The present invention relates to a cyclic peptide compound, and a preparation method, pharmaceutical composition and use thereof. In particular, the cyclic peptide compound of the present invention has a structure as shown by general formula (I). The compound of general formula (I), and isomers, racemates, pharmaceutically acceptable salts, crystalline hydrates, solvates or mixtures thereof have a use in the preparation of medicaments for preventing or treating mammalian diseases associated with histone deacetylase dysregulations. [structure]

Description

95 parts

›TECHNICAL FIELD

The present invention relates to the field of medicinal chemistry and chemotherapy domain. More specifically, the present invention relates to a compound with a chemical structure shown as formula (I), its preparation, pharmaceutical compositions and applications of in preparing pharmaceuticals for preventing or treating mammalian diseases related to the dysregulation of histone deacetylase, especially cancer, neurodegenerative diseases, malaria and diabetes, etc.

›BACKGROUND TECHNOLOGY

Histone deacetylase HDAC (histone) is a kind of protease, which plays an important role in the structural modification and regulation of gene expression. Under normal circumstances, the acetylation of histone is suitable for DNA and histone octamer dissociated, nucleosome structure relaxation, so that a variety of transcription factors and synergistic transcription factors to DNA binding site specificity combined activation of gene transcription. In the nucleus, histone acetylation and histone to acetylation process is in a dynamic balance, and the histone acetyl transfer enzymes (histone acetyltransferase, hat) and histone deacetylases (histone deacetylase, HDAC) common regulation.

Histone acetylation modification plays an important role in the occurrence and development of tumor. In the normal cell body, once there is an imbalance between the acetylation of histone and histone acetylation, which'd leads to the change of normal cell cycle and cell metabolism behavior and induce tumors accordingly. Histone to acetylation enzyme catalyzed by histone deacetylation, maintain histone acetylation and de acetylation state of equilibrium, many processes and cancer related gene expression, cell proliferation, differentiation and apoptosis is closely related. In cancer cells, HDAC overexpression leads to the enhancement of acetylation and histone through a return to positive charge, thereby increasing the gravitational force between DNA and histone, the relaxation of the nucleosome becomes very closely, is not conducive to the specific gene expression, including several tumor suppressor genes.

With the further development of life science, molecular biology research on the pathogenesis and mechanism of tumor has provided the basis for the development of anti-tumor drugs with low toxicity and high efficiency. Histone deacetylases (HDACs) is one of the key enzymes for the maintenance of chromosomal basic composition unit of the nucleosome organization protein acetylation balance, the catalyzed by histone acetylation, and transcriptional repressor of genes that are closely related, involved in promoting gene silencing of many processes is a hot target for anticancer drug design. Histone deacetylase inhibitors (HDACi) can increase acetylation of protein in a specific region of chromatin histone acetylation, thereby regulating the expression and stability of apoptosis and differentiation-related protein, induction of apoptosis and differentiation, become a new class of anticancer drugs. HDACi not only have a good therapeutic effect against a variety of hematological malignancies and solid tumors, but also has a relatively high selectivity and low toxicity advantages of tumor cells.

›SUMMARY OF THE INVENTION · 1 of 2

One aspect of the invention is to provide a cyclic peptide compound with a chemical structure shown as formula (I) and its isomer, racemic body, pharmacy acceptable salt, crystalline hydrate, solvents or their mixtures.

Another aspect of the present invention is to provide processes for preparing formula (I).

Another aspect of the invention is to provide a pharmaceutical composition comprised a therapeutically effective amount of a compound selected from the compound of formula (I), its isomers, racemates, pharmaceutically acceptable salts, crystalline hydrate, solvate or their mixture, and one or more pharmaceutically acceptable carrier.

Another aspect of the invention provides applications of the compound of Formula (I), its isomers, racemates, pharmaceutically acceptable salts, crystalline hydrate, solvate or their mixture in preparing pharmaceuticals for preventing or treating mammalian diseases related to the dysregulation of histone deacetylase.

According to one aspect of the invention, it provides a cyclic peptide compound with a chemical structure shown as formula (I), its isomer, racemic body, pharmacy acceptable salt, crystalline hydrate, solvents or their mixtures:

Wherein: R 1 is hydrogen, C 1-16 alkyl, C 3-16 cycloalkyl, —(C═O)—(C 1-16 alkyl), —(C═S)—(C 1-16 alkyl) or —S—(C 1-16 alkyl);

R 2 is hydrogen, C 1-12 alkyl, —CH 2 —O—(C 1-12 alkyl), —CH 2 —NH—(C 1-12 alkyl), —CH 2 —S—(C 1-12 alkyl), C 6-12 aryl, heteroaryl, —CH 2 —(C 6-12 aryl)-CH 2 — or heteroaryl; wherein the C 6-12 aryl, heteroaryl, —CH 2 —C 6-12 aryl, —CH 2 -heteroaryl, can contain one or more substituents, the substituents can be halo, amino, hydroxy, nitro, cyano, C 1-12 alkyl, C 1-12 alkoxy, amino C 1-12 alkyl, acyl, acyloxy, thio C 1-12 alkyl, phenyl or carboxyl;

R 3 , R 4 are each independently selected from hydrogen, C 1-12 alkyl, —O—(C 1-12 alkyl), —NH—(C 1-12 alkyl), —S—(C 1-12 alkyl), C 6-12 aryl and heteroaryl;

One of X and Y is C, and the other is N, or both X and Y are N;

R 5 , R 6 , R 7 are independently selected from hydrogen, halo, —S—(C 1-12 alkyl), C 1-12 alkyl or t-butoxycarbonyl;

Z is —CH 2 —, —NH—, —O—, —S— or

M is 0, 1, 2, 3, 4, 5 or 6.

In the preferred embodiment,

R 1 are hydrogen, C 1-16 alkyl, C 3-16 cycloalkyl, —(C═O)—(C 1-16 alkyl), —(C═S)—(C 1-16 alkyl) or —S—(C 1-16 alkyl);

R 2 is hydrogen, C 1-12 alkyl, —CH2-O—(C 1-12 -alkyl), —CH 2 —NH—(C 1-12 alkyl), —CH 2 —S—(C 1-12 alkyl), C 6-12 aryl, heteroaryl, —CH 2 —(C 6-12 aryl)-CH 2 — or heteroaryl;

R 3 , R 4 are each independently selected from hydrogen, C 1-12 alkyl, —O—(C 1-12 alkyl), —NH—(C 1-12 alkyl), —S—(C 1-12 alkyl), C 6-12 aryl and heteroaryl;

One of X and Y is C, and the other is N, or both X and Y is N;

R 5 , R 6 , R 7 are independently selected from hydrogen, halo, —S—(C 1-12 alkyl), C 1-12 alkyl and t-butoxycarbonyl;

Z is —O—, —S— or

m is 0, 1 or 2.

In the further preferred embodiments,

R 1 is hydrogen or C 1-16 alkyl;

R 2 is hydrogen, C 1-12 alkyl, or C 6-12 aryl;

R 3 , R 4 groups are each independently selected from hydrogen, C 1-12 alkyl, —O—(C 1-12 alkyl), —NH—(C 1-12 alkyl), —S—(C 1-12 alkyl), C 6-12 aryl and heteroaryl;

X is N;

Y is C;

R 5 , R 6 , R 7 are independently selected from hydrogen, F, —S—(C1-12 alkyl);

Z is —S— or

m is 0, 1 or 2.

In a more preferred embodiment of the invention, the compound of Formula (I) is particularly preferred compound as follows:

The present invention also provides a method of preparing compound of Formula (I), comprising the following steps:

(1) The compound of Formula (II) with alkali affords the compound of Formula (III) via hydrolysis reaction; the reaction process is shown as follows:

(2) Compound of Formula (III) and compound of Formula (IV) with organic alkali under condensation agent affords compound of Formula (V) compound; the reaction process is shown as follows:

(3) The compound of Formula (V) and MsCl with organic alkali affords the compound of Formula (VI) via condensation reaction; the reaction process is shown as follows:

(4) The compound of Formula (VI) affords the compound of Formula (VII) via elimination reaction; the reaction process is shown as follows:

(5) The compound of Formula (VII) with alkali affords the compound of Formula (VIII) via hydrolysis reaction; the reaction process is shown as follows:

(6) Compound of Formula (VIII) and compound of Formula (IX) with organic alkali under condensation agent affords the compound of Formula (X) via condensation reaction; the reaction process is shown as follows:

(7) Remove the amino protecting group P and carboxyl protecting group Q of the compound of Formula (X), and then under condensation agent with organic alkali affords the compound of Formula (XI) via the intramolecular closed loop reaction; the reaction procedure is shown as follows:

(8) To remove protecting group T of the compound of Formula (XI), the compound of Formula (XII) was obtained; the reaction procedure is shown as follows:

(9) The compound of Formula (XII) and compound R 1 -L affords the compound of Formula (XIII); the reaction procedure is shown as follows:

Wherein, the definition of R 1 ˜R 7 , X, Y, Z, m are the same as above;

P is an amino protecting group;

Q is a carboxyl protecting group;

T is O, S, NH heteroatom protecting group;

L is selected from halo, OH, OMs, SH, MeO, t-butO.

Further,

The organic alkalis in the step (2), (3), (6) and (7) are selected from imidazole, triethylamine, diisopropylethylamine, piperidine, dimethyl pyridine, LiHMDS, NaHMDS, khmds, N-methyl morpholine, DABCO or pyridine;

The condensing agents in the step (2), (6) are selected from DCC, EDC, HATU, HOAt, HOBt, DEAD, HBTU or PyBOP;

The amino protecting P is selected from Boc, Cbz, Bn, Fmoc, Alloc, Tos, Trt, or Bn;

The carboxyl protecting Q is selected from TMSOH, tertiary-butyl, ethyl, methyl.

The synthesis process described above, the organic solvent used may be selected from dichloromethane, tetrahydrofuran (THF), dimethylformamide (DMF), ethylene glycol dimethyl ether, 1,2-dichloroethane, dimethyl phthalate (DMP), methanol, ethanol, petroleum ether, hexane or diethyl ether; necessary inorganic alkali can selected from sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, calcium carbonate; necessary acid may be selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid or nitric acid. The oxidant may be Dess-Martin oxidant, Swern oxidizing agent, m-chloroperbenzoic acid, chlorine pyridinium dichromate (PDC) or pyridinium chlorochromate (PCC).

›SUMMARY OF THE INVENTION · 2 of 2

Further, the present invention provides applications of the compound of formula (I), its isomers, racemates, pharmaceutically acceptable salts, crystalline hydrate, solvate or a mixture thereof in preparing pharmaceuticals for preventing or treating mammalian diseases related to the dysregulation of histone deacetylase. The mammalian diseases related to the dysregulation of histone deacetylase include cancer, neurodegenerative diseases, malaria and AIDS, and more particularly include lymphoma, lung cancer, stomach cancer, pancreatic cancer, breast cancer, prostate cancer, leukemia and cervical cancer.

The present invention also provides a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I), its isomers, racemates, pharmaceutically acceptable salts, crystalline hydrate, solvate or their mixture, and one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable salts include non-toxic salts with inorganic or organic acids formed by the reaction, the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and amine, the organic acids include propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid.

The compound and the pharmaceutical composition provided by the invention can be in a variety of forms, such as tablet, capsule, powder, syrup, like solution, suspending liquid and aerosol agent, and can be present in the suitable solid or liquid carrier or diluent and suitable for injection or infusion of fire toxic instruments in.

It should be explained that the terms used in this paper, such as “alkyl”, “aryl”, “miscellaneous aryl group”, “halogen”, “acyl” and so on, are not significantly different from the general meaning of the term in the field.

For example, the term “alkyl” refers to the straight or branched chain, C1˜n alkyl said 1˜n carbon atoms of saturated aliphatic group, include straight chain and branched one, for example “C1 to C12 alkyl” refers to is the group is alkyl and alkyl carbon chain of carbon atoms number in 1˜12 between. It should be stated that, when there is no special restriction on the number of carbon atoms, only the number of carbon atoms in the alkyl moiety is specified, and the number of substituents on the alkyl group is not included.

The general technical personnel in the field shall know the meaning of the following terms or abbreviations.

The term “pharmaceutically acceptable salt” refers to that which applies to mammals, especially human contact with the tissues without undue toxicity, irritation, allergic response, and with a reasonable benefit/risk ratio of salt within reasonable medical judgment. For example, medical amines, carboxylic acids, and other types of compounds acceptable salts in the art is well known.

The term “isomer” refers to two or more compounds with the same molecular structure, but with different structures and properties.

The term “racemate” refers to a equimolar mixture having its optically active enantiomers of chiral molecules, which is opposite to the direction of rotation, optical rotatory power mixing equal amounts of the same molecule, these molecules due to its optical rotation the role of the inter offset each other, so it is optically inactive.

The term “solvate” refers to a mixture of compound and solvent composition, i.e., e.g., a crystalline solvate.

The material corresponding to the English abbreviations used in the statement of claim or statement are:

DCC (N,N′-dicyclohexylcarbodiimide, Cas No.: 538-75-0), EDCI [1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, Cas No.: 25952-53-8], HATU (Cas No.: 148893-10-1), HOAt (Cas No.: 39968-33-7), HOBt (1-hydroxy-benzo-triazole, Cas No.: 2592-95-2), DEAD (diethyl azodicarboxylate, Cas No.: 1972-28-7), HBTU (Cas No.: 94790-37-1), PyBOP (hexafluorophosphate benzotriazol-1-yl-yloxy tripyrrolidinophosphonium phosphorus, Cas No.: 132705-51-2), DIPEA (N,N-diisopropylethylamine, CAS: 7087-68-5); LiHMDS [bis (trimethylsilyl) amide], NaHMDS (sodium hexamethyldisilazide amino), KHMDS (potassium hexamethyldisilazide amine), DABCO (1,4-diazepine bicyclo [2.2.2] octane); Boc (tert-butoxycarbonyl), Cbz (benzyloxycarbonyl), Bn (benzyl), Fmoc (Fluorenylmethoxycarbonyl), Alloc (propoxycarbonyl), Tos (tosyl), Tfa (trifluoroacetyl) or Trt (trityl), OMs (methylsulfonyl oxy), MeO (oxymethyl), t-butO (tert-butoxy).

›EXAMPLES

The following examples will further illustrate the present invention. These examples are intended to illustrate the present invention but not in any way limit the present invention only.

The present invention is used in the starting reactant unless otherwise specified, are commercially available

It should be noted that in the following examples, the conventional post-processing method is: After completion of the reaction, adding an appropriate amount of water in the reaction mixture to separate the organic and aqueous phases, and combine organic phase; if necessary, followed by the use of 5% HCl solution and/or saturated NaSO4 dried, filtered under reduced pressure after the election anhydrousness to give the crude product, after column chromatography purification of the final product.

›Examples90

›Example 1 · 1 of 2

1.1

15 ml LiOH aqueous solution (456 mg, 19 mmol) were added dropwise to the reactant (2 g, 7.6 mmol) of 30 ml THF, then reacted for 2 h at room temperature. The reaction solution was adjusted by dilute hydrochloric acid to with the pH value of 3, then 100 ml ethyl acetate was added. The organic matter was washed by water and saturated salt water. The organic layer was dried by anhydrous sodium sulfate, and the solvent evaporated to give a 1.86 g white flocculent solid, and the yield was 97%.

1.2

At 0° C., DIPEA (1.2 ml, 6 mmol) was added slowly to the reactant (0.7 g, 2.7 mmol), stirred slightly, then added S2 (456 mg, 2.7 mmol), PyBop (2.5 g, 4 mmol), and then stirred at room temperature overnight. The reaction solution was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution. The product was dried with anhydrous sodium sulfate and spinned solvent by column chromatography and 0.7 g white floc was obtained, and the yield was 75%. 1 H NMR (400 MHz, CDCl 3 ): δ 8.64 (d, J=8.4 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.81 (t, J=8 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 5.44 (s, 1H), 4.77 (d, J=7.2 Hz, 1H), 4.48-4.45 (m, J=3H), 3.78 (s, 3H), 1.45 (s, 9H), 1.26 (d, J=5.6 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 171.1, 164.6, 157.4, 156.0, 148.9, 137.9, 134.6, 124.2, 121.8, 121.0, 80.7, 79.8, 78.7, 70.3, 68.2, 61.1, 57.8, 52.7, 52.2, 47.7, 32.1, 28.3, 28.2, 28.1, 28.0, 22.6, 19.8 ppm.

1.3

At 0° C., DMAP (25 mg, 0.184 mmol), NEt 3 (0.42 ml, 3 mmol), MsCl (0.186 ml, 2.4 mmol) was added to the reactants (675 mg, 1.84 mmol) in anhydrous DCM (10 ml) successively, then raised to room temperature and stirred overnight. The product was spinned anhydrous, pumped with oil pump and directly put into next step.

1.4

DABOCO (1 g, 9.22 mmol) was added to the anhydrous DCM liquid (10 ml) obtained above and stirred 8 h at room temperature. The reaction solution was washed by saturated sodium bicarbonate solution, saturated ammonium chloride solution, saturated sodium chloride solution in sequence, and dried by anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and 500 mg white floc was obtained, and the yield was 76%. 1 H NMR (400 MHz, CDCl 3 ): δ 9.38 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.78 (t, J=8 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 6.86 (q, J=7.6 Hz, 1H), 5.57 (s, 1H), 4.44 (d, J=5.6 Hz, 2H), 3.74 (s, 9H), 1.80 (d, J=7.6 Hz, 3H), 1.40 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 164.8, 162.1, 157.4, 156.0, 148.9, 148.8, 138.1, 133.9, 126.3, 124.2, 121.7, 121.0, 79.7, 52.1, 45.9, 28.3, 14.6 ppm.

1.5

5 ml LiOH aqueous solution (90 mg, 3.6 mmol) were added dropwise to reactants (500 mg, 1.44 mmol) with THF (10 ml), then spinned anhydrous the organic phase after three hours. 10 ml water and 15 ml ethyl acetate were added to the organic phase. The aqueous phase was removed after liquid separation. Then the solution was added 15 ml ethyl acetate, adjusted the acid. Anhydrous sodium sulfate was used for the separation of organic phase after liquid separation. 453 mg solid white floc was obtained after spinned anhydrous. The yield was 94%. 1 H NMR (400 MHz, CDCl 3 ): δ 9.40 (s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.80 (t, J=8.2 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 6.88 (q, J=7.8 Hz, 1H), 5.58 (s, 1H), 4.46 (d, J=5.8 Hz, 2H), 3.76 (s, 9H), 1.83 (d, J=7.8 Hz, 3H), 1.43 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 165.3, 162.7, 157.8, 156.2, 149.0, 148.8, 138.3, 133.7, 126.5, 124.5, 121.9, 121.0, 52.5, 46.3, 28.5, 14.8 ppm.

1.6

At 0° C., DIPEA (0.7 ml), carboxylic acid (610 mg), HATU (760 mg), HOAT (326 mg) were sequentially added to the reactant (336 mg, 1 mmol) in DCM solution (10 ml). Then raised to room temperature with stirring. After 8 h, the reaction was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and 750 mg white flocculent solid was obtained, and the yield was 92%. 1 H NMR (400 MHz, CDCl 3 ): δ 9.41 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.39-7.17 (m, 12H), 6.66-6.61 (m, 2H), 5.68-5.59 (m, 2H), 5.46 (s, 1H), 5.38-5.32 (m, 1H), 4.59 (dd, J=8.8 Hz, 4 Hz, 1H), 4.49 (d, J=4.2 Hz, 2H), 4.15-4.10 (m, 3H), 2.66 (dd, J=15.6 Hz, 7.6 Hz, 1H), 2.52 (dd, J=15.6 Hz, 5.6 Hz, 1H), 2.18-2.14 (m, 3H), 2.04 (t, J=6.8 Hz, 4H), 1.82 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 1.25 (t, J=6.8 Hz, 2H), 0.97-0.90 (m, 5H), 0.80 (d, J=6.8 Hz, 3H), 0.02 (s, 9H) ppm. 13 C NMR (125 MHz, CDCl3) δ 171.0, 170.7, 169.5, 164.3, 162.6, 157.3, 155.9, 148.5, 144.7, 138.2, 133.9, 129.6, 129.4, 129.0, 127.7, 127.6, 126.5, 124.6, 121.1, 79.7, 71.8, 66.5, 63.0, 60.3, 57.0, 45.6, 39.5, 31.5, 31.2, 31.0, 28.3, 20.9, 18.8, 17.5, 17.2, 14.1, 13.8, 0.9, −1.5, −1.6 ppm.

1.7

Tetrabutylammonium fluoride in tetrahydrofuran solution (1 mol/l, 2.3 ml) was added to the reaction (750 mg, 0.92 mmol) in redistilled THF (5 ml). After 3 h, the reaction was immediately spinned anhydrous by column chromatography to obtain a white solid.

Trifluoroacetic acid (6 ml) was added to DCM solution (25 ml) of the resulting resultant of the last step. After 5 h, spinned and removed DCM, the residue was added toluene (8 ml). Without further treatment, a brown viscous material was obtained after pumped organic solvent with oil pump. Chromatography pure acetonitrile (200 ml) obtained above was dissolved, slowly dropped in HATU (3 g), DIPEA (4 ml) of HPLC grade acetonitrile (550 ml). After 24 h, spinned anhydrous solvents, the product was diluted with ethyl acetate (20 ml) and then washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and 540 mg pale yellow solid was obtained. The yield was 82%. 1 H NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.37-7.16 (m, 15H), 7.07 (q, J=7.2 Hz, 1H), 6.67 (d, J=4.4 Hz, 1H), 6.43 (d, J=10.4 Hz, 1H), 5.62-5.56 (m, 2H), 5.39-5.34 (m, 1H), 5.06 (dd, J=17.2 Hz, 8 Hz, 1H), 4.74 (dd, J=6.4 Hz, 3.6 Hz, 1H), 4.19-4.08 (m, 2H), 2.69-2.64 (m, 2H), 2.30-2.27 (m, 1H), 2.21-2.17 (m, 2H), 1.84 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz, 3H) ppm. 13C NMR (125 MHz, DMSO) δ 133.6, 132.0, 131.3, 126.1, 124.7, 118.4, 111.1, 107.1, 101.0, 97.3, 95.2, 92.0, 90.4, 90.3, 89.5, 89.1, 87.5, 83.8, 39.8, 39.5, 39.3, 34.1, 29.1, 22.9, 19.5 ppm.

›Example 1 · 2 of 2

1.8

At 0° C., TES (0.1 ml), TFA (0.65 ml) were sequentially added to the reactants (150 mg, 0.21 mmol) in anhydrous DCM solution (5 ml). 15 min later, the product was directly spinned anhydrous solvent by column chromatography and 63 mg pale yellow solid was obtained, and the yield was 63%. [α] 20 D: 6.13 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 8.18 (d, J=7.6 Hz, 1H), 7.89 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.06 (dd, J=14.4 Hz J=7.2 Hz, 1H), 6.58 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.45 (d, J=8 Hz, 1H), 5.74-5.64 (m, 2H), 5.50 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.10 (m, 1H), 4.74 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.34-4.28 (m, 1H), 2.74-2.69 (m, 2H), 2.56-2.50 (m, 2H), 2.34-2.29 (m, 3H), 1.36 (t, J=7.6 Hz, 1H), 0.80 (d, J=6.8 Hz, 3H), 0.6 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl3) δ 169.6, 168.9, 163.6, 162.9, 155.7, 148.6, 138.3, 134.7, 132.4, 128.6, 127.0, 124.9, 121.4, 71.9, 56.9, 43.3, 41.0, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 2

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (60 mg, 0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then caprylate chloride (0.1 ml) was added. After 7 h, The product was directly spinned anhydrous solvent by column chromatography and 60 mg pale yellow solid was obtained, and the yield was 80%. [α] 20 D: 3.71 (c 0.5, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.21 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.91 (t, J=7.6 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 3

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then heptanoyl chloride (0.05 ml) was added. After 7 h, The product was directly spinned anhydrous solvent by column chromatography and 31 mg pale yellow solid was obtained, and the yield was 83%. [α] 20 D: 4.11 (c 0.7, CHCl 3 ). 1H NMR (400 MHz, CDCl 3 ): δ 9.23 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.93 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.08 (m, J=7.2 Hz, 1H), 6.73 (d, J=4.4 Hz, 1H), 6.48 (d, J=10 Hz, 1H), 5.72-5.63 (m, 2H), 5.62-5.45 (m, 1H), 5.15 (dd, J=17.2 Hz, 8 Hz, 1H), 4.75-4.71 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.86-2.71 (m, 4H), 2.63-2.62 (m, 1H), 2.50 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.85-1.82 (m, 3H), 1.62-1.59 (m, 2H), 1.26-1.24 (m, 9H), 0.85 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.5, 169.0, 163.5, 162.1, 155.7, 148.8, 138.6, 134.5, 132.6, 132.1, 130.9, 128.9, 128.5, 127.5, 125.1, 121.3, 72.2, 71.7, 57.3, 44.1, 43.2, 40.9, 38.6, 33.8, 32.2, 31.5, 30.9, 29.7, 29.1, 28.8, 27.7, 27.6, 25.5, 22.5, 19.1, 18.9, 16.4, 14.6, 14.0 ppm.

›Example 4

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then hexanoyl chloride (0.04 ml) was added. After 7 h, The product was directly spinned anhydrous solvent by column chromatography and 32 mg pale yellow solid was obtained, and the yield was 85%. [α] 20 D: 3.11 (c 0.3, CHCl 3 ). 1H NMR (400 MHz, CDCl 3 ): δ 9.22 (s, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.95 (t, J=7.6 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.46 (d, J=10.0 Hz, 1H), 5.74-5.68 (m, 2H), 5.50 (m, 1H), 5.17 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.76-4.73 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.88-2.75 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.84-1.82 (m, 3H), 1.63-1.60 (m, 2H), 1.26-1.24 (m, 7H), 0.84 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.59 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl3) δ 169.3, 169.0, 163.2, 162.0, 155.6, 148.9, 138.8, 134.8, 132.7, 132.0, 130.9, 128.9, 128.6, 127.7, 125.3, 121.5, 72.3, 71.8, 57.5, 44.3, 43.4, 41.2, 38.9, 33.9, 32.5, 31.7, 30.9, 29.8, 29.2, 28.9, 27.8, 27.6, 25.6, 22.6, 19.0, 16.5, 14.7, 13.9 ppm.

›Example 5

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, thenpivaloyl chloride (0.04 ml) was added. After 7 h, The product was directly spinned anhydrous solvent by column chromatography and 30 mg pale yellow solid was obtained, and the yield was 84%. [α] 20 D: 3.31 (c 0.6, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.20 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.96 (t, J=7.6 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.73 (d, J=4.4 Hz, 1H), 6.49 (d, J=10.0 Hz, 1H), 5.73-5.69 (m, 2H), 5.51 (m, 1H), 5.15 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.75-4.73 (m, 2H), 4.29 (d, J=17.2 Hz, 1H), 2.89-2.75 (m, 4H), 2.62 (m, 1H), 2.47 (t, J=7.8 Hz, 3H), 2.31-2.26 (m, 3H), 1.85-1.83 (m, 3H), 1.62-1.60 (m, 2H), 1.25-1.23 (m, 5H), 0.83 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl3) δ 169.2, 169.0, 163.3, 162.2, 155.7, 148.7, 138.9, 134.5, 132.8, 132.1, 130.8, 128.9, 128.5, 127.6, 125.2, 121.3, 72.1, 71.6, 57.8, 44.2, 43.5, 41.3, 38.8, 33.8, 32.6, 31.6, 30.8, 29.9, 29.3, 28.8, 27.6, 25.7, 22.7, 19.1, 16.6, 14.9, 13.8 ppm.

›Example 6

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then butyryl chloride (0.05 ml) was added. After 7 h, The product was directly spinned anhydrous solvent by column chromatography and 29 mg pale yellow solid was obtained, and the yield was 86%. [α] 20D : 6.51 (c 0.5, CHCl 3 ). 1H NMR (400 MHz, CDCl 3 ): δ 9.23 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.98 (t, J=7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.76-5.71 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77-4.74 (m, 2H), 4.27 (d, J=17.2 Hz, 1H), 2.88-2.74 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.33-2.28 (m, 3H), 1.86-1.83 (m, 3H), 1.66-1.62 (m, 2H), 1.27-1.24 (m, 3H), 0.86 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.56 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl3) δ 169.4, 169.1, 163.5, 162.3, 155.8, 148.8, 138.9, 134.7, 132.9, 132.3, 130.9, 128.9, 128.4, 127.5, 125.3, 121.5, 72.2, 71.7, 57.6, 44.5, 43.6, 41.4, 38.9, 33.9, 32.7, 31.7, 30.9, 29.9, 29.5, 28.9, 27.7, 25.8, 22.9, 19.3, 15.5, 13.8 ppm.

›Example 7

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, propionyl chloride (0.05 ml) was added. After 7 h, The product was directly spinned anhydrous solvent by column chromatography and 35 mg pale yellow solid was obtained, and the yield was 88%. [α] 20 D: 5.50 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.25 (s, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.99 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H), 6.48 (d, J=10.0 Hz, 1H), 5.75-5.72 (m, 2H), 5.55 (m, 1H), 5.19 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.78-4.75 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.89-2.75 (m, 4H), 2.65 (m, 1H), 2.48 (t, J=7.8 Hz, 3H), 2.35-2.29 (m, 3H), 1.88-1.85 (m, 3H), 1.66 (m, 2H), 0.86 (m, 3H), 0.77 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 169.2, 163.3, 162.2, 155.9, 148.9, 138.8, 134.8, 132.9, 132.2, 130.8, 128.9, 128.5, 127.6, 125.5, 121.6, 72.3, 71.8, 57.8, 44.6, 43.7, 41.5, 38.8, 33.9, 32.8, 31.8, 30.8, 29.9, 29.6, 28.9, 27.8, 25.9, 22.9, 19.5, 14.8 ppm.

›Example 8

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, acetyl chloride (0.05 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and 33 mg pale yellow solid was obtained, and the yield was 85%. [α]20D: 4.66 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.26 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.98 (t, J=7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.79 (d, J=4.4 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.73-5.70 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.88-2.78 (m, 4H), 2.67 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.36-2.33 (m, 3H), 1.89-1.86 (m, 3H), 0.88 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ 169.8, 169.3, 163.5, 162.5, 155.8, 148.8, 138.7, 134.7, 132.8, 132.3, 130.9, 128.8, 128.7, 127.7, 125.6, 121.7, 72.5, 71.9, 57.9, 44.7, 43.9, 41.6, 38.9, 33.8, 32.9, 31.9, 30.9, 29.8, 29.5, 28.8, 27.7, 15.0 ppm.

›Example 9

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, methanesulfonyl chloride (0.02 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and 26 mg pale yellow solid was obtained, and the yield was 75%. [α] 20 D: 1.96 (c 0.1, CHCl3). 1 H NMR (400 MHz, CDCl 3 ): δ 9.63 (s, 1H), 9.23 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.88 (t, J=7.6 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.07 (dd, J=14.4 Hz, J=7.2 Hz, 1H), 6.56 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.48 (d, J=8 Hz, 1H), 5.73 (m, 2H), 5.52 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.12 (m, 1H), 4.76 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.33 (m, 1H), 2.72 (m, 2H), 2.53 (m, 2H), 2.34-2.29 (m, 3H), 1.38 (t, J=7.6 Hz, 1H), 0.82 (d, J=6.8 Hz, 3H), 0.62 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 176.5, 169.8, 169.4, 163.6, 162.6, 155.7, 148.8, 138.5, 134.7, 132.5, 132.3, 130.9, 128.8, 127.8, 125.6, 121.8, 72.5, 71.7, 56.9, 44.8, 43.6, 41.5, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 10

10.1

The Fmoc-L-Pra (0.976 g, 3.00 mmol), EDCI (584 mg, 3.05 mmol) and DMAP (25 mg, 0.203 mmol) was dissolved in anhydrous dichloromethane (15 mL), DIPEA (0.50 mL, 3.05 mmol) and the alcohol (526 mg, 1.02 mmol) was added at 0° C., was stirred for 12 h at room temperature, and added diluted with methylene chloride. The reaction solution was washed with sodium bicarbonate solution (50 mL×3). The organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate, concentrated and the residue was purified by silica gel column chromatography to give a pale yellow solid compound (716 mg, 85%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.77 (d, J=7.6 Hz, 2H), 7.61 (m, 2H), 7.42-7.32 (m 19H), 5.85-5.78 (m, 1H), 5.68 (dd, J=13.6, 7.2 Hz, 1H), 5.55 (dd, J=15.2, 7.2 Hz, 1H), 5.35 (d, J=8.8 Hz, 1H), 4.37 (t, J=6.8 Hz, 2H), 4.28 (dd, J=9.2, 4.4 Hz, 1H), 4.25 (t, J=7.2, 1H), 4.18 (t, J=8.4 Hz, 2H), 2.89 (t, J=7.2 Hz, 2H), 2.73 (dd, J=15.6, 7.6 Hz, 1H), 2.61 (dd, J=15.6, 5.6 Hz, 1H), 2.55 (t, J=7.2 Hz, 2H), 2.28 (dt, J=13.6, 6.8 Hz, 2H), 2.19 (m, 1H), 1.67 (m, 2H), 0.90-0.85 (m, 4H), 0.03 (s, 9H) ppm.

10.2

The reaction (660 mg, 0.80 mmol) was dissolved in acetonitrile (8 mL), diethylamine (0.25 mL, 2.44 mmol) was added and stirred for 2 h, decompressed and removed acetonitrile. The residue was purified by silica gel column chromatography and 463 mg anhydrous oil was obtained. The yield was 96%. 1 H NMR (400 MHz, CDCl3): δ 7.41-7.39 (m, 6H), 7.29-7.24 (m, 6H), 7.21-7.18 (m, 3H), 5.69-5.57 (m, 2H), 5.37 (dd, J=15.4 Hz, 7.4 Hz, 1H), 4.15-4.09 (m, 2H), 3.23 (d, J=4.8 Hz, 1H), 2.65 (dd, J=15.6 Hz, 8.4 Hz, 1H), 2.54 (dd, J=15.6 Hz, 5.2 Hz, 1H), 2.19-2.16 (m, 2H), 2.07-1.98 (m, 2H), 1.97-1.93 (m, 1H), 0.95 (m, 1H), 0.82 (d, J=6.8 Hz, 3H), 0.03 (s, 9H) ppm.

10.3

At 0° C., DIPEA (0.7 ml), the product (610 mg) of Example 1.5, HATU (760 mg), HOAT (326 mg) were added sequentially to the reactant (603 mg, 1 mmol) in DCM solution (10 ml), And raised to room temperature with stirring. After 8 h, the reaction was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and 739 mg white flocculent solid solid was obtained. The yield was 93%. 1 H NMR (400 MHz, CDCl 3 ): δ 9.36 (s, 1H), 8.11 (d, J=7.6 Hz, 1H), 7.85 (t, J=7.6 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.39-7.18 (m, 12H), 6.68-6.63 (m, 2H), 5.66-5.60 (m, 2H), 5.47 (s, 1H), 5.38-5.32 (m, 1H), 4.61 (dd, J=8.8 Hz, 4 Hz, 1H), 4.51 (d, J=4.2 Hz, 2H), 4.16-4.11 (m, 3H), 2.67 (dd, J=15.6 Hz, 7.6 Hz, 1H), 2.53 (dd, J=15.6 Hz, 5.6 Hz, 1H), 2.19-2.15 (m, 3H), 2.05 (t, J=6.8 Hz, 4H), 1.83 (d, J=7.2 Hz, 3H), 1.49 (s, 9H), 1.27 (t, J=6.8 Hz, 2H), 0.95-0.91 (m, 3H), 0.82 (d, J=6.8 Hz, 3H), 0.02 (s, 9H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 171.1, 170.8, 169.6, 164.2, 162.7, 157.4, 155.9, 148.6, 144.7, 138.4, 133.9, 129.7, 129.4, 129.0, 127.6, 126.5, 124.6, 121.1, 79.7, 71.8, 66.5, 63.0, 60.3, 57.0, 45.6, 39.5, 31.5, 31.2, 31.0, 28.3, 20.9, 18.8, 17.5, 17.2, 14.1, 0.9, −1.5, −1.6 ppm.

10.4

Tetrabutylammonium fluoride in tetrahydrofuran solution (1 mol/l, 2.3 ml) was added to the reaction (723 mg, 0.90 mmol) in redistilled THF (5 ml). After 3 h, the reaction was immediately spinned anhydrous by column chromatography to obtain a white solid. DCM solution (25 ml) of the resulting resultant was added trifluoroacetic acid (6 ml). After 5 h, spinned and removed DCM, the residue was added toluene (8 ml). Without further treatment, a brown viscous material was obtained after pumped organic solvent with oil pump. Chromatography pure acetonitrile (200 ml) obtained above was dissolved, slowly dropped in HATU (3 g), DIPEA (4 ml) of HPLC grade acetonitrile (550 ml). After 24 h, spinned anhydrous solvents, the product was diluted with ethyl acetate (20 ml) and then washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and 537 mg pale yellow solid was obtained. The yield was 85%. 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.37-7.16 (m, 15H), 7.07 (q, J=7.2 Hz, 1H), 6.67 (d, J=4.4 Hz, 1H), 6.43 (d, J=10.4 Hz, 1H), 5.62-5.56 (m, 2H), 5.39-5.34 (m, 1H), 5.06 (dd, J=17.2 Hz, 8 Hz, 1H), 4.74 (dd, J=6.4 Hz, 3.6 Hz, 1H), 4.19-4.08 (m, 2H), 2.69-2.64 (m, 2H), 2.30-2.27 (m, 1H), 2.21-2.17 (m, 2H), 1.84 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO) δ 133.64, 132.05, 131.39, 126.08, 124.66, 118.36, 111.05, 107.13, 100.97, 97.27, 95.22, 91.96, 90.37, 90.32, 89.54, 89.11, 87.45, 83.79, 39.76, 39.50, 39.25, 34.06, 29.13, 22.85, 19.48 ppm.

10.5

At 0° C., TES (0.1 ml), TFA (0.65 ml) were sequentially added to the reactants (150 mg, 0.21 mmol) in anhydrous DCM solution (5 ml). 15 min later, the product was directly spinned anhydrous solvent by column chromatography and 63 mg yellow solid was obtained, and the yield was 63%. [α] 20 D: 6.13 (c 0.5, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 8.18 (d, J=7.6 Hz, 1H), 7.89 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.06 (dd, J=14.4 Hz J=7.2 Hz, 1H), 6.58 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.45 (d, J=8 Hz, 1H), 5.74-5.64 (m, 2H), 5.50 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.10 (m, 1H), 4.74 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.34-4.28 (m, 1H), 2.74-2.69 (m, 2H), 2.56-2.50 (m, 2H), 2.34-2.29 (m, 3H), 1.36 (t, J=7.6 Hz, 1H), 0.80 (d, J=6.8 Hz, 3H), 0.6 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 168.9, 163.6, 162.9, 155.7, 148.6, 138.3, 134.7, 132.4, 128.6, 127.0, 124.9, 121.4, 77.2, 76.9, 76.7, 71.9, 56.9, 43.3, 41.0, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 11

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (60 mg, 0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and 60 mg pale yellow solid was obtained, and the yield was 80%. [α] 20 D: 3.71 (c 0.5, CHCl 3 ). 1H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.91 (t, J=7.6 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 199.5, 169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 77.2, 77.0, 76.7, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 12

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (60 mg, 0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and 60 mg yellow solid was obtained, and the yield was 80%. [α] 20 D: 3.71 (c 0.5, CHCl 3 ). 1′H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.91 (t, J=7.6 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 199.5, 169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 77.2, 77.0, 76.7, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 13

13.1

The Fmoc-L-Pra (0.976 g, 3.05 mmol), EDCI (584 mg, 3.045 mmol) and DMAP (25 mg, 0.203 mmol) was dissolved in anhydrous dichloromethane (15 mL), DIPEA (0.50 mL, 3.045 mmol) and the compound 2-23 (526 mg, 1.02 mmol) were added at 0° C., was stirred for 12 h at room temperature, and added diluted with methylene chloride. The reaction solution was washed with sodium bicarbonate solution (50 mL×3). The organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate, concentrated and the residue was purified by silica gel column chromatography to give a pale yellow solid compound 2-24 (682 mg, 80%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.76 (d, J=7.6 Hz, 2H), 7.60 (m, 2H), 7.40-7.31 (m 19H), 5.84 and 5.76 (m, 1H), 5.67 (dd, J=13.6, 7.2 Hz, 1H), 5.53 (dd, J=15.2, 7.2 Hz, 1H), 5.32 (d, J=8.8 Hz, 1H), 4.39 (t, J=6.8 Hz, 2H), 4.29 (dd, J=9.2, 4.4 Hz, 1H), 4.23 (t, J=7.2, 1H), 4.17 (t, J=8.4 Hz, 2H), 2.88 (t, J=7.2 Hz, 2H), 2.71 (dd, J=15.6, 7.6 Hz, 1H), 2.59 (dd, J=15.6, 5.6 Hz, 1H), 2.52 (t, J=7.2 Hz, 2H), 2.29 (dt, J=13.6, 6.8 Hz, 2H), 2.18 (m, 1H), 1.65 (m, 2H), 0.97-0.83 (m, 8H), 0.03 (s, 9H) ppm.

13.2

The reaction (682 mg, 0.81 mmol) was dissolved in acetonitrile (8 mL), diethylamine (0.25 mL, 2.44 mmol) was added and stirred for 2 h, decompressed and removed acetonitrile. The residue was purified by silica gel column chromatography and 477 mg anhydrous oil was obtained. The yield was 95%. 1 H NMR (400 MHz, CDCl 3 ): δ 7.40-7.38 (m, 6H), 7.29-7.25 (m, 6H), 7.22-7.18 (m, 3H), 5.69-5.57 (m, 2H), 5.36 (dd, J=15.4 Hz, 7.4 Hz, 1H), 4.16-4.09 (m, 2H), 3.21 (d, J=4.8 Hz, 1H), 2.64 (dd, J=15.6 Hz, 8.4 Hz, 1H), 2.53 (dd, J=15.6 Hz, 5.2 Hz, 1H), 2.19-2.15 (m, 2H), 2.07-1.98 (m, 2H), 1.97-1.93 (m, 1H), 0.98-0.93 (m, 2H), 0.92 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H), 0.03 (s, 9H) ppm.

13.3

At 0° C., DIPEA (0.7 ml) the product (610 mg) of Example 1.5, HATU (760 mg), HOAT (326 mg) were sequentially added to the reactant (336 mg, 1 mmol) in DCM solution (10 ml), and raised to room temperature with stirring. After 8 h, the reaction was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and 750 mg white flocculent solid solid was obtained. The yield was 92%. 1 H NMR (400 MHz, CDCl 3 ): δ 9.41 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.39-7.17 (m, 12H), 6.66-6.61 (m, 2H), 5.68-5.59 (m, 2H), 5.46 (s, 1H), 5.38-5.32 (m, 1H), 4.59 (dd, J=8.8 Hz, 4 Hz, 1H), 4.49 (d, J=4.2 Hz, 2H), 4.15-4.10 (m, 3H), 2.66 (dd, J=15.6 Hz, 7.6 Hz, 1H), 2.52 (dd, J=15.6 Hz, 5.6 Hz, 1H), 2.18-2.14 (m, 3H), 2.04 (t, J=6.8 Hz, 4H), 1.82 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 1.25 (t, J=6.8 Hz, 2H), 0.97-0.90 (m, 5H), 0.80 (d, J=6.8 Hz, 3H), 0.02 (s, 9H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 171.0, 170.7, 169.5, 164.3, 162.6, 157.3, 155.9, 148.5, 144.7, 138.2, 133.9, 129.6, 129.4, 129.0, 127.7, 127.6, 126.5, 124.6, 121.1, 79.7, 77.2, 77.0, 76.7, 71.8, 66.5, 63.0, 60.3, 57.0, 45.6, 39.5, 31.5, 31.2, 31.0, 28.3, 20.9, 18.8, 17.5, 17.2, 14.1, 13.8, 0.9, −1.5, −1.6 ppm.

13.4

Trifluoroacetic acid (6 ml) was added to DCM solution (25 ml) of the resulting resultant. After 5 h, spinned and removed DCM, the residue was added toluene (8 ml). Without further treatment, a brown viscous material was obtained after pumped organic solvent with oil pump. Chromatography pure acetonitrile (200 ml) obtained above was dissolved, slowly dropped in HATU (3 g), DIPEA (4 ml) of HPLC grade acetonitrile (550 ml). After 24 h, spinned anhydrous solvents, the product was diluted with ethyl acetate (20 ml) and then washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and 540 mg pale yellow solid was obtained. The yield was 82%. 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.37-7.16 (m, 15H), 7.07 (q, J=7.2 Hz, 1H), 6.67 (d, J=4.4 Hz, 1H), 6.43 (d, J=10.4 Hz, 1H), 5.62-5.56 (m, 2H), 5.39-5.34 (m, 1H), 5.06 (dd, J=17.2 Hz, 8 Hz, 1H), 4.74 (dd, J=6.4 Hz, 3.6 Hz, 1H), 4.19-4.08 (m, 2H), 2.69-2.64 (m, 2H), 2.30-2.27 (m, 1H), 2.21-2.17 (m, 2H), 1.84 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO) δ 133.64, 132.05, 131.39, 126.08, 124.66, 118.36, 111.05, 107.13, 100.97, 97.27, 95.22, 91.96, 90.37, 90.32, 89.54, 89.11, 87.45, 83.79, 39.76, 39.50, 39.25, 34.06, 29.13, 22.85, 19.48 ppm.

13.5

At 0° C., TES (0.1 ml), TFA (0.65 ml) were sequentially added to the reactants (150 mg, 0.21 mmol) in anhydrous DCM solution (5 ml). 15 min later, the product was directly spinned anhydrous solvent by column chromatography and 63 mg yellow solid was obtained, and the yield was 63%. [α] 20 D: 6.13 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 8.18 (d, J=7.6 Hz, 1H), 7.89 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.06 (dd, J=14.4 Hz J=7.2 Hz, 1H), 6.58 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.45 (d, J=8 Hz, 1H), 5.74-5.64 (m, 2H), 5.50 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.10 (m, 1H), 4.74 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.34-4.28 (m, 1H), 2.74-2.69 (m, 2H), 2.56-2.50 (m, 2H), 2.34-2.29 (m, 3H), 1.36 (t, J=7.6 Hz, 1H), 0.80 (d, J=6.8 Hz, 3H), 0.6 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 168.9, 163.6, 162.9, 155.7, 148.6, 138.3, 134.7, 132.4, 128.6, 127.0, 124.9, 121.4, 77.2, 76.9, 76.7, 71.9, 56.9, 43.3, 41.0, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 14

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (60 mg, 0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and 60 mg yellow solid was obtained, and the yield was 80%. [α] 20 D: 3.71 (c 0.5, CHCl 3 ). 1H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.91 (t, J=7.6 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 199.5, 169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 77.2, 77.0, 76.7, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 15

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (60 mg, 0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and 60 mg yellow solid was obtained, and the yield was 80%. [α] 20 D: 3.71 (c 0.5, CHCl 3 ). 1H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.91 (t, J=7.6 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl3) δ 199.5, 169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 77.2, 77.0, 76.7, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 16 · 1 of 2

16.1

15 ml LiOH aqueous (19 mmol) solution (7.6 mmol) were added dropwise to the reactant (7.6 mmol) of 30 ml THF, then reacted 2 h at room temperature. The reaction solution was adjusted by dilute hydrochloric acid to with the pH value of 3, then 100 ml ethyl acetate was added. The organic matter was washed by water and saturated salt water. The organic layer was dried by anhydrous sodium sulfate, and the solvent evaporated to give a white flocculent solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.05 (s, J=8.0 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 5.55 (s, 1H), 4.48 (d, J=4.2 Hz, 1H), 1.34 (s, 9H) ppm.

16.2

At 0° C., S2 (2.7 mmol), PyBop (4 mmol) and DIPEA (6 mmol) were added slowly to the reactant (2.7 mmol), stirred slightly, then added, and then stirred at room temperature overnight. The reaction solution was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution. The product was dried with anhydrous sodium sulfate and spinned solvent by column chromatography and white floc was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 8.64 (d, J=8.4 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.81 (d, J=8 Hz, 1H), 5.44 (s, 1H), 4.48-4.45 (m, J=3H), 3.78 (s, 3H), 1.45 (s, 9H), 1.26 (d, J=5.6 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 171.1, 164.6, 157.4, 156.0, 148.9, 137.9, 134.6, 124.2, 121.8, 121.0, 80.7, 79.8, 78.7, 70.3, 68.2, 61.1, 57.8, 52.7, 52.2, 47.7, 32.1, 28.3, 28.2, 28.1, 28.0, 22.6, 19.8 ppm.

16.3

At 0° C., DMAP (0.184 mmol), NEt 3 (3 mmol), MsCl (2.4 mmol) were successively added to anhydrous DCM (10 ml) of the reactants (1.84 mmol), then raised to room temperature and stirred overnight. The product was spinned anhydrous, pumped with oil pump and directly put into next step.

16.4

DABOCO (9.22 mmol) was added to Anhydrous DCM liquid (10 ml) obtained above and stirred 8 h at room temperature. The reaction solution was washed by saturated sodium bicarbonate solution, saturated ammonium chloride solution, saturated sodium chloride solution in sequence, and dried by anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and white floc was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.38 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 6.86 (q, J=7.6 Hz, 1H), 5.57 (s, 1H), 4.44 (d, J=5.6 Hz, 1H), 3.74 (s, 9H), 1.80 (d, J=7.6 Hz, 3H), 1.40 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 164.8, 162.1, 157.4, 156.0, 148.9, 148.8, 138.1, 133.9, 126.3, 124.2, 121.7, 121.0, 79.7, 52.1, 45.9, 28.3, 14.6 ppm.

16.5

5 ml LiOH aqueous solution (3.6 mmol) were added dropwise to reactants (1.44 mmol) with THF (10 ml), then spinned anhydrous the organic phase after three hours. 10 ml water and 15 ml ethyl acetate were added to the organic phase. The aqueous phase was removed after liquid separation. Then the solution was added 15 ml ethyl acetate, adjusted the acid. Anhydrous sodium sulfate was used for the separation of organic phase after liquid separation. 453 mg solid white floc was obtained after spinned anhydrous. 1 H NMR (400 MHz, CDCl 3 ): δ 9.40 (s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 6.88 (q, J=7.8 Hz, 1H), 5.58 (s, 1H), 3.76 (s, 9H), 1.83 (d, J=7.8 Hz, 3H), 1.43 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 165.3, 162.7, 157.8, 156.2, 149.0, 148.8, 138.3, 133.7, 126.5, 124.5, 121.9, 121.0, 52.5, 46.3, 28.5, 14.8 ppm.

16.6

At 0° C., DIPEA (0.7 ml), carboxylic acid, HATU, HOAT were sequentially added to the reactant (1 mmol) in DCM solution (10 ml). Then raised to room temperature with stirring. After 8 h, the reaction was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and white flocculent solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.41 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.39-7.17 (m, 12H), 6.66-6.61 (m, 2H), 5.68-5.59 (m, 2H), 5.46 (s, 1H), 5.38-5.32 (m, 1H), 4.59 (dd, J=8.8 Hz, 4 Hz, 1H), 4.49 (d, J=4.2 Hz, 1H), 4.15-4.10 (m, 3H), 2.66 (dd, J=15.6 Hz, 7.6 Hz, 1H), 2.52 (dd, J=15.6 Hz, 5.6 Hz, 1H), 2.18-2.14 (m, 3H), 2.04 (t, J=6.8 Hz, 4H), 1.82 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 1.25 (t, J=6.8 Hz, 2H), 0.97-0.90 (m, 5H), 0.80 (d, J=6.8 Hz, 3H), 0.02 (s, 9H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 171.0, 170.7, 169.5, 164.3, 162.6, 157.3, 155.9, 148.5, 144.7, 138.2, 133.9, 129.6, 129.4, 129.0, 127.7, 127.6, 126.5, 124.6, 121.1, 79.7, 71.8, 66.5, 63.0, 60.3, 57.0, 45.6, 39.5, 31.5, 31.2, 31.0, 28.3, 20.9, 18.8, 17.5, 17.2, 14.1, 13.8, 0.9, −1.5, −1.6 ppm.

16.7

Trifluoroacetic acid (6 ml) was added to DCM solution (25 ml) of the resulting resultant. After 5 h, spinned and removed DCM, toluene (8 ml) was added to the residue. Without further treatment, a brown viscous material was obtained after pumped organic solvent with oil pump. Chromatography pure acetonitrile (200 ml) obtained above was dissolved, slowly dropped in HATU (3 g), DIPEA (4 ml) of HPLC grade acetonitrile (550 ml). After 24 h, spinned anhydrous solvents, the product was diluted with ethyl acetate (20 ml) and then washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and 540 mg pale yellow solid was obtained. The yield was 82%. 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.37-7.16 (m, 15H), 7.07 (q, J=7.2 Hz, 1H), 6.67 (d, J=4.4 Hz, 1H), 5.62-5.56 (m, 2H), 5.39-5.34 (m, 1H), 5.06 (dd, J=17.2 Hz, 8 Hz, 1H), 4.74 (dd, J=6.4 Hz, 3.6 Hz, 1H), 4.19-4.08 (m, 2H), 2.69-2.64 (m, 2H), 2.30-2.27 (m, 1H), 2.21-2.17 (m, 2H), 1.84 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO) δ 133.6, 132.0, 131.3, 126.1, 124.7, 118.4, 111.1, 107.1, 101.0, 97.3, 95.2, 92.0, 90.4, 90.3, 89.5, 89.1, 87.5, 83.8, 39.8, 39.5, 39.3, 34.1, 29.1, 22.9, 19.5 ppm.

›Example 16 · 2 of 2

16.8

At 0° C., TES (0.1 ml), TFA (0.65 ml) were sequentially added to the reactants (0.21 mmol) in anhydrous DCM solution (5 ml). 15 min later, the product was directly spinned anhydrous solvent by column chromatography and yellow solid was obtained. [α] 20 D : 6.13 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 8.18 (d, J=7.6 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.06 (dd, J=14.4 Hz J=7.2 Hz, 1H), 6.58 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.45 (d, J=8 Hz, 1H), 5.74-5.64 (m, 2H), 5.50 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.10 (m, 1H), 4.74 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.34-4.28 (m, 1H), 2.74-2.69 (m, 2H), 2.56-2.50 (m, 2H), 2.34-2.29 (m, 3H), 1.36 (t, J=7.6 Hz, 1H), 0.80 (d, J=6.8 Hz, 3H), 0.6 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 168.9, 163.6, 162.9, 155.7, 148.6, 138.3, 134.7, 132.4, 128.6, 127.0, 124.9, 121.4, 71.9, 56.9, 43.3, 41.0, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 17

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and yellow solid was obtained. [α] 20 D : 3.71 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 18

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added heptanoyl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and yellow solid was obtained. [α] 20 D : 4.11 (c 0.7, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.23 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.08 (m, J=7.2 Hz, 1H), 6.73 (d, J=4.4 Hz, 1H), 6.48 (d, J=10 Hz, 1H), 5.72-5.63 (m, 2H), 5.62-5.45 (m, 1H), 5.15 (dd, J=17.2 Hz, 8 Hz, 1H), 4.75-4.71 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.86-2.71 (m, 4H), 2.63-2.62 (m, 1H), 2.50 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.85-1.82 (m, 3H), 1.62-1.59 (m, 2H), 1.26-1.24 (m, 9H), 0.85 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.5, 169.0, 163.5, 162.1, 155.7, 148.8, 138.6, 134.5, 132.6, 132.1, 130.9, 128.9, 128.5, 127.5, 125.1, 121.3, 72.2, 71.7, 57.3, 44.1, 43.2, 40.9, 38.6, 33.8, 32.2, 31.5, 30.9, 29.7, 29.1, 28.8, 27.7, 27.6, 25.5, 22.5, 19.1, 18.9, 16.4, 14.6, 14.0 ppm.

›Example 19

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added hexanoyl chloride (0.04 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and yellow solid was obtained. [α] 20 D : 3.11 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.22 (s, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.46 (d, J=10.0 Hz, 1H), 5.74-5.68 (m, 2H), 5.50 (m, 1H), 5.17 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.76-4.73 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.88-2.75 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.84-1.82 (m, 3H), 1.63-1.60 (m, 2H), 1.26-1.24 (m, 7H), 0.84 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.59 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.3, 169.0, 163.2, 162.0, 155.6, 148.9, 138.8, 134.8, 132.7, 132.0, 130.9, 128.9, 128.6, 127.7, 125.3, 121.5, 72.3, 71.8, 57.5, 44.3, 43.4, 41.2, 38.9, 33.9, 32.5, 31.7, 30.9, 29.8, 29.2, 28.9, 27.8, 27.6, 25.6, 22.6, 19.0, 16.5, 14.7, 13.9 ppm.

›Example 20

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added pivaloyl chloride (0.04 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and yellow solid was obtained. [α] 20 D : 3.31 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.20 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.73 (d, J=4.4 Hz, 1H), 6.49 (d, J=10.0 Hz, 1H), 5.73-5.69 (m, 2H), 5.51 (m, 1H), 5.15 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.75-4.73 (m, 2H), 4.29 (d, J=17.2 Hz, 1H), 2.89-2.75 (m, 4H), 2.62 (m, 1H), 2.47 (t, J=7.8 Hz, 3H), 2.31-2.26 (m, 3H), 1.85-1.83 (m, 3H), 1.62-1.60 (m, 2H), 1.25-1.23 (m, 5H), 0.83 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.2, 169.0, 163.3, 162.2, 155.7, 148.7, 138.9, 134.5, 132.8, 132.1, 130.8, 128.9, 128.5, 127.6, 125.2, 121.3, 72.1, 71.6, 57.8, 44.2, 43.5, 41.3, 38.8, 33.8, 32.6, 31.6, 30.8, 29.9, 29.3, 28.8, 27.6, 25.7, 22.7, 19.1, 16.6, 14.9, 13.8 ppm.

›Example 21

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added butyryl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and yellow solid was obtained. [α] 20 D : 6.51 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.23 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.76-5.71 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77-4.74 (m, 2H), 4.27 (d, J=17.2 Hz, 1H), 2.88-2.74 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.33-2.28 (m, 3H), 1.86-1.83 (m, 3H), 1.66-1.62 (m, 2H), 1.27-1.24 (m, 3H), 0.86 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.56 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.4, 169.1, 163.5, 162.3, 155.8, 148.8, 138.9, 134.7, 132.9, 132.3, 130.9, 128.9, 128.4, 127.5, 125.3, 121.5, 72.2, 71.7, 57.6, 44.5, 43.6, 41.4, 38.9, 33.9, 32.7, 31.7, 30.9, 29.9, 29.5, 28.9, 27.7, 25.8, 22.9, 19.3, 15.5, 13.8 ppm.

›Example 22

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, was added propionyl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and yellow solid was obtained. [α] 20 D : 5.50 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.25 (s, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H), 6.48 (d, J=10.0 Hz, 1H), 5.75-5.72 (m, 2H), 5.55 (m, 1H), 5.19 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.78-4.75 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.89-2.75 (m, 4H), 2.65 (m, 1H), 2.48 (t, J=7.8 Hz, 3H), 2.35-2.29 (m, 3H), 1.88-1.85 (m, 3H), 1.66 (m, 2H), 0.86 (m, 3H), 0.77 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 169.2, 163.3, 162.2, 155.9, 148.9, 138.8, 134.8, 132.9, 132.2, 130.8, 128.9, 128.5, 127.6, 125.5, 121.6, 72.3, 71.8, 57.8, 44.6, 43.7, 41.5, 38.8, 33.9, 32.8, 31.8, 30.8, 29.9, 29.6, 28.9, 27.8, 25.9, 22.9, 19.5, 14.8 ppm.

›Example 23

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, acetyl chloride (0.05 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and yellow solid was obtained. [α] 20 D : 4.66 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.26 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.79 (d, J=4.4 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.73-5.70 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.88-2.78 (m, 4H), 2.67 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.36-2.33 (m, 3H), 1.89-1.86 (m, 3H), 0.88 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.8, 169.3, 163.5, 162.5, 155.8, 148.8, 138.7, 134.7, 132.8, 132.3, 130.9, 128.8, 128.7, 127.7, 125.6, 121.7, 72.5, 71.9, 57.9, 44.7, 43.9, 41.6, 38.9, 33.8, 32.9, 31.9, 30.9, 29.8, 29.5, 28.8, 27.7, 15.0 ppm.

›Example 24

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, methanesulfonyl chloride (0.02 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and yellow solid was obtained. [α] 20 D : 1.96 (c 0.1, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.63 (s, 1H), 9.23 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.07 (dd, J=14.4 Hz, J=7.2 Hz, 1H), 6.56 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.48 (d, J=8 Hz, 1H), 5.73 (m, 2H), 5.52 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.12 (m, 1H), 4.76 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.33 (m, 1H), 2.72 (m, 2H), 2.53 (m, 2H), 2.34-2.29 (m, 3H), 1.38 (t, J=7.6 Hz, 1H), 0.82 (d, J=6.8 Hz, 3H), 0.62 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 176.5, 169.8, 169.4, 163.6, 162.6, 155.7, 148.8, 138.5, 134.7, 132.5, 132.3, 130.9, 128.8, 127.8, 125.6, 121.8, 72.5, 71.7, 56.9, 44.8, 43.6, 41.5, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 25 · 1 of 2

25.1

15 ml LiOH aqueous solution (19 mmol) were added dropwise to the reactant (7.6 mmol) of 30 ml THF, then reacted 2 h at room temperature. The reaction solution was adjusted by dilute hydrochloric acid to with the pH value of 3, then 100 ml ethyl acetate was added. The organic matter was washed by water and saturated salt water. The organic layer was dried by anhydrous sodium sulfate, and the solvent evaporated to give white flocculent solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.66 (d, J=8.0 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 5.55 (s, 1H), 4.48 (d, J=4.2 Hz, 2H), 3.48 (s, 3H), 1.36 (s, 9H) ppm.

25.2

At 0° C., DIPEA (1.2 ml, 6 mmol) was added to the reactant (2.7 mmol) slowly, stirred slightly, then added S2 (2.7 mmol), PyBop (4 mmol), and then stirred at room temperature overnight. The reaction solution was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution. The product was dried with anhydrous sodium sulfate and spinned solvent by column chromatography and white floc was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 8.64 (d, J=8.4 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 5.44 (s, 1H), 4.77 (d, J=7.2 Hz, 1H), 4.48-4.45 (m, J=3H), 3.78 (s, 3H), 3.48 (s, 3H), 1.45 (s, 9H), 1.26 (d, J=5.6 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 171.1, 164.6, 157.4, 156.0, 148.9, 137.9, 134.6, 124.2, 121.8, 121.0, 80.7, 79.8, 78.7, 70.3, 68.2, 61.1, 57.8, 52.7, 52.2, 47.7, 32.1, 28.3, 28.2, 28.1, 28.0, 22.6, 19.8 ppm.

25.3

At 0° C., DMAP (0.184 mmol), NEt 3 (0.42 ml, 3 mmol), MsCl (0.186 ml, 2.4 mmol) were added to anhydrous DCM (10 ml) of the reactants (1.84 mmol) successively, then raised to room temperature and stirred overnight. The product was spinned anhydrous, pumped with oil pump and directly put into next step.

25.4

DABOCO (1 g, 9.22 mmol) was added to anhydrous DCM liquid (10 ml) obtained above and stirred 8 h at room temperature. The reaction solution was washed by saturated sodium bicarbonate solution, saturated ammonium chloride solution, saturated sodium chloride solution in sequence, and dried by anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and white floc was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.38 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 6.86 (q, J=7.6 Hz, 1H), 5.57 (s, 1H), 4.44 (d, J=5.6 Hz, 2H), 3.74 (s, 9H), 3.48 (s, 3H), 3.48 (s, 3H), 1.80 (d, J=7.6 Hz, 3H), 1.40 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 164.8, 162.1, 157.4, 156.0, 148.9, 148.8, 138.1, 133.9, 126.3, 124.2, 123.5, 121.7, 121.0, 79.7, 52.1, 45.9, 28.3, 14.6 ppm.

25.5

5 ml LiOH aqueous solution (90 mg, 3.6 mmol) were added dropwise to reactants (1.44 mmol) with THF (10 ml), then spinned anhydrous the organic phase after three hours. 10 ml water and 15 ml ethyl acetate were added to the organic phase. The aqueous phase was removed after liquid separation. Then the solution was added 15 ml ethyl acetate, adjusted the acid. Anhydrous sodium sulfate was used for the separation of organic phase after liquid separation. Solid white floc was obtained after spinned anhydrous. 1 H NMR (400 MHz, CDCl 3 ): δ 9.40 (s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 6.88 (q, J=7.8 Hz, 1H), 5.58 (s, 1H), 4.46 (d, J=5.8 Hz, 2H), 3.76 (s, 9H), 3.48 (s, 3H), 1.83 (d, J=7.8 Hz, 3H), 1.43 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 165.3, 162.7, 157.8, 156.2, 149.0, 148.8, 138.3, 133.7, 126.5, 124.5, 123.7, 121.9, 121.0, 52.5, 46.3, 28.5, 14.8 ppm.

25.6

At 0° C., DIPEA (0.7 ml), carboxylic acid (610 mg), HATU (760 mg), HOAT (326 mg) were added to the reactant (336 mg, 1 mmol) in DCM solution (10 ml) sequentially. Then raised to room temperature with stirring. After 8 h, the reaction was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and white flocculent solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.41 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.39-7.17 (m, 12H), 6.66-6.61 (m, 2H), 5.68-5.59 (m, 2H), 5.46 (s, 1H), 5.38-5.32 (m, 1H), 4.59 (dd, J=8.8 Hz, 4 Hz, 1H), 4.49 (d, J=4.2 Hz, 2H), 4.15-4.10 (m, 3H), 3.48 (s, 3H), 2.66 (dd, J=15.6 Hz, 7.6 Hz, 1H), 2.52 (dd, J=15.6 Hz, 5.6 Hz, 1H), 2.18-2.14 (m, 3H), 2.04 (t, J=6.8 Hz, 4H), 1.82 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 1.25 (t, J=6.8 Hz, 2H), 0.97-0.90 (m, 5H), 0.80 (d, J=6.8 Hz, 3H), 0.02 (s, 9H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 171.0, 170.7, 169.5, 164.3, 162.6, 157.3, 155.9, 148.5, 144.7, 138.2, 133.9, 129.6, 129.4, 129.0, 127.7, 127.6, 126.5, 124.6, 123.5, 121.1, 79.7, 71.8, 66.5, 63.0, 60.3, 57.0, 45.6, 39.5, 31.5, 31.2, 31.0, 28.3, 20.9, 18.8, 17.5, 17.2, 14.1, 13.8, 0.9, −1.5, −1.6 ppm.

25.7

Tetrabutylammonium fluoride in tetrahydrofuran solution (1 mol/l, 2.3 ml) was added to the reaction (0.92 mmol) in redistilled THF (5 ml). After 3 h, the reaction was immediately spinned anhydrous by column chromatography to obtain a white solid. DCM solution (25 ml) of the resulting resultant was added trifluoroacetic acid (6 ml). After 5 h, spinned and removed DCM, the residue was added toluene (8 ml). Without further treatment, a brown viscous material was obtained after pumped organic solvent with oil pump. Chromatography pure acetonitrile (200 ml) obtained above was dissolved, slowly dropped in HATU (3 g), DIPEA (4 ml) of HPLC grade acetonitrile (550 ml). After 24 h, spinned anhydrous solvents, the product was diluted with ethyl acetate (20 ml) and then washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and pale yellow solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.37-7.16 (m, 15H), 7.07 (q, J=7.2 Hz, 1H), 6.43 (d, J=10.4 Hz, 1H), 5.62-5.56 (m, 2H), 5.39-5.34 (m, 1H), 5.06 (dd, J=17.2 Hz, 8 Hz, 1H), 4.74 (dd, J=6.4 Hz, 3.6 Hz, 1H), 4.19-4.08 (m, 2H), 3.48 (s, 3H), 2.69-2.64 (m, 2H), 2.30-2.27 (m, 1H), 2.21-2.17 (m, 2H), 1.84 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO) δ 133.6, 132.0, 131.3, 126.1, 124.7, 123.3, 118.4, 111.1, 107.1, 101.0, 97.3, 95.2, 92.0, 90.4, 90.3, 89.5, 89.1, 87.5, 83.8, 39.8, 39.5, 39.3, 34.1, 29.1, 22.9, 19.5 ppm.

›Example 25 · 2 of 2

25.8

At 0° C., TES (0.1 ml), TFA (0.65 ml) were added to the reactants (150 mg, 0.21 mmol) in anhydrous DCM solution (5 ml) sequentially. 15 min later, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 6.13 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 8.18 (d, J=7.6 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.06 (dd, J=14.4 Hz J=7.2 Hz, 1H), 6.58 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.45 (d, J=8 Hz, 1H), 5.74-5.64 (m, 2H), 5.50 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.10 (m, 1H), 4.74 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.34-4.28 (m, 1H), 3.48 (s, 3H), 2.74-2.69 (m, 2H), 2.56-2.50 (m, 2H), 2.34-2.29 (m, 3H), 1.36 (t, J=7.6 Hz, 1H), 0.80 (d, J=6.8 Hz, 3H), 0.6 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 168.9, 163.6, 162.9, 155.7, 148.6, 138.3, 134.7, 132.4, 128.6, 127.0, 124.9, 123.8, 121.4, 71.9, 56.9, 43.3, 41.0, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 26

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.71 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 3.48 (s, 3H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 123.6, 121.3, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 27

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added heptanoyl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 4.11 (c 0.7, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.23 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.08 (m, J=7.2 Hz, 1H), 6.73 (d, J=4.4 Hz, 1H), 6.48 (d, J=10 Hz, 1H), 5.72-5.63 (m, 2H), 5.62-5.45 (m, 1H), 5.15 (dd, J=17.2 Hz, 8 Hz, 1H), 4.75-4.71 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.86-2.71 (m, 4H), 2.63-2.62 (m, 1H), 2.50 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.85-1.82 (m, 3H), 1.62-1.59 (m, 2H), 1.26-1.24 (m, 9H), 0.85 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.5, 169.0, 163.5, 162.1, 155.7, 148.8, 138.6, 134.5, 132.6, 132.1, 130.9, 128.9, 128.5, 127.5, 125.1, 124.1, 121.3, 72.2, 71.7, 57.3, 44.1, 43.2, 40.9, 38.6, 33.8, 32.2, 31.5, 30.9, 29.7, 29.1, 28.8, 27.7, 27.6, 25.5, 22.5, 19.1, 18.9, 16.4, 14.6, 14.0 ppm.

›Example 28

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added hexanoyl chloride (0.04 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.11 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.22 (s, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.46 (d, J=10.0 Hz, 1H), 5.74-5.68 (m, 2H), 5.50 (m, 1H), 5.17 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.76-4.73 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.88-2.75 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.84-1.82 (m, 3H), 1.63-1.60 (m, 2H), 1.26-1.24 (m, 7H), 0.84 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.59 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.3, 169.0, 163.2, 162.0, 155.6, 148.9, 138.8, 134.8, 132.7, 132.0, 130.9, 128.9, 128.6, 127.7, 125.3, 124.3, 121.5, 72.3, 71.8, 57.5, 44.3, 43.4, 41.2, 38.9, 33.9, 32.5, 31.7, 30.9, 29.8, 29.2, 28.9, 27.8, 27.6, 25.6, 22.6, 19.0, 16.5, 14.7, 13.9 ppm.

›Example 29

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added pivaloyl chloride (0.04 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.31 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.20 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.73 (d, J=4.4 Hz, 1H), 6.49 (d, J=10.0 Hz, 1H), 5.73-5.69 (m, 2H), 5.51 (m, 1H), 5.15 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.75-4.73 (m, 2H), 4.29 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.89-2.75 (m, 4H), 2.62 (m, 1H), 2.47 (t, J=7.8 Hz, 3H), 2.31-2.26 (m, 3H), 1.85-1.83 (m, 3H), 1.62-1.60 (m, 2H), 1.25-1.23 (m, 5H), 0.83 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.2, 169.0, 163.3, 162.2, 155.7, 148.7, 138.9, 134.5, 132.8, 132.1, 130.8, 128.9, 128.5, 127.6, 125.2, 123.1, 121.3, 72.1, 71.6, 57.8, 44.2, 43.5, 41.3, 38.8, 33.8, 32.6, 31.6, 30.8, 29.9, 29.3, 28.8, 27.6, 25.7, 22.7, 19.1, 16.6, 14.9, 13.8 ppm.

›Example 30

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added butyryl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 6.51 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.23 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.76-5.71 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77-4.74 (m, 2H), 4.27 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.88-2.74 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.33-2.28 (m, 3H), 1.86-1.83 (m, 3H), 1.66-1.62 (m, 2H), 1.27-1.24 (m, 3H), 0.86 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.56 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.4, 169.1, 163.5, 162.3, 155.8, 148.8, 138.9, 134.7, 132.9, 132.3, 130.9, 128.9, 128.4, 127.5, 125.3, 123.9, 121.5, 72.2, 71.7, 57.6, 44.5, 43.6, 41.4, 38.9, 33.9, 32.7, 31.7, 30.9, 29.9, 29.5, 28.9, 27.7, 25.8, 22.9, 19.3, 15.5, 13.8 ppm.

›Example 31

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, was added propionyl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 5.50 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.25 (s, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H), 6.48 (d, J=10.0 Hz, 1H), 5.75-5.72 (m, 2H), 5.55 (m, 1H), 5.19 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.78-4.75 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.89-2.75 (m, 4H), 2.65 (m, 1H), 2.48 (t, J=7.8 Hz, 3H), 2.35-2.29 (m, 3H), 1.88-1.85 (m, 3H), 1.66 (m, 2H), 0.86 (m, 3H), 0.77 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 169.2, 163.3, 162.2, 155.9, 148.9, 138.8, 134.8, 132.9, 132.2, 130.8, 128.9, 128.5, 127.6, 125.5, 124.7, 121.6, 72.3, 71.8, 57.8, 44.6, 43.7, 41.5, 38.8, 33.9, 32.8, 31.8, 30.8, 29.9, 29.6, 28.9, 27.8, 25.9, 22.9, 19.5, 14.8 ppm.

›Example 32

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, acetyl chloride (0.05 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 4.66 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.26 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 6.79 (d, J=4.4 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.73-5.70 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.88-2.78 (m, 4H), 2.67 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.36-2.33 (m, 3H), 1.89-1.86 (m, 3H), 0.88 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.8, 169.3, 163.5, 162.5, 155.8, 148.8, 138.7, 134.7, 132.8, 132.3, 130.9, 128.8, 128.7, 127.7, 125.6, 123.4, 121.7, 72.5, 71.9, 57.9, 44.7, 43.9, 41.6, 38.9, 33.8, 32.9, 31.9, 30.9, 29.8, 29.5, 28.8, 27.7, 15.0 ppm.

›Example 33

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, was added methanesulfonyl chloride (0.02 ml). After 7 h, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 1.96 (c 0.1, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.63 (s, 1H), 9.23 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.07 (dd, J=14.4 Hz, J=7.2 Hz, 1H), 6.56 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.48 (d, J=8 Hz, 1H), 5.73 (m, 2H), 5.52 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.12 (m, 1H), 4.76 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.33 (m, 1H), 3.48 (s, 3H), 2.72 (m, 2H), 2.53 (m, 2H), 2.34-2.29 (m, 3H), 1.38 (t, J=7.6 Hz, 1H), 0.82 (d, J=6.8 Hz, 3H), 0.62 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 176.5, 169.8, 169.4, 163.6, 162.6, 155.7, 148.8, 138.5, 134.7, 132.5, 132.3, 130.9, 128.8, 127.8, 125.6, 123.6, 121.8, 72.5, 71.7, 56.9, 44.8, 43.6, 41.5, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 34

34.1

The Fmoc-L-Pra (3.00 mmol), EDCI (584 mg, 3.05 mmol) and DMAP (25 mg, 0.203 mmol) was dissolved in anhydrous dichloromethane (15 mL), DIPEA (0.50 mL, 3.05 mmol) and the alcohol (526 mg, 1.02 mmol) was added at 0° C., was stirred for 12 h at room temperature, and added diluted with methylene chloride. The reaction solution was washed with sodium bicarbonate solution (50 mL×3). The organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate, concentrated and the residue was purified by silica gel column chromatography to give a pale yellow solid compound. 1 H NMR (400 MHz, CDCl 3 ): δ 7.77 (d, J=7.6 Hz, 2H), 7.61 (m, 2H), 7.42-7.32 (m 19H), 5.85-5.78 (m, 1H), 5.68 (dd, J=13.6, 7.2 Hz, 1H), 5.55 (dd, J=15.2, 7.2 Hz, 1H), 5.35 (d, J=8.8 Hz, 1H), 4.37 (t, J=6.8 Hz, 2H), 4.28 (dd, J=9.2, 4.4 Hz, 1H), 4.25 (t, J=7.2, 1H), 4.18 (t, J=8.4 Hz, 2H), 3.48 (s, 3H), 2.89 (t, J=7.2 Hz, 2H), 2.73 (dd, J=15.6, 7.6 Hz, 1H), 2.61 (dd, J=15.6, 5.6 Hz, 1H), 2.55 (t, J=7.2 Hz, 2H), 2.28 (dt, J=13.6, 6.8 Hz, 2H), 2.19 (m, 1H), 1.67 (m, 2H), 0.90-0.85 (m, 4H), 0.03 (s, 9H) ppm.

34.2

The reaction (0.80 mmol) was dissolved in acetonitrile (8 mL), diethylamine (0.25 mL, 2.44 mmol) was added and stirred for 2 h, decompressed and removed acetonitrile. The residue was purified by silica gel column chromatography and anhydrous oil was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 7.40-7.38 (m, 6H), 7.29-7.25 (m, 6H), 7.22-7.18 (m, 3H), 5.69-5.57 (m, 2H), 5.36 (dd, J=15.4 Hz, 7.4 Hz, 1H), 4.16-4.09 (m, 2H), 3.21 (d, J=4.8 Hz, 1H), 2.64 (dd, J=15.6 Hz, 8.4 Hz, 1H), 2.53 (dd, J=15.6 Hz, 5.2 Hz, 1H), 2.19-2.15 (m, 2H), 2.07-1.98 (m, 2H), 1.97-1.93 (m, 1H), 0.98-0.93 (m, 2H), 0.92 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H), 0.03 (s, 9H) ppm.

34.3

At 0° C., DIPEA (0.7 ml), the product (610 mg) of Example 16.5, HATU (760 mg), HOAT (326 mg) were sequentially added to the reactant (1 mmol) in DCM solution (10 ml), and raised to room temperature with stirring. After 8 h, the reaction was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and white flocculent solid solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.41 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.39-7.17 (m, 12H), 6.66-6.61 (m, 2H), 5.68-5.59 (m, 2H), 5.46 (s, 1H), 5.38-5.32 (m, 1H), 4.59 (dd, J=8.8 Hz, 4 Hz, 1H), 4.49 (d, J=4.2 Hz, 2H), 4.15-4.10 (m, 3H), 2.66 (dd, J=15.6 Hz, 7.6 Hz, 1H), 2.52 (dd, J=15.6 Hz, 5.6 Hz, 1H), 2.18-2.14 (m, 3H), 2.04 (t, J=6.8 Hz, 4H), 1.82 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 1.25 (t, J=6.8 Hz, 2H), 0.97-0.90 (m, 5H), 0.80 (d, J=6.8 Hz, 3H), 0.02 (s, 9H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 171.0, 170.7, 169.5, 164.3, 162.6, 157.3, 155.9, 148.5, 144.7, 138.2, 133.9, 129.6, 129.4, 129.0, 127.7, 127.6, 126.5, 124.6, 121.1, 79.7, 77.2, 77.0, 76.7, 71.8, 66.5, 63.0, 60.3, 57.0, 45.6, 39.5, 31.5, 31.2, 31.0, 28.3, 20.9, 18.8, 17.5, 17.2, 14.1, 13.8, 0.9, −1.5, −1.6 ppm.

34.4

Tetrabutylammonium fluoride in tetrahydrofuran solution (1 mol/l, 2.3 ml) was added to the reaction (0.90 mmol) in redistilled THF (5 ml). After 3 h, the reaction was immediately spinned anhydrous by column chromatography to obtain a white solid. DCM solution (25 ml) of the resulting resultant was added trifluoroacetic acid (6 ml). After 5 h, spinned and removed DCM, the residue was added toluene (8 ml). Without further treatment, a brown viscous material was obtained after pumped organic solvent with oil pump. Chromatography pure acetonitrile (200 ml) obtained above was dissolved, slowly dropped in HATU (3 g), DIPEA (4 ml) of HPLC grade acetonitrile (550 ml). After 24 h, spinned anhydrous solvents, the product was diluted with ethyl acetate (20 ml) and then washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and pale yellow solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.37-7.16 (m, 15H), 7.07 (q, J=7.2 Hz, 1H), 6.43 (d, J=10.4 Hz, 1H), 5.62-5.56 (m, 2H), 5.39-5.34 (m, 1H), 5.06 (dd, J=17.2 Hz, 8 Hz, 1H), 4.74 (dd, J=6.4 Hz, 3.6 Hz, 1H), 4.19-4.08 (m, 2H), 2.69-2.64 (m, 2H), 2.30-2.27 (m, 1H), 2.21-2.17 (m, 2H), 1.84 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO) δ 133.64, 132.05, 131.39, 126.08, 124.66, 118.36, 111.05, 107.13, 100.97, 97.27, 95.22, 91.96, 90.37, 90.32, 89.54, 89.11, 87.45, 83.79, 39.76, 39.50, 39.25, 34.06, 29.13, 22.85, 19.48 ppm.

34.5

At 0° C., TES (0.1 ml), TFA (0.65 ml) were sequentially added to the reactants (0.21 mmol) in anhydrous DCM solution (5 ml). 15 min later, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 6.13 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 8.18 (d, J=7.6 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.06 (dd, J=14.4 Hz J=7.2 Hz, 1H), 6.58 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.45 (d, J=8 Hz, 1H), 5.74-5.64 (m, 2H), 5.50 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.10 (m, 1H), 4.74 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.34-4.28 (m, 1H), 2.74-2.69 (m, 2H), 2.56-2.50 (m, 2H), 2.34-2.29 (m, 3H), 1.36 (t, J=7.6 Hz, 1H), 0.80 (d, J=6.8 Hz, 3H), 0.6 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 168.9, 163.6, 162.9, 155.7, 148.6, 138.3, 134.7, 132.4, 128.6, 127.0, 124.9, 121.4, 77.2, 76.9, 76.7, 71.9, 56.9, 43.3, 41.0, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 35

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.71 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 199.5, 169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 77.2, 77.0, 76.7, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 36

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added acetyl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 4.66 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.26 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.79 (d, J=4.4 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.73-5.70 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.88-2.78 (m, 4H), 2.67 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.36-2.33 (m, 3H), 1.89-1.86 (m, 3H), 0.88 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.8, 169.3, 163.5, 162.5, 155.8, 148.8, 138.7, 134.7, 132.8, 132.3, 130.9, 128.8, 128.7, 127.7, 125.6, 121.7, 72.5, 71.9, 57.9, 44.7, 43.9, 41.6, 38.9, 33.8, 32.9, 31.9, 30.9, 29.8, 29.5, 28.8, 27.7, 15.0 ppm.

›Example 37 · 1 of 2

37.1

15 ml LiOH aqueous solution (19 mmol) were added dropwise to the reactant (7.6 mmol) of 30 ml THF, then reacted 2 h at room temperature. The reaction solution was adjusted by dilute hydrochloric acid to with the pH value of 3, then 100 ml ethyl acetate was added. The organic matter was washed by water and saturated salt water. The organic layer was dried by anhydrous sodium sulfate, and the solvent evaporated to give a white flocculent solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.05 (s, J=8.0 Hz, 1H), 7.75 (s, 1H), 7.61 (s, 1H), 5.55 (s, 1H), 4.48 (d, J=4.2 Hz, 2H), 1.34 (s, 9H) ppm.

37.2

At 0° C., S2 (2.7 mmol), PyBop (4 mmol) were added to the reactant (2.7 mmol), stirred slightly, then added, and then stirred at room temperature overnight. The reaction solution was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution. The product was dried with anhydrous sodium sulfate and spinned solvent by column chromatography and white floc was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 8.64 (d, J=8.4 Hz, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 5.44 (s, 1H), 4.48-4.45 (m, J=3H), 3.78 (s, 3H), 1.45 (s, 9H), 1.26 (d, J=5.6 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 171.1, 164.6, 157.4, 156.0, 148.9, 137.9, 134.6, 124.2, 121.8, 121.0, 80.7, 79.8, 78.7, 70.3, 68.2, 61.1, 57.8, 52.7, 52.2, 47.7, 32.1, 28.3, 28.2, 28.1, 28.0, 22.6, 19.8 ppm.

37.3

At 0° C., DMAP (0.184 mmol), NEt 3 (3 mmol), MsCl (2.4 mmol) were added to anhydrous DCM (10 ml) of the reactants (1.84 mmol) successively, then raised to room temperature and stirred overnight. The product was spinned anhydrous, pumped with oil pump and directly put into next step.

37.4

DABOCO (9.22 mmol) was added to anhydrous DCM liquid (10 ml) obtained above, and stirred 8 h at room temperature. The reaction solution was washed by saturated sodium bicarbonate solution, saturated ammonium chloride solution, saturated sodium chloride solution in sequence, and dried by anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and white floc was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.38 (s, 1H), 7.45 (s, 1H), 7.41 (s, 1H), 6.86 (q, J=7.6 Hz, 1H), 5.57 (s, 1H), 4.44 (d, J=5.6 Hz, 1H), 3.74 (s, 9H), 1.80 (d, J=7.6 Hz, 3H), 1.40 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 164.8, 162.1, 157.4, 156.0, 148.9, 148.8, 138.1, 133.9, 126.3, 124.2, 121.7, 121.0, 79.7, 52.1, 45.9, 28.3, 14.6 ppm.

37.5

5 ml LiOH aqueous solution (3.6 mmol) were added dropwise to reactants (1.44 mmol) with THF (10 ml), then spinned anhydrous the organic phase after three hours. 10 ml water and 15 ml ethyl acetate were added to the organic phase. The aqueous phase was removed after liquid separation. Then the solution was added 15 ml ethyl acetate, adjusted the acid. Anhydrous sodium sulfate was used for the separation of organic phase after liquid separation. White floc solid was obtained after spinned anhydrous. 1 H NMR (400 MHz, CDCl 3 ): δ 9.40 (s, 1H), 8.03 (s, 1H), 7.11 (s, 1H), 6.88 (q, J=7.8 Hz, 1H), 5.58 (s, 1H), 3.76 (s, 9H), 1.83 (d, J=7.8 Hz, 3H), 1.43 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 165.3, 162.7, 157.8, 156.2, 149.0, 148.8, 138.3, 133.7, 126.5, 124.5, 121.9, 121.0, 52.5, 46.3, 28.5, 14.8 ppm.

37.6

At 0° C., DIPEA (0.7 ml), carboxylic acid, HATU, HOAT were added to the reactant (1 mmol) in DCM solution (10 ml) sequentially. Then raised to room temperature with stirring. After 8 h, the reaction was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and white flocculent solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.41 (s, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 7.39-7.17 (m, 12H), 6.66-6.61 (m, 2H), 5.68-5.59 (m, 2H), 5.46 (s, 1H), 5.38-5.32 (m, 1H), 4.59 (dd, J=8.8 Hz, 4 Hz, 1H), 4.49 (d, J=4.2 Hz, 1H), 4.15-4.10 (m, 3H), 2.66 (dd, J=15.6 Hz, 7.6 Hz, 1H), 2.52 (dd, J=15.6 Hz, 5.6 Hz, 1H), 2.18-2.14 (m, 3H), 2.04 (t, J=6.8 Hz, 4H), 1.82 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 1.25 (t, J=6.8 Hz, 2H), 0.97-0.90 (m, 5H), 0.80 (d, J=6.8 Hz, 3H), 0.02 (s, 9H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 171.0, 170.7, 169.5, 164.3, 162.6, 157.3, 155.9, 148.5, 144.7, 138.2, 133.9, 129.6, 129.4, 129.0, 127.7, 127.6, 126.5, 124.6, 121.1, 79.7, 71.8, 66.5, 63.0, 60.3, 57.0, 45.6, 39.5, 31.5, 31.2, 31.0, 28.3, 20.9, 18.8, 17.5, 17.2, 14.1, 13.8, 0.9, −1.5, −1.6 ppm.

37.7

Tetrabutylammonium fluoride in tetrahydrofuran solution (1 mol/l, 2.3 ml) was added to the reaction (0.92 mmol) in redistilled THF (5 ml). After 3 h, the reaction was immediately spinned anhydrous by column chromatography to obtain a white solid. DCM solution (25 ml) of the resulting resultant was added trifluoroacetic acid (6 ml). After 5 h, spinned and removed DCM, the residue was added toluene (8 ml). Without further treatment, a brown viscous material was obtained after pumped organic solvent with oil pump. Chromatography pure acetonitrile (200 ml) obtained above was dissolved, slowly dropped in HATU (3 g), DIPEA (4 ml) of HPLC grade acetonitrile (550 ml). After 24 h, spinned anhydrous solvents, the product was diluted with ethyl acetate (20 ml) and then washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and 540 mg pale yellow solid was obtained. The yield was 82%. 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (s, 1H), 8.10 (s, 1H), 7.37-7.16 (m, 15H), 7.07 (q, J=7.2 Hz, 1H), 6.67 (d, J=4.4 Hz, 1H), 6.51 (d, J=10.3 Hz, 1H), 5.62-5.56 (m, 2H), 5.39-5.34 (m, 1H), 5.06 (dd, J=17.2 Hz, 8 Hz, 1H), 4.74 (dd, J=6.4 Hz, 3.6 Hz, 1H), 4.19-4.08 (m, 2H), 2.69-2.64 (m, 2H), 2.30-2.27 (m, 1H), 2.21-2.17 (m, 2H), 1.84 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO) δ 133.6, 132.0, 131.3, 126.1, 124.7, 118.4, 111.1, 107.1, 101.0, 97.3, 95.2, 92.0, 90.4, 90.3, 89.5, 89.1, 87.5, 83.8, 39.8, 39.5, 39.3, 34.1, 29.1, 22.9, 19.5 ppm.

›Example 37 · 2 of 2

37.8

At 0° C., TES (0.1 ml), TFA (0.65 ml) were added to the reactants (0.21 mmol) in anhydrous DCM solution (5 ml) sequentially. 15 min later, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 6.13 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 8.18 (s, 1H), 7.41 (s, 1H), 7.06 (dd, J=14.4 Hz J=7.2 Hz, 1H), 6.58 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.45 (s, 1H), 5.74-5.64 (m, 2H), 5.50 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.10 (m, 1H), 4.74 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.34-4.28 (m, 1H), 2.74-2.69 (m, 2H), 2.56-2.50 (m, 2H), 2.34-2.29 (m, 3H), 1.36 (t, J=7.6 Hz, 1H), 0.80 (d, J=6.8 Hz, 3H), 0.6 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 168.9, 163.6, 162.9, 155.7, 148.6, 138.3, 134.7, 132.4, 128.6, 127.0, 124.9, 121.4, 71.9, 56.9, 43.3, 41.0, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 38

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.71 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 8.10 (s, J=7.6 Hz, 1H), 7.91 (s, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (s, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 39

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added heptanoyl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and 31 mg pale yellow solid was obtained. [α] 20 D : 4.11 (c 0.7, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.23 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.93 (s, 1H), 7.08 (m, J=7.2 Hz, 1H), 6.73 (s, 1H), 6.48 (d, J=10 Hz, 1H), 5.72-5.63 (m, 2H), 5.62-5.45 (m, 1H), 5.15 (dd, J=17.2 Hz, 8 Hz, 1H), 4.75-4.71 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.86-2.71 (m, 4H), 2.63-2.62 (m, 1H), 2.50 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.85-1.82 (m, 3H), 1.62-1.59 (m, 2H), 1.26-1.24 (m, 9H), 0.85 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.5, 169.0, 163.5, 162.1, 155.7, 148.8, 138.6, 134.5, 132.6, 132.1, 130.9, 128.9, 128.5, 127.5, 125.1, 121.3, 72.2, 71.7, 57.3, 44.1, 43.2, 40.9, 38.6, 33.8, 32.2, 31.5, 30.9, 29.7, 29.1, 28.8, 27.7, 27.6, 25.5, 22.5, 19.1, 18.9, 16.4, 14.6, 14.0 ppm.

›Example 40

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added hexanoyl chloride (0.04 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.11 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.22 (s, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.95 (s, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.75 (s, 1H), 6.46 (d, J=10.0 Hz, 1H), 5.74-5.68 (m, 2H), 5.50 (m, 1H), 5.17 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.76-4.73 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.88-2.75 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.84-1.82 (m, 3H), 1.63-1.60 (m, 2H), 1.26-1.24 (m, 7H), 0.84 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.59 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.3, 169.0, 163.2, 162.0, 155.6, 148.9, 138.8, 134.8, 132.7, 132.0, 130.9, 128.9, 128.6, 127.7, 125.3, 121.5, 72.3, 71.8, 57.5, 44.3, 43.4, 41.2, 38.9, 33.9, 32.5, 31.7, 30.9, 29.8, 29.2, 28.9, 27.8, 27.6, 25.6, 22.6, 19.0, 16.5, 14.7, 13.9 ppm.

›Example 41

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added pivaloyl chloride (0.04 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.11 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.22 (s, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.95 (s, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.75 (s, 1H), 6.46 (d, J=10.0 Hz, 1H), 5.74-5.68 (m, 2H), 5.50 (m, 1H), 5.17 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.76-4.73 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.88-2.75 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.84-1.82 (m, 3H), 1.63-1.60 (m, 2H), 1.26-1.24 (m, 7H), 0.84 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.59 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.3, 169.0, 163.2, 162.0, 155.6, 148.9, 138.8, 134.8, 132.7, 132.0, 130.9, 128.9, 128.6, 127.7, 125.3, 121.5, 72.3, 71.8, 57.5, 44.3, 43.4, 41.2, 38.9, 33.9, 32.5, 31.7, 30.9, 29.8, 29.2, 28.9, 27.8, 27.6, 25.6, 22.6, 19.0, 16.5, 14.7, 13.9 ppm.

›Example 42

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added butyryl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 6.51 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.23 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.98 (s, 1H), 7.09 (s, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.76-5.71 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77-4.74 (m, 2H), 4.27 (d, J=17.2 Hz, 1H), 2.88-2.74 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.33-2.28 (m, 3H), 1.86-1.83 (m, 3H), 1.66-1.62 (m, 2H), 1.27-1.24 (m, 3H), 0.86 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.56 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.4, 169.1, 163.5, 162.3, 155.8, 148.8, 138.9, 134.7, 132.9, 132.3, 130.9, 128.9, 128.4, 127.5, 125.3, 121.5, 72.2, 71.7, 57.6, 44.5, 43.6, 41.4, 38.9, 33.9, 32.7, 31.7, 30.9, 29.9, 29.5, 28.9, 27.7, 25.8, 22.9, 19.3, 15.5, 13.8 ppm.

›Example 43

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, propionyl chloride (0.05 ml) was added. After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 5.50 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.25 (s, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.08 (s, 1H), 6.77 (s, 1H), 6.48 (d, J=10.0 Hz, 1H), 5.75-5.72 (m, 2H), 5.55 (m, 1H), 5.19 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.78-4.75 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.89-2.75 (m, 4H), 2.65 (m, 1H), 2.48 (t, J=7.8 Hz, 3H), 2.35-2.29 (m, 3H), 1.88-1.85 (m, 3H), 1.66 (m, 2H), 0.86 (m, 3H), 0.77 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 169.2, 163.3, 162.2, 155.9, 148.9, 138.8, 134.8, 132.9, 132.2, 130.8, 128.9, 128.5, 127.6, 125.5, 121.6, 72.3, 71.8, 57.8, 44.6, 43.7, 41.5, 38.8, 33.9, 32.8, 31.8, 30.8, 29.9, 29.6, 28.9, 27.8, 25.9, 22.9, 19.5, 14.8 ppm.

›Example 44

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, acetyl chloride (0.05 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 4.66 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.26 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.09 (s, 1H), 6.79 (s, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.73-5.70 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.88-2.78 (m, 4H), 2.67 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.36-2.33 (m, 3H), 1.89-1.86 (m, 3H), 0.88 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.8, 169.3, 163.5, 162.5, 155.8, 148.8, 138.7, 134.7, 132.8, 132.3, 130.9, 128.8, 128.7, 127.7, 125.6, 121.7, 72.5, 71.9, 57.9, 44.7, 43.9, 41.6, 38.9, 33.8, 32.9, 31.9, 30.9, 29.8, 29.5, 28.8, 27.7, 15.0 ppm.

›Example 45

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, methanesulfonyl chloride (0.02 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 1.96 (c 0.1, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.63 (s, 1H), 9.23 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.88 (s, 1H), 7.07 (dd, J=14.4 Hz, J=7.2 Hz, 1H), 6.56 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.48 (s, 1H), 5.73 (m, 2H), 5.52 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.12 (m, 1H), 4.76 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.33 (m, 1H), 2.72 (m, 2H), 2.53 (m, 2H), 2.34-2.29 (m, 3H), 1.38 (t, J=7.6 Hz, 1H), 0.82 (d, J=6.8 Hz, 3H), 0.62 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 176.5, 169.8, 169.4, 163.6, 162.6, 155.7, 148.8, 138.5, 134.7, 132.5, 132.3, 130.9, 128.8, 127.8, 125.6, 121.8, 72.5, 71.7, 56.9, 44.8, 43.6, 41.5, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 46 · 1 of 2

46.1

15 ml LiOH aqueous solution (19 mmol) were added dropwise to the reactant (7.6 mmol) of 30 ml THF, then reacted 2 h at room temperature. The reaction solution was adjusted by dilute hydrochloric acid to with the pH value of 3, then 100 ml ethyl acetate was added. The organic matter was washed by water and saturated salt water. The organic layer was dried by anhydrous sodium sulfate, and the solvent evaporated to give a white flocculent solid. 1 H NMR (400 MHz, CDCl 3 ): δ7.77 (d, J=7.8 Hz, 1H), 7.56 (s, 1H), 7.48 (s, 1H), 5.55 (s, 1H), 4.48 (d, J=4.2 Hz, 2H), 3.48 (s, 3H), 1.36 (s, 9H) ppm.

46.2

At 0° C., DIPEA (1.2 ml, 6 mmol) was added to the reactant (2.7 mmol) slowly, stirred slightly, then added S2 (2.7 mmol), PyBop (4 mmol), and then stirred at room temperature overnight. The reaction solution was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution. The product was dried with anhydrous sodium sulfate and spinned solvent by column chromatography and white floc was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 8.64 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.81 (s, 1H), 7.44 (s, 1H), 5.44 (s, 1H), 4.77 (d, J=7.2 Hz, 1H), 4.48-4.45 (m, J=3H), 3.78 (s, 3H), 3.48 (s, 3H), 1.45 (s, 9H), 1.26 (d, J=5.6 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 171.1, 164.6, 157.4, 156.0, 148.9, 137.9, 134.6, 124.2, 121.8, 121.0, 80.7, 79.8, 78.7, 70.3, 68.2, 61.1, 57.8, 52.7, 52.2, 47.7, 32.1, 28.3, 28.2, 28.1, 28.0, 22.6, 19.8 ppm.

46.3

46.4

DABOCO (1 g, 9.22 mmol) was added to anhydrous DCM liquid (10 ml) obtained above, and stirred 8 h at room temperature. The reaction solution was washed by saturated sodium bicarbonate solution, saturated ammonium chloride solution, saturated sodium chloride solution in sequence, and dried by anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and white floc was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.38 (s, 1H), 7.78 (s, 1H), 7.41 (s, 1H), 6.86 (q, J=7.6 Hz, 1H), 5.57 (s, 1H), 4.44 (d, J=5.6 Hz, 2H), 3.74 (s, 9H), 3.48 (s, 3H), 3.48 (s, 3H), 1.80 (d, J=7.6 Hz, 3H), 1.40 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 164.8, 162.1, 157.4, 156.0, 148.9, 148.8, 138.1, 133.9, 126.3, 124.2, 123.5, 121.7, 121.0, 79.7, 52.1, 45.9, 28.3, 14.6 ppm.

46.5

5 ml LiOH aqueous solution (90 mg, 3.6 mmol) were added dropwise to reactants (1.44 mmol) with THF (10 ml), then spinned anhydrous the organic phase after three hours. 10 ml water and 15 ml ethyl acetate were added to the organic phase. The aqueous phase was removed after liquid separation. Then the solution was added 15 ml ethyl acetate, adjusted the acid. Anhydrous sodium sulfate was used for the separation of organic phase after liquid separation. Solid white floc was obtained after spinned anhydrous. 1 H NMR (400 MHz, CDCl 3 ): δ 9.40 (s, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 6.88 (q, J=7.8 Hz, 1H), 5.58 (s, 1H), 4.46 (d, J=5.8 Hz, 2H), 3.76 (s, 9H), 3.48 (s, 3H), 1.83 (d, J=7.8 Hz, 3H), 1.43 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 165.3, 162.7, 157.8, 156.2, 149.0, 148.8, 138.3, 133.7, 126.5, 124.5, 123.7, 121.9, 121.0, 52.5, 46.3, 28.5, 14.8 ppm.

46.6

At 0° C., DIPEA (0.7 ml), carboxylic acid (610 mg), HATU (760 mg), HOAT (326 mg) were added to the reactant (336 mg, 1 mmol) in DCM solution (10 ml) sequentially. Then raised to room temperature with stirring. After 8 h, the reaction was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and white flocculent solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.41 (s, 1H), 7.48 (s, 1H), 7.34 (s, 1H), 7.39-7.17 (m, 12H), 6.66-6.61 (m, 2H), 5.68-5.59 (m, 2H), 5.46 (s, 1H), 5.38-5.32 (m, 1H), 4.59 (dd, J=8.8 Hz, 4 Hz, 1H), 4.49 (d, J=4.2 Hz, 2H), 4.15-4.10 (m, 3H), 3.48 (s, 3H), 2.66 (dd, J=15.6 Hz, 7.6 Hz, 1H), 2.52 (dd, J=15.6 Hz, 5.6 Hz, 1H), 2.18-2.14 (m, 3H), 2.04 (t, J=6.8 Hz, 4H), 1.82 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 1.25 (t, J=6.8 Hz, 2H), 0.97-0.90 (m, 5H), 0.80 (d, J=6.8 Hz, 3H), 0.02 (s, 9H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 171.0, 170.7, 169.5, 164.3, 162.6, 157.3, 155.9, 148.5, 144.7, 138.2, 133.9, 129.6, 129.4, 129.0, 127.7, 127.6, 126.5, 124.6, 123.5, 121.1, 79.7, 71.8, 66.5, 63.0, 60.3, 57.0, 45.6, 39.5, 31.5, 31.2, 31.0, 28.3, 20.9, 18.8, 17.5, 17.2, 14.1, 13.8, 0.9, −1.5, −1.6 ppm.

46.7

Tetrabutylammonium fluoride in tetrahydrofuran solution (1 mol/l, 2.3 ml) was added to the reaction (0.92 mmol) in redistilled THF (5 ml). After 3 h, the reaction was immediately spinned anhydrous by column chromatography to obtain a white solid. DCM solution (25 ml) of the resulting resultant was added trifluoroacetic acid (6 ml). After 5 h, spinned and removed DCM, the residue was added toluene (8 ml). Without further treatment, a brown viscous material was obtained after pumped organic solvent with oil pump. Chromatography pure acetonitrile (200 ml) obtained above was dissolved, slowly dropped in HATU (3 g), DIPEA (4 ml) of HPLC grade acetonitrile (550 ml). After 24 h, spinned anhydrous solvents, the product was diluted with ethyl acetate (20 ml) and then washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and pale yellow solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.37-7.16 (m, 15H), 7.07 (q, J=7.2 Hz, 1H), 6.67 (s, 1H), 6.43 (s, 1H), 5.62-5.56 (m, 2H), 5.39-5.34 (m, 1H), 5.06 (dd, J=17.2 Hz, 8 Hz, 1H), 4.74 (dd, J=6.4 Hz, 3.6 Hz, 1H), 4.19-4.08 (m, 2H), 3.48 (s, 3H), 2.69-2.64 (m, 2H), 2.30-2.27 (m, 1H), 2.21-2.17 (m, 2H), 1.84 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO) δ 133.6, 132.0, 131.3, 126.1, 124.7, 123.3, 118.4, 111.1, 107.1, 101.0, 97.3, 95.2, 92.0, 90.4, 90.3, 89.5, 89.1, 87.5, 83.8, 39.8, 39.5, 39.3, 34.1, 29.1, 22.9, 19.5 ppm.

›Example 46 · 2 of 2

46.8

At 0° C., TES (0.1 ml), TFA (0.65 ml) were added to the reactants (150 mg, 0.21 mmol) in anhydrous DCM solution (5 ml) sequentially. 15 min later, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 6.13 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ7.41 (s, 1H), 7.21 (s, 1H), 7.06 (dd, J=14.4 Hz J=7.2 Hz, 1H), 6.58 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.45 (d, J=8 Hz, 1H), 5.74-5.64 (m, 2H), 5.50 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.10 (m, 1H), 4.74 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.34-4.28 (m, 1H), 3.48 (s, 3H), 2.74-2.69 (m, 2H), 2.56-2.50 (m, 2H), 2.34-2.29 (m, 3H), 1.36 (t, J=7.6 Hz, 1H), 0.80 (d, J=6.8 Hz, 3H), 0.6 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 168.9, 163.6, 162.9, 155.7, 148.6, 138.3, 134.7, 132.4, 128.6, 127.0, 124.9, 123.8, 121.4, 71.9, 56.9, 43.3, 41.0, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 47

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.71 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 7.24 (s, 1H), 7.11 (s, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 3.48 (s, 3H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 123.6, 121.3, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 48

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added heptanoyl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 4.11 (c 0.7, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.23 (s, 1H), 7.33 (s, 1H), 7.25 (s, 1H), 7.08 (m, J=7.2 Hz, 1H), 6.73 (d, J=4.4 Hz, 1H), 6.48 (d, J=10 Hz, 1H), 5.72-5.63 (m, 2H), 5.62-5.45 (m, 1H), 5.15 (dd, J=17.2 Hz, 8 Hz, 1H), 4.75-4.71 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.86-2.71 (m, 4H), 2.63-2.62 (m, 1H), 2.50 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.85-1.82 (m, 3H), 1.62-1.59 (m, 2H), 1.26-1.24 (m, 9H), 0.85 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.5, 169.0, 163.5, 162.1, 155.7, 148.8, 138.6, 134.5, 132.6, 132.1, 130.9, 128.9, 128.5, 127.5, 125.1, 124.1, 121.3, 72.2, 71.7, 57.3, 44.1, 43.2, 40.9, 38.6, 33.8, 32.2, 31.5, 30.9, 29.7, 29.1, 28.8, 27.7, 27.6, 25.5, 22.5, 19.1, 18.9, 16.4, 14.6, 14.0 ppm.

›Example 49

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added hexanoyl chloride (0.04 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.11 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.22 (s, 1H), 7.45 (s, 1H), 7.16 (s, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.46 (d, J=10.0 Hz, 1H), 5.74-5.68 (m, 2H), 5.50 (m, 1H), 5.17 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.76-4.73 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.88-2.75 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.84-1.82 (m, 3H), 1.63-1.60 (m, 2H), 1.26-1.24 (m, 7H), 0.84 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.59 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.3, 169.0, 163.2, 162.0, 155.6, 148.9, 138.8, 134.8, 132.7, 132.0, 130.9, 128.9, 128.6, 127.7, 125.3, 124.3, 121.5, 72.3, 71.8, 57.5, 44.3, 43.4, 41.2, 38.9, 33.9, 32.5, 31.7, 30.9, 29.8, 29.2, 28.9, 27.8, 27.6, 25.6, 22.6, 19.0, 16.5, 14.7, 13.9 ppm.

›Example 50

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added pivaloyl chloride (0.04 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and 30 mg pale yellow solid was obtained. The yield was 84%. [α] 20 D : 3.31 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.20 (s, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.21 (s, 1H), 7.08 (s, 1H), 6.73 (d, J=4.4 Hz, 1H), 6.49 (d, J=10.0 Hz, 1H), 5.73-5.69 (m, 2H), 5.51 (m, 1H), 5.15 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.75-4.73 (m, 2H), 4.29 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.89-2.75 (m, 4H), 2.62 (m, 1H), 2.47 (t, J=7.8 Hz, 3H), 2.31-2.26 (m, 3H), 1.85-1.83 (m, 3H), 1.62-1.60 (m, 2H), 1.25-1.23 (m, 5H), 0.83 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.2, 169.0, 163.3, 162.2, 155.7, 148.7, 138.9, 134.5, 132.8, 132.1, 130.8, 128.9, 128.5, 127.6, 125.2, 123.1, 121.3, 72.1, 71.6, 57.8, 44.2, 43.5, 41.3, 38.8, 33.8, 32.6, 31.6, 30.8, 29.9, 29.3, 28.8, 27.6, 25.7, 22.7, 19.1, 16.6, 14.9, 13.8 ppm.

›Example 51

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added butyryl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 6.51 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.23 (s, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.09 (s, 1H), 6.75 (s, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.76-5.71 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77-4.74 (m, 2H), 4.27 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.88-2.74 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.33-2.28 (m, 3H), 1.86-1.83 (m, 3H), 1.66-1.62 (m, 2H), 1.27-1.24 (m, 3H), 0.86 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.56 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.4, 169.1, 163.5, 162.3, 155.8, 148.8, 138.9, 134.7, 132.9, 132.3, 130.9, 128.9, 128.4, 127.5, 125.3, 123.9, 121.5, 72.2, 71.7, 57.6, 44.5, 43.6, 41.4, 38.9, 33.9, 32.7, 31.7, 30.9, 29.9, 29.5, 28.9, 27.7, 25.8, 22.9, 19.3, 15.5, 13.8 ppm.

›Example 52

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, was added propionyl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 5.50 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.25 (s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.08 (s, 1H), 6.77 (s, 1H), 6.48 (d, J=10.0 Hz, 1H), 5.75-5.72 (m, 2H), 5.55 (m, 1H), 5.19 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.78-4.75 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.89-2.75 (m, 4H), 2.65 (m, 1H), 2.48 (t, J=7.8 Hz, 3H), 2.35-2.29 (m, 3H), 1.88-1.85 (m, 3H), 1.66 (m, 2H), 0.86 (m, 3H), 0.77 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 169.2, 163.3, 162.2, 155.9, 148.9, 138.8, 134.8, 132.9, 132.2, 130.8, 128.9, 128.5, 127.6, 125.5, 124.7, 121.6, 72.3, 71.8, 57.8, 44.6, 43.7, 41.5, 38.8, 33.9, 32.8, 31.8, 30.8, 29.9, 29.6, 28.9, 27.8, 25.9, 22.9, 19.5, 14.8 ppm.

›Example 53

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, acetyl chloride (0.05 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 4.66 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.26 (s, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.09 (s, 1H), 6.79 (s, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.73-5.70 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.88-2.78 (m, 4H), 2.67 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.36-2.33 (m, 3H), 1.89-1.86 (m, 3H), 0.88 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.8, 169.3, 163.5, 162.5, 155.8, 148.8, 138.7, 134.7, 132.8, 132.3, 130.9, 128.8, 128.7, 127.7, 125.6, 123.4, 121.7, 72.5, 71.9, 57.9, 44.7, 43.9, 41.6, 38.9, 33.8, 32.9, 31.9, 30.9, 29.8, 29.5, 28.8, 27.7, 15.0 ppm.

›Example 54

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, methanesulfonyl chloride (0.02 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 1.96 (c 0.1, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.63 (s, 1H), 9.23 (s, 1H), 7.18 (s, 1H), 7.02 (s, 1H), 7.07 (dd, J=14.4 Hz, J=7.2 Hz, 1H), 6.56 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.48 (d, J=8 Hz, 1H), 5.73 (m, 2H), 5.52 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.12 (m, 1H), 4.76 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.33 (m, 1H), 3.48 (s, 3H), 2.72 (m, 2H), 2.53 (m, 2H), 2.34-2.29 (m, 3H), 1.38 (t, J=7.6 Hz, 1H), 0.82 (d, J=6.8 Hz, 3H), 0.62 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 176.5, 169.8, 169.4, 163.6, 162.6, 155.7, 148.8, 138.5, 134.7, 132.5, 132.3, 130.9, 128.8, 127.8, 125.6, 123.6, 121.8, 72.5, 71.7, 56.9, 44.8, 43.6, 41.5, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 55

55.1

At 0° C., DIPEA (0.7 ml), the product of Example 37.5, HATU (760 mg), HOAT (326 mg) were added to the reactant (1 mmol) in DCM solution (10 ml) sequentially, and raised to room temperature with stirring. After 8 h, the reaction was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and white flocculent solid solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.41 (s, 1H), 7.14 (s, 1H), 7.08 (s, 1H), 7.39-7.17 (m, 12H), 6.66-6.61 (m, 2H), 5.68-5.59 (m, 2H), 5.46 (s, 1H), 5.38-5.32 (m, 1H), 4.59 (dd, J=8.8 Hz, 4 Hz, 1H), 4.49 (d, J=4.2 Hz, 2H), 4.15-4.10 (m, 3H), 2.66 (dd, J=15.6 Hz, 7.6 Hz, 1H), 2.52 (dd, J=15.6 Hz, 5.6 Hz, 1H), 2.18-2.14 (m, 3H), 2.04 (t, J=6.8 Hz, 4H), 1.82 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 1.25 (t, J=6.8 Hz, 2H), 0.97-0.90 (m, 5H), 0.80 (d, J=6.8 Hz, 3H), 0.02 (s, 9H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 171.0, 170.7, 169.5, 164.3, 162.6, 157.3, 155.9, 148.5, 144.7, 138.2, 133.9, 129.6, 129.4, 129.0, 127.7, 127.6, 126.5, 124.6, 121.1, 79.7, 77.2, 77.0, 76.7, 71.8, 66.5, 63.0, 60.3, 57.0, 45.6, 39.5, 31.5, 31.2, 31.0, 28.3, 20.9, 18.8, 17.5, 17.2, 14.1, 13.8, 0.9, −1.5, −1.6 ppm.

55.2

Tetrabutylammonium fluoride in tetrahydrofuran solution (1 mol/l, 2.3 ml) was added to the reaction (0.90 mmol) in redistilled THF (5 ml). After 3 h, the reaction was immediately spinned anhydrous by column chromatography to obtain a white solid. DCM solution (25 ml) of the resulting resultant was added trifluoroacetic acid (6 ml). After 5 h, spinned and removed DCM, the residue was added toluene (8 ml). Without further treatment, a brown viscous material was obtained after pumped organic solvent with oil pump. Chromatography pure acetonitrile (200 ml) obtained above was dissolved, slowly dropped in HATU (3 g), DIPEA (4 ml) of HPLC grade acetonitrile (550 ml). After 24 h, spinned anhydrous solvents, the product was diluted with ethyl acetate (20 ml) and then washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and pale yellow solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.07 (s, 1H), 7.37-7.16 (m, 15H), 7.07 (q, J=7.2 Hz, 1H), 6.33 (s, 1H), 5.62-5.56 (m, 2H), 5.39-5.34 (m, 1H), 5.06 (dd, J=17.2 Hz, 8 Hz, 1H), 4.74 (dd, J=6.4 Hz, 3.6 Hz, 1H), 4.19-4.08 (m, 2H), 2.69-2.64 (m, 2H), 2.30-2.27 (m, 1H), 2.21-2.17 (m, 2H), 1.84 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO) δ 133.64, 132.05, 131.39, 126.08, 124.66, 118.36, 111.05, 107.13, 100.97, 97.27, 95.22, 91.96, 90.37, 90.32, 89.54, 89.11, 87.45, 83.79, 39.76, 39.50, 39.25, 34.06, 29.13, 22.85, 19.48 ppm.

55.3

At 0° C., TES (0.1 ml), TFA (0.65 ml) were added to the reactants (0.21 mmol) in anhydrous DCM solution (5 ml) sequentially. 15 min later, the product was directly spinned anhydrous solvent by column chromatography and yellow solid was obtained. [α] 20 D : 6.13 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ7.88 (d, J=7.6 Hz, 1H), 7.19 (s, 1H), 7.06 (dd, J=14.4 Hz J=7.2 Hz, 1H), 6.58 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.45 (s, 1H), 5.74-5.64 (m, 2H), 5.50 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.10 (m, 1H), 4.74 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.34-4.28 (m, 1H), 2.74-2.69 (m, 2H), 2.56-2.50 (m, 2H), 2.34-2.29 (m, 3H), 1.36 (t, J=7.6 Hz, 1H), 0.80 (d, J=6.8 Hz, 3H), 0.6 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 168.9, 163.6, 162.9, 155.7, 148.6, 138.3, 134.7, 132.4, 128.6, 127.0, 124.9, 121.4, 77.2, 76.9, 76.7, 71.9, 56.9, 43.3, 41.0, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 56

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.71 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.36 (s, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 199.5, 169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 77.2, 77.0, 76.7, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 57

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, acetyl chloride (0.05 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and yellow solid was obtained. [α] 20 D : 4.66 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.26 (s, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.09 (m, J=7.8 Hz, 1H), 6.79 (s, 1H), 6.47 (s, J=10.0 Hz, 1H), 5.73-5.70 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.88-2.78 (m, 4H), 2.67 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.36-2.33 (m, 3H), 1.89-1.86 (m, 3H), 0.88 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.8, 169.3, 163.5, 162.5, 155.8, 148.8, 138.7, 134.7, 132.8, 132.3, 130.9, 128.8, 128.7, 127.7, 125.6, 121.7, 72.5, 71.9, 57.9, 44.7, 43.9, 41.6, 38.9, 33.8, 32.9, 31.9, 30.9, 29.8, 29.5, 28.8, 27.7, 15.0 ppm.

›Example 58 · 1 of 2

58.1

15 ml LiOH aqueous solution (456 mg, 19 mmol) were added dropwise to the reactant (7.6 mmol) of 30 ml THF, then reacted 2 h at room temperature. The reaction solution was adjusted by dilute hydrochloric acid to with the pH value of 3, then 100 ml ethyl acetate was added. The organic matter was washed by water and saturated salt water. The organic layer was dried by anhydrous sodium sulfate, and the solvent evaporated to give white flocculent solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.96 (d, J=8.0 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 5.55 (s, 1H), 4.48 (d, J=4.2 Hz, 2H), 1.36 (s, 9H) ppm.

58.2

At 0° C., DIPEA (1.2 ml, 6 mmol) was added to the reactant (2.7 mmol) slowly, stirred slightly, then added S2 (2.7 mmol), PyBop (2.5 g, 4 mmol), and then stirred at room temperature overnight. The reaction solution was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution. The product was dried with anhydrous sodium sulfate and spinned solvent by column chromatography and white floc was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 8.64 (d, J=8.4 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 5.44 (s, 1H), 4.77 (d, J=7.2 Hz, 1H), 4.48-4.45 (m, J=3H), 3.78 (s, 3H), 1.45 (s, 9H), 1.26 (d, J=5.6 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 171.1, 164.6, 157.4, 156.0, 148.9, 137.9, 134.6, 124.2, 121.8, 121.0, 80.7, 79.8, 78.7, 70.3, 68.2, 61.1, 57.8, 52.7, 52.2, 47.7, 32.1, 28.3, 28.2, 28.1, 28.0, 22.6, 19.8 ppm.

58.3

At 0° C., DMAP (25 mg, 0.184 mmol), NEt 3 (0.42 ml, 3 mmol), MsCl (0.186 ml, 2.4 mmol) were added to anhydrous DCM (10 ml) of the reactants (1.84 mmol) successively, then raised to room temperature and stirred overnight. The product was spinned anhydrous, pumped with oil pump and directly put into next step.

58.4

DABOCO (1 g, 9.22 mmol) was added to anhydrous DCM liquid (10 ml) obtained above and stirred 8 h at room temperature. The reaction solution was washed by saturated sodium bicarbonate solution, saturated ammonium chloride solution, saturated sodium chloride solution in sequence, and dried by anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and white floc was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.38 (s, 1H), 7.88 (d, J=8 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 6.86 (q, J=7.6 Hz, 1H), 5.57 (s, 1H), 4.44 (d, J=5.6 Hz, 2H), 3.74 (s, 9H), 1.80 (d, J=7.6 Hz, 3H), 1.40 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 164.8, 162.1, 157.4, 156.0, 148.9, 148.8, 138.1, 133.9, 126.3, 124.2, 121.7, 121.0, 79.7, 52.1, 45.9, 28.3, 14.6 ppm.

58.5

5 ml LiOH aqueous solution (90 mg, 3.6 mmol) were added dropwise to reactants (1.44 mmol) with THF (10 ml), then spinned anhydrous the organic phase after three hours. 10 ml water and 15 ml ethyl acetate were added to the organic phase. The aqueous phase was removed after liquid separation. Then the solution was added 15 ml ethyl acetate, adjusted the acid. Anhydrous sodium sulfate was used for the separation of organic phase after liquid separation. Solid white floc was obtained after spinned anhydrous. 1 H NMR (400 MHz, CDCl 3 ): δ 9.40 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 6.88 (q, J=7.8 Hz, 1H), 5.58 (s, 1H), 4.46 (d, J=5.8 Hz, 2H), 3.76 (s, 9H), 1.83 (d, J=7.8 Hz, 3H), 1.43 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 165.3, 162.7, 157.8, 156.2, 149.0, 148.8, 138.3, 133.7, 126.5, 124.5, 121.9, 121.0, 52.5, 46.3, 28.5, 14.8 ppm.

58.6

At 0° C., DIPEA (0.7 ml), carboxylic acid (610 mg), HATU (760 mg), HOAT (326 mg) were added to the reactant (1 mmol) in DCM solution (10 ml) sequentially. Then raised to room temperature with stirring. After 8 h, the reaction was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and white flocculent solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.41 (s, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.39-7.17 (m, 12H), 6.66-6.61 (m, 2H), 5.68-5.59 (m, 2H), 5.46 (s, 1H), 5.38-5.32 (m, 1H), 4.59 (dd, J=8.8 Hz, 4 Hz, 1H), 4.49 (d, J=4.2 Hz, 2H), 4.15-4.10 (m, 3H), 2.66 (dd, J=15.6 Hz, 7.6 Hz, 1H), 2.52 (dd, J=15.6 Hz, 5.6 Hz, 1H), 2.18-2.14 (m, 3H), 2.04 (t, J=6.8 Hz, 4H), 1.82 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 1.25 (t, J=6.8 Hz, 2H), 0.97-0.90 (m, 5H), 0.80 (d, J=6.8 Hz, 3H), 0.02 (s, 9H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 171.0, 170.7, 169.5, 164.3, 162.6, 157.3, 155.9, 148.5, 144.7, 138.2, 133.9, 129.6, 129.4, 129.0, 127.7, 127.6, 126.5, 124.6, 121.1, 79.7, 71.8, 66.5, 63.0, 60.3, 57.0, 45.6, 39.5, 31.5, 31.2, 31.0, 28.3, 20.9, 18.8, 17.5, 17.2, 14.1, 13.8, 0.9, −1.5, −1.6 ppm.

58.7

Tetrabutylammonium fluoride in tetrahydrofuran solution (1 mol/l, 2.3 ml) was added to the reaction (0.92 mmol) in redistilled THF (5 ml). After 3 h, the reaction was immediately spinned anhydrous by column chromatography to obtain a white solid. DCM solution (25 ml) of the resulting resultant was added trifluoroacetic acid (6 ml). After 5 h, spinned and removed DCM, the residue was added toluene (8 ml). Without further treatment, a brown viscous material was obtained after pumped organic solvent with oil pump. Chromatography pure acetonitrile (200 ml) obtained above was dissolved, slowly dropped in HATU (3 g), DIPEA (4 ml) of HPLC grade acetonitrile (550 ml). After 24 h, spinned anhydrous solvents, the product was diluted with ethyl acetate (20 ml) and then washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and pale yellow solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (s, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.37-7.16 (m, 15H), 7.07 (q, J=7.2 Hz, 1H), 6.43 (d, J=10.4 Hz, 1H), 5.62-5.56 (m, 2H), 5.39-5.34 (m, 1H), 5.06 (dd, J=17.2 Hz, 8 Hz, 1H), 4.74 (dd, J=6.4 Hz, 3.6 Hz, 1H), 4.19-4.08 (m, 2H), 2.69-2.64 (m, 2H), 2.30-2.27 (m, 1H), 2.21-2.17 (m, 2H), 1.84 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO) δ 133.6, 132.0, 131.3, 126.1, 124.7, 118.4, 111.1, 107.1, 101.0, 97.3, 95.2, 92.0, 90.4, 90.3, 89.5, 89.1, 87.5, 83.8, 39.8, 39.5, 39.3, 34.1, 29.1, 22.9, 19.5 ppm.

›Example 58 · 2 of 2

58.8

At 0° C., TES (0.1 ml), TFA (0.65 ml) were added to the reactants (0.21 mmol) in anhydrous DCM solution (5 ml) sequentially. 15 min later, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 6.13 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 8.18 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.06 (dd, J=14.4 Hz J=7.2 Hz, 1H), 6.58 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.45 (d, J=8 Hz, H), 5.74-5.64 (m, 2H), 5.50 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.10 (m, 1H), 4.74 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.34-4.28 (m, 1H), 2.74-2.69 (m, 2H), 2.56-2.50 (m, 2H), 2.34-2.29 (m, 3H), 1.36 (t, J=7.6 Hz, 1H), 0.80 (d, J=6.8 Hz, 3H), 0.6 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 168.9, 163.6, 162.9, 155.7, 148.6, 138.3, 134.7, 132.4, 128.6, 127.0, 124.9, 121.4, 71.9, 56.9, 43.3, 41.0, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 59

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.71 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.51 (d, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 60

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added heptanoyl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 4.11 (c 0.7, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.23 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.08 (m, J=7.2 Hz, 1H), 6.73 (d, J=4.4 Hz, 1H), 6.48 (d, J=10 Hz, 1H), 5.72-5.63 (m, 2H), 5.62-5.45 (m, 1H), 5.15 (dd, J=17.2 Hz, 8 Hz, 1H), 4.75-4.71 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.86-2.71 (m, 4H), 2.63-2.62 (m, 1H), 2.50 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.85-1.82 (m, 3H), 1.62-1.59 (m, 2H), 1.26-1.24 (m, 9H), 0.85 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.5, 169.0, 163.5, 162.1, 155.7, 148.8, 138.6, 134.5, 132.6, 132.1, 130.9, 128.9, 128.5, 127.5, 125.1, 121.3, 72.2, 71.7, 57.3, 44.1, 43.2, 40.9, 38.6, 33.8, 32.2, 31.5, 30.9, 29.7, 29.1, 28.8, 27.7, 27.6, 25.5, 22.5, 19.1, 18.9, 16.4, 14.6, 14.0 ppm.

›Example 61

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added hexanoyl chloride (0.04 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.11 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.22 (s, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.46 (d, J=10.0 Hz, 1H), 5.74-5.68 (m, 2H), 5.50 (m, 1H), 5.17 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.76-4.73 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.88-2.75 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.84-1.82 (m, 3H), 1.63-1.60 (m, 2H), 1.26-1.24 (m, 7H), 0.84 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.59 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.3, 169.0, 163.2, 162.0, 155.6, 148.9, 138.8, 134.8, 132.7, 132.0, 130.9, 128.9, 128.6, 127.7, 125.3, 121.5, 72.3, 71.8, 57.5, 44.3, 43.4, 41.2, 38.9, 33.9, 32.5, 31.7, 30.9, 29.8, 29.2, 28.9, 27.8, 27.6, 25.6, 22.6, 19.0, 16.5, 14.7, 13.9 ppm.

›Example 62

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added pivaloyl chloride (0.04 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.31 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.20 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.73 (d, J=4.4 Hz, 1H), 6.49 (d, J=10.0 Hz, 1H), 5.73-5.69 (m, 2H), 5.51 (m, 1H), 5.15 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.75-4.73 (m, 2H), 4.29 (d, J=17.2 Hz, 1H), 2.89-2.75 (m, 4H), 2.62 (m, 1H), 2.47 (t, J=7.8 Hz, 3H), 2.31-2.26 (m, 3H), 1.85-1.83 (m, 3H), 1.62-1.60 (m, 2H), 1.25-1.23 (m, 5H), 0.83 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.2, 169.0, 163.3, 162.2, 155.7, 148.7, 138.9, 134.5, 132.8, 132.1, 130.8, 128.9, 128.5, 127.6, 125.2, 121.3, 72.1, 71.6, 57.8, 44.2, 43.5, 41.3, 38.8, 33.8, 32.6, 31.6, 30.8, 29.9, 29.3, 28.8, 27.6, 25.7, 22.7, 19.1, 16.6, 14.9, 13.8 ppm.

›Example 63

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added butyryl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 6.51 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.23 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.76-5.71 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77-4.74 (m, 2H), 4.27 (d, J=17.2 Hz, 1H), 2.88-2.74 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.33-2.28 (m, 3H), 1.86-1.83 (m, 3H), 1.66-1.62 (m, 2H), 1.27-1.24 (m, 3H), 0.86 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.56 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.4, 169.1, 163.5, 162.3, 155.8, 148.8, 138.9, 134.7, 132.9, 132.3, 130.9, 128.9, 128.4, 127.5, 125.3, 121.5, 72.2, 71.7, 57.6, 44.5, 43.6, 41.4, 38.9, 33.9, 32.7, 31.7, 30.9, 29.9, 29.5, 28.9, 27.7, 25.8, 22.9, 19.3, 15.5, 13.8 ppm.

›Example 64

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, was added propionyl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 5.50 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.25 (s, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H), 6.48 (d, J=10.0 Hz, 1H), 5.75-5.72 (m, 2H), 5.55 (m, 1H), 5.19 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.78-4.75 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.89-2.75 (m, 4H), 2.65 (m, 1H), 2.48 (t, J=7.8 Hz, 3H), 2.35-2.29 (m, 3H), 1.88-1.85 (m, 3H), 1.66 (m, 2H), 0.86 (m, 3H), 0.77 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 169.2, 163.3, 162.2, 155.9, 148.9, 138.8, 134.8, 132.9, 132.2, 130.8, 128.9, 128.5, 127.6, 125.5, 121.6, 72.3, 71.8, 57.8, 44.6, 43.7, 41.5, 38.8, 33.9, 32.8, 31.8, 30.8, 29.9, 29.6, 28.9, 27.8, 25.9, 22.9, 19.5, 14.8 ppm.

›Example 65

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, acetyl chloride (0.05 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 4.66 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.26 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.79 (d, J=4.4 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.73-5.70 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.88-2.78 (m, 4H), 2.67 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.36-2.33 (m, 3H), 1.89-1.86 (m, 3H), 0.88 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.8, 169.3, 163.5, 162.5, 155.8, 148.8, 138.7, 134.7, 132.8, 132.3, 130.9, 128.8, 128.7, 127.7, 125.6, 121.7, 72.5, 71.9, 57.9, 44.7, 43.9, 41.6, 38.9, 33.8, 32.9, 31.9, 30.9, 29.8, 29.5, 28.8, 27.7, 15.0 ppm.

›Example 66

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, methanesulfonyl chloride (0.02 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and 26 mg pale yellow solid was obtained. The yield was 75%. [α] 20 D : 1.96 (c 0.1, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.63 (s, 1H), 9.23 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.07 (dd, J=14.4 Hz, J=7.2 Hz, 1H), 6.56 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.48 (d, J=8 Hz, 1H), 5.73 (m, 2H), 5.52 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.12 (m, 1H), 4.76 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.33 (m, 1H), 2.72 (m, 2H), 2.53 (m, 2H), 2.34-2.29 (m, 3H), 1.38 (t, J=7.6 Hz, 1H), 0.82 (d, J=6.8 Hz, 3H), 0.62 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 176.5, 169.8, 169.4, 163.6, 162.6, 155.7, 148.8, 138.5, 134.7, 132.5, 132.3, 130.9, 128.8, 127.8, 125.6, 121.8, 72.5, 71.7, 56.9, 44.8, 43.6, 41.5, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 67

67.1

At 0° C., DIPEA (0.7 ml), the product (610 mg) of Example 58.5, HATU (760 mg), HOAT (326 mg) were added to the reactant (1 mmol) in DCM solution (10 ml) sequentially, and raised to room temperature with stirring. After 8 h, the reaction was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and white flocculent solid solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.36 (s, 1H), 8.11 (d, J=7.6 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.39-7.18 (m, 12H), 6.68-6.63 (m, 2H), 5.66-5.60 (m, 2H), 5.47 (s, 1H), 5.38-5.32 (m, 1H), 4.61 (dd, J=8.8 Hz, 4 Hz, 1H), 4.51 (d, J=4.2 Hz, 2H), 4.16-4.11 (m, 3H), 2.67 (dd, J=15.6 Hz, 7.6 Hz, 1H), 2.53 (dd, J=15.6 Hz, 5.6 Hz, 1H), 2.19-2.15 (m, 3H), 2.05 (t, J=6.8 Hz, 4H), 1.83 (d, J=7.2 Hz, 3H), 1.49 (s, 9H), 1.27 (t, J=6.8 Hz, 2H), 0.95-0.91 (m, 3H), 0.82 (d, J=6.8 Hz, 3H), 0.02 (s, 9H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 171.1, 170.8, 169.6, 164.2, 162.7, 157.4, 155.9, 148.6, 144.7, 138.4, 133.9, 129.7, 129.4, 129.0, 127.6, 126.5, 124.6, 121.1, 79.7, 71.8, 66.5, 63.0, 60.3, 57.0, 45.6, 39.5, 31.5, 31.2, 31.0, 28.3, 20.9, 18.8, 17.5, 17.2, 14.1, 0.9, −1.5, −1.6 ppm.

67.2

Tetrabutylammonium fluoride in tetrahydrofuran solution (1 mol/l, 2.3 ml) was added to the reaction (0.90 mmol) in redistilled THF (5 ml). After 3 h, the reaction was immediately spinned anhydrous by column chromatography to obtain a white solid. DCM solution (25 ml) of the resulting resultant was added trifluoroacetic acid (6 ml). After 5 h, spinned and removed DCM, the residue was added toluene (8 ml). Without further treatment, a brown viscous material was obtained after pumped organic solvent with oil pump. Chromatography pure acetonitrile (200 ml) obtained above was dissolved, slowly dropped in HATU (3 g), DIPEA (4 ml) of HPLC grade acetonitrile (550 ml). After 24 h, spinned anhydrous solvents, the product was diluted with ethyl acetate (20 ml) and then washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and pale yellow solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.37-7.16 (m, 15H), 7.17 (d, J=7.6 Hz, 1H), 7.07 (q, J=7.2 Hz, 1H), 6.43 (d, J=10.4 Hz, 1H), 5.62-5.56 (m, 2H), 5.39-5.34 (m, 1H), 5.06 (dd, J=17.2 Hz, 8 Hz, 1H), 4.74 (dd, J=6.4 Hz, 3.6 Hz, 1H), 4.19-4.08 (m, 2H), 2.69-2.64 (m, 2H), 2.30-2.27 (m, 1H), 2.21-2.17 (m, 2H), 1.84 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO) δ 133.64, 132.05, 131.39, 126.08, 124.66, 118.36, 111.05, 107.13, 100.97, 97.27, 95.22, 91.96, 90.37, 90.32, 89.54, 89.11, 87.45, 83.79, 39.76, 39.50, 39.25, 34.06, 29.13, 22.85, 19.48 ppm.

67.3

At 0° C., TES (0.1 ml), TFA (0.65 ml) were added to the reactants (0.21 mmol) in anhydrous DCM solution (5 ml) sequentially. 15 min later, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 6.13 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 8.18 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.06 (dd, J=14.4 Hz J=7.2 Hz, 1H), 6.58 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.45 (d, J=8 Hz, 1H), 5.74-5.64 (m, 2H), 5.50 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.10 (m, 1H), 4.74 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.34-4.28 (m, 1H), 2.74-2.69 (m, 2H), 2.56-2.50 (m, 2H), 2.34-2.29 (m, 3H), 1.36 (t, J=7.6 Hz, 1H), 0.80 (d, J=6.8 Hz, 3H), 0.6 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 168.9, 163.6, 162.9, 155.7, 148.6, 138.3, 134.7, 132.4, 128.6, 127.0, 124.9, 121.4, 77.2, 76.9, 76.7, 71.9, 56.9, 43.3, 41.0, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 68

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.71 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 199.5, 169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 77.2, 77.0, 76.7, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 69

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.71 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 199.5, 169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 77.2, 77.0, 76.7, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 70

70.1

At 0° C., DIPEA (0.7 ml), the product (610 mg) of Example 1.5, HATU (760 mg), HOAT (326 mg) were added to the reactant (1 mmol) in DCM solution (10 ml) sequentially, and raised to room temperature with stirring. After 8 h, the reaction was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and white flocculent solid solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.41 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.39-7.17 (m, 12H), 6.66-6.61 (m, 2H), 5.68-5.59 (m, 2H), 5.46 (s, 1H), 5.38-5.32 (m, 1H), 4.59 (dd, J=8.8 Hz, 4 Hz, 1H), 4.49 (d, J=4.2 Hz, 2H), 4.15-4.10 (m, 3H), 2.66 (dd, J=15.6 Hz, 7.6 Hz, 1H), 2.52 (dd, J=15.6 Hz, 5.6 Hz, 1H), 2.18-2.14 (m, 3H), 2.04 (t, J=6.8 Hz, 4H), 1.82 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 1.25 (t, J=6.8 Hz, 2H), 0.97-0.90 (m, 5H), 0.80 (d, J=6.8 Hz, 3H), 0.02 (s, 9H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 171.0, 170.7, 169.5, 164.3, 162.6, 157.3, 155.9, 148.5, 144.7, 138.2, 133.9, 129.6, 129.4, 129.0, 127.7, 127.6, 126.5, 124.6, 121.1, 79.7, 77.2, 77.0, 76.7, 71.8, 66.5, 63.0, 60.3, 57.0, 45.6, 39.5, 31.5, 31.2, 31.0, 28.3, 20.9, 18.8, 17.5, 17.2, 14.1, 13.8, 0.9, −1.5, −1.6 ppm.

70.2

Tetrabutylammonium fluoride in tetrahydrofuran solution (1 mol/l, 2.3 ml) was added to the reaction (0.90 mmol) in redistilled THF (5 ml). After 3 h, the reaction was immediately spinned anhydrous by column chromatography to obtain a white solid. DCM solution (25 ml) of the resulting resultant was added trifluoroacetic acid (6 ml). After 5 h, spinned and removed DCM, the residue was added toluene (8 ml). Without further treatment, a brown viscous material was obtained after pumped organic solvent with oil pump. Chromatography pure acetonitrile (200 ml) obtained above was dissolved, slowly dropped in HATU (3 g), DIPEA (4 ml) of HPLC grade acetonitrile (550 ml). After 24 h, spinned anhydrous solvents, the product was diluted with ethyl acetate (20 ml) and then washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and pale yellow solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.37-7.16 (m, 15H), 7.07 (q, J=7.2 Hz, 1H), 6.43 (d, J=10.4 Hz, 1H), 5.62-5.56 (m, 2H), 5.39-5.34 (m, 1H), 5.06 (dd, J=17.2 Hz, 8 Hz, 1H), 4.74 (dd, J=6.4 Hz, 3.6 Hz, 1H), 4.19-4.08 (m, 2H), 2.69-2.64 (m, 2H), 2.30-2.27 (m, 1H), 2.21-2.17 (m, 2H), 1.84 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO) δ 133.64, 132.05, 131.39, 126.08, 124.66, 118.36, 111.05, 107.13, 100.97, 97.27, 95.22, 91.96, 90.37, 90.32, 89.54, 89.11, 87.45, 83.79, 39.76, 39.50, 39.25, 34.06, 29.13, 22.85, 19.48 ppm.

70.3

At 0° C., TES (0.1 ml), TFA (0.65 ml) were added to the reactants (150 mg, 0.21 mmol) in anhydrous DCM solution (5 ml) sequentially. 15 min later, the product was directly spinned anhydrous solvent by column chromatography and 63 mg yellow solid was obtained, and the yield was 63%. [α] 20 D : 6.13 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 8.18 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.06 (dd, J=14.4 Hz J=7.2 Hz, 1H), 6.58 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.45 (d, J=8 Hz, 1H), 5.74-5.64 (m, 2H), 5.50 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.10 (m, 1H), 4.74 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.34-4.28 (m, 1H), 2.74-2.69 (m, 2H), 2.56-2.50 (m, 2H), 2.34-2.29 (m, 3H), 1.36 (t, J=7.6 Hz, 1H), 0.80 (d, J=6.8 Hz, 3H), 0.6 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 168.9, 163.6, 162.9, 155.7, 148.6, 138.3, 134.7, 132.4, 128.6, 127.0, 124.9, 121.4, 77.2, 76.9, 76.7, 71.9, 56.9, 43.3, 41.0, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 71

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.71 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 199.5, 169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 77.2, 77.0, 76.7, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 72

At 0° C., redistilled NEt 3 (0.04 ml) was added to the reactant (0.126 mmol) in anhydrous DCM (5 ml), stirred slightly, then added caprylate chloride (0.1 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and yellow solid was obtained. [α] 20 D : 3.71 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.21 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.70 (d, J=4.4 Hz, 1H), 6.46 (d, J=10 Hz, 1H), 5.70-5.64 (m, 2H), 5.59-5.46 (m, 1H), 5.13 (dd, J=17.2 Hz, 8 Hz, 1H), 4.73-4.70 (m, 2H), 4.27 (d, J=J=17.2 Hz, 1H), 2.85-2.71 (m, 4H), 2.62-2.61 (m, 1H), 2.49 (t, J=7.6 Hz, 3H), 2.29-2.23 (m, 3H), 1.84-1.81 (m, 3H), 1.61-1.58 (m, 2H), 1.24 (s, 11H), 0.86-0.57 (m, 7H), 0.53 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 199.5, 169.6, 169.1, 167.6, 165.7, 163.7, 162.3, 155.8, 148.6, 138.5, 134.7, 132.5, 132.2, 130.8, 128.7, 128.2, 127.2, 124.9, 121.3, 77.2, 77.0, 76.7, 72.0, 71.6, 56.9, 44.0, 43.2, 40.8, 38.5, 33.7, 32.1, 31.5, 30.8, 29.6, 29.0, 28.8, 28.8, 27.7, 27.6, 25.5, 24.7, 22.5, 19.0, 18.9, 16.4, 14.6, 13.9 ppm.

›Example 73

73.1

15 ml LiOH aqueous (19 mmol) solution (7.6 mmol) were added dropwise to the reactant (7.6 mmol) of 30 ml THF, then reacted 2 h at room temperature. The reaction solution was adjusted by dilute hydrochloric acid to with the pH value of 3, then 100 ml ethyl acetate was added. The organic matter was washed by water and saturated salt water. The organic layer was dried by anhydrous sodium sulfate, and the solvent evaporated to give a white flocculent solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.77 (d, J=8.0 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 5.55 (s, 1H), 4.48 (d, J=4.2 Hz, 2H), 3.48 (s, 3H), 1.36 (s, 9H) ppm.

73.2

At 0° C., DIPEA (1.2 ml, 6 mmol) was added to the reactant (2.7 mmol) slowly, stirred slightly, then added S2 (2.7 mmol), PyBop (4 mmol), and then stirred at room temperature overnight. The reaction solution was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution. The product was dried with anhydrous sodium sulfate and spinned solvent by column chromatography and white floc was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 8.64 (d, J=8.4 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.81 (d, J=8 Hz, 1H), 5.44 (s, 1H), 4.77 (d, J=7.2 Hz, 1H), 4.48-4.45 (m, J=3H), 3.78 (s, 3H), 3.48 (s, 3H), 1.45 (s, 9H), 1.26 (d, J=5.6 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 171.1, 164.6, 157.4, 156.0, 148.9, 137.9, 134.6, 124.2, 123.2, 121.8, 121.0, 80.7, 79.8, 78.7, 70.3, 68.2, 61.1, 57.8, 52.7, 52.2, 47.7, 32.1, 28.3, 28.2, 28.1, 28.0, 22.6, 19.8 ppm.

73.3

73.4

DABOCO (1 g, 9.22 mmol) was added to anhydrous DCM liquid (10 ml) obtained above and stirred 8 h at room temperature. The reaction solution was washed by saturated sodium bicarbonate solution, saturated ammonium chloride solution, saturated sodium chloride solution in sequence, and dried by anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and white floc was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.38 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 6.86 (q, J=7.6 Hz, 1H), 5.57 (s, 1H), 4.44 (d, J=5.6 Hz, 2H), 3.74 (s, 9H), 3.48 (s, 3H), 3.48 (s, 3H), 1.80 (d, J=7.6 Hz, 3H), 1.40 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 164.8, 162.1, 157.4, 156.0, 148.9, 148.8, 138.1, 133.9, 126.3, 124.2, 123.5, 121.7, 121.0, 79.7, 52.1, 45.9, 28.3, 14.6 ppm.

73.5

5 ml LiOH aqueous solution (90 mg, 3.6 mmol) were added dropwise to reactants (1.44 mmol) with THF (10 ml), then spinned anhydrous the organic phase after three hours. 10 ml water and 15 ml ethyl acetate were added to the organic phase. The aqueous phase was removed after liquid separation. Then the solution was added 15 ml ethyl acetate, adjusted the acid. Anhydrous sodium sulfate was used for the separation of organic phase after liquid separation. Solid white floc was obtained after spinned anhydrous. 1 H NMR (400 MHz, CDCl 3 ): δ 9.40 (s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 6.88 (q, J=7.8 Hz, 1H), 5.58 (s, 1H), 4.46 (d, J=5.8 Hz, 2H), 3.76 (s, 9H), 3.48 (s, 3H), 1.83 (d, J=7.8 Hz, 3H), 1.43 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl 3 ) δ 165.3, 162.7, 157.8, 156.2, 149.0, 148.8, 138.3, 133.7, 126.5, 124.5, 123.7, 121.9, 121.0, 52.5, 46.3, 28.5, 14.8 ppm.

73.6

At 0° C., DIPEA (0.7 ml), carboxylic acid (610 mg), HATU (760 mg), HOAT (326 mg) were added to the reactant (1 mmol) in DCM solution (10 ml) sequentially. Then raised to room temperature with stirring. After 8 h, the reaction was washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The product was filtered and spinned solvent by column chromatography and white flocculent solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.41 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.39-7.17 (m, 12H), 6.66-6.61 (m, 2H), 5.68-5.59 (m, 2H), 5.46 (s, 1H), 5.38-5.32 (m, 1H), 4.59 (dd, J=8.8 Hz, 4 Hz, 1H), 4.49 (d, J=4.2 Hz, 2H), 4.15-4.10 (m, 3H), 3.48 (s, 3H), 2.66 (dd, J=15.6 Hz, 7.6 Hz, 1H), 2.52 (dd, J=15.6 Hz, 5.6 Hz, 1H), 2.18-2.14 (m, 3H), 2.04 (t, J=6.8 Hz, 4H), 1.82 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 1.25 (t, J=6.8 Hz, 2H), 0.97-0.90 (m, 5H), 0.80 (d, J=6.8 Hz, 3H), 0.02 (s, 9H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 171.0, 170.7, 169.5, 164.3, 162.6, 157.3, 155.9, 148.5, 144.7, 138.2, 133.9, 129.6, 129.4, 129.0, 127.7, 127.6, 126.5, 124.6, 123.5, 121.1, 79.7, 71.8, 66.5, 63.0, 60.3, 57.0, 45.6, 39.5, 31.5, 31.2, 31.0, 28.3, 20.9, 18.8, 17.5, 17.2, 14.1, 13.8, 0.9, −1.5, −1.6 ppm.

73.7

Tetrabutylammonium fluoride in tetrahydrofuran solution (1 mol/l, 2.3 ml) was added to the reaction (0.92 mmol) in redistilled THF (5 ml). After 3 h, the reaction was immediately spinned anhydrous by column chromatography to obtain a white solid. DCM solution (25 ml) of the resulting resultant was added trifluoroacetic acid (6 ml). After 5 h, spinned and removed DCM, the residue was added toluene (8 ml). Without further treatment, a brown viscous material was obtained after pumped organic solvent with oil pump. Chromatography pure acetonitrile (200 ml) obtained above was dissolved, slowly dropped in HATU (3 g), DIPEA (4 ml) of HPLC grade acetonitrile (550 ml). After 24 h, spinned anhydrous solvents, the product was diluted with ethyl acetate (20 ml) and then washed with saturated sodium bicarbonate solution, dilute hydrochloric acid solution, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered and spinned anhydrous by column chromatography and pale yellow solid was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.37-7.16 (m, 15H), 7.07 (q, J=7.2 Hz, 1H), 6.67 (d, J=4.4 Hz, 1H), 6.43 (d, J=10.4 Hz, 1H), 5.62-5.56 (m, 2H), 5.39-5.34 (m, 1H), 5.06 (dd, J=17.2 Hz, 8 Hz, 1H), 4.74 (dd, J=6.4 Hz, 3.6 Hz, 1H), 4.19-4.08 (m, 2H), 3.48 (s, 3H), 2.69-2.64 (m, 2H), 2.30-2.27 (m, 1H), 2.21-2.17 (m, 2H), 1.84 (d, J=7.2 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO) δ 133.6, 132.0, 131.3, 126.1, 124.7, 123.3, 118.4, 111.1, 107.1, 101.0, 97.3, 95.2, 92.0, 90.4, 90.3, 89.5, 89.1, 87.5, 83.8, 39.8, 39.5, 39.3, 34.1, 29.1, 22.9, 19.5 ppm.

›Example 74

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, was added propionyl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 5.50 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.25 (s, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H), 6.48 (d, J=10.0 Hz, 1H), 5.75-5.72 (m, 2H), 5.55 (m, 1H), 5.19 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.78-4.75 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.89-2.75 (m, 4H), 2.65 (m, 1H), 2.48 (t, J=7.8 Hz, 3H), 2.35-2.29 (m, 3H), 1.88-1.85 (m, 3H), 1.66 (m, 2H), 0.86 (m, 3H), 0.77 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 169.2, 163.3, 162.2, 155.9, 148.9, 138.8, 134.8, 132.9, 132.2, 130.8, 128.9, 128.5, 127.6, 125.5, 123.4, 121.6, 72.3, 71.8, 57.8, 44.6, 43.7, 41.5, 38.8, 33.9, 32.8, 31.8, 30.8, 29.9, 29.6, 28.9, 27.8, 25.9, 22.9, 19.5, 14.8 ppm.

›Example 75

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, acetyl chloride (0.05 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and 33 mg pale yellow solid was obtained, and the yield was 85%. [α] 20 D : 4.66 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.26 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.79 (d, J=4.4 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.73-5.70 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 2.88-2.78 (m, 4H), 2.67 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.36-2.33 (m, 3H), 1.89-1.86 (m, 3H), 0.88 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.8, 169.3, 163.5, 162.5, 155.8, 148.8, 138.7, 134.7, 132.8, 132.3, 130.9, 128.8, 128.7, 127.7, 125.6, 123.4, 121.7, 72.5, 71.9, 57.9, 44.7, 43.9, 41.6, 38.9, 33.8, 32.9, 31.9, 30.9, 29.8, 29.5, 28.8, 27.7, 15.0 ppm.

›Example 76

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added heptanoyl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 4.11 (c 0.7, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ9.63 (s, 1H), 9.23 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.08 (dd, J=14.4, 7.2 Hz, 1H), 6.73 (d, J=4.4 Hz, 1H), 6.48 (d, J=10 Hz, 1H), 5.72-5.63 (m, 2H), 5.62-5.45 (m, 1H), 5.15 (dd, J=17.2 Hz, 8 Hz, 1H), 4.75-4.71 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.86-2.71 (m, 4H), 2.63-2.62 (m, 1H), 2.50 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.85-1.82 (m, 3H), 1.62-1.59 (m, 2H), 1.26-1.24 (m, 9H), 0.85 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.5, 169.0, 163.5, 162.1, 155.7, 148.8, 138.6, 134.5, 132.6, 132.1, 130.9, 128.9, 128.5, 127.5, 125.1, 124.1, 121.3, 72.2, 71.7, 57.3, 44.1, 43.2, 40.9, 38.6, 33.8, 32.2, 31.5, 30.9, 29.7, 29.1, 28.8, 27.7, 27.6, 25.5, 22.5, 19.1, 18.9, 16.4, 14.6, 14.0 ppm.

›Example 77

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added hexanoyl chloride (0.04 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.11 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.22 (s, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.06 (m, J=7.2 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.46 (d, J=10.0 Hz, 1H), 5.74-5.68 (m, 2H), 5.50 (m, 1H), 5.17 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.76-4.73 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.88-2.75 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.30-2.25 (m, 3H), 1.84-1.82 (m, 3H), 1.63-1.60 (m, 2H), 1.26-1.24 (m, 7H), 0.84 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.59 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.3, 169.0, 163.2, 162.0, 155.6, 148.9, 138.8, 134.8, 132.7, 132.0, 130.9, 128.9, 128.6, 127.7, 125.3, 124.3, 121.5, 72.3, 71.8, 57.5, 44.3, 43.4, 41.2, 38.9, 33.9, 32.5, 31.7, 30.9, 29.8, 29.2, 28.9, 27.8, 27.6, 25.6, 22.6, 19.0, 16.5, 14.7, 13.9 ppm.

›Example 78

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added pivaloyl chloride (0.04 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 3.31 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.20 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.73 (d, J=4.4 Hz, 1H), 6.49 (d, J=10.0 Hz, 1H), 5.73-5.69 (m, 2H), 5.51 (m, 1H), 5.15 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.75-4.73 (m, 2H), 4.29 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.89-2.75 (m, 4H), 2.62 (m, 1H), 2.47 (t, J=7.8 Hz, 3H), 2.31-2.26 (m, 3H), 1.85-1.83 (m, 3H), 1.62-1.60 (m, 2H), 1.25-1.23 (m, 5H), 0.83 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.2, 169.0, 163.3, 162.2, 155.7, 148.7, 138.9, 134.5, 132.8, 132.1, 130.8, 128.9, 128.5, 127.6, 125.2, 123.1, 121.3, 72.1, 71.6, 57.8, 44.2, 43.5, 41.3, 38.8, 33.8, 32.6, 31.6, 30.8, 29.9, 29.3, 28.8, 27.6, 25.7, 22.7, 19.1, 16.6, 14.9, 13.8 ppm.

›Example 79

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, then added butyryl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 6.51 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.23 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.76-5.71 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77-4.74 (m, 2H), 4.27 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.88-2.74 (m, 4H), 2.63 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.33-2.28 (m, 3H), 1.86-1.83 (m, 3H), 1.66-1.62 (m, 2H), 1.27-1.24 (m, 3H), 0.86 (m, 3H), 0.79 (d, J=7.6 Hz, 3H), 0.56 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.4, 169.1, 163.5, 162.3, 155.8, 148.8, 138.9, 134.7, 132.9, 132.3, 130.9, 128.9, 128.4, 127.5, 125.3, 123.9, 121.5, 72.2, 71.7, 57.6, 44.5, 43.6, 41.4, 38.9, 33.9, 32.7, 31.7, 30.9, 29.9, 29.5, 28.9, 27.7, 25.8, 22.9, 19.3, 15.5, 13.8 ppm

›Example 80

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, was added propionyl chloride (0.05 ml). After 7 h, The product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 5.50 (c 0.3, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.25 (s, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H), 6.48 (d, J=10.0 Hz, 1H), 5.75-5.72 (m, 2H), 5.55 (m, 1H), 5.19 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.78-4.75 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.89-2.75 (m, 4H), 2.65 (m, 1H), 2.48 (t, J=7.8 Hz, 3H), 2.35-2.29 (m, 3H), 1.88-1.85 (m, 3H), 1.66 (m, 2H), 0.86 (m, 3H), 0.77 (d, J=7.6 Hz, 3H), 0.57 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.6, 169.2, 163.3, 162.2, 155.9, 148.9, 138.8, 134.8, 132.9, 132.2, 130.8, 128.9, 128.5, 127.6, 125.5, 124.7, 121.6, 72.3, 71.8, 57.8, 44.6, 43.7, 41.5, 38.8, 33.9, 32.8, 31.8, 30.8, 29.9, 29.6, 28.9, 27.8, 25.9, 22.9, 19.5, 14.8 ppm.

›Example 81

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, acetyl chloride (0.05 ml) was added. After 7 h, the product was directly spinned anhydrous solvent by column chromatography and pale yellow solid was obtained. [α] 20 D : 4.66 (c 0.6, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.26 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.79 (d, J=4.4 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 5.73-5.70 (m, 2H), 5.53 (m, 1H), 5.18 (dd, J=17.2 Hz, 8.0 Hz, 1H), 4.77 (m, 2H), 4.28 (d, J=17.2 Hz, 1H), 3.48 (s, 3H), 2.88-2.78 (m, 4H), 2.67 (m, 1H), 2.49 (t, J=7.8 Hz, 3H), 2.36-2.33 (m, 3H), 1.89-1.86 (m, 3H), 0.88 (m, 3H), 0.78 (d, J=7.6 Hz, 3H), 0.58 (d, J=7.6 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 169.8, 169.3, 163.5, 162.5, 155.8, 148.8, 138.7, 134.7, 132.8, 132.3, 130.9, 128.8, 128.7, 127.7, 125.6, 123.4, 121.7, 72.5, 71.9, 57.9, 44.7, 43.9, 41.6, 38.9, 33.8, 32.9, 31.9, 30.9, 29.8, 29.5, 28.8, 27.7, 15.0 ppm.

›Example 82

At 0° C., redistilled NEt 3 (0.02 ml) was added to the reactant (30 mg, 0.063 mmol) in anhydrous DCM (2 ml), stirred slightly, methanesulfonyl chloride (0.02 ml). After 7 h, the product was directly spinned anhydrous solvent by column chromatography and 26 mg pale yellow solid was obtained, and the yield was 75%. [α] 20 D : 1.96 (c 0.1, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 9.63 (s, 1H), 9.23 (s, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.07 (dd, J=14.4 Hz, J=7.2 Hz, 1H), 6.56 (dd, J=7.6 Hz, J=3.6 Hz, 1H), 6.48 (d, J=8 Hz, 1H), 5.73 (m, 2H), 5.52 (dd, J=15.6 Hz, J=6.8 Hz, 1H), 5.12 (m, 1H), 4.76 (dd, J=10 Hz, J=3.6 Hz, 1H), 4.33 (m, 1H), 2.72 (m, 2H), 2.53 (m, 2H), 2.34-2.29 (m, 3H), 1.38 (t, J=7.6 Hz, 1H), 0.82 (d, J=6.8 Hz, 3H), 0.62 (d, J=6.8 Hz, 3H) ppm. 13 C NMR (125 MHz, CDCl 3 ) δ 176.5, 169.8, 169.4, 163.6, 162.6, 155.7, 148.8, 138.5, 134.7, 132.5, 132.3, 130.9, 128.8, 127.8, 125.6, 124.3, 121.8, 72.5, 71.7, 56.9, 44.8, 43.6, 41.5, 36.0, 30.8, 23.7, 18.9, 16.5, 14.6 ppm.

›Example 83 HDAC Biochemical Activity Measurement

1. Measurement Principle:

The chemical activity of the compound is determined according to the degree of deacetylation inhibition of the HDAC enzyme. This experiment measured the degree of deacetylation related to tumor proliferation and metastasis of HDAC1, HDAC2, HDAC3, HDAC8, HDAC11 five subtypes HDAC enzymes. After the substrate containing an acetylated lysine side chain and HDAC enzyme are labeled with a fluorescent label, the fluorescent substrate is de acetyl. The fluorescent labeled substrate is cleaved by the enzyme, and the fluorescent substance is released, which generates 460 nm emission light under the excitation of 360 nm light.

2. Specific Steps:

HDAC substrate was diluted with reaction buffer to 200M (reaction concentration of 20M), the HDAC enzyme was diluted to the appropriate concentration, then added different concentrations of the test compounds and acted at 37° C. 30 minutes, and then added the same volume of 2-times concentration substrate developing solution (developer), incubated at room temperature for 15 minutes. Finally, the last reading measured with a microplate plate reader, excitation light was 360 nm, the emitted light was 460 nm, data processing software was Prime 4, and the results are shown in Table 1. In the embodiment of the invention, SAHA is suberoylanilide hydroxamic acid; no activity indicates no activity.

3. Test Results and Analysis:

IC50 in the table above is the concentration of the inhibitor (50% inhibitory concentration), which is inhibited by half.

From the table it can be indicated that the compounds mentioned above had HDAC enzymes (mainly HDAC1, HDAC2, HDAC3, HDAC8, HDAC11) to acetylation activity with significant inhibition of tumor proliferation and metastasis, compared with the positive control (SAHA). But HDAC7 which has less relation to the tumor proliferation and metastasis has no effect.

Compared with the related compounds of the patent public CN102391359A, the compound structure of the invention is shown in Table 2, which shows a significant advantage and the difference is several times to several hundreds of times.

Six-membered ring with substituents in the compounds of the present invention showed a significant advantage, compared to non-substituted group in related compounds in HDAC1. The results were shown in Table 3.

›Example 84 Detection of the Activity of Compounds on Cancer Cell

Experimental principles: compounds inhibit cancer cell growth by MTT method to detect. MTT assay principle is yellow MTT can penetrate membrane into the cell, succinic dehydrogenase of the mitochondria in living cells can make exogenous MTT reduction of insoluble in water of blue-violet acicular formazan for crystallization and deposition in the cell, crystallization can be dissolved dimethyl sulfoxide (DMSO) solution, detected its absorbance at 490 nm/570 nm wavelength by enzyme-linked immunosorbent assay, which can reflect the number of cells.

Experimental Materials: cancer cell lines used are for the Hela (human cervical cancer cells), MCF-7 (human breast cancer cells), BGC-823 (human gastric cancer cells), A549 (human lung cancer cells), HT1080 (human fibrosarcoma cells), A431 (human epidermal squamous cell carcinoma cells), HUVEC (human umbilical vein endothelial cells), DU145 (human prostate cancer cells), lncap (prostate cancer cells), K562 (human leukemia cells), U937 (human leukemia cells), Pac-1 (human pancreatic cancer cells), MOLT-4 (human acute lymphoblastic leukemia cells), KBM-5 (human chronic myelogenous leukemia), KBM5-T315I (human chronic myelogenous leukemia), SGC-7901 (human gastric cancer cells), N-87 (human gastric cancer cells), Bel-7402 (human hepatoma cells), Huh-7 (human hepatoma cells) K562 (human leukemia cells), H1975 (non-small cell lung adenocarcinoma fine), HCC827 (human non-small cell lung cancer cells), MDA-MB-231 (breast cancer cells). Using DMEM+10% FBS culture medium or using 1640+10% FBS culture, respectively.

Experimental Method and Result Analysis:

Experimental group: 190 μl cell suspension+10 μl different concentrations of drugs (the final concentration is 10 −5 ˜10 −10 M)

Control group: 200 μl PBS

Negative control group: 190 μl cell suspension+10 μl 2% DMSO (DMSO final concentration is 0.1%)

Positive control group: 190 μl cell suspension+10 μl different concentrations of compounds

a) Cells were seeded in 96-well plates with the inoculation of 1500/well, 190 μl/hole, 37° C., 5% of CO 2 incubator overnight;

b) The next day each well was added 10 μl of different drugs. The final concentration of drug was 10 −5 ˜10 −10 M, three parallel holes; 37° C., 5% CO 2 culture incubator for 72 hours incubation;

c) Per well was added 20 μl 5 mg/ml of MTT, 37° C., 5% CO 2 culture incubator for 4 hours incubation;

d) The supernatant was discarded. Each well was added 100 μl of DMSO and oscillation;

e) 570 nm readings. Calculate cell viability. GI50 calculation based on the results. The results are shown in Tables 4-5.

The GI50 in the upper table represents the drug concentration (50% growth inhibition) required for 50% of cell growth inhibition.

The results from the above table can be seen: compared with the positive control (SAHA), the above drugs significantly inhibit the growth of the tumor cells.

Compared with the related compound of patent CN102391359A, the compound of the invention has obvious advantages. The result is shown in tables 6 and 7.

It should be noted that the above-described embodiments are merely illustrative and not limiting aspect of the present invention. Any equivalent replacement or change shall be deemed to have been included within the scope of the present invention.

›Tables in the description — 7

TABLE 1 — HDAC activity and biochemical test results

Com-	IC50 (μM)
pound No.	HDAC1	HDAC2	HDAC3	HDAC8	HDAC11	HDAC7
SAHA	0.18	0.35	0.56	0.78	0.62	no activity
1	0.041	0.022	0.035	0.03	0.38	no activity
2	0.192	0.163	0.177	0.252	0.102	no activity
3	0.171	0.158	0.145	0.169	0.100	no activity
4	0.183	0.251	0.152	0.161	0.201	no activity
5	0.074	0.053	0.049	0.067	0.111	no activity
6	0.075	0.059	0.061	0.063	0.135	no activity
7	0.087	0.017	0.007	0.039	0.011	no activity
8	0.153	0.162	0.051	0.041	0.097	no activity
9	0.045	0.064	0.034	0.049	0.101	no activity
10	0.092	0.067	0.041	0.050	0.103	no activity
11	0.029	0.055	0.045	0.071	0.081	no activity
12	0.081	0.054	0.052	0.038	0.091	no activity
13	0.187	0.261	0.337	0.159	0.094	no activity
14	0.094	0.059	0.043	0.057	0.103	no activity
15	0.191	0.047	0.057	0.043	0.106	no activity
16	0.181	0.056	0.049	0.061	0.095	no activity
17	0.176	0.061	0.069	0.081	0.097	no activity
18	0.187	0.055	0.067	0.073	0.107	no activity
19	0.179	0.063	0.039	0.069	0.103	no activity
20	0.183	0.077	0.045	0.065	0.087	no activity
21	0.088	0.067	0.051	0.053	0.089	no activity
22	0.093	0.054	0.061	0.047	0.097	no activity
23	0.061	0.074	0.059	0.059	0.105	no activity
24	0.074	0.083	0.043	0.063	0.097	no activity
25	0.081	0.094	0.038	0.075	0.089	no activity
26	0.091	0.064	0.046	0.064	0.094	no activity
27	0.004	0.021	0.033	0.051	0.024	no activity
28	0.055	0.061	0.074	0.071	0.079	no activity
29	0.043	0.068	0.079	0.069	0.103	no activity
30	0.012	0.056	0.034	0.043	0.084	no activity
31	0.057	0.051	0.043	0.039	0.091	no activity
32	0.069	0.042	0.068	0.052	0.097	no activity
33	0.023	0.043	0.036	0.059	0.089	no activity
34	0.043	0.051	0.026	0.042	0.082	no activity
35	0.056	0.062	0.024	0.034	0.083	no activity
36	0.011	0.043	0.037	0.035	0.085	no activity
37	0.071	0.044	0.048	0.043	0.091	no activity
38	0.061	0.061	0.059	0.053	0.095	no activity
39	0.059	0.065	0.036	0.026	0.082	no activity
40	0.043	0.053	0.042	0.045	0.096	no activity
41	0.076	0.225	0.119	0.322	0.056	no activity
42	0.062	0.113	0.092	0.131	0.077	no activity
43	0.027	0.051	0.046	0.043	0.094	no activity
44	0.051	0.043	0.043	0.042	0.091	no activity
45	0.064	0.032	0.041	0.025	0.092	no activity
46	0.022	0.041	0.025	0.035	0.082	no activity
47	0.071	0.026	0.039	0.0.16	0.083	no activity
48	0.081	0.015	0.047	0.014	0.093	no activity
49	0.016	0.046	0.048	0.038	0.073	no activity
50	0.064	0.043	0.052	0.037	0.107	no activity
51	0.046	0.052	0.051	0.041	0.103	no activity
52	0.045	0.062	0.038	0.053	0.107	no activity
53	0.084	0.043	0.029	0.026	0.105	no activity
54	0.074	0.024	0.034	0.034	0.099	no activity
55	0.013	0.034	0.035	0.043	0.083	no activity
56	0.061	0.035	0.039	0.035	0.081	no activity
57	0.051	0.026	0.047	0.044	0.095	no activity
58	0.032	0.021	0.029	0.051	0.097	no activity
59	0.071	0.029	0.024	0.061	0.091	no activity
60	0.081	0.037	0.016	0.053	0.088	no activity
61	0.013	0.038	0.038	0.038	0.083	no activity
62	0.046	0.027	0.037	0.037	0.079	no activity
63	0.041	0.058	0.039	0.029	0.091	no activity
64	0.024	0.029	0.029	0.027	0.093	no activity
65	0.048	0.026	0.027	0.035	0.086	no activity
66	0.041	0.016	0.031	0.026	0.094	no activity
67	0.0.64	0.034	0.028	0.016	0.092	no activity
68	0.079	0.043	0.037	0.021	0.082	no activity
69	0.061	0.038	0.028	0.052	0.081	no activity
70	0.033	0.043	0.024	0.034	0.097	no activity
71	0.051	0.029	0.034	0.041	0.096	no activity
72	0.064	0.331	0.135	0.453	0.276	no activity
73	0.182	0.325	0.426	0.562	0.375	no activity
74	0.273	0.129	0.231	0.435	0.672	no activity
75	0.443	0.334	0.543	0.163	0.181	no activity
76	0.051	0.036	0.042	0.028	0.094	no activity
77	0.094	0.029	0.026	0.037	0.088	no activity
78	0.063	0.037	0.038	0.039	0.094	no activity
79	0.057	0.019	0.027	0.042	0.093	no activity
80	0.067	0.038	0.034	0.053	0.097	no activity
81	0.037	0.031	0.016	0.026	.095	no activity
82	0.094	0.049	0.053	0.034	0.092	no activity
83	0.051	0.046	0.026	0.038	0.082	no activity
84	0.042	0.043	0.029	0.029	0.091	no activity
85	0.034	0.038	0.037	0.027	0.092	no activity
86	0.084	0.033	0.039	0.034	0.082	no activity
87	0.083	0.022	0.026	0.035	0.087	no activity
88	0.031	0.035	0.041	0.043	0.094	no activity
89	0..073	0.036	0.052	0.062	0.086	no activity
90	0.084	0.029	0.063	0.051	0.075	no activity
91	0.061	0.037	0.033	0.034	0.079	no activity
92	0.052	0.035	0.035	0.037	0.086	no activity
93	0.043	0.024	0.039	0.029	0.084	no activity
94	0.042	0.035	0.028	0.028	0.091	no activity
95	0.072	0.026	0.017	0.034	0.099	no activity
96	0.094	0.034	0.051	0.032	0.098	no activity
97	0.052	0.037	0.601	0.052	0.086	no activity
98	0.061	0.019	0.062	0.061	0.089	no activity
99	0.076	0.028	0.051	0.022	0.097	no activity
100	0.049	0.022	0.071	0.031	0.095	no activity
101	0.038	0.034	0.059	0.035	0.092	no activity
102	0.049	0.038	0.048	0.026	0.094	no activity
103	0.038	0.029	0.053	0.016	0.093	no activity
104	0.051	0.026	0.043	0.019	0.083	no activity
105	0.053	0.025	0.015	0.027	0.084	no activity
106	0.061	0.035	0.041	0.037	0.078	no activity
107	0.076	0.038	0.042	0.023	0.084	no activity
108	0.077	0.029	0.053	0.026	0.083	no activity
109	0.066	0.034	0.062	0.034	0.087	no activity
110	0.088	0.028	0.051	0.035	0.098	no activity
111	0.054	0.061	0.053	0.042	0.095	no activity
112	0.075	0.051	0.047	0.043	0.092	no activity
113	0.086	0.053	0.041	0.053	0.093	no activity
114	0.061	0.049	0.027	0.038	0.099	no activity
115	0.055	0.043	0.038	0.029	0.091	no activity
116	0.041	0.052	0.039	0.027	0.098	no activity
117	0.039	0.133	0.156	0.217	0.125	no activity
118	0.053	0.109	0.228	0.197	0.126	no activity
119	0.051	0.042	0.041	0.037	0.092	no activity
120	0.072	0.112	0.093	0.043	0.032	no activity
121	0.051	0.207	0.199	0.086	0.142	no activity
122	0.065	0.143	0.202	0.092	0.127	no activity
123	0.052	0.026	0.052	0.026	0.089	no activity
124	0.033	0.092	0.117	0.059	0.121	no activity
125	0.087	0.122	0.103	0.098	0.102	no activity
126	0.035	0.023	0.059	0.037	0.068	no activity
127	0.048	0.026	0.057	0.033	0.062	no activity
128	0.052	0.119	0.114	0.072	0.083	no activity
129	0.027	0.029	0.052	0.034	0.061	no activity
130	0.037	0.042	0.053	0.039	0.043	no activity
131	0.076	0.031	0.035	0.022	0.089	no activity
132	0.033	0.117	0.093	0.092	0.163	no activity
133	0.043	0.021	0.053	0.042	0.077	no activity
134	0.058	0.025	0.067	0.031	0.068	no activity
135	0.083	0.031	0.034	0.027	0.082	no activity
136	0.052	0.047	0.031	0.042	0.089	no activity
137	0.033	0.036	0.017	0.099	0.076	no activity
138	0.039	0.024	0.029	0.077	0.062	no activity
139	0.072	0.035	0.052	0.039	0.087	no activity
140	0.085	0.043	0.032	0.056	0.089	no activity
141	0.042	0.068	0.025	0.037	0.062	no activity
142	0.053	0.023	0.063	0.075	0.081	no activity
143	0.046	0.041	0.063	0.049	0.097	no activity
144	0.042	0.038	0.024	0.017	0.082	no activity
145	0.051	0.029	0.026	0.029	0.083	no activity
146	0.073	0.034	0.028	0.043	0.097	no activity
147	0.061	0.041	0.051	0.028	0.086	no activity
148	0.049	0.052	0.035	0.029	0.082	no activity
149	0.051	0.063	0.043	0.034	0.094	no activity
150	0.044	0.026	0.031	0.035	0.083	no activity
151	0.061	0.024	0.023	0.038	0.095	no activity
152	0.062	0.026	0.035	0.037	0.076	no activity
153	0.072	0.031	0.036	0.028	0.072	no activity
154	0.084	0.011	0.042	0.031	0.085	no activity
155	0.094	0.012	0.043	0.036	0.084	no activity
156	0.095	0.016	0.053	0.029	0.086	no activity
157	0.082	0.019	0.051	0.027	0.091	no activity
158	0.081	0.028	0.053	0.043	0.092	no activity
159	0.054	0.037	0.042	0.044	0.095	no activity
160	0.053	0.024	0.052	0.051	0.097	no activity
161	0.061	0.033	0.063	0.062	0.086	no activity
162	0.073	0.027	0.024	0.035	0.083	no activity
163	0.072	0.026	0.053	0.039	0.084	no activity
164	0.073	0.029	0.026	0.031	0.081	no activity
165	0.084	0.031	0.025	0.062	0.092	no activity
166	0.082	0.032	0.035	0.032	0.097	no activity
167	0.065	0.058	0.013	0.022	0.074	no activity
168	0.091	0.041	0.034	0.013	0.099	no activity
169	0.072	0.052	0.016	0.015	0.092	no activity
170	0.076	0.062	0.019	0.042	0.098	no activity
171	0.068	0.035	0.018	0.035	0.095	no activity
172	0.059	0.029	0.029	0.038	0.093	no activity
173	0.0.38	0.031	0.037	0.039	0.097	no activity
174	0.084	0.032	0.026	0.021	0.098	no activity
175	0.041	0.032	0.011	0.069	0.055	no activity
176	0.025	0.039	0.032	0.059	0.081	no activity
177	0.085	0.033	0.027	0.042	0.088	no activity
178	0.091	0.026	0.035	0.036	0.099	no activity
179	0.073	0.051	0.034	0.042	0.092	no activity
180	0.043	0.037	0.029	0.033	0.091	no activity
181	0.086	0.061	0.031	0.022	0.086	no activity
182	0.072	0.032	0.023	0.055	0.082	no activity
183	0.058	0.033	0.013	0.065	0.084	no activity
184	0.046	0.041	0.034	0.054	0.091	no activity
185	0.063	0.053	0.038	0.041	0.093	no activity
186	0.053	0.083	0.026	0.053	0.097	no activity
187	0.051	0.073	0.024	0.026	0.098	no activity
188	0.043	0.063	0.042	0.023	0.086	no activity
189	0.086	0.024	0.041	0.037	0.084	no activity
190	0.085	0.025	0.053	0.029	0.081	no activity
191	0.092	0.036	0.062	0.018	0.085	no activity
192	0.073	0.026	0.038	0.053	0.091	no activity
193	0.043	0.025	0.039	0.049	0.093	no activity
194	0.061	0.032	0.042	0.043	0.079	no activity
195	0.065	0.035	0.053	0.059	0.078	no activity
196	0.092	0.026	0.024	0.048	0.095	no activity
197	0.072	0.024	0.035	0.052	0.096	no activity
198	0.0.84	0.025	0.037	0.034	0.098	no activity
199	0.082	0.034	0.041	0.059	0.092	no activity
200	0.088	0.038	0.052	0.049	0.093	no activity
201	0.081	0.042	0.037	0.019	0.089	no activity
202	0.072	0.043	0.043	0.029	0.082	no activity
203	0.083	0.053	0.062	0.018	0.084	no activity
204	0.086	0.061	0.053	0.035	0.087	no activity
205	0.091	0.052	0.038	0.062	0.077	no activity
206	0.051	0.037	0.037	0.031	0.086	no activity
207	0.062	0.027	0.042	0.033	0.092	no activity
208	0.051	0.017	0.031	0.055	0.098	no activity
209	0.061	0.018	0.041	0.042	0.096	no activity
210	0.2082	0.024	0.026	0.041	0.092	no activity
211	0.091	0.026	0.052	0.028	0.089	no activity
212	0.073	0.035	0.035	0.037	0.086	no activity
213	0.077	0.034	0.063	0.029	0.087	no activity
214	0.064	0.039	0.032	0.059	0.0830	no activity
215	0.066	0.041	0.044	0.057	.086	no activity
216	0.155	0.033	0.062	0.052	0.081	no activity
217	0.035	0.043	0.122	0.078	0.093	no activity
218	0.043	0.034	0.352	0.562	0.178	no activity
219	0.055	0.741	0.922	0.138	0.291	no activity
220	0.167	0.534	0.821	0.433	0.320	no activity
221	0.296	0.655	0.813	0.132	0.211	no activity
222	0.175	0.126	0.516	0.756	0.377	no activity
223	0.156	0.238	0.762	0.243	0.273	no activity
224	0.184	0.335	0.563	0.752	0.279	no activity
225	0.142	0.539	0.438	0.241	0.668	no activity
226	0.062	0.035	0.046	0.022	0.083	no activity
227	0.072	0.639	0.538	0.341	0.198	no activity
228	0.135	0.039	0.061	0.025	0.086	no activity
229	0.097	0.036	0.057	0.132	0.119	no activity
230	0.028	0.169	0.041	0.058	0.112	no activity
231	0.053	0.046	0.057	0.032	0.103	no activity
232	0.066	0.093	0.021	0.059	0.152	no activity
233	0.107	0.129	0.028	0.031	0.053	no activity
234	0.018	0.085	0.032	0.078	0.065	no activity
235	0.008	0.019	0.035	0.047	0.019	no activity
236	0.043	0.038	0.066	0.067	0.072	no activity
237	0.072	0.032	0.035	0.043	0.077	no activity
238	0.044	0.083	0.059	0.078	0.065	no activity
239	0.077	0.056	0.047	0.089	0.028	no activity
240	0.045	0.021	0.053	0.052	0.056	no activity
241	0.028	0.036	0.062	0.033	0.069	no activity
242	0.019	0.043	0.032	0.055	0.067	no activity
243	0.087	0.056	0.048	0.129	0.187	no activity
244	0.092	0.053	0.032	0.089	0.037	no activity
245	0.066	0.074	0.052	0.102	0.126	no activity
246	0.090	0.069	0.087	0.132	0.235	no activity
247	0.062	0.049	0.037	0.041	0.088	no activity
248	0.056	0.029	0.022	0.039	0.051	no activity
249	0.038	0.023	0.028	0.042	0.076	no activity
250	0.077	0.045	0.063	0.053	0.035	no activity
251	0.033	0.058	0.027	0.037	0.039	no activity
252	0.042	0.038	0.056	0.069	0.077	no activity
253	0.053	0.026	0.083	0.062	0.045	no activity
254	0.061	0.042	0.069	0.067	0.062	no activity
255	0.032	0.089	0.049	0.121	0.072	no activity

TABLE 2 — Comparison of the results of the present invention with CN102391359A

Compounds No.	IC50 (μM)
Compounds No. of the	Compounds No. of	HDAC1
present invention (a)	CN102391359A (b)	a	b
235	1-1	<0.01	<0.1
9	1-2	<0.05	<0.19
1	1-3	<0.05	<10
11	1-4	<0.03	<1.0
236	1-5	<0.05	<10
237	1-6	<0.08	<10
14	1-7	<0.1	<10
238	1-8	<0.05	<0.102
239	1-9	<0.10	<10
240	1-10	<0.05	<0.10
241	1-11	<0.03	<0.10
242	1-12	<0.02	<0.1
1	2-1	<0.05	<0.1
243	2-2	<0.10	<10
243	2-3	<0.10	<10
1	2-4	<0.05	<10
1	2-5	<0.05	<10
1	2-6	<0.05	<10
1	2-7	<0.05	<10
244	3-1	<0.10	<10
245	3-2	<0.10	<10
246	3-3	<0.10	<10
27	6-1	<0.005	<0.1
7	6-2	<0.5	<10

TABLE 3 — Result comparison of six-membered ring with substituent and without substituent data

	Compounds No.		IC50 (μM)
of the present invention		HDAC1
substituents (C)	non-substituent (D)	C	D
30	1	0.012	0.041
33	2	0.023	0.192
36	3	0.011	0.171
40	4	0.043	0.183
43	5	0.027	0.074
46	6	0.022	0.075
49	7	0.016	0.087
52	8	0.045	0.153
55	9	0.013	0.045
58	10	0.032	0.092
61	11	0.013	0.029
64	12	0.024	0.081
66	13	0.041	0.187
70	14	0.033	0.094
72	15	0.064	0.191
76	16	0.051	0.181
78	17	0.063	0.176
81	18	0.037	0.187
84	19	0.042	0.179
88	20	0.031	0.183

TABLE 4 — Test results of compounds on cancer cells (1) GI50 (μM)

Compound	Hela	MCF	A54	BG	HT1	lnca	Du1	U93	PAN	Mol
SAHA	30.2	1.64	8.53	5.23	3.97	4.61	15.2	2.35	7.62	10.0
1	0.02	0.03	0.01	0.06	0.01	0.00	0.00	0.00	0.02	0.00
2	0.03	0.03	0.04	0.06	0.05	0.00	0.00	0.00	0.03	0.00
3	0.05	0.03	0.05	0.06	0.06	0.00	0.00	0.00	0.03	0.00
4	0.05	0.04	0.05	0.06	0.07	0.00	0.00	0.00	0.06	0.00
5	0.05	0.04	0.05	0.06	0.07	0.00	0.00	0.00	0.06	0.00
6	0.06	0.06	0.06	0.07	0.08	0.00	0.00	0.00	0.06	0.00
7	0.04	0.03	0.05	0.03	0.02	0.00	0.01	0.00	0.00	0.02
8	0.07	0.08	0.08	0.09	0.09	0.00	0.00	0.00	0.08	0.00
9	0.05	0.03	0.08	0.00	0.04	0.00	0.00	0.00	0.06	0.01
10	0.07	0.06	0.06	0.09	0.08	0.00	0.00	0.00	0.08	0.00
11	0.12	0.05	0.43	0.41	0.14	0.02	0.03	0.03	0.06	0.01
12	0.05	0.06	0.07	0.09	0.06	0.00	0.00	0.00	0.08	0.00
13	0.09	0.3	0.05	0.1	0.2	0.1	0.02	0.08	0.07	0.02
14	0.22	0.4	0.1	0.2	0.3	0.2	0.01	0.03	0.53	0.02
15	15.7	19.8	2.3	1.22	38.7	0.4	0.48	1.12	2.58	19.7
16	21	49.5	4.2	2.1	1.3	82.1	6.1	17.9	4.1	0.7
17	11	22	1.93	19.7	0.97	0.53	5.22	20.1	23.3	0.92
18	0.37	0.49	3.8	53.1	10.8	10.3	0.42	11.3	42.1	59.7
19	0.06	0.08	0.09	0.09	0.07	0.58	0.00	0.00	0.6	1.9
20	0.01	1.9	0.32	1.1	0.98	5.1	1.98	20.2	10.1	0.13
21	0.4	0.1	0.33	0.87	1.05	1.21	0.99	5.11	1.17	1.01
22	0.39	1.11	1.03	5.88	0.05	0.39	0.04	0.12	4.07	2.06
23	0.27	0.64	0.22	1.1	1.01	5.05	6.33	0.01	19.7	10.0
24	0.5	0.05	0.1	0.22	0.04	0.03	0.02	0.00	0.22	0.49
25	67.7	53.6	15.4	3.3	39.2	0.7	1.3	2.29	0.55	0.3
26	37	53.7	38.9	5.4	18	9	11.7	9.5	0.77	3.35
27	0.53	0.03	0.09	0.31	0.04	0.03	0.02	0.00	0.21	0.51
28	0.81	0.93	0.42	1.1	0.04	0.39	0.43	2.11	0.02	0.08
29	0.91	1.21	0.27	0.09	0.06	0.05	0.07	0.45	0.08	0.07
30	0.08	0.02	0.03	0.03	0.08	0.03	0.03	0.03	0.08	0.03
31	0.09	0.06	0.07	0.05	0.05	0.01	0.02	0.04	0.05	0.01
32	0.07	0.05	0.04	0.06	0.06	0.03	0.03	0.05	0.06	0.03
33	0.08	0.05	0.05	0.06	0.08	0.03	0.01	0.02	0.08	0.03
34	0.07	0.05	0.04	0.06	0.09	0.04	0.05	0.03	0.09	0.04
35	0.07	0.05	0.06	0.06	0.05	0.04	0.02	0.03	0.05	0.04
36	0.06	0.05	0.04	0.03	0.06	0.04	0.02	0.02	0.06	0.04
37	0.05	0.06	0.05	0.04	0.03	0.03	0.03	0.02	0.03	0.03
38	0.07	0.06	0.03	0.04	0.08	0.03	0.03	0.03	0.08	0.03
39	0.07	0.06	0.04	0.05	0.08	0.02	0.02	0.03	0.08	0.02
40	0.07	0.05	0.04	0.07	0.07	0.03	0.04	0.04	0.07	0.03
41	0.05	0.06	0.03	0.03	0.07	0.24	0.10	0.01	0.12	0.02
42	0.05	0.10	0.04	0.03	0.04	0.05	0.10	0.07	0.04	0.08
43	0.08	0.05	0.05	0.03	0.07	0.03	0.05	0.06	0..0	0.03
44	0.08	0.06	0.03	0.05	0.08	0.02	0.06	0.05	0.08	0.02
45	0.09	0.05	0.04	0.05	0.06	0.03	0.03	0.03	0.06	0.03
46	0.09	0.04	0.05	0.04	0.05	0.03	0.03	0.03	0.05	0.03
47	0.08	0.05	0.04	0.06	0.04	0.02	0.03	0.02	0.04	0.02
48	0.07	0.06	0.06	0.08	0.04	0.03	0.02	0.02	0.04	0.03
49	0.08	0.05	0.06	0.07	0.07	0.02	0.01	0.03	0.07	0.02
50	0.07	0.06	0.03	0.06	0.08	0.02	0.04	0.03	0.08	0.02
51	0.08	0.07	0.04	0.06	0.07	0.02	0.04	0.06	0.07	0.02
52	0.08	0.06	0.05	0.05	0.09	0.03	0.02	0.06	0.09	0.03
53	0.09	0.05	0.06	0.04	0.04	0.02	0.03	0.05	0.04	0.02
54	0.09	0.06	0.06	0.04	0.05	0.03	0.02	0.04	0.05	0.03
55	0.08	0.07	0.05	0.05	0.08	0.02	0.03	0.05	0.08	0.02
56	0.08	0.06	0.05	0.04	0.09	0.03	0.04	0.05	0.09	0.03
57	0.07	0.05	0.09	0.05	0.07	0.02	0.03	0.05	0.07	0.02
58	0.06	0.08	0.05	0.06	0.04	0.03	0.02	0.06	0.04	0.03
59	0.06	0.07	0.05	0.05	0.08	0.03	0.03	0.03	0.08	0.03
60	0.07	0.08	0.04	0.06	0.05	0.01	0.02	0.04	0.05	0.01
61	0.08	0.09	0.03	0.07	0.06	0.03	0.03	0.05	0.06	0.03
62	0.09	0.06	0.04	0.06	0.08	0.03	0.01	0.02	0.08	0.03
63	0.09	0.05	0.05	0.05	0.09	0.04	0.05	0.03	0.09	0.04
64	0.08	0.02	0.03	0.03	0.05	0.04	0.02	0.03	0.05	0.04
65	0.09	0.06	0.07	0.05	0.06	0.04	0.02	0.02	0.06	0.04
66	0.09	0.03	0.02	0.06	0.03	0.03	0.03	0.02	0.03	0.03
67	0.04	0.02	0.03	0.05	0.08	0.03	0.03	0.03	0.08	0.03
68	0.05	0.03	0.02	0.04	0.08	0.02	0.02	0.03	0.08	0.02
69	0.08	0.02	0.03	0.05	0.07	0.03	0.04	0.04	0.07	0.03
70	0.09	0.03	0.04	0.05	0..0	0.03	0.05	0.06	0..0	0.03
71	0.07	0.02	0.03	0.05	0.08	0.02	0.06	0.05	0.08	0.02
72	0.04	0.03	0.02	0.06	0.06	0.03	0.03	0.03	0.06	0.03
73	0.08	0.02	0.02	0.03	0.05	0.03	0.03	0.03	0.05	0.03
74	0.03	0.35	0.04	0.03	0.04	0.02	0.03	0.02	0.04	0.02
75	0.06	0.02	0.04	0.02	0.04	0.03	0.02	0.02	0.04	0.03
76	0.09	0.03	0.05	0.03	0.07	0.02	0.01	0.03	0.07	0.02
77	0.05	0.03	0.60	0.05	0.08	0.02	0.04	0.03	0.08	0.02
78	0.06	0.01	0.06	0.06	0.07	0.02	0.04	0.06	0.07	0.02
79	0.07	0.02	0.05	0.02	0.09	0.03	0.02	0.06	0.09	0.03
80	0.04	0.02	0.07	0.03	0.04	0.02	0.03	0.05	0.04	0.02
81	0.03	0.03	0.05	0.03	0.05	0.03	0.02	0.04	0.05	0.03
82	0.04	0.03	0.04	0.02	0.08	0.02	0.03	0.05	0.08	0.02
83	0.03	0.02	0.05	0.01	0.09	0.03	0.04	0.05	0.09	0.03
84	0.05	0.02	0.04	0.01	0.07	0.02	0.03	0.05	0.07	0.02
85	0.05	0.02	0.01	0.02	0.04	0.03	0.02	0.06	0.04	0.03
86	0.06	0.03	0.02	0.03	0.08	0.03	0.03	0.03	0.08	0.03
87	0.08	0.03	0.03	0.02	0.05	0.01	0.02	0.04	0.05	0.01
88	0.07	0.02	0.02	0.03	0.06	0.03	0.03	0.05	0.06	0.03
89	0.09	0.03	0.03	0.01	0.08	0.03	0.01	0.02	0.08	0.03
90	0.08	0.02	0.03	0.03	0.09	0.04	0.05	0.03	0.09	0.04
91	0.09	0.03	0.04	0.06	0.05	0.04	0.02	0.03	0.05	0.04
92	0.04	0.02	0.05	0.01	0.06	0.04	0.02	0.02	0.06	0.04
93	0.05	0.03	0.06	0.02	0.03	0.03	0.03	0.02	0.03	0.03
94	0.06	0.03	0.04	0.03	0.08	0.03	0.03	0.03	0.08	0.03
95	0.07	0.03	0.04	0.02	0.08	0.02	0.02	0.03	0.08	0.02
96	0.06	0.02	0.04	0.02	0.04	0.03	0.02	0.02	0.04	0.03
97	0.09	0.03	0.05	0.03	0.07	0.02	0.01	0.03	0.07	0.02
98	0.05	0.03	0.60	0.05	0.08	0.02	0.04	0.03	0.08	0.02
99	0.06	0.01	0.06	0.06	0.07	0.02	0.04	0.06	0.07	0.02
100	0.07	0.02	0.05	0.02	0.09	0.03	0.02	0.06	0.09	0.03
101	0.04	0.02	0.07	0.03	0.04	0.02	0.03	0.05	0.04	0.02
102	0.03	0.03	0.05	0.03	0.05	0.03	0.02	0.04	0.05	0.03
103	0.04	0.03	0.04	0.02	0.08	0.02	0.03	0.05	0.08	0.02
104	0.03	0.02	0.05	0.01	0.09	0.03	0.04	0.05	0.09	0.03
105	0.05	0.02	0.04	0.01	0.07	0.02	0.03	0.05	0.07	0.02
106	0.05	0.03	0.06	0.02	0.03	0.03	0.03	0.02	0.03	0.03
107	0.06	0.03	0.04	0.03	0.08	0.03	0.03	0.03	0.08	0.03
108	0.07	0.03	0.04	0.02	0.08	0.02	0.02	0.03	0.08	0.02
109	0.07	0.02	0.05	0.02	0.07	0.03	0.04	0.04	0.07	0.03
110	0.06	0.03	0.06	0.03	0.07	0.03	0.05	0.06	0..0	0.03
111	0.08	0.02	0.05	0.03	0.08	0.02	0.06	0.05	0.08	0.02
112	0.07	0.06	0.06	0.08	0.09	0.07	0.06	0.06	0.08	0.09
113	0.08	0.05	0.06	0.07	0.10	0.08	0.05	0.06	0.07	0.10
114	0.07	0.06	0.03	0.06	0.10	0.07	0.06	0.03	0.06	0.10
115	0.08	0.07	0.04	0.06	0.08	0.08	0.07	0.04	0.06	0.08
116	0.04	0.06	0.06	0.05	0.05	0.03	0.02	0.02	0.04	0.03
117	0.08	0.02	0.06	0.07	0.04	0.02	0.01	0.03	0.06	0.02
118	0.07	0.06	0.03	0.06	0.08	0.02	0.04	0.03	0.08	0.02
119	0.09	0.05	0.06	0.04	0.09	0.09	0.05	0.06	0.04	0.09
120	0.03	0.10	0.05	0.03	0.01	0.03	0.05	0.01	0.10	0.02
121	0.05	0.02	0.21	0.19	0.07	0.11	0.03	0.06	0.07	0.03
122	0.05	0.03	0.11	0.02	0.03	0.03	0.08	0.11	0.03	0.10
123	0.09	0.06	0.06	0.04	0.09	0.09	0.06	0.06	0.04	0.09
124	0.03	0.03	0.05	0.03	0.03	0.07	0.02	0.10	0.69	0.05
125	0.05	0.06	0.06	0.03	0.04	0.11	0.03	0.05	0.12	0.11
126	0.13	0.02	0.03	0.10	0.05	0.02	0.06	0.07	0.03	0.09
127	0.08	0.07	0.05	0.05	0.08	0.08	0.07	0.05	0.05	0.08
128	0.04	0.05	0.03	0.07	0.07	0.10	0.05	0.05	0.13	0.02
129	0.04	0.03	0.08	0.03	0.13	0.07	0.03	0.01	0.05	0.06
130	0.13	0.07	0.07	0.05	0.10	0.02	0.03	0.03	0.04	0.03
131	0.08	0.06	0.05	0.04	0.08	0.08	0.06	0.05	0.04	0.08
132	0.02	0.10	0.02	0.04	0.03	0.03	0.15	0.04	0.07	0.03
133	0.02	0.07	0.05	0.05	0.08	0.08	0.07	0.05	0.05	0.08
134	0.04	0.08	0.03	0.17	0.07	0.10	0.05	0.05	0.13	0.05
135	0.07	0.05	0.09	0.05	0.09	0.07	0.05	0.09	0.05	0.09
136	0.08	0.05	0.04	0.07	0.04	0.03	0.01	0.03	0.08	0.02
137	0.07	0.03	0.02	0.03	0.08	0.02	0.03	0.03	0.08	0.04
138	0.06	0.02	0.04	0.02	0.02	0.05	0.02	0.02	0.03	0.05
139	0.07	0.01	0.05	0.06	0.07	0.19	0.08	0.05	0.07	0.09
140	0.13	0.08	0.03	0.10	0.05	0.02	0.06	0.07	0.03	0.05
141	0.08	0.07	0.05	0.03	0.08	0.08	0.07	0.05	0.05	0.08
142	0.05	0.05	0.13	0.07	0.07	0.11	0.05	0.05	0.13	0.02
143	0.06	0.07	0.08	0.08	0.09	0.06	0.07	0.08	0.08	0.09
144	0.05	0.06	0.07	0.07	0.07	0.05	0.06	0.07	0.07	0.07
145	0.04	0.06	0.07	0.06	0.10	0.04	0.06	0.07	0.06	0.10
146	0.04	0.05	0.03		0.08	0.04	0.05	0.03		0.08
147	0.05	0.04	0.03	0.05	0.08	0.05	0.04	0.03	0.05	0.08
148	0.04	0.05	0.02	0.04	0.08	0.04	0.05	0.02	0.04	0.08
149	0.05	0.06	0.02	0.03	0.08	0.05	0.06	0.02	0.03	0.08
150	0.06	0.04	0.03	0.03	0.08	0.06	0.04	0.03	0.03	0.08
151	0.07	0.04	0.04	0.04	0.09	0.07	0.04	0.04	0.04	0.09
152	0.06	0.06	0.05	0.05	0.09	0.06	0.06	0.05	0.05	0.09
153	0.05	0.06	0.03	0.02	0.08	0.05	0.06	0.03	0.02	0.08
154	0.04	0.05	0.04	0.04	0.09	0.04	0.05	0.04	0.04	0.09
155	0.04	0.05	0.04	0.04	0.09	0.04	0.05	0.04	0.04	0.09
156	0.03	0.02	0.03	0.05	0.08	0.03	0.08	0.02	0.05	0.01
157	0.07	0.02	0.02	0.03	0.09	0.05	0.07	0.02	0.02	0.02
158	0.06	0.02	0.03	0.03	0.07	0.04	0.06	0.04	0.02	0.08
159	0.07	0.05	0.03	0.08	0.05	0.06	0.04	0.06	0.05	0.05
160	0.05	0.04	0.03	0.09	0.04	0.05	0.04	0.05	0.04	0.05
161	0.01	0.07	0.08	0.02	0.05	0.07	0.02	0.06	0.01	0.03
162	0.08	0.04	0.09	0.05	0.07	0.05	0.01	0.05	0.07	0.07
163	0.01	0.02	0.05	0.06	0.01	0.03	0.04	0.03	0.07	0.04
164	0.02	0.03	0.06	0.34	0.02	0.03	0.05	0.06	0.08	0.05
165	0.06	0.03	0.03	0.02	0.06	0.02	0.06	0.05	0.07	0.04
166	0.05	0.06	0.01	0.07	0.08	0.07	0.06	0.03	0.02	0.03
167	0.04	0.03	0.03	0.04	0.10	0.06	0.04	0.02	0.07	0.02
168	0.05	0.06	0.08	0.01	0.13	0.02	0.05	0.04	0.06	0.10
169	0.02	0.07	0.04	0.06	0.06	0.05	0.07	0.02	0.04	0.04
170	0.03	0.06	0.06	0.02	0.05	0.07	0.02	0.09	0.05	0.03
171	0.05	0.01	0.05	0.07	0.04	0.05	0.01	0.02	0.01	0.02
172	0.05	0.06	0.03	0.06	0.06	0.02	0.04	0.04	0.08	0.02
173	0.06	0.02	0.06	0.04	0.07	0.04	0.06	0.01	0.04	0.03
174	0.02	0.08	0.05	0.03	0.01	0.03	0.05	0.07	0.10	0.02
175	0.01	0.02	0.10	0.02	0.05	0.08	0.03	0.04	0.05	0.02
176	0.05	0.01	0.08	0.02	0.03	0.03	0.05	0.01	0.06	0.05
177	0.10	0.05	0.02	0.04	0.03	0.01	0.06	0.06	0.02	0.06
178	0.06	0.03	0.03	0.06	0.02	0.05	0.02	0.09	0.35	0.05
179	0.03	0.06	0.06	0.03	0.04	0.10	0.03	0.05	0.06	0.08
180	0.10	0.02	0.03	0.05	0.05	0.02	0.06	0.07	0.03	0.05
181	0.07	0.07	0.05	0.03	0.06	0.08	0.06	0.02	0.04	0.08
182	0.06	0.03	0.06	0.07	0.03	0.10	0.05	0.08	0.09	0.03
183	0.11	0.04	0.07	0.06	0.05	0.06	0.03	0.02	0.05	0.06
184	0.02	0.11	0.11	0.05	0.08	0.02	0.06	0.03	0.06	0.03
185	0.05	0.06	0.01	0.03	0.05	0.08	0.03	0.05	0.03	0.05
186	0.07	0.05	0.03	0.04	0.02	0.03	0.10	0.04	0.05	0.03
187	0.04	0.02	0.06	0.06	0.02	0.06	0.05	0.06	0.06	0.03
188	0.05	0.03	0.02	0.03	0.08	0.06	0.03	0.04	0.05	0.03
189	0.04	0.03	0.03	0.01	0.11	0.05	0.03	0.04	0.08	0.05
190	0.06	0.03	0.02	0.05	0.02	0.03	0.02	0.05	0.06	0.07
191	0.13	0.17	0.07	0.10	0.05	0.31	0.04	0.03	0.05	0.05
192	0.29	0.05	0.09	0.07	0.05	0.02	0.08	0.02	0.06	0.09
193	0.43	0.07	0.04	0.03	0.01	0.08	0.03	0.05	0.08	0.04
194	0.05	0.04	0.03	0.05	0.01	0.02	0.03	0.06	0.04	0.03
195	0.06	0.03	0.09	0.02	0.03	0.09	0.05	0.05	0.03	0.02
196	0.08	0.06	0.02	0.05	0.07	0.06	0.13	0.06	0.06	0.03
197	0.07	0.05	0.06	0.04	0.05	0.03	0.05	0.08	0.04	0.04
198	0.03	0.11	0.05	0.07	0.02	0.09	0.05	0.05	0.03	0.02
199	0.03	0.08	0.04	0.09	0.04	0.04	0.05	0.03	0.01	0.03
200	0.03	0.03	0.02	0.08	0.04	0.08	0.06	0.05	0.07	0.04
201	0.03	0.04	0.03	0.05	0.06	0.07	0.03	0.04	0.06	0.02
202	0.02	0.03	0.05	0.04	0.03	0.02	0.07	0.02	0.03	0.05
203	0.03	0.04	0.03	0.08	0.06	0.03	0.04	0.02	0.03	0.03
204	0.06	0.03	0.03	0.02	0.03	0.05	0.05	0.02	0.02	0.04
205	0.07	0.07	0.05	0.05	0.01	0.06	0.06	0.04	0.03	0.05
206	0.00	0.03	0.05	0.02	0.01	0.07	0.01	0.06	0.02	0.02
207	0.02	0.04	0.03	0.03	0.03	0.05	0.03	0.04	0.05	0.01
208	0.08	0.03	0.05	0.05	0.07	0.03	0.04	0.06	0.03	0.04
209	0.09	0.02	0.02	0.04	0.03	0.02	0.07	0.03	0.02	0.07
210	0.03	0.03	0.05	0.01	0.02	0.05	0.03	0.02	0.05	0.05
211	0.06	0.07	0.04	0.07	0.04	0.03	0.06	0.04	0.07	0.03
212	0.02	0.07	0.04	0.06	0.03	0.08	0.03	0.06	0.05	0.07
213	0.05	0.09	0.07	0.03	0.02	0.07	0.02	0.07	0.08	0.04
214	0.06	0.05	0.09	0.02	0.04	0.11	0.04	0.05	0.04	0.05
215	0.02	0.03	0.05	0.04	0.02	0.10	0.03	0.09	0.04	0.07
216	0.07	0.05	0.08	0.06	0.05	0.01	0.02	0.08	0.02	0.04
217	0.01	0.06	0.07	0.03	0.02	0.03	0.02	0.09	0.07	0.09
218	0.08	0.04	0.03	0.06	0.02	0.05	0.05	0.06	0.05	0.09
219	0.09	0.06	0.03	0.05	0.07	0.06	0.05	0.07	0.08	0.08
220	0.03	0.02	0.04	0.03	0.08	0.06	0.03	0.08	0.03	0.05
221	0.03	0.08	0.02	0.05	0.08	0.02	0.05	0.07	0.05	0.07
222	0.02	0.07	0.05	0.04	0.07	0.06	0.03	0.08	0.03	0.03
223	0.05	0.04	0.02	0.03	0.08	0.01	0.06	0.02	0.05	0.05
224	0.06	0.04	0.05	0.03	0.09	0.03	0.05	0.03	0.06	0.03
225	0.07	0.03	0.04	0.04	0.02	0.02	0.02	0.03	0.03	0.06
226	0.09	0.02	0.06	0.05	0.02	0.03	0.03	0.04	0.02	0.03
227	0.07	0.02	0.02	0.05	0.07	0.02	0.06	0.04	0.01	0.06
228	0.01	0.03	0.03	0.06	0.04	0.02	0.02	0.04	0.03	0.05
229	0.03	0.07	0.06	0.74	0.01	0.03	0.05	0.02	0.05	0.03
230	0.02	0.07	0.02	0.03	0.02	0.05	0.05	0.02	0.03	0.03
231	0.04	0.08	0.06	0.01	0.03	0.03	0.05	0.08	0.01	0.05
232	0.03	0.08	0.03	0.05	0.02	0.03	0.05	0.09	0.01	0.05
233	0.05	0.02	0.02	0.06	0.07	0.02	0.05	0.08	0.02	0.03
234	0.06	0.03	0.02	0.08	0.01	0.02	0.05	0.02	0.03	0.03
235	0.04	0.05	0.03	0.04	0.02	0.04	0.03	0.06	0.23	0.07
236	0.81	0.76	0.51	0.09	0.19	0.05	0.09	0.07	0.21	0.86
237	0.88	0.35	0.42	0.17	0.99	0.94	0.04	0.11	0.93	0.97
238	0.05	0.02	0.01	0.14	0.02	0.11	0.01	0.01	0.07	0.00
239	0.011	0.01	0.01	0.02	0.01	0.01	0.00	0.00	0.13	0.00
240	0.07	0.00	0.01	0.19	0.01	0.01	0.00	0.03	0.11	0.03
241	0.011	0.02	0.11	0.10	0.03	0.02	0.00	0.00	0.17	0.00
242	0.08	0.07	0.19	0.01	0.03	0.17	0.09	0.01	0.95	0.03
243	0.23	0.12	0.94	0.86	0.84	0.47	0.13	0.87	0.52	0.49
244	0.00	0.33	0.12	0.39	0.76	0.99	0.95	0.89	0.77	0.11
245	0.53	0.04	0.11	0.77	0.65	0.86	0.13	0.84	0.14	0.35
246	0.01	0.31	0.11	1.02	0.01	0.13	0.02	0.11	0.87	0.91
247	0.05	0.05	0.06	0.01	0.06	0.02	0.02	0.07	0.05	0.03
248	0.06	0.03	0.03	0.06	0.05	0.03	0.03	0.08	0.02	0.03
249	0.08	0.07	0.05	0.03	0.04	0.04	0.03	0.07	0.02	0.05
250	0.07	0.04	0.04	0.04	0.06	0.05	0.05	0.08	0.03	0.03
251	0.02	0.04	0.06	0.03	0.02	0.09	0.02	0.03	0.05	0.07
252	0.05	0.02	0.05	0.03	0.04	0.05	0.07	0.04	0.06	0.09
253	0.05	0.06	0.03	0.05	0.05	0.02	0.02	0.03	0.06	0.08
254	0.04	0.05	0.04	0.06	0.06	0.01	0.06	0.04	0.01	0.04
255	0.01	0.08	0.03	0.03	0.06	0.05	0.04	0.02	0.04	0.05

TABLE 5 — Test results of compounds on 249 cancer cells (2) GI50 (μM)

	KBM-	KBM5-	SGC-		Bel-					MDA-MB-
Compound No.	5	T315I	7901	N-87	7402	Huh-7	K562	H1975	HCC827	231
SAHA	11.2	86.7	12.5	13.2	12.7	18.3	10.1	15.2	16.7	22.5
1	0.037	0.046	0.053	0.018	0.029	0.033	0.078	0.122	0.179	0.095
2	0.051	0.029	0.026	0.029	0.083	0.073	0.051	0.034	0.042	0.092
3	0.073	0.034	0.028	0.043	0.097	0.043	0.037	0.029	0.033	0.091
4	0.074	0.022	0.034	0.053	0.092	0.086	0.061	0.031	0.022	0.086
5	0.072	0.033	0.043	0.037	0.093	0.072	0.032	0.023	0.055	0.082
6	0.061	0.041	0.051	0.028	0.086	0.058	0.033	0.013	0.065	0.084
7	0.049	0.052	0.035	0.029	0.082	0.046	0.041	0.034	0.054	0.091
8	0.051	0.063	0.043	0.034	0.094	0.061	0.053	0.038	0.041	0.093
9	0.044	0.026	0.031	0.035	0.083	0.053	0.083	0.026	0.053	0.097
10	0.061	0.024	0.023	0.038	0.095	0.051	0.073	0.024	0.026	0.098
11	0.062	0.026	0.035	0.037	0.076	0.043	0.063	0.042	0.023	0.086
12	0.072	0.031	0.036	0.028	0.072	0.086	0.024	0.041	0.037	0.084
13	0.084	0.011	0.042	0.031	0.085	0.085	0.025	0.053	0.029	0.081
14	0.094	0.012	0.043	0.036	0.084	0.092	0.036	0.062	0.018	0.085
15	0.095	0.016	0.053	0.029	0.086	0.073	0.026	0.038	0.051	0.091
16	0.082	0.019	0.051	0.027	0.091	0.043	0.025	0.039	0.049	0.093
17	0.081	0.028	0.053	0.043	0.092	0.061	0.032	0.042	0.043	0.079
18	0.054	0.037	0.042	0.044	0.095	0.065	0.035	0.053	0.059	0.078
19	0.053	0.024	0.052	0.051	0.097	0.092	0.026	0.024	0.048	0.095
20	0.061	0.033	0.063	0.062	0.086	0.072	0.024	0.035	0.052	0.096
21	0.073	0.027	0.024	0.035	0.083	0.084	0.025	0.037	0.034	0.098
22	0.072	0.026	0.053	0.039	0.084	0.082	0.034	0.041	0.059	0.092
23	0.076	0.062	0.019	0.042	0.098	0.091	0.052	0.038	0.062	0.077
24	0.068	0.035	0.018	0.035	0.095	0.051	0.037	0.037	0.031	0.086
25	0.059	0.029	0.029	0.038	0.093	0.062	0.027	0.042	0.033	0.092
26	0.0.38	0.031	0.037	0.039	0.097	0.051	0.017	0.031	0.055	0.098
27	0.091	0.026	0.035	0.036	0.099	0.091	0.026	0.052	0.028	0.089
28	0.073	0.051	0.034	0.042	0.092	0.073	0.035	0.035	0.037	0.086
29	0.043	0.037	0.029	0.033	0.091	0.077	0.034	0.063	0.029	0.087
30	0.082	0.022	0.035	0.03	0.082	0.037	0.038	0.039	0.082	0.037
31	0.092	0.063	0.077	0.052	0.057	0.019	0.027	0.042	0.057	0.019
32	0.071	0.058	0.045	0.069	0.067	0.038	0.034	0.053	0.067	0.038
33	0.083	0.051	0.052	0.061	0.083	0.031	0.016	0.026	0.083	0.031
34	0.074	0.053	0.049	0.067	0.094	0.049	0.053	0.034	0.094	0.049
35	0.075	0.059	0.061	0.063	0.051	0.046	0.026	0.038	0.051	0.046
36	0.061	0.057	0.047	0.039	0.062	0.043	0.029	0.019	0.062	0.043
37	0.053	0.062	0.051	0.041	0.034	0.038	0.037	0.027	0.034	0.038
38	0.077	0.064	0.034	0.049	0.084	0.033	0.039	0.034	0.084	0.033
39	0.072	0.067	0.041	0.050	0.083	0.022	0.026	0.035	0.083	0.022
40	0.079	0.055	0.045	0.071	0.074	0.035	0.041	0.043	0.074	0.035
41	0.031	0.076	0.027	0.039	0.082	0.033	0.066	0.032	0.033	0.072
42	0.046	0.053	0.032	0.084	0.055	0.019	0.057	0.035	0.035	0.035
43	0.081	0.054	0.052	0.038	0.073	0.036	0.052	0.062	0..073	0.036
44	0.087	0.061	0.037	0.059	0.084	0.029	0.063	0.051	0.084	0.029
45	0.094	0.059	0.043	0.067	0.061	0.037	0.033	0.034	0.061	0.037
46	0.091	0.047	0.057	0.043	0.052	0.035	0.035	0.037	0.052	0.035
47	0.081	0.056	0.049	0.061	0.043	0.024	0.039	0.029	0.043	0.024
48	0.076	0.061	0.069	0.081	0.042	0.035	0.028	0.028	0.042	0.035
49	0.087	0.055	0.067	0.073	0.072	0.026	0.017	0.034	0.072	0.026
50	0.079	0.063	0.039	0.069	0.083	0.025	0.042	0.035	0.083	0.025
51	0.083	0.077	0.045	0.065	0.072	0.029	0.046	0.063	0.072	0.029
52	0.088	0.067	0.051	0.053	0.091	0.031	0.027	0.061	0.091	0.031
53	0.093	0.054	0.061	0.047	0.046	0.026	0.037	0.051	0.046	0.026
54	0.099	0.063	0.064	0.049	0.051	0.034	0.029	0.043	0.051	0.034
55	0.089	0.073	0.059	0.055	0.081	0.029	0.036	0.052	0.081	0.029
56	0.081	0.069	0.053	0.042	0.093	0.037	0.043	0.053	0.093	0.037
57	0.074	0.054	0.092	0.053	0.073	0.028	0.035	0.055	0.073	0.028
58	0.069	0.082	0.051	0.061	0.049	0.039	0.026	0.061	0.049	0.039
59	0.061	0.074	0.059	0.059	0.082	0.037	0.038	0.039	0.082	0.037
60	0.074	0.083	0.043	0.063	0.057	0.019	0.027	0.042	0.057	0.019
61	0.081	0.094	0.038	0.075	0.067	0.038	0.034	0.053	0.067	0.038
62	0.091	0.064	0.046	0.064	0.083	0.031	0.016	0.026	0.083	0.031
63	0.093	0.057	0.051	0.059	0.094	0.049	0.053	0.034	0.094	0.049
64	0.082	0.022	0.035	0.03	0.051	0.046	0.026	0.038	0.051	0.046
65	0.092	0.063	0.077	0.052	0.062	0.043	0.029	0.029	0.062	0.043
66	0.091	0.031	0.025	0.061	0.034	0.038	0.037	0.027	0.034	0.038
67	0.046	0.026	0.037	0.051	0.084	0.033	0.039	0.034	0.084	0.033
68	0.051	0.034	0.029	0.043	0.083	0.022	0.026	0.035	0.083	0.022
69	0.081	0.029	0.036	0.052	0.074	0.035	0.041	0.043	0.074	0.035
70	0.093	0.037	0.043	0.053	0..073	0.036	0.052	0.062	0..073	0.036
71	0.073	0.028	0.035	0.055	0.084	0.029	0.063	0.051	0.084	0.029
72	0.049	0.039	0.026	0.061	0.061	0.037	0.033	0.034	0.061	0.037
73	0.086	0.024	0.028	0.038	0.052	0.035	0.035	0.037	0.052	0.035
74	0.037	0.35	0.049	0.037	0.043	0.024	0.039	0.029	0.043	0.024
75	0.061	0.026	0.041	0.022	0.042	0.035	0.028	0.028	0.042	0.035
76	0.094	0.034	0.051	0.032	0.072	0.026	0.017	0.034	0.072	0.026
77	0.052	0.037	0.601	0.052	0.083	0.025	0.042	0.035	0.083	0.025
78	0.061	0.019	0.062	0.061	0.072	0.029	0.046	0.063	0.072	0.029
79	0.076	0.028	0.051	0.022	0.091	0.031	0.027	0.061	0.091	0.031
80	0.049	0.022	0.071	0.031	0.046	0.026	0.037	0.051	0.046	0.026
81	0.038	0.034	0.059	0.035	0.051	0.034	0.029	0.043	0.051	0.034
82	0.049	0.038	0.048	0.026	0.081	0.029	0.036	0.052	0.081	0.029
83	0.038	0.029	0.053	0.016	0.093	0.037	0.043	0.053	0.093	0.037
84	0.051	0.026	0.043	0.019	0.073	0.028	0.035	0.055	0.073	0.028
85	0.053	0.025	0.015	0.027	0.049	0.039	0.026	0.061	0.049	0.039
86	0.061	0.034	0.028	0.037	0.082	0.037	0.038	0.039	0.082	0.037
87	0.082	0.037	0.037	0.021	0.057	0.019	0.027	0.042	0.057	0.019
88	0.071	0.024	0.029	0.031	0.067	0.038	0.034	0.053	0.067	0.038
89	0.093	0.038	0.034	0.013	0.083	0.031	0.016	0.026	0.083	0.031
90	0.083	0.024	0.036	0.034	0.094	0.049	0.053	0.034	0.094	0.049
91	0.091	0.031	0.048	0.062	0.051	0.046	0.026	0.038	0.051	0.046
92	0.042	0.029	0.057	0.015	0.062	0.043	0.022	0.029	0.062	0.043
93	0.053	0.034	0.068	0.028	0.034	0.038	0.037	0.027	0.034	0.038
94	0.061	0.035	0.041	0.037	0.084	0.033	0.039	0.034	0.084	0.033
95	0.076	0.038	0.042	0.023	0.083	0.022	0.026	0.035	0.083	0.022
96	0.072	0.054	0.037	0.027	0.061	0.048	0.019	0.073	0.065	0.057
97	0.093	0.026	0.024	0.031	0.059	0.013	0.029	0.042	0.039	0.031
98	0.029	0.058	0.036	0.021	0.043	0.028	0.037	0.081	0.035	0.037
99	0.019	0.022	0.069	0.031	0.016	0.031	0.042	0.058	0.088	0.024
100	0.035	0.031	0.057	0.032	0.071	0.027	0.034	0.053	0.017	0.078
101	0.041	0.036	0.048	0.026	0.045	0.036	0.021	0.069	0.039	0.052
102	0.067	0.071	0.031	0.046	0.011	0.073	0.028	0.035	0.058	0.026
103	0.031	0.051	0.037	0.051	0.025	0.047	0.034	0.026	0.055	0.039
104	0.079	0.068	0.026	0.096	0.057	0.089	0.033	0.038	0.049	0.020
105	0.023	0.053	0.016	0.093	0.021	0.056	0.019	0.097	0.047	0.086
106	0.056	0.076	0.035	0.012	0.066	0.031	0.027	0.068	0.043	0.019
107	0.072	0.041	0.027	0.035	0.053	0.024	0.038	0.057	0.013	0.027
108	0.011	0.024	0.036	0.034	0.076	0.043	0.059	0.033	0.093	0.049
109	0.082	0.071	0.042	0.061	0.056	0.046	0.028	0.031	0.051	0.126
110	0.041	0.029	0.057	0.035	0.062	0.048	0.017	0.059	0.062	0.013
111	0.053	0.035	0.073	0.028	0.036	0.038	0.037	0.027	0.057	0.038
112	0.021	0.031	0.041	0.073	0.023	0.035	0.055	0.016	0.073	0.058
113	0.036	0.051	0.095	0.042	0.034	0.021	0.047	0.024	0.048	0.031
114	0.099	0.028	0.043	0.011	0.042	0.054	0.038	0.032	0.071	0.022
115	0.053	0.028	0.023	0.045	0.036	0.099	0.041	0.023	0.041	0.036
116	0.018	0.036	0.021	0.043	0.028	0.052	0.016	0.093	0.021	0.046
117	0.022	0.059	0.033	0.016	0.034	0.066	0.035	0.072	0.086	0.058
118	0.041	0.057	0.039	0.061	0.027	0.041	0.029	0.035	0.053	0.031
119	0.062	0.028	0.034	0.038	0.037	0.026	0.036	0.038	0.037	0.027
120	0.045	0.033	0.084	0.053	0.066	0.071	0.023	0.035	0.055	0.016
121	0.046	0.023	0.033	0.023	0.026	0.045	0.038	0.028	0.042	0.075
122	0.038	0.026	0.061	0.048	0.049	0.091	0.046	0.055	0.032	0.032
123	0.068	0.067	0.051	0.062	0.027	0.035	0.036	0.021	0.069	0.039
124	0.057	0.015	0.042	0.045	0.072	0.016	0.076	0.028	0.035	0.051
125	0.064	0.058	0.039	0.031	0.057	0.025	0.047	0.036	0.029	0.075
126	0.041	0.037	0.081	0.033	0.049	0.051	0.079	0.033	0.038	0.029
127	0.053	0.028	0.036	0.046	0.037	0.071	0.028	0.036	0.038	0.037
128	0.041	0.053	0.023	0.035	0.053	0.049	0.073	0.023	0.039	0.055
129	0.035	0.042	0.033	0.021	0.041	0.038	0.042	0.033	0.022	0.041
130	0.023	0.011	0.042	0.058	0.032	0.041	0.028	0.042	0.054	0.038
131	0.063	0.045	0.031	0.095	0.043	0.023	0.045	0.016	0.059	0.046
132	0.024	0.043	0.028	0.057	0.077	0.026	0.048	0.028	0.052	0.016
133	0.036	0.016	0.035	0.066	0.032	0.033	0.016	0.031	0.036	0.035
134	0.031	0.061	0.027	0.041	0.029	0.092	0.038	0.054	0.035	0.063
135	0.011	0.051	0.044	0.026	0.039	0.087	0.033	0.079	0.093	0.041
136	0.009	0.035	0.051	0.031	0.022	0.036	0.046	0.035	0.041	0.058
137	0.048	0.026	0.081	0.029	0.016	0.043	0.035	0.053	0.049	0.045
138	0.042	0.045	0.072	0.016	0.076	0.036	0.021	0.043	0.022	0.052
139	0.069	0.021	0.057	0.025	0.043	0.051	0.047	0.015	0.034	0.067
140	0.031	0.033	0.044	0.055	0.079	0.042	0.039	0.063	0.021	0.031
141	0.036	0.043	0.017	0.067	0.058	0.028	0.031	0.038	0.037	0.026
142	0.073	0.035	0.053	0.042	0.073	0.038	0.084	0.059	0.066	0.051
143	0.036	0.034	0.063	0.032	0.042	0.075	0.053	0.049	0.073	0.025
144	0.011	0.127	0.041	0.029	0.035	0.023	0.011	0.038	0.012	0.037
145	0.008	0.031	0.018	0.031	0.018	0.058	0.032	0.031	0.078	0.041
146	0.033	0.023	0.035	0.023	0.035	0.065	0.043	0.073	0.045	0.056
147	0.023	0.026	0.045	0.083	0.028	0.057	0.037	0.026	0.028	0.078
148	0.035	0.053	0.051	0.047	0.053	0.064	0.062	0.039	0.016	0.051
149	0.021	0.041	0.042	0.039	0.063	0.075	0.032	0.070	0.029	0.035
150	0.026	0.039	0.087	0.033	0.058	0.046	0.055	0.079	0.063	0.021
151	0.031	0.022	0.036	0.046	0.026	0.035	0.067	0.058	0.038	0.037
152	0.041	0.029	0.023	0.035	0.047	0.028	0.011	0.038	0.035	0.065
153	0.028	0.031	0.083	0.028	0.096	0.075	0.032	0.031	0.028	0.057
154	0.029	0.071	0.012	0.063	0.053	0.047	0.028	0.038	0.075	0.053
155	0.035	0.056	0.033	0.032	0.041	0.038	0.075	0.023	0.023	0.011
156	0.017	0.033	0.045	0.065	0.023	0.035	0.031	0.018	0.043	0.063
157	0.036	0.023	0.072	0.036	0.083	0.029	0.023	0.035	0.037	0.026
158	0.046	0.027	0.027	0.038	0.045	0.041	0.048	0.049	0.091	0.046
159	0.035	0.053	0.075	0.063	0.023	0.058	0.062	0.024	0.035	0.036
160	0.028	0.026	0.081	0.049	0.036	0.042	0.042	0.071	0.016	0.017
161	0.013	0.012	0.091	0.037	0.047	0.079	0.031	0.057	0.065	0.046
162	0.042	0.016	0.078	0.018	0.035	0.081	0.073	0.049	0.051	0.079
163	0.075	0.023	0.049	0.039	0.026	0.107	0.058	0.045	0.047	0.058
164	0.073	0.047	0.028	0.041	0.038	0.095	0.062	0.081	0.028	0.096
165	0.041	0.034	0.076	0.032	0.030	0.028	0.057	0.012	0.043	0.053
166	0.05	0.053	0.042	0.073	0.068	0.056	0.046	0.026	0.031	0.017
167	0.014	0.033	0.097	0.042	0.075	0.029	0.045	0.043	0.028	0.091
168	0.022	0.036	0.034	0.094	0.044	0.056	0.034	0.066	0.035	0.012
169	0.051	0.047	0.062	0.055	0.046	0.061	0.037	0.044	0.029	0.035
170	0.049	0.057	0.037	0.062	0.043	0.088	0.037	0.026	0.096	0.038
171	0.033	0.068	0.028	0.039	0.038	0.053	0.046	0.071	0.023	0.065
172	0.035	0.041	0.031	0.084	0.073	0.023	0.026	0.045	0.032	0.078
173	0.013	0.012	0.023	0.083	0.022	0.071	0.053	0.036	0.027	0.048
174	0.015	0.096	0.026	0.031	0.041	0.011	0.013	0.057	0.046	0.016
175	0.042	0.047	0.062	0.049	0.105	0.027	0.039	0.042	0.013	0.029
176	0.034	0.038	0.031	0.028	0.031	0.031	0.021	0.031	0.038	0.032
177	0.080	0.013	0.039	0.037	0.084	0.035	0.029	0.083	0.033	0.049
178	0.093	0.022	0.076	0.055	0.058	0.042	0.053	0.089	0.032	0.026
179	0.061	0.028	0.019	0.073	0.065	0.015	0.071	0.054	0.025	0.051
180	0.029	0.057	0.035	0.062	0.048	0.017	0.049	0.097	0.013	0.056
181	0.015	0.033	0.028	0.036	0.038	0.037	0.023	0.035	0.041	0.018
182	0.031	0.041	0.071	0.023	0.035	0.035	0.083	0.039	0.023	0.035
183	0.051	0.065	0.048	0.037	0.025	0.047	0.025	0.041	0.046	0.049
184	0.078	0.043	0.011	0.042	0.056	0.038	0.023	0.058	0.062	0.074
185	0.028	0.013	0.044	0.026	0.091	0.071	0.036	0.012	0.082	0.071
186	0.036	0.021	0.043	0.028	0.052	0.016	0.039	0.063	0.089	0.039
187	0.021	0.041	0.038	0.042	0.043	0.085	0.045	0.023	0.075	0.011
188	0.018	0.036	0.071	0.028	0.042	0.079	0.036	0.053	0.029	0.023
189	0.045	0.043	0.023	0.045	0.036	0.021	0.032	0.041	0.041	0.038
190	0.057	0.017	0.086	0.048	0.028	0.075	0.063	0.023	0.056	0.067
191	0.036	0.032	0.033	0.011	0.051	0.089	0.041	0.032	0.049	0.052
192	0.021	0.029	0.099	0.032	0.054	0.071	0.023	0.035	0.037	0.083
193	0.031	0.041	0.073	0.023	0.035	0.033	0.035	0.011	0.018	0.043
194	0.051	0.025	0.043	0.036	0.027	0.084	0.029	0.023	0.035	0.027
195	0.026	0.043	0.014	0.042	0.054	0.045	0.081	0.038	0.079	0.091
196	0.028	0.093	0.045	0.056	0.089	0.023	0.058	0.062	0.064	0.085
197	0.086	0.021	0.043	0.028	0.052	0.076	0.049	0.045	0.071	0.016
198	0.099	0.043	0.016	0.038	0.063	0.047	0.079	0.031	0.057	0.045
199	0.017	0.029	0.067	0.027	0.042	0.035	0.081	0.078	0.047	0.051
200	0.028	0.034	0.058	0.039	0.026	0.026	0.107	0.059	0.045	0.046
201	0.029	0.035	0.051	0.032	0.069	0.09	0.035	0.073	0.011	0.038
202	0.038	0.026	0.031	0.029	0.076	0.031	0.015	0.058	0.032	0.041
203	0.053	0.026	0.043	0.077	0.023	0.022	0.035	0.065	0.023	0.073
204	0.063	0.019	0.073	0.028	0.036	0.083	0.028	0.067	0.037	0.056
205	0.015	0.027	0.059	0.049	0.056	0.047	0.053	0.064	0.062	0.039
206	0.027	0.039	0.082	0.097	0.048	0.039	0.061	0.075	0.012	0.076
207	0.038	0.021	0.057	0.019	0.027	0.033	0.048	0.046	0.055	0.079
208	0.018	0.049	0.026	0.056	0.017	0.026	0.076	0.035	0.067	0.018
209	0.046	0.031	0.041	0.051	0.013	0.023	0.039	0.017	0.085	0.035
210	0.052	0.049	0.105	0.027	0.047	0.022	0.086	0.025	0.056	0.072
211	0.031	0.028	0.071	0.031	0.021	0.024	0.019	0.073	0.055	0.085
212	0.069	0.037	0.084	0.035	0.039	0.057	0.035	0.062	0.048	0.097
213	0.078	0.054	0.058	0.042	0.053	0.035	0.028	0.076	0.028	0.037
214	0.019	0.073	0.068	0.095	0.071	0.041	0.071	0.063	0.035	0.015
215	0.025	0.042	0.048	0.017	0.019	0.065	0.048	0.037	0.015	0.047
216	0.038	0.036	0.038	0.037	0.023	0.049	0.056	0.087	0.059	0.062
217	0.041	0.083	0.028	0.057	0.037	0.019	0.062	0.043	0.029	0.019
218	0.021	0.043	0.053	0.065	0.062	0.021	0.036	0.038	0.037	0.027
219	0.042	0.039	0.063	0.075	0.082	0.049	0.084	0.033	0.039	0.034
220	0.083	0.033	0.028	0.046	0.055	0.053	0.083	0.057	0.026	0.045
221	0.036	0.041	0.026	0.065	0.057	0.041	0.074	0.035	0.041	0.043
222	0.043	0.035	0.047	0.098	0.014	0.039	0.083	0.083	0.063	0.052
223	0.053	0.028	0.096	0.075	0.032	0.054	0.055	0.019	0.027	0.035
224	0.016	0.063	0.093	0.017	0.023	0.036	0.023	0.096	0.052	0.062
225	0.033	0.038	0.041	0.038	0.072	0.059	0.081	0.029	0.013	0.071
226	0.075	0.065	0.023	0.035	0.031	0.068	0.061	0.037	0.033	0.034
227	0.049	0.055	0.053	0.019	0.072	0.017	0.023	0.035	0.045	0.051
228	0.062	0.033	0.012	0.035	0.056	0.035	0.062	0.048	0.017	0.069
229	0.071	0.053	0.091	0.077	0.037	0.028	0.086	0.038	0.077	0.023
230	0.026	0.087	0.048	0.036	0.023	0.091	0.023	0.035	0.035	0.083
231	0.038	0.057	0.011	0.036	0.058	0.048	0.037	0.025	0.077	0.025
232	0.008	0.043	0.063	0.045	0.035	0.021	0.042	0.056	0.038	0.023
233	0.097	0.046	0.051	0.035	0.081	0.041	0.024	0.051	0.081	0.036
234	0.012	0.032	0.039	0.023	0.082	0.042	0.038	0.052	0.016	0.039
235	0.027	0.092	0.042	0.063	0.091	0.038	0.042	0.063	0.085	0.045
236	0.033	0.053	0.048	0.026	0.075	0.067	0.073	0.072	0.026	0.017
237	0.049	0.087	0.033	0.058	0.042	0.049	0.069	0.083	0.025	0.012
238	0.052	0.066	0.056	0.026	0.031	0.055	0.065	0.082	0.029	0.046
239	0.029	0.023	0.035	0.046	0.028	0.051	0.063	0.091	0.031	0.025
240	0.071	0.083	0.024	0.096	0.079	0.061	0.047	0.056	0.066	0.037
241	0.071	0.082	0.063	0.057	0.047	0.064	0.041	0.051	0.034	0.029
242	0.056	0.033	0.032	0.031	0.088	0.059	0.055	0.021	0.079	0.016
243	0.093	0.045	0.025	0.023	0.035	0.053	0.032	0.043	0.037	0.093
244	0.023	0.012	0.036	0.083	0.029	0.092	0.053	0.073	0.028	0.035
245	0.011	0.012	0.063	0.053	0.087	0.031	0.083	0.028	0.096	0.065
246	0.056	0.033	0.032	0.041	0.038	0.021	0.012	0.063	0.053	0.047
247	0.032	0.045	0.065	0.023	0.095	0.053	0.033	0.032	0.041	0.038
248	0.023	0.072	0.026	0.083	0.029	0.033	0.048	0.065	0.093	0.045
249	0.047	0.027	0.033	0.045	0.041	0.043	0.072	0.076	0.023	0.029
250	0.053	0.079	0.063	0.043	0.058	0.027	0.027	0.038	0.045	0.021
251	0.066	0.081	0.049	0.036	0.042	0.055	0.035	0.063	0.053	0.038
252	0.072	0.081	0.035	0.067	0.079	0.026	0.081	0.09	0.076	0.042
253	0.016	0.078	0.018	0.035	0.087	0.072	0.011	0.057	0.037	0.069
254	0.053	0.042	0.087	0.064	0.031	0.046	0.078	0.018	0.035	0.081
255	0.032	0.037	0.048	0.051	0.035	0.045	0.056	0.068	0.057	0.023

TABLE 6 — Comparison of the cellular activity of compounds of the present invention and patent CN102391359A (1) Compound No.

present		GI50 (μM)
invention	CN102391359A	Hela	MCF7	A549	BGC823	HT1080
(a)	(b)	a	b	a	b	a	b	a	b	a	b
235	1-1	0.047	0.4	0.056	0.09	0.034	0.09	0.043	0.1	0.024	0.05
9	1-2	0.05	0.1	0.03	0.05	0.08	0.3	0.007	0.02	0.04	0.1
1	1-3	0.02	1.0	0.03	1.2	0.01	10.0	0.06	0.06	0.01	4.0
11	1-4	0.12	1.3	0.05	0.2	0.43	2.9	0.41	2.5	0.14	0.8
236	1-5	0.81	2.0	0.76	0.8	0.51	0.6	0.093	0.1	0.197	1.0
237	1-6	0.88	1.0	0.35	0.6	0.42	0.5	0.17	0.4	0.99	1.3
14	1-7	0.22	5.0	0.4	0.7	0.1	0.4	0.2	0.3	0.3	0.3
238	1-8	0.055	0.1	0.023	0.1	0.016	0.1	0.14	0.3	0.026	0.07
239	1-9	0.011	0.05	0.019	0.05	0.012	0.03	0.022	0.05	0.011	0.04
240	1-10	0.018	0.1	0.001	0.001	0.036	0.1	0.11	0.2	0.033	0.1
241	1-11	0.011	0.1	0.028	0.09	0.11	5.09	0.10	0.16	0.034	0.08
242	1-12	0.088	0.9	0.073	0.8	0.19	1.2	0.014	0.06	0.33	1.0
1	2-1	0.02	0.2	0.03	0.5	0.03	0.9	0.06	5	0.03	4.1
243	2-2	0.23	0.6	0.12	2.3	0.94	2.0	0.86	1.6	0.84	4.5
243	2-3	0.23	26.5	0.12	21.4	0.94	2.6	0.86	1.56	0.84	40.5
1	2-4	0.02	23	0.03	52.6	0.01	4.5	0.06	2.6	0.01	1.6
1	2-5	0.02	12	0.03	26	0.01	2.13	0.06	20.6	0.01	1.02
1	2-6	0.02	0.5	0.03	0.65	0.01	4.2	0.06	56.2	0.01	12.0
1	2-7	0.02	0.1	0.03	0.09	0.01	0.09	0.06	0.1	0.01	0.08
244	3-1	0.008	0.01	0.33	2.1	0.12	0.35	0.39	1.2	0.76	1.06
245	3-2	0.53	0.6	0.041	0.1	0.11	0.36	0.77	1.02	0.65	1.35
246	3-3	0.013	0.45	0.31	1.20	0.11	1.09	1.02	5.94	0.017	0.06
27	6-1	0.53	0.6	0.03	0.059	0.095	0.1	0.31	0.36	0.04	0.05
7	6-2	0.04	73.5	0.03	59.6	0.052	15.6	0.031	4.6	0.027	41.02

TABLE 7 — Comparison of the cellular activity of compounds of the present invention and patent CN102391359A (2) Compound No.

Present		GI50 (μM)
Invention		lncap	Du145	U937	PANC-1	Molt-4
(a)	CN102391359A	a	b	a	b	a	b	a	b	a	b
235	1-1	0.04	0.05	0.003	0.008	0.006	0.007	0.23	0.3	0.007	0.009
9	1-2	0.009	0.07	0.002	0.004	0.001	0.004	0.06	0.2	0.011	0.03
1	1-3	0.009	2.0	0.004	0.3	0.005	0.5	0.32	6.0	0.032	1.0
11	1-4	0.025	0.2	0.033	0.36	0.035	0.03	0.06	1.6	0.017	0.1
236	1-5	0.53	0.6	0.091	0.1	0.077	0.1	0.21	3.0	0.86	1.0
237	1-6	0.94	1.2	0.04	0.05	0.11	0.2	0.93	3.0	0.97	1.0
14	1-7	0.2	0.5	0.012	0.02	0.003	0.02	0.53	1.5	0.02	0.1
238	1-8	0.11	0.2	0.012	0.03	0.015	0.02	0.077	0.1	0.008	0.02
239	1-9	0.017	0.03	0.001	0.003	0.003	0.005	0.13	0.6	0.004	0.01
240	1-10	0.07	0.08	0.004	0.01	0.012	0.02	0.19	1.3	0.018	0.02
241	1-11	0.025	0.03	0.003	0.006	0.007	0.009	0.17	0.8	0.003	0.01
242	1-12	0.17	0.3	0.091	0.1	0.012	0.1	0.95	6.0	0.032	0.1
1	2-1	0.009	2.01	0.004	0.05	0.005	1.3	0.32	2.06	0.011	0.1
243	2-2	0.47	23.6	0.13	56.5	0.87	10.2	0.52	0.6	0.49	26.2
243	2-3	0.47	0.5	0.13	0.56	0.87	1.23	0.52	2.65	0.49	23.1
1	2-4	0.009	85.2	0.004	6.4	0.005	18.6	0.02	4.2	0.005	0.9
1	2-5	0.009	0.56	0.004	5.46	0.005	21.03	0.02	26.4	0.005	1.03
1	2-6	0.009	11.65	0.004	0.56	0.005	12.6	0.02	45.01	0.005	64.5
1	2-7	0.009	0.65	0.004	0.006	0.005	0.009	0.02	0.8	0.005	2.1
244	3-1	0.99	5.4	0.95	2.03	0.89	21.5	0.77	10.6	0.11	0.15
245	3-2	0.86	1.42	0.13	1.06	0.84	5.26	0.14	1.23	0.35	1.06
246	3-3	0.13	0.45	0.02	0.05	0.11	0.14	0.87	4.13	0.91	2.12
27	6-1	0.038	0.042	0.021	0.034	0.004	0.005	0.21	0.23	0.51	0.65
7	6-2	0.003	0.9	0.013	1.6	0.008	2.65	0.005	0.68	0.021	0.4

Claims as granted

10 claims

Classifications

4 codes

IPC · International Patent Classification

Section A — Human necessities

A61K38/00

Section C — Chemistry; metallurgy

C07K5/062
C07K1/12
C07K5/02

Claim changes

Soon

Coming soonHow the claims changed between publication and grant

See which claims were amended, added or cancelled during examination, with every added and removed word marked.

AmendedAddedCancelledUnchanged

The published claims of this application are not paired with the granted ones in what we hold.

File wrapper

⤢ drag to zoom

USPTOApplicanthover for detail · click to open

Pendency

4.0 y

1,463 days filing → grant

Office actions

after a restriction

Responses

no RCE

Examiner

Garcia Marcela M Cordero

art unit 1676 · TC 1600

Law firm

Law firm · Log in to unlock

Citations: 10 back · 1 forward

See the full prosecution history — every USPTO and applicant action on this file, in order.

Documents

Log in to open the documents of this file: the application as filed, every office action and response, the notice of allowance.

Chain of title

⤢ drag to zoom

Titlehover for detail · click to open

See the full assignment history — every owner this patent has passed through, with recordation dates and reel/frame numbers.