COMPOUND FOR ADJUSTING ACTIVITY OF NMDA RECEPTOR, AND PHARMACEUTICAL COMPOSITION AND USE THEREOF

Abstract

Provided are a compound for adjusting the activity of an NMDA receptor, and a pharmaceutical composition and the use thereof. In particular, provided are a compound as represented by formula I, a pharmaceutically acceptable salt or ester, a stereoisomer, or a solvate thereof. The compound has the effect of enhancing the activity of the NMDA receptor, and can be used to prepare drugs for preventing/treating depression, anxiety disorder, tension, learning and cognitive defects, neuropathic pain and other diseases,

##STR00001##

Claims

1. A compound represented by a formula I: ##STR00906## or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein, Ring A is 3- to 8-membered aliphatic heterocycle; R.sub.1 is selected from H, C1-C6 alkyl, aryl-C1-C4 alkyl, C2-C6 acyl, —CONRR′ and natural amino acid fragments; R.sub.2 is selected from H, C1-C6 alkyl, C1-C6 alkoxycarbonyl, C2-C6 acyl, —CONRR′ and natural amino acid fragments; R.sub.3 is selected from H, cyano, 3- to 8-membered nitrogen-containing aliphatic heterocycle-C1-C4 acyl, C1-C6 alkoxycarbonyl and —CONHR.sub.4; R and R′ are each independently selected from H and C1-C6 alkyl; R.sub.4 is selected from H, C1-C6 alkyl, natural amino acid fragments and carboxylic acid derivatives of the said natural amino acid fragments; optionally, the C1-C6 alkyl, aryl-C1-C4 alkyl, C2-C6 acyl, 3- to 8-membered nitrogen-containing aliphatic heterocycle-C1-C4 acyl, C1-C6 alkoxycarbonyl, —CONRR′, —CONHR.sub.4 and natural amino acid fragments are each independently substituted by one or more substituents selected from: halogen, amino, hydroxyl, cyano, carboxyl, nitro, C1-C6 alkyl and C1-C6 alkoxy; and, R.sub.1, R.sub.2 and R.sub.3 satisfy: (1) R.sub.1, R.sub.2 and R.sub.3 are not H at the same time; (2) when R.sub.1 and R.sub.3 are H, R.sub.2 is not Boc; (3) when the formula I is ##STR00907## R.sub.1 is ##STR00908## and R.sub.3 is H; R.sub.2 is not ##STR00909## (4) when the formula I is ##STR00910## R.sub.1 is ##STR00911## and R.sub.3 is H; R.sub.2 is not C2-C6 acyl or —CONRR′; (5) when the formula I is ##STR00912## R.sub.1 and R.sub.3 are H; R.sub.2 is not C1-C4 alkyl, acetyl, ##STR00913## (6) the compound of the formula I is not ##STR00914##

2. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein Ring A is selected from 4- to 7-membered aliphatic heterocycle.

3. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein, R.sub.1 is selected from H, C1-C6 alkyl, phenyl-C1-C4 alkyl, C2-C6 acyl and natural amino acid fragments.

4. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein, R.sub.2 is selected from H, C1-C6 alkyl, C1-C6 alkoxycarbonyl, C2-C6 acyl and natural amino acid fragments; optionally, the C1-C6 alkyl, phenyl-C1-C4 alkyl, C2-C6 acyl, and natural amino acid fragments are each independently substituted by one or more substituents selected from: halogen, amino, hydroxyl, cyano, carboxyl, nitro, C1-C6 alkyl and C1-C6 alkoxy.

5. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein, R.sub.3 is selected from H, cyano, 5- to 7-membered nitrogen-containing aliphatic heterocycle-C1-C3 acyl, C1-C4 alkoxycarbonyl and —CONHR.sub.4; R.sub.4 is selected from H, natural amino acid fragments, amide derivatives of the said natural amino acid fragments and cyano derivatives of the said natural amino acid fragments.

6. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein the said natural amino acid fragments are selected from the carboxyl or amino residues of the following amino acids: Thr, Ser, Val, Gly, Ala, Ile, Phe, Gln and Tyr preferably, the said natural amino acid fragments are selected from the

7. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein the compound is selected from: ##STR00915## ##STR00916## ##STR00917## ##STR00918## ##STR00919## ##STR00920## ##STR00921## ##STR00922## ##STR00923## ##STR00924## ##STR00925## ##STR00926## ##STR00927## ##STR00928## ##STR00929## ##STR00930## ##STR00931## ##STR00932## ##STR00933## ##STR00934## ##STR00935## ##STR00936## ##STR00937## ##STR00938## ##STR00939## ##STR00940## ##STR00941## ##STR00942## ##STR00943## ##STR00944## ##STR00945## ##STR00946## ##STR00947## ##STR00948## ##STR00949## ##STR00950## ##STR00951## ##STR00952## ##STR00953## ##STR00954## ##STR00955## ##STR00956## ##STR00957## ##STR00958## ##STR00959## ##STR00960## ##STR00961## ##STR00962## ##STR00963## ##STR00964## ##STR00965## ##STR00966## ##STR00967## ##STR00968## ##STR00969## ##STR00970## ##STR00971## ##STR00972## ##STR00973## ##STR00974## ##STR00975## ##STR00976## ##STR00977## ##STR00978## ##STR00979## ##STR00980## ##STR00981## ##STR00982## ##STR00983## ##STR00984## ##STR00985## ##STR00986## ##STR00987## ##STR00988## ##STR00989## ##STR00990## ##STR00991## ##STR00992## ##STR00993## ##STR00994## ##STR00995## ##STR00996## ##STR00997## ##STR00998## ##STR00999## ##STR01000## ##STR01001## ##STR01002## ##STR01003## ##STR01004## ##STR01005## ##STR01006## ##STR01007## ##STR01008## ##STR01009## ##STR01010## ##STR01011## ##STR01012## ##STR01013## ##STR01014## ##STR01015## ##STR01016## ##STR01017## ##STR01018## ##STR01019## ##STR01020## ##STR01021## ##STR01022##

8. The compound of the formula I according to claim 1, a pharmaceutically acceptable salt or ester, stereoisomers or solvate thereof, wherein the said solvate is a hydrate.

9. A pharmaceutical composition comprising an effective amount of the compound of the formula I according to claim 1, a pharmaceutically acceptable salt or ester, stereoisomer or solvate thereof optionally, the pharmaceutical composition also comprise.

10-13. (canceled)

14. A method for preventing and/or treating depression, anxiety, stroke, Huntington's disease, Alzheimer's disease, neuralgia or schizophrenia in subjects, including administering an effective amount of the compound of the formula I according to claim 1, pharmaceutically acceptable salt or ester, stereoisomer or solvate thereof to the subjects in need.

15. A method for regulating activity of NMDA receptor in vivo or in vitro, including providing a subject, a mammalian cell or an NMDA receptor with an effective amount of the compound of the formula I according to claim 1, pharmaceutically acceptable salt or ester, stereoisomer or solvate thereof.

16. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein Ring A is selected from 4- to 7-membered nitrogen-containing aliphatic heterocycle.

17. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein Ring A is selected from ##STR01023##

18. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein R.sub.1 is selected from H, C1-C6 alkyl and C2-C6 acyl.

19. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein R.sub.1 is selected from H, acetyl, methyl, ##STR01024##

20. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein R.sub.2 is selected from H, C1-C4 alkoxycarbonyl, C2-C6 acyl and carboxyl residues of the natural amino acids.

21. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein R.sub.2 is selected from H, methyl, ethyl, propyl, butyl, tert-butoxycarbonyl, acetyl, ##STR01025##

22. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein R.sub.3 is selected from H, cyano, 5-to 7-membered nitrogen-containing aliphatic heterocycle-C1-C3 acyl, C1-C4 alkoxycarbonyl and —CONHR.sub.4; R.sub.4 is selected from H, natural amino acid fragments and amide derivatives of the said natural amino acid fragments.

23. The compound according to claim 1, or a pharmaceutically acceptable salt or ester, stereoisomer, or solvate thereof, wherein R.sub.3 is selected from H, cyano, ##STR01026##

24. The pharmaceutical composition according to claim 9, wherein, the pharmaceutical composition also comprises one or more pharmaceutically acceptable excipients.

Description

EXEMPLARY SYNTHETIC SCHEME

Examples of Synthesis of A-001 and A-002

[0182] ##STR00523##

[0183] At −15° C., 1.14 g (10 mmol, 1.0eq) of a raw material mercaptoethylamine hydrochloride was dissolved in 100 ml of methanol, 1.75 ml (15 mmol, 1.5eq) of triethylamine was added and sufficiently dissociated, 1.8 g (10 mmol, 1.0eq) of 1-Boc-3-azetidinone was added, the materials were continuously reacted at a low temperature for 15 min and then transferred to room temperature; after the completion of the materials reaction was monitored by TLC, vacuum concentration was performed, a concentrate was dissolved with 100 ml of ethyl acetate, washed with a small amount of water for many times (15 ml×4), dried with anhydrous sodium sulfate, filtered, and then concentrated. A crude product was purified with a silica gel column (PE:EtOAc=2:1) to obtain a total of 2.25 g of a white solid A-002 with a yield of 92.6%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.37 (s, 9H, —CH.sub.3), 3.12 (t, 2H, J=8.2 Hz), 3.34 (t, 2H, J=6.1 Hz), 4.1-4.20 (d, 2H, J=9.2 Hz), 4.59-4.62 (d, 2H, J=9.5 Hz), 9.3 (s, 1H). M+1:231.11.

[0184] 1 g (6 mmol) of an intermediate A-002 was dissolved in 10 mL of anhydrous ethyl acetate, and then 10 mL of 4 mol/L HCl/EtOAc was added and stirred overnight at room temperature, and a white solid was generated in the system; after the completion of the materials reaction was monitored by TLC, the reaction was terminated. Filtration and washing with anhydrous diethyl ether were performed, and then a total of 0.54 g of a white solid A-001 was obtained with a yield of 76%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 3.10 (t, 2H, J=6.8 Hz), 3.37 (t, 2H, J=6.4 Hz), 4.1-4.15 (d, 2H, J=11.2 Hz), 4.55-4.6 (d, 2H, J=10.5 Hz), 9.5 (s, 1H), 9.8 (s, 1H). M+1:131.06.

[0185] According to the preparation method of A-002, the corresponding products A-016, A-030 and A-044 of five-membered ring or six-membered ring can be prepared. The methods were the same as that of A-002, except that the corresponding cycloketone was replaced; similarly, the corresponding products A-015, A-029 and A-043 of five-membered ring or six-membered ring were prepared according to the preparation method of A-001. [0186] A-016: the raw material 1-Boc-3-azetidinone in the synthesis step of A-002 was replaced with N-Boc-3-pyrrolidone, and the rest operations were the same as those in the synthesis of A-002. M+1: 245.12. [0187] A-030: the raw material 1-Boc-3-azetidinone in the synthesis step of A-002 was replaced with N-Boc-4-piperidone and the rest operations were the same as those in the synthesis of A-002. M+1: 259.14. [0188] A-044: the raw material 1-Boc-3-azetidinone in the synthesis step of A-002 was replaced with N-Boc-3-piperidone, and the rest operations were the same as those in the synthesis of A-002. M+1: 259.14. [0189] A-015: the intermediate A-002 in the synthesis step of A-001 was replaced with A-016, and the rest operations were the same as those in the synthesis of A-001. M+1: 145.07. [0190] A-029: the intermediate A-002 in the synthesis step of A-001 was replaced with A-030, and the rest operations were the same as those in the synthesis of A-001. M+1: 159.09. [0191] A-043: the intermediate A-002 in the synthesis step of A-001 was replaced with A-044, and the rest operations were the same as those in the synthesis of A-001. M+1: 159.09.

Example of A-003

[0192] ##STR00524##

[0193] A total of 0.4 g (2.4 mmol) of the compound A-001 was dissolved in 20 ml of anhydrous DCM, and 665 μL (4.8 mmol) of TEA was added for dissociation; 155 μL (2.2 mmol) of acetyl chloride was added to 5 ml of DCM, and it was slowly dripped to the above reaction system with a dropper funnel under ice bath conditions, and the materials were continuously reacted at low temperature for half an hour and then moved to room temperature; the reaction was performed for 4 h at room temperature; when the completion of the materials reaction was monitored by TLC, the reaction was terminated. A small amount of water was used for washing (5 ml×3), an organic phase was taken, dried, filtered, concentrated, and separated through a silica gel column to obtain a brown oily substance, after stirring with hydrochloric acid to generate salt, a solid was generated, and a total of 0.31 g of a product A-003 was obtained with a yield of 61.9%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 2.03 (s, 3H), 3.15 (t, 2H, J=6.8 Hz), 3.29 (t, 2H, J=7.4 Hz), 4.11-4.21 (d, 2H, J=7.1 Hz), 4.51-4.63 (d, 2H, J=8.1 Hz), 9.53 (s, 1H). M+1:173.07.

Examples of Preparation of A-004 and A-005

[0194] A-004: acetyl chloride in the synthesis step of A-003 was replaced with isobutyryl chloride, and the rest operations were the same as those in the synthesis of A-003. M+1: 201.10. [0195] A-005: acetyl chloride in the synthesis step of A-003 was replaced with pivaloyl chloride, and the rest operations were the same as those in the synthesis of A-003. M+1: 215.11.

[0196] Examples of preparation of A-017 to A-019: A-017: A-001 in the synthesis step of A-003 was replaced with A-015, and the rest operations were the same as those in the synthesis of A-003. M+1: 187.08. [0197] A-018: A-001 in the synthesis step of A-003 was replaced with A-015 and acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in the synthesis of A-003. M+1: 215.11. [0198] A-019: A-001 in the synthesis step of A-003 was replaced with A-015 and acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in the synthesis of A-003. M+1: 229.13.

[0199] Examples of preparation of A-031 to A-033: A-031: A-001 in the synthesis step of A-003 was replaced with A-029, and the rest operations were the same as those in the synthesis of A-003. M+1: 201.10. [0200] A-032: A-001 in the synthesis step of A-003 was replaced with A-029 and acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in the synthesis of A-003. M+1: 229.13. [0201] A-033: A-001 in the synthesis step of A-003 was replaced with A-029 and acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in the synthesis of A-003. M+1: 243.15.

[0202] Examples of preparation of A-045 to A-047: A-045: A-001 in the synthesis step of A-003 was replaced with A-043, and the rest operations were the same as those in the synthesis of A-003. M+1: 201.10. [0203] A-046: A-001 in the synthesis step of A-003 was replaced with A-043 and acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in the synthesis of A-003. M+1: 229.13. [0204] A-047: A-001 in the synthesis step of A-003 was replaced with A-043 and acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in the synthesis of A-003. M+1: 243.15.

Example of A-006

[0205] The example illustrates a synthesis method of compound A-006.

##STR00525##

[0206] A total of 0.4 g (2.4 mmol) of the intermediate A-001 was dissolved in 20 ml of anhydrous DCM, 665 μL (4.8 mmol) of TEA was added for dissociation, and after stirring for 5 min, 0.63 g (2.3 mmol) of Boc-tBu-Thr, 0.49 g (3.6 mmol) of HOBt, and 0.62 g (3.6 mmol) of EDCI were added and the raw materials were reacted overnight at room temperature. When the completion of the raw materials reaction was monitored by TLC, the reaction was terminated. A saturated citric acid aqueous solution was used for washing (10 mL×2), and an organic phase was taken, dried with anhydrous sodium sulfate, filtered, concentrated, and separated through a silica gel column to obtain a total of 0.61 g of a colorless oily substance of intermediate 1a with a yield of 68.8%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.14-1.20 (m, 12H), 1.37 (s, 9H), 3.24 (t, 2H, J=7.2 Hz), 3.38-3.65 (m, 2H), 3.72-3.95 (m, 3H), 4.10-4.30 (m, 1H), 4.65-4.94 (m, 3H), 7.34 (s, 1H), 8.23 (s, 1H). M+1: 388.22.

[0207] A total of 0.5 g (1.3 mmol) of the intermediate 1a was dissolved in 5 ml of anhydrous ethyl acetate, and 10 mL of 4 mol/L HCl/EtOAc was added and the raw materials were reacted overnight at room temperature, and a white solid was generated in the system; when the completion of the materials reaction was monitored by TLC, the reaction was terminated. The product was filtered under reduced pressure and washed with anhydrous diethyl ether to obtain a total of 0.25 g of a white solid A-006 with a yield of 73%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.21 (m, 3H), 3.21 (t, 2H, J=6.4 Hz), 3.36-3.65 (m, 2H), 3.7-3.97 (m, 3H), 4.10-4.30 (m, 1H), 4.60-4.71 (m, 2H), 4.86-5.01 (m, 1H), 5.65 (s, 1H), 8.23-8.28 (d, 2H, J=21 Hz). M+1: 232.10.

Examples of Preparation of A-007 to A-014

[0208] A-007:

##STR00526##

in the synthesis step of A-006 was replaced with

##STR00527##

and the rest operations were the same as those in A-006 synthesis. M+1: 218.09. [0209] A-007-1:

##STR00528##

in the synthesis step of A-006 was replaced with

##STR00529##

and the rest operations were the same as those in A-006 synthesis. M+1: 218.09. [0210] A-008:

##STR00530##

Boc in the synthesis step of A-006 was replaced with

##STR00531##

and the rest operations were the same as those in A-006 synthesis. M+1: 230.12. [0211] A-008-1:

##STR00532##

in the synthesis step of A-006 was replaced with

##STR00533##

and the rest operations were the same as those in A-006 synthesis. M+1: 230.12. [0212] A-009:

##STR00534##

in the synthesis step of A-006 was replaced with

##STR00535##

and the rest operations were the same as those in A-006 synthesis. M+1: 188.08. [0213] A-010:

##STR00536##

in the synthesis step of A-006 was replaced with

##STR00537##

and the rest operations were the same as those in A-006 synthesis. M+1: 202.09. [0214] A-011:

##STR00538##

in the synthesis step of A-006 was replaced with

##STR00539##

and the rest operations were the same as those in A-006 synthesis. M+1: 244.14. [0215] A-012:

##STR00540##

in the synthesis step of A-006 was replaced with

##STR00541##

and the rest operations were the same as those in A-006 synthesis. M+1: 278.12. [0216] A-013:

##STR00542##

in the synthesis step of A-006 was replaced with

##STR00543##

and the rest operations were the same as those in A-006 synthesis. M+1: 245.10. [0217] A-014:

##STR00544##

in the synthesis step of A-006 was replaced with

##STR00545##

and the rest operations were the same as those in A-006 synthesis. M+1: 294.12.

Examples of Preparation of A-020 to A-028

[0218] A-020: A-001 in the synthesis step of A-006 was replaced with A-015, and the rest operations were the same as those in A-006 synthesis. M+1: 246.12. [0219] A-021: A-001 in the synthesis step of A-006 was replaced with A-015,

##STR00546##

was replaced with

##STR00547##

and the rest operations were the same as those in A-006 synthesis. M+1: 232.10. [0220] A-022: A-001 in the synthesis step of A-006 was replaced with A-015,

##STR00548##

was replaced with

##STR00549##

and the rest operations were the same as those in A-006 synthesis. M+1: 244.14. [0221] A-023: A-001 in the synthesis step of A-006 was replaced with A-015,

##STR00550##

was replaced with

##STR00551##

and the rest operations were the same as those in A-006 synthesis. M+1: 202.09. [0222] A-024: A-001 in the synthesis step of A-006 was replaced with A-015,

##STR00552##

was replaced with

##STR00553##

and the rest operations were the same as those in A-006 synthesis. M+1: 216.11. [0223] A-025: A-001 in the synthesis step of A-006 was replaced with A-015,

##STR00554##

was replaced with

##STR00555##

and the rest operations were the same as those in A-006 synthesis. M+1: 258.16. [0224] A-026: A-001 in the synthesis step of A-006 was replaced with A-015,

##STR00556##

was replaced with

##STR00557##

and the rest operations were the same as those in A-006 synthesis. M+1: 292.14. [0225] A-027: A-001 in the synthesis step of A-006 was replaced with A-015,

##STR00558##

was replaced with

##STR00559##

and the rest operations were the same as those in A-006 synthesis. M+1: 259.12. [0226] A-028: A-001 in the synthesis step of A-006 was replaced with A-015,

##STR00560##

was replaced with

##STR00561##

and the rest operations were the same as those in A-006 synthesis. M+1: 308.14.

Examples of Preparation of A-034 to A-042

[0227] A-034: A-001 in the synthesis step of A-006 was replaced with A-029, and the rest operations were the same as those in A-006 synthesis. M+1: 260.14. [0228] A-035: A-001 in the synthesis step of A-006 was replaced with A-029,

##STR00562##

was replaced with

##STR00563##

and the rest operations were the same as those in A-006 synthesis. M+1: 246.12. [0229] A-036: A-001 in the synthesis step of A-006 was replaced with A-029,

##STR00564##

was replaced with

##STR00565##

and the rest operations were the same as those in A-006 synthesis. M+1: 258.16. [0230] A-037: A-001 in the synthesis step of A-006 was replaced with A-029,

##STR00566##

was replaced with

##STR00567##

and the rest operations were the same as those in A-006 synthesis. M+1: 216.11. [0231] A-038: A-001 in the synthesis step of A-006 was replaced with A-029,

##STR00568##

was replaced with

##STR00569##

and the rest operations were the same as those in A-006 synthesis. M+1: 230.12. [0232] A-039: A-001 in the synthesis step of A-006 was replaced with A-029,

##STR00570##

was replaced with

##STR00571##

and the rest operations were the same as those in A-006 synthesis. M+1: 272.17. [0233] A-040: A-001 in the synthesis step of A-006 was replaced with A-029,

##STR00572##

was replaced with

##STR00573##

and the rest operations were the same as those in A-006 synthesis. M+1: 306.16. [0234] A-041: A-001 in the synthesis step of A-006 was replaced with A-029,

##STR00574##

was replaced with

##STR00575##

and the rest operations were the same as those in A-006 synthesis. M+1: 273.13. [0235] A-042: A-001 in the synthesis step of A-006 was replaced with A-029,

##STR00576##

was replaced with

##STR00577##

and the rest operations were the same as those in A-006 synthesis. M+1: 322.15.

Examples of Preparation of A-048 to A-056

[0236] A-048: A-001 in the synthesis step of A-006 was replaced with A-043, and the rest operations were the same as those in A-006 synthesis. M+1: 260.14. [0237] A-049: A-001 in the synthesis step of A-006 was replaced with A-043,

##STR00578##

was replaced with

##STR00579##

and the rest operations were the same as those in A-006 synthesis. M+1: 246.12. [0238] A-050: A-001 in the synthesis step of A-006 was replaced with A-043,

##STR00580##

was replaced with

##STR00581##

and the rest operations were the same as those in A-006 synthesis. M+1: 258.16. [0239] A-051: A-001 in the synthesis step of A-006 was replaced with A-043,

##STR00582##

was replaced with

##STR00583##

and the rest operations were the same as those in A-006 synthesis. M+1: 216.11. [0240] A-052: A-001 in the synthesis step of A-006 was replaced with A-043,

##STR00584##

was replaced with

##STR00585##

and the rest operations were the same as those in A-006 synthesis. M+1: 230.12. [0241] A-053: A-001 in the synthesis step of A-006 was replaced with A-043,

##STR00586##

was replaced with

##STR00587##

and the rest operations were the same as those in A-006 synthesis. M+1: 272.17. [0242] A-054: A-001 in the synthesis step of A-006 was replaced with A-043,

##STR00588##

was replaced with

##STR00589##

and the rest operations were the same as those in A-006 synthesis. M+1: 306.16. [0243] A-055: A-001 in the synthesis step of A-006 was replaced with A-043,

##STR00590##

was replaced with

##STR00591##

and the rest operations were the same as those in A-006 synthesis. M+1: 273.13. [0244] A-056: A-001 in the synthesis step of A-006 was replaced with A-043,

##STR00592##

was replaced with

##STR00593##

and the rest operations were the same as those in A-006 synthesis. M+1: 322.15.

Example of A-059

[0245] The example illustrates a synthesis method of compound A-059.

##STR00594##

1. Synthesis of an Intermediate A-058

[0246] A total of 0.6 g (2.6 mmol) of the compound A-002 was dissolved in 20 ml of anhydrous DCM, and 1.4 mL (10 mmol) of TEA was added; 350 μL (5 mmol) of acetyl chloride was added to 5 mL of DCM, and it was slowly dripped to the above reaction system with a dropper funnel under ice bath conditions, and the materials were reacted at low temperature for half an hour and then moved to room temperature, the reaction was continually performed for 4 h at room temperature; when the completion of the materials reaction was monitored by TLC, the reaction was terminated. After washing with water (10 mL×3), an organic phase was taken, dried, filtered, concentrated, and separated through a silica gel column to obtain a total of 0.57 g of a brown oily substance A-058 with a yield of 81.4%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.38 (s, 9H), 2.05 (s, 3H), 3.14 (t, 2H, J=7.8 Hz), 3.35 (t, 2H, J=5.8 Hz), 4.13-4.22 (d, 2H, J=8.7 Hz), 4.60-4.63 (d, 2H, J=10.2 Hz). M+1: 273.12.

2. Synthesis of an Intermediate A-057

[0247] A-057 was obtained by deprotecting A-058 and was synthesized in the same method as that of A-001. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 2.06 (s, 3H), 3.17 (t, 2H, J=6.3 Hz), 3.34 (t, 2H, J=5.8 Hz), 4.09-4.17 (d, 2H, J=6.9 Hz), 4.49-4.61 (d, 2H, J=7.9 Hz), 9.21 (s, 1H). M+1:173.07.

3. Synthesis of the End Product A-059

[0248] A synthesis method of the end product A-059 was the same as that of the A-058. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.73 (s, 3H), 2.06 (s, 3H), 3.01 (t, 2H, J=6 Hz), 3.74-3.82 (m, 3H), 4.05-4.07 (d, 1H, J=10 Hz), 4.64-4.66 (d, 1H, J=9.6 Hz), 4.90-4.92 (d, 1H, J=8.8 Hz). M+1: 215.08.

[0249] According to the synthesis method of A-058, the following products were prepared:

Examples of Preparation of A-070, A-078, A-086

[0250] A-070: A-002 was replaced with A-016, and the rest operations were the same as those in A-058 synthesis. M+1: 287.14. [0251] A-078: A-002 was replaced with A-030, and the rest operations were the same as those in A-058 synthesis. M+1: 301.15. [0252] A-086: A-002 was replaced with A-044, and the rest operations were the same as those in A-058 synthesis. M+1: 301.15.

Examples of Preparation of A-094, A-102, A-110, A-118

[0253] A-094: acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-058 synthesis. M+1: 301.15. [0254] A-102: A-002 was replaced with A-016, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-058 synthesis. M+1: 315.17. [0255] A-110: A-002 was replaced with A-030, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-058 synthesis. M+1: 329.18. [0256] A-118: A-002 was replaced with A-044, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-058 synthesis. M+1: 329.18.

Examples of Preparation of A-126, A-134, A-142, A-150

[0257] A-126: acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-058 synthesis. M+1: 315.17. [0258] A-134: A-002 was replaced with A-016, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-058 synthesis. M+1: 329.18. [0259] A-142: A-002 was replaced with A-030, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-058 synthesis. M+1: 343.20. [0260] A-150: A-002 was replaced with A-044, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-058 synthesis. M+1: 343.20.

Examples of Preparation of A-158, A-166, A-174, A-182

[0261] A-158: The solvent was replaced with DMF, acetyl chloride was replaced with isobutyl iodide, TEA was replaced with potassium carbonate, and the rest operations were the same as those in A-058 synthesis. M+1: 287.17. [0262] A-166: A-002 was replaced with A-016, the solvent was replaced with DMF, acetyl chloride was replaced with isobutyl iodide, TEA was replaced with potassium carbonate, and the rest operations were the same as those in A-058 synthesis. M+1: 301.19. [0263] A-174: A-002 was replaced with A-030, the solvent was replaced with DMF, acetyl chloride was replaced with isobutyl iodide, TEA was replaced with potassium carbonate, and the rest operations were the same as those in A-058 synthesis. M+1: 315.20. [0264] A-182: A-002 was replaced with A-044, the solvent was replaced with DMF, acetyl chloride was replaced with isobutyl iodide, TEA was replaced with potassium carbonate, and the rest operations were the same as those in A-058 synthesis. M+1: 315.20.

Examples of Preparation of A-190, A-198, A-206, A-214

[0265] A-190: isobutyl iodide was replaced with benzyl bromide, and the rest operations were the same as those in A-158 synthesis. M+1: 321.16. [0266] A-198: isobutyl iodide was replaced with benzyl bromide, and the rest operations were the same as those in A-158 synthesis. M+1: 335.17. [0267] A-206: isobutyl iodide was replaced with benzyl bromide, and the rest operations were the same as those in A-158 synthesis. M+1: 349.19. [0268] A-214: isobutyl iodide was replaced with benzyl bromide, and the rest operations were the same as those in A-158 synthesis. M+1: 349.19.

Examples of Preparation of A-222, A-230, A-238, A-246

[0269] A-222: the solvent was replaced with DMF, acetyl chloride was replaced with iodomethane, TEA was replaced with potassium carbonate, and the rest operations were the same as those in A-058 synthesis. M+1: 245.12. [0270] A-230: A-002 was replaced with A-016, the solvent was replaced with DMF, acetyl chloride was replaced with iodomethane, TEA was replaced with potassium carbonate, and the rest operations were the same as those in A-058 synthesis. M+1: 259.14. [0271] A-238: A-002 was replaced with A-030, the solvent was replaced with DMF, acetyl chloride was replaced with iodomethane, TEA was replaced with potassium carbonate, and the rest operations were the same as those in A-058 synthesis. M+1: 273.16. [0272] A-246: A-002 was replaced with A-044, the solvent was replaced with DMF, acetyl chloride was replaced with iodomethane, TEA was replaced with potassium carbonate, and the rest operations were the same as those in A-058 synthesis. M+1: 273.16.

[0273] According to the synthesis method of A-057, the following products were prepared:

Examples of Preparation of A-069, A-077 and A-085

[0274] A-069: A-058 was replaced with A-070, and the rest operations were the same as those in A-057 synthesis. M+1: 187.08. [0275] A-077: A-058 was replaced with A-078, and the rest operations were the same as those in A-057 synthesis. M+1: 201.10. [0276] A-085: A-058 was replaced with A-086, and the rest operations were the same as those in A-057 synthesis. M+1: 201.10.

Examples of Preparation of A-093, A-101, A-109 and A-117

[0277] A-093: A-058 was replaced with A-094, and the rest operations were the same as those in A-057 synthesis. M+1: 201.10. [0278] A-101: A-058 was replaced with A-102, and the rest operations were the same as those in A-057 synthesis. M+1: 215.11. [0279] A-109: A-058 was replaced with A-110, and the rest operations were the same as those in A-057 synthesis. M+1: 229.13. [0280] A-117: A-058 was replaced with A-118, and the rest operations were the same as those in A-057 synthesis. M+1: 229.13.

Examples of Preparation of A-125, A-133, A-141 and A-149

[0281] A-125: A-058 was replaced with A-126, and the rest operations were the same as those in A-057 synthesis. M+1: 215.11. [0282] A-133: A-058 was replaced with A-134, and the rest operations were the same as those in A-057 synthesis. M+1: 229.13. [0283] A-141: A-058 was replaced with A-142, and the rest operations were the same as those in A-057 synthesis. M+1: 243.15. [0284] A-149: A-058 was replaced with A-150, and the rest operations were the same as those in A-057 synthesis. M+1: 243.15.

Examples of Preparation of A-157, A-165, A-173 and A-181

[0285] A-157: A-058 was replaced with A-158, and the rest operations were the same as those in A-057 synthesis. M+1: 187.12. [0286] A-165: A-058 was replaced with A-166, and the rest operations were the same as those in A-057 synthesis. M+1: 201.13. [0287] A-173: A-058 was replaced with A-174, and the rest operations were the same as those in A-057 synthesis. M+1: 215.15. [0288] A-181: A-058 was replaced with A-182, and the rest operations were the same as those in A-057 synthesis. M+1: 215.15.

Examples of Preparation of A-189, A-197, A-205 and A-213

[0289] A-189: A-058 was replaced with A-190, and the rest operations were the same as those in A-057 synthesis. M+1: 221.10. [0290] A-197: A-058 was replaced with A-198, and the rest operations were the same as those in A-057 synthesis. M+1: 235.12. [0291] A-205: A-058 was replaced with A-206, and the rest operations were the same as those in A-057 synthesis. M+1: 249.13. [0292] A-213: A-058 was replaced with A-214, and the rest operations were the same as those in A-057 synthesis. M+1: 249.13.

Examples of Preparation of A-221, A-229, A-237 and A-245

[0293] A-221: A-058 was replaced with A-222, and the rest operations were the same as those in A-057 synthesis. M+1: 145.07. [0294] A-229: A-058 was replaced with A-230, and the rest operations were the same as those in A-057 synthesis. M+1: 159.09. [0295] A-237: A-058 was replaced with A-238, and the rest operations were the same as those in A-057 synthesis. M+1: 173.10. [0296] A-245: A-058 was replaced with A-246, and the rest operations were the same as those in A-057 synthesis. M+1: 173.10.

[0297] According to the synthesis method of A-059, the following products were prepared:

Examples of Preparation of A-060, A-061

[0298] A-060: A-057 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 243.11. [0299] A-061: A-057 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 257.12.

Examples of Preparation of A-062 to A-064

[0300] A-062: A-057 was used as a raw material, the solvent was replaced with DMF, acetyl chloride was replaced with iodomethane, TEA was replaced with potassium carbonate, and the rest operations were the same as those in A-059 synthesis. M+1: 187.08. [0301] A-063: A-057 was used as a raw material, the solvent was replaced with DMF, acetyl chloride was replaced with iodoethane, TEA was replaced with potassium carbonate, and the rest operations were the same as those in A-062 synthesis. M+1: 201.10. [0302] A-064: A-057 was used as a raw material, the solvent was replaced with DMF, acetyl chloride was replaced with

##STR00595##

TEA was replaced with potassium carbonate, and the rest operations were the same as those in A-062 synthesis. M+1: 230.09.

Examples of Preparation of A-071 to A-073

[0303] A-071: A-069 was used as a raw material, and the rest operations were the same as those in A-059. M+1: 229.09. [0304] A-072: A-069 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 257.12. [0305] A-073: A-069 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 271.14.

Examples of Preparation of A-079 to A-081

[0306] A-079: A-077 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 243.11. [0307] A-080: A-077 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 271.14. [0308] A-081: A-077 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 285.16.

Examples of Preparation of A-087 to A-089

[0309] A-087: A-085 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 243.11. [0310] A-088: A-085 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 271.14. [0311] A-089: A-085 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 285.16.

Examples of Preparation of A-095 to A-097

[0312] A-095: A-093 was used as a raw material, acetyl chloride was replaced with

##STR00596##

and the rest operations were the same as those in A-059 synthesis. M+1: 258.12. [0313] A-096: A-093 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 271.14. [0314] A-097: A-093 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 285.16.

Examples of Preparation of A-103 to A-105

[0315] A-103: A-101 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 257.12. [0316] A-104: A-101 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 285.16. [0317] A-105: A-101 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 299.17.

Examples of Preparation of A-111 to A-113

[0318] A-111: A-109 was used as a raw material, and the rest operations were the same as those in A-059 synthesis; [0319] A-112: A-109 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 299.17. [0320] A-113: A-109 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 313.19.

Examples of Preparation of A-119 to A-121

[0321] A-119: A-117 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 271.14. [0322] A-120: A-117 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 299.17. [0323] A-121: A-117 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 313.19.

Examples of Preparation of A-127 to A-129

[0324] A-127: A-125 was used as a raw material, and the rest operations were the same as those in A-059. M+1: 257.12. [0325] A-128: A-125 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 285.16. [0326] A-129: A-125 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 299.17.

Examples of Preparation of A-135 to A-137

[0327] A-135: A-133 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 271.14. [0328] A-136: A-133 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 299.17. [0329] A-137: A-133 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 313.19.

Examples of Preparation of A-143 to A-145

[0330] A-143: A-141 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 285.16. [0331] A-144: A-141 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 313.19. [0332] A-145: A-141 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 327.20.

Examples of Preparation of A-151 to A-153

[0333] A-151: A-149 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 285.16. [0334] A-152: A-149 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 313.19. [0335] A-153: A-149 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 327.20.

Examples of Preparation of A-159 to A-161

[0336] A-159: A-157 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 229.13. [0337] A-160: A-157 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 257.16. [0338] A-161: A-157 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 271.18.

Examples of Preparation of A-167 to A-169

[0339] A-167: A-165 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 243.15. [0340] A-168: A-165 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 271.18. [0341] A-169: A-165 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 285.19.

Examples of Preparation of A-175 to A-177

[0342] A-175: A-173 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 257.16. [0343] A-176: A-173 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 285.19. [0344] A-177: A-173 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 299.21.

Examples of Preparation of A-183 to A-185

[0345] A-183: A-181 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 257.16. [0346] A-184: A-181 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 285.19. [0347] A-185: A-181 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 299.21.

Examples of Preparation of A-191 to A-193

[0348] A-191: A-189 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 263.11. [0349] A-192: A-189 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 291.15. [0350] A-193: A-189 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 305.16.

Examples of Preparation of A-199 to A-201

[0351] A-199: A-197 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 277.13. [0352] A-200: A-197 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 305.16. [0353] A-201: A-197 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 319.18.

Examples of Preparation of A-207 to A-209

[0354] A-207: A-205 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 291.15. [0355] A-208: A-205 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 319.18. [0356] A-209: A-205 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 333.19.

Examples of Preparation of A-215 to A-217

[0357] A-215: A-213 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 291.15. [0358] A-216: A-213 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 319.18. [0359] A-217: A-213 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 333.19.

Examples of Preparation of A-223 to A-225

[0360] A-223: A-221 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 187.08. [0361] A-224: A-221 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 215.11. [0362] A-225: A-221 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 229.13.

Examples of Preparation of A-231 to A-233

[0363] A-231: A-229 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 201.10. [0364] A-232: A-229 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 229.13. [0365] A-233: A-229 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride and the rest operations were the same as those in A-059 synthesis. M+1: 243.15.

Examples of Preparation of A-239 to A-241

[0366] A-239: A-237 was used as a raw material, and the rest operations were the same as those in A-059 synthesis. M+1: 215.11. [0367] A-240: A-237 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 243.15. [0368] A-241: A-237 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride and the rest operations were the same as those in A-059 synthesis. M+1: 257.16.

Examples of Preparation of A-247 to A-249

[0369] A-247: A-245 was used as a raw material, and the rest operations were the same as those in A-059. M+1: 215.11. [0370] A-248: A-245 was used as a raw material, acetyl chloride was replaced with isobutyryl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 243.15. [0371] A-249: A-245 was used as a raw material, acetyl chloride was replaced with pivaloyl chloride, and the rest operations were the same as those in A-059 synthesis. M+1: 257.16.

Example of A-066

[0372] The example illustrates a synthesis method of compound A-066.

##STR00597##

1. Synthesis Method of an Intermediate 2a

[0373] Under ice bath conditions, a total of 0.3 g (1.74 mmol) of the compound A-057 was dissolved in 20 ml of anhydrous DCM, and 490 μL (3.5 mmol) of TEA was added and stirred for dissociation for 5 min, 0.49 g (1.74 mmol) of Boc-tBu-Thr, 0.35 g (2.6 mmol) of HOBt and 0.5 g (2.6 mmol) of EDCI were added, the raw materials were gradually returned to room temperature, the reaction was performed for 6 h at room temperature; when the completion of the raw materials reaction was monitored by TLC, the reaction was terminated. A saturated citric acid aqueous solution was used for washing (10 mL×3), and an organic phase was taken, dried with anhydrous sodium sulfate, filtered, concentrated, and separated through a silica gel column to obtain a total of 0.59 g of a colorless oily substance of an intermediate 2a with a yield of 78%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13-1.22 (m, 12H), 1.37 (s, 9H), 2.34 (s, 3H), 3.25 (t, 2H, J=5.9 Hz), 3.37-3.98 (m, 4H), 4.09-4.28 (m, 1H), 4.58-4.89 (m, 3H), 7.89 (s, 1H). M+1: 430.23.

2. Synthesis Method of the End Product A-066

[0374] A total of 0.5 g (1.17 mmol) of the intermediate 2a was dissolved in 5 mL of anhydrous ethyl acetate, 10 mL of 4 mol/L HCl/EtOAc was added, and the materials were reacted overnight at room temperature, and a white solid was generated in the system; when the completion of the materials reaction was monitored by TLC, the reaction was terminated.

[0375] The product was filtered under reduced pressure and washed with anhydrous diethyl ether to obtain a total of 0.26 g of a white solid A-066 with a yield of 72.6%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.17-1.22 (m, 3H), 2.36 (s, 3H), 3.23 (t, 2H, J=6.7 Hz), 3.35-3.95 (m, 4H), 4.12-4.32 (m, 1H), 4.58-4.92 (m, 3H), 5.65 (s, 1H), 8.21-8.29 (d, 2H, J=19 Hz). M+1: 274.11.

Examples of Preparation of A-065, A-067 and A-068

[0376] A-065: the raw material

##STR00598##

was replaced with

##STR00599##

and the rest operations were the same as those in A-066 synthesis. M+1: 230.09. [0377] A-067: the raw material

##STR00600##

was replaced with

##STR00601##

and the rest operations were the same as those in A-066 synthesis. M+1: 260.10. [0378] A-068: the raw material

##STR00602##

was replaced with

##STR00603##

and the rest operations were the same as those in A-066 synthesis. M+1: 272.14.

Examples of Preparation of A-074 to A-076

[0379] A-074: A-057 was replaced with A-069, and the rest operations were the same as those in A-066 synthesis. M+1:288.13. [0380] A-075: A-057 was replaced with A-069, the raw material

##STR00604##

was replaced with

##STR00605##

and the rest operations were the same as those in A-066. M+1: 274.11. [0381] A-076: A-057 was replaced with A-069, the raw material

##STR00606##

was replaced with

##STR00607##

and the rest operations were the same as those in A-066. M+1: 286.15.

Examples of Preparation of A-082 to A-084

[0382] A-082: A-057 was replaced with A-077, and the rest operations were the same as those in A-066 synthesis. [0383] A-083: A-057 was replaced with A-077, the raw material

##STR00608##

was replaced with

##STR00609##

and the rest operations were the same as those in A-066 synthesis. M+1: 288.13. [0384] A-084: A-057 was replaced with A-077, the raw material

##STR00610##

was replaced with

##STR00611##

and the rest operations were the same as those in A-066 synthesis. M+1: 300.17.

Examples of Preparation of A-090 to A-092

[0385] A-090: A-057 was replaced with A-085, and the rest operations were the same as those in A-066 synthesis. M+1: 302.15. [0386] A-091: A-057 was replaced with A-085, the raw material

##STR00612##

was replaced with

##STR00613##

and the rest operations were the same as those in A-066 synthesis. M+1: 288.13. [0387] A-092: A-057 was replaced with A-085, the raw material

##STR00614##

was replaced with

##STR00615##

and the rest operations were the same as those in A-066 synthesis. M+1: 300.17.

Examples of Preparation of A-098 to A-100

[0388] A-098: A-057 was replaced with A-093, and the rest operations were the same as those in A-066 synthesis. M+1: 302.15. [0389] A-099: A-057 was replaced with A-093, the raw material

##STR00616##

was replaced with

##STR00617##

and the rest operations were the same as those in A-066. M+1: 288.13. [0390] A-100: A-057 was replaced with A-093, the raw material

##STR00618##

was replaced with

##STR00619##

and the rest operations were the same as those in A-066 synthesis. M+1: 300.17.

Examples of Preparation of A-106 to A-108

[0391] A-106: A-057 was replaced with A-101, and the rest operations were the same as those in A-066 synthesis. M+1: 316.16. [0392] A-107: A-057 was replaced with A-101, the raw material

##STR00620##

was replaced with

##STR00621##

and the rest operations were the same as those in A-066 synthesis. M+1: 302.15. [0393] A-108: A-057 was replaced with A-101, the raw material

##STR00622##

was replaced with

##STR00623##

and the rest operations were the same as those in A-066 synthesis. M+1: 314.18.

Examples of Preparation of A-114 to A-116

[0394] A-114: A-057 was replaced with A-109, and the rest operations were the same as those in A-066 synthesis. M+1: 330.18. [0395] A-115: A-057 was replaced with A-109, the raw material

##STR00624##

was replaced with

##STR00625##

and the rest operations were the same as those in A-066 synthesis. M+1: 316.16. [0396] A-116: A-057 was replaced with A-109, the raw material

##STR00626##

was replaced with

##STR00627##

and the rest operations were the same as those in A-066 synthesis. M+1: 328.20.

Examples of Preparation of A-122 to A-124

[0397] A-122: A-057 was replaced with A-117, and the rest operations were the same as those in A-066 synthesis. M+1: 330.18. [0398] A-123: A-057 was replaced with A-117, the raw material

##STR00628##

was replaced with

##STR00629##

and the rest operations were the same as those in A-066 synthesis. M+1: 316.16. [0399] A-124: A-057 was replaced with A-117, the raw material

##STR00630##

was replaced with

##STR00631##

and the rest operations were the same as those in A-066 synthesis. M+1: 328.20.

Examples of Preparation of A-130 to A-132

[0400] A-130: A-057 was replaced with A-125, and the rest operations were the same as those in A-066 synthesis. M+1: 316.16. [0401] A-131: A-057 was replaced with A-125, the raw material

##STR00632##

was replaced with

##STR00633##

and the rest operations were the same as those in A-066 synthesis. M+1: 302.15. [0402] A-132: A-057 was replaced with A-125, the raw material

##STR00634##

was replaced with

##STR00635##

and the rest operations were the same as those in A-066 synthesis. M+1: 314.18.

Examples of Preparation of A-138 to A-140

[0403] A-138: A-057 was replaced with A-133, and the rest operations were the same as those in A-066 synthesis. M+1: 330.18. [0404] A-139: A-057 was replaced with A-133, the raw material

##STR00636##

was replaced with

##STR00637##

and the rest operations were the same as those in A-066 synthesis. M+1: 316.16. [0405] A-140: A-057 was replaced with A-133, the raw material

##STR00638##

was replaced with

##STR00639##

and the rest operations were the same as those in A-066 synthesis. M+1: 328.20.

Examples of Preparation of A-146 to A-148

[0406] A-146: A-057 was replaced with A-141, and the rest operations were the same as those in A-066 synthesis. M+1: 344.19. [0407] A-147: A-057 was replaced with A-141, the raw material

##STR00640##

was replaced with

##STR00641##

and the rest operations were the same as those in A-066 synthesis. M+1: 330.18. [0408] A-148: A-057 was replaced with A-141, the raw material

##STR00642##

was replaced with

##STR00643##

and the rest operations were the same as those in A-066 synthesis. M+1: 342.21.

Examples of Preparation of A-154 to A-156

[0409] A-154: A-057 was replaced with A-149, and the rest operations were the same as those in A-066 synthesis. M+1: 344.19. [0410] A-155: A-057 was replaced with A-149, the raw material

##STR00644##

was replaced with

##STR00645##

and the rest operations were the same as those in A-066 synthesis. M+1: 330.18. [0411] A-156: A-057 was replaced with A-149, the raw material

##STR00646##

was replaced with

##STR00647##

and the rest operations were the same as those in A-066 synthesis. M+1: 342.21.

Examples of Preparation of A-162 to A-164

[0412] A-162: A-057 was replaced with A-157, and the rest operations were the same as those in A-066 synthesis. M+1: 288.17. [0413] A-163: A-057 was replaced with A-157, the raw material

##STR00648##

was replaced with

##STR00649##

and the rest operations were the same as those in A-066 synthesis. M+1: 274.15. [0414] A-164: A-057 was replaced with A-157, the raw material

##STR00650##

was replaced with

##STR00651##

and the rest operations were the same as those in A-066 synthesis. M+1: 286.19.

Examples of Preparation of A-170 to A-172

[0415] A-170: A-057 was replaced with A-165, and the rest operations were the same as those in A-066 synthesis. M+1: 302.18. [0416] A-171: A-057 was replaced with A-165, the raw material

##STR00652##

was replaced with

##STR00653##

and the rest operations were the same as those in A-066 synthesis. M+1: 288.17. [0417] A-172: A-057 was replaced with A-165, the raw material

##STR00654##

was replaced with

##STR00655##

and the rest operations were the same as those in A-066 synthesis. M+1: 300.20.

Examples of Preparation of A-178 to A-180

[0418] A-178: A-057 was replaced with A-173, and the rest operations were the same as those in A-066 synthesis. M+1: 316.20. [0419] A-179: A-057 was replaced with A-173, the raw material

##STR00656##

was replaced with

##STR00657##

and the rest operations were the same as those in A-066 synthesis. M+1: 302.18. [0420] A-180: A-057 was replaced with A-173, the raw material

##STR00658##

was replaced with

##STR00659##

and the rest operations were the same as those in A-066 synthesis. M+1: 314.22.

Examples of Preparation of A-186 to A-188

[0421] A-186: A-057 was replaced with A-181, and the rest operations were the same as those in A-066 synthesis. M+1: 315.20. [0422] A-187: A-057 was replaced with A-181, the raw material

##STR00660##

was replaced with

##STR00661##

and the rest operations were the same as those in A-066 synthesis. M+1: 302.18. [0423] A-188: A-057 was replaced with A-181, the raw material

##STR00662##

was replaced with

##STR00663##

and the rest operations were the same as those in A-066 synthesis. M+1: 314.22.

Examples of Preparation of A-194 to A-196

[0424] A-194: A-057 was replaced with A-189, and the rest operations were the same as those in A-066 synthesis. M+1: 322.15. [0425] A-195: A-057 was replaced with A-189, the raw material

##STR00664##

was replaced with

##STR00665##

and the rest operations were the same as those in A-066 synthesis. M+1: 308.14. [0426] A-196: A-057 was replaced with A-189, the raw material

##STR00666##

was replaced with

##STR00667##

and the rest operations were the same as those in A-066 synthesis. M+1: 320.17.

Examples of Preparation of A-202 to A-204

[0427] A-202: A-057 was replaced with A-197, and the rest operations were the same as those in A-066 synthesis. M+1: 336.17. [0428] A-203: A-057 was replaced with A-197, the raw material

##STR00668##

was replaced with

##STR00669##

and the rest operations were the same as those in A-066 synthesis. M+1: 322.15. [0429] A-204: A-057 was replaced with A-197, the raw material

##STR00670##

was replaced with

##STR00671##

and the rest operations were the same as those in A-066 synthesis. M+1: 334.19.

Examples of Preparation of A-210 to A-212

[0430] A-210: A-057 was replaced with A-205, and the rest operations were the same as those in A-066 synthesis. M+1: 350.18. [0431] A-211: A-057 was replaced with A-205, the raw material

##STR00672##

was replaced with

##STR00673##

and the rest operations were the same as those in A-066 synthesis. M+1: 336.17. [0432] A-212: A-057 was replaced with A-205, the raw material

##STR00674##

was replaced with

##STR00675##

and the rest operations were the same as those in A-066 synthesis. M+1: 348.20.

Examples of Preparation of A-218 to A-220

[0433] A-218: A-057 was replaced with A-213, and the rest operations were the same as those in A-066 synthesis. M+1: 350.18. [0434] A-219: A-057 was replaced with A-213, the raw material

##STR00676##

was replaced with

##STR00677##

and the rest operations were the same as those in A-066 synthesis. M+1: 336.17. [0435] A-220: A-057 was replaced with A-213, the raw material

##STR00678##

was replaced with

##STR00679##

and the rest operations were the same as those in A-066 synthesis. M+1: 348.20.

Examples of Preparation of A-226 to A-228

[0436] A-226: A-057 was replaced with A-221, and the rest operations were the same as those in A-066 synthesis. M+1: 246.12. [0437] A-227: A-057 was replaced with A-221, the raw material

##STR00680##

was replaced with

##STR00681##

and the rest operations were the same as those in A-066 synthesis. M+1: 232.10. [0438] A-228: A-057 was replaced with A-221, the raw material

##STR00682##

was replaced with

##STR00683##

and the rest operations were the same as those in A-066 synthesis. M+1: 244.14.

Examples of Preparation of A-234 to A-236

[0439] A-234: A-057 was replaced with A-229, and the rest operations were the same as those in A-066 synthesis. M+1: 260.14. [0440] A-235: A-057 was replaced with A-229, the raw material

##STR00684##

was replaced with

##STR00685##

and the rest operations were the same as those in A-066 synthesis. M+1: 246.12. [0441] A-236: A-057 was replaced with A-229, the raw material

##STR00686##

was replaced with

##STR00687##

and the rest operations were the same as those in A-066 synthesis. M+1: 258.16.

Examples of Preparation of A-242 to A-244

[0442] A-242: A-057 was replaced with A-237, and the rest operations were the same as those in A-066 synthesis. M+1: 274.15. [0443] A-243: A-057 was replaced with A-237, the raw material

##STR00688##

was replaced with

##STR00689##

and the rest operations were the same as those in A-066 synthesis. M+1: 260.14. [0444] A-244: A-057 was replaced with A-237, the raw material

##STR00690##

was replaced with

##STR00691##

and the rest operations were the same as those in A-066 synthesis. M+1: 272.17.

Examples of Preparation of A-250 to A-252

[0445] A-250: A-057 was replaced with A-245, and the rest operations were the same as those in A-066 synthesis. M+1: 274.15. [0446] A-251: A-057 was replaced with A-245, the raw material

##STR00692##

was replaced with

##STR00693##

and the rest operations were the same as those in A-066 synthesis. M+1: 260.14. [0447] A-252: A-057 was replaced with A-245, the raw material

##STR00694##

was replaced with

##STR00695##

and the rest operations were the same as those in A-066 synthesis. M+1: 272.17.

Example a-253

[0448] The example illustrates a synthesis method of compound A-253.

##STR00696##

1. Synthesis Method of an Intermediate 3a

[0449] Under −15° C., 1.8 g (10 mmol) of a raw material L-cysteine methyl ester hydrochloride was dissolved in 100 mL of methanol, fully stirred to be dissolved, 1.75 mL (15 mmol) of TEA was added, after the raw material was fully dissociated, 1.8 g (10 mmol, 1.0 eq) of a raw material 1-Boc-3-azetidinone was added, then continued to be subjected to a low-temperature reaction for 15 min, and transferred to room temperature. After reaction at room temperature for 4 h, when the completion of the materials reaction was monitored by TLC, a reaction solution was subjected to rotary evaporation, a concentrate was dissolved with 100 mL of ethyl acetate, washed with a small amount of water for multiple times (15 ml×4), dried with anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation. A crude product was purified with a silica column (PE:EtOAc=2:1) to obtain a total of 2.4 g of a yellow transparent oily intermediate 3a with a yield of 83%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.37 (s, 9H), 3.06-3.55 (m, 6H), 3.91-4.19 (m, 4H), 8.69 (s, 1H). M+1: 289.11.

2. Synthesis Method of an Intermediate A-254

[0450] A total of 0.8 g (2.8 mmol) of the intermediate 3a was dissolved in 5 mL of anhydrous methanol, 5 mL of 7 mol/L NH.sub.3/CH.sub.3OH solution was added, stirred overnight at room temperature; when the completion of the materials reaction was monitored by TLC, the reaction was terminated. After vacuum concentration, a white solid was obtained, the traits were improved by stirring with petroleum ether, and the material was filtered to obtain 0.68 g of a white solid, namely A-254, with a yield of 90.7%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.37 (s, 9H), 3.02-3.27 (m, 2H), 3.36-3.45 (m, 1H), 3.94-4.23 (m, 4H), 8.14 (s, 2H), 8.78 (s, 1H). M+1: 274.11.

3. Synthesis Method of Product A-253

[0451] 0.4 g of A-254 was dissolved in 3 mL of anhydrous ethyl acetate, a total of 5 mL of 4 mol/L HCl/EtOAc was added, and stirred at room temperature for 4 h; when the completion of the materials reaction was monitored by TLC, a white solid was obtained in the system, then filtered and washed with the anhydrous ether to obtain 0.21 g of the end product A-253 with a yield of 70%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 3.04-3.28 (m, 2H), 3.37-3.42 (m, 1H), 3.91-4.22 (m, 4H), 8.15 (s, 2H), 8.54 (s, 1H). M+1: 174.06.

[0452] Similarly, in the synthesis of the intermediate 3a, the raw material 1-Boc-3-azetidinone was replaced with N-Boc-3-pyrrolidone, N-Boc-4-piperidone, and N-Boc-3-piperidone, and the other operations were the same as those of the synthesis of the intermediate 3a, and an intermediate 3b, an intermediate 3c, and an intermediate 3d were prepared respectively.

##STR00697##

Examples of Preparation of A-262, A-270, A-278

[0453] A-262: the intermediate 3a was replaced with the intermediate 3b, and the rest operations were the same as those in A-254 synthesis. M+1: 288.13. [0454] A-270: the intermediate 3a was replaced with the intermediate 3c, and the rest operations were the same as those in A-254 synthesis. M+1: 302.15. [0455] A-278: the intermediate 3a was replaced with the intermediate 3d, and the rest operations were the same as those in A-254 synthesis. M+1: 302.15.

Examples of Preparation of A-261, A-269 and A-277

[0456] A-261: A-254 was replaced with A-262, and the rest operations were the same as those in A-253 synthesis. M+1: 188.08. [0457] A-269: A-254 was replaced with A-270, and the rest operations were the same as those in A-253 synthesis. M+1: 202.09. [0458] A-277: A-254 was replaced with A-278, and the rest operations were the same as those in A-253 synthesis. M+1: 202.09.

Example a-255

[0459] The example illustrates a synthesis method of compound A-255.

##STR00698##

1. Synthesis Method of an Intermediate 4a

[0460] A total of 2.4 g (8.3 mmol) of the intermediate 3a was dissolved in 10 mL of anhydrous ethyl acetate, and 20 mL of 4 mol/L hydrochloric acid/ethyl acetate solution was added under ice bath, the raw materials were reacted overnight, an off-white solid was precipitated; when the completion of the raw materials reaction was monitored by TLC, 1.8 g of an intermediate 4a was obtained after filtration, washed with anhydrous ether, and dried. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 3.05-3.55 (m, 6H), 3.91-4.19 (m, 4H), 8.26 (s, 1H), 8.69 (s, 1H). M+1: 189.06.

2. Synthesis Method of an Intermediate 5a

[0461] 1.6 g (7.15 mmol) of the intermediate 4a was dissolved in 20 mL DCM under ice bath, and after being added 4 mL (28 mmol) of TEA for dissociation, 1 mL (14 mmol) of acetyl chloride was slowly added dropwise, the raw materials were gradually returned to room temperature and reacted overnight; when the completion of the raw materials reaction was monitored by TLC, the reaction was terminated; a saturated citric acid aqueous solution was used for washing (10 mL×3), an organic phase was taken, dried with anhydrous sodium sulfate, filtered, concentrated, and separated through a silica gel column to obtain 1.53 g of a yellowish oily substance, namely an intermediate 5a, with a yield of 76.5%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 2.05 (s, 3H), 3.07-3.53 (m, 6H), 3.95-4.21 (m, 4H), 8.48 (s, 1H). M+1: 231.07.

3. Synthesis Method of a Product A-255

[0462] The intermediate 5a was ammonolyzed, and the synthesis method of this step was the same as that of A-254. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 2.04 (s, 3H), 3.02-3.25 (m, 2H), 3.38-3.47 (m, 1H), 3.97-4.22 (m, 4H), 8.23 (s, 2H), 9.01 (s, 1H). M+1: 216.07.

[0463] In the synthesis of the intermediate 4a, the raw material intermediate 3a was replaced with the intermediate 3b, the intermediate 3c and the intermediate 3d respectively, and the other operations were the same as those in the synthesis of the intermediate 4a, and an intermediate 4b, an intermediate 4c and an intermediate 4d were prepared respectively;

[0464] similarly, in the synthesis process of the intermediate 5a, the raw material intermediate 4a was replaced with the intermediate 4b, the intermediate 4c and the intermediate 4d respectively, and the other operations were the same as those in the synthesis of the intermediate 5a, and an intermediate 5b, an intermediate 5c and an intermediate 5d were prepared respectively;

[0465] similarly, in the synthesis of the intermediate 5a, acetyl chloride was replaced with isobutyryl chloride and pivaloyl chloride respectively, and an intermediate 6a, an intermediate 6b, an intermediate 6c, and an intermediate 6d, and an intermediate 7a, an intermediate 7b, an intermediate 7c, and an intermediate 7d were prepared respectively.

##STR00699## ##STR00700## ##STR00701##

Preparation of A-256 and A-257

[0466] A-256: the intermediate 5a was replaced with the intermediate 6a, and other operations were the same as those in A-255 synthesis. M+1: 244.10. [0467] A-257: the intermediate 5a was replaced with the intermediate 7a, and other operations were the same as those in A-255 synthesis. M+1: 258.12.

Preparation of A-263 and A-265

[0468] A-263: the intermediate 5a was replaced with the intermediate 5b, and other operations were same as those in A-255 synthesis. M+1: 230.09. [0469] A-264: the intermediate 5a was replaced with the intermediate 6b, and other operations were same as those in A-255 synthesis. M+1: 258.12. [0470] A-265: the intermediate 5a was replaced with the intermediate 7b, and other operations were same as those in A-255 synthesis. M+1: 272.14.

Preparation of A-271 and A-273

[0471] A-271: the intermediate 5a was replaced with the intermediate 5c, and other operations were same as those in A-255 synthesis. M+1: 244.10. [0472] A-272: the intermediate 5a was replaced with the intermediate 6c, and other operations were same as those in A-255 synthesis. M+1: 272.14. [0473] A-273: the intermediate 5a was replaced with the intermediate 7c, and other operations were same as those in A-255 synthesis. M+1: 286.15.

Preparation of A-279 and A-281

[0474] A-279: the intermediate 5a was replaced with the intermediate 5d, and other operations were same as those in A-255 synthesis. M+1: 244.10. [0475] A-280: the intermediate 5a was replaced with the intermediate 6d, and other operations were same as those in A-255 synthesis. M+1: 272.14. [0476] A-281: the intermediate 5a was replaced with the intermediate 7d, and other operations were same as those in A-255 synthesis. M+1: 286.15.

Example of A-258

[0477] The example illustrates a synthesis method of compound A-258.

##STR00702##

1. Synthesis Method of an Intermediate 8a

[0478] A total of 1.8 g (8 mmol) of the intermediate 4a was dissolved in 50 mL of dichloromethane, 0.89 g (8.8 mmol) of triethylamine was added under ice bath, and the materials were fully dissociated, then 2.2 g (8 mmol) of Boc-tBu-Thr, 1.18 g (8.8 mmol) of HOBt and 1.68 g (8.8 mmol) of EDCI were added, and the raw materials were naturally returned to room temperature for a reaction; after the completion of the raw materials reaction was monitored by TLC, a citric acid aqueous solution, a saturated sodium bicarbonate solution and a saturated sodium chloride solution were used for washing in order, and the material was dried with anhydrous sodium sulfate, filtered and concentrated. A concentrate was purified with a silica gel column, wherein the ratio of petroleum ether to ethyl acetate was 1:1, and a total of 1.9 g of an intermediate 8a was obtained with a yield of 53%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.12-1.20 (m, 12H), 1.37 (s, 9H), 3.14-3.41 (m, 2H), 3.59-3.87 (m, 5H), 4.04-4.84 (m, 5H), 7.84 (s, 1H), 8.52 (s, 1H). M+1: 446.22.

2. Synthesis Method of an Intermediate 9a

[0479] A total of 1.5 g (3.37 mmol) of the intermediate 8a was dissolved in a small amount of methanol, and 10 mL of 7 mol/L NH.sub.3/CH.sub.3OH solution was added under ice bath, and the raw materials were reacted overnight; after the completion of the raw materials reaction was monitored by TLC, a reaction solution was subjected to rotary evaporation to obtain a total of 1.45 g of an off-white solid intermediate 9a with a yield of 99.4%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.12-1.22 (m, 12H), 1.37 (s, 9H), 3.15-3.43 (m, 2H), 3.59-3.89 (m, 2H), 4.07-4.81 (m, 5H), 7.84 (s, 1H), 8.24 (s, 2H), 8.57 (s, 1H). M+1: 431.22

3. Synthesis Method of a Product A-258

[0480] A total of 1.3 g (3 mmol) of the intermediate 9a was dissolved in 10 mL of anhydrous ethyl acetate, and 10 mL of 4 mol/L HCl/EtOAc solution was added under ice bath, and the materials were gradually returned to room temperature and reacted for 6 h; when the completion of the raw materials reaction was monitored by TLC, a white solid was precipitated in the system, filtered, and washed with anhydrous diethyl ether to obtain a total of 0.81 g of the end product A-258 with a yield of 86.1%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.12-1.17 (m, 3H), 3.05-3.17 (m, 1H), 3.39-3.43 (m, 1H), 3.72-3.92 (m, 2H), 4.06-4.81 (m, 5H), 5.65 (s, 1H), 7.55 (s, 1H), 7.93 (s, 2H), 8.24 (s, 2H). M+1: 275.11.

[0481] The intermediate 4a was respectively replaced with the intermediate 4b, the intermediate 4c and the intermediate 4d, and an intermediate 8b, an intermediate 8c and an intermediate 8d were respectively prepared; and an intermediate 9b, an intermediate 9c and an intermediate 9d were prepared accordingly.

[0482] The intermediate 4a was respectively replaced with the intermediate 4b, the intermediate 4c and the intermediate 4d, the raw material

##STR00703##

was replaced with

##STR00704##

and an intermediate 10a, an intermediate 10b, an intermediate 10c and an intermediate 10d were prepared respectively; and an intermediate 11a, an intermediate 11b, an intermediate 11c and an intermediate 11d were prepared accordingly.

[0483] The intermediate 4a was respectively replaced with the intermediate 4b, the intermediate 4c and the intermediate 4d, the raw material

##STR00705##

was replaced with

##STR00706##

and an intermediate 12a, an intermediate 12b, an intermediate 12c and an intermediate 12d were prepared respectively; and an intermediate 13a, an intermediate 13b, an intermediate 13c and an intermediate 13d were prepared accordingly.

##STR00707## ##STR00708## ##STR00709## ##STR00710## ##STR00711##

Examples of Preparation of A-259 to A-260

[0484] A-259: the raw material

##STR00712##

was replaced with

##STR00713##

and the rest operations were the same as those in A-258 synthesis. M+1: 261.09. [0485] A-260: the raw material

##STR00714##

was replaced with

##STR00715##

and the rest operations were the same as those in A-258 synthesis. M+1: 273.13.

Examples of Preparation of A-266 to A-268

[0486] A-266: the raw material intermediate 4a was replaced with the intermediate 4b, and the rest operations were the same as those in A-258 synthesis. M+1: 289.13. [0487] A-267: the raw material intermediate 4a was replaced with the intermediate 4b, the raw material

##STR00716##

was replaced with

##STR00717##

and the rest operations were the same as those in A-258 synthesis. M+1: 275.11. [0488] A-268: the raw material intermediate 4a was replaced with the intermediate 4b, the raw material

##STR00718##

was replaced with

##STR00719##

and the rest operations were the same as those in A-258 synthesis. M+1: 287.15.

Examples of Preparation of A-274 to A-276

[0489] A-274: the raw material intermediate 4a was replaced with the intermediate 4c, and the rest operations were the same as those in A-258 synthesis. M+1: 303.14. [0490] A-275: the raw material intermediate 4a was replaced with the intermediate 4c, the raw material

##STR00720##

was replaced with

##STR00721##

and the rest operations were the same as those in A-258 synthesis. M+1: 289.13. [0491] A-276: the raw material intermediate 4a was replaced with the intermediate 4c, the raw material

##STR00722##

was replaced with

##STR00723##

and the rest operations were the same as those in A-258 synthesis. M+1: 301.16.

Examples of Preparation of A-282 to A-284

[0492] A-282: the raw material intermediate 4a was replaced with the intermediate 4d, and the rest operations were the same as those in A-258 synthesis. M+1: 303.14. [0493] A-283: the raw material intermediate 4a was replaced with the intermediate 4d, the raw material

##STR00724##

was replaced with

##STR00725##

and the rest operations were the same as those in A-258 synthesis. M+1: 289.13. [0494] A-284: the raw material intermediate 4a was replaced with the intermediate 4d, the raw material

##STR00726##

was replaced with

##STR00727##

and the the rest operations were the same as those in A-258 synthesis. M+1: 301.16.

Example of A-285

[0495] The example illustrates a synthesis method of compound A-285.

##STR00728##

[0496] Under ice bath conditions, 0.8 g (1.74 mmol) of the intermediate 8a was dissolved in 10 mL of anhydrous ethyl acetate, and a total of 5 mL of 4 mol/L HCl/EtOAc was added, and the raw materials were gradually returned to room temperature and reacted for 4 hours; when the completion of the raw materials reaction was monitored by TLC, a white solid was generated in the system. The reaction was terminated, after vacuum filtration a filter cake was taken, continuously stirred for 10 min in 15 mL of anhydrous ethyl acetate, and then filtered to obtain a total of 0.51 g of white solid A-285 with a yield of 90.1%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.12-1.17 (m, 3H), 3.07-3.19 (m, 1H), 3.38-3.42 (m, 1H), 3.68-3.91 (m, 5H), 4.07-4.83 (m, 5H), 5.63 (s, 1H), 7.53 (s, 1H), 7.88 (s, 2H). M+1: 290.11.

Examples of Preparation of A-286 and A-287

[0497] A-286: the intermediate 8a was replaced with the intermediate 10a, and the rest operations were the same as those in A-285 synthesis. M+1: 276.09. [0498] A-287: the intermediate 8a was replaced with the intermediate 12a, and the rest operations were the same as those in A-285 synthesis. M+1: 288.13.

Examples of Preparation of A-288 and A-290

[0499] A-288: the intermediate 8a was replaced with the intermediate 8b, and the rest operations were the same as those in A-285 synthesis. M+1: 304.13. [0500] A-289: the intermediate 8a was replaced with the intermediate 10b, and the rest operations were the same as those in A-285 synthesis. M+1: 290.11. [0501] A-290: the intermediate 8a was replaced with the intermediate 12b, and the rest operations were the same as those in A-285 synthesis. M+1: 302.15.

Examples of Preparation of A-291 and A-293

[0502] A-291: the intermediate 8a was replaced with the intermediate 8c, and the rest operations were the same as those in A-285 synthesis. M+1: 318.14. [0503] A-292: the intermediate 8a was replaced with the intermediate 10c, and the rest operations were the same as those in A-285 synthesis. M+1: 304.13. [0504] A-293: the intermediate 8a was replaced with the intermediate 12c, and the rest operations were the same as those in A-285 synthesis. M+1: 316.16.

Examples of Preparation of A-294 and A-296

[0505] A-294: the intermediate 8a was replaced with the intermediate 8d, and the rest operations were the same as those in A-285 synthesis. M+1: 318.14. [0506] A-295: the intermediate 8a was replaced with the intermediate 10d, and the rest operations were the same as those in A-285 synthesis. M+1: 304.13. [0507] A-296: the intermediate 8a was replaced with the intermediate 12d, and the rest operations were the same as those in A-285 synthesis. M+1: 316.16.

Example of A-302

[0508] The example illustrates a synthesis method of compound A-302.

##STR00729##

1. Synthesis Method of an Intermediate 14a

[0509] 0.7 g (1.6 mmol) of the intermediate 9a was dissolved in 10 mL of anhydrous DCM, 832 μL (6 mmol) of TEA was added, 0.7 g of trifluoroacetic anhydride (TFAA, 3.2 mmol) was added under ice bath conditions, and the materials were gradually returned to room temperature, and stirred at the room temperature for 12 h; when the completion of the raw materials reaction was monitored by TLC, the reaction was terminated; an organic phase was washed with 10 mL of water and 10 mL of saturated aqueous sodium chloride respectively, dried with anhydrous sodium sulfate, filtrated, concentrated, and separated through a silica gel column (PE:EtOAc=2:1) to obtain a total of 0.62 g of an end-product intermediate 14a with a yield of 92%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13-1.21 (m, 12H), 1.37 (s, 9H), 3.03-3.14 (m, 1H), 3.39-3.42 (m, 1H), 3.69-3.86 (m, 2H), 4.03-4.75 (m, 5H), 7.81 (s, 1H), 8.34 (s, 1H). M+1: 413.21.

2. Preparation of A-302

[0510] 0.5 g of the intermediate 14a was dissolved in 10 mL of anhydrous ethyl acetate under ice bath conditions, fully stirred and dissolved, a total of 5 mL of 4 mol/L HCl/EtOAc was added, the raw material was gradually returned to room temperature and reacted at room temperature for 5 hours, and a yellow solid was generated in the system; when the completion of the raw materials reaction was monitored by TLC, the reaction was terminated. After filtration, a filter cake was taken and stirred with anhydrous ethyl acetate for 15 min and then filtered to obtain a total of 0.26 g of A-302 with a yield of 83%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13-1.18 (m, 3H), 3.06-3.18 (m, 1H), 3.39-3.42 (m, 1H), 3.74-3.91 (m, 2H), 4.05-4.79 (m, 5H), 5.68 (s, 1H), 8.29 (s, 2H), 8.52 (s, 1H). M+1: 257.10.

Examples of Preparation of A-297 to A-301, A-303 and A-304

[0511] A-297: the intermediate 9a was replaced with A-254, and the rest operations were the same as those of A-302. M+1: 156.05. [0512] A-298: the intermediate 9a was replaced with A-254, and the rest operations were the same as those of the intermediate 14a. M+1: 256.10. [0513] A-299: the intermediate 9a was replaced with A-255, and the rest operations were the same as those of the intermediate 14a. M+1: 198.06. [0514] A-300: the intermediate 9a was replaced with A-256, and the rest operations were the same as those of the intermediate 14a. M+1: 226.09. [0515] A-301: the intermediate 9a was replaced with A-257, and the rest operations were the same as those of the intermediate 14a. M+1: 240.11. [0516] A-303: the intermediate 9a was replaced with the intermediate 11a, and the rest operations were the same as those of A-302. M+1: 243.08. [0517] A-304: the intermediate 9a was replaced with the intermediate 13a, and the rest operations were the same as those of A-302. M+1: 255.12.

Examples of Preparation of A-305 to A-312

[0518] A-305: the intermediate 9a was replaced with A-262, and the rest operations were the same as those of A-302. M+1: 170.07. [0519] A-306: the intermediate 9a was replaced with A-262, and the rest operations were the same as those of the intermediate 14a. M+1: 270.12. [0520] A-307: the intermediate 9a was replaced with A-263, and the rest operations were the same as those of the intermediate 14a. M+1: 212.08. [0521] A-308: the intermediate 9a was replaced with A-264, and the rest operations were the same as those of the intermediate 14a. M+1: 240.11. [0522] A-309: the intermediate 9a was replaced with A-265, and the rest operations were the same as those of the intermediate 14a. M+1: 254.12. [0523] A-310: the intermediate 9a was replaced with the intermediate 9b, and the rest operations were the same as those of A-302. M+1: 271.12. [0524] A-311: the intermediate 9a was replaced with the intermediate 11b, and the rest operations were the same as those of A-302. M+1: 257.10. [0525] A-312: the intermediate 9a was replaced with the intermediate 13b, and the rest operations were the same as those of A-302. M+1: 269.14.

Examples of Preparation of A-313 to A-320

[0526] A-313: the intermediate 9a was replaced with A-270, and the rest operations were the same as those of A-302. M+1: 184.08 [0527] A-314: the intermediate 9a was replaced with A-270, and the rest operations were the same as those of the intermediate 14a. M+1: 284.14. [0528] A-315: the intermediate 9a was replaced with A-271, and the rest operations were the same as those of the intermediate 14a. M+1: 226.09. [0529] A-316: the intermediate 9a was replaced with A-272, and the rest operations were the same as those of the intermediate 14a. M+1: 254.12. [0530] A-317: the intermediate 9a was replaced with A-273, and the rest operations were the same as those of the intermediate 14a. M+1: 268.14. [0531] A-318: the intermediate 9a was replaced with the intermediate 9c, and the rest operations were the same as those of A-302. M+1: 285.13. [0532] A-319: the intermediate 9a was replaced with the intermediate 11c, and the rest operations were the same as those of A-302. M+1: 271.12. [0533] A-320: the intermediate 9a was replaced with the intermediate 13c, and the rest operations were the same as those of A-302. M+1: 283.15.

Examples of Preparation of A-321 to A-328

[0534] A-321: the intermediate 9a was replaced with A-278, and the rest operations were the same as those of A-302. M+1: 184.08. [0535] A-322: the intermediate 9a was replaced with A-278, and the rest operations were the same as those of the intermediate 14a. M+1: 284.14. [0536] A-323: the intermediate 9a was replaced with A-279, and the rest operations were the same as those of the intermediate 14a. M+1: 226.09. [0537] A-324: the intermediate 9a was replaced with A-280, and the rest operations were the same as those of the intermediate 14a. M+1: 254.12. [0538] A-325: the intermediate 9a was replaced with A-281, and the rest operations were the same as those of the intermediate 14a. M+1: 268.14. [0539] A-326: the intermediate 9a was replaced with the intermediate 9d, and the rest operations were the same as those of A-302. M+1: 285.13. [0540] A-327: the intermediate 9a was replaced with the intermediate 11d, and the rest operations were the same as those of A-302. M+1: 271.12. [0541] A-328: the intermediate 9a was replaced with the intermediate 13d, and the rest operations were the same as those of A-302. M+1: 283.15.

Example of Synthesis of A-329

[0542] ##STR00730##

1. Synthesis of Intermediate 15a

[0543] Under ice bath, 0.5 g (1.5 mmol) of Fmoc-Val was dissolved in 10 mL of anhydrous DCM, 2 drops of DMF were added for catalysis, then 230 μL (1.65 mmol) of TEA was added, 133 μL (1.58 mmol) of oxalyl chloride was added drop by drop, and the raw materials were returned to room temperature, and reacted overnight; when the completion of the raw materials reaction was monitored by TLC, 0.35 g (1.5 mmol) of compound A-002 was added to the reaction system, and the reaction system was continuously stirred at the room temperature for 4 h; when the completion of the raw materials reaction was monitored by TLC, the reaction was terminated; saturated citric acid was used for washing twice, saturated sodium chloride solution was used for washing once, and an organic phase was taken, dried with anhydrous sodium sulfate, filtered, concentrated, and separated through a silica gel column (PE:EtOAC=3:1) to obtain a total of 0.69 g of colorless oily substance with a yield of 83.3%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.12-1.23 (m, 6H), 1.37 (9H), 2.15-2.25 (m, 1H), 3.16-3.73 (m, 5H), 4.16-4.79 (m, 8H), 7.21-8.29 (m, 9H). M+1: 552.25.

2. Synthesis of Intermediate 16a

[0544] 0.48 g of the intermediate 15a was dissolved in 5 mL of anhydrous acetonitrile, 5 mL of diethylamine was added, and the raw materials were reacted at 50° C. for 4 h; when the completion of the raw materials reaction was monitored by TLC, the reaction was terminated; the reaction product was subjected to rotary evaporation under reduced pressure, 10 ml of DCM was added, and the product was continuously subjected to rotary evaporation, then the above steps were repeated twice; and then 0.25 g of an oily substance with a yield of 87.2% was obtained by separating through a silica gel column. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.12-1.20 (m, 6H), 1.37 (s, 9H), 2.14-2.27 (m, 1H), 3.13-3.77 (m, 5H), 4.13-4.57 (m, 4H), 8.23 (s, 2H). M+1: 330.18.

3. Synthesis of A-329

[0545] 0.25 g of the intermediate 16 was dissolved in 4 mL of ethyl acetate, 3 mL of 4 mol/L HCl/EtOAc was added, and the raw materials were stirred at room temperature for 3 h; when the completion of the raw materials reaction was monitored by TLC, a white solid was generated in the system, filtered, and dried to obtain 0.16 g of the white solid with a yield of 79%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.12-1.19 (m, 6H), 2.14-2.25 (m, 1H), 3.13-3.75 (m, 5H), 4.16-4.61 (m, 4H), 8.29 (s, 2H), 9.01 (s, 1H). M+1: 230.12.

Example of Synthesis of A-330

[0546] ##STR00731##

Synthesis of Intermediate 17a

[0547] The synthesis method was similar to that of A-329, and a total of 0.65 g of a yellowish solid was obtained with a yield of 89.3%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.14-1.27 (m, 6H), 2.15-2.25 (m, 1H), 3.16-3.73 (m, 5H), 4.16-4.79 (m, 8H), 7.21-8.29 (m, 9H). M+1: 452.19.

Synthesis of Intermediate 18a

[0548] Under ice bath conditions, a total of 0.62 g of the intermediate 17 was dissolved in 10 mL of anhydrous DCM, 300 μL of TEA was added for dissociation, 185 μL of acetic anhydride was slowly added dropwise, and the raw materials were gradually returned to room temperature and continuously reacted for 6 h; when the completion of the raw materials reaction was monitored by TLC, the reaction was terminated; the mixture was washed with a saturated citric acid aqueous solution and then with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated, and separated through a silica gel column to obtain 0.52 g of an oily substance with a yield of 83%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13-1.27 (m, 6H), 2.05-2.27 (m, 4H), 3.15-3.70 (m, 5H), 4.12-4.75 (m, 8H), 7.21-8.28 (m, 9H). M+1: 494.2.

Example of Synthesis of A-330

[0549] The synthesis method was similar to that of the intermediate 16a, and a total of 0.38 g of an oily substance was obtained, HCl/EtOAc was added and the mixture was stirred, then a white solid was generated in the system, filtered, and dried to obtain 0.34 g of a product A-330. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.12-1.18 (m, 6H), 2.05-2.24 (m, 4H), 3.11-3.78 (m, 5H), 4.12-4.65 (m, 4H), 8.60 (s, 2H). M+1: 272.14.

Example of Synthesis of A-331

[0550] ##STR00732##

Synthesis of intermediate 19a

[0551] The synthesis method was similar to that of the intermediate 8a, and a total of 1.52 g of a colorless oily substance was obtained with a yield of 81.3%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.03-1.37 (m, 27H), 2.32-2.38 (m, 1H), 3.02-3.73 (m, 4H), 4.14-4.68 (m, 10H), 7.12-8.32 (m, 10H). M+1: 709.36.

Synthesis of Intermediate 20a

[0552] The synthesis method was similar to that of the intermediate 16a, and 0.84 g of an oily substance was obtained with a yield of 86.9%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.01-1.38 (m, 27H), 2.32-2.38 (m, 1H), 3.05-3.77 (m, 4H), 4.12-4.71 (m, 7H), 7.76 (s, 1H), 8.35 (s, 2H). M+1: 487.29.

Example of Synthesis of A-331

[0553] The synthesis method was similar to that of A-329, and 0.49 g of a white solid was obtained with a yield of 87.5%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.07-1.22 (m, 9H), 2.18-2.27 (m, 1H), 3.07-3.78 (m, 7H), 4.14-4.59 (m, 4H), 5.72 (s, 1H), 8.21-8.32 (m, 4H). M+1: 331.17.

Example of Synthesis of A-347 and A-348

[0554] A-347:

##STR00733##

in the synthesis steps of A-331 was replaced with

##STR00734##

and the rest operation was the same as that in the A-331 synthesis. M+1: 317.16. [0555] A-348:

##STR00735##

in the synthesis steps of A-331 was replaced with

##STR00736##

and the rest operations were the same as those in A-331 synthesis. M+1: 329.20.

Example of Synthesis of A-332

[0556] ##STR00737##

Synthesis of Intermediate 21a

[0557] 5.2 g (18 mmol) of the intermediate 3a was dissolved in 20 mL of methanol, 3.6 g (90 mmol) of NaOH was taken and dissolved in 10 mL of water to obtain an aqueous NaOH solution, the aqueous NaOH solution was slowly added to the system of the intermediate 3a under ice bath conditions and the color of the reaction solution became darker, and the raw materials were gradually returned to room temperature and reacted for 3 hours; when the completion of the raw materials reaction was monitored by TLC, the reaction was terminated; the mixture was concentrated under reduced pressure to remove methanol in the system, pH value of the concentrate was adjusted to slightly acidic with dilute hydrochloric acid, a white solid was precipitated from the system, filtered, and dried by infrared lamp, and 4.3 g of the white solid was obtained with a yield of 86.9%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.37 (s, 9H), 3.06-3.56 (m, 3H), 3.94-4.23 (m, 4H), 8.54 (s, 1H). M−1: 273.1.

Synthesis of Intermediate 22a

[0558] Under ice bath conditions, a total of 0.8 g (2.9 mmol) of the intermediate 21a was dissolved in 20 mL of acetonitrile, 0.8 mL (5.8 mmol) of TEA and 1.1 g (3.5 mmol) of TBTU were added, then 0.53 g (3.1 mmol) of O-tert-butyl-L-serine methyl ester hydrochloride was added, and the raw materials were gradually returned to the room temperature and reacted for 4 hours; when the completion of the raw materials reaction was monitored by TLC, the reaction was terminated. The mixture was washed with saturated citric acid and then washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, concentrated, and separated through a silica gel column to obtain 0.86 g of an oily substance with a yield of 76.1%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13 (s, 9H), 1.42 (s, 9H), 2.67-4.38 (m, 13H), 7.43 (s, 1H), 8.21 (s, 1H). M+1: 432.21.

Synthesis of Intermediate 23a

[0559] The synthesis method was similar to that of the intermediate 9a, and a total of 0.76 g of an oily substance was obtained with a yield of 93.5%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13 (s, 9H), 1.42 (s, 9H), 2.67-4.38 (m, 10H), 7.06-7.21 (m, 3H), 8.21 (s, 1H). M+1: 417.21.

Example of Synthesis of A-332

[0560] The synthesis method was similar to that of A-329, and a total of 0.53 g of a white solid was obtained with a yield of 81.3%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 2.67-4.54 (m, 10H), 4.94 (s, 1H), 7.21-8.11 (m, 5H). M+1: 261.10.

Example of Synthesis of A-370

[0561] A-370: the synthesis method was similar to that of A-332,

##STR00738##

in A-332 synthesis was replaced with

##STR00739##

and the rest operations were the same as those of A-332. M+1: 275.11.

Examples of Synthesis of A-383, A-390 and A-397

[0562] A-383: the intermediate 5a in A-332 synthesis was replaced with the intermediate 5b,

##STR00740##

was replaced with

##STR00741##

and the rest operations were the same as those in the A-332 synthesis. M+1: 289.13. [0563] A-390: the intermediate 5a in A-332 synthesis was replaced with the intermediate 5c,

##STR00742##

was replaced with

##STR00743##

and the rest operations were the same as those in the A-332 synthesis. M+1: 303.14. [0564] A-397: the intermediate 5a in A-332 synthesis was replaced with the intermediate 5d,

##STR00744##

was replaced with

##STR00745##

and the rest operations were the same as those in the A-332 synthesis. M+1: 303.14.

Example of Synthesis of A-371

[0565] ##STR00746##

Synthesis of Intermediate 24a

[0566] The synthesis method was similar to that of the intermediate 21a, and a total of 0.68 g of an oily substance was obtained with a yield of 76.7%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 2.10 (s, 3H), 2.67-2.92 (m, 2H), 3.67 (m, 1H), 4.12-4.38 (m, 4H), 7.06 (s, 1H), 12.39 (s, 1H). M+1: 217.06.

Synthesis of Intermediate 25a

[0567] The synthesis method was similar to that of the intermediate 22a, and a total of 0.93 g of an oily substance was obtained with a yield of 79.1%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13 (s, 12H), 2.10 (s, 3H), 2.67-2.92 (m, 2H), 3.67 (s, 3H), 3.69-4.38 (m, 7H), 7.06 (s, 1H), 8.32 (s, 1H). M+1: 374.17.

Synthesis of Intermediate 26a

[0568] The synthesis method was similar to that of the intermediate 23a, and a total of 0.67 g of a substance was obtained with a yield of 75.2%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13 (s, 12H), 2.10 (s, 3H), 2.67-2.92 (m, 2H), 3.33-4.38 (m, 7H), 7.06 (s, 1H), 7.21 (s, 2H), 8.32 (s, 1H). M+1: 359.17.

Synthesis of A-371

[0569] The synthesis method was similar to that of A-332, and a total of 0.48 g of a colorless oily substance was obtained, and then evacuated by an oil pump to obtain a white solid with a yield of 85.7%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 2.10 (s, 6H), 2.33-2.85 (m, 2H), 4.12-4.54 (m, 7H), 4.94 (s, 1H), 7.21 (s, 2H), 8.26 (s, 2H). M+1: 303.11.

Example of Synthesis of A-333

[0570] A-333:

##STR00747##

in the synthesis steps of A-371 was replaced with

##STR00748##

and the rest operations were the same as those of A-371. M+1: 317.12.

Examples of A-372 and A-373

[0571] A-372: 5a in the synthesis steps of A-371 was replaced with 6a, and the rest operations were the same as those of A-371. M+1: 345.16. [0572] A-373: 5a in the synthesis steps of A-371 was replaced with 7a, and the rest operations were the same as those of A-371. M+1: 359.17.

Examples of Synthesis of A-384, A-391 and A-398

[0573] A-384: the intermediate 5a in the synthesis steps of A-371 was replaced with the intermediate 5b, and the rest operations were the same as those of A-371. M+1: 331.14. [0574] A-391: the intermediate 5a in the synthesis steps of A-371 was replaced with the intermediate 5c, and the rest operations were the same as those of A-371. M+1: 345.16. [0575] A-398: the intermediate 5a in the synthesis steps of A-371 was replaced with the intermediate 5d, and the rest operations were the same as those of A-371. M+1: 345.16.

Examples of Synthesis of A-385 and A-386

[0576] A-385: the intermediate 5a in the synthesis steps of A-371 was replaced with the intermediate 6b, and the rest operations were the same as those of A-371. M+1: 359.17. [0577] A-386: the intermediate 5a in the synthesis steps of A-371 was replaced with the intermediate 7b, and the rest operations were the same as those of A-371. M+1: 373.19.

Examples of Synthesis of A-392 and A-393

[0578] A-392: the intermediate 5a in the synthesis steps of A-371 was replaced with the intermediate 6c, and the rest operations were the same as those of A-371. M+1: 373.18. [0579] A-393: the intermediate 5a in the synthesis steps of A-371 was replaced with the intermediate 7c, and the rest operations were the same as those of A-371. M+1: 387.2.

Examples of Synthesis of A-399 and A-400

[0580] A-399: the intermediate 5a in the synthesis steps of A-371 was replaced with the intermediate 6d, and the rest operations were the same as those of A-371. M+1: 373.19. [0581] A-400: the intermediate 5a in the synthesis steps of A-371 was replaced with the intermediate 7d, and the rest operations were the same as those of A-371. M+1: 387.21.

Example of Synthesis of A-334

[0582] ##STR00749##

Synthesis of Intermediate 27a

[0583] The synthesis method was similar to that of the intermediate 19a, and a total of 0.56 g of a colorless oily substance was obtained with a yield of 75.4%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.19 (s, 9H), 1.42 (s, 9H), 2.32-2.67 (m, 2H), 3.33-4.54 (m, 11H), 4.94 (s, 1H), 7.06 (s, 1H), 7.21 (s, 2H), 7.31 (s, 1H), 8.06 (s, 1H). M+1: 504.24.

Synthesis of A-334

[0584] The synthesis method was similar to that of A-371, and a total of 0.31 g of a white solid was obtained with a yield of 87.9%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 2.67-2.92 (m, 2H), 3.54-4.52 (m, 11H), 5.08 (s, 2H), 7.06-7.21 (m, 3H), 8.32 (s, 1H), 8.92 (s, 2H). M+1: 348.13.

Example of Synthesis of A-335

[0585] ##STR00750##

Synthesis of Intermediate 28a

[0586] Under ice bath conditions, a total of 0.7 g of the intermediate 8a was dissolved in 20 mL of DCM, 0.4 g of K.sub.2CO.sub.3 was added, 170 μL of acetyl chloride was dissolved in 5 mL of DCM to obtain a solution, and the solution was dripped to the reaction system and the raw materials were gradually returned to room temperature and reacted for 4 hours; when the completion of the raw materials reaction was monitored by TLC, the reaction was terminated; the mixture was washed with a saturated citric acid solution and then washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated, and separated by a silica gel column to obtain a total of 0.53 g of a colorless oily substance intermediate 27a with a yield of 69%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13-1.23 (m, 12H), 1.37 (s, 9H), 2.05 (s, 3H), 3.15-3.43 (m, 2H), 3.61-3.87 (m, 5H), 4.05-4.87 (m, 5H), 7.84 (s, 1H). M+1: 488.24.

Synthesis of Intermediate 29a

[0587] The synthesis method was similar to that of the intermediate 23a, and a total of 0.46 g of an oily substance was obtained with a yield of 92.6%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13-1.25 (m, 12H), 1.37 (s, 9H), 2.04 (s, 3H), 3.16-3.44 (m, 2H), 3.62-3.87 (m, 2H), 4.06-4.85 (m, 5H), 7.84 (s, 1H), 8.35 (s, 2H). M+1: 473.24.

Synthesis of A-335

[0588] The synthesis method was similar to that of A-329, and a total of 0.25 g of a white solid was obtained with a yield of 87.5%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13-1.17 (m, 3H), 2.03 (s, 3H), 3.07-3.18 (m, 1H), 3.39-3.43 (m, 1H), 3.73-3.92 (m, 2H), 4.07-4.83 (m, 5H), 5.63 (s, 1H), 7.57 (s, 1H), 7.95 (s, 1H), 8.25 (s, 2H). M+1: 317.12.

Example of Synthesis of A-336

[0589] ##STR00751##

Synthesis of Intermediate 30a

[0590] The synthesis method was similar to that of the intermediate 15a, and a total of 0.89 g of a yellow powdered solid was obtained with a yield of 78.6%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13-1.42 (m, 21H), 2.7-3.57 (m, 4H), 4.26-4.51 (m, 9H), 7.28-7.91 (m, 9H). M+1: 610.29.

Synthesis of Intermediate 31a

[0591] The synthesis method was similar to that of the intermediate 16a, and a total of 0.45 g of a yellow solid was obtained with a yield of 80.3%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13-1.42 (m, 21H), 2.7-3.57 (m, 4H), 4.26-4.51 (m, 9H), 8.96 (s, 1H). M+1: 388.22.

Synthesis of A-336

[0592] The synthesis method was similar to that of A-329, and a total of 0.22 g of white powder was obtained with a yield of 70.9%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.16 (d, 3H), 2.70 (t, 2H), 3.47-4.21 (m, 8H), 5.37 (s, 1H), 8.96 (s, 3H). M+1: 232.11.

Examples of Synthesis of A-349, A-356 and A-363

[0593] A-349: A-002 in the synthesis steps of A-336 was replaced with A-016, and the rest operations were the same as those in A-336 synthesis. M+1: 246.12. [0594] A-356: A-002 in the synthesis steps of A-336 was replaced with A-030, and the rest operations were the same as those in A-336 synthesis. M+1: 260.14. [0595] A-363: A-002 in the synthesis steps of A-336 was replaced with A-044, and the rest operations were the same as those in A-336 synthesis. M+1: 260.11.

Example of Synthesis of A-337

[0596] ##STR00752##

Synthesis of Intermediate 32a

[0597] The synthesis method was similar to that of the intermediate 17a, and a total of 0.42 g of white powder was obtained with a yield of 102.4%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.43 (s, 3H), 2.7-3.57 (m, 4H), 4.26-4.51 (m, 9H), 5.44 (s, 1H), 7.28-7.91 (m, 10H). M+1: 454.18.

Synthesis of Intermediate 33a

[0598] The synthesis method was similar to that of 18a, and a total of 0.33 g of a solid was obtained with a yield of 77.6%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.43 (s, 3H), 2.10 (s, 3H), 2.7-3.57 (m, 4H), 4.26-4.51 (m, 9H), 5.44 (s, 1H), 7.28-7.91 (m, 9H). M+1: 496.19.

Synthesis of A-337

[0599] The synthesis method was similar to that of A-330, and a total of 0.14 g was obtained with a yield of 70%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.43 (s, 3H), 2.10 (s, 3H), 2.7-3.57 (m, 4H), 4.26-4.51 (m, 9H), 5.44 (s, 1H), 7.8 (s, 2H). M+1: 274.12.

[0600] In the synthesis process of the intermediate 30a, the intermediate A-002 was replaced with the intermediate A-016, the intermediate A-030 and the intermediate A-044 respectively, and the other operations were the same as those of the synthesis of the intermediate 30a, and an intermediate 30b, an intermediate 30c and an intermediate 30d were prepared respectively;

[0601] similarly, in the synthesis of the intermediate 32a, the intermediate 30a was replaced with the intermediate 30b, the intermediate 30c and the intermediate 30d respectively, and the other operations were the same as those of the synthesis of the intermediate 32a, and the intermediate 32b, intermediate 32c and intermediate 32d were prepared respectively.

[0602] similarly, in the synthesis process of the intermediate 33a, the intermediate 30a was replaced with the intermediate 30b, the intermediate 30c and the intermediate 30d respectively, and the other operations were the same as those in the synthesis of the intermediate 33a, and an intermediate 33b, an intermediate 33c and an intermediate 33d were prepared respectively;

[0603] similarly, in the synthesis of the intermediate 33a, acetyl chloride was replaced with isobutyryl chloride and pivaloyl chloride respectively, and an intermediate 34a, an intermediate 34b, an intermediate 34c, and an intermediate 34d, and an intermediate 35a, an intermediate 35b, an intermediate 35c, and an intermediate 35d were prepared respectively.

##STR00753## ##STR00754## ##STR00755## ##STR00756## ##STR00757##

Examples of Synthesis of A-338 to A-343

[0604] A-338:

##STR00758##

in A-337 synthesis was replaced with

##STR00759##

and the rest operations were the same as those in A-337 synthesis. M+1: 230.09. [0605] A-339:

##STR00760##

in A-337 synthesis was replaced with

##STR00761##

and the rest operations were the same as those in A-337 synthesis. M+1: 244.11. [0606] A-340:

##STR00762##

in A-337 synthesis was replaced with

##STR00763##

and the rest operations were the same as those in A-337 synthesis. M+1: 286.15. [0607] A-341:

##STR00764##

in A-337 synthesis was replaced with

##STR00765##

and the rest operations were the same as those in A-337 synthesis. M+1: 320.14. [0608] A-342:

##STR00766##

in A-337 synthesis was replaced with

##STR00767##

and the rest operations were the same as those of A-337. M+1: 287.11. [0609] A-343:

##STR00768##

in A-337 synthesis was replaced with

##STR00769##

and the rest operations were the same as those in A-337 synthesis. M+1: 336.13.

Examples of Synthesis of A-344 and A-345

[0610] A-344: 33a in A-337 synthesis was replaced with 34a, and the rest operations were the same as those of A-337. M+1: 302.15. [0611] A-345: 33a in A-337 synthesis was replaced with 35a, and the rest operations were the same as those of A-337. M+1: 316.17.

Examples of Synthesis of A-350, A-357 and A-364

[0612] A-350: 33a in A-337 synthesis was replaced with 33b, and the rest operations were the same as those of A-337. M+1: 288.13. [0613] A-357: 33a in A-337 synthesis was replaced with 33c, and the rest operations were the same as those of A-337. M+1: 302.15. [0614] A-364: 33a in A-337 synthesis was replaced with 33d, and the rest operations were the same as those of A-337. M+1: 302.1.

Examples of Synthesis of A-351, A-352, A-358, A-359, A-365 and A-366

[0615] A-351: 33a in A-337 synthesis was replaced with 34b, and the rest operations were the same as those of A-337. M+1: 316.17. [0616] A-352: 33a in A-337 synthesis was replaced with 35b, and the rest operations were the same as those of A-337. M+1: 330.18. [0617] A-358: 33a in A-337 synthesis was replaced with 34c, and the rest operations were the same as those of A-337. M+1: 330.18. [0618] A-359: 33a in A-337 synthesis was replaced with 35c, and the rest operations were the same as those of A-337. M+1: 344.20. [0619] A-365: 33a in the A-337 synthesis was replaced with 34d, and the rest operations were the same as those of A-337. M+1: 330.16. [0620] A-366: 33a in A-337 synthesis was replaced with 35d, and the rest operations were the same as those of A-337. M+1: 344.15.

Example of Synthesis of A-346

[0621] ##STR00770##

Synthesis of Intermediate 36a

[0622] The synthesis method was similar to that of 1a, and a total of 0.22 g of yellow powder was obtained with a yield of 37%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13-1.42 (m, 24H), 2.7-3.57 (m, 4H), 4.26-4.70 (m, 11H), 5.37 (s, 1H), 7.28-7.90 (m, 10H). M+1: 711.34.

Synthesis of Intermediate 37a

[0623] The synthesis method was similar to that of the intermediate 16a, and 0.13 g of a solid was obtained with a yield of 41%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13-1.42 (m, 24H), 2.7 (t, 2H), 3.47-4.64 (m, 10H), 5.37 (s, 1H), 7.28-7.90 (m, 3H). M+1: 489.27.

Synthesis of A-346

[0624] The synthesis method was similar to that of A-331, 59 mg of a substance was obtained with a yield of 22.3%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.16 (s, 6H), 2.7 (t, 2H), 3.47-4.64 (m, 10H), 5.37 (s, 2H), 8.95 (s, 4H). M+1: 333.16.

[0625] In the synthesis of an intermediate 36a, the intermediate 32a was replaced with 32b, 32c and 32d respectively, and the other operations were the same as those of the synthesis of the intermediate 36a, and an intermediate 36b-1, an intermediate 36c-1 and an intermediate 36d-1 were prepared respectively;

[0626] similarly, in the synthesis of the intermediate 36a, the raw material intermediate was respectively replaced with 32b, 32c and 32d,

##STR00771##

was respectively replaced with

##STR00772##

so that 36b-2, 36b-3, 36c-2, 36c-3, 36d-2 and 36d-3 were obtained respectively.

##STR00773## ##STR00774##

Examples of Synthesis of A-353, A-360 and A-367

[0627] A-353: 36a in A-346 synthesis was replaced with 36b-1, and the rest operations were the same as those of A-346. M+1: 347.17. [0628] A-360: 36a in A-346 synthesis was replaced with 36c-1, and the rest operations were the same as those of A-346. M+1: 361.19. [0629] A-367: 36a in A-346 synthesis was replaced with 36d-1, and the rest operations were the same as those of A-346. M+1: 361.2.

Examples of Synthesis of A-354, A-355, A-361, A-362, A-368 and A-369

[0630] A-354: 36a in A-346 synthesis was replaced with 36b-2, and the rest operations were the same as those of A-346. M+1: 333.16. [0631] A-355: 36a in A-346 synthesis was replaced with 36b-3, and the rest operations were the same as those of A-346. M+1: 345.19. [0632] A-361: 36a in A-346 synthesis was replaced with 36c-2, and the rest operations were the same as those of A-346. M+1: 347.17. [0633] A-362: 36a in A-346 synthesis was replaced with 36c-3, and the rest operations were the same as those of A-346. M+1: 359.21. [0634] A-368: 36a in the synthesis of A-346 was replaced with 36d-2, and the rest operations were the same as those of A-346. M+1: 347.3. [0635] A-369: 36a in A-346 synthesis was replaced with 36d-3, and the rest operations were the same as those of A-346. M+1: 359.25.

Example of Synthesis of A-374

[0636] ##STR00775##

Synthesis of Intermediate 38a

[0637] 8.0 g (18 mmol) of the intermediate 8a was dissolved in 30 mL of methanol, 3.6 g (90 mmol) of NaOH was taken and dissolved in 10 mL of water to obtain an aqueous NaOH solution, the aqueous NaOH solution was slowly added to the reaction system of the intermediate 8a under ice bath conditions, the color of the reaction solution became darker, and the raw materials were gradually returned to room temperature and reacted for 3 hours; when the completion of the raw materials reaction was monitored by TLC, the reaction was terminated; the mixture was concentrated under reduced pressure to remove methanol in the system, pH value of the system was adjusted to slightly acidic by dilute hydrochloric acid, a white solid was precipitated from the system, filtered, and dried by infrared lamp, and 4.3 g of the white solid was obtained with a yield of 58.1%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13 (s, 12H), 1.37 (s, 9H), 2.67-3.77 (m, 3H), 4.12-4.64 (m, 6H), 7.39-7.06 (m, 2H), 12.01 (s, 1H). M−1: 432.1.

Synthesis of Intermediate 39a

[0638] Under ice bath conditions, a total of 4.3 g (10 mmol) of the intermediate 38a was dissolved in 20 mL of acetonitrile, 2.7 mL (20 mmol) of TEA and 3.78 g (12 mmol) of TBTU were added, then 1.83 g (10.7 mmol) of O-tert-butyl-L-serine methyl ester hydrochloride was added, and the raw materials were gradually returned to room temperature and reacted for 4 hours; when the completion of the raw materials reaction was monitored by TLC, the reaction was terminated. The mixture was washed with saturated citric acid and then washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, concentrated, and separated by a silica gel column to obtain 4.58 g of an oily substance with a yield of 76.1%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13 (s, 24H), 1.37 (s, 9H), 2.67-3.84 (m, 3H), 3.67 (s, 3H), 4.12-4.64 (m, 8H), 7.39-8.06 (m, 3H). M+1: 603.34.

Synthesis of Intermediate 40a

[0639] A total of 4.58 g (7.60 mmol) of the intermediate 39a was dissolved in a small amount of methanol, and 10 mL of 7 mol/L NH.sub.3/CH.sub.3OH solution was added under ice bath, and the raw materials were reacted overnight; after the completion of the raw materials reaction was monitored by TLC, a reaction solution was subjected to rotary evaporation to obtain a total of 4.04 g of an off-white solid intermediate 40a with a yield of 90.4%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.13 (s, 24H), 1.37 (s, 9H), 2.67-3.84 (m, 3H), 4.12-4.64 (m, 8H), 7.39-8.06 (m, 5H). M+1: 588.34.

Synthesis of A-374

[0640] 1 g of the intermediate 40a was dissolved in 4 mL of ethyl acetate, 3 mL of 4 mol/L HCl/EtOAc was added, and the raw materials were stirred at room temperature for 3 h; when the completion of the raw materials reaction was monitored by TLC, a white solid was generated in the system, then filtered, and dried to obtain 0.51 g of a white solid with a yield of 79%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.16 (m, 6H), 2.67-4.62 (m, 11H), 5.32 (s, 2H), 7.3 (s, 2H), 8.96 (s, 4H). M+1: 376.16.

[0641] In the synthesis of the intermediate 38a, the raw material

##STR00776##

was replaced with

##STR00777##

respectively, and the other operations were the same as those of the synthesis of the intermediate 38a, so that an intermediate 38b and an intermediate 38c were prepared respectively;

##STR00778##

[0642] similarly, in the synthesis of the intermediate 39a, the raw material

##STR00779##

was respectively replaced with

##STR00780##

and 39b, 39c and 39d were obtained respectively;

##STR00781##

Examples of Synthesis of A-375 and A-376

[0643] A-375: the intermediate 38a in A-374 synthesis was replaced with 38b, and the rest operations were the same as those of A-374. M+1: 362.15. [0644] A-376: the intermediate 38a in the A-374 synthesis was replaced with 38c, and the rest operations were the same as those of A-374. M+1: 374.18.

Examples of Synthesis of A-377, A-378, A-379, A-380, A-381 and A-382

[0645] A-377: the intermediate 39a in A-374 synthesis was replaced with 39b, and the rest operations were the same as those of A-374. M+1: 332.13. [0646] A-378: 39a in the synthesis step of the intermediate 39a was replaced with 39c, and the rest operations were the same as those of A-374. M+1: 346.15. [0647] A-379: the intermediate 39a in A-374 synthesis was replaced with 39d, and the rest operations were the same as those of A-374. M+1: 388.20. [0648] A-380: the intermediate 38a in A-374 synthesis was replaced with 38c,

##STR00782##

in the synthesis step of the intermediate 39a was replaced with

##STR00783##

and the rest operations were the same as those of A-374. M+1: 422.18. [0649] A-381: the intermediate 38a in A-374 synthesis was replaced with 38b,

##STR00784##

in the synthesis step of the intermediate 39a was replaced with

##STR00785##

and the rest operations were the same as those of A-374. M+1: 389.16. [0650] A-382: The intermediate 38a in A-374 synthesis was replaced with 38c,

##STR00786##

in the synthesis step of the intermediate 39a was replaced with

##STR00787##

and the rest operations were the same as those of A-374. M+1: 438.18.

Examples of Synthesis of A-387, A-388 and A-389

[0651] A-387: the intermediate 3a in A-374 synthesis was replaced with 3b, and the rest operations were the same as those of A-374. M+1: 390.18. [0652] A-388: the intermediate 3a in A-374 synthesis was replaced with 3b,

##STR00788##

in the synthesis step of the intermediate 38a was replaced with

##STR00789##

and the rest operations were the same as those of A-374. M+1: 376.16. [0653] A-389: the intermediate 3a in A-374 synthesis was replaced with 3b,

##STR00790##

in the synthesis step of the intermediate 38a was replaced with

##STR00791##

Boc, and the rest operations were the same as those of A-374. M+1: 388.2.

Examples of Synthesis of A-394, A-395 and A-396

[0654] A-394: the intermediate 3a in A-374 synthesis was replaced with 3c, and the rest operations were the same as those of A-374. M+1: 404.19. [0655] A-395: the intermediate 3a in A-374 synthesis was replaced with 3c,

##STR00792##

the synthesis step of the intermediate 38a was replaced with

##STR00793##

and the rest operations were the same as those of A-374. M+1: 390.18. [0656] A-396: the intermediate 3a in A-374 synthesis was replaced with 3c,

##STR00794##

in the synthesis step of the intermediate 38a was replaced with

##STR00795##

and the rest operations were the same as those of A-374. M+1: 402.21.

Examples of Synthesis of A-401, A-402 and A-403

[0657] A-401: the intermediate 3a in A-374 synthesis was replaced with 3d, and the rest operations were the same as those of A-374. M+1: 404.19. [0658] A-402: the intermediate 3a in A-374 synthesis was replaced with 3d,

##STR00796##

in the synthesis step of the intermediate 38a was replaced with

##STR00797##

and the rest operations were the same as those of A-374. M+1: 390.18. [0659] A-403: the intermediate 3a in A-374 synthesis was replaced with 3d,

##STR00798##

in the synthesis step of the intermediate 38a was replaced with

##STR00799##

and the rest operations were the same as those of A-374. M+1: 402.21.

Example of Synthesis of A-405

[0660] ##STR00800##

Synthesis of Intermediate 41a

[0661] 21a (4.32 g, 15.7 mmol) was added to 100 ml of DCM (insoluble) under ice bath conditions, a solid in the solution was gradually dissolved after adding 2.5 eq of TEA, 1.1 eq of piperidine, 1.2 eq of HOBt and 1.2 eq of EDCI were added, and the raw materials were subjected to a thermal reaction for 10 min and then reacted overnight at room temperature; after the completion of the raw materials reaction was monitored by TLC (PE:EA=1:1), the mixture was washed sequentially with water, saturated citric acid solution and saturated saline, dried with anhydrous sodium sulfate and filtered, and a filtrate was concentrated and separated by column chromatography to obtain 4.9 g of a substance with a yield of 90%. 1H-NMR (400 MHz, DMSO-d6), δ ppm: 1.42 (s, 9H), 1.55-2.92 (m, 8H), 3.54-4.38 (m, 9H), 7.28 (s, 1H). M+1: 342.18.

Synthesis of A-404

[0662] The intermediate 41a (4.9 g, 14.4 mmol) was added to ethyl acetate for complete dissolution, then 28 ml of HCl-EtOAc solution was added, the raw materials were stirred at room temperature for 6 h; when the completion of the raw materials reaction was monitored by TLC (PE:EA=1:2), the mixture was filtered, and a filter cake was washed with ethyl acetate, and dried to obtain 4.69 g of a white solid with a yield of 93%. .sup.1H-NMR (400 MHz, DMSO-d6), δ ppm: 1.55-2.92 (m, 8H), 3.54-4.38 (m, 9H), 7.28 (s, 2H). M+1: 242.13.

Synthesis of Intermediate 42a

[0663] Under ice bath conditions, A-404 (0.5 g, 1.8 mmol) was added to 20 ml of DCM, a solid was insoluble, and the solid was gradually dissolved after adding 2.5 eq of TEA, 1.1 eq of Boc-tBu-Thr, 1.2 eq of HOBt and 1.2 eq of EDCI were added, and the raw materials were subjected to a thermal reaction for 10 min and reacted at room temperature for 5 h; after the completion of the raw materials reaction was monitored by TLC (DCM:MeOH=10:1), the mixture was sequentially washed with water, saturated citric acid solution and saturated saline, then dried with anhydrous sodium sulfate and filtered, and a filtrate was concentrated and separated by column chromatography to obtain 0.85 g substance with a yield of 94%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.16 (s, 21H), 1.55-2.92 (m, 8H), 3.54-4.64 (m, 11H), 7.28 (s, 2H). M+1: 499.29.

Synthesis of A-405

[0664] The intermediate 42a was added to 8 ml ethyl acetate for complete dissolution, 8 ml of HCl-EtOAc solution was added, the raw materials were stirred at room temperature for 6 h; after the completion of the raw materials reaction was monitored by TLC (PE:EA=1:2), the mixture was filtered, and a filter cake was washed with ethyl acetate, and then dried to obtain 0.45 g of a white solid with a yield of 69.6%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.16 (s, 3H), 1.55-2.92 (m, 8H), 3.54-4.38 (m, 11H), 5.37 (s, 1H), 7.28 (s, 1H), 8.93 (s, 2H). M+1: 343.18.

Examples of Synthesis of A-408, A-412 and A-416

[0665] A-408:

##STR00801##

in A-404 synthesis was replaced with

##STR00802##

and the rest operations were the same as those in A-404 synthesis. M+1: 244.11. [0666] A-412:

##STR00803##

in A-404 synthesis was replaced with

##STR00804##

and the rest operations were the same as those in A-404 synthesis. M+1: 257.14. [0667] A-416:

##STR00805##

in A-404 synthesis was replaced with

##STR00806##

and the rest operations were the same as those in A-404 synthesis. M+1: 260.08.

Examples of Synthesis of A-406 and A-407

[0668] A-406:

##STR00807##

in A-405 synthesis was replaced with

##STR00808##

and the rest operations were the same as those in A-405 synthesis. M+1: 341.20. [0669] A-407:

##STR00809##

in A-405 synthesis was replaced with

##STR00810##

and the rest operations were the same as those in A-405 synthesis. M+1: 329.16.

Examples of Synthesis of A-409, A-410 and A-411

[0670] A-409: A-404 in A-405 synthesis was replaced with A-408, and the rest operations were the same as those in A-405 synthesis. M+1: 345.16. [0671] A-410: A-404 in A-405 synthesis was replaced with A-408,

##STR00811##

was replaced with

##STR00812##

and the rest operations were the same as those of A-405. M+1: 343.18. [0672] A-411: A-404 in A-405 synthesis was replaced with A-408,

##STR00813##

was replaced with

##STR00814##

and the rest operations were the same as those of A-405. M+1: 331.14.

Examples of Synthesis of A-413, A-414 and A-415

[0673] A-413: A-404 in A-405 synthesis was replaced with A-412, and the rest operations were the same as those in A-405 synthesis. M+1: 358.19. [0674] A-414: A-404 in A-405 synthesis was replaced with A-412,

##STR00815##

was replaced with

##STR00816##

and the rest operations were the same as those in A-405 synthesis. M+1: 356.21. [0675] A-415: A-404 in A-405 synthesis was replaced with A-412,

##STR00817##

was replaced with

##STR00818##

and the rest operations were the same as those of A-405. M+1: 344.17.

Examples of Synthesis of A-417, A-418 and A-419

[0676] A-417: A-404 in A-405 synthesis was replaced with A-416, and the rest operations were the same as those in A-405 synthesis. M+1: 361.13. [0677] A-418: A-404 in A-405 synthesis was replaced with A-416,

##STR00819##

was replaced with

##STR00820##

and the rest operations were the same as those of A-405. M+1: 359.15. [0678] A-419: A-404 in A-405 synthesis was replaced with A-416,

##STR00821##

was replaced with

##STR00822##

and the rest operations were the same as those of A-405. M+1: 347.12.

Examples of Synthesis of A-420, A-436 and A-452

[0679] A-420: the intermediate 3a in A-404 synthesis was replaced with 3b, and the rest operations were the same as those of A-404. M+1: 256.14. [0680] A-436: the intermediate 3a in A-404 synthesis was replaced with 3c, and the rest operations were the same as those of A-404. M+1: 270.16. [0681] A-452: the intermediate 3a in A-404 synthesis was replaced with 3d, and the rest operations were the same as those of A-404. M+1: 270.16.

Examples of Synthesis of A-421, A-422 and A-423

[0682] A-421: A-404 in A-405 synthesis was replaced with A-420, and the rest operations were the same as those in A-405 synthesis. M+1: 357.19. [0683] A-422: A-404 in A-405 synthesis was replaced with A-420,

##STR00823##

was replaced with

##STR00824##

and the rest operations were the same as those in A-405 synthesis. M+1: 355.21. [0684] A-423: A-404 in A-405 synthesis was replaced with A-420,

##STR00825##

was replaced with

##STR00826##

and the rest operations were the same as those in A-405 synthesis. M+1: 343.18.

Examples of Synthesis of A-424, A-428 and A-432

[0685] A-424: 3a in A-404 synthesis was replaced with 3b,

##STR00827##

was replaced with

##STR00828##

and the rest operations were the same as those of A-404. M+1: 258.12. [0686] A-428: 3a in A-404 synthesis was replaced with 3b,

##STR00829##

was replaced with

##STR00830##

and the rest operations were the same as those of A-404. M+1: 271.15. [0687] A-432: 3a in A-404 synthesis was replaced with 3b,

##STR00831##

was replaced with

##STR00832##

and the rest operations were the same as those of A-404. M+1: 274.10.

Examples of Synthesis of A-425, A-426 and A-427

[0688] A-425: A-404 in A-405 synthesis was replaced with A-424, and the rest operations were the same as those in A-405 synthesis. M+1: 359.17. [0689] A-426: A-404 in A-405 synthesis was replaced with A-424,

##STR00833##

was replaced with

##STR00834##

and the rest operations were the same as those of A-405. M+1: 357.19. [0690] A-427: A-404 in A-405 synthesis was replaced with A-424,

##STR00835##

was replaced with

##STR00836##

and the rest operations were the same as those in A-405 synthesis. M+1: 345.16.

Examples of Synthesis of A-429, A-430 and A-431

[0691] A-429: A-404 in A-405 synthesis was replaced with A-428, and the rest operations were the same as those in A-405 synthesis. M+1: 372.20. [0692] A-430: A-404 in A-405 synthesis was replaced with A-428,

##STR00837##

was replaced with

##STR00838##

and the rest operations were the same as those of A-405. M+1: 370.22. [0693] A-431: A-404 in A-405 synthesis was replaced with A-428,

##STR00839##

was replaced with

##STR00840##

and the rest operations were the same as those in A-405 synthesis. M+1: 358.19.

Examples of Synthesis of A-433, A-434 and A-435

[0694] A-433: A-404 in A-405 synthesis was replaced with A-432, and the rest operations were the same as those in A-405 synthesis. M+1: 375.15. [0695] A-434: A-404 in A-405 synthesis was replaced with A-432,

##STR00841##

was replaced with

##STR00842##

and the rest operations were the same as those in A-405 synthesis. M+1: 373.17. [0696] A-435: A-404 in A-405 synthesis was replaced with A-432,

##STR00843##

was replaced with

##STR00844##

and the rest operations were the same as those in A-405 synthesis. M+1: 361.13.

Examples of Synthesis of A-437, A-438 and A-439

[0697] A-437: A-404 in A-405 synthesis was replaced with A-436, and the rest operations were the same as those in A-405 synthesis. M+1: 371.21. [0698] A-438: A-404 in A-405 synthesis was replaced with A-436,

##STR00845##

replaced with

##STR00846##

and the rest operations were the same as those in A-405 synthesis. M+1: 369.23. [0699] A-439: A-404 in A-405 synthesis was replaced with A-436,

##STR00847##

was replaced with

##STR00848##

and the rest operations were the same as those in A-405 synthesis. M+1: 357.19.

Examples of Synthesis of A-440, A-444 and A-448

[0700] A-440: 3a in A-404 synthesis was replaced with 3c,

##STR00849##

was replaced with

##STR00850##

and the rest operations were the same as those of A-404, M+1: 272.14. [0701] A-444: 3a in A-404 synthesis was replaced with 3c,

##STR00851##

was replaced with

##STR00852##

and the rest operations were the same as those of A-404. M+1: 285.17. [0702] A-448: 3a in A-404 synthesis was replaced with 3c,

##STR00853##

was replaced with

##STR00854##

and the rest operations were the same as those of A-404. M+1: 288.12.

Examples of Synthesis of A-441, A-442 and A-443

[0703] A-441: A-404 in A-405 synthesis was replaced with A-440, and the rest operations were the same as those in A-405 synthesis. M+1: 373.19. [0704] A-442: A-404 in A-405 synthesis was replaced with A-440,

##STR00855##

was replaced with

##STR00856##

and the rest operations were the same as those in A-405 synthesis. M+1: 371.21. [0705] A-443: A-404 in A-405 synthesis was replaced with A-440,

##STR00857##

was replaced with

##STR00858##

and the rest operations were the same as those in A-405 synthesis. M+1: 359.17.

Examples of Synthesis of A-445, A-446 and A-447

[0706] A-445: A-404 in A-405 synthesis was replaced with A-444, and the rest operations were the same as those in A-405 synthesis. M+1: 386.22. [0707] A-446: A-404 in A-405 synthesis was replaced with A-444,

##STR00859##

was replaced with

##STR00860##

and the rest operations were the same as those in A-405 synthesis. M+1: 384.24. [0708] A-447: A-404 in A-405 synthesis was replaced with A-444,

##STR00861##

was replaced with

##STR00862##

and the rest operations were the same as those in A-405 synthesis. M+1: 372.20.

Examples of Synthesis of A-449, A-450 and A-451

[0709] A-449: A-404 in A-405 synthesis was replaced with A-448, and the rest operations were the same as those in A-405 synthesis. M+1: 389.16. [0710] A-450: A-404 in A-405 synthesis was replaced with A-448,

##STR00863##

was replaced with

##STR00864##

and the rest operations were the same as those in A-405 synthesis. M+1: 387.18. [0711] A-451: A-404 in A-405 synthesis was replaced with A-448,

##STR00865##

was replaced with

##STR00866##

and the rest operations were the same as those in A-405 synthesis. M+1: 375.15.

Examples of Synthesis of A-456, A-460 and A-464

[0712] A-456: 3a in A-404 synthesis was replaced with 3d,

##STR00867##

was replaced with

##STR00868##

and the rest operations were the same as those of A-404. M+1: 272.14. [0713] A-460: 3a in A-404 synthesis was replaced with 3d,

##STR00869##

was replaced with

##STR00870##

and the rest operations were the same as those of A-404. M+1: 285.17. [0714] A-464: 3a in A-404 synthesis was replaced with 3d,

##STR00871##

was replaced with

##STR00872##

and the rest operations were the same as those of A-404. M+1: 288.12.

Examples of Synthesis of A-453, A-454 and A-455

[0715] A-453: A-404 in A-405 synthesis was replaced with A-452, and the rest operations were the same as those in A-405 synthesis. M+1: 371.21. [0716] A-454: A-404 in A-405 synthesis was replaced with A-452,

##STR00873##

was replaced with

##STR00874##

and the rest operations were the same as those in A-405 synthesis. M+1: 369.23.

[0717] A-455: A-404 in A-405 synthesis was replaced with A-452,

##STR00875##

was replaced with

##STR00876##

and the rest operations were the same as those in A-405 synthesis. M+1: 357.19.

Examples of Synthesis of A-457, A-458 and A-459

[0718] A-457: A-404 in A-405 synthesis was replaced with A-456, and the rest operations were the same as those in A-405 synthesis. M+1: 373.19. [0719] A-458: A-404 in A-405 synthesis was replaced with A-456,

##STR00877##

was replaced with

##STR00878##

and the rest operations were the same as those in A-405 synthesis. M+1: 371.21. [0720] A-459: A-404 in A-405 synthesis was replaced with A-456,

##STR00879##

replaced with

##STR00880##

and the rest operations were the same as those in A-405 synthesis. M+1: 359.17.

Examples of Synthesis of A-461, A-462 and A-463

[0721] A-461: A-404 in A-405 synthesis was replaced with A-460, and the rest operations were the same as those in A-405 synthesis. M+1: 386.22. [0722] A-462: A-404 in A-405 synthesis was replaced with A-460,

##STR00881##

was replaced with

##STR00882##

and the rest operations were the same as those in A-405 synthesis. M+1: 384.24. [0723] A-463: A-404 in A-405 synthesis was replaced with A-460,

##STR00883##

was replaced with

##STR00884##

and the rest operations were the same as those in A-405 synthesis. M+1: 372.20.

Examples of Synthesis of A-465, A-466 and A-467

[0724] A-465: A-404 in A-405 synthesis was replaced with A-464, and the rest operations were the same as those in A-405 synthesis. M+1: 389.16. [0725] A-466: A-404 in A-405 synthesis was replaced with A-464,

##STR00885##

was replaced with

##STR00886##

and the rest operations were the same as those in A-405 synthesis. M+1: 387.18. [0726] A-467: A-404 in A-405 synthesis was replaced with A-464,

##STR00887##

replaced with

##STR00888##

and the rest operations were the same as those in A-405 synthesis. M+1: 375.15.

Example of Synthesis of 468

[0727] ##STR00889##

Synthesis of Intermediate 43a

[0728] Under ice bath conditions, the intermediate 38a (1.1 g, 2.55 mmol) was added into 50 ml of DCM, a solid was insoluble, and the solid was gradually dissolved after 2.5eq of TEA was added, then 1.1eq of N-Boc piperazine, 1.2eq of HOBt and 1.2eq of EDCI were added, and the raw materials were subjected to thermal reaction for 10 min and then reacted at room temperature overnight; after the completion of the raw materials reaction was monitored by TLC (DCM:MeOH=5:1), a mixture was washed sequentially with water, saturated citric acid solution and saturated saline, dried with anhydrous sodium sulfate, and filtered, and then a filtrate was concentrated and separated by column chromatography to obtain 0.87 g of substance with a yield of 57.2%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.16 (s, 12H), 1.42 (s, 18H), 2.67-4.64 (m, 17H), 7.38 (s, 2H). M+1: 600.34.

Synthesis of A-468

[0729] The intermediate 43a (0.87 g, 1.45 mmol) was added to 10 ml of ethyl acetate, 10 ml of HCl-EtOAc solution was added, and the raw materials were stirred at room temperature for 6 h; when the completion of the raw materials reaction was monitored by TLC (PE:EA=1:2), a mixture was filtered, and a filter cake was washed with ethyl acetate, and dried to obtain 0.74 mg of a white solid with a yield of 95%. .sup.1H-NMR (400 MHz, DMSO-d.sub.6), δ ppm: 1.16 (s, 3H), 2.81-4.38 (m, 17H), 5.37 (s, 1H), 7.28 (s, 4H). M+1: 344.17.

Examples of Synthesis of A-469 and A-470

[0730] A-469:

##STR00890##

in A-468 synthesis was replaced with

##STR00891##

and the rest operations were the same as those of A-468. M+1: 342.19. [0731] A-470:

##STR00892##

in A-468 synthesis was replaced with

##STR00893##

and the rest operations were the same as those in A-468 synthesis. M+1: 330.16.

Examples of Synthesis of A-471, A-472 and A-473

[0732] A-471: the intermediate 3a in A-468 synthesis was replaced with 3b, and the rest operations were the same as those of A-468. M+1: 358.19. [0733] A-472: the intermediate 3a in A-468 synthesis was replaced with 3b,

##STR00894##

was replaced with

##STR00895##

and the rest operations were the same as those of A-468. M+1: 356.21. [0734] A-473: the intermediate 3a in A-468 synthesis was replaced with 3b,

##STR00896##

was replaced with

##STR00897##

and the rest operations were the same as those of A-468. M+1: 344.17.

Examples of Synthesis of A-474, A-475 and A-476

[0735] A-474: the intermediate 3a in A-468 synthesis was replaced with 3c, and the rest operations were the same as those of A-468. M+1: 372.20. [0736] A-475: the intermediate 3a in A-468 synthesis was replaced with 3c,

##STR00898##

was replaced with

##STR00899##

and the rest operations were the same as those of A-468. M+1: 370.22. [0737] A-476: the intermediate 3a in A-468 synthesis was replaced with 3c,

##STR00900##

was replaced with

##STR00901##

and the rest operations were the same as those of A-468. M+1: 358.19.

Examples of Synthesis of A-477, A-478 and A-479

[0738] A-477: the intermediate 3a in A-468 synthesis was replaced with 3c, and the rest operations were the same as those of A-468. M+1: 372.1. [0739] A-478: the intermediate 3a in A-468 synthesis was replaced with 3c,

##STR00902##

was replaced with

##STR00903##

and the rest operations were the same as those of A-468. M+1: 370.2. [0740] A-479: the intermediate 3a in A-468 synthesis was replaced with 3c,

##STR00904##

was replaced with

##STR00905##

and the rest operations were the same as those of A-468. M+1: 358.19.

Test Example 1: In-Vitro Receptor Binding Assay

1. Experimental Purpose

[0741] The affinity of the tested compounds on NMDA receptor was researched by receptor ligand binding assays.

2. Experimental Method

[0742] Ten SD male rats of SPF grade were ordered and acclimated for 7 days for future use.

[0743] (1) Preparation of Crude Synaptosomes in Prefrontal Cortex and Hippocampus

[0744] After the rats were decapitated, the prefrontal cortex and hippocampus were rapidly separated on ice and weighed, 10 volumes of 50 mM Tris-HCl buffer (50 mM Tris-HCl, 5 mM MgCl.sub.2.Math.6H.sub.2O, 1 mM EDTA, 0.5% (W/V) BSA, 1 mM PMSF, 0.32 M sucrose, pH 7.4) was added, and the mixture was homogenized for five times at 1500 revolutions/min with 30 s each time. A homogenate was centrifuged for 10 min at 1000×g, and a supernatant was taken and centrifuged for 10 min at 40,000×g, the precipitates were collected, re-suspended with volumes of Tris-HCl buffer, incubated at 37° C. for 10 min, and centrifuged for 10 min at 40,000×g, finally the precipitates were re-suspended with the above buffer, aliquoted and stored at −80° C. for later use.

[0745] (2) Detection of Inhibitory Function of Tested Medicines on Binding of Crude Synaptosomes in Rats to [.sup.3H]-MK-801

[0746] 50 μg of rat crude synaptosomal proteins was added to all tubes respectively. A volume of 50 μl of MK-801 (dizocilpine) was added to a non-specific binding tube to achieve a final concentration of 100 μM, and the materials were reacted for 15 min in advance. 20 μL of control drug at corresponding concentration was added to the test tube for reaction for 15 min. A volume of 30 μl of labeled ligand [.sup.3H]-MK-801 was successively added to all tubes to achieve a final concentration of 10 nM. All reaction tubes were supplemented to a volume of 200 μl with 50 mM Tris-HCl buffer (50 mM Tris-HCl, 5 mM MgCl.sub.2.Math.6H.sub.2O, 1 mM EDTA, 0.5% (WN) BSA, 0.1% NaN.sub.3, pH 7.4). A reaction was carried out at 37° C. for 10 min. A type-49 glass fiber filter membrane was prepared and a sample was applied at the same time. The filter membrane was placed in a multi-head cell collector, and a reaction system was subjected to suction filtration under negative pressure and washed with an ice-cold 50 mM Tris-HCl buffer, 10 ml each time, for a total of 5 times. After suction drying, 1 ml of scintillation liquid was added to the filter membrane, the filter membrane was placed on a shaker for shaking for 1.5 h and then placed in a liquid scintillation counter on the next day to determine the radioactive intensity.

[0747] (3) Detection of Influence of Tested Medicines on NMDA Receptor Agonistic Properties in Rat Crude Synaptosomal Proteins

[0748] 100 μg of rat crude synaptosomal proteins was added to all tubes respectively. 50 μl of 5,7-dichlorokynurenic acid was added to a non-specific binding tube to achieve a final concentration of 10 μM. All tubes were preloaded with 50 μM of glutamic acid, and the materials were reacted for 15 min in advance. 20 μL of control drug at corresponding concentration was added to the test tube, and then reacted for 15 min. 1 mM glycine was added to the maximum reaction tube. A volume of 30 μl of labeled ligand [.sup.3H]-MK-801 was successively added to all tubes to achieve a final concentration of 10 nM, and reacted for 15 min. All reaction tubes were supplemented to a volume of 500 μl with 50 mM Tris-HCl buffer (50 mM Tris-HCl, 5 mM MgCl.sub.2.Math.6H.sub.2O, 1 mM EDTA, 0.5% (WN) BSA, 0.1% NaN.sub.3, pH 7.4). A reaction was carried out at 37° C. for 15 min. A type-49 glass fiber filter membrane was prepared and a sample was applied at the same time. The filter membrane was placed in a multi-head cell collector, and the reaction system was subjected to suction filtration under negative pressure and washed with an ice-cold 50 mM Tris-HCl buffer, 10 ml each time, for a total of 5 times. After suction drying, 1 ml of scintillation liquid was added to the filter membrane, the filter membrane was placed on the shaker for shaking for 1.5 h and then placed in the liquid scintillation counter on the next day to determine the radioactive intensity.

[0749] (4) Data Processing and Statistical Analysis

[0750] GraphPad5.0 software was used to analyze the data, and the percentage of competitive inhibition was calculated through nonlinear fitting, wherein:

Percentage of competitive inhibition %=((total binding tube cpm−compound cpm)/(total binding tube cpm−non-specific binding tube cpm))×100%;

[0751] Specific binding amount=total binding amount−non-specific binding amount, wherein each binding site was determined by double compound tubes.

[0752] In an agonistic experiment, maximum [.sup.3H]-MK-801 binding %=((tested compounds cpm−5,7 dichlorokynurenic acid cpm)/(1 mM glycine cpm−5,7 dichlorokynurenic acid cpm))×100%.

TABLE-US-00003 TABLE 2 Affinity and maximum agonistic efficacy of compounds of examples on NMDA Maximum Maximum agonistic agonistic Number IC.sub.50(nM) efficacy (%) Number IC.sub.50(nM) efficacy (%) A-002 0.33 45 A-006 0.44 32 A-007 0.89 56 A-008 0.89 35 A-016 0.35 56 A-020 0.25 42 A-030 0.35 39 A-031 0.35 52 A-034 0.89 25 A-035 0.88 19 A-036 0.89 28 A-044 0.66 28 A-048 0.55 38 A-059 0.75 33 A-066 0.35 29 A-068 1.30 48 A-074 0.89 38 A-078 1.59 56 A-079 1.25 41 A-082 0.89 45 A-090 0.45 36 A-093 0.48 65 A-098 0.98 28 A-111 1.58 38 A-114 0.89 35 A-119 1.89 35 A-122 1.65 38 A-130 0.48 43 A-162 0.45 38 A-195 0.43 46 A-226 0.33 45 A-234 1.58 75 A-256 0.89 28 A-258 0.33 21 A-260 0.26 26 A-266 3.2 45 A-272 0.54 19 A-274 0.28 55 A-275 0.35 12 A-276 0.25 28 A-282 0.32 35 A-291 0.88 13 A-303 0.24 35 A-329 0.73 26 A-331 0.59 31 A-333 0.41 19 A-334 0.38 34 A-335 0.48 42 A-342 0.56 32 A-353 0.48 53 A-358 0.86 78 A-367 0.29 39 A-370 0.36 46 A-378 1.66 49 A-384 0.42 39 A-390 0.39 55 A-394 0.79 63 A-401 0.44 75 A-409 0.56 36 A-421 0.38 45 A-429 0.66 57 A-437 0.33 42 A-449 0.47 38 A-463 0.52 59 A-470 0.35 33 A-476 0.96 56

[0753] The experimental results show that all the compounds of examples have NMDA receptor agonistic activity, and the maximum agonistic efficacy is between 12% and 78%, and the compounds belong to NMDA receptor partial agonists.

Test Example 2: In-Vivo Metabolism Study in Rats

[0754] The pharmacokinetic parameters such as exposure of plasma concentrations of the compounds of examples were evaluated by oral/tail intravenous injection model tests in rats in order to evaluate the in-vivo metabolic stability in rats.

[0755] The male SD rats weighing 200±20 g and being SPF grade were used in this experiment and purchased from SPF.

[0756] Preparation of intravenous solution: 1 mg of each tested medicine was weighed accurately, and a volume was metered to 5 mL with 0.9% sodium chloride solution to prepare 0.2 mg/mL. A dose volume was 1 mL for per 200 g of weight, and the dose was 1 mg for per 1 kg of weight based on the concentration conversion.

[0757] Preparation of intragastric solution: 10 mg of each tested medicine was accurately weighed, and a volume was metered to 10 mL with 0.9% sodium chloride solution to prepare 1 mg/mL of the solution. A dose volume was 2 mL for per 200 g of weight, and the dose was 10 mg for per 1 kg of weight based on the concentration conversion.

[0758] Rats were randomly divided into 8 groups, 6 rats were in each group, oral gavage administration and tail intravenous administration were performed according to the above doses. About 0.2 mL of orbital blood was collected before administration and at 2 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h and 6 h after administration, respectively, and centrifuged at 3000 rpm for 10 min at 4° C., and a supernatant was taken for LC/MS/MS determination. A DAS pharmacokinetics program was used to analyze the measured data and calculate the main pharmacokinetic parameters. The experimental results are shown in the following table.

TABLE-US-00004 TABLE 3 Pharmacokinetic parameters of compounds of examples Mode of C.sub.max AUC.sub.(0 .fwdarw. t) Example administration (ng/mL) (ng/mL*h) F (%) A-006 Oral 18360 34957 21.2 Intravenous injection 11633 16470 A-066 Oral 2083 7556 54.5 Intravenous injection 1692 1385 A-082 Oral 5580 13431 19.6 Intravenous injection 18267 6852 A-098 Oral 767 1822 19.1 Intravenous injection 1094 952 A-258 Oral 4907 11400 27.3 Intravenous injection 3630 4178 A-260 Oral 6212 10849 74.6 Intravenous injection 2240 1454 A-274 Oral 1883 3354 62.7 Intravenous injection 2477 1628

[0759] The results shows that the compounds of examples have good pharmacokinetic properties after oral/injection in rats.

Test Example 3: Animal Pharmacodynamic Test

[0760] Pharmacodynamic evaluation was performed by the forced swimming tests in rats. The experimental animals were male SD rats weighing 150 g-180 g and being SPF grade, and acclimated for one week after purchase, and then subjected to forced swimming tests, the rats need be fasted for 12 hours before the tests. The compounds of examples were dissolved with normal saline, and blank control group (normal saline) and example compound administration group were established. 8-10 rats were provided for each group.

[0761] On the day before the tests, the rats were placed in a glass cylinder with a height of 40 cm, an inner diameter of 18 cm, and a water depth of 23 cm for pre-swimming for 15 min, and a water temperature was 28° C. After the pre-swimming the rats were removed, wiped with a dry cloth, and dried with an electrical heater, then returned to a rearing cage, and administered. A formal forced swimming test was performed on the next day for a total of 5 min. The accumulated immobility time within 5 min was recorded, and a second forced swimming test was performed on the seventh day; the criteria for determining immobility were that the rats stopped struggling in the water, were in a floating state, and had only slight limb movements to keep the head floating on the water surface. The results are shown in Table 4, and the experimental data were statistically analyzed by GraphPad Prism 5.0 software.

TABLE-US-00005 TABLE 4 Forced swimming test results of compounds of examples in rats Reduction percentage (%) Mode of Dose of floating time Group administration (mg/kg) Day 2 Day 7 A-006 Po 0.1 36.4%*  22.2% A-007 Po 0.1 35.1%*  32.4% A-008 Po 0.1 54.9%** 57.3%* A-020 Po 0.1 51.8%*  59.3%* A-034 Po 0.1 71.9%** 60.1* A-066 Po 0.1 .sup. 68%** 55.3%* A-098 Po 0.1 64.5%** 13.9% A-258 Po 0.1 74.8%** 56.4%* A-260 Po 0.1 31.6%*  15.5% Note: n = 8-10, *P < 0.05 **P < 0.01 ***P < 0.001 compared with the control group

[0762] The experimental results show that intragastric administration with the compounds of examples is effective and the efficacy can be maintained after 2 to 7 days.

[0763] Although the embodiments of the invention have been described in detail, the technicians in the field will understand that various modifications and replacements may be made to those details according to all the instructions already disclosed, and these changes are within the scope of protection of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereto.