WO2022089556A1 - 一种c-Myc蛋白抑制剂及其制备方法和用途 - Google Patents
一种c-Myc蛋白抑制剂及其制备方法和用途 Download PDFInfo
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Definitions
- the invention belongs to the field of medicine, in particular to a c-Myc protein inhibitor and a preparation method and application thereof.
- Oncogenes are genes that exist in the genome of cells or viruses, and whose encoded products can transform normal cells to form tumors. When such genes are in a normal state, they are proto-oncogenes. Studies have found that proto-oncogenes exist widely in the biological world, and have many important functions such as maintaining normal physiological functions, regulating cell growth and differentiation, including ras family, myc family, myb family, src family, sis family and so on. When affected by physical, chemical, microbial and other factors, the proto-oncogene can be mutated, amplified, and activated, so that it can be transformed into an oncogene, and the encoded product of the oncogene can induce tumorigenesis in animals.
- the human c-Myc proto-oncogene is located on human chromosome 8q24 and contains 3 exons and 2 introns, of which exon 1 plays a regulatory role and does not participate in encoding proteins, and exon 2 and exon 3 co-encode c-Myc protein.
- the c-Myc protein is composed of the following structures, including: the N-terminal transcriptional activation domain (TAD), which is necessary to activate the expression of target genes, including two conserved domains, MBI and MBII; the MBIII domain, It will affect the transcription and stability of c-Myc; the PEST region is involved in regulating the hydrolysis of c-Myc; CAPN is the site of c-Myc cleavage by calpain, and the truncated Myc-Nick will promote tumor survival and metastasis; MBIV region , involved in the process of apoptosis; NLS is a nuclear localization region, which regulates the entry of Myc protein into the nucleus and exerts its transcriptional function; the C-terminal helix-turn-helix leucine zipper domain (bHLH-LZ) can form with the ligand protein Max Heterodimers, bind to specific DNA sequences and activate transcription of associated genes (Herbst A et al.,
- c-Myc As an extremely unstable protein, c-Myc has a very short half-life in cells, and is mainly degraded by ubiquitin-proteasome or kept stable by deubiquitination. c-Myc can regulate a variety of biological functions in cells Functions, such as cell proliferation, apoptosis, cell cycle progression, cell metabolism and embryonic development, play a very important role in the occurrence, development and evolution of diseases, especially in the occurrence and progression of tumors .
- c-Myc In normal cells, the expression of c-Myc is tightly regulated. In quiescent cells, the expression of c-Myc is very small. When stimulated by growth factors, c-Myc accumulates rapidly as an initial response gene and maintains a high level throughout the cell cycle, affecting downstream target genes The expression returned to the original level until the cells entered stationary phase (Magid R et al., J Biol Chem, 2003; 278(35): 32994-9).
- c-Myc is closely related to 70% of tumor diseases, including lymphoma, breast cancer, prostate cancer, colon cancer, cervical cancer, multiple myeloma, myeloid leukemia, melanoma, osteosarcoma, malignant glia tumor, small cell lung cancer, and medulloblastoma.
- c-Myc can promote tumorigenesis and growth in multiple aspects. After c-Myc is activated, the protein it encodes is overexpressed, causing cell transformation and tumor formation. Felsher et al.
- c-Myc transgenic model was constructed in mouse hematopoietic cells, the expression of the transgene could lead to malignant lymphoma and myeloid The occurrence of tumors.
- the role of c-Myc in regulating the cell cycle is more effective in tumor cells and accelerates cell proliferation, while knocking out c-Myc in tumor cells in vitro can hinder cell proliferation and arrest the cell cycle. In the process of tumorigenesis, new blood vessels are the guarantee for its survival.
- hypoxia-inducible factor-1 ⁇ can promote tumor angiogenesis
- c-Myc can induce HIF -1 ⁇ expression promotes angiogenesis
- down-regulation of c-Myc and HIF-1 ⁇ ultimately inhibits VEGF and angiogenesis.
- the poor prognosis of various tumors is related to the amplification of c-Myc, and in uterine carcinosarcoma with elevated c-Myc expression, the recurrence rate reaches 30% to 50% even in early stage patients (Salvi S et al. , Int J Mol Sci, 2014, 15(7):12458-12468).
- Dysregulation of c-Myc is a hallmark of many types of B-cell lymphomas, in which overexpression of c-Myc inhibits normal B-cell development, resulting in cellular recoding. Nearly 70% of B-cell lymphomas also carry mutations in upstream regulators involved in the TCF3-ID3 pathway, leading to increased cell survival, among which c-Myc can affect the regulation of TCF3-ID3, thereby affecting the expression of cyclin 3 and promoting tumorigenesis Cell proliferation and growth (Petra Korac et al., Genes, 2017, 8, 115).
- c-Myc is expressed in almost all types of leukemia.
- Wickstrom and Holt respectively synthesized the antisense oligodeoxynucleotide ASODN of c-Myc mRNA and co-cultured with HL60 cells in vitro, effectively inhibiting c-Myc
- the expression of c-Myc gene was inhibited, and the formation of leukemia cell colonies was inhibited, indicating that the c-Myc gene plays an important role in leukemogenesis.
- c-Myc is one of the most highly expressed oncogenes in liver cancer, and found that c-Myc overexpression is frequently detected in advanced liver fibrosis patients and models, after chronic injury in mouse models due to c-Myc - Regulation of Myc leads to hepatocyte apoptosis, increased proliferation, and abnormal expression of platelet-derived growth factor subunit (PDGF-B).
- PDGF-B platelet-derived growth factor subunit
- Liver cirrhosis and chronic liver disease often lead to liver cancer.
- the hypomethylation of c-Myc gene is related to the occurrence and development of liver cancer, and through the study of mouse experimental models, it is found that it can be used as a new marker in liver cirrhosis and chronic liver disease.
- c-Myc is an indicator of poor prognosis in liver cancer, and the survival time of patients with c-Myc overexpression is significantly shortened. Compared with primary liver cancer, higher c-Myc expression was detected in metastatic and recurrent liver cancer (Wang , Y. et al., Cancer, 2002, 95, 2346-2352). In addition, the metastasis of liver cancer cells is mediated through multiple signaling pathways of c-Myc (Pedica F et al., PLoS One, 2013, 8(7)).
- c-Myc is also an important mediator of tumorigenesis and maintenance.
- c-Myc initiates and maintains tumorigenesis by regulating multiple programs, including cellular DNA replication, survival, death, self-renewal, and energy metabolism, in the tumor microenvironment (eg, regulation of secreted factors and angiogenesis) and in response to immune responses. Impact (Yulin Li, J Intern Med., 2014, Jul;276(1):52-60). Inhibition of c-Myc can reverse tumorigenesis, resulting in a proliferation arrest. In addition, c-Myc inactivation was found to remodel the microenvironment, restore normal tissue structure and block angiogenesis.
- T- and B-cell lymphomas T- and B-cell lymphomas, leukemias
- epithelial hepatocyte, breast, and squamous cell carcinomas
- mesenchymal tumors osteosarcoma
- c-Myc is also associated with several other diseases. Diabetes is caused by the complete or relative absence of beta islet cells. In diabetes, with the increase in the expression of c-Myc, the insulin-producing beta islet cells dedifferentiate or die, and their insulin secretion decreases. This is because c-Myc increases. -Myc lacks the function of activating insulin gene expression and inhibits gene transcription and expression by competing with the transcription factor NeuroD for the E-box structure of the collective insulin gene promoter (Magid R et al., J Biol Chem, 2003, 278: 32994).
- Atherosclerotic and vascular proliferative diseases share some pathological mechanisms with tumors.
- enhanced expression of c-Myc in vivo correlates with the generation of aortic and carotid plaques, and indeed in early onset coronary lesions and hypercholesterolemia in the Watanabe hyperlipidemia rabbit model Activation of c-Myc-dependent signaling pathways was found in early coronary vessel wall lipid accumulation in ill pigs, and more importantly, antioxidants downregulated c-Myc overexpression in a manner similar to that observed in tumor cells ( Prasad KN et al., Biochem Cell Biol, 68, 1250-55).
- c-Myc has been found to be essential for the proliferation of vascular smooth muscle cells. After the balloon is injured, the mRNA level of c-Myc reaches a peak at 2 hours. The c-Myc protein binds to DNA and promotes genes related to cell proliferation.
- vascular endothelial growth factor VEGFA Open, stimulate quiescent smooth muscle cells to proliferate, and c-Myc can also regulate the expression level of vascular endothelial growth factor VEGFA, which has an important impact on angiogenesis and maturation (Kokai et al., Circulation Reserach, 2009, 1151) .
- c-Myc as an anti-tumor target
- no highly active c-Myc inhibitor has been reported.
- the drug resistance problem of anti-tumor drugs is becoming more and more serious, and drugs with novel mechanisms of action are urgently needed to meet the huge clinical needs.
- the present disclosure provides compounds with potent inhibitory activity targeting c-Myc.
- the purpose of the present invention is to provide a c-Myc protein inhibitor and its preparation method and use.
- the present invention provides compounds of formula (I) and pharmaceutically acceptable salts, solvates, stereoisomers, isotopes and prodrugs thereof:
- T, U, Z are independently selected from: chemical bond, CR 4 R 5 or two or three of T, U, Z together form C 3 -C 6 cycloalkyl, aryl, with the condition that -TUZ - the skeleton is -CC- or -CCC-;
- W is BZ 1 Z 2 ;
- R 8 heterocyclyl, aryl, heteroaryl, fused arylcycloalkyl, fused heteroarylheterocyclyl, aryl-cycloalkyl, aryl-heterocyclyl, cycloalkyl- Heterocyclyl, heterocyclyl-heterocyclyl, RA may be optionally substituted with one or more R6 ;
- R 2 is selected from: hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl;
- R 3 is selected from: hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or benzyl, said alkyl, cycloalkyl, phenyl or benzyl optionally 1-3 substituted with a group respectively selected from halogen, cyano, C 1 -C 3 alkyl or C 1 -C 3 alkoxy, R 3 and R 11 can be C 4 -C 6 cycloalkyl;
- R 7 is selected from: C 1 -C 4 alkyl
- R 11 is hydrogen, C 1 -C 3 alkyl, C 3 cycloalkyl
- Z 1 and Z 2 are independently selected from: hydroxyl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy or aryloxy, and B, Z 1 and Z 2 can form together N, S or O the heterocyclic group.
- the compound is a compound of formula (II) and pharmaceutically acceptable salts, solvates, stereoisomers, isotopes and prodrugs thereof:
- T, U, Z, R 1 , R 2 , R 3 and R 11 are as defined above.
- the specific invention provides the following compounds:
- the compound is a compound of formula (III) and pharmaceutically acceptable salts, solvates, stereoisomers, isotopes and prodrugs thereof:
- the present invention provides the following specific compounds:
- the pharmaceutically acceptable salts of the present invention include hydrochloride, phosphate, hydrogen phosphate, dihydrogen phosphate, sulfate, nitrate, bicarbonate, carbonate, glutarate, hydrobromide Acid salt, acetate, citrate, lactate, maleate, benzoate, mesylate, oxalate, benzenesulfonate, p-toluenesulfonate, tartaric acid, malic acid Salt, succinate, ascorbate, gluconate, lactate, etc.
- the solvent compound of the present invention is selected from: hemihydrate, monohydrate, dihydrate, etc.; the stereoisomer is selected from: enantiomer, diastereomer, and the like.
- Another object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the above-mentioned compounds and their pharmaceutically acceptable salts, solvates, stereoisomers, isotopes and prodrugs thereof.
- Another object of the present invention is to provide the use of the compounds of the present invention and their pharmaceutically acceptable salts, solvates, stereoisomers, isotopes and prodrugs thereof in the preparation of c-Myc protein inhibitors.
- Another object of the present invention is to provide the use of the compounds of the present invention and their pharmaceutically acceptable salts, solvates, stereoisomers, isotopes and prodrugs thereof in the preparation and treatment of c-Myc protein disorders related diseases.
- the c-Myc protein dysregulation is selected from c-Myc protein overexpression.
- the diseases related to c-Myc protein imbalance are selected from cancer, cardiovascular and cerebrovascular diseases, diseases related to viral infection, and the like.
- the cancer is selected from the group consisting of liver cancer, lung cancer, kidney cancer, pancreatic cancer, oral cancer, gastric cancer, esophagus cancer, throat cancer, nasopharyngeal cancer, skin cancer, breast cancer, colon cancer, rectal cancer, cervical cancer, ovary cancer cancer, prostate cancer, brain cancer, nerve cancer, granulocytic leukemia, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, leukemia, lymphoma, etc.; the virus infection-related diseases are selected from HIV, hepatitis B, hepatitis C, hepatitis A, influenza , Japanese encephalitis, herpes, etc.
- Still another object according to the present invention is to provide a method for the treatment of c-Myc protein dysregulation-related diseases, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the present invention (such as formula (I)-formula (III) Any of the compounds or compounds A1-A180) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
- the protein dysregulation is selected from c-Myc protein overexpression, and the c-Myc protein dysregulation-related disease is consistent with the above definition.
- Another object of the present invention is to provide a pharmaceutical composition for treating c-Myc protein disorders related diseases, comprising the compounds of the present invention (such as any of the compounds of formula (I)-(III) or compound A1- A180) or its stereoisomer, its pharmaceutically acceptable salt or its solvate.
- the protein dysregulation is selected from c-Myc protein overexpression, and the c-Myc protein dysregulation-related disease is consistent with the above definition.
- the compounds provided by the present invention have excellent c-Myc protein inhibitory effect, so that they can be used for the prevention and treatment of c-Myc related diseases, such as cancer, cardiovascular and cerebrovascular diseases, viral infections and other diseases, and the synthesis method of the compounds is simple and convenient , the inhibitory effect of c-Myc protein is exact.
- Figure 1 Graph of compound binding to c-Myc protein
- Figure 2 Western blot image of compound A102.
- the raw material A80 (100 mg, 0.18 mmol) and the compound isobutylboronic acid (73 mg, 0.72 mmol) were dissolved in methanol, diluted hydrochloric acid (1 N, 1 mL) was added, and the reaction was carried out at 70° C. for 6 h. Point plate monitoring, the raw material reaction is complete. The solvent was pulled dry and purified directly by medium pressure prep to give a white solid (23 mg, 30% yield).
- HL-60 cell culture medium RPMI-1640 (+L-glutamine) was added with 10% fetal bovine serum, 100 units of penicillin and 100 ⁇ g of streptomycin per ml.
- Cell culture conditions 5% CO 2 , 95% humidity, constant temperature at 37°C.
- HL-60 cells in logarithmic growth phase were seeded into 96-well cell culture plates at 2 x 104 cells per well. Different concentrations of active compound (dissolved in DMSO stock solution) were added, the final concentration of DMSO was 0.2%, and the control group was DMSO. Repeat each set three times.
- MTT MTT (5 mg/ml, prepared and used, dissolved in 1 ⁇ PBS for cell culture) was added to each well, and incubated at 37° C. for 3 hours.
- Centrifuge the 96-well cell culture plate 1000 rpm, for 10 minutes. Discard the supernatant, add 200 ⁇ L of DMSO to each well, and shake for 5 minutes.
- Table 1 IC50 values of compounds of the present invention on HL60 cells
- A means the compound IC 50 is below 100 nM
- B means the compound IC 50 is 100-500 nM
- C means the compound IC 50 is 500 nM-2 ⁇ M
- D means the compound IC 50 is between 2-10 ⁇ M.
- Table 1 show that the compounds of the present invention have excellent inhibitory effects on HL60 cells, and can be used for cancer prevention and treatment.
- Effect Example 2 Test of the binding effect of the compound of the present invention to c-Myc protein
- the c-Myc370-412-biotin polypeptide stock solution was added to 1.05 ⁇ PBS-P buffer to prepare a 50 ⁇ M solution, and then diluted to 1 ⁇ g/ml with 1.00 ⁇ PBS-P buffer (5% DMSO) for protein immobilization.
- the experimental conditions were that the flow rate was 10 ⁇ L/min, the binding time was 120 seconds, and the dissociation time was 240 seconds. After each binding-dissociation test, the tubing was rinsed with 50% DMSO, and the chip surface was rinsed with 10 mM glycine-HCl buffer (pH 2.1) to wash away residual compound molecules. The experimental results are shown in Table 2 and Figure 1.
- Activity data (A represents the compound Kd value is below 100 nM, B represents the compound Kd value is 100-500 nM, C represents the compound Kd value is 500 nM-2 ⁇ M).
- Effect example 3 Test of the degradation effect of the compound of the present invention on c-Myc protein
- HL60 cells When HL60 cells were in exponential growth phase, after centrifugation and counting, the cells were plated in 6-well plates, 1 ⁇ 10 6 cells per well, and cultured with drugs, and the protein was extracted after 24 hours of drug treatment.
- the cells were collected in a 1.5mL centrifuge tube, centrifuged to discard the supernatant, and washed with PBS. After that, 100 ⁇ L of RIPA lysis solution (containing 100 ⁇ M PMSF) was added to each tube. Centrifuge at 12000 rpm for 20 min at °C, take the supernatant for WB experiment, and store the samples at -80 °C.
- the sample to be tested can be diluted and tested
- a 96-well plate to add samples. After each well is supplemented with PBS to 20 ⁇ l, add 200 ⁇ l of BCA to work. After mixing, place it at 60°C for 10 min, and then measure the absorbance at 562 nm. After recording the reading, use the standard concentration gradient as a standard curve, and substitute the sample absorbance to calculate the sample protein concentration.
- Protein denaturation Take the protein lysate, add 5 ⁇ Loading Buffer, and denature at 100°C for 5min.
- PVDF membrane needs to be activated with methanol for 1min before use
- 300mA, 2h a large amount of heat is generated during the membrane transfer process, need to use Cool the ice box.
- Membrane washing and exposure After incubation with the secondary antibody, the membrane was shaken and washed three times in TBST with a shaker for 10 min each time. After washing the membrane, the ECL method was used to excite the fluorescence on the membrane.
- the experimental results are shown in Figure 2.
- the compound A102 of the present invention can promote the degradation of c-Myc protein.
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Abstract
本发明涉及一类c-Myc蛋白抑制剂及其制备方法和用途，所述c-Myc蛋白抑制剂可选择性的抑制c-Myc蛋白，因此，可用于c-Myc蛋白失调相关疾病，如癌症、心脑血管疾病、病毒感染相关疾病等的预防和治疗。
Description
相关申请的引用
本发明要求2020年10月30日在中国提交的，名称为“一种c-Myc蛋白抑制剂及其制备方法和用途”、申请号为202011189778.3的发明专利申请的优先权，通过引用的方式将该专利申请的全部内容并入本文。
本发明属于药物领域，具体涉及一种c-Myc蛋白抑制剂及其制备方法和用途。
癌基因是指存在于细胞或病毒基因组内，其编码产物能转化正常细胞形成肿瘤的基因，当这类基因处于正常状态时即为原癌基因。经研究发现，原癌基因广泛存在于生物界，具有维持正常生理功能、调控细胞生长和分化等多种重要的功能，包括了ras家族、myc家族、myb家族、src家族、sis家族等。当受物理、化学、微生物等因素影响时，原癌基因可发生突变、扩增、激活，从而可以转化为癌基因，而癌基因编码产物可以在动物体内诱导肿瘤的发生。
人c-Myc原癌基因位于人染色体8q24，包含3个外显子和2个内含子，其中外显子1起调节作用，不参与编码蛋白，外显子2和外显子3共同编码的c-Myc蛋白。c-Myc蛋白由以下结构组成，包含：N-端的转录激活结构域(transcriptional activation domain,TAD)，是激活靶基因表达所必需的，包含MBI和MBII这两个保守结构域；MBIII结构域，会影响c-Myc的转录和稳定性；PEST区域，参与调控c-Myc的水解作用；CAPN是钙蛋白酶裂解c-Myc的位点，截断的Myc-Nick会促进肿瘤的存活和转移；MBIV区域，参与细胞凋亡进程；NLS是核定位区域，调控Myc蛋白进入细胞核以及发挥其转录功能；C-端的螺旋-转角-螺旋亮氨酸拉链结构域(bHLH-LZ)可以与配体蛋白Max形成异二聚体，与特定的DNA序列结合并激活相关基因的转录(Herbst A et al.,Oncogene,2004；23(21):3863-71)。c-Myc作为一种极不稳定的蛋白，在细胞中半衰期极短，主要通过泛素-蛋白酶体进行降解或通过去泛素化作用保持稳定，c-Myc能够调节细胞内的多种生物学功能，如细胞增殖、凋亡、细胞周期进展、细胞代谢和胚胎发育，在疾病的发生、发展及演进过程中起到非常重要的作用，尤其是在肿瘤的发生和进展过程中起到重要作用。
在正常细胞中，c-Myc的表达是被严格调控的。在静止期的细胞中，c-Myc的表达是很微量的，当有生长因子刺激时，c-Myc作为最初的应答基因快速积累，并在整个细胞周期中维持较高水平，影响下游靶基因的表达直到细胞进入静止期后又恢复到原有的水平(Magid R et al.,J Biol Chem,2003；278(35):32994-9)。
大量的研究表明c-Myc与70％的肿瘤疾病密切相关，包括淋巴瘤、乳腺癌、前列腺癌、结肠癌、宫颈癌、多发性骨髓瘤、髓性白血病、黑色素瘤、骨肉瘤、恶性胶质瘤、小细胞肺癌以及成神经管细胞瘤。c-Myc能在多个方面促进肿瘤的发生和生长。c-Myc被激活后，其编码的蛋白过表达，引起细胞转化和肿瘤形成，Felsher等的研究发现，在小鼠造血细胞中构建c-Myc转基因模型，转基因的表达会导致恶性淋巴瘤和髓系肿瘤的发生。c-Myc调节细胞周期的作用在肿瘤细胞中更能发挥作用，加速细胞的增殖，而在体外敲除肿瘤细胞中的c-Myc后能 够阻碍细胞增殖，使细胞周期停滞。在肿瘤的发生进程中，新生血管是其赖以生存的保障，在肿瘤内部低氧的环境下，低氧诱导因子-1α(HIF-1α)可以促进肿瘤血管生成，而c-Myc能够诱导HIF-1α的表达，促进血管生成，当下调c-Myc和HIF-1α最终会抑制血管内皮生长因子VEGF和血管形成。此外，多种肿瘤的预后不良与c-Myc的扩增相关，在c-Myc表达升高的子宫癌肉瘤中，即使是早期患者其复发率也达到30％～50％(Salvi S et al.,Int J Mol Sci,2014,15(7):12458-12468)。
c-Myc失调是多种类型B细胞淋巴瘤的特点，在这些淋巴瘤中，c-Myc过表达抑制正常B细胞的发育，导致细胞重编码。近70％的B细胞淋巴瘤还携带参与TCF3-ID3通路的上游调控因子突变，导致细胞存活率增加，其中c-Myc可以影响TCF3-ID3的调控，从而影响细胞周期蛋白3的表达，促进肿瘤细胞的增殖和生长(Petra Korac et al.,Genes,2017,8,115)。
c-Myc在几乎各型白血病中都有表达，在1988年Wickstrom和Holt分别合成了c-Myc mRNA的反义寡聚脱氧核苷酸ASODN在体外与HL60细胞共培养，有效抑制了c-Myc的表达，细胞生长受到了抑制，并且抑制了白血病细胞集落的形成，表明了c-Myc基因在白血病发生中起重要作用。在其后的研究中发现急性淋巴细胞白血病和急性非淋巴细胞白血病c-Myc表达最强，慢粒(CML)、骨髓增殖异常综合征(MDS)和多发性骨髓瘤(MM)中c-Myc表达远低于急性白血病，但明显高于对照细胞。研究发现c-Myc mRNA高表达的患者很难再化疗药物的诱导下缓解，c-Myc表达越低，完全缓解率越高，无病生存期也越长(Evingerhodges M J et al.,Leukemia,1988,2(1):45.)。
在乳腺癌中，大约有30％的病人有c-Myc高表达的情况，而在一组临床数据中发现c-Myc高表达组的术后无病生存期相比正常表达组从大于6.4年下降为1.4年，并且在极端情况下，淋巴结阴性、雌激素和孕激素受体阳性、c-Myc低表达的术后复发率为0％，而有淋巴结转移，雌激素和孕激素受体阴性、高表达c-Myc的患者复发率为93％(Pertschuk et al.,Cancer,1993,71(1):162)。
最近的研究发现在肝癌中c-Myc是最高表达的癌基因之一，并且发现在晚期肝纤维化患者和模型中经常检测到c-Myc的过表达，在小鼠模型慢性损伤发生后由于c-Myc的调节导致肝细胞凋亡，增殖增加，血小板来源的生长因子亚单位(PDGF-B)异常表达。肝硬化和慢性肝病常常导致肝癌，目前发现c-Myc基因的低甲基化和肝癌的发生发展有关，并且通过对小鼠实验模型研究发现在肝硬化和慢性肝病中可以作为新的标志物和治疗的新靶点(Kang Zheng et al.,Genes,2017,8,123；doi:10.3390)。同时，c-Myc是肝癌预后不良的指标，而且c-Myc过表达患者生存期明显缩短，与原发性肝癌相比，转移性和复发性肝癌中检测到较高的c-Myc表达(Wang,Y.et al.,Cancer,2002,95,2346-2352)。此外，肝癌细胞的转移是通过c-Myc的多种信号通路介导的(Pedica F et al.,PLoS One,2013,8(7))。
c-Myc还是肿瘤发生和维持的重要介质。c-Myc通过调节多个程序启动和维持肿瘤的发生，包括细胞的DNA复制、生存、死亡、自我更新和能量代谢，在肿瘤微环境(如分泌因子和血管生成的调控)和对免疫应答的影响(Yulin Li,J Intern Med.,2014,Jul；276(1):52-60)。c-Myc被抑制后可以逆转肿瘤发生，导致增殖阻滞。此外还发现c-Myc失活可以重构微环境，恢复正常组织结构并阻断血管生成。在多种肿瘤中观察到类似的结果，包括造血(T细胞和B细胞淋巴瘤,白血病)，上皮(肝细胞，乳腺和鳞状细胞癌)和间充质肿瘤(成骨肉瘤)(Felsher DW,Bishop JM,Mol Cell.,1999,Aug；4(2):199-207)因此，以c-Myc为抗肿瘤靶标将具有广阔的应 用前景。
除癌症外，c-Myc还与一些其他疾病相关。糖尿病是由于β胰岛细胞完全或相对缺失导致的，在糖尿病中，伴随着c-Myc表达的增加，产生胰岛素的β胰岛细胞去分化或者凋亡，其胰岛素的分泌随之下降，这是因为c-Myc缺乏激活胰岛素基因表达的功能，通过与转录因子NeuroD竞争性的集合胰岛素基因启动子的E-box结构而抑制基因的转录和表达(Magid R et al.,J Biol Chem,2003,278:32994)。
动脉粥样硬化和血管增生性疾病与肿瘤具有部分相似的病理机制。在动脉粥样硬化产生的单克隆假说中，c-Myc在体内表达增强与主动脉和颈动脉斑块的产生相关，实际上在渡边高血脂兔模型中的早起冠状动脉病变和高胆固醇血症猪的早期冠状动脉血管壁脂质积累中发现了c-Myc依赖性信号通路的激活，更重要的是抗氧化剂以在肿瘤细胞中观察到的类似的方式下调了c-Myc的过表达(Prasad KN et al.,Biochem Cell Biol,68,1250-55)。在动脉发生损伤后再狭窄主要是由于血管细胞增殖引起的并最终导致动脉闭塞。另外，细胞迁移、基质沉积和血管重构也参与了动脉损伤后再狭窄的发生。c-Myc已经被发现与血管平滑肌细胞的增殖至关重要，在球囊发生损伤后，c-Myc的mRNA水平在2小时达到高峰，c-Myc蛋白与DNA结合,促进与细胞增殖的相关基因开放，刺激静止期的平滑肌细胞产生增殖效应，并且c-Myc还能调控血管内皮生长因子VEGFA的表达水平，对血管的新生和成熟产生重要影响(Kokai et al.,Circulation Reserach,2009,1151)。
目前，诸多研究证实了c-Myc作为抗肿瘤靶标的临床开发前景，但是目前尚未报道有高活性的c-Myc抑制剂。抗肿瘤药物耐药性问题愈发严重，亟需新型作用机制的药物以满足临床上的巨大需求。本发明公开内容提供了以c-Myc为靶标的强抑制活性化合物。
发明内容
本发明的目的是提供一种c-Myc蛋白抑制剂及其制备方法和用途。
一方面，本发明提供式(I)所示的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药：
其中，T、U、Z分别独立的选自：化学键、CR
4R
5或T、U、Z中的两个或三个共同形成C
3-C
6环烷基、芳基，条件是-T-U-Z-骨架为-C-C-或-C-C-C-；
W为BZ
1Z
2；
R
1选自：RAC(＝O)-、RACH
2C(＝O)-、RACH
2CH
2C(＝O)-、RACH
2-、RANHC(＝O)-、RACH
2NHC(＝O)-、RACH
2OC(＝O)-、RACH
2CH
2OC(＝O)-、RAOC(＝O)-、RAS(＝O)
2-或RA；
RA选自：C
1-C
4烷基、C
3-C
10环烷基、C
3-C
10桥环基、C
3-C
10任含O、S、SO
2、N或NHC(＝O)R
8的杂环基、芳基、杂芳基、稠合芳基环烷基、稠合杂芳基杂环基、芳基-环烷基、芳基-杂环基、环烷基-杂环基、杂环基-杂环基，RA可任选的被一个或多个R
6取代；
R
2选自：氢、C
1-C
3烷基、C
3-C
6环烷基；
任选的R
2可以与所连接的N及任选T、U、Z中的一个或多个形成杂环基，所述杂环基为包含N及任选的O、S的5-10元杂环基，任选的所述杂环基包含C(＝O)；
任选的R
1、R
2可以与所共同连接的N形成RA-杂环基、RACH
2-杂环基，所述杂环基为包含N及任选的O、S的5-6元杂环基，任选的所述杂环基包含C(＝O)；
R
3选自：氢、C
1-C
6的烷基、C
3-C
6环烷基、苯基或苄基，所述烷基、环烷基、苯基或者苄基任选1-3个分别选自卤素、氰基、C
1-C
3烷基或C
1-C
3烷氧基的基团取代，R
3可与R
11成C
4-C
6的环烷基；
R
4、R
5分别独立的选自：氢、羟基、氨基、-NHBoc、-NHCbz、-R
7NHC(＝O)R
8、-R
7C(＝O)OR
8、-C(＝O)OR
8、-R
7C(＝O)NHR
8、-C(＝O)NHR
8、-C
1-C
6烷基、-C
1-C
6烷基苄氧基、-C
1-C
6烷基杂环基、-C
1-C
6烷基芳基、-C
1-C
6烷基杂芳基、-C
1-C
6烷氧基、-C
1-C
6烷硫基、-C
1-C
6烷硫基C
1-C
6烷基、-C
1-C
6烷胺基、-C
3-C
8环烷基，芳基、含有1-3个杂原子的5-6元杂芳基或含有1-3个杂原子的3-10元杂环基，所述烷基、烷氧基、烷胺基、烷硫基、环烷基、芳基、杂芳基、杂环基任选的被1-3个分别选自卤素、氰基、C
1-C
3烷基、C
1-C
3卤代烷基或C
1-C
3烷氧基的基团取代，其中R
4、R
5与其所共同连接的C可以成C
3-C
6的饱和环、芳基或任含O、S、SO
2、N、NBoc、或NHC(＝O)R
8的饱和杂环或羰基；
R
6选自：氢、卤素、羟基、氰基、氨基、-R
7NHC(＝O)R
8、-R
7C(＝O)OR
8、C
1-C
6烷基、C
1-C
6的烷氧基、C
1-C
6的烷硫基、C
1-C
6的烷胺基、C
3-C
8的环烷基、C
2-C
8的烯基、C
2-C
8的炔基、芳基、含有1-3个杂原子的5-6元杂芳基或含有1-3个杂原子的3-10元杂环基，所述烷基、烷氧基、烷胺基、烷硫基、环烷基、芳基、杂芳基、杂环基任选被1-3个分别选自卤素、氰基、C
1-C
3烷基或C
1-C
3烷氧基的基团取代；
R
7选自：C
1-C
4的烷基；
R
8选自：氢、氨基、C
1-C
4的烷基、C
1-C
4的烷氧基、烯丙基或苄基，所述C
1-C
4的烷基、C
1-C
4的烷氧基、烯丙基或苄基任选的被芳基、-C(＝O)OR
7所取代；
R
11为氢、C
1-C
3的烷基、C
3环烷基；
Z
1、Z
2分别独立的选自：羟基、C
1-C
10烷基、C
1-C
10烷氧基或芳氧基，B、Z
1和Z
2可一起形成含N、S或O的杂环基。
在一些实施方案中，所述化合物为式(II)所示的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药：
其中T、U、Z、R
1、R
2、R
3、R
11定义同前。
具体的本发明提供以下化合物：
在一些实施方案中，所述化合物为式(III)所示的化合物及其药学上可药用的盐、溶剂化合物、立体异构体、同位素及其前药：
其中T、U、Z、R1、R2、R3、R11取代基定义同前。
具体的，本发明提供以下具体化合物：
本发明所述的药学上可接受的盐，包括盐酸盐，磷酸盐，磷酸氢盐，磷酸二氢盐，硫酸盐，硝酸盐，碳酸氢盐，碳酸盐，戊二酸盐，氢溴酸盐，醋酸盐，枸橼酸盐，乳酸盐，马来酸盐，苯甲酸盐，甲磺酸盐，草酸盐，苯磺酸盐、对甲苯磺酸盐、酒石酸、苹果酸盐，琥珀酸盐，抗坏血酸盐，葡萄糖酸盐，乳酸盐等。
本发明所述溶剂化合物选自：半水合物、一水合物、二水合物等；所述立体异构体选自：对应异构体或非对应异构体等。
本发明再一个目的是提供一种药物组合物，包含药学上可接受的载体和上述化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药。
本发明的再一个目的是提供本发明所述化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药在制备c-Myc蛋白抑制剂中的用途。
本发明的再一个目的是提供本发明所述化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药在制备治疗c-Myc蛋白失调相关疾病中的用途。
优选的，所述c-Myc蛋白失调选自c-Myc蛋白过表达。
优选的，所述c-Myc蛋白失调相关疾病选自：癌症、心脑血管疾病、病毒感染相关疾病等。
优选的，所述癌症选自：肝癌、肺癌、肾癌、胰腺癌、口腔癌、胃癌、食道癌、喉癌、鼻咽癌、皮肤癌、乳腺癌、结肠癌、直肠癌、宫颈癌、卵巢癌、前列腺癌、脑癌、神经癌、粒细胞性白血病、横纹肌肉瘤、成骨肉瘤、软骨肉瘤、白血病、淋巴癌等；所述病毒感染相关疾病选自：HIV、乙肝、丙肝、甲肝、流感、流行性乙脑炎、疱疹等。
根据本发明的再一个目的是提供了一种治疗c-Myc蛋白失调相关疾病的方法，包括向有此需要的受试者施用治疗有效量的本发明所述化合物(如式(I)-式(III)所述任意化合物或化合物A1-A180)或其立体异构体、其药学上可接受的盐或其溶剂化物。所述蛋白失调选自c-Myc蛋白过表达，所述c-Myc蛋白失调相关疾病与上述定义一致。
根据本发明的再一个目的是提供了一种治疗c-Myc蛋白失调相关疾病的药物组合物，包括本发明所述化合物(如式(I)-式(III)所述任意化合物或化合物A1-A180)或其立体异构体、其药学上可接受的盐或其溶剂化物。所述蛋白失调选自c-Myc蛋白过表达，所述c-Myc蛋白失调相关疾病与上述定义一致。
本发明的有益效果
本发明提供的化合物具有优异的c-Myc蛋白抑制效果，从而可用于c-Myc相关疾病，如癌症、心脑血管疾病、病毒感染等多种疾病的预防和治疗，所述化合物的合成方法简便，c-Myc 蛋白抑制效果确切。
图1：化合物和c-Myc蛋白结合的曲线图；
图2：化合物A102的蛋白印迹(western blot)图。
下面将结合附图以及进一步的详细说明来举例说明本发明。需要指出的是，以下说明仅仅是对本发明要求保护的技术方案的举例说明，并非对这些技术方案的任何限制。本发明的保护范围以所附权利要求书记载的内容为准。
实施例1：化合物A1的合成
化合物A1：
化合物A1-1(156mg,0.5mmol)和A1-2(227mg,0.6mmol)溶于DCM(3mL)中，加入HATU(285mg,0.75mmol)和TEA(151mg,1.5mmol)，室温反应两个小时。加水，用DCM萃取(15mL*3)，合并有机相，拉干溶剂后，用中压制备纯化粗产品得到白色固体化合物A1(28mg,产率10％)。
1H NMR(400MHz,DMSO)δ9.28(s,1H),7.90(d,J＝7.5Hz,2H),7.68(d,J＝7.3Hz,2H),7.49-7.37(m,2H),7.34(t,J＝7.2Hz,3H),4.30(dd,J＝12.2,6.6Hz,2H),4.22(t,J＝6.8Hz,1H),4.00(d,J＝6.8Hz,1H),3.21(dd,J＝13.2,6.8Hz,2H),2.46-2.39(m,2H),2.17(dd,J＝12.2,10.1Hz,1H),2.01(dd,J＝14.6,6.9Hz,2H),1.85-1.75(m,2H),1.74-1.65(m,1H),1.61(d,J＝14.1Hz,1H),1.36(dd,J＝12.7,10.3Hz,1H),1.25(dd,J＝19.3,15.2Hz,8H),0.91-0.75(m,9H).
化合物A2-A19、28-41、44-55、57-58、66-69、93、95、97-101合成方法同A1。
化合物A2：
1H NMR(400MHz,DMSO)δ9.29(s,1H),7.89(d,J＝7.5Hz,2H),7.68(d,J＝7.1Hz,2H),7.41(t,J＝7.3Hz,2H),7.37-7.24(m,3H),4.30(d,J＝6.4Hz,2H),4.21(t,J＝6.7Hz,1H),3.99(dd,J＝8.5,2.0Hz,1H),3.89-3.79(m,1H),2.40(t,J＝6.9Hz,1H),2.31(dd,J＝14.0,8.3Hz,1H),2.20-2.12(m,1H),2.01-1.93(m,1H),1.82-1.74(m,2H),1.72-1.63(m,1H),1.60(d,J＝13.6Hz,2H),1.37(d,J＝9.9Hz,1H),1.22(d,J＝7.7Hz,8H),1.05(d,J＝6.4Hz,3H),0.87-0.76(m,9H).
化合物A3：
1H NMR(400MHz,DMSO)δ9.31(s,1H),7.89(d,J＝7.5Hz,2H),7.68(t,J＝6.4Hz,2H),7.42(t,J＝7.1Hz,2H),7.36-7.32(m,2H),7.29(d,J＝8.0Hz,1H),4.38-4.28(m,2H),4.27-4.19(m,1H),3.98(d,J＝7.3Hz,1H),3.90-3.81(m,1H),2.50-2.38(m,2H),2.36-2.29(m,1H),2.20-2.11(m,1H),2.01-1.92(m,1H),1.83-1.74(m,2H),1.71-1.64(m,1H),1.62-1.55(m,1H),1.36(d,J＝9.8Hz,1H),1.27-1.23(m,2H),1.21(d,J＝3.0Hz,6H),1.05(d,J＝6.5Hz,3H),0.89-0.76(m,9H).
化合物A4：
1H NMR(400MHz,DMSO)δ9.29(s,1H),7.89(d,J＝7.5Hz,2H),7.68(t,J＝8.4Hz,2H),7.41(t,J＝7.4Hz,2H),7.32(td,J＝7.4,2.2Hz,2H),7.20(d,J＝8.8Hz,1H),4.39-4.15(m,3H),4.03-3.87(m,1H),3.70(s,1H),2.45-2.30(m,3H),2.14(d,J＝11.6Hz,1H),1.96(s,1H),1.81-1.73(m,2H),1.67(d,J＝6.2Hz,1H),1.58(d,J＝11.7Hz,1H),1.44(d,J＝6.9Hz,1H),1.39-1.31(m,2H),1.21(t,J＝7.6Hz,8H),0.87-0.74(m,12H).
化合物A5：
1H NMR(400MHz,DMSO)δ9.22(d,J＝5.4Hz,1H),7.88(d,J＝7.5Hz,2H),7.68(dd,J＝14.9,7.9Hz,2H),7.41(t,J＝7.4Hz,2H),7.32(dd,J＝12.8,7.1Hz,2H),7.19-7.11(m,1H),4.37-4.18(m,3H),3.99-3.89(m,1H),3.74(dd,J＝14.0,5.7Hz,1H),2.46-2.40(m,1H),2.40-2.29(m,2H),2.18-2.05(m,1H),1.97(d,J＝26.0Hz,1H),1.80-1.71(m,2H),1.68(dd,J＝13.1,6.9Hz,2H),1.60-1.51(m,1H),1.34(t,J＝10.3Hz,1H),1.20(t,J＝9.6Hz,8H),0.91-0.67(m,15H).
化合物A6：
1H NMR(400MHz,DMSO)δ9.28(s,1H),7.88(d,J＝7.5Hz,2H),7.67(dd,J＝10.0,5.7Hz,2H),7.41(t,J＝7.4Hz,2H),7.32(td,J＝7.3,3.1Hz,2H),7.19(d,J＝7.9Hz,1H),4.36-4.17(m,3H),4.00-3.92(m,1H),3.76(s,1H),2.39(d,J＝5.0Hz,3H),2.20-2.08(m,1H),1.96(s,1H),1.77(dd,J＝10.2,4.5Hz,2H),1.64(d,J＝27.3Hz,2H),1.36(dd,J＝9.7,3.8Hz,3H),1.21(t,J＝7.2Hz,12H),0.91-0.73(m,12H).
化合物A7：
1H NMR(400MHz,DMSO)δ9.35(s,1H),7.89(d,J＝7.5Hz,2H),7.68(dt,J＝7.7,4.0Hz,2H),7.42(t,J＝7.4Hz,2H),7.33(dt,J＝10.7,5.5Hz,2H),7.20(d,J＝8.8Hz,1H),4.40-4.27(m,2H),4.27-4.19(m,1H),3.98(d,J＝6.6Hz,1H),3.86(s,1H),3.32(s,1H),2.47-2.27(m,3H),2.15(d,J＝10.5Hz,1H),2.05-1.92(m,2H),1.82-1.72(m,2H),1.60(d,J＝13.1Hz,2H),1.35(t,J＝11.7Hz,2H),1.24(s,3H),1.20(t,J＝9.2Hz,7H),0.87-0.78(m,13H).
化合物A8：
1H NMR(400MHz,DMSO)δ9.30(s,1H),7.89(d,J＝7.5Hz,2H),7.68(dd,J＝7.2,3.6Hz,2H),7.41(t,J＝7.4Hz,2H),7.37-7.24(m,3H),4.40-4.18(m,3H),3.99(d,J＝6.6Hz,1H),3.85(s,1H),2.46-2.32(m,4H),2.14(d,J＝11.2Hz,1H),1.99(d,J＝5.5Hz,3H),1.78(dd,J＝12.3,6.5Hz,2H),1.72-1.53(m,5H),1.35(d,J＝9.8Hz,1H),1.20(d,J＝3.6Hz,9H),0.87-0.75(m,9H).
化合物A9：
1H NMR(400MHz,DMSO)δ9.22(s,1H),7.89(d,J＝7.5Hz,2H),7.71(t,J＝7.2Hz,2H),7.44-7.20(m,10H),4.50(d,J＝14.3Hz,2H),4.38-4.28(m,2H),4.27-4.16(m,2H),4.09-3.93(m,2H),2.56(dd,J＝14.6,5.7Hz,1H),2.39(t,J＝7.5Hz,1H),2.18-2.09(m,1H),1.96(dd,J＝17.8,6.5Hz,2H),1.60(s,2H),1.37(d,J＝4.9Hz,6H),1.32-1.23(m,8H),0.81(dd,J＝12.5,10.8Hz,9H).
化合物A10：
1H NMR(400MHz,DMSO)δ9.39(s,1H),7.89(d,J＝7.5Hz,2H),7.68(t,J＝7.1Hz,2H),7.41(t,J＝7.4Hz,2H),7.34(dd,J＝14.3,7.1Hz,3H),4.38-4.26(m,2H),4.25-4.15(m,1H),4.00-3.90(m,1H),3.24(dd,J＝15.9,8.0Hz,1H),2.44-2.30(m,1H),2.21-2.06(m,1H),1.98(dd,J＝26.3,5.6Hz,1H),1.78(dd,J＝11.1,5.4Hz,2H),1.71-1.62(m,1H),1.58(d,J＝13.3Hz,1H),1.36(dd,J＝9.6,6.3Hz,1H),1.30-1.08(m,9H),0.82(dd,J＝10.5,8.8Hz,10H),0.40-0.14(m,4H).
化合物A11：
1H NMR(400MHz,DMSO)δ9.27(s,1H),7.89(d,J＝7.5Hz,2H),7.69(dd,J＝16.5,7.4Hz,2H),7.42(t,J＝7.5Hz,2H),7.33(q,J＝7.2Hz,2H),7.17(d,J＝9.3Hz,1H),4.27(dd,J＝16.3,5.9Hz,3H),3.94(d,J＝6.8Hz,1H),3.79-3.69(m,1H),2.36(dd,J＝16.9,8.3Hz,2H),2.13(d,J＝13.4Hz,1H),1.94(d,J＝8.3Hz,1H),1.79-1.52(m,9H),1.33(d,J＝9.7Hz,2H),1.21(d,J＝7.2Hz,3H),1.20(d,J＝3.8Hz,6H),1.18-1.01(m,5H),0.85-0.73(m,9H).
化合物A12：
1H NMR(400MHz,DMSO)δ9.02(s,1H),8.34(d,J＝7.4Hz,1H),7.90(d,J＝7.5Hz,2H),7.74-7.65(m,2H),7.51(d,J＝8.5Hz,1H),7.42(t,J＝7.3Hz,2H),7.33(q,J＝7.0Hz,2H),7.27-7.15(m,5H),4.46(dd,J＝8.0,6.0Hz,2H),4.32-4.01(m,3H),3.99(d,J＝7.0Hz,1H),3.59(s,3H),3.07-2.90(m,2H),2.69-2.62(m,1H),2.58-2.53(m,1H),2.58-2.39(m,1H),2.15(dd,J＝20.3,9.0Hz,1H),2.01-1.91(m,1H),1.77(dd,J＝12.2,6.2Hz,3H),1.60(d,J＝13.7Hz,1H),1.34-1.23(m,3H),1.20(d,J＝7.3Hz,6H),0.84(dd,J＝6.5,2.6Hz,6H),0.79(d,J＝6.9Hz,3H).
化合物A13：
1H NMR(400MHz,DMSO)δ9.03(t,J＝11.5Hz,1H),7.90(d,J＝7.5Hz,2H),7.81(d,J＝8.3Hz,1H),7.67(dt,J＝33.5,16.8Hz,2H),7.42(s,2H),7.33(m,J＝7.3,3.6,1.2Hz,7H),5.12(d,J＝3.8Hz,2H),4.66-4.48(m,1H),4.41-4.25(m,2H),4.21(dd,J＝14.8,7.9Hz,1H),4.10-4.01(m,1H),2.81(dd,J＝15.4,6.1Hz,1H),2.66(dd,J＝15.4,8.0Hz,1H),2.52(s,1H),2.17(dd,J＝12.3,9.9Hz,1H),1.99(dd,J＝8.6,5.7Hz,1H),1.82(t,J＝5.6Hz,1H),1.76(t,J＝12.0Hz,1H),1.66(dt,J＝26.9,10.2Hz,2H),1.37-1.26(m,2H),1.21(d,J＝7.2Hz,7H),0.87-0.76(m,9H).
化合物A14：
1H NMR(400MHz,DMSO)δ9.31(s,1H),7.90(d,J＝7.5Hz,2H),7.71-7.67(m,2H),7.42(t,J＝7.4Hz,2H),7.34(t,J＝7.4Hz,2H),7.30-7.20(m,2H),6.75(s,1H),4.35-4.16(m,3H),3.99(d,J＝7.1Hz,1H),3.76(s,1H),2.47-2.34(m,3H),2.21-1.92(m,5H),1.84-1.72(m,2H),1.70-1.54(m,4H),1.39-1.33(m,1H),1.26-1.17(m,7H),0.85-0.75(m,9H).
化合物A15：
1H NMR(400MHz,DMSO)δ9.32(s,1H),7.89(d,J＝7.4Hz,2H),7.79(t,J＝5.5Hz,1H),7.68(dd,J＝7.2,3.1Hz,2H),7.41(t,J＝7.4Hz,2H),7.33(t,J＝7.3Hz,2H),7.25(d,J＝8.7Hz,1H),4.34-4.26(m,2H),4.22(dd,J＝13.5,6.5Hz,1H),3.98(d,J＝10.2Hz,1H),3.83-3.70(m,1H),3.05-2.89(m,3H),2.43-2.36(m,4H),2.18-2.10(m,1H),2.03-1.93(m,2H),1.79-1.71(m,5H),1.70-1.55(m,2H),1.47-1.30(m,4H),1.21(s,6H),0.82(dd,J＝14.0,7.3Hz,9H).
化合物A16：
1H NMR(400MHz,DMSO)δ9.33(s,1H),7.89(d,J＝7.4Hz,2H),7.67(s,2H),7.31(ddd,J＝38.0,31.0,7.9Hz,11H),5.32(t,J＝4.8Hz,2H),4.98(s,2H),4.34-4.26(m,2H),4.22(dd,J＝13.5,6.5Hz,1H),3.98(d,J＝10.2Hz,1H),3.83-3.70(m,1H),3.05-2.89(m,3H),2.43-2.36(m,1H),2.18-2.10(m,1H),2.03-1.93(m,2H),1.79-1.71(m,5H),1.70-1.55(m,2H),1.47-1.30(m,4H),1.21(s,6H),0.82(dd,J＝14.0,7.3Hz,9H).
化合物A17：
1H NMR(400MHz,DMSO)δ9.39(s,1H),7.89(d,J＝7.5Hz,2H),7.71(d,J＝7.4Hz,2H),7.42(t,J＝7.4Hz,2H),7.34(t,J＝7.4Hz,2H),7.22(s,1H),4.22(s,3H),3.98(d,J＝6.7Hz,1H),2.67(s,1H),2.38(dd,J＝13.7,6.5Hz,1H),2.18(d,J＝8.4Hz,3H),2.05-1.90(m,2H),1.81(dd,J＝12.6,7.2Hz,2H),1.73-1.57(m,2H),1.41(d,J＝9.9Hz,3H),1.35-1.25(m,10H),0.81(d,J＝11.7Hz,9H).
化合物A18：
1H NMR(400MHz,DMSO)δ9.43(s,1H),7.87(d,J＝7.2Hz,2H),7.69(d,J＝7.2Hz,2H),7.55(s,1H),7.41(t,J＝7.4Hz,2H),7.33(t,J＝7.2Hz,2H),4.28-4.17(m,3H),3.96(d,J＝6.9Hz,1H),2.75(s,2H),2.37(t,J＝7.5Hz,1H),2.24-2.09(m,5H),2.07-1.92(m,1H),1.83-1.72(m,4H),1.68(dd,J＝13.3,6.7Hz,1H),1.61(d,J＝13.6Hz,1H),1.40(d,J＝8.8Hz,1H),1.25-1.17(m,8H),0.84-0.75(m,9H).
化合物A19：
1H NMR(400MHz,DMSO)δ9.44(s,1H),7.89(d,J＝7.5Hz,2H),7.73(d,J＝7.1Hz,2H),7.41(t,J＝7.5Hz,2H),7.33(t,J＝7.3Hz,2H),7.05(s,1H),4.19(s,3H),3.94(d,J＝6.8Hz,1H),2.67(s,2H),2.33(t,J＝7.7Hz,1H),2.21-2.10(m,1H),2.07-1.89(m,3H),1.76-1.68(m,3H),1.59(d,J＝13.8Hz,1H),1.39(d,J＝9.9Hz,9H),1.19(s,8H),0.83-0.75(m,9H).
化合物A28：
1H NMR(400MHz,DMSO)δ9.11(s,1H),7.95(d,J＝8.6Hz,1H),7.89(d,J＝7.3Hz,2H),7.67(t,J＝6.5Hz,2H),7.41(dd,J＝12.4,7.1Hz,2H),7.32(t,J＝7.9Hz,5H),7.25(d,J＝4.3Hz,2H),4.96(d,J＝8.0Hz,1H),4.36-4.12(m,3H),4.01(d,J＝7.0Hz,1H),2.79-2.62(m,2H),2.37(t,J＝7.5Hz,1H),2.15(d,J＝10.7Hz,1H),2.02-1.94(m,1H),1.80(dd,J＝13.4,7.4Hz,2H),1.60(d,J＝13.0Hz,2H),1.34(d,J＝9.8Hz,1H),1.26-1.20(m,8H),0.83(dt,J＝12.7,5.8Hz,9H).
化合物A29：
1H NMR(400MHz,DMSO)δ9.06(d,J＝3.4Hz,1H),7.94(t,J＝8.2Hz,1H),7.88(d,J＝7.5Hz,2H),7.66(t,J＝6.9Hz,2H),7.46-7.35(m,3H),7.35-7.24(m,3H),7.21-7.08(m,2H),5.28-5.15(m,1H),4.33-4.16(m,3H),3.99(d,J＝8.5Hz,1H),2.80-2.63(m,2H),2.40(t,J＝6.7Hz,1H),2.19-2.09(m,1H),2.03-1.92(m,1H),1.82-1.70(m,2H),1.64-1.48(m,2H),1.30(t,J＝9.6Hz,1H),1.24-1.12(m,8H),0.86-0.71(m,9H).
化合物A30：
1H NMR(400MHz,DMSO)δ9.09(s,1H),8.01(d,J＝8.5Hz,1H),7.89(d,J＝7.5Hz,2H),7.66(t,J＝8.1Hz,2H),7.47-7.26(m,7H),4.94(dd,J＝16.5,8.0Hz,1H),4.27(ddt,J＝17.0,13.1,6.6Hz,3H),4.01(d,J＝7.0Hz,1H),2.68(d,J＝7.7Hz,2H),2.35(d,J＝7.3Hz,1H),2.28-2.10(m,1H),2.00(dd,J＝14.9,7.1Hz,2H),1.87-1.71(m,2H),1.59(d,J＝13.7Hz,1H),1.44(dd,J＝13.3,6.7Hz,1H),1.37-1.15(m,7H),1.06(t,J＝7.2Hz,2H),0.86-0.68(m,9H).
化合物A31：
1H NMR(400MHz,DMSO)δ9.02(d,J＝8.5Hz,1H),8.03(dd,J＝12.7,8.7Hz,1H),7.89(d,J＝7.5Hz,2H),7.66(s,2H),7.56(d,J＝13.3Hz,2H),7.40(d,J＝7.4Hz,2H),7.31(d,J＝7.8Hz,3H),4.92(d,J＝7.8Hz,1H),4.30(s,3H),4.04(s,1H),2.71(dd,J＝14.3,7.0Hz,2H),2.38(dd,J＝19.8,12.9Hz,1H),2.17(s,1H),2.00(t,J＝10.9Hz,1H),1.79(dd,J＝11.7,5.5Hz,2H),1.66-1.39(m,2H),1.22(d,J＝10.2Hz,8H),1.06(dd,J＝15.4,7.7Hz,1H),0.88-0.67(m,9H).
化合物A32：
1H NMR(400MHz,DMSO)δ9.15(d,J＝12.3Hz,1H),8.02-7.80(m,3H),7.67(t,J＝6.8Hz,2H),7.49-7.10(m,8H),5.16-4.75(m,1H),4.39-3.67(m,4H),2.86(dt,J＝13.8,6.9Hz,1H),2.71(dd,J＝24.6,11.1Hz,2H),2.20-2.10(m,1H),2.20-1.86(m,2H),1.86-1.62(m,2H),1.62-1.47(m,2H),1.34(dd,J＝9.8,5.8Hz,1H),1.30-1.01(m,14H),1.01-0.70(m,9H).
化合物A33：
1H NMR(400MHz,DMSO)δ9.06(d,J＝11.8Hz,1H),8.10(s,1H),7.89(d,J＝7.5Hz,2H),7.72-7.52(m,6H),7.41(t,J＝6.0Hz,2H),7.36-7.22(m,2H),5.05(d,J＝8.2Hz,1H),4.28(d,J＝5.5Hz,2H),4.21(d,J＝4.6Hz,1H),4.02(s,1H),2.76(s,2H),2.39(d,J＝8.7Hz,1H),2.17(s,1H),1.99(d,J＝6.3Hz,1H),1.79(d,J＝6.3Hz,2H),1.59(d,J＝13.1Hz,1H),1.51-1.40(m,1H),1.30-1.12(m,9H),0.87-0.69(m,9H).
化合物A34：
1H NMR(400MHz,DMSO)δ9.14(s,1H),7.90(dd,J＝16.7,8.1Hz,3H),7.66(t,J＝8.4Hz,2H),7.46-7.36(m,2H),7.36-7.26(m,2H),7.18(d,J＝8.1Hz,2H),7.10(d,J＝8.1Hz,2H),4.93(d,J＝8.1Hz,1H),4.24(dt,J＝15.1,10.3Hz,4H),3.99(d,J＝7.9Hz,1H),2.69(t,J＝11.7Hz,2H),2.33(d,J＝3.8Hz,1H),2.26(s,3H),2.15(s,1H),2.00(dd,J＝14.5,7.0Hz,2H),1.82-1.72(m,2H),1.58(d,J＝13.9Hz,1H),1.46(d,J＝6.0Hz,1H),1.32(dd,J＝9.9,5.2Hz,1H),1.24-1.17(m,6H),0.77(dd,J＝12.5,6.7Hz,9H).
化合物A35：
1H NMR(400MHz,DMSO)δ9.15(s,1H),8.10(s,1H),7.84(dd,J＝27.7,15.5Hz,6H),7.66(d,J＝7.8Hz,2H),7.50(d,J＝6.8Hz,3H),7.44-7.36(m,2H),7.33-7.24(m,2H),5.13(s,1H),4.31-4.18(m,3H),4.00(d,J＝8.1Hz,1H),2.79(s,2H),2.33(s,1H),2.16(s,1H),1.98(d,J＝6.4Hz,2H),1.78(s,2H),1.58(d,J＝15.0Hz,2H),1.45(s,1H),1.24-1.19(m,10H),0.75(dd,J＝19.2,15.4Hz,6H).
化合物A36：
1H NMR(400MHz,DMSO)δ9.30(s,1H),7.89(d,J＝7.5Hz,2H),7.62(d,J＝6.7Hz,2H),7.42(d,J＝2.3Hz,2H),7.36-7.13(m,8H),4.16(s,3H),4.03(d,J＝7.0Hz,2H),2.77-2.61(m,2H),2.46(s,3H),2.22-2.13(m,1H),2.00(d,J＝14.3Hz,1H),1.80(dd,J＝13.6,7.6Hz,2H),1.72-1.57(m,2H),1.40(d,J＝9.9Hz,1H),1.23(d,J＝16.1Hz,8H),0.90-0.76(m,9H).
化合物A37：
1H NMR(400MHz,DMSO)δ9.29(s,2H),7.89(d,J＝7.5Hz,4H),7.66-7.54(m,3H),7.42(t,J＝7.4Hz,4H),4.28-4.14(m,6.7Hz,6H),2.36-2.24(m,2H),1.77(s,3H),1.78-1.62(m,4H),1.37(t,J＝11.4Hz,3H),0.95-0.83(m,16H).
化合物A38：
1H NMR(400MHz,DMSO)δ9.23(s,1H),7.89(d,J＝7.5Hz,2H),7.65(t,J＝6.8Hz,2H),7.47-7.24(m,6H),6.92(dd,J＝5.1,3.4Hz,1H),6.81(d,J＝2.9Hz,1H),4.32-4.15(m,3H),3.98(d,J＝7.0Hz,2H),2.95(ddd,J＝23.2,14.7,6.6Hz,2H),2.44(t,J＝7.3Hz,3H),2.18-2.09(m,1H),2.00-1.91(m,1H),1.81-1.54(m,4H),1.36(d,J＝9.9Hz,1H),1.20(d,J＝10.6Hz,8H),0.88-0.75(m,9H).
化合物A39：
1H NMR(400MHz,DMSO)δ9.38(s,1H),7.87(d,J＝7.7Hz,3H),7.78(dd,J＝20.6,7.6Hz,2H),7.67(s,1H),7.61-7.52(m,2H),7.47(dd,J＝9.2,5.8Hz,2H),7.44-7.31(m,4H),7.27(t,J＝ 7.3Hz,1H),7.20(t,J＝7.4Hz,1H),4.14(dt,J＝13.4,7.0Hz,4H),4.04(d,J＝7.3Hz,1H),2.86(dt,J＝30.9,11.1Hz,2H),2.46-2.41(m,1H),2.23-2.12(m,1H),2.00(dd,J＝14.4,7.1Hz,2H),1.81(dd,J＝13.9,7.9Hz,2H),1.72-1.59(m,2H),1.41(d,J＝9.9Hz,1H),1.28(s,3H),1.23(d,J＝8.1Hz,6H),0.88-0.79(m,9H).
化合物A40：
1H NMR(400MHz,DMSO)δ9.31(s,1H),7.97-7.90(m,2H),7.88(d,J＝7.8Hz,2H),7.61(t,J＝7.4Hz,2H),7.45-7.38(m,3H),7.37-7.33(m,4H),7.32-7.27(m,1H),4.25-4.18(m,2H),4.16-4.02(m,3H),3.04-2.90(m,2H),2.53(dd,J＝11.5,4.3Hz,2H),2.46(s,1H),2.22-2.12(m,1H),2.02-1.91(m,1H),1.80(dd,J＝16.6,10.8Hz,2H),1.72-1.59(m,2H),1.40(d,J＝9.9Hz,1H),1.25-1.18(m,8H),0.86-0.78(m,9H).
化合物A41：
1H NMR(400MHz,DMSO)δ10.84(s,1H),9.35(s,1H),7.89(d,J＝7.6Hz,2H),7.69-7.54(m,3H),7.46-7.36(m,2H),7.36-7.27(m,3H),7.12-7.02(m,2H),6.94(t,J＝7.4Hz,1H),4.25-4.15(m,3H),4.09-3.96(m,2H),3.32(s,1H),2.84(d,J＝6.5Hz,2H),2.47-2.40(m,2H),2.15(t,J＝10.8Hz,1H),2.04-1.91(m,2H),1.83-1.74(m,2H),1.72-1.57(m,2H),1.40(d,J＝9.9Hz,1H),1.23(d,J＝14.8Hz,8H),0.91-0.70(m,9H).
化合物A44：
1H NMR(400MHz,DMSO)δ9.20(s,1H),7.89(d,J＝7.5Hz,2H),7.68(dd,J＝7.2,3.0Hz,2H),7.41(t,J＝7.4Hz,2H),7.38-7.27(m,3H),4.35-4.18(m,3H),4.00(d,J＝6.8Hz,1H),3.18-3.10(m,1H),3.06-2.99(m,1H),2.68-2.57(m,1H),2.45-2.39(m,1H),2.21-2.12(m,1H),2.03-1.93(m,1H),1.84-1.56(m,4H),1.27-1.20(m,9H),1.00(d,J＝6.9Hz,3H),0.84-0.76(m,9H).
化合物A45：
1H NMR(400MHz,DMSO)δ9.20(s,1H),7.89(d,J＝7.5Hz,2H),7.68(d,J＝7.4Hz,2H),7.41(t,J＝7.4Hz,2H),7.34-7.28(m,3H),4.34-4.23(m,2H),4.22-4.20(m,1H),4.01(d,J＝8.5Hz,1H),3.21-3.13(m,1H),3.06-2.98(m,1H),2.65-2.56(m,1H),2.45-2.41(m,1H),2.21-2.12(m,1H),2.03-1.94(m,1H),1.82-1.59(m,4H),1.37(d,J＝9.9Hz,1H),1.25-1.20(m,8H),1.01(d,J＝7.0Hz,3H),0.82(dd,J＝9.0,4.9Hz,9H).
化合物A46：
1H NMR(400MHz,DMSO)δ8.62(s,1H),7.89(d,J＝7.5Hz,2H),7.67(d,J＝7.4Hz,2H),7.41(t,J＝7.4Hz,2H),7.32(t,J＝7.4Hz,2H),7.23(d,J＝5.5Hz,1H),6.88(d,J＝8.4Hz,1H),4.33-3.99(m,5H),3.31-3.14(m,2H),2.61(s,1H),2.23-2.12(m,1H),2.01(s,1H),1.82(dd,J＝17.5,12.1Hz,2H),1.64(dd,J＝21.4,10.1Hz,2H),1.39-1.19(m,18H),0.86-0.75(m,9H).
化合物A47：
1H NMR(400MHz,DMSO)δ8.68(s,1H),7.89(d,J＝7.5Hz,2H),7.67(d,J＝7.4Hz,2H),7.41(t,J＝7.4Hz,2H),7.32(t,J＝7.5Hz,2H),7.21(s,1H),6.83(d,J＝8.0Hz,1H),4.33-4.20(m,3H),4.18-3.99(m,2H),3.28-3.23(m,2H),2.62-2.56(m,1H),2.23-2.10(m,1H),2.07-1.92(m,2H),1.84-1.81(m,1H),1.79-1.73(m,1H),1.70-1.59(m,2H),1.42-1.28(m,11H),1.22(d,J＝9.8Hz,6H),0.82(dd,J＝16.5,10.0Hz,9H).
化合物A48：
1H NMR(400MHz,DMSO)δ8.75(s,1H),7.90(d,J＝7.5Hz,2H),7.68(d,J＝7.4Hz,2H),7.41(dd,J＝14.8,7.4Hz,2H),7.38(s,9H),5.02(q,J＝12.5Hz,2H),4.36-4.17(m,4H),4.10(d,J＝7.3Hz,1H),2.61(s,1H),2.28-2.13(m,1H),2.09-1.92(m,2H),1.88-1.80(m,1H),1.78(s,1H),1.64(dd,J＝19.8,10.3Hz,2H),1.39-1.28(m,3H),1.23(d,J＝11.5Hz,7H),0.83(dd,J＝16.0,9.6Hz,9H).
化合物A49：
1H NMR(400MHz,DMSO)δ8.75(s,1H),7.89(d,J＝7.5Hz,2H),7.70(d,J＝7.4Hz,2H),7.42(t,J＝7.4Hz,2H),7.33(t,J＝7.4Hz,2H),7.23(dd,J＝12.9,7.1Hz,1H),5.89(dd,J＝10.4,5.7Hz,1H),4.34-4.17(m,3H),4.09(d,J＝8.6Hz,2H),3.03(d,J＝5.4Hz,1H),2.59(s,1H),2.19(s,1H),2.00(dd,J＝14.7,7.1Hz,2H),1.87-1.58(m,4H),1.32(dd,J＝12.5,6.2Hz,2H),1.25-1.20(m,7H),0.83(dd,J＝13.6,7.1Hz,9H).
化合物A50：
1H NMR(400MHz,DMSO)δ9.16(d,J＝34.3Hz,1H),7.89(d,J＝7.6Hz,2H),7.64(d,J＝7.4Hz,2H),7.49-7.18(m,10H),4.32-4.14(m,3H),4.11(d,J＝6.8Hz,1H),3.90(dd,J＝16.4,7.7Hz,1H),3.51-3.42(m,1H),2.44(s,1H),2.26-2.15(m,1H),2.01(s,1H),1.87-1.76(m,2H),1.71-1.54(m,2H),1.39-1.14(m,10H),0.79(dd,J＝12.4,5.8Hz,9H).
化合物A51：
1H NMR(400MHz,DMSO)δ9.05(s,1H),7.90(d,J＝7.5Hz,2H),7.71-7.58(m,3H),7.42(t,J＝7.4Hz,2H),7.34(t,J＝7.4Hz,2H),4.43-4.32(m,2H),4.24(t,J＝6.5Hz,1H),3.94(dd,J＝8.5,2.0Hz,1H),3.36(d,J＝8.6Hz,1H),3.24(dd,J＝15.1,6.0Hz,1H),2.42(t,J＝7.6Hz,1H),2.15(dd,J＝12.2,9.9Hz,1H),2.01-1.91(m,1H),1.82-1.69(m,3H),1.57(d,J＝13.8Hz,1H),1.36(d,J＝9.8Hz,1H),1.24(s,1H),1.19(d,J＝11.1Hz,7H),1.12-1.07(m,1H),1.06-1.01(m,1H),0.99(s,2H),0.88-0.76(m,9H).
化合物A52：
1H NMR(400MHz,DMSO)δ9.16(s,1H),7.89(d,J＝7.5Hz,2H),7.70(d,J＝5.1Hz,2H),7.38(ddd,J＝24.1,14.7,7.3Hz,4H),4.30(ddt,J＝30.8,13.5,6.8Hz,3H),3.97(d,J＝6.7Hz,1H),2.49(dd,J＝13.9,12.2Hz,7H),2.48-2.41(m,1H),2.23-2.10(m,3H),2.02(dd,J＝24.6,16.9Hz,3H),1.90-1.81(m,4H),1.39-1.22(m,8H),0.98-0.80(m,8H).
化合物A53：
1H NMR(400MHz,DMSO)δ9.21(s,1H),7.89(d,J＝5.2Hz,2H),7.70(s,2H),7.37(d,J＝35.9Hz,4H),7.20(s,1H),4.29(d,J＝37.6Hz,3H),3.93(s,1H),3.10(s,2H),2.46(d,J＝40.9Hz,4H),2.10(d,J＝13.9Hz,1H),1.96(s,3H),1.76(s,3H),1.55(d,J＝30.7Hz,4H),1.20(s,11H),0.81(d,J＝11.3Hz,9H).
化合物A54：
1H NMR(400MHz,DMSO)δ9.14(s,1H),7.88(d,J＝7.4Hz,2H),7.67(dd,J＝15.6,10.7Hz,2H),7.41(t,J＝7.3Hz,2H),7.31(dd,J＝15.0,7.3Hz,3H),4.33(dd,J＝9.2,4.8Hz,1H),4.28-4.20(m,2H),3.98(d,J＝6.9Hz,1H),3.71(d,J＝12.3Hz,2H),3.15(d,J＝6.6Hz,2H),2.73(s,2H),2.17-2.10(m,1H),1.99-1.91(m,4H),1.83-1.67(m,4H),1.61-1.28(m,17H),0.82(dd,J＝16.3,9.6Hz,12H).
化合物A55：
1H NMR(400MHz,DMSO)δ9.37(s,1H),7.88(t,J＝9.4Hz,2H),7.72(dd,J＝7.0,5.1Hz,2H),7.41(q,J＝8.1Hz,2H),7.33(td,J＝8.4,1.0Hz,2H),7.02(d,J＝9.2Hz,1H),5.05(d,J＝5.3Hz,1H),4.41-4.32(m,1H),4.28(dd,J＝10.3,6.9Hz,1H),4.22(t,J＝6.9Hz,1H),3.96(dd,J＝8.4,1.9Hz,1H),3.83(dt,J＝8.8,4.4Hz,1H),3.58(t,J＝9.8Hz,1H),2.38(dd,J＝20.0,5.8Hz,2H),2.20(ddd,J＝31.5,12.5,9.1Hz,2H),2.04-1.88(m,1H),1.86-1.66(m,4H),1.66-1.47(m,2H),1.43-1.30(m,9H),1.31(d,J＝5.6Hz,14H).
化合物A57：
1H NMR(400MHz,DMSO)δ9.23(s,1H),7.88(d,J＝7.5Hz,2H),7.74(d,J＝7.2Hz,1H),7.67(d,J＝7.4Hz,1H),7.41(t,J＝7.3Hz,2H),7.35-7.32(m,2H),7.10(d,J＝8.0Hz,1H),4.28-4.12(m,4H),3.97-3.91(m,1H),2.94(q,J＝7.4Hz,1H),2.35(t,J＝7.6Hz,1H),2.13-2.03(m,1H),1.97-1.85(m,3H),1.84-1.76(m,3H),1.76-1.63(m,3H),1.63-1.42(m,3H),1.39-1.26(m,2H),1.20(d,J＝12.3Hz,6H),0.76(d,J＝9.2Hz,9H).
化合物A58：
1H NMR(400MHz,DMSO)δ9.27(s,1H),7.89(d,J＝7.5Hz,2H),7.74-7.67(m,2H),7.42(t,J＝7.1Hz,2H),7.32(t,J＝7.5Hz,2H),6.62(d,J＝8.7Hz,1H),4.26-4.13(m,4H),4.04(d,J＝6.2Hz,1H),2.96-2.87(m,1H),2.48-2.41(m,1H),2.22-2.12(m,1H),2.03-1.94(m,1H),1.91-1.75(m,6H),1.72-1.62(m,3H),1.58-1.49(m,1H),1.43(d,J＝9.8Hz,1H),1.26-1.18(m,8H),0.81(dd,J＝10.4,6.7Hz,9H).
化合物A66：
1H NMR(400MHz,DMSO)δ8.98(s,1H),7.89(d,J＝7.5Hz,2H),7.71-7.63(m,2H),7.41(t,J＝7.4Hz,2H),7.37-7.29(m,2H),7.16(d,J＝8.7Hz,1H),4.23(s,3H),3.96(d,J＝7.4Hz,1H),3.53-3.43(m,2H),2.40-2.32(m,2H),2.15-2.08(m,1H),2.00-1.90(m,1H),1.85-1.60(m,7H),1.55(d,J＝13.7Hz,1H),1.45(d,J＝10.5Hz,1H),1.35(d,J＝9.9Hz,1H),1.28-1.22(m,3H),1.21-1.15(m,8H),0.81-0.70(m,8H).
化合物A67：
1H NMR(400MHz,DMSO)δ9.10(s,1H),7.86(d,J＝7.5Hz,2H),7.69(dd,J＝15.4,7.5Hz,2H),7.41(t,J＝7.5Hz,2H),7.32(dd,J＝13.6,6.4Hz,2H),6.91(d,J＝7.2Hz,1H),4.27-4.18(m,3H),3.99(d,J＝8.1Hz,1H),3.92-3.83(m,1H),2.75-2.64(m,1H),2.44-2.36(m,1H),2.20-2.10(m,1H),2.03-1.92(m,2H),1.87-1.72(m,4H),1.72-1.46(m,6H),1.41(d,J＝10.0Hz,1H),1.39-1.30(m,1H),1.26-1.20(m,8H),0.89-0.74(m,9H).
化合物A68：
1H NMR(400MHz,DMSO)δ9.02(s,1H),7.88(d,J＝7.5Hz,2H),7.67(d,J＝7.4Hz,1H),7.63(d,J＝7.4Hz,1H),7.40(t,J＝7.4Hz,2H),7.32(dd,J＝16.0,7.8Hz,2H),7.20(d,J＝8.9Hz,1H),4.34-4.13(m,3H),3.92(d,J＝7.0Hz,1H),3.69-3.56(m,1H),2.39-2.33(m,2H),2.17-2.05(m,1H),1.94-1.86(m,1H),1.85-1.60(m,7H),1.60-1.39(m,2H),1.32(d,J＝9.8Hz,1H),1.24-1.07(m,11H),0.86-0.73(m,9H).
化合物A69：
1H NMR(400MHz,DMSO)δ9.17(s,1H),7.88(d,J＝7.5Hz,2H),7.76(d,J＝7.4Hz,1H),7.67(d,J＝7.3Hz,1H),7.41(t,J＝7.2Hz,2H),7.33(dt,J＝15.9,4.5Hz,2H),7.22(d,J＝8.4Hz,1H),4.32-4.23(m,2H),4.16-4.07(m,1H),4.04-3.87(m,2H),2.77-2.67(m,1H),2.33(t,J＝7.2 Hz,1H),2.14-2.03(m,1H),1.98-1.90(m,1H),1.88-1.81(m,1H),1.79-1.69(m,3H),1.68-1.42(m,6H),1.36(d,J＝9.8Hz,2H),1.30-1.25(m,3H),1.19(d,J＝9.2Hz,6H),0.82-0.73(m,9H).
化合物A93：
1H NMR(400MHz,DMSO)δ9.39(s,1H),7.90(d,J＝7.5Hz,2H),7.64(d,J＝7.4Hz,2H),7.42(t,J＝7.4Hz,2H),7.35(t,J＝7.3Hz,2H),4.36-4.22(m,3H),3.99(d,J＝6.8Hz,1H),3.42(t,J＝6.6Hz,1H),2.81(d,J＝4.6Hz,3H),2.49-2.35(m,3H),2.20-2.11(m,1H),1.97(s,1H),1.82-1.74(m,2H),1.72-1.54(m,2H),1.36(t,J＝8.8Hz,1H),1.25-1.19(m,9H),0.87-0.82(m,6H),0.80(s,3H).
化合物A95：
1H NMR(400MHz,DMSO)δ9.40(s,1H),7.89(d,J＝7.5Hz,2H),7.66(t,J＝11.7Hz,2H),7.41(t,J＝7.4Hz,2H),7.33(t,J＝7.2Hz,3H),4.31(d,J＝6.8Hz,2H),4.21(t,J＝6.8Hz,1H),3.96(d,J＝6.7Hz,1H),2.99(dd,J＝12.7,6.5Hz,2H),2.38(t,J＝7.6Hz,1H),2.30-2.11(m,3H),1.96(s,1H),1.78(dd,J＝12.3,6.4Hz,2H),1.72-1.56(m,4H),1.37(d,J＝9.8Hz,1H),1.30-1.12(m,8H),0.83(dd,J＝14.7,8.9Hz,9H).
化合物A97：
1H NMR(400MHz,DMSO)δ9.32(s,1H),7.90(d,J＝7.6Hz,3H),7.72(d,J＝7.4Hz,2H),7.42(s,2H),7.39-7.26(m,7H),5.14(s,2H),4.36-4.18(m,3H),4.18-4.06(m,1H),3.98(d,J＝6.6Hz,1H),2.39(dd,J＝17.1,11.2Hz,3H),2.14(dd,J＝27.6,19.0Hz,1H),2.08-1.92(m,2H),1.79(dd,J＝13.6,7.7Hz,2H),1.72-1.56(m,2H),1.37(d,J＝9.8Hz,1H),1.21(s,9H),0.91-0.75(m,9H).
化合物A98：
1H NMR(400MHz,DMSO)δ8.92(d,J＝3.1Hz,1H),7.90(d,J＝7.5Hz,2H),7.64(d,J＝7.5Hz,2H),7.43(t,J＝7.2Hz,2H),7.34(t,J＝7.1Hz,2H),4.27(d,J＝8.8Hz,3H),4.14(dd,J＝8.6,1.9Hz,1H),4.00(d,J＝62.4Hz,4H),3.51-3.39(m,1H),2.67-2.56(m,1H),2.30-2.22(m,1H),2.09-1.94(m,1H),1.90-1.76(m,3H),1.67(t,J＝10.7Hz,2H),1.38-1.25(m,8H),0.90-0.81(m,9H).
化合物A99：
1H NMR(400MHz,DMSO)δ9.38(d,J＝67.5Hz,1H),7.90(d,J＝7.0Hz,2H),7.66(d,J＝7.2Hz,2H),7.46-7.30(m,4H),3.98(d,J＝8.0Hz,2H),3.26(dd,J＝16.4,8.8Hz,2H),2.68(t,J＝20.0Hz,1H),2.54-2.42(m,3H),2.17(s,1H),1.99(d,J＝15.5Hz,2H),1.82-1.66(m,4H),1.63(dd,J＝27.1,15.8Hz,3H),1.36-1.26(m,1H),1.19-1.00(m,10H),0.93-0.79(m,9H).
化合物A100：
1H NMR(400MHz,DMSO)δ9.31(s,1H),7.90(d,J＝7.5Hz,2H),7.70(d,J＝7.4Hz,2H),7.44-7.32(m,5H),4.33-4.17(m,4H),2.41(t,J＝6.9Hz,1H),2.20-2.08(m,2H),1.99(dt,J＝13.5,6.7Hz,1H),1.83-1.70(m,6H),1.68-1.62(m,3H),1.37(d,J＝11.8Hz,2H),1.23(d,J＝11.4Hz,9H),1.00-0.81(m,9H).
化合物A101：
1H NMR(400MHz,DMSO)δ9.33(s,1H),7.89(d,J＝7.2Hz,2H),7.69(d,J＝7.4Hz,2H),7.41(t,J＝7.4Hz,2H),7.33(t,J＝7.4Hz,3H),4.30(s,2H),4.20(s,1H),3.97(d,J＝7.7Hz,1H),2.89(s,1H),2.38(s,1H),2.21-2.12(m,1H),2.04-1.85(m,4H),1.81-1.67(m,2H),1.59(d,J＝12.6Hz,1H),1.37(d,J＝10.4Hz,1H),1.21(d,J＝3.0Hz,13H),0.85(dd,J＝6.6,4.0Hz,9H).
实施例2：化合物A72的合成
化合物A72：
化合物A72-2的合成
将化合物A72-1(150mg,0.617mmol)溶于甲苯/甲醇＝1/3的混合溶剂(2mL)中，室温搅拌下，加入TMSCHN2(2mL,0.6M,1.23mmol)，反应液为浅黄色澄清液，室温搅拌5min后，TLC显示反应完全，旋干反应液，加入二氯甲烷(3mL)和三氟乙酸(1mL)，室温搅拌1h后，反应完全，旋干溶剂得化合物粗品A72-2(250mg,粗品)。
化合物A72-4的合成
将化合物A72-2(250mg,粗品)，化合物A72-3(120mg,0.53mmol)和HATU(243mg,0.63mmol)溶于二氯甲烷(8mL)中，室温搅拌下加入三乙胺(235uL,1.7mmol)，室温搅拌2h后，TLC显示反应完全，反应液中加入适量水，用二氯甲烷萃取(15mL*3)，合并有机相后经无水硫酸钠干燥，旋干有机相，经厚制备板分离纯化，展开剂(EA:PE＝1:1)得化合物A72-4(93mg，产率：48.2％)。
化合物A72-5的合成
将化合物A72-4(93mg,0.255mmol)溶于甲醇(5mL)中，室温搅拌下加入LiOH水溶液(1M,0.5mL,0.51mmol)，室温搅拌2h后，TLC显示未反应，油浴70℃搅拌1h，反应完全，自然冷却后,有白色固体析出，过滤，滤饼用少量甲醇洗涤，得到化合物A72-5(70mg，产率：77.8％)。
化合物A72的合成
将化合物A72-5(70mg,0.2mmol)，化合物A1-2(91mg,0.24mmol)和HATU(91mg,0.24mmol)溶于DMF(8mL)中，室温搅拌下加入三乙胺(61uL,0.44mmol)，室温搅拌1h后，TLC显示反应完全，反应液直接经中压制备分离纯化，得化合物A72(76mg，产率：63.4％)。
1H NMR(400MHz,DMSO)δ9.15(s,1H),8.94(s,1H),8.39-8.36(m,2H),8.26(d,J＝7.8Hz,1H),8.12(d,J＝7.9Hz,1H),7.66(d,J＝8.3Hz,1H),7.57(t,J＝7.7Hz,1H),7.28(t,J＝7.4Hz,1H),5.13-5.02(m,2H),4.04(d,J＝6.7Hz,1H),3.90-3.81(m,1H),2.45-2.38(m,2H),2.28-2.18(m,1H),2.08-2.00(m,1H),1.86(dd,J＝12.7,7.0Hz,1H),1.83-1.75(m,3H),1.74-1.62(m,3H),1.49(d,J＝9.8Hz,1H),1.38-1.13(m,13H),0.86-0.80(m,9H).
化合物A20：
1H NMR(400MHz,DMSO)δ9.33(s,1H),8.13(t,J＝5.6Hz,1H),7.87(d,J＝7.4Hz,2H),7.52(d,J＝7.4Hz,2H),7.38(t,J＝7.3Hz,2H),7.32(t,J＝7.4Hz,2H),4.36(t,J＝7.5Hz,1H),4.02(dd,J＝8.5,1.9Hz,1H),3.45-3.37(m,2H),2.57-2.51(m,4H),2.49-2.42(m,1H),2.27-2.13(m,1H),2.04-1.95(m,1H),1.83-1.75(m,2H),1.71-1.63(m,1H),1.63-1.57(m,1H),1.38(d,J＝9.9Hz,1H),1.31-1.28(m,8H),0.91-0.76(m,9H).
化合物A21：
1H NMR(400MHz,CD3OD)δ8.12-8.07(m,2H),7.62-7.52(m,2H),4.16(dd,J＝8.6,2.2Hz,1H),3.85-3.65(m,2H),2.81-2.69(m,2H),2.65-2.61(m,1H),2.38-2.28(m,1H),2.13-2.05(m,1H),1.93(t,J＝5.5Hz,1H),1.84-1.80(m,2H),1.71-1.62(m,1H),1.47(d,J＝10.2Hz,1H),1.37-1.24(m,8H),0.87(dt,J＝13.0,6.3Hz,9H).
化合物A22：
1H NMR(400MHz,DMSO)δ9.30(s,1H),8.04(d,J＝8.3Hz,1H),7.32-7.20(m,5H),4.11-4.03(m,1H),4.00(dd,J＝8.5,1.9Hz,1H),3.39(d,J＝2.7Hz,2H),2.42-2.35(m,4H),2.34-2.26(m,1H),2.20-2.13(m,1H),2.04-1.92(m,5H),1.83-1.75(m,2H),1.70-1.57(m,4H),1.30-1.28(m,2H),1.21(s,6H),0.83(dd,J＝14.0,7.8Hz,9H).
化合物A24：
1H NMR(400MHz,DMSO)δ9.31(s,1H),7.90(d,J＝7.9Hz,1H),7.21-7.14(m,2H),7.13-7.09(m,2H),4.14-4.03(m,1H),4.00(dd,J＝8.5,2.0Hz,1H),3.17-3.09(m,1H),3.06-3.03(m,4H),2.52-2.47(m,1H),2.42-2.32(m,2H),2.20-2.14(m,1H),2.00-1.95(m,1H),1.82-1.73(m,2H),1.69-1.66(m,1H),1.62-1.58(m,1H),1.38(d,J＝9.9Hz,1H),1.26-1.21(m,8H),1.09(d,J＝6.6Hz,3H),0.89-0.76(m,9H).
化合物A25：
1H NMR(400MHz,DMSO)δ9.31(s,1H),7.83(d,J＝7.9Hz,1H),7.23-7.15(m,2H),7.13-7.05(m,2H),4.14-4.04(m,1H),3.99(dd,J＝8.5,1.9Hz,1H),2.98(dd,J＝15.3,7.7Hz,2H),2.77-2.66(m,1H),2.55(dd,J＝15.5,7.1Hz,2H),2.48-2.46(m,1H),2.42-2.38(m,1H),2.35-2.29(m,1H),2.20(d,J＝7.4Hz,2H),2.18-2.12(m,1H),2.00-1.98(m,1H),1.81-1.58(m,4H),1.26-1.21(m,9H),1.06(d,J＝6.7Hz,3H),0.90-0.76(m,9H).
化合物A26：
1H NMR(400MHz,DMSO)δ9.24(s,1H),9.05(d,J＝8.6Hz,1H),8.23(d,J＝7.8Hz,1H),8.11(d,J＝7.7Hz,1H),7.67-7.53(m,2H),4.45-4.31(m,1H),4.06-3.94(m,1H),2.68-2.63(m,1H),2.57-2.53(m,1H),2.47-2.42(m,1H),2.18-2.08(m,1H),1.98-1.89(m,1H),1.78(t,J＝5.5 Hz,1H),1.74-1.69(m,1H),1.67-1.52(m,2H),1.35(d,J＝8.5Hz,1H),1.27-1.13(m,11H),0.82-0.67(m,9H).
化合物A27：
1H NMR(400MHz,DMSO)δ9.36(s,1H),8.48(d,J＝8.0Hz,1H),8.41(s,1H),8.03-7.95(m,3H),7.91(dd,J＝8.6,1.6Hz,1H),7.64-7.56(m,2H),4.44-4.31(m,1H),3.99(dd,J＝8.5,2.0Hz,1H),2.65(dd,J＝14.1,6.5Hz,1H),2.53-2.47(m,1H),2.42(t,J＝7.6Hz,1H),2.19-2.11(m,1H),1.99-1.91(m,1H),1.82-1.71(m,2H),171-1.64(m,1H),1.61-1.56(m,1H),1.37(d,J＝9.9Hz,1H),1.26-1.16(m,11H),0.80(dd,J＝16.8,6.2Hz,9H).
化合物A42：
1H NMR(400MHz,DMSO)δ10.85(s,1H),9.37(s,1H),7.97(d,J＝8.2Hz,1H),7.84(d,J＝7.6Hz,2H),7.65(d,J＝11.6Hz,1H),7.44(d,J＝7.5Hz,1H),7.37-7.25(m,5H),7.18(t,J＝7.4Hz,1H),7.13(d,J＝2.1Hz,1H),7.09(dd,J＝9.9,5.6Hz,1H),6.97(t,J＝7.1Hz,1H),4.55-4/47(m,1H),4.30(t,J＝7.3Hz,1H),4.07(d,J＝10.3Hz,1H),2.96-2.89(m,1H),2.87-2.78(m,1H),2.60-2.52(m,2H),2.47-2.41(m,3H),2.21-2.15(m,1H),2.04-1.95(m,2H),1.85-1.62(m,4H),1.33-1.28(m,2H),1.22(d,J＝6.2Hz,6H),0.84(dd,J＝9.9,3.2Hz,9H).
化合物A43：
1H NMR(400MHz,DMSO)δ10.81(s,1H),9.31(s,1H),7.68(d,J＝8.2Hz,1H),7.57(d,J＝7.8Hz,1H),7.31(d,J＝8.1Hz,1H),7.10(d,J＝2.2Hz,1H),7.05(t,J＝7.5Hz,1H),6.94(t,J＝7.4Hz,1H),4.24(dt,J＝14.7,7.4Hz,1H),4.04-3.94(m,1H),3.17(d,J＝5.3Hz,2H),2.82(qd,J＝14.3,6.6Hz,2H),2.48-2.38(m,3H),2.18(dd,J＝12.1,9.7Hz,1H),2.00(dd,J＝16.9,6.9Hz,3H),1.83-1.73(m,2H),1.70(dd,J＝13.8,6.9Hz,1H),1.65-1.41(m,6H),1.37(d,J＝12.7Hz,1H),1.27-1.20(m,8H),1.09-0.94(m,2H),0.84(dd,J＝14.1,8.0Hz,9H).
化合物A56：
1H NMR(400MHz,DMSO)δ11.17(s,1H),9.33(d,J＝4.1Hz,1H),8.54(d,J＝8.3Hz,1H),7.88(dd,J＝7.5,2.8Hz,2H),7.75(dd,J＝7.9,1.2Hz,1H),7.65-7.49(m,3H),7.41-7.36(m,2H),7.32-7.27(m,2H),7.25-7.18(m,1H),4.45(t,J＝7.6Hz,1H),3.96(dd,J＝8.8,2.1Hz,1H),2.80(dd,J＝15.3,7.4Hz,1H),2.75-2.60(m,2H),1.95-1.87(m,1H),1.76-1.64(m,3H),1.55-1.43(m,1H),1.40-1.23(m,4H),1.04(d,J＝5.7Hz,6H),0.90-0.79(m,6H),0.64(s,3H).
化合物A59：
1H NMR(400MHz,DMSO)δ9.34(s,1H),7.99(d,J＝7.8Hz,1H),7.21-7.15(m,2H),7.12-7.07(m,2H),4.21-4.12(m,1H),3.98(dd,J＝8.5,2.0Hz,1H),3.03-2.93(m,2H),2.76-2.70(m,1H),2.65-2.60(m,1H),2.59-2.52(m,2H),2.42-2.34(m,1H),2.21(d,J＝7.5Hz,2H),2.16-2.14(m,1H),2.03-1.88(m,4H),1.81-1.75(m,2H),1.73-1.57(m,4H),1.53-1.43(m,2H),1.29-1.21(m,8H),0.87-0.79(m,9H).
化合物A60：
1H NMR(400MHz,DMSO)δ9.32(s,1H),8.59(d,J＝7.8Hz,1H),8.43(s,1H),8.03-7.95(m,3H),7.92(dd,J＝8.6,1.6Hz,1H),7.65-7.55(m,2H),4.44(dd,J＝15.2,7.7Hz,1H),3.98(dd,J＝8.5,2.0Hz,1H),2.90-2.79(m,1H),2.42-2.35(m,1H),2.21-2.11(m,1H),2.09-1.89(m,3H),1.83-1.68(m,6H),1.67-1.53(m,2H),1.36(d,J＝9.8Hz,1H),1.28-1.16(m,8H),0.84-0.69(m,9H).
化合物A61：
1H NMR(400MHz,DMSO)δ9.38(s,1H),8.14(d,J＝7.6Hz,1H),7.91-7.83(m,2H),7.52(d,J＝7.6Hz,2H),7.42-7.27(m,4H),4.35(t,J＝7.2Hz,2H),4.03(dd,J＝8.5,2.2Hz,1H),2.74-2.67(m,1H),2.45(dd,J＝15.5,7.6Hz,2H),2.24-2.15(m,1H),2.08-1.92(m,3H),1.87-1.60(m,7H),1.54(dd,J＝12.7,6.9Hz,1H),1.42(d,J＝9.8Hz,1H),1.33-1.17(m,9H),0.92-0.76(m,9H).
化合物A63：
1H NMR(400MHz,DMSO)δ9.23(s,1H),8.53(d,J＝7.7Hz,1H),8.14(d,J＝7.7Hz,2H),7.54-7.37(m,4H),7.20(dd,J＝10.9,3.9Hz,2H),5.03-4.91(m,2H),4.23-4.14(m,1H),3.97(d,J＝6.4Hz,1H),2.78-2.70(m,1H),2.35(t,J＝7.7Hz,1H),2.21-2.11(m,1H),2.04-1.89(m,3H),1.82-1.53(m,8H),1.37(d,J＝9.8Hz,1H),1.24-1.17(m,8H),0.78(dd,J＝6.7,2.7Hz,9H).
化合物A64：
1H NMR(400MHz,DMSO)δ9.32(s,1H),8.06(d,J＝7.7Hz,1H),7.22-7.05(m,4H),4.16(p,J＝7.4Hz,1H),3.98(dd,J＝8.4,2.0Hz,1H),3.16-3.10(m,1H),3.04(d,J＝7.8Hz,4H),2.66(dd,J＝14.9,6.8Hz,1H),2.37(t,J＝7.0Hz,1H),2.23-2.11(m,1H),2.02-1.91(m,3H),1.82-1.75(m,2H),1.74-1.63(m,4H),1.62-1.50(m,2H),1.37(d,J＝9.8Hz,1H),1.30-1.24(m,1H),1.20(d,J＝6.8Hz,7H),0.87-0.75(m,9H).
化合物A65：
1H NMR(400MHz,DMSO)δ9.26-9.13(m,2H),8.23(d,J＝7.8Hz,1H),8.13(d,J＝7.5Hz,1H),7.66-7.54(m,2H),4.47-4.34(m,1H),3.98(d,J＝6.5Hz,1H),2.99-2.92(m,1H),2.42-2.35(m,1H),2.19-2.11(m,1H),2.07-1.91(m,3H),1.82-1.67(m,6H),1.63-1.53(m,2H),1.33(d,J＝9.9Hz,1H),1.22-1.13(m,8H),0.80-0.69(m,9H).
化合物A70：
1H NMR(400MHz,DMSO)δ9.05(s,1H),7.72(d,J＝8.6Hz,1H),7.23-7.15(m,2H),7.12-7.04(m,2H),3.96(dd,J＝8.4,1.9Hz,1H),3.86-3.73(m,1H),3.05-2.93(m,2H),2.74-2.66(m, 1H),2.56-2.53(m,1H),2.39-2.29(m,2H),2.18-2.10(m,3H),2.00-1.92(m,1H),1.81-1.75(m,4H),1.69-1.53(m,4H),1.47-1.35(m,2H),1.30-1.14(m,12H),0.81(dd,J＝6.6,4.8Hz,9H).
化合物A71：
1H NMR(400MHz,DMSO)δ9.03(s,1H),8.38(s,1H),8.29(d,J＝8.5Hz,1H),8.00-7.95(m,3H),7.88(dd,J＝8.6,1.6Hz,1H),7.64-7.55(m,2H),4.05-3.95(m,1H),3.94-3.89(m,1H),2.65-2.55(m,1H),2.37-2.31(m,1H),2.13-2.04(m,1H),2.01-1.87(m,2H),1.86-1.78(m,1H),1.76-1.70(m,4H),1.64-1.48(m,3H),1.43-1.34(m,2H),1.30(d,J＝9.9Hz,1H),1.26-1.22(m,1H),1.18(d,J＝5.5Hz,6H),1.09-1.03(m,2H),0.76(s,3H),0.71(d,J＝6.5Hz,3H),0.52(d,J＝6.6Hz,3H).
化合物A94：
1H NMR(400MHz,DMSO)δ9.46(s,1H),7.86(dd,J＝7.5,3.6Hz,2H),7.63(d,J＝7.6Hz,2H),7.38(t,J＝7.2Hz,2H),7.30(t,J＝7.4Hz,2H),4.47-4.38(m,1H),4.04-3.93(m,1H),3.64(t,J＝7.1Hz,1H),2.92(d,J＝9.7Hz,3H),2.76(d,J＝7.1Hz,1H),2.61(t,J＝6.8Hz,1H),2.48-2.39(m,2H),2.16(s,1H),2.04-1.95(m,2H),1.84-1.56(m,4H),1.44-1.36(m,1H),1.34-1.19(m,9H),1.16(s,1H),0.90-0.75(m,8H).
化合物A96：
1H NMR(400MHz,DMSO)δ9.41(s,1H),8.41(t,J＝5.6Hz,1H),7.88(d,J＝7.5Hz,2H),7.52(d,J＝7.4Hz,2H),7.42(t,J＝7.4Hz,2H),7.35-7.29(m,2H),4.80(s,1H),4.02-3.97(m,1H),3.16(dd,J＝13.5,6.6Hz,2H),2.42(t,J＝7.3Hz,1H),2.33(t,J＝7.7Hz,2H),2.22-2.15(m,1H),2.01-1.95(m,1H),1.83-1.69(m,5H),1.61(d,J＝13.8Hz,1H),1.39(d,J＝9.8Hz,1H),1.24(d,J＝8.7Hz,9H),0.92-0.74(m,9H).
化合物A20-A22、24-27、42-43、56、59-61、63-65、70-71、94、96合成方法同A72。
实施例3：化合物A91的合成
化合物A91：
化合物A91-1(176mg,0.5mmol)和A91-2(202mg,0.6mmol)溶于DCM(3mL)中，加入HATU(285mg,0.75mmol)和TEA(151mg,1.5mmol)，室温反应两个小时。加水，用DCM萃取(15mL*3)，合并有机相，拉干溶剂后，用中压制备纯化粗产品得到白色固体化合物A91(17mg,产率6％)
1H NMR(400MHz,DMSO)δ9.48(d,J＝10.6Hz,1H),7.89(d,J＝7.5Hz,2H),7.72-7.63(m,2H),7.44-7.25(m,5H),4.25(dt,J＝17.6,5.2Hz,3H),3.94(t,J＝6.9Hz,1H),3.23(dd,J＝15.5,8.5Hz,1H),2.39(d,J＝7.3Hz,1H),2.20-2.09(m,1H),1.98(d,J＝21.6Hz,1H),1.77(dd,J＝11.0,5.4Hz,2H),1.58(d,J＝13.5Hz,1H),1.39-1.32(m,1H),1.21(t,J＝7.8Hz,8H),0.98(dd,J＝7.0,4.1Hz,3H),0.86(t,J＝10.8Hz,1H),0.78(s,3H),0.42-0.27(m,2H),0.22(d,J＝3.5Hz,2H).
化合物92合成方法同A91。
化合物A92：
1H NMR(400MHz,DMSO)δ9.32(d,J＝10.5Hz,1H),7.89(d,J＝7.5Hz,2H),7.69(dd,J＝13.4,5.4Hz,2H),7.42(t,J＝7.4Hz,2H),7.33(dd,J＝12.9,6.8Hz,2H),7.20(d,J＝9.2Hz,1H),4.35-4.18(m,3H),3.94(dd,J＝18.3,6.8Hz,1H),3.81-3.64(m,1H),2.43-2.30(m,2H),2.20-2.08(m,1H),2.05-1.89(m,2H),1.73(qd,J＝12.2,5.6Hz,3H),1.64-1.51(m,1H),1.35(t,J＝9.9Hz,1H),1.22(d,J＝15.6Hz,6H),0.96(dd,J＝7.1,3.2Hz,3H),0.82(ddd,J＝14.9,14.1,4.9Hz,9H).
实施例4：化合物A23的合成
化合物A23：
化合物A23-2的合成
化合物A23-1(500mg,1.9mmol)溶于甲醇(20mL)，滴入几滴浓硫酸，升至70℃反应16h，加饱和碳酸氢钠溶液调pH至8-9，拉干甲醇，用乙酸乙酯萃取(20mL*3)，合并有机相，拉干溶剂，得到粗品化合物A23-2(215mg)。
化合物A23-4的合成
三光气(45mg,0.14mmol)溶于二氯甲烷(5mL)中，降至-15℃，滴加化合物A23-3(80mg，0.36mmol)和TEA(110mg)的二氯甲烷(5mL)混合液，反应20min。再滴加化合物A23-2(50mg，0.28mmol)和TEA(60mg，0.58mmol)的二氯甲烷(5mL)混合液，室温下反应1h，加水用二氯甲烷萃取(30mL*3)，合并有机相，拉干溶剂后，薄层色谱分离得到化合物A23-4(100mg,产率91％)。
化合物A23-5的合成
化合物A23-4(100mg，0.26mmol)溶于1,4-二氧六环(8mL)和水(10mL)中，滴入几滴浓硫酸，升至100℃反应1.5h，用乙酸乙酯萃取(30mL*3)，合并有机相，拉干溶剂，得到粗品化合物A23-5(100mg)。
化合物A23的合成
化合物A23-5(100mg,0.27mmol)和化合物A1-2(85mg,0.32mmol)溶于二氯甲烷(12mL)中，加入HATU(130mg,0.4mmol)和三乙胺(95mg,0.95mmol)，室温反应16h。加水用二氯甲烷萃取(30mL*3)，合并有机相，拉干溶剂后，用中压制备纯化粗产品得到化合物A23(18mg,产率10％)。
1H NMR(400MHz,DMSO)δ9.44(s,1H),7.83(d,J＝7.5Hz,2H),7.54(dd,J＝7.2,2.5Hz,2H),7.40(t,J＝7.4Hz,2H),7.31(t,J＝6.9Hz,2H),6.51(d,J＝8.7Hz,1H),5.92(d,J＝8.6Hz,1H),5.82(d,J＝8.7Hz,1H),4.13-4.05(m,1H),4.00(d,J＝8.6Hz,1H),2.62-2.55(m,2H),2.47-2.39(m,3H),2.23-2.13(m,1H),2.05(s,3H),2.00-1.95(m,2H),1.79-1.60(m,6H),1.29-1.26(m,2H),1.21(s,6H),0.90-0.76(m,9H).
化合物A62合成方法同A23。
化合物A62：
1H NMR(400MHz,DMSO)δ9.59(s,1H),7.83(d,J＝7.5Hz,2H),7.54(dd,J＝7.4,0.8Hz,2H),7.40(t,J＝7.4Hz,2H),7.31(tdd,J＝7.4,4.3,1.0Hz,2H),6.42(d,J＝8.6Hz,1H),6.11(d,J＝7.9Hz,1H),5.82(d,J＝8.6Hz,1H),4.19(p,J＝7.5Hz,1H),4.00(dd,J＝8.5,2.0Hz,1H),2.70(dd,J＝15.4,7.4Hz,1H),2.42(t,J＝7.4Hz,1H),2.19(dt,J＝10.9,9.8Hz,1H),2.05-1.91(m,3H),1.79(dt,J＝14.0,6.6Hz,3H),1.74-1.59(m,4H),1.51(dt,J＝20.3,7.7Hz,1H),1.42(d,J＝9.8Hz,1H),1.34-1.19(m,9H),0.90-0.79(m,9H).
实施例5：化合物A73的合成
化合物A73：
化合物A73-2的合成
化合物A73-1(5g，23.7mmol)溶于二氯甲烷(40mL)中，滴入几滴DMF，慢慢加入草酰氯(9g，71.4mmol)，室温下反应1h。拉干溶剂，用四氢呋喃(20mL)溶解，加入氨水(15mL)，室温下反应2h，加水后用乙酸乙酯萃取(30mL*3)，合并有机相，拉干溶剂，柱层析分离得到化合物A73-2(1.1g,产率22％)。
化合物A73-3的合成
化合物A73-2(1.1g，5.3mmol)溶于四氢呋喃(20mL)中，加入硼烷二甲硫醚络合物(1.1mL，10M)，70℃反应2h。加稀盐酸淬灭，加入碳酸氢钠溶液调pH至8-9，用乙酸乙酯萃取(30mL*3)，合并有机相，拉干溶剂，薄层色谱分离得到化合物A73-3(430mg,产率42％)。
化合物A73-5的合成
化合物A73-3(150mg,0.77mmol)和化合物A73-4(135mg,0.92mmol)溶于二氯甲烷(15mL)中，加入HATU(440mg,1.2mmol)和三乙胺(240mg,2.3mmol)，室温反应2h。加水用二氯甲烷萃取(30mL*3)，合并有机相，拉干溶剂后，薄层色谱分离得到化合物A73-5(120mg,产率48％)。
化合物A73-6的合成
化合物A73-5(120mg，0.37mmol)溶于甲醇(12mL)和水(4mL)中，加入氢氧化锂水溶液(1mL,1M)，室温下反应2h，拉干溶剂，加稀盐酸调pH至3-4，用乙酸乙酯萃取(20mL*3)，合并有机相，拉干溶剂，得到粗品化合物A73-6(90mg,产率78％)。
化合物A73的合成
化合物A73-6(90mg,0.29mmol)和化合物A1-2(95mg,0.35mmol)溶于二氯甲烷(15mL)中，加入HATU(160mg,0.44mmol)和三乙胺(130mg,1mmol)，室温反应2h。加水用二氯甲烷萃取(30mL*3)，合并有机相，拉干溶剂后，薄层色谱分离得到化合物A73(50mg, 产率30％)。
1H NMR(400MHz,DMSO)δ9.31(s,1H),8.37(t,J＝5.8Hz,1H),7.87(d,J＝7.4Hz,2H),7.60(d,J＝7.5Hz,2H),7.40(t,J＝7.2Hz,2H),7.33(dd,J＝7.4,6.5Hz,2H),4.10(t,J＝7.3Hz,1H),3.98(dd,J＝8.5,2.1Hz,1H),3.43-3.37(m,2H),2.54-2.38(m,5H),2.20-2.10(m,1H),2.03-1.93(m,1H),1.82-1.59(m,4H),1.40-1.32(m,1H),1.27-1.15(m,8H),0.90-0.77(m,9H).
化合物A74-75合成方法同A73。
化合物A74：
1H NMR(400MHz,DMSO)δ9.28(s,1H),8.92(t,J＝6.0Hz,1H),8.04(d,J＝7.4Hz,1H),7.94(d,J＝8.0Hz,1H),7.53-7.46(m,1H),7.45-7.36(m,1H),4.65(d,J＝6.2Hz,2H),3.98(dd,J＝8.5,2.1Hz,1H),2.57-2.52(m,2H),2.49-2.46(m,2H),2.44-2.39(m,1H),2.22-2.13(m,1H),2.04-1.92(m,1H),1.82-1.74(m,2H),1.73-1.57(m,2H),1.37(d,J＝9.9Hz,1H),1.26-1.18(m,8H),0.87-0.75(m,9H).
化合物A75：
1H NMR(400MHz,DMSO)δ9.31(s,1H),7.99(t,J＝5.6Hz,1H),7.20-7.08(m,4H),3.97(dd,J＝8.5,2.0Hz,1H),3.10(t,J＝6.2Hz,2H),2.94(dd,J＝15.2,7.3Hz,2H),2.62-2.47(m,4H),2.42-2.34(m,3H),2.20-2.11(m,1H),2.03-1.92(m,1H),1.81-1.74(m,2H),1.73-1.65(m,1H),1.60(d,J＝13.8Hz,1H),1.37(d,J＝9.8Hz,1H),1.25-1.20(m,9H),0.89-0.77(m,9H).
实施例6：化合物A166的合成
化合物A166：
化合物A166-2的合成
化合物A166-1(1.7g,8.1mmol)溶于甲醇(20mL)，降至0℃，缓慢滴加氯化亚砜(4mL)。室温下反应1h，拉干溶剂，加入饱和碳酸氢钠溶液调PH至8-9，用乙酸乙酯萃取(20mL*3)，合并有机相，拉干溶剂，得到粗品化合物A166-2(1.8g)。
化合物A166-3的合成
化合物A166-2(1.8g,8.1mmol)溶于甲醇(20mL)和四氢呋喃(6mL)中，加入水合肼(5mL,85％)，70℃下反应2h，拉干溶剂，加入水(20mL)，过滤，滤饼用石油醚洗涤，干燥得到化合物A166-3(2g，产率100％)。
化合物A166-5的合成
化合物A166-3(1g,4.5mmol)和化合物A166-4(710mg,4.5mmol)溶于乙醇(40mL)中，加入DIEA(2.3mL,13.5mmol)，90℃下反应16h，加水后用乙酸乙酯萃取(30mL*3)，合并有机相，拉干溶剂，薄层色谱分离得到化合物A166-5(170mg产率12％)。
化合物A166-6的合成
化合物A166-5(170mg，0.53mmol)溶于甲醇(9mL)和水(3mL)中，加入LiOH水溶液(0.5mL，1.06mmol)，室温20℃反应2h，拉干溶剂，加稀盐酸调pH至3-4，用乙酸乙酯萃取(20mL*3)，合并有机相，拉干溶剂，得到粗品化合物A166-6(100mg，产率64％)。
化合物A166-7的合成
化合物A166-6(100mg,0.34mmol)和化合物A1-2(110mg,0.4mmol)溶于DCM(12mL)中，加入HATU(200mg,0.51mmol)和TEA(120mg,1.2mmol)，室温20℃反应2h。加水用DCM萃取(30mL*3)，合并有机相，拉干溶剂后，用重压制备纯化粗产品得到化合物8(12mg产率6.5％)。
化合物A166的合成
化合物A166-7(12mg,0.02mmol)和异丁基硼酸(10mg,0.08mmol)溶于甲醇(9mL)中，加入稀盐酸(2N,2mL)，室温20℃反应6h。点板监测，原料反应完全。拉干溶剂，直接用中压制备纯化，得到白色固体化合物A166(2mg产率22％)
1H NMR(400MHz,CD3OD)δ7.88(d,J＝7.6Hz,2H),7.50-7.39(m,4H),7.31(t,J＝7.4Hz,2H),5.39(s,1H),2.72-2.67(m,1H),1.69-1.53(m,1H),1.38-1.28(m,2H),0.90(dd,J＝6.6,2.8Hz,6H).
实施例7：化合物A159的合成
化合物A159：
化合物A159-2的合成
化合物A159-1(200mg,0.84mmol)溶于四氢呋喃(6mL)中，再加入溶于四氢呋喃(4mL)的化合物丙二酸甲酯酰氯(189mg,1.26mmol)，最后滴加三乙胺(253mg,2.52mmol)，室温20℃搅拌反应2h，TLC显示原料反应完全。拉干溶剂，加水后用乙酸乙酯萃取(20mL*3)，合并有机相，拉干溶剂得到化合物A159-2(220mg，产率74.6％)。
化合物A159-3的合成
化合物A159-2(220mg,0.625mmol)和Burgess试剂(595mg,2.5mmol)溶于四氢呋喃(10mL)中，微波120℃下反应10分钟，TLC监测显示原料反应完全。冷却至室温，加入水后用乙酸乙酯萃取(20mL*3)，合并有机相，用厚制备板纯化得到化合物A159-3(100mg，产率48％)。
化合物A159-4的合成
化合物A159-3(100mg,0.3mmol)溶于甲醇(6mL)中，0℃下加入LiOH(41mg，0.6 mmol)水溶液，常温搅拌反应2h。TLC监测显示反应完全，拉干溶剂，加稀盐酸调PH至3～4。有白色沉淀析出，加入乙酸乙酯萃取(20mL*3)，合并有机相，拉干溶剂得化合物A159-4(84mg，产率92.3％)。
化合物A159-5的合成
化合物A159-4(84mg,0.27mmol)和化合物A1-2(125mg,0.33mmol)溶于二氯甲烷(8mL)中，再加入HATU(154mg,0.4mmol)和三乙胺(82mg,0.81mmol)，室温搅拌反应2h后，TLC监测显示原料反应完全。加水后用二氯甲烷萃取(15mL*3)，合并有机相，拉干溶剂，经厚制备板分离纯化(展开剂DCM：MeOH＝20:1)，再用重压制备纯化粗品得化合物A159-5(18mg，产率12％)。
化合物A159的合成
化合物A159-5(18mg,0.033mmol)和异丁基硼酸(14mg,0.13mmol)溶于甲醇(3mL)中，加入稀盐酸(0.5mL,2N)，室温搅拌反应过夜，TLC监测显示原料反应完全，拉干溶剂，经中压制备纯化得化合物A159(2mg，产率14％)。
1H NMR(400MHz,CD3OD)δ7.80(d,J＝8.2Hz,2H),7.42-7.36(m,4H),7.33-7.27(m,2H),4.45(t,J＝7.1Hz,1H),3.41(d,J＝7.2Hz,2H),2.90-2.83(m,1H),1.71-1.55(m,1H),1.46-1.34(m,2H),0.95-0.88(m,6H).
实施例8：化合物A160的合成
化合物A160：
化合物A160-1的合成
化合物丁二酸单苄酯(580mg,2.8mmol)溶于DCM(10mL)中，滴入几滴DMF，慢慢 加入草酰氯(1.06g,8.3mmol)，室温反应1h。拉干溶剂，用THF(10mL)溶解，加入化合物A166-3(500mg,2.2mmol)和TEA(850mg,8.3mmol)，室温下反应16h，加水后用乙酸乙酯萃取(30mL*3)，合并有机相，拉干溶剂，薄层色谱分离得到化合物A160-1(840mg,产率72％)。
化合物A160-2的合成
化合物A160-1(300mg，0.72mmol)溶于THF(8mL)中，加入伯吉斯试剂(700mg,2.7mmol)，120℃微波反应10min。加水后用乙酸乙酯萃取(30mL*3)，合并有机相，拉干溶剂，薄层色谱分离得到化合物A160-2(65mg,产率22.6％)。
化合物A160-3的合成
化合物A160-2(65mg,0.16mmol)溶于甲醇(15mL)中，加入适量Pd/C(10mg)。氢气氛围室温反应16h后，硅藻土过滤后拉干溶剂，得到化合物A160-3(50mg,产率99％)。
化合物A160-4的合成
化合物A160-3(50mg,0.16mmol)和化合物A1-2(70mg,0.19mmol)溶于二氯甲烷(12mL)中，加入HATU(95mg,0.24mmol)和TEA(60mg,0.57mmol)，室温反应2h。加水用DCM萃取(30mL*3)，合并有机相，拉干溶剂后，用重压制备纯化粗产品得到化合物A160-4(12mg,产率13％)。
化合物A160的合成
化合物A160-4(12mg,0.02mmol)和异丁基硼酸(10mg,0.08mmol)溶于甲醇(9mL)中，加入稀盐酸(2N,2mL)，室温反应6h。TLC板监测，原料反应完全。拉干溶剂，直接用重压制备纯化，得到白色固体化合物A160(1mg产率11％)。
1H NMR(400MHz,CD3OD)δ7.89(d,J＝7.6Hz,2H),7.56(d,J＝7.6Hz,2H),7.48(t,J＝7.5Hz,2H),7.37(t,J＝7.5Hz,2H),3.19(t,J＝7.0Hz,2H),2.90(t,J＝7.0Hz,2H),2.64-2.55(m,1H),1.65-1.57(m,1H),1.29-1.23(m,2H),0.91(dd,J＝6.6,2.2Hz,6H).
实施例9：化合物A76的合成
化合物A76：
化合物A76-2的合成
化合物A76-1(3.5g,21mmol)溶于水(30mL)中，加入NaOH(3.36g,84mmol)溶液。100℃反应6h。TLC显示原料完全反应完。加稀盐酸调节pH值到3-4，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，拉干，得到黄色固体化合物A76-2(3g,产率77％)。
化合物A76-3的合成
化合物A76-2(2.8g,15mmol)溶于甲醇(8mL)和甲苯(30mL)中，加入TMSCHN2(30mL,18mmol,0.6M)。室温反应30min后，点板监测，原料反应完全。拉干溶剂，得粗品A76-3(2.8g)。
化合物A76-4的合成
化合物A76-3(2.4g,12mmol)溶于甲醇(30mL)中，加入水合肼(8mL,85％)，70℃反应6h。TLC显示原料完全反应完全。拉干溶剂，加入石油醚：乙酸乙酯(4:1,10mL),过滤，滤饼拉干得到黄色固体化合物A76-4(2.3g,产率96％)。
化合物A76-5的合成
化合物A76-4(0.6g,3mmol)和化合物丙二酸甲酯酰氯(0.9g,6mmol)溶于四氢呋喃(8mL)中，加入三乙胺(505mg,5mmol)，于室温反应2h。TLC显示原料完全反应完全。拉干溶剂，加水，用乙酸乙酯(15mL*3)萃取，拉干，得到黄色固体化合物A76-5(410mg,产率43.5％)。
化合物A76-6的合成
化合物A76-5(410mg,1.3mmol)和伯吉斯试剂(1.36g,5.73mmol)溶于四氢呋喃(8mL)中，在微波反应仪中，120℃下反应20min。TLC显示原料完全反应完全，拉干溶剂，过柱纯化得到黄色固体化合物A76-6(320mg,产率83％)。
化合物A76-7的合成
化合物A76-6(200mg,0.68mmol)溶于甲醇(3mL)中，冰浴下加入LiOH水溶液(1.5mL,1M)，常温反应1.5h。TLC显示原料完全反应完全。拉干溶剂，加入稀盐酸调节pH至4-5,用乙酸乙酯(20mL*3)萃取，拉干，得到白色固体化合物A76-7(163mg,产率89.4％)。
化合物A76的合成
化合物A76-7(163mg,0.6mmol)和化合物A1-2(273mg,0.72mmol)溶于二氯甲烷(3mL)中，加入三乙胺(180mg,1.8mmol)和HATU(274mg,0.72mmol)，于室温反应1.5h。TLC显示原料完全反应完全。加水(20mL)，用二氯甲烷(25mL*3)萃取，拉干，厚制备板纯化，再用重压制备纯化得到白色固体化合物A76(130mg,产率42％)。
1H NMR(400MHz,DMSO)δ8.72(s,1H),7.89(t,J＝8.2Hz,3H),7.83(s,1H),7.51(t,J＝6.4Hz,2H),7.44(d,J＝8.3Hz,1H),4.43(s,2H),4.08(d,J＝7.4Hz,1H),3.88(s,2H),2.81-2.68(m,1H),2.21-2.10(m,1H),2.04-1.96(m,1H),1.82(t,J＝5.5Hz,1H),1.74(s,1H),1.66-1.53(m,2H),1.3-1.31(m,1H),1.28-1.14(m,5H),1.12(s,3H),0.87-0.78(m,6H),0.75(s,3H).
实施例10：化合物A77的合成
化合物A77：
化合物A77-2的合成
将化合物A77-1(500mg,3mmol)溶于DMF(10mL)中，冰浴下缓慢加入NaH(143mg,3.6mmol)。15min后，向反应液中加入溴乙酸乙酯(590mg,3.6mmol)，室温反应2h，TLC显示原料反应完全。向反应液中加入25mL乙酸乙酯和75mL水，萃取3次，合并有机相经无水硫酸钠干燥后，旋干经柱层析分离纯化(洗脱剂EA:PE＝1:3～1:1)，得化合物A77-2(480mg，产率：63.2％)。
化合物A77-3的合成
将化合物A77-2(230mg,0.91mmol)加入到甲醇(5mL)中，室温搅拌下加入水合肼(113 uL,1.81mmol)，室温搅拌1h后，TLC显示反应完全，黄色固体大量析出，将反应液过滤，少量甲醇洗涤滤饼，滤饼干燥后，得化合物A77-3(200mg，产率：91.7％)。
化合物A77-4的合成
将化合物A77-3(200mg,0.83mmol)溶于DMF(6mL)中，室温搅拌下加入化合物丙二酸甲酯酰氯(188mg,1.25mmol)和三乙胺(139uL,1mmol)。室温搅拌2h后，TLC显示反应完全。旋干反应液，甲醇打浆过滤，滤饼经甲醇洗涤后烘干，得化合物A77-4(220mg，产率：75.9％)。
化合物A77-5的合成
将化合物A77-4(480mg,1.36mmol)和伯吉斯试剂(700mg,2.71mmol)溶于无水四氢呋喃(6mL)中，微波120℃搅拌反应20min，TLC显示反应完全。向反应液中加入30mL二氯甲烷和30mL水，萃取两次，合并有机相旋干，柱层析分离纯化，得到化合物A77-5(210mg，产率：50.2％)。
化合物A77-6的合成
将化合物A77-5(210mg,0.625mmol)溶于甲醇(5mL)中，室温搅拌下加入LiOH一水合物(50mg,1.25mmol)，室温搅拌反应1h后，TLC显示原料反应完全，稀盐酸调pH至4～5，过滤固体，得到化合物A77-6(150mg，产率：78.1％)。
化合物A77的合成
将化合物A77-6(100mg,0.32mmol)，化合物A1-2(148mg,0.39mmol)和HATU(148mg,0.39mmol)溶于DMF(8mL)中，室温搅拌下加入三乙胺(100uL,0.71mmol)，室温搅拌1h后，TLC显示原料反应完全，拉干溶剂，直接用中压制备分离纯化，得到化合物A77(45mg，产率：26.0％)。
1H NMR(400MHz,DMSO)δ9.09(s,1H),8.63(d,J＝4.2Hz,1H),8.43(d,J＝5.2Hz,1H),8.30(d,J＝7.8Hz,1H),8.17(d,J＝5.2Hz,1H),7.77(d,J＝8.3Hz,1H),7.63(t,J＝7.3Hz,1H),7.33(t,J＝7.5Hz,1H),6.12(s,2H),4.07(d,J＝7.0Hz,1H),3.85(s,2H),2.77-2.64(m,1H),2.23-2.14(m,1H),2.05-1.95(m,1H),1.82(t,J＝5.5Hz,1H),1.78-1.72(m,1H),1.62-1.53(m,2H),1.37-1.27(m,1H),1.24-1.07(m,8H),0.86-0.71(m,9H).
实施例11：化合物A78的合成
化合物A78：
化合物A78-2的合成
将化合物2-溴甲基萘(442mg,2mmol)和化合物A78-1(312mg,2mmol)溶于四氢呋喃(10mL)中，室温搅拌下加入三乙胺(333uL,2.4mmol)，70℃油浴中反应3h后，TLC显示原料反应完全。拉干溶剂，加水，用二氯甲烷(30mL*3)萃取，有机相合并后经无水硫酸钠干燥，旋干有机相，经柱层析分离纯化，得到化合物A78-2(200mg，产率：33.6％)。
化合物A78-3的合成
将化合物A78-2(200mg,0.68mmol)溶于甲醇(5mL)中，室温搅拌下加入LiOH水溶液(1mL,1M)，室温搅拌1h后，TLC显示原料反应完全。加稀盐酸调pH至4-5，用二氯甲烷(20mL*3)萃取，有机相合并后经无水硫酸钠干燥，旋干有机相，得到化合物A78-3(140mg，产率：77.0％)。
化合物A78的合成
将化合物A78-3(50mg,0.187mmol)，化合物A1-2(85mg,0.224mmol)和HATU(85mg,0.224mmol)溶于二氯甲烷(8mL)中，室温搅拌下加入三乙胺(57uL,0.41mmol)，室温搅拌2h后，TLC显示原料反应完全，加水，用二氯甲烷(15mL*3)萃取，有机相合并后经无水硫酸钠干燥，旋干有机相，经厚制备板分离纯化(展开剂EA:PE＝1:1)，得到化合物A78(40mg，产率：41.7％)。
1H NMR(400MHz,DMSO)δ8.97(s,1H),7.94-7.91(m,4H),7.54(dd,J＝6.2,3.3Hz,2H),7.48-7.41(m,1H),6.07(s,2H),4.02(d,J＝6.9Hz,1H),3.88(s,2H),2.65-2.58(m,1H),2.20-2.09(m,1H),2.01-1.92(m,1H),1.79(t,J＝5.5Hz,1H),1.76-1.71(m,1H),1.68-1.52(m,2H),1.35-1.26(m,1H),1.25-1.09(m,8H),0.87-0.70(m,9H).
化合物A79的合成方法同A78。
化合物A79：
1H NMR(400MHz,DMSO)δ8.75(d,J＝4.0Hz,1H),7.95-7.85(m,4H),7.56-7.52(m,2H),7.43(dd,J＝8.5,1.4Hz,1H),5.78(s,2H),4.15(d,J＝7.0Hz,1H),4.11-3.99(m,2H),2.88-2.75(m,1H),2.25-2.16(m,1H),2.09-1.98(m,1H),1.87(t,J＝5.5Hz,1H),1.80-1.74(m,1H),1.69-1.55(m,2H),1.44-1.35(m,1H),1.30-1.18(m,8H),0.88-0.71(m,9H).
实施例12：化合物A84的合成
化合物A84：
化合物A84-1的合成
化合物2-胺甲基萘(500mg,2.6mmol)溶于二氯甲烷(20mL)中，加入三乙胺(800mg，7.7mmol)，再加入2-氯异氰酸乙酯(410mg，3.9mmol)，室温反应16h，加水后用二氯甲烷萃取(30mL*3)，合并有机相，拉干溶剂，用乙酸乙酯：石油醚＝1：4打浆，过滤干燥，得到化合物A84-1(600mg，产率88％)。
化合物A84-2的合成
化合物A84-1(600mg，2.3mmol)溶于四氢呋喃(20mL)中，降至0℃，加入NaH(180mg，4.6mmol)，反应2h，加水后用乙酸乙酯萃取(30mL*3)，合并有机相，拉干溶剂，得到化合物A84-2(500mg,产率96％)。
化合物A84-3的合成
化合物A84-2(500mg,2.2mmol)溶于四氢呋喃(10mL)中，降至0℃，加入NaH(180mg，4.4mmol)，反应1h，加入溴乙酸叔丁酯(520mg,2.63mmol)，反应1h，加水后用乙酸乙酯萃取(30mL*3),合并有机相，拉干溶剂，薄层色谱分离得到化合物A84-3(420mg,产率55％)。
化合物A84-4的合成
化合物A84-3(150mg,0.44mmol)溶于DCM(10mL)中，加入三氟乙酸(2mL)，室温反应1h，拉干溶剂，得到化合物A84-4(125mg产率99％)。
化合物A84的合成
化合物7(125mg,0.44mmol)和化合物8(190mg,0.53mmol)溶于DCM(15mL)中，加入HATU(260mg,0.66mmol)和TEA(155mg,1.5mmol)，室温反应16h。加水用DCM萃取(30mL*3)，合并有机相，拉干溶剂后，用重压制备纯化粗产品得到白色固体化合物A84(36mg,产率15％)。
1H NMR(400MHz,DMSO)δ8.94(s,1H),7.89(d,J＝7.9Hz,3H),7.77(s,1H),7.57-7.45(m,2H),7.40(d,J＝9.6Hz,1H),4.54-4.38(m,2H),4.10(d,J＝7.0Hz,1H),3.90(q,J＝16.9Hz,2H),3.34-3.31(m,2H),3.24-3.20(m,2H),2.60(t,J＝9.0Hz,1H),2.25-1.98(m,1H),2.04-1.98 (m,1H),1.84(t,J＝5.5Hz,1H),1.79-1.72(m,1H),1.70-1.58(m,2H),1.37-1.21(m,9H),0.90-0.68(m,9H).
实施例13：化合物A80的合成
化合物A80：
化合物A80-2的合成
化合物A80-1(100mg,0.6mmol)溶于乙醇(12mL)中，加入盐酸羟胺(85mg,1.2mmol)和三乙胺(245mg,2.4mmol),75℃下反应16h，拉干溶剂，加水后用乙酸乙酯萃取(30mL*3)，合并有机相，拉干溶剂，得到化合物A80-2(130mg,产率100％)。
化合物A80-3的合成
化合物A80-2(130mg,0.65mmol)溶于DMF(5mL)中，加入丙二酸甲酯酰氯(110mg,0.84mmol)和DIEA(250mg,1.95mmol)，80℃下反应16h，拉干溶剂，加水后用乙酸乙酯萃取(30mL*3)，合并有机相，拉干溶剂，薄层色谱分离得到化合物A80-3(70mg,产率36％)。
化合物A80-4的合成
化合物A80-3(70mg,0.24mmol)溶于甲醇(9mL)和水(3mL)中，加入LiOH水溶液(0.5mL,0.48mmol)，室温反应2h，拉干溶剂，加稀盐酸调pH至3-4，用乙酸乙酯萃取(20mL*3)，合并有机相，拉干溶剂，得到化合物A80-4(80mg，产率100％)。
化合物A80的合成
化合物A80-4(80mg,0.3mmol)和化合物A1-2(130mg,0.36mmol)溶于二氯甲烷(15mL)中，加入HATU(160mg,0.45mmol)和TEA(105mg,1.04mmol)，室温反应16h。加水用二氯甲烷萃取(30mL*3)，合并有机相，拉干溶剂后，用中压制备纯化粗产品得到白色固体化合物A80(25mg，产率16％)。
1H NMR(400MHz,DMSO-d6)δ8.66(d,J＝4.3Hz,1H),7.93-7.76(m,4H),7.55-7.41(m,3H),4.24(s,2H),4.15(dd,J＝8.7,1.8Hz,1H),3.93(s,2H),2.81-2.77(m,1H),2.25-2.14(m,1H),2.05-1.96(m,1H),1.84(t,J＝5.5Hz,1H),1.77-1.72(m,1H),1.68-1.55(m,2H),1.42-1.32(m,1H),1.23-1.17(m,8H),0.85-0.75(m,9H).
实施例14：化合物A81的合成
化合物A81：
化合物A81-2的合成
将化合物A76-2(298mg,1.6mmol)，化合物A81-1(387mg,1.6mmol)和HATU(669mg,1.76mmol)溶于二氯甲烷(8mL)中，室温搅拌下加入三乙胺(488uL,3.52mmol)，室温搅拌2h后，TLC显示反应完全，加水，用二氯甲烷(25mL*3)萃取，有机相合并后经无水硫酸钠干燥，旋干，经厚制备板分离纯化(展开剂EA:PE＝1:1)，得到化合物A81-2(170mg，产率：33.3％)。
化合物A81-3的合成
将化合物A81-2(170mg,0.543mmol)溶于DMF(5mL)中，室温搅拌下加入三氯氧磷(152uL,1.63mmol)，室温反应2h后，TLC显示原料反应完全，将反应液滴加到冰水中淬灭后，用二氯甲烷(20mL*3)萃取，有机相合并后经无水硫酸钠干燥，旋干，经厚制备板分离纯化，得化合物A81-3(35mg，产率：21.9％)。
化合物A81-4的合成
将化合物A81-3(35mg,0.12mmol)溶于甲醇(5mL)中，室温搅拌下加入LiOH水溶液(0.2mL,1M)，室温反应2h后，TLC显示原料反应完全，加稀盐酸调pH至4-5，用二氯甲烷(20mL*3)萃取，有机相合并后经无水硫酸钠干燥，旋干得到化合物A81-4(20mg，产率：63.0％)。
化合物81的合成
将化合物A81-4(20mg,0.075mmol)，化合物A1-2(34mg,0.09mmol)和HATU(34mg,0.09mmol)溶于二氯甲烷(8mL)中，室温搅拌下加入三乙胺(23uL,0.165mmol)，室温搅拌2h后，TLC显示反应完全，用二氯甲烷(20mL*3)萃取，有机相合并后经无水硫酸钠干燥，旋干，经中压制备分离纯化，得到化合物A81(21mg，产率：54.5％)。
1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),7.87(dd,J＝8.9,6.6Hz,3H),7.78(s,1H),7.55-7.45(m,2H),7.41(dd,J＝8.5,1.6Hz,1H),6.89(s,1H),4.25(s,2H),4.05(d,J＝8.5Hz,1H),3.66(s,2H),2.61-2.56(m,1H),2.23-2.12(m,1H),2.05-1.93(m,1H),1.81(t,J＝5.5Hz,1H),1.77-1.72(m,1H),1.65-1.58(m,2H),1.33-1.22(m,3H),1.20(s,3H),1.16(s,3H),0.84-0.81(m,6H),0.77(s,3H).
实施例15：化合物A82的合成
化合物A82：
化合物A82-1的合成
化合物A76-6(250mg,0.79mmol)和劳森试剂(638mg,1.6mmol)溶于四氢呋喃(10mL)中，微波120℃下反应10分钟，TLC监测显示原料反应完全。冷却至室温，加水后用乙酸乙酯萃取(20mL*3)，合并有机相，用厚制备板纯化得到化合物A82-1(218mg，产率88.3％)。
化合物A82-2的合成
化合物A82-1(218mg,0.70mmol)溶于甲醇(6mL)中，加入氢氧化锂(60mg,1.4mmol)的水溶液，常温搅拌反应2h。TLC监测显示反应完全，拉干溶剂，加稀盐酸调pH调至3～4。有白色沉淀析出，加入乙酸乙酯(20mL*3)萃取合并有机相，拉干溶剂得化合物A82-2(130mg，产率65.3％)。
化合物A82的合成
化合物A82-2(130mg,0.46mmol)和化合物A1-2(192mg,0.51mmol)溶于二氯甲烷(6mL)中，再加入HATU(192mg,0.51mmol)和三乙胺(102mg,1.0mmol)，室温搅拌反应2h后，TLC监测显示原料反应完全。加水后用二氯甲烷萃取(20mL*3)，合并有机相，拉干溶剂，经厚制备板分离纯化，展开剂DCM：MeOH＝20:1，得目标产物A82(155mg，产率63.5％)。
1H NMR(400MHz,DMSO)δ8.79(d,J＝4.1Hz,1H),7.91-7.84(m,4H),7.54-7.47(m,2H),7.45(dd,J＝8.4,1.7Hz,1H),4.58(s,2H),4.05(dd,J＝8.8,2.0Hz,1H),4.02(s,2H),2.73-2.64(m,1H),2.09-2.03(m,1H),1.94-1.90(m,1H),1.74(t,J＝5.5Hz,1H),1.66-1.54(m,2H),1.53-1.45(m,1H),1.37-1.29(m,1H),1.25-1.16(m,2H),1.16(s,3H),1.07(s,3H),0.81(dd,J＝6.6,2.0Hz,6H),0.70(s,3H).
实施例16：化合物A83的合成
化合物A83：
化合物A83-2的合成
化合物A76-2(100mg,0.54mmol)溶于二氯甲烷(8mL)中，滴入几滴DMF，加入草酰氯(205mg,1.6mmol)，室温反应1h后拉干溶剂。溶质用DMF(8mL)溶解，加入化合物A83-1(120mg,0.64mmol)和DIEA(240mg,1.9mmol)，80℃下反应16h，加水后用乙酸乙酯萃取(30mL*3)，合并有机相，拉干溶剂，薄层色谱分离得到化合物A83-2(55mg，产率34％)。
化合物A83-3的合成
化合物3(55mg,0.18mmol)溶于甲醇(9mL)和水(3mL)中，加入LiOH水溶液(0.4mL,0.37mmol)，室温反应2h，拉干溶剂，加稀盐酸调pH至3-4，用乙酸乙酯萃取(20mL*3)，合并有机相，拉干溶剂，得到化合物A83-3(50mg产率100％)。
化合物A83的合成
化合物A83-3(50mg,0.18mmol)和化合物A1-2(80mg,0.22mmol)溶于二氯甲烷(15mL)中，加入HATU(110mg,0.28mmol)和TEA(66mg,0.65mmol)，室温反应16h。加水用二氯甲烷萃取(30mL*3)，合并有机相，拉干溶剂后，用中压制备纯化粗产品得到白色固体化合物A83(40mg，产率41％)。
1H NMR(400MHz,DMSO)δ8.83(s,1H),7.96-7.83(m,4H),7.53-7.43(m,3H),4.51(s,2H),4.08(dd,J＝8.6,1.9Hz,1H),3.70(s,2H),2.71-2.64(m,1H),2.20-2.12(m,1H),2.04-1.98(m,1H),1.82(t,J＝5.6Hz,1H),1.78-1.72(m,1H),1.69-1.54(m,2H),1.37-1.17(m,9H),0.88-0.70(m,9H).
实施例17：化合物A85的合成
化合物A85：
化合物A85-1的合成
将化合物A81-2(70mg,0.224mmol)加入到甲苯(10mL)中，室温搅拌下加入劳森试剂(100mg,0.246mmol)，70℃搅拌1h后，TLC显示原料反应完全，直接旋干反应液，用厚制备板分离纯化(展开剂EA:PE＝1:1)得到化合物A85-1(45mg，产率：64.7％)。
化合物A85-2的合成
将化合物A85-1(45mg,0.145mmol)溶于甲醇(5mL)中，室温搅拌下加入LiOH水溶液(0.3mL,1M)，室温搅拌2h后，TLC显示反应完全，加稀盐酸调pH至4-5，用二氯甲烷(20mL*3)萃取，有机相合并后经无水硫酸钠干燥，旋干后得到化合物A85-2(40mg，产率：97.6％)。
化合物A85的合成
将化合物A85-2(40mg,0.141mmol)，化合物A1-2(64mg,0.17mmol)和HATU(64mg,0.17mmol)溶于二氯甲烷(8mL)中，室温搅拌下加入三乙胺(43uL,0.31mmol)，室温搅拌2h后，TLC显示原料反应完全，用二氯甲烷(20mL*3)萃取，有机相合并后经无水硫酸钠干燥，旋干后用中中压制备分离纯化，得到化合物A85(55mg，产率：73.6％)。
1H NMR(400MHz,DMSO)δ8.96(s,1H),7.93-7.80(m,4H),7.52-7.42(m,4H),4.43(s,2H),4.01(dd,J＝8.6,1.8Hz,1H),3.73(s,2H),2.60-2.51(m,1H),2.16-2.05(m,1H),1.98-1.87(m,1H),1.77-1.74(m,1H),1.72-1.67(m,1H),1.65-1.57(m,1H),1.56-1.52(m,1H),1.30-1.26(m,2H),1.23-1.14(m,4H),1.11(s,3H),0.81(d,J＝6.6Hz,6H),0.75(s,3H).
实施例18：化合物A88的合成
化合物A88：
化合物A88-2的合成
化合物A88-1(770mg,3.0mmol)溶于二甲亚砜(6mL)中，加入叠氮化钠(350mg,4.0mmol)，室温反应5h。TLC显示原料完全反应完全。加水(20mL),用乙酸乙酯(25mL*3)萃取，拉干，得到粗品黄色固体化合物A88-2(368mg,产率67％)。
化合物A88-3的合成
化合物A88-2(368mg,2mmol)和3-丁炔酸(252mg,3mmol)溶于叔丁醇(3mL)和水(3mL)中，加入L-抗坏血酸钠盐(79mg,0.4mmol)和醋酸铜(72mg,0.4mmol)，于室温反应18h。TLC显示原料完全反应完全。加水(25mL)，用乙酸乙酯萃取(25mL*3)，合并有机相，拉干溶剂，得到粗品黄色固体化合物A88-3(215mg,产率40％)。
化合物A88的合成
化合物A88-3(100mg,0.37mmol)和化合物A1-2(184mg,0.48mmol)溶于二氯甲烷(3mL)中，加入三乙胺(110mg,1.1mmol)和HATU(185mg,0.48mmol)，于室温反应1.5h。TLC显示原料完全反应完全。加水(20mL)，用二氯甲烷(20mL*3)萃取，拉干，厚制备板纯化后，再用中压制备纯化得到白色固体化合物A88(35mg,产率18％)。
1H NMR(400MHz,DMSO)δ9.18(s,1H),8.39(d,J＝8.5Hz,1H),8.02(s,1H),8.01-7.96(m,2H),7.83-7.73(m,1H),7.64-7.60(m,1H),7.36(d,J＝8.5Hz,1H),5.90(s,2H),3.97(dd,J＝8.5,1.9Hz,1H),3.72(s,2H),2.15-2.09(m,1H),1.94-1.90(m,1H),1.79-1.62(m,3H),1.57-1.52(m,1H),1.31-1.22(m,4H),1.18(s,3H),1.10(s,3H),0.83(dd,J＝6.5,1.5Hz,6H),0.75(s,3H).
实施例19：化合物A86的合成
化合物A86：
化合物A86-2的合成
化合物A86-1(500mg,2.3mmol)和叠氮化钠(149mg,2.3mmol)溶于二甲亚砜(8mL)中，室温搅拌反应30分钟，TLC监测原料反应完全。加水后用二氯甲烷萃取(30mL*3)，合并有机相，拉干溶剂得到粗品油状化合物A86-2(421mg，粗品)。
化合物A86-3的合成
化合物A86-2(421mg，2.3mmol)溶于叔丁醇：水＝1：1混合溶剂(12mL)中，再加入 抗坏血酸钠(452mg,2.3mmol)，3-丁炔酸(192mg,2.3mmol)和醋酸铜(205mg,1.1mmol)。室温搅拌过夜，TLC监测显示反应完全，加水后用二氯甲烷萃取(25mL*3)，合并有机相，拉干溶剂，经厚制备板纯化(展开剂DCM:MeOH＝10:1)得到化合物A86-3(360mg,产率59％)。
化合物A86的合成
化合物A86-3(360mg,1.3mmol)和化合物A1-2(592mg,1.5mmol)溶于二氯甲烷(8mL)中，再加入HATU(592mg,1.5mmol)和TEA(150mg,3.0mmol)，室温搅拌反应2h后，TLC监测显示原料反应完全。加水后用二氯甲烷萃取(20mL*3)，合并有机相，拉干溶剂，经厚制备板分离纯化，展开剂DCM：MeOH＝15:1，得目标产物A86(238mg，产率34％)。
1H NMR(400MHz,DMSO)δ9.14(s,1H),8.20-8.14(m,1H),8.01-7.92(m,2H),7.83(s,1H),7.60-7.52(m,2H),7.53-7.47(m,1H),7.43(d,J＝6.9Hz,1H),6.08(s,2H),3.95(dd,J＝8.5,1.8Hz,1H),3.65(s,2H),2.48-2.45(m,1H),2.19-2.09(m,1H),1.98-1.89(m,1H),1.78-1.71(m,2H),1.70-1.58(m,1H),1.57-1.52(m,1H),1.30-1.13(m,6H),1.10(s,3H),0.82(dd,J＝6.5,3.3Hz,6H),0.79(s,3H).
实施例20：化合物A87的合成
化合物A87：
化合物A87-2的合成
化合物A87-1(622mg,2mmol)溶于二甲亚砜(5mL)中，加入叠氮化钠(143mg,2.2mmol)，室温反应5h。TLC显示原料完全反应完全。加水(30mL),用乙酸乙酯(30mL*3)萃取，合并有机相拉干溶剂，得到粗品黄色固体化合物A87-2(490mg，90％)。
化合物A87-3的合成
化合物A87-2(490mg,1.8mmol)和3-丁炔酸(227mg,2.7mmol)溶于叔丁醇(4mL)和水(4mL)中，加入L-抗坏血酸钠盐(71mg,0.36mmol)和醋酸铜(65mg,0.36mmol)，于室温反应18h。TLC显示原料完全反应完全，拉干溶剂，加稀盐酸(20mL,1N)，用乙酸乙酯萃取(25mL*3)，合并有机相，拉干溶剂，厚制备板纯化得到黄色固体化合物A87-3(200mg,产率31％)。
化合物A87的合成
化合物A87-3(200mg,0.56mmol)和化合物A1-2(276mg,0.73mmol)溶于二氯甲烷(3mL)中，加入三乙胺(170mg,1.68mmol)和HATU(277mg,0.73mmol)，于室温反应1.5h。 TLC显示原料完全反应完全。加水(20mL)，用二氯甲烷(20mL*3)萃取，拉干，厚制备板纯化后，再用中压制备纯化得到白色固体化合物A87(40mg,产率11％)。
1H NMR(400MHz,DMSO)δ9.18(s,1H),8.05(d,J＝8.3Hz,1H),7.87(d,J＝12.4Hz,2H),7.58(d,J＝7.8Hz,1H),7.34(t,J＝7.7Hz,1H),7.23(t,J＝7.5Hz,1H),5.74(s,2H),3.93(d,J＝6.8Hz,1H),3.63(d,J＝16.7Hz,2H),2.46(d,J＝6.7Hz,1H),2.12(dd,J＝13.7,8.8Hz,1H),1.91(dd,J＝9.1,5.4Hz,1H),1.74(t,J＝5.5Hz,2H),1.63(s,9H),1.53(d,J＝13.8Hz,1H),1.32-1.15(m,7H),1.06(s,3H),0.86-0.77(m,9H).
实施例21：化合物A89的合成
化合物A89：
化合物A89-2的合成
化合物A89-1(200mg,1.26mmol)溶于二氯甲烷(12mL)中，加入三乙胺(250mg,2.51mmol)，再加入甲基磺酰氯(220mg,1.88mmol)，室温反应1h，加水用二氯甲烷萃取(30mL*3)，合并有机相，拉干溶剂后，薄层色谱分离得到化合物A89-2(240mg，产率80％)。
化合物A89-3的合成
化合物A89-2(240mg,1.01mmol)溶于二甲亚砜(5mL)中，加入叠氮化钠(100mg,1.5mmol)，室温反应1h，加水用乙酸乙酯萃取(30mL*3)，合并有机相，拉干溶剂后，薄层色谱分离得到化合物A89-3(80mg，产率42％)。
化合物A89-4的合成
化合物A89-3(36mg,0.43mmol)溶于叔丁醇(4mL)和水(4mL)中，加入3-丁炔酸(80mg,0.43mmol)，抗坏血酸钾(88mg,0.43mmol)和醋酸铜(40mg,0.22mmol)，室温反应16h，用中压制备纯化粗产品得到化合物A89-4(30mg，产率25％)。
化合物A89的合成
化合物A89-4(30mg,0.11mmol)和化合物A1-2(50mg,0.13mmol)溶于二氯甲烷(15mL)中，加入HATU(65mg,0.17mmol)和三乙胺(40mg,0.39mmol)，室温反应16h。加水用二氯甲烷萃取(30mL*3)，合并有机相，拉干溶剂后，用中压制备纯化粗产品得到白色固体化合物A89(1mg，产率1％)。
1H NMR(400MHz,DMSO)δ9.15(s,1H),8.91(d,J＝2.1Hz,1H),8.28(d,J＝1.6Hz,1H),8.03(d,J＝9.0Hz,2H),7.97(d,J＝7.8Hz,1H),7.82-7.74(m,1H),7.63(t,J＝7.5Hz,1H),5.84 (s,2H),3.94(dd,J＝8.5,1.7Hz,1H),3.69(s,2H),2.45-2.43(m,1H),2.15-2.05(m,1H),1.95-1.87(m,1H),1.75-1.60(m,3H),1.57-1.49(m,1H),1.32-1.23(m,3H),1.17(s,3H),1.05(s,3H),0.82(d,J＝6.4Hz,6H),0.74(s,3H).
实施例22：化合物A90的合成
化合物A90：
化合物A90-2的合成
将化合物A90-1(480mg,2.71mmol)溶于二甲亚砜(8mL)中，室温搅拌下，加入叠氮化钠(194mg,2.98mmol)，室温搅拌0.5h后，TLC显示原料反应完全。加水，用乙酸乙酯(30mL*3)萃取，有机相合并后经无水硫酸钠干燥，拉干后用厚制备板分离纯化(展开剂EA:PE＝2:1)，得到化合物A90-2(300mg，产率：60％)。
化合物A90-3的合成
将化合物A90-2(300mg,2.71mmol)和3-丁炔酸(227mg,2.71mmol)溶于叔丁醇/水(1/1)的混合溶剂(8mL)中，室温搅拌下，加入醋酸铜(99mg,0.54mmol)和抗坏血酸钠(107mg,0.54mmol)，室温搅拌过夜，TLC显示反应完全，反应液经硅藻土过滤，滤液拉干后用中压制备分离纯化，得到化合物A90-3(71mg，产率：10％)。
化合物A90的合成
将化合物A90-3(71mg,0.26mmol)，化合物A1-2(121mg,0.32mmol)和HATU(121mg,0.32mmol)溶于二氯甲烷(8mL)中，室温搅拌下加入三乙胺(81uL,0.583mmol)，室温搅拌1h后，TLC显示原料反应完全，加水，用二氯甲烷(20mL*3)萃取，有机相合并后经无水硫酸钠干燥，拉干后用中压制备分离纯化，得到化合物A90(85mg，产率：62％)。
1H NMR(400MHz,DMSO)δ9.30(s,1H),9.18(s,1H),8.14(d,J＝8.1Hz,1H),7.97-7.94(m,2H),7.84-7.76(m,2H),7.71(t,J＝7.5Hz,1H),5.82(s,2H),3.95(dd,J＝8.5,1.9Hz,1H),3.70(s,2H),2.15-2.07(m,1H),1.96-1.86(m,1H),1.74-1.64(m,3H),1.57-1.50(m,1H),1.33-1.18(m,4H),1.17(s,3H),1.07(s,3H),0.83(d,J＝6.7Hz,6H),0.74(s,3H).
实施例23：化合物A102的合成
化合物A102：
将原料A80(100mg,0.18mmol)和化合物异丁基硼酸(73mg,0.72mmol)溶于甲醇中，加入稀盐酸(1N,1mL)，70℃下反应6h。点板监测，原料反应完全。拉干溶剂，直接用中压制备纯化，得到白色固体(23mg,30％产率)。
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.63(d,J＝7.5Hz,2H),7.38(t,J＝7.4Hz,2H),7.30(t,J＝7.4Hz,2H),4.36(d,J＝6.8Hz,2H),4.19(t,J＝6.7Hz,1H),3.51-3.37(m,2H),2.69-2.56(m,3H),1.69-1.57(m,3H),1.38-1.23(m,6H).
化合物A103-A158、A161-A165、A167-A180合成方法同A102。
化合物A103：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.3Hz,2H),7.65(d,J＝7.2Hz,2H),7.39(t,J＝7.3Hz,2H),7.32(t,J＝7.1Hz,2H),4.36(d,J＝5.8Hz,2H),4.23-3.98(m,2H),2.69-2.48(m,3H),1.74-1.55(m,1H),1.43-1.12(m,5H),0.92(d,J＝6.2Hz,6H).
化合物A104：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.64(d,J＝7.5Hz,2H),7.39(t,J＝7.4Hz,2H),7.31(t,J＝7.4Hz,2H),4.40-4.32(m,2H),4.19(t,J＝6.6Hz,1H),4.05(dd,J＝13.2,6.5Hz,1H),2.65-2.54(m,3H),1.69-1.58(m,1H),1.35-1.29(m,2H),1.22(d,J＝6.7Hz,3H),0.90(dd,J＝6.6,1.5Hz,6H).
化合物A105：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.65(d,J＝7.4Hz,2H),7.39(t,J＝7.4Hz,2H),7.31(t,J＝7.3Hz,2H),4.61(s,1H),4.42-4.32(m,2H),4.19(t,J＝6.5Hz,1H),3.20(q,J＝7.3Hz,1H),2.66-2.57(m,3H),2.27-2.16(m,2H),1.89-1.73(m,2H),1.64-1.59(m,1H),1.31-1.27(m,1H),0.88(dd,J＝6.6,2.0Hz,6H).
化合物A106：
1H NMR(400MHz,CD3OD)δ7.80(d,J＝7.5Hz,2H),7.65(d,J＝7.5Hz,2H),7.39(t,J＝7.5Hz,2H),7.31(t,J＝7.4Hz,2H),4.47-4.30(m,2H),4.19(t,J＝6.5Hz,1H),3.99-3.91(m,1H),3.18-3.13(m,2H),2.68-2.52(m,3H),1.92(s,3H),1.69-1.43(m,5H),1.35-1.32(m,2H),0.89(d,J＝6.7Hz,6H).
化合物A107：
1H NMR(400MHz,CD3OD)δ7.39-7.27(m,5H),5.07(s,2H),3.45(t,J＝5.7Hz,2H),2.67-2.60(m,3H),1.69-1.60(m,1H),1.35-1.30(m,2H),0.91(dd,J＝7.6,4.3Hz,6H).
化合物A108：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.3Hz,2H),7.56(d,J＝7.3Hz,2H),7.39-7.28(m,4H),4.07(t,J＝6.0Hz,1H),3.96(t,J＝7.1Hz,2H),3.42-3.34(m,2H),2.65-2.38(m,3H),2.31(dd,J＝13.4,6.8Hz,2H),1.71-1.53(m,1H),1.37-1.20(m,2H),0.89(d,J＝6.5Hz,6H).
化合物A109：
1H NMR(400MHz,CD3OD)δ7.78(d,J＝7.5Hz,2H),7.49(dd,J＝7.5,0.9Hz,2H),7.36(t,J＝7.3Hz,2H),7.32-7.24(m,2H),4.38(t,J＝7.6Hz,1H),3.68-3.55(m,2H),2.71(t,J＝6.6Hz,2H),2.67-2.51(m,3H),1.69-1.60(m,1H),1.38-1.22(m,2H),0.92(dd,J＝6.5,4.8Hz,6H).
化合物A110：
1H NMR(400MHz,CD3OD)δ7.77(d,J＝7.0Hz,2H),7.55(d,J＝7.3Hz,2H),7.40-7.28(m,4H),4.06(t,J＝5.2Hz,1H),3.40-3.31(m,2H),2.58(t,J＝7.6Hz,1H),2.55-2.48(m,2H),2.42-2.37(m,2H),1.84-1.75(m,2H),1.61-1.53(m,1H),1.26-1.22(m,2H),0.91-0.83(m,6H).
化合物A111：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.60(d,J＝7.5Hz,2H),7.38(t,J＝7.4Hz,2H),7.31(dt,J＝7.4,3.7Hz,2H),4.11(t,J＝6.3Hz,1H),3.67-3.55(m,2H),3.42(t,J＝6.3Hz,2H),2.66-2.53(m,3H),1.68-1.58(m,1H),1.30-1.27(m,2H),0.90(d,J＝6.6Hz,6H).
化合物A112：
1H NMR(400MHz,CD3OD)δ8.95(s,1H),8.41(s,1H),8.32-8.29(m,2H),7.73-7.67(m,1H),7.60(d,J＝8.8Hz,1H),7.39(t,J＝7.4Hz,1H),5.20(s,2H),3.55(t,J＝6.6Hz,2H),2.67-2.59(m,3H),1.67-1.56(m,1H),1.38-1.26(m,2H),0.91(dd,J＝6.6,1.5Hz,6H).
化合物A113：
1H NMR(400MHz,DMSO)δ9.20-9.00(m,1H),8.77(s,1H),8.21(dd,J＝11.6,3.9Hz,1H),8.12(t,J＝7.1Hz,1H),7.67-7.46(m,2H),3.62-3.46(m,2H),2.68-2.54(m,2H),2.45-2.40(m,1H),1.61-1.48(m,1H),1.35-1.15(m,2H),0.81-0.70(m,6H).
化合物A114：
1H NMR(400MHz,CD3OD)δ3.50-3.45(m,2H),2.64(d,J＝6.1Hz,3H),1.98-1.91(m,5H),1.75(d,J＝12.1Hz,3H),1.70-1.60(m,10H),1.34-1.29(m,2H),0.92(dd,J＝6.6,2.6Hz,6H).
化合物A115：
1H NMR(400MHz,CD3OD)δ7.17-7.15(m,2H),7.09-7.06(m,2H),4.34-4.26(m,1H),3.06(dd,J＝15.3,7.6Hz,2H),2.84-2.78(m,1H),2.65-2.59(m,5H),2.33(d,J＝7.5Hz,2H),1.72-1.60(m,1H),1.40-1.31(m,2H),1.24(d,J＝6.8Hz,3H),0.92(d,J＝6.6Hz,6H).
化合物A116：
1H NMR(400MHz,CD3OD)δ7.85-7.80(,3H),7.75(s,1H),7.49-7.40(m,3H),4.30(dd,J＝13.2,6.6Hz,1H),3.66(s,2H),2.67-2.51(m,3H),1.66-1.56(m,1H),1.31-1.22(m,5H),0.92-0.86(m,6H).
化合物A117：
1H NMR(400MHz,CD3OD)δ8.38(s,1H),8.00-7.85(m,4H),7.63-7.53(m,2H),4.63-4.53(m,1H),2.67-2.72(m,2H),2.69-2.62(m 1H),1.69-1.58(m,1H),1.40(d,J＝6.8Hz,3H),1.35-1.30(m,2H),0.88(dd,J＝18.1,6.6Hz,6H).
化合物A118：
1H NMR(400MHz,CD3OD)δ7.20-7.14(m,2H),7.13-7.09(m,2H),4.37-4.24(m,1H),3.22-3.10(m,5H),2.71-2.58(m,3H),1.70-1.63(m,1H),1.39-1.31(m,2H),1.27(d,J＝6.8Hz,3H),0.93(dd,J＝6.6,3.1Hz,6H).
化合物A119：
1H NMR(400MHz,CD3OD)δ8.12-8.07(m,2H),7.62-7.52(m,2H),4.63-4.47(m,1H),2.90-2.69(m,2H),2.63(dd,J＝9.1,6.1Hz,1H),1.64-1.53(m,1H),1.41(d,J＝6.8Hz,3H),1.33-1.18(m,2H),0.83(dd,J＝27.3,6.6Hz,6H).
化合物A120：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.52(dd,J＝11.9,7.6Hz,2H),7.42-7.25(m,4H),4.49-4.37(m,2H),2.75(dd,J＝14.6,6.7Hz,1H),2.69(d,J＝8.2Hz,2H),2.66-2.62(m,1H),2.55-2.44(m,3H),2.08(d,J＝18.9Hz,3H),1.86(ddd,J＝27.7,14.8,8.5Hz,3H),1.71-1.58(m,2H),0.92(dd,J＝17.5,6.8Hz,6H).
化合物A121：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.66(d,J＝7.5Hz,2H),7.39(t,J＝7.3Hz,2H),7.31(t,J＝7.4,2H),4.28(s,2H),4.20(d,J＝6.4Hz,1H),2.94-2.78(m,2H),2.59(t,J＝7.4Hz,1H),1.68-1.54(m,1H),1.39(s,5H),1.28(t,J＝7.3Hz,3H),0.87(t,J＝6.4,6H).
化合物A122：
1H NMR(400MHz,CD3OD)δ7.80(d,J＝7.5Hz,2H),7.71-7.63(m,2H),7.39(t,J＝7.5Hz,2H),7.32(t,J＝7.4Hz,2H),4.42-4.27(m,2H),4.21-4.15(m,1H),2.95(s,2H),2.60-2.56(m,1H),2.37-2.14(m,4H),2.06-1.85(m,2H),1.66-1.55(m,1H),1.32-1.21(m,2H),0.94-0.79(m,6H).
化合物A123：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.67(d,J＝7.4Hz,2H),7.39(t,J＝7.3Hz,2H),7.31(t,J＝7.4Hz,2H),4.40-4.24(m,2H),4.20-4.15(m,1H),3.06-2.78(m,2H),2.62-2.51(m,1H),2.15-2.05(m,2H),1.79-1.65(m,5H),1.63-1.56(m,1H),1.33-1.21(m,3H),0.84(dd,J＝19.0,11.3Hz,6H).
化合物A124：
1H NMR(400MHz,CD3OD)δ7.80(d,J＝7.5Hz,2H),7.69(d,J＝7.4Hz,2H),7.39(t,J＝7.3Hz,2H),7.32(t,J＝7.4Hz,2H),7.14(br s,1H),4.50-4.29(m,2H),4.21(d,J＝6.2Hz,1H),3.81-3.44(m,4H),2.89-2.78(m,2H),2.58(t,J＝7.3Hz,1H),2.17(d,J＝14.3Hz,2H),1.78-1.65(m,2H),1.64-1.54(m,1H),1.32-1.23(m,2H),0.92-0.80(m,6H).
化合物A125：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.4Hz,2H),7.62-7.54(m,2H),7.40-7.24(m,5H),7.11-7.05(m,2H),7.00(t,J＝7.4Hz,1H),4.40-4.21(m,3H),4.18-4.10(m,1H),3.06-2.96(m,2H),2.71-2.51(m,3H),1.65-1.57(m,1H),1.34-1.23(m,4H),0.94-0.83(m,6H).
化合物A126：
1H NMR(400MHz,CD3OD)δ7.60(d,J＝7.9Hz,1H),7.33(d,J＝8.1Hz,1H),7.13-7.05(m,2H),7.01(t,J＝7.4Hz,1H),4.60-4.50(m,1H),3.02(d,J＝7.1Hz,2H),2.75-2.57(m,3H),2.14-2.00(m,3H),1.70-1.42(m,7H),1.41-1.22(m,3H),1.12-1.00(m,2H),0.98-0.85(m,6H).
化合物A127：
1H NMR(400MHz,CD3OD)δ7.75(d,J＝7.6Hz,2H),7.65(d,J＝7.9Hz,1H),7.41-7.29(m,4H),7.24(dd,J＝15.3,7.7Hz,2H),7.16-7.08(m,3H),7.03(t,J＝7.4Hz,1H),4.77-4.73(m,1H),4.31(t,J＝7.5Hz,1H),3.08(d,J＝6.6Hz,2H),2.80-2.60(m,4H),2.44-2.39(m,1H),1.70-1.57(m,1H),1.39-1.26(m,2H),0.91(dd,J＝6.6,2.2Hz,6H).
化合物A128：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.64(d,J＝7.5Hz,2H),7.39(t,J＝7.4Hz,2H),7.31(t,J＝7.4Hz,2H),4.38-4.35(m,2H),4.19(t,J＝6.7Hz,1H),3.30-3.18(m,2H),2.86-2.77(m,1H),2.66-2.58(m,1H),1.68-1.57(m,1H),1.37-1.29(m,2H),1.17(d,J＝7.0Hz,3H),0.90(dd,J＝9.6,6.6Hz,6H).
化合物A129：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.63(d,J＝7.5Hz,2H),7.39(t,J＝7.4Hz,2H),7.30(t,J＝7.4Hz,2H),4.37(d,J＝6.7Hz,2H),4.20(t,J＝6.7Hz,1H),3.28(d,J＝7.0Hz,2H),2.81(dd,J＝14.0,7.0Hz,1H),2.64(t,J＝7.6Hz,1H),1.65(dt,J＝13.4,6.7Hz,1H),1.31(t,J＝7.3Hz,2H),1.17(d,J＝7.0Hz,3H),0.91(dd,J＝6.6,3.8Hz,6H).
化合物A130：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.63(dd,J＝7.3,2.9Hz,2H),7.39(t,J＝7.4Hz,2H),7.30(t,J＝7.4Hz,2H),4.39-4.31(m,2H),4.20(t,J＝6.7Hz,1H),3.38-3.31(m,1H),3.20(dd,J＝13.8,9.2Hz,1H),2.89-2.78(m,1H),2.68-2.57(m,1H),1.69-1.48(m,3H),1.35-1.24(m,3H),0.97-0.82(m,12H).
化合物A131：
1H NMR(400MHz,CD3OD)δ7.80(d,J＝7.5Hz,2H),7.64(d,J＝7.4Hz,2H),7.39(t,J＝7.4Hz,2H),7.31(t,J＝7.4Hz,2H),4.45-4.31(m,3H),4.21(t,J＝6.7Hz,1H),3.52-3.36(m,2H),2.72(t,J＝7.6Hz,1H),1.67-1.57(m,1H),1.42(s,9H),1.35-1.30(m,2H),0.90(t,J＝6.3Hz,6H).
化合物A132：
1H NMR(400MHz,CD3OD)δ8.21(d,J＝8.3Hz,1H),7.81(d,J＝7.6Hz,2H),7.75(dd,J＝7.9,1.4Hz,1H),7.72-7.66(m,1H),7.53(dd,J＝7.5,1.6Hz,2H),7.41-7.25(m,5H),4.51(t,J＝7.6Hz,1H),2.87-2.75(m,3H),1.78-1.66(m,1H),1.48-1.38(m,2H),0.93(d,J＝8.4Hz,6H).
化合物A133：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.63(d,J＝7.4Hz,2H),7.39(t,J＝7.4Hz,2H),7.31(t,J＝7.4Hz,2H),4.36(d,J＝6.7Hz,2H),4.25-4.13(m,2H),2.75(dd,J＝16.3,8.2Hz,1H),2.62-2.58(m,1H),2.13-2.00(m,2H),1.94-1.73(m,3H),1.71-1.55(m,2H),1.43-1.28(m,2H),0.89-0.86(m,6H).
化合物A134：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.66(t,J＝6.8Hz,2H),7.39(t,J＝7.4 Hz,2H),7.31(t,J＝7.4Hz,2H),4.47-4.38(m,1H),4.30-4.14(m,3H),3.19-3.12(m,1H),2.57(dd,J＝9.3,5.9Hz,1H),2.08-1.90(m,4H),1.87-1.78(m,1H),1.72-1.50(m,2H),1.30-1.21(m,2H),0.83(dd,J＝24.1,6.6Hz,6H).
化合物A135：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.63(d,J＝7.4Hz,2H),7.39(t,J＝7.4Hz,2H),7.30(t,J＝7.4Hz,2H),4.35(t,J＝8.6Hz,2H),4.24-4.07(m,2H),2.75(dd,J＝16.2,8.0Hz,1H),2.71-2.58(m,1H),2.13-2.01(m,2H),1.84(ddd,J＝20.6,13.1,6.5Hz,3H),1.71-1.55(m,2H),1.33-1.24(m,2H),0.89(dd,J＝6.6,2.5Hz,6H).
化合物A136：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.64(d,J＝7.4Hz,2H),7.39(t,J＝7.4Hz,2H),7.31(t,J＝7.4Hz,2H),4.42-4.29(m,2H),4.28-4.14(m,2H),3.13(dd,J＝13.7,7.5Hz,1H),2.60(t,J＝7.6Hz,1H),2.07-1.74(m,5H),1.71-1.57(m,2H),1.29(t,J＝7.3Hz,2H),0.88(dd,J＝12.2,6.6Hz,6H).
化合物A137：
1H NMR(400MHz,CD3OD)δ7.74(d,J＝7.5Hz,2H),7.54(dd,J＝11.1,4.1Hz,2H),7.38(t,J＝7.5Hz,2H),7.32-7.27(m,2H),5.89(s,1H),4.39(q,J＝7.8Hz,1H),2.83(dd,J＝16.4,8.2Hz,1H),2.70(dd,J＝9.6,5.6Hz,1H),2.22-2.09(m,2H),1.97-1.69(m,4H),1.65-1.58(m,1H),1.49-1.42(m,1H),1.35-1.28(m,1H),0.95(dd,J＝6.6,2.1Hz,6H).
化合物A138：
1H NMR(400MHz,CD3OD)δ7.78(d,J＝7.4Hz,2H),7.49(d,J＝7.5Hz,2H),7.39-7.27(m,4H),4.50(dd,J＝14.7,7.4Hz,1H),4.38(t,J＝7.5Hz,1H),2.76(dd,J＝16.1,7.6Hz,1H),2.71-2.60(m,2H),2.54(dd,J＝14.4,7.8Hz,1H),2.20-2.08(m,2H),1.94-1.77(m,3H),1.74-1.59(m,2H),1.47-1.40(m,1H),1.38-1.27(m,1H),0.98-0.89(m,6H).
化合物A139：
1H NMR(400MHz,CD3OD)δ8.09(d,J＝7.8Hz,2H),7.48-7.38(m,4H),7.25-7.20(m,2H),5.05-4.92(m,2H),4.46-4.39(m,1H),2.87-2.78(m,1H),2.57-2.53(m,1H),2.15-2.00(m,2H),1.90-1.75(m,3H),1.71-1.52(m,2H),1.31-1.25(m,2H),0.83(dd,J＝14.0,6.5Hz,6H).
化合物A140：
1H NMR(400MHz,CD3OD)δ7.17-7.13(m,2H),7.12-7.05(m,2H),4.41(q,J＝7.7Hz,1H),3.05(dd,J＝15.5,7.6Hz,2H),2.89-2.73(m,2H),2.66-2.59(m,3H),2.33(d,J＝7.5Hz,2H),2.14-2.09(m,2H),1.88-1.81(m,2H),1.73-1.61(m,2H),1.45-1.26(m,3H),0.93(d,J＝6.5Hz,6H).
化合物A141：
1H NMR(400MHz,CD3OD)δ7.19-7.13(m,2H),7.13-7.09(m,2H),4.41(q,J＝7.7Hz,1H),3.24-3.06(m,5H),2.85-2.75(m,1H),2.63(dd,J＝9.6,5.6Hz,1H),2.18-2.05(m,2H),1.97-1.80(m,3H),1.75-1.61(m,2H),1.46-1.25(m,2H),0.92(dd,J＝6.6,3.4Hz,6H).
化合物A142：
1H NMR(400MHz,CD3OD)δ8.16-8.06(m,2H),7.63-7.52(m,2H),4.66-4.60(m,1H),3.06-2.98(m,1H),2.62(dd,J＝9.9,5.3Hz,1H),2.26-2.12(m,2H),2.07-1.85(m,4H),1.66-1.49(m,1H),1.43-1.28(m,2H),0.84(dd,J＝21.9,6.6Hz,6H).
化合物A143：
1H NMR(400MHz,CD3OD)δ8.37(s,1H),8.01-7.83(m,4H),7.60-7.56(m,2H),4.70-4.63(m,1H),2.98(q,J＝8.2Hz,1H),2.64(dd,J＝9.8,5.4Hz,1H),2.29-2.12(m,2H),2.06-1.82(m,4H),1.70-1.56(m,1H),1.46-1.33(m,2H),0.88(dd,J＝19.2,6.6Hz,6H).
化合物A144：
1H NMR(400MHz,CD3OD)δ7.81(d,J＝7.5Hz,2H),7.64(d,J＝7.4Hz,2H),7.40(t,J＝7.5Hz,2H),7.36-7.29(m,2H),4.38-4.28(m,2H),4.18(t,J＝6.6Hz,1H),3.76-3.66(m,1H),2.61-2.52(m,2H),1.95(d,J＝12.2Hz,2H),1.80(d,J＝10.7Hz,2H),1.69-1.55(m,2H),1.45-1.36(m,2H),1.29(t,J＝7.3Hz,3H),0.89(t,J＝15.7,9.0Hz,6H).
化合物A145：
1H NMR(400MHz,CD3OD)δ7.80(d,J＝7.5Hz,2H),7.65(d,J＝7.4Hz,2H),7.39(t,J＝7.4Hz,2H),7.31(t,J＝7.4Hz,2H),4.36(d,J＝6.7Hz,2H),4.21(t,J＝6.6Hz,1H),3.99-3.91(m,1H),2.99-2.91(m,1H),2.60(t,J＝7.4Hz,1H),1.97-1.82(m,2H),1.80-1.69(m,3H),1.67-1.59(m,2H),1.53-1.39(m,2H),1.31-1.27(m,2H),0.90(dd,J＝8.5,6.6Hz,6H).
化合物A146：
1H NMR(400MHz,CD3OD)δ7.78(t,J＝9.0Hz,2H),7.71-7.60(m,2H),7.39(t,J＝7.4Hz,2H),7.31(t,J＝7.4Hz,2H),4.43-4.34(m,1H),4.34-4.24(m,1H),4.19(t,J＝6.7Hz,1H),4.00-3.88(m,1H),3.03-2.94(m,1H),2.62-2.48(m,1H),1.99-1.70(m,4H),1.69-1.57(m,2H),1.52-1.40(m,2H),1.37-1.22(m,3H),0.86(dd,J＝17.6,6.6Hz,6H).
化合物A147：
1H NMR(400MHz,CD3OD)δ7.81(d,J＝7.5Hz,2H),7.64(d,J＝7.5Hz,2H),7.40(t,J＝7.4Hz,2H),7.33(t,J＝7.4Hz,2H),4.40-4.29(m,2H),4.21-4.18(m,1H),3.78-3.68(m,1H),2.61(t,J＝7.6Hz,1H),2.54-2.44(m,1H),2.00-1.90(m,2H),1.87-1.76(m,2H),1.68-1.57(m,2H),1.44-1.36(m,1H),1.34-1.27(m,4H),0.91-0.82(m,6H).
化合物A148：
1H NMR(400MHz,CD3OD)δ7.20-7.12(m,2H),7.11-7.04(m,2H),4.04-3.97(m,1H),3.07-3.03(m,2H),2.85-2.73(m,1H),2.66-2.48(m,4H),2.29(d,J＝7.2Hz,2H),2.01-1.93(m,2H),1.88-1.74(m,2H),1.67-1.54(m,2H),1.46-1.38(m,2H),1.30-1.26(m,3H),0.95-0.84(m,6H).
化合物A149：
1H NMR(400MHz,CD3OD)δ8.32(s,1H),8.02-7.90(m,3H),7.84(dd,J＝8.6,1.6Hz,1H), 7.64-7.48(m,2H),4.35-4.17(m,1H),2.81(t,J＝10.0Hz,1H),2.63-2.48(m,1H),2.04(t,J＝14.3Hz,2H),1.88(t,J＝11.8Hz,2H),1.77-1.30(m,5H),1.23-1.13(m,2H),0.74(dd,J＝64.6,6.6Hz,6H).
化合物A150：
1H NMR(400MHz,CD3OD)δ7.79(d,J＝7.5Hz,2H),7.61(d,J＝7.5Hz,2H),7.38(t,J＝7.3Hz,2H),7.31(td,J＝7.4,1.1Hz,2H),4.13(t,J＝6.7Hz,1H),3.64-3.57(m,2H),2.67-2.57(m,5H),1.69-1.60(m,1H),1.39-1.30(m,2H),0.92(d,J＝6.6Hz,6H).
化合物A151：
1H NMR(400MHz,CD3OD)δ7.75(d,J＝7.5Hz,2H),7.53(dd,J＝7.4,1.8Hz,2H),7.40(t,J＝7.4Hz,2H),7.31(dd,J＝7.4,6.7Hz,2H),6.07(s,1H),2.81(t,J＝6.2Hz,2H),2.73-2.64(m,3H),1.72-1.62(m,1H),1.39-1.32(m,2H),0.95(dd,J＝6.6,3.4Hz,6H).
化合物A152：
1H NMR(400MHz,CD3OD)δ7.18-7.14(m,2H),7.11-7.05(m,2H),3.23(d,J＝6.4Hz,2H),3.09-2.97(m,2H),2.74-2.54(m,8H),1.71-1.60(m,1H),1.36-1.27(m,2H),0.93-0.91(m,6H).
化合物A153：
1H NMR(400MHz,CD3OD)δ7.94(dd,J＝10.0,8.7Hz,2H),7.53-7.47(m,1H),7.45-7.39 (m,1H),4.77(s,2H),2.81-2.68(m,4H),2.64(dd,J＝9.2,6.0Hz,1H),1.70-1.57(m,1H),1.37-1.24(m,2H),0.90(s,6H).
化合物A154：
1H NMR(400MHz,CD3OD)δ7.86-7.78(m,3H),7.74(s,1H),7.49-7.39(m,3H),4.57-4.46(m,2H),2.76-2.72(m,2H),2.69-2.61(m,3H),1.70-1.58(m,1H),1.40-1.23(m,2H),0.91(dd,J＝6.6,1.1Hz,6H).
化合物A155：
1H NMR(400MHz,CD3OD)δ7.35-7.20(m,5H),4.41-4.30(m,2H),2.76-2.68(m,2H),2.68-2.60(m,3H),1.72-1.60(m,1H),1.37-1.25(m,2H),0.94-0.90(m,6H).
化合物A156：
1H NMR(400MHz,CD3OD)δ7.84(d,J＝7.8Hz,1H),7.79(d,J＝7.5Hz,1H),7.51(d,J＝7.5Hz,1H),7.47-7.26(m,5H),4.37-4.31(m,1H),3.78-3.68(m,1H),3.68-3.59(m,1H),3.19-3.03(m,3H),2.88-2.84(m,1H),2.75-2.70(m,1H),2.62-2.51(m,1H),2.46-2.41(m,1H),2.26-2.17(m,1H),1.70-1.57(m,1H),1.38-1.27(m,2H),0.91(dt,J＝6.5,3.2Hz,6H).
化合物A157：
1H NMR(400MHz,CD3OD)δ7.79(dd,J＝7.4,2.7Hz,2H),7.66-7.58(m,2H),7.38(dd,J＝12.4,7.7Hz,2H),7.31(dd,J＝13.8,6.0Hz,2H),4.16-4.10(m,1H),3.85-3.68(m,1H),3.63-3.50(m,1H),3.00-2.75(m,1H),2.71-2.54(m,2H),2.42-2.34(m,1H),2.21-2.01(m,1H),1.71-1.57 (m,1H),1.37-1.25(m,1H),1.11-0.99(m,3H),0.95-0.84(m,6H).
化合物A158：
1H NMR(400MHz,CD3OD)δ7.78(d,J＝7.5Hz,2H),7.60(d,J＝7.4Hz,2H),7.37(t,J＝7.3Hz,2H),7.30(td,J＝7.4,1.1Hz,2H),4.13(t,J＝6.1Hz,1H),3.76-3.64(m,2H),2.65-2.61(m,1H),2.27(t,J＝7.5Hz,2H),2.20(t,J＝7.3Hz,2H),1.86-1.78(m,2H),1.69-1.59(m,1H),1.39-1.26(m,2H),0.93(dd,J＝6.6,3.5Hz,6H).
化合物A161：
1H NMR(400MHz,DMSO)δ7.79(d,J＝7.5Hz,2H),7.39(dd,J＝13.4,7.2Hz,4H),7.30(t,J＝7.1Hz,2H),4.45(t,J＝6.8Hz,1H),3.43(d,J＝6.8Hz,2H),3.18(t,J＝7.0Hz,2H),2.87(t,J＝7.1Hz,2H),2.69-2.62(m,1H),1.69-1.58(m,1H),1.34-1.27(m,2H),0.90(d,J＝6.6Hz,6H).
化合物A162：
1H NMR(400MHz,CD3OD)δ7.86-7.78(m,4H),7.51-7.45(m,2H),7.44-7.40(m,1H),4.41(s,2H),4.07(s,1H),2.79(t,J＝8.7,1H),1.66-1.56(m,1H),1.37-1.27(m,2H),0.91-0.84(m,6H).
化合物A163：
1H NMR(400MHz,CD3OD)δ7.92-7.79(m,4H),7.56-7.42(m,3H),6.01(s,2H),4.08(s,2H),2.75-2.66(m,1H),1.69-1.57(m,1H),1.39-1.25(m,2H),0.90(d,J＝6.5Hz,6H).
化合物A164：
1H NMR(400MHz,CD3OD)δ7.93-7.79(m,4H),7.53-7.50(m,2H),7.40(d,J＝7.5Hz,1H),5.92-5.80(m,2H),4.11-4.08(m,1H),2.80-2.72(m,1H),1.64-1.53(m,1H),1.43-1.16(m,2H),0.89(dd,J＝6.5,2.9Hz,6H).
化合物A165：
1H NMR(400MHz,CD3OD)δ7.97(s,1H),7.90-7.79(m,4H),7.54-7.46(m,2H),7.41(dd,J＝8.5,1.7Hz,1H),5.76(s,2H),3.88(s,2H),2.67(dd,J＝8.7,6.5Hz,1H),1.70-1.55(m,1H),1.38-1.18(m,2H),0.90(d,J＝6.6Hz,6H).
化合物A167：
1H NMR(400MHz,CD3OD)δ7.85-7.76(m,4H),7.49-7.37(m,3H),4.23(s,2H),2.88-2.74(m,1H),1.66-1.52(m,1H),1.40-1.32(m,2H),0.87(d,J＝6.6Hz,6H).
化合物A168：
1H NMR(400MHz,CD3OD)δ7.81(dd,J＝8.6,4.1Hz,3H),7.73(s,1H),7.46(dd,J＝6.7,3.0Hz,2H),7.41-7.35(m,1H),7.00(s,1H),4.27(s,2H),2.71-2.58(m,1H),1.65-1.52(m,1H),1.29-1.24(m,2H),0.87(d,J＝6.6Hz,6H).
化合物A169：
1H NMR(400MHz,CD3OD)δ7.83(dd,J＝10.6,6.9Hz,4H),7.51-7.44(m,2H),7.42(dd,J＝8.4,1.7Hz,1H),4.60(s,2H),2.80-2.76(m,1H),1.68-1.53(m,1H),1.39-1.24(m,2H),0.89(dd,J＝6.6,0.9Hz,6H).
化合物A170：
1H NMR(400MHz,CD3OD)δ7.88-7.78(m,4H),7.52-7.41(m,3H),4.45(s,2H),2.76-2.69(m,1H),1.69-1.56(m,1H),1.39-1.28(m,2H),0.90(d,J＝6.6Hz,6H).
化合物A171：
1H NMR(400MHz,CD3OD)δ7.87-7.78(m,4H),7.58(s,1H),7.51-7.44(m,2H),7.42(dd,J＝8.5,1.7Hz,1H),4.48(s,2H),3.94(s,2H),2.67(dt,J＝14.5,7.3Hz,1H),1.67-1.55(m,1H),1.36-1.23(m,2H),0.89(d,J＝6.6Hz,6H).
化合物A172：
1H NMR(400MHz,CD3OD)δ8.10-8.02(m,1H),7.92-7.79(m,2H),7.76(s,1H),7.55-7.45(m,4H),6.04(s,2H),3.81(s,2H),2.67-2.59(m,1H),1.68-1.52(m,1H),1.36-1.18(m,2H),0.88(d,J＝6.6Hz,6H).
化合物A173：
1H NMR(400MHz,CD3OD)δ7.76(s,1H),7.49-7.43(m,2H),7.38(d,J＝8.2Hz,1H),7.13(t,J＝7.3Hz,1H),7.01(t,J＝7.5Hz,1H),5.76(s,2H),3.81(s,2H),2.68-2.58(m,1H),1.58(dd,J＝16.9,10.3Hz,1H),1.28-1.23(m,2H),0.89(d,J＝8.1Hz,6H).
化合物A174：
1H NMR(400MHz,CD3OD)δ7.93-7.71(m,4H),7.53-7.36(m,3H),4.55(s,2H),4.16(s,2H),3.55-3.42(m,2H),3.38-3.34(m,2H),2.74(t,J＝7.4Hz,1H),1.75-1.61(m,1H),1.39-1.33(m,2H),0.93(d,J＝6.4Hz,6H).
化合物A175：
1H NMR(400MHz,CD3OD)δ9.16(d,J＝8.6Hz,1H),8.39-8.31(m,3H),8.23(t,J＝8.3Hz,1H),8.01(t,J＝7.7Hz,1H),7.79(d,J＝8.6Hz,1H),6.31(s,2H),3.98(s,2H),2.80-2.72(m,1H),1.69-1.63(m,1H),1.37-1.30(m,2H),0.93(d,J＝6.6Hz,6H).
化合物A176：
1H NMR(400MHz,CD3OD)δ9.23(s,1H),8.11(d,J＝8.2Hz,1H),8.07(s,1H),7.93(d,J＝8.2Hz,1H),7.85-7.75(m,2H),7.72(dd,J＝11.1,4.0Hz,1H),5.85(s,2H),3.91(s,2H),2.77-2.64(m,1H),1.68-1.60(m,1H),1.35-1.29(m,2H),0.92(s,J＝6.4Hz,6H).
化合物A177：
1H NMR(400MHz,CD3OD)δ8.89(d,J＝2.1Hz,1H),8.32(d,J＝1.3Hz,1H),8.09(s,1H),8.05(d,J＝8.5Hz,1H),7.95(d,J＝8.1Hz,1H),7.84-7.77(m,1H),7.65(t,J＝7.5Hz,1H),5.87(s,2H),3.90(s,2H),2.74-2.64(m,1H),1.70-1.58(m,1H),1.36-1.22(m,2H),0.91(d,J＝6.6Hz,6H).
化合物A178：
1H NMR(400MHz,CD3OD)δ9.37(d,J＝7.5Hz,2H),9.17(d,J＝7.0Hz,2H),8.96(t,J＝7.3Hz,2H),8.88(t,J＝7.2Hz,2H),6.02(dd,J＝32.9,5.7Hz,2H),5.81(d,J＝6.2Hz,1H),5.13(s,1H),4.96(s,1H),4.41(s,3H),4.25-4.12(m,2H),3.92(t,J＝6.6Hz,1H),3.24-3.15(m,1H),2.90-2.82(m,2H),2.46(d,J＝6.1Hz,6H).
化合物A179：
1H NMR(400MHz,CD3OD)δ7.76(d,J＝7.5Hz,2H),7.52(d,J＝7.2Hz,2H),7.34(t,J＝7.4Hz,2H),7.27(t,J＝7.4Hz,2H),4.46(t,J＝7.3Hz,1H),3.79(t,J＝6.8Hz,1H),3.59-3.52(m,1H),3.05(s,1H),2.94(s,2H),2.86-2.74(m,3H),2.69(dd,J＝9.0,6.0Hz,1H),2.56(t,J＝6.6Hz,1H),1.72-1.54(m,1H),1.42-1.21(m,2H),0.99-0.84(m,6H).
化合物A180：
1H NMR(400MHz,CD3OD)δ8.06(t,J＝5.1Hz,1H),7.82(d,J＝7.5Hz,2H),7.56(d,J＝7.5Hz,2H),7.42(t,J＝7.5Hz,2H),7.36-7.28(m,2H),4.76(s,1H),3.26(dd,J＝13.0,6.7Hz,2H),2.64(s,1H),2.41(t,J＝7.7Hz,2H),1.92-1.79(m,2H),1.70-1.60(m,1H),1.34-1.28(m,1H),0.92 (dd,J＝6.6,2.4Hz,6H).
效果例1：本发明化合物的抗癌活性测试
实验方法：
1.细胞培养方法。
HL-60细胞培养基：RPMI-1640(+左旋谷氨酰胺)中加入10％胎牛血清，每毫升100单位青霉素、100μg链霉素。
细胞培养条件：5％CO
2，95％湿度，37℃恒温培养。
2.细胞接种、加药培养。
将对数生长期的HL-60细胞接种至96-孔细胞培养板中，每孔2×10
4细胞。加入不同浓度的活性化合物(溶于DMSO储液)，DMSO终浓度为0.2％，对照组为DMSO。每组重复三次。
3.MTT实验。
培养72小时后，每孔加入20μL的MTT(5mg/ml，现配现用，溶于细胞培养用1×PBS)，37℃孵育3小时。
离心96孔细胞培养板，1000rpm，10分钟。弃去上清，每孔加入200μL的DMSO，摇匀5分钟。
用酶标仪检测每孔在570nm波长处的吸收值，计算化合物的IC
50。
表1：本发明化合物对HL60细胞的IC
50值
注：A代表化合物IC
50在100nM以下，B代表化合物IC
50在100～500nM，C代表化合物IC
50在500nM～2μM，D代表化合物IC
50在2～10μM之间。
表1实验结果显示了本发明化合物对HL60细胞均具有优异的抑制效果，可用于癌症的预防和治疗。
效果例2：本发明化合物对c-Myc蛋白的结合效果测试
1.实验准备。
将10×PBS-P稀释成1.05×PBS-P缓冲液备用。将c-Myc370-412-biotin多肽溶解于色谱纯DMSO配制成1mM储液。活性分子溶解于色谱纯DMSO配制成10mM储液。将部分1.05×PBS-P缓冲液加入色谱纯DMSO配制成1.00×PBS-P缓冲液(5％DMSO，现配现用)。
分别测试每个小分子在1.00×PBS-P缓冲液(5％DMSO)体系中可达到的最高溶解度。将该溶解度作为小分子活性测试的最高浓度。
2.蛋白固定。
将c-Myc370-412-biotin多肽储液加入1.05×PBS-P缓冲液配制成50μM溶液，再用1.00×PBS-P缓冲液(5％DMSO)稀释至1μg/ml用于固定蛋白。
使用1.00×PBS-P缓冲液(5％DMSO)冲洗芯片样品道和参比道后，选用自动模式固定蛋白在样品道。目标固定蛋白量为500RU。固定成功。缓冲液继续冲洗至平衡。
3.小分子活性测试。
使用缓冲液配置不同浓度的小分子化合物用于样品测试，体系为1.00×PBS-P缓冲液(5％DMSO)。检测小分子流经样品道和参比道响应的差值。
实验条件为流速10μL/min，结合时间为120秒，解离时间为240秒。在每一次结合解离测试后使用50％DMSO冲洗管路，10mM glycine-HCl缓冲液(pH 2.1)冲洗芯片表面以洗去残留的化合物分子。实验结果参见表2、图1。
表2：本发明化合物与c-Myc蛋白的Kd值
| 化合物编号 | SPR Kd | 化合物编号 | SPR Kd |
| A103 | B | A139 | B |
| A112 | A | A144 | C |
| A138 | A |
活性数据(A代表化合物Kd值在100nM以下，B代表化合物Kd值在100～500nM，C代表化合物Kd值在500nM～2μM)。
效果例3：本发明化合物对c-Myc蛋白降解效果测试
1细胞药物处理和蛋白质提取
1.1细胞处理
HL60细胞在指数生长期时，离心计数后将细胞铺板于6孔板中，每孔1×10
6个细胞，，加药物培养，药物处理24h后提取蛋白质。
1.2细胞蛋白质提取
将细胞收集于1.5mL离心管中，离心弃去上清后加入PBS清洗一遍后，每管中加入100μL RIPA裂解液(含100μM PMSF)，充分混合后冰上静置30min，之后用离心机4℃12000rpm离心20min，取上清用于WB实验，样品可放于-80℃保存。
1.3蛋白质浓度测定
使用BCA蛋白浓度测定试剂盒，按照下表配制BSA标准测定溶液和待测样品(待测样品可稀释后检测)，使用96孔板加样，各孔用PBS补足至20μl后，分别加入200μlBCA工作液(按试剂盒配制)，混匀后于60℃放置10min后于562nm处检测吸光度，记录读数后以标 准品浓度梯度作标准曲线，代入样品吸光度计算样品蛋白质浓度。
表3：溶液配比表
2 Western bloting实验标准流程
2.1蛋白质变性：取蛋白裂解液，加入5×Loading Buffer，100℃变性5min。
2.2上样及电泳：使用10％预制胶及专用电泳液，每孔上样同质量蛋白样品及蛋白marker后，200V电泳30min。
2.3封闭：将胶取下后切下多余部分，通过湿转法转移到PVDF膜上(PVDF膜需要先用甲醇活化1min后使用)，300mA，2h，转膜过程中大量产热，需要用冰盒降温。
2.4封闭：将转膜结束的PVDF膜放于5％脱脂牛奶中室温摇晃封闭1h。
2.5孵育一抗：将PVDF膜按照marker上指示分子量大小分别剪开，分别置于c-Myc和GAPDH一抗中，抗体按照1:1000比例用TBST稀释，4℃摇床封闭过夜。
2.6孵育二抗：孵育一抗后的PVDF膜在摇床上用TBST清洗3次，每次10min，清洗后将膜分别置于对应种属二抗中，摇床振荡室温孵育2h。
洗膜及曝光：孵育二抗结束后将膜放于TBST中摇床振荡清洗3次，每次10min，洗膜后使用ECL法激发膜上荧光。
实验结果见图2，本发明化合物A102可以促进c-Myc蛋白的降解。
本发明内容仅仅举例说明了要求保护的一些具体实施方案，其中一个或更多个技术方案中所记载的技术特征可以与任意的一个或多个技术方案相组合，这些经组合而得到的技术方案也在本申请保护范围内，就像这些经组合而得到的技术方案已经在本发明公开内容中具体记载一样。
Claims (13)
- 式(I)所示的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药：
其中，T、U、Z分别独立的选自：化学键、CR 4R 5或T、U、Z中的两个或三个共同形成C 3-C 6环烷基、芳基，条件是-T-U-Z-骨架为-C-C-或-C-C-C-；W为BZ 1Z 2；R 1选自：RAC(＝O)-、RACH 2C(＝O)-、RACH 2CH 2C(＝O)-、RACH 2-、RANHC(＝O)-、RACH 2NHC(＝O)-、RACH 2OC(＝O)-、RACH 2CH 2OC(＝O)-、RAOC(＝O)-、RAS(＝O) 2-或RA；RA选自：C 1-C 4烷基、C 3-C 10环烷基、C 3-C 10桥环基、C 3-C 10任含O、S、SO 2、N或NHC(＝O)R 8的杂环基、芳基、杂芳基、稠合芳基环烷基、稠合杂芳基杂环基、芳基-环烷基、芳基-杂环基、环烷基-杂环基、杂环基-杂环基，RA可任选的被一个或多个R 6取代；R 2选自：氢、C 1-C 3烷基、C 3-C 6环烷基；任选的R 2可以与所连接的N及任选T、U、Z中的一个或多个形成杂环基，所述杂环基为包含N及任选的O、S的5-10元杂环基，任选的所述杂环基包含C(＝O)；任选的R 1、R 2可以与所共同连接的N形成RA-杂环基、RACH 2-杂环基，所述杂环基为包含N及任选的O、S的5-6元杂环基，任选的所述杂环基包含C(＝O)；R 3选自：氢、C 1-C 6的烷基、C 3-C 6环烷基、苯基或苄基，所述烷基、环烷基、苯基或者苄基任选1-3个分别选自卤素、氰基、C 1-C 3烷基或C 1-C 3烷氧基的基团取代，R 3可与R 11成C 4-C 6的环烷基；R 4、R 5分别独立的选自：氢、羟基、氨基、-NHBoc、-NHCbz、-R 7NHC(＝O)R 8、-R 7C(＝O)OR 8、-C(＝O)OR 8、-R 7C(＝O)NHR 8、-C(＝O)NHR 8、-C 1-C 6烷基、--C 1-C 6烷基苄氧基、-C 1-C 6烷基杂环基、-C 1-C 6烷基芳基、-C 1-C 6烷基杂芳基、-C 1-C 6烷氧基、-C 1-C 6烷硫基、-C 1-C 6烷硫基C 1-C 6烷基、-C 1-C 6烷胺基、-C 3-C 8环烷基，芳基、含有1-3个杂原子的5-6元杂芳基或含有1-3个杂原子的3-10元杂环基，所述烷基、烷氧基、烷胺基、烷硫基、环烷基、芳基、杂芳基、杂环基任选的被1-3个分别选自卤素、氰基、C 1-C 3烷基、C 1-C 3卤代烷基或C 1-C 3烷氧基的基团取代，其中R 4、R 5与其所共同连接的C可以成C 3-C 6的饱和环、芳基或任含O、S、SO 2、N、NBoc、或NHC(＝O)R 8的饱和杂环或羰基；R 6选自：氢、卤素、羟基、氰基、氨基、-R 7NHC(＝O)R 8、-R 7C(＝O)OR 8、C 1-C 6烷基、C 1-C 6的烷氧基、C 1-C 6的烷硫基、C 1-C 6的烷胺基、C 3-C 8的环烷基、C 2-C 8的烯基、C 2-C 8的炔基、芳基、含有1-3个杂原子的5-6元杂芳基或含有1-3个杂原子的3-10元杂环基，所述烷基、烷氧基、烷胺基、烷硫基、环烷基、芳基、杂芳基、杂环基任选被1-3个分别选自卤素、氰基、C 1-C 3烷基或C 1-C 3烷氧基的基团取代；R 7选自：C 1-C 4的烷基；R 8选自：氢、氨基、C 1-C 4的烷基、C 1-C 4的烷氧基、烯丙基或苄基，所述C 1-C 4的烷基、C 1-C 4的烷氧基、烯丙基或苄基任选的被芳基、-C(＝O)OR 7所取代；R 11为氢、C 1-C 3的烷基、C 3环烷基；Z 1、Z 2分别独立的选自：羟基、C 1-C 10烷基、C 1-C 10烷氧基或芳氧基，B、Z 1和Z 2可一起形成含N、S或O的杂环基。 - 根据权利要求1所述的式(I)所示的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药，其特征在于，所述药学上可接受的盐选自：盐酸盐，磷酸盐，磷酸氢盐，磷酸二氢盐，硫酸盐，硝酸盐，碳酸氢盐，碳酸盐，戊二酸盐，氢溴酸盐，醋酸盐，枸橼酸盐，乳酸盐，马来酸盐，苯甲酸盐，甲磺酸盐，草酸盐，苯磺酸盐、对甲苯磺酸盐、酒石酸、苹果酸盐，琥珀酸盐，抗坏血酸盐，葡萄糖酸盐，乳酸盐，所述溶剂化物选自：半水合物、一水合物、二水合物；所述立体异构体选自：对映异构体或非对映异构体。
- 根据权利要求1所述的式(I)所示的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药，其特征在于，B、Z 1和Z 2可一起形成含N、S或O的杂环基。
- 根据权利要求3所述的式(I)所示的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药，其特征在于，W为
- 式(II)所示的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药：
其中T、U、Z、R 1、R 2、R 3、R 11取代基定义同权利要求1。 - 式(III)所示的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药：
其中T、U、Z、R 1、R 2、R 3、R 11取代基定义同权利要求1。 - 权利要求1-6任一项所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药，其特征在于具有如下结构:
- 一种药物组合物，其特征在于，包含药学上可接受的载体和权利要求1-7任一项所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药。
- 权利要求1-7任一项所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药在制备c-Myc蛋白抑制剂中的用途。
- 权利要求1-7任一项所述的化合物及其药学上可用的盐、溶剂化合物、立体异构体、同位素及其前药在制备治疗c-Myc蛋白失调相关疾病药物中的用途。
- 根据权利要求10所述的用途，其特征在于，所述c-Myc蛋白失调选自c-Myc蛋白过表达。
- 根据权利要求10所述的用途，其特征在于，所述c-Myc蛋白失调相关疾病选自：癌症、心脑血管疾病、病毒感染相关疾病。
- 根据权利要求12所述的用途，其特征在于，所述癌症选自：肝癌、肺癌、肾癌、胰腺癌、口腔癌、胃癌、食道癌、喉癌、鼻咽癌、皮肤癌、乳腺癌、结肠癌、直肠癌、宫颈癌、卵巢癌、前列腺癌、脑癌、神经癌、粒细胞性白血病、横纹肌肉瘤、成骨肉瘤、软骨肉瘤、白血病、淋巴癌；所述病毒感染相关疾病选自:HIV、乙肝、丙肝、甲肝、流感、流行性乙脑炎、疱疹。
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