C-MYC PROTEIN INHIBITOR, AND PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

Provided are a c-Myc protein inhibitor, and a preparation method therefor and use thereof. The c-Myc protein inhibitor selectively inhibits c-Myc protein. Therefore, the inhibitor can be used for prevention and treatment of diseases related to c-Myc protein disorders, such as cancers, cardiovascular and cerebrovascular diseases, diseases related to virus infection.

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt, a solvate, a stereoisomer or a prodrug thereof: ##STR00231## wherein: T is selected from CHR.sub.4, CR.sub.4R.sub.5; W is BZ.sub.1Z.sub.2; R.sub.1 is selected from RAC(═O)—, RANHC(═O)—, RAOC(═O)—, RACH.sub.2C(═O)—, RAS(═O).sub.2— or RA; RA is selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 heterocyclyl optionally containing O, S, SO.sub.2, N or NHC(═O)R.sub.8, aryl, heteroaryl, aryl-cycloalkyl, aryl-heterocyclyl, cycloalkyl-heterocyclyl, heterocyclyl-heterocyclyl, RA may be optionally substituted by one or more R.sub.6; R.sub.2 is selected from: hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.6 cycloalkyl; R.sub.3 is selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, phenyl or benzyl, the alkyl, cycloalkyl, phenyl or benzyl is optionally substituted by 1-3 substituents independently selected from halogen, cyano, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 alkoxy, R.sub.3 and R.sub.11 can form C.sub.4-C.sub.6 cycloalkyl; R.sub.4 and R.sub.5 are independently selected from hydroxyl, amino, R.sub.7NHC(═O)R.sub.8, R.sub.7C(═O)OR.sub.8, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 alkylamine, C.sub.3-C.sub.8 cycloalkyl, aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms or 3-10 membered heterocyclyl containing 1-3 heteroatoms, the alkyl, alkoxy, alkylamine, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclyl are optionally substituted by 1-3 substituents independently selected from halogen, cyano, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 alkoxy, wherein R.sub.4 and R.sub.5 can form a saturated C.sub.3-C.sub.6 ring or a saturated heterocyclic ring optionally containing O, S, SO.sub.2, N or NHC(═O)R.sub.8; R.sub.6 is selected from hydrogen, halogen, hydroxyl, cyano, amino, R.sub.7NHC(═O)R.sub.8, R.sub.7C(═O)OR.sub.8, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 alkylamino, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms or 3-10 membered heterocyclyl containing 1-3 heteroatoms, the alkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclyl are optionally substituted with 1-3 groups selected from halogen, cyano, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 alkoxy; R.sub.7 is selected from C.sub.1-C.sub.4 alkyl; R.sub.8 is selected from hydrogen, C.sub.1-C.sub.4 alkyl, allyl or benzyl; R.sub.11 is hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.3 cycloalkyl; Z.sub.1 and Z.sub.2 are independently selected from hydroxyl, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy or aryloxy, B, Z.sub.1 and Z.sub.2 can together form heterocyclyl containing N, S or O.

2. The compound represented by formula (I) or the pharmaceutically acceptable salt, the solvate, the stereoisomer, or the prodrug thereof according to claim 1, wherein the pharmaceutically acceptable salt is selected from hydrochloride, phosphate, hydrogen phosphate, dihydrogen phosphate, sulfate, nitrate, bicarbonate, carbonate, glutarate, hydrobromide, acetate, citrate, lactate, maleate, benzoate, methanesulfonate, oxalate, benzenesulfonate, p-toluenesulfonate, tartaric acid, malate, succinate, ascorbate, gluconate, lactate; the solvate is selected from hemihydrate, monohydrate, and dihydrate; the stereoisomer is selected from enantiomer or diastereomer.

3. The compound represented by formula (I) or the pharmaceutically acceptable salt, the solvate, the stereoisomer, or the prodrug thereof according to claim 1, wherein Z.sub.1 and Z.sub.2 can together form heterocyclyl containing N, S or O.

4. The compound represented by formula (I) or the pharmaceutically acceptable salt, the solvate, the stereoisomer, or the prodrug thereof according to claim 1, wherein W is ##STR00232##

5. The compound represented by formula (I) or the pharmaceutically acceptable salt, the solvate, the stereoisomer, or the prodrug thereof according to claim 1, wherein R.sub.1 is selected from RAC(═O)—, RANHC(═O)—, RAOC(═O)—, RACH.sub.2C(═O)—, RAS(═O).sub.2— or RA; RA is selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 heterocyclyl optionally containing O, S, SO.sub.2, N or NHC(═O)R.sub.8, aryl, heteroaryl, aryl-cycloalkyl, aryl-heterocyclyl, cycloalkyl-heterocyclyl, heterocyclyl-heterocyclyl, wherein RA may be optionally substituted by one or more R.sub.6.

6. A compound represented by formula (II) or a pharmaceutically acceptable salt, a solvate, a stereoisomer or a prodrug thereof, ##STR00233## wherein the substituents T, R.sub.1, R.sub.2, R.sub.3 and R.sub.11 have the same definition as in claim 1.

7. A compound represented by formula (III) or a pharmaceutically acceptable salt, a solvate, a stereoisomer or a prodrug thereof, ##STR00234## wherein the substituents T, R.sub.1, R.sub.2, R.sub.3 and R.sub.11 have the same definition as in claim 1.

8. The compound or the pharmaceutically acceptable salt, the solvate, the stereoisomer or the prodrug thereof according to claim 1, wherein the compound has the following structures: ##STR00235## ##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247## ##STR00248## ##STR00249## ##STR00250## ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260##

9. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and the compound or the pharmaceutically acceptable salt, the solvate, the stereoisomer or the prodrug thereof according to claim 1.

10. A method for preparing c-Myc protein inhibitors, comprising using the compound or the pharmaceutically acceptable salt, the solvate, the stereoisomer or the prodrug thereof according to claim 1.

11. A method of treating diseases related to c-Myc protein disorders, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or the pharmaceutically acceptable salt, the solvate, the stereoisomer or the prodrug thereof according to claim 1.

12. The method according to claim 11, wherein the c-Myc protein disorder is selected from c-Myc protein overexpression or enhanced protein stability.

13. The method according to claim 11, wherein the diseases related to c-Myc protein disorders are selected from the group consisting of cancers, cardiovascular and cerebrovascular diseases, or viral infection-related diseases.

14. The method according to claim 13, wherein the cancer is selected from the group consisting of liver cancer, lung cancer, kidney cancer, pancreatic cancer, oral cancer, gastric cancer, esophageal cancer, laryngeal cancer, nasopharyngeal cancer, skin cancer, breast cancer, colon cancer, rectal cancer, cervical cancer, ovarian cancer, prostate cancer, brain cancer, nerve cancer, granulocytic leukemia, rhabdomyosarcoma, osteogenic sarcoma, chondrosarcoma, leukemia, lymphoma; the viral infection-related diseases are selected from HIV, hepatitis B, hepatitis C, hepatitis A, influenza, Japanese encephalitis, herpes.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0044] FIG. 1: Single-cycle binding kinetics curve of A5 and c-Myc peptide LE40.

[0045] FIG. 2: The binding K.sub.D of A5 and c-Myc peptide LE40 is 0.16 μM.

[0046] FIG. 3: Single-cycle binding kinetic curve of A5 and c-Myc peptide LE40 (S373A), no obvious binding.

[0047] FIG. 4: Compound A13 can compete for the binding of c-Myc and Max.

[0048] FIG. 5: A5 and A13 promote the degradation of c-Myc protein.

[0049] FIG. 6: A13 selectively inhibits tumor cells with high expression of c-Myc.

DETAILED DESCRIPTION

[0050] The present disclosure will be exemplified below in combination with the accompanying drawings and further detailed description. It should be pointed out that the following description is only examples of the technical solutions claimed by the present disclosure, and does not limit these technical solutions in any way. The protection scope of the present disclosure is subject to the content recorded in the appended claims.

Example 1

[0051] ##STR00111##

[0052] Compound A1 was synthesized as follows:

##STR00112##

[0053] Compound A1-1 (2.98 g, 5 mmol) was dissolved in dichloromethane (DCM) (150 mL), and 1-hydroxybenzotriazole (HOBt) (810 mg, 6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.15 g, 6 mmol) were added under ice bath. After reacting for 30 min, A1-2 (1.90 g, 5 mmol) and N,N-diisopropylethylamine (DIEA) (1.3 mL, 7.4 mmol) were added and reacted at room temperature for 2 hours. Water was added, and the mixture was extracted with DCM (100 mL*3). The organic phases were combined. After the solvent was spin-dried, the crude product was purified by medium pressure preparative liquid chromatography to obtain a white solid compound A1 (280 mg, yield 6.8%).

[0054] .sup.1H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 8.60 (s, 1H), 7.90 (d, J=7.6 Hz, 2H), 7.78-7.66 (m, 3H), 7.47-7.37 (m, 2H), 7.33 (t, J=7.4 Hz, 1H), 7.20 (dt, J=13.0, 6.7 Hz, 15H), 4.44 (d, J=22.6 Hz, 1H), 4.34 (d, J=16.0 Hz, 1H), 4.29-4.15 (m, 2H), 4.08 (d, J=8.4 Hz, 1H), 2.72 (t, J=14.8 Hz, 1H), 2.58 (d, J=6.8 Hz, 1H), 2.46 (s, 1H), 2.24-2.14 (m, 1H), 2.05-1.96 (m, 1H), 1.86-1.79 (m, 1H), 1.80-1.75 (m, 1H), 1.70-1.61 (m, 2H), 1.36-1.20 (m, 9H), 0.84-0.74 (m, 9H).

[0055] ESI-MS (M+H).sup.+: 844.

[0056] The synthesis method of compound A2-A10 is the same as that of A1, except that the Fmoc protected L-asparagine (NH-Trt) was replaced with the corresponding Fmoc protected amino acid.

Example 2

[0057] ##STR00113##

[0058] .sup.1H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.88 (d, J=7.3 Hz, 2H), 7.73 (t, J=6.4 Hz, 2H), 7.41 (t, J=7.1 Hz, 2H), 7.31 (t, J=7.2 Hz, 2H), 7.06 (d, J=9.3 Hz, 1H), 4.48-4.28 (m, 2H), 4.24 (d, J=6.2 Hz, 1H), 4.12 (dd, J=18.6, 8.5 Hz, 2H), 3.85 (t, J=13.9 Hz, 1H), 2.57 (d, J=21.7 Hz, 1H), 2.18 (dd, J=24.5, 14.7 Hz, 1H), 2.01 (s, 1H), 1.81 (d, J=24.2 Hz, 2H), 1.73-1.57 (m, 2H), 1.34 (d, J=9.4 Hz, 2H), 1.26 (s, 3H), 1.21 (s, 3H), 1.10 (s, 9H), 1.03 (d, J=5.7 Hz, 3H), 0.90-0.75 (m, 9H).

[0059] ESI-MS (M+Na).sup.+: 667.

Example 3

[0060] ##STR00114##

[0061] .sup.1H NMR (400 MHz, DMSO) δ 8.53 (s, 1H), 7.89 (d, J=7.6 Hz, 2H), 7.72 (d, J=7.7 Hz, 3H), 7.40 (t, J=7.4 Hz, 2H), 7.35-7.29 (m, 12H), 7.25 (dt, J=12.0, 4.6 Hz, 5H), 4.33-4.16 (m, 3H), 4.16-4.00 (m, 2H), 2.61 (t, J=9.3 Hz, 1H), 2.39 (t, J=12.8 Hz, 1H), 2.30 (dd, J=11.8, 5.5 Hz, 1H), 2.17 (dd, J=17.7, 13.3 Hz, 1H), 1.98 (dd, J=13.2, 8.4 Hz, 1H), 1.83-1.71 (m, 2H), 1.66-1.53 (m, 2H), 1.33 (dd, J=29.0, 15.1 Hz, 3H), 1.17 (t, J=13.8 Hz, 6H), 0.86-0.70 (m, 9H).

[0062] ESI-MS (M+Na)+: 855.

Example 4

[0063] ##STR00115##

[0064] .sup.1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 7.88 (d, J=7.3 Hz, 2H), 7.66 (d, J=6.0 Hz, 2H), 7.57 (d, J=8.3 Hz, 1H), 7.40-7.38 (m, 2H), 7.36-7.22 (m, 12H), 7.05 (d, J=6.6 Hz, 6H), 6.77 (s, 1H), 4.43 (t, J=10.3 Hz, 1H), 4.29-4.09 (m, 3H), 4.01 (d, J=7.8 Hz, 1H), 2.99-2.74 (m, 2H), 2.66-2.53 (m, 1H), 2.17-2.12 (m, 1H), 1.96 (s, 1H), 1.82-1.51 (m, 4H), 1.41-1.04 (m, 9H), 0.85-0.76 (m, 9H).

[0065] ESI-MS (M+H).sup.+: 867.

Example 5

[0066] ##STR00116##

[0067] .sup.1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 7.89 (d, J=7.5 Hz, 2H), 7.71 (t, J=7.8 Hz, 2H), 7.64 (d, J=8.1 Hz, 1H), 7.42 (t, J=7.4 Hz, 2H), 7.32 (dd, J=11.7, 7.2 Hz, 2H), 4.32-4.14 (m, 4H), 4.10 (t, J=8.3 Hz, 1H), 2.67-2.53 (m, 1H), 2.48-2.40 (m, 2H), 2.22-2.18 (m, 1H), 2.08-2.00 (m, 4H), 1.90-1.74 (m, 4H), 1.70-1.60 (m, 2H), 1.35-1.12 (m, 9H), 0.90-0.72 (m, 9H).

[0068] ESI-MS (M+H).sup.+: 619.

Example 6

[0069] ##STR00117##

[0070] .sup.1H NMR (400 MHz, DMSO) δ 8.78 (s, 1H), 8.57 (s, 1H), 7.89 (d, J=7.2 Hz, 2H), 7.71 (d, J=7.1 Hz, 2H), 7.53 (d, J=12.7 Hz, 1H), 7.42 (t, J=7.2 Hz, 2H), 7.37-7.30 (m, 2H), 7.25-7.24 (m, 6H), 7.21-7.15 (m, 9H), 4.30-4.27 (m, 2H), 4.22 (d, J=12.7 Hz, 1H), 4.11-4.04 (m, 2H), 2.20-2.14 (m, 1H), 2.01-1.97 (m, 1H), 1.83-1.76 (m, 2H), 1.77-1.73 (m, 1H), 1.69-1.58 (m, 2H), 1.36-1.16 (m, 10H), 0.85-0.77 (m, 9H).

[0071] ESI-MS (M+H).sup.+: 858.

Example 7

[0072] ##STR00118##

[0073] .sup.1H NMR (400 MHz, DMSO) δ 8.72 (s, 1H), 7.89 (d, J=7.5 Hz, 2H), 7.72 (t, J=8.1 Hz, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.42 (t, J=7.4 Hz, 2H), 7.32 (t, J=9.1 Hz, 2H), 4.28-4.20 (m, 3H), 4.17-4.04 (m, 2H), 2.66-2.59 (m, 1H), 2.30-2.14 (m, 3H), 2.04-1.98 (m, 1H), 1.87-1.73 (m, 4H), 1.68-1.61 (m, 2H), 1.39 (s, 9H), 1.34-1.29 (m, 2H), 1.22 (d, J=9.1 Hz, 6H), 0.87-0.74 (m, 9H).

[0074] ESI-MS (M+Na)+: 695.

Example 8

[0075] ##STR00119##

[0076] .sup.1H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.90-7.80 (m, 3H), 7.73 (d, J=7.3 Hz, 1H), 7.67-7.53 (m, 3H), 7.46-7.15 (m, 6H), 4.62-4.39 (m, 1H), 4.20-4.10 (m, 4H), 3.13-2.87 (m, 2H), 2.67-2.50 (m, 1H), 2.30-2.11 (m, 1H), 2.06-1.95 (m, 1H), 1.85-1.72 (m, 2H), 1.70-1.47 (m, 11H), 1.37-1.12 (m, 9H), 0.90-0.68 (m, 9H).

[0077] ESI-MS (M+Na)+: 796.

Example 9

[0078] ##STR00120##

[0079] .sup.1H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 8.60 (s, 1H), 7.90 (d, J=7.6 Hz, 2H), 7.82-7.70 (m, 2H), 7.42 (dd, J=15.8, 7.9 Hz, 2H), 7.34 (d, J=7.3 Hz, 1H), 7.28-7.06 (m, 17H), 4.47-4.30 (m, 2H), 4.25-4.18 (m, 2H), 4.12-4.08 (m, 1H), 2.80-2.64 (m, 1H), 2.62-2.52 (m, 1H), 2.25-2.16 (m, 1H), 2.03-2.00 (m, 1H), 1.86-1.73 (m, 2H), 1.67-1.60 (m, 2H), 1.45-1.18 (m, 9H), 0.84-0.72 (m, 9H).

[0080] ESI-MS (M+H).sup.+: 844.

Example 10

[0081] ##STR00121##

[0082] .sup.1H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 7.90 (d, J=7.5 Hz, 2H), 7.71 (t, J=7.6 Hz, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.42 (t, J=7.4 Hz, 2H), 7.33 (q, J=7.0 Hz, 2H), 4.29 (d, J=7.1 Hz, 2H), 4.24-4.12 (m, 2H), 4.06 (d, J=7.0 Hz, 1H), 2.31-2.10 (m, 1H), 2.10-1.88 (m, 1H), 1.88-1.63 (m, 4H), 1.63-1.33 (m, 4H), 1.33-1.17 (m, 9H), 0.94-0.75 (m, 13H).

[0083] ESI-MS (M+Na)+: 623.

Example 11

[0084] ##STR00122##

[0085] It is synthesized as follows:

[0086] 1. Synthesis of Intermediate A11-1

[0087] L-threonine (119 mg, 1 mmol) and sodium carbonate (159 mg, 1.5 mmol) were dissolved in 1,4-dioxane (3 mL) and water (2 mL), and 9-fluorenylmethyl-N-succinimidyl carbonate (337 mg, 1 mmol) in 1,4-dioxane (3 mL) solution was added slowly. The reaction was carried out at room temperature for 6 h. Thin layer chromatography (TLC) showed that the raw materials were completely reacted. The solvent was spin-dried, diluted hydrochloric acid was added to adjust the pH to 3-4, a solid precipitated. The mixture was filtered. The filter cake was washed with ethyl acetate, dried with anhydrous sodium sulfate, filtered, and spin-dried to obtain a white solid compound A11-1 (280 mg, yield 82%).

[0088] 2. Synthesis of Compound A11

[0089] Compound A11-1 (170 mg, 0.5 mmol) and A1-2 (227 mg, 0.6 mmol) were dissolved in DCM (3 mL), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU) (285 mg, 0.75 mmol) and triethylamine (TEA) (151 mg, 1.5 mmol) were added. The mixture was reacted at room temperature for 2 hours. After that, water was added, and the mixture was extracted with DCM (15 mL*3). The organic phases were combined, and after the solvent was spin-dried, the crude product was purified by medium pressure preparative liquid chromatography to obtain a white solid compound A11 (20 mg, yield 6.8%).

[0090] .sup.1H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 7.90 (d, J=7.5 Hz, 2H), 7.75 (t, J=8.2 Hz, 2H), 7.53 (d, J=9.1 Hz, 1H), 7.43 (t, J=7.4 Hz, 2H), 7.34 (dd, J=12.8, 6.6 Hz, 2H), 4.94 (d, J=5.2 Hz, 1H), 4.29 (d, J=7.1 Hz, 2H), 4.24 (d, J=5.9 Hz, 1H), 4.09 (t, J=8.3 Hz, 2H), 3.88 (dd, J=11.6, 6.2 Hz, 1H), 3.61 (t, J=6.6 Hz, 2H), 2.18 (d, J=8.9 Hz, 1H), 2.00 (d, J=7.3 Hz, 2H), 1.84 (t, J=5.5 Hz, 1H), 1.80-1.75 (m, 2H), 1.36 (s, 2H), 1.34-1.29 (m, 2H), 1.25 (d, J=9.3 Hz, 7H), 1.22 (s, 4H), 1.07 (d, J=6.2 Hz, 3H), 0.85 (d, J=6.4 Hz, 6H), 0.81 (s, 3H).

[0091] ESI-MS (M+H).sup.+: 589.

[0092] The synthetic method of compound A12-A18 is the same as that of A11, except that the L-threonine was replaced with the corresponding amino acid.

Example 12

[0093] ##STR00123##

[0094] .sup.1H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 7.90 (d, J=7.5 Hz, 2H), 7.72 (t, J=8.1 Hz, 2H), 7.64 (d, J=7.7 Hz, 1H), 7.43 (t, J=7.4 Hz, 2H), 7.33 (td, J=7.3, 3.6 Hz, 2H), 4.39-4.11 (m, 4H), 4.07 (d, J=6.6 Hz, 1H), 2.57 (s, 1H), 2.26-2.14 (m, 1H), 2.01 (dd, J=14.9, 7.1 Hz, 2H), 1.82 (t, J=5.6 Hz, 1H), 1.76 (s, 1H), 1.71-1.53 (m, 2H), 1.40-1.15 (m, 14H), 0.84 (d, J=6.5 Hz, 6H), 0.80 (s, 3H).

[0095] ESI-MS (M+H).sup.+: 573.

Example 13

[0096] ##STR00124##

[0097] .sup.1H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 7.90 (d, J=7.5 Hz, 2H), 7.71 (t, J=7.5 Hz, 2H), 7.58 (d, J=8.1 Hz, 1H), 7.42 (t, J=7.4 Hz, 2H), 7.33 (dd, J=12.4, 7.1 Hz, 2H), 6.76 (s, 1H), 4.34-4.16 (m, 3H), 4.07 (d, J=8.1 Hz, 2H), 2.89 (d, J=5.8 Hz, 2H), 2.56 (s, 1H), 2.25-2.13 (m, 1H), 2.04 (d, J=32.9 Hz, 2H), 1.81 (dd, J=16.8, 11.2 Hz, 2H), 1.72-1.52 (m, 5H), 1.36 (d, J=11.2 Hz, 13H), 1.22 (d, J=6.1 Hz, 11H), 0.84 (d, J=6.4 Hz, 7H), 0.80 (s, 3H).

[0098] ESI-MS (M+H).sup.+: 716.

Example 14

[0099] ##STR00125##

[0100] .sup.1H NMR (400 MHz, DMSO) δ 8.73 (s, 1H), 7.90 (d, J=7.5 Hz, 2H), 7.72 (t, J=7.8 Hz, 2H), 7.61 (d, J=8.2 Hz, 1H), 7.43 (t, J=7.4 Hz, 2H), 7.33 (td, J=7.3, 3.4 Hz, 2H), 4.28 (d, J=6.8 Hz, 2H), 4.25-4.17 (m, 1H), 4.13 (t, J=8.5 Hz, 2H), 3.60 (s, 3H), 2.66 (d, J=17.5 Hz, 2H), 2.34 (t, J=14.6 Hz, 2H), 2.29-2.15 (m, 1H), 2.10-1.97 (m, 2H), 1.94-1.74 (m, 4H), 1.73-1.58 (m, 2H), 1.37-1.17 (m, 11H), 0.93-0.72 (m, 9H).

[0101] ESI-MS (M+H).sup.+: 645.

Example 15

[0102] ##STR00126##

[0103] .sup.1H NMR (400 MHz, DMSO) δ 8.89 (d, J=2.8 Hz, 1H), 7.89 (d, J=7.5 Hz, 2H), 7.75 (d, J=8.6 Hz, 2H), 7.64 (d, J=7.5 Hz, 2H), 7.41 (t, J=7.5 Hz, 2H), 7.29 (td, J=14.9, 7.6 Hz, 5H), 4.36 (dd, J=14.1, 9.1 Hz, 1H), 4.28-4.14 (m, 4H), 3.05-2.98 (m, 2H), 2.01 (d, J=15.3 Hz, 2H), 1.83 (dd, J=18.6, 13.1 Hz, 2H), 1.39-1.23 (m, 9H), 0.83 (dd, J=12.8, 6.1 Hz, 8H).

[0104] ESI-MS (M+H).sup.+: 635.

Example 16

[0105] ##STR00127##

[0106] .sup.1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 7.89 (d, J=7.5 Hz, 2H), 7.70 (d, J=8.0 Hz, 3H), 7.42 (t, J=7.4 Hz, 2H), 7.33 (t, J=7.5 Hz, 2H), 4.48 (dd, J=13.9, 8.4 Hz, 1H), 4.34-4.19 (m, 3H), 4.14-4.09 (m, 1H), 3.59 (s, 3H), 2.66 (dd, J=11.0, 6.2 Hz, 2H), 2.25-2.15 (m, 1H), 2.00 (dd, J=14.1, 6.6 Hz, 2H), 1.84 (t, J=5.6 Hz, 1H), 1.77 (s, 1H), 1.64 (t, J=12.7 Hz, 2H), 1.30-1.22 (m, 9H), 0.85-0.76 (m, 9H).

[0107] ESI-MS (M+Na).sup.+: 639.

Example 17

[0108] ##STR00128##

[0109] .sup.1H NMR (400 MHz, DMSO) δ 8.87 (d, J=2.8 Hz, 1H), 7.90 (d, J=7.5 Hz, 2H), 7.74 (t, J=8.6 Hz, 3H), 7.42 (t, J=7.4 Hz, 2H), 7.37-7.27 (m, 4H), 7.19 (t, J=7.6 Hz, 3H), 4.32 (d, J=7.0 Hz, 2H), 4.24 (t, J=7.0 Hz, 1H), 4.10 (dd, J=12.9, 7.1 Hz, 2H), 2.68-2.54 (m, 3H), 2.19 (d, J=2.3 Hz, 1H), 2.08 (s, 1H), 2.05-1.96 (m, 1H), 1.88 (dd, J=15.4, 7.9 Hz, 2H), 1.82 (t, J=5.6 Hz, 1H), 1.76 (s, 1H), 1.71-1.59 (m, 2H), 1.32 (dd, J=15.2, 6.2 Hz, 2H), 1.23 (s, 3H), 1.20 (s, 3H), 0.84 (d, J=6.5 Hz, 6H), 0.79 (s, 3H).

[0110] ESI-MS (M+H).sup.+: 649.

Example 18

[0111] ##STR00129##

[0112] .sup.1H NMR (400 MHz, DMSO) δ 10.87 (s, 1H), 9.05 (s, 1H), 7.86 (d, J=7.6 Hz, 2H), 7.63 (dd, J=15.2, 7.7 Hz, 4H), 7.38 (dd, J=13.1, 6.9 Hz, 2H), 7.31 (d, J=8.8 Hz, 2H), 7.25 (dd, J=14.5, 6.7 Hz, 1H), 7.17 (s, 1H), 7.05 (t, J=7.2 Hz, 1H), 6.97 (t, J=7.3 Hz, 1H), 4.39 (d, J=5.8 Hz, 1H), 4.19-4.05 (m, 4H), 3.08-2.93 (m, 2H), 2.52 (s, 1H), 2.16 (s, 2H), 2.06-1.90 (m, 2H), 1.81 (dd, J=18.0, 12.2 Hz, 2H), 1.64 (d, J=14.8 Hz, 2H), 1.30-1.20 (m, 7H), 0.88-0.73 (m, 9H).

[0113] ESI-MS (M+H).sup.+: 674.

Example 19

[0114] ##STR00130##

[0115] Compound A19 was synthesized as follows:

##STR00131##

[0116] N.sup.2-boc-N.sup.4-Trt-L-asparagine (200 mg, 0.42 mmol) was dissolved in dichloromethane (10 mL), and 1-propyl phosphoric anhydride (T3P) (50% wt, ethyl acetate (EtOAc, 1.2 mL)), A1-2 (135 mg, 0.51 mmol) and TEA (1.2 mL) were added. After reacting at room temperature for 3 hours, it was diluted with water (30 mL). The mixture was extracted with dichloromethane (20 mL*3) and then combined, dried and spin-dried. The solute was purified by medium pressure preparative liquid chromatography to obtain a white solid (100 mg, 33% yield).

[0117] .sup.1H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.60 (s, 1H), 7.23 (dt, J=13.5, 7.8 Hz, 15H), 7.13 (d, J=8.4 Hz, 1H), 4.39-4.27 (m, 1H), 4.07 (d, J=7.2 Hz, 1H), 2.67 (dd, J=14.2, 10.4 Hz, 1H), 2.53 (d, J=9.5 Hz, 1H), 2.43 (dd, J=14.6, 4.0 Hz, 1H), 2.20 (dd, J=21.4, 10.0 Hz, 1H), 2.09-1.95 (m, 3H), 1.83 (t, J=5.5 Hz, 1H), 1.79 (d, J=5.4 Hz, 1H), 1.66 (dd, J=18.1, 10.3 Hz, 2H), 1.34 (dd, J=12.2, 7.8 Hz, 6H), 1.31-1.16 (m, 10H), 0.89-0.75 (m, 9H).

[0118] ESI-MS (M−H)−: 720.

[0119] The synthesis method of compound A20-A21 is the same as that of A19, except that the raw material N.sup.2-boc-N.sup.4-Trt-L-asparagine was replaced with N.sup.2-Cbz-N.sup.4-Trt-L-asparagine and Cbz-L-tryptophan.

Example 20

[0120] ##STR00132##

[0121] .sup.1H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.76 (d, J=12.1 Hz, 2H), 7.64 (d, J=8.3 Hz, 1H), 7.49-7.34 (m, 5H), 7.30 (s, 2H), 7.25-7.01 (m, 14H), 5.12-5.01 (m, 2H), 4.11 (dd, J=12.5, 7.2 Hz, 3H), 2.70 (dd, J=14.6, 10.4 Hz, 1H), 2.51 (dt, J=3.6, 1.8 Hz, 5H), 2.25-2.16 (m, 1H), 1.98 (m, 1H), 1.74 (m, 2H), 1.16 (m, 9H), 0.85 (dd, J=20.2, 13.6 Hz, 9H).

[0122] ESI-MS (M+H).sup.+: 844.

Example 21

[0123] ##STR00133##

[0124] .sup.1H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 9.09 (s, 1H), 7.59 (dd, J=23.8, 8.1 Hz, 2H), 7.37-7.29 (m, 3H), 7.28-7.22 (m, 2H), 7.17 (d, J=2.2 Hz, 1H), 7.07 (t, J=7.5 Hz, 1H), 6.99 (t, J=7.2 Hz, 1H), 4.96 (q, J=12.7 Hz, 2H), 4.45-4.34 (m, 1H), 4.11 (d, J=7.0 Hz, 1H), 3.10-3.02 (m, 1H), 2.98 (dd, J=14.4, 9.1 Hz, 1H), 2.55 (d, J=8.5 Hz, 1H), 2.29-2.18 (m, 1H), 2.07-1.97 (m, 1H), 1.85 (dd, J=18.0, 12.3 Hz, 2H), 1.64 (dd, J=19.1, 10.5 Hz, 2H), 1.38 (d, J=10.0 Hz, 1H), 1.29 (s, 3H), 1.22 (d, J=12.5 Hz, 6H), 0.84 (t, J=6.0 Hz, 8H).

[0125] ESI-MS (M+H).sup.+: 586.

Example 22

[0126] ##STR00134##

[0127] Compound A22 was synthesized as follows:

##STR00135##

1. Synthesis of Intermediate A22-1:

[0128] L-leucine (131 mg, 1 mmol) and sodium carbonate (159 mg, 1.5 mmol) were dissolved in 1,4-dioxane (3 mL) and water (2 mL), and 9-fluorenylmethyl-N-succinimidyl carbonate (337 mg, 1 mmol) in 1,4-dioxane (3 mL) solution was added slowly. The reaction was carried out at room temperature for 6 h. TLC showed that the raw materials were completely reacted. The solvent was spin-dried, and diluted hydrochloric acid was added to adjust the pH to 3-4, and a solid precipitated. The mixture was filtered, and the filter cake was washed with ethyl acetate, dried with anhydrous sodium sulfate, filtered, and spin-dried to obtain a white solid compound A22-1 (250 mg, yield 71%).

1. Synthesis of Compound A22

[0129] Compound A87-1 (176 mg, 0.5 mmol) and compound A22-2 (227 mg, 0.6 mmol) were dissolved in DCM (3 mL), and HATU (285 mg, 0.75 mmol) and TEA (151 mg, 1.5 mmol) were added. The mixture was reacted at room temperature for 2 hours. Water was added, and the mixture was extracted with DCM (15 mL*3). The organic phases were combined, and after the solvent was spin-dried, the crude product was purified by medium pressure preparative liquid chromatography to obtain white solid compound A22 (18 mg, yield 6.4%).

[0130] .sup.1H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 7.89 (d, J=7.5 Hz, 2H), 7.71 (t, J=7.7 Hz, 2H), 7.64 (d, J=8.3 Hz, 1H), 7.41 (t, J=7.4 Hz, 2H), 7.32 (dt, J=14.2, 7.0 Hz, 2H), 4.36-4.24 (m, 2H), 4.21 (t, J=6.9 Hz, 1H), 4.13 (td, J=9.7, 5.1 Hz, 1H), 4.04 (d, J=6.9 Hz, 1H), 2.57-2.51 (m, 1H), 2.18 (dd, J=12.2, 9.9 Hz, 1H), 2.05-1.92 (m, 1H), 1.81 (t, J=5.6 Hz, 1H), 1.77 (d, J=5.2 Hz, 1H), 1.68-1.56 (m, 2H), 1.56-1.48 (m, 1H), 1.40 (ddd, J=21.4, 10.7, 6.3 Hz, 1H), 1.33 (d, J=10.0 Hz, 1H), 1.23 (t, J=7.2 Hz, 9H), 1.00 (d, J=7.2 Hz, 3H), 0.89 (d, J=6.5 Hz, 3H), 0.84 (d, J=6.4 Hz, 4H), 0.79 (s, 3H).

[0131] ESI-MS (M+H).sup.+: 601.

[0132] The synthesis method of compound A23 is the same as that of A22, except that L-leucine is replaced with Boc-L-lysine.

Example 23

[0133] ##STR00136##

[0134] .sup.1H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 7.90 (d, J=7.5 Hz, 2H), 7.72 (t, J=7.5 Hz, 2H), 7.62 (d, J=8.0 Hz, 1H), 7.42 (t, J=7.4 Hz, 2H), 7.33 (dd, J=12.4, 7.1 Hz, 2H), 6.76 (s, 1H), 4.26 (dd, J=23.9, 6.5 Hz, 3H), 4.05 (d, J=8.4 Hz, 2H), 2.89 (d, J=6.0 Hz, 2H), 2.55 (s, 1H), 2.25-2.14 (m, 1H), 2.06-1.95 (m, 1H), 1.83 (t, J=5.5 Hz, 1H), 1.77 (s, 1H), 1.69-1.48 (m, 3H), 1.37 (s, 13H), 1.23 (d, J=7.6 Hz, 9H), 1.01 (d, J=7.2 Hz, 3H), 0.80 (s, 3H).

[0135] ESI-MS(M+H).sup.+:674.

Example 24

[0136] ##STR00137##

[0137] Compound A24 was synthesized as follows:

##STR00138##

1. Synthesis of Intermediate A24-1

[0138] 9-Fluoreneacetic acid (224 mg, 1 mmol) and L-leucine ethyl ester (286 mg, 1.8 mmol) were dissolved in DCM (4 mL), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU) (760 mg, 2 mmol) and TEA (350 mg, 3.5 mmol) were added. The mixture was reacted at room temperature for 2 hours. Water was added, and the mixture was extracted with DCM (20 mL*3). The organic phases were combined, and after the solvent was spin-dried, the organic phases were purified with a prep-TLC to obtain white solid compound A24-1 (145 mg, yield 40%).

2. Synthesis of Intermediate A24-2

[0139] Compound A24-1 (145 mg, 0.4 mmol) was dissolved in methanol (MeOH) (4 mL), lithium hydroxide (LiOH) (1 mL, 1M) aqueous solution was added at low temperature, and the reaction was carried out at room temperature for 2 hours. TLC showed that the raw materials were completely reacted. The solvent was spin-dried. Diluted hydrochloric acid was added to adjust the pH to 3-4. The mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, and the solvent was spin-dried to obtain compound A24-2 (102 mg, yield 75.6%).

3. Synthesis of Compound A24

[0140] Compound A24-2 (100 mg, 0.3 mmol) and compound A1-2 (170 mg, 0.45 mmol) were dissolved in DCM (3 mL), and HATU (228 mg, 0.6 mmol) and TEA (120 mg, 1.2 mmol) were added. The mixture was reacted at room temperature for 2 hours. Water was added, and the mixture was extracted with DCM (15 mL*3). The organic phases were combined, and after the solvent was spin-dried, the crude product was purified by medium pressure preparative liquid chromatography to obtain a white solid compound A24 (25 mg, yield 14.3%).

[0141] .sup.1H NMR (400 MHz, DMSO) δ 9.06 (d, J=2.5 Hz, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.86 (d, J=7.5 Hz, 2H), 7.54 (d, J=7.4 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.38 (t, J=7.4 Hz, 2H), 7.33-7.22 (m, 2H), 4.65-4.55 (m, 1H), 4.36 (t, J=7.5 Hz, 1H), 4.08 (dd, J=8.5, 1.7 Hz, 1H), 2.69 (dd, J=14.8, 6.9 Hz, 1H), 2.59 (dd, J=10.6, 4.6 Hz, 1H), 2.47 (d, J=8.3 Hz, 1H), 2.26-2.14 (m, 1H), 2.07-1.96 (m, 1H), 1.85 (t, J=5.6 Hz, 1H), 1.81-1.69 (m, 2H), 1.68-1.56 (m, 2H), 1.55-1.38 (m, 2H), 1.38-1.26 (m, 3H), 1.24 (d, J=12.3 Hz, 6H), 0.89 (dd, J=15.5, 6.6 Hz, 12H), 0.81 (s, 3H).

[0142] ESI-MS (M+H).sup.+: 584.

[0143] The synthesis method of compound A25-A38 is the same as that of A24, except that the raw materials in the first step, 9-fluorene acetic acid and L-leucine ethyl ester are replaced with corresponding acids and amino acid esters.

Example 25

[0144] ##STR00139##

[0145] .sup.1H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 9.03 (s, 1H), 7.92 (dd, J=45.2, 8.1 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.20-7.12 (m, 1H), 7.05 (t, J=7.5 Hz, 1H), 6.98 (t, J=7.4 Hz, 1H), 4.69 (dt, J=16.4, 8.3 Hz, 1H), 4.18-4.01 (m, 1H), 3.12-3.00 (m, 1H), 2.99-2.88 (m, 1H), 2.28-2.16 (m, 1H), 2.02 (d, J=6.6 Hz, 1H), 1.90-1.84 (m, 1H), 1.80 (s, 6H), 1.71-1.61 (m, 2H), 1.61 (s, 3H), 1.45 (d, J=11.6 Hz, 3H), 1.38 (s, 6H), 1.30 (d, J=13.2 Hz, 4H), 1.23 (s, 6H), 0.83 (d, J=5.2 Hz, 9H).

[0146] ESI-MS(M+H).sup.+: 628.

Example 26

[0147] ##STR00140##

[0148] .sup.1H NMR (400 MHz, DMSO) δ 10.85 (d, J=5.3 Hz, 1H), 8.78 (d, J=3.0 Hz, 1H), 7.66-7.55 (m, 1H), 7.31 (d, J=7.9 Hz, 2H), 7.16 (d, J=2.2 Hz, 1H), 7.06 (s, 1H), 6.98 (s, 1H), 4.72-4.53 (m, 1H), 4.17-4.03 (m, 1H), 3.19-2.96 (m, 2H), 2.30-2.14 (m, 1H), 2.10-1.98 (m, 1H), 1.91 (s, 5H), 1.62 (dd, J=25.6, 13.3 Hz, 14H), 1.29 (d, J=6.2 Hz, 3H), 1.24 (d, J=2.7 Hz, 4H), 0.90-0.78 (m, 9H).

[0149] ESI-MS (M+H).sup.+: 614.

Example 27

[0150] ##STR00141##

[0151] .sup.1H NMR (400 MHz, DMSO) δ 8.89 (dd, J=77.4, 3.0 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.51 (s, 1H), 7.29 (dt, J=26.5, 7.3 Hz, 2H), 5.99 (dt, J=5.9, 3.0 Hz, 1H), 5.74 (ddd, J=20.9, 5.5, 2.7 Hz, 1H), 4.64 (d, J=6.5 Hz, 1H), 4.20-4.02 (m, 1H), 3.16 (d, J=14.3 Hz, 1H), 3.08-2.89 (m, 2H), 2.80 (dd, J=11.2, 5.3 Hz, 2H), 2.28-2.14 (m, 1H), 2.02 (dd, J=14.2, 6.7 Hz, 1H), 1.90-1.76 (m, 2H), 1.73-1.54 (m, 11H), 1.39-1.26 (m, 5H), 1.29-1.09 (m, 9H), 0.92-0.72 (m, 9H).

[0152] ESI-MS (M+H).sup.+: 672.

Example 28

[0153] ##STR00142##

[0154] .sup.1H NMR (400 MHz, DMSO) δ 8.99 (d, J=2.9 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.53 (s, 1H), 7.29 (dt, J=24.3, 7.0 Hz, 2H), 4.69 (dd, J=14.9, 8.5 Hz, 1H), 4.12 (t, J=12.1 Hz, 1H), 3.04 (s, 2H), 2.59-2.53 (m, 1H), 2.38 (s, 2H), 2.22 (dd, J=12.3, 9.9 Hz, 1H), 2.09-1.76 (m, 16H), 1.61 (s, 9H), 1.25 (d, J=18.9 Hz, 9H), 0.86-0.80 (m, 9H).

[0155] ESI-MS (M+H).sup.+: 728.

Example 29

[0156] ##STR00143##

[0157] .sup.1H NMR (400 MHz, DMSO) δ 10.87 (d, J=1.7 Hz, 1H), 9.09 (s, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.16 (d, J=2.2 Hz, 1H), 7.06 (dd, J=11.1, 4.0 Hz, 1H), 6.99 (dd, J=10.9, 3.9 Hz, 1H), 4.66 (td, J=8.6, 5.5 Hz, 1H), 4.08 (dd, J=8.5, 1.8 Hz, 1H), 3.00 (ddd, J=23.6, 14.5, 7.2 Hz, 2H), 2.26-2.19 (m, 1H), 2.08-1.97 (m, 1H), 1.94-1.88 (m, 2H), 1.86 (dd, J=11.4, 6.2 Hz, 1H), 1.83-1.78 (m, 2H), 1.69-1.48 (m, 5H), 1.37 (d, J=7.9 Hz, 4H), 1.29 (d, J=6.2 Hz, 3H), 1.25-1.18 (m, 6H), 1.15-0.99 (m, 4H), 0.82 (dd, J=13.3, 8.8 Hz, 9H).

[0158] ESI-MS (M+H).sup.+: 576.

Example 30

[0159] ##STR00144##

[0160] .sup.1H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 9.07 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.15 (d, J=2.2 Hz, 1H), 7.05 (t, J=7.1 Hz, 1H), 6.98 (t, J=7.4 Hz, 1H), 4.70-4.59 (m, 1H), 4.13-4.03 (m, 1H), 3.00 (ddd, J=23.5, 14.6, 7.2 Hz, 2H), 2.27-2.14 (m, 1H), 2.00 (dd, J=9.2, 5.0 Hz, 4H), 1.84 (t, J=5.6 Hz, 1H), 1.80 (d, J=5.2 Hz, 1H), 1.70-1.34 (m, 10H), 1.27-1.16 (m, 10H), 1.10-0.92 (m, 2H), 0.82 (dd, J=4.5, 1.7 Hz, 9H).

[0161] ESI-MS (M+Na).sup.+: 561.56.

Example 31

[0162] ##STR00145##

[0163] .sup.1H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 9.02-8.90 (m, 1H), 7.98-7.83 (m, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 7.02 (t, J=7.5 Hz, 1H), 6.94 (t, J=7.4 Hz, 1H), 4.60 (dt, J=10.4, 6.7 Hz, 1H), 4.06 (d, J=6.7 Hz, 1H), 3.09-2.97 (m, 1H), 2.97-2.84 (m, 1H), 2.23-2.12 (m, 1H), 1.98 (dd, J=14.5, 6.8 Hz, 2H), 1.86-1.73 (m, 2H), 1.67-1.48 (m, 2H), 1.29-1.10 (m, 9H), 0.83-0.76 (m, 9H).

[0164] ESI-MS (M+H).sup.+: 534.

Example 32

[0165] ##STR00146##

[0166] .sup.1H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 8.91 (d, J=3.3 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.39-7.26 (m, 4H), 7.19 (dd, J=7.7, 2.2 Hz, 3H), 7.11-6.97 (m, 2H), 4.18 (ddd, J=39.6, 24.2, 10.7 Hz, 3H), 3.91 (d, J=13.7 Hz, 1H), 3.03 (ddd, J=22.1, 14.4, 7.2 Hz, 2H), 2.59 (d, J=9.3 Hz, 1H), 2.26-2.17 (m, 1H), 2.07-1.99 (m, 1H), 1.83 (dd, J=15.4, 9.6 Hz, 2H), 1.67 (d, J=13.9 Hz, 1H), 1.51-1.44 (m, 1H), 1.36 (d, J=10.2 Hz, 1H), 1.28 (s, 3H), 1.26-1.20 (m, 5H), 1.20-1.16 (m, 1H), 0.79 (dd, J=6.7, 3.5 Hz, 9H).

[0167] ESI-MS (M+H).sup.+: 606.

Example 33

[0168] ##STR00147##

[0169] .sup.1H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 9.11 (d, J=2.9 Hz, 1H), 8.92 (d, J=8.2 Hz, 1H), 8.70 (dd, J=4.5, 1.5 Hz, 2H), 7.75-7.63 (m, 3H), 7.30 (d, J=8.0 Hz, 1H), 7.22 (d, J=2.2 Hz, 1H), 7.05 (t, J=7.0 Hz, 1H), 6.98 (t, J=7.4 Hz, 1H), 4.89-4.78 (m, 1H), 4.12 (d, J=6.7 Hz, 1H), 3.24-3.12 (m, 2H), 2.59 (t, J=7.7 Hz, 1H), 2.27-2.15 (m, 1H), 2.06-1.98 (m, 1H), 1.83 (dd, J=17.2, 11.5 Hz, 2H), 1.63 (dd, J=13.3, 7.7 Hz, 2H), 1.32 (dd, J=18.5, 9.1 Hz, 3H), 1.26 (s, 3H), 1.22 (s, 4H), 0.88-0.75 (m, 9H).

[0170] ESI-MS (M+H).sup.+: 557.

Example 34

[0171] ##STR00148##

[0172] .sup.1H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 8.94 (dd, J=23.9, 6.0 Hz, 2H), 8.28-8.07 (m, 2H), 7.72-7.52 (m, 3H), 7.31 (d, J=8.1 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 6.96 (t, J=7.4 Hz, 1H), 4.86 (dt, J=13.5, 6.8 Hz, 1H), 4.18 (d, J=8.6 Hz, 1H), 3.32-3.23 (m, 2H), 2.69 (d, J=3.6 Hz, 1H), 2.29-2.19 (m, 1H), 2.03 (dd, J=17.1, 8.9 Hz, 1H), 1.87 (t, J=5.6 Hz, 1H), 1.80 (s, 1H), 1.65 (t, J=12.8 Hz, 2H), 1.37-1.21 (m, 10H), 0.90-0.76 (m, 8H).

[0173] ESI-MS (M+H).sup.+: 613.

Example 35

[0174] ##STR00149##

[0175] .sup.1H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 9.20-9.11 (m, 1H), 8.99 (dd, J=4.2, 1.6 Hz, 1H), 8.86 (t, J=9.5 Hz, 1H), 8.50-8.41 (m, 2H), 8.19-8.10 (m, 1H), 8.06 (dd, J=8.8, 3.1 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.62 (dd, J=8.3, 4.2 Hz, 1H), 7.29 (dd, J=19.5, 5.1 Hz, 2H), 7.10-6.96 (m, 2H), 4.93 (dd, J=14.7, 7.9 Hz, 1H), 4.12 (d, J=6.6 Hz, 1H), 3.27-3.15 (m, 2H), 2.60 (t, J=6.1 Hz, 1H), 2.30-2.17 (m, 1H), 2.05 (t, J=11.3 Hz, 1H), 1.92-1.77 (m, 2H), 1.69-1.57 (m, 2H), 1.34-1.19 (m, 9H), 0.89-0.77 (m, 9H).

[0176] ESI-MS (M+H).sup.+: 607.

Example 36

[0177] ##STR00150##

[0178] .sup.1H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 9.30-9.09 (m, 2H), 9.02 (dd, J=20.6, 8.2 Hz, 1H), 8.78 (dd, J=13.2, 2.0 Hz, 1H), 8.07 (t, J=7.9 Hz, 2H), 7.88 (t, J=7.7 Hz, 1H), 7.71 (t, J=7.6 Hz, 2H), 7.37-7.23 (m, 2H), 7.11-6.95 (m, 2H), 4.93 (dd, J=8.6, 5.4 Hz, 1H), 4.14 (t, J=6.4 Hz, 1H), 3.24 (ddd, J=15.1, 9.6, 5.4 Hz, 2H), 2.60 (t, J=6.5 Hz, 1H), 2.23 (s, 1H), 2.02 (d, J=6.1 Hz, 1H), 1.90-1.77 (m, 2H), 1.75-1.60 (m, 2H), 1.39 (t, J=10.2 Hz, 1H), 1.35-1.29 (m, 2H), 1.30-1.17 (m, 7H), 0.84 (ddd, J=10.5, 6.9, 4.5 Hz, 8H).

[0179] ESI-MS (M+H).sup.+: 607.

Example 37

[0180] ##STR00151##

[0181] .sup.1H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 9.23-9.12 (m, 1H), 8.77 (dd, J=19.8, 8.2 Hz, 1H), 8.42 (d, J=14.0 Hz, 1H), 8.04-7.94 (m, 3H), 7.89 (ddd, J=12.6, 8.6, 1.6 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.66-7.56 (m, 2H), 7.36-7.25 (m, 2H), 7.04 (dt, J=14.8, 6.9 Hz, 2H), 4.97-4.82 (m, 1H), 4.18-4.06 (m, 1H), 3.25 (t, J=6.5 Hz, 2H), 2.59 (d, J=7.1 Hz, 1H), 2.29-2.17 (m, 1H), 2.04-1.98 (m, 1H), 1.91-1.76 (m, 2H), 1.73-1.60 (m, 2H), 1.37 (dd, J=22.5, 12.6 Hz, 3H), 1.29-1.21 (m, 7H), 0.84 (ddd, J=11.4, 7.0, 4.0 Hz, 9H).

[0182] ESI-MS (M+H).sup.+: 606.

Example 38

[0183] ##STR00152##

[0184] .sup.1H NMR (400 MHz, DMSO) δ 8.84 (t, J=19.4 Hz, 1H), 8.30 (dd, J=23.1, 7.9 Hz, 1H), 7.86 (d, J=7.5 Hz, 2H), 7.54 (t, J=8.1 Hz, 2H), 7.33 (dtd, J=25.0, 7.3, 2.7 Hz, 5H), 6.97 (s, 1H), 4.90 (dd, J=13.1, 8.1 Hz, 1H), 4.33 (t, J=7.3 Hz, 1H), 4.10 (d, J=6.7 Hz, 1H), 2.63 (dd, J=14.7, 7.0 Hz, 2H), 2.57-2.51 (m, 1H), 2.49-2.40 (m, 2H), 2.25-2.16 (m, 1H), 2.00 (dd, J=14.8, 6.9 Hz, 1H), 1.86 (t, J=5.6 Hz, 1H), 1.79 (s, 1H), 1.72 (dd, J=13.6, 6.9 Hz, 1H), 1.64 (d, J=13.6 Hz, 1H), 1.38-1.28 (m, 3H), 1.23 (s, 5H), 0.84 (dd, J=17.2, 8.0 Hz, 10H).

[0185] ESI-MS (M+Na).sup.+: 608.2.

Example 39

[0186] ##STR00153##

[0187] Compound A39 was synthesized as follows:

##STR00154##

[0188] 1. Synthesis of Intermediate A39-1

[0189] 9H-pyrido[3,4-b]indole (3 g, 18 mmol) was dissolved in N,N-dimethylformamide (DMF) (25 mL), potassium hydroxide solid (3 g, 54 mmol) was added at low temperature. The reaction was carried out at room temperature for 1 h. Ethyl bromoacetate (7.4 g, 45 mmol) was added, and the reaction was carried out at room temperature for 16 h. TLC showed that the reaction of the raw materials was complete. After adding water, it was extracted with ethyl acetate (80 mL*3), the organic phases were combined, and the solvent was spin-dried to obtain yellow solid compound A39-1 (1 g, yield 22%).

[0190] 2. Synthesis of Intermediate A39-2

[0191] A39-1 (lg, 4 mmol) was dissolved in MeOH (15 mL), and LiGH (6 mL, 1M) aqueous solution was added at low temperature. The mixture was reacted at room temperature for 2 h. TLC showed that the raw materials were completely reacted. The solvent was spin-dried, and diluted hydrochloric acid was added to adjust the pH to 3-4. The mixture was extracted with ethyl acetate (20 mL*3), the organic phases were combined, and the solvent was spin-dried to obtain compound A39-2 (790 mg, yield 88%).

[0192] 3. Synthesis of Intermediate A39-3

[0193] A39-2 (225 mg, 1 mmol) and L-leucine ethyl ester (353 mg, 1.8 mmol) were dissolved in DCM (4 mL), and HATU (760 mg, 2 mmol) and TEA (350 mg, 3.5 mmol) were added. The mixture was reacted at room temperature for 2 hours. After adding water, the mixture was extracted with DCM (20 mL*3). The organic phases were combined, and after the solvent was spin-dried, the organic phases were purified with prep-TLC to obtain white solid compound A39-3 (160 mg, yield 44%).

[0194] 4. Synthesis of Intermediate A39-4

[0195] A39-3 (160 mg, 0.44 mmol) was dissolved in MeOH (4 mL), and LiGH (1 mL, 1M) aqueous solution was added at low temperature and the mixture was reacted at room temperature for 2 h. TLC showed that the raw materials were completely reacted. The solvent was spin-dried, and diluted hydrochloric acid was added to adjust the pH to 3-4. The mixture was extracted with ethyl acetate (10 mL*3), the organic phases were combined, and the solvent was spin-dried to obtain compound A39-4 (110 mg, yield 74%).

[0196] 5. Synthesis of Compound A39

[0197] A39-4 (100 mg, 0.3 mmol) and A1-2 (170 mg, 0.45 mmol) were dissolved in DCM (3 mL), and HATU (230 mg, 0.6 mmol) and TEA (120 mg, 1.2 mmol) were added and the mixture was reacted at room temperature for 2 hours. After adding water, the mixture was extracted with DCM (15 mL*3). The organic phases were combined, and after the solvent was spin-dried, the crude product was purified by medium pressure preparative liquid chromatography to obtain a white solid compound A39 (12 mg, yield 6.8%).

[0198] .sup.1H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.96 (s, 1H), 8.78 (d, J=8.3 Hz, 1H), 8.38 (d, J=5.2 Hz, 1H), 8.30-8.24 (m, 2H), 8.13 (d, J=5.2 Hz, 1H), 7.65-7.53 (m, 2H), 7.29 (t, J=7.3 Hz, 1H), 5.22 (q, J=16.9 Hz, 2H), 4.43 (dd, J=14.3, 8.9 Hz, 1H), 4.10 (d, J=6.7 Hz, 1H), 2.55 (d, J=8.8 Hz, 1H), 2.27-2.16 (m, 1H), 2.08-1.95 (m, 2H), 1.85 (t, J=5.6 Hz, 1H), 1.81 (d, J=5.5 Hz, 1H), 1.65 (dd, J=16.6, 9.4 Hz, 4H), 1.58-1.40 (m, 3H), 1.33 (d, J=10.1 Hz, 1H), 1.28 (s, 4H), 1.22 (d, J=9.9 Hz, 6H), 0.93-0.89 (m, 3H), 0.83 (dd, J=9.6, 4.4 Hz, 12H).

[0199] ESI-MS (M+H).sup.+: 545.

[0200] The synthesis method of compound A40-A41 is the same as that of A39, except that the 9H-pyrido[3,4-b]indole in the first step was replaced with the corresponding amine.

Example 40

[0201] ##STR00155##

[0202] .sup.1H NMR (400 MHz, DMSO) δ 8.92 (d, J=2.9 Hz, 1H), 8.63 (d, J=8.1 Hz, 1H), 8.48 (d, J=1.8 Hz, 2H), 7.57 (dt, J=18.6, 5.3 Hz, 4H), 5.11 (d, J=19.7 Hz, 2H), 4.41 (dd, J=14.4, 8.8 Hz, 1H), 4.10 (d, J=6.8 Hz, 1H), 1.86 (s, 2H), 1.64 (d, J=13.7 Hz, 5H), 1.39-1.25 (m, 7H), 1.23 (d, J=9.3 Hz, 5H), 0.91 (d, J=6.6 Hz, 3H), 0.88-0.75 (m, 12H).

[0203] ESI-MS (M+H).sup.+: 744.

Example 41

[0204] ##STR00156##

[0205] .sup.1H NMR (400 MHz, DMSO) δ 8.96 (s, 1H), 8.73 (d, J=7.9 Hz, 1H), 8.35 (dd, J=8.0, 1.5 Hz, 2H), 7.77 (t, J=7.0 Hz, 2H), 7.61 (s, 2H), 7.35 (s, 2H), 5.24 (s, 2H), 4.52-4.43 (m, 1H), 4.12 (d, J=6.8 Hz, 1H), 2.58 (s, 1H), 2.22 (d, J=11.3 Hz, 1H), 2.01 (dd, J=14.4, 7.0 Hz, 3H), 1.87 (t, J=5.6 Hz, 1H), 1.83 (d, J=6.2 Hz, 1H), 1.66 (d, J=13.8 Hz, 3H), 1.59-1.44 (m, 3H), 1.35-1.25 (m, 6H), 0.93 (d, J=6.6 Hz, 3H), 0.85 (dd, J=6.5, 4.0 Hz, 12H).

[0206] ESI-MS (M+H).sup.+: 614.

Example 42

[0207] ##STR00157##

[0208] Compound A42 was synthesized as follows:

##STR00158##

[0209] 1. Synthesis of Intermediate A42-1

[0210] 9-Aminofluorene hydrochloride (1 g, 4.60 mmol) was dissolved in 20 mL of dichloromethane, and triethylamine (1.91 mL) and triphosgene (550 mg, 1.85 mmol) were sequentially added under ice bath. After stirring for 30 min L-leucine ethyl ester (920 mg, 5.04 mmol) was added thereto. After reacting at room temperature for 1 hour, the reaction was quenched by adding water (10 mL), and extracted with dichloromethane (20 mL*3). The organic phases were combined, dried and spin-dried. The solute was slurried with petroleum ether/ethyl acetate mixed solution, and then filtered to obtain a white solid (400 mg, 200 yield).

[0211] 2. Synthesis of Intermediate A42-2

[0212] A42-1 (290 mg, 0.79 mmol) was dissolved in 10 mL of dioxane/water (10:1), and one drop of concentrated sulfuric acid was added. After refluxing overnight, it was cooled to room temperature. The mixture was diluted with 20 mL ofwater. The aqueous phase was extracted with ethyl acetate (20 mL*3) and then combined, dried and spin-dried to obtain a white solid (200 mg, 7400 yield).

[0213] 3. Synthesis of Compound A42

[0214] Compound A42-2 (200 mg, 0.59 mmol) was dissolved in dichloromethane (20 mL), HATU (340 mg, 0.89 mmol), A1-2 (190 mg, 0.71 mmol) and triethylamine (0.3 mL) were added in sequence. After reacting at room temperature for 3 hours, the mixture was diluted with water (20 mL). The aqueous phase was extracted with dichloromethane (20 mL*3). The organic phases were combined, dried and spin-dried, and the solute was purified by medium pressure preparative liquid chromatography to obtain a white solid (45 mg, 13% yield).

[0215] .sup.1H NMR (400 MHz, DMSO) δ 9.16 (s, 1H), 7.84 (d, J=7.5 Hz, 2H), 7.51 (d, J=7.4 Hz, 2H), 7.41 (t, J=7.4 Hz, 2H), 7.31 (dt, J=9.8, 7.9 Hz, 2H), 6.55 (d, J=8.6 Hz, 1H), 6.13 (d, J=8.3 Hz, 1H), 5.82 (d, J=8.8 Hz, 1H), 4.45 (dd, J=15.3, 7.7 Hz, 1H), 4.07 (d, J=6.5 Hz, 1H), 2.56 (s, 1H), 2.21 (d, J=11.2 Hz, 1H), 2.00 (dd, J=14.3, 6.8 Hz, 3H), 1.85 (t, J=5.5 Hz, 1H), 1.78 (s, 1H), 1.64 (d, J=11.4 Hz, 2H), 1.50-1.35 (m, 4H), 1.26 (t, J=11.7 Hz, 11H), 0.90 (dd, J=17.8, 6.5 Hz, 10H).

[0216] ESI-MS (M+Na).sup.+: 608.

Example 43

[0217] ##STR00159##

[0218] Compound A43 was synthesized as follows:

##STR00160##

[0219] 1. Synthesis of Intermediate A43-1

[0220] 9-Fluorenic acid (10 g, 47.6 mmol) was dissolved in 50 mL DMF, and HATU (27 g, 71.0 mmol), ammonium chloride (25.5 g, 476.6 mmol) and triethylamine (66 mL) were added in sequence. After reacting at room temperature for 48 hours, the mixture was diluted with water (200 mL). The aqueous phase was extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried and spin-dried, and the solute was purified by column to obtain a white solid (1.6 g, 16% yield).

[0221] 2. Synthesis of Intermediate A43-2

[0222] A43-1 (1.4 g, 6.69 mmol) was dissolved in 20 mL THF, and borane dimethyl sulfide solution (BH3.Me2S) (10M, 1.35 mL) was added and the mixture was refluxed for 3 h. After cooling to room temperature, the reaction was quenched with 1M HCl. The aqueous phase was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (20 mL*3). The organic phases were combined, dried and spin-dried, and the solute was purified by column to obtain a pale yellow solid (540 mg, 41% yield).

[0223] 3. Synthesis of Intermediate A43-3

[0224] A43-2 (540 mg, 2.77 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (1.15 mL) and triphosgene (330 mg, 1.11 mmol) were sequentially added under ice bath. After stirring for 30 min, L-leucine ethyl ester (590 mg, 3.01 mmol) was added. After reacting at room temperature for 1 hour, the reaction was quenched by adding water (10 mL), and extracted with dichloromethane (20 mL*3). The organic phases were combined, dried and spin-dried, and the solute was slurried with petroleum ether/ethyl acetate mixed solution, and then filtered to obtain a white solid (850 mg, 80% yield).

[0225] 4. Synthesis of Intermediate A43-4

[0226] A43-3 (370 mg, 0.97 mmol) was dissolved in 10 mL of dioxane/water (10:1), and one drop of concentrated sulfuric acid was added. After refluxing overnight, it was cooled to room temperature. The mixture was diluted with 20 mL of water. The aqueous phase was extracted with ethyl acetate (20 mL*3) and then combined, dried and spin-dried to obtain a white solid (240 mg, 70% yield).

[0227] 5. Synthesis of Compound A43

[0228] Compound A43-4 (240 mg, 0.68 mmol) was dissolved in dichloromethane (20 mL), and HATU (460 mg, 1.21 mmol), A27-2 (250 mg, 0.94 mmol) and triethylamine (0.4 mL) were added in sequence. After reacting at room temperature for 3 hours, it was diluted with water (20 mL). The aqueous phase was extracted with dichloromethane (20 mL*3). The organic phases were combined, dried and spin-dried, and the solute was purified by medium pressure preparative liquid chromatography to obtain a white solid (70 mg, 11% yield).

[0229] .sup.1H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 7.87 (d, J=7.5 Hz, 2H), 7.60 (t, J=6.7 Hz, 2H), 7.39 (td, J=7.3, 2.6 Hz, 2H), 7.31 (ddd, J=15.0, 7.5, 3.8 Hz, 2H), 6.30 (d, J=8.5 Hz, 1H), 6.20 (t, J=5.7 Hz, 1H), 4.31 (dd, J=14.9, 8.5 Hz, 1H), 4.05 (dd, J=12.1, 6.6 Hz, 2H), 3.52-3.36 (m, 2H), 2.23-2.13 (m, 1H), 2.05-1.92 (m, 2H), 1.80 (dd, J=14.0, 8.0 Hz, 2H), 1.72-1.32 (m, 6H), 1.19 (d, J=13.5 Hz, 6H), 0.84 (ddd, J=13.9, 12.1, 7.0 Hz, 17H).

[0230] ESI-MS (M+Na).sup.+: 622.1.

Example 44

[0231] ##STR00161##

[0232] Compound A44 was synthesized as follows:

##STR00162##

[0233] 1. Synthesis of Intermediate A44-1

[0234] Cyclopentylamine (115 mg, 1.35 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (270 mg, 2.67 mmol) and triphosgene (160 mg, 0.54 mmol) were added sequentially under ice bath. After reacting for 30 min, L-tryptophan hydrochloride (325 mg, 1.35 mmol) was added. After reacting at room temperature for 1 hour, 1M HCl was added to adjust to acidity. The mixture was extracted with dichloromethane (20 mL*3). The organic phases were combined, dried and spin-dried to obtain a crude product (260 mg, 60%).

[0235] 2. Synthesis of Compound A44

[0236] A44-1 (260 mg, 0.82 mmol) was dissolved in 15 mL of dichloromethane, and HATU (470 mg, 1.23 mmol), A1-2 (260 mg, 0.98 mmol) and triethylamine (125 mg, 1.24 mmol) were sequentially added thereto. After reacting at room temperature for 2 hours, it was diluted with water (10 mL). The organic phase was extracted with dichloromethane (10 mL*3) and then combined, dried and spin-dried. The solute was purified by medium pressure preparative liquid chromatography to obtain a white solid (70 mg, 15% yield).

[0237] .sup.1H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 9.02 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.14-7.02 (m, 2H), 6.97 (t, J=7.0 Hz, 1H), 6.09 (d, J=7.3 Hz, 1H), 5.85 (d, J=8.3 Hz, 1H), 4.52 (dd, J=14.9, 7.0 Hz, 1H), 4.08 (d, J=6.6 Hz, 1H), 3.80 (dd, J=13.2, 6.5 Hz, 1H), 3.07-2.89 (m, 2H), 2.49-2.45 (m, 2H), 2.27-2.15 (m, 1H), 2.00 (d, J=7.7 Hz, 1H), 1.85 (t, J=5.6 Hz, 1H), 1.79 (s, 1H), 1.77-1.62 (m, 3H), 1.61-1.42 (m, 5H), 1.37 (d, J=9.9 Hz, 1H), 1.25-1.15 (m, 8H), 0.82 (dd, J=11.9, 9.4 Hz, 10H).

[0238] ESI-MS (M+Na).sup.+: 585.1.

[0239] The synthesis method of compound A45 is the same as that of A44, except that raw material cyclopentylamine in the first step was replaced with cyclopentanol.

Example 45

[0240] ##STR00163##

[0241] .sup.1H NMR (400 MHz, DMSO) δ 10.87 (s, 1H), 9.05 (s, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.24-7.12 (m, 2H), 7.06 (t, J=7.5 Hz, 1H), 6.98 (t, J=7.4 Hz, 1H), 4.86 (s, 1H), 4.42-4.18 (m, 1H), 4.09 (d, J=7.0 Hz, 1H), 3.09-2.88 (m, 2H), 2.51 (s, 1H), 2.27-2.16 (m, 1H), 2.02-1.94 (m, 1H), 1.85 (t, J=5.6 Hz, 1H), 1.80 (s, 1H), 1.76-1.40 (m, 10H), 1.37 (d, J=9.9 Hz, 1H), 1.26-1.17 (m, 7H), 0.86-0.79 (m, 9H).

[0242] ESI-MS (M+Na).sup.+: 586.2.

Example 46

[0243] ##STR00164##

[0244] Compound A46 was synthesized as follows

##STR00165##

[0245] 1. Synthesis of Intermediate A46-1

[0246] L-tryptophan methyl ester (500 mg, 2.29 mmol), benzyl bromide (550 mg, 3.21 mmol) and potassium carbonate (640 mg, 4.64 mmol) were dissolved in 10 mL DMF. After reacting at room temperature for 2 hours, the mixture was diluted with 100 mL water. The aqueous phase was extracted with ethyl acetate (20 mL*3). The organic phases were combined, dried, spin-dried, and purified with a preparation plate to obtain a white solid (420 mg, 59% yield).

[0247] 2. Synthesis of Intermediate A46-2

[0248] A46-1 (420 mg, 1.36 mmol) and LiGH (120 mg, 2.72 mmol) were dissolved in methanol/water (3:1, 24 mL). After reacting at 70° C. for 2 hours, the methanol was spun off, and the aqueous phase was adjusted to acidity with 2M HCl. The obtained solid was filtered to obtain a white solid (350 mg, 87% yield).

[0249] 3. Synthesis of Compound A46

[0250] A46-2 (350 mg, 1.19 mmol) was dissolved in 15 mL of dichloromethane, and HATU (680 mg, 1.78 mmol), A1-2 (380 mg, 1.43 mmol) and triethylamine (580 mg, 5.74 mmol) were added sequentially. After reacting at room temperature for 2 hours, it was diluted with water (10 mL). The organic phase was extracted with dichloromethane (10 mL*3) and then combined, dried and spin-dried. The solute was purified by medium pressure preparative liquid chromatography to obtain a white solid (180 mg, 27% yield).

[0251] .sup.1H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 9.03 (s, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.35-7.17 (m, 7H), 7.14 (d, J=2.2 Hz, 1H), 7.05 (t, J=7.0 Hz, 1H), 6.95 (t, J=7.0 Hz, 1H), 4.09 (d, J=6.7 Hz, 1H), 3.69 (dd, J=13.2, 4.9 Hz, 1H), 3.61-3.55 (m, 1H), 3.51 (d, J=7.2 Hz, 1H), 3.01 (tt, J=14.2, 6.9 Hz, 2H), 2.44 (d, J=7.6 Hz, 1H), 2.21 (s, 2H), 1.86 (t, J=5.5 Hz, 1H), 1.79 (s, 1H), 1.65 (d, J=13.9 Hz, 1H), 1.49 (ddd, J=48.1, 21.7, 8.6 Hz, 3H), 1.29 (s, 4H), 1.16 (d, J=7.5 Hz, 2H), 0.81 (dd, J=19.4, 8.4 Hz, 10H).

[0252] ESI-MS (M+H).sup.+: 542.2.

Example 47

[0253] ##STR00166##

[0254] Compound A47 was synthesized as follows

##STR00167##

[0255] 1. Synthesis of Intermediate A47-1

[0256] 9-Fluoreneacetic acid (500 mg, 2.23 mmol), N-hydroxysuccinimide (256 mg, 2.23 mmol) and DCC (460 mg, 2.23 mmol) were dissolved in 20 mL of dichloromethane. After reacting overnight at room temperature, the mixture was filtered. The filtrate was spin-dried, and the solute was purified with prep-TLC to obtain a white solid (850 mg, 100%).

[0257] 2. Synthesis of Intermediate A47-2

[0258] L-aspartic acid-beta-methyl ester hydrochloride (490 mg, 2.66 mmol) and sodium carbonate (850 mg, 7.94 mmol) were dissolved in dioxane/water (3.1, 16 mL), and A47-1 (850 mg, 2.33 mmol) was added under ice bath. After reacting overnight at room temperature, the solvent was spin-dried. The aqueous phase was adjusted to acidity with 2M HCl and extracted with ethyl acetate (20 mL*3). The organic phases were combined, dried and spin-dried to obtain a pale yellow solid (690 mg, 83% yield).

[0259] 3. Synthesis of Compound A47

[0260] A47-2 (690 mg, 1.95 mmol) was dissolved in 25 mL of dichloromethane, and HATU (1120 mg, 2.93 mmol), A1-2 (620 mg, 2.34 mmol) and triethylamine (950 mg, 9.45 mmol) were added sequentially. After reacting at room temperature for 2 hours, it was diluted with water (20 mL). The organic phase was extracted with dichloromethane (20 mL*3), and then combined, dried and spin-dried. The solute was purified by medium pressure preparative liquid chromatography to obtain a white solid (140 mg, 11% yield).

[0261] .sup.1H NMR (400 MHz, DMSO) δ 8.65 (d, J=3.8 Hz, 1H), 8.37 (d, J=8.2 Hz, 1H), 7.86 (d, J=7.5 Hz, 2H), 7.53 (dd, J=19.1, 7.6 Hz, 2H), 7.38 (t, J=7.3 Hz, 2H), 7.29 (t, J=6.9 Hz, 2H), 4.91 (dd, J=13.6, 8.1 Hz, 1H), 4.35 (t, J=7.4 Hz, 1H), 4.15 (d, J=6.7 Hz, 1H), 3.61 (d, J=4.4 Hz, 3H), 2.77-2.58 (m, 4H), 2.46 (d, J=8.1 Hz, 1H), 2.27-2.18 (m, 1H), 2.00 (dd, J=14.5, 6.9 Hz, 1H), 1.88 (t, J=5.6 Hz, 1H), 1.80 (s, 1H), 1.68 (dd, J=22.6, 10.3 Hz, 2H), 1.40-1.24 (m, 8H), 0.84 (dd, J=17.5, 8.9 Hz, 10H).

[0262] ESI-MS (M+Na).sup.+:623.2.

[0263] The synthesis method of compound A48 is the same as that of A47, except that the raw material L-aspartic acid-beta-methyl ester was replaced with L-asparagine or N.sup.4-methyl-L-asparagine.

Example 48

[0264] ##STR00168##

[0265] .sup.1H NMR (400 MHz, DMSO) δ 8.84 (d, J=36.1 Hz, 1H), 8.26 (d, J=6.9 Hz, 1H), 7.85 (d, J=6.7 Hz, 2H), 7.78 (s, 1H), 7.61-7.46 (m, 2H), 7.37 (s, 2H), 7.29 (s, 2H), 4.93 (s, 1H), 4.34 (s, 1H), 4.10 (d, J=7.4 Hz, 1H), 2.56 (d, J=15.2 Hz, 7H), 1.86 (ddd, J=65.9, 58.1, 43.7 Hz, 10H), 1.38 (d, J=55.7 Hz, 3H), 1.03-0.65 (m, 12H).

[0266] ESI-MS (M+Na).sup.+: 622.2.

Example 49

[0267] ##STR00169##

[0268] Compound A49 was synthesized as follows:

##STR00170##

[0269] A22-1 (210 mg, 0.59 mmol) was dissolved in 5 mL of dichloromethane, and HATU (340 mg, 0.89 mmol), A49-1 (229 mg, 0.80 mmol) and triethylamine (180 mg, 1.78 mmol) were added sequentially. After reacting at room temperature for 2 hours, it was diluted with water (10 mL). The organic phase was extracted with dichloromethane (10 mL*3) and then combined, dried and spin-dried. The solute was purified by medium pressure preparative liquid chromatography to obtain a white solid (180 mg, 52% yield).

[0270] .sup.1H NMR (400 MHz, DMSO) δ 7.90 (d, J=7.5 Hz, 2H), 7.73 (d, J=7.5 Hz, 2H), 7.68 (d, J=8.2 Hz, 1H), 7.42 (t, J=7.3 Hz, 2H), 7.37-7.28 (m, 2H), 4.33-4.12 (m, 5H), 3.66 (t, J=8.4 Hz, 1H), 3.38 (s, 1H), 2.90 (dd, J=10.5, 6.6 Hz, 1H), 2.33-2.21 (m, 1H), 2.09-1.99 (m, 2H), 1.96-1.80 (m, 4H), 1.73-1.55 (m, 3H), 1.53-1.44 (m, 1H), 1.37 (td, J=8.6, 4.3 Hz, 1H), 1.31 (s, 3H), 1.28-1.19 (m, 5H), 0.89 (dd, J=11.1, 6.6 Hz, 5H), 0.80 (d, J=13.1 Hz, 3H).

[0271] ESI-MS (M+H).sup.+: 584.

Example 50

[0272] ##STR00171##

[0273] Compound A50 was synthesized as follows

##STR00172##

[0274] A50-1 (367 mg, 1 mmol) was dissolved in 5 mL of dichloromethane, and HATU (494 mg, 1.3 mmol), A1-2 (493 mg, 1.3 mmol) and triethylamine (303 mg, 3 mmol) were added sequentially. After reacting at room temperature for 2 hours, it was diluted with water (10 mL). The organic phase was extracted with dichloromethane (10 mL*3) and then combined, dried and spin-dried. The solute was purified by medium pressure preparative liquid chromatography to obtain a white solid (58 mg, 9% yield).

[0275] .sup.1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 7.92 (d, J=7.5 Hz, 2H), 7.64 (d, J=7.2 Hz, 2H), 7.44 (t, J=7.4 Hz, 2H), 7.35 (t, J=7.4 Hz, 2H), 4.77 (s, 1H), 4.46 (d, J=7.1 Hz, 1H), 4.33 (dt, J=17.2, 6.3 Hz, 2H), 4.10 (d, J=8.2 Hz, 1H), 2.74 (s, 3H), 2.21 (d, J=8.4 Hz, 1H), 2.03 (s, 1H), 1.83 (d, J=20.3 Hz, 2H), 1.62 (ddd, J=43.2, 20.8, 6.4 Hz, 4H), 1.39-1.28 (m, 3H), 1.25 (d, J=6.4 Hz, 7H), 0.97-0.75 (m, 15H).

[0276] ESI-MS (M+H).sup.+: 615.

Example 51

[0277] ##STR00173##

[0278] .sup.1H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 7.89 (d, J=7.5 Hz, 2H), 7.71 (d, J=7.5 Hz, 2H), 7.65 (t, J=6.1 Hz, 1H), 7.42 (t, J=7.4 Hz, 2H), 7.33 (t, J=7.3 Hz, 2H), 4.34-4.16 (m, 3H), 4.06 (d, J=7.3 Hz, 1H), 3.75 (d, J=6.0 Hz, 2H), 2.56 (s, 1H), 2.23-2.13 (m, 1H), 2.05-1.96 (m, 1H), 1.83 (t, J=5.6 Hz, 1H), 1.80-1.73 (m, 1H), 1.72-1.58 (m, 2H), 1.36-1.27 (m, 2H), 1.22 (d, J=9.9 Hz, 7H), 0.89-0.73 (m, 9H).

[0279] The synthesis method of compound A51 is the same as that of compound A22.

Example 52

[0280] ##STR00174##

[0281] .sup.1H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 9.11 (d, J=10.1 Hz, 1H), 8.61 (dd, J=22.6, 8.1 Hz, 1H), 8.33 (d, J=13.6 Hz, 1H), 7.94-7.80 (m, 3H), 7.69 (d, J=7.7 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H), 7.34-7.19 (m, 3H), 7.08-6.98 (m, 2H), 4.95-4.84 (m, 1H), 4.14-4.07 (m, 1H), 3.89 (s, 3H), 3.24-3.18 (m, 2H), 2.61-2.55 (m, 1H), 2.27-2.16 (m, 1H), 2.06-1.97 (m, 1H), 1.89-1.76 (m, 2H), 1.72-1.60 (m, 2H), 1.38 (t, J=10.1 Hz, 1H), 1.32-1.21 (m, 8H), 0.85-0.80 (m, 9H).

[0282] The synthesis method of compound A52 is the same as that of compound A24.

Example 53

[0283] ##STR00175##

[0284] .sup.1H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 9.07 (d, J=7.2 Hz, 1H), 8.95 (s, 1H), 8.44 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.08-7.98 (m, 1H), 5.20 (dd, J=12.9, 5.4 Hz, 1H), 4.63 (t, J=7.2 Hz, 1H), 4.08 (d, J=6.6 Hz, 1H), 2.98-2.84 (m, 1H), 2.70-2.52 (m, 3H), 2.25-2.16 (m, 1H), 2.13-2.05 (m, 1H), 2.04-1.97 (m, 1H), 1.84-1.72 (m, 2H), 1.73-1.57 (m, 2H), 1.38 (d, J=7.3 Hz, 3H), 1.33-1.25 (m, 3H), 1.22 (t, J=4.1 Hz, 6H), 0.89-0.74 (m, 9H).

[0285] The synthesis method of compound A53 is the same as that of compound A24.

Example 54

[0286] ##STR00176##

[0287] .sup.1H NMR (400 MHz, DMSO) δ 11.15 (d, J=2.7 Hz, 1H), 9.29 (dd, J=22.3, 7.3 Hz, 1H), 8.76 (d, J=3.3 Hz, 1H), 8.08-7.91 (m, 3H), 5.20 (ddd, J=12.9, 5.3, 2.4 Hz, 1H), 4.64-4.56 (m, 1H), 4.12 (d, J=8.6 Hz, 1H), 2.98-2.82 (m, 1H), 2.68-2.52 (m, 3H), 2.27-2.18 (m, 1H), 2.13-1.97 (m, 2H), 1.86 (t, J=5.4 Hz, 1H), 1.83-1.75 (m, 1H), 1.71-1.58 (m, 2H), 1.36-1.32 (m, 4H), 1.28-1.19 (m, 8H), 0.87-0.78 (m, 9H).

[0288] The synthesis method of compound A54 is the same as that of compound A24.

Example 55

[0289] ##STR00177##

[0290] .sup.1H NMR (400 MHz, DMSO) δ 8.92-8.79 (m, 1H), 8.25-8.12 (m, 1H), 7.24 (t, J=7.9 Hz, 4H), 7.03-6.89 (m, 6H), 4.48-4.38 (m, 1H), 4.38-4.29 (m, 2H), 4.12-4.05 (m, 1H), 2.57-2.51 (m, 1H), 2.24-2.16 (m, 1H), 2.05-1.97 (m, 1H), 1.84 (t, J=5.5 Hz, 1H), 1.80-1.75 (m, 1H), 1.71-1.60 (m, 2H), 1.54-1.38 (m, 3H), 1.36-1.29 (m, 1H), 1.28-1.20 (m, 8H), 0.87-0.72 (m, 15H).

[0291] The synthesis method of compound A55 is the same as that of compound A39.

Example 56

[0292] ##STR00178##

[0293] .sup.1H NMR (400 MHz, DMSO) δ 8.94-8.82 (m, 1H), 8.65-8.53 (m, 2H), 8.44-8.42 (m, 1H), 8.21 (d, J=7.7 Hz, 1H), 7.54-7.39 (m, 2H), 7.31-7.22 (m, 2H), 5.22-5.11 (m, 2H), 4.47-4.37 (m, 1H), 4.15-4.06 (m, 1H), 2.60-2.52 (m, 1H), 2.27-2.16 (m, 1H), 2.08-1.98 (m, 1H), 1.89-1.76 (m, 2H), 1.74-1.60 (m, 3H), 1.59-1.42 (m, 2H), 1.34 (dt, J=12.5, 6.3 Hz, 1H), 1.30-1.20 (m, 8H), 0.95-0.76 (m, 15H).

[0294] The synthesis method of compound A56 is the same as compound 39.

Example 57

[0295] ##STR00179##

[0296] .sup.1H NMR (400 MHz, DMSO) δ 8.88 (dd, J=18.4, 3.1 Hz, 1H), 8.60 (dd, J=27.6, 8.4 Hz, 1H), 8.00 (t, J=8.8 Hz, 2H), 7.43 (t, J=7.7 Hz, 1H), 7.34-7.26 (m, 1H), 7.15 (t, J=7.4 Hz, 1H), 7.09 (t, J=1.9 Hz, 1H), 6.80 (dd, J=8.5, 1.3 Hz, 1H), 5.13-4.95 (m, 2H), 4.50-4.41 (m, 1H), 4.15-4.09 (m, 1H), 3.85 (s, 3H), 2.59-2.53 (m, 1H), 2.27-2.17 (m, 1H), 2.08-1.98 (m, 1H), 1.89-1.78 (m, 2H), 1.71-1.59 (m, 3H), 1.55-1.43 (m, 2H), 1.38-1.31 (m, 1H), 1.28-1.18 (m, 8H), 0.89 (dd, J=6.3, 5.3 Hz, 3H), 0.84-0.80 (m, 12H).

[0297] The synthesis method of compound A57 is the same as that of compound 39.

Example 58

[0298] ##STR00180##

[0299] .sup.1H NMR (400 MHz, DMSO) δ 9.35 (s, 1H), 8.98 (d, J=2.9 Hz, 1H), 8.71 (d, J=8.2 Hz, 1H), 8.45 (d, J=5.8 Hz, 1H), 8.26 (d, J=7.7 Hz, 1H), 7.58-7.53 (m, 2H), 7.52-7.46 (m, 1H), 7.31 (t, J=7.4 Hz, 1H), 5.13 (dd, J=35.0, 16.9 Hz, 2H), 4.47-4.38 (m, 1H), 4.14-4.05 (m, 1H), 2.59-2.53 (m, 1H), 2.26-2.17 (m, 1H), 2.08-1.98 (m, 1H), 1.89-1.77 (m, 2H), 1.71-1.60 (m, 3H), 1.58-1.41 (m, 2H), 1.34 (d, J=10.1 Hz, 1H), 1.31-1.19 (m, 8H), 0.92-0.81 (m, 15H).

[0300] The synthesis method of compound A58 is the same as that of compound 39.

Example 59

[0301] ##STR00181##

[0302] .sup.1H NMR (400 MHz, DMSO) δ 8.96 (s, 1H), 8.65 (d, J=7.9 Hz, 1H), 8.33 (d, J=1.7 Hz, 2H), 7.59-7.56 (m, 2H), 7.48-7.44 (m, 2H), 5.11 (dd, J=36.1, 16.9 Hz, 2H), 4.45-4.34 (m, 1H), 4.09 (d, J=8.5 Hz, 1H), 2.58-2.52 (m, 1H), 2.26-2.16 (m, 1H), 2.07-1.97 (m, 1H), 1.88-1.76 (m, 2H), 1.70-1.57 (m, 3H), 1.57-1.40 (m, 2H), 1.33 (d, J=9.9 Hz, 1H), 1.28-1.15 (m, 8H), 0.93-0.73 (m, 15H).

[0303] The synthesis method of compound A59 is the same as that of compound 39.

Example 60

[0304] ##STR00182##

[0305] .sup.1H NMR (400 MHz, DMSO) δ 9.00-8.90 (m, 1H), 8.71-8.62 (m, 1H), 8.16 (d, J=7.8 Hz, 1H), 8.00 (dd, J=9.2, 2.5 Hz, 1H), 7.56-7.48 (m, 2H), 7.46-7.41 (m, 1H), 7.30-7.23 (m, 1H), 7.20 (t, J=7.4 Hz, 1H), 5.20-4.98 (m, 2H), 4.47-4.40 (m, 1H), 4.16-4.09 (m, 1H), 2.57-2.52 (m, 1H), 2.28-2.17 (m, 1H), 2.08-2.00 (m, 1H), 1.90-1.78 (m, 2H), 1.72-1.60 (m, 3H), 1.57-1.41 (m, 2H), 1.35 (d, J=8.7 Hz, 1H), 1.31-1.16 (m, 8H), 0.95-0.76 (m, 15H).

[0306] The synthesis method of compound A60 is the same as that of compound 39.

Example 61

[0307] ##STR00183##

[0308] .sup.1H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.68 (d, J=8.2 Hz, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.28 (d, J=7.8 Hz, 1H), 8.16 (s, 1H), 7.60 (d, J=7.8 Hz, 2H), 7.54 (t, J=7.7 Hz, 1H), 7.30 (t, J=7.4 Hz, 1H), 5.26-5.12 (m, 2H), 4.44-4.37 (m, 1H), 4.09 (d, J=6.8 Hz, 1H), 2.58-2.54 (m, 1H), 2.26-2.17 (m, 1H), 2.06-1.95 (m, 1H), 1.87-1.77 (m, 2H), 1.73-1.52 (m, 4H), 1.49-1.40 (m, 1H), 1.31 (d, J=8.1 Hz, 1H), 1.29-1.17 (m, 8H), 0.94-0.78 (m, 15H).

[0309] The synthesis method of compound A61 is the same as that of compound 39.

Example 62

[0310] ##STR00184##

[0311] .sup.1H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 8.16 (d, J=7.7 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.82 (d, J=1.4 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.44 (t, J=7.4 Hz, 1H), 7.34 (dd, J=8.3, 1.5 Hz, 1H), 7.23 (t, J=7.3 Hz, 1H), 5.10 (s, 2H), 4.43 (dd, J=14.1, 9.3 Hz, 1H), 4.10 (d, J=7.0 Hz, 1H), 2.60-2.53 (m, 1H), 2.27-2.16 (m, 1H), 2.07-2.00 (m, 1H), 1.89-1.77 (m, 2H), 1.75-1.52 (m, 4H), 1.50-1.41 (m, 1H), 1.33 (d, J=10.2 Hz, 1H), 1.28-1.22 (m, 8H), 0.92-0.80 (m, 15H).

[0312] The synthesis method of compound A62 is the same as that of compound 39.

Example 63

[0313] ##STR00185##

[0314] .sup.1H NMR (400 MHz, DMSO) δ 9.00-8.85 (m, 1H), 8.73 (dd, J=19.6, 8.3 Hz, 1H), 8.56 (d, J=4.5 Hz, 1H), 8.27 (d, J=7.8 Hz, 1H), 8.13 (d, J=7.3 Hz, 1H), 7.60 (ddd, J=18.2, 14.1, 7.3 Hz, 3H), 7.34 (t, J=7.3 Hz, 1H), 5.31-5.12 (m, 2H), 4.46-4.38 (m, 1H), 4.16-4.08 (m, 1H), 2.53 (d, J=8.4 Hz, 1H), 2.28-2.13 (m, 1H), 2.09-2.00 (m, 1H), 1.89-1.77 (m, 2H), 1.71-1.58 (m, 3H), 1.56-1.42 (m, 2H), 1.38-1.19 (m, 10H), 0.94-0.75 (m, 14H).

[0315] The synthesis method of compound A63 is the same as that of compound 39.

Example 64

[0316] ##STR00186##

[0317] .sup.1H NMR (400 MHz, DMSO) δ 8.61 (dd, J=7.7, 1.2 Hz, 2H), 8.49 (dd, J=4.8, 1.2 Hz, 2H), 8.44 (d, J=8.2 Hz, 1H), 7.85 (t, J=5.5 Hz, 1H), 7.34 (dd, J=7.6, 4.9 Hz, 2H), 5.15 (q, J=16.5 Hz, 2H), 4.23 (t, J=7.5 Hz, 1H), 3.06 (qd, J=13.1, 6.0 Hz, 2H), 2.23 (ddd, J=17.1, 16.7, 7.4 Hz, 1H), 2.03-1.74 (m, 2H), 1.72-1.40 (m, 5H), 1.32-1.18 (m, 9H), 0.85 (ddd, J=15.9, 11.4, 5.2 Hz, 16H).

[0318] The synthesis method of compound A64 is the same as that of compound 39.

Example 65

[0319] ##STR00187##

[0320] Compound A65 was synthesized as follows:

##STR00188##

[0321] The raw material A10 (150 mg, 0.25 mmol) and the compound isobutylboronic acid (102 mg, 1 mmol) were dissolved in methanol, and diluted hydrochloric acid (1N, 1.5 mL) was added. The reaction was carried out at 70° C. for 6 h. Through spot plate monitoring, the raw material was reacted completely. The solvent was spin-dried. The produce was purified by medium pressure preparative liquid chromatography directly to obtain a white solid (42 mg, 36% yield).

[0322] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.85 (d, J=7.6 Hz, 1H), 7.66 (t, J=6.8 Hz, 1H), 7.41 (t, J=7.4 Hz, 1H), 7.31 (td, J=7.4, 2.3 Hz, 1H), 4.33-4.14 (m, 4H), 3.95 (dd, J=9.0, 6.0 Hz, 1H), 3.00 (dd, J=9.1, 5.8 Hz, 1H), 1.57-1.44 (m, 2H), 1.44-1.34 (m, 2H), 1.34-1.16 (m, 3H), 0.85 (d, J=6.5 Hz, 3H), 0.82-0.72 (m, 9H).

[0323] ESI-MS (M+H).sup.+: 467.

[0324] The synthesis method of compound A66-A83 is the same as that of A65, except that A10 was replaced with the corresponding borate.

Example 66

[0325] ##STR00189##

[0326] .sup.1H NMR (400 MHz, MeOD) δ 7.57 (d, J=7.8 Hz, 1H), 7.37-7.24 (m, 6H), 7.14-7.07 (m, 2H), 7.03 (t, J=7.3 Hz, 1H), 5.05 (q, J=12.4 Hz, 2H), 4.64 (t, J=7.6 Hz, 1H), 3.25 (dt, J=16.2, 8.0 Hz, 2H), 2.55 (dd, J=9.5, 5.6 Hz, 1H), 1.25-1.16 (m, 1H), 1.12-0.99 (m, 2H), 0.77 (t, J 5=6.0 Hz, 6H).

[0327] ESI-MS (M+H).sup.+: 452.

Example 67

[0328] ##STR00190##

[0329] .sup.1H NMR (400 MHz, MeOD) δ 7.78 (d, J=7.5 Hz, 2H), 7.55 (t, J=9.9 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.36 (t, J=7.4 Hz, 2H), 7.33-7.23 (m, 2H), 4.72 (dd, J=9.7, 5.2 Hz, 1H), 4.38 (t, J=7.4 Hz, 1H), 2.77 (dd, J=14.6, 7.0 Hz, 2H), 2.58 (dd, J=14.7, 8.0 Hz, 1H), 1.73-1.53 (m, 4H), 1.37 (dd, J=12.9, 5.5 Hz, 2H), 0.97 (dd, J=15.0, 6.6 Hz, 12H).

[0330] ESI-MS (M+H).sup.+: 451.

Example 68

[0331] ##STR00191##

[0332] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.61 (d, J=7.6 Hz, 1H), 7.32 (dd, J=7.9, 3.5 Hz, 1H), 7.14 (s, 1H), 7.11-7.00 (m, 2H), 4.93 (d, J=8.0 Hz, 1H), 3.17 (dd, J=18.1, 12.0 Hz, 1H), 2.67-2.57 (m, 1H), 1.95-1.86 (m, 2H), 1.81 (d, J=19.8 Hz, 3H), 1.64 (t, J=14.0 Hz, 3H), 1.56-1.37 (m, 7H), 1.31 (d, J=12.0 Hz, 5H), 1.13 (d, J=5.6 Hz, 1H), 0.89 (d, J=6.8 Hz, 3H), 0.85-0.78 (m, 3H).

[0333] ESI-MS (M+H).sup.+: 494.

Example 69

[0334] ##STR00192##

[0335] .sup.1H NMR (400 MHz, MeOD) δ 7.60 (d, J=7.7 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.18-7.00 (m, 3H), 4.87 (d, J=8.4 Hz, 1H), 3.28-3.16 (m, 2H), 2.65-2.54 (m, 1H), 2.22-2.16 (m, 2H), 1.75-1.44 (m, 6H), 1.32-0.95 (m, 6H), 0.90-0.76 (m, 6H).

[0336] ESI-MS (M+Na).sup.+: 450.0.

Example 70

[0337] ##STR00193##

[0338] .sup.1H NMR (400 MHz, DMSO) δ 10.83 (d, J=26.1 Hz, 1H), 8.67 (s, 1H), 7.92 (dd, J=37.5, 8.2 Hz, 1H), 7.53 (s, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.15 (dd, J=21.9, 1.9 Hz, 1H), 7.05 (t, J=7.4 Hz, 1H), 6.96 (dd, J=15.9, 7.9 Hz, 1H), 4.67 (dd, J=13.5, 8.3 Hz, 1H), 4.55-4.45 (m, 1H), 3.25-3.07 (m, 1H), 3.01 (dd, J=14.7, 8.7 Hz, 1H), 2.90 (t, J=11.8 Hz, 1H), 2.64 (s, 1H), 2.06-1.90 (m, 2H), 1.59 (ddd, J=25.0, 13.3, 6.3 Hz, 1H), 1.44-1.16 (m, 3H), 0.84 (d, J=6.2 Hz, 6H).

[0339] ESI-MS (M+H).sup.+: 400.

Example 71

[0340] ##STR00194##

[0341] .sup.1H NMR (400 MHz, MeOD) δ 7.50 (d, J=7.8 Hz, 1H), 7.37-7.27 (m, 4H), 7.22 (dd, J=7.7, 1.6 Hz, 2H), 7.14-7.03 (m, 3H), 4.24 (dd, J=8.4, 7.1 Hz, 1H), 4.11 (d, J=13.8 Hz, 1H), 4.01 (d, J=13.8 Hz, 1H), 3.21 (dd, J=14.1, 8.5 Hz, 1H), 3.11 (dd, J=14.1, 6.9 Hz, 1H), 2.58 (dd, J=9.8, 5.4 Hz, 1H), 1.18 (dq, J=12.7, 6.4 Hz, 1H), 1.12-0.96 (m, 2H), 0.81-0.72 (m, 6H).

[0342] ESI-MS (M+H).sup.+: 472.

Example 72

[0343] ##STR00195##

[0344] .sup.1H NMR (400 MHz, MeOD) δ 8.68 (dd, J=4.5, 1.6 Hz, 2H), 7.73 (dd, J=4.5, 1.6 Hz, 2H), 7.64 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.17 (s, 1H), 7.08 (ddd, J=14.9, 13.9, 7.0 Hz, 2H), 5.05 (dd, J=8.5, 7.3 Hz, 1H), 3.45-3.33 (m, 2H), 2.61 (dd, J=9.6, 5.6 Hz, 1H), 1.35-1.19 (m, 2H), 1.10-1.04 (m, 1H), 0.79 (t, J=6.4 Hz, 6H).

[0345] ESI-MS (M+H).sup.+: 423.

Example 73

[0346] ##STR00196##

[0347] .sup.1H NMR (400 MHz, MeOD) δ 8.09 (dt, J=12.6, 6.5 Hz, 2H), 7.72-7.49 (m, 3H), 7.34 (d, J=8.0 Hz, 1H), 7.21 (d, J=4.3 Hz, 1H), 7.07 (dt, J=25.7, 7.2 Hz, 2H), 5.10 (dd, J=15.9, 8.6 Hz, 1H), 3.54-3.37 (m, 2H), 2.64 (dd, J=9.2, 6.2 Hz, 1H), 1.31 (dd, J=14.1, 6.7 Hz, 2H), 1.18-1.09 (m, 1H), 0.83 (ddd, J=20.3, 6.4, 4.2 Hz, 6H).

[0348] ESI-MS (M+H).sup.+: 479.

Example 74

[0349] ##STR00197##

[0350] .sup.1H NMR (400 MHz, MeOD) δ 8.95 (dd, J=4.3, 1.6 Hz, 1H), 8.45 (d, J=8.4 Hz, 1H), 8.39 (d, J=1.7 Hz, 1H), 8.12 (dt, J=19.3, 5.4 Hz, 2H), 7.68 (d, J=7.7 Hz, 1H), 7.63 (dd, J=8.3, 4.3 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.20 (s, 1H), 7.09 (dt, J=23.0, 7.0 Hz, 2H), 5.12 (t, J=7.8 Hz, 1H), 3.55-3.39 (m, 2H), 2.63 (dd, J=9.6, 5.7 Hz, 1H), 1.27 (d, J=19.9 Hz, 3H), 1.13-1.05 (m, 2H), 0.80 (t, J=6.6 Hz, 6H).

[0351] ESI-MS (M+H).sup.+: 473.

Example 75

[0352] ##STR00198##

[0353] .sup.1H NMR (400 MHz, MeOD) δ 9.14 (d, J=20.0 Hz, 1H), 8.66 (d, J=34.7 Hz, 1H), 8.12-7.93 (m, 2H), 7.87 (d, J=5.5 Hz, 1H), 7.68 (t, J=7.3 Hz, 2H), 7.35 (d, J=8.1 Hz, 1H), 7.22 (d, J=5.1 Hz, 1H), 7.08 (dt, J=13.7, 6.7 Hz, 2H), 5.18 (dt, J=15.3, 7.4 Hz, 1H), 3.54-3.35 (m, 2H), 2.73-2.58 (m, 1H), 1.39-1.21 (m, 2H), 1.16-1.06 (m, 1H), 0.92-0.74 (m, 6H).

[0354] ESI-MS (M+H).sup.+: 473.

Example 76

[0355] ##STR00199##

[0356] .sup.1H NMR (400 MHz, MeOD) δ 8.29 (d, J=28.9 Hz, 1H), 7.98-7.88 (m, 3H), 7.82 (ddd, J=16.7, 8.6, 1.8 Hz, 1H), 7.69 (t, J=7.1 Hz, 1H), 7.63-7.51 (m, 2H), 7.36 (d, J=7.8 Hz, 1H), 7.21 (d, J=4.6 Hz, 1H), 7.16-7.03 (m, 2H), 5.24-5.07 (m, 1H), 3.57-3.38 (m, 2H), 2.72-2.56 (m, 1H), 1.37-1.26 (m, 2H), 1.14-1.06 (m, 1H), 0.91-0.75 (m, 6H).

[0357] ESI-MS (M+H).sup.+: 472.

Example 77

[0358] ##STR00200##

[0359] .sup.1H NMR (400 MHz, MeOD) δ 7.60 (d, J=7.7 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.14-7.00 (m, 3H), 4.74 (t, J=7.4 Hz, 1H), 3.92 (p, J=6.4 Hz, 1H), 3.19 (d, J=7.4 Hz, 2H), 2.57 (dd, J=9.5, 5.8 Hz, 1H), 1.87 (dt, J=12.8, 6.5 Hz, 2H), 1.73-1.53 (m, 4H), 1.35-1.20 (m, 3H), 1.17-1.01 (m, 2H), 0.79 (dd, J=6.5, 4.1 Hz, 6H).

[0360] ESI-MS (M+Na).sup.+: 450.9.

Example 78

[0361] ##STR00201##

[0362] .sup.1H NMR (400 MHz, MeOD) δ 7.59 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.17-7.00 (m, 3H), 4.96 (d, J=19.7 Hz, 1H), 4.61 (t, J=7.6 Hz, 1H), 3.28-3.12 (m, 2H), 2.57 (dd, J=9.5, 5.4 Hz, 1H), 1.89-1.45 (m, 8H), 1.31-0.99 (m, 3H), 0.79 (t, J=6.3 Hz, 6H).

[0363] ESI-MS (M+Na).sup.+: 452.2.

Example 79

[0364] ##STR00202##

[0365] .sup.1H NMR (400 MHz, MeOD) δ 7.52 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.30-7.18 (m, 5H), 7.13-7.06 (m, 2H), 7.04-6.97 (m, 1H), 3.74 (dd, J=14.8, 10.2 Hz, 2H), 3.62 (d, J=13.1 Hz, 1H), 3.24-3.15 (m, 2H), 2.56 (dd, J=9.8, 5.5 Hz, 1H), 1.24 (dd, J=12.6, 6.4 Hz, 1H), 1.18-1.00 (m, 2H), 0.80 (dd, J=6.5, 4.8 Hz, 6H).

[0366] ESI-MS (M−H.sub.2O).sup.+:390.1.

Example 80

[0367] ##STR00203##

[0368] .sup.1H NMR (400 MHz, MeOD) δ 7.78 (d, J=7.5 Hz, 2H), 7.53 (dd, J=17.4, 7.4 Hz, 2H), 7.37 (t, J=7.4 Hz, 2H), 7.30 (td, J=7.4, 2.7 Hz, 2H), 5.11 (t, J=6.7 Hz, 1H), 4.39 (t, J=7.4 Hz, 1H), 3.70 (s, 3H), 2.88 (d, J=6.7 Hz, 2H), 2.83-2.70 (m, 2H), 2.60 (dd, J=14.8, 7.9 Hz, 1H), 1.69 (dt, J=13.6, 6.7 Hz, 1H), 1.38 (t, J=7.3 Hz, 2H), 0.93 (t, J=9.8 Hz, 6H).

[0369] ESI-MS (M+Na).sup.+: 489.

Example 81

[0370] ##STR00204##

[0371] .sup.1H NMR (400 MHz, MeOD) δ 7.78 (d, J=7.4 Hz, 2H), 7.54 (dd, J=17.9, 7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 2H), 7.31 (dt, J=11.7, 3.7 Hz, 2H), 5.11 (t, J=6.6 Hz, 1H), 4.59 (s, 4H), 4.39 (t, J=7.4 Hz, 1H), 2.83-2.68 (m, 4H), 2.67-2.57 (m, 1H), 1.68 (dd, J=13.5, 7.0 Hz, 1H), 1.39 (dd, J=15.2, 7.5 Hz, 2H), 0.93 (t, J=9.4 Hz, 6H).

[0372] ESI-MS (M+Na).sup.+: 474.

Example 82

[0373] ##STR00205##

[0374] .sup.1H NMR (400 MHz, MeOD) δ 7.80 (d, J=7.5 Hz, 2H), 7.70-7.58 (m, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.32 (q, J=7.4 Hz, 2H), 4.46-4.37 (m, 2H), 4.21 (t, J=6.6 Hz, 1H), 3.72 (t, J=9.6 Hz, 1H), 3.41 (dd, J=17.1, 9.9 Hz, 1H), 3.07 (dd, J=11.2, 6.4 Hz, 1H), 2.85 (d, J=7.2 Hz, 1H), 2.14 (d, J=9.9 Hz, 1H), 2.03-1.88 (m, 2H), 1.76-1.42 (m, 4H), 0.94 (dt, J=18.1, 9.1 Hz, 5H).

[0375] ESI-MS (M+H).sup.+: 451.

Example 83

[0376] ##STR00206##

[0377] .sup.1H NMR (400 MHz, MeOD) δ 7.80 (d, J=7.5 Hz, 2H), 7.61 (t, J=6.6 Hz, 2H), 7.40 (t, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 5.02-4.90 (m, 1H), 4.57 (d, J=6.5 Hz, 2H), 4.48 (d, J=5.8 Hz, 1H), 4.26 (t, J=5.8 Hz, 1H), 2.78 (d, J=29.8 Hz, 3H), 2.65 (t, J=7.5 Hz, 1H), 1.78 (s, 1H), 1.62 (ddd, J=20.6, 13.7, 7.7 Hz, 2H), 1.40-1.26 (m, 3H), 0.93 (dd, J=17.9, 6.5 Hz, 12H).

[0378] ESI-MS (M+H).sup.+: 481.

Example 84

[0379] ##STR00207##

[0380] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.80 (d, J=7.5 Hz, 2H), 7.64 (t, J=13.9 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 4.47-4.32 (m, 2H), 4.23 (t, J=6.8 Hz, 1H), 4.01 (s, 2H), 2.70 (t, J=7.6 Hz, 1H), 1.71-1.61 (m, 1H), 1.34 (t, J=7.3 Hz, 2H), 0.91 (d, J=6.6 Hz, 6H).

[0381] The synthesis method of compound A84 is the same as that of compound A51.

Example 85

[0382] ##STR00208##

[0383] .sup.1H NMR (400 MHz, CD3OD) δ 7.80 (d, J=7.5 Hz, 2H), 7.71-7.60 (m, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.32 (t, J=7.4 Hz, 2H), 4.47-4.31 (m, 3H), 4.22 (t, J=6.6 Hz, 1H), 2.68 (t, J=7.5 Hz, 1H), 1.72-1.62 (m, 1H), 1.39 (t, J=9.8 Hz, 3H), 1.34 (t, J=7.3 Hz, 2H), 0.91 (d, J=6.6 Hz, 6H).

[0384] The synthesis method of compound A85 is the same as that of compound A51.

Example 86

[0385] ##STR00209##

[0386] .sup.1H NMR (400 MHz, CD3OD) δ 7.80 (d, J=7.5 Hz, 2H), 7.67 (t, J=6.8 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.32 (t, J=7.4 Hz, 2H), 4.44-4.33 (m, 3H), 4.22 (t, J=6.7 Hz, 1H), 2.69 (t, J=7.6 Hz, 1H), 1.70-1.58 (m, 1H), 1.41 (d, J=7.2 Hz, 3H), 1.32 (t, J=7.3 Hz, 2H), 0.91 (d, J=6.6 Hz, 6H).

[0387] The synthesis method of compound A86 is the same as that of compound A51.

Example 87

[0388] ##STR00210##

[0389] .sup.1H NMR (400 MHz, CD3OD) δ 8.26-8.14 (m, 1H), 7.87-7.74 (m, 3H), 7.69 (dd, J=7.2, 6.3 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.28 (dd, J=5.2, 2.5 Hz, 1H), 7.23-7.16 (m, 2H), 7.16-7.00 (m, 2H), 5.21-5.07 (m, 1H), 3.93 (s, 3H), 3.55-3.34 (m, 2H), 2.67-2.61 (m, 1H), 1.38-1.31 (m, 1H), 1.30-1.02 (m, 2H), 0.89-0.78 (m, 6H).

[0390] The synthesis method of compound A87 is the same as that of compound A51.

Example 88

[0391] ##STR00211##

[0392] .sup.1H NMR (400 MHz, CD3OD) δ 8.10 (d, J=25.3 Hz, 1H), 7.72-7.63 (m, 3H), 7.55 (t, J=8.3 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.20 (d, J=3.5 Hz, 1H), 7.15-7.02 (m, 3H), 6.97 (dd, J=4.5, 2.2 Hz, 1H), 5.17-5.07 (m, 1H), 3.50-3.36 (m, 2H), 2.68-2.59 (m, 1H), 1.65-1.54 (m, 1H), 1.39-1.31 (m, 2H), 0.91-0.78 (m, 6H).

[0393] The synthesis method of compound A88 is the same as that of compound A51.

Example 89

[0394] ##STR00212##

[0395] .sup.1H NMR (400 MHz, CD3OD) δ 7.79 (d, J=7.4 Hz, 2H), 7.65 (dd, J=7.1, 3.2 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.33-7.15 (m, 17H), 4.68 (dd, J=7.6, 5.4 Hz, 1H), 4.47-4.37 (m, 2H), 4.21 (t, J=6.5 Hz, 1H), 2.94-2.67 (m, 3H), 1.69-1.56 (m, 1H), 1.38-1.27 (m, 2H), 0.93-0.81 (m, 6H).

[0396] The synthesis method of compound A89 is the same as that of compound A51.

Example 90

[0397] ##STR00213##

[0398] .sup.1H NMR (400 MHz, CD3OD) δ 8.37 (d, J=0.7 Hz, 1H), 8.32 (dd, J=7.8, 1.5 Hz, 1H), 8.00 (dd, J=7.8, 0.6 Hz, 1H), 5.18 (dd, J=12.5, 5.5 Hz, 1H), 4.81-4.76 (m, 1H), 2.94-2.69 (m, 4H), 2.22-2.11 (m, 1H), 1.73-1.60 (m, 1H), 1.56 (d, J=8.6 Hz, 3H), 1.36 (t, J=7.3 Hz, 2H), 0.93 (d, J=6.6 Hz, 6H).

[0399] The synthesis method of compound A90 is the same as that of compound A51.

Example 91

[0400] ##STR00214##

[0401] .sup.1H NMR (400 MHz, CD3OD) δ 8.17-8.07 (m, 2H), 7.99 (t, J=7.6 Hz, 1H), 5.25 (dd, J=12.6, 5.5 Hz, 1H), 4.59 (s, 1H), 3.00-2.86 (m, 1H), 2.85-2.70 (m, 3H), 2.26-2.17 (m, 1H), 1.77-1.62 (m, 1H), 1.56 (d, J=10.9 Hz, 3H), 1.46-1.32 (m, 2H), 0.98-0.89 (m, 6H).

[0402] The synthesis method of compound A91 is the same as that of compound A51.

Example 92

[0403] ##STR00215##

[0404] .sup.1H NMR (400 MHz, CD3OD) δ 8.86 (s, 1H), 8.36 (d, J=5.3 Hz, 1H), 8.24 (d, J=7.9 Hz, 1H), 8.15 (d, J=5.3 Hz, 1H), 7.67-7.60 (m, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.34 (t, J=7.4 Hz, 1H), 5.31-5.11 (m, 2H), 4.64-4.57 (m, 1H), 2.66 (t, J=7.6 Hz, 1H), 1.82-1.66 (m, 2H), 1.65-1.55 (m, 2H), 1.28 (t, J=7.3 Hz, 2H), 0.98 (d, J=6.3 Hz, 3H), 0.92 (d, J=6.3 Hz, 3H), 0.88 (d, J=6.6 Hz, 6H).

[0405] The synthesis method of compound A92 is the same as that of compound A51.

Example 93

[0406] ##STR00216##

[0407] .sup.1H NMR (400 MHz, CD3OD) δ 7.26 (t, J=7.9 Hz, 4H), 7.08-7.01 (m, 4H), 6.98 (t, J=7.4 Hz, 2H), 4.72-4.63 (m, 1H), 4.48-4.34 (m, 2H), 2.74-2.62 (m, 1H), 1.72-1.59 (m, 2H), 1.58-1.37 (m, 2H), 1.40-1.29 (m, 2H), 0.92-0.82 (m, 12H).

[0408] The synthesis method of compound A93 is the same as that of compound A51.

Example 94

[0409] ##STR00217##

[0410] .sup.1H NMR (400 MHz, CD3OD) δ 8.49 (dd, J=7.7, 1.1 Hz, 1H), 8.41 (dt, J=4.9, 1.6 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.56-7.45 (m, 2H), 7.34-7.24 (m, 2H), 5.28-5.14 (m, 2H), 4.72-4.61 (m, 1H), 2.67 (t, J=7.6 Hz, 1H), 1.78-1.57 (m, 4H), 1.36-1.27 (m, 2H), 1.00-0.85 (m, 12H).

[0411] The synthesis method of compound A94 is the same as that of compound A51.

Example 95

[0412] ##STR00218##

[0413] .sup.1H NMR (400 MHz, CD3OD) δ 7.95 (dd, J=12.0, 8.1 Hz, 2H), 7.40-7.29 (m, 2H), 7.18 (dd, J=10.7, 4.5 Hz, 1H), 6.95 (t, J=2.2 Hz, 1H), 6.84 (dd, J=8.5, 1.6 Hz, 1H), 5.09-4.96 (m, 2H), 4.73-4.63 (m, 1H), 3.90 (s, 3H), 2.70-2.61 (m, 1H), 1.75-1.54 (m, 4H), 1.32-1.27 (m, 2H), 0.96-0.86 (m, 12H).

[0414] The synthesis method of compound A95 is the same as that of compound A51.

Example 96

[0415] ##STR00219##

[0416] .sup.1H NMR (400 MHz, CD3OD) δ 9.29 (s, 1H), 8.54-8.37 (m, 1H), 8.26 (d, J=7.8 Hz, 1H), 7.64-7.53 (m, 3H), 7.44-7.35 (m, 1H), 5.28-5.10 (m, 2H), 4.67-4.62 (m, 1H), 2.68 (t, J=7.6 Hz, 1H), 1.84-1.68 (m, 2H), 1.66-1.54 (m, 2H), 1.32-1.27 (m, 2H), 1.01-0.86 (m, 12H).

[0417] The synthesis method of compound A96 is the same as that of compound A51.

Example 97

[0418] ##STR00220##

[0419] .sup.1H NMR (400 MHz, CD3OD) δ 8.09 (s, 2H), 7.43 (s, 4H), 5.08 (q, J=16.9 Hz, 2H), 4.63-4.59 (m, 1H), 2.67 (t, J=7.5 Hz, 1H), 1.80-1.54 (m, 4H), 1.31-1.27 (m, 2H), 1.02-0.85 (m, 12H).

[0420] The synthesis method of compound A97 is the same as that of compound A51.

Example 98

[0421] ##STR00221##

[0422] .sup.1H NMR (400 MHz, CD3OD) δ 8.07 (d, J=7.8 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.50-7.38 (m, 3H), 7.24-7.17 (m, 2H), 5.14-5.02 (m, 2H), 4.67-4.61 (m, 1H), 2.67 (t, J=7.3 Hz, 1H), 1.77-1.52 (m, 4H), 1.38-1.24 (m, 2H), 1.01-0.87 (m, 12H).

[0423] The synthesis method of compound A98 is the same as that of compound A51.

Example 99

[0424] ##STR00222##

[0425] .sup.1H NMR (400 MHz, CD3OD) δ 8.06 (dd, J=12.1, 8.1 Hz, 2H), 7.50-7.40 (m, 3H), 7.24 (dd, J=10.6, 5.1 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 5.13-5.02 (m, 2H), 4.67-4.63 (m, 1H), 2.71-2.63 (m, 1H), 1.78-1.55 (m, 4H), 1.33-1.26 (m, 2H), 1.02-0.88 (m, 12H).

[0426] The synthesis method of compound A99 is the same as that of compound A51.

Example 100

[0427] ##STR00223##

[0428] .sup.1H NMR (400 MHz, CD3OD) δ 8.04 (d, J=8.3 Hz, 2H), 7.51 (d, J=1.6 Hz, 2H), 7.23 (dd, J=8.3, 1.7 Hz, 2H), 5.07 (s, 2H), 4.68-4.64 (m, 1H), 2.68 (t, J=7.6 Hz, 1H), 1.77-1.56 (m, 4H), 1.29-1.25 (m, 2H), 1.01-0.89 (m, 12H).

[0429] The synthesis method of compound A100 is the same as that of compound A51.

Example 101

[0430] ##STR00224##

[0431] .sup.1H NMR (400 MHz, CD3OD) δ 8.26 (d, J=8.0 Hz, 1H), 8.20 (d, J=7.9 Hz, 1H), 7.90 (s, 1H), 7.55-7.52 (m, 3H), 7.32 (t, J=7.3 Hz, 1H), 5.24-5.10 (m, 2H), 4.63 (dd, J=9.5, 5.5 Hz, 1H), 2.67 (t, J=7.6 Hz, 1H), 1.81-1.67 (m, 2H), 1.66-1.56 (m, 2H), 1.31-1.27 (m, 2H), 1.03-0.87 (m, 12H).

[0432] The synthesis method of compound A101 is the same as that of compound A51.

Example 102

[0433] ##STR00225##

[0434] .sup.1H NMR (400 MHz, CD3OD) δ 8.08 (d, J=7.8 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.64 (d, J=1.4 Hz, 1H), 7.50-7.41 (m, 2H), 7.34 (dd, J=8.3, 1.5 Hz, 1H), 7.29-7.21 (m, 1H), 5.13-5.01 (m, 2H), 4.67-4.60 (m, 1H), 2.68 (t, J=7.6 Hz, 1H), 1.80-1.66 (m, 2H), 1.67-1.56 (m, 2H), 1.32-1.28 (m, 2H), 1.02-0.85 (m, 12H).

[0435] The synthesis method of compound A102 is the same as that of compound A51.

Example 103

[0436] ##STR00226##

[0437] .sup.1H NMR (400 MHz, CD3OD) δ 8.07-8.04 (m, 2H), 7.45-7.38 (m, 2H), 7.27-7.16 (m, 2H), 7.00-6.94 (m, 1H), 5.06 (q, J=17.2 Hz, 2H), 4.67-4.63 (m, 1H), 2.67 (t, J=7.6 Hz, 1H), 1.82-1.55 (m, 4H), 1.34-1.28 (m, 2H), 1.01-0.84 (m, 12H).

[0438] The synthesis method of compound A103 is the same as that of compound A51.

Example 104

[0439] ##STR00227##

[0440] .sup.1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=4.7 Hz, 1H), 8.32 (d, J=7.8 Hz, 1H), 7.97-7.89 (m, 1H), 7.62-7.44 (m, 3H), 7.34 (t, J=7.4 Hz, 1H), 5.23-5.06 (m, 2H), 4.72-4.60 (m, 1H), 2.67 (t, J=7.6 Hz, 1H), 1.81-1.55 (m, 4H), 1.29 (t, J=7.3 Hz, 2H), 1.00-0.83 (m, 12H).

[0441] The synthesis method of compound A104 is the same as that of compound A51.

Example 105

[0442] ##STR00228##

[0443] .sup.1H NMR (400 MHz, CD3OD) δ 7.96 (t, J=8.1 Hz, 2H), 7.49 (d, J=7.3 Hz, 2H), 7.42-7.29 (m, 5H), 7.18 (t, J=7.2 Hz, 1H), 7.06 (d, J=2.1 Hz, 1H), 6.92 (dd, J=8.5, 2.1 Hz, 1H), 5.21-5.13 (m, 2H), 5.09-4.97 (m, 2H), 4.66-4.62 (m, 1H), 2.66 (t, J=7.6 Hz, 1H), 1.76-1.51 (m, 4H), 1.35-1.26 (m, 2H), 0.95-0.85 (m, 12H).

[0444] The synthesis method of compound A105 is the same as that of compound A51.

Example 106

[0445] ##STR00229##

[0446] .sup.1H NMR (400 MHz, CD3OD) δ 7.94 (d, J=7.7 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.36-7.29 (m, 2H), 7.20-7.11 (m, 1H), 6.80-6.70 (m, 2H), 5.06-4.91 (m, 2H), 4.69-4.64 (m, 1H), 2.68 (t, J=7.6 Hz, 1H), 1.77-1.50 (m, 4H), 1.31-1.24 (m, 2H), 1.00-0.85 (m, 12H).

[0447] The synthesis method of compound A106 is the same as that of compound A51.

Example 107

[0448] ##STR00230##

[0449] .sup.1H NMR (400 MHz, CD3OD) δ 8.56 (dd, J=7.7, 1.4 Hz, 2H), 8.49 (dd, J=5.0, 1.4 Hz, 2H), 7.36 (dd, J=7.7, 5.0 Hz, 2H), 5.39-5.25 (m, 2H), 4.63 (dd, J=9.4, 5.4 Hz, 1H), 2.67 (t, J=7.2 Hz, 1H), 1.85-1.61 (m, 4H), 1.15 (t, J=7.2 Hz, 3H), 1.00-0.86 (m, 12H).

[0450] The synthesis method of compound A107 is the same as that of compound A51.

Effect Example 1: Anti-Cancer Activity Test of the Compound of the Present Disclosure

[0451] Experimental Method:

[0452] 1. Cell Culture Method.

[0453] Cell culture medium: Roswell medium RPMI-1640 (+L-glutamine) was added with 10% fetal bovine serum, with 100 units penicillin and 100 μg streptomycin per ml.

[0454] Cell culture conditions: 5% CO.sub.2, 95% humidity, cultured at 37° C. constant temperature.

[0455] 2. Cell Inoculation, Drugs Dosing and Culture.

[0456] Logarithmic growth phase HL-60, human chronic myeloid leukemia cells (K562), human esophageal squamous cell carcinoma cells (KYSE510), human large cell lung cancer cells (H460) were inoculated into 96-well cell culture plates, 2×10.sup.4 cells per well. Different concentrations of active compounds (dissolved in dimethyl sulfoxide (DMSO) stock solution) were added, so that the final concentration of DMSO was 0.2%, and the control group was DMSO. Each group was repeated three times.

[0457] 3. Mtt Experiment.

[0458] After culturing for 72 hours, 20 L of thiazolyl blue (MTT) (5 mg/ml, ready for use, dissolved in 1 xPBS for cell culture) was added to each well, and incubated at 37° C. for 3 hours.

[0459] The 96-well cell culture plates were centrifuged at 1000 rpm for 10 minutes. The supermatant was discarded; 200 aL of DMSO was added to each well and the plate was shaken for 5 minutes.

[0460] The absorbance of each well was detected at 570 nm wavelength with a microplate reader, and the IC50 of the compounds was calculated.

TABLE-US-00003 TABLE 1 The IC50 value of the compound of the present disclosure on the inhibition of HL60 cells. Compound No. HL60/IC50 A1 A A2 A A3 C A4 A A5 A A6 A A7 A A8 A A9 B A10 A A11 B A12 A A13 A A14 A A15 A A16 A A17 A A18 A A19 B A20 A A21 A A22 B A23 B A24 A A25 A A26 C A27 A A28 C A29 A A30 A A31 A A32 A A33 C A34 B A35 B A36 A A37 A A38 B A39 C A40 C A41 C A42 A A43 A A44 A A45 A A46 B A47 A A48 A A49 D A50 D A51 A A52 A A53 D A54 D A55 C A56 C A57 C A58 B A59 C A60 C A61 B A62 B A63 B A64 C A65 A A66 A A67 A A68 B A69 A A70 A A71 A A72 C A73 A A74 A A75 A A76 A A77 A A78 A A79 B A80 A A81 B A82 D A83 D A84 A A85 B A86 A A87 A A88 A A89 B A90 D A91 D A92 B A93 C A94 C A95 C A96 B A97 C A98 C A99 B A100 C A101 B A102 B A103 C A104 B A105 B A106 B A107 C

[0461] Note: A represents that the IC50 of the compound is below 100 nM, B represents that the IC50 of the compound is 100˜500 nM, C represents that the IC50 of the compound is 500 nM˜2 aM, and D represents the IC50 of the compound is 2˜10 μM.

[0462] The experimental results of Tables 1, 2 shows that the compound of the present disclosure has excellent inhibitory effects on HL60, K562, KYSE510, and H460 cells, and can be used for cancer prevention and treatment.

TABLE-US-00004 TABLE 2 The IC50 value of the compound of the present disclosure on the inhibition of other c-Myc high-expressing cells. Compound No. K562/IC50 KYSE510/IC50 H460/IC50 A10 A A A A67 A A A A69 A A A

[0463] Note: A represents that the IC50 of the compound is below 100 nM.

Effect Example 2: Test of the Binding Affinity Effect of the Compound of the Present Disclosure on C-Myc Protein

[0464] 1. Experiment Preparation

[0465] 10×PBS-P was diluted into 1.05×PBS-P buffer solution for later use. The c-Myc370-412-biotin peptide was dissolved in chromatographic pure DMSO to prepare a 1 mM stock solution. The molecules were dissolved in chromatographic pure DMSO to prepare a 10 mM stock solution. Part of 1.05×PBS-P buffer was added to chromatographic pure DMSO to prepare 1.00×PBS-P buffer (5% DMSO, ready for use).

[0466] The highest solubility of each small molecule in the 1.00×PBS-P buffer (5% DMSO) system was tested respectively. This solubility was used as the highest concentration tested for small molecule activity.

[0467] 2. Protein Immobilization

[0468] The c-Myc370-412-biotin peptide stock solution was added to 1.05×PBS-P buffer to prepare a 50 μM solution, and then diluted with 1.00×PBS-P buffer (5% DMSO) to 1 g/ml for protein immobilization.

[0469] After washing the sample channel and reference channel of the chip with 1.00×PBS-P buffer (5% DMSO), an automatic mode was used to immobilize the protein in the sample channel. The target amount of the immobilized protein was 500RU. The immobilization was successful. The buffer was used continuously to flush until equilibrium.

[0470] 3. Small Molecule Activity Test.

[0471] Buffer was used to prepare different concentrations of small molecule compounds for sample testing. The system was 1.00×PBS-P buffer (5% DMSO). The difference was detected between the response of small molecules flowing through the sample channel and the reference channel.

[0472] The experimental conditions were a flow rate of 30 μL/min, binding time of 120 seconds, and dissociation time of 240 seconds. After each binding and dissociation test, 50% DMSO was used to flush the tubing, and 10 mM glycine-HCl buffer (pH 2.1) was used to flush the surface of the chip to wash away the remaining compound molecules.

TABLE-US-00005 TABLE 2 Determination of the binding constant of the compound of the present disclosure on the c-Myc protein. Compound No. SPR Kd A2 B A3 B A4 A A5 B A6 A A7 A

[0473] Note: A represents that the Kd of the compound is below 100 nM, B represents that the Kd of the compound is 100˜500 nM

[0474] The content of the present disclosure only exemplifies some specific implementations as claimed, in which the technical features recorded in one or more technical solutions can be combined with any one or more technical solutions, and these technical solutions obtained by combination are also within the protection scope of the present application, just as these combined technical solutions have been specifically recorded in the present disclosure.