), 0. 78 (d,J= 6.6Hz,3H),0.73(d,J= 6.6Hz,3H)Q13CNMR(126MHz,DMS0)S210.46,207.51,198.88,169. 22, 166. 97, 145. 86, 139. 30, 137. 84, 137. 11, 132. 34, 130. 42, 126. 99, 124. 88, 122. 73, 116. 86, 111. 70, 111. 52, 99. 00, 85. 50, 82. 46, 1HNMR (500MHz, DMS0) S7.82 (s, lH), 6.89 (t, J = 9 · 1Ηζ, 2Η), 6 · 67-6. 60 (m, 1Η), 6 · 46 (s, 1Η), 6 · 43-6. 32 (m, 1Η), 6 · 28-6. 18 (m, 1Η), 6 · 17-6. 03 (m, 2Η), 5. 59-5. 51 (m, 1Η ), 5. 46 (dd, J = 14. 9, 9. 6Hz, 1Η), 5. 27 (s, 1Η), 5. 13-5. 06 (m, 1Η), 5. 02-4. 96 (m, 1Η), 4. 96-4. 90 (m, 1Η), 4. 47-4. 38 (m, 4Η), 4. 05-3. 97 (m, 2Η), 3. 97-3 . 92 (m, 1Η), 3 .89-3. 79 (m, 2Η), 3. 65-3. 59 (m, 1Η), 3. 47-3. 40 (m, 1Η), 3. 32 (s, 3Η), 3. 16 (s, 3Η), 3. 05 (s, 3Η), 2. 91-2. 83 (m, 2Η), 2. 77-2. 69 (m, 1Η), 2. 44-2. 35 (m, 2Η), 2. 28-2. 18 (m, 1Η), 2. 15-2. 0 6 (m, 2Η), 2. 05-1. 98 (m, 2Η), 1. 92-1. 79 (m, 3Η), 1. 74 (s, 3Η), L63 (s, 3Η), 1. 58-1. 01 (m, 10 Η), 0. 98 ( d, J = 6. 5Hz, 3Η), 0. 87 (d, J = 6. 5Hz, 3Η), 0. 83 (d, J = 6. 3Hz, 4Η), 0. 78 (d, J = 6.6 hz, 3H), 0.73 (d, J = 6.6Hz, 3H) Q13CNMR (126MHz, DMS0) S210.46,207.51,198.88,169. 22, 166. 97, 145. 86, 139. 30, 137. 84, 137. 11, 132.34, 130.42, 126.99, 124.88, 122.73, 116.86, 111.70, 111.52, 99.00, 85.50, 82.46, 82. 24, 81. 97, 75. 74, 73. 58, 67. 79, 66. 19, 56. 92, 56. 56, 55. 45, 50. 75, 49. 88, 45. 20, 43. 48, 40. 47, 38. 14, 35. 63, 35. 17, 34. 79, 33. 35, 32. 11,30. 78, 29. 57, 29. 42, 26. 42, 26. 22, 24. 45, 21. 63, 20. 35, 15. 57, 15. 54, 14. 70, 13. 44, 13. 3 6, 10. 46〇 82.24, 81.97, 75.74, 73.58, 67.79, 66.19, 56.92, 56.56, 55.45, 50.75, 49.88, 45.20, 43. 48, 40.47, 38.14, 35.63, 35.17, 34.79, 33.35, 32. 11, 30. 78, 29.57, 29.42, 26.42, 26.22, 24.45, 21.63, 20.35, 15.57, 15.54, 14.70, 13.44, 13.3. 6, 10. 46〇

[0179] 实施例13 :43-0-(2-(4-((2-氟苯基)氨基甲基)-1Η-1, 2, 3-三氮唑-1-基)乙基)氧雷帕霉素(X-19) [0179] Example 13: 43-0- (2- (4 - ((2-fluorophenyl) aminomethyl) -1Η-1, 2, 3- triazole-1-yl) ethyl) oxy rapamycin (X-19)

[0180] 将43-0-(2-置氣乙基)-氧雷帕霉素(0. 3mmoL, 0. 3g)和N-(丙块基)氣苯胺(〇. Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0. Ig)和五水硫酸铜(0. 08g),室温搅拌2h,反应完毕后,将反应倒加入40mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 08g,收率: 23.2%。 [0180] The 43-0- (2-ethyl opposing gas) - rapamycin oxygen (0. 3mmoL, 0. 3g) and N- (prop-block-yl) aniline gas (. Square Ig) was added to a DMF ( IOmL) was added sodium ascorbate (0. Ig) and copper sulfate pentahydrate (0. 08g) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 40mL of water was added, the precipitated pale yellow solid was filtered off with suction , washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 08g, yield: 23.2%. MS(ESI)m/z:1154.7(M+Na)+。 MS (ESI) m / z: 1154.7 (M + Na) +. 1H NMR(500MHz,DMS0)S7.90(s,lH),6.98(dd,J = 12. 2, 8. 0Hz, 1H),6. 91 (t, J = 7. 7Hz, 1H),6. 74 (t, J = 8. 5Hz, 1H), 6. 56-6. 49 (m, 1H),6. 48 (s, 1H),6. 44-6. 36 (m, 1H),6. 27-6. 18 (m, 2H),5. 95 (m, 1H),5. 46 (dd, J = 14. 9, 9. 6Hz, 1H), 5. 29 (s, 1H), 5. 08 (d,J= 10. 0Hz, 1H), 4. 99-4. 95(m,1H), 4. 97-4. 91(m,1H), 4. 43(m,2H), 4 .36 (s, 2H),4. 06-3. 98(m,2H),3. 96(m,1H),3. 90-3. 76(m,4H),3. 63(m,1H),3. 48-3. 39(m,IH),3. 29-3. 21 (m, 1H),3. 15 (s, 3H),3. 14 (s, 3H),3. 05 (s, 3H),2. 93-2. 83 (m, 1H),2. 77-2. 68 (m,1H),2. 45-2. 31(m,2H),2. 29-2. 16(m,1H),2. 10(m,1H),2. 05-1. 96(m,1H),I. 90-1. 79 ( m,3H),I. 74 (s, 3H),I. 63 (s, 3H),I. 60-1. 00(m,10H),0. 98 (d,J= 6. 6Hz, 3H),0. 86 (d,J= 6. 5Hz, 3H),0· 82 (d,J= 6. 4Hz, 3H),0· 77 (d,J= 6. 8Hz, 3H),0· 73 (d,J= 6. 6Hz, 3H)。 1H NMR (500MHz, DMS0) S7.90 (s, lH), 6.98 (dd, J = 12. 2, 8. 0Hz, 1H), 6. 91 (t, J = 7. 7Hz, 1H), 6. 74 (t, J = 8. 5Hz, 1H), 6. 56-6. 49 (m, 1H), 6. 48 (s, 1H), 6. 44-6. 36 (m, 1H), 6. 27-6. 18 (m, 2H), 5. 95 (m, 1H), 5. 46 (dd, J = 14. 9, 9. 6Hz, 1H), 5. 29 (s, 1H), 5. 08 (d, J = 10. 0Hz, 1H), 4. 99-4. 95 (m, 1H), 4. 97-4. 91 (m, 1H), 4. 43 (m, 2H), 4. 36 (s, 2H), 4. 06-3. 98 (m, 2H), 3. 96 (m, 1H), 3. 90-3. 76 (m, 4H), 3. 63 (m, 1H) , 3. 48-3. 39 (m, IH), 3. 29-3. 21 (m, 1H), 3. 15 (s, 3H), 3. 14 (s, 3H), 3. 05 (s , 3H), 2. 93-2. 83 (m, 1H), 2. 77-2. 68 (m, 1H), 2. 45-2. 31 (m, 2H), 2. 29-2. 16 (m, 1H), 2. 10 (m, 1H), 2. 05-1. 96 (m, 1H), I. 90-1. 79 (m, 3H), I. 74 (s, 3H), I. 63 (s, 3H), I. 60-1. 00 (m, 10H), 0. 98 (d, J = 6. 6Hz, 3H), 0. 86 (d, J = 6. 5Hz, 3H ), 0 · 82 (d, J = 6. 4Hz, 3H), 0 · 77 (d, J = 6. 8Hz, 3H), 0 · 73 (d, J = 6. 6Hz, 3H). 13C NMR(126MHz,DMSO)δ210. 47, 207. 55, 198. 93, 169. 24, 167. 00, 151. 88, 149. 99, 145. 47, 139 .33, 137. 87, 137. 15, 136. 30, 136. 20, 132. 36, 130. 46, 127. 05, 124. 85, 124. 59, 123. 06, 115 .72, 115. 67, 114. 28, 114. 13, 112. 25, 99. 03, 85. 48, 82. 40, 82. 25, 81. 98, 75. 76, 73. 60, 67. 71, 66. 20, 56. 93, 56. 60, 55. 49, 50. 78, 49. 92, 45. 23, 43. 51, 38. 18, 35. 64, 35. 20, 34. 82, 33 .37, 32. 12, 30. 80, 29. 63, 29. 40, 29. 01, 26. 45, 26. 24, 24. 49, 21. 66, 20. 40, 15. 62, 15. 54,I 4. 70, 13. 51, 13. 33, 10. 48〇 13C NMR (126MHz, DMSO) δ210. 47, 207. 55, 198. 93, 169. 24, 167. 00, 151. 88, 149. 99, 145. 47, 139 .33, 137. 87, 137. 15 , 136.30, 136.20, 132.36, 130.46, 127.05, 124.85, 124.59, 123.06, 115.72, 115.67, 114.28, 114.13, 112 25, 99.03, 85.48, 82.40, 82.25, 81.98, 75.76, 73.60, 67.71, 66.20, 56.93, 56.60, 55.49 , 50.78, 49.92, 45.23, 43.51, 38.18, 35.64, 35.20, 34.82, 33.37, 32.12, 30.80, 29.63, 29 . 40, 29. 01, 26. 45, 26. 24, 24. 49, 21. 66, 20. 40, 15. 62, 15. 54, I 4. 70, 13. 51, 13. 33, 10. 48〇

[0181] 实施例14 :43-0-(3-(4-(4-氟苯基2, 3-三氮唑-I-基)正丙基)氧雷帕霉素(X-26) [0181] Example 14: 43-0- (3- (4- (4-fluorophenyl 2,3-triazole -I--yl) propyl) oxy rapamycin (X-26)

[0182] 步骤A:43-0-(3-溴丙基)_氧雷帕霉素的制备 [0182] Step A: Preparation of 43-0- (3-bromopropyl) rapamycin oxygen _

[0183]将雷帕霉素(8. 0g, 8.7mmol)、二异丙基乙胺(5.6g,44mmol)加入到50mL的甲苯溶液中,加入3-溴丙基磺酸酯侧链(11.8g,28.5mmol),加毕,升温至60°C反应3h。 [0183] Rapamycin (8. 0g, 8.7mmol), diisopropylethylamine (5.6g, 44mmol) was added to 50mL of toluene was added 3-bromopropyl sulfonate side chains (11.8 g, 28.5mmol), the addition was completed, the reaction was warmed to 60 ° C 3h. 反应完毕后,将反应液冷却至室温,分别经稀盐酸、饱和碳酸氢钠和饱和食盐水中,有机层经无水硫酸钠干燥,蒸干得淡黄色固体,经柱层析分离得4.Sg白色固体,收率:53.3%, 1056. 5(M+Na)+。 After completion of the reaction, the reaction solution was cooled to room temperature, were treated with dilute hydrochloric acid, saturated sodium bicarbonate and saturated saline, the organic layer was dried over anhydrous sodium sulfate, and evaporated to dryness to give a pale yellow solid, was isolated by column chromatography 4.Sg as a white solid, yield: 53.3%, 1056. 5 (M + Na) +.

[0184] 步骤B:43-0-(3-叠氮丙基)-氧雷帕霉素的制备 B [0184] Step: 43-0- (3-azido-propyl) - Preparation oxygen rapamycin

[0185] 分别将43-0-(3-溴丙基)-氧雷帕霉素(4. 8g, 4. 6mmol)和叠氮化钠(I. 3g,19. 5mmol)加入到(30mL)DMF溶液中,加入催化剂KI(0.Ig),加料完毕后升温到50°C,反应完全后,将反应液倾入IOOmL水中,乙酸乙酯提取2次,合并提取液,水洗, 无水硫酸钠干燥。 [0185] respectively, 43-0- (3-bromopropyl) - oxo rapamycin (4. 8g, 4. 6mmol) and sodium azide (. I. 3g, 19 5mmol) was added to (30mL) DMF was added catalyst KI (0.Ig), after completion of the addition was warmed to 50 ° C, after completion of the reaction, the reaction solution was poured into IOOmL water and extracted twice with ethyl acetate, the combined extracts washed with water, dried over anhydrous sulfate sodium sulfate. 蒸干得油状物,经柱层析分离分别得到2. 4g,收率:52%。 Evaporated to dryness to give an oil which was purified by column chromatography respectively 2. 4g, yield: 52%. MS(ESI)m/ z:1019. 6(M+Na)+。 MS (ESI) m / z:. 1019 6 (M + Na) +.

[0186] 步骤C:43-0-(3-(4-(4 -氣苯基)2, 3-二氣卩坐基)正丙基)氧雷帕霉素的制备(X-26) [0186] Step C: 43-0- (3- (4- (4 - gas phenyl) 2, 3-Jie gas take-yl) propyl) Preparation of oxygen of rapamycin (X-26)

[0187] 将43-0-(3-叠氮丙基)-氧雷帕霉素(0. 35mmoL,0. 35g)和4-氟苯乙炔(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0. 08g),室温搅拌2h,反应完毕后,将反应倒加入60mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 19g,收率: 43.4%。 [0187] The 43-0- (3-azido-propyl) - oxo rapamycin (. 0. 35mmoL, 0 35g) and 4-fluorophenyl acetylene (0.Ig) was added to a DMF (IOmL) solution of , was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0. 08g) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 60mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to give 0. 19g, yield of the pure product: 43.4%. MS(ESI)m/z:1139.7(M+Na)+。 MS (ESI) m / z: 1139.7 (M + Na) +. 1HNMR(500MHz,DMS0)S8.56(s,lH),7.87(dd,J= 7. 9, 5. 8Hz, 2H),7. 28 (t,J= 8. 7Hz, 2H),6. 44 (s, 1H),6. 41-6. 32 (m, 1H),6. 26-6. 18 (m,IH ),6. 17-6. 08 (m, 2H),5. 51-5. 42 (m, 1H),5. 25 (s, 1H),5. 10 (d,J= 10. 2Hz, 1H),5. 02-4. 97 (m, 1H),4. 97-4. 91 (m, 1H),4. 50-4. 43 (m, 2H),4. 06-3. 98 (m, 2H),3. 97-3. 91 (m, 1H),3. 67- 3. 58 (m, 1H), 3. 57-3. 42 (m, 3H), 3. 34 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 90-2. 65 (m, 2H), 2. 45-2. 34 (m, 2H),2. 28-2. 17 (m, 1H),2. 14-2. 03 (m, 2H),2. 01-1. 90 (m, 2H),I. 89-1. 78 (m ,2H),I. 74 (s,3H),I. 64 (s,3H),I. 60-1. 04 (m,10H),0· 98 (d,J = 6. 3Hz,3H),0· 88 (d,J = 6. 3Hz,3H),0· 83 (d,J = 6. 1Hz,3H),0· 78 (d,J = 6. 4Hz,3H),0· 74 (d,J = 6. 4Hz,3H)。 1HNMR (500MHz, DMS0) S8.56 (s, lH), 7.87 (dd, J = 7. 9, 5. 8Hz, 2H), 7. 28 (t, J = 8. 7Hz, 2H), 6. 44 (s, 1H), 6. 41-6. 32 (m, 1H), 6. 26-6. 18 (m, IH), 6. 17-6. 08 (m, 2H), 5. 51-5 . 42 (m, 1H), 5. 25 (s, 1H), 5. 10 (d, J = 10. 2Hz, 1H), 5. 02-4. 97 (m, 1H), 4. 97-4 . 91 (m, 1H), 4. 50-4. 43 (m, 2H), 4. 06-3. 98 (m, 2H), 3. 97-3. 91 (m, 1H), 3. 67 -. 3. 58 (m, 1H), 3. 57-3 42 (m, 3H), 3. 34 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 90-2. 65 (m, 2H), 2. 45-2. 34 (m, 2H), 2. 28-2. 17 (m, 1H), 2. 14-2. 03 (m, 2H ), 2. 01-1. 90 (m, 2H), I. 89-1. 78 (m, 2H), I. 74 (s, 3H), I. 64 (s, 3H), I. 60- 1. 04 (m, 10H), 0 · 98 (d, J = 6. 3Hz, 3H), 0 · 88 (d, J = 6. 3Hz, 3H), 0 · 83 (d, J = 6. 1Hz , 3H), 0 · 78 (d, J = 6. 4Hz, 3H), 0 · 74 (d, J = 6. 4Hz, 3H). 13C NMR(126MHz, DMSO) δ 210. 43, 207. 48, 198. 85, 169. 18, 166. 96, 162. 64, 160. 70, 145. 34, 139 .27, 137. 82, 137. 10, 132. 31, 130. 40, 127. 43, 127. 06, 126. 99, 124. 90, 121. 29, 115. 82, 115 .65, 98. 98, 85. 51, 82. 42, 82. 23, 81. 97, 75. 73, 73. 59, 66. 18, 65. 45, 56. 91, 56. 88, 55. 43, 5 0. 74, 46. 84, 45. 18, 43. 46, 38. 21, 35. 82, 35. 14, 34. 77, 33. 34, 32. 23, 30. 83, 30. 36, 29. 61, 29. 52, 26. 40, 26. 21, 24. 43, 21. 61, 20. 33, 15. 52, 14. 69, 13. 39, 13. 36, 10. 44〇 13C NMR (126MHz, DMSO) δ 210. 43, 207. 48, 198. 85, 169. 18, 166. 96, 162. 64, 160. 70, 145. 34, 139 .27, 137. 82, 137. 10, 132.31, 130.40, 127.43, 127.06, 126.99, 124.90, 121.29, 115.82, 115.65, 98.98, 85.51, 82.42, 82.23, 81.97, 75.73, 73.59, 66.18, 65.45, 56.91, 56.88, 55.43, 5 0.74, 46.84, 45.18, 43 46, 38.21, 35.82, 35.14, 34.77, 33.34, 32.23, 30.83, 30.36, 29.61, 29.52, 26.40, 26.21 , 24.43, 21.61, 20.33, 15.52, 14.69, 13.39, 13.36, 10. 44〇

[0188] 实施例15 :43-0-(3-(4-(4-氯苯基2, 3-三氮唑-I-基)正丙基)氧雷帕霉素(X-27) [0188] Example 15: 43-0- (3- (4- (4-chlorophenyl 2, 3-triazole -I--yl) propyl) oxy rapamycin (X-27)

[0189] 将43-0-(3-叠氮丙基)-氧雷帕霉素(0. 35mmoL, 0. 35g)和4-氯苯乙炔(0.Ig) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入60mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 16g,收率:41. 0%。 [0189] The 43-0- (3-azido-propyl) - rapamycin oxygen (0. 35mmoL, 0. 35g) and 4-chlorophenyl acetylene (0.Ig) was added to a DMF (IOmL) solution of , was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 60mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 16g, yield: 410%. MS(ESI)m/ z:1155.7(M+Na)+。 MS (ESI) m / z: 1155.7 (M + Na) +. 1HNMR(500MHz,DMS0)S8.62(s,lH),7.86(d,J= 8.5Hz,2H),7.51(d,J =8. 6Hz,2H),6. 45 (s,1H),6. 44-6. 35 (m,1H),6. 26-6. 17 (m,1H),6. 17-6. 09 (m,2H),5. 46 ( dd,J= 14. 9, 9. 6Hz,1H),5. 26 (s,1H),5. 10 (d,J= 10. 1Hz,1H),5. 01-4. 96 (m,1H),4. 96-4 •91 (m,1H),4. 50-4. 42 (m,2H),4. 06-3. 98 (m,2H),3. 97-3. 93 (m,1H),3. 65-3. 60 (m,1H),3. 5 8-3. 38 (m,3H),3. 33 (s,3H),3. 29-3. 22 (m,1H),3. 16 (s,3H),3. 05 (s,3H),2. 87-2. 69 (m,2H ),2. 44-2. 33 (m,2H),2. 27-2. 17 (m,1H),2. 13-2. 01 (m,2H),2. 00-1. 91 (m,2H),I. 90-1. 79 ( m, 2H),I. 75 (s, 3H),I. 63 (s, 3H),I. 60-1. 02 (m, 10H),0. 98 (d,J= 6. 6Hz, 3H),0. 87 (d,J= 6. 5Hz, 3H),0· 82 (d,J= 6. 5Hz, 3H),0· 78 (d,J= 6. 7Hz, 3H),0· 73 (d,J= 6. 6Hz, 3H)。 1HNMR (500MHz, DMS0) S8.62 (s, lH), 7.86 (d, J = 8.5Hz, 2H), 7.51 (d, J = 8. 6Hz, 2H), 6. 45 (s, 1H), 6 . 44-6. 35 (m, 1H), 6. 26-6. 17 (m, 1H), 6. 17-6. 09 (m, 2H), 5. 46 (dd, J = 14. 9, 9. 6Hz, 1H), 5. 26 (s, 1H), 5. 10 (d, J = 10. 1Hz, 1H), 5. 01-4. 96 (m, 1H), 4. 96-4 • 91 (m, 1H), 4. 50-4. 42 (m, 2H), 4. 06-3. 98 (m, 2H), 3. 97-3. 93 (m, 1H), 3. 65- 3. 60 (m, 1H), 3. 5 8-3. 38 (m, 3H), 3. 33 (s, 3H), 3. 29-3. 22 (m, 1H), 3. 16 (s , 3H), 3. 05 (s, 3H), 2. 87-2. 69 (m, 2H), 2. 44-2. 33 (m, 2H), 2. 27-2. 17 (m, 1H ), 2. 13-2. 01 (m, 2H), 2. 00-1. 91 (m, 2H), I. 90-1. 79 (m, 2H), I. 75 (s, 3H), I. 63 (s, 3H), I. 60-1. 02 (m, 10H), 0. 98 (d, J = 6. 6Hz, 3H), 0. 87 (d, J = 6. 5Hz, 3H ), 0 · 82 (d, J = 6. 5Hz, 3H), 0 · 78 (d, J = 6. 7Hz, 3H), 0 · 73 (d, J = 6. 6Hz, 3H). 13C NMR(126MHz,DMSO)δ210. 43, 207. 51, 198. 88, 169. 20, 166. 98, 145. 13, 139. 28, 137. 84, 137 .12, 132. 33, 132. 15, 130. 42, 129. 77, 128. 91, 127. 01, 126. 73, 124. 87, 121. 77, 99. 00, 85. 5 0, 82. 43, 82. 23, 81. 98, 75. 74, 73. 60, 66. 19, 65. 46, 56. 91, 55. 46, 50. 76, 46. 91, 45. 19, 43. 49, 38. 23, 35. 82, 35. 16, 34. 79, 33. 34, 32. 22, 30. 84, 30. 35, 29. 63, 29. 54, 26. 42, 26. 23, 24 .45, 21. 63, 20. 36, 15. 57, 15. 53, 14. 69, 13. 44, 13. 34, 10. 46〇 13C NMR (126MHz, DMSO) δ210. 43, 207. 51, 198. 88, 169. 20, 166. 98, 145. 13, 139. 28, 137. 84, 137 .12, 132. 33, 132. 15 , 130.42, 129.77, 128.91, 127.01, 126.73, 124.87, 121.77, 99.00, 85.5 0 82.43, 82.23, 81.98, 75.74, 73.60, 66.19, 65.46, 56.91, 55.46, 50.76, 46.91, 45.19, 43.49, 38.23, 35.82, 35. 16, 34.79, 33.34, 32.22, 30.84, 30.35, 29.63, 29.54, 26.42, 26.23, 24.45, 21.63, 20.36, 15.57, 15.53, 14.69, 13.44, 13.34, 10. 46〇

[0190] 实施例16 :43-0-(3-(4-(4-甲基苯基2, 3-三氮唑-I-基)正丙基)氧雷帕霉素(X-21) [0190] Example 16: 43-0- (3- (4- (4-phenyl-2, 3-triazole -I--yl) propyl) oxy rapamycin (X-21)

[0191] 将43-0-(3-叠氮丙基)-氧雷帕霉素(0.35臟〇1^0.35 8)和4-甲基苯乙炔(0.18) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入60mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 18g,收率:46. 1%。 [0191] The 43-0- (3-azido-propyl) - oxo rapamycin (0.35 ^ 0.35 dirty 〇1 8) and 4-phenylacetylene (0.18) was added to a DMF (IOmL) solution, sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 60mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 18g, yield: 461%. MS(ESI)m/ z: 1135. 7 (M+Na)+。 MS (ESI) m / z: 1135. 7 (M + Na) +. 1HNMR(500MHz,DMS0)δ8. 52 (s,1H),7. 72 (d,J= 8. 0Hz,2H),7. 25 (d,J =7. 8Hz, 2H),6. 48 (s, 1H),6. 44-6. 36 (m, 1H),6. 26-6. 19 (m, 1H),6. 17-6. 08 (m, 2H),5. 51- 5. 42 (m, 1H), 5. 30 (s, 1H), 5. 02-4. 96 (m, 1H), 4. 94 (m, 1H), 4. 49-4. 40 (m, 1H), 4. 06-3. 97(m ,2H),3. 98-3. 92 (m, 1H),3. 66-3. 57 (m, 1H),3. 57-3. 40 (m, 3H),3. 30-3. 23 (m, 1H),3. 34 ( s, 3H),3. 15 (s, 3H),3. 05 (s, 3H),2. 85-2. 78 (m, 1H),2. 77-2. 68 (m, 1H),2. 43-2. 34 (m,IH ),2. 33 (s, 3H),2. 27-2. 17 (m, 1H),2. 14-2. 00 (m, 2H),2. 00-1. 87 (m, 2H),I. 89-1. 79 (m, 2 H),I. 75 (s, 3H),I. 63 (s, 3H),I. 60-1. 02 (m, 10H),0. 98 (d,J= 6. 5Hz, 3H),0. 87 (d,J= 6. 5Hz, 3H), 0· 82 (d,J= 6. 4Hz, 3H), 0· 78 (d,J= 6. 6Hz, 3H), 0· 73 (d,J= 6. 6Hz, 3H)。 1HNMR (500MHz, DMS0) δ8. 52 (s, 1H), 7. 72 (d, J = 8. 0Hz, 2H), 7. 25 (d, J = 7. 8Hz, 2H), 6. 48 (s , 1H), 6. 44-6. 36 (m, 1H), 6. 26-6. 19 (m, 1H), 6. 17-6. 08 (m, 2H), 5. 51- 5. 42 (m, 1H), 5. 30 (s, 1H), 5. 02-4. 96 (m, 1H), 4. 94 (m, 1H), 4. 49-4. 40 (m, 1H), 4. 06-3. 97 (m, 2H), 3. 98-3. 92 (m, 1H), 3. 66-3. 57 (m, 1H), 3. 57-3. 40 (m, 3H ), 3. 30-3. 23 (m, 1H), 3. 34 (s, 3H), 3. 15 (s, 3H), 3. 05 (s, 3H), 2. 85-2. 78 ( m, 1H), 2. 77-2. 68 (m, 1H), 2. 43-2. ​​34 (m, IH), 2. 33 (s, 3H), 2. 27-2. 17 (m, 1H), 2. 14-2. 00 (m, 2H), 2. 00-1. 87 (m, 2H), I. 89-1. 79 (m, 2 H), I. 75 (s, 3H ), I. 63 (s, 3H), I. 60-1. 02 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 5Hz , 3H), 0 · 82 (d, J = 6. 4Hz, 3H), 0 · 78 (d, J = 6. 6Hz, 3H), 0 · 73 (d, J = 6. 6Hz, 3H). 13C NMR(126MHz,DMSO)δ210. 46, 207. 56, 198. 93, 169. 24, 167. 01, 146. 30, 139. 31, 137. 88, 137 .17, 137. 03, 132. 35, 130. 47, 129. 42, 128. 12, 127. 03, 125. 01, 124. 86, 121. 04, 99. 04, 85. 4 8, 82. 45, 82. 25, 82. 03, 75. 76, 73. 61, 66. 20, 65. 49, 56. 95, 55. 49, 50. 78, 46. 80, 45. 23, 43. 52, 38. 24, 35. 86, 35. 20, 34. 83, 33. 36, 32. 22, 30. 88, 30. 41, 29. 55, 26. 45, 26. 24, 24. 48, 21 .65, 20. 83, 20. 40, 15. 62, 15. 54, 14. 70, 13. 51, 13. 32, 10. 48〇 13C NMR (126MHz, DMSO) δ210. 46, 207. 56, 198. 93, 169. 24, 167. 01, 146. 30, 139. 31, 137. 88, 137 .17, 137. 03, 132. 35 , 130.47, 129.42, 128.12, 127.03, 125.01, 124.86, 121.04, 99.04, 85.4 8 82.45, 82.25, 82.03, 75.76, 73.61, 66.20, 65.49, 56.95, 55.49, 50.78, 46.80, 45.23, 43.52, 38.24, 35.86, 35. 20, 34.83, 33.36, 32.22, 30.88, 30.41, 29.55, 26.45, 26.24, 24.48, 21.65, 20.83, 20.40, 15.62, 15.54, 14.70, 13.51, 13.32, 10. 48〇

[0192] 实施例17 :43-0-(3-(苯基-1H-1,2, 3-三氮唑-I-基)正丙基)氧雷帕霉素(X-22) [0192] Example 17: 43-0- (3- (phenyl -1H-1,2, 3- triazole -I--yl) propyl) oxy rapamycin (X-22)

[0193] 将43-0- (3-叠氮丙基)-氧雷帕霉素(0. 35mmoL, 0. 35g)和苯乙炔(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入60mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 15g,收率:38. 4%。 [0193] The 43-0- (3-azido-propyl) - rapamycin oxygen (0. 35mmoL, 0. 35g) and phenylacetylene (0.Ig) was added to a DMF (IOmL) solution to the reaction was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 60mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 15g, yield: 384%. MS(ESII)m/ z:1121.7(M+Na)+。 MS (ESII) m / z: 1121.7 (M + Na) +. 1HNMR(500MHz,DMS0)S8.58(s,lH),7.83(d,J= 7.7Hz,2H),7.45(t,J =7. 6Hz,2H),7. 37-7. 28 (m,1H),6. 48 (s,1H),6. 45-6. 37 (m,1H),6. 21 (m,1H),6. 17-6. 09 ( m, 2H),5. 51-5. 42 (m, 1H), 5. 29 (s, 1H),5. 13-5. 05 (m, 1H),5. 00-4. 96 (m, 1H),4. 95 (m, 1H),4 • 50-4. 42 (m,2H),4. 06-3. 99 (m,2H),3. 96 (d,J= 4. 2Hz,1H),3. 66-3. 59 (m,1H),3. 57-3. 41 (m,3H),3. 34 (s,3H),3. 27 (m,1H),3. 15 (s,3H),3. 05 (s,3H),2. 86-2. 77 (m,1H),2. 77-2. 69 (m,1H),2. 43-2. 33 (m,2H),2. 22 (m,1H),2. 14-1. 99 (m,2H),2. 01-1. 88 (m,2H),I. 89-1. 79 ( m, 2H), I. 75 (s, 3H), I. 63 (s, 3H), I. 60-1. 00 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0· 82 (d, J = 6. 4Hz, 3H), 0· 78 (d, J = 6. 5Hz, 3H), 0· 73 (d, J = 6. 6Hz, 3H)。 1HNMR (500MHz, DMS0) S8.58 (s, lH), 7.83 (d, J = 7.7Hz, 2H), 7.45 (t, J = 7. 6Hz, 2H), 7. 37-7. 28 (m, 1H), 6. 48 (s, 1H), 6. 45-6. 37 (m, 1H), 6. 21 (m, 1H), 6. 17-6. 09 (m, 2H), 5. 51 -5. 42 (m, 1H), 5. 29 (s, 1H), 5. 13-5. 05 (m, 1H), 5. 00-4. 96 (m, 1H), 4. 95 (m , 1H), 4 • 50-4. 42 (m, 2H), 4. 06-3. 99 (m, 2H), 3. 96 (d, J = 4. 2Hz, 1H), 3. 66-3 . 59 (m, 1H), 3. 57-3. 41 (m, 3H), 3. 34 (s, 3H), 3. 27 (m, 1H), 3. 15 (s, 3H), 3. 05 (s, 3H), 2. 86-2. 77 (m, 1H), 2. 77-2. 69 (m, 1H), 2. 43-2. ​​33 (m, 2H), 2. 22 ( m, 1H), 2. 14-1. 99 (m, 2H), 2. 01-1. 88 (m, 2H), I. 89-1. 79 (m, 2H), I. 75 (s, 3H), I. 63 (s, 3H), I. 60-1. 00 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0 · 82 (d, J = 6. 4Hz, 3H), 0 · 78 (d, J = 6. 5Hz, 3H), 0 · 73 (d, J = 6. 6Hz, 3H). 13C NMR(126MHz, DMSO) δ 210. 45, 207. 56, 198. 92, 169. 24, 167. 01, 146. 24, 139. 31, 137. 88, 137 .16, 132. 35, 130. 88, 130. 47, 128. 88, 127. 77, 127. 03, 125. 07, 121. 46, HO. 97, 99. 03, 85. 4 8, 82. 45, 82. 24, 82. 03, 75. 76, 73. 61, 66. 20, 65. 48, 56. 95, 55. 49, 50. 78, 46. 84, 45. 23, 43. 52, 38. 25, 35. 85, 35. 20, 34. 83, 33. 37, 32. 22, 30. 87, 30. 41, 29. 63, 29. 56, 26. 44, 26. 25, 24 .48, 21. 66, 20. 41,15. 62, 15. 55, 14. 71,13. 51,13. 32, 10. 48。 13C NMR (126MHz, DMSO) δ 210. 45, 207. 56, 198. 92, 169. 24, 167. 01, 146. 24, 139. 31, 137. 88, 137 .16, 132. 35, 130. 88, 130. 47, 128. 88, 127. 77, 127. 03, 125. 07, 121. 46, HO. 97, 99. 03, 85. 4 8, 82. 45, 82. 24, 82. 03 , 75.76, 73.61, 66.20, 65.48, 56.95, 55.49, 50.78, 46.84, 45.23, 43.52, 38.25, 35.85, 35 20, 34.83, 33.37, 32.22, 30.87, 30.41, 29.63, 29.56, 26.44, 26.25, 24.48, 21.66, 20.41 , 15.62, 15.55, 14. 71,13. 51,13. 32, 10.48.

[0194] 实施例18 :43-0-(3-(4-(3-甲基苯基)-1Η-1,2, 3-三氮唑-I-基)正丙基)氧雷帕霉素(X-31) [0194] Example 18: 43-0- (3- (4- (3-methylphenyl) -1Η-1,2, 3- triazole -I--yl) propyl) oxy-rapamycin Su (X-31)

[0195] 将43-0-(3-叠氮丙基)-氧雷帕霉素(0.35臟〇1^0.358)和3-甲基苯乙炔(0.]^) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g), 室温搅拌2h,反应完毕后,将反应倒加入60mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 19g,收率:48. 7%。 [0195] The 43-0- (3-azido-propyl) - oxo rapamycin (0.35 dirty 〇1 ^ 0.358) phenylacetylene and 3-methyl (. 0] ^) was added to a DMF (IOmL) was was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 60mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 19g, yield: 487%. MS(ESII) 7.8Hz,lH),7.32(t,J= 7.6Hz,1H),7.14 (d,J= 7.6Hz,1H),6.45 (s,lH) ,6.44-6· 33 (m, 1H), 6. 27-6. 17 (m, 1H), 6. 17-6. 07 (m, 2H), 5. 46 (dd,J= 14. 8, 9. 7Hz, 1H), 5. 27 (s, 1H), 5. 02-4. 96 (m, 1H),4. 96-4. 92 (m, 1H),4. 50-4. 41 (m, 2H),4. 06-3. 97 (m, 2H),4. 00-3. 90 ( m, 1H), 3. 67-3. 59 (m, 1H), 3. 58-3. 41 (m, 3H), 3. 34 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 85 -2. 69 (m,2H),2. 45-2. 37 (m,2H),2. 35 (s,3H),2. 27-2. 18 (m,1H),2. 13-2. 02 (m,3H),I. 97 -I. 90 (m, 2H),I. 89-1. 78 (m, 2H),I. 74 (s, 3H),I. 63 (s, 3H),I. 60-1. 02 (m, 10H), 0. 98 (d,J =6. 5Hz, 3H), 0. 87 (d,J= 6. 5Hz, 3H), 0. 83 (d,J= 6. 4Hz, 3H), 0. 78 (d,J= 6. 6Hz, 3H), 0· 74(d,J= 6. 6Hz, 3H)。 MS (ESII) 7.8Hz, lH), 7.32 (t, J = 7.6Hz, 1H), 7.14 (d, J = 7.6Hz, 1H), 6.45 (s, lH), 6.44-6 · 33 (m, 1H ), 6. 27-6. 17 (m, 1H), 6. 17-6. 07 (m, 2H), 5. 46 (dd, J = 14. 8, 9. 7Hz, 1H), 5. 27 (s, 1H), 5. 02-4. 96 (m, 1H), 4. 96-4. 92 (m, 1H), 4. 50-4. 41 (m, 2H), 4. 06-3 . 97 (m, 2H), 4. 00-3. 90 (m, 1H), 3. 67-3. 59 (m, 1H), 3. 58-3. 41 (m, 3H), 3. 34 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 85 -2. 69 (m, 2H), 2. 45-2. 37 (m, 2H), 2. 35 (s, 3H), 2. 27-2. 18 (m, 1H), 2. 13-2. 02 (m, 3H), I. 97 -I. 90 (m, 2H), I. 89-1. 78 (m, 2H), I. 74 (s, 3H), I. 63 (s, 3H), I. 60-1. 02 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 5Hz, 3H), 0. 83 (d, J = 6. 4Hz, 3H), 0. 78 (d, J = 6. 6Hz, 3H ), 0 · 74 (d, J = 6. 6Hz, 3H). 13CNMR(126MHz,DMSO)δ210. 44, 198. 89, 169. 20, 166 .98, 146. 31, 139. 29, 137. 95, 137. 84, 137. 13, 132. 33, 130. 78, 130. 43, 128. 73, 128. 37, 127 .01, 125. 63, 124. 89, 122. 23, 121. 35, 99. 00, 85. 51, 82. 43, 82. 24, 81. 99, 75. 74, 73. 60, 66. 19, 65. 47, 56. 91, 55. 45, 50. 75, 46. 80, 45. 20, 43. 49, 38. 22, 35. 82, 35. 17, 34. 80, 33. 35, 32 .23, 30. 85, 30. 36, 29. 54, 26. 42, 26. 22, 24. 45, 21. 63, 21. 03, 15. 57, 15. 53, 14. 70, 13. 43,I 3. 35, 10. 45。 13CNMR (126MHz, DMSO) δ210. 44, 198. 89, 169. 20, 166 .98, 146. 31, 139. 29, 137. 95, 137. 84, 137. 13, 132. 33, 130. 78, 130.43, 128.73, 128.37, 127.01, 125.63, 124.89, 122.23, 121.35, 99.00, 85.51, 82.43, 82.24, 81. 99, 75.74, 73.60, 66.19, 65.47, 56.91, 55.45, 50.75, 46.80, 45.20, 43.49, 38.22, 35.82, 35.17, 34.80, 33.35, 32.23, 30.85, 30.36, 29.54, 26.42, 26.22, 24.45, 21.63, 21.03, 15. 57, 15. 53, 14. 70, 13. 43, I 3. 35, 10. 45.

[0196] 实施例19 :43-0-(3-(4-(2-氯苯基)-1Η-1,2, 3-三氮唑-I-基)正丙基)氧雷帕霉素(X-32) [0196] Example 19: 43-0- (3- (4- (2-chlorophenyl) -1Η-1,2, 3- triazole -I--yl) propyl) oxy-rapamycin (X-32)

[0197] 将43-0-(3-叠氮丙基)-氧雷帕霉素(0.35臟〇1^,0.358)和2-氯苯乙炔(0.18) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0. Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入60mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 16g,收率:40. 5%。 [0197] The 43-0- (3-azido-propyl) - oxo rapamycin (0.35 ^ 〇1 dirty, 0.358), and 2-chlorophenyl acetylene (0.18) was added to a DMF (IOmL) solution of the sodium ascorbate (0. Ig) and the reaction mixture was added copper sulfate pentahydrate (0.08 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 60mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 16g, yield: 405%. MS(ESI)m/ z: 1155. 6 (M+Na)+。 MS (ESI) m / z: 1155. 6 (M + Na) +. 1H NMR (500MHz,DMS0) δ 8. 63 (s,1H),8. 07 (d,J = 7. 8Hz,1H),7. 56 (d,J =9. 1Hz, 1H),7. 47-7. 43 (m, 1H),7. 42-7. 35 (m, 1H),6. 45 (s, 1H),6. 43-6. 34 (m, 1H),6. 26-6. 18 (m, 1H),6. 17-6. 08 (m, 2H),5. 46 (dd, J = 14. 8, 9. 7Hz, 1H),5. 27 (s, 1H),5. 09 ( d, J = 10. 2Hz, 1H),5. 01-4. 95 (m, 1H),4. 94-4. 92 (m, 1H),4. 55-4. 49 (m, 2H),4. 05-3. 9 8 (m,2H),3. 96-3. 91 (m,1H),3. 66-3. 58 (m,1H),3. 57-3. 39 (m,3H),3. 33 (s,3H),3. 30-3 .23 (m, 1H) ,3.15 (s, 3H), 3. 05 (s, 3H), 2. 84-2. 70 (m, 2H), 2. 47-2. 35 (m, 2H), 2. 25-2. 17 (m, 1H), 2. 14-2. 04 (m, 3H), 2. 02-1. 90 (m, 2H),I. 89-1. 79 (m, 2H),I. 74 (s, 3H),I. 63 (s, 3H),L60-1. 01(m, 10H), 0. 98(d,J= 6. 5Hz, 3H), 0. 87 (d,J= 6. 5Hz, 3H), 0. 82 (d,J= 6. 4Hz, 3H), 0. 78 (d,J= 6. 7Hz, 3H), 0. 73 (d,J= 6. 6Hz, 3H) 〇13CNMR(126MHz,DMSO)δ210 .47, 207. 50, 198. 90, 169. 18, 166. 97, 142. 46, 139. 28, 137. 83, 137. 13, 132. 31, 130. 41, 130 .26, 130. 16, 129. 46, 129. 32, 127. 47, 127. 00, 124. 92, 124 1H NMR (500MHz, DMS0) δ 8. 63 (s, 1H), 8. 07 (d, J = 7. 8Hz, 1H), 7. 56 (d, J = 9. 1Hz, 1H), 7. 47 -7. 43 (m, 1H), 7. 42-7. 35 (m, 1H), 6. 45 (s, 1H), 6. 43-6. 34 (m, 1H), 6. 26-6 . 18 (m, 1H), 6. 17-6. 08 (m, 2H), 5. 46 (dd, J = 14. 8, 9. 7Hz, 1H), 5. 27 (s, 1H), 5 . 09 (d, J = 10. 2Hz, 1H), 5. 01-4. 95 (m, 1H), 4. 94-4. 92 (m, 1H), 4. 55-4. 49 (m, 2H), 4. 05-3. 9 8 (m, 2H), 3. 96-3. 91 (m, 1H), 3. 66-3. 58 (m, 1H), 3. 57-3. 39 (m, 3H), 3. 33 (s, 3H), 3. 30-3 .23 (m, 1H), 3.15 (s, 3H), 3. 05 (s, 3H), 2. 84-2. 70 (m, 2H), 2. 47-2. 35 (m, 2H), 2. 25-2. 17 (m, 1H), 2. 14-2. 04 (m, 3H), 2. 02- 1. 90 (m, 2H), I. 89-1. 79 (m, 2H), I. 74 (s, 3H), I. 63 (s, 3H), L60-1. 01 (m, 10H) , 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 5Hz, 3H), 0. 82 (d, J = 6. 4Hz, 3H), 0. 78 ( d, J = 6. 7Hz, 3H), 0. 73 (d, J = 6. 6Hz, 3H) 〇13CNMR (126MHz, DMSO) δ210 .47, 207. 50, 198. 90, 169. 18, 166. 97, 142.46, 139.28, 137.83, 137.13, 132.31, 130.41, 130.26, 130.16, 129.46, 129.32, 127.47, 127.00, 124.92, 124 . 41,HO. 92, 98. 99, 85. 51, 82. 41 ,82. 24, 82. 04, 75. 72, 73. 60, 66. 18, 65. 39, 56. 90, 55. 44, 50. 72, 46. 81, 45. 18, 43. 47, 38.I 9, 35. 79, 35. 16, 34. 79, 33. 34, 32. 21, 30. 86, 30. 40, 29. 52, 26. 41, 26. 21, 24. 44, 21. 62, 20. 35, 15. 55, 15. 52, 14. 68, 13. 37, 10. 45〇 . 41, HO. 92, 98. 99, 85. 51, 82. 41, 82. 24, 82. 04, 75. 72, 73. 60, 66. 18, 65. 39, 56. 90, 55. 44 , 50. 72, 46. 81, 45. 18, 43. 47, 38.I 9, 35. 79, 35. 16, 34. 79, 33. 34, 32. 21, 30. 86, 30. 40, 29.52, 26.41, 26.21, 24.44, 21.62, 20.35, 15.55, 15.52, 14.68, 13.37, 10. 45〇

[0198] 实施例20 :43-0-(3-(4-(4-溴苯基2, 3-三氮唑-I-基)正丙基)氧雷帕霉素(X-30) [0198] Example 20: 43-0- (3- (4- (4-bromophenyl 2,3-triazole -I--yl) propyl) oxy rapamycin (X-30)

[0199] 将43-0-(3-叠氮丙基)-氧雷帕霉素(0.35臟〇1^0.35 8)和4-溴苯乙炔(0.18) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入60mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 14g,收率:34. 0%。 [0199] The 43-0- (3-azido-propyl) - oxo rapamycin (0.35 ^ 0.35 dirty 〇1 8) and 4-bromophenyl acetylene (0.18) was added to a DMF (IOmL) solution of the the reaction mixture was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 60mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 14g, yield: 340%. MS(ESI)m/ z: 1200. 3 (M+Na)+。 MS (ESI) m / z: 1200. 3 (M + Na) +. 1HNMR(500MHz,DMS0)δ8. 63 (s,1H),7. 79 (d,J= 8. 2Hz,2H),7. 64 (d,J =8. 2Hz,2H),6. 46 (s,1H),6. 44-6. 34 (m,1H),6. 27-6. 19 (m,1H),6. 17-6. 08 (m,2H),5. 46 (dd,J= 14. 7, 9. 6Hz,1H),5. 27 (s,1H),5. 13-5. 07 (m,1H),5. 02-4. 96 (m,1H),4. 97-4. 91 ( m,1H),4. 52-4. 42 (m,2H),4. 06-3. 97 (m,2H),3. 98-3. 91 (m,1H),3. 63 (m,1H),3. 57-3. 40 ( m, 3H), 3. 33 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 86-2. 68 (m, 2H), 2. 44-2. 34 (m, 2H), 2. 25- 2. 18 (m,1H),2. 14-2. 01 (m,3H),I. 98-1. 90 (m,2H),I. 89-1. 79 (m,2H),I. 75 (s,3H),I. 63 ( s, 3H), I. 60-1. 02 (m, 10H), 0. 98 (d, J= 6. 4Hz, 3H), 0. 87 (d, J= 6. 3Hz, 3H), 0. 83 (d,J= 6. 3Hz, 3H),0· 78 (d,J= 6. 4Hz, 3H),0· 73 (d,J= 6. 5Hz, 3H)。 1HNMR (500MHz, DMS0) δ8. 63 (s, 1H), 7. 79 (d, J = 8. 2Hz, 2H), 7. 64 (d, J = 8. 2Hz, 2H), 6. 46 (s , 1H), 6. 44-6. 34 (m, 1H), 6. 27-6. 19 (m, 1H), 6. 17-6. 08 (m, 2H), 5. 46 (dd, J = 14. 7, 9. 6Hz, 1H), 5. 27 (s, 1H), 5. 13-5. 07 (m, 1H), 5. 02-4. 96 (m, 1H), 4. 97 -4. 91 (m, 1H), 4. 52-4. 42 (m, 2H), 4. 06-3. 97 (m, 2H), 3. 98-3. 91 (m, 1H), 3 . 63 (m, 1H), 3. 57-3. 40 (m, 3H), 3. 33 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 86-2. 68 (m, 2H), 2. 44-2. 34 (m, 2H), 2. 25- 2. 18 (m, 1H), 2. 14-2. 01 (m, 3H), I. 98-1. 90 (m, 2H), I. 89-1. 79 (m, 2H), I. 75 (s, 3H), I. 63 (s, 3H), I. 60-1. 02 (m, 10H), 0. 98 (d, J = 6. 4Hz, 3H), 0. 87 (d, J = 6. 3Hz, 3H), 0. 83 (d, J = 6. 3Hz, 3H ), 0 · 78 (d, J = 6. 4Hz, 3H), 0 · 73 (d, J = 6. 5Hz, 3H). 13CNMR(126MHz,DMSO)δ210 .43, 207. 51,198. 88, 169. 21,166. 98, 145. 16, 139. 29, 137. 84, 137. 12, 132. 33, 131. 82, 130 .42, 130. 12, 127. 02, 124. 88, 121. 80, 120. 68, 99. 00, 85. 50, 82. 43, 82. 23, 81. 98, 75. 74, 73 .60, 66. 19, 65. 46, 56. 91, 55. 46, 50. 75, 46. 91, 45. 20, 43. 49, 38. 23, 35. 83, 35. 17, 34. 79, 3 3. 34, 32. 23, 30. 84, 30. 34, 29. 64, 29. 54, 26. 42, 26. 23, 24. 45, 21. 63, 20. 37, 15. 57, 15. 53, 14. 70, 13. 44, 13. 34, 10. 46〇 13CNMR (126MHz, DMSO) δ210 .43, 207. 51,198. 88, 169. 21,166. 98, 145. 16, 139. 29, 137. 84, 137. 12, 132. 33, 131. 82, 130.42, 130.12, 127.02, 124.88, 121.80, 120.68, 99.00, 85.50, 82.43, 82.23, 81.98, 75.74, 73. 60, 66.19, 65.46, 56.91, 55.46, 50.75, 46.91, 45.20, 43.49, 38.23, 35.83, 35.17, 34.79, 3 3.34, 32.23, 30.84, 30.34, 29.64, 29.54, 26.42, 26.23, 24.45, 21.63, 20.37, 15.57, 15 53, 14.70, 13.44, 13.34, 10. 46〇

[0200] 实施例21 :43-0-(3-(4-(4-甲氧基苯基2, 3-三氮唑-I-基)正丙基)氧雷帕霉素(X-29) [0200] Example 21: 43-0- (3- (4- (4-methoxyphenyl 2,3-triazole -I--yl) propyl) oxy rapamycin (X-29 )

[0201] 将43-0- (3-叠氮丙基)-氧雷帕霉素(0. 35mmoL, 0. 35g)和4-甲氧基苯乙炔(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0. 08g),室温搅拌2h,反应完毕后,将反应倒加入60mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 19g,收率: 48. 1 %。 [0201] The 43-0- (3-azido-propyl) - rapamycin oxygen (0. 35mmoL, 0. 35g) and 4-methoxyphenylacetylene (0.Ig) was added to a DMF (IOmL) solution, sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0. 08g) was added to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 60mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 19g, yield: 48.1%. MS(ESII)m/z:1151. 5 (M+Na)+。 MS (ESII) m / z:. 1151 5 (M + Na) +. 1HNMR(500MHz,DMS0)δ8. 45 (s,1H),7. 75 (d,J =8· 7Hz,2Η),7· 01 (d,J= 8· 8Hz,2Η),6· 45 (s,1Η),6· 44-6. 30 (m,1Η),6· 27-6. 19 (m,I Η), 6. 17-6. 04(m, 2Η), 5. 46(dd,J= 14. 8, 9. 6Ηζ, 1Η), 5. 28 (s, 1Η), 5. 10 (d,J= 10. 2Η ζ, 1Η), 5. 02-4. 96 (m, 1Η), 4. 96-4. 92 (m, 1Η), 4. 48-4. 37 (m, 2Η), 4. 06-3. 97 (m, 2Η), 3. 9 7-3. 89 (m, 1Η), 3. 79 (s, 3Η), 3. 66-3. 59 (m, 1Η), 3. 58-3. 39 (m, 3Η), 3. 34 (s, 3Η), 3. 16(s ,3Η), 3. 05 (s, 3Η), 2. 85-2. 68 (m, 1Η), 2. 44-2. 34 (m, 2Η), 2. 29-2. 14 (m, 1Η), 2. 15-2. 0 I(m, 3Η), 2. 01-1. 89 (m, 2Η), 1. 89-1. 77 (m, 2Η), 1. 75 (s, 3Η), 1. 63 (s, 3Η), 1. 62-1. 03 (-m, 10Η), 0. 98 (d,J= 6. 6Hz, 3Η), 0. 87 (d,J= 6. 5Hz, 3Η), 0. 83 (d,J= 6. 5Hz, 3Η), 0. 78 (d,J =6· 7Ηζ, 3Η), 0· 74(d,J= 6· 6Ηζ, 3Η)。 1HNMR (500MHz, DMS0) δ8. 45 (s, 1H), 7. 75 (d, J = 8 · 7Hz, 2Η), 7 · 01 (d, J = 8 · 8Hz, 2Η), 6 · 45 (s , 1Η), 6 · 44-6. 30 (m, 1Η), 6 · 27-6. 19 (m, I Η), 6. 17-6. 04 (m, 2Η), 5. 46 (dd, J = 14. 8, 9. 6Ηζ, 1Η), 5. 28 (s, 1Η), 5. 10 (d, J = 10. 2Η ζ, 1Η), 5. 02-4. 96 (m, 1Η) , 4. 96-4. 92 (m, 1Η), 4. 48-4. 37 (m, 2Η), 4. 06-3. 97 (m, 2Η), 3. 9 7-3. 89 (m , 1Η), 3. 79 (s, 3Η), 3. 66-3. 59 (m, 1Η), 3. 58-3. 39 (m, 3Η), 3. 34 (s, 3Η), 3. 16 (s, 3Η), 3. 05 (s, 3Η), 2. 85-2. 68 (m, 1Η), 2. 44-2. 34 (m, 2Η), 2. 29-2. 14 ( m, 1Η), 2. 15-2. 0 I (m, 3Η), 2. 01-1. 89 (m, 2Η), 1. 89-1. 77 (m, 2Η), 1. 75 (s , 3Η), 1. 63 (s, 3Η), 1. 62-1. 03 (-m, 10Η), 0. 98 (d, J = 6. 6Hz, 3Η), 0. 87 (d, J = 6. 5Hz, 3Η), 0. 83 (d, J = 6. 5Hz, 3Η), 0. 78 (d, J = 6 · 7Ηζ, 3Η), 0 · 74 (d, J = 6 · 6Ηζ, 3Η ). 13CNMR(126MHz,DMS0)δ210. 44, 207. 51,198. 88, 1 69. 20, 166. 98, 158. 90, 146. 15, 139. 29, 137. 84, 137. 13, 132. 33, 130. 42, 127. 01,126. 38, 1 24. 88, 123. 47, 120. 45, 114. 25, 99. 00, 85. 50, 82. 43, 82. 23, 82. 00, 75. 74, 73. 60, 66. 19, 65 .48, 56. 92, 55. 45, 55. 10, 50. 75, 46. 74, 45. 20, 43. 49, 38. 23, 35. 83, 35. 16, 34. 79, 33. 35, 3 2. 23, 30. 86, 30. 40, 29. 64, 29. 54, 26. 42, 26. 23, 24. 45, 21. 63, 20. 37, 15. 57, 15. 52, 14. 70, 13. 44, 13. 34, 10. 46〇 13CNMR (126MHz, DMS0) δ210. 44, 207. 51,198. 88, 1 69. 20, 166. 98, 158. 90, 146. 15, 139. 29, 137. 84, 137. 13, 132. 33 , 130.42, 127. 01,126. 38, 1 24.88, 123.47, 120.45, 114.25, 99.00, 85.50, 82.43, 82.23, 82.00, 75.74, 73.60, 66.19, 65.48, 56.92, 55.45, 55.10, 50.75, 46.74, 45.20, 43.49, 38.23, 35. 83, 35.16, 34.79, 33.35, 3 2.23, 30.86, 30.40, 29.64, 29.54, 26.42, 26.23, 24.45, 21.63 , 20.37, 15.57, 15.52, 14.70, 13.44, 13.34, 10. 46〇

[0202] 实施例22 :43-0-(3-(4-((2, 5二氯苯基)氨基甲基2, 3-三氮唑-1-基) 正丙基)氧雷帕霉素(Χ-23) [0202] Example 22: 43-0- (3- (4 - ((2, 5-dichlorophenyl) aminomethyl 2, 3-triazole-1-yl) propyl) oxy-rapamycin Su (Χ-23)

[0203]将43-0-(3-叠氮丙基)-氧雷帕霉素(0· 35mmoL,0· 35g)和N-(丙-2-炔基)-2, 5-二氯苯胺(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig) 和五水硫酸铜(0. 08g),室温搅拌2h,反应完毕后,将反应倒加入60mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 09g,收率:21.5%。 [0203] The 43-0- (3-azido-propyl) - rapamycin oxygen (0 · 35mmoL, 0 · 35g) and N- (prop-2-ynyl) -2, 5-dichloroaniline (0.Ig) was added to a DMF (IOmL) was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0. 08g) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured added 60mL water, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid, was isolated by silica gel column chromatography and C18 preparative chromatography to give 0. 09g, yield of the pure product: 21.5%. ]\^伍511)111/2:1218.7(]\1+似)+。 ] \ ^ Ng 511) 111/2: 1218.7 (] \ 1+ like) +. 1!1匪1?(500皿取,01^0)3 7.92(8,1!1),7.24((1,了=8. 4Hz, 1H),6. 75 (s, 1H),6. 59 (d,J= 8. 4Hz, 1H),6. 44 (s, 1H),6. 41-6. 33 (m, 1H),6. 26 -6. 17 (m, 2H),6. 16-6. 09 (m, 2H),5. 47 (dd,J= 14. 9, 9. 6Hz, 1H),5. 26 (s, 1H),5. 13-5. 07 ( m, 1H),5. 03-4. 96 (m, 1H),4. 97-4. 90 (m, 1H),4. 47-4. 35 (m, 4H),4. 07-3. 92 (m, 3H),3. 66- 3. 59 (m, 1H),3. 49-3. 39 (m, 2H),3. 29 (s, 3H),3. 16 (s, 3H), 3. 05 (s, 3H),2. 98-2. 89 (m, 2H) ,2. 87-2. 77 (m, 1H),2. 77-2. 68 (m, 1H),2. 46-2. 35 (m, 2H), 2. 28-2. 18 (m, 1H),2. 16-2. 06 ( m, 1H),2. 06-1. 96 (m, 3H),I. 94-1. 79 (m, 3H),I. 74 (s, 3H), I. 63 (s, 3H),L60-1. 00 (m, IOH ),0. 98 (d,J= 6. 5Hz, 3H),0. 88 (d,J= 6. 5Hz, 3H),0. 83 (d,J= 6. 4Hz, 3H),0. 78 (d,J= 6. 7Hz, 3H), 0· 74(d,J= 6. 6Hz, 3H)。13CNMR(126MHz,DMSO)δ210. 44, 207. 47, 198. 85, 169 .19, 166. 95, 144. 83, 144. 72, 139. 28, 137. 82, 137. 10, 132. 44, 132. 32, 130. 00, 126. 96, 124 .89, 122. 85, 116. 50, 115. 96,HO. 87, 98. 98, 85. 51, 82. 33, 82. 24, 81. 96, 75. 73, 73. 59, 66. 3 1! 1 1 bandit? (500 take dish, 01 ^ 0) 3 7.92 (8,1! 1), 7.24 ((1, a = 8. 4Hz, 1H), 6. 75 (s, 1H), 6. 59 (d, J = 8. 4Hz, 1H), 6. 44 (s, 1H), 6. 41-6. 33 (m, 1H), 6. 26 -6. 17 (m, 2H), 6. 16-6. 09 (m, 2H), 5. 47 (dd, J = 14. 9, 9. 6Hz, 1H), 5. 26 (s, 1H), 5. 13-5. 07 (m, 1H ), 5. 03-4. 96 (m, 1H), 4. 97-4. 90 (m, 1H), 4. 47-4. 35 (m, 4H), 4. 07-3. 92 (m , 3H), 3. 66- 3. 59 (m, 1H), 3. 49-3. 39 (m, 2H), 3. 29 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 98-2. 89 (m, 2H), 2. 87-2. 77 (m, 1H), 2. 77-2. 68 (m, 1H), 2. 46- 2. 35 (m, 2H), 2. 28-2. 18 (m, 1H), 2. 16-2. 06 (m, 1H), 2. 06-1. 96 (m, 3H), I. 94-1. 79 (m, 3H), I. 74 (s, 3H), I. 63 (s, 3H), L60-1. 00 (m, IOH), 0. 98 (d, J = 6. 5Hz, 3H), 0. 88 (d, J = 6. 5Hz, 3H), 0. 83 (d, J = 6. 4Hz, 3H), 0. 78 (d, J = 6. 7Hz, 3H), 0 · 74 (d, J = 6. 6Hz, 3H) .13CNMR (126MHz, DMSO) δ210. 44, 207. 47, 198. 85, 169 .19, 166. 95, 144. 83, 144. 72, 139 . 28, 137. 82, 137. 10, 132. 44, 132. 32, 130. 00, 126. 96, 124 .89, 122. 85, 116. 50, 115. 96, HO. 87, 98. 98 , 85.51, 82.33, 82.24, 81.96, 75.73, 73.59, 66.3 1, 66. 18, 65. 27, 56. 92, 56. 82, 55. 44, 50. 75, 46. 53, 45. 19, 43. 46, 38. 22, 35. 74, 35. 15, 34 .77, 33. 36, 32. 22, 30. 81, 30. 38, 29. 62, 29. 43, 26. 41, 26. 22, 24. 44, 21. 61, 20. 34, 15. 55,I 5. 52, 14. 73, 13. 40, 13. 37, 10. 45〇 1, 66.18, 65.27, 56.92, 56.82, 55.44, 50.75, 46.53, 45.19, 43.46, 38.22, 35.74, 35.15, 34.77, 33.36, 32.22, 30.81, 30.38, 29.62, 29.43, 26.41, 26.22, 24.44, 21.61, 20.34, 15. 55, I 5. 52, 14. 73, 13. 40, 13. 37, 10. 45〇

[0204] 实施例23 :43-0-(3-(4-((2, 4二氯苯基)氨基甲基2, 3-三氮唑-I-基) 正丙基)氧雷帕霉素(X-25) [0204] Example 23: 43-0- (3- (4 - ((2, 4-dichlorophenyl) aminomethyl 2, 3-triazole -I--yl) propyl) oxy-rapamycin Su (X-25)

[0205] 将43-0-(3-叠氮丙基)-氧雷帕霉素(0· 35mmoL,0· 35g)和N-(丙-2-炔基)-2,4-二氯苯胺(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入60mL水中, 析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品〇·l〇g,收率:23.9 %。 [0205] The 43-0- (3-azido-propyl) - rapamycin oxygen (0 · 35mmoL, 0 · 35g) and N- (prop-2-ynyl) -2,4-dichloroaniline (0.Ig) was added to a DMF (IOmL) was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured in water was added 60mL , the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure square-l〇g, yield: 23.9%. MS(ESI)m/z:1218.6(M+Na)+。 MS (ESI) m / z: 1218.6 (M + Na) +. 1HNMR(500MHz,DMS0) δ7. 89 (s, 1H),7. 32 (s, 1H),7. 13(d,J=8. 7Hz, 1H),6.72(d,J=8. 8Hz, 1H),6. 44(s, 1H) ,6. 41-6. 31 (m, 1H),6. 29-6. 17 (m, 1H),6. 18-6. 05 (m, 2H),5. 51-5. 41 (m, 1H),5. 26 (s, 1H), 5. 10 (d,J= 9. 6Hz, 1H), 5. 02-4. 96 (m, 1H), 4. 96-4. 93 (m, 1H), 4. 43 (s, 2H), 4. 41-4. 32(m ,2H),4. 05-3. 97 (m, 2H),3. 94 (m, 1H),3. 66-3. 59 (m, 1H),3. 49-3. 38 (m, 3H),3. 29 (s, 3H), 3. 16 (s, 3H),3. 05 (s, 3H),2. 97-2. 86 (m, 2H),2. 84-2. 66 (m, 2H),2. 44-2. 34 (m, 2H),2. 28-2. 15 (m, 1H),2. 14-2. 00 (m, 2H),2. 01-1. 93 (m, 2H),I. 93-1. 79 (m, 2H),I. 74 (s, 3H),I. 63 ( s, 3H),I. 60-1. 02 (m, 11H),0. 98 (d,J= 6. 4Hz, 3H),0. 87 (d,J= 6. 5Hz, 3H),0. 83 (d,J= 6. 5Hz, 3H),0· 78 (d,J= 6. 6Hz, 3H),0· 73 (d,J= 6. 6Hz, 3H)。 1HNMR (500MHz, DMS0) δ7. 89 (s, 1H), 7. 32 (s, 1H), 7. 13 (d, J = 8. 7Hz, 1H), 6.72 (d, J = 8. 8Hz, 1H ), 6. 44 (s, 1H), 6. 41-6. 31 (m, 1H), 6. 29-6. 17 (m, 1H), 6. 18-6. 05 (m, 2H), 5. 51-5. 41 (m, 1H), 5. 26 (s, 1H), 5. 10 (d, J = 9. 6Hz, 1H), 5. 02-4. 96 (m, 1H), 4. 96-4. 93 (m, 1H), 4. 43 (s, 2H), 4. 41-4. 32 (m, 2H), 4. 05-3. 97 (m, 2H), 3. 94 (m, 1H), 3. 66-3. 59 (m, 1H), 3. 49-3. 38 (m, 3H), 3. 29 (s, 3H), 3. 16 (s, 3H) , 3. 05 (s, 3H), 2. 97-2. 86 (m, 2H), 2. 84-2. 66 (m, 2H), 2. 44-2. 34 (m, 2H), 2 . 28-2. 15 (m, 1H), 2. 14-2. 00 (m, 2H), 2. 01-1. 93 (m, 2H), I. 93-1. 79 (m, 2H) , I. 74 (s, 3H), I. 63 (s, 3H), I. 60-1. 02 (m, 11H), 0. 98 (d, J = 6. 4Hz, 3H), 0. 87 (d, J = 6. 5Hz, 3H), 0. 83 (d, J = 6. 5Hz, 3H), 0 · 78 (d, J = 6. 6Hz, 3H), 0 · 73 (d, J = 6. 6Hz, 3H). 13CNMR(126MHz,DMSO)δ210 .42, 207. 46, 198. 84, 169. 18, 166. 95, 144. 92, 142. 79, 139. 27, 137. 82, 137. 09, 132. 31, 130 .39, 128. 12, 127. 60, 126. 95, 124. 88, 122. 83, 119. 14, 118. 38, 112. 45, 98. 98, 85. 50, 82. 32 ,82. 23, 81. 95, 75. 73, 73. 57, 66. 17, 65. 26, 56. 91, 56. 80, 55. 43, 50. 75, 46. 48, 45. 18, 43. 4 6, 38. 40, 38. 19, 35. 73, 35. 14, 34. 77, 33. 37, 32. 22, 30. 77, 30. 36, 29. 42, 26. 41, 26. 22, 24. 43, 21. 61, 20. 34, 15. 55, 15. 52, 14. 75, 13. 40, 13. 36, 10. 45〇 13CNMR (126MHz, DMSO) δ210 .42, 207. 46, 198. 84, 169. 18, 166. 95, 144. 92, 142. 79, 139. 27, 137. 82, 137. 09, 132. 31, 130.39, 128.12, 127.60, 126.95, 124.88, 122.83, 119.14, 118.38, 112.45, 98.98, 85.50, 82.32, 82. 23, 81.95, 75.73, 73.57, 66.17, 65.26, 56.91, 56.80, 55.43, 50.75, 46.48, 45.18, 43.4. 6 , 38.40, 38.19, 35.73, 35.14, 34.77, 33.37, 32.22, 30.77, 30.36, 29.42, 26.41, 26.22, 24 43, 21.61, 20.34, 15.55, 15.52, 14.75, 13.40, 13.36, 10. 45〇

[0206] 实施例24 :43-0-(3-(4-((2, 6二氟苯基)氨基甲基2, 3-三氮唑-I-基) 正丙基)氧雷帕霉素(X-24) [0206] Example 24: 43-0- (3- (4 - ((2, 6-difluorophenyl) aminomethyl-2, 3-triazole -I--yl) propyl) oxy-rapamycin Su (X-24)

[0207]将43-0-(3-叠氮丙基)-氧雷帕霉素(0· 35mmoL,0· 35g)和N-(丙-2-炔基)-2, 6-二氟苯胺(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig) 和五水硫酸铜(0. 08g),室温搅拌2h,反应完毕后,将反应倒加入60mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 12g,收率:29.8%。 [0207] The 43-0- (3-azido-propyl) - rapamycin oxygen (0 · 35mmoL, 0 · 35g) and N- (prop-2-ynyl) -2, 6-difluoroaniline (0.Ig) was added to a DMF (IOmL) was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0. 08g) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured added 60mL water, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid, was isolated by silica gel column chromatography and C18 preparative chromatography to give 0. 12g, yield of the pure product: 29.8%. ]\^伍511)111/2:1186.7(]\1+似)+。 ] \ ^ Ng 511) 111/2: 1186.7 (] \ 1+ like) +. 1!1匪1?(5001取,01^0)3 7.84(8,1!1),6.89(^ =9. 0Hz, 2H),6. 70-6. 60 (m, 1H),6. 44 (s, 1H),6. 41-6. 32 (m, 1H),6. 28-6. 17 (m, 1H),6. 18 -6. 07 (m, 2H),5. 53-5. 42 (m, 2H),5. 26 (s, 1H),5. 10(d,J=9. 9Hz, 1H),5. 03-4. 97 (m, 1H), 4. 96 (m, 1H), 4. 45 (s, 2H), 4. 38-4. 33 (m, 2H), 4. 05-3. 98 (m, 2H), 3. 98-3. 92 (m, 1H), 3. 67- 3. 60 (m, 1H), 3. 48-3. 36 (m, 3H), 3. 31 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 99-2. 93 (m, 2H) ,2. 86-2. 78 (m, 1H), 2. 76-2. 70 (m, 1H), 2. 46-2. 35 (m, 2H), 2. 27-2. 17 (m, 1H), 2. 15-2. 02 ( m, 2H), 1. 99-1. 89 (m, 2H), 1. 89-1. 78 (m, 2H), 1. 75 (s, 3H), 1. 64 (s, 3H), 1. 58-1. 01 (m,IOH ),0. 98 (d,J= 6. 4Hz, 3H), 0. 88 (d,J= 6. 4Hz, 3H), 0. 83 (d,J= 6. 4Hz, 3H), 0. 78 (d,J= 6. 6Hz, 3H),0· 74 (d,J= 6. 5Hz, 3H)。 1! 1 1 bandit? (Take 5001, 01 ^ 0) 3 7.84 (8,1! 1), 6.89 (^ = 9. 0Hz, 2H), 6. 70-6. 60 (m, 1H), 6. 44 (s, 1H), 6. 41-6. 32 (m, 1H), 6. 28-6. 17 (m, 1H), 6. 18 -6. 07 (m, 2H), 5. 53- 5. 42 (m, 2H), 5. 26 (s, 1H), 5. 10 (d, J = 9. 9Hz, 1H), 5. 03-4. 97 (m, 1H), 4. 96 ( m, 1H), 4. 45 (s, 2H), 4. 38-4. 33 (m, 2H), 4. 05-3. 98 (m, 2H), 3. 98-3. 92 (m, 1H), 3. 67- 3. 60 (m, 1H), 3. 48-3. 36 (m, 3H), 3. 31 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 99-2. 93 (m, 2H), 2. 86-2. 78 (m, 1H), 2. 76-2. 70 (m, 1H), 2. 46-2 . 35 (m, 2H), 2. 27-2. 17 (m, 1H), 2. 15-2. 02 (m, 2H), 1. 99-1. 89 (m, 2H), 1. 89 -1. 78 (m, 2H), 1. 75 (s, 3H), 1. 64 (s, 3H), 1. 58-1. 01 (m, IOH), 0. 98 (d, J = 6 . 4Hz, 3H), 0. 88 (d, J = 6. 4Hz, 3H), 0. 83 (d, J = 6. 4Hz, 3H), 0. 78 (d, J = 6. 6Hz, 3H) , 0 · 74 (d, J = 6. 5Hz, 3H).

[0208] 实施例25 :43-0-(3-(4-((2-氟苯基)氨基甲基)-1Η-1,2, 3-三氮唑-I-基)正丙基)氧雷帕霉素(X-28) [0208] Example 25: 43-0- (3- (4 - ((2-fluorophenyl) aminomethyl) -1Η-1,2, 3- triazole -I--yl) propyl) oxygen rapamycin (X-28)

[0209] 将43-0-(3-叠氮丙基)-氧雷帕霉素(0· 35mmoL,0· 35g)和N-(丙-2-炔基)-2-氟苯胺(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(〇. 〇8g),室温搅拌2h,反应完毕后,将反应倒加入60mL水中,析出淡黄色固体, 抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 10g,收率: 24.7%。 [0209] The 43-0- (3-azido-propyl) - rapamycin oxygen (0 · 35mmoL, 0 · 35g) and N- (prop-2-ynyl) -2-fluoro-aniline (0. Ig) was added to a DMF (IOmL) was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (square. 〇8g), stirred for 2h at room temperature the reaction solution, after completion of the reaction, the reaction was poured added 60mL of water, precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to give 0. 10g, yield of the pure product: 24.7%. MS(ESII)m/z:1168.5(M+Na)+。 MS (ESII) m / z: 1168.5 (M + Na) +. 1HNMR(500MHz,DMS0)S7.91(s,lH),6.99(dd,J= 12. 2, 7. 9Hz, 1H),6. 91 (t,J= 7. 6Hz, 1H),6. 74 (t,J= 8. 7Hz, 1H),6. 54 (dd,J= 12. 4, 6. 4H z, 1H),6. 46 (s, 1H),6. 44-6. 34 (m, 1H),6. 26-6. 18 (m, 1H),6. 17-6. 08 (m, 2H),5. 90 (s, 1H), 5. 51-5. 43 (m, 1H), 5. 28 (s, 1H), 5. 10 (d,J = 10. 2Hz, 1H), 5. 01-4. 96 (m, 1H), 4. 97-4. 90(m ,1H), 4. 41-4. 31 (m, 4H), 4. 05-3. 97 (m, 2H), 3. 98-3. 92 (m, 1H), 3. 66-3. 58 (m, 1H), 3. 49-3 .35 (m, 3H), 3. 32 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 3. 00-2. 89 (m, 2H), 2. 85-2. 69 (m, 2H), 2. 43-2. 34 (m, 2H),2. 27-2. 17 (m, 1H),2. 15-2. 02 (m, 2H),2. 02-1. 93 (m, 2H),I. 93-1. 79(m ,2H),I. 75 (s, 3H),I. 63 (s, 3H),I. 62-1. 02 (m, 10H),0. 98 (d,J= 6. 5Hz, 3H),0. 87 (d,J= 6. 4Hz, 3H),0· 83 (d,J= 6. 3Hz, 3H),0· 78 (d,J= 6. 6Hz, 3H),0· 74 (d,J= 6. 5Hz, 3H)。 1HNMR (500MHz, DMS0) S7.91 (s, lH), 6.99 (dd, J = 12. 2, 7. 9Hz, 1H), 6. 91 (t, J = 7. 6Hz, 1H), 6. 74 (t, J = 8. 7Hz, 1H), 6. 54 (dd, J = 12. 4, 6. 4H z, 1H), 6. 46 (s, 1H), 6. 44-6. 34 (m , 1H), 6. 26-6. 18 (m, 1H), 6. 17-6. 08 (m, 2H), 5. 90 (s, 1H), 5. 51-5. 43 (m, 1H ), 5. 28 (s, 1H), 5. 10 (d, J = 10. 2Hz, 1H), 5. 01-4. 96 (m, 1H), 4. 97-4. 90 (m, 1H ), 4. 41-4. 31 (m, 4H), 4. 05-3. 97 (m, 2H), 3. 98-3. 92 (m, 1H), 3. 66-3. 58 (m , 1H), 3. 49-3 .35 (m, 3H), 3. 32 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 3. 00-2. 89 (m, 2H), 2. 85-2. 69 (m, 2H), 2. 43-2. ​​34 (m, 2H), 2. 27-2. 17 (m, 1H), 2. 15- 2. 02 (m, 2H), 2. 02-1. 93 (m, 2H), I. 93-1. 79 (m, 2H), I. 75 (s, 3H), I. 63 (s, 3H), I. 62-1. 02 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0 · 83 ( d, J = 6. 3Hz, 3H), 0 · 78 (d, J = 6. 6Hz, 3H), 0 · 74 (d, J = 6. 5Hz, 3H). 13C NMR(126MHz,DMSO)δ210. 43, 207. 51, 198. 87, 169. 21, 166. 97, 145. 50, 139. 30, 137. 84, 137 .12, 136. 30, 136. 21, 132. 33, 130. 42, 127. 02, 124. 86, 124. 56, 122. 79, 115. 71, 114. 28, 114 .14, 112. 22, 99. 00, 85. 49, 82. 36, 82. 23, 81. 96, 75. 75, 73. 59, 66. 19, 65. 35, 56. 91, 56. 87, 55. 46, 50. 77, 46. 50, 45. 20, 43. 49, 38. 26, 35. 79, 35. 17, 34. 79, 33. 36, 32. 21, 30. 81, 30. 44 ,29. 63, 29. 57, 29. 47, 26. 43, 26. 23, 24. 46, 21. 63, 20. 36, 15. 57, 15. 53, 14. 72, 13. 46, 13. 3 4, 10. 46。 13C NMR (126MHz, DMSO) δ210. 43, 207. 51, 198. 87, 169. 21, 166. 97, 145. 50, 139. 30, 137. 84, 137 .12, 136. 30, 136. 21 , 132.33, 130.42, 127.02, 124.86, 124.56, 122.79, 115.71, 114.28, 114.14, 112.22, 99.00, 85.49, 82 36, 82.23, 81.96, 75.75, 73.59, 66.19, 65.35, 56.91, 56.87, 55.46, 50.77, 46.50, 45.20 , 43.49, 38.26, 35.79, 35.17, 34.79, 33.36, 32.21, 30.81, 30.44, 29.63, 29.57, 29.47, 26 43, 26.23, 24.46, 21.63, 20.36, 15.57, 15.53, 14.72, 13.46, 13.3 4 10.46.

[0210] 实施例26 :43-0-(2-(4-(4-氟苯基)-1Η-1,2, 3-三氮唑-I-基)乙酰基)氧雷帕霉素(X-39) [0210] Example 26: 43-0- (2- (4- (4-fluorophenyl) -1Η-1,2, 3- triazole -I- yl) acetyl) oxy-rapamycin ( X-39)

[0211] 步骤A:28-氧基二甲基娃烧基-雷帕霉素的制备 [0211] Step A: - Preparation of rapamycin 28-yl group baby burn dimethyl

[0212] 分别将雷帕霉素(5. 5mmol,5.Og)和咪唑(I. 5g)加入到乙酸乙酯(80mL)溶液中, 加料完毕后冷却至〇_5°C,滴加三甲基氯硅烷(40mmol,4. 3g),保温反应2小时。 [0212] Rapamycin, respectively (5. 5mmol, 5.Og) and imidazole (I. 5g) was added to ethyl acetate (80 mL) solution, after the addition was complete was cooled to 〇_5 ° C, added dropwise chlorotrimethylsilane (40mmol, 4. 3g), incubated for 2 hours. 当形成双硅醚保护产品后,向反应液倾加入稀硫酸(15mL,INH2SO4),继续搅拌反应约16h,反应完毕后, 反应液分别经饱和碳酸氢钠,饱和食盐水洗涤,有机层经无水硫酸钠干燥,蒸干得白色泡沫状固体5.lg,收率:95%。 After the formation of bis silyl ether protecting products, the reaction solution was poured into dilute sulfuric acid (15mL, INH2SO4), stirring was continued for about for 16 h, after completion of the reaction, the reaction liquid were treated with saturated sodium bicarbonate, saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and evaporated to dryness to give a white foamy solid 5.lg, yield: 95%. MS(ESI)m/z:1008. 5(M+Na)+。 MS (ESI) m / z:. 1008 5 (M + Na) +.

[0213] 步骤B:28_氧基二甲基娃烧基-43-0-(2-氣乙醜基)-氧雷帕霉素的制备 [0213] Step B: 28_ dimethyl baby burn-yl group -43-0- (2 gas Chou-yl) - Preparation oxygen rapamycin

[0214] 将28-0TMS-雷帕霉素(2. 6g,2. 6mmol)和无水二氯甲烷(40mL)加入到三颈瓶中, 加入三乙胺(3mL),0-5°C下逐滴加入氯乙酰氯(0. 59g,5. 2mmol),加毕,0-5°C反应6h。 [0214] The 28-0TMS- rapamycin (2. 6g, 2. 6mmol) and anhydrous dichloromethane (40 mL) was added to a three-neck flask, was added triethylamine (3mL), 0-5 ° C was added dropwise chloroacetyl chloride (0. 59g, 5. 2mmol), the addition is complete, 0-5 ° C the reaction 6h. 反应完毕后,将反应液倾入300mL水中,二氯甲烷提取,合并提取液,水洗,无水硫酸钠干燥。 After completion of the reaction, the reaction solution was poured into 300mL water and extracted with dichloromethane, combined extracts were washed with water, dried over anhydrous sodium sulfate. 蒸干得白色固体2.lg,收率:76. 1%MS(ESI)m/z:1084. 6(M+Na)+。 Evaporated to dryness to give a white solid 2.lg, yield:. 76 1% MS (ESI) m / z:. 1084 6 (M + Na) +.

[0215] 步骤C:43-0-(2-氯乙酰基)-氧雷帕霉素的制备 [0215] Step C: 43-0- (2- chloroacetyl) - Preparation oxygen rapamycin

[0216] 将28-0TMS-43-0-(2-氯乙酰基)-氧雷帕霉素(2mmol,2.Ig)加入到丙酮(36mL) 溶液中,加料完毕后冷却至〇_5°C,向反应液加入稀硫酸(10mL,INH2SO4),继续搅拌反应约2h,反应完毕后,反应液分别经饱和碳酸氢钠,饱和食盐水洗涤,有机层经无水硫酸钠干燥, 蒸干得白色泡沫状固体I. 8g,收率:91%。 [0216] The 28-0TMS-43-0- (2- chloroacetyl) - oxo rapamycin (2mmol, 2.Ig) was added to acetone (36mL) solution, after the addition was complete was cooled to ° 〇_5 C, and the reaction solution to dilute sulfuric acid (10mL, INH2SO4), stirring was continued for about 2h, after completion of the reaction, the reaction liquid were treated with saturated sodium bicarbonate, saturated brine, the organic layer was dried over anhydrous sodium sulfate, and evaporated to dryness to give as a white foamy solid I. 8g, yield: 91%. MS(ESI)m/z:1012. 5(M+Na)+。 MS (ESI) m / z:. 1012 5 (M + Na) +.

[0217] 步骤D:43-0-(2-叠氮乙酰基)-氧雷帕霉素的制备 [0217] Step D: 43-0- (2- azido-acetyl) - Preparation oxygen rapamycin

[0218] 分别将43-0-(2-氯乙酰基)_氧雷帕霉素(I. 8g,I. 8mmol)和叠氮化钠(0. 3g,4.6mmol)加入到(300mL)DMF溶液中,加料完毕后升温到50°C,反应完全后,将反应液倾入IOOmL水中,乙酸乙酯提取2次,合并提取液,水洗,无水硫酸钠干燥。 [0218] respectively, 43-0- (2-chloroacetyl) _ oxygen rapamycin (I. 8g, I. 8mmol) and sodium azide (0. 3g, 4.6mmol) was added to (300mL) DMF solution, after completion of the addition was warmed to 50 ° C, after completion of the reaction, the reaction solution was poured into IOOmL water and extracted twice with ethyl acetate, the combined extracts washed with water, dried over anhydrous sodium sulfate. 蒸干得油状物, 经柱层析分离分别得到〇. 6g,收率为33%。 Evaporated to dryness to give an oil which was purified by column chromatography billion respectively. 6g, 33% yield. MS(ESI)m/z:1019. 5 (M+Na)+。 MS (ESI) m / z:. 1019 5 (M + Na) +.

[0219] 步骤E:43-0-(2-(4-(4-氟苯基)-1Η-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素的制备 [0219] Step E: (3- triazole-1-yl) acetyl-2- (4- (4-fluorophenyl) -1Η-1,2,) preparing rapamycin 43-0- oxygen

[0220] 将43-0-(2-叠氮乙酰基)-氧雷帕霉素(0. 35mmoL, 0. 35g)和丙炔醇(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 14g,收率:34. 6%。 [0220] The 43-0- (2-azido-acetyl) - oxo rapamycin (0. 35mmoL, 0. 35g) and propargyl alcohol (0.Ig) was added to a DMF (IOmL) solution of the the reaction mixture was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 14g, yield: 346%. MS(ESI)m/ z: 1139. 6 (M+Na)+。 MS (ESI) m / z: 1139. 6 (M + Na) +. 1HNMR(500MHz,DMSO)δ8. 57 (s,1H),7. 94-7. 87 (m,2H),7. 33-7. 27 (m,2H ),6· 46 (s,1H),6· 43-6. 35 (m,1H),6· 26-6. 18 (m,1H),6· 17-6. 09 (m,2H),5· 51-5. 43 (m,2H), 5· 29 (s,1H),5· 10 (d,J= 9. 9Hz,1H),5· 00-4. 96 (m,1H),4· 96-4. 92 (m,1H),4· 70-4. 60 (m,I Η),4· 05-3. 98 (m,2H),3· 99-3. 93 (m,1H),3· 66-3. 58 (m,1H),3· 48-3. 38 (m,1H),3· 27 (s,3H) ,3· 16 (s,3Η),3· 05 (s,3Η),2· 86-2. 69 (m,2Η),241 - 2· 37 (m,2Η),2· 26-2. 16 (m,1Η),2· 14-2 • 06 (m,2Η),2· 07-1. 89 (m,3Η),I. 87-1. 77 (m,2Η),I. 75 (s,3Η),I. 63 (s,3Η),I. 60-1. 03 (m,I OH),0. 98 (d,J= 6. 3Hz, 3H),0. 87 (d,J= 6. 4Hz, 3H),0. 82 (d,J= 6. 3Hz, 3H),0. 78 (d,J= 6.5Hz,3H),0.73(d,J= 6.3Hz,3H)。 1HNMR (500MHz, DMSO) δ8. 57 (s, 1H), 7. 94-7. 87 (m, 2H), 7. 33-7. 27 (m, 2H), 6 · 46 (s, 1H), 6 · 43-6. 35 (m, 1H), 6 · 26-6. 18 (m, 1H), 6 · 17-6. 09 (m, 2H), 5 · 51-5. 43 (m, 2H ), 5 · 29 (s, 1H), 5 · 10 (d, J = 9. 9Hz, 1H), 5 · 00-4. 96 (m, 1H), 4 · 96-4. 92 (m, 1H ), 4 · 70-4. 60 (m, I Η), 4 · 05-3. 98 (m, 2H), 3 · 99-3. 93 (m, 1H), 3 · 66-3. 58 ( m, 1H), 3 · 48-3. 38 (m, 1H), 3 · 27 (s, 3H), 3 · 16 (s, 3Η), 3 · 05 (s, 3Η), 2 · 86-2 . 69 (m, 2Η), 241 -. 2 · 37 (m, 2Η), 2 · 26-2 16 (m, 1Η), 2 · 14-2 • 06 (m, 2Η), 2 · 07-1 . 89 (m, 3Η), I. 87-1. 77 (m, 2Η), I. 75 (s, 3Η), I. 63 (s, 3Η), I. 60-1. 03 (m, I OH), 0. 98 (d, J = 6. 3Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0. 82 (d, J = 6. 3Hz, 3H), 0. 78 (d, J = 6.5Hz, 3H), 0.73 (d, J = 6.3Hz, 3H). 13CNMR(126MHz,DMS0)δ210·38,207·53,198·86,169 .22, 166. 99, 166. 70, 160. 82, 145. 48, 139. 31, 137. 86, 137. 15, 132. 34, 130. 41, 127. 21, 127 .14, 127. 09, 126. 99, 124. 81, 122. 66, 115. 94, 115. 77, 99. 01, 85. 46, 82. 22, 79. 85, 77. 74, 7 5. 73, 73. 65, 66. 19, 56. 89, 56. 76, 55. 45, 50. 78, 50. 67, 45. 23, 43. 50, 38. 01, 35. 16, 34. 80, 33. 32, 31. 87, 30. 43, 29. 65, 29. 14, 26. 40, 26. 23, 24. 44, 21. 62, 20. 37, 15. 52, 14. 63, 13. 50 ,13. 29, 10. 45。 13CNMR (126MHz, DMS0) δ210 · 38,207 · 53,198 · ​​86,169 .22, 166. 99, 166. 70, 160. 82, 145. 48, 139. 31, 137. 86, 137. 15, 132. 34, 130.41, 127.21, 127.14, 127.09, 126.99, 124.81, 122.66, 115.94, 115.77, 99.01, 85.46, 82.22, 79.85, 77.74, 7 5.73, 73.65, 66.19, 56.89, 56.76, 55.45, 50.78, 50.67, 45.23, 43.50, 38 01, 35.16, 34.80, 33.32, 31.87, 30.43, 29.65, 29.14, 26.40, 26.23, 24.44, 21.62, 20.37 , 15.52, 14.63, 13.50, 13.29, 10.45.

[0221] 实施例27 :43-0-(2-(4-(4-氯苯基)-1Η-1,2, 3-三氮唑-I-基)乙酰基)氧雷帕霉素(X-35) [0221] Example 27: 43-0- (2- (4- (4-chlorophenyl) -1Η-1,2, 3- triazole -I- yl) acetyl) oxy-rapamycin ( X-35)

[0222] 将43-0-(2-叠氮乙酰基)-氧雷帕霉素(0.35臟〇1^,0.358)和4-氟苯乙炔(0.1 8) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 13g,收率:33. 1%。 [0222] The 43-0- (2-azido-acetyl) - oxo rapamycin (0.35 ^ 〇1 dirty, 0.358), and 4-fluorophenyl acetylene (0.1 8) were added to DMF (IOmL) solution, sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 13g, yield: 331%. MS(ESI)m/ z: 1155. 6 (M+Na)+。 MS (ESI) m / z: 1155. 6 (M + Na) +. 1HNMR(500MHz,DMS0)δ8. 62 (s,1H),7. 89 (d,J= 8. 4Hz,2H),7. 52 (d,J =8. 4Hz,2H),6. 44 (s,1H),6. 43-6. 35 (m,1H),6. 26-6. 17 (m,1H),6. 16-6. 07 (m,2H),5. 4 7 (s, 2H),5. 26 (s, 1H),5. 10 (d,J= 10. 0Hz, 1H),5. 01-4. 96 (m, 1H),4. 95-4. 90 (m, 1H),4. 70-4. 58 (m,1H),4. 06-3. 97 (m,2H),3. 98-3. 90 (m,1H),3. 66-3. 58 (m,1H),3. 48-3. 40 (m,IH),3. 27 (s,3H),3. 16 (s,3H),3. 05 (s,3H),2. 86-2. 68 (m,2H),2. 44-2. 33 (m,2H),2. 28-2 • 18 (m,1H),2. 15-2. 07 (m,2H),2. 07-1. 97 (m,2H),I. 96-1. 79 (m,3H),I. 74 (s,3H),I. 63(s ,3H),I. 60-1. 03(m, 10H), 0. 98(d,J= 6. 3Hz, 3H),0. 87 (d,J= 6. 4Hz, 3H),0. 82 (d,J= 6. 3Hz, 3H),0· 78 (d,J= 6. 5Hz, 3H),0· 73 (d,J= 6. 3Hz, 3H)。 1HNMR (500MHz, DMS0) δ8. 62 (s, 1H), 7. 89 (d, J = 8. 4Hz, 2H), 7. 52 (d, J = 8. 4Hz, 2H), 6. 44 (s , 1H), 6. 43-6. 35 (m, 1H), 6. 26-6. 17 (m, 1H), 6. 16-6. 07 (m, 2H), 5. 4 7 (s, 2H), 5. 26 (s, 1H), 5. 10 (d, J = 10. 0Hz, 1H), 5. 01-4. 96 (m, 1H), 4. 95-4. 90 (m, 1H), 4. 70-4. 58 (m, 1H), 4. 06-3. 97 (m, 2H), 3. 98-3. 90 (m, 1H), 3. 66-3. 58 ( m, 1H), 3. 48-3. 40 (m, IH), 3. 27 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 86-2 . 68 (m, 2H), 2. 44-2. 33 (m, 2H), 2. 28-2 • 18 (m, 1H), 2. 15-2. 07 (m, 2H), 2. 07 -1. 97 (m, 2H), I. 96-1. 79 (m, 3H), I. 74 (s, 3H), I. 63 (s, 3H), I. 60-1. 03 (m , 10H), 0. 98 (d, J = 6. 3Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0. 82 (d, J = 6. 3Hz, 3H), 0 · 78 (d, J = 6. 5Hz, 3H), 0 · 73 (d, J = 6. 3Hz, 3H). 13CNMR(126MHz,DMSO)δ210 .38, 207. 49, 198. 83, 169. 19, 166. 97, 166. 63, 145. 25, 139. 29, 137. 83, 137. 12, 132. 34, 130 .38, 129. 41, 128. 95, 126. 96, 126. 83, 124. 84, 123. 07, 98. 98, 85. 48, 82. 22, 79. 85, 77. 74, 7 5. 71, 73. 64, 66. 18, 56. 89, 56. 73, 55. 42, 50. 76, 50. 68, 45. 21, 43. 47, 37. 98, 35. 27, 35. 14, 34. 78, 33. 32, 31. 88, 30. 42, 29. 64, 29. 54, 29. 12, 26. 39, 26. 21, 24. 42, 21. 60, 20. 34, 15. 52 ,15. 50, 14. 63, 13. 45, 13. 32, 10. 43。 13CNMR (126MHz, DMSO) δ210 .38, 207. 49, 198. 83, 169. 19, 166. 97, 166. 63, 145. 25, 139. 29, 137. 83, 137. 12, 132. 34, 130.38, 129.41, 128.95, 126.96, 126.83, 124.84, 123.07, 98.98, 85.48, 82.22, 79.85, 77.74, 75 71, 73.64, 66.18, 56.89, 56.73, 55.42, 50.76, 50.68, 45.21, 43.47, 37.98, 35.27, 35.14 , 34.78, 33.32, 31.88, 30.42, 29.64, 29.54, 29.12, 26.39, 26.21, 24.42, 21.60, 20.34, 15 52, 15.50, 14.63, 13.45, 13.32, 10.43.

[0223] 实施例28 :43-0-(2-(4-(4-甲基苯基2, 3-三氮唑-I-基)乙酰基)氧雷帕霉素(X-36) [0223] Example 28: 43-0- (2- (4- (4-phenyl-2, 3-triazole -I- yl) acetyl) oxy-rapamycin (X-36)

[0224] 将43-0- (2-叠氮乙酰基)-氧雷帕霉素(0. 35mmoL, 0. 35g)和4-甲基苯乙炔(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0. 08g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 15g,收率: 38.3 %。 [0224] The 43-0- (2-azido-acetyl) - oxo rapamycin (0. 35mmoL, 0. 35g) and 4-phenylacetylene (0.Ig) was added to a DMF (IOmL) was was added to the reaction mixture of sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0. 08g), room temperature and stirred for 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to give 0. 15g, yield of the pure product: 38.3%. MS(ESI)m/z:1135.7(M+Na)+。 MS (ESI) m / z: 1135.7 (M + Na) +. 1HNMR(500MHz,DMS0)S8.51(s,lH),7.74(d,J= 7. 9Hz, 2H), 7. 27 (d,J= 7. 8Hz, 2H), 6. 46 (s, 1H), 6. 44-6. 34 (m, 1H), 6. 26-6. 17 (m, 1H), 6.I 6-6. 08 (m, 2H),5. 51-5. 41 (m, 3H),5. 29 (s, 1H),5. 10 (d,J= 10. 0Hz, 1H),5. 00-4. 96 (m, 1H) ,4. 96-4. 92 (m, 1H),4. 69-4. 60 (m, 1H),4. 05-3. 99 (m, 2H),3. 98-3. 92 (m, 1H),3. 66-3. 58 (m, 1H),3. 49-3. 39 (m, 1H),3. 27 (s, 3H),3. 16 (s, 3H),3. 05 (s, 3H),2. 86-2. 69 (m, 2H),2. 42-2. 3 5 (m, 2H),2. 33 (s, 3H),2. 24-2. 21 (m, 1H),2. 16-2. 07 (m, 2H),2. 05-1. 96 (m, 2H),I. 97-1. 78 ( m, 2H),I. 75 (s, 3H),I. 63 (s, 3H),I. 61-1. 02 (m, 10H),0. 98 (d,J= 6. 4Hz, 3H),0. 87 (d,J= 6. 4Hz, 3H),0· 82 (d,J= 6. 3Hz, 3H),0· 78 (d,J= 6. 5Hz, 3H),0· 73 (d,J= 6. 4Hz, 3H)。 1HNMR (500MHz, DMS0) S8.51 (s, lH), 7.74 (d, J = 7. 9Hz, 2H), 7. 27 (d, J = 7. 8Hz, 2H), 6. 46 (s, 1H ), 6. 44-6. 34 (m, 1H), 6. 26-6. 17 (m, 1H), 6.I 6-6. 08 (m, 2H), 5. 51-5. 41 ( m, 3H), 5. 29 (s, 1H), 5. 10 (d, J = 10. 0Hz, 1H), 5. 00-4. 96 (m, 1H), 4. 96-4. 92 ( m, 1H), 4. 69-4. 60 (m, 1H), 4. 05-3. 99 (m, 2H), 3. 98-3. 92 (m, 1H), 3. 66-3. 58 (m, 1H), 3. 49-3. 39 (m, 1H), 3. 27 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 86 -2. 69 (m, 2H), 2. 42-2. 3 5 (m, 2H), 2. 33 (s, 3H), 2. 24-2. 21 (m, 1H), 2. 16- 2. 07 (m, 2H), 2. 05-1. 96 (m, 2H), I. 97-1. 78 (m, 2H), I. 75 (s, 3H), I. 63 (s, 3H), I. 61-1. 02 (m, 10H), 0. 98 (d, J = 6. 4Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0 · 82 ( d, J = 6. 3Hz, 3H), 0 · 78 (d, J = 6. 5Hz, 3H), 0 · 73 (d, J = 6. 4Hz, 3H). 13C NMR(126MHz,DMSO)δ210. 39, 207. 54, 198. 86, 169. 22, 166. 99, 166. 75, 146. 39, 139. 31,137 .86, 137. 23, 132. 34, 130. 41, 129. 46, 127. 76, 127. 00, 125. 07, 124. 81, 122. 33,HO. 93, 99. 01, 85. 46, 82. 22, 79. 86, 77. 72, 75. 72, 73. 66, 66. 18, 56. 89, 56. 77, 55. 45, 50. 78, 50. 62, 45 .23, 43. 49, 37. 99, 35. 27, 35. 16, 34. 80, 33. 33, 31. 87, 30. 45, 29. 66, 29. 57, 29. 14, 26. 41, 2 6. 22, 24. 45, 21. 63, 20. 80, 20. 38, 15. 56, 15. 52, 14. 62, 13. 50, 13. 30, 10. 45〇 13C NMR (126MHz, DMSO) δ210. 39, 207. 54, 198. 86, 169. 22, 166. 99, 166. 75, 146. 39, 139. 31,137 .86, 137. 23, 132. 34 , 130. 41, 129. 46, 127. 76, 127. 00, 125. 07, 124. 81, 122. 33, HO. 93, 99. 01, 85. 46, 82. 22, 79. 86, 77 72, 75.72, 73.66, 66.18, 56.89, 56.77, 55.45, 50.78, 50.62, 45.23, 43.49, 37.99, 35.27 , 35.16, 34.80, 33.33, 31.87, 30.45, 29.66, 29.57, 29.14, 26.41, 2 6.22, 24.45, 21.63, 20.80, 20.38, 15.56, 15.52, 14.62, 13.50, 13.30, 10. 45〇

[0225] 实施例29 :43-0- (2- (4-(苯基)-1H-1,2, 3-三氮唑-I-基)乙酰基)氧雷帕霉素(X-34) [0225] Example 29: 43-0- (2- (4- (phenyl) -1H-1,2, 3- triazole -I- yl) acetyl) oxy-rapamycin (X-34 )

[0226] 将43-0-(2-叠氮乙酰基)-氧雷帕霉素(0. 35mmoL,0. 35g)和苯乙炔(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 18g,收率:44. 0%。 [0226] The 43-0- (2-azido-acetyl) - oxo rapamycin (. 0. 35mmoL, 0 35g) and phenylacetylene (0.Ig) was added to a DMF (IOmL) solution to the reaction was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 18g, yield: 440%. MS(ESII)m/ z:1121.8(M+Na)+。 MS (ESII) m / z: 1121.8 (M + Na) +. 1HNMR(400MHz,DMS0)S8.59(s,lH),7.86(d,J= 7.3Hz,2H),7.46(t,J =7. 6Hz, 2H), 7. 40-7. 25 (m, 1H), 6. 48 (s, 1H), 6. 46-6. 36 (m, 1H), 6. 27-6. 17 (m, 1H), 6. 18-6. 07 (m, 2H),5. 47 (s, 2H),5. 31 (s, 1H),5. 14-5. 04 (m, 1H),5. 01-4. 90 (m, 2H),4. 71-4. 59(m ,1H),4. 06-3. 93 (m, 3H),3. 67-3. 58 (m, 1H),3. 51-3. 39 (m, 1H),3. 27 (s, 3H),3. 15 (s, 3H) ,3. 05 (s, 3H), 2. 86-2. 68 (m, 2H), 2. 43-2. 30 (m, 2H), 2. 28-2. 16 (m, 1H), 2. 16-2. 07 (m,IH),2. 06-1. 96 (m, 2H),I. 96-1. 78 (m, 3H),I. 75 (s, 3H),I. 63 (s, 3H),I. 58-1. 02 (m, 10H), 0. 98(d,J= 6. 5Hz, 3H), 0. 86(d,J= 6. 5Hz, 3H), 0. 82 (d,J= 6. 4Hz, 3H), 0. 78 (d,J= 6. 6Hz, 3H), 0· 73(d,J= 6. 5Hz, 3H)。 1HNMR (400MHz, DMS0) S8.59 (s, lH), 7.86 (d, J = 7.3Hz, 2H), 7.46 (t, J = 7. 6Hz, 2H), 7. 40-7. 25 (m, 1H), 6. 48 (s, 1H), 6. 46-6. 36 (m, 1H), 6. 27-6. 17 (m, 1H), 6. 18-6. 07 (m, 2H) , 5. 47 (s, 2H), 5. 31 (s, 1H), 5. 14-5. 04 (m, 1H), 5. 01-4. 90 (m, 2H), 4. 71-4 . 59 (m, 1H), 4. 06-3. 93 (m, 3H), 3. 67-3. 58 (m, 1H), 3. 51-3. 39 (m, 1H), 3. 27 (s, 3H), 3. 15 (s, 3H), 3. 05 (s, 3H), 2. 86-2. 68 (m, 2H), 2. 43-2. ​​30 (m, 2H), 2. 28-2. 16 (m, 1H), 2. 16-2. 07 (m, IH), 2. 06-1. 96 (m, 2H), I. 96-1. 78 (m, 3H ), I. 75 (s, 3H), I. 63 (s, 3H), I. 58-1. 02 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 86 (d, J = 6. 5Hz, 3H), 0. 82 (d, J = 6. 4Hz, 3H), 0. 78 (d, J = 6. 6Hz, 3H), 0 · 73 (d, J = 6. 5Hz, 3H). 13CNMR(101MHz,DMS0)δ210. 90, 208. 05, 199. 37, 169 .72, 167. 49, 167. 23, 146. 84, 139. 82, 138. 36, 137. 65, 132. 85, 131. 02, 130. 91,129. 43, 128 .43, 127. 50, 125. 64, 125. 32, 123. 26, 99. 51, 85. 97, 82. 72, 80. 36, 78. 24, 76. 23, 74. 17, 66. 69, 57. 40, 57. 27, 55. 96, 51. 28, 51. 16, 45. 73, 44. 01, 38. 49, 35. 78, 35. 67, 35. 30, 33. 83, 32 .37, 30. 96, 30. 15, 29. 65, 26. 92, 26. 72, 24. 95, 22. 13, 20. 88, 16. 06, 16. 02, 15. 13, 14. 00,I 3. 81,10. 95。 13CNMR (101MHz, DMS0) δ210. 90, 208. 05, 199. 37, 169 .72, 167. 49, 167. 23, 146. 84, 139. 82, 138. 36, 137. 65, 132. 85, 131.02, 130. 91,129. 43, 128.43, 127.50, 125.64, 125.32, 123.26, 99.51, 85.97, 82.72, 80.36, 78. 24, 76.23, 74.17, 66.69, 57.40, 57.27, 55.96, 51.28, 51.16, 45.73, 44.01, 38.49, 35.78, 35.67, 35.30, 33.83, 32.37, 30.96, 30.15, 29.65, 26.92, 26.72, 24.95, 22.13, 20.88, 16. 06, 16. 02, 15. 13, 14. 00, I 3. 81,10. 95.

[0227] 实施例30 :43-0- (2- (4- (4-戊基苯基)-1H-1,2, 3-三氮唑-I-基)乙酰基)氧雷帕霉素(X-37) [0227] Example 30: 43-0- (2- (4- (4-pentylphenyl) -1H-1,2, 3- triazole -I- yl) acetyl) oxy-rapamycin (X-37)

[0228] 将43-0- (2-叠氮乙酰基)-氧雷帕霉素(0. 35mmoL,0. 35g)和4-正戊基苯乙炔(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 13g,收率: 31.7 %。 [0228] The 43-0- (2-azido-acetyl) - oxo rapamycin (. 0. 35mmoL, 0 35g) and 4-n-pentyl phenyl acetylene (0.Ig) was added to a DMF (IOmL) solution, sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of) was added to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to give 0. 13g, yield of the pure product: 31.7%. MS(ESI)m/z:1191.7(M+Na)+。 MS (ESI) m / z: 1191.7 (M + Na) +. 1HNMR(500MHz,DMS0)S8.51(s,lH),7.75(d,J= 8. 1Hz, 2H), 7. 27 (d,J= 8. 1Hz, 2H), 6. 46 (s, 1H), 6. 43-6. 34 (m, 1H), 6. 25-6. 18 (m, 1H), 6.I 6-6. 07 (m, 2H), 5. 45 (s, 2H), 5. 29 (s, 1H), 5. 10 (d,J= 10. 1Hz, 1H), 5. 01-4. 96 (m, 1H), 4. 9 5-4. 89 (m,1H),4. 70-4. 55 (m,1H),4. 06-3. 98 (m,2H),3. 98-3. 91 (m,1H),3. 66-3. 58 (m,1H) ,3. 48-3. 38 (m,1H),3. 27 (s,3H),3. 15 (s,3H),3. 05 (s,3H),2. 86-2. 68 (m,2H),2. 62-2. 56 (m,2H),2. 44-2. 33 (m,2H),2. 26-2. 17 (m,1H),2. 15-2. 06 (m,1H),2. 05-1. 97 (m,2H),I. 95-1 .77 (m, 3H),I. 74 (s, 3H),L63 (s, 3H),I. 60-1. 03 (m, 10H), 0. 98 (d,J= 6. 5Hz, 3H), 0. 89-0 • 84 (m, 5H),0· 82 (d,J= 6. 4Hz, 3H),0· 78 (d,J= 6. 7Hz, 3H),0· 73 (d,J= 6. 6Hz, 3H)。 1HNMR (500MHz, DMS0) S8.51 (s, lH), 7.75 (d, J = 8. 1Hz, 2H), 7. 27 (d, J = 8. 1Hz, 2H), 6. 46 (s, 1H ), 6. 43-6. 34 (m, 1H), 6. 25-6. 18 (m, 1H), 6.I 6-6. 07 (m, 2H), 5. 45 (s, 2H) , 5. 29 (s, 1H), 5. 10 (d, J = 10. 1Hz, 1H), 5. 01-4. 96 (m, 1H), 4. 9 5-4. 89 (m, 1H ), 4. 70-4. 55 (m, 1H), 4. 06-3. 98 (m, 2H), 3. 98-3. 91 (m, 1H), 3. 66-3. 58 (m , 1H), 3. 48-3. 38 (m, 1H), 3. 27 (s, 3H), 3. 15 (s, 3H), 3. 05 (s, 3H), 2. 86-2. 68 (m, 2H), 2. 62-2. 56 (m, 2H), 2. 44-2. 33 (m, 2H), 2. 26-2. 17 (m, 1H), 2. 15- 2. 06 (m, 1H), 2. 05-1. 97 (m, 2H), I. 95-1 .77 (m, 3H), I. 74 (s, 3H), L63 (s, 3H) , I. 60-1. 03 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 89-0 • 84 (m, 5H), 0 · 82 (d, J = 6. 4Hz, 3H), 0 · 78 (d, J = 6. 7Hz, 3H), 0 · 73 (d, J = 6. 6Hz, 3H). 13C NMR(126MHz,DMSO)δ210. 95, 208. 02, 199. 37, 169. 72, 167. 51, 167. 21, 146. 94, 142. 69, 139 .84, 138. 36, 137. 66, 132. 87, 130. 91, 129. 30, 128. 53, 127. 51, 125. 63, 125. 43, 122. 84, 99. 52, 86. 07, 82. 77, 80. 41, 78. 24, 76. 25, 74. 21, 67. 02, 66. 74, 57. 45, 57. 28, 55. 96, 51. 30, 51 .16, 45. 74, 44. 00, 38. 52, 35. 82, 35. 67, 35. 33, 34. 60, 33. 87, 32. 45, 31. 33, 30. 96, 30. 19, 2 9. 67, 26. 92, 26. 75, 24. 96, 22. 41, 22. 15, 20. 87, 16. 62, 16. 05, 15. 18, 14. 37, 13. 92, 10. 98〇 13C NMR (126MHz, DMSO) δ210. 95, 208. 02, 199. 37, 169. 72, 167. 51, 167. 21, 146. 94, 142. 69, 139 .84, 138. 36, 137. 66 , 132.87, 130.91, 129.30, 128.53, 127.51, 125.63, 125.43, 122.84, 99.52, 86.07, 82.77, 80.41, 78 24, 76.25, 74.21, 67.02, 66.74, 57.45, 57.28, 55.96, 51.30, 51.16, 45.74, 44.00, 38.52 , 35.82, 35.67, 35.33, 34.60, 33.87, 32.45, 31.33, 30.96, 30.19, 2 9.67, 26.92, 26.75, 24.96, 22.41, 22.15, 20.87, 16.62, 16.05, 15.18, 14.37, 13.92, 10. 98〇

[0229] 实施例31 :43-0-(2-(4-(3-甲基苯基2, 3-三氮唑-I-基)乙酰基)氧雷帕霉素(X-40) [0229] Example 31: 43-0- (2- (4- (3-phenyl-2, 3-triazole -I- yl) acetyl) oxy-rapamycin (X-40)

[0230] 将43-0-(2-叠氮乙酰基)-氧雷帕霉素(0. 35mmoL, 0. 35g)和丙炔醇(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 16g,收率:39. 0%。 [0230] The 43-0- (2-azido-acetyl) - oxo rapamycin (0. 35mmoL, 0. 35g) and propargyl alcohol (0.Ig) was added to a DMF (IOmL) solution of the the reaction mixture was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 16g, yield: 390%. MS(ESI) 7. 8Hz, 1H), 7. 34 (t,J= 7. 6Hz, 1H), 7. 16 (d,J= 7. 6Hz, 1H), 6. 46 (s, 1H), 6. 44-6. 36(m ,1H), 6. 26-6. 18 (m, 1H), 6. 17-6. 08 (m, 2H), 5. 50-5. 42 (m, 3H), 5. 29 (s, 1H), 5. 10 (d,J= 10. 2Hz, 1H),5. 00-4. 96 (m, 1H),4. 95-4. 93 (m, 1H),4. 69-4. 62 (m, 1H),4. 05-3. 99 (m, 2H),3 .98-3. 94 (m, 1H), 3. 65-3. 60 (m, 1H), 3. 48-3. 40 (m, 1H), 3. 27 (s, 3H), 3. 16 (s, 3H), 3. 05(s ,3H), 2. 84-2. 69 (m, 2H), 2. 44-2. 38 (m, 2H), 2. 36 (s, 3H), 2. 27-2. 17 (m, 1H) ,2.13-1.9 7 (m, 3H),I. 96-1. 88 (m, 2H),I. 87-1. 78 (m, 2H),I. 75 (s, 3H),I. 63 (s, 3H),I. 56-1. 01 (-m, 10H), 0. 98 (d,J= 6. 5Hz, 3H), 0. 87 (d,J= 6. 5Hz, 3H), 0. 82 (d,J= 6. 4Hz, 3H), 0. 78 (d,J =6. 6Hz, 3H), 0· 73(d,J= 6. 6Hz, 3H)。 MS (ESI) 7. 8Hz, 1H), 7. 34 (t, J = 7. 6Hz, 1H), 7. 16 (d, J = 7. 6Hz, 1H), 6. 46 (s, 1H), 6. 44-6. 36 (m, 1H), 6. 26-6. 18 (m, 1H), 6. 17-6. 08 (m, 2H), 5. 50-5. 42 (m, 3H ), 5. 29 (s, 1H), 5. 10 (d, J = 10. 2Hz, 1H), 5. 00-4. 96 (m, 1H), 4. 95-4. 93 (m, 1H ), 4. 69-4. 62 (m, 1H), 4. 05-3. 99 (m, 2H), 3 .98-3. 94 (m, 1H), 3. 65-3. 60 (m , 1H), 3. 48-3. 40 (m, 1H), 3. 27 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 84-2. 69 (m, 2H), 2. 44-2. 38 (m, 2H), 2. 36 (s, 3H), 2. 27-2. 17 (m, 1H), 2.13-1.9 7 (m, 3H ), I. 96-1. 88 (m, 2H), I. 87-1. 78 (m, 2H), I. 75 (s, 3H), I. 63 (s, 3H), I. 56- 1. 01 (-m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 5Hz, 3H), 0. 82 (d, J = 6. 4Hz, 3H), 0. 78 (d, J = 6. 6Hz, 3H), 0 · 73 (d, J = 6. 6Hz, 3H). 13CNMR(126MHz,DMSO)δ210. 40, 207. 54, 198. 86,I 69. 22, 166. 99, 166. 73, 146. 41,139. 31,138. 06, 137. 85, 137. 15, 132. 34, 130. 43, 128. 81,I 28. 56, 126. 99, 125. 68, 124. 81, 122. 69, 122. 32, 99. 01, 85. 46, 82. 21, 79. 86, 77. 73, 75. 72, 73. 66, 66. 18, 56. 90, 56. 77, 55. 45, 50. 78, 50. 64, 45. 23, 43. 50, 37. 99, 35. 28, 35. 17, 34. 80 ,33. 33, 32. 07, 31. 87, 30. 45, 29. 66, 29. 15, 26. 40, 26. 22, 24. 44, 21. 63, 21. 02, 20. 37, 15. 5 6, 15. 52, 14. 62, 13. 51, 13. 30, 10. 45〇 13CNMR (126MHz, DMSO) δ210. 40, 207. 54, 198. 86, I 69. 22, 166. 99, 166. 73, 146. 41,139. ​​31,138. 06, 137. 85, 137. 15 , 132. 34, 130. 43, 128. 81, I 28. 56, 126. 99, 125. 68, 124. 81, 122. 69, 122. 32, 99. 01, 85. 46, 82. 21, 79.86, 77.73, 75.72, 73.66, 66.18, 56.90, 56.77, 55.45, 50.78, 50.64, 45.23, 43.50, 37. 99, 35.28, 35.17, 34.80, 33.33, 32.07, 31.87, 30.45, 29.66, 29.15, 26.40, 26.22, 24.44, 21.63, 21.02, 20.37, 15.5 6 15.52, 14.62, 13.51, 13.30, 10. 45〇

[0231] 实施例32 :43-0-(2-(4-(2-氯苯基2, 3-三氮唑-I-基)乙酰基)氧雷帕霉素(X-38) [0231] Example 32: 43-0- (2- (4- (2-chlorophenyl 2,3-triazole -I- yl) acetyl) oxy-rapamycin (X-38)

[0232] 将43-0-(2-叠氮乙酰基)-氧雷帕霉素(0.35臟〇1^,0.35 8)和2-氯苯乙炔(0.18) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 17g,收率:41. 4%。 [0232] The 43-0- (2-azido-acetyl) - oxo rapamycin (0.35 ^ 〇1 dirty, 8 0.35) and 2-chlorophenyl acetylene (0.18) was added to a DMF (IOmL) solution, sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 17g, yield: 414%. MS(ESI)m/ z: 1155. 7 (M+Na)+。 MS (ESI) m / z: 1155. 7 (M + Na) +. 1HNMR(500MHz,DMS0)δ8. 73 (s,1H),8. 12 (d,J= 7. 8Hz,1H),7. 58 (d,J =8. 0Hz, 1H), 7. 50-7. 46 (m, 1H), 7. 43-7. 39 (m, 1H), 6. 46 (s, 1H), 6. 44-6. 34 (m, 1H), 6. 27-6. 17 (m,1H),6. 17-6. 07 (m,2H),5. 51 (s,2H),5. 49-5. 43 (m,1H),5. 29 (s,1H),5. 10 ( d,J= 10. 0Hz,1H),5. 01-4. 96 (m,1H),4. 96-4. 92 (m,1H),4. 68-4. 61 (m,1H),4. 05-3. 98 (m,2H),3. 97-3. 93 (m,1H),3. 64-3. 62 (m,1H),3. 48-3. 40 (m,1H),3. 32 (s,3H),3. 16 (s,3 H),3. 05 (s,3H),2. 86-2. 70 (m,2H),2. 42-2. 34 (m,2H),2. 27-2. 17 (m,1H),2. 14-1. 98 (m, 3H),I. 97-1. 89 (m,2H),I. 89-1. 79 (m,2H),I. 75 (s,3H),I. 63 (s,3H),I. 60-1. 01 (m,10H) ,0. 98 (d,J= 6. 5Hz, 3H), 0. 87 (d,J= 6. 4Hz, 3H), 0. 82 (d,J= 6. 4Hz, 3H), 0. 78 (d,J= 6. 6Hz, 3H), 0· 73(d,J= 6. 6Hz, 3H)。 1HNMR (500MHz, DMS0) δ8. 73 (s, 1H), 8. 12 (d, J = 7. 8Hz, 1H), 7. 58 (d, J = 8. 0Hz, 1H), 7. 50-7 . 46 (m, 1H), 7. 43-7. 39 (m, 1H), 6. 46 (s, 1H), 6. 44-6. 34 (m, 1H), 6. 27-6. 17 (m, 1H), 6. 17-6. 07 (m, 2H), 5. 51 (s, 2H), 5. 49-5. 43 (m, 1H), 5. 29 (s, 1H), 5. 10 (d, J = 10. 0Hz, 1H), 5. 01-4. 96 (m, 1H), 4. 96-4. 92 (m, 1H), 4. 68-4. 61 (m , 1H), 4. 05-3. 98 (m, 2H), 3. 97-3. 93 (m, 1H), 3. 64-3. 62 (m, 1H), 3. 48-3. 40 (m, 1H), 3. 32 (s, 3H), 3. 16 (s, 3 H), 3. 05 (s, 3H), 2. 86-2. 70 (m, 2H), 2. 42 -2. 34 (m, 2H), 2. 27-2. 17 (m, 1H), 2. 14-1. 98 (m, 3H), I. 97-1. 89 (m, 2H), I . 89-1. 79 (m, 2H), I. 75 (s, 3H), I. 63 (s, 3H), I. 60-1. 01 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0. 82 (d, J = 6. 4Hz, 3H), 0. 78 (d, J = 6. 6Hz, 3H), 0 · 73 (d, J = 6. 6Hz, 3H). 13CNMR(126MHz,DMS0)δ210. 41,207. 53, 198. 88, 169 .21, 166. 99, 166. 67, 142. 45, 139. 31, 137. 86, 137. 16, 132. 34, 130. 28, 130. 23, 129. 49, 129 .39, 128. 96, 127. 58, 126. 99, 125. 74, 99. 01, 85. 48, 82. 23, 79. 86, 77. 77, 75. 72, 73. 65, 66. 19, 56. 90, 56. 81, 55. 45, 50. 76, 50. 61, 45. 23, 43. 50, 37. 99, 35. 31, 35. 17, 34. 80, 33. 34, 31 .89, 30. 44, 29. 65, 29. 15, 26. 41, 26. 23, 24. 45, 21. 63, 20. 38, 15. 52, 14. 64, 13. 49, 13. 32,I 0· 45。 13CNMR (126MHz, DMS0) δ210. 41,207. 53, 198. 88, 169 .21, 166. 99, 166. 67, 142. 45, 139. 31, 137. 86, 137. 16, 132. 34, 130.28, 130.23, 129.49, 129.39, 128.96, 127.58, 126.99, 125.74, 99.01, 85.48, 82.23, 79.86, 77. 77, 75.72, 73.65, 66.19, 56.90, 56.81, 55.45, 50.76, 50.61, 45.23, 43.50, 37.99, 35.31, 35.17, 34.80, 33.34, 31.89, 30.44, 29.65, 29.15, 26.41, 26.23, 24.45, 21.63, 20.38, 15. 52, 14. 64, 13. 49, 13. 32, I 0 · 45.

[0233] 实施例33 :43-0- (2- (4- (4-溴苯基)-1H-1, 2, 3-三氮唑-I-基)乙酰基)氧雷帕霉素(X-41) [0233] Example 33: 43-0- (2- (4- (4-bromophenyl) -1H-1, 2, 3- triazole -I- yl) acetyl) oxy-rapamycin ( X-41)

[0234] 将43-0-(2-叠氮乙酰基)-氧雷帕霉素(0.35臟〇1^0.35 8)和4-溴苯乙炔(0.18) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 10g,收率:24. 3%。 [0234] The 43-0- (2-azido-acetyl) - oxo rapamycin (0.35 ^ 0.35 dirty 〇1 8) and 4-bromophenyl acetylene (0.18) was added to a DMF (IOmL) solution of the the reaction mixture was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid by silica gel column chromatography and C18 preparative chromatography to give 0. 10g, yield pure product: 243%. MS(ESI)m/ z: 1200. 3 (M+Na)+。 MS (ESI) m / z: 1200. 3 (M + Na) +. 1HNMR(500MHz,DMS0)δ8. 73 (s,1H),8. 12 (d,J= 7. 8Hz,1H),7. 58 (d,J =8. 0Hz, 1H),7. 50-7. 46 (m, 1H),7. 43-7. 39 (m, 1H),6. 46 (s, 1H),6. 44-6. 34 (m, 1H),6. 27-6. 17 (m,1H),6. 17-6. 07 (m,2H),5. 51 (s,2H),5. 49-5. 43 (m,1H),5. 29 (s,1H),5. 10 ( d,J= 10. 0Hz,1H),5. 01-4. 96 (m,1H),4. 96-4. 92 (m,1H),4. 68-4. 61 (m,1H),4. 05-3. 98 (m,2H),3. 97-3. 93 (m,1H),3. 64-3. 62 (m,1H),3. 48-3. 40 (m,1H),3. 32 (s,3H),3. 16 (s,3 H),3. 05 (s,3H),2. 86-2. 70 (m,2H),2. 42-2. 34 (m,2H),2. 27-2. 17 (m,1H),2. 14-1. 98 (m, 3H),I. 97-1. 89 (m,2H),I. 89-1. 79 (m,2H),I. 75 (s,3H),I. 63 (s,3H),I. 60-1. 01 (m,10H) ,0. 98 (d,J= 6. 5Hz, 3H),0. 87 (d,J= 6. 4Hz, 3H),0. 82 (d,J= 6. 4Hz, 3H),0. 78 (d,J= 6. 6Hz, 3H), 0· 73(d,J= 6. 6Hz, 3H)。 1HNMR (500MHz, DMS0) δ8. 73 (s, 1H), 8. 12 (d, J = 7. 8Hz, 1H), 7. 58 (d, J = 8. 0Hz, 1H), 7. 50-7 . 46 (m, 1H), 7. 43-7. 39 (m, 1H), 6. 46 (s, 1H), 6. 44-6. 34 (m, 1H), 6. 27-6. 17 (m, 1H), 6. 17-6. 07 (m, 2H), 5. 51 (s, 2H), 5. 49-5. 43 (m, 1H), 5. 29 (s, 1H), 5. 10 (d, J = 10. 0Hz, 1H), 5. 01-4. 96 (m, 1H), 4. 96-4. 92 (m, 1H), 4. 68-4. 61 (m , 1H), 4. 05-3. 98 (m, 2H), 3. 97-3. 93 (m, 1H), 3. 64-3. 62 (m, 1H), 3. 48-3. 40 (m, 1H), 3. 32 (s, 3H), 3. 16 (s, 3 H), 3. 05 (s, 3H), 2. 86-2. 70 (m, 2H), 2. 42 -2. 34 (m, 2H), 2. 27-2. 17 (m, 1H), 2. 14-1. 98 (m, 3H), I. 97-1. 89 (m, 2H), I . 89-1. 79 (m, 2H), I. 75 (s, 3H), I. 63 (s, 3H), I. 60-1. 01 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0. 82 (d, J = 6. 4Hz, 3H), 0. 78 (d, J = 6. 6Hz, 3H), 0 · 73 (d, J = 6. 6Hz, 3H). 13CNMR(126MHz,DMS0)δ210. 41,207. 53, 198. 88, 169 .21, 166. 99, 166. 67, 142. 45, 139. 31, 137. 86, 137. 16, 132. 34, 130. 28, 130. 23, 129. 49, 129 .39, 128. 96, 127. 58, 126. 99, 125. 74, 99. 01, 85. 48, 82. 23, 79. 86, 77. 77, 75. 72, 73. 65, 66. 19, 56. 90, 56. 81, 55. 45, 50. 76, 50. 61, 45. 23, 43. 50, 37. 99, 35. 31, 35. 17, 34. 80, 33. 34, 31 .89, 30. 44, 29. 65, 29. 15, 26. 41, 26. 23, 24. 45, 21. 63, 20. 38, 15. 52, 14. 64, 13. 49, 13. 32,I 0· 45。 13CNMR (126MHz, DMS0) δ210. 41,207. 53, 198. 88, 169 .21, 166. 99, 166. 67, 142. 45, 139. 31, 137. 86, 137. 16, 132. 34, 130.28, 130.23, 129.49, 129.39, 128.96, 127.58, 126.99, 125.74, 99.01, 85.48, 82.23, 79.86, 77. 77, 75.72, 73.65, 66.19, 56.90, 56.81, 55.45, 50.76, 50.61, 45.23, 43.50, 37.99, 35.31, 35.17, 34.80, 33.34, 31.89, 30.44, 29.65, 29.15, 26.41, 26.23, 24.45, 21.63, 20.38, 15. 52, 14. 64, 13. 49, 13. 32, I 0 · 45.

[0235] 实施例34 :43-0-(2-(4-(4-甲氧基苯基2, 3-三氮唑-I-基)乙酰基)氧雷帕霉素(X-66) [0235] Example 34: 43-0- (2- (4- (4-methoxyphenyl 2,3-triazole -I- yl) acetyl) oxy-rapamycin (X-66)

[0236] 将43-0- (2-叠氮乙酰基)-氧雷帕霉素(0. 35mmoL, 0. 35g)和4-甲氧基苯乙炔(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(0.08g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 16g,收率: 39.4%。 [0236] The 43-0- (2-azido-acetyl) - oxo rapamycin (0. 35mmoL, 0. 35g) and 4-methoxyphenylacetylene (0.Ig) was added to a DMF (IOmL) solution, sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0.08 g of) was added to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to give 0. 16g, yield of the pure product: 39.4%. MS(ESII)m/z:1151.6(M+Na)+。 MS (ESII) m / z: 1151.6 (M + Na) +. 1HNMR(500MHz,DMS0)S8.46(s,lH),7.78(d,J= 8. 7Hz, 2H), 7. 02 (d,J= 8. 8Hz, 2H), 6. 46 (s, 1H), 6. 45-6. 34 (m, 1H), 6. 26-6. 18 (m, 1H), 6.I 7-6. 06 (m, 2H),5. 44 (s, 2H),5. 27 (s, 1H),5. 10 (d,J= 10. 1Hz, 1H), 5. 00-4. 91 (m, 2H),4. 69 -4. 58 (m, 1H),4. 06-3. 98 (m, 2H),3. 99-3. 92 (m, 1H),3. 79 (s, 3H),3. 68-3. 57 (m, 1H),3. 49-3 .39 (m, 1H),3. 27 (s, 3H),3. 16 (s, 3H),3. 05 (s, 3H),2. 88-2. 67 (m, 2H),2. 44-2. 33 (m, 2H),2. 27-2. 18 (m, 2H),2. 14-2. 07 (m, 1H),2. 05-1. 96 (m, 2H),I. 96-1. 78 (m, 3H),I. 75 (s, 3H),I. 63 (s, 3H),I. 55-1. 03 (m, 10H),0. 98 (d,J= 6. 5Hz, 3H),0. 87 (d,J= 6. 4Hz, 3H),0. 82 (d,J= 6. 4Hz, 3H),0· 78 (d,J= 6. 7Hz, 3H),0· 73 (d,J= 6. 5Hz, 3H)。 1HNMR (500MHz, DMS0) S8.46 (s, lH), 7.78 (d, J = 8. 7Hz, 2H), 7. 02 (d, J = 8. 8Hz, 2H), 6. 46 (s, 1H ), 6. 45-6. 34 (m, 1H), 6. 26-6. 18 (m, 1H), 6.I 7-6. 06 (m, 2H), 5. 44 (s, 2H) , 5. 27 (s, 1H), 5. 10 (d, J = 10. 1Hz, 1H), 5. 00-4. 91 (m, 2H), 4. 69 -4. 58 (m, 1H) , 4. 06-3. 98 (m, 2H), 3. 99-3. 92 (m, 1H), 3. 79 (s, 3H), 3. 68-3. 57 (m, 1H), 3 . 49-3 .39 (m, 1H), 3. 27 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 88-2. 67 (m, 2H ), 2. 44-2. 33 (m, 2H), 2. 27-2. 18 (m, 2H), 2. 14-2. 07 (m, 1H), 2. 05-1. 96 (m , 2H), I. 96-1. 78 (m, 3H), I. 75 (s, 3H), I. 63 (s, 3H), I. 55-1. 03 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0. 82 (d, J = 6. 4Hz, 3H), 0 · 78 (d, J = 6. 7Hz, 3H), 0 · 73 (d, J = 6. 5Hz, 3H). 13CNMR(126MHz,DMS0)δ210 .39, 207. 54, 198. 86, 169. 22, 166. 99, 166. 77, 159. 03, 146. 27, 139. 31, 137. 86, 137. 15, 132 .35, 130. 42, 127. 01, 126. 49, 123. 11, 121. 78, 114. 33, 99. 01, 85. 46, 82. 22, 79. 86, 77. 71, 7 5. 73, 73. 66, 66. 19, 56. 90, 56. 77, 55. 45, 55. 12, 50. 78, 50. 60, 45. 23, 43. 50, 37. 99, 35. 28, 35. 17, 34. 80, 33. 32, 31. 87, 29. 66, 29. 56, 29. 22, 29. 15, 26. 42, 26. 22, 24. 44, 21. 63, 20. 38 ,15. 56, 15. 52, 14. 63, 13. 51, 13. 30, 10. 45〇 13CNMR (126MHz, DMS0) δ210 .39, 207. 54, 198. 86, 169. 22, 166. 99, 166. 77, 159. 03, 146. 27, 139. 31, 137. 86, 137. 15, 132.35, 130.42, 127.01, 126.49, 123.11, 121.78, 114.33, 99.01, 85.46, 82.22, 79.86, 77.71, 75 73, 73.66, 66.19, 56.90, 56.77, 55.45, 55.12, 50.78, 50.60, 45.23, 43.50, 37.99, 35.28 , 35.17, 34.80, 33.32, 31.87, 29.66, 29.56, 29.22, 29.15, 26.42, 26.22, 24.44, 21.63, 20 38, 15.56, 15.52, 14.63, 13.51, 13.30, 10. 45〇

[0237] 实施例35 :43-0-(2-(4-((2, 5二氯苯基)氨基甲基2, 3-三氮唑-I-基) 乙酰基)氧雷帕霉素(X-46) [0237] Example 35: 43-0- (2- (4 - ((2, 5-dichlorophenyl) aminomethyl 2, 3-triazole -I- yl) acetyl) oxy-rapamycin (X-46)

[0238] 将43-0- (2-叠氮乙酰基)-氧雷帕霉素(0. 35mmoL,0. 35g)和N-(丙-2-炔基)-2, 5-二氯苯胺(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig) 和五水硫酸铜(0. 08g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 15g,收率:35. 8%〇MS(ESII)m/z:1218. 5(M+Na)VHNMR(500MHz,DMS0)δ7. 94(s,1H),7. 25(d,J= 8. 4Hz, 1H), 6. 77 (s, 1H), 6. 58 (d,J= 8. 4Hz, 1H), 6. 45 (s, 1H), 6. 43-6. 35 (m, 1H), 6. 29 (s,IH), 6. 26-6. 17 (m, 1H), 6. 18-6. 07 (m, 2H), 5. 46 (dd,J= 14. 8, 9. 5Hz, 1H), 5. 37 (s, 2H), 5. 28 (s, 1H), 5. 14-5. 05 (m, 1H), 5. 01-4. 92 (m, 2H), 4. 62-4. 56 (m, 1H), 4. 47 (s, 2H), 4. 06-3. 96(m ,2H), 3. 98-3. 87 (m, 1H), 3. 66-3. 57 (m, 1H), 3. 49-3. 39 (m, 1H), 3. 39-3. 24 (m, 2H), 3. 18 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 85-2. 69 (m, 2H), 2. 43-2. 33 (m, 2H), 2. [0238] The 43-0- (2-azido-acetyl) - oxo rapamycin (. 0. 35mmoL, 0 35g) and N- (prop-2-ynyl) -2, 5-dichloroaniline (0.Ig) was added to a DMF (IOmL) was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (0. 08g) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured added 30mL water, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid, was isolated by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 15g, yield: 35 8% 〇MS (ESII) m / z:... 1218 5 (M + Na) VHNMR (500MHz, DMS0) δ7 94 (s, 1H), 7 25 (d, J = 8. 4Hz, 1H), 6. 77 (s, 1H), 6 . 58 (d, J = 8. 4Hz, 1H), 6. 45 (s, 1H), 6. 43-6. 35 (m, 1H), 6. 29 (s, IH), 6. 26-6 . 17 (m, 1H), 6. 18-6. 07 (m, 2H), 5. 46 (dd, J = 14. 8, 9. 5Hz, 1H), 5. 37 (s, 2H), 5 . 28 (s, 1H), 5. 14-5. 05 (m, 1H), 5. 01-4. 92 (m, 2H), 4. 62-4. 56 (m, 1H), 4. 47 (s, 2H), 4. 06-3. 96 (m, 2H), 3. 98-3. 87 (m, 1H), 3. 66-3. 57 (m, 1H), 3. 49-3 . 39 (m, 1H), 3. 39-3. 24 (m, 2H), 3. 18 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 85-2. 69 (m, 2H), 2. 43-2. ​​33 (m, 2H), 2. 28-2. 17 (m, 1H), 2. 13 -2. 06 (m, 1H), 2. 05-1. 90 (m, 2H),I. 90-1. 78 (m, 3H),I. 74 (s, 3H),I. 63 (s, 3H),I. 60-1. 03(m ,10H), 0. 98 (d,J= 6. 6Hz, 3H), 0. 87 (d,J= 6. 5Hz, 3H), 0. 82 (d,J= 6. 4Hz, 3H), 0. 79 (d,J=6. 7Hz, 3H), 0. 73 (d,J= 6. 6Hz, 3H) 〇13CNMR(126MHz,DMSO)δ210. 45, 207. 53, 198. 88,I 69. 20, 166. 99, 166. 60, 145. 01, 144. 77, 139. 32, 137. 86, 137. 15, 132. 48, 132. 34, 130. 40,I 30. 05, 126. 98, 124. 88, 124. 20, 116. 53, 115. 97,HO. 87, 99. 00, 85. 50, 82. 23, 79. 86, 77. 50 ,75. 71, 73. 69, 66. 19, 56. 91, 56. 75, 55. 45, 50. 77, 50. 49, 45. 22, 37. 98, 35. 17, 34. 80, 33. 3 2, 32. 04, 31. 87, 30. 48, 29. 66, 29. 56, 29. 09, 26. 41, 26. 22, 24. 43, 21. 64, 20. 38, 15. 55, 15. 53, 14. 59, 13. 44, 13. 37, 10. 45〇 28-2. 17 (m, 1H), 2. 13 -2. 06 (m, 1H), 2. 05-1. 90 (m, 2H), I. 90-1. 78 (m, 3H), I. 74 (s, 3H), I. 63 (s, 3H), I. 60-1. 03 (m, 10H), 0. 98 (d, J = 6. 6Hz, 3H), 0. 87 ( d, J = 6. 5Hz, 3H), 0. 82 (d, J = 6. 4Hz, 3H), 0. 79 (d, J = 6. 7Hz, 3H), 0. 73 (d, J = 6 . 6Hz, 3H) 〇13CNMR (126MHz, DMSO) δ210. 45, 207. 53, 198. 88, I 69. 20, 166. 99, 166. 60, 145. 01, 144. 77, 139. 32, 137 . 86, 137. 15, 132. 48, 132. 34, 130. 40, I 30. 05, 126. 98, 124. 88, 124. 20, 116. 53, 115. 97, HO. 87, 99. 00, 85.50, 82.23, 79.86, 77.50, 75.71, 73.69, 66.19, 56.91, 56.75, 55.45, 50.77, 50.49, 45.22, 37.98, 35.17, 34.80, 33.3 2 32.04, 31.87, 30.48, 29.66, 29.56, 29.09, 26.41, 26 22, 24.43, 21.64, 20.38, 15.55, 15.53, 14.59, 13.44, 13.37, 10. 45〇

[0239] 实施例36 :43-0-(2-(4-((2-氟苯基)氨基甲基2, 3-三氮唑-I-基)乙酰基)氧雷帕霉素(X-43) [0239] Example 36: 43-0- (2- (4 - ((2-fluorophenyl) aminomethyl-2, 3-triazole -I- yl) acetyl) oxy-rapamycin (X -43)

[0240] 将43-0- (2-叠氮乙酰基)-氧雷帕霉素(0. 35mmoL,0. 35g)和N-(丙-2-炔基)-2-氟苯胺(0.Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.Ig)和五水硫酸铜(〇. 〇8g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体, 抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 13g,收率: 32. 4 %。 [0240] The 43-0- (2-azido-acetyl) - oxo rapamycin (. 0. 35mmoL, 0 35g) and N- (prop-2-ynyl) -2-fluoro-aniline (0. Ig) was added to a DMF (IOmL) was added sodium ascorbate (0.Ig) and copper sulfate pentahydrate (square. 〇8g), stirred for 2h at room temperature the reaction solution, after completion of the reaction, the reaction was poured added 30mL of water, precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 13g, yield: 32.4%. MS(ESII)m/z: 1168. 6 (M+Na)+。 MS (ESII) m / z: 1168. 6 (M + Na) +. 1HNMR(500MHz,DMS0)δ7. 93 (s,1H),6. 99 (dd,J =11.9, 8. 1Hz, 1H), 6. 92 (t,J= 7. 7Hz, 1H), 6. 75 (t,J= 8. 5Hz, 1H), 6. 57-6. 50 (m, 1H), 6. 46 (s, 1H), 6. 43-6. 33 (m, 1H), 6. 28-6. 18 (m, 1H), 6. 18-6. 08 (m, 2H), 6. 03-5. 89 (m, 1H), 5 .54-5. 42 (m, 1H), 5. 35 (s, 2H), 5. 28 (s, 1H), 5. 02-4. 96 (m, 1H), 5. 12-5. 08 (m, 1H), 4. 95-4 • 89 (m, 1H),4. 64-4. 51 (m, 1H),4. 40 (s, 2H),4. 05-3. 97 (m, 2H),3. 97-3. 93 (m, 1H),3. 65-3 • 59 (m,1H),3. 50-3. 39 (m,1H),3. 20 (s,3H),3. 16 (s,3H),3. 05 (s,3H),2. 86-2. 70 (m,2H), 2. 43-2. 34 (m,2H),2. 28-2. 15 (m,1H),2. 14-2. 06 (m,1H),2. 07-1. 92 (m,2H),I. 91-1. 80(m ,3H),I. 75 (s, 3H),I. 63 (s, 3H),I. 60-1. 02 (m, 10H), 0. 98 (d,J= 6. 5Hz, 3H), 0. 87 (d,J= 6. 4Hz, 3H), 0· 82 (d,J= 6. 3Hz, 3H), 0· 79 (d,J= 6. 6Hz, 3H), 0· 73 (d,J= 6. 6Hz, 3H)。 1HNMR (500MHz, DMS0) δ7. 93 (s, 1H), 6. 99 (dd, J = 11.9, 8. 1Hz, 1H), 6. 92 (t, J = 7. 7Hz, 1H), 6. 75 (t, J = 8. 5Hz, 1H), 6. 57-6. 50 (m, 1H), 6. 46 (s, 1H), 6. 43-6. 33 (m, 1H), 6. 28 -6. 18 (m, 1H), 6. 18-6. 08 (m, 2H), 6. 03-5. 89 (m, 1H), 5 .54-5. 42 (m, 1H), 5 . 35 (s, 2H), 5. 28 (s, 1H), 5. 02-4. 96 (m, 1H), 5. 12-5. 08 (m, 1H), 4. 95-4 • 89 (m, 1H), 4. 64-4. 51 (m, 1H), 4. 40 (s, 2H), 4. 05-3. 97 (m, 2H), 3. 97-3. 93 (m , 1H), 3. 65-3 • 59 (m, 1H), 3. 50-3. 39 (m, 1H), 3. 20 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 86-2. 70 (m, 2H), 2. 43-2. ​​34 (m, 2H), 2. 28-2. 15 (m, 1H), 2. 14- 2. 06 (m, 1H), 2. 07-1. 92 (m, 2H), I. 91-1. 80 (m, 3H), I. 75 (s, 3H), I. 63 (s, 3H), I. 60-1. 02 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0 · 82 ( d, J = 6. 3Hz, 3H), 0 · 79 (d, J = 6. 6Hz, 3H), 0 · 73 (d, J = 6. 6Hz, 3H). 13C NMR(126MHz,DMSO)δ210. 41, 207. 54, 198. 87, 169. 22, 166. 99, 166. 68, 151. 90, 150. 01, 145 .75, 139. 32, 137. 86, 137. 15, 136. 21, 136. 12, 132. 35, 130. 42, 127. 01, 124. 60, 124. 13, 115 .71, 114. 31, 114. 16, 112. 27, 99. 01, 85. 47, 82. 22, 79. 81, 77. 52, 75. 72, 73. 66, 66. 18, 56. 9 0, 56. 75, 55. 45, 50. 78, 50. 41, 45. 23, 43. 50, 38. 05, 35. 24, 35. 17, 34. 80, 33. 32, 31. 86, 30. 44, 29. 66, 29. 57, 29. 09, 28. 98, 26. 41, 26. 22, 24. 45, 21. 63, 20. 37, 15. 56, 15. 52, 14. 60, 13 .49, 13. 31, 10. 45。 13C NMR (126MHz, DMSO) δ210. 41, 207. 54, 198. 87, 169. 22, 166. 99, 166. 68, 151. 90, 150. 01, 145 .75, 139. 32, 137. 86 , 137.15, 136.21, 136.12, 132.35, 130.42, 127.01, 124.60, 124.13, 115.71, 114.31, 114.16, 112.27, 99 01, 85.47, 82.22, 79.81, 77.52, 75.72, 73.66, 66.18, 56.9 0 56.75, 55.45, 50.78, 50. 41, 45.23, 43.50, 38.05, 35.24, 35.17, 34.80, 33.32, 31.86, 30.44, 29.66, 29.57, 29.09, 28.98, 26.41, 26.22, 24.45, 21.63, 20.37, 15.56, 15.52, 14.60, 13.49, 13.31, 10.45.

[0241]实施例37 :43-0-(2-(4-(吡咯烷基-1-亚甲基)-1Η-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-92) [0241] Example 37: 43-0- (2- (4- (l-methyl-pyrrolidinyl) -1Η-1,2, 3- triazole-1-yl) acetyl) oxy Ray rapamycin (X-92)

[0242]将43-0-(2-叠氮乙酰基)-氧雷帕霉素(0.35臟〇1^,0.358)和1-(丙-2-炔基) 吡咯烷(〇. Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0. Ig)和五水硫酸铜(0. 08g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. llg,收率:28. 9%。 [0242] The 43-0- (2-azido-acetyl) - oxo rapamycin (0.35 ^ 〇1 dirty, 0.358) and 1- (prop-2-ynyl) pyrrolidine (. Square Ig) was added to DMF (IOmL) was added sodium ascorbate (0. Ig) and copper sulfate pentahydrate (0. 08g) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added to precipitate a light yellow solid , filtered off with suction, washed with water, and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. llg, yield: 289%. MS (ESII)m/z: 1093. 4 (M+H)+。 MS (ESII) m / z: 1093. 4 (M + H) +. 1H (400MHz,DMS0) δ 7. 96 (s,1H),6. 46 (s,1H),6. 41-6. 3 2 (m, 1H), 6. 25-6. 16 (m, 1H), 6. 16-6. 09 (m, 2H), 5. 43 (dd, J = 14. 7, 9. 6Hz, 1H), 5. 35 (s, 2H ),5. 32 (s, 1H), 5. 15-5. 05 (m, 1H), 5. 02 - 4. 90 (m, 2H), 4. 63-4. 42 (m, 2H), 4. 32-4. 10 (m, 2H ),4. 05-3. 92 (m, 2H), 3. 75-3. 57 (m, 2H), 3. 25 (s, 3H), 3. 16 (s, 3H), 3. 06 (s, 3H), 2. 91-2. 67 (m, 2H), 2. 45-2. 32 (m, 4H), 2. 29-2. 16 (m, 1H), 2. 13-2. 04 (m, 2H), 2. 03-1. 94 (m, 2H) ,1.91- 1. 81 (m, 3H), I. 76 (s, 3H), I. 63 (s, 3H), L 57-1. 06 (m, 10H), I. 05-0. 89 (m, 5H), 0. 85 (d, J = 6. 5Hz, 3H), 0· 82 (d, J = 6. 5Hz, 3H), 0· 79 (d, J = 6. 7Hz, 3H), 0· 72 (d, J = 6. 5Hz, 3H)。 1H (400MHz, DMS0) δ 7. 96 (s, 1H), 6. 46 (s, 1H), 6. 41-6. 3 2 (m, 1H), 6. 25-6. 16 (m, 1H ), 6. 16-6. 09 (m, 2H), 5. 43 (dd, J = 14. 7, 9. 6Hz, 1H), 5. 35 (s, 2H), 5. 32 (s, 1H ), 5. 15-5 05 (m, 1H), 5. 02 -... 4. 90 (m, 2H), 4. 63-4 42 (m, 2H), 4. 32-4 10 (m , 2H), 4. 05-3. 92 (m, 2H), 3. 75-3. 57 (m, 2H), 3. 25 (s, 3H), 3. 16 (s, 3H), 3. 06 (s, 3H), 2. 91-2. 67 (m, 2H), 2. 45-2. 32 (m, 4H), 2. 29-2. 16 (m, 1H), 2. 13- 2. 04 (m, 2H), 2. 03-1. 94 (m, 2H), 1.91- 1. 81 (m, 3H), I. 76 (s, 3H), I. 63 (s, 3H) , L 57-1. 06 (m, 10H), I. 05-0. 89 (m, 5H), 0. 85 (d, J = 6. 5Hz, 3H), 0 · 82 (d, J = 6 . 5Hz, 3H), 0 · 79 (d, J = 6. 7Hz, 3H), 0 · 72 (d, J = 6. 5Hz, 3H). 13C NMR(101MHz, DMS0) δ 210. 92, 208. 86, 199. 40, 169. 73, 168. 49, 167. 51, 167. 21, 139. 72, 138 .35, 137. 55, 130. 83, 127. 31, 125. 48, 99. 61, 85. 93, 82. 56, 80. 29, 78. 02, 76. 55, 74. 42, 68. 23, 66. 53, 57. 49, 57. 38, 56. 69, 56. 08, 55. 88, 51. 17, 50. 64, 47. 00, 46. 52, 45. 73, 44. 05, 37 .64, 37. 17, 35. 66, 35. 59, 32. 68, 32. 28, 31. 02, 30. 82, 30. 16, 29. 54, 26. 81, 26. 61, 25. 00, 2 2. 96, 22. 66, 22. 02, 21. 39, 16. 06, 15. 00, 14. 00, 13. 68, 12. 28, 10. 84〇 13C NMR (101MHz, DMS0) δ 210. 92, 208. 86, 199. 40, 169. 73, 168. 49, 167. 51, 167. 21, 139. 72, 138 .35, 137. 55, 130. 83, 127.31, 125.48, 99.61, 85.93, 82.56, 80.29, 78.02, 76.55, 74.42, 68.23, 66.53, 57.49, 57.38, 56.69, 56.08, 55.88, 51.17, 50.64, 47.00, 46.52, 45.73, 44.05, 37.64, 37.17, 35. 66, 35.59, 32.68, 32.28, 31.02, 30.82, 30.16, 29.54, 26.81, 26.61, 25.00, 2 2.96, 22.66 , 22.02, 21.39, 16.06, 15.00, 14.00, 13.68, 12.28, 10. 84〇

[0243]实施例38 :43-0-(2-(4-(二乙氨基甲基2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素(Χ-76) [0243] Example 38: 43-0- (2- (4- (2-diethylamino-methyl, 3-triazole-1-yl) acetyl) oxy rapamycin (Χ-76)

[0244]将43-0-(2-叠氮乙酰基)-氧雷帕霉素(0.35臟〇1^0.358)和1^二乙基丙炔胺(〇. Ig)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0. Ig)和五水硫酸铜(0. 08g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经硅胶柱层析和C18制备色谱分离,得纯品0. 15g,收率:39. 1%。 [0244] The 43-0- (2-azido-acetyl) - oxo rapamycin (0.35 dirty 〇1 0.358 ^) and ^ 1 diethyl propargylamine (. Square Ig) was added to a DMF (IOmL) was added to the reaction mixture of sodium ascorbate (0. Ig) and copper sulfate pentahydrate (0. 08g), room temperature and stirred for 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water and dried to give a light yellow solid by silica gel column chromatography and C18 preparative chromatography to yield pure 0. 15g, yield: 391%. 36 (m,1H),6. 27-6. 18 (m,1H),6. 16-6. 07 (m,2H),5. 46 (dd,J = 14. 7, 9. 6Hz,1H),5. 37 (s,2 H),5. 33 (s,1H),5. 13-5. 03 (m,1H),5. 01-4. 91 (m,2H),4. 67-4. 54 (m,2H),4. 30-4. 13 (m,2H ),4. 07-3. 94 (m,3H),3. 75-3. 57 (m,3H),3. 26 (s,3H),3. 15 (s,3H),3. 05 (s,3H),2. 90-2. 66 (m, 2H), 2. 46-2. 33 (m, 4H), 2. 28-2. 15 (m, 1H), 2. 14-2. 06 (m, 2H), 2. 04-1. 93 (m, 2H), I. 92- 1. 80 (m,3H),I. 75 (s,3H),I. 62 (s,3H),I. 56-1. 08 (m,10H),I. 07-0. 89 (m,5H),0· 86 (d,J = 6. 4Hz,3H),0· 81 (d,J = 6. 4Hz,3H),0· 78 (d,J = 6. 7Hz,3H),0· 73 (d,J = 6. 7Hz,3H)。 36 (m, 1H), 6. 27-6. 18 (m, 1H), 6. 16-6. 07 (m, 2H), 5. 46 (dd, J = 14. 7, 9. 6Hz, 1H ), 5. 37 (s, 2 H), 5. 33 (s, 1H), 5. 13-5. 03 (m, 1H), 5. 01-4. 91 (m, 2H), 4. 67 -4. 54 (m, 2H), 4. 30-4. 13 (m, 2H), 4. 07-3. 94 (m, 3H), 3. 75-3. 57 (m, 3H), 3 . 26 (s, 3H), 3. 15 (s, 3H), 3. 05 (s, 3H), 2. 90-2. 66 (m, 2H), 2. 46-2. 33 (m, 4H ), 2. 28-2. 15 (m, 1H), 2. 14-2. 06 (m, 2H), 2. 04-1. 93 (m, 2H), I. 92- 1. 80 (m , 3H), I. 75 (s, 3H), I. 62 (s, 3H), I. 56-1. 08 (m, 10H), I. 07-0. 89 (m, 5H), 0 · 86 (d, J = 6. 4Hz, 3H), 0 · 81 (d, J = 6. 4Hz, 3H), 0 · 78 (d, J = 6. 7Hz, 3H), 0 · 73 (d, J = 6. 7Hz, 3H). 13C NMR(101MHz, DMS0) δ 210. 91, 208. 86, 199. 39, 169. 72, 168. 39, 167. 50, 167. 31, 139. 82, 138 .37, 137. 66, 130. 93, 127. 51, 125. 57, 99. 51, 85. 95, 82. 72, 80. 37, 78. 08, 76. 22, 74. 12, 68. 98, 66. 67, 57. 39, 57. 28, 56. 29, 56. 18, 55. 96, 51. 27, 50. 84, 46. 98, 46. 52, 45. 73, 44. 00, 37 .74, 37. 27, 35. 67, 35. 58, 32. 58, 32. 38, 31. 12, 30. 92, 30. 06, 29. 44, 26. 91, 26. 71, 24. 96, 2 2. 86, 22. 16, 22. 12, 21. 59, 16. 07, 16. 00, 15. 10, 14. 00, 13. 78, 12. 38, 10. 94〇 13C NMR (101MHz, DMS0) δ 210. 91, 208. 86, 199. 39, 169. 72, 168. 39, 167. 50, 167. 31, 139. 82, 138 .37, 137. 66, 130. 93, 127.51, 125.57, 99.51, 85.95, 82.72, 80.37, 78.08, 76.22, 74.12, 68.98, 66.67, 57.39, 57.28, 56.29, 56.18, 55.96, 51.27, 50.84, 46.98, 46.52, 45.73, 44.00, 37.74, 37.27, 35. 67, 35.58, 32.58, 32.38, 31.12, 30.92, 30.06, 29.44, 26.91, 26.71, 24.96, 2 2.86, 22.16 , 22.12, 21.59, 16.07, 16.00, 15.10, 14.00, 13.78, 12.38, 10. 94〇

[0245]实施例39 :43-0- (2- (4- (4-氟苯基)-1H-1, 2, 3-三氮唑-I-基)异丙酰基)氧雷帕霉素(X-57) [0245] Example 39: 43-0- (2- (4- (4-fluorophenyl) -1H-1, 2, 3- triazole -I--yl) propyl) oxy-rapamycin (X-57)

[0246]步骤A :28_氧基二甲基娃烧基-43-〇-(2_漠异丙醜基)-氧雷帕霉素的制备 [0246] Step A: 28_-yl oxy-dimethyl baby burn 〇- -43- (2_ desert isopropyl ugly yl) - Preparation oxygen rapamycin

[0247] 将28-0TMS-雷帕霉素(2. 5g,2. 5mmol)和无水二氯甲烷(40mL)加入到三颈瓶中, 加入三乙胺(3mL,20mmol),0-5°C下逐滴加入2-溴丙酰溴(I. 62g,7. 5mmol),加毕,0-5°C反应8h。 [0247] The 28-0TMS- rapamycin (2. 5g, 2. 5mmol) and anhydrous dichloromethane (40 mL) was added to a three-necked flask, triethylamine (3mL, 20mmol), 0-5 at ° C was added dropwise 2-bromo-propionyl bromide (I. 62g, 7. 5mmol), plus complete, 0-5 ° C the reaction 8h. 反应完毕后,将反应液倾入300mL水中,二氯甲烷提取,合并提取液,水洗,无水硫酸钠干燥。 After completion of the reaction, the reaction solution was poured into 300mL water and extracted with dichloromethane, combined extracts were washed with water, dried over anhydrous sodium sulfate. 蒸干得白色固体I. 9g,收率:67. 8% MS(ESI)m/z:1142. 5(M+Na)+。 Evaporated to dryness to give a white solid I. 9g, yield:. 67 8% MS (ESI) m / z:. 1142 5 (M + Na) +.

[0248] 步骤B :43-0-(2-溴异丙酰基)-氧雷帕霉素的制备 B [0248] Step: (2-bromo-iso-propionyl) 43-0--- oxygen rapamycin prepared

[0249] 将28-0TMS-43-0-(2-溴异丙酰基)-氧雷帕霉素(1.9g,1.8mmol)加入到丙酮(40mL)溶液中,加料完毕后冷却至0-5°C,向反应液加入稀硫酸(10mL,IN H2SO4),继续搅拌反应约2h,反应完毕后,反应液分别经饱和碳酸氢钠,饱和食盐水洗涤,有机层经无水硫酸钠干燥,蒸干得白色泡沫状固体I. 6g,收率84. 8 %。 [0249] The 28-0TMS-43-0- (2- bromo-iso-propionyl) - oxo rapamycin (1.9g, 1.8mmol) was added to acetone (40 mL) solution, cooled to 0-5 after the addition was complete ° C, the reaction solution was added to the dilute sulfuric acid (10mL, IN H2SO4), reaction was stirred for about 2h, after completion of the reaction, the reaction liquid were treated with saturated sodium bicarbonate, saturated brine, the organic layer was dried over anhydrous sodium sulfate, and evaporated as a white foamy solid did I. 6g, 84. 8% yield. MS (ESI) m/z: 1070. 5 (M+Na)+。 MS (ESI) m / z: 1070. 5 (M + Na) +.

[0250] 步骤C :43-0-(2-叠氮异丙酰基)-氧雷帕霉素的制备 [0250] Step C: 43-0- (2- isopropyl-azido group) - Preparation oxygen rapamycin

[0251 ]分别将43-0- (2-溴异丙酰基)-氧雷帕霉素(I. 6g, I. 5mmol)和叠氮化钠(0. 2g,3mmol)加入到(30mL)DMF溶液中,加料完毕后升温到50°C,反应完全后,将反应液倾入90mL水中,乙酸乙酯提取2次,合并提取液,水洗,无水硫酸钠干燥。 [0251] respectively, 43-0- (2-bromo-iso-propionyl) - rapamycin oxygen (I. 6g, I. 5mmol) and sodium azide (0. 2g, 3mmol) was added to (30mL) DMF solution, after completion of the addition was warmed to 50 ° C, after completion of the reaction, the reaction solution was poured into 90mL water and extracted twice with ethyl acetate, the combined extracts washed with water, dried over anhydrous sodium sulfate. 蒸干得油状物,经柱层析分离得到〇. 8g,收率为52. 7 %。 Evaporated to dryness to give an oil which was purified by column chromatography to give billion. 8g, yield 52.7%. MS (ESI) m/z: 1033. 6 (M+Na)+。 MS (ESI) m / z: 1033. 6 (M + Na) +.

[0252] 步骤D :43-0- (2- (4- (4-氟苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素(X-57)的制备 [0252] Step D: 43-0- (2- (4- (4- fluorophenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin ( X-57) preparation of

[0253] 将43-0-(2-叠氮异丙酰基)-氧雷帕霉素(0.2臟〇1^0.28)和4-氟苯乙炔(0.078) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.08g)和五水硫酸铜(0.09g), 室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经柱层析分离得纯品〇. l〇g,收率:42. 9%。 [0253] The 43-0- (2-azido acid isopropyl) - oxo rapamycin (dirty 〇1 0.2 ^ 0.28) and 4-fluorophenyl acetylene (0.078) was added to a DMF (IOmL) solution of the the reaction mixture was added sodium ascorbate (0.08 g of) and copper sulfate pentahydrate (0.09 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by column chromatography to give pure square l〇g, yield: 429%. MS(ESI)m/z: 1153. 7 (M+Na)+。 MS (ESI) m / z: 1153. 7 (M + Na) +. 1H NMR(500MHz,DMS0)S8.74(s,lH),8.00-7.87(m,2H),7.36-7.22(m,2H),6.45(s,lH),6.43-6· 34 (m,1H),6· 25-6. 17 (m,1H),6· 17-6. 06 (m,2H),5· 75-5. 57 (m,1H),5· 48-5. 41 (m,1H),5 .27 (s, 1Η), 5. 12-5. 06 (m, 1Η), 4. 99-4. 91 (m, 2Η), 4. 70-4. 57 (m, 1Η), 4. 04-3. 91 (m, 3Η), 3. 64-3. 57 (m,1Η),3· 46-3. 40 (m,1Η),3· 24 (s,3Η),3· 15 (s,3Η),3· 04 (s,3Η),2· 85-2. 66 (m,2 Η),2· 44-2. 31 (m,2Η),2· 25-2. 16 (m,1Η),2· 12-2. 05 (m,2Η),2· 05-1. 91 (m,2Η),L 90-1. 77 ( m,5Η),L 74 (s,3Η),L 62 (s,3Η),1. 57-1. 01 (m,10Η),0· 97 (d,J = 6· 5Hz,3Η),0· 86 (d,J = 6· 3Hz, 3Η),0· 81 (d, J = 6· 3Hz, 3Η),0· 77 (d, J = 6· 4Hz, 3Η),0· 72 (d, J = 6· 6Hz, 3Η)。 1H NMR (500MHz, DMS0) S8.74 (s, lH), 8.00-7.87 (m, 2H), 7.36-7.22 (m, 2H), 6.45 (s, lH), 6.43-6 · 34 (m, 1H ), 6 · 25-6. 17 (m, 1H), 6 · 17-6. 06 (m, 2H), 5 · 75-5. 57 (m, 1H), 5 · 48-5. 41 (m , 1H), 5 .27 (s, 1Η), 5. 12-5. 06 (m, 1Η), 4. 99-4. 91 (m, 2Η), 4. 70-4. 57 (m, 1Η ), 4. 04-3. 91 (m, 3Η), 3. 64-3. 57 (m, 1Η), 3 · 46-3. 40 (m, 1Η), 3 · 24 (s, 3Η), 3 · 15 (s, 3Η), 3 · 04 (s, 3Η), 2 · 85-2. 66 (m, 2 Η), 2 · 44-2. 31 (m, 2Η), 2 · 25-2 . 16 (m, 1Η), 2 · 12-2. 05 (m, 2Η), 2 · 05-1. 91 (m, 2Η), L 90-1. 77 (m, 5Η), L 74 (s , 3Η), L 62 (s, 3Η), 1. 57-1. 01 (m, 10Η), 0 · 97 (d, J = 6 · 5Hz, 3Η), 0 · 86 (d, J = 6 · 3Hz, 3Η), 0 · 81 (d, J = 6 · 3Hz, 3Η), 0 · 77 (d, J = 6 · 4Hz, 3Η), 0 · 72 (d, J = 6 · 6Hz, 3Η). 13C NMR(126MHz, DMS0) δ 210. 38, 207. 52, 198. 85, 169. 20, 168. 98, 166. 97, 162. 72, 160. 78, 145 .35, 139. 30, 137. 84, 137. 13, 132. 34, 130. 39, 127. 12, 127. 06, 126. 98, 124. 79, 120. 97, 115 .90, 115. 73, 98. 99, 85. 44, 82. 20, 80. 10, 77. 48, 75. 71, 73. 65, 68. 46, 66. 17, 57. 69, 56. 88, 56. 67, 55. 44, 50. 76, 45. 21, 43. 48, 37. 96, 35. 14, 34. 79, 33. 33, 32. 05, 31. 87, 30. 41, 29. 55 ,28. 98, 26. 38, 26. 20, 24. 43, 21. 61, 20. 35, 17. 05, 15. 54, 15. 50, 14. 63, 13. 28, 10. 43〇 13C NMR (126MHz, DMS0) δ 210. 38, 207. 52, 198. 85, 169. 20, 168. 98, 166. 97, 162. 72, 160. 78, 145 .35, 139. 30, 137. 84, 137.13, 132.34, 130.39, 127.12, 127.06, 126.98, 124.79, 120.97, 115.90, 115.73, 98.99, 85.44, 82.20, 80.10, 77.48, 75.71, 73.65, 68.46, 66.17, 57.69, 56.88, 56.67, 55.44, 50.76, 45. 21, 43.48, 37.96, 35.14, 34.79, 33.33, 32.05, 31.87, 30.41, 29.55, 28.98, 26.38, 26.20, 24.43, 21.61, 20.35, 17.05, 15.54, 15.50, 14.63, 13.28, 10. 43〇

[0254] 实施例40 :43-0- (2- (4- (4-氯苯基)-1Η-1, 2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素(X-52) [0254] Example 40: 43-0- (2- (4- (4-chlorophenyl) -1Η-1, 2, 3- triazole-1-yl) propyl) oxy-rapamycin (X-52)

[0255] 将43-0-(2-叠氮异丙酰基)-氧雷帕霉素(0. 2mmoL, 0. 2g)和4-氯苯乙炔(0. 07g) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.08g)和五水硫酸铜(0.09g), 室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经柱层析分离得纯品〇. llg,收率:46. 6%。 [0255] The 43-0- (2-azido acid isopropyl) - oxo rapamycin (0. 2mmoL, 0. 2g) and 4-chlorophenyl acetylene (0. 07g) was added to a DMF (IOmL) was , the sodium ascorbate (0.08 g of) and copper sulfate pentahydrate (0.09 g of) was added to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give light yellow solid, was isolated by column chromatography pure square LLG, yield: 466%. MS(ESI)m/z:1169. 7(M+Na)+。 MS (ESI) m / z:. 1169 7 (M + Na) +. 1H NMR(500MHz,DMS0)S8.80(s,lH),7.90(d,J = 8.4Hz,2H),7.53(d,J = 8·4Ηζ,2Η),6 • 46 (s,1H),6· 44-6. 35 (m,1H),6· 27-6. 16 (m,1H),6· 16-6. 04 (m,2H),5· 73-5. 61 (m,1H), 5· 46 (dd,J = 14. 6, 9. 7Hz,1H),5· 28 (s,1H),5· 14-5. 05 (m,1H),5· 00-4. 90 (m,2H),4· 68 -4· 54 (m,1H),4· 05-3. 96 (m,2H),3· 97-3. 88 (m,1H),3· 66-3. 56 (m,1H),3· 48-3. 37 (m,IH ),3.24(s,3H),3.15(s,3H),3.04(s,3H),2.85-2.65(m,2H),2.44-2.32(m,2H),2.30-2. 16 (m,1H),2· 15-2. 05 (m,2H),2· 05-1. 92 (m,2H),I. 93-1. 77 (m,6H),I. 74 (s,3H),I. 62 (s ,3H), 1.53-1.01(m, l〇H),〇. 97(d, J = 6. 4Hz, 3H),0. 86 (d, J = 6. 4Hz, 3H),0. 81 (d, J = 6. 3Hz, 3H),0· 77 (d, J = 6. 4Hz, 3H),0· 72 (d, J = 6. 6Hz, 3H)。 1H NMR (500MHz, DMS0) S8.80 (s, lH), 7.90 (d, J = 8.4Hz, 2H), 7.53 (d, J = 8 · 4Ηζ, 2Η), 6 • 46 (s, 1H), 6 · 44-6. 35 (m, 1H), 6 · 27-6. 16 (m, 1H), 6 · 16-6. 04 (m, 2H), 5 · 73-5. 61 (m, 1H ), 5 · 46 (dd, J = 14. 6, 9. 7Hz, 1H), 5 · 28 (s, 1H), 5 · 14-5. 05 (m, 1H), 5 · 00-4. 90 (m, 2H), 4 · 68 -4 · 54 (m, 1H), 4 · 05-3. 96 (m, 2H), 3 · 97-3. 88 (m, 1H), 3 · 66-3 . 56 (m, 1H), 3 · 48-3. 37 (m, IH), 3.24 (s, 3H), 3.15 (s, 3H), 3.04 (s, 3H), 2.85-2.65 (m, 2H) , 2.44-2.32 (m, 2H), 2.30-2. 16 (m, 1H), 2 · 15-2. 05 (m, 2H), 2 · 05-1. 92 (m, 2H), I. 93 -1. 77 (m, 6H), I. 74 (s, 3H), I. 62 (s, 3H), 1.53-1.01 (m, l〇H), square. 97 (d, J = 6. 4Hz , 3H), 0. 86 (d, J = 6. 4Hz, 3H), 0. 81 (d, J = 6. 3Hz, 3H), 0 · 77 (d, J = 6. 4Hz, 3H), 0 · 72 (d, J = 6. 6Hz, 3H). 13C NMR(126MHz, DMSO) δ 210 .91, 208. 03, 199. 37, 169. 73, 169. 47, 167. 49, 145. 66, 139. 83, 138. 36, 137. 65, 132. 83, 130 .91, 130. 04, 129. 48, 127. 50, 127. 29, 125. 34, 121. 96, 99. 52, 85. 99, 82. 74, 80. 63, 78. 03, 7 6. 24, 74. 18, 66. 70, 58. 26, 57. 41, 57. 19, 55. 96, 51. 28, 45. 74, 44. 01, 38. 49, 35. 67, 35. 31, 33. 86, 32. 41, 30. 93, 30. 17, 29. 51, 26. 91, 26. 74, 24. 96, 22. 14, 20. 88, 17. 56, 17. 44, 16. 06 ,16. 03, 15. 17, 14. 00, 13. 83, 10. 96〇 13C NMR (126MHz, DMSO) δ 210 .91, 208. 03, 199. 37, 169. 73, 169. 47, 167. 49, 145. 66, 139. 83, 138. 36, 137. 65, 132. 83, 130.91, 130.04, 129.48, 127.50, 127.29, 125.34, 121.96, 99.52, 85.99, 82.74, 80.63, 78.03, 7 6.24, 74.18, 66.70, 58.26, 57.41, 57.19, 55.96, 51.28, 45.74, 44.01, 38.49, 35.67, 35 31, 33.86, 32.41, 30.93, 30.17, 29.51, 26.91, 26.74, 24.96, 22.14, 20.88, 17.56, 17.44 , 16.06, 16.03, 15.17, 14.00, 13.83, 10. 96〇

[0256]实施例41 :43-0-(2-(4-(4-甲基苯基2, 3-三氮唑-I-基)异丙酰基)氧雷帕霉素(X-54) [0256] Example 41: 43-0- (2- (4- (4-phenyl-2, 3-triazole -I--yl) propyl) oxy-rapamycin (X-54)

[0257] 将43-0- (2-叠氮异丙酰基)-氧雷帕霉素(0. 2mmoL, 0. 2g)和4-甲基苯乙炔(0.07g)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.08g)和五水硫酸铜(0. 09g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体, 抽滤,水洗,干燥得淡黄色固体,经柱层析分离得纯品〇. 13g,收率:56. 6 %。 [0257] The 43-0- (2-azido acid isopropyl) - oxo rapamycin (0. 2mmoL, 0. 2g) and 4-phenylacetylene (0.07 g of) was added to a DMF (IOmL) was was added to the reaction mixture of sodium ascorbate (0.08 g of) and copper sulfate pentahydrate (0. 09g), room temperature and stirred for 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, dried light yellow solid, was isolated by column chromatography pure square 13g, yield: 566%. MS(ESI)m/ z: 1149. 7 (M+Na)+。 MS (ESI) m / z: 1149. 7 (M + Na) +. 1HNMR(500MHz,DMS0)δ8. 68 (s,1H),7. 76 (d,J= 7. 1Hz,2H),7. 26 (d,J = 6.8Hz,2H),6.46(s,lH),6.43-6.33(m,lH),6.29-6.17(m,lH),6.17-6.05(m,2H),5. 71-5. 59 (m, 1H),5. 52-5. 40 (m, 1H),5. 27 (s, 1H),5. 14-5. 04 (m, 1H),5. 00-4. 88 (m, 2H),4- • 64-4. 55 (m,1H),4. 08-3. 92 (m,3H),3. 67-3. 55 (m,1H),3. 49-3. 38 (m,1H),3. 24 (s,3H),3 • 15 (s,3H),3. 04 (s,3H),2. 85-2. 68 (m,2H),2. 44-2. 34 (m,1H),2. 33 (s,3H),2. 26-2. 15 ( m,1H),2. 13-2. 06 (m,1H),2. 06-1. 90 (m,3H),I.82 (d,J = 6. 8Hz,3H),I.74 (s,3H),I.62 ( s, 3H),I. 58-1. 02 (m, 10H),0. 97 (d, J = 5. 1Hz, 3H),0. 86 (d, J = 5. 1Hz, 3H),0. 81 (d, J = 5. 1Hz,3H),0· 77(d,J = 5. 0Hz,3H),0· 73(d,J = 4. 9Hz,3H)。 1HNMR (500MHz, DMS0) δ8. 68 (s, 1H), 7. 76 (d, J = 7. 1Hz, 2H), 7. 26 (d, J = 6.8Hz, 2H), 6.46 (s, lH) , 6.43-6.33 (m, lH), 6.29-6.17 (m, lH), 6.17-6.05 (m, 2H), 5. 71-5. 59 (m, 1H), 5. 52-5. 40 (m , 1H), 5. 27 (s, 1H), 5. 14-5. 04 (m, 1H), 5. 00-4. 88 (m, 2H), 4- • 64-4. 55 (m, 1H), 4. 08-3. 92 (m, 3H), 3. 67-3. 55 (m, 1H), 3. 49-3. 38 (m, 1H), 3. 24 (s, 3H) , 3 • 15 (s, 3H), 3. 04 (s, 3H), 2. 85-2. 68 (m, 2H), 2. 44-2. 34 (m, 1H), 2. 33 (s , 3H), 2. 26-2. 15 (m, 1H), 2. 13-2. 06 (m, 1H), 2. 06-1. 90 (m, 3H), I.82 (d, J = 6. 8Hz, 3H), I.74 (s, 3H), I.62 (s, 3H), I. 58-1. 02 (m, 10H), 0. 97 (d, J = 5. 1Hz , 3H), 0. 86 (d, J = 5. 1Hz, 3H), 0. 81 (d, J = 5. 1Hz, 3H), 0 · 77 (d, J = 5. 0Hz, 3H), 0 · 73 (d, J = 4. 9Hz, 3H). 13C NMR(126MHz,DMS0) δ 210 .95, 208. 01, 199. 36, 169. 72, 169. 51, 167. 50, 146. 80, 139. 83, 138. 36, 137. 68, 132. 87, 130 .90, 129. 92, 128. 40, 127. 49, 125. 56, 125. 43, 121. 12, 99. 51, 86. 06, 82. 77, 80. 65, 78. 01, 7 6. 25, 74. 23, 66. 74, 58. 19, 58. 14, 57. 45, 57. 20, 55. 95, 51. 29, 45. 74, 44. 00, 38. 50, 35. 67, 35. 32, 33. 88, 32. 46, 30. 98, 30. 19, 29. 52, 26. 98, 26. 91, 26. 75, 24. 95, 22. 15, 21. 30, 20. 87 ,17. 57, 17. 46, 16. 06, 16. 04, 15. 19, 13. 92, 10. 98〇 13C NMR (126MHz, DMS0) δ 210 .95, 208. 01, 199. 36, 169. 72, 169. 51, 167. 50, 146. 80, 139. 83, 138. 36, 137. 68, 132. 87, 130.90, 129.92, 128.40, 127.49, 125.56, 125.43, 121.12, 99.51, 86.06, 82.77, 80.65, 78.01, 7 6.25, 74.23, 66.74, 58.19, 58.14, 57.45, 57.20, 55.95, 51.29, 45.74, 44.00, 38.50, 35 67, 35.32, 33.88, 32.46, 30.98, 30.19, 29.52, 26.98, 26.91, 26.75, 24.95, 22.15, 21.30 , 20.87, 17.57, 17.46, 16.06, 16.04, 15.19, 13.92, 10. 98〇

[0258]实施例42 :43-0- (2- (4-(苯基)-1H-1,2, 3-三氮唑-I-基)异丙酰基)氧雷帕霉素(X-53) [0258] Example 42: 43-0- (2- (4- (phenyl) -1H-1,2, 3- triazole -I--yl) propyl) oxy-rapamycin (X- 53)

[0259]将43-0- (2-叠氮异丙酰基)-氧雷帕霉素(0. 2mmoL, 0. 2g)和苯乙炔(0. 07g) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.08g)和五水硫酸铜(0.09g), 室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经柱层析分离得纯品〇. 12g,收率:52. 2%。 [0259] The 43-0- (2-azido acid isopropyl) - oxo rapamycin (0. 2mmoL, 0. 2g) and phenylacetylene (0. 07g) was added to a DMF (IOmL) solution of the the reaction mixture was added sodium ascorbate (0.08 g of) and copper sulfate pentahydrate (0.09 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid by column chromatography to give pure square 12g, yield: 522%. MS (ESI) m/z :1135. 8(M+Na)+。 MS (ESI) m / z:. 1135 8 (M + Na) +. 1H NMR (500MHz, DMSO) δ 8. 75 (s, 1H),7. 87 (d, J = 7. 5Hz, 2H),7. 46 (t, J = 7. 4Hz, 2H),7. 37-7. 31 (m, 1H),6. 46 (s, 1H),6. 43-6. 35 (m, 1H),6. 26-6. 18 (m, 1H),6. 17-6. 06 (m, 2H),5. 72-5. 62 (m, 1H), 5. 50-5. 42 (m, 1H), 5. 28 (s, 1H), 5. 10 (d, J = 10. 7Hz, 1H), 4. 99-4. 96 (m, 1H), 4. 95- 4. 92 (m, 1H), 4. 67-4. 56 (m, 1H), 4. 06-3. 97 (m, 2H), 3. 97-3. 92 (m, 1H), 3. 66-3. 59 (m, 1H), 3. 47-3. 40 (m, 1H), 3. 24 (s, 3H), 3. 15 (s, 3H), 3. 05 (s, 3H), 2. 84-2. 68 (m, 2H), 2. 43-2. 34 (m, 2H ),2· 25-2. 18 (m, 1H),2· 14-2. 07 (m, 2H),2· 05-1. 93 (m, 2H),I. 89-1. 79 (m, 5H),I. 74 (s, 3H), 1. 62 (s, 3Η), 1. 60-1. 02 (m, 10Η), 0. 98 (d, J = 6. 4Hz, 3Η), 0. 87 (d, J = 6. 2Hz, 3Η), 0. 82 (d, J =6· 2Ηζ, 3Η),0· 78 (d, J = 6· 3Ηζ, 3Η),0· 73 (d, J = 6· 6Ηζ, 3Η)。 1H NMR (500MHz, DMSO) δ 8. 75 (s, 1H), 7. 87 (d, J = 7. 5Hz, 2H), 7. 46 (t, J = 7. 4Hz, 2H), 7. 37 -7. 31 (m, 1H), 6. 46 (s, 1H), 6. 43-6. 35 (m, 1H), 6. 26-6. 18 (m, 1H), 6. 17-6 . 06 (m, 2H), 5. 72-5. 62 (m, 1H), 5. 50-5. 42 (m, 1H), 5. 28 (s, 1H), 5. 10 (d, J = 10. 7Hz, 1H), 4. 99-4. 96 (m, 1H), 4. 95- 4. 92 (m, 1H), 4. 67-4. 56 (m, 1H), 4. 06 -3. 97 (m, 2H), 3. 97-3. 92 (m, 1H), 3. 66-3. 59 (m, 1H), 3. 47-3. 40 (m, 1H), 3 . 24 (s, 3H), 3. 15 (s, 3H), 3. 05 (s, 3H), 2. 84-2. 68 (m, 2H), 2. 43-2. ​​34 (m, 2H ), 2 · 25-2. 18 (m, 1H), 2 · 14-2. 07 (m, 2H), 2 · 05-1. 93 (m, 2H), I. 89-1. 79 (m , 5H), I. 74 (s, 3H), 1. 62 (s, 3Η), 1. 60-1. 02 (m, 10Η), 0. 98 (d, J = 6. 4Hz, 3Η), 0. 87 (d, J = 6. 2Hz, 3Η), 0. 82 (d, J = 6 · 2Ηζ, 3Η), 0 · 78 (d, J = 6 · 3Ηζ, 3Η), 0 · 73 (d , J = 6 · 6Ηζ, 3Η). 13C NMR(126MHz, DMSO) δ 2 10. 39, 207. 53, 198. 86, 169. 21, 169. 02, 166. 98, 146. 22, 139. 31, 137. 85, 137. 14, 132. 35, 1 30. 63, 130. 41, 128. 88, 127. 88, 126. 99, 125. 08, 124. 81, 121. 07, 99. 00, 85. 46, 82. 22, 80. 1 1, 77. 49, 75. 72, 73. 68, 66. 18, 57. 69, 56. 89, 56. 70, 55. 45, 50. 77, 45. 23, 43. 50, 37. 97, 35. 16, 34. 80, 33. 35, 31. 88, 30. 44, 29. 66, 29. 00, 26. 40, 26. 22, 24. 44, 21. 62, 20. 37, 17. 06, 16 .96, 15. 52, 14. 64, 13. 50, 13. 30, 10. 45〇 13C NMR (126MHz, DMSO) δ 2 10. 39, 207. 53, 198. 86, 169. 21, 169. 02, 166. 98, 146. 22, 139. 31, 137. 85, 137. 14, 132 35, 1 30.63, 130.41, 128.88, 127.88, 126.99, 125.08, 124.81, 121.07, 99.00, 85.46, 82.22, 80. 11, 77.49, 75.72, 73.68, 66.18, 57.69, 56.89, 56.70, 55.45, 50.77, 45.23, 43.50, 37.97 , 35.16, 34.80, 33.35, 31.88, 30.44, 29.66, 29.00, 26.40, 26.22, 24.44, 21.62, 20.37, 17 06, 16.96, 15.52, 14.64, 13.50, 13.30, 10. 45〇

[0260]实施例43 :43-0- (2- (4- (4-戊基苯基)-1Η-1, 2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素(X-55) [0260] Example 43: 43-0- (2- (4- (4-pentylphenyl) -1Η-1, 2, 3- triazole-1-yl) propyl) oxy-rapamycin Su (X-55)

[0261 ]将43-0- (2-叠氮异丙酰基)-氧雷帕霉素(0. 2mmoL, 0. 2g)和4-正戊基苯乙炔(0. 07g)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0. 08g)和五水硫酸铜(0. 09g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体, 抽滤,水洗,干燥得淡黄色固体,经柱层析分离得纯品〇.〇5g,收率:21. 2 %。 [0261] The 43-0- (2-azido acid isopropyl) - oxo rapamycin (0. 2mmoL, 0. 2g) and 4-n-pentyl phenyl acetylene (0. 07g) was added to a DMF (IOmL ) was added to the reaction solution, sodium ascorbate (0. 08g) and copper sulfate pentahydrate (0. 09g), room temperature and stirred for 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid which was purified by column chromatography to give pure 〇.〇5g, yield: 212%. MS(ESI)m/ z: 1205. 8 (M+Na)+。 MS (ESI) m / z: 1205. 8 (M + Na) +. 1H NMR (500MHz,DMS0) δ 8. 67 (s,1H),7. 76 (d,J = 7. 9Hz,2H),7. 26 (d,J =8. 0Hz,2H),6. 45 (s,1H),6. 43-6. 33 (m,1H),6. 27-6. 17 (m,1H),6. 14-6. 09 (m,2H),5. 70-5 .60 (m, 1H), 5. 46 (dd, J = 14. 7, 9. 7Hz, 1H), 5. 27 (s, 1H), 5. 13-5. 06 (m, 1H), 4. 99-4. 91 (m, 2 H),4. 67-4. 53 (m, 1H),4. 04-3. 97 (m, 2H),3. 98-3. 90 (m, 1H),3. 66-3. 56 (m, 1H),3. 47-3. 38 ( m,1H),3. 24 (s,3H),3. 15 (s,3H),3. 04 (s,3H),2. 84-2. 68 (m,2H),2. 62-2. 56 (m,2H),2. 40-2 • 36 (m,2H),2. 25-2. 16 (m,1H),2. 14-2. 06 (m,1H),2. 06-1. 94 (m,2H),I. 85-1. 78 (m,6H),I. 7 4 (s,3H),I. 62 (s,3H),I. 60-1. 00 (m,15H),0· 97 (d,J = 6. 5Hz,3H),0· 93-0. 81 (m,6H),0· 81 (d, J = 6. 3Hz, 3H), 0. 77 (d, J = 6. 5Hz, 3H), 0. 72 (d, J = 6. 5Hz, 3H)〇13C NMR(126MHz, DMSO) δ 210. 37, 207. 51, 198. 85, 169. 19, 169. 01, 166. 96, 146. 29, 142. 10, 139. 30, 137. 84, 137. I 3, 132. 34, 130. 39, 128. 74, 128. 09, 126. 97, 125 1H NMR (500MHz, DMS0) δ 8. 67 (s, 1H), 7. 76 (d, J = 7. 9Hz, 2H), 7. 26 (d, J = 8. 0Hz, 2H), 6. 45 (s, 1H), 6. 43-6. 33 (m, 1H), 6. 27-6. 17 (m, 1H), 6. 14-6. 09 (m, 2H), 5. 70-5 .60 (m, 1H), 5. 46 (dd, J = 14. 7, 9. 7Hz, 1H), 5. 27 (s, 1H), 5. 13-5. 06 (m, 1H), 4 . 99-4. 91 (m, 2 H), 4. 67-4. 53 (m, 1H), 4. 04-3. 97 (m, 2H), 3. 98-3. 90 (m, 1H ), 3. 66-3. 56 (m, 1H), 3. 47-3. 38 (m, 1H), 3. 24 (s, 3H), 3. 15 (s, 3H), 3. 04 ( s, 3H), 2. 84-2. 68 (m, 2H), 2. 62-2. 56 (m, 2H), 2. 40-2 • 36 (m, 2H), 2. 25-2. 16 (m, 1H), 2. 14-2. 06 (m, 1H), 2. 06-1. 94 (m, 2H), I. 85-1. 78 (m, 6H), I. 7 4 (s, 3H), I. 62 (s, 3H), I. 60-1. 00 (m, 15H), 0 · 97 (d, J = 6. 5Hz, 3H), 0 · 93-0. 81 (m, 6H), 0 · 81 (d, J = 6. 3Hz, 3H), 0. 77 (d, J = 6. 5Hz, 3H), 0. 72 (d, J = 6. 5Hz, 3H) 〇13C NMR (126MHz, DMSO) δ 210. 37, 207. 51, 198. 85, 169. 19, 169. 01, 166. 96, 146. 29, 142. 10, 139. 30, 137. 84, 137 . I 3, 132. 34, 130. 39, 128. 74, 128. 09, 126. 97, 125 . 04, 124. 80, 120. 64, 98. 99, 85. 45, 82. 21, 8 0. 10, 79. 89, 77. 46, 75. 71, 66. 17, 57. 64, 56. 87, 56. 69, 55. 43, 50. 75, 45. 21, 43. 48, 37. 94, 35. 15, 34. 81, 33. 33, 31. 87, 30. 82, 30. 47, 29. 65, 29. 55, 28. 98, 26. 38, 26. 20, 24. 43, 21. 90 ,21. 61, 20. 36, 17. 04, 15. 54, 15. 50, 14. 62, 13. 87, 13. 48, 13. 29, 10. 43〇 04, 124.80, 120.64, 98.99, 85.45, 82.21, 8 0.10, 79.89, 77.46, 75.71, 66.17, 57.64, 56. 87, 56.69, 55.43, 50.75, 45.21, 43.48, 37.94, 35.15, 34.81, 33.33, 31.87, 30.82, 30.47, 29.65, 29.55, 28.98, 26.38, 26.20, 24.43, 21.90, 21.61, 20.36, 17.04, 15.54, 15.50, 14. 62, 13.87, 13.48, 13.29, 10. 43〇

[0262]实施例44 :43-0-(2-(4-(3-甲基苯基2, 3-三氮唑-I-基)异丙酰基)氧雷帕霉素(X-58) [0262] Example 44: 43-0- (2- (4- (3-phenyl-2, 3-triazole -I--yl) propyl) oxy-rapamycin (X-58)

[0263]将43-0- (2-叠氮异丙酰基)-氧雷帕霉素(0. 2mmoL, 0. 2g)和3-甲基苯乙炔(0.07g)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.08g)和五水硫酸铜(0. 09g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体, 抽滤,水洗,干燥得淡黄色固体,经柱层析分离得纯品〇. l〇g,收率:43. 5 %。 [0263] The 43-0- (2-azido acid isopropyl) - oxo rapamycin (0. 2mmoL, 0. 2g) and 3-methyl phenylacetylene (0.07 g of) was added to a DMF (IOmL) was was added to the reaction mixture of sodium ascorbate (0.08 g of) and copper sulfate pentahydrate (0. 09g), room temperature and stirred for 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, dried to give a pale yellow solid which was purified by column chromatography to give pure square l〇g, yield: 435%. MS (ESI) 7. 7Hz, 1H), 7. 33 (t, J = 7. 6Hz, 1H), 7. 15 (d, J = 7. 5Hz, 1H), 6. 45 (s, 1H), 6. 43-6. 34 (m, I Η), 6. 25-6. 18 (m, 1H), 6. 16-6. 06 (m, 2H), 5. 70-5. 63 (m, 1H), 5. 46 (dd, J = 14. 8, 9. 8Hz, IH ),5· 27 (s,1H),5· 09 (d,J = 10. 1Hz,1H),4· 98-4. 95 (m,1H),4· 95-4. 92 (m,1H),4· 66-4. 57 (m,1H),4· 03-3. 98 (m,2H),3· 97-3. 93 (m,1H),3· 65-3. 58 (m,1H),3· 46-3. 39 (m,1H),3· 24 ( s, 3H), 3. 15 (s, 3H), 3. 04 (s, 3H), 2. 83-2. 69 (m, 2H), 2. 42-2. 38 (m, 2H), 2. 36 (s, 3H), 2. 25-2· 17 (m,1H),2· 14-2. 06 (m,2H),2· 05-1. 95 (m,3H),I. 90-1. 83 (m,2H),I. 82 (d,J = 7. 3Hz ,3H),I. 74 (s,3H),I. 62 (s,3H),I. 58-1. 02 (m,10H),0· 97 (d,J = 6. 5Hz,3H),0· 86 (d,J = 6. 4Hz, 3H),0· 81 (d, J = 6. 3Hz, 3H),0· 77 (d, J = 6. 5Hz, 3H),0· 72 (d, J = 6. 6Hz, 3H)。 MS (ESI) 7. 7Hz, 1H), 7. 33 (t, J = 7. 6Hz, 1H), 7. 15 (d, J = 7. 5Hz, 1H), 6. 45 (s, 1H), 6. 43-6. 34 (m, I Η), 6. 25-6. 18 (m, 1H), 6. 16-6. 06 (m, 2H), 5. 70-5. 63 (m, 1H), 5. 46 (dd, J = 14. 8, 9. 8Hz, IH), 5 · 27 (s, 1H), 5 · 09 (d, J = 10. 1Hz, 1H), 4 · 98- 4. 95 (m, 1H), 4 · 95-4. 92 (m, 1H), 4 · 66-4. 57 (m, 1H), 4 · 03-3. 98 (m, 2H), 3 · 97-3. 93 (m, 1H), 3 · 65-3. 58 (m, 1H), 3 · 46-3. 39 (m, 1H), 3 · 24 (s, 3H), 3. 15 ( s, 3H), 3. 04 (s, 3H), 2. 83-2. 69 (m, 2H), 2. 42-2. 38 (m, 2H), 2. 36 (s, 3H), 2 . 25-2 · 17 (m, 1H), 2 · 14-2. 06 (m, 2H), 2 · 05-1. 95 (m, 3H), I. 90-1. 83 (m, 2H) , I. 82 (d, J = 7. 3Hz, 3H), I. 74 (s, 3H), I. 62 (s, 3H), I. 58-1. 02 (m, 10H), 0 · 97 (d, J = 6. 5Hz, 3H), 0 · 86 (d, J = 6. 4Hz, 3H), 0 · 81 (d, J = 6. 3Hz, 3H), 0 · 77 (d, J = 6. 5Hz, 3H), 0 · 72 (d, J = 6. 6Hz, 3H). 13C NMR(126MHz, DMSO) δ 210. 38, 207. 51, 198. 85, 169. 20, 169. 01, 166. 96, 146. 29, 139. 30, 138 .00, 137. 84, 137. 13, 132. 33, 130. 53, 130. 39, 128. 76, 128. 50, 126. 97, 125. 64, 124. 79, 122 .24, 120. 97, 98. 99, 85. 45, 82. 21, 80. 11, 77. 47, 75. 70, 73. 66, 66. 17, 57. 66, 56. 87, 56. 69, 55. 44, 50. 75, 45. 21, 43. 48, 37. 95, 35. 15, 34. 79, 33. 33, 31. 87, 30. 43, 29. 65, 28. 99, 26. 39 ,26. 20, 24. 43, 21. 61, 21. 01, 20. 35, 17. 04, 16. 93, 15. 54, 15. 50, 14. 62, 13. 49, 13. 29, 10. 4 3〇 13C NMR (126MHz, DMSO) δ 210. 38, 207. 51, 198. 85, 169. 20, 169. 01, 166. 96, 146. 29, 139. 30, 138 .00, 137. 84, 137. 13, 132.33, 130.53, 130.39, 128.76, 128.50, 126.97, 125.64, 124.79, 122.24, 120.97, 98.99, 85.45, 82.21, 80.11, 77.47, 75.70, 73.66, 66.17, 57.66, 56.87, 56.69, 55.44, 50.75, 45.21, 43. 48, 37.95, 35.15, 34.79, 33.33, 31.87, 30.43, 29.65, 28.99, 26.39, 26.20, 24.43, 21.61, 21.01, 20.35, 17.04, 16.93, 15.54, 15.50, 14.62, 13.49, 13.29, 10.4 3〇

[0264]实施例45 :43-0- (2- (4- (2-氯苯基)-1H-1, 2, 3-三氮唑-I-基)异丙酰基)氧雷帕霉素(X-56) [0264] Example 45: 43-0- (2- (4- (2-chlorophenyl) -1H-1, 2, 3- triazole -I--yl) propyl) oxy-rapamycin (X-56)

[0265]将43-0-(2-叠氮异丙酰基)_氧雷帕霉素(0.2111111〇1^0.28)和2-氯苯乙炔(0.078) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.08g)和五水硫酸铜(0.09g), 室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经柱层析分离得纯品〇. 13g,收率:56. 5%。 [0265] The 43-0- (2-azido-isopropyl group) _ oxygen rapamycin (0.2111111〇1 ^ 0.28) and 2-chlorophenyl acetylene (0.078) was added to a DMF (IOmL) solution to the reaction was added sodium ascorbate (0.08 g of) and copper sulfate pentahydrate (0.09 g of), stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a light yellow solid, by column chromatography to give pure square 13g, yield: 565%. MS(ESI)m/z:1169. 7(M+Na)+。 MS (ESI) m / z:. 1169 7 (M + Na) +. 1H NMR(400MHz,DMS0)S8.76(s,lH),8.08(d,J = 7.3Hz,lH),7.58(d,J = 7·7Ηζ,1Η),7 • 50-7. 40 (m,1H),6· 48 (s,1H),6· 46-6. 33 (m,1H),6· 29-6. 17 (m,1H),6· 17-6. 03 (m,2H),5 • 81-5. 67 (m,1H),5· 46 (dd,J = 14. 4, 9. 9Hz,1H),5· 30 (s,1H),5· 13-5. 03 (m,1H),5· 01-4 • 88 (m,2H),4· 68-4. 55 (m,1H),4· 07-3. 90 (m,3H),3· 68-3. 55 (m,1H),3· 53-3. 41 (m,1H),3 • 24 (s,3H),3. 15 (s,3H),3. 04 (s,3H),2. 83-2. 67 (m,2H),2. 43-2. 30 (m,2H),2. 28-2. 15 (m ,2H),2. 14-1. 98 (m,2H),I. 94-1. 78 (m,5H),I. 74 (s,3H),I. 62 (s,3H),I. 56-1. 03 (m,9H) ,0. 97(d, J = 6. 1Hz, 3H), 0. 86(d, J = 5. 9Hz, 3H), 0. 81 (d, J = 6. 0Hz, 3H), 0. 77 (d, J = 5. 7Hz, 3H), 0· 72(d, J = 6. 1Hz, 3H)。 1H NMR (400MHz, DMS0) S8.76 (s, lH), 8.08 (d, J = 7.3Hz, lH), 7.58 (d, J = 7 · 7Ηζ, 1Η), 7 • 50-7. 40 (m , 1H), 6 · 48 (s, 1H), 6 · 46-6. 33 (m, 1H), 6 · 29-6. 17 (m, 1H), 6 · 17-6. 03 (m, 2H ), 5 • 81-5. 67 (m, 1H), 5 · 46 (dd, J = 14. 4, 9. 9Hz, 1H), 5 · 30 (s, 1H), 5 · 13-5. 03 (m, 1H), 5 · 01-4 • 88 (m, 2H), 4 · 68-4. 55 (m, 1H), 4 · 07-3. 90 (m, 3H), 3 · 68-3 . 55 (m, 1H), 3 · 53-3. 41 (m, 1H), 3 • 24 (s, 3H), 3. 15 (s, 3H), 3. 04 (s, 3H), 2. 83-2. 67 (m, 2H), 2. 43-2. ​​30 (m, 2H), 2. 28-2. 15 (m, 2H), 2. 14-1. 98 (m, 2H), I. 94-1. 78 (m, 5H), I. 74 (s, 3H), I. 62 (s, 3H), I. 56-1. 03 (m, 9H), 0. 97 (d, J = 6. 1Hz, 3H), 0. 86 (d, J = 5. 9Hz, 3H), 0. 81 (d, J = 6. 0Hz, 3H), 0. 77 (d, J = 5. 7Hz , 3H), 0 · 72 (d, J = 6. 1Hz, 3H). 13C NMR(101MHz,DMS0) δ 210. 95, 208. 03, 199. 38, 169 .71, 169. 38, 167. 48, 142. 97, 139. 82, 138. 35, 137. 65, 132. 85, 130. 90, 130. 84, 130. 74, 130 .03, 129. 58, 128. 03, 127. 48, 125. 36, 124. 69, 99. 50, 82. 73, 80. 62, 78. 07, 76. 21, 74. 17, 66 .69, 58. 25, 57. 41, 57. 27, 55. 95, 51. 25, 45. 73, 44. 00, 38. 46, 35. 81, 35. 67, 35. 31, 33. 86, 3 2. 41, 30. 93, 30. 16, 29. 51, 26. 90, 26. 72, 24. 95, 22. 13, 20. 86, 17. 46, 17. 38, 16. 04, 16. 02, 15. 15, 13. 96, 13. 84, 10. 95〇 13C NMR (101MHz, DMS0) δ 210. 95, 208. 03, 199. 38, 169 .71, 169. 38, 167. 48, 142. 97, 139. 82, 138. 35, 137. 65, 132. 85, 130.90, 130.84, 130.74, 130.03, 129.58, 128.03, 127.48, 125.36, 124.69, 99.50, 82.73, 80.62, 78.07, 76.21, 74.17, 66.69, 58.25, 57.41, 57.27, 55.95, 51.25, 45.73, 44.00, 38.46, 35. 81, 35.67, 35.31, 33.86, 3 2.41, 30.93, 30.16, 29.51, 26.90, 26.72, 24.95, 22.13, 20.86 , 17.46, 17.38, 16.04, 16.02, 15.15, 13.96, 13.84, 10. 95〇

[0266]实施例46 :43-0- (2- (4- (4-溴苯基)-1H-1, 2, 3-三氮唑-I-基)异丙酰基)氧雷帕霉素(X-59) [0266] Example 46: 43-0- (2- (4- (4-bromophenyl) -1H-1, 2, 3- triazole -I--yl) propyl) oxy-rapamycin (X-59)

[0267]将43-0-(2_叠氮异丙酰基)-氧雷帕霉素(0.21111]1〇1^0.28)和4-溴苯乙炔(0.08区) 加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.08g)和五水硫酸铜(0.09g), 室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经柱层析分离得纯品〇.〇7g,收率:29. 2%。 [0267] The 43-0- (2_ acyl azide isopropyl) - oxo rapamycin (0.21111] 1〇1 ^ 0.28) and 4-bromophenyl acetylene (0.08 area) were added to DMF (IOmL) solution of , was added sodium ascorbate (0.08 g of) and copper sulfate pentahydrate (0.09 g of) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale as a yellow solid which was purified by column chromatography to give pure 〇.〇7g, yield: 292%. MS(ESI)m/z:1214. 3(M+Na)+。 MS (ESI) m / z:. 1214 3 (M + Na) +. 1H NMR (500MHz, DMSO) δ8. 81(s, 1Η),7. 84(d, J = 8. 3Ηζ, 2Η), 7. 66 (d, J = 8. 3Hz, 2Η), 6. 46 (s ,1Η), 6. 43-6. 35 (m, 1Η), 6. 26-6. 17 (m, 1Η), 6. 16-6. 08 (m, 2Η), 5. 72-5. 65 (m, 1Η), 5. 46 (dd, J = 14. 6, 9. 7Hz,1H),5· 28 (s,1H),5· 10 (d,J = 9. 7Hz,1H),5· 00-4. 96 (m,1H),4· 96-4. 89 ( m, 1Η),4. 66-4. 57 (m, 1Η),4. 04-3. 98 (m, 2Η),3. 98-3. 91 (m, 1Η),3. 64-3. 59 (m, 1Η),3. 47-3. 39 (m,1Η),3· 24 (s,3Η),3· 15 (s,3Η),3· 05 (s,3Η),2· 84-2. 68 (m,2Η),2· 44-2. 33 (m,2Η),2· 2 6-2. 17 (m,1Η),2· 14-2. 06 (m,1Η),2· 05-1. 94 (m,2Η),L 93-1. 84 (m,2Η),L 82 (d,J = 7· 4Η ζ,3Η),I. 74 (s,3Η),I. 62 (s,3Η),I. 57-1. 02 (m,10Η),0· 98 (d,J = 6· 4Hz,3Η),0· 87 (d,J = 6. 4Hz,3H),0· 82 (d,J = 6. 3Hz,3H),0· 78 (d,J = 6. 4Hz,3H),0· 73 (d,J = 6. 5Hz,3H)。 1H NMR (500MHz, DMSO) δ8. 81 (s, 1Η), 7. 84 (d, J = 8. 3Ηζ, 2Η), 7. 66 (d, J = 8. 3Hz, 2Η), 6. 46 ( s, 1Η), 6. 43-6. 35 (m, 1Η), 6. 26-6. 17 (m, 1Η), 6. 16-6. 08 (m, 2Η), 5. 72-5. 65 (m, 1Η), 5. 46 (dd, J = 14. 6, 9. 7Hz, 1H), 5 · 28 (s, 1H), 5 · 10 (d, J = 9. 7Hz, 1H), 5 · 00-4. 96 (m, 1H), 4 · 96-4. 89 (m, 1Η), 4. 66-4. 57 (m, 1Η), 4. 04-3. 98 (m, 2Η ), 3. 98-3. 91 (m, 1Η), 3. 64-3. 59 (m, 1Η), 3. 47-3. 39 (m, 1Η), 3 · 24 (s, 3Η), 3 · 15 (s, 3Η), 3 · 05 (s, 3Η), 2 · 84-2. 68 (m, 2Η), 2 · 44-2. 33 (m, 2Η), 2 · 2 6-2 . 17 (m, 1Η), 2 · 14-2. 06 (m, 1Η), 2 · 05-1. 94 (m, 2Η), L 93-1. 84 (m, 2Η), L 82 (d , J = 7 · 4Η ζ, 3Η), I. 74 (s, 3Η), I. 62 (s, 3Η), I. 57-1. 02 (m, 10Η), 0 · 98 (d, J = 6 · 4Hz, 3Η), 0 · 87 (d, J = 6. 4Hz, 3H), 0 · 82 (d, J = 6. 3Hz, 3H), 0 · 78 (d, J = 6. 4Hz, 3H ), 0 · 73 (d, J = 6. 5Hz, 3H). 13C NMR(126MHz, DMSO) δ 210. 39, 207. 52, 198. 86, 169. 21, 168. 95, 166. 98, 145. 19, 139. 31, 137 .85, 137. 14, 132. 35, 131. 87, 130. 41, 129. 88, 127. 07, 126. 99, 124. 81, 121. 48, 120. 86, 99. 00. 85. 46, 82. 22, 80. 11, 77. 51, 75. 73, 73. 66, 66. 18, 57. 75, 56. 89, 56. 68, 55. 45, 50. 77, 45 .23, 43. 49, 37. 98, 35. 16, 34. 80, 33. 34, 31. 88, 30. 42, 29. 67, 28. 99, 26. 40, 26. 22, 24. 44, 2 1. 63, 20. 37, 17. 05, 15. 55, 15. 52, 14. 65, 13. 50, 13. 30, 10. 45〇 13C NMR (126MHz, DMSO) δ 210. 39, 207. 52, 198. 86, 169. 21, 168. 95, 166. 98, 145. 19, 139. 31, 137 .85, 137. 14, 132. 35, 131.87, 130.41, 129.88, 127.07, 126.99, 124.81, 121.48, 120.86, 99. 00. 85.46, 82.22, 80.11, 77.51, 75.73, 73.66, 66.18, 57.75, 56.89, 56.68, 55.45, 50.77, 45.23, 43.49, 37.98, 35. 16, 34.80, 33.34, 31.88, 30.42, 29.67, 28.99, 26.40, 26.22, 24.44, 2 1.63, 20.37, 17.05 , 15.55, 15.52, 14.65, 13.50, 13.30, 10. 45〇

[0268] 实施例47 :43-0-(2-(4-(4-甲氧基苯基2, 3-三氮唑-I-基)异丙酰基) 氧雷帕霉素(X-66) [0268] Example 47: 43-0- (2- (4- (4-methoxyphenyl 2,3-triazole -I--yl) propyl) oxy-rapamycin (X-66 )

[0269] 将43-0- (2-叠氮异丙酰基)-氧雷帕霉素(0. 2mmoL, 0. 2g)和4-甲基苯乙炔(0.07g)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.08g)和五水硫酸铜(0. 09g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体, 抽滤,水洗,干燥得淡黄色固体,经柱层析分离得纯品〇.l〇g,收率:43. 4%。 [0269] The 43-0- (2-azido acid isopropyl) - oxo rapamycin (0. 2mmoL, 0. 2g) and 4-phenylacetylene (0.07 g of) was added to a DMF (IOmL) was was added to the reaction mixture of sodium ascorbate (0.08 g of) and copper sulfate pentahydrate (0. 09g), room temperature and stirred for 2h, after completion of the reaction, the reaction was poured 30mL of water was added, the precipitated pale yellow solid was filtered off with suction, washed with water, dried light yellow solid, was isolated by column chromatography pure 〇.l〇g, yield: 434%. MS(ESI)m/ z: 1165. 7 (M+Na)+。 MS (ESI) m / z: 1165. 7 (M + Na) +. 1HNMR(500MHz,DMS0)δ8. 46 (s,1H),7. 78 (d,J= 8. 7Hz,2H),7. 02 (d,J =8. 8Hz,2H),6. 46 (s,1H),6. 45-6. 34 (m,1H),6. 26-6. 18 (m,1H),6. 17-6. 06 (m,2H),5. 44(s ,2H),5. 27 (s, 1H),5. 10 (d,J= 10. 1Hz, 1H),5. 00-4. 91 (m, 2H),4. 69-4. 58 (m, 1H),4. 06-3. 98 (m, 2H),3. 99-3. 92 (m, 1H),3. 79 (s, 3H),3. 68-3. 57 (m, 1H),3. 49-3. 39 (m, 1H),3. 27 (s, 3H ),3.16 (s, 3H),3. 05 (s, 3H),2. 88-2. 67 (m, 2H),2. 44-2. 33 (m, 2H),2. 27-2. 18 (m, 2H),2. 14- 2. 07 (m,1H),2. 05-1. 96 (m,2H),I. 96-1. 78 (m,3H),I. 75 (s,3H),I. 63 (s,3H),I. 55-1. 03 (m, 10H),0. 98 (d, J = 6. 5Hz, 3H),0. 87 (d, J = 6. 4Hz, 3H),0. 82 (d, J = 6. 4Hz, 3H),0. 78 (d, J = 6. 7Hz, 3H),0· 73 (d, J = 6. 5Hz, 3H)。 1HNMR (500MHz, DMS0) δ8. 46 (s, 1H), 7. 78 (d, J = 8. 7Hz, 2H), 7. 02 (d, J = 8. 8Hz, 2H), 6. 46 (s , 1H), 6. 45-6. 34 (m, 1H), 6. 26-6. 18 (m, 1H), 6. 17-6. 06 (m, 2H), 5. 44 (s, 2H ), 5. 27 (s, 1H), 5. 10 (d, J = 10. 1Hz, 1H), 5. 00-4. 91 (m, 2H), 4. 69-4. 58 (m, 1H ), 4. 06-3. 98 (m, 2H), 3. 99-3. 92 (m, 1H), 3. 79 (s, 3H), 3. 68-3. 57 (m, 1H), 3. 49-3. 39 (m, 1H), 3. 27 (s, 3H), 3.16 (s, 3H), 3. 05 (s, 3H), 2. 88-2. 67 (m, 2H) , 2. 44-2. 33 (m, 2H), 2. 27-2. 18 (m, 2H), 2. 14- 2. 07 (m, 1H), 2. 05-1. 96 (m, 2H), I. 96-1. 78 (m, 3H), I. 75 (s, 3H), I. 63 (s, 3H), I. 55-1. 03 (m, 10H), 0. 98 (d, J = 6. 5Hz, 3H), 0. 87 (d, J = 6. 4Hz, 3H), 0. 82 (d, J = 6. 4Hz, 3H), 0. 78 (d, J = 6. 7Hz, 3H), 0 · 73 (d, J = 6. 5Hz, 3H). 13C NMR(126MHz, DMSO) δ 210. 39, 207. 54, 198. 86, 169 .22, 166. 99, 166. 77, 159. 03, 146. 27, 139. 31,137. 86, 137. 15, 132. 35, 130. 42, 127. 01,126 .49, 123. 11,121. 78, 114. 33, 99. 01,85. 46, 82. 22, 79. 86, 77. 71,75. 73, 73. 66, 66. 19, 56. 9 0, 56. 77, 55. 45, 55. 12, 50. 78, 50. 60, 45. 23, 43. 50, 37. 99, 35. 28, 35. 17, 34. 80, 33. 32, 31. 87, 29. 66, 29. 56, 29. 22, 29. 15, 26. 42, 26. 22, 24. 44, 21. 63, 20. 38, 15. 56, 15. 52, 14. 63, 13 • 51,13. 30, 10. 45。 13C NMR (126MHz, DMSO) δ 210. 39, 207. 54, 198. 86, 169 .22, 166. 99, 166. 77, 159. 03, 146. 27, 139. 31,137. 86, 137. 15, 132.35, 130.42, 127. 01,126 .49, 123. 11, 121 78, 114.33, 99. 01,85. 46, 82.22, 79.86, 77.71, 75.73, 73.66, 66.19, 56.9 0 56.77, 55.45, 55.12, 50.78, 50.60, 45.23, 43.50, 37.99, 35 28, 35.17, 34.80, 33.32, 31.87, 29.66, 29.56, 29.22, 29.15, 26.42, 26.22, 24.44, 21.63 , 20. 38, 15. 56, 15. 52, 14. 63, 13 • 51,13. 30, 10. 45.

[0270] 实施例48 :43-0-(2-(4-((2, 5二氯苯基)氨基甲基)-1Η-1,2, 3-三氮唑-I-基) 异丙酰基)氧雷帕霉素(X-65) [0270] Example 48: 43-0- (2- (4 - ((2, 5-dichlorophenyl) aminomethyl) -1Η-1,2, 3- triazole -I--yl) propyl ) oxy-rapamycin (X-65)

[0271]将43-〇- (2_叠氣异丙醜基)-氧雷帕霉素(CL 2mmoL, CL 2g)和N-(丙_2_块基)-2,5-二氯苯胺(0.07g)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0. 08g)和五水硫酸铜(0. 09g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中, 析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经柱层析分离得纯品〇. llg,收率: 45.8 %。 [0271] The 43- 〇- (2_ stack gas isopropyl ugly yl) - oxo rapamycin (CL 2mmoL, CL 2g) and N- (prop-_2_ block yl) -2,5-dichloroaniline (0.07 g of) was added to a DMF (IOmL) was added to the reaction solution, sodium ascorbate (0. 08g) and copper sulfate pentahydrate (0. 09g), room temperature and stirred for 2h, after completion of the reaction, the reaction was poured in water was added 30mL , the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid which was purified by column chromatography to give pure square LLG, yield: 45.8%. MS(ESI)m/z:1232.6(M+Na)+。 MS (ESI) m / z: 1232.6 (M + Na) +. 1H NMR(400MHz,DMS0)S8.11(s,lH),7.31(d,J = 8. 3Hz, 1H),6. 84 (s, 1H),6. 64 (d, J = 8. 4Hz, 1H),6. 53 (s, 1H),6. 51-6. 40 (m, 1H),6. 35-6 .27 (m, 1H),6. 26-6. 13 (m, 2H),5. 75-5. 62 (m, 1H),5. 52 (dd, J = 14. 2, 9. 6Hz, 1H),5. 35 (s ,1H), 5. 20-5. 11 (m, 1H),5. 07-4. 95 (m, 2H),4. 64-4. 54 (m, 1H),4. 52 (s, 2H),4. 12-3. 96( m, 3H), 3. 71 - 3. 65 (m, 1H),3. 54-3. 44 (m, 1H), 3. 21 (s, 3H), 3. 19 (s, 3H),3. 11 (s, 3H),2. 98-2. 72 (m, 2H),2. 51-2. 39 (m, 2H),2. 36-2. 24 (m, 1H),2. 21-2. 05 (m, 2H),2. 03-1. 86 (m, 3H),I. 80 (s, 3H),I. 68 (s, 3H),I. 65-1. 08 (m, 10H),L〇4 (d, J = 6. 2Hz, 3H),0. 93 (d, J = 6. 3Hz, 3H),0· 88 (d, J = 6. 3Hz, 3H),0· 84 (d, J = 5. 5Hz, 3H),0· 79 (d, J = 6. 2Hz, 3H)。 1H NMR (400MHz, DMS0) S8.11 (s, lH), 7.31 (d, J = 8. 3Hz, 1H), 6. 84 (s, 1H), 6. 64 (d, J = 8. 4Hz, 1H), 6. 53 (s, 1H), 6. 51-6. 40 (m, 1H), 6. 35-6 .27 (m, 1H), 6. 26-6. 13 (m, 2H) , 5. 75-5. 62 (m, 1H), 5. 52 (dd, J = 14. 2, 9. 6Hz, 1H), 5. 35 (s, 1H), 5. 20-5. 11 ( m, 1H), 5. 07-4. 95 (m, 2H), 4. 64-4. 54 (m, 1H), 4. 52 (s, 2H), 4. 12-3. 96 (m, 3H), 3. 71 -... 3. 65 (m, 1H), 3 54-3 44 (m, 1H), 3. 21 (s, 3H), 3. 19 (s, 3H), 3 11 (s, 3H), 2. 98-2. 72 (m, 2H), 2. 51-2. 39 (m, 2H), 2. 36-2. 24 (m, 1H), 2. 21-2 . 05 (m, 2H), 2. 03-1. 86 (m, 3H), I. 80 (s, 3H), I. 68 (s, 3H), I. 65-1. 08 (m, 10H ), L〇4 (d, J = 6. 2Hz, 3H), 0. 93 (d, J = 6. 3Hz, 3H), 0 · 88 (d, J = 6. 3Hz, 3H), 0 · 84 (d, J = 5. 5Hz, 3H), 0 · 79 (d, J = 6. 2Hz, 3H). 13C NMR(101MHz, DMSO) δ 210. 46, 207. 50, 198. 86, 169. 18, 168. 79, 166. 97, 144. 79, 139. 32, 137 .83, 137. 14, 132. 44, 132. 33, 130. 38, 129. 99, 126. 96, 124. 91, 122. 65, 116. 53, 115. 94, HO .87, 98. 98, 85. 51, 82. 22, 80. 04, 77. 33, 75. 69, 73. 72, 66. 18, 57. 43, 56. 91, 56. 69, 55. 42, 5 0. 74, 45. 20, 43. 47, 38. 05, 37. 83, 35. 15, 35. 04, 34. 78, 33. 34, 31. 86, 30. 47, 29. 65, 28. 86, 26. 38, 26. 18, 24. 41, 21. 61, 20. 36, 20. 34, 16. 88, 15. 52, 14. 59, 13. 39, 10. 44〇 13C NMR (101MHz, DMSO) δ 210. 46, 207. 50, 198. 86, 169. 18, 168. 79, 166. 97, 144. 79, 139. 32, 137 .83, 137. 14, 132. 44, 132. 33, 130. 38, 129. 99, 126. 96, 124. 91, 122. 65, 116. 53, 115. 94, HO .87, 98. 98, 85. 51, 82. 22, 80.04, 77.33, 75.69, 73.72, 66.18, 57.43, 56.91, 56.69, 55.42, 5 0.74, 45.20, 43.47, 38 05, 37.83, 35.15, 35.04, 34.78, 33.34, 31.86, 30.47, 29.65, 28.86, 26.38, 26.18, 24.41 , 21.61, 20.36, 20.34, 16.88, 15.52, 14.59, 13.39, 10. 44〇

[0272] 实施例49 :43-0-(2-(4-((2, 4二氯苯基)氨基甲基2, 3-三氮唑-I-基) 异丙酰基)氧雷帕霉素(X-64) [0272] Example 49: 43-0- (2- (4 - ((2, 4-dichlorophenyl) aminomethyl 2, 3-triazole -I--yl) propyl) oxy-rapamycin Su (X-64)

[0273] 将43-0- (2_叠氣异丙醜基)-氧雷帕霉素(0. 2mmoL, 0. 2g)和N-(丙_2_块基)-2,4-二氯苯胺(0.07g)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0. 08g)和五水硫酸铜(0. 09g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经柱层析分离得纯品〇.〇9g,收率:37. 5%。 [0273] The 43-0- (2_ stack gas isopropyl ugly yl) - oxo rapamycin (0. 2mmoL, 0. 2g) and N- (prop-_2_ block yl) -2,4- chloroaniline (0.07 g of) was added to a DMF (IOmL) was added sodium ascorbate (0. 08g) and copper sulfate pentahydrate (0. 09g) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured added 30mL of water, the precipitated pale yellow solid was filtered off with suction, washed with water, and dried to give a pale yellow solid which was purified by column chromatography to give pure 〇.〇9g, yield: 375%. MS(ESI)m/z:1232.4(M+Na)+。 MS (ESI) m / z: 1232.4 (M + Na) +. 1H (400MHz,DMS0) δ 8.09 (s,lH),7.39 (s,lH),7.20 (d,J =8. 8Hz,1H),6. 82 (d,J = 8. 9Hz,1H),6. 54 (s,1H),6. 50-6. 41 (m,1H),6. 34-6. 23 (m,1H),6 •23-6. 11 (m,2H),5. 70-5. 61 (m,1H),5. 52 (dd,J = 14. 7, 9. 6Hz,1H),5. 36 (s,1H),5. 20-5. II (m,1H),5. 07-4. 93 (m,2H),4. 66-4. 53 (m,1H),4. 51 (s,2H),4. 13-3. 98 (m,3H),3. 73-3. 63 ( m, 1H),3. 56-3. 46 (m, 1H),3. 22 (s, 3H),3. 21 (s, 3H),3. 11 (s, 3H),2. 91-2. 74 (m, 2H),2. 49 -2. 40 (m, 2H), 2. 34-2. 21 (m, 1H),2. 22-2. 11 (m, 2H),2. 11-1. 97 (m, 2H),I. 96-1. 83 (m, 3H ),I. 80 (s, 3H),I. 69 (s, 3H),I. 66-1. 08 (m, 10H),I. 04 (d, J = 6. 5Hz, 3H),0. 93 (d, J = 6. 5Hz, 3H),0· 88 (d, J = 6. 4Hz, 3H),0· 85 (d, J = 6. 6Hz, 3H),0· 79 (d, J = 6. 6Hz, 3H)。 1H (400MHz, DMS0) δ 8.09 (s, lH), 7.39 (s, lH), 7.20 (d, J = 8. 8Hz, 1H), 6. 82 (d, J = 8. 9Hz, 1H), 6 . 54 (s, 1H), 6. 50-6. 41 (m, 1H), 6. 34-6. 23 (m, 1H), 6 • 23-6. 11 (m, 2H), 5. 70 -5. 61 (m, 1H), 5. 52 (dd, J = 14. 7, 9. 6Hz, 1H), 5. 36 (s, 1H), 5. 20-5. II (m, 1H) , 5. 07-4. 93 (m, 2H), 4. 66-4. 53 (m, 1H), 4. 51 (s, 2H), 4. 13-3. 98 (m, 3H), 3 . 73-3. 63 (m, 1H), 3. 56-3. 46 (m, 1H), 3. 22 (s, 3H), 3. 21 (s, 3H), 3. 11 (s, 3H ), 2. 91-2. 74 (m, 2H), 2. 49 -2. 40 (m, 2H), 2. 34-2. 21 (m, 1H), 2. 22-2. 11 (m , 2H), 2. 11-1. 97 (m, 2H), I. 96-1. 83 (m, 3H), I. 80 (s, 3H), I. 69 (s, 3H), I. 66-1. 08 (m, 10H), I. 04 (d, J = 6. 5Hz, 3H), 0. 93 (d, J = 6. 5Hz, 3H), 0 · 88 (d, J = 6 . 4Hz, 3H), 0 · 85 (d, J = 6. 6Hz, 3H), 0 · 79 (d, J = 6. 6Hz, 3H). 13C NMR(101MHz, DMSO) δ 227. 19, 210. 43, 207. 50, 198. 86, 169. 17, 168. 81, 166. 97, 144. 94, 142 .73, 139. 32, 137. 84, 137. 13, 132. 33, 130. 38, 128. 10, 127. 63, 126. 97, 122. 62, 119. 19, 118 .41, 112. 51, 98. 99, 85. 51, 82. 22, 80. 02, 77. 34, 75. 70, 73. 73, 66. 18, 57. 42, 56. 90, 56. 68, 55. 43, 50. 74, 45. 22, 43. 47, 38. 22, 37. 91, 35. 15, 34. 79, 33. 35, 31. 93, 30. 48, 29. 65, 28. 91 ,26. 39, 26. 22, 24. 42, 21. 62, 20. 35, 16. 91, 15. 52, 14. 62, 13. 38, 10. 44〇 13C NMR (101MHz, DMSO) δ 227. 19, 210. 43, 207. 50, 198. 86, 169. 17, 168. 81, 166. 97, 144. 94, 142 .73, 139. 32, 137. 84, 137.13, 132.33, 130.38, 128.10, 127.63, 126.97, 122.62, 119.19, 118.41, 112.51, 98.99, 85.51, 82.22, 80.02, 77.34, 75.70, 73.73, 66.18, 57.42, 56.90, 56.68, 55.43, 50.74, 45.22, 43. 47, 38.22, 37.91, 35.15, 34.79, 33.35, 31.93, 30.48, 29.65, 28.91, 26.39, 26.22, 24.42, 21.62, 20.35, 16.91, 15.52, 14.62, 13.38, 10. 44〇

[0274] 实施例50 :43-0-(2-(4-((2-氟苯基)氨基甲基2, 3-三氮唑-I-基)异丙酰基)氧雷帕霉素(X-62) [0274] Example 50: 43-0- (2- (4 - ((2-fluorophenyl) aminomethyl-2, 3-triazole -I--yl) propyl) oxy-rapamycin ( X-62)

[0275]将43-0- (2_叠氣异丙醜基)-氧雷帕霉素(0. 2mmoL, 0. 2g)和N-(丙_2_块基)-2-氟苯胺(0.07g)加入到DMF(IOmL)溶液中,向反应液中加入抗坏血酸钠(0.08g) 和五水硫酸铜(0. 09g),室温搅拌2h,反应完毕后,将反应倒加入30mL水中,析出淡黄色固体,抽滤,水洗,干燥得淡黄色固体,经柱层析分离得纯品0. 08g,收率:34. 7 %。 [0275] The 43-0- (2_ stack gas isopropyl ugly yl) - oxo rapamycin (0. 2mmoL, 0. 2g) and N- (prop-_2_ block yl) -2-fluoroaniline ( 0.07 g of) was added to a DMF (IOmL) was added sodium ascorbate (0.08 g of) and copper sulfate pentahydrate (0. 09g) to the reaction mixture, stirred at room temperature 2h, after completion of the reaction, the reaction was poured 30mL of water was added to precipitate light yellow solid, filtered off with suction, washed with water, and dried to give a pale yellow solid which was purified by column chromatography to give pure 0. 08g, yield: 347%. MS (ESI) m/ z: 1182. 7 (M+Na)+。 MS (ESI) m / z: 1182. 7 (M + Na) +. 1H (500MHz,DMSO) δ 8. 04 (s,1H),7. 04-6. 96 (m,1H),6. 95-6. 87 (m, 1H),6· 79-6. 70 (m,1H),6· 56-6. 50 (m,1H),6· 46 (s,1H),6· 44-6. 32 (m,1H),6· 26-6. 17 (m,IH ),6· 17-6. 07 (m,2Η),5· 97-5. 91 (m,1Η),5· 63-5. 55 (m,1Η),5· 52-5. 43 (m,1Η),5· 28 (s,1Η), 5. 14-5. 07 (m,1Η),5. 00-4. 90 (m,2Η),4. 59-4. 50 (m,1Η),4. 39 (s,2Η),4. 08-3. 93 (m,3Η).6 7-3. 59 (m, 1H), 3. 49-3. 39 (m, 1H), 3. 17 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 85-2. 68 (m, 2H),2· 45-2. 31 (m,2H),2· 27-2. 16 (m,1H),2· 16-2. 06 (m,2H),2· 06-1. 92 (m,3H),I. 90-1. 78 ( m,2Η),I. 74 (s,3Η),I. 62 (s,3Η),I. 57-1. 01 (m,10Η),0· 98 (d,J= 5· 5Hz,3Η),0· 87 (d,J= 5. 8Hz, 3H),0· 82 (d,J= 4. 9Hz, 3H),0· 78 (d,J= 4.OHz, 3H),0· 73 (d,J= 5. 7Hz, 3H)。 1H (500MHz, DMSO) δ 8. 04 (s, 1H), 7. 04-6. 96 (m, 1H), 6. 95-6. 87 (m, 1H), 6 · 79-6. 70 ( m, 1H), 6 · 56-6. 50 (m, 1H), 6 · 46 (s, 1H), 6 · 44-6. 32 (m, 1H), 6 · 26-6. 17 (m, IH), 6 · 17-6. 07 (m, 2Η), 5 · 97-5. 91 (m, 1Η), 5 · 63-5. 55 (m, 1Η), 5 · 52-5. 43 ( m, 1Η), 5 · 28 (s, 1Η), 5. 14-5. 07 (m, 1Η), 5. 00-4. 90 (m, 2Η), 4. 59-4. 50 (m, 1Η), 4. 39 (s, 2Η), 4. 08-3. 93 (m, 3Η) .6 7-3. 59 (m, 1H), 3. 49-3. 39 (m, 1H), 3. 17 (s, 3H), 3. 16 (s, 3H), 3. 05 (s, 3H), 2. 85-2. 68 (m, 2H), 2 · 45-2. 31 (m, 2H), 2 · 27-2. 16 (m, 1H), 2 · 16-2. 06 (m, 2H), 2 · 06-1. 92 (m, 3H), I. 90-1. 78 ( m, 2Η), I. 74 (s, 3Η), I. 62 (s, 3Η), I. 57-1. 01 (m, 10Η), 0 · 98 (d, J = 5 · 5Hz, 3Η) , 0 · 87 (d, J = 5. 8Hz, 3H), 0 · 82 (d, J = 4. 9Hz, 3H), 0 · 78 (d, J = 4.OHz, 3H), 0 · 73 ( d, J = 5. 7Hz, 3H). 13C NMR(126MHz,DMSO)δ210. 42, 207. 53, 198. 85, 191. 52, 169. 20, 168. 88, 166. 97, 152. 23, 151 .88, 149. 98, 147. 76, 145. 51, 139. 31, 137. 84, 137. 13, 136. 24, 136. 15, 132. 34, 130. 39, 12 6. 97, 124. 80, 124. 58, 122. 53, 122. 47, 115. 75, 115. 69, 114. 26, 114. 12, 112. 25, 112. 23, 99 .73, 98. 99, 85. 46, 82. 21, 79. 99, 77. 34, 75. 70, 73. 66, 66. 18, 57. 39, 56. 89, 56. 68, 55. 44, 5 0. 77, 45. 21, 43. 49, 42. 12, 38. 12, 37. 89, 35. 15, 34. 79, 33. 32, 31. 84, 30. 41, 29. 64, 29. 55, 28. 95, 28. 93, 26. 39, 26. 22, 24. 43, 21. 61, 20. 35, 16. 97, 15. 54, 15. 52, 14. 60, 13. 47, 13. 31 ,10. 44。 13C NMR (126MHz, DMSO) δ210. 42, 207. 53, 198. 85, 191. 52, 169. 20, 168. 88, 166. 97, 152. 23, 151 .88, 149. 98, 147. 76 , 145.51, 139.31, 137.84, 137.13, 136.24, 136.15, 132.34, 130.39, 12 6.97, 124.80, 124.58, 122.53, 122.47, 115.75, 115.69, 114.26, 114.12, 112.25, 112.23, 99.73, 98.99, 85.46, 82.21, 79.99, 77. 34, 75.70, 73.66, 66.18, 57.39, 56.89, 56.68, 55.44, 5 0.77, 45.21, 43.49, 42.12, 38.12 , 37.89, 35.15, 34.79, 33.32, 31.84, 30.41, 29.64, 29.55, 28.95, 28.93, 26.39, 26.22, 24 43, 21.61, 20.35, 16.97, 15.54, 15.52, 14.60, 13.47, 13.31, 10.44.

[0276] 试骀例I:抗肿瘤活件测试 [0276] Test Example tired I: antitumor activity test member

[0277] 将肺癌细胞A549、肺癌细胞NCI-H1299、原位胰腺癌BxPC-3、胃癌细胞MGC80-3、 宫颈癌细胞Caski、人白血病细胞HL-60和人白血病细胞K-562细胞株复苏并传代2-3 次,使细胞活力稳定以用于体外细胞活性测试。 [0277] The lung cancer cell A549, lung cancer cell NCI-H1299, orthotopic pancreatic cancer BxPC-3, gastric cancer cells MGC80-3, cervical cancer cells Caski, human leukemia cells HL-60 and K-562 human leukemia cell lines and recovery passaged 2-3 times to stabilize cell viability for cell viability in vitro tests. 悬浮细胞不需消化,贴壁细胞胰蛋白酶(0. 25% )进行消化,加入含血清的细胞培养液终止消化,用移液管转移细胞液至离心管, 1500r/min下离心3min,轻轻弃去上清液后加入5mL培养液,吹打混勻细胞,计数,贴壁细胞5000-10000个/孔,悬浮细胞20000个/孔,加入96孔板,于37°C、5%C02培养,细胞培养24小时后加入测试药物。 Cell suspension without digestion, adherent cells were trypsinized (0.25%) digestion, cell culture medium containing serum was added to terminate the digestion with cell suspension pipetted into a centrifuge tube 3min centrifugation, 1500r / min, gently after removal of the supernatant was added to 5mL broth, cells were mixed by pipetting, counted 5000-10000 adherent cells / well, 20000 suspension cells / well added to 96-well plates at 37 ° C, 5% C02 culture, cells test drugs were added after 24 hours. 测试本发明化合物的生物学活性,并以雷帕霉素(Rapa)和替西罗莫司(CCI-779)作对照,用二甲基亚砜溶解受试样品作为母液,然后用细胞培养液稀释受试样品:取IOul样品母液,加入990ul细胞培养液,稀释样品至测试浓度。 Biologically active compound of the invention were tested, and rapamycin (Rapa) and temsirolimus (CCI-779) as a control, a test sample was dissolved in dimethyl sulfoxide as the mother liquor, followed by cell culture diluted test sample: a sample taken IOul liquor, was added 990ul cell culture medium, samples were diluted to the test concentrations. 将样品稀释液加入已经在96孔板中培养24h的细胞培养液中,每个浓度加入3孔,设空白对照(未加药物处理)。 The cell culture was added to sample diluent have been cultured for 24h in 96 well plates, each added at a concentration of 3 wells, blank control (without drug treatment). 将96孔板于37°C、5%C02继续培养96h,在每孔中加入MTT(四氮唑)(5mg/ mL) 20μL,放入培养箱中8h后,悬浮细胞于4000r/min离心lOmin,弃去上清液,加入二甲基亚砜150μL,使存活细胞与MTT反应产物甲臜充分溶解,放入酶标仪中测定结果,通过Bliss法可求出药物IC5tl值(μmol/L)。 The 96-well plates at 37 ° C, 5% C02 cultured for 96h, added MTT (tetrazolium) (5mg / mL) 20μL per well, after placed in incubator for 8h, cells were suspended 4000r / min centrifugation at lOmin the supernatant was discarded, 150 L dimethyl sulfoxide was added, and the viable cells are MTT formazan reaction product was sufficiently dissolved, the measurement result into the plate reader, the drug can be obtained by Bliss method IC5tl value (μmol / L) . 结果显示,本发明制备的化合物对各种癌细胞均具有比雷帕霉素和替西罗莫司明显更优良的生物学活性,例如:对A549细胞,Rapa和CCI-779 的IC5tl值(μmol/L)分别为24和15,而本发明实施例1-50各化合物的IC5tl值(μmol/L) 均在0. 1〜13范围内,例如实施例38化合物的IC5tl值(μmol/L)为0.I;对H1299细胞, Rapa和CCI-779的IC5tl值(μmol/L)分别为14和19,而本发明实施例1-50各化合物的IC5。 The results show, for the preparation of compounds of the present invention, various cancer cells have a significantly better than rapamycin and temsirolimus biological activity, for example: IC5tl value of A549 cells, Rapa of CCI-779 and ([mu] mol / L), respectively 24 and 15, IC5tl value of each compound of example 1-50 ([mu] mol / L) and the embodiment of the present invention are within the scope 0. 1~13, e.g. IC5tl value of the compound of example 38 (μmol / L embodiment) is 0.I; of H1299 cells, Rapa IC5tl of CCI-779, and the value (μmol / L) were 14 and 19, IC5 1-50 each compound of the present invention according to the embodiment. 值(μmol/L)均在1〜15范围内,例如实施例38化合物的IC5tl值(μmol/L)为I. 1 ;对宫颈癌细胞Caski,Rapa的IC5tl值(μmol/L)为23,而本发明实施例1-50各化合物的IC5tl 值(μmol/L)均在1〜26范围内,例如实施例7化合物的IC5tl值(μmol/L)为2. 1 ;对人白血病细胞HL-60,Rapa的IC5tl值(μmol/L)为25,而本发明实施例1-50各化合物的IC5tl 值(μmol/L)均在0· 6〜19范围内,例如实施例40化合物的IC5tl值(μmol/L)为0· 3。 Value (μmol / L) are within the range of 1~15, the compounds of Examples 38 IC5tl values ​​(μmol / L) for example, as I. 1; IC5tl value on cervical cancer cells Caski, Rapa of (μmol / L) was 23, and IC5tl value (μmol / L) 1-50 various embodiments of the present invention is a compound of embodiment are within the scope 1~26, e.g. IC5tl value example 7 compound (μmol / L) was 2.1 embodiment; on human leukemia cell HL- 60, Rapa of IC5tl value (μmol / L) was 25, IC5tl value of each compound of example 1-50 (μmol / L) and the embodiment of the present invention are within the range of 0.5 6~19, e.g. the compound of example 40 value IC5tl (μmol / L) to 0 · 3.

[0278] 产业适用性:本发明化合物生物学活性例如抗癌活性,可制备成抗癌药物以治疗和/或预防癌症。 [0278] Industrial Applicability: The present invention is a biologically active compound of anticancer activity, for example, be prepared as anticancer drugs for the treatment and / or prevention of cancer.

Claims (9)

  1. 1. 以下式I化合物: 1. The compounds of the following formula I:
    Figure CN104341434AC00021
    或其药学可接受的盐、溶剂合物、异构体、酯、前药,其中, n为1、2或3 ; Or a pharmaceutically acceptable salt, solvate, isomers, esters, prodrugs, where, n-1, 2 or 3;
    Figure CN104341434AC00022
    R为氢、甲基、或(C1-C4)烷基; R1为(C1-C4)烷基氨基甲基-、苯胺基甲基-、或苯基-,其中苯基或者苯胺基甲基-上的苯环任选被1-4个相同或不同的R2基团取代; R2选自:氢、羟基、卤素、三氟甲基、三氟甲氧基、氨基、羧基、氰基、(C1-C4)烷基、(C 1-C6) 烷基、(C1-C4)烷氧基、(C「C4)烯基、(C1-C 4)炔基、N-(CrC4)烷基氨基、N,N-二(C「C4)烷基氨基、(C1-C4)烷基硫基、(C1-C4)烷基亚磺酰基、(C 1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷氧基乙基、(C1-C4)烷基酰基、氨基甲酰基、N-(C 1-C4)烷基氨基甲酰基、N,N-二(C1-C4)烷基氨基甲酰基、(C1-C3)亚烷基二氧基。 R is hydrogen, methyl, or (C1-C4) alkyl; Rl is (C1-C4) alkylamino methyl -, methyl anilino -, or phenyl -, wherein the phenyl or anilino methyl - optionally substituted on the phenyl ring with 1-4 of the same or different groups R2; R2 is selected from: hydrogen, hydroxy, halo, trifluoromethyl, trifluoromethoxy, amino, carboxy, cyano, (C1 -C4) alkyl, (C 1-C6) alkyl, (C1-C4) alkoxy, (C "C4) alkenyl, (C1-C 4) alkynyl, N- (CrC4) alkylamino, N, N- di (C "C4) alkylamino, (C1-C4) alkylthio, (C1-C4) alkylsulfinyl, (C 1-C4) alkylsulfonyl, (C1-C4 ) alkoxymethyl, (C1-C4) alkoxy-ethyl, (C1-C4) alkyl group, carbamoyl, N- (C 1-C4) alkylcarbamoyl, N, N- two (C1-C4) alkylcarbamoyl, (C1-C3) alkylenedioxy.
  2. 2. 权利要求1的化合物,其中所述(C「C4)烷基选自甲基、乙基、丙基、异丙基、正丁基、 异丁基、叔丁基。 2. The compound of claim 1, wherein said (C "C4) alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl group.
  3. 3. 权利要求1的化合物,其中所述卤素选自氟、氯、溴、碘。 3. The compound of claim 1, wherein said halogen is selected from fluoro, chloro, bromo, iodo.
  4. 4. 权利要求1的化合物,其中R为氢、或甲基。 4. The compound of claim 1, wherein R is hydrogen or methyl.
    Figure CN104341434AC00023
  5. 6. 权利要求1的化合物,其中X为单键,n为2或3。 6. The compound of claim 1, wherein X is a single bond, is 2 or n-3.
  6. 7. 权利要求1的化合物,其为选自下列的化合物或其药学可接受的盐、溶剂合物、异构体、酯、前药: 43-0- (2- (4- (4-氟苯基)-1H-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素43-0- (2- (4- (4-氯苯基)-1H-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素43-0- (2- (4- (4-甲基苯基)-1H-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素43-0- (2- (4-(苯基)-1H-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素43-0- (2- (4- (4-戊基苯基)-1H-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素43-0- (2- (4- (3-甲基苯基)-1H-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素43-0- (2- (4- (2-氯苯基)-1H-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素43-0- (2- (4- (4-溴苯基)-1H-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素43-0- (2- (4- (4-甲氧基苯基)-1H-1,2, 3-三氮唑-1-基)乙基)氧雷帕霉素43-〇- (2- (4- ((2, 5二氯苯基)氨基甲基)-1H-1, 2, 3-二氮唑-1-基)乙基)氧雷帕 43-0- (2- (4- (4: 1, which is a compound selected from the group consisting of a compound or a pharmaceutically acceptable salt, solvate, isomers, esters, prodrugs as claimed in claim 7, phenyl) -1H-1,2, 3- triazole-1-yl) ethyl) oxy rapamycin, 43-0- (2- (4- (4-chlorophenyl) -1H-1, 2, 3-triazole-1-yl) ethyl) oxy rapamycin, 43-0- (2- (4- (4-methylphenyl) -1H-1,2, 3- triazole 1-yl) ethyl) oxy rapamycin, 43-0- (2- (4- (phenyl) -1H-1,2, 3- triazole-1-yl) ethyl) oxy-rapamycin rapamycin 43-0- (2- (4- (4-pentylphenyl) -1H-1,2, 3- triazole-1-yl) ethyl) oxy rapamycin 43-0- ( 2- (4- (3-methylphenyl) -1H-1,2, 3- triazole-1-yl) ethyl) oxy rapamycin, 43-0- (2- (4- (2 - chlorophenyl -1H-1,2-yl), 3-triazole-1-yl) ethyl) oxy rapamycin, 43-0- (2- (4- (4-bromophenyl) lH- 1,2,3-triazole-1-yl) ethyl) oxy rapamycin, 43-0- (2- (4- (4-methoxyphenyl) -1H-1,2, 3- triazole-l-yl) ethyl) oxy 〇- rapamycin 43- (2- (4- ((2, 5-dichlorophenyl) aminomethyl) -1H-1, 2, 3- two triazole-l-yl) ethyl) oxy-rapamycin 素43-0-(2-(4-((2, 4二氯苯基)氨基甲基)-lH-l,2, 3-三氮唑-1-基)乙基)氧雷帕霉素43-0-(2-(4-((2, 6二氟苯基)氨基甲基)-lH-l,2, 3-三氮唑-1-基)乙基)氧雷帕霉素43-0-(2-(4-((2-氟苯基)氨基甲基)-lH-l,2, 3-三氮唑-1-基)乙基)氧雷帕霉素43-0- (3- (4- (4-氟苯基)-1H-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素43-0- (3- (4- (4-氯苯基)-1H-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素43-0- (3- (4- (4-甲基苯基)-1H-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素43-0-(3-(苯基-1H-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素43-0- (3- (4- (3-甲基苯基)-1H-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素43-0- (3- (4- (2-氯苯基)-1H-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素43-0- (3- (4- (4-溴苯基)-1H-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素43-0- (3- (4- (4-甲氧基苯基)-1H-1,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素 Su 43-0- (2- (4 - ((2, 4-dichlorophenyl) aminomethyl) -lH-l, 2, 3- triazole-1-yl) ethyl) oxy-rapamycin 43-0- (2- (4 - ((2, 6-difluorophenyl) aminomethyl) -lH-l, 2, 3- triazole-1-yl) ethyl) oxy rapamycin 43 -0- (2- (4 - ((2-fluorophenyl) aminomethyl) -lH-l, 2, 3- triazole-1-yl) ethyl) oxy rapamycin 43-0- (3- (4- (4-fluorophenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy rapamycin 43-0- (3- (4- ( 4-chlorophenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy rapamycin 43-0- (3- (4- (4-methylphenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy rapamycin 43-0- (3- (phenyl -1H-1,2, 3- triazole -1 - yl) propyl) oxy rapamycin 43-0- (3- (4- (3-methylphenyl) -1H-1,2, 3- triazole-1-yl) propyl ) oxy rapamycin 43-0- (3- (4- (2-chlorophenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy rapamycin 43 -0- (3- (4- (4-bromophenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy rapamycin 43-0- (3- ( 4- (4-methoxyphenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin 43-0-(3-(4-((2, 5二氯苯基)氨基甲基2, 3-三氮唑-1-基)正丙基)氧雷帕霉素43-0-(3-(4-((2, 4二氯苯基)氨基甲基)-lH-l,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素43-0-(3-(4-((2, 6二氟苯基)氨基甲基2, 3-三氮唑-1-基)正丙基)氧雷帕霉素43-0-(3-(4-((2-氟苯基)氨基甲基)-lH-l,2, 3-三氮唑-1-基)正丙基)氧雷帕霉素43-0- (2- (4- (4-氟苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素43-0- (2- (4- (4-氯苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素43-0-(2-(4-(4-甲基苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素43-0- (2- (4-(苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素43-0- (2- (4- (4-戊基苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素43-0-(2-(4-(3-甲基苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素43-0- (2- (4- (2-氯苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素4 43-0- (3- (4 - ((2, 5-dichlorophenyl) aminomethyl 2, 3-triazole-1-yl) propyl) oxy rapamycin 43-0- (3 - (4 - ((2, 4-dichlorophenyl) aminomethyl) -lH-l, 2, 3- triazole-1-yl) propyl) oxy rapamycin 43-0- (3 - (4 - ((2, 6-difluorophenyl) aminomethyl-2, 3-triazole-1-yl) propyl) oxy rapamycin 43-0- (3- (4 - (( 2-fluorophenyl) aminomethyl) -lH-l, 2, 3- triazole-1-yl) propyl) oxy rapamycin, 43-0- (2- (4- (4-fluoro phenyl) -1H-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin, 43-0- (2- (4- (4-chlorophenyl) -1H-1, 2, 3-triazole-1-yl) acetyl) oxy rapamycin, 43-0- (2- (4- (4-methylphenyl) -1H-1,2, 3- triazole 1-yl) acetyl) oxy-rapamycin, 43-0- (2- (4- (phenyl) -1H-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin rapamycin 43-0- (2- (4- (4-pentylphenyl) -1H-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin 43-0- ( 2- (4- (3-methylphenyl) -1H-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin, 43-0- (2- (4- (2 - chlorophenyl) -1H-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin 4 3-0- (2- (4- (4-溴苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素43-0-(2-(4-(4-甲氧基苯基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素43-0-(2-(4-((2, 5二氯苯基)氨基甲基)-lH-l,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素43-0-(2-(4-((2-氟苯基)氨基甲基2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素43-0- (2- (4-(吡咯烷基-1-亚甲基)-1H-1,2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素43-0-(2-(4-(二乙氨基甲基2, 3-三氮唑-1-基)乙酰基)氧雷帕霉素43-0- (2- (4- (4-氟苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素43-0- (2- (4- (4-氯苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素43-0-(2-(4-(4-甲基苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素43-0- (2- (4-(苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素43-0- (2- (4- (4-戊基苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素43-0 3-0- (2- (4- (4-bromophenyl) -1H-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin, 43-0- (2- ( 4- (4-methoxyphenyl) -1H-1,2, 3- triazole-1-yl) acetyl) oxy rapamycin, 43-0- (2- (4 - ((2, 5-dichlorophenyl) aminomethyl) -lH-l, 2, 3- triazole-1-yl) acetyl) oxy rapamycin, 43-0- (2- (4 - ((2-fluoro phenyl) aminomethyl 2, 3-triazole-1-yl) acetyl) oxy rapamycin, 43-0- (2- (4- (l-pyrrolidinyl methyl) lH- 1,2,3-triazole-1-yl) acetyl) oxy rapamycin, 43-0- (2- (4- (2-diethylamino-methyl, 3-triazole-1-yl) acetyl) oxy-rapamycin, 43-0- (2- (4- (4-fluorophenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin Su 43-0- (2- (4- (4-chlorophenyl -1H-1,2-yl), 3-triazole-1-yl) propyl) oxy-rapamycin 43-0- (2 - (4- (4-methylphenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin, 43-0- (2- (4- (phenyl yl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin, 43-0- (2- (4- (4-pentylphenyl) -1H-1 , 2,3-triazole-1-yl) propyl) oxy-rapamycin 43-0 -(2-(4-(3-甲基苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素43-0- (2- (4- (2-氯苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素43-0- (2- (4- (4-溴苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素43-0-(2-(4-(4-甲氧基苯基)-1H-1,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素43-0-(2-(4-((2, 5二氯苯基)氨基甲基2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素43-0-(2-(4-((2, 4二氯苯基)氨基甲基2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素43-0-(2-(4-((2-氟苯基)氨基甲基)-lH-l,2, 3-三氮唑-1-基)异丙酰基)氧雷帕霉素。 - (2- (4- (3-methylphenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin, 43-0- (2- (4 - (2-chlorophenyl) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin, 43-0- (2- (4- (4-bromophenyl ) -1H-1,2, 3- triazole-1-yl) propyl) oxy-rapamycin, 43-0- (2- (4- (4-methoxyphenyl) -1H-1 , 2,3-triazole-1-yl) propyl) oxy-rapamycin, 43-0- (2- (4 - ((2, 5-dichlorophenyl) aminomethyl 2, 3-triethoxysilylpropyl triazole-l-yl) propyl) oxy-rapamycin, 43-0- (2- (4 - ((2, 4-dichlorophenyl) aminomethyl 2, 3-triazole-1-yl ) propyl) oxy-rapamycin, 43-0- (2- (4 - ((2-fluorophenyl) aminomethyl) -lH-l, 2, 3- triazole-1-yl) iso propanoyl) oxy-rapamycin.
  7. 8. -种药物组合物,其包括权利要求1-7任一项的化合物,以及任选的药学可接受的载体或辅料。 8. - pharmaceutical compositions comprising a compound of any one of claims 1-7 optionally in a pharmaceutically acceptable carrier or excipient claims, as well.
  8. 9. 权利要求1-7任一项的化合物在制备用于预防或治疗肿瘤和/或癌症的药物中的用途;进一步地,所述肿瘤和/或癌症选自:肺癌、胰腺癌、食道癌、胃癌、宫颈癌、前列腺癌、白血病、肾癌。 9. A compound according to any one of claims 1-7 in the preparation for the prevention or treatment of tumors and / or cancer use medicament; Further, the tumor and / or cancer selected from: lung cancer, pancreatic cancer, esophageal , gastric cancer, cervical cancer, prostate cancer, leukemia, kidney cancer.
  9. 10. 制备权利要求1-7任一项的化合物的方法,其包括以下步骤: The method of any of claims 1-7 10. The compound of claim preparation, comprising the steps of:
    Figure CN104341434AC00041
    接着使A-2化合物与Rl芳基(例如苯基)取代的炔类化合物经五水硫酸酮和抗坏血酸钠反应得到式I化合物: Compound A-2 then causes Rl and aryl (e.g. phenyl) substituted alkynyl compounds via one sulfate pentahydrate and sodium ascorbate to obtain a compound of formula I:
    Figure CN104341434AC00051
    任选地使式I化合物形成其药学可接受的盐、溶剂合物、异构体、酯、前药;其中各取代基如权利要求1-7任一项所述; 进一步地,当X为"一",R为氢时,A-2化合物的制备方法为: 以AI化合物为原料,与BI所示三氟甲磺酸酯化合物侧链反应得到B-2化合物: Optionally reacting the compound of formula I form pharmaceutically acceptable salts, solvates, isomers, esters, prodrugs; wherein the substituents are as described in any one of claims 1-7; further, when X is "a", R is hydrogen, prepared as the compound a-2: the compound as a raw material AI, BI and triflate compound shown in the side chain obtained by reacting compound B-2:
    Figure CN104341434AC00052
    接着使B-2化合物与叠氮化钠反应得到A-2化合物;或者Q 当X为时,A-2化合物的制备方法为: 以AI化合物为原料与三甲基氯硅烷反应,得到以下式CI化合物: B-2 compound is then make with sodium azide to give Compound A-2; when X or Q too, prepared as the compound A 2-: AI compound to a reaction with trimethylsilyl chloride starting material, to give the following formula CI compound:
    Figure CN104341434AC00053
    Sr 接着使CI化合物与式的C-2化合物酯化,得到以下式C-3化合物: m Sr compound is then esterified so CI C-2 compound of formula to give a compound of the following formula C-3: m
    Figure CN104341434AC00061
CN 201410547357 2014-10-16 2014-10-16 Rapamycin substituted triazole derivatives and uses CN104341434B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 201410547357 CN104341434B (en) 2014-10-16 2014-10-16 Rapamycin substituted triazole derivatives and uses

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 201410547357 CN104341434B (en) 2014-10-16 2014-10-16 Rapamycin substituted triazole derivatives and uses

Publications (2)

Publication Number Publication Date
CN104341434A true true CN104341434A (en) 2015-02-11
CN104341434B CN104341434B (en) 2016-04-06

Family

ID=52497958

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 201410547357 CN104341434B (en) 2014-10-16 2014-10-16 Rapamycin substituted triazole derivatives and uses

Country Status (1)

Country Link
CN (1) CN104341434B (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5310903A (en) * 1993-03-05 1994-05-10 Merck & Co., Inc. Imidazolidyl rapamycin derivatives
US5378696A (en) * 1990-09-19 1995-01-03 American Home Products Corporation Rapamycin esters
WO1995014697A1 (en) * 1993-11-22 1995-06-01 American Home Products Corporation Heterocyclic esters of rapamycin and pharmaceutical compositions containing them
US20110098241A1 (en) * 2008-04-14 2011-04-28 Poniard Pharmaceuticals, Inc. Rapamycin analogs as anti-cancer agents
CN103739616A (en) * 2013-12-27 2014-04-23 福建省微生物研究所 Thiazolyl-containing rapamycin type derivative and application thereof
WO2014082286A1 (en) * 2012-11-30 2014-06-05 Hangzhou Zylox Pharma Co., Ltd. Rafamycin analogs and methods for making same

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5378696A (en) * 1990-09-19 1995-01-03 American Home Products Corporation Rapamycin esters
US5310903A (en) * 1993-03-05 1994-05-10 Merck & Co., Inc. Imidazolidyl rapamycin derivatives
WO1995014697A1 (en) * 1993-11-22 1995-06-01 American Home Products Corporation Heterocyclic esters of rapamycin and pharmaceutical compositions containing them
US20110098241A1 (en) * 2008-04-14 2011-04-28 Poniard Pharmaceuticals, Inc. Rapamycin analogs as anti-cancer agents
WO2014082286A1 (en) * 2012-11-30 2014-06-05 Hangzhou Zylox Pharma Co., Ltd. Rafamycin analogs and methods for making same
CN103739616A (en) * 2013-12-27 2014-04-23 福建省微生物研究所 Thiazolyl-containing rapamycin type derivative and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HEINZ FRETZ ET AL.: ""Rapamycin and FK506 Binding Proteins (Immunophilins)"", 《JOURNAL OF THE AMERICAN CHEMISTRY SOCIETY》 *
SHUANG CAO ET AL.: ""Selective Substitution of 31/42–OH in Rapamycin Guided by an in Situ IR Technique"", 《MOLECULES》 *
谢立君 等: ""雷帕霉素新衍生物及其初步生物学活性研究"", 《第十二届全国抗生素学术会议论文集》 *

Also Published As

Publication number Publication date Type
CN104341434B (en) 2016-04-06 grant

Similar Documents

Publication Publication Date Title
WO2005005426A1 (en) Isethionate salt of a selective cdk4 inhibitor
JPH11302173A (en) Histone deacetylase inhibitors
WO2005092099A1 (en) Hiv integrase inhibitors
WO2007116866A1 (en) Hetero compound
JP2004067635A (en) Dgat inhibitor
WO2008007661A1 (en) Tricyclic heterocyclic compound and use thereof
EP0656360A1 (en) Trifluoromethylpyrroloindole carboxylic ester derivative and process for producing the same
JPH0977791A (en) Peptide derivative and its use
US20140023614A1 (en) Substituted fused tricyclic compounds, compositions and medicinal applications thereof
WO2012005227A1 (en) Tetrahydrocarboline derivative
WO2011109274A1 (en) Fluorouracil derivatives
WO2011134831A1 (en) Pyrazole compounds as jak inhibitors
JP2000169479A (en) Nf-kappa b activation inhibitor
EP2116543A1 (en) Novel aminopyrimidine derivative as plk1 inhibitor
JP2008509162A (en) Its use in the treatment of the quinazoline derivative with thrombocythemia
WO2010150739A1 (en) Hydroxyl-containing pyripyropene derivatives exhibiting acat2-inhibitory activity
WO2003045952A2 (en) Condensed camptothecins as antitumor agents
JP2006219481A (en) Method for producing acylaminothiazole derivative
US20170066769A1 (en) Therapeutic compounds for pain and synthesis thereof
US20090325996A1 (en) Camptothecin derivatives and their use
US20120322821A1 (en) Ghrelin receptor agonist for treatment of cachexia
EP1221445A1 (en) Pentacyclic taxane compounds
EP2308877A1 (en) Imidazopyridin-2-on derivative
WO2013021051A1 (en) Antibacterial homopiperidinyl substituted 3,4 dihydro 1h [1,8]naphthyridinones
US6372775B1 (en) Reversal of multidrug resistance in human colon carcinoma cells

Legal Events

Date Code Title Description
C06 Publication
C10 Entry into substantive examination
C14 Grant of patent or utility model