CN102372711B - Imidazo quinoline PI3K and mTOR (mammalian target of rapamycin) dual inhibitor - Google Patents

Imidazo quinoline PI3K and mTOR (mammalian target of rapamycin) dual inhibitor Download PDF

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CN102372711B
CN102372711B CN 201110245003 CN201110245003A CN102372711B CN 102372711 B CN102372711 B CN 102372711B CN 201110245003 CN201110245003 CN 201110245003 CN 201110245003 A CN201110245003 A CN 201110245003A CN 102372711 B CN102372711 B CN 102372711B
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黄振华
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山东轩竹医药科技有限公司
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Abstract

本发明属于医药技术领域,具体涉及通式(I)所示的咪唑并喹啉类PI3K和mTOR双重抑制剂、其药学上可接受的盐或其立体异构体:其中R1、R2、R3、R3'、R4、R4'、R5和X如说明书中所定义;本发明还涉及这些化合物的制备方法,含有这些化合物的药物制剂,以及这些化合物在制备治疗和/或预防增殖性疾病的药物中的应用。 The present invention belongs to the field of medical technology, particularly relates to imidazole general formula (I) and quinoline dual PI3K inhibitor and mTOR, pharmaceutically acceptable salt or a stereoisomer thereof: wherein R1, R2, R3, R3 ', R4, R4', R5 and X are as defined in the specification; the present invention further relates to a method for preparing these compounds, pharmaceutical formulations comprising these compounds, these compounds for treating and / or prophylaxis of a proliferative disease in Applications.

Description

咪唑并喹啉类PI3K和mTOR双重抑制剂1、 技术领域 Imidazo quinoline 1 PI3K and mTOR dual inhibitor TECHNICAL FIELD

[〇〇〇1] 本发明属于医药技术领域,具体涉及咪唑并喹啉类PI3K和mTOR双重抑制剂、其药学上可接受的盐或其立体异构体,这些化合物的制备方法,含有这些化合物的药物制剂,以及这些化合物在制备治疗和/或预防增殖性疾病的药物中的应用。 [〇〇〇1] The present invention belongs to the field of medical technology, and particularly relates to imidazo quinoline dual PI3K and mTOR inhibitor, its pharmaceutically acceptable salt or stereoisomer thereof, the preparation of these compounds, these compounds comprising pharmaceutical formulations, and the use of these compounds in the preparation of the treatment and / or prophylaxis of proliferative diseases. 2、 背景技术 2. Background of the Invention

[0002] 肿瘤是机体在各种致瘤因子作用下,引起细胞遗传物质改变,导致基因表达失常, 细胞异常增殖而形成的新生物。 [0002] In various cancer is the body under the action of oncogenic factors, genetically altered cells causing material, resulting in abnormal gene expression, abnormal proliferation of cells and formation of new organisms. 肿瘤细胞失去正常生长调节功能,具有自主或相对自主生长能力,当致瘤因子停止后仍能继续生长,大量消耗人体的营养物质。 Tumor cells lose their normal growth regulation, with independent or relatively independent growth ability, when the stop can continue oncogenic growth factor, human consumption of large quantities of nutrients. 如果发现和治疗不及时,癌细胞还可转移到全身各处生长繁殖,并释放出多种毒素,导致人体销售、贫血、脏器功能受损至死亡。 If it is found and treated early, the cancer cells can be transferred throughout the body growth and reproduction, and release a variety of toxins, causes the body to sales, anemia, organ failure death.

[0003] 肿瘤治疗的方法,主要包含三个方面:药物治疗、手术治疗和放射治疗。 Method [0003] treatment of tumors, comprising three main aspects: drug therapy, surgery and radiation therapy. 由于手术治疗、放射治疗难以彻底根除肿瘤,而且对中晚期肿瘤病人作用不明显,因此药物治疗在肿瘤治疗中的地位越来越明显。 Due to surgery, radiation therapy is difficult to completely eradicate the tumor, and advanced cancer patients had no obvious effect, so drug therapy in cancer therapy is becoming increasingly evident. 传统抗肿瘤药物无法区分肿瘤细胞和正常组织细胞,常导致严重的副作用,靶向药物以癌细胞作为特异性靶点,能准确的作用于肿瘤,极大的提高了治疗水平,并减轻了不良反应率,例如使晚期大肠癌的中位生存时间增加66. 7%,晚期乳腺癌的治疗有效率提高71. 3%。 Traditional anticancer drugs can not distinguish between cancer cells and normal cells, often cause serious side effects, targeted drugs to cancer cells as specific targets, can accurately to the tumor, which greatly improves the level of treatment and reduce the adverse the reaction rate, for example the median survival time of advanced colorectal cancer increased 66.7%, the treatment of advanced breast cancer with a 71.3% efficiency.

[0004] 由于各制药公司对靶向类抗肿瘤药的研制加速,再加上市场对这一类别的抗肿瘤药需求强劲,分子靶向药物已经成为了全球抗肿瘤药物市场中增长最快的单元。 [0004] Since the pharmaceutical companies to accelerate the development of targeted anticancer drugs, coupled with the strong market demand for this class of antineoplastic agents, molecular targeted drugs have become a global anti-tumor drug market in the fastest-growing unit. PI3K通路是人体癌细胞中最常发生变异的地方,可导致细胞增殖,活化,放大信号。 PI3K pathway in human cancer is where the most frequently occurring mutation, may lead to cell proliferation, activation, amplified signal. 磷脂酰肌醇3激酶(PI3K)和哺乳动物雷帕霉素靶蛋白(mTOR)是PI3K信号通路的重要激酶。 Phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (of mTOR) kinase PI3K is an important signaling pathway.

[0005] 磷脂酰肌醇3激酶(PI3K)是脂激酶家族成员,可通过磷脂酰醇的3位磷酸化产生磷脂酰肌醇三磷酸脂(PIP3)来调节细胞代谢和生长。 [0005] The phosphatidylinositol 3-kinase (PI3K) are lipid kinase family, phosphatidylinositol-ol by 3 phosphorylation creates three phosphatidylinositol phosphate (of PIP3) regulate cell metabolism and growth. 该脂类的第二信使PIP3可以使P13K 与下游的效应物(特别是Akt)配对结合,从而导致膜募集和磷酸化,细胞增殖,活化。 The lipid second messenger PIP3 can P13K downstream effector (especially Akt) binding pair, resulting in membrane recruitment and phosphorylation, cell proliferation and activation. 因此抑制磷脂酰肌醇3激酶,可以影响PI3K通路,从而抑制癌细胞增殖,活化。 Thus inhibition of phosphatidylinositol 3-kinase may affect PI3K pathway, thereby inhibiting cancer cell proliferation, activation.

[0006] mTOR是存在于胞浆中的一种丝/苏氨酸蛋白激酶,属于磷酸肌醇激酶相关蛋白激酶家族,在生物体内以两种复合物的形式存在,即mT0RCl(雷帕霉素的作用靶点)和mT0RC2 (不被雷帕霉素抑制)。 [0006] mTOR is present in one wire cytoplasm / threonine protein kinases, the phosphoinositide kinase-related protein belonging kinase family, in the form of two complexes in vivo, i.e. mT0RCl (rapamycin the targets) and mT0RC2 (not inhibited by rapamycin). mTOR是一种细胞信号转导蛋白,它调节肿瘤细胞对养分和生长因子的反应,并通过对血管内皮生长因子的作用,控制肿瘤的血液供给。 mTOR is a cellular signal transduction protein, which regulates the response of tumor cells to nutrients and growth factors, and by the action of vascular endothelial growth factor, controlling tumor blood supply. mTOR抑制剂会使癌细胞饥饿,并且通过抑制mTOR的作用使肿瘤体积缩小。 mTOR inhibitors cause starvation cancer cells, and the tumor volume was reduced by the action of inhibition of mTOR.

[0007] 诺华专利W02006122806(公开日2006. 11. 23)和辉瑞专利W0201003816(公开日2010. 04. 08)中,均报道了PI3K/mT0R双重抑制剂在肿瘤治疗中的有效性。 [0007] Novartis patent W02006122806 (Publication date 2006. 11.23) and in Pfizer patent W0201003816 (disclosed in Japanese 2010. 04.08), we have reported the effectiveness of the PI3K / mT0R dual inhibitors in cancer therapy. 目前,暂无PI3K/ mTOR双重抑制剂类药物上市,因此,需要研发更多的PI3K/mT0R双重抑制剂结构类型,选择有效性和安全性较好的化合物,用于癌症的治疗。 Currently, no PI3K / mTOR dual inhibitor class of drugs on the market, therefore, need to develop more of the PI3K / mT0R dual inhibitor structure type, choose better efficacy and safety of compounds for the treatment of cancer. 3、 发明内容 3. SUMMARY OF THE INVENTION

[0008] 本发明的目的在于提供一种PI3K和mTOR双重抑制剂。 [0008] The object of the present invention is to provide a dual inhibitor of PI3K and mTOR.

[0009] 本发明的技术方案如下: [0009] aspect of the present invention is as follows:

[0010] 通式(I)所示的化合物、其药学上可接受的盐或其立体异构体: [0010] Formula (I), a compound, pharmaceutically acceptable salt or a stereoisomer thereof:

[0011] [0011]

[0012] X为0,S,或NH; [0012] X is 0, S, or NH;

[0013]R1为氢,或未被取代或被至少一个R6a取代的(^_6烷基、C3_8环烷基、C3_8烯基、C3_8 炔基、3-14元杂环基、6-12元螺环基; [0013] R1 is hydrogen, or unsubstituted or substituted by at least one of R6a (^ _6 alkyl, C3_8 cycloalkyl, C3_8 alkenyl, C3_8 alkynyl, 3-14 membered heterocyclyl, 6-12 membered spiro cycloalkyl group;

[0014]R2为氢,或未被取代或被至少一个R6b取代的(^_6烷基、C3_8环烷基、芳基、3-14元杂环基; [0014] R2 is hydrogen, unsubstituted or substituted with at least one of R6b or substituted (^ _6 alkyl, C3_8 cycloalkyl group, an aryl group, a 3-14 membered heterocyclic group;

[0015]R3' 为氢,羟基,羧基,-(CH2)nNR7aR7b,_(CH2)nC(0)R8, _(CH2)nS(0)mR8, _(CH2) nS(0)mNR7aR7b,_(CH2)nNR7aS(0)mR8, _(CH2)nC(0) (CH2)nNR7aR7b,-(CH2)n0C(0)R8, -(CH2)nC(0) OR8, - (CH2)nNR7aC(0)R8, - (CH2)nNR7aC(0)NR7aR7b,或未被取代或被至少一个齒素、羟基、羧基取代的Ci_6烧基、Ci_6烧氧基; [0015] R3 'is hydrogen, hydroxy, carboxy, - (CH2) nNR7aR7b, _ (CH2) nC (0) R8, _ (CH2) nS (0) mR8, _ (CH2) nS (0) mNR7aR7b, _ ( CH2) nNR7aS (0) mR8, _ (CH2) nC (0) (CH2) nNR7aR7b, - (CH2) n0C (0) R8, - (CH2) nC (0) OR8, - (CH2) nNR7aC (0) R8 , - (CH2) nNR7aC (0) NR7aR7b, or unsubstituted or substituted by at least one tooth, hydroxy, carboxyl group Ci_6 burn, burn Ci_6 alkoxy;

[0016]R3、R4、R4' 分别独立的为氢,齒素,氰基,羟基,羧基,-(CH2)nNR7aR7b,_(CH2)nC(0) R8, - (CH2)nS(0)mR8, - (CH2)nS(0)mNR7aR7b, - (CH2)nNR7aS(0)mR8, - (CH2)nC(0) (CH2)nNR7aR7b, - (CH2) n0C(0)R8, - (CH2)nC(0)OR8, - (CH2)nNR7aC(0)R8, - (CH2)nNR7aC(0)NR7aR7b,或未被取代或被至少一个齒素、轻基、竣基取代的Ci_6烧基、Ci_6烧氧基; [0016] R3, R4, R4 'are independently hydrogen, teeth, cyano, hydroxy, carboxy, - (CH2) nNR7aR7b, _ (CH2) nC (0) R8, - (CH2) nS (0) mR8 , - (CH2) nS (0) mNR7aR7b, - (CH2) nNR7aS (0) mR8, - (CH2) nC (0) (CH2) nNR7aR7b, - (CH2) n0C (0) R8, - (CH2) nC ( 0) OR8, - (CH2) nNR7aC (0) R8, - (CH2) nNR7aC (0) NR7aR7b, or a substituted or unsubstituted at least one tooth element, light group, Jun group substituted Ci_6 burn, burn Ci_6 alkoxy ;

[0017]R5为氢,-(CHiSWj?8,或未被取代或被至少一个R6。取代的(^_6烷基; [0017] R5 is hydrogen, - (CHiSWj 8, or at least one R6 is unsubstituted or substituted (^ _6 alkyl;?.

[0018]R6a、R6b、R6。 [0018] R6a, R6b, R6. 分别独立的为羟基,齒素,氰基,-(CH2)nNR7aR7b,_(CH2)nC(0)R8, _(CH2) nS(0)mR8,-(CH2)nS(0)mNR7aR7b,-(CH2)nNR7aS(0)mR8,-(CH2)nC(0)(CH2)nNR7aR7b,-(CH2)n0C(0) R8, _(CH2)nC(0)0R8, _(CH2)nNR7aC(0)R8, _(〇12)11殿73(:(0)殿1'或未被取代或被至少一个1? 9 取代的Ci_6烧基、C2_8稀基、C2_8块基、Ci_6烧氧基、C3_8环烧基、芳基、3-14兀杂环基; Are each independently a hydroxyl group, teeth, cyano, - (CH2) nNR7aR7b, _ (CH2) nC (0) R8, _ (CH2) nS (0) mR8, - (CH2) nS (0) mNR7aR7b, - ( CH2) nNR7aS (0) mR8, - (CH2) nC (0) (CH2) nNR7aR7b, - (CH2) n0C (0) R8, _ (CH2) nC (0) 0R8, _ (CH2) nNR7aC (0) R8 , _ (〇12) temple 11 73 (0 :() temple 1 'or 1 unsubstituted or substituted with at least one? 9-yl substituted Ci_6 burning, C2_8 dilute group, C2_8 block group, Ci_6 alkoxy burning, C3_8 cycloalkyl burn group, an aryl group, a 3-14 heterocyclyl group Wu;

[0019]R7a和R7b分别独立的为氢,或未被取代或被至少一个R9取代的烷基、C3_8环烷基,芳基、3-14元杂环基; [0019] R7a and R7b are independently hydrogen, or a substituted or unsubstituted alkyl group substituted with at least one of R9, C3_8 cycloalkyl group, an aryl group, a 3-14 membered heterocyclic group;

[0020] R8为氢,或未被取代或被至少一个R9取代的(^_6烷基、(V6烷氧基、C3_8环烷基、芳基、3-14兀杂环基; [0020] R8 is hydrogen, or unsubstituted or substituted by at least one R9 (^ _6 alkyl, (V6 alkoxy, C3_8 cycloalkyl group, an aryl group, a 3-14 heterocyclyl group Wu;

[0021] R9为轻基,1¾素,氛基,二氣甲基,(V6烧基,C2_8稀基,C2_8块基,(^_6烧氧基,C3_8环烧基,芳基,3-14 元杂环基,-(CH2)nNR1(laR1(lb,_(CH2)nC(0)Rn,-(CH2)nC(0)NR1(laR1(lb,_(CH2)nS(0) mRn, -(CH2)nS(0)mNR10aR10b, -(CH2)nNR10aS(0)mRn, -(CH2)n0C(0)Rn, -(CH2)nC(0)OR11, -(CH2) nNR10aC(0)R11,或-(CH2)nNR10aC(0)NR10aR10b ; [0021] R9 is a light group, 1¾ prime, atmosphere group, two methyl gas, (V6 burning yl, C2_8 dilute group, C2_8 block group, (6 ^ _ burned group, C3_8 cycloalkyl burning, aryl, 3-14 membered heterocyclyl group, - (CH2) nNR1 (laR1 (lb, _ (CH2) nC (0) Rn, - (CH2) nC (0) NR1 (laR1 (lb, _ (CH2) nS (0) mRn, - (CH2) nS (0) mNR10aR10b, - (CH2) nNR10aS (0) mRn, - (CH2) n0C (0) Rn, - (CH2) nC (0) OR11, - (CH2) nNR10aC (0) R11, or - (CH2) nNR10aC (0) NR10aR10b;

[0022] R1(la和R1(lb分别独立的为氢,Cu烷基,C3_8环烷基,芳基,或3-14元杂环基; [0022] R1 (la and R1 (lb each independently hydrogen, Cu alkyl, C3_8 cycloalkyl group, an aryl group, or a 3-14 membered heterocyclic group;

[0023]R11为(^_6烧基,C3_8环烧基,芳基,或3-14兀杂环基; [0023] R11 is (^ _6 burned group, C3_8 cycloalkyl group burning, an aryl group, a heterocyclic group or a 3-14 Wu;

[0024]m为1 或2; [0024] m is 1 or 2;

[0025]η为0 〜4。 [0025] η is 0 ~ 4.

[0026] 通式(I)所示的化合物、其药学上可接受的盐或其立体异构体,优选的技术方案为: [0026] The compounds of general formula (I), and pharmaceutically acceptable salt or a stereoisomer thereof, for the preferred technical solution:

[0027] X为0 ; [0027] X is 0;

[0028] R1为未被取代或被至少一个R6a取代的k烷基、C3_8环烷基、4-10元杂环基、7-10 元螺环基; [0028] R1 is unsubstituted or substituted with at least one of R6a k-alkyl, C3_8 cycloalkyl, 4-10 membered heterocyclyl, 7-10 membered spiro ring group;

[0029] R2为未被取代或被至少一个R6b取代的(^_6烷基,C3_8环烷基、芳基、4-10元杂环基; [0029] R2 is unsubstituted or substituted with at least one of R6b (^ _6 alkyl, C3_8 cycloalkyl group, an aryl group, a 4-10 membered heterocyclic group;

[0030] R3' 为氢,-(CH2)nS(0)mNR7aR7b,_(CH2)nNR7aS(0)mR8,或未被取代或被至少一个卤素、 轻基、竣基取代的Ci_6烧基、Ci_6烧氧基; [0030] R3 'is hydrogen, - (CH2) nS (0) mNR7aR7b, _ (CH2) nNR7aS (0) mR8, or unsubstituted or substituted by at least one halogen, light group, substituted Ci_6 burn Jun group, Ci_6 burning group;

[0031] ^^'分别独立的为氢肩素廣基厂⑴托"⑶^^-仰上邮巧⑶^^或未被取代或被至少一个齒素、轻基、竣基取代的CV6烧基、Ci_6烧氧基; [0031] ^^ 'are each independently hydrogen shoulder element sessile ⑴ Tropsch plant "⑶ ^^ - ^^ Upward Post Qiao ⑶ unsubstituted or substituted with at least one tooth element, light group, substituted CV6 burn Jun group, Ci_6 alkoxy burning;

[0032] R5为氢,或未被取代或被至少一个R6e取代的(V6烷基; [0032] R5 is hydrogen, or unsubstituted or substituted by at least one of R6e (V6 alkyl;

[0033] R6a、俨、R6。 [0033] R6a, Yan, R6. 分别独立的为羟基,_(CH2)nNR7aR7b,_(CH2)nC(0)R8, _(CH2)nS(0) mR8, _(CH2)nS(0)mNR7aR7b,-(CH2)nNR7aS(0)mR8, -(CH2)nC(0) (CH2)nNR7aR7b,-(CH2)n0C(0) R8, _(CH2)nC(0)0R8, _(CH2)nNR7aC(0)R8, _(〇12)11殿73(:(0)殿1'或未被取代或被至少一个1? 9 取代的Ci_6烧基、Ci_6烧氧基、C3_8环烧基、芳基、4_10兀杂环基; Are each independently a hydroxyl group, _ (CH2) nNR7aR7b, _ (CH2) nC (0) R8, _ (CH2) nS (0) mR8, _ (CH2) nS (0) mNR7aR7b, - (CH2) nNR7aS (0) mR8, - (CH2) nC (0) (CH2) nNR7aR7b, - (CH2) n0C (0) R8, _ (CH2) nC (0) 0R8, _ (CH2) nNR7aC (0) R8, _ (〇12) ? Hall 11 73 (0 :() temple 1 'or at least one substituted or unsubstituted 19 substituted Ci_6 group burn, burn Ci_6 alkoxy, C3_8 cycloalkyl burning, aryl, heterocyclyl 4_10 Wu;

[0034] R7a和R7b分别独立的为氢,或未被取代或被至少一个R9取代的(^_6烷基; [0034] R7a and R7b are independently hydrogen, or unsubstituted or substituted by at least one R9 (^ _6 alkyl;

[0035] R8为氢,或未被取代或被至少一个R9取代的(^_6烷基、(V6烷氧基、C3_8环烷基、芳基、4-10元杂环基; [0035] R8 is hydrogen, or unsubstituted or substituted by at least one R9 (^ _6 alkyl, (V6 alkoxy, C3_8 cycloalkyl group, an aryl group, a 4-10 membered heterocyclic group;

[0036] R9为轻基,齒素,氛基,二氣甲基,(V6烧基,C2_8稀基,C2_8块基,(^_6烧氧基,C3_8环烷基,芳基,4-10元杂环基,或-(CH2)nNR1(laR1(lb ; [0036] R9 is a group of light teeth Su, atmosphere group, two methyl gas, (V6 burning yl, C2_8 dilute group, C2_8 block group, (6 ^ _ burned group, C3_8 cycloalkyl group, an aryl group, 4-10 membered heterocyclic group, or - (CH2) nNR1 (laR1 (lb;

[0037] R1(la和R1(lb分别独立的为氢,Cu烷基,C3_8环烷基,芳基,或4-10元杂环基; [0037] R1 (la and R1 (lb each independently hydrogen, Cu alkyl, C3_8 cycloalkyl group, an aryl group, or a 4-10 membered heterocyclic group;

[0038] m为1 或2 ; [0038] m is 1 or 2;

[0039] η为0 〜4。 [0039] η is 0 ~ 4.

[〇〇4〇] 通式(I)所示的化合物、其药学上可接受的盐或其立体异构体,优选的技术方案为: [〇〇4〇] Compound of formula (I), and pharmaceutically acceptable salt or a stereoisomer thereof, for the preferred technical solution:

[0041] X为0; [0041] X is 0;

[0042] R1为未被取代或被至少一个R6a取代的(V6烷基、C4_7环烷基、5-10元杂环基; [0042] R1 is unsubstituted or substituted with at least one of R6a (V6 alkyl, C4_7 cycloalkyl, 5-10 membered heterocyclyl;

[0043] R2为未被取代或被至少一个R6b取代的苯基、萘基、5-10元杂环基; [0043] R2 is unsubstituted or substituted with at least one of R6b phenyl, naphthyl, 5-10 membered heterocyclyl;

[0044] R3、R3'、R4、R4' 分别为氢; [0044] R3, R3 ', R4, R4' are hydrogen;

[0045] R5为氢,或未被取代或被至少一个R6e取代的(V6烷基; [0045] R5 is hydrogen, or unsubstituted or substituted by at least one of R6e (V6 alkyl;

[0046] R6a、俨、R6。 [0046] R6a, Yan, R6. 分别独立的为羟基,_(CH2)nNR7aR7b,_(CH2)nC(0)R8, _(CH2)nS(0) mR8, _(CH2)nS(0)mNR7aR7b,-(CH2)nNR7aS(0)mR8, -(CH2)nC(0) (CH2)nNR7aR7b,-(CH2)n0C(0) R8, _(CH2)nC(0)0R8, _(CH2)nNR7aC(0)R8, _(〇12)11殿73(:(0)殿1'或未被取代或被至少一个1? 9 取代的Ck烧基、(^_6烧氧基、C4_7环烧基、苯基、5-10兀杂环基; Are each independently a hydroxyl group, _ (CH2) nNR7aR7b, _ (CH2) nC (0) R8, _ (CH2) nS (0) mR8, _ (CH2) nS (0) mNR7aR7b, - (CH2) nNR7aS (0) mR8, - (CH2) nC (0) (CH2) nNR7aR7b, - (CH2) n0C (0) R8, _ (CH2) nC (0) 0R8, _ (CH2) nNR7aC (0) R8, _ (〇12) Hall 11 73 (0 :() temple 1 'or 1 unsubstituted or substituted with at least one? 9 Ck burning substituted group, (6 ^ _ burned group, C4_7 cycloalkyl burning, phenyl, heterocyclyl 5-10 Wu ;

[0047] R7a和R7b分别独立的为氢,或未被取代或被至少一个R9取代的k烷基; [0047] R7a and R7b are independently hydrogen, or unsubstituted or substituted by at least one R9 group k;

[0048] R8为氢,或未被取代或被至少一个R9取代的(^_6烷基、(V6烷氧基、C4_7环烷基、苯基、5-10元杂环基; [0048] R8 is hydrogen, or unsubstituted or substituted by at least one R9 (^ _6 alkyl, (V6 alkoxy, C4_7 cycloalkyl, phenyl, 5-10 membered heterocyclyl;

[0049] R9为轻基,氣,氣,氛基,二氣甲基,(V6烧基,C2_8稀基,C2_8块基,(^_6烧氧基,C4_7环烷基,苯基,5-10元杂环基,或-(CHiNR^R1% ; [0049] R9 is a group of light, air, gas, atmosphere group, two methyl gas, (V6 burning yl, C2_8 dilute group, C2_8 block group, (6 ^ _ burned group, C4_7 cycloalkyl, phenyl, 5- 10-membered heterocyclyl group, or a - (CHiNR ^ R1%;

[0050] R1(la和R1(lb分别独立的为氢,(:卜6烷基,C4_7环烷基,苯基,或5-10元杂环基; [0050] R1 (la and R1 (lb each independently hydrogen, (: Bu 6 alkyl, C4_7 cycloalkyl, phenyl, or 5-10 membered heterocyclyl;

[0051] m为1 或2; [0051] m is 1 or 2;

[0052] η为0 〜3。 [0052] η 0 ~ 3.

[0053] 通式(I)所示的化合物、其药学上可接受的盐或其立体异构体,优选的技术方案为: [0053] The compounds of general formula (I), and pharmaceutically acceptable salt or a stereoisomer thereof, for the preferred technical solution:

[0054] X为0 ; [0054] X is 0;

[0055] R1为未被取代或被至少一个R6a取代的C4_7环烷基、5-6元单杂环基; [0055] R1 is unsubstituted or substituted with at least one of R6a C4_7 cycloalkyl, 5-6 membered monocyclic heterocyclyl group;

[0056] R2为未被取代或被至少一个R6b取代的苯基、5-6元单杂环基、9-10元稠杂环基; [0056] R2 is unsubstituted or substituted with at least one of R6b phenyl, 5-6 membered monocyclic heterocyclyl, 9-10 membered fused heterocyclic group;

[0057] R3、R3'、R4、R4' 分别为氢; [0057] R3, R3 ', R4, R4' are hydrogen;

[0058] R5为氢,或Ck烷基; [0058] R5 is hydrogen, alkyl or Ck;

[0059] R6a、R6b 分别独立的为羟基,三氟甲基,_(CH2)nNR7aR7b,_(CH2)nC(0)R8, _(CH2)nC(0) (CH2)nNR7aR7b,- (CH2)n0C(0)R8, - (CH2)nC(0)OR8, - (CH2)nNR7aC(0)R8,或未被取代或被至少一个R9取代的(^_6烷基、(V6烷氧基; [0059] R6a, R6b are each independently a hydroxyl group, a trifluoromethyl group, _ (CH2) nNR7aR7b, _ (CH2) nC (0) R8, _ (CH2) nC (0) (CH2) nNR7aR7b, - (CH2) n0C (0) R8, - (CH2) nC (0) OR8, - (CH2) nNR7aC (0) R8, or R9 is unsubstituted or substituted with at least one of (^ _6 alkyl, (V6 alkoxy;

[0060] R7a和R7b分别独立的为氢,或Ck烷基; [0060] R7a and R7b are independently hydrogen, alkyl or Ck;

[0061] R8为氢,或未被取代或被至少一个R9取代的(^_6烷基、(V6烷氧基; [0061] R8 is hydrogen, or unsubstituted or substituted by at least one R9 (^ _6 alkyl, (alkoxy V6;

[0062] R9为羟基,氟,氯,氰基,或三氟甲基; [0062] R9 is hydroxy, fluoro, chloro, cyano, or trifluoromethyl;

[0063] η为0 〜2。 [0063] η 0 ~ 2.

[0064] 通式(I)所示的化合物、其药学上可接受的盐或其立体异构体,优选的技术方案为: [0064] The compounds of general formula (I), and pharmaceutically acceptable salt or a stereoisomer thereof, for the preferred technical solution:

[0065] X为0 ; [0065] X is 0;

[0066] R1为未被取代或被至少一个R6a取代的环戊基、环己基、哌啶基、哌嗪基、咪唑烷基、吡唑烷基、四氢呋喃基、吗啉基、批啶基、嘧啶基、吡唑基; [0066] R1 is unsubstituted or substituted with at least one of R6a cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl batch, pyrimidyl, pyrazolyl;

[0〇67]R6a 为羟基,三氟甲基,-(CH2)nNR7aR7b,_(CH2)nC(0)R8,-(CH2)nC(0)(CH2)nNR7aR7b,- (CH2)n0C(0)R8, - (CH2)nC(0)OR8, - (CH2)nNR7aC(0)R8,或未被取代或被至少一个R9 取代的Ci_4烧基、Ci_4烧氧基; [0〇67] R6a is hydroxy, trifluoromethyl, - (CH2) nNR7aR7b, _ (CH2) nC (0) R8, - (CH2) nC (0) (CH2) nNR7aR7b, - (CH2) n0C (0 ) R8, - (CH2) nC (0) OR8, - (CH2) nNR7aC (0) R8, or R9 is unsubstituted or substituted by at least one group Ci_4 burning, Ci_4 alkoxy burning;

[0068] R2为未被取代或被至少一个R6b取代的苯基、吡啶基、嘧啶基、吡唑基、喷唑基、喹啉基、喷哚基、吡唑并吡啶基; [0068] R2 is unsubstituted or substituted with at least one of R6b phenyl, pyridyl, pyrimidinyl, pyrazolyl, oxazolyl spray, quinolyl, indolyl spray, pyrazolyl and pyridyl;

[0069] R6b为羟基,三氟甲基,或未被取代或被至少一个R9取代的(V6烷基、Cm烷氧基; [0069] R6b is a hydroxyl group, a trifluoromethyl group, or an unsubstituted or substituted by at least one R9 (V6 alkyl, Cm is an alkoxy group;

[0070] R3、R3'、R4、R4' 分别为氢; [0070] R3, R3 ', R4, R4' are hydrogen;

[0071] R5为氢,或Q_4烷基; [0071] R5 is hydrogen, alkyl or Q_4;

[0072] R7a和R7b分别独立的为氢,或Q_4烷基; [0072] R7a and R7b are independently hydrogen, alkyl or Q_4;

[0073] R8为未被取代或被至少一个R9取代的Cg烷基、(V4烷氧基; [0073] R8 is unsubstituted or substituted with at least one of R9 Cg alkyl, (V4 alkoxy;

[0074] R9为羟基,氰基,或三氟甲基; [0074] R9 is hydroxy, cyano, or trifluoromethyl;

[0075] η为0 〜2。 [0075] η 0 ~ 2.

[0076] 通式(I)所示的化合物、其药学上可接受的盐或其立体异构体,优选的技术方案为: [0076] The compounds of general formula (I), and pharmaceutically acceptable salt or a stereoisomer thereof, for the preferred technical solution:

[0077] X为0 ; [0077] X is 0;

[0078] R1为未被取代或被至少一个R6a取代的环戊基、环己基、哌啶基、哌嗪基、吡啶基、 嘧啶基; [0078] R1 is unsubstituted or substituted with at least one of R6a cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl;

[0〇79]R6a 为羟基,三氟甲基,-(CH2)nNR7aR7b,_(CH2)nC(0)R8,-(CH2)nC(0)(CH2)nNR7aR7b,- (CH2)n0C(0)R8, - (CH2)nC(0)OR8, - (CH2)nNR7aC(0)R8,或未被取代或被至少一个R9 取代的烧基、Ci_2烧氧基; [0〇79] R6a is hydroxy, trifluoromethyl, - (CH2) nNR7aR7b, _ (CH2) nC (0) R8, - (CH2) nC (0) (CH2) nNR7aR7b, - (CH2) n0C (0 ) R8, - (CH2) nC (0) OR8, - (CH2) nNR7aC (0) R8, or R9 is unsubstituted or substituted with at least one group of firing, Ci_2 burning group;

[0080] R2为未被取代或被至少一个R6b取代的苯基、吡啶基、嘧啶基、喷唑基、喹啉基、喷哚基、吡唑并吡啶基; [0080] R2 is unsubstituted or substituted with at least one of R6b phenyl, pyridyl, pyrimidinyl, oxazolyl spray, quinolyl, indolyl spray, pyrazolo-pyridyl;

[0081]R6b为羟基,三氟甲基,或未被取代或被至少一个R9取代的Ci_3烷基、Ci_2烷氧基; [0081] R6b is a hydroxyl group, a trifluoromethyl group, or an unsubstituted or substituted by at least one R9 is Ci_3 alkyl, Ci_2 alkoxy;

[0082]R3、R3'、R4、R4' 分别为氢; [0082] R3, R3 ', R4, R4' are hydrogen;

[0083] R5为氢,甲基,乙基或丙基; [0083] R5 is hydrogen, methyl, ethyl or propyl;

[0084] R7a和R7b分别独立为氢,甲基或乙基; [0084] R7a and R7b are each independently hydrogen, methyl or ethyl;

[0085] R8为未被取代或被至少一个R9取代的Q_4烷基、(V3烷氧基; [0085] R8 is unsubstituted or substituted with at least one of R9 Q_4 alkyl, (V3 alkoxy;

[0086] R9为羟基,氰基,或三氟甲基; [0086] R9 is hydroxy, cyano, or trifluoromethyl;

[0087]η为0 〜2。 [0087] η 0 ~ 2.

[0088] 通式(I)所示的化合物、其药学上可接受的盐或其立体异构体,优选的技术方案为: [0088] The compounds of general formula (I), and pharmaceutically acceptable salt or a stereoisomer thereof, for the preferred technical solution:

[0089]X为0 ; [0089] X is 0;

[〇〇9〇] R1为未被取代或被1〜3个R6a取代的环己基、哌啶基、吡啶基; [〇〇9〇] Rl is unsubstituted or substituted with R6a ~ 3 a cyclohexyl group, a piperidinyl group, a pyridyl group;

[0091]R6a 为羟基,三氟甲基,-(CH2)nC(0)R8, - (CH2)nC(0)NR7aR7b,- (CH2)nC(0)OR8, - (CH2) nNR7aC(0)R8,或未被取代或被1〜3个R9取代的Ch烷基、Ch烷氧基; [0091] R6a is hydroxy, trifluoromethyl, - (CH2) nC (0) R8, - (CH2) nC (0) NR7aR7b, - (CH2) nC (0) OR8, - (CH2) nNR7aC (0) R8, or R9 is unsubstituted or substituted with a Ch ~ 3 alkyl, alkoxy Ch;

[0092]R2为未被取代或被1〜3个R6b取代的吡啶基、吡唑并吡啶基; [0092] R2 is unsubstituted or substituted with R6b a ~ 3-pyridyl, pyrazolyl and pyridyl;

[0093]R6b为羟基,三氟甲基,(V3烷基,或(V2烷氧基; [0093] R6b is hydroxy, trifluoromethyl, (V3 alkyl, or (V2 alkoxy;

[0094]R3、R3'、R4、R4'分别独立的为氢; [0094] R3, R3 ', R4, R4' each independently is hydrogen;

[0095] R5为甲基; [0095] R5 is methyl;

[0096] R7a和R7b分别独立的为氢,甲基或乙基; [0096] R7a and R7b are independently hydrogen, methyl or ethyl;

[0097] R8为未被取代或被1〜3个R9取代的k烷基; [0097] R8 is unsubstituted or substituted by R9 k th ~ 3 alkyl;

[0098] R9为羟基; [0098] R9 is hydroxy;

[0099]η为0或1。 [0099] η is 0 or 1.

[〇1〇〇] 表1本发明的部分化合物 [〇1〇〇] Table 1 some compounds according to the invention

[0101] [0101]

[0102] [0102]

[0103] [0103]

[0104] [0104]

[0105] [0105]

[0106] 本发明所述的"卤素"包括氟原子、氯原子、溴原子、碘原子。 [0106] according to the present invention, "halogen" includes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom.

[0107] 本发明所述的"Cm烷基"指含有1-6个碳原子的烃部分去除一个氢原子衍生的直链或支链的烧基,如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、 异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3, 3-二甲基丁基、2, 2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3_二甲基丁基、2,3_二甲基丁基、2-乙基丁基、1-甲基-2-甲基丙基等。 [0107] The present invention is "Cm is alkyl" refers to a hydrocarbon moiety containing from 1 to 6 carbon atoms derived by removing one hydrogen atom burning group of straight or branched chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl group, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, dimethylbutyl 1,3_, 2,3_-dimethylbutyl, 2-ethylbutyl, 1- 2-methylpropyl group and the like. 本发明所述的"Ch烷基"、"Ci_3烷基"分别指上述实例中的含有1-4个、1-3个碳原子的具体实例。 According to the present invention "Ch alkyl", "Ci_3 alkyl" refers to a specific example containing 1-4, 1-3 carbon atoms in the above examples.

[0108] 本发明所述的"C3_8环烷基"指含有3-8个碳原子的环状烷基,如环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷、环辛烷等。 [0108] The present invention "C3_8 cycloalkyl" refers to cyclic alkyl groups containing 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl alkoxy, cyclooctane and the like. 本发明所述的"C4_7环烷基"指上述实例中的含有4-7个碳原子的具体实例。 According to the present invention "C4_7 cycloalkyl" refers to a specific example containing 4-7 carbon atoms in the above examples.

[0109] 本发明所述的"C2_8烯基"是指含有双键的碳原子数为2-8的直链或支链或环状的稀基,如乙稀基、1 _丙稀基、2-丙稀基、I- 丁稀基、2_ 丁稀基、1,3_ 丁二稀、1-戊稀基、2_戊稀基、3_戊稀基、1,3_戊二稀、1,4_戊二稀、1-己稀基、2_己稀基、3_己稀基、1,4_己二稀、 环戊烯基、1,3-环戊二烯基、环己烯基、1,4-环己二烯基、环庚烯基、1,4-环庚二烯基、环辛烯基、1,5-环辛二烯基等。 [0109] The present invention "C2_8 alkenyl" refers to a double bond containing 2-8 carbon atoms, straight or branched chain or cyclic dilute base, such as ethylene group, propylene group _ 1, 2- propenyl, I- butyl group dilute, dilute 2_ butyl group, 1,3_ butadiene, 1-pentyl group dilute, dilute 2_ pentyl group, 3_ pentyl group dilute, dilute 1,3_ glutaric, 1,4_ glutaric dilute, dilute 1-hexyl group, a hexene group 2_, 3_ hexene group, 1,4_ adipic dilute, cyclopentenyl, 1,3-cyclopentadienyl group, a cycloalkyl hexenyl, 1,4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadienyl, cyclooctenyl, 1,5-cyclooctadienyl and the like. 本发明所述的C3_8烯基是指上述实例中的含有3-8个碳原子的具体实例。 C3_8 alkenyl groups of the present invention refers to a specific example containing 3-8 carbon atoms in the above examples.

[0110] 本发明所述的"c2_8炔基"是指含有三键的碳原子数为2-8的直链或支链的炔基, 如乙炔基、丙炔基、2-丁炔基、2-戊炔基、3-戊炔基、4-甲基-2-戊炔基、2-己炔基、3-己炔基、5-甲基-2-己炔基、2-庚炔基、5-甲基-2-庚炔基、2-辛炔基、3-辛炔基等。 [0110] The present invention "c2_8 alkynyl group" refers to the number of carbon atoms containing a triple bond is 2-8 straight-chain or branched alkynyl groups such as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, 5-methyl-2-hexynyl, 2-heptynyl group, 5-methyl-2-heptynyl, 2-octynyl, 3-octynyl and the like. 本发明所述的C3_8炔基是指上述实例中的含有3-8个碳原子的具体实例。 C3_8 alkynyl groups according to the present invention refers to a specific example containing 3-8 carbon atoms in the above examples.

[0111] 本发明所述的"Cm烷氧基"指"Cm烷基"通过氧原子与其他结构相连接的基团, 如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、仲丁氧基、戊氧基、新戊氧基、己氧基等。 [0111] The present invention is "Cm is alkoxy" refers to "alkyl Cm is" group via an oxygen atom connecting with other structures, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neo-pentyloxy, hexyloxy and the like. 术语"Ci_4烧氧基"、Ci_3烧氧基"、"Ci_2烧氧基"分别指上述实例中的含有1-4个、1-3个、1-2个碳原子的具体实例。 The term "Ci_4 alkoxy burn", Ci_3 burn group "," Ci_2 burn group "refer to specific examples contain 1-4, 1-3, 1-2 carbon atoms in the above examples.

[0112] 本发明所述的"芳基"是指芳香族环例如苯基、取代的苯基(例如苄基、苯乙基)以及桐和的芳香环基(例如蔡基、菲)等。 [0112] The present invention "aryl" means an aromatic ring such as phenyl, substituted phenyl (e.g. benzyl, phenethyl), and an aromatic ring group and Tong (e.g. Cai, phenanthrene) and the like.

[0113]本发明所述的"3-14元杂环基"是指含有3-14个环原子(其中至少含有一个杂原子)的全部饱和、部分饱和、不饱和的环状基团,所述"杂原子"是指氮原子、氧原子、硫原子等。 [0113] according to the present invention, "3-14 membered heterocyclyl" refers to a fully saturated ring containing 3-14 atoms (containing at least one hetero atom), partially saturated, unsaturated, cyclic group, the He said "hetero atom" means a nitrogen atom, an oxygen atom, a sulfur atom and the like. "杂3-14元杂环基"包括3-8元单杂环基和6-14元稠杂环基。 "3-14 membered heteroaryl heterocyclyl" include 3-8 membered monocyclic heterocyclic group and a 6-14 membered fused heterocyclyl.

[0114]所述的"3-8元单杂环基",其所述的单杂环可以是全部饱和、部分饱和、不饱和的,实例有:氮杂环丙烷、2H-氮杂环丙烷、二氮杂环丙烷、3H-二氮杂环丙烯、氮杂环丁烷、 1,2-二氮杂环丁烷、氮杂环丁二烯、1,2-二氮杂环丁烯、吡咯、二氢吡咯、吡咯烷、咪唑、4, 5-二氢咪唑、咪唑烷、吡唑、4, 5-二氢吡唑、吡唑烷、1,2, 3-三唑、1,2,4-三唑、四唑、吡啶、 2_吡啶酮、4-吡啶酮、哌啶、哒嗪、嘧啶、吡嗪、哌嗪、1,2, 3-三嗪、1,2,4-三嗪、1,3, 5-三嗪、1,2,4, 5-四嗪、氮杂环庚三烯、1,2-二氮杂环庚三烯、1,3-二氮杂环庚三烯、1,4-二氮杂环庚三烯、氮杂环辛四烯、1,4_二氢-1,4-二氮杂环辛三烯、环氧乙烷、二氧杂环丙烷、硫杂环丙烷、氧杂环丁烷、1,2-二氧杂环丁烷、硫杂环丁烷、1,2-二硫杂环丁烯、呋喃、四氢呋喃、噻吩、2, 5-二氢噻吩、四 [0114] The term "3-8 membered monocyclic heterocyclic group", which may be a single heterocyclic ring fully saturated, partially saturated, unsaturated, examples are: aziridine, 2H- aziridine , diaziridines, 3H- two azirine, azetidine, 1,2-azetidine, aziridine-butadiene, 1,2-diazabicyclo-butene, pyrrole, dihydro-pyrrole, pyrrolidine, imidazole, 4, 5-dihydro-imidazole, imidazolidine, pyrazole, 4, 5-dihydro-pyrazole, pyrazolidine, 1,2, 3-triazole, 1,2 , 4-triazole, tetrazole, pyridine, 2_ pyridone, 4-pyridone, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, 1,2,3-triazine, 1,2,4- triazine, 1,3,5-triazine, 2,4, 5-tetrazine, azepine, 1,2-azepine, 1,3-diazabicyclo cycloheptatriene, 1,4-azepine, azepine cyclooctatetraene, 1,4_-dihydro-1,4-diaza-cyclooctatriene, oxirane, dioxane, cyclopropane, thiirane, oxetane, 1,2-dioxetane, thietane, 1,2-dithiole-butene, furan, tetrahydrofuran, thiophene, 2, 5- dihydro-thiophene, tetrakis 噻吩、1,3-二氧杂环戊烷、1,3-二氧杂环戊烯-2-酮、1,2-二硫杂环戊烯、1,3_二硫杂环戊烷、2H-吡喃、2H-吡喃-2-酮、3,4_二氢-2H-吡喃、4H-吡喃、四氢吡喃、4H-吡喃-4-酮、1,4-二氧杂环己二烯、1,4-二硫杂环己二烯、1,4-氧硫杂环己二烯、1,4-二氧杂环己烷、1,3-二氧杂环己烷、1,3-氧硫杂环己烷、氧杂环庚三烯、硫杂环庚三烯、1,4-二氧杂环辛三烯、氧氮杂环丙烷、噁唑、4, 5-二氢噁唑、异噁唑、4, 5-二氢异噁唑、2, 3-二氢异噁唑、1,2, 3-噁二唑、1,2, 5-噁二唑、噻唑、4, 5-二氢噻唑、异噻唑、1, 2,3_ 噻二唑、1,2,4-噻二唑、1,3,4-噻二唑、2H-1,2-噁嗪、4H-1,2-噁嗪、6H-1,2-噁嗪、 2H-1,3-噁嗪、4H-1,3-噁嗪、5,6_ 二氢-4H-1,3-噁嗪、6H-1,3-噁嗪、2H-1,4-噁嗪、4H-1, 4-噁嗪、2H-1,3-噻嗪、4H-1,3-噻嗪、5,6_ 二氢-4H-1,3-噻嗪、6H-1,3-噻嗪、2H-1,4-噻嗪、4H-1 Thiophene, 1,3-dioxolane, 1,3-dioxole-2-one, 1,2-dithioles, 1,3_ dithiolane, 2H- pyran, 2H- pyran-2-one, 3,4_ dihydro -2H- pyran, 4H- pyran, tetrahydropyran, 4H- pyran-4-one, 1,4-bis oxetane-hexadiene, 1,4-hexadiene-dithiol, 1,4-oxathiolane-hexadiene, 1,4-dioxane, 1,3-dioxin hexane, 1,3-oxathiane, oxepin, thietanyl cycloheptatriene, 1,4-dioxin-octatriene, oxaziridine, oxazole, 4 , 5-dihydro-oxazole, isoxazole, 4, 5-dihydroisoxazole, 2, 3-dihydro-isoxazole, 1,2,3-oxadiazole, 1,2, 5-oxadiazol oxazole, thiazole, 4, 5-dihydro-thiazole, isothiazole, 1, 2,3_-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 2H-1,2- oxazine, 4H-1,2- oxazine, 6H-1,2- oxazine, 2H-1,3- oxazine, 4H-1,3- oxazine, dihydro -4H-1,3 5,6_ - oxazine, 6H-1,3- oxazine, 2H-1,4- oxazine, 4H-1, 4- oxazine, 2H-1,3- thiazine, 4H-1,3- thiazine, 5 , 6_ dihydro -4H-1,3- thiazine, 6H-1,3- thiazine, 2H-1,4- thiazine, 4H-1 ,4-噻嗪、吗啉等。 , 4-thiazine, morpholine and the like. 优选为"5-6元单杂环基",其环可以是全部饱和、部分饱和、不饱和的,其实例包括不限于"3-8元单杂环基"中,含有5-6个环原子的具体实例。 Preferably a "5-6 membered monocyclic heterocyclic group", which ring may be fully saturated, partially saturated, unsaturated, examples thereof including but not limited to "3-8 membered monocyclic heterocyclic group", a ring containing 5-6 specific examples of atoms.

[0115]所述的"6-14元稠杂环基",其所述的稠杂环可以是全部饱和、部分饱和、不饱和的,实例有吲哚、异吲哚、咔唑、苯并咪唑、吲唑、苯并三唑、四氢咪唑并[4, 5-c]吡啶、喹啉、 异喹啉、2-喹啉酮、4-喹啉酮、1-异喹啉酮、吖啶、菲啶、噌啉、酞嗪、喹唑啉、3,4-二氢喹唑啉、喹喔啉、1,2-二氢喹喔啉、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶、2, 7-萘啶、2, 6_萘啶、嘌呤、蝶啶、吩嗪、苯并[b]呋喃、异苯并[b]呋喃、二苯并[b]呋喃、苯并[b]噻吩、 苯并[C]噻吩、苯并[d][l,3]二氧杂环戊烯、3-氧代-1,3-二氢异苯并呋喃、2H-色原烯、 2H-色原烯-2-酮、4H-色烯、4H-色烯-4-酮、色满、苯并噁唑、苯并噻唑、4H-1,3-苯并噁嗪、吩嗪、吩噻嗪、4,6_二氢-1H-呋喃并[3,4-d]咪唑、3a,4,6,6a-四氢-1H-呋喃并[3, 4-(1]咪唑、4,6-二氢-1!1-噻吩并[3,4-(1]咪唑、4,6-二氢-1!1-吡咯并[3,4-(1 [0115] The term "6-14 membered fused heterocyclic group", which is the fused heterocyclic ring may be fully saturated, partially saturated, unsaturated, exemplified by indole, isoindole, carbazole, benzo imidazole, indazole, benzotriazole, tetrahydro-imidazo [4, 5-c] pyridine, quinoline, isoquinoline, 2-quinolyl-one, 4-quinolinone, 1-isoquinolinone, acridine , phenanthridine, cinnoline, phthalazine, quinazoline, 3,4-dihydro-quinazoline, quinoxaline, 1,2-dihydro-quinoxaline, 1,8-naphthyridine, 1,7- naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2, 7-naphthyridine, 2, 6_ naphthyridine, purine, pteridine, phenazine, benzo [b] furan, isobenzofuran [ b] furan, dibenzo [b] furan, benzo [b] thiophene, benzo [C] thiophene, benzo [d] [l, 3] dioxol, 3-oxo-1, 3- dihydro-isobenzofuran, 2H- chromene, 2H- chromen-2-one, 4H- chromene, 4H- chromen-4-one, chroman, benzoxazole, benzothiazole , 4H-1,3- benzoxazine, phenazine, phenothiazine, 4,6_ -1H- dihydro-furo [3,4-d] imidazole, 3a, 4,6,6a- tetrahydro - 1H- furo [3, 4- (1] imidazole, 4,6-dihydro-1! 1- thieno [3,4- (1] imidazole, 4,6-dihydro-1! 1-pyrrolidinyl and [3,4 (1 ]咪唑、4,5, 6, 7-四氢-1H-苯并[d]咪唑等。优选为"9-10元稠杂环基",其环可以是全部饱和、部分饱和、不饱和的,其实例包括不限于"6-14元稠杂环基"中,含有9-10个环原子的具体实例。 ] Imidazole, 4, 5, 6, 7-tetrahydro -1H- benzo [d] imidazole and the like. Preferably the "9-10 membered fused heterocyclic group", which ring may be fully saturated, partially saturated, unsaturated, , examples thereof including but not limited to "6-14 membered fused heterocyclic group", specific examples containing 9-10 ring atoms.

[0116] 本发明所述的"4-10元杂环基"、"5-10元杂环基"分别是指上述"3-14元杂环基" 中含有4-10个环原子(至少含有一个杂原子)、5-10个环原子(至少含有一个杂原子)的环状基团,包括所有单环或者稠环,且环可以是全部饱和、部分饱和、不饱和的。 [0116] "4-10 membered heterocyclic group" of the present invention, "5-10 membered heterocyclyl" refer to the above "3-14 membered heterocyclyl" ring containing 4-10 atoms (at least containing a hetero atom), containing 5 to 10 ring atoms (at least one hetero atom a cyclic group), including all single ring or a condensed ring, and the ring may be fully saturated, partially saturated, unsaturated.

[0117] 本发明所述的"6-12元螺环"是指一类至少有两个环共享一个原子形成的含有6-12个碳原子或/及杂原子的结构,所述的杂原子有氮、氧和硫等。 [0117] "6-12 membered spiro ring" according to the present invention refers to a class rings share at least two atoms form a structure containing 6 to 12 carbon atoms or / and hetero atoms, said hetero atoms nitrogen, oxygen and sulfur. 6-12元螺环包括6-12 元饱和螺环、6-12元部分饱和螺环。 6-12 membered spiro ring comprising 6-12 membered saturated spiro ring, partially saturated 6-12 membered spiro ring.

[0118] 6-12元饱和螺环,是指该螺环中的所有环均为饱和的环状基团,具体实例包括但不仅限于: [0118] 6-12 membered saturated spiro ring, means that all rings in the ring are saturated spiro cyclic group, specific examples include, but are not limited to:

[0120] 本发明所述的"7-10元螺环基"是指"6-12元螺环基"中含有7-10个环原子的结构,包括饱和的、部分饱和的。 [0120] according to the present invention, "7-10 membered spiro ring group" refers to a structure 7 to 10 ring atoms "6-12 membered spiro ring group" contains, including saturated, partially saturated.

[0121] 本发明所述的"被至少一个1^取代的"、"被至少一个1^取代的"、"被至少一个R6c;、被至少一个R9取代的"、"被至少一个卤素、羟基、羧基取代的"等术语中的"至少一个", 是指被取代的基团上可以有一个或多个取代基,其最多取代基的个数取决于被取代的基团上的所有化学可行的可以被相应的取代基取代的位置的个数,一般来说,优选为1-3个取代基。 [0121] according to the present invention, "at least one substituted 1 ^" "^ 1 with at least one substituent" and "at least one R6c ;, R9 is substituted with at least one," "at least one halogen, hydroxy , carboxy-substituted "in terms such as" at least one "means that there may be one or more substituents on the substituted groups, the number of which depends on all group substituted with up to a chemically viable group substituted It may be substituted with the corresponding number of the substituent positions, in general, preferably 1 to 3 substituents.

[0122] 本发明上述化合物可以采用下述流程中描述的方法和/或本领域普通技术人员已知的其它技术来合成,但不仅限于以下方法。 The above-mentioned compound [0122] The present invention may employ a method described in the following scheme and other techniques and / or known to those of ordinary skill in the art to be synthesized, but is not limited to the following methods.

[0123] 通式⑴所示的化合物,当X为0时, [0123] compound of formula ⑴, when X is 0,

[0124] [0124]

[0125] 反应步骤: [0125] Reaction Step:

[0126] 步骤lTM-a的制备将SM-a加入冰浴冷却的冰和NaOH的混合物中,于室温下搅拌反应,将溶液加入冰和浓盐酸中,制成溶液A,准备立即投入下一步反应中。 [0126] Preparation of Step lTM-a mixture of SM-a cooled ice bath was added ice and NaOH, and stirred at room temperature, the solution was added ice and concentrated hydrochloric acid to prepare solution A, ready for the next step immediately reaction.

[0127] 步骤2TM_b的制备将SM-b在H20_HC1的溶液中搅拌,过滤,制成溶液B,将溶液A 和溶液B室温下合并,搅拌反应,滤除沉淀,用水洗涤,干燥即得。 Preparation [0127] Step 2TM_b of the SM-b H20_HC1 stirred solution was filtered to prepare solution B, and the combined solutions A and B at room temperature, the reaction was stirred, the precipitate filtered off, washed with water, and dried to obtain.

[0128] 步骤3TM-C的制备向TM-b中加入乙酸钾和乙酸酐,回流搅拌反应,滤出沉淀,用乙酸洗至滤液无色,然后用水洗涤,干燥即得。 Preparation [0128] Step 3TM-C of potassium acetate and acetic anhydride were added to the TM-b, the reaction was stirred at reflux, the precipitate filtered off, washed with acetic acid until the filtrate was colorless, then washed with water, and dried to obtain.

[0129] 步骤4TM_d的制备将TM-c加入到三氯氧磷中搅拌回流,将混合物冷至室温,减压蒸馏除去多余的三氯氧磷,得到的固体用短硅胶柱柱层析,洗脱剂用石油醚-乙酸乙酯,减压蒸干即得。 Preparation [0129] Step 4TM_d the TM-c is added to the phosphorus oxychloride was stirred at reflux, the mixture was cooled to room temperature, evaporated under reduced pressure to remove the excess phosphorus oxychloride, the resulting solid by column chromatography on a short silica gel column, washed degreasing agent with petroleum ether - ethyl acetate, evaporated to dryness under reduced pressure to obtain.

[0130] 步骤5TM_e的制备将TM-d和SM-c-同加入到二氯甲烷中,加入三乙胺,室温搅拌过夜。 Preparation [0130] Step 5TM_e of the TM-d and added to the SM-c- with dichloromethane, triethylamine, stirred overnight at room temperature. 减压旋蒸除去二氯甲烷,得到的糖浆状固体用柱层析纯化,即得。 Methylene chloride was removed by rotary evaporation under reduced pressure to give a syrupy solid was purified by column chromatography, to obtain.

[0131] 步骤6TM_f的制备将TM-e加入到还原试剂中,还原即得。 Preparation [0131] Step 6TM_f TM-e will be added to the reducing agent, the reduction to obtain.

[0132] 步骤7TM_g的制备将TM-f加入到二氯甲烷中,滴加三乙胺,冰水浴下加入SM-d(1, 1-羰基二咪唑),回流,加入饱和NaHC03水溶液,搅拌,分液,有机相用无水硫酸钠干燥,蒸干溶剂即得。 Preparation [0132] Step 7TM_g TM-f will be added to the methylene chloride was added dropwise triethylamine was added SM-d (1, 1- carbonyldiimidazole) in an ice-water bath, reflux, was added a saturated aqueous solution of NaHC03, followed by stirring, liquid separation, the organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated to dryness to obtain.

[0133] 步骤8TM_h的制备将TM-g、SM_e和四丁基溴化铵加入到二氯甲烷中,加入NaOH水溶液,室温搅拌,加入碘甲烷和NaOH配成的水溶液,继续搅拌,反应混合物用水淬灭,用二氯甲烷萃取两遍,有机相用盐水洗涤,无水硫酸钠干燥,过滤并蒸干滤液即得产物。 Preparation [0133] Step 8TM_h of the TM-g, SM_e and tetrabutylammonium bromide was added to the methylene chloride, was added aqueous NaOH, stirred at room temperature, iodomethane dubbed and aqueous NaOH, and stirring was continued, the reaction mixture was washed with water quenched and extracted twice with dichloromethane, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness to give the product.

[0134] 步骤9化合物i的制备将TM-h溶于DMF中,加入SM-f、双(三苯基磷)二氯化钯(II)和Na2C03,加热搅拌,反应混合物用NaHC03饱和水溶液淬灭,乙酸乙酯萃取两次,有机层用饱和食盐水洗,经无水硫酸钠干燥,过滤并减压蒸干,残余物用硅胶柱柱层析纯化,即得。 [0134] Step 9 Preparation of compound i to TM-h is dissolved in DMF, SM-f, bis (triphenylphosphine) palladium (II) dichloride and Na2C03, heating and stirring, the reaction mixture was quenched with saturated aqueous NaHC03 off, extracted twice with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure, the residue was purified by silica gel column to obtain.

[0135] 通式(I)所示的化合物,当X为S或NH时,可参照上述方法制备。 A compound represented by [0135] Formula (I), when X is S or NH, can be prepared as described above with reference.

[0136] 反应方程式中,以SM代表原料,以TM代表产物,R1、R2、R3、R4、R4'、R5如前文所定义。 [0136] In the schemes, to SM representative of raw material, the product representative of TM, R1, R2, R3, R4, R4 ', R5 are as defined above. 当R5为氢时,可将TM-g直接与SM-f反应,得到本发明式⑴化合物。 When R5 is hydrogen, may be reacted directly with TM-g SM-f, to give a compound of the invention of formula ⑴.

[0137] 反应过程中,不应当参与反应的原料化合物的官能团可以以未报护的形式存在, 或者可以被保护,然后根据常规的方法全部或者部分除去保护基。 [0137] During the reaction, the functional groups of the starting compounds should not participate in the reaction may be present in the form of protection is not reported, or may be protected, according to conventional methods and then fully or partially removing the protective group. 例如,如果存在氨基酸性质子,可用常规的"氨基保护基"进行保护,所述"氨基保护基"的实例包括:甲基、环丙甲基、1-甲基-1-环丙甲基、二异丙甲基、9-芴甲基、9-(2-硫代)芴甲基、2-呋喃甲基、2,2, 2_三氯甲基、2-卤代甲基、乙基、2-碘乙基、2-三甲基甲硅烷基乙基、2-甲硫基乙基、2-甲磺酰基乙基、2_(对甲苯磺酰基)乙基、2-磷鎗基乙基、1,1_二甲基-3-(N,N-二甲基甲酰氛基)丙基、1,1_二苯基_3_(N,N-二乙氛基)丙基、1-甲基_1_(金刚烧基)乙基、1-甲基苯乙基、I-甲基(3, 5- _甲氧苯基)乙基、1_甲基-1-(4-联苯基)乙基、I-甲基_1_ (对苯偶氣基苯基)乙基、1,1_ _甲基_2,2,2-二氣乙基、1,1- _甲基_2-氛乙基、 异丁基、叔丁基、叔戊基、环丁基、1-甲基环丁基、环戊基、环己基、1-甲基环己基、1-金刚烷基、异冰片基、乙烯基、烯丙基、肉桂基、苯基、2,4,6-三叔 For example, if the amino acid proton, using conventional "amino protecting group" for the presence of protected, examples of the "amino protecting group" include: methyl, cyclopropylmethyl, 1-methyl-1-cyclopropylmethyl, diisopropyl methyl, 9-fluorenylmethyl, 9- (2-thio) fluorenylmethyl, 2-furylmethyl, 2,2, 2_ trichloromethyl, 2-halomethyl, ethyl , 2-iodoethyl, 2-trimethyl silyl ethyl, 2-methylthioethyl, 2-methanesulfonyl-ethyl, 2_ (p-toluenesulfonyl) ethyl, 2- phosphorus gun ethyl group, 1,1_-dimethyl -3- (N, N- dimethylformamide atmosphere yl) propyl, 1,1_ diphenyl _3_ (N, N- diethyl atmosphere yl) propyl, 1-methyl _1_ (adamantan burn-yl) ethyl, 1-methyl-phenylethyl, I- methyl (3, 5-_-methoxyphenyl) ethyl, 1_-methyl-1- (4- biphenylyl) ethyl, I- _1_ methyl (p-benzoin gas-yl) ethyl, methyl _2,2,2- two gas _ 1,1_ ethyl, methyl 1,1_ _2- atmosphere ethyl, isobutyl, t-butyl, t-amyl, cyclobutyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl group, 1-adamantyl , isobornyl, vinyl, allyl, cinnamyl, phenyl, 2,4,6-tri 基苯基、间硝基苯基、S-苯基、 8-喹啉基、N-羟基哌啶基、4-(1,4-二甲基哌啶基)、4, 5-二苯基-3-噁唑啉-2-酮、苄基、 2,4,6-三甲基苄基,对甲氧基苄基、3, 5-二甲氧基苄基、对癸氧基苄基、对硝基苄基、邻硝基苄基、3,4-二甲氧基-6-硝基苄基、对溴苄基、氯苄基、2,4-二氯苄基、对氰基苄基、邻(N, N-二甲基甲酰氨基)苄基、间-氯-对-酰氧基苄基、对(二羟基硼烷基)苄基、对(苯偶氮基)苄基、对(对甲氧基苯偶氮基)苄基、5-苯并异噁唑基甲基、9-蒽基甲基、二苯甲基、 苯基(邻硝基苯基)甲基、二(2-吡啶基)甲基、1-甲基-1-(4-吡啶基)乙基、异烟碱基、 S-苄基、Ν' -哌啶基羰基、Ν' -对甲苯磺酰基氨基羰基及Ν' -苯氨基硫代羰基的氨基甲酸酯;甲酰基、乙酰基、乙酰基-吡啶鎗、(Ν' -二硫代苄氧羰基氨基)乙酰基、3-苯基丙酰基、 3_(对羟苯基 Phenyl, m-nitrophenyl, S- phenyl, 8-quinolyl, N- hydroxypiperidine, 4- (1,4-dimethyl-piperidinyl), 4, 5-diphenyl 3-oxazolidinyl-2-one, benzyl, 2,4,6-trimethyl-benzyl, p-methoxybenzyl, 3,5-dimethoxybenzyl group, a decyloxy benzyl , p-nitrobenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, p-bromobenzyl, chlorobenzyl, 2,4-dichlorobenzyl, p-cyanobenzyl benzyl, o- (N, N- dimethyl-carboxamido) benzyl, m - chloro - on - acyloxy benzyl, p- (dihydroxyboryl) benzyl, p- (phenylazo) benzyl group, p- (p-methoxyphenyl-azo) benzyl, 5-benzisoxazolyl-methyl, 9-anthrylmethyl, diphenylmethyl, phenyl (o-nitrophenyl) methyl , bis (2-pyridyl) methyl, 1-methyl-1- (4-pyridyl) ethyl, isonicotinyl groups, S- benzyl, Ν '- piperidinyl carbonyl, Ν' - p sulfonyl aminocarbonyl and Ν '- phenylamino thiocarbonyl carbamate; formyl, acetyl, acetyl - pyridine gun, (Ν' - dithiobis benzyloxycarbonylamino) acetyl, 3-phenyl propionyl, 3_ (p-hydroxyphenyl 丙酰基、3-(邻硝基苯基)丙酰基、2-甲基-2-(邻硝基苯氧基)丙酰基、 2-甲基-2-(邻苯偶氮基苯氧基)丙酰基、4-氯代丁酰基、异丁酰基、邻硝基肉桂酰基、吡啶甲酰基、Ν' -乙酰甲硫氨酰基、Ν' -苯甲酰基-苯基烷基、苯甲酰基、对苯基苯甲酰基、对甲氧基苯甲酰基、邻硝基苯甲酰基、邻(苯甲酰氧基甲基)苯甲酰基和对-Ρ-苯甲酰基的酰胺;邻苯二甲酰基、2,3_二苯基马来酰基和二硫代琥珀酰基的环亚酰胺;烯丙基、烯丙氧基羰基、叔丁氧基羰基、对硝基苄氧基羰基、对甲氧基苄氧基羰基、苯甲酰甲基、3-乙酰氧基丙基、4 -硝基环己基氧代批略烧基、季按盐、甲氧基甲基、2-氣乙氧基甲基、 节氧基甲基、新戊醜基甲基、[1 _ (烧氧撰基氨基)]_2, 2, 2,二氟乙基、[1-二氟甲基-1-(对氣苯氧基甲氧基)2, 2, 2,-二氣]乙基、2-四氧批喃基、2,4- _硝基苯基、节基、3,4- Propionyl, 3- (o-nitrophenyl) propionyl, 2-methyl-2- (o-nitrophenoxy) propionyl, 2-methyl-2- (o-phenoxy phenylazo) propionyl, 4-chloro-butyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, Ν '- acetyl methionyl, Ν' - benzoyl - a phenylalkyl group, a benzoyl group, amide-phenylbenzoyl, p-methoxy benzoyl group, o-nitrobenzoyl, o- (benzoyloxymethyl) benzoyl and p -Ρ- benzoyl; phthaloyl , 2,3_ maleic acid and diphenyl dithiophosphoric succinyl cyclic amide; an allyl group, allyloxycarbonyl group, tert-butoxycarbonyl group, a p-nitrobenzyloxycarbonyl group, p-methoxybenzyl benzyloxycarbonyl, phenacyl, 3-acetoxypropyl, 4 - nitro-oxo-cyclohexyl group batch slightly burned, a quaternary salt according to, methoxymethyl, 2-ethoxymethyl gas section methyl group, neopentyl ugly-ylmethyl, [1 _ (oxy-fired essays ylamino)] _ 2, 2, 2, difluoroethyl, [1-difluoromethyl-1- (p-phenylene gas methoxymethoxy) 2, 2, 2, - two gas] ethyl group, 2-oxo four batches, tetrahydrothiopyranyl, 2,4 _ nitrophenyl, section, 3,4 _甲氧基节基、邻硝基节基、-(对甲氧苯基)甲基、二苯甲基、(对甲氧苯基)-苯基甲基、- 苯基-4-吡啶基甲基、2-吡啶甲基Ν' -氧化物、5-二苯丙环庚烷基、(Ν',Ν' -二甲氨基亚甲基)、Ν,Ν' -异亚丙基、亚苄基、对甲氧基亚苄基、对硝基亚苄基、亚水杨基、5-氯亚水杨基、二苯亚甲基、(5-氯-2-羟苯基)苯基亚甲基、酰基乙烯基、5,6-二甲基-3-氧代-1-环己稀基、砸烧、[苯基(五撰基络或鹤)]撰基、铜或锋整合物、硝基、亚硝基、氧化物、-苯基勝基、-甲硫基氧勝基、-苯硫基氧勝基、-乙基憐醜基、-节基憐醜基、-苯基憐醜基、憐酰基、三甲基甲硅烷基、苯硫基、邻硝基苯硫基、2,4-二硝基苯硫基、2-硝基-4-甲氧基苯硫基、三苯甲硫基、苯磺酰基、对甲氧基苯磺酰基、2,4,6-三甲基苯磺酰基、甲基磺酰基、苯甲磺酰基、对甲苯甲磺酰基、三氟甲基磺酰基、 _ Section methoxy group, o-section group, - (phenyl-methoxy) methyl, diphenylmethyl, (p-methoxyphenyl) - phenylmethyl, - phenyl-4-pyridyl methyl, 2-pyridylmethyl Ν '- oxide, 5-phenylpropyl cycloheptyl, (Ν', Ν '- dimethylaminomethylene), Ν, Ν' - isopropylidene, ethylene benzyl, p-methoxybenzylidene, for nitrobenzylidene, salicylidene, 5-chloro-salicylidene, diphenylmethylene, (5-chloro-2-hydroxyphenyl) phenyl a methylene group, vinyl group, 5,6-dimethyl-3-oxo-1-cyclohexene group, drop burning, [phenyl (or five essays network crane group)] group essays, copper or integrated front thereof, nitro, nitroso, oxide, - a phenyl group wins, - methylthio wins oxo group, - phenylthio wins oxo group, - pity ugly ethyl group, - section pity ugly yl group, - a phenyl pity ugly group, pity acyl group, trimethylsilyl group, phenyl group, o-nitrophenyl group, 2,4-dinitrophenyl group, a 2-nitro-4-methoxyphenoxy group, trityl a methylthio group, a benzenesulfonyl group, a p-methoxybenzenesulfonyl, 2,4,6-trimethylbenzene sulfonyl group, methylsulfonyl group, phenylmethylsulfonyl group, methylsulfonyl p-toluenesulfonyl, trifluoromethanesulfonyl acyl, 苯甲酰甲基磺酰基等。 Methylsulfonyl-benzoyl group and the like.

[0138] 本发明式⑴化合物的"药学上可接受的盐",是指具有碱性氮原子的式⑴化合物与无机酸形、有机酸或者有机质子酸所形成的盐。 [0138] The present invention of formula ⑴ "pharmaceutically acceptable salt" of a compound means salts having the formula ⑴ basic nitrogen atom form a compound with an inorganic acid, an organic acid or organic protonic acid is formed.

[0139]本发明式(I)化合物的"立体异构体",是指本发明式(I)化合物存在不对称碳原子,碳碳双键等,其所有对映异构体、非对映异构体、消旋异构体、顺反异构体、互变异构体及其混合物,均包括在本发明中。 [0139] invention of formula (I) of the present "stereoisomers" of a compound means a compound of formula (I) according asymmetric carbon atoms, carbon-carbon double bond, which all enantiomers, diastereomers isomers, racemic isomers, cis and trans isomers, tautomers and mixtures thereof, are included in the present invention.

[0140] 本发明式(I)化合物、其药学上可接受的盐或其异构体,可以与一种或多种药用载体制成药学上可接受的药物制剂,以口服、肠胃外等方式施用于需要这种治疗的患者。 [0140] The compounds of formula (I) present, pharmaceutically acceptable salt or an isomer, a pharmaceutical formulation may be a pharmaceutically acceptable carrier with one or more pharmaceutically acceptable made to oral, parenteral, etc. manner administered to a patient in need of such treatment. 口服给药时,可以与常规的填充剂、粘合剂、崩解剂、润滑剂、稀释剂等制成常规的固体制剂, 如片剂、胶囊剂、丸剂、颗粒剂等;用于肠胃外给药时,可制成注射剂,包括注射液、注射用无菌粉末与注射用浓溶液。 For oral administration, a conventional solid formulation with conventional fillers, binders, disintegrants, lubricants, diluents or the like, such as tablets, capsules, pills, granules and the like; for parenteral when administered, it can be made into injections, including injections, sterile powder for injection with a concentrated solution for injection. 制成注射剂时,可采用现有制药领域中的常规方法生产,配制注射剂时,可以不加入附加剂,也可根据药物的性质加入适宜的附加剂。 When prepared as injectables, using conventional methods conventional in the pharmaceutical art production, formulating injections, additives may not be added, may be added suitable additives according to the nature of the drug.

[0141] 本发明要求保护式(I)化合物、其药学上可接受的盐或其立体异构体与一种或多种抗肿瘤剂和免疫抑制剂的药物组合物,联合用药,用于制备治疗和/或预防增殖性疾病的药物。 [0141] The present claimed invention of formula (I) compound, pharmaceutically acceptable salt or a stereoisomer thereof with one or more anti-neoplastic agents and immunosuppressants pharmaceutical composition, combination, for the preparation of treatment and / or prophylaxis of proliferative diseases.

[0142] 抗肿瘤剂和免疫抑制剂选自抗代谢物,包括但不仅限于卡培他滨、吉西他滨、培美曲塞二钠;生长因子抑制剂,包括但不仅限于帕唑帕尼、伊马替尼、埃罗替尼、拉帕替尼、吉非替尼、凡德他尼;抗体,包括但不仅限于赫赛汀、贝伐单抗;有丝分裂抑制剂,包括但不仅限于紫杉醇、长春瑞滨、多西他赛、多柔比星;抗肿瘤激素类,包括但不仅限于来曲唑、他莫西芬、氟维司群、氟他胺、曲普瑞林;烷化剂类,包括但不仅限于环磷酰胺、卡莫司汀;金属钼类,包括但不仅限于卡钼、顺钼、奥沙利钼;拓扑异构酶抑制剂,包括但不仅限于拓扑特肯;免疫抑制类,包括但不仅限于依维莫司、西罗莫司、特癌适。 [0142] antineoplastic agents and immunosuppressants is selected from antimetabolites, including, but not limited to, capecitabine, gemcitabine, pemetrexed disodium; growth factor inhibitors, including but not limited pazopanib, ima imatinib, erlotinib, lapatinib, gefitinib, vandetanib; antibodies, including, but not limited to, Herceptin, Avastin; mitotic inhibitors, including but not limited to paclitaxel, vinorelbine Bin, docetaxel, doxorubicin; antineoplastic hormones, including but not limited to letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; alkylating agents, comprising but not limited to cyclophosphamide, carmustine; molybdenum metal, molybdenum card including but not limited to, cis molybdenum, molybdenum oxaliplatin; topoisomerase inhibitors, including, but not limited to Topotecan; immunosuppression class, It is including but not limited to everolimus, sirolimus, suitable for special cancer.

[0143] 本发明要求保护式(I)化合物、其药学上可接受的盐或其立体异构体在制备治疗和/或预防增殖性疾病的药物中的用途。 [0143] The present claimed invention of formula (I) compound, its pharmaceutically acceptable salt or a stereoisomer thereof in the manufacture of the treatment and / or prophylaxis of proliferative diseases.

[0144] 所述的增殖性疾病包括癌症和非癌性疾病,所述癌症选自脑瘤、肺癌、非小细胞性肺癌、鳞状上皮细胞、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、结直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、实体瘤、非霍奇金淋巴瘤、神经胶质瘤、多形性胶质母细胞瘤、胶质肉瘤、前列腺癌、甲状腺癌、雌性生殖道癌、原位癌、淋巴瘤、组织细胞淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、小细胞肺癌、胃肠道间质瘤、前列腺肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤、胶质母细胞瘤、 星形细胞瘤、神经母细胞瘤、肉瘤;非癌性疾病选自皮肤或前列腺的良性增生。 [0144] The proliferative diseases, including cancer and non-cancer disease, the cancer is selected from brain tumor, lung cancer, non-small cell lung cancer, squamous cell, bladder, gastric, ovarian cancer, peritoneal cancer, pancreas cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, solid tumors, non-Hodgkin's lymphoma, glioma , pleomorphic glioblastoma, glial sarcoma, prostate cancer, thyroid cancer, female reproductive tract cancer, in situ carcinoma, lymphoma, histiocytic lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer between colon cancer, testis cancer, small-cell lung cancer, gastrointestinal stromal tumors, prostate tumors, mast cell tumors, multiple myeloma, melanoma, glioma, glioblastoma, astrocytoma, neuroblastoma , sarcoma; skin disease is selected from non-cancerous or benign prostatic hyperplasia.

[0145] 以下通过部分本发明化合物的体外实验进一步阐述本发明化合物的有益效果,本发明其它化合物与试验中所列举的部分本发明化合物具有相同的有益效果,但不应将此理解为本发明化合物仅具有下列有益效果。 [0145] The following compounds further illustrate the advantageous effects of the present invention in vitro by compounds of this invention, other compounds of the present invention with the test compound recited in the present invention has the same portion beneficial effect, but the present invention should not be understood only compounds having the following advantageous effects.

[0146] 实骀例本发明化合物的体外酶学抑制活件 [0146] In vitro enzymatic solid tired embodiment of the present invention is a compound member inhibitory activity

[0147] 供试品本发明化合物,自制,其化学名称和结构式见各化合物的制备实施例; [0147] the test compound of the present invention, made, and the chemical name see Example structural formula of each compound was prepared;

[0148]TO2006122806(公开日2006. 11. 23)中公开的化合物BGT-226 和BEZ-235,参照专利方法制备,作为对照品。 [0148] TO2006122806 (Publication date 2006. 11.23) the compounds disclosed in BGT-226 and BEZ-235, prepared with reference to the patented process, as the reference.

[0149] [0149]

[0150] 实验方法 [0150] Experimental Method

[0151] 1.试剂终浓度和化合物配制 [0151] 1. Final reagent concentrations and formulated compound

[0152] 1. 1PI3Kα激酶溶液8. 469nM,kinasetracerl710, 57. 29nM; [0152] 1. 1PI3Kα kinase solution 8. 469nM, kinasetracerl710, 57. 29nM;

[0153] 1. 2mT0R(24. 72nM)激酶溶液,kinasetracer314, 32. 50nM; [0153] 1. 2mT0R (24 72nM.) Kinase solution, kinasetracer314, 32. 50nM;

[0154] 1. 35倍激酶缓冲液溶液,kinasetracer抗体6nM; [0154] 1.35-fold kinase buffer solution, kinasetracer antibody 6nM;

[0155] 1. 4测试化合物lOmM储液。 [0155] 1.4 lOmM stock solution of the test compound.

[0156] 2.实验步骤 [0156] 2. Experimental procedure

[0157] 2. 1测试化合物30μM,用激酶缓冲液4倍梯度稀释; [0157] 2.1 test compound 30μM, with kinase buffer diluted four-fold gradient;

[0158] 2. 2384孔板中每孔加入5μL系列稀释的化合物; [0158] 2.2384 added to 5μL per well plates serially diluted compound;

[0159] 2. 3 每孔加入5μL3 倍kinasetracer; [0159] 2.3 was added to each well 5μL3 times kinasetracer;

[0160] 2· 4每孔加入5μL激酶/kinasetracer抗体溶液; [0160] 2.4 Add 5μL per well kinase / kinasetracer antibody solution;

[0161] 2· 5ΡΙ3Κα室温孵育50min,mTOR孵育40min; [0161] 2 · 5ΡΙ3Κα incubated at room temperature 50min, mTOR incubated for 40min;

[0162] 2. 6Envision读取数据(激发波长340nM,发射波长615和665nM)。 [0162] 2. 6Envision data is read (excitation wavelength of 340nM, emission wavelength 615 and 665nM).

[0163] 3.数据处理 [0163] The data processing

[0164] 抑制率% = (100 %Emissionratio-样本Emissionratio) / (100 %Emission ratio-0%Emissionratio)*100 ; [0164] inhibition rate% = (100% Emissionratio- sample Emissionratio) / (100% Emission ratio-0% Emissionratio) * 100;

[0165]输入GraphPadPrism5. 0 作图,得到曲线及IC50。 [0165] Input GraphPadPrism5. 0 obtained by plotting the curve and IC50.

[0166] 实验结果 [0166] The results

[0167] 表2本发明化合物体外酶学活性测定(IC50) [0167] TABLE invention compounds In vitro enzymatic activity assay 2 (IC50)

[0168] [0168]

[0169] 实验结论 [0169] The experimental results

[0170] 由表2可以看出,本发明化合物对ΡΙ3Κα和mTOR酶具有很好的抑制作用,比对照药BGT-226和BEZ-235更好,说明本发明化合物与现有技术相比,具有显著的进步。 [0170] As can be seen from Table 2, the compounds of the present invention have good and mTOR enzyme inhibition ΡΙ3Κα better than the control and drug BGT-226 BEZ-235, the compounds of this invention over the prior art, having remarkable progress. 4、具体实施方式 4. DETAILED DESCRIPTION

[0171] 以下通过实施例形式的具体实施方式,对本发明的上述内容作进一步的详细说明。 [0171] DETAILED DESCRIPTION The following embodiments by the form of the above-described present invention will be described in further detail. 但不应将此理解为本发明上述主题的范围仅限于以下实施例。 However, this should not be understood that the present invention relating to the above-described range is limited to the following embodiments.

[0172]实施例18-(2-甲氣某吡啶-5-某)-3_甲某-2-氣代-1-(哌啶-4-某)-2,3-二氧眯啤并「4,5-cl喹啉(化合物1)的制各 [0172] Example 18 (2-a-5 a gas) -2- -3_ Jiamou gas-1- (piperidin-4-one) -2,3-dioxo beer and squint "4,5-cl quinoline (compound 1) is prepared for each

[0173] 步骤Ι-a2_硝基-1-轻基氛基乙稀的制备 Preparation of light-nitro-1-yl group atmosphere of ethylene [0173] Step Ι-a2_

[0174] [0174]

[0175] 将6. 4g(105mmol)硝基甲烷加入冰浴冷却的28g冰和12. 4g(310mmol)Na0H的混合物中,〇°C搅拌1小时,然后于室温下搅拌1小时,将溶液于0°C下加入22. 4g冰和32. 8mL 浓盐酸(37% )中(溶液A),准备立即投入下一步反应中。 [0175] The mixture (310mmol) Na0H of 6. 4g (105mmol) was added nitromethane was cooled in an ice bath and 12. 4g 28g ice, the square ° C was stirred for 1 hour and then stirred at room temperature for 1 h, the solution was Add ice and 22. 4g 32. 8mL of concentrated hydrochloric acid (37%) 0 ° C for (solution A), ready for the next reaction immediately.

[0176] 步骤Ι-b5_溴_2_ (2_硝基-乙烯基氨基)苯甲酸的制备[01771 [0176] Step Ι-b5_ bromo _2_ (2_ nitro - vinylamino) benzoic acid [01771

[0178]将10g(46. 3mmol)2-氨基-5-溴-苯甲酸在H20-HC1(37% ) (10 : 1)的溶液中搅拌2小时,然后过滤,制成溶液B,将溶液A和溶液B室温下合并,搅拌18小时,滤出黄色沉淀,用水洗涤,干燥得产物10. 2g,收率76. 8%。 [0178] A 10g (46 3mmol.) 2- amino-5-bromo - acid in H20-HC1 (37%): was stirred for 2 hours (101) was then filtered to prepare a solution B, and solution the combined A and solution B at room temperature, stirred for 18 hours, the yellow precipitate was filtered off, washed with water and dried to give the product 10. 2g, 76. 8% yield.

[0179] 步骤1-c6-溴-4-羟基-3-硝基喹啉的制备 Preparation of bromo-4-hydroxy-3-nitroquinoline [0179] Step 1-c6-

[0180] [0180]

[0181]向15g(52. 3mmol)5_ 溴-2-(2-硝基-乙烯基氨基)-苯甲酸加入6.lg(62. 7mmol) 乙酸钾和70mL乙酸酐,120°C回流搅拌2小时,滤出沉淀,用乙酸洗至滤液无色,然后用水洗涤,干燥得产物7. 77g,收率55. 2 %。 [0181] To a solution (52 3mmol.) 5_-bromo (2-nitro - vinylamino) - 15g -2- potassium acetate acid was added 6.lg (. 62 7mmol) and 70mL of acetic anhydride, 120 ° C was stirred at reflux for 2 h, the precipitate was filtered off, washed with acetic acid until the filtrate was colorless, then washed with water, and dried to give the product 7. 77g, yield 55.2%.

[0182] 步骤1-d6-溴-4-氯-3-硝基喹啉的制备 Preparation of 3-nitro quinoline [0182] Step 1-d6- bromo-4-

[0183] [0183]

[0184] 将2. 5g(9. 3mmol)6_溴-4-轻基-3-硝基喹啉加入50mL三氯氧磷中搅拌回流2 小时,将混合物冷至室温,减压蒸馏除去多余的三氯氧磷,得到的固体用短硅胶柱柱层析, 洗脱剂用石油醚-乙酸乙酯(3 : 1)约600mL,减压蒸干得产物2.lg,收率78. 5%。 [0184] A 2. 5g (9. 3mmol) 6_ light-bromo-4-yl-3-nitroquinoline was added 50mL of phosphorus oxychloride was stirred at reflux for 2 hours, the mixture was cooled to room temperature, distilled under reduced pressure to remove the excess phosphorus oxychloride, the resulting solid was short silica gel column chromatography, eluent petroleum ether - ethyl acetate (3: 1) to about 600 mL, and evaporated to dryness under reduced pressure to give the product 2.lg, yield 78.5 %.

[0185] 步骤1-e4-(6-溴-3-硝基喹啉-4-基氨基)哌啶-1-叔丁基碳酸酯的制备 [0185] Step 1-e4- (6- bromo-3-nitro-quinolin-4-ylamino) piperidine-tert-butyl carbonate

[0186] [0186]

[0187]将7. 6g(26mmol) 6_ 漠_4_ 氣_3_ 硝基喧琳、5. 6g三乙胺(55mmol)和7. 9g(40mmol) 4-氨基哌陡-1-叔丁基碳酸酯一同加入50mL二氯甲烧中,室温搅拌过夜。 [0187] A 7. 6g (26mmol) 6_ desert _4_ gas _3_ nitro noise Lin, 5. 6g triethylamine (55mmol) and 7. 9g (40mmol) 4- aminopiperidine-tert-butyl-carbonate steep ester was added along with 50mL dichloromethane burn stirred overnight at room temperature. 减压旋蒸除去二氯甲烷,得到的糖浆状固体用柱层析纯化,得产物8. 7g,收率75%。 Methylene chloride was removed by rotary evaporation under reduced pressure to give a syrupy solid was purified by column chromatography to give the product 8. 7g, 75% yield.

[0188] 步骤l_f4-(3-氨基-6-溴喹啉-4-基氨基)哌啶-1-叔丁基碳酸酯的制备 Preparation [0188] Step l_f4- (3- amino-6-bromo-quinolin-4-ylamino) piperidine-1-tert-butyl carbonate

[0189] [0189]

[0190] 将2. 25g(5mmol)4-(6-溴-3-硝基喹啉-4-基氨基)哌陡-1-叔丁基碳酸酯加入H20-CH30H(15 : 25)混合液中,加入Zn(L3g,20mmol)和NH4Cl(0.4g),加热至55°C,搅拌2h,纯化得产物0. 7g,收率34%。 [0190] A 2. 25g (5mmol) 4- (6- bromo-3-nitro-quinolin-4-yl-amino) piperidin steep tert-butyl carbonate was added H20-CH30H (15: 25) mixture was added Zn (L3g, 20mmol) and NH4Cl (0.4g), was heated to 55 ° C, stirred for 2h, the product was purified to give 0. 7g, 34% yield.

[0191] 步骤1巧4-(8-溴-2-氧代-2,3-二氢-1!1-咪唑并[4,5-(3]喹啉-1-基)哌啶-1-叔丁基碳酸酯的制备 [0191] Qiao Step 1 4- (8-bromo-2-oxo-2,3-dihydro-1! 1- imidazo [4,5- (3] quinolin-1- yl) piperidine -1 - preparation of tert-butyl carbonate

[0192] [0192]

[0193] 将L8g(4. 3mmol)4-(3_氨基-6-溴喹啉-4-基氨基)哌陡-1-叔丁基碳酸酯加入50mL二氯甲烷中,滴加2滴三乙胺,冰水浴下滴加二光气(1. 0g,4. 8mmol),搅拌2h,力口入饱和NaHC03水溶液淬灭,搅拌5分钟,分液,有机相用无水硫酸钠干燥,蒸干溶剂得产物0· 86g,产率46%。 [0193] The L8g (4. 3mmol) 4- (3_-amino-6-bromo-quinolin-4-yl-amino) piperidin steep tert-butyl carbonate was added 50mL of dichloromethane was added dropwise 2 drops of three triethylamine, was added dropwise under ice-water bath diphosgene (1. 0g, 4. 8mmol), stirred for 2h, saturated NaHC03 aqueous force mouth quenched stirred for 5 minutes, separated, the organic phase was dried over anhydrous sodium sulfate, and evaporated dry the solvent gave the product 0 · 86g, 46% yield.

[0194]步骤1-114-(8-溴-3-甲基-2-氧代-2,3-二氢-1!1-咪唑并[4,5-(3]喹啉-1-基) 哌啶-1-叔丁基碳酸酯的制备 [0194] Step 1-114- (8-bromo-3-methyl-2-oxo-2,3-dihydro-1! 1- imidazo [4,5- (3] quinolin-1-yl ) piperidine tert-butyl carbonate

[0195] [0195]

[0196]将1. 78g(4mmol)4-(8-溴-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]喹啉-1-基) 哌啶-1-叔丁基碳酸酯、0. 8g(6mmol)碘甲烷和0. 2g四丁基碘化铵加入15mL二氯甲烷中和10%NaOH50mL配置成的水溶液,室温搅拌2h,用二氯甲烧萃取两遍,有机相用盐水洗漆,无水硫酸钠干燥,过滤并蒸干滤液即得产物1.lg,收率61 %。 [0196] A 1. 78g (4mmol) 4- (8- bromo-2-oxo-2,3-dihydro -1H- imidazo [4,5-c] quinolin-1-yl) piperidine - tert-butyl carbonate, 0. 8g (6mmol) of methyl iodide and tetrabutylammonium iodide 0. 2g 15mL dichloromethane and was added an aqueous solution of 10% NaOH50mL arranged, and stirred at room temperature 2h, burning with methylene was extracted twice, the organic phase washed with brine paint, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness to give the product 1.LG, 61% yield.

[0197] 步骤1-i4-(8-(6-甲氧基吡啶-3-基)-3_甲基-2-氧代-2, 3-二氢-1H-咪唑并 [0197] Step 1-i4- (8- (6- methoxypyridin-3-yl) -3_-2-oxo-2,3-dihydro -1H- imidazo

[4, 5-c]喹啉-1-基)哌陡-1-叔丁基碳酸酯的制备[01981 Preparation of tert-butyl piperidin steep carbonate [4, 5-c] quinolin-1-yl) [01981

[0199]将1.lg(2.4mmol)4-(8-溴-3-甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-c] 喹啉-1-基)哌陡-1-叔丁基碳酸酯溶于10mLDMF中,加入0. 81g(4. 8mmol)2_甲氧基批啶-5-硼酸、100mg双(三苯基磷)二氯化钯(II)和6mL1MNa2C03,加热到100°C搅拌2小时,反应混合物用NaHC03饱和水溶液淬灭,用乙酸乙酯萃取两次,有机层用饱和食盐水洗, 经无水硫酸钠干燥,过滤并减压蒸干,残余物用硅胶柱柱层析纯化,得到产品0. 45g,产率38%。 [0199] The 1.lg (2.4mmol) 4- (8- bromo-3-methyl-2-oxo-2,3-dihydro -1H- imidazo [4,5-c] quinolin-l - yl) piperidine steep tert-butyl carbonate were dissolved in 10mLDMF added 0. 81g (4 8mmol) 2_ batch-methoxy-5-yl-boronic acid, 100 mg bis (triphenylphosphine) dichloride. palladium (II) and 6mL1MNa2C03, heated to 100 ° C for 2 hours, the reaction mixture was quenched with saturated aqueous NaHC03, washed with brine and extracted twice with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and reduced pressure to dryness, the residue was purified by silica gel column chromatography to give the product 0. 45g, 38% yield.

[0200] 步骤ι-j化合物1的制备 Preparation [0200] Step 1 compound ι-j

[0201] [0201]

[0202] 将2mL三氟乙酸在冰浴下加入(455mg,0. 9mmol)4-(8_(6-甲氧基批啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]喹啉-1-基)哌啶-1-叔丁基碳酸酯的15mL二氯甲烷溶液中,搅拌2h,反应液水洗,干燥有机相,得产品0. 3g,产率86%。 [0202] 2mL of trifluoroacetic acid was added (455mg, 0. 9mmol) 4- (8_ (6- methoxy-batch 3-yl) methyl-2-oxo-2 in an ice bath, 3- dihydro -1H- imidazo [4,5-c] quinolin-1-yl) piperidine-1 15 mL of dichloromethane was t-butyl carbonate and stirred for 2h, the reaction was washed with water, dried organic phase, the products 0. 3g, 86% yield.

[0203]分子式:C22H23N502 分子量:389. 45MS: 390 (M+H+) [0203] Molecular Formula: C22H23N502 molecular weight: 389 45MS:. 390 (M + H +)

[0204] NMR(400MHz, DMS0+D20) δ 8. 83 (d, 1Η) ,8. 59 (d, 1H) ,8. 28 (s, 1H), 7. 91-8. 17 (m, 2H) ,7. 93 (dd, 1H) ,6. 98 (d, 1H) ,5. 11-5. 17 (m, 1H) ,3. 89(s,3H) ,3. 44-3. 46 (m, 5H), 3. 19 (t, 2H), 2. 83-2. 92 (m, 2H), 2. 18 (d, 2H). [0204] NMR (400MHz, DMS0 + D20) δ 8. 83 (d, 1Η), 8. 59 (d, 1H), 8. 28 (s, 1H), 7. 91-8. 17 (m, 2H ), 7. 93 (dd, 1H), 6. 98 (d, 1H), 5. 11-5. 17 (m, 1H), 3. 89 (s, 3H), 3. 44-3. 46 ( m, 5H), 3. 19 (t, 2H), 2. 83-2. 92 (m, 2H), 2. 18 (d, 2H).

[0205] 实施例28-(2-甲氣某吡啶-5-某)-3-甲某-2-氣代-l-「N-「(R)-2-羟某丙酰某1哌啶-4-某1-2,3-二氧眯啤并「4,5-cl喹啉(化合物2)的制各 [0205] Example 28 (2-a-5 a gas) -3 Jiamou -2- -l- gas substituting "N -" (R) -2- hydroxyethyl piperidine 1 a Moubing acid -4- 1-2,3- dioxo a squint and beer "4,5-cl quinoline (compound 2) each made

[0206] [0206]

[0207]将化合物1 (160mg,0· 41mmol)、1_ 轻基苯并三唑(lOOmg,1.lmmol)、1_ (3_ 二甲氛基丙基)_3_乙基碳二亚胺盐酸盐(150mg,0. 8mmol)、三乙胺(360mg)和D-乳酸(72mg, 0. 8mmol),反应液室温搅拌17h,反应液蒸干,过制备液相得产品18mg,产率9. 5%。 [0207] Compound 1 (160mg, 0 · 41mmol), 1_ light benzotriazole (lOOmg, 1.lmmol), 1_ (3_ atmosphere yl-dimethyl propyl) _3_ ethylcarbodiimide hydrochloride (150mg, 0. 8mmol), triethylamine (360mg) and D- lactic acid (72mg, 0. 8mmol), the reaction solution was stirred 17H at room temperature, the reaction solution was evaporated to dryness, 18 mg of the product obtained preparative liquid, yield 9.5 %.

[0208]分子式:C25H27N504 分子量:461. 51MS:462 (M+H+) [0208] Molecular Formula: C25H27N504 molecular weight:. 461 51MS: 462 (M + H +)

[0209]4MMR(d6-DMS0)δ1. 19(2H,m),1. 21 (3H,s),2· 02-2. 07(2H,m),2. 56(1H,m), 2. 87 (1H,m),3. 50 (3H,s),3. 92 (3H,s),4. 16-4. 20 (1H,m),4. 49-4. 57 (2H,m),5. 13 (1H,m), 7. 01 (1H,d),8. 24 (1H,dd),8. 72 (1H,d),8. 79 (1H,d),9. 00 (1H,s),9. 26 (1H,d) · [0209] 4MMR (d6-DMS0) δ1. 19 (2H, m), 1. 21 (3H, s), 2 · 02-2. 07 (2H, m), 2. 56 (1H, m), 2 . 87 (1H, m), 3. 50 (3H, s), 3. 92 (3H, s), 4. 16-4. 20 (1H, m), 4. 49-4. 57 (2H, m ), 5. 13 (1H, m), 7. 01 (1H, d), 8. 24 (1H, dd), 8. 72 (1H, d), 8. 79 (1H, d), 9. 00 (1H, s), 9. 26 (1H, d) ·

[0210] 实施例38- (2-甲氣某吡啶-5-某)-3-甲某-2-氣代-1- (N-羟某乙酰某哌啶-4-某)-2,3-二氧眯啤并「4, 5-cl喹啉(化合物3)的制各 [0210] Example 38- (2-pyridin-5-one in a gas) -3-generation gas Jiamou -2- -1- (N- hydroxyethyl piperidin-4-one in a one-acetyl) -2,3 - Mi-dioxo beer and "4, 5-cl quinoline (compound 3) each made of

[0211] [0211]

[0212] 将化合物1 (130mg0· 33mmol)、1_ 轻基苯并三唑(lOOmg,1.lmmol)、1- (3-二甲氛基丙基)_3_乙基碳二亚胺盐酸盐(120mg,0.63mmol)、三乙胺(350mg)和乙醇酸(50mg, 0. 66mmol),反应液室温搅拌48h,反应液蒸干,过制备液相得产品18mg,产率12. 3%。 [0212] Compound 1 (130mg0 · 33mmol), 1_ light benzotriazole (lOOmg, 1.lmmol), 1- (3- dimethylamino-propyl atmosphere yl) _3_ ethylcarbodiimide hydrochloride (120mg, 0.63mmol), triethylamine (350 mg of) and glycolic acid (50mg, 0. 66mmol), the reaction was stirred at rt for 48h, the reaction solution was evaporated to dryness, 18 mg of preparative liquid product obtained, yield 12.3%.

[0213]分子式:C24H25N504 分子量:447. 49MS:448 (M+H+) [0213] Molecular Formula: C24H25N504 molecular weight:. 447 49MS: 448 (M + H +)

[0214]屮M1R(CDC13) δ 8. 73(s,1H),8. 46(d,1H),8. 25(s,1H),8. 24(s,1H),7. 86(dd, 1H),7· 79-7. 82 (m,1H),6· 92 (d,1H),5· 10 (s,1H),4· 93-4. 95 (m,1H),4· 22-4. 30 (m,2H), 4. 02 (s,3H),3. 79-3. 83 (m,1H),3. 60 (s,3H),3. 20-3. 26 (m,1H),2. 76-2. 92 (m,3H),2. 10 (d, 2H) [0214] Che M1R (CDC13) δ 8. 73 (s, 1H), 8. 46 (d, 1H), 8. 25 (s, 1H), 8. 24 (s, 1H), 7. 86 (dd , 1H), 7 · 79-7. 82 (m, 1H), 6 · 92 (d, 1H), 5 · 10 (s, 1H), 4 · 93-4. 95 (m, 1H), 4 · 22-4. 30 (m, 2H), 4. 02 (s, 3H), 3. 79-3. 83 (m, 1H), 3. 60 (s, 3H), 3. 20-3. 26 ( m, 1H), 2. 76-2. 92 (m, 3H), 2. 10 (d, 2H)

[0215] 实施例48- (2-甲氣某吡啶-5-某)-3-甲某-2-氣代-1- (N-甲氣羰某哌啶-4-某)-2,3-二氧眯啤并「4, 5-cl喹啉(化合物4)的制各 [0215] Example 48- (2-pyridin-5-one in a gas) -3-generation gas Jiamou -2- -1- (N- A gas-carbonyl piperidin-4-one a) 2,3 - Mi-dioxo beer and "4, 5-cl quinoline (compound 4) braking each

[0216] [0216]

[0217]将化合物1 (130mg0. 33mmol)、三乙胺(50mg,0. 5mmol)和氯甲酸甲酯(31.lmg, 0. 33mmol)加入10mL二氯甲烷中,冰浴搅拌2h,反应液蒸干,过制备液相得产品128mg,产率87%。 [0217] Compound 1 (130mg0. 33mmol), triethylamine (50mg, 0. 5mmol) and methyl chloroformate (31.lmg, 0. 33mmol) was added 10mL of methylene chloride, the ice bath was stirred for 2h, the reaction solution evaporated to dryness, 128 mg of the product obtained preparative liquid, yield 87%.

[0218]分子式:C24H25N504 分子量:447. 49MS:448 (M+H+) [0218] Molecular Formula: C24H25N504 molecular weight:. 447 49MS: 448 (M + H +)

[0219]理论值:C,62. 42% ;Η,5· 63% ;N,15. 65%; [0219] Theory: C, 62 42%; Η, 5 · 63%; N, 15 65%;..

[0220] 实测值:C,62. 30 % ;H,5· 78 % ;N,15. 55 % [0220] Found: C, 62 30%; H, 5 · 78%; N, 15 55%..

[0221] 实施例58-(2-甲氣某吡啶-5-某)-3-甲某-2-氣代乙酰某哌啶-4-某)-2,3-二氧眯啤并「4, 5-cl喹啉(化合物5)的制各 [0221] Example 58- (2-pyridin-5-one in a gas) -3 Jiamou -2- gas acetimidoyl piperidin-4-one a) 2,3-dioxo squint and beer "4 , 5-cl quinoline (compound 5) prepared in each

[02221 [02221

[0223]将化合物1 (130mg0. 33mmol)、三乙胺(50mg, 0. 5mmol)和乙酰氯(26mg, 0. 33mmol)加入10mL二氯甲烧中,冰浴搅拌2h,反应液蒸干,过制备液相得产品115mg,产率81%。 [0223] Compound 1 (130mg0. 33mmol), triethylamine (50mg, 0. 5mmol) and acetyl chloride (26mg, 0. 33mmol) was added in 10mL of dichloromethane burning, the ice bath was stirred for 2h, the reaction solution was evaporated to dryness, preparative liquid product obtained 115mg, yield 81%.

[0224]分子式:C24H25N503 分子量:43L49MS:432 (M+H+) [0224] Molecular Formula: C24H25N503 molecular weight: 43L49MS: 432 (M + H +)

[0225]屮M1R(CDC13)δ8. 72(s,1H),8. 48(d,1H),8. 25(s,1H),8. 23(s,1H),7. 86(dd, 1H),7· 81 (dd,1H),6· 93 (d,1H),4· 96-5. 06 (m,2H),4· 07-4. 10 (m,1H),4· 02 (s,3H),3· 60 (s, 3H),3. 25-3. 31 (m,1H),2. 74-2. 76 (m,1H),2. 69-2. 71 (m,2H),2. 16 (s,3H),2. 03-2. 07 (m, 2H) [0225] Che M1R (CDC13) δ8. 72 (s, 1H), 8. 48 (d, 1H), 8. 25 (s, 1H), 8. 23 (s, 1H), 7. 86 (dd, 1H), 7 · 81 (dd, 1H), 6 · 93 (d, 1H), 4 · 96-5. 06 (m, 2H), 4 · 07-4. 10 (m, 1H), 4 · 02 (s, 3H), 3 · 60 (s, 3H), 3. 25-3. 31 (m, 1H), 2. 74-2. 76 (m, 1H), 2. 69-2. 71 (m , 2H), 2. 16 (s, 3H), 2. 03-2. 07 (m, 2H)

[0226]实施例68-(2-甲氣某吡啶-5-某)-3-甲某-2-氣代-l-「5_(2-羟某-丙酰胺某)-4-三氟甲某-吡啶-2-某1-2,3-二氧眯啤并「4, 5-cl喹啉(化合物6)的制各 [0226] Example 68- (2-pyridin-5-one in a gas) -3 Jiamou -2- -l- gas substituting "5_ (a 2-hydroxy - propionamide a) -4-trifluoromethyl a - pyridin-2-1-2,3- dioxo a squint and beer "4, 5-cl quinoline (6 compound) braking each

[0227] [0227]

[0228] 制备方法参照实施例le,投2.88g(lOmmol) 6_溴-4-氯-3-硝基喹啉和2. 49g(lOmmol) 5_ (2_轻基-丙醜胺基)_4_二氣甲基_2_氛基批陡,5mL二乙胺,得广物3. 29g,产率65. 8%。 [0228] Preparation method of Reference Example le, cast 2.88g (lOmmol) 6_-bromo-4-chloro-3-nitroquinoline and 2. 49g (lOmmol) 5_ (2_ light-yl - propan ugly amino) _4 _ two gas atmosphere _2_ methyl group batch steep, 5 mL of diethylamine to give extensive material 3. 29g, yield 65.8%.

[0229] 步骤6-f至6-h8-溴-3-甲基-2-氧代-1-[5-(2-羟基-丙酰胺基)-4_三氟甲基-吡啶-2-基]-2, 3-二氢咪唑并[4, 5-c]喹啉的制备 [0229] Step 6-f to 6-h8- bromo-3-methyl-2-oxo-1- [5- (2-hydroxy - propionamide yl) -4_ trifluoromethyl - pyridin-2 ] -2,3-dihydro-imidazo [4 5-c preparation yl,] quinoline

[0230] [0230]

[0231] 制备方法参照实施例步骤Ι-f至Ι-h,投3. 5g(6. 96mmol) 6-溴-4- [5-(2-羟基-丙酰胺基)_4_二氟甲基-批陡-2-氨基]-3-硝基喹啉,得产物1. 14g,总产率32. 1%。 [0231] Preparation method of Reference Example Step Ι-f to Ι-h, cast 3. 5g (6 96mmol.) 6- Bromo-4- [5- (2-hydroxy - propionamide yl) _4_ difluoromethyl - batch steep -2-amino] -3-nitro-quinoline to give the product 1. 14g, 32.1% overall yield.

[0232] 步骤6-i制备方法参照实施例1-i [0232] Step 6-i with reference to Preparation Example 1-i

[0233] [0233]

[0234] 制备方法参照实施例步骤l_i,投102mg(0. 2mmol)8_溴-3-甲基-2-氧代-1-[5-(2-羟基-丙酰胺基)-4-三氟甲基-吡啶-2-基]-2, 3-二氢咪唑并[4, 5-c]喹啉和46mg(0. 3mmol)2_甲氧基批陡-5-硼酸、8mg双(三苯基磷)二氯化钮(II)和0· 5mL 1MNa2C03,得产物64mg,产率59. 9 %。 [0234] Preparation method of Reference Example Step l_i, cast 102mg (0 2mmol.) 8_-bromo-3-methyl-2-oxo-1- [5- (2-hydroxy - propionamide yl) -4- fluoro-methyl - pyridin-2-yl] -2,3-dihydro-imidazo [4, 5-c] quinoline and 46mg (. 0 3mmol) 2_ batch steep methoxy-5-boronic acid, 8mg bis ( triphenylphosphine) dichloride button (II) and 0 · 5mL 1MNa2C03, to give product 64mg, yield 59.9%.

[0235]分子式:C26H21F3N604 分子量:538· 4SMS:539 (M+H+) [0235] Molecular Formula: C26H21F3N604 molecular weight: 538 · 4SMS: 539 (M + H +)

[0236]理论值:C,57. 99% ;Η,3· 93% ;N,15. 61% ; [0236] Theory: C, 57 99%; Η, 3 · 93%; N, 15 61%;..

[0237]实测值:C,57. 89 % ;Η,3· 99 %;N,15. 55 % ; [0237] Found: C, 57 89%; Η, 3 · 99%; N, 15 55%;..

[0238]实施例78-(2-甲氣某吡啶-5-某)-3-甲某-2-氣代-1-(3,5-二甲某-4-羟某乙氣某环R烷-1-某)-2,3-二氧眯啤并「4, 5-cl喹啉(化合物7)的制各 [0238] Example 78- (2-pyridin-5-one in a gas) -3 Jiamou -2- gas-1- (3,5-dimethoxy-4-hydroxyphenyl person B in a gas of a ring R a-l) -2,3-dioxo-blind beer and "4, 5-cl quinoline (compound 7) each made

[0239] 步骤7-e6-溴-4- (3, 5-二甲基-4-羟基乙氧基环己烷-1-基)-3-硝基喹啉的制备 Preparation [0239] Step 7-e6- bromo-4- (3, 5-dimethyl-4-hydroxy-cyclohexane-1-yl-ethoxy) -3-nitroquinoline

[0240] [0240]

[0241] 制备方法参照实施例步骤Ι-e,投2. 88g(10mmol)6-溴-4-氯-3-硝基喹啉和1. 87g(10mmol) 3, 5-二甲基-4-轻基乙氧基-1-氨基环己烧,5mL三乙胺,得产物2. 82g,产率64. 4%。 [0241] Preparation method of Reference Example Step Ι-e, cast 2. 88g (10mmol) 6- bromo-4-chloro-3-nitroquinoline and 1. 87g (10mmol) 3, 5- dimethyl-4 - light-ethoxy-1-amino cyclohexyl group burned, 5 mL triethylamine, to give product 2. 82g, yield 64.4%.

[0242] 步骤7-f至7-h8-溴-3-甲基-2-氧代-1-(3, 5-二甲基-4-羟基乙氧基环己烷-1-基)-2, 3-二氢咪唑并[4, 5-c]喹啉的制备 [0242] Step 7-f to 7-h8- bromo-3-methyl-2-oxo-1- (3, 5-dimethyl-4-hydroxy-cyclohexane-1-yl-ethoxy) - 2, 3-dihydro-imidazo [4 5-c,] quinoline

[0243] [0243]

[0244] 制备方法参照实施例步骤l_f至1-h,投3.lg(6. 96mmol)6_溴-4-(3,5-二甲基-4-羟基乙氧基环己烷-1-基)-3-硝基喹啉,得产物1. 43g,总产率45. 9%。 [0244] Reference Example prepared through the steps l_f 1-h, cast 3.lg (6. 96mmol) 6_ bromo-4- (3,5-dimethyl-4-hydroxyethoxy cyclohexane -1 - yl) -3-nitro-quinoline to give the product 1. 43g, 45.9% overall yield.

[0245] 步骤7-i化合物7的制备 Preparation [0245] Step 7-i Compound 7

[0246] [0246]

[0247] 制备方法参照实施例步骤l_i,投89mg(0.2mmol)8-溴-3-甲基-2-氧代-l-(3,5-二甲基-4-羟基乙氧基环己烷-1-基)-2,3_二氢咪唑并[4,5-c]喹啉和46mg(0. 3mmol)2_甲氧基批陡-5-硼酸、8mg双(三苯基磷)二氯化钮(II)和0· 5mL1M Na2C03,得产物69mg,产率72. 6 %。 [0247] Preparation method of Reference Example Step l_i, cast 89mg (0.2mmol) 8- bromo-3-methyl-2-oxo--l- (3,5- dimethyl-4-cyclohexyl-hydroxyethoxy 1-yl) -2,3_ dihydro-imidazo [4,5-c] quinoline and 46mg (0. 3mmol) 2_ batch steep methoxy-5-boronic acid, 8mg bis (triphenylphosphine ) button dichloride (II) and 0 · 5mL1M Na2C03, to give product 69mg, yield 72.6%.

[0248]分子式:C27H32N404 分子量:476. 57MS:477 (M+H+) [0248] Molecular Formula: C27H32N404 molecular weight:. 476 57MS: 477 (M + H +)

[0249]理论值:C,68. 05% ;Η,5· 77% ;N,11. 76%; [0249] Theory: C, 68 05%; Η, 5 · 77%; N, 11 76%;..

[0250]实测值:C,67. 98%;H,5· 86%;N,11· 70% [0250] Found: C, 67 98%; H, 5 · 86%; N, 11 · 70%.

[0251] 实施例88-(2-甲某吡啶-5-某)-3-甲某-2-氣代-1-「N_「(R)-2-羟某丙酰某1 哌啶-4-某1-23-二氧眯啤并「4, 5-cl喹啉(化合物8)的制各 [0251] Example 88 (2-5 Jiamou a) -3 Jiamou -2- gas-1- "N _ '(R) -2- hydroxypropyl Moubing acid piperidin-4-one 1 - a blind 1-23- dioxo beer and "4, 5-cl quinoline (compound 8) each manufactured by

[0252] 参照实施例1和2可制得化合物8。 [0252] Reference Example 1 and 2 can be prepared compound 8.

[0253] [0253]

[0254] 制备方法参照实施例Ι-i,投86mg(0. 2mmol)8-溴-3-甲基-2-氧代-l-[N-[(R)-2-羟基丙酰基]哌啶-4-基]-2,3-二氢咪唑并[4,5-c]喹啉, 41mg(0. 3mmol)2-甲基吡啶-5-硼酸,得白色固体产物72mg,产率81. 2%。 [0254] Preparation method of Reference Example Ι-i, administered 86mg (0 2mmol.) 8- bromo-3-methyl-2-oxo -l- [N - [(R) -2- hydroxy-propionyl] piperidine 4-yl] -2,3-dihydro-imidazo [4,5-c] quinoline, 41mg (0. 3mmol) 2- methyl-5-boronic acid, 72 mg of product as a white solid, yield 81 . 2%.

[0255]分子式:C25H27N503 分子量:445. 51MS:446 (M+H+) [0255] Molecular Formula: C25H27N503 molecular weight: 445 51MS:. 446 (M + H +)

[0256]理论值:C,67. 40% ;Η,6· 11% ;N,15. 72% ; [0256] Theory: C, 67 40%; Η, 6 · 11%; N, 15 72%;..

[0257]实测值:C,67. 32% ;H,6·17% ;N,15. 66% [0257] Found: C, 67 32%; H, 6 · 17%; N, 15 66%..

[0258] 实施例98- (2-甲某吡啶-5-某)-3-甲某-2-氣代-1- (N-羟某乙酰某哌啶-4-某)-2,3-二氧眯啤并「4, 5-cl喹啉(化合物9)的制各 [0258] Example 98- (2 Jiamou-5-one) -3-generation gas Jiamou -2- -1- (N- hydroxyethyl piperidin-4-one in a one-acetyl) -2,3- Mi-dioxo beer and "4, 5-cl quinoline (compound 9) prepared in each of

[0259] 参照实施例1和2可制得化合物9。 [0259] Reference Example 1 and 2 can be prepared compound 9.

[0260] [0260]

[0261] 制备方法参照实施例Ι-i,投84mg(0. 2mmol)8-溴-3-甲基-2-氧代-1-(N-羟基乙酰基哌啶-4-基)-2, 3-二氢咪唑并[4, 5-c]喹啉,41mg(0. 3mmol) 2-甲基吡啶-5-硼酸, 得白色固体产物72mg,产率83. 4%。 [0261] Preparation method of Reference Example Ι-i, administered 84mg (0. 2mmol) 8- bromo-3-methyl-2-oxo -1- (N- hydroxyacetyl piperidin-4-yl) -2 , 3-dihydro-imidazo [4, 5-c] quinoline, 41mg (0. 3mmol) 2- methyl-5-boronic acid, 72 mg of product as a white solid, a yield of 83.4%.

[0262]分子式:C24H25N503 分子量:4:31· 4_S:432 (M+H+) [0262] Molecular Formula: C24H25N503 molecular weight: 4: 31 · 4_S: 432 (M + H +)

[0263]理论值:C,66. 81% ;Η,5· 84% ;0,16. 23% ; [0263] Theory: C, 66 81%; Η, 5 · 84%; 0,16 23%;..

[0264]实测值:C,66. 74% ;Η,5· 88% ;0,16. 20% [0264] Found: C, 66 74%; Η, 5 · 88%; 0,16 20%..

[0265]实施例108-(2-甲某吡啶-5-某)-3-甲某-2-氣代-1_(N-甲氣羰某哌啶-4-某)-2,3-二氧眯啤并「4, 5-cl喹啉(化合物10)的制各 [0265] Example 108- (2-Jiamou-5-one) -3-generation gas Jiamou -2- -1_ (N- A gas-carbonyl piperidin-4-one a) 2,3- Mi oxygen and beer "4, 5-cl quinoline (compound 10) is prepared for each

[0266] 参照实施例1和2可制得化合物10。 [0266] Reference Example 1 and 2 can be prepared compound 10.

[02671 [02671

[0268] 制备方法参照实施例Ι-i,投84mg(0. 2mmol)8-溴-3-甲基-2-氧代-1-(N-甲氧羰基哌啶-4-基)-2,3_二氢咪唑并[4,5-c]喹啉,41mg(0. 3mmol)2-甲基吡啶-5-硼酸,得灰白色固体产物74mg,产率85. 7%。 [0268] Preparation method of Reference Example Ι-i, administered 84mg (0. 2mmol) 8- bromo-3-methyl-2-oxo -1- (N- methoxycarbonyl-4-yl) -2 , 3_-dihydro-imidazo [4,5-c] quinoline, 41mg (0. 3mmol) 2- methyl-5-boronic acid to give 74 mg of an off-white solid product, a yield of 85.7%.

[0269]分子式:C24H25N503 分子量:431. 49MS:432 (M+H+) [0269] Molecular Formula: C24H25N503 molecular weight:. 431 49MS: 432 (M + H +)

[0270]理论值:C,66. 81% ;Η,5· 84% ;0,16. 23% ; [0270] Theory: C, 66 81%; Η, 5 · 84%; 0,16 23%;..

[0271]实测值:C,66. 70% ;Η,5· 92% ;0,16. 16% [0271] Found: C, 66 70%; Η, 5 · 92%; 0,16 16%..

[0272]实施例118-(2-甲某吡啶-5-某)-3-甲某-2-氧,代乙酰某哌啶-4-某)-2, 3-二氧眯啤并「4, 5-cl喹啉(化合物11)的制各 Example 118- [0272] (2-Jiamou-5-one) -3-oxo Jiamou, an acetimidoyl piperidin-4-one) -2,3-dioxo-blind and beer "4 , 5-cl quinoline (compound 11) is prepared for each

[0273] 参照实施例1和2可制得化合物11。 [0273] Reference Example 1 and 2 can be prepared compound 11.

[0274] [0274]

[0275] 制备方法参照实施例Ι-i,投81mg(0. 2mmol)8-溴-3-甲基-2-氧代-1-(N-乙酰基哌啶-4-基)-2,3_二氢咪唑并[4,5-c]喹啉,41mg(0. 3mmol)2-甲基吡啶-5-硼酸,得白色固体产物75mg,产率89. 6%。 [0275] Preparation method of Reference Example Ι-i, administered 81mg (0. 2mmol) 8- bromo-3-methyl-2-oxo -1- (N- acetyl-piperidin-4-yl) -2, 3_ dihydro-imidazo [4,5-c] quinoline, 41mg (0. 3mmol) 2- methyl-5-boronic acid as a white solid product 75mg, yield 89.6%.

[0276]分子式:C24H25N502 分子量:415. 4_S:416 (M+H+) [0276] Molecular Formula: C24H25N502 molecular weight: 415 4_S:. 416 (M + H +)

[0277]理论值:C,69. 38% ;H,6. 06% ;N,16. 86% ; [0277] Theory: C, 69 38%; H, 6 06%; N, 16 86%;...

[0278]实测值:C,69. 32% ;H,6· 12% ;N,16. 80% [0278] Found: C, 69 32%; H, 6 · 12%; N, 16 80%..

[0279]实施例128-(2-甲基吡啶-5-基)-3-甲基-2-氧代-1-(哌啶-4-基)-2,3-二氡咪唑并「4, 5-cl喹啉(化合物12)的制备 [0279] Example 128- (2-Methyl-5-yl) -3-methyl-2-oxo-1- (piperidin-4-yl) -2,3-imidazo radon "4 preparation 5-cl quinoline (compound 12)

[0280] 参照实施例1可制得化合物12。 [0280] Reference Example 12 Compound 1 can be prepared.

[0281] [0281]

[0282] 制备方法参照实施例l_j,投4. 74g(10mm〇l)8-(2-甲基吡啶-5-基)-3-甲基-2-氧代-1-(N-叔丁氧羰基-哌啶-4-基)-2, 3-二氢咪唑并[4, 5-c]喹啉,得产物3. 61g,产率96. 7%。 [0282] Preparation method of Reference Example l_j, cast 4. 74g (10mm〇l) 8- (2-methyl-5-yl) -3-methyl-2-oxo -1- (N- tert oxycarbonyl - piperidin-4-yl) -2,3-dihydro-imidazo [4, 5-c] quinoline to give the product 3. 61g, yield 96.7%.

[0283] 分子式:C22H23N50分子量:373. 45MS:374 (M+H+) [0283] Molecular Formula: C22H23N50 molecular weight:. 373 45MS: 374 (M + H +)

[0284] 理论值:C,70. 76% ;Η,6· 21% ;N,18. 75% ; [0284] Theory: C, 70 76%; Η, 6 · 21%; N, 18 75%;..

[0285] 实测值:C,70. 71% ;Η,6· 28% ;N,18. 70% [0285] Found: C, 70 71%; Η, 6 · 28%; N, 18 70%..

[0286]实施例138-(2-甲某吡啶-5-某)-3-甲某-2-氣代-1_「5-(2-羟某-丙酰胺某)-4-三氟甲某-吡啶-2-某1-2,3-二氧眯啤并「4, 5-cl喹啉(化合物13)的制各 [0286] Example 138- (2-5 Jiamou a) -3 Jiamou -2- -1_ gas substituting "5- (2-hydroxy a - propionamide a) -4-trifluoromethyl Jiamou - a 1-2,3- dioxo-pyridin-2-blind beer and "4, 5-cl quinoline (compound 13) is prepared for each

[0287] 参照实施例6可制得化合物13。 [0287] Reference Example 6 Compound 13 can be prepared.

[02881 [02881

[0289] 制备方法参照实施例Ι-i,投102mg(0· 2mmol) 8-溴-3-甲基-2-氧代-1-[5- (2-羟基-丙酰胺基)-4_三氟甲基-吡啶-2-基]-2,3-二氢咪唑并[4,5-c]喹啉, 41mg(0. 3mmol)2-甲基吡啶-5-硼酸,得灰色固体产物83mg,产率79. 1%。 [0289] Preparation method of Reference Example Ι-i, cast 102mg (0 · 2mmol) 8- bromo-3-methyl-2-oxo-1- [5- (2-hydroxy - propionamide yl) -4_ trifluoromethyl - pyridin-2-yl] -2,3-dihydro-imidazo [4,5-c] quinoline, 41mg (. 0 3mmol) 2- methyl-5-boronic acid to give a gray solid product 83mg, yield 79.1%.

[0290] 分子式:C26H21F3N603分子量:522· 4MS:523(M+H+) [0290] Molecular Formula: C26H21F3N603 molecular weight: 522 · 4MS: 523 (M + H +)

[0291] 理论值:C,59. 77% ;Η,4· 05% ;N,16. 08% ; [0291] Theory: C, 59 77%; Η, 4 · 05%; N, 16 08%;..

[0292] 实测值:C,59. 73% ;H,4· 09% ;N,16. 02 % [0292] Found: C, 59 73%; H, 4 · 09%; N, 16 02%..

[0293] 实施例148-(2-甲某吡啶-5-某)-3-甲某2-氣代-1-(3,5-二甲某-4-羟某乙氣某环己烷-l-某)-2,3-二氧眯啤并「4, 5-cl喹啉(化合物14)的制各 [0293] Example 148- (2-a-5 Jiamou) -3- 2- Jiamou gas-1- (3,5-dimethoxy-4-hydroxyphenyl person B in a gas of a cyclohexane - l- a) 2,3-dioxo squint beer and "4, 5-cl quinoline (compound 14) is prepared for each

[0294] 参照实施例7可制得化合物14。 [0294] Reference Example 7 Compound 14 can be prepared.

[0295] [0295]

[0296] 制备方法参照实施例1-i,投81mg(0. 2mmol)8-溴-3-甲基-2-氧代-l-(3,5-二甲基-4-轻基乙氧基环己烧-1-基)-2,3-二氢咪唑并[4,5_c]喹啉,41mg(0. 3mmol)2_甲基吡啶-5-硼酸,得白色固体产物69mg,产率75. 1 %。 [0296] Preparation method of Reference Example 1-i, administered 81mg (0. 2mmol) 8- bromo-3-methyl-2-oxo--l- (3,5- dimethyl-4-yl-ethoxy light cyclohexyl burn-yl) -2,3-dihydro-imidazo [4,5_c] quinoline, 41mg (0. 3mmol) 2_ methylpyridine-5-boronic acid, 69 mg of product as a white solid, yield 75.1%.

[0297]分子式:C27H32N403 分子量:460. 57MS:461 (M+H+) [0297] Molecular Formula: C27H32N403 molecular weight:. 460 57MS: 461 (M + H +)

[0298]理论值:C,70. 41% ;Η,7· 00% ;N,12. 16%; [0298] Theory: C, 70 41%; Η, 7 · 00%; N, 12 16%;..

[0299]实测值:C,70. 35 % ;H,7· 10%;N,12. 10% [0299] Found: C, 70 35%; H, 7 · 10%; N, 12 10%..

[0300]实施例158-「1H-吡啤并「3,4-bl卩比啶-5-某1-3-甲某-2-氣代-l-「N-「(R)-2-羟某丙酰某1哌啶-4-某1-2,3-二氧眯啤并「4, 5-cl喹啉(化合物15)的制各 [0300] Example 158- "1H- pyrazol beer and" 3,4-bl Jie than a certain gas substituting 1-3- Jiamou -2- piperidine -5- -l- "N -" (R) -2- a hydroxyl acid 1 Moubing a 1-2,3- dioxo-piperidin-4 Mi beer and "4, 5-cl quinoline (compound 15) is prepared for each

[0301] 参照实施例1和2可制得化合物15。 [0301] Reference Example 1 and 2 can be prepared compound 15.

[0302] [0302]

[0303]将86mg(0· 2mmol) 8-溴-3-甲基-2-氧代-1- [N-[(R) -2-羟基丙酰基]哌啶-4-基]_2,3-二氢咪唑并[4,5-(:]喹啉溶于21111^1^中,加入75.911^(0.3臟〇1)1-苄基-1H-吡唑并[3,4-b]吡啶-5-硼酸,8mg双(三苯基磷)二氯化钯(II)和0.5mL1M Na2C03,加热到100°C搅拌1小时,反应混合物用NaHC03饱和水溶液淬灭,用乙酸乙酯萃取两次,有机层用饱和食盐水洗,经无水硫酸钠干燥,过滤并减压蒸干,残余物用硅胶柱柱层析纯化,得到白色固体,然后将该固体溶于10mL甲醇,加入50mgPd/C,l滴甲酸,通入氢气,室温搅拌5h,过滤收集滤液,减压蒸干,得固体产品76. 5mg,收率81 %。 [0303] The 86mg (0 · 2mmol) 8- bromo-3-methyl-2-oxo -1- [N - [(R) -2- hydroxy-propionyl] piperidin-4-yl] _2,3 - dihydro-imidazo [4,5 - (:] quinoline was dissolved in 1 ^ 21111 ^ added 75.911 ^ (dirty 〇1 0.3) 1-benzyl--1H- pyrazolo [3,4-b] pyridine 5-boronic acid, 8mg bis (triphenylphosphine) palladium (II) dichloride and 0.5mL1M Na2C03, heated to 100 ° C stirred for 1 hour, reaction mixture was quenched with saturated aqueous NaHC03, twice extracted with ethyl acetate the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure, the residue was purified by silica gel column to give a white solid, solid was dissolved in 10mL of methanol was then added 50mgPd / C, l drops of formic acid hydrogen was stirred at room temperature 5h, the filtrate was collected by filtration, evaporated to dryness under reduced pressure to give the solid product 76. 5mg, yield 81%.

[0304]分子式:C25H25N703 分子量:471. 51MS:472 (M+H+) [0304] Molecular Formula: C25H25N703 molecular weight:. 471 51MS: 472 (M + H +)

[0305]理论值:C,63. 68% ;Η,5· 34% ;Ν,20· 79%; [0305] Theory: C, 63 68%; Η, 5 · 34%; Ν, 20 · 79%;.

[0306]实测值:C,63. 61% ;Η,5· 38% ;Ν,20· 74% [0306] Found: C, 63 61%; Η, 5 · 38%; Ν, 20 · 74%.

[0307]实施例168-「1Η_吡啤并「3,4-bl吡啶-5-某1-3-甲某-2-氣代羟某乙酰某哌啶-4-某)-2,3-二氧眯啤并「4, 5-cl喹啉(化合物16)的制各 [0307] Example 168- "1Η_ pyrazol embodiment beer and" 3,4-bl pyridine-5-a-hydroxyacid 1-3- Jiamou a gas -2- piperidin-4-acetyl-a a) 2,3 - Mi-dioxo beer and "4, 5-cl quinoline (compound 16) is prepared for each

[0308] 参照实施例1和2可制得化合物16。 [0308] Reference Example 1 and 2 can be prepared compound 16.

[0309] [0309]

[0310] 制备方法参照实施例15,投84mg(0. 2mmol)8-溴-3-甲基-2-氧代-1-(N-羟基乙酰基哌啶-4-基)-2, 3-二氢咪唑并[4, 5-c]喹啉,75. 9mg(0. 3mmol) 1-苄基-1H-吡唑并[3,4-b]吡啶-5-硼酸,得白色固体产物71mg,产率78. 0%。 [0310] Preparation method of Reference Example 15, administered 84mg (0. 2mmol) 8- bromo-3-methyl-2-oxo -1- (N- hydroxyacetyl piperidin-4-yl) -2, 3 - dihydro-imidazo [4, 5-c] quinoline, 75 9mg (0 3mmol.) 1- benzyl -1H- pyrazolo [3,4-b] pyridine-5-boronic acid to give the product as a white solid. 71mg, yield 78.0%.

[0311] 分子式:C24H23N703 分子量:457. 48MS:458 (M+H+) [0311] Molecular Formula: C24H23N703 molecular weight: 457 48MS:. 458 (M + H +)

[0312] 理论值:C,63. 01% ;Η,5· 07% ;Ν,21· 43% ; [0312] Theoretical value: C, 63 01%; Η, 5 · 07%; Ν, 21 · 43%;.

[0313] 实测值:C,62. 96% ;Η,5· 18% ;Ν,21· 37% [0313] Found: C, 62 96%; Η, 5 · 18%; Ν, 21 · 37%.

[0314] 实施例178-「1Η-吡啤并「3,4-bl吡啶-5-某1-3-甲某-2-氣代甲氣羰某哌啶-4-某)-2,3-二氧眯啤并「4, 5-cl喹啉(化合物17)的制各 [0314] Example 178- "1Η- pyrazol embodiment beer and" a 3,4-bl pyridine-5-carboxylic substituting 1-3- Jiamou -2- gas air-carbonyl piperidin-4-one a) 2,3 - Mi-dioxo beer and "4, 5-cl quinoline (compound 17) is prepared for each

[0315] 参照实施例1和2可制得化合物17。 [0315] Reference Example 1 and 2 can be prepared compound 17.

[0316] [0316]

[0317] 制备方法参照实施例15,投84mg(0. 2mmol)8-溴-3-甲基-2-氧代-1-(N-甲氧羰基哌啶-4-基)-2,3_二氢咪唑并[4,5-c]喹啉,75.9mg(0.3mmol)l-苄基-1H-吡唑并[3, 4_b]吡啶-5-硼酸,得白色固体产物74mg,产率81. 3%。 [0317] Preparation method of Reference Example 15, administered 84mg (0. 2mmol) 8- bromo-3-methyl-2-oxo -1- (N- methoxycarbonyl-4-yl) -2,3 _-dihydro-imidazo [4,5-c] quinoline, 75.9mg (0.3mmol) l- benzyl -1H- pyrazolo [3, 4_b] pyridine-5-boronic acid, 74 mg of product as a white solid, yield 81.3%.

[0318] 分子式:C24H23N703 分子量:457. 48MS:458 (M+H+) [0318] Molecular Formula: C24H23N703 molecular weight: 457 48MS:. 458 (M + H +)

[0319] 理论值:C,63. 01% ;Η,5· 07% ;Ν,21· 43% ; [0319] Theoretical value: C, 63 01%; Η, 5 · 07%; Ν, 21 · 43%;.

[0320] 实测值:C,62. 95% ;Η,5· 12% ;Ν,21· 36% [0320] Found: C, 62 95%; Η, 5 · 12%; Ν, 21 · 36%.

[0321] 实施例188-「1Η_吡啤并「3,4-bl吡啶-5-某1-3-甲某-2-氣代乙酰某哌啶-4-某)-2,3-二氧眯啤并「4, 5-cl喹啉(化合物18)的制各 [0321] Example 188 "1Η_ pyrazol embodiment beer and" a 3,4-bl pyridine-5-1-3- Jiamou -2- gas acetimidoyl piperidin-4-one a) 2,3- Mi oxygen and beer "4, 5-cl quinoline (compound 18) is prepared for each

[0322] 参照实施例1和2可制得化合物18。 [0322] Reference Example 1 and 2 can be prepared compound 18.

[0323] [0323]

[0324] 制备方法参照实施例15,投81mg(0. 2mmol)8-溴-3-甲基-2-氧代-1-(N-乙酰基哌啶-4-基)-2,3_二氢咪唑并[4,5-c]喹啉,75.9mg(0.3mmol)l-苄基-1H-吡唑并[3, 4_b]吡啶-5-硼酸,得白色固体产物76mg,产率85. 7%。 [0324] Preparation method of Reference Example 15, administered 81mg (0. 2mmol) 8- bromo-3-methyl-2-oxo -1- (N- acetyl-piperidin-4-yl) -2,3_ dihydro-imidazo [4,5-c] quinoline, 75.9mg (0.3mmol) l- benzyl -1H- pyrazolo [3, 4_b] pyridine-5-boronic acid to give the product as a white solid 76 mg, yield 85 7%.

[0325] 分子式:C24H23N702 分子量:441. 49MS:442 (M+H+) [0325] Molecular Formula: C24H23N702 molecular weight: 441 49MS:. 442 (M + H +)

[0326] 理论值:C,65. 29% ;Η,5· 25% ;Ν,22· 21% ; [0326] Theory: C, 65 29%; Η, 5 · 25%; Ν, 22 · 21%;.

[0327] 实测值:C,65. 23% ;Η,5· 34% ;Ν,22· 15% [0327] Found: C, 65 23%; Η, 5 · 34%; Ν, 22 · 15%.

[0328] 实施例198-「1Η_吡啤并「3,4-bl吡啶-5-某1-3-甲某-2-氣代-1-(哌啶-4-某)-2,3-二氧眯啤并「4, 5-cl喹啉(化合物19)的制各 [0328] Example 198- "1Η_ pyrazol embodiment beer and" a 3,4-bl pyridine-5-1-3- Jiamou -2- gas-1- (piperidin-4-one) -2,3 - dioxo blind beer and "4, 5-cl quinoline (compound 19) is prepared for each

[0329] 参照实施例1和2可制得化合物19。 [0329] Reference Example 1 and 2 can be prepared compound 19.

[0330] ] [0330]]

[0331] 制备方法参照实施例15,投92mg(0. 2mmol)8-溴-3-甲基-2-氧代-1-(N-叔丁氧羰基-哌啶-4-基)-2, 3-二氢咪唑并[4, 5-c]喹啉,75. 9mg(0. 3mmol) 1-苄基-1H-吡唑并[3,4-b]批啶-5-硼酸,得白色固体中间产物88mg,产率88. 6%。 [0331] Preparation method of Reference Example 15, administered 92mg (0 2mmol.) 8- bromo-3-methyl-2-oxo -1- (N- tert-butoxycarbonyl group - piperidin-4-yl) -2 , 3-dihydro-imidazo [4, 5-c] quinoline, 75. 9mg (0. 3mmol) 1- benzyl--1H- pyrazolo [3,4-b] pyridine batch 5-boronic acid to give intermediate white solid product 88mg, yield 88.6%. 该中间产物投入5mL二氯甲烷中,加lmLTFA,室温搅拌lh,减压蒸干溶剂,得黄色固体68mg,两步总收率85. 5%。 The intermediate product was put into 5mL of dichloromethane, was added lmLTFA, LH stirring at room temperature, solvent was evaporated under reduced pressure to give 68 mg of a yellow solid, 85.5% yield over two steps.

[0332] 分子式:C22H21N70 分子量:399. 45MS:400 (M+H+) [0332] Molecular Formula: C22H21N70 molecular weight:. 399 45MS: 400 (M + H +)

[0333] 理论值:C,66. 15% ;Η,5· 30% ;Ν,24· 55% ; [0333] Theory: C, 66 15%; Η, 5 · 30%; Ν, 24 · 55%;.

[0334] 实测值:C,66. 10 % ;Η,5· 36 % ;Ν,24. 50 % [0334] Found: C, 66 10%; Η, 5 · 36%; Ν, 24 50%..

[0335] 实施例208-「1Η_吡啤并「3. 4-bl吡啶-5-某1-3-甲某-2-氣代-1-「5_(2-羟某-丙酰胺某)-4-三氟甲某-吡啶-2-某1-2,3-二氧眯啤并「4, 5-cl喹啉(化合物20) 的制各 [0335] 208- "1Η_ pyrazole Example beer and" 3. 4-bl pyridine-5-one-1- 1-3- Jiamou -2- gas "5_ (a 2-hydroxy - propionamide a) Jiamou -4-trifluoromethyl - pyridin-2-one 1-2,3- dioxo Mi beer and "4, 5-cl quinoline (compound 20) is prepared for each

[0336] 参照实施例6可制得化合物20。 [0336] Reference Example 6 Compound 20 can be prepared.

[0337] [0337]

[0338] 制备方法参照实施例15,投102mg(0. 2mmol)8-溴-3-甲基-2-氧代-l-[5-(2-羟基-丙酰胺基)-4_三氟甲基-吡啶-2-基]-2,3-二氢咪唑并[4,5-c]喹啉, 75. 9mg(0. 3mmol) 1-苄基-1H-吡唑并[3,4-b]吡啶-5-硼酸,得黄色固体产物80mg,产率73. 4%。 [0338] Preparation method of Reference Example 15, administered 102mg (0 2mmol.) 8- bromo-3-methyl-2-oxo -l- [5- (2- hydroxy - propionamide yl) trifluoroacetic -4_ methyl - pyridin-2-yl] -2,3-dihydro-imidazo [4,5-c] quinoline, 75. 9mg (. 0 3mmol) 1- benzyl--1H- pyrazolo [3,4- -b] pyridine 5-boronic acid to give a yellow solid product 80mg, yield 73.4%.

[0339]分子式:C26H19F3N803 分子量:548. 48MS:549 (M+H+) [0339] Molecular Formula: C26H19F3N803 molecular weight:. 548 48MS: 549 (M + H +)

[0340]理论值:C,56. 94% ;Η,3· 49% ;Ν,20· 43% ; [0340] Theory: C, 56 94%; Η, 3 · 49%; Ν, 20 · 43%;.

[0341]实测值:C,56. 90 % ;Η,3· 55 % ;Ν,20. 37 % [0341] I Found: C, 56 90%; Η, 3 · 55%; Ν, 20 37%..

[0342]实施例218-「1Η-吡啤并「3,4-bl批啶-5-某1-3-甲某-2-氣代-1-(3,5-二甲某-4-羟某乙氣某环己烷-1-某)-2,3-二氧眯啤并「4, 5-cl喹啉(化合物21)的制各 [0342] Example 218- "1Η- pyrazol beer and" 3,4-bl-5-one batch gas-1- 1-3- Jiamou -2- (3,5 particular -4- a cyclohexane-l-hydroxyethyl gas person B a) 2,3-dioxo squint beer and "4, 5-cl quinoline (compound 21) is prepared for each

[0343] 参照实施例7可制得化合物21。 [0343] Reference Example 7 Compound 21 can be prepared.

[0344] [0344]

[0345] 制备方法参照实施例15,投90mg(0. 2mmol)8-溴-3-甲基-2-氧代-1-(3,5-二甲基-4-羟基乙氧基环己烷-1-基)-2,3_二氢咪唑并[4,5-c]喹啉,75. 9mg(0. 3mmol)l-苄基-1!1-吡唑并[3,4-13]吡啶-5-硼酸,得黄色固体产物7511^,产率76.6%。 [0345] Preparation method of Reference Example 15, administered 90mg (0. 2mmol) 8- bromo-3-methyl-2-oxo-1- (3,5-dimethyl-4-cyclohexyl-hydroxyethoxy 1-yl) -2,3_ dihydro-imidazo [4,5-c] quinoline, 75. 9mg (0. 3mmol) l- benzyl-1! 1- pyrazolo [3,4- 13] pyridine-5-boronic acid to give the product as a yellow solid ^ 7511, a yield of 76.6%.

[0346]分子式:C27H3(iN603 分子量:486. 57MS:487 (M+H+) [0346] Molecular Formula: C27H3 (iN603 molecular weight: 486 57MS:. 487 (M + H +)

[0347]理论值:C,66. 65% ;Η,6· 21% ;N,17. 27% ; [0347] Theory: C, 66 65%; Η, 6 · 21%; N, 17 27%;..

[0348]实测值:C,66. 61% ;Η,6· 26% ;N,17. 22% [0348] Found: C, 66 61%; Η, 6 · 26%; N, 17 22%..

[0349]实施例22(S)-1-(1_(2-羟某丙酰某)哌啶-4-某)-8-(6-甲氣某吡啶-3-某)-3-甲某-1H-眯啤并「4, 5-cl喹啉-2 (3H)-酮(化合物22)的制各 [0349] Example 22 (S) -1- (1_ (2- hydroxyethyl Moubing acid a) piperidin-4-a) -8- (6-a-3 a gas) -3- Jiamou -1H- blind beer and "4, 5-cl quinoline -2 (3H) - one (compound 22) is prepared for each

[0350] [0350]

[0351]将化合物1 (200mg,0· 5mmol)、1_ 轻基苯并三唑(200mg,2. 2mmol)、1_(3_ 二甲氛基丙基)_3_乙基碳二亚胺盐酸盐(230mg,1.2mmol)、三乙胺(300mg,2.9mmol)和L-乳酸(250mg,2. 8mmol)加入20mL二氯甲烧中,反应液室温搅拌17h,反应液蒸干,过制备液相得产品19mg,产率8. 3%。 [0351] Compound 1 (200mg, 0 · 5mmol), 1_ light benzotriazole (200mg, 2. 2mmol), 1_ (3_ atmosphere yl-dimethyl propyl) _3_ ethylcarbodiimide hydrochloride (230mg, 1.2mmol), triethylamine (300mg, 2.9mmol) and L- lactic acid (250mg, 2. 8mmol) was added in 20mL of dichloromethane burning, 17H reaction was stirred at room temperature, the reaction solution was evaporated to dryness, preparative liquid to give product 19mg, yield 8.3%.

[0352]分子式:C25H27N504 分子量:461. 51MS :462 (M+H+) [0352] Molecular Formula: C25H27N504 molecular weight:. 461 51MS: 462 (M + H +)

[0353]屮MMR(d6-DMS0) δ 8. 87(s,1H),8. 67(s,1H),8. 35(s,1H),8. 17(d,1H),8. 12(d, 1H),7· 93 (d,1H),7· 01 (d,1H),5· 15 (s,1H),4· 93-4. 98 (m,1H),4· 50-4. 62 (m,2H),4· 21 (s, 1H),3. 93 (s,3H),3. 49 (s,3H),3. 29-3. 35 (m,2H),2. 87-2. 92 (m,1H),2. 63-2. 66 (m,1H), 2. 03-2. 05(m,2H),l. 21(d,3H) [0353] Che MMR (d6-DMS0) δ 8. 87 (s, 1H), 8. 67 (s, 1H), 8. 35 (s, 1H), 8. 17 (d, 1H), 8. 12 (d, 1H), 7 · 93 (d, 1H), 7 · 01 (d, 1H), 5 · 15 (s, 1H), 4 · 93-4. 98 (m, 1H), 4 · 50- 4. 62 (m, 2H), 4 · 21 (s, 1H), 3. 93 (s, 3H), 3. 49 (s, 3H), 3. 29-3. 35 (m, 2H), 2 . 87-2. 92 (m, 1H), 2. 63-2. 66 (m, 1H), 2. 03-2. 05 (m, 2H), l. 21 (d, 3H)

[0354]实施例232-(4-(8-(6-甲氣某吡啶-3-某)-3-甲某-2-氣代-2,3-二氧-1H-眯啤并「4, 5-cl喹啉-1-某)哌啶-1-某)乙酰胺(化合物23)的制各 [0354] Example 232- embodiment (4- (8- (6-a-3 a gas) -3 Jiamou -2- gas -1H- 2,3-dioxo squint and beer "4 , 5-cl quinoline-1-a) piperidin-1-a) acetamide (compound 23) is prepared for each

[0355] [0355]

[0356] 将化合物1(13011^,0.33臟〇1),三乙胺0.31^,2-碘乙酰胺(1.848 10臟〇1)加入到20mL乙腈中,加热至回流,搅拌2h,反应完毕用水和二氯甲烷的混合液萃取,干燥有机相, 过制备液相得产品27mg,收率:18. 4%。 [0356] Compound 1 (13011 ^, dirty 〇1 0.33), 0.31 ^ triethylamine, 2-iodoacetamide (1.848 dirty 〇1 10) was added to 20mL of acetonitrile, heated to reflux, stirred for 2h, the reaction is completed water and the mixture was extracted with dichloromethane, the organic phase was dried, 27 mg of preparative liquid product obtained, yield: 184%.

[0357]分子式:C24H26N603 分子量:447. 49MS :448 (M+H+) [0357] Molecular Formula: C24H26N603 molecular weight:. 447 49MS: 448 (M + H +)

[0358]屮MMR(400MHz,DMS0) δ 8. 89(s,1H),8. 68(d,1H),8· 41-8. 52(m,1H),8. 22(d, 1H),8· 12(d,1H),7· 95(d,1H),7· 12-7. 17(m,2H),7· 01 (d,1H),4· 81-4. 92(m,1H),3· 92(s, 3H),3. 50 (s,3H),3. 03-3. 05 (m,2H),2. 97 (s,2H),2. 69-2. 79 (m,2H),2. 22-2. 48 (m,2H), 1. 91-1. 99(m,2H). [0358] Che MMR (400MHz, DMS0) δ 8. 89 (s, 1H), 8. 68 (d, 1H), 8 · 41-8. 52 (m, 1H), 8. 22 (d, 1H) , 8 · 12 (d, 1H), 7 · 95 (d, 1H), 7 · 12-7. 17 (m, 2H), 7 · 01 (d, 1H), 4 · 81-4. 92 (m , 1H), 3 · 92 (s, 3H), 3. 50 (s, 3H), 3. 03-3. 05 (m, 2H), 2. 97 (s, 2H), 2. 69-2. 79 (m, 2H), 2. 22-2. 48 (m, 2H), 1. 91-1. 99 (m, 2H).

[0359]实施例241-(1-(2-羟某-2-甲某丙酰某)哌啶-4-某)-8-(6-甲氣某吡啶3-某)-3-甲某-1H-眯啤并「4,5-cl喹啉-2(3H)_酮(化合物24)的制各 [0359] Example 241- (1- (2-hydroxy-2-Moubing a certain acid) piperidin-4-a) -8- (pyridin-6-one 3- a gas) -3- Jiamou -1H- blind beer and "4,5-cl quinoline -2 (3H) _ -one (compound 24) is prepared for each

[0360] [0360]

[0361]将化合物1 (130mg,0· 33mmol)、1-轻基苯并三唑(100mg,1.lmmol)、1-(3_ 二甲氛基丙基)_3_乙基碳二亚胺盐酸盐(120mg,0.63mmol)、三乙胺(300mg,2.9mmol)和2-甲基-2-轻基丙酸(67. 6mg,0. 65mmol)加入20mL二氯甲烧中,反应液室温搅拌48h,反应液蒸干,过制备液相得产品26mg,产率20. 3%。 [0361] Compound 1 (130mg, 0 · 33mmol), 1- light benzotriazole (100mg, 1.lmmol), 1- (3_ atmosphere yl-dimethyl propyl) ethylcarbodiimide salt _3_ acid (120mg, 0.63mmol), triethylamine (300mg, 2.9mmol) and 2-methyl-2-yl mild acid (67. 6mg, 0. 65mmol) was added 20mL of dichloromethane burning reaction solution at room temperature was stirred for 48h, the reaction solution was evaporated to dryness, to obtain a liquid phase product 26mg, yield 20.3% preparative.

[0362]分子式:C26H29N504 分子量:475. 22MS:476 (M+H+) [0362] Molecular Formula: C26H29N504 molecular weight: 475 22MS:. 476 (M + H +)

[0363]屮匪R(400MHz,DMS0)δ8. 90(s,1H),8. 68(s,1H),8. 39(s,1H),8. 15(d,1H), 7· 96 (dd,1H),7· 79-7. 82 (m,1H),6· 99 (d,1H),5· 47 (s,1H),4· 67-5. 78 (m,1H),3· 94 (s,3H), 3. 51 (s,3H),2. 50-2. 51 (m,2H),2. 01-2. 07 (m,2H),1. 66 (s,2H),δ1. 33 (s,6H) [0363] Che bandit R (400MHz, DMS0) δ8. 90 (s, 1H), 8. 68 (s, 1H), 8. 39 (s, 1H), 8. 15 (d, 1H), 7 · 96 (dd, 1H), 7 · 79-7. 82 (m, 1H), 6 · 99 (d, 1H), 5 · 47 (s, 1H), 4 · 67-5. 78 (m, 1H), 3 · 94 (s, 3H), 3. 51 (s, 3H), 2. 50-2. 51 (m, 2H), 2. 01-2. 07 (m, 2H), 1. 66 (s, 2H), δ1. 33 (s, 6H)

[0364]实施例25(R)-2_羟某-N-(4-(8_(6-甲氣某吡啶-3-某)-3-甲某-2-氣代-2, 3-二氣-1H-眯啤并「4, 5-cl喹啉-1-某)环己某)丙酰胺(化合物25)的制各 [0364] Example 25 (R) -2_ a hydroxyalkyl -N- (4- (8_ (6- methyl-3-a a gas) -3 Jiamou -2- gas-2, 3- beer and gas -1H- squint "4, 5-cl quinoline-1-a) a cyclohexyl) propanamide (compound 25) is prepared for each

[0365] 步骤a_d同实施例步骤l_a至l_d。 [0365] Step a_d to the same procedure of Example l_a l_d.

[0366] 步骤25-e4- (6-溴-3-硝基喹啉-4-基氨基)环己基叔丁基碳酸脂的制备 Preparation [0366] Step 25-e4- (6- bromo-3-nitro-quinolin-4-ylamino) cyclohexyl-t-butyl carbonate of

[0367] [0367]

[0368]将6_ 漠_4_ 氣_3_ 硝基喧琳(6. 4g,22. 5mmol)、三乙胺(6. 6g,66mmol)和4_ 氛基环己基叔丁基碳酸脂(6. 4g,30mmol)加入50mL二氯甲烧中,室温搅拌15小时,反应液旋干,过硅胶柱纯化得产品7. 8g,产率:74%。 [0368] The gas _3_ 6_ Desert _4_ nitro noise Lin (6. 4g, 22. 5mmol), triethylamine (6. 6g, 66mmol) 4_ atmosphere and t-butyl cyclohexyl carbonate (6. 4g , 30mmol) was added 50mL of dichloromethane burn stirred at room temperature for 15 hours the reaction solution by rotary evaporation, purified by silica gel column to give product 7. 8g, yield: 74%.

[0369] 步骤25-f4- (3-氨基-6-溴喹啉-4-基氨基)环己基叔丁基碳酸脂的制备 Preparation [0369] Step 25-f4- (3- amino-6-bromo-quinolin-4-ylamino) cyclohexyl-t-butyl carbonate of

[0370] [0370]

[0371] 将4-(6-溴-3-硝基喹啉-4-基氨基)环己基叔丁基碳酸脂(7. 8g,16. 8mmol)、锌粉(4.368,67.2臟〇1)、氯化铵(3.58,67臟〇1)加入到!1 20-〇130!1(50:150)的溶液中,升温至75C,搅拌2h,反应液用乙酸乙酯萃取,用水洗,干燥,蒸干,用硅胶柱纯化得产品2. 9g,产率:40!%。 [0371] 4- (6-bromo-3-nitro-quinolin-4-ylamino) cyclohexyl-t-butyl carbonate (7. 8g, 16. 8mmol), zinc dust (4.368,67.2 dirty 〇1) , ammonium chloride (dirty 〇1 3.58,67) was added to a 120- 〇130 1!!: solution (50 150), the temperature was raised to. 75C, stirred for 2h, the reaction solution was extracted with ethyl acetate, washed with water, dried , evaporated to dryness, purified by silica gel column chromatography to give product 2. 9g, yield:! 40%.

[0372] 步骤25-g4_(8-溴-2-氧代-2,3_二氢-1H-咪唑并[4,5_c]喹啉-1-基)环己基叔丁基碳酸脂的制备 Preparation [0372] Step 25-g4_ (8- bromo-dihydro-2-oxo--2,3_ -1H- imidazo [4,5_c] quinolin-1-yl) cyclohexyl-t-butyl carbonate of

[0373] [0373]

[0374] 将4-(3-氨基-6-溴喹啉-4-基氨基)环己基叔丁基碳酸脂(2. 9g,6. 6mmol)溶于60mL二氯甲烷在冰浴下,40分钟内滴加入30mL三光气(2. 96g,10mmol)的二氯甲烷溶液中,控制稳定搅拌2h,用饱和NaHC03溶液淬灭,用水洗,有机层干燥,蒸干,过硅胶柱纯化得产品2.4g,收率:80%。 [0374] 4- (3-amino-6-bromo-quinolin-4-ylamino) cyclohexyl-t-butyl carbonate (2. 9g, 6. 6mmol) was dissolved in 60mL of dichloromethane under ice-cooling, 40 was added dropwise 30mL within minutes triphosgene (2. 96g, 10mmol) in dichloromethane, stirring stability control 2h, quenched with saturated NaHC03 solution, washed with water, the organic layer was dried, evaporated to dryness, purified by silica gel column to give product 2.4 g, yield: 80%.

[0375] 步骤25-h4-(8-溴-3-甲基-2-氧代-2,3_二氢-1H-咪唑并[4,5_c]喹啉-1-基) 环己基叔丁基碳酸脂的制备 [0375] Step 25-h4- (8- bromo-3-methyl-2-oxo--2,3_ dihydro -1H- imidazo [4,5_c] quinolin-1-yl) cyclohexyl tert preparation of the carbonate group

[0376] [0376]

[0377] 将4-(8-溴-2-氧代-2, 3-二氢-1H-咪唑并[4, 5-c]喹啉-1-基)环己基叔丁基碳酸脂(2. 4g,5. 3mmol)的二氯甲烷溶液20mL加入含有碘甲烷(0. 76g,5. 3mmol)、四丁基碘化胺500mg的10%NaOH溶液中,搅拌2h,用二氯甲烷和水的混合液萃取,有机层干燥,过硅胶柱纯化得产品2. 0g,产率:81%。 [0377] 4- (8-bromo-2-oxo-2,3-dihydro -1H- imidazo [4, 5-c] quinolin-1-yl) cyclohexyl-t-butyl carbonate (2 . 4g, 5. 3mmol) in 20mL dichloromethane was added a solution containing methyl iodide (0. 76g, 5. 3mmol), 10% NaOH solution, tetrabutylammonium iodide 500mg of amine, stirred 2h, dichloromethane and water the mixture was extracted, the organic layer was dried, purified by silica gel column to give product 2. 0g, yield: 81%.

[0378] 步骤25-i4-(8-(6-甲氧基吡啶-3-基)-3_甲基-2-氧代-2, 3-二氢-1H-咪唑并[4, 5-c]喹啉-1-基)环己基叔丁基碳酸脂的制备 [0378] Step 25-i4- (8- (6- methoxypyridin-3-yl) -3_-2-oxo-2,3-dihydro -1H- imidazo [4, 5- preparation c] quinolin-1-yl) cyclohexyl-t-butyl carbonate of

[0379] [0379]

[0380]将2_ 甲氧基_5_ 批陡砸酸(1. 4g,3mmol)、Pd2 (dba) 3140mg和4_ (8_ 漠_3_ 甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]喹啉-1-基)环己基叔丁基碳酸脂(0.6g, 3mmol)加入15mLDMF和10mL1M的NaC03溶液中,氮气保护下升温至100°C,搅拌2h,反应完毕用水和乙酸乙酯的混合液萃取,分离有机层,干燥,过硅胶柱纯化得产品〇. 6g,产率: 90%。 [0380] The batch 2_ methoxy _5_ steep drop acid (1. 4g, 3mmol), Pd2 (dba) 3140mg and 4_ (8_ desert _3_ methyl-2-oxo-2,3-dihydro -1H - imidazo [4,5-c] quinolin-1-yl) cyclohexyl-t-butyl carbonate (0.6g, 3mmol) was added and 15mLDMF 10mL1M NaC03 solution, the temperature was raised to 100 ° C under nitrogen, stirred for 2h , After the reaction mixture was extracted with water and ethyl acetate, the organic layer was separated, dried, purified by silica gel column to give product square 6g, yield: 90%.

[0381] 步骤25-j1-(4-氨基环己基)-8-(6-甲氧基吡啶-3-基)-3_甲基-1H-咪唑并 [0381] Step 25-j1- (4- aminocyclohexyl) -8- (6-methoxy-3-yl) methyl -1H- imidazo -3_

[4, 5-c]喹啉-2 (3H)-酮的制备 -One - [4, 5-c] quinolin -2 (3H)

[0382] [0382]

[0383] 将4-(8-(6-甲氧基吡啶-3-基)-3-甲基-2-氧代-2,3_二氢-1H-咪唑并[4, 5-c]喹啉-1-基)环己基叔丁基碳酸脂(0. 6g,1.2mmol)溶于15mL二氯甲烧溶液中,加入2mL三氟乙酸,搅拌2h,反应液蒸干得粗品0.2g,收率70%。 [0383] 4- (8- (6-methoxy-3-yl) -3-methyl-2-oxo -2,3_ dihydro -1H- imidazo [4, 5-c] quinolin-1-yl) cyclohexyl-t-butyl carbonate (0. 6g, 1.2mmol) was dissolved in 15mL dichloromethane burning was added 2mL of trifluoroacetic acid, stirred for 2h, the reaction solution was evaporated to dryness to give the crude product 0.2g, yield of 70%.

[0384] 步骤25-k化合物25的制备 Preparation [0384] Step 25-k of Compound 25

[0385] [0385]

[0386] 将1-(4-氨基环己基)-8-(6-甲氧基吡啶-3-基)-3_甲基-1H-咪唑并[4, 5-c]喹啉-2(3H)-酮(200mg,0.5mmol)、l-羟基苯并三唑(20〇11^,2.2_〇1)、1-(3-二甲氨基丙基)_3_乙基碳二亚胺盐酸盐(230mmg,1. 2mmol)、三乙胺(360mg)和L-乳酸(72mg, 0. 8mmol),反应液室温搅拌17h,反应液蒸干,过制备液相得产品58mg,产率30%。 [0386] 1- (4-aminocyclohexyl) -8- (6-methoxy-3-yl) methyl -3_ -1H- imidazo [4, 5-c] quinolin-2 ( 3H) - one (200mg, 0.5mmol), l- hydroxybenzotriazole (20〇11 ^, 2.2_〇1), 1- (3-dimethylaminopropyl) ethylcarbodiimide salt _3_ acid (230mmg, 1. 2mmol), triethylamine (360mg) and L- lactic acid (72mg, 0. 8mmol), the reaction solution was stirred 17H at room temperature, the reaction solution was evaporated to dryness, preparative liquid products obtained 58 mg, yield 30 %.

[0387] 分子式:C26H29N504 分子量:475. 22MS:476 (M+H+) [0387] Molecular Formula: C26H29N504 molecular weight: 475 22MS:. 476 (M + H +)

[0388] 屮MMR(d6-DMS0)δ8. 88(s,1H),8. 66(d,1H),8· 31 (s,1H),8. 14(d,1H),7. 93(d, 1H),7· 60(d,1H),7· 02(d,1H),5· 49-5. 50 (m,1H),4· 93-4. 98 (m,1H),3· 93(s,3H), 3. 41-3. 45 (m,1H),3. 39 (s,3H),2. 56-2. 60 (m,2H),2. 01-2. 07 (m,1H),1. 90-1. 93 (m,2H), 1. 60-1. 63 (m,2H),1. 21-1. 23 (m,5H)参照上述方法,还可以制备如下化合物: [0388] Che MMR (d6-DMS0) δ8. 88 (s, 1H), 8. 66 (d, 1H), 8 · 31 (s, 1H), 8. 14 (d, 1H), 7. 93 ( d, 1H), 7 · 60 (d, 1H), 7 · 02 (d, 1H), 5 · 49-5. 50 (m, 1H), 4 · 93-4. 98 (m, 1H), 3 · 93 (s, 3H), 3. 41-3. 45 (m, 1H), 3. 39 (s, 3H), 2. 56-2. 60 (m, 2H), 2. 01-2. 07 (m, 1H), 1. 90-1. 93 (m, 2H), 1. 60-1. 63 (m, 2H), 1. 21-1. 23 (m, 5H) referring to the methods described above, may also be preparation of the following compounds:

[0391] 上述式(1-1)、(1-2)、(1-3)中的取代基R1,分别为如下基团: , (1-2), in (1-3) substituted with [0391] the above formula (1-1) group R1, are the following groups:

[0389] (1-2) [0389] (1-2)

[0390] [0390]

[0392] 表4 [0392] TABLE 4

[0393] [0393]

Claims (4)

1. 如下所述的化合物或其药学上可接受的盐,所述化合物选自: 1. A compound or a pharmaceutically acceptable salt thereof, as described below, the compound is selected from:
代-1-[^[〇〇-2-羟基丙酰基]哌啶-4-基]-2,3-二氢咪唑并[4,5-(:]喹啉, -1 - [^ [thousand and -2- hydroxypropanoyl] piperidin-4-yl] -2,3-dihydro-imidazo [4,5 (:] quinoline,
代-1-[^[〇〇-2-羟基丙酰基]哌啶-4-基]-2,3-二氢咪唑并[4,5-(:]喹啉, -1 - [^ [thousand and -2- hydroxypropanoyl] piperidin-4-yl] -2,3-dihydro-imidazo [4,5 (:] quinoline,
2. 含有权利要求1所述的化合物或其药学上可接受的盐的药物制剂,其特征在于包括一种或多种药用载体。 2. A pharmaceutical formulation comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof as claimed in claim, characterized by comprising one or more pharmaceutically acceptable carriers.
3. 含有权利要求1所述的化合物或其药学上可接受的盐的药物组合物,其特征在于包括一种或多种抗肿瘤剂和免疫抑制剂,所述的抗肿瘤剂和免疫抑制剂选自抗代谢物、生长因子抑制剂、抗体、有丝分裂抑制剂、抗肿瘤激素类、烷化剂类、金属钼类、拓扑异构酶抑制齐U、免疫抑制类, 所述的抗代谢物,选自卡培他滨、吉西他滨、培美曲塞二钠;所述的生长因子抑制剂, 选自帕唑帕尼、伊马替尼、埃罗替尼、拉帕替尼、吉非替尼、凡德他尼;所述的抗体,选自赫赛汀、贝伐单抗;所述的有丝分裂抑制剂,选自紫杉醇、长春瑞滨、多西他赛、多柔比星;所述的抗肿瘤激素类,选自来曲唑、他莫西芬、氟维司群、氟他胺、曲普瑞林;所述的烷化剂类,选自环磷酰胺、卡莫司汀;所述的金属钼类,选自卡钼、顺钼、奥沙利钼;所述的拓扑异构酶抑制剂选自 The compound or a pharmaceutically acceptable according to claim 3 comprising a pharmaceutical salt thereof, which comprises one or more anti-neoplastic agents and immunosuppressants, anti-tumor agents and the immunosuppressant selected from anti-metabolites, growth factor inhibitors, antibodies, mitotic inhibitors, antitumor hormones, alkylating agents, molybdenum-based metal, topoisomerase inhibiting homogeneous U, based immunosuppression, the anti-metabolite, is selected from capecitabine, gemcitabine, pemetrexed disodium; growth factor inhibitors, the selected pazopanib, imatinib, erlotinib, lapatinib, gefitinib , vandetanib; the antibody selected from Herceptin, Avastin; the mitotic inhibitor selected from paclitaxel, vinorelbine, docetaxel, doxorubicin; the antineoplastic hormones, selected from letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; said alkylating agents are selected from cyclophosphamide, carmustine; the molybdenum-described metal selected from molybdenum card, cis molybdenum, molybdenum oxaliplatin; topoisomerase inhibitor is selected from the 拓扑特肯;所述的免疫抑制类,选自依维莫司、西罗莫司、特癌适。 Topotecan; the immunosuppressive species selected everolimus, sirolimus, suitable Laid cancer.
4. 权利要求1所述的化合物或其药学上可接受的盐在制备治疗和/或预防增殖性疾病的药物中的用途,所述的增殖性疾病包括癌症和非癌性疾病,所述癌症选自肺癌、膀胱癌、 胃癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、结直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、 实体瘤、非霍奇金淋巴瘤、前列腺癌、甲状腺癌、雌性生殖道癌、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、前列腺肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤、星形细胞瘤、神经母细胞瘤、肉瘤;非癌性疾病选自皮肤或前列腺的良性增生。 The compound or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of the treatment and / or prophylaxis of a proliferative disease in a mammal, said proliferative diseases, including cancer and non-cancer disease, the cancer is selected from lung cancer, bladder cancer, stomach cancer, cancer of the peritoneum, pancreatic, breast, head and neck cancer, colorectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, a solid tumor, non-Hodgkin's lymphoma, prostatic cancer, thyroid cancer, female genital tract carcinoma, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumors, prostate tumors, mast cell cancer, multiple myeloma, melanoma, glioma, astrocytoma, neuroblastoma, sarcoma; skin disease is selected from non-cancerous or benign prostatic hyperplasia.
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